6-(2,6-difluorophenylmethyl)-3,4-dihydro-5-methyl-2-methylthiopyrimidin-4-one | 221122-15-2

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 6-(2,6-difluorophenylmethyl)-3,4-dihydro-5-methyl-2-methylthiopyrimidin-4-one
• 英文别名: 6-(2,6-difluorophenylmethyl)-3,4-dihydro-2-methylthio-5-methylpyrimidin-4(3H)-one；6-(2,6-difluorophenylmethyl)-3,4-dihydro-5-methyl-2-methylthiopyrimidin-4(3H)-one；6-(2,6-Difluorophenylmethyl)-3,4-dihydro-5-methyl-2-(methylthio)pyrimidin-4(3H)-one；4-[(2,6-difluorophenyl)methyl]-5-methyl-2-methylsulfanyl-1H-pyrimidin-6-one
• CAS: 221122-15-2
• 化学式: C₁₃H₁₂F₂N₂OS
• 分子量: 282.314
• InChiKey: XRNOWFHRLDKKSO-UHFFFAOYSA-N

物化性质

• 沸点：
  388.3±52.0 °C(Predicted)
• 密度：
  1.34±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-甲基环己胺 、 6-(2,6-difluorophenylmethyl)-3,4-dihydro-5-methyl-2-methylthiopyrimidin-4-one 以44%的产率得到2-[cyclohexyl(methyl)amino]-4-[(2,6-difluorophenyl)methyl]-5-methyl-1H-pyrimidin-6-one
  参考文献：
  名称：

  Synthesis and Biological Properties of Novel 2-Aminopyrimidin-4(3H)-ones Highly Potent against HIV-1 Mutant Strains

  摘要：

  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.

  DOI：

  10.1021/jm070811e
• 作为产物：
  描述：

  2,6-二氟苯乙酸 在 sodium ethanolate 、 三乙胺 、 magnesium chloride 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 33.0h， 生成 6-(2,6-difluorophenylmethyl)-3,4-dihydro-5-methyl-2-methylthiopyrimidin-4-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

文献信息

• Structure-Based Design, Synthesis, and Biological Evaluation of Conformationally Restricted Novel 2-Alkylthio-6-[1-(2,6-difluorophenyl)alkyl]- 3,4-dihydro-5-alkylpyrimidin-4(3<i>H</i>)-ones as Non-nucleoside Inhibitors of HIV-1 Reverse Transcriptase
  作者：Antonello Mai、Gianluca Sbardella、Marino Artico、Rino Ragno、Silvio Massa、Ettore Novellino、Giovanni Greco、Antonio Lavecchia、Chiara Musiu、Massimiliano La Colla、Chiara Murgioni、Paolo La Colla、Roberta Loddo

  DOI：10.1021/jm010853h

  日期：2001.8.1

  5-Alkyl-2-(alkylthio)-6-(2,6-difluorobenzyl)-3,4-dihydropyrimidin-4(3H)-ones (S-DABOs, 2) have been recently described as a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) active at nanomolar concentrations (Mai, A. et al. J. Med. Chem. 1999, 42, 619-627). In pursuing our lead optimization efforts, we designed novel conformationally

  最近已将5-烷基-2-（烷硫基）-6-（2,6-二氟苄基）-3,4-二氢嘧啶-4（3H）-ones（S-DABOs，2）描述为一类新的人类免疫缺陷在纳摩尔浓度下具有活性的病毒1型（HIV-1）非核苷逆转录酶（RT）抑制剂（Mai，A. et al.J.Med.Chem.1999，42，619-627）。为了进行领先的优化工作，我们设计了新颖的构象受限的S-DABO，3，其苄基碳原子（Y = Me）和嘧啶5位（R = Me）具有甲基。构象分析和对接模拟表明，两种甲基的存在将显着降低构象柔性，而不会损害R对映异构体适合RT非核苷结合口袋的能力。要发展结构与活动的关系，我们准备了几种3型同源物，它们属于胸腺嘧啶（R = Me）和尿嘧啶（R = H）系列，具有各种2-烷硫基侧链（X = Me，i-Pr，n-Bu，i-Bu，s -Bu，c-戊基和c-己基）和不同于2,6-二氟苯基（Ar =苯基，2,
• Computer-Aided Design, Synthesis, and Anti-HIV-1 Activity in Vitro of 2-Alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3<i>H</i>)- ones as Novel Potent Non-Nucleoside Reverse Transcriptase Inhibitors, Also Active Against the Y181C Variant
  作者：Rino Ragno、Antonello Mai、Gianluca Sbardella、Marino Artico、Silvio Massa、Chiara Musiu、Massimo Mura、Flavia Marturana、Alessandra Cadeddu、Paolo La Colla

  DOI：10.1021/jm0309856

  日期：2004.2.1

  strongly suggested the synthesis of the designed amino-DABOs. F(2)-NH-DABOs were shown to be highly active in both anti-RT and anti-HIV biological assays with IC(50) and EC(50) comparable with that of the reference compound MKC-442. Interestingly, 2-cyclopentylamino-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methyl pyrimidin-4(3H)-one (9d) was active against the Y181C HIV-1 mutant strain at submicromolar

  二氢-烷氧基-苄基-氧嘧啶（DABO）是在过去十年中开发的强大的NNRTIs系列。试图提高其效力和选择性的尝试导致了硫代DABO（S-DABO），DATNO和二氟硫代DABO（F（2）-S-DABO）。最近，我们报道了S-DABO系列新型构象受限亚型的合成和分子模型研究，其特征为在连接嘧啶环与芳基部分的亚甲基键上存在取代基（Mai，A.等。 J. Med。Chem。2001，44，2544-2554）。现在，我们报告四个新DABO原型（5-烷基-2-环戊基氨基-6- [1-（2,6-二氟苯基）烷基] -3,4-二氢嘧啶-4的计算机辅助设计，合成和生物学评估。 （3H）-ones，F（2）-NH-DABOs，其中相关的F（2）-S-DABOs的硫原子被氨基取代。对于这些研究，我们将共结晶的MKC-442 / RT复合物用作参考模型。新设计的F（2）-NH-DABOs与Autodock的对接研
• Oxo-pyrimidine compounds
  申请人：Storer Richard

  公开号：US20050014774A1

  公开（公告）日：2005-01-20

  Oxo-pyrimidine compounds for the treatment of retroviral infections, and particularly for HIV, are described. Also included are compositions comprising the oxo-pyrimidine derivatives alone or in combination with other anti-retroviral agents, processes for their preparation, and methods of manufacturing a medicament incorporating these compounds.

  描述了用于治疗逆转录病毒感染，特别是艾滋病毒的氧代嘧啶化合物。此外，还包括由氧化嘧啶衍生物单独或与其他抗逆转录病毒药物组合而成的组合物、其制备工艺以及生产含有这些化合物的药物的方法。
• 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.
• OXO-PYRIMIDINE COMPOUNDS
  申请人：Idenix (Cayman) Limited

  公开号：EP1620407A2

  公开（公告）日：2006-02-01