3-(4-氯苯基)-4-(1-甲基-1H-吲哚-3-基)-1H-吡咯-2,5-二酮 | 125313-99-7

• 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
• 中文名称: 3-(4-氯苯基)-4-(1-甲基-1H-吲哚-3-基)-1H-吡咯-2,5-二酮
• 英文名称: 3-(4-chlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione
• 英文别名: 3-(4-chlorophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione；3-(4-chlorophenyl)-4-(1-methylindol-3-yl)pyrrole-2,5-dione
• CAS: 125313-99-7
• 化学式: C₁₉H₁₃ClN₂O₂
• 分子量: 336.777
• InChiKey: LGGVBRRKUKTEEO-UHFFFAOYSA-N

物化性质

• 密度：
  1.38

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  51.1
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  3-(4-氯苯基)-4-(1-甲基-1H-吲哚-3-基)-1H-吡咯-2,5-二酮 在 正丁基锂 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 6-chloro-8-methylbenzo[a]pyrrolo[3,4-c]carbazole-1,3(2H,8H)-dione
  参考文献：
  名称：

  Synthesis and Initial in Vivo Studies with [¹¹C]SB-216763: The First Radiolabeled Brain Penetrative Inhibitor of GSK-3

  摘要：

  Quantifying glycogen synthase kinase-3 (GSK-3) activity in vivo using positron emission tomography (PET) imaging is of interest because dysregulation of GSK-3 is implicated in numerous diseases and neurological disorders for which GSK-3 inhibitors are being considered as therapeutic strategies. Previous PET radiotracers for GSK-3 have been reported, but none of the published examples cross the blood-brain barrier. Therefore, we have an ongoing interest in developing a brain penetrating radiotracer for GSK-3. To this end, we were interested in synthesis and preclinical evaluation of [C-11]SB-216763, a high-affinity inhibitor of GSK-3 (K-i = 9 nM; IC50 = 34 nM). Initial radiosyntheses of [C-11]SB-216763 proved ineffective in our hands because of competing [3 + 3] sigmatropic shifts. Therefore, we have developed a novel one-pot two-step synthesis of [C-11]SB-216763 from a 2,4-dimethoxybenzyl-protected maleimide precursor, which provided high specific activity [C-11]SB-216763 in 1% noncorrected radiochemical yield (based upon [C-11]CH3I) and 97-100% radiochemical purity (n = 7). Initial preclinical evaluation in rodent and nonhuman primate PET imaging studies revealed high initial brain uptake (peak rodent SUV = 2.5 @ 3 min postinjection; peak nonhuman primate SUV = 1.9 @ 5 min postinjection) followed by washout. Brain uptake was highest in thalamus, striatum, cortex, and cerebellum, areas known to be rich in GSK-3. These results make the arylindolemaleimide skeleton our lead scaffold for developing a PET radiotracer for quantification of GSK-3 density in vivo and ultimately translating it into clinical use.

  DOI：

  10.1021/acsmedchemlett.5b00044
• 作为产物：
  描述：

  对氯苯乙酸 在 ammonium hydroxide 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 生成 3-(4-氯苯基)-4-(1-甲基-1H-吲哚-3-基)-1H-吡咯-2,5-二酮
  参考文献：
  名称：

  Inhibitors of protein kinase C. 1. 2,3-bisarylmaleimides

  摘要：

  The design and synthesis of a series of novel inhibitors of protein kinase C (PKC) is described. These 2,3-bisarylznaleimides were derived from the structural lead provided by the indolocarbazoles, staurosporine and K252a. Optimum activity required the imide NH, both carbonyl groups, and the olefinic bond of the maleimide ring. 2,3-Bisindolylmaleimides were the most active, and the potency of these was improved by a chloro substituent at the 5-position of one indole ring (compound 28, IC50 0.11-mu-M). In a series of (phenylindolyl)maleimides, nitro compound 74 was most active (IC50 0.67-mu-M). Naphthalene 19 and benzothiophene 21 showed greater than 100-fold selectivity for inhibition of PKC over the closely related cAMP-dependent protein kinase (PKA).

  DOI：

  10.1021/jm00079a024

文献信息

• Substituierte Pyrrole
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP0328026A1

  公开（公告）日：1989-08-16

  Pyrrole der allgemeinen Formel worin R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X und Y die in der Beschreibung angegebene Bedeutung haben sind verwendbar bei der Behandlung oder Prophylaxe von inflammatorischen, immunologischen, bronchopulmonären oder cardiovaskulären Krankheiten. Sie werden ausgehend von entsprechend substituierten Furanen oder von auf andere Weise substituierten Pyrrolen hergestellt.

  通式如下的吡咯 其中 R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、X 和 Y 具有说明中给出的含义，可用于治疗或预防炎症、免疫学、支气管肺病或心血管疾病。 它们由适当取代的呋喃或其他取代的吡咯制备而成。
• US5057614A
  申请人：——

  公开号：US5057614A

  公开（公告）日：1991-10-15
• USRE36736E
  申请人：——

  公开号：USRE36736E

  公开（公告）日：2000-06-13
• Inhibitors of protein kinase C. 1. 2,3-bisarylmaleimides
  作者：Peter D. Davis、Christopher H. Hill、Geoffrey Lawton、John S. Nixon、Sandra E. Wilkinson、Steven A. Hurst、Elizabeth Keech、Susan E. Turner

  DOI：10.1021/jm00079a024

  日期：1992.1

  The design and synthesis of a series of novel inhibitors of protein kinase C (PKC) is described. These 2,3-bisarylznaleimides were derived from the structural lead provided by the indolocarbazoles, staurosporine and K252a. Optimum activity required the imide NH, both carbonyl groups, and the olefinic bond of the maleimide ring. 2,3-Bisindolylmaleimides were the most active, and the potency of these was improved by a chloro substituent at the 5-position of one indole ring (compound 28, IC50 0.11-mu-M). In a series of (phenylindolyl)maleimides, nitro compound 74 was most active (IC50 0.67-mu-M). Naphthalene 19 and benzothiophene 21 showed greater than 100-fold selectivity for inhibition of PKC over the closely related cAMP-dependent protein kinase (PKA).
• Synthesis and Initial <i>in Vivo</i> Studies with [¹¹C]SB-216763: The First Radiolabeled Brain Penetrative Inhibitor of GSK-3
  作者：Lei Li、Xia Shao、Erin L. Cole、Stephan A. Ohnmacht、Valentina Ferrari、Young T. Hong、David J. Williamson、Tim D. Fryer、Carole A. Quesada、Phillip Sherman、Patrick J. Riss、Peter J. H. Scott、Franklin I. Aigbirhio

  DOI：10.1021/acsmedchemlett.5b00044

  日期：2015.5.14

  Quantifying glycogen synthase kinase-3 (GSK-3) activity in vivo using positron emission tomography (PET) imaging is of interest because dysregulation of GSK-3 is implicated in numerous diseases and neurological disorders for which GSK-3 inhibitors are being considered as therapeutic strategies. Previous PET radiotracers for GSK-3 have been reported, but none of the published examples cross the blood-brain barrier. Therefore, we have an ongoing interest in developing a brain penetrating radiotracer for GSK-3. To this end, we were interested in synthesis and preclinical evaluation of [C-11]SB-216763, a high-affinity inhibitor of GSK-3 (K-i = 9 nM; IC50 = 34 nM). Initial radiosyntheses of [C-11]SB-216763 proved ineffective in our hands because of competing [3 + 3] sigmatropic shifts. Therefore, we have developed a novel one-pot two-step synthesis of [C-11]SB-216763 from a 2,4-dimethoxybenzyl-protected maleimide precursor, which provided high specific activity [C-11]SB-216763 in 1% noncorrected radiochemical yield (based upon [C-11]CH3I) and 97-100% radiochemical purity (n = 7). Initial preclinical evaluation in rodent and nonhuman primate PET imaging studies revealed high initial brain uptake (peak rodent SUV = 2.5 @ 3 min postinjection; peak nonhuman primate SUV = 1.9 @ 5 min postinjection) followed by washout. Brain uptake was highest in thalamus, striatum, cortex, and cerebellum, areas known to be rich in GSK-3. These results make the arylindolemaleimide skeleton our lead scaffold for developing a PET radiotracer for quantification of GSK-3 density in vivo and ultimately translating it into clinical use.