phenyl (ethyloxy-dimethylglycinyl)phosphorochloridate | 840506-41-4

• 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: phenyl (ethyloxy-dimethylglycinyl)phosphorochloridate
• 英文别名: phenyl(ethoxy-dimethylglycinyl)phosphorochloridate；2-phenyl-(ethyl-2-amino-2-methylpropanoate)phosphorochloridate；phenyl-(ethyl-2-amino-2-methylpropanoate)-phosphorochloridate；Ethyl 2-[[chloro(phenoxy)phosphoryl]amino]-2-methylpropanoate
• CAS: 840506-41-4
• 化学式: C₁₂H₁₇ClNO₄P
• 分子量: 305.698
• InChiKey: LYTCPFOHUFMUAU-UHFFFAOYSA-N

物化性质

• 沸点：
  376.5±44.0 °C(Predicted)
• 密度：
  1.253±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  19
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  phenyl (ethyloxy-dimethylglycinyl)phosphorochloridate 在 甲酸 、 叔丁基氯化镁 作用下， 以 四氢呋喃 为溶剂， 反应 21.25h， 生成 2-{[(2R,3S,4R,5R)-2-azido-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-2-methyl-propionic acid ethyl ester
  参考文献：
  名称：

  Application of the Phosphoramidate ProTide Approach to 4‘-Azidouridine Confers Sub-micromolar Potency versus Hepatitis C Virus on an Inactive Nucleoside

  摘要：

  We report the application of our phosphoramidate ProTide technology to the ribonucleoside analogue 4'-azidouridine to generate novel antiviral agents for the inhibition of hepatitis C virus (HCV). 4'-Azidouridine did not inhibit HCV, although 4'-azidocytidine was a potent inhibitor of HCV replication under similar assay conditions. However 4'-azidouridine triphosphate was a potent inhibitor of RNA synthesis by HCV polymerase, raising the question as to whether our phosphoramidate ProTide approach could effectively deliver 4'-azidouridine monophosphate to HCV replicon cells and unleash the antiviral potential of the triphosphate. Twenty-two phosphoramidates were prepared, including variations in the aryl, ester, and amino acid regions. A number of compounds showed sub-micromolar inhibition of HCV in cell culture without detectable cytotoxicity. These results confirm that phosphoramidate ProTides can deliver monophosphates of ribonucleoside analogues and suggest a potential path to the generation of novel antiviral agents against HCV infection. The generic message is that ProTide synthesis from inactive parent nucleosides may be a warranted drug discovery strategy.

  DOI：

  10.1021/jm0613370
• 作为产物：
  描述：

  2-氨基异丁酸乙酯盐酸盐 、 二氯磷酸苯酯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 phenyl (ethyloxy-dimethylglycinyl)phosphorochloridate
  参考文献：
  名称：

  Anti-cancer ProTides: tuning the activity of BVDU phosphoramidates related to thymectacin

  摘要：

  Based on our wide ranging knowledge of phosphoramidate ProTides as anti-viral agents we have tuned the lead anti-cancer agent thymectacin in the ester and amino acid regions and revealed a substantial enhancement in in vitro potency versus colon and prostate cancer cell lines. Twelve analogues have been reported, with yields of 29-78%. The compounds are fully characterised and data clearly reveal the presence of two phosphate diastereoisomers, as expected, in roughly equi-molar proportions. The compounds were evaluated in tissue culture versus three different tumour cell lines, using thymectacin as the control. It is notable that minor structural modification of the parent phenyl methoxyalaninyl structure of thymectacin leads to significant enhancements in potency. In particular, replacement of the methyl ester moiety in the lead by a benzyl ester gave a 175-fold boost in potency versus colon cancer HT115. This derivative emerges as a low micromolar inhibitor of HT115 cells and a new lead for further optimisation. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.02.041

文献信息

• [EN] COMPOSITIONS AND METHODS FOR TREATING HCV INFECTION<br/>[FR] COMPOSITIONS ET MÉTHODES POUR LE TRAITEMENT D'UNE INFECTION À VHC
  申请人：ABBVIE INC

  公开号：WO2018093717A1

  公开（公告）日：2018-05-24

  The present invention features compositions and methods for the treatment of HCV infection. In one embodiment, the compositions of the invention comprise (1) Compound 1 or a pharmaceutically acceptable salt thereof, and (2) Compound 2a or a pharmaceutically acceptable salt thereof. In another embodiment, the compositions of the invention comprise (1) Compound 1 or a pharmaceutically acceptable salt thereof, and (2) a prodrug of Compound 2a (e.g., one of Compounds 2b-2k or Examples 3-1 to 3-10) or a pharmaceutically acceptable salt of said prodrug.

  本发明提供了用于治疗HCV感染的组合物和方法。在一个实施例中，发明的组合物包括（1）化合物1或其药用可接受的盐，以及（2）化合物2a或其药用可接受的盐。在另一个实施例中，发明的组合物包括（1）化合物1或其药用可接受的盐，以及（2）化合物2a的前药（例如，化合物2b-2k中的一种或示例3-1至3-10）或所述前药的药用可接受的盐。
• Chemical compounds
  申请人：NuCana BioMed Limited

  公开号：EP2955190A2

  公开（公告）日：2015-12-16

  Phosphoramidate derivatives of nucleotides and their use in the treatment of cancer are described. The base moieties of, for example, each of deoxyuridine, cytarabine, gemcitabine and citidine may be substituted at the 5-position. The phosphoramidate moiety has attached to the P atom an aryl-O moiety and an α-amino acid moiety. The α-amino acid moiety may correspond to or be derived from either a naturally occurring or a non-naturally occurring amino acid.

  本文介绍了核苷酸的磷酰胺衍生物及其在治疗癌症中的应用。例如，脱氧尿苷、阿糖胞苷、吉西他滨和枸橼酸的碱基可在 5 位被取代。磷酰胺基团的 P 原子上连接有一个芳基-O 基团和一个α-氨基酸基团。α-氨基酸分子可以是天然氨基酸或非天然氨基酸，也可以来自天然氨基酸。
• CHEMICAL COMPOUNDS
  申请人：NuCana plc

  公开号：EP3486251A1

  公开（公告）日：2019-05-22

  Phosphoramidate derivatives of nucleotides and their use in the treatment of cancer are described. The base moieties of, for example, each of deoxyuridine, cytarabine, gemcitabine and citidine may be substituted at the 5-position. The phosphoramidate moiety has attached to the P atom an aryl-O moiety and an α-amino acid moiety. The α-amino acid moiety may correspond to or be derived from either a naturally occurring or a non-naturally occurring amino acid.

  本文介绍了核苷酸的磷酰胺衍生物及其在治疗癌症中的应用。例如，脱氧尿苷、阿糖胞苷、吉西他滨和枸橼酸的碱基可在 5 位被取代。磷酰胺基团的 P 原子上连接有一个芳基-O 基团和一个α-氨基酸基团。α-氨基酸分子可以是天然氨基酸或非天然氨基酸，也可以来自天然氨基酸。
• Phosphoramidate ProTides of the Anticancer Agent FUDR Successfully Deliver the Preformed Bioactive Monophosphate in Cells and Confer Advantage over the Parent Nucleoside
  作者：Christopher McGuigan、Paola Murziani、Magdalena Slusarczyk、Blanka Gonczy、Johan Vande Voorde、Sandra Liekens、Jan Balzarini

  DOI：10.1021/jm200815w

  日期：2011.10.27

  The fluorinated pyrimidine family of nucleosides continues to represent major current chemotherapeutic agents for treating solid tumors. We herein report their phosphate prodrugs, ProTides, as promising new derivatives, which partially bypass the dependence of the current drugs on active transport and nucleoside kinase-mediated activation. They are also resistant to metabolic deactivation by phosphorolytic enzymes. We report 39 ProTides of the fluorinated pyrimidine FUDR with variation in the aryl, ester, and amino acid. regions. Notably, only certain ProTide motifs are successful in delivering the nucleoside monophosphate into intact cells. We also find that the ProTides retain activity in mycoplasma infected cells, unlike FUDR. Data suggest these compounds to be worthy of further progression.
• Discovery of a 2′-fluoro-2′- C -methyl C -nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties
  作者：Thorsten A. Kirschberg、Sammy Metobo、Michael O. Clarke、Vangelis Aktoudianakis、Darius Babusis、Ona Barauskas、Gabriel Birkus、Thomas Butler、Daniel Byun、Gregory Chin、Edward Doerffler、Thomas E. Edwards、Martijn Fenaux、Rick Lee、Willard Lew、Michael R. Mish、Eisuke Murakami、Yeojin Park、Neil H. Squires、Neeraj Tirunagari、Ting Wang、Mark Whitcomb、Jie Xu、Huiling Yang、Hong Ye、Lijun Zhang、Todd C. Appleby、Joy Y. Feng、Adrian S. Ray、Aesop Cho、Choung U. Kim

  DOI：10.1016/j.bmcl.2017.02.037

  日期：2017.4

  A series of 2'-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2'-fluoro-2'-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacolcinetic properties including efficient liver delivery in animals. (C) 2017 Published by Elsevier Ltd.