N-(3-amino-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide | 1039933-69-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(3-amino-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide
• 英文别名: N-(3-amino-4-methylphenyl)-2,3-dihydro-1,4-benzodioxine-6-carboxamide
• CAS: 1039933-69-1
• 化学式: C₁₆H₁₆N₂O₃
• 分子量: 284.315
• InChiKey: MFQAWAUKKKUROS-UHFFFAOYSA-N

物化性质

• 沸点：
  415.0±45.0 °C(Predicted)
• 密度：
  1.317±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  73.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(3-amino-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二甲胺 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 生成 N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-2-methyl-4-(2-(pyrrolidin-1-yl)ethylamino)quinoline-6-carboxamide
  参考文献：
  名称：

  [EN] FUSED 1,4-DIHYDRODIOXIN DERIVATIVES AS INHIBITORS OF HEAT SHOCK TRANSCRIPTION FACTOR 1
  [FR] DÉRIVÉS DE 1,4-DIHYDRODIOXINE FUSIONNÉS À UTILISER EN TANT QU'INHIBITEURS DE FACTEUR DE TRANSCRIPTION 1 DU CHOC THERMIQUE

  摘要：

  本发明涉及式I的化合物，其中A1、A2、R4和Q如本文所定义。本发明的化合物是热休克因子1（HSF1）的抑制剂。具体来说，本发明涉及将这些化合物用作治疗和/或预防增殖性疾病，如癌症的治疗剂。本发明还涉及制备这些化合物的方法，以及包含它们的药物组合物。

  公开号：

  WO2015049535A1
• 作为产物：
  描述：

  2,3-二氢-1,4-苯并二恶烷-6-羰酰氯 在 吡啶 、 palladium 10% on activated carbon 、 氢气 作用下， 以 乙醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， 20.0~28.0 ℃ 、101.33 kPa 条件下， 反应 2.0h， 生成 N-(3-amino-4-methylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide
  参考文献：
  名称：

  Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen

  摘要：

  Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy for drug discovery. In this article, we describe the discovery of a new chemical probe, bisamide (CCT251236), identified using an unbiased phenotypic screen to detect inhibitors of the HSF1 stress pathway. The chemical probe is orally bioavailable and displays efficacy in a human ovarian carcinoma xenograft model. By developing cell:based SAP. and using chemical proteomics, we identified pirin as a high affinity molecular target, which was confirmed by SPR and crystallography.

  DOI：

  10.1021/acs.jmedchem.6b01055

文献信息

• Synthesis of aminoquinazoline derivatives and their antiproliferative activities against melanoma cell line
  作者：Junsang Lee、Bong Soo Nam、Hwan Kim、Chang-Hyun Oh、So Ha Lee、Seung Joo Cho、Tae Bo Sim、Jung-Mi Hah、Dong Jin Kim、Jinsung Tae、Kyung Ho Yoo

  DOI：10.1016/j.bmcl.2010.08.010

  日期：2010.10

  The synthesis of a novel series of aminoquinazoline derivatives 1a–r and their antiproliferative activities against A375 human melanoma cell line were described. Among them, six compounds showed superior antiproliferative activities to Sorafenib as a reference compound. In particular, the representative compound 1q bearing chromen-4-one moiety exhibited excellent antiproliferative activity (IC50 = 0

  描述了一系列新的氨基喹唑啉衍生物1a – r的合成及其对A375人黑素瘤细胞系的抗增殖活性。其中，有6种化合物显示出比索拉非尼（作为参考化合物）优越的抗增殖活性。尤其是，具有代表性的化合物1q带有chromen-4-one的部分表现出优异的抗增殖活性（IC 50  = 0.006μM）和相对于HS27成纤维细胞系的良好选择性。
• HSF1 Pathway Inhibitor Clinical Candidate (CCT361814/NXP800) Developed from a Phenotypic Screen as a Potential Treatment for Refractory Ovarian Cancer and Other Malignancies
  作者：A. Elisa Pasqua、Swee Y. Sharp、Nicola E. A. Chessum、Angela Hayes、Loredana Pellegrino、Michael J. Tucker、Asadh Miah、Birgit Wilding、Lindsay E. Evans、Carl S. Rye、N. Yi Mok、Manjuan Liu、Alan T. Henley、Sharon Gowan、Emmanuel De Billy、Robert te Poele、Marissa Powers、Suzanne A. Eccles、Paul A. Clarke、Florence I. Raynaud、Paul Workman、Keith Jones、Matthew D. Cheeseman

  DOI：10.1021/acs.jmedchem.3c00156

  日期：2023.4.27

  CCT251236 1, a potent chemical probe, was previously developed from a cell-based phenotypic high-throughput screen (HTS) to discover inhibitors of transcription mediated by HSF1, a transcription factor that supports malignancy. Owing to its activity against models of refractory human ovarian cancer, 1 was progressed into lead optimization. The reduction of P-glycoprotein efflux became a focus of early

  CCT251236 1是一种有效的化学探针，之前是通过基于细胞的表型高通量筛选 (HTS) 开发的，用于发现 HSF1（一种支持恶性肿瘤的转录因子）介导的转录抑制剂。由于其对难治性人类卵巢癌模型的活性， 1已进入先导化合物优化阶段。 P-糖蛋白外流的减少成为早期化合物优化的焦点；通过匹配分子对分析证明中心环卤素取代是减轻这种可能性的有效策略。进一步的多参数优化导致了临床候选药物 CCT361814/NXP800 22的设计，这是一种有效的口服生物可利用的氟双酰胺，它在人卵巢腺癌异种移植模型中引起肿瘤消退，具有途径生物标志物调节和干净的体外安全性。在对人类进行有利的剂量预测后， 22现已进入一期临床试验，作为难治性卵巢癌和其他恶性肿瘤的未来潜在治疗方法。
• Fused 1,4-dihydrodioxin derivatives as inhibitors of heat shock transcription factor I
  申请人：Cancer Research Technology Limited

  公开号：US10189821B2

  公开（公告）日：2019-01-29

  The present invention relates to compounds of formula I as defined herein. The compounds of the present invention are inhibitors of heat shock factor 1 (HSF1). In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising them.

  本发明涉及本文定义的式 I 化合物。本发明的化合物是热休克因子 1（HSF1）的抑制剂。特别是，本发明涉及将这些化合物用作治疗剂来治疗和/或预防增殖性疾病，如癌症。本发明还涉及这些化合物的制备工艺以及包含这些化合物的药物组合物。
• Demonstrating In-Cell Target Engagement Using a Pirin Protein Degradation Probe (CCT367766)
  作者：Nicola E. A. Chessum、Swee Y. Sharp、John J. Caldwell、A. Elisa Pasqua、Birgit Wilding、Giampiero Colombano、Ian Collins、Bugra Ozer、Meirion Richards、Martin Rowlands、Mark Stubbs、Rosemary Burke、P. Craig McAndrew、Paul A. Clarke、Paul Workman、Matthew D. Cheeseman、Keith Jones

  DOI：10.1021/acs.jmedchem.7b01406

  日期：2018.2.8

  Demonstrating intracellular protein target engagement is an essential step in the development and progression of new chemical probes and potential small molecule therapeutics. However, this can be particularly challenging for poorly studied and noncatalytic proteins, as robust proximal biomarkers are rarely known. To confirm that our recently discovered chemical probe 1 (CCT251236) binds the putative transcription factor regulator pirin in living cells, we developed a heterobifunctional protein degradation probe. Focusing on linker design and physicochemical properties, we generated a highly active probe 16 (CCT367766) in only three iterations, validating our efficient strategy for degradation probe design against nonvalidated protein targets.
• FUSED 1,4-DIHYDRODIOXIN DERIVATIVES AS INHIBITORS OF HEAT SHOCK TRANSCRIPTION FACTOR 1
  申请人：Cancer Research Technology Limited

  公开号：EP3052492A1

  公开（公告）日：2016-08-10