A New Series of Antiallergic Agents. I. Synthesis and Activity of 11-(2-Aminoethyl)thio-6, 11-dihydrodibenz[b, e]oxepin Derivatives

• Published in: Chemical & pharmaceutical bulletin Vol. 39; no. 10; pp. 2724 - 2728
• Main Authors: OHSHIMA, Etsuo, KUMAZAWA, Toshiaki, TAKIZAWA, Hiroshi, HARAKAWA, Hiroyuki, SATO, Hideyuki, OBASE, Hiroyuki, OIJI, Yoshimasa, ISHII, Akio, ISHII, Hidee, OHMORI, Kenji
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 1991
• Subjects: 6, 11-dihydrodibenz[b, e]oxepin; Animals; anti-passive cutaneous anaphylaxis activity; antiallergic agent; antiasthmatic agent; Benzoxepins - chemical synthesis; Benzoxepins - pharmacology; Benzoxepins - therapeutic use; Bronchoconstriction - drug effects; Corpus Striatum - metabolism; Guinea Pigs; H1-antihistaminic activity; Histamine H1 Antagonists - chemical synthesis; Histamine H1 Antagonists - pharmacology; Histamine H1 Antagonists - therapeutic use; Hypersensitivity, Delayed - drug therapy; In Vitro Techniques; Male; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; prostagrandin D2; receptor antagonist; Receptors, Cholinergic - metabolism; Structure-Activity Relationship; Trachea - drug effects; Trachea - physiology
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.39.2724

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-(dimethylamino)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/lg 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 prostagrandin 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.