5-bromo-N-(4-fluorobenzyl)-4-hydroxy-6-methylnicotinamide | 880261-44-9

• 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: 5-bromo-N-(4-fluorobenzyl)-4-hydroxy-6-methylnicotinamide
• 英文别名: 5-bromo-N-(4-fluorobenzyl)-4-hydroxy-6-methylnicotineamide；5-bromo-N-[(4-fluorophenyl)methyl]-6-methyl-4-oxo-1H-pyridine-3-carboxamide
• CAS: 880261-44-9
• 化学式: C₁₄H₁₂BrFN₂O₂
• 分子量: 339.164
• InChiKey: MFTBFQQACJNLNZ-UHFFFAOYSA-N

物化性质

• 沸点：
  501.8±50.0 °C(Predicted)
• 密度：
  1.550±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  58.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-bromo-N-(4-fluorobenzyl)-4-hydroxy-6-methylnicotinamide 在 copper(l) iodide 、 三丁基膦 、 偶氮二甲酸二异丙酯 、 碘 、 sodium methylate 、 三氧化硫吡啶 、 乙酸酐 、 三乙胺 、 间氯过氧苯甲酸 、 potassium hydroxide 作用下， 以 四氢呋喃 、 氯仿 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 9.0h， 生成 methyl 4-(benzyloxy)-5-{((4-fluorobenzyl)carbanoyl)}-3-methoxypyridine-2-carboxylate
  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
• 作为产物：
  描述：

  4-羟基-6-甲基烟酸 在 溴 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 水 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.0h， 生成 5-bromo-N-(4-fluorobenzyl)-4-hydroxy-6-methylnicotinamide
  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。
• Bicyclic Carbamoylpyridone Derivative Having Hiv Integrase Inhibitory Activity
  申请人：Yoshida Hiroshi

  公开号：US20080161271A1

  公开（公告）日：2008-07-03

  [Object] Is to provide a novel compound having an anti-viral activity, particularly a HIV integrase inhibitory activity, and an agent, particularly an anti-HIV agent. [Solving means] A compound represented by the formula: (wherein Z 1 is NR 4 (R 4 is hydrogen, optionally substituted lower alkyl etc.), O or CH 2 ; Z 2 is optionally substituted lower alkylene or optionally substituted lower alkenylene, each may be intervened by a heteroatom group selected from group consisting O, S, SO, SO 2 , NR 5 (R 5 is selected independently from the same substituent group of R 4 )—N═ and ═N—; R 1 is hydrogen or lower alkyl; X is a single bond, a heteroatom group selected from O, S, SO, SO 2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group; R 2 is optionally substituted aryl; R 3 is hydrogen, halogen, hydroxy, optionally substituted alkyl group etc.)

  [目的]提供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和一种药剂，特别是抗HIV药剂。 [解决方法]一种由以下公式表示的化合物： （其中Z1为NR4（R4为氢，可选择性取代的低碳基等），O或CH2； Z2为可选择性取代的低位撑链或可选择性取代的低位烯链，每个可以由从O，S，SO，SO2，NR5（R5为独立选择自R4的相同取代基团）-N═和═N-组成的杂原子基团隔开； R1为氢或低碳基； X为单键，从O，S，SO，SO2和NH中选择的杂原子基团，或者可选择性被杂原子基团隔开的低位撑链或低位烯链； R2为可选择性取代的芳基； R3为氢，卤素，羟基，可选择性取代的烷基等。
• Bicyclic carbamoylpyridone derivative having HIV integrase inhibitory activity
  申请人：Shionogi & Co., Ltd.

  公开号：US07858788B2

  公开（公告）日：2010-12-28

  Is to provide a novel compound having an anti-viral activity, particularly a HIV integrase inhibitory activity, and an agent, particularly an anti-HIV agent. A compound represented by the formula: (wherein Z1 is NR4 (R4 is hydrogen, optionally substituted lower alkyl etc.), O or CH2; Z2 is optionally substituted lower alkylene or optionally substituted lower alkenylene, each may be intervened by a heteroatom group selected from group consisting O, S, SO, SO2, NR5 (R5 is selected independently from the same substituent group of R4) —N═ and ═N—; R1 is hydrogen or lower alkyl; X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group; R2 is optionally substituted aryl; R3 is hydrogen, halogen, hydroxy, optionally substituted alkyl group etc.)

  提供一种具有抗病毒活性，特别是HIV整合酶抑制活性的新型化合物和制剂，特别是抗HIV制剂。该化合物的表示式为：（其中Z1为NR4（R4为氢，可选取取代基较低的烷基等），O或CH2; Z2为可选取取代基较低的亚烷基或可选取取代基较低的烯基，每个均可由从O、S、SO、SO2、NR5（R5从与R4相同的取代基群中独立选择）-N═和═N-组成的杂原子基团中介；R1为氢或较低的烷基；X为单键，从O、S、SO、SO2和NH中选择的杂原子基团，或可选取取代基较低的亚烷基或可选取取代基较低的烯基，每个均可由杂原子基团中介；R2为可选取取代基的芳基；R3为氢，卤素，羟基，可选取取代基的烷基等。
• Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity
  申请人：Shionogi & Co., Ltd.

  公开号：US08188271B2

  公开（公告）日：2012-05-29

  Is to provide a novel compound having an anti-viral activity, particularly a HIV integrase inhibitory activity, and a pharmaceutical composition, particularly an anti-HIV agent. (wherein R1 is hydrogen or lower alkyl; X is lower alkylene etc.; R2 is optionally substituted aryl; R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl etc.; R4 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic lower alkyl etc.; A broken line indicates the presence or absence of a bond; B1 and B2 are such that any one of them is CR20R21, and the other is NR22 and, in this case, there is no broken line. When B2 is NR22, R4 and R22 may be connected together to form an optionally substituted heterocycle; When B2 is CHR21, R4 and R21 may be connected together to form an optionally substituted heterocycle. Alternatively, B1 and B2 are independently C, CR23 or N and, in this case, B1 and B2 may be taken together to form a heterocycle. R20, R21, R22 and R23 are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl etc.)

  提供一种具有抗病毒活性的新化合物，特别是具有HIV整合酶抑制活性的化合物，以及一种制药组合物，特别是一种抗HIV药物。（其中R1为氢或较低的烷基；X为较低的烷基等；R2为可选取代的芳基；R3为氢、卤素、羟基、可选取代的较低烷基等；R4为氢、可选取代的较低烷基、可选取代的环烷基、可选取代的环烷基较低烷基、可选取代的芳基、可选取代的芳基较低烷基、可选取代的杂环基、可选取代的杂环较低烷基等；破折线表示键的存在或不存在；B1和B2是这样的，其中任意一个是CR20R21，另一个是NR22，此时没有破折线。当B2为NR22时，R4和R22可以连接在一起形成可选取代的杂环；当B2为CHR21时，R4和R21可以连接在一起形成可选取代的杂环。或者，B1和B2独立地为C、CR23或N，此时B1和B2可以结合形成一个杂环。R20、R21、R22和R23独立地为氢、可选取代的较低烷基、可选取代的环烷基、可选取代的环烷基较低烷基等。）
• POLYCYCLIC CARBAMOYLPYRIDONE DERIVATIVE HAVING HIV INTEGRASE INHIBITORY ACTIVITY
  申请人：YOSHIDA Hiroshi

  公开号：US20120208998A1

  公开（公告）日：2012-08-16

  A compound having an anti-viral activity, particularly a HIV integrase inhibitory activity, and a pharmaceutical composition, particularly an anti-HIV agent, of the formula: wherein R 1 , R 2 , R 3 , R 4 , B 1 and B 2 are defined in the specification.

  一种具有抗病毒活性，特别是HIV整合酶抑制活性的化合物，以及公式为：其中R1、R2、R3、R4、B1和B2在说明书中定义的制药组合物，特别是抗HIV制剂。