phenyl(methoxy-D-alaninyl) phosphorochloridate | 180077-12-7

• 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: phenyl(methoxy-D-alaninyl) phosphorochloridate
• 英文别名: methyl N-[chloro(phenoxy)phosphoryl]-D-alaninate；phenyl-(methoxy-L-alaninyl)-phosphorochloridate；phenyl methoxyalaninylphosphorochloridate；methyl (2R)-2-[[chloro(phenoxy)phosphoryl]amino]propanoate
• CAS: 180077-12-7
• 化学式: C₁₀H₁₃ClNO₄P
• 分子量: 277.644
• InChiKey: GISNGKRLBICLGJ-OEWHWVHBSA-N

物化性质

• 沸点：
  353.8±44.0 °C(Predicted)
• 密度：
  1.314±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  17
• 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：

  phenyl(methoxy-D-alaninyl) phosphorochloridate 、 阿巴卡韦 在 叔丁基氯化镁 作用下， 以 四氢呋喃 为溶剂， 反应 36.0h， 以318.6 mg的产率得到methyl (2R)-2-[[[(1S,4R)-4-[2-amino-6-(cyclopropylamino)purin-9-yl]cyclopent-2-en-1-yl]methoxy-phenoxy-phosphoryl]amino]propanoate
  参考文献：
  名称：

  Application of Phosphoramidate Pronucleotide Technology to Abacavir Leads to a Significant Enhancement of Antiviral Potency

  摘要：

  We report the first application of pronucleotide (ProTide) technology to the antiviral agent abacavir (Ziagen), used for the treatment of HIV infection. The phenylmethoxyalaninyl phosphoramidate of abacavir was prepared in good yield in one step. Also prepared was the corresponding phosphoramidate of the guanine nucleoside analogue "carbovir". The antiviral profile of each of the parent nucleosides was compared to that of the phosphoramidate ProTides. A significant (28- to 60-fold) increase in anti-HIV potency was noted for the ProTide of abacavir but not for that of carbovir. These findings were in agreement with the markedly higher (ca. 37-fold) levels of carbovir triphosphate that are formed in CEM cells upon response to the abacavir ProTide compared with the parent abacavir compound. In contrast the anti-HBV potency of both abacavir and carbovir were improved (10- and 20-fold, respectively) by ProTide formation. As in CEM cells, the abacavir ProTide provided significantly enhanced carbovir triphosphate levels in HepG2 2.2.15 cells over that of the parent nucleoside. On the basis of these data, a series of phosphoramidate analogues with structural variation in the ester and amino acid regions were prepared and their antiviral profiles described. In addition, the pharmacokinetic disposition of the abacavir phenylethoxyalaninyl phosphoramidate was evaluated in Cynomolgus monkeys.

  DOI：

  10.1021/jm0491400
• 作为产物：
  描述：

  对甲苯磺酸 在 三乙胺 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 生成 phenyl(methoxy-D-alaninyl) phosphorochloridate
  参考文献：
  名称：

  氨基磷酸酯ProTide技术的应用显着提高了碳环腺苷衍生物的抗病毒效力。

  摘要：

  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。

  DOI：

  10.1021/jm060776w

文献信息

• 一种多取代嘌呤类化合物及其制备方法和应用
  申请人：中国药科大学

  公开号：CN113549076B

  公开（公告）日：2022-12-06

  本发明公开了一类如式(I)所示的一种多取代嘌呤化合物及其药学上可接受的盐、其制备方法及其应用。本发明还公开了上述化合物对作用于RNA腺苷脱氨酶1(ADAR1)有明显的抑制作用，可用于预防和/或治疗因这种酶活性异常所引起的癌症或肿瘤相关疾病，特别是前列腺癌、白血病、乳腺癌、多发性骨髓瘤、肺癌、胃癌、卵巢癌、结肠癌、肝癌、胰腺癌以及人神经胶质瘤等疾病。
• Aryl phosphate derivatives of d4T having anti-HIV activity
  申请人：Parker Hughes Institute

  公开号：US06350736B1

  公开（公告）日：2002-02-26

  Aryl phosphate derivatives of d4T with para-bromo substitution on the aryl group show markedly increased potency as anti-HIV agents without undesirable levels of cytotoxic activity. In particular, these derivatives are potent inhibitors of HIV reverse transcriptase. In a preferred aspect of the present invention, the phosphorus of the aryl phosphate group is further substituted with an amino acid residue that may be esterified or substituted, such as a methoxy alaninyl group.

  d4T的芳基磷酸酯衍生物，在芳基上对位溴取代，显示出明显增强的抗HIV活性，而无不良水平的细胞毒活性。特别是，这些衍生物是HIV反转录酶的强效抑制剂。在本发明的首选方面，芳基磷酸酯基的磷进一步取代为氨基酸残基，该残基可以酯化或取代，如甲氧基丙氨基基团。
• Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds
  作者：Gian Filippo Ruda、Pui Ee Wong、Vincent P. Alibu、Suzanne Norval、Kevin D. Read、Michael P. Barrett、Ian H. Gilbert

  DOI：10.1021/jm1004754

  日期：2010.8.26

  survival and make it an attractive drug target for the development of new treatments against human African trypanosomiasis. 2,3-O-Isopropylidene-4-erythrono hydroxamate is a potent inhibitor of parasite Trypanosoma brucei 6-phosphogluconate dehydrogenase (6-PGDH), the third enzyme of the pentose phosphate pathway. However, this compound does not have trypanocidal activity due to its poor membrane permeability

  RNAi 和酶促研究表明，布氏锥虫中 6-磷酸葡萄糖酸脱氢酶 (6-PGDH)对寄生虫存活的重要性，使其成为开发针对人类非洲锥虫病的新疗法的有吸引力的药物靶点。2,3- O -Isopropylidene-4-erythrono hydroxamate 是寄生虫布氏锥虫的有效抑制剂6-磷酸葡萄糖酸脱氢酶 (6-PGDH)，戊糖磷酸途径的第三种酶。然而，由于其膜渗透性差，该化合物不具有杀锥虫活性。因此，我们之前已经报道了一种前药方法，通过将磷酸基团转化为带电荷较少的磷酸前药来提高该抑制剂的抗寄生虫活性。前药的活性似乎取决于它们在磷酸盐缓冲液中的稳定性。在这里，我们成功地进一步扩展了 2,3- O的芳基氨基磷酸酯前药的开发。-isopropylidene-4-erythrono hypoxamate 通过合成一个小的氨基磷酸酯文库并在各种测定中评估它们的生物活性和稳定性。一些化合物显示出较高的
• 2'-Fluoro-6'-Methylene Carbocyclic Nucleosides and Methods of Treating Viral Infections
  申请人：Chu Chung K.

  公开号：US20110244027A1

  公开（公告）日：2011-10-06

  The present invention relates to 2′-Fluoro-6′-methylene carbocyclic nucleosides, pharmaceutical compositions containing these nucleosides and their use in the treatment or prophylaxis of a number of viral infections and secondary disease states and conditions thereof, especially including Hepatitis B virus (HBV) and secondary disease states and conditions thereof (cirrhosis and liver cancer), Heptatitis C virus (HCV), Herpes Simplex virus I and II (HSV-1 and HSV-2), cytomegalovirus (CMV), Varicella-Zoster Virus (VZV) and Epstein Barr virus (EBV) and secondary cancers which occur thereof (lymphoma, nasopharyngeal cancer, including drug resistant (especially including lamivudine and/or adefovir resistant) and other mutant forms of these viruses.

  本发明涉及2'-氟-6'-亚甲基环烷基核苷，以及含有这些核苷的制药组合物及其在治疗或预防多种病毒感染和其次生疾病状态和条件中的应用，特别是包括乙型肝炎病毒（HBV）及其次生疾病状态和条件（肝硬化和肝癌），丙型肝炎病毒（HCV），单纯疱疹病毒I和II（HSV-1和HSV-2），巨细胞病毒（CMV），水痘-带状疱疹病毒（VZV）和EB病毒及其次生癌症（淋巴瘤，鼻咽癌，包括耐拉米夫定和/或阿德福韦耐药的和其他突变形式的这些病毒）。
• [EN] STEREOSELECTIVE PROCESS OF MANUFACTURE OF PURINE PHOSPHORAMIDATES<br/>[FR] PROCÉDÉ STÉRÉOSÉLECTIF DE FABRICATION DE PHOSPHORAMIDATES DE PURINE
  申请人：ATEA PHARMACEUTICALS INC

  公开号：WO2021216722A1

  公开（公告）日：2021-10-28

  The present invention provides stereoselective processes of manufacture for the phosphoramidate nucleotide Compound 1 or a pharmaceutically acceptable salt thereof.

  本发明提供了制备磷酰胺酰核苷化合物1或其药学上可接受的盐的立体选择性制造过程。