3-amino-pyridine derivatives for the treatment of metabolic disorders

Abstract

Compounds represented by the general formula (1): pharmaceutically acceptable salts or solvates thereof, a process for their manufacture; pharmaceutical compositions containing them; and use of the compounds in the treatment of metabolic disorders related to insulin resistance or hyperglycemia are described.

1 . A method for the treatment of a metabolic disorder related to insulin resistance or hyperglycemia, comprising:
 administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, the formula (I) being represented by:   
       
         
           
           
               
               
           
         
         
           where:
 Ar is isoquinolin-3-yl; 
 B is —O—; 
 R 1  is H; 
 R 2  is —S(O) 2 R 4 ; 
 R 3  is chlorine; and 
 R 4  is 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 3-chloro-4-methylphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 4-chlorophenyl, 2-chloro-4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-4-chlorophenyl; 4-cyanophenyl, phenyl-3-carboxylic acid [phenyl-3-COOH], or 4-acetamidophenyl [CH 3 CONH-phenyl]. 
 
         
       
     
     
         2 . The method according to  claim 1 ;
 wherein the compound of formula (I) is selected from:
 2,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide; 
 3-(N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)sulfamoyl)benzoic acid; 
 3-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide; 
 N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,4,6-trimethyl benzenesulfonamide; 
 N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-1-cyanobenzenesulfonamide; 
 N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3,5-dimethylbenzenesulfonamide; 
 3,5-Dichloro-N (5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide; 
 N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2-methylbenzenesulfonamide; 
 N-(5-Chloro-6 (isoquinolin-3-yloxy)pyridin-3-yl)-3-methylbenzenesulfonamide; 
 N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide; 
 N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide; 
 4-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide; 
 4-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2-fluorobenzenesulfonamide; 
 N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide; 
 2-Chloro-N-(5 chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide; 
 N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide; 
 3,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide; 
 N-(5-Chloro-6 (isoquinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethoxy)benzene-sulfonamide; 
 N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,5-dimethoxybenzenesulfonamide; 
 2-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4(trifluoromethyl)benzene sulfonamide; 
 N-(4-(N-(5 Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)sulfamoyl)phenyl)acetamide; 
 N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide; 
 N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,4-dimethoxybenzenesulfonamide; 
 N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methoxybenzenesulfonamide; and 
 N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide. 
   
     
     
         3 . The method according to  claim 1 ;
 wherein the compound of formula (I) is selected from:
 2,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-Yl)benzenesulfonamide; 
 2-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide; 
 N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide; and 
 3,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide. 
   
     
     
         4 . The method according to  claim 1 ;
 wherein the metabolic disorder related to insulin resistance or hyperglycemia is selected from:
 type 2 diabetes, obesity, glucose intolerance, dyslipidemia, hyperinsulinemia, atherosclerotic disease, polycystic ovary syndrome, coronary artery disease, hypertension, or non alcoholic fatty liver disease. 
   
     
     
         5 . The method according to  claim 4 ;
 wherein the metabolic disorder related to insulin resistance or hyperglycemia is type 2 diabetes.   
     
     
         6 . The method according to  claims 4 ;
 wherein the metabolic disorder related to insulin resistance or hyperglycemia is dyslipidemia.