phenyl (3-cyano-5-(trifluoromethyl)phenyl)carbamate | 1229454-69-6

• 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: phenyl (3-cyano-5-(trifluoromethyl)phenyl)carbamate
• 英文别名: (3-cyano-5-trifluoromethyl-phenyl)-carbamic acid phenyl ester；phenyl N-[3-cyano-5-(trifluoromethyl)phenyl]carbamate
• CAS: 1229454-69-6
• 化学式: C₁₅H₉F₃N₂O₂
• 分子量: 306.244
• InChiKey: KWPPYUGKZPMVJK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  62.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  phenyl (3-cyano-5-(trifluoromethyl)phenyl)carbamate 、 (1S,3S)-3-(4-(trifluoromethyl)phenoxy)cyclopentanamine 在 吡啶 作用下， 反应 4.0h， 以70%的产率得到1-(3-cyano-5-(trifluoromethyl)phenyl)-3-((1S,3S)-3-(4-(trifluoromethyl)phenoxy)cyclopentyl)urea
  参考文献：
  名称：

  New activators of eIF2α Kinase Heme-Regulated Inhibitor (HRI) with improved biophysical properties

  摘要：

  Heme-regulated inhibitor (HRI), a eukaryotic translation initiation factor 2 alpha (eIF2 alpha) kinase, is critically important for coupling protein synthesis to heme availability in reticulocytes and adaptation to various environmental stressors in all cells. HRI modifies the severity of several hemoglobin misfolding disorders including beta-thalassemia. Small molecule activators of HRI are essential for studying normaland patho-biology of this kinase as well as for the treatment of various human disorders for which activation of HRI or phosphorylation of eIF2 alpha may be beneficial. We previously reported development of 14(1,4-trans)-4-aryloxycyclohexyl)-3-arylureas (cHAUs) as specific HRI activators and demonstrated their potential as molecular probes for studying HRI biology and as lead compounds for treatment of various human disorders. To develop more druglike cHAUs for in vivo studies and drug development and to expand the chemical space, we undertook bioassay guided structure-activity relationship studies replacing cyclohexyl ring with various 4-6-membered rings and explored further substitutions on the N-phenyl ring. We tested all analogs in the surrogate eIF2 alpha phosphorylation and cell proliferation assays, and a subset of analogs in secondary mechanistic assays that included endogenous eIF2 alpha phosphorylation and expression of C/EBP homologous protein (CHOP), a downstream effector. Finally, we determined specificity of these compounds for HRI by testing their anti-proliferative activity in cells transfected with siRNA targeting HRI or mock. These compounds have significantly improved cLogPs with no loss of potencies, making them excellent candidates for lead optimization for development of investigational new drugs that potently and specifically activate HRI. (C) 2019 Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2019.111973
• 作为产物：
  描述：

  3-氨基-5-氰基三氟甲苯 、 氯甲酸苯酯 在 吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 phenyl (3-cyano-5-(trifluoromethyl)phenyl)carbamate
  参考文献：
  名称：

  Development of 1-((1,4-trans)-4-Aryloxycyclohexyl)-3-arylurea Activators of Heme-Regulated Inhibitor as Selective Activators of the Eukaryotic Initiation Factor 2 Alpha (eIF2α) Phosphorylation Arm of the Integrated Endoplasmic Reticulum Stress Response

  摘要：

  Heme-regulated inhibitor (HRI), an eukaryotic translation initiation factor 2 alpha (eIF2 alpha) kinase, plays critical roles in cell proliferation, differentiation, adaptation to stress, and hemoglobin disorders. HRI phosphorylates eIF2 alpha, which couples cellular signals, including endoplasmic reticulum (ER) stress, to translation. We previously identified 1,3-diarylureas and 1-((1,4-trans)-4-aryloxycydohexyl)-3-arylureas (cHAUs) as specific activators of HRI that trigger the eIF2 alpha phosphorylation arm of ER stress response as molecular probes for studying HRI biology and its potential as a druggable target. To develop drug-like cHAUs needed for in vivo studies, we undertook bioassay-guided structure-activity relationship studies and tested them in the surrogate eIF2 alpha phosphorylation and cell proliferation assays. We further evaluated some of these cHAUs in endogenous eIF2 alpha phosphorylation and in the expression of the transcription factor C/EBP homologous protein (CHOP) and its mRNA, demonstrating significantly improved solubility and/or potencies. These cHAUs are excellent candidates for lead optimization for development of investigational new drugs that potently and specifically activate HRI.

  DOI：

  10.1021/acs.jmedchem.7b00059

文献信息

• CYCLOPROPANECARBOXAMIDO-SUBSTITUTE AROMATIC COMPOUNDS AS ANTI-TUMOR AGENTS
  申请人：Crown Bioscience Inc. (Taiwan)

  公开号：US20150197511A1

  公开（公告）日：2015-07-16

  Provided are cyclopropanecarboxamido-substituted aromatic compounds that inhibit protein kinases and their use in anti-tumor area. In particular, tyrosine-kinase inhibitors and Raf-kinase inhibitors as anti-tumor agents, their preparation, pharmaceutical composition, and their use in the treatment of cancer are also provided.

  提供了一种环丙烷羧胺基取代芳香化合物，可抑制蛋白激酶，并在抗肿瘤领域中使用。具体来说，提供了酪氨酸激酶抑制剂和Raf激酶抑制剂作为抗肿瘤药物，以及它们的制备、药物组合物和在癌症治疗中的应用。
• HETEROBICYCLIC CARBOXAMIDES AS INHIBITORS FOR KINASES
  申请人：ARTMANN, III Gerald David

  公开号：US20120245187A1

  公开（公告）日：2012-09-27

  The invention relates to novel organic compounds of formula (I) and their use in the treatment of the animal or human body, to pharmaceutical compositions comprising a compound of formula I and to the use of a compound of formula I for the preparation of pharmaceutical compositions for use in the treatment of protein kinase dependent diseases, especially of proliferative diseases, such as in the treatment of tumour diseases and ocular neovascular diseases.

  本发明涉及一种新型有机化合物(I)及其在动物或人体治疗中的应用，包括含有化合物I的制药组合物以及利用化合物I制备用于治疗蛋白激酶依赖性疾病的制药组合物的应用，特别是在治疗增殖性疾病，如肿瘤疾病和眼部新生血管疾病方面的应用。
• Heterobicyclic Carboxamides as inhibitors for kinases
  申请人：Artmann, III Gerald David

  公开号：US20100168082A1

  公开（公告）日：2010-07-01

  The invention relates to novel organic compounds of formula (I) and their use in the treatment of the animal or human body, to pharmaceutical compositions comprising a compound of formula I and to the use of a compound of formula I for the preparation of pharmaceutical compositions for use in the treatment of protein kinase dependent diseases, especially of proliferative diseases, such as in the treatment of tumour diseases and ocular neovascular diseases.

  本发明涉及一种新型有机化合物(I)及其在动物或人体治疗中的应用，包括含有化合物I的药物组合物，以及利用化合物I制备用于治疗蛋白激酶依赖性疾病的药物组合物，特别是用于治疗增殖性疾病，如肿瘤疾病和眼部新生血管疾病的治疗。
• Heterobicyclic carboxamides as inhibitors for kinases
  申请人：Novartis AG

  公开号：US08242125B2

  公开（公告）日：2012-08-14

  The invention relates to novel organic compounds of formula (I) and their use in the treatment of the animal or human body, to pharmaceutical compositions comprising a compound of formula I and to the use of a compound of formula I for the preparation of pharmaceutical compositions for use in the treatment of protein kinase dependent diseases, especially of proliferative diseases, such as in the treatment of tumor diseases and ocular neovascular diseases.

  本发明涉及公式（I）的新型有机化合物及其在动物或人体内治疗中的应用，包括含有公式I化合物的制药组合物，以及公式I化合物用于制备用于治疗蛋白激酶依赖性疾病的制药组合物的应用，特别是用于治疗增殖性疾病，例如治疗肿瘤疾病和眼部新生血管疾病。
• Development of 1-((1,4-<i>trans</i>)-4-Aryloxycyclohexyl)-3-arylurea Activators of Heme-Regulated Inhibitor as Selective Activators of the Eukaryotic Initiation Factor 2 Alpha (eIF2α) Phosphorylation Arm of the Integrated Endoplasmic Reticulum Stress Response
  作者：Revital Yefidoff-Freedman、Jing Fan、Lu Yan、Qingwen Zhang、Guillermo Rodrigo Reis dos Santos、Sandeep Rana、Jacob I. Contreras、Rupam Sahoo、Debin Wan、Jun Young、Karina Luiza Dias Teixeira、Christophe Morisseau、Jose Halperin、Bruce Hammock、Amarnath Natarajan、Peimin Wang、Michael Chorev、Bertal H. Aktas

  DOI：10.1021/acs.jmedchem.7b00059

  日期：2017.7.13

  Heme-regulated inhibitor (HRI), an eukaryotic translation initiation factor 2 alpha (eIF2 alpha) kinase, plays critical roles in cell proliferation, differentiation, adaptation to stress, and hemoglobin disorders. HRI phosphorylates eIF2 alpha, which couples cellular signals, including endoplasmic reticulum (ER) stress, to translation. We previously identified 1,3-diarylureas and 1-((1,4-trans)-4-aryloxycydohexyl)-3-arylureas (cHAUs) as specific activators of HRI that trigger the eIF2 alpha phosphorylation arm of ER stress response as molecular probes for studying HRI biology and its potential as a druggable target. To develop drug-like cHAUs needed for in vivo studies, we undertook bioassay-guided structure-activity relationship studies and tested them in the surrogate eIF2 alpha phosphorylation and cell proliferation assays. We further evaluated some of these cHAUs in endogenous eIF2 alpha phosphorylation and in the expression of the transcription factor C/EBP homologous protein (CHOP) and its mRNA, demonstrating significantly improved solubility and/or potencies. These cHAUs are excellent candidates for lead optimization for development of investigational new drugs that potently and specifically activate HRI.