(S)-3-amino-5-ethyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride | 958488-88-5

• 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: (S)-3-amino-5-ethyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride
• 英文别名: (3S)-3-amino-5-ethyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one hydrochloride；(3S)-3-amino-5-ethyl-2,3-dihydro-1,5-benzoxazepin-4-one;hydrochloride
• CAS: 958488-88-5
• 化学式: C₁₁H₁₄N₂O₂*ClH
• 分子量: 242.705
• InChiKey: GAGJTVAVSFAALP-QRPNPIFTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.18
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  55.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (S)-3-amino-5-ethyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride 、 (3R,4R,5S)-4-hydroxy-5-((E)-(R)-1-hydroxy-4,4-dimethylpent-2-enyl)-3-methoxydihydrofuran-2-one 在 sodium 2-ethylhexanoic acid 作用下， 以 四氢呋喃 为溶剂， 反应 24.0h， 生成 (2R,3R,4S,5R,6E)-N-[(3S)-5-ethyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide
  参考文献：
  名称：

  DERIVATIVES OF 2-ALKOXY-3,4,5-TRIHYDROXY-ALKYL AMIDES, PREPARATION AND USE THEREOF, AND COMPOSITIONS CONTAINING THE SAME

  摘要：

  本发明涉及2-烷氧基-3,4,5-三羟基烷基酰胺衍生物，包括这种化合物的药物组合物，包括这种化合物的治疗方法，制备这种化合物的方法，以及这种化合物的中间体前体。

  公开号：

  US20090075971A1
• 作为产物：
  描述：

  (S)-2-tert-butoxycarbonylamino-3-(2-nitrophenoxy)propionic acid 在 盐酸 、 palladium on activated charcoal 、 氢气 、 caesium carbonate 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 1,4-二氧六环 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.5h， 生成 (S)-3-amino-5-ethyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride
  参考文献：
  名称：

  Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases

  摘要：

  RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting, its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.

  DOI：

  10.1021/acs.jmedchem.6b01751
• 作为试剂：
  描述：

  (S)-tert-butyl (5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate 、 、 盐酸 在 氩 、 (S)-3-amino-5-ethyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride 作用下， 以 1,4-二氧六环 为溶剂， 反应 16.0h， 生成 (S)-3-amino-5-ethyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride
  参考文献：
  名称：

  DERIVATIVES OF 2-ALKOXY-3,4,5-TRIHYDROXY-ALKYL AMIDES, PREPARATION AND USE THEREOF, AND COMPOSITIONS CONTAINING THE SAME

  摘要：

  本发明涉及2-烷氧基-3,4,5-三羟基烷基酰胺衍生物，包括这些化合物的制药组合物，包括通过给予这些化合物的治疗方法，包括制备这些化合物的过程，以及这些化合物的中间体前体。

  公开号：

  US20090075971A1

文献信息

• Derivatives of 2-alkoxy-3,4,5-trihydroxy-alkyl amides, preparation and use thereof, and compositions containing the same
  申请人：Sanofi-Aventis

  公开号：US07994161B2

  公开（公告）日：2011-08-09

  The present invention relates to 2-alkoxy-3,4,5-trihydroxyalkylamide derivatives, to pharmaceutical compositions comprising such compounds, to methods of treatment comprising administering such compounds, to processes for the preparation of such compounds, and to intermediate precursors to such compounds.

  本发明涉及2-烷氧基-3,4,5-三羟基烷基酰胺衍生物，包括这些化合物的制药组合物，包括给予这些化合物的治疗方法，包括制备这些化合物的过程，以及这些化合物的中间前体。
• INHIBITORS OF RECEPTOR-INTERACTING PROTEIN KINASE 1
  申请人：Denali Therapeutics Inc.

  公开号：EP3414239A2

  公开（公告）日：2018-12-19
• US7994161B2
  申请人：——

  公开号：US7994161B2

  公开（公告）日：2011-08-09
• [EN] COMPOUNDS, COMPOSITIONS AND METHODS<br/>[FR] COMPOSÉS, COMPOSITIONS ET PROCÉDÉS
  申请人：DENALI THERAPEUTICS INC

  公开号：WO2017136727A2

  公开（公告）日：2017-08-10

  The present disclosure relates generally to compounds and compositions, and their use as kinase inhibitors.
• Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases
  作者：Philip A. Harris、Scott B. Berger、Jae U. Jeong、Rakesh Nagilla、Deepak Bandyopadhyay、Nino Campobasso、Carol A. Capriotti、Julie A. Cox、Lauren Dare、Xiaoyang Dong、Patrick M. Eidam、Joshua N. Finger、Sandra J. Hoffman、James Kang、Viera Kasparcova、Bryan W. King、Ruth Lehr、Yunfeng Lan、Lara K. Leister、John D. Lich、Thomas T. MacDonald、Nathan A. Miller、Michael T. Ouellette、Christina S. Pao、Attiq Rahman、Michael A. Reilly、Alan R. Rendina、Elizabeth J. Rivera、Michelle C. Schaeffer、Clark A. Sehon、Robert R. Singhaus、Helen H. Sun、Barbara A. Swift、Rachel D. Totoritis、Anna Vossenkämper、Paris Ward、David D. Wisnoski、Daohua Zhang、Robert W. Marquis、Peter J. Gough、John Bertin

  DOI：10.1021/acs.jmedchem.6b01751

  日期：2017.2.23

  RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting, its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.