Structural studies on bio-active compounds. Part 5. Synthesis and properties of 2,4-diaminopyrimidine dihydrofolate reductase inhibitors bearing lipophilic azido groups

Abstract

A series of 2,4-diamino-5-(azidoaryl)-6-alkylpyrimidines has been prepared. The azide (36)(MZP) can be reduced by thiol reagents to the corresponding amine (28) but reductive deazidation occurred when the series of azidophenyl derivatives was heated with hydrazine hydrate. Degradation of azide (36) in a trifluoroacetic acid–trifluoromethanesulphonic acid mixture at 0 °C affords a means of introducing the bulky trifluoromethylsulphonyloxy substituent into the hindered ortho-position of the 5-aryl substituent. The products formed from thermolysis and photolysis of the azide (36) and the planar analogue 2,4-diamino-6-azidoquinazoline (70) derive from the triplet nitrene reactive intermediates.

The azido compounds are potent inhibitors of rat liver dihydrofolate reductase although not as active as metoprin. The azide (36), as its ethanesulphonic acid salt, was selected for clinical trial on the basis of its ease of synthesis and suitable biological and pharmaceutical properties, and has a shorter biological half-life than compounds of comparable hydrophobicity.