The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analoguesM. D. Ivanovic, I. V. Micovic, S. Vuckovic, M. Prostran, Z. Todovic, V. D. Kiricojevic, J. B. Djordjevic and LJ. Dosen-MicovicJ. Serb. Chem. Soc. 69(7), 511–526 (2004)AbstractA 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,
alpha-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 (LiAlH
4/THF) yielded
cis/
trans mixtures of 3-alkyl-4-anilinopiperidines
5.1–
5.6. Quantitative separation of the diastereoisomers by column chromatography of Al
2O
3 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 synthesis was 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 × fentanyl), and the novel (±)-
cis-3-Et fentanyl
6.2cis, (1.5 × 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.
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