7-trifluoromethyl-N-acetyl-1,2,3,4-tetrahydroisoquinoline

• 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: 7-trifluoromethyl-N-acetyl-1,2,3,4-tetrahydroisoquinoline
• 英文别名: 1-[7-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone
• 化学式: C₁₂H₁₂F₃NO
• 分子量: 243.229
• InChiKey: KPHDBLUELDEDJS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  17
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  20.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  7-trifluoromethyl-N-acetyl-1,2,3,4-tetrahydroisoquinoline 在 盐酸 作用下， 以 乙醇 为溶剂， 反应 4.0h， 以67%的产率得到7-(三氟甲基)-1,2,3,4-四氢异喹啉
  参考文献：
  名称：

  Synthesis, Biochemical Evaluation, and Classical and Three-Dimensional Quantitative Structure−Activity Relationship Studies of 7-Substituted-1,2,3,4-tetrahydroisoquinolines and Their Relative Affinities toward Phenylethanolamine N-Methyltransferase and the α₂-Adrenoceptor^,1

  摘要：

  7-Substituted-1,2,3,4-tetrahydroisoquinolines (7-substituted-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), the enzyme involved in the biosynthesis of epinephrine. Unfortunately, most of these compounds also exhibit strong affinity for the aa-adrenoceptor. To design a selective (PNMT vs alpha(2)-adrenoceptor affinity) inhibitor of PNMT, the steric and electrostatic factors responsible for PNMT inhibitory activity and alpha(2)-adrenoceptor affinity were investigated by evaluating a number of 7-substituted-THIQs. A classical quantitative structure-activity relationship (QSAR) study resulted in a three-parameter equation for PNMT (PNMT pK(i) = 0.599 pi - 0.0725MR + 1.55 sigma(m) + 5.80; n = 27, r = 0.885, s = 0.573) and a three-parameter equation for the alpha(2)-adrenoceptor (alpha(2) pK(i) = 0.599 pi - 0.0542MR - 0.951 sigma(m) + 6.45; n = 27, r = 0.917, s = 0.397). These equations indicated that steric effects and lipophilicity play a similar role at either active site but that electronic effects play opposite roles at either active site. Two binding orientations for the THIQs were postulated such that lipophilic and hydrophilic 7-substituents would not occupy the same region of space at either binding site. Using these two binding orientations, based on the lipophilicity of the 7-substituent, comparative molecular field analysis (CoMFA) models were developed that showed that the steric and electrostatic interactions at both sites were similar to those previously elaborated in the QSAR analyses. Both the QSAR and the CoMFA analyses showed that the steric interactions are similar at the PNMT active site and at the alpha(2)-adrenoceptor and that the electrostatic interactions were different at the two sites. This difference in electrostatic interactions might be responsible for the selectivity of THIQs bearing a nonlipophilic electron-withdrawing group at the 7-position, These QSAR and CoMFA results will be useful in the design of potent and selective (PNMT vs alpha(2)-adrenoceptor affinity) inhibitors of PNMT.

  DOI：

  10.1021/jm980429p
• 作为产物：
  描述：

  1-(7-氨基-3,4-二氢-2(1h)-异喹啉)乙酮 在 盐酸 、 potassium fluoride 、 copper(l) iodide 、 potassium iodide 、 sodium nitrite 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 15.5h， 生成 7-trifluoromethyl-N-acetyl-1,2,3,4-tetrahydroisoquinoline
  参考文献：
  名称：

  Synthesis, Biochemical Evaluation, and Classical and Three-Dimensional Quantitative Structure−Activity Relationship Studies of 7-Substituted-1,2,3,4-tetrahydroisoquinolines and Their Relative Affinities toward Phenylethanolamine N-Methyltransferase and the α₂-Adrenoceptor^,1

  摘要：

  7-Substituted-1,2,3,4-tetrahydroisoquinolines (7-substituted-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), the enzyme involved in the biosynthesis of epinephrine. Unfortunately, most of these compounds also exhibit strong affinity for the aa-adrenoceptor. To design a selective (PNMT vs alpha(2)-adrenoceptor affinity) inhibitor of PNMT, the steric and electrostatic factors responsible for PNMT inhibitory activity and alpha(2)-adrenoceptor affinity were investigated by evaluating a number of 7-substituted-THIQs. A classical quantitative structure-activity relationship (QSAR) study resulted in a three-parameter equation for PNMT (PNMT pK(i) = 0.599 pi - 0.0725MR + 1.55 sigma(m) + 5.80; n = 27, r = 0.885, s = 0.573) and a three-parameter equation for the alpha(2)-adrenoceptor (alpha(2) pK(i) = 0.599 pi - 0.0542MR - 0.951 sigma(m) + 6.45; n = 27, r = 0.917, s = 0.397). These equations indicated that steric effects and lipophilicity play a similar role at either active site but that electronic effects play opposite roles at either active site. Two binding orientations for the THIQs were postulated such that lipophilic and hydrophilic 7-substituents would not occupy the same region of space at either binding site. Using these two binding orientations, based on the lipophilicity of the 7-substituent, comparative molecular field analysis (CoMFA) models were developed that showed that the steric and electrostatic interactions at both sites were similar to those previously elaborated in the QSAR analyses. Both the QSAR and the CoMFA analyses showed that the steric interactions are similar at the PNMT active site and at the alpha(2)-adrenoceptor and that the electrostatic interactions were different at the two sites. This difference in electrostatic interactions might be responsible for the selectivity of THIQs bearing a nonlipophilic electron-withdrawing group at the 7-position, These QSAR and CoMFA results will be useful in the design of potent and selective (PNMT vs alpha(2)-adrenoceptor affinity) inhibitors of PNMT.

  DOI：

  10.1021/jm980429p

文献信息

• NHPI-Mediated Electrochemical α-Oxygenation of Amides to Benzimides
  作者：Fang Bai、Ning Wang、Yinshan Bai、Xiaowei Ma、Chengzhi Gu、Bin Dai、Jianpeng Chen

  DOI：10.1021/acs.joc.2c02700

  日期：2023.3.3
• SEPIAPTERIN REDUCTASE INHIBITORS
  申请人：QUARTET MEDICINE, INC.

  公开号：US20170096435A1

  公开（公告）日：2017-04-06

  Inhibitors of sepiapterin reductase and uses of sepiapterin reductase inhibitors in analgesia, treatment of acute and chronic pain, anti-inflammation, and immune cell regulation are disclosed.
• [EN] NAMPT MODULATORS<br/>[FR] MODULATEURS DE NAMPT
  申请人：CYTOKINETICS INC

  公开号：WO2021226276A2

  公开（公告）日：2021-11-11

  Provided are compounds of Formula (II): or a pharmaceutically acceptable salt thereof, wherein R1, n, and Y1 are as defined herein. Also provided is a pharmaceutically acceptable composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
• Synthesis, Biochemical Evaluation, and Classical and Three-Dimensional Quantitative Structure−Activity Relationship Studies of 7-Substituted-1,2,3,4-tetrahydroisoquinolines and Their Relative Affinities toward Phenylethanolamine <i>N</i>-Methyltransferase and the α₂-Adrenoceptor^,1
  作者：Gary L. Grunewald、Vilas H. Dahanukar、Ravi K. Jalluri、Kevin R. Criscione

  DOI：10.1021/jm980429p

  日期：1999.1.1

  7-Substituted-1,2,3,4-tetrahydroisoquinolines (7-substituted-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), the enzyme involved in the biosynthesis of epinephrine. Unfortunately, most of these compounds also exhibit strong affinity for the aa-adrenoceptor. To design a selective (PNMT vs alpha(2)-adrenoceptor affinity) inhibitor of PNMT, the steric and electrostatic factors responsible for PNMT inhibitory activity and alpha(2)-adrenoceptor affinity were investigated by evaluating a number of 7-substituted-THIQs. A classical quantitative structure-activity relationship (QSAR) study resulted in a three-parameter equation for PNMT (PNMT pK(i) = 0.599 pi - 0.0725MR + 1.55 sigma(m) + 5.80; n = 27, r = 0.885, s = 0.573) and a three-parameter equation for the alpha(2)-adrenoceptor (alpha(2) pK(i) = 0.599 pi - 0.0542MR - 0.951 sigma(m) + 6.45; n = 27, r = 0.917, s = 0.397). These equations indicated that steric effects and lipophilicity play a similar role at either active site but that electronic effects play opposite roles at either active site. Two binding orientations for the THIQs were postulated such that lipophilic and hydrophilic 7-substituents would not occupy the same region of space at either binding site. Using these two binding orientations, based on the lipophilicity of the 7-substituent, comparative molecular field analysis (CoMFA) models were developed that showed that the steric and electrostatic interactions at both sites were similar to those previously elaborated in the QSAR analyses. Both the QSAR and the CoMFA analyses showed that the steric interactions are similar at the PNMT active site and at the alpha(2)-adrenoceptor and that the electrostatic interactions were different at the two sites. This difference in electrostatic interactions might be responsible for the selectivity of THIQs bearing a nonlipophilic electron-withdrawing group at the 7-position, These QSAR and CoMFA results will be useful in the design of potent and selective (PNMT vs alpha(2)-adrenoceptor affinity) inhibitors of PNMT.