ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate | 221121-46-6

• 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 4-(2,6-difluorophenyl)-3-oxobutanoate
• 英文别名: ethyl-(2,6-difluorophenyl)-3-oxobutyrate；ethyl 2-(2,6-difluorophenyl)acetylacetate
• CAS: 221121-46-6
• 化学式: C₁₂H₁₂F₂O₃
• 分子量: 242.222
• InChiKey: LUTFKQFZOOYKTH-UHFFFAOYSA-N

物化性质

• 沸点：
  287.3±30.0 °C(Predicted)
• 密度：
  1.227±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  17
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate 在 sodium ethanolate 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 29.0h， 生成 6-(2,6-difluorophenylmethyl)-3,4-dihydro-2-methylthiopyrimidin-4(3H)-one
  参考文献：
  名称：

  5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones:  Novel Potent and Selective Dihydro-alkoxy-benzyl-oxopyrimidine Derivatives

  摘要：

  Molecular modeling analysis of compounds belonging to the recently published series of dihydroalkoxy-benzyl-oxopyrimidines (DABOs), such as S-DABOs and DATNOs, gave support to the design of new 2,6-disubstituted benzyl-DABO derivatives as highly potent and specific inhibitors of the HIV-1 reverse transcriptase (RT). To follow up on the novel DABO derivatives, we decided to investigate the effect of electron-withdrawing substituents in the benzyl unit of the S-DABO skeleton versus their anti-HIV-1 activity. Such chemical modifications impacted the inhibitory activity, especially when two halogen units were introduced at positions 2 and 6 in the phenyl portion of the benzyl group bound to C-6 of the pyrimidine ring. Various 5-alkyl-2-(alkyl(or cycloalkyl)thio)-6-(2,B-dichloro(or 2, 6-difluoro)phenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones were then synthesized and tested as anti-HIV-1 agents in both cell-based and enzyme (recombinant reverse transcriptase, rRT) assays. Among the various mono- and disubstituted phenyl derivatives, the most potent were those containing a 6-(2,6-difluorophenylmethyl) substituent (F-DABOs), which showed EC50's ranging between 40 and 90 nM and selectivity indexes up to greater than or equal to 5000. An excellent correlation was found between EC50 and IC50 values which confirmed that these compounds act as inhibitors of the HIV-1 RT. The structure-activity relationships of the newly synthesized pyrimidinones are presented herein.

  DOI：

  10.1021/jm980260f
• 作为产物：
  描述：

  2,6-二氟苯乙酸 在 五氯化磷 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 2.0h， 生成 ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate
  参考文献：
  名称：

  对5-羟基苯并[g]吲哚-3-羧酸乙酯及其生物立体异构体作为抑制炎症的5-LO / m-PGES-1双重抑制剂的结构进行优化的结构见解

  摘要：

  花生四烯酸（AA）级联产生的促炎介质，例如前列腺素（PGs）和白三烯（LTs）的释放在引发，维持和调节炎症过程中起着至关重要的作用。新出现的5-脂氧合酶（5-LO）和微粒体前列腺素E 2合酶-1（mPGES-1）的双重抑制剂，同时阻止PGE 2和LT的形成，是一种非常有趣的药物。更好的炎症相关疾病药物治疗的候选药物。根据先前的研究，我们在此进行了基于结构的苯并[g]吲哚-3-羧酸酯衍生物的详细设计，揭示了影响这两种酶活性的几个新关键因素。2-（3,4-二氯苄基）-5-羟基-1H-苯并[g]吲哚-3-羧酸乙酯（4 b， RAF-01）和2-（3,4-二氯苯基）-5-羟基-1H-苯并[g]吲哚-3-羧酸乙酯（7 h， RAF-02）成为最活跃的化合物系列。另外，与选定的基于结构的类似物一起，两种衍生物均显示出显着的体内抗炎特性。 总之，建模和实验研究导致发现了新的候选化合物，这些化合物易于作为炎症途径的多靶点抑制剂进行进一步开发。

  DOI：

  10.1016/j.ejmech.2018.05.041

文献信息

• Substituted 6-benzyl-4-oxopyrimidines, process for their preparation and pharmaceutical compositions containing them
  申请人：Idenix Pharmaceuticals, Inc.

  公开号：US06635636B1

  公开（公告）日：2003-10-21

  The invention concerns novel substituted 6-benzyl-4-oxopyrimidines and pharmaceutically acceptable salts thereof. These compounds inhibit reverse transcriptase encoded by human immunodeficiency virus (HIV), and are useful to prevent and treat HIV infection and acquired immune deficiency syndrome (AIDS). Pharmaceutical compositions containing the compounds and a method of use of the present compounds and other agents for the treatment of AIDS and viral infection by HIV are also envisaged.

  该发明涉及新型的取代6-苄基-4-氧基嘧啶及其药用盐。这些化合物抑制人类免疫缺陷病毒（HIV）编码的逆转录酶，可用于预防和治疗HIV感染和获得性免疫缺陷综合征（AIDS）。还设想了含有这些化合物的药物组合物以及用于治疗AIDS和HIV病毒感染的其他药物的方法。
• Diarylpyrimidine−Dihydrobenzyloxopyrimidine Hybrids: New, Wide-Spectrum Anti-HIV-1 Agents Active at (Sub)-Nanomolar Level
  作者：Dante Rotili、Domenico Tarantino、Marino Artico、Maxim B. Nawrozkij、Emmanuel Gonzalez-Ortega、Bonaventura Clotet、Alberta Samuele、José A. Esté、Giovanni Maga、Antonello Mai

  DOI：10.1021/jm101626c

  日期：2011.4.28

  Here, we describe a novel small series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine peculiar structural features of diarylpyrimidines (DAPYs) and dihydro-alkoxy-benzyl-oxopyrimidines (DABOs). These DAPY−DABO hybrids (1−4) showed a characteristic SAR profile and a nanomolar anti-HIV-1 activity at both enzymatic and cellular level. In particular, the two compounds 4d and 2d

  在这里，我们描述了一个新颖的小系列非核苷类逆转录酶抑制剂（NNRTIs），该抑制剂结合了二芳基嘧啶（DAPYs）和二氢-烷氧基-苄基-氧嘧啶（DABOs）的独特结构特征。这些DAPY-DABO杂种（1 - 4）显示出特征的SAR轮廓和在两个酶活性和细胞水平纳摩尔的抗HIV-1活性。特别是，对野生型和临床相关的HIV-1突变株具有（亚）纳摩尔活性的两种化合物4d和2d被选作主要化合物，用于下一步的优化研究。
• Sbardella, Gianluca; Mai, Antonello; Artico, Marino, Medicinal Chemistry Research, 2000, vol. 10, # 1, p. 30 - 39
  作者：Sbardella, Gianluca、Mai, Antonello、Artico, Marino、Massa, Silvio、Marceddu, Tiziana、Vargiu, Laura、Marongiu, Maria Elena、La Colla, Paolo

  DOI：——

  日期：——
• Synthesis and Biological Properties of Novel 2-Aminopyrimidin-4(3<i>H</i>)-ones Highly Potent against HIV-1 Mutant Strains
  作者：Antonello Mai、Marino Artico、Dante Rotili、Domenico Tarantino、Imma Clotet-Codina、Mercedes Armand-Ugón、Rino Ragno、Silvia Simeoni、Gianluca Sbardella、Maxim B. Nawrozkij、Alberta Samuele、Giovanni Maga、José A. Esté

  DOI：10.1021/jm070811e

  日期：2007.11.1

  Following the disclosure of dihydro-alkoxy-, dihydro-alkylthio-, and dihydro-alkylamino-benzyl-oxopyrimidines (DABOs, S-DABOs, and NH-DABOs) as potent and selective anti-HIV-1 agents belonging to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, we report here the synthesis and biological evaluation of a novel series of DABOs bearing a NN-disubstituted amino group or a cyclic amine at the pyrimidine-C, position, a hydrogen atom or a small alkyl group at C-5 and/or at the benzylic position, and the favorable 2,6-difluorobenzyl moiety at the C-6 position (F,NN-DABOs). The new compounds were highly active up to the subnanomolar level against both wt HIV-1 and the Y181C mutant and at the submicromolar to nanomolar range against the K103N and Y188L mutant strains. Such derivatives were more potent than S-DABOs, NH-DABOs, and nevirapine and efavirenz were chosen as reference drugs. The higher inhibitor adaptability to the HIV- I RT non-nucleoside binding site (NNBS) may account for the higher inhibitory effect exerted by the new molecules against the mutated RTs.
• 5-Alkyl-2-alkylamino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones, a new series of potent, broad-spectrum non-nucleoside reverse transcriptase inhibitors belonging to the DABO family
  作者：Antonello Mai、Marino Artico、Rino Ragno、Gianluca Sbardella、Silvio Massa、Chiara Musiu、Massimo Mura、Flavia Marturana、Alessandra Cadeddu、Giovanni Maga、Paolo La Colla

  DOI：10.1016/j.bmc.2005.01.005

  日期：2005.3

  2-Alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)-ones (F-2-NH-DABOs) 4, 5 belonging to the dihydro-alkoxy-benzyl-oxopyrimidine (DABO) family and bearing different alkyl- and arylamino side chains at the C-2-position of the pyrimidine ring were designed as active against wild type (wt) human immunodeficiency virus type 1 (HIV-1) and some relevant HIV-1 mutants. Biological evaluation indicated the importance of the further anchor point of compounds 4, 5 into the nonnucleoside binding site (NNBS): newly synthesized compounds were highly active against both wild type and the Y181C HIV-1 strains. In anti-wt HIV-1 assay the potency of amino derivatives did not depend on the size or shape of the C-2-amino side chain, but it associated with the presence of one or two methyl groups (one at the pyrimidine C-5-position and the other at the benzylic carbon), being thymine, alpha-methyluracil or alpha-methylthymine derivatives almost equally active in reducing wt HIV-1-induced cytopathogenicity in MT-4 cells. Against the Y181C mutant strain, 2,6-difluorobenzyl-alpha-methylthymine derivatives 4d, 5h'-n' showed the highest potency and selectivity among tested compounds, both a properly sized C-2-NH side chain and the presence of two methyl groups (at C-5 and benzylic positions) being crucial for high antiviral action. (c) 2005 Elsevier Ltd. All rights reserved.