Biaryloxymethylarenecarboxylic acids as glycogen synthase activators

Abstract

The present invention relates to compounds of formula (I) wherein Ar, Ar 2 , R 2 , R 3 , R 4 , m, p and s are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prophylaxis of diseases that are associated with the activation of the glycogen synthase enzyme, such as diabetes.

1 . A compound of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein 
     Ar is a phenyl ring; 
     Ar 2  is a substituted or unsubstituted cyclic ring selected from the group consisting of benzo[1,3]dioxol-5-yl, furan-2-yl, isoquinolin-5-yl, isoxazol-4-yl, 1-naphthyl, pyrazol-1-yl, pyrazol-4-yl, pyridin-3-yl, thiophen-2-yl, thiophen-3-yl and phenyl and where substituted the substituents are selected from the group consisting of acetamido, aminocarbonyl, benzyl, benzyloxy, halogen, hydroxyl-lower alkyl, lower alkyl, lower alkoxy-lower alkyl, phenoxy, phenyl, lower alkoxy and trifluoro-methoxy; 
     R 2  and R 3  are independently selected from the group consisting of lower alkyl, lower alkoxy, trifluoromethyl, halogen, hydroxy, amino, alkylamino, diakylamino, cyano and nitro; 
     R 4  is hydroxy or an amino acid attached through a nitrogen atom of the amino acid; 
     m is 0, 1, 2, 3 or 4; 
     p is 0, 1 or 2, and 
     s is 0, 1 or 2 or a pharmaceutically acceptable salt thereof, 
     provided that when Ar 2  is phenyl, the phenyl ring is substituted by at least one substituent selected from the group consisting of acetamido, aminocarbonyl, benzloxy, hydroxyl-lower alkyl, lower-alkoxy-lower alkyl, phenoxy, phenyl, pyrazol-1-yl and trifluoromethoxy and when Ar2 is substituted or unsubstituted phenyl, there are not two lower alkyl substituents ortho to the point of attachment of the Ar2 ring. 
   
   
       2 . The compound of  claim 1  wherein Ar 2  is phenyl substituted in the meta position by acetamido, aminocarbonyl or hydroxymethyl. 
   
   
       3 . The compound of  claim 1  wherein Ar 2  is pyridin-3-yl. 
   
   
       4 . The compound of  claim 3  wherein the pyridin-3-yl is substituted by halogen. 
   
   
       5 . The compound of  claim 1  wherein Ar 2  is phenyl substituted in the ortho position by trifluoromethoxy. 
   
   
       6 . The compound of  claim 1  wherein Ar 2  is phenyl substituted in the ortho position by methoxymethyl, benzyloxy or phenoxy. 
   
   
       7 . The compound of  claim 1  wherein Ar 2  is 1-naphthyl. 
   
   
       8 . The compound of  claim 1  wherein Ar 2  is benzo[1,3]dioxol-5-yl. 
   
   
       9 . The compound of  claim 1  wherein Ar 2  is thiophen-3-yl. 
   
   
       10 . A compound of  claim 1  having the formula 
     
       
         
         
             
             
         
       
     
     wherein 
     Ar 2  is a substituted or unsubstituted cyclic ring selected from the group consisting of benzo[1,3]dioxol-5-yl, furan-2-yl, isoquinolin-5-yl, isoxazol-4-yl, 1-naphthyl, pyrazol-1-yl, pyrazol-4-yl, pyridin-3-yl, thiophen-2-yl, thiophen-3-yl and phenyl and where substituted the substituents are selected from the group consisting of acetamido, aminocarbonyl, benzyl, benzyloxy, halogen, hydroxyl-lower alkyl, lower alkyl, lower alkoxy-lower alkyl, phenoxy, phenyl, lower alkoxy and trifluoro-methoxy; 
     R 2  is selected from the group consisting of lower alkyl, lower alkoxy, trifluoromethyl, halogen, hydroxy, amino, alkylamino, diakylamino, cyano and nitro; 
     provided that when Ar 2  is phenyl, the phenyl ring is substituted by at least one substituent selected from the group consisting of acetamido, aminocarbonyl, benzloxy, hydroxyl-lower alkyl, lower-alkoxy-lower alkyl, phenoxy, phenyl, pyrazol-1-yl and trifluoromethoxy and when Ar2 is substituted or unsubstituted phenyl, there are not two lower alkyl substituents ortho to the point of attachment of the Ar2 ring; 
     m is 0, 1, 2, 3 or 4
 and the pharmaceutically acceptable salts thereof. 
 
   
   
       11 . A compound of  claim 1  having the formula 
     
       
         
         
             
             
         
       
     
     wherein 
     Ar 2  is a substituted or unsubstituted cyclic ring selected from the group consisting of benzo[1,3]dioxol-5-yl, furan-2-yl, isoquinolin-5-yl, isoxazol-4-yl, 1-naphthyl, pyrazol-1-yl, pyrazol-4-yl, pyridin-3-yl, thiophen-2-yl, thiophen-3-yl and phenyl and where substituted the substituents are selected from the group consisting of acetamido, aminocarbonyl, benzyl, benzyloxy, halogen, hydroxyl-lower alkyl, lower alkyl, lower alkoxy-lower alkyl, phenoxy, phenyl, lower alkoxy and trifluoro-methoxy; 
     R 2  is selected from the group consisting of lower alkyl, lower alkoxy, trifluoromethyl, halogen, hydroxy, amino, alkylamino, diakylamino, cyano and nitro; 
     provided that when Ar 2  is phenyl, the phenyl ring is substituted by at least one substituent selected from the group consisting of acetamido, aminocarbonyl, benzloxy, hydroxyl-lower alkyl, lower-alkoxy-lower alkyl, phenoxy, phenyl, pyrazol-1-yl and trifluoromethoxy and when Ar2 is substituted or unsubstituted phenyl, there are not two lower alkyl substituents ortho to the point of attachment of the Ar2 ring; 
     m is 0, 1, 2, 3 or 4
 and the pharmaceutically acceptable salts thereof. 
 
   
   
       12 . A compound selected from the group consisting of 
     3-(3′-Acetylamino-biphenyl-4-yloxymethyl)-benzoic acid; 
     3-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-benzoic acid; 
     3-(3′-Carbamoyl-biphenyl-4-yloxymethyl)-benzoic acid; 
     3-[4-(2-Chloro-pyridin-3-yl)-phenoxymethyl]-benzoic acid; 
     3-[4-(6-Chloro-pyridin-3-yl)-phenoxymethyl]-benzoic acid; 
     3-[4-(3,5-Dimethyl-isoxazol-4-yl)-phenoxymethyl]-benzoic acid; 
     3-[4-(2-Fluoro-pyridin-3-yl)-phenoxymethyl]-benzoic acid; 
     3-[4-(6-Fluoro-pyridin-3-yl)-phenoxymethyl]-benzoic acid; 
     3-(4-Furan-2-yl-phenoxymethyl)-benzoic acid; 
     3-(3′-Hydroxymethyl-biphenyl-4-yloxymethyl)-benzoic acid; 
     3-(4-Isoquinolin-5-yl-phenoxymethyl)-benzoic acid; 
     3-(2′-Methoxymethyl-biphenyl-4-yloxymethyl)-benzoic acid; 
     3-(3′-Methoxymethyl-biphenyl-4-yloxymethyl)-benzoic acid; 
     3-(4-Naphthalen-1-yl-phenoxymethyl)-benzoic acid; 
     3-(2′-Phenoxy-biphenyl-4-yloxymethyl)-benzoic acid; 
     3-(3′-Pyrazol-1-yl-biphenyl-4-yloxymethyl)-benzoic acid; 
     3-(4-Pyridin-3-yl-phenoxymethyl)-benzoic acid; 
     3-(4-Thiophen-3-yl-phenoxymethyl)-benzoic acid; 
     3-(2′-Trifluoromethoxy-biphenyl-4-yloxymethyl)-benzoic acid; 
     3-(4′-Trifluoromethoxy-biphenyl-4-yloxymethyl)-benzoic acid; 
     [3-(3′-Acetylamino-biphenyl-4-yloxymethyl)-phenyl]-acetic acid; 
     [3-(3′-Hydroxymethyl-biphenyl-4-yloxymethyl)-phenyl]-acetic acid; 
     [3-(2′-Methoxymethyl-biphenyl-4-yloxymethyl)-phenyl]-acetic acid; 
     {3-[4-(2-Methoxy-pyridin-3-yl)-phenoxymethyl]-phenyl}-acetic acid; and 
     [3-(2′-Trifluoromethoxy-biphenyl-4-yloxymethyl)-phenyl]-acetic acid 
   
   
       13 . A pharmaceutical composition comprising a compound of the formula 
     
       
         
         
             
             
         
       
     
     wherein 
     Ar is a phenyl ring; 
     Ar 2  is a substituted or unsubstituted cyclic ring selected from the group consisting of benzo[1,3]dioxol-5-yl, furan-2-yl, isoquinolin-5-yl, isoxazol-4-yl, 1-naphthyl, pyrazol-1-yl, pyrazol-4-yl, pyridin-3-yl, thiophen-2-yl, thiophen-3-yl and phenyl and where substituted the substituents are selected from the group consisting of acetamido, aminocarbonyl, benzyl, benzyloxy, halogen, hydroxyl-lower alkyl, lower alkyl, lower alkoxy-lower alkyl, phenoxy, phenyl, lower alkoxy and trifluoro-methoxy; 
     R 2  and R 3  are independently selected from the group consisting of lower alkyl, lower alkoxy, trifluoromethyl, halogen, hydroxy, amino, alkylamino, diakylamino, cyano and nitro; 
     R 4  is hydroxy or an amino acid attached through a nitrogen atom of the amino acid; 
     m is 0, 1, 2, 3 or 4; 
     p is 0, 1 or 2, and 
     s is 0, 1 or 2 or a pharmaceutically acceptable salt thereof, 
     provided that when Ar 2  is phenyl, the phenyl ring is substituted by at least one substituent selected from the group consisting of acetamido, aminocarbonyl, benzloxy, hydroxyl-lower alkyl, lower-alkoxy-lower alkyl, phenoxy, phenyl, pyrazol-1-yl and trifluoromethoxy and when Ar2 is substituted or unsubstituted phenyl, there are not two lower alkyl substituents ortho to the point of attachment of the Ar2 ring, 
     together with a pharmaceutically acceptable carrier and/or excipient.