- 著者
- 熊沢 利昭 大島 悦男 原川 洋行 佐藤 秀幸 小場瀬 宏之 生地 由昌 石井 昭男 石井 秀衛 大森 健守
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.39, no.10, pp.2729-2733, 1991-10-25 (Released:2008-03-31)
- 参考文献数
- 14
- 被引用文献数
- 2 4
New methods for the preparation of multi-functionallized-6, 11-dihydrodibenz[b, e]oxepins were developed. The structural requirements of KW-4994 (1), a promising orally active antiallergic agent, were defined. A carboxyl group at C-2 was critical for enhanced antiallergic of 1. The introduction of bromine atom at C-9 of 1 could elongate the duration of the action of the parent. Antiplatelet acetivity, a new pharmacological property of this series of compounds, was observed in one of the derivatives of 1.
- 著者
- 大島 悦男 熊沢 利昭 滝沢 博 原川 洋行 佐藤 秀幸 小場瀬 宏之 生地 由昌 石井 昭男 石井 秀衛 大森 健守
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.39, no.10, pp.2724-2728, 1991-10-25 (Released:2008-03-31)
- 参考文献数
- 28
- 被引用文献数
- 2 3
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.