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

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

Conformational study of fentanyl and its analogs .1. Conformational space of the N-phenethyl substituent

The computational method, based on molecular mechanics, with Monte Carlo type searching in dihedral angle space, was applied to the study of seven physiologically highly active fentanyl analogs, with different substituents in a phenethyl side chain. The low energy regions of the conformational space of these molecules have been compared in an effort to establish the receptor-recognized conformation of a phenethyl side chain, and to explain the mechanisms by which a hydroxyl substituent increases potency of the fentanyl analogs. It has been found that the extended conformation of a phenethyl side chain is the only one available to all the active analogs of fentanyl. Activities of the compounds with alkyl substituents in the phenethyl side chain correlate with their hydrophobicities, A hydroxyl substituent affects potency by reducing the flexibility of the phenethyl side chain, by reducing the energy difference between the global minimum and the receptor-recognized conformation and by specific interactions with the receptor

Preparation of secondary amines by reductive amination with metallic magnesium

A novel and efficient method for the preparation of secondary amines by reductive amination of carbonyl compounds with primary amines has been developed, The reduction, effected with metallic magnesium in methanol, utilizing triethylamine-acetic acid as a buffer, gave pure secondary amines, mostly in good yields (65-80%). No formation of tertiary amines or alcohols was observed. Use of ammonium acetate as an amino component gave primary amines in modest yields (ca. 50%), together with variable amounts of secondary amines. Enamines failed to undergo reduction. The method is inexpensive, relatively rapid, operationally simple and suitable for large-scale preparations, In addition, a simple method for separation of primary amines from secondary ones has been developed

The synthesis of lactam analogues of fentanyl

Fentanyl, sufentanil and alfentanil are clinically widely used anaesthetics and are structurally related to drugs with entirely different pharmacological activity such as droperidol, loperamide and lorcainide, etc. Therefore, in order to test their pharmacological activity, lactam analogues of fentanyl, a novel class of compounds, have been synthesized. In the first step, various primary amines have been selectively added to 1 equiv, of alpha,beta-unsaturated esters, to afford the beta-amino esters. N-Acylation of these intermediates with dimethyl malonate yields the amido esters, which have been further subjected to Dieckmann-type cyclization, to produce the corresponding 3-methoxycarbonylpiperidine-2,4-diones. The cyclization has been effected under phase-transfer conditions, utilizing potassium carbonate as base and 18-crown-6 as catalyst, This eliminates the need for strong and hazardous bases such as molten sodium or NaH, In the next step, acid hydrolysis and decarboxylation furnish the substituted piperidine-2,4-diones in good yields, as pure products. Alkylation of the N-phenethylpiperidine-2,4-dione with methyl iodide and potassium carbonate in DMSO gives the 3,3-dimethyl derivative, The alkylation procedure is also applicable to other alkylating agents. Reductive amination of the prepared piperidine-2,4-diones with aniline and NaBH3CN in buffered methanol gives the corresponding pure 4-anilino-2-piperidones. The lactam function can be readily reduced (NaBH4-BF3 . Et(2)O), as exemplified with the 3,3-dimethyl derivative, thus providing access to additional fentanyl analogues, not readily accessible by other routes. The synthesis is completed by N-acylation of the anilines with propionyl chloride using triethylamine as base. The prepared 4-propionanilido-2-piperidones and 4-propionanilidopiperidines are expected to provide useful structure-activity relationship data in the pharmacological studies

The synthesis and preliminary pharmacological evaluation of 4-methyl fentanyl

The synthesis of 4-methyl fentanyl, a prototype of a novel class of fentanyl analogues has been effected in 5 steps, starting from N-ethoxycarbonyl-4-piperidone (similar to 20% overall yield). In the key step, N-phenylation of secondary aliphatic amide intermediate was achieved by a novel reaction, using diphenyliodonium chloride for the phenyl group transfer. Preliminary pharmacological results indicate that 4-methyl fentanyl is a super potent narcotic analgesic, about four times more potent than fentanyl. (C) 2000 Elsevier Science Ltd. All rights reserved

3-carbomethoxy fentanyl: Synthesis, pharmacology and conformational analysis

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

The synthesis, pharmacological evaluation and conformational analysis of (+/-)cis- and (+/-)trans3-carbomethoxy fentanyl-"iso-carfentanil"

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

The synthesis, pharmacological evaluation and conformational analysis of (+/-)cis- and (+/-)trans3-carbomethoxy fentanyl-"iso-carfentanil"

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