Novel prodrug approach for tertiary amines: Synthesis and preliminary evaluation of N-phosphonooxymethyl prodrugs

Jeffrey P. Krise, Jan Zygmunt, Gunda I. Georg, Valentino J. Stella

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44 Scopus citations

Abstract

The synthesis and preliminary evaluation of a novel prodrug approach for improving the water solubility of drugs containing a tertiary amine group are reported. The prodrug synthesis involves a nucleophilic substitution reaction between the parent tertiary amine and a novel derivatizing reagent, di-tert- butyl chloromethyl phosphate, resulting in formation of the quaternary salt. The tertiary butyl groups are easily removed under acidic conditions with trifluoroacetic acid giving the N-phosphonooxymethyl prodrug in the free phosphoric acid form, which can subsequently be converted to the desired salt form. The synthesis was successfully applied to a model compound (quinuclidine) and to three tertiary amine-containing drugs (cinnarizine, loxapine, and amiodarone). The prodrugs were designed to undergo a two-step bioreversion process. The first step was an enzyme-catalyzed rate-determining dephosphorylation followed by spontaneous chemical breakdown of the N- hydroxymethyl intermediate to give the parent drug. Selected prodrugs were shown to be substrates for alkaline phosphatase in vitro. A preliminary in vivo study confirmed the ability of the cinnarizine prodrug to be rapidly and completely converted to cinnarizine in a beagle dog following iv administration.

Original languageEnglish (US)
Pages (from-to)3094-3100
Number of pages7
JournalJournal of Medicinal Chemistry
Volume42
Issue number16
DOIs
StatePublished - Aug 12 1999

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