Cyclosporine A is well known for its immunosuppressive activity and a range of therapeutic uses, including antifungal, anti-parasitic, and anti-inflammatory as well as anti-HIV activity. Cyclosporine A and certain derivatives have been reported as having anti-HCV activity, see Watashi et al., Hepatology, 2003, 38: 1282-1288, Nakagawa et al., Biochem. Biophys. Res. Commun. 2004, 313: 42-7, and Shimotohno and K. Watashi, 2004, American Transplant Congress, Abstract No. 648 (American Journal of Transplantation 2004, Volume 4, Issue s8, Pages 1-653).
Cyclosporine A (cyclosporine) derivatives modified in the 4-position to introduce hydroxyl are known in the literature. For example, [4′-Hydroxy-N-methylleucine]4cyclosporine A is disclosed in European Patent No. 484,281, and is stated to be active against HIV-1 replication. 3-Ether/thioether-[4′-hydroxy-N-methylleucine]4cyclosporine A derivatives are described in U.S. Pat. Nos. 5,948,755, 5,994,299, 5,948,884, and 6,583,265; and International Patent Publication Nos. WO2006/039668 and WO07/041631. Certain cyclosporine A derivatives with (4-acetoxy-N-methylleucine) in the 4-position and (3′-acetoxy-N-methyl-Bmt) in the 1-position are described in International Patent Publication No. WO2006/039668, U.S. Pat. No. 7,196,161 B2 and Carry et al., Synlett (2004), No. 2, pages 316-320. Cyclosporine A derivatives with (4-acetoxy-N-methylleucine) in the 4-position are described in International Patent Publication No. WO 98/49193, U.S. Pat. No. 5,977,067 and Carry et al., Synlett (2004), No. 2, pages 316-320. These compounds are not disclosed as having biological activity.
USPTO Backgrounds
USPTO Backgrounds