SYNTHESIS AND SAR IN 1-SUBSTITUTED-4-[4-FLUOROBENZOYL 6,7-DIMETHOXY-3,4-DIHYDROISOQUINOLYL]PIPERIDINES AND RELATED-COMPOUNDS/

The key intermediate 4-piperidyl]-3,4-dihydro-6,7-dimethoxyisoquinolin e 4 is prepared by the Bischler Napieralski cyclisation of 1-[1-(3,4-d imethoxyphenyl)]-2-(1-acetyl-4-carbomyl piperidino)ethane 2 followed b y the acidic hydrolysis of the intermediate 3 thus obtained. Condensat ion of 4 with r-chloro-(4-fluorophenyl) butyrophenone furnishes 1-[4-( 6,7-dimethoxy-3,4-dihydroisoquinoline-1-yl) piperidino]-3-(4-fluoroben zoyl)propane 5 which on reduction with NaBH4 and H-2 (Pd/c) give the r educed derivatives 6 and 7 respectively. Condensation of 9 with methyl vinylketone and 2-bromopropionyl chloride yields 10 and 11 respectivel y, The condensation of 11 with substituted phenols and thiophenol affo rds the aryloxy/thioaryloxy compounds 12-14. Reduction of 12 with lith ium aluminium hydride give the aminoethyl derivative 15. Among these c ompounds 5,10 and 14 showed potent CNS depressant activity.