Claims for Patent: 7,928,086

Summary for Patent: 7,928,086

Title:	.beta.-L-2\'-deoxynucleosides for the treatment of resistant HBV strains and combination therapies
Abstract:	It has been discovered that .beta.-L-2\'-deoxynucleosides are active against drug-resistant hepatitis B virus with mutations. A method for treating lamivudine resistant HBV (M552V) in a host is provided that includes administering a .beta.-L-2\'-deoxynucleoside or its pharmaceutically acceptable salt, ester or prodrug. In addition, a method for preventing lamivudine resistant HBV (M552V) mutation from occurring in a naive host is provided that includes administering a .beta.-L-2\'-deoxynucleoside or its pharmaceutically acceptable salt, ester or prodrug. A method for preventing and/or suppressing the emergence of the HBV double mutant (L528M/M552V) in a host is also provided that includes administering a .beta.-L-2\'-deoxynucleoside or its pharmaceutically acceptable salt, ester or prodrug.
Inventor(s):	Standring; David (Milton, MA), Sommadossi; Jean-Pierre (Cambridge, MA), Patty; April L. (Medford, MA), Seifer; Maria (Clinton, MA)
Assignee:	Novartis AG (Basel, CH)
Application Number:	11/651,353
Patent Claims:	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 .beta.-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 .beta.-L-2'-doexynucleoside is .beta.-L-2'-deoxythymidine, or a pharmaceutically acceptable salt, ester or prodrug thereof. 3. The method of claim 1, wherein the .beta.-L-2'-doexynucleoside is .beta.-L-2'-deoxycytidine, or a pharmaceutically acceptable salt, ester or prodrug thereof. 4. The method of claim 1, wherein the .beta.-L-2'-doexynucleoside has the formula (I): ##STR00044## or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein: R.sup.1 and R.sup.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.sub.2 or CH.sub.2; and BASE is a purine or pyrimidine base that may optionally be substituted. 5. The method of claim 1, wherein the .beta.-L-2'-doexynudeoside has the formula: ##STR00045## or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein: R.sup.1 and R.sup.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.sup.3, NR.sup.3R.sup.4 or SR.sup.3; X.sup.1 and X.sup.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.sup.5, NR.sup.5R.sup.6 or SR.sup.5; and R.sup.3, R.sup.4, R.sup.5 and R.sup.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 .beta.-L-2'-doexynucleoside has the formula: ##STR00046## or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein: R.sup.1 and R.sup.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.sup.3, NR.sup.3R.sup.4 or SR.sup.3; X.sup.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.sup.5, NR.sup.5R.sup.6 or SR.sup.5; and R.sup.3, R.sup.4, R.sup.5 and R.sup.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 .beta.-L-2'-doexynucleoside has the formula: ##STR00047## or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein: R.sup.1 and R.sup.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.sup.3 and R.sup.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.sup.3 and/or R.sup.4 is H. 9. The method of claim 7, wherein R.sup.1 and/or R.sup.2 is H. 10. The method of claim 7, wherein at least one of R.sup.1, R.sup.2 or R.sup.4 is an amino acid residue of the formula: C(O)C(R.sup.8)(R.sup.9)(NR.sup.10R.sup.11) wherein: R.sup.8 is the side chain of an amino acid, alkyl, aryl, heteroaryl, heterocyclic, or can optionally attach to R.sup.10 to form a ring structure; R.sup.9 is hydrogen, alkyl, or aryl; and R.sup.10 and R.sup.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 .beta.-L-2'-doexynucleoside has the formula: ##STR00048## or a pharmaceutically acceptable salt, ester or prodrug thereof. 13. The method of claim 7, wherein the .beta.-L-2'-doexynucleoside has the formula: ##STR00049## or a pharmaceutically acceptable salt, ester or prodrug thereof. 14. The method of claim 7, wherein the .beta.-L-2'-doexynucleoside has the formula: ##STR00050## or a pharmaceutically acceptable salt, ester or prodrug thereof. 15. The method of claim 7, wherein the .beta.-L-2'-doexynucleoside has the formula: ##STR00051## or a pharmaceutically acceptable salt, ester or prodrug thereof. 16. The method of claim 6, wherein the .beta.-L-2'-doexynudeoside has the formula: ##STR00052## or a pharmaceutically acceptable salt, ester or prodrug thereof; R.sup.1 and R.sup.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.sup.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.sup.3 is H. 18. The method of claim 16, wherein R.sup.1 and/or R.sup.2 is H. 19. The method of claim 16, wherein at least one of R.sup.1 or R.sup.2 is an amino acid residue of the formula: C(O)C(R.sup.8)(R.sup.9)(NR.sup.10R.sup.11) wherein: R.sup.8 is the side chain of an amino acid, alkyl, aryl, heteroaryl, heterocyclic, or can optionally attach to R.sup.10 to form a ring structure; R.sup.9 is hydrogen, alkyl, or aryl; and R.sup.10 and R.sup.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 .beta.-L-2'-doexynucleoside has the formula: ##STR00053## or a pharmaceutically acceptable salt, ester or prodrug thereof. 22. The method of claim 4, wherein the .beta.-L-2'-doexynucleoside has the formula: ##STR00054## or a pharmaceutically acceptable salt, ester or prodrug thereof. 23. The method of claim 4, wherein the .beta.-L-2'-doexynucleoside has the formula: ##STR00055## or a pharmaceutically acceptable salt, ester or prodrug thereof. 24. The method of claim 4, wherein the .beta.-L-2'-doexynucleoside has the formula: ##STR00056## or a pharmaceutically acceptable salt, ester or prodrug thereof. 25. The method of claim 4, wherein the .beta.-L-2'-doexynudeoside has the formula: ##STR00057## 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 .beta.-L-2'-doexynucleoside has the formula: ##STR00058## or a pharmaceutically acceptable salt, ester or prodrug thereof. 31. The method of claim 4, wherein the .beta.-L-2'-doexynucleoside has the formula: ##STR00059## or a pharmaceutically acceptable salt, ester or prodrug thereof. 32. The method of claim 4, wherein the .beta.-L-2'-doexynucleoside has the formula: ##STR00060## or a pharmaceutically acceptable salt, ester or prodrug thereof.

Details for Patent 7,928,086

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Biogen Inc.	AVONEX	interferon beta-1a	For Injection	103628	05/17/1996		2022-09-13
Biogen Inc.	AVONEX	interferon beta-1a	Injection	103628	05/28/2003		2022-09-13
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