3-acetyl-5-(2,4-difluorobenzyl)-1-(2-fluorobenzyl)pyridin-2(1H)-one | 1310875-99-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-acetyl-5-(2,4-difluorobenzyl)-1-(2-fluorobenzyl)pyridin-2(1H)-one
• 英文别名: 3-acetyl-5-[(2,4-difluorophenyl)methyl]-1-[(2-fluorophenyl)methyl]pyridin-2-one
• CAS: 1310875-99-0
• 化学式: C₂₁H₁₆F₃NO₂
• 分子量: 371.359
• InChiKey: PHMQJZDVVJUVPE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  37.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-acetyl-5-(2,4-difluorobenzyl)-1-(2-fluorobenzyl)pyridin-2(1H)-one 在 盐酸 、 水 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium t-butanolate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 4-(5-(2,4-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-hydroxy-4-oxo-N-(2-oxopyrrolidin-1-yl)but-2-enamide
  参考文献：
  名称：

  [EN] PYRIDINONE HYDROXYCYCLOPENTYL CARBOXAMIDES: HIV INTEGRASE INHIBITORS WITH THERAPEUTIC APPLICATIONS
  [FR] PYRIDINONE HYDROXYCYCLOPENTYLCARBOXAMIDES : INHIBITEURS DE L'INTÉGRASE DU VIH AYANT DES APPLICATIONS THÉRAPEUTIQUES

  摘要：

  公开号：

  WO2011071849A3
• 作为产物：
  描述：

  2,4-二氟苯甲醛 在 三乙基硅烷 、 bis-triphenylphosphine-palladium(II) chloride 、 N-溴代丁二酰亚胺(NBS) 、 正丁基锂 、 sodium hydride 、 sodium iodide 作用下， 以 甲基叔丁基醚 、 氯仿 、 环己烷 、 N,N-二甲基甲酰胺 、 乙腈 、 mineral oil 为溶剂， 反应 30.25h， 生成 3-acetyl-5-(2,4-difluorobenzyl)-1-(2-fluorobenzyl)pyridin-2(1H)-one
  参考文献：
  名称：

  Discovery of a Potent HIV Integrase Inhibitor That Leads to a Prodrug with Significant anti-HIV Activity

  摘要：

  Worldwide research efforts in drug discovery involving HIV integrase have produced only one compound, raltegravir, that has been approved for clinical use in HIV/AIDS. As resistance, toxicity, and drug-drug interactions are recurring issues with all classes of anti-HIV drugs, the discovery of novel integrase inhibitors remains a significant scientific challenge. We have designed a lead HIV-1 strand transfer (ST) inhibitor (IC(50) 70 nM), strategically assembled on a pyridinone scaffold. A focused structure-activity investigation of this parent compound led to a significantly more potent ST inhibitor, 2 (IC(50) 6 +/- 3 nM). Compound 2 exhibits good stability in pooled human liver microsomes. It also displays a notably favorable profile with respect to key human cytochrome P450 (CYP) isozymes and human UDP glucuronosyl transferases (UGTs). The prodrug of inhibitor 2, i.e., compound 10, was found to possess remarkable anti-HIV-1 activity in cell culture (EC(50) 9 +/- 4 nM, CC(50) 135 +/- 7 mu M, therapeutic index = 15 000).

  DOI：

  10.1021/ml2001246

文献信息

• PYRIDINONE HYDROXYCYCLOPENTYL CARBOXAMIDES: HIV INTEGRASE INHIBITORS WITH THERAPEUTIC APPLICATIONS
  申请人：Nair Vasu

  公开号：US20120282218A1

  公开（公告）日：2012-11-08

  New chiral and achiral oxy-substituted cyclopentyl pyridinone diketocarboxamides and their derivatives and methods for their preparations are disclosed. The compounds include tautomers, regioisomers and geometric isomers. These complex carboxamides are designed as inhibitors of HIV replication through inhibition of HIV integrase. The compounds are useful in the prevention or treatment of infection by HIV and in the treatment of AIDS and ARC, either as the compounds, or as pharmaceutically acceptable salts, with pharmaceutically acceptable carriers, used alone or in combination with antivirals, immunomodulators, antibiotics, vaccines, and other therapeutic agents, especially other anti-HIV compounds (including other anti-HIV integrase agents), which can be used to create combination anti-HIV cocktails. Methods of treating AIDS and ARC and methods of treating or preventing infection by HIV are also described.

  本发明公开了新的手性和非手性氧取代的环戊基吡啶酮二酮羧酰胺及其衍生物的制备方法。这些化合物包括互变异构体、区域异构体和几何异构体。这些复杂的羧酰胺被设计为通过抑制HIV整合酶来抑制HIV复制的抑制剂。这些化合物可用于预防或治疗HIV感染以及治疗艾滋病和ARC，可以作为化合物或药学上可接受的盐，与药学上可接受的载体一起使用，单独使用或与抗病毒药物、免疫调节剂、抗生素、疫苗和其他治疗剂（尤其是其他抗HIV化合物，包括其他抗HIV整合酶剂）组合使用，以创建组合抗HIV鸡尾酒。还描述了治疗艾滋病和ARC以及治疗或预防HIV感染的方法。
• Pyridinone hydroxycyclopentyl carboxamides: HIV integrase inhibitors with therapeutic applications
  申请人：Nair Vasu

  公开号：US08703801B2

  公开（公告）日：2014-04-22

  New chiral and achiral oxy-substituted cyclopentyl pyridinone diketocarboxamides and their derivatives and methods for their preparations are disclosed. The compounds include tautomers, regioisomers and geometric isomers. These complex carboxamides are designed as inhibitors of HIV replication through inhibition of HIV integrase. The compounds are useful in the prevention or treatment of infection by HIV and in the treatment of AIDS and ARC, either as the compounds, or as pharmaceutically acceptable salts, with pharmaceutically acceptable carriers, used alone or in combination with antivirals, immunomodulators, antibiotics, vaccines, and other therapeutic agents, especially other anti-HIV compounds (including other anti-HIV integrase agents), which can be used to create combination anti-HIV cocktails. Methods of treating AIDS and ARC and methods of treating or preventing infection by HIV are also described.

  本发明公开了新型手性和非手性氧取代环戊基吡啶酮二酮羧酰胺及其衍生物的制备方法。这些化合物包括互变异构体、区域异构体和几何异构体。这些复杂的羧酰胺被设计为通过抑制HIV整合酶来抑制HIV复制的抑制剂。这些化合物可用于预防或治疗HIV感染以及治疗艾滋病和ARC，作为化合物或药学上可接受的盐，与药学上可接受的载体一起使用，单独使用或与抗病毒药物、免疫调节剂、抗生素、疫苗和其他治疗剂，特别是其他抗HIV化合物（包括其他抗HIV整合酶剂）结合使用，可用于创建联合抗HIV鸡尾酒。还描述了治疗艾滋病和ARC的方法以及治疗或预防HIV感染的方法。
• Notable difference in anti-HIV activity of integrase inhibitors as a consequence of geometric and enantiomeric configurations
  作者：Maurice Okello、Sanjay Mishra、Malik Nishonov、Vasu Nair

  DOI：10.1016/j.bmcl.2013.05.050

  日期：2013.7

  While some examples are known of integrase inhibitors that exhibit potent anti-HIV activity, there are very few cases reported of integrase inhibitors that show significant differences in anti-HIV activity that result from distinctions in cis- and trans-configurations as well as enantiomeric stereostructure. We describe here the design and synthesis of two enantiomeric trans-hydroxycyclopentyl carboxamides which exhibit notable difference in anti-HIV activity. This difference is explained through their binding interactions within the active site of the HIV-1 integrase intasome. The more active enantiomer 3 (EC50 25 nM) was relatively stable in human liver microsomes. Kinetic data revealed that its impact on key cytochrome P450 isozymes, as either an inhibitor or an activator, was minor, suggesting a favorable CYP profile. (C) 2013 Elsevier Ltd. All rights reserved.
• US8703801B2
  申请人：——

  公开号：US8703801B2

  公开（公告）日：2014-04-22