The synthesis of lactam analogues of fentanyl

Mićović, Ivan V.; Roglić, Goran; Ivanović, Milan; Došen‐Mićović, Ljiljana; Kiricojević, Vesna D.; Popović, Jelena B.

doi:10.1039/p19960002041

Cited by 22 publications

(10 citation statements)

References 27 publications

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“…For example, (2 R )-1-phenethyl-4-( N -phenylpropionamido) piperidine-2-carboxamide has been synthesized, which was 110- and 450-times less potent than fentanyl in the GPI and MVD assays, respectively (Supplementary Information 17) [145]. Other types of functionalization of the second position of the piperidine ring have been examined and lactam analogs of fentanyl were synthesized [146,147], but pharmacological studies were not given (Supplementary Information 14). …”

Section: Insertion Of Substituents Other Than Methyl Into the Differementioning

confidence: 99%

Fentanyl-Related Compounds and Derivatives: Current Status and Future Prospects for Pharmaceutical Applications

2014

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Fentanyl and its analogs have been mainstays for the treatment of severe to moderate pain for many years. In this review, we outline the structural and corresponding synthetic strategies that have been used to understand the structure–biological activity relationship in fentanyl-related compounds and derivatives and their biological activity profiles. We discuss how changes in the scaffold structure can change biological and pharmacological activities. Finally, recent efforts to design and synthesize novel multivalent ligands that act as mu and delta opioid receptors and NK-1 receptors are discussed.

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Section: Insertion Of Substituents Other Than Methyl Into the Differementioning

confidence: 99%

Fentanyl-Related Compounds and Derivatives: Current Status and Future Prospects for Pharmaceutical Applications

2014

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“…A typical example of the crystallization/distillation process is the purification of n ‐dodecanal isomers reported by Micovic et al . The corresponding flow sheet is displayed in Fig.…”

Section: Principle Of Hybrid Distillation/crystallization Technologymentioning

confidence: 99%

“…Specifically considering the distillation/crystallization process, the heuristic method can be used to give all possible physical processes before simulation . This method has been applied in the separation of isomeric long‐chain aldehydes ( n ‐dodecanal and iso ‐dodecanal) by Micovic et al . Due to the lack of adequate experimental data, six possible variant processes were proposed as shown in Fig.…”

Section: Design and Optimization Of The Hybrid Distillation/crystallimentioning

confidence: 99%

“…Marquardt's three‐step design approach could not be applied when the parameters of modeling and cost functions were not sufficient. So, Micovic et al proposed a four‐step approach, including generation of alternatives, evaluation of alternatives, determination of parameters, and process optimization. Among them, the second step is crucial, and many methods have been introduced.…”

Section: Design and Optimization Of The Hybrid Distillation/crystallimentioning

confidence: 99%

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Research Progress of Hybrid Distillation/Crystallization Technology

Zhou

et al. 2018

Chem Eng & Technol

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The hybrid distillation/crystallization process is successfully applied to separate azeotropes and closely boiling mixtures. This process can not only provide pure products, but also allow for significant energy savings. The research progress and industrial applications of hybrid distillation/crystallization are reviewed. Different sequences of hybrid distillation/crystallization process are presented based on the optimized design. The specific developments of each single unit, namely, distillation and crystallization, in the hybrid process are outlined. Applications of hybrid distillation/crystallization in practical cases are highlighted and analyzed. Finally, the key issues and perspectives for further research of this integrated process are illustrated.

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“…Lactam analogues of therapeutically-relevant natural products are well-established targets in medicinal chemistry. [81][82][83][84][85] These elaborations are usually intended to add to an understanding of SARs, and in some cases increase stability. Sterner and co-workers synthesised 81 lactam analogues of the lactone-containing natural product galiellalactone, an inhibitor of the transcription factor STAT3 in prostate cancer cells.…”

Section: Lactam Analogues Of Natural Productsmentioning

confidence: 99%

Toward the Synthesis of (–)-TAN-2483B Lactam Analogues

Stirrat¹

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<p>Natural products continue to be an abundant source of lead compounds for drug discovery and development. (–)-TAN-2483A and (–)-TAN-2483B, isolated from the culture of a filamentous fungus, incorporate an unusual furo[3,4-b]pyran-5-one scaffold. TAN-2483A was initially reported to inhibit the c-Src tyrosine kinase enzyme, a potential anticancer target, and parathyroid hormone-induced bone resorption. TAN-2483B, on the other hand, was not isolated in sufficient quantities for biological testing. The synthesis of TAN-2483B is therefore desirable from a drug discovery perspective. Several analogues of TAN-2483B that are functionalised at the propenyl sidechain have previously been synthesised in the Harvey group and have shown promising biological activity. For example, the (Z)-ethyl ester analogue showed micromolar inhibition of HL-60 cells and Bruton’s tyrosine kinase, a protein involved in B-cell maturation that is implicated in certain cancers. The lactone moiety of TAN-2483B and its sidechain analogues, however, appears to be unstable to nucleophilic attack. The aim of this thesis was to investigate the viability of a synthetic route toward lactam analogues of TAN-2483B. It was proposed that substituting the lactone for a lactam would increase the stability of the compound in nucleophilic media. Moreover, the lactam nitrogen may provide a site for further functionalisation of the compound for future structure-activity relationship studies. Because installation of the (Z)-ethyl ester sidechain via Wittig conditions has previously been found to be more facile than installation of the (E)-propenyl sidechain found in the natural product, investigations into forming the lactam ring system were carried out on the ethyl ester advanced intermediates. Reductive amination of a ketone intermediate was envisaged to install the amine prior to a palladium-catalysed carbonylation/lactam formation step. The promising bioactivity of the (Z)-ethyl ester analogue was anticipated to be retained in the target lactam analogues. It was found that the substrates of the proposed reductive amination, the advanced ketone intermediates, were incompatible with the tested conditions, presumably due to base sensitivity. Three by-products from the reductive amination experiments were isolated and tentatively characterised by NMR spectroscopy and HRMS. An alternative route toward lactam analogues of TAN-2483B, via intermediate amines accessed by the substitution of an activated alcohol, was briefly investigated with encouraging results. Further optimisation of the synthetic route toward analogues of TAN-2483B was also achieved. Removal of a purification step enabled the more expedient two-step synthesis of a diol intermediate. The two-step transformation to (Z)- and (E)-ethyl ester intermediates, via sodium periodate-mediated diol cleavage and Wittig olefination, proceeded in the highest yield obtained to date. Investigations into the desilylation of a trimethylsilyl-protected acetylene were also conducted. Although lactam analogues of TAN-2483B were not obtained in this study, progress was made toward their synthesis. The alternative route toward amines that was briefly explored here appears promising, and work is ongoing in the Harvey group to access lactam (and other) analogues of TAN-2483B, in addition to the natural product itself.</p>

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The synthesis of lactam analogues of fentanyl

Cited by 22 publications

References 27 publications

Fentanyl-Related Compounds and Derivatives: Current Status and Future Prospects for Pharmaceutical Applications

Fentanyl-Related Compounds and Derivatives: Current Status and Future Prospects for Pharmaceutical Applications

Research Progress of Hybrid Distillation/Crystallization Technology

Toward the Synthesis of (–)-TAN-2483B Lactam Analogues

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