P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]mono[3-(hexadecyloxy)propyl]ester sodium

• 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: P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]mono[3-(hexadecyloxy)propyl]ester sodium
• 英文别名: 3-(hexadecyloxy)propyl toluenesulfonyloxymethylphosphonate sodium salt；sodium 3-(hexadecyloxy)propyl tosyloxymethylphosphonate；phosphonic acid, P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-, mono[3-(hexadecyloxy)propyl]ester, sodium salt；Sodium 3-(hexadecyloxy)propyl ((tosyloxy)methyl)phosphonate；sodium;3-hexadecoxypropoxy-[(4-methylphenyl)sulfonyloxymethyl]phosphinate
• 化学式: C₂₇H₄₈O₇PS*Na
• 分子量: 570.703
• InChiKey: OPERKVZSSDIIPR-UHFFFAOYSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  4.12
• 重原子数：
  37
• 可旋转键数：
  24
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  110
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]mono[3-(hexadecyloxy)propyl]ester sodium 在 sodium hydride 、 溶剂黄146 、 三乙胺 作用下， 生成 3-(hexadecyloxy)propyl (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine sodium salt
  参考文献：
  名称：

  Alkoxyalkyl Esters of ( S )-9-[3-Hydroxy-2-(Phosphonomethoxy)Propyl]Adenine Are Potent Inhibitors of the Replication of Wild-Type and Drug-Resistant Human Immunodeficiency Virus Type 1 In Vitro

  摘要：

  摘要 ( S )-9-[3-羟基-2-(磷酰甲氧基)丙基]腺嘌呤[( S )-HPMPA]是一种对多种 DNA 病毒有效的广谱抗病毒药物，但据报道对人类免疫缺陷病毒（HIV）无效。我们合成了几种(S)-HPMPA 的烷氧基烷基酯。 S )-HPMPA的几种烷氧基烷基酯，现在报告说，十六烷氧基丙基-( S )-HPMPA[HDP-( S )-HPMPA]和十八烷氧基乙基-( S )-HPMPA[ODE-( S )-HPMPA]的50%有效浓度为0.4至7.0纳摩尔，对具有逆转录酶突变M184V和K103N的HIV变体以及具有突变D67N、K70R、T215Y和K219Q的齐多夫定耐药变体几乎完全有效。对 HDP-( S )-HPMPA和ODE-( S )-HPMPA的耐药性。HDP-( S )-HPMPA对 1 型单纯疱疹病毒、人类巨细胞病毒、乙型肝炎病毒、腺病毒和正疱疹病毒也有活性，值得作为一种可能的艾滋病病毒感染疗法进行进一步评估。

  DOI：

  10.1128/aac.01223-05
• 作为产物：
  描述：

  十六烷基甲烷磺酸酯 在 吡啶 、 sodium hydride 作用下， 以 N-甲基吡咯烷酮 、 二氯甲烷 、 mineral oil 为溶剂， 反应 1.25h， 生成 P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]mono[3-(hexadecyloxy)propyl]ester sodium
  参考文献：
  名称：

  Phosphonate Ester Derivatives and Methods of Synthesis Thereof

  摘要：

  该披露描述了合成膦酸酯衍生物的方法。根据该披露的首选方法允许大规模制备高纯度的膦酸酯化合物。在一些实施例中，根据该披露的首选方法还允许在比以往用于制备这类化合物的方法更好的产率下制备膦酸酯衍生物，而无需使用色谱纯化方法。还披露了膦酸酯衍生物的形态形式。

  公开号：

  US20120058976A1

文献信息

• Morphic forms of hexadecyloxypropyl-phosphonate esters and methods of synthesis thereof
  申请人：Chimerix, Inc.

  公开号：US08962829B1

  公开（公告）日：2015-02-24

  The disclosure describes methods of synthesis of phosphonate ester compounds. The methods according to the disclosure allow for large-scale preparation of phosphonate ester compounds having high purity and stability. Also disclosed are morphic forms of phosphonate ester compounds.

  该披露描述了合成膦酸酯化合物的方法。根据该披露的方法，可以实现高纯度和稳定性的大规模制备膦酸酯化合物。还披露了膦酸酯化合物的形态形式。
• Evaluation of Hexadecyloxypropyl-9- <i>R</i> -[2-(Phosphonomethoxy)Propyl]- Adenine, CMX157, as a Potential Treatment for Human Immunodeficiency Virus Type 1 and Hepatitis B Virus Infections
  作者：George R. Painter、Merrick R. Almond、Lawrence C. Trost、Bernhard M. Lampert、Johan Neyts、Erik De Clercq、Brent E. Korba、Kathy A. Aldern、James R. Beadle、Karl Y. Hostetler

  DOI：10.1128/aac.00460-07

  日期：2007.10

  9- R -[2-(Phosphonomethoxy)propyl]-adenine (tenofovir) is an acyclic nucleoside phosphonate with antiviral activity against human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV). Tenofovir is not orally bioavailable but becomes orally active against HIV-1 infection as the disoproxil ester (tenofovir disoproxil fumarate [Viread]). We have developed an alternative strategy for promoting the oral availability of nucleoside phosphonate analogs which involves esterification with a lipid to form a lysolecithin mimic. This mimic can utilize natural lysolecithin uptake pathways in the gut, resulting in high oral availability. Since the mimic is not subject to cleavage in the plasma by nonspecific esterases, it remains intact in the circulation and facilitates uptake by target cells. Significant drops in apparent antiviral 50% effective concentrations (EC ₅₀ s) of up to 3 logs have been observed in comparison with non-lipid-conjugated parent compounds in target cells. We have applied this technology to tenofovir with the goal of increasing oral availability, decreasing the apparent EC ₅₀ , and decreasing the potential for nephrotoxicity by reducing the exposure of the kidney to the free dianionic tenofovir. Here we report that, in vitro, the hexadecyloxypropyl ester of tenofovir, CMX157, is 267-fold more active than tenofovir against HIV-1 and 4.5-fold more active against HBV. CMX157 is orally available and has no apparent toxicity when given orally to rats for 7 days at doses of 10, 30, or 100 mg/kg/day. Consequently, CMX157 represents a second-generation tenofovir analog which may have an improved clinical profile.

  摘要 9- R -[2-（膦酰甲氧基）丙基]-腺嘌呤（替诺福韦）是一种无环核苷膦酸盐，对 1 型人类免疫缺陷病毒（HIV-1）和乙型肝炎病毒（HBV）具有抗病毒活性。替诺福韦不能口服，但其二丙羟酯（富马酸替诺福韦二丙酯 [Viread]）具有口服抗 HIV-1 感染的活性。我们开发了一种促进核苷膦酸盐类似物口服可用性的替代策略，包括与脂质发生酯化反应，形成一种溶脂卵磷脂模拟物。这种模拟物可以利用肠道中天然的溶脂卵磷脂摄取途径，从而提高口服可用性。由于这种模拟物在血浆中不会被非特异性酯酶裂解，因此它在血液循环中保持完好无损，有利于靶细胞吸收。表观抗病毒 50%有效浓度（EC 50 s）显著下降，与非脂质结合的母体化合物相比，在靶细胞中的降幅可达 3 个对数。我们已将这项技术应用于替诺福韦，目的是提高口服的可用性，降低表观 EC 50 ，并通过减少肾脏与游离二离子替诺福韦的接触来降低肾毒性的可能性。我们在此报告，在体外，替诺福韦的十六烷氧基丙酯 CMX157 对 HIV-1 的活性是替诺福韦的 267 倍，对 HBV 的活性是替诺福韦的 4.5 倍。CMX157 可口服，按 10、30 或 100 毫克/千克/天的剂量给大鼠口服 7 天后，无明显毒性。因此，CMX157代表了第二代替诺福韦类似物，可能具有更好的临床表现。
• Synthesis and Antiviral Evaluation of Alkoxyalkyl Derivatives of 9-(<i>S</i>)-(3-Hydroxy-2-phosphonomethoxypropyl)adenine against Cytomegalovirus and Orthopoxviruses
  作者：James R. Beadle、William B. Wan、Stephanie L. Ciesla、Kathy A. Keith、Caroll Hartline、Earl R. Kern、Karl Y. Hostetler

  DOI：10.1021/jm050473m

  日期：2006.3.1

  9-(S)-(3-Hydroxy-2-phosphonomethoxypropyl)adenine [(S)-HPMPA] was one of the first acyclic nucleoside phosphonates described and has been reported to have good antiviral activity against most double-stranded DNA viruses, including the herpes group viruses and the orthopoxviruses. However, (S)-HPMPA is not orally bioavailable and has not been developed for clinical use. We have prepared orally bioavailable lipid esters of (S)-HPMPA and report their synthesis and antiviral evaluation against cytomegalovirus and orthopoxviruses. These esters were evaluated in vitro in cells infected with human cytomegalovirus (HCMV), murine cytomegalovirus (MCMV), vaccinia (VV), and cowpox viruses (CV). The most active compound, oleyloxyethyl-(S)-HPMPA, was found to have EC50 value of 0.003 mu M against HCMV vs 1.4 mu M for unmodified HPMPA. In cells infected with VV and CV, octadecyloxyethyl-(S)-HPMPA had EC50 values of 0.01-0.02 mu M versus 2.7 -4.0 mu M for unmodified HPMPA. When compared with the alkoxyalkyl esters of cidofovir, the corresponding alkoxyalkyl esters of (S)-HPMPA were equally active against HCMV and MCMV but were 15-20-fold more active against VV and CV in vitro. The alkoxyalkyl esters of (S)-HPMPA are promising new compounds worthy of further investigation for treatment of infections caused by herpes viruses and orthopoxviruses.
• [EN] METHODS FOR PREPARATION OF NUCLEOSIDE PHOSPHONATE ESTERS<br/>[FR] ELABORATION DE PHORPHONATES-ESTERS NUCLEOSIDIQUES
  申请人：UNIV CALIFORNIA

  公开号：WO2005087788A3

  公开（公告）日：2005-12-29
• Synthesis of phosphonomethoxyethyl or 1,3-bis(phosphonomethoxy)propan-2-yl lipophilic esters of acyclic nucleoside phosphonates
  作者：Silvie Vrbková、Martin Dračínský、Antonín Holý

  DOI：10.1016/j.tet.2007.08.081

  日期：2007.11

  A new alternative synthetic pathway towards mono and diesters of acyclic nucleoside phosphonates (PMEA, PMEC and PMEG) or [1,3-bis(phosphonomethoxy) propan-2-yl] adenine bearing one or two hexadecyloxypropyl ester groups (CH2)(3)O-n-C16H33 is reported. (C) 2007 Elsevier Ltd. All rights reserved.