N-[(4-fluorophenyl)methyl]-9-hydroxy-2-(2-isopropoxyethyl)-1,8-dioxo-pyrido[1,2-a]pyrazine-7-carboxamide | 906656-34-6

• 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: N-[(4-fluorophenyl)methyl]-9-hydroxy-2-(2-isopropoxyethyl)-1,8-dioxo-pyrido[1,2-a]pyrazine-7-carboxamide
• 英文别名: N-[(4-fluorophenyl)methyl]-9-hydroxy-1,8-dioxo-2-(2-propan-2-yloxyethyl)pyrido[1,2-a]pyrazine-7-carboxamide
• CAS: 906656-34-6
• 化学式: C₂₁H₂₂FN₃O₅
• 分子量: 415.421
• InChiKey: JPCKEEIALFXZIM-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：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 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：

  N-[(4-fluorophenyl)methyl]-9-hydroxy-2-(2-isopropoxyethyl)-1,8-dioxo-pyrido[1,2-a]pyrazine-7-carboxamide 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， 生成 N-[(4-fluorophenyl)methyl]-9-hydroxy-2-(2-isopropoxyethyl)-1,8-dioxo-3,4-dihydropyrido[1,2-a]pyrazine-7-carboxamide
  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：

  3-(苄氧基)-2-甲基-4H-吡喃-4-酮 在 manganese(IV) oxide 、 potassium osmate(VI) dihydrate 、 sodium chlorite 、 sodium periodate 、 N-溴代丁二酰亚胺(NBS) 、 1,3-双(二苯基膦)丙烷 、 氨基磺酸 、 氨 、 sodium methylate 、 palladium diacetate 、 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 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 氯仿 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 39.16h， 生成 N-[(4-fluorophenyl)methyl]-9-hydroxy-2-(2-isopropoxyethyl)-1,8-dioxo-pyrido[1,2-a]pyrazine-7-carboxamide
  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

文献信息

• 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。
• 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。
• POLYCYCLIC CARBAMOYLPYRIDONE DERIVATIVE HAVING INHIBITORY ACTIVITY ON HIV INTEGRASE
  申请人：Shionogi Co., Ltd.

  公开号：EP1950212A1

  公开（公告）日：2008-07-30

  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.)

  目的是提供一种具有抗病毒活性，特别是艾滋病毒整合酶抑制活性的新型化合物，以及一种药物组合物，特别是一种抗艾滋病毒制剂。 其中 R1 是氢或低级烷基 X 是低级亚烷基等 R2 是任选取代的芳基； R3 是氢、卤素、羟基、任选取代的低级烷基等； R4 是氢、任选取代的低级烷基、任选取代的环烷基、任选取代的环烷基低级烷基、任选取代的芳基、任选取代的芳基低级烷基、任选取代的杂环基团、任选取代的杂环低级烷基等； 断线表示存在或不存在键； B1 和 B2 中的任意一个是 CR20R21，另一个是 NR22，在这种情况下，没有折线。 当 B2 为 NR22 时，R4 和 R22 可以连接在一起，形成一个任选取代的杂环； 当 B2 为 CHR21 时，R4 和 R21 可连接在一起，形成一个任选取代的杂环。 或者，B1 和 B2 独立地为 C、CR23 或 N，在这种情况下，B1 和 B2 可连接在一起形成杂环。 R20、R21、R22 和 R23 独立地是氢、任选取代的低级烷基、任选取代的环烷基、任选取代的环烷基低级烷基等）。
• US7858788B2
  申请人：——

  公开号：US7858788B2

  公开（公告）日：2010-12-28
• US8188271B2
  申请人：——

  公开号：US8188271B2

  公开（公告）日：2012-05-29