addition of methyl group to the 4-position on the imidazole ring to favor the tautomer of thiaburimamide which binds better to the H2 receptor
These changes increased the bioavailability metiamide so that it is ten times more potent than burimamide in inhibiting histamine-stimulated release of gastric acid. The clinical trials that began in 1973 demonstrated the ability of metiamide to provide symptomatic relief for ulcerous patients by increasing healing rate of peptic ulcers. However, during these trials, an unacceptable number of patients dosed with metiamide developed agranulocytosis (decreased white blood cell count).
The nitro and cyano groups are sufficiently electronegative to reduce the pKa of the neighboring nitrogens to the same acidity of the thiourea group, hence preserving the activity of the drug in a physiological environment.
Reacting ethyl 2-chloroacetoacetate (1) with 2 molar equivalents of formamide (2) gives 4-carboethoxy-5-methylimidazole (3). Reduction of the carboxylic ester (3) with sodium in liquid ammonia via Birch reduction gives the corresponding alcohol (4). Reaction of that with cysteamine (mercaptoethylamine), as its hydrochloride, leads to intermediate 5. In the strongly acid medium, the amine is completely protonated; this allows the thiol to express its nucleophilicity without competition and the acid also activates the alcoholic function toward displacement. Finally, condensation of the amine with methyl isothiocyanate gives metiamide (6).
^Durant, G. J.; Emmett, J. C.; Ganellin, C. R.; Roe, A. M.; Slater, R. A. (1976). "Potential histamine H2-receptor antagonists. 3. Methylhistamines". Journal of Medicinal Chemistry. 19 (7): 923. doi:10.1021/jm00229a013. PMID7675.
^Durant, G. J.; Emmett, J. C.; Ganellin, C. R.; Miles, P. D.; Parsons, M. E.; Prain, H. D.; White, G. R. (1977). "Cyanoguanidine-thiourea equivalence in the development of the histamine H2-receptor antagonist, cimetidine". Journal of Medicinal Chemistry. 20 (7): 901. doi:10.1021/jm00217a007. PMID17751.