(2S)-benzyl-2-(((((4R,5R,7R,8R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-8-hydroxy-1,6-dioxaspiro[3.4]octan-7-yl)methoxy)(phenoxy)phosphoryl)amino)butanoate | 1255860-37-7

• 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: (2S)-benzyl-2-(((((4R,5R,7R,8R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-8-hydroxy-1,6-dioxaspiro[3.4]octan-7-yl)methoxy)(phenoxy)phosphoryl)amino)butanoate
• 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]butanoate
• CAS: 1255860-37-7
• 化学式: C₂₈H₃₂N₃O₁₀P
• 分子量: 601.55
• InChiKey: QXIHDDYMYBYCMH-HBERQUHCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  42
• 可旋转键数：
  13
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.39
• 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 (2S)-benzyl-2-(((((4R,5R,7R,8R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-8-hydroxy-1,6-dioxaspiro[3.4]octan-7-yl)methoxy)(phenoxy)phosphoryl)amino)butanoate
  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

• Uracyl Spirooxetane Nucleosides
  申请人：Jonckers Tim Hugo Maria

  公开号：US20120065156A1

  公开（公告）日：2012-03-15

  Compounds of the formula I: including any possible stereoisomers thereof, wherein: R 4 is a monophosphate, diphosphate or triphosphate ester; or R 4 is R 7 is optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted indolyl; R 8 and R 8′ are hydrogen, C 1 -C 6 alkyl, benzyl, or phenyl; or R 8 and R 8′ form C 3 -C 7 cycloalkyl; R 9 is C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, phenyl or phenyl-C 1 -C 6 alkyl, wherein the phenyl moiety in phenyl or phenyl-C 1 -C 6 alkyl is optionally substituted; or a pharmaceutically acceptable salt or solvate thereof; pharmaceutical formulations and the use of compounds I as HCV inhibitors.

  化合物I的公式，包括其任何可能的立体异构体，其中： R4是单磷酸酯、二磷酸酯或三磷酸酯；或R4是R7，R7是可选取代的苯基、可选取代的萘基或可选取代的吲哚基； R8和R8'是氢、C1-C6烷基、苄基或苯基；或R8和R8'形成C3-C7环烷基； R9是C1-C10烷基、C3-C7环烷基、苯基或苯基-C1-C6烷基，其中苯基或苯基-C1-C6烷基中的苯基基团是可选的； 或其药学上可接受的盐或溶剂； 化合物I作为HCV抑制剂的药物配方和用途。
• US8481510B2
  申请人：——

  公开号：US8481510B2

  公开（公告）日：2013-07-09
• US8933052B2
  申请人：——

  公开号：US8933052B2

  公开（公告）日：2015-01-13
• 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.