Claims for Patent: 7,157,489

Summary for Patent: 7,157,489

Title:	HIV protease inhibitors
Abstract:	Compounds useful for inhibiting HIV protease are disclosed. Methods of making the compounds, and their use as therapeutic agents, for example, in treating wild-type HIV and of multidrug-resistant strains of HIV, also are disclosed.
Inventor(s):	Ghosh; Arun K. (River Forest, IL), Bilcer; Geoffrey M. (Chicago, IL), Devasamudram; Thippeswamy (Chicago, IL)
Assignee:	The Board of Trustees of the University of Illinois (Urbana, IL)
Application Number:	10/382,435
Patent Claims:	1. A compound having a formula ##STR00230## wherein R.sup.1 is ##STR00231## R.sup.2 is selected from the group consisting of ##STR00232## R.sup.3 is ##STR00233## X is selected from the group consisting of O, NR.sup.e, and S; R.sup.d is selected from the group consisting of C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.1-3alkyleneC.sub.3-8heterocycloalkyl, OR.sup.e, C.sub.1-3alkyleneOR.sup.e, N(R.sup.e).sub.2, SR.sup.e, halo, nitro, CHO, cyano, NC, C(.dbd.O)R.sup.e, OC(.dbd.O)R.sup.e, C(.dbd.O)OR.sup.e, C(.dbd.O)N(R.sup.e).sub.2, CH.dbd.NOH, CH.dbd.CHCH.sub.2OH, N(R.sup.e)COR.sup.e, and C.sub.1-3alkyleneN(R.sup.e).sub.2, or two R.sup.d groups are taken together to form a five-, six-, or seven-mernbered aliphatic ring optionally containing one or two of the moiety X; R.sup.e is selected from the group consisting of hydro, C.sub.1-6alkyl, C.sub.2-6alkenyl, aryl, heteroaryl, C.sub.1-8cycloalkyl, THP, Ts, Boc, and C.sub.3-8heterocycloalkyl; q is 0 through 3; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 wherein R.sup.1 is ##STR00234## 3. The compound of claim 1 wherein R.sup.2 is selected from the group consisting of ##STR00235## 4. The compound of claim 1 wherein R.sup.2 is selected from the group consisting of ##STR00236## 5. The compound of claim 2 wherein R.sup.d, independently, is selected from the group consisting of CH.sub.2OH, NH.sub.2, OH, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2NH.sub.2, CHO, Cl, F, nitro, OTHP, OCH.sub.3, CH.sub.2NHCH.sub.3, CH.dbd.N--OH, and CH.sub.2OCH.sub.3, or two R.sup.d groups are taken together with the carbons to which they are attached to form ##STR00237## 6. The compound of claim 1 wherein said compound has an IC.sub.50 value vs. HIV-1 protease of less than about 500 nM. 7. The compound of claim 6 wherein said compound has an IC.sub.50 value vs. HIV-1 protease of less than about 20 nM. 8. A compound of claim 1 selected from the group consisting of ##STR00238## ##STR00239## 9. A compound having a formula ##STR00240## 10. A compound having a formula ##STR00241## wherein R.sup.1 is ##STR00242## R.sup.2 is selected from the group consisting of C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-3alkyleneN(R.sup.e).sub.2, heterocycloalkyl, --NH.sub.2, --NHBoc, C.sub.1-3alkyleneheterocycloalkyl, ##STR00243## optionally substituted with oxo(.dbd.O), ##STR00244## optionally substituted with oxo, ##STR00245## optionally substituted with oxo, ##STR00246## R.sup.3 is selected from the group consisting of ##STR00247## X is selected from the group consisting of O, NR.sup.e, and S; C is a five- or six-mernbered aliphatic ring containing one to three of the moiety X, and optionally substituted with oxo; R.sup.b and R.sup.c, independently, are selected from the group consisting of hydro, OH, C.sub.1-3alkyl, C.sub.1-3alkyleneOH, and C.sub.1-3alkyleneN(R.sup.e).sub.2, or R.sup.b and R.sup.c are taken together to form a five-, six-, or seven-membered aliphatic ring optionally containing one or two of the moiety X; R.sup.d is selected from the group consisting of C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.1-3alkyleneC.sub.3-8heterocycloalkyl, OR.sup.e, C.sub.1-3alkyleneOR.sup.e, N(R.sup.e).sub.2, SR.sup.e, halo, nitro, CHO, cyano, NC, C(.dbd.O)R.sup.e, OC(O)R.sup.e, C(.dbd.O)OR.sup.e, C(.dbd.O)N(R.sup.e).sub.2, CH.dbd.NOH, CH.dbd.CHCH.sub.2OH, N(R.sup.e)COR.sup.e, and C.sub.1-3alkyleneN(R.sup.e).sub.2, or two R.sup.d groups are taken together to form a five-, six-, or seven-membered aliphatic ring optionally containing one or two of the moiety X; R.sup.e is selected from the group consisting of hydro, C.sub.1-6alkyl, C.sub.2-6alkenyl, aryl, heteroaryl, C.sub.3-8cycloalkyl, THP, Ts, Boc, and C.sub.3-8heterocycloalkyl; q is 0 through 3; or a pharmaceutically acceptable salt thereof. 11. A compound having a formula ##STR00248## wherein R.sup.1 is selected from the group consisting of C.sub.1-6alkyl, aryl, C.sub.1-3alkyleneheteroaryl, ##STR00249## R.sup.2 is selected from the group consisting of ##STR00250## R.sup.3 is selected from the group consisting of ##STR00251## X is selected from the group consisting of O, NR.sup.e, S, SO, and SO.sub.2; A and B, independently, are a five-, six-, or seven-membered aliphatic ring, wherein at least one ring contains one or two of the moiety X; C is a five- or six-membered aliphatic ring containing one to three of the moiety X, and optionally substituted with oxo; R.sup.b and R.sup.c, independently, are selected from the group consisting of hydro, OH, C.sub.1-3alkyl, C.sub.1-3alkyleneOH, and C.sub.1-3alkyleneN(R.sup.e).sub.2, or R.sup.b and R.sup.c are taken together to form a five-, six-, or seven-membered aliphatic ring optionally containing one or two of the moiety X; R.sup.d is selected from the group consisting of C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.1-3alkyleneC.sub.3-8heterocycloalkyl, OR.sup.e, C.sub.1-3alkyleneOR.sup.e, N(R.sup.e).sub.2, SR.sup.e, halo, nitro, CRO, cyano, NC, C(.dbd.O)R.sup.e, OC(.dbd.O)R.sup.e, C(.dbd.0)OR.sup.e, C(.dbd.O)N(R.sup.e).sub.2, CH.dbd.NOH, CH.dbd.CHCH.sub.2OH, N(R.sup.e)COR.sup.e, and C.sub.1-3alkyleneN(R.sup.e).sub.2, or two R.sup.d groups are taken together to form a five-, six-, or seven-membered aliphatic ring optionally containing one or two of the moiety X; R.sup.e is selected from the group consisting of hydro, C.sub.1-6alkyl, C.sub.2-6alkenyl, aryl, heteroaryl, C.sub.3-8cycloalkyl, THP, Ts, Boc, and C.sub.3-8heterocycloalkyl; q is 0 through 3; or a pharmaceutically acceptable salt thereof. 12. A composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent or carrier. 13. A method of treating a male or female mammal suffering from HIV or AIDS wherein inhibition of HIV-1 protease provides a therapeutic benefit comprising administering to said mammal a therapeutically effective amount of a compound of claim 1. 14. The method of claim 13 wherein the mammal is a human. 15. A method of treating a male or female mammal suffering from HIV or AIDS wherein inhibition of HIV-1 protease provides a therapeutic benefit comprising administering to said mammal an effective amount of a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent or carrier. 16. A method of treating a male or female mammal suffering from where HIV or AIDS wherein inhibition of HIV-1 protease provides a therapeutic benefit comprising administering a therapeutically effective amount of (a) a compound of claim 1, and (b) a second therapeutically active ingredient effective against HIV or AIDS. 17. The method of claim 16 wherein (a) and (b) are administered simultaneously, separately, or sequentially. 18. The method of claim 16 wherein the second therapeutically active agent is selected from the group consisting of a second HIV protease inhibitor, an antiviral agent, an immunomodulator, a nucleoside analog, a tat antagonist, a glycosidase inhibitor, and mixtures thereof. 19. The method of claim 18 wherein the second therapeutically active ingredient is selected from the group consisting of Ro 31-859, KNI-272, AZT, DDI, DDC, 3TC, D4T, PMEA, Ro 5-3335, Ro 24-7429, indinavir, ritonavir, saquinavir, nelfinavir, amprenavir, abacavir, castanospremine, castanospermine 6-butryl ester, N-butyl-1-deoxynojirimycin, N-butyl-1-deoxynojirimycin per-butryl ester, 097, acemannan, acyclovir, AD-439, AD5-519, adefovir clipivoxil, AL-721, alpha interferon, ansamycin, beta-fluoro-ddA, BMS-232623, BMS-234475, CI-1012, cidofovir, delaviridine, EL-10, efaviren, famciclovir, FTC, hypericin, Compound Q, ISIS 2922, lobucavir, nevirapine, novapren, peptide T, octapeptide, PNU-140690, probacol, stavudine, valacicbovir, virazole, zalcitabine, ABT-378, bropirimine, gamma interferon, interleukin-2, TNF, etanercept, infliximab, fluconalzole, piritrexim, trimetrexate, daunorubicin, leukotriene B4 receptor antagonist, and analogs and prodrugs thereof.

Details for Patent 7,157,489

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Janssen Biotech, Inc.	REMICADE	infliximab	For Injection	103772	08/24/1998		2022-03-12
Immunex Corporation	ENBREL	etanercept	For Injection	103795	11/02/1998		2022-03-12
Immunex Corporation	ENBREL	etanercept	For Injection	103795	05/27/1999		2022-03-12