Goro Tsukamoto

Studies on Prodrugs. VI. Preparation and Characterization of (5-Substituted 2-Oxo-1, 3-dioxol-4-yl) methyl Esters of Mecillinam

Mecillinam is a unique penicillin derivative which exhibits strong antimicrobial activities against Escherichia coli and other gram-negative bacilli.1) As it is not absorbed orally,2) its sodium salt is used parenterally and two of its esters, namely pivmecillinam3) and bacmecillinam4) are clinically used as oral prodrugs mainly for urinary tract infections. We have been developing the (5-substituted 2-oxo-1,3-dioxo1-4-yl)methyl group as a new, useful pro-moiety, and the effectiveness of the prodrugs of ampicillie and norfloxacie has been reported recently. As an extension of this prodrug study we prepared some new mecillinam (5-substituted 2-oxo-1,3-dioxol-4-yl)methyl esters and examined their oral absorbabilities. The *present paper describes the preparation and characterization of these mecillinam esters.

[29] Oxidation products of thiamine derivatives

Publisher Summary The chemical oxidation of thiol-form thiamine derivatives makes it clear that various derivatives, which are easily converted to thiamine in vivo, provide thiaminic acid as a final product. It is confirmed that thiamine alkyl sulfides, which are hard to revert to thiamine in vivo, afford the corresponding sulfoxides and sulfones. Hypothiaminic acid as an intermediate in the oxidation is synthesized from thiamine disulfide monosulfoxide, the formation of which is the first step in the oxidation of thiamine disulfide. The monosulfoxide and hypothiaminic ester are biologically active. However, these hypothiaminic and thiaminic acids, the toxicity of which is extremely low, have neither thiamine nor antithiamine activity but have a degree of analgesic and antiinflammatory effect similar to that of easily absorbable thiamine derivatives. Although no evidence has been obtained in support of the formation of these oxidation products as metabolites, it has been assumed that their formation may occur as with the metabolic reactions of cysteine and cystine.