5-(2-(二甲基氨基)乙氧基)-1H-吲哚-2-羧酸乙酯 | 204915-67-3

• 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: 5-(2-(二甲基氨基)乙氧基)-1H-吲哚-2-羧酸乙酯
• 英文名称: ethyl 5-<2-(dimethylamino)ethoxy>-1H-indole-2-carboxylate
• 英文别名: ethyl 5-(2-dimethylaminoethoxy)indole-2-carboxylate；5-[2-(dimethylamino)-ethoxy]-1H-indole-2-carboxylic acid ethyl ester；ethyl 5-[2-(dimethylamino)ethoxy]indole-2-carboxylate；Ethyl 5-(2-(dimethylamino)ethoxy)-1H-indole-2-carboxylate；ethyl 5-[2-(dimethylamino)ethoxy]-1H-indole-2-carboxylate
• CAS: 204915-67-3
• 化学式: C₁₅H₂₀N₂O₃
• 分子量: 276.335
• InChiKey: QSQXPRJUZJUTIP-UHFFFAOYSA-N

物化性质

• 熔点：
  110 °C
• 沸点：
  432.6±35.0 °C(Predicted)
• 密度：
  1.165±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  20
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  54.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-(2-(二甲基氨基)乙氧基)-1H-吲哚-2-羧酸乙酯 在 水 、 1-羟基苯并三唑 、 caesium carbonate 、 N,N'-二异丙基碳二亚胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 1,1-dimethylethyl N-(3-(5-(2-(dimethylamino)ethoxy)indole-2-carbonyl)-1-((2,2,6,6-tetramethylpiperidin-1-yloxy)methyl)-2,3-dihydrobenzo[e]indol-5-yl)carbamate
  参考文献：
  名称：

  Initial development of a cytotoxic amino-seco-CBI warhead for delivery by prodrug systems

  摘要：

  Cyclopropabenzaindoles (CBIs) are exquisitely potent cytotoxins which bind and alkylate in the minor groove of DNA. They are not selective for cancer cells, so prodrugs are required. CBIs can be formed at physiological pH by Winstein cyclisation of 1-chloromethyl-3-substituted-5-hydroxy-2,3-dihydro-benzo[e] indoles (5-OH-seco-CBIs). Corresponding 5-NH2-seco-CBIs should also undergo Winstein cyclisation similarly. A key triply orthogonally protected intermediate on the route to 5-NH2-seco-CBIs has been synthesised, via selective monotrifluoroacetylation of naphthalene-1,3-diamine, Boc protection, electrophilic iodination, selective allylation at the trifluoroacetamide and 5-exo radical ring-closure with TEMPO. This intermediate has potential for introduction of peptide prodrug masking units (deactivating the Winstein cyclisation and cytotoxicity), addition of diverse indole-amide side-chains (enhancing non-covalent binding prior to alkylation) and use of different leaving groups (replacing the usual chlorine, allowing tuning of the rate of Winstein cyclisation). This key intermediate was elaborated into a simple model 5-NH2-seco-CBI with a dimethylaminoethoxyindole side-chain. Conversion to a bio-reactive entity and the bioactivity of this system were confirmed through DNA-melting studies (Delta T-m = 13 degrees C) and cytotoxicity against LNCaP human prostate cancer cells (IC50 = 18 nM). (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.04.034
• 作为产物：
  描述：

  5-羟基吲哚-2-甲酸 在 盐酸 、 potassium carbonate 作用下， 以 氯仿 、 水 为溶剂， 反应 21.0h， 生成 5-(2-(二甲基氨基)乙氧基)-1H-吲哚-2-羧酸乙酯
  参考文献：
  名称：

  Initial development of a cytotoxic amino-seco-CBI warhead for delivery by prodrug systems

  摘要：

  Cyclopropabenzaindoles (CBIs) are exquisitely potent cytotoxins which bind and alkylate in the minor groove of DNA. They are not selective for cancer cells, so prodrugs are required. CBIs can be formed at physiological pH by Winstein cyclisation of 1-chloromethyl-3-substituted-5-hydroxy-2,3-dihydro-benzo[e] indoles (5-OH-seco-CBIs). Corresponding 5-NH2-seco-CBIs should also undergo Winstein cyclisation similarly. A key triply orthogonally protected intermediate on the route to 5-NH2-seco-CBIs has been synthesised, via selective monotrifluoroacetylation of naphthalene-1,3-diamine, Boc protection, electrophilic iodination, selective allylation at the trifluoroacetamide and 5-exo radical ring-closure with TEMPO. This intermediate has potential for introduction of peptide prodrug masking units (deactivating the Winstein cyclisation and cytotoxicity), addition of diverse indole-amide side-chains (enhancing non-covalent binding prior to alkylation) and use of different leaving groups (replacing the usual chlorine, allowing tuning of the rate of Winstein cyclisation). This key intermediate was elaborated into a simple model 5-NH2-seco-CBI with a dimethylaminoethoxyindole side-chain. Conversion to a bio-reactive entity and the bioactivity of this system were confirmed through DNA-melting studies (Delta T-m = 13 degrees C) and cytotoxicity against LNCaP human prostate cancer cells (IC50 = 18 nM). (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.04.034

文献信息

• Mesylate salt of 5-(2-dimethylaminoethoxy)-1H-indole-2-carboxylic acid [3-(4-hydroxycarbamoylphenyl)prop-2-ynyl]amide
  申请人：Verner J. Erik

  公开号：US20070105939A1

  公开（公告）日：2007-05-10

  The present invention is directed to the mesylate salt of 5-(2-dimethylamino-ethoxy)-1H-indole-2-carboxylic acid [3-(4-hydroxycarbamoylphenyl)prop-2-ynyl]amide, pharmaceutical compositions and processes for preparing the same.

  本发明涉及5-(2-二甲基氨基乙氧基)-1H-吲哚-2-羧酸[3-(4-羟基氨甲酰基苯基)丙-2-炔基]酰胺的甲磺酸盐，药物组合物以及制备该盐的方法。
• Condensed N-aclyindoles as antitumor agents
  申请人：Cancer Research Campaign Technology Limited

  公开号：US06130237A1

  公开（公告）日：2000-10-10

  The invention provides compounds of general formula (I), wherein: X is halogen or OSO.sub.2 R, where R represents H or is unsubstituted or hydroxy-or amino-substituted lower alkyl; Y is a nitro or amine group or a substituted derivative thereof; W is selected from the structures of formulae (Ia, Ib or Ic), where E is --N.dbd. or --CH.dbd., G is O, S, or NH, and Q is either up to three of R, OR, NRR, NO.sub.2, CONHR, NHCOR or NHCONHR, or is an additional group of formulae (Ia, Ib or Ic) and HET represents a 5- or 6-membered carbocycle or heterocycle; and A and B collectively represent a fused benzene or 2-CO.sub.2 R pyrrole ring. In one embodiment, the group Y is an amine derivative substituted by a group which is a substrate for a nitroreductase or carboxypeptidase enzyme such that one of said enzymes is able to bring about removal of that group. ##STR1##

  本发明提供了一般式（I）的化合物，其中：X是卤素或OSO.sub.2 R，其中R代表H或未取代或羟基或氨基取代的低碳基；Y是硝基或胺基或其取代衍生物；W从式（Ia、Ib或Ic）的结构中选择，其中E是--N.dbd.或--CH.dbd.，G是O、S或NH，Q是R、OR、NRR、NO.sub.2、CONHR、NHCOR或NHCONHR中的最多三个，或是公式（Ia、Ib或Ic）的另外一个基团，HET代表一个5-或6-成员的碳环或杂环；A和B共同代表融合苯或2-CO.sub.2R吡咯环。在一个实施例中，群Y是胺衍生物，被一个硝基还原酶或羧肽酶酶的底物取代，以便其中一种酶能够去除该基团。##STR1##
• Synthesis of 1-Substituted 3-(Chloromethyl)-6-aminoindoline (6-Amino-<i>seco</i>-CI) DNA Minor Groove Alkylating Agents and Structure−Activity Relationships for Their Cytotoxicity
  作者：Jared B. J. Milbank、Moana Tercel、Graham J. Atwell、William R. Wilson、Alison Hogg、William A. Denny

  DOI：10.1021/jm980545s

  日期：1999.2.1

  A series of racemic 6-amino-seco-cyclopropylindole (seco-CI) compounds was prepared by coupling 1-(tert-butyloxycarbonyl)-3-(chloromethyl)-6-nitroindoline with appropriate acids, followed by nitro group reduction, and evaluated for cytotoxicity in AA8, UV4, EMT6, and SKOV3 cell lines. These compounds are of interest due to their close structural relationship to known AT-specific alkylating agents and cytotoxins and also for the possible construction of stable amine-based prodrugs designed for tumor-specific release. Variations included indole or furan side chains with different substituents, sulfonamide or carboxamide linkers, extension of the minor groove binding side chain to two subunits, and the use of a pyrroylacryloyl unit previously reported to give extremely potent analogues. The parent compound, with a trimethoxyindole side chain, was a moderately potent cytotoxin (IC50 = 0.34 mu M in AA8 cells, 4 h exposure). A single 5-methoxy group on the indole minor groove binding unit was sufficient to maintain potency, and a series of dimethylaminoethoxy-substituted analogues retained the cytotoxicity of the parent compound, while providing increased aqueous solubility.
• CYCLOPROPYLINDOLE COMPOUNDS AND THEIR USE AS PRODRUGS
  申请人：AUCKLAND UNISERVICES LIMITED

  公开号：EP0938474B1

  公开（公告）日：2005-11-23
• US6130237A
  申请人：——

  公开号：US6130237A

  公开（公告）日：2000-10-10