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The synthesis and pharmacological evaluation of (±)-2, 3- seco-fentanyl analogues

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

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2004
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Authors
Ivanović, Milovan D.
Mićović, I.V.
Vučković, Sonja M.
Prostran, Milica Š.
Todorović, Zoran M.
Ivanović, Evica
Kiricojević, Vesna D.
Popović-Djordjević, Jelena
Došen-Mićović, Ljiljana I.
Article (Published version)
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Abstract
An 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 genera...ted 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.

Razvijen 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 pr...inosima 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.

Keywords:
open-chain fentanyl analogues / 1,3-diamines / opioid analgesics
Source:
JOURNAL OF THE SERBIAN CHEMICAL SOCIETY, 2004, 69, 11, 955-968
Publisher:
  • Srpsko hemijsko društvo, Beograd

DOI: 10.2298/JSC0411955I

ISSN: 0352-5139

WoS: 000226120300015

Scopus: 2-s2.0-31644433403
[ Google Scholar ]
5
5
URI
http://aspace.agrif.bg.ac.rs/handle/123456789/833
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Poljoprivredni fakultet
TY  - JOUR
AU  - Ivanović, Milovan D.
AU  - Mićović, I.V.
AU  - Vučković, Sonja M.
AU  - Prostran, Milica Š.
AU  - Todorović, Zoran M.
AU  - Ivanović, Evica
AU  - Kiricojević, Vesna D.
AU  - Popović-Djordjević, Jelena
AU  - Došen-Mićović, Ljiljana I.
PY  - 2004
UR  - http://aspace.agrif.bg.ac.rs/handle/123456789/833
AB  - An 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.
AB  - Razvijen 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.
PB  - Srpsko hemijsko društvo, Beograd
T2  - JOURNAL OF THE SERBIAN CHEMICAL SOCIETY
T1  - The synthesis and pharmacological evaluation of (±)-2, 3- seco-fentanyl analogues
T1  - Sinteza i farmakološko ispitivanje (±)-2,3-seco-analoga fentanila
EP  - 968
IS  - 11
SP  - 955
VL  - 69
DO  - 10.2298/JSC0411955I
UR  - conv_4179
ER  - 
@article{
author = "Ivanović, Milovan D. and Mićović, I.V. and Vučković, Sonja M. and Prostran, Milica Š. and Todorović, Zoran M. and Ivanović, Evica and Kiricojević, Vesna D. and Popović-Djordjević, Jelena and Došen-Mićović, Ljiljana I.",
year = "2004",
abstract = "An 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., Razvijen 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.",
publisher = "Srpsko hemijsko društvo, Beograd",
journal = "JOURNAL OF THE SERBIAN CHEMICAL SOCIETY",
title = "The synthesis and pharmacological evaluation of (±)-2, 3- seco-fentanyl analogues, Sinteza i farmakološko ispitivanje (±)-2,3-seco-analoga fentanila",
pages = "968-955",
number = "11",
volume = "69",
doi = "10.2298/JSC0411955I",
url = "conv_4179"
}
Ivanović, M. D., Mićović, I.V., Vučković, S. M., Prostran, M. Š., Todorović, Z. M., Ivanović, E., Kiricojević, V. D., Popović-Djordjević, J.,& Došen-Mićović, L. I.. (2004). The synthesis and pharmacological evaluation of (±)-2, 3- seco-fentanyl analogues. in JOURNAL OF THE SERBIAN CHEMICAL SOCIETY
Srpsko hemijsko društvo, Beograd., 69(11), 955-968.
https://doi.org/10.2298/JSC0411955I
conv_4179
Ivanović MD, Mićović I, Vučković SM, Prostran MŠ, Todorović ZM, Ivanović E, Kiricojević VD, Popović-Djordjević J, Došen-Mićović LI. The synthesis and pharmacological evaluation of (±)-2, 3- seco-fentanyl analogues. in JOURNAL OF THE SERBIAN CHEMICAL SOCIETY. 2004;69(11):955-968.
doi:10.2298/JSC0411955I
conv_4179 .
Ivanović, Milovan D., Mićović, I.V., Vučković, Sonja M., Prostran, Milica Š., Todorović, Zoran M., Ivanović, Evica, Kiricojević, Vesna D., Popović-Djordjević, Jelena, Došen-Mićović, Ljiljana I., "The synthesis and pharmacological evaluation of (±)-2, 3- seco-fentanyl analogues" in JOURNAL OF THE SERBIAN CHEMICAL SOCIETY, 69, no. 11 (2004):955-968,
https://doi.org/10.2298/JSC0411955I .,
conv_4179 .

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