IP Library › Granted Patent US 7,105,527

Granted Patent B2

US 7,105,527 · App. 10/318,511 · Granted Sep 12, 2006

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Quick Facts

Patent No.: US 7,105,527
App. No.: 10/318,511
Granted: Sep 12, 2006
Kind: B2

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Abstract

The present invention is directed to a method and composition of treating or preventing viral infections, in particular, human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections, in human patients or other animal hosts, comprising the administration of N 4 -acyl-2′,3′-dideoxy-5-fluorocytidine or N 4 -acyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine, and pharmaceutically acceptable salts, prodrugs, and other derivatives thereof.

Claims (79)

1. A compound of the following formula:

or a pharmaceutically acceptable salt thereof, wherein

i) X is O;

ii) R 1 is fluorine;

iii) R 2 is chosen from C2–C8 alkenyl, C2–C8 alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, heteroaryl, and C 6 H 4 R 6 wherein R 6 is chosen from F, Cl, Br, I, CN, CF 3 , N 3 CH 3 , ethyl, t-butyl, haloalkyl, aminoalkyl, CH 3 O, alkenyl, alkynyl, and aryl;

iv) R 3 and R 3 ′ are chosen independently from hydrogen and halogen;

v) R 4 is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, or other pharmaceutically acceptable leaving group, which, when administered in vivo, is capable of providing a compound wherein R 4 is H or phosphate.

2. A pharmaceutical composition that comprises an effective HIV treatment amount of a compound of claim 1 in a pharmaceutically acceptable carrier or diluent.

3. A method for the treatment of a host infected with HIV that comprises administering an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

4. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

5. A method for the treatment of a host infected with HIV that comprises administering an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.

6. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier in combination with another anti-HIBV agent.

7. The compound of claim 1 wherein R 3 and R 3 ′ are H.

8. The method of one of claims 3 – 6 wherein R 1 is fluorine.

9. The method of one of claims 3 – 6 wherein R 3 and R 3 ′ are H.

10. The compound of claim 1 selected from the group consisting of

β-D-N 4 -p-bromobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,

β-D-N 4 -p-fluorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,

β-D-N 4 -p-chlorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,

β-D-N 4 -p-iodobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,

β-D-N 4 -p-ethylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine, and

β-D-N 4 -p-t-butylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine.

11. The pharmaceutical composition of claim 2 wherein the compound is selected from the group consisting of

β-D-N 4 -p-bromobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,

β-D-N 4 -p-fluorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,

β-D-N 4 -p-chlorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,

β-D-N 4 -p-iodobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,

β-D-N 4 -p-ethylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine, and

β-D-N 4 -p-t-butylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine.

12. The method of claim 3 wherein the compound is selected from the group consisting of

β-D-N 4 -p-bromobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,

β-D-N 4 -p-fluorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,

β-D-N 4 -p-chlorobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,

β-D-N 4 -p-iodobenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine,

β-D-N 4 -p-ethylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine, and

β-D-N 4 -p-t-butylbenzoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine.

13. A compound selected from the following, or its pharmaceutically acceptable salt:

β-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N 4 -(4-iodobenzoyl)cytidine of the structure:

β-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N 4 -(4-fluorobenzoyl)cytidine of the structure:

β-D-N 4 -(4-chlorobenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine of the structure:

β-D-N 4 -(4-bromobenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine of the structure:

β-D-N 4 -p-anisoyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine of the structure:

β-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N 4 -p-toluoylcytidine of the structure:

β-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N 4 -m-toluoylcytidine of the structure:

β-D-N 4 -(4-t-butylbenzoyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine of the structure:

β-D-N 4 -cyclopentanecarbonyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine of the structure:

β-D-N 4 -(cyclohexanecarbonyl)-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine of the structure:

14. A method for the treatment of a host infected with HIV that comprises administering an effective amount of a compound of claim 13 in a pharmaceutically acceptable carrier.

15. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound of claim 13 in a pharmaceutically acceptable carrier.

16. A method for the treatment of a host infected with HTV that comprises administering an effective amount of a compound of claim 13 in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.

17. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound of claim 13 in a pharmaceutically acceptable carrier in combination with another anti-HBV agent.

18. The compound of claim 1 wherein R 2 is cycloalkyl.

19. The compound of claim 1 wherein R 2 is C 6 H 4 R 6 .

20. A pharmaceutical composition that comprises an effective HBV treatment amount of a compound of claim 1 in a pharmaceutically acceptable carrier or diluent.

21. A pharmaceutical composition that comprises an effective HIV treatment amount of a compound of claim 13 in a pharmaceutically acceptable carrier or diluent.

22. A pharmaceutical composition that comprises an effective HBV treatment amount of a compound of claim 13 in a pharmaceutically acceptable carrier or diluent.

23. The composition of claim 2 or 21 further comprising another anti-HIV agent.

24. The composition of claim 20 or 22 further comprising another anti-HBV agent.

25. The compound of claim 13 wherein the compound is β-D-2′,3′-didehydro-2′,3′-dideoxy-5-fluoro-N 4 -(4-iodobenzoyl)cytidine of the structure: