Cholinergic Agents Structurally Related to Furtrethonium. 2. Synthesis and Antimuscarinic Activity of a Series of N-[5-[(1'-Substituted-acetoxy)methyl]-2-furfuryl]dialkylamines

Abstract

In the first part of this study, devoted to the discovery of selective antimuscarinic agents, (+/-)- N-[5-[(1'-phenyl-1'-cyclohexylacetoxy)methyl]-2-furfuryl]dimeth yla mine (5a) proved to be at least 20 times more potent in the rat ileum and bladder than in guinea pig atria. Several (+/-)-N- [5-[(1'-substituted-acetoxy)methyl]-2-furfuryl]dialkylamine analogs of 5a were subsequently prepared. This involved exploration of the tertiary nitrogen substituents and modulation of the lipophilic side chain at position 5 of the furan ring, using the Hansch approach. A QSAR study was conducted to correlate activity with physicochemical properties of substituents. The possibility of describing all compounds in a single model indicates that variations of nitrogen and the lipophilic side chain contribute independently to activity. Compounds 5b, c,j, with bulky lipophilic substituents at the tertiary nitrogen, showed unprecedented selectivity between the two smooth muscle tissues, their antimuscarinic potency being from 10 to 90 times higher in the ileum than in the bladder. It is suggested that their interesting tissue selectivity is probably related to nonspecific phenomena involving the receptor environment, rather than real differences between the muscarinic receptors in the two tissues.

Receptor binding studies of soft anticholinergic agents

“…The electronic character of the molecules has already been considered as one of the most important parameters related to the antagonist activity of anticholinergic agents (54,57,58). This is particularly true for the present set of molecules.…”

Chemicals from Biomass: Selective Synthesis of N-Substituted Furfuryl Amines by the One-Pot Direct Reductive Amination of Furanic Aldehydes

“…2 Among them, furfural and 5-hydroxymethyl furfural (HMF), which can be obtained from lignocellulosic biomass by dehydration of hexoses and pentoses respectively, are versatile platform molecules that can be converted in a variety of important chemicals. 3,4 N-substituted 5-(hydroxymethyl)-2-furfuryl amines, represent an important class of compounds due to their recognized pharmaceutical activities 5,6,7 such as calcium antagonistic activity, cholinergic agent, antimuscarinic agent, and carcinogenesis inhibitors. Moreover with the appropriated amines interesting surfactants can be also obtained.…”

Preparation of 5‐(Aminomethyl)‐2‐furanmethanol by direct reductive amination of 5‐Hydroxymethylfurfural with aqueous ammonia over the Ni/SBA‐15 catalyst

“…2‐arylaminomethyl‐hydroxymethylfuran derivatives, as important chemical intermediates, are widely used in synthetic chemistry . Among these derivatives, 5‐aminomethyl‐2‐furanmethanol (AMF), as a potential platform molecule for further derivatization due to the active hydroxy and amino group, has attracted considerable interest in recent years.…”