Novel potassium channel activators: synthesis and structure-activity relationship studies of 3,4-dihydro-2H-1,4-benzoxazine derivatives.
Strong potassium channel-activating effects were found among a series of novel 4-substituted 3,4-dihydro-2H-1,4-benzoxazine derivatives. The key step in preparation was the nucleophilic substitution of 3,4-dihydro-2H-1,4-benzoxazine (3) with activated halogenopyridines, such as halogenopyridine N-oxides (15a--c) and the borane adduct (15d) of 4-bromopyridine. Structure-activity relationship studies identified 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridin e-1-oxide (16a: YM934) as the optimal compound. This compound (16a) showed a more potent oral antihypertensive effect than cromakalim in conscious spontaneously hypertensive rats.
Matsumoto
Y
Y
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, Ibaraki, Japan.
Tsuzuki
R
R
Matsuhisa
A
A
Takayama
K
K
Yoden
T
T
Uchida
W
W
Asano
M
M
Fujita
S
S
Yanagisawa
I
I
Fujikura
T
T
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D010078:Oxazines; D015221:Potassium Channels