Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 44, Issue 2, Pages 519-525Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2008.03.033
Keywords
sigma Receptor ligands; 1,4-Diazepanes; Homopiperazines
Categories
Funding
- Deutsche Forschungsgemeinschaft
- Fonds der Chemischen Industrie
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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. (C) 2008 Elsevier Masson SAS. All rights reserved.
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