| 摘要 |
#CMT# #/CMT# N-(Benzo-heterocyclyl)-1-heteroaryl-1H-indole-2-carboxamide derivatives (I) are new. #CMT# : #/CMT# Indole derivatives of formula (I) and their acid addition salts, hydrates and solvates are new. X 1-X 4H, halo, alkyl, cycloalkyl, cycloalkyl-(1-3C) alkyl, fluoroalkyl, alkoxy, fluoroalkoxy, CN, CONR 1R 2, NO 2, NR 1R 2, alkylthio, alkylsulfinyl, alkylsulfonyl, SO 2NR 1R 2, NR 3COR 4, NR 3SO 2R 5 or aryl (optionally substituted (os) by one or more of alkyl, cycloalkyl, cycloalkyl-(1-3C) alkyl, fluoroalkyl, alkoxy, fluoroalkoxy, CN or NO 2); W' : benzo-fused 5-7 membered heterocycle, (i) containing 1-3 of S, O and/or N as heteroatom(s), (ii) bonded to the N of (I) via the benzo ring, (iii) os on C of the heterocyclic ring by one or more of alkyl, cycloalkyl, cycloalkyl-(1-3C) alkyl, fluoroalkyl, alkoxy, cycloalkoxy, cycloalkyl-(1-3C) alkoxy, aryl, arylalkyl, = O or thio and (iv) os on N by R 6 if the N is adjacent to = O or in other cases by R 7; Y' : heteroaryl (os by one or more of halo, alkyl, cycloalkyl, cycloalkyl-(1-3C) alkyl, fluoroalkyl, OH, alkoxy, fluoroalkoxy, CN, CONR 1R 2, NO 2, NR 1R 2, alkylthio, SH, alkylsulfinyl, alkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, SO 2NR 1R 2, NR 3COR 4, NR 3SO 2R 5, aryl or arylalkyl (where aryl moieties are os as in X 1-X 4); R 1, R 2H, alkyl, cycloalkyl, cycloalkyl-(1-3C) alkyl, arylalkyl or aryl; or NR 1R 2azetidino, pyrrolidone, piperidino, azepino, morpholino, thiomorpholino, piperazino or homopiperazino (all os by alkyl, cycloalkyl, cycloalkyl-(1-3C) alkyl, arylalkyl or aryl); R 3, R 4H, alkyl, arylalkyl or aryl; R 5alkyl, arylalkyl or aryl; R 6H, alkyl, cycloalkyl, cycloalkyl-(1-3C) alkyl, fluoroalkyl, arylalkyl, alkylcarbonyl, cycloalkyl-(1-3C) alkylcarbonyl, fluoroalkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulfonyl, fluoroalkylsulfonyl, cycloalkylsulfonyl, cycloalkyl-(1-3C) alkylsulfonyl, arylsulfonyl or aryl; ring S and N atoms in W' and Y' are optionally in oxidized form; unless specified otherwise alkyl moieties have 1-6C and cycloalkyl moieties 3-7C. An independent claim is included for the preparation of (I) #CMT#[Image]#/CMT# #CMT#ACTIVITY : #/CMT# Analgesic; Antiinflammatory; Urolopathic; Gynecological; Antipsoriatic; Antipruritic; Dermatological; Ophthalmological; Virucide; Neuroprotective; Antidepressant; Antiulcer; Hepatotropic; Antiasthmatic; Antitussive. #CMT#MECHANISM OF ACTION : #/CMT# TRPV1 receptor antagonist. In a TRPV1 receptor antagonist assay based on inhibtion of the current induced in rat dorsal root ganglions, N-(1,2-dimethyl-1H-benzimidazol-5-yl)-5-fluoro-1-(4,6-dimethyl-pyridin-2-yl)-1H-indole-2-carboxamide (Ia) gave 70% inhibition at a concentration of 10 nM. #CMT#USE : #/CMT# (I) are used as medicaments, specifically for treating pain, inflammation, metabolic, urological, gynecological, gastrointestinal or respiratory disorders, psoriasis, pruritis, irritation of the skin, eyes or mucosa, herpes, shingles, plaque sclerosis and depression (all claimed). Typically the metabolic disorder is diabetes; the gastrointestinal disorders are gastro-esophageal reflux, gastric or duodenal ulcers, dyspepsia, colitis, irritable bowel syndrome, Crohn's disease, pancreatitis, esophagitis or hepatic colic; and the respiratory disorders are asthma, coughs, chronic obstructive pneumopathy, chronic obstructive pulmonary disease and bronchoconstriction. #CMT#ADVANTAGE : #/CMT# (I) show strong TRPV1 receptor antagonist activity in vitro and in vivo, and are effective in combating disorders involving stimulation of the TRPV1 receptor. #CMT#ORGANIC CHEMISTRY : #/CMT# Preparation: Claimed preparation of (I) involves reacting an indole-2-carboxylate ester of formula (IV) with an amide derived from a heterocyclic amine of formula W-NH 2 (V) at reflux temperature in a solvent, the amide being formed from (V) by preliminary reaction with trimethyl-aluminum. D' : 1-6C alkoxy. #CMT#[Image]#/CMT# #CMT#DEFINITIONS : #/CMT# Preferred Definitions: X 1, X 3, X 4H; X 2halo; W : benzimidazol-5-yl or indol-5-yl (both os on C or N in the heterocyclic ring by one or more 1-6C alkyl); Y : pyridinyl (os by one or more 1-6C alkyl). #CMT#ADMINISTRATION : #/CMT# (I) are administered by oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal routes, at a daily dose of 0.001-30 mg/kg. #CMT#SPECIFIC COMPOUNDS : #/CMT# 11 Compounds (I) are disclosed, e.g. N-(1,2-dimethyl-1H-benzimidazol-5-yl)-5-fluoro-1-(4,6-dimethyl-pyridin-2-yl)-1H-indole-2-carboxamide of formula (Ia), N-(1-methyl-1H-indol-5-yl)-5-fluoro-1-(pyridin-4-yl)-1H-indole-2-carboxamide, N-(1-methyl-1H-indol-5-yl)-5-fluoro-1-(pyridin-3-yl)-1H-indole-2-carboxamide, N-(1,2-dimethyl-1H-benzimidazol-5-yl)-5-fluoro-1-(pyridin-4-yl)-1H-indole-2-carboxamide and N-(1,2-dimethyl-1H-benzimidazol-5-yl)-5-fluoro-1-(2-methyl-pyridin-4-yl)-1H-indole-2-carboxamide. #CMT#[Image]#/CMT# #CMT#EXAMPLE : #/CMT# A solution of 0.34 g 5-amino-1,2-dimethyl-1H-benzimidazole in 19.2 ml toluene was treated with 1.54 ml of 2N solution of trimethylaluminum in toluene, stirred for 15 minutes at 50[deg] C, treated with 0.6 g ethyl 5-fluoro-1-(4,6-dimethyl-pyridin-2-yl)-1H-indole-2-carboxylate, heated at reflux for 4 hours, stirred at room temperature overnight, poured onto ice and extracted with ethyl acetate. The organic phase was worked up to give, after chromatographic purification, 0.71 g of N-(1,2-dimethyl-1H-benzimidazol-5-yl)-5-fluoro-1-(4,6-dimethyl-pyridin-2-yl)-1H-indole-2-carboxamide (Ia), m.pt. 130-140[deg] C. |
