McMaster P D, Byrnes E W, Block A J, Tenthorey P A
J Med Chem. 1981 Jan;24(1):53-8. doi: 10.1021/jm00133a012.
The synthesis of aminoaceto-2',6'-xylidides substituted on the amide nitrogen with 2-(diethylamino)ethyl, 2-aminoethyl, 2-hydroxyethyl, and 2-ethoxyethyl groups is described. The 2-aminoethyl derivatives were prepared by treatment of N-(2-phthalimidoethyl)-2',6'-xylidine with chloroacetyl chloride, followed by treatment with either potassium phthalmide or diethylamine. Hydrazinolysis of the phthalimides liberated the free amines. The remaining target compounds were produced by alkylation of lidocaine or of 2-phthalimidoaceto-2',6'-xylidide with the appropriate halide and sodium hydride, followed by hydrazinolysis where necessary. All target compounds were evaluated for antiarrhythmic efficacy against chloroform-induced ventricular tachycardia, as well as for acute CNS toxicity in mice. Most of the target compounds were more potent than the corresponding secondary amides and had improved therapeutic margins toward CNS toxicity. The diamines N-(2-aminoethyl)-2-aminoaceto-2',6'-xylidide (13) and N-(2-aminoethyl)--2-(diethylamino)aceto-2',6'-xylidide (29) are especially promising in this respect. Several compounds were tested as spinal anesthetics.
描述了在酰胺氮上被2-(二乙氨基)乙基、2-氨基乙基、2-羟乙基和2-乙氧基乙基取代的氨基乙酰-2',6'-二甲苯胺的合成。2-氨基乙基衍生物是通过用氯乙酰氯处理N-(2-邻苯二甲酰亚胺基乙基)-2',6'-二甲苯胺，然后用邻苯二甲酸钾或二乙胺处理来制备的。邻苯二甲酰亚胺的肼解反应释放出游离胺。其余目标化合物是通过用适当的卤化物和氢化钠对利多卡因或2-邻苯二甲酰亚胺基乙酰-2',6'-二甲苯胺进行烷基化反应，必要时再进行肼解反应来制备的。对所有目标化合物进行了抗氯仿诱导的室性心动过速的抗心律失常疗效评估，以及对小鼠的急性中枢神经系统毒性评估。大多数目标化合物比相应的仲酰胺更有效，并且对中枢神经系统毒性的治疗指数有所提高。在这方面，二胺N-(2-氨基乙基)-2-氨基乙酰-2',6'-二甲苯胺(13)和N-(2-氨基乙基)-2-(二乙氨基)乙酰-2',6'-二甲苯胺(29)尤其有前景。几种化合物被测试用作脊髓麻醉剂。
