ethyl 2-amino-4-(3-(trifluoromethyl)phenyl)thiophene-3-carboxylate | 1018830-98-2

• 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: ethyl 2-amino-4-(3-(trifluoromethyl)phenyl)thiophene-3-carboxylate
• 英文别名: ethyl 2-amino-4-[3-(trifluoromethyl)phenyl]thiophene-3-carboxylate
• CAS: 1018830-98-2
• 化学式: C₁₄H₁₂F₃NO₂S
• 分子量: 315.316
• InChiKey: AFZMELADLMEJDJ-UHFFFAOYSA-N

物化性质

• 沸点：
  397.5±42.0 °C(Predicted)
• 密度：
  1.345±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  80.6
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ethyl 2-amino-4-(3-(trifluoromethyl)phenyl)thiophene-3-carboxylate 在 4-二甲氨基吡啶 、 水 、 potassium hydroxide 作用下， 以 吡啶 、 乙醇 为溶剂， 反应 8.17h， 生成 2-{[(tert-butoxy)carbonyl]amino}-4-[3-(trifluoromethyl)phenyl]thiophene-3-carboxylic acid
  参考文献：
  名称：

  Synthesis and structure–activity relationships of 2-amino-3-carboxy-4-phenylthiophenes as novel atypical protein kinase C inhibitors

  摘要：

  Recent evidence suggests atypical protein kinase C (aPKC) isoforms are required for both TNF- and VEGF-induced breakdown of the blood-retinal barrier (BRB) and endothelial permeability to 70 kDa dextran or albumin. A chemical library screen revealed a series of novel small molecule phenylthiophene based inhibitors of aPKC isoforms that effectively block permeability in cell culture and in vivo. In an effort to further elucidate the structural requirements of this series of inhibitors, we detail in this study a structure-activity relationship (SAR) built on screening hit 1, which expands on our initial pharmacophore model. The biological activity of our analogues was evaluated in models of bona fide aPKC-dependent signaling including NF kappa B driven-gene transcription as a marker for an inflammatory response and VEGF/TNF-induced vascular endothelial permeability. The EC50 for the most efficacious inhibitors (6, 32) was in the low nanomolar range in these two cellular assays. Our study demonstrates the key structural elements that confer inhibitory activity and highlights the requirement for electron-donating moieties off the C-4 aryl moiety of the 2-amino-3-carboxy-4-phenylthiophene backbone. These studies suggest that this class has potential for further development into small molecule aPKC inhibitors with therapeutic efficacy in a host of diseases involving increased vascular permeability and inflammation. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.03.019
• 作为产物：
  描述：

  ethyl 2-cyano-3-(3-(trifluoromethyl)phenyl)but-2-enoate 在 sulfur 、 二乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 1.5h， 以1.52 g的产率得到ethyl 2-amino-4-(3-(trifluoromethyl)phenyl)thiophene-3-carboxylate
  参考文献：
  名称：

  [EN] A1 ADENOSINE RECEPTOR ALLOSTERIC ENHANCERS
  [FR] AMPLIFICATEURS ALLOSTÉRIQUES DES RÉCEPTEURS DE L'ADÉNOSINE A1

  摘要：

  本发明一般涉及化合物及其使用和制备方法。具体地，本发明涉及可能具有有用的治疗活性的化合物，用于治疗促进血管生成有益的疾病，这些化合物在治疗中的使用以及药物的制造，以及含有这些化合物的组合物。

  公开号：

  WO2009049362A1

文献信息

• [EN] RETINOID-RELATED ORPHAN RECEPTOR GAMMA MODULATORS, COMPOSITION CONTAINING THEM AND USES THEREOF<br/>[FR] MODULATEURS DES RÉCEPTEURS ORPHELINS GAMMA APPARENTÉS AU RÉCEPTEUR DES RÉTINOÏDES, COMPOSITION LES CONTENANT ET UTILISATIONS ASSOCIÉES
  申请人：GLAXO GROUP LTD

  公开号：WO2012100732A1

  公开（公告）日：2012-08-02

  Provided are retinoid-related orphan receptor gamma(ROR γ) modulators of formula (I), processes for their preparation, pharmaceutical compositions containing them, and their uses in the treatment of diseases mediated by ROR γ.

  提供了公式（I）的与视黄醛相关孤儿受体γ（ROR γ）调节剂，它们的制备方法，含有它们的药物组合物，以及它们在治疗由ROR γ介导的疾病中的用途。
• Novel 4-Oxothienopyrimidinyl Propanoic Acid Derivatives as AMPActivated Protein Kinase (AMPK) Activators
  作者：Pradip Sasmal、Mahaboobi Jaleel、P. Rao、M. Munikumar、Megha Bhattacharya、Nutakki Kumar、Poondla. Neelima、Khaji Rawoof、P. Rao、Chandrasekhar Abbineni、M. Roshaiah、S. Sridhar、Thammera Kumar、Menon Vinu、Vijay Potluri、Parimal Misra、Rashmi Talwar、Saibal Das

  DOI：10.2174/1570180811666140122003044

  日期：2014.5.31

  Adenosine 5’-monophosphate (AMP) activated protein kinase (AMPK) is a highly conserved sensor of cellular energy. AMPK has been recognized as a key regulator of mammalian metabolic function and has emerged as an attractive target for the treatment of metabolic disorders, including obesity and type 2 diabetes. The synthesis and biological evaluation of novel 3-(4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)propanoic acid derivatives as AMPK activators are described. The in vivo proof of principle for plasma glucose lowering effect is exemplified with a lead compound from this series.

  腺苷5'-单磷酸(AMP)激活的蛋白激酶(AMPK)是一种高度保守的细胞能量感应器。AMPK已被确认为调节哺乳动物代谢功能的关键因子,并已成为治疗包括肥胖和2型糖尿病在内的代谢紊乱的理想靶点。本文描述了新型3-(4-氧代噻吩并[2,3-d]嘧啶-3(4H)-基)丙酸衍生物作为AMPK激活剂的合成和生物学评价。体内实验证明了本系列中的先导化合物具有降低血浆葡萄糖水平的原理验证作用。
• Discovery of novel N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides as potent RORγt inhibitors
  作者：Yonghui Wang、Wei Cai、Guifeng Zhang、Ting Yang、Qian Liu、Yaobang Cheng、Ling Zhou、Yingli Ma、Ziqiang Cheng、Sijie Lu、Yong-Gang Zhao、Wei Zhang、Zhijun Xiang、Shuai Wang、Liuqing Yang、Qianqian Wu、Lisa A. Orband-Miller、Yan Xu、Jing Zhang、Ruina Gao、Melanie Huxdorf、Jia-Ning Xiang、Zhong Zhong、John D. Elliott、Stewart Leung、Xichen Lin

  DOI：10.1016/j.bmc.2013.12.021

  日期：2014.1

  Novel series of N-(5-(arylcarbonyl) thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl) amides were discovered as potent retinoic acid receptor-related orphan receptor-gamma-t (ROR gamma t) inhibitors. SAR studies of the ROR gamma t HTS hit 6a led to identification of thiazole ketone amide 8h and thiophene ketone amide 9g with high binding affinity and inhibitory activity of Th17 cell differentiation. Compound 8h showed in vivo efficacy in both mouse experimental autoimmune encephalomyelitis (EAE) and collagen induced arthritis (CIA) models via oral administration. (C) 2013 Elsevier Ltd. All rights reserved.
• 5-Substituted 2-aminothiophenes as A1 adenosine receptor allosteric enhancers
  作者：Luigi Aurelio、Heidi Figler、Bernard L. Flynn、Joel Linden、Peter J. Scammells

  DOI：10.1016/j.bmc.2007.10.065

  日期：2008.2.1

  Two series of 5-substituted 2-amino-4-(3-trifluoromethylphenyl)thiophenes were prepared and evaluated as allosteric enhancers at the A(1) adenosine receptor (A(1)AR). In the 3-benzoyl series, a 5-phenyl group was found to confer the greatest potency (9a: ED50 = 2.1 mu M, AE score = 18%). However, the analogue with no 5-substituent (6b: ED50 = 15.8 mu M, AE score = 77%) proved to be the most efficacious. In the 3-ethoxycarbonyl series, the 5-(4-chlorophenyl) analogue was clearly the most potent and efficacious (91: ED50 = 6.6 mu M, AE score = 57%). The antagonist activity of all compounds was measured using a [H-3]CPX competitive binding assay. (c) 2007 Elsevier Ltd. All rights reserved.
• Synthesis and structure–activity relationships of 2-amino-3-carboxy-4-phenylthiophenes as novel atypical protein kinase C inhibitors
  作者：Paul M. Titchenell、H.D. Hollis Showalter、Jean-François Pons、Alistair J. Barber、Yafei Jin、David A. Antonetti

  DOI：10.1016/j.bmcl.2013.03.019

  日期：2013.5

  Recent evidence suggests atypical protein kinase C (aPKC) isoforms are required for both TNF- and VEGF-induced breakdown of the blood-retinal barrier (BRB) and endothelial permeability to 70 kDa dextran or albumin. A chemical library screen revealed a series of novel small molecule phenylthiophene based inhibitors of aPKC isoforms that effectively block permeability in cell culture and in vivo. In an effort to further elucidate the structural requirements of this series of inhibitors, we detail in this study a structure-activity relationship (SAR) built on screening hit 1, which expands on our initial pharmacophore model. The biological activity of our analogues was evaluated in models of bona fide aPKC-dependent signaling including NF kappa B driven-gene transcription as a marker for an inflammatory response and VEGF/TNF-induced vascular endothelial permeability. The EC50 for the most efficacious inhibitors (6, 32) was in the low nanomolar range in these two cellular assays. Our study demonstrates the key structural elements that confer inhibitory activity and highlights the requirement for electron-donating moieties off the C-4 aryl moiety of the 2-amino-3-carboxy-4-phenylthiophene backbone. These studies suggest that this class has potential for further development into small molecule aPKC inhibitors with therapeutic efficacy in a host of diseases involving increased vascular permeability and inflammation. (C) 2013 Elsevier Ltd. All rights reserved.