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

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

i) R 1 is chosen from hydrogen and halogen;

ii) R 2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C 6 H 4 R 6 where R 6 is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;

iii) R 3 is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;

iv) R 3′ is chosen from H, halogen, methyl, or ethyl; and

v) R 4 is chosen from 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 R 1 is fluorine.

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

4. A compound selected from the group consisting of β-D-N 4 -p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane, β-D-N 4 -p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane, and β-D-N 4 -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-N 4 -(4-iodobenzoyl)cytidine-1,3-dioxolane of the structure:

β-D-5-fluoro-N 4 -(4-fluorobenzoyl)cytidine-1,3-dioxolane of the structure:

β-D-N 4 -(4-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure:

β-D-N 4 -(4-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure:

β-D-5-fluoro-N 4 -(3-fluorobenzoyl)cytidine-1,3-dioxolane of the structure:

β-D-N 4 -(3-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure:

β-D-N 4 -(3-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure:

β-D-5-fluoro-N 4 -(4-nitrobenzoyl)cytidine-1,3-dioxolane of the structure:

β-D-5-fluoro-N 4 -p-toluoylcytidine-1,3-dioxolane of the structure:

β-D-5-fluoro-N 4 -(m-toluoyl)cylidine-1,3-dioxolane of the structure:

β-D-N 4 -(4-ethylbenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure:

β-D-5-fluoro-N 4 -(4-propylbenzoyl)cytidine-1,3-dioxolane of the structure:

β-D-N 4 -(4-tert-butylbenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure:

β-D-5-fluoro-N 4 -(2-thiophenecarbonyl)cytidine-1,3-dioxolane of the structure:

β-D-N 4 -(benzo-[b]-thiophene-2-carbonyl)-5-fluorocytidine-1,3-dioxolane of the structure:

and β-D-N 4 -(cyclohexane-carbonyl)-5-fluorocytidine-1,3-dioxolane of the structure:

6. The compound of claim 5 wherein the compound is: β-D-5-fluoro-N 4 -(iodobenzoyl)cytidine-1,3-dioxolane of the structure:

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

β-D-5-fluoro-N 4 -(4-fluorobenzoyl)cytidine-1,3-dioxolane of the structure:

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

β-D-N 4 -(4-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure:

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

β-D-N 4 -(4-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure:

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

β-D-5-fluoro-N 4 -(3-fluorobenzoyl)cytidine-1,3-dioxolane of the structure:

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

β-D-N 4 -(3-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure:

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

β-D-N 4 -(3-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure:

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

β-D-5-fluoro-N 4 -(4-nitrobenzoyl)cytidine-1,3-dioxolane of the structure:

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

β-D-5-fluoro-N 4 -p-toluoylcytidine-1,3-dioxolane of the structure:

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

β-D-5-fluoro-N 4 -(m-toluoyl)cytidine-1,3-dioxolane of the structure:

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

β-D-N 4 -(4-ethylbenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure:

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

β-D-5-fluoro-N 4 -(4-propylbenzoyl)cytidine-1,3-dioxolane of the structure:

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

β-D-N 4 -(4-tert-butylbenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure:

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

β-D-N 4 -(cyclohexane-carbonyl)-5-fluorocytidine-1,3-dioxolane of the structure:

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

β-D-5-fluoro-N 4 -(2-thiophenecarbonyl)cytidine-1,3-dioxolane of the structure:

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

β-D-N 4 -(benzo-[b]-thiophene-2-carbonyl)-5-fluorocytidine-1,3-dioxolane of the structure:

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.

23. A pharmaceutical composition that includes an effective HIV or HBV treatment amount of a compound selected from the group consisting of β-D-N 4 -p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane, β-D-N 4 -p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane, and β-D-N 4 -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) R 1 is chosen from hydrogen and halogen;

v) R 2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C 6 H 4 R 6 where R 6 is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;

vi) R 3 is chosen from H, halogen, CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;

vii) R 3′ is chosen from H, halogen, methyl, or ethyl; and

viii) R 4 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.

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) R 1 is chosen from hydrogen and halogen;

x) R 2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C 6 H 4 R 6 where R 6 is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;

xi) R 3 is chosen from H, halogen, CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;

xii) R 3′ is chosen from H, halogen, methyl, or ethyl; and

xiii) R 4 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) R 1 is chosen from hydrogen and halogen;

xv) R 2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C 6 H 4 R 6 where R 6 is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;

xvi) R 3 is chosen from H, halogen, CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;

xvii) R 3′ is chosen from H, halogen, methyl, or ethyl; and

xviii) R 4 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) R 1 is chosen from hydrogen and halogen;

xx) R 2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C 6 H 4 R 6 where R 6 is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;

xxi) R 3 is chosen from H, halogen, CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;

xxii) R 3′ is chosen from H, halogen, methyl, or ethyl; and

xxiii) R 4 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 anti- HBV agent.

28. The method of claims 24 , 25 , 26 or 27 wherein R 1 is fluorine.

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

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-N 4 -p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane, β-D-N 4 -p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane, and β-D-N 4 -p-t-butylbenzoyl-5-fluoro-cytidine-1,3-dioxolane.

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 according to any one of claims 5 - 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 according to any one of claims 5 - 21 in a pharmaceutically acceptable carrier.

33. 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 according to any one of claims 5 - 21 in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.

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

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

or a pharmaceutically acceptable salt thereof, wherein

i ) R 1 is hydrogen;

ii ) R 2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C 6 H 4 R 6 where R 6 is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;

iii ) R 3 is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;

iv ) R 3′ is chosen from H, halogen, methyl, or ethyl; and

v ) R 4 is chosen from H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol.

36. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound in a pharmaceutically acceptable carrier in combination with another anti- HBV agent, wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof, wherein

i ) R 1 is hydrogen;

ii ) R 2 is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C 6 H 4 R 6 where R 6 is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;

iii ) R 3 is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;

iv ) R 3′ is chosen from H, halogen, methyl, or ethyl; and

v ) R 4 is chosen from H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol.

37. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

i ) R 1 is hydrogen;

ii ) R 2 is chosen from alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C 6 H 4 R 6 where R 6 is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;

iii ) R 3 is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;

iv ) R 3′ is chosen from H, halogen, methyl, or ethyl; and

v ) R 4 is chosen from H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol.

38. The compound of claim 37 wherein R 2 is C 6 H 4 R 6 where R 6 is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl.

39. A pharmaceutical composition that comprises an effective HIV or HBV treatment amount of a compound of claim 37 in a pharmaceutically acceptable carrier or diluent.

40. A method for the treatment of a host infected with HIV that comprises administering an effective amount of a compound of claim 37 .

41. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound of claim 37 .

42. A method for the treatment of a host infected with HIV that comprises administering an effective amount of a compound of claim 37 in a pharmaceutically acceptable carrier in combination with another anti- HIV agent.

43. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound of claim 37 in a pharmaceutically acceptable carrier in combination with another anti- HBV agent.