9-bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile | 1256579-66-4

• 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: 9-bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
• 英文别名: 9-bromo-6,6-dimethyl-8-(4-oxetan-3-ylpiperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile；9-bromo-6,6-dimethyl-8-[4-(oxetan-3-yl)piperazin-1-yl]-11-oxo-5H-benzo[b]carbazole-3-carbonitrile
• CAS: 1256579-66-4
• 化学式: C₂₆H₂₅BrN₄O₂
• 分子量: 505.414
• InChiKey: RUHPGASDSDOKTE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  33
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  72.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  9-bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile 在 双(乙腈)氯化钯(II) 、 palladium 10% on activated carbon 、 氢气 、 caesium carbonate 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 四氢呋喃 、 甲醇 、 乙腈 为溶剂， 反应 16.0h， 生成 9-(2-cyclopentylethyl)-6,6-dimethyl-8-(4-(oxetan-3-yl)piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
  参考文献：
  名称：

  9-Substituted 6,6-Dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles as Highly Selective and Potent Anaplastic Lymphoma Kinase Inhibitors

  摘要：

  9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E(0) region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compound 13d showed highly selective and potent inhibitory activity against ALK with an IC(50) value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC(50) value of 12.8 nM. The compound also displayed significant antitumor efficacy in an established ALK fusion gene-positive anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body weight loss.

  DOI：

  10.1021/jm200652u
• 作为产物：
  描述：

  7-甲氧基-1,1-二甲基-3,4-二氢萘-2(1H)-酮 在 吡啶 、 N-溴代丁二酰亚胺(NBS) 、 吡啶盐酸盐 、 sodium cyanoborohydride 、 三氟乙酸 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 甲醇 、 水 、 溶剂黄146 、 乙腈 为溶剂， 反应 35.0h， 生成 9-bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
  参考文献：
  名称：

  9-Substituted 6,6-Dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles as Highly Selective and Potent Anaplastic Lymphoma Kinase Inhibitors

  摘要：

  9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E(0) region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compound 13d showed highly selective and potent inhibitory activity against ALK with an IC(50) value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC(50) value of 12.8 nM. The compound also displayed significant antitumor efficacy in an established ALK fusion gene-positive anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body weight loss.

  DOI：

  10.1021/jm200652u

文献信息

• Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802)
  作者：Kazutomo Kinoshita、Kohsuke Asoh、Noriyuki Furuichi、Toshiya Ito、Hatsuo Kawada、Sousuke Hara、Jun Ohwada、Takuho Miyagi、Takamitsu Kobayashi、Kenji Takanashi、Toshiyuki Tsukaguchi、Hiroshi Sakamoto、Takuo Tsukuda、Nobuhiro Oikawa

  DOI：10.1016/j.bmc.2011.12.021

  日期：2012.2

  Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, especially non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains

  间变性淋巴瘤激酶（ALK）受体酪氨酸激酶被认为是人类癌症，尤其是非小细胞肺癌（NSCLC）的有吸引力的治疗靶标。我们以前的研究表明，6,6-二甲基-11-氧代-6,11-二氢-5 H-苯并[ b ]咔唑支架的8,9侧链会严重影响激酶的选择性，细胞活性和代谢稳定性。在这项工作中，我们优化了侧链，并确定了具有高度选择性，口服活性且有效的ALK抑制剂CH5424802（18a）作为临床候选药物。
• TETRACYCLIC COMPOUND
  申请人：Kinoshita Kazutomo

  公开号：US20120083488A1

  公开（公告）日：2012-04-05

  A compound represented by the general Formula (I) below, or a salt or solvate thereof, which is useful as an ALK inhibitor, and is useful for prophylaxis or treatment of a disease accompanied by abnormality in ALK, for example, cancer, cancer metastasis, depression or cognitive function disorder: (meanings of the symbols that are included in the formula are as given in the specification).

  一种由下面的一般式（I）表示的化合物，或其盐或溶剂化物，可用作ALK抑制剂，对于伴有ALK异常的疾病的预防或治疗是有用的，例如癌症、癌症转移、抑郁症或认知功能障碍（方程式中包含的符号的含义如规范中所述）。
• COMPOSITION COMPRISING TETRACYCLIC COMPOUND
  申请人：Furumoto Kentaro

  公开号：US20130143877A1

  公开（公告）日：2013-06-06

  A composition which comprises substance represented by Formula (I), [Meanings of the symbols that are included in the formula are given in the specification as definitions] a pharmaceutically acceptable carrier, and a dissolution aid. is useful for improving solubility, oral absorbability and/or absorbability in blood of a poorly water-soluble or water insoluble tetracyclic compounds having an ALK inhibitory activity that are useful as a prophylactic and/or therapeutic agent for cancer, depression, and cognitive function disorder.

  由公式（I）代表的物质，药用可接受的载体和溶解助剂组成的组合物，可用于改善具有ALK抑制活性的水溶性差或水不溶的四环化合物的溶解度、口服吸收性和/或血液吸收性，这些化合物可用作癌症、抑郁症和认知功能障碍的预防和/或治疗药物。
• Composition comprising tetracyclic compound
  申请人：Furumoto Kentaro

  公开号：US09365514B2

  公开（公告）日：2016-06-14

  A composition which comprises substance represented by Formula (I), [Meanings of the symbols that are included in the formula are given in the specification as definitions] a pharmaceutically acceptable carrier, and a dissolution aid is useful for improving solubility, oral absorbability and/or absorbability in blood of a poorly water-soluble or water insoluble tetracyclic compounds having an ALK inhibitory activity that are useful as a prophylactic and/or therapeutic agent for cancer, depression, and cognitive function disorder.

  该组合物包括公式（I）所代表的物质，[公式中包含的符号的含义已在规范中作为定义给出]，一种药学上可接受的载体和一种溶解助剂，用于改善难溶或不溶于水的四环素类化合物的溶解度，口服吸收性和/或在血液中的吸收性，这些化合物具有ALK抑制活性，可用作预防和/或治疗癌症、抑郁症和认知功能障碍的药物。
• COMPOSITION CONTAINING TETRACYCLIC COMPOUND
  申请人：Chugai Seiyaku Kabushiki Kaisha

  公开号：EP2606886A1

  公开（公告）日：2013-06-26

  A composition which comprises substance represented by Formula (I), [Meanings of the symbols that are included in the formula are given in the specification as definitions] a pharmaceutically acceptable carrier, and a dissolution aid.is useful for improving solubility, oral absorbability and/or absorbability in blood of a poorly water-soluble or water insoluble tetracyclic compounds having an ALK inhibitory activity that are useful as a prophylactic and/or therapeutic agent for cancer, depression, and cognitive function disorder.

  一种由式 (I) 所代表的物质组成的组合物、 式（I）代表的物质，[式（I）中包含的符号的含义在说明书中作为定义给出]。 用于改善具有 ALK 抑制活性的水溶性差或不溶于水的四环化合物的溶解度、口服可吸收性和/或血液可吸收性，该化合物可用作癌症、抑郁症和认知功能障碍的预防剂和/或治疗剂。