Claims for Patent: 7,829,665

Summary for Patent: 7,829,665

Title:	Macrocyclic inhibitors of hepatitis C virus replication
Abstract:	The embodiments provide compounds of the general Formulae I through general Formula VIII, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.
Inventor(s):	Blatt; Lawrence M. (Brisbane, CA), Seiwert; Scott D. (Pacifica, CA), Andrews; Steven W. (Longmont, CO), Martin; Pierre (Rheinfelden, CH), Schumacher; Andreas (Efringen-Kirchen, DE), Barnett; Bradley (Northglenn, CO), Eary; C. Todd (Longmont, CO), Kaus; Robert (Longmont, CO), Kercher; Timothy (Boulder, CO), Liu; Weidong (Superior, CO), Lyon; Michael (Superior, CO), Nichols; Paul (Firestone, CO), Wang; Bin (Longmont, CO), Sammakia; Tarek (Boulder, CO), Kennedy; April (Denver, CO), Jiang; Yutong (Longmont, CO)
Assignee:	InterMune, Inc. (Brisbane, CA)
Application Number:	11/491,126
Patent Claims:	1. A compound having the Formula V: ##STR00766## or a pharmaceutically acceptable salt, prodrug, or ester thereof wherein: R.sup.1 is H, C.sub.1-7 alkyl, C.sub.3-7 cycloalkyl, pyridyl, thioazolo, naphthyl, fused heterocycle, phenyl, substituted phenyl, benzyloxy, or substituted benzyloxy; R.sup.2 is H, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.4-10 cycloalkyl-alkyl, phenyl, substituted phenyl, C.sub.1-6 alkoxy, or substituted C.sub.1-6 alkoxy; R.sup.3 is H, C.sub.1-6 alkyl, C(O)R.sup.5, C(O)OR.sup.5, C(O)NR.sup.5R.sup.6, C(S)NR.sup.5R.sup.6, or S(O).sub.2R.sup.5; R.sup.5 and R.sup.6 are each independently selected from H, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.4-10 cycloalkyl-alkyl, C.sub.3-7 cycloalkyl fused to C.sub.6 aryl or C.sub.6 aryl heterocyclyl, benzyl, phenyl, or substituted phenyl; Y is a sulfonimide of the formula --C(O)NHS(O).sub.2R.sup.4 or a carboxylic acid of the formula --C(O)OH, wherein R.sup.4 is C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.4-10 cycloalkyl-alkyl, C.sub.6 aryl, or substituted C.sub.6 aryl; Z is a bond, O, or S; and the dashed line represents an optional double bond. 2. The compound of claim 1, wherein R.sup.1 is phenyl substituted with halo, C.sub.1-3 alkyl, substituted C.sub.1-3 alkyl substituted with up to 3 fluoro, C.sub.1-3 alkoxy, substituted C.sub.1-3 alkoxy substituted with up to 3 fluoro, cyano, hydroxy, nitro, NH.sub.2, NHR.sub.2, or NR.sub.2R.sub.3. 3. The compound of claim 1, wherein R.sup.1 is benzyloxy substituted with halo, C.sub.1-3 alkyl, substituted C.sub.1-3 alkyl with up to 3 fluoro, C.sub.1-3 alkoxy, substituted C.sub.1-3 alkoxy substituted with up to 3 fluoro, cyano, hydroxy, nitro, NH.sub.2, NHR.sub.2, or NR.sub.2R.sub.3. 4. The compound of claim 1, wherein R.sup.2 is phenyl substituted with halo, cyano, nitro, hydroxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.4-10 cycloalkyl-alkyl, C.sub.2-6 alkenyl, C.sub.1-6 alkoxy, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkyl, substituted C.sub.1-6 alkyl substituted with up to 5 fluoro, C.sub.1-6 alkoxy, or substituted C.sub.1-6 alkoxy substituted with up to 5 fluoro. 5. The compound of claim 1, wherein R.sup.5 and R.sup.6 are each individually phenyl substituted with halo, cyano, nitro, hydroxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.4-10 cycloalkyl-alkyl, C.sub.2-6 alkenyl, C.sub.1-6 alkoxy, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkyl, substituted C.sub.1-6 alkyl substituted with up to 5 fluoro, C.sub.1-6 alkoxy, or substituted C.sub.1-6 alkoxy substituted with up to 5 fluoro. 6. The compound of claim 1, wherein R.sup.4 is C.sub.6 aryl substituted with up to three halo. 7. A compound having a formula selected from the group consisting of the compounds in Tables 1 through 7 as described in the specification and compounds numbered 100, 701-706, 801, 922, 927, 1001-1018, 2001-2011, 2101-2154, 2201-2252, 2301-2322, 2401-2404, 2501-2502, and 2601-2604. 8. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 or 7. 9. A method of inhibiting NS3/NS4 protease activity, comprising contacting a NS3/NS4 protease with a compound of claim 1 or 7. 10. The method of claim 9 in which the contacting is conducted in vivo. 11. The method of claim 9, further comprising identifying a subject suffering from a hepatitis C infection and administering the compound or composition to the subject in an amount effective to treat the infection. 12. The method of claim 9 in which the contacting is conducted ex vivo. 13. A method of treating a hepatitis C virus infection, liver fibrosis resulting from or associated with a hepatitis C virus infection, or impaired liver function resulting from or associated with a hepatitis C virus infection, the method comprising administering to an individual in need thereof an amount of a compound of claim 1 or 7 that is effective to treat a least one condition selected from the group consisting of a hepatitis C virus infection, liver fibrosis resulting from or associated with a hepatitis C virus infection, and impaired liver function resulting from or associated with a hepatitis C virus infection. 14. The method of claim 13, wherein a sustained viral response is achieved. 15. The method of claim 13, wherein the method further comprises administering to the individual a nucleoside analog. 16. The method of claim 15, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine. 17. The method of claim 13, wherein the method further comprises administering to the individual pirfenidone or a pirfenidone analog administered orally daily in an amount of from about 400 mg to about 3600 mg. 18. The method of claim 13, wherein the method further comprises administering to the individual an NS5B RNA-dependent RNA polymerase inhibitor. 19. The method of claim 13, wherein the method further comprises administering to the individual a tumor necrosis factor antagonist selected from the group consisting of etanercept, infliximab, and adalimumab. 20. The method of claim 13, wherein the method further comprises administering to the individual interferon-gamma (IFN-.gamma.). 21. The method of claim 20, wherein the IFN-.gamma. is administered subcutaneously in an amount of from about 10 .mu.g to about 300 .mu.g. 22. The method of claim 13, wherein the method further comprises administering to the individual interferon-alpha (IFN-.alpha.). 23. The method of claim 22, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylate consensus IFN-.alpha. administered at a dosing interval of every 8 days to every 14 days. 24. The method of claim 22, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. administered at a dosing interval of once every 7 days. 25. The method of claim 22, wherein the IFN-.alpha. is INFERGEN consensus IFN-.alpha.. 26. The method of claim 22, wherein the IFN-.alpha. is PEGASYS.RTM. PEGylated IFN-.alpha.2a or PEG-INTRON.RTM. PEGylated IFN-.alpha.2b. 27. The method of claim 13, further comprising administering an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine, 2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, ritonavir, and an inosine monophosphate dehydrogenase inhibitor. 28. The method of claim 13, further comprising administering interferon, another NS3 protease inhibitor, a NS5b polymerase inhibitor, or a NS3 helicase inhibitor. 29. The method of claim 28, wherein the another NS3 protease inhibitor is selected from ##STR00767## ##STR00768##

Details for Patent 7,829,665

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Kadmon Pharmaceuticals Llc	INFERGEN	interferon alfacon-1	Injection	103663	10/06/1997		2025-07-25
Janssen Biotech, Inc.	REMICADE	infliximab	For Injection	103772	08/24/1998		2025-07-25
Immunex Corporation	ENBREL	etanercept	For Injection	103795	11/02/1998		2025-07-25
Immunex Corporation	ENBREL	etanercept	For Injection	103795	05/27/1999		2025-07-25
Immunex Corporation	ENBREL	etanercept	Injection	103795	09/27/2004		2025-07-25