N-acyl-2-substituted-1,3-thiazolidines, a new class of non-narcotic antitussive agents: studies leading to the discovery of ethyl 2-[(2-methoxyphenoxy)methyl]-beta-oxothiazolidine-3-propanoate.

Abstract

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 2-[(2-methoxyphenoxy)methyl]-beta-oxothiazolidine-3-propanoate (BBR 2173, moguisteine, 7) and other structurally related compounds showed a significant level of activity, comparable to that of codeine and dextromethorphan. The compounds presented in this paper are characterized by the N-acyl-2-substituted-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 process on N-acyl-2-substituted-1,3-thiazolidines led to the initial identification 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 insights for the design of newer related derivatives. The observation that the metabolic oxidation on the lateral chain's sulfur of 18a to sulfoxide maintained the antitussive properties suggested the introduction 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 assure high antitussive activity. This optimization ultimately led to the selection of moguisteine (7) as the most effective and safest representative of the series. Moguisteine is completely devoid of unwanted side effects (such as sedation and addiction), and its activity was demonstrated also in clinical studies.