2-(3,5-difluorophenyl)-N-[6-(4-fluorobenzylamino)-2-(morpholin-4-yl)pyridin-3-yl]acetamide | 1228076-12-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-(3,5-difluorophenyl)-N-[6-(4-fluorobenzylamino)-2-(morpholin-4-yl)pyridin-3-yl]acetamide
• 英文别名: NS15370；2-(3,5-difluorophenyl)-N-[6-(4-fluorobenzylamino)-2-morpholin-4-yl-pyridin-3-yl]-acetamide；2-(3,5-difluorophenyl)-N-[6-[(4-fluorophenyl)methylamino]-2-morpholin-4-ylpyridin-3-yl]acetamide
• CAS: 1228076-12-7
• 化学式: C₂₄H₂₃F₃N₄O₂
• 分子量: 456.467
• InChiKey: IHJZOQXINPOVRJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  66.5
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-(3,5-difluorophenyl)-N-[6-(4-fluorobenzylamino)-2-(morpholin-4-yl)pyridin-3-yl]acetamide 在 盐酸 作用下， 以 乙醇 为溶剂， 以84%的产率得到2-(3,5-difluorophenyl)-N-[6-(4-fluorobenzylamino)-2-(morpholin-4-yl)pyridin-3-yl]acetamide hydrochloride
  参考文献：
  名称：

  Characterization of a novel high-potency positive modulator of Kv7 channels

  摘要：

  K(v)7 channel activators decrease neuronal excitability and might potentially treat neuronal hyperexcitability disorders like epilepsy and mania. Here we introduce NS15370 ((2-(3,5-difluorophenyl)-N-[6-[(4-fluorophenyl)methylamino]-2-morpholino-3-pyridyl]acetamide)hydrochloride, an in vitro high-potency chemical analogue of retigabine, without effects on GABA(A) receptors. NS15370 activates recombinant homo- and heteromeric K(v)7.2-K(v)7.5 channels in HEK293 cells at sub-micromolar concentrations (EC50 similar to 100 nM, as quantified by a fluorescence based TI+-influx assay). In voltage clamp experiments NS15370 exhibits a complex, concentration-dependent mode-of-action: At low concentrations it accelerates voltage-dependent activation rates, slows deactivations, and increases steady-state current amplitudes. Quantified by the peak-tail current method, the V-1/2 value of the steady-state activation curve is shifted towards hyperpolarized potentials at concentrations similar to 100 times lower than retigabine. However, in contrast to retigabine, NS15370 also introduces a distinct time-dependent current decrease, which eventually, at higher concentrations, causes suppression of the current at depolarized potentials, and an apparent "cross-over" of the voltage-activation curve. In brain slices, NS15370 hyperpolarizes and increases spike frequency adaptation of hippocampal CA1 neurons and the compound reduces the autonomous firing of dopaminergic neurons in the substantia-nigra pars compacta. NS15370 is effective in rodent models of hyperexcitability: (i) it yields full protection against mouse 6 Hz seizures and rat amygdala kindling discharges, two models of partial epilepsia; (ii) it reduces (+)-MK-801 hydrogen maleate (MK-801)-induced hyperactivity as well as chlordiazepoxide (CDP)+d-amphetamine (AMP)-induced hyperactivity, models sensitive to classic anti-psychotic and anti-manic treatments, respectively. Our findings with NS15370 consolidate neuronal K(v)7 channels as targets for anti-epileptic and psychiatric drug development. (C) 2013 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ejphar.2013.03.039
• 作为产物：
  描述：

  (4-fluorobenzyl)(6-(morpholin-4-yl)-5-nitropyridin-2-yl)amine 在 一水合肼 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 生成 2-(3,5-difluorophenyl)-N-[6-(4-fluorobenzylamino)-2-(morpholin-4-yl)pyridin-3-yl]acetamide
  参考文献：
  名称：

  Characterization of a novel high-potency positive modulator of Kv7 channels

  摘要：

  K(v)7 channel activators decrease neuronal excitability and might potentially treat neuronal hyperexcitability disorders like epilepsy and mania. Here we introduce NS15370 ((2-(3,5-difluorophenyl)-N-[6-[(4-fluorophenyl)methylamino]-2-morpholino-3-pyridyl]acetamide)hydrochloride, an in vitro high-potency chemical analogue of retigabine, without effects on GABA(A) receptors. NS15370 activates recombinant homo- and heteromeric K(v)7.2-K(v)7.5 channels in HEK293 cells at sub-micromolar concentrations (EC50 similar to 100 nM, as quantified by a fluorescence based TI+-influx assay). In voltage clamp experiments NS15370 exhibits a complex, concentration-dependent mode-of-action: At low concentrations it accelerates voltage-dependent activation rates, slows deactivations, and increases steady-state current amplitudes. Quantified by the peak-tail current method, the V-1/2 value of the steady-state activation curve is shifted towards hyperpolarized potentials at concentrations similar to 100 times lower than retigabine. However, in contrast to retigabine, NS15370 also introduces a distinct time-dependent current decrease, which eventually, at higher concentrations, causes suppression of the current at depolarized potentials, and an apparent "cross-over" of the voltage-activation curve. In brain slices, NS15370 hyperpolarizes and increases spike frequency adaptation of hippocampal CA1 neurons and the compound reduces the autonomous firing of dopaminergic neurons in the substantia-nigra pars compacta. NS15370 is effective in rodent models of hyperexcitability: (i) it yields full protection against mouse 6 Hz seizures and rat amygdala kindling discharges, two models of partial epilepsia; (ii) it reduces (+)-MK-801 hydrogen maleate (MK-801)-induced hyperactivity as well as chlordiazepoxide (CDP)+d-amphetamine (AMP)-induced hyperactivity, models sensitive to classic anti-psychotic and anti-manic treatments, respectively. Our findings with NS15370 consolidate neuronal K(v)7 channels as targets for anti-epileptic and psychiatric drug development. (C) 2013 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ejphar.2013.03.039

文献信息

• [EN] NOVEL 2-MORPHOLINO-3-AMIDO-PYRIDINE DERIVATIVES AND THEIR MEDICAL USE<br/>[FR] NOUVEAUX DÉRIVÉS DE 2-MORPHOLINO-3-AMIDOPYRIDINE ET LEUR UTILISATION MÉDICALE
  申请人：NEUROSEARCH AS

  公开号：WO2010060955A1

  公开（公告）日：2010-06-03

  The present application discloses novel 2-morpholino-3-amido-pyhcline derivatives and their use as modulators of the voltage gated KV7 (KCNQ) potassium ion channels in the treatment of pain, neurodegenerative disorders, urinary incontinence, etc... In other aspects the application discloses the use of these compounds, in a method for therapy and to pharmaceutical compositions comprising these compounds.

  本申请公开了新颖的2-吗啉基-3-酰胺基吡啶衍生物，以及它们作为调节电压门控KV7（KCNQ）钾离子通道在治疗疼痛、神经退行性疾病、尿失禁等方面的用途。在其他方面，该申请公开了这些化合物的用途，以及用于治疗的方法和包含这些化合物的药物组合物。
• NOVEL 2-MORPHOLINO-3-AMIDO-PYRIDINE DERIVATIVES AND THEIR MEDICAL USE
  申请人：Brown William Dalby

  公开号：US20110312962A1

  公开（公告）日：2011-12-22

  The present application discloses novel 2-morpholino-3-amido-pyhcline derivatives and their use as modulators of the voltage gated K v 7 (KCNQ) potassium ion channels in the treatment of pain, neurodegenerative disorders, urinary incontinence, etc. . . . . In other aspects the application discloses the use of these compounds, in a method for therapy and to pharmaceutical compositions comprising these compounds.

  本申请公开了新型2-吗啉基-3-酰胺基吡啶衍生物及其在治疗疼痛、神经退行性疾病、尿失禁等方面作为电压门控Kv7（KCNQ）钾离子通道调节剂的用途。此外，该申请还公开了这些化合物的用途，用于治疗方法和包含这些化合物的药物组合物。
• Characterization of a novel high-potency positive modulator of Kv7 channels
  作者：William Dalby-Brown、Carsten Jessen、Charlotte Hougaard、Marianne L. Jensen、Thomas A. Jacobsen、Karin S. Nielsen、Helle K. Erichsen、Morten Grunnet、Philip K. Ahring、Palle Christophersen、Dorte Strøbæk、Susanne Jørgensen

  DOI：10.1016/j.ejphar.2013.03.039

  日期：2013.6

  K(v)7 channel activators decrease neuronal excitability and might potentially treat neuronal hyperexcitability disorders like epilepsy and mania. Here we introduce NS15370 ((2-(3,5-difluorophenyl)-N-[6-[(4-fluorophenyl)methylamino]-2-morpholino-3-pyridyl]acetamide)hydrochloride, an in vitro high-potency chemical analogue of retigabine, without effects on GABA(A) receptors. NS15370 activates recombinant homo- and heteromeric K(v)7.2-K(v)7.5 channels in HEK293 cells at sub-micromolar concentrations (EC50 similar to 100 nM, as quantified by a fluorescence based TI+-influx assay). In voltage clamp experiments NS15370 exhibits a complex, concentration-dependent mode-of-action: At low concentrations it accelerates voltage-dependent activation rates, slows deactivations, and increases steady-state current amplitudes. Quantified by the peak-tail current method, the V-1/2 value of the steady-state activation curve is shifted towards hyperpolarized potentials at concentrations similar to 100 times lower than retigabine. However, in contrast to retigabine, NS15370 also introduces a distinct time-dependent current decrease, which eventually, at higher concentrations, causes suppression of the current at depolarized potentials, and an apparent "cross-over" of the voltage-activation curve. In brain slices, NS15370 hyperpolarizes and increases spike frequency adaptation of hippocampal CA1 neurons and the compound reduces the autonomous firing of dopaminergic neurons in the substantia-nigra pars compacta. NS15370 is effective in rodent models of hyperexcitability: (i) it yields full protection against mouse 6 Hz seizures and rat amygdala kindling discharges, two models of partial epilepsia; (ii) it reduces (+)-MK-801 hydrogen maleate (MK-801)-induced hyperactivity as well as chlordiazepoxide (CDP)+d-amphetamine (AMP)-induced hyperactivity, models sensitive to classic anti-psychotic and anti-manic treatments, respectively. Our findings with NS15370 consolidate neuronal K(v)7 channels as targets for anti-epileptic and psychiatric drug development. (C) 2013 Elsevier B.V. All rights reserved.