4-Benzyloxy-3-methoxy-pyridine-2,5-dicarboxylic acid 2-amide 5-(4-fluoro-benzylamide) | 880261-53-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 4-Benzyloxy-3-methoxy-pyridine-2,5-dicarboxylic acid 2-amide 5-(4-fluoro-benzylamide)
• 英文别名: 5-N-[(4-fluorophenyl)methyl]-3-methoxy-4-phenylmethoxypyridine-2,5-dicarboxamide
• CAS: 880261-53-0
• 化学式: C₂₂H₂₀FN₃O₄
• 分子量: 409.417
• InChiKey: VGUXIIXRHAYECZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-Benzyloxy-3-methoxy-pyridine-2,5-dicarboxylic acid 2-amide 5-(4-fluoro-benzylamide) 在 吡啶盐酸盐 、 水 作用下， 以 水 为溶剂， 反应 0.08h， 以93%的产率得到3-Hydroxy-4-oxo-1,4-dihydro-pyridine-2,5-dicarboxylic acid 2-amide 5-(4-fluoro-benzylamide)
  参考文献：
  名称：

  CARBAMOYLPYRIDONE DERIVATIVE HAVING HIV INTEGRASE INHIBITORY ACTIVITY

  摘要：

  公开号：

  EP1790638B1
• 作为产物：
  描述：

  methyl 4-(benzyloxy)-5-{((4-fluorobenzyl)carbanoyl)}-3-methoxypyridine-2-carboxylate 在 氯化铵 、 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 hydroxide 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 4-Benzyloxy-3-methoxy-pyridine-2,5-dicarboxylic acid 2-amide 5-(4-fluoro-benzylamide)
  参考文献：
  名称：

  Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 1. Molecular Design and Establishment of an Advanced Two-Metal Binding Pharmacophore

  摘要：

  Our group has focused on expanding the scope of a two-metal binding pharmacophore concept to explore HIV-1 integrase inhibitors through medicinal chemistry efforts to design novel scaffolds which allow for improvement of pharmacokinetic (PK) and resistance profiles. A novel chelating scaffold was rationally designed to effectively coordinate two magnesium cofactors and to extend an aromatic group into an optimal hydrophobic pharmacophore space. The new chemotype, consisting of a carbamoyl pyridone core unit, shows high inhibitory potency in both enzymatic and antiviral assay formats with low nM IC50 and encouraging potency shift effects in the presence of relevant serum proteins. The new inhibitor design displayed a remarkable PK profile suggestive of once daily dosing without the need for a PK booster as demonstrated by robust drug concentrations at 24 h after oral dosing in rats, dogs, and cynomolgus monkeys.

  DOI：

  10.1021/jm3010459

文献信息

• Carbamoylpyridone Derivatives Having Inhibitory Activity Against Hiv Integrase
  申请人：Yoshida Hiroshi

  公开号：US20070249687A1

  公开（公告）日：2007-10-25

  An object of the present invention provides a novel compound having the anti-viral activity, particularly, the HIV integrase inhibitory activity, and a drug containing the same, particularly, an anti-HIV drug. There is provided a compound represented by the formula: wherein, Y is NR 4 (R 4 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted aralkyl), O, S, SO, or SO 2 ; R A is 1) a group represented by the formula: —COR 5 (wherein R 5 is a group selected from a substituent group A), or 2) a group represented by the formula: (wherein A C ring is an optionally substituted nitrogen-containing aromatic heterocycle in which, among atoms adjacent to an atom having a bond, at least one atom is an unsaturated nitrogen atom, and a broken line represents the presence or the absence of a bond); R 1 is a hydrogen or lower alkyl; X is a single bond, a hetero atom group selected from O, S, SO, SO 2 and NH, or lower alkylene or lower alkenylene in which the hetero atom group may intervene; R 2 is a group selected from a substituent group A; R 3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted amino, optionally substituted lower alkylamino, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclic group, or optionally substituted heterocyclic lower alkyl) or a pharmaceutically acceptable salt thereof, or a solvate thereof.

  本发明的对象提供了一种具有抗病毒活性，特别是HIV整合酶抑制活性的新化合物，以及包含该化合物的药物，特别是抗HIV药物。提供了一种由以下式表示的化合物：其中，Y是NR4（R4是氢，可选地取代的低碳基，可选地取代的芳基或可选地取代的芳基烷基），O，S，SO或SO2;RA是1）由以下式表示的基团：—COR5（其中R5是从取代基A中选择的基团），或2）由以下式表示的基团：（其中A C环是一种可选地取代的含氮芳香杂环，在具有化学键的原子中，至少有一个原子是不饱和氮原子，而断裂线表示化学键的存在或缺失）；R1是氢或低碳基；X是单键，从O，S，SO，SO2和NH中选择的杂原子基团，或低碳基亚烷基或低碳基亚烯基，其中杂原子基团可以介入；R2是从取代基A中选择的基团；R3是氢，卤素，羟基，可选地取代的低碳基，可选地取代的低碳烯基，可选地取代的低碳氧基，可选地取代的氨基，可选地取代的低碳基氨基，可选地取代的环烷基，可选地取代的环烷基低碳基，可选地取代的芳基，可选地取代的芳基烷基，可选地取代的杂环基团，或可选地取代的杂环低碳基）或其药学上可接受的盐，或其溶剂化物。
• CARBAMOYLPYRIDONE DERIVATIVE HAVING HIV INTEGRASE INHIBITORY ACTIVITY
  申请人：Shionogi Co., Ltd.

  公开号：EP1790638B1

  公开（公告）日：2013-04-03
• US7550463B2
  申请人：——

  公开号：US7550463B2

  公开（公告）日：2009-06-23
• Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 1. Molecular Design and Establishment of an Advanced Two-Metal Binding Pharmacophore
  作者：Takashi Kawasuji、Brian A. Johns、Hiroshi Yoshida、Teruhiko Taishi、Yoshiyuki Taoda、Hitoshi Murai、Ryuichi Kiyama、Masahiro Fuji、Tomokazu Yoshinaga、Takahiro Seki、Masanori Kobayashi、Akihiko Sato、Tamio Fujiwara

  DOI：10.1021/jm3010459

  日期：2012.10.25

  Our group has focused on expanding the scope of a two-metal binding pharmacophore concept to explore HIV-1 integrase inhibitors through medicinal chemistry efforts to design novel scaffolds which allow for improvement of pharmacokinetic (PK) and resistance profiles. A novel chelating scaffold was rationally designed to effectively coordinate two magnesium cofactors and to extend an aromatic group into an optimal hydrophobic pharmacophore space. The new chemotype, consisting of a carbamoyl pyridone core unit, shows high inhibitory potency in both enzymatic and antiviral assay formats with low nM IC50 and encouraging potency shift effects in the presence of relevant serum proteins. The new inhibitor design displayed a remarkable PK profile suggestive of once daily dosing without the need for a PK booster as demonstrated by robust drug concentrations at 24 h after oral dosing in rats, dogs, and cynomolgus monkeys.