5-benzyloxy-1-methyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylic acid 4-fluorobenzylamide | 1421314-73-9

• 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-benzyloxy-1-methyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylic acid 4-fluorobenzylamide
• 英文别名: N-[(4-fluorophenyl)methyl]-4-methyl-9,12-dioxo-11-phenylmethoxy-1,4,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-13-carboxamide
• CAS: 1421314-73-9
• 化学式: C₂₇H₂₇FN₄O₄
• 分子量: 490.534
• InChiKey: SEDSIYGIPJPXNO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  82.2
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-benzyloxy-1-methyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylic acid 4-fluorobenzylamide 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 5-hydroxy-1-methyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylic acid 4-fluorobenzylamide
  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 、 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 37.5h， 生成 5-benzyloxy-1-methyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylic acid 4-fluorobenzylamide
  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

• Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 2. Bi- and Tricyclic Derivatives Result in Superior Antiviral and Pharmacokinetic Profiles
  作者：Takashi Kawasuji、Brian A. Johns、Hiroshi Yoshida、Jason G. Weatherhead、Toshiyuki Akiyama、Teruhiko Taishi、Yoshiyuki Taoda、Minako Mikamiyama-Iwata、Hitoshi Murai、Ryuichi Kiyama、Masahiro Fuji、Norihiko Tanimoto、Tomokazu Yoshinaga、Takahiro Seki、Masanori Kobayashi、Akihiko Sato、Edward P. Garvey、Tamio Fujiwara

  DOI：10.1021/jm301550c

  日期：2013.2.14

  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.