(4-fluorophenoxy)((1S)-(1-methoxycarbonylethyl)amino)phosphinyl chloride | 147907-39-9

• 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: (4-fluorophenoxy)((1S)-(1-methoxycarbonylethyl)amino)phosphinyl chloride
• 英文别名: methyl (2S)-2-[[chloro-(4-fluorophenoxy)phosphoryl]amino]propanoate
• CAS: 147907-39-9
• 化学式: C₁₀H₁₂ClFNO₄P
• 分子量: 295.635
• InChiKey: UGDDGQXFCWHDCA-QNUGLTPUSA-N

物化性质

• 沸点：
  356.4±52.0 °C(Predicted)
• 密度：
  1.372±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (4-fluorophenoxy)((1S)-(1-methoxycarbonylethyl)amino)phosphinyl chloride 在 N-甲基咪唑 、 溴 作用下， 以 四氢呋喃 为溶剂， 生成 methyl (2S)-2-[[[(2S,3S,5R)-3-azido-5-(5-bromo-6-methoxy-5-methyl-2,4-dioxo-hexahydropyrimidin-1-yl)tetrahydrofuran-2-yl]methoxy-(4-fluorophenoxy)phosphoryl]amino]propanoate
  参考文献：
  名称：

  Benyumov, Alexey O.; Venkatachalam, Taracad K.; Grigoriants, Olga O., Arzneimittel-Forschung/Drug Research, 2005, vol. 55, # 2, p. 114 - 122

  摘要：

  DOI：
• 作为产物：
  描述：

  4-氟苯酚 在 三乙胺 、 三氯氧磷 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 反应 2.0h， 生成 (4-fluorophenoxy)((1S)-(1-methoxycarbonylethyl)amino)phosphinyl chloride
  参考文献：
  名称：

  一种前药化合物及其在治疗癌症方面的应用

  摘要：

  本发明提供了式(I)的化合物及其药物上可接受的盐或酯，及其药物组合物；以及将本发明的化合物、药物组合物用于抑制或调节酪氨酸激酶的活性、治疗由酪氨酸激酶介导的包括癌症在内的疾病症状或病症。

  公开号：

  CN112442011A

文献信息

• [EN] PRODRUGS OF THE TYROSINE KINASE INHIBITOR FOR TREATING CANCER<br/>[FR] PROMÉDICAMENTS DE L'INHIBITEUR DE TYROSINE KINASE POUR LE TRAITEMENT DU CANCER
  申请人：RISEN SUZHOU PHARMA TECH CO LTD

  公开号：WO2021035360A1

  公开（公告）日：2021-03-04

  There are provided compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof, and pharmaceutical compositions thereof, useful for inhibition or modulation of the activity of tyrosine kinases and treatment of disease states or conditions mediated by tyrosine kinases, including cancers. (I)

  提供了化合物的化学式(I)，以及其药用盐和酯，以及包含它们的药物组合物，用于抑制或调节酪氨酸激酶的活性，以及治疗由酪氨酸激酶介导的疾病状态或病况，包括癌症。
• The Presence of Substituents on the Aryl Moiety of the Aryl Phosphoramidate Derivative of d4T Enhances Anti-HIV Efficacy in Cell Culture:  A Structure−Activity Relationship
  作者：Adam Q. Siddiqui、Carlo Ballatore、Christopher McGuigan、Erik De Clercq、Jan Balzarini

  DOI：10.1021/jm9803931

  日期：1999.2.1

  used to establish the stability of the compounds to enzymatic degradation. While there was no apparent correlation between in vitro activity and half-life of enzymatic degradation, there was a close correlation between compound lipophilicity, determined by octanol/water partition coefficient, and in vitro potency. We suggest that substitutions made to the aryl moiety of the aryl phosphoramidate of d4T

  合成了抗HIV药物d4T的新的取代芳基氨基磷酸酯衍生物，作为膜溶性细胞内前药，用于游离的生物活性磷酸盐，从而建立化合物结构与体外抗病毒活性之间的关系。相对于亲本核苷，大多数化合物表现出体外效力的提高，并且与d4T不同，它们在胸苷激酶缺陷型细胞中均保留了全部活性。带有对氯芳基（8e）的化合物在体外表达纳摩尔活性，相对于未取代的氨基磷酸酯而言，活性提高了14倍（与d4T相比，提高了100倍）。使用猪肝酯酶的测定用于建立化合物对酶促降解的稳定性。虽然在体外活性和酶促降解的半衰期之间没有明显的相关性，但由辛醇/水分配系数确定的化合物亲脂性与体外效能之间却有着密切的相关性。我们建议对d4T的氨基磷酸氨基磷酸酯的芳基部分进行取代，从而导致亲脂性增强，这可能通过被动扩散增加前药的细胞摄取，从而导致前药浓度降低时抗病毒效力的表达。
• 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 and phosphate prodrugs of (−)-β-d-(2R,4R)-dioxolane-thymine: Synthesis, anti-HIV activity and stability studies
  作者：Yuzeng Liang、Janarthanan Narayanasamy、Raymond F. Schinazi、Chung K. Chu

  DOI：10.1016/j.bmc.2005.11.008

  日期：2006.4

  A series of phosphoramidate and phosphate prodrugs of DOT were synthesized via dichlorophosphate or H-phosphonate chemistry and evaluated for their anti-HIV activity against LAI M 184V mutants in PBM cells as well as for their cytotoxicity. The antiviral and cytotoxic profiles of the prodrugs were compared with that of the parent compound (DOT), and it was found that four aryl phosphoramidates 5, 18, 20, and 26 showed a significant enhancement (8- to 12-fold) in anti-HIV activity without cytotoxicity. Chemical stability of these prodrugs was evaluated in phosphate buffer at pH values of biological relevance (i.e., pH 2.0 and 7.4). Enzymatic hydrolysis was also studied in esterase or lipase in buffer solution. Chemical stability studies indicate that the phosphoramidates have good chemical stability at pH 2.0 and at pH 7.4 phosphate buffer. Phosphoramidate prodrugs were hydrolyzed in vitro by esterase or lipase and found to be better substrates for lipases than for esterases. 1,3-Diol cyclic phosphates showed potent anti-HIV activity without increasing the cytotoxicity compared with that of DOT and have good chemical and enzymatic stability. Long-chain lipid phosphates, although showed potent anti-HIV activity, exhibited increased cytotoxicity. (c) 2005 Elsevier Ltd. All rights reserved.
• Intracellular delivery of bioactive AZT nucleotides by aryl phosphate derivatives of AZT
  作者：Christopher McGuigan、Ranjith N. Pathirana、Jan Balzarini、Erik De Clercq

  DOI：10.1021/jm00060a013

  日期：1993.4

  Novel aryl phosphate derivatives of the anti-HIV nucleoside analogue AZT have been prepared by phosphorochloridate chemistry. These materials were designed to act as membrane-soluble prodrugs of the bioactive free nucleotides. In vitro evaluation revealed the compounds to have a pronounced, selective anti-HIV activity in CEM cells; the magnitude of the biological effect varied considerably depending on the nature of the phosphate blocking group. Moreover, several of the compounds retain marked antiviral activity iri TK- (thymidine kinase-deficient) mutant CEM cells in which AZT was virtually inactive. These data strongly support the hypothesis that the AZT phosphate derivatives exert their biological effects via intracellular release of AZT nucleotide forms and suggest that the potential of nucleoside drugs in antiviral chemotherapy may be enhanced by suitable nucleotide delivery strategies.