Anti-viral nucleoside analogs and methods for treating viral infections, especially HIV infections
The present invention relates to novel compounds according to the general formulas I, II, III, IV or V: wherein B is nucleoside base according to the structure: and the remaining variables as defined in the specification, and pharmaceutical compositions comprising the compounds. The compounds are useful interalia as anti-viral agents in viral therapy.
1. A method of treating a viral infection in a patient in need thereof comprising administering to said patient an effective amount of a compound according to the structure:
where R 2 is H, a C 2 -C 21 acyl group, a phosphate, diphosphate, triphosphate or phosphodiester group, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable additive, carrier or excipient, wherein said viral infection is caused by human immunodeficiency virus (HIV).
2. The method according to claim 1 wherein said viral infection is caused by human immunodeficiency virus 1 (HIV 1).
3. The method according to claim 1 wherein said viral infection is caused by human immunodeficiency virus 2 (HIV 2).
4. The method according to claim 1 wherein said compound is coadministered with at least one additional anti-HIV agent.
5. The method according to claim 4 wherein said additional anti-HIV agent is selected from the group consisting of ddC, abacavir, ddI, ddA, 3TC, AZT, D4T, FTC, FddC, Fd4C, Atazanavir, Adefovir dipivoxyl, Tenofovir disoproxil, Etecavir, Indinavir, KHI-227.2-[3-[3-(S)-[[(Tetrahydrofuranyloxy)carbonyl]amino]-4-phenyl-2(R)-hydroxybutyl]]-N-(1,1-dimethylethyl)decahydro-3-isoquinolinecarboxamide, VB-11,328, KNI-174, Val-Val-Sta, CPG53820, HOEt-N2 aza-peptide isostere, 2,5-Diamino-N,N′-bis(N-benzyloxycarbonyluelyl)-1,6-diphenyl-3(S),4(S)-hexanediol BzOCValPhe[diCHOH(SS]PheValBzOC, 2,5,-Diamino-N,N′-bis(N-benzyloxycarbonyluelyl)-1,6-diphenyl-3(R),4(R)-hexanediol BzOCValPhe[diCHOH(RR]PheValBzOC, [bis(SATE)ddAMP], BILA 2186 BS, Agenerase, A-98881, A-83962, A-80987, (2-Naphthalcarbonyl)Asn[decarbonylPhe-hydroxyethyl]ProOtertButyl, A-81525, XM323, Tipranavir, SDZ PRI 053, SD146, Telinavir, (R)2QuinCOAsnPhe[CHOHCH2]PipCONHtBu, Saquinavir, R-87366, DMP 460, L685,434, L685,434-OEtNMe2, L689,502, Lasinavir, Aluviran P9941, Palinavir, and Penicillin.
6. The method according to claim 4 wherein said additional anti-HIV agent is at least one agent selected from the group consisting of ddC, abacavir, ddI, ddA, 3TC, AZT, D4T, FTC, FddC and Fd4C.
7. A method of reducing the likelihood or delaying the onset of a viral infection in a patient at risk for infection, said method comprising administering to said patient an effective amount of a compound according to the structure:
where R 2 is H, a C 2 -C 21 acyl group, a phosphate, diphosphate, triphosphate or phosphodiester group, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable additive, carrier or excipient, wherein said viral infection is caused by human immunodeficiency virus (HIV).
8. The method according to claim 7 wherein said human immunodeficiency virus is human immunodeficiency virus 1 (HIV-1).
9. The method according to claim 8 wherein said human immunodeficiency virus is HIV 2.
10. The method according to claim 9 wherein said compound is coadministered with at least one additional anti-HIV agent.
11. The method according to claim 9 wherein said additional anti-HIV agent is selected from the group consisting of ddC, abacavir, ddI, ddA, 3TC, AZT, D4T, FTC, FddC, Fd4C, Atazanavir, Adefovir dipivoxyl, Tenofovir disoproxil, Etecavir, Indinavir, KHI-227, 2-[3-[3-(S)-[[(Tetrahydrofuranyloxy)carbonyl]amino]-4-phenyl-2(R)-hydroxybutyl]]-N-(1,1-dimethylethyl)decahydro-3-isoquinolinecarboxamide, vB-11,328, KNI-174, val-Val-Sta, CPG53820, bis-Val HOEt-N2 aza-peptide isostere, 2,5-Diamino-N,N′-bis(N-benzyloxycarbonyluelyl)-1,6-diphenyl-3(S),4(S)-hexanediol BzOCValPhe[diCHOH(SS]PheValBzOC, 2,5,-Diamino-N,N′-bis(N-benzyloxycarbonyluelyl)-1,6-diphenyl-3(R),4(R)-hexanediol BzOCValPhe[diCHOH(RR]PheValBzOC, [bis(SATE)ddAMP], BILA 2186 BS, Agenerase, A-98881, A-83962, A-80987, (2-Naphthalcarbonyl)Asn[decarbonylPhe-hydroxyethyl]ProOtertButyl, A-81525, XM323, Tipranavir, SDZ PRI 053, SD146, Telinavir, (R)2QuinCOAsnPhe[CHOHCH2]PipCONHtBu, Saquinavir, R-87366, DMP 460, L685,434, L685,434-OEtNMe2, L689,502, Lasinavir, Aluviran, P9941, Palinavir, and Penicillin.
12. The method according to claim 10 wherein said additional anti-HIV agent is selected from the group consisting of ddC, abacavir, ddI, ddA, 3TC, AZT, D4T, FTC, FddC and Fd4C.
13. A method of reducing the likelihood or delaying the onset of a condition secondary to a viral infection in a patient at risk for the development of said condition, said method comprising administering to said patient an effective amount of a compound according to the structure:
where R 2 is H, a C 2 -C 21 acyl group, a phosphate, diphosphate, triphosphate or phosphodiester group, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable additive, carrier or excipient, wherein said viral infection is caused by human immunodeficiency virus 1 and/or 2.
14. The method according to claim 13 wherein said condition is AIDS.
15. A method of treating a patient in need thereof for an HIV infection with combination therapy, said method comprising administering to said patient an effective amount of a combination of at least compound according to the structure:
where R 2 is H, a C 2 -C 21 acyl group, a phosphate, diphosphate, triphosphate or phosphodiester group, or a pharmaceutically acceptable salt thereof, in combination with at least one compound selected from the group consisting of nucleoside reverse transcriptase inhibitors (NRTI), non-nucloeoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors and mixtures thereof.
16. A method of treating a patient in need thereof for an HIV infection with combination therapy, said method comprising administering to said patient an effective amount of a combination of at least compound according to the structure:
where R 2 is H, a C 2 -C 21 acyl group, a phosphate, diphosphate, triphosphate or phosphodiester group, or a pharmaceutically acceptable salt thereof with at least one compound selected from the group consisting of 3TC (Lamivudine), AZT (Zidovudine), (−)-FTC, ddI (Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T (Stavudine), Racivir, L-FddC, L-D4FC, NVP (Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavir mesylate), RTV (Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV (Nelfinavir), APV (Amprenavir), LPV (Lopinavir), T20, fuseon and mixtures thereof.
17. The method according to claim 1 wherein R 2 is H and said virus is drug resistant.
18. The method according to claim 2 wherein R 2 is H and said virus is drug resistant.
19. The method according to claim 3 wherein R 2 is H and said virus is drug resistant.
20. The method according to claim 4 wherein R 2 is H and said virus is drug resistant.
21. The method according to claim 5 wherein R 2 is H and said virus is drug resistant.
22. The method according to claim 6 wherein R 2 is H and said virus is drug resistant.
23. The method according to claim 1 wherein R 2 is H and said compound is administered by oral administration.
24. The method according to claim 2 wherein R 2 is H and said compound is administered by oral administration.
25. The method according to claim 3 wherein R 2 is H and said compound is administered by oral administration.
26. The method according to claim 4 wherein R 2 is H and said compound and said additional anti-HIV agent are administered by oral administration.
27. The method according to claim 5 wherein R 2 is H and said compound and said additional anti-HIV agent are administered by oral administration.
28. The method according to claim 6 wherein R 2 is H and said compound and said additional anti-HIV agent are administered by oral administration.
29. The method according to claim 7 wherein R 2 is H and said compound is administered by oral administration.
30. The method according to claim 13 wherein R 2 is H and said compound is administered by oral administration.
31. A method of treating a viral infection in a patient in need thereof comprising orally administering to said patient an effective amount of a compound according to the structure
wherein said viral infection is caused by human immunodeficiency virus (HIV).