SYNTHESIS, STEREOCHEMISTRY, AND OPIOID RECEPTOR-BINDING ACTIVITY OF HETEROCYCLIC-ANALOGS OF BW373U86

The synthesis of a series of heterocyclic analogues of (+/-)-4-((alpha piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (BW373U86) for scr eening against opioid receptors is described. The intermediate alpha-h eterocyclic benzyl alcohols 24 were synthesized either by low temperat ure reaction of lithioheterocycles with 3-((tert-butyldimethylsilyl)ox y)benzaldehyde (10) or by reaction of 3-((tert-butyldimethylsilyl)oxy) phenylmagnesium bromide (19) with heterocyclic carbaldehydes. The alph a-heterocyclic benzyl alcohols 24 were converted to chloromethines (25 ) with thionyl chloride and used to alkylate with trans-1-allyl-2,5-di methylpiperazine (5) to give diastereomeric pairs of the target compou nds. The bromoheterocycles were then derivatized to produce amides. Co mpounds that are potent and selective for the delta or mu opioid recep tors and some mixed delta/mu analogues are reported.