Isoxazole derivatives

Abstract

A compound represented by the formula (I) wherein one of R 1 and R 2 is a hydrogen atom or a substituent and the other is an optionally substituted cyclic group; W is a bond or a divalent aliphatic hydrocarbon group; Y is a group of the formula: —OR 3 (wherein R is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group) or an optionally esterified or amidated carboxyl group, or a salt thereof or a prodrug thereof has a superior insulin secretion promoting action and a hypoglycemic action and shows low toxicity. Therefore, the compound is useful as a pharmaceutical agent, particularly as an agent for the prophylaxis or treatment of diabetes and diabetic complications, and the like.

1 . A pharmaceutical composition for the prophylaxis or treatment of diabetes, which comprises a compound represented by the formula (Ia)  
     
       
         
         
             
             
         
       
       wherein one of R 1  and R 2  is a hydrogen atom or a substituent and the other is an optionally substituted cyclic group;  
       W is a bond or a divalent aliphatic hydrocarbon group;  
       Y is a group of the formula: —OR 3 , wherein R 3  is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or Y is an optionally esterified or amidated carboxyl group, provided that when R 1  or R 2  is 3,5-di-tert-butyl-4-hydroxyphenyl and W is C 1-4  alkylene, Y should not be OH, or a salt thereof or a prodrug thereof.  
     
   
   
       2 . A pharmaceutical composition for the prophylaxis or treatment of impaired glucose tolerance, which comprises a compound represented by the formula (I)  
     
       
         
         
             
             
         
       
       wherein one of R 1  and R 2  is a hydrogen atom or a substituent and the other is an optionally substituted cyclic group;  
       W is a bond or a divalent aliphatic hydrocarbon group;  
       Y is a group of the formula: —OR 3 , wherein R 3  is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or Y is an optionally esterified or amidated carboxyl group, or a salt thereof or a prodrug thereof.  
     
   
   
       3 . An insulin secretagogue comprising a compound represented by the formula (I)  
     
       
         
         
             
             
         
       
       wherein one of R 1  and R 2  is a hydrogen atom or a substituent and the other is an optionally substituted cyclic group;  
       W is a bond or a divalent aliphatic hydrocarbon group;  
       Y is a group of the formula: —OR 3 , wherein R 3  is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or Y is an optionally esterified or amidated carboxyl group, or a salt thereof or a prodrug thereof.  
     
   
   
       4 . A pharmaceutical composition for the prophylaxis or treatment of diabetic complications, which comprises 
 a compound represented by the formula (I)                        wherein one of R 1  and R 2  is a hydrogen atom or a substituent and the other is an optionally substituted cyclic group;    W is a bond or a divalent aliphatic hydrocarbon group;    Y is a group of the formula: —OR 3 , wherein R 3  is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or Y is an optionally esterified or amidated carboxyl group,    wherein at least one of R 1 , R 2 , R 3  or Y comprises a heterocycle or a heteroaryl,      or a salt thereof or a prodrug thereof.    
   
   
       5 . The composition of  claim 4 , wherein the diabetic complication is neuropathy.  
   
   
       6 . A compound represented by the formula (II)  
     
       
         
         
             
             
         
       
       wherein one of R 1a  and R 2a  is a hydrogen atom and the other is an optionally substituted cyclic group;  
       Wa is a divalent aliphatic hydrocarbon group;  
       Y is a group of the formula: —OR 3 , wherein R 3  is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or Y is an optionally esterified or amidated carboxyl group,  
       wherein at least one of R 1a , R 2 , R 3  or Y comprises a heterocycle or a heteroaryl,  
       provided that when Wa is C 1-3  alkylene and Y is a group of the formula: —OR 3  (wherein R 3  is as defined above) or an optionally methylesterified carboxyl group, R 1a  should be a hydrogen atom and R 2a  should be an optionally substituted cyclic group,  
       or a salt thereof.  
     
   
   
       7 . The compound of  claim 6 , wherein the optionally substituted cyclic group represented by R 1a  or R 2a  is an optionally substituted aromatic group.  
   
   
       8 . The compound of  claim 6 , wherein R 1a  is a hydrogen atom and R 2a  is an optionally substituted cyclic group.  
   
   
       9 . The compound of  claim 8 , wherein R 2a  is an optionally substituted aromatic group.  
   
   
       10 . The compound of  claim 6 , wherein Wa is a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms.  
   
   
       11 . The compound of  claim 6 , wherein Y is an optionally amidated carboxyl group.  
   
   
       12 . A prodrug of the compound of  claim 6 .  
   
   
       13 . The compound of  claim 6 , which is 
 N-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-3-(5-phenyl-4-isoxazolyl)propionamide;    N-benzyl-N-(1-benzyl-3-pyrrolidinyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide.    
   
   
       14 . A pharmaceutical composition comprising the compound of  claim 6  or a prodrug thereof.  
   
   
       15 . A glucose-dependent insulin secretagogue comprising an isoxazole derivative.  
   
   
       16 . A method for the prophylaxis or treatment of diabetes in a mammal, which comprises administering to said mammal an effective amount of a compound represented by the formula (Ia)  
     
       
         
         
             
             
         
       
       wherein one of R 1  and R 2  is a hydrogen atom or a substituent and the other is an optionally substituted cyclic group;  
       W is a bond or a divalent aliphatic hydrocarbon group;  
       Y is a group of the formula: —OR 3 , wherein R 3  is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or Y is an optionally esterified or amidated carboxyl group, provided that when R 1  or R 2  is 3,5-di-tert-butyl-4-hydroxyphenyl and W is C 1-4  alkylene, Y should not be OH, or a salt thereof or a prodrug thereof.  
     
   
   
       17 . A method for the prophylaxis or treatment of diabetic complication in a mammal, which comprises administering to said mammal an effective amount of a compound represented by the formula (I)  
     
       
         
         
             
             
         
       
       wherein one of R 1  and R 2  is a hydrogen atom or a substituent and the other is an optionally substituted cyclic group;  
       W is a bond or a divalent aliphatic hydrocarbon group;  
       Y is a group of the formula: —OR 3 , wherein R 3  is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or Y is an optionally esterified or amidated carboxyl group,  
       wherein at least one of R 1 , R 2 , R 3  or Y comprises a heterocycle or a heteroaryl,  
       or a salt thereof or a prodrug thereof.  
     
   
   
       18 . A method for the prophylaxis or treatment of impaired glucose tolerance in a mammal, which comprises administering to said mammal an effective amount of a compound represented by the formula (I)  
     
       
         
         
             
             
         
       
       wherein one of R 1  and R 2  is a hydrogen atom or a substituent and the other is an optionally substituted cyclic group;  
       W is a bond or a divalent aliphatic hydrocarbon group;  
       Y is a group of the formula: —OR 3 , wherein R 3  is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or Y is an optionally esterified or amidated carboxyl group, or a salt thereof or a prodrug thereof.  
     
   
   
       19 . A method for promoting an insulin secretion in a mammal, which comprises administering to said mammal an effective amount of a compound represented by the formula (I)  
     
       
         
         
             
             
         
       
       wherein one of R 1  and R 2  is a hydrogen atom or a substituent and the other is an optionally substituted cyclic group;  
       W is a bond or a divalent aliphatic hydrocarbon group;  
       Y is a group of the formula: —OR 3 , wherein R 3  is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or Y is an optionally esterified or amidated carboxyl group, or a salt thereof or a prodrug thereof.  
     
   
   
       20 - 23 . (canceled)  
   
   
       24 . A commercial package comprising the pharmaceutical composition for the prophylaxis or treatment of diabetes according to  claim 1  and written matter associated therewith, the written matter stating that the composition can or should be used for the prophylaxis or treatment of diabetes.  
   
   
       25 . A commercial package comprising the pharmaceutical composition for the prophylaxis or treatment of impaired glucose tolerance according to  claim 2  and written matter associated therewith, the written matter stating that the composition can or should be used for the prophylaxis or treatment of impaired glucose tolerance.  
   
   
       26 . A commercial package comprising the insulin secretagogue of  claim 3  and written matter associated therewith, the written matter stating that the insulin secretagogue can or should be used for promoting insulin secretion.  
   
   
       27 . A commercial package comprising 
 the pharmaceutical composition for the prophylaxis or treatment of diabetic complications according to  claim 4  and    written matter associated therewith, 
 the written matter stating that the composition can or should be used for the prophylaxis or treatment of diabetic complications.