2-[[2-乙氧基-4-(4-羟基-1-哌啶基)苯基]氨基]-5,11-二氢-5,11-二甲基-6H-嘧啶并[4,5-B][1,4]苯并二氮杂卓-6-酮 | 1234480-50-2

• 物质功能分类: 生物化工 - 抑制剂 - 丝裂原活化蛋白激酶(MAPK)
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 2-[[2-乙氧基-4-(4-羟基-1-哌啶基)苯基]氨基]-5,11-二氢-5,11-二甲基-6H-嘧啶并[4,5-B][1,4]苯并二氮杂卓-6-酮
• 英文名称: XMD8-92
• 英文别名: 2-{[2-ethoxy-4-(4-hydroxypiperidin-1-yl)phenyl]amino}-5,11-dimethyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one；2-[2-ethoxy-4-(4-hydroxypiperidin-1-yl)anilino]-5,11-dimethylpyrimido[4,5-b][1,4]benzodiazepin-6-one
• CAS: 1234480-50-2
• 化学式: C₂₆H₃₀N₆O₃
• 分子量: 474.563
• InChiKey: QAPAJIZPZGWAND-UHFFFAOYSA-N

物化性质

• 沸点：
  741.8±70.0 °C(Predicted)
• 密度：
  1.301
• 溶解度：
  DMSO 中≥23.75 mg/mL；不溶于水；不溶于乙醇

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  35
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  94.1
• 氢给体数：
  2
• 氢受体数：
  8

安全信息

• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302

制备方法与用途

生物活性

XMD8-92 是一种强效的选择性 BMK1/ERK5 抑制剂，其 Kd 值为 80 nM。此外，它还是一种 BMK1 和 bromodomain-containing proteins (BRDs, BET) 的双重抑制剂，对 ERK5 和 BRD4 的 Kd 分别为 80 nM 和 170 nM。

体外研究

XMD8-92 通过抑制 BMK1 活化，显著诱导细胞中 p21 表达，并介导对癌细胞增殖的抑制作用。它还能够显著废除羟基红花黄色素 A (HSYA) 对肝星状细胞 (HSC) 的活化抑制作用，并阻断 HSYA 介导的 MEF2C 下调。

体内研究

XMD8-92 (50 毫克/千克，腹腔注射) 能显著抑制异种移植人或同源小鼠肿瘤的生长，通过阻断肿瘤细胞增殖以及肿瘤相关的血管生成。此外，它还能通过显著下调 DCLK1 及其几个下游靶点来抑制胰腺肿瘤异种移植物的生长。

文献信息

• [EN] DIAZEPANE DERIVATIVES AND USES THEREOF<br/>[FR] DÉRIVÉS DE DIAZÉPANE ET LEURS UTILISATIONS
  申请人：DANA FARBER CANCER INST INC

  公开号：WO2015117083A1

  公开（公告）日：2015-08-06

  The present invention provides compounds of any one of Formulae (I), (II-C) (e.g., Formula (II)), and (III), and pharmaceutically compositions thereof. Compounds of any one of Formulae (I), (II-C), and (III) are believed to be binders of bromodomains and/or bromodomain-containing proteins (e.g., bromo and extra terminal (BET) proteins). Also provided are methods, uses, and kits using the compounds and pharmaceutical compositions for inhibiting the activity (e.g., increased activity) of bromodomains and/or bromodomain- containing proteins and for treating and/or preventing in a subject diseases associated with bromodomains or bromodomain-containing proteins (e.g., proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning). The compounds, pharmaceutical compositions, and kits are also useful for male contraception.

  本发明提供了任一式（I）、（II-C）（例如，式（II））和（III）的化合物，以及其药物组合物。据信，任一式（I）、（II-C）和（III）的化合物被认为是溴结构域和/或含溴结构域蛋白（例如，溴和额外末端（BET）蛋白）的结合物。还提供了使用这些化合物和药物组合物的方法、用途和试剂盒，用于抑制溴结构域和/或含溴结构域蛋白的活性（例如，增加活性），并用于治疗和/或预防与溴结构域或含溴结构域蛋白相关的疾病（例如，增殖性疾病、心血管疾病、病毒感染、纤维化疾病、代谢性疾病、内分泌疾病和放射性中毒）。这些化合物、药物组合物和试剂盒也适用于男性避孕。
• [EN] USES OF DIAZEPANE DERIVATIVES<br/>[FR] UTILISATIONS DES DÉRIVÉS DE DIAZÉPANE
  申请人：DANA FARBER CANCER INST INC

  公开号：WO2015117087A1

  公开（公告）日：2015-08-06

  The present invention provides compounds of Formula (II) (e.g., compounds of Formula (I)), and pharmaceutically compositions thereof. Compounds of Formula (II) are believed to be binders of bromodomains and/or bromodomain-containing proteins (e.g., bromo and extra terminal (BET) proteins). Also provided are methods, uses, and kits using the compounds and pharmaceutical compositions for inhibiting the activity (e.g., increased activity) of bromodomains and/or bromodomain-containing proteins and for treating and/or preventing in a subject diseases associated with bromodomains or bromodomain-containing proteins (e.g., proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning). The compounds, pharmaceutical compositions, and kits are also useful for male contraception.

  本发明提供了式（II）的化合物（例如，式（I）的化合物），以及其药物组成物。式（II）的化合物被认为是溴域和/或含溴域蛋白（例如，溴和额外终端（BET）蛋白）的结合剂。还提供了使用这些化合物和药物组成物的方法、用途和工具包，用于抑制溴域和/或含溴域蛋白的活性（例如，增加的活性），并用于治疗和/或预防与溴域或含溴域蛋白相关的疾病（例如，增生性疾病、心血管疾病、病毒感染、纤维性疾病、代谢性疾病、内分泌疾病和放射性中毒）。这些化合物、药物组成物和工具包还可用于男性避孕。
• Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo
  申请人：Brown Dennis M.

  公开号：US10383847B2

  公开（公告）日：2019-08-20

  The present invention describes methods and compositions for improving the therapeutic efficacy of therapeutically active agents previously limited by suboptimal therapeutic performance by either improving efficacy as monotherapy or reducing side effects. Such methods and compositions are particularly applicable to therapeutically active agents selected from the group consisting of: (i) indirubin; (ii) an analog of indirubin; (iii) a derivative of indirubin or of an analog of indirubin; and (iv) a pharmaceutical composition comprising indirubin, an analog of indirubin, or a derivative of indirubin or of an analog of indirubin, especially meisoindigo. In particular, the therapeutically active agents selected from the group consisting of: (i) indirubin; (ii) an analog of indirubin; (iii) a derivative of indirubin or of an analog of indirubin; and (iv) a pharmaceutical composition comprising indirubin, an analog of indirubin, or a derivative of indirubin or of an analog of indirubin, especially meisoindigo, are effective Nek9 inhibitors. The active agent, such as meisoindigo, can act as a Nek9 inhibitor. The active agent can be used together with Nek9 inhibitors or agents that inhibit the expression of Nek9.

  本发明描述了通过提高单一疗法的疗效或减少副作用来提高以前受次优治疗性能限制的治疗活性制剂的疗效的方法和组合物。这种方法和组合物特别适用于选自以下组别的治疗活性剂：(i) 靛红素；(ii) 靛红素的类似物；(iii) 靛红素或靛红素类似物的衍生物；(iv) 包含靛红素、靛红素类似物或靛红素或靛红素类似物衍生物的药物组合物，特别是甲异靛。特别是，选自以下组别的治疗活性剂是有效的 Nek9 抑制剂：(i) 靛红素；(ii) 靛红素的类似物；(iii) 靛红素的衍生物或靛红素的类似物；以及 (iv) 由靛红素、靛红素的类似物或靛红素的衍生物或靛红素的类似物，特别是 meisoindigo 组成的药物组合物。活性剂，如 meisoindigo，可作为 Nek9 抑制剂。活性剂可与 Nek9 抑制剂或抑制 Nek9 表达的制剂一起使用。
• Pyrimido-diazepinone kinase scaffold compounds and methods of treating disorders
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US10570154B2

  公开（公告）日：2020-02-25

  The present invention relates to novel pyrimido-diazepinone compounds, methods of modulating protein kinases, including MPS1 (TTK), ERK5 (BMK1, MAPK7), polo kinase 1, 2, 3, or 4, Ack1, Ack2, Abl, DCAMKL1, ABL1, Abl mutants, DCAMKL2, ARK5, BRK, MKNK2, FGFR4, TNK1, PLK1, ULK2, PLK4, PRKD1, PRKD2, PRKD3, ROS1, RPS6KA6, TAOK1, TAOK3, TNK2, Bcr-Abl, GAK, cSrc, TPR-Met, Tie2, MET, FGFR3, Aurora, Axl, Bmx, BTK, c-kit, CHK2, Flt3, MST2, p70S6K, PDGFR, PKB, PKC, Raf, ROCK-H, Rsk1, SGK, TrkA, TrkB and TrkC, and the use of such compounds in the treatment of various diseases, disorders or conditions.

  本发明涉及新型嘧啶类二氮杂卓酮化合物、调节蛋白激酶的方法，包括MPS1（TTK）、ERK5（BMK1、MAPK7）、polo 激酶 1、2、3 或 4、Ack1、Ack2、Abl、DCAMKL1、ABL1、Abl 突变体、DCAMKL2、ARK5、BRK、MKNK2、FGFR4、TNK1、PLK1、ULK2、PLK4、PRKD1、PRKD2、PRKD3, ROS1, RPS6KA6, TAOK1, TAOK3, TNK2, Bcr-Abl, GAK, cSrc, TPR-Met, Tie2, MET, FGFR3, Aurora, Axl, Bmx, BTK, c-kit, CHK2, Flt3, MST2, p70S6K, PDGFR、PKB、PKC、Raf、ROCK-H、Rsk1、SGK、TrkA、TrkB 和 TrkC。
• Combination therapy of transcription inhibitors and kinase inhibitors
  申请人：Dana-Farber Cancer Institute, Inc.

  公开号：US10702527B2

  公开（公告）日：2020-07-07

  The present disclosure provides combination therapy of a transcription inhibitor and a kinase inhibitor. The combination of the transcription inhibitor and the kinase inhibitor may be useful in treating and/or preventing in a subject a proliferative disease, such as proliferative a disease that is resistant to the transcription inhibitor alone or the kinase inhibitor alone. In certain embodiments, the proliferative disease is a cancer. The combination of the transcription inhibitor and the kinase inhibitor is expected to be synergistic.

  本公开提供了转录抑制剂和激酶抑制剂的组合疗法。转录抑制剂和激酶抑制剂的组合可用于治疗和/或预防受试者的增殖性疾病，如对单独转录抑制剂或单独激酶抑制剂耐药的增殖性疾病。在某些实施方案中，增殖性疾病是癌症。转录抑制剂和激酶抑制剂的组合可望产生协同作用。