Claims for Patent: 7,635,695

Summary for Patent: 7,635,695

Title:	Antiinflammation agents
Abstract:	Compounds, compositions and methods that are useful in the treatment of inflammatory, immunoregulatory, metabolic, infectious and cell proliferative diseases or conditions are provided herein. In particular, the invention provides compounds which modulate the expression and/or function of proteins involved in inflammation, metabolism, infection and cell proliferation. The subject compounds contain a fused heterobicyclic ring.
Inventor(s):	Burkitt; Simon A. (Kirkby-in-Ashfield, GB), Cardozo; Mario G. (San Francisco, CA), Cushing; Timothy D. (Pacifica, CA), DeGraffenreid; Michael R. (San Francisco, CA), Farthing; Christopher N. (Macclesfield, GB), Hao; Xiaolin (Foster City, CA), Jaen; Juan C. (Burlingame, CA), Jiao; Xian Yun (San Mateo, CA), Kopecky; David J. (San Francisco, CA), Labelle; Marc (Burlingame, CA), Lively; Sarah E. (Congleton, GB), McMinn; Dustin L. (Pacifica, CA), Rasmussen; Sven P. (Congleton, GB), Shin; Youngsook (San Mateo, CA), Smith; Marie-Louise (Half Moon Bay, CA), Smith; Andrew (Macclesfield, GB)
Assignee:	Amgen Inc. (South San Francisco, CA)
Application Number:	11/709,895
Patent Claims:	1. A compound having the formula (Ia.1): ##STR00074## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is selected from the group consisting of --C(O)NR.sup.1aR.sup.1b, --C(O)R.sup.1a, --CH(.dbd.NOH), --N(R.sup.1b)C(O)R.sup.1a, --SO.sub.2NR.sup.1aR.sup.1b, --SO.sub.2R.sup.1a, --C(O)N(R.sup.1a)OR.sup.1b, --(C.sub.1-C.sub.4)alkylene-N(R.sup.1b)C(O)R.sup.1a, and --(C.sub.1-C.sub.4)alkylene-C(O)NR.sup.1aR.sup.1b; wherein R.sup.1a and R.sup.1b are selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.6)heteroalkyl, hydroxy(C.sub.1-C.sub.4)alkyl, fluoro(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, cyclo(C.sub.3-C.sub.8)alkyl, and mono- or di-hydroxycyclo(C.sub.3-C.sub.8)alkyl; R.sup.2 is selected from the group consisting of --C(O)NR.sup.2aR.sup.2b and --OH; wherein R.sup.2a and R.sup.2bare selected from hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.6)heteroalkyl, mono- or di-hydroxy(C.sub.1-C.sub.4)alkyl, fluoro(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, cyclo(C.sub.3-C.sub.8)alkyl, mono- or di-hydroxycyclo(C.sub.3-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.4)alkyl, --C(O)--(C.sub.1-C.sub.4)alkyl, --C(O)--(C.sub.1-C.sub.4)alkoxy, and C(O)-fluoro(C.sub.1-C.sub.4)alkyl; L is a single bond; Q is selected from the group consisting of(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, aryl, aryl(C.sub.1-C.sub.4)alkyl, cyclo(C.sub.3-C.sub.8)alkyl, and cyclo(C.sub.5-C.sub.8)alkenyl, wherein each of the moieties is optionally further substituted, X.sup.1, X.sup.2 and X.sup.3 are independently selected from the group consisting of .dbd.C--, and --CH--; Y.sup.2 is --S(O).sub.m--; Y.sup.1 and Y.sup.3 are independently selected from the group consisting of .dbd.C(R.sup.5a)--, and --C(R.sup.5)(R.sup.6)--; Y.sup.4 is .dbd.N-- or --N(R.sup.5)--; Z.sup.1 and Z.sup.2 are independently CH, or .dbd.C--; each R.sup.5 and R.sup.6 is independently selected from the group consisting of hydrogen, (C.sub.1-C.sub.6)alkyl, cyclo(C.sub.3-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.4)alkyl, hetero(C.sub.1-C.sub.6)alkyl, and arylhetero(C.sub.1-C.sub.4)alkyl; each R.sup.5a is independently selected from the group consisting of hydrogen, halogen, (C.sub.1-C.sub.6)alkyl, cyclo(C.sub.3-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.4)alkyl, hetero(C.sub.1-C.sub.6)alkyl, and arylhetero(C.sub.1-C.sub.4)alkyl; and the subscript m is 0; with the proviso that said compound is other than ##STR00075## 2. The compound of claim 1, wherein Q is selected from the group consisting of phenyl, naphthyl, cyclopentyl and cyclohexyl. 3. The compound of claim 1, wherein Q is unsubstituted phenyl or phenyl substituted with from 1 to 3 substituents selected from the group consisting of halogen, cyano. nitro, cyano(C.sub.2-C.sub.6)alkenyl, nitro(C.sub.2-C.sub.6)alkenyl, --R', --OR', --NR'R'', --C(O)R', --CO.sub.2R', --C(O)NR'R'', --NR''C(O)R', --NR''CO.sub.2R', --NR'C(O)NR''R''', --S(O)R', --SO.sub.2R, --SO.sub.2NR'R'', --NR''SO.sub.2R', --OC(O)NR'R'', --X--C(O)R', --X--CO.sub.2R', --X--C(O)NR'R'', --X--NR''C(O)R', --X--NR''CO.sub.2R', --X--NR'C(O)NR''R''', --X--S(O)R', --X--SO.sub.2R', --X--SO.sub.2NR'R'', --X--NR''SO.sub.2R' and --X--OC(O)NR'R'', and optionally R' or R''is attached to an adjacent ring atom on the phenyl group to form a 5- or 6-membered fused ring; (a) wherein (b) X is (C.sub.1-C.sub.6)alkylene; and R', R'' and R''' are independently selected from the group consisting of hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.1-C.sub.6)heteroalkyl, hydroxy(C.sub.1-C.sub.4)alkyl, fluoro(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)haloalkyl, cyclo(C.sub.3-C.sub.8)alkyl, mono- or di-hydroxycyclo(C.sub.3-C.sub.8)alkyl, heterocyclo(C.sub.3-C.sub.8)alkyl, heterocyclo(C.sub.3-C.sub.8)alkyl-(C.sub.1-C.sub.4)alkyl, aryl, aryl(C,-C.sub.4)alkyl, heteroaryl, heteroaryl(C.sub.1-C.sub.4)alkyl, --C(O)--(C.sub.1-C.sub.4)alkyl, --C(O)--(C.sub.1-C.sub.4)alkoxy, --C(O)-heterocyclo(C.sub.3-C.sub.8)alkyl and --C(O)-fluoro(C.sub.1-C.sub.4)alkyl; and optionally, any two of R', R''and R''' can be combined with their intervening atom(s) to form a 5-, 6- or 7-membered ring containing from 1-3 heteroatoms selected from N, O and S. 4. The compound of claim 1, wherein R.sup.1 is selected from the group consisting of --C(O)NR.sup.1aR.sup.1b, --SO.sub.2NR.sup.1aR.sup.1b, --SO.sub.2R.sup.1aR.sup.1b, --SO.sub.2R.sup.1a, and --C(O)R.sup.1a. 5. The compound of claim 1, having the formula (III): ##STR00076## 6. The compound of claim 1, having the formula (V): ##STR00077## 7. The compound of claim 1, having the formula (VI): ##STR00078## wherein each R.sup.5a is independently from the group consisting of hydrogen, halogen, (C.sub.1-C.sub.6)alkyl, cyclo(C.sub.3-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.4)alkyl, hetero(C.sub.1-C.sub.6)alkyl, and arylhetero(C.sub.1-C.sub.4)alkyl. 8. The compound of claim 7, wherein R.sup.2 is --NHR.sup.2b. 9. The compound of claim 7, wherein R.sup.1 is selected from the group consisting of --C(O)NHR.sup.1a, --SO.sub.2NHR.sup.1a, --SO.sub.2R.sup.1a and --C(O)CH.sub.3 and R.sup.2 is --NHR.sup.2b. 10. The compound of claim 7, wherein R.sup.1 is selected from the group consisting of --C(O)NHR.sup.1a, --SO.sub.2NHR.sup.1a, --SO.sub.2R.sup.1a and --C(O)CH.sub.3, R.sup.2 is --NHR.sup.2band each R.sup.5a is hydrogen. 11. The compound of claim 10, selected from the group consisting of: ##STR00079## ##STR00080## ##STR00081## 12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent and a compound of claim 1. 13. A method for treating an inflammatory, metabolic or immune disease or condition selected from rheumatoid arthritis, inflammatory bowel disease, psoriasis, type 1 diabetes, type 2 diabetes, asthma, multiple sclerosis and graft rejection said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1. 14. The method of claim 13, wherein said compound is administered orally, topically, intravenously or intramuscularly. 15. The method of claim 13, wherein said compound is administered in combination with a second therapeutic agent selected from the group consisting of prednisone, dexamethasone, beclomethasone, methylprednisone, betamethasone, hydrocortisone, methotrexate, cyclosporin, rapamycin, tacrolimus, an antihistamine, a TNF antibody, an IL-1 antibody, a soluble TNF receptor, a soluble IL-1 receptor, a TNF or IL-1 receptor antagonist, a non-steroidal antiinflammatory agent, a COX-2 inhibitor, an antidiabetic agent, an anticancer agent, hydroxycloroquine, D-penicillamine, infliximab, etanercept, auranofin, aurothioglucose, sulfasalazine, sulfasalazine analogs, mesalamine, corticosteroids, corticosteroid analogs, 6-mercaptopurine, interferon .beta.-1.beta., interferon .beta.-1.alpha., azathioprine, glatiramer acetate, a glucocorticoid and cyclophosphamide. 16. A method for modulating IKK, comprising contacting a cell with a compound of claim 1. 17. The method of claim 16, wherein said compound inhibits IKK. 18. The method of claim 16, wherein said compound inhibits IKK.beta.. 19. The method of claim 16, wherein said compound inhibits IKK.beta. and IKK.alpha.. 20. The compound of claim 1, selected from the group consisting of: ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090##

Details for Patent 7,635,695

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Janssen Biotech, Inc.	REMICADE	infliximab	For Injection	103772	08/24/1998		2022-10-31
Immunex Corporation	ENBREL	etanercept	For Injection	103795	11/02/1998		2022-10-31
Immunex Corporation	ENBREL	etanercept	For Injection	103795	05/27/1999		2022-10-31
Immunex Corporation	ENBREL	etanercept	Injection	103795	09/27/2004		2022-10-31
Immunex Corporation	ENBREL	etanercept	Injection	103795	02/01/2007		2022-10-31
Immunex Corporation	ENBREL MINI	etanercept	Injection	103795	09/14/2017		2022-10-31
Immunex Corporation	ENBREL	etanercept	Injection	103795			2022-10-31