4-methyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-amine | 1415089-74-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-methyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-amine
• 英文别名: 2-amino-4-methyl-5-[4-(trifluoromethyl)phenyl]imidazole；4-Methyl-5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-amine；5-methyl-4-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-amine
• CAS: 1415089-74-5
• 化学式: C₁₁H₁₀F₃N₃
• 分子量: 241.216
• InChiKey: CBOPWBLFBHYYHX-UHFFFAOYSA-N

物化性质

• 沸点：
  375.6±52.0 °C(Predicted)
• 密度：
  1.352±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  54.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-methyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-amine 在 盐酸 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 16.0h， 生成 2-(difluoromethyl)-5-(propionamidomethyl)-N-(4-methyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)nicotinamide
  参考文献：
  名称：

  Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors

  摘要：

  As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 mu M. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8 center dot H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.

  DOI：

  10.1021/acs.jmedchem.5b01249
• 作为产物：
  描述：

  2-溴-1-(4-(三氟甲基)苯基)-1-丙酮 在 羟胺 作用下， 以 乙醇 为溶剂， 反应 72.0h， 生成 4-methyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-amine
  参考文献：
  名称：

  Novel Imidazole Derivatives Useful for the Treatment of Arthritis

  摘要：

  本发明提供了以下式的化合物： 其中A、X和R1-R6如本文所述，其药用盐，以及含有该化合物的药物组合物；使用其中一种化合物或其药用盐治疗与骨关节炎相关的疼痛的方法，以及制备这些化合物的方法。

  公开号：

  US20120302608A1

文献信息

• Imidazole derivatives useful for the treatment of arthritis
  申请人：Hughes Norman Earle

  公开号：US08648200B2

  公开（公告）日：2014-02-11

  The present invention provides compounds of the formula below: where A, X and R1-R6 are as described herein, a pharmaceutical salt thereof, and a pharmaceutical composition containing this compound; methods of treating pain associated with osteoarthritis using one of the compounds or a pharmaceutically acceptable salt thereof, and processes for preparing the compounds.

  本发明提供以下式子的化合物：其中A，X和R1-R6如本文所述，其药物盐以及含有该化合物的药物组合物；使用其中一种化合物或其药学上可接受的盐治疗与骨关节炎相关的疼痛的方法，以及制备这些化合物的过程。
• Identification and Mitigation of Reactive Metabolites of 2-Aminoimidazole-Containing Microsomal Prostaglandin E Synthase-1 Inhibitors Terminated Due to Clinical Drug-Induced Liver Injury
  作者：Bryan H. Norman、Matthew J. Fisher、Matthew A. Schiffler、Steven L. Kuklish、Norman E. Hughes、Boris A. Czeskis、Kenneth C. Cassidy、Trent L. Abraham、Jeffrey J. Alberts、Debra Luffer-Atlas

  DOI：10.1021/acs.jmedchem.7b01806

  日期：2018.3.8

  Two 2-aminoimidazole-based inhibitors, LY3031207 (1) and LY3023703 (2), of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme were found to cause drug-induced liver injury (DILI) in humans. We studied imidazole ring substitutions to successfully mitigate reactive metabolite (RM) formation. These studies support the conclusion that RM formation may play a role in the observations of DILI and the consideration of 2-aminoimidazoles as structure alerts, due to the high likelihood of bioactivation to generate RMs.
• US8648200B2
  申请人：——

  公开号：US8648200B2

  公开（公告）日：2014-02-11
• [EN] NOVEL IMIDAZOLE DERIVATIVES USEFUL FOR THE TREATMENT OF ARTHRITIS<br/>[FR] NOUVEAUX DÉRIVÉS D'IMIDAZOLE UTILES POUR LE TRAITEMENT DE L'ARTHRITE
  申请人：LILLY CO ELI

  公开号：WO2012161965A1

  公开（公告）日：2012-11-29

  The present invention provides compounds of the formula below: where A, X and R1-R6 are as described herein, a pharmaceutical salt thereof, and a pharmaceutical composition containing this compound; methods of treating pain associated with osteoarthritis using one of the compounds or a pharmaceutically acceptable salt thereof, and processes for preparing the compounds.
• Novel Imidazole Derivatives Useful for the Treatment of Arthritis
  申请人：Hughes Norman Earle

  公开号：US20120302608A1

  公开（公告）日：2012-11-29

  The present invention provides compounds of the formula below: where A, X and R1-R6 are as described herein, a pharmaceutical salt thereof, and a pharmaceutical composition containing this compound; methods of treating pain associated with osteoarthritis using one of the compounds or a pharmaceutically acceptable salt thereof, and processes for preparing the compounds.

  本发明提供了以下式的化合物： 其中A、X和R1-R6如本文所述，其药用盐，以及含有该化合物的药物组合物；使用其中一种化合物或其药用盐治疗与骨关节炎相关的疼痛的方法，以及制备这些化合物的方法。