(1R,2R,5S)-8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-((S)-2-hydroxypropyl)-9',10'-dihydro-1'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(2'H,8'H)-trione | 1549802-58-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: (1R,2R,5S)-8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-((S)-2-hydroxypropyl)-9',10'-dihydro-1'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(2'H,8'H)-trione
• 英文别名: (1r,2r,5s)-8'-(3-Chloro-4-Fluorobenzyl)-6'-Hydroxy-2'-[(2s)-2-Hydroxypropyl]-9',10'-Dihydro-2'h-Spiro[bicyclo[3.1.0]hexane-2,3'-Imidazo[5,1-A][2,6]naphthyridine]-1',5',7'(8'h)-Trione；(1'R,3R,5'S)-8-[(3-chloro-4-fluorophenyl)methyl]-6-hydroxy-2-[(2S)-2-hydroxypropyl]spiro[9,10-dihydroimidazo[5,1-a][2,6]naphthyridine-3,2'-bicyclo[3.1.0]hexane]-1,5,7-trione
• CAS: 1549802-58-5
• 化学式: C₂₅H₂₅ClFN₃O₅
• 分子量: 501.942
• InChiKey: SUYSDXIXCVFTRC-UCVJIWRCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.46
• 重原子数：
  35.0
• 可旋转键数：
  4.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  103.08
• 氢给体数：
  2.0
• 氢受体数：
  6.0

制备方法与用途

一种有效的HIV整合酶链转移抑制剂（InSTI）在HIV复制试验中的IC50为8 nM，显示E92Q、Y143R、Q148R、Q148K、N155H和G140S-Q148H突变倍数变化分别为1/1/1/2/4与野生型酶相比。该抑制剂还表现出所需的病毒学特征和临床前药代动力学特性。

反应信息

• 作为反应物：
  描述：

  (1R,2R,5S)-8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-((S)-2-hydroxypropyl)-9',10'-dihydro-1'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(2'H,8'H)-trione 在 四氯三氧化二磷 作用下， 以 四氢呋喃 为溶剂， 反应 0.67h， 以77%的产率得到(S)-1-((1R,2R,5S)-8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-1',5',7'-trioxo-7',8',9',10'-tetrahydro-1'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridin]-2'(5'H)-yl)propan-2-yl dihydrogen phosphate
  参考文献：
  名称：

  [EN] SUBSTITUTED NAPHTHYRIDINEDIONE DERIVATIVES AS HIV INTEGRASE INHIBITORS
  [FR] DÉRIVÉS DE NAPHTHYRIDINEDIONE SUBSTITUÉS EN TANT QU'INHIBITEURS DE L'INTÉGRASE DU VIH

  摘要：

  本发明涉及取代萘啶二酮衍生物及其药用盐。本发明还涉及包含至少一种取代萘啶二酮衍生物的组合物，以及使用该取代萘啶二酮衍生物治疗或预防受试者的HIV感染的方法。

  公开号：

  WO2014018449A1
• 作为产物：
  描述：

  (1R,5S)-bicyclo[3.1.0]hexan-2-one 、 (S)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N-(2-hydroxypropyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 在 正硅酸甲酯 、 三氟甲磺酸三甲基硅酯 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 生成 (1R,2R,5S)-8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-((S)-2-hydroxypropyl)-9',10'-dihydro-1'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(2'H,8'H)-trione
  参考文献：
  名称：

  Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV

  摘要：

  HIV integrase strand transfer inhibitcirs (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naive patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.02.039

文献信息

• Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors
  作者：Izzat T. Raheem、Abbas M. Walji、Daniel Klein、John M. Sanders、David A. Powell、Pravien Abeywickrema、Guillaume Barbe、Amrith Bennet、Sophie−Dorothee Clas、David Dubost、Mark Embrey、Jay Grobler、Michael J. Hafey、Timothy J. Hartingh、Daria J. Hazuda、Michael D. Miller、Keith P. Moore、Natasa Pajkovic、Sangita Patel、Vanessa Rada、Paul Rearden、John D. Schreier、John Sisko、Thomas G. Steele、Jean-François Truchon、John Wai、Min Xu、Paul J. Coleman

  DOI：10.1021/acs.jmedchem.5b01037

  日期：2015.10.22

  resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical

  寻找类似于HIV整合酶链转移抑制所必需的关键的两种金属结合药效基团的新分子构建体，是药物发现领域中一个充满活力的研究领域。在这里，我们介绍了一种基于MK-0536的2-吡啶酮核心的新型HIV整合酶链转移抑制剂的发现。这些努力导致鉴定出具有出色抗病毒活性和临床前药代动力学特征的两种先导化合物，以支持每天一次的人类剂量预测。在狗中进行的剂量递增PK研究表明，口服吸收受限存在重大问题，需要创新的前药策略来增强母体分子的大剂量血浆暴露。
• SUBSTITUTED NAPHTHYRIDINEDIONE DERIVATIVES AS HIV INTEGRASE INHIBITORS
  申请人：MERCK SHARP & DOHME CORP.

  公开号：US20150218164A1

  公开（公告）日：2015-08-06

  The present invention relates to Substituted Naphthyridinedione Derivatives and pharmaceutically acceptable salts thereof. The present invention also relates to compositions comprising at least one Substituted Naphthyridinedione Derivative, and methods of using the Substituted Naphthyridinedione Derivatives for treating or preventing HIV infection in a subject.

  本发明涉及取代萘啶二酮衍生物及其药学上可接受的盐。本发明还涉及包含至少一种取代萘啶二酮衍生物的组合物，以及使用该取代萘啶二酮衍生物治疗或预防受HIV感染的受试者的方法。
• [EN] SUBSTITUTED NAPHTHYRIDINEDIONE DERIVATIVES AS HIV INTEGRASE INHIBITORS<br/>[FR] DÉRIVÉS DE NAPHTHYRIDINEDIONE SUBSTITUÉS EN TANT QU'INHIBITEURS DE L'INTÉGRASE DU VIH
  申请人：MERCK SHARP & DOHME

  公开号：WO2014018449A1

  公开（公告）日：2014-01-30

  The present invention relates to Substituted Naphthyridinedione Derivatives and pharmaceutically acceptable salts thereof. The present invention also relates to compositions comprising at least one Substituted Naphthyridinedione Derivative, and methods of using the Substituted Naphthyridinedione Derivatives for treating or preventing HIV infection in a subject.

  本发明涉及取代萘啶二酮衍生物及其药用盐。本发明还涉及包含至少一种取代萘啶二酮衍生物的组合物，以及使用该取代萘啶二酮衍生物治疗或预防受试者的HIV感染的方法。
• Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV
  作者：John D. Schreier、Mark W. Embrey、Izzat T. Raheem、Guillaume Barbe、Louis-Charles Campeau、David Dubost、Jamie McCabe Dunn、Jay Grobler、Timothy J. Hartingh、Daria J. Hazuda、Daniel Klein、Michael D. Miller、Keith P. Moore、Natalie Nguyen、Natasa Pajkovic、David A. Powell、Vanessa Rada、John M. Sanders、John Sisko、Thomas G. Steele、John Wai、Abbas Walji、Min Xu、Paul J. Coleman

  DOI：10.1016/j.bmcl.2017.02.039

  日期：2017.5

  HIV integrase strand transfer inhibitcirs (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naive patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction. (C) 2017 Elsevier Ltd. All rights reserved.