Synthesis and antiarrhythmic activity of 5,11-dihydro[1]benzoxepino[3,4-b]pyridines.

Abstract

During further modification of the new antiulcer agent 5 (KW-5805), a 5,11-dihydro[1]benzoxepino[3,4-b]pyridine derivative, we found that some new derivatives had antiarrhythmic activity. So we continued synthesis and evaluation of a series of 5-substituted 5,11-dihydro[1]benzoxepino[3,4-b]pyridines for antiarrhythmic activity in chloroform-induced ventricular arrhythmias in mice and in ouabain-induced ventricular arrhythmias in dogs. In chloroform-induced ventricular arrhythmias, the 7-methoxy group played an important role in activity and the type of terminal side chain at position 5 had not obvious effect on potency. On the other hand, in ouabain-induced ventricular arrhythmias, the structure-activity relationship was highly specific and only four compounds, 9, 30, 34, and 35, were effective. Compound 9,5-[[2-(diethylamino)ethyl]amino]-7-methoxy-5,11-dihydro[1] benzoxepino[3,4-b]pyridine 1.5-fumarate, which exhibited low affinity for muscarinic acetylcholine receptors and a high ED100(mydriasis)/ED50(antiarrhythmic activity) ratio, was selected for further development and clinical evaluation as KW-3407. The synthesis and antiarrhythmic activity of optically active 9 is described. The order of potency of antiarrhythmic activity in ouabain-induced ventricular arrhythmias in dogs was (-)-9, (+/-)-9, and (+)-9.

• Authors: T Kumazawa, H Harakawa, H Obase, Y Oiji, M Nito, K Kubo, A Ishii, S Tomioka, Y Yamada
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 33 Issue 11 Pg. 3095-100 (Nov 1990) ISSN: 0022-2623 [Print] United States
• PMID: 2231611 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anti-Arrhythmia Agents
• Benzoxepins
• Pyridines
• Receptors, Muscarinic
• 5-((2-(diethylamino)ethyl)amino)-7-methoxy-5,11-dihydro(1)benzoxepino(3,4-b)pyridine
• Ouabain
• Chloroform

Topics

• Animals
• Anti-Arrhythmia Agents (chemical synthesis, chemistry, therapeutic use)
• Arrhythmias, Cardiac (chemically induced, drug therapy)
• Benzoxepins (chemical synthesis, chemistry, therapeutic use)
• Chemical Phenomena
• Chemistry
• Chloroform
• Dogs
• Female
• Heart Ventricles
• Male
• Mice
• Molecular Structure
• Ouabain
• Pyridines (chemical synthesis, chemistry, therapeutic use)
• Receptors, Muscarinic (metabolism)
• Structure-Activity Relationship