Patent FR-2904316-A1 (FR)
Title: New N-(amino-heteroaryl)-1H-indole-2-carboxamide compounds are transient receptor potential vanilloid 1 receptor anagonists, useful to prevent/treat e.g. pain, inflammation, urological/gynecological/gastrointestinal disorders and pruritus
Inventor: DUBOIS LAURENT
IPC: A61P25/04
Filed: 2006-07-31
Abstract: N-(Amino-heteroaryl)-1H-indole-2-carboxamide compounds (I) in the form of bases, acid addition salts, hydrates or solvates are new. N-(Amino-heteroaryl)-1H-indole-2-carboxamide compounds of formula (I) optionally in the form of bases, acid addition salts, hydrates or solvates, are new. X 1 : H, halo, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkylene, 1-6C fluoroalkyl, CN, C(O)NR 1R 2, NO 2, 1-6C thioalkyl, -S(O)-1-6C alkyl, -S-(O) 2-1-6C alkyl, -SO 2NR 1R 2, aryl-1-6C alkylene or T; T : (hetero)aryl (optionally substituted by halo, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkylene, 1-6C fluoroalkyl, 1-6C alkoxyl, 1-6C fluoroalkoxyl, NO 2 or CN); X 2 : H, halo, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkylene, 1-6C fluoroalkyl, 1-6C alkoxyl, 3-7C cycloalkyl-1-3C alkylene-O-, 1-6C fluoroalkoxyl, CN, C(O)NR 1R 2, 1-6C-thioalkyl, -S(O)-1-6C alkyl-, -SO 2-alkyl-, SO 2-NR 1R 2, aryl-1-6C alkylene or T; X 3, X 4 : H, halo, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkylene, 1-6C fluoroalkyl, 1-6C alkoxyl, 3-7C cycloalkyl-1-3C alkylene-O-, 1-6C fluoroalkoxyl, CN, C(O)NR 1R 2, NO 2, NR 1R 2, 1-6C thioalkyl, -S(O)-1-6C alkyl, -S(O) 2-1-6C alkyl, -SO 2NR 1R 2, NR 3COR 4, NR 3SO 2R 5, aryl-1-6C alkylene or T; Z 1-Z 4 : N or C(R 6) (nitrogen atom present in the cycle i.e. defined as nitrogen position 1, is substituted by R 7 and the carbon atom in 2 or 4 position in relation to the reference nitrogen is substituted by thio or oxo group); n : 0-3; Y 1 : (hetero)aryl (optionally substituted by halo, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkylene, 1-6C fluoroalkyl, OH, 1-6C alkoxyl, 3-7C cycloalkyl-1-6C alkylene-O-, 1-6C fluoroalkoxyl, CN, -C(O) NR 1R 2, NO 2, NR 1R 2, 1-6C thioalkyl, thiol, -S(O)-1-6C alkyl, -S(O) 2-1-6C alkyl, SO 2NR 1R 2, NR 3COR 4, -NR 3SO 2R 5, aryl-1-6C alkylene or aryl, where aryl-1-6C alkylene or aryl optionally substituted by halo, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkylene, 1-6C fluoroalkyl, 1-6C alkoxyl, 1-6C fluoroalkoxyl, NO 2 or CN); Z : a cyclic amine moiety linked through a nitrogen atom, of formula (II) (where the carbon atoms optionally substituted by R 12); A 1 : 1-7C alkylene (optionally substituted by 1-2 groups of R 8); A 2 : 1-7C alkylene (optionally substituted by 1-2 groups of R 9); L : a bond, S, O or N (optionally substituted by R 10 or R 12); either R 1, R 2 : H, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cyclo alkyl-1-3C alkylene, aryl-1-3C alkylene or aryl; or NR 1R 2 : azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, thiomorpholinyl, piperazinyl or homopiperazinyl (optionally substituted by 1-6C alkyl, 3-7C cycloalkyl, 3-7c cycloalkyl-1-3C alkylene, aryl-1-3C alkylene or (hetero)aryl); R 3, R 4 : H or R 5; R 5 : 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkylene, 1-6C aryl-alkylene or (hetero)aryl; R 6 : H, halo, 1-6C alkyl, 3-7C cycloalkyl, 3-7C isopropyl-1-3C alkylene, 1-6C fluoroalkyl, 1-6C alkoxyl, 3-7C cycloalkyl 1-6C alkylene-O-, 1-6C fluoroalkoxyl, 1-6C thioalkyl, -S(O)-1-6C alkyl-, -S-(O) 2-1-6C alkyl-, aryl-1-6C alkylene, (hetero)aryl, hydroxyl, thiol, oxo or thio; R 7 : H, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-6C alkylene, 1-6C fluoroalkyl, 1-6C alkoxyl, 3-7C cycloalkyl-1-6C alkylene-O-, 1-6C fluoroalkoxyl, aryl-1-6C alkylene or (hetero)aryl; R 8 + R 8, R 9 + R 9, R 8 + R 9, R 8 + R 10, R 9 + R 10 : a bond or 1-6C alkylene; R 11 : H, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkylene, 1-6C fluoroalkyl, 1-6C alkoxyl, 3-7C cycloalkoxyl, 3-7C cycloalkyl-1-6C alkylene-O-, 1-6C fluoroalkoxyl, OH, COOR 5, C(O)NR 1R 2, aryl-1-6C alkylene or T; R 12 : F, 1-6C alkyl (optionally substituted by R 13), 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkylene, 1-6C fluoroalkyl, 1-6C cycloalk-1,1-diyl, 3-7C heterocycloalk-1,1-diyl (optionally substituted on the nitrogen atom by R 11), 1-6C alkoxyl, 3-7C cycloalkoxyl, 3-7C cycloalkyl-1-6C alkylene-O-, 1-6C fluoroalkoxyl, C(O)NR 1R 2, NR 1R 2, NR 3COR 4, OC(O)NR 1R 2, NR 3COOR 5, NR 3CONR 1R 2, OH, thiol, oxo, thio, aryl-1-6C alkylene, aryl (optionally substituted by halo, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkylene, 1-6C fluoroalkyl, 1-6C alkoxyl, 3-7C cycloalkoxyl, 1-6C fluoroalkoxyl, NO 2 or CN); and R 13 : 1-6C alkoxyl, 3-7C cycloalkoxyl, 3-7C cycloalkyl-1-6C alkylene-O-, C(O)NR 1R 2, NR 1R 2, NR 3COR 4, OC(O)NR 1R 2, NR 3COOR 5 or OH. The N-atoms and S-atoms in (I) may be in the oxidized form. An independent claim is included for the preparation of (I). [Image] [Image] ACTIVITY : Analgesic; Antiinflammatory; Uropathic; Gynecological; Gastrointestinal-Gen.; Respiratory-Gen.; Antipsoriatic; Antipruritic; Dermatological; Virucide; Antidepressant; Antidiabetic; Antiulcer. MECHANISM OF ACTION : Transient receptor potential vanilloid 1 (TRPV1) receptor antagonist. The ability of (I) to inhibit the current induced by capsaicin was tested in primary culture of dorsal rout ganglion (DRG) cells of rat. The results showed that N-[6-(pyrrolidin-1-yl)-pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide exhibited 46% inhibition in the DRG patch thus good antagonistic activity against TRPV1 receptor.