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Claims for Patent: 6,566,344

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Claims for Patent: 6,566,344

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-pentoftiranonucleoside 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: Idenix Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:10/022,148
Patent Claims: 1. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of .beta.-L-2'-deoxycytidine of the formula: ##STR19## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO--alkyl, --CO--aryl, --CO--alkoxyalkyl, --CO--aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug.

2. The method of claim 1, wherein the .beta.-L-2'-deoxycytidine is at least 95% in its designated enantiomeric form.

3. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of .beta.-L-2'-deoxythymidine of the formula: ##STR20## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO--alkyl, --CO--aryl, --CO--alkoxyalkyl, --CO--aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug.

4. The method of claim 3, wherein the .beta.-L-2'-deoxythymidine is at least 95% in its designated enantiomeric form.

5. A method for the treatment of a hepatitis B virus in a human comprising administering a effective combination of the compounds: ##STR21## or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or acyl.

6. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR22## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO--alkyl, --CO--aryl, --CO--alkoxyalkyl, --CO--aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; 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 (3 TC), cis-2-hydroxymethyl-5-(5-fluorocytosin- 1 -yl)- 1,3-oxathiolane (FTC), .beta.-L-2'-fluoro-5-methyl-arabinofuranosyluridine (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); 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir), ganciclovir and ribavirin.

7. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR23## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO--alkyl, --CO--aryl, --CO--alkoxyalkyl, --CO--aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; 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-arabinofuranosyluridine (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); 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir), ganciclovir and ribavirin.

8. A method for the prophylaxis of a hepatitis B virus infection in a a human comprising administering an effective amount of .beta.-L-2'-deoxycytidine of the formula: ##STR24## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO--alkyl, --CO--aryl, --CO--alkoxyalkyl, --CO--aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug.

9. A method for the prophylaxis of a hepatitis B virus infection in a human comprising administering an effective amount of .beta.-L-2'-deoxythymidine of the formula: ##STR25## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug.

10. A method for the prophylaxis of a hepatitis B virus in a human comprising administering a effective combination of the compounds ##STR26## or a pharmaceutically acceptable prodrug thereof, wherein R is hydrogen or acyl.

11. A method for the prophylaxis of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR27## or a pharmgaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO--alkyl, --CO-aryl, --CO--alkoxyalkyl, -CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; 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-arabinofuranosyluridine (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); 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir), ganciclovir and ribavirin.

12. A method for the prophylaxis of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR28## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; 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-arabinofuranosyluridine (L-FMAU), P-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); 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir), ganciclovir and ribavirin.

13. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR29## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC).

14. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR30## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of cis-2-hydroxymethyl-5-(5-fluorocytosin- 1-yl)-1,3-oxathiolane (FTC).

15. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR31## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of .beta.-L-2'-fluoro-5-methyl-arabinofuranosyluridine (L-FMAU).

16. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR32## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of .beta.-D-2,6-diaminopurine dioxolane (DAPD).

17. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR33## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of famciclovir.

18. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR34## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of penciclovir.

19. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR35## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl] -6H-purin-6-one (entecavir, BMS-200475).

20. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR36## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil).

21. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR37## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir).

22. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR38## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of ganciclovir.

23. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR39## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of ribavirin.

24. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR40## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of .beta.-L-2-hydroxymethyl-5-(cytosin- 1-yl)- 1,3-oxathiolane (3TC).

25. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR41## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of cis-2-hydroxymethyl-5-(5-fluorocytosin- 1-yl)- 1,3-oxathiolane (FTC).

26. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR42## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of .beta.-L-2'-fluoro-5-methyl-arabinofuranosyluridine (L-FMAU).

27. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR43## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of .beta.-D-2,6-diaminopurine dioxolane (DAPD).

28. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR44## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of famciclovir.

29. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR45## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of penciclovir.

30. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR46## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyc lopentyl]-6H-purin-6-one (entecavir, BMS-200475).

31. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR47## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil).

32. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR48## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir).

33. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR49## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of ganciclovir.

34. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR50## or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, --CO-alkyl, --CO-aryl, --CO-alkoxyalkyl, --CO-aryloxyalkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid acyl residue, mono, di, and triphosphate and a stabilized nucleotide prodrug; in combination or alternation with an effective amount of ribavirin.

35. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of compound of the formula: ##STR51## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue.

36. The method of claim 35, wherein the amino acid is L-valinyl.

37. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of compound of the formula: ##STR52## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue.

38. The method of clam 37, wherein the amino acid is L-valinyl.

39. A method for the treatment of a hepatitis B virus in a human comprising administering a effective combination of the compounds ##STR53## or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or an amino acid acyl residue.

40. The method of claim 39, wherein the amino acid is L-valinyl.

41. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR54## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl 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-arabinofuranosyluridine (L-FMAU), .beta.-D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1 ,9-dihydro-9-[4-hydroxy-3-(hydroxy-methyl)-2-methylenecyclopentyl]-6H-puri n-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil); 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir), ganciclovir and ribavirin.

42. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR55## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl 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-arabinofuranosyluridine (L-FMAU), .beta.-D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxy-methyl)-2-methylenecyclopentyl ]-6H-purin-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil); 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir), ganciclovir and ribavirin.

43. The method of claim 41 or 42, wherein the amino acid is L-valinyl.

44. A method for the prophylaxis of a hepatitis B virus infection in a human comprising administering an effective amount of compound of the formula: ##STR56## or a pharmaceutically acceptable prodrug thereof, wherein R is an amino acid acyl residue.

45. The method of claim 44, wherein the amino acid is L-valinyl.

46. A method for the prophylaxis of a hepatitis B virus infection in a human comprising administering an effective amount of compound of the formula: ##STR57## or a pharmaceutically acceptable prodrug thereof, wherein R is an amino acid acyl residue.

47. The method of claim 46, wherein the amino acid is L-valinyl.

48. A method for the prophylaxis of a hepatitis B virus in a human comprising administering a effective combination of the compounds ##STR58## or a pharmaceutically acceptable prodrug thereof, wherein R is hydrogen or an amino acid acyl residue.

49. The method of claimn 48, wherein the amino acid is L-valinyl.

50. A method for the prophylaxis of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR59## or a pharmaceutically acceptable prodrug thereof, wherein R is an amino acid acyl 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-arabinofuranosyluridine (L-FMAU), .beta.-D-2,6-diarninopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino- 1,9-dihydro-9-[4-hydroxy-3-(hydroxy-methyl)-2-methylenecyclopentyl]-6H-pur in-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil); 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir), ganciclovir and ribavirin.

51. A method for the prophylaxis of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR60## or a pharmaceutically acceptable prodrug thereof, wherein R is an amino acid acyl 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-arabinofuranosyluridine (L-FMAU), .beta.-D-2,6-diaminopurine dioxolane (DAPD), famciclovir, penciclovir, 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxy-methyl)-2-methylenecyclopentyl ]-6H-purin-6-one (entecavir, BMS-200475), 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil); 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir), ganciclovir and ribavirin.

52. The method of claim 50 or 51 wherein the amino acid is L-valinyl.

53. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR61## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC).

54. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR62## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC).

55. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR63## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of .beta.-L-2'-fluoro-5-methyl-arabinofuranosyluridine (L-FMAU).

56. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR64## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of .beta.-D-2,6-diaminopurine dioxolane (DAPD).

57. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR65## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of famciclovir.

58. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR66## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of a penciclovir.

59. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR67## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxy-methyl)-2-methylenecyclopentyl ]-6H-purin-6-one (entecavir, BMS-200475).

60. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR68## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of 9-[2-(phosphono-methoxy)ethyl]adenine (PNEA, adefovir, dipivoxil).

61. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR69## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir).

62. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR70## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of ganciclovir.

63. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR71## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of ribavirin.

64. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR72## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC).

65. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR73## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of cis-2-hydroxymethyl-5-(5-fluorocytosin- 1-yl)-1 ,3-oxathiolane (FTC).

66. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR74## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of .beta.-L-2'-fluoro-5-methyl-arabinofuranosyluridine (L-FMAU).

67. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR75## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of .beta.-D-2,6-diaminopurine dioxolane (DAPD).

68. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR76## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of famciclovir.

69. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR77## or a pharmnaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of a penciclovir.

70. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR78## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxy-methyl)-2-methylenecyclopentyl ]-6H-purin-6-one (entecavir, BMS-200475).

71. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR79## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxi1).

72. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR80## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir).

73. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR81## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of ganciclovir.

74. A method for the treatment of a hepatitis B virus infection in a human comprising administering an effective amount of a compound of the formula: ##STR82## or a pharmaceutically acceptable salt thereof, wherein R is an amino acid acyl residue; in combination or alternation with an effective amount of ribavirin.

75. The method of any one of claims 53 or 74, wherein the amino acid is L-valinyl.

76. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR83## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3 TC).

77. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR84## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathio-lane (FTC).

78. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR85## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with .beta.-L-2'-fluoro-5-methyl-arabinofuranosyluridine (L-FMAU).

79. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR86## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with .beta.-D-2,6-diaminopurine dioxolane (DAPD).

80. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR87## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with famciclovir.

81. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR88## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with penciclovir.

82. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR89## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclo-pentyl ]-6H-purin-6-one (entecavir, BMS-200475).

83. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR90## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil).

84. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR91## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir).

85. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR92## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with ganciclovir.

86. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR93## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with ribavirin.

87. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR94## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with .beta.-L-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC).

88. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR95##

or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathio-lane (FTC).

89. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR96## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with .beta.-L-2'-fluoro-5-methyl-arabinofuranosyluridine (L-FMAU).

90. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR97## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with .beta.-D-2,6-diaminopurine dioxolane (DAPD).

91. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR98## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with famciclovir.

92. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR99## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with penciclovir.

93. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR100## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with 2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclo-pentyl ]-6H-purin-6-one (entecavir, BMS-200475).

94. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR101## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with 9-[2-(phosphono-methoxy)ethyl]adenine (PMEA, adefovir, dipivoxil).

95. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR102## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir).

96. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR103## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with ganciclovir.

97. A pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR104## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with ribavirin.

98. A method for treating a human infected with hepatitis B comprising administering an effective amount of .beta.-L-2'-deoxycytidine of the formula: ##STR105## or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier.

99. The method of claim 98, wherein the method further comprises administering the .beta.-L-2'-deoxycytidine in combination with a pharmaceutically acceptable carrier.

100. The method of claim 98, 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.

101. The method of claim 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-arabinofuranosyluridine (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 (PNEA, adefovir, dipivoxil); 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir), ganciclovir and fibavifin.

102. A method for treating a human infected with hepatitis B comprising administering an effective amount of .beta.-L-2'-deoxythymidine of the formula: ##STR106## or its pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

103. The method of claim 102, wherein the method further comprises administering the .beta.-L-2'-deoxycytidine in combination with a pharmaceutically acceptable carrier.

104. The method of claim 102 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.

105. The method of claim 104, 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-arabinofuranosyluridine (L-FMAU), P-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); 9-((1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl)guanine (lobucavir), ganciclovir and ribavirin.
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