3-(1-(tert-butyldimethylsilyloxy)cyclobutyl)propane-1,2-diol | 939411-88-8

• 分子结构分类: 有机化合物 - 有机金属化合物 - 有机类金属化合物
• 英文名称: 3-(1-(tert-butyldimethylsilyloxy)cyclobutyl)propane-1,2-diol
• 英文别名: 3-[1-[tert-butyl(dimethyl)silyl]oxycyclobutyl]propane-1,2-diol
• CAS: 939411-88-8
• 化学式: C₁₃H₂₈O₃Si
• 分子量: 260.449
• InChiKey: RSXBSCALZWRCLO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.67
• 重原子数：
  17
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  49.7
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-(1-(tert-butyldimethylsilyloxy)cyclobutyl)propane-1,2-diol 在 2,2,6,6-四甲基哌啶 、 盐酸 、 sodium periodate 、 正丁基锂 、 copper(II) sulfate 、 N,N-二异丙基乙胺 、 cesium fluoride 、 原甲酸三甲酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 、 二甲基亚砜 、 甲苯 、 叔丁醇 为溶剂， 反应 47.75h， 生成 N-[(2S,3R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-[[(4S)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]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：

  叔丁基二甲硅基三氟甲磺酸酯 在 四氧化锇 、 N-甲基吗啉氧化物 作用下， 以 四氢呋喃 、 乙醚 、 水 、 叔丁醇 为溶剂， 反应 4.5h， 生成 3-(1-(tert-butyldimethylsilyloxy)cyclobutyl)propane-1,2-diol
  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

文献信息

• Design and Synthesis of Potent, Orally Efficacious Hydroxyethylamine Derived β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors
  作者：Thomas A. Dineen、Matthew M. Weiss、Toni Williamson、Paul Acton、Safura Babu-Khan、Michael D. Bartberger、James Brown、Kui Chen、Yuan Cheng、Martin Citron、Michael D. Croghan、Robert T. Dunn、Joel Esmay、Russell F. Graceffa、Scott S. Harried、Dean Hickman、Stephen A. Hitchcock、Daniel B. Horne、Hongbing Huang、Ronke Imbeah-Ampiah、Ted Judd、Matthew R. Kaller、Charles R. Kreiman、Daniel S. La、Vivian Li、Patricia Lopez、Steven Louie、Holger Monenschein、Thomas T. Nguyen、Lewis D. Pennington、Tisha San Miguel、E. Allen Sickmier、Hugo M. Vargas、Robert C. Wahl、Paul H. Wen、Douglas A. Whittington、Stephen Wood、Qiufen Xue、Bryant H. Yang、Vinod F. Patel、Wenge Zhong

  DOI：10.1021/jm300118s

  日期：2012.11.8

  We have previously shown that hydroxyethylamines can be potent inhibitors of the BACE1 enzyme and that the generation of BACE1 inhibitors with CYP 3A4 inhibitory activities in this scaffold affords compounds (e.g., 1) with sufficient bioavailability and pharmacokinetic profiles to reduce central amyloid-β peptide (Aβ) levels in wild-type rats following oral dosing. In this article, we describe further

  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。
• Beta-secretase modulators and methods of use
  申请人：Albrecht K. Brian

  公开号：US20070185103A1

  公开（公告）日：2007-08-09

  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 A, B, R 3 , R 4 , R 5 , i and j are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula I, methods of use for these compounds, including treatment of AD and related diseases, by administering the compound(s) of Formula I, or compositions including them, to a subject. The invention also comprises further embodiments of Formulas II and III, intermediates and processes useful for the preparation of compounds of the invention.

  本发明涉及一类新的化合物，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。 在一种实施方式中，该化合物具有一般式I，其中A，B，R3，R4，R5，i和j在此定义。 本发明还包括包括一种或多种I式化合物的制药组合物，以及使用这些化合物的方法，包括通过向受体注射I式化合物或包含它们的组合物来治疗AD和相关疾病。 本发明还包括II式和III式的进一步实施方式，以及用于制备本发明化合物的中间体和过程。
• Beta-Secretase modulators and methods of use
  申请人：Amgen Inc.

  公开号：US07872009B2

  公开（公告）日：2011-01-18

  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 A, B, R3, R4, R5, i and j are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula I, methods of use for these compounds, including treatment of AD and related diseases, by administering the compound(s) of Formula I, or compositions including them, to a subject. The invention also comprises further embodiments of Formulas II and III, intermediates and processes useful for the preparation of compounds of the invention.

  本发明涉及一种新型化合物类别，可用于调节β-秘鲁酶酶活性和治疗β-秘鲁酶介导的疾病，包括阿尔茨海默病（AD）和相关病症。在一种实施例中，该化合物具有一般式I，其中A、B、R3、R4、R5、i和j在此定义。本发明还包括包括一种或多种I式化合物的制药组合物，使用这些化合物的方法，包括通过将I式化合物或包括它们的组合物用于治疗AD和相关疾病来给予受试者。本发明还包括II式和III式的进一步实施例，中间体和制备本发明化合物的有用过程。
• BETA-SECRETASE MODULATORS AND METHODS OF USE
  申请人：Albrecht Brian K.

  公开号：US20110118250A1

  公开（公告）日：2011-05-19

  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 A, B, R 3 , R 4 , R 5 , i and j are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula I, methods of use for these compounds, including treatment of AD and related diseases, by administering the compound(s) of Formula I, or compositions including them, to a subject. The invention also comprises further embodiments of Formulas II and III, intermediates and processes useful for the preparation of compounds of the invention.

  本发明涉及一类新型化合物，可用于调节β-分泌酶酶活性和治疗β-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，所述化合物具有一般式I，其中A、B、R3、R4、R5、i和j在此被定义。本发明还包括包括一种或多种式I化合物的制药组合物，以及使用这些化合物的方法，包括将式I化合物或包含它们的组合物用于治疗AD和相关疾病，通过将式I化合物或包含它们的组合物用于给予受试者的方法。本发明还包括式II和III的进一步实施例，以及用于制备本发明化合物的中间体和方法。
• WO2007/62007
  申请人：——

  公开号：——

  公开（公告）日：——