methyl 1-(4-fluoro-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate | 1357192-13-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: methyl 1-(4-fluoro-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate
• 英文别名: Methyl 1-(4-fluoro-1,3,3-trimethyl-2-oxoindol-5-yl)-5-methoxy-4-oxopyridazine-3-carboxylate；methyl 1-(4-fluoro-1,3,3-trimethyl-2-oxoindol-5-yl)-5-methoxy-4-oxopyridazine-3-carboxylate
• CAS: 1357192-13-2
• 化学式: C₁₈H₁₈FN₃O₅
• 分子量: 375.356
• InChiKey: CRQZQDCLTJBZJJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  88.5
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  methyl 1-(4-fluoro-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以100%的产率得到1-(4-fluoro-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid
  参考文献：
  名称：

  Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor

  摘要：

  Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl) phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER) = 6.2) despite the potent PDE10A inhibitory activity (IC50 = 0.94 nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER = 1.4) and an excellent PDE10A inhibitory activity (IC50 = 0.080 nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3 mg/kg by oral administration in mice. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.10.002
• 作为产物：
  描述：

  4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one 在 盐酸 、 5%-palladium/activated carbon 、 氢气 、 sodium nitrite 作用下， 以 甲醇 、 水 、 乙腈 为溶剂， 反应 0.25h， 生成 methyl 1-(4-fluoro-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate
  参考文献：
  名称：

  Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor

  摘要：

  Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl) phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER) = 6.2) despite the potent PDE10A inhibitory activity (IC50 = 0.94 nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER = 1.4) and an excellent PDE10A inhibitory activity (IC50 = 0.080 nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3 mg/kg by oral administration in mice. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.10.002

文献信息

• HETEROCYCLIC COMPOUND
  申请人：Yoshikawa Masato

  公开号：US20130150344A1

  公开（公告）日：2013-06-13

  The present invention provides a compound represented by the formula (1): wherein each symbol is as defined in the specification, or a salt thereof, a prodrug of the compound or a salt thereof, a medicament containing the compound or a salt thereof, the medicament which is a phosphodiesterase 10A inhibitor, and a medicament which is for preventing or treating schizophrenia.

  本发明提供了一种由以下式（1）表示的化合物： 其中每个符号如规范中定义，或其盐，该化合物的前药或其盐，含有该化合物或其盐的药物，该药物是磷酸二酯酶10A抑制剂，以及用于预防或治疗精神分裂症的药物。
• US9090586B2
  申请人：——

  公开号：US9090586B2

  公开（公告）日：2015-07-28
• Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor
  作者：Masato Yoshikawa、Haruhi Kamisaki、Jun Kunitomo、Hideyuki Oki、Hironori Kokubo、Akihiro Suzuki、Tomomi Ikemoto、Kosuke Nakashima、Naomi Kamiguchi、Akina Harada、Haruhide Kimura、Takahiko Taniguchi

  DOI：10.1016/j.bmc.2015.10.002

  日期：2015.11

  Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl) phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER) = 6.2) despite the potent PDE10A inhibitory activity (IC50 = 0.94 nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER = 1.4) and an excellent PDE10A inhibitory activity (IC50 = 0.080 nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3 mg/kg by oral administration in mice. (C) 2015 Elsevier Ltd. All rights reserved.