Patent FR-2919610-A1 (FR)
Title: New tricyclic N-heteroaryl carboxamide derivatives are transient receptor potential vanilloid 1 inhibitors useful to prevent/treat e.g. pain, inflammation, metabolic disorders, urological disorders, gastrointestinal disorders and psoriasis
Inventor: DUBOIS LAURENT
IPC: A61K31/437
Filed: 2007-08-02
Abstract: Tricyclic N-heteroaryl carboxamide derivatives (I) and their acid or base addition salts, hydrates or solvates are new. Tricyclic N-heteroaryl carboxamide derivatives of formula (I) and their acid or base addition salts, hydrates or solvates are new. A : bicycle to which it is merged with Z 2-Z 3, 4-7C cycloalkyl group, monocyclic heterocyclic ring or monocyclic heteroaryl of 4-7 membered ring having 1-3 heteroatoms of O, S or N, including Z 2-Z 3atoms; either Z 1, Z 5-Z 8 : N, C or a C-R 2; and Z 1-Z 9 : form bicyclic heteroaryl linked to N atom of amide or thioamide of (I), where the positions of Z 5-Z 8are correspond to C, and the positions of Z 4-Z 9are correspond to N; W 1 : O or S; P 1 : indolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl linked in position C-2 at carbonyl of amide or thiocarbonyl of thioamide of (I) or indole derivative of formula (a); X 1-X 4 : N or C-R 1group (where other three is C-R 1group when one of X 1, X 2, X 3or X 4is N); R 1 : H, halo, 1-6C alkyl, 3-7C cycloalkyl, 3-7C-cycloalkyl-1-3C-alkylene, 1-6C-fluoroalkyl, aryloxy-1-6C-alkyl, heteroaryloxy-1-6C-alkyl, aryl-1-3C-alkylenoxy-1-6C-alkyl, heteroaryl-1-3C-alkylenoxy-1-6C-alkyl, arylthio-1-6C-alkyl, heteroarylthio-1-6C-alkyl, aryl-1-3C-alkylene-thio-1-6C-alkyl, heteroaryl-1-3C-alkylene-thio-1-6C-alkyl, 1-6C-alkoxy, 3-7C-cycloalkyloxy, 3-7C-cycloalkyl-1-3C-alkylenoxy, 1-6C-fluoroalkoxy, CN, C(O)NR 4R 5, N, NR 4R 5, 1-6C-thioalkyl, 3-7C-cycloalkylthio, 3-7C-cycloalkyl-1-3C-alkylene-thio, -S(O)-1-6C-alkyl, -S(O)-3-7C-cycloalkyl, -S(O)-1-3C-alkylene-3-7C-cycloalkyl, 1-6C-alkyl-S(O) 2-, 1-6C-fluoroalkyl-S(O) 2-, 3-7C-cycloalkyl-S(O) 2-, 3-7-cycloalkyl-1-3C-alkylene-S(O) 2-, SO 2NR 4R 5, SF 5, NR 6C(O)R 7, NR 6SO 2R 8, C(O)NR 4R 5, OC(O)NR 4R 5, aryl, heteroaryl, aryl-1-5C-alkylene, heteroaryl-1-5C-alkylene, aryloxy, arylthio, heteroaryloxy or heteroarylthio, heteroaryl or aryl groups (optionally substituted by R 9); n : 0.1, 2 or 3; Y 1 : aryl or heteroaryl (optionally substituted by halo,1-6C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-3C-alkylene, 1-6C-fluoroalkyl, OH, 1-6C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-6C-alkylene-O-, 1-6C-fluoroalkoxy, CN, C(O)NR 4R 5, N, NR 4R 5, 1-6C-thioalkyl, thiol,-S(O)-1-6C-alkyl, -S(O) 2-1-6C-alkyl, SO 2NR 4R 5, NR 6C(O)R 7, NR 6SO 2R 8, C(O)NR 4R 5, OC(O)NR 4R 5, aryl-1-5C-alkylene or aryl, heteroaryl-1-5C-alkylene or heteroaryl, or optionally substituted by halo, 1-6C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-3C-alkylene, 1-6C fluoroalkyl, 1-6C-alkoxy, 3-7C cycloalkyloxy, 3-7C-cycloalkyl-1-3C-alkylenoxy, 1-6C-fluoroalkoxy, N or CN); R 2 : H, halo, 1-6C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-3C-alkylene, 1-6C-fluoroalkyl, 1-6C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-3C-alkylenoxy, thiol, -S(O)-1-6C-alkyl, -S(O) 2-1-6C-alkyl, OH, 1-6C-alkoxy, 3-7C-cycloalkyloxy, 3-7C-cycloalkyl-1-6C-alkylene-O-, 1-6C-fluoroalkoxy; either R 3, R 3a (when carried by the C atom) : substituents of A excluding substituents of Z 2and Z 3atoms, H, halo, 1-6C alkyl, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkyleneoxy, aryl-C(O)-O-, 1-6C alkyl-C(O)-O-, 3-7C cycloalkyl-C(O)-O, 3-7C cycloalkyl-1-3C alkylene-C(O)-O, 1-6C fluoroalkyl-C(O)-O-, OXO, thio, NR 4R 5, NR 6C(O)R 7, heteroaryl or aryl (where the heteroaryl and aryl are optionally substituted by halo, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkylene, 1-6C fluoroalkyl, 1-6C alkoxy, 3-7C cycloalkyloxy-1-3C alkylenoxy, 1-6C fluoroalkoxy, NO 2or CN); and R 3, R 3a (when carried by the N atom) : H, 1-6C alkyl, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkyleneoxy, aryl-C(O)-O-, 1-6C alkyl-C(O)-O-, 3-7C cycloalkyl-C(O)-O, 3-7C cycloalkyl-1-3C alkylene-C(O)-O, 1-6C fluoroalkyl-C(O)-O-, OXO, thio, NR 4R 5, NR 6C(O)R 7, heteroaryl or aryl (where the heteroaryl and aryl are optionally substituted by comprising halo, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkylene, 1-6C fluoroalkyl, 1-6C alkoxy, 3-7C cycloalkyloxy-1-3C alkylenoxy, 1-6C fluoroalkoxy, NO 2or CN); or CR 3R 3a : 3-7C cycloalk-1,1-diyl; either R 4, R 5 : H, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C-alkylene, aryl-1-6C-alkylene or aryl; or NR 4R 5 : azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazine, homopiperazine (where the group NR 4R 5is substituted by a group of 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C-alkylene, aryl-1-6C-alkylene, aryl, heteroaryl, aryl-S(O) 2-, 1-6C alkyl-S(O) 2-, 1-6C-fluoroalkyl-S(O) 2, 3-7C-cycloalkyl-S(O) 2-, 3-7C cycloalkyl-1-3C-alkylene-S(O) 2-, aryl-C(O)-, 1-6C-alkyl-C(O)-, 3-7C-cycloalkyl-C(O)-, 3-7C cycloalkyl-1-3C-alkylene-C(O)-, 1-6C-fluoroalkyl-C(O)-, OH, 1-6C-alkyloxy, 3-7C cycloalkyloxy, 3-7C-cycloalkyl-1-3C-alkylenoxy, 1-6C-fluoroalkyl, aryloxy-1-6C-alkylene, aryloxy, heteroaryloxy-1-6C-alkylene or heteroaryloxy); either R 6, R 7 : H, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C-alkylene, aryl-1-6C-alkylene or aryl (where the aryl group is optionally substituted by comprising halo, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkylene, 1-6C fluoroalkyl, 1-6C alkoxy, 3-7C cycloalkyloxy-1-3C alkylenoxy, 1-6C fluoroalkoxy, NO 2or CN); and R 8 : R 6or R 7; or R 6R 7 : lactam of 4-7 membered ring containing N atom and C(O) group; or R 6R 8 : sultame of 4-7 membered ring containing N atom and S(O) 2group; and R 9 : halo, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C-alkylene, 1-6C fluoroalkyl, 1-6C alkoxy, 3-7C cycloalkyloxy-1-3C alkylenoxy, 1-6C fluoroalkoxy, NO 2, CN, NR 4R 5or R 4R 5N-1-3C alkylene. [Image] [Image] ACTIVITY : Analgesic; Antiinflammatory; Metabolic; Gynecological; Gastrointestinal-Gen; Respiratory-Gen; Antipsoriatic; Antipruritic; Uropathic; Virucide; Dermatological; Antidepressant. MECHANISM OF ACTION : Transient receptor potential vanilloid 1 inhibitor. The ability of (I) to inhibit transient receptor potential vanilloid 1 was tested using primary culture cells of rat dorsal root ganglion. The result showed that N-(2,3-dihydro-1H-pyrrolo[1',2':1,2]imidazo[5,4-b]pyridin-6-yl)-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide exhibited an inhibition of 69% at a concentration of 10 nM.