Structural studies on bio-active compounds. Part 25. Synthesis and properties of potential metabolites of the diaminopyrimidine antifolate 2,4-diamino-5-(3-azido-4-chlorophenyl)-6-ethylpyrimidine (MZPES)

Abstract

A series of potential metabolites of the antitumour diaminopyrimidine m-azidopyrimethamine (2, MZP) has been prepared. Selective reduction of the nitro substituent of the nitropyrimidine 3-oxide 8, prepared by performic acid oxidation and diazotisation–azidation of the resulting amine N-oxide 10, afforded MZP 3-oxide 11. Direct oxidation of compound 2 with performic acid gave compound 11 and the isomeric 1-oxide 12, without azide decomposition. Sodium tungstate-catalysed oxidation of 2, 4-diamino-5-(3-amino-4-chlorophenyl)-6-ethylpyrimidine (3, MAP) furnished the corresponding nitropyrimidine 6 and its 3-oxide 8. Protection of the hydroxyl substituent of 6-(1-hydroxyethyl)pyrimethamine 13 as the heptafluorotolyl ether enabled successful aromatic nitration, but hydrogenolysis to afford 3 occurred upon reduction with hydrazine–Raney nickel.

Although the nitropyrimidine 3-oxide 8 retained inhibitory activity, other putative MZP metabolites were all markedly less active than the parent azide 2 as inhibitors of rat liver dihydrofolate reductase, consistent with the short biological half-life required for the antifolate in vivo.