Nitrogen Mustard amine

Some hydantoias are very useful carriers of the nitrogen mustard moiety bis (P-chloroethyl)amine, and are useful ia several tumors and multiagent therapy regimens (128,129). Besides that, some 3-(2-chloro-ethyl)hydantoiQS (32) (130) and oxyranyLmethyUiydantoias, eg,... 

The adventitious discovery of the antitumor action of the nitrogen mustard poison war gases led to intensive investigation of the mode of action of these compounds. In brief, it has been fairly well established that these agents owe their effect to the presence of the highly reactive bis(2-chloroethyl)amine group. The cytotoxic activity of... 

O. M. Friedman and E. Boger, Colorimetric estimation of nitrogen mustards in aqueous media. Hydrolytic behavior of bis(2-chloroethyl)amine, nor-HN2. Analytical Chemistry, 1961,33,906-910. 

In an analogous manner, reaction of 2,3-dichloroaniline (77-1) with nitrogen mustard gives the arylpiperazine (77-2). The remaining amine is then alkylated with 4-chlorobromobutane (77-3). Alkylation of the alkoxide from the hydroxycar-bostyril (77-4) affords the antipsychotic agent aripiprazole (77-5) [78]. 

Many aziridines form picrates and other salts which are stable in the crystalline state. - 4 Attempts to rocrystallize such compounds frequently result in decomposition. The quaternary azjridinium salts (XLII) are somewhat more stable, and have been much studied in connexion with the reaction of the jU-chloroalkyl tertiary amines ( nitrogen mustards ). 

Caution. The free amine is related to nitrogen mustards and must be handled carefully in an efficient hood. 

Cyclophosphamide (6.31) is a nitrogen mustard used for cancer treatment (Scheme 6.9). In the body, cyclophosphamide is oxidized to aminal 6.32. Compound 6.32 opens and loses acrolein to form phosphoramide mustard (6.33). Structure 6.33 is a strong bis-electrophile and reacts readily with nucleophiles. In DNA, the nucleophile tends to be N7 of guanine, which is oriented outward into the major groove (Figure 6.6). By reacting twice, 6.33 crosslinks DNA either within the same strand (intrastrand) or across the double helix (interstrand).16... 

Chemically, it is a bis(2-chloroethyl)amine (a nitrogen mustard), and its biological activity is related to the ability to function as an alkylating -gent in physiological conditions. 

Melphalan and the racemic analog have been prepared by two general routes (Scheme I). In Approach (A) the amino acid function is protected, and the nitrogen mustard moiety is prepared by conventional methods from aromatic nitro-derivatives. Thus, the ethyl ester of N-phthaloyl-phenylalanine was nitrated and reduced catalytically to amine I. Compound I was reacted with ethylene oxide to form the corresponding bis(2-hydroxyethyl)amino derivative II, which was then treated with phosphorus oxychloride or thionyl chloride. The blocking groups were removed by acidic hydrolysis. Melphalan was precipitated by addition of sodium acetate and was recrystallized from methanol. No racemization was detected [10,28—30]. The hydrochloride was obtained in pure form from the final hydrolysis mixture by partial neutralization to pH 0.5 [31]. Variants of this approach, used for the preparation of the racemic compound, followed the same route via the a-acylamino-a-p-aminobenzyl malonic ester III [10,28—30,32,33] or the hydantoin IV [12]. 

A large number of medications are amines, and a few examples are shown in Figure 11.29. It is interesting to note that mechlorethamine, one of the first anticancer chemotherapy drugs, belongs to a class of compounds known as nitrogen mustards, the same class of compounds used in chemical warfare during World War I. 

The Mannich reaction of various 3(2Jy)-pyridazinones with 2,2 -dichlorodiethylamine was investigated. In few cases the expected nitrogen-mustard derivatives were obtained, but in most cases iV -hydroxymethyl derivatives were isolated. With other amines the corresponding N-Mannich bases were formed in good yields. Reaction with 4(l I)-pyridazinones was also investigated. 

Nitrogen mustards include HNl [bis(2-chloroethyl) ethylamine], HN2 (2,2 -dichloro-V-methyldiethylamine), and HN3 [tris(2-chloroethyl)amine hydrochloride]. As will be discussed later, some of these found application in therapeutic arenas rather than in warfare. 

Nitrogen mustards are tertiary hw(2-chloroethyl)amines with vesicant activity (NDRC, 1946). AH are active alkylating agents. The nomenclature, chemical and physical properties of HNl, HN2, and HN3 are summarized in Tables 8.3 and 8.4. Due to their toxicity and various... 

Contractor, S.F. (1963). Protection against nitrogen mustard hy cysteine and related substances, investigated using [3H] methyl-DI-(2-chloroethyl) amine. Biochem. Pharmacol. 12(8) 821-32. 

Goodman, L.S., Wintrobe, M.M., Dameshek, W., Goodman, M.J., Gilman, A., McLennan, M.T. (1984). Landmark article Sept. 21, 1946 nitrogen mustard therapy. Use of methyl-bis(beta-chloroethyl)amine hydrochloride and tris(beta-chloroethyl)-amine hydrochloride for Hodgkin s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. JAMA 251 2255-61. 

EMBICHIN ENT 25,294 HN2 MBA MECHLORETHAMINE N-METHYL-BIS-CHLORAETHYLAMIN (GERMAN) METHYLBIS(P-CHLOROETHYL)AMINE N-METHYL-BIS(p-CHLOROETHYL)AMINE N-METHYL-BIS(2-CHLOROETHYL)AMINE (MAK) N-METHYL-2,2 -DICHLORODIETHYLAMINE METHYLDI(2-CHLOROETHYL)AMINE N-METHYL-LOST MUSTARGEN MUSTINE MUTAGEN NITROGEN MUSTARD N-LOST (GERMAN) NSC-762 TL 146... 

SYNS 2,2 -DICHLORO-N-METH [ LDIETHYLAi IINE-N-OXIDE DIETHYLAMINE, 2,2 -DICHLORO-N-METH-YL-, OXIDE HN2 AxMINE OXIDE HN2 OXIDE MUSTARD xMBAO MECHLORETHAMINE OXIDE METHYL-BIS(P-CHLOROETHYL)Ai nNE OXIDE METHYLBIS(P-CHLOROETHYL)AMINE N-OXIDE N-METH [ L-DI-2-CHLOROETHYL. MI E-N-OXIDE MITOMEN MITOMIN NITROGEN MUSTARD OXIDE NITROGEN MUSTARD-N-OXIDE NTTROMIN NMO N-OXYD-LOST N-OXYD-xMUSTARD NSC-10107 OXY-NH2... 

HN-3 Tris(2-chloroethyl)amine 2-Chloro-N,N-bis(2-chloroethyl)ethanamine Trichlorotriethyla-mine Nitrogen mustard-3 Mechlorethamine Mustargen... 

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