4-cyanophenyl dichlorophosphate | 73759-41-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-cyanophenyl dichlorophosphate
• 英文别名: p-cyanophenyl phosphorodichloridate；4-cyanophenyl phosphodichloridate；4-Dichlorophosphoryloxybenzonitrile
• CAS: 73759-41-8
• 化学式: C₇H₄Cl₂NO₂P
• 分子量: 235.994
• InChiKey: MZGUVHPBBIZJRE-UHFFFAOYSA-N

物化性质

• 沸点：
  324.8±25.0 °C(Predicted)
• 密度：
  1.51±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  50.1
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-cyanophenyl dichlorophosphate 在 N-甲基咪唑 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 8.0h， 生成 (S)-2-{(4-Cyano-phenoxy)-[(2R,4R)-4-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-[1,3]dioxolan-2-ylmethoxy]-phosphorylamino}-propionic acid methyl ester
  参考文献：
  名称：

  Phosphoramidate and phosphate prodrugs of (−)-β-d-(2R,4R)-dioxolane-thymine: Synthesis, anti-HIV activity and stability studies

  摘要：

  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.

  DOI：

  10.1016/j.bmc.2005.11.008
• 作为产物：
  描述：

  4-羟基苯甲腈 在 sodium chloride 、 三氯氧磷 作用下， 反应 6.0h， 以53%的产率得到4-cyanophenyl dichlorophosphate
  参考文献：
  名称：

  磷酰乙醇胺二酯的水解机理。分子内亲核胺参与

  摘要：

  在35°C的水中，已在一系列N-烷基-O-芳基磷酰基乙醇胺中检测了磷下的分子内置换反应。pH速率曲线的检查以及31 P nmr对反应产物的直接观察表明该胺具有亲核作用。观察到速率提高了10 6 –10 7。通过改变P由来结构反应性的相关性ķ一个的胺和离去基团屈服值β NUC ≃0.7和β 1克1.25–1.25并支持非耦合的协调机制。讨论了涉及胺和氧阴离子与分子间和分子内磷酸二酯和三酯的亲核反应机理。

  DOI：

  10.1039/p29800000373

文献信息

• Cyclic Phosphopantothenic Acid Prodrugs for Treatment of Pantothenate Kinase-Associated Neurodegeneration
  作者：Giulio Auciello、Annalise Di Marco、Odalys Gonzalez Paz、Savina Malancona、Steven Harper、Maria Beconi、Ilaria Rossetti、Alina Ciammaichella、Paola Fezzardi、Andrea Vecchi、Elena Bracacel、Daniel Cicero、Edith Monteagudo、Daniel Elbaum

  DOI：10.1021/acs.jmedchem.0c01531

  日期：2020.12.24

  low levels of coenzyme-A (CoA) in the CNS due to impaired production of phosphopantothenic acid (PPA) from vitamin B5. Restoration of central PPA levels by delivery of exogenous PPA is a recent strategy to reactivate CoA biosynthesis in PKAN patients. Fosmetpantotenate is an oral PPA prodrug. We report here the development of a new PANk2–/– knockout model that allows CoA regeneration in brain cells

  人类PANK2基因的突变与神经退行性疾病（如泛酸激酶相关的神经退行性疾病（PKAN））有关，由于维生素B5的磷酸泛酸（PPA）的生产受损，导致CNS中的辅酶A（CoA）含量较低。通过递送外源PPA恢复中枢PPA水平是重新激活PKAN患者CoA生物合成的最新策略。泛泛酸磷酯为口服PPA前药。我们在这里报告新PANk2的开发– / –可以评估脑细胞中CoA再生的基因剔除模型，并描述了两个新系列的PPA环状磷酸酯前药，能够在该系统中再生优异水平的CoA。在小鼠中进行的概念验证研究证明，这类新型前药在口服后可将PPA递送至大脑，并证实将前药衍生的PPA纳入CoA。
• [EN] PANOTHENATE DERIVATIVES FOR THE TREATMENT OF NEUROLOGICAL DISORDERS<br/>[FR] DÉRIVÉS PANOTHÉNATE POUR LE TRAITEMENT DE TROUBLES NEUROLOGIQUES
  申请人：RETROPHIN INC

  公开号：WO2015061792A1

  公开（公告）日：2015-04-30

  Compounds having the following formula (E): Formula E or a pharmaceutically acceptable salt thereof, wherein R, R', R'', X and n are as defined herein are provided. Methods comprising use of such compounds for the treatment of neurologic disorders, such as pantothenate kinase-associated neurodegeneration, and pharmaceutical compositions containing such compounds, and their use in treatment of neurologic disorders are also provided.

  提供具有以下公式（E）的化合物：公式E或其药学上可接受的盐，其中R、R'、R''、X和n如本文所定义。还提供了使用这些化合物治疗神经系统疾病（如泛酸激酶相关性神经退行性疾病）的方法，以及含有这些化合物的药物组合物，以及它们在治疗神经系统疾病中的应用。
• PANOTHENATE DERIVATIVES FOR THE TREATMENT OF NEUROLOGICAL DISORDERS
  申请人：Retrophin, Inc.

  公开号：US20160264607A1

  公开（公告）日：2016-09-15

  Compounds having the following formula (E): Formula E or a pharmaceutically acceptable salt thereof, wherein R, R′, R″, X and n are as defined herein are provided. Methods comprising use of such compounds for the treatment of neurologic disorders, such as pantothenate kinase-associated neurodegeneration, and pharmaceutical compositions containing such compounds, and their use in treatment of neurologic disorders are also provided.

  本发明提供具有下列化学式(E)或其药学上可接受的盐的化合物，其中R、R′、R″、X和n如本文所定义。本发明还提供了使用这些化合物治疗神经系统疾病（例如泛酸激酶相关的神经退行性疾病）的方法，以及包含这些化合物的制药组合物和它们在神经系统疾病治疗中的用途。
• Pantothenate derivatives for the treatment of neurological disorders
  申请人：Retrophin, Inc.

  公开号：US10407447B2

  公开（公告）日：2019-09-10

  Compounds having the following formula (E): or a pharmaceutically acceptable salt thereof, wherein R, R′, R″, X and n are as defined herein are provided. Methods comprising use of such compounds for the treatment of neurologic disorders, such as pantothenate kinase-associated neurodegeneration, and pharmaceutical compositions containing such compounds, and their use in treatment of neurologic disorders are also provided.

  具有下式（E）的化合物： 或其药学上可接受的盐，其中 R、R′、R″、X 和 n 如本文所定义。还提供了包括使用此类化合物治疗神经系统疾病（如泛酸激酶相关的神经变性）的方法和含有此类化合物的药物组合物，以及它们在治疗神经系统疾病中的用途。
• PANTOTHENATE DERIVATIVES FOR THE TREATMENT OF NEUROLOGICAL DISORDERS
  申请人：Retrophin, Inc.

  公开号：EP3060570B1

  公开（公告）日：2018-09-19