Combination of FBPase Inhibitors and Antidiabetic Agents Useful for the Treatment of Diabetes

Abstract

A combination therapy of at least one FBPase inhibitor and at least one other antidiabetic agent is disclosed.

1 - 114 . (canceled) 
   
   
       115 . A method of treating diabetes comprising administering to a mammal having diabetes a pharmaceutical composition comprising a pharmaceutically effective amount of at least one insulin secretagogue and a pharmaceutically effective amount of at least one FBPase inhibitor, wherein said insulin secretagogue is selected from a group consisting of sulfonylurea antidiabetic agents and non-sulfonylurea antidiabetic agents, and the FBPase inhibitor is selected from the group consisting of formulae I and IA and pharmaceutically acceptable prodrugs and salts thereof, wherein formulae I and IA are as follows: 
     
       
         
         
             
             
         
       
     
     wherein in vivo or in vitro compounds of formulae I and IA are converted to M-PO 3   2− , which inhibits FBPase, and wherein:
 Y is independently selected from —O— and —NR 6 , with the provisos that:
 when Y is —O—, the R 1  attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted alicyclic where the cyclic moiety contains a carbonate or a thiocarbonate, optionally substituted -arylalkyl, —C(R 2 ) 2 OC(O)NR 2   2 , —NR 2 —C(O)—R 3 , —C(R 2 ) 2 —OC(O)R 3 , —C(R 2 ) 2 —O—C(O)OR 3 , —C(R 2 ) 2 OC(O)SR 3 , -alkyl-S—C(O)R 3 , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy; 
 when Y is —NR 6 —, the R 1  attached to —NR 6 — is independently selected from —H, —[C(R 2 ) 2 ] q —COOR 3 , —C(R 4 ) 2 COOR 3 , —[C(R 2 ) 2 ] q —C(O)SR, and -cycloalkylene-COOR 3 , where q is 1 or 2; 
 when only one Y is —O—, which —O— is not part of a cyclic group containing the other Y, the other Y is —N(R 18 )—(CR 12 R 13 )—C(O)—R 14 ; and 
 when Y is independently selected from —O— and —NR 6 , together R 1  and R 1  are alkyl-S—S-alkyl- and form a cyclic group, or together, R 1  and R 1  form: 
 
 
     
       
         
         
             
             
         
       
       wherein 
       a) V is selected from the group of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl; or
 together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V; or 
 Z is selected from the group of —CHR 2 OH , —CHR 2 OC(O)R 3 —CHR 2 OC(S)R 3 , —CHR 2 OC(S)OR 3 , —CHR 2 OC(O)SR 3 , —CHR 2 OCO 2 R 3 , —OR 2 , —SR 2 , —CHR 2 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —R 2 , —NR 2   2 , —OCOR 3 , —OCO 2 R 3 , —SCOR 3 , —SCO 2 R 3 , —NHCOR 2 , —NHCO 2 R 3 , —CH 2 NHaryl, —(CH 2 ) p —OR 2 , and —(CH 2 ) p —SR 2 , where p is an integer 2 or 3; or 
 together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or 
 W and W′ are independently selected from the group of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or 
 together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; 
 
       b) V 2 , W 2  and W″ are independently selected from the group of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
 Z 2  is selected from the group of —CHR 2 OC(O)R 3 , —CHR 2 OC(S)R 3 , —CHR 2 OCO 2 R 3 , —CHR 2 OC(O)SR, —CHR 2 OC(S)OR 3 , —CH(aryl)OH, —CH(CH═CR 2   2 )OH, —CH(C≡CR 2 )OH, —SR 2 , —CH 2 NHaryl, —CH 2 aryl; or 
 together V 2  and Z 2  are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally containing 1 heteroatom, and substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from a Y attached to phosphorus; 
 
       c) Z′ is selected from the group of —OH, —OC(O)R 3 , —OCO 2 R 3 , and —OC(O)SR 3 ;
 D′ is —H; 
 D″ is selected from the group of —H, alkyl, —OR 1 , —OH, and —OC(O)R 3 ; 
 each W 3  is independently selected from the group of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; 
 with the proviso that: 
 i) V, Z, W, W′ are not all —H and V 2 , Z 2 , W 2 , W″ are not al —H; and 
 
       R 2  is selected from R 3  and —H; 
       R 3  is selected from alkyl, aryl, alicyclic, and aralkyl; 
       each R 4  is independently selected from the group of —H, alkylene, -alkylenearyl and aryl, or together R 4  and R 4  are connected via 2-6 atoms, optionally including one heteroatom selected from the group of O, N, and S; 
       R 6  is selected from —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; 
       n is an integer from 1 to 3; 
       R 18  is independently selected from H, lower alkyl, aryl, and aralkyl, or, together, R 12  and R 18  are connected via 1-4 carbon atoms to form a cyclic group; 
       each R 12  and each R 13  is independently selected from 11, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R 12  and R 13 , together, are connected via 2-6 carbon atoms, optionally including 1 heteroatom selected from the group of O, N, and S, to form a cyclic group; 
       each R 14  is independently selected from —OR 17 , —N(R 17 ) 2 , —NHR 17 , —SR 17 , and —NR 2 R 20 ; 
       R 15  is selected from —H, lower alkyl, lower aryl, and lower aralkyl, or, together, R 15  and R 16  are connected via 2-6 atoms to form a cyclic group, wherein the cyclic group optionally includes one heteroatom selected from O, N, and S; 
       R 16  is selected from —(CR 12 R 13 ) n —C(O)—R 14 , —H, lower alkyl, lower aryl, and lower aralkyl, or, together, R 15  and R 16  are connected via 2-6 atoms to form a cyclic group, wherein the cyclic group optionally includes one heteroatom selected from O, N, and S; 
       each R 17  is independently selected from lower alkyl, lower aryl, and lower aralkyl, or, when R 14  is —N(R 17 ) 2 , together, both R 17 s are connected via 2-6 atoms to form a cyclic group, wherein the cyclic group optionally includes one heteroatom selected from O, N, and S; 
       R 20  is selected from the group of —H, lower R 3 , and —C(O)-lower R 3 ; and 
       M is selected from the group consisting of 
     
     
       
         
         
             
             
         
       
     
     wherein:
 U 6  and V 6  are independently selected from hydrogen, hydroxy, and acyloxy, or, when taken together, U 6  and V 6  form a lower cyclic ring containing at least one oxygen;
 W 6  is selected from amino and lower alkyl amino; and 
 Z 6  is selected from alkyl and halogen; 
 
 
     
       
         
         
             
             
         
       
     
     wherein:
 A2 is selected from —NR 8   2 , —NHSO 2 R 3 , —OR 25 , —SR 25 , halogen, lower alkyl, —CON(R 4 ) 2 , guanidine, amidine, —H, and perhaloalkyl; 
 E 2  is selected from —H. halogen, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, —CN, and —NR 7   2 ; 
 X 3  is selected from -alkyl(hydroxy); -alkyl-; -alkynyl-; -aryl-; -carbonyl-alkyl-; -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 —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, optionally substituted; 
 each R 4  is independently selected from —H and alkyl, or, together, both R 4 s form a cyclic alkyl group; 
 R 25  is selected from lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; 
 each R 7  is independently selected from —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C(O)R 10 ; 
 each R 8  is independently selected from —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C(O)R 10 , or, together, both R 8 s form a bidentate alkyl; 
 R 10  is selected from —H, lower alkyl, —NH 2 , lower aryl, and lower perhaloalkyl; and 
 R 11  is selected from alkyl, aryl, —NR 2   2 , and —OR 2 ; 
 
     
       
         
         
             
             
         
       
     
     wherein:
 A, E, and L are independently selected from —NR 8   2 , —NO 2 , —H, —OR 7 , —SR 7 , —C(O)NR 2 , halo, —COR 11 , —SO 2 R 3 , guanidine, amidine, —NHSO 2 R 25 , —SO 2 NR 4   2 , —CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C 1 -C 8  alkyl, C 2 -C 5  alkenyl, C 2 -C 5  alkynyl, and lower alicyclic, or, together, A and L form a cyclic group, or, together, L and E form a cyclic group, or, together, E and J form a cyclic group selected from the group of aryl, cyclic alkyl, and heterocyclic; 
 J is selected from —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, J and Y form a cyclic group selected from the group of aryl, cyclic alkyl, and heterocyclic alkyl; 
 X 3  is selected from -alkyl(hydroxy); -alkyl-; -alkynyl-; -aryl-; -carbonyl-alkyl-; 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 ; 
 Y 3  is selected from —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; 
 each R 4  is independently selected from —H and alkyl, or, together, both R 4 s form a cyclic alkyl group; 
 R 25  is selected from lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; 
 each R 7  is independently selected from —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C(O)R 10 ; 
 each R 8  is independently selected from —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C(O)R 10 , or, together, both R 8 s form a bidentate alkyl; 
 R 10  is selected from —H, lower alkyl, —NH 2 , lower aryl, and lower perhaloalkyl; and 
 R 11  is selected from alkyl, aryl, —NR 2   2 , and —OR 2 ; 
 
     
       
         
         
             
             
         
       
     
     wherein:
 B 5  is selected from —NH—, —N═ and —CH—; 
 D 5  is selected from 
 
     
       
         
         
             
             
         
       
       Q 5  is selected from —C═ and —N—; 
       with the provisos that:
 when B 5  is —NH—, Q 5  is —C═ and D 5  is 
 
     
     
       
         
         
             
             
         
       
       
         when B 5  is —CH═, Q 5  is —N— and D 5  is 
       
     
     
       
         
         
             
             
         
       
       
          and 
         when B 5  is —N═, D 5  is 
       
     
     
       
         
         
             
             
         
       
       
          and Q 5  is —C═; 
         A, E, and L are independently selected from —NR 8   2 , —NO 2 , —H, —OR 7 , —SR 7 , —C(O)NR 4   2 , halo, —COR 1 , —SO 2 R 3 , guanidine, amidine, —NHSO 2 R 25 , —SO 2 NR 4   2 , —CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C 1 -C 5  alkyl, C 2 -C 5  alkenyl, C 2 -C 5  alkynyl, and lower alicyclic, or, together, A and L form a cyclic group, or, together, L and E form a cyclic group, or, together, E and J form a cyclic group selected from the group of aryl, cyclic alkyl, and heterocyclic; 
         J is selected from —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 forms a cyclic group selected from the group of aryl, cyclic alkyl and heterocyclic alkyl; 
         X 3  is selected from -alkyl(hydroxy), -alkyl-, -alkynyl-, -aryl-, -carbonyl-alkyl-, -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 —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 4  is independently selected from —H and alkyl, or together R 4  and R 4  form a cyclic alkyl group; 
         R 25  is selected from lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; 
         R 7  is independently selected from —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C(O)R 10 ; 
         R 8  is independently selected from —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C(O)R 10 , or together they form a bidentate alkyl; 
         R 10  is selected from —H, lower alkyl, —NH 2 , lower aryl, and lower perhaloalkyl; 
         R 11  is selected from alkyl, aryl, —NR 2   2  and —OR 3 ; 
       
     
     
       
         
         
             
             
         
       
     
     wherein:
 each G is independently selected from C, N, O, S, and Se, and wherein not more than one G is O, S, or Se, and not more than one G is N; 
 each G′ is independently selected from C and N and wherein no more than two G′ groups are N; 
 A is selected from —H, —NR 4   2 , —CONR 4   2 , —CO 2 R 3 , halo, —S(O)R 3 , —SO 2 R 3 , alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, —CH 2 OH, —CH 2 NR 4   2 , —CH 2 CN, —CN, —C(S)NH 2 , —OR 3 , —SR 3 , —N 3 , —NHC(S)NR 4   2 , —NHAc, and null; 
 each B and D are independently selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C(O)R 11 , —C(O)SR 3 , —SO 2 R 11 , —S(O)R 3 , —CN, —NR 9   2 , —OR 3 , —SR 3 , perhaloalkyl, halo, —NO 2 , and null, all except —H, —CN, perhaloalkyl, —NO 2 , and halo are optionally substituted; 
 E is selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, —C(O)OR 3 , —CONR 4   2 , —CN, —NR 9   2 , —NO 2 , —OR 3 , —SR 3 , perhaloalkyl, halo, and null, all except —H, —CN, perhaloalkyl, and halo are optionally substituted; 
 J is selected from —H and null; 
 X is an optionally substituted linking group that links R 5  to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there are 2 heteroatoms, measured by the shortest path between R 5  and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from furan-2,5-diyl, -alkyl(hydroxy), -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkyl-, -thio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X is not substituted with —COOR 2 , —SO 3 H, or —PO 3 R 2   2 ; 
 R 2  is selected from R 3  and —H; 
 R 3  is selected from alkyl, aryl, alicyclic, and aralkyl; 
 each R 4  is independently selected from —H, and alkyl, or together R 4  and R 4  form a cyclic alkyl group; 
 each R 9  is independently selected from —H, alkyl, aralkyl, and alicyclic, or together R 9  and R 9  form a cyclic alkyl group or a heterocyclic group where the heteroatom is selected from the group of O, S and N; 
 R 11  is selected from alkyl, aryl, —NR 2   2 , and —OR 2 ; 
 and with the proviso that: 
 1) when G′ is N, then the respective A, B, D, or E is null; 
 2) at least one of A and B, or A, B, D, and E is not selected from —H or null; 
 3) when R 5  is a six-membered ring, then X is not any 2 atom linker, an optionally substituted -alkyloxy-, or an optionally substituted -alkylthio-; 
 4) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom; 
 5) when X is not an -aryl-group, then R 5  is not substituted with two or more aryl groups; 
 
     
       
         
         
             
             
         
       
     
     wherein:
 G″ is selected from —O— and —S—; 
 A 2 , L 2 , E 2 , and J 2  are selected from —NR 4   2 , —NO 2 , —H, —OR 2 , —SR 2 , —C(O)NR 4   2 , halo, —COR 11 , —SO 2 R 3 , guanidinyl, amidinyl, aryl, aralkyl, alkoxyalkyl, —SCN, —NHSO 2 R 9 , —SO 2 NR 4   2 , —CN, —S(O)R 3 , perhaloacyl, perhaloalkyl, perhaloalkoxy, C 1 -C 5  alkyl, C 2 -C 5  alkenyl, C 2 -C 5  alkynyl, and lower alicyclic, or together L 2  and E 2  or E 2  and J 2  form an annulated cyclic group; 
 X 2  is selected from —CR 2   2 —, —CF 2 —, —CR 2   2 —O—, —CR 2   2 —S—, —C(O)—O—, —C(O)—S—, —C(S)—O—, and —CR 2   2 —NR 19 —, and wherein in the atom attached to the phosphorus is a carbon atom; with the proviso that X 2  is not substituted with —COOR 2 , —SO 3 H, or —PO 3 R 2   2 ; 
 R 2  is selected from R 3  and —H; 
 R 3  is selected from alkyl, aryl, alicyclic, and aralkyl; 
 each R 4  is independently selected from —H, and alkyl, or together R 4  and R 4  form a cyclic alkyl group; 
 each R 9  is independently selected from —H, alkyl, aralkyl, and alicyclic, or together R 9  and R 9  form a cyclic alkyl group; 
 R 11  is selected from alkyl, aryl, —NR 2   2 , and —OR 2 ; 
 R 19  is selected from lower alkyl, —H, and —COR 2 . 
 
   
   
       116 . The method according to  claim 115 , wherein M is 
     
       
         
         
             
             
         
       
       A″ is of —H, —NR 4   2 , —CONR 4   2 , —CO 2 R 3 , halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  perhaloalkyl, C 1 -C 6  haloalkyl, aryl, —CH 2 OH, —CH 2 NR 4   2 , —CH 2 CN, —CN, —C(S)NH 2 , —OR 3 , —SR 3 , —N 3 , —NHC(S)NR 4   2 , and —NHAc; 
       B″ is —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C(O)R 11 , —C(O)SR 3 , —SO 2 R 11 , —S(O)R 3 , —CN, —NR 9   2 , —OR 3 , —SR 3 , perhaloalkyl, and halo, all except —H, —CN, perhaloalkyl, and halo are optionally substituted; 
       X is selected from the group consisting of methylenoxycarbonyl and furan-2,5-diyl; 
       YR 1  is OH or Y is NR 6 , wherein R 6  is selected from H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, or lower acyl; and R 1  is independently selected from the group consisting of —H, —[C(R 2 ) 2 ] q —COOR 3 , —C(R 4 ) 2 COOR 3 , —[C(R 2 ) 2 ] q —C(O)SR 3 , and -cycloalkylene-COOR 3 , wherein R 4  is, independently, alkyl or H and R 3  is alkyl, aryl, alicyclic or aralkyl. 
     
   
   
       117 . The method according to  claim 116 , wherein A″ is —NH 2 , —Cl, —Br, or —CH 3 ; B″ is —H, —C(O)OR 3 , —C(O)SR 3 , C 1 -C 6  alkyl, C(O)R 11 , alicyclic, halo, heteroaryl, or —SR 3  and all except —H, and halo are optionally substituted. 
   
   
       118 . The method according to  claim 117 , wherein A″ is —NH 2 ; B″ is a C 1 -C 6  alkyl or C(O)R 11 , wherein R 11  is alkyl. 
   
   
       119 . The method according to  claim 116 , wherein X is furan-2,5-diyl. 
   
   
       120 . The method according to  claim 116 , wherein when Y is NR 6 , R 6  is selected from H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, or lower acyl; and R 1  is independently selected from the group consisting of —H, —[C(R 2 ) 2 ] q —COOR 3 , —C(R 4 ) 2 COOR 3 , —[C(R 2 ) 2 ] q —C(O)SR 3 , and -cycloalkylene-COOR 3 , wherein R 4  is, independently, alkyl or H and R 3  is alkyl, aryl, alicyclic or aralkyl. 
   
   
       121 . The method according to  claim 120 , wherein Y is NR 6  and R 6  is H; and R 1  is —C(R 4 ) 2 COOR 3 , wherein R 4  is, independently, H or methyl; and R 3  is alkyl. 
   
   
       122 . The method according to  claim 116 , wherein A″ is —NH 2 ; B″ is a C 1 -C 6  alkyl or C(O)R 11 , wherein R 11  is alkyl; and X is selected from the group consisting of methylenoxycarbonyl and furan-2,5-diyl. 
   
   
       123 . The method according to  claim 122 , wherein X is furan-2,5-diyl. 
   
   
       124 . The method according to  claim 116 , wherein A″ is —NH 2 ; B″ is a C1-C6 alkyl or C(O)R 11 , wherein R 11  is alkyl; and YR1 is OH. 
   
   
       125 . The method according to  claim 116 , wherein A″ is —NH 2 ; B″ is a C1-C6 alkyl or C(O)R 11 , wherein R 11  is alkyl; Y is NR 6  and R 6  is H; and R 1  is —C(R 4 ) 2 COOR 3 , wherein R 4  is, independently, H or methyl; and R 3  is alkyl. 
   
   
       126 . The method according to  claim 116 , wherein X is furan-2,5-diyl and YR 1  is OH. 
   
   
       127 . The method according to  claim 116 , wherein X is furan-2,5-diyl; Y is NR 6  and R 6  is H; and R 1  is —C(R 4 ) 2 COOR 3 , wherein R 4  is, independently, H or methyl; and R 3  is alkyl. 
   
   
       128 . The method according to  claim 116 , wherein A″ is —NH 2 ; B″ is a C 1 -C 6  alkyl or C(O)R 11 , wherein R 11  is alkyl; X is selected from the group consisting of methylenoxycarbonyl and furan-2,5-diyl; and YR 1  is OH. 
   
   
       129 . The method according to  claim 128 , wherein X is furan-2,5-diyl. 
   
   
       130 . The method according to  claim 116 , wherein A″ is —NH 2 ; B″ is a C1-C6 alkyl or C(O)R 11 , wherein R 11  is alkyl; X is selected from the group consisting of methylenoxycarbonyl and furan-2,5-diyl; Y is NR 6  and R 6  is H; and R 1  is —C(R 4 ) 2 COOR 3 , wherein R 4  is, independently, H or methyl; and R 3  is alkyl. 
   
   
       131 . The method according to  claim 130 , wherein X is furan-2,5-diyl. 
   
   
       132 . The method according to  claim 116 , wherein said FBPase inhibitor is
 Compound J   
     
       
         
         
             
             
         
       
     
   
   
       133 . The method according to  claim 115 , wherein said sulfonylurea antidiabetic agent is glyburide and said FBPase inhibitor is
 Compound J   
     
       
         
         
             
             
         
       
     
   
   
       134 . The method according to  claim 115 , wherein said sulfonylurea antidiabetic agent is a compound of formula XV: 
     
       
         
         
             
             
         
       
     
     wherein
 A is selected from hydrogen, halo, alkyl, alkanoyl, aryl, aralkyl, heteroaryl, and cycloalkyl; and 
 B is selected from alkyl, cycloalkyl, and heterocyclic alkyl. 
 
   
   
       135 . The method according to  claim 134 , wherein said sulfonylurea antidiabetic agent is selected from glyburide, glisoxepid, acetohexamide, chlorpropamide, glibomuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, and glimepiride. 
   
   
       136 . The method according to  claim 132 , wherein said sulfonylurea antidiabetic agent is a compound of formula XV: 
     
       
         
         
             
             
         
       
     
     wherein
 A is selected from hydrogen, halo, alkyl, alkanoyl, aryl, aralkyl, heteroaryl, and cycloalkyl; and 
 B is selected from alkyl, cycloalkyl, and heterocyclic alkyl. 
 
   
   
       137 . The method according to  claim 136 , wherein said sulfonylurea antidiabetic agent is selected from glisoxepid, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, and glimepiride. 
   
   
       138 . The method according to  claim 130 , wherein said sulfonylurea antidiabetic agent is a compound of formula XV: 
     
       
         
         
             
             
         
       
     
     wherein
 A is selected from hydrogen, halo, alkyl, alkanoyl, aryl, aralkyl, heteroaryl, and cycloalkyl; and 
 B is selected from alkyl, cycloalkyl, and heterocyclic alkyl. 
 
   
   
       139 . The method according to  claim 138 , wherein said sulfonylurea antidiabetic agent is selected from glyburide, glisoxepid, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, and glimepiride. 
   
   
       140 . The method according to  claim 131 , wherein said sulfonylurea antidiabetic agent is a compound of formula XV: 
     
       
         
         
             
             
         
       
     
     wherein
 A is selected from hydrogen, halo, alkyl, alkanoyl, aryl, aralkyl, heteroaryl, and cycloalkyl; and 
 B is selected from alkyl, cycloalkyl, and heterocyclic alkyl. 
 
   
   
       141 . The method according to  claim 140 , wherein said sulfonylurea antidiabetic agent is selected from glyburide, glisoxepid, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, and glimepiride. 
   
   
       142 . The method according to  claim 128 , wherein said sulfonylurea antidiabetic agent is a compound of formula XV: 
     
       
         
         
             
             
         
       
     
     wherein
 A is selected from hydrogen, halo, alkyl, alkanoyl, aryl, aralkyl, heteroaryl, and cycloalkyl; and 
 B is selected from alkyl, cycloalkyl, and heterocyclic alkyl. 
 
   
   
       143 . The method according to  claim 142 , wherein said sulfonylurea antidiabetic agent is selected from glyburide, glisoxepid, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, and glimepiride. 
   
   
       144 . The method according to  claim 129 , wherein said sulfonylurea antidiabetic agent is a compound of formula XV: 
     
       
         
         
             
             
         
       
     
     wherein
 A is selected from hydrogen, halo, alkyl, alkanoyl, aryl, aralkyl, heteroaryl, and cycloalkyl; and 
 B is selected from alkyl, cycloalkyl, and heterocyclic alkyl. 
 
   
   
       145 . The method according to  claim 144 , wherein said sulfonylurea antidiabetic agent is selected from glyburide, glisoxepid, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, and glimepiride. 
   
   
       146 . The method according to  claim 117 , wherein said sulfonylurea antidiabetic agent is a compound of formula XV: 
     
       
         
         
             
             
         
       
     
     wherein
 A is selected from hydrogen, halo, alkyl, alkanoyl, aryl, aralkyl, heteroaryl, and cycloalkyl; and 
 B is selected from alkyl, cycloalkyl, and heterocyclic alkyl. 
 
   
   
       147 . The method according to  claim 146 , wherein said sulfonylurea antidiabetic agent is selected from glyburide, glisoxepid, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, and glimepiride.