1-benzyl-6'-methoxy-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] | 1070709-12-4

• 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-6'-methoxy-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran]
• 英文别名: 1-Benzyl-6-methoxy-6,7-dihydrospiro[piperidine-4,4-thieno[3.2-c]pyran]；1'-benzyl-6-methoxyspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]
• CAS: 1070709-12-4
• 化学式: C₁₉H₂₃NO₂S
• 分子量: 329.463
• InChiKey: NHVGXRUGDHMMSO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  49.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-benzyl-6'-methoxy-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] 在 水 硫酸 、 三氟化硼乙醚 作用下， 以 二氯甲烷 为溶剂， 反应 41.5h， 生成 methyl 1-benzyl-6',7'-dihyrospiro[piperidine-4,4'-thieno[3,2-c]pyran]-6'-carboxylate
  参考文献：
  名称：

  WO2008/155132

  摘要：

  公开号：
• 作为产物：
  描述：

  2-(3-bromothiophen-2-yl)acetaldehyde dimethyl acetal 在 正丁基锂 、 对甲苯磺酸 、 原甲酸三甲酯 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 为溶剂， 反应 27.3h， 生成 1-benzyl-6'-methoxy-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran]
  参考文献：
  名称：

  WO2008/155132

  摘要：

  公开号：

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。
• spiro[piperidine-4,4'-thieno[3,2-c]pyran] derivatives and related compounds as inhibitors of the sigma receptor for the treatment of psychosis
  申请人：Laboratorios del Dr. Esteve S.A.

  公开号：EP2020414A1

  公开（公告）日：2009-02-04

  The present invention relates to compounds having pharmacological activity towards the sigma (σ) receptor, and more particularly to some thieno-pyrano-pyrazole derivatives, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy and prophylaxis, in particular for the treatment of psychosis or pain.

  本发明涉及对 sigma（σ）受体具有药理活性的化合物，特别是一些噻吩并吡喃并吡唑衍生物，涉及此类化合物的制备工艺，涉及包含这些化合物的药物组合物，还涉及它们在治疗和预防中的用途，特别是用于治疗精神病或疼痛。
• Thiophene Bioisosteres of Spirocyclic σ Receptor Ligands. 1. N-Substituted Spiro[piperidine-4,4′-thieno[3,2-<i>c</i>]pyrans]
  作者：Christoph Oberdorf、Dirk Schepmann、Jose Miguel Vela、Jose Luis Diaz、Jörg Holenz、Bernhard Wünsch

  DOI：10.1021/jm8007739

  日期：2008.10.23

  Herein, the synthesis and pharmacological evaluation of thiophene bioisosteres of the highly potent spirocyclic benzopyran 1 are detailed. The synthesis of 1-benzyl-6'-methoxy-6',7'-dihydrospiro[piperidine-4,4'-thieno[3.2-c]pyran] (2a) was performed starting with 3-bromothiophene (3). After introduction of the acetaldehyde substructure (7), halogen metal exchange, addition of 1-benzylpiperidin-4-one, and cyclization led to the spirocyclic thienopyran 2a. The removal of the benzyl group afforded the secondary amine 2f, which was substituted with various residues. With respect to a, affinity the N-benzyl derivative 2a, the N-cyclohexylmethyl derivative 2d, and the N-p-fluorobenzyl derivative 2i represent the most potent compounds of this series binding with K-i values of 0.32, 0.29, and 0.62 nM, respectively. Electronic properties of the substituents have only little impact on sigma(1) affinity. The most potent sigma(1) ligands display high selectivity against sigma(2), 5-HT1A, 5-HT6, 5-HT7, alpha(1A), alpha(2), and NMDA receptors. The activity of 2a in the mouse capsaicin assay seems to indicate sigma(1) antagonistic activity.
• Thiophene Bioisosteres of Spirocyclic σ Receptor Ligands: Relationships between Substitution Pattern and σ Receptor Affinity
  作者：Christoph Oberdorf、Dirk Schepmann、Jose Miguel Vela、Helmut Buschmann、Jörg Holenz、Bernhard Wünsch

  DOI：10.1021/jm300302p

  日期：2012.6.14

  On the basis of the 6',7'-dihydrospiro-[piperidine-4,4'-thieno[3,2-c]pyran] framework, a series of more than 30 sigma ligands with versatile substituents in 1-, 2'-, and 6'-position has been synthesized and pharmacologically evaluated in order to find novel structure-affinity relationships. It was found that a cyclohexylmethyl residue at the piperidine N-atom instead of a benzyl moiety led to increased sigma(2) affinity and therefore to decreased sigma(1)/sigma(2), selectivity. Small substituents (e.g., OH, OCH3, CN, CH2OH) in 6'-position adjacent to the O-atom were well tolerated by the sigma(1) receptor. Removal of the substituent in 6'-position resulted in very potent but unselective a ligands (13). A broad range of substituents with various lipophilic and H-bond forming properties was introduced in 2'-position adjacent to the S-atom without loss of a, affinity. However, very polar and basic substituents in both 2'- and 6'-position decreased the a, affinity considerably. It is postulated that the electron density of the thiophene moiety has a big impact on the sigma(1) affinity.
• 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.