{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}carbamate | 1425947-63-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: {[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}carbamate
• 英文别名: N-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}-2-(9H-fluoren-9-yl)acetamide；9H-fluoren-9-ylmethyl {[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}carbamate；9H-fluoren-9-ylmethyl N-[[(3S,4R,6R)-3-(2,4-difluorophenyl)-4-(hydroxymethyl)-6-(phenylmethoxymethyl)oxan-3-yl]carbamothioyl]carbamate
• CAS: 1425947-63-2
• 化学式: C₃₆H₃₄F₂N₂O₅S
• 分子量: 644.739
• InChiKey: BXZMRZUXDSWCLD-KRZVZTLSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  46
• 可旋转键数：
  10
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  121
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  {[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}carbamate 在 哌啶 、 盐酸 、 二乙胺基三氟化硫 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 正戊烷 为溶剂， 反应 43.0h， 生成 tert-butyl [(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]carbamate
  参考文献：
  名称：

  Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design

  摘要：

  The identification of centrally efficacious beta-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Upon oral administration, these inhibitors exhibit robust brain availability and are efficacious in lowering central Amyloid beta (A beta) levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of A beta-derived plaques. Most importantly, evaluation of 36 in a 2-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors.

  DOI：

  10.1021/jm501833t
• 作为产物：
  描述：

  (R)-苄氧甲基环氧乙烷 在 盐酸 、 sodium hypochlorite 、 copper(l) iodide 、 三氟化硼乙醚 、 sodium acetate 、 sodium hydride 、 溶剂黄146 、 三乙胺 、 锌 作用下， 以 四氢呋喃 、 乙醚 、 乙醇 、 二氯甲烷 、 异丙醚 、 水 、 甲苯 、 mineral oil 为溶剂， 反应 117.58h， 生成 {[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}carbamate
  参考文献：
  名称：

  Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design

  摘要：

  The identification of centrally efficacious beta-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Upon oral administration, these inhibitors exhibit robust brain availability and are efficacious in lowering central Amyloid beta (A beta) levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of A beta-derived plaques. Most importantly, evaluation of 36 in a 2-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors.

  DOI：

  10.1021/jm501833t

文献信息

• Hexahydropyrano[3,4-d][1,3]Thiazin-2-Amine Compounds
  申请人：BRODNEY Michael Aaron

  公开号：US20130053373A1

  公开（公告）日：2013-02-28

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I, as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  所述化合物及其药用可接受的盐被揭示，其中所述化合物具有规范中定义的Formula I的结构。相应的药物组合物、治疗方法、合成方法和中间体也被揭示。
• Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
  申请人：Brodney Michael Aaron

  公开号：US08933221B2

  公开（公告）日：2015-01-13

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I, as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  本文揭示了具有结构式I的化合物及其药学上可接受的盐，其定义在说明书中。同时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：EP2751116B1

  公开（公告）日：2016-10-12
• US8933221B2
  申请人：——

  公开号：US8933221B2

  公开（公告）日：2015-01-13
• US9550795B2
  申请人：——

  公开号：US9550795B2

  公开（公告）日：2017-01-24