(-)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one | 183720-25-4

• 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-6-(trifluoromethyl)-2H-indol-2-one
• 英文别名: (3R)-3-(5-chloro-2-methoxyphenyl)-3-hydroxy-6-(trifluoromethyl)-1H-indol-2-one
• CAS: 183720-25-4
• 化学式: C₁₆H₁₁ClF₃NO₃
• 分子量: 357.716
• InChiKey: LMNFTYDGFXTVRA-OAHLLOKOSA-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-6-(trifluoromethyl)-2H-indol-2-one 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 以100%的产率得到3-(5-chloro-2-hydroxyphenyl)-3-hydroxy-6-trifluoromethyl-1,3-dihydroindol-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：

  3-(5-氯-2-甲氧基苯基)-1,3-二氢-3-羟基-6-(三氟甲基)-2H-吲哚-2-酮 在 三乙基硅烷 、 (+)-(10-camphorsulfonyl) oxaziridine 、 双(三甲基硅烷基)氨基钾 、 三氟乙酸 作用下， 反应 2.0h， 生成 (-)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one
  参考文献：
  名称：

  DISCOVERY OF A NOVEL CLASS OF BK CHANNEL OPENERS: ENANTIOSPECIFIC SYNTHESIS AND BK CHANNEL OPENING ACTIVITY OF 3-(5-CHLORO-2-HYDROXYPHENYL)-1,3-DIHYDRO-3-HYDROXY-6-(TRIFLUOROMETHYL)-2H-INDOL-2-ONE

  摘要：

  3-Aryl-3-hydroxyindol-2-ones have been identified as a novel class of BK channel openers. Synthesis of both racemic and chiral 3-aryl-3-hydroxyindolones is described along with their electrophysiological evaluation as activators of the cloned BK channel mSlo expressed in Xenopus laevis oocytes. The preliminary SAR data indicate the importance of both an electron-withdrawing substituent on the oxindole nucleus and the phenolic hydroxyl for expression of BK channel opening properties. Moreover, the dependence of BK channel opening activity on the absolute configuration of the chiral center in this pharmacophore has been demonstrated. (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0960-894x(97)00202-3

文献信息

• DISCOVERY OF A NOVEL CLASS OF BK CHANNEL OPENERS: ENANTIOSPECIFIC SYNTHESIS AND BK CHANNEL OPENING ACTIVITY OF 3-(5-CHLORO-2-HYDROXYPHENYL)-1,3-DIHYDRO-3-HYDROXY-6-(TRIFLUOROMETHYL)-2H-INDOL-2-ONE
  作者：Piyasena Hewawasam*、Nicholas A. Meanwell、Valentin K. Gribkoff、Steven I. Dworetzky、Christopher G. Boissard

  DOI：10.1016/s0960-894x(97)00202-3

  日期：1997.5

  3-Aryl-3-hydroxyindol-2-ones have been identified as a novel class of BK channel openers. Synthesis of both racemic and chiral 3-aryl-3-hydroxyindolones is described along with their electrophysiological evaluation as activators of the cloned BK channel mSlo expressed in Xenopus laevis oocytes. The preliminary SAR data indicate the importance of both an electron-withdrawing substituent on the oxindole nucleus and the phenolic hydroxyl for expression of BK channel opening properties. Moreover, the dependence of BK channel opening activity on the absolute configuration of the chiral center in this pharmacophore has been demonstrated. (C) 1997 Elsevier Science Ltd.
• 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.