(Acyloxy)alkyl carbamates as novel bioreversible prodrugs for amines: increased permeation through biological membranes

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Abstract
(Acyloxy)alkyl carbamates of the type R1R2N.sbd.CO.sbd.O.sbd.CHR3.sbd.OCO.sbd.R4 are described as novel bioreversible prodrugs for primary and secondary amines. These were prepared either by a one-step reaction involving nucleophilic attack on p-nitrophenyl .alpha.-(acyloxy)alkyl carbonates with displacement of p-nitrophenol or by reaction of .alpha.-haloalkyl carbamates with silver or mercury salts of carboxylic acids. Enzymatic hydrolysis of the ester bond in these ester carbamates leads to a cascade reaction resulting in rapid regeneration of the parent amine. Permeability measurements of such nonionic derivatives of atenolol, betaxolol, pindolol, propranolol, and timolol through fuzzy rat skin and rabbit cornea mounted on diffusion cells showed that derivatization of the hydrophilic .beta.-blockers results in several-fold increase in permeation through these biological membranes. However, prodrug modification of the lipophilic .beta.-blockers leads to little advantage in permeability characteristics.