3-[(1E)-2-羧基乙烯基]-4,6-二氯-1H-吲哚-2-甲酸乙酯 | 159054-14-5

• 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-[(1E)-2-羧基乙烯基]-4,6-二氯-1H-吲哚-2-甲酸乙酯
• 英文名称: ethyl (E)-3-(2'-carboxyethenyl)-4,6-dichloro-1H-indole-2-carboxylate
• 英文别名: (E)-3-(2-carboxyethenyl)-4,6-dichloroindole-2-carboxylic acid ethyl ester；(E)-3-(4,6-dichloro-2-(ethoxycarbonyl)-1H-indol-3-yl)acrylic acid；Ethyl 3-(2-carboxy-vinyl)-4,6-dichloro-1H-indole-2-carboxylate；(E)-3-(4,6-dichloro-2-ethoxycarbonyl-1H-indol-3-yl)prop-2-enoic acid
• CAS: 159054-14-5
• 化学式: C₁₄H₁₁Cl₂NO₄
• 分子量: 328.152
• InChiKey: LKKCOOJMPHIVOU-ONEGZZNKSA-N

物化性质

• 沸点：
  559.7±50.0 °C(Predicted)
• 密度：
  1.520

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  79.4
• 氢给体数：
  2
• 氢受体数：
  4

安全信息

• 危险性防范说明：
  P261,P280,P301+P312,P302+P352,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

反应信息

• 作为反应物：
  描述：

  3-[(1E)-2-羧基乙烯基]-4,6-二氯-1H-吲哚-2-甲酸乙酯 在 三苯基膦 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 5.5h， 生成 (E)-3-[2-[(4-aminophenyl)carbamoyl]vinyl]-4,6-dichloro-1H-indole-2-carboxylic acid ethyl ester
  参考文献：
  名称：

  Substituted Analogues of GV150526 as Potent Glycine Binding Site Antagonists in Animal Models of Cerebral Ischemia

  摘要：

  A series of analogues of the indole-2-carboxylate GV150526, currently in clinical trials as a potential neuroprotective agent for the control of the cerebral damage after stroke onset, was designed based on previous studies dealing with the electronic features of the north-east region of the glycine binding site associated with the NMDA receptor. In particular, the substitution of the para position of the terminal phenyl ring of GV150526 with suitable hydrophilic groups resulted in the identification of a new class of glycine antagonists. These compounds exhibited nanomolar in vitro affinity to the glycine binding site, high receptor selectivity, and outstanding in vivo potency. In particular, 3-[(E)-2-[(4-ureidomethylphenyl)aminocarbonyl]ethenyl]-4,6-dichloroindole-2-carboxylic acid was found to be highly effective in the middle cerebral artery occlusion (MCAo) model in the rat, an animal model of focal ischemia, when given both prior to and after the occlusion of the middle cerebral artery. Notably, a significant; neuroprotective effect was seen in this model postischamia, when the administration of this compound was delayed up to 6 h from the occlusion of the middle cerebral artery, further confirming the wide therapeutic window seen for GV150526A.

  DOI：

  10.1021/jm980576n
• 作为产物：
  描述：

  4,6-二氯-3-甲酰基-1H-吲哚-2-甲酸乙酯 在 三氟乙酸 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 1.0h， 生成 3-[(1E)-2-羧基乙烯基]-4,6-二氯-1H-吲哚-2-甲酸乙酯
  参考文献：
  名称：

  3取代的1H-吲哚-2-羧酸衍生物作为一类新的CysLT1选择性拮抗剂的发现。

  摘要：

  吲哚衍生物3-（（E）-3-（（3-（（E）-2-（7-氯喹啉-2基）乙烯基）苯基）氨基）-3-氧代丙-1-烯-1-基） -7-甲氧基-1H-吲哚-2-羧酸（17k）被确定为一种新型且高效的选择性CysLT1拮抗剂，CysLT1和CysLT2的IC50值为0.0059 +/- 0.0011和15 +/- 4μM，分别。

  DOI：

  10.1021/acsmedchemlett.5b00482

文献信息

• Substituted Indole-2-carboxylates as <i>in Vivo</i> Potent Antagonists Acting as the Strychnine-Insensitive Glycine Binding Site
  作者：Romano Di Fabio、Anna M. Capelli、Nadia Conti、Alfredo Cugola、Daniele Donati、Aldo Feriani、Paola Gastaldi、Giovanni Gaviraghi、Cheryl T. Hewkin、Fabrizio Micheli、Andrea Missio、Manolo Mugnaini、Angelo Pecunioso、Anna M. Quaglia、Emiliangelo Ratti、Luciana Rossi、Giovanna Tedesco、David G. Trist、Angelo Reggiani

  DOI：10.1021/jm960644a

  日期：1997.3.1

  strychnine-insensitive glycine binding site (noncompetitive inhibition of the binding of [3H]TCP, pA2 = 8.1) displaying nanomolar affinity for the glycine binding site (pKi = 8.5), coupled with high glutamate receptor selectivity (> 1000-fold relative to the affinity at the NMDA, AMPA, and kainate binding sites). This indole derivative inhibited convulsions induced by NMDA in mice, when administered by both

  合成了一系列在吲哚核的C-3位置带有合适链的吲哚-2-羧酸盐，并使用[3H]甘氨酸结合测定对体外亲和力进行了评估，并通过抑制N-诱导的惊厥来对体内效力进行了评估。小鼠中的D-天冬氨酸甲酯（NMDA）。3- [2-[（（苯基氨基）羰基]乙烯基] -4,6-二氯吲哚-2-羧酸（8）是对苯丙氨酸不敏感的甘氨酸结合位点的拮抗剂（对[3H] TCP的结合进行非竞争性抑制，pA2 = 8.1），显示出对甘氨酸结合位点的纳摩尔亲和力（pKi = 8.5），并具有高谷氨酸受体选择性（相对于NMDA，AMPA和海藻酸酯结合位点的亲和力> 1000倍）。当通过静脉和口服途径给药时（ED50 = 0.06和6 mg / kg，分别）。研究了取代基对C-3侧链的末端苯环的影响。QSAR分析表明，pKi值随亲脂性和取代基的空间体积而降低，并随存在于末端苯环对位的基团的电子供体共振效应而增加。根据这些结果，C-3侧链
• Synthesis and characterization of 4,6-dichloroindole-based radioligands for imaging the glycine site of the NMDA ion channel
  作者：R. N. Waterhouse、A. Sultana、N. Guo、Bora Lee、N. Simpson、Lee Collier、M. Laruelle

  DOI：10.1002/jlcr.528

  日期：2002.2

  To provide effective PET or SPECT ligands for the glycine binding site of the NMDA ion channel, we have synthesized and characterized in vitro four substituted derivatives of the potent glycine site antagonist 3-[2-[(phenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxylic acid (Ki=3.0 nM). These new ligands contain groups amenable to labeling with C-11 for PET, or I-123 for SPECT. In vitro analysis of these compounds revealed that placement of a methoxy group at either the ortho or para position of the phenylaminocarbonyl group significantly reduced receptor affinity (Ki=74.0±8.1 and 26.5±4.9 nM, respectively), as did placement of an iodine at the para position (Ki=60.4±8.2 nM). However, the meta-methoxy derivative (4b) maintained high affinity (Ki=4.8±0.9 nM) for the glycine site and was therefore labeled with carbon-11 by reacting the corresponding desmethyl derivative with [11C]methyl iodide. Radiochemical yields of 14±10% (EOS), and high specific activity (1.2±0.5 Ci/μmol (EOS, n=7)) were realized, and the product was prepared in a sterile saline solution suitable for in vivo use. Copyright © 2002 John Wiley & Sons, Ltd.

  为了提供有效的正电子发射断层扫描(PET)或单光子发射计算机断层扫描(SPECT)配体，针对NMDA离子通道的甘氨酸结合位点，我们合成并在体外表征了四种强效甘氨酸位点拮抗剂3-[2-[(苯胺基)羧酰乙烯基]-4,6-二氯吲哚-2-羧酸的取代衍生物（Ki=3.0 nM）。这些新配体包含可用于用C-11进行PET标记或I-123进行SPECT标记的基团。对这些化合物的体外分析显示，在苯胺羧酰基的邻位或对位放置甲氧基会显著降低受体亲和力（Ki分别为74.0±8.1 nM和26.5±4.9 nM），在对位放置碘亦会导致亲和力下降（Ki=60.4±8.2 nM）。然而，邻位甲氧基衍生物（4b）对甘氨酸位点保持了高亲和力（Ki=4.8±0.9 nM），因此通过将相应的脱甲基衍生物与[11C]碘甲烷反应进行C-11标记。最终获得的放射化学产率为14±10%（EOS），且高特异活性为1.2±0.5 Ci/μmol（EOS，n=7），所制备的产物使用适合体内使用的无菌生理盐水溶液。版权 © 2002 John Wiley & Sons, Ltd.
• [EN] INDOLE DERIVATIVES AS EAA ANTAGONISTS<br/>[FR] DERIVES DE L'INDOLE UTILISES COMME ANTAGONISTES D'ACIDES AMINES EXCITATEURS
  申请人：GLAXO WELLCOME S.P.A.

  公开号：WO1996027588A1

  公开（公告）日：1996-09-12

  (EN) Compounds of formula (I), or a salt, or metabolically labile ester thereof, processes for their preparation, their use in medicine and intermediates for use in their preparation.(FR) L'invention concerne des composés de la formule (I), un sel de celui-ci, ou un ester de ce composé labile du point de vue métabolique, ainsi que des procédés permettant de les préparer, leur utilisation en médecine et des intermédiaires utilisables pour leur préparation.

  (I)式化合物，或其盐或代谢易变酯类化合物，其制备方法，其在医学上的应用以及用于其制备的中间体。
• Cycloalkyl Indole-2-Carboxylates as Useful Tools for Mapping the "North-Eastern" Region of the Glycine Binding Site Associated with the NMDA Receptor
  作者：Fabrizio Micheli、Romano Di Fabio、Anna M. Capelli、Alfredo Cugola、Ornella Curcuruto、Aldo Feriani、Paola Gastaldi、Giovanni Gaviraghi、Carla Marchioro、Alessandra Orlandi、Alfonso Pozzan、Anna M. Quaglia、Angelo Reggiani、Frank van Amsterdam

  DOI：10.1002/(sici)1521-4184(19993)332:3<73::aid-ardp73>3.0.co;2-5

  日期：1999.3

  A novel series of indole-2-carboxylate analogues of GV 150526 (1) in-which the terminal phenyl ring belonging to the side chain present in the position C-3 has been replaced with a bridged cycloalkyl group was synthesized and evaluated for its pharmacological profile. Modelling studies on this class of novel glycine antagonist allowed us to identify an asymmetric lipophilic pocket present in the "North-Eastern" region of the pharmacophoric model of the glycine binding site associated to the NMDA receptor. Among the derivatives prepared, 3-[2-(1-adamantylaminocarbonyl)ethenyl]-4,6-dichloroindole-2-carboxylic acid 6b and 3-[2(norbornylaminocarbonyl)ethenyl]-4,6-dichloroindole-2-carboxylic acid 61 were found to be antagonists acting at the strychnine-insensitive glycine binding site, showing nanomolar affinity for the glycine binding site (K-i = 63 and 19 nM, respectively), coupled with high glutamate receptor selectivity (IC50 > 10(-5) M at the NMDA, AMPA, KA binding sites) and high in vivo potency after :systemic administration by inhibition of convulsion induced by NMDA in mice.
• Westerberg, Goeran; Carr, Richard M.; Laengstroem, Bengt, Journal of labelled compounds and radiopharmaceuticals, 1997, vol. 40, p. 656 - 657
  作者：Westerberg, Goeran、Carr, Richard M.、Laengstroem, Bengt、Sutherland, Derek R.

  DOI：——

  日期：——