New antiarrhythmic agents. 5. α-Aminoaceto-2,6-xylidides with functionalized amide alkyl substituents

Article abstract of 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 phthalimide or diethylamine. Hydrazinolysis of the phthalimides liberated the free amines. The remaining target compounds were produced by alkylation of lidocaine or 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',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.