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; 
 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 12 R 13 ) n —C(O)—R 14 , —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 is 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 ; 
 
     M is 
     
       
         
         
             
             
         
       
     
     wherein:
 A 3 , E 3 , and L 3  are selected from the group consisting of —NR 8   2 , —NO 2 , —H, —OR 7 , —SR 7 , —C(O)NR 4   2 , halo, —COR 11 , —SO 2 R 3 , guanidine, amidine, —NHSO 2 R 3 , —SO 2 NR 4   2 , —CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A 3  and L 3  form a cyclic group, or together L 3  and E 3  form a cyclic group, or together E 3  and J 3  form a cyclic group including aryl, cyclic alkyl, and heterocyclic; 
 J 3  is selected from the group consisting of —NR 8   2 , —NO 2 , —H, —OR 7 , —SR 7 , —C(O)NR 4   2 , halo, —C(O)R 11 , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl; alicyclic, aryl, and aralkyl, or together with Y 3  forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl; 
 X 3  is selected from the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, 
 -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X 3  is not substituted with —COOR 2 , —SO 3 H, or —PO 3 R 2   2 ; 
 Y 3  is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R 3 , —S(O) 2 R 3 , —C(O)—R 11 , —CONHR 3 , —NR 2   2 , and 
 —OR 3 , all except H are optionally substituted; 
 R 2  is selected from the group consisting of R 3  and —H; 
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; 
 each R 4  is independently selected from the group consisting of —H, and alkyl, or together R 4  and R 4  form a cyclic alkyl group; 
 R 7  is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C(O)R 10 ; 
 R 8  is independently selected from the group consisting of —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C(O)R 10 , or together they form a bidentate alkyl; 
 each R 9  is independently selected from the group consisting of —H, -alkyl, aralkyl, and alicyclic, or together R 9  and R 9  form a cyclic alkyl group; 
 R 10  is selected from the group consisting of —H, lower alkyl, —NH 2 , lower aryl, and lower perhaloalkyl; 
 R 11  is selected from the group consisting of alkyl, aryl, —NR 2   2 , and —OR 2 ; and 
 pharmaceutically acceptable salts thereof. 
 
   
   
       2 . The compound of  claim 1 , wherein A 3 , L 3 , and E 3  are independently selected from the group consisting of —H, —NR 8   2 , —NO 2 , hydroxy, halogen, —OR 7 , alkylaminocarbonyl, —SR 7 , lower perhaloalkyl, and C1-C5 alkyl, or together E 3  and J 3  together form a cyclic group; and wherein J 3  is selected from the group consisting of —H, halogen, lower alkyl, lower hydroxyalkyl, —NR 8   2 , lower R 8   2 N-alkyl, lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocyclic, and alicyclic; and wherein Y 3  is selected from the group consisting of alicyclic and lower alkyl; wherein X 3  is selected from the group consisting of -heteroaryl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, and -alkoxycarbonyl-. 
   
   
       3 . The compounds of  claim 1 , wherein
 n is 1;   R 12  and R 13  are independently selected from the group consisting of —H, lower alkyl, lower perhaloalkyl, and lower aryl, optionally substituted with —OR 19 , —NR 19   2 , —SR 19 , —C(O)NR 2 R 3 , halo, —CO 2 R 2 , 3-indolyl, 4-imidazolyl, and guanidinyl, or R 2  and R 13  are connected via 2-5 carbon atoms to form a cycloalkyl group;   R 14  is selected from the group consisting of —OR 17 , —SR 17 , and —NR 2 OR 19      R 15  is selected from the group consisting of —H and C1-C6 alkyl;   R 16  is selected from the group consisting of —H, C1-C6 alkyl, and —(CR 12 R 13 ) n —C(O)—R 4 ; or together R 15  and R 16  are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of N, O and S.   R 17  is selected from the group consisting of C1-C7 alkyl, phenyl, indolyl, sesimol, and benzyl, wherein said phenyl, indolyl, sesimol, and benzyl may be optionally substituted with 1-3 groups selected from the group of —CO 2 R 2 , —OR 3 , —NHC(O)R 3 , halo and lower alkyl; and   R 18  is selected from the group consisting of —H, C1-C6 alkyl, and benzyl.   
   
   
       4 . The compound of  claim 1 , wherein A 3  is selected from the group consisting of —H, —NH 2 , —F, and —CH 3 ;
 L 3  is selected from the group consisting of —H, —F, —OCH 3 , Cl and —CH 3 ;   E 3  is selected from the group consisting of —H, and —Cl;   J 3  is selected from the group consisting of —H, halo, C1-C5 hydroxyalkyl, C1-C5 haloalkyl, R 8   2 N—C1-C5 alkyl, C1-C5 alicyclic, and C1-C5 alkyl;   X 3  is selected from the group consisting of —CH 2 OCH 2 —, -methyleneoxycarbonyl- and -furan-2,5-diyl-; and   Y 3  is lower alkyl.   
   
   
       5 . The compound of  claim 4 , where A 3  is —NH 2 , L 3  is —F, E 3  is —H, J 3  is ethyl, Y 3  is isobutyl, and X 3  is -furan-2,5-diyl-. 
   
   
       6 . The compound of  claim 4 , where A 3  is —NH 2 , L 3  is —F, E 3  is —H, J 3  is N,N-dimethylaminopropyl, Y 3  is isobutyl, and X 3  is -furan-2,5-diyl-. 
   
   
       7 . The compound of  claim 5 , wherein 
     
       
         
         
             
             
         
       
     
     is selected from the group consisting of 
     
       
         
         
             
             
         
       
       wherein C* has S stereochemistry. 
     
   
   
       8 . The compounds of  claim 6 , wherein 
     
       
         
         
             
             
         
       
     
     is selected from the group consisting of 
     
       
         
         
             
             
         
       
       wherein C* has S stereochemistry. 
     
   
   
       9 . A method of treating an animal for diabetes comprising administering to said animal a therapeutically effective amount of a compound of formula XI: 
     
       
         
         
             
             
         
       
     
     wherein:
 A 3 , E 3 , and L 3  are selected from the group consisting of —NR 8   2 , —NO 2 , —H, —OR 7 , —SR 7 , —C(O)NR 4   2 , halo, —COR 11 , —SO 2 R 3 , guanidine, amidine, —NHSO 2 R 3 , —SO 2 NR 4   2 , —CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A 3  and L 3  form a cyclic group, or together L 3  and E 3  form a cyclic group, or together E 3  and J 3  form a cyclic group including aryl, cyclic alkyl, and heterocyclic; 
 J 3  is selected from the group consisting of —NR 8   2 , —NO 2 , —H, —OR 7 , —SR 7 , —C(O)NR 4   2 , halo, —C(O)R 11 , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl; alicyclic, aryl, and aralkyl, or together with Y 3  forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl; 
 X 3  is selected from the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, 
 -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X 3  is not substituted with —COOR 2 , —SO 3 H, or —PO 3 R 2   2 ; 
 Y 3  is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R 3 , —S(O) 2 R 3 , —C(O)—R 11 , —CONHR 3 , —NR 2   2 , and —OR 3 , all except H are optionally substituted; 
 n is an integer from 1 to 3; 
 R 2  is selected from the group consisting of R 3  and —H; 
 R 3  is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; 
 each R 4  is independently selected from the group consisting of —H, and alkyl, or together R 4  and R 4  form a cyclic alkyl group; 
 R 7  is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C(O)R 10 ; 
 R 8  is independently selected from the group consisting of —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C(O)R 10 , or together they form a bidentate alkyl; 
 each R 9  is independently selected from the group consisting of —H.-alkyl, aralkyl, and alicyclic, or together R 9  and R 9  form a cyclic alkyl group; 
 R 10  is selected from the group consisting of —H, lower alkyl, —NH 2 , lower aryl, and lower perhaloalkyl; 
 R 11  is selected from the group consisting of alkyl, aryl, —NR 2   2 , and —OR 2 ; 
 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 12 R 13 ) n —C(O)—R 14 , —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 is 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. 
 
   
   
       10 . A method of lowering blood glucose levels in an animal in need thereof, comprising administering to said animal a pharmaceutically acceptable amount of a compound of  claim 1 . 
   
   
       11 . A method of inhibiting gluconeogenesis in an animal in need thereof comprising administering to said animal a pharmaceutically effective amount of a compound of  claim 1 .