Claims
- 1. A compound of the formula:
- 2. A compound according to claim 1 wherein R1 and R2 are arylalkyl, R3 is loweralkyl, R4 is aryl, R5 is
- 3. A compound according to claim 1 wherein R1 and R2 are benzyl or R1 is benzyl and R2 is loweralkyl, R3 is loweralkyl, R4 is (a) phenyl which is substituted with two loweralkyl groups and which is optionally substituted with a third substituent selected from the group consisting of loweralkyl, hydroxy, amino and halo or (b) pyridyl or pyrimidinyl either of which is substituted with two loweralkyl groups and which is optionally substituted with a third substituent selected from the group consisting of loweralkyl, hydroxy, amino and halo, R5 is
- 4. A compound according to claim 1 wherein R1 and R2 are benzyl or R1 is benzyl and R2 is isopropyl, R3 is loweralkyl, R4 is 2,6-dimethylphenyl which is optionally substituted with a third substituent selected from the group consisting of loweralkyl and halo, R5 is
- 5. A compound according to claim 1 wherein R1 and R2 are benzyl or R1 is benzyl and R2 is isopropyl, R3 is loweralkyl, R4 is 2,6-dimethylphenyl which is optionally substituted with a third substituent selected from the group consisting of loweralkyl and halo, R5 is
- 6. A compound selected from the group consisting of:
(2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3,3-dimethyl butanoyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-thionyl)-3-methyl butanoyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,4,6-trimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(4-fluoro-2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-pyrrolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-pyrrolidin-2,5-dionyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(trans-3-(2,6-dimethylphenyl)propenoyl)amino-3-hydroxy-5-(2S-1-tetrahydropyrimidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(3-(2,6-dimethylphenyl)propanoyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2,4-dionyl)-3-methylbutanoyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(4-aza-1-tetrahydro-pyrimid-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S- (1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl)amino-1-phenyl-6-methylheptane; (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2,4-dionyl)-3-methylbutanoyl)amino-1-phenyl-6-methylheptane; and (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(4-aza-4,5-dehydro-1-pyrimid-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane; or a pharmaceutically acceptable salt, ester or prodrug thereof.
- 7. The compound (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane; or a pharmaceutically acceptable salt, ester or prodrug thereof.
- 8. A pharmaceutical composition for inhibiting HIV protease comprising a pharmaceutical carrier and a therapeutically effective amount of the compound of claim 1.
- 9. A pharmaceutical composition for inhibiting HIV protease comprising a pharmaceutical carrier and a therapeutically effective amount of the compound of claim 7.
- 10. A method for inhibiting HIV protease comprising administering to a human in need of such treatment a therapeuctially effective amount of the compound of claim 1.
- 11. A method for inhibiting inhibiting HIV protease comprising administering to a human in need of such treatment a therapeuctially effective amount of the compound of claim 7.
- 12. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeuctially effective amount of the compound of claim 1.
- 13. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeuctially effective amount of the compound of claim 7.
- 14. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective amount of the compound of claim 1 in combination with a therapeutically effective amount of a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors.
- 15. The method of claim 14 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddI (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delviridine, trovirdine, PMEA, bis-POMPMEA and MSA-300 or a combination thereof.
- 16. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective amount of the compound of claim 7 in combination with a therapeutically effective amount of a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors.
- 17. The method of claim 16 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddI (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delviridine, trovirdine, PMEA, bis-POMPMEA and MSA-300.
- 18. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective amount of the compound of claim 1 in combination with a therapeutically effective amount of another HIV protease inhibitor or a combination of HIV protease inhibitors.
- 19. The method of claim 18 wherein the other HIV protease inhibitor is selected from the group consisting of ritonavir, saquinavir, indinavir,
5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide; 1-Naphthoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-t-butylamide; 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-t-butylamide; (1S-(1R*(R*),2S*)}-N1(3-((((1,1-dimethylethyl)amino)carbonyl)(2-methylpropyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)-butanediamide; 102or a pharmaceutically acceptable salt thereof, or a combination of two or more of these HIV protease inhibitors.
- 20. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective amount of the compound of claim 7 in combination with a therapeutically effective amount of another HIV protease inhibitor or a combination of HIV protease inhibitors.
- 21. The method of claim 20 wherein the other HIV protease inhibitor is selected from the group consisting of ritonavir, saquinavir, indinavir,
5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide; 1-Naphthoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-t-butylamide; 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-t-butylamide; (1S-(1R*(R*),2S*)}-N1(3-((((1,1-dimethylethyl)amino)carbonyl)(2-methylpropyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)-butanediamide; 103or a pharmaceutically acceptable salt thereof, or a combination of two or more of these HIV protease inhibitors.
- 22. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective amount of the compound of claim 7 in combination with a therapeutically effective amount of ritonavir or a pharmaceutically acceptable salt thereof.
- 23. An HIV protease inhibiting compound comprising a substituent of the formula:
- 24. A compound according to claim 23 wherein R3 is loweralkyl and R5 is
- 25. A compound according to claim 23 wherein R3 is loweralkyl and R5 is
- 26. A compound according to claim 23 wherein R3 is isopropyl and R5 is
- 27. A compound according to claim 23 wherein R3 is isopropyl and R5 is
- 28. A compound according to claim 23 wherein R3 is isopropyl and R5 is
- 29. A compound according to claim 23 selected from the group consisting of:
cis-N-tert-butyl-decahydro-2-(2(R)-hydroxy-4-phenyl-3(S)-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)aminobutyl)-(4aS,8aS)-isoquinoline-3(S)-carboxamide; cis-N-tert-butyl-decahydro-2-(2(R)-hydroxy-4-thiophenyl-3(S)-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)aminobutyl)-(4aS,8aS)-isoquinoline-3(S)-carboxamide; and 4-Amino-N-((2syn, 3S)-2-hydroxy-4-phenyl-3-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoylamino)-butyl)-N-isobutyl-benzenesulfonamide; or pharmaceutically acceptable salts thereof
- 30. A compound of the formula:
- 31. A compound according to claim 30 wherein R3 is loweralkyl and R5 is
- 32. A compound according to claim 30 wherein R3 is loweralkyl and R5 is
- 33. A compound according to claim 30 wherein R3 is isopropyl and R5 is
- 34. A compound according to claim 30 wherein R3 is isopropyl and R5 is
- 35. A compound according to claim 30 wherein R3 is isopropyl and R5 is
- 36. The compound according to claim 30 which is 2S-(1-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid or a salt or an activated ester derivative thereof.
- 37. A compound of the formula:
- 38. A compound according to claim 37 wherein P3 and P4 are hydrogen or benzyl, R1 and R2 are arylalkyl, R3 is loweralkyl and R5 is
- 39. A compound according to claim 37 wherein P3 and P4 are hydrogen or benzyl, R1 and R2 are benzyl or R1 is benzyl and R2 is loweralkyl, R3 is loweralkyl and R5 is
- 40. A compound according to claim 37 wherein P3 and P4 are hydrogen or benzyl, R1 and R2 are benzyl or R1 is benzyl and R2 is isopropyl, R3 is loweralkyl and R5 is
- 41. A compound according to claim 37 wherein P3 and P4 are hydrogen or benzyl, R1 and R2 are benzyl or R1 is benzyl and R2 is isopropyl, R3 is loweralkyl and R5 is
- 42. A compound according to claim 37 wherein P3 and P4 are hydrogen or benzyl, R1 and R2 are benzyl or R1 is benzyl and R2 is isopropyl, R3 is loweralkyl and R5 is
- 43. A compound according to claim 37 selected from the group consisting of:
(2S, 3S, 5S)-2-N,N-dibenzylamino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane; and (2S, 3S, 5S)-2-Amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane; or a salt thereof.
- 44. The compound according to claim 43 which is (2S, 3S, 5S)-2-Amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane (S)-Pyroglutamic acid salt.
- 45. A process for the preparation of a compound of the formula:
- 46. The process of claim 45 wherein R3 is loweralkyl.
- 47. The process of claim 45 wherein R3 is isopropyl and Q is chloro.
- 48. The process of claim 45 wherein R3 is loweralkyl and the carbonyl equivalent is Q′—C(O)—Q″ wherein Q′ and Q″ are Cl, Br, I, —O-loweralkyl, —O-aryl or imidazolyl.
- 49. The process of claim 48 wherein R3 is isopropyl.
- 50. The process of claim 45 wherein R3 is loweralkyl and R30 is loweralkyl.
- 51. The process of claim 50 wherein R3 is isopropyl and R30 is methyl.
- 52. A process for the preparation of a compound of claim 1 comprising reacting a compound of the formula:
- 53. A process for the preparation of (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane; or a pharmaceutically acceptable salt, ester or prodrug thereof, comprising reacting (2S, 3S, 5S)-2-amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane with 2,6-dimethylphenoxyacetic acid, or a salt of activated ester derivative thereof.
- 54. The process according to claim 53 wherein (2S, 3S, 5S)-2-amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane is reacted with 2,6-dimethylphenoxyacetyl chloride.
- 55. A process for the preparation of a compound of claim 1 comprising
(a) reacting a compound of the formula: 164 wherein P3 is hydrogen and P4 is an N-protecting group or both P3 and P4 are N-protecting groups and R1 and R2 are as defined therein with a compound of the formula: 165 or a salt or activated ester derivative thereof, wherein R3 and R5 are as defined therein, to provide a compound of the formula: 166 wherein P3, P4, R1, R2, R3 and R5 are as defined above; (b) N-deprotecting the product of step (a) to provide a compound of the formula: 167 wherein R1, R2, R3 and R5 are as defined above; and (c) reacting the product of step (b) with a compound of the formula: 168 or a salt or activated ester derivative thereof, wherein R4 and L1 are as defined therein.
- 56. A process for the preparation of (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane; or a pharmaceutically acceptable salt, ester or prodrug thereof, comprising
(a) reacting (2S, 3S, 5S)-2-N,N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane with 2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid or a salt or activated ester derivative thereof to provide (2S, 3S, 5S)-2-N,N-dibenzylamino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane; (b) debenzylating the product of step (a) to provide (2S, 3S, 5S)-2-amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane; and (c) reacting the product of step (b) with 2,6-dimethylphenoxyacetic acid, or a salt of activated ester derivative thereof.
- 57. The process according to claim 56 wherein
(a) (2S, 3S, 5S)-2-N,N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane is reacted with 2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl chloride to provide (2S, 3S, 5S)-2-N,N-dibenzylamino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane; (b) the product of step (a) is hydrogenated to provide (2S, 3S, 5S)-2-amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenyihexane; and (c) the product of step (b) is reacted with 2,6-dimethylphenoxyacetyl chloride.
- 58. A process for the preparation of (2S, 3S, 5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-amino-1,6-diphenylhexane or a salt thereof, comprising reacting (2S, 3S, 5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane with trifluoroacetic acid in methylene chloride, aqueous hydrochloric acid in acetonitrile or aqueous hydrochloric acid in acetic acid.
- 59. A process for the preparation of a compound of the formula:
- 60. The process of claim 59 wherein R3 is loweralkyl and Q is chloro.
- 61. The process of claim 59 wherein R3 is isopropyl and Q is chloro.
- 62. A process for the preparation of (2S, 3S, 5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane, or a pharmaceutically acceptable salt, ester or prodrug thereof, as an amorphous solid, comprising dissolving (2S, 3S, 5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane in an organic solvent, followed by adding the solution to water.
- 63. The process according to claim 62 wherein (2S, 3S, 5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane is dissolved in ethanol (from about 2 to about 4 mL/g) and the ethanolic solution is added to water (from about 10 about 100 mL/g).
Parent Case Info
[0001] This is a continuation-in-part of U.S. patent application Ser. No. 08/572,226, filed Dec. 13, 1995.
Divisions (3)
|
Number |
Date |
Country |
Parent |
09837280 |
Apr 2001 |
US |
Child |
10280652 |
Oct 2002 |
US |
Parent |
09207873 |
Dec 1998 |
US |
Child |
09837280 |
Apr 2001 |
US |
Parent |
08753201 |
Nov 1996 |
US |
Child |
09207873 |
Dec 1998 |
US |
Continuation in Parts (1)
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Number |
Date |
Country |
Parent |
08572226 |
Dec 1995 |
US |
Child |
08753201 |
Nov 1996 |
US |