US 6,312,662 B1 · Prodrugs phosphorus-containing compounds

Abstract

Prodrugs of formula I, their uses, their intermediates, and their method of manufacture are described:

Claims183

Dependent claims

A method of enhancing oral bioavailability of a parent drug by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR21, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is -R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said prodrug of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of delivering a biologically active drug to an animal for a sustained period using a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of delivering a biologically active drug to an animal with greater selectivity for the liver using a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of increasing the therapeutic index of a drug by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fuised to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of bypassing drug resistance by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of treating cancer by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of treating viral infections by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH , —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of treating liver fibrosis by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fuised to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of treating hyperlipidemia by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of treating parasitic infections by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH , —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O9−4 is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of delivering diagnostic imaging agents to the liver comprising administration to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH , —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of making a prodrug of a compound drug having a —PO32− moiety comprising,

a) transforming said phosph(on)ate into a compound of formula I:
wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of —CHR2OH , —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR12, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is -R2, then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63−, or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
and pharmaceutically acceptable prodrugs and salts thereof.

18 more elements

A method of making a prodrug of formula I by

a) converting a hydroxyl or amino or MH to a phosph(oramid)ite by reaction with L—P(—OCH(V)CH(Z)—CW(W′)O—) wherein L selected from the group consisting of NR12, and halogen;
b) transforming said phosph(oramid)ite into a compound of formula I by reaction with an oxidizing agent, wherein
wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63−, or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

The method of making a prodrug of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the grouip consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, PO63− or P3O94− is a biologcally active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
and pharmaceutically acceptable prodrugs and salts thereof;
comprising converting a hydroxyl or an amino to a phosphate or phosphoramidate, respectively, by reaction with L′—P(O)(—OCH(V)CH(Z)—CW(W′)O—) wherein L′ is a leaving group selected from the group consisting of —NR2, aryloxy, and halogen.

19 more elements

A compound, R12N—P—(—OCH(V)CH(Z)—CW(W′)O—)

wherein:
V, 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 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of —CHR2OH , —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(CCR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63−, or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
and pharmaceutically acceptable prodrugs and salts thereof;
each R1 is independently selected from the group consisting of alkyl, aryl, and aralkyl;
or together R1 and R1 form a cyclic group, optionally containing a heteroatom;
with the proviso that both R1 groups are not benzyl or ethyl at the same time.

19 more elements

A compound R12N—P(O)(—OCH(V)CH(Z)—CW(W′)O—) wherein:

V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
each R1 is independently selected from the group consisting of alkyl, aryl, and aralkyl;
or together R1 and R1 form a cyclic group, optionally containing a heteroatom;
with the proviso that both R1 groups are not benzyl or ethyl at the same time.

17 more elements

A compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom with the proviso that M—PO32− is not an FBPase inhibitor;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OC2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
wherein said compound of formula I is converted to M—PO3H2 by human liver microsomes, and wherein M is attached to the phosphorus in formula I via an oxygen atom;
with the provisos that:
a) V, Z, W, W′ are not all —H;
b) when Z is —R2, then at least one of V and W is not —H or R9;
and
c) MPO32− is not an FBPase inhibitor;
and pharmaceutically acceptable prodrugs and salts thereof.

23 more elements

A compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH , —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
wherein said compound of formula I is converted to M—PO3H2 by human liver microsomes, and wherein M is attached to the phosphorus in formula I via a carbon atom;
with the provisos that:
a) V, Z, W, W′ are not all —H;
b) when Z is —R2, then at least one of V and W is not —H or R9;
and
c) MPO32− is not an FBPase inhibitor;
and pharmaceutically acceptable prodrugs and salts thereof.

23 more elements

A compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH , —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
wherein said compound of formula I is converted to M—PO3H2 by human liver microsomes, and wherein M is attached to the phosphorus in formula I via a nitrogen atom;
with the provisos that:
a) V, Z, W, W′ are not all —H;
b) when Z is —R2, then at least one of V and W is not —H or R9;
and
c) MPO32− is not an FBPase inhibitor;
and pharmaceutically acceptable prodrugs and salts thereof.

23 more elements

A compound of formula I:

wherein:
W and W′ are independently selected from the group of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
V is selected from the group of aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkynyl and 1-alkenyl;
Z is selected from the group of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
or
together V and Z are connected via 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the oxygen attached to the phosphorus;
p is an integer 2 or 3;
R2 is selected from the group of R3 and —H;
R3 is selected from the group of alkyl, aryl, alicyclic, and aralkyl;
wherein said compound of formula I is converted to M—PO3H2 by human liver microsomes, with the proviso that MPO32− is not an FBPase inhibitor;
and pharmaceutically acceptable prodrugs and salts thereof.

8 more elements

A compound of formula I:

wherein
V, W and W′ are independently selected from the group of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
Z is selected from the group of:
—CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OCO2R3, —CHR2OC(O)SR3, —CHR2OC(S)OR3, —CH(aryl)OH, —CH(CH═CR22)OH, CH(C≡CR2)OH, —SR2, —CH2NHaryl, —CH2aryl;
or
together V and Z are connected via 3-5 carbon atoms to form a cyclic group, optionally containing heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from an oxygen attached to phosphorus;
R2 is selected from the group of R3 and —H;
R3 is selected from the group of alkyl, aryl, alicyclic, and aralkyl;
wherein said compound of formula I is converted to M—PO3H2 by human liver microsomes, with the proviso that MPO32− is not an FBPase inhibitor;
and pharmaceutically acceptable prodrugs and salts thereof.

7 more elements

A method treating liver disease by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p;
—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

20 more elements

Dependencies are inferred from the claim text.

Facts

Application

09/392,352Filed 8 Sep 1999 · continuation in part

Priority

6 Mar 1998

Granted

6 Nov 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07H 19/10
Pyrimidine radicals: with the saccharide radical esterified by phosphoric or polyphosphoric acids
A61K 31/7056
Having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides: containing five-membered rings with nitrogen as a ring hetero atom
A61K 31/7072
Having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid: having two oxo groups directly attached to the…
A61K 31/7076
Containing condensed or non-condensed pyrimidines: containing purines, e.g. adenosine, adenylic acid

Family

Application60/077,164Us provisional application · filed 6 Mar 1998

Application60/077,165Us provisional application · filed 6 Mar 1998

Application09/263,976Parent of this continuation-in-part · filed 5 Mar 1999

US 6,312,662 B1This patent

From the US filing history. Foreign family members aren’t listed.

Abstract

Prodrugs of formula I, their uses, their intermediates, and their method of manufacture are described:

Claims183

Dependent claims

A method of enhancing oral bioavailability of a parent drug by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR21, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is -R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said prodrug of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of delivering a biologically active drug to an animal for a sustained period using a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of delivering a biologically active drug to an animal with greater selectivity for the liver using a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of increasing the therapeutic index of a drug by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fuised to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of bypassing drug resistance by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of treating cancer by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of treating viral infections by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH , —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of treating liver fibrosis by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fuised to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of treating hyperlipidemia by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of treating parasitic infections by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH , —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O9−4 is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of delivering diagnostic imaging agents to the liver comprising administration to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH , —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A method of making a prodrug of a compound drug having a —PO32− moiety comprising,

a) transforming said phosph(on)ate into a compound of formula I:
wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of —CHR2OH , —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR12, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is -R2, then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63−, or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
and pharmaceutically acceptable prodrugs and salts thereof.

18 more elements

A method of making a prodrug of formula I by

a) converting a hydroxyl or amino or MH to a phosph(oramid)ite by reaction with L—P(—OCH(V)CH(Z)—CW(W′)O—) wherein L selected from the group consisting of NR12, and halogen;
b) transforming said phosph(oramid)ite into a compound of formula I by reaction with an oxidizing agent, wherein
wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63−, or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

The method of making a prodrug of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the grouip consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, PO63− or P3O94− is a biologcally active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
and pharmaceutically acceptable prodrugs and salts thereof;
comprising converting a hydroxyl or an amino to a phosphate or phosphoramidate, respectively, by reaction with L′—P(O)(—OCH(V)CH(Z)—CW(W′)O—) wherein L′ is a leaving group selected from the group consisting of —NR2, aryloxy, and halogen.

19 more elements

A compound, R12N—P—(—OCH(V)CH(Z)—CW(W′)O—)

wherein:
V, 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 together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of —CHR2OH , —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(CCR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63−, or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
and pharmaceutically acceptable prodrugs and salts thereof;
each R1 is independently selected from the group consisting of alkyl, aryl, and aralkyl;
or together R1 and R1 form a cyclic group, optionally containing a heteroatom;
with the proviso that both R1 groups are not benzyl or ethyl at the same time.

19 more elements

A compound R12N—P(O)(—OCH(V)CH(Z)—CW(W′)O—) wherein:

V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
each R1 is independently selected from the group consisting of alkyl, aryl, and aralkyl;
or together R1 and R1 form a cyclic group, optionally containing a heteroatom;
with the proviso that both R1 groups are not benzyl or ethyl at the same time.

17 more elements

A compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom with the proviso that M—PO32− is not an FBPase inhibitor;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

19 more elements

A compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OC2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
wherein said compound of formula I is converted to M—PO3H2 by human liver microsomes, and wherein M is attached to the phosphorus in formula I via an oxygen atom;
with the provisos that:
a) V, Z, W, W′ are not all —H;
b) when Z is —R2, then at least one of V and W is not —H or R9;
and
c) MPO32− is not an FBPase inhibitor;
and pharmaceutically acceptable prodrugs and salts thereof.

23 more elements

A compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH , —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
wherein said compound of formula I is converted to M—PO3H2 by human liver microsomes, and wherein M is attached to the phosphorus in formula I via a carbon atom;
with the provisos that:
a) V, Z, W, W′ are not all —H;
b) when Z is —R2, then at least one of V and W is not —H or R9;
and
c) MPO32− is not an FBPase inhibitor;
and pharmaceutically acceptable prodrugs and salts thereof.

23 more elements

A compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH , —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
wherein said compound of formula I is converted to M—PO3H2 by human liver microsomes, and wherein M is attached to the phosphorus in formula I via a nitrogen atom;
with the provisos that:
a) V, Z, W, W′ are not all —H;
b) when Z is —R2, then at least one of V and W is not —H or R9;
and
c) MPO32− is not an FBPase inhibitor;
and pharmaceutically acceptable prodrugs and salts thereof.

23 more elements

A compound of formula I:

wherein:
W and W′ are independently selected from the group of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
V is selected from the group of aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkynyl and 1-alkenyl;
Z is selected from the group of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p—OR12, and —(CH2)p—SR12;
or
together V and Z are connected via 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the oxygen attached to the phosphorus;
p is an integer 2 or 3;
R2 is selected from the group of R3 and —H;
R3 is selected from the group of alkyl, aryl, alicyclic, and aralkyl;
wherein said compound of formula I is converted to M—PO3H2 by human liver microsomes, with the proviso that MPO32− is not an FBPase inhibitor;
and pharmaceutically acceptable prodrugs and salts thereof.

8 more elements

A compound of formula I:

wherein
V, W and W′ are independently selected from the group of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
Z is selected from the group of:
—CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OCO2R3, —CHR2OC(O)SR3, —CHR2OC(S)OR3, —CH(aryl)OH, —CH(CH═CR22)OH, CH(C≡CR2)OH, —SR2, —CH2NHaryl, —CH2aryl;
or
together V and Z are connected via 3-5 carbon atoms to form a cyclic group, optionally containing heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from an oxygen attached to phosphorus;
R2 is selected from the group of R3 and —H;
R3 is selected from the group of alkyl, aryl, alicyclic, and aralkyl;
wherein said compound of formula I is converted to M—PO3H2 by human liver microsomes, with the proviso that MPO32− is not an FBPase inhibitor;
and pharmaceutically acceptable prodrugs and salts thereof.

7 more elements

A method treating liver disease by administering to an animal a compound of formula I:

wherein:
V, 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
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus;
or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus;
or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or heteroaryl;
Z is selected from the group consisting of —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OC(S)OR3, —CHR2OC(O)SR3, —CHR2OCO2R3, —OR2, —SR2, —CHR2N3, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH, —R2, —NR22, —OCOR3, —OCO2R3, —SCOR3, —SCO2R3, —NHCOR2, —NHCO2R3, —CH2NHaryl, —(CH2)p;
—OR12, and —(CH2)p—SR12;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H;
and
b) when Z is —R2, then at least one of V, W and W′ is not —H, alkyl, aralkyl or alicyclic;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R12 is selected from the group consisting of —H, and lower acyl;
M is selected from the group that attached to PO32−, P2O63− or P3O94− is a biologically active agent, and is attached to the phosphorus in formula I via a carbon, oxygen, sulfur or nitrogen atom;
wherein said compound of formula I is converted to MPO3H2 by human liver microsomes;
and pharmaceutically acceptable prodrugs and salts thereof.

20 more elements

Dependencies are inferred from the claim text.

Prodrugs phosphorus-containing compounds

Life of this patent

Abstract

Claims183

Prodrugs phosphorus-containing compounds

Life of this patent

Abstract

Claims183