N4-Acylcytosine Nucleosides for Treatment of Viral Infections

1 . A compound of formula (I) or (II):

or a pharmaceutically acceptable salt or prodrug thereof, wherein

i) X is O, S, NR 5 , CH 2 , CHF or CF 2 ;

ii) Y is CH 2 , CHF or CF 2 ;

iii) R 1 is chosen from hydrogen, halogen (F, Cl, Br, I), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF 3 , N 3 , NO 2 , aryl, heteroaryl and acyl;

iv) 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 (F, Cl, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy; thioalkyl, alkenyl, alkynyl, and aryl;

v) R 3 and R 3′ are chosen independently from H, halogen (F, Cl, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;

vi) 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 3 and R 3′ are H or phosphate, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol; and

vii) R 5 is H, acyl, alkyl, alkenyl, alkynyl, or cycloalkyl.

2 . 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.

3 . A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of claim 1 or 17 in a pharmaceutically acceptable carrier.

4 . A method for the treatment of a host infected with HBV that includes administering an effective amount of a compound of claim 1 or 17 in a pharmaceutically acceptable carrier.

5 . A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of claim 1 or 17 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 includes administering an effective amount of a compound of claim 1 or 17 in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.

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

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

9 . The method of claims 3 , 4 , 5 or 6 wherein R 1 is hydrogen or fluorine.

10 . The method of claims 3 , 4 , 5 , or 6 wherein R 3 is H or fluorine and R 3′ is H.

11 . The compound of claim 1 selected from the group consisting of β-D-N 4 -p-iodobenzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-fluoro-benzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-chlorobenzoyl-2′,3′-dideoxy-5-fluoro-cytidine, β-D-N 4 -p-bromobenzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-ethyl-benzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-t-butylbenzoyl-2′,3′-dideoxy-5-fluoro-cytidine.

12 . 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.

13 . The method of claim 2 wherein the compound is selected from the group consisting of β-D-N 4 -p-iodobenzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-fluoro-benzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-chlorobenzoyl-2′,3′-dideoxy-5-fluoro-cytidine, β-D-N 4 -p-bromobenzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-ethyl-benzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-t-butylbenzoyl-2′,3′-dideoxy-5-fluoro-cytidine.

14 . The method 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.

15 . The method of claim 3 wherein the compound is selected from the group consisting of β-D-N 4 -p-iodobenzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-fluoro-benzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-chlorobenzoyl-2′,3′-dideoxy-5-fluoro-cytidine, β-D-N 4 -p-bromobenzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-ethyl-benzoyl-2′,3′-dideoxy-5-fluorocytidine, β-D-N 4 -p-t-butylbenzoyl-2′,3′-dideoxy-5-fluoro-cytidine.

16 . 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.

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

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

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

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

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

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

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

or a pharmaceutically acceptable salt or prodrug thereof.

In one preferred embodiment, the active compound is β-D-N 4 -(3-bromobenzoyl)-2′,3′-dideoxy-5-fluorocytidine of the structure:

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

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

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

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

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

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

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

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

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

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 -(3-nitrobenzoyl)cytidine 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:

or a pharmaceutically acceptable salt or prodrug thereof.

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

or a pharmaceutically acceptable salt or prodrug thereof.

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