TUMOUR CHEMOTHERAPY Ⅸ.NITROGEN MUSTARDS OF PHOSPHORAMIDE,PHOSPHORAMIDE ESTER AND THIOESTER

Tris-(1-aziridinyl)-phosphine oxide(I, TEPA) and 2-bis-(2-chloroethyl)-amino-tetrahydro-1, 3, 2-oxazaphospholidine-2-oxide(Ⅲ, B-518) possess inhibitory action against a variety of animal tumours and have been used clinically. Recently, bis-(1-aziridinyl)-phosphinyl carbamic acid ethyl ester(Ⅱ, AB-100) was found to possess significant activity with low toxicity on experimental animal tumours. In order to examine the relationship between chemical structure and pharmacological activity, bis-(1-aziridinyl)-bis-(2-chloroethyl)-amino-phosphine oxide(Ⅳ), nitrogen mustards of cyclic phosphoramide ester and thioester (Ⅴ & Ⅵ) were then prepared. Compound Ⅳ, Ⅴ and Ⅵ were prepared by treating N, N-bis-(2-chloroethyl)-phosphoramide dichloride in anhydrous dioxane or benzene with the corresponding amino or mercapto-compounds in the presence of a base such as triethylamine. Compound Ⅳ (designated as AT-222) exhibited broad antitumour effecots on sarcoma 180, spindle cell sarcoma and lymphatic leukemia in mice as well as on Jensen sarcoma and fibrosarcoma in rat, and has been recommended for clinical trials.