肿瘤的化学治疗ⅩⅩⅫ.N-乙酰基-N-{3-[双-(β-氯乙基)-氨基]-6-甲基(或氢)-苯基}-甘氨酸的合成

从3-硝基-6-甲基-苯胺为原料经过六步反应合成了N-乙酰基-N-{3-双-(β-氯乙基)-氨基]-6-甲基-苯基}-甘氨酸(Ⅲ₂),并从硝基苯胺以制备Ⅲ_a相似的步骤合成N-乙酰基-N-{3-双-(β-氯乙基)-氨基]-苯基}-甘氨酸(Ⅲ_b)和N-乙酰基-N-{4-双-(β-氯乙基)-氨基]-苯基}-甘氨酸(Ⅲ_c).药理试验表明:化合物Ⅲ_a对小白鼠肉瘤-180有显著的抑制作用,但化合物Ⅲ_b和Ⅲ_c无明显作用.Ⅲ_a-c对体外组织培养的Hela瘤细胞都无抑制作用.

TUMOUR CHEMOTHERAPY SYNTHESES OF N-ACETYL-N-{3-[BIS-(β-CHLOROETHYL)-AMINO]-6-METHYL-PHENYL}-GLYCINE AND ITS DEMETHYL ANALOGUES

In a previous paper, it was reported by one of us that bis-(β-chloroethyl)-amino]- indole-2-carboxylic acids (I_a-c) were found to have pronounced antitumour activity. For the purpose of studying the relationships between chemical structures and antitumour acti- vities of I_a-c and also of searching for new antitumour agents, in the present paper, N- acetyl-N-{3-bis-(β-chloroethyl)-amino]-6-methyl-phenyl}-glycine (III_a) has been pre- pared. III_a may be considered as the ring-cleft product of the 6-bis-(β-chloroethyl)- amino]-indole-2-carboxylic acid (I_b) at the position a. Two demethyl analogues, N- acetyl-N- {3-bis-(β-chloroethyl)-amino] -phenyl}-glycine (III_b) and N-acetyl-N-{4-bis- (β-chloroethyl)-amino] -phenyl}-glycine (III_c) have also been prepared and they can also be regarded as the ring-cleft products at the positions a and b of I_a and I_b respectively. Compounds III_a-b were prepared by a six-step synthesis, the sequence of reactions is described in the Chinese text. The starting meterials of III_a-c employed were ethyl N-(nitro-phenyl)-glycinates (VI_a-c) which were conveniently prepared by the condensa- tion of the corresponding nitro-anilines and ethyl chloroacetate or ethyl bromoacetate in the presence of sodium carbonate and sodium iodide in dimethylformamide. VI_a-c were acylated with acetic anhydride to give VII_a-c, which were subjected to catalytic hydrogena- tion in the presence of Raney-Ni or Pd-C to give N-acetyl-N-(amino-phenyl)-glycinates (VIII_a-c). The latters were treated with a solution of ethylene oxide in dilute acetic acid to yield N-acetyl-N-bis-(β-hydroxyethyl)-amino-phenyl]-glycinates (IX_a-c) which afforded III_a-c on chlorination with phosphorus oxychloride, hydrolysis with 6 N hydro- chloric acid, and acetylation. Pharmacological studies showed that compound III_a possessed marked antitumour activity against Sarcoma-180, but neither III_b nor III_c showed any significant activity against the same tumour.