Synthesis and antiarrhythmic activity of 5,11-dihydro[1]benzoxepino[3,4-b]pyridines.
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.
Kumazawa
T
T
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Company Ltd., Shizuoka, Japan.
Harakawa
H
H
Obase
H
H
Oiji
Y
Y
Nito
M
M
Kubo
K
K
Ishii
A
A
Tomioka
S
S
Yamada
Y
Y
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy*; D001584:Benzoxepins / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D002725:Chloroform; D004285:Dogs; D005260:Female; D006352:Heart Ventricles; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010042:Ouabain; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D011976:Receptors, Muscarinic / Q000378:metabolism; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D001584:Benzoxepins; D011725:Pyridines; D011976:Receptors, Muscarinic; C066284:5-((2-(diethylamino)ethyl)amino)-7-methoxy-5,11-dihydro(1)benzoxepino(3,4-b)pyridine; D010042:Ouabain; D002725:Chloroform