ethyl (+/-)-N-tert-butyloxycarbonyl-2-azanorborn-5-ene-3-exo-carboxylate | 81357-21-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: ethyl (+/-)-N-tert-butyloxycarbonyl-2-azanorborn-5-ene-3-exo-carboxylate
• 英文别名: 2-tert-butyl 3-ethyl (3SR)-exo-2-azabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate；2-O-tert-butyl 3-O-ethyl (1S,3S,4R)-2-azabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate
• CAS: 81357-21-3
• 化学式: C₁₄H₂₁NO₄
• 分子量: 267.325
• InChiKey: WOUSLVASGANOEU-AXFHLTTASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl (+/-)-N-tert-butyloxycarbonyl-2-azanorborn-5-ene-3-exo-carboxylate 在 RhCl(PPh₃)3 硼烷 、 戴斯-马丁氧化剂 、 儿萘酚硼烷 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 14.75h， 生成 ethyl (+/-)-N-tert-butyloxycarbonyl-5-exo-(hydroxymethyl)-2-azanorbornane-3-exo-carboxylate
  参考文献：
  名称：

  Rational Design, Synthesis, and Pharmacological Evaluation of 2-Azanorbornane-3-exo,5-endo-dicarboxylic Acid:  A Novel Conformationally Restricted Glutamic Acid Analogue

  摘要：

  The design and synthesis of conformationally restricted analogues of alpha-amino acids is an often used strategy in medicinal chemistry research. Here we present the rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid (1), a novel conformationally restricted (S)-glutamic acid (Glu) analogue intended as a mimic of the folded Glu conformation. The synthesis of 1 was completed in its racemic form in eight steps from commercially available starting materials. As a key step, the first facially selective hydroboration of a 5-methylidene[2.2.1]bicyclic intermediate was investigated. In this transformation, the catalytic methodology of Wilkinson's/catechol borane proved superior to stoichiometric borane or dialkyl borane reagents, in terms of higher diastereomeric excess and chemical yield. To our surprise (+/-)-1 did not show affinity in binding studies on native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) (IC50 > 300 muM, [H-3]AMPA) or kainic acid (IC50 > 160 muM, [H-3]kainic acid) receptors nor in binding studies on the cloned iGluR5,6 subtypes (IC50 > 300 muM, [H-3]kainic acid).

  DOI：

  10.1021/jo026509p
• 作为产物：
  描述：

  N-BOC-脒三苯基膦 以 乙二醇二甲醚 、 苯 为溶剂， 反应 15.0h， 生成 ethyl (+/-)-N-tert-butyloxycarbonyl-2-azanorborn-5-ene-3-exo-carboxylate
  参考文献：
  名称：

  Preparation of di- and triacylimines and their use in the synthesis of nitrogen heterocycles

  摘要：

  DOI：

  10.1016/s0040-4039(01)82993-2

文献信息

• [EN] SUBSTITUTED 2-AZA-BICYCLO[2.2.1]HEPTANE-3-CARBOXYLIC ACID (BENZYL-CYANO-METHYL)-AMIDES INHIBITORS OF CATHEPSIN C<br/>[FR] (BENZYL-CYANO-MÉTHYL)-AMIDES SUBSTITUÉS DE L'ACIDE 2-AZA-BICYCLO[2.2.1]HEPTANE-3-CARBOXYLIQUE UTILISÉS COMME INHIBITEURS DE LA CATHÉPSINE C
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2014140075A1

  公开（公告）日：2014-09-18

  This invention relates to 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)- amides of formula (1) and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.

  本发明涉及2-氮杂-双环[2.2.1]庚烷-3-羧酸（苄基-氰甲基）酰胺的化合物（1）及其作为组织蛋白酶C抑制剂的用途，包含该化合物的药物组合物，以及使用该化合物作为治疗和/或预防与二肽基肽酶I活性相关疾病的方法，例如呼吸系统疾病。
• Novel <scp>l</scp>-prolyl-<scp>l</scp>-leucylglycinamide (PLG) tripeptidomimetics based on a 2-azanorbornane scaffold as positive allosteric modulators of the D₂R
  作者：Ivo E. Sampaio-Dias、Carlos A. D. Sousa、Xerardo García-Mera、Joana Ferreira da Costa、Olga Caamaño、José E. Rodríguez-Borges

  DOI：10.1039/c6ob02248k

  日期：——

  Replacement of l-prolyl residue in the PLG sequence by an enantiopure (1R,3S,4S)-2-azanorbornane scaffold afforded active peptidomimetics compatible with suppression of the C-terminal carboxamide pharmacophore.

  在PLG序列中用(1R,3S,4S)-2-氮杂-2-环辛烷支架替换l-脯氨酰残基，得到了与抑制C-末端羧酰胺药效团相容的活性肽类模拟物。
• Synthesis of Enantiopure 3,5-Disubstituted Pyrrolidines by Ring-Opening/Cross-Metathesis Reaction of 2-Azanorbornene Derivatives
  作者：Odón Arjona、Ana Querejeta、Ma José Cabas、José Nieto-Rubio

  DOI：10.3987/com-06-10825

  日期：——

  A concise method for the synthesis of enantiopure 3,5-disubstituted pyrrolidines from 2-azanorbomene derivatives is described. The method is also applied to the synthesis of 3,5-disubstituted prolines.

  描述了一种从 2-azanorbomene 衍生物合成对映纯 3,5-二取代吡咯烷的简明方法。该方法也适用于3,5-二取代脯氨酸的合成。
• Design, Synthesis and Biological Evaluation of Neogliptin, a Novel 2-Azabicyclo[2.2.1]heptane-Based Inhibitor of Dipeptidyl Peptidase-4 (DPP-4)
  作者：Ivan O. Maslov、Tatiana V. Zinevich、Olga G. Kirichenko、Mikhail V. Trukhan、Sergey V. Shorshnev、Natalya O. Tuaeva、Maxim A. Gureev、Amelia D. Dahlén、Yuri B. Porozov、Helgi B. Schiöth、Vladimir M. Trukhan

  DOI：10.3390/ph15030273

  日期：——

  5-trifluorophenyl)butanoic acid substituted with bicyclic amino moiety (2-aza-bicyclo[2.2.1]heptane) were designed using molecular modelling methods, synthesised, and found to be potent DPP-4 (dipeptidyl peptidase-4) inhibitors. Compound 12a (IC50 = 16.8 ± 2.2 nM), named neogliptin, is a more potent DPP-4 inhibitor than vildagliptin and sitagliptin. Neogliptin interacts with key DPP-4 residues in the active site

  使用分子建模方法设计了含有被双环氨基部分（2-氮杂-双环[2.2.1]庚烷）取代的（R）-3-氨基-4-（2,4,5-三氟苯基）丁酸的化合物，合成，并被发现是有效的 DPP-4（二肽基肽酶 4）抑制剂。化合物 12a (IC50 = 16.8 ± 2.2 nM)，名为新格列汀，是比维格列汀和西格列汀更有效的 DPP-4 抑制剂。新格列汀与活性位点中的关键 DPP-4 残基相互作用，并具有与维格列汀和西格列汀相似的药效团参数。与西格列汀相比，它被发现具有较低的心脏毒性作用，并且在 ADME 特性方面优于维格列汀。此外，由于其低分子内环化电位，化合物 12a 在水溶液中是稳定的。
• METHODS FOR TREATING PULMONARY EMPHYSEMA USING SUBSTITUTED 2-AZA-BICYCLO[2.2.1]HEPTANE-3-CARBOXYLIC ACID (BENZYL-CYANO-METHYL)-AMIDES INHIBITORS OF CATHEPSIN C
  申请人：Boehringer Ingelheim International GmbH

  公开号：US20150105375A1

  公开（公告）日：2015-04-16

  This invention relates to 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides of formula 1 and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.

  本发明涉及公式1中的2-Aza-bicyclo[2.2.1]庚烷-3-羧酸（苄基-氰甲基）-酰胺及其作为Cathepsin C抑制剂的用途，含有它们的制药组合物，以及将其作为治疗和/或预防与二肽基肽酶I活性相关的疾病，例如呼吸道疾病的药剂使用的方法。