Patent EA-001920-B1 (EA)
Title: Synthesis, anti-human immunodeficiency virus and anti-hepatitus b virus activities of 1,3-oxaselenolane nucleosides
Inventor: SCHINAZI RAYMOND F
IPC: C07D421/04
Filed: 1998-03-19
Abstract: 1. A 1,3-oxaselenolanenucleoside of the formula:   wherein B is a purine or pyrimidine base, and R is hydrogen, acyl, a mono-, di- or triphosphate ester, a stabilized phosphate, or an lipid residue, or a pharmaceutically acceptable salt thereof and wherein the nucleoside exhibits an EC50 of less than 10 micromolar in HIV-infected PBM cells. 2. The 1,3-oxaselenolanenucleoside of Claim 1, wherein B is a pyrimidine base. 3. The l ,3-oxaselenolanenucleoside of Claim 1, wherein B is a purine base. 4. The l ,3-oxaselenolanenucleoside of Claim 2 or 3, wherein R is hydrogen. 5. The 1,3-oxaselenolanenucleoside of Claim 2 or 3, wherein R is acyl. 6. The 1,3-oxaselenolanenucleoside of Claim 2 or 3, wherein R is monophosphate. 7. The 1,3-oxaselenolanenucleoside of Claim 2 or 3, wherein R is diphosphate. 8. The l ,3-oxaselenolanenucleoside of Claim 2 or 3, wherein R is triphosphate. 9. The 1 ,3-oxaselenolanenucleoside of Claim 2 or 3, wherein R is a stabilized phosphate. 10. The 1,3-oxaselenolanenucleoside of Claim 2 or 3 wherein R is a lipid residue. 11. The 1,3-oxaselenolanenucleoside of Claim 1, wherein B is cytosine. 12. The 1,3-oxaselenolanenucleoside of Claim 1, wherein B is 5-fluorocytosine. 13. The 1,3-oxaselenolanenucleoside of Claim 1, wherein B is guanine. 14. The 1,3-oxaselenolanenucleoside of Claim 1, which is 2-hydroxymethyl-4-(N-5'-cytosin-1'-yl)-1,3-oxaselenolane, or a pharmaceutically acceptable salt thereof. 15. The 1,3-oxaselenolanenucleoside of Claim 1, which is 2-hydroxymethyl-4-(N-5'-fluorocytosin-l'-yl)-l,3-oxaselenolane, or a pharmaceutically acceptable salt thereof. 16. The 1 ,3-oxaselenolanenucleoside of Claim 1, which is (-)-β-L-2-hydroxymethyl-4-(N-5'-cytosin-l'-yl)-1,3-oxaselenolane as an isolated enantiomer, or a pharmaceutically acceptable salt thereof. 17. The 1,3-oxaselenolanenucleoside of Claim 1, which is (-)-β-L-2-hydroxymethyl-4-(N-5'-fluorocytosin-1'-yl)-1,3-oxaselenolane as an isolated enantiomer, or a pharmaceutically acceptable salt thereof. 18. A phanaceutical composition for the treatment of HIV or HBV infection in humans and other host animals, comprising an effective amount of a 1,3-oxaselenolanenucleoside of Claim 1 together with a pharmaceutically acceptable carrier. 19. A pharmaceutical  composition for the treatment of HIV or HBV infection in humans and other host animals, comprising an effective amount of a 1,3-oxaselenolanenucleoside of Claim 2 together with a pharmaceutically acceptable carrier. 20. A pharmaceutical  composition for the treatment of HIV or HBV infection in humans and other host animals, comprising an effective amount of a 1,3-oxaselenolanenucleoside of Claim 3 together with a pharmaceutically acceptable carrier. 21. A pharmaceutical composition for the treatment of HIV or HBV infection in humans and other host animals, comprising an effective amount of a 1 ,3-oxaselenolanenucleoside of one of Claims 4-17 together with a pharmaceutically acceptable carrier. 22. The method for treating HIV in humans comprising administering an HIV-effective amount of a 1,3-oxaselenolanenucleoside of the formula   wherein B is a purine or pyrimidine base, and R is hydrogen, acyl or a phosphate ester, or a pharmaceutically acceptable salt thereof and wherein the nucleosides exhibits an EC50 of less than 10 micromolar in HIV-infected PBM cells. 23. The method for the treatment of HIV of Claim 22, wherein B is a pyrimidine base. 24. The method for the treatment of HIV of Claim 22, wherein B is a purine base. 25. The method for the treatment of HIV of Claim 22, wherein R is hydrogen. 26. The method for the treatment of HIV as claimed in Claim 22, wherein R is acyl. 27. The method for the treatment of HIV as claimed in Claim 22, wherein R is monophosphate. 28. The method for the treatment of HIV as claimed in Claim 22, wherein R is diphosphate. 29. The method for the treatment of HIV as claimed in Claim 22, wherein R is triphosphate. 30. A method for the treatment of HIV as claimed in Claim 25, wherein the 1,3-oxaselenolanenucleoside is 2-hydroxymethyl-4-(N-5'-cytosin-1'-yl)-1,3-oxaselenolane, or a pharmaceutically acceptable salt thereof. 31. A method for the treatment of HIV as claimed in Claim 26, wherein the 1,3-oxaselenolanenuclcoside is 2-hydroxymethyl-4-(N-5'-fluorocytosin-1'-yl)-1,3-oxaselenolane, or a pharmaceutically acceptable salt thereof. 32. A method for the treatment of HIV as claimed in Claim 27, wherein the 1,3-oxaselenolanenucleoside is (-)-β-L-2-hydroxymethyl-4-(N-5'-cytosin-1'-yl)-1,3-oxaselenolane as an isolated enantiomer, or a pharmaceutically acceptable salt thereof. 33. A method for the treatment of HIV as claimed in Claim 28, wherein the 1,3-oxaselenolanenucleoside is (-)-β-L-2-hydroxymethyl-4-(N-5'-fluorocytosin-1'-yl)-1,3-oxaselenolane as an isolated enantiomer, or a pharmaceutically acceptable salt thereof. 34. A method for treating HBV in humans and other host animals comprising administering an HBV-effective amount of a 1,3-oxaselenolanenucleoside of the formula   wherein B is a purine or pyrimidine base, and R is hydrogen, acyl or a phosphate ester, or a pharmaceutically acceptable salt thereof, in the form of racemate or an isolated enantiomer. 35. A method for the treatment of HBV as claimed in Claim 34, wherein B is a pyrimidine base. 36. A method for the treatment of HBV as claimed in Claim 34, wherein B is a purine base. 37. A method for the treatment of HBV as claimed in Claim 34, wherein R is hydrogen. 38. A method for the treatment of HBV as claimed in Claim 34, wherein R is acyl. 39. A method for the treatment of HBV as claimed in Claim 34, wherein R is monophosphate. 40. A method for the treatment of HBV as claimed in Claim 34, wherein R is diphosphate. 41. A method for the treatment of HBV as claimed in Claim 34, wherein R is triphosphate. 42. A method for the treatment of HBV as claimed in Claim 34, wherein the 1,3-oxaselenolanenucleoside is 2-hydroxymethyl-4-(N-5'-cytosin-1'-yl)-1,3-oxaselenolane, or a pharmaceutically acceptable salt thereof. 43. A method for the treatment of HBV as claimed in Claim 34, wherein the 1,3-oxaselenolanenucleoside is 2-hydroxymethyl-4-(N-5'-fluorocytosin-l'-yl)-1,3-oxaselenolane, or a pharmaceutically acceptable salt thereof. 44. A method for the treatment of HBV as claimed in Claim 34, wherein the 1,3-oxaselenolanenucleoside is (-)-β-L-2-hydroxymethyl-4-(N-5'-cytosin-1'-yl)-1,3-oxaselenolane as an isolated enantiomer, or a pharmaceutically acceptable salt thereof. 45. A method for the treatment of HBV as claimed in Claim 34, wherein the 1,3-oxaselenolanenucleoside is (-)-β-L-2-hydroxymethyl-4-(N-5'-fluorocytosin-1'-yl)-l,3-oxaselenolane as an isolated enantiomer, or a pharmaceutically acceptable salt thereof. 46. Use of 1,3-oxaselenolanenucleosides as claimed in Claim 1 and pharmaceutically acceptable derivatives and salts thereof in the manufacture of a medicament for the treatment of HIV or HBV infection. 47. Use of 1,3-oxaselenolanenucleosides as claimed in Claim 1 and pharmaceutically acceptable derivatives and salts thereof in the treatment of viral infections by administration in combination or alternation with another antiviral agent.