Treatment of EBV and KHSV infection and associated abnormal cellular proliferation

• US 20030176392A1
• Filed: 12/19/2002
• Published: 09/18/2003
• Est. Priority Date: 12/20/2001
• Status: Active Grant

• Current Assignee: Beth Israel Deaconess Medical Center, Inc. (Beth Israel Lahey Health, Inc.), Emory University
• Original Assignee: Pharmasset Incorporated (Gilead Sciences Inc.)
• Inventors: Schinazi, Raymond F., Gustafson, Erik, Fingeroth, Joyce D., Shi, Junxing
• Granted Patent: US 7,211,570 B2
• Time in Patent Office: Days
• US Class Current: 514/49
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• 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 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 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/54 as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07H 19/06 Pyrimidine radicals

Abstract

A method and composition for the treatment, prevention and/or prophylaxis of a host, and in particular, a human, infected with Epstein-Barr virus (EBV), is provided that includes administering an effective amount of a 5-substituted uracil nucleoside or its pharmaceutically acceptable salt or prodrug, optionally in a pharmaceutically acceptable diluent or excipient.

Claims

1. A method for treating a host infected with Epstein-Barr virus or KHSV comprising administering an effective amount of a compound of the general formula (I), (II) or (III):

2. The method of claim 1 wherein the compound is 2′

-deoxy-5-vinyluridine.

3. The method of claim 1 wherein the compound is 5-vinyluridine.

4. The method of claim 1 wherein the compound is 2′

-deoxy-5-iodouridine.

5. The method of claim 1 wherein the compound is 2′

-deoxy-5-(hydroxymethyl)uridine.

6. The method of claim 1 wherein the compound is 5-butyl-2′

-deoxyuridine.

7. The method of claim 1 wherein the compound is 5-E-(2-carboxyvinyl)-2′

-deoxyuridine.

8. The method of claim 1, wherein the compound is (2S,4S)-5-(2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

9. The method of claim 1 wherein the compound is (2S,4S)-5-(5-bromo-2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

10. The method of claim 1 wherein the compound is (2S,4S)-5-(2-thienyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

11. The method of claim 1 wherein the compound is (2S,4S)-5-(5-bromthien-2-yl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

12. The method of claim 1 wherein the compound is and (2S,4S)-5-(3-hydroxypropenyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

13. The method of claim 1 wherein the host exhibits acute mononucleosis.

14. The method of claim 1 wherein the host exhibits oral hairy leukoplakia.

15. The method of claim 1 wherein the compound administered is a β

-L isomer and is at least 95% pure.

16. The method of claim 1 wherein the compound administered is a β

-D isomer and is at least 95% pure.

17. The method of claim 1 wherein the host is a human.

18. A method for treating a host with abnormal cellular proliferation or a cellular dysfunction, wherein the cell carries the Epstein-Barr virus or KHSV genome, comprising administering an effective amount of a compound of the general formula (I), (II) or (III):

19. The method of claim 18 wherein the compound is 2′

-deoxy-5-vinyluridine.

20. The method of claim 18 wherein the compound is 5-vinyluridine.

21. The method of claim 18 wherein the compound is 2′

-deoxy-5-iodouridine.

22. The method of claim 18 wherein the compound is 2′

-deoxy-5-(hydroxymethyl)uridine.

23. The method of claim 18 wherein the compound is 5-butyl-2′

-deoxyuridine.

24. The method of claim 18 wherein the compound is 5-E-(2-carboxyvinyl)-2′

-deoxyuridine.

25. The method of claim 18 wherein the compound is (2S,4S)-5-(2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

26. The method of claim 18 wherein the compound is (2S,4S)-5-(5-bromo-2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

27. The method of claim 18 wherein the compound is (2S,4S)-5-(2-thienyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

28. The method of claim 18 wherein the compound is (2S,4S)-5-(5-bromthien-2-yl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

29. The method of claim 18 wherein the compound is and (2S,4S)-5-(3-hydroxypropenyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

30. The method of claim 18 wherein the host exhibits nasopharyngeal carcinoma.

31. The method of claim 18 wherein the host exhibits a B-cell lymphoma

32. The method of claim 18 wherein the host exhibits a B-cell lymphoproliferative disorder.

33. The method of claim 18 wherein the host exhibits Hodgkins disease.

34. The method of claim 18 wherein the host exhibits a T-lymphoma.

35. The method of claim 18 wherein the host exhibits an NK/monocytoid/dendritic cell malignancy.

36. The method of claim 18 wherein the host exhibits a sporadic epithelial carcinoma.

37. The method of claim 18 wherein the host exhibits a leiomyosarcoma.

38. The method of claim 18 wherein the host exhibits a multicentric leiomyosarcoma.

39. The method of claim 18 wherein the host exhibits Kaposi'"'"'s sarcoma.

40. The method of claim 18 wherein the host exhibits multicentric Castleman'"'"'s Disease.

41. The method of claim 18 wherein the host exhibits germanotrophic lymphoma.

42. The method of claim 18 wherein the compound administered is a β

-L isomer and is at least 95% pure.

43. The method of claim 18 wherein the compound administered is a β

-D isomer and is at least 95% pure.

44. The method of claim 18 wherein the host is a human.

72. The pharmaceutical composition of claim 30 wherein the host exhibits acute mononucleosis.

45. A method for treating a host with abnormal cellular proliferation or a cellular dysfunction, wherein the cell does not carry the EBV or KHSV genome, comprising

(i) administering the EBV-TK or KHSV-TK gene to the cell or surrounding cells in a manner that allows the enzyme to be expressed in the cell, and then

(ii) administering an effective amount of a compound of the general formula (I), (II) or (III):

or a pharmaceutically acceptable salt or prodrug thereof, wherein

i) X is O, S, NR⁴, CH₂, CHF or CF₂;

ii) R¹ is chosen from hydrogen, halogen (Cl, Br, I, F), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF₃, N₃, NO₂, aryl, heteroaryl, heteroaryl, acyl or COR⁵ where R⁵ is chosen from one of H, OH, SH, alkyl, aminoalkyl, alkoxy, or thioalkyl;

iii) R² and R^2′

are independently H, carbonyl substituted with a alkyl, alkenyl, alkynyl, aryl;

benzyl, wherein the phenyl group is optionally substituted with one or more substituents;

phosphate, phosphate ester, sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl;

a lipid including a phospholipid;

amino acid;

peptide;

cholesterol, or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein one or both of R² and R^2′

is H;

iv) R³ is chosen from H, OH, halogen (F, Cl, Br, I), protected hydroxyl group or CH₂OR⁴;

v) R⁴ is independently H, acyl, alkyl, alkenyl, alkynyl or cycloalkyl;

vi) Y is chosen from H, OH, halogen (F, Cl, Br, I), N₃, CN, or OR²; and

vii) Z is O or S.

46. The method of claim 45 wherein the compound is 2′

-deoxy-5-vinyluridine.

47. The method of claim 45 wherein the compound is 5-vinyluridine.

48. The method of claim 45 wherein the compound is 2′

-deoxy-5-iodouridine.

49. The method of claim 45 wherein the compound is 2′

-deoxy-5-(hydroxymethyl)uridine.

50. The method of claim 45 wherein the compound is 5-butyl-2′

-deoxyuridine.

51. The method of claim 45 wherein the compound is 5-E-(2-carboxyvinyl)-2′

-deoxyuridine.

52. The method of claim 45 wherein the compound is (2S,4S)-5-(2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

53. The method of claim 45 wherein the compound is (2S,4S)-5-(5-bromo-2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

54. The method of claim 45 wherein the compound is (2S,4S)-5-(2-thienyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

55. The method of claim 45 wherein the compound is (2S,4S)-5-(5-bromthien-2-yl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

56. The method of claim 45 wherein the compound is and (2S,4S)-5-(3-hydroxypropenyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

57. The method of claim 45 wherein the compound administered is a β

-L isomer and is at least 95% pure.

58. The method of claim 45 wherein the compound administered is a β

-D isomer and is at least 95% pure.

59. The method of claim 45 wherein the host is a human.

73. The pharmaceutical composition of claim 52 wherein the compound administered is a β

-L isomer and is at least 95% pure.

74. The pharmaceutical composition of claim 52 wherein the compound administered is a β

-D isomer and is at least 95% pure.

60. A pharmaceutical composition comprising an effective amount to treat a cell carrying the Epstein-Barr virus or KHSV of a compound of the formula:

61. The pharmaceutical composition of claim 60 wherein the compound is 2′

-deoxy-5-vinyluridine.

62. The pharmaceutical composition of claim 60 wherein the compound is 5-vinyluridine.

63. The pharmaceutical composition of claim 60 wherein the compound is 2′

-deoxy-5-iodouridine.

64. The pharmaceutical composition of claim 60 wherein the compound is 2′

-deoxy-5-(hydroxymethyl)uridine.

65. The pharmaceutical composition of claim 60 wherein the compound is 5-butyl-2′

-deoxyuridine.

66. The pharmaceutical composition of claim 60 wherein the compound is 5-E-(2-carboxyvinyl)-2′

-deoxyuridine.

67. The pharmaceutical composition of claim 60 wherein the compound is (2S,4S)-5-(2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

68. The pharmaceutical composition of claim 60 wherein the compound is (2S,4S)-5-(5-bromo-2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

69. The pharmaceutical composition of claim-60 wherein the compound is (2S,4S)-5-(2-thienyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

70. The pharmaceutical composition of claim 60 wherein the compound is (2S,4S)-5-(5-bromthien-2-yl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

71. The pharmaceutical composition of claim 60 wherein the compound is and (2S,4S)-5-(3-hydroxypropenyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

75. An immortalized human embryonic kidney cell transfected with the EBV-TK or KHSV-TK gene.

76. The cell of claim 75 that is a 293 cell.

77. The cell of claim 75 transfected with EBV-TK.

78. The cell of claim 75 transfected with KHSV-TK.

79. A method for treating a host with abnormal cellular proliferation or a cellular dysfunction, wherein the cell does not carry the EBV or KHSV genome, comprising

(i) administering a cell that carries and expresses the EBV-TK or KHSV-TK gene to a location that will enable a bystander effect on the abnormal cell, and then

(ii) administering an effective amount of a compound of the general formula (I), (II) or (III).

80. A method for treating a host with abnormal cellular proliferation or a cellular dysfunction, wherein the cell carries the Epstein-Barr virus or KHSV genome, comprising administering an effective amount of a compound of the general formula (I), (II) or (III):