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

dc.creatorIvanović, Milovan D.
dc.creatorMićović, I.V.
dc.creatorVučković, Sonja M.
dc.creatorProstran, Milica Š.
dc.creatorTodorović, Zoran M.
dc.creatorIvanović, Evica
dc.creatorKiricojević, Vesna D.
dc.creatorPopović-Djordjević, Jelena
dc.creatorDošen-Mićović, Ljiljana I.
dc.date.accessioned2020-12-17T18:21:21Z
dc.date.available2020-12-17T18:21:21Z
dc.date.issued2004
dc.identifier.issn0352-5139
dc.identifier.urihttp://aspace.agrif.bg.ac.rs/handle/123456789/833
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 β-keto-amide 1.1, prepared by the aminolysis of methyl acetoacetate with methylphenethylamine, (93 % yield), was successively reacted with NaH and BuLi, to form the highly reactive α,γ-dienolate anion 1.1a. Regio and chemoselective γ-alkylation of the dienolate with various primary and secondary alkyl halides furnished the β-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 β-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.publisherSrpsko hemijsko društvo, Beograd
dc.rightsopenAccess
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceJOURNAL OF THE SERBIAN CHEMICAL SOCIETY
dc.subjectopen-chain fentanyl analoguesen
dc.subject1,3-diaminesen
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
dc.citation.epage968
dc.citation.issue11
dc.citation.other69(11): 955-968
dc.citation.rankM23
dc.citation.spage955
dc.citation.volume69
dc.identifier.doi10.2298/JSC0411955I
dc.identifier.fulltexthttp://aspace.agrif.bg.ac.rs/bitstream/id/4334/830.pdf
dc.identifier.rcubconv_4179
dc.identifier.scopus2-s2.0-31644433403
dc.identifier.wos000226120300015
dc.type.versionpublishedVersion


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