isopropyl O-[(5S)-5-[(4-amino-2-oxopyrimidin-1(2H)-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-(L)-tyrosinate trifluoroacetate | 1322511-06-7

• 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: isopropyl O-[(5S)-5-[(4-amino-2-oxopyrimidin-1(2H)-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-(L)-tyrosinate trifluoroacetate
• 英文别名: (L)-Tyr((S)-cHPMPC)-O-i-Pr*TFA；propan-2-yl (2S)-2-amino-3-(4-{[(2S,5S)-5-[(4-amino-2-oxo-2H-pyrimidin-1-yl)methyl]-2-oxo-1,4,2λ5-dioxaphosphinan-2-yl]oxy}phenyl)-propanoate trifluoroacetate；propan-2-yl (2S)-2-amino-3-[4-[[(2S,5S)-5-[(4-amino-2-oxopyrimidin-1-yl)methyl]-2-oxo-1,4,2lambda5-dioxaphosphinan-2-yl]oxy]phenyl]propanoate;2,2,2-trifluoroacetic acid；propan-2-yl (2S)-2-amino-3-[4-[[(2S,5S)-5-[(4-amino-2-oxopyrimidin-1-yl)methyl]-2-oxo-1,4,2λ5-dioxaphosphinan-2-yl]oxy]phenyl]propanoate;2,2,2-trifluoroacetic acid
• CAS: 1322511-06-7
• 化学式: C₂HF₃O₂*C₂₀H₂₇N₄O₇P
• 分子量: 580.455
• InChiKey: IHPIWWSCALWUBV-ICAXTDCASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.93
• 重原子数：
  39
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  193
• 氢给体数：
  3
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  isopropyl O-[(5S)-5-[(4-amino-2-oxopyrimidin-1(2H)-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-N-(tert-butoxycarbonyl)-(L)-tyrosinate 、 三氟乙酸 以 二氯甲烷 为溶剂， 生成 isopropyl O-[(5S)-5-[(4-amino-2-oxopyrimidin-1(2H)-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-(L)-tyrosinate trifluoroacetate 、 isopropyl O-[(5S)-5-[(4-amino-2-oxopyrimidin-1(2H)-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-(L)-tyrosinate trifluoroacetate
  参考文献：
  名称：

  TYROSINE-BASED PRODRUGS OF ANTIVIRAL AGENTS

  摘要：

  提供了一种基于酪氨酸的（磷酰甲氧基烷基）嘌呤或嘧啶共轭物。在某些实施例中，该共轭物包括（S）-9-（3-羟基-2-磷酰甲氧基丙基）腺嘌呤或其胞嘧啶类似物的酪氨酸基氨基酸或二肽基团。还提供了一种基于Boc保护氨基酸或二肽合成这种共轭物的方法。此外，提供了一种通过包括酯交换的过程将（S，S）-对映异构体异构化为氨基酸或二肽基共轭物的（S，R）-对映异构体的方法。还提供了一种基于（磷酰甲氧基烷基）嘌呤或嘧啶共轭物来抑制病毒感染和治疗病毒感染的方法。

  公开号：

  US20110263535A1

文献信息

• TYROSINE-BASED PRODRUGS OF ANTIVIRAL AGENTS
  申请人：McKenna Charles E.

  公开号：US20110263535A1

  公开（公告）日：2011-10-27

  A tyrosine-based (phosphonylmethoxyalkyl)purine or -pyrimidine conjugate is provided. In some embodiments, the conjugate includes tyrosine based amino acid or dipeptide moieties of (S)-9-(3-hydroxy-2-phosphonyl-methoxypropyl)adenine or its cytosine analogue. A method of synthesizing such conjugates based on Boc-protected amino acid or dipeptides is also provided. In addition, a method of isomerizing an (S,S)-diastereoisomer to an (S,R)-diastereoisomer of an amino acid-based or dipeptide-based conjugate by a process including transesterification is provided. A method of inhibiting viral infection and a method of treating viral infection based on (phosphonylmethoxyalkyl)purine or -pyrimidine conjugates is also provided.

  提供了一种基于酪氨酸的（磷酰甲氧基烷基）嘌呤或嘧啶共轭物。在某些实施例中，该共轭物包括（S）-9-（3-羟基-2-磷酰甲氧基丙基）腺嘌呤或其胞嘧啶类似物的酪氨酸基氨基酸或二肽基团。还提供了一种基于Boc保护氨基酸或二肽合成这种共轭物的方法。此外，提供了一种通过包括酯交换的过程将（S，S）-对映异构体异构化为氨基酸或二肽基共轭物的（S，R）-对映异构体的方法。还提供了一种基于（磷酰甲氧基烷基）嘌呤或嘧啶共轭物来抑制病毒感染和治疗病毒感染的方法。
• Tyrosine-Based 1-(<i>S</i>)-[3-Hydroxy-2-(phosphonomethoxy)propyl]cytosine and -adenine ((<i>S</i>)-HPMPC and (<i>S</i>)-HPMPA) Prodrugs: Synthesis, Stability, Antiviral Activity, and in Vivo Transport Studies
  作者：Valeria M. Zakharova、Michaela Serpi、Ivan S. Krylov、Larryn W. Peterson、Julie M. Breitenbach、Katherine Z. Borysko、John C. Drach、Mindy Collins、John M. Hilfinger、Boris A. Kashemirov、Charles E. McKenna

  DOI：10.1021/jm2001426

  日期：2011.8.25

  Eight novel single amino acid (6-11) and dipeptide (12, 13) tyrosine P-O esters of cyclic cidofovir ((S)-cHPMPC, 4) and its cyclic adenine analogue ((S)-cHPMPA, 3) were synthesized and evaluated as prodrugs. In vitro IC50 values for the prodrugs (<0.1-50 mu M) vs vaccinia, cowpox, human cytomegalovirus, and herpes simplex type 1 virus were compared to those for the parent drugs ((S)-HPMPC, 2; (S)HPMPA, 1; IC50 0.3-35 mu M); there was no cytoxicity with KB or HFF cells at <= 100 mu M. The prodrugs exhibited a wide range of half-lives in rat intestinal homogenate at pH 6.5 (<30-1732 min) with differences of 3-10x between phostonate diastereomers. The tyrosine allcylamide derivatives of 3 and 4 were the most stable. (L)-Tyr-NH-i-Bu cHPMPA (11) was converted in rat or mouse plasma solely to two active metabolites and had significantly enhanced oral bioavailability vs parent drug 1 in a mouse model (39% vs <5%).