1'-Benzyl-3H-spiro[isobenzofuran-1,4'-piperidine]-3-carbonitrile | 477352-23-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 1'-Benzyl-3H-spiro[isobenzofuran-1,4'-piperidine]-3-carbonitrile
• 英文别名: 1'-benzylspiro[1H-2-benzofuran-3,4'-piperidine]-1-carbonitrile
• CAS: 477352-23-1
• 化学式: C₂₀H₂₀N₂O
• 分子量: 304.392
• InChiKey: DBEPIBIYXBKJKI-UHFFFAOYSA-N

物化性质

• 熔点：
  114-115 °C
• 沸点：
  491.7±45.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  36.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1'-Benzyl-3H-spiro[isobenzofuran-1,4'-piperidine]-3-carbonitrile 在 10% palladium on carbon 、 甲酸铵 作用下， 以 甲醇 为溶剂， 反应 8.0h， 生成 3H-spiro[[2]benzofuran-1,4'-piperidine]-3-carbonitrile
  参考文献：
  名称：

  Synthesis of spirocyclic σ1 receptor ligands as potential PET radiotracers, structure–affinity relationships and in vitro metabolic stability

  摘要：

  Several 3H-spiro[[2] benzofuran-1,40-piperidines] bearing a p-fluorobenzyl residue at the N-atom and various substituents in position 3 of the benzofuran system were synthesized. The crucial reaction steps are the addition of a lithiated benzaldehyde derivative to the p-fluorobenzylpiperidone 5 and the BF3 center dot OEt2 catalyzed substitution of the methoxy group of 2a by various nucleophiles. Structure-affinity relationship studies revealed that compounds with two protons (2d), a methoxy group (2a), and a cyano group (2e) in position 3 possess subnanomolar sigma(1) affinity (K-i = 0.18 nM, 0.79 nM, 0.86 nM) and high selectivity against the sigma(2) subtype. The metabolites of 2a, 2d, and 2e, which were formed upon incubation with rat liver microsomes, were identified. Additionally, the rate of metabolic degradation of 2a, 2d, and 2e was determined and compared with the degradation rate of the non-fluorinated spirocyclic compound 1. For the synthesis of the potential PET tracers [F-18] 2a and [F-18]2e two different radiosynthetic approaches were followed. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.03.060
• 作为产物：
  描述：

  N-苄基哌啶酮 在 正丁基锂 、 三氟化硼乙醚 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 7.75h， 生成 1'-Benzyl-3H-spiro[isobenzofuran-1,4'-piperidine]-3-carbonitrile
  参考文献：
  名称：

  [EN] SPIRO PIPERIDINE DERIVATIVES AS INHIBITORS OF APOL1 AND METHODS OF USING SAME
  [FR] DÉRIVÉS DE SPIRO PIPÉRIDINE UTILISÉS EN TANT QU'INHIBITEURS DE APOL1 ET LEURS PROCÉDÉS D'UTILISATION

  摘要：

  The disclosure provides at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formula I, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, compositions comprising the same, and methods of using the same, including uses in treating APOL1-mediated diseases, including pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and/or non-diabetic kidney disease (NDKD).

  公开号：

  WO2023154314A1

文献信息

• Novel σ Receptor Ligands. Part 2. SAR of Spiro[[2]benzopyran-1,4‘-piperidines] and Spiro[[2]benzofuran-1,4‘-piperidines] with Carbon Substituents in Position 3
  作者：Christoph A. Maier、Bernhard Wünsch

  DOI：10.1021/jm020889p

  日期：2002.10.1

  whereas the spirobenzopyran nitrile 13 with a methylene spacer is 10-fold less potent. Among the reported compounds, 1'-benzyl-3,4-dihydrospiro[[2]benzopyran-1,4'-piperidine]-3-carbonitrile 5 represents the most potent sigma(1) receptor ligand with a K(i) value of 1.54 nM and a sigma(1)/sigma(2) selectivity ratio of 1030.

  合成了几个螺[[2]苯并吡喃-1,4'-哌啶]和螺[[2]苯并呋喃-1,4'-哌啶]，并评估了它们与sigma（1）和sigma（2）受体的结合特性。引入一个碳残基的关键步骤是使环状甲基缩醛2a和3a与三甲基甲硅烷基氰化物反应，生成腈5和20。乳糖醇2b和3b与稳定的磷烷反应得到螺哌啶并带有两个碳原子3位残基。与先前报道的sigma（1）和sigma（2）受体结合数据一致，研究的螺化合物显示出比sigma（2）受体更高的亲和力。在螺环的3位具有氰基的化合物显示出较高的sigma（1）受体亲和力和选择性。螺并苯并吡喃腈5和同源螺并苯并呋喃腈20和23显示几乎相同的sigma（1）亲和力，而具有亚甲基间隔基的螺并苯并吡喃腈13的效力低10倍。在报道的化合物中，1'-苄基-3,4-二氢螺[[2]苯并吡喃-1,4'-哌啶] -3-腈5代表最有效的sigma（1）受体配体，其K（i）值1.54 nM的色散和sigma（1）/
• Synthesis, radiofluorination and pharmacological evaluation of a fluoromethyl spirocyclic PET tracer for central σ1 receptors and comparison with fluoroalkyl homologs
  作者：Aurélie Maisonial、Eva Große Maestrup、Christian Wiese、Achim Hiller、Dirk Schepmann、Steffen Fischer、Winnie Deuther-Conrad、Jörg Steinbach、Peter Brust、Bernhard Wünsch

  DOI：10.1016/j.bmc.2011.11.002

  日期：2012.1

  The spirocyclicr1 receptor ligand 1 (1'-benzyl-3-(fluoromethyl)-3H-spiro[[2] benzofuran-1,4'-piperidine]) was prepared in four steps starting from methoxy derivative 5. Due to its high sigma(1) affinity (K-i = 0.74 nM) and selectivity against several other relevant targets, 1 was investigated as F-18-labeled PET tracer and its biological properties were compared with those of homologous fluoroalkyl derivatives 2-4. The fluoromethyl derivative 1 was faster metabolized in vitro than homologs 2-4. In contrast to the radiosynthesis of [F-18]2-4, the nucleophilic substitution of the tosylate 15 using the K[F-18]F-K-222-carbonate complex required heating to 150 degrees C in DMSO to achieve high labeling efficiencies. Whereas radiometabolites of [F-18]2-4 were not detected in vivo in the brain of mice, two radiometabolites of [F-18]1 were found. Analysis of ex vivo autoradiography images provided rather low target-to-nontarget ratio for [F-18]1 compared with [F-18]2-4. [F-18]1 showed a fast uptake in the brain, which decreased continuously over time. The brain-to-plasma ratio of the radiotracer [F-18]1 was only exceeded by the fluoroethyl tracer [F-18]2. (C) 2011 Elsevier Ltd. All rights reserved.
• Synthesis of spirocyclic σ1 receptor ligands as potential PET radiotracers, structure–affinity relationships and in vitro metabolic stability
  作者：Eva Große Maestrup、Christian Wiese、Dirk Schepmann、Achim Hiller、Steffen Fischer、Matthias Scheunemann、Peter Brust、Bernhard Wünsch

  DOI：10.1016/j.bmc.2009.03.060

  日期：2009.5

  Several 3H-spiro[[2] benzofuran-1,40-piperidines] bearing a p-fluorobenzyl residue at the N-atom and various substituents in position 3 of the benzofuran system were synthesized. The crucial reaction steps are the addition of a lithiated benzaldehyde derivative to the p-fluorobenzylpiperidone 5 and the BF3 center dot OEt2 catalyzed substitution of the methoxy group of 2a by various nucleophiles. Structure-affinity relationship studies revealed that compounds with two protons (2d), a methoxy group (2a), and a cyano group (2e) in position 3 possess subnanomolar sigma(1) affinity (K-i = 0.18 nM, 0.79 nM, 0.86 nM) and high selectivity against the sigma(2) subtype. The metabolites of 2a, 2d, and 2e, which were formed upon incubation with rat liver microsomes, were identified. Additionally, the rate of metabolic degradation of 2a, 2d, and 2e was determined and compared with the degradation rate of the non-fluorinated spirocyclic compound 1. For the synthesis of the potential PET tracers [F-18] 2a and [F-18]2e two different radiosynthetic approaches were followed. (C) 2009 Elsevier Ltd. All rights reserved.
• [EN] SPIRO PIPERIDINE DERIVATIVES AS INHIBITORS OF APOL1 AND METHODS OF USING SAME<br/>[FR] DÉRIVÉS DE SPIRO PIPÉRIDINE UTILISÉS EN TANT QU'INHIBITEURS DE APOL1 ET LEURS PROCÉDÉS D'UTILISATION
  申请人：[en]VERTEX PHARMACEUTICALS INCORPORATED

  公开号：WO2023154314A1

  公开（公告）日：2023-08-17

  The disclosure provides at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formula I, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, compositions comprising the same, and methods of using the same, including uses in treating APOL1-mediated diseases, including pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and/or non-diabetic kidney disease (NDKD).