Claims for Patent: 6,180,639

Summary for Patent: 6,180,639

Title:	1,3-oxathiolane nucleoside analogues
Abstract:	(-)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one, its pharmaceutically acceptable derivatives, pharmaceutical formulation thereof, methods for its preparation and its uses as an antiviral agent are described.
Inventor(s):	Coates; Jonathan Allan (Greenford, GB), Mutton; Ian Martin (Greenford, GB), Penn; Charles Richard (Greenford, GB), Williamson; Christopher (Greenford, GB), Storer; Richard (Greenford, GB)
Assignee:	BioChem Pharma Inc. (Laval, CA)
Application Number:	07/835,964
Patent Claims:	1. A method for treating a human suffering from HIV infection comprising administering to said human a pharmaceutical composition comprising: a compound which is (-)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5yl)-(1H)-pyrimidin-2-on e or a pharmaceutically acceptable salt thereof, another agent having antiviral activity, and a pharmaceutically acceptable carrier, and wherein the amount of the (+)-enantiomer of said compound or of said pharmaceutically acceptable salt present in said composition is no more than 5% w/w, relative to the combined weight of the (-) and (+)-enantiomers thereof. 2. A method according to claim 1, wherein said agent is an acyclic nucleoside, an interferon, a renal excretion inhibitor, a nucleoside transport inhibitor, a 2',3'-dideoxynucleoside, an immunomodulator, erythropoietin, ampligen, thyomodulin, thymopentin, foscarnet, ribavirin, or an inhibitor of HIV binding to CD4. 3. A method according to claim 1, wherein the amount of said compound or pharmaceutically acceptable salt is 10-1500 mg. 4. A method according to claim 3, wherein the amount of said compound or pharmaceutically acceptable salt is 20-1000 mg. 5. A method according to claim 4, wherein the amount of said compound or pharmaceutically acceptable salt is 50-70 mg. 6. A method according to claim 1, wherein said composition contains an amount of the (+)-enantiomer of no more than 2% w/w. 7. A method according to claim 6, wherein said composition contains an amount of the (+)-enantiomer of no more than 1% w/w. 8. A method according to claim 1, wherein said compound or pharmaceutically acceptable salt and said agent are administered sequentially. 9. A method according to claim 1, wherein said compound or pharmaceutically acceptable salt and said agent are administered simultaneously. 10. A method according to claim 1, wherein said compound is administered at a dosage of 0.1-750 mg/kg of body weight per day. 11. A method according to claim 10, wherein said compound or pharmaceutically acceptable salt is administered at a dosage of 0.5-60 mg/kg of body weight per day. 12. A method according to claim 11, wherein said compound or pharmaceutically acceptable salt is administered at a dosage of 1-20 mg/kg of body weight per day. 13. A pharmaceutical composition comprising: a pharmaceutically acceptable carrier, a compound which is (-)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-o ne or a pharmaceutically acceptable salt thereof, and another agent having antiviral activity wherein the amount of the (+)-enantiomer of said compound or of said pharmaceutically acceptable salt present in said composition is no more than 5% w/w, relative to the combined weight of the (-) and (+)-enantiomers thereof. 14. A composition according to claim 13, wherein said agent is an acyclic nucleoside, an interferon, a renal excretion inhibitor, a nucleoside transport inhibitor, a 2',3'-dideoxynucleoside, an immunomodulator, erythropoetin, ampligen, thyomodulin, thymopentin, foscarnet, ribavirin, or an inhibitor of HIV binding to CD4. 15. A composition according to claim 13, wherein said composition contains 10-1500 mg of said compound or pharmaceutically acceptable salt. 16. A composition according to claim 15, wherein said composition contains 20-1000 mg of said compound or pharmaceutically acceptable salt. 17. A composition according to claim 16, wherein said composition contains 50-700 mg of said compound or pharmaceutically acceptable salt. 18. A composition according to claim 13, wherein said compound is (-)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-o ne. 19. A composition according to claim 18, wherein said agent is an acyclic nucleoside, an interferon, a renal excretion inhibitor, a nucleoside transport inhibitor, a 2',3'-dideoxynucleoside, an immunomodulator, erythropoetin, ampligen, thyomodulin, thymopentin, foscarnet, ribavirin, or an inhibitor of HIV binding to CD4. 20. A composition according to claim 18, wherein said composition contains 10-1500 mg of said compound. 21. A composition according to claim 20, wherein said composition contains 20-1000 mg of said compound. 22. A composition according to claim 21, wherein said composition contains 50-700 mg of said compound. 23. A composition according to claim 13, wherein said composition contains an amount of the (+)-enantiomer of no more than 2% w/w. 24. A composition according to claim 23, wherein said composition contains an amount of the (+)-enantiomer of no more than 1% w/w. 25. A composition according to claim 18, wherein said composition contains an amount of the (+)-enantiomer of no more than 2% w/w. 26. A composition according to claim 25, wherein said composition contains an amount of the (+)-enantiomer of no more than 1% w/w. 27. A method according to claim 1, wherein said compound is (-)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-o ne. 28. A method according to claim 2, wherein said compound is (-)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-o ne. 29. A method according to claim 28, wherein the amount of said compound is 10-1500 mg. 30. A method according to claim 29, wherein the amount of said compound is 20-1000 mg. 31. A method according to claim 30, wherein the amount of said compound is 50-700 mg. 32. A method according to claim 28, wherein said composition contains an amount of the (+)-enantiomer of no more than 2% w/w. 33. A method according to claim 32, wherein said composition contains an amount of the (+)-enantiomer of no more than 1% w/w. 34. A method according to claim 27, wherein said composition contains an amount of the (+)-enantiomer of no more than 2% w/w. 35. A method according to claim 34, wherein said composition contains an amount of the (+)-enantiomer of no more than 1% w/w. 36. A method according to claim 28, wherein said compound and said agent are administered sequentially. 37. A method according to claim 28, wherein said compound and said agent are administered sequentially. 38. A method according to claim 28, wherein said compound is administered at a dosage of 0.1-750 mg/kg of body weight per day. 39. A method according to claim 38, wherein said compound is administered at a dosage of 0.5-60 mg/kg of body weight per day. 40. A method according to claim 38, wherein said compound is administered at a dosage of 1-20 mg/kg of body weight per day. 41. A composition according to claim 19, wherein said composition contains 10-1500 mg of said compound or pharmaceutically acceptable salt. 42. A composition according to claim 41, wherein said composition contains 20-1000 mg of said compound or pharmaceutically acceptable salt. 43. A composition according to claim 42, wherein said composition contains 50-700 mg of said compound or pharmaceutically acceptable salt. 44. A composition according to claim 41, wherein said composition contains an amount of the (+)-enantiomer of no more than 2% w/w. 45. A composition according to claim 44, wherein said composition contains an amount of the (+)-enantiomer of no more than 1% w/w. 46. A method according to claim 1, wherein said compound or pharmaceutically acceptable salt and said agent are administered in combination. 47. A method according to claim 2, wherein said compound or pharmaceutically acceptable and said agent are administered in combination. 48. A method according to claim 28, wherein said compound and said agent are administered in combination. 49. A method for treating a human suffering from HIV infection comprising administering to said human a pharmaceutical composition comprising: a compound which is (-)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-1H)-pyrimidin-2-on e or a pharmaceutically acceptable salt thereof, and another agent having antiviral activity, wherein the amount of the (+)-enantiomer of said compound or of said pharmaceutically acceptable salt present in said composition is not more than 5% w/w, relative to the combined weight of the (-) and (+)-enantiomers thereof. 50. A method according to claim 49, wherein said composition contains (-)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-o ne. 51. A method according to claim 49, wherein said agent is an acyclic nucleoside, an interferon, a renal excretion inhibitor, a nucleoside transport inhibitor, a 2',3'-dideoxynucleoside, an immunomodulator, erythropoietin, ampligen, thyomodulin, thymopentin, foscarnet, ribavirin, or an inhibitor of HIV binding to CD4. 52. A method according to claim 50, wherein said agent is an acyclic nucleoside, an interferon, a renal excretion inhibitor, a nucleoside transport inhibitor, a 2',3'-dideoxynucleoside, an immunomodulator, erythropoietin, ampligen, thyomodulin, thymopentin, foscarnet, ribavirin, or an inhibitor of HIV binding to CD4. 53. A pharmaceutical composition comprising: a compound which is (-)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-o ne or a pharmaceutically acceptable salt thereof, and another agent having antiviral activity wherein the amount of the (+)-enantiomer of said compound or of said pharmaceutically acceptable salt present in said composition is no more than 5% w/w, relative to the combined weight of the (-) and (+)-enantiomers thereof. 54. A composition according to claim 53, wherein said composition contains (-)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-o ne. 55. A composition according to claim 53, wherein said agent is an acyclic nucleoside, an interferon, a renal excretion inhibitor, a nucleoside transport inhibitor, a 2',3'-dideoxynucleoside, an immunomodulator, erythropoietin, ampligen, thyomodulin, thymopentin, foscarnet, ribavirin, or an inhibitor of HIV binding to CD4. 56. A composition according to claim 54, wherein said agent is an acyclic nucleoside, an interferon, a renal excretion inhibitor, a nucleoside transport inhibitor, a 2',3'-dideoxynucleoside, an immunomodulator, erythropoietin, ampligen, thyomodulin, thymopentin, foscarnet, ribavirin, or an inhibitor of HIV binding to CD4. 57. A combination comprising: a compound which is (-)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H )-pyrimidin-2-one or a pharmaceutically accepted salt thereof, and another agent having antiviral activity wherein the amount of the (+)-enantiomer of said compound or of said pharmaceutically acceptable salt present in said combination is no more than 5% w/w, relative to the combined weight of the (-) and (+)-enantiomers thereof. 58. A combination accroding to claim 57, wherein said combination contains (-)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H )-pyrimidin-2-one. 59. A combination according to claim 57, wherein said agent is an acyclic nucleoside, an interferon, a renal extretion inhibitor, a nucleoside transport inhibitor, a 2',3'-dideoxynucleoside, an immunomodulator, erythropoietin, ampligen, thyomodulin, thymopentin, foscarnet, ribavirin, or an inhibitor of HIV binding to CD4. 60. A combination according to claim 58, wherein said agent is an acyclic nucleoside, an interferon, a renal excretion inhibitor, a nucleoside transport inhibitor, a 2',3'-dideoxynucleoside, an immunomodulator, erythropoietin, ampligen, thyomodulin, thymopentin, foscarnet, ribavirin, or an inhibitor of HIV binding to CD4. 61. An article of manufacture according to claim 61, wherein said first amount contains (-)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-o ne or a pharmaceutically acceptable salt thereof, wherein the content of the (+)-enantiomer of said compound or of said pharmaceutically acceptable salt present in said fist amount is no more than 5% w/w/, relative to the combined weight of the (-) and (+)-enantiomers thereof, and a second amount of another agent having antiviral activity. 62. An article of manufacture according to claim 61, wherein said first amount contains (-)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-o ne. 63. An article of manufacture according to claim 61, wherein said agent is an acyclic nucleoside, an interferon, a renal excretion inhibitor, a nucleoside transport inhibitor, a 2',3'-dideoxynucleoside, an immunomodulator, erythropoietin, ampligen, thyomodulin, thymopentin, foscarnet, ribavirin, or an inhibitor of HIV binding to CD4. 64. An article of manufacture according to claim 61, wherein said agent is an acyclic nucleoside, an interferon, a renal excretion inhibitor, a nucleoside transport inhibitor, a 2',3'-dideoxynucleoside, an immunomodulator, erythropoietin, ampligen, thyomodulin, thymopentin, foscarnet, ribavirin, or an inhibitor of HIV binding to CD4.