3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one | 183720-17-4

• 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-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one
• 英文别名: 3-(5-chloro-2-hydroxyphenyl)-3-hydroxy-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one；(+/-)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one；3-Hydroxy-3-(2-hydroxy-5-chlorophenyl)-6-(trifluoromethyl)indoline-2-one；3-(5-chloro-2-hydroxyphenyl)-3-hydroxy-6-(trifluoromethyl)-1H-indol-2-one
• CAS: 183720-17-4
• 化学式: C₁₅H₉ClF₃NO₃
• 分子量: 343.69
• InChiKey: GMUVMLWENGMHNR-UHFFFAOYSA-N

物化性质

• 熔点：
  200-201 °C
• 沸点：
  521.6±50.0 °C(Predicted)
• 密度：
  1.601±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  69.6
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one 在 caesium carbonate 、 4,4'-二氨基二苯乙烯-2,2'-二磺酸 作用下， 以 乙醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.5h， 生成 (S)-3-(5-chloro-2-[OC3H3]methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one
  参考文献：
  名称：

  Synthesis of3H and14C labeled (S)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one, maxipost?. An agent for post-stroke neuroprotection

  摘要：

  报告了氚标记的(S)-3-(5-氯-2-[OC3H3]甲氧基苯基)-1,3-二氢-3-氟-6-(三氟甲基)-1H-吲哚-2-酮和碳-14标记的(S)-3-(5-氯-2-甲氧基苯基)-1,3-二氢-3-氟-6-(三氟甲基)-2H-[2,3-14C2]吲哚-2-酮的合成。3H标记的化合物是通过从C3H3I进行两步合成制备的。最终产物通过手性HPLC纯化，得到所需的对映体，放化产率为4%，比活度为60 Ci/mmol。14C标记的化合物是通过从二乙基[羧酸-14C1,2]草酸酯进行四步合成制备的。最终产物通过手性HPLC纯化，得到所需的对映体，放化产率为20%，比活度为28.4 μCi/mg。版权所有 © 2002 John Wiley & Sons, Ltd.

  DOI：

  10.1002/jlcr.652
• 作为产物：
  描述：

  2-methoxy-5-chlorophenylmagnesium bromide 在 三溴化硼 、 sodium hydride 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 3-(5-Chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(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

• 3-substituted oxindole derivatives as potassium channel modulators
  申请人：Bristol-Myers Squibb Company

  公开号：US05602169A1

  公开（公告）日：1997-02-11

  There is provided novel substituted 3-phenyl oxindole derivatives of the formula ##STR1## wherein R is hydrogen, hydroxy or fluoro; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each are independently hydrogen, C.sub.1-4 alkyl, halogen, trifluoromethyl, phenyl, p-methylphenyl or p-trifluoromethylphenyl; or R.sup.1 and R.sup.2, R.sup.2 and R.sup.3 or R.sup.3 and R.sup.4 are joined together to form a benzo fused ring; R.sup.5 is hydrogen or C.sub.1-4 alkyl; and R.sup.6 is chlorine or trifluoromethyl; or a nontoxic pharmaceutically acceptable salt, solvate or hydrate thereof, which are openers of the large-conductance calcium-activated potassium channels and are useful in the treatment of disorders which are responsive to the opening of the potassium channels.

  提供了一种新颖的取代3-苯基噁唑酮衍生物，其化学式为##STR1##其中R为氢、羟基或氟；R.sup.1、R.sup.2、R.sup.3和R.sup.4分别独立地为氢、C.sub.1-4烷基、卤素、三氟甲基、苯基、对甲基苯基或对三氟甲基苯基；或者R.sup.1和R.sup.2、R.sup.2和R.sup.3或R.sup.3和R.sup.4结合在一起形成苯并环；R.sup.5为氢或C.sub.1-4烷基；R.sup.6为氯或三氟甲基；或其无毒药学上可接受的盐、溶剂或水合物，这些化合物是大导电性钙激活钾通道的开放剂，可用于治疗对钾通道开放有响应的疾病。
• Methods for treating hyperactive gastric motility
  申请人：Wyeth

  公开号：US20020183395A1

  公开（公告）日：2002-12-05

  This invention provides methods and pharmaceutical compositions for treating, inhibiting or preventing hyperactive gastric motility in a mammal utilizing agonists of KCNQ potassium channels, including KCNQ2, KCNQ3, KCNQ4 and KCNQ5 potassium channels, alone or in combination. The hyperactive gastric motility may be associated with maladies including, colitis, irritable bowel syndrome and Crohn's disease. Compounds useful in these methods include the 1,2,4-triamino-benzene derivatives described in U.S. Pat. No. 5,384,330 (Dieter et al.) and the substituted 3-phenyl oxindole compounds described in U.S. Pat. No. 5,565,483 (Hewawasam et al.). Among the preferred compounds of this invention is N-[2-amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester, also referred to as retigabine.

  这项发明提供了治疗、抑制或预防哺乳动物胃动力亢进的方法和药物组合，利用KCNQ钾通道的激动剂，包括KCNQ2、KCNQ3、KCNQ4和KCNQ5钾通道，单独或组合使用。胃动力亢进可能与疾病有关，包括结肠炎、肠易激综合征和克罗恩病。这些方法中有用的化合物包括美国专利号5,384,330（Dieter等人）中描述的1,2,4-三氨基苯衍生物和美国专利号5,565,483（Hewawasam等人）中描述的取代3-苯基恩哌啶化合物。这项发明的首选化合物之一是N-[2-氨基-4-(4-氟苯基氨基)苯基]碳酸乙酯，也称为雷替加宾。
• 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。
• Fluoro oxindole derivatives as modulators of KCNQ potassium channels
  申请人：——

  公开号：US20020156120A1

  公开（公告）日：2002-10-24

  There is provided novel 3-fluoro-3-phenyl oxindole derivatives of Formula I 1 wherein R 1 , R 2 , R 3 and R 4 each are independently hydrogen, C 1-4 alkyl, halogen, fluoromethyl, trifluoromethyl, phenyl, 4-methylphenyl or 4-trifluoromethylphenyl; R 5 is C 1-6 alkyl optionally substituted with one to three same or different groups selected from fluoro and chloro, provided R 5 is not C 1-6 alkyl when Y is O; Y is O or S; and R 6 and R 7 each are independently hydrogen, chloro, bromo or trifluoromethy; which are openers of the KCNQ potassium channels and are useful in the treatment of disorders which are responsive to the opening of the KCNQ potassium channels.

  提供了一种新的式I1的3-氟-3-苯基吲哚衍生物，其中R1、R2、R3和R4各自独立地为氢、C1-4烷基、卤素、氟甲基、三氟甲基、苯基、4-甲基苯基或4-三氟甲基苯基；R5为C1-6烷基，可选地取代一到三个相同或不同的氟或氯基，但当Y为O时，R5不为C1-6烷基；Y为O或S；R6和R7各自独立地为氢、氯、溴或三氟甲基；它们是KCNQ钾通道的开放剂，可用于治疗对KCNQ钾通道开放有反应的疾病。
• Fluoro oxindole derivatives as modulators if KCNQ potassium channels
  申请人：Bristol-Myers Squibb Company

  公开号：US06469042B1

  公开（公告）日：2002-10-22

  There is provided novel 3-fluoro-3-phenyl oxindole derivatives of Formula I wherein R1, R2, R3 and R4 each are independently hydrogen, C1-4 alkyl, halogen, fluoromethyl, trifluoromethyl, phenyl, 4-methylphenyl or 4-trifluoromethylphenyl; R5 is C1-6 alkyl optionally substituted with one to three same or different groups selected from fluoro and chloro, provided R5 is not C1-6 alkyl when Y is O; Y is O or S; and R6 and R7 each are independently hydrogen, chloro, bromo or trifluoromethy; which are openers of the KCNQ potassium channels and are useful in the treatment of disorders which are responsive to the opening of the KCNQ potassium channels.

  提供了一种新型的公式I的3-氟-3-苯基氧吲哚衍生物，其中R1、R2、R3和R4各自独立地为氢、C1-4烷基、卤素、氟甲基、三氟甲基、苯基、4-甲基苯基或4-三氟甲基苯基；R5为C1-6烷基，可选地取代一到三个相同或不同的氟或氯基，当Y为O时，R5不是C1-6烷基；Y为O或S；R6和R7各自独立地为氢、氯、溴或三氟甲基。这些化合物是KCNQ钾通道的开放剂，可用于治疗对KCNQ钾通道的开放有反应的疾病。