Preparation and antitumor activities of 5-azaheterocyclic-2,4-diaminopyrimidines

A series of 6-alkyluracils 1-10 with azaheterocyclic substitutions at C-5 position were synthesized by condensation of 6-alkyl-5-bromouracils with relevant azaheterocycles with the catalysis of potassium fluoride. Chlorination and subsequent amination of the uracils afforded 6-alkyl-5-(1-azaheterocyclic)-2,4-diaminopyrimidines 21-30. Most of the diaminopyrimidines exhibited moderate to high cytotoxicity on L1210 murine leukemia cell line with 5-(azabicyclo[3,2,2]non-3-yl)-6-ethyl-2,4-diaminopyrimidine (30) the most active with ID₅₀ of 2.6 x 10^-9 M. This compound is unfortunately devoid of in vivo antitumor activity on mice bearing lymphocytic leukemia P388. Most of the diaminopyrimidines except compounds 22 and 24 exhibited moderate cytotoxic activity against human colon adenocarcinoma cell line with ID₅₀'s between 10^-6 to 10^-8 M.