2-fluoronucleosides
View Patent ↗2′-Fluoro-nucleoside compounds are disclosed which are useful in the treatment of hepatitis B infection, hepatitis C infection, HIV and abnormal cellular proliferation, including tumors and cancer. The compounds have the general formulae: wherein Base is a purine or pyrimidine base; R 1 is OH, H, OR 3 , N 3 , CN, halogen, CF 3 , lower alkyl, amino, loweralkylamino, di(lower)alkylamino, or alkoxy; R 2 is H, phosphate, or a stabilized phosphate prodrug; acyl, or other pharmaceutically acceptable leaving benzyl, a lipid, an amino acid, peptide, or cholesterol; and R 3 is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group; or a pharmaceutically acceptable salt thereof.
1. A method for the treatment of a HCV infection in a host in need thereof comprising administering an effective treatment amount of a β-D-2′-fluoronucleoside wherein the 2′-fluoro of the β-D-2′-fluoronucleoside is alpha (α), or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier or diluent.
2. The method of claim 1 , wherein the β-D-2′-fluoronucleoside has a pyrimidine base.
3. The method of claim 2 , wherein the pyrimidine base is selected from the group consisting of thymine, uracil, 5-halouracil, 5-fluorouracil, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-aza-pyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrimidine, C 5 -alkylpyrimidine, C 5 -benzylpyrimidine, C 5 -halopyrimidine, C 5 -vinylpyrimidine, C 5 -acetylenic pyrimidine, C 5 -acyl pyrimidine, C 5 -hydroxyalkyl purine, C 5 -amidopyrimidine, C 5 -cyanopyrimidine, C 5 -nitropyrimidine, and C 5 -aminopyrimidine.
4. The method of claim 2 , wherein the pyrimidine base is thymine.
5. The method of claim 2 , wherein the pyrimidine base is uracil.
6. The method of claim 2 , wherein the pyrimidine base is 5-halouracil.
7. The method of claim 2 , wherein the pyrimidine base is cytosine.
8. The method of claim 2 , wherein the pyrimidine base is 5-fluorocytosine.
9. The method of claim 1 , wherein the β-D-2′-fluoronucleoside has a purine base.
10. The method of claim 9 , wherein the purine base is selected from the group consisting of N 6 -alkylpurine, N 6 -acylpurine (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -thioalkyl purine, N 2 -alkylpurines, N 2 -alkyl-6-thiopurines, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, 5-azacytidinyl, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine.
11. The method of claim 1 , wherein the β-D-2′-fluoronucleoside has a triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, or pyrazolopyrimidinyl base.
12. The method of claim 1 , wherein the β-D-2′-fluoronucleoside is in substantially pure form.
13. The method of claim 1 , wherein the β-D-2′-fluoronucleoside is administered in the form of a dosage unit.
14. The method of claim 13 , wherein the dosage unit contains 50-1000 mg of the β-D-2′-fluoronucleoside.
15. The method of claim 13 , wherein the dosage unit is in the form of a tablet or capsule.
16. The method of claim 1 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.
17. The method of claim 5 , wherein the β-D-2′-fluoronucleoside is in substantially pure form.
18. The method of claim 5 , wherein the β-D-2′-fluoronucleoside is administered in the form of a dosage unit.
19. The method of claim 18 , wherein the dosage unit contains 50-1000 mg of the β-D-2′-fluoronucleoside.
20. The method of claim 18 , wherein the dosage unit is in the form of a tablet or capsule.
21. The method of claim 5 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.
22. The method of claim 7 , wherein the β-D-2′-fluoronucleoside is in substantially pure form.
23. The method of claim 7 , wherein the β-D-2′-fluoronucleoside is administered in the form of a dosage unit.
24. The method of claim 23 , wherein the dosage unit contains 50-1000 mg of the β-D-2′-fluoronucleoside.
25. The method of claim 23 , wherein the dosage unit is in the form of a tablet or capsule.
26. The method of claim 7 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.
27. The method of claim 9 , wherein the β-D-2′-fluoronucleoside is in substantially pure form.
28. The method of claim 9 , wherein the β-D-2′-fluoronucleoside is administered in the form of a dosage unit.
29. The method of claim 28 , wherein the dosage unit contains 50-1000 mg of the β-D-2′-fluoronucleoside.
30. The method of claim 28 , wherein the dosage unit is in the form of a tablet or capsule.
31. The method of claim 9 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.
32. A method for the treatment of a HCV infection in a host in need thereof comprising administering an effective treatment amount of a β-D-2′-α-fluoronucleoside, or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier or diluent.
33. The method of claim 32 , wherein the β-D-2′-α-fluoronucleoside has a pyrimidine base.
34. The method of claim 33 , wherein the pyrimidine base is selected from the group consisting of thymine, uracil, 5-halouracil, 5-fluorouracil, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-aza-pyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrimidine, C 5 -alkylpyrimidine, C 5 -benzylpyrimidine, C 5 -halopyrimidine, C 5 -vinylpyrimidine, C 5 -acetylenic pyrimidine, C 5 -acyl pyrimidine, C 5 -hydroxyalkyl purine, C 5 -amidopyrimidine, C 5 -cyanopyrimidine, C 5 -nitropyrimidine, and C 5 -aminopyrimidine.
35. The method of claim 33 , wherein the pyrimidine base is thymine.
36. The method of claim 33 , wherein the pyrimidine base is uracil.
37. The method of claim 33 , wherein the pyrimidine base is 5-halouracil.
38. The method of claim 33 , wherein the pyrimidine base is cytosine.
39. The method of claim 33 , wherein the pyrimidine base is 5-fluorocytosine.
40. The method of claim 32 , wherein the β-D-2′-α-fluoronucleoside has a purine base.
41. The method of claim 40 , wherein the purine base is selected from the group consisting of N 6 -alkylpurine, N 6 -acylpurine (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -thioalkyl purine, N 2 -alkylpurines, N 2 -alkyl-6-thiopurines, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, 5-azacytidinyl, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine.
42. The method of claim 32 , wherein the β-D-2′-α-fluoronucleoside has a triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, or pyrazolopyrimidinyl base.
43. The method of claim 32 , wherein the β-D-2′-α-fluoronucleoside is in substantially pure form.
44. The method of claim 32 , wherein the β-D-2′-α-fluoronucleoside is administered in the form of a dosage unit.
45. The method of claim 44 , wherein the dosage unit contains 50-1000 mg of the β-D-2′-α-fluoronucleoside.
46. The method of claim 44 , wherein the dosage unit is in the form of a tablet or capsule.
47. The method of claim 32 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.
48. The method of claim 36 , wherein the β-D-2′-α-fluoronucleoside is in substantially pure form.
49. The method of claim 36 , wherein the β-D-2′-α-fluoronucleoside is administered in the form of a dosage unit.
50. The method of claim 49 , wherein the dosage unit contains 50-1000 mg of the β-D-2′-α-fluoronucleoside.
51. The method of claim 49 , wherein the dosage unit is in the form of a tablet or capsule.
52. The method of claim 36 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.
53. The method of claim 38 , wherein the β-D-2′-α-fluoronucleoside is in substantially pure form.
54. The method of claim 38 , wherein the β-D-2′-α-fluoronucleoside is administered in the form of a dosage unit.
55. The method of claim 54 , wherein the dosage unit contains 50-1000 mg of the β-D-2′-α-fluoronucleoside.
56. The method of claim 54 , wherein the dosage unit is in the form of a tablet or capsule.
57. The method of claim 38 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.
58. The method of claim 40 , wherein the β-D-2′-α-fluoronucleoside is in substantially pure form.
59. The method of claim 40 , wherein the β-D-2′-α-fluoronucleoside is administered in the form of a dosage unit.
60. The method of claim 59 , wherein the dosage unit contains 50-1000 mg of the β-D-2′-α-fluoronucleoside.
61. The method of claim 59 , wherein the dosage unit is in the form of a tablet or capsule.
62. The method of claim 40 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.