Preparation of 2-Amino-4(3H)-oxopyrimido[5,4-b][l,4]thiazines (5-Thiapterins¹) and Their Evaluation as Cofactors for Phenylalanine Hydroxylase

Reaction of diethyl chloromalonate with β-mercapto amines, 9, gave l,4-thiazin-3-ones, 10, which were alkylated exclusively at the lactam oxygen with triethyloxonium tetrafluoroborate and subsequently condensed with guanidine to give the first reported 5-thiapterins, 8. Oxidation of 8 with m-chloroperoxybenzoic acid gave the S-oxides, 12. Both 8 and 12 were found to be good inhibitors of rat liver phenylalanine hydroxylase competitive with 6-methyltetrahydropterin, with 8 exhibiting lower K₁'s than the corresponding 12. The 8-thiapterin 4 was a much poorer inhibitor.