The synthesis, in vitro reactivity, and evidence for formation in humans of 5-phenyl-1,3-oxazinane-2,4-dione, a metabolite of felbamate

Previously we have proposed and provided evidence for a metabolic scheme le ading to 3-carbamoyl-2-phenylpropionaldehyde from the antiepileptic drug fe lbamate. This aldehyde was found to undergo reversible cyclization to form the more stable cyclic carbamate 4-hydroxy-5-phenyl-tetrahydro-1,3-oxazin-2 -one or undergo elimination to form 2-phenylpropenal. The cyclic carbamate bears structural similarity to 4-hydroxycyclophosphamide and there is an in triguing parallelism between the pathway from the cyclic carbamate to 2-phe nylpropenal and the known pathway from 4-hydroxycyclophosphamide to acrolei n. The similarity of these transformations led us to consider 5-phenyl-1,3- oxazinane-2,4-dione, which could arise from an oxidation of the cyclic carb amate, as a potential metabolite of felbamate. As the formation of this dio ne species may have both potential pharmacologic and toxicologic implicatio ns for felbamate therapy, we wished to study its reactivity. We have develo ped a synthesis of 5-phenyl-1,3-oxazinane-2,4-dione and evaluated its react ivity in vitro. This dione was found to undergo base-catalyzed decompositio n to three products, one of which is the major human metabolite of felbamat e, 3-carbamoyl-2-phenylpropionic acid. Furthermore, we have found evidence for the presence of the dione in human urine after felbamate treatment thro ugh the identification of its major in vitro decomposition product, 2-pheny lacrylamide 11.