2-(4-isopropylphenyl)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one | 645388-88-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 2-(4-isopropylphenyl)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one
• 英文别名: 6-Methoxy-2-(4-propan-2-ylphenyl)-3,4-dihydroisoquinolin-1-one
• CAS: 645388-88-1
• 化学式: C₁₉H₂₁NO₂
• 分子量: 295.381
• InChiKey: YONSGHVDBRUGOH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-(4-isopropylphenyl)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 在 三氯化铝 、 sodium hydride 、 N,N-二甲基苯胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醚 、 正己烷 、 二氯甲烷 为溶剂， 反应 0.17h， 生成 2-(4-Isopropyl-phenyl)-6-methoxy-1-methyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1,2,3,4-tetrahydro-isoquinoline
  参考文献：
  名称：

  Estrogen Receptor Modulators:  Identification and Structure−Activity Relationships of Potent ERα-Selective Tetrahydroisoquinoline Ligands

  摘要：

  As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was discovered by high throughput screening. Successive replacements of the p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20. These compounds showed potencies in a cell-based reporter gene assay (ERE assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range of 2-36 nM. The effect of N-phenyl substituents on the activity and pharmacokinetic properties of tetrahydroisoquinoline analogues was explored. As a result of this investigation, two potent derivatives bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates suitable for further profiling. To gain insight into the ligand-receptor interaction, the X-ray crystallographic structure of the 1-H tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand binding domain (LBD)(301-553)/C-->S triple mutant was solved to 2.28 Angstrom. An overlay of this X-ray crystal structure with that reported for the complex of ERalpha-LBD301-553/carboxymethylated C and raloxifene (5) shows that both compounds bind to the same cleft of the receptor and display comparable binding modes, with differences being observed in the conformation of their "D-ring" phenyl groups.

  DOI：

  10.1021/jm030086h
• 作为产物：
  描述：

  1-碘-4-异丙苯 、 6-甲氧基-3,4-二氢-1(2H)-异喹啉 在 copper(l) iodide 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 72.0h， 以53%的产率得到2-(4-isopropylphenyl)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one
  参考文献：
  名称：

  [EN] 1,2,3,4-TETRAHYDROISOQUINOLINE COMPOUNDS AND COMPOSITIONS AS SELECTIVE ESTROGEN RECEPTOR ANTAGONISTS AND DEGRADERS
  [FR] COMPOSÉS ET COMPOSITIONS DE 1,2,3,4-TÉTRAHYDROISOQUINOLÉINE EN TANT QU'ANTAGONISTES ET AGENTS DE DÉGRADATION SÉLECTIFS DES RÉCEPTEURS DES ŒSTROGÈNES

  摘要：

  本发明涉及式(I)化合物，其中n、R1、R2、R3、R4和R5如权利要求所述；能够作为雌激素受体的强效拮抗剂和降解剂。还描述了制备本发明化合物的方法，并且本发明进一步提供了包含该化合物的药物制剂以及使用该化合物和组合物管理与异常雌激素受体活性相关疾病或失调的方法。

  公开号：

  WO2015092634A1

文献信息

• Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer
  作者：Heather E. Burks、Tinya Abrams、Christina A. Kirby、Jason Baird、Alexander Fekete、Lawrence G. Hamann、Sunkyu Kim、Franco Lombardo、Alice Loo、Danuta Lubicka、Kaitlin Macchi、Donald P. McDonnell、Yuji Mishina、John D. Norris、Jill Nunez、Chitra Saran、Yingchuan Sun、Noel M. Thomsen、Chunrong Wang、Jianling Wang、Stefan Peukert

  DOI：10.1021/acs.jmedchem.6b01468

  日期：2017.4.13

  as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast

  四氢异喹啉40已被确定为有效的ERα拮抗剂和选择性雌激素受体降解剂（SERD），在体内具有良好的口服生物利用度，抗肿瘤功效和SERD活性。我们概述了导致THIQ 40的THIQ支架的发现和化学优化，并展示了支架的消旋作用，临床前物种的药代动力学研究以及THIQ 40在MCF-7人乳腺癌异种移植模型中的体内功效。