ethyl 3-(2-((chloro(((S)-1-ethoxy-1-oxopropan-2-yl)amino)-phosphoryl)oxy)phenyl)propanoate | 1412427-04-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: ethyl 3-(2-((chloro(((S)-1-ethoxy-1-oxopropan-2-yl)amino)-phosphoryl)oxy)phenyl)propanoate
• 英文别名: ethyl 3-(2-((chloro(((R)-1-ethoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)phenyl)propanoate；ethyl (2S)-2-[[chloro-[2-(3-ethoxy-3-oxopropyl)phenoxy]phosphoryl]amino]propanoate
• CAS: 1412427-04-3
• 化学式: C₁₆H₂₃ClNO₆P
• 分子量: 391.788
• InChiKey: LJNAYYDEGFIOKH-UNHBDAOFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  25
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  90.9
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ethyl 3-(2-((chloro(((S)-1-ethoxy-1-oxopropan-2-yl)amino)-phosphoryl)oxy)phenyl)propanoate 在 叔丁基氯化镁 、 三乙胺 作用下， 以 四氢呋喃 、 乙醚 为溶剂， 反应 93.0h， 生成 ethyl 3-(2-(((R)-(((2R,3R,4R,5R)-5-(2,6-diamino-9H-pu r in-9-y l )-3, 4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(((S)-1-ethoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)phenyl)propanoate
  参考文献：
  名称：

  [EN] PURINE MONOPHOSPHATE PRODRUGS FOR TREATMENT OF VIRAL INFECTIONS
  [FR] PROMÉDICAMENTS À BASE DE MONOPHOSPHATE DE PURINE POUR TRAITER LES INFECTIONS VIRALES

  摘要：

  公开号：

  WO2012158811A3
• 作为产物：
  描述：

  氢化肉桂酸内酯 在 硫酸 、 三乙胺 、 三氯氧磷 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 反应 36.0h， 生成 ethyl 3-(2-((chloro(((S)-1-ethoxy-1-oxopropan-2-yl)amino)-phosphoryl)oxy)phenyl)propanoate
  参考文献：
  名称：

  β-d-2′-C-Methyl-2,6-diaminopurine Ribonucleoside Phosphoramidates are Potent and Selective Inhibitors of Hepatitis C Virus (HCV) and Are Bioconverted Intracellularly to Bioactive 2,6-Diaminopurine and Guanosine 5′-Triphosphate Forms

  摘要：

  The conversion of selected beta-d-2,6-diaminopurine nucleosides (DAPNs) to their phosphoramidate prodrug (PD) substantially blocks the conversion to the G-analog allowing for the generation of two bioactive nucleoside triphosphates (NTPs) in human hepatocytes. A variety of 2'-C-methyl DAPN-PDs were prepared and evaluated for inhibition of HCV viral replication in Huh-7 cells, cytotoxicity in various cell lines, and cellular pharmacology in both Huh-7 and primary human liver cells. The DAPN-PDs were pan-genotypic, effective against various HCV resistant mutants, and resistant variants could not be selected. 2'-C-Me-DAPN-TP and 2'-C-Me-GTP were chain terminators for genotype 1b HCV-pol, and single nucleotide incorporation assays revealed that 2'-C-Me-DAPN-TP was incorporated opposite U. No cytotoxicity was observed with our DAPN-PD when tested up to 50 mu M. A novel, DAPN-PD, 15c, has been selected for further evaluation because of its good virologic and toxicologic profile and its ability to deliver two active metabolites, potentially simplifying HCV treatment.

  DOI：

  10.1021/jm501874e

文献信息

• Adenosine Dioxolane Nucleoside Phosphoramidates As Antiviral Agents for Human Immunodeficiency and Hepatitis B Viruses
  作者：Lavanya Bondada、Mervi Detorio、Leda Bassit、Sijia Tao、Catherine M. Montero、Tyana M. Singletary、Hongwang Zhang、Longhu Zhou、Jong-Hyun Cho、Steven J. Coats、Raymond F. Schinazi

  DOI：10.1021/ml4001497

  日期：2013.8.8

  currently six nucleoside reverse transcriptase inhibitors (NRTI) that are FDA approved for human clinical use and these remain the backbone of current HIV therapy. In order for these NRTIs to be effective they need to be phosphorylated consecutively by cellular kinases to their triphosphate forms. Herein, we report the synthesis of C-6 modified (-)-beta-D-(2R,4R)-1,3-dioxolane adenosine nucleosides and their

  FDA目前批准了六种核苷类逆转录酶抑制剂（NRTI）供人类临床使用，它们仍然是当前HIV治疗的基础。为了使这些NRTI有效，它们需要被细胞激酶连续磷酸化为其三磷酸形式。在这里，我们报告了C-6修饰的（-）-β-D-（2R，4R）-1,3-二氧戊环腺苷核苷及其核苷酸的合成，包括我们新的氨基磷酸酯前药技术。我们已经在氨基磷酸酯的酚部分上引入了侧链部分，以降低潜在的毒性。与相应的亲本核苷相比，合成的氨基磷酸酯显示出比HIV-1高出3600倍的效价，而与HBV相比则具有高达300倍的效价。在测试的各种细胞系统中，直至100μM都未观察到细胞毒性，除了化合物17和18在Huh-7细胞中的CC50分别为7.3和12μM。这些新的氨基磷酸酯核苷具有改善的和显着的双重抗病毒活性，其部分原因是三磷酸腺苷二氧戊环的细胞内形成增加。
• PURINE MONOPHOSPHATE PRODRUGS FOR TREATMENT OF VIRAL INFECTIONS
  申请人：Schinazi Raymond F.

  公开号：US20140212382A1

  公开（公告）日：2014-07-31

  The present invention is directed to compounds, compositions and methods for treating or preventing viral infections using nucleoside analog monophosphate prodrugs. More specifically, HCV, Norovirus, Saporovirus, Dengue virus, Chikungunya virus and Yellow fever in human patients or other animal hosts. The compounds are certain 2,6-diamino 2-C-methyl purine nucleoside monophosphate prodrugs and modified prodrug analogs, and pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof. In particular, the compounds show potent antiviral activity against HCV, Norovirus, Saporovirus, Dengue virus, Chikungunya virus and Yellow fever. This invention teaches how to modify the metabolic pathway of 2,6-diamino 2′-C-methyl purine and deliver nucleotide triphosphate(s) to polymerases at heretofore unobtainable therapeutically-relevant concentrations.

  本发明涉及使用核苷类似物单磷酸前药治疗或预防病毒感染的化合物、组合物和方法。更具体地说，本发明适用于治疗人类患者或其他动物宿主的丙型肝炎病毒、诺如病毒、萨波罗病毒、登革热病毒、基孔肯雅病毒和黄热病等病毒感染。所述化合物是特定的2,6-二氨基2-C-甲基嘌呤核苷单磷酸前药和修饰的前药类似物，以及其药学上可接受的盐、前药和其他衍生物。特别地，所述化合物对丙型肝炎病毒、诺如病毒、萨波罗病毒、登革热病毒、基孔肯雅病毒和黄热病毒表现出强效的抗病毒活性。本发明教导如何修改2,6-二氨基2'-C-甲基嘌呤的代谢途径，并以迄今为止无法获得的治疗相关浓度向聚合酶提供核苷酸三磷酸。
• β-<scp>d</scp>-2′-<i>C</i>-Methyl-2,6-diaminopurine Ribonucleoside Phosphoramidates are Potent and Selective Inhibitors of Hepatitis C Virus (HCV) and Are Bioconverted Intracellularly to Bioactive 2,6-Diaminopurine and Guanosine 5′-Triphosphate Forms
  作者：Longhu Zhou、Hong-wang Zhang、Sijia Tao、Leda Bassit、Tony Whitaker、Tamara R. McBrayer、Maryam Ehteshami、Sheida Amiralaei、Ugo Pradere、Jong Hyun Cho、Franck Amblard、Drew Bobeck、Mervi Detorio、Steven J. Coats、Raymond F. Schinazi

  DOI：10.1021/jm501874e

  日期：2015.4.23

  The conversion of selected beta-d-2,6-diaminopurine nucleosides (DAPNs) to their phosphoramidate prodrug (PD) substantially blocks the conversion to the G-analog allowing for the generation of two bioactive nucleoside triphosphates (NTPs) in human hepatocytes. A variety of 2'-C-methyl DAPN-PDs were prepared and evaluated for inhibition of HCV viral replication in Huh-7 cells, cytotoxicity in various cell lines, and cellular pharmacology in both Huh-7 and primary human liver cells. The DAPN-PDs were pan-genotypic, effective against various HCV resistant mutants, and resistant variants could not be selected. 2'-C-Me-DAPN-TP and 2'-C-Me-GTP were chain terminators for genotype 1b HCV-pol, and single nucleotide incorporation assays revealed that 2'-C-Me-DAPN-TP was incorporated opposite U. No cytotoxicity was observed with our DAPN-PD when tested up to 50 mu M. A novel, DAPN-PD, 15c, has been selected for further evaluation because of its good virologic and toxicologic profile and its ability to deliver two active metabolites, potentially simplifying HCV treatment.
• [EN] PURINE MONOPHOSPHATE PRODRUGS FOR TREATMENT OF VIRAL INFECTIONS<br/>[FR] PROMÉDICAMENTS À BASE DE MONOPHOSPHATE DE PURINE POUR TRAITER LES INFECTIONS VIRALES
  申请人：RFS PHARMA LLC

  公开号：WO2012158811A3

  公开（公告）日：2013-02-28