2-[4-[[4-amino-2-(trifluoromethyl)phenyl]methyl]piperazin-1-yl] ethanol | 859027-17-1

• 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: 2-[4-[[4-amino-2-(trifluoromethyl)phenyl]methyl]piperazin-1-yl] ethanol
• 英文别名: 2-(4-(4-Amino-2-(trifluoromethyl)benzyl)piperazin-1-yl)ethanol；2-[4-[[4-amino-2-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]ethanol
• CAS: 859027-17-1
• 化学式: C₁₄H₂₀F₃N₃O
• 分子量: 303.328
• InChiKey: AFSUGKYOSCPBCP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  52.7
• 氢给体数：
  2
• 氢受体数：
  7

安全信息

• 海关编码：
  2933599090

反应信息

• 作为反应物：
  描述：

  2-[4-[[4-amino-2-(trifluoromethyl)phenyl]methyl]piperazin-1-yl] ethanol 、 3-碘-4-甲基苯甲酰氯 在 4-二甲氨基吡啶 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 以69%的产率得到N-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide
  参考文献：
  名称：

  Rapid Discovery of a Novel Series of Abl Kinase Inhibitors by Application of an Integrated Microfluidic Synthesis and Screening Platform

  摘要：

  Drug discovery faces economic and scientific imperatives to deliver lead molecules rapidly and efficiently. Using traditional paradigms the molecular design, synthesis, and screening loops enforce a significant time delay leading to inefficient use of data in the iterative molecular design process. Here, we report the application of a flow technology platform integrating the key elements of structure activity relationship (SAR) generation to the discovery of novel Abl kinase inhibitors. The platform utilizes flow chemistry for rapid in-line synthesis, automated purification, and analysis coupled with bioassay. The combination of activity prediction using Random-Forest regression with chemical space sampling algorithms allows the construction of an activity model that refines itself after every iteration of synthesis and biological result. Within just 21 compounds, the automated process identified a novel template and hinge binding motif with pIC(50) > 8 against Abl kinase - both wild type and clinically relevant mutants. Integrated microfluidic synthesis and screening coupled with machine learning design have the potential to greatly reduce the time and cost of drug discovery within the hit-to-lead and lead optimization phases.

  DOI：

  10.1021/jm400099d
• 作为产物：
  描述：

  1-(溴甲基)-4-硝基-2-(三氟甲基)苯 在 raney nickel (catcart) 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 2-[4-[[4-amino-2-(trifluoromethyl)phenyl]methyl]piperazin-1-yl] ethanol
  参考文献：
  名称：

  Rapid Discovery of a Novel Series of Abl Kinase Inhibitors by Application of an Integrated Microfluidic Synthesis and Screening Platform

  摘要：

  Drug discovery faces economic and scientific imperatives to deliver lead molecules rapidly and efficiently. Using traditional paradigms the molecular design, synthesis, and screening loops enforce a significant time delay leading to inefficient use of data in the iterative molecular design process. Here, we report the application of a flow technology platform integrating the key elements of structure activity relationship (SAR) generation to the discovery of novel Abl kinase inhibitors. The platform utilizes flow chemistry for rapid in-line synthesis, automated purification, and analysis coupled with bioassay. The combination of activity prediction using Random-Forest regression with chemical space sampling algorithms allows the construction of an activity model that refines itself after every iteration of synthesis and biological result. Within just 21 compounds, the automated process identified a novel template and hinge binding motif with pIC(50) > 8 against Abl kinase - both wild type and clinically relevant mutants. Integrated microfluidic synthesis and screening coupled with machine learning design have the potential to greatly reduce the time and cost of drug discovery within the hit-to-lead and lead optimization phases.

  DOI：

  10.1021/jm400099d

文献信息

• [EN] ISOQUINOLINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF DISEASES<br/>[FR] DÉRIVÉS D'ISOQUINOLINE ET COMPOSITIONS PHARMACEUTIQUES ASSOCIÉES POUR LE TRAITEMENT DE MALADIES
  申请人：GALAPAGOS NV

  公开号：WO2022008383A1

  公开（公告）日：2022-01-13

  The present invention discloses compounds according to Formula (I) wherein R1, R2, R3, L1, L2, and L3 are as defined herein. The present invention relates to compounds inhibiting discoidin domain receptors (DDRs), methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases by administering a compound of the invention.

  本发明揭示了根据式（I）中R1、R2、R3、L1、L2和L3的定义的化合物。本发明涉及抑制盘状结构域受体（DDRs）的化合物，其生产方法，包含相同化合物的药物组合物，以及使用相同化合物进行预防和/或治疗纤维化疾病、炎症性疾病、呼吸系统疾病、自身免疫疾病、代谢性疾病、心血管疾病和/或增殖性疾病的方法，通过给予本发明的化合物。
• HETEROARYL ALKYNE COMPOUND AND USE THEREOF
  申请人：NANJING SANHOME PHARMACEUTICAL CO., LTD.

  公开号：US20150299202A1

  公开（公告）日：2015-10-22

  In the field of pharmaceutical chemistry compounds of general formula I having heteroaryl alkynyl moiety or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, and pharmaceutical compositions including these compounds, as well as uses of these compounds and compositions thereof in the manufacture of a medicament. The compounds have a strong inhibitory effect on BCR-ABL tyrosine kinase and are useful for treating diseases, such as tumors.

  在药物化学领域，具有异杂环炔基团或其药学上可接受的盐、异构体、溶剂化物、晶体或前药的通式I化合物，以及包括这些化合物的药物组合物，以及这些化合物和组合物在制造药物方面的用途。这些化合物对BCR-ABL酪氨酸激酶具有强烈的抑制作用，可用于治疗肿瘤等疾病。
• [EN] COMPOSITIONS FOR INDUCING TUMOR IMMUNITY AND REDUCING DRUG TOLERANCE<br/>[FR] COMPOSITIONS POUR INDUIRE UNE IMMUNITÉ TUMORALE ET RÉDUIRE LA TOLÉRANCE AUX MÉDICAMENTS
  申请人：BRIGHAM & WOMENS HOSPITAL INC

  公开号：WO2022082108A1

  公开（公告）日：2022-04-21

  Described herein are HSP-90 inhibitors conjugated to lipids, compositions comprising the conjugates, and methods of use thereof for treating cancer.

  本文描述了与脂质结合的HSP-90抑制剂，包括该结合物的组合物，以及使用该组合物治疗癌症的方法。
• HETEROARYL ALKYNE COMPOUND AND APPLICATION THEREOF
  申请人：Nanjing Sanhome Pharmaceutical Co., Ltd.

  公开号：EP2927232A1

  公开（公告）日：2015-10-07

  The present invention belongs to the field of pharmaceutical chemistry. Specifically, the invention relates to compounds of general formula I having heteroaryl alkynyl moiety or pharmceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, and pharmaceutical compositions comprising these compounds, as well as uses of these compounds and compositions thereof in the manufacture of a medicament. The compounds of the present invention have a strong inhibitory effect on BCR-ABL tyrosine kinase and are useful for treating diseases, such as tumors.

  本发明属于药物化学领域。具体而言，本发明涉及具有杂芳基炔基的通式 I 化合物或其药学上可接受的盐、异构体、溶液剂、晶体或原药，以及包含这些化合物的药物组合物，以及这些化合物及其组合物在制造药物中的用途。本发明的化合物对BCR-ABL酪氨酸激酶有很强的抑制作用，可用于治疗肿瘤等疾病。
• Discovery of 3-[2-(Imidazo[1,2-<i>b</i>]pyridazin-3-yl)ethynyl]-4-methyl-<i>N</i>-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a Potent, Orally Active Pan-Inhibitor of Breakpoint Cluster Region-Abelson (BCR-ABL) Kinase Including the T315I Gatekeeper Mutant
  作者：Wei-Sheng Huang、Chester A. Metcalf、Raji Sundaramoorthi、Yihan Wang、Dong Zou、R. Mathew Thomas、Xiaotian Zhu、Lisi Cai、David Wen、Shuangying Liu、Jan Romero、Jiwei Qi、Ingrid Chen、Geetha Banda、Scott P. Lentini、Sasmita Das、Qihong Xu、Jeff Keats、Frank Wang、Scott Wardwell、Yaoyu Ning、Joseph T. Snodgrass、Marc I. Broudy、Karin Russian、Tianjun Zhou、Lois Commodore、Narayana I. Narasimhan、Qurish K. Mohemmad、John Iuliucci、Victor M. Rivera、David C. Dalgarno、Tomi K. Sawyer、Tim Clackson、William C. Shakespeare

  DOI：10.1021/jm100395q

  日期：2010.6.24

  In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of I1e315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC(50)s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL(T315I) expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CM L, including patients refractory to all currently approved therapies.