Design, synthesis and antalgic activities of aralkyl-ketone-4-piperidol derivatives

A series of aralkyl-ketone-4-piperidol derivatives were synthesized and tested for their analgesic activities.  All of the novel 30 compounds were prepared from 4-piperidone and α-halo-aralkyl-ketone through five steps, including Boc protection, nucleophilic addition in presence of CeCl₃/NaI catalyst, deprotection,   condensation and salification.  Their structures were confirmed by ¹H NMR and HRMS.  Preliminary in vivo pharmacological trials showed that most of the synthesized compounds revealed analgesic effects.  Among the tested compounds, 8, 13 and 22 exhibited potent analgesic activities in both mice writhing and mice hot plate model.  The three compounds have low affinity for μ, δ, κ receptors, which is a chance to find a better precursor of non-opioid analgesic for further optimization.