Antitumor imidazotetrazines. 20. Preparation of the 8-acid derivative of mitozolomide and its utility in the preparation of active antitumor agents

Abstract

The preparation of 3-(2-chlorethyl)-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.

Antitumor imidazotetrazines. 38. New 8-substituted derivatives of the imidazo[5,1-d]-1,2,3,5-tetrazines temozolomide and mitozolomide

“…Following water quench of the intermediate nitrilium species (12), the secondary amides (13) (Scheme 2) were formed. As expected the same amide (13a) was formed from 7a and 2-methyl-1-pentene (10a) or the isomeric 2-methyl-2-pentene.…”

“…A logical route to the 8-hydrazide analogues of temozolomide and mitozolomide, from the interaction of the 8-acid chlorides and hydrazine, was thwarted by facile hydrazinolysis of the tetrazine ring. 12 In the present work the 8-acid derivatives (15a, b) were coupled with t-butylcarbazate (t-BOC-NHNH 2 ) in the presence of benzotriazole-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) and triethylamine.…”

“…Surprisingly, catalytic hydrogenation of the N-nitroamide analogue of mitozolomide (1b; X = NHNO 2 ) (see Scheme 4), formed by nitration of mitozolomide in a nitric-sulphuric acid mixture, 12 did not produce the free base of hydrazide (18) …”

“…We have previously shown 12 that thermal degradation of the tetrazine ring preceeds Curtius rearrangement of the acylazide derivative (21) even in the low boiling anhydrous solvents acetone, chloroform, benzene or toluene, and no 23 was isolated. Attempted Lossen rearrangement of the hydroxamic acid (22) 12 in refluxing thionyl chloride was also unsuccessful.…”

“…We now report chemistries exploiting the acid stability of the tetrazine ring which have allowed us to access further novel C(8) modifications of imidazotetrazines (1). 12 However this route suffers the disadvantage that stoichiometric precision in the incorporation of the amine component is required to avoid base-induced degradation of the bicyclic nucleus. In the present work we have adapted the Ritter reaction (the electrophilic addition of olefins to nitriles under acidic conditions) to yield secondary amides after hydrolysis.…”