2-amino-N-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-amino-N-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide
• 化学式: C₁₆H₁₇ClN₂OS
• mdl: MFCD01176891
• 分子量: 320.843
• InChiKey: ZKPKEDIFSSNEQC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  83.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-amino-N-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide 在 吡啶 、 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 生成 N-(4-chlorophenyl)-2-(2-hydroxybenzamido)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide
  参考文献：
  名称：

  Exploring the cycloheptathiophene-3-carboxamide scaffold to disrupt the interactions of the influenza polymerase subunits and obtain potent anti-influenza activity

  摘要：

  With the aim to identify small molecules able to disrupt PA-PB1 subunits interaction of influenza virus (flu) RNA-dependent RNA polymerase, and based on previous structural and computational information, in this paper we have designed and synthesized a new series of cycloheptathiophene-3-carboxamide (cHTC) derivatives. Their biological evaluation led to highlight important structural insights along with new interesting compounds, such as the 2-hydroxybenzamido derivatives 29, 31, and 32, and the 4-aminophenyl derivative 54, which inhibited viral growth in the low micromolar range (EC50 = 0.18 -1.2 mu M) at no toxic concentrations (CC50 > 250 mu M).This study permitted to obtain among the most potent anti-flu compounds within the PA-PB1 interaction inhibitors, confirming the cHTC scaffold as particularly suitable to achieve innovative anti-flu agents. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.06.015
• 作为产物：
  描述：

  4’-氯-2-环乙酰苯胺 在 吗啉 、 1,2,3,4,5,6,7,8-八硫杂环辛烷 、 ammonium acetate 、 溶剂黄146 、 sodium sulfate 作用下， 以 乙醇 为溶剂， 反应 6.0h， 生成 2-amino-N-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide
  参考文献：
  名称：

  Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A)

  摘要：

  Transmembrane protein 16A (TMEM16A), also called anoctamin 1 (ANO1), is a calcium-activated chloride channel expressed widely mammalian cells, including epithelia, vascular smooth muscle tissue, electrically excitable cells, and some tumors. TMEM16A inhibitors have been proposed for treatment of disorders of epithelial fluid and mucus secretion, hypertension, asthma, and possibly cancer. Herein we report, by screening, the discovery of 2-acylaminocycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as inhibitors of TMEM16A and analysis of 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa). Structure activity studies indicated the importance of benzene substituted as 2- or 4-methyl, or 4-fluoro, and defined the significance of thiophene substituents and size of the cycloalkylthiophene core. The most potent compound (10bm), which contains an unusual bromodifluoroacetamide at the thiophene 2-position, had IC50 of similar to 30 nM, similar to 3.6-fold more potent than the most potent previously reported TMEM16A inhibitor 4 (Ani9), and >10-fold improved metabolic stability. Direct and reversible inhibition of TMEM16A by 10bm was demonstrated by patch-clamp analysis. AACTs may be useful as pharmacological tools to study TMEM16A function and as potential drug development candidates.

  DOI：

  10.1021/acs.jmedchem.7b00020

文献信息

• From cycloheptathiophene-3-carboxamide to oxazinone-based derivatives as allosteric HIV-1 ribonuclease H inhibitors
  作者：Serena Massari、Angela Corona、Simona Distinto、Jenny Desantis、Alessia Caredda、Stefano Sabatini、Giuseppe Manfroni、Tommaso Felicetti、Violetta Cecchetti、Christophe Pannecouque、Elias Maccioni、Enzo Tramontano、Oriana Tabarrini

  DOI：10.1080/14756366.2018.1523901

  日期：2019.1.1

  Abstract The paper focussed on a step-by-step structural modification of a cycloheptathiophene-3-carboxamide derivative recently identified by us as reverse transcriptase (RT)-associated ribonuclease H (RNase H) inhibitor. In particular, its conversion to a 2-aryl-cycloheptathienoozaxinone derivative and the successive thorough exploration of both 2-aromatic and cycloheptathieno moieties led to identify

  抽象的 本文重点研究了最近被我们鉴定为逆转录酶（RT）相关的核糖核酸酶H（RNase H）抑制剂的环庚噻吩-3-甲酰胺衍生物的逐步结构修饰。特别地，其向2-芳基-环庚硫基杂氮杂酮衍生物的转化以及对2-芳族和环庚二硫基部分的连续深入探索导致将基于恶嗪酮的化合物鉴定为新的抗RNA酶H化学型。支架C-2位置上邻苯二酚部分的出现对于实现有效的抗RNA酶H活性至关重要，该活性还包括三环衍生物的抗RNA依赖性DNA聚合酶（RDDP）活性。苯并噻吩并恶嗪酮衍生物22产生的最强双重抑制剂表现出IC 50相对于RNase H和RDDP功能的s分别为0.53和2.90μM。诱变和对接研究表明，化合物22结合了RT中的两个变构口袋，一个位于RNase H活性位点和引物结合区之间，另一个位于DNA聚合酶催化中心附近。
• THIOPHENS AND THEIR USE AS ANTI-TUMOR AGENTS
  申请人：Compass Pharmaceuticals LLC

  公开号：EP1802634A2

  公开（公告）日：2007-07-04
• Thiophens and Their Use as Anti-Tumor Agents
  申请人：Ward John

  公开号：US20090143411A1

  公开（公告）日：2009-06-04

  The present invention provides novel compounds and pharmaceutical compositions thereof, as well as methods for using the compounds and pharmaceutical compositions for treating tumors. Examples of specific tumor types that the compounds may be used to treat include, but are not limited to sarcomas, melanomas, neuroblastomas, carcinomas (including but not limited to lung, renal cell, ovarian, liver, bladder, and pancreatic carcinomas), and mesotheliomas.
• [EN] COMPOSITIONS AND THEIR USE AS ANTI-TUMOR AGENTS<br/>[FR] COMPOSITIONS ET LEUR UTILISATION EN TANT QU'AGENTS ANTITUMORAUX
  申请人：COMPASS PHARMACEUTICALS LLC

  公开号：WO2006044826A2

  公开（公告）日：2006-04-27

  [EN] The present invention provides novel compounds and pharmaceutical compositions thereof, as well as methods for using the compounds and pharmaceutical compositions for treating tumors. Examples of specific tumor types that the compounds may be used to treat include, but are not limited to sarcomas, melanomas, neuroblastomas, carcinomas (including but not limited to lung, renal cell, ovarian, liver, bladder, and pancreatic carcinomas), and mesotheliomas.
  [FR] L'invention concerne de nouveaux composés et des compositions pharmaceutiques comportant ces nouveaux composés, ainsi que des méthodes pour utiliser les composés et les compositions pharmaceutiques de l'invention pour traiter des tumeurs. Des exemples de types de tumeur spécifiques pouvant être traités par l'utilisation des composés de l'invention comprennent, de manière non exhaustive: les sarcomes, les mélanomes, les neuroblastomes, les carcinomes (comprenant, de manière non exhaustive, les carcinomes de poumons, des cellules rénales, des ovaires, du foie, de la vessie et du pancréas), et des mésothéliomes.
• Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A)
  作者：Eric C. Truong、Puay W. Phuan、Amanda L. Reggi、Loretta Ferrera、Luis J. V. Galietta、Sarah E. Levy、Alannah C. Moises、Onur Cil、Elena Diez-Cecilia、Sujin Lee、Alan S. Verkman、Marc O. Anderson

  DOI：10.1021/acs.jmedchem.7b00020

  日期：2017.6.8

  Transmembrane protein 16A (TMEM16A), also called anoctamin 1 (ANO1), is a calcium-activated chloride channel expressed widely mammalian cells, including epithelia, vascular smooth muscle tissue, electrically excitable cells, and some tumors. TMEM16A inhibitors have been proposed for treatment of disorders of epithelial fluid and mucus secretion, hypertension, asthma, and possibly cancer. Herein we report, by screening, the discovery of 2-acylaminocycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as inhibitors of TMEM16A and analysis of 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa). Structure activity studies indicated the importance of benzene substituted as 2- or 4-methyl, or 4-fluoro, and defined the significance of thiophene substituents and size of the cycloalkylthiophene core. The most potent compound (10bm), which contains an unusual bromodifluoroacetamide at the thiophene 2-position, had IC50 of similar to 30 nM, similar to 3.6-fold more potent than the most potent previously reported TMEM16A inhibitor 4 (Ani9), and >10-fold improved metabolic stability. Direct and reversible inhibition of TMEM16A by 10bm was demonstrated by patch-clamp analysis. AACTs may be useful as pharmacological tools to study TMEM16A function and as potential drug development candidates.