N-ACYL-2-SUBSTITUTED-1,3-THIAZOLIDINES, A NEW CLASS OF NONNARCOTIC ANTITUSSIVE AGENTS - STUDIES LEADING TO THE DISCOVERY OF ETHYL YPHENOXY)METHYL]-BETA-OXOTHIAZOLIDINE-3-PROPANOATE

The synthesis of a novel class of antitussive agents is described. The compounds were examined for antitussive activity in guinea pig after cough induction by electrical or chemical stimulation. Ethyl yphenoxy) methyl]-beta-oxothiazolidine-3-propanoate (BBR 2173, moguisteine, 7) a nd other structurally related compounds showed a significant level of activity, comparable to that of codeine and dextromethorphan. The comp ounds presented in this paper are characterized by the N-acyl-2-substi tuted-1,3-thiazolidine moiety, which is a novel entry in the field of antitussive agents. The serendipitous discovery of the role played by the thiazolidine moiety in determining the antitussive effect promoted extensive investigations on these structures. This optimization proce ss on N-acyl-2-substituted-1,3-thiazolidines led to the initial identi fication of 2-[(2-methoxypheoxy)methyl]-3-[2-(acetylthio) acetyl]-1,3- thiazolidine (18a) as an interesting lead compound. The careful study of the rapid and very complicated metabolism of 18a provided further i nsights for the design of newer related derivatives. The observation t hat the metabolic oxidation on the lateral chain's sulfur of 18a to su lfoxide maintained the antitussive properties suggested the introducti on of isosteric functional groups with respect to the sulfoxide moiety . Subsequent structural modifications showed that hydrolyzable malonic residues in the 3-position of the thiazolidine ring were able to assu re high antitussive activity. This optimization ultimately led to the selection of moguisteine (7) as the most effective and safest represen tative of the series. Moguisteine is completely devoid of unwanted sid e effects (such as sedation and addiction), and its activity was demon strated also in clinical studies.