Hexahydrofuro[2,3-B]furan-3-YL-N-{3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-1-benzyl-2-hydroxypropyl}carbamate as retroviral protease inhibitor
View Patent ↗Compositions comprising bis-tetrahydrofuran benzodioxyolyl sulfonamide compounds that are surprisingly effective protease inhibitors and a second antiretroviral compound are disclosed. Methods of inhibiting retrovirus proteases, in particular multi-drug resistant retrovirus proteases, methods of treating or preventing infection or disease associated with retrovirus infection in a mammal, and methods of inhibiting viral replication are also disclosed.
1. A composition comprising:
(a) a first antiretroviral compound of the formula:
or an N-oxide, salt, ester, prodrug or metabolite thereof, in any stereoisomeric form, or a mixture thereof
(b) a second antiretroviral compound; and
(c) a pharmaceutically tolerable excipient.
2. A composition according to claim 1 , wherein said first antiretroviral compound has the formula:
or an N-oxide, salt, ester, prodrug or metabolite thereof.
3. A composition according to claim 1 , further comprising an immunomodulator.
4. A composition according to claim 1 , further comprising an antibiotic.
5. A composition according to claim 1 , wherein said second antiretroviral compound is a binding inhibitor, a fusion inhibitor, a co-receptor binding inhibitors, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a nucleotide reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; a RNAse H inhibitor, a TAT inhibitor, an integrase inhibitor, a protease inhibitor or a glycosylation inhibitor.
6. A composition according to claim 5 , wherein said second antiretroviral compound is a fusion inhibitor, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; an integrase inhibitor or a protease inhibitor.
7. A composition according to claim 6 , wherein said second antiretroviral compound is T20, T1249, foscarnet, a prodrug of foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, TMC-125, TMC-120, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir.
8. A composition according to claim 7 , wherein said second antiretroviral compound is T20, foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir.
9. A kit comprising:
(a) a first antiretroviral compound of the formula:
or an N-oxide, salt, ester, prodrug or metabolite thereof, in any stereoisomeric form, or a mixture thereof;
(b) a second antiretroviral compound;
(c) instructions for administering said first antiretroviral compound, said second antiretroviral compound and optional components simultaneously, separately or sequentially; and
(d) a pharmaceutically tolerable excipient.
10. A kit according to claim 9 , further comprising an immunomodulator.
11. A kit according to claim 9 , further comprising an antibiotic.
12. A kit according to claim 9 , wherein said first antiretroviral compound has the formula:
or an N-oxide, salt, ester, prodrug or metabolite thereof.
13. A kit according to claim 9 , wherein said second antiretroviral compound is a binding inhibitor, a fusion inhibitor, a co-receptor binding inhibitors, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a nucleotide reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; a RNAse H inhibitor, a TAT inhibitor, an integrase inhibitor, a protease inhibitor or a glycosylation inhibitor.
14. A kit according to claim 13 , wherein said second antiretroviral compound is a fusion inhibitor, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; an integrase inhibitor or a protease inhibitor.
15. A kit according to claim 14 , wherein said second antiretroviral compound is T20, T1249, foscarnet, a prodrug of foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, TMC-125, TMC-120, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir.
16. A kit according to claim 15 , wherein said second antiretroviral compound is T20, foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir.
17. A method of treating a retroviral infection in a mammal, comprising the step of:
administering to said mammal an effective amount of said composition according to claim 1 .
18. A method according to claim 17 , wherein said mammal is a human.
19. A method according to claim 17 , wherein said composition further comprises a pharmaceutically tolerable excipient.
20. A method according to claim 17 , wherein said composition further comprising an immunomodulator.
21. A method according to claim 17 , wherein said composition further comprising an antibiotic.
22. A method according to claim 17 , wherein said first antiretroviral compound has the formula:
or an N-oxide, salt, ester, prodrug or metabolite thereof.
23. A method according to claim 17 , wherein said second antiretroviral compound is a binding inhibitor, a fusion inhibitor, a co-receptor binding inhibitors, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a nucleotide reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; a RNAse H inhibitor, a TAT inhibitor, an integrase inhibitor, a protease inhibitor or a glycosylation inhibitor.
24. A method according to claim 23 , wherein said second antiretroviral compound is a fusion inhibitor, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; an integrase inhibitor or a protease inhibitor.
25. A method according to claim 24 , wherein said second antiretroviral compound is T20, T1249, foscarnet, a prodrug of foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, TMC-125, TMC-120, capravirine, amprenavir, ntonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir.
26. A method according to claim 25 , wherein said second antiretroviral compound is T20, foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir.
27. A method according to claim 17 , wherein said infection or disease associated with retrovirus infection is a human immunodeficiency virus.
28. A method according to claim 27 , wherein said human immunodeficiency virus is a multiple drug-resistant strain.
29. A method of inhibiting retroviral replication, comprising the step of:
contacting a retrovirus with an effective amount of said composition according to claim 1 .
30. A method according to claim 29 , wherein said composition further comprises a pharmaceutically tolerable excipient.
31. A method according to claim 29 , wherein said composition further comprising an immunomodulator.
32. A method according to claim 29 , wherein said composition further comprising an antibiotic.
33. A method according to claim 29 , wherein said first antiretroviral compound has the formula:
or an N-oxide, salt, ester, prodrug or metabolite thereof.
34. A method according to claim 29 , wherein said second antiretroviral compound is a binding inhibitor, a fusion inhibitor, a co-receptor binding inhibitors, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a nucleotide reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; a RNAse H inhibitor, a TAT inhibitor, an integrase inhibitor, a protease inhibitor or a glycosylation inhibitor.
35. A method according to claim 34 , wherein said second antiretroviral compound is a fusion inhibitor, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; an integrase inhibitor or a protease inhibitor.
36. A method according to claim 35 , wherein said second antiretroviral compound is T20, T1 249, foscarnet, a prodrug of foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, TMC-125, TMC-120, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir.
37. A method according to claim 36 , wherein said second antiretroviral compound is T20, foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir.
38. A method according to claim 29 , wherein said retrovirus is a human immunodeficiency virus.
39. A method according to claim 38 , wherein said human immunodeficiency virus is a multiple drug-resistant strain.
40. A method of inhibiting a protease of a retrovirus in a mammal infected with said retrovirus, comprising the step of:
administering a protease inhibiting amount of said composition according to claim 1 .
41. A method according to claim 40 , wherein said mammal is a human.
42. A method according to claim 40 , wherein said composition further comprises a pharmaceutically tolerable excipient.
43. A method according to claim 40 , wherein said composition further comprising an immunomodulator.
44. A method according to claim 40 , wherein said composition further comprising an antibiotic.
45. A method according to claim 40 , wherein said first antiretroviral compound has the formula:
or an N-oxide, salt, ester, prodrug or metabolite thereof.
46. A method according to claim 40 , wherein said second antiretroviral compound is a binding inhibitor, a fusion inhibitor, a co-receptor binding inhibitors, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a nucleotide reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; a RNAse H inhibitor, a TAT inhibitor, an integrase inhibitor, a protease inhibitor or a glycosylation inhibitor.
47. A method according to claim 46 , wherein said second antiretroviral compound is a fusion inhibitor, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; an integrase inhibitor or a protease inhibitor.
48. A method according to claim 47 , wherein said second antiretroviral compound is T20, T1249, foscarnet, a prodrug of foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, TMC-125, TMC-120, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir.
49. A method according to claim 48 , wherein said second antiretroviral compound is T20, foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir.
50. A method according to claim 40 , wherein said retrovirus is a human immunodeficiency virus.
51. A method according to claim 50 , wherein said human immunodeficiency virus is a multiple drug-resistant strain.