US2005277616A1PendingUtilityA1

Thymine nucleosides with anti-hepatitis B virus activity

Individually held — no corporate assignee on recordPriority: Jun 7, 1995Filed: Jul 12, 2005Published: Dec 15, 2005

Est. expiryJun 7, 2015(expired)· nominal 20-yr term from priority

Inventors:Raymond F. Schinazi Jean-Pierre Sommadossi Gilles Gosselin Jean-Louis Imbach

A61P 31/18A61P 31/12A61P 31/20A61P 43/00A61P 1/16A61K 31/70A61K 31/7076A61K 38/21A61K 31/7068A61K 31/7072A61K 47/544

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References

Claims

Abstract

A method for the treatment of a host, and in particular, a human, infected with hepatitis B virus (HBV) is provided that includes administering an effective amount of a β-L-thymine nucleotide, or a phosphate prodrug thereof, optionally in combination therapy with other drugs for the treatment of HBV.

Claims

exact text as granted — not AI-modified

1 . A method comprising administering to a human infected with hepatitis B virus, in an amount effective to treat Hepatitis B, a β-L enantiomer of one or more compounds of the formula,

wherein
Base is thymine;
Y 2 is OH, N 3 , NR 1 R 2 , NO 2 , NOR 3 , —O-alkyl, —O-aryl, halo, —CN, —C(O)NH 2 , SH, —S-alkyl, or —S-aryl;
Y 1 , Y 3 , and Y 4 are H;
wherein R 1 , R 2 , and R 3 , are independently alkyl, aryl, aralkyl, alkaryl, acyl, or hydrogen; and
R is H, monophosphate, diphosphate, triphosphate, alkyl, acyl, or a phosphate derivative;
or a pharmaceutically acceptable salt thereof; and
wherein the compounds either possess anti-HBV activity or are metabolized to a compound or compounds that exhibit anti-HBV activity:

2 . The method of claim 1 wherein R 1 , R 2 , and R 3 are lower alkyl.

3 . The method of claim 2 wherein aryl is phenyl.

4 . The method of claim 3 wherein R is H or a phosphate derivative.

5 . The method of claim 4 wherein the phosphate derivative is a mono, di, or triphosphate ester that stabilizes the phosphate in vivo.

6 . The method of claim 5 wherein the mono, di, or triphosphate ester is a phospholipid.

7 . The method of claim 5 wherein the mono, di, or triphosphate ester comprises one or more alkyl, acyl, aryl, steroid, carbohydrate, 1,2-diacylglycerol, or alcohol substitutents.

8 . The method of claim 3 wherein R is a phosphate derivative.

9 . The method of claim 8 wherein the phosphate derivative is a mono, di, or triphosphate ester that stabilizes the phosphate in vivo.

10 . The method of claim 9 wherein the mono, di, or triphosphate ester is a phospholipid.

11 . The method of claim 9 wherein the mono, di, or triphosphate ester comprises one or more alkyl, acyl, aryl, steroid, carbohydrate, 1,2-diacylglycerol, or alcohol substitutents.

12 . The method of claim 3 wherein three of Y 1 , Y 2 , Y 3 , and Y 4 are either H or OH.

13 . The method of claim 1 wherein the one or more compounds has the structure

14 . The method of claim 13 wherein R 1 , R 2 , and R 3 are lower alkyl.

15 . The method of claim 14 wherein aryl is phenyl.

16 . The method of claim 15 wherein the β-L enantiomer of the one or more compounds or the pharmaceutically acceptable salt thereof is provided in enantiomerically enriched form.

17 . The method of claim 15 wherein the β-L enantiomer of the one or more compounds or the pharmaceutically acceptable salt thereof has an enantiomeric purity of at least 95% of the illustrated enantiomer.

18 . The method of claim 1 wherein the β-L enantiomer of the one or more compounds or the pharmaceutically acceptable salt thereof has an enantiomeric purity of at least 97% of the illustrated enantiomer.

19 . The method of claim 3 wherein the β-L enantiomer of the one or more compounds or the pharmaceutically acceptable salt thereof has an enantiomeric purity of at least 98% of the illustrated enantiomer.

20 . The method of claim 3 wherein the β-L enantiomer of the one or more compounds or the pharmaceutically acceptable salt thereof has an enantiomeric purity of at least 99% of the illustrated enantiomer.

21 . The method of claim 3 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered in a pharmaceutically acceptable carrier or diluent.

22 . The method of claim 21 , wherein the pharmaceutically acceptable carrier or diluent comprises water.

23 . The method of claim 21 , wherein the pharmaceutically acceptable carrier or diluent is physiological saline, or phosphate buffered saline.

24 . The method of claim 3 , one or more compounds or the pharmaceutically acceptable salt thereof is administered in a liposome, microsphere, or nanosphere.

25 . The method of claim 3 wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered to the human orally, intraveneously, intradermally, subcutaneously, or topically.

26 . The method of claim 3 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered to the human orally.

27 . The method of claim 3 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered in the form of capsules, tablets, or troches.

28 . The method of claim 3 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered in the form of an elixir, suspension, syrup, wafer, or chewing gum.

29 . The method of claim 3 , wherein the amount of one or more compounds or the pharmaceutically acceptable salt thereof administered to the human is from 0.1 to 100 mg per kilogram body weight of the human per day.

30 . The method of claim 3 , wherein the amount of the one or more compounds or the pharmaceutically acceptable salt thereof administered to the human is from 1 to 60 mg per kilogram body weight of the human per day.

31 . The method of claim 3 , wherein the amount of the one or more compounds or the pharmaceutically acceptable salt thereof administered to the human is from 1 to 20 mg per kilogram body weight of the human per day.

32 . The method of claim 3 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered at a dosage of from 7 mg to 3,000 mg.

33 . The method of claim 3 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered at a dosage of from 7 mg to 1,400 mg.

34 . The method of claim 3 , wherein when the one or more compounds or the pharmaceutically acceptable salt thereof is administered orally, the dosage of the compound is from 50 mg to 1,000 mg.

35 . The method of claim 1 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof are administered in alternation or combination with one or more other anti-HBV agents.

36 . The method of claim 3 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof are administered in alternation or combination with one or more other anti-HBV agents.

37 . The method of claim 15 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof are administered in alternation or combination with one or more other anti-HBV agents.

38 . The method of claim 3 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered in combination with an antibiotic, an antiviral compound, an antifungal agent, or a pharmaceutical agent used for the treatment of a secondary infection.

39 . The method of claim 3 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered in combination with anti-HIV medications to a patient who has been exposed to HIV or is anti-HIV antibody or HIV antigen positive.

40 . The method of claim 3 , wherein the pharmaceutically acceptable salt comprises an acid addition salt formed from an inorganic acid, a salt formed from an organic acid, a base addition salt formed from a cation, or a combination thereof

41 . The method of claim 3 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is capable of providing directly or indirectly the parent active compound upon administration to the human.

42 . The method of claim 1 , wherein when the one or more compounds or a salt thereof is administered to HBV virion infected cell cultures at a concentration of 0.01 to 10 μM, the levels of both intracellular and extracellular HBV DNA are depressed at least 3.0 fold as compared to the average levels in untreated cell cultures.

43 . The method of claim 42 wherein the HBV virion infected cell cultures are HepG2 cells transformed with hepatitis virion.

44 . The method of claim 42 wherein wherein the HBV virion infected cell cultures are 2.2.15 cell cultures.

45 . A method comprising administering to a human infected with hepatitis B virus, in an amount effective to treat Hepatitis B, one or more compounds of the formula,

wherein
Base is thymine; and
Y 2 is OH, N 3 , NR 1 R 2 , NO 2 , N—OR 3 , —O-alkyl, —O-aryl, halo, —CN, —C(O)NH 2 , SH, —S-alkyl, or —S-aryl, wherein R 1 , R 2 , and R 3 are independently alkyl, aryl, aralkyl, alkaryl, acyl, or hydrogen; and
wherein the hydrogen of the 5′-OH group can be optionally replaced by a lipophilicly modified mono-, di -or tri-phosphate;
or a pharmaceutically acceptable salt thereof.

46 . The method of claim 45 wherein the compounds either possess anti-HBV activity or are metabolized to a compound or compounds that exhibit anti-HBV activity.

47 . The method of claim 45 wherein R 1 , R 2, and R 3 are lower alkyl.

48 . The method of claim 47 wherein aryl is phenyl.

49 . The method of claim 48 wherein the hydrogen of the 5′-OH group is optionally replaced by a mono, di, or triphosphate ester.

50 . The method of claim 49 wherein the mono, di, or triphosphate ester is a phospholipid.

51 . The method of claim 49 wherein the mono, di, or triphosphate ester comprises one or more alkyl, acyl, aryl, steroid, carbohydrate, 1,2-diacylglycerol, or alcohol substitutents.

52 . The method of claim 48 wherein the hydrogen of the 5′-OH group is replaced by a mono, di, or triphosphate ester.

53 . The method of claim 48 wherein the hydrogen of the 5′-OH group is replaced by mono, di, or triphosphate ester that stabilizes the phosphate in vivo.

54 . The method of claim 52 wherein the mono, di, or triphosphate ester is a phospholipid.

55 . The method of claim 52 wherein the mono, di, or triphosphate ester comprises one or more alkyl, acyl, aryl, steroid, carbohydrate, 1,2-diacylglycerol, or alcohol substitutents.

56 . The method of claim 45 wherein the one or more compounds or the pharmaceutically acceptable salt thereof is provided in enantiomerically enriched form.

57 . The method of claim 46 wherein the one or more compounds or the pharmaceutically acceptable salt thereof has an enantiomeric purity of at least 95% of the illustrated enantiomer.

58 . The method of claim 48 wherein the one or more compounds or the pharmaceutically acceptable salt thereof has an enantiomeric purity of at least 97% of the illustrated enantiomer.

59 . The method of claim 48 wherein the one or more compounds or the pharmaceutically acceptable salt thereof has an enantiomeric purity of at least 98% of the illustrated enantiomer.

60 . The method of claim 48 wherein the one or more compounds or the pharmaceutically acceptable salt thereof has an enantiomeric purity of at least 99% of the illustrated enantiomer.

61 . The method of claim 48 wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered in a pharmaceutically acceptable carrier or diluent.

62 . The method of claim 61 , wherein the pharmaceutically acceptable carrier or diluent comprises water.

63 . The method of claim 61 , wherein the pharmaceutically acceptable carrier or diluent is physiological saline, or phosphate buffered saline.

64 . The method of claim 48 , one or more compounds or the pharmaceutically acceptable salt thereof is administered in a liposome, microsphere, or nanosphere.

65 . The method of claim 48 wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered to the human orally, intraveneously, intradermally, subcutaneously, or topically.

66 . The method of claim 48 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered to the human orally.

67 . The method of claim 48 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered in the form of capsules, tablets, or troches.

68 . The method of claim 48 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered in the form of an elixir, suspension, syrup, wafer, or chewing gum.

69 . The method of claim 48 , wherein the amount of one or more compounds or the pharmaceutically acceptable salt thereof administered to the human is from 0.1 to 100 mg per kilogram body weight of the human per day.

70 . The method of claim 48 , wherein the amount of the one or more compounds or the pharmaceutically acceptable salt thereof administered to the human is from 1 to 60 mg per kilogram body weight of the human per day.

71 . The method of claim 48 , wherein the amount of the one or more compounds or the pharmaceutically acceptable salt thereof administered to the human is from 1 to 20 mg per kilogram body weight of the human per day.

72 . The method of claim 48 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered at a dosage of from 7 mg to 3,000 mg.

73 . The method of claim 48 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered at a dosage of from 7 mg to 1,400 mg.

74 . The method of claim 48 , wherein when the one or more compounds or the pharmaceutically acceptable salt thereof is administered orally, the dosage of the compound is from 50 mg to 1,000 mg.

75 . The method of claim 48 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof are administered in alternation or combination with one or more other anti-HBV agents.

76 . The method of claim 48 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof are administered in alternation or combination with one or more other anti-HBV agents.

77 . The method of claim 48 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered in combination with an antibiotic, an antiviral compound, an antifungal agent, or a pharmaceutical agent used for the treatment of a secondary infection.

78 . The method of claim 48 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is administered in combination with anti-HIV medications to a patient who has been exposed to HIV or is anti-HIV antibody or HIV antigen positive.

79 . The method of claim 48 , wherein the pharmaceutically acceptable salt comprises an acid addition salt formed from an inorganic acid, a salt formed from an organic acid, a base addition salt formed from a cation, or a combination thereof

80 . The method of claim 48 , wherein the one or more compounds or the pharmaceutically acceptable salt thereof is capable of providing directly or indirectly the parent active compound upon administration to the human.

81 . The method of claim 45 , wherein when the one or more compounds or a salt thereof is administered to HBV virion infected cell cultures at a concentration of 0.01 to 10 μM, the levels of both intracellular and extracellular HBV DNA are depressed at least 3.0 fold as compared to the average levels in untreated cell cultures.

82 . The method of claim 81 wherein the HBV virion infected cell cultures are HepG2 cells transformed with hepatitis virion.

83 . The method of claim 82 wherein wherein the HBV virion infected cell cultures are 2.2.15 cell cultures.

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