Discovery of 2-Aminothiazole-4-carboxamides, a Novel Class of Muscarinic M3 Selective Antagonists, through Solution-Phase Parallel Synthesis

Abstract

To date, five distinct but homologous gene sequences coding for muscarinic receptors (m1, m2, m3, m4, m5) have been identified and cloned. [1][2][3][4][5] Pharmacologically, four subtypes (M 1 , M 2 , M 3 , M 4 ) have been defined. [6][7][8] Among these muscarinic receptor subtypes, M 3 receptors are localized in smooth muscle and mucosal glands and mediate contraction and mucus secretion. M 1 receptors, localized to the post-ganglionic cholinergic nerve terminals and glands, facilitate neurotransmission and gastric secretion. Neuronal M 2 receptors provide a functional negative feedback modulation of acetylcholine (ACh) release.9,10) Extensive efforts have been directed to the identification of potent and subtype-selective M 3 antagonists to complete the classification of the receptor subtypes and to provide more ideal therapeutic agents, [11][12][13] however, few structure classes with sufficient M 3 selectivity have been discovered to date. 14)As a part of our program for developing a muscarinic M 3 receptor antagonist for the treatment of pulmonary or urinary diseases, we pursued M 3 antagonists that are structurally distinct from a series of 2-(4,4-difluorocyclopentyl)-2-phenylacetamide derivatives such as Compound A 13) and have selectivity for M 3 receptors two orders of magnitude greater than those for M 1 and M 2 receptors. As a result of screening of our in-house chemical collection, a thiazole-4-carboxamide derivative (1) was identified as a new lead structure. Avoiding the structural complexity of 1 due to the five chiral centers, we first replaced the perhydronaphtylmethyl moiety with a naphtylmethyl group, without regard for the binding affinity of the compound. Optimization of the compound (2) by using a solution-phase parallel synthesis method led us to the identification of M 3 selective antagonists (3e, f) showing high potency (K i ϭca. 1 nM) for M 3 receptors and greater than 100-fold selectivity for M 3 over M 1 and M 2 receptors.In this paper, we describe the synthesis of aminothiazole derivatives, their binding affinities for M 1 -M 3 receptors in the binding assay, and their selectivity for M 3 over M 1 and M 2 receptors, and discuss their structure-activity and structure-selectivity relationships. ChemistryPreparation of 3f was outlined in Chart 1 as a representative procedure for the series of 2-aminothiazole-4-carboxamide derivatives. The 2-aminothiazole-4-carboxylic acid (5) was derived from a thiourea (4) and ethyl 2-bromopyruvate by a conventional method in 86% yield. The (3S)-3-aminomethylpiperidine (10), a component of 3f, was prepared from a racemic ethyl nipecotate (7).15) Optical resolution of ethyl nipecotate was performed using a standard method using L-tartaric acid to give a (3R)-ethyl nipecotate (8). Following the reduction of 8 with LAH, the piperidine Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd.; Okubo-3, Tsukuba, Ibaraki 300-2611, Japan. Received October 14, 2004 accepted January 7, 2005; published online January 19, 2005 Synthesis and structure-activi...

Medicinal chemistry and therapeutic potential of muscarinic M3 antagonists

“…Heteroaryl scaffolds have also been considered, such as the 2-2-(N-phenyl)-thiazole derivatives described by Banyu, 134,135 leading to highly potent and selective antagonists (with selectivity toward the M2 receptor greater than 300-fold).…”

Synthesis of heterocycles on the basis of products of arylation of unsaturated compounds 22.* 3-Aryl-2-chloropropanal in the synthesis of N-Aryl-5-(R-benzyl)-1,3-thiazole-2-amines

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Derivatives of 2-aminothiazole cover a wide spectrum of biological activity [2][3][4][5][6][7][8] and are also used in various fields of technology [9,10]. One of the most suitable methods for the synthesis of 2-aminothiazole is the interaction of α-halocarbonyl compounds with thioamides and thioureas [11][12][13].

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