A new series of antiallergic agents. I. Synthesis and activity of 11-(2-aminoethyl)thio-6,11-dihydrodibenz[b,e]oxepin derivatives.
A new series of 11-substituted 6,11-dihydrodibenz[b,e]oxepin derivatives was synthesized and evaluated for antiallergic activity. Convenient methods for the preparation of sulfides from alcohols were developed. Structure-activity relationships are described. Compound 7, 11-[2-(dimethylamin)ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylic acid hydrochloride, was the most potent in the rat passive cutaneous anaphylaxis test (ED50 = 0.92 mg/kg p.o.). It had a potent inhibitory effect on anaphylactic bronchoconstriction in guinea pigs (ED50 = 0.029 mg/kg p.o.) and H1 receptor antagonistic effect (Ki = 14 nM) with few central nervous system side effects. Additionally, an antagonistic effect against prostaglandin D2-induced contraction of isolated guinea pig trachea (pA2 = 5.73) was an attractive mechanism of action of the new antiallergic agent. Compound 7 was selected for further evaluation as KW-4994.
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
E
E
Ohshima
T
T
Kumazawa
H
H
Takizawa
H
H
Harakawa
H
H
Sato
H
H
Obase
Y
Y
Oiji
A
A
Ishii
H
H
Ishii
K
K
Ohmori
D000818:Animals; D001584:Benzoxepins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D016084:Bronchoconstriction / Q000187:drug effects; D003342:Corpus Striatum / Q000378:metabolism; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D006968:Hypersensitivity, Delayed / Q000188:drug therapy; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011950:Receptors, Cholinergic / Q000378:metabolism; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D001584:Benzoxepins; D006634:Histamine H1 Antagonists; D011950:Receptors, Cholinergic