4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butanenitrile | 669067-79-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butanenitrile
• 英文别名: 4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butanenitrile
• CAS: 669067-79-2
• 化学式: C₁₅H₂₀N₂O₂
• 分子量: 260.336
• InChiKey: AULPCDSMYATQPV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  45.5
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butanenitrile 在 lithium aluminium tetrahydride 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 4.0h， 生成 N-(4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butyl)-1-(4-(2-fluoroethoxy)phenyl)-1H-1,2,3-triazole-4-carboxamide
  参考文献：
  名称：

  Synthesis and Structure–Activity Relationship Studies of Conformationally Flexible Tetrahydroisoquinolinyl Triazole Carboxamide and Triazole Substituted Benzamide Analogues as σ₂ Receptor Ligands

  摘要：

  Two novel classes of compounds targeting the sigma-2 (sigma(2)) receptor were synthesized, and their bioactivities to binding sigma(1) and sigma(2) receptors were measured. Four novel triazole carboxamide analogues, 24d, 24e, 24f, and 39c, demonstrated high affinity and selectivity for the sigma(2) receptor. These data suggest C-11-labeled versions of these compounds may be potential sigma(2)-selective radiotracers for imaging the proliferative status of solid tumors.

  DOI：

  10.1021/jm5001453
• 作为产物：
  描述：

  6,7-二甲氧基-1,2,3,4-四氢异喹啉 、 4-氯丁腈 在 sodium carbonate 、 sodium iodide 作用下， 以 叔丁醇 为溶剂， 反应 24.0h， 以65%的产率得到4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butanenitrile
  参考文献：
  名称：

  In vitro activity of novel dual action MDR anthranilamide modulators with inhibitory activity at CYP-450

  摘要：

  Synthesis and in vitro cytotoxicity assays of new anthranilamide MDR modulators have been performed to assess their inhibition potency of the P-glycoprotein (P-gp) transporter. The aromatic spacer group between nitrogen atoms (N1 and N2) in the known inhibitor XR9576 was replaced with a flexible alkyl chain of 2 to 6 carbon atoms in length. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline and their open-chain N-methylhomoveratrylamine counterparts were shown to be potent P-gp inhibitors. The maximal inhibition was obtained when using an ethyl or propyl spacer. Several compounds were more potent than verapamil and intrinsically less cytotoxic than XR9576. In addition, in vitro metabolism studies of 23a with a subset of human CYP-450 isoforms revealed that, unlike XR9576, 23a inhibited CYP3A4, an enzyme that colocalizes with P-gp in the intestine and contributes to tumor cell chemoresistance by enhancing the biodisposition of anticancer drugs such as paclitaxel toward metabolism. In this context, 22a might be a suitable candidate for further drug development.

  DOI：

  10.1016/j.bmc.2006.07.055

文献信息

• PEGYLATED FLUOROBENZAMIDE ANALOGUES, THEIR SYNTHESIS AND USE IN DIAGNOSTIC IMAGING
  申请人：Mach Robert H.

  公开号：US20120171119A1

  公开（公告）日：2012-07-05

  Pegylated fluoroalkoxybenzamide compounds which selectively bind Sigma-2 receptors are disclosed. These compounds, when labeled with a positron-emitting radioisotope such as 18 F, can be used as radiotracers for medical imaging such as imaging of tumors by positron emission tomography (PET). In addition, these compounds, when labeled with 123 I, can be used as radiotracers for imaging of tumors by single photon emission computed tomography (SPECT). Methods for synthesis of these compounds are also disclosed.

  揭示了选择性结合Sigma-2受体的聚乙二醇化氟烷氧基苯酰胺化合物。这些化合物，当与正电子发射放射性同位素如18F标记时，可用作医学成像的放射示踪剂，例如通过正电子发射断层扫描（PET）成像肿瘤。此外，这些化合物，当与123I标记时，可用作单光子发射计算机断层扫描（SPECT）成像肿瘤的放射示踪剂。还揭示了合成这些化合物的方法。
• Synthesis and in vitro evaluation of tetrahydroisoquinolines with pendent aromatics as sigma-2 (σ₂) selective ligands
  作者：Mark E. Ashford、Vu H. Nguyen、Ivan Greguric、Tien Q. Pham、Paul A. Keller、Andrew Katsifis

  DOI：10.1039/c3ob42254b

  日期：——

  Sigma-2 selective ligands – a SAR study showing increased potency and selectivity with derivatives showing the potential to be converted into radiolabelled ligands.

  Sigma-2 选择性配体 - 一项结构活性关系研究表明，衍生物的效力和选择性增加，有潜力转化为放射标记配体。
• Novel Sigma Receptor Ligand–Nitric Oxide Photodonors: Molecular Hybrids for Double-Targeted Antiproliferative Effect
  作者：Emanuele Amata、Maria Dichiara、Emanuela Arena、Valeria Pittalà、Venerando Pistarà、Venera Cardile、Adriana Carol Eleonora Graziano、Aurore Fraix、Agostino Marrazzo、Salvatore Sortino、Orazio Prezzavento

  DOI：10.1021/acs.jmedchem.7b00791

  日期：2017.12.14

  This contribution reports the synthesis and evaluation of novel hybrid compounds that conjugate a sigma (σ) receptor pharmacophore and a nitric oxide (NO) photodonor. All compounds preserve their capability to generate NO under visible light and possess overall σ receptor nanomolar affinity, with one of them (8b) exhibiting remarkable σ2 receptor selectivity. Compounds 8b, 11a, and 11b were tested

  这项贡献报告了新型混合化合物的合成和评估，这些化合物结合了sigma（σ）受体药效团和一氧化氮（NO）光供体。所有化合物保留其能力，以产生在可见光下NO，并具有整体σ受体纳摩尔亲和力，与它们中的一个（图8b显示出显着的σ）2受体的选择性。化合物8b的，图11A和11B分别对致瘤性的MCF-7和A2058细胞中测试表达高水平的σ 2和σ 1受体。在光激发下检测到细胞活力的显着损失，而在黑暗中检测到的影响可忽略不计。此外，它们在黑暗中或在非致瘤性NCTC-2544角质形成细胞上照射下均未显示任何明显的细胞毒性。通过细胞内NO检测和总亚硝酸盐估计证明了NO诱导的细胞活力降低。首次报道了σ受体部分和NO光供体的组合，提供了可用于癌症治疗的独特配体。
• ^99mTc-Cyclopentadienyl Tricarbonyl Chelate-Labeled Compounds as Selective Sigma-2 Receptor Ligands for Tumor Imaging
  作者：Dan Li、Yuanyuan Chen、Xia Wang、Winnie Deuther-Conrad、Xin Chen、Bing Jia、Chengyan Dong、Jörg Steinbach、Peter Brust、Boli Liu、Hongmei Jia

  DOI：10.1021/acs.jmedchem.5b01378

  日期：2016.2.11

  receptor affinity (Ki = 2.97 nM) and moderate subtype selectivity (10-fold). Moreover, it showed high selectivity toward vesicular acetylcholine transporter (2374-fold), dopamine D2L receptor, NMDA receptor, opiate receptor, dopamine transporter, norepinephrine transporter, and serotonin transporter. Its corresponding radiotracer [99mTc]20b showed high uptake in a time- and dose-dependent manner in DU145

  我们设计并合成了含有5,6- dimethoxyisoindoline或6,7-二甲氧基-1,2,3,4-四氢异喹啉作为药效σ一系列环戊二烯基三羰基铼配合2受体配体。铼化合物20A具有低纳摩尔σ 2受体的亲和力（ķ我= 2.97 nM）的和中度的亚型选择性（10倍）。此外，它对水泡乙酰胆碱转运蛋白（2374倍），多巴胺D 2L受体，NMDA受体，阿片受体，多巴胺转运蛋白，去甲肾上腺素转运蛋白和5-羟色胺转运蛋白显示出很高的选择性。其相应的放射性示踪剂[ 99m Tc] 20b在DU145前列腺细胞和C6胶质瘤细胞中显示出高吸收，呈时间和剂量依赖性。此外，该示踪剂在裸鼠中显示出高的肿瘤吸收率（在240分钟时为5.92％ID / g）和高的肿瘤/血液和肿瘤/肌肉比率（在240分钟时分别为21和16）以及与σ受体的特异性结合带有C6胶质瘤异种移植物。C6胶质瘤异种移植模型中[ 99m Tc] 20b的小动物SPECT
• Conformationally-flexible benzamide analogues as dopamine D3 and σ2 receptor ligands
  作者：Robert H Mach、Yunsheng Huang、Rebekah A Freeman、Li Wu、Suwanna Vangveravong、Robert R Luedtke

  DOI：10.1016/j.bmcl.2003.09.083

  日期：2004.1

  A series of conformationally-flexible analogues was prepared and their affinities for D2-like dopamine(D-2, D-3 and D-4) were determined using in vitro radioligand binding assays. The results of this structure-activity relationship study identified one compound, 15, that bound with high affinity (K-i value = 2 nM) and moderate selectivity (30-fold) for D-3 compared to D-2 receptors. In addition, this series of compounds were also tested for affinity at sigma(1) and sigma(2) receptors. We evaluated the affinity of these dopaminergic compounds at sigma receptors because (a) several antipsychotic drugs, which are high affinity antagonists at dopamine D2-like receptors, also bind to sigma receptors and (b) sigma receptors are expressed ubiquitously and at high levels (picomoles per mg proteins). It was observed that a number of analogues displayed high affinity and excellent selectivity for sigma(2) versus sigma(1) receptors. Consequently, these novel compounds may be useful for characterizing the functional role of sigma(2) receptors and for imaging the sigma(2) receptor status of tumors in vivo with PET. (C) 2003 Elsevier Ltd. All rights reserved.