Isoquinolines. 5. Synthesis and antiarrhythmic activity of benzylisoquinoline derivatives.
The synthesis of a series of benzylisoquinolines 2-9 containing aminoacetamide side chains is described. The method involved reduction of the appropriately substituted nitrobenzylisoquinolines followed by acylation to the chloroacylamide derivatives. Amination with the appropriate amine yielded the desires secondary and tertiary amines. The primary amines were prepared via the phthalimides. Two acetanilides 14 and 15 are also described and compared with the benzylisoquinoline derivatives. All compounds were evaluated for their ability to protect against chloroform-induced ventricular fibrillation in mice. The active compounds 6 and 7 were tested for their effect against ventricular arrhythmias in dogs with myocardial infarction. All compounds with the exception of 5 and 12 exhibited some antiarrhythmic effect. The most potent compound, 1-[2-(2-ethylaminoacetyl)amino-3,4-dimethoxybenzyl]isoquinoline (7), showed greater antiarrhythmic potency, was considerably less toxic than lidocaine, and is a candidate for further evaluation.
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis*; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000517:prevention & control; D002725:Chloroform; D004285:Dogs; D005260:Female; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D051379:Mice; D009203:Myocardial Infarction / Q000150:complications; D013329:Structure-Activity Relationship; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000517:prevention & control
D000889:Anti-Arrhythmia Agents; D007546:Isoquinolines; D002725:Chloroform