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首页> 外国专利> Compounds derived from N - (aminoheteroaril) - 1H indole - 3 - carboxamide,TRPV1 receptor modulators; procedures for Preparation of the pharmaceutical Intermediate Compounds; Compounds; composition; and their use in the treatment of inflammation, Pain, depression,Respiratory and Gastrointestinal Disorders, among others.

Compounds derived from N - (aminoheteroaril) - 1H indole - 3 - carboxamide,TRPV1 receptor modulators; procedures for Preparation of the pharmaceutical Intermediate Compounds; Compounds; composition; and their use in the treatment of inflammation, Pain, depression,Respiratory and Gastrointestinal Disorders, among others.

机译：衍生自N-（氨基杂芳基）-1H吲哚-3-羧酰胺，TRPV1受体调节剂的化合物;药物中间体化合物的制备程序;化合物;组成;及其在治疗炎症，疼痛，抑郁，呼吸道和胃肠道疾病等方面的用途。

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摘要

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.
机译：以碱，酸加成盐，水合物或溶剂化物形式存在的N-（氨基-杂芳基）-1H-吲哚-2-羧酰胺化合物（I）是新的。任选以碱，酸加成盐，水合物或溶剂化物形式存在的式（I）的N-（氨基-杂芳基）-1H-吲哚-2-羧酰胺化合物是新的。 X 1：H，卤素，1-6C烷基，3-7C环烷基，3-7C环烷基-1-3C亚烷基，1-6C氟代烷基，CN，C（O）NR 1R 2，NO 2，1-6C硫代烷基， -S（O）-1-6C烷基，-S-（O）2-1-6C烷基，-SO 2NR 1R 2，芳基-1-6C亚烷基或T; T ：(杂）芳基（任选地被卤素，1-6C烷基，3-7C环烷基，3-7C环烷基-1-3C亚烷基，1-6C氟代烷基，1-6C烷氧基，1-6C氟代烷氧基，NO 2或CN）; X 2：H，卤素，1-6C烷基，3-7C环烷基，3-7C环烷基-1-3C亚烷基，1-6C氟代烷基，1-6C烷氧基，3-7C环烷基-1-3C亚烷基-O-， 1-6C氟代烷氧基，CN，C（O）NR 1R 2，1-6C-硫代烷基，-S（O）-1-6C烷基-，-SO 2-烷基-，SO 2-NR 1R 2，芳基-1 -6C亚烷基或T; X 3，X 4：H，卤素，1-6C烷基，3-7C环烷基，3-7C环烷基-1-3C亚烷基，1-6C氟代烷基，1-6C烷氧基，3-7C环烷基-1-3C亚烷基- O-，1-6C氟代烷氧基，CN，C（O）NR 1R 2，NO 2，NR 1R 2，1-6C硫代烷基，-S（O）-1-6C烷基，-S（O）2-1- 6C烷基，-SO 2NR 1R 2，NR 3COR 4，NR 3SO 2R 5，芳基-1-6C亚烷基或T; Z 1-Z 4：N或C（R 6）（循环中存在的氮原子，即定义为氮位置1）被R 7取代，相对于参考氮的2或4位碳原子被取代硫代或氧代基团）; n：0-3; Y 1 ：(杂）芳基（任选被卤素，1-6C烷基，3-7C环烷基，3-7C环烷基-1-3C亚烷基，1-6C氟代烷基，OH，1-6C烷氧基，3-7C环烷基-取代） 1-6C亚烷基-O-，1-6C氟代烷氧基，CN，-C（O）NR 1R 2，NO 2，NR 1R 2，1-6C硫代烷基，硫醇，-S（O）-1-6C烷基，- S（O）2-1-6C烷基，SO 2NR 1R 2，NR 3COR 4，-NR 3SO 2R 5，芳基-1-6C亚烷基或芳基，其中芳基-1-6C亚烷基或芳基任选被卤素取代，1 -6C烷基，3-7C环烷基，3-7C环烷基-1-3C亚烷基，1-6C氟代烷基，1-6C烷氧基，1-6C氟代烷氧基，NO 2或CN）; Z：通过氮原子连接的式（II）的环胺部分（其中碳原子任选地被R 12取代）; A 1：1-7C亚烷基（任选地被R 8的1-2个基团取代）; A 2：1-7C亚烷基（可选地被1-2个R 9基团取代）; L：键，S，O或N（任选被R 10或R 12取代）; R 1，R 2：H，1-6C烷基，3-7C环烷基，3-7C环烷基-1-3C亚烷基，芳基-1-3C亚烷基或芳基;或或NR 1R 2：氮杂环丁烷基，吡咯烷基，哌啶基，氮杂吡啶基，吗啉基，硫代吗啉基，哌嗪基或高哌嗪基（可选地被1-6C烷基，3-7C环烷基，3-7c环烷基-1-3C亚烷基，芳基-1-3C亚烷基取代）或（杂）芳基）; R 3，R 4：H或R 5; R 5：1-6C烷基，3-7C环烷基，3-7C环烷基-1-3C亚烷基，1-6C芳基-亚烷基或（杂）芳基; R 6：H，卤素，1-6C烷基，3-7C环烷基，3-7C异丙基-1-3C亚烷基，1-6C氟烷基，1-6C烷氧基，3-7C环烷基1-6C亚烷基-O-，1 -6C氟代烷氧基，1-6C硫代烷基，-S（O）-1-6C烷基-，-S-（O）2-1-6C烷基-，芳基-1-6C亚烷基，（杂）芳基，羟基，硫醇，氧代或硫代; R 7：H，1-6C烷基，3-7C环烷基，3-7C环烷基-1-6C亚烷基，1-6C氟代烷基，1-6C烷氧基，3-7C环烷基-1-6C亚烷基-O-，1- 6C氟代烷氧基，芳基-1-6C亚烷基或（杂）芳基; R 8 + R 8，R 9 + R 9，R 8 + R 9，R 8 + R 10，R 9 + R 10：键或1-6C亚烷基; R 11：H，1-6C烷基，3-7C环烷基，3-7C环烷基-1-3C亚烷基，1-6C氟代烷基，1-6C烷氧基，3-7C环烷氧基，3-7C环烷基-1-6C亚烷基- O-，1-6C氟代烷氧基，OH，COOR 5，C（O）NR 1R 2，芳基-1-6C亚烷基或T; R 12：F，1-6C烷基（任选地被R 13取代），3-7C环烷基，3-7C环烷基-1-3C亚烷基，1-6C氟代烷基，1-6C环烷-1,1-二基，3- 7C杂环烷基-1,1-二基（在氮原子上可选被R 11取代），1-6C烷氧基，3-7C环烷氧基，3-7C环烷基-1-6C亚烷基-O-，1-6C氟代烷氧基，C（ O）NR 1R 2，NR 1R 2，NR 3COR 4，OC（O）NR 1R 2，NR 3COOR 5，NR 3CONR 1R 2，OH，硫醇，氧代，硫代，芳基1-6C亚烷基，芳基（可选通过卤素，1-6C烷基，3-7C环烷基，3-7C环烷基-1-3C亚烷基，1-6C氟烷基，1-6C烷氧基，3-7C环烷氧基，1-6C氟烷氧基，NO 2或CN）;和R 13：1-6C烷氧基，3-7C环烷氧基，3-7C环烷基-1-6C亚烷基-O-，C（O）NR 1R 2，NR 1R 2，NR 3COR 4，OC（O）NR 1R 2，NR 3COOR 5或OH。 （I）中的N原子和S原子可以是氧化形式。包括独立权利要求用于制备（I）。 [图像] [图像]活动：止痛药;消炎（药;尿毒症;妇科胃肠源呼吸器;对牛皮癣;止痒;皮肤;杀病毒剂;抗抑郁药抗糖尿病抗溃疡。作用机理：瞬态受体电位香草醛1（TRPV1）受体拮抗剂。在大鼠背痛神经节（DRG）细胞的原代培养中测试了（I）抑制辣椒素诱导的电流的能力。结果表明，N- [6-（吡咯烷-1-基）-吡啶-3-基] -5-氟-1-（3-氟苄基）-1H-吲哚-2-羧酰胺对DRG的抑制作用为46％因此对TRPV1受体具有良好的拮抗活性。

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