TY  - JOUR
AU  - Mićović, Ivan V.
AU  - Ivanović, Milovan
AU  - Vuckovic, S
AU  - Jovanovic-Micic, D
AU  - Beleslin, D.
AU  - Došen-Mićović, Ljiljana
AU  - Kiricojevic, VD
PY  - 1998
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/370
AB  - A novel analogue of fentanyl, 3-carbomethoxyfentanyl, or "iso-carfentanil", was synthesized by a simple and efficient route. In the first step phenethylamine was condensed with two equivalents of methyl acrylate to afford the amino-diester Ib in quantitative yield. Dieckmann cyclization of this intermediate yielded 3-carbomethoxy N-phenethyl-4-piperidone 2 in ca. 80% yield, after mild hydrolysis. Condensation of this beta-keto ester with aniline in acetic acid gave the stable enamine 3 (70% yield) which was then reduced with NaBH3CN in methanol at pH approximate to 5, to yield 4-anilino-3-carbomethoxy-N-phenethyl piperidine, quantitatively. This intermediate was obtained as a 50:50 mixture of the (+/-) cis and (+/-) trans isomers, 4a and 4b, respectively. After the mixture of diastereoisomers was separated on a neutral aluminium oxide column, the pure 4a and 4b isomers were acylated with propionyl chloride, thus completing the synthesis of 3-carbomethoxy fentanyl 5a and 5b. The relative stereochemistry was H-1-NMR spectroscopy. These compounds present regioisomers of determined by carfentanil, one of the most potent narcotic analgesic known to date. Preliminary pharmacological evaluation (tail-withdrawal test in rats) revealed substantially reduced potency of both diastereoisomers, the (+/-) trans 5b in particular, compared to carfentanil. The computational (molecular mechanics) search of the low energy regions of the conformational space of the cis 5a and trans 5b isomers revealed the difference in their conformational mobility. Besides being more conformationaly flexible, the trans isomer has unfavorable orientation of the 4-N-phenylpropanamide group compared to the other active analogs of fentanyl. This is believed to be the reason of its reduced potency relative to fentanyl.
PB  - Serbian Chemical Soc, Belgrade
T2  - Journal of the Serbian Chemical Society
T1  - The synthesis, pharmacological evaluation and conformational analysis of (+/-)cis- and (+/-)trans3-carbomethoxy fentanyl-"iso-carfentanil"
VL  - 63
IS  - 2
SP  - 93
EP  - 112
UR  - https://hdl.handle.net/21.15107/rcub_cherry_370
ER  - 

@article{
author = "Mićović, Ivan V. and Ivanović, Milovan and Vuckovic, S and Jovanovic-Micic, D and Beleslin, D. and Došen-Mićović, Ljiljana and Kiricojevic, VD",
year = "1998",
abstract = "A novel analogue of fentanyl, 3-carbomethoxyfentanyl, or "iso-carfentanil", was synthesized by a simple and efficient route. In the first step phenethylamine was condensed with two equivalents of methyl acrylate to afford the amino-diester Ib in quantitative yield. Dieckmann cyclization of this intermediate yielded 3-carbomethoxy N-phenethyl-4-piperidone 2 in ca. 80% yield, after mild hydrolysis. Condensation of this beta-keto ester with aniline in acetic acid gave the stable enamine 3 (70% yield) which was then reduced with NaBH3CN in methanol at pH approximate to 5, to yield 4-anilino-3-carbomethoxy-N-phenethyl piperidine, quantitatively. This intermediate was obtained as a 50:50 mixture of the (+/-) cis and (+/-) trans isomers, 4a and 4b, respectively. After the mixture of diastereoisomers was separated on a neutral aluminium oxide column, the pure 4a and 4b isomers were acylated with propionyl chloride, thus completing the synthesis of 3-carbomethoxy fentanyl 5a and 5b. The relative stereochemistry was H-1-NMR spectroscopy. These compounds present regioisomers of determined by carfentanil, one of the most potent narcotic analgesic known to date. Preliminary pharmacological evaluation (tail-withdrawal test in rats) revealed substantially reduced potency of both diastereoisomers, the (+/-) trans 5b in particular, compared to carfentanil. The computational (molecular mechanics) search of the low energy regions of the conformational space of the cis 5a and trans 5b isomers revealed the difference in their conformational mobility. Besides being more conformationaly flexible, the trans isomer has unfavorable orientation of the 4-N-phenylpropanamide group compared to the other active analogs of fentanyl. This is believed to be the reason of its reduced potency relative to fentanyl.",
publisher = "Serbian Chemical Soc, Belgrade",
journal = "Journal of the Serbian Chemical Society",
title = "The synthesis, pharmacological evaluation and conformational analysis of (+/-)cis- and (+/-)trans3-carbomethoxy fentanyl-"iso-carfentanil"",
volume = "63",
number = "2",
pages = "93-112",
url = "https://hdl.handle.net/21.15107/rcub_cherry_370"
}

Mićović, I. V., Ivanović, M., Vuckovic, S., Jovanovic-Micic, D., Beleslin, D., Došen-Mićović, L.,& Kiricojevic, V.. (1998). The synthesis, pharmacological evaluation and conformational analysis of (+/-)cis- and (+/-)trans3-carbomethoxy fentanyl-"iso-carfentanil". in Journal of the Serbian Chemical Society
Serbian Chemical Soc, Belgrade., 63(2), 93-112.
https://hdl.handle.net/21.15107/rcub_cherry_370

Mićović IV, Ivanović M, Vuckovic S, Jovanovic-Micic D, Beleslin D, Došen-Mićović L, Kiricojevic V. The synthesis, pharmacological evaluation and conformational analysis of (+/-)cis- and (+/-)trans3-carbomethoxy fentanyl-"iso-carfentanil". in Journal of the Serbian Chemical Society. 1998;63(2):93-112.
https://hdl.handle.net/21.15107/rcub_cherry_370 .

Mićović, Ivan V., Ivanović, Milovan, Vuckovic, S, Jovanovic-Micic, D, Beleslin, D., Došen-Mićović, Ljiljana, Kiricojevic, VD, "The synthesis, pharmacological evaluation and conformational analysis of (+/-)cis- and (+/-)trans3-carbomethoxy fentanyl-"iso-carfentanil"" in Journal of the Serbian Chemical Society, 63, no. 2 (1998):93-112,
https://hdl.handle.net/21.15107/rcub_cherry_370 .

TY  - JOUR
AU  - Mićović, Ivan V.
AU  - Ivanović, Milovan
AU  - Jovanovic-Micic, D
AU  - Beleslin, D.
AU  - Došen-Mićović, Ljiljana
AU  - Kiricojevic, VD
PY  - 1998
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/381
AB  - The synthesis of a novel analogue of fentanyl, 3-carbomethoxy fentanyl or "iso-carfentanil" has been accomplished in five steps, by simple and efficient route, starting from phenethyl amine and methyl acrylate. Both (+/-)  lt (cis)under bar gt  and -(+/-)  lt (trans)under bar gt  isomers were obtained in pure form and tested pharmacologically for the central analgesic activity: Preliminary results (rat-withdrawal test) revealed significant but substantially reduced potency of both isomers, the  lt (trans)under bar gt  in particular, compared to carfentanil. The computational (molecular mechanics) search of the conformational space low energy regions of  lt (5a)under bar gt  ((+/-)  lt (cis)under bar gt ) and  lt (5b)under bar gt  ((+/-)  lt (trans)under bar gt  isomers revealed the difference in their conformational mobility. Besides being more conformationaly flexible trans isomer has unfavorable orientation of the 4-N-phenylpropanamide group compared to the other active analogs of fentanyl. This is believed to be the reason of its reduced potency relative to fentanyl.
PB  - Walter De Gruyter Gmbh, Berlin
T2  - Heterocyclic Communications
T1  - 3-carbomethoxy fentanyl: Synthesis, pharmacology and conformational analysis
VL  - 4
IS  - 2
SP  - 171
EP  - 179
UR  - https://hdl.handle.net/21.15107/rcub_cherry_381
ER  - 

@article{
author = "Mićović, Ivan V. and Ivanović, Milovan and Jovanovic-Micic, D and Beleslin, D. and Došen-Mićović, Ljiljana and Kiricojevic, VD",
year = "1998",
abstract = "The synthesis of a novel analogue of fentanyl, 3-carbomethoxy fentanyl or "iso-carfentanil" has been accomplished in five steps, by simple and efficient route, starting from phenethyl amine and methyl acrylate. Both (+/-)  lt (cis)under bar gt  and -(+/-)  lt (trans)under bar gt  isomers were obtained in pure form and tested pharmacologically for the central analgesic activity: Preliminary results (rat-withdrawal test) revealed significant but substantially reduced potency of both isomers, the  lt (trans)under bar gt  in particular, compared to carfentanil. The computational (molecular mechanics) search of the conformational space low energy regions of  lt (5a)under bar gt  ((+/-)  lt (cis)under bar gt ) and  lt (5b)under bar gt  ((+/-)  lt (trans)under bar gt  isomers revealed the difference in their conformational mobility. Besides being more conformationaly flexible trans isomer has unfavorable orientation of the 4-N-phenylpropanamide group compared to the other active analogs of fentanyl. This is believed to be the reason of its reduced potency relative to fentanyl.",
publisher = "Walter De Gruyter Gmbh, Berlin",
journal = "Heterocyclic Communications",
title = "3-carbomethoxy fentanyl: Synthesis, pharmacology and conformational analysis",
volume = "4",
number = "2",
pages = "171-179",
url = "https://hdl.handle.net/21.15107/rcub_cherry_381"
}

Mićović, I. V., Ivanović, M., Jovanovic-Micic, D., Beleslin, D., Došen-Mićović, L.,& Kiricojevic, V.. (1998). 3-carbomethoxy fentanyl: Synthesis, pharmacology and conformational analysis. in Heterocyclic Communications
Walter De Gruyter Gmbh, Berlin., 4(2), 171-179.
https://hdl.handle.net/21.15107/rcub_cherry_381

Mićović IV, Ivanović M, Jovanovic-Micic D, Beleslin D, Došen-Mićović L, Kiricojevic V. 3-carbomethoxy fentanyl: Synthesis, pharmacology and conformational analysis. in Heterocyclic Communications. 1998;4(2):171-179.
https://hdl.handle.net/21.15107/rcub_cherry_381 .

Mićović, Ivan V., Ivanović, Milovan, Jovanovic-Micic, D, Beleslin, D., Došen-Mićović, Ljiljana, Kiricojevic, VD, "3-carbomethoxy fentanyl: Synthesis, pharmacology and conformational analysis" in Heterocyclic Communications, 4, no. 2 (1998):171-179,
https://hdl.handle.net/21.15107/rcub_cherry_381 .