Compounds that stimulate glucose utilization and methods of use

Abstract

The invention provides novel compounds of the Formula (I) that stimulate rates of glucose oxidation in myocardial cells: wherein W, Cyc, p, Y, X, Z, R, R 1 , R 2 , R 3 , R 4 , i and n are as defined for Formula (I) herein. The invention also relates to pharmaceutical compositions comprising compounds capable of stimulation of glucose oxidation, methods for increasing glucose oxidation rates in myocardial cells, and methods of treatment of myocardial ischemia.

1 . A compound represented by Formula (I):  
       
         
           
           
               
               
           
         
         wherein  
         W is C 1 -C 6  alkyl, halogen, or aryl;  
         Cyc is C 3  or C 4  cycloalkyl;  
         p is an integer from 0 to 3 when Cyc is C 4  cycloalkyl, or p is an integer from 0 to 2 when Cyc is C 3  cycloalkyl;  
         Y is O, S, or NR;  
         X is O, S, NR, or CR 3 R 4 ;  
         R is H, alkyl, aryl, or  
         
           
             
             
                 
                 
             
           
         
          where i is an integer from 2 to 4;  
         Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl or  
         
           
             
             
                 
                 
             
           
         
          if X is NR and R is  
         
           
             
             
                 
                 
             
           
         
         R 1  is H, alkyl, aryl or O;  
         R 2  is H, alkyl or aryl;  
         R 3  and R 4  are, independently, H, alkyl or aryl; and  
         n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.  
       
     
     
         2 . A compound according to  claim 1  represented by Formula (Ia):  
       
         
           
           
               
               
           
         
         wherein  
         W is C 1 -C 6  alkyl, halogen, or aryl;  
         Cyc is C 3  or C 4  cycloalkyl;  
         p is an integer from 0 to 3 when Cyc is C 4  cycloalkyl, or p is an integer from 0 to 2 when Cyc is C 3  cycloalkyl;  
         Y is O, S, or NR;  
         X is O, S, NR, or CR 3 R 4 ;  
         R is H, alkyl or aryl;  
         Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl;  
         R 1  is H, alkyl, aryl or O;  
         R 2  is H, alkyl or aryl;  
         R 3  and R 4  are, independently, H, alkyl or aryl; and  
         n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.  
       
     
     
         3 . The compound according to  claim 1 , wherein p is 0.  
     
     
         4 . The compound according to  claim 3 , wherein Y is O; 
 X is NR or O;    R 1 , R 2 , R 3  and R 4  are H;    n is 1 to 4; and    Z is lower alkyl, cycloalkyl or phenyl.    
     
     
         5 . The compound according to  claim 3 , wherein Y is NR; 
 X is O;    R 1 , R 2 , R 3  and R 4  are H;    n is 1 or 2; and    Z is H.    
     
     
         6 . The compound according to  claim 3 , wherein said compound is selected from 
 cyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester;    cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester;    (cyclobutanecarbonyl-amino)-acetic acid;    cyclopropanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester;    2-(cyclopropanecarbonyl-amino)-propionic acid;    cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester;    cyclobutanecarboxylic acid, 2-(2-butoxy-ethoxy)-ethyl ester;    cyclobutanecarboxylic acid, 2-(2-ethoxy-ethoxy)-ethyl ester;    cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;    cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;    cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester;    cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester;    cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;    cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;    cyclopropanecarboxylic acid 2-ethoxy-ethyl ester;    cyclobutanecarboxylic acid 2-ethoxy-ethyl ester;    cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester;    cyclobutanecarboxylic acid 2-isopropoxy-ethyl ester;    cyclopropanecarboxylic acid, 2-(2-cyclopropanecarbonyloxy-ethoxy)-ethyl ester;    cyclopropanecarboxylic acid, 2-[2-(2-cyclopropanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester; and    cyclobutanecarboxylic acid, 2-[2-(2-cyclobutanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester.    
     
     
         7 . A pharmaceutical composition comprising at least one compound represented by Formula (I), or Formula (II):  
       
         
           
           
               
               
           
         
         wherein  
         W is C 1 -C 6  alkyl, halogen, or aryl;  
         Cyc is C 3  or C 4  cycloalkyl;  
         p is an integer from 0 to 3 when Cyc is C 4  cycloalkyl, or p is 0 to 2 when Cyc is C 3  cycloalkyl;  
         Y is O, S, or NR;  
         X is O, S, NR, or CR 3 R 4 ;  
         Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl or  
         
           
             
             
                 
                 
             
           
         
          if X is NR and R is  
         
           
             
             
                 
                 
             
           
         
         R is H, alkyl, aryl, or  
         
           
             
             
                 
                 
             
           
         
          where i is an integer from 2 to 4;  
         R 1  is H, alkyl, aryl or O;  
         R 2  is H, alkyl or aryl;  
         R 3  and R 4  are, independently, H, alkyl or aryl; and  
         n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof; and  
         a pharmaceutically acceptable carrier, diluent, excipient or mixtures thereof.  
       
     
     
         8 . A pharmaceutical composition according to  claim 7 , wherein said compound is represented by Formula (I), and wherein 
 p is 0;    Y is O;    X is NR or O;    R 1 , R 2 , R 3  and R 4  are H;    n is 1 to 4; and    Z is lower alkyl, cycloalkyl or phenyl.    
     
     
         9 . A pharmaceutical composition according to  claim 7 , wherein said compound is represented by the Formula (I), and wherein 
 p is 0;    Y is NR;    X is O;    R 1 , R 2 , R 3  and R 4  are H;    n is 1 or 2; and    Z is H.    
     
     
         10 . A pharmaceutical composition according to  claim 7 , wherein said compound is represented by the Formula (II), wherein p is 0.  
     
     
         11 . A pharmaceutical composition according to  claim 7 , wherein said composition is in the form of tablets, pills, capsules, aqueous solutions, or sterile suspensions or solutions.  
     
     
         12 . A pharmaceutical composition according to  claim 7 , wherein said at least one compound is selected from the group consisting of cyclopropanecarboxylic acid; cyclobutanecarboxylic acid; cyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; (cyclobutanecarbonyl-amino)-acetic acid; cyclopropanecarboxylic acid, 2-(2-benzyloxy-ethoxy)-ethyl ester; 2-(cyclopropanecarbonyl-amino)-propionic acid; cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-butoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-ethoxy-ethyl ester; cyclobutanecarboxylic acid 2-ethoxy-ethyl ester; cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester; cyclobutanecarboxylic acid 2-isopropoxy-ethyl ester; cyclopropanecarboxylic acid, 2-(2-cyclopropanecarbonyloxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid, 2-[2-(2−cyclopropanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester; and cyclobutanecarboxylic acid, 2-[2-(2-cyclobutanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester.  
     
     
         13 . A method for increasing glucose utilization in a cell, tissue or organ of a warm blooded animal comprising treating said cell, tissue or organ with glucose utilization effective amount of at least one compound represented by Formula (I) or Formula (II)  
       
         
           
           
               
               
           
         
       
       wherein 
 W is C 1 -C 6  alkyl, halogen, or aryl;  
 Cyc is C 3  or C 4  cycloalkyl;  
 p is an integer from 0 to 3 when Cyc is C 4  cycloalkyl, or p is an integer from 0 to 2 when Cyc is C 3  cycloalkyl;  
 Y is O, S, or NR;  
 X is O, S, NR, or CR 3 R 4 ,  
 Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl or  
                     
  if X is NR and R is  
                     
 R is H, alkyl, aryl or  
                     
  where i is an integer from 2 to 4;  
 R 1  is H, alkyl, aryl or O;  
 R 2  is H, alkyl or aryl;  
 R 3  and R 4  are, independently, H, alkyl or aryl; and  
 n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.  
 
     
     
         14 . A method according to  claim 13 , wherein said compound is represented by Formula (I), and wherein p=0; 
 Y is O;    X is NR or O;    R 1 , R 2 , R 3  and R 4  are H;    n is 1-4; and    Z is lower alkyl, cycloalkyl or phenyl.    
     
     
         15 . The method as claimed in  claim 13 , wherein said compound is represented by Formula (I), and wherein p=0; 
 Y is NR;    X is O;    R 1 , R 2 , R 3  and R 4  are H;    n is 1 or 2; and    Z is H.    
     
     
         16 . A method according to  claim 13 , wherein said compound is represented by Formula (II), wherein p is 0.  
     
     
         17 . A method according to  claim 13 , wherein said organ is heart.  
     
     
         18 . A method according to  claim 13 , wherein said cell is a myocardial cells.  
     
     
         19 . The method according to  claim 13 , wherein said at least one compound is selected from the group consisting of cyclopropanecarboxylic acid; cyclobutanecarboxylic acid; cyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; (cyclobutanecarbonyl-amino)-acetic acid; cyclopropanecarboxylic acid, 2-(2-benzyloxy-ethoxy)-ethyl ester; 2-(cyclopropanecarbonyl-amino)-propionic acid; cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-butoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2−hexyloxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid (2-methoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-ethoxy-ethyl ester; cyclobutanecarboxylic acid 2-ethoxy-ethyl ester; cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester; cyclobutanecarboxylic acid 2-isopropoxy-ethyl ester; cyclopropanecarboxylic acid, 2-(2-cyclopropanecarbonyloxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid, 2-[2-(2-cyclopropanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester; and cyclobutanecarboxylic acid, 2-[2-(2-cyclobutanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester.  
     
     
         20 . A method for treatment of physiological conditions or disorders treatable by increasing glucose utilization comprising: 
 administering to a patient in need of such treatment, effective amount to increase glucose utilization of a pharmaceutical composition comprising at least one compound represented by Formula (I) or Formula (II)                          wherein    W is C 1 -C 6  alkyl, halogen, or aryl;    Cyc is C 3  or C 4  cycloalkyl;    p is an integer from 0 to 3 when Cyc is C 4  cycloalkyl, or p is an integer from 0 to 2 when Cyc is C 3  cycloalkyl;    Y is O, S, or NR;    X is O, S, NR, or CR 3 R 4 ;    Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl or                           if X is NR and R is                          R is H, alkyl, aryl or                           where i is an integer from 2 to 4;    R 1  is H, alkyl, aryl or O;    R 2  is H, alkyl or aryl;    R 3  and R 4  are, independently, H, alkyl or aryl; and    n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.    
     
     
         21 . A method according to  claim 20 , wherein said disorder or condition is ischemic/reperfusion injury, post myocardial infarction, angina, heart failure, a cardiomyopathy, peripheral vascular disease, diabetes, and lactic acidosis, or symptoms or side effects associated with open heart surgery, bypass surgery, or heart transplant.  
     
     
         22 . A method according to  claim 21 , wherein said disorder or condition is ischemic/reperfusion injury.  
     
     
         23 . A method according to  claim 20 , wherein said compound is represented by the Formula (I), and wherein p is 0; 
 Y is O;    X is NR or O;    R 1 , R 2 , R 3  and R 4  are H;    n is 1 to 4; and    Z is lower alkyl, cycloalkyl or phenyl.    
     
     
         24 . The method according to  claim 20 , wherein said compound is represented by the Formula (I), and wherein p=0; 
 Y is NR;    X is O;    R 1 , R 2 , R 3  and R 4  are H;    n is 1 or 2; and    Z is H.    
     
     
         25 . A method according to  claim 20 , wherein said compound is represented by the Formula (II), wherein p is 0.  
     
     
         26 . The method according to  claim 20 , wherein said at least one compound is selected from the group consisting of cyclopropanecarboxylic acid; cyclobutanecarboxylic acid; cyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; (cyclobutanecarbonyl-amino)-acetic acid; cyclopropanecarboxylic acid, 2-(2-benzyloxy-ethoxy)-ethyl ester; 2-(cyclopropanecarbonyl-amino)-propionic acid; cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-butoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-ethoxy-ethyl ester; cyclobutanecarboxylic acid 2-ethoxy-ethyl ester; cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester; cyclobutanecarboxylic acid 2-isopropoxy-ethyl ester; cyclopropanecarboxylic acid, 2-(2-cyclopropanecarbonyloxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid, 2-[2-(2-cyclopropanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester; and cyclobutanecarboxylic acid, 2-[2-(2-cyclobutanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester.  
     
     
         27 . A kit containing a pharmaceutical composition according to  claim 7 .  
     
     
         28 . A kit according to  claim 27 , wherein said kit comprises a label or packaging insert containing instructions for use, in vitro, in vivo, or ex vivo, of components of said kit.