阿拉氟韦 | 193681-12-8

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 中文名称: 阿拉氟韦
• 英文名称: Alamifovir
• 英文别名: bis(2,2,2-trifluoroethyl)((2-(2-amino-6-((4-methoxyphenyl)sulfanyl)-9H-purin-9-yl)ethoxy)methyl)phosphonate；2-amino-6-(4-methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester；LY-582563；MCC-478；9-[2-[bis(2,2,2-trifluoroethoxy)phosphorylmethoxy]ethyl]-6-(4-methoxyphenyl)sulfanylpurin-2-amine
• CAS: 193681-12-8
• 化学式: C₁₉H₂₀F₆N₅O₅PS
• 分子量: 575.428
• InChiKey: VDBGPMJFHCJMOL-UHFFFAOYSA-N

物化性质

• 熔点：
  84-85℃
• 沸点：
  671.5±65.0 °C(Predicted)
• 密度：
  1.60

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  37
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  149
• 氢给体数：
  1
• 氢受体数：
  16

制备方法与用途

阿拉米福韦（LY582563；MCC-478）是一种嘌呤核苷酸类似物前药，对野生型及拉米夫定耐药的乙型肝炎病毒（HBV）表现出强大的抑制作用。它具有高效抗HBV复制和持续抗病毒的作用[1][2]。

反应信息

• 作为反应物：
  描述：

  阿拉氟韦 在 sodium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 以98%的产率得到Sodium;2-[2-amino-6-(4-methoxyphenyl)sulfanylpurin-9-yl]ethoxymethyl-(2,2,2-trifluoroethoxy)phosphinate
  参考文献：
  名称：

  2-Amino-6-arylthio-9-[2-(phosphonomethoxy)ethyl]purine Bis(2,2,2-trifluoroethyl) Esters as Novel HBV-Specific Antiviral Reagents

  摘要：

  Novel 2-amino-6-arylthio-9-[2-(phosphonomethoxy)ethyl] purine bis(2,2,2-trifluoroethyl) esters were synthesized and evaluated for antihepatitis B virus (HBV) activity in vitro using HB611, HuH-6 cell line, stably transfected with the HBV genome. Among the compounds synthesized, 2-amino-6-phenylthio-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester (8), 2-amino-6-(4-methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl] purine bis(2,2,2-trifluoroethyl) ester (16), 2-amino-6-(3-methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester (17), and 2-amino-6-(2-methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester (18) showed considerably high anti-HBV activity, as represented by IC50 values of 0.05, 0.03, 0.04, and 0.08 muM, respectively, and exhibited low cytotoxicity, as represented by CC50 values of more than 1000 muM. It was suggested that these compounds did not have anti-HIV activity, and compound 8 showed only weak anti-HSV-1 activity. An antiviral agent, 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), which was used as a control in the present study, showed moderate anti-HBV activity, as represented by an IC50 value of 0.2 muM. Furthermore, compound 16 was administered orally to mice at a dose of 100 mg/kg in order to examine its gastrointestinal absorbability. Consequently, the main active metabolite was observed in mouse plasma, with especially high concentrations in the liver.

  DOI：

  10.1021/jm020036x
• 作为产物：
  描述：

  4-甲氧基苯硫酚 在 吡啶 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三氟乙酸酐 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.67h， 生成 阿拉氟韦
  参考文献：
  名称：

  Synthesis of 2-amino-6-(4-[11C]methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester as a novel potential PET gene reporter probe for HBV and HSV-tk in cancers

  摘要：

  Acyclic nucleoside 2-amino-6-(4-methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester (ABE, 1) is a new hepatitis B virus (HBV) specific antiviral reagent and shows high anti-HBV activity. Carbon-11 labeled ABE may serve as a novel reporter probe for positron emission tomography (PET) to image HBV and herpes simplex virus thymidine kinase (HSV-tk) in cancers. The radiolabeling precursors 2-amino-6-(4-hydroxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester (10) and 2-N-Boc protected analogue 2-N-bis(Boc)amino-6-(4-hydroxyphenylthio)9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester (12), and the reference standard ABE were synthesized from bis(trifluoroethyl) (2-iodoethoxy)methylphosphonate (5), guanine (6), and 2-amino-6-chloropurine (8). The target radiotracer 2-amino-6-(4-[C-11]methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2,2,2-trifluoroethyl) ester ([C-11]ABE, [C-11]1) was prepared by O-[C-11]methylation of the unprotected HO-precursor 10, or 2-N-Boc protected HO-precursor 12 with [C-11]methyl triflate followed by a quick deprotection reaction, and isolated by solid-phase extraction (SPE) purification in 40-55% radiochemical yields. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.10.007

文献信息

• PHOSPHORIC ACID/PHOSPHONIC ACID DERIVATIVES AND MEDICINAL USES THEREOF
  申请人：BEIJING MEIBEITA DRUG RES CO., LTD.

  公开号：US20160115186A1

  公开（公告）日：2016-04-28

  The present invention relates to phosphoric acid/phosphonic acid derivatives shown by formula (I), wherein, R 1 or R 2 represents the following structures: (Q1), or (Q2), or (Q3). Q1 represents ester derivatives of L-amino acid, wherein R 3 is alkyl with 1-6 carbon atoms or cycloalkyl, R 4 is H or alkyl with 1-6 carbon atoms; Q2 represents hydroxyl substituted benzodioxane derivatives; Q3 represents hydroxyl substituted benzodioxolane derivatives; R 1 or R 2 is the same or different, but at least one of them is Q2 or Q3; D represents residues of pharmacologically active molecules containing a phosphate/phosphonate group, i.e. formula (II) represents pharmacologically active molecules containing a phosphate/phosphonate group; and when R 1 and R 2 are different, the configuration of the P atom connected to R 1 and R 2 is of R or S type.

  本发明涉及由式（I）所示的磷酸/膦酸衍生物，其中，R1或R2代表以下结构：（Q1），或（Q2），或（Q3）。Q1代表L-氨基酸的酯衍生物，其中R3是具有1-6个碳原子的烷基或环烷基，R4是H或具有1-6个碳原子的烷基；Q2代表羟基取代的苯二噁烷衍生物；Q3代表羟基取代的苯二噁唑烷衍生物；R1或R2相同或不同，但它们中至少有一个是Q2或Q3；D代表含有磷酸/膦酸基团的药理活性分子的残基，即式（II）代表含有磷酸/膦酸基团的药理活性分子；当R1和R2不同时，连接到R1和R2的P原子的构型为R型或S型。
• Design, synthesis and in vitro evaluation of mono (2, 2, 2-trifluoroethyl) esters, mono l-amino acid ester prodrugs of acyclic nucleoside phosphonates as anti-HBV agents
  作者：Xiao Zhong Fu、Yu Ou、Jan Xin、Yu She Yang

  DOI：10.1016/j.cclet.2011.09.005

  日期：2011.12

  Abstract A series of novel mono (2, 2, 2-trifluoroethyl) esters, mono l -amino acid ester prodrugs of acyclic nucleoside phosphonates was synthesized and their in vitro anti-HBVactivity was evaluated in HepG 2 2.2.15 cells. Compound 1d exhibited more potent anti-HBV activity and lower cytotoxicity than those of adefovir dipivoxil and alamifovir (MCC-478) with EC 50 and CC 50 values of 0.01 μmol/L and

  摘要合成了一系列新型的无环核苷膦酸酯单（2，2，2-三氟乙基）酯，单1-氨基酸酯前药，并在HepG 2 2.2.15细胞中评估了它们的体外抗HBV活性。与阿德福韦酯和阿拉米福韦（MCC-478）相比，化合物1d表现出更强的抗HBV活性和较低的细胞毒性，EC 50和CC 50值分别为0.01μmol/ L和> 8000μmol/ L。
• Acyclic Nucleoside Phosphonate Derivatives and Medical Uses Thereof
  申请人：Zhong Bohua

  公开号：US20120322764A1

  公开（公告）日：2012-12-20

  The present invention relates to an acyclic nucleoside phosphonate derivative and medical uses thereof. Specifically, the present invention relates to an acyclic nucleoside phosphonate derivative of Formula I having strong potency against viruses, such as hepatitis B virus, and low cytotoxicity, or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof, wherein R 1 is H or methyl; each R 2 is independently —R 3 or —OR 3 , each R 3 is independently C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl. The present invention further relates to a process for preparing the compounds of Formula I, a pharmaceutical composition comprising the compound, and the medical uses of the compound. The acyclic nucleoside phosphonate derivative of the present invention has activity against virus such as hepatitis B virus and good in vivo behavioral traits.

  本发明涉及一种无环核苷酸膦酸酯衍生物及其医药用途。具体而言，本发明涉及一种式I的无环核苷酸膦酸酯衍生物，其对病毒（如乙型肝炎病毒）具有强效力且细胞毒性低，或其药学上可接受的盐、异构体、水合物或溶剂化物，其中R1为H或甲基；每个R2独立地是—R3或—OR3，每个R3独立地是C1-C8烷基、C3-C8环烷基。本发明还涉及制备式I化合物的方法、包含该化合物的制药组合物以及该化合物的医药用途。本发明的无环核苷酸膦酸酯衍生物具有对乙型肝炎病毒等病毒的活性和良好的体内行为特性。
• 医薬製剤組成物
  申请人：——

  公开号：JP2004175798A

  公开（公告）日：2004-06-24

  【課題】 ２−アミノ−６−（４−メトキシフェニルチオ）−９−[２−（ホスホノメトキシ）エチル]プリン ビス（２，２，２−トリフルオロエチル）エステルを有効成分とする安定な医薬製剤組成物を提供する。【解決手段】 ２−アミノ−６−（４−メトキシフェニルチオ）−９−[２−（ホスホノメトキシ）エチル]プリン ビス（２，２，２−トリフルオロエチル）エステルを有効成分とし、該２−アミノ−６−（４−メトキシフェニルチオ）−９−[２−（ホスホノメトキシ）エチル]プリン ビス（２，２，２−トリフルオロエチル）エステルの二量体及び／または加水分解物の生成が実質的に抑制された医薬製剤組成物。【選択図】 なし

  2-氨基-6-(4-甲氧基苯硫基)-9-[2-(磷酰甲氧基)乙基]嘌呤双(2,2,2-三氟乙基)酯本发明提供了一种以嘌呤双(2,2,2-三氟乙基)酯为活性成分的稳定的药物制剂组合物。溶液：2-氨基-6-(4-甲氧基苯硫基)-9-[2-(磷酰甲氧基)乙基]嘌呤双(2,2,2-三氟乙基)酯作为活性成分，所述 2-氨基-6-(4-甲氧基苯硫基)-9-[2-(磷酰甲氧基)-9-[2-(膦酰甲氧基)乙基]嘌呤双(2,2,2-三氟乙基)酯的二聚体和/或水解物的形成受到极大抑制的药物制剂组合物。无。
• ２−アミノ−６−（４−メトキシフェニルチオ）−９−［２−（ホスホノメトキシ）エチル］プリンビス（２，２，２−トリフルオロエチル）エステルの結晶
  申请人：——

  公开号：JP2004175788A

  公开（公告）日：2004-06-24

  【課題】 抗ウイルス剤として有用な２−アミノ−６−（４−メトキシフェニルチオ）−９−[２−（ホスホノメトキシ）エチル]プリン ビス（２，２，２−トリフルオロエチル）エステルの新規な結晶を提供する。【解決手段】 ２−アミノ−６−（４−メトキシフェニルチオ）−９−[２−（ホスホノメトキシ）エチル]プリン ビス（２，２，２−トリフルオロエチル）エステルの新規な結晶及びそれを有効成分とする抗ウイルス剤に代表される医薬組成物。【選択図】 なし

  2-氨基-6-(4-甲氧基苯硫基)-9-[2-((磷酰甲氧基)乙基]嘌呤双(2,2,2-三氟乙基)酯的新晶体，该晶体可用作抗病毒剂。溶液：2-氨基-6-(4-甲氧基苯硫基)-9-[2-(磷酰甲氧基)乙基]嘌呤双(2,2,2-三氟乙基)酯。溶液：2-氨基-6-(4-甲氧基苯硫基)-9-[2-(磷酰甲氧基)乙基]嘌呤双(2,2,2-三氟乙基)酯的新晶体和以该晶体为有效成分的抗病毒药物为代表的药物组合物。无。