ANTITUMOR IMIDAZOTETRAZINES .20. PREPARATION OF THE 8-ACID DERIVATIVE OF MITOZOLOMIDE AND ITS UTILITY IN THE PREPARATION OF ACTIVE ANTITUMOR AGENTS

The preparation of 3-(2-chloroethyl)-4-oxo-3H-imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid, a key derivative of mitozolomide in our exploration of the structure-activity relationships of this class of antitumor agents, is described. The facile conversion to the 8-carbonyl chloride gave a derivative that reacted preferentially with nucleophiles at the 8-position rather than at the reactive 4-oxo group, allowing the preparation of a wide range of ester, thioester, amide (including an amide derived from an amino acid), hydroxamic acid, hydrazide and sulfoximide, azide and diazoacetyl derivatives. The in vivo activity is presented of a range of these compounds against TLX5 lymphoma and L1210 leukemia cell lines. © 1990, American Chemical Society. All rights reserved.