Resistance-repellent retroviral protease inhibitors

1. An HIV protease inhibitor represented by a formula:

X-A-B-A′-X′

wherein:

X is

where Y and Z are O;

A is ZCZNH, wherein Z is O;

B is

wherein D is aralkyl optionally substituted with one or more groups selected from alkyl, halo, nitro, cyano, CF 3 , C3-C7 cycloalkyl, C5-C7 cycloalkenyl, R6, OR2, SR2, NHR2, OR3, SR3, NHR3, OR6, SR6, or NHR6;

A′ is N(D′)E′, wherein D′ is alkyl, and E′ is —SO 2 —;

X′ is

wherein G1 is O;

wherein G2 is CH;

wherein Z′″ is C1-C6 alkyl substituted with;

R is H or is selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo and heteroaryl; optionally substituted by halo, hydroxy, alkoxy, aryloxy, cycloalkoxy, heteroaryloxy, cyano, nitro, alkylthio, arylthio, cycloalkylthio, amino, or mono- or dialkylamino, mono- or diarylamino, mono- or di-cycloalkylamino, mono- or di-heteroarylamino, alkanoyl, cycloalkanoyl, aroyl, heteroaroyl, carboxamido, mono- or dialkylcarboxamido, mono- or diarylcarboxamido, sulfonamido, mono- or dialkylsulfonamido, mono- or diarylsulfonamido, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl;

R2 is H or C1-C6 alkyl; optionally substituted by C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, heterocyclo; which groups may be optionally substituted with one or more substituents selected from the group consisting of halo, OR, ROH, R-halo, NO 2 , CN, CO n R, CON(R) 2 , C(S)R, C(S)N(R) 2 , SO n N(R) 2 , SR, SO n R, N(R) 2 , N(R)CO n R, NRS(O) n R, NRC[═N(R)]N(R) 2 , N(R)N(R)CO n R, NRPO n N(R) 2 , NRPO n OR, oxo, ═N—OR, ═N—N(R) 2 , ═NR, ═NNRC(O)N(R) 2 , ═NNRCO n R, ═NNRS(O) n N(R) 2 , or ═NNRS(O) n (R);

or R2 is C1-C6 alkyl; substituted by aryl or heteroaryl; which groups may be optionally substituted with one or more substituents selected from the group consisting of halo, OR, ROH, R-halo, NO 2 , CN, CO n R, CON(R) 2 , C(S)R, C(S)N(R) 2 , SO n N(R) 2 , SR, SO n R, N(R) 2 , N(R)CO n R, NRS(O) n R, NRC[═N(R)]N(R) 2 , N(R)N(R)CO n R, NRPO n N(R) 2 NRPO n OR;

or R2 is C1-C6 alkyl; optionally substituted by halo, OR, ROH, R-halo, NO 2 , CN, CO n R, CON(R) 2 , C(S)R, C(S)N(R) 2 , SO n N(R) 2 , SR, SO n R, N(R) 2 , N(R)CO n R, NRS(O) n R, NRC[═N(R)]N(R) 2 , N(R)N(R)CO n R, NRPO n N(R) 2 , NRPO n OR, oxo, ═N—OR, ═N—N(R) 2 , ═NR, ═NNRC(O)N(R) 2 , ═NNRCO n R, ═NNRS(O) n N(R) 2 , or ═NNRS(O) n (R);

R3 is C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, or heterocyclo; which groups may be optionally substituted with one or more substituents selected from the group consisting of halo, OR2, R2-OH, R2-halo, NO 2 , CN, CO n R2, C(O)N(R2) 2 , C(O)N(R2)N(R2) 2 , C(S)R2, C(S)N(R2) 2 , S(O) n N(R2) 2 , SR2, SO n R2, N(R) 2 , N(R2)CO n R2, NR2S(O) n R2, NR2C[═N(R2)]N(R2) 2 , N(R2)N(R2)CO n R2, NR2PO n N(R2) 2 , NR2PO n OR2, oxo, ═N—OR2, ═N—N(R2) 2 , ═NR2, —NNRC(O)N(R2) 2 , ═NNR2C(O) n R2, ═NNR2S(O) n N(R2) 2 , or ═NNR2S(O) n (R2);

R6 is aryl or heteroaryl, wherein said aryl or heteroaryl may be optionally substituted with one or more groups selected from aryl, heteroaryl, R2, R3, halo, OR2, R2OH, R2-halo, NO 2 , CN, CO n R2, C(O)N(R2) 2 , C(O)N(R2)N(R2) 2 , C(S)R2, C(S)N(R2) 2 , S(O) n N(R2) 2 , SR2, SO n R2, N(R) 2 , N(R2)CO n R2, NR2S(O) n R, NR2C [═N(R2)]N(R2) 2 , N(R2)N(R2)CO n R2, NR2PO n N(R2) 2 , NR2PO n OR2, OC(O)R2, OC(S)R2, OC(O)N(R2) 2 , OC(S)N(R2) 2 , OPO n (R2) 2 ; and

each n is independently 1 or 2.

2. The HIV protease inhibitor of claim 1 , wherein:

is

wherein D is benzyl; and

A′ is N(D′)E′, wherein D′ is isobutyl and E′ is —SO 2 —.

3. The HIV protease inhibitor of claim 2 , wherein Z′″ is selected from the group consisting of CH2NHCOiPr, CH2NHCOPh, CH2NHCO2Pr, CH2NHCOMe, CH2NHBoc, CH2NHCO2Et, CH2NHCOEt, CH2NHCbz, CH2NHCO-3-pyridyl, CH2NHCOCH2SCH2Ph, CH2NHCOCH2Ph, CH2NHCO-2-furanyl, CH2N(CO2Et)CH2CH2OMe, CH2NHCO2iPr, CH2NHCOCF3, CH2NHCOCF2CF3, and CH2N(Ac)CH2CF3.

4. A compound according to claim 1 , wherein said compound is bound in a complex with wild type or drug resistant mutant forms of HIV-1 protease.

5. A pharmaceutical composition comprising an effective amount of an inhibitor according to claim 1 and a pharmaceutically acceptable additive, excipient, or diluent.

6. A pharmaceutical composition comprising an effective amount inhibitor according to claim 1 and another antiretroviral agent.

7. A pharmaceutical composition comprising an effective amount of an inhibitor according to claim 1 and a second HIV inhibitor.

8. The composition according to claim 7 wherein said second HIV inhibitor is an HIV protease inhibitor.

9. The composition according to claim 7 wherein said second HIV inhibitor is an HIV reverse transcriptase inhibitor.

10. A method of treating a patient suffering from HIV infection, comprising administering to said patient a composition according to claim 5 .

11. A method of treatment according to claim 10 wherein said patient is suffering from a multi-drug resistant HIV infection.

12. A composition comprising an effective amount of an HIV protease inhibitor according to claim 1 and an effective amount of a compound that inhibits the activity of cytochrome p450.

13. The composition according to claim 12 , wherein said compound that inhibits the activity of cytochrome p450 is selected from the group consisting of ritonavir, cyclosporine, Fk-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629 (N,N-dimethylglycyl-N-(2-hyrdoxy-3-(((4-methoxyphenyl) sulphonyl)(2-methyl-propyl)amino)-1-(phenylmethyl)propyl)-3-methyl-L-valinamide), KNI-272, CGP 53437, CGP 57813 and U-103017.

14. The composition according to claim 13 , wherein said compound that inhibits the activity of cytochrome p450 is ritonavir.

15. An HIV protease inhibitor having the formula

16. A compound according to claim 15 , wherein said compound is bound in a complex with wild type or drug resistant mutant forms of HIV-1 protease.

17. A pharmaceutical composition comprising an effective amount of an inhibitor according to claim 15 and a pharmaceutically acceptable additive, excipient, or diluent.

18. A pharmaceutical composition comprising an effective amount inhibitor according to claim 15 and another antiretroviral agent.

19. A pharmaceutical composition comprising an effective amount of an inhibitor according to claim 15 and a second HIV inhibitor.

20. The composition according to claim 19 wherein said second HIV inhibitor is an HIV protease inhibitor.

21. The composition according to claim 19 wherein said second HIV inhibitor is an HIV reverse transcriptase inhibitor.

22. A method of treating a patient suffering from HIV infection, comprising administering to said patient a composition according to claim 15 .

23. A method of treatment according to claim 22 wherein said patient is suffering from a multi-drug resistant HIV infection.

24. A composition comprising an effective amount of an HIV protease inhibitor according to claim 15 and an effective amount of a compound that inhibits the activity of cytochrome p450.

25. The composition according to claim 24 , wherein said compound that inhibits the activity of cytochrome p450 is selected from the group consisting of ritonavir, cyclosporine, FK-506, rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629 (N,N-dimethlglycyl-N-(2-hyrdoxy-3-(((4-methoxyphenyl) sulphonyl)(2-methyl-propyl)amino)-1-(phenylmethyl)propyl)-3-methyl-L-valinamide), KNI-272, CGP 53437, CGP 57813 and U-103017.

26. The composition according to claim 25 , wherein said compound that inhibits the activity of cytochrome p450 is ritonavir.