Claims for Patent: 7,132,438

Summary for Patent: 7,132,438

Title:	Benzimidazole derivatives
Abstract:	Compounds, pharmaceutical compositions and methods are provided that are useful in the treatment of inflammatory and immune-related conditions or disorders. In particular, the invention provides compounds which modulate the expression and/or function of proteins involved in inflammation, immune response regulation and cell proliferation. The subject compounds are 2-amino-imidazole derivatives.
Inventor(s):	Frenkel; Alexander David (Buxton, GB), Lively; Sarah Elizabeth (Congleton, GB), Powers; Jay P. (Pacifica, CA), Smith; Andrew (Macclesfield, GB), Sun; Daqing (Foster City, CA), Tomooka; Craig (San Mateo, CA), Wang; Zhulun (Foster City, CA)
Assignee:	Amgen Inc. (Thousand Oaks, CA)
Application Number:	10/268,412
Patent Claims:	1. A compound of formula (I): ##STR00057## or a pharmaceutically acceptable salt or prodrug thereof, wherein R.sup.1 is cyclo(C.sub.3 C.sub.8)alkyl, substituted or unsubstituted; R.sup.2 is aryl substituted or unsubstituted; Y is C(O); Z.sup.1 and Z.sup.2 are combined to form an additional fused 6-membered aromatic ring, substituted or unsubstituted. 2. The compound of claim 1, wherein R.sup.1 is cyclohexyl. 3. The compound of claim 1, wherein R.sup.1 is selected from the group consisting of: ##STR00058## 4. The compound of claim 1, wherein Z.sup.1 and Z.sup.2 are combined to form an additional fused benzene ring. 5. The compound of claim 1, having the formula (II): ##STR00059## wherein D, E, F and G are independently CR''', wherein each R''' is independently selected from the group consisting of H, halogen, (C.sub.1 C.sub.4)alkyl, perfluoro(C.sub.1 C.sub.4)alkyl, (C.sub.1 C.sub.4)heteroalkyl, aryl, aryl(C.sub.1 C.sub.4)alkyl, heteroaryl, CN, CO.sub.2R', CONR'R'', NR'R'', NO.sub.2, OR', SR', C(O)R', OC(O)R', N(R'')C(O)R', N(R'')CO.sub.2R', N(R'')C(O)NR'R'', S(O).sub.mNR'R'', S(O).sub.mR' and N(R'')S(O).sub.mR', wherein the subscript m is an integer from 1 to 2, or combined with adjacent R''' to form an additional fused 5-, 6-, 7- or 8-membered ring, and wherein R' and R'' are independent selected from the group consisting of H, (C.sub.1 C.sub.4)alkyl, hetero(C.sub.1 C.sub.4)alkyl, aryl and aryl(C.sub.1 C.sub.4)alkyl. 6. The compound of claim 5, having the formula (IIa): ##STR00060## wherein R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group consisting of H, halogen, (C.sub.1 C.sub.4)alkyl, perfluoro(C.sub.1 C.sub.4)alkyl, (C.sub.1 C.sub.4)heteroalkyl, aryl, aryl(C.sub.1 C.sub.4)alkyl, heteroaryl, CN, CO.sub.2R', CONR'R'', NR'R'', NO.sub.2, OR', SR', C(O)R', OC(O)R', N(R'')C(O)R', N(R'')CO.sub.2R', N(R'')C(O)NR'R'', S(O).sub.mNR'R'', S(O).sub.mR', and N(R'')S(O).sub.mR', wherein the subscript m is an integer from 1 to 2; alternatively, R.sup.5, R.sup.6 or R.sup.7 may be combined with an adjacent R group selected from the group consisting of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 to form an additional fused 5-, 6-, 7- or 8-membered ring and R.sup.8 may be combined with R.sup.1 to form an additional fused 5-, 6-, 7- or 8-membered ring. 7. The compound of claim 6, wherein R.sup.6 and R.sup.7 are independently selected from the group consisting of H, halogen, (C.sub.1 C.sub.4)alkyl, CO.sub.2R', NR'R'', OR', OC(O)R', N(R'')C(O)R' and N(R'')C(O)NR'R''. 8. The compound of claim 6, wherein R.sup.6 is selected from the group consisting of ##STR00061## ##STR00062## 9. The compound of claim 6, wherein R.sup.8 is H or OH. 10. The compound of claim 1, wherein R.sup.2 is phenyl. 11. The compound of claim 1, wherein R.sup.2 is phenyl substituted with at least one substituent selected from the group consisting of halogen, (C.sub.1 C.sub.4)alkyl, perfluoro(C.sub.1 C.sub.4)alkyl, hetero(C.sub.1 C.sub.4)alkyl, aryl, aryl(C.sub.1 C.sub.4)alkyl, heteroaryl, CN, CO.sub.2R', CONR'R'', NR'R'', NO.sub.2, OR', SR', C(O)R', N(R'')C(O)R', N(R'')CO.sub.2R', N(R'')C(O)NR'R'', S(O),NR'R'', S(O).sub.mR' and N(R'')S(O).sub.mR', wherein the subscript m is an integer from 1 to 2, and wherein R' and R'' are independently selected from the group consistently of H, (C.sub.1 C.sub.4)alkyl, hetero(C.sub.1 C.sub.4)alkyl, aryl, aryl(C.sub.1 C.sub.4)alkyl. 12. The compound of claim 11, wherein R.sup.2 is phenyl substituted with at least one substituent selected from the group consisting of perfluoro(C.sub.1 C.sub.4)alkyl, aryl, heteroaryl, CONR'R'', NO.sub.2, S(O).sub.mNR'R'' and S(O).sub.mR'. 13. The compound of claim 12, wherein R.sup.2 is phenyl substituted with at least one substituent selected from the group consisting of CF.sub.3, CF.sub.2R', phenyl, tetrazolyl, triazolyl, CONHR', NO.sub.2, SO.sub.2NHR' and SO.sub.2R'. 14. The compound of claim 1, having the formula (IV): ##STR00063## wherein R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group consisting of H, halogen, (C.sub.1 C.sub.4)alkyl, perfluoro(C.sub.1 C.sub.4)alkyl, (C.sub.1 C.sub.4)heteroalkyl, aryl, aryl(C.sub.1 C.sub.4)alkyl, heteroaryl, CN, CO.sub.2R', CONR'R'', NR'R'', NO.sub.2, OR', SR', C(O)R', OC(O)R', N(R'')C(O)R', N(R'')CO.sub.2R', N(R'')C(O)NR'R'', S(O).sub.mNR'R'', S(O).sub.mR', and N(R'')S(O).sub.mR', wherein the subscript m is an integer from 1 to 2; alternatively, R.sup.5, R.sup.6 or R.sup.7 may be combined with an adjacent R group selected from the group consisting of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 to form an additional fused 5-, 6-, 7- or 8-membered ring and R.sup.8 may be combined with R.sup.1 to form an additional fused 5-, 6-, 7- or 8-membered ring. 15. A compound of claim 14, having the formula (VII): ##STR00064## wherein R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are independently selected from the group consisting of H, halogen, (C.sub.1 C.sub.4)alkyl, perfluoro(C.sub.1 C.sub.4)alkyl, hetero(C.sub.1 C.sub.4)alkyl, aryl, aryl(C.sub.1 C.sub.4)alkyl, heteroaryl, CN, CO.sub.2R', CONR'R'', NR'R'', NO.sub.2, OR', SR', C(O)R', N(R'')C(O)R', N(R'')CO.sub.2R', N(R'')C(O)NR'R'', S(O).sub.mNR'R'', S(O).sub.mR' and N(R'')S(O).sub.mR', wherein the subscript m is an integer from 1 to 2; alternatively, R.sup.9, R.sup.10, R.sup.11, R.sup.12 or R.sup.13 may be combined with an adjacent R group selected from the group consisting of R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 to form an additional fused 5-, 6-, 7- or 8-membered ring. 16. The compound of claim 15, wherein at least one of R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 is selected from halogen, (C.sub.1 C.sub.4)alkyl, perfluoro(C.sub.1 C.sub.4)alkyl, (C.sub.1 C.sub.4)heteroalkyl, aryl, aryl(C.sub.1 C.sub.4)alkyl, heteroaryl, CN, CO.sub.2R', CONR'R'', NR'R'', NO.sub.2, OR', SR', C(O)R', N(R'')C(O)R', N(R'')CO.sub.2R', N(R'')C(O)NR'R'', S(O).sub.mNR'R'', S(O).sub.mR' and N(R'')S(O).sub.mR'. 17. The compound of claim 16, wherein at least one of R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 is selected from perfluoro(C.sub.1 C.sub.4)alkyl, aryl, heteroaryl, CONR'R'', NO.sub.2, S(O).sub.mNR'R'' and S(O).sub.mR'. 18. The compound of claim 15, wherein R.sup.10 is CF.sub.3. 19. The compound of claim 18, having the formula (VIId): ##STR00065## 20. The compound of claim 1, having a formula selected from the group consisting of ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071## 21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 1, 2, 3, 4, 5, 8, 9, 10, 13, 14, 15, 17, 18, 19 or 20. 22. A method of treating rheumatoid arthritis, inflammatory bowel disease, allergic disease, psoriasis, asthma, multiple sclerosis, graft rejection or sepsis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1, 2, 3, 4, 5, 8, 9, 10, 13, 14, 15, 17, 18, 19 or 20. 23. The method of claim 22, wherein said compound is administered orally, parenterally or topically. 24. The method of claim 22, wherein said compound is administered in combination with a second therapeutic agent selected from the group consisting of a COX-2 inhibitor, hydroxychloroquine, D-penicillamine, infliximab, etanercept, auranofin, aurothioglucose, sulfasalazine, sulfasalazine analogs, mesalamine, corticosteroids, corticosteroid analogs, 6-mercaptopurine, cyclosporine A, methotrextate and infliximab, interferon .beta.-1.beta., interferon .beta.-1.alpha., azathioprine, glatiramer acetate, a glucocorticoid and cyclophosphamide. 25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of formula (I): ##STR00072## or a pharmaceutically acceptable salt or prodrug thereof, wherein R.sup.1 is cyclo(C.sub.3 C.sub.8)alkyl, substituted or unsubstituted; R.sup.2 is aryl, substituted or unsubstituted; Y is C(O); Z.sup.1 and Z.sup.2 are combined to form an additional fused 6-membered aromatic ring, substituted or unsubstituted. 26. A method of treating rheumatoid arthritis, inflammatory bowel disease, allergic disease, psoriasis, asthma, multiple sclerosis, graft rejection or sepsis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim of formula (I): ##STR00073## or a pharmaceutically acceptable salt or prodrug thereof, wherein R.sup.1 is cyclo(C.sub.3 C.sub.8)alkyl, substituted or unsubstituted; R.sup.2 is aryl, substituted or unsubstituted; Y is C(O); Z.sup.1 and Z.sup.2 are combined to form an additional fused 6-membered aromatic ring, substituted or unsubstituted. 27. A method of treating rheumatoid arthritis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I): ##STR00074## or a pharmaceutically acceptable salt or prodrug thereof, wherein R.sup.1 is cyclo(C.sub.3 C.sub.8)alkyl, substituted or unsubstituted; R.sup.2 is aryl, substituted or unsubstituted; Y is C(O); Z.sup.1 and Z.sup.2 are combined to form an additional fused 6-membered aromatic ring, substituted or unsubstituted. 28. A method of treating inflammatory bowel disease, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I): ##STR00075## or a pharmaceutically acceptable salt or prodrug thereof, wherein R.sup.1 is cyclo(C.sub.3 C.sub.8)alkyl, substituted or unsubstituted; R.sup.2 is aryl, substituted or unsubstituted; Y is C(O); Z.sup.1 and Z.sup.2 are combined to form an additional fused 6-membered aromatic ring, substituted or unsubstituted. 29. A method of treating multiple sclerosis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I): ##STR00076## or a pharmaceutically acceptable salt or prodrug thereof, wherein R.sup.1 is cyclo(C.sub.3 C.sub.8)alkyl, substituted or unsubstituted; R.sup.2 is aryl, substituted or unsubstituted; Y is C(O); Z.sup.1 and Z.sup.2 are combined to form an additional fused 6-membered aromatic ring, substituted or unsubstituted.

Details for Patent 7,132,438

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Janssen Biotech, Inc.	REMICADE	infliximab	For Injection	103772	08/24/1998		2021-10-09
Immunex Corporation	ENBREL	etanercept	For Injection	103795	11/02/1998		2021-10-09
Immunex Corporation	ENBREL	etanercept	For Injection	103795	05/27/1999		2021-10-09
Immunex Corporation	ENBREL	etanercept	Injection	103795	09/27/2004		2021-10-09
Immunex Corporation	ENBREL	etanercept	Injection	103795	02/01/2007		2021-10-09
Immunex Corporation	ENBREL MINI	etanercept	Injection	103795	09/14/2017		2021-10-09
Immunex Corporation	ENBREL	etanercept	Injection	103795			2021-10-09