Studies on antiulcer agents. III. Plausible mechanism of antisecretory action of ethyl 2[(1H-benzimadazol-2-yl)sulfinylmethyl]-4-dimethylamino- 5-pyrimidinecarboxylate, an H+/K(+)-ATPase inhibitor, based on its reaction with thiols.

Abstract

To explore the mechanism of the gastric antisecretion activity of ethyl 2-[(1H-benzimidazol-2-yl)sulfinylmethyl]- 4-dimethylamino-5-pyrimidinecarboxylate (5), a potential H+/K(+)-ATPase inhibitor, in the acid compartment of parietal cells, its reaction with some alkylthiols in the presence of hydrochloric acid was investigated. Upon treatment with 2-mercaptoethanol under acidic conditions, 5 gave a characteristic 1:2 adduct, ethyl 4-[2-(2-hydroxyethyldithio)- 1-(2-hydroxyethylthio)ethylidenamino]pyrimido[1,2-a]benzimid azole-3- carboxylate (6), instead of providing a disulfide of type 3, 2-(2-alkyldithiomethylpyridino)benzimidazolide, the product predicted to be formed according to the reaction mechanism of common H+/K(+)-ATPase inhibitors, such as omeprazole or lansoprazole, with mercaptans. With a large excess of 2-mercaptoethanol, 5 provided 2-(2-hydroxyethylthio)-1H-benzimidazole (8) and ethyl 4-dimethylamino-2-(2-hydroxyethyldithio)-5-pyrimidinecarboxylat e (9) as well as 6. The transformation mechanisms and their implications are discussed.