Claims for Patent: 6,444,652

Summary for Patent: 6,444,652

Title:	.beta.-L-2'-deoxy-nucleosides for the treatment of hepatitis B
Abstract:	This invention is directed to a method for treating a host infected with hepatitis B comprising administering an effective amount of an anti-HBV biologically active 2'-deoxy-.beta.-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof, wherein the 2'-deoxy-.beta.-L-erythro-pentofuranonucleoside has the formula: ##STR1## wherein R is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative; and BASE is a purine or pyrimidine base which may be optionally substituted. The 2'-deoxy-.beta.-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof may be administered either alone or in combination with another 2'-deoxy-.beta.-L-erythro-pentofuranonucleoside or in combination with another anti-hepatitis B agent.
Inventor(s):	Gosselin; Gilles (Montpellier, FR), Imbach; Jean-Louis (Montpellier, FR), Bryant; Martin L. (Carlisle, MA)
Assignee:	Novirio Pharmaceuticals Limited (Grand Cayman, CY) Centre National da la Recherche Scientifique (Paris, FR)
Application Number:	09/459,150
Patent Claims:	1. A method for the treatment or prophylaxis of a hepatitis B virus infection in a host comprising administering an effective amount of .beta.-L-2'-deoxycytidine of the formula: ##STR21## or a pharmaceutically acceptable salt or prodrug thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate or a stabilized nucleotide. 2. A method for the treatment or prophylaxis of a hepatitis B virus infection in a host comprising administering an effective amount of .beta.-L-thymidine of the formula: ##STR22## or a pharmaceutically acceptable salt or prodrug thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate or a stabilized nucleotide. 3. A method for the treatment or prophylaxis of a hepatitis B virus in a host comprising administering a effective combination of the compounds ##STR23## or a pharmaceutically acceptable salt or prodrug thereof, wherein R is hydrogen or acyl. 4. A method for the treatment or prophylaxis of a hepatitis B virus infection in a host comprising administering an effective amount of a compound of the formula: ##STR24## or a pharmaceutically acceptable salt or prodrug thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate or a stabilized nucleotide; in combination or alternation with an effective amount of a compound selected from the group consisting of .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), .beta.-L-2'-fluoro-5-methyl-arabinouridine (L-FMAU), .beta.-D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl] -6H-purin-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil); lobucavir, ganciclovir and ribavirin. 5. A method for the treatment or prophylaxis of a hepatitis B virus infection in a host comprising administering an effective amount of a compound of the formula: ##STR25## or a pharmaceutically acceptable salt or prodrug thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate or a stabilized nucleotide; in combination or alternation with an effective amount of a compound selected from the group consisting of .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), .beta.-L-2'-fluoro-5-methyl-arabinouridine (L-FMAU), .beta.-D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl] -6H-purin-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil); lobucavir, ganciclovir and ribavirin. 6. A compound or pharmaceutically acceptable salt or prodrug thereof of the formula: ##STR26## wherein R is H, mono, di or tri phosphate, amino acid residue, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug). 7. A method for the treatment or prophylaxis of a hepatitis B virus infection in a host comprising administering an effective amount of compound of the formula: ##STR27## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid residue. 8. The method of claim 7, wherein the amino acid is L-valinyl. 9. A method for the treatment or prophylaxis of a hepatitis B virus infection in a host comprising administering an effective amount of compound of the formula: ##STR28## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid residue. 10. The method of claim 9, wherein the amino acid is L-valinyl. 11. A method for the treatment or prophylaxis of a hepatitis B virus in a host comprising administering a effective combination of the compounds ##STR29## or a pharmaceutically acceptable salt or prodrug thereof, wherein R is hydrogen or an amino acid residue. 12. The method of claim 11, wherein the amino acid is L-valinyl. 13. A method for the treatment or prophylaxis of a hepatitis B virus infection in a host comprising administering an effective amount of a compound of the formula: ##STR30## or a pharmaceutically acceptable salt or prodrug thereof, wherein R is an amino acid residue; in combination or alternation with an effective amount of a compound selected from the group consisting of .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), .beta.-L-2'-fluoro-5-methyl-arabinouridine (L-FMAU), .beta.-D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl] -6H-purin-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil); lobucavir, ganciclovir and ribavirin. 14. The method of claim 13, wherein the amino acid is L-valinyl. 15. A method for the treatment or prophylaxis of a hepatitis B virus infection in a host comprising administering an effective amount of a compound of the formula: ##STR31## or a pharmaceutically acceptable salt or prodrug thereof, wherein R is an amino acid residue; in combination or alternation with an effective amount of a compound selected from the group consisting of .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), .beta.-L-2'-fluoro-5-methyl-arabinouridine (L-FMAU), .beta.-D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino- 1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-puri n-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil); lobucavir, ganciclovir and ribavirin. 16. The method of claim 15, wherein the amino acid is L-valinyl. 17. A compound of the formula: ##STR32## or pharmaceutically acceptable salt thereof. 18. A pharmaceutical composition comprising an effective amount of a compound of claim 17 in combination with a pharmaceutically acceptable carrier. 19. A pharmaceutical composition comprising an effective amount of a compound of claim 17, optionally in a pharmaceutically acceptable carrier, with another anti-hepatitis B virus agent. 20. The pharmaceutical composition of claim 19, wherein the additional anti-hepatitis B virus agent is selected from the group consisting of .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), .beta.-L-2'-fluoro-5-methyl-arabinouridine (L-FMAU), .beta.-D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl] -6H-purin-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil); lobucavir, ganciclovir and ribavirin. 21. A compound of the formula: ##STR33## or pharmaceutically acceptable salt thereof. 22. A pharmaceutical composition comprising an effective amount of a compound of claim 21 in combination with a pharmaceutically acceptable carrier. 23. A pharmaceutical composition comprising an effective amount of a compound of claim 21, optionally in a pharmaceutically acceptable carrier, with another anti-hepatitis B virus agent. 24. The pharmaceutical composition of claim 23, wherein the additional anti-hepatitis B virus agent is selected from the group consisting of .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), .beta.-L-2'-fluoro-5-methyl-arabinouridine (L-FMAU), .beta.-D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl] -6H-purin-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil); lobucavir, ganciclovir and ribavirin. 25. A method for treating a host infected with hepatitis B comprising administering an effective amount of .beta.-L-2'-deoxycytidine of the formula: ##STR34## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier. 26. The method of claim 25, wherein the method further comprises administering the .beta.-L-2'-deoxycytidine in combination with a pharmaceutically acceptable carrier. 27. The method of claim 25, wherein the method further comprises administering the .beta.-L-2'-deoxycytidine, optionally with a pharmaceutically acceptable carrier, in combination or alternation with another anti-HBV agent. 28. The method of claim 27, wherein the anti-HBV agent is selected from the group consisting of .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), cis-2-hydroxymethyl-5-(5-fluorocytosin- 1-yl)-1,3-oxathiolane (FTC), .beta.-L-2'-fluoro-5-methyl-arabinouridine (L-FMAU), .beta.-D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl] -6H-purin-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil); lobucavir, ganciclovir and ribavirin. 29. A method for treating a host infected with hepatitis B comprising administering an effective amount of .beta.-L-2'-deoxythymidine of the formula: ##STR35## or its pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. 30. The method of claim 29, wherein the method further comprises administering the .beta.-L-2'-deoxycytidine in combination with a pharmaceutically acceptable carrier. 31. The method of claim 29, wherein the method further comprises administering the .beta.-L-2'-deoxycytidine, optionally with a pharmaceutically acceptable carrier, in combination or alternation with another anti-HBV agent. 32. The method of claim 31, wherein the anti-HBV agent is selected from the group consisting of .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), .beta.-L-2'-fluoro-5-methyl-arabinouridine (L-FMAU), .beta.D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl] -6H-purin-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil); lobucavir, ganciclovir and ribavirin. 33. The method of claim 1, wherein the .beta.-L-2'-deoxycytidine is at least 95% in its designated enantiomeric form. 34. The method of claim 2, wherein the .beta.-L-thymidine is at least 95% in its designated enantiomeric form.