6-(2,6-difluorophenylmethyl)-3,4-dihydro-2-methylthiopyrimidin-4(3H)-one | 221122-01-6

• 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-2-methylthiopyrimidin-4(3H)-one
• 英文别名: 4-[(2,6-difluorophenyl)methyl]-2-methylsulfanyl-1H-pyrimidin-6-one
• CAS: 221122-01-6
• 化学式: C₁₂H₁₀F₂N₂OS
• 分子量: 268.287
• InChiKey: NHESDAKFXMABDL-UHFFFAOYSA-N

物化性质

• 沸点：
  380.4±52.0 °C(Predicted)
• 密度：
  1.37±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 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：

  2-甲基哌啶 、 6-(2,6-difluorophenylmethyl)-3,4-dihydro-2-methylthiopyrimidin-4(3H)-one 以49%的产率得到4-[(2,6-difluorophenyl)methyl]-2-(2-methylpiperidin-1-yl)-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-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

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,
• 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。
• Methods for inhibiting the transmission of HIV using topically applied substituted 6-benzyl-4-oxopyrimidines
  申请人：——

  公开号：US20030008887A1

  公开（公告）日：2003-01-09

  A method for inhibiting sexual transmission of HIV comprising topically applying to the skin or epithelial tissue of a human a composition comprising a non-nucleoside reverse transcriptase inhibitor (“NNRTI”) that is able to inhibit viral replication for periods exceeding 12, 24, or even 36 days, at concentrations below even 10 &mgr;M. In one embodiment the NNRTI is a dihydro-alkyloxy-benzyl-oxopyrimidine (DABO).

  一种抑制HIV性传播的方法，包括将一种含有非核苷类反转录酶抑制剂（“NNRTI”）的组合物局部涂抹于人体的皮肤或上皮组织上，该NNRTI能够在浓度低于10 &mgr;M的情况下抑制病毒复制，持续时间超过12、24或36天。在一种实施方式中，NNRTI是一种二氢烷氧基苯基嘧啶（DABO）。
• 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
• Methods for inhibiting the transmission of HIV using topically applied substituted 6-benzyl-4- oxopyrimidines
  申请人：Idenix Pharmaceuticals, Inc.

  公开号：US20030225114A1

  公开（公告）日：2003-12-04

  A method for inhibiting sexual transmission of HIV comprising topically applying to the skin or epithelial tissue of a human a composition comprising a non-nucleoside reverse transcriptase inhibitor (“NNRTI”) that is able to inhibit viral replication for periods exceeding 12, 24, or even 36 days, at concentrations below even 10 &mgr;M. In one embodiment the NNRTI is a dihydro-alkyloxy-benzyl-oxopyrimidine (DABO).

  一种抑制艾滋病毒性传播的方法，包括在人的皮肤或上皮组织局部施用一种组合物，该组合物包含一种非核苷类逆转录酶抑制剂（"NNRTI"），它能够抑制病毒复制超过 12、24 或甚至 36 天，浓度甚至低于 10 &mgr;M。在一个实施方案中，NNRTI 是一种二氢-烷氧基-苄基-氧代嘧啶（DABO）。