Method of treating diabetes, metabolic syndrome and obesity using phenylacetamide derivative

Abstract

Phenylacetamide compounds of the formula having sulfonyl group and cycloalkyl group on the phenyl group and having heteroaryl group on the nitrogen atom in the amide have an excellent glucokinase activation action. The compound of the present invention is useful as an agent for treating diabetes, in particular, type II diabetes, as well as metabolic syndrome and obesity.

1 . (canceled) 
     
     
         2 . The method of  claim 18 , wherein n is 0. 
     
     
         3 . The method of  claim 2 , wherein R 1  is methyl, trifluoromethyl, or cyclopropyl. 
     
     
         4 . The method of  claim 3 , wherein R 2  is cyclopropyl. 
     
     
         5 . The method of  claim 4 , wherein formula (I) is 
       
         
           
           
               
               
           
         
         m is 4 or 5, and 
         none or one X is —CH(F)—, —CH(OH)—, —C(O)—, or —O—, and the remaining X is —CH 2 —. 
       
     
     
         6 . The method of  claim 5 , wherein Ring A is pyrazolyl, thiazolyl, thiadiazolyl, pyridyl or pyrazinyl, each of which may be substituted with up to five moieties independently selected from the group consisting of halogen, cyano, lower alkyl which may be substituted with —OR 0 , —OR 0 , —O-lower alkylene —OR 0 , and —C(O)R 0 . 
     
     
         7 . The method of  claim 6 , wherein [Chem. 21]   is a single bond. 
     
     
         8 . The method of  claim 6 , wherein [Chem. 22]   is a double bond. 
     
     
         9 . The method of  claim 18 , wherein the compound is selected from the group consisting of:
 (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-methylpyrazin-2-yl)-3-[(1S)-3-oxocyclopentyl]acrylamide,   (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(1-methyl-1H-pyrazol-3-yl)-3-[(1S)-3-oxocyclopentyl]acrylamide,   (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-fluoro-1,3-thiazol-2-yl)-3-[(1S)-3-oxocyclopentyl]acrylamide,   (2R)—N-(4-acetyl-1,3-thiazol-2-yl)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanamide,   (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-methylpyridin-2-yl)-3-[(1R)-3-oxocyclopentyl]propanamide,   (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-methylpyrazin-2-yl)-3-[(1R)-3-oxocyclopentyl]propanamide,   (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(hydroxymethyl)pyrazin-2-yl]-3-[(1R)-3-oxocyclopentyl]propanamide,   (2R)—N-(5-chloropyrazin-2-yl)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanamide,   (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-methoxypyrazin-2-yl)-3-[(1R)-3-oxocyclopentyl]propanamide,   (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-hydroxycyclopentyl]-N-(5-methylpyrazin-2-yl)propanamide,   (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-hydroxycyclopentyl]-N-(5-methoxypyrazin-2-yl)propanamide,   (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(2-hydroxy ethoxy)pyrazin-2-yl]-3-[(1R)-3-oxocyclopentyl]propanamide, and   (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(2-hydroxy-2-methylpropoxy)pyrazin-2-yl]-3-[(1R)-3-oxocyclopentyl]propanamide,   or a pharmaceutically acceptable salt thereof.   
     
     
         10 .- 11 . (canceled) 
     
     
         12 . The method of  claim 9 , which is a method for treating diabetes. 
     
     
         13 . The method of  claim 12 , which is a method for treating type II diabetes. 
     
     
         14 . The method of  claim 9 , which is a method for treating obesity. 
     
     
         15 . The method of  claim 9 , which is a method for treating metabolic syndrome. 
     
     
         16 - 17 . (canceled) 
     
     
         18 . A method for treating diabetes, metabolic syndrome or obesity, comprising administering to a patient a therapeutically effective amount of compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  is lower alkyl, halogeno-lower alkyl, or cycloalkyl, 
         R 2  is cycloalkyl, 
         R 3  is halogen, lower alkyl, halogeno-lower alkyl, —OR 0 , or —O-halogeno-lower alkyl, 
         R 0  independently represents —H or lower alkyl, 
         Ring A is heteroaryl which may be substituted with up to five moieties independently selected from the group consisting of halogen, cyano, lower alkyl which may be substituted with —OR 0 , halogen-lower alkyl, lower alkylene-OC(O)R 0 , lower alkylene-O-hetero ring group, —OR 0 , —O-halogeno-lower alkyl, —O-lower alkylene-OR 0 , —S(O) p -lower alkyl, —S(O) p -lower alkylene-OR 0 , —C(O)R 0 , —C(O)-lower alkylene-OR 0 , —CO 2 R 0 , lower alkylene-CO 2 R 0 , —O-lower alkylene-CO 2 R 0 , —S(O) p -lower alkylene-CO 2 R 0 , —C(O)N(R 0 ) 2  and a hetero ring group, wherein the hetero ring group may be substituted with up to five moieties independently selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR 0 , —O-halogeno-lower alkyl and oxo, 
         Ring B is aryl or heteroaryl which may each be substituted with up to five moieties independently selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR 0 , and —O-halogeno-lower alkyl, or 
       
       
         
           
           
               
               
           
         
       
       wherein 
          represents formula (I),
 X independently represents —C(R 4 )(R 5 )—, —C(O)—, —O—, —S(O) p —, or —N(R 0 )—, 
 m is 2, 3, 4, 5, 6 or 7, 
 R 4  and R 5  independently represent —H, halogen, lower alkyl, halogeno-lower alkyl, —OR 0 , or —O-halogeno-lower alkyl, and 
 n and p independently represent 0, 1 or 2, provided that   means a single bond or a double bond. 
 
     
     
         19 . The method of  claim 18 , wherein the compound is
 (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(hydroxymethyl)pyrazin-2-yl]-3-[(1R)-3-oxocyclopentyl]propanamide or a pharmaceutically acceptable salt thereof.   
     
     
         20 . The method of  claim 18 , wherein the compound is
 (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-methylpyrazin-2-yl)-3-[(1R)-3-oxocyclopentyl]propanamide or a pharmaceutically acceptable salt thereof.   
     
     
         21 . The method of  claim 18 , wherein the compound is
 (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-methoxypyrazin-2-yl)-3-[(1R)-3-oxocyclopentyl]propanamide or a pharmaceutically acceptable salt thereof.   
     
     
         22 . The method of  claim 18 , wherein the compound is
 (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-methylpyrazin-2-yl)-3-[(1S)-3-oxocyclopentyl]acrylamide or a pharmaceutically acceptable salt thereof.   
     
     
         23 . The method of  claim 18 , wherein the compound is
 (2R)—N-(5-acetylpyrazin-2-yl)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanamide or a pharmaceutically acceptable salt thereof.   
     
     
         24 . The method of  claim 8 , wherein Ring B and the benzene ring of formula (I) are in a Z configuration with respect to the double bond.