Novel potassium channel activators. III. Synthesis and pharmacological evaluation of 3,4-dihydro-2H-1,4-benzoxazine derivatives: modification at the 2 position.
A new series of 3,4-dihydro-2H-1,4-benzoxazine derivatives, where various substituents were introduced into one of the geminal dimethyl groups at the 2 position, were synthesized and their potassium channel-activating activity was evaluated. Introduction of a hydroxyl group, as in compound 5, resulted in good solubility in water and a long duration of action compared with the parent compound 1. Introduction of a nitrato group, as in compound 8, produced typical nitrate activity such as exhibited by nitroglycerine in addition to potassium channel-activating activity. X-ray structural analysis of compound 5 showed that the sum of the bond angles around the N atom at the 4 position was 357.8 degrees, suggesting that the N atom had an approximately sp2-like planar bond configuration.
Matsumoto
Y
Y
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
Uchida
A
A
Nakahara
H
H
Yanagisawa
I
I
Shibanuma
T
T
Nohira
H
H
D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects; D018360:Crystallography, X-Ray; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D005996:Nitroglycerin / Q000494:pharmacology; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists*; D011817:Rabbits; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology
D010078:Oxazines; D015221:Potassium Channels; D014665:Vasodilator Agents; D005996:Nitroglycerin