4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one | 1448754-38-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: 4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one
• 英文别名: 4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one
• CAS: 1448754-38-8
• 化学式: C₂₁H₁₆F₃N₃O₂
• 分子量: 399.372
• InChiKey: XOFKKGMAEWHODX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  55.3
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  7-溴-2,3-二氢-1,4-苯并氮杂卓-5(4H)-酮 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium carbonate 、 sodium hydroxide 作用下， 以 水 、 N,N-二甲基甲酰胺 、 异丙醇 、 甲苯 为溶剂， 反应 9.0h， 生成 4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one
  参考文献：
  名称：

  Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late I_Nai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties

  摘要：

  Late sodium current (late I-Na) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na-v 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late INa, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-velitricular fibrillation (VT-VF). We will describe structure-activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late I-Na inhibitor 1 (ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S-T segment elevation, 15 min left anterioior descending, LAD, occlusion in rabbits); with EC50 values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late I-Na inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.

  DOI：

  10.1021/acs.jmedchem.6b00939

文献信息

• [EN] COMBINATION THERAPIES USING LATE SODIUM ION CHANNEL BLOCKERS AND POTASSIUM ION CHANNEL BLOCKERS<br/>[FR] THÉRAPIES DE COMBINAISON À L'AIDE DE BLOQUEURS DE CANAUX IONIQUES AU SODIUM TARDIFS ET DE BLOQUEURS DE CANAUX IONIQUES AU POTASSIUM
  申请人：GILEAD SCIENCES INC

  公开号：WO2013112932A1

  公开（公告）日：2013-08-01

  Described herein is a method for the treatment or prevention of atrial fibrillation and/or atrial flutter comprising administration of an effective amount of one or more of a potassium channel blocker and an effective amount of one or more of a late sodium channel blocker. Also provided are methods for modulating ventricular and atrial rhythm and rate. Also provided are pharmaceutical formulations that are suitable for such combined administration.

  本文描述了一种用于治疗或预防心房颤动和/或心房扑动的方法，包括给予有效量的一个或多个钾通道阻滞剂和一个或多个晚期钠通道阻滞剂。还提供了调节心室和心房节律和频率的方法。还提供了适合进行这种联合给药的药物配方。
• METHODS OF TREATING HYPERTROPHIC CARDIOMYOPATHY
  申请人：Gilead Sciences, Inc.

  公开号：US20150038487A1

  公开（公告）日：2015-02-05

  The present disclosure relates to a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, for use in the treatment of hypertrophic cardiomyopathy.

  本公开涉及一种具有化学式(I)或化学式(II)或其药学上可接受的盐的化合物，用于治疗肥厚型心肌病。
• COMPOUND AND METHODS FOR TREATING LONG QT SYNDROME
  申请人：Gilead Sciences, Inc.

  公开号：US20150038489A1

  公开（公告）日：2015-02-05

  Described herein is a method of treating long QT syndrome by administration of an effective amount of a potent and selective late sodium ion channel blocker

  本文描述了一种治疗长QT综合征的方法，通过给予有效剂量的强效和选择性晚期钠离子通道阻滞剂进行治疗。
• [EN] FUSED BENZOXAZEPINONES AS ION CHANNEL MODULATORS<br/>[FR] BENZOXAZÉPINONES FUSIONNÉS EN TANT QUE MODULATEURS DES CANAUX IONIQUES
  申请人：GILEAD SCIENCES INC

  公开号：WO2013006485A1

  公开（公告）日：2013-01-10

  The present disclosure relates to compounds that are sodium channel inhibitors and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula I: wherein Z1, Z2, Z3, Z4, X, Y, R2, R3 and R4 are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.

  本公开涉及的化合物是钠通道抑制剂，可用于治疗各种疾病状态，包括心血管疾病和糖尿病。在特定实施例中，化合物的结构由公式I给出：其中Z1、Z2、Z3、Z4、X、Y、R2、R3和R4如本文所述，以及制备和使用该化合物的方法，以及含有该化合物的药物组合物。
• [EN] COMPOUND AND METHODS FOR TREATING LONG QT SYNDROME<br/>[FR] COMPOSÉ ET PROCÉDÉS POUR LE TRAITEMENT DU SYNDROME DU QT LONG
  申请人：GILEAD SCIENCES INC

  公开号：WO2015017661A1

  公开（公告）日：2015-02-05

  Described herein is a method of treating long QT syndrome by administration of an effective amount of a potent and selective late sodium ion channel blocker.

  本文描述了一种通过给予有效量的强效和选择性晚期钠离子通道阻滞剂来治疗长QT综合症的方法。