Prodrugs for liver specific drug delivery

A compound of formula I:

• wherein
• W and W′ are independently selected from the group of —H, alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• V is selected from the group of aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl and 1-alkynyl;
• Z is selected from the group of —OR2, —SR2, —R2, —NR22, —OCOR3, —OCO2, R3, —SCOR3—SCO2R3, —NHCOR2, —NHCO2R3, —(CH2)p—OR12, and —(CH2)p—SR12;
• p is an integer 2 or 3;
• with the provisos that:
• a) when V is aryl or substituted aryl, then M is not —O(D) where D is hydrogen, a metal ion or an ammonium ion;
• and
• b) when Z is CHR2OH, then M is not —NH(lower alkyl), —N(lower alkyl)2, —NH(lower alkylhalide), —N(lower alkylhalide)2 or —N(lower alkyl)(lower alkylhalide);
• R2 is selected from the group of R3 and —H;
• R3 is selected from the group of alkyl, aryl, alicyclic, and aralkyl;
• R6 is selected from the group of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
• R12 is selected from the group of —H, and lower acyl;
• each Y is independently selected from the group of —O—, and —NR6—;
• M is selected from the group of drugs MH having an —OH, —NHR2, or —SH group, and that is attached to the phosphorus in formula I via O, N, or S of said OH, —NHR2, or SH group;
• and pharmaceutically acceptable prodrugs and salts thereof.

A compound of formula I:

• wherein
• Z is selected from the group of:
• —CHR2OH, —CHR2OC(O)R3, —CHR2OC(S)R3, —CHR2OCO2R3, —CHR2OC(O)SR3, —CHR2OC(S)OR3, —SR2, —CH2aryl, —CH(aryl)OH, —CH(CH═CR22)OH, —CH(C≡CR2)OH;
• and —CH2NHaryl;
• V, W and W′ are independently selected from the group of —H, alkyl, aralkyl, and alicyclic;
• with the provisos that:
• a) when Z is CHR2OH, then M is not —NH(lower alkyl), —N(lower alkyl)2, —NH(lower alkylhalide), —N(lower alkylhalide)2 or —N(lower alkyl)(lower alkylhalide);
• b) when V is aryl or substituted aryl, then M is not —O(D) where D is hydrogen, a metal ion or an ammonium ion;
• and
• R2 is selected from the group of R3 and —H;
• R3 is selected from the group of alkyl, aryl, alicyclic, and aralkyl;
• R6 is selected from the group of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
• each Y is independently selected from the group of —O—, and —NR6—;
• M is selected from the group of drugs MH containing an —OH, —NHR2, or —SH group, and that is attached to the phosphorus in formula I via O, N, or S of said OH, —NHR2, or SH group;
• and pharmaceutically acceptable prodrugs and salts thereof.

A method of treating diseases of the liver or metabolic diseases where the liver is responsible for the overproduction of a biochemical end product by administering to an animal a pharmaceutically effective amount of 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;
• 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 Y 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, said cyclic group is fused to an aryl group at the beta and gamma position to the Y adjacent to V;
• 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 of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y 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 of —CHR2OH , —CHR2OC(O)R3, —HR2OC(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;
• b) when Z is —R2 or —OR2, then V is not —H, alkyl, aralkyl, or alicyclic;
• c) when Z is CHR2OH, then M is not —NH(lower alkyl), —N(lower alkyl)2, —NH(lower alkylhalide), —N(lower alkylhalide)2 or —N(lower alkyl)(lower alkylhalide);
• and
• d) when V is aryl or substituted aryl, then M is not —O(D) where D is hydrogen, a metal ion or an ammonium ion;
• R2 is selected from the group of R3 and —H;
• R3 is selected from the group of alkyl, aryl, alicyclic, and aralkyl;
• R6 is selected from the group of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
• R12 is selected from the group of —H, and lower acyl;
• each Y is independently selected from the group of —O—, and —NR6—;
• M is selected from the group of drugs MH containing an —OH, —NHR2,or —SH group, and that is attached to the phosphorus in formula I via O, N or S of said OH, —NHR2, or —SH group;
• and pharmaceutically acceptable prodrugs and salts thereof.