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Updated: Jul 5, 2026

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Published on: June 13, 2022
1,4-Diazepanes derived from (S)-serine--homopiperazines with improved sigma(1) (sigma) receptor affinity and
Stephan Bedürftig1, Bernhard Wünsch
1Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Iniversität Münster, Hittorfstrasse 58-62, 48149 Münster, Germany.
Abstract:
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 sigma(1) receptor affinity and sigma(1)/sigma(2) selectivity. The 1,4-dibenzyl derivative 4a interacts with a K(i) value of 7.4 nM with sigma(1) receptors and shows a 53-fold selectivity for sigma(1) receptors over sigma(2) receptors.
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