6-(3-chloro-4-fluorobenzyl)-3,4-bis[(2,2-dimethylpropanoyl)oxy]-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylic 2,2-dimethylpropanoic anhydride | 1374009-23-0

• 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: 6-(3-chloro-4-fluorobenzyl)-3,4-bis[(2,2-dimethylpropanoyl)oxy]-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylic 2,2-dimethylpropanoic anhydride
• 英文别名: 6-(3-chloro-4-fluorobenzyl)-5-oxo-3,4-bis(pivalyloxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylic pivalic anhydride；2,2-Dimethylpropanoyl 6-[(3-chloro-4-fluorophenyl)methyl]-3,4-bis(2,2-dimethylpropanoyloxy)-5-oxo-7,8-dihydro-2,6-naphthyridine-1-carboxylate；2,2-dimethylpropanoyl 6-[(3-chloro-4-fluorophenyl)methyl]-3,4-bis(2,2-dimethylpropanoyloxy)-5-oxo-7,8-dihydro-2,6-naphthyridine-1-carboxylate
• CAS: 1374009-23-0
• 化学式: C₃₁H₃₆ClFN₂O₈
• 分子量: 619.087
• InChiKey: GIFZRQRDZTYGAJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  43
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  129
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  6-(3-chloro-4-fluorobenzyl)-3,4-bis[(2,2-dimethylpropanoyl)oxy]-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylic 2,2-dimethylpropanoic anhydride 在 potassium tert-butylate 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 、 甲苯 为溶剂， 反应 3.25h， 生成 (4R)-11-(3-chloro-4-fluorobenzyl)-9-methoxy-2,5,5-trimethyl-4-((tetrahydro-2H-pyran-2-yl)oxy)-3,4,5,6,12,13-hexahydro-2H-[1,4]diazocino[2,1-a][2,6]naphthyridine-1,8,10(11H)-trione
  参考文献：
  名称：

  强大的HIV-1整合酶抑制剂的不对称合成。

  摘要：

  描述了有效的HIV-1整合酶抑制剂5的实际不对称全合成的发展。关键的转化包括以高效方式构建萘啶核心，然后将8元环环化。还描述了中间体和最终化合物5的阻转异构体的控制。

  DOI：

  10.1021/acs.joc.6b01229
• 作为产物：
  描述：

  1-(3-chloro-4-fluorobenzyl)-3-(phenylsulfinyl)piperidin-2-one 在 盐酸 、 甲烷磺酸 、 乙酸酐 、 三乙胺 、 N,N-二异丙基乙胺 、 sodium hydroxide 、 lithium tert-butoxide 作用下， 以 四氢呋喃 、 乙醇 、 水 、 甲苯 、 乙腈 为溶剂， 反应 49.45h， 生成 6-(3-chloro-4-fluorobenzyl)-3,4-bis[(2,2-dimethylpropanoyl)oxy]-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylic 2,2-dimethylpropanoic anhydride
  参考文献：
  名称：

  2-吡啶酮类缩醛胺的发现：前药策略，以推进第二代HIV-1整合酶链转移抑制剂。

  摘要：

  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。

  DOI：

  10.1021/acs.jmedchem.5b01037

文献信息

• [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。
• 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。
• 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.
• HIV INTEGRASE INHIBITORS
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP2632454A1

  公开（公告）日：2013-09-04
• [EN] HIV INTEGRASE INHIBITORS<br/>[FR] INHIBITEURS D'INTÉGRASE DE VIH
  申请人：MERCK SHARP & DOHME

  公开号：WO2012058173A1

  公开（公告）日：2012-05-03

  Tricyclic compounds of Formula I are inhibitors of HIV integrase and inhibitors of HIV replication: (I), wherein R1A, R1B, R1C, R2A, R2B, R3A, R3B, R4, R5 and R6 are defined herein. The compounds are useful for the prophylaxis or treatment of infection by HIV and the prophylaxis, treatment, or delay in the onset of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.