Histamine H2 receptor antagonists. 1. Synthesis of N-cyano and N-carbamoyl amidine derivatives and their biological activities.

A large number of N-cyano amidine derivatives were prepared as potential histamine H2 receptor antagonists and evaluated for their inhibitory action on histamine-stimulated chronotropic response of isolated right atria from guinea pigs. Several selected compounds were assessed as inhibitors of gastric acid secretion induced by histamine in anesthetized dogs. Of these compounds, furan (8c) and [(diaminomethylene)amino]thiazole derivatives (16c) were found to be more potent than cimetidine in both assays. In contrast to the guanidine series, methyl substitution at the terminal nitrogen of the cyano amidines was detrimental to the activities. Furthermore, acid hydrolysis of the cyano amidines gave carbamoyl amidines, which proved to be more active than the cyano amidines, the converse of the case for guanidines. 3-[[[2-[(Diaminomethylene)amino]-4- thiazolyl]methyl]thio]-N'-carbamoylpropionamidine (16d) was the most potent of all the compounds tested and was approximately 30 times more active in vitro and 50 times more active in vivo than cimetidine.