Preparation of Benzo[<i>b</i>]furans Having Five-Membered Heterocycles at the 2-Position and 2-(4-Alkylcarbamoylbuta-1,3-dienyl)benzo[<i>b</i>]furans, and Their Cysteinyl Leukotriene Receptor (cysLT1, cysLT2) Inhibitory Activity

Abstract

1-5) CysLTs mediate their effects through two different receptors, cysLT1 and cysLT2. 6) CysLT1 selective antagonists, such as pranlukast, montelukast and zafirlukast, have been shown to be clinically beneficial against chronic asthma. However, the synthesis of cysLT1 and/or cysLT2 antagonist still remains challenging. BAY u9773 was reported to be a dual cysLT1 and cysLT2 antagonist and a partial agonist of cysLT2.7,8) DUO-LT was also shown to be a dual antagonist (Fig. 1). 4) However, no selective cysLT2 antagonist has yet been developed for clinical applications. Recently, increased expression of cysLT2 receptor has been reported in colon cancer 9) and myocardial ischemia-reperfusion injury.10) The development of a dual antagonist and/or selective cysLT2 antagonist should be of great therapeutic value.In previous papers, we reported the preparation of sev-furan derivatives (A) and their cysLT1 and cysLT2 inhibitory activities 11,12) (Fig. 2). In our current work on leukotriene, we found that (E)-(2-diethylcarbamoyl-1-methylvinyl)-benzo [b] furans (B) showed potent leukotoriene B 4 (LTB 4 ) inhibitory activity, 13,14) and that compound (C) showed more potent LTB 4 inhibitory activity than compounds B. 15,16) In this time, in order to increase the inhibitory activity of the cycLTs receptor, acidic and amide moieties were introduced to the benzo [b] furan skeleton on the compound D on the basis of the structure of the compounds A and characteristic cysLTs molecular structures (Fig. 3). In addition, 2-(4-alkylcarbamoylbuta-1,3-dienyl) benzo [b] furans (E) having a wide range of conjugated systems were also prepared. In our design of compounds D and E, the structure of LTC 4 could be divided into the lipophilic, acidic and amide moieties. In the design of compound D, the benzo[b] furan ring having a fivemembered heterocyclic ring at the 2-position, the 4-oxypropanoic acid and the amide group on the heterocycle could be considered to correspond to the lipophilic, acidic and amide moieties in LTC 4 , respectively. Compound E was designed in the same manner as compound D, as shown in Fig. 3. Here Note * To whom correspondence should be addressed. e-mail: ikuo_k@mukogawa-u.ac.jp; nishide@mukogawa-u.ac.jp; ymohishi@kcc.zaq.ne.jp (1) 17,18) were treated with 2 eq of POCl 3 in N,N-dimethylformamide to give 2-(1-chloro-2-formylvinyl)-benzo [b] furans (2), 19,20) of which the stereochemistry of the (Z)-olefin is discussed below. Aldehydes (2) were converted to 2-(1-chloro-2-cyanovinyl) benzo [b] furans (3a, b) in two steps. 21)Cleavage of the methyl ether of 3b by treatment with BBr 3 afforded the 7-hydroxyl compound (3c) (Chart 1).Preparation of 2-Thienylbenzo[b] furans (4-6) Thiophene ring formation by treatment of 3 with ethyl thioglyco late proceeded smoothly to give 2-(3-amino-2-ethoxycarbonylthiophen-5-yl) benzo [b] furans (4a-c).21,22) The 7-hydroxyl compound (4c) was treated with several alkyl halides to afford the corresponding 7-alkyloxy-2-thienylbenzo[b]-furans (4d-e). Acylation of the 3-aminothiophene co...

Discovery of Gemilukast (ONO-6950), a Dual CysLT1 and CysLT2 Antagonist As a Therapeutic Agent for Asthma

“…As shown in Figure , two potent CysLT 2 selective antagonists have been reported. , However, there are no reports of effective dual antagonists. − …”

Discovery of Highly Potent Dual CysLT1 and CysLT2 Antagonist

“…HAMI3379 and BayCysLT 2 (Figure ) were reported as potent CysLT 2 selective antagonists, and with these compounds, the cardiac effects of CysLTs were shown to be predominantly mediated by the CysLT 2 receptor. , BAY-u9773 was reported as a dual CysLT 1 and CysLT 2 antagonist and a partial agonist of CysLT 2 (Figure ). , Ohishi and Nishide reported dual CysLT 1 and CysLT 2 antagonists. However, their reported dual CysLT 1 and CysLT 2 antagonists showed weak antagonist activities for both receptors (Figure ). − So far, a potent dual CysLT 1 and CysLT 2 antagonist has not yet been identified.…”