Patent
Compounds for the treatment of inflammatory disorders
| العنوان: | Compounds for the treatment of inflammatory disorders |
|---|---|
| Patent Number: | 8,178,553 |
| تاريخ النشر: | May 15, 2012 |
| Appl. No: | 12/690633 |
| Application Filed: | January 20, 2010 |
| مستخلص: | This invention relates to compounds of the Formula (I): [chemical expression included] or a pharmaceutically acceptable salt, solvate or isomer thereof, which can be useful for the treatment of diseases or conditions mediated by MMPs, ADAMs, TACE, aggrecanase, TNF-α or combinations thereof. |
| Inventors: | Lavey, Brian J. (New Providence, NJ, US); Kozlowski, Joseph A. (Princeton, NJ, US); Zhou, Guowei (Somerset, NJ, US); Tong, Ling (Warren, NJ, US); Yu, Wensheng (Edison, NJ, US); Wong, Michael K. C. (Somerset, NJ, US); Bandarpalle, Shankar B. (Branchburg, NJ, US); Shih, Neng-Yang (Lexington, MA, US); Siddiqui, M. Arshad (Newton, MA, US); Rosner, Kristin E. (Watertown, MA, US); Dai, Chaoyang (Acton, MA, US); Popovici-Muller, Janeta (Waltham, MA, US); Girijavallabhan, Vinay M. (Denville, NJ, US); Li, Dansu (Reading, MA, US); Kosinski, Aneta Maria (South Amboy, NJ, US); Kim, Seong-Heon (Livingston, NJ, US); Yang, De-Yi (Morris Plains, NJ, US); Rizvi, Razia K. (Bloomfield, NJ, US) |
| Assignees: | Schering Corporation (Kenilworth, NJ, US) |
| Claim: | 1. A compound of the Formula (I): [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl which is substituted with —Y—R 1 and —Z—R 2 as shown; X is —(C(R 3) 2) m —; T is selected from the group consisting of [chemical expression included] and wherein T is substituted with one to four R 10 moieties; U is absent; V is absent; Y is selected from the group consisting of a covalent bond, —(C(R 4) 2) n —, —N(R 4)—, —C(O)N(R 4)—, —N(R 4)C(O)—, —N(R 4)C(O)N(R 4)—, —S(O) 2 N(R 4)—, —N(R 4)—S(O) 2 , —O—, —S—, —C(O)—, —S(O)—, and —S(O) 2 —; Z is selected from the group consisting of a covalent bond, —(C(R 4) 2) n —, —N(R 4)—, —C(O)N(R 4)—, —N(R 4)C(O)—, —N(R 4)C(O)N(R 4)—, —S(O) 2 N(R 4)—, —N(R 4)—S(O) 2 —, —O—, —S—, —C(O)—, —S(O)—, and —S(O) 2 —; m is 1; n is 1 to 3; R 1 is selected from the group consisting of H, cyano, —C(O)OH, —C(O)O-alkyl, —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , alkynyl, halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, and heterocyclyl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five- to eight-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring; wherein each of the R 1 alkyl, alkynyl, aryl, heteroaryl, and heterocyclyl, optionally with the five to eight-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring is unsubstituted or optionally independently substituted with one to four R 20 moieties which can be the same or different; with the proviso that when Y is —N(R 4)—, —S— or —O—, then R 1 is not halogen or cyano; R 2 is selected from the group consisting of H, cyano, —C(O)OH, —C(O)O-alkyl, —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , alkynyl, halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, and heterocyclyl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five- to eight-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring; wherein each of the R 2 alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, optionally with the five, to eight-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring is unsubstituted or independently substituted with one to four R 20 moieties which can be the same or different; with the proviso that when Z is —N(R 4)—, —S— or —O—, then R 2 is not halogen or cyano; each R 3 is H; each R 4 is the same or different and is independently selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl, hydroxy, -alkylcycloalkyl, -alkyl-N(alkyl) 2 , heterocyclyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl contains two radicals on adjacent carbon atoms, said radicals may be taken together with the carbon atoms to which they are attached to form a five- to eight-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring; R 10 is selected from the group consisting of hydrogen, cyano, nitro, —C(R 4)═N—OR 4 , —OR 4 , —SR 4 , —N(R 4) 2 , —S(O)R 4 , —S(O) 2 R 4 , —N(R 4)S(O) 2 R 4 , —N(R 4)—C(O)—R 4 , —N(R 4)—C(O)—N(R 4) 2 , —N(R 4)—C(O)—OR 4 , —OC(O)N(R 4) 2 , —C(O)N(R 4)—S(O) 2 R 4 , —S(O) 2 N(R 4)—C(O)—R 4 , —C(O)N(R 4)C(O)R 4 , —C(O)N(R 4)C(O)NR 4 , —S(O) 2 N(R 4) 2 , —N(R 4)—C(═NR 4)—N(R 4) 2 , —N(R 4)—C(═N—CN)—N(R 4) 2 , -haloalkoxy, —C(O)OR 4 , —C(O)R 4 , —C(O)N(R 4) 2 , halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl, wherein each of the R 10 alkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl is unsubstituted or substituted with one to four R 30 moieties which can be the same or different; or wherein two R 10 moieties, when attached to the same or adjacent carbon atoms may optionally be taken together with the carbon atom(s) to which they are attached to form a cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl ring; R 20 is selected from the group consisting of cyano, nitro, —C(R 4)═N—OR 4 , —OR 4 , —SR 4 , —N(R 4) 2 , —S(O)R 4 , —S(O) 2 R 4 , —N(R 4)S(O) 2 R 4 , —N(R 4)—C(O)—R 4 , —N(R 4)—C(O)—N(R 4) 2 —N(R 4)—C(O)—OR 4 , —OC(O)N(R 4) 2 , —C(O)N(R 4)—S(O) 2 R 4 , —S(O) 2 N(R 4)—C(O)—R 4 , —C(O)N(R 4)C(O)R 4 , —C(O)N(R 4)C(O)NR 4 , —S(O) 2 N(R 4) 2 , —N(R 4)—C(═NR 4)—N(R 4) 2 , —N(R 4)—C(═N—CN)—N(R 4) 2 , -haloalkoxy, —C(O)OR 4 , —C(O)R 4 , —C(O)N(R 4) 2 , halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl; wherein when each of said R 20 aryl, heteroaryl, heterocyclyl and cycloalkyl contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five- to eight-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring; wherein each of said R 20 alkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl, optionally with said five- to eight-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring is unsubstituted or substituted with one to four moieties selected independently from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cyano, nitro, —NH 2 , —NH(alkyl), and —N(alkyl) 2 ; or when two R 20 moieties when attached to the same or adjacent carbon atoms may optionally be taken together with the carbon atom(s) to which they are attached to form a cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl ring; R 30 is selected from the group consisting of cyano, nitro, —C(R 4)═N—OR 4 , —SR 4 , —N(R 4) 2 , —S(O)R 4 , —S(O) 2 R 4 , —N(R 4)S(O) 2 R 4 , —N(R 4)—C(O)—R 4 , —N(R 4)—C(O)—N(R 4) 2 —N(R 4)—C(O)—OR 4 , —OC(O)N(R 4) 2 , —C(O)N(R 4)—S(O) 2 R 4 , —S(O) 2 N(R 4)—C(O)—R 4 , —C(O)N(R 4)C(O)R 4 , —C(O)N(R 4)C(O)NR 4 , —S(O) 2 N(R 4) 2 , —N(R 4)—C(═NR 4)—N(R 4) 2 , —N(R 4)—C(═N—CN)—N(R 4) 2 , -haloalkoxy, —C(O)OR 4 , —C(O)R 4 , —C(O)N(R 4) 2 , halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl; wherein when each of said R 30 aryl, heteroaryl, heterocyclyl and cycloalkyl contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five- to eight-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring; wherein each of said R 30 alkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl, optionally with said five- to eight-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring is unsubstituted or substituted with one to four moieties selected independently from the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro, —NH 2 , —NH(alkyl), and —N(alkyl) 2 ; or when two R 30 moieties when attached to the same or adjacent carbon atoms may optionally be taken together with the carbon atom(s) to which they are attached to form a cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl ring; with the proviso that T is substituted with at least one R 10 moiety selected from the group consisting of cyano, —C(O)OR 4 , —C(O)R 4 , —C(O)N(R 4) 2 , —C(O)N(R 4)C(O)R 4 , —C(O)N(R 4)C(O)NR 4 , —SR 4 , —S(O) 2 R 4 , —N(R 4)—C(O)OR 4 , —OC(O)N(R 4) 2 , —N(R 4)C(O)N(R 4) 2 , —N(R 4)—C(O)—R 4 , —S(O) 2 N(R 4) 2 , —S(O) 2 N(R 4)—C(O)—R 4 , —N(R 4)—C(═NR 4)—N(R 4) 2 , —N(R 4)—C(═N—CN)—N(R 4) 2 , and —C(R 4)═N—OR 4 , wherein each R 4 independently is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein when each of said R 4 cycloalkyl, heterocyclyl, aryl, and heteroaryl contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five- to eight-membered aryl, heterocyclyl, heteroaryl or cycloalkyl ring. |
| Claim: | 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said T is substituted with at least one R 10 moiety selected from the group consisting of cyano, —C(O)OR 4 , —C(O)R 4 , —C(O)N(R 4) 2 , and —C(R 4)═N—OR 4 . |
| Claim: | 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said T is substituted with at least one R 10 moiety that is cyano. |
| Claim: | 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said T is substituted with at least one R 10 moiety that is —SR 4 . |
| Claim: | 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said T is substituted with at least one R 10 moiety that is —S(O) 2 R 4 . |
| Claim: | 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said T is substituted with at least one R 10 moiety that is —S(O) 2 N(R 4) 2 . |
| Claim: | 7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each of Y and Z is independently selected from the group consisting of a covalent bond and —O—. |
| Claim: | 8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein Y is —O— and Z is a covalent bond. |
| Claim: | 9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each of R 1 and R 2 is independently selected form the group consisting of H and alkyl. |
| Claim: | 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1 is alkyl and R 2 is H. |
| Claim: | 11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl. |
| Claim: | 12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: [chemical expression included] |
| Claim: | 13. The compound of claim 12 or a pharmaceutically acceptable salt thereof wherein the compound is [chemical expression included] |
| Claim: | 14. The compound of claim 12 or a pharmaceutically acceptable salt thereof wherein the compound is [chemical expression included] |
| Claim: | 15. The compound of claim 12 or a pharmaceutically acceptable salt thereof wherein the compound is [chemical expression included] |
| Claim: | 16. The compound of claim 12 or a pharmaceutically acceptable salt thereof wherein the compound is [chemical expression included] |
| Claim: | 17. The compound of claim 12 or a pharmaceutically acceptable salt thereof wherein the compound is [chemical expression included] |
| Claim: | 18. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. |
| Claim: | 19. A pharmaceutical composition comprising the compound of claim 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. |
| Current U.S. Class: | 514/300 |
| Patent References Cited: | 6495565 December 2002 Duan et al. 6534491 March 2003 Levin et al. 6677355 January 2004 Conrad et al. 7041693 May 2006 Sheppeck 7482370 January 2009 Yu et al. 7488745 February 2009 Yu et al. 7504424 March 2009 Yu et al. 7524842 April 2009 Lavey et al. 7683085 March 2010 Yu et al. 7687527 March 2010 Yu et al. 7772263 August 2010 Lavey et al. 7879890 February 2011 Yu et al. 2008/0226618 September 2008 Mansoor et al. WO 02/074750 September 2002 WO 02/096426 December 2002 WO 03/053940 July 2003 WO 03/053941 July 2003 WO 2004/012663 February 2004 WO 2004/024698 March 2004 WO 2004/024715 March 2004 WO 2004/024721 March 2004 WO 2004/056766 July 2004 WO 2006/019768 February 2006 |
| Other References: | Knaggs, A., et al., “Biotransformation of Alosetron: Mechanism of Hydantoin Formation”, Tetrahedron Letters, vol. 36, No. 3, pp. 477-480 (1995). cited by other PCT International Search Report dated Jun. 18, 2007 for corresponding PCT Application No. PCT/US2007/001030. cited by other |
| Primary Examiner: | Chu, Yong |
| Attorney, Agent or Firm: | Meade, Eric A. Camara, Valerie J. |
| رقم الانضمام: | edspgr.08178553 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |