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Sinteza i farmakološko ispitivanje (±)-2,3-seco-analoga fentanila

dc.creatorIvanović, Milovan
dc.creatorMicovic, IV
dc.creatorVuckovic, S
dc.creatorProstran, M
dc.creatorTodorovic, Z
dc.creatorIvanovic, ER
dc.creatorKiricojevic, VD
dc.creatorDjordjevic, JB
dc.creatorDosen-Micovic, LJ
dc.date.accessioned2018-11-22T00:07:42Z
dc.date.available2018-11-22T00:07:42Z
dc.date.issued2004
dc.identifier.issn0352-5139
dc.identifier.urihttp://cherry.chem.bg.ac.rs/handle/123456789/681
dc.description.abstractAn efficient, five-step synthetic approach to various acyclic 1,3-diamines has been developed and applied to the preparation of a novel class of open-chained fentanyl analogues. The acyclic derivatives 5.1-5.5 (all new compounds) were synthesized with the aim of estimating the significance of the piperidine ring for the opioid analgesic activity of anilido-piperidines. The starting beta-keto-amide 1.1, prepared by the aminolysis of methyl acetoacetate with methyl phenethylamine, (93% yield), was successively reacted with NaH and BuLi, to form the highly reactive alpha,gamma-dienolate anion 1.1a. Regio and chemoselective gamma-alkylation of the dienolate with various primary and secondary alkyl halides furnished the beta-keto-amides 1.2-1.5 (76-91%). Reductive amination of the keto-amides 1.1-1.5 with aniline and Zn powder in acetic acid, via the enamine intermediates 2.1-2.5. afforded the beta-anilino amides 3.1-3.5 (74-85%). After reductive deoxygenation of the tertiary amide group, using in situ generated diborane, the corresponding 1,3-diamines 4.1-4.5 were obtained (87-97%). The synthesis of (+/-)-2,3-seco-fentanyls 5.1-5.5 was completed by N-acylation of the diamines 4.1-4.5 with propionyl chloride, followed by precipitation of the monooxalate salts (86-95%). The parent compound, 2,3-seco-fentanyl 5.1, was found to be a 40 times less potent narcotic analgesic than fentanyl but still 5-6 times more active than morphine in rats. while i-Pr derivative 5.3 was inactive. Apart from the pharmacological significance. the general procedure described herein may afford various functionalized, 1,3-diamines as potential complexing agents and building blocks for the synthesis of aza-crown ethers.en
dc.description.abstractRazvijen je efikasan postupak za dobijanje različitih acikličnih 1,3-diamina u pet faza, i primenjen u sintezi nove klase analoga fentanila otvorenog niza. Derivati 5.1–5.5 (svi su nova jedinjenja) sintetisani su sa ciljem da se proceni uticaj piperidinskog prstena na opioidnoanalgetičku aktivnost anilido-piperidina. Polazni β-keto-amid 1.1, dobijen aminolizom metilacetoacetata metilfenetilaminom (prinos 93 %), bio je sukcesivno tretiran sa NaH i BuLi, pri čemu je postao veoma reaktivni α,γ-dienolatni anjon 1.1a. Regio- i hemoselektivnim γ-alkilovanjem ovog dienolata različitim primarnim i sekundarnim alkil-halogenidima, dobijeni su β-keto-amidi 1.2–1.5 (prinos 76–91 %). Reduktivnim aminovanjem keto-amida 1.1–1.5 pomoću Zn praha i sirćetne kiseline, preko enaminskih intermedijera 2.1–2.5, postali su -anilino-amidi 3.1–3.5 (prinos 74–85 %). Posle reduktivne deoksigenacije tercijene amidne funkcije, koristeći in situ generisani diboran, odgovarajući 1,3-diamini 4.1–4.5 izolovani su u prinosima 87–97 %. Sinteza (±)-2,3-seco-fentanila 5.1–5.5 završena je N-acilovanjem diamina 4.1–4.5 propionil-hloridom, a zatim taloženjem u obliku monooksalatnih soli (prinos 86–95 %). Nađeno je da je osnovno jedinjenje, 2,3-seco fentanil 5.1, 40 puta slabiji narkotički analgetik od fentanila, ali još uvek 5–6 puta aktivniji od morfina u pacova, dok je i-Pr derivat 5.3 bio neaktivan. Osim farmakološkog značaja, opštim postupkom prikazanim u ovom radu, mogu se sintetisati različiti 1,3-diamini, uključujući i one sa funkcionalnim grupama. Ova jedinjenja mogu biti potencijalno značajna kao kompleksirajući agensi i kao intermedijeri u sintezi aza-kraun-etara.sr
dc.publisherSerbian Chemical Soc, Belgrade
dc.rightsopenAccess
dc.sourceJournal of the Serbian Chemical Society
dc.subjectopen-chain fentanyl analoguesen
dc.subject1,3-diaminesen
dc.subject1,3-diaminesen
dc.subjectopioid analgesicsen
dc.subjectopioid analgesicsen
dc.titleThe synthesis and pharmacological evaluation of (+/-)-2,3-seco-fentanyl analoguesen
dc.titleSinteza i farmakološko ispitivanje (±)-2,3-seco-analoga fentanilasr
dc.typearticle
dc.rights.licenseBY-NC-ND
dcterms.abstractИвановић, Милован; Мицовиц, ИВ; Кирицојевиц, ВД; Вуцковиц, С; Простран, М; Тодоровиц, З; Дјордјевиц, ЈБ; Досен-Мицовиц, ЛЈ; Ивановиц, ЕР; Синтеза и фармаколошко испитивање (±)-2,3-сецо-аналога фентанила; Синтеза и фармаколошко испитивање (±)-2,3-сецо-аналога фентанила;
dc.citation.volume69
dc.citation.issue11
dc.citation.spage955
dc.citation.epage968
dc.identifier.wos000226120300015
dc.identifier.doi10.2298/JSC0411955I
dc.citation.other69(11): 955-968
dc.citation.rankM23
dc.type.versionpublishedVersion
dc.identifier.scopus2-s2.0-31644433403
dc.identifier.rcubKon_1634


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