Comparative nitrosation of etintidine and cimetidine

Abstract

Etintidine (4), a new histamine H2-receptor antagonist, was compared with cimetidine (1) for susceptibility to in vitro nitrosation at pH 1 and pH 3. Each agent formed two mono-N-nitrosoguanidine derivatives: N-cyano-N′-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethyl}-N″-nitroso-N″-(2-propynyl)guanidine (5) and N-cyano-N′-{2-[5-methyl-1H-imidazol-4-yl)methylthio]ethyl}- N′-nitroso-N″-(2-propynyl)guanidine (6) from etintidine and N-cyano-N′-methyl-N″-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethyl}- N′-nitrosoguanidinc (2) and N-cyano-N′-methyl-N"-{2-[(5-methyl-1H-imidazol-4-yl)methyl-thio]ethyl}-N′-nitrosoguanidine (11) from cimetidine. The N-nitroso derivative 5 from etintidine cyclized to 2-cyanoimino-3-{2-((5-methyl-1H-imidazol-4-yl)methylthio]ethyl}-N″-methylene-1-nitroso-imidazoline (7) at neutral or basic pH's. Both agents were nitrosated less at pH 3 than at pH 1, and at both pH's nitrosation of etintidine was considerably less than that of cimetidine. At pH 1, with a nitrite concentration about 150–500 times that expected in fasting human gastric juice, formation of 5 and 6 from etintidine was barely detectable (each < 0.5%). Comments are made on the standard WHO conditions for investigating nitrosation of drugs.