Novel Substituted Bicyclic Aromatic Compounds as S-Nitrosoglutathione Reductase Inhibitors

Abstract

The present invention is directed to novel substituted bicyclic aromatic compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.

What is claimed is: 
     
         1 . The compound of Formula 1: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of H, F, and Cl; 
         R 2a  and R 2b  are independently selected from the group consisting of H, F, Cl, Br, Me, OCH 3 , and cyano; 
         R 2c  is selected from the group consisting of H, F, Cl, Br, Me, and OCH 3 ; 
         X is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         A is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         R 3  is selected from the group consisting of F, Cl, Br, CH 3 , CF 3 , OCH 3 , cyano, N(CH 3 ) 2 , and morpholino; 
         n is selected from the group consisting of 0, 1, and 2; 
         R 4  is selected from the group consisting of H, F, Cl, Br, CH 3 , CF 3 , OCH 3 , cyano, N(CH 3 ) 2 , and morpholino; 
       
       
         
           
           
               
               
           
         
         with the proviso that when X is and A is COOH, then at least one of R 1 , R 2a , R 2b , R 2c , and R 4  is not hydrogen, or n must be >0, and R 3  when meta to naphthalene, cannot be CH 3 . 
       
     
     
         2 . The compound of  claim 1  wherein
 X is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1  wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 3  wherein R 2c  is hydrogen. 
     
     
         5 . The compound of  claim 3  where R 2b  is hydrogen. 
     
     
         6 . The compound of  claim 1  wherein the compound is a compound of Formula 3 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 6  wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 7  where A is COOH. 
     
     
         9 . The compound of  claim 1  wherein the compound is a compound of Formula 5 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 9  wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 10  wherein A is COOH. 
     
     
         12 . Use of a compound of the Formula 1 as defined in  claim 1  or a pharmaceutically acceptable salt thereof as a GSNOR inhibitor. 
     
     
         13 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 1  together with a pharmaceutically accepted carrier or excipient. 
     
     
         14 . A method of treatment of a disease or condition which comprises administering a therapeutically effective amount of a compound of Formula 1 as defined in  claim 1  to a patient in need thereof wherein the disease or condition is a pulmonary disorder. 
     
     
         15 . The method of  claim 14  wherein the disease or condition is selected from the group consisting of asthma, chronic obstructive pulmonary disorder (COPD) and cystic fibrosis. 
     
     
         16 . A method of treatment of a disease or condition which comprises administering a therapeutically effective amount of a compound of Formula 1 as defined in  claim 1  to a patient in need thereof wherein the disease or condition is an inflammatory disease. 
     
     
         17 . The method of  claim 16  wherein the disease or condition is inflammatory bowel disease (IBD). 
     
     
         18 . A method of making a pharmaceutical composition comprising combining a compound of Formula 1 as defined in  claim 1  with a pharmaceutically acceptable carrier or excipient.