The synthesis and preliminary pharmacological evaluation of racemic cis and trans 3-alkylfentanyl analogues
| Autor: | Ivanović Milovan D., Mićović I.V., Vučković Sonja M., Prostran Milica Š., Todorović Zoran M., Kricojević V.D., Đorđević J.B., Došen-Mićović Ljiljana I. |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2004 |
| Předmět: | |
| Zdroj: | Journal of the Serbian Chemical Society, Vol 69, Iss 7, Pp 511-526 (2004) |
| Druh dokumentu: | article |
| ISSN: | 0352-5139 1820-7421 |
| DOI: | 10.2298/JSC0407511I |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
| Externí odkaz: |
|