Pro-drugs as drug delivery systems XX. Oxazolidines as potential pro-drug types for β-aminoalcohols,aldehydes or ketones

The kinetics of hydrolysis of oxazolidines derived from (-)-ephedrine or (+)- pseudoephedrine and benzaldehyde or salicylaldehyde was studied at 37°C to assess their suitability as pro-drug forms for β-aminoalcohols and carbonyl-containing compounds. The oxazolidines were found to undergo a facile and complete hydrolysis in the pH range 1–11. The oxazolidines derived from benzaldehyde showed bell-shaped pH-rate profiles with rate maxima occurring at pH 4–5.5. The oxazolidine from salicylaldehyde showed a sigmoidal pH-rate profile and was 100-fold more reactive than the corresponding benzaldehyde derivative at pH > 7. At pH 7.4 and 37°C half-lives of hydrolysis from 5s to 28 min were observed for the 3 oxazolidines studied. The oxazolidines are weaker bases than the parent β-aminoalcohols and are more lipophilic than these as determined by partition experiments in an octanol-phosphate buffer system. It is suggested that oxazolidines be considered as potentially useful pro-drug candidates for β-aminoalcohols or drugs containing carbonyl groups.