1-allyl-3-benzyloxy-N5-(4-fluorobenzyl)-N2-(2-methoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide | 906658-37-5

• 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: 1-allyl-3-benzyloxy-N5-(4-fluorobenzyl)-N2-(2-methoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide
• 英文别名: 5-N-[(4-fluorophenyl)methyl]-2-N-(2-methoxyethyl)-4-oxo-3-phenylmethoxy-1-prop-2-enylpyridine-2,5-dicarboxamide
• CAS: 906658-37-5
• 化学式: C₂₇H₂₈FN₃O₅
• 分子量: 493.535
• InChiKey: MNEATUHGTGSBAL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  36
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  97
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1-allyl-3-benzyloxy-N5-(4-fluorobenzyl)-N2-(2-methoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide 在 potassium osmate(VI) dihydrate 、 sodium periodate 、 palladium 10% on activated carbon 、 氢气 作用下， 以 1,4-二氧六环 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 22.0h， 生成 3,9-dihydroxy-2-(2-methoxyethyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrid[1,-2-a]pyrazine-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 、 sodium chlorite 、 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 、 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 、 甲醇 、 乙醇 、 氯仿 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 35.0h， 生成 1-allyl-3-benzyloxy-N5-(4-fluorobenzyl)-N2-(2-methoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide
  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

• 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。
• US7858788B2
  申请人：——

  公开号：US7858788B2

  公开（公告）日：2010-12-28
• 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.