1'-Benzyl-3-methoxyspiro[isobenzofuran-1(3H),4'-piperidine] | 398476-50-1

• 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-3-methoxyspiro[isobenzofuran-1(3H),4'-piperidine]
• 英文别名: 1'-benzyl-1-methoxyspiro[1H-2-benzofuran-3,4'-piperidine]
• CAS: 398476-50-1
• 化学式: C₂₀H₂₃NO₂
• 分子量: 309.408
• InChiKey: RZZAEVQHACUOGI-UHFFFAOYSA-N

物化性质

• 熔点：
  171-173 °C
• 沸点：
  441.0±45.0 °C(Predicted)
• 密度：
  1.17±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：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  21.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1'-Benzyl-3-methoxyspiro[isobenzofuran-1(3H),4'-piperidine] 在 硫酸 、 四氰基乙烯 作用下， 以 乙腈 为溶剂， 反应 7.5h， 生成 1'-tert-butyl 3-ethyl 1'H,3H-spiro[2-benzofuran-1,4'-piperidine]-1',3-dicarboxylate
  参考文献：
  名称：

  新型sigma受体配体。第2部分。螺[[2]苯并吡喃-1,4'-哌啶]和螺[[2]苯并呋喃-1,4'-哌啶]的SAR在3位有碳取代基。

  摘要：

  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）/

  DOI：

  10.1021/jm020889p
• 作为产物：
  描述：

  1-溴-2-(二甲氧基甲基)苯 在 正丁基锂 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 为溶剂， 反应 174.08h， 生成 1'-Benzyl-3-methoxyspiro[isobenzofuran-1(3H),4'-piperidine]
  参考文献：
  名称：

  作为高效和亚型选择性sigma-受体配体的新型螺哌啶。第1部分。

  摘要：

  制备了一系列具有通用结构10的螺[[2]苯并吡喃-1,4'-哌啶]和螺[[2]苯并呋喃-1,4'-哌啶]，并与sigma（1）-和sigma亲和（2）通过放射性配体结合试验研究受体。螺哌啶14a和23的合成是通过溴缩醛11和21的溴/锂交换，添加到哌啶-4-酮12a中以及随后的环化而进行的。进行了氮原子上的取代基R，3位上的基团X和氧杂环的环大小的系统变化。分别使用[（3）H]标记的（+）-戊唑嗪和Ditolylguanidine用豚鼠脑和大鼠肝膜制剂确定sigma（1）-和sigma（2）-受体的亲和力。测试结果表明，哌啶氮原子上的苄基残基和3位上的甲氧基对高σ（1）-受体亲和力有利。在这个系列中，1'-苄基-3-甲氧基-3,4-二氢螺[[2]苯并吡喃-1,4'-哌啶]（14a）和1'-苄基-3-甲氧基-3H-螺[[ 2]苯并呋喃-1,4'-哌啶]（23）是在低纳摩尔范围内与sigma（

  DOI：

  10.1021/jm010992z

文献信息

• 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.
• Evaluation of Spirocyclic 3-(3-Fluoropropyl)-2-benzofurans as σ₁ Receptor Ligands for Neuroimaging with Positron Emission Tomography
  作者：Eva Große Maestrup、Steffen Fischer、Christian Wiese、Dirk Schepmann、Achim Hiller、Winnie Deuther-Conrad、Jörg Steinbach、Bernhard Wünsch、Peter Brust

  DOI：10.1021/jm900909e

  日期：2009.10.8

  A series of various N-substituted 3-(3-fluoropropyl)-3H-spiro[[2]benzofuran-1,4'-piperidines] (7) has been synthesized. In receptor binding studies, the N-benzyl derivative 7a (WMS-1813) revealed extraordinarily high sigma(1) receptor affinity (K-i = 1.4 nM) and excellent sigma(1)/sigma(2) Selectivity (>600fold). In vitro biotransformation of 7a with rat liver microsomes led to three main metabolites. N-Debenzylation was inhibited by introduction of an N-phenylethyl residue (7g). The PET tracer [F-18]7a was synthesized by nucleophilic substitution of the tosylate 13 with K[F-18]F-K222-carbonate complex. The decay corrected radiochemical yield of [F-18]7a was 35-48% with a radiochemical purity of >99.5% and a specific activity of 150-238 GBq/mu mol. The radiotracer properties were evaluated in female CD-1 mice by organ distribution and ex vivo brain autoradiography. The radiotracer uptake in the brain was fast and sufficient, with values of similar to 4% injected dose per gram. Target specificity of [F-18]7a was validated in blocking studies by preapplication of haloperidol, and significant reduction in the uptake of radioactivity was observed in the brain and peripheral organs expressing sigma(1) receptors.
• [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).
• Novel Spiropiperidines as Highly Potent and Subtype Selective σ-Receptor Ligands. Part 1
  作者：Christoph A. Maier、Bernhard Wünsch

  DOI：10.1021/jm010992z

  日期：2002.1.1

  excellent selectivity toward sigma(2)-receptors (sigma(1)/sigma(2) = 2708 and 1130) and several other receptor and reuptake systems. Introduction of a polar hydroxy group in position 3 and elongation of the distance between the piperidine nitrogen atom and the phenyl moiety result in ligands with considerable sigma(2)-receptor affinity and therefore diminished sigma(1)/sigma(2)-receptor selectivity. The

  制备了一系列具有通用结构10的螺[[2]苯并吡喃-1,4'-哌啶]和螺[[2]苯并呋喃-1,4'-哌啶]，并与sigma（1）-和sigma亲和（2）通过放射性配体结合试验研究受体。螺哌啶14a和23的合成是通过溴缩醛11和21的溴/锂交换，添加到哌啶-4-酮12a中以及随后的环化而进行的。进行了氮原子上的取代基R，3位上的基团X和氧杂环的环大小的系统变化。分别使用[（3）H]标记的（+）-戊唑嗪和Ditolylguanidine用豚鼠脑和大鼠肝膜制剂确定sigma（1）-和sigma（2）-受体的亲和力。测试结果表明，哌啶氮原子上的苄基残基和3位上的甲氧基对高σ（1）-受体亲和力有利。在这个系列中，1'-苄基-3-甲氧基-3,4-二氢螺[[2]苯并吡喃-1,4'-哌啶]（14a）和1'-苄基-3-甲氧基-3H-螺[[ 2]苯并呋喃-1,4'-哌啶]（23）是在低纳摩尔范围内与sigma（
• 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）/