Phenylimidazolidin-2-one Derivatives as Selective 5-HT₃Receptor Antagonists and Refinement of the Pharmacophore Model for 5-HT₃Receptor Binding

Abstract

A possible bioisosterism between the benzamido and the phenylimidazolidin-2-one moieties has been suggested on the basis of the similarity between the molecular electrostatic potential (MEP) of metoclopramide, a D2 receptor antagonist with weak 5-HT3 receptor antagonist properties, and zetidoline, a D2 receptor antagonist. Starting from this premise, a series of phenylimidazolidin-2-one derivatives bearing a basic azabicycloalkyl or an imidazolylalkyl moiety were synthesized and evaluated for 5-HT3 receptor radioligand binding affinity ([3H]-GR 43,694). In vitro 5-HT3 receptor antagonist activity was tested in the guinea pig ileum assay (GPI). A number of high-affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the Bezold--Jarisch reflex in the anesthetized rat. In general, the imidazolylalkyl derivatives were found to be more active than azabicycloalkyls. 1-(3,5-Dichlorophenyl)-3-[(5-methyl-1H-imidazol-4-yl)methyl]imidazoli din-2-one (58), in particular, displayed very high affinity for the 5-HT3 receptor (Ki of 0.038 nM) with a Kb of 5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron, tropisetron, granisetron, and BRL 46,470) tested. 58 showed an ID50 comparable to that of ondansetron (2.2 micrograms/kg i.v.) in the Bezold--Jarisch reflex. A molecular modeling study based on this structurally novel series of compounds allowed the refinement of previously reported 5-HT3 receptor antagonist pharmacophore models.

Complementary Ways to Diastereomers of Bridged Aminopiperidine Derivatives - A Stereochemical Challenge

“…Both the formation of sole 3-endoisomers 40b [42] and of mixtures 40b/41b (endo/exo ≈ 2:1) [39] were reported for the reductive amination of a pseudopelletierine 36b with sodium cyanoborohydride and various amines. Catalytic hydrogenation of in situ generated imine 38a (R 1 = H) and oxime 37b serves for commercial syntheses of endo-3-tropylamine 34a and endo-3-granatylamine 34b on an industrial scale, respectively [43].…”

“…Sodium cyanoborohydride (Borch method) or borohydride exchange resin as hydride reagent decreased the stereoselectivity (endo/exo ratio of ≈ 2:1 [36,39] or ≈ 1:1 [40]). No stereoselectivity was observed in the reductive amination of tropinone 36a with triacetoxyborohydride and a secondary amine such as piperidine [37].…”

From new simple aliphatic to aromatic heterocycles built from 2-chloroethylisocyanate

“…Once intermediate XIII is formed (path B), it releases HCl to give XIV and CO leading to the very reactive intermediates XV, from where the pyrazine heterocycle can be formed through XVI-XVIII. Desorption of this structure explains the formation of the radical hydro-1,4-pyrazine (30) which, for instance, could recombine with radical 23 allowing the formation of the other pyrazines (19)(20)(21)(22) after the loss of chlorine and hydrogen abstraction (Scheme 4).…”

Stereoselective synthesis of imidazolidin-2-ones via Pd-catalyzed alkene carboamination. Scope and limitations

“…18 Only one example of Pd-catalyzed carboamination of an N-propargylurea with acrolein has been reported, and this transformation does not lead to generation of new stereocenters. 19 We recently reported a new strategy for the construction of imidazolidin-2-ones via Pdcatalyzed carboamination reactions 20,21 between acyclic N-allylureas (2) and aryl bromides (eq 1). 22 This method overcomes many limitations of existing approaches to the synthesis of these compounds.…”

“…22 This method overcomes many limitations of existing approaches to the synthesis of these compounds. For example, the N-allylurea substrates (2) are prepared in one step and high yield from readily available allylic amines and isocyanates. The carboamination reactions generate two bonds (one C-C and one C-N) and up to two stereocenters in one step to afford products of general structure 3 with excellent diastereoselectivity.…”