TY  - JOUR
AU  - Jevtić, Ivana
AU  - Savić Vujović, Katarina
AU  - Srebro, Dragana
AU  - Vučković, Sonja
AU  - Ivanović, Milovan D.
AU  - Kostić Rajačić, Slađana
PY  - 2020
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/3591
AB  - Background 4-Anilidopiperidine class of synthetic opioid analgesics, with it’s representative fentanyl, are by far the most potent and clinically significant for the treatment of the severe chronic and surgical pain. However, side effects of μ-opioids are often quite serious. In order to improve the pharmacological profile of this class of opioid analgesics, a novel fentanyl analogs were designed, synthesized and evaluated in vivo for their antinociceptive activity.
Methods The title compounds were prepared using known synthetic transformations, including N-bromoacetamide mediated Hofmann rearrangement, highly selective carbamate cleavage with trimethylsilyl iodide and dehydration of carboxamide group to nitrile in the presence of SOCl2. The antinociceptive activity of the synthesized compounds was determined by tail-immersion and formalin test.
Results The scalable synthetic route towards novel fentanyl analogs bearing nitrogen groups in position C3 of piperidine ring is designed. In addition, Hofmann rearrangement was substantially improved for the more efficient synthesis of previously published 3-substituted fentanyl analogs. The series of ten fentanyl analogs was tested in vivo for their antinociceptive activity. The most potent compound of the series was found to be cis-4, based on the determined ED50 values in tail-immersion test.
Conclusion Of ten compounds tested for their antinociceptive activity, compound cis-4 is characterized by high potency, rapid beginning and short duration of action and due to this might be incorporated in different pharmaceutical forms.
PB  - Springer Nature
T2  - Pharmacological Reports
T1  - Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines
VL  - 72
IS  - 4
SP  - 1069
EP  - 1075
DO  - 10.1007/s43440-020-00121-2
ER  - 

@article{
author = "Jevtić, Ivana and Savić Vujović, Katarina and Srebro, Dragana and Vučković, Sonja and Ivanović, Milovan D. and Kostić Rajačić, Slađana",
year = "2020",
abstract = "Background 4-Anilidopiperidine class of synthetic opioid analgesics, with it’s representative fentanyl, are by far the most potent and clinically significant for the treatment of the severe chronic and surgical pain. However, side effects of μ-opioids are often quite serious. In order to improve the pharmacological profile of this class of opioid analgesics, a novel fentanyl analogs were designed, synthesized and evaluated in vivo for their antinociceptive activity.
Methods The title compounds were prepared using known synthetic transformations, including N-bromoacetamide mediated Hofmann rearrangement, highly selective carbamate cleavage with trimethylsilyl iodide and dehydration of carboxamide group to nitrile in the presence of SOCl2. The antinociceptive activity of the synthesized compounds was determined by tail-immersion and formalin test.
Results The scalable synthetic route towards novel fentanyl analogs bearing nitrogen groups in position C3 of piperidine ring is designed. In addition, Hofmann rearrangement was substantially improved for the more efficient synthesis of previously published 3-substituted fentanyl analogs. The series of ten fentanyl analogs was tested in vivo for their antinociceptive activity. The most potent compound of the series was found to be cis-4, based on the determined ED50 values in tail-immersion test.
Conclusion Of ten compounds tested for their antinociceptive activity, compound cis-4 is characterized by high potency, rapid beginning and short duration of action and due to this might be incorporated in different pharmaceutical forms.",
publisher = "Springer Nature",
journal = "Pharmacological Reports",
title = "Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines",
volume = "72",
number = "4",
pages = "1069-1075",
doi = "10.1007/s43440-020-00121-2"
}

Jevtić, I., Savić Vujović, K., Srebro, D., Vučković, S., Ivanović, M. D.,& Kostić Rajačić, S.. (2020). Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines. in Pharmacological Reports
Springer Nature., 72(4), 1069-1075.
https://doi.org/10.1007/s43440-020-00121-2

Jevtić I, Savić Vujović K, Srebro D, Vučković S, Ivanović MD, Kostić Rajačić S. Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines. in Pharmacological Reports. 2020;72(4):1069-1075.
doi:10.1007/s43440-020-00121-2 .

Jevtić, Ivana, Savić Vujović, Katarina, Srebro, Dragana, Vučković, Sonja, Ivanović, Milovan D., Kostić Rajačić, Slađana, "Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines" in Pharmacological Reports, 72, no. 4 (2020):1069-1075,
https://doi.org/10.1007/s43440-020-00121-2 . .

TY  - JOUR
AU  - Jevtić, Ivana
AU  - Savić Vujović, Katarina
AU  - Srebro, Dragana
AU  - Vučković, Sonja
AU  - Ivanović, Milovan D.
AU  - Kostić Rajačić, Slađana
PY  - 2020
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/3591
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/3592
AB  - Background 4-Anilidopiperidine class of synthetic opioid analgesics, with it’s representative fentanyl, are by far the most potent and clinically significant for the treatment of the severe chronic and surgical pain. However, side effects of μ-opioids are often quite serious. In order to improve the pharmacological profile of this class of opioid analgesics, a novel fentanyl analogs were designed, synthesized and evaluated in vivo for their antinociceptive activity.Methods The title compounds were prepared using known synthetic transformations, including N-bromoacetamide mediated Hofmann rearrangement, highly selective carbamate cleavage with trimethylsilyl iodide and dehydration of carboxamide group to nitrile in the presence of SOCl2. The antinociceptive activity of the synthesized compounds was determined by tail-immersion and formalin test.Results The scalable synthetic route towards novel fentanyl analogs bearing nitrogen groups in position C3 of piperidine ring is designed. In addition, Hofmann rearrangement was substantially improved for the more efficient synthesis of previously published 3-substituted fentanyl analogs. The series of ten fentanyl analogs was tested in vivo for their antinociceptive activity. The most potent compound of the series was found to be cis-4, based on the determined ED50 values in tail-immersion test.Conclusion Of ten compounds tested for their antinociceptive activity, compound cis-4 is characterized by high potency, rapid beginning and short duration of action and due to this might be incorporated in different pharmaceutical forms.
PB  - Springer Nature
T2  - Pharmacological Reports
T1  - Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines
DO  - 10.1007/s43440-020-00121-2
ER  - 

@article{
author = "Jevtić, Ivana and Savić Vujović, Katarina and Srebro, Dragana and Vučković, Sonja and Ivanović, Milovan D. and Kostić Rajačić, Slađana",
year = "2020",
abstract = "Background 4-Anilidopiperidine class of synthetic opioid analgesics, with it’s representative fentanyl, are by far the most potent and clinically significant for the treatment of the severe chronic and surgical pain. However, side effects of μ-opioids are often quite serious. In order to improve the pharmacological profile of this class of opioid analgesics, a novel fentanyl analogs were designed, synthesized and evaluated in vivo for their antinociceptive activity.Methods The title compounds were prepared using known synthetic transformations, including N-bromoacetamide mediated Hofmann rearrangement, highly selective carbamate cleavage with trimethylsilyl iodide and dehydration of carboxamide group to nitrile in the presence of SOCl2. The antinociceptive activity of the synthesized compounds was determined by tail-immersion and formalin test.Results The scalable synthetic route towards novel fentanyl analogs bearing nitrogen groups in position C3 of piperidine ring is designed. In addition, Hofmann rearrangement was substantially improved for the more efficient synthesis of previously published 3-substituted fentanyl analogs. The series of ten fentanyl analogs was tested in vivo for their antinociceptive activity. The most potent compound of the series was found to be cis-4, based on the determined ED50 values in tail-immersion test.Conclusion Of ten compounds tested for their antinociceptive activity, compound cis-4 is characterized by high potency, rapid beginning and short duration of action and due to this might be incorporated in different pharmaceutical forms.",
publisher = "Springer Nature",
journal = "Pharmacological Reports",
title = "Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines",
doi = "10.1007/s43440-020-00121-2"
}

Jevtić, I., Savić Vujović, K., Srebro, D., Vučković, S., Ivanović, M. D.,& Kostić Rajačić, S.. (2020). Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines. in Pharmacological Reports
Springer Nature..
https://doi.org/10.1007/s43440-020-00121-2

Jevtić I, Savić Vujović K, Srebro D, Vučković S, Ivanović MD, Kostić Rajačić S. Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines. in Pharmacological Reports. 2020;.
doi:10.1007/s43440-020-00121-2 .

Jevtić, Ivana, Savić Vujović, Katarina, Srebro, Dragana, Vučković, Sonja, Ivanović, Milovan D., Kostić Rajačić, Slađana, "Synthesis and pharmacological evaluation of novel cis and trans 3‑substituted anilidopiperidines" in Pharmacological Reports (2020),
https://doi.org/10.1007/s43440-020-00121-2 . .

TY  - JOUR
AU  - Jevtić, Ivana
AU  - Penjišević, Jelena
AU  - Savić-Vujović, Katarina
AU  - Srebro, Dragana
AU  - Vučković, Sonja
AU  - Ivanović, Milovan
AU  - Kostić Rajačić, Slađana
PY  - 2020
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/3999
AB  - Herein, the synthesis and pharmacological evaluation of 13 novel compounds, designed as potential heterobivalent ligands for μ-opioid receptor (MOR) and dopamine D2 receptors (D2DAR), are reported. The compounds consisted of anilido piperidine and N-aryl piperazine moieties, joined by a variable-length methylene linker. The two moieties represent MOR and D2DAR pharmacophores, respectively. The synthesis encompassed four steps, securing the final products in 28–42 % overall yields. The approach has a considerable synthetic potential, providing access to various related structures. Pharmacological tests involved in vitro competitive assay for D2DAR using [3H] spiperon, as a standard radioligand, and in vivo antinociceptive tests for MOR. The measured dopamine affinities were modest to low, while antinociceptive activity was completely absent. Therefore, the compounds of the general structure prepared in this research are unlikely to be useful as opioid–dopamine receptor heterobivalent ligands.
AB  - У овом раду је приказана синтеза и фармаколошко испитивање 13 нових једињења, дизајнираних са циљем да буду потенцијални бивалентни лиганди за μ-опиоидни рецептор (MOR) и допамински D2 рецептор (D2DAR). Једињења се састоје од анилидо-пиперидинских (МОR фармакофора) и N-арилпиперазинских остатака (D2DAR фармакофора), повезаних метиленским ланцем променљиве дужине. Синтеза је обухватала четири корака, обезбеђујући крајње производе у укупним приносима од 28 до 42 %. Афинитет везивања за D2DAR одређен је in vitro тестом компетиције користећи [3H] спиперон као стандардни радиолиганд док је антиноцицептивна (опиоидна) активност испитана in vivo
антиноцицептивним тестом. Активности новосинтетисаних једињења ка D2DAR биле су умерене до ниске, док је антиноцицептивна активност у потпуности изостала.
PB  - Belgrade : Serbian Chemical Society
T2  - Journal of the Serbian Chemical Society
T1  - μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation
T1  - Ligandi koji sadrže farmakofore za μ-opioidne i D2 dopaminske receptore: Sinteza i farmakološko ispitivanje
VL  - 85
IS  - 6
SP  - 711
EP  - 720
DO  - 10.2298/JSC190912118J
ER  - 

@article{
author = "Jevtić, Ivana and Penjišević, Jelena and Savić-Vujović, Katarina and Srebro, Dragana and Vučković, Sonja and Ivanović, Milovan and Kostić Rajačić, Slađana",
year = "2020",
abstract = "Herein, the synthesis and pharmacological evaluation of 13 novel compounds, designed as potential heterobivalent ligands for μ-opioid receptor (MOR) and dopamine D2 receptors (D2DAR), are reported. The compounds consisted of anilido piperidine and N-aryl piperazine moieties, joined by a variable-length methylene linker. The two moieties represent MOR and D2DAR pharmacophores, respectively. The synthesis encompassed four steps, securing the final products in 28–42 % overall yields. The approach has a considerable synthetic potential, providing access to various related structures. Pharmacological tests involved in vitro competitive assay for D2DAR using [3H] spiperon, as a standard radioligand, and in vivo antinociceptive tests for MOR. The measured dopamine affinities were modest to low, while antinociceptive activity was completely absent. Therefore, the compounds of the general structure prepared in this research are unlikely to be useful as opioid–dopamine receptor heterobivalent ligands., У овом раду је приказана синтеза и фармаколошко испитивање 13 нових једињења, дизајнираних са циљем да буду потенцијални бивалентни лиганди за μ-опиоидни рецептор (MOR) и допамински D2 рецептор (D2DAR). Једињења се састоје од анилидо-пиперидинских (МОR фармакофора) и N-арилпиперазинских остатака (D2DAR фармакофора), повезаних метиленским ланцем променљиве дужине. Синтеза је обухватала четири корака, обезбеђујући крајње производе у укупним приносима од 28 до 42 %. Афинитет везивања за D2DAR одређен је in vitro тестом компетиције користећи [3H] спиперон као стандардни радиолиганд док је антиноцицептивна (опиоидна) активност испитана in vivo
антиноцицептивним тестом. Активности новосинтетисаних једињења ка D2DAR биле су умерене до ниске, док је антиноцицептивна активност у потпуности изостала.",
publisher = "Belgrade : Serbian Chemical Society",
journal = "Journal of the Serbian Chemical Society",
title = "μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation, Ligandi koji sadrže farmakofore za μ-opioidne i D2 dopaminske receptore: Sinteza i farmakološko ispitivanje",
volume = "85",
number = "6",
pages = "711-720",
doi = "10.2298/JSC190912118J"
}

Jevtić, I., Penjišević, J., Savić-Vujović, K., Srebro, D., Vučković, S., Ivanović, M.,& Kostić Rajačić, S.. (2020). μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation. in Journal of the Serbian Chemical Society
Belgrade : Serbian Chemical Society., 85(6), 711-720.
https://doi.org/10.2298/JSC190912118J

Jevtić I, Penjišević J, Savić-Vujović K, Srebro D, Vučković S, Ivanović M, Kostić Rajačić S. μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation. in Journal of the Serbian Chemical Society. 2020;85(6):711-720.
doi:10.2298/JSC190912118J .

Jevtić, Ivana, Penjišević, Jelena, Savić-Vujović, Katarina, Srebro, Dragana, Vučković, Sonja, Ivanović, Milovan, Kostić Rajačić, Slađana, "μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation" in Journal of the Serbian Chemical Society, 85, no. 6 (2020):711-720,
https://doi.org/10.2298/JSC190912118J . .

TY  - JOUR
AU  - Ivanović, Milovan D.
AU  - Mićović, Ivan
AU  - Vučković, Sonja
AU  - Prostran, Milica
AU  - Todorović, Zoran
AU  - Ivanović, Evica
AU  - Kiricojević, Vesna
AU  - Đorđević, Jelena B.
AU  - Došen-Mićović, Ljiljana
PY  - 2004
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/2684
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 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.
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  - Serbian Chemical Soc, Belgrade
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
VL  - 69
IS  - 11
SP  - 955
EP  - 968
DO  - 10.2298/JSC0411955I
ER  - 

@article{
author = "Ivanović, Milovan D. and Mićović, Ivan and Vučković, Sonja and Prostran, Milica and Todorović, Zoran and Ivanović, Evica and Kiricojević, Vesna and Đorđević, Jelena B. and Došen-Mićović, Ljiljana",
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 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., 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 = "Serbian Chemical Soc, Belgrade",
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",
volume = "69",
number = "11",
pages = "955-968",
doi = "10.2298/JSC0411955I"
}

Ivanović, M. D., Mićović, I., Vučković, S., Prostran, M., Todorović, Z., Ivanović, E., Kiricojević, V., Đorđević, J. B.,& Došen-Mićović, L.. (2004). The synthesis and pharmacological evaluation of (+/-)-2,3-seco-fentanyl analogues. in Journal of the Serbian Chemical Society
Serbian Chemical Soc, Belgrade., 69(11), 955-968.
https://doi.org/10.2298/JSC0411955I

Ivanović MD, Mićović I, Vučković S, Prostran M, Todorović Z, Ivanović E, Kiricojević V, Đorđević JB, Došen-Mićović L. 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 .

Ivanović, Milovan D., Mićović, Ivan, Vučković, Sonja, Prostran, Milica, Todorović, Zoran, Ivanović, Evica, Kiricojević, Vesna, Đorđević, Jelena B., Došen-Mićović, Ljiljana, "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 . .

TY  - JOUR
AU  - Ivanović, Milovan D.
AU  - Mićović, Ivan
AU  - Vučković, Sonja
AU  - Prostran, Milica
AU  - Todorović, Zoran
AU  - Kiricojević, Vesna
AU  - Đorđević, Jelena B.
AU  - Došen-Mićović, Ljiljana
PY  - 2004
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/2685
AB  - 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. 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.
AB  - Razvijen 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.
PB  - Serbian Chemical Soc, Belgrade
T2  - Journal of the Serbian Chemical Society
T1  - The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analogues
T1  - Sinteza i preliminarni farmakološki testovi recemskih cis i trans 3-alkilanaloga fentanila
VL  - 69
IS  - 7
SP  - 511
EP  - 526
DO  - 10.2298/JSC0407511I
ER  - 

@article{
author = "Ivanović, Milovan D. and Mićović, Ivan and Vučković, Sonja and Prostran, Milica and Todorović, Zoran and Kiricojević, Vesna and Đorđević, Jelena B. and Došen-Mićović, Ljiljana",
year = "2004",
abstract = "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. 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., Razvijen 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.",
publisher = "Serbian Chemical Soc, Belgrade",
journal = "Journal of the Serbian Chemical Society",
title = "The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analogues, Sinteza i preliminarni farmakološki testovi recemskih cis i trans 3-alkilanaloga fentanila",
volume = "69",
number = "7",
pages = "511-526",
doi = "10.2298/JSC0407511I"
}

Ivanović, M. D., Mićović, I., Vučković, S., Prostran, M., Todorović, Z., Kiricojević, V., Đorđević, J. B.,& Došen-Mićović, L.. (2004). The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analogues. in Journal of the Serbian Chemical Society
Serbian Chemical Soc, Belgrade., 69(7), 511-526.
https://doi.org/10.2298/JSC0407511I

Ivanović MD, Mićović I, Vučković S, Prostran M, Todorović Z, Kiricojević V, Đorđević JB, Došen-Mićović L. The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analogues. in Journal of the Serbian Chemical Society. 2004;69(7):511-526.
doi:10.2298/JSC0407511I .

Ivanović, Milovan D., Mićović, Ivan, Vučković, Sonja, Prostran, Milica, Todorović, Zoran, Kiricojević, Vesna, Đorđević, Jelena B., Došen-Mićović, Ljiljana, "The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analogues" in Journal of the Serbian Chemical Society, 69, no. 7 (2004):511-526,
https://doi.org/10.2298/JSC0407511I . .