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The synthesis and preliminary pharmacological evaluation of racemic cis and trans 3-alkylfentanyl analogues

Ivanović Milovan D. (Faculty of Chemistry, University of Belgrade, Belgrade)
Mićović I.V. (Faculty of Chemistry, University of Belgrade, Belgrade)
Vučković Sonja M. (Department of Clinical Pharmacology, Pharmacology and Toxicology, School of Medicine, University of Belgrade, Belgrade)
Prostran Milica Š. (Department of Clinical Pharmacology, Pharmacology and Toxicology, School of Medicine, University of Belgrade, Belgrade)
Todorović Zoran M. (Department of Clinical Pharmacology, Pharmacology and Toxicology, School of Medicine, University of Belgrade, Belgrade)
Kricojević V.D. (ICTM-Center for Chemistry, Belgrade)
Đorđević J.B. (Faculty of Agriculture, University of Belgrade, Zemun, Serbia and Montenegro)
Došen-Mićović Ljiljana I. (Faculty of Chemistry, University of Belgrade, Belgrade)

A general, five step method for the synthesis of 3-alkylfentanyl analogues (i.e., cis and trans 3-alkyl-4-anilidopiperidines 6.1–6.6) has been developed. The starting N-phenethyl- 4-piperidone 1 was first converted into the cyclohexylimine derivative 2, α-deprotonated with butyllithium and the resulting imine anion efficiently monoalkylated with primary and secondary alkyl halides. After mild acid hydrolysis, the obtained 3-alkyl-4-piperidones 3.1–3.6 were isolated in good yields (79–85 %), then condensed with aniline to form imines 4.1–4.6. Subsequent reduction of the imines (LiAlH4/THF) yielded cis/trans mixtures of 3-alkyl-4-anilinopiperidines 5.1–5.6. Quantitative separation of the diastereoisomers by column chromatography of Al2O3 gave pure cis 5.1–5.6 (29–51 % yield) and trans 5.1–5.6 (19–27%yield) with the cis/trans ratio in the range 7/3–6/4. The synthesiswas concluded by N-acylation of the purified 5.1–5.6, with propionyl chloride, to afford cis and trans 3-alkyl- 4-anilidopiperidines 6.1–6.6 (≈ 95 % yield, as monooxalate salts). No enatioseparation was attempted at any stage. The relative cis/trans stereochemistry was provisionally assigned from the 1H-NMR spectra. Of the twelve synthesized 3-alkylfentanyls, ten compounds (two known and eight novel derivatives, all as the monooxalate salts) were preliminarily tested as analgesics in rats, comparing the potency to fentanyl. Except for the known (±)-cis-3-Me fentanyl 6.1cis, (8 x fentanyl), and the novel (±)-cis-3-Et fentanyl 6.2 cis, (1.5 x fentanyl), all of the others were less active than fentanyl or inactive. Some tentative conclusions on the structure- activity relationship (SAR) in this series of derivatives have been made.