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1. WO1991016313 - BENZIMIDAZOLES SUBSTITUES

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]
What is claimed is:
1. A compound of the formula:


in which:
R1 is -C(O) NH-CH (Y)-(CH2)n-aryl, -C(O)NH-CH(Y)-(CH2)n-heteroaryl, or phenyl unsubstituted or substituted by one to three substituents selected from CI, Br, F, I, C1-6alkyl, C1-6alkoxy, OH, CN, NO2, CO2R4, tetrazol-5-yl, CONR4R4, SO3H, CmF2m+1, SC1-6alkyl, or SO2C1-6alkyl;
R2 is hydrogen, C2-10alkyl, C3-10alkenyl, C3-6- cycloalkyl, CmF2m+1, or (CH2)0-8phenyl unsubstituted or substituted by one to three substituents selected from
C1-6alkyl, C1 -6alkoxy, CI, Br, F, I, OH, NO2, CmF2m+1,
CO2R4, or NR4R4;
R3 is -(CH2)n-Y, -CH=CY-(CH2)n-aryl, -CH=CY-(CH2)n- heteroaryl, - (CH2)n-C(O)-NH-CH(Y)-(CH2)n-aryl, -(CH)2)n- C(O)-NH-CH(Y)-(CH2)nheteroaryl, - (CH2)m-NH-CH(Y) - (CH2)n-aryl or -(CH2)m-NH-CH(Y)-(CH2)n-heteroaryl, when R1 is an
optionally substituted phenyl group; or H when R1 is
-C(O)NH-HH(Y)-(CH2)n-aryl or -C(O)NH-CH(Y)-(CH2)n- heteroaryl;
Y is CO2R4 or tetrazol-5-yl;
X is CI, Br, F, I, CmF2m+1, C1-6alkyl, C1-6alkoxy, OH, O-phenyl, CO2R4, tetrazol-5-yl, CN, or (CH2)0-4phenyl unsubstituted or substituted by CI, Br, F, I, C1 -6alkyl, C1-6alkoxy, OH, CmF2m+1, CN, CO2R4, NO2, or NR4R4;

aryl is phenyl, biphenyl, or naphthyl wherein each aryl group is unsubstituted or substituted by C1-6alkyl,
C1-6alkoxy, CI, Br, F, I, OH, NO2, CF3, CO2R4, or NR4R4;
heteroaryl is 2- or 3-thienyl, 2-, or 3-furanyl, 2-, 3-, or 4- pyridyl, pyrimidyl, imidazolyl, thiazolyl,
triazolyl, or tetrazolyl wherein each heteroaryl group is unsubstituted or substituted by C1-6alkyl, C1-6alkoxy, CI, Br, F, I, OH, NO2, CF3, CO2R4, or NR4R4;
each m independently is 1-3;
each n independently is 0-2; and
each R4 independently is H or C1-6alkyl; or a
pharmaceutically acceptable salt thereof.

2. A compound of claim 1 in which:
R1 is -C(O) NH-CH (Y)-(CH2)n-2-thienyl or phenyl
unsubstituted or substituted by one to three substituents selected from chloro, fluoro, nitro, methyl, cyano,
carbomoyl, trifluoromethyl, carboxy, carboC1-2alkoxy, tetrazol-5-yl, methoxy, or hydroxy;
R2 is hydrogen, C2-8alkyl, or CmF2m+1;
R3 is -(CH2)n-Y-, -CH=CY-(CH2)-2-thienyl, - (CH2)n-C (O) - NH-CH (Y)-(CH2)n-2-thienyl, or - (CH2)m-NH-CH (Y) - (CH2)n-2-thienyl, when R1 is an optionally substituted phenyl group; or H when R1 is -C (O) NH-CH(Y)-(CH2)n-2-thienyl; and
X is absent or present as CO2H, tetrazol-5-yl, CI, Br,

F, CF3, CH3, or (CH2)0-2phenyl taken once or twice; or a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 which is 2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid or a pharmaceutically acceptable salt thereof.

4. A compound of claim 2 which is 5-bromo-2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid or a pharmaceutically acceptable salt thereef.

5. A compound of claim 2 which is 2-n-butyl-1-(4-carboxyphenyl)methyl-5-chloro-1H-benzimidazole-7-carboxylic acid or a pharmaceutically acceptable salt thereof.

6. A compound of claim 2 which is:
2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-6-carboxylic acid;
2-n-butyl-5-phenyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid;
2-n-butyl-1-(2-chloroρhenyl)methyl-7-(1H-tetrazol-5-yl)-1H-benzimidazole;
2-n-butyl-1-(2-chloroρhenyl)methyl-1H-benzimidazole-5,7-dicarboxylic acid;
3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazol-7-yl]-2-(2-thienyl)methyl-2-propenoic acid;
2-n-butyl-5,6-dichloro-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid;
2-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazol-7-yl] acetic acid;
L-α-amino-N-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-ethyl]-2-(2-thienyl)methylpropionic acid;
1-(2-chlorophenyl)methyl-2-heptafluoropropyl-1H-benzimidazole-6-carboxylic acid;
L-α-amino-N-(2-n-butyl-1H-benzimidazole-1-propanoyl)- 2-(2-thienyl)methylpropanoic acid;
L-α-amino-N-(2-n-butyl-1H-benzimidazole-1-acetoyl)-2- (2-thienyl)methylpropionic acid;
L-α-N-[2-n-butyl-1-(2-chlorophenyl)methyl-1H- benzimidazole-7-acetoyl]-2-(2-thienyl)methylpropionic acid; methyl L-α-amino-N-(2-n-butyl-1H-benzimidazole-1- propanoyl)-2-(2-thienyl)methylpropanoate;
2-n-butyl-6-chloro-1-(2-chlorophenyl)methyl-1H- benzimidazole-7-carboxylic acid;
2-n-butyl-1-(4-carboxyphenyl)-5-chloro-1H- benzimidazole-7-carboxylic acid;

1-(4-carboxypenyl)methyl-6-chloro-1H-benzimidazole-7- carboxylic acid;
2-n-butyl-1-(4-carboxyphenyl)ethyl-5-chloro-1H-benzimidazole-7-carboxylic acid;
2-n-butyl-1-(4-carboxyphenyl)methyl-5-chloro-4-methyl- 1H-benzimidazole-7-carboxylic acid; or
2-n-butyl-5-chloro-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid; or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound of claim 1 and suitable pharmaceutical carrier.

8. A pharmaceutical composition of claim 7 wherein the compound is 2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid.

9. A pharmaceutical composition of claim 7 wherein the compound is 5-bromo-2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid.

10. A pharmaceutical composition of claim 7 wherein the compound is 2-n-butyl-1-(4-carboxyphenyl)methyl-5-chloro-1H-benzimidazole-7-carboxylic acid.

11. A pharmaceutical composition of claim 7 wherein the compound is:
2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-6-carboxylic acid;
2-n-butyl-5-phenyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid;
2-n-buty1-1-(2-chlorophenyl)methyl-7-(1H-tetrazol-5-yl)-1H-benzimidazole;
2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-5,7-dicarboxylic acid;

3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazol-7-yl]-2-(2-thienyl)methylmethyl-2-propenoic acid;
2-n-butyl-5,6-dichloro-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid;
2-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-benz-imidazol-7-yl]acetic acid;
L-α-amino-N-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-ethyl]-2-(2-thienyl)methylpropionic acid;
1-(2-chlorophenyl)methyl-2-heptafluoropropyl-1H-benzimidazole-6-carboxylic acid;
L-α-amino-N-(2-n-butyl-1H-benzimidazole-1-propanoyl)-2-(2-thienyl)methylpropanoic acid;
L-α-amino-N-(2-n-butyl-1H-benzimidazole-1-acetoyl)-2- (2-thienyl)methylpropionic acid;
L-α-N-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-acetoyl]-2-(2-thienyl)methylpropionic acid; methyl L-α-amino-N-(2-n-butyl-1H-benzimidazole-1-propanoyl)-2-(2-thienyl)methylpropanoate;
2-n-butyl-6-chloro-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid;
2-n-butyl-1-(4-carboxyphenyl)-5-chloro-1H-benzimidazole-7-carboxylic acid;
1-(4-carboxyphenyl)methyl-6-chloro-1H-benzimidazole-7- carboxylic acid;
2-n-butyl-1-(4-carboxyphenyl)ethyl-5-chloro-1H- benzimidazole-7-carboxylic acid;
2-n-butyl-1-(4-carboxyphenyl)methyl-5-chloro-5-methyl- 1H-benzimidazole-7-carboxylic acid; or
2-n-butyl-5-chloro-1-(2-chlorophenyl)methyl-1H- benzimidazole-7-carboxylic acid.

12. A method of antagonizing angiotensin II receptors in mammals which comprises administering to a subject in need thereof an effective amount of a compound of claim 1.

13. A method of claim 12 wherein the compound is 2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid.

14. A method of claim 12 wherein the compound is 5-bromo-2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid.

15. A method of claim 12 wherein the compound is 2-n-butyl-1-(4-carboxyρhenyl)methyl-5-chloro-1H-benzimidazole-6-carboxylic acid.

16. A method of claim 12 wherein the compound is:
2-n-butyl-1-(2-chloropheny)methyl-1H-benzimidazole-6-carboxylic acid;
2-n-butyl-5-phenyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid;
2-n-butyl-1-(2-chlorophenyl)methyl-7-(1H-tetrazol-5-yl)-1H-benzimidazole;
2-n-butyl-1-1(2-chlorophenyl)methyl-1H-benzimidazole-5,7-dicarboxylic acid;
3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazol-7-yl]-2-(2-thienyl)methylmethyl-2-propenoic acid;
2-n-butyl-5,6-dichloro-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid;
2-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazol-7-yl] acetic acid;
L-α-amino-N-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-ethyl]-2-(2-thienyl)methylpropionic acid;
1-(2-chlorophenyl)methyl-2-heptafluoropropyl-1H-benzimidazole-6-carboxylic acid;
L-α-amino-N-(2-n-butyl-1H-benzimidazole-1-propanoyl)-2-(2-thienyl)methylpropanoic acid;
L-α-amino-N-(2-n-butyl-1H-benzimidazole-1-acetoyl)-2-(2-thienyl)methylpropionic acid;

L-α-N-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-acetoyl]-2-(2-thienyl)methylpropionic acid; methyl L-α-amino-N-(2-n-butyl-1H-benzimidazole-1-propanoyl)-2-(2-thienyl)methylpropanoate;
2-n-butyl-6-chloro-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid;
2-n-butyl-1-(4-carboxyphenyl)-5-chloro-1H-benzimidazole-7-carboxylic acid;
1-(4-carboxyphenyl)methyl-6-chloro-1H-benzimidazole-7-carboxylic acid;
2-n-butyl-1-(4-carboxyphenyl)ethyl-5-chloro-1H-benzimidazole-7-carboxylic acid;
2-n-butyl-1-(4-carboxyphenyl)methyl-5-chloro-4-methyl-1H-benzimidazole-7-carboxylic acid; or
2-n-butyl-5-chloro-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid.

17. A method of treating hypertension in mammals which comprises administering to a subject in need thereof an effective amount of a compound of claim 1.

18. A method of treating congestive heart failure in mammals which comprises administering to a subject in need thereof an effective amount of a compound of claim 1.

19. A method of treating renal failure in mammals which comprises adminstering to a subject in need thereof an effective amount of a compound of claim 1.

20. A method of treating glaucoma in mammals wcich comprises administering to a subject in need thereof an effective amount of a compound of claim 1.