Pyrrole inhibitors of S-nitrosoglutathione reductase as therapeutic agents

1. A method of treatment of heart failure, atherosclerosis, arthritis and ischemic or alcoholic liver injury comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof:

wherein

Ar 1 and Ar 2 are independently selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;

X is selected from the group consisting of C or N;

Y is C when X is N, and N when X is C; and

n is 0-3;

to a patient in need thereof.

2. The method of claim 1 wherein:

Ar 1 is a substituted phenyl; and

Ar 2 is selected from the group consisting of phenyl, substituted phenyl, thiophen-yl, substituted thiophen-yl, pyridinyl, substituted pyridinyl, thiazolyl, substituted thiazolyl, bicyclic aryl, substituted bicyclic aryl, bicyclic heteroaryl, and substituted bicyclic heteroaryl.

3. The method of claim 1 wherein:

Ar 1 is

wherein

R 1 is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, cyano, nitro, CF 3 , 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 2 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, C 1 -C 6 sulfonamido, 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 3 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; and

Ar 2 is selected from the group consisting of phenyl, 4-chlorophenyl, 3-chlorophenyl, 4-chloro-2-methoxyphenyl, 4-bromophenyl, 4-bromo-2-methoxyphenyl, 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 4 is selected from the group consisting of hydrogen, methyl, chloro, fluoro, hydroxy, methoxy, ethoxy, propoxy, carbamoyl, dimethylamino, amino, formamido, and trifluoromethyl; and

R 5 is selected from the group consisting of hydrogen, methyl, and ethyl.

4. The method of claim 1 wherein:

Ar 2 is selected from the group consisting of phenyl, 4-chloro-2-methoxyphenyl, 4-bromophenyl, 4-bromo-2-methoxyphenyl, 4-methoxyphenyl, 4-(1H-imidazol-1-yl)phenyl, 4-(2-methyl-1H-imidazol-1-yl)phenyl, and 5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl.

5. The method of claim 3 wherein:

R 1 is selected from the group consisting of hydrogen and methyl;

R 2 is selected from the group consisting of hydroxyl, carboxyl, carbamoyl, methylsulfonamido, and tert-butyl-carboxy; and

R 3 is hydrogen.

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

4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-phenyl-1H-pyrrol-1-yl)benzamide;

4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-phenyl-1H-pyrrol-1-yl)benzoic acid;

tert-butyl 4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-phenyl-1H-pyrrol-1-yl)benzoate;

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

4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-bromophenyl)-1H-pyrrol-1-yl)phenol;

4-(2-((1H-tetrazol-5-yl)methyl)-5-(4-bromophenyl)-1H-pyrrol-1-yl)phenol;

4-(2-((1H-tetrazol-5-yl)methyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)phenol;

4-(2-(4-(1H-imidazol-1-yl)phenyl)-5-(2-(1H-tetrazol-5-yl)ethyl)-1H-pyrrol-1-yl)phenol;

4-(2-((1H-tetrazol-5-yl)methyl)-5-(4-bromophenyl)-1H-pyrrol-1-yl)-3-methylbenzamide;

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

4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-bromophenyl)-1H-pyrrol-1-yl)-3-methylbenzamide;

4-(2-(4-(1H-imidazol-1-yl)phenyl)-5-((1H-tetrazol-5-yl)methyl)-1H-pyrrol-1-yl)phenol;

4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)phenol;

4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-1-yl)phenol;

4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-bromo-2-methoxyphenyl)-1H-pyrrol-1-yl)phenol;

4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-chloro-2-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzamide;

4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-bromo-2-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzamide;

4-(2-((1H-tetrazol-5-yl)methyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-1-yl)phenol;

4-(2-((1H-tetrazol-5-yl)methyl)-5-(5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-1-yl)-3-methylbenzamide;

4-(2-((1H-tetrazol-5-yl)methyl)-5-(5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-1-yl)phenol;

4-(2-((1H-tetrazol-5-yl)methyl)-5-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-pyrrol-1-yl)-3-methylbenzamide;

N-(4-(2-((1H-tetrazol-5-yl)methyl)-5-(5-(2-methyl-1H-imidazol-1-yl)thiophen-2-yl)-1H-pyrrol-1-yl)-3-methylphenyl)methanesulfonamide;

4-(1-(2-(1H-tetrazol-5-yl)ethyl)-3-(4-methoxyphenyl)-1H-pyrrol-2-yl)-3-methylbenzamide; and

4-(1-((1H-tetrazol-5-yl)methyl)-3-(4-methoxyphenyl)-1H-pyrrol-2-yl)-3-methylbenzamide.

7. 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.

8. A method of making a pharmaceutical composition comprising the step of combining a compound of formula I or a pharmaceutically acceptable salt thereof:

wherein

Ar 1 and Ar 2 are independently selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;

X is selected from the group consisting of C or N;

Y is C when X is N, and N when X is C; and

n is 0-3;

with a pharmaceutically accepted carrier or excipient.