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Stereoselective Synthesis and In Vivo Evaluation of the Analgesic Activity of Polysubstituted Bispidines
Author(s) -
Plas Aurélie,
Marchand Fabien,
Eschalier Alain,
Troin Yves,
Chalard Pierre
Publication year - 2012
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201200919
Subject(s) - chemistry , stereoselectivity , ketone , aldehyde , imide , analgesic , in vivo , stereochemistry , mannich reaction , combinatorial chemistry , organic chemistry , pharmacology , catalysis , microbiology and biotechnology , biology , medicine
Hetero‐Michael addition on a chiral β′‐amino α,β‐unsaturated ketone gave, after some structural modifications, β,β′‐diamino ketals. Mannich‐type reactions of these diamines with an aldehyde led, with high diastereoselectivity, to trisubstituted piperidines. Another highly stereoselective Mannich cyclization, with an N ‐acyliminium ion generated in situ from the corresponding imide, allowed the preparation of original polycyclic bispidine derivatives. The antinociceptive effect of the three compounds prepared was evaluated in vivo by using the writhing test. If the biological results for the analgesic properties were disappointing, compared with the bispidine HZ2, which has a high affinity for opioid receptors, the modularity of the approach offered the possibility of introducing many substituents for new applications, which was promising because the bispidine core has been described to have many different activities.