Oxazolyl-aryloxyacetic acid derivatives and their use as ppar agonists

Abstract

Compounds represented by the following structural formula (I), and pharmaceutically acceptable salts, solvates and hydrates thereof, wherein R1 is an unsubstituted or substituted aryl, heteroaryl, cycloalkyl, aryl-alkyl, heteroaryl-alkyl or cycloalkyl-alkyl, R2 is H, alkyl or haloalkyl, the polymethylene chain (II), is saturated or may contain a carbon-carbon double bond, while n is 2, 3, 4, W is O or S, Y is an unsubstituted or substituted phenylene, naphthylene or 1, 2, 3, 4 tetrahydronaphthylene, R3 is H, alkyl or haloalkyl, R4 is H, alkyl, haloalkyl or a substituted or unsubstituted benzyl, are useful for modulating a preoxisome proliferator activated receptor, particularly in the treatment of diabetes mellitus.

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         11 . A compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, solvates and hydrates thereof, wherein: 
         R1 is an unsubstituted or substituted group selected from aryl, heteroaryl, cycloalkyl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl or cycloalkyl-C1-C4 alkyl; 
         R5 is H, C1-C4 alkyl or aminoalkyl; 
         R6 are each, independently, H, halo, C1-C6 alkyl, C1-C6 
         alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cycloalkyl, cycloalkyl-C1-C4 alkyl, aryl-C1-C4 alkyl, or together with the phenyl to which they are bound form naphthyl or 1,2,3,4-tetrahydronaphthy; 
         R7 are each, independently, H, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 
         C1-C6 haloalkoxy, cycloalkyl-C 1 -C 4  alkyl, or aryl-C1-C4 alkyl; 
         R8 is C1-C4 alkyl or C1-C4 haloalkyl; 
         R9 is C1-C6 alkyl or C1-C6 haloalkyl; and 
         R10 is C1-C10 alkyl, C1-C 10  haloalkyl, or a substituted or unsubstituted benzyl. 
       
     
     
         12 . A compound of  claim 11  wherein R1 is substituted or unsubstituted phenyl. 
     
     
         13 . A compound of  claim 11  wherein R1 is substituted or unsubstituted cyclohexyl. 
     
     
         14 . A compound of  claim 11  wherein R1 is substituted or unsubstituted 2-thienyl. 
     
     
         15 . A compound of  claim 11  wherein R8 and
 R9 are each methyl.   
     
     
         16 . A compound of  claim 11  wherein each R6 is H. 
     
     
         17 . A compound of  claim 11  wherein each R7 is H. 
     
     
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         22 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of  claim 11 , or a pharmaceutically acceptable salt, solvate or hydrate thereof. 
     
     
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         26 . A method of treating diabetes mellitus in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound of  claim 11 , or a pharmaceutically acceptable salt, solvate or hydrate thereof. 
     
     
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         54 . A compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, solvates and hydrates thereof, wherein: 
         R1 is an unsubstituted or substituted group selected from aryl, heteroaryl, cycloalkyl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl or cycloalkyl-C1-C4 alkyl; 
         R5 is H, C1-C4 alkyl or aminoalkyl; 
         R6 are each, independently, H, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cycloalkyl, cycloalkyl-C1-C4 alkyl, aryl-C1-C4 alkyl, or together with the phenyl to which they are bound form naphthyl or 1,2,3,4-tetrahydronaphthy; 
         R7 are each, independently, H, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cycloalkyl-C1-C4 alkyl, or aryl-C1-C4 alkyl or C1-C6alkoxybenzyl, C1-C6 alkoxyaryl or a group of the formula 
       
       
         
           
           
               
               
           
         
         R8 is C1-C4 alkyl or C1-C4 haloalkyl; 
         R9 is C1-C6 alkyl or C1-C6 haloalkyl; 
         R10 is C1-C10 alkyl, C1-C10 haloalkyl, or a substituted or unsubstituted benzyl; and 
         R13 is selected from the group consisting of benzyl, substituted benzyl, aryl, substituted aryl, substituted C1-C6 cycloalkyl, C1-C6 cycloalkyl and C1-C6 alkyl. 
       
     
     
         55 . A compound of  claim 54  wherein R13 is selected from the group consisting of is selected from the group consisting of benzyl, substituted benzyl, C1-C6 cycloalkyl, C1-C6 alkyl. 
     
     
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