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Claims for Patent: 8,597,876

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Claims for Patent: 8,597,876

Title:Method of treating HIV infection
Abstract: Disclosed is a method of treating human immunodeficiency virus (HIV) infection in an antiretroviral treatment-experienced mammal, which involves administering to the mammal an effective amount of a compound of the formula: ##STR00001## or a pharmaceutically acceptable salt, a prodrug, or an ester thereof, or a pharmaceutically acceptable composition of the compound, the salt, the prodrug, or the ester thereof, wherein A, X, Q, W, m, and R.sup.2-R.sup.6 are as defined herein.
Inventor(s): Erickson; John W. (Frederick, MD), Gulnik; Sergei V. (Frederick, MD), Mitsuya; Hiroaki (Chevy Chase, MD), Ghosh; Arun K. (West Lafayette, IN)
Assignee: The United States of America, as represented by the Secretary, Department of Health and Human Services (Washington, DC) N/A (Urbana, IL) Board of Trustees of the University of Illinois (
Application Number:11/870,931
Patent Claims: 1. A method of treating human immunodeficiency virus (HIV) infection in an antiretroviral treatment-experienced mammal, the method comprising administering to the mammal an effective amount of a compound of the formula: ##STR00036## or a pharmaceutically acceptable salt, a prodrug, or an ester thereof, or a pharmaceutically acceptable composition of said compound, said salt, said prodrug, or said ester thereof, wherein: A is of the formula: ##STR00037## R.sup.1 is H or an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkylalkyl, an aryl, an aralkyl, a heterocycloalkyl, a heterocycloalkylalkyl, a heteroaryl, or a heteroaralkyl, in which at least one hydrogen atom is optionally substituted with a substituent selected from the group consisting of OR.sup.7, SR.sup.7, CN, NO.sub.2, N.sub.3, and a halogen, wherein R.sup.7 is H, an unsubstituted alkyl, an unsubstituted alkenyl, or an unsubstituted alkynyl; Y and Z are the same or different and each is selected from the group consisting of CH.sub.2, O, S, SO, SO.sub.2, NR.sup.8, R.sup.8C(O)N, R.sup.8C(S)N, R.sup.8OC(O)N, R.sup.8OC(S)N, R.sup.8SC(O)N, R.sup.8R.sup.9NC(O)N, and R.sup.8R.sup.9NC(S)N, wherein R.sup.8 and R.sup.9 are each selected from the group consisting of H, an unsubstituted alkyl, an unsubstituted alkenyl, and an unsubstituted alkynyl; n is an integer from 1 to 5; X is a covalent bond, CHR.sup.10, CHR.sup.10CH.sub.2, CH.sub.2CHR.sup.10, O, NR.sup.10, or S, wherein R.sup.10 is H, an unsubstituted alkyl, an unsubstituted alkenyl, or an unsubstituted alkynyl; Q is C(O), C(S), or SO.sub.2; R.sup.2 is H, a C.sub.1-C.sub.6 alkyl, a C.sub.2-C.sub.6 alkenyl, or a C.sub.2-C.sub.6 alkynyl; m is an integer from 0 to 6; R.sup.3 is a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl in which at least one hydrogen atom is optionally substituted with a substituent selected from the group consisting of alkyl, (CH.sub.2).sub.pR.sup.11, OR.sup.12, SR.sup.12, CN, N.sub.3, NO.sub.2, NR.sup.12R.sup.13, C(O)R.sup.12, C(S)R.sup.12, CO.sub.2R.sup.12, C(O)SR.sup.12, C(O)NR.sup.12R.sup.13, C(S)NR.sup.12R.sup.13, NR.sup.12C(O)R.sup.13, NR.sup.12C(S)R.sup.13, NR.sup.12CO.sub.2R.sup.13, NR.sup.12C(O)SR.sup.13, and a halogen, wherein: p is an integer from 0 to 5; R.sup.11 is a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl in which at least one hydrogen atom is optionally substituted with a substituent selected from the group consisting of a halogen, OH, OCH.sub.3, NH.sub.2, NO.sub.2, SH, and CN; and R.sup.12 and R.sup.13 are the same or different and each is selected from the group consisting of H, an unsubstituted alkyl, an unsubstituted alkenyl, and an unsubstituted alkynyl; R.sup.4 is OH, .dbd.O (keto), or NH.sub.2, wherein, when R.sup.4 is OH, it is optionally in the form of a pharmaceutically acceptable ester or prodrug, and when R.sup.4 is NH.sub.2, it is optionally an amide, a hydroxylamino, a carbamate, a urea, an alkylamino, a dialkylamino, a protic salt thereof, or a tetraalkylammonium salt thereof; R.sup.5 is H, a C.sub.1-C.sub.6 alkyl radical, a C.sub.2-C.sub.6 alkenyl radical, or (CH.sub.2).sub.qR.sup.14, wherein q is an integer from 0 to 5, and R.sup.14 is a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl radical in which at least one hydrogen atom is optionally substituted with a substituent selected from the group consisting of a halogen, OH, OCH.sub.3, NH.sub.2, NO.sub.2, SH, and CN; W is C(O), C(S), or SO.sub.2; and R.sup.6 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl radical in which at least one hydrogen atom is optionally substituted with a substituent selected from the group consisting of a halogen, OR.sup.15, SR.sup.15, S(O)R.sup.15, SO.sub.2R.sup.15, SO.sub.2NR.sup.15R.sup.16, SO.sub.2N(OH)R.sup.15, CN, CR.sup.15.dbd.NR.sup.16, CR.sup.15.dbd.N(OR.sup.16), N.sub.3, NO.sub.2, NR.sup.15R.sup.16, N(OH)R.sup.15, C(O)R.sup.15, C(S)R.sup.15, CO.sub.2R.sup.15, C(O)SR.sup.15, C(O)NR.sup.15R.sup.16, C(S)NR.sup.15R.sup.16, C(O)N(OH)R.sup.15, C(S)N(OH)R.sup.15, NR.sup.15C(O)R.sup.16, NR.sup.15C(S)R.sup.16, N(OH)C(O)R.sup.15, N(OH)C(S)R.sup.15, NR.sup.15CO.sub.2R.sup.16, N(OH)CO.sub.2R.sup.15, NR.sup.15C(O)SR.sup.16, NR.sup.15C(O)NR.sup.16R.sup.17, NR.sup.15C(S)NR.sup.16R.sup.17, N(OH)C(O)NR.sup.15R.sup.16, N(OH)C(S)NR.sup.15R.sup.16, NR.sup.15C(O)N(OH)R.sup.16, NR.sup.15C(S)N(OH)R.sup.16, NR.sup.15SO.sub.2R.sup.16, NHSO.sub.2NR.sup.15R.sup.16, NR.sup.15SO.sub.2NHR.sup.16, P(O)(OR.sup.15)(OR.sup.16), an alkyl, an alkoxy, an alkylthio, an alkylamino, a cycloalkyl, a cycloalkylalkyl, a heterocycloalkyl, a heterocycloalkylalkyl, an aryl, an aryloxy, an arylamino, an arylthio, an aralkyl, an aryloxyalkyl, an arylaminoalkyl, an aralkoxy, an (aryloxy)alkoxy, an (arylamino)alkoxy, an (arylthio)alkoxy, an aralkylamino, an (aryloxy)alkylamino, an (arylamino)alkylamino, an (arylthio)alkylamino, an aralkylthio, an (aryloxy)alkylthio, an (arylamino)alkylthio, an (arylthio)alkylthio, a heteroaryl, a heteroaryloxy, a heteroarylamino, a heteroarylthio, a heteroaralkyl, a hetero aralkoxy, a heteroaralkylamino, and a heteroaralkylthio, wherein R.sup.15, R.sup.16, and R.sup.17 are the same or different and each is H, an unsubstituted alkyl, or an unsubstituted alkenyl, wherein, when at least one hydrogen atom of R.sup.6 is substituted with a substituent other than a halogen, OR.sup.15, SR.sup.15, CN, N.sub.3, NO.sub.2, NR.sup.15R.sup.16, C(O)R.sup.15, C(S)R.sup.15, CO.sub.2R.sup.15, C(O)SR.sup.15, C(O)NR.sup.15R.sup.16, C(S)NR.sup.15R.sup.16, NR.sup.15C(O)R.sup.16, NR.sup.15C(S)R.sup.16, NR.sup.15CO.sub.2R.sup.16, NR.sup.15C(O)SR.sup.16, NR.sup.15C(O)NR.sup.16R.sup.17, or NR.sup.15C(S)NR.sup.16R.sup.17, at least one hydrogen atom on said substituent is optionally substituted with a halogen, OR.sup.15, SR.sup.15, CN, N.sub.3, NO.sub.2, NR.sup.15R.sup.16, C(O)R.sup.15, C(S)R.sup.15, CO.sub.2R.sup.15, C(O)SR.sup.15, C(O)NR.sup.15R.sup.16, C(S)NR.sup.15R.sup.16, NR.sup.15C(O)R.sup.15, NR.sup.15C(S)R.sup.16, NR.sup.15CO.sub.2R.sup.16, NR.sup.15C(O)SR.sup.16, NR.sup.15C(O)NR.sup.16R.sup.17, or NR.sup.15C(S)NR.sup.16R.sup.17.

2. The method of claim 1, wherein: when R.sup.1 is an alkyl, it is a C.sub.1-C.sub.6 alkyl; when R.sup.1 is an alkenyl it is a C.sub.2-C.sub.6 alkenyl; when R.sup.1 is a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, R.sup.1 is a 4-7 membered ring; when R.sup.7, R.sup.8 or R.sup.9 is an unsubstituted alkyl, it is a C.sub.1-C.sub.6 unsubstituted alkyl; when R.sup.7, R.sup.8 or R.sup.9 is an unsubstituted alkenyl, it is a C.sub.2-C.sub.6 unsubstituted alkenyl; R.sup.3 is a 4-7 membered ring; R.sup.11 is a 4-7 membered ring; when R.sup.12 or R.sup.13 is an unsubstituted alkyl, it is a C.sub.1-C.sub.6 unsubstituted alkyl; when R.sup.12 or R.sup.13 is an unsubstituted alkenyl, it is a C.sub.2-C.sub.6 unsubstituted alkyl; when R.sup.14 is a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, R.sup.14 is a 4-7 membered ring; when R.sup.6 is a cycloalkyl, a heterocycloalkyl, aryl, or a heteroaryl, R.sup.6 is a 4-7 membered ring; when R.sup.6 is substituted with a substituent that is an alkyl, an alkylthio, or an alkylamino, the substituent comprises from one to six carbon atoms; and when R.sup.6 is substituted with a substituent that is a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, the substituent is a 4-7 membered ring.

3. The method of claim 1, wherein Q is C(O), R.sup.2 is H, and W is SO.sub.2.

4. The method of claim 1, wherein the compound is represented by the formula: ##STR00038##

5. The method of claim 4, wherein said compound is represented by the formula: ##STR00039## wherein Ar is a phenyl which is optionally substituted with a substituent selected from the group consisting of methyl, amino, hydroxy, methoxy, methylthio, hydroxymethyl, aminomethyl, and methoxymethyl.

6. The method of claim 5, wherein the compound is represented by the formula: ##STR00040##

7. The method of claim 5, wherein X is oxygen.

8. The method of claim 5, wherein R.sup.5 is isobutyl.

9. The method of claim 5, wherein Ar is a phenyl substituted at the para-position.

10. The method of claim 5, wherein Ar is a phenyl substituted at the meta-position.

11. The method of claim 5, wherein Ar is a phenyl substituted at the ortho-position.

12. The method of claim 5, wherein Ar is selected from the group consisting of para-aminophenyl, para-toluoyl, para-methoxyphenyl, meta-methoxyphenyl, and meta-hydroxymethylphenyl.

13. The method of claim 1, wherein the mammal is infected with a wild-type HIV.

14. The method of claim 1, wherein the mammal is infected by a mutant HIV with least one protease mutation.

15. The method of claim 1, wherein the mammal is infected by a mutant HIV having at least one reverse transcriptase mutation.

16. A method of inhibiting a mutant retroviral infection in a mammal infected with a mutant retrovirus, which method comprises administering to the mammal a mutant retroviral-inhibiting effective amount of a compound of the formula: ##STR00041## wherein: R.sup.1 is H or an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkylalkyl, or an aryl; Y and Z are the same or different and each is selected from the group consisting of CH.sub.2, O, S, SO, and SO.sub.2; n is an integer from 1 to 5; X is O, NR.sup.10, or S, wherein R.sup.10 is H, an unsubstituted alkyl, an unsubstituted alkenyl, or an unsubstituted alkynyl; m is an integer from 0 to 6; R.sup.3 is aryl or heterocycloalkyl, in each of which at least one hydrogen atom is optionally substituted with a substituent selected from the group consisting of alkyl and (CH.sub.2).sub.pR.sup.11, wherein R.sup.11 is an aryl; R.sup.5 is H, a C.sub.1-C.sub.6 alkyl radical, a C.sub.2-C.sub.6 alkenyl radical, or (CH.sub.2).sub.qR.sup.14, wherein q is an integer from 0 to 5, and R.sup.14 is a cycloalkyl; R.sup.6 is aryl, in which at least one hydrogen atom is optionally substituted with a substituent selected from the group consisting of a halogen, OR.sup.15, NR.sup.15R.sup.16, an alkyl, an alkoxy, an alkylthio, or an alkylamino, wherein R.sup.15 and R.sup.16 are the same or different and each is H, an unsubstituted alkyl, or an unsubstituted alkenyl; wherein a mutant virus that is capable of evolving from the HIV virus infecting said mammal has lower fitness, relative to said HIV virus infecting said mammal, in the presence of said compound, or pharmaceutically acceptable salt.

17. The method of claim 16, wherein the mutant retrovirus is a multidrug-resistant mutant retrovirus.

18. The method of claim 16, wherein the mutant retrovirus is a multidrug-resistant HIV.

19. The method of claim 16, wherein the mutant retrovirus is a multidrug-resistant HIV-1.

20. The method of claim 16, wherein the mutant retrovirus is resistant to at least one antiviral agent selected from the group consisting of ritonavir, indinavir, amprenavir and saquinavir.

21. The method of claim 16, wherein the compound is of the formula: ##STR00042## wherein Ar is a phenyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of methyl, amino, hydroxy, methoxy, or methylthio.

22. The method of claim 16, wherein the compound is of the formula: ##STR00043## wherein Ar is a phenyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of methyl, amino, methoxy, and methylthio.

23. The method of claim 22, wherein the compound is of the formula: ##STR00044##

24. The method of claim 23, wherein R.sup.5 is isobutyl.

25. The method of claim 24, wherein Ar is a phenyl substituted at the para-position.

26. The method of claim 24, wherein Ar is selected from the group consisting of p-aminophenyl, p-methoxyphenyl and p-tolyl.

27. The method of claim 24, wherein Ar is p-aminophenyl.

28. The method of claim 24, wherein Ar is p-methoxyphenyl.

29. The method of claim 24, wherein the mutant retrovirus is resistant to at least one antiviral agent selected from the group consisting of ritonavir, indinavir, amprenavir and saquinavir.

30. The method of claim 1, wherein A is of the formula: ##STR00045##

31. The method of claim 24, wherein the multidrug-resistant HIV-1 comprises a protease with at least one mutation selected from the group consisting of V82F, I84V, G48V and V82A.

32. The method of claim 1, which comprises further administration of at least one other antiviral agent selected from the group consisting of ritonavir, indinavir, amprenavir and saquinavir.

33. The method of claim 32, wherein the at least one other antiviral agent is ritonavir.

34. A method of preventing the development of drug resistance in an HIV-infected mammal, the method comprising administering to said HIV-infected the mammal a drug resistance-inhibiting an effective amount of a compound of the formula: ##STR00046## wherein: R.sup.1 is H or an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkylalkyl, or an aryl; Y and Z are the same or different and each is selected from the group consisting of CH.sub.2, O, S, SO, and SO.sub.2; n is an integer from 1 to 5; X is O, NR.sup.10, or S, wherein R.sup.10 is H, an unsubstituted alkyl, an unsubstituted alkenyl, or an unsubstituted alkynyl; m is an integer from 0 to 6; R.sup.3 is aryl or heterocycloalkyl, in each of which at least one hydrogen atom is optionally substituted with a substituent selected from the group consisting of alkyl and (CH.sub.2).sub.pR.sup.11, wherein R.sup.11 is an aryl; R.sup.5 is H, a C.sub.1-C.sub.6 alkyl radical, a C.sub.2-C.sub.6 alkenyl radical, or (CH.sub.2).sub.qR.sup.14, wherein q is an integer from 0 to 5, and R.sup.14 is a cycloalkyl; R.sup.6 is aryl, in which at least one hydrogen atom is optionally substituted with a substituent selected from the group consisting of a halogen, OR.sup.15, NR.sup.15R.sup.16, an alkyl, an alkoxy, an alkylthio, or an alkylamino, wherein R.sup.15 and R.sup.16 are the same or different and each is H, an unsubstituted alkyl, or an unsubstituted alkenyl; and wherein a mutant virus that is capable of evolving from the HIV virus infecting said mammal has lower fitness, relative to said HIV virus infecting said mammal, in the presence of said compound, pharmaceutically acceptable salt or ester thereof.

35. The method of claim 1, wherein the compound is of the formula: ##STR00047##

36. The method of claim 12, wherein the compound is of the formula: ##STR00048##

37. The method of claim 13, wherein the compound is of the formula: ##STR00049##

38. The method of claim 14, wherein the compound is of the formula: ##STR00050##

39. The method of claim 15, wherein the compound is of the formula: ##STR00051##

40. The method of claim 16, wherein the compound is of the formula: ##STR00052##

41. The method of claim 17, wherein the compound is of the formula: ##STR00053##

42. The method of claim 18, wherein the compound is of the formula: ##STR00054##

43. The method of claim 19, wherein the compound is of the formula: ##STR00055##

44. The method of claim 20, wherein the compound is of the formula: ##STR00056##

45. The method of claim 27, wherein the compound is of the formula: ##STR00057##

46. The method of claim 29, wherein the compound is of the formula: ##STR00058##

47. The method of claim 31, wherein the compound is of the formula: ##STR00059##

48. The method of claim 32, wherein the compound is of the formula: ##STR00060##

49. The method of claim 33, wherein the compound is of the formula: ##STR00061##

50. The method of claim 35, which comprises further administration of at least one other antiviral agent selected from the group consisting of ritonavir, indinavir, amprenavir, and saquinavir.

51. The method of claim 50, wherein the at least one other antiviral agent is ritonavir.

52. The method of claim 13, which comprises further administration of at least one other antiviral agent selected from the group consisting of ritonavir, indinavir, amprenavir, and saquinavir.

53. The method of claim 52, wherein the at least one other antiviral agent is ritonavir.

54. The method of claim 14, which comprises further administration of at least one other antiviral agent selected from the group consisting of ritonavir, indinavir, amprenavir, and saquinavir.

55. The method of claim 54, wherein the at least one other antiviral agent is ritonavir.

56. The method of claim 15, which comprises further administration of at least one other antiviral agent selected from the group consisting of ritonavir, indinavir, amprenavir, and saquinavir.

57. The method of claim 56, wherein the at least one other antiviral agent is ritonavir.
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