benzyl (2S)-2-[[[(4R,5R,6R,8R)-8-(2,4-dioxopyrimidin-1-yl)-5-hydroxy-3,7-dioxaspiro[3.4]octan-6-yl]methoxy-phenoxy-phosphoryl]amino]propanoate | 1532523-79-7

• 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: benzyl (2S)-2-[[[(4R,5R,6R,8R)-8-(2,4-dioxopyrimidin-1-yl)-5-hydroxy-3,7-dioxaspiro[3.4]octan-6-yl]methoxy-phenoxy-phosphoryl]amino]propanoate
• 英文别名: benzyl (2S)-2-[[[(4R,5R,6R,8R)-8-(2,4-dioxopyrimidin-1-yl)-5-hydroxy-1,7-dioxaspiro[3.4]octan-6-yl]methoxy-phenoxyphosphoryl]amino]propanoate
• CAS: 1532523-79-7
• 化学式: C₂₇H₃₀N₃O₁₀P
• 分子量: 587.523
• InChiKey: SXMMLCJPVFOSDH-VNHJONDSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  41
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  162
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  (2S,3R,4R,5R)-3-allyl-4-(benzyloxy)-5-(benzyl-oxymethyl)-2-methoxytetrahydrofuran-3-yl benzoate 在 吡啶 、 N-甲基咪唑 、 甲醇 、 sodium tetrahydroborate 、 sodium periodate 、 四氧化锇 、 N,O-双三甲硅基乙酰胺 、 氢气 、 sodium methylate 、 palladium(II) hydroxide 、 sodium hydride 作用下， 以 四氢呋喃 、 水 、 乙腈 、 叔丁醇 为溶剂， 20.0~25.0 ℃ 、103.42 kPa 条件下， 反应 28.5h， 生成 benzyl (2S)-2-[[[(4R,5R,6R,8R)-8-(2,4-dioxopyrimidin-1-yl)-5-hydroxy-3,7-dioxaspiro[3.4]octan-6-yl]methoxy-phenoxy-phosphoryl]amino]propanoate
  参考文献：
  名称：

  Nucleotide Prodrugs of 2′-Deoxy-2′-spirooxetane Ribonucleosides as Novel Inhibitors of the HCV NS5B Polymerase

  摘要：

  The limited efficacy, in particular against the genotype 1 virus, as well as the variety of side effects associated with the current therapy for hepatitis C virus (HCV) infection necessitates more efficacious drugs. We found that phosphoramidate prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying EC50 values ranging from 0.2 to >98 mu M, measured in the Huh7-replicon cell line, with no apparent cytotoxicity (CC50 > 98.4 mu M). Confirming recent findings, the 2'-spirooxetane moiety was identified as a novel structural motif in the field of anti-HCV nucleosides. A convenient synthesis was developed that enabled the synthesis of a broad set of nucleotide prodrugs with varying substitution patterns. Extensive formation of the triphosphate metabolite was observed in both rat and human hepatocyte cultures. In addition, after oral dosing of several phosphoramidate derivatives of compound 21 to rats, substantial hepatic levels of the active triphosphate metabolite were found.

  DOI：

  10.1021/jm4015422

文献信息

• Nucleotide Prodrugs of 2′-Deoxy-2′-spirooxetane Ribonucleosides as Novel Inhibitors of the HCV NS5B Polymerase
  作者：Tim H. M. Jonckers、Koen Vandyck、Leen Vandekerckhove、Lili Hu、Abdellah Tahri、Steven Van Hoof、Tse-I Lin、Leen Vijgen、Jan Martin Berke、Sophie Lachau-Durand、Bart Stoops、Laurent Leclercq、Gregory Fanning、Bertil Samuelsson、Magnus Nilsson、Åsa Rosenquist、Kenny Simmen、Pierre Raboisson

  DOI：10.1021/jm4015422

  日期：2014.3.13

  The limited efficacy, in particular against the genotype 1 virus, as well as the variety of side effects associated with the current therapy for hepatitis C virus (HCV) infection necessitates more efficacious drugs. We found that phosphoramidate prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying EC50 values ranging from 0.2 to >98 mu M, measured in the Huh7-replicon cell line, with no apparent cytotoxicity (CC50 > 98.4 mu M). Confirming recent findings, the 2'-spirooxetane moiety was identified as a novel structural motif in the field of anti-HCV nucleosides. A convenient synthesis was developed that enabled the synthesis of a broad set of nucleotide prodrugs with varying substitution patterns. Extensive formation of the triphosphate metabolite was observed in both rat and human hepatocyte cultures. In addition, after oral dosing of several phosphoramidate derivatives of compound 21 to rats, substantial hepatic levels of the active triphosphate metabolite were found.