New antiarrhythmic agents. 3. Primary .beta.-amino anilides

• Published in: Journal of medicinal chemistry Vol. 22; no. 10; pp. 1182 - 1186
• Main Authors: Tenthorey, Paul A, DiRubio, Robert L, Feldman, Hal S, Takman, Bertil H, Byrnes, Eugene W, McMaster, Paul D
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-10-1979
• Subjects: Anilides - chemical synthesis; Anilides - pharmacology; Anilides - toxicity; Animals; Anti-Arrhythmia Agents - chemical synthesis; Atrial Fibrillation - prevention & control; Chloroform - toxicity; Coronary Vessels - physiology; Dogs; Mice
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00196a007

The synthesis and pharmacologic evaluation of primary beta-amino anilides, as well as comparisons with tocainide, lidocaine, and its beta homologue, are described. Substituted anilines were acylated with 3-bromoacyl chlorides and converted to the title compounds by direct amination or via 3-phthalimido anilides and subsequent hydrazinolysis. Alternatively, anilines were acylated with substituted acryloyl chlorides and the amines prepared by addition of ammonia to the double bond. The target compounds were evaluated for their ability to protect against chloroform-induced fibrillation in mice. All were found to have some antifibrillatory activity; several were more potent than tocainide, a compound in clinical trials as an oral antiarrhythmic drug. Four compounds were tested for their effects against ventricular arrhythmias in dogs with myocardial infarction. 3-Amino-2',6'-butyroxylidide (38) was found to be more potent and less CNS toxic than tocainide.