5,6-dichloro-1,2,3,4-tetrahydroisoquinoline | 75416-53-4

• 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: 5,6-dichloro-1,2,3,4-tetrahydroisoquinoline
• CAS: 75416-53-4
• 化学式: C₉H₉Cl₂N
• mdl: MFCD11203698
• 分子量: 202.083
• InChiKey: LFJDFVQLTLKBJM-UHFFFAOYSA-N

物化性质

• 沸点：
  310.7±42.0 °C(Predicted)
• 密度：
  1.293±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  12
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.333
• 拓扑面积：
  12
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  5,6-dichloro-1,2,3,4-tetrahydroisoquinoline 、 TERT-BUTYL TRANS-4-(2-OXOETHYL)CYCLOHEXYLCARBAMATE 在 三乙酰氧基硼氢化钠 作用下， 以 二氯甲烷 为溶剂， 生成
  参考文献：
  名称：

  D₂ Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine

  摘要：

  Functionally selective G protein-coupled receptor ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both G(i/o)-biased and beta-arrestin2-biased D-2 receptor agonists based on the Food and Drug Administration (FDA)-approved drug aripiprazole. In this work, based on another FDA-approved drug, cariprazine, we conducted a structure-functional selectivity relationship study and discovered compound 38 (MS1768) as a potent partial agonist that selectively activates the G(i/o) pathway over beta-arrestin2. Unlike the dual D2R/D3R partial agonist cariprazine, compound 38 showed selective agonist activity for D2R over D3R. In fact, compound 38 exhibited potent antagonism of dopamine-stimulated beta-arrestin2 recruitment. In our docking studies, compound 38 directly interacts with S193(5.42) on TM5 but has no interactions with extracellular loop 2, which appears to be in contrast to the binding poses of D2R beta-arrestin2-biased ligands. In in vivo studies, compound 38 showed high D2R receptor occupancy in mice and effectively inhibited phencyclidine-induced hyperlocomotion.

  DOI：

  10.1021/acs.jmedchem.9b00508
• 作为产物：
  描述：

  3-(2,3-二氯苯基)丙酸 在 三氯化铝 、 氯化亚砜 、 sodium azide 、 硼烷 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 四氯乙烯 、 水 、 丙酮 、 甲苯 为溶剂， 反应 24.17h， 生成 5,6-dichloro-1,2,3,4-tetrahydroisoquinoline
  参考文献：
  名称：

  Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 1. Chloro-Substituted 1,2,3,4-tetrahydroisoquinolines

  摘要：

  In a search for inhibitors of epinephrine biosynthesis as potential therapeutic agents, a series of 13 ring-chlorinated 1,2,3,4-tetrahydroisoquinolines was prepared. These compounds were tested initially for their ability to inhibit rabbit adrenal phenylethanolamine N-methyltransferase (PNMT) in vitro. Enzyme-inhibitor dissociation constants, determined for the six most potent members of the series, indicated the following order of decreasing potency: 7,8-Cl2 greater than 6,7,8-Cl3 greater than 7-Cl approximately 5,6,7,8-Cl4 greater than 5,7,8-Cl3. These compounds were subsequently examined for PNMT-inhibiting activity in intact rats and mice. 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline (13, SK&F 64139) was the most potent member of the series both in vitro and in vivo and is currently undergoing clinical investigation.

  DOI：

  10.1021/jm00179a007

文献信息

• Affinity of 2-(tetrahydroisoquinolin-2-ylmethyl)- and 2-(isoindolin-2-ylmethyl)imidazolines for .alpha.-adrenoceptors. Differential affinity of imidazolines for the [3H]idazoxan-labeled .alpha.2-adrenoceptor vs the [3H]yohimbine-labeled site
  作者：Robin D. Clark、Jacob Berger、Pushkal Garg、Klaus K. Weinhardt、Michael Spedding、Andrew T. Kilpatrick、Christine M. Brown、Alison C. MacKinnon

  DOI：10.1021/jm00164a021

  日期：1990.2

  A series of 2-(tetrahydroisoquinolin-2-ylmethyl)- and 2-(isoindolin-2-ylmethyl)imidazolines were prepared and tested for alpha 1- and alpha 2-adrenoceptor affinity with radioligand binding. Several compounds, 5-fluoro-(5h), 5-chloro-(5j), 5,8-dimethoxy- (5r), and 5,8-dimethoxy- (5r),1-methyl- (5s) 2-(tetrahydroisoquinolin-2- ylmethyl)imidazoline, were found to be selective alpha 2-adrenoceptor ligands

  制备一系列2-（四氢异喹啉-2-基甲基）-和2-（异吲哚-2-基甲基）咪唑啉，并通过放射性配体结合测试α1-和α2-肾上腺素受体的亲和力。几种化合物5-氟-（5h），5-氯-（5j），5,8-二甲氧基-（5r）和5,8-二甲氧基-（5r），1-甲基-（5s）2-（基于[3H]育亨宾从大鼠大脑皮膜的置换，发现四氢异喹啉-2-基甲基）咪唑啉是选择性的α2-肾上腺素受体配体。一种化合物2-[（（8-氯四氢异喹啉-2-基）甲基]咪唑啉（5m）与[3H]育亨宾相比，对[3H] idazoxan标记的α2-肾上腺素受体的亲和力显示出36倍的差异-标记的位点，可能是α2-肾上腺素受体亚型的证据。
• Intramolecular friedel-crafts alkylations. II. An efficient synthesis of biologically active 1,2,3,4-tetrahydroisoquinolines
  作者：W.L. Mendelson、C.B. Spainhour、S.S. Jones、B.L. Lam、K.L. Wert

  DOI：10.1016/s0040-4039(00)92728-x

  日期：——

  A new synthesis of tetrahydroisoquinolines bearing electron withdrawing groups is presented. The scope and mechanism of the reaction are discussed. Many of these tetrahydroisoquinolines are potent inhibitors of the enzyme PNMT.

  提出了一种带有吸电子基团的四氢异喹啉的新合成方法。讨论了反应的范围和机理。这些四氢异喹啉中的许多是PNMT酶的有效抑制剂。
• SULPHONAMIDE DERIVATIVES BEING 5-HT6 RECEPTOR ANTAGONISTS AND PROCESS FOR THEIR PREPARATION
  申请人：SmithKline Beecham plc

  公开号：EP0994862B1

  公开（公告）日：2005-06-01
• TETRAHYDROISOQUINOLINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS USEFUL FOR THE TREATMENT OF OBESITY AND DIABETES
  申请人：Boehringer Ingelheim International GmbH

  公开号：EP3194367B1

  公开（公告）日：2021-08-18
• D₂ Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine
  作者：Yudao Shen、John D. McCorvy、Michael L. Martini、Ramona M. Rodriguiz、Vladimir M. Pogorelov、Karen M. Ward、William C. Wetsel、Jing Liu、Bryan L. Roth、Jian Jin

  DOI：10.1021/acs.jmedchem.9b00508

  日期：2019.5.9

  Functionally selective G protein-coupled receptor ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both G(i/o)-biased and beta-arrestin2-biased D-2 receptor agonists based on the Food and Drug Administration (FDA)-approved drug aripiprazole. In this work, based on another FDA-approved drug, cariprazine, we conducted a structure-functional selectivity relationship study and discovered compound 38 (MS1768) as a potent partial agonist that selectively activates the G(i/o) pathway over beta-arrestin2. Unlike the dual D2R/D3R partial agonist cariprazine, compound 38 showed selective agonist activity for D2R over D3R. In fact, compound 38 exhibited potent antagonism of dopamine-stimulated beta-arrestin2 recruitment. In our docking studies, compound 38 directly interacts with S193(5.42) on TM5 but has no interactions with extracellular loop 2, which appears to be in contrast to the binding poses of D2R beta-arrestin2-biased ligands. In in vivo studies, compound 38 showed high D2R receptor occupancy in mice and effectively inhibited phencyclidine-induced hyperlocomotion.