New antiarrhythmic agents. 6. Quantitative structure-activity relationships of aminoxylidides

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Abstract
The synthesis and pharmacological evaluation of primary and tertiary aminoxylidides with the amino group in the 2-7 position of the acyl chain are described. 2,6-Xylidine was acylated with haloacyl halides and converted to the target compounds by direct amination or by the Gabriel procedure. 2,6-Xylidine was coupled with keto acids, and the ketoxylidides were converted to the amines by reductive amination. The target compounds were evaluated in mice both for antiarrhythmic efficacy against chloroform-induced tachycardia and CNS toxicity. Experimentally determined values of partition coefficients and pKa [negative log of the Ka] values were used for quantitative structure-activity analyses. While the antiarrhythmic activity could be described as a function of log P alone, the CNS toxicity was best described as a function of both log P and pKa. Antiarrhythmic potency can be increased by increasing lipophilicity, while the therapeutic index can be improved by increasing the pKa.