Oxydecahydronaphthalene modulators of hm74

Abstract

Host cells expressing HM74 were used to obtain oxydecalin-like molecules with agonist activity having the following structure:

1 . A therapeutic method for modulating HM74 signaling activity or signal transduction in a patient in need of treatment comprising administering to said patient a molecule having the structure:  
     
       
         
         
             
             
         
       
       where X is O, NR 2  or S;  
       R 1  is a C 1 -C 18  alkyl, which may be branched, may contain a heteroatom or may be substituted, or combinations thereof; a C 1 -C 18  alkenyl, which may be branched, may contain a heteroatom or may be substituted, or combinations thereof; a C 1 -C 18  alkynl, which may be branched, may contain a heteroatom or may be substituted, or combinations thereof; a C 3 -C 18  aryl which may contain a side group, may contain a bridge, may contain a heteroatom or may be substituted, or combinations thereof; or a C 5 -C 18  cycloalkyl which may contain a side group, may contain a bridge, may contain a heteroatom or may be substituted, or combinations thereof; or combinations thereof;  
       R2is an R1 group; or R2 can be a (C1—C10) alkyl-(C3—C10) cycloalkyl, which may be branched, may contain a heteroatom or may be substituted, or combinations thereof; or X and R2 may form a ring;  
       R3 is H or R1; and  
       Y is carbonyl, a Schiff base, an oxine, a ketal, an acetal, an oxazolidine, a thiazolidine or an enol ester.  
     
   
   
       2 . A method of modulating inflammation comprising exposing a patient in need of treatment an inflammation modulating amount of a pharmaceutical composition comprising a compound of the formula:  
     
       
         
         
             
             
         
       
       where X is O, NR 2  or S;  
       R 1  is a C 1 -C 18  alkyl, which may be branched, may contain a heteroatom or may be substituted, or combinations thereof; a C 1 -C 18  alkenyl, which may be branched, may contain a heteroatom or may be substituted, or combinations thereof; a C 1 -C 18  alkynl, which may may contain a heteroatom or may be substituted, or combinations thereof; a C 3 -C 18  aryl which may contain a side group, may contain a bridge, may contain a heteroatom or may be substituted, or combinations thereof; or a C 5 -C 18  cycloalkyl which may contain a side group, may contain a bridge, may contain a heteroatom or may be substituted, or combinations thereof; or combinations thereof; 
 R 2 is an R 1  group, a (C1—C10) alkyl-(C3—C10) cycloalkyl, which may be branched, may contain a heteroatom or may be substituted, or combinations thereof; or X and R 2  may form a ring;  
 R 3  is H or R 1 ; and  
 
       Y is carbonyl, a Schiff base, an oxine, a ketal, an acetal, an oxazolidine, a thiazolidine a thiazolidine or an enol ester.  
     
   
   
       3 . A compound of the formula:  
     
       
         
         
             
             
         
       
       where X is O, NR 2  or S;  
       R 1  is a C 1 -C 18  alkyl, which may be branched, may contain a heteroatom or may be substituted, or combinations thereof; a C 1 -C 18  alkenyl, which may be branched, may contain a heteroatom or may be substituted, or combinations thereof; a C 1 -C 18  alkynl, which may be branched, may contain a heteroatom or may be substituted, or combinations thereof; a C 3 -C 18  aryl which may contain a side group, may contain a bridge, may contain a heteroatom or may be substituted, or combinations thereof; or a C 5 -C 18  cycloalkyl which may contain a side group, may contain a bridge, may contain a heteroatom or may be substituted, or combinations thereof; or combinations thereof;  
       R 2 is an R 1  group, a (C 1 -C 10 ) alkyl-(C 3 -C 10 ) cycloalkyl, which may be branched, may contain a heteroatom or may be substituted, or combinations thereof; or X and R 2  may form a ring;  
       R 3  is H or R 1 ; and  
       Y is carbonyl, a Schiff base, an oxine, a ketal, an acetal, an oxazolidine, a thiazolidine or an enol ester.  
       with the proviso that when R 2  is methyl, ethyl or cyclohexyl, R 1  is not an n-alkyl or a C 1 -C 4  branched alkyl; or when R 2  is a C 1 -C 4  alcohol or a C 1 -C 4  branched alkyl which may be substituted with an acetyl group, R 1  is not an n-(C 1 -C 8 ) alkyl, a (C 1 -C 4 ) branched alkyl or a thio substituted phenyl.