Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
View Patent ↗The present invention provides nucleoside derivatives which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside derivatives alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside derivatives of the present invention.
1. A method of treating hepatitis C virus (HCV) infection comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of structural formula III, or a pharmaceutically acceptable salt or acyl derivatives thereof,
wherein B is
W is O or S;
Y is H, C 1 -10 alkylcarbonyl, P 3 O 9 H 4 , P 2 O 6 H 3 , or P(O)R 9 R 10 ;
R 1 is CF 3 , or C 1-4 alkyl and one of R 2 and R 3 is OH or C 1-4 alkoxy and the other of R 2 and R 3 is fluoro;
R 6 is H, OH, SH, NH 2 , C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 3-6 cycloalkylamino, halogen, C 1-4 alkyl, C 1-4 alkoxy, or CF 3 ;
R 5 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylamino, CF 3 , or halogen; and
R 9 and R 10 are each independently hydroxy, OCH 2 CH 2 SC(═O)t-butyl, or OCH 2 O(C═O)iPr.
2. The method of claim 1 wherein a compound of structural formula III, or a pharmaceutically acceptable salt or acyl derivatives thereof is in combination with a therapeutic amount of another agent active against HCV infection selected from the group consisting of ribavirin; levovirin; thymosin apha-1; an inhibitor of NS3 serine protease; an inhibitor of inosine monophosphate dehydrogenase; and interferon-α or pegylated interferon-α.