1-methyl-4-(pyridin-3-yl)-1H-pyrazol-3-ol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 1-methyl-4-(pyridin-3-yl)-1H-pyrazol-3-ol
• 英文别名: 2-methyl-4-pyridin-3-yl-1H-pyrazol-5-one
• 化学式: C₉H₉N₃O
• 分子量: 175.19
• InChiKey: ASJQYFZPNKVUJD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  45.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-methyl-4-(pyridin-3-yl)-1H-pyrazol-3-ol 在 盐酸 、 三丁基膦 、 1,1'-azodicarbonyl-dipiperidine 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 12.5h， 生成 2-[4-({[1-methyl-4-(pyridin-3-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline dihydrochloride
  参考文献：
  名称：

  Synthesis, SAR study, and biological evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors with reduced CYP3A4 inhibition

  摘要：

  A novel class of phosphodiesterase 10A inhibitors with potent PDE10A inhibitory activity and reduced CYP3A4 inhibition was designed and synthesized starting from 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl] oxy} methyl) phenyl] quinoline (1). Replacement of pyridine ring of 1 with N-methyl pyridone ring drastically improved CYP3A4 inhibition, and further optimization of these quinoline analogues identified 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl) phenoxy] methyl}-1H-pyrazol-4-yl) pyridin-2(1H)-one (42b), which showed potent PDE10A inhibitory activity and a good CYP3A4 inhibition profile. A PET study with C-11-labeled 42b indicated that 42b exhibited good brain penetration and specifically accumulated in the rodent striatum. Further, oral administration of 42b dose-dependently attenuated phencyclidine-induced hyperlocomotion in mice with an ED50 value of 2.0 mg/kg and improved visual-recognition memory impairment at 0.1 and 0.3 mg/kg in mice novel object recognition test. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.11.039
• 作为产物：
  描述：

  3-吡啶乙酸乙酯 、 N,N-二甲基甲酰胺二甲基缩醛 、 甲基肼 在 溶剂黄146 作用下， 以 N,N-二甲基甲酰胺 、 乙醇 为溶剂， 反应 14.0h， 以29%的产率得到1-methyl-4-(pyridin-3-yl)-1H-pyrazol-3-ol
  参考文献：
  名称：

  Synthesis, SAR study, and biological evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors with reduced CYP3A4 inhibition

  摘要：

  A novel class of phosphodiesterase 10A inhibitors with potent PDE10A inhibitory activity and reduced CYP3A4 inhibition was designed and synthesized starting from 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl] oxy} methyl) phenyl] quinoline (1). Replacement of pyridine ring of 1 with N-methyl pyridone ring drastically improved CYP3A4 inhibition, and further optimization of these quinoline analogues identified 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl) phenoxy] methyl}-1H-pyrazol-4-yl) pyridin-2(1H)-one (42b), which showed potent PDE10A inhibitory activity and a good CYP3A4 inhibition profile. A PET study with C-11-labeled 42b indicated that 42b exhibited good brain penetration and specifically accumulated in the rodent striatum. Further, oral administration of 42b dose-dependently attenuated phencyclidine-induced hyperlocomotion in mice with an ED50 value of 2.0 mg/kg and improved visual-recognition memory impairment at 0.1 and 0.3 mg/kg in mice novel object recognition test. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.11.039

文献信息

• [EN] PYRAZOLE COMPOUND<br/>[FR] COMPOSÉ DE PYRAZOLE
  申请人：ASTELLAS PHARMA INC

  公开号：WO2012133607A1

  公开（公告）日：2012-10-04

  【課題】統合失調症、不安症、ハンチントン舞踏病、薬物依存、及び／若しくはアルツハイマー病の予防並びに／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、PDE10A阻害作用を有する化合物について検討し、ピラゾール化合物がPDE10A阻害作用を有することを確認し、本発明を完成した。本発明のピラゾール化合物はPDE10A阻害作用を有し、統合失調症、不安症、ハンチントン舞踏病、薬物依存、及び／若しくはアルツハイマー病の予防並びに／又は治療剤として使用しうる。
• Synthesis, SAR study, and biological evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors with reduced CYP3A4 inhibition
  作者：Wataru Hamaguchi、Naoyuki Masuda、Satoshi Miyamoto、Yasuhiro Shiina、Shigetoshi Kikuchi、Takuma Mihara、Hiroyuki Moriguchi、Hiroshi Fushiki、Yoshihiro Murakami、Yasushi Amano、Kazuya Honbou、Kouji Hattori

  DOI：10.1016/j.bmc.2014.11.039

  日期：2015.1

  A novel class of phosphodiesterase 10A inhibitors with potent PDE10A inhibitory activity and reduced CYP3A4 inhibition was designed and synthesized starting from 2-[4-([1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl] oxy} methyl) phenyl] quinoline (1). Replacement of pyridine ring of 1 with N-methyl pyridone ring drastically improved CYP3A4 inhibition, and further optimization of these quinoline analogues identified 1-methyl-5-(1-methyl-3-[4-(quinolin-2-yl) phenoxy] methyl}-1H-pyrazol-4-yl) pyridin-2(1H)-one (42b), which showed potent PDE10A inhibitory activity and a good CYP3A4 inhibition profile. A PET study with C-11-labeled 42b indicated that 42b exhibited good brain penetration and specifically accumulated in the rodent striatum. Further, oral administration of 42b dose-dependently attenuated phencyclidine-induced hyperlocomotion in mice with an ED50 value of 2.0 mg/kg and improved visual-recognition memory impairment at 0.1 and 0.3 mg/kg in mice novel object recognition test. (C) 2014 Elsevier Ltd. All rights reserved.