1-benzyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran] | 1398399-65-9

• 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-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]
• 英文别名: 1-benzyl-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]；1'-Benzylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]
• CAS: 1398399-65-9
• 化学式: C₁₈H₂₁NOS
• 分子量: 299.437
• InChiKey: ZZQIGFUYNABBCP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  40.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-benzyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran] 在 1-氯乙基氯甲酸酯 、 甲醇 作用下， 以 四氢呋喃 为溶剂， 反应 2.5h， 生成 4,5-二氢螺[哌啶-4,7-噻吩并[2,3-c]吡喃]
  参考文献：
  名称：

  易于合成的针对肺结核分枝杆菌的活体内具有显着活性的螺环化合物

  摘要：

  社会急需治疗结核病的新的有效药物。为了启动所需的领导才能运动，最近对制药公司的图书馆进行了起点评估。GlaxoSmithKline（GSK）库产生了许多高质量的匹配结果，并将相关数据置于公共领域，以激发更广泛社区的参与。此处描述了一个这样的系列，螺环化合物。这些化合物是通过传统的内部研究和开源方法相结合的方法进行探索的。该系列得益于特别简单的结构和较短的合成化学路线。该系列的许多成员均显示出惊人的效力和低毒性，并且其中一种类似物证实了在小鼠模型中具有高度前景的体内活性。

  DOI：

  10.1021/acs.jmedchem.8b01533
• 作为产物：
  描述：

  2-(4-bromothiophen-3-yl)acetaldehyde dimethyl acetal 在 盐酸 、 正丁基锂 、 10% Pd/C 、 氢气 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 水 为溶剂， 反应 42.42h， 生成 1-benzyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]
  参考文献：
  名称：

  Pd-Catalyzed Direct C–H Bond Functionalization of Spirocyclic σ₁ Ligands: Generation of a Pharmacophore Model and Analysis of the Reverse Binding Mode by Docking into a 3D Homology Model of the σ₁ Receptor

  摘要：

  To explore the hydrophobic binding region of the sigma(1) receptor protein, regioisomeric spirocyclic thiophenes 9-11 were developed as versatile building blocks. Regioselective alpha- and beta-arylation using the catalyst systems PdCl2/bipy/Ag2CO3 and PdCl2/P[OCH(CF3)(2)](3)/Ag2CO3 allowed the introduction of various aryl moieties at different positions in the last step of the synthesis. The increasing sigma(1) affinity in the order 4 < 5/6 < 7/8 indicates that the positions of the additional aryl moiety and the S atom in the spirocyclic thiophene systems control the sigma(1) affinity. The main features of the pharmacophore model developed for this class of sigma(1) ligands are a positive ionizable group, a H-bond acceptor group, two hydrophobic moieties, and one hydrophobic aromatic group. Docking of the ligands into a sigma(1) 3D homology model via molecular mechanics/Poisson-Boltzmann surface area calculations led to a very good correlation between the experimentally determined and estimated free energy of receptor binding. These calculations support the hypothesis of a reverse binding mode of ligands bearing the aryl moiety at the "top" (compounds 2, 3, 7, and 8) and "left" (compounds 4, 5, and 6) positions, respectively.

  DOI：

  10.1021/jm300894h

文献信息

• Late-Stage C-H Bond Arylation of Spirocyclic σ₁Ligands for Analysis of Complementary σ₁Receptor Surface
  作者：Christina Meyer、Dirk Schepmann、Shuichi Yanagisawa、Junichiro Yamaguchi、Kenichiro Itami、Bernhard Wünsch

  DOI：10.1002/ejoc.201200837

  日期：2012.10

  Direct C–H bond arylation in the α- and β-positions of spirocyclic thiophenes containing various functional groups (amine, ether, acetal, lactone) was accomplished. Selective phenylation in the α-position of the thiophene ring was achieved by using the catalytic system PdCl2/bipy/Ag2CO3. The introduction of phenyl moieties to the β-position was performed with the catalytic system PdCl2/P[OCH(CF3)2]3/Ag2CO3

  在含有各种官能团（胺、醚、缩醛、内酯）的螺环噻吩的 α-和 β-位直接进行 C-H 键芳基化。通过使用催化体系 PdCl2/bipy/Ag2CO3 实现了噻吩环 α 位的选择性苯基化。使用催化系统 PdCl2/P[OCH(CF3)2]3/Ag2CO3 将苯基部分引入 β-位。甚至具有直接连接到噻吩环的吸电子羰基部分的五元内酯 10 也被芳基化。在位置 A（顶部）或 B（左侧位置）被苯基部分取代的螺环噻吩显示低纳摩尔 σ1 亲和力（例如，4a：Ki = 1.6 nM；5a：Ki = 2.4 nM），表明在互补的σ1受体蛋白。σ1 受体不耐受 C 位（底部位置）的苯基部分（例如，12：Ki = 483 nM）。然而，A 位的额外苯基部分能够至少部分补偿 C 位苯基部分的不利影响。
• Synthesis and evaluation of 4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran] analogues against both active and dormant Mycobacterium tuberculosis
  作者：Kiran Kumar Alluri、Rudraraju Srilakshmi Reshma、Raghuram Suraparaju、Suryanarayana Gottapu、Dharmarajan Sriram

  DOI：10.1016/j.bmc.2017.12.044

  日期：2018.5

  Need for new drugs to fight against tuberculosis (TB) is increasing day by day. In the present work we have taken a spiro compound (GSK 2200150A) reported by GSK as a lead and we modified the structure of the lead to study the antitubercular activity. For structure activity profiling twenty-one molecules have been synthesized, characterized and evaluated for their antimycobacterial potency against both active and dormant TB. Compound 06, 1-((4-methoxyphenyl) sulfonyl)-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran] was found to be the most potent compound (MIC: 8.23 mu M) in active TB and was less effective than the lead but more potent than standard first line drug ethambutol. It was also found to be more efficacious than Isoniazid and Rifampicin and equipotent as Moxifloxacin against dormant Mycobacterium tuberculosis (MTB). Compound 06 also showed good inhibitory potential against over expressed latent MTB enzyme lysine epsilon-amino transferase with an IC50 of 1.04 +/- 0.32 mu M. This compound is a good candidate for drug development owing to potential against both active and dormant stages of MTB. (C) 2017 Elsevier Ltd. All rights reserved.
• Easy-To-Synthesize Spirocyclic Compounds Possess Remarkable in Vivo Activity against <i>Mycobacterium tuberculosis</i>
  作者：Ana Guardia、Jessica Baiget、Mónica Cacho、Arancha Pérez、Montserrat Ortega-Guerra、Winston Nxumalo、Setshaba D. Khanye、Joaquín Rullas、Fátima Ortega、Elena Jiménez、Esther Pérez-Herrán、María Teresa Fraile-Gabaldón、Jorge Esquivias、Raquel Fernández、Esther Porras-De Francisco、Lourdes Encinas、Marta Alonso、Ilaria Giordano、Cristina Rivero、Juan Miguel-Siles、Javier G. Osende、Katrina A. Badiola、Peter J. Rutledge、Matthew H. Todd、Modesto Remuiñán、Carlos Alemparte

  DOI：10.1021/acs.jmedchem.8b01533

  日期：2018.12.27

  research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain

  社会急需治疗结核病的新的有效药物。为了启动所需的领导才能运动，最近对制药公司的图书馆进行了起点评估。GlaxoSmithKline（GSK）库产生了许多高质量的匹配结果，并将相关数据置于公共领域，以激发更广泛社区的参与。此处描述了一个这样的系列，螺环化合物。这些化合物是通过传统的内部研究和开源方法相结合的方法进行探索的。该系列得益于特别简单的结构和较短的合成化学路线。该系列的许多成员均显示出惊人的效力和低毒性，并且其中一种类似物证实了在小鼠模型中具有高度前景的体内活性。
• Pd-Catalyzed Direct C–H Bond Functionalization of Spirocyclic σ₁ Ligands: Generation of a Pharmacophore Model and Analysis of the Reverse Binding Mode by Docking into a 3D Homology Model of the σ₁ Receptor
  作者：Christina Meyer、Dirk Schepmann、Shuichi Yanagisawa、Junichiro Yamaguchi、Valentina Dal Col、Erik Laurini、Kenichiro Itami、Sabrina Pricl、Bernhard Wünsch

  DOI：10.1021/jm300894h

  日期：2012.9.27

  To explore the hydrophobic binding region of the sigma(1) receptor protein, regioisomeric spirocyclic thiophenes 9-11 were developed as versatile building blocks. Regioselective alpha- and beta-arylation using the catalyst systems PdCl2/bipy/Ag2CO3 and PdCl2/P[OCH(CF3)(2)](3)/Ag2CO3 allowed the introduction of various aryl moieties at different positions in the last step of the synthesis. The increasing sigma(1) affinity in the order 4 < 5/6 < 7/8 indicates that the positions of the additional aryl moiety and the S atom in the spirocyclic thiophene systems control the sigma(1) affinity. The main features of the pharmacophore model developed for this class of sigma(1) ligands are a positive ionizable group, a H-bond acceptor group, two hydrophobic moieties, and one hydrophobic aromatic group. Docking of the ligands into a sigma(1) 3D homology model via molecular mechanics/Poisson-Boltzmann surface area calculations led to a very good correlation between the experimentally determined and estimated free energy of receptor binding. These calculations support the hypothesis of a reverse binding mode of ligands bearing the aryl moiety at the "top" (compounds 2, 3, 7, and 8) and "left" (compounds 4, 5, and 6) positions, respectively.