Bioreversible quaternary N-acyloxymethyl derivatives of the poorly soluble tertiary amine Lu 28-179--synthesis, pharmaceutical chemical characterization and bioavailability studies in dogs.

Quaternary prodrug types of poorly water-soluble tertiary amines have been shown to possess significantly enhanced solubilities as compared to the parent amine. In the present study, the N-acyloxymethylation approach to improve the aqueous solubility of Lu 28-179 a tertiary amine exhibiting an intrinsic solubility in the nanomolar range, have been investigated. The acetyl-, propanoyl-, butanoyl-, isobutanoyl- and pivaloyloxymethyl derivatives were isolated as chloride salts and the aqueous solubilities (S) far exceeded that of the parent tertiary amine (S(0)). S/S(0) ratios in the range 2-4 x 10(6) were found for the most soluble prodrugs. The prodrugs were reasonable stable to hydrolysis in aqueous buffer solutions (pH 0.1-7.4), but susceptible to undergo enzyme-mediated regeneration of Lu 28-179 after incubation in human plasma, simulated intestinal fluid and duodenum juice from pigs and dogs. Despite promising in vitro properties the prodrugs were unable to improve the oral bioavailability of Lu 28-179 as compared to that obtained after administration of a reference formulation of the parent drug in the dog.