4-((4'-amino-[1,1'-biphenyl]-4-yl)amino)-N-(2,4-difluorobenzyl)-1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide | 1613522-18-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-((4'-amino-[1,1'-biphenyl]-4-yl)amino)-N-(2,4-difluorobenzyl)-1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide
• 英文别名: 4-[4-(4-aminophenyl)anilino]-N-[(2,4-difluorophenyl)methyl]-1-hydroxy-2-oxo-1,8-naphthyridine-3-carboxamide
• CAS: 1613522-18-1
• 化学式: C₂₈H₂₁F₂N₅O₃
• 分子量: 513.503
• InChiKey: LEFMOCIIAUSTEG-UHFFFAOYSA-N

物化性质

• 密度：
  1.488±0.06 g/cm3(Temp: 25 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  38
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  121
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2,4-二氟苄胺 在 N,N-diisobutyl ethylamine 、 palladium 10% on activated carbon 、 氢气 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 3.0h， 生成 4-((4'-amino-[1,1'-biphenyl]-4-yl)amino)-N-(2,4-difluorobenzyl)-1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide
  参考文献：
  名称：

  4-Amino-1-hydroxy-2-oxo-1,8-naphthyridine-含化合物对 HIV-1 的 Raltegravir 抗性整合酶突变体具有高效能

  摘要：

  目前有三种 HIV-1 整合酶 (IN) 链转移抑制剂 (INSTI) 被 FDA 批准用于治疗艾滋病。然而，耐药突变体的出现强调了开发其他药物的必要性，这些药物对现有的耐药突变体具有更高的功效。正如本文所报道的，我们修改了我们最近公开的 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides IN 抑制剂，以开发在生化分析中对重组 IN 具有改进功效的化合物。这些新化合物在单轮复制试验中对携带野生型 (WT) IN 的 HIV 载体显示出个位数的纳摩尔抗病毒效力，并且对携带主要形式的抗药性 IN 突变体的载体具有更高的效力。这些化合物对培养细胞也具有低毒性，在一些情况下，50 /EC 50 ) 大于 10000。通过额外的结构修改，这些化合物有可能产生对已知耐药病毒株有效的临床药物。

  DOI：

  10.1021/jm5001908

文献信息

• [EN] COMPOUNDS FOR INHIBITING DRUG-RESISTANT STRAINS OF HIV-1 INTEGRASE<br/>[FR] COMPOSÉS POUR INHIBER DES SOUCHES RÉSISTANTES AUX MÉDICAMENTS D'INTÉGRASE DE VIH-1
  申请人：US HEALTH

  公开号：WO2014186398A1

  公开（公告）日：2014-11-20

  A method of inhibiting drug -resistant HIV-1 integrase in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, having a structure of: wherein X is N, C(OH), or CH; Y is H or OH; each of Z1-Z5 is independently H or halogen; R4 is H, OH, NH2, NHR8, NR8R9 or R8; R5, R6, and R7 is each independently H, halogen, OR8, R8, NHR8, NR8R9, CO2R8, CONR8R9, SO2NR8R9, or R5 and R6 together with the carbon atoms to which R5 and R6 are attached form an optionally-substituted carbocycle or optionally-substituted heterocycle; and R8 and R9 is each independently H, optionally-substituted alkyl, optionally-substituted alkenyl, optionally- substituted alkynyl, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted cycloalkylene, optionally-substituted heterocycle, optionally-substituted amide, optionally-substituted ester, or R8 and R9 together with the nitrogen to which R8 and R9 are attached form an optionally-substituted heterocycle.

  在需要的患者中给予一种化合物（公式I）的治疗有效量，或其药用盐或酯，以抑制患者体内的耐药HIV-1整合酶。该化合物的结构为：其中X为N、C（OH）或CH；Y为H或OH；Z1-Z5中的每一个独立地为H或卤素；R4为H、OH、NH2、NHR8、NR8R9或R8；R5、R6和R7每一个独立地为H、卤素、OR8、R8、NHR8、NR8R9、CO2R8、CONR8R9、SO2NR8R9，或者R5和R6与其连接的碳原子形成一个可选择取代的碳环或可选择取代的杂环；R8和R9每一个独立地为H、可选择取代的烷基、可选择取代的烯基、可选择取代的炔基、可选择取代的芳基、可选择取代的环烷基、可选择取代的环烷基烯、可选择取代的杂环、可选择取代的酰胺、可选择取代的酯，或者R8和R9与其连接的氮原子形成一个可选择取代的杂环。
• COMPOUNDS FOR INHIBITING DRUG-RESISTANT STRAINS OF HIV-1 INTEGRASE
  申请人：THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SEC., DEPT. OF HEALTH AND HUMAN SERVICES

  公开号：US20160083382A1

  公开（公告）日：2016-03-24

  A method of inhibiting drug-resistant HIV-1 integrase in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, having a structure of: wherein X is N, C(OH), or CH; Y is H or OH; each of Z 1 -Z 5 is independently H or halogen; R 4 is H, OH, NH 2 , NHR 8 , NR 8 R 9 or R 8 ; R 5 , R 6 , and R 7 is each independently H, halogen, OR 8 , R 8 , NHR 8 , NR 8 R 9 , CO 2 R 8 , CONR 8 R 9 , SO 2 NR 8 R 9 , or R 5 and R 6 together with the carbon atoms to which R 5 and R 6 are attached form an optionally-substituted carbocycle or optionally-substituted heterocycle; and R 8 and R 9 is each independently H, optionally-substituted alkyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted cycloalkylene, optionally-substituted heterocycle, optionally-substituted amide, optionally-substituted ester, or R 8 and R 9 together with the nitrogen to which R 8 and R 9 are attached form an optionally-substituted heterocycle.

  本方法涉及在需要抑制药物耐药性HIV-1整合酶的主体中向其施用公式I的化合物的治疗有效量，或其药学上可接受的盐或酯，其结构为：其中X为N，C（OH）或CH；Y为H或OH；Z1-Z5中的每一个独立为H或卤素；R4为H，OH，NH2，NHR8，NR8R9或R8；R5、R6和R7各自独立为H，卤素，OR8，R8，NHR8，NR8R9，CO2R8，CONR8R9，SO2NR8R9或R5和R6与R5和R6附着的碳原子一起形成可选地取代的碳环或可选地取代的杂环；R8和R9各自独立为H，可选地取代的烷基，可选地取代的烯基，可选地取代的炔基，可选地取代的芳基，可选地取代的环烷基，可选地取代的环烷基，可选地取代的杂环，可选地取代的酰胺，可选地取代的酯，或R8和R9与R8和R9附着的氮一起形成可选地取代的杂环。
• Compounds for inhibiting drug-resistant strains of HIV-1 integrase
  申请人：The United States of America, as represented by the Secretary, Department of Health and Human Services

  公开号：US10208035B2

  公开（公告）日：2019-02-19

  A method of inhibiting drug-resistant HIV-1 integrase in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, having a structure of: wherein X is N, C(OH), or CH; Y is H or OH; each of Z1-Z5 is independently H or halogen; R4 is H, OH, NH2, NHR8, NR8R9 or R8; R5, R6, and R7 is each independently H, halogen, OR8, R8, NHR8, NR8R9, CO2R8, CONR8R9, SO2NR8R9, or R5 and R6 together with the carbon atoms to which R5 and R6 are attached form an optionally-substituted carbocycle or optionally-substituted heterocycle; and R8 and R9 is each independently H, optionally-substituted alkyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted cycloalkylene, optionally-substituted heterocycle, optionally-substituted amide, optionally-substituted ester, or R8 and R9 together with the nitrogen to which R8 and R9 are attached form an optionally-substituted heterocycle.

  一种抑制受试者体内耐药 HIV-1 整合酶的方法，包括向有需要的受试者施用治疗有效量的式 I 化合物或其药学上可接受的盐或酯，其结构为： 其中 X 是 N、C(OH)或 CH； Y 是 H 或 OH； Z1-Z5 各自独立地为 H 或卤素； R4 是 H、OH、NH2、NHR8、NR8R9 或 R8； R5、R6 和 R7 各自独立地为 H、卤素、OR8、R8、NHR8、NR8R9、CO2R8、CONR8R9、SO2NR8R9，或 R5 和 R6 与 R5 和 R6 所连接的碳原子一起形成任选取代的碳环或任选取代的杂环；以及 R8 和 R9 各自独立地为 H、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的芳基、任选取代的环烷基、任选取代的环亚烷基、任选取代的杂环、任选取代的酰胺、任选取代的酯，或 R8 和 R9 与 R8 和 R9 所连接的氮一起形成任选取代的杂环。
• US9676771B2
  申请人：——

  公开号：US9676771B2

  公开（公告）日：2017-06-13
• 4-Amino-1-hydroxy-2-oxo-1,8-naphthyridine-Containing Compounds Having High Potency against Raltegravir-Resistant Integrase Mutants of HIV-1
  作者：Xue Zhi Zhao、Steven J. Smith、Mathieu Métifiot、Christophe Marchand、Paul L. Boyer、Yves Pommier、Stephen H. Hughes、Terrence R. Burke

  DOI：10.1021/jm5001908

  日期：2014.6.26

  inhibitors to develop compounds that have improved efficacies against recombinant IN in biochemical assays. These new compounds show single-digit nanomolar antiviral potencies against HIV vectors that carry wild-type (WT) IN in a single round replication assay and have improved potency against vectors harboring the major forms of drug resistant IN mutants. These compounds also have low toxicity for cultured

  目前有三种 HIV-1 整合酶 (IN) 链转移抑制剂 (INSTI) 被 FDA 批准用于治疗艾滋病。然而，耐药突变体的出现强调了开发其他药物的必要性，这些药物对现有的耐药突变体具有更高的功效。正如本文所报道的，我们修改了我们最近公开的 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides IN 抑制剂，以开发在生化分析中对重组 IN 具有改进功效的化合物。这些新化合物在单轮复制试验中对携带野生型 (WT) IN 的 HIV 载体显示出个位数的纳摩尔抗病毒效力，并且对携带主要形式的抗药性 IN 突变体的载体具有更高的效力。这些化合物对培养细胞也具有低毒性，在一些情况下，50 /EC 50 ) 大于 10000。通过额外的结构修改，这些化合物有可能产生对已知耐药病毒株有效的临床药物。