(4aR,6R,8aS)-8a-(2,4-difluoro-5-(((2,2,2-trifluoroethyl)amino)-methyl)phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano-[3,4-d][1,3]thiazin-2-amine | 1613393-83-1

• 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: (4aR,6R,8aS)-8a-(2,4-difluoro-5-(((2,2,2-trifluoroethyl)amino)-methyl)phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano-[3,4-d][1,3]thiazin-2-amine
• 英文别名: (4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine；(4aR,6R,8aS)-8a-[2,4-difluoro-5-[(2,2,2-trifluoroethylamino)methyl]phenyl]-6-(fluoromethyl)-4a,5,6,8-tetrahydro-4H-pyrano[3,4-d][1,3]thiazin-2-amine
• CAS: 1613393-83-1
• 化学式: C₁₇H₁₉F₆N₃OS
• 分子量: 427.414
• InChiKey: KXRWMDHPUURSND-USBNGQNGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  84.9
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (4aR,6R,8aS)-8a-(2,4-difluoro-5-(((2,2,2-trifluoroethyl)amino)-methyl)phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano-[3,4-d][1,3]thiazin-2-amine 在 磷酸 作用下， 以 乙醚 、 乙腈 为溶剂， 反应 0.67h， 以77%的产率得到
  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：

  1,5-二溴-2,4-二氟苯 在 盐酸 、 1,1'-双(二苯基膦)二茂铁 、 sodium bromate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 samarium diiodide 、 二乙胺基三氟化硫 、 三氟化硼乙醚 、 氢气 、 镍 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 锌 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 水 、 乙酸乙酯 、 甲苯 、 乙腈 、 正戊烷 为溶剂， -78.0~130.0 ℃ 、482.64 kPa 条件下， 反应 21.5h， 生成 (4aR,6R,8aS)-8a-(2,4-difluoro-5-(((2,2,2-trifluoroethyl)amino)-methyl)phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano-[3,4-d][1,3]thiazin-2-amine
  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

文献信息

• HEXAHYDROPYRANO[3,4-d][1,3]THIAZIN-2-AMINE COMPOUNDS
  申请人：Pfizer Inc.

  公开号：US20140163015A1

  公开（公告）日：2014-06-12

  The present invention provides compounds of Formula I, and the tautomers thereof, and the pharmaceutically acceptable salts of the compounds and tautomers, wherein the compounds have the structure wherein the variables R 1 , R 2 , R 3 , R 4 and x are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  本发明提供了化合物I的结构，以及其互变异构体和药学上可接受的盐，其中化合物具有以下结构，其中变量R1、R2、R3、R4和x如规范中定义。还公开了相应的药物组合物、治疗方法、合成方法和中间体。
• Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
  申请人：Pfizer Inc.

  公开号：US09045498B2

  公开（公告）日：2015-06-02

  The present invention provides compounds of Formula I, and the tautomers thereof, and the pharmaceutically acceptable salts of the compounds and tautomers, wherein the compounds have the structure wherein the variables R1, R2, R3, R4 and x are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  本发明提供了公式I的化合物及其互变异构体和药学上可接受的盐，其中化合物具有以下结构式：其中变量R1、R2、R3、R4和x如规范中所定义。本发明还揭示了相应的药物组合物、治疗方法、合成方法和中间体。
• Hexahydropyrano[3,4-d][1,3]Thiazin-2-Amine Compounds
  申请人：Pfizer Inc.

  公开号：US20140323474A1

  公开（公告）日：2014-10-30

  The present invention provides compounds of Formula I, and the tautomers thereof, and the pharmaceutically acceptable salts of the compounds and tautomers, wherein the compounds have the structure wherein the variables R 1 , R 2 , R 3 , R 4 and x are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  本发明提供了I式化合物及其互变异构体和药学上可接受的化合物和互变异构体的盐，其中化合物具有以下结构式，其中变量R1、R2、R3、R4和x如规范所定义。还公开了相应的药物组合物、治疗方法、合成方法和中间体。
• US8822456B2
  申请人：——

  公开号：US8822456B2

  公开（公告）日：2014-09-02
• US9045498B2
  申请人：——

  公开号：US9045498B2

  公开（公告）日：2015-06-02