Phenyl-substituted analogs of oxotremorine as muscarinic antagonists

Abstract

A series of phenyl-substituted analogues of the muscarinic agent oxotremorine (1) have been prepared. The new compounds (3b-11b and 9c) were assayed for antimuscarinic activity on the isolated guinea pig ileum and in intact mice. They were also evaluated for ability to inhibit the binding of the muscarinic antagonist (-)-[3H]-N-methylscopolamine to homogenates of the rat cerebral cortex. The phenyl-substituted derivatives were devoid of intrinsic muscarinic activity. Instead, they behaved as competitive muscarinic antagonists in these assays with similar or lower affinity for muscarinic receptors than the corresponding methyl-substituted analogues. The succinimide (8b) and the pyrrolidone (3b) derivatives of 1 substituted with a phenyl group at position 1 of the butynyl chain showed the highest antimuscarinic potency with dissociation constants (KD) of 0.10 and 0.20 microM, respectively, in the ileum assay. The phenyl-substituted analogues showed an approximately 10-fold lower in vivo antimuscarinic potency than their corresponding methyl-substituted positional isomers. A correlation was observed between in vitro and in vivo potency within subsets consisting of methyl- and phenyl-substituted derivatives.

Cyclization of Propargylic Amides: Mild Access to Oxazole Derivatives

“…A similar reaction pattern was reported by Hacksell et al, who reported a base-catalyzed isomerization of propargylic amides through allenic intermediates. [16] But the 1 H NMR data reported by Uemura et al did not match the symmetry of intermediate A, which should show only one resonance for the allenic CH 2 group, but two different resonances were reported in footnote 7 of the publication. Furthermore, such an intermediate would contradict our mechanistic findings: [6] As we considered the participation of intermediate dihydrooxazoles (Scheme 2, path b) in our publication, further experimental clarification of the mechanism was required.…”

Gold‐Catalyzed Stereoselective Domino Cyclization/Alkynylation of N‐Propargylcarboxamides with Benziodoxole Reagents for the Synthesis of Alkynyloxazolines

“…Traditional methods for accessing these heterocycles start from carboxylic acids, esters, nitriles, hydroxyamides, aldehydes and olefins . Another versatile and effective way is the transition metal‐catalyzed cyclization of N ‐propargylcarboxamides, with Brønsted acids, or under strong basic conditions . Among these N,O ‐heterocycles, alkynyl‐substituted oxazolines represent a highly interesting class of functionalized building blocks for synthetic chemistry, a fruitful follow‐up chemistry is enabled by the subsequent functionalization of the alkynyl groups .…”

“…[1c] Another versatile and effective way is the transition metal-catalyzed cyclization of Npropargylcarboxamides, [5] with Brønsted acids, [6] or under strong basic conditions. [7] Among these N,Oheterocycles, alkynyl-substituted oxazolines represent a highly interesting class of functionalized building blocks for synthetic chemistry, a fruitful follow-up chemistry is enabled by the subsequent functionalization of the alkynyl groups. [8] Traditionally, these compounds are synthesized by Sonogashira cross coupling reactions.…”

Effect of the ortho-hydroxy group of salicylaldehyde in the A3 coupling reaction: A metal-catalyst-free synthesis of propargylamine

“…Propargylamines are important synthetic intermediates for the preparation of natural products [1], potential therapeutic agents [2], oxotremorine analogues [3] and multifunctional amino derivatives [4–5]. Compounds like resagiline or selegiline (structures 1 and 2 , Scheme 1) bearing a propargylamine moiety, are familiar as potent selective, irreversible monoamine oxidase (MAO) type B inhibitors [6] often used for the treatment of neuropsychiatric disorders such as Alzheimer’s and Parkinson diseases.…”