9-(5-O-acetyl-β-D-arabinofuranosyl)adenine | 65926-28-5

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: 9-(5-O-acetyl-β-D-arabinofuranosyl)adenine
• 英文别名: O⁵-acetyl-1-(6-amino-purin-9-yl)-β-D-1-deoxy-arabinofuranose；9-(5-0-acetyl-β-D-arabinofuranosyl)adenine；9-(5-O-Acetyl-β-D-arabinofuranosyl)-adenin；9-(5-O-acetyl-beta-D-arabinofuranosyl)adenine；[(2R,3S,4S,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl acetate
• CAS: 65926-28-5
• 化学式: C₁₂H₁₅N₅O₅
• 分子量: 309.282
• InChiKey: RMIAANGDAQJRIT-QRKAXHLRSA-N

物化性质

• 熔点：
  198°C
• 沸点：
  449.56°C (rough estimate)
• 密度：
  1.3120 (rough estimate)

计算性质

• 辛醇/水分配系数(LogP)：
  -1
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  146
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  9-(5-O-acetyl-β-D-arabinofuranosyl)adenine 以 水 为溶剂， 生成 阿糖腺苷
  参考文献：
  名称：

  9-β-d-阿拉伯呋喃糖基腺嘌呤前药中水解和溶剂依赖性2'→5'和3'→5'酰基迁移

  摘要：

  作为进一步进行定量体内研究的先决条件，以进一步探索9-β-D-阿拉伯呋喃糖基腺嘌呤（ara-A）的2'，3'-二-O-乙酰基衍生物对疱疹病毒感染的动力学活性研究了2'，3'-二-O-乙酰基衍生物以及2'-，3'-和5'-单乙酸酯的溶液降解。基于对取代基效应的考虑，发现水溶液水解的速率与等级排序预测一致。然而，初步的体内水解数据与这种预测无关，这表明需要对分子结构对酶催化水解的影响进行更系统的研究。2'-3'-二酯和3'-单酯在水溶液中的重要反应，除了酯水解外，还有3'。---- 5'的酰基迁移。乙腈中的研究证实，2'---- 5'酰基迁移不会在水中发生，而是在有机溶剂中的主要迁移途径。1 H NMR光谱用于研究糖环的构象对溶剂环境的依赖性。尽管确实发生了C（2'）内基和C（3'）内基构象状态之间的平衡变化，但这不是一个戏剧性的变化，不能解释在酰基迁移动力学中观察到的溶剂选择性。

  DOI：

  10.1002/jps.2600740805
• 作为产物：
  描述：

  9-<3-O-acetyl-β-D-arabinofuranosyl>adenine 以 水 为溶剂， 生成 阿糖腺苷 、 9-(5-O-acetyl-β-D-arabinofuranosyl)adenine
  参考文献：
  名称：

  9-β-d-阿拉伯呋喃糖基腺嘌呤前药中水解和溶剂依赖性2'→5'和3'→5'酰基迁移

  摘要：

  作为进一步进行定量体内研究的先决条件，以进一步探索9-β-D-阿拉伯呋喃糖基腺嘌呤（ara-A）的2'，3'-二-O-乙酰基衍生物对疱疹病毒感染的动力学活性研究了2'，3'-二-O-乙酰基衍生物以及2'-，3'-和5'-单乙酸酯的溶液降解。基于对取代基效应的考虑，发现水溶液水解的速率与等级排序预测一致。然而，初步的体内水解数据与这种预测无关，这表明需要对分子结构对酶催化水解的影响进行更系统的研究。2'-3'-二酯和3'-单酯在水溶液中的重要反应，除了酯水解外，还有3'。---- 5'的酰基迁移。乙腈中的研究证实，2'---- 5'酰基迁移不会在水中发生，而是在有机溶剂中的主要迁移途径。1 H NMR光谱用于研究糖环的构象对溶剂环境的依赖性。尽管确实发生了C（2'）内基和C（3'）内基构象状态之间的平衡变化，但这不是一个戏剧性的变化，不能解释在酰基迁移动力学中观察到的溶剂选择性。

  DOI：

  10.1002/jps.2600740805

文献信息

• Regioselective enzymatic acylation of pharmacologically interesting nucleosides in 2-methyltetrahydrofuran, a greener substitute for THF
  作者：Yolanda Simeó、José Vicente Sinisterra、Andrés R. Alcántara

  DOI：10.1039/b818992g

  日期：——

  1-β-Arabinofuranosyl uracil, 9-β-arabinofuranosyl adenosine, 2′-O-(2-methoxyethyl)-5-methyl uridine, adenosine and uridine were enzymatically acylated with hexanoic anhydride and vinyl esters by CALB lipase (lipase B from Candida antarctica) with excellent regioselectivity in many cases and analytical reaction yields above 90%. The influence of the stereochemistry of the hydroxyl group on C-2′ was studied. Some of these esterifications were carried out in 2-methyltetrahydrofuran (MeTHF), which is described as an excellent substitute for THF in biocatalysed processes in organic media. This application for this green solvent is a proof-of-concept opening the use of MeTHF in biotransformations.

  1-β-阿拉伯呋喃糖基尿嘧啶、9-β-阿拉伯呋喃糖基腺苷、2′-O-(2-甲氧基乙基)-5-甲基尿苷、腺苷和尿苷在南极假丝酵母酯酶B（CALB）的催化下，与己酸酐和乙烯酯进行酶法酰化反应，具有优异的区域选择性，反应产率高于90%。研究了C-2′羟基的立体化学性质对反应的影响。一些酰化反应在2-甲基四氢呋喃（MeTHF）中进行，该溶剂被认为是生物催化过程中有机介质中四氢呋喃的优良替代品。这种绿色溶剂的应用验证了其在生物转化中使用的概念，为MeTHF的应用开辟了道路。
• 9-(5-O-Acyl-.beta.-D-arabinofuranosyl)adenine compounds
  申请人：Parke, Davis & Company

  公开号：US04069382A1

  公开（公告）日：1978-01-17

  9-(5-O-Acyl-.beta.-D-arabinofuranosyl)adenine compounds and their production by reacting 9-(.beta.-D-arabinofuranosyl)adenine with a reactive derivative of an alkanoic acid. The compounds are useful as antiviral agents. The compounds are water-soluble and lipophilic, thereby being adaptable to a wide variety of pharmaceutical formulations. The present invention relates to new organic compounds that are useful in pharmacological agents and to a method for their production. More particularly, the invention relates to new 9-(5-O-acyl-.beta.-D-arabinofuranosyl)-adenine compounds that are represented by the formula ##STR1## where R is a straight chain alkanoyl group having from 2 to 8 carbon atoms or a branched chain alkanoyl group having 4 to 5 carbon atoms. Examples of alkanoyl groups represented by R are acetyl, propionyl, butyryl, pentanoyl, hexanoyl, octanoyl, 3-methylbutyryl, and 2,2-dimethylpropionyl. In accordance with the invention, 9-(5-O-acyl-.beta.-D-arabinofuranosyl)adenine compounds having formula I are produced by reacting 9-(.beta.-D-arabinofuranosyl)adenine with an equivalent quantity of a reactive derivative of an alkanoic acid that can be represented by the formula ROH where R is a straight chain alkanoyl group having from 2 to 8 carbon atoms or a branched chain alkanoyl group having 4 to 5 carbon atoms. Suitable reactive derivatives of the alkanoic acid that may be used for this purpose are the acid anhydride and an acid halide. When an acid halide, preferably an acid chloride, is used, a tertiary amine such as triethylamine, quinoline, N-methylpiperidine, or pyridine, is added to the reaction mixture in an amount sufficient to bind the hydrohalic acid liberated. When the acid anhydride is employed, it is preferable to add tertiary amine to the reaction mixture, such as one of those named above. The reaction is advantageously carried out in a tertiary amide solvent medium. Suitable solvents for this purpose include N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2-pyrrolidinone; as well as mixtures of these. A preferred base-solvent combination is a 1:1 mixture of pyridine and dimethylformamide. A large excess of this base-solvent mixture is used, in a preferred procedure, together with 1 to 1.2 equivalents of the acid chloride, based on the amount of 9-.beta.-D-arabinofuranosyladenine used. The precise temperature and duration of the reaction are not critical and may be varied widely depending upon the reactants and solvent employed. When either an acid halide or the acid anhydride is used in the presence of tertiary amine, the reaction temperature can be varied between about 0.degree. and about 100.degree. C. for 1 to 24 hours, with the longer times being used at the lower temperatures. In most cases, preferred conditions are temperatures from 20.degree. to 30.degree. C. for 1.5 to 12 hours, although longer times as well as higher temperatures may be used to insure completeness of reaction. When an excess of the alkanoic acid derivative is used, the excess is decomposed at the conclusion of the reaction, by the addition of water, prior to isolation of the product. The 9-(5-O-acyl-.beta.-D-arabinofuranosyl)adenine compounds are new chemical compounds that are useful as pharmacological agents, especially as antiviral agents against herpes virus. Their activity as antiviral agents can be quantitatively measured in an in vitro test by utilizing the plaque reduction technique first developed by Dulbecco (Proc. Natl. Acad. Sci., Volume 38, pages 747-752) and modified by Hsiung and Melnick (Virology, Volume 1, pages 533-535). In this test, a complete cell monolayer is first grown on a glass test unit. The growth medium is then removed, and the virus is adsorbed on the cell monolayer for a measured time period. In the absence of an antiviral agent, the virus will destroy well-defined areas of cells, called plaques, that can be seen macroscopically when the vital stain, neutral red, is added to the system. To test the inhibiting effect of a given compound, the test compound in solution is added to the virus-cell system, and the whole is covered with a nutrient agar overlay containing neutral red. After incubation, the plaques are counted, and the number of plaques produced in the system containing the test compound is compared with the number produced in the control systems, from whch only the test compound is omitted. The inhibitory activity of a test compound is reported as the percentage reduction of the plaque count on the test units compared with that on the controls. When tested by this plaque reduction technique, with 4 oz. glass bottles serving as the test units and H. Ep. No. 2 cells making up the cell monolayer, the compounds of the invention, at a concentration of 50-65 micrograms/ml. in Hank's Balanced Salt Solution (pH 7-8), typically were found to give substantially complete plaque reduction against herpes simplex. As specified above, the ester compounds of the invention are derived from 9-(.beta.-D-arabinofuranosyl)adenine, which is known to be an antiviral agent that is active against herpes virus. The latter compound has been reported to be more active in vitro against herpes virus than its 5'-benzoyl ester whereas its 5'-palmitate ester was inactive in the same test (Renis et al., J. Med. Chem., 16, 754); the compound has also been reported (Repta et al., J. Pharm. Sci., 64, 392) to be poorly soluble in water and its 5'-formate ester, relatively water-soluble, to be unstable in aqueous solution. It is therefore surprising that the compounds of the invention, unlike the prior art compounds, exhibit good antiviral activity and are adaptable to a wide variety of oral, topical and parenteral pharmaceutical formulations, being readily soluble in water and/or lipophilic. Preferred compounds of the invention in this regard are the compounds of Formula I in which R is a straight chain alkanoyl group having from 2 to 8 carbon atoms and, in particular 9-(5-O-acetyl-.beta.-D-arabinofuranosyl)adenine, 9-(5-O-propionyl-.beta.-D-arabinofuranosyl)adenine, 9-(5-O-butyryl-.beta.-D-arabinofuranosyl)adenine, and 9-(5-O-pentanoyl-.beta.-D-arabinofuranosyl)adenine, of which latter compounds the 5-O-pentanoyl compound is the first compound of choice for its antiviral properties. Also preferred for their increased solubility properties and lipophilicity are 9-[5-O-(3-methylbutyryl)-.beta.-D-arabinofuranosyl]adenine and 9-(5-O-butyryl-.beta.-D-arabinofuranosyl)-adenine

  9-(5-O-Acyl-.beta.-D-arabinofuranosyl)腺嘌呤化合物是通过将9-(.beta.-D-阿拉伯糖基)腺嘌呤与烷基酸的反应衍生物反应而成的。这些化合物可用作抗病毒剂。这些化合物是水溶性和亲脂性的，因此适用于各种药物制剂。本发明涉及用于制备药物的新有机化合物及其生产方法。更具体地，本发明涉及新的9-(5-O-酰基-.beta.-D-阿拉伯糖基)-腺嘌呤化合物，其由以下公式表示：##STR1##其中R是直链烷酰基，其碳原子数为2到8个，或支链烷酰基，其碳原子数为4到5个。R代表的烷酰基的例子包括乙酰基、丙酰基、丁酰基、戊酰基、己酰基、辛酰基、3-甲基丁酰基和2,2-二甲基丙酰基。根据本发明，通过将9-(.beta.-D-阿拉伯糖基)腺嘌呤与烷基酸的反应衍生物的等量反应，制备具有公式I的9-(5-O-酰基-.beta.-D-阿拉伯糖基)腺嘌呤化合物。可用于此目的的烷基酸的适当反应衍生物是酸酐和酸卤化物。当使用酸卤化物，优选使用酸氯化物时，向反应混合物中加入三乙胺、喹啉、N-甲基哌啶或吡啪烷等三级胺，以足够量结合释放的氢酸酸。当使用酸酐时，最好向反应混合物中添加三级胺，例如上述任意一种。优选在三级酰胺溶剂介质中进行反应。适用于此目的的溶剂包括N，N-二甲基甲酰胺、N，N-二甲基乙酰胺和N-甲基-2-吡咯烷酮，以及这些的混合物。首选的碱-溶剂组合是吡啶和二甲基甲酰胺的1:1混合物。在首选的程序中，使用这种碱-溶剂混合物的大量过量，以及1到1.2当量的酸氯化物，基于使用的9-.beta.-D-阿拉伯糖基腺嘌呤的量。反应的精确温度和持续时间并不关键，可以根据所使用的反应物和溶剂而广泛变化。当使用酸卤化物或酸酐时，在存在三级胺的情况下，反应温度可以在0℃到100℃之间变化，反应时间为1到24小时，较长的时间在较低的温度下使用。在大多数情况下，首选条件是20℃到30℃的温度，反应时间为1.5到12小时，尽管可以使用更长的时间和更高的温度来确保反应的完整性。当使用烷基酸衍生物的过量时，在分离产物之前，通过添加水分解过量的衍生物。9-(5-O-酰基-.beta.-D-阿拉伯糖基)腺嘌呤化合物是新的化学化合物，可用作药物制剂，特别是抗疱疹病毒药物。它们作为抗病毒剂的活性可以通过利用Dulbecco首先开发的斑块还原技术（Proc. Natl. Acad. Sci.，38卷，第747-752页）和由Hsiung和Melnick修改的技术在体外测试中定量测量。在此测试中，首先在玻璃测试单元上生长完整的细胞单层。然后去除生长培养基，并将病毒吸附在细胞单层上一定时间。在没有抗病毒剂的情况下，病毒将破坏细胞的明确定义区域，称为斑块，当加入活性染料中性红色时，可以在宏观上看到。为了测试给定化合物的抑制效果，将溶液中的测试化合物添加到病毒-细胞系统中，并将其整个覆盖在含有中性红色的营养琼脂上。孵育后，计数斑块，并将包含测试化合物的系统中产生的斑块数与仅省略测试化合物的对照系统中产生的数进行比较。测试化合物的抑制活性报告为测试单元上斑块计数与对照计数之比的百分比减少量。当使用4盎司玻璃瓶作为测试单元，H. Ep. No. 2细胞组成细胞单层时，本发明化合物在汉克平衡盐溶液（pH 7-8）中的浓度为50-65微克/毫升时，通常被发现对单纯疱疹病毒产生完全的斑块还原。如上所述，本发明的酯化合物源自已知的9-(.beta.-D-阿拉伯糖基)腺嘌呤，该化合物已知是对抗疱疹病毒活性的抗病毒剂。后者的化合物据报道在体外对抗疱疹病毒的活性比其5'-苯甲酰酯高，而其5'-棕榈酸酯在相同测试中无活性（Renis等人，J. Med. Chem.，16，754）；该化合物也已报告（Repta等人，J. Pharm. Sci.，64，392）在水中不溶，其5'-甲酸酯相对水溶性较好，在水溶液中不稳定。因此，与先前的化合物不同，本发明的化合物表现出良好的抗病毒活性，并适用于各种口服、局部和静脉药物制剂，易于溶解于水和/或亲脂性。在这方面，本发明的首选化合物是公式I中R是直链烷酰基，其碳原子数为2到8个的化合物，特别是9-(5-O-乙酰基-.beta.-D-阿拉伯糖基)腺嘌呤、9-(5-O-丙酰基-.beta.-D-阿拉伯糖基)腺嘌呤、9-(5-O-丁酰基-.beta.-D-阿拉伯糖基)腺嘌呤和9-(5-O-戊酰基-.beta.-D-阿拉伯糖基)腺嘌呤，其中后一种化合物是其抗病毒性质的首选化合物。此外，由于其增加的溶解性和亲脂性，9-[5-O-(3-甲基丁酰基)-.beta.-D-阿拉伯糖基]腺嘌呤和9-(5-O-丁酰基-.beta.-D-阿拉伯糖基)-腺嘌呤也是首选化合物。
• US4069382A
  申请人：——

  公开号：US4069382A

  公开（公告）日：1978-01-17
• Hydrolysis and Solvent-Dependent 2′→5′ and 3′→5′ Acyl Migration in Prodrugs of 9-β-d-Arabinofuranosyladenine
  作者：Bradley D. Anderson、Man-Cheong Fung、Shiv D. Kumar、David C. Baker

  DOI：10.1002/jps.2600740805

  日期：1985.8

  As a prerequisite to quantitative in vivo studies to further explore the promising topical activity of the 2',3'-di-O-acetyl derivative of 9-beta-D-arabinofuranosyladenine (ara-A) against herpes virus infections, the kinetics of solution degradation of the 2',3'-di-O-acetyl derivative and the 2'-,3'-, and 5'-monoacetates were investigated. The rates of aqueous solution hydrolysis were found to be consistent

  作为进一步进行定量体内研究的先决条件，以进一步探索9-β-D-阿拉伯呋喃糖基腺嘌呤（ara-A）的2'，3'-二-O-乙酰基衍生物对疱疹病毒感染的动力学活性研究了2'，3'-二-O-乙酰基衍生物以及2'-，3'-和5'-单乙酸酯的溶液降解。基于对取代基效应的考虑，发现水溶液水解的速率与等级排序预测一致。然而，初步的体内水解数据与这种预测无关，这表明需要对分子结构对酶催化水解的影响进行更系统的研究。2'-3'-二酯和3'-单酯在水溶液中的重要反应，除了酯水解外，还有3'。---- 5'的酰基迁移。乙腈中的研究证实，2'---- 5'酰基迁移不会在水中发生，而是在有机溶剂中的主要迁移途径。1 H NMR光谱用于研究糖环的构象对溶剂环境的依赖性。尽管确实发生了C（2'）内基和C（3'）内基构象状态之间的平衡变化，但这不是一个戏剧性的变化，不能解释在酰基迁移动力学中观察到的溶剂选择性。