ethyl 3-(2-(((S)-(((2R,3R,4R,5R)-5-(2,6-diamino-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(((S)-1-ethoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)phenyl)-propanoate | 1412427-09-8

• 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-(((S)-(((2R,3R,4R,5R)-5-(2,6-diamino-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(((S)-1-ethoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)phenyl)-propanoate
• 英文别名: (Sp)-ethyl 3-(2-(((((2S,3R,4R,5R)-5-(2,6-diamino-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(((S)-1-ethoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)phenyl)propanoate；ethyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,6-diaminopurin-9-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy-[2-(3-ethoxy-3-oxopropyl)phenoxy]phosphoryl]amino]propanoate
• CAS: 1412427-09-8
• 化学式: C₂₇H₃₈N₇O₁₀P
• 分子量: 651.613
• InChiKey: KYWQWWDOIOCVGA-IROPIVQASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  45
• 可旋转键数：
  16
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  246
• 氢给体数：
  5
• 氢受体数：
  16

反应信息

• 作为产物：
  描述：

  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 在 三氟乙酸 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 以39%的产率得到ethyl 3-(2-(((S)-(((2R,3R,4R,5R)-5-(2,6-diamino-9H-purin-9-yl)-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：

  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

• 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.