9-hydroxy-2-(2-methoxy-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide

• 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: 9-hydroxy-2-(2-methoxy-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide
• 英文别名: N-[(4-fluorophenyl)methyl]-9-hydroxy-2-(2-methoxyethyl)-1,8-dioxo-pyrido[1,2-a]pyrazine-7-carboxamide；N-[(4-fluorophenyl)methyl]-9-hydroxy-2-(2-methoxyethyl)-1,8-dioxopyrido[1,2-a]pyrazine-7-carboxamide
• 化学式: C₁₉H₁₈FN₃O₅
• 分子量: 387.367
• InChiKey: QDDNUKWETDOWFS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  99.2
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  9-hydroxy-2-(2-methoxy-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide 在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 以52%的产率得到9-hydroxy-2-(2-methoxy-ethyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide
  参考文献：
  名称：

  Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 2. Bi- and Tricyclic Derivatives Result in Superior Antiviral and Pharmacokinetic Profiles

  摘要：

  This work is a continuation of our initial discovery of a potent monocyclic carbamoyl pyridone human immunodeficiency virus type-1 (HIV-1) integrase inhibitor that displayed favorable antiviral and pharmacokinetic properties. We report herein a series of bicyclic carbamoyl pyridone analogues to address conformational issues from our initial SAR studies. This modification of the core unit succeeded to deliver low nanomolar potency in standard antiviral assays. An additional hydroxyl substituent on the bicyclic scaffold provides remarkable improvement of antiviral efficacies against clinically relevant resistant viruses. These findings led to additional cyclic tethering of the naked hydroxyl group resulting in tricyclic carbamoyl pyridone inhibitors to address remaining issues and deliver potential clinical candidates. The tricyclic carbamoyl pyridone derivatives described herein served as the immediate leads in molecules to the next generation integrase inhibitor dolutegravir which is currently in late stage clinical evaluation.

  DOI：

  10.1021/jm301550c
• 作为产物：
  描述：

  麦芽醇 在 palladium diacetate 、 1,3-双(二苯基膦)丙烷 甲醇 、 manganese(IV) oxide 、 sodium hydroxide 、 sodium chlorite 、 potassium osmate(VI) 、 sodium periodate 、 N-溴代丁二酰亚胺(NBS) 、 氨基磺酸 、 氨 、 水 、 1-羟基苯并三唑 、 caesium carbonate 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 间氯过氧苯甲酸 、 三氟乙酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 氯仿 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 40.95h， 生成 9-hydroxy-2-(2-methoxy-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide
  参考文献：
  名称：

  WO2006/116764

  摘要：

  公开号：

文献信息

• Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
  申请人：Johns Brian Alvin

  公开号：US20090318421A1

  公开（公告）日：2009-12-24

  The present invention is to provide a novel compound (I) shown below, having the anti-virus activity, particularly the HIV integrase inhibitory activity, and a drug containing the same, particularly an anti-HIV drug, as well as a process and an intermediate thereof. (wherein Z 1 is NR 4 ; R 1 is 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 optionally substituted aryl; R 3 is hydrogen, a halogen, hydroxy, optionally substituted lower alkyl etc; and R 4 and Z 2 part taken together forms a ring, to form a polycyclic compound, including e.g., a tricyclic or tetracyclic compound.

  本发明提供了一种新型化合物(I)，如下所示，具有抗病毒活性，特别是HIV整合酶抑制活性，以及含有该化合物的药物，特别是抗HIV药物，以及其制备方法和中间体。(其中Z1为NR4;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，或低碳基或低碳烯基，在其中杂原子基团可以介入;R2为可选取代芳基;R3为氢、卤素、羟基、可选取代的低碳基等;R4和Z2共同形成环，形成多环化合物，包括例如三环或四环化合物。
• 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。
• POLYCYCLIC CARBAMOYLPYRIDONE DERIVATIVE HAVING HIV INTEGRASE INHIBITORY ACTIVITY
  申请人：Johns Brian Alvin

  公开号：US20120115875A1

  公开（公告）日：2012-05-10

  The present invention is to provide a novel compound (I) shown below, having the anti-virus activity, particularly the HIV integrase inhibitory activity, and a drug containing the same, particularly an anti-HIV drug, as well as a process and an intermediate thereof. (wherein Z 1 is NR 4 ; R 1 is 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 optionally substituted aryl; R 3 is hydrogen, a halogen, hydroxy, optionally substituted lower alkyl etc; and R 4 and Z 2 part taken together forms a ring, to form a polycyclic compound, including e.g., a tricyclic or tetracyclic compound.

  本发明提供了一种新型化合物（I），其具有抗病毒活性，特别是HIV整合酶抑制活性，以及含有该化合物的药物，特别是抗HIV药物，以及其制备方法和中间体。（其中Z1为NR4；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，或低碳基或低碳烯基，其中杂原子基团可以介入；R2为可选取代芳基；R3为氢、卤素、羟基、可选取代的低碳基等；R4和Z2共同形成环，形成多环化合物，包括三环或四环化合物等。）
• Polycylclic Carbamoylpyridone Derivative Having HIV Integrase Inhibitory Acitvity
  申请人：Yoshida Hiroshi

  公开号：US20090143356A1

  公开（公告）日：2009-06-04

  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 R 1 is hydrogen or lower alkyl; X is lower alkylene etc.; R 2 is optionally substituted aryl; R 3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl etc.; R 4 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; B 1 and B 2 are such that any one of them is CR 20 R 21 , and the other is NR 22 and, in this case, there is no broken line. When B 2 is NR 22 , R 4 and R 22 may be connected together to form an optionally substituted heterocycle; When B 2 is CHR 21 , R 4 and R 21 may be connected together to form an optionally substituted heterocycle. Alternatively, B 1 and B 2 are independently C, CR 23 or N and, in this case, B 1 and B 2 may be taken together to form a heterocycle. R 20 , R 21 , R 22 and R 23 are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl etc.)

  提供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，并提供一种药物组合物，特别是一种抗HIV剂。(其中，R1为氢或低碳基；X为低碳基亚烷等；R2为可选取代芳基；R3为氢、卤素、羟基、可选取代低碳基等；R4为氢、可选取代低碳基、可选取代环烷基、可选取代环烷基低碳基、可选取代芳基、可选取代芳基低碳基、可选取代杂环基、可选取代杂环低碳基等；断线表示键的存在或不存在；B1和B2是这样的，其中任何一个是CR20R21，另一个是NR22，此时没有断线。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分别是C、CR23或N，此时B1和B2可以连接在一起形成杂环。R20、R21、R22和R23分别为氢、可选取代低碳基、可选取代环烷基、可选取代环烷基低碳基等。
• SUBSTITUTED CYCLOPENTA[4,5]OXAZOLO[3,2-a]PYRIDO[1,2-d]PYRAZINES AS HIV INTEGRASE INHIBITORS
  申请人：Shionogi & Co., Ltd.

  公开号：US20160137666A1

  公开（公告）日：2016-05-19

  The present invention is to provide a novel compound (I) shown below, having the anti-virus activity, particularly the HIV integrase inhibitory activity, and a drug containing the same, particularly an anti-HIV drug, as well as a process and an intermediate thereof. (wherein Z 1 is NR 4 ; R 1 is 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 optionally substituted aryl; R 3 is hydrogen, a halogen, hydroxy, optionally substituted lower alkyl etc; and R 4 and Z 2 part taken together forms a ring, to form a polycyclic compound, including e.g., a tricyclic or tetracyclic compound.

  本发明提供了一种新型化合物(I)，如下所示，具有抗病毒活性，特别是HIV整合酶抑制活性，以及含有该化合物的药物，特别是抗HIV药物，以及其制备方法和中间体。(其中Z1为NR4;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，或杂原子基团可能介入的低碳基或低烯基;R2为可选取代芳基;R3为氢、卤素、羟基、可选取代的低碳基等;R4和Z2共同形成环，形成多环化合物，包括三环或四环化合物等)。