Substituted (thiazol-2-yl)-amide or sulfonamide as glycokinase activators useful in the treatment of type 2 diabetes

Abstract

Compounds of the formula R—NH-Q  (I) provide pharmacological agents which are glucokinase activators and thus may be employed for the treatment of glucokinase mediated conditions. Accordingly, the compounds of formula (I) may be employed for prevention and treatment of impaired glucose tolerance, Type 2 diabetes and obesity.

1 . A compound of the formula
   R—NH-Q  (I)
   
       wherein
 (i) Q is a 
 
       
         
           
           
               
               
           
         
          radical in which R 1  and R 2  are independently hydrogen or halogen; and
 R is a radical of the formula 
 
       
       
         
           
           
               
               
           
         
         wherein
 R 4  is C 2-4 alkyl, C 3-7 cycloalkyl or C 5-7 heterocycloalkyl; 
 R 5  and R 6  are independently hydrogen, halogen, cyano, R 7 , —C(O)R 7  or —S(O) 2 R 7  wherein
 R 7  is —(CR 8 R 9 ) m —W—R 10  in which
 R 8  and R 9  are independently hydrogen or lower alkyl; 
 W is a bond, O, S or —NR 11  in which 
  R 11  is hydrogen or lower alkyl; 
 R 10  is hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl; or R 10  and R 11 , combined, are alkylene which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring; 
 m is zero or an integer from 1 to 5; 
 
 
 n is zero or an integer of 1 or 2; 
 
       
       or a pharmaceutically acceptable salt thereof; or
 (ii) Q is a 
 
       
         
           
           
               
               
           
         
          radical, wherein R 1  and R 2  are independently hydrogen or halogen; and
 R is a radical of the formula 
 
       
       
         
           
           
               
               
           
         
         wherein
 R 4  is C 2-4 alkyl, C 3-7 cycloalkyl or C 5-7 heterocycloalkyl; 
 R 12  and R 13  are independently hydrogen, halogen, cyano, R 14 , —C(O)R 14 , or —S(O) 2 R 14    
 wherein
 R 14  is —(CR 8 R 9 ) m —W—R 15  in which
 R 8  and R 9  are independently hydrogen or lower alkyl; 
 W is a bond, O, S or —NR 11  in which 
  R 11  is hydrogen or lower alkyl; 
 R 15  is cycloalkyl, aryl or heterocyclyl; or R 15  and R 11 , combined, are alkylene which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring; 
 m is zero or an integer from 1 to 5; 
 
 
 n is zero or an integer of 1 or 2; 
 
         provided that: (1) R 12  and R 13  both are not hydrogen, halogen, cyano or combinations thereof; (2) R 12  is not —S(O) 2 R 14 , wherein R 14  is —(CR 8 R 9 ) m —W—R 15  in which m is zero and W is a bond when n is zero; (3) R 12  is not —S(O) 2 R 14 , wherein R 14  is —(CR 8 R 9 ) m —W—R 15  in which R 8  and R 9  are hydrogen, m is 1 and W is a bond when n is zero; (4) R 12  is not R 14 , wherein R 14  is —(CR 8 R 9 ) m —W—R 15  in which m is zero and W is O when n is zero; or (5) R 12  is not R 14 , wherein R 14  is —(CR 8 R 9 ) m —W—R 15  in which m is zero and W is a bond when n is zero; 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound according to  claim 1  of the formula 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  are independently hydrogen or halogen; 
 R 4  is C 2-4 alkyl, C 3-7 cycloalkyl or C 5-7 heterocycloalkyl; 
 R 5  and R 6  are independently hydrogen, halogen, cyano, R 7 , —C(O)R 7  or —S(O) 2 R 7  wherein
 R 7  is —(CR 8 R 9 ) m —W—R 10  in which
 R 8  and R 9  are independently hydrogen or lower alkyl; 
 W is a bond, O, S or —NR 11  in which
 R 11  is hydrogen or lower alkyl; 
 
 R 10  is hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl; or R 10  and R 11 , combined, are alkylene which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring; 
 m is zero or an integer from 1 to 5; 
 
 
 n is zero or an integer of 1 or 2; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound according to  claim 2 , wherein
 R 4  is cyclopentyl;   n is zero;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 - 9 . (canceled) 
     
     
         10 . The compound according to  claim 1  of the formula (Ie): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  are independently hydrogen or halogen; 
 R 4  is C 2-4 alkyl, C 3-7 cycloalkyl or C 5-7 heterocycloalkyl; 
 R 12  and R 13  are independently hydrogen, halogen, cyano, R 14 , —C(O)R 14 , or —S(O) 2 R 14    
 wherein
 R 14  is —(CR 8 R 9 ) m —W—R 15  in which
 R 8  and R 9  are, independently, hydrogen or lower alkyl; 
 W is a bond, O, S or —NR 11  in which
 R 11  is hydrogen or lower alkyl; 
 
 R 15  is cycloalkyl, aryl or heterocyclyl; or R 15  and R 11 , combined, are alkylene which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring; 
 m is zero or an integer from 1 to 5; 
 
 
 n is zero or an integer of 1 or 2; 
 
       provided that: (1) R 12  and R 13  both are not hydrogen, halogen, cyano or combinations thereof; (2) R 12  is not —S(O) 2 R 14  wherein R 14  is —(CR 8 R 9 ) m —W—R 15  in which m is zero and W is a bond when n is zero; (3) R 12  is not —S(O) 2 R 14 , wherein R 14  is —(CR 8 R 9 ) m —W—R 15  in which R 8  and R 9  are hydrogen, m is 1 and W is a bond when n is zero; (4) R 12  is not R 14 , wherein R 14  is —(CR 8 R 9 ) m —W—R 15  in which m is zero and W is O when n is zero; or (5) R 12  is not R 14 , wherein R 14  is —(CR 8 R 9 ) m —W—R 15  in which m is zero and W is a bond when n is zero; 
       or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The compound according to  claim 10 , wherein
 R 4  is cyclopentyl;   n is zero;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A method for the activation of glucokinase activity in a mammal in need thereof which method comprises administering to the mammal a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A method for the prevention and/or treatment of conditions associated with glucokinase activity in a mammal in need thereof which method comprises administering to the mammal a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The method according to  claim 13 , which method comprises administering said compound, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of insulin, an insulin derivative or mimetic; an insulin secretagogue; an insulinotropic sulfonylurea receptor ligand; a PPAR ligand; an insulin sensitizer; a biguanide; an alpha-glucosidase inhibitors; GLP-1, a GLP-1 analog or mimetic; a DPPIV inhibitor; an HMG-CoA reductase inhibitor; a squalene synthase inhibitor; an FXR or LXR ligand; cholestyramine; a fibrate; nicotinic acid; or aspirin. 
     
     
         15 . A method for the treatment of impaired glucose tolerance, Type 2 diabetes and obesity in a mammal in need thereof which method comprises administering to the mammal a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         16 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers. 
     
     
         17 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of insulin, an insulin derivative or mimetic; an insulin secretagogue; an insulinotropic sulfonylurea receptor ligand; a PPAR ligand; an insulin sensitizer; a biguanide; an alpha-glucosidase inhibitors; GLP-1, a GLP-1 analog or mimetic; a DPPIV inhibitor; an HMG-CoA reductase inhibitor; a squalene synthase inhibitor; an FXR or LXR ligand; cholestyramine; a fibrate; nicotinic acid; or aspirin. 
     
     
         18 - 23 . (canceled)