L. Kosykhova, A. Palaima, Z. Stumbryavichyute
Oct 1, 2000
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Journal
Pharmaceutical Chemistry Journal
Abstract
Phosphonitrites attract the attention of researchers because of their broad spectrum of biological activity [1, 2]. In particular, a rather thorough investigation was devoted to a group of symmetric phosphoric and thiophosphoric acid triamides possessing antitumor and antileukemic properties [2 – 4]. The purpose of this study was to look for new agents possessing antitumor activity in a series of nonsymmetric phosphoric acid triamides (I – XII). The structures of these compounds contain cytoactive ethyleneimine and/or di(2-chloroethyl)amino groups and the residues of aminocyclohexane, cisor trans-4-aminocyclohexanecarboxylic acid ethyl esters, or other aliphatic and heterocyclic amines.Compounds I – XII were synthesized by sequential phosphorylation of the initial amines by phosphoric acid chloroanhydrides in the presence of hydrogen chloride acceptors. The initial reagents were N,N-dimethylamido-, N,N-di(2-chloroethyl)amido-, and N-ethyleneimidophosphoric acid dichloroanhydrides (RPOCl 2 ). Reactions of these substances with a twofold excess of aminocyclohexane or cis (trans )-4-aminocyclohexanecarboxylic acid ethyl ester yielded monochloroanhydrides of the corresponding diamidophosphoric acids. These reactions were conduced in anhydrous diethyl ether in the temperature interval from – 8 to 0°C; the excess amine was necessary for binding hydrogen chloride. In order to avoid unnecessary losses, the final monoanhydrides were not isolated from reaction mixtures and (upon separation of the initial amine hydrochlorides) immediately brought into reaction with the following amine (ethyleneimine, morpholine, monoethanolamine, or dimethylamine) in the same temperature interval. All the target triamides appear as crystalline compounds which are difficult to purify. We have selected conditions ensuring suppression of the reactions leading to the formation of symmetric triamides and providing for a maximum yield and purity of the target products I – XII. The proposed compositions and structures of the synthesized compounds I – XII were confirmed by data of elemental analyses and P and H NMR measurements. The assignment of signals in the H NMR spectra was based on their chemical shifts, multiplicity, and integral intensity. The chemical shifts observed in the P NMR spectra fall within the interval from 14.3 to 26.6 ppm, which is typical of compounds of this type.