4-bromophenyl methoxy-alanyl phosphorochloridate | 217090-42-1

• 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-bromophenyl methoxy-alanyl phosphorochloridate
• 英文别名: Methyl ((4-bromophenoxy)chlorophosphoryl)-L-alaninate；methyl (2S)-2-[[(4-bromophenoxy)-chlorophosphoryl]amino]propanoate
• CAS: 217090-42-1
• 化学式: C₁₀H₁₂BrClNO₄P
• 分子量: 356.54
• InChiKey: ZYOKZJKKIPUATH-QNUGLTPUSA-N

物化性质

• 沸点：
  398.8±52.0 °C(Predicted)
• 密度：
  1.568±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 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：

  4-bromophenyl methoxy-alanyl phosphorochloridate 在 氢溴酸 作用下， 以 四氢呋喃 为溶剂， 生成 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl)methoxyalaninyl phosphate
  参考文献：
  名称：

  Lack of adverse effects on fertility of female cd-1 mice exposed to repetitive intravaginal gel-microemulsion formulation of a dual-function anti-HIV agent: aryl phosphate derivative of bromo-methoxy-zidovudine (compound WHI-07)

  摘要：

  5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07)是齐多夫定（ZDV）的一种新型溴代甲氧基取代芳基磷酸酯衍生物，是一种具有抗艾滋病毒活性的强效双功能避孕药。在将其用作阴道内杀微生物剂的条件下，使用 CD-1 小鼠进行了一系列实验，以评估其潜在的生殖毒性。雌性CD-1小鼠阴道内暴露于含0%、0.5%、1.0%或2.0% WHI-07的凝胶微乳剂配方中长达13周。按摩尔计算，这些浓度分别为体外杀精IC50的1400-5700倍和体外抗艾滋病毒IC50的1.4-5.7（×106）倍。我们研究了阴道内注射WHI-07对以下方面的影响：排卵效率；体内受精和早期胚胎、胎儿发育；以及生殖结果，包括新生儿存活率和幼崽发育。在超排卵期、器官形成期和交配前，分别连续5天、10天和13周阴道内注射化合物WHI-07。在注射人绒毛膜促性腺激素（hCG）14和40小时后，分别对小鼠的排卵效率、受精率和卵裂率进行评估。在妊娠期（GD）6-15天期间，给妊娠小鼠阴道内注射2% WHI-07，并在妊娠期（GD）17天对致畸性进行评估。在短期毒性研究中，小鼠阴道内注射含0%、0.5%、1.0%和2.0% WHI-07的凝胶微乳剂13周，然后与未注射的雄性小鼠交配，以评估潜在的生殖和发育影响。重复阴道内暴露于2% WHI-07对小鼠的排卵反应、平均卵子回收数量或受精卵或裂解卵子的百分比没有不良影响。在器官形成期间，重复阴道内施用2% WHI-07没有发现生殖毒性、胎儿毒性或致畸性的证据。此外，连续13周重复阴道内施用0.5-2.0% WHI-07对小鼠的生殖能力、围产期结果或后代的生长发育没有不良影响。化合物WHI-07作为一种安全的双功能阴道避孕药，在遏制粘膜和围产期艾滋病病毒传播方面显示出独特的临床潜力。Copyright © 2001 John Wiley & Sons, Ltd. 版权所有。

  DOI：

  10.1002/jat.762
• 作为产物：
  描述：

  L-丙氨酸甲酯盐酸盐 、 4-溴苯基二氯磷酸酯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 4-bromophenyl methoxy-alanyl phosphorochloridate
  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

文献信息

• NUCLEOSIDE PHOSPHORAMIDATE PRODRUGS
  申请人：SOFIA MICHAEL JOSEPH

  公开号：US20100016251A1

  公开（公告）日：2010-01-21

  Disclosed herein are phosphoramidate prodrugs of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomer, salt (acid or basic addition salt), hydrate, solvate, or crystalline form thereof, represented by the following structure: Also disclosed are methods of treatment, uses, and processes for preparing each of which utilize the compound represented by formula I.

  本文披露了用于治疗哺乳动物病毒感染的核苷类衍生物的磷酰胺酯前药，该前药是一种化合物，其立体异构体、盐（酸性或碱性加合盐）、水合物、溶剂合物或结晶形式，由以下结构表示：同时还披露了治疗方法、用途和制备过程，每种方法均利用由式I表示的化合物。
• Nucleoside phosphoramidate prodrugs
  申请人：Gilead Pharmasset LLC

  公开号：EP2826784A1

  公开（公告）日：2015-01-21

  Disclosed herein are phosphoramidate prodrugs of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomer, salt (acid or basic addition salt), hydrate, solvate, or crystalline form thereof, represented by the following structure: Also disclosed are methods of treatment, uses, and processes for preparing each of which utilize the compound represented by formula I.

  本文公开了用于治疗哺乳动物病毒感染的核苷衍生物磷酰胺原药，即由以下结构表示的化合物、其立体异构体、盐（酸性或碱性加成盐）、水合物、溶液或结晶形式： 还公开了利用式 I 所代表的化合物的治疗方法、用途和制备工艺。
• Benyumov, Alexey O.; Venkatachalam, Taracad K.; Grigoriants, Olga O., Arzneimittel-Forschung/Drug Research, 2005, vol. 55, # 2, p. 114 - 122
  作者：Benyumov, Alexey O.、Venkatachalam, Taracad K.、Grigoriants, Olga O.、Vassilev, Alexei O.、Tibbles, Heather E.、Downs, Suzanne、Dumez, Darin、Uckun, Fatih M.

  DOI：——

  日期：——
• DuMez, Darin; Venkatachalam, Taracad K.; Uckun, Fatih M., Arzneimittel-Forschung/Drug Research, 2006, vol. 56, # 2 A, p. 136 - 151
  作者：DuMez, Darin、Venkatachalam, Taracad K.、Uckun, Fatih M.

  DOI：——

  日期：——
• Zidampidine, an aryl phosphate derivative of AZT: in vivo pharmacokinetics, metabolism, toxicity, and anti-viral efficacy against hemorrhagic fever caused by Lassa virus
  作者：F.M. Uckun、T.K. Venkatachalam、D. Erbeck、C.L. Chen、A.S. Petkevich、A. Vassilev

  DOI：10.1016/j.bmc.2005.02.031

  日期：2005.5

  The pharmacokinetics, metabolism, and toxicity of Zidampidine, an aryl phosphate derivative of AZT, 3'-azidothymidine-5'-[p-bromophenyl methoxyalaninyl phosphate] were investigated in CD-1 mice. Following iv injection, Zidampidine was rapidly converted to its metabolites Ala-AZT-MP and AZT. Zidampidine was not toxic to mice at doses up to 250 mg/kg. We next examined the therapeutic effect of Zidampidine in CBA mice challenged with intracerebral injections of the Josiah strain of Lassa virus. Mice were treated either with vehicle or non-toxic doses of Zidampidine administered intraperitoneally 24 h prior, 1 h prior, and 24, 48, 72, and 96 h after virus inoculation. The probability of survival following the Lassa challenge was significantly improved for Zidampidine-treated mice (Kaplan Meier, Log-Rank p value < 0.0001). This pilot study provides the basis for future preclinical evaluation of Zidampidine and its potential as a new agent for the treatment of viral hemorrhagic fevers caused by Lassa virus. (c) 2005 Elsevier Ltd. All rights reserved.