Synthesis of 1-aldofosfamide-perhydrothiazines.

Aldofosfamide-perhydrothiazine derivatives are a new class of prodrugs which spontaneously, with half-life times of 2 to > 12 h hydrolyse to the corresponding aldophosphamide in aquous solution. Synthesis of 1-aldofosfamide-perhydrothiazine (N,N'-(2-chloroethyl)-phosphorodiamide-2-(2'-[4'-carboxy-1',3'- perhydrothiazinyl])-ethylester) and a derivative, in which one 2-chlorethyl group of the alkylating function is substituted by a mesyl-ethyl-group (N-(2-Chloroethyl)-N'-(methanesulphonylethyl)- phosphorodiamide-2-(2'-[4'-carboxy-1',3'-perhydro-thiazinyl] )-ethylester), is described.

Increased antitumour activity of mesyl-I-aldophosphamide-perhydrothiazine, in vivo but not in vitro, compared to I-aldophosphamide-perhydrothiazine.

When equitoxic dosages of ifosfamide and I-aldophosphamide-perhydrothiazine (IAP) were tested for antitumour activity in the P388 mouse leukaemia model, 80% long-term survival (for more than 100 days) was achieved with IAP whereas, in the ifosfamide group, all mice died from tumour growth within 60 days. Even better antitumour activity, compared with ifosfamide, was observed with an IAP derivative (SUM-IAP) in which one 2-chloroethyl group of the alkylating function is substituted by a mesylethyl group. Evaluation of tumour growth curves following treatment with IAP and SUM-IAP revealed the antitumour activity of SUM-IAP to be 10(4)-10(5) times higher than that of IAP.

Structure/activity studies with thiazolidinyl- and perhydrothiazinylphosphamide ester.

Structure/activity studies were carried out with thiazolidinyl- and perhydrothiazinylphosphamide ester, which differ in the structure of the phosphamide moiety and in the rate of spontaneous hydrolysis to activated oxazaphosphorines. Antitumour activity in mice with advanced P388 tumours growing subcutaneously was increased 30- to 40-fold when one 2-chloroethyl group in l-aldophosphamide-perhydrothiazine was substituted by a mesylethyl group.

Thiazolidinyl- and perhydrothiazinylphosphamidesters: toxicity and preliminary antitumour evaluation.

Aldophosphamide thiazolidine (NSC 613060) and aldophosphamide perhydrothiazine (NSC 612567), which hydrolyse spontaneously to 4-hydroxycyclophosphamide (4-OH-CP) in aqueous solution, were synthesised. These substances are prototypes of a new class of prodrugs for activated oxazaphosphorines. They were developed according to our hypothesis on the mechanism of action of oxazaphosphorine cytostatics.