(2-ethyl-6-methoxybenzofuran-3-yl)(4-hydroxyphenyl)methanone | 871493-07-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (2-ethyl-6-methoxybenzofuran-3-yl)(4-hydroxyphenyl)methanone
• 英文别名: 2-ethyl-3-(4-hydroxybenzoyl)-6-methoxybenzofuran；2-ethyl-6-methoxy-3-(p-hydroxy-benzoyl)-benzofuran；2-ethyl-3-(p-hydroxybenzoyl)-6-methoxybenzofuran；(2-ethyl-6-methoxy-1-benzofuran-3-yl)-(4-hydroxyphenyl)methanone
• CAS: 871493-07-1
• 化学式: C₁₈H₁₆O₄
• 分子量: 296.323
• InChiKey: XCFYYKUFGSFYAK-UHFFFAOYSA-N

物化性质

• 沸点：
  504.4±50.0 °C(Predicted)
• 密度：
  1.236±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  59.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2-ethyl-6-methoxybenzofuran-3-yl)(4-hydroxyphenyl)methanone 在 N-溴代丁二酰亚胺(NBS) 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 以54%的产率得到(5-bromo-2-ethyl-6-methoxybenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone
  参考文献：
  名称：

  Developing Potent Human Uric Acid Transporter 1 (hURAT1) Inhibitors

  摘要：

  The kidneys are a vital organ in the human body. They serve several purposes including homeostatic functions such as regulating extracellular fluid volume and maintaining acid-base and electrolyte balance and are essential regarding the excretion of metabolic waste. Furthermore, the kidneys play an important role in uric acid secretion/reabsorption. Abnormalities associated with kidney transporters have been associated with various diseases, such as gout. The current study utilized Xenopus oocytes expressing human uric acid transporter 1 (hURAT1; SLC22A12) as an in vitro method to investigate novel compounds and their ability to inhibit (14)C-uric acid uptake via hURAT1. We have prepared and tested a series of 2-ethyl-benzofuran compounds and probed the hURAT1 in vitro inhibitor structure activity relationship. As compared to dimethoxy analogues, monophenols formed on the C ring showed the best in vitro inhibitory potential. Compounds with submicromolar (i.e., IC(50) < 1000 nM) inhibitors were prepared by brominating the corresponding phenols to produce compounds with potent uricosuric activity.

  DOI：

  10.1021/jm1015022
• 作为产物：
  描述：

  2-ethyl-6-methoxybenzofuran 在 aluminum (III) chloride 、 乙硫醇钠 作用下， 以 二氯甲烷 为溶剂， 反应 23.0h， 生成 (2-ethyl-6-methoxybenzofuran-3-yl)(4-hydroxyphenyl)methanone
  参考文献：
  名称：

  Novel Bioactivation Pathway of Benzbromarone Mediated by Cytochrome P450

  摘要：

  苯溴马隆（BBR）是一种具有肝毒性的药物，但其毒性的详细机制仍不清楚。我们通过与化学合成的标准化合物对比，在鼠和人肝微粒体系统中鉴定出两种新的BBR代谢产物：2,6-二溴氢醌（DBH）和单脱溴儿茶酚（2-乙基-3-(3-溴-4,5-二羟基苯甲酰)苯并呋喃；CAT）。我们还阐明了DBH是由细胞色素P450 2C9形成的，而CAT主要由CYP1A1、2D6、2E1和3A4形成。此外，在HepG2细胞中，CAT、DBH以及DBH的氧化形式都比BBR具有更高的细胞毒性。综上所述，我们的数据表明，新型活性代谢物DBH可能与BBR诱导的肝毒性有关。

  DOI：

  10.1124/dmd.115.065037

文献信息

• Novel Bioactivation Pathway of Benzbromarone Mediated by Cytochrome P450
  作者：Yumina Kitagawara、Tomoyuki Ohe、Kumiko Tachibana、Kyoko Takahashi、Shigeo Nakamura、Tadahiko Mashino

  DOI：10.1124/dmd.115.065037

  日期：2015.9

  Benzbromarone (BBR) is a hepatotoxic drug, but the detailed mechanism of its toxicity remains unknown. We identified 2,6-dibromohydroquinone (DBH) and mono-debrominated catechol (2-ethyl-3-(3-bromo-4,5-dihydroxybenzoyl)benzofuran; CAT) as novel metabolites of BBR in rat and human liver microsomal systems by comparison with chemically synthesized authentic compounds, and we also elucidated that DBH is formed by cytochrome P450 2C9 and that CAT is formed mainly by CYP1A1, 2D6, 2E1, and 3A4. Furthermore, CAT, DBH, and the oxidized form of DBH are highly cytotoxic in HepG2 compared with BBR. Taken together, our data demonstrate that DBH, a novel reactive metabolite, may be relevant to BBR-induced hepatotoxicity.

  苯溴马隆（BBR）是一种具有肝毒性的药物，但其毒性的详细机制仍不清楚。我们通过与化学合成的标准化合物对比，在鼠和人肝微粒体系统中鉴定出两种新的BBR代谢产物：2,6-二溴氢醌（DBH）和单脱溴儿茶酚（2-乙基-3-(3-溴-4,5-二羟基苯甲酰)苯并呋喃；CAT）。我们还阐明了DBH是由细胞色素P450 2C9形成的，而CAT主要由CYP1A1、2D6、2E1和3A4形成。此外，在HepG2细胞中，CAT、DBH以及DBH的氧化形式都比BBR具有更高的细胞毒性。综上所述，我们的数据表明，新型活性代谢物DBH可能与BBR诱导的肝毒性有关。
• [EN] MEDICINAL COMPOSITIONS CONTAINING 6-HYDROXYBENZ- BROMARONE OR SALTS THEREOF<br/>[FR] COMPOSITIONS MÉDICINALES CONTENANT DE LA 6-HYDROXYBENZBROMARONE OU DES SELS DE CELLE-CI
  申请人：TORII PHARMACEUTICAL CO LTD

  公开号：WO2005121112A1

  公开（公告）日：2005-12-22

  【課題】　本発明は、尿酸排泄促進作用が強く、かつ重篤な肝障害を引き起こすことなく、安全性の高い高尿酸血症の治療又は予防剤、より詳細には、尿酸排泄促進剤を提供する。【解決手段】　本発明は、６－ヒドロキシベンズブロマロン又はその塩、及び製薬上許容される担体を含有してなる高尿酸血症又は高尿酸血症に起因する疾患の治療・予防のための医薬組成物、並びに６－ヒドロキシベンズブロマロン又はその塩を含有してなる、尿酸排泄促進剤、キサンチンオキシダーゼ阻害剤、及び腎臓における尿酸の取り込み抑制剤に関する。また、本発明は、６－ヒドロキシ－ベンズブロマロンを製造する方法に関する。

  本发明涉及一种具有强烈尿酸排泄促进作用、且不引起严重肝损伤，安全性高的高尿酸血症治疗或预防剂，更详细地说，提供了一种尿酸排泄促进剂。该发明涉及含有6-羟基苯扎溴马隆或其盐以及药用可容许载体的高尿酸血症或因高尿酸血症引起的疾病的治疗和预防药物组合物，以及含有6-羟基苯扎溴马隆或其盐的尿酸排泄促进剂、黄嘌呤氧化酶抑制剂和肾脏尿酸摄取抑制剂。此外，本发明涉及制备6-羟基苯扎溴马隆的方法。
• Medicinal compositions containing 6-hydroxybenzbromarone or salts thereof
  申请人：Endou Hitoshi

  公开号：US20070185195A1

  公开（公告）日：2007-08-09

  [PROBLEMS] To provide highly safe therapeutic or preventive agents for hyperuricemia, more specifically uricosuric agents, which have potent uricosuric effect and do not cause grave hepatic disorder. [MEANS FOR SOLVING PROBLEMS] Medicinal compositions for the treatment or prevention of hyperuricemia or diseases caused by hyperuricemia, which contain 6-hydroxybenzbromarone or salts thereof, and pharmaceutically acceptable carriers; uricosuric agents, xanthine oxidase inhibitors, and inhibitors against the uptake of uric acid in kidney, which contain 6-hydroxybenzbromarone or salts thereof; and a process for the production of 6-hydroxybenzbromarone.

  【问题】提供高度安全的治疗或预防高尿酸血症的药物，更具体地说是具有强效尿酸排泄作用且不会引起严重肝功能障碍的尿酸排泄剂。 【解决问题的方法】含有6-羟基苯并溴隆或其盐以及药学上可接受的载体的用于治疗或预防高尿酸血症或由高尿酸血症引起的疾病的药物组合物；含有6-羟基苯并溴隆或其盐的尿酸排泄剂、黄嘌呤氧化酶抑制剂和抑制肾脏对尿酸吸收的抑制剂；以及生产6-羟基苯并溴隆的方法。
• DEVELOPING POTENT URATE TRANSPORTER INHIBITORS: COMPOUNDS DESIGNED FOR THEIR URICOSURIC ACTION
  申请人：Wempe Michael F.

  公开号：US20130225673A1

  公开（公告）日：2013-08-29

  A compound represented by the general Formula I: a pharmaceutically acceptable salt or ester thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof, a pro-drug thereof, a deuterated radio-labeled analog thereof, and mixtures of any of the foregoing, wherein: A-K are individually selected from carbon or nitrogen; X═—O, —NR 1 , or —S; R 1-11 are individually selected from the group consisting of —H, C 1 -C 6 alkyl, C 6 -C 14 aryl, substituted C 6 -C 14 aryl, C 1 -C 14 -alkoxy, halogen, hydroxyl, carboxy, cyano, C 1 -C 6 -alkanoyloxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfonyl, trifluoromethyl, hydroxy, C 2 -C 6 -alkoxycarbonyl, C 2 -C 6 -alkanoylamino, —O—R 12 , S—R 12 , —SO 2 —R 12 , —NHSO 2 R 12 and —NHCO 2 R 12 , wherein R 12 is phenyl, naphthyl, or phenyl or naphthly substituted with one to three groups selected from C 1 -C 6 -alkyl, C 6 -C 10 aryl, C 1 -C 6 -alkoxy and halogen, and C 4 -C 20 hydroxyheteroaryl wherein the heteroatoms are selected from the group consisting of sulfur, nitrogen, and oxygen.

  一种由通式I表示的化合物：其中，该化合物为药学上可接受的盐或酯、溶剂化物、螯合物、非共价复合物、前药、氘标记的放射性类似物或任何上述物质的混合物，其中：A-K分别选择自碳或氮；X═—O、—NR1或—S；R1-11分别选择自—H、C1-C6烷基、C6-C14芳基、取代的C6-C14芳基、C1-C14烷氧基、卤素、羟基、羧基、氰基、C1-C6-烷酰氧基、C1-C6-烷基硫基、C1-C6-烷基磺酰基、三氟甲基、羟基、C2-C6-烷氧羰基、C2-C6-烷酰胺基、—O—R12、S—R12、—SO2—R12、—NHSO2R12和—NHCO2R12，其中R12为苯基、萘基或苯基或萘基，且其上选择了一到三个来自C1-C6烷基、C6-C10芳基、C1-C6烷氧基和卤素的基团以及C4-C20羟基杂芳基，其中杂原子选择自硫、氮和氧。
• MEDICINAL COMPOSITIONS CONTAINING 6-HYDROXYBENZBROMARONE OR SALTS THEREOF
  申请人：TORII PHARMACEUTICAL CO., LTD.

  公开号：EP1767531A1

  公开（公告）日：2007-03-28

  [PROBLEMS] To provide highly safe therapeutic or preventive agents for hyperuricemia, more specifically uricosuric agents, which have potent uricosuric effect and do not cause grave hepatic disorder. [MEANS FOR SOLVING PROBLEMS] Medicinal compositions for the treatment or prevention of hyperuricemia or diseases caused by hyperuricemia, which contain 6-hydroxybenzbromarone or salts thereof, and pharmaceutically acceptable carriers; uricosuric agents, xanthine oxidase inhibitors, and inhibitors against the uptake of uric acid in kidney, which contain 6-hydroxybenzbromarone or salts thereof; and a process for the production of 6-hydroxybenzbromarone.

  [问题] 提供高度安全的治疗或预防高尿酸血症的药物，更具体地说是尿酸盐药物，它们 具有强效的尿酸盐作用，并且不会引起严重的肝功能紊乱。[解决问题的方法] 用于治疗或预防高尿酸血症或由高尿酸血症引起的疾病的药用组合物，其中含有 6-羟基苯溴马隆或其盐类，以及药学上可接受的载体；含 6-羟基苯溴马隆或其盐类的尿尿剂、黄嘌呤氧化酶抑制剂和肾脏吸收尿酸抑制剂；以及 6-羟基苯溴马隆的生产工艺。