xetra:bayn
|
Bayer
|
Feb 9th, 2010 12:00AM
|
Oct 8th, 2004 12:00AM
|
https://www.uspto.gov?id=US07659297-20100209
|
Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
|
The invention relates to multiply-substituted tetrahydronaphthalene derivatives of formula (I)
process for their production and their use as antiinflammatory agents.
|
7659297
|
1. Compounds of general formula (I),
in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C1-C10)-alkyl group, an optionally substituted (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, a nitro group, or R1 and R2 together mean —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, —N(C1-C3-alkyl)-(CH2)n+1, and —NH—N═CH—,
wherein n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
R8 and R9, independently of one another, mean hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoroalkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
R3 is indazole that is optionally substituted, independently of one another, by one or more
(C1-C5)-alkyl groups, which are optionally substituted by 1-3 hydroxy or 1-3 COOR13 groups, wherein R13 means hydrogen or (C1-C5)-alkyl,
(C1-C5)-alkoxy groups,
halogen atoms,
hydroxy groups,
NR8R9 groups,
exomethylene groups, or
oxygen,
wherein this group is linked via any position to the amine of the tetrahydronaphthalene system and optionally is hydrogenated at one or more sites,
R4 means a hydroxy group, a group OR10 or an O(CO)R10 group, whereby R10 means a hydroxy protective group or a C1-C10-alkyl group,
R5 means a (C1-C10)-alkyl group or an optionally partially or completely fluorinated (C1-C10)-alkyl group, a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, a (C2-C8)alkenyl(C3-C7)cycloalkyl group, a heterocyclyl group, a (C1-C8)alkylheterocyclyl group, a (C2-C8)-alkenylheterocyclyl group, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, (C2-C8)alkinylaryl groups, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2 (C1-C5)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, a (C1-C8)alkenylheteroaryl group or a (C2-C8)alkenylheteroaryl group, or a (C2-C8)alkinylheteroaryl group, wherein this group is linked via any position to the tetrahydronaphthalene system and optionally is hydrogenated at one or more sites, and
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring.
2. A stereoisomer of formula (I)
in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group,
or R1 and R2 together mean —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, —N(C1-C3-alkyl)-(CH2)n+1, or —NH—N═CH—,
wherein n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
R8 and R9, independently of one another, are hydrogen, C1-C5-alkyl or (CO)-C1-C5-alkyl,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoroalkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
R3 is indazole that optionally is substituted by one or more
(C1-C5)-alkyl groups, which are optionally substituted by 1-3 hydroxy or 1-3 COOR13 groups, wherein R13 means hydrogen or (C1-C5)-alkyl,
(C1-C5)-alkoxy groups,
halogen atoms, or
exomethylene groups,
wherein this group is linked via any position to the amine of the tetrahydronaphthalene system and is optionally hydrogenated at one or more sites,
R4 means a hydroxy group, a group OR10 or an 0(CO)R10 group, wherein R10 means a hydroxy protective group or a C1-C10-alkyl group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, a (C2-C8)alkenyl(C3-C7)cycloalkyl group, a heterocyclyl group, a (C1-C8)alkylheterocyclyl group, a (C2-C8)-alkenylheterocyclyl group, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, a (C2-C8)alkinylaryl group,
a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2 (C1-C5)-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups or that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, a (C1-C8)alkylheteroaryl group or a (C2-C8)alkenylheteroaryl group, wherein this group is linked via any position to the tetrahydronaphthalene system and optionally is hydrogenated at one or more sites, and
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group or together with the carbon atom of the tetrahydronaphthalene system mean a (C3-C6)-cycloalkyl ring,
provided that at least three of radicals R1, R2, R11 and R12 are not hydrogen.
3. A compound of formula (I),
in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C1-C10)-alkyl group, an optionally substituted (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoralkyl group, a cyano group, or a nitro group or R1 and R2 together mean —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, —N(C1-C3-alkyl)-(CH2)n+1, and —NH—N═CH—,
wherein n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
R8 and R9, independently of one another, are hydrogen, C1-C5-alkyl or (CO)-C1-C5-alkyl,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoroalkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
R3 is indazole that is optionally substituted, independently of one another, by one or more
(C1-C5)-alkyl groups, which are optionally substituted by 1-3 hydroxy or 1-3 COOR13 groups, wherein R13 means hydrogen or (C1-C5)-alkyl,
(C1-C5)-alkoxy groups,
halogen atoms,
hydroxy group,
NR8R9 groups,
exomethylene groups, or
oxygen,
wherein this group is linked via any position to the amine of the tetrahydronaphthalene system and optionally is hydrogenated at one or more sites,
R4 means a hydroxy group, a group OR10 or an O(CO)R10 group, wherein R10 means a hydroxy protective group or a C1-C10-alkyl group,
R5 means a (C1-C10)-alkyl group or an optionally partially or completely fluorinated (C1-C10)-alkyl group, and
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, mean a (C3-C6)-cycloalkyl ring.
4. A compound of formula (I),
in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C1-C10)-alkyl group, an optionally substituted (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoralkyl group, a cyano group, or a nitro group, or R1 and R2 together mean —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, —N(C1-C3-alkyl)-(CH2)n+1, and —NH—N═CH—,
wherein n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
R8 and R9, independently of one another, are hydrogen, C1-C5-alkyl or (CO)-C1-C5-alkyl,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoralkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
R3 is indazole that is optionally substituted, independently of one another, by one or more
(C1-C5)-alkyl groups, which are optionally substituted by 1-3 hydroxy or 1-3 COOR13 groups, wherein R13 means hydrogen or (C1-C5)-alkyl),
(C1-C5)-alkoxy groups,
halogen atoms,
exomethylene groups, or
oxygen,
wherein this group is linked via any position to the amine of the tetrahydronaphthalene system and optionally is hydrogenated at one or more sites,
R4 means a hydroxy group, or a group OR10, wherein R10 means a C1-C10-alkyl group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, and
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring.
5. A stereoisomer of formula (II),
in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group, or R1 and R2 together mean —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, or —(CH2)n+2—,
wherein n=1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
R8and R9, independently of one another, are hydrogen, C1-C5-alkyl or (CO)-C1-C5-alkyl,
R3 is indazole that is optionally substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2 (C1-C5)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups, wherein this group is linked via any position to the amine of the tetrahydronaphthalene system and optionally is hydrogenated at one or more sites,
R4 means a hydroxy group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, or a (C2-C8)alkenyl(C3-C7)cycloalkyl group, and
R6and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, mean a (C3-C6)-cycloalkyl ring.
6. A compound of formula (II),
in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group, or R1 and R2 together mean —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, N(C1-C3-alkyl)-(CH2)n+1, or —NH—N═CH—,
wherein n=1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
R8 and R9, independently of one another, are hydrogen, C1-C5-alkyl or (CO)-C1-C5-alkyl,
R3 is indazole that is optionally substituted by one or more
(C1-C5)-alkyl groups, which are optionally substituted by 1-3 hydroxy or 1-3 COOR13 groups, wherein R13 is hydrogen or (C1-C5)-alkyl,
(C1-C5)-alkoxy groups,
halogen atoms, or
exomethylene groups,
wherein this group is linked via any position to the amine of the tetrahydronaphthalene system and optionally is hydrogenated at one or more sites,
R4 means a hydroxy group, or a group OR10, wherein R10 means a C1-C10-alkyl group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring.
7. A compound of formula I according to claim 1, wherein R5 is a trifluoromethyl group or a pentafluoroethyl group.
8. A compound of formula I according to claim 1, which is in the form of a salt with a physiologically compatible anion.
9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically compatible vehicle.
10. A process for preparing a compound of formula I according to claim 1, comprising cyclizing a compound of formula III
in which radicals R1, R11, R12, R3, R4, R5, R6, and R7 have the meanings as in the compound of formula I,
to form a compound of formula I with the addition of an organic or inorganic acid or Lewis acid.
11. A compound, which is
(+)-6-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol;
(−)-6-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol;
8-Bromo-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol);
1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol;
6-[(1H-indazol-4-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1,3-dioxol-7-ol;
5-Bromo-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol;
6-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)1,2,3,4-tetrahydronaphthalene-2,5-diol;
7-Chloro-1-[(1H-indazo-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol;
(−)-7-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol;
(+)-7-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahyclronaphthalene-2,5-diol;
7-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol;
7-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol;
(−)-7-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol;
(+)-7-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol;
5-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol;
5-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol;
1-[(1H-indazol-4-yl)amino]4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol;
1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol;
1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol;
7-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol;
1-[(1-Methyl-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol;
7-Ethyl-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol;
7-Ethyl-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol;
1-[(1-Methyl-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol;
Rac.-5,8-Difluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol;
1-[(5-Chloro-1H-indazol-4-yl)amino]-6-fluoro-5 -methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol;
1-(5-Methyl-1H-indazol-4-ylamino)-6-fluoro-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydro-naphthalene-2,5-diol;
7-Bromo-1[(1H-indazol-4-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol;
4-{[6-Chloro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-indazole;
(−)-2-Chloro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8,-tetrahydro-naphthalene-1,6-diol;
(+)-2-Chloro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8,-tetrahydro-naphthalene-1,6-diol;
3-Fluoro-4,7-dihydroxy-8-(1H-indazol-4-ylamino)-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
3-Chloro-2-fluoro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol;
3-Chloro-2-fluoro-5-(5-chloro-1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol;
1,6-Dihydroxy-5-(1H-indazolyl-4-ylamino)-3,8,8,-trimethyl-6-(triftuoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
1,6-Dihydroxy-5-(5-chloro-1H-indazolyl-4-ylamino)-3,8,8,-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile;
2-Chloro-5-(1H-indazol-4-ylamino)-3,8,8-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol; or
2-Fluoro-5-(1H-indazol-4-ylamino)-3,8,8-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol.
12. A pharmaceutical composition comprising a compound according to claim 11 and a pharmaceutically compatable vehicle.
|
12
|
This application claims the benefit of the filing date of U.S. Provisional Applications Ser. Nos. 60/510,152 filed Oct. 14, 2003, 60/511,575 filed Oct. 16, 2003 and 60/560,014 filed Apr. 7, 2004 which are incorporated by reference herein.
The invention relates to tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents.
Open-chain, non-steroidal anti-inflammatory agents are known from the prior art (DE 100 38 639 and WO 02/10143). In the experiment, these compounds show dissociations of action between anti-inflammatory and undesirable metabolic actions and are superior to the previously described nonsteroidal glucocorticoids or exhibit at least just as good an action.
The selectivity as well as the pharmacokinetic parameters of the compounds of the prior art still require improvement, however.
It was therefore the object of this invention to make available compounds whose selectivity relative to the other steroid receptors as well as their pharmacokinetic properties are at least just as good or better than that of the compounds of the prior art.
This object is achieved by the compounds of this invention, explained in the claims.
This invention therefore relates to stereoisomers of general formula (I),
in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C1-C10)-alkyl group, an optionally substituted (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, a nitro group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, —N(C1-C3-alkyl)-(CH2)n+1, and —NH—N═CH—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
whereby R8 and R9, independently of one another, mean hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoroalkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
R3 means a C1-C10-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C1-C5)-alkoxy groups, an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted, independently of one another, by one or more groups selected from (C1-C5)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR13 groups), (C1-C5)-alkoxy groups, halogen atoms, hydroxy groups, NR8R9 groups, exomethylene groups, or oxygen, and that optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group, a group OR10 or an O(CO)R10 group, whereby R10 means any hydroxy protective group or a C1-C10-alkyl group,
R5 means a (C1-C10)-alkyl group or an optionally partially or completely fluorinated (C1-C10)-alkyl group, a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, a (C2-C8)alkenyl(C3-C7)cycloalkyl group, a heterocyclyl group, a (C1-C8)alkylheterocyclyl group, a (C2-C8)-alkenylheterocyclyl group, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, (C2-C8)alkinylaryl groups, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2 (C1-C5)-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, a (C1-C8)alkylheteroaryl group or a (C2-C8)alkenylheteroaryl group, or a (C2-C8)alkinylheteroaryl group, whereby these groups can be linked via any position to the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring.
Stereoisomers of general formula (I) according to claim 2, in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C1-C10)-alkyl group, an optionally substituted (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, —N(C1-C3-alkyl)-(CH2)n+1, and —NH—N═CH—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
whereby R8 and R9, independently of one another, can be hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoroalkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
R3 means a C1-C10-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C1-C5)-alkoxy groups, an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted, independently of one another, by one or more groups selected from (C1-C5)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR13 groups), whereby R13 means hydrogen or (C1-C5)-alkyl), (C1-C5)-alkoxy groups, halogen atoms, hydroxy groups, NR8R9 groups, exomethylene groups, or oxygen, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group, a group OR10 or an O(CO)R10 group whereby R10 means any hydroxy protective group or a C1-C10-alkyl group,
R5 means a (C1-C10)-alkyl group or an optionally partially or completely fluorinated (C1-C10)-alkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group or together with the carbon atom of the tetrahydronaphthalene system mean a (C3-C6)-cycloalkyl ring,
are another subject of this invention.
Stereoisomers of general formula (I), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group,
or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, —N(C1-C3-alkyl)-(CH2)n+1, or —NH—N═CH—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
whereby R8 and R9, independently of one another, can be hydrogen, C1-C5-alkyl or (CO)-C1-C5-alkyl,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoroalkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
R3 means a C1-C10-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C1-C5)-alkoxy groups, an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted, independently of one another, by one or more groups selected from (C1-C5)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR13 groups), (C1-C5)-alkoxy groups, halogen atoms, or exomethylene groups, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group, a group OR10 or an O(CO)R10 group, whereby R10 means any hydroxy protective group or a C1-C10-alkyl group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, a (C2-C8)alkenyl(C3-C7)cycloalkyl group, a heterocyclyl group, a (C1-C8)alkylheterocyclyl group, a (C2-C8)-alkenylheterocyclyl group, (C2-C8)alkinylaryl groups, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2 C1-C5)-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups or that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, a (C1-C8)alkylheteroaryl group or a (C2-C8)alkenylheteroaryl group, whereby these groups can be linked via any position to the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group or together with the carbon atom of the tetrahydronaphthalene system mean a (C3-C6)-cycloalkyl ring,
are another subject of the invention.
Stereoisomers of general formula (I), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoralkyl group, a cyano group, or a nitro group
or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, —N(C1-C3-alkyl)-(CH2)n+1—, and —NH—N═CH—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
whereby R8 and R9, independently of one another, can be hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoroalkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
R3 means a C1-C10-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C1-C5)-alkoxy groups, an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted, independently of one another, by one or more groups selected from (C1-C5)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR13 groups), (C1-C5)-alkoxy groups, halogen atoms, exomethylene groups, or oxygen and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group, a group OR10 or an O(CO)R10 group, whereby R10 means any hydroxy protective group or a C1-C10-alkyl group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, mean a (C3-C6)-cycloalkyl ring,
are another subject of this invention.
Stereoisomers of general formula (I), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoralkyl group, a cyano group, or a nitro group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, —N(C1-C3-alkyl)-(CH2)n+1—, and —NH—N═CH—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
whereby R8 and R9, independently of one another, can be hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoralkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
R3 means a C1-C10-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, or 1-3 (C1-C5)-alkoxy groups, an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups that are selected from (C1-C5)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR13 groups, whereby R13 means hydrogen or (C1-C5)-alkyl), (C1-C5)-alkoxy groups, halogen atoms, or exomethylene groups, or that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group, a group OR10 or an O(CO)R10 group, whereby R10 means any hydroxy protective group or a C1-C10-alkyl group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, a (C2-C8)alkenyl(C3-C7)cycloalkyl group, a heterocyclyl group, a (C1-C8)alkylheterocyclyl group, a (C2-C8)-alkenylheterocyclyl group, (C2-C8)alkinylaryl groups, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2 (C1-C5)-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, a (C1-C8)alkylheteroaryl group or a (C2-C8)alkenylheteroaryl group,
whereby these groups can be linked via any position to the tetrahydronaphthalene system, and optionally can be hydrogenated at one or more sites,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring, provided that at least three of radicals R1, R2, R11 and R12 are not hydrogen,
are another subject of this invention.
Stereoisomers of general formula (I), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, —N(C1-C3-alkyl)-(CH2)n+1—, or —NH—N═CH—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
whereby R8 and R9, independently of one another, can be hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoroalkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
R3 means a C1-C10-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C1-C5)-alkoxy groups, an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups selected from (C1-C5)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR13 groups), (C1-C5)-alkoxy groups, halogen atoms, or exomethylene groups and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system, and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group, a group OR10 or an O(CO)R10 group, whereby R10 means any hydroxy protective group or a C1-C10-alkyl group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, a (C2-C8)alkenyl(C3-C7)cycloalkyl group, a heterocyclyl group, a (C1-C8)alkylheterocyclyl group, a (C2-C8)-alkenylheterocyclyl group, (C2-C8)alkinylaryl groups, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 C1-C5)-alkyl groups, 1-2 C1-C5)-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups or that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, a (C1-C8)alkylheteroaryl group or a (C2-C8)alkenylheteroaryl group,
whereby these groups can be linked via any position to the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, mean a (C3-C6)-cycloalkyl ring, provided that at least three of radicals R1, R2, R11 and R12 are not hydrogen,
are another subject of this invention.
Stereoisomers of general formula (I), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, —N(C1-C3-alkyl)-(CH2)n+1—, and —NH—N═CH—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
whereby R8 and R9, independently of one another, can be hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoroalkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
R3 means a C1-C10-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C1-C5)-alkoxy groups, an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups selected from (C1-C5)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR13 groups), (C1-C5)-alkoxy groups, halogen atoms, or exomethylene groups, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group, a group OR10 or an O(CO)R10 group, whereby R10 means any hydroxy protective group or a C1-C10-alkyl group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or together with the carbon atom of the tetrahydronaphthalene system mean a (C3-C6)-cycloalkyl ring, provided that at least three of radicals R1, R2, R11 and R12 are not hydrogen,
are another subject of this invention.
Stereoisomers of general formula (I), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
whereby R8 and R9, independently of one another, can be hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoralkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
R3 means a C1-C10-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C1-C5)-alkoxy groups, an optionally substituted phenyl group or a naphthyl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2-(C1-C5)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms,
whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system, and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, or a (C2-C8)alkenyl(C3-C7)cycloalkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring, provided that at least three of radicals R1, R2, R11 and R12 are not hydrogen,
are another subject of the invention.
Stereoisomers of general formula (I), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, or —(CH2)n+2—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
whereby R8 and R9, independently of one another, can be hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoroalkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group,
R3 means a C1-C10-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, or 1-3 (C1-C5)-alkoxy groups, an optionally substituted phenyl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2 (C1-C5)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms,
whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, or a (C2-C8)alkenyl(C3-C7)cycloalkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring, provided that at least three of radicals R1, R2, R11 and R12 are not hydrogen,
are another subject of the invention.
Stereoisomers of general formula (I), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C5)-alkyl group, a (C1-C5)-alkoxy group, a (C1-C5)-perfluoroalkyl group, or a cyano group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, and —(CH2)n+2—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoroalkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
R3 means a C1-C10-alkyl group that optionally is substituted by 1-3 hydroxy groups or halogen atoms, a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group that optionally is substituted with C1-C5-alkyl, halogen, hydroxy, or C1-C5-alkoxy, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be substituted in one or more places with 1-2 keto groups, 1-2 (C1-C3)-alkyl groups, 1-2 (C1-C3)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups, and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, mean a (C3-C6)-cycloalkyl ring, provided that at least three of radicals R1, R2, R11 and R12 are not hydrogen,
are another subject of the invention.
Stereoisomers of general formula (I), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C5)-alkyl group, a (C1-C5)-perfluoroalkyl group, a cyano group, a (C1-C5)-alkoxy group, or together mean a (C1-C2)-alkylenedioxy group, whereby then R1 and R2 must be directly adjacent,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoroalkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
R3 means a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group that optionally is substituted with C1-C5-alkyl, halogen, hydroxy, or C1-C5-alkoxy,
whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be substituted in one or more places with 1-2 keto groups, 1-2 (C1-C3)-alkyl groups, or 1-2 exomethylene groups and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring, provided that at least three of the radicals, R1, R2, R11 and R12, are not hydrogen,
are another subject of the invention.
Stereoisomers of general formula (I), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, and —(CH2)n+2—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
whereby R8 and R9, independently of one another, can be hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
R3 means a C1-C10-alkyl group, which optionally can be substituted by a group that is selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (C1-C5)-alkoxy groups,
an optionally substituted phenyl group or a naphthyl group,
a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2 (C1-C5)-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms,
whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, or a (C2-C8)alkenyl(C3-C7)cycloalkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring, provided that at least three of radicals R1, R2, R11 and R12 are not hydrogen,
are another subject of the invention.
Stereoisomers of general formula (I), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, or —(CH2)n+2—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
whereby R8 and R9, independently of one another, mean hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
R3 means a C1-C10-alkyl group, which optionally can be substituted by a group selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (C1-C5)-alkoxy groups,
an optionally substituted phenyl group,
a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2 (C1-C5)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, or a (C2-C8)alkenyl(C3-C7)cycloalkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring, provided that at least three of radicals R1, R2, R11 and R12 are not hydrogen,
are another subject of the invention.
Stereoisomers of general formula (I), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C5)-alkyl group, a (C1-C5)-alkoxy group, a (C1-C5)-perfluoroalkyl group, or a cyano group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, and —(CH2)n+2—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms,
R3 means a C1-C10-alkyl group, which optionally can be substituted by 1-3 hydroxy groups, halogen atoms,
a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group that optionally is substituted with C1-C5-alkyl, halogen, hydroxy, or C1-C5-alkoxy, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be substituted in one or more places with 1-2 keto groups, 1-2 (C1-C3)-alkyl groups, 1-2 (C1-C3)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups, and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring, provided that at least three of radicals R1, R2, R11, and R12are not hydrogen,
are another subject of the invention.
Stereoisomers of general formula (I), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C5)-alkyl group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a (C1-C5)-alkoxy group, or together a (C1-C2)-alkylenedioxy group, whereby then R1 and R2 must be directly adjacent,
R3 means a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group that optionally is substituted with C1-C5-alkyl, halogen, hydroxy, or C1-C5-alkoxy,
whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be substituted in one or more places with 1-2 keto groups, 1-2 (C1-C3)-alkyl groups, 1-2 exomethylene groups and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring, provided that at least three of radicals R1, R2, R11 and R12 are not hydrogen,
are another subject of the invention.
Another subject of this invention relates to stereoisomers of general formula (I),
in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C1-C10)-alkyl group, an optionally substituted (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoralkyl group, a cyano group, or a nitro group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, N(C1-C3-alkyl)-(CH2)n+1, and —NH—N═CH—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
whereby R8 and R9, independently of one another, can be hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
R11 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, or a (C1-C5)-perfluoroalkyl group,
R12 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10)-alkyl group, or a (C1-C10)-alkoxy group,
R3 means a C1-C10-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, or 1-3 (C1-C5)-alkoxy groups, an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted, independently of one another, by one or more groups selected from (C1-C5)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR13 groups), (C1-C5)-alkoxy groups, halogen atoms, exomethylene groups, or oxygen, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group, or a group OR10 whereby R10 means a C1-C10-alkyl group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group,
R6 and R7, independently of one another, means a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring.
The stereoisomers of formula II are also covered by general formula I.
Another subject of this invention relates to stereoisomers of general formula (II),
in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, N(C1-C3-alkyl)-(CH2)n+1, and —NH—N═CH—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
whereby R8 and R9, independently of one another, can be hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
R3 means a C1-C10-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, or 1-3 (C1-C5)-alkoxy groups, an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups selected from (C1-C5)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR13 groups), (C1-C5)-alkoxy groups, halogen atoms, or exomethylene groups, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group, or a group OR10 whereby R10 means a C1-C10-alkyl group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, mean a (C3-C6)-cycloalkyl ring.
Stereoisomers of general formula (II), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, and —(CH2)n+2—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
whereby R8 and R9, independently of one another, can be hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
R3 means a C1-C10-alkyl group, which optionally can be substituted by 1-3 hydroxy groups, halogen atoms, an optionally substituted phenyl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2 (C1-C5)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms,
whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, or a (C2-C8)alkenyl(C3-C7)cycloalkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring, are another subject of the invention.
Stereoisomers of general formula (II), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C10)-alkyl group, a (C1-C10)-alkoxy group, a (C1-C10)-alkylthio group, a (C1-C5)-perfluoroalkyl group, a cyano group, or a nitro group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, and —(CH2)n+2—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or NR8R9,
whereby R8 and R9, independently of one another, can be hydrogen, C1-C5-alkyl or (CO)—C1-C5-alkyl,
R3 means a C1-C10-alkyl group that optionally is substituted by 1-3 hydroxy groups or halogen atoms, an optionally substituted phenyl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2 (C1-C5)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups, and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms,
whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system, and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the chain, a (C3-C6)-cycloalkyl ring,
are another subject of this invention.
Stereoisomers of general formula (II), in which
R1 and R2 independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C5)-alkyl group, or a (C1-C5)-alkoxy group, or R1 and R2 together mean a group that is selected from the groups —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, or —(CH2)n+2—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms,
R3 means a C1-C10-alkyl group that optionally is substituted by 1-3 hydroxy groups or halogen atoms, a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group that optionally is substituted with C1-C5-alkyl, halogen, hydroxy, or C1-C5-alkoxy, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be substituted in one or more places with 1-2 keto groups, 1-2 (C1-C3)-alkyl groups, 1-2 (C1-C3)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups, and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring, are another subject of this invention.
Stereoisomers of general formula (II), in which
R1 and R2, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C1-C5)-alkyl group, or a (C1-C5)-alkoxy group, or together a (C1-C2)-alkylenedioxy group, whereby then R1 and R2 must be directly adjacent,
R3 means a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group that optionally is substituted with C1-C5-alkyl, halogen, hydroxy, or C1-C5-alkoxy, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be substituted in one or more places with 1-2 keto groups, 1-2 (C1-C3)-alkyl groups, or 1-2 exomethylene groups and optionally can be hydrogenated at one or more sites,
R4 means a hydroxy group,
R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group,
R6 and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-C6)-cycloalkyl ring are another subject of this invention.
Stereoisomers according to claim 1, which carry substituents on the aromatic ring of the tetrahydronaphthalene system, selected from the group C1-C5-alkyl, C1-C5-alkoxy, COOR13, NR8R9, C1-C5-perfluoroalkyl, halogen, hydroxy, cyano, nitro, —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1—, —N(C1-C3-alkyl)—(CH2)n+1—or —NH—N═CH—, whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, whereby then the divalent radicals can be counted as two substituents in terms of the invention, are a special subject of the invention.
R13 means hydrogen or C1-C10-alkyl or C1-C5-alkyl. If R1/R2 means COOR13, then tert-butyl is preferred for R13.
A special subject is if R3 is formed by a radical, which contains COOR13 as a substituent, and R13 means C1-C10-alkyl or C1-C5-alkyl.
Stereoisomers according to claim 2, which carry three substituents on the aromatic ring of the tetrahydronaphthalene system, selected from the group C1-C5-alkyl, C1-C5-alkoxy, C1-C5-perfluoroalkyl, halogen, hydroxy, cyano, nitro, —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1—, —N(C1-C3-alkyl)-(CH2)n+1—, or —NH—N═CH—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, and then the divalent radicals can be counted as two substituents in terms of the invention, are another subject of the invention.
The stereoisomers of formula I or II according to claim 2, in which R1 and R2 together mean the radicals —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1—, —N(C1-C3-alkyl)-(CH2)n+1, or —NH—N═CH— are a sub-group of these stereoisomers. The terminal atoms, in each case, of the divalent groups that are presented above are linked to directly adjacent carbon atoms of the tetrahydronaphthalene system.
The stereoisomers according to claim 2, in which R1, R2, R11 or R12 is selected from the group that consists of C1-C5-alkyl, C1-C5-alkoxy, C1-C5-perfluoroalkyl, halogen, hydroxy, cyano, or nitro, are a sub-group.
The stereoisomers according to claim 1 or 2, in which R1, R2, R11 or R12 is selected from the group that consists of optionally substituted C1-C5-alkyl, optionally substituted C1-C5-alkoxy, C1-C5-perfluoroalkyl, halogen, hydroxy, or cyano, are another sub-group.
The stereoisomers of formula I or II according to claim 2 represent another sub-group, in which alkyl radicals R1 and R2 have the meaning —(CH2)n+2— and thus together with the carbon atom of the chain form a 5- to 6-membered ring.
Stereoisomers of general formula I or II, which carry one or two substituents on the aromatic ring of the tetrahydronaphthalene system, selected from the group C1-C5-alkyl, C1-C5-alkoxy, C1-C5-perfluoroalkyl, halogen, hydroxy, nitro, —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1, N(C1-C3-alkyl)-(CH2)n+1, or —NH—N═CH—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, are a special subject of the invention.
Stereoisomers of general formula I, which carry two substituents on the aromatic ring of the tetrahydronaphthalene system, selected from the group C1-C5-alkyl, C1-C5-alkoxy, C1-C5-perfluoroalkyl, halogen, hydroxy, cyano, nitro, —O—(CH2)n—O—, —O—(CH2)n—CH2—, —O—CH═CH—, —(CH2)n+2—, —NH—(CH2)n+1—, —N(C1-C3-alkyl)-(CH2)n+1—, or —NH—N═CH—,
whereby n=1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, whereby then the divalent radicals can be counted as two substituents in terms of the invention, are a sub-group.
Stereoisomers of general formula I or II according to claim 1 or 2, in which R3 means a C1-C10-alkyl group, which optionally can be substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C1-C5)-alkoxy groups, an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups selected from (C1-C5)-alkyl groups, (C1-C5)-alkoxy groups, halogen atoms, or exomethylene groups, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites, are another subject of the invention.
Stereoisomers of formula I or II, in which R3 means a C1-C10-alkyl group, which optionally can be substituted by 1-3 hydroxy groups, halogen atoms, an optionally substituted phenyl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2 (C1-C5)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups, and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, whereby these groups can be linked via any position to the nitrogen atom and optionally can be hydrogenated at one or more sites, are another subject of the invention.
Stereoisomers of general formula I or II, in which R3 means a phenyl or naphthyl group that optionally is substituted with one or more radicals from the group C1-C5-alkyl, C1-C5-alkoxy, hydroxy, halogen, cyano, CF3, nitro, COOR13, or NR8R9, are a subject of the invention.
Compounds of general formula I or II according to claims 1-6, in which R3 means a monocyclic or bicyclic hetereoaryl group that optionally is substituted by one or more groups, independently of one another, selected from (C1-C5)-alkyl groups, which themselves optionally can be substituted by 1-3 hydroxy or 1-3 COOR13 groups, whereby R13 means hydrogen or (C1-C5)-alkyl, (C1-C5)-alkoxy groups, halogen atoms, hydroxy groups, NR8R9 groups, exomethylene groups, or oxygen and that optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites, are a preferred subject of this invention.
Compounds of general formula I or II according to claims 1-6, in which R3 means a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups, independently of one another, selected from (C1-C5)-alkyl groups, which themselves optionally can be substituted by 1-3 hydroxy or 1-3 COOR13 groups, whereby R13 means hydrogen or (C1-C5)-alkyl, (C1-C5)-alkoxy groups, halogen atoms, hydroxy groups, NR8R9 groups, exomethylene groups, or oxygen, and that optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system, and optionally can be hydrogenated at one or more sites, and R5 means an optionally partially or completely fluorinated (C1-C5)-alkyl group, are another preferred subject of this invention.
Stereoisomers of general formula I, in which R3 means a C1-C10-alkyl group, which optionally can be substituted by 1-3 hydroxy groups, halogen atoms, a phenyl, naphthyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydroquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group that optionally is substituted with C1-C5-alkyl, halogen, hydroxy, or C1-C5-alkoxy, are a preferred subject of the invention.
Stereoisomers of general formula I or II, in which R3 means a C1-C10-alkyl group, which optionally can be substituted by 1-3 hydroxy groups, halogen atoms, or a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group that optionally is substituted with C1-C5-alkyl, halogen, hydroxy, or C1-C5-alkoxy, are a special subject of the invention.
Stereoisomers of formula (I), in which R3 means a phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, thiophthalidyl, indazolyl, benzothiazolyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group, are another subject of the invention.
Stereoisomers of formula (I), in which R3 means dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, are another subject of the invention.
Stereoisomers of general formula I, in which R3 means an isoquinolonyl, quinolonyl, quinazolinyl or phthalazinyl group, are another subject of the invention.
Stereoisomers of general formula I or II, in which R3 means an optionally substituted isoquinolonyl, quinolonyl, quinazolinyl, phthalazinyl, indazolyl, quinolinyl, isoquinolinyl, isoquinolonyl, dihydroindolonyl, dihydroindolyl, dihydroindolonyl, naphthyl, pyridyl, or phthalidyl group, are another subject of the invention.
Stereoisomers of general formula I, in which R3 means isoquinolin-1(2H)on-5yl, quinolin-2(1H)-on-5yl, 8- or 7-fluoro-2-methyl-quinazoline, 7,8-difluoro-4-methyl-quinazoline, 7,8-difluoro-2-methyl-quinazoline or 2-methyl-phthalazin-1-one are another subject of the invention.
Radical R3 is bonded via the amine to the tetrahydronaphthalene system. If radical R3 has several positions that are chemically possible to be bonded to the ring system, then this invention comprises all of these possibilities.
Radical R3 is also encompassed by this invention, if it is hydrogenated at one or more sites.
As substituents of monocyclic or bicyclic heteroaryl groups (heterocyclic groups) R3, as they were previously defined, for example, hydroxy, halogen atoms, in particular fluorine and chlorine, (C1-C5)-alkyl groups (which themselves optionally can be substituted by hydroxy groups, (C1-C5)-alkoxy groups or COOR13 groups, whereby R13 means hydrogen or (C1-C5)-alkyl), in particular methyl, (C2-C5)-alkenyl groups, completely or partially fluorinated (C1-C5)-alkyl groups, in particular CF3, CFH2, or C2F5, (C1-C5)-alkoxy groups, in particular methoxy and ethoxy, NR8R9 groups, in particular NH2, N(CH3)2 or NH(CH3), cyano groups as well as keto groups, which are formed with a carbon atom of a ring of the heteroaryl group and oxygen, which forms an N-oxide with an optionally present nitrogen atom of the ring, are suitable at chemically suitable positions. From the above, as a preferred group of substituents for radical R3, as it is defined in claim 1 and for all other claims, the group that consists of fluorine, chlorine, OH, CH3, CF3, CFH2, or C2F5, OCH3, OC2H5, NH2, N(CH3)2 and NH(CH3), cyano, keto, or oxygen follows.
As substituents of the heterocyclic groups R3, as it was previously defined in the above-mentioned subjects of the invention, for example, halogen atoms, (C1-C5)-alkyl groups (which themselves are substituted by hydroxy groups or COOR13 groups), whereby R13 means hydrogen or (C1-C5)-alkyl), (C2-C5)-alkenyl groups, fluorinated (C1-C5)-alkyl groups, (C1-C5)-alkoxy groups or cyano groups are suitable at suitable positions.
Stereoisomers of general formula I or II, in which R3 means a phenyl or naphthyl, phthalidyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group that optionally is substituted with C1-C5-alkyl, halogen, hydroxy, or C1-C5-alkoxy, are an also preferred subject.
Stereoisomers of general formula I, in which R3 means a phenyl, phthalidyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group that optionally is substituted with C1-C5-alkyl, halogen, hydroxy, or C1-C5-alkoxy, are an especially preferred subject.
The heterocyclyl group R3 is not aromatic and can be, for example, pyrrolidine, imidazolidine, pyrazolidine, or piperidine.
The hydroxy group in R4 can be protected by one of the commonly used hydroxy protective groups known to one skilled in the art, such as, for example, silyl ether or ester of organic C1-C10-acids or as C1-C5-ether or benzyl ether, preferably as one or the commonly used hydroxy protective groups or as C1-C5-ether. As radical R4, the hydroxy group is especially preferred.
The commonly used hydroxy protective groups are described in detail in T. W. Greene, P. G. M. Wuts “Protective Groups in Organic Synthesis,” 2nd Edition, John Wiley & Sons, 1991.
The protective groups are preferably alkyl, aryl or mixed alkylaryl-substituted silyl groups, e.g., the trimethylsilyl (TMS), triethylsilyl (TES), tert.-butyldimethylsilyl (TBDMS), tert.-butyldiphenylsilyl (TBDPS) or triisopropylsilyl groups (TIPS) or another standard hydroxy protective group (methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydrofuranyl or tetrahydropyranyl groups).
Radical R5 is bonded directly to the tetrahydronaphthalene system. If radical R5 has several positions, which are chemically possible, to be bonded to the ring system, then this invention comprises all of these possibilities.
Stereoisomers of general formula I, in which R means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, a (C3-C7)cycloalkyl group, a (C1-C5)alkyl(C3-C7)cycloalkyl group, a (C2-C8)alkenyl(C3-C7)cycloalkyl group, a heterocyclyl group, a (C1-C8)alkylheterocyclyl group, a (C2-C8)alkenylheterocyclyl group, an aryl group, a (C1-C8)alkylaryl group, or a (C2-C8)alkenylaryl group, are another subject of the invention.
Stereoisomers of general formula I according to claim 1, in which R means a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, a (C2-C8)alkenyl(C3-C7)cycloalkyl group, a heterocyclyl group, a (C1-C8)alkylheterocyclyl group, a (C2-C8)alkenylheterocyclyl group, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C1-C5)-alkyl groups, 1-2 (C1-C5)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, a (C1-C8)alkylheteroaryl group or a (C2-C8)alkenylheteroaryl group, or a (C2-C8)alkinylheteroaryl group, whereby these groups can be linked via any position to the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites, are another sub-group of the invention.
Stereoisomers of general formula I, in which R means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, an aryl group, a (C1-C8)alkylaryl group, a (C2-C8)alkenylaryl group, a (C3-C7)cycloalkyl group, a (C1-C8)alkyl(C3-C7)cycloalkyl group, or a (C2-C8)alkenyl(C3-C7)cycloalkyl group, are a subject of the invention.
Stereoisomers of general formula I or II according to claims 1 to 6, in which R5 represents a (C1-C10)-alkyl group or an optionally partially or completely fluorinated (C1-C10)-alkyl group, preferably a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, especially preferably a (C1-C3)-alkyl group or an optionally partially or completely fluorinated (C1-C3)-alkyl group, in particular an optionally partially or completely fluorinated (C1-C3)-alkyl group, quite especially CF3 or C2F5, are another subject of the invention.
Stereoisomers of general formula I or II according to claims 5 and 6, in which R5 means a (C1-C5)-alkyl group or an optionally partially or completely fluorinated (C1-C5)-alkyl group, are another subject of the invention. R5 preferably stands for the trifluoromethyl group or the pentafluoroethyl group.
Preferred are stereoisomers according to claims 1 to 6, whose radical R5 means an optionally partially or completely fluorinated (C1-C5)-alkyl group, in particular an optionally partially or completely fluorinated (C1-C3)-alkyl group.
The radicals and all thier subcombinations, which are confirmed by the examples, represent an especially preferred sub-group, as they were disclosed for this invention.
The designation halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom. A fluorine, chlorine or bromine atom is preferred.
The C1-C10- or C1-C5-alkyl groups R1, R2, R4, R5, R6, R7, R11, R12 and R13 can be straight-chain or branched and stand for, for example, a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert.-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group, as well as the hexyl, heptyl, nonyl, or decyl group and their arbitrarily branched derivatives. A methyl or ethyl group is preferred.
The above-mentioned alkyl groups optionally can be substituted by 1-5 groups, independently of one another, selected from hydroxy, cyano, nitro, COOR13, C1-C5-alkoxy groups, halogen, NR8R9, a partially or completely fluorinated C1-C3-alkyl group; the substituents 1-3 halogen atoms and/or 1-3 hydroxy- and/or 1-3 cyano- and/or 1-3 COOR13 groups represent a sub-group. Fluorine atoms, or hydroxy, methoxy and/or cyano groups represent a preferred sub-group.
The alkyl groups optionally can only be substituted by 1-3 hydroxy groups and/or 1-3 COOR13 groups. Hydroxy groups are then preferred.
For a partially or completely fluorinated C1-C3-alkyl group, for example, the following partially or completely fluorinated groups are considered: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl, and pentafluoroethyl. Of the latter, the trifluoromethyl group or the pentafluoroethyl group is preferred, whereby the completely fluorinated group is also referred to as the perfluoroalkyl group. The reagents that optionally are used during the synthesis are commercially available or the published syntheses of the corresponding reagents fall into the category of the prior art, or published syntheses can be used in a similar way.
The C1-C10- or C1-C5-alkoxy groups can be straight-chain or branched and stand for, for example, a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert.-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy group. C1-C5-Alkoxy groups are preferred. A methoxy or ethoxy group is especially preferred.
The above-mentioned alkoxy groups optionally can be substituted with 1-3 groups that are selected from halogen, in particular fluorine, chlorine, hydroxy and cyano.
The C1-C5-alkylthio groups can be straight-chain or branched and stand for, for example, a methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, tert.-butylthio or n-pentylthio, 2,2-dimethylpropylthio, 2-methylbutylthio or 3-methylbutylthio group. A methylthio or ethylthio group is preferred.
The substituent NR8R9 means, for example, NH2, NH(CH3), N(CH3)2, NH(C2H5), N(C2H5)2, NH(C3H7), N(C3H7)2, NH(C4H9), N(C4H9)2, NH(C5H11), N(C5H,1)2, NH(CO)CH3, NH(CO)C2H5, NH(CO)C3H7, NH(CO)C4H9, or NH(CO)C5H11.
The cycloalkyl group means a saturated cyclic group with 3 to 7 ring-carbon atoms that optionally is substituted by one or more groups selected from hydroxy groups, halogen atoms, (C1-C5)-alkyl groups, (C1-C5)-alkoxy groups, NR8R9 groups, COOR13 groups, CHO, or cyano, such as, for example, cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, or methylcycloheptyl.
A (C1-C8)alkyl(C3-C7)cycloalkyl group R5 is defined as a cycloalkyl group that is linked to the ring system via a straight-chain or branched (C1-C8)-alkyl unit.
A (C2-C8)alkenyl(C3-C7)cycloalkyl group R5 is defined as a cycloalkyl group that is linked to the ring system via a straight-chain or branched (C2-C8)-alkenyl unit.
The heterocyclyl group is not aromatic and can be, for example, pyrrolidine, imidazolidine, pyrazolidine, or piperidine. Perhydroquinoline and perhydroisoquinoline are also part of the included heterocyclyl groups.
As substituents for heterocyclyl and heteroaryl groups, for example, substituents from the group optionally substituted C1-C5-alkyl group, hydroxy-, C1-C5-alkoxy-, NR8R9—, halogen, cyano-, COOR13—, and CHO— are considered. The substituents optionally can also be bonded to the nitrogen atom; N-oxides are then also included in the definition.
Aryl groups in terms of the invention are aromatic or partially aromatic carbocyclic groups with 6 to 14 carbon atoms that have a ring, such as, e.g., phenyl or phenylene or several condensed rings, such as, e.g., naphthyl or anthranyl. By way of example, phenyl, naphthyl, tetralinyl, anthranyl, indanyl, and indenyl can be mentioned.
The aryl groups can be substituted at any suitable site that results in a stable stereoisomer, by one or more radicals from the group hydroxy, halogen, or C1-C5-alkyl, C1-C5-alkoxy, cyano, CF3, or nitro that optionally is substituted by 1-3 hydroxy groups, or COOR13 groups. The optionally substituted phenyl group and the naphthyl group are preferred.
A (C1-C8)alkylaryl group is an aryl group, as it is already described above, which is linked to the ring system via a straight-chain or branched (C1-C8)-alkyl unit.
A (C2-C8)alkenylaryl group is an aryl group, as it is already described above, which is linked to the ring system via a straight-chain or branched (C2-C8)-alkenyl unit.
A (C2-C8)alkinylaryl group is an aryl group, as it is already described above, 5which is linked to the ring system via a straight-chain or branched (C2-C8)-alkinyl unit.
The monocyclic or bicyclic heteroaryl group optionally can be substituted by one or more substituents selected from a C1-C5-alkyl group, a C1-C5-alkoxy group, halogen, or exomethylene that optionally is substituted by 1-3 hydroxy groups or 1-3 COOR13 groups. The substituents optionally can also be directly bonded to the heteroatom. N-Oxides are also part of this invention.
The monocyclic or bicyclic heteroaryl group can contain 0-9 groups optionally from the group of nitrogen atoms, oxygen atoms, sulfur atoms or keto groups, of which at most 3 (4?) nitrogen atoms, at most 2 oxygen atoms, at most 2 sulfur atoms and at most 2 keto groups can be contained. Any subcombination of these groups is possible. The heteroaryl group can be hydrogenated at one or more sites.
Monocyclic heteroaryl groups can be, for example, pyridine, pyrazine, pyrimidine, pyridazine, triazine, azaindolizine, 2H- and 4H-pyran, 2H- and 4H-thiopyran, furan, thiophene, 1H- and 4H-pyrazole, 1H- and 2H-pyrrole, oxazole, thiazole, furazan, 1H- and 4H-imidazole, isoxazole, isothiazole, oxadiazole, triazole, tetrazole, or thiadiazole.
Bicyclic heteroaryl groups can be, for example, phthalidyl, thiophthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, indolonyl, dihydroindolonyl, isoindolonyl, dihydroisoindolonyl, benzofuranyl, benzimidazolyl, dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, cumarinyl, isocumarinyl, indolizinyl, isobenzofuranyl, azaindolyl, azaisoindolyl, furanopyridyl, furanopyrimidinyl, furanopyrazinyl, furanopyridazinyl, dihydrobenzofuranyl, dihydrofuranopyridyl, dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl, dihydrofuranopyridazinyl, or dihydrobenzofuranyl groups.
If the heteroaryl groups are partially or completely hydrogenated, stereoisomers of formula I or II, in which R3 means tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl, tetrahydropyridyl, dihydropyridyl, 1H-pyridin-2-onyl, 1H-pyridin-4-onyl, 4-aminopyridyl, 1H-pyridin-4-ylidenaminyl, chromanyl, isochromanyl, thiochromanyl, decahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, 5,6,7,8-tetrahydro-1H-quinolin-4-onyl, decahydroisoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, 3,4-dihydro-2H-benz[1,4]oxazinyl, 1,2-dihydro[1,3]benzoxazin-4-onyl, 3,4-dihydrobenz[1,4]oxazin-4-onyl, 3,4-dihydro-2H-benzo[1,4]thiazinyl, 4H-benzo[1,4]thiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1H-cinnolin-4-onyl, 3H-quinazolin-4-onyl, 1H-quinazolin-4-onyl, 3,4-dihydro-1H-quinoxalin-2-onyl, 2,3-1,2,3,4-tetrahydro[1,5]naphthyridinyl, dihydro-1H-[1,5]naphthyridyl, 1H-[1,5]naphthyrid-4-onyl, 5,6,7,8-tetrahydro-1H-naphthyridin-4-onyl, 1,2-dihydropyrido[3,2-d][1,3]oxazin-4-onyl, octahydro-1H-indolyl, 2,3-dihydro-1H-indolyl, octahydro-2H-isoindolyl, 1,3-dihydro-2H-isoindolyl, 1,2-dihydroindazolyl, 1H-pyrrolo[2,3-b]pyridyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridyl, 2,2-dihydro-1H-pyrrolo[2,3-b]pyridin-3-onyl, are part of this invention.
A (C1-C8)alkylheteroaryl group is a heteroaryl group, as it is already described above, which is linked to the ring system via a straight-chain or branched (C1-C8)-alkyl unit.
A (C2-C8)alkenylheteroaryl group is a heteroaryl group, as it is already described above, which is linked to the ring system via a straight-chain or branched (C2-C8)-alkenyl unit.
A (C2-C8)alkinylheteroaryl group is a heteroaryl group, as it is already described above, which is linked to the ring system via a straight-chain or branched (C2-C8)-alkinyl unit.
A (C1-C8)alkylheterocyclyl group is a heterocyclyl group, as it is already described above, which is linked to the ring system via a straight-chain or branched (C1-C8)-alkyl unit with the ring system.
A (C2-C8)alkenylheterocyclyl group is a heterocyclyl group, as it is already described above, which is linked to the ring system via a straight-chain or branched (C2-C8)-alkenyl unit.
The stereoisomers of general formula I or II according to the invention can be present as stereoisomers because of the presence of asymmetry centers. Subjects of this invention are all possible diastereomers (e.g., RR, RS, SR, SS), both as racemates and in enantiomer-pure form. The term stereoisomers also comprises all possible diastereomers and regioisomers and tautomers (e.g., keto-enol-tautomers), in which the stereoisomers according to the invention can be present, which thus are also subjects of the invention.
The stereoisomers according to the invention can also be present in the form of salts with physiologically compatible anions, for example in the form of hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate.
The stereoisomers according to the invention are produced by the open-chain precursors of general formula III,
being generated according to methods that are known in the prior art, which then are cyclized to the stereoisomers of general formula I or II either without additional reagent in a solvent, preferably chlorinated hydrocarbons, such as, e.g., methylene chloride or dichloroethane or concentrated organic acids, preferably glacial acetic acid, or by adding inorganic or organic acids or Lewis acids under temperatures in the range of −70° C. to +80° C. (preferably in the range of −30° C. to +80° C.).
If a compound IIIa is used, which is distinguished from compound III only in that it carries only two substituents on the tetrahydronaphthalene ring, a compound of general formula II is obtained.
A subject of this invention is thus also a method for the production of stereoisomers of general formula I or II, which is characterized in that imines of general formula III are cyclized to the stereoisomers of general formula I or II, either without additional reagent in a solvent or concentrated organic acids or by adding inorganic or organic acids or Lewis acids under temperatures in the range of −70° C. to +80° C. (preferably in the range of −30° C. to +80° C.), as well as their direct precursors of formula III.
The new imines for the cyclization are also subjects of this invention, in particular those that have been disclosed by the examples.
The binding of substances to the glucocorticoid receptor (GR) and other steroid hormone-receptors (mineral corticoid receptors (MR), progesterone receptors (PR) and androgen receptors (AR)) is examined with the aid of recombinantly produced receptors. Cytosol preparations of Sf9 cells, which had been infected with recombinant baculoviruses that code for the GR, are used for the binding tests. In comparison to the reference substance [3H]-dexamethasone, the substances show a high affinity to the GR. Thus, IC50(GR)=86 nM and IC50(PR)=>1000 were measured for the compound from Example 285, and IC50(GR)=95 nM and IC50(PR)=460 were measured for the compound from Example 49.
The GR-mediated inhibition of the transcription of cytokines, adhesion molecules, enzymes and other pro-inflammatory factors is considered to be an essential, molecular mechanism for the anti-inflammatory action of glucocorticoids. This inhibition is produced by an interaction of the GR with other transcription factors, e.g., AP-1 and NF-kappa-B (for a survey, see Cato, A. C. B., and Wade, E., BioEssays 18, 371-378, 1996).
The stereoisomers of general formula I according to the invention inhibit the secretion of the cytokine IL-8, triggered by lipopolysaccharide (LPS), in the human monocyte cell line THP-1. The concentration of the cytokines was determined in the supernatant by means of commercially available ELISA kits. The compound of Example 285 showed an inhibition IC50(IL8)=40 nM (79% eff); the compound of Example 49 showed an inhibition IC50(IL8)=19 nM.
The anti-inflammatory action of the stereoisomers of general formula I was tested in the animal experiment by tests in the croton oil-induced inflammation in rats and mice (J. Exp. Med. (1995), 182, 99-108). To this end, croton oil in ethanolic solution was applied topically to the animals' ears. The test substances were also applied topically or systemically at the same time or two hours before the croton oil. After 16-24 hours, the ear weight was measured as a yardstick for inflammatory edema, the peroxidase activity as a yardstick for the invasions of granulocytes, and the elastase activity as a yardstick for the invasion of neutrophilic granulocytes. In this test, the stereoisomers of general formula I inhibit the three above-mentioned inflammation parameters both after topical application and after systemic administration.
One of the most frequent undesirable actions of a glucocorticoid therapy is the so-called “steroid diabetes” [cf., Hatz, H. J., Glucocorticoide: Immunologische Grundlagen, Pharmakologie and Therapierichtlinien [Glucocorticoids: Immunological Bases, Pharmacology and Therapy Guidelines], Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998]. The reason for this is the stimulation of gluconeogenesis in the liver by induction of the enzymes responsible in this respect and by free amino acids, which are produced from the degradation of proteins (catabolic action of glucocorticoids). A key enzyme of the catabolic metabolism in the liver is tyrosinamino transferase (TAT). The activity of this enzyme can be determined from liver homogenates by photometry and represents a good measurement of the undesirable metabolic actions of glucocorticoids. To measure the TAT induction, the animals are sacrificed 8 hours after the test substances are administered, the livers are removed, and the TAT activity is measured in the homogenate. In this test, at doses in which they have an anti-inflammatory action, the stereoisomers of general formula I induce little or no tyrosinamino transferase.
Because of their anti-inflammatory action, and, in addition, anti-allergic, immunosuppressive and antiproliferative action, the stereoisomers of general formula I according to the invention can be used as medications for treatment or prophylaxis of the following pathologic conditions in mammals and humans: In this case, the term “DISEASE” stands for the following indications:
(i) Lung diseases that are accompanied by inflammatory, allergic and/or proliferative processes:
Chronic, obstructive lung diseases of any origin, primarily bronchial asthma
Bronchitis of different origins
All forms of restrictive lung diseases, primarily allergic alveolitis,
All forms of pulmonary edema, primarily toxic pulmonary edema
Sarcoidoses and granulomatoses, especially Boeck's disease
(ii) Rheumatic diseases/autoimmune diseases/joint diseases that are accompanied by inflammatory, allergic and/or proliferative processes:
All forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica
Reactive arthritis
Inflammatory soft-tissue diseases of other origins
Arthritic symptoms in the case of degenerative joint diseases (arthroses)
Traumatic arthritides
Collagenoses of any origin, e.g., systemic lupus erythematodes, sclerodermia, polymyositis, dermatomyositis, Sjögren's syndrome, Still's syndrome, Felty's syndrome
(iii) Allergies that are accompanied by inflammatory and/or proliferative processes:
All forms of allergic reactions, e.g., Quincke's edema, hay fever, insect bites, allergic reactions to pharmaceutical agents, blood derivatives, contrast media, etc., anaphylactic shock, urticaria, contact dermatitis
(iv) Vascular inflammations (vasculitides)
Panarteritis nodosa, temporal arteritis, erythema nodosum
(v) Dermatological diseases that are accompanied by inflammatory, allergic and/or proliferative processes:
Atopic dermatitis (primarily in children)
Psoriasis
Pityriasis rubra pilaris
Erythematous diseases, triggered by different noxae, e.g., radiation, chemicals, burns, etc.
Bullous dermatoses
Diseases of the lichenoid group,
Pruritis (e.g., of allergic origin)
Seborrheal eczema
Rosacea
Pemphigus vulgaris
Erythema exudativum multiforme
Balanitis
Vulvitis
Hair loss such as alopecia areata
Cutaneous T-cell lymphoma
(vi) Kidney diseases that are accompanied by inflammatory, allergic and/or proliferative processes:
Nephrotic syndrome
All nephritides
(vii) Liver diseases that are accompanied by inflammatory, allergic and/or proliferative processes:
Acute liver cell decomposition
Acute hepatitis of different origins, e.g., viral, toxic, pharmaceutical agent-induced
Chronic aggressive hepatitis and/or chronic intermittent hepatitis
(viii) Gastrointestinal diseases that are accompanied by inflammatory, allergic and/or proliferative processes:
Regional enteritis (Crohn's disease)
Colitis ulcerosa
Gastritis
Reflux esophagitis
Ulcerative colitis of other origins, e.g., native sprue
(ix) Proctologic diseases that are accompanied by inflammatory, allergic and/or proliferative processes:
Anal eczema
Fissures
Hemorrhoids
Idiopathic proctitis
(x) Eye diseases that are accompanied by inflammatory, allergic and/or proliferative processes:
Allergic keratitis, uveitis, iritis
Conjunctivitis
Blepharitis
Optic neuritis
Chorioiditis
Sympathetic ophthalmia
(xi) Diseases of the ear-nose-throat area that are accompanied by inflammatory, allergic and/or proliferative processes:
Allergic rhinitis, hay fever
Otitis externa, e.g., caused by contact dermatitis, infection, etc.
Otitis media
(xii) Neurological diseases that are accompanied by inflammatory, allergic and/or proliferative processes:
Cerebral edema, primarily tumor-induced cerebral edema
Multiple sclerosis
Acute encephalomyelitis
Meningitis
Various forms of convulsions, e.g., infantile nodding spasms
(xiii) Blood diseases that are accompanied by inflammatory, allergic and/or proliferative processes:
Acquired hemolytic anemia
Idiopathic thrombocytopenia
(xiv) Tumor diseases that are accompanied by inflammatory, allergic and/or proliferative processes:
Acute lymphatic leukemia
Malignant lymphoma
Lymphogranulomatoses
Lymphosarcoma
Extensive metastases, mainly in breast, bronchial and prostate cancers
(xv) Endocrine diseases that are accompanied by inflammatory, allergic and/or proliferative processes:
Endocrine orbitopathy
Thyreotoxic crisis
De Quervain's thyroiditis
Hashimoto's thyroiditis
Basedow's disease
(xvi) Organ and tissue transplants, graft-versus-host disease
(xvii) Severe shock conditions, e.g., anaphylactic shock, systemic inflammatory response syndrome (SIRS)
(xviii) Substitution therapy in:
Innate primary suprarenal insufficiency, e.g., congenital adrenogenital syndrome
Acquired primary suprarenal insufficiency, e.g., Addison's disease, autoimmune adrenalitis, meta-infective tumors, metastases, etc.
Innate secondary suprarenal insufficiency, e.g., congenital hypopituitarism
Acquired secondary suprarenal insufficiency, e.g., meta-infective tumors, etc.
(xix) Vomiting that is accompanied by inflammatory, allergic and/or proliferative processes:
e.g., in combination with a 5-HT3 antagonist in cytostatic-agent-induced vomiting
(xx) Pains of inflammatory origins, e.g., lumbago.
Moreover, the stereoisomers of general formula I according to the invention can be used for treatment and prophylaxis of additional pathologic conditions that are not mentioned above, for which synthetic glucocorticoids are now used (see in this respect Hatz, H. J., Glucocorticoide: Immunologische Grundlagen, Pharmakologie and Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998).
All previously mentioned indications (i) to (xx) are described in more detail in Hatz, H. J., Glucocorticoide: Immunologische Grundlagen, Pharmakologie and Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998.
For the therapeutic actions in the above-mentioned pathologic conditions, the suitable dose varies and depends on, for example, the active strength of the compound of general formula I, the host, the type of administration, and the type and severity of the conditions that are to be treated, as well as the use as a prophylactic agent or therapeutic agent.
The invention relates to the use of the claimed compounds/stereoisomers for the production of a pharmaceutical agent.
In addition, the invention provides:
(i) The use of one of the compounds/isomers of general formula I according to the invention or mixture thereof for the production of a medication for treating a DISEASE;
(ii) A process for treating a DISEASE, said process comprises an administration of an amount of the compound according to the invention, whereby the amount suppresses the disease, and whereby the amount of compound is given to a patient who requires such a medication;
(iii) A pharmaceutical composition for treating a DISEASE, said treatment comprises one of the compounds according to the invention or mixture thereof and at least one pharmaceutical adjuvant and/or vehicle.
In general, satisfactory results can be expected in animals when the daily doses comprise a range of 1 μg to 100,000 μg of the compound according to the invention per kg of body weight. In the case of larger mammals, for example the human, a recommended daily dose lies in the range of 1 μg to 100,000 μg per kg of body weight. Preferred is a dose of 10 to 30,000 μg per kg of body weight, and more preferred is a dose of 10 to 10,000 μg per kg of body weight. For example, this dose is suitably administered several times daily. For treating acute shock (e.g., anaphylactic shock), individual doses can be given that are significantly above the above-mentioned doses.
The formulation of the pharmaceutical preparations based on the new compounds is carried out in a way that is known in the art by the active ingredient being processed with the vehicles, fillers, substances that influence decomposition, binding agents, moisturizers, lubricants, absorbents, diluents, flavoring correctives, coloring agents, etc., that are commonly used in galenicals, and converted into the desired form of administration. In this case, reference is made to Remington's Pharmaceutical Science, 15th Edition, Mack Publishing Company, East Pennsylvania (1980).
For oral administration, especially tablets, coated tablets, capsules, pills, powders, granulates, lozenges, suspensions, emulsions or solutions are suitable.
For parenteral administration, injection and infusion preparations are possible.
For intra-articular injection, correspondingly prepared crystal suspensions can be used.
For intramuscular injection, aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.
For rectal administration, the new compounds can be used in the form of suppositories, capsules, solutions (e.g., in the form of enemas) and ointments both for systemic and for local treatment.
For pulmonary administration of the new compounds, the latter can be used in the form of aerosols and inhalants.
For local application to eyes, outer ear channels, middle ears, nasal cavities, and paranasal sinuses, the new compounds can be used as drops, ointments and tinctures in corresponding pharmaceutical preparations.
For topical application, formulations in gels, ointments, fatty ointments, creams, pastes, powders, milk and tinctures are possible. The dosage of the compounds of general formula I should be 0.01%-20% in these preparations to achieve a sufficient pharmacological action.
The invention also comprises the compounds of general formula I according to the invention as therapeutic active ingredients. In addition, the compounds of general formula I according to the invention are part of the invention as therapeutic active ingredients together with pharmaceutically compatible and acceptable adjuvants and vehicles.
The invention also comprises a pharmaceutical composition that contains one of the pharmaceutically active compounds according to the invention or mixtures thereof or a pharmaceutically compatible salt thereof and a pharmaceutically compatible salt or pharmaceutically compatible adjuvants and vehicles.
Experiments
EXAMPLE 1
4-{[8-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one
4-Amino-2,3-dihydroisoindol-1-one
2-Methyl-3-nitrobenzoic acid methyl ester
30 g (165.6 mmol) of 2-methyl-3-nitrobenzoic acid is added to 150 ml of methanol, and it is refluxed for two days after 2.9 ml of concentrated sulfuric acid is added. After cooling, the crystallizate (25.55 g=79%) is suctioned off and thus incorporated into the next stage.
1H-NMR (300 MHz, DMSO-d6): δ=2.50 (3H), 3.85 (3H), 7.56 (1H), 8.00 (1H), 8.05 (1H).
2-(Bromomethyl)-3-nitrobenzoic acid methyl ester
25.55 g (130.9 mmol) of 2-methyl-3-nitrobenzoic acid methyl ester is added to 300 ml of carbon tetrachloride, and mixed with 25.6 gram (141.7 mmol) of N-bromosuccinimide and 62.8 mg of benzoyl peroxide. After seven days of refluxing, the succinimide is suctioned off after cooling, and then the filtrate is spun in until a dry state is reached. The desired compound that is incorporated in crude form into the next stage remains.
1H-NMR (300 MHz, CDCl3): δ=4.00 (3H), 5.66 (2H), 7.55 (1H), 7.95 (1H), 8.10 (1H).
2-(Azidomethyl)-3-nitrobenzoic acid methyl ester
10 g (36.5 mmol) of 2-(bromomethyl)-3-nitrobenzoic acid methyl ester is mixed with 36 ml of N,N-dimethylformamide and 24 ml of water. After 3.54 g of sodium azide is added, the batch is stirred overnight. The reaction mixture is diluted with methyl tert-butyl ether, and washed twice with water and once with brine. After drying on sodium sulfate, it is filtered, and the solvent is spun off. The desired azide is obtained in a yield of 89.6% (7.72 g) and further incorporated in crude form.
1H-NMR (300 MHz, CDCl3): δ=4.00 (3H), 4.93 (2H), 7.58 (1H), 7.96 (1H), 8.12 (1H).
4-Amino-2,3-dihydroisoindol-1-one
1 g (4.2 mmol) of 2-(azidomethyl)-3-nitrobenzoic acid methyl ester is added to 10 ml of ethanol and 2 ml of glacial acetic acid and mixed with 148.5 mg of Pd/C. After stirring overnight at room temperature under a hydrogen atmosphere, the catalyst is suctioned off via a glass fiber filter, and the filtrate is evaporated to the dry state. The residue is chromatographed on a Flashmaster (mobile solvent). 391.5 mg (62.4%) of the desired compound is isolated.
1H-NMR (300 MHz, DMSO-d6): δ=4.10 (2H), 5.36 (2H), 6.75 (1H), 6.85 (1H), 7.15 (1H), 8.35 (1H).
4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanal
6.55 g (21.11 mmol) of rac-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl)-pentane-1,2-diol (WO 00/32584) is dissolved in 224 ml of dichloromethane and mixed at room temperature with 74 ml of dry dimethyl sulfoxide and 10.68 g (105.55 mmol) of triethylamine. At 15 to 18° C., 10.08 g (63.33 mmol) of the SO3/pyridine complex is added in portions within 40 minutes. After being stirred overnight at room temperature, 84 ml of saturated ammonium chloride solution is added. A slight heating occurs. After 15 minutes of stirring at room temperature, it is extracted twice with 300 ml each of diethyl ether. The organic phases are washed with water and brine and dried (sodium sulfate). After the solvent is filtered off and after the solvent is spun off, the remaining residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 5.85 g (90%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.40 (3H), 1.46 (3H), 2.22 (1H), 3.38 (1H), 3.59 (1H), 3.86 (1H), 6.70-6.80 (1H), 6.82-6.97 (2H), 9.05 (1H).
4-{[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidene]amino}2,3-dihydroisoindol-1-one
400 mg (1.297 mmol) of rac-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanal is stirred with 192.1 mg (1.297 mmol) of 4-amino-2,3-dihydroisoindol-1-one in 1.89 ml of glacial acetic acid for four days at room temperature. The mixture is mixed three times with toluene and evaporated to the dry state in a rotary evaporator. The residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 429.7 mg (75.5%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.37 (3H), 1.52 (3H), 2.22 (1H), 3.42 (1H), 3.84 (3H), 4.37 (2H), 4.68 (1H), 6.53-6.68 (3H), 6.72-6.95 (2H), 7.37 (1H), 7.49 (1H), 7.75 (1H).
4-{[8-Fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one (Diastereomer A)
4-{[8-Fluoro-2,5dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one (Diastereomer A)
4-{[8-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one (Diastereomer B)
420 mg (0.958 mmol) of the compound 4-{[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}2,3-dihydroisoindol-1-one that is described in the paragraph above is mixed with 9.6 ml of a 1 M solution of boron tribromide in dichloromethane, and it is stirred for ¾ of an hour at room temperature. The reaction mixture is mixed drop by drop with saturated sodium bicarbonate at −30° C., specifically up to pH 8. After dilution with ethyl acetate, the cold bath is removed and stirred vigorously for 15 minutes. After being extracted twice with ethyl acetate, the organic phases are washed with water and saturated sodium chloride solution. After the solvent is dried (sodium sulfate) and spun off, the residue is chromatographed on a Flashmaster (silica gel, NH2 phase) (mobile solvent:dichloromethane/methanol). 67.7 mg (16.6%) of 4-{[8-fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one (diastereomer A, F1); 12.9 mg (3.2%) of 4-{[8-fluoro-2,5dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one (diastereomer A, F2), and 32.2 mg (7.9%) of 4-{[8-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one (diastereomer B, F3) are isolated.
F1: 1H-NMR (300 MHz, MeOD): δ=1.47 (3H), 1.60 (3H), 2.07 (1H), 2.25 (1H), 3.49 (3H), 4.19-4.40 (2H), 5.20 (1H), 6.31 (1H), 7.00 (1H), 7.15-7.30 (2H), 7.38 (1H).
F2: 1H-NMR (300 MHz, MeOD): δ=1.50 (3H), 1.59 (3H), 2.05 (1H), 2.28 (1H), 4.20-4.42 (2H), 5.18 (1H), 6.61 (1H), 6.80-6.90 (1H), 7.15 (1H), 7.20-7.40 (2H).
F3: 1H-NMR (300 MHz, MeOD): δ=1.52 (3H), 1.69 (3H), 2.03 (1H), 2.23 (1H), 4.20-4.39 (2H), 5.18 (1H), 6.65-6.80 (2H), 7.10-7.23 (2H), 7.35 (1H).
EXAMPLE 2
5-{[7-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
5-Amino-isoquinolin-1(2H)-one
5-Nitroisocoumarin
16.4 g (84.03 mmol) of the 2-methyl-3-nitrobenzoic acid methyl ester that is described under Example 1 is stirred with 26.8 g (225.1 mmol) of N,N-dimethylformamide dimethylacetal in 85 ml of dimethylformamide for 12 hours at 130° C. The solvent is drawn off in a rotary evaporator, the residue is taken up in methyl tert-butyl ether and washed three times with water. After washing with saturated NaCl solution, the organic phase is dried. After the desiccant is filtered off and the solvent is spun off, the remaining residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 8.73 g (54.4%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=7.39 (1H), 7.45 (1H), 7.68 (1H), 8.49 (1H), 8.65 (1H).
5-Nitroisoquinolin-1(2H)-one
2.51 g (13.13 mmol) of 5-nitroisocoumarin is added in 100 ml of ethanol. Ammonia is pressure-forced in in an autoclave. The product precipitates and is suctioned off. 1.98 g (79.7%) of the desired compound is isolated.
1H-NMR (300 MHz, DMSO-d6): δ=6.97 (1H), 7.45 (1H), 7.65 (1H), 8.43 (1H), 8.57 (1H), 11.5 (1H).
5-Aminoisoquinolin-1(2H)-one
268.3 mg (1.51 mmol) of 5-nitroisoquinolin-1(2H)-one is added with 376.5 mg of ammonium chloride and 2.6 ml of water in 14 ml of ethanol and 5.4 ml of tetrahydrofuran. After addition in portions of 1.23 g of zinc powder (heating to 30 to 35° C.), it is stirred for two hours. The reaction mixture is suctioned off through a glass fiber filter and rewashed with ethyl acetate. After the filtrate is washed with water and saturated sodium chloride solution, the organic phase is dried as usual. Filtering off the desiccant and spinning off the solvent produce 196.5 mg (88.1%) of the desired amine.
1H-NMR (300 MHz, DMSO-d6): δ=5.6 (2H), 6.68 (1H), 6.87.45 (1H), 7.00 (1H), 7.17 (1H), 7.39 (1H), 11.7 (1H).
4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol
A solution of 3 g of 2-hydroxy-4-methylene-2-(trifluoromethyl)valeric acid ethyl ester in 22 ml of 3-chloroanisole is mixed at room temperature in portions with aluminum trichloride. After 48 hours of stirring at room temperature, the batch is mixed with 2N hydrochloric acid and hexane, and it is stirred for another hour. After washing with 2N hydrochloric acid and water, excess 3-chloroanisole is distilled off in a vacuum. The remaining residue is purified by chromatography on silica gel (mobile solvent:hexane/ethyl acetate). 2.85 g of a mixture of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valeric acid ethyl ester and the regioisomeric compound 4-(2-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valeric acid ethyl ester is obtained as a yellow oil. This substance mixture is mixed in 90 ml of ether at 0° C. with 445 mg of lithium aluminum hydride and stirred for 12 hours. The batch is added to saturated sodium bicarbonate solution and filtered through diatomaceous earth. The phases are separated, and the aqueous phase is extracted with ethyl acetate. It is washed with water and brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatography on silica gel (mobile solvent:hexane/ethyl acetate), 1.87 g of the desired compound 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol as a first fraction and 160 mg of the regioisomeric compound 4-(2-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol as a second fraction are obtained as colorless oils.
1st Fraction: 1H-NMR (CDCl3), δ=1.41 (3H), 1.51 (3H), 2.24 (1H), 2.51 (1H), 2.84 (1H), 3.36 (1H), 3.48 (1H), 3.85 (3H), 6.88 (1H), 6.92 (1H), 7.24 (1H).
2nd Fraction: 1H-NMR (CDCl3), δ=1.52 (3H), 1.62 (3H), 2.18 (1H), 2.76 (1H), 2.93 (1H), 3.33 (1H), 3.55 (1H), 3.80 (3H), 6.78 (1H), 6.90 (1H), 7.38 (1H).
4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
854.6 mg (6.733 mmol) of oxalyl chloride in 14.5 ml of dichloromethane is introduced into a heated flask. At −70° C., 1.05 ml of DMSO, dissolved in 3 ml of dichloromethane, is added in drops, and the batch is stirred for five more minutes. Then, 2 g (6.12 mmol) of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentan-1-ol, dissolved in six milliliters of dichloromethane, is added in drops. After 20 minutes of stirring, the batch is carefully mixed with 4.24 ml (30.61 mmol) of triethylamine, specifically in a temperature range of between −70 and −60° C. After five minutes of stirring at −70° C., the reaction mixture can slowly come to room temperature. 25 ml of water is added, and the batch is stirred for another hour at room temperature. After phase separation, the aqueous phase is shaken once with 100 ml of dichloromethane. The combined organic extracts are washed with I% sulfuric acid, 5% sodium bicarbonate solution and brine. According to the usual procedure, 1.92 g (96.9%) of the desired aldehyde is obtained, which is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=1.37 (3H), 1.45 (3H), 2.22 (1H), 3.35 (1H), 3.59 (1H), 3.90 (3H), 6.80-6.92 (2H), 7.04 (1H), 9.02 (1H).
5-{[4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentylidene]amino}isoquinolin-1(2H)-one
300 mg (0.924 mmol) of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal is stirred with 148 mg (0.924 mmol) of 5-amino-isoquinolin-1-one in 1.33 ml of glacial acetic acid for four days at room temperature. The mixture is mixed three times with toluene and evaporated to the dry state in a rotary evaporator. The residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 382.4 mg (88.6%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.37 (3H), 1.58 (3H), 2.26 (1H), 3.43 (1H), 3.85 (3H), 4.80 (1H), 6.43 (1H), 6.59 (1H), 6.70-6.77 (2H), 7.00 (1H), 7.15-7.25 (1H), 7.30-7.45 (2H), 8.32 (1H), 11.00 (1H).
5-{[7-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
50 mg (0.107 mmol) of the compound 5-{[4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}2,3-isoquinolin-1-one that is described in the paragraph above is mixed at −20° C. with 2.1 ml of a 1 M solution of boron tribromide in dichloromethane, and it is stirred for two and one-half hours in a temperature range of between −20° C. and 0° C. The reaction mixture is mixed drop by drop at −20° C. with saturated sodium bicarbonate solution. After dilution with ethyl acetate, the batch is allowed to come to room temperature, stirred for 15 minutes and extracted twice with ethyl acetate. The combined organic extracts are washed with water and saturated NaCl solution. After drying on sodium sulfate, the solvent is spun off, and the remaining residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 12.5 mg (25%) of the desired compound is isolated.
1H-NMR (300 MHz, MeOD): δ=1.55 (3H), 1.65 (3H), 2.03-2.20 (2H), 5.13 (1H), 6.73 (1H), 6.80 (1H), 6.87 (1H), 7.09 (1H), 7.19 (1H), 7.40 (1H), 7.70 (1H).
EXAMPLE 3
(+)-6-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol and
(−)-6-Fluoro-1-[(1-indazol-4-yl)amino]-4.4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
2,6-Difluoroanisole
20 g (153.74 mmol) of 2,6-difluorophenol is dissolved in 200 ml of acetone and mixed under nitrogen with 42.5 g (307.48 mmol) of potassium carbonate. After 19.1 ml of methyl iodide (2 equivalents) is added, it is refluxed for three and one-half hours. After cooling, the reaction mixture is filtered, the filter residue is washed with acetone, and the filtrate is spun in until a dry state is reached. The residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 17.27 g (77.9%) of the desired product is obtained. It should be noted that the product is slightly volatile. The bath temperature should not exceed 30° C., and the vacuum of the rotary evaporator is to be adapted.
1H-NMR (300 MHz, CDCl3): δ=4.00 (3H), 6.80-7.00 (3H).
2-(3-Fluoro-2-methoxyphenyl)-2-methylpropanenitrile
10 g (69.39 mol) of 2,6-difluoroanisole is dissolved in 200 ml of toluene and mixed at room temperature with 5.75 g (83.27 mmol) of isobutyric acid nitrile. 166.5 ml of a 0.5 molar solution of potassium hexamethyldisilazide in toluene is added in drops within 35 minutes. In this case, a slight temperature rise to 27.5° C. takes place. After 16 hours of stirring at room temperature, the reaction mixture is mixed with 200 ml of water and 400 ml of ethyl acetate and acidified with 10% sulfuric acid to a pH of 4. The organic phase is separated, and the aqueous phase is shaken once with ethyl acetate (200 ml). The combined organic extracts are shaken with water and brine. After the solvent is dried, filtered and spun off, the residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 7.66 g (57.1%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.76 (6H), 4.08 (3H), 6.95-7.13 (3H).
2-(3-Fluoro-2-methoxyphenyl)-2-methylpropanal
7.66 g (39.64 mmol) of the above-described nitrile is dissolved in 158 ml of toluene. At −65 to −60° C., 49.5 ml of a 1.2 molar solution of DIBAH in toluene is added in drops within 40 minutes. After one hour of stirring at this temperature, the dropwise addition of 493 ml of a 10% L-(+)-tartaric acid solution is begun. After 100 milliliters, the temperature is increased to −10° C. The remainder of the tartaric acid solution is quickly added, and the batch is stirred vigorously for two hours at room temperature. The reaction mixture is shaken twice with 400 ml each of diethyl ether. The combined organic extracts are shaken with water and brine, dried, and the solvent is spun off. The residue that is obtained (7.8 g=102%) is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=1.40 (6H), 3.88 (3H), 6.95-7.10 (3H), 9.60 (1H).
(E/Z)-4-(3-Fluoro-2-methoxyphenyl)-4-methylpent-2-enoic acid ethyl ester
21.3 ml of a 2 molar LDA solution in THF is added in drops at 0° C. to a solution of 9.87 g (39.75 mmol) of 2-ethoxy-phosphonoacetic acid triethyl ester in 40 ml of absolute THF. After 30 minutes of stirring at 0° C., 7.8 g (39.75 mmol) of 2-(3-fluoro-2-methoxyphenyl)-2-methylpropanal, dissolved in 26 ml of THF, is quickly added in drops at 0° C. The cold bath is removed, and the batch is stirred for 16 hours at room temperature. The reaction mixture is poured into water and extracted twice with ethyl acetate. The combined organic extracts are washed with water and brine, dried, and the solvent is spun off after the desiccant is filtered off. The residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 8.39 g (68.2%) of the desired compound is isolated.
MS (CI): 328 (29%), 265 (100%), 181 (56%), 167 (42%).
(E/Z)-4-(3-Fluoro-2-methoxyphenyl)-4-methylpent-2-enoic acid
8.39 g (27.03 mmol) of (E/Z)-4-(3-fluoro-2-methoxyphenyl)-4-methylpent-2-enoic acid ethyl ester is mixed with 270 ml of 1N NaOH in ethanol/water (2:1) and stirred for two days at room temperature. The ethanol is drawn off in a rotary evaporator, and the residue is extracted twice with 150 ml each of diethyl ether. The combined organic extracts are washed with water and discarded after TLC monitoring. The aqueous phases are acidifed to a pH of 3 with concentrated hydrochloric acid and extracted twice with 300 ml each of diethyl ether. The ether extracts are washed with water and brine, dried, the solvent is spun off, and the residue (5.89 g =77.2%) is incorporated in crude form into the next stage.
MS (CI): 300 (100%), 282 (10%), 237 (27%),167 (26%).
4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid
5.89 g (20.86 mmol) of (E/Z)-4-(3-fluoro-2-methoxyphenyl)-4-methylpent-2-enoic acid is mixed at room temperature with 126 ml of a 1 molar sulfuric acid, and after 21 ml of glacial acetic acid is added, it is stirred for 15 hours at a bath temperature of 90° C. While being cooled in an ice bath, the reaction mixture is carefully mixed (heavily foaming) with solid potassium carbonate until a pH of 9 is reached. It is extracted twice with diethyl ether. The combined organic extracts are washed with water and discarded after TLC. The combined aqueous phases are acidified with concentrated hydrochloric acid until a pH of 4 is reached, and extracted twice with 300 ml each of diethyl ether. The ether extracts are washed with water and brine, dried, and the solvent is spun off. Since the residue still contains acetic acid, it is spun off twice with 100 ml each of toluene. The remaining residue (4.14 g=78.1%) is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=1.50 (6H), 3.53 (2H), 3.93 (3H), 6.90-7.10 (3H).
4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester
4.14 g (16.28 mmol) of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid is dissolved in 97 ml of ethanol, mixed with 1.79 ml of sulfuric acid and refluxed for four hours. The ethanol is drawn off in a rotary evaporator, and the residue is carefully mixed with saturated sodium bicarbonate solution until a pH of 9 is reached. It is extracted twice with 100 ml each of ethyl acetate, and the combined organic extracts are washed with water and then with brine. After the desiccant is dried and filtered off, and after the solvent is spun in, the residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 4.16 g (90.6%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.29 (3H), 1.48 (6H), 3.40 (2H), 3.98 (3H) 6.89-7.09 (3H).
4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentanoic acid ethyl ester
4.16 g (14.74 mmol) of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester is dissolved in 24 ml of THF and mixed at 0° C. with 2.51 g (17.68 mmol) of (trifluoromethyl)-trimethylsilane and 36.1 mg of tetrabutylammonium fluoride. After two and one-half hours of stirring between 0 and 5° C., the batch is poured into 50 ml of ice water. It is extracted twice with 150 ml each of diethyl ether, and the combined organic extracts are worked up as usual. After chromatography on silica gel (mobile solvent:ethyl acetate/hexane), 5.24 g (83.8%) of the desired compound is obtained.
MS (CI): 442 (100%), 425 (41%).
4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentan-1-ol
5.24 g (12.34 mmol) of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-2-trimethylsilyloxy-pentanoic acid ethyl ester is dissolved in 45 ml of diethyl ether and mixed at 0 to 5° C. in portions with 936.9 mg (24.69 mmol) of LiAlH4. After four and one-half hours of stirring at room temperature, the reaction mixture is carefully mixed with saturated NaHCO3 while being cooled in an ice bath, stirred for one hour under cold conditions and overnight at room temperature. After the usual working-up, 4.11 g (87.1%) of a mixture that consists of the desired compound and the compound in which the silyl ether has migrated is obtained. The mixture is incorporated in crude form into the next stage.
4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentan-1-ol
4.11 g (10.75 mmol) of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-2-trimethylsilyloxy-pentan-1-ol is dissolved in 61 ml of THF, mixed with 3.39 g (10.746 mmol) of Bu4NF trihydrate, and stirred for one hour at room temperature. The reaction mixture is poured into water and extracted twice with diethyl ether. The organic phases are washed as usual with water and brine. After the desiccant is dried and filtered off, and after the solvent is spun in, the remaining residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 2.71 g (81.4%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.45 (3H), 1.54 (3H), 2.20 (1H), 2.54 (1H), 2.90 (1H), 3.30-3.50 (2H), 3.98 (3H), 6.90-7.13 (3H).
4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal
765 mg (6.03 mmol) of oxalyl chloride in 13 ml of dichloromethane is introduced into a heated flask. At −78° C., 0.855 ml of DMSO, dissolved in 2.5 ml of dichloromethane, is added in drops, and the batch is stirred for five more minutes. Then, 1.7 g (5.48 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanol, dissolved in five milliliters of dichloromethane, is added in drops. After 15 minutes of stirring, the batch is carefully mixed with 3.79 ml (27.40 mmol) of triethylamine, stirred for five minutes at −78° C. and then allowed to come slowly to room temperature. 20 ml of water is added, and the batch is stirred for another hour at room temperature. After phase separation, the aqueous phase is shaken once with 100 ml of dichloromethane. The combined organic extracts are washed with 1% sulfuric acid, 5% sodium bicarbonate solution and brine. After the usual procedure, 1.617 g (96.2%) of aldehyde is obtained, which is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=1.40 (3H), 1.49 (3H), 2.29 (1H), 3.29 (1H), 3.59 (1H), 4.00 (3H), 6.85-7.08 (3H), 9.13 (1H).
1,1,1-Trifluoro-4-(3fluoro-2-methoxyphenyl)-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol
1.46 g (4.746 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal is stirred with 632 mg (4.746 mmol) of 4-aminoindazole in 6.78 ml of glacial acetic acid for two days at room temperature. The reaction mixture is drawn off three times with toluene in a rotary evaporator, and the residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 1.47 g (73.5%) of the desired compound is isolated.
MS (ES+): 424 (100%).
(+)-6-Fluoro-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol and
(−)-6-Fluoro-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1.32 g (3.117 mmol) of the above-described imine, 1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol, is dissolved in 22.8 ml of dichloromethane. 9.35 ml of a 1M solution of TiCl4 in dichloromethane (3 equivalents) is added to this solution at −30° C., specifically under nitrogen within 15 minutes. The reaction mixture is stirred for three and one-half hours at −30 to −15° C. The batch is mixed drop by drop with saturated sodium bicarbonate solution at −30° C. After dilution with ethyl acetate, it is stirred for 15 minutes at room temperature. After being extracted twice with 150 ml each of ethyl acetate, the organic phases are washed (water, brine), dried (Na2SO4), and the solvent is spun off. After chromatography on silica gel (mobile solvent:dichloromethane/methanol), 1.07 g (81.1%) of the desired product is obtained as a racemate. The product is separated into its enantiomers (Chiralpak AD 5μ; mobile solvent:hexane/ethanol). The (+)-enantiomer shows an angle of rotation of [α]D=+1.6° (c=1, MeOH), and the (−)-enantiomer shows an angle of rotation of [α]D=−1.3° (c=1, MeOH).
(+)-6-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
200 mg (0.472 mmol) of the above-described (+)-6-fluoro-5-methoxy-1-[(1H-indazol-4-yl )amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is mixed at room temperature with 4.7 ml of a 1M solution of BBr3 in dichloromethane and stirred for three and one-half hours at room temperature. The reaction mixture is mixed drop by drop with saturated sodium bicarbonate solution at −30° C., specifically until a pH of 8 is reached. After dilution with ethyl acetate, the cold bath is removed, and the batch is stirred vigorously for 15 minutes. After being shaken twice with ethyl acetate, the combined organic extracts are washed with water and saturated brine. After drying on sodium sulfate, and after the solvent is filtered and spun off, the residue is chromatographed on silica gel (mobile solvent:dichloromethane/methanol). 171.3 mg (88.6%) of the desired compound is obtained. The angle of rotation, measured at room temperature, is [α]D=+7.3 (c=1, MeOH).
(−)-6-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
200 mg (0.472 mmol) of the above-described (−)-6-fluoro-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is mixed at room temperature with 4.7 ml of a 1 M solution of BBr3 in dichloromethane and stirred for three and three-fourths hours at room temperature. The reaction mixture is mixed drop by drop at −30° C. with saturated sodium bicarbonate solution, specifically until a pH of 8 is reached. After dilution with ethyl acetate, the cold bath is removed, and the batch is stirred vigorously for 15 minutes. After being shaken twice with ethyl acetate, the combined organic extracts are washed with water and saturated brine. After drying on sodium sulfate, and after the solvent is filtered and spun off, the residue is chromatographed on silica gel (mobile solvent:dichloromethane/methanol). 179.4 mg (92.8%) of the desired compound is obtained. The angle of rotation, measured at room temperature, is [α]D=−7.8 (c=1, MeOH).
EXAMPLE 4
4-{[8-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-6-fluoro-2,3-dihydroisoindol-1-one
4-Amino-6-fluoro-2,3-dihydroisoindol-1-one
2-Methyl-5-fluoro-3-nitrobenzoic acid
116 ml of sulfuric acid is introduced and mixed in portions at −15° C. with 14.70 g (95.37 mmol) of 5-fluoro-2-methylbenzoic acid. A mixture of nitrating acid (4.79 ml of fuming nitric acid and 21.8 ml of concentrated sulfuric acid) is added in drops to this mixture, specifically at −15 to −10° C. during a period of 90 minutes. After three more hours of stirring, the reaction mixture is poured into ice water and stirred vigorously for about one-half hour. The precipitated crystallizate is suctioned off, washed neutral with water and dried. The yield is 8.56 g (45.1%) of a mixture of various regioisomers and by-products. This mixture is thus incorporated into the next stage (esterification) and purified in this stage.
2-Methyl-5-fluoro-3-nitrobenzoic acid methyl ester
8.56 g (42.99 mmol) of 2-methyl-5-fluoro-3-nitrobenzoic acid is added in 76 ml of N,N-dimethylformamide and mixed with 9.15 g (64.48 mmol) of methyl iodide and 8.91 g (64.48 mmol) of potassium carbonate. After 65 hours of stirring at room temperature, the reaction mixture is added to ice water and extracted several times with ethyl acetate. The combined organic extracts are washed with water and brine. After drying (sodium sulfate), desiccant is suctioned out, and the solvent is spun off. Repeated chromatography on silica gel (mobile solvent:ethyl acetate/hexane) yields the desired compound, specifically in a yield of 25.9% (2.37 g).
1H-NMR (300 MHz, CDCl3): δ=2.60 (3H), 3.96 (3H), 7.61 (1 H), 7.77 (1H).
2-(Bromomethyl)-5-fluoro-3-nitrobenzoic acid methyl ester
2.37 g (11.12 mmol) of 5-fluoro-2-methyl-3-nitrobenzoic acid methyl ester is added in 35 ml of carbon tetrachloride and mixed with 2.24 gram (12.24 mmol) of N-bromosuccinimide and 5.4 mg of benzoyl peroxide. After four days of refluxing, the succinimide is suctioned off (glass fiber filter) after cooling, and then the filtrate is spun in until a dry state is reached. Chromatography on a Flashmaster yields 2.47 g (75.9%) of the desired compound.
1H-NMR (300 MHz, CDCl3): δ=4.01 (3H), 5.13 (2H), 7.72 (1H), 7.87 (1H).
2-(Azidomethyl)-5-fluoro-3-nitrobenzoic acid methyl ester
2.47 g (8.46 mmol) of 2-(bromomethyl)-5-fluoro-3-nitrobenzoic acid methyl ester is mixed with 8.3 ml of N,N-dimethylformamide and 5.5 ml of water. After 0.82 g (12.66 mmol) of sodium azide is added, the batch is stirred overnight. The reaction mixture is added to water and extracted three times with methyl tert-butyl ether. The combined organic extracts are washed with water and with brine. After drying on sodium sulfate, it is filtered, and the solvent is spun off. Chromatography on a Flashmaster yields 2.06 g (95.8%) of the desired azide.
1H-NMR (300 MHz, CDCl3): δ=4.00 (3H), 4.90 (2H), 7.73 (1H), 7.87 (1H).
4-Amino-6-fluoro-2,3-dihydroisoindol-1-one
1.86 g (7.32 mmol) of 2-(azidomethyl)-5-fluoro-3-nitrobenzoic acid methyl ester is added in 46 ml of ethanol and 3.4 ml of glacial acetic acid and mixed with 256.6 mg of Pd/C. After stirring overnight at room temperature under a hydrogen atmosphere, the catalyst is suctioned off via a glass fiber filter, and the filtrate is evaporated to the dry state. The residue, 1.18 mg (97.5%) of the desired compound, is further incorporated in crude form.
1H-NMR (300 MHz, DMSO-d6): δ=4.10 (2H), 5.75 (2H), 6.46-6.57 (2H), 8.50 (1H).
4-{[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidene]amino}6-fluoro-2,3-dihydroisoindol-1-one
400 mg (1.297 mmol) of rac-4-(5-fluoro-2-metboxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentanal is stirred with 215.5 mg (1.297 mmol) of 4-amino-6-fluoro-2,3-dihydroisoindol-1-one in 1.89 ml of glacial acetic acid for four days at room temperature. Since starting material is still present according to TLC, the reaction mixture is mixed with toluene and boiled in a water separator for 20 hours. The mixture is mixed three times with toluene and evaporated to the dry state in a rotary evaporator. The residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 383.4 mg (64.7%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.37 (3H), 1.53 (3H), 2.20 (1H), 3.47 (1H) 3.88 (3H), 4.32 (2H), 4.57 (1H), 6.22 (1H), 6.63-6.88 (4H), 7.42 (1H), 7.48 (1H).
4-{[8-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-6-fluoro-2,3-dihydroisoindol-1-one
380 mg (0.832 mmol) of 4-{[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}6-fluoro-2,3-dihydroisoindol-1-one is mixed at room temperature with 8.3 ml of a 1 M solution of BBr3 in dichloromethane and stirred for one hour at ice bath temperature. The working-up of the batch is carried out as described in Example 4. After chromatography of the crude product on a Flashmaster (amine phase; mobile solvent:methanol/dichloromethane), 9.2 mg (2.7%) of the desired compound is obtained.
1H-NMR (300 MHz, CD3OD): δ=1.53 (3H), 1.69 (3H), 2.02 (1H), 2.22 (1H), 4.28 (2H), 5.09 (1H), 6.60-7.00 (4H).
EXAMPLE 5
4-{[5-Fluoro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one
2-Fluoro-3-methoxybenzaldehyde
27 ml (240.62 mmol) of 2-fluoroanisole is dissolved in 700 ml of tetrahydrofuran. At −70° C., 200 ml of sec-BuLi (1.3 M solution in cyclohexane) is added in drops. It is stirred for one hour at −70° C., and then 152 ml of N,N-dimethylformamide, dissolved in 50 ml of tetrahydrofuran, is added in drops at this temperature. After another hour of stirring at −70° C., 380 ml of hydrochloric acid (w=10%) is added in drops. In this case, the batch slowly comes to room temperature. After stirring overnight at room temperature, methyl tert-butyl ether is added, and the organic phase is separated after vigorous stirring. The aqueous phase is extracted two more times with methyl tert-butyl ether. The combined organic extracts are washed with brine and dried. After the desiccant is filtered off, the solvent is spun off, and the residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 25.66 g (69.2%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=3.95 (3H), 7.13-7.26 (2H), 7.38-7.45 (1H), 10.4 (1H).
2-Fluoro-3-methoxybenzyl alcohol
25.66 g (166.47 mmol) of 2-fluoro-3-methoxybenzaldehyde is dissolved in 140 ml of ethanol and mixed in portions at 0° C. with 3.15 g (83.35 mmol) of sodium borohydride. After one hour of stirring at room temperature, the reaction mixture is mixed with water and extracted three times with methyl tert-butyl ether. The combined organic extracts are shaken with water and brine, dried, the desiccant is suctioned off, and the solvent is spun off. The remaining residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 24.79 g (95.3%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=3.90 (3H), 4.78 (2H), 6.87-7.10 (3H).
2-Fluoro-3-methoxybenzyl chloride
24.79 g (158.75 mmol) of 2-fluoro-3-methoxybenzyl alcohol is dissolved in 35 ml of dichloromethane. While being cooled slightly, 58.4 ml of thionyl chloride is added in drops, and the batch is then stirred overnight at room temperature. The reaction mixture is spun in until a dry state is reached, the residue is dissolved in methyl tert-butyl ether, and it is shaken twice with semi-saturated potassium carbonate solution. The aqueous phase is extracted once with methyl tert-butyl ether. The combined organic extracts are worked up as usual. The residue that is obtained is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=3.90 (3H), 4.65 (2H), 6.90-7.10 (3H).
2-Fluoro-3-methoxybenzyl cyanide
24.89 g (142.56 mmol) of 2-fluoro-3-methoxybenzyl chloride is stirred in 200 ml of DMSO with 8.38 g (171.07 mmol) of sodium cyanide for three hours at 90° C. The reaction mixture is poured into water and extracted four times with methyl tert-butyl ether. The combined organic phases are washed with brine, dried, the desiccant is suctioned off, and the solvent is spun off. First, only a portion of the residue (21.43 g) is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=3.77 (2H), 3.90 (3H), 6.89-7.07 (2H), 7.08-7.15 (1H).
2-(2-Fluoro-3-methoxyphenyl)-2-methylpropanenitrile
4 g (24.22 mmol) of 2-fluoro-3-methoxybenzyl cyanide is dissolved in 38 ml of N,N-dimethylformamide and mixed with 6.87 g (48.35 mmol) of methyl iodide. At 0° C., 2.11 g (48.35 mmol) of sodium hydride (55%) is added in portions within 45 minutes. After 20 hours of stirring at room temperature, the batch is poured into ice water and extracted three times with 200 ml each of diethyl ether. The organic phases are washed with water and brine and dried. After the desiccant is filtered off and after the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 4.66 g (99.5%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.80 (6H), 3.90 (3H), 92-7.02 (1H), 7.02-7.11 (2H).
2-(2-Fluoro-3-methoxyphenyl)-2-methylpropanal
4.66 g (24.12 mmol) of 2-(2-fluoro-3-methoxyphenyl)-2-methylpropanenitrile is dissolved in 96 ml of toluene. At −65° C. to −60° C., 30 ml (36.18 mmol) of a 1.2 molar solution of DIBAH in toluene is added in drops. After three and one-half hours of stirring at −65° C., 276 ml of a 10% L(+)-tartaric acid solution is added in drops at this temperature. In this case, the temperature rises to 0° C. The cold bath is removed, and the batch is stirred vigorously at room temperature for one hour. The reaction mixture is extracted three times with 300 ml each of diethyl ether. The combined organic extracts are treated as usual (water, brine, drying). After the solvent is spun off, 4.78 g (slightly above 100%) of the desired compound remains.
1H-NMR (300 MHz, CDCl3): δ=1.46 (6H), 3.89 (3H), 6.85-6.7.00 (2H), 7.08-7.15 (1H), 9.65 (1H).
E/Z-4-(2-Fluoro-3-methoxyphenyl)-4-methylpent-2-enoic acid methyl ester
20.26 g (111.26 mmol) of phosphonoacetic acid trimethyl ester is introduced into 68 ml of tetrahydrofuran. At 0° C., 61 ml of a 2 M solution of LDA in THF/heptane/ethylbenzene is added in drops. After 45 minutes of stirring, 21.83 g (111.26 mmol) of 2-(2-fluoro-3-methoxyphenyl)-2-methylpropanal, dissolved in 68 ml of tetrahydrofuran, is added in drops at 0° C. After stirring overnight, the reaction mixture is mixed with water while being cooled in an ice bath, and it is extracted three times with methyl tert-butyl ether. The combined organic extracts are treated as usual, and the residue that is obtained is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 23.30 g (75.8%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.50 (6H), 3.73 (3H), 3.88 (3H), 5.74 (1H), 5.80 (1H), 6.80-7.10 (3H).
4-(2-Fluoro-3-methoxyphenyl)-4-methylpentanoic acid methyl ester
23.30 g (84.33 mmol) of E/Z-4-(2-fluoro-3-methoxyphenyl)-4-methylpent-2-enoic acid methyl ester is mixed in 310 ml of ethanol with 1.2 g of palladium on carbon, and it is stirred under a hydrogen atmosphere overnight at room temperature. The catalyst is removed by filtration via a glass fiber filter, and the residue that remains after concentration by evaporation is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 19.58 g (83.4%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.48 (6H), 2.00-2.18 (4H), 3.60 (3H), 3.90 (3H), 6.78-7.03 (3H).
4-(2-Fluoro-3-methoxyphenyl)-2-hydroxy-4-methylpentanoic acid methyl ester
19.58 g (77 mmol) of 4-(2-fluoro-3-methoxyphenyl)-4-methylpentanoic acid methyl ester is introduced into 245 ml of tetrahydrofuran, and the reaction mixture is cooled to −70° C. Within one hour, 220.7 ml of a 0.5 molar solution of potassium-bis-(trimethylsilylamide) in toluene is added in drops, and the reaction mixture is then stirred for 45 more minutes at −70° C. 28.3 g (107.79 mmol) of Davis reagent, dissolved in 245 ml of tetrahydrofuran, is now added in drops within 40 minutes. After two hours of stirring at −70° C., 250 ml of saturated ammonium chloride solution is slowly added in drops, and in this case, the batch is brought to room temperature. After extraction with methyl tert-butyl ether, the combined organic extracts are treated as usual with water and brine. After the solvent is spun off, the residue is chromatographed several times on silica gel (mobile solvent:ethyl acetate/hexane). 12.14 g (58.3%) of the desired compound is ultimately isolated.
1H-NMR (300 MHz, CDCl3): δ=1.45 (3H), 1.49 (3H), 1.90-2.01 (1H), 2.38-2.50 (2H), 3.70 (3H), 3.90 (3H), 3.92-4.03 (1H), 6.80-7.08 (3H).
Methyl-4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-oxopentananoate
11.14 g (41.22 mmol) of methyl 4-(2-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-pentanoate is added in 260 ml of dichloromethane and 71.3 ml of dimethyl sulfoxide. After 20.8 g (205.78 mmol) of triethylamine is added, the batch is mixed with 13 g (81.71) of SO3/pyridine complex and then stirred overnight at room temperature. The reaction mixture is mixed with 100 ml of saturated ammonium chloride solution while being cooled slightly, and it is stirred vigorously. After being extracted three times with methyl tert-butyl ether, the combined organic phases are treated as usual. The residue that remains after the solvent is spun off is chromatographed together with the residue, which results from a sample batch (1g), on silica gel (mobile solvent:ethyl acetate/hexane). 10.03 g (83.2%, from both batches) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.49 (6H), 3.39 (2H), 3.73 (3H), 3.89 (3H), 6.80-6.91 (2H), 6.95-7.07 (1H).
Methyl-4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoate
10.03 g (37.39 mmol) of methyl-4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-oxopentanoate is dissolved in 63 ml of tetrahydrofuran, mixed with 5.68 g (39.98 mmol) of (trifluoromethyl)-trimethylsilane and then with 82.3 mg of tetrabutylammonium fluoride. After stirring overnight at room temperature, the batch is added to ice water, extracted with methyl tert-butyl ether, and the combined organic extracts are treated as usual. After the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). In addition to 6.94 g (45.2%) of the desired product, 2.75 g of starting material (contaminated) is isolated, which is again subjected to the same procedure. As a result, another 1.91 g of methyl-4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoate is included.
MS (CI): 428 (100%), 395 (67%).
4-(2-Fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)pentan-1-ol and
4-(2-Fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-1-(trimethylsilyloxy)pentan-2-ol
8.85 g (21.56 mmol) of methyl-4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoate is dissolved in 77 ml of diethyl ether. 1.64 g (43.12 mmol) of lithium aluminum hydride is added to this solution in portions at 0° C. After four hours of stirring at room temperature, it is cooled again to 0° C. and about 80 ml of saturated sodium bicarbonate solution is carefully added in drops. Then, it is stirred vigorously at room temperature for one hour. The batch is extracted several times with methyl tert-butyl ether. The combined organic extracts are washed with water and then with brine. After drying on sodium sulfate, the desiccant is suctioned off, the solvent is spun in, and the residue (7.36 g; mixture of the two regioisomeric silyl ethers) is incorporated in crude form into the next stage.
4-(2-Fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol
7.36 g (19.24 mmol) of the mixture of the two silyl ethers is dissolved in 108 ml of tetrahydrofuran, mixed with 6.07 g (19.24 mmol) of tetrabutylammonium fluoride trihydrate and stirred overnight at room temperature. The reaction mixture is diluted with methyl tert-butyl ether, washed with water and brine, and then the organic solvent is spun off after drying. After chromatography on silica gel (mobile solvent:ethyl acetatelhexane), 5.3 g (88.8%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.45 (3H), 1.58 (3H), 2.20 (1H), 2.38 (2H), 2.93 (1H), 3.30-3.40 (1H), 3.50-3.60 (1H), 3.89 (3H), 6.85-6.98 (2H), 6.98-7.09 (1H).
4-(2-Fluoro-3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal
2.5 g (8.06 mmol) of rac-4-(2-fluoro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol is introduced into a mixture that consists of 52 ml of dichloromethane, 14 ml of dimethyl sulfoxide and 4.08 g (40.29 mmol) of triethylamine. At room temperature, 2.57 g (16.11 mmol) of SO3/pyridine complex is added, and the batch is stirred overnight at this temperature. The reaction mixture is mixed with saturated ammonium chloride solution and stirred vigorously. After additional common working-up, 2.11 g (85%) of the desired aldehyde is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.45 (3H), 1.50 (3H), 2.30 (1H), 3.12 (1H), 3.62 (1H), 3.89 (3H), 6.75 (1H), 6.90 (1H), 7.00 (1H), 9.15 (1H).
4-{[5-Fluoro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one
150 mg (0.487 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-trifluoromethyl-pentanal is mixed in 0.9 ml of glacial acetic acid with 72.7 mg (0.487 mmol) of 4-amino-2,3-dihydroisoindol-1-one, and it is stirred for two days at room temperature. The batch is spun in until a dry state is reached, and the residue is chromatographed (Flashmaster). 119.8 mg (56.2%) of the desired cyclic compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.50 (3H), 1.65 (3H), 2.05 (1H), 2.20 (1H), 3.83 (3H), 4.29 (2H), 4.40 (1H), 5.00 (1H), 6.79 (1H), 6.93 (1H), 7.00-7.12 (2H), 7.21 (1H), 7.35 (1H).
4-{[5-Fluoro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one
109.8 mg (0.250 mmol) of (rac.) 4-{[5-fluoro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one is mixed with 3.4 ml of a 1 M solution of BBr3 in dichloromethane and stirred for four hours at room temperature. The batch is mixed at 0° C. with saturated sodium bicarbonate solution and extracted twice with ethyl cetate. The combined organic extracts are dried on sodium sulfate. After the desiccant is filtered off, and after the solvent is spun off, the residue is chromatographed on a Flashmaster. 15.6 mg (14.7%) of the final product is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.53 (3H), 1.67 (3H), 2.03-2.20 (2H), 4.28-4.43 (2H), 5.13 (1H), 6.78 (1H), 6.90 (2H), 7.18 (1H), 7.38 (1H).
EXAMPLE 6
4-{[7-Bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-1,3-dihydroindol-2-one
4-Amino-1,3-dihydroindol-2-one
Dimethyl-2-(2,6-dinitrophenyl)-malonate
42.95 g (311.03 mmol) of dimethyl malonate is dissolved in 300 ml of N,N-dimethylformamide and mixed in portions with 35.15 g (296.22 mmol) of potassium-tert butylate. After the tert-butanol that was produced has been distilled off, the reaction mixture is cooled to 20° C. 30 g (148.11 mmol) of 2,6-dichlorobenzene is quickly added in portions to the mixture. After three hours of stirring at 90° C., it is stirred overnight at room temperature. The reaction mixture is added to 800 ml of 1% NaOH solution (ice-cooled) and extracted three times with methyl tert-butyl ether. The combined ether phases are discarded according to TLC monitoring. The aqueous phase is carefully acidified with concentrated nitric acid (w=65%) while being cooled in an ice bath. Six cycles of extraction with methyl tert-butyl ether and common working-up of the combined organic extracts (water, brine, drying, filtering and spinning-off of solvent) yield a residue that is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 12.09 g (27.09%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=3.82 (6H), 5.39 (1H), 7.75 (1H), 8.27 (2H).
Methyl-(2,6-Dinitrophenyl)-acetate
10.08 g (33.8 mmol) of dimethyl-2-(2,6-dinitrophenyl)-malonate is mixed in 54 ml of glacial acetic acid with 2.7 ml of perchloric acid and refluxed at 125° C. In this case, the ethyl acetate that is produced is distilled off. After 90 minutes, the reaction is brought to a halt, since starting material is no longer present according to TLC. The reaction mixture is poured into ice water and extracted three times with ethyl acetate. The combined organic extracts are shaken with 5% sodium bicarbonate solution, with water and with brine. After the organic phase is dried, the desiccant is filtered off and the solvent is spun off, a residue remains that is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 4.69 g of the (2,6-dinitrophenyl)-acetic acid, which then is esterified with methanol (16 ml) and concentrated sulfuric acid (0.4 ml), is isolated. To this end, the acid and the reagents are refluxed for seven hours. The methanol is spun off, and the residue is worked up in the usual way. After chromatography on silica gel (mobile solvent:ethyl acetate/hexane), 4.43 g (89%) of the desired ester is obtained.
1H-NMR (300 MHz, CDCl3): δ=3.75 (3H), 4.20 (2H), 7.69 (1H), 8.19 (2H).
4-Amino-1,3-dihydroindol-2-one
4.43 g (18.45 mmol) of methyl-(2,6-dinitrophenyl)-acetate is added in 38.8 ml of glacial acetic acid and 11 ml of water and mixed with 3.75 g of iron powder and stirred for four more hours. In this case, heating to 40 to 60° C. takes place. The reaction mixture is added to ice water, mixed with ethyl acetate and stirred vigorously for ten minutes. The mixture is filtered through a glass fiber filter, the organic phase is separated, and the aqueous phase is extracted twice more with ethyl acetate. The combined organic extracts are washed with brine, dried, and the solvent is spun off after the desiccant is filtered off. The residue is chromatographed on silica gel (mobile solvent:methanol/dichloromethane). 2.38 g of 4-nitro-indol-2-one is isolated. The nitro compound is mixed again in glacial acetic acid/water with 2.7 g of iron powder, and the above-described cycle is passed through another time. 1.63 g of the desired amine is isolated.
1H-NMR (300 MHz, DMSO-d6): δ=3.19 (2H), 5.03 (2H), 6.08 (1H), 6.22 (1H), 6.85 (1H), 10.10 (1H).
4-(4-Bromo-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol
2.55 g (6.17 mmol) of 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanoic acid ethyl ester (synthesized in two stages starting from 4-(4-bromo-2-methoxyphenyl)-2-oxopentanoic acid, WO 98/54159) is dissolved in 102 ml of diethyl ether, mixed in portions at 0 to −5° C. with 351.3 mg (9.256 mmol) of lithium aluminum hydride and stirred for three and one-half hours at room temperature. The reaction mixture is mixed drop by drop with saturated sodium bicarbonate solution while being cooled in an ice bath and stirred for 15 minutes at 5° C. and then for one hour at room temperature. The deposited precipitate is suctioned off, rewashed with diethyl ether, and the filtrate is concentrated by evaporation in a rotary evaporator. The residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). In addition to 308 mg of the aldehyde (see next stage), 2.025 g (88.4%) of the diol is obtained.
4-(4-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal
2.03 g (5.442 mmol) of 4-(4-bromo-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol is oxidized to aldehyde according to Swern as described in Example 3. 1.839 g (91.4%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.39 (3H), 1.45 (3H), 2.23 (1H), 3.35 (1H), 3.58 (1H), 3.90 (3H), 6.93-7.09 (3H), 9.03 (1H).
4-{[4-(4-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidene]amino}-1,3-dihydroindol-2-one
300 mg (0.812 mmol) of 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is stirred in 1.5 ml of glacial acetic acid with 120.4 mg (0.812 mmol) of 4-amino-1,3-dihydroindol-2-one over a weekend at room temperature. The reaction mixture is evaporated until a dry state is reached, and the residue is put on a Flashmaster column. 235.9 mg (58.1%) of the desired imine is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.35 (3H), 1.53 (3H), 2.20 (1H), 3.30 (1H), 3.42 (2H), 3.85 (3H), 4.71 (1H), 6.05 (1H), 6.78 (1H), 6.80-6.90 (2H), 6.98 (1H), 7.19 (1H), 7.45 (1H), 8.25 (1H).
4-{[7-Bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino}-1,3-dihydroindol-2-one
235.9 mg of 4-{[4-(4bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}-1,3-dihydroindol-2-one is mixed at 0° C. with 6.42 ml of a 1 M solution of BBr3 in dichloromethane and stirred for four hours at room temperature. At 0° C., saturated sodium bicarbonate solution is carefully added in drops. After being extracted three times with ethyl acetate, the organic phases are dried on sodium sulfate. The desiccant is suctioned off, and the solvent is spun off. The residue is chromatographed on a Flashmaster. 125.4 mg (54%) of the desired compound is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.52 (3H), 1.65 (3H), 1.98-2.18 (2H), 3.25-3.49 (2H), 4.98 (1H), 6.37 (1H), 6.47 (1H), 6.87 (1H), 7.02 (1H), 7.11 (1H).
EXAMPLE 7
(+)-4-({7-Hydroxy-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydronaphtho[1,2-d]-1,3-dioxol-6-yl}amino)-2,3-dihydroisoindol-1-one and
(−)-4-({7-Hydroxy-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydronaphtho[1,2-d]-1,3-dioxol-6-yl}amino)-2,3-dihydroisoindol-1-one
1,3-Benzodioxole-4-carboxylic acid-methyl ester
50 g of 2,3-dihydroxybenzoic acid in 450 ml of methanol is mixed drop by drop with 50 ml of thionyl chloride at room temperature. Then, the solution is heated for five hours to 60° C. and still stirred overnight at room temperature. The solvent is completely removed in a vacuum, and the remaining oil is taken up in diethyl ether and extracted with saturated sodium bicarbonate solution. After washing with brine, drying with sodium sulfate and removal of the solvent in a vacuum, 46 g of 2,3-dihydroxybenzoic acid-methyl ester is obtained. The latter is mixed in 575 ml of DMF and 20.2 ml of dibromomethane with 56.7 g of potassium carbonate, and it is heated for five hours under argon to 100° C. Then, it is stirred overnight at room temperature. After mixing with water, it is extracted three times with ethyl acetate. The organic phase is washed several times with water and dried on sodium sulfate. The solvent is removed in a vacuum, and 50.2 g of 1,3-benzodioxole-4-carboxylic acid-methyl ester is obtained as a brown solid.
Melting point: 55-57° C.
4-(1,3-Benzodioxol-4-yl)-4-methyl-2-oxopentanoic acid ethyl ester
4.76 g of 1,3-benzodioxole-4-carboxylic acid-methyl ester in 65 ml of dry THF is added in drops at room temperature to a solution of 21 ml of 3 M methylmagnesium chloride in THF under argon. The reaction mixture is stirred for three hours and then slowly mixed with 1N hydrochloric acid. After extraction with ethyl acetate and after the organic phase is washed with water, it is dried with sodium sulfate, and the solvent is removed in a vacuum. 5 g of 1-(1,3-benzodioxol-4-yl)-1-methylethanol is obtained as a brown oil. The tertiary alcohol (27.17 mmol) is mixed together with 7.8 g (41.6 mmol) of 2-(trimethylsilyloxy)-acrylic acid ethyl ester in 100 ml of dichloromethane at −70° C. with 5.4 g (20.8 mmol) of tin tetrachloride. After 15 minutes of stirring at −70° C., the solution is poured onto semi-saturated sodium carbonate solution, mixed with ethyl acetate and stirred vigorously. The phases are separated, and the aqueous phase is extracted twice with ethyl acetate. The organic phase is washed with brine, dried with sodium sulfate, and the solvent is removed in a vacuum. 7.15 g of a yellow oil that is distilled together with the products from several batches of a similar order of magnitude is obtained.
4-(1,3-Benzodioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanoic acid ethyl ester
6.1 g (21.91 mmol) of 4-(1,3-benzodioxol-4-yl)-4-methyl-2-oxopentanoic acid ethyl ester, dissolved in 130 ml of tetrahydrofuran, is reacted with 9.5 ml (65.7 mmol) of (trifluoromethyl)trimethylsilane and 4.42 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. Carrying out and working up the reaction are carried out as described in Example 3. The crude product that is obtained is purified together with one batch of a similar order of magnitude [9.19 g (33.02 mmol) of 4-(1,3-benzodioxol-4-yl)-4-methyl-2-oxopentanoic acid ethyl ester as a starting material] by chromatography on silica gel (mobile solvent:ethyl acetate/hexane). 16.45 g (86%) of the desired product is isolated from the two batches together.
4-(1,3-Benzodioxol-4-yl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol
12.5 g (36.03 mmol) of 4-(1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanoic acid ethyl ester is introduced into 430 ml of diethyl ether and mixed in portions with 2.05 g (54.1 mmol) of lithium aluminum hydride at 0° C. After stirring overnight at room temperature, the batch is carefully added to sodium bicarbonate solution. It is filtered by means of diatomaceous earth and extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried, and the solvent is spun off after the desiccant is filtered off. Chromatography of the residue on silica gel (mobile solvent:ethyl acetate/hexane) yields 6.7 g (61%) of the desired alcohol.
4-(1,3-Benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
2.26 g (7.38 mmol) of 4-(1,3-benzodioxol-4-yl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol is oxidized to aldehyde as described in Example 3 according to Swern. After the usual working-up, the residue is chromatographed on a Flashmaster. 1.85 g (82.3%) of the desired aldehyde is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.39 (3H), 1.48 (3H), 2.27 (1H), 3.10 (1H), 3.67 (1H), 5.92-6.02 (2H), 6.60-6.70 (1H), 6.70-6.88 (2H), 9.06 (1H).
(+)-4-({7-Hydroxy-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydronaphtho[1,2-d]-1,3-dioxol-6-yl}amino)-2,3-dihydroisoindol-1-one and
(−)-4-({7-Hydroxy-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydronaphtho[1,2-d]-1,3-dioxol-6-yl}amino)-2,3-dihydroisoindol-1-one
800 mg (2.63 mmol) of 4-(1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal is stirred in 5.2 ml of glacial acetic acid with 389 mg (2.63 mmol) of 4-amino-2,3-dihydroisoindol-1-one overnight at room temperature. The reaction mixture is spun in until a dry state is reached, and the residue is chromatographed on a Flashmaster. 725 mg (62.8%) of the desired compound is isolated as a racemate. Racemate cleavage (Chiralpak AD 20μ; mobile solvent:hexane/ethanol/diethylamine) yields 279.2 mg of the (+)-enantiomer {[α]D=+20.7 (c=1.03, methanol)} and 297.5 mg of the (−)-enantiomer {[α]D=−23.4 (c=1.02, methanol)}.
EXAMPLE 8
5-{[8-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
4-(5-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
2 g (6.12 mmol) of 4-(5-chloro-2-methoxyphenyl)-hydroxy-4-methyl-2-trifluoromethyl-pentan-1-ol is oxidized with 854.6 mg (6.733 mmol) of oxalyl chloride and 1.05 ml (14.812 mmol) of DMSO as described in Example 2 according to Swern. After the working-up, 1.95 g (98.4%) of the desired aldehyde is obtained, which is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=1.39 (3H), 1.49 (3H), 2.27 (1H), 3.32 (1H), 3.59 (1H), 3.88 (3H), 6.78 (1H), 7.10 (1H), 7.20 (1H), 9.09 (1H).
5-{[4-(5-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)-pentylidene]amino}isoquinolin-1(2H)-one
300 mg (0.924 mmol) of 4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal is stirred with 148 mg (0.924 mmol) of 5-amino-isoquinolin-1-one in 1.33 ml of glacial acetic acid for four days at room temperature. The mixture is drawn off three times with toluene and evaporated in a rotary evaporator until a dry state is reached. The residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 345.8 mg (80.1 %) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.39 (3H), 1.57 (3H), 2.29 (1H), 3.49 (1H), 3.83 (3H), 4.82 (1H), 6.57-6.65 (2H), 6.72 (1H), 6.89 (1H), 7.03 (1H), 7.18-7.29 (1H), 7.36 (1H), 7.40 (1H), 8.32 (1H), 10.98 (1H).
5-{[8-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
50 mg (0.107 mmol) of the compound 5-{[4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}2,3-isoquinolin-1-one that is described in the paragraph above is mixed at −20° C. with 2.1 ml of a 1 M solution of boron tribromide in dichloromethane, and it is stirred for two and one-half hours in a temperature range of between −20° C. and 0° C. The reaction mixture is mixed drop by drop at −20° C. with saturated sodium bicarbonate solution. After dilution with ethyl acetate, the cold bath is removed, and the batch is stirred for 15 minutes at room temperature. It is extracted twice with 30 ml each of ethyl acetate. The combined organic extracts are washed with water and saturated NaCl solution. After being dried on sodium sulfate, the solvent is spun off, and the remaining residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 16.5 mg (33%) of the desired compound is isolated.
MS (ES+): 453, 455
EXAMPLE 9
8-Bromo-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol)
4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoic acid ethyl ester
34.45 g (258.91 mmol) of aluminum trichloride is introduced into 354.35 g (237.02 mmol) of 4-bromoanisole. 38.95 g (172.19 mmol) of 2-hydroxy-4-methylene-2-(trifluoromethyl)pentanoic acid ethyl ester is added in drops to this mixture within one hour. After stirring overnight at room temperature, the batch is added to ice water and made acidic with 10% hydrochloric acid. After being extracted three times with ethyl acetate, the combined organic extracts are washed with 1N hydrochloric acid and brine. After drying on magnesium sulfate, the solvent is spun off. Most of the excess 4-bromoanisole is distilled off (10 mbar; bath temperature 110° C.). After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 36.87 g (51.8%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.39 (3H), 1.46 (3H), 2.49 (1H), 2.85 (1H), 3.48 (1H), 3.62-3.75 (1H), 3.85 (3H), 4.02-4.15 (1H), 6.73 (1H), 7.23-7.33 (2H).
4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol
3 g (7.25 mmol) of 4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoic acid ethyl ester is dissolved in 120 ml of diethyl ether, and the reaction mixture is cooled to 0° C. 426.5 mg (10.89 mmol) of lithium aluminum hydride is added in portions. After two hours of stirring at room temperature, starting material is no longer present. The batch is mixed with saturated sodium bicarbonate solution while being cooled in an ice bath, the precipitate is suctioned off, and it is washed with diethyl ether. After spinning-in, the residue is chromatographed on a Flashmaster. In addition to 540.5 mg of 4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, 1.14 g of the desired alcohol (which, however, also contains the Desbrom compound) is isolated.
4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
1.13 g (3.06 mmol) of 4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol is added in 20 ml of dichloromethane and 5.4 ml of DMSO. After mixing with 1.55 g (15.32 mmol) of triethylamine and 975.28 mg (6.13 mmol) of SO3/pyridine complex, the batch is stirred overnight at room temperature. After TLC, another spatula tip full of SO3/pyridine complex is added, and it is further stirred for several hours. The reaction mixture is mixed with saturated ammonium chloride solution and shaken out three times with methyl tert-butyl ether. The combined organic extracts are washed with water and brine. After the solvent is dried and spun off, the residue is chromatographed on a Flashmaster. 902.7 mg (79.81%) of the desired aldehyde (together with the Desbrom compound) is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.40 (3H), 1.50 (3H), 2.28 (1H), 3.30 (1H), 3.87 (3H), 6.73 (1H), 7.22 (1H), 7.35 (1H), 9.09 (1H).
1,1,1-Trifluoro-4-(5-bromo-2-methoxyphenyl)-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol
300 mg (0.813 mmol) of 4-(5-bromo-2-methoxyphenyl)-2hydroxy-4-methyl-2-(trifluoromethyl)pentanal is mixed in 1.19 ml of glacial acetic acid with 108.2 mg (0.813 mmol) of 4-aminoindazole, and it is stirred for four days at room temperature. The batch is spun in until a dry state is reached, and the residue is drawn off three times with toluene. Chromatography on silica gel (mobile solvent:ethyl acetate/hexane) yields 352.5 mg (89.5%) of the desired imine (together with the imine of the Desbrom compound).
1H-NMR (300 MHz, CDCl3): δ=1.48 (3H), 1.55 (3H), 2.28 (1H), 3.44 (1H), 3.80 (3H), 4.98 (1H), 6.35 (1H), 6.53 (1H), 6.99 (1H), 7.30 (1H), 7.29-7.40 (1H), 7.55 (1H), 7.99 (1H), 10.28 (1H).
8-Bromo-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
100 mg (0.206 mmol) of 1,1,1-trifluoro-4-(5-bromo-2-methoxyphenyl)-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol is dissolved in one milliliter of dichloromethane, and the reaction mixture is cooled to −30° C. Four milliliters of a 1 M solution of BBr3 in dichloromethane is added in drops within 15 minutes, and the batch is then stirred for 45 more minutes at −30° C. At −30° C., about 10 ml of a saturated sodium bicarbonate solution is carefully added in drops. After dilution with ethyl acetate, it is stirred for ten minutes and then extracted twice with 50 ml each of ethyl acetate. The combined organic extracts are washed with water and brine. The residue that is obtained after the solvent is dried and spun off is chromatographed several times on silica gel (mobile solvent: ethyl acetate/dichloromethane). 21 mg of the desired compound (together with the corresponding Desbrom compound) is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.55 (3H), 1.67 (3H), 2.10 (1H), 2.43 (1H), 3.89 (3H), 5.25 (1H), 6.72 (1H), 6.83 (1H), 6.90 (1H), 7.22 (1H), 7.49 (1H), 8.25 (1H).
8-Bromo-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
21 mg (0.043 mmol) of 8-bromo-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is mixed at room temperature with 0.4 ml of a 1 M BBr3 solution and stirred for 19 hours at room temperature. After the reaction mixture is mixed with ice, saturated sodium bicarbonate solution is added drop by drop, and it is diluted with ethyl acetate. The organic phases are washed neutral as usual, and the residue that remains after the solvent is spun in is chromatographed on silica gel (mobile solvent: methanol/dichloromethane). 17.1 mg (83.8%) of the desired compound (together with the Desbrom compound) is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.59 (3H), 1.71 (3H), 2.10 (1 H), 2.42 (1H) 5.25 (1H), 6.64-6.78 (2H), 6.83 (1H), 7.20-7.34 (2H), 8.25 (1H).
Example 10
1-[(1H-Indazol-4-yl)amino]-4,4-dimethyl-2- trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
2-Hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal
10.4 g of 4-methyl-2-oxo-4-phenylpentanoic acid (WO98/54159) in 250 ml of dimethylformamide is mixed at −5° C. with 4.1 ml of thionyl chloride, and after 15 minutes, it is mixed with 4 ml of methanol. After 15 hours at room temperature, the batch is diluted with water, and extracted with ethyl acetate. The organic extracts are washed with water, dried (Na2SO4) and concentrated by evaporation, whereby 9.3 g of 4-methyl-2-oxo-4-phenylpentanoic acid-methyl ester is obtained. The latter is mixed in 558 ml of DMF at −5° C. with 15.5 ml (104.63 mmol) of (trifluoromethyl)trimethylsilane and 20.5 g (63.28 mmol) of cesium carbonate, and it is stirred for 16 hours at room temperature. Water is added, it is extracted with ethyl acetate, the organic phase is washed with water and dried (Na2SO4). The intermediate product that is concentrated by evaporation is taken up in 200 ml of THF, and 50 ml of a 1 M solution of tetrabutylammonium fluoride in THF is added. It is stirred for 2 hours, water is added, it is extracted with ethyl acetate, the organic phase is washed with water and dried (Na2SO4). After chromatography on silica gel with hexane-ethyl acetate (0-30%), 8.35 g of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanoic acid-methyl ester is obtained. The ester (8.3 g, 28.59 mmol) is dissolved in 180 ml of THF, and over a period of 2.5 hours, 1.52 g (36.20 mmol) of lithium aluminum hydride is added in small portions. After complete conversion, 5 ml of ethyl acetate is added in drops, and after another 10 minutes, 10 ml of water is carefully added. Formed precipitate is filtered out, and it is washed carefully with ethyl acetate. After chromatography on silica gel with hexane-ethyl acetate (0-35%), 5.40 g of 4-methyl-4-phenyl-2-(trifluoromethyl)pentane-1,2-diol is obtained. 5.7 ml (40.3 mmol) of triethylamine is added to 2.5 g (9.53 mmol) of diol in 75 ml of dichloromethane and 28 ml of DMSO, and 5 g of pyridine/SO3 complex is added in portions over 20 minutes. It is stirred over 2 hours, and 40 ml of saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water, and dried on sodium sulfate. The solvent is removed in a vacuum, and 3 g of product is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.34 (s, 3H), 1.44 (s, 3H), 2.34 (d, 2H), 2.66 (d, 1H), 3.64 (s, 1H), 7.03-7.41 (m, 4H), 8.90 (s, 1H).
1,1,1-Trifluoro-4-phenyl-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol
130 mg (0.50 mmol) of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)-pentanal is dissolved in 15 ml of toluene and mixed with 73 mg (0.55 mmol) of 4-amino-indazole and with 0.22 ml of titanium tetraethylate and stirred at 100° C. for 2.5 hours under argon. For working-up, the reaction solution is mixed with 1 ml of saturated sodium chloride solution, and it is stirred for 30 minutes. The suspension is then suctioned off on Celite and washed with 200 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum: 246 mg. Column chromatography on silica gel with pentane-ethyl acetate yields 190 mg of the product.
1H-NMR (300 MHz, DMSO-d6): δ=1.35 (s, 3H), 1.47 (s, 3H), 2.26 (d, 1H), 2.73 (d, 1H), 6.13 (s, 1H), 6.24 (d, 1H), 6.94 (t, 1H), 7.06 (t, 2H), 7.23 (t, 1H), 7.34-7.40 (m, 3H), 7.56 (s, 1H), 8.00 (s, 1H), 13.17 (s, 1H).
1-[(1H-Indazol-4-yl)amino]-4,4-dimethyl-2- trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
190 mg (0.51 mmol) of 1,1,1-trifluoro-4-phenyl-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol is dissolved in 100 ml of dichloromethane and cooled to −70° C. The solution is mixed over 10 minutes with 9 ml of titanium tetrachloride solution (1 mol in dichloromethane), and it is stirred for 1 hour at −70° C. Then, the cold solution is poured into 200 ml of saturated sodium bicarbonate solution and stirred for 15 minutes. For working-up, the mixture is extracted with dichloromethane, the organic phase is washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum: 208 mg. Column chromatography with dichloromethane-methanol yields 53 mg (28%) of the desired product.
1H-NMR (300 MHz, DMSO-d6): δ=1.36 (s, 3H), 1.51 (s, 3H), 2.08 (d, 2H), 5.35 (d, 1H), 5.93 (s, 1H), 6.24 (d, 1H), 6.32 (d, 1H), 6.74 (d, 1H), 7.05-7.12 (m, 2H), 7.21-7.28 (m, 2H), 7.43 (d, 1H), 8.15 (s, 1H), 12.81 (s, 1H).
Example 11
1-[(2-Methylbenzothiazol-7-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1,1,1-Trifluoro-4-phenyl-2-[(2-methylbenzothiazolyl-7-yl)iminomethyl]-4-methylpentan-2-ol
1H-NMR (300 MHz, DMSO-d6): δ=1.33 (s, 3H), 1.47 (s, 3 H), 2.24 (d, 1H), 2.71 (d, 1H), 2.82 (s, 3H), 6.19, (s, 1H), 6.54 (d, 1H), 6.91 (t, 1H), 7.02 (t, 2H), 7.31-7.40 (m, 3H), 7.51 (s, 1H), 7.78 (d, 1H).
1-[(2-Methylbenzothiazol-7-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1H-NMR (300 MHz, DMSO-d6): δ=1.34 (s, 3H), 1.47 (s, 3H), 1.99-2.12 (m, 2H), 2.78 (s, 3H), 5.38 (d, 1H), 5.68 (d, 1H), 6.10 (s, 1H), 6.78 (dd, 1), 7.07-7.16 (m, 2H), 7.20-7.28 (m, 3H), 7.41 (d, 1H).
Example 12
6-[(1H-Indazol-4-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1,3-dioxol-7-ol
4-(1,3-Benzodioxol-4-yl)-1,1,1-trifluoro-2-[1H- indazoly-4-yl)iminomethyl]-4-methylpentan-2-ol
1H-NMR (300 MHz, DMSO-d6): δ=1.34 (s, 3H), 1.48 (s, 3H), 2.28 (d, 1H), 2.93 (d, 1H), 5.90 (s, 2H), 6.15 (s, 1H), 6.29 (d, 1H), 6.45 (t, 1H), 6.56 (dd, 1H), 6.62 (d, 1H), 7.23 (t, 1H), 7.40 (d, 1H), 7.74 (s, 1H), 8.00 (s, 1H), 13.17 (s, 1H).
6-[(1H-Indazol-4-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1,3-dioxol-7-ol
1H-NMR (300 MHz, DMSO-d6): δ=1.43 (s, 3H), 1.55 (s, 3H), 2.04-2.12 (m, 2H), 5.26 (d, 1H), 5.95 (s, 1H), 6.00 (s, 2H), 6.19 (d, 1H), 6.29 (d, 1H), 6.70-6.78 (m, 3H), 7.07 (t, 1H), 8.12 (s, 1H), 12.81 (s, 1H).
Example 13
1-[(2-Methylquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1,1,1-Trifluoro-4-phenyl-2-[(2-methylquinolin-5-yl)iminomethyl]-4-methylpentan-2-ol
120 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal, 67 mg of 5-amino-2-methylquinoline and 163 μl of titanium tetraethylate are stirred in 8 ml of toluene for 2 hours at 100° C. After cooling, the batch is mixed with 2 ml of water, stirred for 15 minutes at room temperature, and concentrated by evaporation in a vacuum. Column chromatography on silica gel with cyclohexane-ethyl acetate yields 111 mg of product.
1H-NMR (300 MHz, CDCl3): δ=1.35 (s, 3H), 1.55 (s, 3H), 2.45 (d, 1H), 2.75 (s, 3H), 2.80 (d, 1H), 5.00 (s, 1H), 6.15 (d, 1H), 6.9-7.1 (m, 3H), 7.30 (m, 3H), 7.35 (d, 1H), 7.45 (t, 1H), 7.90 (d, 1H), 8.35 (d, 1H).
1-[(2-Methylquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
5.1 ml of a 1 M titanium tetrachloride-CH2Cl2 solution is added in drops to a solution of 111 mg of 1,1,1-trifluoro-4-phenyl-2-[(2-methylquinolin-5-yl)iminomethyl]-4-methylpentan-2-ol in 84 ml of CH2Cl2 at −78° C. After 1 hour at −78° C., the batch is mixed with saturated NaHCO3 and heated to room temperature. The phases are separated, the aqueous phase is extracted with CH2Cl2, the combined organic phases are dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with cyclohexane-ethyl acetate yields 94 mg of product.
1H-NMR (300 MHz, CDCl3): δ=1.45 (s, 3H), 1.60 (s, 3H), 2.15 (d, 1H), 2.20 (d, 1H), 2.75 (s, 3H), 3.05 (br., 1H), 4.85 (br. d, 1H), 5.20 (d, 1H), 6.85 (d, 1H), 7.10 (t, 1H), 7.20 (d, 1H), 7.30 (t, 1H), 7.40 (d, 1H), 7.50 (d, 1H), 7.55 (t, 1H), 8.05 (d, 1H).
Example 14
1-[(Quinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1,1,1-Trifluoro-4-phenyl-2-[(quinolin-5-yl)iminomethyl]-4-methylpentan-2-ol
Analogously to Example 13, 120 mg of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentanal and 61 mg of 5-aminoquinoline are converted into 95 mg of product.
1H-NMR (300 MHz, CDCl3): δ=1.35 (s, 3H), 1.60 (s, 3H), 2.45 (d, 1H), 2.80 (d, 1H), 5.00 (s, 1H), 6.20 (d, 1H), 6.95-7.1 (m, 3H), 7.30 (m, 2H), 7.50 (m, 2H), 8.00 (d, 1H), 8.45 (d, 1H), 8.95 (m, 1H).
1-[(Quinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol
Analogously to Example 13, 95 mg of 1,1,1-trifluoro-4-phenyl-2-[(quinolin-5-yl)iminomethyl]-4-methylpentan-2-ol is converted into 90 mg of product.
1H-NMR (300 MHz, CDCl3): δ=1.45 (s, 3H), 1.60 (s, 3H), 2.15 (d, 1H), 2.20 (d, 1H), 3.25 (br., 1H), 4.95 (br. d, 1H), 5.20 (d, 1H), 6.90 (dd, 1H), 7.10 (t, 1H), 7.25-7.35 (m, 4H), 7.40 (d, 1H), 7.60 (m, 2H), 8.15 (d, 1H), 8.90 (m, 1H).
Example 15
5-{[2-Hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
5-{[2-Hydroxy-4-methyl-4-phenyl-2- trifluoromethyl)pentylidene]amino}quinolin-2(1H)-one
Analogously to Example 13, 600 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal and 337 mg of 5-aminoquinolin-2(1H)-one (52313) are converted into 570 mg of product.
1H-NMR (300 MHz, CDCl3): δ=1.35 (s, 3H), 1.55 (s, 3H), 2.40 (d, 1H), 2.80 (d, 1H), 4.70 (br. s, 1H), 5.80 (d, 1H), 6.75 (d, 1H), 7.05 (t, 1H), 7.15 (t, 2H), 7.30 (m, 4H), 8.00 (d, 1H), 9.05 (br. s, 1H).
5-{[2-Hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
Analogously to Example 13, 23 mg of 5-{[2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentylidene]amino}quinolin-2(1H)-one is converted into 11 mg of product.
1H-NMR (300 MHz, DMSO-d6): δ=1.35 (s, 3H), 1.50 (s, 3H), 2.00 (d, 1H), 2.10 (d, 1H), 5.35 (d, 1H), 6.05 (s, 1H), 6.20 (d, 1H), 6.40 (d, 1H), 6.55 (t, 1H), 7.25 (m, 2H), 7.45 (d, 1H), 8.20 (d, 1H), 11.60 (br.s, 1H).
Example 16
1-[(2-Methoxyquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1,1,1-Trifluoro-4-phenyl-2-[(2-methoxyquinolin-5-yl)iminomethyl]-4-methylpentan-2-ol
Analogously to Example 13, 200 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal and 122 mg of 5-amino-2-methoxyquinoline are converted into 190 mg of product.
1H-NMR (300 MHz, CDCl3): δ=1.35 (s, 3H), 1.55 (s, 3H), 2.45 (d, 1H), 2.80 (d, 1H), 4.10 (s, 3H), 5.00 (s, 1H), 6.10 (d, 1H), 6.90 (d, 1H), 6.95 (t, 1H), 7.05 (t, 2H), 7.30 (d, 2H), 7.35 (t, 1H), 7.70 (d, 1H), 8.30 (d, 1H).
1-[(2-Methoxyquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Analogously to Example 13, 185 mg of 1,1,1-trifluoro-4-phenyl-2-[(2-methoxyquinolin-5-yl)iminomethyl]-4-methylpentan-2-ol is converted into 127 mg of product.
1H-NMR (300 MHz, CDCl3): δ=1.45 (s, 3H), 1.60 (s, 3H), 2.15 (d, 1H), 2.20 (d, 1H), 3.10 (s, 1H), 4.10 (s, 3H), 4.75 (br. d, 1H), 5.20 (d, 1H), 6.75 (d, 1H), 6.85 (d, 1H), 7.1 (t, 1H), 7.25-7.45 (m, 4H), 7.50 (t, 1H), 8.00 (d, 1H).
Example 17
1-[(Phenylamino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1,1,1-Trifluoro-4-phenyl-2-[(phenyl)iminomethyl]-4-methylpentan-2-ol
Analogously to Example 1, 200 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal and 64 μl of aniline are converted into 180 mg of product.
1H-NMR (300 MHz, CDCl3): δ=1.35 (s, 3H), 1.50 (s, 3H), 2.35 (d, 1H), 2.70 (d, 1H), 5.05 (s, 1H), 6.65 (d, 2H), 7.05 (t, 1H), 7.15-7.30 (m, 7H).
1-[(Phenylamino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
9.6 ml of a 1 M titanium tetrachloride-CH2Cl2 solution is added in drops to a solution of 175 mg of 1,1,1-trifluoro-4-phenyl-2-[(phenyl)iminomethyl]-4-methylpentan-2-ol in 160 ml of CH2Cl2 at −78° C. First, it is stirred for 1 hour at −78° C., and after another 10 ml of titanium tetrachloride-CH2Cl2 solution is added, it is stirred for 60 hours at room temperature.
The batch is mixed with saturated NaHCO3, the phases are separated, the aqueous phase is extracted with CH2Cl2, the combined organic phases are dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with cyclohexane-ethyl acetate yields 45 mg of product.
1H-NMR (CDCl3): δ=1.40 (s, 3H), 1.50 (s, 3H), 2.00 (d, 1H), 2.20 (d, 1H), 3.40 (s, 1H), 3.80 (d, 1H), 4.95 (d, 1H), 6.80 (d, 2H), 6.85 (t, 1H), 7.15 (m, 1H), 7.20-7.30 (m, 4H), 7.40 (d, 1H).
Example 18
4-{[2-Hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-(trifluoromethyl)benzonitrile
1,1,1-Trifluoro-4-phenyl-2-[(4-cyano-3-(trifluoromethyl)phenyl)iminomethyl]-4-methylpentan-2-ol
Analogously to Example 13, 120 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal and 78 mg of 4-cyano-3-(trifluoromethyl)aniline are converted into 71 mg of product.
1H-NMR (300 MHz, CDCl3): =1.35 (s, 3H), 1.55 (s, 3H), 2.40 (d, 1H), 2.75 (d, 1H), 4.55 (s, 1H), 6.75 (dd, 1H), 6.95 (d, 1H), 7.10 (t, 1H), 7.20 (m, 3H), 7.30 (m, 2H), 7.70 (d, 1H).
4-{([2-Hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-(trifluoromethyl)benzonitrile
Analogously to Example 13, 71 mg of 1,1,1-trifluoro-4-phenyl-2-[(4-cyano-3-(trifluoromethyl)phenyl)iminomethyl]-4-methylpentan-2-ol is converted into 58 mg of product.
1H-NMR (300 MHz, CDCl3): δ=1.40 (s, 3H), 1.50 (s, 3H), 2.15 (s, 2H), 2.60 (s, 1H), 5.05 (d, 1H), 5.10 (d, 1H), 6.85 (dd, 1H), 7.00 (d, 1H), 7.20 (s, 2H), 7.35 (m, 1H), 7.40 (d, 1H), 7.60 (d, 1H).
Example 19
5-{[5-Bromo-2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
(2-Bromophenyl)-acetonitrile
25 g (100 mmol) of 2-bromobenzyl bromide is mixed in 100 ml of N,N-dimethylformamide and 64 ml of water with 9.75 g (150 mmol) of potassium cyanide and stirred overnight at room temperature. The reaction mixture is poured into ice water. After being extracted three times with methyl tert-butyl ether, the combined organic extracts are washed with brine, dried, and the solvent is spun off. The residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 18.9 g (96.4%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=3.85 (2H), 7.23 (1H), 7.48 (1H), 7.55 (1H), 7.62 (1H).
2-(2-Bromophenyl)-2-methyl-propionitrile
18.9 g (96.41 mmol) of (2-bromophenyl)-acetonitrile and 31.41 g (221.74 mmol) of methyl iodide are dissolved in 150 ml of N,N-dimethylformamide. At 0° C., 8.87 g (221.74 mmol) of sodium hydride (as 60% suspension in oil) is added in portions, and the batch is stirred overnight at room temperature. The reaction mixture is poured into ice water and worked up as usual. Since the compound that is isolated after chromatography (20.9 g) still contains 2-(2-bromophenyl)-propionitrile in addition to the desired product, the entire amount is reacted another time with the same amounts of reagent. This reaction also yields only material that still contains mono-methyl compound. After another alkylation with 15 g of methyl iodide and 4.45 g of sodium hydride in 150 ml of N,N-dimethylformamide, 18.57 g of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.91 (6H), 7.20 (1H), 7.35 (1H), 7.49 (1H), 7.68 (1H).
2-(2-Bromophenyl)-2-methyl-propanal
18.57 g (82.21 mmol) of 2-(2-bromophenyl)-2-methyl-propionitrile is reduced in 325 ml of toluene with 102.72 ml of a 1.2 M DIBAH solution in toluene, specifically as described in Example 3. After working-up, 18.17 g (97.34%) of the desired aldehyde is isolated, which is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=1.51 (6H), 7.20 (1H), 7.33-7.45 (2H), 7.61 (1H), 9.8 (1H).
(E/Z)-4-(2-Bromophenyl)-4-methylpent-2-enoic acid ethyl ester
18.17 g (80.02 mmol) of 2-(2-bromophenyl)-2-methyl-propanal is subjected analogously to the Horner-Wittig reaction that is described in Example 3. After the working-up and subsequent chromatography on silica gel (mobile solvent:ethyl acetate/hexane) described there, 22.3 g (81.67%) of the desired product is isolated.
(E/Z)-4-(2-Bromophenyl)-4-methylpent-2-enoic acid
22.3 g (65.349 mmol) of (E/Z)-4-(2-bromophenyl)-4-methylpent-2-enoic acid ethyl ester is saponified with 650 ml of sodium hydroxide solution (1N in ethanol/water 2:1) as described in Example 3. After the working-up, 14.32 g (69.9%) of the desired acid is isolated.
4-(2-Bromophenyl)-4-methyl-2-oxo-pentanoic acid
14.32 g (45.72 mmol) of (E/Z)-4-(2-bromophenyl)-4-methylpent-2-enoic acid is reacted with the aid of sulfuric acid in glacial acetic acid, as described in Example 3, to form the desired ketocarboxylic acid. 13 g (99.6%) is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.60 (6H), 3.91 (2H), 7.09 (1H), 7.30 (1H), 7.49 (1H), 7.57 (1H).
4-(2-Bromophenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester
13 g (45.59 mmol) of 4-(2-bromophenyl)-4-methyl-2-oxo-pentanoic acid is reacted with ethanol and concentrated sulfuric acid to form ester. After implementation and working-up (see Example 3), 13.01 g (91.1%) of the desired compound is obtained after chromatography on silica gel.
1H-NMR (300 MHz, CDCl3): δ=1.30 (3H), 1.60 (6H), 3.72 (2H), 4.17 (2H), 7.05 (1H), 7.27 (1H), 7.47 (1H), 7.57 (1H).
4-(2-Bromophenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol
13 g (41.5 mmol) of 4-(2-bromophenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester is reacted with Rupperts reagent, as described in Example 3. After working-up and chromatography on silica gel (mobile solvent:ethyl acetate/hexane), 16.15 g (85.6%) of the desired compound is isolated.
73.6 ml (88.39 mmol) of a DIBAH solution (1.2 M in toluene) is added in drops (35 minutes) to a solution of 6.1 g (35.45 mmol) of the above-described trifluoromethyl alcohol in 148 ml of toluene at −10° C. After 30 minutes of stirring at a temperature of between −10° C. and −5° C., 24.2 ml of isopropanol and then water are carefully added in drops at −10° C. After two hours of vigorous stirring at room temperature, the precipitate that is produced is suctioned off on a G4 frit, washed with ethyl acetate, and the filtrate is spun in until a dry state is reached. The residue (regioisomeric mixture of the two silyl ethers; 14.5 g=95.4%=35.08 mmol) is reacted with tetrabutylammonium fluoride trihydrate in tetrahydrofuran at room temperature as described in Example 3. After the usual working-up and chromatography, 5.26 g of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.62 (3H), 1.70 (3H), 2.19 (1H), 2.90-3.01 (2H), 3.27-3.89 (1H), 3.59 (1H), 7.09 (1H), 7.30 (1H), 7.53 (1H), 7.60 (1H).
4-(2-Bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal
2 g (5.86 mmol) of 4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentan-1-ol is oxidized with SO3-pyridine complex, as described in Example 1. 1.72 g (86.8 mmol) of the desired aldehyde is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.60 (6H), 2.29 (1H), 3.65 (1H), 3.78 (1H), 7.09 (1H), 7.25 (1H), 7.34 (1H), 7.58 (1H), 9.20 (1H).
4-{[4-(2-Bromophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidene]-amino}}isoquinolin-1(2H)-one
200 mg (0.589 mmol) of 4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is stirred for five days at room temperature with 94.3 mg (0.589 mmol) of 5-aminoisoquinolin-1(2H)-one (Example 2) in 0.86 ml of glacial acetic acid. After the usual working-up and chromatography on silica gel (mobile solvent:ethyl acetate/hexane), 170.8 mg (60.2%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.59 (3H), 1.70 (3H), 2.29 (1H), 3.86 (1H), 4.89 (1H), 6.58 (1H), 6.70-6.90 (3H), 7.15-7.37 (3H), 7.48 (1H), 7.59 (1H), 8.30 (1H), 11.00 (1H).
5-{[5-Bromo-2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
50 mg (0.104 mmol) of 4-{[4-(2-bromophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}}-isoquinolin-1(2H)-one is mixed with one milliliter of a 1 M solution of BBr3 in dichloromethane and stirred for ¾ hour at room temperature. After the usual working-up (see Example 2) and after chromatography on silica gel (mobile solvent:methanol/dichloromethane), 49.2 mg (98.4%) of the desired compound is obtained.
1H-NMR (300 MHz, DMSO-d6): δ=1.67 (3H), 1.79 (3H), 2.09 (1H), 2.21 (1H), 5.48 (1H), 6.02 (1H), 6.26 (1H), 6.81 (1H), 7.00-7.30 (5H), 7.49-7.62 (2H), 11.25 (1H).
With use of the corresponding starting aldehydes and amines that are described in the examples above, the following cyclic compounds are produced via the imines.
Example 20
5-Bromo-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
The product is obtained after cyclization, as described in Example 19.
1H-NMR (300 MHz, CD3OD): δ=1.73 (3H), 1.88 (3H), 2.10-2.30 (2H), 5.30 (1H), 6.39 (1H), 6.85 (1H), 7.01 (1H), 7.24 (1H), 7.48 (1H), 7.58 (1H), 8.13 (1H).
Example 21
5-Bromo-4,4-dimethyl-1-propylamino-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
The product is obtained after cyclization, as described in Example 19.
1H-NMR (300 MHz, CD3OD): δ=0.90-1.02 (3H), 1.48-1.60 (2H), 1.63 (3H), 1.70 (3H), 1.91 (1H), 2.15 (1H), 2.65-2.78 (1H), 2.91-3.05 (1H), 7.12 (1H), 7.45 (1H), 7.56 (1H).
Example 22
5-Bromo-1-[(3-hydroxypropyl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
The product is obtained after cyclization, as described in Example 19.
1H-NMR (300 MHz, CD3OD): δ=1.63 (3H), 1.71 (3H), 1.94 (1H), 1.99-2.11 (2H), 2.17 (1H), 2.84-2.98 (1H), 3.09-3.20 (1H), 3.55 (2H), 7.13 (1H), 7.49 (1H), 7.59 (1H).
Example 23
5-{[8-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
The product is obtained after cyclization, as described in Example 19.
MS (ES+, ACN/H2O+0.01% TFA): 437 (100%)
Example 24
4-{[7-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-6-fluoro-2,3-dihydroisoindol-1-one
The product is obtained after cyclization, as described in Example 19.
1H-NMR (300 MHz, CD3OD): δ=1.58 (3H), 1.65 (3H), 2.01-2.10 (2H), 4.20-4.45 (2H), 5.10 (1H), 6.70-6.89 (4H).
Example 25
5-{[6-Fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
The product is obtained after cyclization, as described in Example 3.
1H-NMR (300 MHz, CD3OD): δ=1.53 (3H), 1.58 (3H), 2.14 (2H), 3.99 (3H), 5.15 (1H), 6.84 (1H), 6.95 (1H), 7.00-7.10 (2H), 7.18 (1H), 7.39 (1H), 7.69 (1H).
The product that is obtained is separated into its enantiomers (Chiralpak AD 20μt; mobile solvent:hexane/ethanol/DEA), and the latter is then used in ether cleavage (analogously to Example 3):
5-{[6-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one (cis, Enantiomer A)
1H-NMR (300 MHz, CD3OD): δ=1.62 (3H), 1.72 (3H), 2.04-2.21 (2H), 5.13 (1H), 6.75-6.92 (3H), 7.05 (1H), 7.18 (1H), 7.39 (1H), 7.69 (1H).
5-{[6-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one (cis, enantiomer B)
1H-NMR (300 MHz, CD3OD): δ=1.62 (3H), 1.72 (3H), 2.04-2.21 (2H), 5.13 (1H), 6.75-6.92 (3H), 7.05 (1H), 7.18 (1H), 7.39 (1H), 7.69 (1H).
Example 26
4-{[6-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1one
The product is obtained after cyclization and ether cleavage, as described in Example 3.
1H-NMR (300 MHz, CD3OD): δ=1.60 (3H), 1.69 (3H), 1.99-2.20 (2H), 4.23-4.45 (2H), 5.13 (1H), 6.80-7.03 (3H), 7.18 (1H), 7.39 (1H).
Example 27
6-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
3-Chloro-2-methoxybenzylcyanide
39.4 g (221.3 mmol) of NBS and 100 mg of benzoyl peroxide are added to 31.6 g (201.7 mmol) of 3-chloro-2-methoxytoluene in 500 ml of CCl4. It is refluxed over 16 hours, allowed to cool and filtered. Solvent is removed from the filtrate, and the filtrate is dissolved in 214 ml of N,N-dimethylformamide and 142 ml of water. 20.9 g (322.1 mmol) of potassium cyanide is added at 0° C. and stirred over 16 hours. The reaction mixture is diluted with water and extracted several times with tert-butyl-methyl ether. The organic phase is washed several times with saturated sodium chloride solution and dried on sodium sulfate. The solvent is removed in a vacuum and after chromatographic purification on silica gel (hexane/ethyl acetate 20%), 29.7 g of product is obtained.
1H-NMR (CDCl3): δ=3.76 (s, 2H), 3.95 (s, 3H), 7.08 (t, 1H), 7.31 (d, 1H), 7.37 (d, 1H).
4-(3-Chloro-2-methoxy-phenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol
29.7 g (163.7 mmol) of 4-chloro-2-methoxybenzylcyanide and 46.5 g (327.4 mmol) of methyl iodide in 260 ml DMF are mixed at 0° C. in portions with 13.2 g (327.4 mmol) of sodium hydride (60% in oil). It is stirred overnight and then mixed with water and ethyl acetate. The phases are separated, and the aqueous phase is extracted several times with ethyl acetate. It is washed with water and saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 95:5), 32.4 g of 2-(4-chloro-2-methoxy-phenyl)-2-methylpropionitrile is obtained as a colorless oil. 7 g (33.4 mmol) of the nitrile is slowly mixed in toluene at −78° C. with 41.6 ml (50.1 mmol) of diisobutylaluminum hydride solution (20% in toluene), and after 3 hours at −78° C., 5.55 ml of isopropanol was added in drops. It is allowed to heat to −5° C., and 380 ml of a 10% aqueous tartaric acid solution is added. After dilution with ether, it is stirred vigorously, the organic phase is separated, and the aqueous phase is extracted several times with ether. It is washed with brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 95:5), 7.1 g of 2-(4-chloro-methoxy-phenyl)-2-methylpropanal is obtained as a colorless oil. A solution of 8.95 g (33.4 mmol) of 2-diethylphosphono-2-ethoxyacetic acid-ethyl ester in 30 ml of tetrahydrofuran is mixed while being cooled with ice within 20 minutes with 19 ml (38 mmol) of a 2 M solution of lithium diisopropylamide in tetrahydrofuran-heptane-toluene, and it is stirred for 15 minutes at 0° C. Within 30 minutes, a solution of 7.1 g (33.4 mmol) of 2-(3-chloro-2-methoxyphenyl)-2-methylpropanal in 27 ml of tetrahydrofuran is added in drops at 0° C. After 20 hours at room temperature, water is added, and it is extracted several times with ether and ethyl acetate. It is washed with saturated ammonium chloride solution, dried (Na2SO4) and concentrated by evaporation. The crude product is purified by column chromatography on silica gel (hexane/ethyl acetate 10%), and 8.5 g of 4-(3-chloro-2-methoxy-phenyl)-4-methyl-3-ethoxy-2-ene-valeric acid ethyl ester is obtained. The intermediate product is saponified with 80 ml of 3 M sodium hydroxide solution/160 ml of ethanol. 5.3 g of acid, which is stirred with 80 ml of 2N sulfuric acid at 90° C. over 16 hours, is obtained. After cooling, it is made basic with potassium carbonate, washed with ether, and acidified with hydrochloric acid. After extraction with ethyl acetate, washing with saturated sodium chloride solution and removal of the solvent, 4.0 g of 4-(3-chloro-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid is obtained. 6.6 g (24.3 mmol) of 4-(3-chloro-2-methoxy-phenyl)-4-methyl-2-oxo-valeric acid and 2.74 ml (51.4 mmol) of sulfuric acid (96%) are refluxed in 150 ml of ethanol for 5 hours. The batch is concentrated by evaporation in a vacuum, and the residue is taken up in saturated sodium bicarbonate solution. It is extracted several times with ethyl acetate, washed with saturated sodium bicarbonate solution, dried (sodium sulfate) and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%), 5.9 g of 4-(3-chloro-2-methoxy-phenyl)-4-methyl-2-oxo-valeric acid-ethyl ester is obtained. This ester and 3.4 g (23.8 mmol) of (trifluoromethyl)-trimethylsilane in 34 ml of THF are mixed with 49 mg of tetrabutylammonium fluoride at 0° C. It is stirred for 16 hours at room temperature, and then the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. 2.96 g of 4-(3-chloro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid-ethyl ester is obtained as a yellow oil. This oil is mixed in 24 ml of diethyl ether at 0° C. with 510 mg of lithium aluminum hydride and stirred for 4 more hours at room temperature. 20 ml of saturated sodium bicarbonate solution is carefully added to the batch at 0° C., and it is stirred vigorously for 1 more hour. It is extracted several times with tert-butyl methyl ether, washed with water and saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. The crude product is mixed in 33 ml of THF with 1.83 (5.79 mmol) of tetrabutylammonium fluoride trihydrate, and it is stirred for 16 hours. It is poured into ice water, extracted several times with tert-butyl methyl ether, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 25%), 1.81 g of 4-(3-chloro-2-methoxy-phenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol is obtained.
1H-NMR (300 MHz, CDCl3), δ=1.47 (s, 3H), 1.56 (s, 3H), 2.21 (d, 1H), 2.54 (d, 1H), 2.91 (s, 1H), 3.31 (dd, 1H), 3.42 (d, 1H), 4.01 (s, 3H), 7.00 (t, 1H), 7.20-7.35 (m, 2H)
4-(3-Chloro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal
1.87 g (18.5 mmol) of triethylamine and, in portions over 10 minutes, 1.17 g (7.4 mmol) of pyridine SO3 complex are added to 1.2 g (3.7 mmol) of diol in 24 ml of dichloromethane and 6.4 ml of DMSO. It is stirred over 5 hours, and 30 ml of saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with tert-butyl methyl ether. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and after chromatographic purification on silica gel (hexane/ethyl acetate, 0-50%), 0.98 g of product is obtained.
1H-NMR (CDCl3): δ=1.44 (s, 3H), 1.50 (s, 3H), 2.29 (d, 2H), 3.28 (d, 1H), 3.55 (s, 1H), 4.01 (s, 3H), 6.95 (t, 1H), 7.07 (dd, 1H), 7.30 (dd, 1H), 8.90 (s, 1H).
1,1,1-Trifluoro-4-(3-chloro-2-methoxyphenyl)-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol
125 mg (0.385 mmol) of 4-(3-chloro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal is mixed in 0.7 ml of glacial acetic acid with 51.3 mg (0.385 mmol) of 4-aminoindazole, and it is stirred overnight at room temperature. After concentration by evaporation until a dry state is reached, it is chromatographed on a Flashmaster. 11.9 mg (74.1%) of the desired compound is isolated.
6-Chloro-1-[(1H-indazol-4-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
116.9 mg (0.285 mmol) of imine is dissolved in 2.6 ml of dichloromethane and mixed at −25° C. with 1.13 ml of a 1 M solution of titanium tetrachloride in dichloromethane. After six more hours of stirring between −20° C. and +10° C., it is mixed with saturated sodium bicarbonate solution and extracted with ethyl acetate. After drying with sodium sulfate, the organic phases are spun in until a dry state is reached. Chromatography of the residue on a Flashmaster yields 91.9 mg (78.6%) of the desired cyclic compound (together with the Deschloro compound).
6-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
69.9 mg (0.159 mmol) of 6-chloro-1-[(1H-indazol-4-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is mixed with 1.45 ml of a one-molar solution of BBr3 in dichloromethane, and it is stirred for five hours at room temperature. After the usual working-up, the residue is chromatographed on a Flashmaster. 28.1 mg (41.5%) of the desired compound is isolated.
Melting point: 112-120° C.
Example 28
cis-7-Chloro-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
4-(4-Chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal
2-(4-Chlorophenyl)-2-methylpropanal
10 g of 4-chlorobenzyl cyanide and 14.3 ml of methyl iodide in 140 ml of DMF are mixed at 0° C. in portions with sodium hydride (60% in oil). It is stirred overnight and then mixed with water and ethyl acetate. The phases are separated, and the aqueous phase is extracted with ethyl acetate.
It is thoroughly extracted with water, washed with brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 95:5), 11.73 g of 2-(4-chlorophenyl)-2-methylpropionitrile is obtained as a colorless oil. The latter is slowly mixed in toluene at −78° C. with 55.4 ml of diisobutylaluminum hydride solution (20% in toluene), and after 4 hours at −78° C., 50 ml of ethyl acetate was added in drops. It is stirred overnight while being heated to room temperature, and water is added. After filtration through diatomaceous earth, the phases are separated, and the aqueous phase is extracted with ethyl acetate. It is washed with water and brine, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 95:5), 10.2 g of 2-(4-chlorophenyl)-2-methylpropanal is obtained as a colorless oil.
1H-NMR (300 MHz, CDCl3), δ=1.46 (s, 6H), 7.20 (d, 1H), 7.29-7.43 (m, 3H), 9.48 (s, 1H)
4-(4-Chlorophenyl)-4-methyl-2-oxo-valeric acid
A solution of 15.04 g of 2-diethylphosphono-2-ethoxyacetic acid-ethyl ester in 50 ml of tetrahydrofuran is mixed with 30 ml of a 2 M solution of lithium diisopropylamide in tetrahydrofuran-heptane-toluene while being cooled with ice within 20 minutes, and it is stirred for 15 minutes at 0° C. Within 30 minutes, a solution of 10.2 g of 2-(4-chlorophenyl)-2-methylpropanal in 50 ml of tetrahydrofuran is added thereto at 0° C. After 20 hours at room temperature, 2N sulfuric acid is added, it is extracted with ethyl acetate, dried (Na2SO4) and concentrated by evaporation. The crude product is saponified with 200 ml of 2 M sodium hydroxide solution/400 ml of ethanol. 13.8 g of acid, which is refluxed for 3 hours with 300 ml of 2N sulfuric acid and 100 ml of glacial acetic acid while being stirred vigorously, is obtained. After extraction with ethyl acetate and washing with water, 10.9 g of 4-(4-chlorophenyl)-4-methyl-2-oxo-valeric acid is obtained as a red oil.
1H-NMR (300 MHz, CDCl3), δ=1.47 (s, 6H), 3.28 (s, 2H), 7.28 (m, 4H), 7.73 (bs, 1H)
4-(4-Chlorophenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol
Analogously to the synthesis of 4-(3-chloro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal (Example 27), 4.22 g of 4-(4-chlorophenyl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol is obtained as a colorless oil by esterification of 10.9 g of 4-(4-chlorophenyl)-4-methyl-2-oxo-valeric acid in ethanol/sulfuric acid, reaction of the product with (trifluoromethyl)trimethylsilane and tetrabutylammonium fluoride and reduction of the formed hydroxy ester with lithium aluminum hydride.
1H-NMR (CDCl3), δ (ppm)=1.39 (s, 3H), 1.49 (s, 3H), 2.07 (d, 1H), 2.19 (d, 1H), 2.83 (bs, 1H), 3.27 (d, 1H), 3.41 (d, 1H), 7.26-7.38 (m, 4H).
4-(4-Chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal
6.8 ml (33.3 mmol) of triethylamine and, in portions over 20 minutes, 1.5 g of pyridine SO3 complex are added to 2 g (6.7 mmol) of diol in 50 ml of dichloromethane and 22 ml of DMSO. It is stirred over 5 hours, and 40 ml of saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and after chromatography on silica gel (hexane/ethyl acetate 0-30%), 1.27 g of product is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.34 (s, 3H), 1.44 (s, 3H), 2.34 (d, 2H), 2.66 (d, 1H), 3.64 (s, 1H), 7.23-7.31 (m, 4H), 8.90 (s, 1H).
7-Chloro-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Starting from the above-described aldehyde, the desired compound is synthesized via the imine as described in Example 83.
1H-NMR (300 MHz, CDCl3); δ=1.45 (s, 3H), 1.63 (s, 3H), 2.19 (d, 1H), 2.31 (d, 1H), 2.87 (s, 3H), 5.05 (d, 1H), 5.98 (d, 1H), 6.78 (d, 1H), 7.28 -7.37 (m, 4H), 7.76 (t, 1H), 9.36 (s, 1H).
Example 29
5,8-Difluoro-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
4-(2,5-Difluorophenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol
5.4 g (15.5 mmol) of 4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester (WO 02/10143) is dissolved at 0° C. in diethyl ether and mixed within 20 minutes with 1.76 g (46.5 mmol) of lithium aluminum hydride. It is allowed to stir at room temperature for 4 hours, and then enough saturated NaHCO3 solution is carefully added until no more gas generation can be observed. The mixture is diluted with ethyl acetate, stirred for 15 more minutes, and then the formed precipitate is filtered off. It is concentrated by evaporation and chromatographed on silica gel with hexane/ethyl acetate (50%). 2.45 g of 2,5-difluorophenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol is obtained as a weakly yellowish crystallizing oil.
4-(2,5-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal
800 mg (2.8 mmol) of 4-(2,5-difluorophenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol is introduced into 20 ml of dichloromethane, and at 0° C., 9.5 ml of DMSO and 1.95 ml of triethylamine are added. The solution is slowly mixed with 1.34 g (8.4 mmol) of SO3-pyridine complex, and it is stirred for 2 hours at 0° C. The mixture is dispersed between saturated ammonium chloride solution and MTBE, the phases are separated, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with water and saturated NaCl solution and dried with NaSO4. It is concentrated by evaporation and chromatographed on silica gel with hexane/ethyl acetate (30%). 710 mg of the desired product is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.41 (s, 3H), 1.48 (s, 3H), 2.39 (d, 2H), 3.02 (d, 1H), 3.61 (s, 1H), 6.84-7.18 (m, 3H), 9.23 (s, 1H).
5,8-Difluoro-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
The desired compound is synthesized via the imine (diastereomer A).
1H-NMR (300 MHz, CDCl3): δ=1.51 (s, 3H), 1.68 (s, 3H), 2.11 (d, J=15 Hz, 1H), 2.23 (d, J=15 Hz, 1H), 2.84 (s, 3H), 4.23 (s, br, 1H), 4.84 (d, J=8 Hz, 1H), 5.32 (d, J=8 Hz, 1H), 6.80-6.90 (m, 1H), 6.95-7.02 (m, 1H), 7.05 (d, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.77 (dd, J=8 Hz/8 Hz, 1H), 9.19 (s, 1H).
Example 30
5-{[4,4-Dimethyl-6-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
5-Aminoquinolin-2(1H)-one
4.5 g of 5-nitroquinolin-2(1H)-one (Chem. Pharm. Bull. (1981), 29, pp. 651-56) is hydrogenated in 200 ml of ethyl acetate and 500 ml of methanol in the presence of 450 mg of palladium on activated carbon as a catalyst under normal pressure with hydrogen until the reaction is completed. The catalyst is removed by filtration through diatomaceous earth, and the reaction solution is concentrated by evaporation in a vacuum. 3.8 g of the title compound is obtained as a yellow solid.
1H-NMR (DMSO): δ=5.85 (bs, 2H), 6.27 (d, 1H), 6.33 (d, 1H), 6.43 (d, 1H), 7.10 (t, 1H), 8.07 (d, 1H), 11.39 (bs, 1H)
5-{[4,4-Dimethyl-6-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
Analogously to Example 3, the corresponding imine is produced starting from 500 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 260 mg of 5-aminoquinolin-2(1H)-one. By reaction of 80 mg of the imine with 0.5 ml of titanium tetrachloride (1 M in dichloromethane), 20 mg of the title compound is obtained.
Examples 31 and 32
5-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one, Diastereomer B
5-{[2,5-Dihydroxy-4,4-dimethyl-2-trifluoromethyl- 1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one, Diastereomer A
4-(2-Methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
19.3 g of 4-(2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester (WO 00/32584) in 630 ml of diethyl ether is mixed in portions at 0° C. with 3.3 g of lithium aluminum hydride. After stirring for 10 hours, it is added to saturated bicarbonate solution and filtered through diatomaceous earth. The phases are separated, and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->10%), 16.3 g of diol is obtained as a yellow oil.
2.0 g of diol, 5.2 ml of triethylamine and 5.12 g of sulfur trioxide-pyridine complex in 24 ml of DMSO are stirred at room temperature for 48 hours. It is added to 0.5N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 0->3%), 1.44 g of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal is obtained as a yellow oil.
1H-NMR (300 MHz, CDCl3), δ=1.40 (s, 3H), 1.47 (s, 3H), 2.2 (d, 1H), 3.46 (d, 1H), 3.60 (s, 1H), 3.88 (s, 3H), 6.83-6.94 (m, 2H), 7.13 (dd, 1H), 7.24 (dt, 1H), 8.94 (s, 1H)
5-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one, Diastereomer B and 5-{[2,5-Dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one, Diastereomer A
Analogously to Example 2, the corresponding imine is produced starting from 1.0 g of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 553 mg of 5-aminoquinolin-2(1H)-one. 21 mg of 5-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one as fraction 1 and 5 mg of 5-{[2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one as fraction 2 are obtained by reaction of 50 mg of the imine with 0.22 ml of BBr3 (1N in dichloromethane).
Fraction 1: 1H-NMR (300 MHz, CD3OD): δ=1.50 (s, 3H), 1.63 (s, 3H), 2.04 (d, 1H), 2.12 (d, 1H), 3.83 (s, 3H), 5.17 (s, 1H), 6.48 (d, 1H), 6.60 (d, 1H), 6.67 (d, 1H), 6.90 (d, 1H), 6.92 (d, 1H), 7.10 (t, 1H), 7.35 (t, 1H), 8.20 (d, 1H)
Flash point=269-270° C.
Fraction 2: 1H-NMR (300 MHz, CD3OD): δ=1.39 (s, 3H), 1.52 (s, 3H), 2.05 (d, 1H), 2.23 (d, 1H), 5.28 (s, 1H), 6.38 (d, 1H), 6.58 (d, 1H), 6.68 (d, 1H), 6.92 (d, 1H), 7.00 (d, 1H), 7.11 (t, 1H), 7.38 (t, 1H), 8.14 (d, 1H)
Examples 33 and 34
(−)-5-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
(+)-5-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
Separation of (±)-5-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
The enantiomer mixture is separated by chromatography on chiral carrier material (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10, vvv). The (−)-enantiomer: MS (ESI): M++1=433, [α]D−70.1° °(c=1.0, CHCl3) and the (+)-enantiomer: MS (ESI): M++1=433, [α]D+78.5° °(c=1.0, CHCl3) are thus obtained.
Example 35
(+)-5-{[2,5-Dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one, Diastereomer B
Analogously to Example 3, 5 mg of the title compound was obtained by reaction of 50 mg of (+)-5-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one and 0.22 ml of BBr3 (1 M in dichloromethane).
1H-NMR (300 MHz, CD3OD): δ=1.56 (s, 3H), 1.68 (s, 3H), 2.06 (d, 1H), 2.15 (d, 1H), 5.15 (s, 1H), 6.51 (d, 1H), 6.62 (d, 1H), 6.68 (d, 1H), 6.70 (d, 1H), 6.81 (d, 1H), 6.95 (t, 1H), 7.37 (t, 1H), 8.23 (d, 1H)
Example 36
(−)-5-{[2,5-Dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one, Diastereomer B
Analogously to Example 3, 32 mg of the title compound is obtained by reaction of 70 mg of (−)-5-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one and 0.32 ml of BBr3 (1 M in dichloromethane).
1H-NMR (300 MHz, CD3OD): δ=1.57 (s, 3H), 1.68 (s, 3H), 2.05 (d, 1H), 2.14 (d, 1H), 5.15 (s, 1H), 6.51 (d, 1H), 6.62 (d, 1H), 6.67 (d, 1H), 6.68 (d, 1H), 6.81 (d, 1H), 6.95 (t, 1H), 7.37 (t, 1H), 8.22 (d, 1H)
Example 37
5-{[7-Chloro-2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
Analogously to Example 2, the corresponding imine is produced starting from 1.0 g of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 492 mg of 5-aminoquinolin-2(1H)-one. 20 mg of the title compound is obtained by reaction of 300 mg of the imine with 3.2 ml of BBr3 (1N in dichloromethane).
1H-NMR (300 MHz, DMSO): δ=1.46 (s, 3H), 1.58 (s, 3H), 1.95 (d, 1H), 2.05 (d, 1H), 5.28 (d, 1H), 6.08 (s, 1H), 6.20 (d, 1H), 6.40 (d, 1H), 6.50-6.66 (m, 3H), 6.77 (s, 1H), 7.24 (t, 1H), 7.35 (t, 1H), 8.19 (d, 1H), 10.04 (bs, 1H), 11.57 (bs, 1H)
Example 38
5-{[2,5-Dihydroxy-4,4-dimethyl-6-fluoro-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
Analogously to Example 2, the corresponding imine is produced starting from 1.0 g of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal (Example 3) and 520 mg of 5-aminoquinolin-2(1H)-one. 255 mg of the title compound is obtained by reaction of 300 mg of imine with 3.3 ml of BBr3 (1N in dichloromethane).
1H-NMR (300 MHz, CD3OD): δ=1.58 (s, 3H), 1.70 (s, 3H), 2.07 (d, 1H), 2.15 (d, 1H), 5.13 (s, 1H), 6.51 (d, 1H), 6.60 (d, 1H), 6.68 (d, 1H), 6.74-6.95 (m, 2H), 7.36 (t, 1H), 8.22 (d, 1H)
Examples 39 and 40
(−)-5-{[2,5-Dihydroxy-4,4-dimethyl-6-fluoro-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one and
(+)-5-{[2,5-Dihydroxy-4,4-dimethyl-6-fluoro-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
Separation of (+/−)-5-{[2,5-Dihydroxy-4,4-dimethyl-6-fluoro-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
The enantiomer mixture is separated by chromatography on chiral carrier material (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10, vvv). The (−)-enantiomer: MS (EI): M+=436, [α]D−23.6° °(c=1.0, CHCl3) and the (+)-enantiomer: MS (EI): M+=436, [α]D+25.0° °(c=1.0, CHCl3) are thus obtained.
Example 41
5-{[4,4-Dimethyl-5-methoxy-7-methyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one, Diastereomer A
4-(2-Methoxy-4-methylphenyl)-4-methyl-2-oxopentanoic acid ethyl ester
Analogously to Example 7, 2-methoxy-4-methylbenzoic acid methyl ester is produced from 30 g of 2,4-cresotic acid and 58.6 ml of methyl iodide with 124.3 g of potassium carbonate in 643 ml of DMF. The ester is reacted by reaction with 141 ml of methylmagnesium chloride (3 M in THF) in 475 ml of THF to form 1-(2-methoxy-4-methylphenyl)-1-methylethanol. 5 g of the product that is obtained is reacted with 6.4 g of 2-(trimethylsilyloxy)-acrylic acid ethyl ester in 102 ml of dichloromethane at −70° C. with 2.3 ml of tin tetrachloride to form 4.84 g of the title compound.
1H-NMR (300 MHz, CDCl3): δ=1.44 (s, 6H), 2.31 (s, 3H), 3.38 (s, 2H), 3.81 (s, 3H), 6.66 (s, 1H), 6.72 (d, 1H), 7.12 (d, 1H)
4-(2-Methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
Analogously to Example 7, 4.84 g of 4-(2-methoxy-4-methylphenyl)-4-methyl-2-oxopentanoic acid ethyl ester is reacted with 7 ml of trifluoromethyltrimethylsilane and 3 ml of tetrabutylammonium fluoride solution (1 M in THF) in 56 ml THF to form 4.14 g of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoic acid ethyl ester. The product is reduced with 856 mg of lithium aluminum hydride in 170 ml of diethyl ether to 3.58 g of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol. The oxidation of the diol is carried out analogously to Example 7 under Swern conditions with 1.1 ml of oxalyl chloride, 2.1 ml of DMSO and 8.0 ml of triethylamine to 3.01 g of the title compound.
1H-NMR (300 MHz, CDCl3): δ=1.38 (s, 3H), 1.43 (s, 3H), 2.18 (d, 1H), 3.45 (d, 1H), 3.87 (s, 3H), 6.67 (s, 1H), 6.70 (d, 1H), 6.98 (d, 1H), 8.92 (s, 1H)
5-{[4,4-Dimethyl-5-methoxy-7-methyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
Analogously to Example 2, the corresponding imine is produced starting from 280 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 156 mg of 5-aminoquinolin-2(1H)-one. The latter is stirred at room temperature with 93 mg of aluminum chloride for 2.5 hours. The batch is added to saturated bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation in a vacuum. After chromatography on silica gel (dichloromethane/2-propanol 0->5%), 24 mg of the title compound is obtained.
1H-NMR (300 MHz, CD3OD): δ=1.50 (s, 3H), 1.62 (s, 3H), 2.04 (d, 1H), 2.13 (d, 1H), 2.20 (s, 3H), 3.85 (s, 3H), 5.13 (s, 1H), 6.51 (d, 1H), 6.62 (d, 1H), 6.70 (d, 1H), 6.75 (s, 1H), 6.78 (s, 1H), 7.39 (t, 1H), 8.23 (d, 1H)
Example 42
5-{[4,4-Dimethyl-7-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
16.8 g of 4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester (WO 00/32584) in 600 ml of diethyl ether is mixed in portions at 0° C. with 2.7 g of lithium aluminum hydride. After stirring for 10 hours, it is added to saturated bicarbonate solution and filtered through diatomaceous earth. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->10%), 6.7 g of diol and 2.65 g of the title compound are obtained.
The production of the title compound from the diol that is obtained is carried out by reaction of 3.0 g of diol, 6.6 ml of triethylamine and 6.5 g of sulfur trioxide-pyridine complex in 34 ml of DMSO at room temperature in 48 hours of reaction time. It is added to 0.5 N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 0->15%), 2.7 g of the title compound is obtained as a yellow oil.
1H-NMR (300 MHz, CDCl3), δ=1.38 (s, 3H), 1.46 (s, 3H), 2.19 (d, 1H), 3.37 (d, 1H), 3.58 (s, 1H), 3.87 (s, 3H), 6.55-6.64 (m, 2H), 7.06 (dd, 1H), 8.97 (s, 1H)
5-{[4,4-Dimethyl-7-fluoro-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
Analogously to Example 41, the corresponding imine is produced starting from 500 mg of 4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 260 mg of 5-aminoquinolin-2(1H)-one. 10 mg of the title compound is obtained by reaction of 220 mg of imine with 197 mg of aluminum chloride.
1H-NMR (CD3OD): δ=1.51 (s, 3H), 1.63 (s, 3H), 2.07 (d, 1H), 2.14 (d, 1H), 5.15 (s, 1H), 6.53 (d, 1H), 6.58-6.77 (m, 4H), 7.40 (t, 1H), 8.23 (d, 1H)
Example 43
(+)-5-{[2,5-Dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
Analogously to Example 3, 5 mg of the title compound is obtained by reaction of 50 mg of (+)-5-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one and 0.22 ml of BBr3 (1 M in dichloromethane).
1H-NMR (300 MHz, CD3OD): δ=1.57 (s, 3H), 1.69 (s, 3H), 2.06 (d, 1H), 2.15 (d, 1H), 5.16 (s, 1H), 6.51 (d, 1H), 6.62 (d, 1H), 6.69 (d, 1H), 6.71 (d, 1H), 6.82 (d, 1H), 6.95 (t, 1H), 7.37 (t, 1H), 8.23 (d, 1H)
Example 44
4-{[2-Hydroxy-4,4-dimethyl-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide
Analogously to Example 10, the corresponding imine is produced starting from 600 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 308 mg of 4-amino-phthalide (Bull. Soc. Sci. Bretagne 26, 1951, Special Edition 5, p. 7, 96). As in Example 2, 650 mg of the imine is reacted by reaction with 7.7 ml of BBr3 (1 M in dichloromethane), and 165 mg of the title compound is obtained.
1H-NMR (300 MHz, DMSO-d6): δ=1.30 (s, 3H), 1.46 (s, 3H), 1.93 (d, 1H), 2.18 (d, 1H), 3.57 (s, 3H), 5.10 (d, 1H), 5.20 (d, 1H), 5.32 (d, 1H), 5.55 (d, 1H), 5.81 (s, 1H), 6.80 (d, 1H), 7.03 (d, 1H), 7.04 (d, 1H), 7.20 (d, 1H), 7.27 (t, 1H), 7.37 (t, 1H)
Example 45
7-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
Analogously to Example 2, the corresponding imine is produced starting from 410 mg of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 168 mg of 4-aminoindazole. 98 mg of the title compound is obtained by reaction of 200 mg of imine with 6.7 ml of BBr3 (1N in dichloromethane).
1H-NMR (300 MHz, DMSO-d6): δ=1.48 (s, 3H), 1.59 (s, 3H), 1.97 (d, 1H), 2.07 (d, 1H), 5.27 (d, 1H), 5.95 (s, 1H), 6.21 (d, 1H), 6.31 (d, 1H), 6.72 (s, 1H), 6.74 (d, 1H), 6.76 (s, 1H), 7.08 (t, 1H), 8.13 (s, 1H), 9.94 (s, 1H), 12.83 (s, 1H)
Examples 46 and 47
(−)-7-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
(+)-7-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
Separation of (+/−)-7-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
The enantiomer mixture is separated by chromatography on chiral carrier material (CHIRALPAK AD®), DAICEL Company) with hexane/2-propanol (98:2, vvv). The (−)-enantiomer: MS (EI): M+=425/427, [α]D−3.0° °(c=1.0, CHCl3) and the (+)-enantiomer: MS (EI): M+=425/427, [α]D+5.0° °(c=1.0, CHCl3) are thus obtained.
Examples 48 and 49
7-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
7-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
Analogously to Example 2, the corresponding imine is produced starting from 1.8 g of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 780 mg of 4-aminoindazole. By reaction of 300 mg of the imine with 10.6 ml of BBr3 (1N in dichloromethane), 13 mg of 7-fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol as fraction 1 and 30 mg of 7-fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol as fraction 2 are obtained.
Fraction 1: 1H-NMR (300 MHz, CDCl3): δ=1.48 (s, 3H), 1.62 (s, 3H), 2.05 (d, 1H), 2.16 (d, 1H), 3.85 (s, 3H), 4.62 (d, 1H), 5.07 (d, 1H), 6.43 (d, 1H), 6.55 (dd, 1H), 6.71 (dd, 1H), 6.92 (d, 1H), 7.27 (t, 1H), 8.01 (s, 1H)
Fraction 2: 1H-NMR (300 MHz, CDCl3): δ=1.54 (s, 3H), 1.65 (s, 3H), 2.07 (d, 1H), 2.17 (d, 1H), 4.62 (d, 1H), 5.07 (d, 1H), 6.37-6.47 (m, 2H), 6.72 (dd, 1H), 6.94 (d, 1H), 7.28 (t, 1H), 8.02 (s, 1H)
Examples 50 and 51
(−)-7-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
(+)-7-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5 -diol
Separation of (+/−)-7-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
The enantiomer mixture is separated by chromatography on chiral carrier material (CHIRALPAK AD®, DAICEL Company) with hexane/2-propanol (98:2, vvv). The (−)-enantiomer: MS (EI): M+=409, [α]D−40.5° °(c=0.2, CHCl3) and the (+)-enantiomer: MS (EI): M+=409 are thus obtained.
Examples 52 and 53
5-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol, Diastereomer A
5-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol, Diastereomer B
4-(2-Fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
4.12 g of 4-(2-fluoro-4-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester in 140 ml of diethyl ether is mixed in portions at 0° C. with 666 mg of lithium aluminum hydride. After stirring for 10 hours, it is added to saturated bicarbonate solution and filtered through diatomaceous earth. The phases are separated, and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->10%), 2.74 g of diol and 416 mg of the title compound are obtained.
The production of the title compound from the diol that is obtained is carried out by reaction of 3.0 g of the diol, 6.6 ml of triethylamine, and 6.5 g of sulfur trioxide-pyridine complex in 34 ml of DMSO at room temperature in 48 hours of reaction time. It is added to 0.5 N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 0->15%), 1.73 g of the title compound is obtained as a yellow oil.
1H-NMR (300 MHz, CDCl3), δ=1.39 (s, 3H), 1.46 (s, 3H), 2.26 (d, 1H), 3.09 (d, 1H), 3.63 (s, 1H), 3.78 (s, 3H), 6.52-6.65 (m, 2H), 7.03 (t, 1H), 9.04 (s, 1H)
5-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol, Diastereomer A and 5-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol, Diastereomer B
Analogously to Example 2, the corresponding imine is produced starting from 1.7 g of 4-(2-fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 736 mg of 4-aminoindazole. By reaction of 300 mg of imine with 10.6 ml of BBr3 (1N in dichloromethane), 12 mg of 5-fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol, Diastereomer B as fraction 1 and 90 mg of 5-fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol, diastereomer A as fraction 2 are obtained.
Fraction 1: 1H-NMR (300 MHz, CDCl3): δ=1.48 (s, 3H), 1.58 (s, 3H), 2.06 (d, 1H), 2.23 (d, 1H), 4.95 (d, 1H), 5.11 (d, 1H), 6.37 (d, 1H), 6.48 (dd, 1H), 6.64 (d, 1H), 6.75 (s, 1H), 7.25 (t, 1H), 7.48 (s, 1H)
Fraction 2: 1H-NMR (300 MHz, CDCl3): δ=1.48 (s, 3H), 1.58 (s, 3H), 2.05 (d, 1H), 2.24 (d, 1H), 5.04 (d, 1H), 5.12 (d, 1H), 6.37 (d, 1H), 6.48 (dd, 1H), 6.58 (dd, 1H), 6.78 (d, 1H), 7.24 (t, 1H), 7.29 (s, 1H)
Example 54
1-[(1H-Indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol, Diastereomer A
Analogously to Example 41, the corresponding imine is produced starting from 850 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 390 mg of 4-aminoindazole. 138 mg of the title compound is obtained by reaction of 500 mg of imine with 495 mg of aluminum chloride.
1H-NMR (300 MHz, CDCl3), δ=1.52 (s, 3H), 1.66 (s, 3H), 2.05 (d, 1H), 2.16 (d, 1H), 3.85 (s, 3H), 4.57 (d, 1H), 5.23 (d, 1H), 6.48 (d, 1H), 6.82 (d, 1H), 6.92 (d, 1H), 6.95 (d, 1H), 7.12 (t, 1H), 7.29 (t, 1H), 7.97 (s, 1H)
Example 55
1-[(1H-Indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol, Diastereomer B
Analogously to Example 2, 300 mg of the imine that is obtained in Example 54 is reacted with 11 ml of BBr3 (1N in dichloromethane) to form 24 mg of the title compound.
1H-NMR (300 MHz, CD3OD), δ=1.42 (s, 3H), 1.55 (s, 3H), 2.08 (d, 1H), 2.23 (d, 1H), 3.33 (s, 3H), 5.33 (s, 1H), 6.63 (d, 1H), 6.72 (d, 1H), 6.88 (d, 1H), 7.06 (d, 1H), 7.20-7.31 (m, 2H), 8.17 (s, 1H)
Example 56
1-[(1H-Indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
100 mg of the compound of Example 54 is reacted analogously to Example 1 with 3.7 ml of BBr3 (1N in dichloromethane) to form 47 mg of the title compound.
1H-NMR (300 MHz, CD3OD), δ=1.40 (s, 3H), 1.54 (s, 3H), 2.10 (d, 1H), 2.25 (d, 1H), 5.36 (s, 1H), 6.60 (d, 1H), 6.94 (d, 1H), 7.12 (t, 1H), 7.18-7.33 (m, 3H), 8.20 (s, 1H)
Example 57
7-Chloro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Analogously to Example 2, the corresponding imine is produced starting from 350 mg of 4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 158 mg of 4-aminoindazole. By reaction of 50 mg of imine with 1.8 ml of BBr3 (1N in dichloromethane), 29 mg of the title compound is obtained.
1H-NMR (300 MHz, CDCl3), δ=1.41 (s, 3H), 1.54 (s, 3H), 2.10 (d, 1H), 2.19 (d, 1H), 4.63 (d, 1H), 5.14 (d, 1H), 6.43 (d, 1H), 6.95 (d, 1H), 7.23-7.37 (m, 4H), 8.03 (s, 1H)
Example 58
1-[(1-Methyl-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
4-Amino-1-methylindazole
6.5 g of 4-nitroindazole (Chem. Ber. (1904), 37, 2583), 1.9 ml of methyl iodide and 14.4 g of cesium carbonate in 110 ml of DMF are stirred for 2 hours at 0° C. and then for 12 hours at room temperature. It is added to water and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation. The residue is recrystallized from ethyl acetate/hexane. 2.49 g of 1-methyl-4-nitroindazole is obtained. The latter is hydrogenated in 70 ml of THF with 420 mg of palladium on activated carbon under normal pressure with hydrogen. The batch is filtered through diatomaceous earth and completely concentrated by evaporation. 2.1 g of the title compound is obtained.
1H-NMR (300 MHz, CD3OD), δ=3.96 (s, 3H), 6.35 (d, 1H), 6.75 (d, 1H), 7.16 (d, 1H), 8.06 (s, 1H)
1-[(1-Methyl-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Analogously to Example 3, the corresponding imine is produced starting from 296 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 150 mg of 4-amino-1-methylindazole. By reaction of 100 mg of the imine with 0.5 ml of titanium tetrachloride, 100 mg of the title compound is obtained.
Melting point: 172-174° C.
Examples 59 and 60
7-Ethyl-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
7-Ethyl-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
2-Hydroxy-4-(4-iodo-2-methoxyphenyl)-4-methyl-2-trifluoromethylvaleric acid methyl ester
3 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid (WO 98/54159) is added in a solution of 1.3 ml of thionyl chloride in 12 ml of methanol at 0° C. and stirred for 10 hours at room temperature. It is added to saturated bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with bicarbonate solution and brine, dried (Na2SO4) and concentrated by evaporation. 3.2 g of 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxovaleric acid methyl ester is obtained as a crude product. This ester is mixed with 4.5 ml of trifluoromethyltrimethylsilane in 70 ml of DMF and 1.63 g of cesium carbonate at 0° C. and stirred for 10 hours at room temperature. 20 mg of tetrabutylammonium fluoride is added, and it is stirred for another 30 minutes at room temperature. The batch is added to water and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->15%), 1.47 g of the title compound is obtained as a yellow oil.
1H-NMR (300 MHz, CDCl3), δ=1.34 (s, 3H), 1.42 (s, 3H), 2.30 (d, 1H), 2.97 (d, 1H), 3.36 (s, 3H), 3.84 (s, 3H), 6.88 (dd, 1H), 7.13 (dd, 1H), 7.23 (dd, 1H)
4-(4-Ethyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanal
1 g of 2-hydroxy-4-(4-iodo-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeric acid methyl ester, 860 mg of tributylvinyl tin, 103 mg of palladium-dibenzylidene acetone complex and 30 mg of triphenylphosphine in 17 ml of THF are refluxed under argon atmosphere for 57 hours. It is filtered through diatomaceous earth and completely concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->2%), 339 mg of 2-hydroxy-4-(2-methoxy-4-vinylphenyl)-4-methyl-2-trifluoromethylvaleric acid methyl ester is obtained. The latter is stirred with 56 mg of lithium aluminum hydride in 11 ml of diethyl ether at room temperature for 10 hours. It is added to saturated bicarbonate solution, filtered through diatomaceous earth and extracted with ethyl acetate. The organic phase is washed with bicarbonate solution and brine, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 0->10%), 148 mg of 2-hydroxy-4-(2-methoxy-4-vinylphenyl)-4-methyl-2-trifluoro-methylpentanol is obtained. The latter is hydrogenated in 4.3 ml of ethyl acetate with 14 mg of palladium on activated carbon under normal pressure with hydrogen. The batch is filtered through diatomaceous earth and completely concentrated by evaporation. 127 mg of 4-(4-ethyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanol is obtained. The diol that is obtained is reacted with 0.29 ml of triethylamine and 280 mg of sulfur trioxide-pyridine complex in 1.3 ml of DMSO at room temperature in 10 hours of reaction time. It is added to saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 0->3%), 94 mg of the title compound is obtained as a colorless oil.
1H-NMR (300 MHz, CDCl3), δ=1.24 (t, 3H), 1.38 (s, 3H), 1.44 (s, 3H), 2.17 (1H), 2.62 (q, 2H), 3.46 (d, 1H), 3.88 (s, 3H), 6.68 (s, 1H), 6.72 (d, 1H), 7.02 (d, 1H), 8.91 (s, 1H)
7-Ethyl-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol and 7-Ethyl-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Analogously to Example 2, the corresponding imine is produced starting from 90 mg of 4-(4-ethyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 38 mg of 4-aminoindazole. By reaction of 68 mg of imine with 0.39 ml of BBr3 (1N in dichloromethane), 16 mg of 7-ethyl-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol as fraction 1 and 7 mg of 7-ethyl-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol as fraction 2 are obtained.
Fraction 1: 1H-NMR (300 MHz, CDCl3), δ=1.24 (t, 3H), 1.42 (s, 3H), 1.51 (s, 3H), 2.03 (d, 1H), 2.14 (d, 1H), 2.63 (q, 2H), 3.18 (s, 3H), 3.74 (bd, 1H), 5.33 (bd, 1H) 6.48 (s, 1H), 6.70 (d, 1H), 6.85 (s, 1H), 6.98 (d, 1H), 7.32 (t, 2H), 7.89 (s, 1H)
Fraction 2: 1H-NMR (300 MHz, CDCl3), δ=1.00 (t, 3H), 1.55 (s, 3H), 1.65 (s, 3H), 2.04 (d, 1H), 2.18 (d, 1H), 2.36 (q, 2H), 3.18 (s, 3H), 4.65 (bd, 1H), 5.09 (bd, 1H) 6.47 (d, 1H), 6.48 (s, 1H), 6.76 (s, 1H), 6.92 (d, 1H), 7.29 (t, 2H), 8.00 (s, 1H)
Example 61
1-[(1-Methyl-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
Analogously to Example 2, 163 mg of the imine that is described according to Example 58 with 0.97 ml of BBr3 (1N in dichloromethane) is reacted to form 44 mg of the title compound.
1H-NMR (300 MHz, CD3OD), δ=1.56 (s, 3H), 1.68 (s, 3H), 2.05 (d, 1H), 2.14 (d, 1H), 4.02 (s, 3H), 5.15 (s, 1H), 6.34 (d, 1H), 6.67 (d, 1H), 6.78 (d, 1H), 6.82-6.98 (m, 2H), 7.25 (t, 2H), 8.07 (s, 1H)
Examples 62 and 63
5-{[7-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
5-{[7-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
Analogously to Example 2, the corresponding imine is produced starting from 385 mg of 4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 200 mg of 5-aminoisoquinolin-1(2H)-one. By reaction of 300 mg of imine with 10.0 ml of BBr3 (1N in dichloromethane), 10 mg of 5-{[7-fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one as fraction 1 and 100 mg of 5-{[7-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one as fraction 2 are obtained.
Fraction 1: 1H-NMR (300 MHz, DMSO-d6), δ=1.32 (s, 3H), 1.47 (s, 3H), 1.95 (d, 1H), 2.24 (d, 1H), 3.44 (s, 3H), 5.01-5.14 (m, 2H), 5.85 (s, 1H), 6.70 (dd, 1H), 6.78 (d, 1H), 6.86 (dd, 1H), 6.98 (dd, 1H), 7.22 (d, 1H), 7.31 (t, 1H), 7.52 (d, 1H), 11.10 (bd, 1H)
Fraction 2: 1H-NMR (300 MHz, DMSO-d6), δ=1.47 (s, 3H), 1.58 (s, 3H), 1.97 (d, 1H), 2.08 (d, 1H), 5.30 (d, 1H), 5.94 (d, 1H), 6.13 (s, 1H), 6.35 (dd, 1H), 6.54 (dd, 1H), 6.81 (d, 1H), 7.03 (d, 1H), 7.17 (dd, 1H), 7.25 (t, 1H), 7.51 (d, 1H), 9.98 (bs, 1H), 11.25 (bd, 1H)
Examples 64 and 65
(−)-5-{[7-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
(+)-5-{[7-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
Separation of (+/−)-5-{[7-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
The enantiomer mixture is separated by chromatography on chiral carrier material (CHIRALPAK AD®), DAICEL Company) with hexane/ethanol (90:10, vvv). The (−)-enantiomer: MS (EI): M+=436, [α]D−62.5° °(c=0.5, CHCl3) and the (+)-enantiomer: MS (EI): M+=436, [α]D+75.6° °(c=0.8, CHCl3) are thus obtained.
Example 66
5-{[6-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one, Diastereomer A
5-Amino-2-methyl-phthalazin-1-one
3-Bromo-4-nitro-phthalide
5.37 g of 4-nitrophthalide (Tetrahedron Lett. (2001), 42, pp. 1647-50), 8.04 g of N-bromosuccinimide and 196 mg of benzoyl peroxide are refluxed in 80 ml of benzotrifluoride and heated by exposure to light until the reaction is completed. It is added to water, extracted with dichloromethane, washed several times with water, dried, and the solvent is removed in a vacuum. 7.24 g of 3-bromo-4-nitro-phthalide is obtained as a solid.
1H-NMR (300 MHz, CDCl3), δ=7.26 (s, 1H), 7.88 (t, 1H), 8.3 (d, 1H), 8.56 (d, 1H)
5-Nitro-phthalazin-1-one
18.25 g of hydrazine sulfate and 14.88 g of sodium carbonate are stirred in 300 ml of DMF at 100° C. for 1 hour. Then, 7.24 g of 3-bromo-4-nitro-phthalide in 100 ml of DMF is added, and it is stirred for another 4 hours at 100° C. It is added to water, extracted several times with ethyl acetate, and the organic phase is washed with water and brine. It is dried, and the solvent is removed in a vacuum. After recrystallization from ethyl acetate, 2.35 g of 5-nitro-phthalazin-1-one is obtained as a solid.
1H-NMR (300 MHz, DMSO-d6), δ=8.05 (t, 1H), 8.57-8.66 (m, 2H), 8.73 (s, 1H), 13.13 (bs, 1H)
2-Methyl-5-nitro-phthalazin-1-one
1.6 g of 5-nitro-phthalazin-1-one and 2.31 g of potassium carbonate are stirred for 10 minutes at room temperature in 60 ml of DMF. 1.1 ml of methyl iodide is added, and it is stirred overnight. It is added to water, extracted several times with ethyl acetate, and the organic phase is washed with water and brine. It is dried, and the solvent is removed in a vacuum. 1.57 g of 2-methyl-5-nitro-phthalazin-1-one is obtained as a yellow solid.
1H-NMR (300 MHz, DMSO-d6), δ=3.73 (s, 3H), 8.05 (t, 1H), 8.62 (d, 2H), 8.75 (s, 1H)
5-Amino-2-methyl-phthalazin-1-one
1.57 g of 2-methyl-5-nitro-phthalazin-1-one and 130 mg of palladium on activated carbon are suspended in 45 ml of ethyl acetate and hydrogenated with hydrogen under normal pressure. It is filtered through diatomaceous earth, and the solvent is removed in a vacuum. 1.26 g of 5-amino-2-methyl-phthalazin-1-one is obtained as a yellow solid.
1H-NMR (300 MHz, CDCl3), =3.81 (s, 3H), 7.0 (d, 1H), 7.5 (t, 1H), 7.8 (d, 1H), 8.16 (s, 1H)
5-{[6-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
Analogously to Example 10, the corresponding imine is produced starting from 200 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 114 mg of 5-amino-2-methyl-phthalazin-1-one. As in Example 3, 50 mg of imine is reacted by reaction with 0.23 ml of titanium tetrachloride, and 12 mg of the title compound is obtained.
Melting point: 262-263° C.
Example 67
5-{[6-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1(2H)-one
5-Amino-phthalazin-1-one
980 mg of 5-nitro-phthalazin-1-one (Example 66) and 100 mg of palladium on activated carbon are suspended in 50 ml of ethyl acetate and 1 ml of triethylamine, and it is hydrogenated with hydrogen under normal pressure. It is filtered through diatomaceous earth, and the solvent is removed in a vacuum. 830 g of 5-amino-phthalazin-1-one as a solid is obtained as a crude product.
1H-NMR (300 MHz, DMSO-d6), δ=6.26 (bs, 2H), 7.00 (d, 1H), 7.32 (d, 1H), 7.44 (t, 1H), 8.48 (s, 1H), 12.35 (bs, 1H)
5-{[6-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1(2H)-one
Analogously to Example 10, the corresponding imine is produced starting from 200 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 105 mg of 5-amino-phthalazin-1-one. As in Example 3, 50 mg of imine is reacted by reaction with 0.22 ml of titanium tetrachloride, and 36 mg of the title compound is obtained.
1H-NMR (300 MHz, CD3OD), δ=1.53 (s, 3H), 1.64 (s, 3H), 2.12 (s, 2H), 3.94 (d, 3H), 5.24 (s, 1H), 6.96 (dd, 1H), 7.03 (dd, 1H), 7.24 (dd, 1H), 7.58-7.65 (m, 2H), 8.55 (s, 1H)
Example 68
5-{[7-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
Analogously to Example 10, the corresponding imine is produced starting from 200 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 108 mg of 5-amino-2-methyl-phthalazin-1-one. As in Example 2, 225 mg of imine is reacted by reaction with 2.3 ml of BBr3 (1 M in dichloromethane), and 12 mg of the title compound is obtained.
1H-NMR (300 MHz, CD3OD), δ=1.55 (s, 3H), 1.66 (s, 3H), 2.08 (d, 1H), 2.14 (d, 1H), 5.22 (s, 1H), 6.74 (s, 1H), 6.78 (s, 1H), 7.18-7.27 (m, 1H), 7.62-7.72 (m, 2H), 8.57 (s, 1H)
Example 69
5-{[6-Fluoro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one, Diastereomer B
Analogously to Example 10, the corresponding imine is produced starting from 200 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 114 mg of 5-amino-2-methyl-phthalazin-1-one. As in Example 2, 112 mg of imine is reacted by reaction with 0.36 ml of BBr3 (1 M in dichloromethane), and 38 mg of the title compound is obtained.
1H-NMR (300 MHz, CDCl3), δ=1.53 (s, 3H), 1.64 (s, 3H), 2.11 (d, 1H), 3.85 (s, 3H), 3.97 (d, 3H), 5.02 (d, 1H), 5.13 (d, 1H), 6.97 (d, 1H), 7.00 (dd, 1H), 7.08 (d, 1H), 7.61 (t, 1H), 7.83 (d, 1H), 8.15 (s, 1H)
Example 70
5-{[6-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
29 mg of the compound of Example 69 is reacted analogously to Example 1 with 0.13 ml of BBr3 (1N in dichloromethane) to form 18 mg of the title compound.
1H-NMR (300 MHz, CD3OD), δ=1.60 (s, 3H), 1.71 (s, 3H), 2.09 (d, 1H), 2.16 (d, 1H), 3.83 (s, 3H), 5.23 (s, 1H), 6.79 (dd, 1H), 6.90 (dd, 1H), 7.22 (dd, 1H), 7.59-7.68 (m, 2H), 8.56 (s, 1H)
Example 71
5-{[6-Fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1(2H)-one
80 mg of the compound of Example 67 is reacted analogously to Example 1 with 0.35 ml of BBr3 (1N in dichloromethane) to form 15 mg of the title compound.
1H-NMR (300 MHz, CD3OD), δ=1.60 (s, 3H), 1.71 (s, 3H), 2.14 (d, 2H), 5.23 (s, 1H), 6.80 (dd, 1H), 6.90 (dd, 1H), 7.25 (dd, 1H), 7.58-7.68 (m, 2H), 8.56 (s, 1H)
Examples 72 and 73
5-{[2-Hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1(2H)-one
5-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1(2H)-one
Analogously to Example 10, the corresponding imine is produced starting from 500 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 277 mg of 5-amino-phthalazin-1-one. As in Example 2, 32 mg of 5-{[2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1(2H)-one as fraction 1 and 35 mg of 5-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1(2H)-one as fraction 3 are obtained by reaction of 470 mg of imine with 5.4 ml of BBr3 (1 M in dichloromethane).
Fraction 1: 1H-NMR (300 MHz, DMSO-d6), δ=1.32 (s, 3H), 1.50 (s, 3H), 1.96 (d, 1H), 2.23 (d, 1H), 3.47 (s, 3H), 5.17 (d, 1H), 5.93 (s, 1H), 6.06 (d, 1H), 6.78 (d, 1H), 7.04 (d, 1H), 7.27 (t, 1H), 7.37 (d, 1H), 7.44 (d, 1H), 7.62 (t, 1H), 8.67 (s, 1H), 12.39 (s, 1H)
Fraction 3: 1H-NMR (300 MHz, CD3OD), δ=1.57 (s, 3H), 1.69 (s, 3H), 2.07 (d, 1H), 2.15 (d, 1H), 5.24 (s, 1H), 6.72 (d, 1H), 6.81 (d, 1H), 6.96 (t, 1H), 7.24 (dd, 1H), 7.57-7.70 (m, 2H), 8.57 (s, 1H)
Examples 74, 75 and 76
5-{[2-Hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
5-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one, Diastereomer A
5-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one, Diastereomer B
Analogously to Example 10, the corresponding imine is produced starting from 500 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 302 mg of 5-amino-2-methylphthalazin-1-one. As in Example 2, 158 mg of 5-{[2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one as fraction 1, 66 mg of 5-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one, diastereomer A as fraction 4, and 77 mg of 5-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one, diastereomer A as fraction 5 are obtained by reaction of 570 mg of imine with 6.4 ml of BBr3 (1 M in dichloromethane).
Fraction 1: 1H-NMR (300 MHz, CD3OD), δ=1.42 (s, 3H), 1.58 (s, 3H), 2.08 (d, 1H), 2.26 (d, 1H), 3.47 (s, 3H), 3.77 (s, 3H), 5.33 (s, 1H), 6.76 (d, 1H), 7.07 (d, 1H), 7.29 (t, 1H), 7.52 (dd, 1H), 7.60-7.71 (m, 2H), 8.51 (s, 1H)
Fraction 4: 1H-NMR (300 MHz, CD3OD), δ=1.42 (s, 3H), 1.56 (s, 3H), 2.09 (d, 1H), 2.27 (d, 1H), 3.78 (s, 3H), 5.33 (s, 1H), 6.62 (d, 1H), 6.95 (d, 1H), 7.14 (t, 1H), 7.56 (dd, 1H), 7.59-7.70 (m, 2H), 8.54 (s, 1H)
Fraction 5: 1H-NMR (300 MHz, CD3OD), δ=1.57 (s, 3H), 1.68 (s, 3H), 2.07 (d, 1H), 2.14 (d, 1H), 3.77 (s, 3H), 5.33 (s, 1H), 6.71 (d, 1H), 6.80 (d, 1H), 6.96 (t, 1H), 7.22 (dd, 1H), 7.58-7.69 (m, 2H), 8.56 (s, 1H)
Examples 77 and 78
(−)-5-{[2-Hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
(+)-5-{[2-Hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
Separation of (+/−)-5-{[2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
The enantiomer mixture is separated by chromatography on chiral carrier material (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10, vvv). The (−)-enantiomer: MS (EI): M+=447, [α]D−48.0° °(c=0.7, CHCl3) and the (+)-enantiomer: MS (EI): M+=447, [α]D+45.6° °(c=0.8, CHCl3) are thus obtained.
Examples 79 and 80
(−)-5-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one, Diastereomer A
(+)-5-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one. Diastereomer A
Separation of (+/−)-5-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one, diastereomer A
The enantiomer mixture is separated by chromatography on chiral carrier material (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (85:15, vvv). The (−)-enantiomer: MS (EI): M+=433, [α]D−25.3° (c=1.0, CHCl3) and the (+)-enantiomer: MS (EI): M+=433 are thus obtained.
Examples 81 and 82
(−)-5-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one, Diastereomer A
(+)-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one, Diastereomer A
Separation of (+/−)-5-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one, diastereomer B
The enantiomer mixture is separated by chromatography on chiral carrier material (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10, vvv). The (−)-enantiomer: MS (EI): M+=433, [α]D−10.1° °(c=0.8, CHCl3) and the (+)-enantiomer: MS (EI): M+=433, [α]D+5.8° °(c=0.9, CHCl3) are thus obtained.
Example 83
cis-1-[(2-Methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol (Markus Berger)
5-Amino-2-methylquinazoline
12.7 g (62 mmol) of 2-methyl-5-nitro-3H-quinazolin-4-one (M. T. Bogert, V. J. Chambers J. Org Chem. 1905, 649-658) and 37.5 g of phosphorus pentachloride are refluxed in 75 ml of phosphoryl chloride over 20 hours. After cooling, it is poured into saturated NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried, and the solvent is removed. 14 g of 4-chloro-2-methyl-5-nitroquinazoline, of which 4.5 g (20.2 mmol) in 225 ml of ethyl acetate and 22.5 ml of triethylamine are dissolved, is obtained. 2 g of palladium on carbon is added, and it is stirred while being cooled with ice for 4 hours under a hydrogen atmosphere at normal pressure. Catalyst is removed from the solution by means of filtration through Celite, whereby it is rewashed with 200 ml of ethanol and concentrated by evaporation. After chromatography on silica gel with ethyl acetate-ethanol (0-10%), 530 mg of the product is obtained.
1H-NMR (300 MHz, CDCl3); δ=2.87 (s, 3H), 4.52 (br., 2H), 6.77 (d, 1H), 7.33 (d, 1H), 7.65 (t, 1H), 9.40 (s, 1H).
(rac)-1,1,1-Trifluoro-4-phenyl-2-[(E/Z)-(2-methyl-quinazol-5-yl)iminomethyl]-4-methyl-pentan-2-ol
0.3 ml of titanium tetraethylate is added to 140 mg (0.54 mmol) of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)-pentanal and 100 mg (0.63 mmol) of 5-amino-2-methylquinazoline in 15 ml of toluene, and the mixture is heated for over 2 hours to 100° C. After cooling, it is poured into water, and vigorous stirring is continued. The suspension is filtered through Celite, and it is rewashed thoroughly with ethyl acetate. The phases of the filtrate are separated, and it is extracted again with ethyl acetate. It is dried on sodium sulfate, and the solvent is removed in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 0-60%), 123 mg of (rac)-1,1,1,-trifluoro-4-phenyl-2-[(E/Z)-(2-methyl-quinazol-5-yl)iminomethyl]-4-methyl-pentan-2-ol is obtained.
cis-1-[(2-Methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
82 mg (0.20 mmol) of imine is taken up in 7 ml of dichloromethane and cooled to −70° C. 0.8 ml (0.8 mmol) of a 1 M titanium tetrachloride solution in dichloromethane is added in drops over 10 minutes, and it is stirred for another 6 hours at −65° C. The solution is poured into a saturated sodium bicarbonate solution and stirred vigorously for 5 minutes. It is extracted with dichloromethane, washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation and chromatography on silica gel (hexane/ethyl acetate 0-65%), 46 mg of the desired product is obtained.
1H-NMR (300 MHz, CDCl3); δ=1.46 (s, 3H), 1.63 (s, 3H), 2.19 (d, 1H), 2.29 (d, 1H), 2.87 (s, 3H), 5.14 (d, 1H), 5.97 (d, 1H), 6.81 (d, 1H), 7.15 (t, 1H), 7.36-7.43 (m, 2H), 7.42 (d, 1H), 7.75 (t, 1H), 9.42 (s, 1H).
Example 84
trans-5-Methoxy-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
The compound was produced analogously to Example 83.
1H-NMR (300 MHz, CDCl3); δ=1.43 (s, 3H), 1.54 (s, 3H), 2.07 (d, 1H), 2.18 (d, 1H), 2.84 (s, 3H), 3.21 (s, 3H), 4.31 (d, 1H), 5.38 (d, 1H), 6.63 (d, 1H), 7.05 (d, 1H), 7.18 (d, 1H), 7.31 (t, 1H), 7.43 (d, 1H), 7.81 (t, 1H), 9.13 (s, 1H).
Example 85
cis-6-Chloro-5-methoxy-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
The compound was produced analogously to Example 83.
1H-NMR (300 MHz, CDCl3); δ=1.58 (s, 3H), 1.74 (s, 3H), 2.14 (d, 1H), 2.25 (d, 1H), 2.88 (s, 3H), 3.97 (s, 3H), 5.05 (d, 1H), 5.92 (d, 1H), 6.79 (d, 1H), 7.09 (d, 1H), 7.19 (d, 1H), 7.30 (d, 1H), 7.75 (t, 1H), 9.39 (s, 1H).
Example 86
cis-6-Fluoro-5-methoxy-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
The compound was produced analogously to Example 83.
1H-NMR (CDCl3); δ=1.57 (s, 3H), 1.74 (s, 3H), 2.13 (d, 1H), 2.26 (d, 1H), (s, 3H), 3.97 (s, 3H), 5.02 (d, 1H), 5.85 (d, 1H), 6.79 (d, 1H), 6.93 (dd, 1H), 7.07 (dd, 1H), 7.29 (d, 1H), 7.74 (d, 1H), 9.33 (s, 1H).
Example 87
cis-6-[(2-Methylquinazolin-5-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1.3-dioxol-7-ol
The compound is synthesized as described in Example 83.
1H-NMR (300 MHz, CDCl3); δ=1.52 (s, 3H), 1.66 (s, 3H), 2.10 (d, 1H), 2.26 (d, 1H), 2.88 (s, 3H), 5.04 (d, 1H), 5.94 (d, 1H), 5.99 (d, 2H), 6.65 (d, 1H), 6.80 (d, 1H), 6.86 (d, 1H), 7.76 (t, 1H), 9.52 (s, 1H).
Example 88
cis-6-Chloro-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
The compound is produced by ether cleavage as described in Example 3.
1H-NMR (300 MHz, CDCl3); δ=1.54 (s, 3H), 1.68 (s, 3H), 2.06 (d, 1H), 2.20 (d, 1H), 2.81 (s, 3H), 4.98 (d, 1H), 5.81 (d, 1H), 5.91 (br., 1H), 6.73 (d, 1H), 6.86 (d, 1H), 7.08 (d, 1H), 7.23 (d, 1H), 9.35 (s, 1H).
Example 89
cis-6-Fluoro-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
The compound is produced by ether cleavage as described in Example 3.
1H-NMR (300 MHz, CDCl3); δ=1.62 (s, 3H), 1.77 (s, 3H), 2.13 (d, 1H), 2.27 (d, 1H), 2.88 (s, 3H), 5.03 (d, 1H), 5.67 (br, 1H), 5.78 (d, 1H), 6.79 (d, 1H), 6.91 (d, 2H), 7.29 (d, 1H), 7.73 (t, 1H), 9.35 (s, 1H).
Example 90
cis-6-[(7-Fluoro-2-methylquinazolin-5-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1,3-dioxol-7-ol
5-Amino-7-fluoro-2-methyquinazoline
17 g (70.5 mmol) of 3,6-difluoro-2-N-pivaloylaminobenzaldehyde (L. Florvall, I. Fagervall, L.-G.- Larsson, S. B. Ross, Eur. J. Med. Chem. 34 (1999) 137-151), 9.2 g of acetamidine hydrochloride, 13.4 g of potassium carbonate and 10.4 g of molecular sieve (4A) are combined in 70 ml of butyronitrile. It is heated while being stirred vigorously for 17 hours to 145° C., and the solvent is removed in a vacuum. After the residue is chromatographed on silica gel with hexane/ethyl acetate (0-70%), 4.5 g of 7-fluoro-5-N-pivaloylamino-2-methyquinazoline is obtained.
1 g (3.82 mmol) of 7-fluoro-5-N-pivaloylamino-2-methyquinazoline is dissolved in 74 ml of toluene and cooled to −70° C. 9.5 ml (11.4 mmol) of a 1.2 M diisobutylaluminum hydride solution in toluene is added in drops over 30 minutes. The reaction mixture is allowed to heat to −40° C. and stirred for 4 hours at −40° C. Water is slowly added and stirred for 30 minutes at room temperature until a precipitate is formed, which is removed by means of filtration through Celite. The phases are separated, washed with saturated sodium chloride solution and dried on sodium sulfate. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 64 mg of the product is obtained.
1H-NMR (300 MHz, CDCl3); δ=2.83 (s, 3H), 4.67 (br., 2H), 6.50 (dd, 1H), 6.93 (dd, 1H), 9.23 (s, 1H).
0.1 ml of titanium tetraethylate is added to 60 mg (0.46 mmol) of rac. 4-(1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 32 mg (0.18 mmol) of 5-amino-7-fluoro-2-methylquinazoline in 7 ml of toluene, and the mixture is heated over 2.5 hours to 100° C. After cooling, it is poured into water, and vigorous stirring is continued. The suspension is filtered through Celite, and is thoroughly rewashed with ethyl acetate. The phases of the filtrate are separated, and it is extracted again with ethyl acetate. It is dried on sodium sulfate, and the solvent is removed in a vacuum. The crude 4-(1,3-benzodioxol-4-yl)-1,1,1-trifluoro-2-[(E/Z)-(7-fluoro-2-methylquinazolin-5-yl)iminomethyl]-4-methyl-pentan-2-ol that is thus obtained is taken up in 8 ml of dichloromethane and cooled to −70° C. 1.1 ml (1.1 mmol) of a 1 M titanium tetrachloride solution in dichloromethane is added in drops over 10 minutes, and it is stirred for another hour at −70° C. The solution is poured into a saturated sodium bicarbonate solution and stirred vigorously for 5 minutes. It is extracted with dichloromethane, washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation and chromatography on silica gel (hexane/ethyl acetate 0-75%), 26 mg of the desired product is obtained.
1H-NMR (300 MHz, CDCl3); δ=1.53 (s, 3H), 1.66 (s, 3H), 2.12 (d, 1H), 2.27 (d, 1H), 2.84 (s, 3H), 4.94 (d, 1H), 5.99 (s, 1H), 6.00 (s, 1H), 6.02 (d, 1H), 6.50 (dd, 1H), 6.68 (d, 1H), 6.83 (d, 1H), 6.89 (dd, 1H), 9.26 (s, 1H).
Example 91
trans-5-Methoxy-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
The compound was produced analogously to Example 83.
1H-NMR (300 MHz, CDCl3); δ=1.42 (s, 3H), 1.55 (s, 3H), 2.07 (d, 1H), 2.17 (d, 1H), 2.80 (s, 3H), 3.33 (s, 3H), 4.57 (d, 1H), 5.31 (d, 1H), 6.66 (d, 1H), 6.88 (dd, 1H), 7.00 (dd, 1H), 7.05 (d, 1H), 7.30 (t, 1H), 9.03 (s, 1H).
Example 92
cis-6-Chloro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
The compound is produced by ether cleavage as described in Example 3.
1H-NMR (300 MHz, CDCl3); δ=1.60 (s, 3H), 1.73 (s, 3H), 2.12 (d, 1H), 2.24 8d, 1H), 2.84 (s, 3H), 4.96 (d, 1H), 5.98 (d, 1H), 6.01 (s, 1H), 6.51 (dd, 1H), 6.88 (d, 1H), 6.91 (dd, 1H), 7.17 (d, 1H), 9.23 (s, 1H).
Example 93
cis-6-Fluoro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
The compound is produced by ether cleavage as described in Example 3.
1H-NMR (300 MHz, CD3OD); δ=1.61 (s, 3H), 1.72 (s, 3H), 2.15 (m, 2H), 2.78 (s, 3H), 5.30 (s, 1H), 6.72-6.82 (m, 3H), 6.92 (dd, 1H), 9.55 (s, 1H).
Example 94
trans-7-Fluoro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1H-NMR (300 MHz, CD3OD); δ=1.40 (s, 3H), 1.53 (s, 3H), 2.07 (d, 1H), 2.18 (d, 1H), 2.81 (s, 3H), 3.34 (s, 3H), 4.52 (d, 1H), 5.25 (d, 1H), 6.41 (dd, 1H), 6.74 (dd, 1H), 6.86 (dd, 1H), 7.01 (dd, 1H), 9.03 (s, 1H).
Example 95
cis-6-Chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
5-Amino-8-fluoro-2-methylquinazoline
A solution of 2.4 g (18.6 mmol) of 2,5-difluoroaniline in 11 ml of water and 1.6 ml of concentrated hydrochloric acid (37%) that is 50° C. is added to a solution of 3.35 g (20.25 mmol) of chloral hydrate and 21.27 g (149.7 mmol) of sodium sulfate in 72 ml of water, which was previously stirred at this temperature for 1 hour. It is stirred for another 30 minutes at room temperature, and after 4.09 g (58.9 mmol) of hydroxylammonium chloride in 19 ml of water is added, it is heated for 45 minutes to 125° C. and kept at this temperature for 5 minutes. After cooling and after another hour, the deposited light-brown precipitate is filtered off, washed with water and dried. 3.0 g (15.0 mmol) of the hydroxylimine is obtained as an intermediate product, which is dissolved in portions in 15 ml of concentrated sulfuric acid at 60° C. After the addition is completed, it is heated for 2 hours to 80° C. and for 4 hours to 90° C. It is allowed to cool off, and the solution is poured into 100 g of ice. It is extracted with ethyl acetate, the organic phase is washed with water, dried on sodium sulfate, and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate (0-45%), 1.2 g (7.1 mmol) of 4,7-difluoroisatin is obtained. 1.8 ml of a 30% hydrogen peroxide solution is added in drops to isatin in 30 ml of a 1 molar sodium hydroxide solution over 10 minutes. After 2 hours of stirring at room temperature, it is cooled to 0° C., and 5 ml of a 4 molar hydrochloric acid is added and diluted with 50 ml of water. It is extracted with ethyl acetate, dried on sodium sulfate, concentrated by evaporation, and 1.27 g of 3,6-difluoroanthranilic acid, which is reacted without further purification, is thus quantitatively obtained.
The 3,6-difluoroanthranilic acid is heated in 8 ml of acetic acid anhydride for 45 minutes to 100° C. After cooling, the acetic acid that is produced and excess acetic acid anhydride are removed azeotropically with toluene in a vacuum. The residue is mixed with 40 ml of a 25% ammonia solution while being cooled with ice, and it is stirred for 72 hours. It is diluted with water and acidified with acetic acid. It is extracted with ethyl acetate, the organic phase is washed with water, dried on sodium sulfate and concentrated by evaporation. The thus obtained 1.03 g (5.25 mmol) of 5,8-difluoro-2-methyl-3H-quinazolin-4-one and 6 g of phosphorus pentachloride are heated in 20 ml of phosphoryl chloride over 12 hours to 125° C. After cooling, it is poured into saturated NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried, and the solvent is removed. 1.7 g of 4-chloro-5,8-difluoro-2-methylquinazoline, which is dissolved in 60 ml of ethyl acetate and 5 ml of triethylamine, is obtained quantitatively. 600 mg of palladium on carbon is added and shaken for 2 hours (480 ml of hydrogen absorption) under a hydrogen atmosphere at normal pressure. Catalyst is removed from the solution by means of filtration on Celite, whereby it is rewashed with 100 ml of ethanol and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate-ethanol (0-40%), 550 mg of 5,8-difluoro-2-methylquinazoline is obtained. 890 mg (13.7 mmol) of sodium azide is added to 240 mg (1.3 mmol) of 5,8-difluoro-2-methylquinazoline, 300 mg (1.13 mmol) of 18-crown-6 in 10 ml of DMF, and the mixture is heated over 8 hours to 125° C. The solvent is removed in a vacuum, and it is chromatographed on silica gel with ethyl acetate, and 52 mg of product is obtained.
1H-NMR (300 MHz, CDCl3); δ=2.92 (s, 3H), 4.31 (br., 2H), 6.67 (dd, 1H), 7.38 (dd, 1H), 9.37 (s, 1H).
0.23 ml (1.1 mmol) of titanium tetraethylate is added to 140 mg (0.46 mmol) of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 100 mg (0.56 mmol) of 5-amino-8-fluoro-2-methylquinazoline in 14 ml of toluene, and the mixture is heated over 2 hours to 100° C. After cooling, it is poured into water, and vigorous stirring is continued. The suspension is filtered through Celite, and thoroughly rewashed with ethyl acetate. The phases of the filtrate are separated, and it is extracted again with ethyl acetate. It is dried on sodium sulfate, and the solvent is removed in a vacuum. The crude 4-(3-chloro-2-methoxyphenyl)-1,1,1-trifluoro-2-[(E/Z)-(8-fluoro-2-methylquinazolin-5-yl)iminomethyl]-4-methyl-pentan-2-ol that is thus obtained is taken up in 23 ml of dichloromethane and cooled to −30° C. 7.8 ml (7.8 mmol) of a 1 M boron tribromide solution in dichloromethane is added in drops over 10 minutes, allowed to come to room temperature over 1 hour, and stirred for another 16 hours. The solution is poured into a mixture of ice and saturated sodium bicarbonate solution and stirred vigorously for 15 minutes. It is extracted with dichloromethane, washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation and chromatography on silica gel (hexane/ethyl acetate 0-50%), 64 mg of the desired product is obtained.
1H-NMR (300 MHz, CDCl3); δ=1.60 (s, 3H), 1.74 (s, 3H), 2.07 (d, 1H), 2.26 (d, 1H), 2.93 (s, 3H), 4.99 (d, 1H), 5.66 (d, 1H), 5.99 (br., 1H), 6.67 (dd, 1H), 6.91 (d, 1H), 7.16 (d, 1H), 7.49 (dd, 1H), 9.41 (s, 1H).
Example 96
cis-1-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1H-NMR (300 MHz, CDCl3); δ=1.45 (s, 3H), 1.61 (s, 3H), 2.17 (d, 1H), 2.26 (d, 1H), 2.92 (s, 3H), 5.08 (d, 1H), 5.69 (d, 1H), 6.69 (dd, 1H), 7.16 (t, 1H), 7.35 (m, 2H), 7.42 (d, 1H), 7.49 (t, 1H), 9.44 (s, 1H).
Example 97
trans-8-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1H-NMR (300 MHz, CDCl3); δ=1.50 (s, 3H), 1.63 (s, 3H), 2.14 (s, 2H), 2.89 (s, 3H), 3.21 (s, 3H), 4.25 (d, 1H), 5.21 (d, 1H), 6.59 (dd, 1H), 6.98 (dd, 1H), 7.04 (dd, 1H), 7.52 (dd, 1H), 9.21 (s, 1H).
Example 98
cis-7-Chloro-1-[(-8-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1H-NMR (300 MHz, CDCl3); δ=1.44 (s, 3H), 1.60 (s, 3H), 2.18 (d, 1H), 2.27 (d, 1H), 2.93 (s, 3H), 5.00 (d, 1H), 5.71 (d, 1H), 6.66 (dd, 1H), 7.28-7.37 (m, 3H), 7.50 (d 1H), 9.39 (s, 1H).
Example 99
cis-6-Chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1H-NMR (300 MHz, CDCl3); δ=1.57 (s, 3H), 1.72 (s, 3H), 2.12 (d, 1H), 2.22 (d, 1H), 2.93 (s, 3H), 3.97 (s, 3H), 4.99 (d, 1H), 5.65 (d, 1H), 6.67 (dd, 1H), 7.07 (d, 1H), 7.21 (d, 1H), 7.49 (dd, 1H), 9.39 (s, 1H).
Example 100
cis-6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1H-NMR (300 MHz, CDCl3); δ=1.56 (s, 3H), 1.71 (s, 3H), 2.11 (d, 1H), 2.22 (d, 1H), 2.93 (s, 3H), 3.97 (s, 3H), 4.97 (d, 1H), 5.60 (d, 1H), 6.67 (dd, 1H), 6.93 (dd, 1H), 7.06 (dd, 1H), 7.48 (dd, 1H), 9.37 (s, 1H).
Example 101
cis-6-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1,3-dioxol-7-ol
1H-NMR (300 MHz, CDCl3); δ=1.52 (s, 3H), 1.67 (s, 3H), 2.10 (d, 1H), 2.27 (d, 1H), 2.94 (s, 3H), 4.96 (d, 1H), 5.67 (d, 1H), 5.99 (s, 1H), 6.01 (s, 1H), 6.67 (d, 1H), 6.68 (dd, 1H), 6.86 (d, 1H), 7.49 (dd, 1H), 9.44 (s, 1H).
Example 102
cis-6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
1H-NMR (300 MHz, CD3OD); δ=1.60 (s, 3H), 1.72 (s, 3H), 2.09 (d, 1H), 2.17 (d, 1H), 2.86 (s, 3H), 5.23 (s, 1H), 6.80-6.93 (m, 3H), 7.57 (dd, 1H), 9.66 (s, 1H).
Example 103
cis-6-[(2-Methylquinolin-5-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1.3-dioxol-7-ol
1H-NMR (300 MHz, CDCl3); δ=1.50 (s, 3H), 1.60 (s, 3H), 2.08 (d, 1H), 2.20 (d, 1H), 2.73 (s, 3H), 4.85 (d, 1H), 5.09 (d, 1H), 5.98 (s, 1H), 5.99 (s, 1H), 6.62 (d, 1H), 6.81 (m, 2H), 7.22 (d, 1H), 7.50 (d, 1H), 7.56 (t, 1H), 8.09 (d, 1H).
Example 104
cis-6-[(2-Methyl-1,7-naphthyridin-5-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1,3-dioxol-7-ol
1H-NMR (300 MHz, CD3OD); δ=1.48 (s, 3H), 1.57 (s, 3H), 2.02 (d, 1H), 2.17 (d, 1H), 2.76 (s, 3H), 5.06 (s, 1H), 5.96 (s, 2H), 6.61 (d, 1H), 6.82 (d, 1H), 7.50 (d, 1H), 7.90 (s, 1H), 8.33 (d, 1H), 8.69 (s, 1H)
Example 105
Rac.-5,8-Difluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol (Diastereomer B)
Melting point: 209-211° C.
Example 106
Rac.-5-Fluoro-1-[(2-methylquinazolin-5-yl)amino]-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-diol (Diastereomer B)
Melting point: 115° C.
Example 107
Rac.-5-Fluoro-1-[(2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol (Diastereomer B)
1H-NMR (300 MHz, CD3OD); δ=1.51 (s, 3H), 1.66 (s, 3H), 2.08 (d, J=14 Hz, 1H), 2.18 (d, J=14 Hz, 1H), 2.82 (s, 3H), 5.21 (s, 1H), 6.71-6.93 (m, 3H), 7.19 (d, J=8 Hz, 1H), 7.77 (dd, J=9 Hz/8 Hz, 1H), 9.57 (s, 1H).)
Example 108
Rac.-5-Fluoro-1-[(2-methylquinazolin-5-yl)amino]-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-diol (Diastereomer A)
MS (ESI): 4590 (M+1)
Example 109
6-Fluoro-1-{[(2-hydroxymethyl)-quinolin-5-yl)amino]}-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
5-[4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]-quinoline-2-carboxylic acid methyl ester
A solution that consists of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoro-methylpentanal (872 mg, 2.84 mmol) and 5-aminoquinoline-2-carboxylic acid methyl ester (570 mg, 2.84 mmol) in 5.0 ml of concentrated acetic acid is allowed to stir for two days at room temperature. After repeated co-evaporation with toluene, the residue is purified on silica gel with hexane/ethyl acetate (0-100% ethyl acetate). 820 mg (59% of theory) of the product is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.41 (s, 3H), 1.59 (s, 3H), 2.35 (d, 1H), 3.33 (d, 1H), 4.00 (d, 3H), 4.11 (s, 3H), 4.76 (s, 1H), 6.32-6.39 (m, 1H), 6.49-6.56 (m, 1H), 6.66 (d, 1H), 6.81 (d, 1H), 7.60-7.65 (m, 2H), 8.14-8.24 (m, 2H), 8.52 (d, 1H).
5-(6-Fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinoline-2-carboxylic acid methyl ester
5-[4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]-quinoline-2-carboxylic acid methyl ester (120 mg, 0.243 mmol) is dissolved in 2.0 ml of dichloromethane. Titanium tetrachloride (1 M solution in dichloromethane, 0.73 ml, 0.73 mmol) is added in drops within 15 minutes at −30° C. Then, the reaction mixture is allowed to stir for 3 hours at −30° C. to −15° C. By adding saturated sodium bicarbonate solution at −30° C., the reaction is brought to a halt. It is extracted with ethyl acetate, the combined organic phases are washed with water and saturated sodium chloride solution. After drying on sodium sulfate and after the solvent is removed in a vacuum as well as subsequent purification on silica gel with dichloromethane/methanol (0-3% methanol), 70 mg (58% of theory) of the product is obtained.
1H-NMR (300 MHz, CD3OD): δ=1.56 (s, 3H), 1.68 (s, 3H), 2.16 (s, 2H), 3.96 (d, 3H), 4.08 (s, 3H), 5.28 (s, 1H), 6.91-6.99 (m, 2H), 7.03-7.09 (m, 1H), 7.57 (d, 1H), 7.68 (t, 1H), 8.12 (d, 1H), 8.72 (d, 1H).
6-Fluoro-1-{[(2-hydroxymethyl)-quinolin-5-yl)amino]}-5-methoxy-4, 4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
5-(6-Fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-quinoline-2-carboxylic acid methyl ester (70 mg, 0.14 mmol) is dissolved in 5.0 ml of methanol and mixed with sodium borohydride (22 mg, 0.57 mmol). After one hour and after 2 hours, in each case the same amounts are added to sodium borohydride (total amounts: 66 mg, 0.171 mmol). By adding water, the reaction is brought to a halt. It is extracted with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried on sodium sulfate. After the solvent is removed in a vacuum, the purification of the residue on silica gel is carried out with hexane/ethyl acetate (0-100% ethyl acetate). 21 mg (32% of theory) of the product is obtained.
1H-NMR (300 MHz, DMSO-d6): δ=1.48 (s, 3H), 1.61 (s, 3H), 2.01 (d, 1H), 2.14 (d, 1H), 3.88 (d, 3H), 4.70 (d, 2H), 5.40 (d, 1H), 5.51 (t, 1H), 6.19 (s, 1H), 6.35 (d, 1H), 6.83 (d, 1H), 6.91-6.96 (m, 1H), 7.04-7.11 (m, 1H), 7.21 (d, 1H), 7.48 (t, 1H), 7.58 (d, 1H), 8.64 (d, 1H).
Example 110
1-[(5-Chloro-1H-indazol-4-yl)amino]-6-fluoro-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
5-Chloro-4-nitro-1H-indazole
2.24 g (12 mmol) of 4-chloro-2-methyl-3-nitrophenylamine, produced according to the literature (Mori et al., Chem. Pharm. Bull. 1986, 34, 4859 ff. as well as Brand and Zöller, Chem. Ber. 1907, 3324 ff.), is dissolved in 100 ml of acetic acid. At 10° C., 6.0 ml of a 2 molar aqueous sodium nitrite solution is added in drops. The suspension is then added to boiling acetic acid (150 ml) within 15 minutes, and the reaction mixture is allowed to reflux for 4 hours. After the acetic acid is removed in a vacuum, the residue is taken up in ethyl acetate and saturated sodium bicarbonate solution. The organic phase is washed with saturated sodium chloride solution and dried on sodium sulfate. After the solvent is removed in a vacuum, the crude product is further reacted (1.81 g, 76%).
1H-NMR (300 MHz, DMSO-d6): δ=7.65 (d, 1H), 7.97 (d, 1H), 8.32 (s, 1H), 13.97 (s, 1H).
5-Chloro-1H-indazol-4-ylamine
A solution that consists of 5-chloro-4-nitro-1H-indazole (872 mg, 4.41 mmol) is mixed with 150 mg of palladium on carbon (10%) and stirred under hydrogen atmosphere at room temperature. After 45 minutes, the catalyst is suctioned off on one frit and washed with methanol. The filtrate is concentrated by evaporation, and the residue is taken up in 200 ml of ethyl acetate and heated. After renewed suctioning-off and concentration by evaporation of the filtrate, the purification on silica gel is carried out with hexane/ethyl acetate (100-33% hexane). 296 mg (40% of theory) of the product is obtained.
1H-NMR (300 MHz, DMSO-d6): δ=5.97 (s, 2H), 6.66 (d, 1H), 7.05 (d, 1H), 8.19 (s, 1H), 12.83 (s, 1H).
2-[(5-Chloro-1H-indazol-4-ylimino)-methyl]-1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-pentan-2-ol
A solution that consists of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoro-methylpentanal (278 mg, 0.9 mmol) and 5-chloro-1H-indazol-4-ylamine (121 mg, 0.72 mmol) in 20 ml of xylene is mixed with titanium(IV)ethylate (0.42 ml, 2.0 mmol) and refluxed for 10 hours. After cooling to room temperature, xylene is distilled off, and the residue is purified on silica gel with hexane/ethyl acetate (30-100% ethyl acetate). 123 mg (37% of theory) of the product is obtained.
1H-NMR (400 MHz, CDCl3): δ=1.43 (s, 3H), 1.57 (s, 3H), 2.38 (d, 1H), 3.22 (d, 1H), 3.94 (d, 3H), 4.91 (s, 1H), 6.41-6.52 (m, 2H), 6.90 (d, 1H), 7.28 (d, 1H), 7.38 (d, 1H), 7.56 (s, 1H), 7.72 (s, 1H), 10.26 (br, 1H).
1-(5-Chloro-1H-indazol-4-ylamino)-6-fluoro-5-methoxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydro-naphthalen-2-ol
Analogously to Example 109, 27 mg (24% of theory) of the product was obtained in the reaction of 2-[(5-chloro-1H-indazol-4-ylimino)-methyl]-1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-pentan-2-ol (111 mg, 0.24 mmol) with titanium tetrachloride (0.72 ml of a 1 M solution in dichloromethane, 0.72 mmol) in 2.0 ml of dichloromethane after purification by means of preparative thin-layer chromatography.
1H-NMR (400 MHz, CDCl3): δ=1.56 (s, 3H), 1.65 (s, 3H), 2.09-2.17 (2d, 2H), 3.97 (d, 3H), 5.34-5.36 (m, 2H), 6.87-6.95 (m, 2H), 7.15 (dd, 1H), 7.32 (d, 1H), 8.05 (s, 1H).
Example 111
1-(5-Methyl-1H-indazol-4-ylamino)-6-fluoro-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydro-naphthalene-2,-diol
5-Methyl-1H-indazol-4-ylamine
In a solution that consists of 2,4-dimethylaniline (12.4 ml, 100 mmol) in 80 ml of concentrated sulfuric acid, it is mixed at 0° C. with 5.0 ml of fuming nitric acid and stirred for 20 minutes at 4° C., and then for 30 minutes at room temperature. The reaction mixture is poured into 600 ml of ice water, and set at a pH of 10 with 5N sodium hydroxide solution. The precipitate is suctioned off, washed with water and dried. 15.72 g (95% of theory) of 2,4-dimethylnitrophenylamine is obtained as a mixture of regioisomers.
Analogously to the production of 5-chloro-4-nitro-1H-indazole, 1.14 g (57% of theory) of the product was obtained as a mixture of the two regioisomers in the reaction of 2,4-dimethylnitrophenylamine (2.0 g, 12 mmol) with 6.0 ml of a 2 molar aqueous sodium nitrite solution in acetic acid (250 ml).
MS (ES+, acetonitrile/water 1:1+0.01% formic acid): m/z(%) 178 (M+1, 100).
Analogously to the production of 5-chloro-1H-indazol-4-ylamine, the regioisomeric mixture of the previous reaction (1.0 g, 5.64 mmol)) is reacted with 100 mg of palladium on carbon in methanol under hydrogen atmosphere for 16 hours at room temperature. After purification on silica gel with hexane/ethyl acetate (33% hexane, then 100% ethyl acetate), 53 mg (6% of theory) of 5-methyl-1H-indazol-4-ylamine is obtained.
1H-NMR (300 MHz, DMSO-d6): δ=2.12 (s, 3H), 5.41 (s, 2H), 6.57 (d, 1H), 6.90 (d, 1H), 8.10 (s, 1H), 12.5 (s, 1H).
1-(5-Methyl-1H-indazol-4-ylamino)-6-fluoro-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalene-2,5-diol
4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal (308 mg, 1.0 mmol) and 5-methyl-1H-indazol-4-ylamine (148 mg, 1.0 mmol) are introduced into 15.0 ml of xylene and mixed with titanium(IV)ethylate (0.42 ml, 2.0 mmol). After 3 hours under reflux, the reaction mixture is allowed to cool to room temperature. After ethyl acetate and saturated sodium chloride solution are added, it is stirred vigorously for 30 minutes at room temperature. The deposited precipitate is suctioned off, the aqueous phase is separated, and the organic phase is dried on sodium sulfate. The purification is carried out by means of chromatography on silica gel with hexane/ethyl acetate (30-40% ethyl acetate). 345 mg (79% of theory) of 1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-[(5-methyl-1H-indazol-4-ylimino)methyl]-pentan-2-ol is obtained.
1,1,1-Trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-[(5-methyl-1H-indazol-4-ylimino)-methyl]-pentan-2-ol (150 mg, 0.34 mmol) is mixed with boron tribromide (3.40 ml of a 1 M solution in dichloromethane, 3.4 mmol) at room temperature. After 4 hours at room temperature, the reaction mixture is allowed to stand overnight at −30° C., then saturated sodium bicarbonate solution and ethyl acetate are added. It is extracted with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried on sodium sulfate. After the solvent is removed in a vacuum as well as purification by means of preparative thin-layer chromatography on silica gel with hexane/ethyl acetate (50% ethyl acetate), 56 mg (39% of theory) of the product is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.61 (s, 3H), 1.68 (s, 3H), 2.09-2.14 (m, 4H), 2.24 (d, 1H), 4.24-4.33 (br, 1H), 5.22-5.23 (m, 1H), 6.84-6.91 (m, 3H), 7.14 (d, 1H), 8.04 (s, 1H).
MS (EI+): m/z(%)=423 (M+, 45), 147 (100).
Example 112
7-Bromo-1-[(1H-indazol-4-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol (SL 4753-4)
1H-NMR (300 MHz, CD3OD): δ=1.52 (3H), 1.66 (3H), 2.00-2.22 (2H), 3.88 (3H), 5.18 (1H), 6.35 (1H), 6.89 (1H), 7.05 (1H), 7.15-7.29 (2H), 8.13 (1H).
Example 113
5-[(2-Hydroxy-4,4-pentamethylene-2-(trifluoromethyl)-1,2,3,4-tetrahydro-1-naphthyl)amino]-2-quinolone
5-[2-Hydroxy-4-phenyl-4,4-pentamethylene-2-trifluoromethylbutyl-1-imino]-2-quinolone
Analogously to Example 15, 150 mg of 2-hydroxy-4-phenyl-4,4-pentamethylene-2-trifluoromethylbutyraldehyde is condensed with 88 mg of 5-aminoquinolone in the presence of 0.21 ml of titanium tetraethylate to form imine (102 mg).
1H-NMR (300 MHz, CDCl3): δ=1.40-2.05 (m, 10 H), 2.40 (d, 1H), 2.65 (d, 1H), 4.80 (br. s, 1H), 6.15 (d, 1H), 6.80 (d, 1H), 6.85 (t, 1H), 7.00 (m, 2H), 7.20-7.35 (m, 4H), 8.20 (d, 1H), 12.00 (br. s, 1H).
5-[(2-Hydroxy-4,4-pentamethylene-2-(trifluoromethyl)-1,2,3,4-tetrahydro-1-naphthyl)amino]-2-quinolone
Analogously to Example 15, 100 mg of imine is converted with 4 ml of a 1 M titanium tetrachloride-CH2Cl2 solution into 59 mg of product.
1H-NMR (DMSO-d6): δ=1.35-1.80 (m, 11 H), 2.15 (m, 1H), 5.35 (d, 1H), 5.95 (s, 1H), 6.25 (d, 1H), 6.40 (d, 1H), 6.55 (t, 2H), 7.15 (m, 2H), 7.25 (t, 1H), 7.30 (m, 1H), 7.55 (d, 1H), 8.20 (d, 1H), 11.55 (br.s, 1H).
Example 114
cis-1-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-diol
200 mg (3.1 mmol) of potassium cyanide in 2 ml of water is added to 0.55 g (2.7 mmol) of 1,1,1-trifluoro-4-phenyl-butan-2-one (D. Yang; M.-K. Wong; Z. Yan J. Org. Chem. (2000); 65; 4179-4184) in 4 ml of THF and 2 ml of water. It is cooled to 0° C., and 1 ml of a 25% sulfuric acid is added, allowed to heat to room temperature and stirred for 16 hours. Saturated sodium bicarbonate solution is added and extracted with ethyl acetate. After washing with saturated sodium chloride solution and drying on sodium sulfate, the crude cyanide, which is dissolved in 15 ml of diethyl ether and cooled to −70° C., is obtained quantitatively. 4.6 ml (5.5 mmol) of a 1.2 M DIBAL solution in toluene is added in drops over 10 minutes. It is allowed to heat for 2 hours to room temperature, quenched with 10% tartaric acid solution, and vigorous stirring is continued. After extraction with ethyl acetate, 5 g of silica gel and 10 ml of a 1 M sulfuric acid are added. It is stirred vigorously for 12 hours and filtered through Celite. The phases are separated, and it is extracted again with ethyl acetate. After chromatography on silica gel (hexane/ethyl acetate 30%), 300 mg of still contaminated 2-hydroxy-4-phenyl-2-(trifluoromethyl)-butanal is obtained.
0.5 ml (2.4 mmol) of titanium tetraethylate is added to the thus obtained aldehyde and 200 mg (1.13 mmol) of 5-amino-8-fluoro-2-methylquinazoline in 15 ml of toluene, and the mixture is heated for 2 hours to 100° C. After the cooling, it is poured into water, and vigorous stirring is continued. The suspension is filtered through Celite and thoroughly rewashed with ethyl acetate. The phases of the filtrate are separated, and it is extracted again with ethyl acetate. It is dried on sodium sulfate, and the solvent is removed in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 30%), 100 mg of 1-(8-fluoro-2-methylquinazolin-5-ylimino)-4-phenyl-2-(trifluoromethyl)butan-2-ol is obtained. The imine is taken up in 5 ml of dichloromethane and cooled to −70° C. 1 ml (1 mmol) of a 1 M titanium tetrachloride solution in dichloromethane is added in drops over 10 minutes and stirred for one hour. The solution is poured into saturated sodium bicarbonate solution and stirred vigorously for 15 minutes. It is extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried on sodium sulfate. After concentration by evaporation and chromatography on silica gel (hexane/ethyl acetate 50%), 44 mg of the desired product is obtained.
1H-NMR (300 MHz, CDCl3); δ=2.25-2.32 (m, 2H), 2.91 (ddd, 1H), 2.92 (s, 3H), 3.19 (ddd, 1H), 5.09 (d, 1H), 5.26 (d, 1H), 6.78 (dd, 1H), 7.15-7.29 (m, 4H), 7.49 (dd, 1H), 9.34 (s, 1H).
Example 115
cis-1-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
1H-NMR (300 MHz, CDCl3); δ=1.59 (s, 3H), 1.72 (s, 3H), 2.11 (d, 1H), 2.21 (d, 1H), 2.93 (s, 3H), 5.05 (d, 1H), 5.28 (br, 1H), 5.40 (d, 1H), 6.66 (d, 1H), 6.71 (dd, 1H), 6.94 (d, 1H), 7.03 (t, 1H), 7.47 (dd, 1H), 9.37 (s, 1H).
Example 116
cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
5-Amino-7,8-difluoro-2-methyquinazoline
156 ml (391 mmol) of a 2.5 M butyllithium solution in hexane is added in drops to 41.7 g (180 mmol) of 2,2-dimethyl-N-(3,4,5-trifluorophenyl)-propionamide in 385 ml of THF at −70° C. It is allowed to stir for one hour, and then 38.6 ml of DMF in 90 ml of THF is added in drops, and the solution may heat to −60° C. It is stirred for another hour at −70° C., and then the cold reaction solution is poured into a mixture of 2 kg of ice and 400 ml of concentrated hydrochloric acid. It is stirred vigorously and extracted after one hour several times with diethyl ether. The organic phase is washed neutral with water and dried on sodium sulfate. After concentration by evaporation, 49.3 g (188 mmol) of crude 4,5,6-trifluoro-2-N-pivaloylaminobenzaldehyde is obtained, which is added together with 26 g (275 mmol) of acetamidine hydrochloride, 38.3 g (277 mmol) of potassium carbonate and 30 g of molecular sieve (4A) in 206 ml of butyronitrile. It is heated while being stirred vigorously for 18 hours to 145° C., and the solvent is removed in a vacuum. After the residue is chromatographed on silica gel with hexane/ethyl acetate (0-100%), 9.1 g of 7,8-difluoro-5-N-pivaloylamino-2-methylquinazoline is obtained.
2.0 g (7.2 mmol) of 7,8-difluoro-5-N-pivaloylamino-2-methyquinazoline is dissolved in 140 ml of toluene and cooled to −70° C. 24 ml (28.8 mmol) of a 1.2 M diisobutyl aluminum hydride solution in toluene is added in drops over 30 minutes. The reaction mixture is allowed to heat to −25° C. over 2 hours and stirred for 2 hours at −25° C. Isopropanol and then water are slowly added and stirred for 12 hours at room temperature until a precipitate, which is removed by means of filtration through Celite, is formed. It is rewashed well with a methylene chloride/methanol mixture and concentrated by evaporation. The residue is stirred vigorously in 200 ml of ethyl acetate and 50 ml of methanol together with 100 g of silica gel and 20 g of manganese dioxide. It is filtered through Celite, rewashed well with a methylene chloride-methanol mixture and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 370 mg of the product is obtained.
1H-NMR (300 MHz, CD3OD); δ=2.81 (s, 3H), 6.64 (dd, 1H), 9.52 (s, 1H).
cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1H-NMR (300 MHz, CDCl3); δ=1.46 (s, 3H), 1.61 (s, 3H), 2.20 (d, 1H), 2.24 (d, 1H), 2.91 (s, 3H), 5.00 (d, 1H), 5.86 (d, 1H), 6.56 (dd, 1H), 6.71 (dd, 1H), 7.18 (t, 1H), 7.29 (d, 1H), 7.32 (t, 1H), 7.43 (d, 1H), 9.28 (s, 1H).
Example 117
cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-6-fluoro-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1H-NMR (300 MHz, CDCl3); δ=1.59 (s, 3H), 1.70 (s, 3H), 2.12 (d, 1H), 2.22 (d, 1H), 2.91 (s, 3H), 3.98 (s, 3H), 4.90 (d, 1H), 5.80 (d, 1H), 6.56 (dd, 1H), 6.94 (dd, 1H), 7.00 (dd, 1H), 9.24 (s, 1H).
Example 118
5-{[2-Hydroxy-4,4-dimethyl-2,5-bis(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
The production is performed as described in Example 15 (13). The cyclization of the imine to the product in trifluoroacetic acid under reflux, however, takes place instead with TiCl4 in toluene.
1H-NMR (300 MHz, CDCl3): δ=1.55 (s, 3H), 1.65 (s, 3H), 2.05 (d, 1H), 2.30 (d, 1H), 5.10 (d, 1H), 5.30 (d, 1H), 6.35 (d, 1H), 6.60 (d, 1H), 6.70 (d, 1H), 7.25 (m, 1H), 7.30 (t, 1H), 7.55 (d, 1H), 7.75 (d, 1H), 7.95 (d, 1H), 10.85 (br. s, 1H).
MS (ES): MH+: 471.
Example 119
5-{[6-Chloro-2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
The synthesis is carried out as described in Example 15.
1H-NMR (300 MHz, CDCl3): δ=1.40 (s, 3H), 1.60 (s, 3H), 2.10 (d, 1H), 2.20 (d, 1H), 5.05 (br., 1H), 5.70 (br., 1H), 6.50 (d, 1H), 6.60 (m, 2H), 7.05 (dd, 1H), 7.20 (d, 1H), 7.35 (m, 2H), 8.30 (d, 1H), 10.40 (br., 1H).
MS (ES): MH+: 437/439 (3:1).
Example 120
5-{[2-Hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-1-methylquinolin-2(1H)-one
1H-NMR (300 MHz, CDCl3): δ=1.40 (s, 3H), 1.60 (s, 3H), 2.10 (d, 1H), 2.20 (d, 1H), 3.60 (s, 3H), 5.15 (d, 1H), 5.45 (d, 1H), 6.60 (d, 1H), 6.65 (d, 1H), 6.75 (d, 1H), 7.10 (t, 1H), 7.30 (m, 1H), 7.40 (m, 2H), 8.00 (d, 1H).
MS (ES): MH+: 417.
Example 121
5-{[2-Hydroxy-4,4-dimethyl-2-(trifluoromethyl)-5,6-trimethylene-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
1H-NMR (300 MHz, CDCl3): δ=1.45 (s, 3H), 1.65 (s, 3H), 1.95-2.15 (m, 3H), 2.20 (d, 1H), 2.80 (m, 2H), 3.15 (m, 2H), 5.10 (d, 1H), 5.25 (d, 1H), 6.55 (m, 3H), 7.00 (d, 1H), 7.10 (d, 1H), 7.30 (t, 1H), 8.00 (d, 1H), 10.10 (br., 1H).
MS (ES): MH+: 443.
Enantiomer separation is carried out via chiral HPLC (Chiralpak AD 20 μ-column with hexane-ethanol 95:5 as an eluant); the (−)-enantiomer is eluted at 11.4 minutes, the (+)-enantiomer at 14.1 minutes.
Example 122
5-{[6-Chloro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
1H-NMR (300 MHz, CDCl3): δ=1.55 (s, 3H), 1.70 (s, 3H), 2.10 (d, 1H), 2.20 (d, 1H), 3.95 (s, 3H), 5.05 (d, 1H), 5.35 (d, 1H), 6.55 (m, 3H), 7.00 (d, 1H), 7.15 (d, 1H), 7.35 (t, 1H), 8.05 (d, 1H), 9.95 (br., 1H).
MS (ES): MH+: 467/469 (3/1).
Example 123
5-{[6-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
1H-NMR (300 MHz, CDCl3): δ=1.60 (s, 3H), 1.70 (s, 3H), 2.05 (d, 1H), 2.20 (d, 1H), 4.20 (br. 1H), 5.05 (d, 1H), 5.40 (d, 1H), 5.95 (br.s, 1H), 6.55 (m, 3H), 6.85 (d, 1H), 7.10 (d, 1H), 7.35 (t, 1H), 8.10 (d, 1H), 9.75 (br., 1H).
MS (ES): MH+: 453/455 (3/1).
Enantiomer separation is carried out via chiral HPLC (Chiracel OD 20 μ-column with hexane-ethanol 85:15 as an eluant); the (+)-enantiomer is eluted at 10.4 minutes, the (−)-enantiomer at 14.8 minutes.
(+)-Enantiomer:
1H-NMR ([D]6-DMSO): δ=1.50 (s, 3H), 1.65 (s, 3H), 1.95 (d, 1H), 2.10 (d, 1H), 5.30 (d, 1H), 6.05 (s, 1H), 6.20 (d, 1H), 6.40 (d, 1H), 6.55 (m, 2H), 6.70 (d, 1H), 7.20 (m, 2H), 8.20 (d, 1H), 9.05 (s, 1H), 11.55 (s, 1H).
(−)-Enantiomer:
1H-NMR ([D]6-DMSO): δ=1.50 (s, 3H), 1.65 (s, 3H), 1.95 (d, 1H), 2.10 (d, 1H), 5.30 (d, 1H), 6.05 (s, 1H), 6.20 (d, 1H), 6.40 (d, 1H), 6.55 (m, 2H), 6.70 (d, 1H), 7.20 (m, 2H), 8.20 (d, 1H), 9.05 (s, 1H), 11.55 (s, 1H).
Example 124
5-{[5-Bromo-2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
The cyclization of the imine precursor to the product is carried out in trifluoroacetic acid under reflux instead of with TiCl4 in toluene.
1H-NMR (300 MHz, CDCl3): δ=1.70 (s, 3H), 1.85 (s, 3H), 2.10 (d, 1H), 2.25 (d, 1H), 5.10 (d, 1H), 5.40 (d, 1H), 6.50 (d, 1H), 6.55 (d, 1H), 6.60 (d, 1H), 6.90 (t, 1H), 7.30 (d, 1H), 7.35 (t, 1H), 7.55 (d, 1H), 8.05 (d, 1H), 10.40 (br. s, 1H).
MS (ES): MH+: 481/483 (1/1).
Example 125
5-{[6-Chloro-2-hydroxy-5-methoxy-2-(trifluoromethyl)-4,4-trimethylene-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
1H-NMR (300 MHz, CDCl3): δ=2.05-2.40 (m, 5H), 2.60 (d, 1H), 2.85 (m, 2H), 4.10 (s, 3H), 4.95 (d, 1H), 5.05 (d, 1H), 6.55 (m, 2H), 6.65 (d, 1H), 6.70 (d, 6.95 (d, 1H), 7.15 (d, 1H), 7.35 (t, 1H), 7.90 (d, 1H), 10.50 (br., 1H).
MS (ES): MH+: 478/480 (3/1).
Example 126
5-{[6-Chloro-2,5-dihydroxy-2-(trifluoromethyl)-4,4-trimethylene-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
1H-NMR ([D]6-DMSO): δ=1.80 (m, 1H), 2.05 (m 2H), 2.20 (d, 1H), 2.30 (m, 1H), 2.60 (d, 1H), 2.90 (q, 1H), 3.25 (q, 1H), 5.30 (d, 1H), 5.90 (s, 1H), 6.10 (d, 1H), 6.35 (d, 1H), 6.55 (d, 2H), 6.70 (d, 1H), 7.20 (d, 1H), 7.25 (t, 1H), 8.15 (d, 1H), 9.30 (s, 1H), 11.55 (br. S, 1H).
MS (ES): MH+: 465/467 (3/1).
Enantiomer separation is carried out via chiral HPLC (Chiralpak AD 20 μ-column with hexane-ethanol as an eluant); the (−)-enantiomer is first eluted.
1H-NMR ([D]6-DMSO): δ=1.80 (m, 1H), 2.05 (m 2H), 2.20 (d, 1H), 2.30 (m, 1H), 2.60 (d, 1H), 2.90 (q, 1H), 3.25 (q, 1H), 5.30 (d, 1H), 5.90 (s, 1H), 6.10 (d, 1H), 6.35 (d, 1H), 6.55 (d, 2H), 6.70 (d, 1H), 7.20 (d, 1H), 7.25 (t, 1H), 8.15 (d, 1H), 9.30 (s, 1H), 11.55 (br. S, 1H).
(+)-Enantiomer:
1H-NMR ([D]6-DMSO): δ=1.80 (m, 1H), 2.05 (m 2H), 2.20 (d, 1H), 2.30 (m, 1H), 2.60 (d, 1H), 2.90 (q, 1H), 3.25 (q, 1H), 5.30 (d, 1H), 5.90 (s, 1H), 6.10 (d, 1H), 6.35 (d, 1H), 6.55 (d, 2H), 6.70 (d, 1H), 7.20 (d, 1H), 7.25 (t, 1H), 8.15 (d, 1H), 9.30 (s, 1H), 11.55 (br. S, 1H).
Example 127
5-{[5-Difluoromethoxy-2-hydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
The cyclization of the imine to the product is carried out in trifluoroacetic acid under reflux instead of with TiCl4 in toluene.
1H-NMR ([D]6-DMSO): δ=1.45 (s, 1H), 1.60 (s, 1H), 2.00 (d, 1H), 2.15 (d, 1H), 5.40 (d, 1H), 6.15 (s, 1H), 6.20 (d, 1H), 6.40 (d, 1H), 6.55 (d, 1H), 6.60 (d, 1H), 7.05 (m, 2H), 7.20 (t, 1H), 7.30 (t, CHF2, JHF=75 Hz), 8.20 (d, 1H), 11.55 (s, 1H).
MS (ES): MH+: 469.
Example 128
4-{[6-Chloro-2-hydroxy-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-indazole
1H-NMR (300 MHz, CDCl3): δ=1.40 (s, 3H), 1.55 (s, 3H), 2.05 (d, 1H), 2.20 (d, 1H), 5.15 (br., 2H), 6.40 (d, 1H), 6.90 (d, 1H), 7.05 (dd, 1H), 7.25-7.35 (m, 4H), 8.55 (br., 1H).
MS (ES): MH+=410/412 (3:1).
Example 129
5-(6-Chloro-2-hydroxy-7-methoxy-4,4 dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one
4-(3-Chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal
75 ml of methylmagnesium chloride (22% in THF) is introduced into 200 ml of THF and at 0° C., a solution of 9.17 g (45.7 mmol) of methyl-3-chloro-4-methoxybenzoate in 200 ml of THF is added in drops within 1 hour. After the conversion is completed, the reaction is ended by adding 30 ml of saturated ammonium chloride solution, and the mixture is dispersed between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate, the combined organic phases are washed with water and saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a rotary evaporator.
4.5 g (22.4 mmol) of the crude product (yield 98%) is introduced into 100 ml of dichloromethane and first 6.0 g (42.7 mmol) of 2-trimethylsilanyloxy-acrylic acid ethyl ester, and then 1.85 ml of tin tetrachloride are added in drops at −70° C. After 10 minutes, the reaction mixture is added to saturated potassium carbonate solution. The aqueous phase is extracted with dichloromethane, the combined organic phases are washed with 1 M hydrochloric acid solution, water and saturated sodium chloride solution, dried with sodium sulfate and evaporated in a rotary evaporator. After column chromatography (silica gel, hexane/ethyl acetate 9:1), 2.0 g (29%) of the desired intermediate product is obtained.
1.5 g (5.0 mmol) of this keto ester is mixed in THF at −70° C. with 2.1 ml of trimethyl-trifluoromethylsilane and 620 μl of tetrabutylammonium fluoride (1 M solution in THF). It is allowed to thaw to room temperature and stirred for 18 hours, then the mixture is mixed at 0° C. with 6 ml of tetrabutylammonium fluoride (1 M solution in THF). After another 10 minutes, the mixture is dispersed between ethyl acetate and 1 M hydrochloric acid solution. The aqueous phase is extracted with ethyl acetate, the combined organic phases are washed with 1 M hydrochloric acid solution, water and saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a rotary evaporator. 1.81 g of the desired intermediate product, which, dissolved in 15 ml of diethyl ether, is added in drops at 0° C. to a suspension of 0.40 g of lithium aluminium hydride in diethyl ether, is obtained. After 1 hour at 0° C. and 18 hours at room temperature, the reaction is ended by adding 25 ml of saturated sodium bicarbonate solution. The precipitate that is formed is filtiered off, rewashed with ethyl acetate, and the filtrate is washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a rotary evaporator. After column chromatography (silica gel, hexane/ethyl acetate 8:2), 1.04 g (65%) of the desired diol-intermediate product is obtained.
In dichloromethane, 109 μl (1.12 mmol) of oxalyl chloride is introduced and at −75° C., first 190 μl (2.68 mmol) of DMSO and, after 15 minutes of stirring, a solution of 366 mg (1.12 mmol) of the diol intermediate stages in dichloromethane are added in drops. After another 15 minutes, 830 μl (5.62 mmol) of triethylamine is added in drops (at −50°). It is allowed to slowly thaw and stirred for another 18 hours. The reaction is ended by adding saturated ammonium chloride solution, the phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with 1 M hydrochloric acid, water and saturated NaCl solution and dried with NaSO4. It is concentrated by evaporation and chromatographed on silica gel with hexane/ethyl acetate (4:1). 302 mg (84%) of the desired 4-(3-chloro-4-methoxy-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is obtained.
1H-NMR (CDCl3): δ=1.34 (s, 3H), 1.40 (s, 3H), 2.30 (d, 1H), 2.62 (d, 1H), 3.66 (s, 1H), 3.90 (s, 3H), 6.84 (d, 1H), 7.13 (dd, 1H), 7.31 (d, 1H), 8.90 (s, 1H).
5-(6-Chloro-2-hydroxy-7-methoxy-4,4 dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one
100 mg (0.31 mmol) of 4-(3-chloro-4-methoxy-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 50 mg (0.31 mmol) of 5-amino-1H-quinolin-2-one are introduced into 30 ml of toluene, and 0.16 ml of titanium tetraethylate is added in drops. The mixture is stirred for 1 hour at a bath temperature of 100° C. After cooling, the solution is added to ice, several ml of saturated sodium bicarbonate solution is added, it is filtered off on diatomaceous earth and rewashed with ethyl acetate and water. The phases are separated, the aqueous phase is extracted with ethyl acetate, the combined organic phases are washed with water and saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a rotary evaporator. The imine (30%) that is obtained after chromatographic purification (silica gel, hexane/ethyl acetate 95:5 to 25:75) is taken up again in dichloromethane and mixed at −50° C. with 3.6 ml of titanium tetrachloride (1 m in toluene). It is allowed to thaw, and after 18 hours of stirring, the mixture is added to ice, the phases are separated, extracted with dichloromethane, washed with saturated sodium chloride solution and dried with sodium sulfate. After concentration by evaporation in a rotary evaporator, the crude product is chromatographed on silica gel (eluant: 2% methanol in dichloromethane). The product that is obtained is recrystallized from hexane/diethyl ether (yield: 28%).
Melting point: 182° C.;
1H-NMR (CD3OD): δ=1.28 (s, 3H), 1.42 (s, 3H), 1.95 (d, 1H), 2.07 (d, 1H), 3.54 (s, 3H), 4.88 (s, 1H), 6.42-6.48 (m, 2H), 6.58 (d, 1H), 6.82 (s, 1H), 7.25-7.30 (m, 2H), 7.97 (d, 1H).
Example 130
5-(6-Chloro-2-hydroxy-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one
This compound was produced with use of the aldehyde described in previous Example 129 and the corresponding amine.
Melting point: 85° C., MS (ESI): 467 (M+1).
Example 131
5-(6-Chloro-2-hydroxy-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-phthalazin-1-one
Example 131 was produced as described in Example 129 with use of the corresponding starting materials.
1H-NMR (CD3OD): δ=1.39 (s, 3H), 1.53 (s, 3H), 2.16 (dd, 2H), 3.12 (s, 3H), 5.30 (s, 1H), 6.94 (s, 1H), 7.31 (dd, 1H), 7.42 (s, 1H), 7.64-7.71 (m, 2H), 8.59 (s, 1H).
Example 132
6-Chloro-7-methoxy-4,4-dimethyl-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Example 132 was synthesized as described in Example 129 with use of the corresponding starting materials.
1H-NMR (CDCl3): δ=1.39 (s, 3H), 1.52 (s, 3H), 2.15 (dd, 2H), 2.73 (s, 3H), 3.49 (s, 3H), 4.97 (d, 1H), 5.10 (d, 1H), 6.80-6.84 (m, 2H), 7.24 (d, 1H), 7.36 (s, 1H), 7.49 (d, 1H), 7.55 (dd, 1H), 8.08 (d, 1H).
Example 133
6-Chloro-1-(8-fluoro-2-methylquinazolin-5-ylamino)-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
The compound was produced analogously to Example 129.
1H-NMR (CDCl3): δ=1.42 (s, 3H), 1.56 (s, 3H), 2.19 (dd, 2H), 3.62 (s, 3H), 4.31 (s, br, 1H), 5.01 (d, 1H), 5.56 (d, 1H), 6.70 (dd, 1H), 6.90 (s, 1H), 7.39 (s, 1H), 7.46-7.52 (m, 1H), 9.39 (s, 1H).
Example 134
5-(6-Chloro-2,7-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one
20 mg of 5-[4-(3-chloro4-methoxyphenyl)-2,2-dihydroxy-4-methylpentylamino]-1H-quinolin-2-one (43 μmol) is introduced into dichloromethane, mixed with 0.86 mmol of boron tribromide (1 M solution in dichloromethane), and stirred for 3 hours at room temperature. The reaction is completed with saturated sodium bicarbonate solution. It is extracted with dichloromethane, the organic phases are washed with saturated sodium chloride solution and dried with sodium sulfate and concentrated by evaporation. The crude product is recrystallized from hexane/diethyl ether. 9 mg (40%) of the desired product is obtained.
Melting point: 158° C.; MS (ESI): 453 (M+1).
Example 135
1-(8-Fluoro-2-methylquinazolin-5-ylamino)-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
2-Hydroxy-4-(4-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal
The aldehyde was produced from 4-methoxybenzyl cyanide as described in Example 5.
1H-NMR (CDCl3): δ=1.34 (s, 3H), 1.43 (s, 3H), 2.30 (d, 1H), 2.69 (d, 1H), 3.66 (s, 1H), 3.80 (s, 3H), 6.85 (d, 2H), 7.21 (d, 2H), 8.76 (s, 1H).
1-(8-Fluoro-2-methylquinazolin-5-ylamino)-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
The compound above was produced with use of the corresponding starting materials, as described in Example 129.
Melting point 97° C.; MS (ESI): 450 (M+1).
Example 136
5-(2-Hydroxy-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one
The production was carried out as described in Example 129 with use of 2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal and the corresponding amine.
Melting point 128° C.; MS (ESI): 433 (M+1).
Example 137
5-(2-Hydroxy-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one
The production was carried out as described in Example 129 with use of the 2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal and the corresponding amine.
Melting point 112° C.; MS (ESI): 433 (M+1).
Example 138
5-(2-Hydroxy-7-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-phthalazin-1-one
The production was carried out as described in Example 129 with use of 2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal and the corresponding amine.
Melting point 197° C.; MS (ESI): 434 (M+1).
Example 139
7-Methoxy-4,4-dimethyl-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol
The production was carried out as described in Example 129 with use of 2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal and the corresponding amine.
Melting point 84° C.; MS (ESI): 431 (M+1).
The racemate was separated into the enantiomers with the aid of chiral HPLC.
Analytical HPLC: Chiralpak AD 10 μ, 250×4.6 mm, 1 ml min−1, hexane/ethanol 90/10
(+)-Enantiomer: Rt=7.0 min; melting point 84° C.; MS (ESI): 431 (M+1);
(−)-Enantiomer: Rt=17.8 min; melting point 85° C.; MS (ESI): 431 (M+1); especially optical rotation: −5.9 (c=0.14, CHCl3).
Example 140
4,4-Dimethyl-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,7-diol
The ether described in Example 139 was subjected to ether cleavage with BBr3 analogously to Example 134.
Melting point 127° C.; MS (ESI): 417 (M+1).
Example 141
5-(2,7-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-phthalazin-1-one
The ether described in Example 138 was subjected to ether cleavage with BBr3 analogously to Example 134.
Melting point 116° C.; MS (ESI): 420 (M+1).
Example 142
1-(8-Fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalene-2,7-diol
The ether described in Example 135 was subjected to ether cleavage with BBr3 analogously to Example 134.
1H-NMR (CD3OD): δ=1.41 (s, 3H), 1.54 (s, 3H), 2.02 (d, 1H), 2.17 (d, 1H), 2.82 (s, 3H), 4.32 (s, 1H), 6.93 (dd, 1H), 7.01 (d, 1H), 7.32-7.43 (m, 2H), 7.52-7.66 (m, 3H);
MS (ESI): 436 (M+1).
Example 143
5-(2,7-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one
The ether described in Example 136 was subjected to ether cleavage with BBr3 analogously to Example 134.
1H-NMR (CD3OD): δ=1.38 (s, 3H), 1.52 (s, 3H), 2.13 (dd, 2H), 5.17 (s, 1H), 6.53 (d, 1H), 6.62 (d, 1H), 6.68-6.78 (m, 2H), 7.26 (d, 1H), 7.39 (dd, 1H), 8.26 (d, 1H);
MS (ESI): 419 (M+1).
Example 144
5-(2-Hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one
The above compound was produced, as described in Example 129, with use of 2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal and the corresponding amine.
Melting point 228° C.; MS (ESI): 405 (M+1)
Example 145
1-(8-Fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol
The above compound was produced as described in Example 129 with use of 2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal and the corresponding amine.
Melting point 132° C.; MS (ESI): 422 (M+1)
Example 146
7-Chloro-1-(8-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol
2-Chloro-5-methylanisole
50 g (350.65 mmol) of 2-chloro-5-methylphenol is dissolved in 450 ml of acetone and mixed under nitrogen with 96.5 g (701.3 mmol) of potassium carbonate. After 43.6 ml of methyl iodide (2 equivalents) is added, it is refluxed for three hours. After cooling, the reaction mixture is filtered, the filter residue is washed with acetone, and the filtrate is spun in until a dry state is reached (bath temperature 30° C.). Since the residue still contains potassium carbonate, it is taken up in a little diethyl ether and filtered repeatedly. After the solvent is spun off, 57 g (103.8%) of the desired compound is obtained, which is incorporated as a crude product into the next stage.
1H-NMR (300 MHz, CDCl3): δ=2.35 (3H), 3.90 (3H), 6.68-6.79 (2H), 7.22 (1H).
4-Chloro-3-methoxybenzyl bromide
57 g (363.96 mmol) of 2-chloro-5-methylanisole is dissolved in 800 ml of carbon tetrachloride and mixed at room temperature with 69.9 g (393.08 mmol) of N-bromosuccinimide. After 174.6 mg of benzoyl peroxide is added, it is refluxed for five hours (bath temperature 105° C.). The reaction mixture is suctioned off via a glass fiber filter, rewashed, and the solution is spun in in a rotary evaporator. 83.6 g (97.5%) of the desired product (contains traces of starting material and dibromide), which is incorporated in crude form into the next stage, is obtained.
1H-NMR (300 MHz, CDCl3): δ=3.91 (3H), 4.48 (2H), 6.90-6.98 (2H), 7.32 (1H).
4-Chloro-3-methoxybenzyl cyanide
83.6 g (354.97 mmol) of crude bromide is dissolved in 255 ml DMF and mixed with 266 ml of water. After adding 34.7 g (532.45 mmol) of potassium cyanide (heating), the mixture is stirred for three hours at room temperature. The reaction mixture is poured into one liter of ice water and extracted three times with 500 ml each of diethyl ether. The combined organic extracts are washed with water and brine. After drying on sodium sulfate, it is filtered, and the solvent is spun off. The residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 44.7 g (69.4%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=3.75 (2H), 3.94 (3H), 6.80-6.91 (2H), 7.38 (1H).
2-(4-Chloro-3-methoxyphenyl)-2-methylpropanenitrile
44.7 g (246.1 mmol) of the above-described nitrile is dissolved in 380 ml of DMF and mixed with 69.8 g (492.2 mmol) of methyl iodide. After cooling to 0° C., 21.5 g (492.2 mmol) of NaH (55% suspension) is added in portions to the reaction mixture within three and one-half hours. After 18 hours at room temperature, the batch is poured into 600 ml of ice water and extracted three times with 500 ml each of diethyl ether. The combined organic phases are washed with water and brine. After drying on sodium sulfate, the dessicant is filtered off, and the solvent is spun off in a rotary evaporator. After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 42.37 g (81.1%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.75 (6H), 3.96 (3H), 6.97 (1H), 7.07 (1H), 7.49 (1H).
2-(4-Chloro-3-methoxyphenyl)-2-methylpropanal
25 g (119.23 mmol) of the above-described nitrile is dissolved in 475 ml of toluene. At −65 to −60° C., 149 ml of a 1.2 molar solution of DIBAH in toluene is added in drops within 60 minutes. After two hours of stirring at this temperature, the dropwise addition of 681 ml of a 20% L-(+)-tartaric acid solution is begun. After 200 milliliters, the temperature is increased to −10° C. The remainder of the tartaric acid solution is quickly added, and the batch is stirred vigorously for 16 hours at room temperature. The reaction mixture is shaken twice with 600 ml each of diethyl ether. The combined organic extracts are shaken with water and brine, dried, and the solvent is spun off. The residue that is obtained (25 g =98.8%) is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=1.48 (6H), 3.90 (3H), 6.70-6.88 (2H), 7.37 (1H), 9.49 (1H).
Ethyl-E-4-(4-chloro-3-methoxyphenyl)-4-methylpent-2-enoate
25.6 g (114.3 mmol) of triethylphosphonoacetate is introduced into 148 ml of tetrahydrofuran. At 0° C., 60.8 ml of a 2 M solution of LDA in THF/heptane/ethylbenzene is added in drops (for one-quarter hour). After one hour of stirring at 0° C., 22.1 g (103.91 mmol) of 2-(4-chloro-3-methoxyphenyl)-2-methylpropanal, dissolved in 100 ml of tetrahydrofuran, is added in drops. After five days of stirring at room temperature, the reaction mixture is poured into 200 ml of dilute ammonium chloride solution and extracted twice with 300 ml each of diethyl ether. The combined organic extracts are treated as usual, and the residue that is obtained is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 24.1 g (82%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.30 (3H), 1.47 (6H), 3.90 (3H), 4.20 (2H), 5.80 (1H), 6.80-6.88 (2H), 7.09 (1H), 7.29 (1H).
Ethyl-4-(4-Chloro-3-methoxyphenyl)-4-methylpentanoate
24.1 g (85.23 mmol) of ethyl-E-4-(4-chloro-3-methoxyphenyl)-4-methylpent-2-enoate is mixed in 228 ml of ethyl acetate with 2.41 g of palladium on carbon (10%) and stirred overnight at room temperature under hydrogen atmosphere. The catalyst is removed by filtration through a glass fiber filter, and the residue that remians after the concentration by evaporation (24.1 g =99.1%) is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=1.21 (3H), 1.34 (6H), 1.90-2.10 (4H), 3.92 (3H), 4.10 (2H), 6.82-6.90 (2H), 7.29 (1H).
Ethyl-4-(4-Chloro-3-methoxyphenyl)-2-hydroxy-4-methylpentanoate
24.1 g (84.63 mmol) of ethyl-4-(4-chloro-3-methoxyphenyl)-4-methylpentanoate is dissolved in 296 ml of tetrahydrofuran, and the reaction mixture is cooled to −70° C. to −65° C. Within ¾ hour, 236.9 ml of a 0.5 molar solution of potassium-bis-(trimethylsilylamide) in toluene is added in drops, and the reaction mixture is then stirred for 75 more minutes at −70° C. 30.9 g (118.48 mmol) of Davis reagent, dissolved in 296 ml of tetrahydrofuran, is now added in drops within 60 minutes. After two hours of stirring at −70° C., 152 ml of saturated ammonium chloride solution is slowly added in drops, the cold bath is removed, and it is stirred vigorously for thirty minutes. After extraction with diethyl ether, the combined organic extracts are treated as usual with water and brine. After the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 21.4 g (84.2%) of the desired compound (slightly contaminated) is isolated.
Ethyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2-oxopentanoate
6.15 g (20.45 mmol) of ethyl 4-(4-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-pentanoate is dissolved in 213 ml of dichloromethane and mixed with 71 ml of dimethyl sulfoxide. After 10.3 g (102.23 mmol) of triethylamine is added, the batch is mixed in portions with 8.1 g (51.12 mmol) of SO3/pyridine complex and then stirred overnight at room temperature. The reaction mixture is mixed with 81 ml of saturated ammonium chloride solution with slight cooling, and it is stirred vigorously. After being extracted twice with diethyl ether, the combined organic phases are treated as usual. The residue that remains after the solvent is spun off is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane) together with the residue, which resulted from another batch (15.27 g). 15.46 g (72.9%, from two batches) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.25 (3H), 1.48 (6H), 3.16 (2H), 3.90 (3H), 4.12 (2H), 6.83-6.94 (2H), 7.28 (1H).
(rac.) Ethyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoate
15.46 g (51.75 mmol) of ethyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2-oxopentanoate is dissolved in 85 ml of tetrahydrofuran and mixed at 0° C. with 8.83 g (62.09 mmol) of (trifluoromethyl)-trimethylsilane. After 126.8 mg of tetrabutylammonium fluoride is added, it is stirred for two hours at 0 to 5° C. The batch is added to 150 ml of ice water, extracted twice with diethyl ether, and the combined organic extracts are treated as usual. After the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 14.11 g (61.8%) of the desired product (contaminated) is isolated, which is thus incorporated into the next stage.
MS (CI): 458 (100%).
Ethyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoate
8.9 g (20.18 mmol) of contaminated ethyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoate is dissolved in 116 ml of tetrahydrofuran and mixed at room temperature with 6.37 g (20.18 mmol) of tetrabutylammonium fluoride trihydrate and stirred for one hour at room temperature. The reaction mixture is mixed with water and extracted twice with 250 ml each of diethyl ether. The combined organic extracts are washed with water and with brine. After drying on sodium sulfate, the dessicant is filtered off, the solvent is spun off, and the remaining residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 4.03 g (54.2%) of the desired compound is isolated. Other batches are implemented analogously.
1H-NMR (300 MHz, CDCl3): δ=1.19 (3H), 1.39 (3H), 1.49 (3H), 2.28 (1H), 2.49 (1H), 3.60-3.71 (2H), 3.93 (3H), 3.98-4.10 (1H), 6.82-6.93 (2H), 7.28 (1H).
4-(4-Chloro-3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal
5.25 g (14.24 mmol) of (rac.) ethyl-4-(4-chloro-3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoate is dissolved in 53 ml of diethyl ether and mixed at 0° C. with 405.2 mg (10.68 mmol) of lithium aluminum hydride within 30 minutes. The reaction mixture is stirred for one more quarter hour at 0° C. For hydrolysis, the mixture is mixed drop by drop with 12.5 ml of saturated sodium bicarbonate solution while being cooled in an ice bath. It is stirred vigorously for 30 minutes while being cooled in an ice bath and for 60 minutes at room temperature. The precipitate is suctioned off and washed with diethyl ether. The filtrate is concentrated by evaporation in a rotary evaporator, and the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 3.29 g (71.2%) of the desired aldehyde, which still contains some starting ester, and 54.7 mg of the corresponding diol are isolated.
1H-NMR (300MHz, CDCl3): δ=1.39 (3H), 1.48 (3H), 2.34 (1H), 2.69 (1H), 3.69 (1H), 3.92 (3H), 6.80-6.93 (2H), 7.30 (1H), 8.90 (1H).
4-(4-Chloro-3-methoxy-phenyl)-1,1,1-trifluoro-2-([(E)-8-fluoro-2-methyl-quinazolin-5-ylimino]-methyl)-4-methyl-pentan-2-ol
350 mg (1.08 mmol) of (rac.)-4-(4-chloro-3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal is mixed in 5.8 ml of o-xylene with 190.9 mg (1.08 mmol) of 5-amino-8-fluoro-2-methylquinazoline. After 0.64 ml (2.16) of titanium(IV) isopropylate is added, it is refluxed for three hours (bath temperature 120° C.). After cooling, the batch is added to saturated sodium chloride solution and stirred vigorously for 20 minutes. After being extracted twice with ethyl acetate, the combined organic extracts are washed with brine. After drying on sodium sulfate, suctioning off the dessicant and spinning off the solvent, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 327.5 mg (62.8%) of the desired imine is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.38 (3H), 1.58 (3H), 2.45 (1H), 2.71 (1H), 2.99 (3H), 3.69 (3H), 4.75 (1H), 6.28 (1H), 6.79-6.90 (2H), 7.08 (1H), 7.37-7.49 (2H), 9.63 (1H).
7-Chloro-1-(8-fluoro-2-methylquinazolin-5-ylamino)-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
80 mg (0.165 mmol) of imine is dissolved in 1.2 ml of dichloromethane, mixed drop by drop at 0° C. with 0.5 ml of titanium tetrachloride and stirred for ¾ hour at this temperature. The reaction mixture is mixed drop by drop at 0° C. with saturated sodium bicarbonate solution, and it is mixed with ethyl acetate. The cold bath is removed, and the batch is stirred vigorously for 20 minutes. After extraction with ethyl acetate, the combined organic extracts are worked up as usual. After chromatography on silica gel (mobile solvent: methanol/dichloromethane), 60.7 mg (75.8%) of the desired compound is obtained.
1H-NMR (300 MHz, DMSO-d6): δ=1.40 (3H), 1.56 (3H), 1.99-2.15 (2H), 2.78 (3H), 3.90 (3H), 5.40 (1H), 6.18 (1H), 6.72-6.90 (2H), 7.10-7.20 (2H), 7.60 (1H), 9.79 (1H).
7-Chloro-1-(8-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol
35 mg (0.072 mmol) of the compound that is described in the previous section is mixed with 0.7 ml of a 1 M solution of boron tribromide in dichloromethane while being cooled in an ice bath, and it is stirred for two hours while being cooled in an ice bath. The reaction mixture is mixed drop by drop at −30° C. with saturated sodium bicarbonate solution, primarily up to pH 8. The cold bath is removed, and the batch is stirred vigorously for 15 minutes at room temperature. After being extracted twice with ethyl acetate, the organic extracts are worked up as usual. After chromatography on silica gel (mobile solvent: methanol/dichloromethane), 17.7 mg (52.2 mg) of the desired compound is ultimately isolated.
1H-NMR (300 MHz, CD3OD): δ=1.40 (3H), 1.56 (3H), 2.07-2.20 (2H), 2.89 (3H), 5.23 (1H), 6.83 (1H), 6.99 (1H), 7.20 (1H), 7.59 (1H), 9.69 (1H).
EXAMPLE 147
5-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-2H-isoquinolin-1-one
5-[4-(4-Chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pent-ylidenamino)-2H-isoquinolin-1-one
400 mg (1.232 mmol) of the 4-(4-chloro-3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal that is described in the example above is reacted to form imine with 197.3 mg (1.232 mmol) of 5-amino-2H-isoquinolin-1-one. After reaction and standard working-up and chromatography, 332.9 mg (57.9%) of the desired imine is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.38 (3H), 1.56 (3H), 2.43 (1H), 2.72 (1H), 3.70 (3H), 4.95 (1H), 6.41 (1H), 6.75-6.98 (3H), 7.08-7.31 (2H), 7.31-7.48 (2H), 11.2 (1H).
5-(7-Chloro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-2H-isoquinolin-1-one
100 mg (0.214 mmol) of imine is reacted with titanium tetrachloride as described in Example 146. 36.9 mg (36.9%) of the desired cyclic compound, specifically as a diastereomer mixture at a 65:35 ratio, is isolated.
MS (ES+): 467 (100%)
5-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-2H-isoquinolin-1-one
27 mg (0.058 mmol) of the ether that is described in the preceding section is reacted with boron tribromide as described in Example 146. After the reaction is implemented and after the usual working-up, 19.9 mg (75.9%) of the desired compound is obtained, specifically as a uniform diastereomer.
1H-NMR (300 MHz, CD3OD): δ=1.29 (3H), 1.43 (3H), 1.98-2.09 (2H), 5.00 (1H), 6.75 (1H), 6.86 (1H), 6.93 (1H), 7.00-7.10 (2H), 7.29 (1H), 7.59 (1H).
EXAMPLE 148
5-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-2-methyl-2H-phthalazin-1-one
5-[4-(4-Chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidenamino)-2-methyl-2H-phthalazin-1-one
350 mg (1.078 mmol) of the above-described 4-(4-chloro-3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal is reacted to form imine with 251.8 mg (1.078 mmol) of 5-amino-2-methyl-2H-phthalazin-1-one. After reaction, usual working up and chromatography, 328.4 mg (63.2%) of the desired imine is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.38 (3H), 1.58 (3H), 2.43 (1H), 2.72 (1H), 3.70 (3H), 3.89 (3H), 4.70 (1H), 6.51 (1H), 6.80-6.89 (2H), 7.10 (1H), 7.40 (1H), 7.63 (1H), 8.33 (1H), 8.42 (1H).
5-(7-Chloro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-2-methyl-2H-phthalazin-1-one
100 mg (0.207 mmol) of imine is cyclized to dichloromethane with titanium tetrachloride as described in Example 146. 30.5 mg (30.5%) of the desired compound, specifically as a diastereomer mixture, is isolated.
MS (ES+): 482 (100%)
5-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-2-methyl-2H-phthalazin-1-one
24 mg (0.049 mmol) of the ether that is described in the previous section is reacted with boron tribromide as described in Example 146. After the reaction is implemented and after the usual working-up, 18.7 mg (75.9%) of the desired compound, specifically as diastereomer mixture, is obtained.
MS (ES+): 468 (100%)
EXAMPLE 149
5-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-1H-quinolin-2-one
5-[4-(4-Chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidenamino)-1H-quinolin-2-one
350 mg (1.078 mmol) of the 4-(4-chloro-3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal that is described in the example above is reacted to form imine with 172.6 mg (1.078 mmol) of 5-amino-1H-quinolin-2-one. After reaction, usual working-up and chromatography, 319.4 mg (63.49%) of the desired imine is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.34 (3H), 1.55 (3H), 2.43 (1H), 2.70 (1H), 3.70 (3H), 4.85 (1H), 6.00 (1H), 6.70-6.90 (3H), 7.13 (1H), 7.29-7.45 (3H), 8.17 (1H), 12.30 (1H).
5-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-1H-quinolin-2-one
106 mg (0.227 mmol) of imine is mixed at −20° C. with 2.3 ml of a 1 M solution of boron tribromide in dichloromethane, and it is stirred for two hours at −20 to 0° C. The reaction mixture is brought to pH 8 with saturated sodium bicarbonate solution and worked up as usual. After chromatography on silica gel (mobile solvent: methanol/dichloromethane), 55.1 mg (53.5%) of the desired cyclic compound is isolated as a free phenol.
1H-NMR (300 MHz, CD3OD): δ=1.41 (3H), 1.55 (3H), 2.05-2.20 (2H), 5.12 (1H), 6.49-6.64 (2H), 6.73 (1H), 6.98 (1H), 7.16 (1H), 7.40 (1H), 8.25 (1H).
EXAMPLE 150
7-Chloro-1-(2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol
4-(4-Chloro-3-methoxyphenyl)-1,1,1-trifluoro-2-[(2-methylquinazolin-5-ylimino)-methyl]-4-methyl-pentan-2-ol
200 mg (0.616 mmol) of (rac.)-4-(4-chloro-3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal is reacted to form imine as described in Example 146 with 98.1 mg (0.616 mmol) of 5-amino-2-methylquinazoline. After the usual working-up and purification, 184.3 mg (64.2%) of the desired imine is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.36 (3H), 1.59 (3H), 2.45 (1H), 2.73 (1H), 2.93 (3H), 3.68 (3H), 4.82 (1H), 6.30 (1H), 6.78-6.90 (2H), 7.08 (1H), 7.48 (1H), 7.71 (1H), 7.84 (1H), 9.60 (1H).
7-Chloro-1-(2-methylquinazolin-5-ylamino)-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
180 mg (0.386 mmol) of imine is cyclized as described with the aid of titanium tetrachloride. 165.6 mg (92%) of the desired cycle is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.49 (3H), 1.61 (3H), 2.10-2.25 (2H), 2.84 (3H), 3.93 (3H), 5.31 (1H), 6.95 (1H), 7.10 (1H), 7.19-7.27 (2H), 7.81 (1H), 9.65 (1H).
7-Chloro-1-(2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol
50 mg (0.107 mmol) of the derivative that is described in the section above is reacted to form the corresponding phenol with the aid of boron tribromide. 30.2 mg (66.1%) of the desired compound is isolated.
1H-NMR (300 MHz, DMSO-d6): δ=1.33 (3H), 1.48 (3H), 1.95-2.13 (2H), 2.72 (3H), 5.39 (1H), 6.15 (1H), 6.80-6.95 (2H), 6.95-7.13 (3H), 7.69 (1H), 9.72 (1H), 10.03 (1H).
EXAMPLE 151
7-Chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol
4-(4-Chloro-3-methoxyphenyl)-1,1,1-trifluoro-2-[(7-fluoro-2-methylquinazolin-5-ylimino)-methyl]-4-methyl-pentan-2-ol
200 mg (0.616 mmol) of aldehyde is reacted with 109.1 mg (0.616) of 5-amino-7-fluoro-2-methylquinazoline as already described several times. 173 mg (58.1%) of the desired imine is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.39 (3H), 1.58 (3H), 2.47 (1H), 2.73 (1H), 2.90 (3H), 3.72 (3H), 4.64 (1H), 6.17 (1H), 6.80-6.90 (2H), 7.09 (1H), 7.40-7.50 (2H), 9.49 (1H).
7-Chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
170 mg (0.351 mmol) of the above-described imine is cyclized with 1.05 ml (1.053 mol) of titanium tetrachloride in dichloromethane. After the usual working-up and subsequent chromatography, 168.4 mg (99%) of the desired cyclic compound is isolated as ether.
1H-NMR (300 MHz, CD3OD): δ=1.49 (3H), 1.61 (3H), 2.20 (2H), 2.80 (3H), 3.93 (3H), 5.33 (1H), 6.70-6.85 (2H), 7.10 (1H), 7.20 (1H), 9.57 (1H).
7-Chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol
50 mg (0.103 mmol) of the ether described in the previous section is subjected as usual to ether cleavage with boron tribromide. After working-up and the usual chromatography on silica gel (mobile solvent: methanol/dichloromethane), 32.2 mg (66.4%) of the desired compound is isolated.
1H-NMR (300 MHz, DMSO-d6): δ=1.32 (3H), 1.49 (3H), 1.95-2.13 (2H), 2.70 (3H), 5.48 (1H), 6.15 (1H), 6.79 (1H), 6.88 (1H), 6.95-7.16 (2H), 9.68 (1H), 10.03 (1H).
EXAMPLE 152
7-Chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol
4-(4-Chloro-3-methoxyphenyl)-1,1,1-trifluoro-2-[(7,8-difluoro-2-methylquinazolin-5-ylimino)-methyl]-4-methyl-pentan-2-ol
200 mg (0.616 mmol) of aldehyde is reacted with 120 mg (0.616) of 5-amino-7,8-difluoro-2-methylquinazoline as already described several times. 201.3 mg (65.1%) of the desired imine is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.38 (3H), 1.58 (3H), 2.46 (1H), 2.72 (1H), 2.96 (3H), 3.72 (3H), 4.59 (1H), 6.28 (1H), 6.80-6.90 (2H), 7.10 (1H), 7.46 (1H), 9.53 (1H).
7-Chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
200 mg (0.398 mmol) of the previously described imine is cyclized with 1.19 ml (1.194 mmol) of titanium tetrachloride in dichloromethane. After the usual working-up and subsequent chromatography, 163.6 mg (81.8%) of the desired cyclic compound is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.48 (3H), 1.61 (3H), 2.19 (2H), 2.86 (3H), 3.93 (3H), 5.30 (1H), 6.88 (1H), 7.09 (1H), 7.21 (1H), 9.62 (1H).
7-Chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol
50 mg (0.099 mmol) of the ether that is described in the previous section is subjected as usual to ether cleavage with boron tribromide. After working-up and purification with flash chromatography (mobile solvent: methanol/dichloromethane), 29.5 mg (60.7%) of the desired compound is isolated.
1H-NMR (300 MHz, DMSO-d6): δ=1.32 (3H), 1.47 (3H), 1.95-2.12 (2H), 2.78 (3H), 5.45 (1H), 6.13 (1H), 6.92-7.18 (4H), 9.73 (1H), 10.02 (1H).
EXAMPLE 153
4-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1,3-dihydroindol-2-one
4-[4-(4-Chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidenamino]-1,3-dihydroindol-2-one
150 mg (0.462 mmol) of aldehyde is boiled in a water separator with 102.7 mg (0.693 mmol) of 4-amino-1,3-dihydroindol-2-one in xylene after titanium tetraisopropylate is added as already described in the preceding examples. After the usual working-up and chromatography, 119.3 mg (56.7%) of the desired imine is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.35 (3H), 1.50 (3H), 2.49 (1H), 2.66 (1H), 3.35-3.59 (2H), 3.75 (3H), 4.89 (1H), 5.98 (1H), 6.70-6.90 (3H), 7.09-7.22 (2H), 7.33 (1H), 8.22 (1H).
4-(7-Chloro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1,3-dihydroindol-2-one
119 mg (0.261 mmol) of the above-described imine is cyclized as usual in dichloromethane with 0.78 ml of titanium tetrachloride. After working-up and chromatography, 78.1 mg (65.6%) of the desired compound is obtained.
1H-NMR (300 MHz, CD3OD): δ=1.42 (3H), 1.59 (3H), 2.00-2.20 (2H), 3.23-3.49 (2H), 3.91 (3H), 5.03 (1H), 6.37 (1H), 6.48 (1H), 7.03 (1H), 7.10 (1H), 7.29 (1H).
4-(7-Chloro-2,6-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1,3-dihydroindol-2-one
65 mg (0.143 mmol) of the ether that is described in the preceding section is mixed with 1.4 boron tribromide in dichloromethane. After working-up and chromatography, 45.4 mg (72.1%) of the desired phenol is obtained.
1H-NMR (300 MHz, CD3OD): δ=1.39 (3H), 1.51 (3H), 1.98-2.20 (2H), 3.25-3.50 (2H), 5.00 (1H), 6.37 (1H), 6.46 (1H), 6.93 (1H), 7.10 (1H), 7.21 (1H).
EXAMPLE 154
8,8-Dimethyl-5-(naphthalen-1-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
1,1,1-Trifluoro-4-(2-methoxyphenyl)-4-methyl-2-(naphthalen-1-yliminomethyl)-pentan-2-ol
150 mg (0.517 mmol) of 2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal is converted into imine with 74 mg (0.517 mmol) of 1-naphthylamine in toluene with the aid of titanium tetraisopropylate. After working-up and chromatography, 166.7 mg (77.7%) of the desired imine is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.42 (3H), 1.59 (3H), 2.29 (1H), 3.57 (1H), 3.88 (3H), 5.09 (1H), 6.10 (1H), 6.48 (1H), 6.79 (1H), 7.00 (1H), 7.10 (1H), 7.22 (1H), 7.40 (1H), 7.47-7.58 (2H), 7.69 (1H), 7.80 (1H), 8.05 (1H).
8,8-Dimethyl-5-(naphthalen-1-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
160.9 mg (0.387 mmol) of the previously described imine is treated as usual with boron tribromide at 0° C., and after usual working-up and chromatography on a Flashmaster, 100.9 mg (62.7%) of the desired cyclic phenol is produced.
1H-NMR (300 MHz, CDCl3): δ=1.60 (3H), 1.73 (3H), 2.00-2.28 (2H), 3.09 (1H), 4.79 (1H), 5.02 (1H), 5.20 (1H), 6.62 (1H), 6.85-7.02 (3H), 7.30-7.58 (4H), 7.73-7.90 (3H).
EXAMPLE 155
8,8-Dimethyl-5-(naphthalen-2-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
1,1,1-Trifluoro-4-(2-methoxyphenyl)-4-methyl-2-(napthalen-2-yliminomethyl)-pentan-2-ol
150 mg (0.517 mmol) of 2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal is converted into imine with 74 mg (0.517 mmol) of 2-naphthylamine in toluene with the aid of titanium tetraisopropylate. After working-up and chromatography, 192.8 mg (89.8%) of the desired amine is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.40 (3H), 1.58 (3H), 2.20 (1H), 3.58 (1H), 3.89 (3H), 5.09 (1H), 6.69 (1H), 6.80-6.90 (2H), 6.95 (1H), 7.05-7.18 (2H), 7.38-7.53 (3H), 7.63-7.85 (3H).
8,8-Dimethyl-5-(naphthalen-2-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
173.0 mg (0.416 mmol) of the previously described imine is treated as usual with boron tribromide at 0° C., and after the usual working-up and chromatography on a Flashmaster, 132.6 mg (76.6%) of the desired cyclic phenol is produced.
1H-NMR (300 MHz, CDCl3): δ=1.60 (3H), 1.66 (3H), 2.00-2.24 (2H), 3.04 (1H), 5.00 (1H), 5.09 (1H), 6.62 (1H), 6.92-7.10 (4H), 7.28 (1H), 7.40 (1H), 7.60-7.78 (3H).
EXAMPLE 156
2-Chloro-5-(6-hydroxynaphthalen-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-naphthalene-1,6-diol
5-(4-(3-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylideneamino]-naphthalen-2-ol
200 mg (0.616 mmol) of 2-hydroxy-4-(3-chloro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal is reacted to form imine as usual with 98.1 mg (0.616 mmol) of 5-amino-2-naphthol. 185.1 mg (64.5%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.47 (3H), 1.62 (3H), 2.40 (1H), 3.23 (1H), 4.00 (3H), 4.99 (1H), 5.15 (1H), 6.39 (1H), 6.49 (1H), 6.83 (1H), 7.00 (1H), 7.05-7.20 (2H), 7.23-7.32 (2H), 7.52-7.63 (2H), 7.95 (1H).
2-Chloro-5-(6-hydroxynaphthalen-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-naphthalene-1,6-diol
185.1 mg (0.397 mmol) of imine is cyclized with boron tribromide, as already described several times. 146.9 mg (81.8%) of the desired phenol is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.59 (3H), 1.70 (3H), 2.02-2.28 (2H), 3.00 (1H), 4.75 (1H), 5.10-5.19 (2H), 5.95 (1H), 6.73 (1H), 6.88 (1H), 7.00-7.12 (2H), 7.12-7.22 (2H), 7.34 (1H), 7.70 (1H).
EXAMPLE 157
2-Chloro-5-(5-hydroxynaphthalen-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-naphthalene-1,6-diol
5-(4-(3-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylideneamino]-naphthalen-1-ol
200 mg (0.616 mmol) of 2-hydroxy-4-(3-chloro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal is reacted to form imine as usual with 98.1 mg (0.616 mmol) of 5-amino-1-naphthol. 145.0 mg (50.5%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.45 (3H), 1.62 (3H), 2.40 (1H), 3.25 (1H), 4.01 (3H), 5.01 (1H), 5.39 (1H), 6.46 (1H), 6.53 (1H), 6.80-6.91 (2H), 7.02 (1H), 7.30-7.40 (2H), 7.59 (1H), 7.64 (1H), 8.10 (1H).
2-Chloro-5-(5-hydroxynaphthalen-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-naphthalene-1,6-diol
145.0 mg (0.311 mmol) of imine is cyclized with boron tribromide as already described several times. 87.6 mg (62.3%) of the desired phenol is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.58 (3H), 1.70 (3H), 2.05-2.28 (2H), 3.00 (1H), 4.78 (1H), 5.15 (1H), 5.49 (1H), 5.95 (1H), 6.80-6.93 (3H), 7.10 (1H), 7.29 (1H), 7.32-7.45 (2H), 7.68 (1H).
EXAMPLE 158
3-Chloro-5-(6-hydroxynaphthalen-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-naphthalene-1,6-diol
5-(4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylideneamino]-naphthalen-2-ol
200 mg (0.616 mmol) of 2-hydroxy-4-(4-chloro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal is reacted to form imine as usual with 98.1 mg (0.616 mmol) of 5-amino-2-naphthol. 113.0 mg (39.4%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.38 (3H), 1.58 (3H), 2.30 (1H), 3.40 (1H), 3.85 (3H), 5.00 (1H), 5.15 (1H), 6.06 (1H), 6.50 (1H), 6.75 (1H), 6.99 (1H), 7.05-7.20 (2H), 7.28 (1H), 7.45 (1H), 7.58 (1H), 7.93 (1H).
3-Chloro-5-(6-hydroxynaphthalen-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydro-naphthalene-1,6-diol
113.0 mg (0.243 mmol) of imine is cyclized with boron tribromide, as already described several times. 85.7 mg (78.2%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.55 (3H), 1.65 (3H), 2.01-2.23 (2H), 2.95 (1H), 4.80 (1H), 5.10 (1H), 5.20 (1H), 5.48 (1H), 6.60-6.75 (2H), 6.93 (1H), 7.09 (1H), 7.10-7.23 (2H), 7.35 (1H), 7.74 (1H).
EXAMPLE 159
2-Chloro-8,8-dimethyl-5-(pyridin-3-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
4-(3-Chloro-2-methoxyphenyl)-1,1,1-(trifluoromethyl)-4-methyl-(pyridin-3-yliminomethyl)-pentan-2-ol
200 mg (0.616 mmol) of 2-hydroxy-4-(3-chloro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal is reacted to form imine as usual with 57.9 mg (0.616 mmol) of 3-aminopyridine. 197.2 mg (79.9%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.43 (3H), 1.60 (3H), 2.28 (1H), 3.25 (1H), 3.98 (3H), 4.70 (1H), 6.75 (1H), 6.95 (1H), 7.00-7.15 (2H), 7.23 (1H), 7.58 (1H), 8.12 (1H), 8.49 (1H).
6-Chloro-5-methoxy-4,4-dimethyl-1-(pyridin-3-ylamino)-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol
190.0 mg (0.474 mmol) of imine is cyclized with titanium tetrachloride, as already described several times. 184.0 mg (96.8%) of the desired cycle is isolated as ether.
1H-NMR (300 MHz, CD3OD): δ=1.54 (3H), 1.62 (3H), 2.11 (2H), 3.95 (3H), 5.05 (1H), 7.11 (1H), 7.15-7.28 (3H), 7.83 (1H), 8.09 (1H).
2-Chloro-8,8-dimethyl-5-(pyridin-3-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
100 mg (0.249 mmol) of the previously described ether is treated as usual with boron tribromide. After the usual working-up and chromatography, 85.8 mg (88.9%) of the desired compound is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.58 (3H), 1.69 (3H), 2.00-2.20 (2H), 5.00 (1H), 6.89 (1H), 7.10-7.30 (3H), 7.81 (1H), 8.06 (1H).
EXAMPLE 160
1,6-Dihydroxy-8,8-dimethyl-5-(pyridin-3-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile
50 mg of the 2-chloro-8,8-dimethyl-5-(pyridin-3-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol that is described in Example 159 is dissolved in 0.12 ml of 1-methyl-2-pyrrolidinone and mixed with 12.6 mg (0.258 mmol) of sodium cyanide and 28.2 mg (0.129 mmol) of nickel(II) bromide. The reaction mixture is brought to reaction in a microwave (200° C., 20 bar) as described in the literature (J. Org. Chem. 68, 9122 (2003)). After cooling, the reaction mixture is diluted with ethyl acetate, and then a small amount of water is added. The mixture is filtered on Extrelute (mobile solvent: ethyl acetate). The solvent is spun off, and the residue is chromatographed on silica gel (mobile solvent: methanol/dichloromethane). 9.4 mg (19.2%) of the desired nitrile is isolated.
MS (CI): 378 (100%); IR (KBr): 2228.
EXAMPLE 161
2-Chloro-8,8-dimethyl-5-(pyridin-4-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
4-(3-Chloro-2-methoxyphenyl)-1,1,1-(trifluoromethyl)-4-methyl-(pyridin-4-yliminomethyl)-pentan-2-ol
200 mg (0.616 mmol) of 2-hydroxy-4-(3-chloro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal is reacted to form imine as usual with 57.9 mg (0.616 mmol) of 4-aminopyridine. 167.9 mg (68.0%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.43 (3H), 1.60 (3H), 2.29 (1H), 3.26 (1H), 4.00 (3H), 4.55 (1H), 6.59-6.65 (2H), 6.80 (1H), 7.01 (1H), 7.11 (1H), 7.55 (1H), 8.46-8.55 (2H).
6-Chloro-5-methoxy-4,4-dimethyl-1-(pyridin-4-ylamino)-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol
160.0 mg (0.399 mmol) of imine is cyclized with titanium tetrachloride, as already described several times. 45.2 mg (28.2%) of the desired cycle is isolated as ether.
1H-NMR (300 MHz, CD3OD): δ=1.55 (3H), 1.69 (3H), 2.12 (2H), 3.98 (3H), 5.28 (1H), 6.80-6.93 (2H), 6.99 (1H), 7.28 (1H), 7.98-8.20 (2H).
2-Chloro-8,8-dimethyl-5-(pyridin-4-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
37 mg (0.092 mmol) of the previously described ether is treated as usual with boron tribromide. After the usual working-up and chromatography, 13.8 mg (38.6%) of the desired compound is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.58 (3H), 1.70 (3H), 2.00-2.20 (2H), 5.19 (1H), 6.70-6.89 (3H), 7.19 (1H), 7.90-8.20 (2H).
EXAMPLE 162
5-(2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one
Methyl-3-isopropyl-2-methoxybenzoate
28 g (156.25 mmol) of 2-hydroxy-3-isopropylbenzoic acid is dissolved in 280 ml of DMF and added in drops to a mixture of 47.5 g of potassium carbonate in 274 ml of DMF. After one more hour of stirring at room temperature, 21.4 ml (343.76 mmol) of iodomethane is added in drops, and the mixture is stirred for one day at room temperature. After acidication with 10% sulfuric acid to pH 3-4 (ice-bath cooling), the reaction mixture is extracted four times with 500 ml each of methyl tert-butyl ether. The combined organic extracts are washed with water and with brine and dried on sodium sulfate. After the dessicant is filtered off, the solvent is spun off, and the residue is chromatographed several times on silica gel (mobile solvent: methyl tert-butyl ether/hexane). 25.59 g (79.02%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.26 (6H), 3.42 (1H), 3.85 (3H), 3.96 (3H), 7.15 (1H), 7.43 (1H), 7.65 (1H).
2-(3-Isopropyl-2-methoxyphenyl)-propan-2-ol
25.59 g (142.81 mmol) of methyl-3-isopropyl-2-methoxybenzoate is dissolved in 250 ml of tetrahydrofuran and added in drops to 114.25 ml (342.74 mmol) of methylmagnesium bromide (3M in diethyl ether). In this case, the temperature increases to 46° C. After three hours of stirring at room temperature, 625 ml of saturated ammonium chloride solution is added in drops to the reaction mixture. After three cycles of extraction with methyl tert-butyl ether, the combined organic extracts are washed with water and brine and dried (sodium sulfate). The dessicant is filtered off, the solvent is spun off, and the residue (28.16 g=95.15%) is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=1.25 (6H), 1.63 (6H), 3.31 (1H), 3.90 (3H), 4.78 (1H), 7.00-7.23 (3H).
Ethyl-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-oxo-pentanoate
15.3 ml (129.71 mmol) of tin tetrachloride is added in drops to a mixture, cooled to −72° C., that consists of 28.16 g (135.19 mmol) of 2-(3-isopropyl-2-methoxyphenyl)-propan-2-ol and 50.9 g (270.38 mmol) of 2-trimethylsilanyloxy-acrylic acid ethyl ester in 420 ml of dichloromethane. In this case, the temperature increased to −65° C. After 30 minutes of stirring in this temperature interval, the reaction mixture is poured onto a mixture that consists of saturated sodium carbonate solution and dichloromethane (in each case 250 ml). After 30 minutes of stirring at room temperature, the batch is transferred into a spherical separating funnel, and a 1:1 mixture that consists of water and dichloromethane is added until a phase separation takes place. After the organic phase is shaken with sodium carbonate, 1N HCl and water, it is dried with sodium sulfate. After the usual procedure, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 20.44 g (48.35%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.15-1.34 (9H), 3.28 (1H), 3.38 (2H), 3.78 (3H), 4.09-4.21 (2H), 7.05 (1H), 7.10-7.19 (2H).
Ethyl-2-hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanoate
11.82 g (38.58 mmol) of ethyl-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-oxopentanoate and 6.58 g (46.29 mmol) of (trifluoromethyl)-trimethylsilane are dissolved in 70 ml of tetrahydrofuran and mixed with 50 mg of tetrabutylammonium fluoride trihydrate (slight temperature increase). Since, after three hours, a complete reaction still has not taken place, the same amount of tetrabutylammonium fluoride trihydrate is added once more. After stirring overnight, 12.17 g of tetrabutylammonium fluoride trihydrate is added to cleave the silyl ether that is produced and thus to get directly to the free hydroxyl compound. The reaction mixture is diluted with methyl tert-butyl ether and the organic extract is washed with water and brine. After drying (sodium sulfate), after the dessicant is filtered off, and after the solvent is filtered off, the residue is chromatographed several times on silica gel (mobile solvent: ethyl acetate/hexane). 11.04 g (76%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.13-1.32 (9H), 1.40-1.48 (6H), 2.48 (1H), 2.72 (1H), 3.32 (1H), 3.57 (1H), 3.65-3.78 (1H), 3.85 (3H), 4.08-4.20 (1H), 6.96-7.09 (2H), 7.18 (1H).
4-(3-Isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol
11.04 g (29.33 mmol) of the ester that is described in the preceding section is dissolved in 90 ml of diethyl ether and mixed at 2° C. in portions with 2.23 g (58.66 mmol) of lithium aluminum hydride. After stirring overnight at room temperature, 50 ml of saturated sodium bicarbonate solution is carefully added in drops while being cooled in an ice bath. After one hour of vigorous stirring at room temperature, it is extracted three times with methyl tert-butyl ether. The combined organic extracts are worked up as usual, and the residue that remains after the solvent is spun off is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 7.15 g (72.9%) of the desired diol is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.25 (3H), 1.29 (3H), 1.50 (3H), 1.58 (3H), 1.80 (1H), 2.23 (1H), 2.61 (1H), 2.83 (1H), 3.23-3.49 (3H), 3.89 (3H), 7.09 (1H), 7.17-7.26 (2H).
2-Hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal
3.17 g (25.04 mmol) of oxalyl chloride is introduced into 83 ml of dichloromethane and cooled to −78° C. At this temperature, 3.9 g (50.08 mmol) of dimethyl sulfoxide, dissolved in 10 ml of dichloromethane, is added in drops. After five minutes of stirring, 7.15 g (21.38 mmol) of 4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol, dissolved in 21.4 ml of dichloromethane, is added. Then, the reaction mixture is stirred for two hours at this low temperature. 10.8 g (106.9 mmol) of triethylamine is carefully added in drops, and the batch is then stirred vigorously at room temperature for one hour. After water is added and after stirring is done for another ten minutes, it is extracted twice with dichloromethane. The combined organic extracts are washed with 1% sulfuric acid, saturated sodium bicarbonate solution and brine. After the solvent is dried and spun off, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 5.93 g (83.44%) of the desired aldehyde is ultimately obtained.
1H-NMR (300 MHz, CDCl3): δ=1.20 (3H), 1.32 (3H), 1.40-1.54 (6H), 2.22 (1H), 3.30 (1H), 3.40 (1H), 3.59 (1H), 3.83 (3H), 6.95-7.07 (2H), 7.20 (1H), 8.91 (1H).
5-[2-Hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentylidenamino]-2H-isoquinolin-1-one
147.3 mg (0.443 mmol) of the aldehyde that is described in the preceding section is stirred with 71 mg (0.443 mmol) of 5-amino-2H-isoquinolin-1-one in 1.3 ml of glacial acetic acid overnight at room temperature. The reaction mixture is drawn off three times with toluene, and the residue is chromatographed on a Flashmaster. 157 mg (75%) of the desired imine is isolated.
1H-NMR (300 MHz, DMSO-d6): δ=0.93 (3H), 1.19 (3H), 1.43 (3H), 1.55 (3H), 2.18 (1H), 3.18 (1H), 3.29 (1H, half under the water of the DMSO), 3.75 (3H), 6.19 (1H), 6.33 (1H), 6.63 (1H), 6.77 (1H), 6.89-6.99 (2H), 7.16-7.32 (3H), 8.03 (1H), 11.33 (1H).
5-(2-Hydroxy-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one
157 mg of imine (0.331 mmol) is dissolved in 2.5 ml of dichloromethane and mixed drop by drop at 0° C. with 0.95 ml (0.993 mmol) of titanium(IV) chloride. After one hour of stirring at 0° C., the reaction mixture is mixed drop by drop with saturated sodium bicarbonate solution and diluted with ethyl acetate. The cold bath is removed, and the batch is stirred vigorously at room temperature for 30 minutes. After being extracted twice with ethyl acetate, the organic extracts are treated as usual. After chromatography of the residue on a Flashmaster, 108 mg (68.98%) of the desired cyclic compound is obtained as a racemate.
1H-NMR (300 MHz, CD3OD): δ=1.10-1.30 (6H), 1.55 (3H), 1.70 (3H), 2.13 (2H), 3.39 (1H, under the signal of CH3OH), 3.80 (3H), 5.19 (1H), 6.86 (1H), 6.99-7.20 (4H), 7.39 (1H), 7.70 (1H).
5-(2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one
70 mg (0.147 mmol) of the previously described cyclic ether is mixed at room temperature with 1.5 ml of a 1 M solution of boron tribromide in dichloromethane and stirred for five hours at room temperature. The reaction mixture is mixed with ice pieces. It is carefully added in drops to saturated sodium bicarbonate solution, specifically to pH 8. After dilution of the mixture with ethyl acetate, it is stirred vigorously. After being extracted twice with ethyl acetate, the combined organic extracts are washed with water and brine and dried (sodium sulfate). After the solvent is filtered and spun off, the remaining residue is chromatographed on silica gel (mobile solvent: methanol/dichloromethane). 43.2 mg (63.6%) of the desired compound is isolated.
1H-NMR (300 MHz, DMSO-d6): δ=0.96-1.20 (6H), 1.52 (3H), 1.68 (3H), 1.90-2.11 (2H), 3.30 (1H, half under the signal of the water), 5.29 (1H), 5.91 (1H), 6.00 (1H), 6.70 (1H), 6.81 (1H), 6.97 (1H), 7.05 (1H), 7.17 (1H), 7.25 (1H), 7.49 (1H), 8.09 (1H), 11.20 (1H).
EXAMPLE 163
5-(2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one
5-[2-Hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-(trifluoromethyl)-pentylidenamino]-1H-quinolin-2-one
300 mg (0.903 mmol) of 2-hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal that is described in Example 162 is reacted and worked up with 5-amino-1H-quinolin-2-one as described in the preceding example. After chromatography on a Flashmaster, 372 mg (86.91%) of the desired imine is isolated.
1H-NMR (300 MHz, DMSO-d6): δ=0.90 (3H), 1.18 (3H), 1.40 (3H), 1.54 (3H), 2.15 (1H), 3.15 (1H), 3.29 (1H, half under the water of DMSO), 3.75 (3H), 5.90 (1H), 6.20 (1H), 6.53 (1H), 6.64 (1H), 6.85-6.98 (2H), 7.13 (1H), 7.22-7.36 (2H), 8.09 (1H), 11.77 (1H).
5-(2-Hydroxy-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-1H-quinolin-2-one
120 mg (0.253 mmol) of the described imine is cyclized with titanium(IV) chloride in dichloromethane as described in Example 162. After working-up and chromatography, 64.3 mg (53.6%) of the desired cycle is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.10-1.30 (6H), 1.58 (3H), 1.71 (3H), 2.00-2.20 (2H), 3.31 (1H), 3.80 (3H), 4.01 (1H), 5.09 (1H), 5.25 (1H), 6.50-6.70 (3H), 7.00-7.12 (2H), 7.35 (1H), 8.01 (1H),10.78 (1H).
5-(2,5-Dihydroxy-6-isopropyl-4,4-&methyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one
114 mg (0.240 mmol) of the described imine is cooled to −20° C. and mixed with 2.4 ml of a 1 M boron tribromide solution in dichloromethane. First, it is stirred for two hours at −20° C. to 0° C. and then for 30 minutes at room temperature. The reaction mixture is mixed drop by drop at −20° C. with saturated sodium bicarbonate solution to pH 8. The cold bath is removed, and the batch is stirred vigorously for 10 minutes at room temperature. After extraction with ethyl acetate, the combined organic extracts are shaken as usual. After the solvent is spun off, 48 mg of a mixture that consists of cyclic ether and cyclic phenol is obtained. To obtain the uniform ether-cleaved compound, the mixture is treated once more with 1.2 ml of boron tribromide solution, but this time at room temperature (three and one-half hours of stirring). After the usual, already described working-up, 52.6 mg (92.9%) of the desired compound is obtained after chromatography on silica gel.
1H-NMR (300 MHz, CD3OD): δ=1.10-1.30 (6H), 1.60 (3H), 1.72 (3H), 2.00-2.20 (2H), 3.25 (1H), 5.15 (1H), 6.51 (1H), 6.63 (1H), 6.70 (1H), 6.88 (1H), 7.01 (1H), 7.39 (1H), 8.24 (1H).
EXAMPLE 164
5-(7-Fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
1,1,1-Trifluoro-2-[(7-fluoro-2-methylquinazolin-5-ylimino)-methyl-]-4-(3-isopropyl-2-methoxy-phenyl)-4-methyl-pentan-2-ol
150 mg (0.451 mmol) of the aldehyde that is described in Example 162 is reacted to form imine with 79.9 mg (0.451 mmol) of 7-fluoro-2-methylquinazolin-5-ylamine in xylene with the aid of titanium(IV) isopropylate. After the usual working-up, 207.8 mg (93.6%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=0.83 (3H), 1.20 (3H), 1.41 (3H), 1.62 (3H), 2.25 (1H), 2.90 (3H), 3.20 (1H), 3.68 (1H), 3.83 (3H), 4.61 (1H), 5.95 (1H), 6.54 (1H), 6.80 (1H), 6.99 (1H), 7.30-7.42 (2H), 9.30 (1H).
1-(7-Fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
207.8 mg (0.422 mmol) of the imine that is described in the preceding section is cyclized with 1.26 ml of titanium(IV) chloride in dichloromethane. According to the process that is described in Example 162, 194.4 mg (93.5%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.10-1.30 (6H), 1.60 (3H), 1.75 (3H), 2.10-2.28 (2H), 2.87 (3H), 3.33 (1H), 3.80 (3H), 4.99 (1H), 6.09 (1H), 6.20 (1H), 6.54 (1H), 6.90 (1H), 7.06-7.19 (2H), 9.20 (1H).
(−)1-(7-Fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
(+)-1-(7-Fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
94 mg of the racemic compound is separated on a chiral column in the ether stage to obtain the two enantiomers. 36 mg of the (−)-enantiomer and 32 mg of the (+)-enantiomer are isolated.
(−)-Enantiomer: [α]D=−34.4° (c=1, CH3OH); (+)-enantiomer: [α]D=+31.77° (c=1, CH3OH)
5-(7-Fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
100 mg (0.203 mmol) of 1-(7-fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-diol is treated with BBr3 in dichloromethane, as already described several times. After working-up and chromatography, 18.5 mg (19.1%) of the desired phenol is obtained.
1H-NMR (300 MHz, CD3OD): δ=1.05-1.30 (6H), 1.65 (3H), 1.74 (3H), 2.28 (2H), 2.79 (3H), 3.27 (1H), 5.30 (1H), 6.65-6.90 (2H), 6.93-7.17 (2H), 9.55 (1H).
(−)-5-(7-Fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
(+)-5-(7-Fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
The above-described enantiomer-pure ethers are converted into the enantiomer-pure phenols as described for the racemate. 10.4 mg (43.5) of the phenol is obtained from 24.7 mg of ether ((−)-enantiomer). 5.1 mg (19.6%) of the phenol is isolated from 26.7 mg of ether ((+)-enantiomer).
EXAMPLE 165
5-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1.6-diol
1,1,1-Trifluoro-2-[(7,8-difluoro-2-methylquinazolin-5-ylimino)-methyl]-1-4-(3-isopropyl-2-methoxy-phenyl)-4-methyl-pentan-2-ol
150 mg (0.451 mmol) of the aldehyde that is described in Example 162 is reacted to form imine with 88 mg (0.451 mmol) of 7,8-difluoro-2-methylquinazolin-5-ylamine in xylene with the aid of titanium(IV) isopropylate. After the usual working-up, 208.6 mg (90.7%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=0.90 (3H), 1.23 (3H), 1.43 (3H), 1.63 (3H), 2.23 (1H), 2.98 (3H), 3.22 (1H), 3.69 (1H), 3.83 (3H), 4.58 (1H), 5.99 (1H), 6.58 (1H), 6.88 (1H), 6.99 (1H), 7.39 (1H), 9.39 (1H).
1-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
208.6 mg (0.409 mmol) of the imine that is described in the preceding section is cyclized with 1.23 ml of titanium(IV) chloride in dichloromethane. According to the process described in Example 162, 198 mg (95.9%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.10-1.30 (6H), 1.63 (3H), 1.76 (3H), 2.09-2.25 (2H), 2.91 (3H), 3.32 (1H), 3.80 (3H), 4.94 (1H), 5.40 (1H), 5.82 (1H), 6.68 (1H), 7.03-7.19 (2H), 9.27 (1H).
(−)1-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
(+)-1-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
80 mg of the racemic compound is separated on a chiral column in the ether stage to obtain the two enantiomers. 38.1 mg of the (−)-enantiomer and 35.5 mg of the (+)-enantiomer are obtained.
(−)-Enantiomer: [α]D=−38.5° (c=1, CH3OH); (+)-enantiomer: [α]D=+37° (c=1, CH3OH)
5-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
100 mg (0.196 mmol) of 1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is treated with BBr3 in dichloromethane as already described several times. After working-up and chromatography, 33 mg (33.9%) of the desired phenol is obtained.
1H-NMR (300 MHz, CD3OD): δ=1.05-1.30 (6H), 1.63 (3H), 1.74 (3H), 2.12 (2H), 2.83 (3H), 3.26 (1H), 5.38 (1H), 6.73-6.90 (2H), 7.03 (1H), 9.59 (1H).
(−)-5-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
(+)-5-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
The above-described enantiomer-pure ethers are converted into the enantiomer-pure phenols as described for the racemate. 6.6 mg (22.9%) of phenol is obtained from 29.7 mg of ether ((−)-enantiomer. 10.7 mg (40.6%) of phenol is isolated from 27.1 mg of ether ((+)-enantiomer).
EXAMPLE 166
5-(8-Fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
1,1,1-Trifluoro-2-[(8-Fluoro-2-methylquinazolin-5-ylimino)-methyl-]-4-(3-isopropyl-2-methoxy-phenyl)-4-methyl-pentan-2-ol
150 mg (0.451 mmol) of the aldehyde that is described in Example 162 is reacted to form imine with 79.9 mg (0.451 mmol) of 8-fluoro-2-methylquinazolin-5-ylamine in xylene with the aid of titanium(IV) isopropylate. After the usual working-up, 176 mg (79.3%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=0.82 (3H), 1.20 (3H), 1.45 (3H), 1.62 (3H), 2.25 (1H), 3.00 (3H), 3.20 (1H), 3.63 (1H), 3.83 (3H), 4.69 (1H), 6.20 (1H), 6.47 (1H), 6.70 (1H), 6.98 (1H), 7.28-7.40 (2H), 9.48 (1H).
1-(8-Fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
176 mg (0.358 mmol) of the imine that is described in the preceding section is cyclized with 1.1 ml of titanium(IV) chloride in dichloromethane. After the working-up and chromatography that are described in Example 162, 147.3 mg (83.6%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.10-1.35 (6H), 1.60 (3H), 1.75 (3H), 2.05-2.25 (2H), 2.93 (3H), 3.33 (1H), 3.80 (3H), 4.88 (1H), 5.02 (1H), 5.52 (1H), 6.70 (1H), 7.00-7.18 (2H), 7.49 (1H), 9.35 (1H).
5-(8-Fluoro-2-methylquinazolin-5-ylamino)-2-isopropyl-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
50 mg (0.102 mmol) of 1-(8-fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is treated with BBr3 in dichloromethane, as already described several times. After working-up and chromatography, 13.7 mg (28.2%) of the desired phenol is obtained.
1H-NMR (300 MHz, CD3OD): δ=1.05-1.30 (6H), 1.65 (3H), 1.76 (3H), 2.00-2.20 (2H), 2.88 (3H), 3.27 (1H), 5.25 (1H), 6.77-6.94 (2H), 7.00 (1H), 7.59 (1H), 9.68 (1H).
EXAMPLE 167
4-(2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-1,3-dihydro-indol-2-one
4-[2-Hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentylidenamino]-1,3-dihydro-indol-2-one
250 mg (0.903 mmol) of the 2-hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal that is described in Example 162 is reacted with 4-amino-1,3-dihydro-indol-2-one as described in the preceding example and worked up. After chromatography, 334.9 mg (92.2%) of the desired imine is isolated.
1H-NMR (300 MHz, CDCl3): δ=0.99 (3H), 1.25 (3H), 1.46 (3H), 1.54 (3H), 2.20 (1H), 3.27 (1H), 3.42 (2H), 3.49 (1H), 3.84 (3H), 4.79 (1H), 5.90 (1H), 6.68-6.82 (2H), 6.90-7.09 (3H), 8.28 (1H).
4-(2-Hydroxy-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-1,3-dihydro-indol-2-one
230 mg (0.497 mmol) of the described imine is cyclized with titanium(IV) chloride in dichloromethane as described in Example 162. After working-up and chromatography, 208.3 mg (90.5%) of the desired cyclized compound is obtained.
1H-NMR (300 MHz, CD3OD): δ=1.10-1.30 (6H), 1.51 (3H), 1.66 (3H), 1.96-2.16 (2H), 3.38 (3H, lie under the methanol signal), 3.79 (3H), 5.03 (1H), 6.33 (1H), 6.49 (1H), 7.00-7.20 (3H).
4-(2,5-Dihydroxy-6-isopropyl-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1,3-dihydro-indol-2-one
50 mg (0.108 mmol) of the described ether is treated with BBr3 solution in dichloromethane. After the previously described working-up and chromatography, 35.6 mg (73.4%) of the desired compound is obtained.
1H-NMR (300 MHz, CD3OD): δ=1.10-1.30 (6H), 1.61 (3H), 1.70 (3H), 1.95-2.18 (2H), 3.27 (1H), 3.38 (2H, lie under the methanol signal), 5.01 (1H), 6.33 (1H), 6.49 (1H), 6.89 (1H), 6.95-7.15 (2H).
The following compounds from the corresponding aldehydes and amines are synthesized analogously.
EXAMPLE 168
cis-6-Chloro-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1H-NMR (300 MHz, CDCl3); δ=1.58 (s, 3H), 1.72 (s, 3H), 2.14 (d, 1H), 2.22 (d 1H), 2.92 (s, 3H), 3.97 (s, 3H), 4.91 (d, 1H), 5.83 (d, 1H), 6.55 (dd, 1H), 7.03 (d, 1H), 7.23 (d, 1H), 9.24 (s, 1H).
EXAMPLE 169
cis-1-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-7-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1H-NMR (300 MHz, CDCl3); δ=2.24-2.34 (m, 2H), 2.86 (ddd, 1H), 2.91 (s, 3H), 3.12 (ddd, 1H), 3.63 (s, 3H), 5.00 (d, 1H), 5.47 (d, 1H), 6.75 (dd, 1H), 6.79 (d, 1H), 6.84 (s, 1H), 7.11 (d, 1H), 7.49 (dd, 1H), 9.35 (s, 1H).
EXAMPLE 170
cis-6-Chloro-1-[(7,8-difluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
1H-NMR (300 MHz, CD3OD); δ=1.60 (s, 3H), 1.72 (s, 3H), 2.16 (s, 2H), 2.84 (s, 3H), 5.30 (s, 1H), 6.84 (d, 1H), 6.86 (dd, 1H), 7.17 (d, 1H), 9.60 (s, 1H).
EXAMPLE 171
cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-6-fluoro-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
1H-NMR (300 MHz, CD3OD); δ=1.61 (s, 3H), 1.72 (s, 3H), 2.14 (s, 2H), 2.84 (s, 3H), 3.98 (s, 3H), 5.27 (s, 1H), 6.76-6.94 (m, 3H), 9.59 (s, 1H).
EXAMPLE 172
cis-1-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,7-diol
1H-NMR (300 MHz, CD3OD); δ=2.16-2.35 (m, 2H), 2.81 (ddd, 1H), 2.85 (s, 3H), 3.08 (ddd, 1H), 5.24 (s, 1H), 6.67 (dd, 1H), 6.78 (d, 1H), 6.89 (dd, 1H), 7.02 (d, 1H), 7.59 (dd, 1H), 9.67 (s, 1H).
EXAMPLE 173
2-Hydroxy-3-(1-phenylcyclohexyl)-2-(trifluoromethyl)propanal
12.6 g (45.9 mmol) of ethyl-2-oxo-3-(1-phenylcyclohexyl)-propionate (WO9854159) and 19.9 ml (138 mmol) of (trifluoromethyl)-trimethylsilane in 215 ml of THF are cooled to −70° C. and mixed with 8.6 ml of a 1 molar tetrabutylammonium fluoride solution in THF. The reaction mixture is allowed to heat over 18 hours to room temperature and then poured onto saturated sodium chloride solution. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 20%), 13.1 g of ethyl-2-hydroxy-3-(1-phenylcyclohexyl)-2-(trifluoromethyl)-propionate is obtained as a yellow oil. At 0° C., a solution of 3.33 g (87.7 mmol) of lithium aluminum hydride in 173 ml of THF is added in drops to 13.1 g (38.1 mmol) of ester in 174 ml of THF, and it is stirred for 16 hours at room temperature. 20 ml of saturated ammonium chloride solution is carefully added to the batch at 0° C., and it is stirred vigorously for 15 more minutes. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 0%-33%), 6.1 g of 3-(1-phenyl)-cyclohexyl)-2-(trifluoromethyl)-propane-1,2-diol is obtained. 15.7 ml (113 mmol) of triethylamine and, in portions over 10 minutes, 13.8 g (87 mmol) of pyridine SO3 complex are added to 6.1 g (20.2 mmol) of diol in 245 ml of dichloromethane and 79 ml of DMSO. It is stirred over 3 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and after chromatographic purification on silica gel (hexane/ethyl acetate, 0-33%), the desired product is obtained quantitatively.
1H-NMR (CDCl3): δ=1.17-1.78 (m, 9H), 1.98-2.05 (m, 1H), 2.41 (d, 1H), 3.46 (d, 1H), 3.66 (s, 1H), 7.18 (d, 2H), 7.24 (t, 2H), 7.31 (d, 1H), 8.55 (s, 1H).
cis-4′-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalen]-3′-ol
1H-NMR (300 MHz, CDCl3); δ=1.25-1.85 (m, 9H), 1.97 (d, 1H), 2.11 (d, 1H), 2.68 (d, 1H), 2.91 (s, 3H), 5.08 (d, 1H), 5.38 (d, 1H), 6.69 (dd, 1H), 7.18 (t, 1H), 7.34 (d, 1H), 7.35 (t, 1H), 7.47 (dd, 1H), 7.56 (d, 1H), 9.36 (s, 1H).
EXAMPLE 174
cis-4′-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-3,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalen]-3′-ol
1H-NMR (300 MHz, CDCl3); δ=1.25-1.90 (m, 9H), 1.93 (d, 1H), 2.02 (d, 1H), 2.64 (d, 1H), 2.89 (s, 3H), 4.99 (d, 1H), 5.66 (d, 1H), 6.54 (dd, 1H), 7.18 (t, 1H), 7.29 (d, 1H), 7.36 (t, 1H), 7.54 (d, 1H), 9.25 (s, 1H).
EXAMPLE 175
cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
1H-NMR (300 MHz, CD3OD); δ=1.58 (s, 3H), 1.70 (s, 3H), 2.13 (s, 2H), 2.84 (s, 3H), 5.28 (s, 1H), 6.71-6.87 (m, 3H), 6.99 (t, 1H), 9.59 (s, 1H).
EXAMPLE 176
trans-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-6-fluoro-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
1H-NMR (300 MHz, CDCl3); δ=1.40 (s, 3H), 1.54 (s, 3H), 2.05 (d, 1H), 2.19 (d, 1H), 2.76 (s, 3H), 3.57 (br, 1H), 4.62 (d, 1H), 5.27 (d, 1H), 6.54 (br, 1H), 6.90-6.97 (m, 2H), 7.07 (dd, 1H), 9.10 (s, 1H).
EXAMPLE 177
cis-5-{3′,4′-Dihydro-3′-hydroxy-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalen-4′-yl]amino}-quinolin-2(1H)-one
1H-NMR (300 MHz, CD3OD); δ=0.91 (m, 1H), 1.12 (m, 3H), 1.89 (d, 1H), 2.44 (d, 1H), 5.29 (s, 1H), 6.51 (d, 1H), 6.67 (d, 1H), 6.71 (d, 1H), 6.79 (d, 1H), 7.09 (t, 1H), 7.21 (t, 1H), 7.24 (d, 1H), 7.39 (t, 1H), 8.24 (d, 1H).
EXAMPLE 178
cis-4′-[(8-Fluoro-2-methylquinazolin-5-yl)amino]-3,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalen]-3′-ol
1H-NMR (300 MHz, CD3OD); δ=0.92-0.98 (m, 1H), 1.13-1.19 (m, 3H), 1.98 (d, 1H), 2.40 (d, 1H), 2.85 (s, 3H), 5.36 (s, 1H), 6.81 (d, 1H), 6.91 (dd, 1H), 7.10 (t, 1H), 7.23 (t, 1H), 7.28 (d, 1H), 7.59 (dd, 1H), 9.68 (s, 1H).
EXAMPLE 179
cis-6-Chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
4-(3-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoroethyl)-pentanal
1.0 g (3.35 mmol) of ethyl-4-(3-chloro-2-methoxyphenyl)-4-methyl-2-oxovalerate and 0.96 (5.0 mmol) of (pentafluoroethyl)-trimethylsilane in 7 ml of THF are mixed with 62 mg (0.67 mmol) of tetramethylammonium fluoride at −40° C. It is stirred for 2 hours at −25° C., then 1 ml of 1N hydrochloric acid is added to the reaction mixture and poured onto water after 10 minutes. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. 1.44 g of ethyl-4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)-valerate, which is mixed in 14.5 ml of diethyl ether at 0° C. with 0.22 g (5.9 mmol) of lithium aluminum hydride and is stirred for 2 hours at room temperature, is obtained. The batch is poured onto ice water, and it is stirred vigorously for 15 more minutes. It is filtered through Celite, extracted several times with diethyl ether, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 0%-20%), 0.77 g of 4-(3-chloro-2-methoxyphenyl)-2-(pentafluoroethyl)-4-methyl-propane-1,2-diol is obtained. 0.84 ml (6.1 mmol) of triethylamine and 388 mg (2.44 mmol) of pyridine SO3 complex are added to 0.46 g (1.22 mmol) of diol in 9.5 ml of dichloromethane and 2.5 ml of DMSO. It is stirred over 2 hours and then another 388 mg (2.44 mmol) of pyridine SO3 complex is dosed in. After 1 hour of stirring, saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with diethyl ether. It is washed with saturated ammonium chloride solution and dried on sodium sulfate. The solvent is removed in a vacuum, and after chromatographic purification on silica gel (hexane/ethyl acetate, 30%), 357 g of product is obtained.
1H-NMR (CDCl3): δ=1.43 (s, 3H), 1.48 (s, 3H), 2.34 (d, 1H), 3.29 (d, 1H), 3.58 (s, 1H), 4.01 (s, 3H) 6.95 (t, 1H), 7.05 (dd, 1H), 7.30 (dd, 1H), 9.10 (s, 1H).
cis-6-Chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
1H-NMR (300 MHz, CD3OD); δ=1.61 (s, 3H), 1.74 (s, 3H), 2.14 (d, 1H), 2.20 (d, 1H), 2.86 (s, 3H), 5.34 (s, 1H), 6.84 (d, 1H), 6.86 (dd, 1H), 7.12 (d, 1H), 7.57 (dd, 1H), 9.65 (s, 1H).
EXAMPLE 180
cis-6-Chloro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
1H-NMR (300 MHz, CDCl3); δ=1.58 (s, 3H), 1.72 (s, 3H), 2.17 (d, 1H), 2.26 (d, 1H), 2.84 (s, 3H), 3.95 (s, 3H), 5.05 (d, 1H), 6.07 (d, 1H), 6.51 (dd, 1H), 6.91 (dd, 1H), 7.04 (d, 1H), 7.18 (d, 1H), 9.17 (s, 1H).
EXAMPLE 181
trans-6-Chloro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
1H-NMR (300 MHz, CD3OD); δ=1.45 (s, 3H), 1.61 (s, 3H), 2.29 (d, 1H), 2.37 (d, 1H), 2.74 (s, 3H), 3.65 (s, 3H), 5.58 (s, 1H), 6.83 (dd, 1H), 6.98 (dd, 1H), 7.30 (dd 1H), 7.42 (d, 1H), 9.52 (s, 1H).
EXAMPLE 182
cis-5-{[6-Chloro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
1H-NMR (300 MHz, CDCl3); δ=1.55 (s, 3H), 1.72 (s, 3H), 2.07 (d, 1H), 2.20 (d, 1H), 3.96 (s, 3H), 5.12 (d, 1H), 5.46 (br, 1H), 5.81 (d, 1H), 6.44-6.53 (m, 3H), 6.95 (d, 1H), 7.06 (d, 1H), 7.32 (t, 1H), 8.28 (d, 1H), 9.92 (s, 1H).
EXAMPLE 183
cis-5-{[2,5-Dihydroxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
1H-NMR (300 MHz, CDCl3); δ=1.58 (s, 3H), 1.76 (s, 3H), 2.08 (d, 1H), 2.24 (d, 1H), 2.63 (s, 1H), 5.11 (d, 1H), 5.54 (s, 1H), 5.85 (d, 1H), 5.97 (s, 1H), 6.42 (d, 1H), 6.49 (d, 1H), 6.49 (d, 1H), 6.52 (d, 1H), 7.00 (dd, 1H), 7.31 (t, 1H), 8.31 (d, 1H), 9.77 (s, 1H).
EXAMPLE 184
cis-7′-Fluoro-4′-[(8-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalen]-3′-ol
3-[1-(3-Fluoro-2-methoxyphenyl)-cyclohexyl]-2-hydroxy-2-(trifluoromethyl)propanal
385 ml of a 0.5 molar (182 mmol) solution of bis-(trimethylsilyl)-potassium amide in toluene is added in drops to 26.5 g (184 mmol) of 2,6-difluoroanisole and 24 ml (198 mmol) of cyclohexylcyanide in 500 ml of toluene at 0° C. over 40 minutes. It is stirred for 18 hours at room temperature and mixed with water while being cooled with ice, and the solution is set at a pH of 4 with 4N hydrochloric acid.
The organic phase is separated, and the aqueous phase is extracted several times with diethyl ether. It is washed with brine, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 5%-10%), 28.5 g of 1-(3-fluoro-2-methoxyphenyl)-cyclohexylnitrile is obtained. 27.5 g (118 mmol) of the nitrile is slowly mixed in 430 ml of toluene at −78° C. with 147 ml (176 mmol) of diisobutyl aluminum hydride solution (20% in toluene), and after 3 hours at −78° C., 35 ml of isopropanol is added in drops. It is allowed to heat to −5° C., and 600 ml of a 10% aqueous tartaric acid solution is added. After dilution with ether, it is stirred vigorously, the organic phase is separated, and the aqueous phase is extracted several times with ethyl acetate. It is washed with brine, dried with sodium sulfate, and concentrated by evaporation in a vacuum. 27.5 g of aldehyde is obtained as a yellow oil. A solution of 5.7 g (21.2 mmol) of 2-diethylphosphono-2-ethoxyacetic acid-ethyl ester in 25 ml of tetrahydrofuran is mixed, while being cooled with ice, within 15 minutes with 13.6 ml (27.2 mmol) of a 2 M solution of lithium diisopropylamide in tetrahydrofuran-heptane-toluene, and it is stirred for 20 minutes at 0° C. Within 30 minutes, a solution of 5 g (21.2 mmol) of 1-(3-fluoro-2-methoxyphenyl)-cyclohexylformanal in 5 ml of tetrahydrofuran is added in drops at 0° C. After 16 hours at room temperature, ice water is added, and it is extracted several times with ether. It is washed with saturated ammonium chloride solution, dried on sodium sulfate, and concentrated by evaporation. The crude product is saponified with 6 g of sodium hydroxide in 100 ml of ethanol and 50 ml of water over 4 days at room temperature. 1.7 g of acid, which is stirred over 30 hours at 90° C. with 35 ml of 2N sulfuric acid and 7 ml of acetic acid, is obtained. After cooling, it is made basic with potassium carbonate, washed with ether and acidified with hydrochloric acid. After extraction with ethyl acetate, washing with saturated sodium chloride solution and removal of the solvent, 1.09 g of crude keto acid is obtained. 1.09 g (3.7 mmol) of 3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionic acid and 0.45 ml of sulfuric acid (96%) are refluxed in 40 ml of ethanol for 2 hours. The batch is concentrated by evaporation in a vacuum, the residue is added to ice water and made basic with saturated sodium bicarbonate solution. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 20%), 1.05 g of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionate is obtained.
1.05 g (3.3 mmol) of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclohexyl]-2-oxopropionate and 0.74 ml (5 mmol) of (trifluoromethyl)-trimethylsilane in 7 ml of THF are mixed with 62 mg of tetramethylammonium fluoride at −40° C. It is stirred for 2 hours at −25° C., and then another 0.35 ml (2.4 mmol) of (trifluoromethyl)-trimethylsilane and 62 mg of tetramethylammonium fluoride are added. After another 2 hours, 1 ml of 2N hydrochloric acid is added, and the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-40%), 800 mg of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)-propionate is obtained as a yellow oil. This oil is mixed in 40 ml of diethyl ether at 0° C. with 150 g (4 mmol) of lithium aluminum hydride and stirred for 2.5 more hours at room temperature. 20 ml of saturated ammonium chloride solution is carefully added to the batch at 0° C., and it is stirred vigorously for 15 minutes. It is extracted several times with diethyl ether, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-15%), 630 g of 3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-(trifluoromethyl)-propane-1,2-diol is obtained.
1H-NMR (CDCl3): δ=1.44-1.87 (m, 10H), 2.19-2.38 (m, 4H), 3.15-3.42 (br, 2H), 3.96 (s, 3H), 6.9 (ddd, 1H), 7.01 (d, 1H), 7.16 (ddd, 1H).
1.6 ml (11 mmol) of triethylamine and, in portions over 10 minutes, 1.4 g (70 mmol) of pyridine SO3 complex are added to 700 mg (2 mmol) of diol in 20 ml of dichloromethane and 7.8 ml of DMSO. It is stirred over 3 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and the desired aldehyde is obtained quantitatively.
cis-7′-Fluoro-4′-[(8-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalen]-3′-ol
1H-NMR (300 MHz, CDCl3); δ=1.25-1.85 (m, 8H), 2.00 (d, 1H), 2.44 (ddd, 1H), 2.64 (ddd, 1H), 2.91 (s, 3H), 2.92 (d, 1H), 4.00 (s, 3H), 4.96 (d, 1H), 5.41 (d, 1H), 6.66 (dd, 1H), 6.93 (dd, 1H), 7.04 (dd, 1H), 7.47 (dd, 1H), 9.34 (s, 1H).
EXAMPLE 185
cis-7′-Fluoro-4′-[(8-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalene]-3′,8′-diol
1H-NMR (300 MHz, CD3OD); δ=1.22-1.85 (m, 8H), 2.03 (d, 1H), 2.82 (ddd, 1H), 2.85 (s, 3H), 2.91 (d, 1H), 3.05 (ddd, 1H), 5.22 (s, 1H), 680-6.95 (m, 3H), 7.56 (dd, 1H), 9.65 (s, 1H).
EXAMPLE 186
cis-7′-Fluoro-4′-[(7-Fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalen]-3′-ol
1H-NMR (300 MHz, CDCl3); δ=1.25-1.90 (m, 10H), 2.17 (d, H), 2.34 (d, 1H), 2.80 (s, 3H), 3.56 (s, 3H), 4.59 (d, 1H), 5.33 (d, 1H), 6.91 (dd, 1H), 7.00 (dd, 1H), 7.10 (dd, 1H), 7.17 (dd, 1H), 9.03 (s, 1H).
EXAMPLE 187
cis-5-{7′-Fluoro-3′,4′-dihydro-3′-hydroxy-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalen-4′-yl]amino}-quinolin-2(1H)-one
1H-NMR (300 MHz, CDCl3); δ=1.25-1.90 (m, 8H), 2.09 (d, 1H), 2.41 (ddd, 1H), 2.60 (ddd, 1H), 2.90 (d, 1H), 3.99 (s, 3H), 4.85 (s, 1H), 5.00 (d, 1H), 5.67 (d, 1H), 6.48-6.55 (m, 3H), 6.83 (dd, 1H), 6.96 (dd, 1H), 7.31 (t, 1H), 8.22 (d, 1H), 9.79 (s, 1H).
EXAMPLE 188
cis-6-Chloro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
1H-NMR (300 MHz, CD3OD); δ=1.61 (s, 3H), 1.74 (s, 3H), 2.18 (s, 2H), 2.79 (s, 3H), 5.42 (s, 1H), 6.76-6.82 (m, 3H), 7.15 (d, 1H), 9.54 (s, 1H).
EXAMPLE 189
cis-6-Chloro-1-[(2-methylquinazolin-5-yl)amino]4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
1H-NMR (300 MHz, CD3OD); δ=1.61 (s, 3H), 1.74 (s, 3H), 2.18 (s, 2H), 2.82 (s, 3H), 5.40 (s, 1H), 6.84 (d, 1H), 6.95 (d, 1H), 7.10 (d, 1H), 7.20 (d, 1H), 7.79 (t, 1H), 9.62 (s, 1H).
EXAMPLE 190
cis-5-{7′-Chloro-3,4′-dihydro-3′,8′-dihydroxy-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalen-4′-yl]-amino}-quinolin-2(1H)-one
1H-NMR (300 MHz, CD3OD); δ=1.25-1.90 (m, 8H), 2.02 (d, 1H), 2.80 (ddd, 1H), 2.91 (d, 1H), 3.05 (ddd, 1H), 5.12 (d, 1H), 5.51 (d, 1H), 6.59 (d, 1H), 6.69 (d, 1H), 6.81 (dd, 1H), 6.986 (dd, 1H), 7.37 (t, 1H), 8.23 (d, 1H).
EXAMPLE 191
cis-6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal
1.0 g (3.54 mmol) of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-oxo-4-methyl-valerate and 0.98 g (5.1 mmol) of (pentafluoroethyl)-trimethylsilane in 7 ml of THF are mixed with 65 mg (0.7 mmol) of tetramethylammonum fluoride at −40° C. The reaction mixture is heated to −25° C. and stirred at this temperature. After 4.5 hours, 1 ml of 2N hydrochloric acid is added, and the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. 1.65 g of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)valerate is obtained as a crude product. The ester is mixed in 80 ml of diethyl ether at 0° C. with 300 mg (8 mmol) of lithium aluminum hydride and stirred for 3.5 more hours at room temperature. A little water is carefully added to the batch at 0° C., and it is stirred vigorously for 15 more minutes. It is filtered by Cellite, and the precipitate is rewashed thoroughly with ethyl acetate. The filtrate is dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-15%), 800 mg of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-(pentafluoroethyl)pentane-1,2-diol is obtained. 1.8 ml (13 mmol) of triethylamine and, in portions over 10 minutes, 1.6 g (10 mmol) of pyridine SO3 complex are added to 800 mg (2.2 mmol) of diol in 25 ml of dichloromethane and 8.9 ml of DMSO. It is stirred for 2.5 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and the desired aldehyde is obtained quantitatively.
1H-NMR (CDCl3): δ=1.40 (s, 3H), 1.46 (s, 3H), 2.35 (d, 1H), 3.28 (d, 1H), 3.60 (s, 1H), 4.02 (s, 3H), 6.86 (dd, 1H), 6.91 (ddd, 1H), 7.01 (ddd, 1H), 9.14 (s, 1H).
cis-6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1H-NMR (300 MHz, CDCl3); δ=1.55 (s, 3H), 1.69 (s, 3H), 2.13 (d, 1H), 2.20 (d, 1H), 2.92 (s, 3H), 3.97 (s, 3H), 5.08 (d, 1H), 5.41 (d, 1H), 6.70 (dd, 1H), 6.90 (dd, 1H), 7.00 (dd, 1H), 7.48 (dd, 1H), 9.33 (s, 1H).
EXAMPLE 192
cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-6-fluoro-5-methoxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1H-NMR (300 MHz, CD3OD); δ=1.55 (s, 3H), 1.68 (s, 3H), 2.14 (d, 1H), 2.21 (d, 1H), 2.84 (s, 3H), 3.97 (s, 3H), 5.39 (s, 1H), 6.88 (dd, 1H), 6.98 (dd, 1H), 7.03 (dd, 1H), 9.59 (s, 1H).
EXAMPLE 193
cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-6-fluoro-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
1H-NMR (300 MHz, CDCl3); δ=1.61 (s, 3H), 1.72 (s, 3H), 2.15 (d, 1H), 2.22 (d, 1H), 2.91 (s, 3H), 5.00 (d, 1H), 5.61 (br, 1H), 5.71 (d, 1H), 6.56 (dd, 1H), 6.83 (dd, 1H), 6.92 (dd, 1H), 9.24 (s, 1H).
EXAMPLE 194
cis-5-{[6-Fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
1H-NMR (300 MHz, CDCl3); δ=1.54 (s, 3H), 1.69 (s, 3H), 2.07 (d, 1H), 2.17 (d, 1H), 3.97 (s, 3H), 4.58 (br, 1H), 5.10 (d, 1H), 5.45 (d, 1H), 6.52-6.56 (m, 3H), 6.83 (dd 1H), 6.94 (dd, 1H), 7.34 (t, 1H), 8.12 (d, 1H), 10.11 (s, 1H).
EXAMPLE 195
cis-6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
1H-NMR (300 MHz, CDCl3); δ=1.61 (s, 3H), 1.72 (s, 3H), 2.15 (d, 1H), 2.23 (d, 1H), 2.92 (s, 3H), 5.08 (d, 1H), 5.38 (d, 1H), 5.64 (br, 1H), 6.70 (dd, 1H), 6.85 (dd, 1H), 6.90 (dd, 1H), 7.48 (dd, 1H), 9.33 (s, 1H).
EXAMPLE 196
cis-4′-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-7′-fluoro-3′,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalen]-3′-ol
Ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionate
396 ml of a 0.5 molar (198 mmol) solution of bis-(trimethylsilyl)-potassium amide in toluene is added in drops at 0° C. over 40 minutes to 26 g (180 mmol) of 2,6-difluoroanisole and 14.6 ml (198 mmol) of cyclopropylcyanide in 500 ml of toluene. It is stirred for 18 hours at room temperature and mixed with water and 1 M sulfuric acid while being cooled with ice. The organic phase is separated, and the aqueous phase is extracted several times with ethyl acetate. It is washed with brine, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-20%), 12.7 g of 1-(3-fluoro-2-methoxyphenyl)-cyclopropylnitrile is obtained. 12.7 g (66.1 mmol) of the nitrile is slowly mixed in toluene at −78° C. with 82.7 ml (99.2 mmol) of diisobutyl aluminum hydride solution (20% in toluene), and after 3 hours at −78° C., 11.1 ml of isopropanol is added in drops. It is allowed to heat to −5° C., and 150 ml of a 10% aqueous tartaric acid solution is added. After dilution with ether, it is stirred vigorously, the organic phase is separated, and the aqueous phase is extracted several times with ethyl acetate. It is washed with brine, dried with sodium sulfate, and concentrated by evaporation in a vacuum. 11.8 g of aldehyde is obtained as a yellow oil. A solution of 16.3 g (60.7 mmol) of 2-diethylphosphono-2-ethoxyacetic acid-ethyl ester in 60 ml of tetrahydrofuran is mixed while being cooled with ice within 20 minutes with 33.4 ml (66.8 mmol) of a 2 M solution of lithium diisopropylamide in tetrahydrofuran-heptane-toluene and stirred for 30 minutes at 0° C. Within 30 minutes, a solution of 11.8 g (60.7 mmol) of 1 in 61 ml of tetrahydrofuran is added in drops at 0° C. After 20 hours at room temperature, ice water is added, and it is extracted several times with ether and ethyl acetate. It is washed with saturated ammonium chloride solution, dried on sodium sulfate and concentrated by evaporation. The crude product is saponified with 170 ml of 2 M sodium hydroxide solution in 170 ml of ethanol for 15 hours at room temperature. 13.9 g of acid, which is stirred with 87 ml of 2N sulfuric acid at 90° C. over 16 hours, is obtained. After cooling, it is made basic with potassium carbonate, washed with ether and acidified with hydrochloric acid. After extraction with ethyl acetate, washing with saturated sodium chloride solution and removal of the solvent, 10.2 g of the crude keto acid is obtained. 10.2 g (40.6 mmol) of 3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionic acid and 4.5 ml (85.3 mmol) of sulfuric acid (96%) are refluxed in 200 ml of ethanol for 1 hour. The batch is concentrated by evaporation in a vacuum, the residue is added to ice water and made basic with saturated sodium bicarbonate solution. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 20%), 9.6 g of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionate is obtained.
1H-NMR (CDCl3): δ=0.90 (m, 4H), 1.29 (t, 3H), 3.09 (s, 2H), 3.99 (d, 3H), 4.20 (q, 2H), 6.87 (ddd, 1H), 6.95 (ddd, 1H), 7.07 (d, 1H), 9.26.
3-[1-(3-Fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)propanal
9.6 g (34.3 mmol) of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionate and 34.5 ml (233 mmol) of (trifluoromethyl)-trimethylsilane in 343 ml of DMF are mixed with 46.9 g of cesium carbonate at 0° C. It is stirred for 2 hours at 0° C. and then the reaction solution is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-40%), 10.4 g of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)-propionate is obtained as a yellow oil. This oil is mixed in 297 ml of diethyl ether at 0° C. with 2.25 g (59.4 mmol) of lithium aluminum hydride and stirred for one more hour at room temperature. 20 ml of saturated ammonium chloride solution is carefully added to the batch at 0° C., and it is stirred vigorously for 15 more minutes. It is extracted several times with diethyl ether, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-50%), 5.6 g of 3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-(trifluoromethyl)-propane-1,2-diol is obtained. 12.4 ml (89 mmol) of triethylamine and, in portions over 10 minutes, 11 g (70 mmol) of pyridine/SO3 complex are added to 5.6 g (18.1 mmol) of diol in 100 ml of dichloromethane and 61 ml of DMSO. It is stirred over 3 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and after chromatographic purification on silica gel (hexane/ethyl acetate, 0-50%), 5.9 g of product is obtained.
1H-NMR (CDCl3): δ=0.68-0.76 (m, 2H), 0.90-1.02 (m, 2H), 2.03 (d, 1H), 2.91 (d, 1H), 3.85 (s, 1H), 4.03 (s, 3H), 6.80 (d, 1H), 6.87 (ddd, 1H), 6.98 (dd, 1H), 9.26 (s, 1H).
cis-4′-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-7′-fluoro-3′,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalen]-3′-ol
1H-NMR (300 MHz, CD3OD); δ=0.83 (ddd, 1H), 0.99 (ddd, 1H), 1.42 (ddd, 1H), 1.89 (ddd, 1H), 2.01 (d, 1H), 2.15 (d, 1H), 2.84 (s, 3H), 3.85 (s, 3H), 5.19 (s, 1H), 6.65 (dd, 1H), 6.96 (dd, 1H), 7.04 (dd, 1H), 9.63 (s, 1H).
EXAMPLE 197
cis-7′-Fluoro-3′,4′-dihydro-8′-methoxy-4′-[(2-methylquinazolin-5-yl)amino]-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalen]-3′-ol
1H-NMR (300 MHz, CDCl3); δ=0.82 (ddd, 1H), 1.00 (ddd, 1H), 1.54 (ddd, 1H), 1.86 (ddd, 1H), 1.91 (d, 1H), 2.32 (d, 1H), 2.84 (s, 3H), 3.87 (s, 3H), 5.08 (d, 1H), 5.78 (d, 1H), 6.67 (d, 1H), 6.88 (dd, 1H), 7.05 (dd, 1H), 7.28 (d, 1H), 7.70 (t, 1H), 9.36 (s, 1H).
EXAMPLE 198
cis-7′-Fluoro-3′,4′-dihydro-4′-[(2-methylquinazolin-5-yl)amino]-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalene-3′,8′-diol
1H-NMR (300 MHz, CD3OD); δ=0.67 (ddd, 1H), 0.90 (ddd, 1H), 1.77 (ddd, 1H), 1.93 (d, 1H), 2.12 (ddd, 1H), 2.21 (d, 1H), 2.81 (s, 3H), 5.28 (s, 1H), 6.75-6.88 (m, 3H), 7.18 (d, 1H), 7.78 (t, 1H), 9.65 (s, 1H).
EXAMPLE 199
cis-4′-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-7′-fluoro-3′,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalene]-3′,8′-diol
1H-NMR (300 MHz, CDCl3); δ=0.71 (ddd, 1H), 0.91 (ddd, 1H), 1.81 (d, 1H), 1.83-2.00 (m, 2H), 2.39 (d, 1H), 2.87 (s, 3H), 4.98 (d, 1H), 5.75 (d, 1H), 6.49 (dd, 1H), 6.78-6.89 (m, 2H), 9.28 (s, 1H).
EXAMPLE 200
cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-5-fluoro-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1H-NMR (300 MHz, CD3OD); δ=1.53 (s, 3H), 1.65 (s, 3H), 2.17 (s, 2H), 2.84 (s, 3H), 3.85 (s, 3H), 5.32 (s, 1H), 6.87 (dd, 1H), 6.95 (dd, 1H), 7.07 (d, 1H), 9.61 (s, 1H).
EXAMPLE 201
cis-1-[(7,8-Difluoro-2-methylquinazolin-5-yl)amino]-5-fluoro-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol
1H-NMR (300 MHz, CD3OD); δ=1.54 (s, 3H), 1.66 (s, 3H), 2.16 (s, 2H), 2.84 (s, 3H), 3.98 (s, 3H), 5.29 (s, 1H), 6.78 (dd, 1H), 6.86 (dd, 1H), 6.94 (dd, 1H), 9.60 (s, 1H).
EXAMPLE 202
cis-7′-Fluoro-4′-[(8-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalene]-3′,8′-diol
1H-NMR (300 MHz, CDCl3); δ=0.71 (ddd, 1H), 0.93 (ddd, 1H), 1.79 (d, 1H), 1.90-2.06 (m, 2H), 2.39 (d, 1H), 2.91 (s, 3H), 3.80 (br, 1H), 5.05 (d, 1H), 5.39 (d, 1H), 5.48 (br, 1H), 6.65 (dd, 1H), 6.80-6.90 (m, 2H), 7.46 (dd, 1H), 9.35 (s, 1H).
EXAMPLE 203
cis-7′-Fluoro-4′-[(7-Fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalene]-3′,8′-diol
1H-NMR (300 MHz, CDCl3); δ=1.20-2.10 (m, 10H), 2.10 (d, 1H), 2.47 (d, 1H), 2.68 (s, 3H), 4.66 (d, 1H), 5.33 (d, 1H), 6.91 (d, 2H), 7.03 (dd, 1H), 7.10 (dd, 1H), 9.01 (s, 1H).
EXAMPLE 204
cis-6-Chloro-5-methoxy-1-[(2-methylquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1H-NMR (300 MHz, CD3OD); δ=1.56 (s, 3H), 1.69 (s, 3H), 2.16 (s, 2H), 2.72 (s, 3H), 3.97 (s, 3H), 5.25 (s, 1H), 6.82 (d, 1H), 7.11 (d, 1H), 7.20 (d, 1H), 7.32 (d, 1H), 7.36 (d, 1H), 7.55 (t, 1H), 8.45 (d, 1H).
EXAMPLE 205
cis-6-Chloro-1-[(2-methylquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
1H-NMR (300 MHz, CD3OD); δ=1.61 (s, 3H), 1.73 (s, 3H), 2.12 (d, 1H), 2.18 (d, 1H), 2.72 (s, 3H), 5.23 (s, 1H), 6.82 (d, 1H), 6.87 (d, 1H), 7.11 (d, 1H), 7.31 (d, 1H), 7.35 (d, 1H), 7.55 (t, 1H), 8.45 (d, 1H).
EXAMPLE 206
cis-1-[(2-Methyl-1-quinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol-N-oxide
1H-NMR (300 MHz, CD3OD); δ=1.44 (s, 3H), 1.58 (s, 3H), 2.19 (s, 2H), 2.76 (s, 3H), 5.35 (s, 1H), 7.00 (dd, 1H), 7.12 (t, 1H), 7.27-7.34 (m, 2H), 7.45-7.52 (m, 2H), 7.71 (t, 1H), 7.96 (d, 1H), 8.29 (d, 1H).
EXAMPLE 207
cis-6-Chloro-1-[(2-methylquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol N-oxide
75 mg of 70% meta-chloroperbenzoic acid is added to 84 mg (0.19 mmol) of cis-6-chloro-1-[(2-methylquinolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol in 8 ml of dichloromethane, and the solution is stirred for two hours. 50 mg of solid sodium bicarbonate is added, and it is poured into water after 30 minutes. It is extracted with dichloromethane, washed with saturated sodium chloride solution, and dried on sodium sulfate. After concentration by evaporation and chromatography on silica gel (hexane/ethyl acetate 0-100%), 58 mg of the title compound is obtained.
1H-NMR (300 MHz, CD3OD); δ=1.61 (s, 3H), 1.73 (s, 3H), 2.13 (d, 1H), 2.18 (d, 1H), 2.75 (s, 3H), 5.30 (s, 1H), 6.85 (d, 1H), 7.01 (d, 1H), 7.13 (d, 1H), 7.48 (d, 1H), 7.70 (t, 1H), 7.96 (d, 1H), 8.27 (d, 1H).
EXAMPLE 208
cis-6-[1(2-Methyl-quinolin-5-yl)amino]-9,9-dimethyl-7-(trifluoromethyl)-6,7,8,9-tetrahydro-naphtho[1,2-d]-1,3-dioxol-7-ol N-oxide
1H-NMR (300 MHz, CDCl3); δ=1.49 (s, 3H), 1.58 (s, 3H), 2.06 (d, 1H), 2.20 (d, 1H), 2.61 (s, 3H), 5.08 (d, 1H), 5.62 (d, 1H), 5.99 (s, 2H), 6.64 (d, 1H), 6.83 (d, 1H), 6.85 (d, 1H), 7.13 (d, 1H), 7.55 (t, 1H), 7.96 (d, 1H), 8.03 (d, 1H).
EXAMPLE 209
cis-7′-Fluoro-4′-[(7-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalene]-3′,8′-diol
1H-NMR (300 MHz, CD3OD); δ=0.66 (ddd, 1H), 0.89 (ddd, 1H), 1.86 (ddd, 1H), 1.93 (d, 1H), 2.10 (ddd, 1H), 2.22 (d, 2H), 2.78 (s, 3H), 5.26 (s, 1H), 6.67 (dd, 1H), 6.75-6.82 (m, 2H), 6.87 (dd, 1H), 9.58 (s, 1H).
EXAMPLE 210
cis-5-{7′-Fluoro-3′,4′-dihydro-3′,8′-dihydroxy-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalen-4′-yl]-amino}-quinolin-2(1H)-one
1H-NMR (300 MHz, CD3OD); δ=0.66 (ddd, 1H), 0.90 (ddd, 1H), 1.71 (ddd, 1H), 1.88 (d, 1H), 2.09 (ddd, 1H), 2.20 (d, 2H), 5.15 (s, 1H), 6.51-6.54 (m, 2H), 6.70 (d, 1H), 6.79 (dd, 1H), 6.85 (dd, 1H), 7.36 (t, 1H), 8.25 (d, 1H).
EXAMPLE 211
cis-7′-Chloro-4′-[(7-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalene]-3′,8′-diol
1H-NMR (300 MHz, CDCl3); δ=0.70 (ddd, 1H), 0.91 (ddd, 1H), 1.70 (ddd, 1H), 1.77 (d, 1H), 2.08 (ddd, 1H), 2.44 (d, 1H), 2.82 (s, 3H), 5.06 (d, 1H) 5.77 (s, 1H), 5.88 (d, 1H), 6.44 (dd, 1H), 6.88 (d, 1H), 6.91 (dd, 1H), 7.13 (d, 1H), 9.23 (s, 1H).
EXAMPLE 212
cis-7′-Chloro-3′,4′-dihydro-4′-[(2-methylquinolin-5-yl)amino]-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalene]-3′,8′-diol
1H-NMR (300 MHz, CD3OD); δ=0.68 (ddd, 1H), 0.91 (ddd, 1H), 1.69 (ddd, 1H), 1.91 (d, 1H), 2.11 (ddd, 1H), 2.22 (d, 1H), 2.72 (s, 3H), 5.20 (s, 1H), 6.70 (d, 1H), 6.78-6.85 (m, 2H), 7.30 (d, 1H), 7.36 (d, 1H), 7.53 (t, 1H), 8.47 (d, 1H).
EXAMPLE 213
cis-7′-Chloro-3′,4′-dihydro-4′-[(2-methyl-quinolin-5-yl)amino]-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalene]-3′,8′-diol N-oxide
1H-NMR (300 MHz, CD3OD); δ=0.67 (ddd, 1H), 0.91 (ddd, 1H), 1.74 (ddd, 1H), 1.91 (d, 1H), 2.10 (ddd, 1H), 2.23 (d, 1H), 2.75 (s, 3H), 5.25 (s, 1H), 6.78 (dd, 1H), 6.84 (dd, 1H), 6.90 (d, 1H), 7.49 (d, 1H), 7.69 (t, 1H), 7.95 (d, 1H), 8.30 (d, 1H).
EXAMPLE 214
cis-7′-Chloro-4′-[(7-fluoro-2-methylquinazolin-5-yl)amino]-3,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalen]-3′-ol
1H-NMR (300 MHz, CDCl3); δ=1.20-1.85 (m, 8H), 2.05 (d, 1H), 2.44 (ddd, 1H), 2.63 (ddd, 1H), 2.82 (s, 3H), 2.97 (d, 1H), 4.00 (s, 3H), 4.95 (d, 1H), 5.92 (d, 1H), 6.49 (dd, 1H), 6.91 (dd, 1H), 7.04 (d, 1H), 7.22 (d, 1H), 9.16 (s, 1H).
EXAMPLE 215
cis-7′-Chloro-4′-[(7-fluoro-2-methylquinazolin-5-yl)amino]-3,4′-dihydro-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalene]-3′,8′-diol
1H-NMR (300 MHz, CDCl3); δ=1.25-1.85 (m, 8H), 1.86 (d, 1H), 2.79 (ddd, 1H), 2.82 (s, 3H), 2.93 (ddd, 1H), 2.97 (d, 1H), 4.95 (d, 1H), 5.85 (d, 1H), 6.14 (s, 1H), 6.48 (dd, 1H), 6.89-6.93 (m, 2H), 7.19 (d, 1H), 9.19 (s, 1H).
EXAMPLE 216
cis-7′-Chloro-3′,4′-dihydro-4′-[(2-methylquinazolin-5-yl)amino]-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalene-3′,8′-diol
1H-NMR (300 MHz, CD3OD); δ=0.69 (ddd, 1H), 0.92 (ddd, 1H), 1.71 (ddd, 1H), 1.95 (d, 1H), 2.13 (ddd, 1H), 2.20 (d, 1H), 2.81 (s, 3H), 5.29 (s, 1H), 6.85 (d, 2H), 7.10 (d, 1H), 7.19 (d, 1H), 7.78 (t, 1H), 9.65 (d, 1H).
EXAMPLE 217
(−)-2-Chloro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8,-tetrahydro-naphthalene-1,6-diol and
(+)-2-Chloro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5.6.7,8,-tetrahydro-naphthalene-1,6-diol
(−)-6-Chloro-1-(1H-indazol-4-ylamino)-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol and
(+)-6-Chloro-1-(1H-indazol-4-ylamino)-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
The racemic compound (324.2 mg), produced according to the processes described in the above examples, is separated in the ether stage on a chiral column (Chiralpak AD 20 μ, eluant hexane/ethanol) into its enantiomers. 122.8 mg of the (−)-enantiomer and 147.1 mg of the (+)-enantiomer are obtained.
(−)-Enantiomer: [α]D=−0.8 (c=1, MeOH)
(+)-Enantiomer: [α]D=−1.0 (c=1, MeOH)
(−)-2-Chloro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8,-tetrahydro-naphthalene-1,6-diol and
(+)-2-Chloro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8,-tetrahydro-naphthalene-1,6-diol
24 mg (21.4%) of the phenol is obtained from 115.8 mg of the (−)-enantiomeric ether by ether cleavage with BBr3.
91.5 mg (66.9%) of the phenol is obtained from 141.2 mg of the (+)-enantiomeric ether by ether cleavage with BBr3.
EXAMPLE 218
5-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
4-(2-Methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal:
Analogously to Example 7, 687 mg of ethyl-4-(2-methoxyphenyl)-4-methyl-2-oxopentanoate (WO 00/32584) with 1 g of (pentafluoroethyl)trimethylsilane and 0.5 ml of (tetrabutylammonium fluoride solution (1 M in THF)) in 18 ml THF are reacted to form g of ethyl-4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)-pentanoate. 450 mg of the ester that is obtained in 12 ml of diethyl ether is mixed in portions at 0° C. with 66 mg of lithium aluminum hydride. After stirring for 11 hours, it is added to saturated bicarbonate solution and filtered through diatomaceous earth. The phases are separated, and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation. 420 mg of diol is obtained as a yellow oil. 400 mg of the diol is oxidized to the corresponding aldehyde with 0.11 ml of oxalyl chloride, 0.21 ml of DMSO and 1 ml of triethylamine. It is washed with water and brine, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 0→5%), 268 mg of the title compound is obtained as a yellow oil.
1H-NMR (CDCl3), δ (ppm)=1.39 (s, 3H), 1.46 (s, 3H), 2.26 (d, 1H), 3.46 (d, 1H), 3.88 (s, 3H), 6.77-6.95 (m, 2H), 7.11 (dd, 1H), 7.13-7.28 (m, 1H), 8.95 (s, 1H)
5-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-(pentafluoroethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
Analogously to Example 10, the corresponding imine is produced starting from 180 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal and 83 mg of 5-aminoquinolin-2(1H)-one. 7 mg of the title compound is obtained by reaction of 70 mg of the imine with 58 mg of aluminum trichloride in 1.5 ml of dichloromethane.
1H-NMR (CD3OD): δ=1.52 (s, 3H), 1.66 (s, 3H), 2.09 (d, 1H), 2.15 (d, 1H), 3.85 (s, 3H), 5.27 (s, 1H), 6.51 (d, 1H), 6.62 (d, 1H), 6.70 (d, 1H), 6.92 (d, 2H), 7.11 (dd, 1H), 7.38 (t, 1H), 8.23 (d, 1H)
EXAMPLE 219
5-{[6-Chloro-4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-6-methylquinolin-2(1H)-one
5-Amino-6-methylquinolin-2(1H)-one
4.12 g of 2-chloro-6-methylquinoline (J. Med. Chem. 1992, pp. 2761-2768) is added at 0° C. to a solution that consists of 15 ml of 100% nitric acid and 2 ml of 96% sulfuric acid. After 4 hours at 0° C., it is added to water, and the product is filtered off. 4.66 g of 2-chloro-6-methyl-5-nitroquinoline is obtained as a beige solid. The latter is reacted for 80 hours at 100° C. in 46 ml of glacial acetic acid and 26 ml of water. The thus obtained 6-methyl-5-nitroquinolin-2(1H)-one is filtered off from the reaction solution. The 3.45 g of product that is obtained is reacted on activated carbon to form aniline with hydrogen under normal pressure in methanol on palladium. 2.89 g of the title compound is obtained as a beige solid.
1H-NMR (DMSO): δ=2.08 (s, 3H), 5.56 (s, 2H), 6.25 (d, 1H), 6.42 (d, 1H), 7.06 (d, 1H═, 8.18 (d, 1H), 11.32 (s, 1H)
5-{[6-Chloro-4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-6-methylquinolin-2(1H)-one
Analogously to Example 10, the corresponding imine is produced starting from 500 mg of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 300 mg of 5-amino-6-methylquinolin-2(1H)-one. 10 mg of the title compound is obtained by reaction of 80 mg of the imine with 2.5 ml of titanium tetrachloride solution (1 M in dichloromethane) in 4.3 ml of dichloromethane.
1H-NMR (DMSO): δ=1.57 (s, 3H), 1.68 (s, 3H), 1.87 (d, 1H), 2.12 (d, 1H), 2.38 (s, 3H), 3.88 (s, 3H), 4.87 (d, 1H), 5.85 (d, 1H), 5.96 (d, 1H), 6.62 (d, 1H), 6.81 (d, 1H), 7.11 (d, 1H), 7.44 (d, 1H), 8.42 (s, 1H), 11.57 (s, 1H)
EXAMPLE 220
5-{[2,5-Dihydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2( 1H)-one
Analogously to Example 3, 19 mg of the title compound is obtained starting from 74 mg of the compound of Example 41 with 0.48 ml of BBr3 solution (1 M in dichloromethane) at 40° C.
1H-NMR (CD3OD): δ=1.53 (s, 3H), 1.65 (s, 3H), 2.01 (d, 1H), 2.10 (s, 3H), 2.12 (d, 1H), 5.10 (s, 1H), 6.47-6.56 (m, 2H), 6.58-6.65 (m, 2H), 6.69 (d, 1H), 7.39 (t, 1H), 8.22 (d, 1H)
EXAMPLE 221
5-{[2-Hydroxy-5-methoxy-2-(pentafluoroethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
4-(2-Methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal
Analogously to the synthesis of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)-pentanal, 1.05 g of the title compound is obtained starting from 1.7 g of ethyl-4-(2-methoxy-4-methylphenyl)-4-methyl-2-oxopentanoate (Example 41) with 1.4 g of (pentafluoroethyl)trimethylsilane, subsequent reduction with 344 mg of lithium aluminum hydride and ultimate oxidation under Swern conditions.
1H-NMR (CDCl3): δ=1.36 (s, 3H), 1.42 (s, 3H), 2.23 (d, 1H), 2.32 (s, 3H), 3.48 (d, 1H), 3.64 (s, 1H), 3.87 (s, 3H), 6.67 (s, 1H), 6.71 (d, 1H), 6.97 (d, 1H), 8.93 (s, 1H)
5-{[2-Hydroxy-5-methoxy-2-(pentafluoroethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
Analogously to Example 10, the corresponding imine is produced starting from 200 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal and 93 mg of 5-aminoquinolin-2(1H)-one. 2 mg of the title compound is obtained by reaction of 80 mg of the imine with 1.6 ml of titanium tetrachloride solution (1 M in dichloromethane) in 5 ml of dichloromethane.
1H-NMR (CD3OD): δ=1.48 (s, 3H), 1.62 (s, 3H), 2.05 (d, 1H), 2.12 d, 1H), 2.16 (s, 3H), 3.83 (s, 3H), 5.21 (s, 1H), 6.52 (d, 1H), 6.62 (d, 1H), 6.71 (d, 1H), 6.75 (s, 2H), 7.40 (t, 1H), 8.23 (d, 1H)
EXAMPLE 222
5-{[2-Hydroxy-5-methoxy-2-(trifluoromethyl)-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
Ethyl-4-(2-methoxy-3-methylphenyl)-4-methyl-2-oxopentanoate
Analogously to Example 7, methyl-2-methoxy-3-methylbenzoate is produced from 30 g of 3-methylsalicylic acid and 60 ml of methyl iodide with 125 g of potassium carbonate in 640 ml of DMF. The ester is reacted to form 1-(2-methoxy-4-methylphenyl)-1-methylethanol by reaction with 129 ml of methylmagnesium chloride (3 M in THF) in 435 ml of THF. 20.8 g of the product that is obtained is reacted with 27.1 g of 2-(trimethylsilyloxy)-acrylic acid ethyl ester in 410 ml of dichloromethane at 0° C. with 10.4 ml of tin tetrachloride to form 12.63 g of the title compound.
1H-NMR (300 MHz, CDCl3): δ=1.28 (t, 3H), 1.48 (s, 6H), 2.29 (s, 3H), 3.37 (s, 2H), 3.76 (s, 3H), 4.14 (q, 2H), 6.95 (t, 1H), 7.05 (d, 1H), 7.13 (d, 1H)
4-(2-Methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
Analogously to Example 7, 14.68 g of ethyl-4-(2-methoxy-4-methylphenyl)-4-methyl-2-oxopentanoate is reacted with 21.6 ml of (trifluoromethyl)trimethylsilane and 9.7 ml of tetrabutylammonium fluoride solution (1 M in THF) in 195 ml of THF to form 13.73 g of ethyl-4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoate. The product is reduced with 2.84 g of lithium aluminum hydride in 560 ml of diethyl ether to 11.62 g of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol. The oxidation of the diol is carried out analogously to Example 7 under Swern conditions with 3.8 ml of oxalyl chloride, 7.1 ml of DMSO and 26.5 ml of triethylamine to 5.91 g of the title compound.
1H-NMR (CDCl3): δ=1.44 (s, 3H), 1.48 (s, 3H), 2.22 (d, 1H), 3.36 (d, 1H), 3.83 (s, 3H), 6.90-7.12 (m, 3H), 8.93 (s, 1H)
5-{[2-Hydroxy-5-methoxy-2-(trifluoromethyl)-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
Analogously to Example 10, the corresponding imine is produced starting from 600 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 315 mg of 5-aminoquinolin-2(1H)-one. 12 mg of the title compound is obtained by reaction of 370 mg of the imine with 8.3 ml of titanium tetrachloride (1 M in dichloromethane) in 20 ml of dichloromethane.
1H-NMR (CD3OD): δ=1.52 (s, 3H), 1.67 (s, 3H), 2.10 (s, 2H), 2.30 (s, 3H), 3.79 (s, 3H), 5.16 (s, 1H), 6.51 (d, 1H), 6.61 (d, 1H), 6.70 (d, 1H), 7.00 (s, 2H), 7.38 (t, 1H), 8.21 (d, 1H)
EXAMPLES 223 AND 224
4-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide and 4-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino }-phthalide
Analogously to Example 10, the corresponding imine is produced starting from 600 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 308 mg of 4-aminophthalide. By reaction of 640 mg of the imine with 7.7 ml of bromotribromide solution (1 M in dichloromethane), 165 mg of 4-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide as fraction 1 and 115 mg of 4-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide as fraction 2 are obtained.
Fraction 1: 1H-NMR (CDCl3): δ=1.40 (s, 3H), 1.49 (s, 3H), 2.03 (d, 1H), 2.13 (d, 1H), 3.17 (d, 1H), 3.32 (s, 1H), 3.90 (s, 3H), 5.01 (d, 1H), 5.11-5.24 (m, 2H), 6.66 (d, 1H), 7.03 (d, 1H), 7.21-7.32 (m, 2H), 7.39-7.50 (m, 2H)
Fraction 2: 1H-NMR (CD3OD): δ=1.55 (s, 3H), 1.67 (s, 3H), 2.04 (d, 1H), 2.12 (d, 1H), 5.15 (s, 1H), 5.21 (d, 1H), 5.32 (d, 1H), 6.70 (d, 1H), 6.84 (d, 1H), 6.96 (t, 1H), 7.07 (d, 1H), 7.18 (d, 1H), 7.42 (t, 1H)
EXAMPLE 225 AND 226
(−)-4-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide and
(+)-4-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide
Separation of (±)-4-{[4,4-Dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide
The enantiomer mixture is separated by chromatography on chiral carrier material (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (95:5, vvv). Thus obtained are the
(−)-Enantiomer: MS (EI): M+=421, [α]D−79.3° (c =0.9, CHCl3) and the
(+)-Enantiomer: MS (EI): M+=421
EXAMPLES 227 AND 228
(−)-4-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide and
(+)-4-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide
Separation of (±)-4-{[2,5-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide
The enantiomer mixture is separated by chromatography on chiral carrier material (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10, vvv). Thus obtained are the
(−)-Enantiomer: MS (EI): M+=407, [α]D−66.0°° (c =1.0, CHCl3) and the
(+)-Enantiomer: MS (EI): M+=407
EXAMPLE 229
5-{[5-Methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
Analogously to Example 10, the corresponding imine is produced starting from 500 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 288 mg of 5-amino-2-methylphthalazin-1-one. As in Example 3, 90 mg of the imine is reacted by reaction with 0.4 ml of titanium tetrachloride (1 M in dichloromethane) in 5 ml of dichloromethane, and 25 mg of the title compound is obtained.
1H-NMR (DMSO): δ=1.42 (s, 3H), 1.57 (s, 3H), 1.95 (d, 1H), 2.05 (d, 1H), 2.14 (s, 3H), 3.70 (s, 3H), 3.80 (s, 3H), 5.38 (d, 1H), 5.98 (s, 1H), 6.57 (d, 1H), 6.66 (s, 1H), 6.80 (s, 1H), 7.25 (d, 1H), 7.47 (d, 1H), 7.58 (t, 1H), 8.63 (s, 1H)
EXAMPLES 230 AND 231
(−)-5-{[5-Methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one and
(+)-5-{[5-Methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
Separation of (±)-5-{[5-Methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
The enantiomer mixture is separated by chromatography on chiral carrier material (CHIRALPAK AD®), DAICEL Company) with ethanol as an eluant. Thus obtained are the
(−)-Enantiomer: MS (EI): M+=461 and the
(+)-Enantiomer: MS (EI): M+=461, [α]D+4.9°° (c=0.7, CHCl3)
EXAMPLE 232
5-{[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
Analogously to Example 10, the corresponding imine is produced starting from 1.0 g of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 542 mg of 5-amino-2-methyl-phthalazin-1-one. As in Example 3, 840 mg of the imine is reacted by reaction with 43.6 ml of titanium tetrachloride (1 M in dichloromethane) in 40 ml of dichloromethane, and 114 mg of the title compound is obtained.
1H-NMR (DMSO): δ=1.47 (s, 3H), 1.61 (s, 3H), 2.00 (d, 1H), 2.14 (d, 1H), 3.71 (s, 3H), 3.88 (s, 3H), 5.46 (d, 1H), 6.17 (s, 1H), 6.61 (d, 1H), 7.00 (d, 1H), 7.27 (d, 1H), 7.33 (d, 1H), 7.49 (d, 1H), 7.60 (t, 1H), 8.64 (s, 1H)
EXAMPLES 233 AND 234
(−)-5-{[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one and
(+)-5-{[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
Separation of (±)-5-{[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
The enantiomer mixture is separated by chromatography on chiral carrier material (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10, vvv). Thus obtained are the
(−)-Enantiomer: MS (EI): M+=481/483 and the
(+)-Enantiomer: MS (EI): M+=481/483, [α]D+10.6°° (c=0.8, CHCl3)
EXAMPLE 235
5-{[6-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-amino}-2-methylphthalazin-1-one
Analogously to Example 3, 19 mg of the title compound is obtained starting from 20 mg of 5-{[6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one with 0.13 ml of BBr3 solution (1 M in dichloromethane) at 40° C.
1H-NMR (DMSO): δ=1.52 (s, 3H), 1.65 (s, 3H), 2.00 (d, 1H), 2.11 (d, 1H), 3.70 (s, 3H), 5.42 (d, 1H), 6.07 (s, 1H), 6.58 (d, 1H), 6.74 (d, 1H), 7.20 (d, 1H), 7.26 (d, 1H), 7.47 (d, 1H), 7.58 (t, 1H), 8.63 (s, 1H), 9.09 (s, 1H)
EXAMPLE 236
(−)-5-{[6-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-amino}-2-methylphthalazin-1-one
Analogously to Example 3, 23 mg of the title compound is obtained starting from 26 mg of (−)-5-{[6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one with 0.5 ml of BBr3 solution (1 M in dichloromethane) in 0.25 ml of dichloromethane at 40° C.
1H-NMR (DMSO): δ=1.52 (s, 3H), 1.65 (s, 3H), 2.00 (d, 1H), 2.11 (d, 1H), 3.70 (s, 3H), 5.42 (d, 1H), 6.07 (s, 1H), 6.58 (d, 1H), 6.74 (d, 1H), 7.20 (d, 1H), 7.26 (d, 1H), 7.47 (d, 1H), 7.58 (t, 1H), 8.63 (s, 1H), 9.09 (s, 1H)
EXAMPLE 237
(+)-5-{[6-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-amino}-2-methylphthalazin-1-one
Analogously to Example 3, 12 mg of the title compound is obtained starting from 20 mg of (+)-5-{[6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one with 0.4 ml of BBr3 solution (1 M in dichloromethane) in 0.25 ml of dichloromethane at 40° C.
1H-NMR (DMSO): δ=1.52 (s, 3H), 1.65 (s, 3H), 2.00 (d, 1H), 2.11 (d, 1H), 3.70 (s, 3H), 5.42 (d, 1H), 6.07 (s, 1H), 6.58 (d, 1H), 6.74 (d, 1H), 7.20 (d, 1H), 7.26 (d, 1H), 7.47 (d, 1H), 7.58 (t, 1H), 8.63 (s, 1H), 9.09 (s, 1H)
EXAMPLE 238
(+)-5-{[2,5-Dihydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-amino}-2-methylphthalazin-1-one
Analogously to Example 3, 19 mg of the title compound is obtained starting from 20 mg of 5-{[5-methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one with 0.13 ml of BBr3 solution (1 M in dichloromethane) at 40° C.
1H-NMR (DMSO): δ=1.46 (s, 3H), 1.60 (s, 3H), 1.94 (d, 1H), 2.01 (d, 1H), 2.06 (s, 3H), 3.70 (s, 3H), 5.35 (d, 1H), 5.92 (s, 1H), 6.51 (s, 1H), 6.53-6.63 (m, 2H), 7.26 (d, 1H), 7.46 (d, 1H), 7.57 (t, 1H), 8.63 (s, 1H), 9.31 (s, 1H)
EXAMPLE 239
5-{[5-Methoxy-2-hydroxy-2-(trifluoromethyl)-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
Analogously to Example 10, the corresponding imine is produced starting from 600 mg of 4-(3-methyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 316 mg of 5-amino-2-methylphthalazin-1-one. As in Example 3, 460 mg of the imine is reacted by reaction with 5.2 ml of titanium tetrachloride (1 M in dichloromethane) in 23 ml of dichloromethane, and 36 mg of the title compound is obtained.
1H-NMR (DMSO): δ=1.45 (s, 3H), 1.60 (s, 3H), 1.96 (d, 1H), 2.10 (d, 1H), 2.24 (s, 3H), 3.70 (s, 3H), 3.72 (s, 3H), 5.40 (d, 1H), 6.03 (s, 1H), 6.57 (d, 1H), 6.87 (d, 1H), 7.03 (d, 1H), 7.25 (d, 1H), 7.46 (d, 1H), 7.58 (t, 1H), 8.63 (s, 1H)
EXAMPLE 240
5-{[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-one
Analogously to Example 10, the corresponding imine is produced starting from 1.0 g of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 494 mg of 5-amino-phthalazin-1-one. As in Example 3, 775 mg of the imine is reacted by reaction with 24.9 ml of titanium tetrachloride (1 M in dichloromethane) in 46 ml of dichloromethane, and 483 mg of the title compound is obtained.
1H-NMR (DMSO): δ=1.47 (s, 3H), 1.61 (s, 3H), 1.99 (d, 1H), 2.13 (d, 1H), 3.88 (s, 3H), 5.45 (d, 1H), 6.17 (s, 1H), 6.57 (d, 1H), 7.00 (d, 1H), 7.28 (d, 1H), 7.33 (d, 1H), 7.46 (d, 1H), 7.57 (t, 1H), 8.61 (s, 1H), 12.56 (s, 1H)
EXAMPLES 241 AND 242
(−)-5-{[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-one and
(+)-5-{[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-one
Separation of (±)-5-{[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-one
The enantiomer mixture is separated by chromatography on chiral carrier material (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10, vvv). Thus obtained are the
(−)-Enantiomer: flash point=267-270° C. and the
(+)-Enantiomer: flash point=263-265° C., [α]D+6.5°° (c=1.2, CHCl3)
EXAMPLE 243
5-{[6-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-amino}-phthalazin-1-one
Analogously to Example 3, 19 mg of the title compound is obtained starting from 20 mg of 5-{[6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-one with 0.13 ml of BBr3 solution (1 M in dichloromethane) at 40° C.
1H-NMR (DMSO): δ=1.43 (s, 1H), 1.56 (s, 3H), 1.91 (d, 1H), 2.01 (d, 1H), 5.33 (d, 1H), 6.00 (s, 1H), 6.44 (d, 1H), 6.65 (d, 1H), 7.12 (d, 1H), 7.18 (d, 1H), 7.36 (d, 1H), 7.49 (t, 1H), 8.52 (s, 1H), 9.02 (s, 1H), 12.46 (s, 1H)
EXAMPLE 244
(−)-5-{[6-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-amino}-2-methylphthalazin-1-one
Analogously to Example 3, 94 mg of the title compound is obtained starting from 100 mg of (−)-5-{[6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-one with 2.1 ml of BBr3 solution (1 M in dichloromethane) in 1 ml of dichloromethane at 40° C.
1H-NMR (DMSO): δ=1.43 (s, 1H), 1.56 (s, 3H), 1.91 (d, 1H), 2.01 (d, 1H), 5.33 (d, 1H), 6.00 (s, 1H), 6.44 (d, 1H), 6.65 (d, 1H), 7.12 (d, 1H), 7.18 (d, 1H), 7.36 (d, 1H), 7.49 (t, 1H), 8.52 (s, 1H), 9.02 (s, 1H), 12.46 (s, 1H)
EXAMPLE 245
(+)-5-{[6-Chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-amino}-phthalazin-1-one
Analogously to Example 3, 82 mg of the title compound is obtained starting from 100 mg of (+)-5-{[6-chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-one with 2.1 ml of BBr3 solution (1 M in dichloromethane) in 1 ml of dichloromethane at 40° C.
1H-NMR (DMSO): δ=1.43 (s, 1H), 1.56 (s, 3H), 1.91 (d, 1H), 2.01 (d, 1H), 5.33 (d, 1H), 6.00 (s, 1H), 6.44 (d, 1H), 6.65 (d, 1H), 7.12 (d, 1H), 7.18 (d, 1H), 7.36 (d, 1H), 7.49 (t, 1H), 8.52 (s, 1H), 9.02 (s, 1H), 12.46 (s, 1H)
EXAMPLE 246
5-{[2-Hydroxy-5-methoxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-one
Analogously to Example 10, the corresponding imine is produced starting from 500 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 287 mg of 5-amino-phthalazin-1-one. As in Example 3, 320 mg of the imine is reacted by reaction with 7.2 ml of titanium tetrachloride (1 M in dichloromethane) in 20 ml of dichloromethane, and 80 mg of the title compound is obtained.
1H-NMR (DMSO): δ=1.43 (s, 1H), 1.57 (s, 3H), 1.95 (d, 1H), 2.06 (d, 1H), 2.15 (s, 3H), 3.80 (s, 3H), 5.38 (d, 1H), 5.99 (s, 1H), 6.53 (d, 1H), 6.66 (s, 1H), 6.79 (s, 1H), 7.25 (d, 1H), 7.44 (d, 1H), 7.57 (t, 1H), 8.61 (s, 1H), 12.54 (s, 1H)
EXAMPLES 247 AND 248
(−)-5-{[2-Hydroxy-5-methoxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-one and
(+)-5-{[2-Hydroxy-5-methoxy-2-(trifluoromethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
Separation of (±)-5-{[6-Chloro-4,4-dimethyl-5-methoxy-2-hydroxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
The enantiomer mixture is separated by chromatography on chiral carrier material (CHIRALPAK AD®, DAICEL Company) with ethanol as an eluant. Thus obtained are the
(−)-Enantiomer: MS (EI): M+=447, [α]D−3.4°° (c=0.7, CHCl3) and the
(+)-Enantiomer: MS (EI): M+=447, [α]D+3.7°° (c=1.1, CHCl3)
EXAMPLE 249
5-{[2-Hydroxy-5-methoxy-2-(pentafluoroethyl)-4,4,7-trimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalazin-1-one
Analogously to Example 10, the corresponding imine is produced starting from 250 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal and 118 mg of 5-amino-phthalazin-1-one. As in Example 3, 65 mg of the imine is reacted by reaction with 0.38 ml of titanium tetrachloride (1 M in dichloromethane) in 6 ml of dichloromethane, and 8 mg of the title compound is obtained.
1H-NMR (CD3OD): δ=1.40 (s, 1H), 1.55 (s, 3H), 2.19 (d, 1H), 2.29 (d, 1H), 2.33 (s, 3H), 3.47 (s, 3H), 5.46 (s, 1H), 6.61 (s, 1H), 6.90 (s, 1H), 7.54-7.63 (m, 2H), 7.63-7.73 (m, 2H), 8.43 (s, 1H)
EXAMPLE 250
5-{[6-Chloro-4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-8-fluoro-quinolin-2(1H)-one
5-Amino-8-fluoroquinolin-2(1H)-one
10 g of 2,5-difluoroaniline and 6 g of pyridine in 350 ml of dichloromethane are mixed drop by drop at 0° C. with 12.9 g of cinnamic acid chloride and stirred until the conversion is completed at 0° C. The batch is added to 2N hydrochloric acid, and it is extracted with dichloromethane. It is washed with water, dried with sodium sulfate, and concentrated by evaporation in a vacuum. The solid that is obtained is mixed with 11.1 g of aluminum chloride and heated for 8 hours to 150° C. After chromatography on silica gel, 2.9 g of 5,8-difluoroquinolin-2(1H)-one is obtained. The latter is reacted in 100 ml of ethylene glycol in the presence of 780 mg of copper (II) oxide for 20 hours at 200° C. in an ammonia atmosphere at 60 bar. After chromatography on silica gel, in this case, 5-amino-8-fluoroquinolin-2(1H)-one is obtained as fraction A and 2,5-diamino-8-fluoroquinoline is obtained as fraction B.
Fraction A: 1H-NMR (DMSO): δ=5.73 (s, 2H), 6.28 (dd, 1H), 6.35 (d, 1H), 7.07 (dd, 1H), 8.08 (dd, 1H), 11.31 (s, 1H).
Fraction B: 1H-NMR (DMSO): δ=5.36 (s, 2H), 6.23 (dd, 1H), 6.47 (s, 2H), 6.63 (d, 1H), 6.96 (dd, 1H), 8.07 (dd, 1H).
5-{[6-Chloro-4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-8-fluoro-quinolin-2(1H)-one
Analogously to Example 10, the corresponding imine is produced starting from 250 g of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 137 mg of 5-amino-8-fluoroquinolin-2(1H)-one. The title compound is obtained analogously to Example 3 by reaction of the formed imine with 1.4 ml of titanium tetrachloride (1 M in dichloromethane).
1H-NMR (CD3OD): δ=1.53 (s, 3H), 1.67 (s, 3H), 2.22 (s, 2H), 3.96 (s, 3H), 5.14 (s, 1H), 6.51-6.61 (m, 2H), 7.09 (d, 1H), 7.20 (d, 1H), 7.24 (dd, 1H), 8.21 (dd, 1H).
EXAMPLE 251
2-Amino-5-{[6-chloro-4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-8-fluoro-quinoline
Analogously to Example 10, the corresponding imine is produced starting from 250 g of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 137 mg of 2,5-diamino-8-fluoroquinoline. The title compound is obtained analogously to Example 3 by reaction of the formed imine with 1.0 ml of titanium tetrachloride solution (1 M in dichloromethane).
1H-NMR (CD3OD): δ=1.54 (s, 3H), 1.67 (s, 3H), 2.20 (s, 2H), 3.94 (s, 3H), 5.11 (s, 1H), 6.43 (dd, 1H), 6.81 (d, 1H), 7.11 (d, 1H), 7.15 (d, 1H), 7.20 (d, 1H), 8.18 (dd, 1H).
EXAMPLES 252 AND 253
5-{[4,4-Dimethyl-6-fluoro-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-8-fluoro-quinolin-2(1H)-one and
2-Amino-5-{[4,4-dimethyl-6-fluoro-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-8-fluoro-quinoline
Analogously to Example 10, a mixture of the corresponding imines is produced starting from 237 g of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 137 mg of a mixture that consists of 5-amino-8-fluoroquinolin-2(1H)-one and 2,5-diamino-8-fluoroquinoline. Analogously to Example 3, the mixture of imines with 2.5 ml of titanium tetrachloride solution (1 M in dichloromethane) is reacted, and the two title compounds are obtained after chromatography on silica gel.
Fraction A: 1H-NMR (CD3OD): δ=1.53 (s, 3H), 1.65 (s, 3H), 2.08 (d, 1H), 2.23 (d, 1H), 3.95 (d, 3H), 5.11 (s, 1H), 6.50-6.61 (m, 2H), 6.98 (dd, 1H), 7.06 (dd, 1H), 7.23 (dd, 1H), 8.22 (dd, 1H).
Frcktion B: 1H-NMR (CD3OD): δ=1.52 (s, 3H), 1.66 (s, 3H), 2.08 (d, 1H), 2.15 (d, 1H), 3.95 (d, 1H), 5.09 (s, 1H), 6.40-6.57 (m, 2H), 6.82 (d, 1H), 6.94 (dd, 1H), 7.02-7.20 (m, 2H), 8.18 (t, 1H).
EXAMPLE 254
5-{[7-Fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclobutane-1,1′-naphthalen-4-yl]amino}-quinolin-2(1H)-one
3-{(3-Fluoro-2-methoxyphenyl)-cyclobutyl}-2-hydroxy-2-(trifluoromethyl)-pentanal
Analogously to the synthesis of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal in Example 3, 3-{(3-fluoro-2-methoxyphenyl)-cyclobutyl}-2-hydroxy-2-(trifluoromethyl)-pentanal is obtained starting from 2,6-difluoroanisole and cyclobutanecarbonitrile.
1H-NMR (CDCl3): δ=1.75-1.90 (m, 1H), 2.10-2.40 (m, 3H), 2.46-2.57 (m, 2H), 2.83 (d, 1H), 3.00 (d, 1H), 3.94 (d, 3H), 6.75 (dt, 1H), 6.83-7.02 (m, 2H), 8.94 (s, 1H).
5-{[7-Fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclobutane-1,1′-naphthalen-4-yl]amino}-quinolin-2(1H)-one
Analogously to Example 10, the corresponding imine is produced starting from 350 g of 3-{(3-fluoro-2-methoxyphenyl)cyclobutyl}-2-hydroxy-2-(trifluoromethyl)pentanal and 200 mg of 5-amino-quinolin-2(1H)-one. Analogously to Example 3, the imine is reacted with 1.6 ml of titanium tetrachloride solution (1 M in dichloromethane), and 35 mg of the title compound is obtained.
1H-NMR (CD3OD): δ=2.10-2.29 (m, 4H), 2.40-2.56 (m, 1H), 2.65-2.80 (m, 2H), 2.93-3.06 (m, 1H), 4.09 (d, 3H), 5.14 (s, 1H), 6.49 (d, 1H), 6.63 (d, 1H), 6.70 (d, 1H), 6.97 (d, 2H), 8.20 (d, 1H).
EXAMPLE 255
5-{[3,8-Dihydroxy-7-fluoro-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclobutane-1,1′-naphthalen-4-yl]amino}-quinolin-2(1H)-one
Analogously to Example 3, 12 mg of the title compound is obtained starting from 20 mg of 5-{[7-fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclobutane-1,1′-naphthalen-4-yl]amino}-quinolin-2( 1H)-one with 0.22 ml of BBr3 solution (1 M in dichloromethane) at room temperature.
1H-NMR (CD3OD): δ=1.81-1.94 (m, 1H), 2.08-2.27 (m, 3H), 2.28-2.41 (m, 1H), 2.75 (d, 1H), 3.08 (q, 1H), 3.44 (q, 1H), 5.13 (s, 1H), 6.48 (d, 1H), 6.63 (d, 1H), 6.68 (d, 1H), 6.73 (dd, 1H), 6.90 (dd, 1H), 7.37 (t, 1H), 8.20 (d, 1H).
EXAMPLE 256
5-{[7-Fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopentane-1,1′-naphthalen-4-yl]amino}-quinolin-2(1H)-one
3-{(3-Fluoro-2-methoxyphenyl)-cyclopentyl}-2-hydroxy-2-(trifluoromethyl)-pentanal
Analogously to the synthesis of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal in Example 3, 3-{(3-fluoro-2-methoxyphenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethyl-pentanal is obtained starting from 2,6-difluoroanisole and cyclopentanecarbonitrile.
1H-NMR (CD3ID): δ=1.15-2.26 (m, 8H), 2.33 (d, 1H), 3.11 (d, 1H), 3.57 (s, 1H), 3.98 (d, 3H), 6.82-6.93 (m, 2H), 6.94-7.05 (m, 1H), 8.98 (s, 1H).
5-{[7-Fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopentane-1,1′-naphthalen-4-yl]amino}-quinolin-2(1H)-one
Analogously to Example 10, the corresponding imine is produced starting from 350 g of 3-{(3-fluoro-2-methoxyphenyl)cyclobutyl}-2-hydroxy-2-(trifluoromethyl)pentanal and 190 mg of 5-amino-quinolin-2(1H)-one. Analogously to Example 3, the imine is reacted with 5.25 ml of titanium tetrachloride solution (1 M in dichloromethane), and 193 mg of the title compound is obtained.
1H-NMR (CDCl3): δ=1.53-1.67 (m, 1), 1.73-2.15 (m, 6H), 2.28-2.48 (m, 3H), 3.95 (d, 3H), 4.81 (bs, 1H), 5.06 (d, 1H), 5.55 (d, 1H), 6.47-6.58 (m, 3H), 6.82 (dd, 1H) 6.93 (dd, 1H), 7.32 (t, 1H), 8.18 (d, 1H).
EXAMPLE 257
5-{[3,8-Dihydroxy-7-fluoro-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopentane-1,1′-naphthalen-4-yl]amino}-quinolin-2(1H)-one
Analogously to Example 3, 17 mg of the title compound is obtained starting from 60 mg of 5-{[7-fluoro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopentane-1,1′-naphthalen-4-yl]amino}-quinolin-2(1H)-one with 0.25 ml of BBr3 solution (1 M in dichloromethane) at room temperature.
1H-NMR (CD3OD): δ=1.45-1.57 (m, 1H), 1.72-1.88 (m, 2H), 1.90-2.12 (m, 3H), 2.18-2.43 (m, 3H), 2.70-2.85 (m, 1H), 5.18 (s, 1H), 6.51 (d, 1H), 6.63 (d, 1H), 6.70 (d, 1H), 6.78 (dd, 1H), 6.87 (dd, 1H), 7.38 (t, 1H), 8.22 (d, 1H).
EXAMPLE 258
5-{[2,5-Dihydroxy-4,4-dimethyl-7-fluoro-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
Analogously to Example 10, the corresponding imine is produced starting from 1.0 g of 4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 560 mg of 5-amino-2-methylphthalazin-1-one. As in Example 3, the imine that is formed is reacted by reaction with 10 ml of boron tribromide solution (1 M in dichloromethane), and 45 mg of the title compound is obtained.
1H-NMR (DMSO): δ=1.47 (s, 3H), 1.59 (s, 3H), 1.97 (d, 1H), 2.07 (d, 1H), 3.70 (s, 3H), 5.41 (s, 1H), 6.11 (s, 1H), 6.41 (dd, 1H), 6.56 (dd, 1H), 7.27 (d, 1H), 7.48 (d, 1H), 7.59 (t, 1H), 8.63 (s, 1H), 10.00 (s, 1H).
EXAMPLES 259 AND 260
(−)-5-{[2,5-Dihydroxy-4,4-dimethyl-7-fluoro-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one and
(+)-5-{[2,5-Dihydroxy-4,4-dimethyl-7-fluoro-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
Separation of (±)-5-{[2,5-Dihydroxy-4,4-dimethyl-7-fluoro-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
The enantiomer mixture is separated by chromatography on chiral support material (CHIRALPAK AD®, DAICEL Company) with hexane/ethanol (90:10, vvv). Thus obtained are the
(−)-Enantiomer: MS (EI): M+=451, [α]D−34.6°° (c=1.3, CHCl3) and the
(+)-Enantiomer: MS (EI): M+=451, [α]D+35.4°° (c=1.3, CHCl3).
EXAMPLES 261 AND 262
5-{[7-Bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one, Diastereomer B and
5-{[7-Bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one, Diastereomer A
Analogously to Example 10, the corresponding imine is produced starting from 800 mg of 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 380 mg of 5-amino-2-methylphthalazin-1-one. As in Example 3, the imine that is formed is reacted by reaction with 9.4 ml of boron tribromide solution (1 M in dichloromethane), and 37 mg of diastereomer B of 5-{[7-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one as fraction A and 11 mg of diastereomer A of 5-{[7-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one as fraction B are obtained.
Fraction A: 1H-NMR (CD3OD): δ=1.40 (s, 3H), 1.55 (s, 3H), 1.92 (d, 1H), 2.25 (d, 1H), 3.84 (s, 3H), 5.27 (s, 1H), 6.70 (d, 1H), 7.19-7.29 (m, 2H), 7.51 (t, 1H), 7.60 (d, 1H), 8.52 (s, 1H).
Fraction B: 1H-NMR (CD3OD): δ=1.55 (s, 3H), 1.66 (s, 3H), 2.07 (d, 1H), 2.15 (d, 1H), 3.83 (s, 3H), 5.24 (s, 1H), 6.88 (d, 1H), 6.94 (d, 1H), 7.18-7.28 (m, 1H), 7.62-7.70 (m, 2H), 8.56 (s, 1H).
EXAMPLE 263
5-{[7-Chloro-3,8-dihydroxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane-1,1′-naphthalen-4-yl)]amino}-quinolin-2(1H)-one
3-[1-(3-Chloro-2-methoxyphenyl)-cyclohexyl]-2-hydroxy-2-(trifluoromethyl)propanal
9.57 g (30.79 mmol) of 3-[1-(3-chloro-2-methoxyphenyl)-cyclohexyl]-2-oxopropionic acid (starting from the corresponding starting materials, this compound was produced analogously according to the instructions described in WO 98/54159) is mixed with 191 ml of ethanol and 3.4 ml of concentrated sulfuric acid. After five hours of refluxing, the batch is spun in until a dry state is reached, and the residue is mixed with 500 ml of saturated sodium bicarbonate solution. The aqueous phase is extracted three times with ethyl acetate, and the combined organic extracts are washed with brine. After the solvent is dried and spun off, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 7.07 g (67.8%) of the desired ester is obtained.
7.07 g (20.87 mmol) of ethyl-3-[1-(3-chloro-2-methoxyphenyl)-cyclohexyl]-2-oxopropionate is dissolved in 33 ml of tetrahydrofuran and mixed with 3.56 g (25.04 mmol) of (trifluoromethyl)-trimethylsilane. After 51.1 mg of tetrabutylammonium fluoride is added, the batch is stirred overnight. The reaction mixture is diluted with methyl tert-butyl ether, washed once with water and then with brine. After the usual working-up, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). The isolated 5.71 g (60.4%) of the product is mixed in 70 ml of tetrahydrofuran with 3.98 g (12.61 mmol) of tetrabutylammonium fluoride and stirred for one hour at room temperature. After the reaction mixture is mixed with water, it is extracted with metyl-tert-butyl ether. After the usual working-up, the residue is chromatographed on a Flashmaster. 2.63 g (51.1%) of the desired compound: ethyl-2-[1-(3-chloro-2-methoxyphenyl)-cyclohexylmethyl]-3,3,3-trifluoro-2-hydroxypropionate is isolated.
1.59 g (3.89 mmol) of the above-described ester is dissolved in 14 ml of diethyl ether and mixed at 0° C. in portions with 110.7 mg (2.92 mmol) of lithium aluminum hydride. After two hours of stirring between 0 and 5° C., 3.4 ml of saturated sodium bicarbonate solution is carefully added in drops. It is stirred vigorously at room temperature for ten minutes. After repeated extraction of the aqueous phase with methyl tert-butyl ether, the combined organic extracts are treated as usual. After chromatography on a Flashmaster, 750 mg (52.8%) of a mixture is obtained, which consists of two thirds of the desired aldehyde and one third of the ester. In addition, 201.4 mg of the corresponding alcohol (contaminated) is obtained.
5-{2-[1-(3-Chloro-2-methoxyphenyl)-cyclohexylmethyl]-3,3,3-trifluoro-2-hydroxy-propylidenamino}-1H-quinolin-2-one
375 mg (0.683 mmol) of the aldehyde that is described in the preceding section (together with the ester) is refluxed in 3.6 ml of xylene with 109.4 mg (0.683 mmol) of 5-amino-1H-quinolin-2-one and 388.3 mg (1.366 mmol) of titanium(IV) isopropylate for three hours. After cooling, the reaction mixture is mixed with saturated sodium chloride solution and ethyl acetate. After ten minutes of vigorous stirring, the mixture is added to Extrelut and eluted with 100 ml of dichloromethane. After the solvent is spun off, the remaining residue is chromatographed on a Flashmaster. In addition to 145 mg of ester, 231.6 mg (66.9%, relative to the content of aldehyde) of the desired imine is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.15-2.18 (9H), 2.38-2.65 (2H), 2.96 (1H), 3.93 (3H), 4.61 (1H), 6.40-6.60 (2H), 6.62-6.81 (2H), 7.08 (1H), 7.29-7.59 (3H), 8.07 (1H), 12.28 (1H).
5-{[7-Chloro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane-1,1′-naphthalen-4-yl)]amino}-quinolin-2(1H)-one
151.6 mg (0.299 mmol) of the above-described imine is dissolved in 2.8 ml of dichloromethane. After the dropwise addition of 1.96 ml (1.796 mmol) of titanium tetrachloride at −15° C., it is stirred for four hours at this temperature. At 0° C., saturated sodium bicarbonate solution is carefully added, and the reaction mixture is extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried, and the solvent is spun off. After chromatography on a Flashmaster, 67.9 mg (44.8%) of the desired compound is obtained.
1H-NMR (300 MHz, CD3OD): δ=1.30-1.90 (8H), 2.18 (1H), 2.30-2.50 (1H), 2.53-2.70 (1H), 2.90 (1H), 4.00 (3H), 5.19 (1H), 6.52 (1H), 6.62 (1H), 6.70 (1H), 7.09 (1H), 7.23 (1H), 7.38 (1H), 8.23 (1H).
5-{[7-Chloro-3,8-dihydroxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane-1,1′-naphthalen-4-yl)]amino}-quinolin-2(1H)-one
65.9 mg (0.13 mmol) of the cyclic ether that is described in the preceding section is mixed with 2.6 ml of boron tribromide (1 M in dichloromethane) and stirred for three hours at room temperature. At −5° C., saturated sodium bicarbonate solution is carefully added in drops, and the reaction mixture is then extracted three times with ethyl acetate. The combined organic extracts are dried via sodium sulfate, and the residue that remains after the solvent is spun off is chromatographed on a Flashmaster. 51.3 mg (80.1%) of the desired phenol is isolated.
1H-NMR (300 MHz, DMSO-d6): δ=1.15-1.87 (8H), 2.01 (1H), 2.40-2.90 (3H, the DMSO signal lies in this range), 5.29 (1H), 6.02 (1H), 6.20 (1H), 6.43 (1H), 6.48-6.65 (2H), 6.75 (1H), 7.15-7.30 (2H), 8.20 (1H), 9.10 (1H), 11.58 (1H).
EXAMPLE 264
5-{[7-Chloro-3,8-dihydroxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane-1,1′-naphthalen-4-yl)]amino}-2H-isoquinolin-1-one
5-{[7-Chloro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane-1,1′-naphthalen-4-yl)]amino}-2H-isoquinolin-1-one
149.7 mg (0.295 mmol) of the imine (produced according to the instructions described in Example 263, with use of the corresponding starting materials) is cyclized with 1.93 ml (1.772 mmol) of titanium tetrachloride. After the usual working-up and chromatography, 34.9 m (23.3%) of the desired compound is obtained.
1H-NMR (300 MHz, DMSO-d6): δ=1.20-1.85 (8H), 2.05-2.50 (3H), 2.69 (1H), 3.93 (3H), 5.34 (1H), 5.98 (1H), 6.13 (1H), 6.80 (1H), 6.97 (1H), 7.05 (1H), 7.18 (1H), 7.20-7.38 (2H), 7.50 (1H), 11.25 (1H).
5-{[7-Chloro-3,8-dihydroxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclohexane-1,1′-naphthalen-4-yl)]amino}-2H-isoquinolin-1-one
26.8 mg (0.053 mmol) of the above-described ether is subjected to ether cleavage as described in Example 263. After the reaction is carried out in the usual way and after the chromatography, 13.5 g (51.8%) of the desired phenol is obtained.
1H-NMR (300 MHz, DMSO-d6): δ=1.15-1.85 (8H), 2.00 (1H), 2.40-2.90 (3H), 5.30 (1H), 5.95 (1H), 6.09 (1H), 6.73 (1H), 6.81 (1H), 7.04 (1H), 7.10-7.30 (3H), 7.50 (1H), 9.12 (1H), 11.23 (1H).
EXAMPLE 265
7′-Chloro-4′-[(8-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclohexane-1,1′(2′H)-naphthalen]-3′-ol
1.61 ml (1.488 mmol) of titanium(IV) chloride is added in drops to 129.8 mg (0.248 mmol) of the corresponding imine, dissolved in 2.4 ml of dichloromethane, at −20° C. After one and one-half hours of stirring in the temperature range of between −20° C. and +5° C., the batch is worked up as usual. After chromatography on a Flashmaster, 11.4 mg (8.8%) of the desired compound is isolated.
MS (CI): 524 (100%)
EXAMPLE 266
5-{[7-Chloro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopropyl-1,1′-naphthalen-4-yl)]amino}-quinolin-2(1H)-one
3-[1-(3-Chloro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)propanal
15.12 g (56.27 mmol) of 3-[1-(3-chloro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionic acid (starting from the corresponding starting materials, this compound was produced analogously according to the instructions described in WO 98/54159) is mixed with 350 ml of ethanol and 6.3 ml of concentrated sulfuric acid. After five hours of refluxing, the batch is spun in until a dry state is reached, and the residue is mixed with 700 ml of saturated sodium bicarbonate solution. The aqueous phase is extracted three times with ethyl acetate, and the combined organic extracts are washed with sodium bicarbonate solution and brine. After the solvent is dried and spun off, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 12.36 g (74%) of the desired ester is obtained.
6.18 g (20.83 mmol) of ethyl-3-[1-(3-chloro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionate is dissolved in 33 ml of tetrahydrofuran and mixed with 3.55 g (24.99 mmol) of (trifluoromethyl)-trimethylsilane. After 51 mg of tetrabutylammonium fluoride is added, the batch is stirred overnight. The reaction mixture is diluted with methyl tert-butyl ether, washed once with water and then with brine. After the usual working-up, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). The isolated 5.65 g (66.4%) of the product is mixed in 76 ml of tetrahydrofuran with 4.34 g (13.75 mmol) of tetrabutylammonium fluoride and stirred for one hour at room temperature. After the reaction mixture is mixed with water, it is extracted with methyl tert-butyl ether. After the usual working-up, the residue is chromatographed on a Flashmaster. 2.39 g (47.4%) of the desired compound: ethyl-2-[1-(3-chloro-2-methoxyphenyl)-cyclopropylmethyl]-3,3,3-trifluoro-2-hydroxypropionate is isolated.
0.850 mg (2.32 mmol) of the above-described ester is dissolved in 8 ml of diethyl ether and mixed in portions at 0° C. with 66 mg (1.74 mmol) of lithium aluminum hydride. After two hours of stirring between 0 and 5° C., 2.7 ml of saturated sodium bicarbonate solution is carefully added in drops. It is stirred vigorously at room temperature for ten minutes. After repeated extraction of the aqueous phase with methyl tert-butyl ether, the combined organic extracts are treated as usual. After chromatography on a Flashmaster, 490 mg (65.5%) of a mixture is obtained, which consists of just under two thirds of the desired aldehyde and a third of the ester.
5-{2-[1-(3-Chloro-2-methoxyphenyl)-cyclopropylmethyl]-3,3,3-trifluoro-2-hydroxy-propylidenamino}-1H-quinolin-2-one
490 mg (0.972 mmol) of the aldehyde described in the preceding section (as a mixture with the ester) is refluxed for three hours in 5.1 ml of xylene with 155.7 mg (0.972 mmol) of 5-amino-1H-quinolin-2-one and 552.6 mg (1.944 mmol) of titanium(IV) isopropylate. After the cooling, the reaction mixture is mixed with saturated sodium chloride solution and ethyl acetate. After ten minutes of vigorous stirring, the mixture is added to Extrelut and eluted with 200 ml of dichloromethane. After the solvent is spun off, the remaining residue is chromatographed on a Flashmaster. In addition to 93.9 mg of ester, 312.8 mg (69.2%, relative to the content of aldehyde) of the desired imine is isolated.
1H-NMR (300 MHz, CDCl3): δ=0.63-0.75 (1H), 0.79-0.90 (1H), 1.04-1.19 (2H), 2.10 (1H), 3.10 (1H), 4.00 (3H), 4.73 (1H), 6.74 (1H), 6.64 (1H), 6.75 (1H), 6.88-7.02 (2H), 7.29-7.43 (2H), 7.70 (1H), 8.10 (1H), 12.32 (1H).
5-{[7-Chloro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopropane-1,1′-naphthalen-4-yl)]amino}-quinolin-2(1H)-one
232.8 mg (0.501 mmol) of the above-described imine is dissolved in 4.7 ml of dichloromethane. After 3.3 ml (3.009 mmol) of titanium tetrachloride is added in drops at −20° C., it is stirred for four hours at this temperature. At 0° C., saturated sodium bicarbonate solution is carefully added, and the reaction mixture is extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried, and the solvent is spun off. After chromatography on a Flashmaster, 111.8 mg (48%) of the desired compound is obtained.
1H-NMR (300 MHz, DMSO-d6): δ=0.78-1.15 (3H), 1.78-2.09 (3H), 3.75 (3H), 5.06 (1H), 6.10-6.30 (3H), 6.45 (1H), 6.60 (1H), 6.98 (1H), 7.20 (1H), 7.30 (1H), 8.23 (1H), 11.60 (1H).
EXAMPLE 267
5-{[7-Chloro-3,8-dihydroxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopropane-1,1′-naphthalen-4-yl)]amino}-2H-isoquinolin-1-one
5-{[7-Chloro-3-hydroxy-8-methoxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopropane-1,1′-naphthalen-4-yl)]amino}-2H-isoquinolin-1-one
113.8 mg (0.245 mmol) of the imine (produced according to the instructions described in Example 263 with use of the corresponding starting materials), dissolved in 2.3 ml of dichloromethane, is cyclized with 1.6 ml (1.472 mmol) of titanium tetrachloride. After the usual working-up and chromatography, 36.8 m (32.3%) of the desired compound is obtained.
1H-NMR (400 MHz, DMSO-d6): δ=0.80-1.12 (3H), 1.82-2.09 (3H), 3.76 (3H), 5.09 (1H), 5.95 (1H), 6.37 (1H), 6.68 (1H), 6.81 (1H), 6.96 (1H), 7.16-7.28 (2H), 7.30 (1H), 7.52 (1H), 11.30 (1H).
5-{[7-Chloro-3,8-dihydroxy-3-(trifluoromethyl)-3,4-dihydro-2H-spiro(cyclopropane-1,1′-naphthalen-4-yl)]amino}-2H-isoquinolin-1-one
22.7 mg (0.049 mmol) of the previously described ether is subjected to ether cleavage as described in Example 263. After the reaction is carried out in the usual way and after chromatography, 10.9 mg (45.5%) of the desired phenol is obtained.
1H-NMR (400 MHz, CD3OD): δ=0.55-0.63 (1H), 0.73-0.84 (1H), 1.40-1.51 (1H), 1.80 (1H), 1.95-2.10 (2H), 5.02 (1H), 6.69 (1H), 6.75 (1H), 6.80 (1H), 6.98 (1H), 7.08 (1H), 7.25 (1H), 7.59 (1H).
EXAMPLE 268
7′-Chloro-4′-[(8-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-3′-(trifluoromethyl)spiro[cyclopropane-1,1′(2′H)-naphthalene]-3′,8′-diol
7′-Chloro-4′-[(8-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-8′-methoxy-3′-(trifluoromethyl)-spiro[cyclopropane-1,1′(2′H)-naphthalen]-3′-ol
1.64 ml (1.512 mmol) of titanium(IV) chloride is added in drops to 121.3 mg (0.252 mmol) of the corresponding imine, dissolved in 2.4 ml of dichloromethane, at −20° C. After one and one-half hours of stirring in a temperature range of between −20° C. and +5° C., the batch is worked up as usual. After chromatography on a Flashmaster, 7.4 mg (6.1%) of the desired compound (slightly contaminated) is isolated.
1H-NMR (400 MHz, CDCl3): δ=0.84-1.10 (3H), 1.92-2.13 (3H), 2.82 (3H), 3.79 (3H), 4.90 (1H), 5.65 (1H), 6.34 (1H), 7.00 (1H), 7.16 (1H), 7.37 (1H), 9.35 (1H).
7′-Chloro-4′-[(8-fluoro-2-methylquinazolin-5-yl)amino]-3′,4′-dihydro-3′-(trifluoromethyl)spiro[cyclopropane-1,1′(2′H)-naphthalene]-3′,8′-diol
40 mg (0.083 mmol) of the corresponding imine is mixed at 0° C. with 1.1 ml of a 1 M solution of boron tribromide in dichloromethane. After ¾ hour of stirring at this temperature, saturated sodium bicarbonate solution is carefully added in drops, and the reaction mixture is then extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried, and the solvent is spun off. After chromatography on a Flashmaster, 15 mg (38.6%) of the desired phenol is obtained.
MS (CI): 468 (100%)
EXAMPLE 269
[6-Hydroxy-1-methoxy-8,8-dimethyl-5-(2-oxo-1,2-dihydroquinolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-acetonitrile
Methyl-2-methoxy-3-methylbenzoate (RS 2690 F2)
199.9 g (1.45 mol) of potassium carbonate is introduced into 1.5 l of dimethylformamide. At room temperature, 100 g (657.29 mmol) of 2-hydroxy-3-methylbenzoic acid, dissolved in 250 ml of dimethylformamide, is added in drops. After 30 minutes of stirring, 90 ml of methyl iodide is added in drops, and the batch is stirred overnight. The reaction mixture is added to ice water and extracted three times with methyl tert-butyl ether. The organic phases are washed with water and brine. After drying, the solvent is spun off, and the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 70.21 g (59.3%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=2.32 (3H), 3.85 (3H), 3.93 (3H), 7.07 (1H), 7.35 (1H), 7.65 (1H).
2-(2-Methoxy-3-methylphenyl)-propan-2-ol
70.21 g (389.64 mmol) of methyl-2-methoxy-3-methylbenzoate, dissolved in 640 ml of tetrahydrofuran, is added in drops to 311.7 ml of methylmagnesium bromide in diethyl ether (3M). In this case, the reaction mixture is heated to about 48° C. The batch is stirred for three hours at room temperature. While being cooled in an ice bath, about 1.5 l of saturated ammonium chloride solution is now added in drops and stirred vigorously for one hour. After being extracted three times with methyl tert-butyl ether, the combined organic extracts are washed with brine, dried, and the solvent is spun off. 71.37 g (>100%) of the desired compound, which is further incorporated in crude form, is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.65 (6H), 2.33 (3H), 3.89 (3H), 4.55 (1H), 6.99 (1H), 7.10 (1H), 7.18 (1H).
Ethyl-4-(2-methoxy-3-methylphenyl)-4-methyl-2-oxopentanoate
71.37 g (395.96 mmol) of 2-(2-methoxy-3-methylphenyl)-propan-2-ol and 149 g (791.92 mmol) of 2-trimethylsilanyloxyacrylic acid ethyl ester are introduced into 1.1 l of dichloromethane. At −78° C., 44.8 ml (379.91 mmol) of tin tetrachloride is added in drops, and the batch is then stirred for three hours at this low temperature. 1.4 l of semiconcentrated potassium carbonate solution is added in drops, and the reaction mixture is thus brought to room temperature. The batch is filtered, and the filtrate is extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried on sodium sulfate, and the solvent is spun off. The residue is chromatographed several times on silica gel (mobile solvent: ethyl acetate/hexane). The residue is chromatographed several times on silica gel (mobile solvent: ethyl acetate/hexane). 45.81 g (41.6%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.30 (3H), 1.50 (6H), 2.30 (3H), 3.39 (2H), 3.78 (3H), 4.17 (2H), 6.97 (1H), 7.07 (1H), 7.15 (1H).
Ethyl-2-hydroxy-4-(2-methoxy-3-methylphenyl)-4-methyl-2-(trifluoromethyl)pentanoate
20 g (71.90) of ethyl-4-(2-methoxy-3-methylphenyl)-4-methyl-2-oxopentanoate and 12.3 g (86.28 mmol) of (trifluoromethyl)trimethylsilane are introduced into 117 ml of tetrahydrofuran. At room temperature, 180 mg of tetrabutylammonium fluoride is added (heating to about 35° C.). After stirring overnight, 22.7 g (71.90 mmol) of tetrabutylammonium fluoride is added, and the batch is stirred for three hours at room temperature. After dilution with methyl tert-butyl ether, the organic phase is washed three times with water and once with brine. After the solvent is dried and spun off, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 16.33 g (65.2%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.19 (3H), 1.43 (3H), 1.49 (3H), 2.30-2.44 (4H), 2.82 (1H), 3.50-3.68 (2H), 3.84 (3H), 4.00-4.13 (2H), 6.92 (1H), 7.00-7.10 (2H).
4-(2-Methoxy-3-methylphenyl)-4-methyl-(trifluoromethyl)-pentane-1,2-diol
16.33 g (46.88 mmol) of the above-described ester is dissolved in 160 ml of diethyl ether and mixed at 0° C. in portions with 3.56 g (93.76 mmol) of lithium aluminum hydride. After stirring over the weekend at room temperature, saturated sodium bicarbonate solution is carefully added in drops and then stirred vigorously for one hour. After being extracted three times with methyl tert-butyl ether, the combined organic extracts are washed with brine, dried, and the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane) after the solvent is spun off. 10.76 g (74.9%) of the desired diol is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.49 (3H), 1.58 (3H), 1.84 (1H), 2.24 (1H), 2.36 (3H), 2.59 (1H), 2.88 (1H), 3.28-3.40 (2H), 3.88 (3H), 6.99 (1H), 7.10 (1H), 7.20 (2H).
4-(3-Bromomethyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentane-1,2-diol
3 g (9.79 mmol) of 4-(2-methoxy-3-methylphenyl)-4-methyl-(trifluoromethyl)-pentane-1,2-diol is dissolved in 22 ml of carbon tetrachloride, mixed with 1.91 g (10.60 mmol) of NBS and 5 mg of benzoyl peroxide, and refluxed for 24 hours. After the succinimide is filtered off with a glass fiber filter, it is rewashed with dichloromethane, and the solvent is spun off. The residue (5.42 g>100%) is incorporated in crude form into the next stage.
[2-Methoxy-3-(4,4,4-trifluoro-3-hydroxy-3-hydroxymethyl-1,1-dimethylbutyl)phenyl]-acetonitrile
5.42 g (14.07 mmol) of the above-described bromine compound is mixed in a mixture that consists of dimethylformamide and water (14 and 10.5 ml) with 1.37 g (14.07 mmol) of potassium cyanide, and it is stirred overnight at room temperature. The reaction mixture is mixed with water and extracted three times with methyl tert-butyl ether. The combined organic phases are washed with brine, and the solvent is spun off after drying. 2.6 g (55.8%) of the desired compound is obtained after chromatography on a Flashmaster.
1H-NMR (300 MHz, CDCl3): δ=1.49 (3H), 1.60 (3H), 1.72 (1H), 2.22 (1H), 2.50 (1H), 2.92 (1H), 3.20-3.45 (2H), 3.80 (2H), 3.88 (3H), 7.13 (1H), 7.30-7.42 (2H).
[2-Methoxy-3-(4,4,4-trifluoro-3-hydroxy-3-formyl-1,1-dimethylbutyl)phenyl]acetonitrile
0.26 ml (2.99 mmol) of oxalyl chloride is cooled in 6.6 ml of dichloromethane to −78° C. After dropwise addition of 0.42 ml (5.98 mmol) of dimethyl sulfoxide, dissolved in 1.2 ml of dichloromethane, it is stirred for 10 more minutes, and then 900 mg (2.72 mmol) of [2-methoxy-3-(4,4,4-trifluoro-3-hydroxy-3-hydroxymethyl-1,1-dimethylbutyl)phenyl]acetonitrile in 2.6 ml of dichloromethane is added in drops. After two hours of stirring at −78° C., 1.88 ml (13.58 mmol) of triethylamine is added in drops, the batch is allowed to come to room temperature, and then it is stirred for one and one-half hours at room temperature. After mixing with water, it is extracted three times with dichloromethane. The combined organic extracts are washed with 1% sulfuric acid, with saturated sodium bicarbonate solution and with brine. After the solvent is dried and spun off, the residue is chromatographed on a Flashmaster. 599.4 mg (67.1%) of the desired aldehyde remains.
1H-NMR (300 MHz, CDCl3): δ=1.45 (3H), 1.51 (3H), 2.32 (1H), 3.20 (1H), 3.51 (1H), 3.78 (2H), 3.89 (3H), 7.09 (1H), 7.19 (1H), 7.35 (1H), 9.06 (1H).
{2-Methoxy-3-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-[(2-oxo-1,2-dihydroquinolin-5-ylimino)-methyl]-butyl)-phenyl}acetonitrile
200 mg (0.607 mmol) of the above-described aldehyde in 3.4 ml of xylene is refluxed for three hours with 97.3 mg (0.607 mmol) of 5-amino-1H-quinolin-2-one and 345.1 mg (1.214 mmol) of titanium(IV) isopropylate. After the reaction is completed, brine solution and ethyl acetate are added. After 30 minutes of vigorous stirring at room temperature, the batch is added to Extrelute and eluted with 200 ml of dichloromethane. After the solvent is spun off, the residue is chromatographed on a Flashmaster. 228.7 mg (79.8%) of the desired imine is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.45 (3H), 1.59 (3H), 2.38 (1H), 3.26 (1H), 3.34-3.55 (2H), 3.85 (3H), 4.66 (1H), 6.29 (1H), 6.69-6.80 (2H), 6.90 (1H), 7.16 (1H), 7.30-7.47 (2H), 7.51 (1H), 7.97 (1H), 12.18 (1H).
[6-Hydroxy-1-methoxy-8,8-dimethyl-5-(2-oxo-1,2-dihydroquinolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-acetonitrile
141.2 mg (0.299 mmol) of imine is mixed at 0° C. with 4.5 ml of a 1 M solution of boron tribromide in dichloromethane, and it is stirred for four hours. After saturated sodium bicarbonate solution is added in drops, it is extracted three times with ethyl acetate. The combined organic extracts are washed with brine. After the solvent is dried and spun off, the residue is chromatographed on a Flashmaster. 8 mg (5.8%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.52 (3H), 1.70 (3H), 2.05 (1H), 2.19 (1H), 3.69 (2H), 3.79 (3H), 5.00-5.16 (2H), 5.64 (1H), 6.38 (1H), 6.50 (1H), 6.62 (1H), 7.05-7.19 (2H), 7.30 (1H), 8.15 (1H), 10.76 (1H).
Example 270
[5-(8-Fluoro-2-methylquinazolin-5-ylamino)-6-hydroxy-1-methoxy-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-acetonitrile
{2-Methoxy-3-[4,4,4-trifluoro-3-(8-fluoro-2-methylquinazolin-5yl-iminomethyl)-3-hydroxy-1,1-dimethylbutyl]phenyl}acetonitrile
200 mg (0.61 mmol) of the aldehyde that is described in Example 269 is refluxed with 107.5 mg (0.61 mmol) of 5-amino-8-fluoro-2-methyquinazoline and 345.1 mg (1.214 mmol) of titanium tetrachloride in 3.4 ml of xylene for 3 hours. After the usual working-up and chromatography, 129.5 mg (43.7%) of the desired imine is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.41 (3H), 1.67 (3H), 2.35 (1H), 2.99 (3H), 3.35 (1H), 3.38-3.56 (2H), 3.85 (3H), 4.61 (1H), 6.50-6.60 (2H), 6.75 (1H), 7.17 (1H), 7.45 (1H), 7.55 (1H), 9.47 (1H).
[5-(8-Fluoro-2-methylquinazolin-5-ylamino)-6-hydroxy-1-methoxy-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-acetonitrile
100.9 mg (0.21 mmol) of the above-described imine is cyclized and worked up as usual with 3.1 ml of a 1 M solution of boron tribromide in dichloromethane at 0° C.
After chromatography on a Flashmaster and subsequent plate separation, 7.5 mg (7.7%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.58 (3H), 1.74 (3H), 2.09-2.28 (2H), 2.95 (3H), 3.78 (2H), 3.83 (3H), 5.02 (1H), 5.30 (1H), 5.61 (1H), 6.69 (1H), 7.18-7.32 (2H), 7.50 (1H), 9.38 (1H).
Example 271
1-(7-Fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,6-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
2-Hydroxy-4-(2-methoxy-3-methylphenyl)-4-methyl-2-(trifluoromethyl)pentanal
2 g (6.53 mmol) of the 4-(2-methoxy-3-methylphenyl)-4-methyl-(trifluoromethyl)-pentane-1,2-diol that is described in Example 269 is oxidized to aldehyde according to Swern analogously to the description in this example. After the usual working-up and purification on a Flashmaster, 1.20 g (60.3%) of the desired aldehyde is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.46 (3H), 1.50 (3H), 2.23 (1H), 2.32 (3H), 3.38 (1H), 3.60 (1H), 3.85 (3H), 6.93 (1H), 7.00 (1H), 7.10 (1H), 8.95 (1H).
1,1,1-Trifluoro-2-[(7-fluoro-2-methylquinazolin-5-ylimino)-methyl]-4-(2-methoxy-3-methylphenyl)-4-methylpentan-2-ol
150 mg (0.493 mmol) of the described aldehyde is reacted to form imine as usual and as already described several times with 87.3 mg (0.493 mmol) of 5-amino-7-fluoro-2-methylquinazoline and 280.3 mg (0.986 mmol) of titanium tetraisopropylate in 2.5 ml of xylene. After chromatography, 174.9 mg (76.6%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.41 (3H), 1.65 (3H), 2.01 (3H), 2.29 (1H), 2.90 (3H), 3.49 (1H), 3.80 (3H), 4.55 (1H), 6.19 (1H), 6.50-6.60 (2H), 7.03 (1H), 7.40 (1H), 7.62 (1H), 9.30 (1H).
1-(7-Fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,6-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
174.9 mg (0.377 mmol) of the previously described imine is cyclized with titanium tetrachloride in dichloromethane at 0° C. The implementation, working-up and chromatography are carried out as already described several times. 159.7 mg (91.3%) of the desired compound is isolated as a diastereomer mixture at a 9:1 ratio (the NMR data relate to the main diastereomer). 1H-NMR (300 MHz, CDCl3): δ=1.59 (3H), 1.73 (3H), 2.10-2.28 (2H), 2.32 (3H), 2.86 (3H), 3.81 (3H), 4.99 (1H), 6.05 (1H), 6.10 (broad, 1H), 6.52 (1H), 6.89 (1H), 6.95-7.16 (2H), 9.20 (1H).
Example 272
1-(78-Difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,6-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
1,1,1-Trifluoro-2-[(7,8-difluoro-2-methylquinazolin-5-ylimino)-methyl]-4-(2-methoxy-3-methylphenyl)-4-methylpentan-2-ol
150 mg (0.493 mmol) of the described aldehyde is reacted to form imine as usual and as already described several times with 96.2 mg (0.493 mmol) of 5-amino-7,8-difluoro-2-methylquinazoline and 280.3 mg (0.986 mmol) titanium tetraisopropylate in 2.5 ml of xylene. After chromatography, 155.5 mg (65.5%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.40 (3H), 1.63 (3H), 2.07 (3H), 2.28 (1H), 2.98 (3H), 3.50 (1H), 3.83 (3H), 4.49 (1H), 6.28 (1H), 6.52-6.62 (2H), 7.03 (1H), 7.62 (1H), 9.36 (1H).
1-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,6-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
155.5 mg (0.323 mmol) of the previously described imine is cyclized with titanium tetrachloride in dichloromethane at 0° C. The implementation, working-up, and chromatography are carried out as already described several times. 101.6 mg (65.3%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.60 (3H), 1.73 (3H), 2.08-2.28 (2H), 2.32 (3H), 2.93 (3H), 3.81 (3H), 4.93 (1H), 5.42 (1H), 5.81 (1H), 6.58 (1H), 6.95-7.09 (2H), 9.24 (1H).
Example 273
5-[2,6-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-2-methyl-2H-phthalazin-1-one
2-(3-Methoxyphenyl)-2-methylpropanenitrile
50 g (339.72 mmol) of 3-methoxybenzyl cyanide is dissolved in 530 ml of DMF and mixed with 96.4 g (6792.4 mmol) of methyl iodide. After cooling to 0° C., 21.5 g (492.2 mmol) of NaH (55% suspension) is added in portions to the reaction mixture within four hours. After 18 hours at room temperature, the batch is poured onto 700 ml of ice water and extracted three times with 500 ml each of diethyl ether. The combined organic phases are washed with water and brine. After drying on sodium sulfate, the dessicant is filtered off, and the solvent is spun off on a rotary evaporator. After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 48.9 g (82.2%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.73 (6H), 3.85 (3H), 6.85 (1H), 7.02 (1H), 7.07 (1H), 7.31 (1H).
2-(3-Methoxyphenyl)-2-methylpropanal
25 g (142.67 mmol) of the above-described nitrile is dissolved in 570 ml of toluene. 178 ml of a 1.2 molar solution of DIBAH in toluene is added in drops at −65 to −60° C. within 75 minutes. After two hours of stirring at this temperature, the dropwise addition of 815 ml of a 20% L-(+)-tartaric acid solution is begun. After 150 milliliters, the temperature is increased to −10° C. The remainder of the tartaric acid solution is quickly added, and the batch is stirred vigorously at room temperature for 16 hours. The reaction mixture is shaken twice with 600 ml each of diethyl ether. The combined organic extracts are shaken with water and brine, dried, and the solvent is spun off. The residue that is obtained (25.1 g=98.8%) is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=1.47 (6H), 3.83 (3H), 6.78-6.90 (3H), 7.30 (1H), 9.50 (1H).
Ethyl-E-4-(3-methoxyphenyl)-4-methylpent-2-enoate
33.6 g (114.3 mmol) of phosphonoacetic acid triethyl ester is introduced into 148 ml of tetrahydrofuran. At 0° C., 79.7 ml of a 2 M solution of LDA in THF/heptane/ethylbenzene is added in drops (one and one-half hours). After one hour of stirring, 24.3 g (136.34 mmol) of 2-(3-methoxyphenyl)-2-methylpropanal, dissolved in 130 ml of tetrahydrofuran, is added in drops at 0° C. After five days of stirring at room temperature, the reaction mixture is poured onto 250 ml of dilute ammonium chloride solution and extracted twice with 400 ml each of diethyl ether. The combined organic extracts are treated as usual, and the residue that is obtained is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 27.2 g (80.4%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.30 (3H), 1.49 (6H), 3.81 (3H), 4.20 (2H), 5.80 (1H), 6.78 (1H), 6.85 (1H), 6.90 (1H), 7.12 (1H), 7.25 (1H).
Ethyl-4-(3-methoxyphenyl)-4-methylpentanoate
27.2 g (109.5 mmol) of ethyl-E-4-(3-methoxyphenyl)-4-methylpent-2-enoate is mixed in 293 ml of ethyl acetate with 2.72 g of palladium on carbon (10%) and stirred for 18 hours at room temperature under a hydrogen atmosphere. The catalyst is removed by filtration through a glass fiber filter, and the residue that remains after the concentration by evaporation (27.2 g=99.2%) is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=1.21 (3H), 1.32 (6H), 1.90-2.10 (4H), 3.82 (3H), 4.05 (2H), 6.74 (1H), 6.89 (1H), 6.93 (1H), 7.25 (1H).
Ethyl-4-(3-methoxyphenyl)-2-hydroxy-4-methylpentanoate
27.2 g (108.65 mmol) of ethyl-4-(3-methoxyphenyl)-4-methylpentanoate is dissolved in 380 ml of tetrahydrofuran, and the reaction mixture is cooled to −70° C. to −65° C. Within two hours, 304 ml of a 0.5 molar solution of potassium-bis-(trimethylsilylamide) in toluene is added in drops, and the reaction mixture is then stirred for 75 more minutes at −70° C. 39.7 g (152.11 mmol) of Davis reagent, dissolved in 380 ml of tetrahydrofuran, is now added in drops within 90 minutes. After two hours of stirring at −70° C., 195 ml of saturated ammonium chloride solution is slowly added in drops, the cold bath is removed, and it is stirred vigorously for thirty minutes. After extraction with diethyl ether (twice with 800 ml each), the combined organic extracts are treated as usual with water and brine. After the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 20.9 g (72.4%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.29 (3H), 1.40 (3H), 1.48 (3H), 1.85 (1H), 2.20 (1H), 2.50 (1H), 3.81 (3H), 3.99 (1H), 4.18 (2H), 6.76 (1H), 6.95 (1H), 7.00 (1H), 7.28 (1H).
Ethyl-4-(3-methoxyphenyl)-4-methyl-2-oxopentanoate
2019 g (78.47 mmol) of ethyl 4-(3-methoxyphenyl)-2-hydroxy-4-methyl-pentanoate is dissolved in 820 ml of dichloromethane and mixed with 273 ml of dimethyl sulfoxide. After 39.7 g (392.36 mmol) of triethylamine is added, the batch is mixed in portions with 31.2 g (196.18 mmol) of SO3/pyridine complex and then stirred for 16 hours at room temperature. About 400 ml of dichloromethane is drawn off in a rotary evaporator. Then, the reaction mixture is mixed with 312 ml of saturated ammonium chloride solution with slight cooling, and it is stirred vigorously for 20 minutes. After being extracted two times with diethyl ether (800 ml each), the combined organic phases are washed with water and brine. The residue that remains after the solvent is spun off is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 15.59 g (75.3%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.28 (3H), 1.48 (6H), 3.18 (2H), 3.80 (3H), 4.12 (2H), 6.74 (1H), 6.90 (1H), 6.95 (1H), 7.25 (1H).
Ethyl-4-(3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoate
15.59 g (58.98 mmol) of ethyl-4-(3-methoxyphenyl)-4-methyl-2-oxopentanoate is dissolved in 96 ml of tetrahydrofuran and mixed at 0° C. with 10.1 g (70.78 mmol) of (trifluoromethyl)-trimethylsilane. After 144.5 mg of tetrabutylammonium fluoride is added, it is stirred for 2 and ¾ hours at 0 to 5° C. The batch is added to 150 ml of ice water, extracted twice with diethyl ether (300 ml each), and the combined organic extracts are treated as usual. After the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 17.10 g (71.3%) of the desired product (contaminated) is isolated, which is thus incorporated into the next stage.
4-(3-Methoxyphenyl)-2-(trifluoromethyl)-pentane-1,2-diol
6.77 g (16.65 mmol) of (rac.) ethyl-4-(3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-(trimethylsilyloxy)-pentanoate is dissolved in 61 ml of diethyl ether and mixed at 0° C. in portions with 1.26 g (33.31 mmol) of lithium aluminum hydride. The reaction mixture is stirred for one hour at 5° C. and for one and one-half hours at room temperature. For hydrolysis, the mixture is mixed drop by drop with 30 ml of saturated NaHCO3 solution while being cooled in an ice bath. It is stirred vigorously for one hour while being cooled in an ice bath and stirred vigorously overnight at room temperature. The precipitate is suctioned off and washed with diethyl ether. The filtrate is concentrated by evaporation in a rotary evaporator, and the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 5.64 g (71.2%) of a mixture in which the trimethylsilyl group sits partially on the primary hydroxyl group and partially on the secondary hydroxyl group is isolated. The mixture (5.64 g) is therefore dissolved without further purification in 72 ml of tetrahydrofuran and mixed with 4 g (1 2.79 mmol) of tetrabutylammonium fluoride trihydrate and stirred for 90 minutes at room temperature. The reaction mixture is diluted with water and extracted twice with 150 ml each of diethyl ether. After the combined organic phases are washed with water and brine, the solvent is dried and spun off. The crude product (5.8 g) is chromatographed together with another implemented batch (7.97 g of feedstock, 10.4 g of yield of crude product) on silica gel (mobile solvent: ethyl acetate/hexane). 10.07 g of the desired diol is isolated from both batches.
1H-NMR (300 MHz, CDCl3): δ=1.40 (3H), 1.53 (3H), 2.10-2.25 (1H), 2.80 (1H), 3.29-3.48 (2H), 3.83 (3H), 6.78 (1H), 6.97 (1H), 7.00 (1H), 7.28 (1H).
4-(3-Methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal
10.07 g (34.45 mmol) of the above-described diol is oxidized to the corresponding aldehyde as already described several times according to Swern. After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 7.16 g (71.6%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.38 (3H), 1.48 (3H), 2.32 (1H), 2.69 (1H), 3.69 (1H), 3.82 (3H), 6.78 (1H), 6.88 (1H), 6.93 (1H), 7.25 (1H), 8.88 (1H).
5-[4-(3-Methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidenamino)-2-methyl-2H-phthalazin-1-one
300 mg (1.033 mmol) of the above-described 4-(3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal is reacted to form imine with 180.9 mg (1.033 mmol) of 5-amino-2-methyl-2H-phthalazin-1-one. After the reaction, usual working-up and chromatography, 318.2 mg (68.8%) of the desired imine is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.36 (3H), 1.55 (3H), 2.49 (1H), 2.78 (1H), 3.50 (3H), 3.90 (3H), 4.72 (1H), 6.40 (1H), 6.59 (1H), 6.78 (1H), 6.90 (1H), 7.05 (1H), 7.28 (1H, virtually under the chloroform), 7.53 (1H), 8.30 (1H), 8.43 (1H).
5-(2-Hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino-2-methyl-2H-phthalazin-1-one
100 mg (0.223 mmol) of imine is cyclized with titanium tetrachloride in dichloromethane as described in Example 146. 43.4 mg (43.4%) of the desired compound, namely as a diastereomer mixture, is isolated.
MS (ES+): 448 (100%)
5-[2,6-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-2-methyl-2H-phthalazin-1-one
37 mg (0.082 mmol) of the ether that is described in the previous section is reacted with boron tribromide as described in Example 146. After the reaction and the usual working-up are implemented, 20.9 mg (58.4%) of the desired compound is obtained, namely as a diastereomer mixture.
MS (ES+): 434 (100%)
Example 274
1-(8-Fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol
4-(3-Methoxyphenyl)-1,1,1-trifluoro-2-{[8-fluoro-2-methylquinazolin-5-ylimino]-methyl}-4-methyl-pentan-2-ol
400 mg (1.722 mmol) of 4-(3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal is reacted to form imine as described in Example 146 with 305.1 mg (1.722 mmol) of 5-amino-8-fluoro-2-methylquinazoline. After chromatography, 494.4 mg (79.8%) of the desired imine is isolated.
1H-NMR (CDCl3): δ=1.34 (3H), 1.58 (3H), 2.40 (1H), 2.79 (1H), 3.00 (3H), 3.48 (3H), 4.78 (1H), 6.29-6.42 (2H), 6.74 (1H), 6.90 (1H), 7.00 (1H), 7.28-7.40 (2H), 9.64 (1H).
1-(8-Fluoro-2-methylquinazolin-5-ylamino)-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol (AM 2016)
150 mg (0.347 mmol) of imine is cyclized in 2.5 ml of dichloromethane at 0° C. with 1 ml of titanium tetrachloride as described in Example 146. After chromatography on silica gel (mobile solvent: methanol/dichloromethane), 87.1 mg (58.1%) of the desired compound is obtained.
1H-NMR (300 MHz, CD3OD): δ=1.42 (3H), 1.58 (3H), 2.08-2.23 (2H), 2.87 (3H), 3.79 (3H), 5.28 (1H), 6.73 (1H), 6.82 (1H), 6.99 (1H), 7.23 (1H), 7.68 (1H), 9.68 (1H).
1-(8-Fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol
60 mg (0.133 mmol) of 4-(3-methoxyphenyl)-1,1,1-trifluoro-2-{[8-fluoro-2-methylquinazolin-5-ylimino]-methyl}-4-methylpentan-2-ol is mixed with 1.3 ml of a 1 M solution of boron tribromide in dichloromethane while being cooled in an ice bath. After 45 minutes of stirring at room temperature, the reaction mixture is mixed with ice, and saturated sodium bicarbonate solution is added drop by drop until a pH of 8 is reached. The cold bath is removed, and the mixture is stirred vigorously for 15 minutes. After extraction with ethyl acetate, the combined organic extracts are washed with water and then with brine. After drying, the solvent is spun off, and the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). Ultimately, 19.5 mg (33.5%) of the desired compound is obtained.
1H-NMR (300 MHz, CD3OD): δ=1.41 (3H), 1.56 (3H), 2.07-2.21 (2H), 2.89 (3H), 5.24 (1H), 6.60 (1H), 6.78-6.91 (2H), 7.13 (1H), 7.59 (1H), 9.68 (1H).
Example 275
5-(2,6-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one
5-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentylidenamino]-2H-isoquinolin-1-one
271 mg (0.936 mmol) of 4-(3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal is reacted to form imine with 150 mg (0.936 mmol) of 5-amino-2H-isoquinolin-1-one as already described several times. After chromatography, 341.1 mg (84.5%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.33 (3H), 1.55 (3H), 2.39 (1H), 2.79 (1H), 3.56 (3H), 4.95 (1H), 6.38-6.55 (2H), 6.78 (1H), 6.79-6.95 (2H), 7.09 (1H), 7.12-7.35 (3H), 8.31 (1H), 11.09 (1H).
5-(2-Hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one
150 mg (0.347 mmol) of the above-described imine is cyclized to the desired compound with titanium tetrachloride in dichloromethane as described in Example 274. After chromatography, 18.8 mg (12.5%) is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.42 (3H), 1.58 (3H), 2.05-2.24 (2H), 3.79 (3H), 5.15 (1H), 6.73 (1H), 6.89 (1H), 6.96 (1H), 7.05 (1H), 7.10-7.25 (2H), 7.49 (1H), 7.70 (1H).
5-(2,6-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one
90 mg (0.208 mmol) of the previously described imine is cyclized to free phenol directly with boron tribromide, as described in Example 274. After the usual working-up and chromatography, 53.8 mg (61.7%) of the desired compound is obtained as a diastereomer mixture in a 3:2 ratio.
MS (ES+): 419 (100%)
Example 276
5-(2,6-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one
5-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentylidenamino]-1H-quinolin-2-one
300 mg (1.033 mmol) of 4-(3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal is reacted to form imine, as already described several times, with 165.4 mg (1.033 mmol) of 5-amino-1H-quinolin-2-one. After chromatography, 414.3 mg (92.7%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.33 (3H), 1.53 (3H), 2.40 (1H), 2.78 (1H), 3.58 (3H), 4.85 (1H), 6.08 (1H), 6.49 (1H), 6.72-6.83 (2H), 6.90 (1H), 7.08 (1H), 7.28-7.38 (3H), 8.18 (1H), 12.53 (1H).
5-(2-Hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one
150 mg (0.347 mmol) of the previously described imine is cyclized to the desired compound with titanium tetrachloride in dichloromethane as described in Example 274. After chromatography, 35.8 mg (23.8%) of diastereomer A is isolated, and another 14.3 mg (9.5%) as a diastereomer mixture. The spectroscopic data relate to the pure diastereomer.
1H-NMR (300 MHz, CD3OD): δ=1.42 (3H), 1.59 (3H), 2.05-2.24 (2H), 3.80 (3H), 5.18 (1H), 6.52 (1H), 6.61 (1H), 6.65-6.79 (2H), 6.95 (1H), 7.20 (1H), 7.39 (1H), 8.23 (1H).
5-(2,6-Dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-1H-quinolin-2-one
90 mg (0.208 mmol) of the previously described imine is cyclized to free phenol directly with boron tribromide as described in Example 274. After the usual working-up and chromatography, 37.6 mg (43.1%) of the desired compound is obtained as a diastereomer mixture in a 4:1 ratio.
MS (ES+): 419 (100%)
Example 277
7-Fluoro-1-(8-Fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol
4-Bromomethyl-1-fluoro-2-methoxybenzene
41.7 g (297.54 mmol) of 2-fluoro-5-methylanisole is refluxed overnight with 59.9 g (327.48 mmol) of N-bromosuccinimide and 145 mg of benzoyl peroxide in 945 ml of carbon tetrachloride. The reaction mixture is filtered through a glass fiber filter, and after the solvent is spun off, the residue (72.85 g>100%) is incorporated in crude form into the next stage.
(4-Fluoro-3-methoxyphenyl)-acetonitrile
72.85 g of the previously described bromine compound in a mixture that consists of 330 ml of dimethylformamide and 209 ml of water is added. After 32.5 g (498.86 mmol) of potassium cyanide is added at room temperature (slight warming), the batch is stirred overnight at room temperature. The reaction mixture is poured onto ice water and extracted three times with methyl tert-butyl ether. The combined organic extracts are washed with brine, and the solvent is spun off after the drying. The residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 33.34 g (61.4%) of the desired nitrile is isolated.
1H-NMR (CDCl3): 3.72 (2H), 3.93 (3H), 6.83 (1H), 6.93 (1H), 7.09 (1H).
2-(4-Fluoro-3-methoxyphenyl)-2-methylpropionitrile
16.67 g (100.93 mmol) of (4-fluoro-3-methoxyphenyl)-acetonitrile is introduced into 158 ml of dimethylformamide with 30.1 g (211.96 mmol) of methyl iodide. At 0° C., 8.50 g (211.96 mmol) of a 55-60% sodium hydride suspension is added in portions. After stirring overnight at room temperature, the reaction mixture is poured onto ice water and then extracted three times with methyl tert-butyl ether. The combined organic extracts are washed with water and with brine. After the solvent is dried and spun off, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 5.11 g (26.2%) of the desired compound and 6.18 g of the monomethyl compound, which is realkylated, are isolated.
1H-NMR (CDCl3): 1.72 (6H), 3.92 (3H), 6.95 (1H), 7.00-7.12 (2H).
2-(4-Fluoro-3-methoxyphenyl)-2-methylpropionaldehyde
9.37 g (48.50 mmol) of 2-(4-fluoro-3-methoxyphenyl)-2-methylpropionitrile is reduced with 39.98 ml (72.48 mmol) of a 1.2 M solution of DIBAL in toluene at −78° C., specifically as described in some previous examples. For hydrolysis, isopropanol and tartaric acid are used. 9.31 g of a mixture that consists of one third of the starting material and two thirds of the desired aldehyde is isolated. This mixture is again subjected to a DIBAL reaction at −78° C. and after working-up produces a mixture (9.18 g) that consists of nitrile, aldehyde and the corresponding alcohol. This mixture is reduced another time with DIBAL, but this time at a temperature of −10 to 0° C. After hydrolysis with isopropanol, 1.45 g of the desired aldehyde and 5.68 g of the corresponding alcohol are isolated. This alcohol is oxidized to aldehyde under Swern conditions as already described several times. After the usual working-up and purification, 5.09 g of the desired aldehyde is isolated.
1H-NMR (CDCl3): 1.48 (6H), 3.90 (3H), 6.75-6.87 (2H), 7.09 (1H), 9.49 (1H).
Ethyl-(E)-(4fluoro-3-methoxyphenyl)-4-methylpent-2-enoate
6.10 g (27.23 mmol) of triethylphosphonoacetate is dissolved in 16.5 ml of tetrahydrofuran. At 0° C., 14.9 ml (29.12 mmol) of LDA is added in drops, and the batch is stirred for 30 minutes at 0° C. After the dropwise addition of 5.34 g (27.22 mmol) of the above-described aldehyde, dissolved in 16.5 ml of tetrahydrofuran, the reaction mixture is stirred overnight at room temperature. At 0° C., water is carefully added in drops, stirred vigorously for ten minutes, and then shaken three times with methyl tert-butyl ether. The combined organic extracts are washed with brine and dried. After the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 5.75 g (79.3%) of the desired compound is isolated.
1H-NMR (CDCl3): 1.29 (3H), 1.48 (6H), 3.90 (3H), 4.20 (2H), 5.80 (1H), 6.79-6.90 (2H), 7.02 (1H), 7.10 (1H).
Ethyl-(4fluoro-3-methoxyphenyl)-4-methylpentanoate
5.75 g (21.59 mmol) of ethyl-(E)-(4-fluoro-3-methoxyphenyl)-4-methylpent-2-enoate is hydrogenated overnight in a hydrogen atmosphere in 80 ml of ethanol with the aid of 307.3 mg of Pd/C (10%). The reaction mixture is suctioned off via a glass fiber filter, and the solvent is spun off. 5.69 g (98.3%) of the desired compound, which is further incorporated in crude form, is isolated.
1H-NMR (CDCl3): 1.22 (3H), 1.31 (6H), 1.90-2.10 (4H), 3.90 (3H), 4.08 (2H), 6.83 (1H), 6.91 (1H), 7.00 (1H).
Ethyl-4-(4fluoro-3-methoxyphenyl)-2-hydroxy-4-methylpentanoate
5.69 g (21.21 mmol) of ethyl-(4-fluoro-3-methoxyphenyl)-4-methylpentanoate is reacted with 7.76 g (26.70 mmol) of Davis reagent as described in Example 273. After the working-up and chromatography on silica gel (mobile solvent: ethyl acetate/hexane) that are described there, 2.98 g (49.5%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.29 (3H), 1.40 (3H), 1.48 (3H), 1.83 (1H), 2.20 (1H), 2.56 (1H), 3.85-3.99 (4H), 4.13 (2H), 6.90 (1H), 6.95-7.08 (2H).
Ethyl-4-(4-fluoro-3-methoxyphenyl)-4-methyl-2-oxopentanoate
2.78 g (9.78 mmol) of ethyl-4-(4-fluoro-3-methoxyphenyl)-2-hydroxy-4-methylpentanoate is oxidized to the corresponding α-ketoester with SO3/Py in dichloromethane as in Example 273. After chromatography on a Flashmaster, 2.48 g (89.9%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.28 (3H), 1.48 (6H), 3.15 (2H), 3.90 (3H), 4.12 (2H), 6.88 (1H), 6.90-7.03 (2H).
4-(4-Fluoro-3-methoxyphenyl)-2-hydroxy-4-methylphenyl-2-(trifluoromethyl)-pentanal
2.48 g (8.79 mmol) of ethyl-4-(4-fluoro-3-methoxyphenyl)-4-methyl-2-oxopentanoate is converted into the aldehyde according to Swern via the sequence, described in Example 273, of trifluoromethylation with Rupperts reagent, reduction of ester with lithium aluminum hydride to alcohol, and subsequent oxidation of alcohol. Ultimately, 382.3 mg of the desired aldehyde is isolated over the three stages.
1H-NMR (300 MHz, CDCl3): δ=1.38 (3H), 1.48 (3H), 2.32 (1H), 2.66 (1H), 3.68 (1H), 3.90 (3H), 6.80-6.92 (2H), 7.02 (1H), 8.88 (1H).
1,1,1-Trifluoro-4-(4-fluoro-3-methoxyphenyl)-2-[(8-fluoro-2-methylquinazolin-5-ylimino)-methyl]-4-methylpentan-2-ol
127.4 mg (0.413 mmol) of 4-(4-fluoro-3-methoxyphenyl)-2-hydroxy-4-methylphenyl-2-(trifluoromethyl)-pentanal is reacted to form the corresponding imine with 73.2 mg (0.413 mmol) of 8-fluoro-2-methylquinazoline and 235.1 mg (0.827 mmol) of titanium(IV) isopropylate in 2.2 ml of xylene, as already described several times. After chromatography on a Flashmaster, 138.5 mg (71.7%) of the desired compound is isolated.
1H-NMR (CDCl3): δ=1.35 (3H), 1.56 (3H), 2.44 (1H), 2.72 (1H), 2.99 (3H), 3.68 (3H), 4.77 (1H), 6.38 (1H), 6.70-6.90 (3H), 7.38-7.48 (2H), 9.65 (1H)
7-Fluoro-1-(8-Fluoro-2-methylquinazolin-5-ylamino)-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2, 6-diol
20 mg (0.043 mmol) of the above-described imine is reacted with 0.6 ml of boron tribromide (1 M solution in dichloromethane) at 0° C. and thus converted into the cyclized phenol. After chromatography on a Flashmaster, 7.1 mg (36.6%) is isolated.
1H-NMR (CD3OD): δ=1.41 (3H), 1.56 (3H), 2.06-2.22 (2H), 2.89 (3H), 5.24(1H), 6.84 (1H), 6.89-7.04 (2H), 7.59 (1H), 9.69 (1H).
Example 278
5-[7-Fluoro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-1H-quinolin-2-one
5-[4-(4-Fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentylidenamino]-1H-quinolin-2-one
127 mg (0.413 mmol) of the aldehyde that is described in Example 277 is reacted to form imine with 66.32 mg (0.413 mmol) of 5-amino-1H-quinolin-2-one as described there. After chromatography on a Flashmaster, 89.2 mg (47.9%) of the desired compound is isolated.
1H-NMR (CDCl3): δ=1.37 (3H), 1.53 (3H), 2.43 (1H), 2.71 (1H), 3.71 (3H), 4.85 (1H), 6.10 (1H), 6.70-6.92 (4H), 7.30-7.42 (3H), 8.15 (1H), 12.42 (1H).
5-[7-Fluoro-2-hydroxy-6-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-1H-quinolin-2-one
89.2 mg (0.198 mmol) of the above-described imine is reacted to form cyclic ether in 1.9 ml of dichloromethane with 1.3 ml (1.188 mmol) of titanium tetrachloride. After chromatography on a Flashmaster, 5.7 mg of the desired compound is obtained.
1H-NMR (CDCl3): δ=1.40 (3H), 1.60 (3H), 2.00-2.29 (2H), 3.88 (3H), 5.00 (1H), 5.07 (1H), 5.68 (1H), 6.45-6.60 (3H), 6.85-7.02 (2H), 7.32 (1H), 8.20 (1H), 10.05 (1H).
Example 279
6-Fluoro-1-[(2-methylquinolin-5-yl)amino]-4-ethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
1H-NMR (300 MHz, CD3OD); δ=0.97 (s, 3H), 1.79 (qdd, 1H), 1.96 (qdd, 1H), 2.19 (dd, 1H), 2.36 (dd, 1H), 2.73 (s, 3H), 3.40 (m, 1H), 4.98 (d, 1H), 5.12 (d, 1H), 6.60 (d, 1H), 6.89 (d, 2H), 7.23 (d, 1H), 7.43 (d, 1H), 7.51 (t, 1H), 8.11 (d, 1H).
Examples 280 and 281
5-{[7-Bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one, Diastereomer A and 5-{[7-Bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one, Diastereomer B
Analogously to Example 10, the corresponding imine is produced starting from 800 mg of 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 348 mg of 5-amino-quinolin-2(1H)-one. 16 mg of diastereomer A of 5-{[7-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one (fraction A) and 79 mg of diastereomer B of 5-{[7-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one are obtained by reaction of 800 mg of the imine with 7.9 ml of boron tribromide solution (1H in dichloromethane).
Fraction A: 1H-NMR (CD3OD): δ=1.40 (s, 3H), 1.55 (s, 3H), 1.90 (d, 1H), 2.25 (d, 1H), 5.22 (s, 1H), 6.11 (d, 1H), 6.58 (d, 1H), 6.67 (d, 1H), 7.12-7.30 (m, 3H), 8.20 (d, 1H).
Fraction B: 1H-NMR (CD3OD): δ=1.54 (s, 3H), 1.65 (s, 3H), 2.05 (d, 1H), 2.14 (d, 1H), 5.13 (s, 1H), 6.53 (d, 1H), 6.62 (d, 1H), 6.72 (d, 1H), 6.87 (s, 1H), 6.94 (s, 1H), 7.40 (t, 1H), 8.22 (d, 1H).
Example 282
1,6-Dihydroxy-8,8-dimethyl-5-(1-oxo-1,2-dihydroisoquinolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
75 mg (0.166 mmol) of 5-(6-chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one is dissolved in 1.3 ml of 1-methyl-2-pyrrolidinone and reacted in the microwave with 16.27 mg (0.332 mmol) of sodium cyanide and 36.27 mg (0.166 mmol) of nickel(II) bromide, as described in Example 160. The black reaction mixture is added via a glass fiber filter. After washing with ethyl acetate, the filtrate is also mixed with an additional 60 ml of ethyl acetate. It is shaken with water and with brine. After drying, the solvent is spun off, and the residue is chromatographed on silica gel (amine plate; mobile solvent: methanol/dichloromethane). 16.2 mg (22.1%) of the desired nitrile is isolated.
MS (ES+): 444 (100%); IR (microscope, matrix: diamond): 2230.
Example 283
(rac.) 5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
5-Amino-isoquinolin-1(2H)-one
2-Methyl-3-nitrobenzoic acid methyl ester
30 g (165.6 mmol) of 2-methyl-3-nitrobenzoic acid is added in 150 ml of methanol and after 2.9 ml of concentrated sulfuric acid is added, it is refluxed for two days. After cooling, the crystallizate (22.55 g=79%) is suctioned off and thus incorporated into the next stage.
1H-NMR (300 MHz, DMSO-d6): δ=2.50 (3H), 3.85 (3H), 7.56 (1H), 8.00 (1H), 8.05 (1H).
2-(Bromomethyl)-3-nitrobenzoic acid methyl ester
25.55 g (130.9 mmol) of 2-methyl-3-nitrobenzoic acid methyl ester is added in 300 ml of carbon tetrachloride and mixed with 25.6 gram (141.7 mmol) of N-bromosuccinimide and 62.8 mg of benzoyl peroxide. After seven days of refluxing, the succinimide is suctioned off after cooling, and then the filtrate is spun in until a dry state is reached. The desired compound, which is incorporated in crude form into the next stage, remains.
1H-NMR (300 MHz, CDCl3): δ=4.00 (3H), 5.66 (2H), 7.55 (1H), 7.95 (1H), 8.10 (1H).
5-Nitroisocoumarin
16.4 g (84.03 mmol) of 2-methyl-3-nitrobenzoic acid methyl ester is stirred with 26.8 g (225.1 mmol) of N,N-dimethylformamide dimethylacetal in 85 ml of dimethylformamide for 12 hours at 130° C. The solvent is drawn off in a rotary evaporator, the residue is taken up in methyl tert-butyl ether and washed three times with water. After washing with saturated NaCl solution, the organic phase is dried. After the dessicant is filtered off and after the solvent is spun off, the remaining residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 8.73 g (54.4%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=7.39 (1H), 7.45 (1H), 7.68 (1H), 8.49 (1H), 8.65 (1H).
5-Nitroisoquinolin-1(2H)-one
2.51 g (13.13 mmol) of 5-nitroisocoumarin is added in 100 ml of ethanol. Ammonia is pressure-forced in in an autoclave. The product precipitates and is suctioned off. 1.98 g (79.7%) of the desired compound is isolated.
1H-NMR (300 MHz, DMSO-d6): δ=6.97 (1H), 7.45 (1H), 7.65 (1H), 8.43 (1H), 8.57 (1H), 11.5 (1H).
5-Aminoisoquinolin-1(2H)-one
268.3 mg (1.51 mmol) of 5-nitroisoquinolin-1(2H)-one is added to 376.5 mg of ammonium chloride and 2.6 ml of water in 14 ml of ethanol and 5.4 ml of tetrahydrofuran. After the addition in portions of 1.23 g of zinc powder (heating to 30 to 35° C.), it is stirred for two hours. The reaction mixture is suctioned off through a glass fiber filter and rewashed with ethyl acetate. After the filtrate is washed with water and saturated sodium chloride solution, the organic phase is dried as usual. Filtering off the dessicant and spinning off the solvent yield 196.5 mg (88.1%) of the desired amine.
1H-NMR (300 MHz, DMSO-d6): δ=5.6 (2H), 6.68 (1H), 6.87.45 (1H), 7.00 (1H), 7.17 (1H), 7.39 (1H), 11.7 (1H).
2-(3-Fluoro-2-methoxy-4-methylphenyl)-2-methylpropanenitrile
14.48 g (91.56 mmol) of 2,6-difluoro-3-methylanisole is dissolved in 800 ml of toluene. After 272.2 ml (137.35 mmol) of a 0.5 molar solution of potassium hexamethyl disilazide in toluene is added, 25.31 g (366.26 mmol) of isobutyronitrile is added in drops. The batch is stirred for 10 days at room temperature and then added to a 1 M HCl solution. After being extracted three times with methyl tert-butyl ether, the combined organic extracts are washed with saturated NaCl solution and dried. After spinning-in and chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 10.32 g (49.5%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.77 (6H), 2.29 (3H), 4.09 (3H), 6.86 (1H), 6.95 (1H).
2-(3-Fluoro-2-methoxy-4-methylphenyl)-2-methylpropanal
10.32 g (45.33 mmol) of the above-described nitrile is dissolved in 138 ml of toluene. Under cover gas, 37.4 ml of a 1.2 molar solution of DIBAH in toluene is added in drops at −70° C. After three hours of stirring, 7.92 ml of isopropanol, and after a brief period of stirring, 516 ml of a 10% L-(+)-tartaric acid solution are added in drops. The temperature increases, and the batch is stirred vigorously overnight at room temperature. The reaction mixture is shaken twice with methyl tert-butyl ether. The combined organic extracts are shaken with brine, dried, and the solvent is spun off. Since the residue that is obtained (11.61 g>100%) still contains about 30% suspended material, it is subjected to the reduction conditions once again, with the difference that during the working-up, the isopropanol is eliminated. 9.94 g of a product, which in addition to the desired aldehyde still contains the starting material and the corresponding alcohol, is isolated. This mixture is mixed again with a 1.2 M DIBAH solution in toluene, but this time at −20° C. and with more stirring at −10 to 0° C. to obtain a uniform compound. After the usual working-up and chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 5.82 g of the corresponding alcohol and 1.50 g of the aldehyde are ultimately obtained. The alcohol (5.82 g=27.42 mmol) is oxidized to aldehyde according to Swern at −78° C. After the usual working-up and chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 5.22 g (90.6%) of the desired aldehyde is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.38 (6H), 2.29 (3H), 3.85 (3H), 6.83-6.98 (2H), 9.59 (1H).
(E/Z)-4-(3-Fluoro-2-methoxy-4-methylphenyl)-4-methylpent-2-enoic acid ethyl ester
17.1 ml of a 2 molar LDA solution in THF is added in drops to a solution of 8.62 g (32.96 mmol) of 2-ethoxy-phosphonoacetic acid triethyl ester in 20 ml of absolute THF at 0° C. After 40 minutes of stirring at 0° C., 6.72 g (31.96 mmol) of 2-(3-fluoro-2-methoxy-4-methylphenyl)-2-methylpropanal, dissolved in 20 ml of THF, is added in drops at 0° C. After stirring overnight at room temperature, the reaction mixture is carefully mixed with 80 ml of water and extracted three times with methyl tert-butyl ether. The combined organic extracts are washed with brine, dried, and the solvent is spun off after the dessicant is filtered off. The residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 8.74 g (84.3%) of a mixture that in addition to the desired compound also contains starting material (aldehyde), which is separated in the next stage, is isolated.
(E/Z)-4-(3-Fluoro-2-methoxy-4-methylphenyl)-4-methylpent-2-enoic acid
8.74 g (26.95 mmol) of (E/Z)-4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methylpent-2-enoic acid ethyl ester is mixed with 245 ml of 1N NaOH in ethanol/water (2:1) and stirred overnight at room temperature. The ethanol is drawn off in a rotary evaporator, and the residue is diluted with water and extracted twice with methyl tert-butyl ether. The combined organic extracts contain the unreacted aldehyde from the above-described reaction. The aqueous phases are carefully acidified with concentrated hydrochloric acid to a pH of 3 while being cooled in an ice bath and extracted three times with 300 ml each of methyl tert-butyl ether. These ether extracts are washed with brine, dried, the solvent is spun off, and the residue (6.41 g=80.3%) is incorporated in crude form into the next stage. The recovered aldehyde is subjected again to the sequence of Homer-Wittig reaction and subsequent saponification. As a result, another 2.29 g of the desired compound (E/Z)-4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methylpent-2-enoic acid is obtained. Since the compound is an E/Z mixture (not a 1:1 ratio), only the positions of the signals are indicated in the NMR spectrum.
1H-NMR (300 MHz, CDCl3): δ=0.98, 1.40, 1.53, 2.21, 3.38, 3.75-3.88, 6.72-6.85, 7.00.
4-(3-Fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid
8.70 g (29.36 mmol) of the (E/Z)-4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methylpent-2-enoic acid that is obtained from the previous batch is mixed with 139 ml of a 1 molar sulfuric acid and 13.9 ml of glacial acetic acid and stirred for two days at a bath temperature of 90° C. After the cooling, the batch is made basic with solid potassium carbonate (caution, foam). It is extracted three times with methyl tert-butyl ether, and the combined organic extracts are discarded after TLC monitoring. The aqueous phase is acidified with concentrated hydrochloric acid and shaken three times with methyl tert-butyl ether. The ether extracts are washed with brine, dried, and the solvent is spun off. The remaining residue (6.04 g=76.6%) is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=1.48 (6H), 2.25 (3H), 3.50 (2H), 3.93 (3H), 6.82 (1H), 6.95 (1H).
4-(3-Fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester
6.04 g (22.52 mmol) of 4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid is dissolved in 140 ml of ethanol, mixed with 2.5 ml of sulfuric acid, and refluxed for six hours. The ethanol is drawn off in a rotary evaporator, and the residue is carefully mixed with 300 ml of saturated sodium bicarbonate solution. It is extracted three times with ethyl acetate. The combined organic extracts are washed once with saturated sodium bicarbonate solution and once with brine. After drying, and after the dessicant is filtered off and the solvent is spun in, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 5.58 g (83.7%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.29 (3H), 1.47 (6H), 2.23 (3H), 3.40 (2H), 3.95 (3H), 4.17 (2H), 6.79 (1H), 6.90 (1H).
4-(3-Fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-trifluoromethyl-2-trimethylsilyloxy-pentanoic acid ethyl ester
5.58 g (18.83 mmol) of 4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester is dissolved in 30 ml of THF and mixed at 0° C. with 3.21 g (22.6 mmol) of (trifluoromethyl)-trimethylsilane and 46.1 mg of tetrabutylammonium fluoride. After six hours of stirring between 0 and 5° C., the batch is added to ice water. It is extracted three times with methyl tert-butyl ether, and the combined organic extracts are washed with brine. After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 7.5 g (90.8%) of the desired compound is obtained.
4-(3-Fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol
7.5 g (17.1 mmol) of 4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentanoic acid ethyl ester is dissolved in 60 ml of diethyl ether and mixed in portions with 1.3 g (34.2 mmol) of LiAlH4 at 0 to 5° C. After five hours of stirring at room temperature, 60 ml of saturated NaHCO3 is added in drops to the reaction mixture while being cooled in an ice bath. It is stirred vigorously for one hour at room temperature. After extraction with methyl tert-butyl ether, the organic phases are shaken with brine, dried, and the solvent is spun off. After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 3.65 g (65.8%) of the desired diol is obtained.
MS (CI): 342 (100%), 181 (18%).
4-(3-Fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal
1.57 g (12.31 mmol) of oxalyl chloride is introduced into 27 ml of dichloromethane and cooled to −78° C. After dropwise addition of 1.93 g of DMSO, dissolved in 5.2 ml of dichloromethane, the batch is stirred for five more minutes. Then, 3.65 (11.26 mmol) of 4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol, dissolved in 11.5 milliliters of dichloromethane, is added in drops. After two hours of stirring, the batch is carefully mixed with 6.61 ml (56.28 mmol) of triethylamine. After one and one-half hours of vigorous stirring at room temperature, water is added, and the batch is shaken twice with dichloromethane. The combined organic extracts are washed with 1% sulfuric acid, saturated sodium bicarbonate solution and brine. After the organic phase is dried, the solvent is spun off. 2.79 g (76.9%) of the aldehyde that is obtained, which is further incorporated in crude form, remains.
1H-NMR (300 MHz, CDCl3): δ=1.41 (3H), 1.45 (3H), 2.15-2.30 (5H), 3.29 (1H), 3.60 (1H), 4.02 (3H), 6.70-6.82 (2H), 9.10 (1H).
(rac.)-5-{[4-(3-Fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentylidene]amino}isoquinolin-1(2H)-one
150 mg (0.465 mmol) of 4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, 74.5 mg (0.465 mmol) of 5-amino-isoquinolin-1(2H)-one and 264.4 mg (0.930 mmol) of titanium tetraisopropylate are stirred in 2.5 ml of xylene for five hours at 120° C. The mixture is diluted with ethyl acetate, and washed once with brine. The solvent is spun off, and the residue is chromatographed on a Flashmaster. 98.6 mg (45.6%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): =1.40 (3H), 1.58 (3H), 1.89 (3H), 2.29 (1H), 3.30 (1H), 4.00 (3H), 4.79 (1H), 6.38 (1H), 6.67-6.78 (2H), 6.80 (1H), 7.20 (1H), 7.38 (1H), 7.55 (1H), 8.32 (1H), 11.0 (1H).
(rac.) 5-{[6-Fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one)
1.39 ml (1.27 mmol) of titanium tetrachloride is carefully added in drops at 0° C. to 98.6 mg (0.212 mmol) of the compound rac-5-{[4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentylidene]amino}isoquinolin-1(2H)-one that is described in the previous paragraph, and then it is stirred for three hours at room temperature. The reaction mixture is carefully mixed at 0° C. with saturated sodium bicarbonate solution. After being extracted three times with ethyl acetate, the combined organic extracts are washed with saturated NaCl solution. After drying on sodium sulfate, the solvent is spun off, and the remaining residue is chromatographed on a Flashmaster. 63.3 mg (64.2%) of the desired compound is isolated.
1H-NMR (300 MHz, CD3OD): =1.52 (3H), 1.67 (3H), 2.05-2.20 (5H), 3.98 (3H), 5.10 (1H), 6.80-6.95 (2H), 7.08 (1H), 7.19 (1H), 7.40 (1H), 7.70 (1H).
(rac.) 5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
59.7 mg (0.128 mmol) of (rac.) 5-{[6-fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one is mixed at 0° C. with 1.3 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for one hour at 0 to 5° C. At -10C, saturated sodium bicarbonate solution is now carefully added in drops. After 10 minutes of vigorous stirring at room temperature, the batch is extracted three times with methyl tert-butyl ether. The organic phases are dried, and after the solvent is spun off, the residue is chromatographed on a Flashmaster. 46.5 mg (80.3%) of the desired compound is isolated.
1H-NMR (300 MHz, CD3OD): =1.56 (3H), 1.70 (3H), 2.00-2.20 (5H), 5.09 (1H), 6.65 (1H), 6.85 (1H), 7.05 (1H), 7.18 (1H), 7.39 (1H), 7.68 (1H).
Example 284
(rac.) 5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
5-Aminoquinolin-2(1H)-one
4.5 g of 5-nitroquinolin-2(1H)-one (Chem. Pharm. Bull. 29, 651 (1981)) is hydrogenated in 200 ml of ethyl acetate and 500 ml of methanol in the presence of 450 mg of palladium on activated carbon as a catalyst under normal pressure with hydrogen until the reaction is completed. The catalyst is removed by filtration through diatomaceous earth, and the reaction solution is concentrated by evaporation in a vacuum. 3.8 g of the title compound is obtained as a yellow solid.
1H-NMR (DMSO): δ=5.85 (bs, 2H), 6.27 (d, 1H), 6.33 (d, 1H), 6.43 (d, 1H), 7.10 (t, 1H), 8.07 (d, 1H), 11.39 (bs, 1H)
rac-5-{[4-(3-Fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentylidene]amino}isoquinolin-2(1H)-one
150 mg (0.465 mmol) of 4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal (described in Example 1), 74.5 mg (0.465 mmol) of 5-amino-isoquinolin-2(1H)-one and 264.4 mg (0.930 mmol) of titanium tetraisopropylate are stirred in 2.5 ml of xylene for five hours at 120° C. The mixture is diluted with ethyl acetate and washed once with brine. The solvent is spun off, and the residue is chromatographed on a Flashmaster. 132.2 mg (61.2%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): =1.40 (3H), 1.56 (3H), 1.82 (3H), 2.29 (1H), 3.28 (1H), 3.98 (3H), 4.70 (1H), 6.30-6.45 (2H), 6.70-6.80 (2H), 7.30 (1H), 7.40 (1H), 7.63 (1H), 8.07 (1H), 12.27 (1H).
(rac.) 5-{[6-Fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-2(1H)-one
1.86 ml (1.708 mmol) of titanium tetrachloride is carefully added in drops to 132.2 mg (0.285 mmol) of the compound rac-5-{[4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}isoquinolin-2(1H)-one that is described in the previous paragraph at 0° C., and then it is stirred for three hours at room temperature. The reaction mixture is carefully mixed at 0° C. with saturated sodium bicarbonate solution. After being extracted three times with ethyl acetate, the combined organic extracts are washed with saturated NaCl solution. After drying on sodium sulfate, the solvent is spun off, and the remaining residue is chromatographed on a Flashmaster. 106.7 mg (80.7%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): =1.52 (3H), 1.68 (3H), 1.98-2.25 (5H), 3.95 (3H), 4.60 (1H), 4.99 (1H), 5.49 (1H), 6.49-6.62 (3H), 6.80 (1H), 7.35 (1H), 8.16 (1H), 10.40 (1H).
(rac.) 5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-2(1H)-one)
101.4 mg (0.218 mmol) of (rac.) 5-{[6-fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-2(1H)-one is mixed at 0° C. with 2.2 ml of a I molar solution of boron tribromide in dichloromethane and stirred for one hour at 0 to 5° C. At −10° C., saturated sodium bicarbonate solution is now carefully added in drops. After 10 minutes of vigorous stirring at room temperature, the batch is extracted three times with methyl tert-butyl ether. The organic phases are dried, and after the solvent is spun off, the residue is chromatographed on a Flashmaster. 93.7 mg (95.3%) of the desired compound is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.58 (3H), 1.69 (3H), 2.00-2.20 (5H), 5.10 (1H), 6.51 (1H), 6.55-6.74 (3H), 7.39 (1H), 8.22 (1H).
Example 285
(rac.)6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
5-Amino-8-fluoro-2-methylquinazoline
A solution of 2.4 g (18.6 mmol) of 2,5-difluoroaniline in 11 ml of water and 1.6 ml of concentrated hydrochloric acid (37%) that is 50° C. is added to a solution of 3.35 g (20.25 mmol) of chloral hydrate and 21.27 g (149.7 mmol) of sodium sulfate in 72 ml of water, which was previously stirred at this temperature for 1 hour. It is stirred for another 30 minutes at room temperature, and after the addition of 4.09 g (58.9 mmol) of hydroxylammonium chloride in 19 ml of water, it is heated over 45 minutes to 125° C. and this temperature is maintained for 5 minutes. After cooling, and after another hour, the deposited light brown precipitate is filtered off, washed with water, and dried. 3.0 g (15.0 mmol) of the hydroxylimine is obtained as an intermediate product, which is dissolved in portions in 15 ml of concentrated sulfuric acid at 60° C. After the addition is completed, it is heated for 2 hours to 80° C. and for 4 hours to 90° C. It is allowed to cool, and the solution is poured onto 100 g of ice. It is extracted with ethyl acetate, the organic phase is washed with water, dried on sodium sulfate and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate (0-45%), 1.2 g (7.1 mmol) of 4,7-difluoroisatin is obtained. 1.8 ml of a 30% hydrogen peroxide solution is added in drops to the isatin in 30 ml of a 1 molar sodium hydroxide solution over 10 minutes. After 2 hours of stirring at room temperature, it is cooled to 0° C., and 5 ml of a 4 molar hydrochloric acid is added and diluted with 50 ml of water. It is extracted with ethyl acetate, dried on sodium sulfate, concentrated by evaporation, and 1.27 g of the 3,6-difluoroanthranilic acid, which is reacted without further purification, is obtained quantitatively. The 3,6-difluoroanthranilic acid is heated in 8 ml of acetic acid anhydride for 45 minutes to 100° C. After cooling, the acetic acid and excess acetic acid anhydride that are produced are removed azeotropically with toluene in a vacuum. The residue is mixed with 40 ml of a 25% ammonia solution while being cooled with ice, and it is stirred for 72 hours. It is diluted with water and acidified with acetic acid. It is extracted with ethyl acetate, the organic phase is washed with water, dried on sodium sulfate, and concentrated by evaporation. The thus obtained 1.03 g (5.25 mmol) of 5,8-difluoro-2-methyl-3H-quinazolin-4-one and 6 g of phosphorus pentachloride are heated in 20 ml of phosphoryl chloride over 12 hours to 125° C. After cooling, it is poured into saturated NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried, and the solvent is removed. 1.7 g of 4-chloro-5,8-difluoro-2-methylquinazoline, which is dissolved in 60 ml of ethyl acetate and 5 ml of triethylamine, is obtained quantitatively. 600 mg of palladium on carbon is added, and it is shaken for 2 hours (480 ml hydrogen absorption) under a hydrogen atmosphere at normal pressure. Catalyst is removed from the solution by means of filtration on Celite, whereby it is rewashed with 100 ml of ethanol and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate-ethanol (0-40%), 550 mg of 5,8-difluoro-2-methylquinazoline is obtained. 890 mg (13.7 mmol) of sodium azide is added to 240 mg (1.3 mmol) of 5,8-difluoro-2-methylquinazoline, 300 mg (1.13 mmol) of 18-crown-6 in 10 ml DMF, and the mixture is heated over 8 hours to 125° C. The solvent is removed in a vacuum, it is chromatographed on silica gel with ethyl acetate, and 52 mg of product is obtained.
1H-NMR (300 MHz, CDCl3); δ=2.92 (s, 3H), 4.31 (br., 2H), 6.67 (dd, 1H), 7.38 (dd, 1H), 9.37 (s, 1H).
1,1,1-Trifluoro-4-(3-fluoro-2-methoxy-3-methylphenyl)-2-[(8-fluoro-2-methyl-quinazolyl-5-yl)iminomethyl]-4-methylpentan-2-ol
150 mg (0.465 mmol) of 4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal (described in Example 1), 83.7 mg (0.465 mmol) of 5-amino-8-fluoro-2-methylquinazoline and 264.4 mg (0.930 mmol) of titanium tetraisopropylate are stirred in 2.5 ml of xylene for five hours at 120° C. The mixture is diluted with ethyl acetate and washed once with brine. The solvent is spun off, and the residue is chromatographed on a Flashmaster. 152.8 mg (68.2%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.40 (3H), 1.55-1.66 (6H), 2.29 (1H), 3.00 (3H), 3.30 (1H), 3.98 (3H), 4.60 (1H), 6.29 (1H), 6.67 (1H), 6.78 (1H), 7.43 (1H), 7.71 (1H), 9.49 (1H).
(rac.)6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
2.1 ml (1.902 mmol) of titanium tetrachloride is carefully added in drops to 152.8 mg (0.317 mmol) of the compound 1,1,1-trifluoro-4-(3-fluoro-2-methoxy-3-methylphenyl)-2-[(8-fluoro-2-methyl-quinazolyl-5-yl)iminomethyl] -4-methylpentan-2-ol, described in the previous paragraph, at 0° C., and then it is stirred for three hours at room temperature. The reaction mixture is carefully mixed at 0° C. with saturated sodium bicarbonate solution. After being extracted three times with ethyl acetate, the combined organic extracts are washed with saturated NaCl solution. After drying on sodium sulfate, the solvent is spun off, and the remaining residue is chromatographed on a Flashmaster. 121.8 mg (79.7%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.57 (3H), 1.72 (3H), 2.05-2.29 (5H), 2.95 (3H), 3.97 (3H), 4.93 (1H), 5.63 (1H), 5.90 (1H), 6.68 (1H), 6.90 (1H), 7.50 (1H) 9.35 (1H).
(rac. )6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
111.2 mg (0.231 mmol) of (rac.)6-fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen -2-ol is mixed at 0° C. with 3.2 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for one and one-half hours at 0 to 5° C. At 0° C., saturated sodium bicarbonate solution is now carefully added in drops. After 10 minutes of vigorous stirring at room temperature, the batch is extracted three times with ethyl acetate. The organic phases are dried, and after the solvent is spun off, the residue is chromatographed on a Flashmaster. 66.4 mg (61.5%) of the desired compound is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.59 (3H), 1.70 (3H), 2.00-2.20 (5H), 2.88 (3H), 5.20 (1H), 6.68 (1H), 6.85 (1H), 7.58 (1H), 9.65 (1H).
Example 286
(rac.) 5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
5-Amino-2-methyl-phthalazin-1-one
3-Bromo-4-nitro-phthalide
5.37 g of 4-nitrophthalide (Tetrahedron Lett. (2001), 42, pp. 1647-50), 8.04 g of N-bromosuccinimide and 196 mg of benzoyl peroxide are refluxed in 80 ml of benzotrifluoride and heated with exposure to light until the reaction is completed. It is added to water, extracted with dichloromethane, washed several times with water, dried, and the solvent is removed in a vacuum. 7.24 g of 3-bromo-4-nitro-phthalide is obtained as a solid.
1H-NMR (300 MHz, CDCl3), δ=7.26 (s, 1H), 7.88 (t, 1H), 8.30 (d, 1H), 8.56 (d, 1H)
5-Nitro-phthalazin-1-one
18.25 g of hydrazine sulfate and 14.88 g of sodium carbonate are stirred in 300 ml of DMF at 100° C. for one hour. Then, 7.24 g of 3-bromo-4-nitro-phthalide in 100 ml of DMF is added, and it is stirred for another 4 hours at 100° C. It is added to water, extracted several times with ethyl acetate, and the organic phase is washed with water and brine. It is dried, and the solvent is removed in a vacuum. After recrystallization from ethyl acetate, 2.35 g of 5-nitro-phthalazin-1-one is obtained as a solid.
1H-NMR (300 MHz, DMSO-d6), δ=8.05 (t, 1H), 8.57-8.66 (m, 2H), 8.73 (s, 1H), 13.13 (bs, 1H)
2-Methyl-5-nitro-phthalazin-1-one
1.6 g of 5-nitro-phthalazin-1-one and 2.31 g of potassium carbonate are stirred for 10 minutes at room temperature in 60 ml of DMF. 1.1 ml of methyl iodide is added, and it is stirred overnight. It is added to water, extracted several times with ethyl acetate, and the organic phase is washed with water and brine. It is dried, and the solvent is removed in a vacuum. 1.57 g of 2-methyl-5-nitro-phthalazin-1-one is obtained as a yellow solid.
1H-NMR (300 MHz, DMSO-d6), δ=3.73 (s, 3H), 8.05 (t, 1H), 8.62 (d, 2H), 8.75 (s, 1H)
5-Amino-2-methyl-phthalazin-1-one
1.57 g of 2-methyl-5-nitro-phthalazin-1-one and 130 mg of palladium on activated carbon are suspended in 45 ml of ethyl acetate and hydrogenated under normal pressure with hydrogen. It is filtered through diatomaceous earth, and the solvent is removed in a vacuum. 1.26 g of 5-amino-2-methyl-phthalazin-1-one is obtained as a yellow solid.
1H-NMR (300 MHz, CDCl3), δ=3.81 (s, 3H), 7.00 (d, 1H), 7.50 (t, 1H), 7.80 (d, 1H), 8.16 (s, 1H)
(rac.)-5-{[4-(3-Fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentylidene]amino}2-methyl-phthalazinon-1-one
400 mg (1.241 mmol) of (rac.) 4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, 271.4 mg (1.241 mmol) of 5-amino-2-methyl-phthalazin-1-one and 705.5 mg (2.482 mmol) of titanium tetraisopropylate are stirred in seven ml of xylene for five hours at 120° C. After cooling, the mixture is diluted with ethyl acetate and washed once with brine. The aqueous phase is extracted twice with ethyl acetate. The combined organic extracts are dried, and the solvent is spun off. The residue is chromatographed on a Flashmaster. 40.9 mg (68.5%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3), δ=1.39 (3H), 1.60 (3H), 1.78 (3H), 2.28 (1H), 3.31 (1H), 3.90 (3H), 3.99 (3H), 4.58 (1H), 6.38 (1H), 6.78 (1H), 6.89 (1H), 7.58-7.68 (2H), 8.27-8.35 (2H).
(rac.) 5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one and (rac.) 5-{[6-Fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
100 mg (0.208 mmol) of (rac.)-5-{[4-(3-fluoro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentylidene]amino}2-methyl-phthalazinon-1-one is mixed at 0° C. with 2.1 ml of a 1 M solution of boron tribromide in dichloromethane, and it is stirred for two hours at 0 to 5° C. After careful mixing with saturated sodium bicarbonate solution, the batch is extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried, and the residue that remains after the spinning-in is chromatographed on a Flashmaster. 38.1 mg of a mixture that consists of the desired compound and the corresponding ether is obtained. First, a separation of the ether from phenol is carried out, namely by means of HPLC (Chiralcel OD 20μ, eluants:hexane/ethanol). The respective racemates are then separated into their respective enantiomers by means of chiral HPLC (Chiralpak AD 20μ, eluants:hexane/2-propanol or hexane/ethanol), so that the following four compounds result:
(+)-5-{[6-fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
(−)-5-{[6-fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
1H-NMR (300 MHz, CD3OD), δ=1.59 (3H), 1.70 (3H), 2.03-2.20 (5H), 3.86 (3H), 5.20 (1H), 6.63 (1H), 7.23 (1H), 7.60-7.72 (2H), 8.58 (1H).
(+)-5-{[6-Fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
1H-NMR (300 MHz, CD3OD), δ=1.40 (3H), 1.59 (3H), 2.09 (1H), 2.20-2.35 (4H), 3.52 (3H), 3.80 (3H), 5.34 (1H), 7.08 (1H), 7.52 (1H), 7.62-7.78 (2H), 8.60 (1H).
(−)-5-{[6-fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-methylphthalazin-1-one
Example 287
(rac.) 5-{[6-Chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
2-(3-Chloro-2-methoxy-4-methylphenyl)-2-methylpropanenitrile
17.6 g (100.8 mmol) of 2-chloro-6-fluoro-3-methylanisole is dissolved in 880 ml of toluene. After 27.8 g (403.2 mmol) of isobutyric acid nitrile is added, 302.4 ml (151.2 mmol) of a 0.5 molar solution of potassium hexamethyl disilazide in toluene is added in drops within 40 minutes (temperature increase to 27° C.). After 19 days of stirring at room temperature, the batch is mixed with 300 ml of water and 400 ml of ethyl acetate and then acidified with 10% sulfuric acid to a pH of 4. The aqueous phase is shaken with 200 ml of ethyl acetate. The combined organic extracts are washed with water and twice with saturated NaCl solution and then dried. After spinning-in and chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 12.01 g (53.4%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.75 (6H), 2.40 (3H), 4.09 (3H), 6.99 (1H), 7.09 (1H).
2-(3-Chloro-2-methoxy-4-methylphenyl)-2-methylpropanal
11 g (49.17 mmol) of the above-described nitrile is dissolved in 196 ml of toluene. At −65° C. to −60° C., 61.5 ml of a 1.2 molar solution of DIBAH in toluene is added in drops under nitrogen. After two hours of stirring at −65° C., 280 ml of a 20% L-(+)-tartaric acid solution is added in drops. The temperature increases up to 0° C. The cold bath is removed, and the batch is stirred vigorously at room temperature for two hours. The reaction mixture is shaken twice with diethyl ether. The combined organic extracts are shaken with water and with brine, dried, and the solvent is spun off. Chromatography on silica gel (mobile solvent:ethyl acetate/hexane) yields 6.12 g of the desired compound.
1H-NMR (300 MHz, CDCl3): δ=1.38 (6H), 2.39 (3H), 3.79 (3H), 7.03 (1H), 7.13 (1H), 9.59 (1H).
(E/Z)-4-(3-Chloro-2-methoxy-4-methylphenyl)-2-ethoxy-4-methylpent-2-enoic acid ethyl ester
14.9 ml of a 2 molar LDA solution in THF is added in drops within 20 minutes to a solution of 7.45 g (27.79 mmol) of 2-ethoxy-phosphonoacetic acid triethyl ester, dissolved in 30 ml of absolute THF, at 0° C. After 45 minutes of stirring at 0° C., 6.3 g (27.79 mmol) of 2-(3-chloro-2-methoxy-4-methylphenyl)-2-methylpropanal, dissolved in 18 ml of THF, is quickly added in drops at 0° C. After stirring overnight at room temperature, the reaction mixture is poured into 100 ml of water and extracted twice with 250 ml each of diethyl ether. The combined organic extracts are washed with water and brine, dried, and the solvent is spun off after the dessicant is filtered off. The residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 8.4 g, which in addition to the desired compound also still contains starting material (aldehyde), which is separated in the next stage, is isolated.
(E/Z)-4-(3-Chloro-2-methoxy-4-methylphenyl)-2-ethoxy-4-methylpent-2-enoic acid
8.4 g (24.65 mmol) of (E/Z)-4-(3-chloro-2-methoxy-4-methylphenyl)-2-ethoxy-4-methylpent-2-enoic acid ethyl ester is mixed with 246 ml of 1 N NaOH in ethanol/water (2:1) and stirred for 19 hours at room temperature. The ethanol is drawn off in a rotary evaporator, and the residue is extracted twice with diethyl ether. The combined organic extracts are washed once with 50 ml of water. After drying, the solvent is spun off. The residue (unreacted aldehyde from the above-described reaction), is 2 g and is used again in the Horner Wittig reaction with subsequent saponification. The combined aqueous phases are carefully acidified with concentrated hydrochloric acid until a pH of 3 is reached while being cooled in an ice bath, and it is extracted twice with 300 ml each of diethyl ether. These ether extracts are washed with water and brine, dried, the solvent is spun off, and the residue (5.62=72.9%) is incorporated in crude form into the next stage. Since the compound is an E/Z mixture that is not a 1:1 ratio, only the positions of the signals are indicated in the NMR spectrum.
1H-NMR (300 MHz, CDCl3): δ=0.98, 1.40, 1.57, 2.31, 2.38, 3.39, 3.78, 3.80-3.90, 5.79, 6.79, 6.88-6.98, 7.18.
4-(3-Chloro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid
7.30 g (23.34 mmol) of the (E/Z)-4-(3-chloro-2-methoxy-4-methylphenyl)-2-ethoxy-4-methylpent-2-enoic acid that is obtained from the previous batch is mixed at room temperature with 143 ml of a 1 molar sulfuric acid and 20 ml of glacial acetic acid, and it is stirred for 30 hours at a bath temperature of 90° C. After three days of stirring at room temperature, it is stirred vigorously for another two days at 90° C. The batch is made basic (pH 9) with solid potassium carbonate while being cooled in an ice bath (caution, foam). It is extracted twice with diethyl ether, and the combined organic extracts are discarded after TLC monitoring. The aqueous phase is acidified with concentrated hydrochloric acid while being cooled in an ice bath until a pH of 4 is reached, and it is shaken twice with diethyl ether. The ether extracts are washed with water and brine, dried, and the solvent is spun off. The remaining residue (5.37 g=80.8%) is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=1.50 (6H), 2.34 (3H), 3.50 (2H), 3.89 (3H), 6.97 (1H), 7.15 (1H).
4-(3-Chloro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester
5.37 g (18.86 mmol) of 4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid is dissolved in 112 ml of ethanol, mixed with 2 ml of concentrated sulfuric acid and refluxed for five hours. The ethanol is drawn off in a rotary evaporator, and the residue is carefully mixed with saturated sodium bicarbonate solution after 50 ml of water is added. It is extracted twice with ethyl acetate. The combined organic extracts are washed with water and with brine. After drying, and after the dessicant is filtered off and the solvent is spun in, the residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 4.81 g (81.6%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.30 (3H), 1.48 (6H), 2.36 (3H), 3.40 (2H), 3.90 (3H), 4.18 (2H), 6.92 (1H), 7.10 (1H).
(rac.) 4-(3-Chloro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentanoic acid ethyl ester
4.8 g (15.35 mmol) of 4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester is dissolved in 25 ml of THF, mixed at 0° C. with 2.62 g (18.41 mmol) of (trifluoromethyl)-trimethylsilane and 37.6 mg of tetrabutylammonium fluoride and stirred for one and one-half hours at between 0 and 5° C. The batch is added to 50 ml of ice water and extracted twice with diethyl ether. The combined organic extracts are washed with water and with brine. After silica gel (mobile solvent:ethyl acetate/hexane) is chromatographed, 4.4 g (63%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=0.03 (9H), 1.22 (3H), 1.38 (3H), 1.42 (3H), 2.35 (3H), 2.52 (1H), 2.69 (1H), 3.78 (1H), 3.99 (3H), 4.03 (1H), 6.90 (1H), 7.00 (1H).
(rac.) 4-(3-Chloro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid ethyl ester
4.4 g (9.67 mmol) of (rac.) 4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentanoic acid ethyl ester is dissolved in 56 ml of tetrahydrofuran and mixed with 3.05 g (9.67 mmol) of tetrabutylammonium fluoride trihydrate and stirred for one and one-half hours at room temperature. The reaction mixture is diluted with water and extracted twice with diethyl ether. The organic phases are washed with water and with brine. After drying, the solvent is spun off, and the remaining residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 1.26 g of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.20 (3H), 1.40 (3H), 1.49 (3H), 2.29-2.40 (4H), 2.82 (1H), 3.55 (1H), 3.65 (1H), 3.98 (3H), 4.08 (1H), 6.90 (1H), 7.02 (1H).
(rac.) 4-(3-Chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and (rac.) 4-(3-Chloro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol
1.05 g (2.74 mmol) of (rac.) 4-(3-chloro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid ethyl ester is dissolved in 10 ml of diethyl ether and mixed in portions at 0° C. with 78 mg (2.06 mmol) of LiAlH4. After one hour of stirring at 0° C. and another hour of stirring at between 0 and 10° C., the reaction mixture is mixed drop by drop with 2.4 ml of saturated NaHCO3 solution while being cooled in an ice bath. It is stirred for 30 minutes while being cooled in an ice bath and stirred vigorously for one and one-half hours at room temperature. The precipitate is suctioned off, washed with ethyl acetate, and the filtrate is concentrated by evaporation in a rotary evaporator. After the residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane), 425 mg (45.8%) of the aldehyde and 420.4 mg (44.9%) of the diol are obtained.
Aldehyde: 1H-NMR (300 MHz, CDCl3): δ=1.46 (3H), 1.49 (3H), 2.28 (1H), 2.39 (3H), 3.30 (1H), 3.59 (1H), 4.00 (3H), 6.89-7.00 (2H), 9.06 (1H)
Alcohol: 1H-NMR (300 MHz, CDCl3): δ=1.48 (3H), 1.57 (3H), 1.82 (1H), 2.20 (1H), 2.38 (3H), 2.55 (1H), 2.91 (1H), 3.29-3.46 (2H), 4.00 (3H), 6.96 (1H), 7.16 (1H).
(rac.)-5-{[4-(3-Chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}isoquinolin-1(2H)-one
225 mg (0.664 mmol) of (rac.) 4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, 106.3 mg (0.664 mmol) of 5-amino-isoquinolin-1(2H)-one and 0.39 ml (1.328 mmol) of titanium tetraisopropylate are stirred in 3.6 ml of o-xylene for two and one-half hours at 120° C. After cooling, the batch is poured into 15 ml of saturated brine and diluted with ethyl acetate. After 20 minutes of vigorous stirring at room temperature, it is filtered on a column, filled with Extrelute. The residue is on silica gel (mobile solvent:ethyl acetate/hexane). 224.7 mg (70.3%) of the desired compound is isolated.
1H-NMR (300 MHz, DMSO-d6): δ=1.49 (3H), 1.52 (3H), 1.89 (3H), 2.25 (1H), 3.04 (1H), 3.89 (3H), 6.15 (1H), 6.65 (1H), 6.72 (1H), 6.79 (1H), 6.99 (1H), 7.20 (1H), 7.37 (1H), 7.57 (1H), 8.06 (1H), 11.35 (1H).
(rac.) 5-{[6-Chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
130 mg (0.27 mmol) of the compound (rac.)-5-{[4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentylidene]amino}isoquinolin-1(2H)-one that is described in the previous paragraph is dissolved in 1.6 ml of dichloromethane and mixed at 0° C. drop by drop with 0.8 ml (0.81 mmol) of titanium tetrachloride and then stirred for two and one-half hours at room temperature. The reaction mixture is carefully mixed at 0° C. with saturated sodium bicarbonate solution (pH 8). It is diluted with ethyl acetate, the cold bath is removed, and it is stirred vigorously at room temperature for 15 minutes. After being extracted twice with ethyl acetate, the combined organic extracts are washed with brine. After drying on sodium sulfate, the solvent is spun off, and the remaining residue is chromatographed on silica gel. 71.3 mg (54.8%) of the desired compound is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.55 (3H), 1.65 (3H), 2.05-2.28 (5H), 3.95 (3H), 5.14 (1H), 6.85 (1H), 7.00-7.12 (2H), 7.19 (1H), 7.40 (1H), 7.70 (1H).
(rac.) 5-{[6-Chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
40 mg (0.083 mmol) of (rac.) 5-{[6-chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one is mixed at room temperature with 0.8 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for four hours at room temperature. Since starting material is still present, another 0.8 ml of boron tribromide solution is added, and it is stirred for 16 hours at room temperature. The reaction mixture is mixed drop by drop at −30° C. with saturated sodium bicarbonate solution (pH 8). The batch is mixed with ethyl acetate, and the cold bath is removed. After 10 minutes of vigorous stirring at room temperature, the batch is extracted twice with ethyl acetate. The organic phases are washed with water and with brine, dried, and the residue is chromatographed on silica gel (mobile solvent:methanol/dichloromethane) after the solvent is spun off. 19.9 mg (51.2%) of the desired compound is isolated.
1H-NMR (300 MHz, DMSO-d6): δ=1.50 (3H), 1.65 (3H), 1.92-2.20 (5H), 5.28 (1H), 5.90 (1H), 6.09 (1H), 6.69 (1H), 6.80 (1H), 7.03 (1H), 7.18 (1H), 7.25 (1H), 7.50 (1H), 8.90 (1H), 11.24 (1H).
Example 288
(rac.) 5-{[6-Chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
(rac. )-5-{([4-(3-Chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentylidene]amino}isoquinolin-2(1H)-one
225 mg (0.664 mmol) of (rac.) 4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal (described in Example 287) and 106.3 mg (0.664 mmol) of 5-amino-isoquinolin-2(1H)-one (described in Example 2) are mixed with 3.6 ml of xylene. After 0.39 ml (1.328 mmol) of titanium tetraisopropylate is added, the batch is stirred for two and one-half hours at 120° C. The mixture is added to 15 ml of saturated brine and diluted with 20 ml of ethyl acetate. The reaction mixture is filtered on Extrelute and washed with 300 ml of a mixture that consists of ethyl acetate/dichloromethane. The solution that is obtained is spun in, and the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 248.5 mg (77.8%) of the desired compound is isolated.
1H-NMR (300 MHz, DMSO-d6): =1.38 (3H), 1.53 (3H), 1.85 (3H), 2.20 (1H), 3.05 (1H), 3.85 (3H), 6.18 (1H), 6.32 (1H), 6.52 (1H), 6.65 (1H), 7.00 (1H), 7.18 (1H), 7.39 (1H), 7.58 (1H), 8.09 (1H), 11.78 (1H).
(rac.) 5-{([6-Chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-2(1H)-one
0.8 ml (0.81 mmol) of titanium tetrachloride is added drop by drop to 130 mg (0.270 mmol) of the compound (rac.)-5-{[4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl)pentylidene]amino}isoquinolin-2(1H)-one, dissolved in 1.6 ml of dichloromethane, that is described in the previous paragraph at 0° C., and the batch is then stirred for two hours at 0° C. and for two hours at room temperature. The reaction mixture is mixed drop by drop with saturated sodium bicarbonate solution and with ethyl acetate at 0° C. After the cold bath is removed, it is stirred vigorously for another 15 minutes at room temperature. After being extracted twice with ethyl acetate, the combined organic extracts are washed with saturated NaCl solution. After drying on sodium sulfate, the solvent is spun off, and the remaining residue is chromatographed on silica gel (mobile solvent:ethyl acetate(hexane). 82 mg (63.1%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): 1.53 (3H), 1.66 (3H), 2.00-2.25 (5H), 3.96 (3H), 4.80 (1H), 5.01 (1H), 5.58 (1H), 6.49-6.62 (3H), 6.92 (1H), 7.35 (1H), 8.19 (1H), 10.25 (1H).
(rac.) 5-{[6-Chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-2(1H)-one
43 mg (0.089 mmol) of (rac.) 5-{[6-chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-2(1H)-one is mixed at room temperature with 0.9 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for two and ¼ hours at room temperature. At −30° C., saturated sodium bicarbonate solution is now added drop by drop. After dilution with ethyl acetate, the cold bath is removed, and the batch is extracted twice with ethyl acetate after 10 minutes of vigorous stirring at room temperature. The combined organic phases are washed with water and brine, dried, and the residue is chromatographed on silica gel (mobile solvent:ethanol/dichloromethane) after the solvent is spun off. 37.8 mg (90.6%) of the desired compound is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.58 (3H), 1.70 (3H), 2.00-2.24 (5H), 5.12 (1H), 6.51 (1H), 6.62 (1H), 6.70 (1H), 6.80 (1H), 7.39 (1H), 8.22 (1H).
Example 289
(rac.) 6-Chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-trimethyl -2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
(rac.) 1,1,1-Trifluoro-4-(3-chloro-2-methoxy-4-methylphenyl)-2-[(8-fluoro-2-methyl-quinazolyl-5-yl)iminomethyl]-4-methylpentan-2-ol
225 mg (0.664 mmol) of (rac.) 4-(3-chloro-2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal (described in Example 287) and 117.6 mg (0.664 mmol) of 5-amino-8-fluoro-2-methylquinazoline are mixed with 3.6 ml of o-xylene. After 0.39 ml (1.328 mmol) of titanium tetraisopropylate is added, the batch is stirred for two hours at 120° C. The mixture is added to 15 ml of saturated brine and diluted with 20 ml of ethyl acetate. The reaction mixture is filtered on Extrelute and washed with 300 m of a mixture that consists of ethyl acetate/dichloromethane. The solution that is obtained is spun in, and the residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 217.5 mg (65.7%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.40 (3H), 1.52 (3H), 1.65 (3H), 2.29 (1H), 3.00 (3H), 3.35 (1H), 3.92 (3H), 4.59 (1H), 6.48 (1H), 6.77 (1H), 7.00 (1H), 7.44 (1H), 7.78 (1H), 9.39 (1H).
(rac.) 6-Chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
110 mg (0.221 mmol) of the compound (rac.) 1,1,1-trifluoro-4-(3-chloro-2-methoxy-3-methylphenyl)-2-[(8-fluoro-2-methyl-quinazolyl-5-yl)iminomethyl]-4-methylpentan-2-ol that is described in the previous paragraph is dissolved in 1.3 ml of dichloromethane and mixed carefully at 0° C. with 0.66 ml (0.663 mmol) of titanium tetrachloride. Then, it is stirred for two hours at 0° C. and for two additional hours at room temperature. The reaction mixture is mixed drop by drop with saturated sodium bicarbonate solution at 0° C. After dilution with ethyl acetate, the cold bath is removed, and the batch is stirred vigorously at room temperature. After being extracted twice with ethyl acetate, the combined organic extracts are washed with saturated NaCl solution. After drying on sodium sulfate, the solvent is spun off, and the remaining residue is chromatographed on silica gel (mobile solvent:methanol/dichloromethane). 76.5 mg (69.5%) of the desired compound is isolated as a 9:1 diastereomer mixture. The signals of the main diastereomers are indicated.
1H-NMR (300 MHz, CD3OD): =1.57 (3H), 1.69 (3H), 2.08-2.29 (5H), 2.89 (3H), 3.95 (3H), 5.28 (1H), 6.87 (1H), 7.05 (1H), 7.59 (1H), 9.65 (1H).
(rac.) 6-Chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
40 mg (0.08 mmol) of (rac.) 6-chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is mixed at room temperature with 0.8 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for four hours at room temperature. Since no reaction was carried out, another 0.8 ml of the boron tribromide solution was added. After 16 hours of stirring at room temperature, the reaction was complete. At −30° C., saturated sodium bicarbonate solution is now carefully added in drops, and the batch is diluted with ethyl acetate. After the cold bath is removed, it is stirred vigorously at room temperature for 10 minutes. The batch is extracted twice with ethyl acetate. The combined organic phases are washed with water and with brine, dried, and the residue is chromatographed on silica gel (mobile solvent:methanol/dichloromethane) after the solvent is spun off. 38.2 mg (98.4%) of the desired compound is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.60 (3H), 1.72 (3H), 2.05-2.25 (5H), 2.88 (3H), 5.22 (1H), 6.80-6.90 (2H), 7.59 (1H), 9.68 (1H).
Example 290
(rac.) 5-{[7-Chloro-6-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
2-(4-Chloro-3-fluoro-2-methoxyphenyl)-2-methylpropanenitrile
16.78 g (93.97 mmol) of 3-chloro-2,6-difluoro-anisole is dissolved in 800 ml of toluene. After 25.97 g (375.88 mmol) of isobutyronitrile is added, 283.97 ml (140.95 mmol) of a 0.5 molar solution of potassium hexamethyl disilazide in toluene is added in drops. In this case, the temperature increases to 28° C. The batch is stirred for seven days at 60° C. After mixing with water and ethyl acetate, the reaction mixture is brought to a pH of 4 with 1 M sulfuric acid. After being extracted twice with ethyl acetate, the combined organic extracts are washed with water and saturated NaCl solution and dried. After spinning-in and chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 7.46 g (21.4%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.75 (6H), 4.10 (3H), 6.95-7.14 (2H).
2-(4-Chloro-3-fluoro-2-methoxyphenyl)-2-methylpropanal
7.46 g (32.78 mmol) of the above-described nitrile is dissolved in 131 ml of toluene. At −65° C. to −60° C., 41.1 ml of a 1.2 molar solution of DIBAH in toluene is added in drops under nitrogen. After two hours of stirring at −65° C., 374 ml of a 10% L-(+)-tartaric acid solution is added in drops. The batch is stirred overnight at room temperature. The reaction mixture is extracted three times with diethyl ether. The combined organic extracts are shaken with water and with brine, dried, and the solvent is spun off. 7.35 g (97.2%) of the desired compound, which is incorporated as a crude product into the next stage, is obtained.
(E/Z)-4-(4-Chloro-3-fluoro-2-methoxyphenyl)-2-ethoxy-4-methylpent-2-enoic acid ethyl ester
19.9 ml of a 2 molar LDA solution in THF (1.25 equivalents) is added in drops at 0° C. to a solution of 10.3 g (38.83 mmol) of 2-ethoxy-phosphonoacetic acid triethyl ester, dissolved in 34 ml of absolute THF. After 45 minutes of stirring at 0° C., 7.35 g (31.86 mmol) of 2-(4-chloro-3-fluoro-2-methoxyphenyl)-2-methylpropanal, dissolved in 21 ml of THF, is quickly added in drops at 0° C. After stirring over the weekend at room temperature, the reaction mixture is added to water and extracted three times with diethyl ether. The combined organic extracts are washed with water and brine, dried, and after the dessicant is filtered off, the solvent is spun off. The residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 8.41 g, which in addition to the desired compound also still contains the starting material (aldehyde), which is separated in the next stage, is isolated.
(E/Z)-4-(4-Chloro-3-fluoro-2-methoxyphenyl)-2-ethoxy-4-methylpent-2-enoic acid
8.41 g (24.39 mmol) of (E/Z)-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-ethoxy-4-methylpent-2-enoic acid ethyl ester is mixed with 222 ml of 1N NaOH in ethanol/water (2:1) and stirred overnight at room temperature. The ethanol is drawn off in a rotary evaporator, and after mixing with water, the residue is extracted three times with methyl tert-butyl ether. Since the organic extracts still contain the desired acid in addition to the unreacted aldehyde, it is extracted with 1 M NaOH. After the organic extracts are dried, the solvent is spun off. The residue (unreacted aldehyde from the above-described reaction) is 1.59 g and is used again in the Homer Wittig reaction with subsequent saponification. The combined aqueous phases are carefully acidified with concentrated hydrochloric acid while being cooled in an ice bath and extracted three times with methyl tert-butyl ether. These ether extracts are washed with brine, dried, the solvent is spun off, and the residue (5.99=77.5%) is incorporated in crude form into the next stage. Since the compound is an E/Z mixture that is not in a 1:1 ratio, only the positions of the signals are indicated in the NMR spectrum.
1H-NMR (300 MHz, CDCl3): δ=0.98, 1.40, 1.49-1.59, 3.40, 3.78-3.90, 5.72, 6.70, 6.92-7.09.
4-(4-Chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid
6.06 g (19.13 mmol) of the (E/Z)-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-ethoxy-4-methylpent-2-enoic acid that is obtained from the previous batch is mixed at room temperature with 126 ml of a 1 molar sulfuric acid and 12.6 ml of glacial acetic acid, and it is stirred for nine days at a bath temperature of 90° C. The batch is made basic (pH 9) while being cooled in an ice bath with solid potassium carbonate (caution, foam), and it is extracted three times with methyl tert-butyl ether. The aqueous phase is acidified while being cooled in an ice bath with concentrated hydrochloric acid until a pH of 4 is reached, and it is shaken three times with methyl tert-butyl ether. The ether extracts are washed with water and brine, dried, and the solvent is spun off. The remaining residue is 2.23 g. Since the first ether phase still contains product, the latter is concentrated by evaporation, and the solid residue is taken up in water and methyl tert-butyl ether. After acidification, the aqueous phase is extracted twice more with methyl tert-butyl ether. After the usual working-up, the combined organic extracts produce another 3.21 g of the desired product. Altogether, 5.44 g (98.5%) acid is obtained, which is incorporated in crude form into the next stage.
1H-NMR (300 MHz, CDCl3): δ=1.45 (6H), 3.55 (2H), 3.97 (3H), 6.95-7.10 (2H).
4-(4-Chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester
5.44 g (18.84 mmol) of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid is dissolved in 117 ml of ethanol, mixed with 2.1 ml of concentrated sulfuric acid, and refluxed for six hours. The reaction mixture is added to 250 ml of saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The combined organic extracts are washed with saturated sodium bicarbonate solution and with brine. After drying, and after the dessicant is filtered off and the solvent is spun in, 5.19 g (87%) of the desired compound is obtained.
1H-NMR (300 MHz, CDCl3): δ=1.30 (3H), 1.45 (6H), 3.40 (2H), 3.98 (3H), 4.20 (2H), 6.92-7.50 (2H).
(rac.) 4-(4-Chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentanoic acid ethyl ester
5.19 g (16.38 mmol) of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester is dissolved in 26 ml of THF, mixed at room temperature with 2.79 g (19.66 mmol) of (trifluoromethyl)-trimethylsilane and 40.1 mg of tetrabutylammonium fluoride and stirred for two days. The reaction mixture is mixed with methyl tert-butyl ether and washed with water and brine. The organic phase is dried, and after the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 4.71 g (62.6%) of the desired compound is obtained.
(rac.) 4-(4-Chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid ethyl ester
4.71 g (10.26 mmol) of (rac.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentanoic acid ethyl ester is dissolved in 57 ml of tetrahydrofuran and mixed with 3.24 g (10.26 mmol) of tetrabutylammonium fluoride: after stirring over the weekend at room temperature, the reaction mixture is mixed with water and extracted three times with methyl tert-butyl ether. The combined organic extracts are washed with brine. After the drying, the solvent is spun off, and the remaining residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 3.07 g (77.4%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.25 (3H), 1.38 (3H), 1.47 (3H), 2.45 (1H), 2.75 (1H), 3.50 (1H), 3.75 (1H), 4.03 (3H), 4.13 (1H), 6.89 (1H), 7.00 (1H).
(rac.) 4-(4-Chloro-3fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
1.00 g (2.59 mmol) of (rac.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid ethyl ester is dissolved in 9.5 ml of diethyl ether and mixed in portions at 0° C. with 73.7 mg (1.94 mmol) of LiAlH4. Stirring is continued at 0° C., and a TLC is taken every quarter hour. After 40 minutes of stirring at 0° C., the reaction mixture is mixed drop by drop with 2.4 ml of saturated NaHCO3 solution while being cooled in an ice bath. It is stirred for 30 minutes while being cooled in an ice bath, and it is stirred vigorously overnight at room temperature. The precipitate is suctioned off, washed with ethyl acetate, and the filtrate is concentrated by evaporation in a rotary evaporator. After the residue is chromatographed on a Flashmaster, 560.2 mg is obtained. In this case, this is a 3:2 mixture of the aldehyde with the starting ester.
(rac.)-5-{[4-(4-Chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}isoquinolin-1(2H)-one
560 mg of the mixture that consists of (rac.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and (rac.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid ethyl ester (since aldehyde constitutes two-thirds of the mixture, 560.2 mg of the mixture corresponds to 336.1 mg (0.981 mmol) of aldehyde) is heated for two hours to 120° C. with 157.1 mg (0.981 mmol) of 5-amino-isoquinolin-1(2H)-one and 0.557 mg (1.962 mmol) of titanium tetraisopropylate in 6 ml of o-xylene. After cooling, the batch is diluted with ethyl acetate and mixed with brine. The organic phase is separated and worked up as usual. After chromatography on a Flashmaster, 144.7 mg (30.4%) of the desired compound is obtained (relative to the proportion of aldehyde in the mixture).
1H-NMR (300 MHz, CDCl3): δ=1.40 (3H), 1.58 (3H), 2.38 (1H), 3.19 (1H), 4.03 (3H), 4.78 (1H), 6.65 (1H), 6.70-6.83 (3H), 7.20 (1H), 7.44 (1H), 7.62 (1H), 8.35 (1H), 10.95 (1H).
(rac.) 5-{[7-Chloro-6-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one
80.3 mg (0.166 mmol) of (rac.) 5-{[4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}isoquinolin-1(2H)-one is mixed at room temperature with 1.7 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for two and one-half hours at room temperature. The reaction mixture is mixed with ice, and then saturated sodium bicarbonate solution is added in drops (pH 8). After ethyl acetate is added, and after ten minutes of vigorous stirring at room temperature, the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with water and with brine, dried, and after the solvent is spun off, the residue is chromatographed on a Flashmaster. 24.6 mg (31.6%) of the desired compound is isolated.
1H-NMR (300 MHz, DMSO-d6): δ=1.50 (3H), 1.60 (3H), 1.90-2.14 (2H), 5.31 (1H), 5.92 (1H), 6.18 (1H), 6.70 (1H), 6.80 (1H), 7.05 (1H), 7.19 (1H), 7.27 (1H), 7.52 (1H), 10.05 (1H), 11.25 (1H).
Example 291
(rac.) 7-Chloro-6-fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
(rac.) 1,1,1-Trifluoro-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-[(8-fluoro-2-methyl-quinazolyl-5-yl)iminomethyl]-4-methylpentan-2-ol
457 mg of the mixture that consists of (rac.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and (rac.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid ethyl ester (described in Example 290) (since aldehyde constitutes two-thirds of the mixture, 457 mg of mixture corresponds to 305.3 (0.891 mmol) of aldehyde) and 158 mg (0.891 mmol) of 5-amino-8-fluoro-2-methylquinazoline are mixed with 5.5 ml of o-xylene. After 506.6 mg (1.782 mmol) of titanium tetraisopropylate is added, the batch is stirred for two hours at 120° C. The mixture is diluted with ethyl acetate and mixed with brine. After ten minutes of vigorous stirring, the reaction mixture is filtered on Extrelute and eluted with dichloromethane. The solution that is obtained is spun in, and the residue is chromatographed on a Flashmaster. 295.8 mg (66.1%) of the desired compound is isolated.
1H-NMR (300 MHz, CDCl3): δ=1.40 (3H), 1.52 (3H), 2.34 (1H), 3.00 (3H), 3.21 (1H), 4.00 (3H), 4.59 (1H), 6.58 (1H), 6.70 (1H), 6.85 (1H), 7.49 (1H), 7.78 (1H), 9.49 (1H).
(rac.) 7-Chloro-6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4.7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
295.8 mg (0.589 mmol) of (rac.) 1,1,1-trifluoro-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-[(8-fluoro-2-methyl-quinazolyl-5-yl)iminomethyl]-4-methylpentan-2-ol is mixed at 0° C. with 6.1 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for two hours at 0 to 5° C. The reaction mixture is mixed with ice. After careful dropwise addition of saturated sodium bicarbonate solution, it is diluted with ethyl acetate and stirred vigorously for ten minutes. The aqueous phase is extracted twice with ethyl acetate. The organic phases are washed with water and brine, dried, and after the solvent is spun off, the residue is chromatographed several times on a Flashmaster. 38 mg (13.2%) of the desired compound is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.60 (3H), 1.70 (3H), 2.05-2.21 (2H), 2.83 (3H), 5.23 (1H), 6.80-6.92 (2H), 7.59 (1H), 9.68 (1H).
Example 292
(rac.) 7-Chloro-6-fluoro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
5-Amino-7-fluoro-2-methylquinazoline
17 g (70.5 mmol) of 3,6-difluoro-2-N-pivaloylaminobenzaldehyde (L. Florvall, I. Fagervall, L.-G- Larsson, S. B. Ross, Eur. J. Med. Chem. 34 (1999) 137-151), 9.2 g of acetamidine hydrochloride, 13.4 g of potassium carbonate and 10.4 g of molecular sieve (4A) are added together in 70 ml of butyronitrile. It is heated for 17 hours to 145° C. while being stirred vigorously, and the solvent is removed in a vacuum. After the residue is chromatographed on silica gel with hexane/ethyl acetate (0-70%), 4.5 g of 7-fluoro-5-N-pivaloylamino-2-methylquinazoline is obtained.
1 g (3.82 mmol) of 7-fluoro-5-N-pivaloylamino-2-methylquinazoline is dissolved in 74 ml of toluene and cooled to −70° C. Over 30 minutes, 9.5 ml (11.4 mmol) of a 1.2 M diisobutylaluminum hydride solution in toluene is added in drops. The reaction mixture is allowed to heat to −40° C. and stirred for four hours at −40° C. Water is slowly added, and it is stirred for 30 minutes at room temperature until a precipitate forms, which is removed by means of filtration through Celite. The phases are separated, washed with saturated sodium chloride solution, and dried on sodium sulfate. After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 64 mg of the product is obtained.
1H-NMR (CDCl3); δ=2.83 (s, 3H), 4.67 (br., 2H), 6.50 (dd, 1H), 6.93 (dd, 1H), 9.23 (s, 1H).
(rac.) 1,1,1-Trifluoro-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-[(7-fluoro-2-methyl-quinazolyl-5-yl)iminomethyl]-4-methylpentan-2-ol
400 mg of the mixture that consists of (rac.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and (rac.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid ethyl ester (described in Example 8) (since aldehyde constitutes two-thirds of the mixture, 400 mg of the mixture corresponds to 266.6 (0.778 mmol) of aldehyde) and 137.8 mg (0.778 mmol) of 5-amino-7-fluoro-2-methylquinazoline are mixed with five ml of o-xylene. After 442.3 mg (1.56 mmol) of titanium tetraisopropylate is added, the batch is stirred for two hours at 120° C. The mixture is diluted with ethyl acetate and mixed with brine. After ten minutes of vigorous stirring, the reaction mixture is filtered on Extrelute and eluted with dichloromethane. The solution that is obtained is spun in, and the residue is chromatographed on a Flashmaster. 312.4 mg (80%) of the desired compound is isolated. The yield relates to the aldehyde that is contained in the mixture.
1H-NMR (300 MHz, CDCl3): δ=1.40 (3H), 1.60 (3H), 2.36 (1H), 2.92 (3H), 3.23 (1H), 4.01 (3H), 4.49 (1H), 6.49 (1H), 6.65 (1H), 6.89 (1H), 7.45 (1H), 7.79 (1H), 9.32 (1H).
(rac.) 7-Chloro-6-Fluoro-1-[(7-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
312.4 mg (0.622 mmol) of (rac.) 1,1,1-trifluoro-4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-[(7-fluoro-2-methyl-quinazolyl-5-yl)iminomethyl]-4-methylpentan-2-ol is mixed at 0° C. with 6.4 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for two hours at 0 to 5° C. The reaction mixture is mixed with ice. After saturated sodium bicarbonate solution is carefully added in drops, it is diluted with ethyl acetate and stirred vigorously for ten minutes. The aqueous phase is extracted twice with ethyl acetate. The organic phases are washed with water and brine, dried, and after the solvent is spun off, the residue is chromatographed several times on a Flashmaster. 51 mg (16.7%) of the desired compound is isolated.
1H-NMR (300 MHz, CD3OD): δ=1.60 (3H), 1.70 (3H), 2.15 (2H), 2.79 (3H), 5.31 (1H), 6.70-6.88 (3H), 9.58 (1H).
Analogously to the compounds described in detail primarily in Examples 283-292, the following structures were synthesized with use of the corresponding starting materials.
Example 293
1-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-6-fluoro-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Example 294
5-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-2-fluoro-3,8,8-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
Examples 295 and 296
1-(2-Ethylquinazolin-5-ylamino)-6-fluoro-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol, Diastereomer A and
1-(2-Ethylquinazolin-5-ylamino)-6-fluoro-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol, Diastereomer B
Example 297
5-(2-Ethylquinazolin-5-ylamino)-2-fluoro-3,8,8-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol, Diastereomer A
Example 298
5-(2-Ethylquinazolin-5-ylamino)-2-fluoro-3,8,8-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol, Diastereomer B
Examples 299 and 300
5-(2-Methylquinazolin-5-ylamino)-2-fluoro-3,8,8-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol, Diastereomer A and
5-(2-Methylquinazolin-5-ylamino)-2-fluoro-3,8,8-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol, Diastereomer B
Examples 301 and 302
(+)-5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one and
(−)-5-{[6-Fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one
83 mg of racemic 5-{[6-fluoro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one is separated on a chiral column (Chiralpak AD-H 5μ eluants:hexane/ethanol) into its enantiomers. 34 mg of (+)-enantiomer and 33 mg of the (−)-enantiomer are obtained.
[a]D=+41.1±0.5 (c=0.51, methanol)
[a]D=−41.8±0.4 (c=0.505, methanol)
Examples 303 and 304
(+)-6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol and
(−)-6-Fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol
50.8 mg of racemic 6-fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalene-2,5-diol is separated on a chiral column (Chiralpak AD-H 5μ, eluants:hexane/ethanol) into its enantiomers. 25.3 mg of the (+)-enantiomer and 23.8 mg of the (−)-enantiomer are isolated.
[a]D=+57.8±1.1 (c=0.50, methanol)
[a]D=−53.3±0.3 (c=0.50, methanol)
Example 305
5-[7-Chloro-6-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-1H-quinolin-2-one
Example 306
5-[7-Chloro-6-fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-1,3dihydroindol-2-one
Example 307
5-[7-Chloro-6-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-1,3dihydroindol-2-one
Example 308
7-Chloro-1-(7,8-difluoro-2-methylguinazolin-5-ylamino)-6-fluoro-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Example 309
3-Chloro-5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
Examples 310 and 311
7-Chloro-1-(2-ethylquinazolin-5-ylamino)-6-fluoro-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol, Diastereomer A and
7-Chloro-1-(2-ethylquinazolin-5-ylamino)-6-fluoro-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol, Diastereomer B
Example 312
3-Chloro-5-(2-ethylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
Examples 313 and 314
3-Chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol, Enantiomer A and
3-Chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol, Enantiomer B
22.5 mg of the racemic compound 3-chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol is separated on a chiral column (Chiralpak AD-H 5μ, eluants:hexane/ethanol) into its enantiomers. 10.5 mg of enantiomer A (retention time 5.28 minutes) and 9.9 mg of enantiomer B (retention time 10.79 minutes) are isolated.
Examples 315 and 316
(+)-3-Chloro-5-(8-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol, Enantiomer A and
(−)-3-Chloro-5-(8-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol. Enantiomer B
40 mg of the racemic compound (+)-3-chloro-5-(8-fluoro-2-methylquinazolin-5-ylamino)-2-fluoro-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol is separated on a chiral column (Chiralpak AD 10□, eluants:hexane/ethanol) into its enantiomers. 16 mg of the two enantiomers in each case is obtained.
[a]D=+53.1±0.6 (c=0.555, methanol)
[a]D=−46.0±0.6 (c=0.58, methanol)
Example 317
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(2-oxo-1,2-dihydroquinolin-5-ylamino)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
IR (microscope, matrix: diamond): 2232
Example 318
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(2-oxo-1,3-dihydroindol-4-ylamino)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
IR (microscope, matrix: diamond): 2238
Example 319
6-Chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Example 320
2-Chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-3,8,8-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
Example 321
6-Chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Example 322
2-Chloro-5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-3,8,8-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
Example 323
4-[6-Chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-1,3-dihydroindol-2-one
Example 324
4-[6-Chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-1,3-dihydroindol-2-one
Example 325
6-Chloro-5-methoxy-4,4,7-trimethyl-1-(2-methylquinazolin-5-ylamino)-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
Example 326
2-Chloro-3,8,8-trimethyl-5-(2-methylquinazolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
Examples 327 and 328
(+)-6-Chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol and
(−)-6-Chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
88 mg of racemic 6-chloro-1-(7,8-difluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is separated on a chiral column (Chiralpak AD-H 5□, eluants:hexane/ethanol). 42.6 mg of the (+)-enantiomer and 41.3 mg of the (−)-enantiomer are obtained.
[a]D=+36.9±0.6 (c=0.50, methanol)
[a]D=−32.8±0.3 (c=0.51, methanol)
Example 329
(+)-2-Chloro-5-(7,8-difuoro-2-methylquinazolin-5-ylamino)-3,8,8-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
33.9 mg of the ether ((+)-enantiomer), described in Example 45, is treated as usual with boron tribromide. 30.1 mg (91.4%) of the enantiomer-pure phenol is isolated.
[a]D=+49.1±0.3 (c=0.55, methanol)
Example 330
(−)-2-Chloro-5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-3,8,8,-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
37.2 mg of the ether ((−)-enantiomer), described in Example 45, is treated as usual with boron tribromide. 30.9 mg (85.6%) of the enantiomer-pure phenol is isolated.
[a]D=−44.7±0.4 (c=0.55, methanol)
Examples 331 and 332
(+)-6-Chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol and
(−)-6-Chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol
143 mg of racemic 6-chloro-1-(7-fluoro-2-methylquinazolin-5-ylamino)-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is separated on a chiral column (Chiralcel OD-H 5□, eluants:hexane/ethanol). 58.4 mg of the (+)-enantiomer and 51.2 mg of the (−)-enantiomer are obtained.
[a]D=+30.5±0.7 (c=0.50, methanol)
[a]D=−27.3±0.8 (c=0.51, methanol)
Example 333
(+)-2-Chloro-5-(7-fluoro-2-methylquinazolin-5-yl amino)-3,8,8,-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
51 mg of the ether ((+)-enantiomer), described in Example 49, is treated as usual with boron tribromide. 47.3 mg (95.5%) of the enantiomer-pure phenol is isolated.
[a]D=+41.6±0.8 (c=0.55, methanol)
Example 334
(−)-2-Chloro-5-(7-fluoro-2-methylquinazolin-5-ylamino)-3,8,8,-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
44.5 mg of the ether ((−)-enantiomer), described in Example 49, is treated as usual with boron tribromide. 41.4 mg (95.8%) of the enantiomer-pure phenol is isolated.
[a]D=−40.2±0.6 (c=0.57, methanol)
Examples 335 and 336
(+)-5-[6-Chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-1H-quinolin-2-one and
(−)-5-[6-Chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-1H-quinolin-2-one
124 mg of racemic 5-[6-chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-1H-quinolin-2-one is separated on a chiral column (Chiralcel OJ-H 5□, eluants:hexane/ethanol). 54.7 mg of the (+)-enantiomer and 47.8 mg of the (−)-enantiomer are obtained.
[a]D=+37.0±0.6 (c=0.57, methanol)
[a]D=−46.6±0.4 (c=0.54, methanol)
Example 336
(+)-5-[6-Chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-1H-quinolin-2-one
47.3 mg of the ether ((+)-enantiomer), described in Example 334, is treated as usual with boron tribromide. 42.6 mg (92.8%) of the enantiomer-pure phenol is isolated.
[a]D=+53.3±0.4 (c=0.52, methanol)
Example 337
(−)-5-[6-Chloro-2,5-dihydroxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-1H-quinolin-2-one
42.4 mg of the ether ((−)-enantiomer), described in Example 334, is treated as usual with boron tribromide. 39.4 mg (95.8%) of the enantiomer-pure phenol is isolated.
[a]D=−56.3±0.4 (c=0.54, methanol)
Example 338
1,6-Dihydroxy-3,8,8-trimethyl-5-(2-oxo-2,3-dihydroindol-4-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
IR (microscope, matrix: diamond): 2235
Example 338
5-(7-Fluoro-2-methylquinazolin-5-ylamino)-1,6-dihydroxy-3,8,8,-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
IR (microscope, matrix:diamond): 2228
Analogously to the described compounds 283-292, the following structures can be synthesized with use of the corresponding starting materials:
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(1-oxo-1,2-dihydroisoquinolin-5-ylamino)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-ylamino)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(2-methyl-1-oxo-1,2-dihydrophthalazin-5-ylamino)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-4,7-dihydroxy-5,5-dimethyl-8-(1-oxo-1,2-dihydrophthalazin-5-ylamino)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-8-(7-fluoro-2-methylquinazolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-8-(8-fluoro-2-methylquinazolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-8-(7,8-difluoro-2-methylquinazolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-8-(2-methylquinazolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-8-(2-ethylquinazolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-8-(2-methylquinolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-8-(2,6-dimethylquinolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-8-(6-chloro-2-methylquinolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-8-(6-fluoro-2-methylquinolin-5-ylamino)-4,7-dihydroxy-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-4,7-dihydroxy-8-(1 H-indazol-4-ylamino)-5,5-dimethyl-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-4,7-dihydroxy-5,5,-dimethyl-8-(naphthalen-1-ylamino)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-4,7-dihydroxy-5,5,-dimethyl-8-(naphthalen-2-ylamino)7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-4,7-dihydroxy-5,5,-dimethyl-8-(6-hydroxynaphthalen-1-ylamino)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Fluoro-4,7-dihydroxy-5,5,-dimethyl-8-(5-hydroxynaphthalen-1-ylamino)-7-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
3-Chloro-2-fluoro-5-(6-hydroxynaphthalen-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
3-Chloro-2-fluoro-5-(5-hydroxynaphthalen-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
3-Chloro-2-fluoro-5-(naphthalen-1-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
3-Chloro-2-fluoro-5-(naphthalen-2-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
3-Chloro-2-fluoro-5-(1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
3-Chloro-2-fluoro-5-(5-chloro-1H-indazol-4-ylamino)-8,8-dimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
5-(7,8-Difluoro-2-methylquinazolin-5-ylamino)-1,6-dihydroxy-3,8,8,-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
5-(8-Fluoro-2-methylquinazolin-5-ylamino)-1,6-dihydroxy-3,8,8,-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
5-(2-Methylquinazolin-5-ylamino)-1,6-dihydroxy-3,8,8,-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
5-(2-Ethylquinazolin-5-ylamino)-1,6-dihydroxy-3,8,8,-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-3,8,8-trimethyl-5-(2-oxo-1,2-dihydroquinolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-3,8,8-trimethyl-5-(1-oxo-1,2-dihydroisoquinolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-3,8,8-trimethyl-5-(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-3,8,8-trimethyl-5-(1-oxo-1,2-dihydrophthalazin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-3,8,8-trimethyl-5-(2-methyl-1-oxo-1,2-dihydrophthalazin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-3,8,8,-trimethyl-5-(2-methylquinolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-3,8,8,-trimethyl-5-(2,6-dimethylquinolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-3,8,8,-trimethyl-5-(6-chloro-2-methylquinolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-3,8,8,-trimethyl-5-(6-fluoro-2-methylquinolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-5-(1H-indazolyl-4-ylamino)-3,8,8,-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-5-(5-chloro-1H-indazolyl-4-ylamino)-3,8,8,-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-3,8,8,-trimethyl-5-(naphthalen-1-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-3,8,8,-trimethyl-5-(naphthalen-2-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-3,8,8,-trimethyl-5-(6-hydroxy-naphthalen-1-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-3,8,8,-trimethyl-5-(5-hydroxy-naphthalen-1-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
2-Chloro-5-(1H-indazol-4-ylamino)-3,8,8-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
2-Fluoro-5-(1H-indazol-4-ylamino)-3,8,8-trimethyl-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
2-Chloro-3,8,8-trimethyl-5-(naphthalen-1-ylamino 6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
2-Fluoro-3,8,8-trimethyl-5-(naphthalen-1-ylamino 6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
2-Chloro-3,8,8-trimethyl-5-(6-hydroxynaphthalen-1-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
2-Fluoro-3,8,8-trimethyl-5-(6-hydroxynaphthalen-1-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
2-Chloro-3,8,8-trimethyl-5-(5-hydroxynaphthalen-1-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
2-Fluoro-3,8,8-trimethyl-5-(5-hydroxynaphthalen-1-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol
1,6-Dihydroxy-8,8-dimethyl-5-(2-methylquinazolin-5-ylamino)-6-(tifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-8,8-dimethyl-5-(2-ethylquinazolin-5-ylamino)-6-(tifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-8,8-dimethyl-5-(7-fluoro-2-methylquinazolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-8,8-dimethyl-5-(7,8-difluoro-2-methylquinazolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-8,8-dimethyl-5-(8-fluoro-2-methylquinazolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
1,6-Dihydroxy-8,8-dimethyl-5-(2-oxo-1,2-dihydroquinolin-5-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
|
10960754
|
bayer schering pharma, ag
|
USA
|
B2
|
Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
|
Open
|
514/403
|
|
Mar 31st, 2022 03:13PM
|
Mar 31st, 2022 03:13PM
|
Bayer
|
Health Care
|
Health Care Equipment & Services
|
xetra:bayn
|
Bayer
|
Jul 12th, 2011 12:00AM
|
Dec 14th, 2005 12:00AM
|
https://www.uspto.gov?id=US07977325-20110712
|
3-amino-pyrazolo[3,4b]pyridines as inhibitors of protein tyrosine kinases, their production and use as pharmaceutical agents
|
This invention relates to compounds of general formula I
in which R1 and R2 are described in this application, the use of the compounds of general formula I as inhibitors of protein tyrosine kinases for treatment of various diseases as well as the compounds of general formulas II and III
as intermediate compounds for the production of compounds of general formula I, wherein X, R1a and R2a have the meaning that is described in general formulas II and III.
|
7977325
|
1. Compounds of general formula (I)
in which
R1 stands for C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, wherein the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and the C3-C10-heterocycloalkyl and/or heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, or for a C3-C10-cycloalkyl, aryl, C3-C10-heterocycloalkyl or heteroaryl that is substituted with the group —O—(CH2)n—O—, wherein the terminal oxygen atoms of the —O—(CH2)n—O— group are linked to the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring-, C3-C10-heterocycloalkyl ring- or heteroaryl ring-carbon atom,
K stands for halogen, hydroxy or the group —O—R3, COR4 or —NR5R6, or for C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, wherein the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
L stands for C1-C6-alkyl or the group —COR4, —OR3, or —NR5R6,
R2 stands for C3-C10-cycloalkyl, aryl, or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M,
R3 stands for C1-C6-alkyl, aryl or —(CH2)n-aryl that optionally is substituted in one or more places, in the same way or differently, with the group —NR5R6,
R4 stands for hydrogen, hydroxy, C1-C6-alkyl or C1-C6-alkoxy,
M stands for cyano, halogen, hydroxy, nitro or for C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C1-C6-alkoxy, or for the group —O—R3, —COR4, or —CO—N—R7,
R5 and R6, independently of one another, stand for hydrogen, C1-C6-alkyl or for the group —COR4,
R7 stands for hydrogen or NH2, and
n stands for 1 to 4,
with the stipulation that if
R1 stands for methyl, then R2 cannot simultaneously stand for phenyl, chlorophenyl, or benzofuranyl, or furanyl that is substituted with hydroxy and/or methoxy, or if
R1 stands for —CH═CH-phenyl, then R2 cannot simultaneously stand for phenyl, or if
R1 stands for —CH═CH-chlorophenyl, then R2 cannot simultaneously stand for phenyl or chlorophenyl, or if
R1 stands for —CH═CH-methoxyphenyl, then R2 cannot simultaneously stand for phenyl or methoxyphenyl, or if
R1 stands for phenyl, then R2 cannot simultaneously stand for methoxyphenyl or phenyl, or if
R1 stands for chlorophenyl, then R2 cannot simultaneously stand for chlorophenyl, or if
R1 stands for dichlorophenyl, then R2 cannot simultaneously stand for trimethoxyphenyl, or if
R1 stands for bromophenyl, then R2 cannot simultaneously stand for trimethoxyphenyl, or if
R1 stands for alkyl, alkenyl, aryl, aralkyl, cycloalkyl, for a phenyl-substituted alkyl or p-methoxyphenyl, then R2 cannot simultaneously also stand for aryl, a heterocyclic radical or cycloalkyl,
or a stereoisomer or salt thereof.
2. A compounds according to claim 1, in which
R1 stands for C1-C6 alkyl, C3-C10-cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, wherein the C3-C10-cycloalkyl optionally is interrupted by one or more —(CO)—, —SO— or —SO2— groups in the ring, and optionally one or more double bonds can be contained in the ring, or for aryl, C3-C10-heterocycloalkyl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, wherein the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one nitrogen, oxygen and/or sulfur, and the C3-C10-heterocycloalkyl and/or heteroaryl can be linked only via a carbon ring atom to the pyrazolopyridine, or for a C3-C10-cycloalkyl, aryl, C3-C10-heterocycloalkyl or heteroaryl that is substituted with the group —O—(CH2)n—O—, wherein the terminal oxygen atoms of the —O—(CH2)n—O— group are linked to the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring-, C3-C10-heterocycloalkyl ring- or heteroaryl ring-carbon atom,
K stands for halogen, hydroxy or the group —OR3 or —COR4, or for C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, wherein the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
R2 stands for C3-C10-cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, wherein the heteroaryl is interrupted by at least one nitrogen, oxygen and/or sulfur,
R3 stands for C1-C6-alkyl, aryl or —(CH2)n-aryl, and
M stands for amino, cyano, halogen, hydroxy, or nitro or for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C1-C6-alkoxy, or for the group —O—C1-C6-alkyl, —O—(CH2)n—NR5R6, —COR4, —O-phenyl, —O—(CH2)n-phenyl or —CO—N—R7,
or a stereoisomer or salt thereof.
3. Compounds according to claim 2, in which
R1 stands for C1-C6 alkyl, C3-C10-cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, wherein the C3-C10-cycloalkyl optionally is interrupted by one or more —(CO)—, —SO— or —SO2— groups in the ring, and optionally one or more double bonds can be contained in the ring, or for aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, wherein the heteroaryl itself is interrupted by at least one nitrogen, oxygen and/or sulfur, and the heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, or for a C3-C10-cycloalkyl, aryl or heteroaryl that is substituted with the group —O—(CH2)n—O—, wherein the terminal oxygen atoms of the —O—(CH2)n—O— group are linked to the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring- or heteroaryl ring-carbon atom,
K stands for halogen, hydroxy or the group —OR3 or COR4 or for C3-C10-cycloalkyl, or C3-C10-heterocycloalkyl that optionally is substituted in one or more places, in the same way or differently, with L, wherein the C3-C10-heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
L stands for C1-C6-alkyl or the group —COR4 or —OR3,
R3 stands for C1-C6-alkyl or aryl, and
M stands for amino, cyano, halogen, hydroxy, or nitro or for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C1-C6-alkoxy, or for the group —O—C1-C6-alkyl, —O—(CH2)n—NR5R6, —CO—C1-C6-alkyl, —O-phenyl, —O—(CH2)n-phenyl or —CO—N—R7,
or a stereoisomer or salt thereof.
4. Compounds according to claim 3, in which
R1 stands for C1-C6 alkyl, C3-C10-cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, wherein the C3-C10-cycloalkyl optionally is interrupted by one or more —(CO)— groups in the ring, or for aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, wherein the heteroaryl itself is interrupted by at least one nitrogen, and the heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, or for a C3-C10-cycloalkyl, aryl or heteroaryl that is substituted with the group —O—(CH2)n—O—, wherein the terminal oxygen atoms of the —O—(CH2)n—O— group are linked to the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring- or heteroaryl ring-carbon atom,
K stands for halogen, hydroxy or for the group —OR3, or C3-C10-heterocycloalkyl that optionally is substituted in one or more places, in the same way or differently, with L, wherein the C3-C10-heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen and/or oxygen in the ring,
L stands for C1-C6-alkyl or —COO—C1-C6-alkyl,
R2 stands for C3-C6-cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, wherein the heteroaryl is interrupted by at least one nitrogen, and
M stands for amino, cyano, halogen, hydroxy, or nitro or for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro or C1-C6-alkoxy or for the group —O—C1-C6-alkyl, —O—(CH2)n—N(C1-C6-alkyl)2, —CO—C1-C6-alkyl, phenoxy, benzyloxy or —CO—N—NH2,
or a stereoisomer or salt thereof.
5. Compounds according to claim 1, in which
M stands for amino, cyano, halogen, hydroxy, nitro or for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro or C1-C6-alkoxy, or for the group —O—C1-C6-alkyl, —O—(CH2)n—N(C1-C6-alkyl)2 or —CO—C1-C6-alkyl,
or a stereoisomer or salt thereof.
6. Compounds according to claim 4, in which
R1 stands for C1-C6-alkyl, C3-C6-cycloalkyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K,
K stands for halogen, hydroxy, C1-C6-alkoxy or morpholinyl, piperazinyl, piperidinyl, or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L,
R2 stands for phenyl or quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, and
M stands for amino, cyano, halogen, hydroxy, nitro, C1-C6-alkyl, —CF3, or for C1-C3-alkoxy or for the group —CO—C1-C6-alkyl, —O—(CH2)n—N(C1-C6-alkyl)2, phenoxy or benzyloxy,
or a stereoisomer or salt thereof.
7. Compounds according to claim 6, in which
R1 stands for C3-C6 alkyl, cyclopropyl, cyclohexyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K,
K stands for halogen, hydroxy, methoxy or morpholinyl, piperazinyl, piperidinyl or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L,
L stands for C1-C3-alkyl or —COO—C3-C5-alkyl,
R2 stands for phenyl, quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, and
M stands for cyano, halogen, hydroxy, nitro, methyl, —CF3 or for methoxy, or for the group —CO—C1-C3-alkyl, or —O—(CH2)3—N(methyl)2
or a stereoisomer or salt thereof.
8. Compounds according to claim 7, in which
R1 stands for tert-butyl, cyclopropyl, cyclohexyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K,
L stands for methyl or —COO-tert-butyl,
R2 stands for phenyl, quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, and
M stands for cyano, halogen, hydroxy, nitro, methyl, —CF3 or for methoxy or for the group —CO-methyl or —O—(CH2)3—N(methyl)2,
or a stereoisomer or salt thereof.
9. A method for preparing a compound of claim 1, comprising converting a compound of formula (II) to a compound of formula (III)
wherein
X stands for halogen or —O—SO2—CmF2m+1,
m stands for 1 to 4,
R1a and R2a have the same meaning as R1 and R2 according to claim 1, wherein K, however, also can stand for the group —COR4, and R3 also can stand for the group trimethylsilyl (TMS), tert-butyl-dimethylsilyl (TBDMS), tert-butyl-diphenylsilyl (TBDPS), triethylsilyl (TES), C1-C2-alkyl, C3-C6-allyl, benzyl or for the group —COR4a, and
R4a stands for hydrogen, C1-C6-alkyl or C1-C6-alkoxy.
10. A Pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of formula I
in which
R1 stands for C1-C6-alkyl, C2-C6-alkenyl, c2-C6-alkinyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one Or more places, in the same way or differently, with K, wherein the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and the C3-C10-heterocycloalkyl and/or heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO — or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, or for a C3-C10-cycloalkyl, aryl, C3-C10-heterocycloalkyl or heteroaryl that is substituted with the group —O—(CH2)n—O—, wherein the terminal oxygen atoms of the —O—(CH2)n—O— group are linked to the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring-, C3-C10-heterocycloalky ring- or heteroaryl ring-carbon atom,
K stands for halogen, hydroxy or the group —O—R3, COR4 or -NR5R6, or for C3-C10-cycloalkyl, C3-C10 -heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, wherein the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
L stands for C1-C6-alkyl or the group —COR4, —OR3, or —NR5R6,
R2 stands for C3-C10-cycloalkyl, aryl, or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M,
R3 stands for C1-C6-alkyl, aryl or —(CH2)n-aryl that optionally is substituted in one or more places, in the same way or differently, with the group —NR5R6,
R4 stands for hydrogen, hydroxy, C1-C6-alkyl or C1-C6-alkoxy,
M stands for cyano, halogen, hydroxy, nitro or for C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C1-C6-alkoxy, or for the group —O—R3, —COR4, or —CO—N—R7,
R5 and R6, independently of one another, stand for hydrogen, C1-C6-alkyl or for the group —COR4,
R7 stands for hydrogen or NH2, and
n stands for 1 to 4,
with the stipulation that if
R1 stands for methyl, then R2 cannot simultaneously stand for phenyl, chlorophenyl, or benzofuranyl, or furanyl that is substituted with hydroxy and/or methoxy, or if
R1 stands for —CH═CH-phenyl, then R2 cannot simultaneously stand for phenyl, or if
R1 stands for —CH═CH-chlorophenyl, then R2 cannot simultaneously stand for phenyl or chlorophenyl, or if
R1 stands for —CH═CH-methoxyphenyl, then R2 cannot simultaneously stand for phenyl or methoxyphenyl, or if
R1 stands for phenyl, then R2 cannot simultaneously stand for methoxyphenyl or phenyl, or if
R1 stands for chlorophenyl, then R2 cannot simultaneously stand for chlorophenyl, or if
R1 stands for dichlorophenyl, then R2 cannot simultaneously stand for trimethoxyphenyl, or if
R1 stands for bromophenyl, then R2 cannot simultaneously stand for trimethoxyphenyl, or if
R1 stands for alkyl, alkenyl, aryl, aralkyl, cycloalkyl, for a phenyl-substituted alkyl or p-methoxyphenyl, then R2 cannot simultaneously also stand for aryl, a heterocyclic radical or cycloalkyl,
with the overriding stipulation that if
R1 stands for alkyl, alkenyl, aryl, aralkyl, or cycloalkyl, or for a phenyl-substituted alkyl or p-methoxyphenyl, then R2 can also simultaneously stand for alkyl, alkenyl, aryl, aralkyl, cyano, a heterocyclic radical or cycloalkyl,
R1 stands for a lower alkyl radical, alkoxy, or a primary, secondary or tertiary amino group, then R2 can also simultaneously stand for a lower alkyl radical.
11. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
12. A pharmaceutically acceptable salt of a compound of formula (I)
in which
R1 stands for C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, wherein the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and the C3-C10-heterocycloalkyl and/or heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, or for a C3-C10-cycloalkyl, aryl, C3-C10-heterocycloalkyl or heteroaryl that is substituted with the group —O—(CH2)n—O—, wherein the terminal oxygen atoms of the —O—(CH2)n—O— group are linked to the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring-, C3-C10-heterocycloalky ring- or heteroaryl ring-carbon atom,
K stands for halogen, hydroxy or the group —O—R3, COR4 or —NR5R6, or for C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, wherein the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
L stands for C1-C6-alkyl or the group —COR4, —OR3, or —NR5R6,
R2 stands for C3-C10-cycloalkyl, aryl, or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M,
R3 stands for C1-C6-alkyl, aryl or -(CH2)n-aryl that optionally is substituted in one or more places, in the same way or differently, with the group —NR5R6,
R4 stands for hydrogen, hydroxy, C1-C6-alkyl or C1-C6-alkoxy,
M stands for cyano, halogen, hydroxy, nitro or for C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C1-C6-alkoxy, or for the group —O—R3, —COR4, or —CO——-R7,
R5 and R6, independently of one another, stand for hydrogen, C1-C6-alkyl or for the group —COR4,
R7 stands for hydrogen or NH2, and
n stands for 1 to 4,
with the stipulation that if
R1 stands for methyl, then R2 cannot simultaneously stand for phenyl, chlorophenyl, or benzofuranyl, or furanyl that is substituted with hydroxy and/or methoxy, or if
R1 stands for —CH═CH-phenyl, then R2 cannot simultaneously stand for phenyl, or if
R1 stands for —CH═CH-chlorophenyl, then R2 cannot simultaneously stand for phenyl or chlorophenyl, or if
R1 stands for —CH═CH-methoxyphenyl, then R2 cannot simultaneously stand for phenyl or methoxyphenyl, or if
R1 stands for phenyl, then R2 cannot simultaneously stand for methoxyphenyl or phenyl, or if
R1 stands for chlorophenyl, then R2 cannot simultaneously stand for chlorophenyl, or if
R1 stands for dichlorophenyl, then R2 cannot simultaneously stand for trimethoxyphenyl, or if
R1 stands for bromophenyl, then R2 cannot simultaneously stand for trimethoxyphenyl, or if
R1 stands for alkyl, alkenyl, aryl, aralkyl, cycloalkyl, for a phenyl-substituted alkyl or p-methoxyphenyl, then R2 cannot simultaneously also stand for.
13. A compound selected from the group consisting of 6-tert-Butyl-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine 6-tert-Butyl-4-(1H-indol-3-yl)-1H-pyrazolo[3,4b]pyridin-3-ylarnine 6-tert-Butyl-4-(1H-indol-3-yl)-1H-pyrazolo[3,4b]pyridin-3-ylamine 6-tert-Butyl-4-(4-phenoxyphenyl)-1H-pyrazolo[3,4-pyridin-3-ylamine 6-tert-Butyl-4-(4-benzyloxyphenyl)-1H-pyrazolo[3,4]pyridin-3-ylamine 6-tert-Butyl-4-(3-methoxyphenyl)-1H-pyrazolo[3,4b]-pyridin-3-ylamine 6-tert-Butyl-4-(3-cyanophenyl)-1H-pyrazolo[3,4b]-pyridin-3-ylamine 1-[4-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4b]pyridin-4-yl)-phenyl]-ethanone 1-[3-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4b]pyridin-4-yl)-phenyl]-ethanone 6-Cyclohexyl-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine 6-(1,4-Dioxa-spiro[4.5]dec-8-yl)-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine 4-(3-Amino-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-6-yl)-cyclohexanone 4-[4-(3-Amino-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-6-yl)-cyclohexyl]-piperazine-1-carboxylic acid tert-butyl ester 6-(4-Piperazin-1-yl-cyclohexyl)-4-p-tolyl-1-pyrazolo[3,4b]pyridin-3-ylamine 6-[4-(4-Methyl-piperazin-1-yl)-cyclohexyl]-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine 6-(4-Piperidin-1-yl-cyclohexyl)-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylarnine 6-(4-Morpholin-4-yl-cyclohexyl)-4-p-tolyl-1H-pyrazolo[3,4b]ppidin-3-ylamine 6-(1,4-Dioxa-spiro[4.5]dec-8-yl)-4-(4-phenoxyphenyl)-1H-pyrazolo[3,4]pyridin-3-ylamine 4-[3-Amino-4-(4-phenoxy-phenyl)-1H-pyrazolo[3,4b]-pyridin-6-yl]-cyclohexanone 4- {4-[3-Amino-4-(4-phenoxy-phenyl)-1H-pyrazolo[3,4b]pyridin-6-yl]-cyclohexyl}-piperazine-1-carboxylic acid tert-butyl ester 4-(4-Phenoxyphenyl)-6-(4-piperazin-1-yl-cyclohexyl)-1H-pyrazolo[3,4b]pyridin-3-ylarnine 6-[4-(4-Methyl-piperazin-1-yl)-cyclohexyl]-4-(4-phenoxyphenyl)-1H-pyrazolo[3,4b]pyridin -3-ylamine 4-(4-Phenoxy-phenyl)-6-(4-piperidin-1-yl-cyclohexyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine 6-(4-Morpholin-4-yl-cyclohexyl)-4-(4-phenoxyphenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine 6-(1,1-Dimethyl-2-piperidin-1-yl-ethyl)-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine 6-(1,1-Dimethyl-2-morpholin-1-yl-ethyl)-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine 6[1,1-Dimethyl-2-(4-methyl-piperazin-1-yl)-ethyl]4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine 4[2-(3-Amino-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-6-yl)-2-methyl-propyl]-piperazine-1-carboxylic acid tert-butyl ester 6-(1,1-Dimethyl-2-piperazin-1-yl-ethyl)-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine 6-(1,1-Dimethyl-2-(4-methyl-piperazin-1-yl)-ethyl]-4-(4-phenoxyphenyl)-1H-pyrazolo [3,4b]pyridin-3-ylamine 6-(1,1-Dimethyl-2-morpholin-4-yl-ethyl)-4-(4-phenoxyphenyl)]-1H-pyrazolo[3,4b]pyridin-3-ylamine 3 -(3-Amino-6-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenol 3 -(3-Amino-6-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-4-yl)-5-methoxyphenol 4-(3,5-Dimethoxy-phenyl)-6-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-3-ylamine 3 -(3-Amino-6-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-methyl-phenol 3-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-5-methoxy-phenol 3-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenol 3-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-methyl-phenol 4-(3,5 -Dimethoxy-phenyl)-6-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-3-ylamine 3-(3-Amino-6-tert-butyl-1 H-pyrazolo[3,4-b]pyridin-4-yl)-5-isopropoxy Phenol 3-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4b]pyridin-4-yl)-4-nitro-phenol 5-(3 -Amino-6-tert-butyl- 1H-pyrazolo[3,4-b]pyridin-4-yl)-2,3dimethoxyphenol 6-Cyclopropyl-4-(3,4-dichlorophenyl)-1H-pyrazolo-[3,4-b]pyridin-3-ylamine 3-(3-Amino-6-cyclopropyl-1H-pyrazolo-[3,4-b]pyridin-4-yl)-phenol 3-(3-Amino-6-cyclohexyl-1H-pyrazolo-[3,4-b]pyridin-4-yl)-phenol 5-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methoxyphenol 5-(3-Amino-6-tert-butyl-1 H-pyrazolo[3,4-b]pyridin-4-yl)-benzene-1,3-diol 4-Isopropyl -6-(3,4-methylenedioxyphenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine 6-(3-Hydroxyphenyl)-4-(4-pyridyl)-1H-pyrazolo[3,4b]-pyridin-3-ylamine 4-(4-Chlorophenyl)-6-phenyl- 1 H-pyrazolo[3,4-b]pyridin-3-ylamine 6-Cyclopropyl-4-(3,4-diehlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine 5-[3-Amino-6-(4-fluorophenyl)-1H-pyrazolo [3,4-b]pyridin-4-yl]-2-methoxyphenol 6-Pyridin-3-yl-4-quinolin-3-yl-1H-pyrazolo[3,4-b]pyridin-3-ylamine 6-(3-Chlorophenyl)-4-(1H-indol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine 4-[3-Amino-6-(3-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-benzonitrile 4-(4-Chlorophenyl)-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-3-ylamine 6-Cyclopropyl-4-(3-nitrophenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine 6-(4-Morpholin-4-yl-phenyl)-4-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-3-ylamine 4-[4-(3-Dimethylaminopropoxy)phenyl]6-(4-fluorophenyl)-1H -pyrazolo[3,4-b]pyridin-3-ylamine 6-Cyclopropyl-4-(4-trifluoromethylphenyl-1H-pyrazolo[3,4-b]pyridin-3-ylamine 4-(3-Amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-benzonitrile 4-(1H-Imidazol-2-yl)-6-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine and 6-tert-Butyl-4-(4-nitro-phenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
and pharmaceutically acceptable salts thereof.
14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of formula I
in which
R1 stands for C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, wherein the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and the C3-C10-heterocycloalkyl and/or heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO—or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, or for a C3-C10-cycloalkyl, aryl, C3-C10-heterocycloalkyl or heteroaryl that is substituted with the group —O—(CH2)n—O—, wherein the terminal oxygen atoms of the —O—(CH2)n—O— group are linked to the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring-, C3-C10-heterocycloalky ring- or heteroaryl ring-carbon atom,
K stands for halogen, hydroxy or the group —O—R3, or COR4, or for C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, wherein the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO—or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
L stands for C1-C6-alkyl or the group —COR4, —OR3, or —NR5R6,
R2 stands for C1-C6-alkyl, C3-C10-cycloalkyl, aryl, or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M,
R3 stands for C1-C6-alkyl, aryl or —(CH2)n-aryl that optionally is substituted in one or more places, in the same way or differently, with the group —NR5R6,
R4 stands for hydrogen, hydroxy, C1-C6-alkyl or C1-C6-alkoxy,
M stands for cyano, halogen, hydroxy, nitro or for C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C1-C6-alkoxy, or for the group —O-R3, —COR4, or —CO—N—R7,
R5 and R6, independently of one another, stand for hydrogen, C1-C6-alkyl or for the group —COR4,
R7 stands for hydrogen or NH2, and n stands for 1 to 4,
with the stipulation that if
R1 stands for methyl, then R2 cannot simultaneously stand for methyl, —CH2—O—CH3,phenyl, chlorophenyl, or benzofuranyl, —CF3, or furanyl that is substituted with hydroxy and/or methoxy, or if
R1 stands for —CH2—O—CH3,then R2 cannot simultaneously stand for methyl, or if
R1stands for —CH═CH-phenyl, then R2 cannot simultaneously stand for phenyl, or if
R1stands for —CH═CH-chlorophenyl, then R2 cannot simultaneously stand for phenyl or chlorophenyl, or if
R1 stands for —CH═CH-methoxyphenyl, then R2 cannot simultaneously stand for phenyl or methoxyphenyl, or if
R1 stands for phenyl, then R2 cannot simultaneously stand for —CF3, methyl, methoxyphenyl or phenyl, or if
R1 stands for methoxyphenyl, then R2 cannot simultaneously stand for —CF3, or if
R1 stands for methylphenyl, then R2 cannot simultaneously stand for —CF3, or if
R1 stands for chlorophenyl, then R2 cannot simultaneously stand for chlorophenyl or —CF3, or if
R1 stands for dichlorophenyl, then R2 cannot simultaneously stand for trimethoxyphenyl, or if
R1 stands for bromophenyl, then R2 cannot simultaneously stand for trimethoxyphenyl, or if
R1 stands for alkyl, alkenyl, aryl, aralkyl, cycloalkyl, for a phenyl-substituted alkyl or p-methoxyphenyl, then R2 cannot simultaneously also stand for alkyl, alkenyl, aryl, a heterocyclic radical or cycloalkyl, or if
R1 stands for a lower alkyl radical, alkoxy, or aryloxy, then R2 cannot simultaneously stand for a lower alkyl radical,
with the overriding stipulation that if
R1 stands for alkyl, alkenyl, aryl, aralkyl, or cycloalkyl, or for a phenyl-substituted alkyl or p-methoxyphenyl, then R2 can also simultaneously stand for alkyl, alkenyl, aryl, aralkyl, cyano, a heterocyclic radical or cycloalkyl,
R1 stands for a lower alkyl radical, alkoxy, or a primary, secondary or tertiary amino group, then R2 can also simultaneously stand for a lower alkyl radical.
15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of formula I
in which
R1 stands for C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, or aryl that optionally is substituted in one or more places, in the same way or differently, with K, wherein the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and the C3-C10-heterocycloalkyl and/or heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, or for a C3-C10-cycloalkyl, aryl, C3-C10-heterocycloalkyl or heteroaryl that is substituted with the group —O—(CH2)n—O—, wherein the terminal oxygen atoms of the —O—(CH2)n—O— group are linked to the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring-, C3-C10-heterocycloalky ring- or heteroaryl ring-carbon atom,
K stands for halogen, hydroxy or the group —O—R3, COR4 or —NR5R6, or for C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, wherein the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
L stands for C1-C6-alkyl or the group —COR4, —OR3, or —NR5R6,
R2 stands for C1-C6-alkyl, C3-C10-cycloalkyl, aryl, or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M,
R3 stands for C1-C6-alkyl, aryl or —(CH2)n-aryl that optionally is substituted in one or more places, in the same way or differently, with the group —NR5R6,
R4 stands for hydrogen, hydroxy, C1-C6-alkyl or C1-C6-alkoxy,
M stands for cyano, halogen, hydroxy, nitro or for C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C1-C6-alkoxy, or for the group —O—R3, —COR4, or —CO—N—R7,
R5 and R6, independently of one another, stand for hydrogen, C1-C6-alkyl or for the group —COR4,
R7 stands for hydrogen or NH2, and
n stands for 1 to 4,
with the stipulation that if
R1 stands for methyl, then R2 cannot simultaneously stand for methyl, —CH2—O—CH3, phenyl, chlorophenyl, or benzofuranyl, —CF3, or furanyl that is substituted with hydroxy and/or methoxy, or if
R1 stands for —CH2—O—CH3, then R2 cannot simultaneously stand for methyl, or if
R1 stands for —CH═CH-phenyl, then R2 cannot simultaneously stand for phenyl, or if
R1 stands for —CH═CH-chlorophenyl, then R2 cannot simultaneously stand for phenyl or chlorophenyl, or if
R1 stands for —CH═CH-methoxyphenyl, then R2 cannot simultaneously stand for phenyl or methoxyphenyl, or if
R1 stands for phenyl, then R2 cannot simultaneously stand for —CF3, methyl, methoxyphenyl or phenyl, or if
R1 stands for methoxyphenyl, then R2 cannot simultaneously stand for —CF3, or if
R1 stands for methylphenyl, then R2 cannot simultaneously stand for —CF3, or if
R1 stands for chlorophenyl, then R2 cannot simultaneously stand for chlorophenyl or —CF3, or if
R1 stands for dichlorophenyl, then R2 cannot simultaneously stand for trimethoxyphenyl, or if
R1 stands for bromophenyl, then R2 cannot simultaneously stand for trimethoxyphenyl, or if
R1 stands for alkyl, alkenyl, aryl, aralkyl, cycloalkyl, for a phenyl-substituted alkyl or p-methoxyphenyl, then R2 cannot simultaneously also stand for alkyl, alkenyl, aryl, a heterocyclic radical or cycloalkyl, or if
R1 stands for a lower alkyl radical, alkoxy, or aryloxy, then R2 cannot simultaneously stand for a lower alkyl radical,
with the overriding stipulation that if
R1 stands for alkyl, alkenyl, aryl, aralkyl, or cycloalkyl, or for a phenyl-substituted alkyl or p-methoxyphenyl, then R2 can also simultaneously stand for alkyl, alkenyl, aryl, aralkyl, cyano, a heterocyclic radical or cycloalkyl,
R1 stands for a lower alkyl radical, alkoxy, or a primary, secondary or tertiary amino group, then R2 can also simultaneously stand for a lower alkyl radical.
|
15
|
This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 60/636,690 filed Dec. 17, 2004 which is incorporated by reference herein.
The invention relates to compounds of general formula (I), production and use as inhibitors of protein tyrosine kinases, in particular Eph (erythropoetin-producing hepatoma amplified sequence) receptors for treating various diseases.
Protein tyrosine kinases catalyze the phosphorylation of specific tyrosine radicals in various proteins. Such phosphorylation reactions play a role in a number of cellular processes that are involved in the regulation of growth and the differentiation of cells. Protein tyrosine kinases are divided into receptor- and non-receptor tyrosine kinases. The family of receptor tyrosine kinases (RTKs) consists of 58 kinases (Manning, G. et al. 2002, Science 298, 1912-1934). RTKs have an extracellular ligand binding domain, a transmembrane domain and an intracellular domain, which generally contains tyrosine kinase activity. RTKs mediate the signal relay of extracellular stimulators such as, e.g., growth factors. The ligand bond results in the dimerization of RTKs and the reciprocal auto-phosphorylation of their intracellular domains. Based on the cell type, specific intracellular binding proteins are thus recruited (i.a., non-receptor tyrosine kinases), via which a signal processing is carried out in the cells (Schlessinger, J. 2000, Cell 103, 211-225). The latter include receptor families of growth factors such as EGF (epidermal growth factor), VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor), PDGF (platelet derived growth factor) and NGF (nerve growth factor), as well as the insulin receptors and the large family of ephrin receptors, etc.
The ephrin (Eph) receptors make up the largest family within the RTKs. They are divided according to their sequential affinity and their ligand specificity into the group of EphA receptors (9 members) and EphB receptors (6 members) (Kullander, K. and Klein, R. 2002, Nat. Rev. Mol. Cell. Biol. 3, 475-486; Cheng, N. et al. 2002, Cyt. and Growth Factor Rev. 13, 75-85). Eph receptors are activated by membrane-fixed ligands of the EphrinA or EphrinB family. EphrinAs are anchored via glycolipids (GPI) in the cell membrane, while EphrinBs have a transmembrane region and an intracellular domain. The interaction between ephrins and the Eph receptors results in a bi-directional signal transfer in the ephrin-expressing cells and in the cells that carry the Eph receptor. Ephrins and Eph receptors play a role in a number of morphogenetic processes in embryonic development and in the adult organism. They are involved in embryonic pattern formation, in the development of the vascular system (Gerety, S. S. et al., 1999, Mol. Cell. 4, 403-414) and in creating neuronal circuits (Flanagan, J. G. and Vanderhaeghen, P., 1998, Annu. Rev. Neurosci. 21, 306-354). In the adult organism, they are involved in the neovascularization process, e.g., in tumor development and in endometriosis, as well as in the morphogenesis of the intestinal epithelium (Battle, E. et al. 2002, Cell 111:251-63). On the cellular plane, they mediate migration, adhesion and juxtacrine cell contacts. Elevated expression of Eph receptors, such as, e.g., EphB2 and EphB4, was also observed in various tumor tissues, such as, e.g., breast tumors and tumors of the intestine (Nakamoto, M. and Bergemann, A. D. 2002, Mic. Res. Tech. 59, 58-67). Knock-out mice of EphB2, EphB3 and EphB4 show defects in the formation of the vascular system. The embryonic mortality of the EphB4-I-mice in embryonic stage d14 shows the special role of EphB4 in this process (Gerety, S. S. et al. 1999, Mol. Cell. 4, 403-414). A modulation of these receptors, e.g., by the inhibition of their kinase activity, results, for example, in that the tumor growth and/or the tumor metastasizing is suppressed either by a direct antitumoral action or by an indirect antiangiogenic action.
Non-receptor tyrosine kinases are present intracellularly in soluble form and are involved in the processing of extracellular signals (e.g., of growth factors, cytokines, antibodies, adhesion molecules) within the cell. They include, i.a., the families of Src (sarcoma) kinases, the Tec (tyrosine kinases expressed in hepatocellular-carcinoma) kinases, the Abl (Abelson) kinases and the Brk (breast-tumor kinase) kinases, as well as the focal adhesion kinase (FAK).
A modified activity of these protein tyrosine kinases can result in the most varied physiological disorders in the human organism and thus cause, e.g., inflammatory, neurological and oncological diseases.
Pyrazolopyridines are described as antimicrobial substances (e.g., Attaby et al., Phosphorus, Sulfur and Silicon and the Related Elements (1999), 149, 49-64; ibid. (1999), 155, 253-270).
In U.S. Pat. No. 5,478,830, pyrazolopyridines are disclosed.
DE 30 01 498 A1 (Agfa-Gevaert AG) discloses pyrazoles that can be used for photographic materials.
Pyrazolopyridines that have an antiphlogistic and in particular antithrombotic action are described in DE 26 43 753 A1 (Dr. Karl Thomae GmbH). The disclosed substituents are always linked via a nitrogen atom to the pyridine in 6-position.
F. E. Goda et al. 2004, Bioorganic & Medicinal Chemistry, 12(8), pp. 1845-1852, discloses pyrazolopyridines that have an antimicrobial action.
B. Narsaiah et al. 2001, Journal of Fluorine Chemistry, 109, 183-7 describes various pyrazolopyridines that are substituted with CF3.
WO 01/19828 A2 discloses a pyrazolopyridine that is substituted with a diaminopyrazolyl group and a methyl group. The substances that are described in this patent can be used as hair dyes.
In WO 01/19828 (BASF AG), the bases for the most varied kinase inhibitors are disclosed. The description contains pyrazolopyridines (structure 95, page 101). In the examples, however, no pyrazolopyridines are disclosed, and the production of the pyrazolopyridines claimed therein is not described.
In other prior art, reference is made to suitable spots in the text. No Eph-receptor inhibitors are described under the receptor tyrosine kinase inhibitors, however.
The object of this invention is to provide compounds that inhibit protein tyrosine kinases, in particular Eph receptors.
FIRST EMBODIMENT OF THE INVENTION
In a first embodiment of this invention, it was now found that compounds of general formula (I)
in which
R1 stands for C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby C3-C10-heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
K stands for halogen, hydroxy or the group —O—R3, or for C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C3-C10-heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
L stands for C1-C6-alkyl or for the group —COR4 or —NR5R6,
R2 stands for C1-C6-alkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M,
R3 stands for C1-C6-alkyl, aryl or —(CH2)n-aryl that optionally is substituted in one or more places, in the same way or differently, with the group —NR5R6,
R4 stands for hydrogen, hydroxy, C1-C6-alkyl or C1-C6-alkoxy,
M stands for cyano, halogen, hydroxy, nitro or for C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, or C1-C6-alkoxy, or for the group —O—R3 or —COR4,
R5 and R6, independently of one another, stand for hydrogen, C1-C6-alkyl or for the group —COR4, and
n stands for 1 to 4,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, with the stipulation that if
R1 stands for methyl, then R2 cannot simultaneously stand for methyl, —CH2—O—CH3, phenyl, chlorophenyl, or benzofuranyl or furanyl that is substituted with hydroxy and/or methoxy, or if
R1 stands for —CH2—O—CH3, then R2 cannot simultaneously stand for methyl, or if
R1 stands for —CH═CH-phenyl, then R2 cannot simultaneously stand for phenyl, or if
R1 stands for —CH═CH-chlorophenyl, then R2 cannot simultaneously stand for phenyl or chlorophenyl, or if
R1 stands for —CH═CH-methoxyphenyl, then R2 cannot simultaneously stand for phenyl or methoxyphenyl, or if
R1 stands for phenyl, then R2 cannot simultaneously stand for —CF3 or phenyl, or if
R1 stands for chlorophenyl, then R2 cannot simultaneously stand for chlorophenyl, or if
R1 stands for hydroxyphenyl, then R2 cannot simultaneously stand for heterocycloalkyl or for —COO-tert-butyl-substituted heterocycloalkyl, or if
R1 stands for benzyloxyphenyl, then R2 cannot simultaneously stand for —COO-tert-butyl-substituted heterocycloalkyl,
inhibit protein tyrosine kinases, in particular Eph receptors.
Compounds of the above-mentioned general formula I, in which
R1 stands for C1-C6 alkyl, C3-C10-cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K,
K stands for halogen, hydroxy or morpholinyl, piperazinyl, piperidinyl or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L,
L stands for C1-C6-alkyl or —COO—C1-C6 alkyl,
R2 stands for C1-C6 alkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M,
M stands for cyano, halogen, hydroxy, nitro or for C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, or C1-C6-alkoxy, or for the group —O—C1-C6-alkyl, —O—(CH2)n—N(C1-C6-alkyl)2, —CO—C1-C6-alkyl, —O-phenyl or —O—(CH2)n-phenyl, and
n stands for 1 to 4,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are preferred.
Compounds of the above-mentioned general formula I, in which
R1 stands for tert-butyl, cyclopropyl, cyclohexyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K,
K stands for halogen, hydroxy or morpholinyl, piperazinyl, piperidinyl, methoxy or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L,
L stands for methyl or —COO-tert-butyl,
R2 stands for isopropyl, phenyl, quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, and
M stands for cyano, halogen, hydroxy, nitro, methyl, —CF3 or for methoxy or for the group —CO-methyl, —O—(CH2)3—N(methyl)2, phenoxy or benzyloxy,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are especially preferred.
In addition, compounds of the above-mentioned general formula I, in which
R1 stands for C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C3-C10-heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
K stands for halogen, hydroxy or the group —O—R3 or —NR5R6 or for C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C3-C10-heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
L stands for C1-C6-alkyl or the group —COR4 or —NR5R6,
R2 stands for C1-C6-alkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M,
R3 stands for C1-C6-alkyl, aryl or —(CH2)n-aryl that optionally is substituted in one or more places, in the same way or differently, with the group —NR5R6,
R4 stands for hydrogen, hydroxy, C1-C6-alkyl or C1-C6-alkoxy,
M stands for cyano, halogen, hydroxy, nitro or for C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, or C1-C6-alkoxy, or for the group —O—C1-C6-alkyl, —O—(CH2)n—NR5R6 or —COR4,
R5 and R6, independently of one another, stand for hydrogen, C1-C6-alkyl or for the group —COR4, and
n stands for 1 to 4,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are preferred.
In addition, those compounds of the above-mentioned general formula I, in which
R1 stands for C1-C6 alkyl, C3-C10-cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K,
K stands for halogen, hydroxy or morpholinyl, piperazinyl, piperidinyl or phenyoxy that optionally is substituted in one or more places, in the same way or differently, with L,
L stands for C1-C6-alkyl or —COO—C1-C6 alkyl,
R2 stands for C1-C6 alkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M,
M stands for cyano, halogen, hydroxy, nitro or for C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, or C1-C6-alkoxy, or for the group —O—C1-C6-alkyl, —O—(CH2)n—N(C1-C6-alkyl)2 or —CO—C1-C6-alkyl, and
n stands for 1 to 4,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers, and salts, are preferred.
Those compounds of the above-mentioned general formula, in which
R1 stands for C1-C6-alkyl, C3-C10-cycloalkyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K,
K stands for halogen, hydroxy or morpholinyl, piperazinyl, piperidinyl, methoxy or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L,
L stands for C1-C6-alkyl or —COO—C1-C6 alkyl,
R2 stands for C1-C6-alkyl, phenyl or quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M,
M stands for cyano, halogen, hydroxy, nitro or for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, or C1-C6-alkoxy, or for the group —O—C1-C6-alkyl, —O—(CH2)n—N(C1-C6-alkyl)2 or —CO—C1-C6-alkyl, and
n stands for 1 to 4,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are especially preferred.
Those compounds of general formula I, in which
R1 stands for tert-butyl, cyclopropyl, cyclohexyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K,
K stands for halogen, hydroxy or morpholinyl, piperazinyl, piperidinyl, methoxy or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L,
L stands for methyl or —COO-tert-butyl,
R2 stands for isopropyl, phenyl, quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, and
M stands for cyano, halogen, hydroxy, nitro, methyl, —CF3 or for methoxy or for the group —CO-methyl, —O—(CH2)3—N(methyl)2, phenoxy or benzyloxy,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are very highly preferred.
The intermediate products that are preferably used for the production of the compounds of general formula I according to the invention in accordance with this first embodiment of the invention are the following compounds of general formulas II and III
in which
X stands for halogen or —O—SO2—CmF2m+1,
m stands for 1 to 4,
R1a stands for C1-C6-alkyl, C1-C6-alkenyl, C2-C6-alkinyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with Ka, whereby the C3-C10-heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
Ka stands for halogen, hydroxy, the group —O—R3a, —COR4a or —NR5aR6a, or for C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with La, whereby the C3-C10-heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
La stands for C1-C6-alkyl or the group —COR4a or —NR5aR6a,
R2a stands for C1-C6-alkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with Ma,
R3a stands for trimethylsilyl (TMS), tert-butyl-dimethylsilyl (TBDMS), tert-butyl-diphenylsilyl (TBDPS), triethylsilyl (TES), C1-C2-alkyl, C3-C6-allyl, benzyl or for the group —COR4a or for C1-C6-alkyl, aryl or —(CH2)n-aryl that optionally is substituted in one or more places, in the same way or differently, with the group —NR5aR6a,
R4a stands for hydrogen, C1-C6-alkyl or C1-C6-alkoxy,
Ma stands for cyano, halogen, hydroxy, nitro or for C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, or C1-C6-alkoxy, or for the group —O—R3a or —COR4a,
R5a and R6a, independently of one another, stand for hydrogen, C1-C6-alkyl or for the group COR4a, and
na stands for 1 to 4,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts.
Alkyl is defined in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl.
Alkoxy is defined in each case as a straight-chain or branched alkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy.
The alkenyl substituents are in each case straight-chain or branched, whereby, for example, the following radicals are meant: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl, or allyl.
Alkinyl is defined in each case as a straight-chain or branched alkinyl radical that contains 2-6, preferably 2-4, C atoms. For example, the following radicals can be mentioned: acetylene, propin-1-yl, propin-3-yl, but-1-in-1-yl, but-1-in-4-yl, but-2-in-1-yl, but-1-in-3-yl, etc.
Heterocyclyl or C3-C10-heterocycloalkyl stands for an alkyl ring that comprises 3-10 carbon atoms and is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and the C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring. Only those combinations are meant, however, that are useful from the viewpoint of one skilled in the art, in particular in reference to ring strain.
As heterocyclyls, there can be mentioned, e.g.: oxiranyl, oxethanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dioxanyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, etc.
Cycloalkyls are defined as monocyclic C3-C10 alkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but also bicyclic rings or tricyclic rings, such as, for example, adamantanyl or 1,4-dioxa-spiro[4,5]dec-8-yl. The cycloalkyl rings can be unsubstituted or substituted in one or more places.
An aryl radical in each case has 6-12 carbon atoms, such as, for example, naphthyl, biphenyl and in particular phenyl.
The heteroaryl radical in each case comprises 3-16 ring atoms and instead of carbon contains one or more of the heteroatoms that are the same or different from the group oxygen, nitrogen or sulfur, can be monocyclic, bicyclic or tricyclic and in addition in each case can be benzocondensed. Only those combinations are meant, however, that are useful from the viewpoint of one skilled in the art, in particular in reference to ring strain.
The heteroaryl rings can be unsubstituted or substituted in one or more places.
For example, there can be mentioned: thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl as well as benzo derivatives thereof, such as, e.g., 1,3-benzodioxolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, oxepinyl, azocinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, purinyl, or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, etc.
Halogen is defined in each case as fluorine, chlorine, bromine or iodine.
ADDITIONAL EMBODIMENT OF THE INVENTION
In an additional embodiment of this invention that achieves the object, there are, according to a 1st aspect, compounds of general formula (I),
in which
R1 stands for C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and the C3-C10-heterocycloalkyl and/or heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, or stands for a C3-C10-cycloalkyl, aryl, C3-C10-heterocycloalkyl or heteroaryl that is substituted with the group —O—(CH2)n—O—, whereby the terminal oxygen atoms of the —O—(CH2)n—O— group are linked to the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring-, C3-C10-heterocycloalkyl ring- or heteroaryl ring-carbon atom,
K stands for halogen, hydroxy or the group —OR3, —COR4 or —NR5R6, or for C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
L stands for C1-C6-alkyl or the group —COR4, —OR3 or —NR5R6,
R2 stands for C1-C6 alkyl, C3-C10-cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M,
R3 stands for C1-C6-alkyl, aryl or —(CH2)n-aryl that optionally is substituted in one or more places, in the same way or differently, with the group —NR5R6,
R4 stands for hydrogen, hydroxy, C1-C6-alkyl or C1-C6-alkoxy,
M stands for amino, cyano, halogen, hydroxy, or nitro or for C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C1-C6-alkoxy, or for the group —OR3, —COR4, or —CO—N—R7,
R5 and R6, independently of one another, stand for hydrogen, C1-C6-alkyl or for the group —COR4, and
R7 stands for hydrogen, or NH2,
n stands for 1 to 4,
with the stipulation that if
R1 stands for methyl, then R2 cannot simultaneously stand for methyl, —CH2—O—CH3, phenyl, chlorophenyl, benzofuranyl that is substituted with hydroxy and/or methoxy, —CF3 or furanyl, or if
R1 stands for —CH2—O—CH3, then R2 cannot simultaneously stand for methyl, or if
R1 stands for —CH═CH-phenyl, then R2 cannot simultaneously stand for phenyl, or if
R1 stands for —CH═CH-chlorophenyl, then R2 cannot simultaneously stand for phenyl or chlorophenyl, or if
R1 stands for —CH═CH-methoxyphenyl, then R2 cannot simultaneously stand for phenyl or methoxyphenyl, or if
R1 stands for phenyl, then R2 cannot simultaneously stand for —CF3, methyl, methoxyphenyl or phenyl, or if
R1 stands for methoxyphenyl, then R2 cannot simultaneously stand for —CF3, or if
R1 stands for methylphenyl, then R2 cannot simultaneously stand for —CF3, or if
R1 stands for chlorophenyl, then R2 cannot simultaneously stand for chlorophenyl or —CF3, or if
R1 stands for dichlorophenyl, then R2 cannot simultaneously stand for trimethoxyphenyl, or if
R1 stands for bromophenyl, then R2 cannot simultaneously stand for trimethoxyphenyl, or if
R1 stands for alkyl, alkenyl, aryl, aralkyl, cycloalkyl, or for an alkyl that is substituted with phenyl or p-methoxyphenyl, then R2 cannot simultaneously also stand for alkyl, alkenyl, aryl, aralkyl, cyano, a heterocyclic radical or cycloalkyl, or if
R1 stands for a lower alkyl radical, alkoxy or aryloxy, then R2 simultaneously cannot stand for a lower alkyl radical, or if
R1 stands for hydroxyphenyl, then R2 cannot simultaneously stand for heterocyclyl or a —COO-tert-butyl-substituted heterocycloalkyl, or if
R1 stands for benzyloxyphenyl, then R2 cannot simultaneously stand for a —COO-tert-butyl-substituted heterocycloalkyl,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts.
In an alternate embodiment,
R1=methyl, then R2 is not=methyl or ethyl, or if
R2=methyl, then R1 is not=methyl or ethyl, or if
R1=chlorophenyl, then R2 is not=chlorophenyl or methylchlorophenyl, or if
R2=chlorophenyl, then R1 is not=—CH2-phenyl, or if
R1=methyl, then R2 is not=chlorophenyl, furanyl, methylchlorophenyl or methylfuranyl, or if
R2=chlorophenyl or furanyl, then R1 is not=methyl or ethyl, or if
R1=—CH═CH-phenyl, then R1 is not=phenyl, or methylphenyl, or if
R2=phenyl, then R1 is not=—C1-3-alkyl-phenyl, C2-3-alkenyl-phenyl, C2-3-alkinyl-phenyl, or —CH═CH-methylphenyl, or if
R1=—CH═CH-methoxyphenyl, then R2 is not=phenyl, methylphenyl, methoxyphenyl, ethoxyphenyl, hydroxyphenyl, or methoxyphenyl with an additional methyl substituent, or if
R2=phenyl or methoxyphenyl, then R1 is not=—C1-3-alkyl-methoxyphenyl, C2-3-alkenyl-methoxyphenyl, or C2-3-alkinyl-methoxyphenyl, or if
R1=—CH═CH-chlorophenyl, then R2 is not=phenyl, methylphenyl, chlorophenyl, or methylchlorophenyl, or if
R2=phenyl or chlorophenyl, then R1 is not=—C1-3-alkyl-chlorophenyl, C2-3-alkenyl-chlorophenyl, C2-3-alkinyl-chlorophenyl, or —CH═CH-methylphenyl, or if
R1=methyl, then R2 is not=—CH2—O—CH3, —CH2—CH2—O—CH3, or —CH2—O—CH2—CH3,
R2=—CH2—O—CH3, then R1 is not=methyl or ethyl, or if
R1=phenyl, then R2 is not=—CF3 or C1-2-alkyl that is optionally substituted with halogen, preferably with 3 F groups, or if
R2=—CF3, then R1 is not=phenyl or —CH2-phenyl, or if
R1=methylphenyl, then R2 is not=—CF3 or C1-2-alkyl optionally substituted with halogen, preferably with 3 F groups, or if
R2=—CF3, then R1 is not=phenyl, methylphenyl, ethylphenyl, or —CH2-methylphenyl, or if
R1=methoxyphenyl, then R2 is not=—CF3 or C1-2-alkyl optionally substituted with halogen, preferably with 3 F groups, or if
R2=—CF3, then R1 is not=methoxyphenyl, ethoxyphenyl, or hydroxyphenyl, or if
R1=chlorophenyl, then R2 is not=—CF3 or C1-2-alkyl optionally substituted with halogen, preferably with 3 F groups, or if
R2=—CF3, then R1 is not=chlorophenyl, or if
R1=phenyl, then R2 is not=phenyl or methylphenyl, or if
R=phenyl, then R1 is not=—CH2-phenyl, or if
R1=methyl, then R2 is not=benzofuranyl that is substituted with hydroxy and/or methoxy or ethoxy, or benzofuranyl that is substituted with hydroxy and/or methoxy and an additional methyl, or if R2=benzofuranyl that is substituted with hydroxy and/or methoxy, then R1 is not=methyl or ethyl, or if
R2=methyl, then R2 is not=—CF3 or C1-2-alkyl optionally substituted with halogen, preferably with 3 F groups, or if
R2=—CF3, then R1 is not=methyl or ethyl, or if
R1=—CH2—O—CH3, then R2 is not=methyl or ethyl, or if
R2=methyl, then R1 is not=—CH2—O—CH3, —CH2—CH2—O—CH3, —CH2—O—CH2—CH3, —CH═CH—O—CH3, —CH2—O—CH═CH2, —C≡C—O—CH3, or —CH2—O—C≡C, or if
R1=methyl, then R2 is not=phenyl or methylphenyl, or if
R2=phenyl, then R1 is not=methyl or ethyl, or if
R1=dichlorophenyl, then R2 is not=trimethoxyphenyl, or a dimethoxyhphenyl group that additionally is substituted with a hydroxy or ethoxy group, or a trimethoxyphenyl that is substituted with a methyl group, or if
R1=bromophenyl, then R2 is not=trimethoxyphenyl or a dimethoxyphenyl group that additionally is substituted with a hydroxy or ethoxy group, or trimethoxyphenyl that is substituted with a methyl group, or if
R1=hydroxyphenyl, then R2 is not=piperidine or methylpiperidine, or if
R1=phenyl, then R2 is not=methoxyphenyl, ethoxyphenyl, or hydroxyphenyl, or if
R2=methoxyphenyl, then R1 is not=phenyl or —CH2-phenyl, or if
R=methyl, then R1 is not=—CH2-phenyl, or if
R1=phenyl, then R2 is not=methyl or ethyl, or if
R1 stands for an unsubstituted alkyl, alkenyl, aryl, aralkyl or cycloalkyl group, then R2 is not an unsubstituted alkyl, alkenyl, aryl, aralkyl or cycloalkyl group, or if
R1 stands for diaminopyrazolyl-, then R2- is not methyl or ethyl, or if
R1 stands for hydrogen, an optionally substituted alkyl, aralkyl-, cycloalkyl-, or aryl radical, for example, a methyl, ethyl or propyl group that is substituted with a phenyl, methylphenyl, p-nitrophenyl, -methylnitrophenyl, p-methoxyphenyl, p-ethoxyphenyl, or p-hydroxyphenyl ring then R2 is not hydrogen, an optionally substituted alkyl-, aralkyl-, cyclo-alkyl-, aryl- or heterocyclic radical or a cyano group, or if
R1 stands for a lower alkyl radical (for example, methyl or ethyl), an alkoxy or aryloxy group or a primary, secondary or tertiary amino group, then R2 is not a lower alkyl radical (for example, a methyl or ethyl group) or a phenyl, —CH2-phenyl or methylphenyl,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts.
The above-described disclaimer was introduced based on the prior art below.
A pyrazolopyridine with R1=methyl and R2=methyl is described by, for example, Kaupp., G. et al. 2003, European Journal of Organic Chemistry, (8) pp. 1545-1551, Gamal, A., 1994, Zagazig Journal of Pharmaceutical Sciences, 3(2) 148-53, Kalme, Z. A. et al., 1992, Khimiya Geterotsiklicheskikh Soedinenii, (9), 1218-22, El-Dean, A. M. Kamal et al., 1991, Bulletin of the Faculty of Science, Assiut University, 20(1), 15-21 or by El-Dean, A. M. et al, 1991, Indian Journal of Chemistry, 30B (9), 878-82.
A pyrazolopyridine with R1=chlorophenyl and R2=chlorophenyl is known by Gamal et al., 2001, Journal of Saudi Chemical Society, 5(2), pp. 183-187.
Mohamed, A. et al., 2000, Phosphorus, Sulfur and Silicon, 167, 161-179 describes pyrazolopyridines in which R1=methyl and at the same time R2=chlorophenyl, and R1=methyl and at the same time R2=furanyl. Attaby, Fawzy A. et al., 1999, Phosphorus, Sulfur and Silicon, 149, 49-64 show that these substances have antimicrobial properties.
Attaby, Fawzy A. et al., 1999, Phosphorus, Sulfur and Silicon, 155, 253-270 disclose, for example, pyrazolopyridines with antimicrobial action in which R1=—CH═CH-phenyl and at the same time R2=phenyl, R1=—CH═CH-methoxyphenyl and at the same time R2=phenyl or methoxyphenyl, R1=—CH═CH-chlorophenyl and at the same time R2=phenyl or chlorophenyl. Sanna, Eldin M. et al., 1998, Egyptian Journal of Pharmaceutical Sciences, 39, (1-3), 197-209 describe the same compounds and show that these substances have antibacterial properties.
Arustamova, I. S. et al., 1999, Chemistry of Heterocyclic Compounds, 35(1), 58-63 describes pyrazolopyridines in which R1=methyl and at the same time R2=—CH2—O—CH3.
Lacan, M. and Tabakovic, K. (1975) Chroatica Chemica Acta 47 (2), 127-133 disclose pyrazolopyridines in which R1 stands for methyl while at the same time R2 also stands for methyl.
Chandra, Sheker Reddy et al., 1997, Journal of Fluorine Chemistry, 86(2) 127-130 describes pyrazolopyridines in which R1=methyl and at the same time R2=methyl, R1=phenyl and at the same time R2=—CF3, R2=methylphenyl and at the same time R2=—CF3, R1=methoxyphenyl and at the same time R2=—CF3, as well as R=chlorophenyl and at the same time R2=—CF3.
Abdel, Hafez et al., 1993, Collection of Czechoslovak Chemical Communications, 58(5), 1198-202; Deeb, Ali, 1991, Collection of Czechoslovak Chemical Communications, 56(7), 1560-3 disclose a pyrazolopyridine with R1=phenyl and at the same time R2=phenyl.
Gohar, Abdel Kerim et al., 1987, Archiv der Pharmazie (Weinheim, Germany), 320(9), 823-9 disclose pyrazolopyridines in which R2=methyl and at the same time R2=benzofuranyl that is substituted with hydroxy and/or methoxy.
Balicki, R. et al., 1979, Polish Journal of Chemistry, 53(7-8), 1515-25 describes a pyrazolopyridine in which R1=methyl and at the same time R2=—CF3.
Pejcic, Marijan et al., 1977, Acta Pharmaceutica Jugoslavia, 27(3), 143-6 disclose pyrazolopyridines with antibacterial properties, in which R1=methyl and at the same time R2=—CH2—O—CH3, and R1=—CH2—O—CH3 and at the same time R2=methyl.
Bomika, Z. et al., 1976, Khimiya Geterotsiklicheskikh Soedinenii, (8), 1085-8 describes a pyrazolopyridine in which R1=phenyl and at the same time R2=phenyl, R1=methyl and at the same time R2=phenyl.
Yoshida, Kei et al., 1976, Yakugaku Zasshi, 96(1), 33-6 describes a pyrazolopyridine in which R1=methyl and at the same time R2=—CH2—O—CH3.
DE 30 01 498 A1 (Agfa-Gevaert AG) discloses pyrazoles that can be used for photographic materials. The patent discloses pyrazolopyridines in which R1 stands for an unsubstituted alkyl, alkenyl, aryl, aralkyl or cycloalkyl group, and R2 simultaneously stands for an unsubstituted alkyl, alkenyl, aryl, aralkyl or cycloalkyl group.
Described in DE 26 43 753 A1 (Dr. Karl Thomae GmbH) are pyrazolopyridines that have an antiphlogistic and in particular antithrombotic action. The disclosed substituents are always linked via a nitrogen atom to the pyridine (of the pyrazolopyridine) at 6-position.
F. E. Goda et al. 2004, Bioorganic & Medicinal Chemistry, 12(8), pp. 1845-1852 discloses pyrazolopyridines that have an antimicrobial action. In this case, R1 stands for dichlorophenyl, and R2 simultaneously stands for trimethoxyphenyl (compound 5b) or R1 stands for bromophenyl, and R2 then simultaneously stands for trimethoxyphenyl (compound 5c). Compounds 3a to 5a in Table 1 on page 1846 relate to precursors of pyrazolopyridines, but not pyrazolopyridines themselves.
Registry Number 774531-14-5 discloses a pyrazolopyridine in which R1=hydroxyphenyl and at the same time R2 is a piperidine. Registry Number 692775-16-9 discloses a pyrazolopyridine in which R1=phenyl and at the same time R2 is a methoxyphenyl. Registry Number 201224-90-0 discloses a pyrazolopyridine in which R1=methoxyphenyl and at the same time R1 is a —CF3.
B. Narsaiah et al. 2001, Journal of Fluorine Chemistry, 109, 183-7 describes different CF3-substituted pyrazolopyridines. In this case, R2 stands for —CF3 while R1 either stands for phenyl, methylphenyl or chlorophenyl.
WO 01/19828 A2 discloses a pyrazolopyridine that is substituted with a diaminopyrazolyl- (at R1-position) and a methyl group (at R1-position). The diaminopyrazolyl is linked via the nitrogen atom to the pyridine (of the pyrazolopyridine) at 6-position. The substances that are described in this patent can be used as hair dyes.
German laid-open specification DE2160780 discloses pyridinopyrazoles for use as diazo components in which R1 stands for phenyl or methyl and at the same time R2 stands for phenyl or methyl.
German laid-open specification DE2238400 pyrazolopyridines as dyes in which R1 stands for hydrogen, an optionally substituted alkyl-, aralkyl-, cycloalkyl-, or aryl radical, and R2 stands for hydrogen, an optionally substituted alkyl-, aralkyl-, cyclo-alkyl-, aryl- or heterocyclic radical or a cyano group. Which substitutions may be suitable is not defined in the application. In the examples, for R1, there is only one ethyl group that is substituted with a phenyl ring, a p-nitrophenyl and a p-methoxyphenyl. For R2, there are no examples with substitutions. Also, for R2 defined as a heterocyclic radical, there are no definitions and also no examples.
German laid-open specification DE2355967 discloses polycyclic dyes in whose production pyrazolopyridines are used in which R1 stands for a lower alkyl radical (in the examples, methyl is mentioned), an alkoxy or aryloxy group or a primary, secondary or tertiary amino group, and R2 simultaneously stands for a lower alkyl radical (in the examples, methyl and phenyl are mentioned for R2).
None of the above-mentioned publications and patents disclose Eph-receptor inhibitors.
According to this embodiment, compounds of general formula I in a 2nd aspect, according to claim 1, in which
R1 stands for C1-C6 alkyl or C3-C10-cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C3-C10-cycloalkyl optionally is interrupted by one or more —(CO)—, —SO— or —SO2— groups in the ring, and optionally one or more double bonds can be contained in the ring, or for aryl, C3-C10-heterocycloalkyl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one nitrogen/oxygen and/or sulfur, and the C3-C10-heterocycloalkyl and/or heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, or for a C3-C10-cycloalkyl, aryl, C3-C10-heterocycloalkyl or heteroaryl that is substituted with the group —O—(CH2)n—O—, whereby the terminal oxygen atoms of the —O—(CH2)n—O— group are linked with the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring-, C3-C10-heterocycloalkyl ring- or heteroaryl ring-carbon atom,
K stands for halogen, hydroxy or the group —OR3, —COR4 or for C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
R2 stands for C1-C6-alkyl, C3-C10-cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, whereby the heteroaryl is interrupted by at least one nitrogen, oxygen and/or sulfur,
R3 stands for C1-C6-alkyl, aryl or —(CH2)n-aryl,
M stands for amino, cyano, halogen, hydroxy, nitro or for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C1-C6-alkoxy, or for the group —O—C1-C6-alkyl, —O—(CH2)n—NR5R6, —COR4—O-phenyl, —O—(CH2)n-phenyl or —CO—N—R7,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are also subjects of the invention.
According to this embodiment, compounds of general formula I in a 3rd aspect, according to the 2nd aspect, in which
R1 stands for C1-C6 alkyl or C3-C10-cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C3-C10-cycloalkyl optionally is interrupted by one or more —(CO)—, —SO— or —SO2 groups in the ring, and optionally one or more double bonds can be contained in the ring, or R1 stands for aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the heteroaryl itself is interrupted by at least one nitrogen, oxygen and/or sulfur, and the heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, or R1 stands for a C3-C10-cycloalkyl, aryl or heteroaryl that is substituted with the group —O—(CH2)n—O—, whereby the terminal oxygen atoms of the —O—(CH2)n—O— group are linked with the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring- or heteroaryl ring-carbon atom,
K stands for halogen, hydroxy or the group —OR3, —COR4 or for C3-C10-cycloalkyl, or C3-C10-heterocycloalkyl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C3-C10-heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring,
L stands for C1-C6-alkyl or the group —COR4, —OR3,
R3 stands for C1-C6-alkyl or aryl,
M stands for amino, cyano, halogen, hydroxy, or nitro or for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C1-C6-alkoxy, or for the group —O—C1-C6-alkyl, —O—(CH2)n—NR5R6, —CO—C1-C6-alkyl, —O-phenyl, —O—(CH2)n-phenyl or —CO—N—R7,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are another subject of this invention.
According to this embodiment, compounds of general formula I in a 4th aspect, according to the 3rd aspect, in which
R1 stands for C1-C6 alkyl, C3-C10-cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C3-C10-cycloalkyl optionally is interrupted by one or more —(CO)— groups in the ring, or for aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the heteroaryl itself is interrupted by at least one nitrogen, and the heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, or for a C3-C10-cycloalkyl, aryl or heteroaryl that is substituted with the group —O—(CH2)n—O—, whereby the terminal oxygen atoms of the —O—(CH2)n—O— group are linked to the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring- or heteroaryl ring-carbon atom,
K stands for halogen, hydroxy or for the group —OR3, or C3-C10-heterocycloalkyl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C3-C10-heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen and/or oxygen in the ring,
L stands for C1-C6-alkyl or —COO—C1-C6-alkyl,
R2 stands for C1-C6 alkyl, C3-C6-cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, whereby the heteroaryl is interrupted by at least one nitrogen,
M stands for amino, cyano, halogen, hydroxy, nitro or for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro or C1-C6-alkoxy, or for the group —O—C1-C6-alkyl, —O—(CH2)n—N(C1-C6-alkyl)2, —CO—C1-C6-alkyl, phenoxy, benzyloxy or —CO—N—NH2,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are also another subject of this invention.
According to this embodiment, compounds of general formula I in a 5th aspect, according to one of aspects 1 to 4, in which
M stands for amino, cyano, halogen, hydroxy, or nitro or for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro or C1-C6-alkoxy, or for the group —O—C1-C6-alkyl, —O—(CH2)n—N(C1-C6-alkyl)2 or —CO—C1-C6-alkyl,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are another subject of this invention.
According to this embodiment, compounds of general formula I in a 6th aspect, according to the 4th aspect, in which
R1 stands for C1-C6-alkyl, C3-C6-cycloalkyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K,
K stands for halogen, hydroxy, C1-C6-alkoxy or morpholinyl, piperazinyl, piperidinyl, or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L,
R2 stands for C1-C6-alkyl, phenyl or quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M,
M stands for amino, cyano, halogen, hydroxy, nitro, C1-C6-alkyl, —CF3, or for C1-C3-alkoxy, or for the group —CO—C1-C6-alkyl, —O—(CH2)n—N(C1-C6-alkyl)2, phenoxy or benzyloxy,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are another subject of this invention.
According to this embodiment, compounds of general formula I in a 7th aspect, according to the 6th aspect, in which
R1 stands for C3-C6 alkyl, cyclopropyl, cyclohexyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K,
K stands for halogen, hydroxy, or methoxy, or morpholinyl, piperazinyl, piperidinyl or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L,
L stands for C1-C3-alkyl or —COO—C3-C5-alkyl,
R2 stands for isopropyl, phenyl, quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, and
M stands for cyano, halogen, hydroxy, nitro, methyl, —CF3 or for methoxy or for the group —CO—C1-C3-alkyl or —O—(CH2)3—N(methyl)2,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are another subject of this invention.
According to this embodiment, compounds of general formula (I), in an 8th aspect, according to the 7th aspect, in which
R1 stands for tert-butyl, cyclopropyl, cyclohexyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K,
L stands for methyl or —COO-tert-butyl,
R2 stands for isopropyl, phenyl, quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, and
M stands for cyano, halogen, hydroxy, nitro, methyl, —CF3 or for methoxy or for the group —CO-methyl or —O—(CH2)3—N(methyl)2,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are another subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R1 stands for C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and the C3-C10-heterocycloalkyl and/or heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, or for a C3-C10-cycloalkyl, aryl, C3-C10-heterocycloalkyl or heteroaryl that can be substituted with the group —O—(CH2)n—O—, whereby the terminal oxygen atoms of the —O—(CH2)n—O— group are linked with the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring-, C3-C10-heterocycloalkyl ring- or heteroaryl ring-carbon atom,
are a subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R1 stands for C1-C6 alkyl or C3-C10-cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C3-C10-cycloalkyl optionally is interrupted by one or more —(CO)—, —SO— or —SO2— groups in the ring and optionally one or more double bonds can be contained in the ring, or for aryl, C3-C10-heterocycloalkyl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one nitrogen, oxygen and/or sulfur, and the C3-C10-heterocycloalkyl and/or heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, or for a C3-C10-cycloalkyl, aryl, C3-C10-heterocycloalkyl or heteroaryl that is substituted with the group —O—(CH2)n—O—, whereby the terminal oxygen atoms of the —O—(CH2)n—O— group are linked with the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring-, C3-C10-heterocycloalkyl ring- or heteroaryl ring-carbon atom,
are another subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R1 stands for C1-C6 alkyl, C3-C10-cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C3-C10-cycloalkyl optionally is interrupted by one or more —(CO)—, —SO— or —SO2— groups in the ring, and optionally one or more double bonds can be contained in the ring, or for aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the heteroaryl itself is interrupted by at least one nitrogen, oxygen and/or sulfur, and the heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, or for a C3-C10-cycloalkyl, aryl or heteroaryl that is substituted with the group —O—(CH2)n—O—, whereby the terminal oxygen atoms of the —O—(CH2)n—O— group are linked with the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring- or heteroaryl ring-carbon atom,
are another subject of the invention.
In another subject of the invention according to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R1 stands for C1-C6 alkyl, C3-C10-cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C3-C10-cycloalkyl optionally is interrupted by one or more —(CO)— groups in the ring, or for aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the heteroaryl itself is interrupted by at least one nitrogen, and the heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, or for a C3-C10-cycloalkyl, aryl or heteroaryl that is substituted with the group —O—(CH2)n—O—, whereby the terminal oxygen atoms of the —O—(CH2)n—O— group are linked with the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring- or heteroaryl ring-carbon atom.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R1 stands for C1-C6-alkyl, C3-C6-cycloalkyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K, are a preferred subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R1 stands for C3-C6 alkyl, cyclopropyl, cyclohexyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K, are a preferred subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R1 stands for tert-butyl, cyclopropyl, cyclohexyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K, are a preferred subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R1 stands for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with K, and especially preferably tert-butyl, are an especially preferred subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R1 stands for C3-C6-cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, and especially preferably cyclopropyl and/or cyclohexyl, are an especially preferred subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R1 stands for C3-C10-cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, which is interrupted by one or more —(CO)— groups in the ring, are an especially preferred subject of the invention. R1 is then especially preferred for cyclohexanone.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R1 stands for a C3-C10-cycloalkyl, aryl or heteroaryl that is substituted with the group —O—(CH2)n—O—, whereby the terminal oxygen atoms of the —O—(CH2)n—O— group are linked with the same or a directly adjacent C3-C10-cycloalkyl ring-, aryl ring- or heteroaryl ring-carbon atom, are an especially preferred subject of the invention. R1 then especially preferably stands for 1,4-dioxa-spiro[4.5]dec-8-yl and/or 1,3-benzodioxolyl.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R1 stands for aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the heteroaryl itself is interrupted by at least one nitrogen, and the heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, are an especially preferred subject of the invention. R1 then especially preferably stands for phenyl and/or pyridinyl.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R1 stands for a C3-C10-heterocycloalkyl and/or heteroaryl, whereby the C3-C10-heterocycloalkyl and/or heteroaryl is linked only via a carbon ring atom with the pyrazolopyridine, are another subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R1 is substituted in one or more places, in the same way or differently, with K, are an especially preferred subject of the invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R1 is substituted in one place with K, are an especially preferred subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which K stands for halogen, hydroxy or the group —OR3, —COR4 or —NR5R6, or for C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, are a subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which K stands for halogen, hydroxy or the group —OR3, —COR4 or C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C3-C10-heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, are another subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which K stands for halogen, hydroxy or the group —OR3, —COR4 or for C3-C10-cycloalkyl, or C3-C10-heterocycloalkyl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C3-C10-heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C3-C10-cycloalkyl and/or C3-C10-heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, are another subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which K stands for halogen, hydroxy or for the group —OR3, or for C3-C10-heterocycloalkyl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C3-C10-heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen and/or oxygen in the ring, are a preferred subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which K stands for halogen, hydroxy, C1-C6-alkoxy or morpholinyl, piperazinyl, piperidinyl, or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L, are a preferred subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which K stands for halogen, hydroxy, methoxy or morpholinyl, piperazinyl, piperidinyl or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L, are a preferred subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which L stands for C1-C6-alkyl or the group —COR4, —OR3 or —NR5R6, are a subject of the invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which L stands for C1-C6-alkyl or the group —COR4 or —OR3, are another subject of the invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which L stands for C1-C6-alkyl or —COO—C1-C6 alkyl, are another subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which L stands for C1-C3-alkyl or —COO—C3-C5-alkyl, are a preferred subject of the invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which L stands for methyl or —COO-tert-butyl, are another preferred subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R2 stands for C1-C6-alkyl, C3-C10-cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, are a subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R2 stands for C1-C6-alkyl, C3-C10-cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, whereby the heteroaryl is interrupted by at least one nitrogen, oxygen and/or sulfur, are another subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R2 stands for C1-C6 alkyl, C3-C6-cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, whereby the heteroaryl is interrupted by at least one nitrogen, are another subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R2 stands for C1-C6-alkyl, phenyl or quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, are a preferred subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R2 stands for isopropyl, phenyl, quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, are another preferred subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R2 stands for isopropyl, phenyl, quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, are another preferred subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R3 stands for C1-C6-alkyl, aryl or —(CH2)n-aryl that optionally is substituted in one or more places, in the same way or differently, with the group —NR5R6 are a subject of the invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R3 stands for C1-C6-alkyl, aryl or —(CH2)n-aryl, are another subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R3 stands for C1-C6-alkyl or aryl, are another subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R3 stands for C1-C6-alkyl or phenyl, are a preferred subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R3 stands for C1-C3-alkyl or phenyl, are another preferred subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R3 stands for C1-C3-alkyl, are another preferred subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R4 stands for hydrogen, hydroxy, C1-C6-alkyl or C1-C6-alkoxy, are a subject of the invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R4 stands for hydrogen, hydroxy, C1-C3-alkyl or C1-C3-alkoxy, are another subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, nitro or for C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, C1-C6-alkoxy or for the group —OR3, —COR4, or —CO—N—R7, are a subject of the invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, nitro or for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C1-C6-alkoxy or for the group —O—C1-C6-alkyl, —O—(CH2)n—NR5R6, —COR4, —O-phenyl, —O—(CH2)n-phenyl or —CO—N—R7, are another subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, nitro or for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C1-C6-alkoxy, or for the group —O—C1-C6-alkyl, —O—(CH2)n—NR5R6, —COR4 or —CO—N—R7, are another preferred subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, nitro or for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, C1-C6-alkoxy or for the group —O—C1-C6-alkyl, —O—(CH2)n—NR5R6, —CO—C1-C6-alkyl, —O-phenyl, O—(CH2)n-phenyl or —CO—N—R7, are another subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, nitro or for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C1-C6-alkoxy or for the group —O—C1-C6-alkyl, —O—(CH2)n—NR5R6, —CO—C1-C6-alkyl or —CO—N—R7 are another preferred subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, or nitro or for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro or C1-C6-alkoxy, or for the group —O—C1-C6-alkyl, —O—(CH2)n—N(C1-C6-alkyl)2, —CO—C1-C6-alkyl, phenoxy, benzyloxy or —CO—N—NH2, are another subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, or nitro or for C1-C6-alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro or C1-C6-alkoxy, or for the group —O—C1-C6-alkyl, —O—(CH2)n—N(C1-C6-alkyl)2, —CO—C1-C6-alkyl or —CO—N—NH2, preferably without —CO—N—NH2, are another preferred subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M also stands for amino, cyano, halogen, hydroxy, nitro, C1-C6-alkyl, —CF3, or for C1-C3-alkoxy or for the group —CO—C1-C6-alkyl, —O—(CH2)n—N(C1-C6-alkyl)2, phenoxy or benzyloxy, are another preferred subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, nitro, C1-C6-alkyl, —CF3, or for C1-C3-alkoxy, or for the group —CO—C1-C6-alkyl or —O—(CH2)n—N(C1-C6-alkyl)2, are another preferred subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for cyano, halogen, hydroxy, nitro, methyl, —CF3 or for methoxy or for the group —CO—C1-C3-alkyl or —O—(CH2)3—N(methyl)2 are another preferred subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M also stands for cyano, halogen, hydroxy, nitro, methyl, —CF3 or for methoxy or for the group —CO-methyl or —O—(CH2)3—N(methyl) are another preferred subject of this invention.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R2 according to general formula (I) is substituted in one or more places, in the same way or differently, with M, are another subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R2 is an aryl or heteroaryl, and the aryl or heteroaryl is substituted in one or more places, in the same way or differently, with M, are another subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R2 is an aryl or heteroaryl, and the aryl or heteroaryl is substituted in one or more places, in the same way or differently, and at least one time in meta-position with M, are another subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R2 is an aryl, and the aryl is substituted in one or more places, in the same way or differently, and at least one time in meta-position with M, are another preferred subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R2 is a phenyl and is substituted in one or more places, in the same way or differently, and at least one time in meta-position with M, are another preferred subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R2 is substituted in several places, in the same way or differently, and at least one time in meta-position with M, are another subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R2 is substituted in several places, in the same way or differently, and twice in meta-position with M, are another preferred subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R2 is the same and is substituted twice in meta-position with M, are another preferred subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R2 is substituted one time in meta-position with M, are another preferred subject of this invention.
Compounds of general formula (I), according to one of aspects 1 to 8, in which R5 and R6, independently of one another, stand for hydrogen, C1-C6-alkyl or for the group —COR4, are a subject of the invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R5 and R6, independently of one another, stand for hydrogen or C1-C6-alkyl, are another subject of this invention.
R7 according to general formula (I), according to one of aspects 1 to 8, stands for hydrogen or NH2.
According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which n stands for 1 to 4, are a subject of the invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which n means 1 to 3, are another subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which n means 1 to 2, are another subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which n means 1, are another subject of this invention
Another subject of this invention according to this embodiment is the use of the compounds of general formula I in a 9th aspect, according to one of aspects 1 to 8, whereby if
R1 stands for alkyl, alkenyl, aryl, aralkyl, cycloalkyl, or for a phenyl substituted alkyl or p-methoxyphenyl, then R1 can simultaneously also stand for alkyl, alkenyl, aryl, aralkyl, cyano, a heterocyclic radical or cycloalkyl, or if
R1 stands for a lower alkyl radical, alkoxy or aryloxy, then R1 can simultaneously also stand for a lower alkyl radical,
for the production of a pharmaceutical agent.
Another preferred subject of this invention according to this embodiment is the use of the compounds of general formula I in a 10th aspect, according to one of aspects 1 to 8, for the production of a pharmaceutical agent.
Another subject of this invention according to this embodiment is the use of the compounds of general formula I in an 11th aspect, according to one of aspects 1 to 8, whereby if
R1 stands for methyl, then R2 can simultaneously also stand for methyl, —CH2—O—CH3, phenyl, chlorophenyl, hydroxy- and/or methoxy-substituted benzofuranyl, —CF3 or furanyl, or if
R1 stands for —CH2—O—CH3, then R2 can simultaneously also stand for methyl, or if
R1 stands for —CH═CH-phenyl, then R2 can simultaneously also stand for phenyl, or if
R1 stands for —CH═CH-chlorophenyl, then R2 can simultaneously also stand for phenyl or chlorophenyl, or if
R1 stands for —CH═CH-methoxyphenyl, then R2 can simultaneously also stand for phenyl or methoxyphenyl, or if
R1 stands for phenyl, then R1 can simultaneously also stand for —CF3, methyl, methoxyphenyl or phenyl, or if
R1 stands for methoxyphenyl, then R1 can simultaneously also stand for —CF3, or if
R1 stands for methylphenyl, then R1 can simultaneously also stand for —CF3, or if
R1 stands for chlorophenyl, then R2 can simultaneously also stand for chlorophenyl or —CF3, or if
R1 stands for dichlorophenyl, then R2 can simultaneously also stand for trimethoxyphenyl, or if
R1 stands for bromophenyl, then R2 can simultaneously also stand for trimethoxyphenyl, or if
R1 stands for alkyl, alkenyl, aryl, aralkyl, cycloalkyl, or for a phenyl -substituted alkyl or p-methoxyphenyl, then R2 can simultaneously also stand for alkyl, alkenyl, aryl, aralkyl, cyano, a heterocyclic radical or cycloalkyl, or if
R1 stands for a lower alkyl radical, alkoxy, aryloxy or a primary, secondary or tertiary amino group, then R2 can simultaneously also stand for a lower alkyl radical, or if
R1 stands for hydroxyphenyl, then R2 can simultaneously also stand for heterocyclyl or —COO-tert-butyl-substituted heterocycloalkyl, or if
R1 stands for benzyloxyphenyl, then R2 can simultaneously also stand for —COO-tert-butyl-substituted heterocycloalkyl, or if
R1 stands for a C3-C10-heterocycloalkyl or a heteroaryl, then the C3-C10-heterocycloalkyl and/or the heteroaryl can be linked via a carbon ring atom to the pyrazolopyridine,
for the production of a pharmaceutical agent for treating diseases in which angiogenesis, lymphangiogenesis or vasculogenesis plays a role, vascular diseases, diseases that are caused by a hyperproliferation of body cells, as well as chronic or acute neurodegenerative diseases.
Another preferred subject of this invention according to this embodiment is the use of the compounds of general formula I in a 12th aspect, according to the 11th aspect, for the production of a pharmaceutical agent for treating diseases in which angiogenesis, lymphangiogenesis or vasculogenesis plays a role, diseases that are caused by a hyperproliferation of body cells, as well as chronic or acute neurodegenerative diseases.
Another preferred subject of this invention according to this embodiment is the use of the compounds of general formula I in a 13th aspect, according to one of aspects 1 to 8, for the production of a pharmaceutical agent for treating diseases in which angiogenesis, lymphangiogenesis or vasculogenesis plays a role, vascular diseases, diseases that are caused by a hyperproliferation of body cells, as well as chronic or acute neurogenerative diseases.
Another subject of this invention according to this embodiment is the use of the compounds of general formula I in a 14th aspect, according to one of aspects 1 to 8, for diagnostic purposes in vitro or in vivo for identifying receptors in tissues by means of autoradiography or PET.
The intermediate products that are preferably used for the production of the compounds of general formula (I) according to the invention in a 15th aspect, according to one of aspects 1 to 8, according to this embodiment of the invention, are the following compounds:
in which
X stands for halogen or —O—SO2—CmF2m+1, preferably for perfluoroalkylsulfonyl,
m stands for 1 to 4, and
R1a and R2a have the same meaning as R1 and R2, according to one of aspects 1 to 8, whereby K, however, also can stand for group —COR4, and R3 also can stand for the group trimethylsilyl (TMS), tert-butyl-dimethylsilyl (TBDMS), tert-butyl-diphenylsilyl (TBDPS), triethylsilyl (TES), C1-C2-alkyl, C3-C6-allyl, benzyl or for the group —COR4a,
as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts as intermediate products for the production of compounds of general formula (I).
Another subject of the invention according to this embodiment is the use of the compounds of general formulas (II) and/or (III) in a 16th aspect, according to the 15th aspect, as intermediate products for the production of compounds of general formula (I).
According to this embodiment, pharmaceutical agents in a 17th aspect, which contain at least one compound of general formula I according to one of aspects 1 to 8, whereby if
R1 stands for alkyl, alkenyl, aryl, aralkyl, or cycloalkyl, or for a phenyl; substituted alkyl or p-methoxyphenyl, then R2 can also simultaneously stand for alkyl, alkenyl, aryl, aralkyl, cyano, a heterocyclic radical or cycloalkyl,
R1 stands for a lower alkyl radical, alkoxy, aryloxy, or a primary, secondary or tertiary amino group, then R2 can also simultaneously stand for a lower alkyl radical,
are another subject of the invention.
According to this embodiment, pharmaceutical agents in aspect 18 that contain at least one compound of general formula I according to one of aspects 1 to 8 are another preferred subject of the invention.
According to this embodiment, compounds according to aspects 1 to 8 or pharmaceutical agents according to aspects 17 or 18 with suitable formulation substances and vehicles in aspect 19 are another preferred subject of the invention.
Alkyl is defined in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl.
The alkyl group of R1 has the meaning that is mentioned in the paragraph above, but C1-C6-alkyl groups are preferred. Preferred for the alkyl group R1 are C1-C5-alkyl groups, still more preferred are C3-C5-alkyl groups, and especially preferred is a C4-alkyl group, in particular a tert-butyl group. Alkyl group R2 has the meaning that is mentioned in the paragraph above, but C1-C6-alkyl groups are preferred, C2-C4-alkyl groups are especially preferred, and a C3-alkyl group, in particular an isopropyl group, is quite especially preferred. Alkyl groups R3, R4, R5, R6, L and M have the meaning that is mentioned in the paragraph above, but C1-C6-alkyl groups are preferred, C1-C3-alkyl groups are especially preferred, and a methyl group is quite especially preferred.
Alkoxy is defined in each case as a straight-chain or branched alkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy.
The alkoxy groups K, R4 and M have the meaning that is mentioned in the paragraph above, but C1-C6-alkoxy groups are preferred, C1-C3-alkoxy groups are especially preferred, and a methoxy group is especially preferred.
The alkenyl substituents are in each case straight-chain or branched, whereby, for example, the following radicals are meant: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl, or allyl.
Alkinyl is defined in each case as a straight-chain or branched alkinyl radical that contains 2-6, preferably 2-4, C atoms. For example, the following radicals can be mentioned: acetylene, propin-1-yl, propin-3-yl, but-1-in-1-yl, but-1-in-4-yl, but-2-in-1-yl, but-1-in-3-yl, etc.
Heterocyclyl or C3-C10-heterocycloalkyl stands for an alkyl ring that comprises 3-10 carbon atoms, preferably for an alkyl ring that comprises 3 to 10 carbon atoms, and especially preferably for an alkyl ring that comprises 5 to 6 carbon atoms, and said alkyl ring is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and optionally can be interrupted by one or more —(CO)—, —SO— or —SO2— groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring. Only those combinations are meant, however, that are useful from the viewpoint of one skilled in the art, in particular in reference to ring strain.
As heterocyclyls, there can be mentioned, e.g.: oxiranyl, oxethanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dioxanyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, etc.
Cycloalkyls are defined as monocyclic C3-C10 alkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but also bicyclic rings or tricyclic rings, such as, for example, adamantanyl, and in the first embodiment of this invention. The cycloalkyl rings can be unsubstituted or substituted in one or more places. Cycloalkyls, according to this embodiment of the invention, contain C3-C10 hydrocarbon atoms; cycloalkyls with C3-C6-hydrocarbon atoms are preferred.
An aryl radical in each case has 6-12 carbon atoms, such as, for example, naphthyl, biphenyl and in particular phenyl. The radical can be monocyclic or bicyclic, for example naphthyl, biphenyl and in particular phenyl.
The heteroaryl radical in each case comprises 3-16 ring atoms, preferably 5 to 10 ring atoms, and especially preferably 5 to 7 ring atoms, and instead of carbon contains one or more of the heteroatoms that are the same or different from the group oxygen, nitrogen or sulfur, can be monocyclic, bicyclic or tricyclic, and in addition in each case can be benzocondensed. Only those combinations are meant, however, that are useful from the viewpoint of one skilled in the art, in particular in reference to ring strain.
The heteroaryl rings can be unsubstituted or substituted in one or more places.
For example, there can be mentioned: thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl as well as benzo derivatives thereof, such as, e.g., benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, oxepinyl, azocinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, purinyl, or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, etc.
Halogen is defined in each case as fluorine, chlorine, bromine or iodine. A fluorine, chlorine or bromine atom is preferred. The fluorine atom and the chlorine atom are especially preferred.
As used in this application, for example in connection with the definition of “C1-C6-alkyl”, “C1-C6” refers to an alkyl group with a finite number of 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5, or 6 carbon atoms. In addition, the definition of “C1-C6” is interpreted such that any possible partial area, such as, for example, C1-C6, C2-C6, C3-C6, C4-C6, C5-C6, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, is co-contained.
Analogously thereto, “C2-C6,” for example in connection with the definition of “C2-C6-alkenyl” and “C2-C6-alkinyl,” refers to an alkenyl group or an alkinyl group with a finite number of 2 to 10 carbon atoms, i.e., 2, 3, 4, 5 or 6 carbon atoms. The definition of “C2-C6” is interpreted such that any possible partial area, such as, for example C2-C6, C3-C6, C4-C6, C5-C6, C2-C3, C2-C4, C2-C8, C2-C6, preferably C2-C4, is co-contained.
In addition, “C1-C6,” for example in connection with the definition of “C1-C6-alkoxy,” refers to an alkoxy group with a finite number of 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5 or 6 carbon atoms. The definition of “C1-C6” is interpreted such that any possible partial area, such as, for example, C1-C6, C2-C8, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, is co-contained in the definition.
All area information of the application not explicitly cited here is defined analogously to the areas “C1-C6,” “C2-C6,” and “C1-C6” that are mentioned above by way of example.
The above-cited definitions relate to the compounds of general formula (I). The definitions are not such that they can be used for interpretation of the excluded (disclaimed) prior art. If, for example, a cycloalkyl is mentioned in the prior art that is cited here, cycloalkyl is not defined such that substituted cycloalkyl could also be co-contained (as mentioned in this application in the case of the definitions on page 32, lines 13 to 18, in particular line 16). The definition of this cycloalkyl depends solely on the original document of the prior art made available to the public.
The Following Information Relates Equally To The Two Embodiments Of The Invention
Isomers are defined as chemical compounds of the same summation formula but of different chemical structure. In general, constitutional isomers and stereoisomers are distinguished.
Constitutional isomers have the same summation formula, but are distinguished by the way in which their atoms or atom groups are linked. These include functional isomers, position isomers, tautomers or valence isomers.
Stereoisomers basically have the same structure (constitution)—and thus also the same summation formula—but are distinguished by the spatial arrangement of the atoms. In general, configuration isomers and conformation isomers are distinguished. Configuration isomers are stereoisomers that can be converted into one another only by bond breaking. These include enantiomers, diastereomers and E/Z (cis/trans) isomers. Enantiomers are stereoisomers that behave toward one another like image and mirror image and do not have any plane of symmetry. All stereoisomers that are not enantiomers are referred to as diastereomers. E/Z (cis/trans) isomers on double bonds are a special case. Conformation isomers are stereoisomers that can be converted into one another by the rotation of single bonds.
To differentiate the types of isomerism from one another, see also the IUPAC Rules, Section E (Pure Appl. Chem. 45, 11-30, 1976).
The compounds of general formula I according to the invention also contain the possible tautomeric forms and comprise the E or Z isomers, or, if a chiral center is present, also the racemates and enantiomers. Double-bond isomers are also defined among the latter.
The compounds according to the invention can also be present in the form of solvates, in particular of hydrates, whereby the compounds according to the invention consequently contain polar solvents, in particular water, as structural elements of the crystal lattice of the compounds according to the invention. The proportion of polar solvent, in particular water, can be present in a stoichiometric or else unstoichiometric ratio. In the case of stoichiometric solvates, hydrates, we also speak of hemi- (semi), mono-, sesqui-, di-, tri-, tetra-, penta-, etc., solvates or hydrates.
If an acid group is included, the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as, for example, the readily soluble alkali and alkaline-earth salts, as well as N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, or 1-amino-2,3,4-butanetriol.
If a basic group is included, the physiologically compatible salts of organic and inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, i.a., are suitable.
Functional groups can optionally be protected by protective groups during the reaction sequence. Such protective groups can be, i.a., esters, amides, ketals/acetals, nitro groups, carbamates, alkyl ethers, allyl ethers, benzyl ethers or silyl ethers. As components of silyl ethers, i.a., the following compounds, such as, e.g., trimethylsilyl (TMS), tert-butyl-dimethylsilyl (TBDMS), tert-butyl-diphenylsilyl (TBDPS), triethylsilyl (TES), etc., can occur. Their production is described in the experimental part.
The compounds of general formula I according to the invention inhibit protein tyrosine kinases, in particular Eph receptors, and this also accounts for their action in, for example, the treatment of diseases, in which angiogenesis, lymphangiogenesis or vasculogenesis plays a role, vascular diseases, diseases that are caused by hyperproliferation of body cells or chronic or acute neurodegenerative diseases. These compounds of general formula (I) of the two embodiments of the invention can accordingly be used for the production of a pharmaceutical agent. These compounds of general formula (I) of the two embodiments of the invention can also be used in particular for the production of a pharmaceutical agent for treating the above-cited diseases.
Treatments are performed preferably on humans but also on related mammal species such as, e.g., dogs and cats.
Angiogenic and/or vasculogenic diseases can be treated by the growth of the blood vessels being inhibited (antiangiogenic) or promoted (proangiogenic). Antiangiogenic uses are carried out, e.g., in the case of tumor angiogenesis, endometriosis, in diabetes-induced or other retinopathies or in age-related macular degeneration.
Proangiogenic uses are carried out in, e.g., myocardial infarction or acute neurodegenerative diseases by ischemias of the brain or neurotraumas.
Vascular diseases are defined as stenoses, arterioscleroses, restenoses or inflammatory diseases, such as rheumatic arthritis.
Hyperproliferative diseases are defined as solid tumors, non-solid tumors or non-carcinogenic cell hyperproliferation, whereby solid tumors are defined as, i.a., breast tumors, colon tumors, kidney tumors, lung tumors and/or brain tumors. Non-solid tumors are defined as, i.a., leukemias, and non-carcinogenic cell hyperproliferation is defined as psoriasis, eczema, and scleroderma in the skin or benign hypertrophy of the prostate.
Chronic neurodegenerative diseases are defined as, i.a., Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS-induced dementia or Alzheimer's disease.
Use of the compounds of general formula I according to the two embodiments of the invention can also be used for diagnostic purposes in vitro or in vivo for identifying corresponding receptors in tissues by means of autoradiography and/or PET.
In particular, the substances can also be radiolabeled for diagnostic purposes.
To use the compounds according to the invention as pharmaceutical agents, the latter are brought into the form of a pharmaceutical preparation, which in addition to the active ingredient for enteral or parenteral application contains suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations can be present in solid form, for example as tablets, coated tablets, suppositories or capsules, or in liquid form, for example as solutions, suspensions or emulsions. They optionally contain, moreover, adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure, or buffers.
These pharmaceutical preparations are also subjects of this invention.
For parenteral application, in particular injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are suitable.
As carrier systems, surface-active adjuvants, such as salts of bile acids or animal or plant phospholipids, but also mixtures thereof as well as liposomes or their components, can also be used.
For oral application, in particular tablets, coated tablets or capsules with talc and/or hydrocarbon vehicles or hydrocarbon binders, such as, for example, lactose, corn or potato starch, are suitable. The application can also be carried out in liquid form, such as, for example, as a juice, to which optionally a sweetener is added.
The enteral, parenteral and oral applications are also subjects of this invention.
The dosage of the active ingredients can vary depending on the method of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors. The daily dose is 0.5-1,000 mg, whereby the dose can be given as an individual dose to be administered once or divided into two or more daily doses.
Pharmaceutical agents for treating the above-cited diseases that preferably contain at least one compound according to general formula (I), as well as pharmaceutical agents with suitable formulation substances and vehicles, are also subjects of the two embodiments of this invention.
If the production of the starting compounds is not described, the latter are known to one skilled in the art or can be produced analogously to known compounds or processes that are described here. It is also possible to perform all reactions described here in parallel reactors or by means of combinatory operating procedures.
According to commonly used methods, such as, for example, crystallization, chromatography or salt formation, the isomer mixtures can be separated into enantiomers or E/Z isomers.
The production of salts is carried out in the usual way by a solution of the compound of formula I being mixed with the equivalent amount of or an excess of a base or acid, which optionally is in solution, and the precipitate being separated, or the solution being worked up in the usual way.
Production of the Compounds of the Invention According to the Two Embodiments of the Invention
Y stands for a C1-C6-alkyl radical, and X stands for halogen or perfluoroalkylsulfonyl.
In the two embodiments, substituents R1a and R2a have the meaning that is described in general formulas II and III.
Substituents R1 and R2 have the meaning that is described in general formula I.
The production of the compounds of general formula I is carried out in the way shown in process variant I. By reaction of aldehyde R2a—CHO with the methylketone R1aC(O)CH3, cyanoacetic acid ester as well as ammonium acetate, first the pyridones of general formula II are produced. Compounds of general formula II are then converted into the compounds of general formula III, in which X has the meaning of halogen or perfluoroalkylsulfonyl. The addition of hydrazine to compounds of general formula III ultimately results in compounds of general formula IV, from which then the compounds of general formula I can be produced optionally by further modifications of radicals R1a and R2a. These modifications contain, e.g., the cleavage of protective groups, but also substitutions, additions, e.g., of carbonyl groups or nitrites, alkylations, reductive aminations, acetylations of OH— or NH— groups and other reactions. Radicals R1a and R2a can also already correspond to later radicals R1 and R2, however, such that then the compounds of general formula I are produced directly by adding hydrazine to compounds of general formula III.
EXAMPLE 1
Production of 6-tert-Butyl-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
EXAMPLE 1a
Production of 6-tert-Butyl-2-oxo-4-p-tolyl-1,2-dihydro-pyridine-3-carbonitrile
A solution of 5.13 g of ammonium acetate, 886 μl of cyanoacetic acid ethyl ester, 1.03 ml of 3,3-dimethyl-2-butanone and 1 g of 4-methylbenzaldehyde in 40 ml of ethanol is stirred for 6 hours at 80° C. Then, it is stirred for 5 more hours at 20° C. The precipitated product is filtered off. The filtrate is rewashed with ethanol and hexane. 630 mg of product is obtained.
1H-NMR (CDCl3): δ 1.44 (9H); 2.42 (3H); 6.30 (1H); 7.31 (2H); 7.52 (2H); 12.41 (1H) ppm.
EXAMPLE 1b
Production of 2-Bromo-6-tert-butyl-4-p-tolyl-nicotinonitrile
403 mg of phosphorus pentoxide and 460 mg of tetrabutylammonium bromide are added to a solution of 315 mg of the substance, described under Example 1a), in 3.5 ml of toluene. It is refluxed for one hour. After cooling, the reaction mixture is diluted with ethyl acetate. Then, it is poured into water, the phases are separated, and the aqueous phase is extracted again with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution. It is dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product that is obtained is chromatographed on silica gel. 120 mg of product is obtained.
1H-NMR (CDCl3): δ=1.39 (9H); 2.43 (3H); 7.32 (3H); 7.47 (2H) ppm.
EXAMPLE 1c
Production of 6-tert-Butyl-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
43 μl of hydrazine hydrate solution (80%) is added to a solution of 117 mg of the compound, described under Example 1b), in 2 ml of propanol. It is stirred at 100° C. for 3 more hours. Then, 22 μl of hydrazine hydrate solution (80%) is added again. It is stirred for another 1.5 hours at 100° C., and then the reaction mixture is cooled to 0° C. Then, it is allowed to stand for 3 hours at 0° C. The precipitated reaction product is suctioned off. It is rewashed with ice-cold propanol.
1H-NMR (CDCl3): δ=1.46 (9H); 2.44 (3H); 3.93 (2H); 7.01 (1H); 7.33 (2H); 7.48 (2H) ppm.
EXAMPLE 2
Production of 6-tert-Butyl-4-(1H-indol-3-yl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
EXAMPLE 2a
Production of 6-tert-Butyl-4-(4-cyanophenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a, 880 mg of product is obtained from 4.7 g of ammonium acetate, 812 μl of cyanoacetic acid ethyl ester, 945 μl of 3,3-dimethyl-2-butanone and 1 g of 4-cyanobenzaldehyde.
1H-NMR (d6-DMSO): δ=1.31 (9H); 6.30 (1H); 7.84 (2H); 8.03 (2H); 11.30 (1H) ppm.
EXAMPLE 2b
Production of 2-Bromo-6-tert-butyl-4-(4-cyanophenyl)-nicotinonitrile
Analogously to Example 1b), 250 mg of product is obtained from 300 mg of the substance, described under Example 2a), in 5 ml of toluene with 370 mg of phosphorus pentoxide and 418 mg of tetrabutylammonium bromide.
1H-NMR (CDCl3): δ=1.40 (9H); 7.33 (1H); 7.68 (2H); 7.83 (2H) ppm.
EXAMPLE 2c
Production of 4-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4b]pyridin-4-yl)-benzonitrile
Analogously to Example 1c), 98 mg of product is produced from 200 mg of the compound that is described under Example 2b) with 71 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.39 (9H); 4.56 (2H); 7.00 (1H); 7.80 (2H); 8.00 (2H); 12.29 (1H) ppm.
EXAMPLE 3
Production of 6-tert-Butyl-4-(1H-indol-3-yl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
EXAMPLE 3a
Production of 6-tert-Butyl-4-(4-cyanophenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a), 240 mg of product is obtained from 4.25 g of ammonium acetate, 733 μl of cyanoacetic acid ethyl ester, 852 μl of 3,3-dimethyl-2-butanone and 1 g of 3-indole carbaldehyde.
1H-NMR (d6-DMSO): δ=1.32 (9H); 6.50 (1H); 7.20 (2H); 7.53 (1H); 7.72 (2H); 8.09 (1H); 11.98 (2H) ppm.
EXAMPLE 3b
Production of 6-tert-Butyl-3-cyano-4-(1H-indol-3-yl)-2-trifluoromethane-sulfonyl pyridine
206 μl of trifluoromethanesulfonic acid anhydride is added in drops to a solution of 200 mg of the compound, described under Example 3a), in 4 ml of pyridine at 0° C. It is allowed to stir for 3 more hours at 0° C., and then another 100 μof trifluoroacetic acid anhydride is added. It is stirred for another 1.5 hours at 0° C. Then, the reaction mixture is poured into saturated sodium bicarbonate solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. After column chromatography on silica gel, 116 mg of product is obtained.
1H-NMR (d6-DMSO): δ=1.34 (9H); 6.50 (1H); 7.20 (2H); 7.54 (1HH); 7.75 (1H); 8.08 (1H); 12.00 (2H) ppm.
EXAMPLE 3c
Production of 6-tert-Butyl-4-(1H-indol-3-yl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 1c), 75 mg of product is produced from 190 mg of the compound that is described under Example 3b) with 55 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.40 (9H); 4.55 (2H); 7.04 (1H); 7.80 (2H); 8.01 (2H); 12.39 (1H) ppm.
EXAMPLE 4
Production of 6-tert-Butyl-4-(4-phenoxyphenyl)-1H-pyrazolo[3,4b]-pyridin-3-ylamine
EXAMPLE 4a
Production of 6-tert-Butyl-2-oxo-4-(4-phenoxyphenyl)-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a), 510 mg of product is obtained from 3.11 g of ammonium acetate, 540 μl of cyanoacetic acid ethyl ester, 624 μl of 3,3-dimethyl-2-butanone and 883 μl of 4-phenoxybenzaldehyde.
1H-NMR: (d6-DMSO): δ=1.30 (9H); 6.27 (1H); 7.13 (4H); 7.20 (1H); 7.45 (2H); 7.70 (2H); 12.20 (1H) ppm.
EXAMPLE 4b
Production of 6-tert-Butyl-3-cyano-4-(4-phenoxyphenyl)-2-trifluoromethanesulfonyl pyridine
Analogously to Example 3b), 138 mg of product is obtained from 150 mg of the substance, described under Example 4a), and 162 μl of trifluoromethanesulfonic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.39 (9H); 7.11 (4H); 7.24 (1H); 7.41 (3H); 7.59 (2H) ppm.
EXAMPLE 4c
6-tert-Butyl-4-(4-phenoxyphenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 3, 32 mg of product is produced from 67 mg of the compound that is described under Example 11 with 35 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.38 (9H); 4.54 (2H); 6.98 (1H); 7.15 (5H); 7.44 (2H); 7.62 (2H), 12.16 (1H) ppm.
EXAMPLE 5
Production of 6-tert-Butyl-4-(4-benzyloxyphenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
EXAMPLE 5a
Production of 4-(4-Benzyloxyphenyl)-6-tert-butyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a), 613 mg of product is obtained from 2.91 g of ammonium acetate, 500 μl of cyanoacetic acid ethyl ester, 585 μl of 3,3-dimethyl-2-butanone and 1 g of 4-benzyloxybenzaldehyde.
1H-NMR (d6-DMSO): δ=1.30 (9H); 5.20 (2H); 6.22 (1H); 7.18 (2H); 7.30-7.50 (5H); 7.65 (1H); 12.18 (1H) ppm.
EXAMPLE 5b
Production of 6-tert-Butyl-3-cyano-4-(4-benzyloxyphenyl)-2-trifluoromethanesulfonyl pyridine
Analogously to Example 3b), 288 mg of product is obtained from 250 mg of the substance that is described under Example 5a) and 258 μl of trifluoromethanesulfonic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.38 (9H); 5.16 (2H); 7.13 (2H); 7.32-7.50 (6H); 7.59 (2H) ppm.
EXAMPLE 5c
Production of 6-tert-Butyl-4-(4-benzyloxyphenyl)-1H-pyrazolo[3,4b]-pyridin-3-ylamine
Analogously to Example 1c), 159 mg of product is produced from 284 mg of the compound that is described under Example 5b) with 70 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.38 (9H); 4.50 (2H); 5.19 (2H); 6.93 (1H); 7.19 (2H); 7.30-7.58 (7H); 12.12 (1H) ppm.
EXAMPLE 6
Production of 6-tert-Butyl-4-(3-methoxyphenyl)-1H-pyrazolo[3,4b]-pyridin-3-ylamine
EXAMPLE 6a
Production of 6-tert-Butyl-4-(3-methoxyphenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a), 618 mg of product is obtained from 4.53 g of ammonium acetate, 782 μl of cyanoacetic acid ethyl ester, 910 μl of 3,3-dimethyl-2-butanone and 895 μl of 3-methoxybenzaldehyde.
1H-NMR (CDCl3): δ=1.45 (9H); 3.86 (3H); 6.31 (1H); 7.04 (1H); 7.16 (2H); 7.42 (1H); 12.40 (1H) ppm.
EXAMPLE 6b
Production of 6-tert-Butyl-3-cyano-4-(3-methoxyphenyl)-2-trifluoromethanesulfonyl pyridine
Analogously to Example 3b), 305 mg of product is obtained from 250 mg of the substance that is described under Example 6a) and 328 μl of trifluoromethanesulfonic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.40 (9H); 3.89 (3H); 7.08-7.20 (3H); 7.48 (2H) ppm.
EXAMPLE 6c
Production of 6-tert-Butyl-4-(3-methoxyphenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 1c), 137 mg of product is produced from 299 mg of the compound that is described under Example 6b) with 88 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (CDCl3): δ=1.45 (9H); 3.89 (3H); 3.97 (2H); 7.03 (2H); 7.14 (2H); 7.45 (1H); 10.40 (1H) ppm.
EXAMPLE 7
Production of 6-tert-Butyl-4-(3-cyanophenyl)-1H-pyrazolo[3,4b]-pyridin-3-ylamine
EXAMPLE 7a
Production of 6-tert-Butyl-4-(3-cyanophenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a), 2.14 g of product is obtained from 14 g of ammonium acetate, 2.43 ml of cyanoacetic acid ethyl ester, 2.83 ml of 3,3-dimethyl-2-butanone and 3 g of 3-cyanobenzaldehyde.
1H-NMR (CDCl3): δ=1.46 (9H); 6.27 (1H); 7.67 (1H); 7.80-7.92 (3H); 12.42 (1H) ppm.
EXAMPLE 7b
Production of 6-tert-Butyl-3-cyano-4-(3-cyanophenyl)-2-trifluoromethane-sulfonyl pyridine
Analogously to Example 3b), 379 mg of product is obtained from 420 mg of the substance that is described under Example 7a) and 560 μL of trifluoromethanesulfonic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.40 (9H); 7.45 (1H); 7.71 (1H); 7.88 (3H) ppm.
EXAMPLE 7c
Production of 6-tert-Butyl-4-(3-cyanophenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 1c), 147 mg of product is produced from 369 mg of the compound that is described under Example 7b) with 165 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.39 (9H); 4.57 (2H); 7.08 (1H); 7.72 (1H); 7.95 (2H); 8.11 (1H); 12.28 (1H) ppm.
EXAMPLE 8
Production of 1-[4-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4b]pyridin-4-yl)-phenyl]-ethanone
2.2 ml of a 1.6 molar solution of methyllithium in diethyl ether is added to a solution of 150 mg of the compound, described under Example 2c), in 5 ml of tetrahydrofuran at 0° C. It is allowed to stir for 2 more hours at 0° C. Then, the reaction mixture is poured into 2N hydrochloric acid. It is allowed to stir for 1 more hour at 25° C. and then neutralized with 5% sodium hydroxide solution. Then, it is extracted with ethyl acetate, and the aqueous phase is washed with saturated sodium chloride solution. It is dried on sodium sulfate. The crude product is purified by column chromatography on silica gel. 67 mg of product is obtained.
1H-NMR (d6-DMSO): δ=1.38 (9H); 2.65 (3H); 4.47 (2H); 7.02 (1H); 7.74 (2H); 8.12 (2H); 12.21 (1H) ppm.
EXAMPLE 9
Production of 1-[3-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4b]pyridin-4-yl)-phenyl]-ethanone
Analogously to Example 8, 82 mg of product is obtained from 169 mg of the compound that is described under Example 7c) and 1.2 ml of a 1.6 molar solution of methyllithium in diethyl ether.
1H-NMR (CDCl3): δ=1.46 (9H); 2.69 (3H); 3.80 (2H); 7.06 (1H); 7.65 (1H); 7.80 (1H); 8.09 (1H); 8.19 (1H); 9.57 (1H) ppm.
EXAMPLE 10
Production of 6-Cyclohexyl-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
EXAMPLE 10a
Production of 6-Cyclohexyl-2-oxo-4-p-tolyl-1,2-dihydropyridine-3-carbonitrile
Analogously to Example 1a), 1.4 g of product is obtained from 5.13 g of ammonium acetate, 886 μl of cyanoacetic acid ethyl ester, 1.14 ml of cyclohexylmethyl ketone and 1 g of 4-methylbenzaldehyde.
1H-NMR (CDCl3): δ=1.30-1.70 (6H); 1.82-2.05 (4H); 2.42 (3H); 2.64 (1H); 6.25 (1H); 7.30 (2H); 7.54 (2H); 13.08 (1H) ppm.
EXAMPLE 10b
Production of 3-Cyano-6-cyclohexyl-4-p-tolyl)-2-trifluoromethane-sulfonyl pyridine
Analogously to Example 3b), 342 mg of product is obtained from 300 mg of the substance that is described under Example 10a) and 380 μl of trifluoromethanesulfonic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.20-1.60 (5H); 1.75 (1H); 1.82-2.00 (4H); 2.44 (3H); 2.78 (1H); 7.30 (1H); 7.35 (2H); 7.51 (1H) ppm.
EXAMPLE 10c
Production of 6-Cyclohexyl-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 1c), 195 mg of product is produced from 342 mg of the compound that is described under Example 10b) with 147 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (CDCl3): δ=1.22-1.60 (5H); 1.77 (1H); 1.88 (2H); 2.02 (2H); 2.47 (3H); 2.80 (1H); 3.92 (2H); 6.82 (1H); 7.32 (2H); 7.48 (2H); 9.80 (1H) ppm.
EXAMPLE 11
Production of 6-(1,4-Dioxa-spiro[4.5]dec-8-yl)-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
EXAMPLE 11a
Production of 1,4-Dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester
A mixture that consists of 7.35 g of 4-oxocyclohexylcarboxylic acid ethyl ester, 28 ml of trimethyl orthoformate, 64 ml of ethylene glycol and 100 mg of p-toluenesulfonic acid in 120 ml of dichloromethane is stirred for 12 hours at 25° C. Then, 2 ml of triethylamine is added. It is washed with saturated sodium bicarbonate solution and then with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product that is obtained is purified by column chromatography on silica gel. 9.22 g of product is obtained.
1H-NMR (CDCl3): δ=1.23 (3H); 1.55 (2H); 1.72-1.86 (4H); 1.94 (2H); 2.31 (1H); 3.93 (4H); 4.12 (2H) ppm.
EXAMPLE 11b
Production of (1,4-Dioxa-spiro[4.5]dec-8-yl)-methanol
13.8 ml of a 1.2 molar solution of diisobutylamine in toluene is added to a solution of 1.18 g of the compound, described under Example 11a), in 20 ml of toluene at 0° C. It is allowed to stir for one more hour at 0° C., and then 6 ml of 2-propanol as well as 6 ml of water are added. It is allowed to stir for another hour, and then the precipitated salts are filtered off over Celite. After drying and concentration by evaporation, the crude product that is obtained is purified by column chromatography on silica gel. 880 mg of product is obtained.
1H-NMR (CDCl3): δ=1.15-1.40 (3H); 1.48-1.62 (3H); 1.78 (4H); 3.49 (2H); 3.95 (4H) ppm.
EXAMPLE 11c
Production of 1,4-Dioxa-spiro[4.5]decane-8-carbaldehyde
7.96 ml of dimethyl sulfoxide is added to a solution of 4.9 ml of oxalyl chloride in 30 ml of dichloromethane at −78° C. It is allowed to stir for 3 more minutes at −78° C., and then a solution of 6.96 g of the compound, described under Example 11c), in 70 ml of dichloromethane is added. It is stirred for 20 more minutes at −78° C. Then, 24 ml of triethylamine is added. The reaction mixture is allowed to heat over 20 minutes to 0° C. Then, it is poured into saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. 6.9 g of product, which is incorporated without purification into the next step, is obtained.
1H-NMR (CDCl3): δ=1.50-1.80 (6H); 1.95 (2H); 2.25 (1H); 3.98 (4H); 9.64 (1H) ppm.
EXAMPLE 11d
Production of 1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-ethanol
38 ml of a 1.6 molar solution of methyllithium diethyl ether is added to a solution of 6.88 g of the compound, described under Example 11c), in 100 ml of tetrahydrofuran at 0° C. It is allowed to stir for one more hour at 0° C., and then the reaction mixture is poured into the saturated ammonium chloride solution. Then, it is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. After chromatography on silica gel, 6.02 g of product is obtained.
1H-NMR (CDCl3): δ=1.18 (3H); 1.25-1.45 (4H); 1.53 (2H); 1.70-1.92 (3H); 3.60 (1H); 3.93 (4H) ppm.
EXAMPLE 11e
Production of 1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-ethanone
7.2 g of N-methylmorpholine-N-oxide, 565 mg of tetrapropylammonium peruthenate as well as some molecular sieve are added to a solution of 6 g of the compound, described under Example 1d), in 100 ml of dichloromethane. It is allowed to stir for 20 hours at 25° C. and then filtered over Celite. After chromatography on silica gel, 5.1 g of product is obtained.
1H-NMR (CDCl3): δ=1.50-1.98 (8H); 2.17 (3H); 2.34 (1H); 3.94 (4H) ppm.
EXAMPLE 11f
Production of 6-(1,4-Dioxa-spiro[4.5]dec-8-yl)-2-oxo-4-p-tolyl-1,2-dihydropyridine-3-carbonitrile
Analogously to Example 1a), 580 mg of product is obtained from 2.17 g of ammonium acetate, 375 μl of cyanoacetic acid ethyl ester, 650 mg of the compound that is described under Example 11e), and 415 μl of 4-methylbenzaldehyde.
1H-NMR (CDCl3): δ=1.70-1.95 (6H); 2.03 (2H); 2.42 (3H); 2.72 (1H); 3.96 (4H); 6.30 (1H); 7.30 (2H); 7.52 (2H) ppm.
EXAMPLE 11g
Production of 3-Cyano-6-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-p-tolyl-2-trifluoromethanesulfonyl pyridine
Analogously to Example 3b, 843 mg of product is obtained from 900 mg of the substance that is described under Example 1f) and 950 μl of trifluoromethanesulfonic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.60-1.78 (2H); 1.80-2.08 (6H); 2.45 (3H); 2.83 (1H); 3.98 (3H); 7.35 (3H); 7.51 (2H) ppm.
EXAMPLE 11h
Production of 6-(1,4-Dioxa-spiro[4.5]dec-8-yl)-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 1c), 496 mg of product is produced from 838 mg of the compound that is described under Example 11g) with 317 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (CDCl3): δ=1.60-2.10 (8H); 2.44 (3H); 3.36 (1H); 3.98 (6H); 6.86 (1H); 7.32 (2H); 7.46 (2H) ppm.
EXAMPLE 12
Production of 4-(3-Amino-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-6-yl)-cyclohexanone
1.2 ml of 4N hydrochloric acid is added to a solution of 342 mg of the substance, described under Example 11h), in 20 ml of acetone. It is allowed to stir for 3.5 more hours at 25° C., and then 1 ml of triethylamine is added. Then, it is filtered, and the filtrate is concentrated by evaporation in a vacuum. The residue is dissolved in ethyl acetate. It is washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation again in a vacuum. After recrystallization from a mixture that consists of dichloromethane/diisopropyl ether, 240 mg of product is obtained.
1H-NMR (CDCl3): δ=2.10-2.45 (4H); 2.46 (3H); 2.52-2.65 (4H); 3.32 (1H); 4.00 (2H); 6.88 (1H); 7.35 (2H); 7.49 (2H); 10.75 (1H) ppm.
EXAMPLE 13
Production of 4-[4-(3-Amino-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-6-yl)-cyclohexyl]-piperazine-1-carboxylic acid tert-butyl ester
291 mg of 1-tert-butoxycarbonylpiperazine, 90 μl of glacial acetic acid as well as molecular sieve are added to a solution of 100 mg of the compound, described under Example 12, in 4 ml of dichloromethane. It is stirred for 30 minutes at 25° C., and then 40 mg of sodium acetoxy borohydride is added. It is stirred for 30 more minutes at 25° C. Then, another 40 mg of sodium acetoxy borohydride is added. It is allowed to stir for 3 more hours at 25° C. and then diluted with ethyl acetate. It is washed with saturated sodium bicarbonate and with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product is purified via column chromatography. 108 mg of product is obtained.
1H-NMR (CDCl3): δ=1.45 (9H); 1.60-2.35 (8H); 2.46 (3H); 2.81 (4H); 3.00 (1H); 3.40 (5H); 3.92 (2H); 6.88 (1H); 7.33 (2H); 7.47 (2H); 9.70 (1H) ppm.
EXAMPLE 14
Production of 6-(4-piperazin-1-yl-cyclohexyl)-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
A solution of 50 mg of the compound, described under Example 13, in 1 ml of dichloromethane is mixed with 300 μl of a 2 molar HCl solution in diethyl ether. It is allowed to stir for one more hour at 25° C., and then 300 μl of a 2 molar HCl solution in diethyl ether is added again. It is stirred for another hour at 25° C. Then, it is concentrated by evaporation in a vacuum and purified by column chromatography. 29 mg of product is obtained.
1H-NMR (d6-DMSO): δ=1.75-2.02 (8H); 2.41 (3H); 3.00-4.00 (12H); 7.20 (1H); 7.38 (2H); 7.60 (2H); 9.80 (2H) ppm.
EXAMPLE 15
Production of 6-[4-(4-Methyl-piperazin-1-yl)-cyclohexyl]-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 13, 41 mg of product is obtained from 48 mg of the compound that is described under Example 12, 85 μl of N-methylpiperazine, 43 μl of glacial acetic acid, and 40 mg of sodium triacetoxy borohydride.
1H-NMR (d6-DMSO): δ=1.50-2.40 (8H); 2.22 (3H); 2.39 (3H); 2.91 (1H); 3.20-3.55 (9H); 4.48 (2H); 6.79 (1H); 7.37 (2H); 7.48 (2H) ppm.
EXAMPLE 16
Production of 6-(4-Piperidin-1-yl-cyclohexyl)-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 13, 52 mg of product is obtained from 70 mg of the compound that is described under Example 12, 110 μl of piperidine, 63 μl of glacial acetic acid and 50 mg of sodium triacetoxy borohydride.
1H-NMR (CDCl3): δ=1.40 (2H); 1.50-1.80 (7H); 1.90 (2H); 2.20-2.38 (5H); 2.40-2.60 (6H); 3.05 (1H); 3.92 (2H); 6.90 (1H); 7.32 (2H); 7.48 (2H) ppm.
EXAMPLE 17
Production of 6-(4-Morpholin-4-yl-cyclohexyl)-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 13, 48 mg of product is obtained from 70 mg of the compound that is described under Example 12, 100 μl of morpholine, 63 μl of glacial acetic acid, and 50 mg of sodium triacetoxy borohydride.
1H-NMR (d6-DMSO): δ=1.50-1.70 (4H); 1.90-2.20 (6H); 2.30-2.50 (6H); 2.95 (1H); 3.58 (4H); 4.46 (2H); 6.79 (1H); 7.37 (2H); 7.49 (2H); 12.11 (1H) ppm.
EXAMPLE 18
Production of 6-(1,4-Dioxa-spiro[4.5]dec-8-yl)-4-(4-phenoxyphenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
EXAMPLE 18a
Production of 6-(1,4-Dioxa-spiro[4.5]dec-8-yl)-2-oxo-4-(4-phenoxy-phenyl)-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a), 1.86 g of product is obtained from 5.28 g of ammonium acetate, 910 μl of cyanoacetic acid ethyl ester, 1.58 g of the compound that is described under Example 11e) and 1.5 ml of 4-phenoxybenzaldehyde.
1H-NMR (CDCl3): δ=1.70-1.95 (6H); 2.05 (2H); 2.70 (1H); 3.98 (4H); 6.30 (1H); 7.08 (4H); 7.19 (1H); 7.40 (2H); 7.60 (2H); 12.89 (1H) ppm.
EXAMPLE 18b
Production of 3-Cyano-6-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-(4-phenoxy-phenyl)-2-trifluoromethanesulfonyl pyridine
Analogously to Example 3b), 2.01 g of product is obtained from 1.86 g of the substance that is described under Example 18 and 1.61 ml of trifluoromethanesulfonic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.60-2.10 (8H); 2.85 (1H); 3.98 (4H); 7.10 (4H); 7.21 (1H); 7.40 (2H); 7.58 (2H) ppm.
EXAMPLE 18c
Production of 6-(1,4-Dioxa-spiro[4.5]dec-8-yl)-4-(4-phenoxyphenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 1c), 970 mg of product is produced from 1.36 mg of the compound that is described under Example 19 with 445 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (CDCl3): δ=1.60-2.10 (8H); 2.88 (1H); 3.99 (4H); 6.88 (1H); 7.05-7.14 (5H); 7.40 (2H); 7.53 (2H); 10.00 (1H) ppm.
EXAMPLE 19
Production of 4-[3-Amino-4-(4-phenoxy-phenyl)-1H-pyrazolo[3,4b]-pyridin-6-yl]-cyclohexanone
Analogously to Example 12, 890 mg of product is obtained from 1.19 g of the compound that is described under Example 18c) by reaction with 4N hydrochloric acid in acetone.
1H-NMR (CDCl3): δ=2.10-2.60 (8H); 3.30 (1H); 3.99 (2H); 6.88 (1H); 7.03-7.22 (5H); 7.40 (2H); 7.55 (2H); 10.08 (1H) ppm.
EXAMPLE 20
Production of 4-{4-[3-Amino-4-(4-phenoxy-phenyl)-1H-pyrazolo[3,4b]pyridin-6-yl]-cyclohexyl}-piperazine-1-carboxylic acid tert-butyl ester
Analogously to Example 13, 142 mg of product is obtained by reaction of 170 mg of the substance that is described under Example 18c) with 400 mg of 1-tert-butoxycarbonylpiperazine, 125 μl of glacial acetic acid, and 100 mg of sodium acetoxy borohydride in dichloromethane.
1H-NMR (d6-DMSO): δ=1.40 (9H); 1.50-1.70 (5H); 1.90 (2H); 2.10 (2H); 2.22 (2H); 2.40 (4H); 2.95 (1H); 4.52 (2H); 6.81 (1H); 7.10-7.25 (5H); 7.45 (2H); 7.60 (2H) ppm.
EXAMPLE 21
Production of 4-(4-Phenoxyphenyl)-6-(4-piperazin-1-yl-cyclohexyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 14, 9 mg of product is obtained by reaction of 20 mg of the substance that is described under Example 20 with 300 μl of HCl solution (2 molar in diethyl ether) in dichloromethane.
1H-NMR (d6-DMSO): δ=1.75-2.00 (8H); 3.10-4.00 (12H); 7.05-7.20 (5H); 7.45 (2H); 7.68 (2H); 9.70 (1H); 11.20 (1H) ppm; 7.20 (1H); 7.38 (2H); 7.60 (2H); 9.80 (2H) ppm.
EXAMPLE 22
Production of 6-[4-(4-Methyl-piperazin-1-yl)-cyclohexyl]-4-(4-phenoxyphenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 13, 32 mg of product is obtained from 37 mg of the compound that is described under Example 19), 52 μl of N-methylpiperazine, 27 μl of glacial acetic acid, and 25 mg of sodium triacetoxy borohydride.
1H-NMR (CDCl3): δ=1.60 (2H); 1.95 (2H); 2.20-2.35 (4H); 2.29 (3H); 2.40-2.65 (8H); 3.00 (1H); 3.92 (2H); 6.89 (1H); 7.05-7.22 (5H); 7.40 (2H); 7.55 (2H); 9.74 (1H) ppm.
EXAMPLE 23
Production of 4-(4-Phenoxy-phenyl)-6-(4-piperidin-1-yl-cyclohexyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 13, 58 mg of product is obtained from 100 mg of the compound that is described under Example 19), 125 μl of piperidine, 72 μl of glacial acetic acid, and 60 mg of sodium triacetoxy borohydride.
1H-NMR (d6-DMSO): δ=1.10-2.00 (10H); 2.05-2.20 (4H); 2.40-2.60 (4H); 2.97 (1H); 4.52 (2H); 6.82 (1H); 7.05-7.25 (5H); 7.43 (2H); 7.60 (2H); 12.12 (1H) ppm.
EXAMPLE 24
Production of 6-(4-Morpholin-4-yl-cyclohexyl)-4-(4-phenoxyphenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 13, 52 mg of product is obtained from 90 mg of the compound that is described under Example 19, 100 μl of morpholine, 63 μl of glacial acetic acid and 50 mg of sodium triacetoxy borohydride.
1H-NMR (d6-DMSO): δ=1.50-1.70 (4H); 1.80-2.20 (6H); 2.40 (4H); 2.98 (1H); 3.60 (4H); 4.52 (2H); 6.81 (1H); 7.10-7.25 (5H); 7.45 (2H); 7.60 (2H); 12.12 (1H) ppm.
EXAMPLE 25
Production of 6-(1,1-Dimethyl-2-piperidin-1-yl-ethyl)-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
EXAMPLE 25a
Production of 3-(tert-Butyldimethylsilyloxy)-2,2-dimethyl-propan-1-ol
A solution of 10 g of 2,2-dimethyl-1,3-propanediol in 100 ml of tetrahydrofuran is added in drops to a suspension of 3.85 g of sodium hydride (60%) in 30 ml of tetrahydrofuran. It is allowed to stir for 45 more minutes, and then 14.5 g of tert-butyldimethylsilyl chloride is added. Then, it is stirred for one more hour at 25° C. Then, the reaction mixture is poured into saturated sodium bicarbonate solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product is purified by column chromatography on silica gel. 18.4 g of product is obtained.
1H-NMR (CDCl3): δ=0.05 (6H); 0.90 (15H); 2.86 (1H); 3.49 (4H) ppm.
EXAMPLE 25b
Production of 3-(tert-Butyldimethylsilyloxy)-2,2-dimethyl-propan-1-al
Analogously to Example 11c), 890 mg of crude product, which is incorporated without purification into the next step, is obtained from 1 g of the compound that is described under Example 25a), 910 μl of dimethyl sulfoxide, 555 μl of oxalyl chloride and 2.8 ml of triethylamine in dichloromethane.
1H-NMR (CDCl3): δ=0.03 (6H); 0.89 (9H); 1.02 (6H); 3.61 (2H); 9.57 (1H) ppm.
EXAMPLE 25c
Production of 4-(tert-Butyldimethylsilyloxy)-3,3-dimethyl-butan-2-ol
Analogously to Example 1d), 2.08 g of product is obtained from 2.6 g of the compound that is described under Example 25b) and 10.8 ml of a 1.6 molar solution of methyllithium in diethyl ether after column chromatography.
1H-NMR (CDCl3): δ=0.09 (6H); 0.80 (3H); 0.90 (12H); 1.10 (3H); 3.48 (2H); 3.70 (1H); 3.82 (11H) ppm.
EXAMPLE 25d
Production of 4-(tert-Butyldimethylsilyloxy)-3,3-dimethyl-butan-2-one
Analogously to Example 11e), 1.61 g of product is obtained from 2.1 g of the compound that is described under Example 25c), 2 g of N-methylmorpholine-N-oxide and 158 mg of tetrapropylammonium peruthenate in dichloromethane.
1H-NMR (CDCl3): δ=0.02 (6H); 0.87 (9H); 1.10 (6H); 2.17 (3H); 3.58 (2H) ppm.
EXAMPLE 25e
Production of 6-(2-Hydroxy-1,1-dimethylethyl)-2-oxo-4-p-tolyl-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a), 4.8 g of product is obtained from 16.6 g of ammonium acetate, 2.9 ml of cyanoacetic acid ethyl ester, 6.2 g of the compound that is described under Example 25d) and 3.2 ml of 4-methylbenzaldehyde.
1H-NMR (d6-DMSO): δ 1.23 (6H); 2.39 (3H); 3.57 (2H); 6.27 (1H); 7.37 (2H); 7.53 (2H) ppm.
EXAMPLE 25f
Production of 6-(1,1-Dimethyl-2-oxo-ethyl)-2-oxo-4-p-tolyl-1,2-dihydro-pyridine-3-carbonitrile
A solution of 680 mg of sulfur trioxide pyridine complex in 7 ml of dimethyl sulfoxide is added at 0° C. to a solution that consists of 400 mg of the compound that is described under Example 25e), 1.5 ml of dimethyl sulfoxide and 980 μl of triethylamine in 8 ml of dichloromethane. It is stirred for 3 more hours at 0° C. Then, water is added to the reaction mixture. It is extracted with dichloromethane, washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. After column chromatography on silica gel, 232 mg of product is obtained.
1H-NMR (CDCl3): δ=1.49 (6H); 2.40 (3H); 6.39 (1H); 7.28 (2H); 7.50 (2H); 9.65 (1H) ppm.
EXAMPLE 25g
Production of 6-(1,1-Dimethyl-2-piperidin-1-yl-ethyl)-2-oxo-4-p-tolyl-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 13, 118 mg of product is obtained from 184 mg of the compound that is described under Example 25f), 325 μl of piperidine and 192 mg of sodium triacetoxy borohydride.
1H-NMR (CDCl3): δ=1.38 (6H); 1.40-1.80 (6H); 2.41 (3H); 2.51 (2H); 2.60 (4H); 6.09 (1H); 7.30 (2H); 7.50 (2H) ppm.
EXAMPLE 25h
Production of 3-Cyano-6-(1,1-dimethyl-2-piperidin-1-yl-ethyl)-4-p-tolyl-2-trifluoromethanesulfonyl pyridine
Analogously to Example 3b), 110 mg of product is obtained from 87 mg of the substance that is described under Example 25g) and 92 μl of trifluoromethanesulfonic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.40 (6H); 1.60 (6H); 2.10-2.30 (4H); 2.47 (3H); 2.53 (2H); 7.37 (2H); 7.52 (3H) ppm.
EXAMPLE 25i
Production of 6-(1,1-Dimethyl-2-piperidin-1-yl-ethyl)-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 1c), 45 mg of product is produced from 106 mg of the compound that is described under Example 25h) with 41 μl of hydrazine hydrate solution (8.0%) in propanol.
1H-NMR (CDCl3): δ=1.40 (6H); 1.50-1.70 (6H); 2.20-2.35 (4H); 2.49 (3H); 2.60 (2H); 3.93 (2H); 7.07 (1H); 7.35 (2H); 7.48 (2H); 9.70 (1H) ppm.
EXAMPLE 26
Production of 6-(1,1-Dimethyl-2-morpholin-1-yl-ethyl)-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
EXAMPLE 26a
Production of 6-(1,1-Dimethyl-2-morpholin-4-yl-ethyl)-2-oxo-4-p-tolyl-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 13, 139 mg of product is obtained from 181 mg of the compound that is described under Example 25f), 282 μl of morpholine and 180 mg of sodium triacetoxy borohydride.
1H-NMR (CDCl3): δ=1.30 (6H); 2.42 (3H); 2.70 (4H); 3.83 (4H); 6.13 (1H); 7.30 (2H); 7.51 (2H) ppm.
EXAMPLE 26b
Production of 3-Cyano-6-(1,1-dimethyl-2-morpholin-1-yl-ethyl)-4-p-tolyl-2-trifluoromethanesulfonyl pyridine
Analogously to Example 3b), 165 mg of product is obtained from 135 mg of the substance that is described under Example 26a) and 142 μl of trifluoromethanesulfonic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.37 (6H); 2.30 (4H); 2.62 (3H); 3.50 (4H); 7.40-7.55 (5H) ppm.
EXAMPLE 26c
Production of 6-(1,1-Dimethyl-2-morpholin-1-yl-ethyl)-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 1c), 65 mg of product is produced from 165 mg of the compound that is described under Example 26b) with 70 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.35 (6H); 2.20 (4H); 2.39 (3H); 2.62 (2H); 3.40 (4H); 4.47 (2H); 6.97 (1H); 7.38 (2H); 7.46 (2H) ppm.
EXAMPLE 27
Production of 6-[1,1-Dimethyl-2-(4-methyl-piperazin-1-yl)-ethyl]-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
EXAMPLE 27a
Production of 6-[1,1-Dimethyl-2-(4-methyl-piperazin-1-yl)-ethyl]-2-oxo-4-p-tolyl-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 13, 68 mg of product is obtained from 106 mg of the compound that is described under Example 25f), 210 μl of N-methylpiperazine and 100 mg of sodium triacetoxy borohydride.
1H-NMR (d6-DMSO): δ=1.24 (6H); 2.13 (3H); 2.30 (4H); 2.38 (3H); 2.45 (4H); 2.58 (2H); 6.23 (1H); 7.38 (2H); 7.55 (2H); 12.52 (1H) ppm.
EXAMPLE 27b
Production of 3-Cyano-6-[1,1-dimethyl-2-(4-methyl-piperazin-1-yl)-ethyl)]-4-p-tolyl-2-trifluoromethanesulfonyl pyridine
Analogously to Example 3b), 50 mg of product is obtained from 44 mg of the substance that is described under Example 27a) and 45 μl of trifluoromethanesulfonic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.37 (6H); 1.98 (4H); 2.30 (3H); 2.35 (3H); 2.43 (4H); 2.68 (2H); 7.40 (2H); 7.50 (3H) ppm.
EXAMPLE 27c
Production of 6-[1,1-Dimethyl-2-(4-methyl-piperazin-1-yl)-ethyl]-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 1c), 24 mg of product is produced from 50 mg of the compound that is described under Example 27b) with 22 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.33 (6H); 2.10 (3H); 2.24 (4H); 2.40 (3H); 2.55 (4H); 2.62 (2H); 4.46 (2H); 6.95 (1H); 7.37 (2H); 7.48 (2H); 12.12 (1H) ppm.
EXAMPLE 28
Production of 4-[2-(3-Amino-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-6-yl)-2-methyl-propyl]-piperazine-1-carboxylic acid tert-butyl ester
EXAMPLE 28a
Production of 4-[2-(5-Cyano-6-oxo-4-p-tolyl-1,6-dihydro-pyridin-2-yl)-2-methyl-propyl]-piperazine-1-carboxylic acid tert-butyl ester
Analogously to Example 13, 245 mg of product is obtained from 182 mg of the compound that is described under Example 25f), 605 mg of 1-tert-butoxycarbonylpiperazine and 150 mg of sodium triacetoxy borohydride.
1H-NMR (CDCl3): δ=1.30 (6H); 1.41 (9H); 2.41 (3H); 2.60 (6H); 3.59 (4H); 6.12 (1H); 7.30 (2H); 7.50 (2H); 12.40 (1H) ppm.
EXAMPLE 28b
Production of 4-[2-(5-Cyano-4-p-tolyl-6-trifluoromethanesulfonyloxy-pyridin-2-yl)-2-methyl-propyl]-piperazine-1-carboxylic acid tert-butyl ester
Analogously to Example 3b), 301 mg of product is obtained from 240 mg of the substance that is described under Example 28a) and 200 μl of trifluoromethanesulfonic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.35 (6H); 1.41 (9H); 2.26 (4H); 2.45 (3H); 2.63 (2H); 3.23 (4H); 7.38 (2H); 7.50 (3H) ppm.
EXAMPLE 28c
Production of 4-[2-(3-Amino-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-6-yl)-2-methyl-propyl]-piperazine-1-carboxylic acid tert-butyl ester
Analogously to Example 1c), 168 mg of product is produced from 300 mg of the compound that is described under Example 28b) with 97 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (CDCl3): δ=1.41 (9H); 1.43 (6H); 2.25 (4H); 2.46 (3H); 2.69 (2H); 3.23 (4H); 3.93 (2H); 7.03 (1H); 7.35 (2H); 7.48 (2H); 9.98 (1H) ppm.
EXAMPLE 29
Production of 6-(1,1-Dimethyl-2-piperazin-1-yl-ethyl)-4-p-tolyl-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 14, 43 mg of product is obtained by reaction of 80 mg of the substance that is described under Example 28c) with 430 μl of HCl solution (2 molar in diethyl ether) in dichloromethane.
1H-NMR (d6-DMSO): δ=1.50 (6H); 2.41 (3H); 2.50 (6H); 3.45 (4H); 3.70 (2H); 7.20 (1H); 7.40 (2H); 7.60 (2H); 9.95 (1H) ppm.
EXAMPLE 30
Production of 6-(1,1-Dimethyl-2-(4-methyl-piperazin-1-yl)-ethyl]-4-(4-phenoxyphenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
EXAMPLE 30a
Production of 6-(2-Hydroxy-1,1-dimethylethyl)-2-oxo-4-(4-phenoxyphenyl)-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a), 1.85 g of product is obtained from 6.7 g of ammonium acetate, 1.15 ml of cyanoacetic acid ethyl ester, 2.5 g of the compound that is described under Example 25d), and 2.15 g of 4-phenoxybenzaldehyde.
1H-NMR (d6-DMSO): δ=1.24 (6H); 3.55 (2H); 6.28 (1H); 7.10 (4H); 7.23 (1H); 7.46 (2H); 7.68 (2H) ppm.
EXAMPLE 30b
Production of 6-(1,1-Dimethyl-2-oxo-ethyl)-2-oxo-4-(4-phenoxyphenyl)-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 25f), 184 mg of product is obtained from 442 mg of the compound that is described under Example 30a), 585 mg of sulfur trioxide-pyridine complex and 850 μl of triethylamine in dimethyl sulfoxide.
1H-NMR (CDCl3): δ=1.60 (6H); 6.27 (1H); 7.10 (4H); 7.20 (1H); 7.40 (2H); 7.59 (2H); 9.70 (1H); 12.55 (1H) ppm.
EXAMPLE 30c
Production of 6-[1,1-Dimethyl-2-(4-methylpiperazin-1-yl)-ethyl]-2-oxo-4-(4-phenoxyphenyl)-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 13, 101 mg of product is obtained from 130 mg of the compound that is described under Example 30b), 200 μl of N-methylpiperazine and 100 mg of sodium triacetoxy borohydride.
1H-NMR (CDCl3): δ=1.31 (6H); 1.63 (4H); 2.32 (3H); 2.58 (2H); 2.62 (2H); 2.72 (2H); 6.10 (1H); 7.08 (4H); 7.19 (1H); 7.40 (2H); 7.58 (2H); 12.70 (1H) ppm.
EXAMPLE 30d
Production of 3-Cyano-6-[1,1-dimethyl-2-(4-methylpiperazin-1-yl)-ethyl]-4-(4-phenoxyphenyl)-2-trifluoromethanesulfonyl pyridine
Analogously to Example 3b), 105 mg of product is obtained from 96 mg of the substance that is described under Example 30c) and 80 μl of trifluoromethanesulfonic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.37 (6H); 1.76 (4H); 2.27 (3H); 2.40 (4H); 2.67 (2H); 7.05-7.28 (6H); 7.40 (2H); 7.60 (2H) ppm.
EXAMPLE 30e
Production of 6-(1,1-Dimethyl-2-(4-methyl-piperazin-1-yl)-ethyl]-4-(4-phenoxyphenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 1c), 49 mg of product is produced from 134 mg of the compound that is described under Example 30d) with 40 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.33 (6H); 2.05 (3H); 2.13 (4H); 2.27 (4H); 2.60 (2H); 4.52 (2H); 7.03-7.25 (6H); 7.43 (2H); 7.60 (2H) ppm.
EXAMPLE 31
Production of 6-(1,1-Dimethyl-2-morpholin-4-yl-ethyl)-4-(4-phenoxyphenyl)]-1H-pyrazolo[3,4b]pyridin-3-ylamine
EXAMPLE 31a
Production of 6-(1,1-Dimethyl-2-morpholin-4-yl-ethyl)-2-oxo-4-(4-phenoxyphenyl)-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 13, 122 mg of product is obtained from 145 mg of the compound that is described under Example 30b), 180 μl of morpholine and 100 mg of sodium triacetoxy borohydride.
1H-NMR (d6-DMSO): δ=1.28 (6H); 2.40 (4H); 2.59 (2H); 3.53 (4H); 6.27 (1H); 7.12 (4H); 7.22 (1H); 7.48 (2H); 7.68 (2H); 12.42 (1H) ppm.
EXAMPLE 31b
Production of 3-Cyano-6-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-4-(4-phenoxyphenyl)-2-trifluoromethanesulfonyl pyridine
Analogously to Example 3b), 139 mg of product is obtained from 118 mg of the substance that is described under Example 31a) and 102 μl of trifluoromethanesulfonic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.37 (6H); 2.30 (4H); 2.65 (2H); 3.53 (4H); 7.18-7.30 (5H); 7.41 (2H); 7.49 (1H); 7.61 (2H)
EXAMPLE 31c
Production of 6-(1,1-Dimethyl-2-morpholin-4-yl-ethyl)-4-(4-phenoxyphenyl)]-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 1c), 89 mg of product is produced from 135 mg of the compound that is described under Example 31b) with 50 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (CDCl3): δ=1.45 (6H); 2.30 (4H); 2.70 (2H); 3.53 (4H); 3.95 (2H); 7.05 (1H); 7.08-7.23 (5H); 7.40 (2H); 7.55 (2H) ppm.
EXAMPLE 32
Production of 3-(3-Amino-6-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenol
EXAMPLE 32a
Production of 4-(3-Hydroxyphenyl)-6-oxo-1,6-dihydro-[2,4′]bipyridinyl-5-carbonitrile
Analogously to Example 1a, 1.82 g of product is obtained from 7.57 g of ammonium acetate, 1.31 ml of cyanoacetic acid ethyl ester, 1.36 ml of 4-acetylpyridine and 1.5 g of 3-hydroxybenzaldehyde.
1H-NMR (d6-DMSO): δ=6.96 (1H); 7.00-7.20 (3H); 7.48 (1H); 7.90 (2H); 8.72 (2H); 9.88 (1H); 12.97 (1H) ppm.
EXAMPLE 32b
Production of Acetic Acid 3-(5-cyano-6-oxo-1,6-dihydro-[2,4′]bipyridinyl-4-yl)-phenyl Ester
580 mg of the compound that is described under Example 32a is dissolved in 6 ml of pyridine. 0.5 ml of acetic acid anhydride is added, and it is allowed to stir for 2 more hours at 80° C. After cooling, 20 ml of water is added. It is stirred for one more hour, and then the precipitate is suctioned off. 564 mg of product is obtained.
1H-NMR (d6-DMSO): δ=2.31 (3H); 7.11 (1H); 7.37 (1H); 7.55 (1H); 7.64 (2H); 7.92 (2H); 8.76 (2H); 13.02 (1H) ppm.
EXAMPLE 32c
Production of Acetic Acid 3-(5-Cyano-6-trifluoromethanesulfonyloxy-[2,4′]bipyridinyl-4-yl)-phenyl Ester
Analogously to Example 3b, 202 mg of product is obtained from 200 mg of the substance that is described under Example 32b and 305 μl of trifluoromethanesulfonic acid in pyridine.
1H-NMR (CDCl3): δ=2.38 (3H); 7.36 (1H); 7.41 (1H); 7.55-7.68 (2H); 7.91 (1H); 8.00 (1H); 8.86 (1H) ppm.
EXAMPLE 32d
Production of 3-(3-Amino-6-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenol
Analogously to Example 1c, 65 mg of product is obtained from 197 mg of the substance that is described under Example 32c with 80 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=6.93 (1H); 7.05 (2H); 7.36 (1H); 7.42 (1H); 8.20 (1H); 8.48 (1H); 8.71 (2H); 9.82 (1H) ppm.
EXAMPLE 33
Production of 3-(3-Amino-6-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-4-yl)-5-methoxyphenol
EXAMPLE 33a
Production of 2-(3,5-Dimethoxyphenyl)-[1,3]dioxolane
4.2 ml of ethylene glycol, 4.1 ml of trimethyl orthoformate and 5 mg of p-toluenesulfonic acid are added to a solution of 5 g of 3,5 dimethoxy benzaldehyde in 100 ml of dichloromethane. It is allowed to stir for 20 more hours at 25° C. Then, it is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product is purified by column chromatography. 5.67 g of product is obtained.
1H-NMR (CDCl3): δ=3.80 (6H); 4.00-4.15 (4H); 5.77 (1H); 6.45 (1H); 6.64 (2H) ppm.
EXAMPLE 33b
Production of 3-[1,3]Dioxolan-2-yl-5-methoxyphenol
5.67 g of the substance that is described under Example 33a is dissolved in 100 ml of dimethylformamide. 7.6 g of sodium methanethiolate is added, and it is refluxed for 4 hours. Then, the reaction mixture is poured into ice water. It is allowed to stir for one more hour and then extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product is purified by column chromatography. 2.84 g of product is obtained.
1H-NMR (CDCl3): δ=3.80 (3H); 4.00-4.15 (4H); 5.18 (1H); 5.73 (1H); 6.40 (1H); 6.55 (1H); 6.61 (1H) ppm.
EXAMPLE 33c
Production of 3-Hydroxy-5-methoxy-benzaldehyde
300 ml of 2N hydrochloric acid is added to a solution of 450 mg of the substance, described under Example 33b, in 10 ml of acetone. It is allowed to stir for 30 minutes at 25° C., then diluted with dichloromethane. The organic phase is dried with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product is purified by column chromatography. 207 mg of product is obtained.
1H-NMR (d6-DMSO): δ=3.79 (3H); 6.65 (1H); 6.90 (2H); 9.85 (1H); 10.00 (1H) ppm.
EXAMPLE 33d
Production of 4-(3-Hydroxy-5-methoxyphenyl)-6-oxo-1,6-dihydro-[2,4′]bipyridinyl-5-carbonitrile
Analogously to Example 1a, 477 mg of product is obtained from 450 mg of the compound that is described under Example 33c, 1.84 g of ammonium acetate, 320 μl of cyanoacetic acid ethyl ester and 330 μl of 4-acetylpyridine.
1H-NMR (d6-DMSO): δ=3.77 (3H); 6.51 (1H); 6.70 (2H); 7.05 (1H); 7.90 (2H); 8.72 (2H); 9.11 (1H) ppm.
EXAMPLE 33e
Production of Acetic Acid 3-(5-cyano-6-oxo-1,6-dihydro-[2,4′]bipyridinyl-4-yl)-5-methoxyphenyl ester
Analogously to Example 32b, 204 mg of product is obtained from 200 mg of the compound that is described under Example 33d and 160 μl of acetic acid anhydride in pyridine.
1H-NMR (d6-DMSO): δ=2.29 (3H); 3.34 (3H); 6.99 (1H); 7.11 (2H); 7.22 (1H); 7.93 (2H); 8.75 (2H) ppm.
EXAMPLE 33f
Production of Acetic Acid 3-(5-cyano-6-trifluoromethane-sulfonyloxy-[2,4′]bipyridinyl-4-yl)-5-methoxyphenyl ester
Analogously to Example 3b, 186 mg of product is obtained from 200 mg of the substance that is described under Example 33e and 280 μl of trifluoromethanesulfonic acid in pyridine.
1H-NMR (CDCl3): δ=2.33 (3H); 3.90 (3H); 6.89 (1H); 7.00 (1H); 7.06 (1H); 7.91 (2H); 7.99 (1H); 8.85 (2H) ppm.
EXAMPLE 33g
Production of 3-(3-Amino-6-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-4-yl)-5-methoxyphenol
Analogously to Example 1c, 67 mg of product is obtained from 181 mg of the substance that is described under Example 33f with 70 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=3.78 (3H); 6.50 (1H); 6.62 (2H); 7.43 (1H); 8.20 (2H); 8.45 (1H); 8.70 (2H); 9.85 (1H) ppm.
EXAMPLE 34
Production of 4-(3,5-Dimethoxy-phenyl)-6-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-3-ylamine
EXAMPLE 34a
Production of 4-(3,5-Dimethoxyphenyl)-6-oxo-1,6-dihydro-[2,4′]bipyridinyl-5-carbonitrile
Analogously to Example 1a, 1.49 g of product is obtained from 5.57 g of ammonium acetate, 960 μl of cyanoacetic acid ethyl ester, 1 ml of 4-acetylpyridine, and 1.5 g of 3,5-dimethoxybenzaldehyde.
1H-NMR (d6-DMSO): δ=3.80 (6H); 6.60 (1H); 6.76 (2H); 6.87 (1H); 7.95 (2H); 8.65 (2H) ppm.
EXAMPLE 34b
Production of Trifluoromethanesulfonic Acid-5-cyano-4-(3,5-dimethoxy-phenyl)-[2,4′]bipyridinyl-6-yl Ester
Analogously to Example 3b, 302 mg of product is obtained from 240 mg of the substance that is described under Example 34a and 360 μl of trifluoromethanesulfonic acid in pyridine.
1H-NMR (d6-DMSO): δ=3.85 (6H); 6.79 (1H); 7.04 (2H); 8.17 (2H); 8.61 (1H); 8.85 (1H) ppm.
EXAMPLE 34c
Production of 4-(3,5-Dimethoxy-phenyl)-6-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-3-ylamine
Analogously to Example 1c, 76 mg of product is obtained from 297 mg of the substance that is described under Example 34b with 120 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=3.85 (6H); 4.73 (2H); 6.68 (1H); 6.84 (2H); 7.65 (1H); 8.15 (2H); 8.71 (2H); 12.51 (1H) ppm.
EXAMPLE 35
Production of 3-(3-Amino-6-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-methyl-phenol
EXAMPLE 35a
Production of 2-Methyl-5-nitro-benzoic Acid Methyl Ester
300 μl of concentrated sulfuric acid is added to a suspension of 2 g of 2-methyl-5-nitrobenzoic acid in 7 ml of methanol. It is refluxed for 6 hours. Then, the reaction mixture is diluted with ethyl acetate and poured into saturated sodium bicarbonate solution. The phases are separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are then washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product that is obtained is incorporated without purification into the next step.
1H-NMR (CDCl3): δ=2.70 (3H); 3.95 (3H); 7.42 (1H); 8.23 (1H); 8.78 (1H) ppm.
EXAMPLE 35b
Production of 5-Amino-2-methylbenzoic Acid-Methyl Ester
3.17 g of the compound that is described under Example 35a is hydrogenated in a mixture that consists of 20 ml of tetrahydrofuran and 5 ml of ethanol with 625 mg of palladium/carbon (10%) under hydrogen. After the reaction is completed, it is filtered over Celite and concentrated by evaporation in a vacuum. The crude product that is obtained is purified by column chromatography on silica gel with a mixture that consists of ethyl acetate/hexane. 2.65 g of product is obtained.
1H-NMR (CDCl3): δ=2.47 (3H); 3.87 (3H); 6.75 (1H); 7.01 (1H); 7.25 (1H) ppm.
EXAMPLE 35c
Production of 5-Hydroxy-2-methyl-benzoic Acid Methyl Ester
3.17 g of the compound that is described under Example 35b is suspended in 18 ml of 50% sulfuric acid. It is cooled to −5° C., and 6.4 ml of a 2.5 molar aqueous sodium nitrite solution is added at such a speed that the internal temperature does not increase above 5° C. Then, it is stirred for 1 more hour at 25° C. and for another 30 minutes at 80° C. Then, saturated sodium bicarbonate solution is slowly added to the reaction solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product that is obtained is purified by column chromatography on silica gel with a mixture that consists of ethyl acetate/hexane. 1.6 g of product is obtained.
1H-NMR (CDCl3): δ=2.50 (3H); 3.88 (3H); 5.08 (1H); 6.90 (1H); 7.10 (1H); 7.40 (1H) ppm.
EXAMPLE 35d
Production of 5-(tert-Butyldimethylsilanyloxy)-2-methylbenzoic Acid Methyl Ester
1 g of tert-butyldimethysilyl chloride is added to a solution of 770 mg of the compound that is described under Example 35c and 760 mg of imidazole in 20 ml of N,N-dimethylformamide. It is allowed to stir for 2 more hours at 25° C., and then the reaction mixture is poured into saturated sodium bicarbonate solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product that is obtained is purified by column chromatography on silica gel with a mixture that consists of ethyl acetate/hexane. 1.12 g of product is obtained.
1H-NMR (CDCl3): δ=0.18 (6H); 0.98 (9H); 2.50 (3H); 3.89 (3H); 6.88 (1H); 7.08 (1H); 7.37 (1H) ppm.
EXAMPLE 35e
Production of [5-(tert-Butyldimethylsilanyloxy)-2-methyl-phenyl]-methanol
2.3 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is added to a solution of 250 mg of the compound, described under Example 35d, in 7 ml of toluene at −30° C. It is allowed to stir for 1 more hour at 0° C., and then 1 ml of 2-propanol is added. It is allowed to stir for another 10 minutes, and 1.3 ml of water is added. It is allowed to stir for another hour and then filtered over Celite. Then, it is concentrated by evaporation in a vacuum. The crude product that is obtained (223 mg) is incorporated without purification into the next step.
1H-NMR (CDCl3): δ=0.18 (6H); 0.98 (9H); 2.26 (3H); 4.64 (2H); 6.68 (1H); 6.88 (1H); 7.01 (1H) ppm.
EXAMPLE 35f
Production of 5-(tert-Butyldimethylsilanyloxy)-2-methyl-benzaldehyde
Analogously to the oxidation that is described under Example 25f), 2.03 g of product is obtained from 2.2 g of the compound that is described under Example 35e).
1H-NMR (CDCl3): δ=0.19 (6H); 0.99 (9H); 2.58 (3H); 6.97 (1H); 7.11 (1H); 7.26 (1H); 10.21 (1H) ppm.
EXAMPLE 35g
Production of 4-[5-(tert-Butyldimethylsilanyloxy)-2-methylphenyl]-6-oxo-1,6-dihydro-[2,4′]bipyridinyl-5-carbonitrile
Analogously to Example 1a, 170 mg of product is obtained from 600 mg of ammonium acetate, 105 μl of cyanoacetic acid ethyl ester, 110 μl of 4-acetylpyridine and 240 mg of the substance that is described under Example 35f.
1H-NMR (CDCl3): δ=0.19 (6H); 0.97 (9H); 2.25 (3H); 6.72 (2H); 6.89 (1H); 7.20 (1H); 7.79 (2H); 8.86 (2H) ppm.
EXAMPLE 35h
Production of Trifluoromethanesulfonic Acid-4-[5-(tert-butyldimethyl-silanyloxy)-2-methyl-phenyl]-5-cyano-[2,4′]bipyridinyl-6-yl ester
Analogously to Example 3b, 85 mg of product is obtained from 107 mg of the substance that is described under Example 35g and 130 μl of trifluoromethanesulfonic acid in pyridine.
1H-NMR (CDCl3): δ=0.21 (6H); 0.98 (9H); 2.19 (3H); 6.73 (1H); 6.92 (1H); 7.23 (1H); 7.86 (1H); 7.91 (2H); 8.82 (2H) ppm.
EXAMPLE 35i
Production of 4-[5-(tert-Butyldimethylsilanyloxy)-2-methyl-phenyl]-6-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-3-ylamine
Analogously to Example 1c, 27 mg of product is obtained from 50 mg of the substance that is described under Example 35h with 20 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=0.21 (6H); 0.93 (9H); 2.07 (3H); 4.38 (2H); 6.79 (1H); 6.93 (1H); 7.30 (1H); 7.52 (1H); 8.13 (2H); 8.70 (2H); 12.45 (1H) ppm.
EXAMPLE 35j
Production of 3-(3-Amino-6-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-methyl-phenol
70 μl of a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran is added to a solution of 24 mg of the substance, described under Example 35i, in 5 ml of tetrahydrofuran at 0° C. It is allowed to stir for one more hour and then poured into saturated sodium bicarbonate solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product that is obtained is purified by column chromatography on silica gel with a mixture that consists of ethyl acetate/hexane. 9.8 mg of product is obtained.
1H-NMR (d6-DMSO): δ=1.85 (3H); 4.22 (2H); 6.52 (1H); 6.67 (1H); 7.02 (1H); 7.35 (1H); 7.95 (2H); 8.50 (2H); 9.36 (1H); 12.27 (1H) ppm.
EXAMPLE 36
Production of 3-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-5-methoxy-phenol
EXAMPLE 36a
Production of 6-tert-Butyl-4-(3-hydroxy-5-methoxy-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a, 164 mg of product is obtained from 820 mg of ammonium acetate, 140 μl of cyanoacetic acid ethyl ester, 165 μl of 3,3-dimethyl-2-butanone and 202 mg of the compound that is described under Example 33c.
1H-NMR (d6-DMSO): δ=1.29 (9H); 3.77 (3H); 6.19 (3H); 6.49 (1H); 6.60 (2H); 9.86 (1H); 12.25 (1H) ppm.
EXAMPLE 36b
Production of Acetic Acid-3-(6-tert-butyl-3-cyano-2-oxo-1,2-dihydro-pyridin-4-yl)-5-methoxy Phenyl Ester
Analogously to Example 32b, 122 mg of product is obtained from 150 mg of the compound that is described under Example 36a and 130 μl of acetic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.42 (9H); 2.31 (3H); 3.88 (3H); 6.29 (1H); 6.80 (1H); 6.91 (1H); 7.02 (1H); 12.12 (1H) ppm.
EXAMPLE 36c
Production of Acetic Acid 3-(6-tert-Butyl-3-cyano-2-trifluoromethanesulfonyloxy-pyridin-4-yl)-5-methoxy-phenyl Ester
Analogously to Example 3b, 133 mg of product is obtained from 120 mg of the substance that is described under Example 36b and 175 μl of trifluoromethanesulfonic acid in pyridine.
1H-NMR (CDCl3): δ=1.39 (9H); 2.35 (3H); 3.88 (3H); 6.84 (1H); 6.90 (1H); 7.01 (1H); 7.46 (1H) ppm.
EXAMPLE 36d
Production of 3-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-5-methoxy-phenol
Analogously to Example 1c, 49 mg of product is obtained from 130 mg of the substance that is described under Example 36c with 55 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.38 (9H); 3.77 (3H); 4.57 (2H); 6.46 (1H); 6.53 (2H); 6.95 (1H); 9.79 (1H); 12.12 (1H) ppm.
EXAMPLE 37
Production of 3-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenol
EXAMPLE 37a
Production of 6-tert-Butyl-4-(3-hydroxyphenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a, 814 mg of product is obtained from 5 g of ammonium acetate, 875 μl of cyanoacetic acid ethyl ester, 1.01 ml of 3,3-dimethyl-2-butanone and 1 g of 3-hydroxybenzaldehyde.
1H-NMR (d6-DMSO): δ=1.28 (9H); 6.20 (1H); 6.93 (1H); 6.98-7.08 (2H); 7.34 (1H); 9.84 (1H); 12.25 (1H) ppm.
EXAMPLE 37b
Production of Acetic Acid 3-(6-tert-Butyl-3-cyano-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl Ester
Analogously to Example 32b, 376 mg of product is obtained from 396 mg of the compound that is described under Example 37a and 370 μl of acetic acid anhydride in pyridine.
1H-NMR (d6-DMSO): δ=1.31 (9H); 2.29 (3H); 6.25 (1H); 7.34 (1H); 7.42 (1H); 7.52-7.65 (2H); 12.35 (1H) ppm.
EXAMPLE 37c
Production of Acetic Acid 3-(6-tert-Butyl-3-cyano-2-trifluoromethane-sulfonyloxy-pyridin-4-yl)-phenyl ester
Analogously to Example 3b, 480 mg of product is obtained from 371 mg of the substance that is described under Example 37a and 605 μl of trifluoromethanesulfonic acid in pyridine.
1H-NMR (CDCl3): δ=1.40 (9H); 2.35 (3H); 7.28-7.37 (2H); 7.45-7.53 (2H); 7.59 (1H) ppm.
EXAMPLE 37d
Production of 3-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenol
Analogously to Example 1c, 147 mg of product is obtained from 477 mg of the substance that is described under Example 37c with 200 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.38 (9H); 4.52 (2H); 6.37-7.00 (4H); 7.36 (1H); 9.75 (1H); 12.14 (1H) ppm.
EXAMPLE 38
Production of 3-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-methyl-phenol
EXAMPLE 38a
Production of 6-tert-Butyl-4-[5-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a, 1.13 g of product is obtained from 5 g of ammonium acetate, 865 μl of cyanoacetic acid ethyl ester, 1 ml of 3,3-dimethyl-2-butanone and 2.03 g of the substance that is described under Example 35f.
EXAMPLE 38b
Production of Trifluoromethanesulfonic Acid 6-tert-Butyl-4-[5-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-3-cyano-pyridin-2-yl Ester
Analogously to Example 3b, 352 mg of product is obtained from 330 mg of the substance that is described under Example 38a and 200 μl of trifluoromethanesulfonic acid in pyridine.
EXAMPLE 38c
Production of 6-tert-Butyl-4-[5-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-1H-pyrazolo[3,4-b]pyridin-3-ylamine
Analogously to Example 1c, 189 mg of product is obtained from 367 mg of the substance that is described under Example 38b with 150 μl of hydrazine hydrate solution (80%) in propanol.
EXAMPLE 38d
Production of 3-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-methyl-phenol
Analogously to Example 35j, 64 mg of product is obtained from 150 mg of the substance that is described under Example 38c.
1H-NMR (d6-DMSO): δ=1.34 (9H); 1.96 (3H); 4.23 (2H); 6.62 (1H); 6.75-6.86 (2H); 7.17 (1H); 9.48 (1H); 12.08 (1H) ppm.
EXAMPLE 39
Production of 4-(3,5-Dimethoxy-phenyl)-6-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-3-ylamine
EXAMPLE 39a
Production of 6-tert-Butyl-4-(3,5-dimethoxyphenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a, 600 mg of product is obtained from 3.71 g of ammonium acetate, 645 μl of cyanoacetic acid ethyl ester, 745 μl of 3,3-dimethyl-2-butanone and 1 g of 3,5-dimethoxy benzaldehyde.
1H-NMR (d6-DMSO): δ=1.30 (9H); 3.80 (6H); 6.27 (1H); 6.68 (1H); 6.77 (2H) ppm.
EXAMPLE 39b
Production of Trifluoromethanesulfonic acid-6-tert-butyl-3-cyano-4-(3,5-dimethoxyphenyl)pyridin-2-yl ester
Analogously to Example 3b, 382 mg of product is obtained from 290 mg of the substance that is described under Example 39a and 470 μl of trifluoromethanesulfonic acid in pyridine.
1H-NMR (CDCl3): δ=1.38 (9H); 3.86 (6H); 6.61 (1H); 6.69 (2H); 7.46 (1H) ppm.
EXAMPLE 39c
Production of 6-tert-Butyl-4-(3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine
Analogously to Example 1c, 126 mg of product is obtained from 377 mg of the substance that is described under Example 39b with 155 μL of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.35 (9H); 3.80 (6H); 4.53 (2H); 6.62 (1H); 6.70 (2H); 7.00 (1H); 12.15 (1H) ppm.
EXAMPLE 40
Production of 3-(3-Amino-6-tert-butyl-1H-pyrazolo3,4-b]pyridin-4-yl)-5-isopropoxy Phenol
EXAMPLE 40a
Production of 2-(3-Isopropoxy-5-methoxy-phenyl)-[1,3]dioxolane
3.42 ml of azodicarboxylic acid diethyl ester is slowly added in drops to a solution of 2.85 g of the compound that is described under Example 33b, 5.7 g of triphenylphosphine and 1.7 ml of 2-propanol in 20 ml of tetrahydrofuran at 0° C. It is allowed to stir for 20 more minutes at 23° C., and then the reaction mixture is poured into 10 ml of hexane. Then, it is stirred for 15 more minutes and then filtered over Celite. The crude product is purified by column chromatography. 2.94 g of product is obtained.
1H-NMR (CDCl3): δ=1.30 (6H); 3.78 (3H); 4.00-4.15 (4H); 4.53 (1H); 5.76 (1H); 6.42 (1H); 6.62 (2H) ppm.
EXAMPLE 40b
Production of 3-[1,3]Dioxolan-2-yl-5-isopropoxy Phenol
Analogously to Example 33b, 1.91 g of product is obtained from 2.94 g of the compound that is described under 40a and 3.46 g of sodium methanethiolate in N,N-dimethylformamide after column chromatography.
1H-NMR (CDCl3): δ=1.30 (6H); 3.98-4.15 (4H); 4.51 (1H); 5.20 (1H); 6.37 (1H); 6.51 (1H); 6.60 (1H) ppm.
EXAMPLE 40c
Production of 3-Hydroxy-5-isopropoxybenzaldehyde
Analogously to Example 33c, 1.46 g of product is obtained from 2.08 g of the substance that is described under 40b with 2N hydrochloric acid in acetone.
1H-NMR (CDCl3): δ=1.35 (6H); 4.58 (1H); 5.61 (1H); 6.66 (1H); 6.91 (1H); 6.98 (1H); 9.87 (1H) ppm.
EXAMPLE 40d
Production of 6-tert-Butyl-4-(3-hydroxy-5-isopropoxy-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
1.12 g of product is obtained [from] 1.46 g of the compound that is described under Example 40c, 5 g of ammonium acetate, 865 μl of cyanoacetic acid ethyl ester and 1 ml of 3,3-dimethyl-2-butanone.
1H-NMR (d6-DMSO): δ=1.20-1.40 (15H); 4.60 (1H); 6.20 (1H); 6.47 (1H); 6.57 (2H); 9.82 (1H) ppm.
EXAMPLE 40e
Production of Acetic Acid 3-(6-tert-butyl-3-cyano-2-oxo-1,2-dihydro-pyridin-4-yl)-5-isopropoxyphenyl Ester
Analogously to Example 32b, 407 mg of product is obtained from 460 mg of the compound that is described under Example 40d and 265 μl of acetic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.36 (6H); 1.42 (9H); 2.31 (3H); 4.58 (1H); 6.30 (1H); 6.77 (1H); 6.89 (1H); 7.00 (1H); 12.26 (1H) ppm.
EXAMPLE 40f
Production of Acetic Acid 3-(6-tert-butyl-3-cyano-2-trifluoromethane-sulfonyloxypyridin-4-yl)-5-isopropoxyphenyl Ester
Analogously to Example 3b, 490 mg of product is obtained from 404 mg of the substance that is described under Example 40e and 555 μl of trifluoromethanesulfonic acid in pyridine.
1H-NMR (CDCl3): δ=1.32-1.42 (15H); 2.32 (3H); 4.58 (1H); 6.80 (1H); 6.88 (1H); 6.96 (1H); 7.46 (1H) ppm.
EXAMPLE 40g
Production of 3-(3-Amino-6-tert-butyl-1H-pyrazolo3,4-b]pyridin-4-yl)-5-isopropoxy-phenol
Analogously to Example 1c, 167 mg of product is obtained from 486 mg of the substance that is described under Example 40f with 180 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.28 (6H); 1.37 (9H); 4.54-4.68 (3H); 6.42 (1H); 6.50 (2H); 6.95 (1H); 9.73 (1H); 12.12 (1H) ppm.
EXAMPLE 41
Production of 3-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4b]pyridin-4-yl)-4-nitro-phenol
EXAMPLE 41a
Production of 6-tert-Butyl-4-(5-hydroxy-2-nitro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a, 690 mg of product is obtained from 3.7 g of ammonium acetate, 640 μl of cyanoacetic acid ethyl ester, 740 μl of 3,3-dimethyl-2-butanone and 1 g of 5-hydroxy-2-nitrobenzaldehyde.
1H-NMR (d6-DMSO): δ=1.29 (9H); 6.25 (1H); 6.81 (1H); 7.06 (1H); 8.21 (1H); 12.37 (1H) ppm.
EXAMPLE 41b
Production of Acetic Acid-3-(6-tert-butyl-3-cyano-2-oxo-1,2-dihydropyridin-4-yl)-4-nitrophenyl Ester
Analogously to Example 33b, 143 mg of product is obtained from 200 mg of the compound that is described under Example 41a and 120 μl of acetic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.35 (3H); 2.35 (3H); 6.10 (1H); 7.22 (1H); 7.42 (1H); 8.29 (1H) ppm.
EXAMPLE 41c
Production of Acetic Acid 3-(6-tert-butyl-3-cyano-2-trifluoromethane-sulfonyloxy-pyridin-4-yl)-4-nitro-phenyl Ester
Analogously to Example 3b, 105 mg of product is obtained from 143 mg of the substance that is described under Example 41b and 205 μl of trifluoromethanesulfonic acid in pyridine.
1H-NMR (CDCl3): δ=1.38 (9H); 1.55 (3H); 7.32 (1H); 7.39 (1H); 7.68 (1H); 8.43 (1H) ppm.
EXAMPLE 41d
Production of 3-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4b]pyridin-4-yl)-4-nitro-phenol
Analogously to Example 1c, 147 mg of product is obtained from 477 mg of the substance that is described under Example 41 with 200 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.35 (9H); 4.30 (2H); 6.72 (1H); 6.88 (1H); 7.00 (1H); 8.16 (1H); 12.10 (1H) ppm.
EXAMPLE 42
Production of 5-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,3-dimethoxyphenol
EXAMPLE 42a
Production of 6-tert-Butyl-4-(3-hydroxy-4,5-dimethoxy-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a, 340 mg of product is obtained from 1.7 g of ammonium acetate, 300 μl of cyanoacetic acid ethyl ester, 340 μl of 3,3-dimethyl-2-butanone and 500 mg of 3,4-dimethoxy-5-hydroxybenzaldehyde.
1H-NMR (d6-DMSO): δ=1.30 (9H); 3.72 (3H); 3.82 (3H); 6.22 (1H); 6.76 (2H); 9.62 (1H); 12.21 (1H) ppm.
EXAMPLE 42b
Production of Acetic Acid 5-(6-tert-butyl-3-cyano-2-oxo-1,2-dihydro-pyridin-4-yl)-2,3-dimethoxyphenyl Ester
Analogously to Example 33b, 180 mg of product is obtained from 160 mg of the compound that is described under Example 42a and 100 μl of acetic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.42 (9H); 2.36 (3H); 3.91 (3H); 3.95 (3H); 6.29 (1H); 6.90 (1H); 7.18 (1H) ppm.
EXAMPLE 42c
Production of Acetic Acid 5-(6-tert-butyl-3-cyano-2-trifluoro-methanesulfonyloxypyridin-4-yl)-2,3-dimethoxyphenyl Ester
Analogously to Example 3b, 215 mg of product is obtained from 180 mg of the substance that is described under Example 42b and 250 μl of trifluoromethanesulfonic acid in pyridine.
1H-NMR (CDCl3): δ=1.40 (9H); 2.36 (3H); 3.92 (3H); 3.97 (3H); 6.90 (1H); 7.11 (1H); 7.43 (1H) ppm.
EXAMPLE 42d
Production of 5-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4b]pyridin-4-yl)-2,3-dimethoxyphenol
Analogously to Example 1c, 90 mg of product is obtained from 210 mg of the substance that is described under Example 42c with 80 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.38 (9H); 3.73 (3H); 3.82 (3H); 4.59 (2H); 6.68 (2H); 6.96 (1H); 9.51 (1H); 12.12 (1H) ppm.
EXAMPLE 43
Production of 6-Cyclopropyl-4-(3,4-dichlorophenyl)-1H-pyrazolo-[3,4-b]pyridin-3-ylamine
EXAMPLE 43a
Production of 6-Cyclopropyl-4-(3,4-dichlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile
While being stirred, 300 ml of ethanol is mixed with 14 g of acetyl cyclopropane, 18 g of cyanoacetic acid ethyl ester, 28 g of 3,4-dichlorobenzaldehyde as well as 100 g of ammonium acetate, and it is subsequently heated to boiling for six hours at a bath temperature of 80-90° C. After some length of time, a portion of the product already precipitates from the reaction solution. To complete the precipitation, it is then allowed to cool to room temperature while being stirred. The precipitate is suctioned off, washed acetate-free with cold ethanol and water and ultimately dried. 15 g of product accumulates, melting point 290-295° C., while decomposing.
EXAMPLE 43b
Production of 2-Chloro-6-cyclopropyl-4-(3,4-dichlorophenyl)-nicotinonitrile
16 g of pyridone (the Example given above) is carefully introduced into 75 ml of phenylphosphonic acid dichloride, and the mixture is then stirred for four hours in a moisture-free environment at 150-160° C. Under these conditions, the pyridone goes into solution as soon as possible. For working-up, it is allowed to cool to room temperature, and then carefully stirred in water. The precipitate that is produced is suctioned off, washed with water and dried in air. Yield 11 g, melting point 158-160° C. (propanol).
EXAMPLE 43c
Production of 6-Cyclopropyl-4-(3,4-dichlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine
A solution of 0.971 g of the chlorocyanopyridine above in 10 ml of propanol and 1 ml of hydrazine hydrate (80%) is heated for four hours at 100° C. After the reaction mixture is cooled, the precipitated product is suctioned off and recrystallized from acetic acid. Yield 250 mg, melting point 256-258° C.
EXAMPLE 44
Production of 3-(3-Amino-6-cyclopropyl-1H-pyrazolo-[3,4-b]pyridin-4-yl)-phenol
EXAMPLE 44a
Production of 6-Cyclopropyl-4-(3-hydroxy-phenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile
Analogously to Example 1a, 750 mg of product is obtained from 5 g of ammonium acetate, 875 μl of cyanoacetic acid ethyl ester, 815 μl of cyclopropylmethylketone and 1 g of 3-hydroxybenzaldehyde.
1H-NMR (d6-DMSO): δ=1.00-1.25 (4H); 1.97 (1H); 5.99 (1H); 6.86-7.05 (3H); 7.30 (1H); 9.80 (1H); 12.58 (1H) ppm.
EXAMPLE 44b
Production of Acetic Acid 3-(3-cyano-6-cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl Ester
Analogously to Example 33b, 570 mg of product is obtained from 750 mg of the compound that is described under Example 44a and 5500 μl of acetic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.12 (2H); 1.31 (2H); 2.07 (1H); 2.33 (3H); 5.96 (1H); 7.20-7.33 (2H); 7.50 (2H); 13.46 (1H) ppm.
EXAMPLE 44c
Production of Acetic Acid 3-(3-cyano-6-cyclopropyl-2-trifluoromethane-sulfonyloxypyridin-4-yl)-phenyl Ester
Analogously to Example 3b, 458 mg of product is obtained from 350 mg of the substance that is described under Example 44b and 600 μl of trifluoromethanesulfonic acid in pyridine.
1H-NMR (CDCl3): δ=1.22 (4H); 2.10 (1H); 2.33 (3H); 7.27-7.38 (2H); 7.39 (1H); 7.49 (1H); 7.56 (1H) ppm.
EXAMPLE 44d
Production of 3-(3-Amino-6-cyclopropyl-1H-pyrazolo-[3,4-b]pyridin-4-yl)-phenol
Analogously to Example 1c, 208 mg of product is obtained from 453 mg of the substance that is described under Example 44c with 200 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=0.93-1.14 (4H); 2.19 (1H); 4.49 (2H); 6.83 (1H); 6.88-7.00 (3H); 7.34 (1H); 9.78 (1H); 12.01 (1H) ppm.
EXAMPLE 45
Production of 3-(3-Amino-6-cyclohexyl-1H-pyrazolo-[3,4-b]pyridin-4-yl)-phenol
EXAMPLE 45a
Production of 6-Cyclohexyl-4-(3-hydroxy-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a, 750 mg of product is obtained from 5 g of ammonium acetate, 875 μl of cyanoacetic acid ethyl ester, 1.13 ml of 3,3-dimethyl-2-butanone and 1 g of 3-hydroxybenzaldehyde.
1H-NMR (d6-DMSO): δ=1.10-1.40 (4H); 1.40-1.60 (2H); 1.62-1.91 (4H); 2.53 (1H); 6.23 (1H); 6.88-7.06 (3H); 7.32 (1H); 9.81 (1H); 12.49 (1H) ppm.
EXAMPLE 45b
Production of Acetic Acid 3-(3-cyano-6-cyclohexyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl Ester
Analogously to Example 33b, 720 mg of product is obtained from 743 mg of the compound that is described under Example 45a and 470 μl of acetic acid anhydride in pyridine.
1H-NMR (d6-DMSO): δ=1.10-1.38 (4H); 1.40-1.60 (2H); 1.60-1.90 (4H); 2.30 (3H); 2.53 (1H); 6.29 (1H); 7.32 (1H); 7.40 (1H); 7.50-7.65 (2H); 12.56 (1H) ppm.
EXAMPLE 45c
Production of Acetic Acid 3-(3-cyano-6-cyclohexyl-2-trifluoromethane-sulfonyloxy-pyridin-4-yl)phenyl Ester
Analogously to Example 3b, 385 mg of product is obtained from 365 mg of the substance that is described under Example 45b and 550 μl of trifluoromethanesulfonic acid in pyridine.
1H-NMR (CDCl3): δ=1.20-1.62 (5H); 1.77 (1H); 1.82-2.02 (4H); 2.33 (3H); 2.78 (1H); 7.23-7.37 (3H); 7.49 (1H); 7.57 (1H) ppm.
EXAMPLE 45d
Production of 3-(3-Amino-6-cyclohexyl-1H-pyrazolo-[3,4-b]pyridin-4-yl)-phenol
Analogously to Example 1c, 165 mg of product is obtained from 380 mg of the substance that is described under Example 45c with 150 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.15-1.50 (4H); 1.50-1.97 (6H); 2.75 (1H); 4.51 (2H); 6.78 (1H); 6.85-7.00 (3H); 7.33 (1H); 9.75 (1H); 12.10 (1H) ppm.
EXAMPLE 46
Production of 5-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methoxyphenol
EXAMPLE 46a
Production of 6-tert-Butyl-4-(3-hydroxy-4-methoxyphenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a, 660 mg of product is obtained from 4.1 g of ammonium acetate, 700 μl of cyanoacetic acid ethyl ester, 815 μl of 3,3-dimethyl-2-butanone and 1 g of 3-hydroxy-4-methoxybenzaldehyde.
1H-NMR (d6-DMSO): δ=1.28 (9H); 3.84 (3H); 6.19 (1H); 7.08 (3H); 9.41 (1H); 12.13 (1H) ppm.
46b
Production of Acetic Acid 5-(6-tert-butyl-3-cyano-2-oxo-1,2-dihydro-pyridin-4-yl)-2-methoxyphenyl Ester
Analogously to Example 33b, 413 mg of product is obtained from 435 mg of the compound that is described under Example 46a and 270 μl of acetic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.42 (9H); 2.34 (3H); 3.91 (3H); 6.29 (1H); 7.10 (1H); 7.31 (1H); 7.60 (1H); 12.18 (1H) ppm.
EXAMPLE 46c
Production of Acetic Acid 5-(6-tert-Butyl-3-cyano-2-trifluoromethane-sulfonyloxy-pyridin-4-yl)-2-methoxy-phenyl Ester
Analogously to Example 3b, 501 mg of product is obtained from 408 mg of the substance that is described under Example 46b and 605 μl of trifluoromethanesulfonic acid in pyridine.
1H-NMR (CDCl3): δ=1.38 (9H); 2.35 (3H); 3.91 (3H); 7.12 (1H); 7.31 (1H); 7.42 (1H); 7.56 (1H) ppm.
EXAMPLE 46d
Production of 5-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-methoxyphenol
Analogously to Example 1c, 145 mg of product is obtained from 496 mg of the substance that is described under Example 46c with 190 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.35 (9H); 3.83 (3H); 4.56 (2H); 6.90 (1H); 6.99 (2H); 7.10 (1H); 9.31 (1H); 12.10 (1H) ppm.
EXAMPLE 47
Production of 5-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-benzene-1,3-diol
EXAMPLE 47A
Production of 6-tert-Butyl-4-(3,5-dihydroxyphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile
Analogously to Example 1a, 850 mg of product is obtained from 6.46 g of ammonium acetate, 770 μl of cyanoacetic acid ethyl ester, 895 μl of 3,3-dimethyl-2-butanone and 1 g of 3,5-dihydroxybenzaldehyde.
1H-NMR (d6-DMSO): δ=1.30 (9H); 6.15 (2H); 6.36 (1H); 6.43 (1H); 9.67 (2H); 12.23 (1H) ppm.
EXAMPLE 47b
Production of Acetic Acid 3-Acetoxy-5-(6-tert-butyl-3-cyano-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl Ester
Analogously to Example 33b, 210 mg of product is obtained from 200 mg of the compound that is described under Example 47a and 350 μl of acetic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.40 (9H); 2.31 (6H); 6.38 (1H); 7.10 (1H); 7.28 (2H); 12.07 (1H) ppm.
EXAMPLE 47c
Production of Acetic Acid 3-Acetoxy-5-(6-tert-butyl-3-cyano-2-trifluoromethanesulfonyloxy-pyridin-4-yl)-phenyl Ester
Analogously to Example 3b, 67 mg of product is obtained from 110 mg of the substance that is described under Example 47b and 150 μl of trifluoromethanesulfonic acid in pyridine.
1H-NMR (CDCl3): δ=1.39 (9H); 2.32 (6H); 7.16 (1H); 7.26 (2H); 7.47 (1H) ppm.
EXAMPLE 47d
Production of 5-(3-Amino-6-tert-butyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-benzene-1,3-diol
Analogously to Example 1c, 25 mg of product is obtained from 60 mg of the substance that is described under Example 47c with 22 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.37 (9H); 4.60 (2H); 6.35 (3H); 6.90 (1H); 9.59 (2H); 12.1 (1H) ppm.
EXAMPLE 48
Production of 4-Isopropyl-6-(3,4-methylenedioxyphenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
EXAMPLE 48a
Production of 4-Isopropyl-6-(3,4-methylenedioxyphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile
100 g of ammonium acetate is added to a solution of 12 g of isobutyraldehyde, 26 g of 3,4-methylenedioxy-acetophenone and 18 g of cyanoacetic acid ethyl ester in 300 ml of ethanol, and it is then refluxed for six hours while being stirred (80-90° C.). After cooling, the precipitate is suctioned off, washed first with cold ethanol and then with water and dried in air. Yield 17 g, melting point 266-268° C.
EXAMPLE 48b
Production of 2-Chloro-4-isopropyl-6-(3,4-methylenedioxyphenyl)-nicotinonitrile
A mixture of 15 g of 2-pyridone (the Example given above) and 75 ml of phenylphosphonic acid dichloride is heated for four hours in a nitrogen atmosphere in a moisture-free environment to 150-160° C. After cooling, the reaction mixture is carefully stirred into ice water, the precipitate is suctioned off, washed carefully with water and dried in air. Yield 16 g, melting point 171-173° C.
EXAMPLE 48c
Production of 4-Isopropyl-6-(3,4-methylenedioxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine
300 mg of chloronicotinonitrile (the Example given above) is mixed in 3 ml of propanol with 1 ml of hydrazine hydrate and heated for four hours while being stirred at 100° C. After half the reaction time, a second portion of hydrazine hydrate (0.5 ml) is added to the reaction solution. For working-up, the product is precipitated by the addition of water. The precipitate is suctioned off, washed with water, cold isopropanol and diethyl ether, and dried in air. Yield 200 mg, melting point 184-186° C.
EXAMPLE 49
Production of 6-(3-Hydroxyphenyl)-4-(4-pyridyl)-1H-pyrazolo[3,4b]-pyridin-3-ylamine
EXAMPLE 49a
Production of 6-(3-Hydroxyphenyl)-2-oxo-4-(4-pyridyl)-1,2-dihydropyridine-3-carbonitrile
According to the general production procedure for 2-pyridones, and after six hours of reaction time at 80° C., a total of 8 g of the title compound accumulates from a batch with 50 g of ammonium acetate, 11 g of 3-hydroxyacetophenone, 9 g of cyanoacetic acid ethyl ester and 8 g of 4-pyridinaldehyde in 300 ml of ethanol.
EXAMPLE 49b
Production of 6-(3-Acetyloxyphenyl)-2-oxo-4-(4-pyridyl)-1,2-dihydropyridine-3-carbonitrile
8 g of pyridone (the Example given above) is introduced into 80 ml of pyridine, mixed with 6 ml of acetic acid anhydride while being stirred quickly, and the reaction mixture is then kept for two hours at 80° C. For working-up, it is allowed to cool and stirred into ice water. The precipitate is suctioned off, washed with water and dried in air. Yield 7 g, melting point 284-286° C.
EXAMPLE 49c
Production of 6-(3-Acetyloxyphenyl)-4-(4-pyridyl)-2-trifluoromethyl-sulfonyl-oxynicotinonitrile
1 ml of trifluoromethanesulfonic acid anhydride is added in drops in a moisture-free environment to a suspension of 1 g of the acetylated pyridone (the Example given above) in 10 ml of pyridine while being cooled in an ice bath. Then, the ice bath is removed, and it is allowed to stir for two hours at room temperature. For working-up, the homogeneous, dark-colored reaction solution is introduced into ice water, the precipitate is suctioned off, washed with water, and dried. The crude product (1 g) can be recrystallized from diethyl ether. Yield 720 mg.
EXAMPLE 49d
Production of 6-(3-Hydroxyphenyl)-4-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine
A suspension of 980 mg of triflate (the Example given above) in 25 ml of propanol is mixed with 1 ml of hydrazine hydrate (80%), and the mixture is stirred for 6 hours at a bath temperature of 100° C. After some length of time, the reaction solution is homogeneous. To complete the reaction, another 0.4 ml of hydrazine hydrate solution is added after three hours. The product precipitates while the reaction solution cools. The precipitate is suctioned off, washed with propanol and ether, and ultimately dried. Yield 420 mg.
1H-NMR (DMSO-d6) δ=4.68 (s, 2H); 6.86 (dd, 1H); 7.29 (t, 1H); 7.45 (s, 1H); 7.59 (m, 2H); 7.70 (d, 2H); 8.76 (d, 2H); 9.55 (brs, 1H); 12.42 (s, 1H) ppm.
The following compounds are produced analogously to the above-described examples:
EXAMPLE 50
4-(4-Chlorophenyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridin-3-ylamine
EXAMPLE 51
6-Cyclopropyl-4-(3,4-dichlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine
EXAMPLE 52
5-[3-Amino-6-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-2-methoxyphenol
EXAMPLE 53
6-Pyridin-3-yl-4-quinolin-3-yl-1H-pyrazolo[3,4-b]pyridin-3-ylamine
EXAMPLE 54
6-(3-Chlorophenyl)-4-(1H-indol-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine
EXAMPLE 55
4-[3-Amino-6-(3-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-benzonitrile
EXAMPLE 56
4-(4-Chlorophenyl)-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-3-ylamine
EXAMPLE 57
6-Cyclopropyl-4-(3-nitrophenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine
EXAMPLE 58
6-(4-Morpholin-4-yl-phenyl)-4-pyridin-4-yl-1H-pyrazolo[3,4-b]pyridin-3-ylamine
EXAMPLE 59
4-[4-(3-Dimethylaminopropoxy)phenyl]-6-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine
EXAMPLE 60
6-Cyclopropyl-4-(4-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine
EXAMPLE 61
4-(3-Amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-benzonitrile
EXAMPLE 62
4-(1H-Imidazol-2-yl)-6-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine
EXAMPLE 63
Production of 6-tert-Butyl-4-(4-nitro-phenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
EXAMPLE 63a
Production of 6-tert-Butyl-4-(4-nitro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Analogously to Example 1a), 1.55 g of product is obtained from 10 g of ammonium acetate, 1.8 ml of cyanoacetic acid ethyl ester, 2.1 ml of 3,3-dimethyl-2-butanone, and 3 g of 4-nitrobenzaldehyde.
1H-NMR (d6-DMSO): δ=1.33 (9H); 6.30 (1H); 7.93 (2H); 8.38 (2H); 12.46 (1H) ppm.
EXAMPLE 63b
Production of 6-tert-Butyl-3-cyano-4-(4-nitro-phenyl)-2-trifluoromethanesulfonylpyridine
Analogously to Example 3b), 1.85 g of product is obtained from 1.55 g of the substance that is described under Example 63a) and 2.63 ml of trifluoromethanesulfonic acid anhydride in pyridine.
1H-NMR (CDCl3): δ=1.41 (9H); 7.48 (1H); 7.78 (2H); 8.43 (2H) ppm.
EXAMPLE 63c
Production of 6-tert-Butyl-4-(4-nitro-phenyl)-1H-pyrazolo[3,4b]pyridin-3-ylamine
Analogously to Example 1c), 969 mg of product is produced from 1.85 g of the compound, described under Example 63b), with 800 μl of hydrazine hydrate solution (80%) in propanol.
1H-NMR (d6-DMSO): δ=1.39 (9H); 4.58 (2H); 7.87 (2H); 8.38 (2H); 12.30 (1H) ppm.
Biological Testing of the Compounds
Test System for EphB4
A mixture that consists of 20 ng/ml of recombinant EphB4 kinase (related to ProQinase GmbH, Freiburg, Germany), 2.67 μg/ml of polyGluAlaTyr, 2 μmol of ATP, 25 mmol of HEPES (pH 7.3), 5 mmol of MgCl2, 1 mmol of MnCl2, 2 mmol of DTT, 0.1 mmol of NaVO4, 1% (v/v) glycerol, 0.02% NP40, EDTA-free protease inhibitors (Complete Fa. [Company] Roche, 1 tablet in 50 ml) is incubated at 20° C. for 10 minutes. Test substances are dissolved in 100% DMSO and introduced in 0.017× volume before the beginning of the reaction. 60 minutes after the addition of 1.7× volume of a solution of 50 mmol of Hepes, pH 7.0, 0.2% BSA, 0.14 μg/ml of PT66-europium, 3.84 μg/ml of SA-XL665, and 75 mmol of EDTA, the batch is measured in a Discovery HTRF-measuring device of the PerkinElmer Company.
The following compounds, i.a., inhibit the EphB4 kinase with an IC50 that is less than 10 μmol: Examples 6, 12, 14, 16, 33, 35, 39, 40, 41, 51, etc. The IC50 of compound 6 is, for example, 6.1 μm.
This illustrates that the substances according to the invention inhibit protein tyrosine kinases, in particular Eph receptors, and here in particular EphB4.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.
The entire disclosures of all applications, patents and publications, cited herein and of corresponding German application No. 10 2004 061 288.9, filed Dec. 14, 2004, and U.S. Provisional Application Ser. No. 60/636,690, filed Dec. 17, 2004, are incorporated by reference herein.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
|
11302307
|
bayer schering pharma ag
|
USA
|
B2
|
Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
|
Open
|
514/183
|
|
Mar 31st, 2022 03:13PM
|
Mar 31st, 2022 03:13PM
|
Bayer
|
Health Care
|
Health Care Equipment & Services
|
xetra:bayn
|
Bayer
|
Sep 14th, 2010 12:00AM
|
Jun 12th, 2007 12:00AM
|
https://www.uspto.gov?id=US07795264-20100914
|
Substituted arylpyrazolopyridines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same
|
The invention relates to substituted arylpyrazolopyridines according to the general formula (I):
in which A, B, D, E, Ra, R1, R2, R3, R4, R5 and q are as defined in the claims, and salts thereof, to pharmaceutical compositions comprising said substituted arylpyrazolopyridines, to methods of preparing said substituted arylpyrazolopyridines as well as the use thereof for manufacturing a pharmaceutical composition for the treatment of diseases of dysregulated vascular growth or of diseases which are accompanied with dysregulated vascular growth, wherein the compounds effectively interfere with Tie2 signalling.
|
7795264
|
1. A compound of formula (I):
in which:
R1 represents —C(O)Rb or is selected from C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by R6;
R2 stands for hydrogen, —NRd1Rd2, —C(O)Rb, or is selected from branched or unbranched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-heterocycloalkyl, aryl, and heteroaryl, which in each case is unsubstituted or singly or multiply substituted, independently from each other, by R7;
R3 is selected from hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, and cyano;
R4, R5, R6, R7,
R8 independently from each other, are selected from hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, and —OP(O)(ORc)2, wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R4, R5, R6, and R7 are each optionally substituted one or more times, in the same way or differently, by R8, and wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R8, are optionally substituted once with R8;
Ra is hydrogen or C1-C6-alkyl;
Rb is selected from hydroxyl, —ORc, —SRc, —NRd1Rd2, and C1-C6-alkyl;
Rc is selected from hydrogen, —C(O)Rb, C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl, wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are optionally substituted one or more times, in the same way or differently, by hydroxyl, halogen, aryl, or —NRd1Rd2 and wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted once with —ORc or —OP(O)(ORc)2;
Rd1, Rd2 independently from each other are selected from hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, —C(O)Rc, —S(O)2Rb, —C(O)NRd1Rd2, —C(O)Rc, —S(O)2Rb, and —C(O)NRd1Rd2, wherein C1-C6-alkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted one or more times, in the same way or differently, by halogen, hydroxy, —ORc, —C(O)Rb, —S(O)2Rb, or —OP(O)(ORc)2 and wherein C1-C6-alkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted once by an —NRd1Rd2 group; or
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, in the same way or differently, by NH, NRd1, oxygen or sulphur, and is optionally interrupted one or more times, in the same way or differently, by a —C(O)—, —S(O)—, and/or —S(O)2—, and optionally contains one or more double bonds;
A is selected from —C(O)—, —C(S)—, —C(═NRa)—, —C(═NRa)NRa—, —S(O)2—, —S(O)(═NRa)—, —S(═NRa)2—, —C(S)NRa—, —C(O)C(O)—, —C(O)C(O)NRa—, —C(O)NRaC(O)—, —C(S)NRaC(O)—, and —C(O)NRaC(S)—;
B is a bond, C1-C6-alkylene, or C3-C10-cycloalkylene;
D, E are, independently from each other, arylene or heteroarylene; and
q represents an integer of 0, 1, or 2;
or a salt or an N-oxide thereof, or an in vivo hydrolysable ester thereof,
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different.
2. The compound according to claim 1, wherein:
R1 represents —C(O)Rb or is selected from C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by R6;
R2 stands for hydrogen, —NRd1Rd2, or —C(O)Rb, or is selected from branched or unbranched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-heterocycloalkyl, aryl, and heteroaryl, which in each case is unsubstituted or singly or multiply substituted independently from each other by R7;
R3 is hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, or cyano;
R4, R5, R6, R7,
R8 independently from each other, are each selected from hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, and —OP(O)(ORc)2, wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R4, R5, R6, and R7, are each optionally substituted one or more times by R8, and wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R8, are optionally substituted once with R8;
Ra is hydrogen or C1-C6-alkyl;
Rb is selected from hydroxyl, —ORc, —SRc, —NRd1Rd2, and C1-C6-alkyl;
Rc is selected from hydrogen, —C(O)Rb, C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl, wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted one or more times by hydroxyl, halogen, aryl, or —NRd1Rd2, and wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted once by —ORc or —OP(O)(ORc)2;
Rd1, Rd2 independently from each other are each hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, —C(O)Rc, —S(O)2Rb, or —C(O)NRd1Rd2, wherein C1-C6-alkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted one or more times, in the same way or differently, by halogen, hydroxy, —ORc, —C(O)Rb, —S(O)2Rb, or —OP(O)(ORc)2, and wherein C1-C6-alkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted once by —NRd1Rd2; or
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NRd1, oxygen or sulphur, and is optionally interrupted one or more times, the same way or differently, by a —C(O)—, —S(O)—, and/or —S(O)2— group, and optionally contains one or more double bonds;
A is selected from —C(O)—, —S(O)2—, —C(S)NRa—, —C(O)C(O)—, —C(O)C(O)NRa—, —C(O)NRaC(O)—, —C(S)NRaC(O)—, and —C(O)NRaC(S)—;
B is a bond, C1-C6-alkylene, or C3-C10-cycloalkylene;
D is phenylene;
E is phenylene or 5- or 6-membered heteroarylene; and
q represents an integer of 0 or 1;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different.
3. The compound according to claim 1, wherein:
R1 represents —C(O)Rb or is selected from C1-C6-alkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by R6;
R2 stands for hydrogen, or is selected from branched or unbranched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-heterocycloalkyl, aryl, and heteroaryl, which in each case is unsubstituted or singly or multiply substituted independently from each other by R7;
R3 is hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, or cyano;
R4, R5, R6, R7,
R8 independently from each other, are selected from hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, and —OP(O)(ORc)2, wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R4, R5, R6, and R7, are each optionally substituted one or more times by R8, and wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R8, are optionally substituted once with R8;
Ra is hydrogen or C1-C6-alkyl;
Rb is selected from hydroxyl, —ORc, —SRc, —NRd1Rd2, and C1-C6-alkyl;
Rc is selected from hydrogen, —C(O)Rb, C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl, wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted one or more times by hydroxyl, halogen, aryl, or —NRd1Rd2, and wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted once with —ORc or —OP(O)(ORc)2;
Rd1, Rd2 independently from each other are each hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, —C(O)Rc, —S(O)2Rb, or —C(O)NRd1Rd2, wherein C1-C6-alkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted one or more times, in the same way or differently, by halogen, hydroxy, —ORc, —C(O)Rb, —S(O)2Rb, or —OP(O)(ORc)2, and wherein C1-C6-alkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted once by —NRd1Rd2; or
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NRd1, oxygen or sulphur, and is optionally interrupted one or more times, the same way or differently, by —C(O)—, —S(O)—, and/or —S(O)2—, and optionally contains one or more double bonds;
A is —C(O)— or —S(O)2—;
B is a bond, C1-C6-alkylene, or C3-C10-cycloalkylene;
D is para-phenylene;
E is phenylene or 5- or 6-membered heteroarylene; and
q represents an integer of 0 or 1;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different.
4. The compound according to claim 1, wherein:
R1 represents —C(O)Rb, or is C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by R6;
R2 is H, or is branched or unbranched C1-C6 alkyl, C3-C6-heterocycloalkyl, aryl, or heteroaryl, which in each case is unsubstituted or singly or multiply substituted, independently from each other, by R7;
R3 is hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6 haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, or cyano;
R4 is hydrogen, C1-C6-alkyl, C1-C6 haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano, nitro, or —ORc, wherein C1-C6-alkyl is optionally substituted one or more times by R8;
R5 is hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6 haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are each optionally substituted one or more times by R8;
R6 is hydrogen, C3-C6-heterocycloalkyl, C1-C6-haloalkoxy, aryl, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C3-C6-heterocycloalkyl is optionally substituted one or more times by R8;
R7 is hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6 haloalkyl, C1-C6haloalkoxy, aryl, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are each optionally substituted one or more times by R8;
R8 is C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2;
Ra is hydrogen;
Rb is —ORc—NRd1Rd2, and C1-C6-alkyl;
Rc is hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl are each optionally substituted one or more times, in the same way or differently, by —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl are each optionally substituted once by —ORc;
Rd1, Rd2 independently from each other are hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C(O)Rc or —C(O)NRd1Rd2, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted one or more times, in the same way or differently, by —ORc, or —C(O)Rb, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted once by —NRd1Rd2; or
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NRd1, or oxygen;
A is —C(O)— or —S(O)2—;
B is a bond C1-C3-alkylene, or C3-C6-cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being be identical or different.
5. The compound according to claim 1, wherein:
R1 represents —C(O)Rb or is C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by R6;
R2 is H, or is branched or unbranched C1-C6-alkyl, or C3-C6-heterocycloalkyl, which in each case is unsubstituted or singly or multiply substituted independently from each other by R7;
R3 is hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6 haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, or cyano;
R4 is hydrogen, C1-C6-alkyl, C1-C6 haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, nitro, halogen, or —ORc, wherein C1-C6-alkyl is optionally substituted one or more times by R8;
R5 is hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6 haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, nitro, halogen, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2; wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times by R8;
R6 is hydrogen, C3-C6-heterocycloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C3-C6-heterocycloalkyl is optionally substituted one or more times by R8;
R7 is hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6 haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, S(O)2Rb, —ORc, or —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are each optionally substituted one or more times by R8;
R8 is C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2;
Ra is hydrogen;
Rb is selected from —ORc, —NRd1Rd2, and C1-C6-alkyl;
Rc is hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl are each optionally substituted one or more times by —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl are optionally substituted once by —ORc;
Rd1, Rd2 independently from each other are selected from hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, —C(O)Rc and —C(O)NRd1Rd2, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted one or more times, in the same way or differently, by —ORc, or —C(O)Rb, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted once by —NRd1Rd2; or,
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NRd1, or oxygen;
A is —C(O)— or —S(O)2—;
B is a bond, C1-C3-alkylene, or C3-cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different.
6. The compound according to claim 1, wherein:
R1 represents —C(O)Rb or is selected from C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl, which in each case is unsubstituted or substituted one or more times,
independently from each other, by R6;
R2 stands for hydrogen, or branched or unbranched C1-C6-alkyl;
R3 is hydrogen, methyl, or fluoro;
R4 is hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, or —ORc, wherein C1-C6-alkyl is optionally substituted one or more times by R8;
R5 is hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are each optionally substituted one or more times by R8;
R6 is hydrogen, C3-C6-heterocycloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C3-C6-heterocycloalkyl is optionally substituted one or more times by R8;
R8 is C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2;
Ra is hydrogen;
Rb is selected from —ORc, and —NRd1Rd2;
Rc is hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are each optionally substituted one or more times by —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl are each optionally substituted once by —ORc;
Rd1, Rd2 independently from each other are selected from hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C(O)Rc and —C(O)NRd1Rd2, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted one or more times, in the same way or differently, by —ORc, or —C(O)Rb, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted once by —NRd1Rd2; or,
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NRd1, or oxygen;
A is —C(O)— or —S(O)2—;
B is a bond, C1-C3-alkylene, or C3-cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd3 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different.
7. The compound according to claim 1, wherein:
R1 is C1-C6-alkyl;
R2 stands for hydrogen, or branched or unbranched C1-C6-alkyl, wherein C1-C6-alkyl is unsubstituted or singly or multiply substituted, independently from each other, by R7;
R3 is hydrogen, methyl, or fluoro;
R4 is hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, or —ORc, wherein C1-C6-alkyl is optionally substituted one or more times by R8;
R5 is hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are each optionally substituted one or more times by R8;
R7 is hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are each optionally substituted one or more times by R8;
R8 is C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2;
Ra is hydrogen;
Rb is —ORc or —NRd1Rd2;
Rc is hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl are each optionally substituted one or more times by —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl are each optionally substituted once by —ORc;
Rd1, Rd2 independently from each other are selected from hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, —C(O)Rc and —C(O)NRd1Rd2 group, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted one or more times, in the same way or differently, by —ORc, or —C(O)Rb, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted once by —NRd1Rd2; or,
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NRd1, or oxygen;
A is —C(O)— or —S(O)2—;
B is a bond, C1-C3-alkylene, or C3-cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 r R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different.
8. The compound according to claim 1 wherein:
R1 is C1-C3-alkyl;
R2 stands for hydrogen or branched or unbranched C1-C6-alkyl;
R3 is hydrogen, methyl, or fluoro;
R4 is hydrogen, halogen, C1-C3-alkyl, or C1-C3-haloalkyl;
R5 is hydrogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-haloalkoxy, halogen, —ORc, or —NRd1Rd2, wherein C1-C3-alkyl is optionally substituted by R8;
R8 is —ORc or —NRd1Rd2;
Ra is hydrogen;
Rc is hydrogen or C1-C3-alkyl, wherein C1-C3-alkyl is optionally substituted one or more times by —NRd1Rd2, and wherein C1-C3-alkyl is optionally substituted once by —ORc;
Rd1, Rd2 independently from each other are selected from hydrogen and C1-C3-alkyl, wherein C1-C3-alkyl is optionally substituted one or more times, in the same way or differently, by —ORc, and wherein C1-C3-alkyl is optionally substituted once by —NRd1Rd2; or,
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 6 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one time, by NH, NRd1, or oxygen;
A is —C(O)—;
B is C1-C3 alkylene or C3-cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1 or Rd2 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1 or Rd2 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1 or Rd2 within a single molecule to be identical or different.
9. The compound according to claim 1, wherein said compound is selected from:
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-2-phenyl-acetamide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-4-methoxy-benzamide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-4-chloro-benzamide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-C-phenyl-methanesulfonamide;
1-Phenyl-cyclopropanecarboxylic acid [4-(3-amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-2-(3-methoxy-phenyl)-acetamide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-2-phenyl-butyramide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-2-phenyl-isobutyramide;
1-(3-Methoxy-phenyl)-cyclopropane-carboxylic acid [4-(3-amino-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide;
1-(3-Trifluoromethyl-phenyl)-cyclopropane-carboxylic acid [4-(3-amino-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide;
1-(4-Trifluoromethyl-phenyl)-cyclopropane-carboxylic acid [4-(3-amino-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide;
1-(4-Methoxy-phenyl)-cyclopropane-carboxylic acid [4-(3-amino-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide;
1-Phenyl-cyclopropanecarboxylic acid [4-(3-amino-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide; and
pharmaceutically acceptable salts thereof.
10. A method of preparing a compound according to claim 1, said method comprising:
reacting a compound of formula 6
in which X represents a leaving group,
with a substituted hydrazine of formula 6′:
H2N—NHR1, 6′
to provide a compound of formula (I):
11. A method of preparing a compound of general formula (I) according to claim 1, said method comprising:
deprotecting an intermediate compound of formula 10
wherein
represents a phthalimide-protected amine of formula 10′:
by reaction with hydrazine,
to provide a compound of formula (I):
12. A method of preparing a compound according to claim 1, said method comprising:
reacting the step of allowing an intermediate compound of formula 11:
with a compound of formula 11′:
X′—R1 11′
wherein X′ is a leaving group,
to provide a compound of formula (I):
13. A pharmaceutical composition comprising a compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, and a pharmaceutically-acceptable diluent or carrier.
14. The compound according to claim 1, wherein R8 is hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, and —OP(O)(ORc)2.
15. The compound according to claim 1, wherein R8 is C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2.
16. The compound according to claim 1, wherein
Ra is H;
R2 is H or C1-C6-alkyl;
R3 is H;
A is —C(O)— or —S(O)2—;
B is a bond, C1-C3-alkylene, or C3-cycloalkylene;
D is para-phenylene;
E is phenylene; and
q is 0.
17. The compound according to claim 1, wherein said compound is selected from:
18. The compound according to claim 1, wherein R2 is hydrogen.
19. The compound according to claim 1, wherein R2 is methyl.
20. The compound according to claim 1, wherein R2 is tert-butyl.
21. The compound according to claim 1, wherein R2 is branched or unbranched C1-C6-alkyl which is singly or multiply substituted by R7.
22. A process according to claim 10, where in X is trifluoromethylsulphonyl, Cl, F, acetate, or methoxy.
23. A process according to claim 12, where in X′ is trifluoromethylsulphonyl, Cl, Br, I, methanesulfonyl, or acetate.
|
23
|
This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 60/816,625, filed Jun. 27, 2006, which is incorporated by reference herein.
The present invention relates to substituted arylpyrazolopyridine compounds of general formula (I) and salts thereof, to pharmaceutical compositions comprising said substituted arylpyrazolopyridine compounds, to methods of preparing said substituted arylpyrazolopyridines as well as to the use thereof.
SCIENTIFIC BACKGROUND
Dysregulated vascular growth plays a critical role in a variety of inflammatory diseases, in particular psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, rheumatoid arthritis and inflammatory bowl disease. Aberrant vascular growth is also involved in neovascular ocular diseases such as age-related macular degeneration and diabetic retinopathy. Additionally, sustained vascular growth is accepted as one hallmark of cancer development (Hanahan, D.; Weinberg, R. A. Cell 2000, 100, 57). While tumours initially grow either as an avascular mass or by co-opting existing host vessels, growth beyond a few mm3 in size is depending on the induction of vessel neogrowth in order to sufficiently provide the tumour with oxygen and nutrients. Induction of angiogenesis is a prerequisite that the tumour surpasses a certain size (the so called angiogenic switch). An intricate signalling interaction network between cancer cells and the tumour microenvironment triggers the induction of vessel growth from existing vasculature. The dependence of tumours on neovascularization has led to a new treatment paradigm in cancer therapy (Ferrara et al. Nature 2005, 438, 967; Carmeliet Nature 2005, 438, 932). Blocking tumour neovascularization by small molecule or antibody-mediated inhibition of relevant signal transduction pathways holds a great promise for extending currently available therapy options.
The development of the cardiovascular system involves two basic stages. In the initial vasculogenesis stage, which only occurs during embryonal development, angioblasts differentiate into endothelial cells which subsequently form a primitive vessel network. The subsequent stage, termed angiogenesis, involves the remodeling of the initial vasculature and sprouting of new vessels (Risau, W. Nature 1997, 386, 671; Jain, R. K. Nat. Med. 2003, 9, 685). Physiologically, angiogenesis occurs in wound healing, muscle growth, the female cycle and in the above mentioned disease states.
It has been found that receptor tyrosine kinases of the vascular endothelial growth factor (VEGF) family and the Tie (tyrosine kinase with immunoglobulin and epidermal growth factor homology domain) receptor tyrosine kinases are essential for both developmental and disease-associated angiogenesis (Ferrara et al Nat. Med. 2003, 9, 669; Dumont et al. Genes Dev. 1994, 8, 1897; Sato et al. Nature 1995, 376, 70).
In adults the Tie2 receptor tyrosine kinase is selectively expressed on endothelial cells (EC) of the adult vasculature (Schlaeger et al. Proc. Nat. Acad. Sci. USA 1997, 94, 3058). Immunohistochemical analysis demonstrated the expression of Tie2 in adult rat tissues undergoing angiogenesis. During ovarian folliculogenesis, Tie2 is expressed in neovessels of the developing corpus luteum. Four endogeneous ligands—angiopoietins 1 to 4—have been identified for the type 1 transmembrane Tie2 (also named Tek) receptor, while no ligands have been identified so far for the Tie1 receptor. Binding of the extracellular Tie2 domain to the C-terminal fibrinogen-like domains of the various angiopoietins leads to significantly different cellular effects. In addition, heterodimerizations between Tie1 and Tie2 receptors have been postulated to influence ligand binding.
Binding of Ang1 to Tie2 expressed on EC induces receptor cross-phosphorylation and kinase activation thus triggering various intracellular signalling pathways. The intracellular C-terminal tail of the Tie2 protein plays a crucial role in Tie2 signalling (Shewchuk et al. Structure 2000, 8, 1105). Upon ligand binding, a conformational change is induced which removes the C-tail out of its inhibitory conformation thus allowing kinase activation by cross-phoshorylation of various Tyr residues in the C-tail, which subsequently function as docking sites for phosphotyrosine-binding (PTB) site possessing down-stream mediators. Cellular effects initiated by Ang1 activation of Tie2 include inhibition of EC apoptosis, stimulation of EC migration and blood vessel reorganization, suppression of inflammatory gene expression and suppression of vascular permeability (Brindle et al. Circ. Res. 2006, 98, 1014). In contrast to VEGF-VEGFR signalling in EC, Ang1 activation of Tie2 does not stimulate EC proliferation in the majority of published assay settings.
The anti-apoptotic effect of Tie2 signalling was shown to be mediated mainly by the PI3K-Akt signalling axis which is activated by binding of the regulatory p85 subunit of PI3K to Y1102 in the Tie2 C-tail (DeBusk et al. Exp. Cell. Res. 2004, 298, 167; Papapetropoulos et al. J. Biol. Chem. 2000, 275, 9102; Kim et al. Circ. Res. 2000, 86, 24). In contrast, the chemotactic response downstream of the activated Tie2 receptor requires crosstalk between PI3K and the adaptor protein Dok-R. Membrane localization of Dok-R via binding of its plekstrin homology (PH) domain to PI3K and simultaneous binding to Y1108 in the Tie2 C-tail via its PTB domain leads to Dok-R phoshorylation and downstream signalling via Nck and Pak-1 (Jones et al. Mol. Cell Biol. 2003, 23, 2658; Master et al. EMBO J. 2001, 20, 5919). PI3K-mediated recruitment of the adaptor protein ShcA to Y1102 of the Tie2 C-tail is also believed to induce cellular sprouting and motility effects involving activation of endothelial nitric oxide synthase (eNOS), focal adhesion kinase (FAK) and the GTPases RhoA and Rac1. Other downstream mediators of Tie2 signalling include the adaptor protein Grb2, which mediates Erk1/2 stimulation, and the SHP-2 phosphatase.
In conclusion, basal activation of the Tie2 pathway by Ang1 is believed to maintain quiescence and integrity of the endothelium of the adult vasculature by providing a cell survival signal for ECs and by maintaining the integrity of the EC lining of blood vessels (Peters et al. Recent Prog. Horm. Res. 2004, 59, 51).
In contrast to Ang1, Ang2 is not able to activate Tie2 on EC unless Ang2 is present in high concentration or for prolonged periods. However, Ang2 functions as a Tie2 agonist in non-endothelial cells tranfected with Tie2. The structural basis for this context-dependence of the Ang2-Tie2 interaction is to date not understood.
In endothelial cells, however, Ang2 functions as Tie2 antagonist and thus blocks the agonistic activity of Ang1 (Maisonpierre et al. Science 1997, 277, 55). Ang2 binding to Tie2 prevents Ang1-mediated Tie2 activation which leads to vessel destabilization and results in vessel regression in the absence of pro-angiogenic stimuli such as VEGF. While Ang1 is widely expressed by periendothelial cells in quiescent vasculature such as pericytes or smooth muscle cells, Ang2 expression occurs in areas of ongoing angiogenesis. Ang2 can be stored in Weibel-Palade bodies in the cytoplasm of EC allowing for a quick vascular response upon stimulation.
Ang1 and Ang2 are expressed in the corpus luteum, with Ang2 localizing to the leading edge of proliferating vessels and Ang1 localizing diffusively behind the leading edge. Ang2 expression is inter alia initiated by hypoxia (Pichiule et al. J. Biol. Chem. 2004, 279, 12171). Ang2 is upregulated in the tumour vasculature and represents one of the earliest tumour markers. In the hypoxic tumour tissue, Ang2 expression induces vessel permeability and—in the presence of e.g. pro-angiogenic VEGF—triggers angiogenesis. After VEGF mediated EC proliferation and vessel sprouting maturation of the newly formed vessels again necessitates Tie2 activation by Ang1. Therefore, a subtle balancing of Tie2 activity plays a pivotal role in the early as well as late stages of neovascularization. These observations render the Tie2 RTK an attractive target for anti-angiogenesis therapy in diseases caused by or associated with dysregulated vascular growth. However, it remains to be shown if targeting the Tie2 pathway alone will be sufficient to achieve efficacious blockade of neovascularization. In certain diseases or disease subtypes it might be necessary or more efficacious to block several angiogenesis-relevant signalling pathways simultaneously.
Various theories have been discussed to explain the differential effects of Ang1 and Ang2 on Tie2 downstream signalling events. Binding of Ang1 and Ang2 in a structurally different manner to the Tie2 ectodomain could induce ligand-specific conformational changes of the intracellular kinase domain explaining different cellular effects. Mutational studies however point toward similar binding sites of Ang1 and Ang2. In contrast, various publications have focussed on different oligomerization states of Ang1 vs. Ang2 as basis for different receptor multimerization states upon ligand binding. Only Ang1 present in its tetramer or higher-order structure initiates Tie2 activation in EC while Ang2 was reported to exist as a homodimer in its native state (Kim et al. J. Biol. Chem. 2005, 280, 20126; Davis et al. Nat. Struc. Biol. 2003, 10, 38; Barton et al. Structure 2005, 13, 825). Finally, specific interactions of Ang1 or Ang2 with additional cell-specific co-receptors could be responsible for the different cellular effects of Ang1 vs. Ang2 binding to Tie2. Interaction of Ang1 with integrin α5β1 has been reported to be essential for certain cellular effects (Carlson et al. J. Biol. Chem. 2001, 276, 26516; Dallabrida et al. Circ. Res. 2005, 96, e8). Integrin α5β1 associates constitutively with Tie2 and increases the receptor's binding affinity for Ang1 resulting in initiation of downstream signalling at lower Ang1 effector concentrations in situations where integrin α5β1 is present. The recently solved crystal structure of the Tie2-Ang2 complex suggests however that neither the oligomerization state nor a different binding mode causes the opposing cellular effects (Barton et al. Nat. Struc. Mol. Biol. 2006, advance online publication).
Ang1-Tie2 signalling plays also a role in the development of the lymphatic system and in lymphatic maintenance and sprouting (Tammela et al. Blood 2005, 105, 4642). An intimate cross-talk between Tie2 and VEGFR-3 signalling in lymphangiogenesis seems to equal the Tie2-KDR cross-talk in blood vessel angiogenesis.
A multitude of studies have underscored the functional significance of Tie2 signalling in the development and maintenance of the vasculature. Disruption of Tie2 function in Tie2−/− transgenic mice leads to early embryonic lethality between days 9.5 and 12.5 as a consequence of vascular abnormalities. Tie2−/− embryos fail to develop the normal vessel hierachy suggesting a failure of vascular branching and differentiation. The heart and vessels in Tie2−/− embryos show a decreased lining of EC and a loosened interaction between EC and underlying pericyte/smooth muscle cell matrix. Mice lacking functional Ang1 expression and mice overexpressing Ang2 display a phenotype reminiscent of the phenotype of Tie2−/− mice (Suri et al. Cell 1996, 87, 1171). Ang2−/− mice have profound defects in the growth and patterning of lymphatic vasculature and fail to remodel and regress the hyaloid vasculature of the neonatal lens (Gale et al. Dev. Cell 2002, 3, 411). Ang1 rescued the lymphatic defects, but not the vascular remodelling defects. Therefore, Ang2 might function as a Tie2 antagonist in blood vasculature but as a Tie2 agonist in developing lymph vasculature suggesting redundant roles of Ang1 and Ang2 in lymphatic development.
Aberrant activation of the Tie2 pathway is involved in various pathological settings. Activating Tie2 mutations leading to increased ligand-dependent and ligand-independent Tie2 kinase activity cause inherited venous malformations (Vikkula et al. Cell 1996, 87, 1181). Increased Ang1 mRNA and protein levels as well as increased Tie2 activation have been reported in patients with pulmonary hypertension (PH). Increased pulmonary arterial pressure in PH patients results from increased coverage of pulmonary arterioles with smooth muscle cells (Sullivan et al. Proc. Natl. Acad. Sci. USA 2003, 100, 12331). In chronic inflammatory diseases, like in psoriasis, Tie2 and the ligands Ang1 and Ang2 are greatly upregulated in lesions, whereas a significant decrease in expression of Tie2 and ligands occur under anti-psoriatic treatment (Kuroda et al. J. Invest. Dermatol 2001, 116, 713). Direct association of pathogenesis of disease with Tie2 expression has been demonstrated recently in transgenic mice overexpressing Tie2 (Voskas et al. Am. J. Pathol. 2005, 166, 843). In these mice overexpression of Tie2 causes a psoriasis-like phenotype (such as epidermal thickening, rete ridges and lymphocyte infiltration). These skin abnormalities are resolved completely upon suppression of transgene expression, thereby illustrating a complete dependence on Tie2 signalling for disease maintenance and progression.
Tie2 expression was investigated in human breast cancer specimens and Tie2 expression was found in the vascular endothelium both in normal breast tissue as well as in tumour tissue. The proportion of Tie2-positive microvessels was increased in tumours as compared to normal breast tissue (Peters et al. Br. J. Canc. 1998, 77, 51). However, significant heterogeneity in endothelial Tie2 expression was observed in clinical specimen from a variety of human cancers (Fathers et al. Am. J. Path. 2005, 167, 1753). In contrast, Tie2 and angiopoietins were found to be highly expressed in the cytoplasm of human colorectal adenocarcinoma cells indicating at the potential presence of an autocrine/paracrine growth loop in certain cancers (Nakayama et al. World J. Gastroenterol. 2005, 11, 964). A similar autocrine/paracrine Ang1-Ang2-Tie2 loop was postulated for certain human gastric cancer cell lines (Wang et al. Biochem. Biophys. Res. Comm. 2005, 337, 386).
The relevance of the Ang1-Tie2 signalling axis was challenged with various biochemical techniques. Inhibition of Ang1 expression by an antisense RNA approach resulted in decreased xenograft tumour growth (Shim et al. Int. J. Canc. 2001, 94, 6; Shim et al. Exp. Cell Research 2002, 279, 299). However, other studies report that experimental overexpression of Ang1 in tumour models leads to decreased tumour growth (Hayes et al. Br. J. Canc. 2000, 83, 1154; Hawighorst et al. Am. J. Pathol. 2002, 160, 1381; Stoeltzing et al. Cancer Res. 2003, 63, 3370). The latter results can be rationalized by the ligand's ability to stabilize the endothelial lining of vessels rendering vessels less sensitive for angiogenic stimuli. Interference with the dynamics of Ang1-Tie2 signalling either by over-stimulation or by stimulus deprivation seemingly leads to similar phenotypes.
The pharmacological relevance of inhibiting Tie2 signalling was tested applying various non-small molecule approaches. A peptidic inhibitor of Ang1/2 binding to Tie2 was shown to inhibit Ang1-induced HUVEC migration and angiogenesis induction in an in vivo model (Tournaire et al. EMBO Rep. 2005, 5, 1). Corneal angiogenesis induced by tumour cell conditioned medium was inhibited by a recombinant soluble Tie2 receptor (sTie2) despite the presence of VEGF (Lin et al. J. Clin. Invest. 1997, 100, 2072; see also Singh et al. Biochem. Biophys. Res. Comm. 2005, 332, 194). Gene therapy by adenoviral vector delivered sTie2 was capable of reducing tumour growth rates of a murine mammary carcinoma and a murine melanoma and resulted in reduction of metastasis formation (Lin et al. Proc. Natl. Acad. Sci. USA 1998, 95, 8829). Similar effects were observed with related sTie2 constructs (Siemeister et al. Cancer Res. 1999, 59, 3185) and a Tek-Fc construct (Fathers et al. Am. J. Path. 2005, 167, 1753).
Adenovirus-delivered anti-Tie2 intrabodies were shown to inhibit growth of a human Kaposi's sarcoma and a human colon carcinoma upon peritumoural administration (Popkov et al. Cancer Res. 2005, 65, 972). Histopathological analysis revealed a marked decrease in vessel density in treated vs. control tumours. Phenotypic simultaneous knockout of KDR and Tie2 by an adenovirus delivered intradiabody resulted in significantly higher growth inhibition of a human melanoma xenograft model than KDR knockout alone (Jendreyko et al. Proc. Natl. Acad. Sci. USA 2005, 102, 8293). Similarly, the bispecific Tie2-KDR intradiabody was more active in an in vitro EC tube formation inhibition assay than the two monospecific intrabodies alone (Jendreyko et al. J. Biol. Chem. 2003, 278, 47812). Systematic treatment of tumour-bearing mice with Ang2-blocking antibodies and peptide-Fc fusion proteins led to tumour stasis and elimination of tumour burden in a subset of animals (Oliner et al. Cancer Cell 2004, 6, 507). For a recent report on an immunization approach, see Luo et al. Clin. Cancer Res. 2006, 12, 1813.
However, from the above studies using biochemical techniques to interfere with Tie2 signalling it is not clear, whether similar phenotypes will be observed with small molecule inhibitors of the Tie2 kinase activity. Small molecule inhibitors of kinases by definition block only those cellular effects which are mediated by the receptor's kinase activity and not those which might involve the kinase only as a co-receptor or scaffolding component in multi-enzyme complexes. So far, only a single study using a small molecule Tie2 inhibitor has been published (Scharpfenecker et al. J. Cell Sci. 2005, 118, 771). It remains to be shown that small molecule inhibitors of the Tie2 kinase will be as efficacious in inhibiting angiogenesis as e.g. ligand antibodies, soluble decoy receptors or receptor intrabodies. As discussed above, in certain settings inhibition of Tie2 signalling alone might not be sufficient to induce an adequate antiangiogenic effect. Simultaneous inhibition of several angiogenesis relevant signalling pathways could overcome such inadequacies. In conclusion, there is a great need for novel chemotypes for small mocule inhibitors of the Tie2 kinase. Fine tuning of additive anti-angiogenic activities as well as pharmacokinetic parameters such as e.g. solubility, membrane permeability, tissue distribution and metabolism will finally allow for chosing compounds of accurate profiles for various diseases caused by or associated with dysregulated vascular growth.
PRIOR ART
To date, a small number of therapeutic agents with antiangiogenic activity have been approved for cancer treatment. Avastin (Bevacizumab), a VEGF neutralizing antibody, blocks KDR and VEGFR1 signalling and has been approved for first-line treatment of metastatic colorectal cancer. The small molecule multi-targeted kinase inhibitor Nexavar (Sorafenib) inhibits inter alia members of the VEGFR family and has been approved for the treatment of advanced renal cell carcinoma. Sutent (Sunitinib), another multi-targeted kinase inhibitor with activity vs. VEGFR family members, has been approved by the FDA for treatment of patients with gastrointestinal stromal tumours (GIST) or advanced kidney tumours. Several other small molecule inhibitors of angiogenesis-relevant targets are in clinical and pre-clinical development.
AMG-386, an angiopoietin-targeting recombinant Fc fusion protein, is in phase I clinical development in patients with advanced solid tumours. Several multi-targeted small molecule inhibitors with activity against Tie2 are (or have been) in preclinical evaluation for cancer therapy, including ABT-869, GW697465A and A-422885.88 (BSF466895). The first and most recent compound, however, was reported to possess higher inhibitory activity against other kinase targets including non-angiogenesis kinases and oncogenic kinases. This agent is therefore not considered to be a purely antiangiogenic agent and its applicability to non-cancer diseases remains to be shown.
Pyrazolopyridines have been disclosed as antimicrobiotic substances (e.g. Attaby et al., Phosphorus, Sulphur and Silicon and the related Elements 1999, 149, 49-64; Goda et al. Bioorg. Med. Chem. 2004, 12, 1845). A single 3-amino-1H-pyrazolo[3,4-b]pyridine with modest EGFR inhibitory activity has been published by Cavasotto et al. (Bioorg. Med. Chem. Lett. 2006, 16, 1969). 5-aryl-1H-3-aminopyrazolo[3,4-b]pyridines have been reported as GSK-3 inhibitors (Witherington et al. Bioorg. Med. Chem. Lett. 2003, 13, 1577). WO 2003068773 discloses 3-acylaminopyrazolopyridine derivatives as GSK-3 inhibitors.
DE2232038 and DE2160780 disclose 3-amino-pyrazolo[3,4-b]pyridines i.a. as intermediates for the preparation of azo-dyes.
U.S. Pat. No. 4,224,322, U.S. Pat. No. 4,260,621 and DE2643753 further disclose 3-Amino-pyrazolo[3,4-b]pyridines as antithrombotic substances.
U.S. Pat. No. 5,478,830 further discloses fused heterocycles for the treatment of atherosclerosis.
WO 2001019828 discloses 125 templates, including 3-amino-1H-pyrazolopyridines, as modulators of the activity of receptor and non-receptor tyrosine and serine/threonine kinases.
WO 2002024679 discloses tetrahydropyridine-substituted pyrazolopyridines as IKK inhibitors.
WO 2004076450 further discloses 5-heteroaryl-pyrazolopyridines as p38 inhibitors.
WO 2004113304 discloses indazoles, benzisoxazoles and benzisothiazoles as inhibitors of protein tyrosine kinases, particularly of KDR kinase. However, an exemplary compound from this patent (termed Abt-869; see above) is reported to be ˜40 times less active against Tie2 vs. KDR in enzymatic assays and even ˜1000 times less active against Tie2 than KDR in cellular assays (Albert et al. Mol. Cancer Ther. 2006, 5, 995).
WO 2006/050109 discloses pyrazolopyridines as protein tyrosine kinase inhibitors, particularly as KDR kinase inhibitors.
Technical Problem to be Solved
There is a high demand for compounds which can be used not only as potent inhibitors of Tie-2 kinase, in particular inhibitors not only of the isolated kinase domain, but more importantly of cellular Tie-2 autophosphorylation, for the treatment of diseases of dysregulated vascular growth or diseases which are accompanied with dysregulated vascular growth, but which optionally also display inhibition of a further kinase, the inhibition of which is in response to particular therapeutic needs. Said further kinase may mediate e.g. angiogenesis, inflammation, or may be involved in oncological diseases. More specifically, inhibition of Tie2 or said further kinase can be tuned according to the appropriate therapeutic needs. Such pharmacological profiles are highly desirable for treating diseases of dysregulated vascular growth or diseases which are accompanied with dysregulated vascular growth, in particular solid tumours and metastases thereof, and also for treating non-oncological diseases of dysregulated vascular growth or non-oncological diseases which are accompanied with dysregulated vascular growth, such as retinopathy, other angiogenesis dependent diseases of the eye, in particular cornea transplant rejection or age-related macular degeneration, rheumatoid arthritis, and other inflammatory diseases associated with angiogenesis, in particular psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, stroke, and diseases of the bowel, diseases such as coronary and peripheral artery disease.
DESCRIPTION OF THE INVENTION
The solution to the above-mentioned novel technical problem is achieved by providing compounds derived, in accordance with the present invention, from a class of substituted arylpyrazolopyridines and salts thereof, methods of preparing substituted arylpyrazolopyridines, a pharmaceutical composition containing said substituted arylpyrazolopyridines, use of said substituted arylpyrazolopyridines and a method for treating diseases with said substituted arylpyrazolopyridines, all in accordance with the description, as defined in the claims of the present application.
The present invention thus relates to compounds of general formula (I):
in which:
R1 represents —C(O)Rb or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times, independently from each other, with R6;
R2 stands for hydrogen, —NRd1Rd2, —C(O)Rb, or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, wherein said residues are unsubstituted or singly or multiply substituted independently from each other with R7;
R3 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano;
R4, R5, R6, R7,
R8 independently from each other, are selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, —OP(O)(ORc)2, wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R4, R5, R6, and R7, are optionally substituted one or more times, in the same way or differently, with R8, and wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R8, are optionally substituted once with R8;
Ra is selected from the group comprising, preferably consisting of, hydrogen or C1-C6-alkyl;
Rb is selected from the group comprising, preferably consisting of, hydroxyl, —ORc, —SRc, —NRdRd2, and C1-C6-alkyl;
Rc is selected from the group comprising, preferably consisting of, hydrogen, —C(O)Rb, C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted one or more times, in the same way or differently, with hydroxyl, halogen, aryl, or —NRd1Rd2, and wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted once with —ORc, or —OP(O)(ORc)2;
Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, or for a —C(O)Rc, —S(O)2Rb, or —C(O)NRd1Rd2 group, wherein C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted one or more times, in the same way or differently, with halogen, hydroxy or an —ORc, —C(O)Rb, —S(O)2Rb, OP(O)(ORc)2 group, and wherein C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted once with an —NRd1Rd2 group; or
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, in the same way or differently, by a member of the group comprising, preferably consisting of, NH, NRd1, oxygen or sulphur, and is optionally interrupted one or more times, in the same way or differently, with a —C(O)—, —S(O)—, and/or —S(O)2— group, and optionally contains one or more double bonds;
A is selected from the group comprising, preferably consisting of, —C(O)—, —C(S)—, —C(═NRa), —C(═NRa)NRa—, —S(O)2—, —S(O)(═NRa), —S(═NRa)2—, —C(S)NRa—, —C(O)C(O)—, —C(O)C(O)NRa—, —C(O)NRaC(O)—, —C(S)NRaC(O)—, and —C(O)NRaC(S)—;
B is a bond or a group selected from the group comprising, preferably consisting of C1-C6-alkylene, or C3-C10-cycloalkylene;
D, E are, independently from each other, arylene or heteroarylene; and
q represents an integer of 0, 1, or 2;
or a salt or an N-oxide, thereof,
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
In accordance with a preferred embodiment, the present invention relates to compounds of general formula (I), in which
R1 represents —C(O)Rb or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times, independently from each other, with R6;
R2 stands for hydrogen, —NRd1Rd2, —C(O)Rb, or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, wherein said residues are unsubstituted or singly or multiply substituted independently from each other with R7;
R3 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano;
R4, R5, R6, R7,
R8 independently from each other, are selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, —OP(O)(ORc)2, wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R4, R5, R6, and R7, are optionally substituted one or more times with R8, and wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R8, are optionally substituted once with R8;
Ra is selected from the group comprising, preferably consisting of, hydrogen or C1-C6-alkyl;
Rb is selected from the group comprising, preferably consisting of, hydroxyl, —ORc, —SRc, —NRd1Rd2, and C1-C6-alkyl;
Rc is selected from the group comprising, preferably consisting of, hydrogen, —C(O)Rb, C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted one or more times, in the same way or differently, with hydroxyl, halogen, aryl, or —NRd1Rd2, and wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted once with —ORc, or —OP(O)(ORc)2;
Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, or for a group —C(O)Rc, —S(O)2Rb, or —C(O)NRd1Rd2, wherein C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted one or more times, in the same way or differently, with halogen, hydroxy or an —ORc, —C(O)Rb, —S(O)2Rb, —OP(O)(ORc)2 group, and wherein C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted once with the group —NRd1Rd2; or
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group comprising, preferably consisting of, NH, NRd1, oxygen or sulphur, and is optionally interrupted one or more times, the same way or differently, with a —C(O)—, —S(O)—, and/or —S(O)2— group, and optionally contains one or more double bonds;
A is selected from the group comprising, preferably consisting of, —C(O)—, —S(O)2—, —C(S)NRa—, —C(O)C(O)—, —C(O)C(O)NRa—, —C(O)NRaC(O)—, —C(S)NRaC(O)—, and —C(O)NRaC(S)—;
B is a bond or a group selected from the group comprising, preferably consisting of C1-C6-alkylene, C3-C10-cycloalkylene
D is phenylene;
E is phenylene or 5- or 6-membered heteroarylene; and
q represents an integer of 0 or 1;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
In accordance with a particularly preferred embodiment, the present invention relates to compounds of general formula (I), in which:
R1 represents —C(O)Rb or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times, independently from each other, with R6;
R2 stands for hydrogen, or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, wherein said residues are unsubstituted or singly or multiply substituted independently from each other with R7;
R3 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano;
R4, R5, R6, R7,
R8 independently from each other, are selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, —OP(O)(ORc)2, wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R4, R5, R6, and R7, are optionally substituted one or more times with R8, and wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R8, are optionally substituted once with R8;
Ra is selected from the group comprising, preferably consisting of, hydrogen or C1-C6-alkyl;
Rb is selected from the group comprising, preferably consisting of, hydroxyl, —ORc, —SRc, —NRd1Rd2, and C1-C6-alkyl;
Rc is selected from the group comprising, preferably consisting of, hydrogen, —C(O)Rb, C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted one or more times with hydroxyl, halogen, aryl, or —NRd1Rd2, and wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted once with —ORc, or —OP(O)(ORc)2;
Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, or for a group —C(O)Rc, —S(O)2Rb, or —C(O)NRd1Rd2, wherein C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted one or more times, in the same way or differently, with halogen, hydroxy or an —ORc, —C(O)Rb, —S(O)2Rb, —OP(O)(ORc)2 group, and wherein C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted once with an —NRd1Rd2 group; or
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group comprising, preferably consisting of, NH, NRd1, oxygen or sulphur, and is optionally interrupted one or more times, the same way or differently, with a —C(O)—, —S(O)—, and/or —S(O)2— group, and optionally contains one or more double bonds;
A is selected from the group comprising, preferably consisting of, —C(O)—, —S(O)2—;
B is a bond or a group selected from the group comprising, preferably consisting of C1-C6-alkylene, C3-C10-cycloalkylene;
D is para-phenylene;
E is phenylene or 5- or 6-membered heteroarylene; and
q represents an integer of 0 or 1;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
In accordance with a more particularly preferred embodiment, the present invention relates to compounds of general formula (I), in which:
R1 represents —C(O)Rb or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times, independently from each other, with R6;
R2 stands for hydrogen, or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C3-C6-heterocycloalkyl, aryl, heteroaryl, wherein said residues are unsubstituted or singly or multiply substituted independently from each other with R7;
R3 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano;
R4 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano, nitro, —ORc, wherein C1-C6-alkyl is optionally substituted one or more times with R8;
R5 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times with R8;
R6 is selected from the group comprising, preferably consisting of, hydrogen, C3-C6-heterocycloalkyl, C1-C6-haloalkoxy, aryl, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C3-C6-heterocycloalkyl is optionally substituted one or more times with R8;
R7 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times with R8;
R8 is selected from the group comprising, preferably consisting of, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2;
Ra is hydrogen;
Rb is selected from the group comprising, preferably consisting of, —ORc, —NRd1Rd2, and C1-C6-alkyl;
Rc is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted one or more times, in the same way or differently, with —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted once with —ORc;
Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or for a —C(O)Rc or —C(O)NRd1Rd2 group, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted one or more times, in the same way or differently, with an —ORc, or —C(O)Rb group, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted once with an —NRd1Rd2 group; or,
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group comprising, preferably consisting of, NH, NRd1, and oxygen;
A is selected from the group comprising, preferably consisting of, —C(O)—, —S(O)2—;
B is a bond or a group selected from the group comprising, preferably consisting of C1-C3-alkylene, C3-C6-cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
In accordance with an even more particularly preferred embodiment, the present invention relates to compounds of general formula (I), in which:
R1 represents —C(O)Rb or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times, independently from each other, with R6;
R2 stands for hydrogen, or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C3-C6-heterocycloalkyl, wherein said residues are unsubstituted or singly or multiply substituted independently from each other with R7;
R3 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano;
R4 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, nitro, halogen, —ORc, wherein C1-C6-alkyl is optionally substituted one or more times with R8;
R5 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, nitro, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times with R8;
R6 is selected from the group comprising, preferably consisting of, hydrogen, C3-C6-heterocycloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C3-C6-heterocycloalkyl is optionally substituted one or more times with R8;
R7 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times with R8;
R8 is selected from the group comprising, preferably consisting of, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2;
Ra is hydrogen;
Rb is selected from the group comprising, preferably consisting of, —ORc, —NRd1Rd2, and C1-C6-alkyl;
Rc is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted one or more times with —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted once with —ORc;
Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or for a —C(O)Rc or —C(O)NRd1Rd2 group, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted one or more times, in the same way or differently, with an —ORc, or —C(O)Rb group, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted once with an —NRd1Rd2 group; or,
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group comprising, preferably consisting of, NH, NRd1, and oxygen;
A is —C(O)— or —S(O)2—;
B is a bond or a group selected from the group comprising, preferably consisting of C1-C3-alkylene, C3-cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
In accordance with a yet even more particularly preferred embodiment, the present invention relates to compounds of general formula (I), in which:
R1 represents —C(O)Rb or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times, independently from each other, with R6;
R2 stands for hydrogen, or C1-C6-alkyl;
R3 is selected from the group comprising, preferably consisting of, hydrogen, methyl, or fluoro;
R4 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —ORc, wherein C1-C6-alkyl is optionally substituted one or more times with R8;
R5 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times with R8;
R6 is selected from the group comprising, preferably consisting of, hydrogen, C3-C6-heterocycloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C3-C6-heterocycloalkyl is optionally substituted one or more times with R8;
R8 is selected from the group comprising, preferably consisting of, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2;
Ra is hydrogen;
Rb is selected from the group comprising, preferably consisting of, —ORc, and —NRd1Rd2;
Rc is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted one or more times with —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted once with —ORc;
Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or for a —C(O)Rc or —C(O)NRd1Rd2 group, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted one or more times, in the same way or differently, with an —ORc, or —C(O)Rb group, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted once with an —NRd1Rd2 group; or,
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group comprising, preferably consisting of, NH, NRd1, and oxygen;
A is —C(O)— or —S(O)2—;
B is a bond or a group selected from the group comprising, preferably consisting of C1-C3-alkylene, C3-cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
In accordance with a yet even more very particularly preferred embodiment, the present invention relates to compounds of general formula (I), in which
R1 is C1-C6-alkyl;
R2 stands for hydrogen, or C1-C6-alkyl, wherein C1-C6-alkyl is unsubstituted or singly or multiply substituted independently from each other with R7;
R3 is selected from the group comprising, preferably consisting of, hydrogen, methyl, or fluoro;
R4 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —ORc, wherein C1-C6-alkyl is optionally substituted one or more times with R8;
R5 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times with R8;
R7 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times with R8;
R8 is selected from the group comprising, preferably consisting of, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2;
Ra is hydrogen;
Rb is selected from the group comprising, preferably consisting of, —ORc, and —NRd1Rd2;
Rc is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted one or more times with —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted once with —ORc;
Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or for a —C(O)Rc or —C(O)NRd1Rd2 group, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted one or more times, in the same way or differently, with an —ORc, or —C(O)Rb group, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted once with an —NRd1Rd2 group; or,
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group comprising, preferably consisting of, NH, NRd1, and oxygen;
A is —C(O)— or —S(O)2—;
B is a bond or a group selected from the group comprising, preferably consisting of C1-C3-alkylene, C3-cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
Even more particularly preferably, the present invention relates to compounds of general formula (I), in which
R1 is C1-C3-alkyl;
R2 stands for hydrogen or C1-C6-alkyl;
R3 is selected from the group comprising, preferably consisting of, hydrogen, methyl, or fluoro;
R4 is selected from the group comprising, preferably consisting of, hydrogen, halogen, C1-C3-alkyl, or C1-C3-haloalkyl;
R5 is selected from the group comprising, preferably consisting of, hydrogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-haloalkoxy, halogen, —ORc, —NRd1Rd2, wherein C1-C3-alkyl is optionally substituted by R8;
R8 is selected from the group comprising, preferably consisting of, —ORc, and —NRd1Rd2;
Ra is hydrogen;
Rc is selected from the group comprising, preferably consisting of, hydrogen, and C1-C3-alkyl, wherein C1-C3-alkyl is optionally substituted one or more times with —NRd1Rd2, and wherein C1-C3-alkyl is optionally substituted once with —ORc;
Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C3-alkyl, wherein C1-C3-alkyl is optionally substituted one or more times, in the same way or differently, with an —ORc group, and wherein C1-C3-alkyl is optionally substituted once with an —NRd1Rd2 group; or,
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 6 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one time, by a member of the group comprising, preferably consisting of, NH, NRd1, and oxygen;
A is —C(O)—;
B is C1-C3 alkylene or C3-cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1 or Rd2 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1 or Rd2 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1 or Rd2 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
DEFINITIONS
The terms as mentioned herein below and in the claims have preferably the following meanings:
The term “alkyl” is to be understood as preferably meaning branched and unbranched alkyl, meaning e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, pentyl, iso-pentyl, hexyl, heptyl, octyl, nonyl and decyl and the isomers thereof.
The term “haloalkyl” is to be understood as preferably meaning branched and unbranched alkyl, as defined supra, in which one or more of the hydrogen substituents is replaced in the same way or differently with halogen. Particularly preferably, said haloalkyl is, e.g. chloromethyl, fluoropropyl, fluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, bromobutyl, trifluoromethyl, iodoethyl, and isomers thereof.
The term “alkoxy” is to be understood as preferably meaning branched and unbranched alkoxy, meaning e.g. methoxy, ethoxy, propyloxy, iso-propyloxy, butyloxy, iso-butyloxy, tert-butyloxy, sec-butyloxy, pentyloxy, iso-pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy and dodecyloxy and the isomers thereof.
The term “haloalkoxy” is to be understood as preferably meaning branched and unbranched alkoxy, as defined supra, in which one or more of the hydrogen substituents is replaced in the same way or differently with halogen, e.g. chloromethoxy, fluoromethoxy, pentafluoroethoxy, fluoropropyloxy, difluoromethyloxy, trichloromethoxy, 2,2,2-trifluoroethoxy, bromobutyloxy, trifluoromethoxy, iodoethoxy, and isomers thereof.
The term “cycloalkyl” is to be understood as preferably meaning a C3-C10 cycloalkyl group, more particularly a saturated cycloalkyl group of the indicated ring size, meaning e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl group; and also as meaning an unsaturated cycloalkyl group containing one or more double bonds in the C-backbone, e.g. a C3-C10 cycloalkenyl group, such as, for example, a cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or cyclodecenyl group, wherein the linkage of said cyclolaklyl group to the rest of the molecule can be provided to the double or single bond.
The term “heterocycloalkyl” is to be understood as preferably meaning a C3-C10 cycloalkyl group, as defined supra, featuring the indicated number of ring atoms, wherein one or more ring atom(s) is (are) (a) heteroatom(s) such as NH, NRd1, O, S, or (a) group(s) such as a C(O), S(O), S(O)2, or, otherwise stated, in a Cn-cycloalkyl group, (wherein n is an integer of 3, 4, 5, 6, 7, 8, 9, or 10), one or more carbon atom(s) is (are) replaced by said heteroatom(s) or said group(s) to give such a Cn cycloheteroalkyl group. Thus, said Cn cycloheteroalkyl group refers, for example, to a three-membered heterocycloalkyl, expressed as C3-heterocycloalkyl, such as oxiranyl (C3). Other examples of heterocycloalkyls are oxetanyl (C4), aziridinyl (C3), azetidinyl (C4), tetrahydrofuranyl (C5), pyrrolidinyl (C5), morpholinyl (C6), dithianyl (C6), thiomorpholinyl (C6), piperidinyl (C6), tetrahydropyranyl (C6), piperazinyl (C6), trithianyl (C6) and chinuclidinyl (C8).
The term “halogen” or “Hal” is to be understood as preferably meaning fluorine, chlorine, bromine, or iodine.
The term “alkenyl” is to be understood as preferably meaning branched and unbranched alkenyl, e.g. a vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, but-1-en-3-yl, 2-methyl-prop-2-en-1-yl, or 2-methyl-prop-1-en-1-yl group.
The term “alkynyl” is to be understood as preferably meaning branched and unbranched alkynyl, e.g. an ethynyl, prop-1-yn-1-yl, but-1-yn-1-yl, but-2-yn-1-yl, or but-3-yn-1-yl group.
As used herein, the term “aryl” is defined in each case as having 3-14 carbon atoms, preferably 6-12 carbon atoms, such as, for example, cyclopropenyl, phenyl, tropyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl etc, phenyl being preferred.
As used herein, the term “heteroaryl” is understood as meaning an aromatic ring system which comprises 3-16 ring atoms, preferably 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulphur, and can be monocyclic, bicyclic, or tricyclic, and in addition in each case can be benzocondensed. Preferably, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives thereof, such as, e.g., benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc.
The term “alkylene”, as used herein in the context of the compounds of general formula (I) is to be understood as meaning an optionally substituted alkyl chain or “tether”, having 1, 2, 3, 4, 5, or 6 carbon atoms, i.e. an optionally substituted —CH2— (“methylene” or “single membered tether” or e.g. —C(Me)2-), —CH2—CH2— (“ethylene”, “dimethylene”, or “two-membered tether”), —CH2—CH2—CH2— (“propylene”, “trimethylene”, or “three-membered tether”), —CH2—CH2—CH2—CH2— (“butylene”, “tetramethylene”, or “four-membered tether”), —CH2—CH2—CH2—CH2—CH2— (“pentylene”, “pentamethylene” or “five-membered ether”), or —CH2—CH2—CH2—CH2—CH2—CH2— (“hexylene”, “hexamethylene”, or six-membered tether”) group. Preferably, said alkylene tether is 1, 2, 3, 4, or 5 carbon atoms, more preferably 1 or 2 carbon atoms.
The term “cycloalkylene”, as used herein in the context of the compounds of general formula (I) is to be understood as meaning an optionally substituted cycloalkyl ring, having 3, 4, 5, 6, 7, 8, 9 or 10, preferably 3, 4, 5, or 6, carbon atoms, i.e. an optionally substituted cyclopropyl, cyclobutyl, cyclopenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl ring, preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
The term “heterocycloalkylene”, as used herein in the context of the compounds of general formula (I) is to be understood as meaning a cycloalkylene ring, as defined supra, but which contains at least one heteroatom which may be identical or different, said heteroatom being such as O, N, S, S(O) or S(O)2.
The term “arylene”, as used herein in the context of the compounds of general formula (I) which include the groups D and E, is to be understood as meaning an optionally substituted monocyclic or polycyclic arylene aromatic system e.g. arylene, naphthylene and biarylene, preferably an optionally substituted phenyl ring or “tether”, having 6 or 10 carbon atoms. More preferably, said arylene tether is a ring having 6 carbon atoms. If the term “arylene” is used it is to be understood that the linking residues can be arranged to each other in ortho-, para- and meta-position, e.g. an optionally substituted moiety of structure
in which linking positions on the rings are shown as non-attached bonds.
The term “heteroarylene”, as used herein in the context of the compounds of general formula (I) which include the groups D and E, is to be understood as meaning an optionally substituted monocyclic or polycyclic heteroarylene aromatic system, e.g. heteroarylene, benzoheteroarylene, preferably an optionally substituted 5-membered heterocycle, such as, for example, furan, pyrrole, thiazole, oxazole, isoxazole, or thiophene or “tether”, or a 6-membered heterocycle, such as, for example, pyridine, pyrimidine, pyrazine, pyridazine. More preferably, said heteroarylene tether is a ring having 6 carbon atoms, e.g. an optionally substituted structure as shown supra for the arylene moieties, but which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulphur. If the term “heteroarylene” is used it is to be understood that the linking residues can be arranged to each other in ortho-, para- and meta-position.
As used herein, the term “C1-C6”, as used throughout this text, e.g. in the context of the definition of “C1-C6-alkyl”, or “C1-C6-alkoxy”, is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C1-C6” is to be interpreted as any sub-range comprised therein, e.g. C1-C6, C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5 C1-C6; preferably C1-C2, C1-C3, C1-C4, C1-C5, C1-C6; more preferably C1-C4.
Similarly, as used herein, the term “C2-C6”, as used throughout this text, e.g. in the context of the definitions of “C2-C6-alkenyl” and “C2-C6-alkynyl”, is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C2-C6” is to be interpreted as any sub-range comprised therein, e.g. C2-C6, C3-C5, C3-C4, C2-C3, C2-C4, C2-C5; preferably C2-C3.
As used herein, the term “C3-C10”, as used throughout this text, e.g. in the context of the definitions of “C3-C10-cycloalkyl” or “C3-C10-heterocycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 10, i.e. 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3-C10” is to be interpreted as any sub-range comprised therein, e.g. C3-C10, C4-C9, C5-C8, C6-C7; preferably C3-C6.
As used herein, the term “C3-C6”, as used throughout this text, e.g. in the context of the definitions of “C3-C6-cycloalkyl” or “C3-C6-heterocycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C3-C6” is to be interpreted as any sub-range comprised therein, e.g. C3-C4, C4-C6, C5-C6.
As used herein, the term “C6-C11”, as used throughout this text, e.g. in the context of the definitions of “C6-C11-aryl”, is to be understood as meaning an aryl group having a finite number of carbon atoms of 5 to 11, i.e. 5, 6, 7, 8, 9, 10 or 11 carbon atoms, preferably 5, 6, or 10 carbon atoms. It is to be understood further that said term “C6-C11” is to be interpreted as any sub-range comprised therein, e.g. C5-C10, C6-C9, C7-C8; preferably C5-C6.
As used herein, the term “C5-C10”, as used throughout this text, e.g. in the context of the definitions of “C5-C10-heteroaryl”, is to be understood as meaning a heteroaryl group having a finite number of carbon atoms of 5 to 10, in addition to the one or more heteroatoms present in the ring i.e. 5, 6, 7, 8, 9, or 10 carbon atoms, preferably 5, 6, or 10 carbon atoms. It is to be understood further that said term “C5-C10” is to be interpreted as any sub-range comprised therein, e.g. C6-C9, C7-C8, C7-C8; preferably C5-C6.
As used herein, the term “C1-C3”, as used throughout this text, e.g. in the context of the definitions of “C1-C3-alkylene”, is to be understood as meaning an alkylene group as defined supra having a finite number of carbon atoms of 1 to 3, i.e. 1, 2, or 3. It is to be understood further that said term “C1-C3” is to be interpreted as any sub-range comprised therein, e.g. C1-C2, or C2-C3.
As used herein, the term “one or more times”, e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning “one, two, three, four or five times, particularly one, two, three or four tines, more particularly one, two or three times, more particularly one or two times”.
The term “isomers” is to be understood as meaning chemical compounds with the same number and types of atoms as another chemical species. There are two main classes of isomers, constitutional isomers and stereoisomers.
The term “constitutional isomers” is to be understood as meaning chemical compounds with the same number and types of atoms, but they are connected in differing sequences. There are functional isomers, structural isomers, tautomers or valence isomers.
The term “stereoisomers” is to be understood as meaning chemical compounds having atoms which are connected sequentially in the same way, such that condensed formulae for two isomeric molecules are identical. The isomers differ, however, in the way the atoms are arranged in space. There are two major sub-classes of stereoisomers: conformational isomers, which interconvert through rotations around single bonds, and configurational isomers, which are not readily interconvertable.
Configurational isomers are, in turn, can be enantiomers and/or diastereomers. Enantiomers are stereoisomers which are related to each other as mirror images. Enantiomers can contain any number of stereogenic centers, as long as each center is the exact mirror image of the corresponding center in the other molecule. If one or more of these centers differs in configuration, the two molecules are no longer mirror images. Stereoisomers which are not enantiomers are called diastereomers. Diastereomers which still have a different constitution, are another sub-class of diastereomers, the best known of which are simple cis-trans isomers.
In order to limit different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).
The compound according to Formula (I) can exist in free form or in a salt form. A suitably pharmaceutically acceptable salt of the pyrazolopyridines of the present invention may be, for example, an acid-addition salt of a pyrazolopyridine of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, para-toluenesulphonic, methylsulphonic, citric, tartaric, succinic or maleic acid. In addition, another suitably pharmaceutically acceptable salt of a pyrazolopyridine of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1-amino-2,3,4-butantriol.
The compound according to Formula (I) can exist as N-oxides which are defined in that at least one nitrogen of the compounds of the general Formula (I) may be oxidized.
The compound according to Formula (I) can exist as solvates, in particular as hydrate, wherein the compound according to Formula (I) may contain polar solvents, in particular water, as structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may exist in a stoichiometric or unstoichiometric ratio. In case of stoichiometric solvates, e.g. hydrate, are possible hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-etc. solvates or hydrates, respectively.
The compounds of the present invention according to Formula (I) can exist as prodrugs, e.g. as in vivo hydrolysable esters. As used herein, the term “in vivo hydrolysable ester” is understood as meaning an in vivo hydrolysable ester of a compound of formula (I) containing a carboxy or hydroxyl group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C1-C6 alkoxymethyl esters, e.g. methoxymethyl, C1-C6 alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C3-C8 cycloalkoxy-carbonyloxy-C1-C6 alkyl esters, e.g. 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, e.g. 5-methyl-1,3-dioxolen-2-onylmethyl; and C1-C6-alkoxycarbonyloxyethyl esters, e.g. 1-methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compounds of this invention. An in vivo hydrolysable ester of a compound of formula (I) containing a hydroxyl group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxyl group. Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxyl include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
The compounds of the present invention according to Formula (I), or salts, N-oxides, or prodrugs thereof, may contain one or more asymmetric centers. Asymmetric carbon atoms may be present in the (R) or (S) configuration or (R,S) configuration. Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention. Preferred stereoisomers are those with the configuration which produces the more desirable biological activity. Separated, pure or partially purified configurational isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification of said isomers and the separation of said isomeric mixtures can be accomplished by standard techniques known in the art.
Further another embodiment of the present invention relates to the use of a compound of general formula (6) as mentioned supra for the preparation of a compound of general formula (I) as defined supra.
The compounds of the present invention can be used in treating diseases of dysregulated vascular growth or diseases which are accompanied with dysregulated vascular growth. Especially, the compounds effectively interfere with Tie2 signalling. In addition, the compounds of the present invention allow for tunability of the inhibition of an additional kinase target according to the appropriate therapeutic needs.
Therefore, another aspect of the present invention is a use of the compound of general formula (I) described supra for manufacturing a pharmaceutical composition for the treatment of diseases of dysregulated vascular growth or of diseases which are accompanied with dysregulated vascular growth.
Preferably, the use is in the treatment of diseases, wherein the diseases are tumours and/or metastases thereof.
Another preferred use is in the treatment of diseases, wherein the diseases are retinopathy, other angiogenesis dependent diseases of the eye, in particular cornea transplant rejection or age-related macular degeneration, rheumatoid arthritis, and other inflammatory diseases associated with angiogenesis, in particular psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, stroke, and diseases of the bowel.
A further use is in the treatment of diseases, wherein the diseases are coronary and peripheral artery disease.
Another use is in the treatment of diseases, wherein the diseases are ascites, oedema such as brain tumour associated oedema, high altitude trauma, hypoxia induced cerebral oedema, pulmonary oedema and macular oedema or oedema following burns and trauma, chronic lung disease, adult respiratory distress syndrome, bone resorption and for benign proliferating diseases such as myoma, benign prostate hyperplasia and wound healing for the reduction of scar formation, reduction of scar formation during regeneration of damaged nerves, endometriosis, pre-eclampsia, postmenopausal bleeding and ovarian hyperstimulation.
Yet another aspect of the invention is a method of treating a disease of dysregulated vascular growth or diseases which are accompanied with dysregulated vascular growth, by administering an effective amount of a compound of general formula (I) described supra.
Preferably, the diseases of said method is tumour and/or metastases thereof.
Also, the diseases of said method are retinopathy, other angiogenesis dependent diseases of the eye, in particular cornea transplant rejection or age-related macular degeneration, e.g. rheumatoid arthritis, and other inflammatory diseases associated with angiogenesis, in particular psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, stroke, and diseases of the bowel.
Further, the disease of the method are coronary and peripheral artery disease.
Other diseases of the method are ascites, oedema such as brain tumour associated oedema, high altitude trauma, hypoxia induced cerebral oedema, pulmonary oedema and macular oedema or oedema following burns and trauma, chronic lung disease, adult respiratory distress syndrome, bone resorption and for benign proliferating diseases such as myoma, benign prostate hyperplasia and wound healing for the reduction of scar formation, reduction of scar formation during regeneration of damaged nerves, endometriosis, pre-eclampsia, postmenopausal bleeding and ovarian hyperstimulation.
The compounds of the present invention can thus be applied for the treatment of diseases accompanied by neoangiogenesis. This holds principally for all solid tumours, e.g. breast, colon, renal, lung and/or brain tumours or metastases thereof and can be extended to a broad range of diseases, where pathologic angiogenesis is persistent. This applies for diseases with inflammatory association, diseases associated with oedema of various forms and diseases associated with stromal proliferation and pathologic stromal reactions broadly. Particularly suited is the treatment for gynaecological diseases where inhibition of angiogenic, inflammatory and stromal processes with pathologic character can be inhibited. The treatment is therefore an addition to the existing armament to treat diseases associated with neoangiogenesis.
The compounds of the present invention can be used in particular in therapy and prevention of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment if the tumour growth is accompanied with persistent angiogenesis. However, it is not restricted to tumour therapy but is also of great value for the treatment of other diseases with dysregulated vascular growth. This includes retinopathy and other angiogenesis dependent diseases of the eye (e.g. cornea transplant rejection, age-related macular degeneration), rheumatoid arthritis, and other inflammatory diseases associated with angiogenesis such as psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, stroke and inflammatory diseases of the bowel, such as Crohn's disease. It includes coronary and peripheral artery disease. It can be applied for disease states such as ascites, oedema, such as brain tumour associated oedema, high altitude trauma, hypoxia induced cerebral oedema, pulmonary oedema and macular oedema or oedema following burns and trauma. Furthermore, it is useful for chronic lung disease, adult respiratory distress syndrome. Also for bone resorption and for benign proliferating diseases such as myoma, benign prostate hyperplasia and wound healing for the reduction of scar formation. It is therapeutically valuable for the treatment of diseases, where deposition of fibrin or extracellular matrix is an issue and stroma proliferation is accelerated (e.g. fibrosis, cirrhosis, carpal tunnel syndrome etc). In addition it can be used for the reduction of scar formation during regeneration of damaged nerves, permitting the reconnection of axons. Further uses are endometriosis, pre-eclampsia, postmenopausal bleeding and ovarian hyperstimulation.
Another aspect of the present invention is a pharmaceutical composition which contains a compound of Formula (I) or pharmaceutically acceptable salts thereof, N-oxides, solvates, hydrates, isomers or mixtures of isomers thereof, in admixture with one or more suitable excipients. This composition is particularly suited for the treatment of diseases of dysregulated vascular growth or of diseases which are accompanied with dysregulated vascular growth as explained above.
In order that the compounds of the present invention be used as pharmaceutical products, the compounds or mixtures thereof may be provided in a pharmaceutical composition, which, as well as the compounds of the present invention for enteral, oral or parenteral application contain suitably pharmaceutically acceptable organic or inorganic inert base material, e.g. purified water, gelatin, gum Arabic, lactate, starch, magnesium stearate, talcum, vegetable oils, polyalkylenglycol, etc.
The pharmaceutical compositions of the present invention may be provided in a solid form, e.g. as tablets, dragées, suppositories, capsules or in liquid form, e.g. as a solution, suspension or emulsion. The pharmaceutical composition may additionally contain auxiliary substances, e.g. preservatives, stabilisers, wetting agents or emulsifiers, salts for adjusting the osmotic pressure or buffers.
For parenteral applications, (including intravenous, subcutaneous, intramuscular, intravascular or infusion), sterile injection solutions or suspensions are preferred, especially aqueous solutions of the compounds in polyhydroxyethoxy containing castor oil.
The pharmaceutical compositions of the present invention may further contain surface active agents, e.g. salts of gallenic acid, phosphorlipids of animal or vegetable origin, mixtures thereof and liposomes and parts thereof.
For oral application tablets, dragées or capsules with talcum and/or hydrocarbon-containing carriers and binders, e.g. lactose, maize and potato starch, are preferred. Further application in liquid form is possible, for example as juice, which contains sweetener if necessary.
The dosage will necessarily be varied depending upon the route of administration, age, weight of the patient, the kind and severity of the illness being treated and similar factors. The daily dose is in the range of 0.5 to 1,500 mg. A dose can be administered as unit dose or in part thereof and distributed over the day. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
It is possible for compounds of general formula (I) of the present invention to be used alone or, indeed in combination with one or more further drugs, particularly anti-cancer drugs or compositions thereof. Particularly, it is possible for said combination to be a single pharmaceutical composition entity, e.g. a single pharmaceutical formulation containing one or more compounds according to general formula (I) together with one or more further drugs, particularly anti-cancer drugs, or in a form, e.g. a “kit of parts”, which comprises, for example, a first distinct part which contains one or more compounds according to general formula I, and one or more further distinct parts each containing one or more further drugs, particularly anti-cancer drugs. More particularly, said first distinct part may be used concomitantly with said one or more further distinct parts, or sequentially.
Another aspect of the present invention is a method which may be used for preparing the compounds according to the present invention.
Experimental Details and General Processes
The following table lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. Chemical names were generated using AutoNom2000 as implemented in MDL ISIS Draw. The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. from Separtis such as Isolute® Flash silica gel or Isolute® Flash NH2 silica gel in combination with a Flashmaster II autopurifier (Argonaut/Biotage) and eluants such as gradients of hexane/EtOAc or DCM/ethanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluants such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid or aqueous ammonia.
Abbreviation
Meaning
Ac
Acetyl
Boc
tert-butyloxycarbonyl
br
Broad
c-
cyclo-
Cl
chemical ionisation
d
Doublet
dd
doublet of doublet
DCM
Dichloromethane
DIPEA
N,N-diisopropylethyl amine
DMAP
N,N-dimethylaminopyridine
DMF
N,N-dimethylformamide
DMSO
dimethyl sulfoxide
eq.
Equivalent
ESI
electrospray ionisation
GP
general procedure
HPLC
high performance liquid chromatography
LC-MS
Liquid chromatography mass spectrometry
m
Multiplet
mc
centred multiplet
MS
mass spectrometry
MTBE
methyl-tert-butyl ether
NMR
nuclear magnetic resonance spectroscopy:
chemical shifts (δ) are given in ppm.
OTf
Trifluoromethylsulphonyl
Pg
protecting groups
q
Quartet
rf
at reflux
r.t. or rt
room temperature
s
Singlet
Sept.
Septet
t
Triplet
T3P
1-propanephosphonic acid cyclic anhydride
TEA
Triethylamine
TFA
trifluoroacetic acid
THF
Tetrahydrofuran
The following schemes and general procedures illustrate general synthetic routes to the compounds of general formula I of the invention and are not intended to be limiting. Specific examples are described in the subsequent paragraph.
Scheme 1 General procedure for the preparation of compounds of the general formula (I), wherein X stands for OTf, Cl, F, OAc, OMe, Y stands for Me, Et and A, B, D, E, Ra, R1, R2, R3, R4, R5 and q are as defined in the description and claims of this invention.
Compounds of general formula (I) can be synthesized according to the procedure depicted in Scheme 1. Pyridones of general formula 3 are accessible by multi-component coupling of a (hetero)aryl carbaldehyde 1, a methylketone 2, an alkyl cyanoacetate (e.g. methyl cyano acetate or ethyl cyano acetate) and an ammonium salt, preferably ammonium acetate, in a suitable solvent, preferably ethanol, at temperatures up to the boiling point of the solvent, whereby in the case of ethanol 80° C. is preferred.
The so formed pyridones 3 are transformed into pyridines of general formula 4 carrying a leaving group X at the C2 position, wherein X stands for, but is not limited to, trifluoromethanesulfonyl (OTf), acetate (OAc), methoxy (OMe), Cl or F. Preferably, X stands for Cl, even more preferably X stands for OTf. Conversion of intermediate compounds of general formula 3 into intermediates of general formula 4 may be achieved by a variety of methods, e.g. when X═Cl, by reaction with phosphorus oxychloride, optionally in the presence of DMF; or, for example, when X═OTf by reaction with trifluoromethanesulfonic acid anhydride, in the presence of a suitable base, e.g. pyridine, which may also be used as solvent, optionally in the presence of an inert solvent, e.g. dichloromethane, at temperatures ranging from −20° C. to room temperature, whereby 0° C. up to room temperature is preferred.
Reduction of the nitro group in intermediate compounds of general formula 4 gives rise to intermediate compounds of general formula 5. The person skilled in the art is well aware of many methods for nitro group reduction, whereby preferred is the reduction of intermediate compounds of general formula 4 with tin (II) chloride dihydrate in a suitable solvent, e.g. ethanol, at temperatures ranging from room temperature to the boiling point of the solvents, whereby in the case of ethanol 80° C. is preferred.
Intermediate compounds of general formula 6 are formed from intermediate compounds of general formula 5 by reaction with, for example, a suitably functionalized carboxylic acid or acid chloride (leading to carboxylic amides), or a suitably functionalized sulfonyl chloride (leading to sulfonamides), in the presence of a suitable base as necessary, e.g. pyridine, which may also be used as solvent, optionally in the presence of an inert solvent, e.g. dichloromethane, acetonitrile, DMF or THF, at temperatures ranging from −20° C. to the boiling point of the solvent, whereby room temperature is preferred.
Reaction of intermediate compounds of general formula 6 with substituted hydrazines in a suitable solvent, e.g. 1-propanol, at temperatures from room temperature up to the boiling point of the solvent, whereby in the case of 1-PrOH 100° C. is preferred, leads to compounds of general formula I.
In the case of transformation of amines of general formula 5 into amides, it is also possible to react amines of general formula 5 with an appropriate ester according to a method described in J. Org. Chem. 1995, 8414 in the presence of trimethylaluminium and in suitable solvents such as toluene, at temperatures of 0° C. to the boiling point of the solvent. For amide formation, however, all processes that are known from peptide chemistry to the person skilled in the art are also available. For example, the corresponding acid, which may be obtained from the corresponding ester by saponification, can be reacted with amines of general formula 5 in aprotic polar solvents, such as, for example, DMF, via an activated acid derivative, which is obtainable, for example, with hydroxybenzotriazole and a carbodiimide, such as, for example, diisopropylcarbodiimide (DIC), at temperatures of between 0° C. and the boiling point of the solvent, preferably at 80° C., or else with preformed reagents, such as, for example, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (see for example Chem. Comm. 1994, 201), at temperatures of between 0° C. and the boiling point of the solvent, preferably at room temperature, or else with activating agents such as dicyclohexylcarbodiimid (DCC)/dimethylaminopyridine (DMAP) or N-ethyl-N′-dimethylaminopropylcarbodiimide (EDCI)/dimethylaminopyridine (DMAP) or T3P. The addition of a suitable base such as N-methylmorpholine, for example, may be necessary. Amide formation may also be accomplished via the acid halide, mixed acid anhydride, imidazolide or azide.
The carboxylic acids required for the amide coupling reactions above described are either commercially available or are accessible from commercially available carboxylic esters or nitriles. Alternatively, (hetero)aryls bearing a methylenenitrile substituent are easily accessible from the respective halides via a nucleophilic substitution reaction (e.g. KCN, cat. KI, EtOH/H2O). Incorporation of additional functionality into commercially available starting materials can be accomplished by a multitude of aromatic transformation reactions known to the person skilled in the art, including, but not limited to, electrophilic halogenations, electrophilic nitrations, Friedel-Crafts acylations, nucleophilic displacement of fluorine by oxygen nucleophiles and transformation of (hetero)aryl carboxylic acids into amides and subsequent reduction into benzylic amines, whereby the latter two methods are of particular relevance for the introduction of ether and/or aminomethylene side chains.
Benzylic nitrites and esters (and heteroaryl analogs thereof) can be efficiently alkylated at the benzylic position under basic conditions and subsequently hydrolyzed to the corresponding alkylated acids. Conditions for α-alkylations of nitrites and esters include, but are not limited to, the use of alkyl bromides or alkyl iodides as electrophiles under basic conditions in the presence or absence of a phase-transfer catalyst in a mono- or biphasic solvent system. Particularly, by using excess alkyl iodides as electrophilic species α,α-dialkylated nitrites are accessible. More particularly, by using 1,Ω-dihaloalkyls as electrophiles cycloalkyl moieties can be installed at the benzylic position of nitrites and esters (J. Med. Chem. 1975, 18, 144; WO2003022852). The hydrolysis of nitrites to yield carboxylic acids can be accomplished, as known to the person skilled in the art, under acid or base-mediated conditions. As an exemplification of the described general synthetic route toward functionalized carboxylic acids the more particular synthesis of substituted 1-Phenylcyclopropylcarboxylic acids is described in the following scheme (Scheme 2).
Scheme 2 Preparation of substituted 1-Phenylcyclopropylcarboxylic acids as an exemplification of the general route toward a-alkylated carboxylic acids as substrates for amide formations as described in Scheme 1 and 3, wherein E, R4, and R5 are as defined in the description and claims of this invention
The above described general route to (hetero)aryl-cyclopropyl carboxylic acids is also applicable for the synthesis of the analogous higher homologs of (hetero)aryl-cycloalkyl carboxylic acids.
A variety of substituted hydrazine building blocks required e.g. for the conversion of pyridines 6 into compounds of the general formula (I) is commercially available, either in form of their free base or as various types of salts (e.g. hydrochlorides, oxalates), which can be transformed into their respective free bases by alkaline treatment either before the cyclization or in situ. Additionally, substituted alkyl-, allyl-, and benzylhydrazines (or their respective hydrochloride salts) are accessible from the respective alkyl-, allyl- and benzylhalides, preferably the respective alkyl-, allyl- and benzylbromides, by nucleophilic substitution reaction with a protected hydrazine, e.g. BocNHNH2, in an inert solvent, preferably MeOH, in the presence of an amine promoter, e.g. Et3N, at temperatures ranging from room temperature up to the boiling point of the solvent, followed by deprotection employing conditions known to the person skilled in the art, preferably by treatment with HCl in a mixture of diethyl ether and methanol (for a representative procedure, see J. Med. Chem. 2006, 49, 2170).
The substituents Ra, R1, R2, R3, R4, R5 may be further modified on each step (general formula 1 to general formula 13) or in the last step (general formula I). These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, substitution or other reactions. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999).
Scheme 3 Alternative general procedure for the preparation of compounds of the general formula (I), wherein X stands for OTf, Cl, F, OAc, OMe, and A, B, D, E, Ra, R1, R2, R3, R4, R5 and q are as defined in the description and claims of this invention. The 3-amino group at the pyrazolo ring of compounds of the general formula 8, 9, and 10 may be substituted with one or two protecting groups (Pg), preferably one or two Boc groups or even more preferably said amino group may be protected in form of a phthalimide.
An alternative synthetic route toward compounds of general formula (I) is depicted in Scheme 3. Pyridines of the general formula 4, which can be prepared as described above, can be transformed into the respective pyrazolopyridines of general formula 7 by cyclization with substituted hydrazines in a suitable solvent, e.g. 1-propanol, at temperatures from room temperature up to the boiling point of the solvent, whereby in the case of 1-PrOH 100° C. is preferred.
Protection of the 3-amino group of the pyrazole nucleus leads to compounds of the general formula 8. Suitable protecting groups for amino functions are well known to the person skilled in the art (see for example T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Preferably, the 3-amino group is protected by formation of the respective phthalimide. In particular, phthalimido protection of 3-aminopyrazoles can be achieved by reaction of the amine with phthalic anhydride in a suitable inert solvent, e.g. acetonitrile or dioxane, optionally in the presence of a basic mediator, e.g. Et3N, DIPEA or DMAP, at temperatures from room temperature up to the boiling point of the respective solvent.
Nitro reduction yielding amino compounds of the general formula 9 and e.g. sulfonamide or amide formation to give compounds of general formula 10 are feasible as described above. Finally, the compounds of the present invention (I) are accessible by deprotection of the amino group in compounds of the general formula 10. Preferably, cleavage of the phthalimido group can be achieved, as known to the person skilled in the art, by reaction with hydrazine or hydrazine hydrate in solvents such as EtOH at temperatures from room temperature up to the boiling point of the respective solvent.
Scheme 4 Additional general procedure for the preparation of compounds of the general formula (I) employing a late-stage N1-functionalization, wherein X stands for OTf, Cl, F, OAc, OMe, and X′ represents OTf, Cl, Br, I, OMs (methanesulfonyl), OAc, and A, B, D, E, Ra, R1, R2, R3, R4, R5 and q are as defined in the description and claims of this invention.
As a further optional process to compounds of the present invention, introduction of R1-substituents as present in compounds of the present invention of general formula I can be accomplished after formation of 1H-pyrazolopyridines 11 by subsequent acylation or alkylation (Scheme 4). This process is of particular importance if the appropriately substituted hydrazines are not readily available. 1H-Pyrazolopyridines of general formula 11 are accessible from synthetic intermediates of formula 6 (which can be prepared as described above) by cyclization with hydrazine or more preferably with hydrazine hydrate in a suitable solvent, preferably 1-propanol, at temperatures from room temperature up to the boiling point of the solvent, whereby in the case of 1-PrOH 100° C. is preferred. Introduction of R1-groups to yield compounds of the present invention of general formula I can be achieved employing various conditions for introducing substituents to nitrogen atoms as known to the person skilled in the art. These conditions include, but are not limited to, alkylations under basic conditions employing alkyl-, allyl-, benzylhalides or α-halocarbonyl compounds as electrophiles (e.g. WO2005056532; Chem. Pharm. Bull. 1987, 35, 2292; J. Med. Chem. 2005, 48, 6843), alkylations under reductive conditions employing aldehydes as electrophiles and an appropriate reducing agent (e.g. BH3.pyr, NaBH(OAc)3, NaBH3CN, NaBH4), Mitsunobu-type alkylations employing primary or secondary alcohols as electrophiles (e.g. Tetrahedron 2006, 62, 1295; Bioorg. Med. Chem. Lett. 2002, 12, 1687), or N-acylations (see for example J. Med. Chem. 2005, 48, 6843) optionally followed by amide reduction. The presence of the 3-amino group or other nucleophilic nitrogen atoms may give rise to regioisomeric product mixtures under some of these conditions requiring separation of regioisomeric products by methods known to the person skilled in the art. Intermittent protection of the 3-amino group, e.g. by formation of a phthalimido group under conditions as described above, followed by N1 substitution and protective group cleavage may instead allow regioselective introduction of substituents at N1 (see for example US20040235892). Conditions for N1-alkylation of 3-aminopyrazoles of the general formula 11 include, but are not limited to, treatment with an excess of the respective electrophile (e.g. alkyl-, allyl-, benzylhalides or α-halocarbonyl compounds) in the presence of a base, e.g. potassium carbonate or cesium carbonate, in DMF at temperatures from room temperature up to the boiling point of the solvent. Even more preferably, 1H-pyrazoles of general formula 11 are deprotonated with sodium hydride in DMF at temperatures from 0° C. up to 80° C. followed by reaction with the respective electrophile (e.g. alkyl-, allyl-, benzylhalides or α-halocarbonyl compounds) in DMF at temperatures from room temperature up to the boiling point of the solvent.
Scheme 5 Alternative order of transformations for the preparation of compounds of the general formula (I), wherein X, stands for OTf, Cl, F, OAc, OMe, Y stands for Me, Et and A, B, D, E, Ra, R1, R2, R3, R4, R5 and q are as defined in the description and claims of this invention.
Alternatively to the process shown in Scheme 1, the order of transformations may be changed as exemplified in Scheme 5. A fully functionalized northern part of compounds of the present invention may already be present in aldehydes of general formula 12, which lead upon multicomponent coupling as described above to pyridones of general formula 13. Transformation of pyridones of general formula 13 into pyridines of general formula 6 can be accomplished as described above.
Scheme 6 Synthesis of pyridones of formula 3a, wherein G stands for C1-C6-alkyl, Y represents Me, Et and D, R3, and q are as defined in the description and claims of this invention.
Scheme 6 depicts the more specific synthesis of pyridones of formula 3a, which in turn may be used as substrates in those conversions described above, especially those in Scheme 1. In addition, methyl ketone 2a may be used in the conversion shown in Scheme 5 replacing substrate 2. Methyl ketone 2a is either commercially available or accessible from the corresponding α-ketoester by alkylation by various conditions known to the person skilled in the art, for example analogous to those described in US20030065212 and U.S. Pat. No. 5,286,723 and those described above. Optionally, the ethyl ester functionality in substrate 2a, in pyridone 3a and subsequent products may be further modified. These modifications may include, but are not limited to, transesterifications, saponifications, amide formations, reductions and subsequent aminations or etherifications or Curtius rearrangements and subsequent amine functionalizations known to the person skilled in the art.
Synthesis of Key Intermediates
In the subsequent paragraphs detailed procedures for the synthesis of key intermediates for compounds of the present invention are described.
In the subsequent paragraphs general procedures for the synthesis of the below mentioned specific example compounds are summarized.
General Procedure 1 (GP1): Pyridone Multi-Component Coupling
To a suspension of ammonium acetate (8 eq.) in EtOH (60 mL per mmol NH4OAc) were added successively the respective methylketone component (1 eq.), methyl cyanoacetate (1 eq.), and 4-nitrobenzaldehyde (1 eq.). The resulting mixture was stirred at reflux for 1-5 h and subsequently for 16 h at r.t. The precipitate was filtered off, washed with EtOH and hexane and dried to yield the pyridone in sufficient purity for use in subsequent transformation without additional purification steps. Concentration of the filtrate gave rise to additional pyridone precipitation improving the overall yield of the multi-component coupling.
General Procedure 2 (GP 2): Triflate Formation
To a solution of the respective pyridone (1 eq.) in DCM (8 mL per mmol pyridone) was added pyridine (1.5 eq.) and subsequently at 0° C. dropwise trifluoromethanesulfonic acid anhydride (1.5 eq.). The resulting mixture was gradually warmed to room temperature and stirring was continued for 2 h. The reaction mixture was diluted with DCM and quenched with water. The aqueous layer was extracted with DCM and the combined organic layers were dried and concentrated in vacuo. Flash column chromatography provided the 2-pyridyl triflates.
General Procedure 3 (GP 3): Nitro Reduction
The respective nitro compound (1 eq.) was dissolved in EtOH (7 mL per mmol nitro compound) and treated in a counterflow of argon portionwise with SnCl2.2H2O (5 eq.). The resulting slurry was vigorously stirred and heated to 70° C., for 30 to 120 min. The reaction mixture was poured into 25% NH3 solution (25 mL per mmol nitro compound), extracted with EtOAc, the combined organic layers were washed with brine twice, dried and concentrated in vacuo. The resulting aniline was usually used for subsequent reactions without additional purification steps.
General Procedure 4 (GP 4): Amide Formation and Cyclization
Step 1
The respective aniline (1 eq.) was dissolved in DCM (12 mL per mmol aniline) and treated with pyridine (1.5 eq.) and the respective carboxylic acid chloride (1.2 eq.; prepared from the respective carboxylic acid by treatment with thionyl chloride and subsequent concentration in vacuo). The reaction mixture was stirred at room temperature until TLC indicated complete consumption of the starting aniline (usually 16 h). The reaction mixture was quenched with NaHCO3 and extracted with ethyl acetate. The organic layers were dried and concentrated in vacuo. In most cases, the crude amide was used in the subsequent cyclization without further purification, however, in cases with incomplete amide formation (as judged by TLC) flash column chromatography was applied for purification.
Step 2
The crude or purified amide from step 1 (1 eq.) was dissolved in 1-PrOH (12-15 mL per mmol amide) and treated optionally with Et3N (1.5 eq) and subsequently with the respective commercially available substituted hydrazine (1-3 eq.). The resulting mixture was stirred at 100° C. for 3 h, concentrated in vacuo and the pyrazolopyridine product was isolated by flash column chromatography followed by re-crystallization and/or preparative HPLC purification.
General Procedure 5 (GP 5): Sulfonamide Formation and Cyclization
Step 1
The respective aniline (1 eq.) was dissolved in DCM (12 mL per mmol aniline) and treated with pyridine (1.5 eq.) and the respective sulfonyl chloride (1.2 eq.). The reaction mixture was stirred at room temperature until TLC indicated complete consumption of the starting aniline (usually 16 h). The reaction mixture was quenched with NaHCO3 and extracted with ethyl acetate. The organic layers were dried and concentrated in vacuo. In most cases, the crude sulfonamide was used in the subsequent cyclization without further purification, however, in cases with incomplete sulfonamide formation (as judged by TLC) flash column chromatography was applied for purification.
Step 2
The crude or purified sulfonamide from step 1 (1 eq.) was dissolved in 1-PrOH (12-15 mL per mmol sulfonamide) and treated optionally with Et3N (1.5 eq) and subsequently with the respective commercially available substituted hydrazine (1-3 eq.). The resulting mixture was stirred at 100° C. for 3 h, concentrated in vacuo and the pyrazolopyridine product was isolated by flash column chromatography followed by re-crystallization and/or preparative HPLC purification.
General Procedure 6a (GP 6a): Preparation of 1H-pyrazolopyridines (Conditions A)
Step 1
As described for GP 4 step 1.
Step 2
The crude or purified amide from step 1 (1 eq.) was dissolved in 1-PrOH (12-15 mL per mmol amide) and treated optionally with Et3N (1.5 eq) and subsequently with 80% hydrazine hydrate (1-3 eq.). The resulting mixture was stirred at 100° C. for 3 h, concentrated in vacuo and the pyrazolopyridine product was isolated by flash column chromatography followed by re-crystallization and/or preparative HPLC purification.
General Procedure 6b (GP 6b): Preparation of 1 H-pyrazolopyridines (Conditions B)
Step 1
As described for GP 5 step 1.
Step 2
The crude or purified sulphonamide from step 1 (1 eq.) was dissolved in 1-PrOH (12-15 mL per mmol sulphonamide) and treated optionally with Et3N (1.5 eq) and subsequently with 80% hydrazine hydrate (1-3 eq.). The resulting mixture was stirred at 100° C. for 3 h, concentrated in vacuo and the pyrazolopyridine product was isolated by flash column chromatography followed by re-crystallization and/or preparative HPLC purification.
General Procedure 7 (GP 7): N1-Alkylation of 1H-pyrazolopyridines
The respective 1H-pyrazolopyridine was dissolved in dry DMF under an atmosphere of argon and treated with sodium hydride and subsequently stirred at 50° C. for 1 h.
A solution of the respective alkyl halide in DMF was added dropwise and stirring was continued at 50° C. for 1 h. [In cases were the respective halide is only available as a salt (e.g. hydrochloride or hydrobromide salt), this salt was dissolved in DMF and treated with Et3N, and the resulting slurry was added to the deprotonated 1H-pyrazolopyridine upon filtration through a Millipore filter.] The reaction mixture was diluted with EtOAc, quenched with water, the aqueous layer was extracted with EtOAc and the combined organic layers were dried and concentrated in vacuo. Flash column chromatography optionally followed by recrystallization or preparative HPLC purification yielded the desired alkylated pyrazolopyridines.
General Procedure 8a (GP 8a): Cyclopropanation Conditions A
To a stirred mixture of the respective benzyl cyanide (1.0 eq.), triethylbenzylammonium chloride (2 mol %) and 1,2-dibromoethane (2 eq.) was added dropwise 50% aq. NaOH solution (6-7 eq.). After complete addition the reaction is stirred at 40-50° C. until complete turnover. The reaction mixture was then diluted with water, the organic products extracted with benzene, the combined organic extracts were washed with 15% aq. HCl and subsequently with water, dried and concentrated in vacuo. The crude products were in general used for the subsequent nitrite hydrolysis without further purification.
General Procedure 8b (GP 8b): Cyclopropanation Conditions B
To a stirred mixture of the respective benzyl cyanide (1.0 eq.), triethylbenzylammonium chloride (2 to 4 mol %) and 1-bromo-2-chloroethane (2 to 5 eq.) was added dropwise 50% aq. NaOH solution (6-8 eq.). After complete addition the reaction is stirred at 40-50° C. until complete turnover. The reaction mixture was then diluted with water, the organic products extracted with benzene, the combined organic extracts were washed with 5% aq. HCl and subsequently with water, dried and concentrated in vacuo. The crude products were in general used for the subsequent nitrite hydrolysis without further purification.
General Procedure 9a (GP 9a): Nitrile Hydrolysis Conditions A
To a stirred mixture of the respective substituted phenylcyclopropanecarbonitrile (1.0 eq.) in EtOH (˜7 mL per mmol nitrite) was added a 10% aq. NaOH solution (2.0 to 2.5 eq.) and the resulting mixture was refluxed for 24 h, after which the mixture was concentrated in vacuo and the residual aqueous phase was extracted with MTBE. The aqueous layer was then acidified with concentrated HCl under ice cooling and the thus formed precipitate filtered off. The filter cake was washed with water and dried to yield the analytically pure carboxylic acid.
General Procedure 9b (GP 9b): Nitrile Hydrolysis Conditions B
The respective phenylcyclopropanecarbonitrile (1.0 eq.) together with concentrated HCl (1 mL per mmol nitrite) was stirred in a pressure tube at 100° C. for 16 h. The mixture was poured on ice. After extraction with dichloromethane, the organic extract was washed with water, with brine and dried. After concentration the carboxylic acid crystallized upon standing.
Synthetic Intermediates
Intermediate 1
Preparation of 6-tert-Butyl-4-(4-nitro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
In analogy to GP 1, reaction of 61.7 g ammonium acetate (800 mmol, 8 eq.), 10.73 ml ethyl cyanoacetate (100 mmol, 1 eq.), 12.55 ml 3,3-dimethylbutan-2-one (100 mmol, 1 eq.), and 15.12 g 4-nitrobenzaldehyde (100 mmol, 1 eq.) yielded 10.02 g product (34% yield).
1H-NMR (d6-DMSO; 300 MHz): 12.38 (br. s, 1 H); 8.34 (d, 2 H); 7.89 (d, 2 H); 6.28 (s, 1 H); 1.28 (s, 9 H).
MS (ESI): [M+H]+=298.
Intermediate 2
Preparation of 6-Isopropyl-4-(4-nitro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
In analogy to GP 1, reaction of 61.7 g ammonium acetate (800 mmol, 8 eq.), 10.67 ml ethyl cyanoacetate (100 mmol, 1 eq.), 10.71 ml 3-methyl-butan-2-one (100 mmol, 1 eq.), and 15.12 g 4-nitrobenzaldehyde (100 mmol, 1 eq.) yielded 4.24 g product (15% yield).
1H-NMR (d6-DMSO; 300 MHz): 12.62 (br. s, 1 H); 8.34 (d, 2 H); 7.87 (d, 2 H); 6.35 (s, 1 H); 2.87 (sept, 1 H); 1.20 (d, 6 H).
MS (ESI): [M+H]+=284.
Intermediate 3
Preparation of 6-Methyl-4-(4-nitro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
In analogy to GP 1, reaction of 8.16 g ammonium acetate (106 mmol, 8 eq.), 1.41 ml ethyl cyanoacetate (13.23 mmol, 1 eq.), 0.98 ml dry acetone (13.23 mmol, 1 eq.), and 2 g 4-nitrobenzaldehyde (13.23 mmol, 1 eq.) yielded 1.56 g product (46% yield).
1H-NMR (d6-DMSO; 400 MHz): 12.76 (br. s, 1 H); 8.34 (d, 2 H); 7.84 (d, 2 H); 6.36 (s, 1 H); 2.30 (s, 3 H).
Intermediate 4
Preparation of 2-[5-Cyano-4-(4-nitro-phenyl)-6-oxo-1,6-dihydro-pyridin-2-yl]-2-methyl-propionic acid ethyl ester
In analogy to GP 1, reaction of 1.85 g ammonium acetate (24 mmol, 8 eq.), 0.28 ml ethyl cyanoacetate (3 mmol, 1 eq.), 475 mg 2,2-dimethyl-3-oxo-butyric acid ethyl ester (3 mmol, 1 eq.), and 453 mg 4-nitrobenzaldehyde (3 mmol, 1 eq.) yielded 125 mg product (11% yield).
1H-NMR (d6-DMSO; 300 MHz): 8.30 (d, 2 H); 7.79 (d, 2 H); 6.16 (s, 1 H); 4.04 (q, 2 H); 1.41 (s, 6 H); 1.11 (t, 3 H) (isolated as acetate salt).
Intermediate 5
Preparation of 6-Furan-2-yl-4-(4-nitro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
In analogy to GP 1, reaction of 1.85 g ammonium acetate (24 mmol, 8 eq.), 0.28 ml ethyl cyanoacetate (3 mmol, 1 eq.), 330 mg furan-2-carbaldehyde (3 mmol, 1 eq.), and 453 mg 4-nitrobenzaldehyde (3 mmol, 1 eq.) yielded 362 mg product (39% yield).
1H-NMR (d6-DMSO; 300 MHz): 8.29 (d, 2 H); 7.79 (d, 2 H); 7.73 (m, 1 H); 7.01 (d, 1 H); 6.57 (dd, 1 H); 6.50 (s, 1 H) (isolated as acetate salt).
Intermediate 6
Preparation of 4-(4-Nitro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Step 1
In a flask fitted with a Dean-Stark water separator glacial AcOH (6 ml, 0.100 mol) and ammonium acetate (3.85 g, 0.050 mol) were placed. The flask was gently heated to dissolve ammonium acetate. Then a solution of 4-nitroacetophenone (20.6 g, 0.125 mol) in benzene (150 ml) and malononitrile (8.25 g, 0.125 mol) were added. The solution was heated to vigorous reflux during 4 h, cooled, washed with water (3×100 ml), and dried over Na2SO4. Benzene was removed under reduced pressure to give a thick, brown oil. The oil was dissolved in hot ethanol (100 ml), chilled to 0° C., the precipitate was filtered off and dried. Yield 20.9 g (98 mmol, 79%).
1H-NMR (d6-DMSO; 300 MHz): 8.38 (d, 2 H); 7.71 (d, 2 H); 2.40 (s, 3 H).
Step 2
Dimethylformamide dimethyl acetal (10 ml, 72.8 mmol) was added to the suspension of the product from step 1 (13.0 g, 61 mmol) and AcOH (4.4 ml, 72.8 mmol). The mixture was heated until it began to boil. After cooling, 25 ml of isopropanol was added to the mixture, it was filtered, washed with isopropanol and dried. 13.0 g of crude product containing 85% of the desired enamine was obtained.
1H-NMR (CDCl3; 300 MHz): 8.35 (d, 2 H); 7.50 (d, 2 H); 6.50 (d, 1 H); 5.85 (d, 1 H); 3.05 (s, 6 H).
Step 3
The crude enamine from step 2 (13.0 g, 41.2 mmol) was dissolved in acetic acid (130 ml) containing 98% sulfuric acid (26 ml) and water (39 ml). The solution was refluxed for 2 h. After cooling, the precipitate was filtered and washed with water. Yield 6.8 g (28 mmol, 58%).
1H-NMR (DMSO; 300 MHz): 12.80 (br. s, 1 H); 8.40 (d, 2 H); 7.85-7.95 (m, 3 H); 6.5 (d, 1 H);
MS (LCMS): [M+H]+=242.
Intermediate 7
Preparation of Trifluoromethanesulfonic acid 6-tert-butyl-3-cyano-4-(4-nitro-phenyl)-pyridin-2-yl ester
In analogy to GP 2, reaction of 3.51 g Intermediate 1 (11.8 mmol, 1 eq.), 1.43 mL dry pyridine (17.7 mmol, 1.5 eq.), 2.98 ml trifluoromethanesulfonic acid anhydride (17.7 mmol, 1.5 eq.) in 95 mL DCM yielded 4.42 g 2-pyridyl triflate (10.4 mmol, 88% yield).
1H-NMR (d6-DMSO; 300 MHz): 8.47 (d, 2 H); 8.08 (d, 2 H); 7.93 (s, 1 H); 1.38 (s, 9 H).
Intermediate 8
Preparation of Trifluoromethanesulfonic acid 3-cyano-6-isopropyl-4-(4-nitro-phenyl)-pyridin-2-yl ester
In analogy to GP 2, reaction of 4.19 g Intermediate 2 (14.8 mmol, 1 eq.), 1.79 mL dry pyridine (22.2 mmol, 1.5 eq.), 3.73 ml trifluoromethanesulfonic acid anhydride (22.2 mmol, 1.5 eq.) in 110 mL DCM yielded 5.6 g 2-pyridyl triflate (13.5 mmol, 91% yield).
1H-NMR (d6-DMSO; 300 MHz): 8.42 (d, 2 H); 8.01 (d, 2 H); 7.87 (s, 1 H); 3.20 (sept, 1 H); 1.24 (d, 6 H).
MS (ESI): [M+H]+=416.
Intermediate 9
Preparation of Trifluoromethanesulfonic acid 3-cyano-6-methyl-4-(4-nitro-phenyl)-pyridin-2-yl ester
In analogy to GP 2, reaction of 4.5 g Intermediate 3 (17.6 mmol, 1 eq.), 2.13 mL dry pyridine (26.4 mmol, 1.5 eq.), 4.45 ml trifluoromethanesulfonic acid anhydride (26.4 mmol, 1.5 eq.) in 140 mL DCM yielded 2.9 g 2-pyridyl triflate (7.4 mmol, 42% yield).
1H-NMR (d6-DMSO; 300 MHz): 8.42 (d, 2 H); 7.98 (d, 2 H); 7.88 (s, 1 H); 2.62 (S, 3 H).
Intermediate 10
Preparation of Trifluoromethanesulfonic acid 3-cyano-4-(4-nitro-phenyl)-pyridin-2-yl ester
In analogy to GP 2, reaction of 11.3 g Intermediate 6 (47 mmol, 1 eq.), 5.6 mL dry pyridine (70 mmol, 1.5 eq.), 12 ml trifluoromethanesulfonic acid anhydride (70 mmol, 1.5 eq.) in 450 mL DCM yielded 12.2 g 2-pyridyl triflate (33 mmol, 70% yield).
1H-NMR (d6-DMSO; 300 MHz): 8.85 (d, 1 H); 8.50 (d, 2 H); 8.00-8.20 (m, 3 H).
MS (LCMS): [M+H]+=374.
Intermediate 11
Preparation of Trifluoromethanesulfonic acid 4-(4-amino-phenyl)-6-tert-butyl-3-cyano-pyridin-2-yl ester
In analogy to GP 3, reaction of 4.7 g Intermediate 7 (11.3 mmol, 1 eq.) with 12.8 g tin(II) chloride dihydrate (56.6 mmol, 5 eq.) in 80 mL EtOH yielded 4 g of the aniline (10 mmol, 88% yield), which was used without further purification.
1H-NMR (d6-DMSO; 400 MHz): 7.61 (s, 1 H); 7.51 (d, 2 H); 6.68 (d, 2 H); 5.91 (br. s, 2 H); 1.29 (s, 9 H).
Intermediate 12
Preparation of Trifluoromethanesulfonic acid 4-(4-amino-phenyl)-3-cyano-6-isopropyl-pyridin-2-yl ester
In analogy to GP 3, reaction of 5.6 g Intermediate 8 (13.5 mmol, 1 eq.) with 15.6 g tin(II) chloride dihydrate (69.1 mmol, 5 eq.) in 100 mL EtOH yielded the desired amine in a quantitative yield.
1H-NMR (d6-DMSO; 400 MHz): 7.63 (s, 1 H); 7.50 (d, 2 H); 6.67 (d, 2 H); 5.91 (br. s, 2 H); 3.10 (sept, 1 H); 1.20 (d, 6 H).
MS (ESI): [M+H]+=386.
Intermediate 13
Preparation of Trifluoromethanesulfonic acid 4-(4-amino-phenyl)-3-cyano-6-methyl-pyridin-2-yl ester
In analogy to GP 3, reaction of 866 mg Intermediate 9 (2.24 mmol, 1 eq.) with 2.52 g tin(II) chloride dihydrate (11.18 mmol, 5 eq.) in 11 mL EtOH yielded the desired amine in a quantitative yield.
1H-NMR (d6-DMSO; 300 MHz): 7.66 (s, 1 H); 7.48 (d, 2 H); 6.67 (d, 2 H); 5.91 (br. s, 2 H); 2.52 (s, 3 H).
MS (ESI): [M+H]+=358.
Intermediate 14
Preparation of Trifluoromethanesulfonic acid 4-(4-amino-phenyl)-3-cyano-pyridin-2-yl ester
In analogy to GP 3, reaction of 5.6 g Intermediate 10 (15 mmol, 1 eq.) with 16.92 g tin(II) chloride dihydrate (75 mmol, 5 eq.) in 75 mL EtOH yielded 4.41 g of the desired product (86% yield).
1H-NMR (d6-DMSO; 300 MHz): 8.52 (d, 1 H); 7.75 (d, 1 H); 7.51 (d, 2 H); 6.68 (d, 2 H); 5.98 (br. s, 2 H).
Non-Commercial Carboxylic Acid Based Building Blocks
Non-commercial carboxylic acid derivatives were prepared as exemplified below:
GP 8a was applied in the synthesis of the following nitrites
Intermediate
E
R4
R5
15
phenyl
2-CH3
H
16
phenyl
3-Cl
H
17
phenyl
3-F
H
GP 8b was applied in the synthesis of the following nitriles:
Intermediate
E
R4
R5
18
phenyl
3-MeO
H
19
phenyl
2-F
H
20
phenyl
4-F
H
21
phenyl
3-CF3
H
22
phenyl
4-CF3
H
23
phenyl
2-F
5-CF3
GP 9a was applied in the synthesis of the following carboxylic acids:
Intermediate
E
R4
R5
24
phenyl
2-CH3
H
25
phenyl
3-MeO
H
26
phenyl
3-Cl
H
27
phenyl
2-F
H
28
phenyl
3-F
H
29
phenyl
4-F
H
GP 9b was applied in the synthesis of the following carboxylic acids:
Intermediate
E
R4
R5
30
phenyl
3-CF3
H
31
phenyl
4-CF3
H
32
phenyl
2-F
5-CF3
EXAMPLE COMPOUNDS
The following example compounds 1 to 13 were prepared by applying GP 4 or GP 5 using the respective aniline intermediates as resulting from GP 3, the respective carboxylic acid chlorides or sulfonyl chlorides and subsequently methyl hydrazine for cyclization.
1
N-[4-(3-Amino-6-tert- butyl-1-methyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-2-phenyl- acetamide
1H-NMR: (DMSO, 400 MHz) 10.36 (1H, s); 7.75 (2H, d); 7.51 (2H, d); 7.28-7.33 (4H, m); 7.20-7.24 (1H, m); 6.91 (1H, s); 4.53-4.55 (2H, m); 3.76 (3H, s); 3.65 (2H, s); 1.35 (9H, s).
2
N-[4-(3-Amino-6-tert- butyl-1-methyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-4-methoxy- benzamide
1H-NMR: (DMSO, 300 MHz) 10.26 (1H, s); 7.93-7.97 (4H, m); 7.55 (2H, d); 7.05 (2H, d); 6.96 (1H, s); 4.55-4.57 (2H, m); 3.82 (3H, s); 3.77 (3H, s); 1.37 (9H, s).
3
N-[4-(3-Amino-6-tert- butyl-1-methyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-4-chloro- benzamide
1H-NMR: (DMSO, 300 MHz) 10.49 (1H, s); 7.92-8.00 (4H, m); 7.56-7.62 (4H, m); 6.96 (1H, s); 4.57 (2H, br s); 3.77 (3H, s); 1.37 (9H, s).
4
N-[4-(3-Amino-6-tert- butyl-1-methyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-C-phenyl- methanesulfonamide
1H-NMR: (DMSO, 400 MHz) 10.07 (1H, s); 7.51 (2H, s); 7.25-7.33 (7H, s); 6.93 (1H, s); 4.58-4.60 (2H, m); 4.52 (2H, s); 3.77 (3H, s); 1.36 (9H, s).
5
1-Phenyl- cyclopropanecarboxylic acid [4-(3-amino-6- tert-butyl-1-methyl- 1H-pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-amide
1H-NMR: (DMSO, 400 MHz) 9.31 (1H, s); 7.72 (2H, d); 7.47 (2H, d); 7.24-7.39 (5H, m); 6.90 (1H, s); 4.53 (2H, s); 3.76 (3H, s); 1.42-1.45 (2H, m); 1.35 (9H, s); 1.10-1.13 (2H, m).
6
N-[4-(3-Amino-6-tert- butyl-1-methyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-2-(3- methoxy-phenyl)- acetamide
1H-NMR: (DMSO, 300 MHz) 10.33 (1H, s); 7.74 (2H, d); 7.51 (2H, d); 7.19-7.24 (1H, m); 6.88-6.92 (3H, m); 6.78- 6.81 (1H, m); 4.55 (2H, br s); 3.76 (3H, s); 3.71 (3H, s); 3.61 (2H,s); 1.35 (9H, s).
7
N-[4-(3-Amino-6-tert- butyl-1-methyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-2-phenyl- butyramide
1H-NMR: (DMSO, 400 MHz) 10.27 (1H, s); 7.75 (2H, d); 7.49 (2H, d); 7.37-7.39 (2H, m); 7.28-7.32 (2H, m); 7.19- 7.23 (1H, m); 6.90 (1H, s); 4.54 (2H, s); 3.75 (3H, s); 3.56-3.60 (1H, m); 1.99-2.10 (1H, s); 1.63-1.74 (1H, s); 1.34 (9H, s); 0.85 (3H, t).
8
N-[4-(3-Amino-6-tert- butyl-1-methyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-2-phenyl- isobutyramide
1H-NMR: (DMSO, 400 MHz) 9.28 (1H, s); 7.78 (2H, d); 7.48 (2H, d); 7.31-7.36 (4H, m); 7.20-7.24 (1H, m); 6.90 (1H, s); 4.54 (2H, br s); 3.76 (3H, s); 1.55 (6H, s); 1.35 (9H, s).
9
1-(3-Methoxy- phenyl)- cyclopropane- carboxylic acid [4-(3- amino-1,6-dimethyl- 1H-pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-amide
MS (LC-MS): [M + H]+ = 428.
10
1-(3-Trifluoromethyl- phenyl)- cyclopropane- carboxylic acid [4-(3- amino-1,6-dimethyl- 1H-pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-amide
1H-NMR: (DMSO, 300 MHz) 9.57 (s, 1H); 7.72-7.78 (m, 4H); 7.66 (t, 1H); 7.60 (d, 1H); 7.51 (d, 2H); 6.80 (s, 1H); 4.58 (br. 2H); 3.78 (s, 3H); 2.56 (s, 3H);1.53-1.57 (m, 2H); 1.23-1.27 (m, 2H).
11
1-(4-Trifluoromethyl- phenyl)- cyclopropane- carboxylic acid [4-(3- amino-1,6-dimethyl- 1H-pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-amide
1H-NMR: (DMSO, 300 MHz) 9.58 (s, 1H); 7.77 (d, 2H); 7.73 (d, 2H); 7.61 (d, 2H); 7.51 (d, 2H); 6.80 (s, 1H); 4.58 (br. s, 2H); 3.78 (s, 3H); 2.56 (s, 3H);1.54-1.58 (m, 2H); 1.22-1.26 (m, 2H).
12
1-(4-Methoxy- phenyl)- cyclopropane- carboxylic acid [4-(3- amino-1,6-dimethyl- 1H-pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-amide
1H-NMR: (CDCl3, 400 MHz) 7.52 (d, 2H); 7.46 (d, 2H); 7.43 (d, 2H); 6.98 (d, 2H); 6.74 (s, 1H); 4.01 (s, 3H); 3.86 (s, 3H); 2.71 (s, 3H); 1.71-1.73 (m, 2H);1.16- 1.18 (m, 2H).
13
1-Phenyl- cyclopropanecarboxylic acid [4-(3-amino- 1,6-dimethyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-amide
1H-NMR: (DMSO, 400 MHz) 9.28 (s, 1H); 7.71 (d, 2H); 7.45 (d, 2H); 7.32-7.40 (m, 4H); 7.24-7.28 (m, 1H); 6.74 (s, 1H); 4.53 (br. s, 2H); 3.73 (s, 3H); 2.51 (s, 3H); 1.42-1.45 (m,2H); 1.10- 1.13 (m, 2H).
The following exemplary compounds 14 to 65 of the present invention are accessible applying procedures described above using the respective aniline intermediates, as resulting from GP 3, via amide or sulfonamide formation as exemplified above, followed by cyclization with substituted hydrazines. Alternatively, said amide or sulfonamide formation may be followed by cyclization with e.g. 80% hydrazine hydrate, and R1 is introduced in the final step e.g. by alkylation, (compare to GP 4, 5, 6a, 6b and 7):
Biological Data
Assay 1: Tie2 ELISA Assay
Cellular activity of compounds of the present invention as inhibitors of Tie2 kinase activity was measured employing a Tie2 ELISA assay as described in the following paragraphs. Herein CHO cell-cultures, which are stably transfected by known techniques with Tie2 using DHFR deficiency as selection marker, are stimulated by angiopoietin-2. The specific autophosphorylation of Tie2 receptors is quantified with a sandwich-ELISA using anti-Tie2 antibodies for catch and anti-phosphotyrosine antibodies coupled to HRP for detection.
Materials:
96 well tissue culture plate, sterile, Greiner
96 well FluoroNunc plate MaxiSorp Surface C, Nunc
96 well plate polypropylene for compound dilution in DMSO
CHO Tie2/DHFR (transfected cells)
PBS−; PBS++, DMSO
MEM alpha Medium with Glutamax-I without Ribonucleosides and
Deoxyribonucleosides (Gibco #32561-029)
with 10% FCS after dialysis! and 1% PenStrep
Lysis buffer: 1 Tablet “Complete” protease inhibitor
1 cap Vanadate (1 mL>40 mg/mL; working solution 2 mM)
ad 50 mL with Duschl-Puffer
pH 7.6
Anti-Tie2-antibody 1: 425 in Coating Buffer pH 9.6
Stock solution: 1.275 mg/mL>working.: 3 μg/mL
PBST: 2 bottles PBS (10×)+10 ml Tween, fill up with VE-water
RotiBlock 1:10 in VE-water
Anti-Phosphotyrosine HRP-Conjugated 1:10000 in 3% TopBlock
3% TopBlock in PBST
BM Chemiluminescence ELISA Substrate (POD)
solution B1:100 solution A
SF9 cell culture medium
Ang2-Fc in SF9 cell culture medium
Cell Experiment:
Dispense 5×104 cells/well/98 μL in 96 well tissue culture plate
Incubate at 37° C./5% CO2
After 24 h add compounds according to desired concentrations
Add also to control and stimulated values without compounds 2 μL DMSO
And mix for a few min at room temperature
Add 100 μL Ang2-Fc to all wells except control, which receives insect medium
Incubate 20 min at 37° C.
Wash 3× with PBS++
Add 100 μl Lysis buffer/well and shake a couple of min at room temperature
Store lysates at 20° C. before utilizing for the ELISA
Performance of Sandwich-ELISA
Coat 96 well FluoroNunc Plate MaxiSorp Surface C with anti-Tie2 mAb
1: 425 in Coating buffer pH 9.6; 100 μL/well overnight at 4° C.
Wash 2× with PBST
Block plates with 250 μL/well RotiBlock 1:10 in VE-water
Incubate for 2 h at room temperature or overnight at 4° C. shaking
Wash 2× in PBST
Add thawed lysates to wells and incubate overnight shaking at 4° C.
Wash 2× with PBST
Add 100 μL/well anti-Phosphotyrosine HRP-Conjugated 1:10000 in 3%
TopBlock (3% TopBlock in PBST) and incubate overnight under shaking
Wash 6× with PBST
Add 100 μL/well BM Chemiluminescence ELISA Substrate (POD)
solutions 1 und 2 (1:100)
Determine luminescence with the LumiCount.
Assay 2: Tie-2-Kinase HTRF-Assay without Kinase Preactivation
Tie2-inhibitory activity of compounds of the present invention was quantified employing two Tie2 HTRF assay as described in the following paragraphs.
A recombinant fusion protein of GST and the intracellular domains of Tie-2, expressed in insect cells (Hi-5) and purified by Glutathion-Sepharose affinity chromatography was used as kinase. Alternatively, commercially available GST-Tie2-fusion protein (Upstate Biotechnology, Dundee, Scotland) can be used As substrate for the kinase reaction the biotinylated peptide biotin-Ahx-EPKDDAYPLYSDFG (C-terminus in amid form) was used which can be purchased e.g. from the company Biosynthan GmbH (Berlin-Buch, Germany). Detection of phosphorylated product is achieved specifically by a trimeric detection complex consisting of the phosphorylated substrate, streptavidin-XLent (SA-XLent) which binds to biotin, and Europium Cryptate-labeled anti-phosphotyrosine antibody PT66 which binds to phosphorylated tyrosine.
Tie-2 (3.5 ng/measurement point) was incubated for 60 min at 22° C. in the presence of 10 μM adenosine-tri-phosphate (ATP) and 1 μM substrate peptide (biotin-Ahx-EPKDDAYPLYSDFG-NH2) with different concentrations of test compounds (0 μM and concentrations in the range 0.001-20 μM) in 5 μl assay buffer [50 mM Hepes/NaOH pH 7, 10 mM MgCl2, 0.5 mM MnCl2, 1.0 mM dithiothreitol, 0.01% NP40, protease inhibitor mixture (“Complete w/o EDTA” from Roche, 1 tablet per 2.5 ml), 1% (v/v) dimethylsulfoxide]. The reaction was stopped by the addition of 5 μl of an aqueous buffer (25 mM Hepes/NaOH pH 7.5, 0.28% (w/v) bovine serum albumin) containing EDTA (90 mM) and the HTRF (Homogeneous Time Resolved Fluorescence) detection reagents streptavidine-XLent (0.2 μM, from Cis Biointernational, Marcoule, France) and PT66-Eu-Chelate (0.3 ng/μl; a europium-chelate labelled anti-phospho-tyrosine antibody from Perkin Elmer).
The resulting mixture was incubated 1 h at 22° C. to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XLent and the PT66-Eu-Chelate. Subsequently the amount of phosphorylated substrate peptide was evaluated by measurement of the resonance energy transfer from the PT66-Eu-Chelate to the streptavidine-XLent. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate peptide. The data were normalised (enzyme reaction without inhibitor=0% inhibition, all other assay components but no enzyme=100% inhibition) and IC50 values were calculated by a 4 parameter fit using an inhouse software.
Assay 3: Tie-2-Kinase HTRF-Assay with Kinase Preactivation
A recombinant fusion protein of GST and the intracellular domains of Tie-2, expressed in insect cells (Hi-5) and purified by Glutathion-Sepharose affinity chromatography was used as kinase. As substrate for the kinase reaction the biotinylated peptide biotin-Ahx-EPKDDAYPLYSDFG (C-terminus in amid form) was used which can be purchased e.g. from the company Biosynthan GmbH (Berlin-Buch, Germany).
For activation, Tie-2 was incubated at a conc. 12.5 ng/μl of for 20 min at 22° C. in the presence of 250 μM adenosine-tri-phosphate (ATP) in assay buffer [50 mM Hepes/NaOH pH 7, 10 mM MgCl2, 0.5 mM MnCl2, 1.0 mM dithiothreitol, 0.01% NP40, protease inhibitor mixture (“Complete w/o EDTA” from Roche, 1 tablet per 2.5 ml)].
For the subsequent kinase reaction, the preactivated Tie-2 (0.5 ng/measurement point) was incubated for 20 min at 22° C. in the presence of 10 μM adenosine-tri-phosphate (ATP) and 1 μM substrate peptide (biotin-Ahx-EPKDDAYPLYSDFG-NH2) with different concentrations of test compounds (0 μM and concentrations in the range 0.001-20 μM) in 5 μl assay buffer [50 mM Hepes/NaOH pH 7, 10 mM MgCl2, 0.5 mM MnCl2, 0.1 mM sodium ortho-vanadate, 1.0 mM dithiothreitol, 0.01% NP40, protease inhibitor mixture (“Complete w/o EDTA” from Roche, 1 tablet per 2.5 ml), 1% (v/v) dimethylsulfoxide]. The reaction was stopped by the addition of 5 μl of an aqueous buffer (25 mM Hepes/NaOH pH 7.5, 0.28% (w/v) bovine serum albumin) containing EDTA (90 mM) and the HTRF (Homogeneous Time Resolved Fluorescence) detection reagents streptavidine-XLent (0.2 μM, from Cis Biointernational, Marcoule, France) and PT66-Eu-Chelate (0.3 ng/μl; a europium-chelate labelled anti-phospho-tyrosine antibody from Perkin Elmer).
The resulting mixture was incubated 1 h at 22° C. to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XLent and the PT66-Eu-Chelate. Subsequently the amount of phosphorylated substrate peptide was evaluated by measurement of the resonance energy transfer from the PT66-Eu-Chelate to the streptavidine-XLent. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate peptide. The data were normalised (enzyme reaction without inhibitor=0% inhibition, all other assay components but no enzyme=100% inhibition) and IC50 values were calculated by a 4 parameter fit using an inhouse software.
Assay 4: cKIT-Kinase HTRF-Assay
c-Kit-inhibitory activity of compounds of the present invention was quantified employing the c-kit HTRF assay as described in the following paragraphs.
GST-tagged recombinant kinase domain of the human c-kit expressed in SF-9 cells was used as kinase. As substrate for the kinase reaction biotinylated poly-(Glu, Tyr) (Cis biointernational, France) was used.
c-Kit was incubated for 30 min at 22° C. in the presence of different concentrations of test compounds in 5 μl assay buffer [50 mM Hepes/NaOH pH 7.0, 1 mM MgCl2, 5 mM MnCl2, 1.0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 10 μM adenosine-tri-phosphate (ATP), 1.3 μg/ml substrate, 0.001% (v/v) Nonidet-P40 (Sigma), 1% (v/v) dimethylsulfoxide]. The concentration of c-kit was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range. The reaction was stopped by the addition of 5 μl of a solution of HTRF detection reagents (0.1 μM streptavidine-XLent and 1 nM PT66-Eu-Chelate, an europium-chelate labelled anti-phospho-tyrosine antibody from Perkin Elmer) in an aqueous EDTA-solution (80 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.0).
The resulting mixture was incubated 1 h at 22° C. to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XLent and the PT66-Eu-Chelate. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the PT66-Eu-Chelate to the streptavidine-XLent. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalised (enzyme reaction without inhibitor=0% inhibition, all other assay components but no enzyme=100% inhibition) and IC50 values were calculated by a 4 parameter fit using an inhouse software.
Compounds of the present invention possess enzymatic and cellular activity as inhibitors of Tie2.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.
The entire disclosures of all applications, patents and publications, cited herein and of corresponding European application No. 06090107.1, filed Jun. 13, 2006, and U.S. Provisional Application Ser. No. 60/816,625, filed Jun. 27, 2006, are incorporated by reference herein.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
|
11761605
|
bayer schering pharma ag
|
USA
|
B2
|
Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
|
Open
|
514/253.04
|
|
Mar 31st, 2022 03:13PM
|
Mar 31st, 2022 03:13PM
|
Bayer
|
Health Care
|
Health Care Equipment & Services
|