ethyl 2-(2,4-difluorobenzoyl)-3-(dimethylamino)acrylate | 1048039-26-4

• 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-(2,4-difluorobenzoyl)-3-(dimethylamino)acrylate
• 英文别名: Ethyl 2-(2,4-difluorobenzoyl)-3-(dimethylamino)prop-2-enoate
• CAS: 1048039-26-4
• 化学式: C₁₄H₁₅F₂NO₃
• 分子量: 283.275
• InChiKey: PJYHVFYSNRLFGP-UHFFFAOYSA-N

物化性质

• 沸点：
  365.3±42.0 °C(Predicted)
• 密度：
  1.217±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl 2-(2,4-difluorobenzoyl)-3-(dimethylamino)acrylate 在 potassium carbonate 、 三氟乙酸 、 sodium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.5h， 生成 7-amino-1-cyclohexyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
  参考文献：
  名称：

  设计和合成新型的脱氟喹诺酮-氨基嘧啶杂化物，作为具有低hERG活性的有效抗MRSA药物。

  摘要：

  尽管事实上在C-6位置引入了氟原子导致了氟喹诺酮类药物的发展，但氟喹诺酮类引起的心脏毒性引起了相当大的关注。在这种情况下，设计并合成了基于C-7氨基嘧啶官能团的基于脱氟喹诺酮的杂种。生物学结果显示，尽管缺乏典型的C-6氟原子，但这些杂种中的大多数仍显示出有效的抗MRSA活性，MIC值为0.38-1.5μg/ mL。特别地，最具活性的B14在亚微摩尔浓度下对一组MRSA菌株具有活性，这些菌株包括万古霉素中间菌株，耐左氧氟沙星的分离株和耐利奈唑胺的分离株等。。如预期的那样，它还显示出对细菌细胞的高度选择性毒性和低hERG抑制作用。进一步的抗药性研究表明，MRSA不太可能获得针对B14的抗药性。对接研究表明，在C-7取代基和周围的DNA碱基之间形成了两个氢键，这可能有助于通过减少对镁-水桥与拓扑异构酶IV的依赖性来克服耐药性。这些结果表明开发一种新的抗生素喹诺酮类药物以对抗多药耐药性和心脏毒性的有希望的策略。

  DOI：

  10.1016/j.bioorg.2020.104176
• 作为产物：
  描述：

  2,4-二氟苯甲酸 在 氯化亚砜 、 三乙胺 作用下， 生成 ethyl 2-(2,4-difluorobenzoyl)-3-(dimethylamino)acrylate
  参考文献：
  名称：

  4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B

  摘要：

  Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.

  DOI：

  10.1016/j.bmc.2014.05.028

文献信息

• Investigations on the 4-quinolone-3-carboxylic acid motif. 6. Synthesis and pharmacological evaluation of 7-substituted quinolone-3-carboxamide derivatives as high affinity ligands for cannabinoid receptors
  作者：Serena Pasquini、Maria De Rosa、Alessia Ligresti、Claudia Mugnaini、Antonella Brizzi、Nicola P. Caradonna、Maria Grazia Cascio、Daniele Bolognini、Roger G. Pertwee、Vincenzo Di Marzo、Federico Corelli

  DOI：10.1016/j.ejmech.2012.09.035

  日期：2012.12

  synthesized and evaluated for their binding ability to cannabinoid type 1 (CB1) and type 2 (CB2) receptors. Most of the compounds showed affinity for one or both cannabinoid receptors at nanomolar concentration, with Ki(CB1) and Ki(CB2) values ranging from 2.45 to >10,000 nM and from 0.09 to 957 nM, respectively. The N-(3,4-dichlorobenzyl)amide derivatives 27 and 40 displayed relatively low affinity, but high

  在我们对4-喹诺酮-3-羧酰胺作为大麻素配体的结构-活性关系的研究中，合成了一系列新化合物，其特征是在7位为氟或苯硫基，在N1和羧酰胺氮上具有不同的取代基，并对其进行了评估。与1型大麻素（CB1）和2型大麻素（CB2）受体的结合能力。大多数化合物在纳摩尔浓度下均显示对一种或两种大麻素受体具有亲和力，其K i（CB1）和K i（CB2）值分别为2.45至> 10,000 nM和0.09至957 nM。所述ñ - （3,4-二氯苄基）酰胺衍生物27和40显示出相对较低的亲和力，但对CB1受体的选择性高。在[ 35 S]GTPγS分析中，化合物4和40分别为CB2和CB1配体充当部分激动剂。它们显示出极低的通过（MDCK-MDR1）细胞的渗透性，因此可能代表了可能的铅结构，可用于进一步优化寻找无法穿越血脑屏障的大麻素配体。
• 一种含嘧啶环的喹诺酮类衍生物及其制备方法 和用途
  申请人：复旦大学

  公开号：CN103965163B

  公开（公告）日：2016-01-20

  本发明属于医药技术领域,具体为一种含嘧啶环的喹诺酮类衍生物及其制备方法和用途。本发明的化合物为含嘧啶环的喹诺酮类衍生物，还包括其药用盐，水合物和溶剂化物，其多晶或共晶，其同样生物功能的前体和衍生物。本发明还包括其制备方法，以及含有一个或多个此类化合物的组合物在治疗艾滋病等相关药物中的应用。药理实验结果表明，该类化合物具有显著的抗HIV-1病毒活性，可以有效地抑制HIV-1感染的MT-4细胞的复制，而且具有较低的细胞毒性。
• 一种嘧啶-喹诺酮类杂合物及其制备方法和用 途
  申请人：复旦大学

  公开号：CN108484577B

  公开（公告）日：2021-03-30

  本发明属于医药技术领域，具体为一种嘧啶‑喹诺酮类杂合物及其制备方法和用途。本发明的嘧啶‑喹诺酮类杂合物是由嘧啶类化合物和喹诺酮类化合物两种结构进行杂合而得到；本发明还包括该杂合物的药用盐、水合物和溶剂化物，其多晶或共晶，其同样生物功能的前体和衍生物；本发明还提供该杂合物的制备方法；药理实验结果表明，该类化合物具有显著的抗肿瘤活性和抗菌活性；可用于制备治疗癌症和抗菌等相关药物。
• Anti-HIV diarylpyrimidine–quinolone hybrids and their mode of action
  作者：Tian-Qi Mao、Qiu-Qin He、Zheng-Yong Wan、Wen-Xue Chen、Fen-Er Chen、Gang-Feng Tang、Erik De Clercq、Dirk Daelemans、Christophe Pannecouque

  DOI：10.1016/j.bmc.2015.03.037

  日期：2015.7

  A molecular hybridization approach is a powerful tool in the design of new molecules with improved affinity and efficacy. In this context, a series of diarylpyrimidine-quinolone hybrids were synthesized and evaluated against both wt HIV-1 and mutant viral strains. The most active hybrid 5a displayed an EC50 value of 0.28 +/- 0.07 mu M against HIV-1 IIIB. A couple of enzyme-based assays clearly pinpoint a RT-targeted mechanism of action. Docking studies revealed that these hybrids could be well located in the NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid moiety in the molecules. (C) 2015 Elsevier Ltd. All rights reserved.
• Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 2. Synthesis and Structure−Activity Relationship of Potent and Selective Cannabinoid-2 Receptor Agonists Endowed with Analgesic Activity in Vivo
  作者：Serena Pasquini、Lorenzo Botta、Teresa Semeraro、Claudia Mugnaini、Alessia Ligresti、Enza Palazzo、Sabatino Maione、Vincenzo Di Marzo、Federico Corelli

  DOI：10.1021/jm800552f

  日期：2008.8.1

  Quinolone-3-carboxamides 11 bearing at position 5, 6, 7, or 8 diverse substituents such as halides, alkyl, aryl, alkoxy, and aryloxy groups differing in their steric/electronic properties, were prepared. The new compounds were tested in vitro for CB1 and CB2 receptor affinity in comparison with the reference compounds rimonabant and SR144528. The tested compounds exhibited CB2 affinity in the ran, e from 55.9 to 0.8 nM and CB1 affinity in the range from > 10 000 to 5.3 nM, with selectivity indeces [K-i(CB1)/K-i(CB2)] varying from > 2666.6 to 1.23. On the basis of the structure-selectivity relationship developed, the presence of a substituent at C6/C8 or C7 well accounts for the high or low CB2 selectivity, respectively. Compound 11c, characterized by high CB2 affinity and selectivity, showed analgesic activity in the formalin test of acute peripheral and inflammatory pain in mice as a result of selective CB2 agonistic activity.