Methods and compositions for treating hepatitis C virus
A method and composition for treating a host infected with hepatitis C comprising administering an effective hepatitis C treatment amount of a described 1′, 2′ or 3′-modified nucleoside or a pharmaceutically acceptable salt or prodrug thereof, is provided.
1. A method for the treatment of a hepatitis C virus infection in a host, comprising administering to the host an antivirally effective amount of a compound of Formula V:
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or a pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein R 1 is H or phosphate;
R 2 is H;
R 3 is H;
Y is hydrogen, bromo, chloro, fluoro, iodo, OH or NH 2 ; and
X 1 is selected from the group consisting of H and CH 3 .
2. The method of claim 1 , comprising administering the compound or a pharmaceutically acceptable salt thereof in combination or alternation with a second anti-hepatitis C virus agent.
3. The method of claim 2 , wherein the second anti-hepatitis C virus agent is selected from the group consisting of interferon, ribavirin, a protease inhibitor, a thiazolidine derivative, a polymerase inhibitor, and a helicase inhibitor.
4. The method of claim 2 , wherein the second anti-hepatitis C virus agent is a protease inhibitor.
5. The method of claim 2 , wherein the second anti-hepatitis C virus agent is ribavirin.
6. The method of claim 1 , wherein the compound is in the form of a dosage unit.
7. The method of claim 6 , wherein the dosage unit contains from about 50 to about 1000 mg of the compound.
8. The method of claim 6 , wherein the dosage unit is a tablet or capsule.
9. The method of claim 1 , wherein the host is a human.
10. The method of claim 1 , wherein the compound is in substantially pure form.
11. The method of claim 1 , wherein the compound is at least 90% by weight of the β-D-isomer.
12. The method of claim 1 , wherein the compound is at least 95% by weight of the β-D-isomer.
13. The method of claim 1 , wherein:
R 1 is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, lower acyl, or a pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein R 1 is H or phosphate.
14. The method of claim 1 , wherein R 1 is monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug.
15. The method of claim 1 , wherein said host is a human.
16. The method of claim 15 , wherein X 1 is H, and Y is either OH or NH 2 .
17. The method of claim 16 , wherein Y is OH.
18. The method of claim 17 , wherein R 1 is a stabilized phosphate prodrug.
19. The method of claim 17 , wherein R 1 is a pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein R 1 is phosphate.
20. The method of claim 17 , wherein R 1 is a triphosphate.
21. A method for inhibiting the replication of a hepatitis C virus in a host, comprising contacting the host with an antivirally effective amount of a compound of Formula X:
or a pharmaceutically acceptable salt thereof;
wherein:
Base is a pyrimidine base;
R 1 is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or a pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein R 1 is H or phosphate;
R 2 is H;
R 3 is H;
R 6 alkyl; and
X is O.
22. The method of claim 21 , wherein the host is a cell.
23. The method of claim 21 , wherein R 6 is methyl.
24. The method of claim 21 , wherein:
R 1 is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, lower acyl, or a pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein R 1 is H or phosphate.
25. The method of claim 21 , wherein R 1 is monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug.
26. The method of claim 21 , wherein R 1 is monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, or a pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein R 1 is phosphate.
27. The method of claim 26 , wherein said host is a human.
28. The method of claim 27 , wherein R 6 is methyl.
29. The method of claim 28 , wherein said pyrimidine base is either uracil or cytosine.
30. The method of claim 29 , wherein said pyrimidine base is uracil.
31. The method of claim 30 , wherein R 1 is a stabilized phosphate prodrug.
32. The method of claim 30 , wherein R 1 is a pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein R 1 is phosphate.
33. The method of claim 29 , wherein R 1 is a triphosphate.