N-[(2S,3R)-4-[[(4S)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-1-(4-fluoro-3-methylphenyl)-3-hydroxybutan-2-yl]acetamide | 939444-45-8

• 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: N-[(2S,3R)-4-[[(4S)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-1-(4-fluoro-3-methylphenyl)-3-hydroxybutan-2-yl]acetamide
• CAS: 939444-45-8
• 化学式: C₂₉H₄₀FN₃O₃
• 分子量: 497.653
• InChiKey: NHIPWBOQIBZBNP-KKUQBAQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  36
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  83.5
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 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 、 三乙酰氧基硼氢化钠 、 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 、 甲醇 、 乙醚 、 二氯甲烷 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 16.0h， 生成 N-[(2S,3R)-4-[[(4S)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-1-(4-fluoro-3-methylphenyl)-3-hydroxybutan-2-yl]acetamide
  参考文献：
  名称：

  A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of β-Secretase

  摘要：

  beta-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as 1 with low nanomolar potency against beta-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce A beta(40) levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 as a novel, potent, and orally efficacious BACE inhibitor.

  DOI：

  10.1021/ml3000148

文献信息

• Beta-secretase modulators and methods of use
  申请人：Zhong Wenge

  公开号：US20070185144A1

  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, W, 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。在一种实施方式中，化合物具有通式I，其中A、B、W、R3、R4、R5、i和j在此定义。本发明还包括包含一个或多个通式I化合物的药物组合物，以及使用这些化合物的方法，包括通过将通式I化合物或包含它们的组合物给予受试者治疗AD和相关疾病。本发明还包括通式II和III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：Zhong Wenge

  公开号：US20100222338A1

  公开（公告）日：2010-09-02

  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, W, 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，该化合物具有一般式I，其中A、B、W、R3、R4、R5、i和j在此被定义。本发明还包括包含一种或多种I式化合物的制药组合物，以及使用这些化合物的方法，包括通过将I式化合物或包含它们的组合物用于治疗AD和相关疾病来给受试者施用。本发明还包括进一步的II式和III式的实施例，以及用于制备本发明化合物的中间体和方法。
• US7745484B2
  申请人：——

  公开号：US7745484B2

  公开（公告）日：2010-06-29
• [EN] SUBSTITUTED HYDROXYETHYL AMINE COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE<br/>[FR] COMPOSÉS D'HYDROXYÉTHYLAMINE SUBSTITUÉS EN TANT QUE MODULATEURS DE LA BÊTA-SÉCRÉTASE ET PROCÉDÉS D'UTILISATION
  申请人：AMGEN INC

  公开号：WO2008147547A1

  公开（公告）日：2008-12-04

  [EN] 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 or Formula II wherein RIa, RIb, RIc, B, R3, R4, R5 and W of Formula I, and RIa, RIb, RIc, R2, R2a, R3, R4, R5, R6, Al, A2, A3, A4, W, X, Z, m and n of Formula II are defined herein.
  [FR] La présente invention concerne une nouvelle classe de composés utilisés pour moduler l'activité enzymatique de bêta-sécrétase et pour traiter des maladies à médiation bêta-sécrétase, y compris la maladie d'Alzheimer et des troubles associés. Dans un mode de réalisation, les composés ont une formule générale I ou une formule générale II, RIa, RIb, RIc, B, R3, R4, R5 et W de la formule I, et RIa, RIb, RIc, R2, R2a, R3, R4, R5, R6, Al, A2, A3, A4, W, X, Z, m et n de la formule II sont tels que définis ci-après.
• A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of β-Secretase
  作者：Matthew R. Kaller、Scott S. Harried、Brian Albrecht、Patricia Amarante、Safura Babu-Khan、Michael D. Bartberger、James Brown、Ryan Brown、Kui Chen、Yuan Cheng、Martin Citron、Michael D. Croghan、Russell Graceffa、Dean Hickman、Ted Judd、Chuck Kriemen、Daniel La、Vivian Li、Patricia Lopez、Yi Luo、Craig Masse、Holger Monenschein、Thomas Nguyen、Lewis D. Pennington、Tisha San Miguel、E. Allen Sickmier、Robert C. Wahl、Matthew M. Weiss、Paul H. Wen、Toni Williamson、Stephen Wood、May Xue、Bryant Yang、Jianhua Zhang、Vinod Patel、Wenge Zhong、Stephen Hitchcock

  DOI：10.1021/ml3000148

  日期：2012.11.8

  beta-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as 1 with low nanomolar potency against beta-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce A beta(40) levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 as a novel, potent, and orally efficacious BACE inhibitor.