(S)-6′-neopentyl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-amine | 939411-93-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡喃吡啶类
• 英文名称: (S)-6′-neopentyl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-amine
• 英文别名: (4S)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-amine
• CAS: 939411-93-5
• 化学式: C₁₆H₂₄N₂O
• 分子量: 260.379
• InChiKey: OJOFJZKKMACTKG-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  48.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (S)-6′-neopentyl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-amine 在 盐酸 、 N,N-二异丙基乙胺 、 原甲酸三甲酯 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.33h， 生成 N-((1S,2R)-1-((3,4-bis(methyloxy)phenyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxypropyl)acetamide
  参考文献：
  名称：

  Design and Preparation of a Potent Series of Hydroxyethylamine Containing β-Secretase Inhibitors That Demonstrate Robust Reduction of Central β-Amyloid

  摘要：

  A series of potent hydroxyethyl amine (HEA) derived inhibitors of beta-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS beta-amyloid (A beta) in Sprague-Dawley rats following oral administration.

  DOI：

  10.1021/jm300119p
• 作为产物：
  描述：

  2-氟-5-溴吡啶 在 2,2,6,6-四甲基哌啶 、 盐酸 、 正丁基锂 、 cesium fluoride 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 二甲基亚砜 、 甲苯 为溶剂， 反应 17.75h， 生成 (S)-6′-neopentyl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-amine
  参考文献：
  名称：

  有效的，口服有效的羟乙基胺衍生的β-位淀粉样前体蛋白裂解酶（BACE1）抑制剂的设计与合成

  摘要：

  先前我们已经证明羟乙胺可能是BACE1酶的有效抑制剂，并且在该支架中具有CYP 3A4抑制活性的BACE1抑制剂的产生提供了具有足够生物利用度和药代动力学特征的化合物（例如1），以减少中央淀粉样β肽（口服给药后野生型大鼠的Aβ）水平。在本文中，我们描述了羟乙胺系列的P1-苯环的进一步修饰，以提供有效的双BACE1 / CYP 3A4抑制剂，该抑制剂表现出对CNS的改善渗透性。这些化合物中的几种引起口服给药后大鼠CSF和大脑中Aβ含量的强烈降低，并且化合物37的心血管安全性相对于1有所改善。

  DOI：

  10.1021/jm300118s

文献信息

• Substituted hydroxyethyl amine compounds as beta-secretase modulators and methods of use
  申请人：Zhong Wenge

  公开号：US20090036478A1

  公开（公告）日：2009-02-05

  The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer's disease (AD) and related conditions. In one embodiment, the compounds have a general Formula I wherein R 1a , R 1b , R 1c , B, W, R 3 , R 4 and R 5 are defined herein. In another embodiment, the invention provides compounds of general Formula II wherein A 1 , A 2 , A 3 , A 4 , R 1a , R 1b , R 1c , R 2 , R 4 , R 5 , W, X and Z are defined herein. The invention also includes use of these compounds in pharmaceutical compositions for treatment, prophylactic or therapeutic, of disorders and conditions related to the activity of beta-secretase protein. Such disorders include, for example, Alzheimer's Disease (AD), cognitive deficits and impairment, schizophrenia and other similar central nervous system conditions. The invention also comprises further embodiments of Formula II, intermediates and processes useful for the preparation of compounds of Formulas I and II.

  本发明涉及一类新化合物，适用于调节Beta-分泌酶酶活性和治疗Beta-分泌酶介导的疾病，包括阿尔茨海默病（AD）和相关疾病。在一种实施例中，该化合物具有一般的I式，其中R1a、R1b、R1c、B、W、R3、R4和R5在此定义。在另一种实施例中，本发明提供了一般式II的化合物，其中A1、A2、A3、A4、R1a、R1b、R1c、R2、R4、R5、W、X和Z在此定义。本发明还包括这些化合物在制药组合物中的使用，用于治疗与Beta-分泌酶蛋白活性相关的疾病和症状。这些疾病包括阿尔茨海默病（AD）、认知缺陷和损伤、精神分裂症和其他类似的中枢神经系统疾病。本发明还包括进一步的II式实施例、中间体和制备I式和II式化合物的有用工艺。
• SUBSTITUTED HYDROXYETHYL AMINE COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE
  申请人：ZHONG Wenge

  公开号：US20120220583A1

  公开（公告）日：2012-08-30

  The present invention comprises a new class of compounds useful for the modulation of Beta-secretase activity and for the treatment of diseases, including Alzheimer's disease (AD) and related CNS conditions, mediated thereby. In one embodiment, the compounds have a general Formula I or Formula II wherein R 1a-1c , B, R 3-5 and W of Formula I, and R 1a-1c , R 2-5 , A 1-4 , W, X, Z, m and n of Formula II are defined herein. The invention further provides compounds of Formula III and IV and sub-Formulas II-A-II-D and III-A-III-D. The compounds may be used in pharmaceutical compositions for treating, prophylactically or therapeutically, disorders related to the activity of beta-secretase protein, including without limitation, AD, cognitive deficits and impairment, schizophrenia and other similar central nervous system conditions.

  本发明涉及一种新的化合物类别，用于调节Beta-分泌酶活性和治疗由此介导的疾病，包括阿尔茨海默病（AD）和相关的中枢神经系统疾病。在一种实施方案中，所述化合物具有通式I或通式II，其中式I中的R1a-1c、B、R3-5和W，式II中的R1a-1c、R2-5、A1-4、W、X、Z、m和n在此定义。本发明还提供了通式III和IV以及亚式II-A-II-D和III-A-III-D的化合物。所述化合物可用于制备药物组合物，用于预防或治疗与Beta-分泌酶蛋白活性相关的疾病，包括但不限于AD、认知缺陷和损伤、精神分裂症和其他类似的中枢神经系统疾病。
• WO2007/62007
  申请人：——

  公开号：——

  公开（公告）日：——
• WO2008/147547
  申请人：——

  公开号：——

  公开（公告）日：——
• Hydroxyethylamine-based inhibitors of BACE1: P1–P3 macrocyclization can improve potency, selectivity, and cell activity
  作者：Lewis D. Pennington、Douglas A. Whittington、Michael D. Bartberger、Steven R. Jordan、Holger Monenschein、Thomas T. Nguyen、Bryant H. Yang、Qiufen M. Xue、Filisaty Vounatsos、Robert C. Wahl、Kui Chen、Stephen Wood、Martin Citron、Vinod F. Patel、Stephen A. Hitchcock、Wenge Zhong

  DOI：10.1016/j.bmcl.2013.05.028

  日期：2013.8

  We describe a systematic study of how macrocyclization in the P-1-P-3 region of hydroxyethylamine-based inhibitors of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid beta-peptide (A beta)-lowering activity in HEK293T cells stably expressing APP(SW). However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme. (C) 2013 Elsevier Ltd. All rights reserved.