Studies on Histamine H2 Receptor Antagonists. 2. Synthesis and Pharmacological Activities of N-Sulfamoyl and N-Sulfonyl Amidine Derivatives

Article abstract of DOI:10.1021/jm00393a018

A series of N-sulfamoyl and N-sulfonyl amidines have been prepared and tested in vitro for H₂ antihistamine activity on quinea pig atrium.In addition, several selected compounds were assessed as inhibitors of gastric acid secretion induced by histamine in anesthetized dogs.Structure-activity relationship studies showed that those compounds containing 2-<(diaminomethylene)amino>thiazole exhibited potent H₂-receptor antagonist activity.Introduction of alkyl or aralkyl groups to the terminal nitrogen of the sulfamoyl moiety reduced biological activities.Sulfamoyl amidines were more potent in both tests than sulfonyl amidines.Of these compounds, 3-<<<2-<(diaminomethylene)amino>-4-thiazolyl>methyl>thio>-N²-sulfamoylpropionamide (2e, famotidine) showed extremely high potency in both assays and was selected for clinical trials as an antiulcer agent.Acid-catalyzed hydrolysis of famotidine gave the sulfamoyl amide 6 at room temperature and the carboxylic acid 7 at elevated temperatures. 15 N NMR spectrum showed that famotidine in solution existed in only one of several possible tautomers derived from the amidine and the guanidine moieties.Nitrosation of famotidine was performed under mild condition and proved to occur on the 5-position of the thiazole ring.