ethyl 5,8-difluoro-1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate | 1203711-96-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: ethyl 5,8-difluoro-1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate
• 英文别名: Ethyl 5,8-difluoro-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate；ethyl 5,8-difluoro-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate
• CAS: 1203711-96-9
• 化学式: C₂₀H₁₇F₂NO₄
• 分子量: 373.356
• InChiKey: YIUCCVBAXWKCMU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ethyl 5,8-difluoro-1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 21.0h， 生成 5,8-difluoro-1-(4-methoxybenzyl)-4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide
  参考文献：
  名称：

  DIHYDROQUINOLINONE COMPOUNDS AS MODULATORS OF THE MUSCARININC M1 RECEPTOR

  摘要：

  公开号：

  EP2821401B1
• 作为产物：
  描述：

  2,5-二氟苯胺 在 Eaton's reagent 、 potassium carbonate 、 potassium iodide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 ethyl 5,8-difluoro-1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate
  参考文献：
  名称：

  Synthesis and Pharmacological Profiling of Analogues of Benzyl Quinolone Carboxylic Acid (BQCA) as Allosteric Modulators of the M₁ Muscarinic Receptor

  摘要：

  Established therapy in Alzheimer's disease involves potentiation of the endogenous orthosteric ligand, acetylcholine, at the M, muscarinic receptors found in higher concentrations in the cortex and hippocampus. Adverse effects, due to indiscriminate activation of other muscarinic receptor subtypes, are common. M, muscarinic positive allosteric modulators/allosteric agonists such as BQCA offer an attractive solution, being exquisitely M-1-selective over other muscarinic subtypes. A common difficulty with allosteric ligands is interpreting SAR, based on composite potency values derived in the presence of fixed concentration of agonist. In reality these values encompass multiple pharmacological parameters, each potentially and differentially sensitive to structural modification of the ligand. We report novel BQCA analogues which appear to augment ligand affinity for the receptor (pK(B)), intrinsic efficacy (tau(B)), and both binding (alpha) and functional (beta) cooperativity with acetylcholine. Ultimately, development of such enriched SAR surrounding allosteric modulators will provide insight into their mode of action.

  DOI：

  10.1021/jm400540b

文献信息

• HETEROCYCLIC COMPOUND AND USE THEREFOR
  申请人：Takeda Pharmaceutical Company Limited

  公开号：US20150126487A1

  公开（公告）日：2015-05-07

  The present invention provides a compound having a cholinergic muscarinic M1 receptor positive allosteric modulator activity, and useful as a prophylactic or therapeutic drug for Alzheimer's disease, schizophrenia, pain, a sleep disorder and the like. The present invention relates to a compound represented by the formula (I): wherein R 1 is an optionally substituted amino group or an optionally substituted cyclic amino group, R 2 and R 3 are each independently a hydrogen atom or a substituent, X is —CH═ or —N═, and ring A is an optionally substituted 5- to 10-membered ring, or a salt thereof.

  本发明提供了一种具有胆碱能肌动蛋白M1受体正变构调节剂活性的化合物，可用作预防或治疗阿尔茨海默病、精神分裂症、疼痛、睡眠障碍等药物。本发明涉及一种由式(I)表示的化合物：其中R1是可选取代的氨基或可选取代的环状氨基，R2和R3各自独立地是氢原子或取代基，X是—CH═或—N═，环A是可选取代的5-至10-成员环，或其盐。
• Parallel synthesis of N-biaryl quinolone carboxylic acids as selective M1 positive allosteric modulators
  作者：Feng V. Yang、William D. Shipe、Jaime L. Bunda、M. Brad Nolt、David D. Wisnoski、Zhijian Zhao、James C. Barrow、William J. Ray、Lei Ma、Marion Wittmann、Matthew A. Seager、Kenneth A. Koeplinger、George D. Hartman、Craig W. Lindsley

  DOI：10.1016/j.bmcl.2009.11.100

  日期：2010.1

  An iterative analog library synthesis approach was employed in the exploration of a quinolone carboxylic acid series of selective M-1 positive allosteric modulators, and strategies for improving potency and plasma free fraction were identified. (C) 2009 Elsevier Ltd. All rights reserved.
• DIHYDROQUINOLINONE COMPOUNDS AS MODULATORS OF THE MUSCARININC M1 RECEPTOR
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP2821401B1

  公开（公告）日：2020-09-09
• US9403802B2
  申请人：——

  公开号：US9403802B2

  公开（公告）日：2016-08-02
• Synthesis and Pharmacological Profiling of Analogues of Benzyl Quinolone Carboxylic Acid (BQCA) as Allosteric Modulators of the M₁ Muscarinic Receptor
  作者：Shailesh N. Mistry、Celine Valant、Patrick M. Sexton、Ben Capuano、Arthur Christopoulos、Peter J. Scammells

  DOI：10.1021/jm400540b

  日期：2013.6.27

  Established therapy in Alzheimer's disease involves potentiation of the endogenous orthosteric ligand, acetylcholine, at the M, muscarinic receptors found in higher concentrations in the cortex and hippocampus. Adverse effects, due to indiscriminate activation of other muscarinic receptor subtypes, are common. M, muscarinic positive allosteric modulators/allosteric agonists such as BQCA offer an attractive solution, being exquisitely M-1-selective over other muscarinic subtypes. A common difficulty with allosteric ligands is interpreting SAR, based on composite potency values derived in the presence of fixed concentration of agonist. In reality these values encompass multiple pharmacological parameters, each potentially and differentially sensitive to structural modification of the ligand. We report novel BQCA analogues which appear to augment ligand affinity for the receptor (pK(B)), intrinsic efficacy (tau(B)), and both binding (alpha) and functional (beta) cooperativity with acetylcholine. Ultimately, development of such enriched SAR surrounding allosteric modulators will provide insight into their mode of action.