2-chloro-7-hydroxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one | 1221486-48-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 二苯并环庚烯
• 英文名称: 2-chloro-7-hydroxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one
• 英文别名: 2-chloro-7-hydroxy-10,11-dihydro-dibenzo[a,d]cyclohepten-5-one；2-chloro-7-hydroxydibenzosuberone；13-chloro-5-hydroxytricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-one
• CAS: 1221486-48-1
• 化学式: C₁₅H₁₁ClO₂
• 分子量: 258.704
• InChiKey: BTAKXKSVUMREGV-UHFFFAOYSA-N

物化性质

• 沸点：
  452.1±45.0 °C(Predicted)
• 密度：
  1.356±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  18
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-chloro-7-hydroxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one 在 palladium diacetate 、 potassium carbonate 、 sodium t-butanolate 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 、 叔丁醇 为溶剂， 反应 3.5h， 生成 2-(2-aminophenylamino)-7-(2-morpholin-4-yl-ethoxy)-10,11-dihydro-dibenzo[a,d]-cyclohepten-5-one
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Novel Disubstituted Dibenzosuberones as Highly Potent and Selective Inhibitors of p38 Mitogen Activated Protein Kinase

  摘要：

  Synthesis, biological testing, structure-activity relationships (SARs), and selectivity of novel disubstituted dibenzosuberone derivatives as p38 MAP kinase inhibitors are described. Hydrophilic moieties were introduced at the 7-, 8-, and 9-position of the 2-phenylamino-dibenzosuberones, improving physicochemical properties as well as potency. Extremely potent inhibitors were obtained, with half-maximal inhibitory concentration (IC50) values in the low nM range in a whole blood assay measuring the inhibition of cytokine release. The high potency of the target compounds together with the outstanding selectivity of this novel class of compounds toward p38 mitogen activated protein (MAP) kinase compared to other kinases indicate them to be most applicable as tools in pharmacological research and eventually they may foster a new generation of anti-inflammatory drugs.

  DOI：

  10.1021/jm300327h
• 作为产物：
  描述：

  6-甲氧基-3H-异苯并呋喃-1-酮 在 N-溴代丁二酰亚胺(NBS) 、 氯化亚砜 、 偶氮二异丁腈 、 palladium on activated charcoal 、 氢溴酸 、 氢气 、 溶剂黄146 、 三苯基膦 作用下， 以 甲醇 、 二氯甲烷 、 水 、 乙酸乙酯 、 氯苯 、 乙腈 为溶剂， 反应 15.0h， 生成 2-chloro-7-hydroxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Novel Disubstituted Dibenzosuberones as Highly Potent and Selective Inhibitors of p38 Mitogen Activated Protein Kinase

  摘要：

  Synthesis, biological testing, structure-activity relationships (SARs), and selectivity of novel disubstituted dibenzosuberone derivatives as p38 MAP kinase inhibitors are described. Hydrophilic moieties were introduced at the 7-, 8-, and 9-position of the 2-phenylamino-dibenzosuberones, improving physicochemical properties as well as potency. Extremely potent inhibitors were obtained, with half-maximal inhibitory concentration (IC50) values in the low nM range in a whole blood assay measuring the inhibition of cytokine release. The high potency of the target compounds together with the outstanding selectivity of this novel class of compounds toward p38 mitogen activated protein (MAP) kinase compared to other kinases indicate them to be most applicable as tools in pharmacological research and eventually they may foster a new generation of anti-inflammatory drugs.

  DOI：

  10.1021/jm300327h

文献信息

• DIBENZOCYCLOHEPTATONE DERIVATIVES AND PHARMACEUTICAL AGENTS CONTAINING SAID COMPOUNDS
  申请人：Laufer Stefan

  公开号：US20120115862A1

  公开（公告）日：2012-05-10

  The present invention relates to compounds of the formula I wherein R1, R2, R3, R4, X and Y have the meanings given in the description. The compounds have an action which is immunomodulating and inhibits or regulates the release of IL-1β and/or TNF-α. They can therefore be used for treatment of diseases connected with a disturbance in the immune system.

  本发明涉及公式I中的化合物，其中R1、R2、R3、R4、X和Y的含义如描述中所述。这些化合物具有免疫调节作用，并抑制或调节IL-1β和/或TNF-α的释放。因此，它们可以用于治疗与免疫系统紊乱有关的疾病。
• Improved Multigram Route to a Tricyclic Key Intermediate for Dibenzosuberone-Based p38 Inhibitors via an Optimized Early-Stage Heck Coupling
  作者：Michael Forster、Heike K. Wentsch-Teltschik、Stefan A. Laufer

  DOI：10.1021/acs.oprd.1c00081

  日期：2021.8.20

  inflammatory as well as oncologic indications. The increasing demand of key intermediates and final compounds caused by the ongoing development of this inhibitor class urged the conception of an optimized route for the preparation of the core dibenzosuberone scaffold in multigram quantities. Rerouting of the initial discovery route resulted in an almost 4-fold increase of overall yield to 46%, the elimination

  在过去的二十年中，p38α MAP 激酶一直是一个深入研究的目标。基于二苯并芴酮的 p38 抑制剂的结构类别，以有希望的候选 skepinone-L 为例，已经在多个炎症和肿瘤适应症的体内模型中得到成功验证。由于此类抑制剂的持续开发，对关键中间体和最终化合物的需求不断增加，促使人们构思出用于制备数克数量的核心二苯并芴酮支架的优化路线。最初发现路线的改道导致总产率提高了近 4 倍，达到 46%，消除了色谱纯化，并取代了两个关键反应步骤，这阻碍了可行的放大。关键的改进是基于 Buchwald 预催化剂的早期 Heck 偶联的引入和优化，允许在多克规模下始终保持高产率（约 90%），并具有 0.1 mol% 的低 Pd 负载。这种新开发的合成获得了二苯并芴酮中间体 2-chloro-7-hydroxy-10,11-dihydro-5H -dibenzo[ a , d ][7] annulen-5-one
• Dibenzocycloheptanonderivate und pharmazeutische Mittel, welche diese Verbindungen enthalten
  申请人：c-a-i-r biosciences GmbH

  公开号：EP2206534A1

  公开（公告）日：2010-07-14

  Die vorliegende Erfindung betrifft Verbindungen der Formel I worin R1, R2, R3, R4, X und Y die in der Beschreibung angegebenen Bedeutungen besitzen. Die Verbindungen besitzen immunmodulierende und die Freisetzung von IL-1β und/oder TNF-α inhibierende bzw. regulierende Wirkung. Sie sind daher zur Behandlung von Erkrankungen brauchbar, die im Zusammenhang mit einer Störung des Immunsystems stehen.

  本发明涉及式 I 的化合物 其中 R1、R2、R3、R4、X 和 Y 具有说明中给出的含义。这些化合物具有免疫调节和 IL-1β 和/或 TNF-α 释放抑制或调节活性。因此，它们可用于治疗与免疫系统紊乱有关的疾病。
• Dibenzosuberones as p38 Mitogen-Activated Protein Kinase Inhibitors with Low ATP Competitiveness and Outstanding Whole Blood Activity
  作者：Stefan Fischer、Heike K. Wentsch、Svenja C. Mayer-Wrangowski、Markus Zimmermann、Silke M. Bauer、Kirsten Storch、Raimund Niess、Solveigh C. Koeberle、Christian Grütter、Frank M. Boeckler、Daniel Rauh、Stefan A. Laufer

  DOI：10.1021/jm301539x

  日期：2013.1.10

  p38 alpha mitogen-activated protein (MAP) kinase is a main target in drug research concerning inflammatory diseases. Nevertheless, no inhibitor of p38 alpha MAP kinase has been introduced to the market. This might be attributed to the fact that there is no inhibitor which combines outstanding activity in biological systems and selectivity. Herein an approach to the development of such inhibitors on the basis of the highly selective molecular probe Skepinone-L is described. Introduction of a "deep pocket" moiety addressing the DFG motif led to an increased activity of the compounds. Hydrophilic moieties, addressing the solvent-exposed area adjacent to hydrophilic region II, conserved a high activity of the compounds in a whole blood assay. Combined with their outstanding selectivity and low ATP competitiveness, these inhibitors are very interesting candidates for use in biological systems and in therapy.
• DIBENZOCYCLOHEPTANONDERIVATE UND PHARMAZEUTISCHE MITTEL, WELCHE DIESE VERBINDUNGEN ENTHALTEN
  申请人：c-a-i-r biosciences GmbH

  公开号：EP2349964A2

  公开（公告）日：2011-08-03