2-(8-bromo-6-chloroimidazo[1,2-b]pyridazin-2-yl)-3-methylquinoxaline

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2-(8-bromo-6-chloroimidazo[1,2-b]pyridazin-2-yl)-3-methylquinoxaline
• 英文别名: 2-(8-Bromo-6-chloroimidazo[1,2-b]pyridazin-2-yl)-3-methylquinoxaline
• 化学式: C₁₅H₉BrClN₅
• 分子量: 374.627
• InChiKey: AFIIWFHVEZXNHY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  56
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(8-bromo-6-chloroimidazo[1,2-b]pyridazin-2-yl)-3-methylquinoxaline 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 103.0h， 生成 2-(3-methylquinoxalin-2-yl)-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b]pyridazin-8-amine
  参考文献：
  名称：

  Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety

  摘要：

  We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a] pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-a-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.

  DOI：

  10.1016/j.bmc.2019.06.021
• 作为产物：
  描述：

  3-氨基-4-溴-6-氯哒嗪 、 2-bromo-1-(3-methylquinoxalin-2-yl)ethanone 以 甲苯 为溶剂， 反应 24.0h， 以53%的产率得到2-(8-bromo-6-chloroimidazo[1,2-b]pyridazin-2-yl)-3-methylquinoxaline
  参考文献：
  名称：

  Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety

  摘要：

  We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a] pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-a-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.

  DOI：

  10.1016/j.bmc.2019.06.021

文献信息

• [EN] NOVEL COMPOUND AND USE THEREOF AS PDE10 INHIBITOR<br/>[FR] NOUVEAU COMPOSÉ ET SON UTILISATION À TITRE D'INHIBITEUR DE PDE10
  申请人：MITSUBISHI TANABE PHARMA CORP

  公开号：WO2013027794A1

  公开（公告）日：2013-02-28

  式〔I〕：〔式中、環Aは、置換されていてもよい含窒素へテロアリールを表し；　環Bは、置換されていてもよい脂肪族単環式基を表し；　X1～X5は、以下の(1)～(4)のいずれかを表し： (1)X1及びX3がN、X2がC－R1、X4がC、X5がCH、 (2)X1がC、X2、X3及びX4がN、X5がCH、 (3)X1がC、X2及びX4がN、X3及びX5がCH、又は (4)X1がC、X2がC－R1、X3、X4及びX5がN；　R1は、水素原子、ハロゲン、低級アルキル又はシアノを表し；　Yは、置換されていてもよいアミノ、置換されていてもよいサイクリックアミノ、置換されていてもよいアミノカルボニル、ヒドロキシ、置換されていてもよい低級アルコキシ、置換されていてもよい低級シクロアルコキシ、置換されていてもよい脂肪族複素単環－Ｏ－、又は置換されていてもよい低級アルキルを表し；　ただし、X1～X5が(1)又は(2)のとき、環Bは、窒素原子の数が1以下である置換されていてもよい脂肪族単環式基である。〕 で示される化合物又はその薬理的に許容し得る塩。
• Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety
  作者：Yuuki Koizumi、Yoshihito Tanaka、Takehiko Matsumura、Yoichi Kadoh、Haruko Miyoshi、Mitsuya Hongu、Kei Takedomi、Jun Kotera、Takashi Sasaki、Hiroyuki Taniguchi、Yumi Watanabe、Misae Takakuwa、Koki Kojima、Nobuyuki Baba、Itsuko Nakamura、Eiji Kawanishi

  DOI：10.1016/j.bmc.2019.06.021

  日期：2019.8

  We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a] pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-a-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.