benzyl (2S,4R)-4-cyano-4-[(3-fluorophenyl)amino]-2-methylpiperidine-1-carboxylate | 1193782-19-2

• 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: benzyl (2S,4R)-4-cyano-4-[(3-fluorophenyl)amino]-2-methylpiperidine-1-carboxylate
• 英文别名: benzyl (2S,4R)-4-cyano-4-(3-fluoroanilino)-2-methylpiperidine-1-carboxylate
• CAS: 1193782-19-2
• 化学式: C₂₁H₂₂FN₃O₂
• 分子量: 367.423
• InChiKey: KTEGGOXSIVMIRM-HRAATJIYSA-N

物化性质

• 沸点：
  548.2±50.0 °C(Predicted)
• 密度：
  1.24±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  65.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  benzyl (2S,4R)-4-cyano-4-[(3-fluorophenyl)amino]-2-methylpiperidine-1-carboxylate 在 氨 、 氢气 、 palladium(II) hydroxide 、 sodium hydride 、 3-(imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium triflate 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 20.0 ℃ 、344.75 kPa 条件下， 反应 33.5h， 生成 (5R,7S)-1-(3-fluorophenyl)-3,7-dimethyl-2-thia-1,3,8-triazaspiro[4.5]decane 2,2-dioxide
  参考文献：
  名称：

  Spirocyclic Sulfamides as β-Secretase 1 (BACE-1) Inhibitors for the Treatment of Alzheimer’s Disease: Utilization of Structure Based Drug Design, WaterMap, and CNS Penetration Studies To Identify Centrally Efficacious Inhibitors

  摘要：

  beta-Secretase 1 (BACE-1) is an attractive therapeutic target for the treatment and prevention of Alzheimer's disease (AD). Herein, we describe the discovery of a novel class of BACE-1 inhibitors represented by sulfamide 14g, using a medicinal chemistry strategy to optimize central nervous system (CNS) penetration by minimizing hydrogen bond donors (HBDs) and reducing P-glycoprotein (P-gp) mediated efflux. We have also taken advantage of the combination of structure based drug design (SBDD) to guide the optimization of the sulfamide analogues and the in silico tool WaterMap to explain the observed SAR. Compound 14g is a potent inhibitor of BACE-1 with excellent permeability and a moderate P-gp liability. Administration of 14g to mice produced a significant, dose-dependent reduction in central A beta(X-40) levels at a free drug exposure equivalent to the whole cell IC50 (100 nM). Furthermore, studies of the P-gp knockout mouse provided evidence that efflux transporters affected the amount of A beta lowering versus that observed in wild-type (WT) mouse at an equivalent dose.

  DOI：

  10.1021/jm3009426
• 作为产物：
  描述：

  (S)-1-CBZ-2-甲基-4-哌啶酮 在 溶剂黄146 作用下， 以 甲醇 、 二氧化碳 为溶剂， 生成 benzyl (2S,4R)-4-cyano-4-[(3-fluorophenyl)amino]-2-methylpiperidine-1-carboxylate 、 benzyl (2S,4S)-4-cyano-4-[(3-fluorophenyl)amino]-2-methylpiperidine-1-carboxylate
  参考文献：
  名称：

  [EN] NOVEL CLASS OF SPIRO PIPERIDINES FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
  [FR] NOUVELLE CLASSE DE SPIRO PIPÉRIDINES POUR LE TRAITEMENT DE MALADIES NEURODÉGÉNÉRATIVES

  摘要：

  本发明揭示了化合物及其在规范中定义的结构为化学式（I）的药用可接受盐。同时还揭示了相应的药用组合物、治疗方法、合成方法和中间体。

  公开号：

  WO2009136350A1

文献信息

• [EN] LACTAMS AS BETA SECRETASE INHIBITORS<br/>[FR] LACTAMES EN TANT QU'INHIBITEURS DE BÊTA-SÉCRÉTASE
  申请人：PFIZER

  公开号：WO2010058333A1

  公开（公告）日：2010-05-27

  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.

  本文披露了化合物及其药学上可接受的盐，其中这些化合物具有规范中定义的Formula (I)的结构。同时还披露了相应的药物组合物、治疗方法、合成方法和中间体。
• Novel Sultam Compounds
  申请人：Brodney Michael Aaron

  公开号：US20130150376A1

  公开（公告）日：2013-06-13

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

  本发明揭示了化合物及其在规范中定义的Formula I（I）结构下的药用盐。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。
• Spiropiperidine beta-secretase inhibitors for the treatment of Alzheimer's disease
  申请人：Coburn A. Craig

  公开号：US20070021454A1

  公开（公告）日：2007-01-25

  The present invention is directed to spiropiperidine compounds of formula (I) and tautomers thereof, which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.

  本发明涉及式（I）及其互变异构体的螺环吡啶化合物，这些化合物是β-分泌酶酶的抑制剂，并且在治疗β-分泌酶酶参与的疾病，如阿尔茨海默病方面是有用的。本发明还涉及包括这些化合物的制药组合物以及在治疗β-分泌酶酶参与的这些疾病中使用这些化合物和组合物的用途。
• Novel Class of Spiro Piperidines for the Treatment of Neurodegenerative Diseases
  申请人：Brodney Michael A.

  公开号：US20110046160A1

  公开（公告）日：2011-02-24

  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.

  本发明公开了化合物及其药用可接受盐，其中该化合物具有规范中定义的公式（I）的结构。同时还公开了相应的药物组合物、治疗方法、合成方法和中间体。
• Novel Lactams as Beta Secretase Inhibitors
  申请人：Brodney Michael A.

  公开号：US20110224231A1

  公开（公告）日：2011-09-15

  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.

  本发明揭示了具有以下式子(I)结构的化合物及其在药学上可接受的盐。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。