Ugi reaction for the synthesis of 4-aminopiperidine-4-carboxylic acid derivatives. Application to the synthesis of carfentanil and remifentanil

Malaquin, Stéphanie; Jida, Mouhamad; Gesquière, Jean‐Claude; Deprez-Poulain, Rébecca; Déprez, Benoît; Laconde, Guillaume

doi:10.1016/j.tetlet.2010.03.120

Cited by 41 publications

(20 citation statements)

References 14 publications

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“…Remifentanil ( 56 ) occupied its own place in the arsenal of opioid analgesics and described and discussed in many pharmacological reviews [115–124], including an originally titled review “Remifentanil: do we need another opioid?” [116]. Many modifications of the scheme of synthesis were proposed [125–129], among which is an interesting approach that applies the Ugi reaction for the synthesis of remifentanil ( 56 ) and carfentanil ( 45 ) (Supplementary Information 10) [129]. …”

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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“…15 In the present work, four-component Ugi reactions were carried out between N -alkylpiperidones, aniline, propionic acid and an array of aliphatic isocyanides. The reaction has previously been used to synthesize a carfentanil precursor 16 and bivalent ligands. 17 We herein report the synthesis and pharmacological characterization of novel carfentanil amide analogues.…”

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confidence: 99%

Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction

Váradi

Palmer

Haselton

et al. 2015

ACS Chem. Neurosci.

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We report a novel approach to synthesize carfentanil amide analogues utilizing the isocyanide-based four-component Ugi multicomponent reaction. A small library of bis-amide analogues of carfentanil was created using N-alkylpiperidones, aniline, propionic acid, and various aliphatic isocyanides. Our lead compound showed high affinity for mu (MOR) and delta opioid receptors (DOR) with no appreciable affinity for kappa (KOR) receptors in radioligand binding assays. The compound was found to be a mixed MOR agonist/partial DOR agonist in [35S]GTPγS functional assays, and it showed moderate analgesic potency in vivo. The compound showed no visible signs of physical dependence or constipation in mice. In addition, it produced less respiratory depression than morphine. Most mixed MOR/DOR opioids reported in the literature are peptides and thereby systemically inactive. Our approach utilizing a multicomponent reaction has the promise to deliver potent and efficacious small-molecule analgesics with potential clinical utility.

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“…Malaquin and coworkers applied Ugi reaction to the preparation of remifentanil in 2010. (Scheme 15) (Malaquin et al, 2010). Its big advantage lies in the effectiveness of the synthetic sequence (3 steps starting from commercially available compounds), one equivalent Ugi procedure (no excess required) and good yield.…”

Section: Methodsmentioning

confidence: 99%