Beta-L-2'-deoxynucleosides for the treatment of resistant HBV strains and combination therapies

• US 20050080034A1
• Filed: 09/15/2003
• Published: 04/14/2005
• Est. Priority Date: 09/13/2002
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Inventors: Sommadossi, Jean-Pierre, Seifer, Maria, Patty, April L., Standring, David
• Granted Patent: US 7,186,700 B2
• Time in Patent Office: Days
• US Class Current: 514/46
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

It has been discovered that β-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 β-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 naïve host is provided that includes administering a β-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 β-L-2′-deoxynucleoside or its pharmaceutically acceptable salt, ester or prodrug.

Claims

1. A method for the treatment of a host infected with a drug-resistant form of HBV, comprising administering an effective amount of a β

-L-2′

-deoxynucleoside, or a pharmaceutically acceptable salt, ester or prodrug thereof.

70. The method of any one of claims 1-69, further comprising administering in combination and/or alternation an effective amount of one or more other anti-HBV agents.

71. The method of claim 70 wherein at the other anti-HBV agents 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, foscarnet (trisodium phosphonoformate), isoprinosine, levamizole, N-acetylcystine (NAC), interferon, pegylated interferon, ISS, ribavirin, PC 323 or polyadencyclic polyuridylic acid.

72. The method of claim 71 wherein at least one of the other anti-HBV agents is interferon.

73. The method of claim 72, 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 ROFERON®

-A (interferon alpha-2a), PEGASYS®

(pegylated interferon alpha-2a), INTRON®

A (Interferon alpha-2b), PEG-INTRON®

(pegylated Interferon alpha-2b), interferon beta, interferon gamma, interferon tau, interferon omega, consensus interferon, INFERGEN (interferon alphacon-1), OMNIFERON (natural interferon), REBIF (interferon beta-1a), omega interferon, oral interferon alpha, interferon gamma-1b, SuperFeron (natural human multi-subtype IFN-alpha), and HuFeron (human IFN-beta).

74. The method of any one of claims 1-5, wherein the host is a mammal.

75. The method of claim 74, wherein the host is a human.

2. A method for the treatment of a host infected with a drug-resistant form of HBV, comprising administering an effective amount of a β

-L-2′

-deoxythymidine, or a pharmaceutically acceptable salt, ester or prodrug thereof.

3. A method for the treatment of a host infected with a drug-resistant form of HBV, comprising administering an effective amount of a β

-L-2′

-deoxycytidine, or a pharmaceutically acceptable salt, ester or prodrug thereof.

4. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a β

-L-2′

-deoxynucleoside, or a pharmaceutically acceptable salt, ester or prodrug.

5. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula (I):

6. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:

7. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:

8. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:

9. The method of claims 8, wherein R³ and/or R⁴ is H.

10. The method of claim 8, wherein R¹ and/or R² is H.

11. The method of claim 8, wherein at least one of R¹, R² or R⁴ is an amino acid residue of the formula:

C(O)C(R⁸)(R⁹)(NR¹⁰R¹¹)

wherein;

R⁸ is the side chain of an amino acid, alkyl, aryl, heteroaryl, heterocyclic, or can optionally attach to R¹⁰ to form a ring structure;

R⁹ is hydrogen, alkyl, or aryl; and

R¹⁰ and R¹¹ are independently hydrogen, acyl, or alkyl.

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

13. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:

14. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:

15. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:

16. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:

17. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:

18. The method of claim 17, wherein R³ is H.

19. The method of claim 17, wherein R¹ and/or R² is H.

20. The method of claim 17, wherein at least one of R¹ or R² is an amino acid residue of the formula:

C(O)C(R⁸)(R⁹)(NR¹⁰R¹¹)

wherein;

R¹ is the side chain of an amino acid, alkyl, aryl, heteroaryl, heterocyclic, or can optionally attach to R¹⁰ to form a ring structure;

R⁹ is hydrogen, alkyl, or aryl; and

R¹⁰ and R¹¹ are independently hydrogen, acyl, or alkyl.

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

22. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:

23. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:

24. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:

25. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:

26. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a β

-L-2′

-deoxynucleoside,

or a pharmaceutically acceptable salt, ester or prodrug.

27. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula (I):

28. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

29. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

30. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

31. The method of claims 30, wherein R³ and/or R⁴ are H.

32. The method of claim 30, wherein R¹ and/or R² is H.

33. The method of claim 30, wherein at least one of R¹, R² or R⁴ is an amino acid residue of the formula:

C(O)C(R⁸)(R⁹)(NR¹⁰R¹¹)

wherein;

R⁸ is the side chain of an amino acid, alkyl, aryl, heteroaryl, heterocyclic, or can optionally attach to R¹⁰ to form a ring structure;

R⁹ is hydrogen, alkyl, or aryl; and

R¹⁰ and R¹¹ are independently hydrogen, acyl, or alkyl.

34. The method of claim 33, wherein the amino acid residue is L-valinyl.

35. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

36. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

37. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

38. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

39. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

40. The method of claim 39, wherein R³ is H.

41. The method of claim 39, wherein R¹ and/or R² is H.

42. The method of claim 39, wherein at least one of R¹ or R² is an amino acid residue of the formula:

C(O)C(R⁸)(R⁹)(NR¹⁰R¹¹)

wherein;

R⁸ is the side chain of an amino acid, alkyl, aryl, heteroaryl, heterocyclic, or can optionally attach to R¹⁰ to form a ring structure;

R⁹ is hydrogen, alkyl, or aryl; and

R¹⁰ and R¹¹ are independently hydrogen, acyl, or alkyl.

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

44. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

45. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

46. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

47. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

48. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine and at the 526 or 528 codon from leucine to methionine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a β

-L-2′

-deoxynucleoside, or a pharmaceutically acceptable salt, ester or prodrug.

49. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine and at the 526 or 528 codon from leucine to methionine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula (I):

50. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine and at the 526 or 528 codon from leucine to methionine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

51. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine and at the 526 or 528 codon from leucine to methionine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

52. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine and at the 526 or 528 codon from leucine to methionine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

53. The method of claims 52, wherein R³ and/or R⁴ is H.

54. The method of claim 52, wherein R¹ and/or R² is H.

55. The method of claim 52, wherein at least one of R¹, R² or R⁴ is an amino acid residue of the formula:

C(O)C(R⁸)(R⁹)(NR¹⁰R¹¹)

wherein;

R⁸ is the side chain of an amino acid, alkyl, aryl, heteroaryl, heterocyclic, or can optionally attach to R¹⁰ to form a ring structure;

R⁹ is hydrogen, alkyl, or aryl; and

R¹⁰ and R¹¹ are independently hydrogen, acyl, or alkyl.

56. The method of claim 55, wherein the amino acid residue is L-valinyl.

57. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine and at the 526 or 528 codon from leucine to methionine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

58. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine and at the 526 or 528 codon from leucine to methionine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

59. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine and at the 526 or 528 codon from leucine to methionine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

60. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine and at the 526 or 528 codon from leucine to methionine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

61. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine and at the 526 or 528 codon from leucine to methionine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

62. The method of claim 61, wherein R³ is H.

63. The method of claim 61, wherein R¹ and/or R² is H.

64. The method of claim 61, wherein at least one of R¹ or R² is an amino acid residue of the formula:

C(O)C(R⁸)(R⁹)(NR¹⁰R¹¹) wherein;

R⁸ is the side chain of an amino acid, alkyl, aryl, heteroaryl, heterocyclic, or can optionally attach to R¹⁰ to form a ring structure;

R⁹ is hydrogen, alkyl, or aryl; and

R¹⁰ and R¹¹ are independently hydrogen, acyl, or alkyl.

65. The method of claim 64, wherein the amino acid residue is L-valinyl.

66. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine and at the 526 or 528 codon from leucine to methionine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

67. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine and at the 526 or 528 codon from leucine to methionine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

68. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine and at the 526 or 528 codon from leucine to methionine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula:

69. A method for preventing or suppressing the expression of a mutation at the 552 codon from methionine to valine and at the 526 or 528 codon from leucine to methionine in the DNA polymerase region of HBV in a host, comprising administering an effective amount of a compound of the formula: