3-[(E)-2-(4-fluorophenyl)ethenyl]-[1,4]benzodioxino[3,2-c]pyridazine | 1436847-96-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-[(E)-2-(4-fluorophenyl)ethenyl]-[1,4]benzodioxino[3,2-c]pyridazine
• CAS: 1436847-96-9
• 化学式: C₁₈H₁₁FN₂O₂
• 分子量: 306.296
• InChiKey: NWVOUUGZBZXNKZ-JXMROGBWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  44.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-[(E)-2-(4-fluorophenyl)ethenyl]-[1,4]benzodioxino[3,2-c]pyridazine 在 palladium 10% on activated carbon 、 potassium tert-butylate 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 8.5h， 生成 6-[2-(4-fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one
  参考文献：
  名称：

  4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors

  摘要：

  D-Amino acid oxidase (DAAO) catalyzes the oxidation of D-amino acids including D-serine, a coagonist of the N-methyl-D-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-ydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze.

  DOI：

  10.1021/jm400095b
• 作为产物：
  描述：

  3-chlorobenzo[5,6][1,4]dioxino[2,3-c]pyridazine 、 (E)-2-(4-fluorophenyl)vinylboronic acid 在 四(三苯基膦)钯 、 sodium carbonate 作用下， 以 乙二醇二甲醚 为溶剂， 反应 1.0h， 生成 3-[(E)-2-(4-fluorophenyl)ethenyl]-[1,4]benzodioxino[3,2-c]pyridazine
  参考文献：
  名称：

  4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors

  摘要：

  D-Amino acid oxidase (DAAO) catalyzes the oxidation of D-amino acids including D-serine, a coagonist of the N-methyl-D-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-ydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze.

  DOI：

  10.1021/jm400095b

文献信息

• DIHYDROXY AROMATIC HETEROCYCLIC COMPOUND
  申请人：TAKEDA PHARMACEUTICAL COMPANY LIMITED

  公开号：US20140336165A1

  公开（公告）日：2014-11-13

  Provided is a compound having a D-amino acid oxidase (DAAO) inhibitory action, and useful as, for example, a prophylaxis and/or therapeutic agent for schizophrenia or neuropathic pain. The present inventors have studied a compound that inhibits DAAO, and confirm that a dihydroxy aromatic heterocyclic compound has a DAAO inhibitory action, and completed the present invention. That is, the dihydroxy aromatic heterocyclic compound of the present invention has a good DAAO inhibitory action, and can be used as a prophylaxis and/or therapeutic agent for, for example, schizophrenia or neuropathic pain.

  提供的是一种具有D-氨基酸氧化酶（DAAO）抑制作用的化合物，可用作例如精神分裂症或神经病性疼痛的预防和/或治疗剂。本发明人员研究了一种能够抑制DAAO的化合物，并确认一种二羟基芳香杂环化合物具有DAAO抑制作用，并完成了本发明。换言之，本发明的二羟基芳香杂环化合物具有良好的DAAO抑制作用，并可用作例如精神分裂症或神经病性疼痛的预防和/或治疗剂。
• Dihydroxy aromatic heterocyclic compound
  申请人：Takeda Pharmaceutical Company Limited

  公开号：US10202399B2

  公开（公告）日：2019-02-12

  Provided is a compound having a D-amino acid oxidase (DAAO) inhibitory action, and useful as, for example, a prophylaxis and/or therapeutic agent for schizophrenia or neuropathic pain. The present inventors have studied a compound that inhibits DAAO, and confirm that a dihydroxy aromatic heterocyclic compound has a DAAO inhibitory action, and completed the present invention. That is, the dihydroxy aromatic heterocyclic compound of the present invention has a good DAAO inhibitory action, and can be used as a prophylaxis and/or therapeutic agent for, for example, schizophrenia or neuropathic pain.

  本发明提供了一种具有 D-氨基酸氧化酶（DAAO）抑制作用的化合物，可用作精神分裂症或神经病理性疼痛的预防和/或治疗剂等。本发明人对一种抑制 DAAO 的化合物进行了研究，确认一种二羟基芳香杂环化合物具有 DAAO 抑制作用，并完成了本发明。也就是说，本发明的二羟基芳香杂环化合物具有良好的 DAAO 抑制作用，可用作精神分裂症或神经病理性疼痛等的预防和/或治疗剂。
• US9212147B2
  申请人：——

  公开号：US9212147B2

  公开（公告）日：2015-12-15
• US9562020B2
  申请人：——

  公开号：US9562020B2

  公开（公告）日：2017-02-07
• [EN] DIHYDROXY AROMATIC HETEROCYCLIC COMPOUND<br/>[FR] COMPOSÉ HÉTÉROCYCLIQUE AROMATIQUE DIHYDROXY
  申请人：ASTELLAS PHARMA INC

  公开号：WO2013073577A1

  公开（公告）日：2013-05-23

  【課題】D-アミノ酸酸化酵素(DAAO)阻害作用を有し、例えば、統合失調症、神経因性疼痛の予防及び／又は治療剤として有用な化合物を提供する。 【解決手段】本発明者らは、DAAOを阻害する化合物について検討し、ジヒドロキシ芳香族へテロ環化合物がDAAO阻害作用を有することを確認し、本発明を完成した。即ち、本発明のジヒドロキシ芳香族へテロ環化合物は、良好なDAAO阻害作用を有しており、例えば、統合失調症、神経因性疼痛の予防及び／又は治療剤として使用しうる。