(±)-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氧烷类
• 英文名称: (±)-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole
• 英文别名: rel-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano-[3,4-c][1,2]oxazole；rac-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole；rel-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole；(3aR,5R)-5-cyclopropyl-3a,4,5,7-tetrahydro-3H-pyrano[3,4-c][1,2]oxazole
• 化学式: C₉H₁₃NO₂
• 分子量: 167.208
• InChiKey: STAYBCAOJDIOOP-IONNQARKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  12
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  30.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (±)-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole 在 吡啶 、 三氟甲磺酸酐 、 二氧化碳 、 三氟化硼乙醚 、 溶剂黄146 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 异丙胺 、 锌 作用下， 以 甲醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 45.25h， 生成 (4aR,6R,8aS)-6-cyclopropyl-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine
  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：

  1-环丙基-丁-3-烯-1-醇 在 盐酸 、 sodium hypochlorite 、 盐酸羟胺 、 水 、 sodium acetate 、 sodium hydride 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 mineral oil 为溶剂， 反应 57.75h， 生成 (±)-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole
  参考文献：
  名称：

  HEXAHYDROPYRANO[3,4-d][1,3]THIAZIN-2-AMINE COMPOUNDS

  摘要：

  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。

  公开号：

  US20140163015A1

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。
• [EN] CARBOCYCLIC- AND HETEROCYCLIC-SUBSTITUTED HEXAHYDROPYRANO[3,4-d][1,3]THIAZIN-2-AMINE COMPOUNDS<br/>[FR] COMPOSÉS HEXAHYDROPYRANO[3,4-D][1,3]THIAZIN-2-AMINE SUBSTITUÉS CARBOCYCLIQUES ET HÉTÉROCYCLIQUES
  申请人：PFIZER

  公开号：WO2014097038A1

  公开（公告）日：2014-06-26

  The present invention provides compounds of formula (I), wherein the variables R1, R2, R5 and b are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  本发明提供了式（I）的化合物，其中变量R1、R2、R5和b如规范中定义。相应的药物组合物、治疗方法、合成方法和中间体也被揭示。
• [EN] C5-C6-OXACYCLIC FUSED IMINOPYRIMIDINONE COMPOUNDS AS BACE INHIBITORS, COMPOSITIONS, AND THEIR USE<br/>[FR] COMPOSÉS IMINOPYRIMIDINONES CONDENSÉS OXACYCLIQUES EN C5-C6 UTILISÉS COMME INHIBITEURS DE BACE, COMPOSITIONS ET UTILISATION ASSOCIÉES
  申请人：MERCK SHARP & DOHME

  公开号：WO2016085780A1

  公开（公告）日：2016-06-02

  In its many embodiments, the present invention provides certain C5-C6-oxacyclic fused iminopyrimidinone compounds, including compounds Formula (I): or a tautomer thereof, and pharmaceutically acceptable salts of said compounds and said tautomers, wherein RN, R1, RA, ring A, m, n, -L1-, ring B, RB, and p are as defined herein. The novel compounds of the invention are useful as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including for the possible treatment of Alzheimer's disease, are also disclosed.

  在其多种实施方式中，本发明提供了某些C5-C6-氧杂环融合咪唑嘧啶酮化合物，包括化合物式（I）所示的化合物或其互变异构体，以及该化合物和该互变异构体的药学上可接受的盐，其中RN、R1、RA、环A、m、n、-L1-、环B、RB和p如本文所定义。本发明的新化合物可用作BACE抑制剂和/或用于治疗和预防与之相关的各种病理。还披露了包括一种或多种此类化合物（单独使用和与一种或多种其他活性剂组合使用）的药物组合物，以及其制备和使用方法，包括可能用于治疗阿尔茨海默病的方法。
• 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。