(+/-)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-4-(trifluoromethyl)-2H-indol-2-one | 385764-32-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (+/-)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-4-(trifluoromethyl)-2H-indol-2-one
• 英文别名: 3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-4-(trifluoromethyl)-2H-indol-2-one；3-(5-chloro-2-methoxyphenyl)-3-hydroxy-4-(trifluoromethyl)-1H-indol-2-one
• CAS: 385764-32-9
• 化学式: C₁₆H₁₁ClF₃NO₃
• 分子量: 357.716
• InChiKey: YPRZABXOGOECNI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  58.6
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (+/-)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-4-(trifluoromethyl)-2H-indol-2-one 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 生成 (+/-)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-4-(trifluoromethyl)-2H-indol-2-one
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of 3-Aryloxindoles:  A New Class of Calcium-Dependent, Large Conductance Potassium (Maxi-K) Channel Openers with Neuroprotective Properties

  摘要：

  A series of 3-aryloxindole derivatives were synthesized and evaluated as activators of the cloned maxi-K channel mSlo expressed in Xenopus laevis oocytes using electrophysiological methods. The most promising maxi-K openers to emerge from this study were (+/-)-3(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one ((+/-)-8c) and its 3-deshydroxy analogue (+/-)-11b. The individual enantiomers of (+/-)-8c were synthesized, and the maxi-K channel-opening properties were shown to depend on the absolute configuration of the single stereogenic center with the efficacy of (-)-8c superior to that of both (+)-8c and the racemic mixture when evaluated at a concentration of 20 muM. Racemic 11b exhibited greater efficacy than either the racemic Se or the more active enantiomer in the electrophysiological evaluation. In vitro metabolic stability studies conducted with (+/-)-8c and (+/-)-11b in rat liver S9 microsomal fractions revealed significant oxidative degradation with two hydroxylated metabolites observed by liquid chromatography/mass spectrometry for each compound in addition to the production of Se from 11b. The pharmacokinetic properties of (+/-)-8c and (+/-)11b were determined in rats as a prelude to evaluation in a rat model of stroke that involved permanent occlusion of the middle cerebral artery (MCAO model). In the MCAO model, conducted in the spontaneously hypertensive rat, the more polar 3-hydroxy derivative (+/-)-8c did not demonstrate a significant reduction in cortical infarct volume when administered intravenously at doses ranging from 0.1 to 10 mg/kg as a single bolus 2 h after middle cerebral artery occlusion when compared to vehicle-treated controls. In contrast, intravenous administration of (+/-)-11b at a dose of 0.03 mg/kg was found to reduce the measured cortical infarct volume by approximately 18% when compared to vehicle-treated control animals. Intraperitoneal administration of (+/-)-11b at a dose of 10 mg/kg 2 h following artery occlusion was shown to reduce infarct volume by 26% when compared to vehicle-treated controls. To further probe the effects of compounds (+/-)-8c and (+/-)-11b on neurotransmitter release in vitro, both compounds were examined for their ability to reduce electrically stimulated [H-3]-glutamate release from rat hippocampal slices that had been preloaded with [H-3]-glutamate. Only (+/-) 11b was able to demonstrate a significant inhibition [3H]-glutamate release in this assay at a concentration of 20 muM, providing concordance with the profile of these compounds in the MCAO model. Although (+/-)-11b showed some promise as a potential developmental candidate for the treatment of the sequelae of stroke based on its efficacy in the rat MCAO model, the pharmacokinetic profile of this compound was considered to be less than optimal and was not pursued in favor of derivatives with enhanced metabolic stability.

  DOI：

  10.1021/jm0101850
• 作为产物：
  描述：

  4-三氟甲基-1H-吲哚-2,3-二酮 、 2-methoxy-5-chlorophenylmagnesium bromide 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 生成 (+/-)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-4-(trifluoromethyl)-2H-indol-2-one
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of 3-Aryloxindoles:  A New Class of Calcium-Dependent, Large Conductance Potassium (Maxi-K) Channel Openers with Neuroprotective Properties

  摘要：

  A series of 3-aryloxindole derivatives were synthesized and evaluated as activators of the cloned maxi-K channel mSlo expressed in Xenopus laevis oocytes using electrophysiological methods. The most promising maxi-K openers to emerge from this study were (+/-)-3(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one ((+/-)-8c) and its 3-deshydroxy analogue (+/-)-11b. The individual enantiomers of (+/-)-8c were synthesized, and the maxi-K channel-opening properties were shown to depend on the absolute configuration of the single stereogenic center with the efficacy of (-)-8c superior to that of both (+)-8c and the racemic mixture when evaluated at a concentration of 20 muM. Racemic 11b exhibited greater efficacy than either the racemic Se or the more active enantiomer in the electrophysiological evaluation. In vitro metabolic stability studies conducted with (+/-)-8c and (+/-)-11b in rat liver S9 microsomal fractions revealed significant oxidative degradation with two hydroxylated metabolites observed by liquid chromatography/mass spectrometry for each compound in addition to the production of Se from 11b. The pharmacokinetic properties of (+/-)-8c and (+/-)11b were determined in rats as a prelude to evaluation in a rat model of stroke that involved permanent occlusion of the middle cerebral artery (MCAO model). In the MCAO model, conducted in the spontaneously hypertensive rat, the more polar 3-hydroxy derivative (+/-)-8c did not demonstrate a significant reduction in cortical infarct volume when administered intravenously at doses ranging from 0.1 to 10 mg/kg as a single bolus 2 h after middle cerebral artery occlusion when compared to vehicle-treated controls. In contrast, intravenous administration of (+/-)-11b at a dose of 0.03 mg/kg was found to reduce the measured cortical infarct volume by approximately 18% when compared to vehicle-treated control animals. Intraperitoneal administration of (+/-)-11b at a dose of 10 mg/kg 2 h following artery occlusion was shown to reduce infarct volume by 26% when compared to vehicle-treated controls. To further probe the effects of compounds (+/-)-8c and (+/-)-11b on neurotransmitter release in vitro, both compounds were examined for their ability to reduce electrically stimulated [H-3]-glutamate release from rat hippocampal slices that had been preloaded with [H-3]-glutamate. Only (+/-) 11b was able to demonstrate a significant inhibition [3H]-glutamate release in this assay at a concentration of 20 muM, providing concordance with the profile of these compounds in the MCAO model. Although (+/-)-11b showed some promise as a potential developmental candidate for the treatment of the sequelae of stroke based on its efficacy in the rat MCAO model, the pharmacokinetic profile of this compound was considered to be less than optimal and was not pursued in favor of derivatives with enhanced metabolic stability.

  DOI：

  10.1021/jm0101850

文献信息

• Use of 3-substituted oxindole derivatives as kcnq potassium channel modulators
  申请人：——

  公开号：US20030181507A1

  公开（公告）日：2003-09-25

  The present invention relates to a novel method of treating of pain or anxiety, using compounds that modulate KCNQ potassium channels and currents. 1

  本发明涉及一种治疗疼痛或焦虑的新方法，使用调节KCNQ钾通道和电流的化合物。
• Use of 3-substituted oxindole derivatives as KCNQ potassium channel modulators
  申请人：NEUROSEARCH A/S

  公开号：EP1634594A1

  公开（公告）日：2006-03-15

  The present invention relates to the use of substituted 3-phenyl oxindole derivatives as modulators of the potassium KCNQ channels, to pharmaceutical compositions comprising these compounds, and to methods of treatment herewith.

  本发明涉及取代的 3-苯基吲哚衍生物作为 KCNQ 钾通道调节剂的用途、包含这些化合物的药物组合物以及治疗方法。
• USE OF 3-SUBSTITUTED OXINDOLE DERIVATIVES AS KCNQ POTASSIUM CHANNEL MODULATORS
  申请人：NEUROSEARCH A/S

  公开号：EP1303269B1

  公开（公告）日：2005-12-07
• [EN] USE OF 3-SUBSTITUTED OXINDOLE DERIVATIVES AS KCNQ POTASSIUM CHANNEL MODULATORS<br/>[FR] UTILISATION DE DERIVES D'OXINDOLE 3-SUBSTITUE COMME MODULATEURS DU CANAL POTASSIQUE KCNQ
  申请人：NEUROSEARCH AS

  公开号：WO2002000217A1

  公开（公告）日：2002-01-03

  The present invention relates to the use of substituted 3-phenyl oxindole derivatives having general formula (I), as modulators of the potassium KCNQ channels, to pharmaceutical compositions comprising these compounds, and to methods of treatment herewith.
• Synthesis and Structure−Activity Relationships of 3-Aryloxindoles:  A New Class of Calcium-Dependent, Large Conductance Potassium (Maxi-K) Channel Openers with Neuroprotective Properties
  作者：Piyasena Hewawasam、Matthew Erway、Sandra L. Moon、Jay Knipe、Harvey Weiner、Christopher G. Boissard、Debra J. Post-Munson、Qi Gao、Stella Huang、Valentin K. Gribkoff、Nicholas A. Meanwell

  DOI：10.1021/jm0101850

  日期：2002.3.1

  A series of 3-aryloxindole derivatives were synthesized and evaluated as activators of the cloned maxi-K channel mSlo expressed in Xenopus laevis oocytes using electrophysiological methods. The most promising maxi-K openers to emerge from this study were (+/-)-3(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one ((+/-)-8c) and its 3-deshydroxy analogue (+/-)-11b. The individual enantiomers of (+/-)-8c were synthesized, and the maxi-K channel-opening properties were shown to depend on the absolute configuration of the single stereogenic center with the efficacy of (-)-8c superior to that of both (+)-8c and the racemic mixture when evaluated at a concentration of 20 muM. Racemic 11b exhibited greater efficacy than either the racemic Se or the more active enantiomer in the electrophysiological evaluation. In vitro metabolic stability studies conducted with (+/-)-8c and (+/-)-11b in rat liver S9 microsomal fractions revealed significant oxidative degradation with two hydroxylated metabolites observed by liquid chromatography/mass spectrometry for each compound in addition to the production of Se from 11b. The pharmacokinetic properties of (+/-)-8c and (+/-)11b were determined in rats as a prelude to evaluation in a rat model of stroke that involved permanent occlusion of the middle cerebral artery (MCAO model). In the MCAO model, conducted in the spontaneously hypertensive rat, the more polar 3-hydroxy derivative (+/-)-8c did not demonstrate a significant reduction in cortical infarct volume when administered intravenously at doses ranging from 0.1 to 10 mg/kg as a single bolus 2 h after middle cerebral artery occlusion when compared to vehicle-treated controls. In contrast, intravenous administration of (+/-)-11b at a dose of 0.03 mg/kg was found to reduce the measured cortical infarct volume by approximately 18% when compared to vehicle-treated control animals. Intraperitoneal administration of (+/-)-11b at a dose of 10 mg/kg 2 h following artery occlusion was shown to reduce infarct volume by 26% when compared to vehicle-treated controls. To further probe the effects of compounds (+/-)-8c and (+/-)-11b on neurotransmitter release in vitro, both compounds were examined for their ability to reduce electrically stimulated [H-3]-glutamate release from rat hippocampal slices that had been preloaded with [H-3]-glutamate. Only (+/-) 11b was able to demonstrate a significant inhibition [3H]-glutamate release in this assay at a concentration of 20 muM, providing concordance with the profile of these compounds in the MCAO model. Although (+/-)-11b showed some promise as a potential developmental candidate for the treatment of the sequelae of stroke based on its efficacy in the rat MCAO model, the pharmacokinetic profile of this compound was considered to be less than optimal and was not pursued in favor of derivatives with enhanced metabolic stability.