Patent EA-004767-B1 (EA)
Title: Nucleoside analogues and use thereof, combination for the treatment of viral infections, pharmaceutical composition
Inventor: NGUYEN-BA NGHE
IPC: C07H19/16
Filed: 1999-12-22
Abstract: 1. A cis-nucleoside of formula (I): and pharmaceutically acceptable salts thereof, wherein: n is 1 or 2, R4 is chosen from H, COOH, CONH2, OH, SH, NH2, NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, CORa wherein Ra is a C1-6alkyl, C2-6alkenyl, C2-6alkynyl and COORb wherein Rb is a C1-6alkyl, C2-6alkenyl, or C2-6alkynyl; R3 is H or a C1-6alkyl, C2-6alkenyl, C2-6alkynyl; X is chosen from H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl; wherein said nucleoside is in the form of the (-) enantiomer, (+) enantiomer and mixtures thereof, including racemic mixtures. 2. A nucleoside according to claim 1 wherein said nucleoside is present in the (-) form by at least 95%. 3. A nucleoside according to claim 1 wherein said nucleoside is present in the (-) form by at least 97%. 4. A nucleoside according to claim 1 wherein said nucleoside is present in the (-) form by at least 99%. 5. A nucleoside according to claim 1 wherein the hydroxy protecting group is chosen from acetyl-2-thioethyl ester, pivaloyloxymethyl ester or isopropyloxycarbonyloxymethyl ester. 6. A nucleoside according to claim 1 wherein X is H. 7. A nucleoside according to claim 1 wherein n is 1. 8. A nucleoside according to claim 7 wherein R3 is H or methyl or R4 is H. 9. A nucleoside according to claim 7 wherein R4 is H; COOH; CONH2; C1-6alkyl, C2-6alkenyl, C2-6alkynyl or COORb wherein Rb is a C1-6alkyl, C2-6alkenyl, C2-6alkynyl. 10. A nucleoside according to claim 7 wherein R4 is H, COOH, or C1-6alkyl. 11. A nucleoside according to claim 7 wherein R4 is methyl or ethyl. 12. A nucleoside according to claim 7 wherein R4 is COOH. 13. A nucleoside according to claim 7 wherein R3 and R4 are H. 14. Cis-2-hydroxymethyl-4-(2'-amino-6'-cyclopropylamino-purine-9'-yl)-1,3-dioxolane and pharmaceutically acceptable salts thereof. 15. Cis-2-hydroxymethyl-4-(2'-amino-6'-cyclobutylamino-purine-9'-yl)-1,3-dioxolane and pharmaceutically acceptable salts thereof. 16. Cis-2-hydroxymethyl-4-(2'-amino-6'-[1-carboxylicacid-cyclopropylamino]-purine-9'-yl)-1,3-dioxolane and pharmaceutically acceptable salts thereof. 17. (-)-(2R, 4R)-2-hydroxymethyl-4-(2'-amino-6'-cyclopropylamino-purine-9'-yl)-1,3-dioxolane present in the (-) form by at least 97%. 18. (+)-(2S, 4S)-2-hydroxymethyl-4-(2'-amino-6'-cyclopropylamino-purine-9'-yl)-1,3-dioxolane present in the (() form by at least 97%. 19. (-)-(2R, 4R)-2-hydroxymethyl-4-(2'-amino-6'-cyclobutylamino-purine-9'-yl)-1,3-dioxolane present in the (-) form by at least 97%. 20. The compound (+)-(2S, 4S)-2-hydroxymethyl-4-(2'-amino-6'-cyclobutylamino-purine-9'-yl)-1,3-dioxolane present in the (() form by at least 97%. 21. The compound (-)-(2R, 4R)-2-hydroxymethyl-4-(2'-amino-6'-[1-carboxylic acid-cyclopropylamino]-purine-9'-yl)-1,3-dioxolane present in the (-) form by at least 97%. 22. The compound (+)-(2S, 4S)-2-hydroxymethyl-4-(2'-amino-6'-[1-carboxylic acid-cyclopropylamino]-purine-9'-yl)-1,3-dioxolane present in the (() form by at least 97%. 23. A nucleoside according to anyone of claim 1 to 22 for use as a medicament in medical therapy. 24. A nucleoside according to claim 23 for use as a medicament in the treatment of viral infections. 25. A nucleoside according to claim 24 for use as a medicament in the treatment of HIV infection. 26. A nucleoside according to claim 24 for use as a medicament in the treatment of HBV infection. 27. A nucleoside according to claim 23 as an active component of a medicament for the treatment of viral infections. 28. A combination useful for the treatment of viral infections comprising at least one compound according to anyone of claims 1 to 21 or pharmaceutically acceptable salts thereof comprising at least one further therapeutic agent chosen from nucleoside analogues; NNRTIs; or protease inhibitors. 29. The combination of claim 28 wherein the nucleoside analogue is chosen from zidovudine, didanosine, zalcitabine, stavudine or lamivudine. 30. The combination of claim 28 wherein the non-nucleoside reverse transcriptase inhibitor is chosen from nevirapine, delavirdine or efavirenz. 31. The combination of claim 28 wherein the protease inhibitor is chosen from indinavir, nelfinavir, saquinavir or ritonavir. 32. A method for the treatment of viral infections comprising administering a therapeutically effective amount of a compound according to anyone of claims 1 to 22 to a subject in need of such treatment. 33. The method according to claim 32 wherein the viral infection is an HIV infection. 34. The method according to claim 32 wherein the viral infection is an HBV infection. 35. A pharmaceutical formulation comprising at least one compound according to anyone of claims 1 to 22 together with at least one pharmaceutically acceptable carrier or excipient.