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Sinteza i preliminarni farmakološki testovi recemskih cis i trans 3-alkilanaloga fentanila

dc.creatorIvanović, Milovan D.
dc.creatorMićović, Ivan
dc.creatorVučković, Sonja
dc.creatorProstran, Milica
dc.creatorTodorović, Zoran
dc.creatorKiricojević, Vesna
dc.creatorĐorđević, Jelena B.
dc.creatorDošen-Mićović, Ljiljana
dc.date.accessioned2019-04-24T15:26:14Z
dc.date.available2019-04-24T15:26:14Z
dc.date.issued2004
dc.identifier.issn0352-5139
dc.identifier.urihttp://cer.ihtm.bg.ac.rs/handle/123456789/2685
dc.description.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 die 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 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 (approximate to 95% yield, as monooxalate salts). No enatioseparation was attempted at any stage. The relative cis/trans stereochemistry was provisionally assigned from the H-1-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 6.2cis. (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.en
dc.description.abstractRazvijen je opšti metod za sintezu 3-alkil analoga fentanila (tj. cis i trans 3-alkil-4-anilidopiperidina 6.1–6.6) u pet faza. Polazni N-fenetil-4-piperidon 1 prvo je preveden u cikloheksiliminski derivat 2, α-deprotonovan butillitijumom, a postali iminski anjon efikasno monoalkilovan primarnim i sekundarnim alkilhalogenidima. Posle blage kisele hidrolize, nastali 3-alkil-4-piperidoni 3.1–3.6 izolovani su u dobrim prinosima (79–85 %), zatim kondenzovani sa anilinom do imina 4.1–4.6. Redukcijom ovih imina (LiAlH4/THF) dobijene su cis/trans smese 3-alkil-4-anilinopiperidina 5.1–5.6. Kvantitativnim hromatografskim razdvajanjem dijastereoizomera na stubu Al2O3 izolovani su čisti cis 5.1–5.6 (prinos 29–51 %) i trans 5.1–5.6 (prinos 19–27 %), gde je cis/trans odnos bio u opsegu 7/3–6/4. Sinteza je završena N-acilovanjem prečišćenih intermedijera 5.1–5.6 pomoću propionil-hlorida, pri čemu su postali cis i trans 3-alkil-4-anilidopiperidini 6.1–6.6 (prinos _ 95 %, kao monooksalatne soli). Ni u jednoj fazi nije pokušano razdvajanje enantiomera. Relativna, cis/trans, stereohemija preliminarno je određena iz 1H-NMRspektra. Od dvanaest sintetisanih 3-alkil-fentanila, deset jedinjenja (dva poznata i osam novih, sva u obliku monookasalatnih soli) preliminarno su testirana kao analgetici na pacovima, poredeći aktivnost sa fentanilom.Osim poznatog (±)-cis-3-Me fentanila 6.1 cis, (8 x fentanil), i novog (±)-cis-3-Et fentanila 6.2 cis, (1,5 x fentanil), svi ostali bili su manje aktivni ili neaktivni. Izvedeni su određeni, preliminarni zaključci u vezi odnosa strukture i aktivnosti u ovoj seriji derivata.sr
dc.publisherSerbian Chemical Soc, Belgrade
dc.rightsopenAccess
dc.sourceJournal of the Serbian Chemical Society
dc.titleThe synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analoguesen
dc.titleSinteza i preliminarni farmakološki testovi recemskih cis i trans 3-alkilanaloga fentanilasr
dc.typearticle
dc.rights.licenseBY-NC-ND
dcterms.abstractМицовиц, ИВ; Простран, М; Ивановић, Милован; Вуцковиц, С; Досен-Мицовиц, ЛЈ; Дјордјевиц, ЈБ; Кирицојевиц, В. Д.; Тодоровиц, З; Синтеза и прелиминарни фармаколошки тестови рецемских цис и транс 3-алкиланалога фентанила; Синтеза и прелиминарни фармаколошки тестови рецемских цис и транс 3-алкиланалога фентанила;
dc.citation.volume69
dc.citation.issue7
dc.citation.spage511
dc.citation.epage526
dc.citation.other69(7): 511-526
dc.citation.rankM23
dc.identifier.doi10.2298/JSC0407511I
dc.identifier.fulltexthttp://cer.ihtm.bg.ac.rs//bitstream/id/6357/0352-51390407511I.pdf
dc.identifier.scopus2-s2.0-31644432012
dc.identifier.wos000222831500001
dc.type.versionpublishedVersion


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