Antiviral nucleosides

Abstract

Compounds having the formula I wherein R1 is as herein defined are Hepatitis C virus NS5b polymerase inhibitors. Also disclosed are compositions and methods for inhibiting hepatitis replication, processes for making the compounds and synthetic intermediates used in the process

Description

Claims

1. A compound of formula I

2. A compound according to claim 1 wherein R1 is ethyl, n-propyl, iso-propyl, n-butyl or iso-butyl.

3. A compound according to claim 2 wherein R1 is ethyl or iso-propyl.

4. A compound according to claim 3 wherein R1 is iso-propyl and the compound is the hydrochloride, mesylate, hemisulfate or sulfate salt.

5. A method for treating a disease mediated by the Hepatitis C Virus (HCV) virus comprising administering to a mammal in need thereof, a therapeutically effective quantity of a compound according to claim 1.

6. The method of claim 5 wherein the compound a dose of between 0.1 and 10 g per day is administered to the patient.

7. A method according to claim 6 wherein a dose of between 0.5 and 7.5 g per day is administered to the patient.

8. A method according to claim 7 wherein a dose of between 1.0 and 6.0 g per day is administered to the patient. (ii) optionally adding sufficient saturated aqueous NaCl to produce a biphasic reaction mixture;(iii) adding an acylating agent and additional base sufficient to maintain the pH from about 7.5 to about 12;(iv) monitoring the reaction and discontinuing addition of said acylating agent and said base when the conversion reaches a satisfactory level;(v) optionally contacting the O-acyl nucleoside with a pharmaceutically acceptable acid to form an acid additional salt of the O-acyl nucleoside.

9. The method of claim 5 further comprising co-administering at least one immune system modulator and/or at least one antiviral agent that inhibits replication of HCV.

10. The method of claim 9 wherein the immune system modulator is an interferon, interleukin, tumor necrosis factor or colony stimulating factor.

11. The method of claim 10 wherein the immune system modulator is an interferon or chemically derivatized interferon.

12. The method of claim 9 further comprising co-administering at least one other antiviral agent.

13. The method of claim 12 where the antiviral compound is selected from the group consisting of an HCV protease inhibitor, another nucleoside HCV polymerase inhibitor, a non-nucleoside HCV polymerase inhibitor, an HCV helicase inhibitor, an HCV primase inhibitor and an HCV fusion inhibitor.

14. A pharmaceutical composition comprising a therapeutically effective quantity of a compound according to claim 1 admixed with at least one pharmaceutically acceptable carrier, diluent or excipient.

15. A process for the selective O-acylation of a nucleoside I to afford an O-acyl nucleoside II under basic reaction conditions