4-(6-氯-3-硝基-吡啶-2-基)-吗啉 | 1094323-33-7

• 分子结构分类: 有机化合物 - 有机1,3-偶极化合物 - 烯丙基型1,3-偶极有机化合物
• 中文名称: 4-(6-氯-3-硝基-吡啶-2-基)-吗啉
• 英文名称: 4-(6-chloro-3-nitropyridin-2-yl)morpholine
• 英文别名: 4-(6-Chloro-3-nitro-pyridin-2-yl)-morpholine
• CAS: 1094323-33-7
• 化学式: C₉H₁₀ClN₃O₃
• 分子量: 243.65
• InChiKey: QCGWQBVJEDWUQF-UHFFFAOYSA-N

物化性质

• 沸点：
  421.3±45.0 °C(Predicted)
• 密度：
  1.435±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  71.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-(6-氯-3-硝基-吡啶-2-基)-吗啉 在 一水合肼 、 三乙胺 作用下， 以 乙醇 、 水 、 乙腈 为溶剂， 生成 N-2-(4-fluorobenzyl)-6-morpholin-4-yl-pyridine-2,5-diamine
  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：

  吗啉 、 2,6-二氯-3-硝基吡啶 在 三乙胺 作用下， 以 乙腈 为溶剂， 反应 4.0h， 以72%的产率得到4-(6-氯-3-硝基-吡啶-2-基)-吗啉
  参考文献：
  名称：

  氟吡汀和瑞替加滨的硫化物类似物，具有纳摩尔KV 7.2 / KV 7.3通道开放活性。

  摘要：

  钾通道开放剂氟吡汀和瑞替加滨已被证明是有价值的镇痛药或抗癫痫药。它们最近分别由于偶发的肝毒性和组织变色而退出治疗，这使得治疗领域没有被填补。两种药物的代谢氧化都会导致亲电子醌的形成。在长期摄入瑞替加滨后发生氟吡汀和蓝色组织变色的情况下，这些难以捉摸的，高反应性的代谢物可能引起肝损伤。我们研究了可以改变哪些结构特征，以避免芳香环的有害氧化，并使氧化向更良性代谢物的形成转移。进行了结构活性关系研究，以评估45种衍生物的KV 7.2 / 3通道开放活性。鉴定出硫化物类似物没有形成醌的风险，但具有有效的KV 7.2 / 3打开活性。例如，氟吡汀类似物3-（3,5-二氟苯基）-N-（6-（异丁硫基）-2-（吡咯烷-1-基）吡啶-3-基）丙酰胺（48）具有100倍的增强活性（ EC50 = 1.4 nm），大大提高了毒性/活性比，并具有与体外瑞替加滨相同的功效。

  DOI：

  10.1002/cmdc.201900112

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。
• Flupirtine and retigabine as templates for ligand-based drug design of K_V7.2/3 activators
  作者：Abdrrahman S. Surur、Christian Bock、Kristin Beirow、Konrad Wurm、Lukas Schulig、Markus K. Kindermann、Werner Siegmund、Patrick J. Bednarski、Andreas Link

  DOI：10.1039/c9ob00511k

  日期：——

  of the closely related drugs flupirtine and retigabine, respectively. Experience gained with these drugs strongly suggests that heterotetramer, voltage-gated potassium channels 2 and 3 (KV7.2/3) are valid targets for effective treatment of pain and epilepsy. Because the adverse effects are not related to the mechanism of action, it appears promising to investigate chemical modifications of these clinically

  药物性肝损伤（DILI）和组织变色分别导致密切相关的药物氟吡汀和瑞替加滨的治疗最近中断。这些药物获得的经验强烈表明，异四聚体，电压门控钾通道2和3（K V 7.2 / 3）是有效治疗疼痛和癫痫的有效靶点。由于不良反应与作用机理无关，因此研究这些经过临床验证的药物样前导物的化学修饰似乎很有希望。在目前的逆代谢药物设计研究中，合成了一系列43种化合物，并针对K V 7.2 / 3的打开活性和功效进行了表征。活性最高的化合物22d作为K V 7.2 / 3开瓶器，具有出色的效力（EC 50 = 4 nM）和功效（154％）。在高于63μM的浓度下，有限的水溶性阻碍了毒性测试，但是该浓度对培养中的两种肝细胞系（HEP-G2和TAMH）无毒。活性稍差但更易溶的化合物25b（EC 50 = 11 nM，功效111％）与氟吡汀相比，毒性/活性比提高了三个数量级，并代表了引人注目的铅结构，可用于开发更安全的镇痛药和抗癫痫药。
• 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。
• EP3885346
  申请人：——

  公开号：——

  公开（公告）日：——
• 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.