β-L-2'-deoxy-nucleosides for the treatment of HIV infection
Compounds and pharmaceutical compositions active against HIV are provided, as is a method for the treatment of HIV infection in humans and other host animals is provided comprising administering an effective amount of a β-L-(2′ or 3′-azido)-2′,3′-dideoxy-5-fluorocytosine of the formula wherein R is H, acyl, monophosphate, diphosphate, or triphosphate, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug), and R′ is H, acyl, or alkyl.
1. A method for the treatment of HIV infection in a host comprising administering an effective amount of a β-L-(2′-azido)-2′,3′-dideoxy-5-fluorocytidine compound or a pharmaceutically acceptable ester, salt or prodrug thereof of the formula:
wherein R is H, acyl, monophosphate, diphosphate, or triphosphate, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug), and R′ is H, acyl, or alkyl; in a pharmaceutically acceptable carrier.
2. The method of claim 1 , wherein R is H.
3. The method of claim 1 , wherein R is acyl.
4. The method of claim 1 , wherein R is monophosphate.
5. The method of claim 1 , wherein R is diphosphate.
6. The method of claim 1 , wherein R is triphosphate.
7. The method of claim 1 , wherein R is a stabilized phosphate derivative.
8. A method for the treatment of HIV infection in a host comprising administering an effective amount of a β-L-(3′-azido)-2′,3′-dideoxy-5-fluorocytidine compound or a pharmaceutically acceptable ester, salt or prodrug thereof of the formula:
wherein R is H, acyl, monophosphate, diphosphate, or triphosphate, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug), R′ is H, acyl, or alkyl; in a pharmaceutically acceptable carrier.
9. The method of claim 8 , wherein R is H.
10. The method of claim 8 , wherein R is acyl.
11. The method of claim 8 , wherein R is monophosphate.
12. The method of claim 8 , wherein R is diphosphate.
13. The method of claim 8 , wherein R is triphosphate.
14. The method of claim 8 , wherein R is a stabilized phosphate derivative.
15. The method of any one of claims 1 - 14 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.
16. The method of any one of claims 1 - 14 , wherein the pharmaceutically acceptable carrier is suitable for intravenous delivery.
17. The method of any one of claims 1 - 14 , wherein the pharmaceutically acceptable carrier is suitable for parenteral delivery.
18. The method of any one of claims 1 - 14 , wherein the pharmaceutically acceptable carrier is suitable for intradermal delivery.
19. The method of any one of claims 1 - 14 , wherein the pharmaceutically acceptable carrier is suitable for subcutaneous delivery.
20. The method of any one of claims 1 - 14 , wherein the pharmaceutically acceptable carrier is suitable for topical delivery.
21. The method of any one of claims 1 - 14 , wherein the compound is in the form of a dosage unit.
22. The method of claim 21 , wherein the dosage unit is a tablet or capsule.
23. The method of claim 21 , wherein the dosage unit contains 10 to 1500 mg of the compound.
24. The method of claim 23 , wherein the dosage unit is a tablet or capsule.
25. A method for the treatment of HIV infection in a host comprising administering an effective amount of a β-L-(2′-azido)-2′,3′-dideoxy-5-fluorocytidine compound or a pharmaceutically acceptable ester, salt or prodrug thereof of the formula:
wherein R is H, acyl, monophosphate, diphosphate, or triphosphate, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug), and R′ is H, acyl, or alkyl; in combination or alternation with another effective anti-HIV agent, optionally in a pharmaceutically acceptable carrier.
26. The method of claim 25 , wherein R is H.
27. The method of claim 25 , wherein R is acyl.
28. The method of claim 25 , wherein R is monophosphate.
29. The method of claim 25 , wherein R is diphosphate.
30. The method of claim 25 , wherein R is triphosphate.
31. The method of claim 25 , wherein R is a stabilized phosphate derivative.
32. A method for the treatment of HIV infection in a host comprising administering an effective amount of a β-L-(3′-azido)-2′,3′-dideoxy-5-fluorocytidine compound or a pharmaceutically acceptable ester, salt or prodrug thereof of the formula:
wherein R is H, acyl, monophosphate, diphosphate, or triphosphate, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug), R′ is H, acyl, or alkyl; in combination or alternation with another effective anti-HIV agent.
33. The method of claim 32 , wherein R is H.
34. The method of claim 32 , wherein R is acyl.
35. The method of claim 32 , wherein R is monophosphate.
36. The method of claim 32 , wherein R is diphosphate.
37. The method of claim 32 , wherein R is triphosphate.
38. The method of claim 32 , wherein R is a stabilized phosphate derivative.
39. The method of any one of claims 25 - 38 wherein the other anti-HIV agent is selected from the group consisting of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC); carbovir, acyclovir, interferon, AZT, DDI, DDC, D4T, CS-92 (3′-azido-2′,3′-dideoxy-5 -methyl-cytidine), β-D-dioxolanyl-guanine (DXG), β-D-dioxolanyl-2,6-diaminopurine (DAPD), β-D-dioxolanyl-6-chloropurine (ACP), MKC-442 (6-benzyl-1-(ethoxymethyl)-5-isopropyl uracil; crixovan, nelfinavir, ritonavir, saquinavir and DMP-450.
40. The method of claim 39 wherein the other anti-HIV agent is 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC).
41. The method of claim 39 wherein the other anti-HIV agent is AZT.
42. The method of claim 39 wherein the other anti-HIV agent is β-D-dioxolanyl-guanine (DXG).
43. The method of claim 39 wherein the other anti-HIV agent is β-D-dioxolanyl-2,6-diaminopurine (DAPD).
44. The method of claim 39 wherein the other anti-HIV agent is ritonavir.
45. The method of claim 39 wherein the other anti-HIV agent is saquinavir.
46. The method of any one of claims 25 - 32 , further comprising a pharmaceutically acceptable carrier.
47. The method of claim 46 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.
48. The method of claim 46 , wherein the pharmaceutically acceptable carrier is suitable for intravenous delivery.
49. The method of claim 46 , wherein the pharmaceutically acceptable carrier is suitable for parenteral delivery.
50. The method of claim 46 , wherein the pharmaceutically acceptable carrier is suitable for intradermal delivery.
51. The method of claim 46 , wherein the pharmaceutically acceptable carrier is suitable for subcutaneous delivery.
52. The method of claim 46 , wherein the pharmaceutically acceptable carrier is suitable for topical delivery.
53. The method of claim 46 , wherein the compound is in the form of a dosage unit.
54. The method of claim 53 , wherein the dosage unit is a tablet or capsule.
55. The method of claim 53 , wherein the dosage unit contains 10 to 1500 mg of the compound.
56. The method of claim 55 , wherein the dosage unit is a tablet or capsule.
57. A method for the treatment of HIV infection in a human comprising administering an effective amount of a β-L-(2′-azido)-2′,3′-dideoxy-5-fluorocytidine compound or a pharmaceutically acceptable ester, salt or prodrug thereof of the formula:
wherein R is H, acyl, monophosphate, diphosphate, or triphosphate, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug), and R′ is H, acyl, or alkyl.
58. The method of claim 57 , wherein R is H.
59. The method of claim 57 , wherein R is acyl.
60. The method of claim 57 , wherein R is monophosphate.
61. The method of claim 57 , wherein R is diphosphate.
62. The method of claim 57 , wherein R is triphosphate.
63. The method of claim 57 , wherein R is a stabilized phosphate derivative.
64. A method for the treatment of HIV infection in a human comprising administering an effective amount of a β-L-(3′-azido)-2′,3′-dideoxy-5-fluorocytidine compound or a pharmaceutically acceptable ester, salt or prodrug thereof of the formula:
wherein R is H, acyl, monophosphate, diphosphate, or triphosphate, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug), R′ is H, acyl, or alkyl.
65. The method of claim 64 , wherein R is H.
66. The method of claim 64 , wherein R is acyl.
67. The method of claim 64 , wherein R is monophosphate.
68. The method of claim 64 , wherein R is diphosphate.
69. The method of claim 64 , wherein R is triphosphate.
70. The method of claim 64 , wherein R is a stabilized phosphate derivative.
71. The method of any one of claims 57 - 70 , further comprising a pharmaceutically acceptable carrier.
72. The method of claim 71 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.
73. The method of claim 71 , wherein the pharmaceutically acceptable carrier is suitable for intravenous delivery.
74. The method of claim 71 , wherein the pharmaceutically acceptable carrier is suitable for parenteral delivery.
75. The method of claim 71 , wherein the pharmaceutically acceptable carrier is suitable for intradermal delivery.
76. The method of claim 71 , wherein the pharmaceutically acceptable carrier is suitable for subcutaneous delivery.
77. The method of claim 71 , wherein the pharmaceutically acceptable carrier is suitable for topical delivery.
78. The method of claim 71 , wherein the compound is in the form of a dosage unit.
79. The method of claim 78 , wherein the dosage unit is a tablet or capsule.
80. The method of claim 78 , wherein the dosage unit contains 10 to 1500 mg of the compound.
81. The method of claim 80 , wherein the dosage unit is a tablet or capsule.
82. The method of claim 1 , wherein the compound is a pharmaceutically acceptable ester.
83. The method of claim 1 , wherein the compound is a pharmaceutically acceptable salt.
84. The method of claim 1 , wherein the compound is a pharmaceutically acceptable stabilized phosphate derivative to form a stabilized nucleotide prodrug.
85. The method of claim 8 , wherein the compound is a pharmaceutically acceptable ester.
86. The method of claim 8 , wherein the compound is a pharmaceutically acceptable salt.
87. The method of claim 8 , wherein the compound is a pharmaceutically acceptable stabilized phosphate derivative to form a stabilized nucleotide prodrug.
88. The method of claim 25 , wherein the compound is a pharmaceutically acceptable ester.
89. The method of claim 25 , wherein the compound is a pharmaceutically acceptable salt.
90. The method of claim 25 , wherein the compound is a pharmaceutically acceptable stabilized phosphate derivative to form a stabilized nucleotide prodrug.
91. The method of claim 32 , wherein the compound is a pharmaceutically acceptable ester.
92. The method of claim 32 , wherein the compound is a pharmaceutically acceptable salt.
93. The method of claim 32 , wherein the compound is a pharmaceutically acceptable stabilized phosphate derivative to form a stabilized nucleotide prodrug.
94. The method of claim 57 , wherein the compound is a pharmaceutically acceptable ester.
95. The method of claim 57 , wherein the compound is a pharmaceutically acceptable salt.
96. The method of claim 57 , wherein the compound is a pharmaceutically acceptable stabilized phosphate derivative to form a stabilized nucleotide prodrug.
97. The method of claim 64 , wherein the compound is a pharmaceutically acceptable ester.
98. The method of claim 64 , wherein the compound is a pharmaceutically acceptable salt.
99. The method of claim 64 , wherein the compound is a pharmaceutically acceptable stabilized phosphate derivative to form a stabilized nucleotide prodrug.
100. The method of any one of claim 1 , 8 , 25 , 32 , 57 , or 64 , wherein the host is a human.