Chromone Inhibitors of S-Nitrosoglutathione Reductase

Abstract

The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.

1 . A method of treatment of a disease or condition which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein the disease or condition is a disease where there is risk of apoptosis occurring 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of CF 3 , CF 2 H, CF 2 CH 3 , CF 2 CH 2 CH 3 , isopropyl, isobutyl, cyclopentyl, CH 2 OCH 3 , SCH 3 , benzyl, thiophen-2-yl, and thiophen-3-yl; 
 R 2  is selected from H, F, Cl, methoxy, and cyano; and 
 R 3  is selected from H, F, Cl, and methoxy. 
 
     
     
         2 . The method of  claim 1  wherein R 1  is selected from the group consisting of CF 3 , CF 2 H, and CF 2 CH 3 ; and R 2  is hydrogen. 
     
     
         3 . The method of  claim 1  wherein R 1  is selected from the group consisting of CF 3 , isopropyl, and isobutyl; and R 2  and R 3  are both hydrogen. 
     
     
         4 . The method of  claim 1  wherein R 1  is selected from the group consisting of CF 3 , isopropyl, isobutyl, CF 2 H, CF 2 CH 3 , and CF 2 CH 2 CH 3 ; and R 2  and R 3  are both hydrogen. 
     
     
         5 . The method of  claim 1  wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of
 4-(2-(difluoromethyl)-7-hydroxy-4-oxo-4H-chromen-3-yl)benzoic acid; 
 4-(7-hydroxy-2-(methoxymethyl)-4-oxo-4H-chromen-3-yl)benzoic acid; 
 4-(7-hydroxy-2-isopropyl-4-oxo-4H-chromen-3-yl)benzoic acid; 
 4-(2-cyclopentyl-7-hydroxy-4-oxo-4H-chromen-3-yl)benzoic acid; 
 4-(2-benzyl-7-hydroxy-4-oxo-4H-chromen-3-yl)benzoic acid; 
 4-(7-hydroxy-4-oxo-2-(thiophen-2-yl)-4H-chromen-3-yl)benzoic acid; 
 4-(7-hydroxy-4-oxo-2-(thiophen-3-yl)-4H-chromen-3-yl)benzoic acid; 
 4-(7-hydroxy-2-isobutyl-4-oxo-4H-chromen-3-yl)benzoic acid; 
 4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid; 
 4-(7-hydroxy-2-(methylthio)-4-oxo-4H-chromen-3-yl)benzoic acid; 
 4-(6-chloro-7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid; 
 4-(6-fluoro-7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid; 
 2-fluoro-4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid; 
 3-chloro-4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid; 
 4-(2-(1,1-difluoroethyl)-7-hydroxy-4-oxo-4H-chromen-3-yl)benzoic acid; 
 4-(7-hydroxy-6-methoxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid; 
 2-chloro-4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid; 
 4-(2-(1,1-difluoropropyl)-7-hydroxy-4-oxo-4H-chromen-3-yl)benzoic acid; 
 4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)-3-methoxybenzoic acid; and 
 4-(6-cyano-7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid. 
 
     
     
         6 . The method of  claim 1  comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically accepted carrier or excipient. 
     
     
         7 . The method of  claim 1  wherein said disease or condition is liver injury. 
     
     
         8 . The method of  claim 7  wherein the liver injury is ischemic. 
     
     
         9 . The method of  claim 7  wherein the liver injury is alcoholic. 
     
     
         10 . The method of  claim 1  wherein the said disease or condition is selected from heart failure, atherosclerosis, degenerative neurologic disorders, and arthritis.