Synthesis of bridged piperazines with σ receptor affinity

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 LiAlH4 reduction of the ketones 7. NaBH4 reduction, Williamson ether synthesis and LiAlH4 reduction led to the methyl and benzyl ethers 12 and 13. High σ1 affinity is attained when one large substituent is introduced either at N-8 or O-2. The most potent σ1 ligand in this series of compounds is the methyl ether 12b with the N-butyl substituent (Ki = 13.2 nM, selectivity σ2:σ1 = 16). Moreover, the N-methyl derivatives 13a (σ2: Ki = 30.4 nM) and 12a (σ2 preference) represent promising starting points for the development of potent and selective σ2 ligands.

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