Purine inhibitors of fructose 1,6-bisphosphatase

A method of treating an animal for a disease derived from abnormally elevated insulin levels, comprising administering to said animal a therapeutically effective amount of a fructose-1,6-bisphosphatase inhibitor wherein said inhibitor is a compound of formula (1):

• wherein
• A is selected from the group consisting of —NR82, NHSO2R3, —OR5, —SR5, halo, lower alkyl, —CON(R4)2, guanidino, amidino, —H, and perhaloalkyl;
• E is selected from the group consisting of —H, halo, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, —CN, and —NR72;
• X is selected from the group consisting of -alk-NR—, alkylene, alkenylene, alkynylene, arylene, heteroarylene, -alk-NR-alk-, -alk-O-alk-, -alk-S-alk-, -alk-S—, alicyclicene, heteroalicyclicene, 1,1-dihaloalkylene, —C(O)-alk-, —NR—C(O)—NR′—, -alk-NR—C(O)—, -alk-C(O)—NR—, -Ar-alk-, and -alk-Ar-, all optionally substituted, wherein each R and R′ is independently selected from —H and lower alkyl, and wherein each “alk” and “Ar” is an independently selected alkylene or arylene, respectively;
• Y is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, heteroalicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R3, —S(O)2R3, —C(O)—OR3, —CONHR3, —NR22, and —OR3, all except H are optionally substituted;
• R1 is independently selected from the group consisting of —H, alkyl, aryl, heteroalicyclic where the cyclic moiety contains a carbonate or thiocarbonate, —C(R2)2-aryl, -alk-aryl, —C(R2)2OC(O)NR22, —NR2—C(O)—R3, —C(R2)2—OC(O)R3, —C(R2)2—O—C(O)OR3, —C(R2)2OC(O)SR3, -alk-S—C(O)R3, -alk-S—S-alkylhydroxy, and -alk-S—S—S-alkylhydroxy, or together R1 and R1 are -alk-S—S-alk- to form a cyclic group, wherein each “alk” is an independently selected alkylene, or together R1 and R1 are
• wherein
• V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —R9;
• or
• together V and Z are connected via a chain of 3-5 atoms, only one of which can be a heteroatom, to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
• or
• together V and W are connected via a chain of 3 carbon atoms to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
• Z is selected from the group consisting of —CH2OH, —CH2OCOR3, —CH2OC(O)SR3, —CH2OCO2R3, —SR3, —S(O)R3, —CH2N3, —CH2NR22, —CH2Ar, —CH(Ar)OH, —CH(CH═CR2R2)OH, —CH(C≡CR2)OH, and —R2;
• with the provisos that:
• a) V, Z, W are not all —H;
• and
• b) when Z is —R2, then at least one of V and W is not —H or —R9;
• R2 is selected from the group consisting of R3 and —H;
• R3 is selected from the group consisting of alkyl, aryl, alicyclic, heteroalicyclic, and aralkyl;
• R4 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, and lower aryl;
• R5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, lower alicyclic, and lower heteroalicyclic;
• R6 is independently selected from the group consisting of —H, and lower alkyl;
• R7 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, lower aryl, and —C(O)R10;
• R8 is independently selected from the group consisting of —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C(O)R10, or together said R8 groups form a bidendate alkylene;
• R9 is selected from the group consisting of alkyl, aralkyl, alicyclic, and heteroalicyclic;
• R10 is selected from the group consisting of —H, lower alkyl, —NH2, lower aryl, and lower perhaloalkyl;
• R11 is selected from the group consisting of alkyl, aryl, —OH, —NH2 and —OR3;
• and
• pharmaceutically acceptable prodrugs and salts thereof.

A method of treating an animal for diabetes mellitus, comprising administering to said animal a therapeutically effective amount of a compound of formula (1):

• wherein
• A is selected from the group consisting of —NR82, NHSO2R3, —OR5, —SR5, halo, lower alkyl, —CON(R4)2, guanidino, amidino, —H, and perhaloalkyl;
• E is selected from the group consisting of —H, halo, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, —CN, and —NR72;
• X is selected from the group consisting of -alk-NR—, alkylene, alkenylene, alkynylene, arylene, heteroarylene, -alk-NR-alk-, -alk-O-alk-, -alk-S-alk-, -alk-S—, alicyclicene, heteroalicyclicene, 1,1-dihaloalkylene, —C(O)-alk-, —NR—C(O)—NR′—, -alk-NR—C(O)—, -alk-C(O)—NR—, -Ar-alk-, and -alk-Ar-, all optionally substituted, wherein each R and R′ is independently selected from —H and lower alkyl, and wherein each “alk” and “Ar” is an independently selected alkylene or arylene, respectively;
• Y is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, heteroalicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R3, —S(O)2R3, —C(O)—OR3, —CONHR3, —NR22, and —OR3, all except H are optionally substituted;
• R1 is independently selected from the group consisting of —H, alkyl, aryl, heteroalicyclic where the cyclic moiety contains a carbonate or thiocarbonate, —C(R2)2-aryl, -alk-aryl, —C(R2)2OC(O)NR22, —NR2—C(O)—R3, —C(R2)2—OC (O)R3, —C(R2)2—O—C(O)OR3, —C(R2)2OC(O)SR3, -alk-S—C(O)R3, -alk-S—S-alkylhydroxy, and -alk-S—S—S-alkylhydroxy, or together R1 and R1 are -alk-S—S-alk- to form a cyclic group, wherein each “alk” is an independently selected alkylene, or together R1 and R1 are
• wherein
• V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —R9;
• or
• together V and Z are connected via a chain of 3-5 atoms, only one of which can be a heteroatom, to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
• or
• together V and W are connected via a chain of 3 carbon atoms to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
• Z is selected from the group consisting of —CH2OH, —CH2OCOR3, —CH2OC(O)SR3, —CH2OCO2R3, —SR3, —S(O)R3, —CH2N3, —CH2NR22, —CH2Ar, —CH(Ar)OH, —CH(CH═CR2R2)OH, —CH(C≡CR2)OH, and —R2;
• with the provisos that:
• a) V, Z, W are not all —H;
• and
• b) when Z is —R2, then at least one of V and W is not —H or —R9;
• R2 is selected from the group consisting of R3 and —H;
• R3 is selected from the group consisting of alkyl, aryl, alicyclic, heteroalicyclic, and aralkyl;
• R4 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, and lower aryl;
• R5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, lower alicyclic, and lower heteroalicyclic;
• R6 is independently selected from the group consisting of —H, and lower alkyl;
• R7 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, lower aryl, and —C(O)R10;
• R8 is independently selected from the group consisting of —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C(O)R10, or together said R8 groups form a bidendate alkylene;
• R9 is selected from the group consisting of alkyl, aralkyl, alicyclic, and heteroalicyclic;
• R10 is selected from the group consisting of —H, lower alkyl, —NH2, lower aryl, and lower perhaloalkyl;
• R11 is selected from the group consisting of alkyl, aryl, —OH, —NH2 and —OR3;
• and
• pharmaceutically acceptable prodrugs and salts thereof.

A method of lowering blood glucose levels in an animal in need thereof, comprising administering to said animal a pharmaceutically acceptable amount of a compound of formula (1):

• wherein
• A is selected from the group consisting of —NR82, NHSO2R3, —OR5, —SR5, halo, lower alkyl, —CON(R4)2, guanidino, amidino, —H, and perhaloalkyl;
• E is selected from the group consisting of —H, halo, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, —CN, and —NR72;
• X is selected from the group consisting of -alk-NR—, alkylene, alkenylene, alkynylene, arylene, heteroarylene, -alk-NR-alk-, -alk-O-alk-, -alk-S-alk-, -alk-S—, alicyclicene, heteroalicyclicene, 1,1-dihaloalkylene, —C(O)-alk-, —NR—C(O)—NR′—, -alk-NR—C(O)—, -alk-C(O)—NR—, -Ar-alk-, and -alk-Ar-, all optionally substituted wherein each R and R1 is independently selected from —H and lower alkyl, and wherein each “alk” and “Ar” is an independently selected alkylene or arylene, respectively;
• Y is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, heteroalicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R3, —S(O)2R3, —C(O)—OR3, —CONHR3, —NR22, and —OR3, all except H are optionally substituted;
• R1 is independently selected from the group consisting of —H, alkyl, aryl, heteroalicyclic where the cyclic moiety contains a carbonate or thiocarbonate, —C(R2)2-aryl, -alk-aryl, —C(R2)2OC(O)NR22, —NR2—C(O)—R3, —C(R2)2—OC (O)R3, —C(2)2—O—C(O)OR3, —C(R2)2OC(O)SR3, -alk-S—C(O)R3, -alk-S—S-alkylhydroxy, and -alk-S—S—S-alkylh droxy, or together R1 and R1 are -alk-S—S-alk- to form a cyclic group, wherein each “alk” is an independently selected alkylene, or together R1 and R1 are
• wherein
• V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —R9;
• or
• together V and Z are connected via a chain of 3-5 atoms, only one of which can be a heteroatom, to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
• or
• together V and W are connected via a chain of 3 carbon atoms to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
• Z is selected from the group consisting of —CH2OH, —CH2OCOR3, —CH2OC(O)SR3, —CH2OCO2R3, —SR3, —S(O)R3, —CH2N3, —CH2NR22, —CH2Ar, —CH(Ar)OH, —CH(CH═CR2R2)OH, —CH(C≡CR2)OH, and —R2;
• with the provisos that:
• a) V, Z, W are not all —H;
• and
• b) when Z is —R2, then at least one of V and W is not —H or —R9;
• R2 is selected from the group consisting of R3 and —H;
• R3 is selected from the group consisting of alkyl, aryl, alicyclic, heteroalicyclic, and aralkyl;
• R4 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, and lower aryl;
• R5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, lower alicyclic, and lower heteroalicyclic;
• R6 is independently selected from the group consisting of —H, and lower alkyl;
• R7 is independently selected from the group consisting of —H, lower alkyl lower alicyclic, lower heteroalicyclic, lower aralkyl, lower aryl, and —C(O)R10;
• R8 is independently selected from the group consisting of —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C(O)R10, or together said R8 groups form a bidendate alkylene;
• R9 is selected from the group consisting of alkyl, aralkyl, alicyclic, and heteroalicyclic;
• R10 is selected from the group consisting of —H, lower alkyl, —NH2, lower aryl, and lower perhaloalkyl;
• R11 is selected from the group consisting of alkyl, aryl, —OH, —NH2 and —OR3;
• and
• pharmaceutically acceptable prodrugs and salts thereof.

A method of treating an animal with excess glycogen storage disease, comprising administering to said animal in need thereof a therapeutically effective amount of a fructose-1,6-bisphosphatase inhibitor, wherein said inhibitor is a compound of formula (1):

• wherein
• A is selected from the group consisting of —NR82, NHSO2R3, —OR5, —SR5, halo, lower alkyl, —CON(R4)2, guanidino, amidino, —H, and perhaloalkyl;
• E is selected from the group consisting of —H, halo, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, —CN, and —NR72;
• X is selected from the group consisting of -alk-NR—, alkylene, alkenylene, alkynylene, arylene, heteroarylene, -alk-NR-alk-, -alk-O-alk-, -alk-S-alk-, -alk-S—, alicyclicene, heteroalicyclicene, 1,1-dihaloalkylene, —C(O)-alk-, —NR—C(O)—NR′—, -alk-NR—C(O)—, -alk-C(O)—NR—, -Ar-alk-, and -alk-Ar-, all optionally substituted, wherein each R and R′ is independently selected from —H and lower alkyl, and wherein each “alk” and “Ar” is an independently selected alkylene or arylene, respectively;
• Y is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, heteroalicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R3, —S(O)2R3, —C(O)—OR3, —CONHR3, —NR22, and —OR3, all except H are optionally substituted;
• R1 is independently selected from the group consisting of —H, alkyl, aryl, heteroalicyclic where the cyclic moiety contains a carbonate or thiocarbonate, —C(R2)2-aryl, -alk-aryl, —C(R2)2OC(O)NR22, —NR2—C(O)—R3, —C(R2)2—OC(O)R3, —C(R2)2—O—C(O)OR3, —C(R2)2OC(O)SR3, -alk-S—C(O)R3, -alk-S—S-alkylhydroxy, and -alk-S—S—S-alkylhydroxy, or together R1 and R1 are -alk-S—S-alk- to form a cyclic group, wherein each “alk” is an independently selected alkylene, or together R1 and R1 are
• wherein
• V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —R9;
• or
• together V and Z are connected via a chain of 3-5 atoms, only one of which can be a heteroatom, to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
• or
• together V and W are connected via a chain of 3 carbon atoms to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
• Z is selected from the group consisting of —CH2OH, —CH2OCOR3, —CH2OC(O)SR3, —CH2OCO2R3, —SR3, —S(O)R3, —CH2N3, —CH2NR22, —CH2Ar, —CH(Ar)OH, —CH(CH═CR2R2)OH, —CH(C≡CR2)OH, and —R2;
• with the provisos that:
• a) V, Z, W are not all —H;
• and
• b) when Z is —R2, then at least one of V and W is not —H or —R9;
• R2 is selected from the group consisting of R3 and —H;
• R3 is selected from the group consisting of alkyl, aryl, alicyclic, heteroalicyclic, and aralkyl;
• R4 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, and lower aryl;
• R5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, lower alicyclic, and lower heteroalicyclic;
• R6 is independently selected from the group consisting of —H, and lower alkyl;
• R7 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, lower aryl, and —C(O)R10;
• R8 is independently selected from the group consisting of —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C(O)R10, or together said R8 groups form a bidendate alkylene;
• R9 is selected from the group consisting of alkyl, aralkyl, alicyclic, and heteroalicyclic;
• R10 is selected from the group consisting of —H, lower alkyl, —NH2, lower aryl, and lower perhaloalkyl;
• R11 is selected from the group consisting of alkyl, aryl, —OH, —NH2 and —OR3;
• and
• pharmaceutically acceptable prodrugs and salts thereof.

A method of inhibiting gluconeogenesis in animal in need thereof, comprising administering to said animal an effective amount of a compound of formula (1):

• wherein
• A is selected from the group consisting of —NR82, NHSO2R3, —OR5, —SR5, halo, lower alkyl, —CON(R4)2, guanidino, amidino, —H, and perhaloalkyl;
• E is selected from the group consisting of —H, halo, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, —CN, and —NR72;
• X is selected from the group consisting of -alk-NR—, alkylene, alkenylene, alkynylene, arylene, heteroarylene, -alk-NR-alk-, -alk-O-alk-, -alk-S-alk-, -alk-S—, alicyclicene, heteroalicyclicene, 1,1-dihaloalkylene, —C(O)-alk-, —NR—C(O)—NR′—, -alk-NR—C(O)—, -alk-C(O)—NR—, -Ar-alk-, and -alk-Ar-, all optionally substituted, wherein each R and R′ is independently selected from —H and lower alkyl, and wherein each “alk” and “Ar” is an independently selected alkylene or arylene, respectively;
• Y is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, heteroalicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R3, —S(O)2R3, —C(O)—OR3, —CONHR3, —NR22, and —OR3, all except H are optionally substituted;
• R1 is independently selected from the group consisting of —H, alkyl, aryl, heteroalicyclic where the cyclic moiety contains a carbonate or thiocarbonate, —C(R2)2-aryl, -alk-aryl, —C(R2)2OC(O)NR22, —NR2—C(O)—R3, —C(R2)2—OC(O)R3, —C(R2)2—O—C(O)OR3, —C(R2)2OC(O)SR3, -alk-S—C(O)R3, -alk-S—S-alkylhydroxy, and -alk-S—S—S-alkylhydroxy, or together R1 and R1 are -alk-S—S-alk- to form a cyclic group, wherein each “alk” is an independently selected alkylene, or together R1 and R1 are
• wherein
• V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —R9;
• or
• together V and Z are connected via a chain of 3-5 atoms, only one of which can be a heteroatom, to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
• or
• together V and W are connected via a chain of 3 carbon atoms to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
• Z is selected from the group consisting of —CH2OH, —CH2OCOR3, —CH2OC(O)SR3, —CH2OCO2R3, —SR3, —S(O)R3, —CH2N3, —CH2NR22, —CH2Ar, —CH(Ar)OH, —CH(CH═CR2R2)OH, —CH(C≡CR2)OH, and —R2;
• with the provisos that:
• a) V, Z, W are not all —H;
• and
• b) when Z is —R2, then at least one of V and W is not —H or —R9;
• R2 is selected from the group consisting of R3 and —H;
• R3 is selected from the group consisting of alkyl, aryl, alicyclic, heteroalicyclic, and aralkyl;
• R4 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, and lower aryl;
• R5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, lower alicyclic, and lower heteroalicyclic;
• R6 is independently selected from the group consisting of —H, and lower alkyl
• R7 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, lower aryl, and —C(O)R10;
• R8 is independently selected from the group consisting of —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C(O)R10, or together said R1 groups form a bidendate alkylene;
• R9 is selected from the group consisting of alkyl, aralkyl, alicyclic, and heteroalicyclic;
• R10 is selected from the group consisting of —H, lower alkyl, —NH2, lower aryl, and lower perhaloalkyl;
• R11 is selected from the group consisting of alkyl, aryl, —OH, —NH2 and —OR3;
• and
• pharmaceutically acceptable prodrugs and salts thereof.