A number of 3-alkyl analogues of the experimental antitumor drug mitozolomide [8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one] have been screened against murine tumors in vivo. Only the compounds with a 3-methyl- or 3-bromoethyl group possessed significant antitumor activity against the TLX5 lymphoma. The 3-methyl analogue, 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045), was investigated further and found to possess good activity, when administered i.p., against the L1210 and P388 leukemias, the M5076 reticulum cell sarcoma, B16 melanoma, and ADJ/PC6A plasmacytoma. The drug was also active when administered p.o. to mice bearing the L1210 leukemia. A daily for 5 days schedule of 100 mg/kg CCRG 81045 produced increases of survival time of treated animals compared to controls of 176 and >235% against the P388 and L1210 leukemias, respectively. In the female C57BL × DBA/2 F1 mouse the 10% lethal dose was 125 mg/kg daily for 5 days. CCRG 81045 was found to undergo mild alkaline hydrolysis and ring fission to form the linear triazene 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide, which is the putative metabolite formed upon metabolic activation of the antitumor drug dacarbazine [5-(3,3-dimethyltriazen-1-yl)imidazole-4-carboxamide]. The half-life of CCRG 81045 at 37°C in 0.2 m phosphate buffer (pH 7.4) was 1.24 h, whereas that of 5-(3-methyltriazen-1-yl)imidazole-4-carbox-amide at 25°C was reported to be 8 min (F. H. Shealy and C. A. Krauth, J. Med. Chem., 9: 34–37, 1966). The half-life of CCRG 81045 in human plasma in vitro at 37°C was 0.42 h. Pharmacokinetic experiments conducted in BALB/c mice produced plasma profiles of CCRG 81045, administered i.p. or p.o., which showed a rapid absorption phase, elimination half-lives of 1.13 h (i.p.) and 1.29 h (p.o.), and a bioavailability of 0.98.

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Part 13 of the series “Antitumor Imidazotetrazines.” Part 12 is Ref. 1. Supported by the Cancer Research Campaign, United Kingdom, Grant SP 1518, and in collaboration with May and Baker, Ltd., and Rhone Poulenc Santé.

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