Syntheses of 4-(benzo[b]furan-2 or 3-yl)- and 4-(benzo[b]-thiophen-3-yl)piperidines with 5-HT2 antagonist activity

The syntheses of 4-(benzob]furan-3-yl)piperidines, 4-(benzob]furan-2-yl)piperidines and 4-(benzob]thiophen-3-yl)piperidines with 5-HT₂ antagonist activity are described. Reaction of 1-acetyl-4-(2,4-difluorobenzo-yl)piperidine 2 with methyl glycolate gave methyl 6-fluoro-3-(1-acetylpiperidin-4-yl)benzob]furan-2-carboxylate 3 , which was converted to 2-2-4-(benzob]furan-3-yi)piperidin-1-yl]ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo-4,3-a]pyridin-3(2H)-one hydrochloride 9 . Analogous benzob]furans 17a-d and benzob]thiophenes 10a,b and 18a were prepared by a similar method. Cyclization of 4-fluoro-2-(4-pyridinylmethoxy)acetophenones 20a,b afforded 4-(benzob]furan-2-yl)pyridines 21a,b , which were converted to 2-2-4-(benzob]furan-2-yl)-piperidin-1-yl]ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo4,3-a]pyridin-3(2H)-one hydrochlorides 24a,b. Among them, benzob]furans 9 and 17a,d and benzob]thiophenes 10 and 18a showed potent 5-HT₂ antagonist activity in vitro.