6-(3-fluoropyridin-4-yl)-2-mercapto-3-methyl-3H-pyrimidin-4-one | 881919-88-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 6-(3-fluoropyridin-4-yl)-2-mercapto-3-methyl-3H-pyrimidin-4-one
• 英文别名: 6-(3-fluoropyridin-4-yl)-2-mercapto-3-methylpyrimidin-4(3H)-one；6-(3-fluoropyridin-4-yl)-3-methyl-2-sulfanylidene-1H-pyrimidin-4-one
• CAS: 881919-88-6
• 化学式: C₁₀H₈FN₃OS
• 分子量: 237.257
• InChiKey: JJASKOMKGLGUBV-UHFFFAOYSA-N

物化性质

• 沸点：
  364.4±52.0 °C(Predicted)
• 密度：
  1.47±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  77.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-(3-fluoropyridin-4-yl)-2-mercapto-3-methyl-3H-pyrimidin-4-one 在 三乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 6-(3-fluoropyridin-4-yl)-3-methyl-2-(morpholin-4-yl)-3H-pyrimidin-4-one
  参考文献：
  名称：

  Discovery of novel 2-(alkylmorpholin-4-yl)-6-(3-fluoropyridin-4-yl)-pyrimidin-4(3H)-ones as orally-active GSK-3β inhibitors for Alzheimer’s disease

  摘要：

  We herein describe the results of further evolution of GSK-3 beta inhibitors for Alzheimer's disease from our promising compounds with in vivo tau phosphorylation inhibitory activity by oral administration. Introduction of a low alkyl group instead of the phenyl group at the 3-position of the morpholine moiety aiming to improve pharmacokinetic profiles resulted in potent low molecular weight GSK-3 beta inhibitors with good in vitro pharmacokinetic profiles, which also showed in vivo tau phosphorylation inhibitory activity by oral administration. Effect of the stereochemistry of the alkyl moiety is also discussed using docking models. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.01.005
• 作为产物：
  描述：

  3-氟吡啶 在 Carbonyldiimidazole 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 8.0h， 生成 6-(3-fluoropyridin-4-yl)-2-mercapto-3-methyl-3H-pyrimidin-4-one
  参考文献：
  名称：

  Discovery of novel 2-(alkylmorpholin-4-yl)-6-(3-fluoropyridin-4-yl)-pyrimidin-4(3H)-ones as orally-active GSK-3β inhibitors for Alzheimer’s disease

  摘要：

  We herein describe the results of further evolution of GSK-3 beta inhibitors for Alzheimer's disease from our promising compounds with in vivo tau phosphorylation inhibitory activity by oral administration. Introduction of a low alkyl group instead of the phenyl group at the 3-position of the morpholine moiety aiming to improve pharmacokinetic profiles resulted in potent low molecular weight GSK-3 beta inhibitors with good in vitro pharmacokinetic profiles, which also showed in vivo tau phosphorylation inhibitory activity by oral administration. Effect of the stereochemistry of the alkyl moiety is also discussed using docking models. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.01.005

文献信息

• 2-(2-Phenylmorpholin-4-yl)pyrimidin-4(3H)-ones; A new class of potent, selective and orally active glycogen synthase kinase-3β inhibitors
  作者：Kenji Fukunaga、Fumiaki Uehara、Keiichi Aritomo、Aya Shoda、Shinsuke Hiki、Masahiro Okuyama、Yoshihiro Usui、Kazutoshi Watanabe、Koichi Yamakoshi、Toshiyuki Kohara、Tokushi Hanano、Hiroshi Tanaka、Susumu Tsuchiya、Shinji Sunada、Ken-Ichi Saito、Jun-ichi Eguchi、Satoshi Yuki、Shoichi Asano、Shinji Tanaka、Akiko Mori、Keiji Yamagami、Hiroshi Baba、Takashi Horikawa、Masatake Fujimura

  DOI：10.1016/j.bmcl.2013.09.020

  日期：2013.12

  A series of 2-(2-phenylmorpholin-4-yl)pyrimidin-4(3H)-ones was synthesized and examined for their inhibitory activity against glycogen synthase kinase-3β (GSK-3β). We found 21, 29 and 30 to possess potent in vitro GSK-3β inhibitory activity with good in vitro PK profiles. 21 demonstrated significant decrease of tau phosphorylation after oral administration in mice and excellent PK profiles.

  合成了一系列2-（2-苯基吗啉-4-基）嘧啶-4（3 H）-酮，并检查了它们对糖原合酶激酶-3β（GSK-3β）的抑制活性。我们发现21，29和30，以在体外具有GSK-3β在体外PK性能良好的抑制活性有效。21显示在小鼠口服后tau磷酸化显着降低，PK表现出色。
• 6- (PYRIDINYL) -4-PYRIMIDONE DERIVATES AS TAU PROTEIN KINASE 1 INHIBITORS
  申请人：Watanabe Kazutoshi

  公开号：US20090239864A1

  公开（公告）日：2009-09-24

  A compound represented by the formula (I), an optically active isomer thereof, or a pharmaceutical acceptable salt thereof: wherein R 1 represents a C 1 -C 12 alkyl; R 2 represents a hydrogen atom or the like; R 3 represents a halogen or the like; q represents an integer of 1 to 7; R 4 represents a halogen or the like; p represents 0 or an integer of 1 to 5; R 5 represents a C 6 -C 10 aryl, a heterocycle or the like; and X represents oxygen, NH, or the like, which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity such as a neurodegenerative diseases (e.g. Alzheimer disease).

  化合物的化学式为（I），其手性异构体，或其药学可接受的盐：其中R1表示C1-C12烷基；R2表示氢原子或类似物；R3表示卤素或类似物；q表示1至7的整数；R4表示卤素或类似物；p表示0或1至5的整数；R5表示C6-C10芳基，杂环或类似物；X表示氧，NH或类似物，用于预防和/或治疗由tau蛋白激酶1高活性引起的疾病，例如神经退行性疾病（如阿尔茨海默病）。
• 6-(pyridinyl)-4-pyrimidone derivates as tau protein kinase 1 inhibitors
  申请人：Mitsubishi Tanabe Pharma Corporation

  公开号：US08129377B2

  公开（公告）日：2012-03-06

  A compound represented by the formula (I), an optically active isomer thereof, or a pharmaceutical acceptable salt thereof: wherein R1 represents a C1-C12 alkyl; R2 represents a hydrogen atom or the like; R3 represents a halogen or the like; q represents an integer of 1 to 7; R4 represents a halogen or the like; p represents 0 or an integer of 1 to 5; R5 represents a C6-C10 aryl, a heterocycle or the like; and X represents oxygen, NH, or the like, which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity such as a neurodegenerative diseases (e.g. Alzheimer disease).

  化合物的化学式为（I），其手性异构体或药物可接受的盐：其中，R1代表C1-C12烷基；R2代表氢原子或类似物；R3代表卤素或类似物；q代表1至7的整数；R4代表卤素或类似物；p代表0或1至5的整数；R5代表C6-C10芳基，杂环或类似物；X代表氧、NH或类似物，用于预防和/或治疗由tau蛋白激酶1过度活化引起的疾病，如神经退行性疾病（例如阿尔茨海默病）。
• Pyrimidone Compounds As GSK-3 Inhibitors
  申请人：Lefker Bruce A.

  公开号：US20100292205A1

  公开（公告）日：2010-11-18

  The invention pertains to pyrimidone compounds that serve as effective GSK-3 inhibitors. The invention further relates to pharmaceutical compositions and methods comprising such pyrimidone compounds; and the use of such compounds for treating certain disorders.

  本发明涉及一种作为有效的GSK-3抑制剂的嘧啶酮化合物。本发明还涉及包含这种嘧啶酮化合物的药物组合物和方法；以及使用这些化合物治疗某些疾病的方法。
• Rh-Catalyzed Sequential Asymmetric Hydrogenations of 3-Amino-4-Chromones Via an Unusual Dynamic Kinetic Resolution Process
  作者：Yunnan Xu、Yicong Luo、Jianxun Ye、Yu Deng、Delong Liu、Wanbin Zhang

  DOI：10.1021/jacs.2c09266

  日期：2022.11.2

  first time via an unprecedented dynamic kinetic resolution under neutral conditions, providing (S,R)-3-amino-4-chromanols in high yields (up to 98%) with excellent enantio- and diastereoselectivities (up to 99.9% ee and 20:1 dr). The mechanistic studies based on control experiments and density functional theory (DFT) calculations suggest that the dynamic kinetic resolution process for the intermediate

  Rh 催化的 3-amino-4-chromones 连续不对称氢化已首次通过中性条件下前所未有的动态动力学分辨率实现，提供 ( S , R)-3-amino-4-chromanols，产率高（高达 98%），具有出色的对映和非对映选择性（高达 99.9% ee 和 20:1 dr）。基于控制实验和密度泛函理论 (DFT) 计算的机理研究表明，在第一个氢化步骤中生成的中间体对映体的动态动力学拆分过程是通过从不需要的对映体到所需的立体突变（或称为手性同化）途径进行的对映异构体，而不是通过不需要的对映异构体的传统外消旋化。该协议可以在克规模上以相对较低的催化剂负载进行，并为合成一系列具有生物活性的苯二酚及其衍生物提供了一种实用且方便的途径。