RESEARCH ARTICLESEnamine Prodrugs

Five enamine derivatives of phenylpropanolamine were prepared in a search for novel amine prodrug derivatives. The compounds hydrolyzed in vitro at vastly different rates in phosphate buffer at pH 7.4, but the rates were not accelerated by dilute plasma. As expected, these enamines hydrolyzed faster as the pH was lowered. Two compounds were chosen for pharmacologic tests. Acid hydrolysis data suggested that Compound III would hydrolyze in vivo to give phenylpropanolamine but that Compound IV would not. Compound III was less toxic and also less potent in the pressor and antitussive tests than phenylpropanolamine (molar basis), giving further support to the suggestion that III was converted in vivo to phenylpropanolamine. In contrast, IV was more toxic than phenylpropanolamine (molar basis) but was not active in the pressor test. Thus, IV did not behave as a prodrug of phenylpropanolamine. While the authors did not pharmacologically evaluate Compounds I and II, which hydrolyze faster than III, it is predicted that they would have been more potent than III in these tests. Thus, it has been shown that enamines are potentially useful prodrug derivatives of amines.