N4-ACYLCYTOSINE NUCLEOSIDES FOR TREATMENT OF VIRAL INFECTIONS

• US 20090176730A1
• Filed: 01/04/2008
• Published: 07/09/2009
• Est. Priority Date: 12/14/2001
• Status: Active Grant

• Current Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Original Assignee: Pharmasset Incorporated (Gilead Sciences Inc.)
• Inventors: Otto, Michael J., Watanabe, Kyoichi A., Shi, Junxing
• Granted Patent: US 8,114,997 B2
• Time in Patent Office: Days
• US Class Current: 514/49
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals

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.sup.4-acyl-2′,3′-dideoxy-5-fluorocytidine or N.sup.4-acyl-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine, and pharmaceutically acceptable salts, prodrugs, and other derivatives thereof.

Claims

1. A compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein

X is O, S, NR⁵, CH₂, CHF or CF₂;

R¹ is chosen from hydrogen, halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF₃, N₃, NO₂, aryl, heteroaryl and acyl;

R² is chosen from alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C₆H₄R⁶ where R⁶ is chosen from halogen, CN, CF₃, N₃, NO₂, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;

R³ and R^3′

are chosen independently from H, halogen, CN, CF₃, N₃, NO₂, alkyl, alkenyl, and alkynyl; and

R⁴ 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 R³ and R^3′

are H or phosphate, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol.

R⁵ is H, acyl, alkyl, alkenyl, alkynyl, or cycloalkyl.

2. A pharmaceutical composition that comprises an effective HIV or HBV 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-HBV agent.

7. The compound of claim 1 wherein R¹ is hydrogen or fluorine.

8. The compound of claim 1 wherein R³ is H or fluorine and R^3′

is H.

9. The method of claim 3, wherein R¹ is hydrogen or fluorine.

10. The method of claim 3, wherein R³ is H or fluorine and R^3′

is H.

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

β -D-N⁴-p-bromobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-fluorobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-chlorobenzoyl-2′

,3′

-didehydro-2′

3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-iodobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-ethylbenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine, and

β

-D-N⁴-p-t-butylbenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine.

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

β

-D-N⁴-p-bromobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-fluorobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-chlorobenzoyl-2′

,3′

-didehydro-2′

3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-iodobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-ethylbenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine, and

β

-D-N⁴-p-t-butylbenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine.

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

β

-D-N⁴-p-bromobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-fluorobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-chlorobenzoyl-2′

,3′

-didehydro-2′

3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-iodobenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine,

β

-D-N⁴-p-ethylbenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine, and

β

-D-N⁴-p-t-butylbenzoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine.

18. The method of claim 4 wherein R¹ is hydrogen or fluorine.

19. The method of claim 4 wherein R³ is H or fluorine and R^3′

is H.

11. (canceled)

13. (canceled)

15. (canceled)

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

β

-D-2′

,3′

-dideoxy-5-fluoro-N⁴-(4-iodobenzoyl)cytidine of the structure;

β

-D-2′

,3′

-dideoxy-5-fluoro-N⁴-(4-fluorobenzoyl)cytidine of the structure;

β

-D-N⁴-(4-chlorobenzoyl)-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-N⁴-(4-bromobenzoyl)-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-2′

,3′

-dideoxy-5-fluoro-N⁴-(3-fluorobenzoyl)cytidine of the structure;

β

-D-N⁴-(3-chlorobenzoyl)-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-N⁴-(3-bromobenzoyl)-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-2′

,3′

-dideoxy-5-fluoro-N⁴-(4-nitrobenzoyl)cytidine of the structure;

β

-D-2′

,3′

-dideoxy-5-fluoro-N⁴-p-toluoylcytidine of the structure;

β

-D-2′

,3′

-dideoxy-5-fluoro-N⁴-(m-toluoyl)cytidine of the structure;

β

-D-2′

,3′

-dideoxy-N⁴-(4-ethylbenzoyl)-5-fluorocytidine of the structure;

β

-D-2′

,3′

-dideoxy-5-fluoro-N⁴-(4-propylbenzoyl)cytidine of the structure;

β

-D-N⁴-(4-tert-butylbenzoyl)-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-2′

,3′

-dideoxy-5-fluoro-N⁴-(2-thiophenecarbonyl)cytidine of the structure;

β

-D-N⁴-(benzo-[b]-thiophene-2-carbonyl)-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-N⁴-(cyclohexane-carbonyl)-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluoro-N⁴-(4-iodobenzoyl)cytidine of the structure;

β

-D-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluoro-N⁴-(4-fluorobenzoyl)cytidine of the structure;

β

-D-N⁴-(4-chlorobenzoyl)-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-N⁴-(4-bromobenzoyl)-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-N⁴-p-anisoyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

β

-D-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluoro-N⁴-(3-nitrobenzoyl)cytidine of the structure;

β

-D-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluoro-N⁴-p-toluoylcytidine of the structure;

β

-D-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluoro-N⁴-m-toluoylcytidine of the structure;

β

-D-N⁴-(4-t-butylbenzoyl)-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

or a pharmaceutically acceptable salt thereof.

β

-D-N⁴-cyclopentanecarbonyl-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

or a pharmaceutically acceptable salt thereof.

β

-D-N⁴-(cyclohexanecarbonyl)-2′

,3′

-didehydro-2′

,3′

-dideoxy-5-fluorocytidine of the structure;

20. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

i) X is O, S, NR⁵, CH₂, CHF or CF₂;

ii) Y is CH₂, CHF or CF₂;

iii) R¹ is chosen from hydrogen, halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF₃, N₃, NO₂, aryl, heteroaryl and acyl;

iv) R² is chosen from alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C₆H₄R⁶ where R⁶ is chosen from halogen, CN, CF₃, N₃, NO₂, alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;

v) R³ and R^3′

are chosen independently from H, halogen, CN, CF₃, N₃, NO₂, alkyl, alkenyl, and alkynyl; and

vi) R⁴ 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 R³ and R^3′

are H or phosphate, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol.

vii) R⁵ is H, acyl, alkyl, alkenyl, alkynyl, or cycloalkyl.

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

22. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of claim 20 in a pharmaceutically acceptable carrier.

23. A method for the treatment of a host infected with HBV that includes administering an effective amount of a compound of claim 20 in a pharmaceutically acceptable carrier.

24. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of claim 20 in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.

25. A method for the treatment of a host infected with HBV that includes administering an effective amount of a compound of claim 20 in a pharmaceutically acceptable carrier in combination with another anti-HBV agent.

26. A compound of claim 20 for use in the treatment of host infected with HIV.

27. A compound of claim 20 for use in the treatment of a host infected with HBV infection.