β-L-2′-deoxynucleosides for the treatment of resistant HBV strains and combination therapies

1. A method for the treatment of a host infected with a drug-resistant form of HBV, said HBV exhibiting a mutation at the 552 codon from methionine to valine in the DNA polymerase region, said method comprising administering an effective amount of a β-L-2′-deoxynucleoside having thymine or cytosine as base, or a pharmaceutically acceptable salt, ester or prodrug thereof; in combination or alternation with at least one other anti-HBV agent.

2. The method of claim 1 , wherein the β-L-2′-doexynucleoside is β-L-2′-deoxythymidine, or a pharmaceutically acceptable salt, ester or prodrug thereof.

3. The method of claim 1 , wherein the β-L-2′-doexynucleoside is β-L-2′-deoxycytidine, or a pharmaceutically acceptable salt, ester or prodrug thereof.

4. The method of claim 1 , wherein the β-L-2′-doexynucleoside has the formula (I):

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein:

R 1 and R 2 are independently hydrogen, straight chained, branched or cyclic alkyl, acyl, acetyl, butyryl, CO-alkyl, CO-aryl, CO-aikoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate;

X is O, S, SO 2 or CH 2 ; and

BASE is a purine or pyrimidine base that may optionally be substituted.

5. The method of claim 1 , wherein the β-L-2′-doexynudeoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein:

R 1 and R 2 are independently hydrogen, straight chained, branched or cyclic alkyl, acyl, acetyl, butyryl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate;

Y is OR 3 , NR 3 R 4 or SR 3 ;

X 1 and X 2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, acyl, acetyl, butyryl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, halogen, OR 5 , NR 5 R 6 or SR 5 ; and

R 3 , R 4 , R 5 and R 6 are independently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, acyl, acetyl, butyryl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.

6. The method of claim 1 , wherein the β-L-2′-doexynucleoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein:

R 1 and R 2 are independently hydrogen, straight chained, branched or cyclic alkyl, acyl, acetyl, butyryl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate;

Y is OR 3 , NR 3 R 4 or SR 3 ;

X 1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, acyl, acetyl, butyryl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, halogen, OR 5 , NR 5 R 6 or SR 5 ; and

R 3 , R 4 , R 5 and R 6 are independently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, acyl, acetyl, butyryl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.

7. The method of claim 6 , wherein the β-L-2′-doexynucleoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein:

R 1 and R 2 are independently hydrogen, straight chained, branched or cyclic alkyl, acyl, acetyl, butyryl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate; and

R 3 and R 4 are independently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, acyl, acetyl, butyryl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.

8. The method of claim 7 , wherein R 3 and/or R 4 is H.

9. The method of claim 7 , wherein R 1 and/or R 2 is H.

10. The method of claim 7 , wherein at least one of R 1 , R 2 or R 4 is an amino acid residue of the formula:

C(O)C(R 8 )(R 9 )(NR 10 R 11 )

wherein:

R 8 is the side chain of an amino acid, alkyl, aryl, heteroaryl, heterocyclic, or can optionally attach to R 10 to form a ring structure;

R 9 is hydrogen, alkyl, or aryl; and

R 10 and R 11 are independently hydrogen, acyl, or alkyl.

11. The method of claim 10 , wherein the amino acid residue is L-valinyl.

12. The method of claim 7 , wherein the β-L-2′-doexynucleoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof.

13. The method of claim 7 , wherein the β-L-2′-doexynucleoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof.

14. The method of claim 7 , wherein the β-L-2′-doexynucleoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof.

15. The method of claim 7 , wherein the β-L-2′-doexynucleoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof.

16. The method of claim 6 , wherein the β-L-2′-doexynudeoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof;

R 1 and R 2 are independently hydrogen, straight chained, branched or cyclic alkyl, acyl, acetyl, butyryl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate; and

R 3 is hydrogen, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, acyl, acetyl, butyryl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.

17. The method of claim 16 , wherein R 3 is H.

18. The method of claim 16 , wherein R 1 and/or R 2 is H.

19. The method of claim 16 , wherein at least one of R 1 or R 2 is an amino acid residue of the formula:

C(O)C(R 8 )(R 9 )(NR 10 R 11 )

wherein:

R 8 is the side chain of an amino acid, alkyl, aryl, heteroaryl, heterocyclic, or can optionally attach to R 10 to form a ring structure;

R 9 is hydrogen, alkyl, or aryl; and

R 10 and R 11 are independently hydrogen, acyl, or alkyl.

20. The method of claim 19 , wherein the amino acid residue is L-valinyl.

21. The method of claim 4 , wherein the β-L-2′-doexynucleoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof.

22. The method of claim 4 , wherein the β-L-2′-doexynucleoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof.

23. The method of claim 4 , wherein the β-L-2′-doexynucleoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof.

24. The method of claim 4 , wherein the β-L-2′-doexynucleoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof.

25. The method of claim 4 , wherein the β-L-2′-doexynudeoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof.

26. The method of claim 1 or 25 wherein the other anti-HBV agent is selected from the group consisting of 3TC, FTC, L-FMAU, DAPD, DXG, famciclovir, penciclovir, BMS-200475, bis pom PMEA (adefovir, dipivoxil), lobucavir, ganciclovir, tenofovir, Lfd4C, foscamet (trisodium phosphonoformate), isoprinosine, levamizole, N-acetylcystine (NAC), interferon, pegylated interferon, ISS, ribavirin, PC 1323 and polyadencyclic polyuridylic acid.

27. The method of claim 26 wherein the other anti-HBV agent is interferon.

28. The method of claim 27 , wherein the interferon is selected from the group consisting of interferon alpha, pegylated interferon alpha, interferon alpha-2a, interferon alpha-2b, pegylated interferon alpha-2a, pegylated interferon alpha-2b interferon beta, interferon gamma, interferon tau, interferon omega, consensus interferon, interferon alphacon-1, natural interferon, interferon beta-1a, omega interferon, oral interferon alpha, interferon gamma-1b, natural human multi-subtype IFN-alpha, and human IFN-beta.

29. The method of claim 1 or 25 , wherein the host is a human.

30. The method of claim 4 , wherein the β-L-2′-doexynucleoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof.

31. The method of claim 4 , wherein the β-L-2′-doexynucleoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof.

32. The method of claim 4 , wherein the β-L-2′-doexynucleoside has the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof.