Synthesis of 2-, 4- and 5-(2-alkylcarbamoyl-1-methylvinyl)-7-alkyloxybenzo[b]furans and their leukotriene B4 receptor antagonistic activity

Kumiko Ando; Eriko Tsuji; Yuko Ando; Jun-ichi Kunitomo; Reina Kobayashi; Takehiko Yokomizo; Takao Shimizu; Masayuki Yamashita; Shunsaku Ohta; Takeshi Nabe; Shigekatsu Kohno; Yoshitaka Ohishi

doi:10.1039/B503615A

Synthesis of 2-, 4- and 5-(2-alkylcarbamoyl-1-methylvinyl)-7-alkyloxybenzo[b]furans and their leukotriene B₄ receptor antagonistic activity†‡

Kumiko Ando,^a Eriko Tsuji,^a Yuko Ando,^a Jun-ichi Kunitomo,^a Reina Kobayashi,^b Takehiko Yokomizo,^bc Takao Shimizu,^b Masayuki Yamashita,^d Shunsaku Ohta,^d Takeshi Nabe,^d Shigekatsu Kohno^d and Yoshitaka Ohishi*^a

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* Corresponding authors

^a School of Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien Kyuban-cho, Nishinomiya 663-8179, Japan
E-mail: yohishi@mwu.mukogawa-u.ac.jp
Fax: +798 41 2792
Tel: +798 45 9953

^b Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, Japan

^c PRESTO, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-0033, Japan

^d Kyoto Pharmaceutical University, Misasagi, Yamashinaku, Kyoto 607-8412, Japan

Abstract

Variable benzo[b]furan derivatives having (E)- and (Z)-2-alkylcarbamoyl-1-methylvinyl groups at the 2-, 4- and 5-positions and a carboxylpropoxy or (1-phenyl)ethoxy group at the 7-position were prepared to find novel and selective leukotriene B₄ (LTB₄) receptor antagonists. (E)-2-(2-Diethylcarbamoyl-1-methylvinyl)-7-(1-phenylethoxy)benzo[b]furan (4v) showed selective inhibition to the human BLT₂ receptor (hBLT₂). On the other hand, (E)-2-acetyl-4-(2-diethylcarbamoyl-1-methylvinyl)-7-(1-phenylethoxy)benzo[b]furan (7v) inhibited both human BLT₁ receptor (hBLT₁) and hBLT₂. The (E)-2-(2-diethylcarbamoyl-1-methylvinyl) group lay on approximately the same plane as the benzo[b]furan ring, whereas the (E)-4-(2-diethylcarbamoyl-1-methylvinyl) group had the torsion angle (45.7°) from the benzo[b]furan ring plane. However, the (Z)-(2-alkylcarbamoyl-1-methylvinyl)benzo[b]furans were inactive. The inhibitory activity depended on the conformation of the 2-diethylcarbamoyl-1-methylvinyl group.

Organic & Biomolecular Chemistry

Synthesis of 2-, 4- and 5-(2-alkylcarbamoyl-1-methylvinyl)-7-alkyloxybenzo[b]furans and their leukotriene B₄ receptor antagonistic activity†‡

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Synthesis of 2-, 4- and 5-(2-alkylcarbamoyl-1-methylvinyl)-7-alkyloxybenzo[b]furans and their leukotriene B₄ receptor antagonistic activity

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Organic & Biomolecular Chemistry