ethyl 5-(aminomethyl)-2-(difluoromethyl)nicotinate dihydrochloride

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: ethyl 5-(aminomethyl)-2-(difluoromethyl)nicotinate dihydrochloride
• 英文别名: Ethyl 5-(aminomethyl)-2-(difluoromethyl)nicotinate hydrochloride；ethyl 5-(aminomethyl)-2-(difluoromethyl)pyridine-3-carboxylate;hydrochloride
• 化学式: C₁₀H₁₂F₂N₂O₂*2ClH
• 分子量: 303.136
• InChiKey: NLQRGPFXNCTQTO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.08
• 重原子数：
  17
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  65.2
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl 5-(aminomethyl)-2-(difluoromethyl)nicotinate dihydrochloride 在 盐酸 、 lithium hydroxide monohydrate 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 33.67h， 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：

  ethyl 5-bromo-2-(difluoromethyl)nicotinate 在 四(三苯基膦)钯 、 5%-palladium/activated carbon 盐酸 、 水 、 氢气 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 甲基叔丁基醚 、 水 、 N,N-二甲基甲酰胺 为溶剂， 20.0~100.0 ℃ 、413.7 kPa 条件下， 反应 20.17h， 生成 ethyl 5-(aminomethyl)-2-(difluoromethyl)nicotinate dihydrochloride
  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

• 酰胺类衍生物、其制备方法及其在医药上的应 用
  申请人：江苏恒瑞医药股份有限公司

  公开号：CN105523996B

  公开（公告）日：2020-03-06

  本发明涉及酰胺类衍生物、其制备方法及其在医药上的应用。具体而言，本发明涉及一种通式(I)所示酰胺类衍生物、其制备方法及含有该衍生物的药物组合物，以及其作为治疗剂，特别是作为微粒体前列腺素E合成酶‑1(mPGES‑1)抑制剂的用途和其在制备治疗和/或预防炎症和/或疼痛等疾病或病症的药物中的用途，其中通式(I)中的各取代基的定义与说明书中的定义相同。
• 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。
• Amide derivatives and pharmaceutically acceptable salts thereof, preparation method thereof and medicinal application thereof
  申请人：Shanghai Hengrui Pharmaceutical Co., Ltd.

  公开号：US10081629B2

  公开（公告）日：2018-09-25

  Amide derivatives and pharmaceutically acceptable salts thereof, preparation method thereof and medicinal application thereof are provided. Specifically, amide derivatives represented by general formula (I) are provided. The amide derivatives represented by general formula (I) can be used as a therapeutic agent, particularly as an inhibitor for microsomal prostaglandin E synthase-1 (mPGES-1), and also to treat and/or prevent diseases or illnesses such as inflammation and/or pain etc. The definition of each substituent group in general formula (I) is the same as the definition in the description.

  本发明提供了酰胺衍生物及其药学上可接受的盐、制备方法和药物应用。具体而言，本发明提供了通式（I）代表的酰胺衍生物。通式（I）代表的酰胺衍生物可用作治疗剂，特别是作为微粒体前列腺素 E 合酶-1（mPGES-1）的抑制剂，还可用于治疗和/或预防炎症和/或疼痛等疾病。通式（I）中各取代基的定义与说明中的定义相同。
• 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.
• AMIDE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, PREPARATION METHOD THEREFOR AND MEDICINAL APPLICATION THEREOF
  申请人：Shanghai Hengrui Pharmaceutical Co. Ltd.

  公开号：EP3133068B1

  公开（公告）日：2020-11-25