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Claims for Patent: 6,444,652

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Claims 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.
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