New applications of Imidazotetrazinone prodrugs. Synthesis and mechanistic investigation of novel imidazotetrazinones as prodrugs of aziridines and as traceless carriers for drug delivery to the central nervous system.

摘要

New imidazotetrazinones have been synthesised that possess features in their structuresudto release aziridinium ions upon ring opening. Unstable 2-aminoethylisocyanates wereudrequired in this preparation, which were synthesized with BOC-protection of the aminoudgroup to counteract the reactivity of the amine towards the isocyanate group in the caseudof aliphatic amines; in contrast, anilinoethylisocyanates were synthesized unprotected.udSubstituents with a range of electron-withdrawing and electron-releasing propertiesudwere introduced at the p-position of the aniline ring. A 13C-labelled study confirmed theudrelease of the aziridinium ion by these imidazotetrazinones in neutral pH bufferudsolution. Furthermore the kinetics of the hydrolysis in neutral aqueous solution of someudthese new tetrazines were similar to temozolomide, in addition to useful acid stability.udOther imidazotetrazinones were synthesised for the purpose of releasing alcohols andudphenols. Their synthesis was performed with a one-carbon linker between theudimidazotetrazinone 3-position and the alcohols or phenols to be released. The releaseudof alcohol and phenol through the hydrolysis of the intermediate diazonium ions to theudunstable hemiacetals that decomposed to the alcohol and phenol was confirmed by 1HudNMR. The kinetics of the hydrolysis of these tetrazines in neutral aqueous solutionudshowed a faster reaction rate compared with temozolomide (t1/2 = 0.53 and 0.36 hudcompared with temozolomide 1.4 h).