(S)-tert-butyl 4-(5-bromo-2,4-difluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-ylcarbamate | 1194044-58-0

• 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: (S)-tert-butyl 4-(5-bromo-2,4-difluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-ylcarbamate
• 英文别名: tert-butyl N-[(4S)-4-(5-bromo-2,4-difluorophenyl)-4-methyl-5,6-dihydro-1,3-thiazin-2-yl]carbamate
• CAS: 1194044-58-0
• 化学式: C₁₆H₁₉BrF₂N₂O₂S
• 分子量: 421.306
• InChiKey: LIGCEYNSJDPHHL-INIZCTEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  76
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (S)-tert-butyl 4-(5-bromo-2,4-difluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-ylcarbamate 在 甲基锂 、 三乙酰氧基硼氢化钠 作用下， 以 乙醚 、 1,2-二氯乙烷 为溶剂， 反应 4.0h， 生成 tert-butyl (S)-(4-(2,4-difluoro-5-(((1-(trifluoromethyl)-cyclopropyl)amino)methyl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-yl)carbamate
  参考文献：
  名称：

  Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality

  摘要：

  A growing subset of beta-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability, and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor.

  DOI：

  10.1021/acs.jmedchem.6b01451
• 作为产物：
  描述：

  二碳酸二叔丁酯 、 (S)-4-(5-bromo-2,4-difluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine 在 碳酸氢钠 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 1.08h， 以78%的产率得到(S)-tert-butyl 4-(5-bromo-2,4-difluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-ylcarbamate
  参考文献：
  名称：

  BACE INHIBITORS

  摘要：

  本发明提供了Formula I的BACE抑制剂：它们的使用方法，以及它们的制备中间体和方法。

  公开号：

  US20090275566A1

文献信息

• BACE inhibitors
  申请人：Eli Lilly and Company

  公开号：US07648983B2

  公开（公告）日：2010-01-19

  The present invention provides BACE inhibitors of Formula I: methods for their use, and intermediates and methods for their preparation.

  本发明提供了一种公式I的BACE抑制剂：它们的使用方法，以及它们的中间体和制备方法。
• AMINODIHYDROTHIAZINE DERIVATIVES AS BACE INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE
  申请人：Eli Lilly & Company

  公开号：EP2297120B1

  公开（公告）日：2015-08-19
• US7648983B2
  申请人：——

  公开号：US7648983B2

  公开（公告）日：2010-01-19