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Claims for Patent: 6,284,767

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Claims for Patent: 6,284,767

Title: Retroviral protease inhibiting compounds
Abstract:A compound of the formula: ##STR1## is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
Inventor(s): Sham; Hing Leung (Vernon Hills, IL), Norbeck; Daniel W. (Grayslake, IL), Kempf; Dale J. (Libertyville, IL), Chen; Xiaoqi (San Mateo, CA), Betebenner; David A. (Lawrenceville, NJ), Herrin; Thomas R. (Waukegan, IL), Kumar; Gondi N. (Newbury Park, CA), Lipari; John M. (Racine, WI), Alani; Laman (Morris Plains, NJ), Ghosh; Soumojeet (Lindenhurst, IL), Gao; Rong R. (Edison, NJ), Kaul; Dilip (Edison, NJ)
Assignee: Abbott Laboratories (Abbott Park, IL)
Application Number:09/207,873
Patent Claims: 1. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective combination of a compound of the formula: ##STR87##

wherein R.sub.1 and R.sub.2 are independently selected from the group consisting of loweralkyl, cycloalkylalkyl and arylalkyl;

R.sub.3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl;

R.sub.4 is aryl or heterocyclic;

R.sub.5 is ##STR88##

wherein n is 1, 2 or 3, m is 1, 2 or 3, m' is 1 or 2, X is O, S or NH, Y is --CH.sub.2 --, --O--, --S--or --N(R.sub.6)-- wherein R.sub.6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y" is --CH.sub.2 -- or --N(R.sub.6")-- wherein R.sub.6 " is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y' is --N(R.sub.6')-- wherein R.sub.6' is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O, S or NH; and

L.sub.1 is

a) --O--,

b) --S--,

c) --N(R.sub.7)-- wherein R.sub.7 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl,

d) --O-alkylenyl-,

e) --S-alkylenyl-,

f) --S(O)-alkyleneyl-,

g) --S(O).sub.2 -alkylenyl-,

h) --N(R.sub.7)-alkylenyl- wherein R.sub.7 is defined as above,

i) -alkylenyl--O--,

j) -alkylenyl--S--,

k) -alkylenyl-N(R.sub.7)-- wherein R.sub.7 is defined as above,

l) alkylenyl or

m) alkenylenyl;

or a pharmaceutically acceptable salt, ester or prodrug thereof, and a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors.

2. The method of claim 1 wherein the reverse transcriptase inhibitor is selected from the group consisting of 5-halo-3'-thia-dideoxycytidine, AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delavirdine, trovirdine, PMEA, bis-POMPMEA, MSA-300 and combinations of two or more thereof.

3. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective combination of the compound (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane, or a pharmaceutically acceptable salt, ester or prodrug thereof and a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors.

4. The method of claim 3 wherein the reverse transcriptase inhibitor is selected from the group consisting of 5-halo-3'-thia-dideoxycytidine, AZT (zidovudine), ddI (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delavirdine , trovirdine, PMEA, bis-POMPMEA, MSA-300 and combinations of two or more thereof.

5. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective combination of a compound of the formula: ##STR89##

wherein R.sub.1 and R.sub.2 are independently selected from the group consisting of loweralkyl, cycloalkylalkyl and arylalkyl;

R.sub.3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl;

R.sub.4 is aryl or heterocyclic;

R.sub.5 is ##STR90##

wherein n is 1, 2 or 3, m is 1, 2 or 3, m' is 1 or 2, X is O, S or NH, Y is --CH.sub.2 --, --O--, --S--or --N(R.sub.6)-- wherein R.sub.6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y" is --CH.sub.2 -- or --N(R.sub.6")-- wherein R.sub.6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y' is --N(R.sub.6')-- wherein R.sub.6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O, S or NH; and

L.sub.1 is

a) --O--,

b) --S--,

c) --N(R.sub.7)-- wherein R.sub.7 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl,

d) --O-alkylenyl-,

e) --S--alkylenyl-,

f) --S(O)-alkyleneyl-,

g) --S(O).sub.2 -alkylenyl-,

h) --N(R.sub.7)-alkylenyl- wherein R.sub.7 is defined as above,

i) -alkylenyl-O--,

j) -alkylenyl-S--,

k) -alkylenyl-N(R.sub.7)-- wherein R.sub.7 is defined as above,

l) alkylenyl or

m) alkenylenyl;

or a pharmaceutically acceptable salt, ester or prodrug thereof, and another HIV protease inhibitor or a combination of other HIV protease inhibitors.

6. The method of claim 5 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-butyiamide;

5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-buta noyl-1,3-thiazolidine-4-t-butylamide;

(1S-(1R*(R*),2S*)}-N.sup.1 (3-((((1,1-dimethylethyl)amino)carbonyl)(2-methyipropyl)amino)-2-hydroxy-1 -(phenylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)-butanediamide; ##STR91##

or a pharmaceutically acceptable salt thereof, or a combination of two or more of these HIV protease inhibitors.

7. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective combination of the compound (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane, or a pharmaceutically acceptable salt, ester or prodrug thereof and another HIV protease inhibitor or a combination of other HIV protease inhibitors.

8. The method of claim 7 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-buta noyl-1,3-thiazolidine-4-t-butylamide;

(1S-(1R*(R*),2S*)}-N.sup.1 (3-((((1,1-dimethylethyl)amino)carbonyl)(2-methylpropyl)amino)-2-hydroxy-1 -(phenylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)-butanediamide; ##STR92##

or a pharmaceutically acceptable salt thereof, or a combination of two or more of these HIV protease inhibitors.

9. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective combination of the compound (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane, or a pharmaceutically acceptable salt, ester or prodrug thereof and ritonavir or a pharmaceutically acceptable salt thereof.

10. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective combination of a compound of the formula: ##STR93##

wherein R.sub.1 and R.sub.2 are independently selected from the group consisting of loweralkyl, cycloalkylalkyl and arylalkyl;

R.sub.3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl;

R.sub.4 is aryl or heterocyclic;

R.sub.5 is ##STR94##

wherein n is 1, 2 or 3, m is 1, 2 or 3, m' is 1 or 2, X is O, S or NH, Y is --CH.sub.2 --, --O--, --S--or --N(R.sub.6)-- wherein R.sub.6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y" is --CH.sub.2 -- or --N(R.sub.6")-- wherein R.sub.6" is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y' is --N(R.sub.6")-- wherein R.sub.6" is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O, S or NH; and

L.sub.1 is

a) --O--,

b) --S--,

c) --N(R.sub.7)-- wherein R.sub.7 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl,

d) --O-alkylenyl-,

e) --S-alkylenyl-,

f) --S(O)-alkyleneyl-,

g) --S(O).sub.2 -alkylenyl-,

h) --N(R.sub.7)-alkylenyl- wherein R.sub.7 is defined as above,

i) -alkylenyl-O--,

j) -alkylenyl-S--,

k) -alkylenyl-N(R.sub.7)-- wherein R.sub.7 is defined as above,

l) alkylenyl or

m) alkenylenyl;

or a pharmaceutically acceptable salt, ester or prodrug thereof, and another HIV protease inhibitor or a combination of other HIV protease inhibitors and a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors.

11. The method according to claim 10 wherein said compound of formula I is (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.

12. The method according to claim 10 wherein said compound of formula I is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl) -3-methyl butanoyl)amino-1,6-diphenylhexane.

13. The method according to claim 10 wherein said other HIV protease inhibitor is selected from the group consisting of ritonavir, saquinavir, VX-478, U-140690, nelfinavir and combinations of two or more thereof, or a pharmaceutically acceptable salt thereof.

14. The method according to claim 12 wherein said other HIV protease inhibitor is ritonavir.

15. The method according to claim 10 wherein said reverse transcriptase inhibitor is selected from the group consisting of 5-halo-3'-thia-dideoxycytidine, AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delavirdine, trovirdine, PMEA, bis-POMPMEA, MSA-300, and combinations of two or more thereof.

16. The method according to claim 15 wherein said reverse transcriptase inhibitor is selected from the group consisting of 5-halo-3'-thia-dideoxycytidine, AZT (zidovudine), 3TC (lamivudine), and d4T (stavudine).

17. The method according to claim 15 wherein said reverse transcriptase inhibitor is 5-halo-3'-thia-dideoxycytidine.

18. The method according to claim 15 wherein said reverse transcriptase inhibitor is 3TC (lamivudine).

19. The method according to claim 15 wherein said reverse transcriptase inhibitor is d4T (stavudine).

20. The method according to claim 15 wherein said reverse transcriptase inhibitor is nevirapine.

21. The method according to claim 15 wherein said reverse transcriptase inhibitor is delavirdine.

22. The method according to claim 15 wherein said compound of formula I is (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, said other HIV protease inhibitor is ritonavir, and said reverse transcriptase inhibitor is 5-halo-3'-thia-dideoxycytidine.

23. The method according to claim 15 wherein said compound of formula I is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(l-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane,

or a pharmaceutically acceptable salt, ester or prodrug thereof, said other HIV protease inhibitor is ritonavir, and said reverse transcriptase inhibitor is 3TC (lamivudine).

24. The method according to claim 15 wherein said compound of formula I is (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, said other HIV protease inhibitor is ritonavir, and said reverse transcriptase inhibitor is d4T (stavudine).

25. The method according to claim 15 wherein said compound of formula I is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(l-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane,

or a pharmaceutically acceptable salt, ester or prodrug thereof, said other HIV protease inhibitor is ritonavir, and said reverse transcriptase inhibitor is nevirapine.

26. The method according to claim 15 wherein said compound of formula I is (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, said other HIV protease inhibitor is ritonavir, and said reverse transcriptase inhibitor is delavirdine.

27. The method according to claim 15 wherein said compound of formula I is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane,

said other HIV protease inhibitor is ritonavir, and said reverse transcriptase inhibitor is 5-halo-3'-thia-dideoxycytidine.

28. The method according to claim 15 wherein said compound of formula I is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane,

said other HIV protease inhibitor is ritonavir, and said reverse transcriptase inhibitor is 3TC (lamivudine).

29. The method according to claim 15 wherein said compound of formula I is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane,

said other HIV protease inhibitor is ritonavir, and said reverse transcriptase inhibitor is d4T (stavudine).

30. The method according to claim 15 wherein said compound of formula I is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(l-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane,

said other HIV protease inhibitor is ritonavir, and said reverse transcriptase inhibitor is nevirapine.

31. The method according to claim 15 wherein said compound of formula I is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane,

said additional HIV protease inhibitor is ritonavir, and said reverse transcriptase inhibitor is delavirdine.

32. A pharmaceutical composition comprising a pharmaceutical carrier and therapeutically effective combination of a compound of the formula: ##STR95##

wherein R.sub.1 and R.sub.2 are independently selected from the group consisting of loweralkyl, cycloalkylalkyl and arylalkyl;

R.sub.3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl;

R.sub.4 is aryl or heterocyclic; ##STR96##

wherein n is 1, 2 or 3, m is 1, 2 or 3, m' is 1 or 2, X is O, S or NH, Y is --CH.sub.2 --, --O--, --S--or --N(R.sub.6)-- wherein R.sub.6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y" is --CH.sub.2 -- or --N(R.sub.6")-- wherein R.sub.6" is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y' is --N(R.sub.6')-- wherein R.sub.6' is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O, S or NH; and

L.sub.1 is

a) --O--,

b) --S--,

c) --N(R.sub.7)-- wherein R.sub.7 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl,

d) --O-alkylenyl-,

e) --S-alkylenyl-,

f) --S(O)-alkyleneyl-,

g) --S(O).sub.2 -alkylenyl-,

h) --N(R.sub.7)-alkylenyl- wherein R.sub.7 is defined as above,

i) -alkylenyl-O--,

j) -alkylenyl-S--,

k) -alkylenyl-N(R.sub.7)-- wherein R.sub.7 is defined as above,

l) alkylenyl or

m) alkenylenyl;

or a pharmaceutically acceptable salt, ester or prodrug thereof, and another HIV protease inhibitor or a combination of other HIV protease inhibitors.

33. A pharmaceutical composition comprising a pharmaceutical carrier and therapeutically effective combination of a compound of the formula: ##STR97##

wherein R.sub.1 and R.sub.2 are independently selected from the group consisting of loweralkyl, cycloalkylalkyl and arylalkyl;

R.sub.3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl;

R.sub.4 is aryl or heterocyclic;

R.sub.5 is ##STR98##

wherein n is 1, 2 or 3, m is 1, 2 or 3, m' is 1 or 2, X is O, S or NH, Y is --CH.sub.2 --, --O--, --S--or --N(R.sub.6)-- wherein R.sub.6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y" is --CH.sub.2 -- or --N(R.sub.6")-- wherein R.sub.6" is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y' is --N(R.sub.6')-- wherein R.sub.6' is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O, S or NH; and

L.sub.1 is

a) --O--,

b) --S--, 1

c) --N(R.sub.7)-- wherein R.sub.7 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl,

d) --O-alkylenyl-,

e) --S-alkylenyl-,

f) --S(O)-alkyleneyl-,

g) --S(O) .sub.2 -alkylenyl-,

h) --N(R.sub.7)-alkylenyl- wherein R.sub.7 is defined as above,

i) -alkylenyl-O--,

j) -alkylenyl--S--,

k) -alkylenyl-N(R.sub.7)-- wherein R.sub.7 is defined as above,

l) alkylenyl or

m) alkenylenyl;

or a pharmaceutically acceptable salt, ester or prodrug thereof, and a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors.

34. The pharmaceutical composition according to claim 32 which further comprises a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors.

35. The pharmaceutical composition according to claim 32 wherein said compound of formula I is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane, or a pharmaceutically acceptable salt, ester or prodrug thereof.

36. The pharmaceutical composition according to claim 32 wherein said compound of formula I is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane.

37. The pharmaceutical composition according to claim 34 wherein said other HIV protease inhibitor is ritonavir.

38. The pharmaceutical composition according to claim 34 wherein said reverse transcriptase inhibitor is 5-halo-3'-thia-dideoxycytidine.

39. The pharmaceutical composition according to claim 34 wherein said reverse transcriptase inhibitor is 3TC (lamivudine).

40. The pharmaceutical composition according to claim 34 wherein said reverse transcriptase inhibitor is d4T (stavudine).

41. The pharmaceutical composition according to claim 34 wherein said reverse transcriptase inhibitor is nevirapine.

42. The pharmaceutical composition according to claim 34 wherein said reverse transcriptase inhibitor is delavirdine.

43. The pharmaceutical composition according to claim 37 wherein said compound of formula I is (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.

44. The pharmaceutical composition according to claim 37 wherein said compound of formula I is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane.

45. The pharmaceutical composition according to claim 32 wherein said other HIV protease inhibitor is selected from the group consisting of ritonavir, saquinavir, VX-478, U-140690, indinavir, nelfinavir and combinations of two or more thereof, or a pharmaceutically acceptable salt thereof.

46. The pharmaceutical composition according to claim 45 wherein said additional HIV protease inhibitor is ritonavir.

47. The pharmaceutical composition according to claim 32 wherein said compound of formula I is present in the amount of from about 1% to about 50% by weight of the total composition.

48. The pharmaceutical composition according to claim 32 wherein said compound of formula I is present in the amount of from about 5% to about 30% by weight of the total composition.

49. The pharmaceutical composition according to claim 46 wherein said compound of formula I is present in the amount of from about 1% to about 50% by weight of the total composition.

50. The pharmaceutical composition according to claim 46 wherein said compound of formula I is present in the amount of from about 5% to about 30% by weight of the total composition.

51. The pharmaceutical composition according to claim 46 wherein said compound of formula I is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane, or a pharmaceutically acceptable salt, ester or prodrug thereof.

52. The pharmaceutical composition according to claim 46 wherein said compound of formula I is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane.

53. The pharmaceutical composition according to claim 33 wherein said reverse transcriptase inhibitor is 5-halo-31-thia-dideoxycytidine.

54. The pharmaceutical composition according to claim 33 wherein said reverse transcriptase inhibitor is 3TC (lamivudine).

55. The pharmaceutical composition according to claim 33 wherein said reverse transcriptase inhibitor is d4T (stavudine).

56. The pharmaceutical composition according to claim 33 wherein said reverse transcriptase inhibitor is nevirapine.

57. The pharmaceutical formulation according to claim 33 wherein said reverse transcriptase inhibitor is delavirdine.

58. The pharmaceutical composition according to claim 33 wherein said compound of formula I is present in the amount of from about 1% to about 50% by weight of the total composition.

59. The pharmaceutical composition according to claim 33 wherein said compound of formula I is present in the amount of from about 5% to about 30% by weight of the total composition.

60. The pharmaceutical composition according to claim 33 wherein said compound of formula I is (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.

61. The pharmaceutical composition according to claim 33 wherein said compound of formula I is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methyl butanoyl)amino-1,6-diphenylhexane.

62. The pharmaceutical composition according to claim 60 wherein said additional HIV protease inhibitor is ritonavir.

63. The pharmaceutical composition according to claim 60 wherein said reverse transcriptase inhibitor is 5-halo-3.sup.1 -thia-dideoxycytidine.

64. The pharmaceutical composition according to claim 60 wherein said reverse transcriptase inhibitor is 3TC (lamivudine).

65. The pharmaceutical composition according to claim 60 wherein said reverse transcriptase inhibitor is d4T (stavudine).

66. The pharmaceutical composition according to claim 60 wherein said reverse transcriptase inhibitor is nevirapine.

67. The pharmaceutical formulation according to claim 60 wherein said reverse transcriptase inhibitor is delavirdine.

68. The pharmaceutical composition according to claim 60 wherein said compound of formula I is present in the amount of from about 1d to about 50% by weight of the total composition.

69. The pharmaceutical composition according to claim 60 wherein said compound of formula I is present in the amount of from about 5% to about 30% by weight of the total composition.

70. The pharmaceutical composition according to claim 43 wherein said compound of formula I is present in the amount of from about 1% to about 50% by weight of the total composition, and ritonavir is present in the amount of from about 1% to about 30% by weight of the total composition.

71. The pharmaceutical composition according to claim 43 wherein said compound of formula I is present in the amount of from about 5% to about 30% by weight of the total composition, and ritonavir is present in the amount of from about 1% to about 30% by weight of the total composition.

72. The pharmaceutical composition according to claim 51 wherein said compound of formula I is present in the amount of from about 1% to about 50% by weight of the total composition, and ritonavir is present in the amount of from about 1% to about 30% by weight of the total composition.

73. The pharmaceutical composition according to claim 51 wherein said compound of formula I is present in the amount of from about 5% to about 30% by weight of the total composition, and ritonavir is present in the amount of from about 1% to about 30% by weight of the total composition.

74. The pharmaceutical composition according to claim 62 wherein said compound of formula I is present in the amount of from about 1% to about 50% by weight of the total composition, and ritonavir is present in the amount of from about 1% to about 30% by weight of the total composition.

75. The pharmaceutical composition according to claim 62 wherein said compound of formula I is present in the amount of from about 5% to about 30% by weight of the total composition, and ritonavir is present in the amount of from about 1% to about 30% by weight of the total composition.

76. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective combination of the compound (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane, and a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors.

77. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective combination of the compound (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane and another HIV protease inhibitor or a combination of other HIV protease inhibitors.

78. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective combination of the compound (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane and ritonavir or a pharmaceutically acceptable salt thereof.

79. A pharmaceutical composition comprising (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl) amino-1,6-diphenylhexane and ritonavir in a ratio (w/w) of from about 16:1 to about 1:5.

80. A pharmaceutical composition comprising (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6-diphenylhexane and ritonavir in a ratio (w/w) of from about 6:1 to about 1:3.

81. The pharmaceutical composition according to claim 61 wherein said other HIV protease inhibitor is ritonavir.

82. The pharmaceutical composition according to claim 61 wherein said reverse transcriptase inhibitor is 5-halo-3'-thia-dideoxycytidine.

83. The pharmaceutical composition according to claim 61 wherein said reverse transcriptase inhibitor is 3TC (lamivudine).

84. The pharmaceutical composition according to claim 61 wherein said reverse transcriptase inhibitor is d4T (stavudine).

85. The pharmaceutical composition according to claim 61 wherein said reverse transcriptase inhibitor is nevirapine.

86. The pharmaceutical composition according to claim 61 wherein said reverse transcriptase inhibitor is delavirdine.

87. The pharmaceutical composition according to claim 61 wherein said compound of formula I is present in the amount of from about 1% to about 50% by weight of the total composition.

88. The pharmaceutical composition according to claim 61 wherein said compound of formula I is present in the amount of from about 5% to about 30% by weight of the total composition.

89. The pharmaceutical composition according to claim 44 wherein said compound of formula I is present in the amount of from about 1% to about 50% by weight of the total composition, and ritonavir is present in the amount of from about 1% to about 30% by weight of the total composition.

90. The pharmaceutical composition according to claim 44 wherein said compound of formula I is present in the amount of from about 5% to about 30% by weight of the total composition, and ritonavir is present in the amount of from about 1% to about 30% by weight of the total composition.

91. The pharmaceutical composition according to claim 52 wherein said compound of formula I is present in the amount of from about 1% to about 50% by weight of the total composition, and ritonavir is present in the amount of from about 1% to about 30% by weight of the total composition.

92. The pharmaceutical composition according to claim 52 wherein said compound of formula I is present in the amount of from about 5% to about 30% by weight of the total composition, and ritonavir is present in the amount of from about 1% to about 30% by weight of the total composition.

93. The pharmaceutical composition according to claim 61 wherein said compound of formula I is present in the amount of from about 1% to about 50% by weight of the total composition, and ritonavir is present in the amount of from about 1% to about 30% by weight of the total composition.

94. The pharmaceutical composition according to claim 61 wherein said compound of formula I is present in the amount of from about 5% to about 30% by weight of the total composition, and ritonavir is present in the amount of from about 1% to about 30% by weight of the total composition.

95. The method of claim 76 wherein the reverse transcriptase inhibitor is selected from the group consisting of 5-halo-3'-thia-dideoxycytidine, AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delavirdine, trovirdine, PMEA, bis-POMPMEA, MSA-300 and combinations of two or more thereof.

96. The method of claim 77 wherein the other HIV protease inhibitor is selected from the group consisting of ritonavir, saquinavir, indinavir, nelfinavir, VX-478, DMP-323, DMP-450, BMS 186,318, SC-55389a, BILA 1096 BS, U-140690,

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-buta noyl-1,3-thiazolidine-4-t-butylamide,

(1S-(1R*(R*),2S*))--N.sup.1 (3-((((1,1-dimethylethyl)amino)carbonyl)(2-methylpropyl)amino)-2-hydroxy-1 -(phenylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)-butanediamide and combinations of two or more thereof; or a pharmaceutically acceptable salt thereof.

97. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective combination of the compound (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane and ritonavir.

98. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective combination of the compound (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydr o-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane and ritonavir.
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