1,4-Diazepanes derived from (S)-serine – Homopiperazines with improved σ1 (sigma) receptor affinity and selectivity

Starting from the proteinogenic amino acid (S)-serine chiral non-racemic 1,4-diazepanes 4 with a hydroxymethyl residue in position 2 are synthesized and pharmacologically evaluated. The key step in the synthesis is the formation of the bicyclic system 8 by consecutive nucleophilic substitution of the chloropropionamide 7 with primary amines and intramolecular aminolysis. Both reaction steps require catalysis with the Lewis acid Ti(O-iPr)4. Homologation of the piperazine to the 1,4-diazepane ring results in a remarkable improvement of σ1 receptor affinity and σ1/σ2 selectivity. The 1,4-dibenzyl derivative 4a interacts with a Ki value of 7.4 nM with σ1 receptors and shows a 53-fold selectivity for σ1 receptors over σ2 receptors.

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