RU2003103436A - COMBINATION OF FBP-ASE INHIBITORS AND ANTI-DIABETIC MEDICINES FOR TREATING DIABETES - Google Patents

Claims (114)

1. A pharmaceutical composition comprising a pharmaceutically effective amount of at least one insulin secretion enhancing agent and a pharmaceutically effective amount of at least one FBPase inhibitor. 2. The pharmaceutical composition according to claim 1, where the specified insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 3. The pharmaceutical composition of claim 2, wherein said sulfonylurea antidiabetic agent is a compound of formula XV

where A is selected from hydrogen, halogen, alkyl, alkanoyl, aryl, aralkyl, heteroaryl and cycloalkyl; and B is selected from alkyl, cycloalkyl and heterocyclic alkyl. 4. The pharmaceutical composition according to claim 2, wherein said sulfonylurea antidiabetic agent is selected from glyburide, glyoxoxide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide and. 5. The pharmaceutical composition according to claim 1, where the specified agent that enhances the secretion of insulin, is a non-sulfonylurea. 6. The pharmaceutical composition according to claim 5, wherein said non-sulfonylurea is selected from mitiglinide, BTS-67582, repaglinide and nateglinide. 7. The pharmaceutical composition according to claim 1, wherein said insulin secretion enhancing agent is a dipeptidyl peptidase-IV inhibitor (DPP-IV). 8. The pharmaceutical composition according to claim 7, where the specified dipeptidyl peptidase-IV inhibitor (DPP-IV) is selected from the group comprising NVP-DPP728 and P32 / 98. 9. The pharmaceutical composition according to claim 1, wherein said insulin secretion enhancing agent is a glucagon-like peptide-1 receptor agonist (GLP-1). 10. The pharmaceutical composition according to claim 9, wherein said glucagon-like peptide-1 receptor agonist (GLP-1) is NN-2211, an exendin, or an exendin agonist. 11. The pharmaceutical composition according to claim 1, wherein said FBPase inhibitor is a compound selected from formulas I and IA, and pharmaceutically acceptable prodrugs and salts thereof, wherein formulas I and IA are as follows:

where the compounds of formulas I and IA are converted in vivo or in vitro to M-PO $\genfrac{}{}{0ex}{}{\text{2-}}{\text{3}}$ which inhibits FBP-ase, and where: Y is independently selected from —O— and —NR ⁶ , provided that: when Y is —O—, then R ¹ attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, where the cyclic moiety contains carbonate or thiocarbonate, optionally substituted α-arylalkyl, —C (R ² ) ₂ OC (O) NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ , -NR ² -C (O) -R ³ , -C (R ² ) ₂ -OC (O) R ³ , -C (R ² ) ₂ -OC (O) OR ³ , -C (R ² ) ₂ OC (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkyl hydroxy and -alkyl-SSS-alkyl hydroxy; when Y is —NR ⁶ , then 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—, where —O— is not part of a cyclic group containing another Y, then 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 , then R ¹ and R ¹ together are alkyl-SS-alkyl and form a cyclic group, or R ¹ and R ¹ together form

where a) V is selected from the group comprising aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl; or V and Z are joined together by additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group in beta and gamma positions of Y adjacent to V; or Z is selected from the group consisting of —CHR ² OH, —CHR ² OC (O) R ³ , —CHR ² CO (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 $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ) OH, -CH (CCR ² ) OH, -R ² , -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ , -OCOR ³ , -OCO ₂ R ³ , -SCOR ³ , -SCO ₂ R ³ , -NHCOR ² , -NHCO ₂ R ³ , -CH ₂ NH-aryl, - (CH ₂ ) _p OR ² and - (CH ₂ ) _p -SR ² where p is an integer of 2 or 3; or Z and W are joined together by 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 consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or W and W ’are joined together by 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 consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; Z ^{2 is} selected from the group consisting of —CHR ² OH, —CHR ² OC (O) R ³ , —CHR ² OC (S) R ³ , —CHR ² OCO ₂ R ³ , —CHR ² OC (O) SR ³ , -CHR ² OC (S) OR ³ , -CH (aryl) OH, -CH (CH = CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ) OH, -CH (CCR ² ) OH, -SR ² , -CH ₂ NH-aryl, -CH ₂ -aryl; or V ² and Z ^{2 are} joined together by additional 3-5 atoms to form a cyclic group containing 5-7 atoms in the ring, optionally containing 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom, which is three atoms from Y attached to phosphorus; c) Z 'is selected from the group consisting of —OH, —OC (O) R ³ , —OCO ₂ R ^3, and —OC (O) SR ³ ; D ’means -H; D "is selected from the group consisting of —H, alkyl, —OR ² , —OH and —OC (O) R ³ ; each W ^{3 is} independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; provided that a) V, Z, W, W ', all do not mean -H, and V ² , Z ² , W ² , W ", all do not mean -H; and R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from the group consisting of —H, alkyl, alkylene, alkylene aryl and aryl, or R ⁴ and R ^{4 are} joined together by 2-6 atoms, optionally including one heteroatom selected from the group consisting 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 R ¹² and R ^{18 are} joined together by 1-4 carbon atoms to form a cyclic group; each R ¹² and each R ^{13 is} independently selected from H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ^{13 are} joined together by 2-6 carbon atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S, with the formation of 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 R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group, wherein the cyclic group optionally contains 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 R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group where the cyclic group optionally contains 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 , then two R ^{17 are} joined together by 2-6 atoms to form a cyclic group, where the cyclic group optionally contains one heteroatom selected from O, N and S; R ^{20 is} selected from the group consisting of —H, lower R ^3, and —C (O) —lower — R ³ . 12. The pharmaceutical composition according to claim 11, where M means

where U ⁶ and V ^{6 are} independently selected from hydrogen, hydroxy and acyloxy, or U ⁶ and V ⁶ taken together form a lower cyclic ring containing at least one oxygen; W ^{6 is} selected from amino and lower alkylamino; and Z ^{6 is} selected from alkyl and halogen. 13. The pharmaceutical composition of claim 11, wherein said insulin secretion enhancing agent is a sulfonylurea antidiabetic agent. 14. The pharmaceutical composition according to claim 11, where M means

where A ^{2 is} selected from -NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , —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 $\genfrac{}{}{0ex}{}{\text{7}}{\text{2}}$ ; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; -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 $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; 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 $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or two R ⁴ together 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 two R ⁸ together form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; R ¹¹ selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and -OR ² ; and their pharmaceutically acceptable prodrugs and salts. 15. The pharmaceutical composition of claim 14, wherein said insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 16. The pharmaceutical composition according to claim 11, where M means:

where A, E and L are independently selected from -NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , -NO ₂ , -H, -OR ⁷ , -SR ⁷ , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR ¹¹ , —SO ₂ R ³ , guanidine, amidine, —NHSO ₂ R ²⁵ , —SO ₂ NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl and lower alicyclic, or A and L together form a cyclic group, or L and E together form a cyclic group, or E and J together form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocycle; J is selected from -NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , -NO ₂ , -H, -OR ⁷ , -SR ⁷ , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or J and Y together form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; aralkyl-; -alkylaryl-; alkoxycarbonyl; -carbonyloxyalkyl-; alkoxycarbonylamino; and -alkylaminocarbonylamino, all optionally substituted, provided that X ^{3 is} not substituted with —COOR ² , —SO ₃ H or —PO ₃ R $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; 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 $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or two R ⁴ together 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 two R ⁸ together form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; and R ¹¹ selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and -OR ² ; and their pharmaceutically acceptable prodrugs and salts. 17. The pharmaceutical composition according to clause 16, where the specified agent that enhances the secretion of insulin, is an antidiabetic agent based on sulfonylurea. 18. The pharmaceutical composition according to claim 11, wherein said sulfonylurea-based antidiabetic agent is selected from glyburide, glisoxepide, acetohexamide, chlorpropapamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide. 19. The pharmaceutical composition according to clause 16, where the specified insulin secretion enhancing agent is selected from mitiglinide, BTS-67582, repaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucagon-like peptide-1 receptor agonists (GLP- 1). 20. The pharmaceutical composition according to claim 11, where M means

where B ^{5 is} selected from —NH—, —N = and CH =; D ^{5 is} selected from

and

Q ^{5 is} selected from —C = and —N—; provided that when B ⁵ means —NH— then Q ⁵ means —C = and D ⁵ means

when B ⁵ means —CH =, then Q ⁵ means —N— and D ⁵ means

and when B ⁵ means -M =, then D ⁵ means

and Q ⁵ means —C =; A, E and L are independently selected from —NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , -NO ₂ , -H, -OR ⁷ , -SR ⁷ , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR ¹¹ , —SO ₂ R ³ , guanidine, amidine, —NHSO ₂ R ²⁵ , —SO ₂ NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl and lower alicyclic, or A and L together form a cyclic group, or L and E together form a cyclic group, or E and J together form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocycle; J is selected from -NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , -NO ₂ , -H, -OR ⁷ , -SR ⁷ , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR 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 consisting of aryl cyclic alkyl and heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; an alicyclic; -aralkyl-; -alkylaryl-; alkoxycarbonyl; -carbonyloxyalkyl-; alkoxycarbonylamino; and -alkylaminocarbonylamino, all optionally substituted, provided that X ^{3 is} not substituted -COOR ² , -SO ₃ H or -RO ₃ R $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; 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 $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and —OR ³ , all except H, are optionally substituted; R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together 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; and R ¹¹ selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and -OR ² ; and their pharmaceutically acceptable prodrugs and salts. 21. The pharmaceutical composition of claim 20, wherein said insulin secretion enhancing agent is a sulfonylurea-based antidiabetic agent. 22. The pharmaceutical composition according to claim 11, where M means —XR ⁵ , where R ^{5 is} selected from

where each G is independently selected from C, N, O, S, and Se, and where 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 where no more than two groups G’ mean N; A is selected from -H, -NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CONR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , —CO ₂ R ³ , halogen, —S (O) R ³ , —SO ₂ R ³ , alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, —CH ₂ OH, —CH ₂ NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , -NHC (S) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -NHAc or absent; each B and D is 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 $\genfrac{}{}{0ex}{}{\text{9}}{\text{2}}$ , —OR ³ , —SR ³ , perhaloalkyl, halogen, —NO ₂ or absent, with the exception of —H, —CN, perhaloalkyl, —NO ₂ and halogen, all optionally substituted; E is selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, —C (O) OR ³ , —CONR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CN, -NR $\genfrac{}{}{0ex}{}{\text{9}}{\text{2}}$ , -NO ₂ , -OR ³ , -SR ³ , perhalogenated, halogen or absent, with the exception of -H, -CN, perhalogenated and halogen, all are optionally substituted; J is selected from —H or absent; X is an optionally substituted linking group that binds R ⁵ to a phosphorus atom through 2-4 atoms including 0-1 heteroatoms selected from N, O and S, except that when X is urea or carbamate, then there are 2 heteroatoms located along the shortest path between R ⁵ and the phosphorus atom, and where the atom attached to the phosphorus means a carbon atom, and where X is selected from furan-2,5-diyl, -alkyl (hydroxy) -; alkynyl; heteroaryl; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; alkylalkyl; -alkylaminocarbonyl-; -alkylcarbonylamino; alkoxycarbonyl-; -carbonyloxyalkyl-; alkoxycarbonylamino; and -alkylaminocarbonylamino, all optionally substituted, provided that X is not substituted with —COOR ² , —SO ₃ H or —PO ₃ R $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; each R ^{9 is} independently selected from —H, alkyl, aralkyl and alicyclic, R ⁹ and R ⁹ together form a cyclic alkyl group or heterocyclic group, wherein the heteroatom is selected from the group consisting of O, S and N; R ¹¹ selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and-OR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; and provided that: 1) when G ’means N, then the corresponding A, B, D or E are absent; 2) at least one of A and B, or A, B, D and E cannot be selected from -H or absent; 3) when R ⁵ means a six-membered ring, then X does not mean any 2 atomic linkers, optionally substituted -alkyloxy-, or optionally substituted -alkylthio; 4) when G is N, then the corresponding A or B does not mean a 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; and their pharmaceutically acceptable prodrugs and salts. 23. The pharmaceutical compositions of claim 22, wherein R ^{5 is} selected from pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thidiazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl and 1,3-selenazolyl, all of which contain at least one substituent. 24. The pharmaceutical composition according to item 22, where R ⁵ does not mean 2-thiazolyl or 2-oxazolyl. 25. The pharmaceutical composition according to item 22, where R ⁵ selected from the group including

where A "is selected from -H, -NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CONR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ -CO ₂ R ³ , halogen, -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 $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , -NHC (S) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ and -NHAc; In "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 $\genfrac{}{}{0ex}{}{\text{9}}{\text{2}}$ , —OR ³ , —SR ³ , perhaloalkyl, halogen, with the exception of —H, —CN, perhaloalkyl and halogen, are all optionally substituted; E "is selected from —H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₄ -C ₆ alicyclic, alkoxyalkyl, —C (O) OR ³ , - CONR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CN, -NR $\genfrac{}{}{0ex}{}{\text{9}}{\text{2}}$ , —OR ³ , —SR ³ , C ₁ -C ₆ perhaloalkyl and; halogen, all except —H, —CN, perhaloalkyl and halogen are optionally substituted; and each R ^{3 is} independently selected from C ₁ -C ₆ alkyl, C ₆ aryl, C ₃ -C ₆ heteroaryl, C ₃ -C ₈ alicyclic, C ₂ -C ₇ heteroalicycle, C ₇ -C ₁₀ aralkyl and C ₄ -C ₉ heteroaryl; each R ⁴ and R ^{9 is} independently selected from —H and C ₁ -C ₁ alkyl; X is selected from -heteroaryl-, -alkylcarbonylamino, alkylaminocarbonyl- and -alkoxycarbonyl-; each R ^{11 is} selected from -NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , —OH, —OR ³ , C ₁ -C ₆ alkyl and C ₆ aryl, C ₃ -C ₆ heteroaryl; 26. The pharmaceutical composition according A.25, where X is selected from -heteroaryl- and -alkoxycarbonyl-. 27. The pharmaceutical composition according A.25, where the specified compound is a compound of formulas XII, XIII or XIV

28. The pharmaceutical composition according A.25, where A "selected from -NH ₂ , -Cl, -Br and CH ₃ ; each B "is selected from —H, —C (O) OR ³ , —C (O) SR ³ , C ₁ —C ₆ alkyl, alicyclic, halogen, heteroaryl, and —SR ³ ; D "is selected from —H, —C (O) OR ³ , lower alkyl, alicyclic, and halogen; and E "is selected from —H, —Br, and —Cl. 29. The pharmaceutical composition according to item 27, where R ¹⁸ selected from -H, methyl and ethyl; each R ¹² and R ^{13 is} independently selected from —H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, —CH ₂ CH ₂ SCH ₃ , phenyl and benzyl, or R ¹² and R ^{13 are} connected together via a chain from 2-5 carbon atoms to form a cycloalkyl group; n is 1 or 2; each R ^{14 is} independently selected from —OR ¹⁷ where R ^{17 is} selected from methyl, ethyl, propyl, and benzyl; and R ¹⁵ and R ^{16 are} independently selected from lower alkyl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by a chain of 2-6 atoms, optionally containing 1 heteroatom selected from O, N and S. 30. The pharmaceutical composition according to item 27, where R ¹⁶ means - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ . 31. The pharmaceutical composition according to item 27, where R ^{18 is} selected from —H, methyl, and ethyl; R ¹² and R ^{13 are} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or are joined together by a chain of 2-5 carbon atoms to form a cycloalkyl group; R ¹⁴ is —OR ¹⁷ ; R ^{17 is} selected from methyl, ethyl, propyl, tert-butyl and benzyl; and R ¹⁵ and R ^{16 are} independently selected from lower alkyl and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by a chain of 2-6 atoms, optionally including 1 heteroatom selected from O and N. 32. The pharmaceutical composition of claim 22, wherein said FBPase inhibitor is a compound of the formula

where X is selected from furan-2,5-diyl, alkoxycarbonyl and alkylaminocarbonyl-. 33. The pharmaceutical composition according p, where n is 1; R ¹² and R ^{13 are} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or R ¹² and R ^{13 are} joined together by a chain of 2-5 carbon atoms to form a cycloalkyl group, and when R ¹² and R ¹³ are not identical, then H ₂ N-CR ¹² R ¹³ -C (O) -R ¹⁴ means an ester or thioester of a natural amino acid; R ^{14 is} selected from —OR ¹⁷ and —SR ¹⁷ ; R ^{17 is} selected from methyl, ethyl, propyl, tert-butyl and benzyl; and R ^{18 is} selected from —H, methyl, and ethyl. 34. The pharmaceutical composition according A.25, where R ⁵ means

A "is selected from —NH ₂ , —CONH ₂ , halogen, —CH ₃ , —CF ₃ , —CH ₂ halogen, —CN, —OCH ₃ , —SCH ₃ , and —H; In "selected from -H, -C (O) R ¹¹ , -C (O) SR ³ , alkyl, aryl, alicyclic, halogen, -CN, -SR ³ , -OR ³ and -NR $\genfrac{}{}{0ex}{}{\text{9}}{\text{2}}$ ; and X is selected from -heteroaryl-, -alkoxycarbonyl- and -alkylaminocarbonyl-, all optionally substituted. 35. The pharmaceutical compositions of claim 34, wherein said FBPase inhibitor is a compound of Formula 1A and where

selected from

and

where C * is the S configuration; R ¹⁸ and R ^{15 are} independently selected from H and methyl; R ¹² and R ^{13 are} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or R ¹² and R ^{13 are} joined together via a chain of 2-5 carbon atoms to form a cycloalkyl group; n is 1; R ¹⁴ is —OR ¹⁷ ; R ¹⁶ means - (CR ¹² R ¹³ ) _n —C (O) —R ¹⁴ ; and R ^{17 is} selected from methyl, ethyl, propyl, phenyl and benzyl. 36. The pharmaceutical composition according to clause 34, where A "means -NH ₂ , X means furan-2,5-diyl and B" means -S (CH ₂ ) ₂ CH ₃ . 37. The pharmaceutical composition according to clause 34, where A "means -NH ₂ , X means furan-2,5-diyl and B" means -CH ₂ CH (CH ₃ ) ₂ . 38. The pharmaceutical composition according to clause 37, where the specified FBPase inhibitor is a compound of formula 1A and where

means

39. The pharmaceutical composition according to clause 37, where the specified FBPase inhibitor is a compound of formula 1A and where

means

where C * is the S configuration. 40. The pharmaceutical composition of claim 22, wherein said insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 41. The pharmaceutical composition according to claim 40, wherein said sulfonylurea-based antidiabetic agent is selected from glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide. 42. The pharmaceutical composition of claim 22, wherein said insulin secretion enhancing agent is selected from mitiglinide, BTS-67582, hepatlinide, nateglinide, dipeptidyl peptidase-IV inhibitors (DPP-IV) and glucagon-like peptide-1 receptor agonists ( GLP-1). 43. The pharmaceutical composition according to claim 11, where M means

where G "is selected from -O- and -S-; A ² , L ² , E ^2, and J ^{2 are} selected from —NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -NO ₂ , -H, -OR ² , -SR ² , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR ¹¹ , —SO ₂ R ³ , guanidinyl, amidinyl, aryl, aralkyl, alkoxyalkyl, —SCN, —NHSO ₂ R ⁹ , —SO ₂ NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -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 L ² and E ² or E ² and J ² together form an annelated cyclic group; X ^{2 is} selected from -CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ -, -CF ₂ -, -CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ -O, -CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ -S, -C (O) -O-, -C (O) -S-, -C (S) -O-, and -CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ —NR ¹⁹ -, and where an atom attached to phosphorus means a carbon atom; with the proviso that X ^{2 is} not substituted with —COOR ² , —SO ₃ H or —PO ₃ R $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; each R ^{9 is} independently selected from —H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group; R ¹¹ selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and -OR ² ; R ^{19 is} selected from lower alkyl, —H and —COR ² ; and their pharmaceutically acceptable prodrugs and salts. 44. The pharmaceutical composition according to item 43, where G "means -S-. 45. The pharmaceutical composition according to item 43, where the specified agent that enhances the secretion of insulin, is an antidiabetic agent based on sulfonylurea. 46. A method of treating a mammal having diabetes, comprising administering to said mammal a pharmaceutically effective amount of component (a) containing at least one insulin secretion enhancing agent and a pharmaceutically effective amount of component (b) containing at least one inhibitor FBP aza. 47. The method of claim 46, wherein said insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 48. The method according to clause 47, wherein said sulfonylurea-based antidiabetic agent is selected from glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide and. 49. The method of claim 46, wherein said insulin secretion enhancing agent is selected from mitiglinide, BTS-67582, replaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors, and glucagon-like peptide-1 receptor agonists (GLP-1 ) 50. The method of claim 46, wherein said FBPase inhibitor is a compound selected from formulas I and IA

where the compounds of formulas I and IA are converted in vivo or in vitro to M-PO $\genfrac{}{}{0ex}{}{\text{2-}}{\text{3}}$ that inhibits FBP-ase, and where Y is independently selected from —O— and —NR ⁶ , provided that: when Y is —O—, then R ¹ attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, where the cyclic moiety contains carbonate or thiocarbonate, optionally substituted α-arylalkyl, —C (R ² ) ₂ OC (O) NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ , -NR ² -C (O) -R ³ , -C (R ² ) ₂ -OC (O) R ³ , -C (R ² ) ₂ -OC (O) OR ³ , -C (R ² ) ₂ OC (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy and -alkyl-SSS-alkylhydroxy; when Y is —NR ⁶ , then 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) S) and cycloalkylene-COOR ³ , where q is 1 or 2; when only one Y is —O—, where —O— is not part of a cyclic group containing another Y, then 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 , then R ¹ and R ¹ together are alkyl-SS-alkyl and form a cyclic group, or R ¹ and R ¹ together form

where a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl; or V and Z are joined together by an additional 3-5 atoms to form a cyclic group optionally containing 1 heteroatom, said cyclic group is fused to an aryl group in beta and gamma positions of Y adjacent to V; or Z is selected from the group consisting 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 $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ) OH, -CH (CCR ² ) OH, -R ² , -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ , -OCOR ³ , -OCO ₂ R ³ , -SCOR ³ , -SCO ₂ R ³ , -NHCOR ² , -NHCO ₂ R ³ , -CH ₂ NH-aryl, - (CH ₂ ) _p OR ² and - (CH ₂ ) _p -SR ² where p is an integer of 2 or 3; or Z and W are joined together by 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 consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or W and W ’are joined together by 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 consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; Z ^{2 is} selected from the group consisting of —CHR ² OH, —CHR ² OC (O) R ³ , —CHR ² OC (S) R ³ , —CHR ² OCO ₂ R ³ , —CHR ² OC (O) SR ³ , -CHR ² OC (S) OR ³ , -CH (aryl) OH, -CH (CH = CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ) OH, -CH (CCR ² ) OH, -SR ² , -CH ₂ NH-aryl, -CH ₂ -aryl; or V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 ring atoms, optionally containing 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom, which is three atoms from Y attached to phosphorus; c) Z 'is selected from the group consisting of —OH, —OC (O) R ³ , —OCO ₂ R ^3, and —OC (O) SR ³ ; D ’means -H; D ”is selected from the group consisting of —H, alkyl, —OR ² , —OH and —OC (O) R ³ ; each W ^{3 is} independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; provided that a) V, Z, W, W ', all do not mean -H, and V ² , Z ² , W ² , W', all do not mean -H; and R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from the group consisting of —H, alkylene, α-alkylenearyl and aryl, or R ⁴ and R ^{4 are} joined together by 2-6 atoms optionally containing one heteroatom selected from the group consisting 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 R ¹² and R ^{18 are} joined together by 1-4 carbon atoms to form a cyclic group; each R ¹² and each R ^{13 is} independently selected from H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ^{13 are} joined together by 2-6 carbon atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S, with the formation of 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 R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group, wherein the cyclic group optionally contains 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 R ¹⁵ and R ^{16 are} joined together by 2-6 atoms to form a cyclic group where the cyclic group optionally contains 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 , then two R ^{17 are} joined together by 2-6 atoms to form a cyclic group, where the cyclic group optionally contains one heteroatom selected from O, N and S; R ^{20 is} selected from the group consisting of —H, lower R ³ and —C (O) —lower — R ³ ; and their pharmaceutically acceptable prodrug and salts. 51. The method according to item 50, where M means

where A ^{2 is} selected from -NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , —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 $\genfrac{}{}{0ex}{}{\text{7}}{\text{2}}$ ; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; -aralkyl-; -alkylaryl-; alkoxycarbonyl; -carbonyloxyalkyl-; alkoxycarbonylamino; and alkylaminocarbonylamino, all optionally substituted, provided that X ^{3 is} not substituted with —COOR ² , —SO ₃ H, or —PO ₃ R $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ 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 $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together 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 two R ⁸ together form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; R ¹¹ selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and -OR ₂ , and their pharmaceutically acceptable prodrugs and salts. 52. The method of claim 51, wherein said insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 53. The method of claim 52, wherein said sulfonylurea antidiabetic agent is selected from glyburide, glycosoxide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide and. 54. The method of claim 51, wherein said insulin secretion enhancing agent is selected from mitiglinide, BTS-67582, replaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 ) 55. The method according to item 50, where M means

where A, E and L are independently selected from -NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , -NO ₂ , -H, -OR ⁷ , -SR ⁷ , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR ¹¹ , —SO ₂ R ³ , guanidine, amidine, —NHSO ₂ R ²⁵ , —SO ₂ NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl and lower alicyclic, or A and L together form a cyclic group, or L and E together form a cyclic group, or E and J together form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocycle; J is selected from -NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , -NO ₂ , -H, -OR ⁷ , -SR ⁷ , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR 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 consisting of aryl cyclic alkyl and heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; -aralkyl-; -alkylaryl-; alkoxycarbonyl; -carbonyloxyalkyl-; alkoxycarbonylamino; and alkylaminocarbonylamino, all optionally substituted, provided that X ^{3 is} not substituted with —COOR ² , —SO ₃ H, or —PO ₃ R $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; 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 $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together 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 two R ⁸ together form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; R ¹¹ selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and -OR ² ; and their pharmaceutically acceptable prodrugs and salts. 56. The method of claim 55, wherein said insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 57. The method of claim 56, wherein said sulfonylurea antidiabetic agent is selected from glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide and. 58. The method of claim 55, wherein said insulin secretion enhancing agent is selected from mitiglinide, BTS-67582, replaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 ) 59. The method according to item 50, where M means

where B ^{5 is} selected from —NH—, —N = and —CH =; D ^{5 is} selected from

and

Q ^{5 is} selected from —C = and —N—; provided that: when B ⁵ means —NH— then Q ⁵ means —C = and D ⁵ means

when B ⁵ means —CH =, then Q ⁵ means —N— and D ⁵ means

and when B ⁵ means -N =, then D ⁵ means

and Q ⁵ means —C =; A, E and L are independently selected from —NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , -NO ₂ , -H, -OR ⁷ , -SR ⁷ , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR ¹¹ , —SO ₂ R ³ , guanidine, amidine, —NHSO ₂ R ²⁵ , —SO ₂ NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl and lower alicyclic, or A and L together form a cyclic group, or L and E together form a cyclic group, or E and J together form a cyclic group selected from the group consisting of aryl, cyclic alkyl and heterocycle; J is selected from -NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , -NO ₂ , -H, -OR ⁷ , -SR ⁷ , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR 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 consisting of aryl, cyclic alkyl and heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; -aralkyl-; -alkylaryl-; alkoxycarbonyl; -carbonyloxyalkyl-; alkoxycarbonylamino; and -alkylaminocarbonylamino, all optionally substituted, provided that X ^{3 is} not substituted with —COOR ² , —SO ₃ H or —PO ₃ R $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; 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 $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together 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; and R ¹¹ selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and -OR ² ; and their pharmaceutically acceptable prodrugs and salts. 60. The method of claim 59, wherein said insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 61. The method of claim 60, wherein said sulfonylurea antidiabetic agent is selected from glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide and. 62. The method of claim 59, wherein said insulin secretion enhancing agent is selected from mitiglinide, BTS-67582, replaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 ) 63. The method according to item 50, where M means -XR ⁵ , where R ^{5 is} selected from

where each G is independently selected from C, N, O, S and Se, and where no more than one G is O, S or Se, and no more than one G is N; each G ’is independently selected from C and N, and where no more than two groups G’ mean N; A is selected from -H, -NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CONR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , —CO ₂ R ³ , halogen, —S (O) R ³ , —SO ₂ R ³ , alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, —CH ₂ OH, —CH ₂ NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , -NHC (S) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -NHAc or absent; 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 $\genfrac{}{}{0ex}{}{\text{9}}{\text{2}}$ , -OR ³ , -SR ³ , perhalogenated, halogen and -NO ₂ or absent, with the exception of -H, -CN, perhalogenated, -NO ₂ and halogen, all optionally substituted; E is selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, —C (O) OR ³ , —CONR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ -CN, -NR $\genfrac{}{}{0ex}{}{\text{9}}{\text{2}}$ , -NO ₂ , -OR ³ , -SR ³ , perhalogenated and halogen or absent, with the exception of -H, -CN, perhalogenated and halogen, all optionally substituted; J is selected from —H or absent; X is an optionally substituted linking group that binds R ⁵ to a phosphorus atom through 2-4 atoms including 0-1 heteroatoms selected from N, O and S, except that when X is urea or carbamate, then there are 2 heteroatoms located along the shortest path between R ⁵ and the phosphorus atom, and where the atom attached to the phosphorus means a carbon atom, and where X is selected from -alkyl (hydroxy) -; alkynyl; heteroaryl; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; alkoxycarbonyl-; -carbonyloxyalkyl-; alkoxycarbonylamino; and -alkylamino-carbonylamino, all optionally substituted, provided that X is not substituted -COOR ² , -SO ₃ H or -RO ₃ R $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; each R ^{9 is} independently selected from —H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group; R ¹¹ selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and -OR ² ; and provided that: 1) when G ’means N, then the corresponding A, B, D or E are absent; 2) at least one of A and B, or A, B, D and E cannot be selected from -H or absent; 3) when R ⁵ means a six-membered ring, then X does not mean a 2 atom linker, optionally substituted -alkyloxy-, or optionally substituted -alkylthio; 4) when G is N, then the corresponding A or B does not mean a 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; and their pharmaceutically acceptable prodrugs and salts. 64. The method of claim 63, wherein said insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 65. The method according to clause 64, wherein said sulfonylurea antidiabetic agent is selected from glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide and. 66. The method of claim 63, wherein said insulin secretion enhancing agent is selected from mitiglinide, BTS-67582, replaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 ) 67. The method according to item 50, where M means

G ”is selected from —O— and — S—; A ² , L ² , E ^2, and J ^{2 are} selected from —NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -NO ₂ , -H, -OR ² , -SR ² , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR ¹¹ , —SO ₂ R ³ , guanidinyl, amidinyl, aryl, aralkyl, alkoxyalkyl, —SCN, —NHSO ₂ R ⁹ , —SO ₂ NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -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 L ² and E ² or E ² and J ² together form an annelated cyclic group; X ^{2 is} selected from -CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ -, -CF ₂ -, -CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ -O, -CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ -S, -C (O) -O-, -C (O) -S-, -C (S) -O-, and -CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ —NR ¹⁹ -, and where an atom attached to phosphorus means a carbon atom; with the proviso that X ^{2 is} not substituted with —COOR ² , —SO ₃ H or —PO ₃ R $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; each R ^{9 is} independently selected from —H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group; R ¹¹ selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and -OR ² ; R ^{19 is} selected from lower alkyl, —H and —COR ² ; and their pharmaceutically acceptable prodrugs and salts. 68. The method of claim 67, wherein said insulin secretion enhancing agent is an sulfonylurea-based antidiabetic agent. 69. The method of claim 68, wherein said sulfonylurea-based antidiabetic agent is selected from glyburide, glisoxepide, acetohexamide, chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide, glyclazide, glychidone, glyhexamide, fenbutamide, tolcylamide and. 70. The method of claim 67, wherein said insulin secretion enhancing agent is selected from mitiglinide, BTS-67582, replaglinide, nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitors, and glucagon-like peptide-1 receptor agonists (GLP-1 ) 71. The method according to item 46, where the specified combination is administered orally. 72. The method according to item 46, where the specified disease is characterized by hyperglycemia. 73. The method according to item 46, where the specified disease is obesity. 74. The method of claim 46, wherein said mammal is administered from about 100 to 2000 mg of said FBPase inhibitor and from about 3 to 250 mg of said sulfonylurea antidiabetic agent. 75. A pharmaceutical composition that comprises a pharmaceutically effective amount of insulin or an insulin analogue and a pharmaceutically effective amount of an FBPase inhibitor. 76. The pharmaceutical composition of claim 75, wherein said insulin or insulin analog is selected from insulin, lispro insulin, aspart insulin, and garglin insulin. 77. A pharmaceutical composition that comprises a pharmaceutically effective amount of biguanide and a pharmaceutically effective amount of an FBPase inhibitor. 78. The pharmaceutical composition according p, where the specified biguanide selected from metformin, phenformin and buformin. 79. A pharmaceutical composition that comprises a pharmaceutically effective amount of an alpha glucosidase inhibitor and a pharmaceutically effective amount of an FBPase inhibitor. 80. The pharmaceutical composition according to p, where the alpha glucosidase inhibitor is selected from acarbose, miglitol and voglibose. 81. A pharmaceutical composition that comprises a pharmaceutically effective amount of an FBPase inhibitor and a pharmaceutically effective amount of a liver glucose inhibitor selected from glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, amylin agonists and fatty acid oxidation inhibitors. 82. The pharmaceutical composition according p, where the specified amylin agonist is pramlintide. 83. The pharmaceutical composition according to claims 75, 77 or 79, wherein said FBPase inhibitor is a compound selected from formulas I and IA

where the compounds of formulas I and IA are converted in vivo or in vitro to M-PO $\genfrac{}{}{0ex}{}{\text{2-}}{\text{3}}$ that inhibits FBP-ase, and where Y is independently selected from —O— and —NR ⁶ , provided that: when Y is —O—, then R ¹ attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, where the cyclic moiety contains carbonate or thiocarbonate, optionally substituted α-arylalkyl, —C (R ² ) ₂ OC (O) NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ , -NR ² -C (O) -R ³ , -C (R ² ) ₂ -OC (O) R ³ , -C (R ² ) ₂ -OC (O) OR ³ , -C (R ² ) ₂ OC (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy and -alkyl-SSS-alkylhydroxy; when Y is —NR ⁶ , then 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) S) and cycloalkylene-COOR ³ , where q is 1 or 2; when only one Y is —O—, where —O— is not part of a cyclic group containing another Y, then 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 , then R ¹ and R ¹ together are alkyl-SS-alkyl and form a cyclic group, or R ¹ and R ¹ together form:

where a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl; or V and Z are joined together by an additional 3-5 atoms to form a cyclic group optionally containing 1 heteroatom, said cyclic group is fused to the aryl group in beta and gamma positions of Y adjacent to V; or Z is selected from the group consisting 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 $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ) OH, -CH (CCR ² ) OH, -R ² , -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ , -OCOR ³ , -OCO ₂ R ³ , -SCOR ³ , -SCO ₂ R ³ , -NHCOR ² , -NHCO ₂ R ³ , -CH ₂ NH-aryl, - (CH ₂ ) _p OR ² and - (CH ₂ ) _p -SR ² where p is an integer of 2 or 3; or Z and W are joined together by 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 consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or W and W ’are joined together by 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 consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; Z ^{2 is} selected from the group consisting of —CHR ² OH, —CHR ² OC (O) R ³ , —CHR ² OC (S) R ³ , —CHR ² OCO ₂ R ³ , —CHR ² OC (O) SR ³ , -CHR ² OC (S) OR ³ , -CH (aryl) OH, -CH (CH = CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ) OH, -CH (CCR ² ) OH, -SR ² , -CH ₂ NH-aryl, -CH ₂ -aryl; or V ² and Z ^{2 are} joined together by an additional 3-5 atoms to form a cyclic group containing 5-7 atoms in the ring, optionally containing 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom, which is three atoms from Y attached to phosphorus; c) Z 'is selected from the group consisting of —OH, —OC (O) R ³ , —OCO ₂ R ^3, and —OC (O) SR ³ ; D ’means -H; D "is selected from the group consisting of —H, alkyl, —OR ² , —OH and —OC (O) R ³ ; each W ^{3 is} independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; provided that a) V, Z, W, W ', all do not mean -H, and V ² , Z ² , W ² , W ", all do not mean -H; R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from the group consisting of —H, and alkyl, or R ⁴ and R ^{4 are} joined together to form a cyclic alkyl group; 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 is joined together with R ¹² via 1-4 carbon atoms to form a cyclic group; each R ¹² and R ^{13 is} independently selected from H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ^{13 are} joined together by 2-6 carbon atoms to form a cyclic group; each R ^{14 is} independently selected from —OR ¹⁷ , —N (R ¹⁷ ) ₂ , —NHR ¹⁷ , and —SR ¹⁷ ; R ^{15 is} selected from —H, lower alkyl, lower aryl, and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms, optionally including 1 heteroatom selected from O, N, and S; R ^{16 is} selected from - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ , lower alkyl, lower aryl, lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms, optionally including 1 heteroatom selected from O, N and S; each R ^{17 is} independently selected from lower alkyl, lower aryl and lower aralkyl, or R ¹⁷ and R ^{17 are} joined together on N by 2-6 atoms, optionally including 1 heteroatom selected from O, N and S; and their pharmaceutically acceptable prodrugs and salts 84. The pharmaceutical composition according p, where the specified composition contains insulin or an insulin analogue selected from insulin, insulin lispro, insulin aspart and insulin garglin. 85. The pharmaceutical composition according p, where the specified composition contains a biguanide selected from metformin, phenformin and buformin. 86. The pharmaceutical composition according p, where the specified composition contains an alpha glucosidase inhibitor selected from acarbose, miglitol and voglibose. 87. The pharmaceutical composition according p, where M means

where Z ^{6 is} selected from alkyl or halogen; U ⁶ and V ^{6 are} independently selected from hydrogen, hydroxy, acyloxy or, taken together, form a lower cyclic ring containing at least one oxygen; W ^{6 is} selected from amino and lower alkylamino; and their pharmaceutically acceptable prodrugs and salts. 88. The pharmaceutical composition according p, where M means

where A ^{2 is} selected from -NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , —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 $\genfrac{}{}{0ex}{}{\text{7}}{\text{2}}$ ; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; -aralkyl-; -alkylaryl-; alkoxycarbonyl; -carbonyloxyalkyl-; alkoxycarbonylamino; and -alkylaminocarbonylamino, all optionally substituted, provided that X ^{3 is} not substituted with —COOR ² , —SO ₃ H or —PO ₃ P $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; 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 $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together 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 ; each R ^{8 is} independently selected from —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C (O) R ¹⁰ ; or two R ⁸ together form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; and R ¹¹ selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and -OR ₂ , and their pharmaceutically acceptable prodrugs and salts. 89. The pharmaceutical composition according p, where M means

where A, E and L are independently selected from -NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , -NO ₂ , -H, -OR ⁷ , -SR ⁷ , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ halogen, —COR ¹¹ , —SO ₂ R ³ , guanidine, amidine, —NHSO ₂ R ²⁵ , —SO ₂ NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl and lower alicyclic, or A and L together form a cyclic group, or L and E together form a cyclic group, or E and J together form a cyclic group, including aryl, cyclic alkyl and heterocycle; J is selected from -NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , -NO ₂ , -H, -OR ⁷ , -SR ⁷ , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y forms a cyclic group, including aryl, cyclic heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; -aralkyl-; -alkylaryl-; alkoxycarbonyl; -carbonyloxyalkyl-; alkoxycarbonylamino; and alkylaminocarbonylamino, all optionally substituted, provided that X ^{3 is} not substituted with —COOR ² , —SO ₃ H, or —PO ₃ R $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; 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 $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and —OR ³ , all except H, are optionally substituted; R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together 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 two R ⁸ together form a bidentate alkyl; R ^{10 is} selected from —H, lower alkyl, —NH ₂ , lower aryl, and lower perhaloalkyl; and R ¹¹ selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and -OR ² ; and their pharmaceutically acceptable prodrugs and salts. 90. The pharmaceutical composition according p, where M means

where B ^{5 is} selected from —NH—, —N = and —CH =; D ^{5 is} selected from

and

Q ^{5 is} selected from —C = and —N—; provided that: when B ⁵ means —NH— then O ⁵ means —C = and D ⁵ means

when B ⁵ means —CH =, then Q ⁵ means —N— and D ⁵ means

and when B ⁵ means -N =, then D ⁵ means

and Q ⁵ means -C = A, E and L are independently selected from —NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , -NO ₂ , -H, -OR ⁷ , -SR ⁷ , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR ¹¹ , —SO ₂ R ³ , guanidine, amidine, —NHSO _z R ²⁵ , —SO ₂ NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl and lower alicyclic, or A and L together form a cyclic group, or L and E together form a cyclic group, or E and J together form a cyclic group including aryl, cyclic alkyl and heterocycle; J is selected from -NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , -NO ₂ , -H, -OR ⁷ , -SR ⁷ , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y forms a cyclic group, including aryl, cyclic heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; -aralkyl-; -alkylaryl-; alkoxycarbonyl; -carbonyloxyalkyl-; alkoxycarbonylamino; and -alkylaminocarbonylamino, all optionally substituted, provided that X ^{3 is} not substituted with —COOR ² , —SO ₃ H or —PO ₃ R $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; 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 $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and —OR ³ , all except H, are optionally substituted; R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together 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 selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and -OR ³ ; and their pharmaceutically acceptable prodrugs and salts. 91. The pharmaceutical composition according p, where M means -XR ⁵ where R ⁵ selected from

where each G is independently selected from C, N, O, S and Se, and where no more than one G is O, S or Se, and no more than one G is N; each G 'is independently selected from C and N, and where no more than two groups G ⁷ mean N; A is selected from -H, -NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CONR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , —CO ₂ R ³ , halogen, —S (O) R ³ , —SO ₂ R ³ , alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, —CH ₂ OH, —CH ₂ NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , -NHC (S) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -NHAc or absent; each B and D is 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 $\genfrac{}{}{0ex}{}{\text{9}}{\text{2}}$ , -OR ³ , -SR ³ , perhalogenated, halogen, -NO ₂ or absent, all, with the exception of -H, -CN, perhalogenated, -NO ₂ and halogen, are optionally substituted; E is selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, —C (O) OR ³ , —CONR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CN, -NR $\genfrac{}{}{0ex}{}{\text{9}}{\text{2}}$ , -NO ₂ , -OR ³ , -SR ³ , perhalogenated, halogen or absent, all except -H, -CN, perhalogenated and halogen are optionally substituted; J is selected from —H or absent; X is an optionally substituted linking group that binds R ⁵ to a phosphorus atom through 2-4 atoms including 0-1 heteroatoms selected from N, O and S, except that when X is urea or carbamate, then there are two heteroatoms located along the shortest path between R ⁵ and the phosphorus atom, and where the atom attached to the phosphorus means a carbon atom, and where X is selected from -alkyl (hydroxy) -; alkynyl; heteroaryl; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; alkoxycarbonyl-; -carbonyloxyalkyl-; alkoxycarbonylamino; and alkylaminocarbonylamino, all optionally substituted, provided that X is not substituted with —COOR ² , —SO ₃ H or —PO ₃ R $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; each R ^{9 is} independently selected from —H, alkyl, aralkyl, and alicyclic; R ⁹ and R ⁹ together form a cyclic alkyl group; R ¹¹ selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and-OR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; and provided that: 1) when G ’means N, then the corresponding A, B, D or E. are absent; 2) at least one of A and B, or A, B, D and E cannot be selected from -H or absent; 3) when R ⁵ means a six-membered ring, then X does not mean a 2 atom linker, optionally substituted alkyloxy, or optionally substituted -alkylthio; 4) when G is N, then the corresponding A or B does not mean a 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; and their pharmaceutically acceptable prodrugs and salts. 92. The pharmaceutical composition of claim 91, wherein R ^{5 is} selected from pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl and 1,3-selenazolyl, all of which contain at least one substituent. 93. The pharmaceutical composition according p, where R ⁵ selected from

where A "is selected from -H, -NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CONR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CO ₂ R ³ , halogen, -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 $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N ₃ , -NHC (S) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ i-NHAc; In "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 $\genfrac{}{}{0ex}{}{\text{9}}{\text{2}}$ , —OR ³ , —SR ³ , perhaloalkyl and halogen, all except —H, —CN, perhaloalkyl and halogen are optionally substituted; E "is selected from —H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₄ -C ₆ alicyclic, alkoxyalkyl, —C (O) OR ³ , - CONR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ -CN, -NR $\genfrac{}{}{0ex}{}{\text{9}}{\text{2}}$ , -OR ³ , -SR ³ , C ₁ -C ₆ -perhaloalkyl and halogen, all except -H, -CN, perhaloalkyl and halogen are optionally substituted; and each R ^{3 is} independently selected from C ₁ -C ₆ alkyl, C ₆ aryl, C ₃ -C ₆ heteroaryl, C ₃ -C ₈ alicyclic, C ₂ -C ₇ heteroalicycle, C ₇ -C ₁₀ aralkyl and C ₄ -C ₉ heteroaryl; each R ⁴ and R ^{9 is} independently selected from —H and C ₁ -C ₂ alkyl; X is selected from -heteroaryl-, -alkylcarbonylamino, alkylaminocarbonyl- and -alkoxycarbonyl-; each R ^{11 is} selected from -NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , —OH, —OR ³ , C ₁ -C ₆ alkyl and C ₆ aryl, C ₃ -C ₆ heteroaryl; 94. The pharmaceutical composition according to p, where the specified FBPase inhibitor is a compound of formula IA and where R ⁵ means

A "is selected from —NH ₂ , —CONH ₂ , halogen, —CH ₃ , —CF ₃ , —CH ₂ halogen, —CN, —OCH ₃ , —SCH _3, and —H; each B "is selected from —H, —C (O) R ¹¹ , —C (O) SR ³ , alkyl, aryl, alicyclic, halogen, —CN, —SR ³ , —OR ^3, and —NR $\genfrac{}{}{0ex}{}{\text{9}}{\text{2}}$ ; X is selected from -heteroaryl-, -alkoxycarbonyl- and -alkylaminocarbonyl-, all optionally substituted; and Where

selected from

and

where C * is the S configuration; R ¹⁸ and R ^{15 are} each independently selected from H and methyl; each R ¹² and R ^{13 is} independently selected from —H, methyl, isopropyl, isobutyl and benzyl, or R ¹² and R ^{13 are} joined together by 2-5 carbon atoms to form a cycloalkyl group; n is 1; R ¹⁴ is —OR ¹⁷ ; R ¹⁶ means - (CR ¹² R ¹³ ) _n —C (O) —R ¹⁴ ; and R ^{17 is} selected from methyl, ethyl, propyl, phenyl and benzyl. 95. The pharmaceutical composition according p, where the specified composition contains insulin or an insulin analogue selected from insulin, insulin lispro, insulin aspart and insulin garglin. 96. The pharmaceutical composition according p, where the specified composition contains a biguanide selected from metformin, phenformin and buformin. 97. The pharmaceutical composition according to clause 94, wherein said composition comprises an alpha glucosidase inhibitor selected from acarbose, miglitol and voglibose. 98. The pharmaceutical composition according p, where M means

where G "is selected from -O- and -S-; A ² , L ² , E ^2, and J ² are selected from —NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ -NO ₂ , -H, -OR ² , -SR ² , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR ¹¹ , —SO ₂ R ³ , guanidinyl, amidinyl, aryl, aralkyl, alkoxyalkyl, —SCN, —NHSO ₂ R ⁹ , —SO ₂ NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ —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 L ² and E ² or E ² and J ² together form an annelated cyclic group; X ^{2 is} selected from -CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ -, -CF ₂ -, -CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ -O, -CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ -S, -C (O) -O-, -C (O) -S-, -C (S) -O-, and -CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ —NR ¹⁹ -, and where an atom attached to phosphorus means a carbon atom; with the proviso that X ^{2 is} not substituted with —COOR ² , —SO ₃ H or —PO ₃ R $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; each R ^{9 is} independently selected from —H, alkyl, aralkyl, and alicyclic, or R ⁹ and R ⁹ together form a cyclic alkyl group; R ¹¹ selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and -OR ² ; R ^{19 is} selected from lower alkyl, —H and —COR ² ; and their pharmaceutically acceptable prodrugs and salts. 99. A method of treating a mammal with diabetes, comprising administering to said mammal: a pharmaceutically effective amount of component (a) containing at least one agent of: insulin, an insulin analog, a biguanide, an inhibitor of glucose production in the liver, or an alpha glucosidase inhibitor; and a pharmaceutically effective amount of component (b) containing at least one FBPase inhibitor. 100. The method of claim 99, wherein said insulin or insulin analog is selected from insulin, lispro insulin, aspart insulin and garglin insulin. 101. The method of claim 99, wherein said biguanide is selected from metformin, phenformin, and buformin. 102. The method of claim 99, wherein said liver glucose production inhibitor is selected from glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, amylin agonists and fatty acid oxidation inhibitors. 103. The method of claim 102, wherein said amylin agonist is pramlintide. 104. The method according to claim 99, wherein said alpha glucosidase inhibitor is selected from acarbose, miglitol and voglibose. 105. The method of claim 99, wherein said FBPase inhibitor is a compound selected from formulas I and IA

where the compounds of formulas I and IA are converted in vivo or in vitro to M-PO $\genfrac{}{}{0ex}{}{\text{2-}}{\text{3}}$ that inhibits FBP-ase, and where Y is independently selected from —O— and —NR ⁶ , provided that: when Y is —O—, then R ¹ attached to —O— is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted alicyclic, where the cyclic moiety contains carbonate or thiocarbonate, optionally substituted α-arylalkyl, —C ( R ² ) ₂ OC (O) NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ , -NR ² -C (O) -R ³ , -C (R ² ) ₂ -OC (O) R ³ , -C (R ² ) ₂ -OC (O) OR ³ , -C (R ² ) ₂ OC (O) SR ³ , -alkyl-SC (O) R ³ , -alkyl-SS-alkylhydroxy and -alkyl-SSS-alkylhydroxy; when Y is —NR ⁶ , then 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) S) and cycloalkylene-COOR ³ , where q is 1 or 2; when only one Y is —O—, where —O— is not part of a cyclic group containing another Y, then 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 , then R ¹ and R ¹ together are alkyl-SS-alkyl and form a cyclic group, or R ¹ and R ¹ together form:

where a) V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl; or V and Z are joined together by additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, said cyclic group is fused to an aryl group in beta and gamma positions of Y adjacent to V; or Z is selected from the group consisting of —CHR ² OH, —CHR ² OC (O) R ³ , —CHR ² CO (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 $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ) OH, -CH (CCR ² ) OH, -R ² , -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ , -OCOR ³ , -OCO ₂ R ³ , -SCOR ³ , -SCO ₂ R ³ , -NHCOR ² , -NHCO ₂ R ³ , -CH ₂ NH-aryl, - (CH ₂ ) _p OR ² and - (CH ₂ ) _p -SR ² where p is an integer of 2 or 3; or Z and W are joined together by 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 consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; or W and W ’are joined together by 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 consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; Z ^{2 is} selected from the group consisting of —CHR ² OH, —CHR ² OC (O) R ³ , —CHR ² OC (S) R ³ , —CHR ² OCO ₂ R ³ , —CHR ² OC (O) SR ³ , -CHR ² OC (S) OR ³ , -CH (aryl) OH, -CH (CH = CR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ) OH, -CH (CCR ² ) OH, -SR ² , -CH ₂ NH-aryl, -CH ₂ -aryl; or V ² and Z ^{2 are} joined together by additional 3-5 atoms to form a cyclic group containing 5-7 atoms in the ring, optionally containing 1 heteroatom, and substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom, which is three atoms from Y attached to phosphorus; c) Z 'is selected from the group consisting of —OH, —OC (O) R ³ , —OCO ₂ R ^3, and —OC (O) SR ³ ; D ’means -H; D "is selected from the group consisting of —H, alkyl, —OR ² , —OH and —OC (O) R ³ ; each W ^{3 is} independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl; provided that a) V, Z, W, W ', all do not mean -H, and V ² , Z ² , W ² , W ", all do not mean -H; and R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from the group consisting of —H, and alkyl, or R ⁴ and R ^{4 are} joined together to form a cyclic alkyl group; 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 is joined together with R ¹² via 1-4 carbon atoms to form a cyclic group; each R ¹² and R ^{13 is} independently selected from H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R ¹² and R ^{13 are} joined together by 2-6 carbon atoms to form a cyclic group; each R ^{14 is} independently selected from —OR ¹⁷ , —N (R ¹⁷ ) ₂ , —NHR ¹⁷ , and —SR ¹⁷ ; R ^{15 is} selected from —H, lower alkyl, lower aryl, and lower aralkyl, or R ¹⁵ and R ^{16 are} joined together by 2-6 atoms, optionally including 1 heteroatom selected from O, N, and S; R ^{16 is} selected from - (CR ¹² R ¹³ ) _n -C (O) -R ¹⁴ , lower alkyl, lower aryl, lower aralkyl, or is joined together with R ¹⁵ by 2-6 atoms, optionally including 1 heteroatom selected from O , N and S; each R ^{17 is} independently selected from lower alkyl, lower aryl and lower aralkyl, or R ¹⁷ and R ^{17 are} joined together on N by 2-6 atoms, optionally including 1 heteroatom selected from O, N and S; M contains:

where A, E and L are independently selected from -NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , -NO ₂ , -H, -OR ⁷ , -SR ⁷ , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR ¹¹ , —SO ₂ R ³ , guanidine, amidine, —NHSO ₂ R ²⁵ , —SO ₂ NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl and lower alicyclic, or A and L together form a cyclic group, or L and E together form a cyclic group, or E and J together form a cyclic group including aryl, cyclic alkyl and heterocycle; J is selected from -NR $\genfrac{}{}{0ex}{}{\text{8}}{\text{2}}$ , -NO ₂ , -H, -OR ⁷ , -SR ⁷ , -C (O) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , halogen, —COR ¹¹ , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl and aralkyl, or together with Y forms a cyclic group including aryl, cyclic heterocyclic alkyl; X ^{3 is} selected from -alkyl (hydroxy) -; -alkyl-; alkynyl; -aryl-; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; -alicyclo-; -aralkyl-; -alkylaryl-; alkoxycarbonyl; -carbonyloxyalkyl-; alkoxycarbonylamino; and -alkylaminocarbonylamino, all optionally substituted, provided that X ^{3 is} not substituted with —COOR ² , —SO ₃ H or —PO ₃ R $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; 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 $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and —OR ³ , all except H, are optionally substituted; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together 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 selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and -OR ² ; and M means —XR ⁵ , where R ^{5 is} selected from

where each G is independently selected from C, N, O, S, and Se, and where only one G is O, S, or Se, and at most one G is N; each G ’is independently selected from C and N, and where no more than two groups G’ mean N; A is selected from -H, -NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CONR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , —CO ₂ R ³ , halogen, —S (O) R ³ , —SO ₂ R ³ , alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, —CH ₂ OH, —CH ₂ NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CH ₂ CN, -CN, -C (S) NH ₂ , -OR ³ , -SR ³ , -N3, -NHC (S) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -NHAc or absent; each B and D is 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 $\genfrac{}{}{0ex}{}{\text{9}}{\text{2}}$ , -OR ³ , -SR ³ , perhalogenated, halogen, -NO ₂ or absent, all, with the exception of -H, -CN, perhalogenated, -NO ₂ and halogen, are optionally substituted; E is selected from —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, —C (O) OR ³ , —CONR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CN, -NR $\genfrac{}{}{0ex}{}{\text{9}}{\text{2}}$ , -NO ₂ , -OR ³ , -SR ³ , perhalogenated, halogen or absent, with the exception of -H, -CN, perhalogenated and halogen, all are optionally substituted; J is selected from —H or absent; X is an optionally substituted linking group that binds R ⁵ to a phosphorus atom through 2-4 atoms including 0-1 heteroatoms selected from N, O and S, except that if X is urea or carbamate, then there are two heteroatoms determined by the shortest path between R ⁵ and the phosphorus atom, and where the atom attached to the phosphorus means a carbon atom, and where X is selected from -alkyl (hydroxy) -; alkynyl; heteroaryl; -carbonylalkyl-; -1,1-dihaloalkyl-; alkoxyalkyl-; -alkyloxy-; -alkylthioalkyl-; -alkylthio; -alkylaminocarbonyl-; -alkylcarbonylamino; alkoxycarbonyl-; -carbonyloxyalkyl-; alkoxycarbonylamino; and -alkylaminocarbonylamino, all optionally substituted, provided that X is not substituted with —COOR ² , —SO ₃ H or —PO ₃ R $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; R ^{2 is} selected from R ³ and —H; R ³ selected from alkyl, aryl, alicyclic and aralkyl; each R ^{4 is} independently selected from —H and alkyl, or R ⁴ and R ⁴ together form a cyclic alkyl group; each R ^{9 is} independently selected from —H, alkyl, aralkyl, and alicyclic; R ⁹ and R ⁹ together form a cyclic alkyl group; R ¹¹ selected from alkyl, aryl, -NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and-OR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ ; and provided that: 1) when G ’means N, then the corresponding A, B, D or E is absent; 2) at least one of A and B, or A, B, D and E cannot be selected from -H or absent; 3) when R ⁵ means a six-membered ring, then X does not mean a 2 atom linker, optionally substituted alkyloxy, or optionally substituted -alkylthio; 4) when G is N, then the corresponding A or B does not mean a 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; 106. The pharmaceutical composition according to claim 11, where M means X ⁴ -R ⁵⁵ , where R ^{55 is} selected from

where G ² selected from the group of C, O and S; G ³ and G ^{4 are} independently selected from the group C, N, O, and S; where a) no more than one of G ² , G ³ and G ⁴ means O or S; b) if G ² means O or S, then no more than one of G ³ and G ⁴ means N; c) at least one of G ² , G ³ and G ⁴ is C; and d) G ² , G ³ and G ⁴ - all do not mean C; G ⁶ , G ⁶ and G ^{7 are} independently selected from the group of C and N, where no more than two of G ⁵ , G ⁶ and G ^{7 are} N; J ³ , J ⁴ , J ⁵ , J ⁶ and J ^{7 are} independently selected from the group of —H, —NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CONR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -CO ₂ R ³ , halogen, -S (O) ₂ NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -S (O) R ³ , -SO ₂ R ³ , alkyl, alkenyl, alkynyl, alkylene aryl, perhaloalkyl, haloalkyl, aryl, heteroaryl, alkylene-OH, -C (O) R ¹¹ , -OR ¹¹ , -alkylene- Nr $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -alkylene-CN, -CN, -C (S) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , -OR ² , -SR ² , -N ₃ , -NO ₂ , -NHC (S) NR $\genfrac{}{}{0ex}{}{\text{4}}{\text{2}}$ , and -NR ²¹ COR ² ; X ^{4 is} selected from i) a linking group having 2-4 atoms located on the smallest number of atoms connecting the carbon of the aromatic ring and the phosphorus atom, which is selected from the group consisting of -furanyl-, -thienyl-, -pyridyl-, -oxazolyl-, -imidazolyl- , -phenyl-, -pyrimidinyl-, -pyrazinyl- and -alkynyl-, all of which are optionally substituted; and ii) a linking group that contains 3-4 atoms located on the smallest number of atoms connecting the carbon of the aromatic ring and the phosphorus atom, and is selected from the group of alkylenecarbonylamino, alkyleneaminocarbonyl-, alkyleneoxycarbonyl-, alkyleneoxy and alkyleneoxyalkylene, all of which optionally substituted; R ^{11 is} selected from the group consisting of alkyl, aryl, —NR $\genfrac{}{}{0ex}{}{\text{2}}{\text{2}}$ and -OR ² ; R ^{20 is} selected from the group consisting of —H, lower R ³ and —C (O) - (lower R ³ ); R ^{21 is} selected from —H and lower R ³ ; provided that: 1) when G ⁵ , G ⁶ or G ⁷ means N, then the corresponding J ⁴ , J ⁵ or J ^{6 is} absent; 2) when X ⁴ is substituted furanyl, then at least one of J ³ , J ⁴ , J ⁵ and J ⁶ cannot mean —H or be absent; 3) when X ⁴ does not mean substituted furanyl, then at least two of J ³ , J ⁴ , J ⁵ and J ⁶ in formula VII-5 or J ³ , J ⁴ , J ⁵ , J ⁶ and J ⁷ in formula VII-6 cannot mean -H or absent; 4) when G ² , G ³ or G ⁴ means O or S, then the corresponding J ³ , J ⁴ or J ^{5 is} absent; 5) when G ³ or G ⁴ means N, then the corresponding J ⁴ or J ⁵ does not mean halogen or a group directly bonded to G ³ or G ⁴ via a heteroatom; 6) when two Y groups mean —NR ⁶ -, and R ¹ and R ^{1 are} not connected to form a cyclic phosphoramidate, then at least one R ¹ means - (CR ¹² R ¹³ ) n — C (O) —R ¹⁴ ; 7) when X ⁴ is —alkylenecarbonylamino or —alkyleneaminocarbonyl— then G ⁵ , G ⁶ and G ⁷ all do not mean C; 8) when X ⁴ is -alkelenoxyalkylene-, and G ⁵ , G ⁶ and G ⁷ , all are C, then neither J ⁴ nor J ⁶ can be substituted with an acylated amine; 9) when R ^{55 is} substituted with phenyl, then J ⁴ , J ⁵ and J ⁶ do not mean purinyl, purinylalkylene, deaza-purinyl or deazapurinylalkylene; 10) R ¹ can be selected from lower alkyl only when the other YR ¹ is —NR ¹⁸ —C (R ¹² R ¹³ ) _n —C (O) —R ¹⁴ ; 11) when R ^{55 is} substituted with phenyl and X ⁴ is 1,2-ethynyl, then J ⁴ or J ⁶ does not mean a heterocyclic group; 12) when X ⁴ is 1,2-ethynyl, then G ⁵ or G ^{7 is} not. may be N; and their pharmaceutically acceptable prodrugs and salts. 107. The pharmaceutical composition of claim 40, wherein the FBPase inhibitor is

108. The method according to any one of claims 46 or 99, wherein said component (a) and said component (b) are administered one after the other with an interval of one hour. 109. The method according to p, where the specified component (a) and the specified component (b) is administered one after the other with an interval of 10 minutes. 110. The method according to any one of claims 46 or 99, wherein one of said component (a) and said component (b) is administered first, and another of said component (a) and said component (b) is administered after 1 to 12 hours . 111. The method according to any one of claims 46 or 99, wherein said mammal is suffering from labile diabetes. 112. The method according to any one of claims 46 or 99, wherein said mammal is suffering from NIDDM. 113. The method according to any one of claims 46 or 99, wherein said mammal suffers from IDDM. 114. The pharmaceutical composition according to claim 9, wherein said glucagon-like peptide-1 receptor agonist (GLP-1) is NN-2211 or exendin.