Synthesis of bridged piperazines with σ receptor affinity

Abstract

Bridged piperazines 4 were designed as conformationally restricted piperazine σ receptor ligands. The chiral pool synthesis started from ( S)-glutamate, which was transformed in five reaction steps into the piperazinediones 5 bearing a propionic acid ester side chain. A two-step Dieckmann analogous cyclization provided the bicyclic ketones 7 as key intermediates. The alcohols 8 were prepared by LiAlH 4 reduction of the ketones 7. NaBH 4 reduction, Williamson ether synthesis and LiAlH 4 reduction led to the methyl and benzyl ethers 12 and 13. High σ 1 affinity is attained when one large substituent is introduced either at N-8 or O-2. The most potent σ 1 ligand in this series of compounds is the methyl ether 12b with the N-butyl substituent ( K i = 13.2 nM, selectivity σ 2:σ 1 = 16). Moreover, the N-methyl derivatives 13a (σ 2: K i = 30.4 nM) and 12a (σ 2 preference) represent promising starting points for the development of potent and selective σ 2 ligands.