Biphenyl and biphenyl-analogous compounds as integrin antagonists
The present invention relates to biphenyl and biphenyl-analogous compounds, their preparation and use as pharmaceutical compositions, as integrin antagonists and in particular for the production of pharmaceutical compositions for the treatment and prophylaxis of cancer, arteriosclerosis, restenosis, osteolytic disorders such as osteoporosis and ophthalmic diseases. The compounds according to the invention have the formula (1) wherein R 1 , R 2 , U, V, A, B, W, R 3 , C and R 4 have the meaning as defined in the claims.
1. A compound of the formula (1):
where
R 1 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
R 2 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue, —NR 2′ SO 2 R 2″ , —NR 2′ COOR 2″ , —NR 2′ COR 2′ , —NR 2′ CONR 2′ 2 or —NR 2′ CSNR 2′ 2 ;
R 2′ is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
R 2″ is a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
U is a direct bond or a substituted or unsubstituted alkylene group;
V is a substituted or unsubstituted alkylene group, —NR 2′ CO— or —NR 2′ SO 2 —;
A and B are each independently of one another a 1,3- or 1,4-bridging phenylene group or a 2,4- or 2,5-bridging thienylene group each of which may optionally have additional substituents wherein together A and B represent one 1,3- or 1,4-bridging phenylene group and one 2,4- or 2,5-bridging thienylene group each of which may optionally have additional substituents,
W is a direct bond or a substituted or unsubstituted alkylene group;
C is a direct bond or
R 3 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an alkylamine residue, an alkylamide residue or is connected to one of R 4 , Y, R 5 or R 6 , if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R 3 is bonded, and can be saturated or unsaturated and/or can contain further heteroatoms;
R 4 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, an alkylamine residue, an alkylamide residue or is connected to one of R 3 , Y, or R 6 , if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R 4 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
X is CHNO 2 , CHCN, O, N or S;
Y is a direct bond or an optionally substituted alkylene or alkine group;
R 5 is absent, or is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, —NO 2 , —CN, —COR 5′ , —COOR 5′ , or is connected to one of to one of R 3 or Y, if present, with formation of an optionally substituted carbocyclic or heterocyclic ring system which includes X and can be saturated or unsaturated and/or can contain further heteroatoms;
R 5′ is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue which can be saturated or unsaturated and/or can contain further heteroatoms;
R 6 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl or arylcarbonyl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an alkylamine residue, an alkylamide residue or is connected to one of R 3 , R 4 , or Y, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R 6 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
and their physiologically acceptable salts and stereoisomers.
2. A compound as claimed in claim 1 ,
wherein
R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof;
R 2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue, —NR 2′ SO 2 R 2″ , —NR 2′ COOR 2″ , —NR 2′ COR 2′ , —NR 2′ CONR 2′ 2 or —NR 2′ CSNR 2 ′ 2 ;
R 2′ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof as, for example, 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
R 2″ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, 1,1,1-trifluorobutyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, 4-ethylphenyl, —C 6 H 2 (CH 3 ) 3 , 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoro-methylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-di-fluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4-chloro-2-trifluorophenyl, 2-trifluoromethoxy-4-bromo-phenyl, 2-fluoro-4-trifluoromethylphenyl, 8-quinolinyl or a group of the formula
U is a direct bond,
V is an optionally substituted C 1-5 -alkylene group;
A is an unsubstituted 2,4- or 2,5-bridging thienylene group;
B is a 1,3- or 1,4-bridging phenylene group which is unsubstituted or has at least one alkyl residue;
W is a direct bond or an optionally substituted C 1-4 -alkylene group;
C is a direct bond or
R 3 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, isobutyl, t-butyl, pentyl, 2-methylbutyl, isopentyl, neopentyl, hexyl, C 1-4 -perfluoroalkyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, allyl, propinyl, phenyl, benzyl, tolyl, benzoyl or a substituted derivative thereof, C 1-4 -alkylamino-C 1-4 -alkyl, C 1-4 -dialkylamino-C 1-4 -alkyl, amino-C 1-4 -alkyl, C 1-4 -alkyloxy-C 1-4 -alkyl, C 1-2 -perfluoroalkyl-C 1-4 -alkyl,
wherein
Z is hydrogen, —NO 2 or NH 2 , or
R 3 is connected to one of R 4 , Y, R 5 or R 6 , if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R 3 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
R 4 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, isobutyl, t-butyl, pentyl, 2-methylbutyl, isopentyl, neopentyl, hexyl, C 1-4 -perfluoroalkyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, allyl, propinyl, phenyl, benzyl, tolyl, benzoyl or a substituted derivative thereof, C 1-4 -alkylamino-C 1-4 -alkyl, C 1-4 -dialkylamino-C 1-4 -alkyl, amino-C 1-4 -alkyl, C 1-4 -alkyloxy-C 1-4 -alkyl, C 1-2 -perfluoroalkyl-C 1-4 -alkyl, or is connected to one of R 3 , Y, or R 6 , if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R 4 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
X is CHNO 2 , CHCN, O, N or S;
Y is a direct bond or a substituted or unsubstituted methylene or methine group;
R 5 is absent, or is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, —NO 2 , —CN, —COR 5′ , —COOR 5′ or is connected to one of R 3 or Y, if present, with formation of an optionally substituted carbocyclic or heterocyclic 4- to 6-membered ring system which includes X and can be saturated or unsaturated and/or can contain further heteroatoms;
R 5′ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof;
R 6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, isobutyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, hexyl, C 1-4 -perfluoroalkyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, allyl, propinyl, phenyl, benzyl, tolyl, benzoyl or a substituted derivative thereof, C 1-4 -alkylamino-C 1-4 -alkyl, C 1-4 -dialkylamino-C 1-4 -alkyl, amino-C 1-4 -alkyl, C 1-4 -alkyloxy-C 1-4 -alkyl, C 1-2 -perfluoroalkyl-C 1-4 -alkyl, one of the residues (a1) to (a51) or is connected to one of R 3 , Y, or R 4 , if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R 6 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms.
3. A compound as claimed in claim 2 ,
wherein
R 2 is —NR 2′ SO 2 R 2″ , —NR 2′ COOR 2″ , —NR 2′ COR 2′ , —NR 2 ′CONR 2′ 2 or —NR 2′ CSNR 2′ 2 ;
R 2′ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof;
R 2″ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, 1,1,1-trifluorobutyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, 4-ethylphenyl, —C 6 H 2 (CH 3 ) 3 , 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoro-methylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4-chloro-2-trifluorophenyl, 2-trifluoromethoxy-4-bromo-phenyl, 2-fluoro-4-trifluoromethylphenyl, 8-quinolinyl or a group of the formula
and the other substituents are as defined in claim 2 .
4. A compound as claimed in claim 2 ,
wherein,
R 2 is —NR 2′ SO 2 R 2″ or —NR 2′ COOR 2″ ;
R 2′ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof as, for example, 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorphenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
R 2″ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, 1,1,1-trifluorobutyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, 4-ethylphenyl, —C 6 H 2 (CH 3 ) 3 , 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4-chloro-2-trifluorophenyl, 2-trifluoromethoxy-4-bromo-phenyl, 2-fluoro-4-trifluoromethylphenyl, 8-quinolinyl or a group of the formula
A is an unsubstituted 2,4- or 2,5-bridging thienylene group;
B is an optionally methyl-substituted 1,3- or 1,4-bridging phenylene group;
C is
R 5 is absent, —NO 2 , —CN, or is connected to one of R 3 or Y, if present, with formation of an optionally substituted carbocyclic or heterocyclic 4- to 6-membered ring system which includes X and can be saturated or unsaturated and/or can contain further heteroatoms;
and the other substituents are as defined in claim 2 .
5. A compound as claimed in claim 2 ,
wherein
R 2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue,
U is a direct bond,
V is —CHR 7 — or —CHR 7 (CH 2 ) 1-4 —;
R 7 is —NR 7′ SO 2 R 7″ , —NR 7′ COOR 7″ , —NR 7′ COR 7′ , —NR 7 ′CONR 7′ 2 or —NR 7′ CSNR 7′ 2 ;
R 7′ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof;
R 7″ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, —C 6 H 2 (CH 3 ) 3 , 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorphenyl, 3-fluorphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluormethoxyphenyl, or 8-quinolinyl,
and the other substituents are as defined in claim 2 .
6. A compound as claimed in claim 2 ,
wherein
R 2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue,
U is a direct bond;
V is —CHR 7 —;
R 7 is —NR 7′ SO 2 R 7″ or —NR 7′ COOR 7″ ;
R 7′ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof;
R 7″ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, —C 6 H 2 (CH 3 ) 3 , 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorphenyl, 3-fluorphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluormethoxyphenyl, or 8-quinolinyl,
A is an unsubstituted 2,4- or 2,5-bridging thienylene group;
B is an optionally methyl-substituted 1,3- or 1,4-bridging phenylene group;
C is
W is a direct bond or a —CH 2 — group;
X is O or S;
Y is a direct bond;
R 5 is absent;
and the other substituents are as defined in claim 2 .
7. A compound as claimed in claim 2 ,
wherein
R 2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue,
U is a direct bond,
V is a C 1-5 -alkylene group which is optionally substituted by one or more residues R 7 which are selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl, a substituted derivative or a saturated or unsaturated, optionally substituted heterocyclic analog thereof, an optionally substituted alkenyl residue or an optionally substituted alkinyl residue;
and the other substituents are as defined in claim 2 .
8. A compound as claimed in claim 2 ,
wherein
R 2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue,
U is a direct bond,
V is —CHR 7 —;
R 7 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue,
A is an unsubstituted 2,4- or 2,5-bridging thienylene group;
B is an optionally methyl-substituted 1,3- or 1,4-bridging phenylene group;
C is
W is a direct bond or a —CH 2 — group;
X is O or S;
Y is a direct bond;
R 5 is absent;
and the other substituents are as defined in claim 2 .
9. A compound as claimed in claim 1 ,
wherein
R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof;
R 2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl, phenylethyl, a substituted derivative or a saturated or unsaturated, optionally substituted heterocyclic analog thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue;
U is a direct bond or an optionally substituted C 1-3 -alkylene group;
V is —NR 8 CO— or —NR 8 SO 2 —;
R 8 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl, phenylethyl, phenylpropyl, phenoxyethyl or a substituted derivative thereof;
A is a 2,4- or 2,5-bridging thienylene group which is unsubstituted;
B is a 1,3- or 1,4-bridging phenylene group which is unsubstituted or has at least one alkyl residue;
W is a direct bond or an optionally substituted C 1-3 -alkylene group;
C is
R 3 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, isobutyl, t-butyl, pentyl, 2-methylbutyl, isopentyl, neopentyl, hexyl, C 1-4 -perfluoroalkyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, allyl, propinyl, phenyl, benzyl, tolyl, benzoyl or a substituted derivative thereof, C 1-4 -alkylamino-C 1-4 -alkyl, C 1-4 -dialkylamino-C 1-4 -alkyl, amino-C 1-4 -alkyl, C 1-4 -alkyloxy-C 1-4 -alkyl, C 1-2 -perfluoroalkyl-C 1-4 -alkyl, or is connected to one of R 4 , Y or R 6 , if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R 3 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
R 4 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, 1-methyl-propyl, isobutyl, t-butyl, pentyl, 2-methyl-butyl, isopentyl, neopentyl, hexyl, C 1-4 -perfluoroalkyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, allyl, propinyl, phenyl, benzyl, tolyl, benzoyl or a substituted derivative thereof, C 1-4 -alkylamino-C 1-4 -alkyl, C 1-4 -dialkylamino-C 1-4 -alkyl, amino-C 1-4 alkyl, C 1-4 -alkyloxy-C 1-4 -alkyl, C 1-2 -perfluoroalkyl-C 1-4 -alkyl, or is connected to one of R 3 , Y or R 6 , if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R 4 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
X is CHNO 2 , CHCN, O or S;
Y is a direct bond or a substituted or unsubstituted methylene or methine group;
R 5 is absent;
R 6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, isobutyl, t-butyl, pentyl, isopentyl, 2-methyl-butyl, neopentyl, hexyl, C 1-4 -perfluoroalkyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, allyl, propinyl, phenyl, benzyl, tolyl, benzoyl or a substituted derivative thereof, C 1-4 -alkylamino-C 1-4 -alkyl, C 1-4 -dialkylamino-C 1-4 -alkyl, amino-C 1-4 -alkyl, C 1-4 -alkyloxy-C 1-4 -alkyl, C 1-2 -perfluoroalkyl-C 1-4 -alkyl, one of the residues (a1) to (a51) or is connected to one of R 3 , Y or R 4 , if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R 6 is bonded, and can be saturated or unsaturated and/or can contain further heteroatoms.
10. A compound as claimed in claim 9 ,
wherein
U is a direct bond or —CHR 7 —;
R 7 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue;
A is an unsubstituted 2,4- or 2,5-bridging thienylene group;
B is an optionally methyl-substituted 1,3- or 1,4-bridging phenylene group;
W is a direct bond or a —CH2-group;
C is
X is O or S;
Y is a direct bond;
R 5 is absent;
and the other substituents are as defined in claim 9 .
11. A compound as claimed in claim 4 ,
wherein
R 2′ is 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
and the other substituents are as defined in claim 4 .
12. A compound as claimed in claim 4 ,
wherein
R 2′ is 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
and the other substituents are as defined in claim 4 .
13. A compound as claimed in claim 5 ,
wherein
R 7′ is 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
and the other substituents are as defined in claim 5 .
14. A compound as claimed in claim 6 ,
wherein
R 7′ is 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
and the other substituents are as defined in claim 6 .
15. A pharmaceutical composition comprising at least one of the compounds as claimed in one of claims 1 to 11 and a pharmaceutically acceptable carrier or excipient.
16. A method for treating osteoporosis said method comprising administering to said patient an effective amount therefor of at least one compound according to claim 1 .
17. A process for the preparation of compounds as claimed in claim 1 having the formula (1)
which comprises
the steps
a) reaction of a carboxylic acid derivative of the formula (2)
where
P is a protective group, a solid phase used for carrying Out a solid-phase reaction or R 1 is as defined in claim 1 ;
A is a thienylene group which is 2,4- or 2,5-substituted with respect to V and L and optionally has additional residues;
L is —H, —F, —Cl, —Br, —I, —SCN, —N 2 + or an organometallic residue; and the other residues are as defined in claim 1 ;
with a phenyl compound of the formula (3)
M-B—W-D (3)
where
M is —H, —I, —N 2 + , —COOCOBNO 2 or an organometallic residue;
B is a phenylene group which is 1,3- or 1,4-substituted with respect to M and W-D and optionally has additional residues;
W is as defined in claim 1 ;
D is —NO 2 , —NH 2 or —CHO;
to give a thienyl-phenyl compound of the formula (4)
where the residues are as defined above;
b) conversion of the residue D into the corresponding amino group, if D is not —NH 2 ; and
c) optionally, derivatization of nitrogen atoms into one of its physiologically acceptable salts by reaction with an inorganic or organic base or acid and/or the conversion of the compound obtained into the free acid and/or the conversion of the compound obtained into one of its physiologically acceptable salts by reaction with an inorganic or organic base or acid.
18. The process as claimed in claim 17 ,
wherein
all steps during the bonding of the carboxylic acid derivative of the formula (2) are carried out on a solid phase.
19. The process as claimed in claim 17 ,
wherein
a carboxylic acid derivative of the formula (2), in which L is —F, —Cl , —Br or —I
and the other residues are as defined in claim 17 ,
is reacted with a phenyl compound of the formula (3), in which M is an organometallic residue;
and the other residues are as defined in claim 17 ,
in the presence of a palladium compound and of a phosphane.
20. The process as claimed in claim 17 ,
wherein
the carboxylic acid derivative of the formula (2) contains a sulfonamide or carbamate group which was formed by reaction of an amino group of the corresponding precursor of the carboxylic acid derivative of the formula (2) with a sulfonyl halide or a carbamoyl halide.
21. The process as claimed in claim 17 ,
wherein
if D is —NO 2 in the compound of the formula (4), the conversion of D into an amino group is carried out in the presence of a tin-(II) compound.
22. The process as claimed in claim 17 ,
wherein
if D is —CHO in the compound of the formula (4), the conversion of D into an amino group is carried out by reaction with an amine under reducing conditions.
23. The process as claimed in claim 17 ,
wherein
the compound of the formula (4) in which D is an amino group is converted into a urea or thiourea unit, where R 4 and R 6 are as defined in claim 17 , by a reaction of this amino group with a carbonic acid derivative or thiocarbonic acid derivative and a subsequent reaction to this with an amine of the formula NHR 4 R 6 .