(((1S)-(4-chlorophenoxy)-(1-methyl)oxycarbonylethyl)amino)phosphinyl chloride | 217090-41-0

• 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: (((1S)-(4-chlorophenoxy)-(1-methyl)oxycarbonylethyl)amino)phosphinyl chloride
• 英文别名: (4-chlorophenoxy)((1S-1-methoxycarbonylethyl)amino)phosphinylchloride；4-chlorophenyl-(methoxy-L-alaninyl)-phosphorochloridate；4-chlorophenyl [[(1S)-1-methoxycarbonylethyl]amino]phosphorochloridate；methyl (2S)-2-[[chloro-(4-chlorophenoxy)phosphoryl]amino]propanoate
• CAS: 217090-41-0
• 化学式: C₁₀H₁₂Cl₂NO₄P
• 分子量: 312.089
• InChiKey: KGLVSCYDEKUYIH-QNUGLTPUSA-N

物化性质

• 沸点：
  384.0±52.0 °C(Predicted)
• 密度：
  1.398±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 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：
  5

反应信息

• 作为反应物：
  描述：

  司他夫定 、 (((1S)-(4-chlorophenoxy)-(1-methyl)oxycarbonylethyl)amino)phosphinyl chloride 在 N-甲基咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 以72%的产率得到2',3'-didehydro-2',3'-dideoxythymidine 5'-(4-chlorophenyl (methoxyalaninyl)phosphate)
  参考文献：
  名称：

  d4T的芳基氨基磷酸酯衍生物的芳基部分上存在取代基，可以增强细胞培养中的抗HIV功效：结构-活性关系。

  摘要：

  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。

  DOI：

  10.1021/jm9803931
• 作为产物：
  描述：

  对氯苯酚 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 (((1S)-(4-chlorophenoxy)-(1-methyl)oxycarbonylethyl)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。
• Application of Phosphoramidate ProTide Technology Significantly Improves Antiviral Potency of Carbocyclic Adenosine Derivatives
  作者：Christopher McGuigan、Alshaimaa Hassan-Abdallah、Sheila Srinivasan、Yikang Wang、Adam Siddiqui、Susan M. Daluge、Kristjan S. Gudmundsson、Huiqiang Zhou、Ed W. McLean、Jennifer P. Peckham、Thimysta C. Burnette、Harry Marr、Richard Hazen、Lynn D. Condreay、Lance Johnson、Jan Balzarini

  DOI：10.1021/jm060776w

  日期：2006.11.30

  phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes

  我们报告了氨基磷酸酯原核苷酸（ProTide）技术在抗病毒剂碳环L-d4A（L-Cd4A）中的应用。L-Cd4A的苯基甲基丙氨酸基母体ProTide是通过格利雅（Grignard）介导的磷酰氯反应制备的，得到的化合物具有显着改善的抗HIV（2600倍）和HBV活性。我们描述了ProTide的芳基，酯和氨基酸区域的修饰，以及这些变化如何影响抗病毒活性和代谢稳定性。注意到针对HIV和HBV的SAR分别且不同。另外，由D-核苷D-Cd4A和双脱氧类似物L-CddA和D-CddA制备ProTide。与母体药物相比，这些化合物显示出更适度的效能改善。综上所述，当将ProTide方法应用于L-Cd4A时，在体外的效价提高了9000倍，非常成功，抗HIV的能力提高了。为了临床前候选人的选择，我们使用食蟹猴肝脏和肠道S9馏分进行了代谢稳定性研究。
• 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.
• The novel phosphoramidate derivatives of NSAID 3-hydroxypropylamides: Synthesis, cytostatic and antiviral activity evaluations
  作者：K. Wittine、K. Benci、Z. Rajić、B. Zorc、M. Kralj、M. Marjanović、K. Pavelić、E. De Clercq、G. Andrei、R. Snoeck

  DOI：10.1016/j.ejmech.2008.03.037

  日期：2009.1

  The target phosphoramidates 5a-e were prepared in one step from 3-hydroxypropyl derivatives 3a-e of nonsteroidal anti-inflammatory drugs (fenoprofen, ketoprofen, ibuprofen, indomethacin, diclofenac). The products 3a-e and 5a-e were evaluated for their cytostatic and antiviral activity against malignant tumour cell lines and normal human fibroblasts (WI 38). All phosphoramidate derivatives 5a-e possess significantly greater inhibitory activities than the corresponding 3-hydroxypropyl derivatives 3a-e, whereby compound 5a showed the most potent inhibitory activities against cervical, pancreatic and colon carcinoma cell lines (IC50 = 5 - 7 mu M), (C) 2008 Elsevier Masson SAS. All rights reserved.
• Synthesis and Biological Evaluation of LNA Phosphoramidates
  作者：Jacob Jensen、Gitte Sjøgren、Jens Bo Hansen、Christoph Rosenbohm、Troels Koch

  DOI：10.1080/15257770701571834

  日期：2008.1

  The synthesis of LNA phosphoramidates is presented. The LNA phosphoramidates were evaluated for their ability to inhibit cell proliferation of the human prostate cancer cell line 15PC3. A number of the LNA phosphoramidates showed cell proliferation inhibition determined by the MTS assay.