SEROTOMIN AND 5HT1A RECEPTOR ANTAGONIST PHENOXYPROPYLAMINE DERIVATIVES AND USE THEREOF

摘要

Phenoxypropylamine compounds (I) are new. Phenoxypropylamine compounds of formula (I), their optical isomers, salts and hydrates are new. [Image] X : H, OH, 1-8C alkoxy, acyloxy or oxo; R 1NHY 1R 2 or a group of formula (i)-(vi); Y : O or S; m, n : 0-2; Ar : optionally substituted aromatic hydrocarbyl; R 2, R 5optionally substituted aryl or heteroaryl; Z : absent or CH 2; R 6H, OH, acetamido, COOH, alkoxycarbonyl, CN or 1-8C alkoxy; Y 1optionally substituted 3-8C cycloalkylene, 1-4C alkeneoxy or 1-8C alkylene; R 3H, 1-18C alkyl or halo; V : CH 2, O, S or NR 4; R 4H, 1-18C alkyl or optionally substituted aralkyl; W : a bond, CH 2 or CO or V + W : H and are not bonded to one another; R 71-4C hydroxyalkyl, acyl, 1-4C alkylsulfonyl, QR 9 or optionally substituted, optionally unsaturated heterocyclyl or fused heterocyclyl; Q : CO, CS, CH 2 or SO 2; R 9NR 10R 11, 3-R 12-pyrrolidin-1-yl, 4-R 12-piperidin-1-yl, 4-morpholinyl, 4-R 12-piperazin-1-yl, 4-R 12-1-aza-cycloheptan-1-yl, NHNHR 15 or pyrrolyl, imidazolyl or pyrazole (all substituted by R 12); R 10, R 11H, 1-18C alkyl, alkoxy or optionally substituted aryl or aralkyl; R 12H, optionally substituted aryl, 1-18C alkyl, 1-8C alkoxy, or acyl; R 15H, phenyl, 1-4C alkyl, 1-2C haloalkyl, halo, 2-4C alkenyl, 1-4C hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, acetamido, COOH, acyl, alkylthio, CN or optionally substituted amino or alkoxy; or R 7 + W : T; T : optionally substituted 4-7 membered heterocyclyl containing 1 or 2 N or O 2-substituted by oxo or thioxo and attached via a single or double bond; R a-R cH, 1-18C alkyl, hydroxy, 1-8C alkoxy, halo, acyl, NO 2 or amino; provided that when V and W are H, then R 7 is not COR 9. [Image] Independent claims are also included for intermediates of formula (II) and (III). [Image] R 14H or 1-4C alkyl; R : H, 1-4C alkyl, allyl or 2,3-epoxypropan-1-yl; Q' : 4-7 membered heterocyclyl with 1 or 2 O or N heteroatoms (optionally substituted) and E : O or S. ACTIVITY : Antidepressant; tranquilizer; nootropic; hypotensive; gastrointestinal; anabolic; anorectic. MECHANISM OF ACTION : Serotonin (5-HT 1A) antagonist; serotonin reuptake inhibitor. In assays, (S)-3-(4-(3,4-dichlorophenyl)piperidino)-1-(2-(5-hydroxymethyl-1,3,4-oxadiazol-2-yl)benzo(b)furan-4-yloxy)-2-propanol exhibited K i values of 0.37 nM for 5HT 1A receptor binding and 0.18 nM for 5-HT transport binding compared to 0.16 nM and 55 nM respectively for WAY-100635.