N4-acylcytosine-1,3-dioxolane nucleosides for treatment of viral infections

• US 6,908,924 B2
• Filed: 12/16/2002
• Issued: 06/21/2005
• Est. Priority Date: 12/14/2001
• Status: Expired

• Current Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Original Assignee: Pharmasset Incorporated (Gilead Sciences Inc.)
• Inventors: Otto, Michael J., Watanabe, Kyoichi A., Shi, Junxing
• Primary Examiner(s): McKenzie, Thomas C.
• Application Number:
  US10/320,350
• Publication Number:
  US 20030176319A1
• Time in Patent Office: 918 Days
• Field of Search: 544/243, 544/320, 544/321, 514/272
• US Class Current: 514/272
• 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 compound, 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 N⁴-acylcytosine-1,3-dioxolane and pharmaceutically acceptable salts, prodrugs, and other derivatives thereof.

Claims

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

i) R¹ is chosen from hydrogen and halogen;

ii) 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;

iii) R³ is chosen from halogen, CN, CF₃, N₃, NO₂, alkyl, alkenyl, and alkynyl;

iv) R^3′

is chosen from H, halogen methyl or ethyl; and

v) R⁴ is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol.

2. The compound of claim 1 wherein R¹ is fluorine.

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

is H.

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

4. A compound selected from the group consisting of β

-D-N⁴-p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane, β

-D-N⁴-p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane, β

-D-N⁴-p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane, β

-D-N⁴-p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane, β

-D-N⁴-p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane, β

-D-N⁴-p-t-butylbenzoyl-5-fluoro-cytidine-1,3-dioxolane.

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

β

-D-5-fluoro-N⁴-(4-iodobenzoyl)cytidine-1,3-dioxolane of the structure;

β

-D-5-fluoro-N⁴-(4-fluorobenzoyl)cytidine-1,3-dioxolane of the structure;

β

-D-N⁴-(4-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;

β

-D-N⁴-(4-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;

β

-D-5-fluoro-N⁴-(3-fluorobenzoyl)cytidine-1,3-dioxolane of the structure;

β

-D-N⁴-(3-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;

β

-D-N⁴-(3-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;

β

-D-5-fluoro-N⁴-(4-nitrobenzoyl)cytidine-1,3-dioxolane of the structure;

β

-D-5-fluoro-N⁴-p-toluoylcytidine-1,3-dioxolane of the structure;

β

-D-5-fluoro-N⁴-(m-toluoyl)cytidine-1,3-dioxolane of the structure;

β

-D-N⁴-(4-ethylbenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;

β

-D-5-fluoro-N⁴-(4-propylbenzoyl)cytidine-1,3-dioxolane of the structure;

β

-D-N⁴-(4-tert-butylbenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;

β

-D-5-fluoro-N⁴-(2-thiophenecarbonyl)cytidine-1,3-dioxolane of the structure;

β

-D-N⁴-(benzo-[b]-thiophene-2-carbonyl)-5-fluorocytidine-1,3-dioxolane of the structure;

and β

-D-N⁴-(cyclohexane-carbonyl)-5-fluorocytidine-1,3-dioxolane of the structure;

6. The compound of claim 5 wherein the compound is:

β

-D-5-fluoro-N⁴-(iodobenzoyl)cytidine-1,3-dioxolane of the structure;

7. The compound of claim 5 wherein the compound is:

β

-D-5-fluoro-N⁴-(4-fluorobenzoyl)cytidine-1,3-dioxolane of the structure;

8. The compound of claim 5 wherein the compound is:

β

-D-N⁴-(4-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;

9. The compound of claim 5 wherein the compound is:

β

-D-N⁴-(4-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;

10. The compound of claim 5 wherein the compound is:

β

-D-5-fluoro-N⁴-(3-fluorobenzoyl)cytidine-1,3-dioxolane of the structure;

11. The compound of claim 5 wherein the compound is:

β

-D-N⁴-(3-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;

12. The compound of claim 5 wherein the compound is:

β

-D-N⁴-(3-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;

13. The compound of claim 5 wherein the compound is:

β

-D-5-fluoro-N⁴-(4-nitrobenzoyl)cytidine-1,3-dioxolane of the structure;

14. The compound of claim 5 wherein the compound is:

β

-D-5-fluoro-N⁴-p-toluoylcytidine-1,3-dioxolane of the structure;

15. The compound of claim 5 wherein the compound is:

β

-D-5-fluoro-N⁴-(m-toluoyl)cytidine-1,3-dioxolane of the structure;

16. The compound of claim 5 wherein the compound is:

β

-D-N⁴-(4-ethylbenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;

17. The compound of claim 5 wherein the compound is:

β

-D-5-fluoro-N⁴-(4-propylbenzoyl)cytidine-1,3-dioxolane of the structure;

18. The compound of claim 5 wherein the compound is:

β

-D-N⁴-(4-tert-butylbenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure;

19. The compound of claim 5 wherein the compound is:

β

-D-N⁴-(cyclohexane-carbonyl)-5-fluorocytidine-1,3-dioxolane of the structure;

20. The compound of claim 5 wherein the compound is:

β

-D-5-fluoro-N⁴-(2-thiophenecarbonyl)cytidine-1,3-dioxolane of the structure;

21. The compound of claim 5 wherein the compound is;

β

-D-N⁴-(benzo-[b]-thiophene-2-carbonyl)-5-fluorocytidine-1,3-dioxolane of the structure;

31. A method for the treatment of a host infected with HBV that includes administering an effective amount of a compound of one of claim 5 or 6-21 in a pharmaceutically acceptable carrier.

32. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of one of claim 5 or 6-21 in a pharmaceutically acceptable carrier.

33. A method for the treatment of a host infected wit HIV that includes administering an effective amount of a compound of one of claim 5 or 6-21 in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.

34. A method forte treatment of a host infected with HBV that includes administrating an effective amount of a compound of one of claim 5 or 6-21 in a pharmaceutically acceptable carrier in combination with another anti-HBV agent.

23. A pharmaceutical composition that includes an effective HIV or HBV treatment amount of a compound selected from the group consisting of β

-D-N⁴-p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane, β

-D-N⁴-p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane, β

-D-N⁴-p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane, β

-D-N⁴-p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane, β

-D-N⁴-p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane, β

-D-N⁴-p-t-butylbenzoyl-5-fluoro-cytidine-1,3-dioxolane.

24. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

iv) R¹ is chosen from hydrogen and halogen;

v) 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;

vi) R³ is chosen from H, halogen, CN, CF₃, N₃, NO₂, alkyl, alkenyl, and alkynyl;

vii) R^3′

is chosen from H, halogen methyl or ethyl; and

viii) R⁴ is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol,

in a pharmaceutically acceptable carrier.

28. The method of claims 24, 25, 26 or 27 wherein R¹ is fluorine.

29. The method of claims 24, 25, 26, or 27 wherein R³ is fluorine and R^3′

is H.

25. A method for the treatment of a host infected with HBV that includes administering an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

ix) R¹ is chosen from hydrogen and halogen;

x) 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;

xi) R³ is chosen from H, halogen, CN, CF₃, N₃, NO₂, alkyl, alkenyl, and alkynyl;

xii) R^3′

is chosen from H, halogen methyl or ethyl; and

xiii) R⁴ is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol,

in a pharmaceutically acceptable carrier.

26. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

xiv) R¹ is chosen from hydrogen and halogen;

xv) 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;

xvi) R³ is chosen from H, halogen, CN, CF₃, N₃, NO₂, alkyl, alkenyl, and alkynyl;

xvii) R^3′

is chosen from H, halogen, methyl or ethyl; and

xviii) R⁴ is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol,

in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.

27. A method for the treatment of a host infected with HBV that includes administering an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

xix) R¹ is chosen from hydrogen and halogen;

xx) 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;

xxi) R³ is chosen from H, halogen, CN, CF₃, N₃, NO₂, alkyl, alkenyl, and alkynyl;

xxii) R^3′

is chosen from H, halogen methyl or ethyl; and

xxiii) R⁴ is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol,

in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.

30. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound selected from the group consisting of β

-D-N⁴-p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane, β

-D-N⁴-p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane, β

-D-N⁴-p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane, β

-D-N⁴-p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane, β

-D-N⁴-p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane, β

-D-N⁴-p-t-butylbenzoyl-5-fluoro-cytidine-1,3-dioxolane.