Novel bisamidate phosphonate prodrugs

Abstract

Novel bisamidate phosphonate prodrugs of FBPase inhibitors of the Formula IA: and their use in the treatment of diabetes and other conditions associated with elevated blood glucose.

1 . A compound of formula IA:  
       
         
           
           
               
               
           
         
       
       wherein compounds of formula IA are converted in vivo or in vitro to M-PO 3 H 2  which is an inhibitor of fructose-1,6-bisphosphatase and 
 n is an integer from 1 to 3;  
 R 2  is selected from the group of —R 3  and —H;  
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;  
 each R 12  and R 13  is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R 12  and R 13  together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;  
 each R 14  is independently selected from the group consisting of —OR 17 , —N(R 17 ) 2 , —NHR 17 , —NR 2 OR 19  and —SR 17 ;  
 R 15  is selected from the group consisting of —H, lower alkyl, lower aryl, lower aralkyl, or together with R 16  is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;  
 R 16  is selected from the group consisting of —(CR 2 R 3 ) n —C(O)—R 4 , —H, lower alkyl, lower aryl, lower aralkyl, or together with R 15  is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;  
 each R 17  is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R 17  and R 17  on N are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;  
 R 18  is independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R 12  is connected via 1-4 carbon atoms to form a cyclic group;  
 each R 19  is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 ;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         2 . The compounds of  claim 1  wherein M-PO 3 H 2  has an IC 50  on isolated human liver FBPase enzyme of less than or equal to 10 μM.  
     
     
         3 . The compounds of  claim 2  wherein said IC 50  is less than or equal to 1 μM.  
     
     
         4 .- 115 . (Cancelled)