Pyrrole inhibitors of S-nitrosoglutathione reductase

1. A method of treatment of chronic inflammatory disease comprising administering a therapeutically effective amount of a compound of formula I:

wherein

R 1 is selected from the group consisting of R 5 and R 6 ;

R 1 ′ is R 5 when R 1 is R 6 , and R 6 when R 1 is R 5 ;

R 2 is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, cyano, nitro, trifluoromethyl, carbamoyl, C 1 -C 6 alkylcarbamoyl, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 alkoxyl, and C 3 -C 6 cycloalkoxyl;

R 3 is selected from the group consisting of halogen, hydroxyl, carbamoyl, substituted carbamoyl, C 1 -C 6 alkylcarbamoyl, sulfamoyl, C 1 -C 6 alkylsulfamoyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, cyano, nitro, amino, CF 3 , carboxyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, arylamino, heteroarylamino, C 1 -C 6 alkoxyl, C 3 -C 6 cycloalkoxyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R 4 is selected from the group consisting of hydrogen, hydroxyl, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, cyano, nitro, carbamoyl, C 1 -C 6 alkylcarbamoyl, sulfamoyl, C 1 -C 6 alkyl sulfamoyl, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 alkoxyl, and C 3 -C 6 cycloalkoxyl;

R 5 is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R 6 is selected from the group consisting of —CR 7 R 8 CR 9 R 10 (CR 11 R 12 ) n R 13 and

R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently selected from the group consisting of hydrogen, hydroxyl, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl and wherein R 9 and R 10 together form a C 3 -C 6 cycloalkyl;

R 13 is selected from the group consisting of COOH and NH 2 SO 2 CF 3 ;

R 14 is selected from the group consisting of OH, COOH, and SO 2 NH 2 ;

R 15 and R 16 are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, NO 2 , and halogen;

n is 0 or 1; and

X and Y are independently selected from the group consisting of C and N.

2. The method of claim 1 wherein R 5 is selected from the group consisting of 4-chlorophenyl, 3-chlorophenyl, 4-chloro-2-methoxyphenyl, 4-bromophenyl, 3-bromophenyl, 4-fluorophenyl, 3-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-chlorothiophen-2-yl, 5-chlorothiophen-2-yl, 3-bromothiophen-2-yl, 4-bromothiophen-2-yl, 5-bromothiopheny-2-yl, 5-bromothiophen-3-yl,

wherein

R 17 is selected from the group consisting of hydrogen, methyl, chloro, fluoro, hydroxy, methoxy, ethoxy, propoxy, carbamoyl, dimethylamino, amino, formamido, and trifluoromethyl; and

R 18 is selected from the group consisting of hydrogen, methyl, and ethyl.

3. The method of claim 2 wherein R 2 is C 1 -C 6 alkyl, R 3 is carbamoyl, and R 4 is hydrogen.

4. The method of claim 3 wherein R 5 is selected from the group consisting of 4-methoxyphenyl, 4-chloro-2-methoxyphenyl, 4-(1H-imidazol-1-yl)phenyl, and 4-(2-methyl-1H-imidazol-1-yl)phenyl.

5. The method of claim 1 wherein the compound of formula I is selected from the group consisting of:

3-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)propanoic acid;

3-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-phenylpropanoic acid;

3-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)-2-methylpropanoic acid;

4-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)butanoic acid;

3-(3-(4-(1H-imidazol-1-yl)phenyl)-2-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-1-yl)propanoic acid;

3-(2-(4-carbamoyl-2-methylphenyl)-1-(4-methoxyphenyl)-1H-pyrrol-3-yl)propanoic acid;

3-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)butanoic acid;

1-((2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)methyl)cyclopropanecarboxylic acid;

3-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)-2,2-difluoropropanoic acid;

3-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)-2-hydroxypropanoic acid;

3-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)hexanoic acid;

3-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)-4-methylpentanoic acid;

3-(1-(4-(1H-imidazol-1-yl)phenyl)-2-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-3-yl)propanoic acid;

3-(2-(4-carbamoyl-2-methylphenyl)-1-(4-chloro-2-methoxyphenyl)-1H-pyrrol-3-yl)propanoic acid;

4-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)-2-hydroxybenzoic acid;

4-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)-2-fluorobenzoic acid;

4-(1-(4-hydroxy-3-nitrophenyl)-3-(4-methoxyphenyl)-1H-pyrrol-2-yl)-3-methylbenzamide;

4-(1-(6-hydroxypyridin-3-yl)-3-(4-methoxyphenyl)-1H-pyrrol-2-yl)-3-methylbenzamide;

4-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)benzoic acid;

4-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)-2-chlorobenzoic acid;

4-(3-(4-methoxyphenyl)-1-(2-(trifluoromethylsulfonamido)ethyl)-1H-pyrrol-2-yl)-3-methylbenzamide;

4-(3-(4-methoxyphenyl)-1-(4-sulfamoylphenyl)-1H-pyrrol-2-yl)-3-methylbenzamide;

4-(1-(3-fluoro-4-hydroxyphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-2-yl)-3-methylbenzamide;

5-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)picolinic acid;

4-(1-(3,5-difluoro-4-hydroxyphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-2-yl)-3-methylbenzamide;

4-(1-(5-hydroxypyridin-2-yl)-3-(4-methoxyphenyl)-1H-pyrrol-2-yl)-3-methylbenzamide;

5-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)-2-hydroxybenzoic acid;

6-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)nicotinic acid;

4-(1-(3-fluoro-4-hydroxyphenyl)-3-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)-3-methylbenzamide; and

4-(1-(3,5-difluoro-4-hydroxyphenyl)-3-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-2-yl)-3-methylbenzamide.

6. The method of claim 1 comprising a pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 together with a pharmaceutically accepted carrier or excipient.

7. The method of claim 1 , wherein said chronic inflammatory disease is selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, colitis, psoriasis, and AIDS related dementia.

8. The method of claim 7 , wherein said chronic inflammatory disease is inflammatory bowel disease (IBD).

9. The method of claim 7 , wherein said chronic inflammatory disease is Crohn's disease.

10. The method of claim 7 , wherein said chronic inflammatory disease is colitis.

11. A method of making a pharmaceutical composition comprising the step of combining a compound of formula I:

wherein

R 1 is selected from the group consisting of R 5 and R 6 ;

R 1 ′ is R 5 when R 1 is R 6 , and R 6 when R 1 is R 5 ;

R 2 is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, cyano, nitro, trifluoromethyl, carbamoyl, C 1 -C 6 alkylcarbamoyl, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 alkoxyl, and C 3 -C 6 cycloalkoxyl;

R 3 is selected from the group consisting of halogen, hydroxyl, carbamoyl, substituted carbamoyl, C 1 -C 6 alkylcarbamoyl, sulfamoyl, C 1 -C 6 alkylsulfamoyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, cyano, nitro, amino, CF 3 , carboxyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, arylamino, heteroarylamino, C 1 -C 6 alkoxyl, C 3 -C 6 cycloalkoxyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R 4 is selected from the group consisting of hydrogen, hydroxyl, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, cyano, nitro, carbamoyl, C 1 -C 6 alkylcarbamoyl, sulfamoyl, C 1 -C 6 alkyl sulfamoyl, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 alkoxyl, and C 3 -C 6 cycloalkoxyl;

R 5 is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R 6 is selected from the group consisting of —CR 7 R 8 CR 9 R 10 (CR 11 R 12 ) n R 13 and

R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently selected from the group consisting of hydrogen, hydroxyl, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl and wherein R 9 and R 10 together form a C 3 -C 6 cycloalkyl;

R 13 is selected from the group consisting of COOH and NH 2 SO 2 CF 3 ;

R 14 is selected from the group consisting of OH, COOH, and SO 2 NH 2 ;

R 15 and R 16 are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, NO 2 , and halogen;

n is 0 or 1; and

X and Y are independently selected from the group consisting of C and N;

with a pharmaceutically accepted carrier or excipient.