Synthesis and evaluation of 3-aminopropionyl substituted fentanyl analogues for opioid activity

Abstract

An enkephalin analogue coupled to 'aminofentanyl' has been synthesized and tested for biological activities at the mu and delta opioid receptors. Aminofentanyl which represents a structural derivative of fentanyl has been synthesized by acylation of 1-(2-phenethyl)-4-(N-anilino)piperidine with phthaloyl protected beta-alaninyl chloride in the presence of DIPEA, followed by deprotection with hydrazine hydrate. Aminofentanyl has also been successfully acylated with ethyl isocyanate, various acid anhydrides, to further investigate structure-activity relationships of these new fentanyl derivatives. Among the new derivatives compound 7 which carries a Tyr-D-Ala-Gly-Phe opioid message sequence showed good opioid affinity (1 nM at both delta and mu opioid receptors) and bioactivity (34.9 nM in MVD and 42 nM in GPI/LMMP bioassays).

Scheme 1

Reagents and conditions: (i) Pht-AA-Cl (β-Ala), DIPEA , DCM, 0 °C, 92%; (ii) N₂H₄·nH₂O, ethanol, reflux, 63%; (iii) EtNCO or acid anhydride, DIPEA, DCM, 65–97%; (iv) Boc-Phe-OH, DCC, DIPEA, DCM; (v) TFA, DCM, 94% (two steps); (vi) Ac₂O, DIPEA, 72%; (vii) stepwise chain elongation using (i) and (ii) (ethanolamine instead of N₂H₄·nH₂O) methods for Gly (80%) and d-Ala (94%), and (iv) and (v) for Tyr (65%).