6-(4-methoxyphenyl)-3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-5H-imidazol[1,2-a]purine | 231629-80-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 6-(4-methoxyphenyl)-3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-5H-imidazol[1,2-a]purine
• 英文别名: 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-6-(4-methoxyphenyl)-9-oxo-5H-imidazo[1,2-a]purine；3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-6-(4-methoxyphenyl)-5H-imidazo[1,2-a]purine；6-(4-MeOPh)-TRIC-ACV；3-(2-hydroxyethoxymethyl)-6-(4-methoxyphenyl)-5H-imidazo[1,2-a]purin-9-one
• CAS: 231629-80-4
• 化学式: C₁₇H₁₇N₅O₄
• 分子量: 355.353
• InChiKey: XWCDMALRJYUKBH-UHFFFAOYSA-N

物化性质

• 沸点：
  777.6±70.0 °C(Predicted)
• 密度：
  1.51±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-(4-methoxyphenyl)-3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-5H-imidazol[1,2-a]purine 在 水 作用下， 反应 504.0h， 生成 阿昔洛韦
  参考文献：
  名称：

  含三环碱基的核苷类似物的合成、抗病毒活性和稳定性

  摘要：

  以9-[4-α-(羟甲基)环戊-2-烯-1为原料合成了一系列3,9-dihydro-9-oxo-5 H - imidazo [1,2- A ]嘌呤核苷(三环核苷) -α-基]鸟嘌呤 (CBV) 5 , (-)-β-D-(2 R ,4 R )-1,3-二氧戊环-鸟苷 (DXG) 6 , 3'-叠氮基-3'-脱氧-鸟苷(AZG) 7和 2'- C-甲基鸟苷8。他们对 HIV 和 HCV 的体外活性进行了评估，并与它们降解为嘌呤对应物的能力相关联。

  DOI：

  10.1016/j.ejmech.2009.04.003
• 作为产物：
  描述：

  阿昔洛韦 在 ammonium hydroxide 、 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 6-(4-methoxyphenyl)-3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-5H-imidazol[1,2-a]purine
  参考文献：
  名称：

  Fluorescent Tricyclic Analogues of Acyclovir and Ganciclovir. A Structure−Antiviral Activity Study

  摘要：

  Of a series of new guanine base modified tricyclic analogues of acyclovir (ACV, 1) and ganciclovir (GCV, 2), derivatives of the 3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purine system, evaluated for activity against herpes simplex virus type 1 and 2, several fluorescent analogues, 6-(4-MeOPli)-TACV (8), 7-Me-6-Ph-TACV (17), 6-(4-MeOPh)-TGCV (27), and 7-Me-6-Ph-TGCV (28), were obtained that showed similar potency and selectivity as the parent compounds. The activity was found to Le strongly dependent on the nature and steric demands of the substituents in the 6 and/or 7 position.

  DOI：

  10.1021/jm010922s

文献信息

• Substituent — Directed Aralkylation and Alkylation Reactions of the Tricyclic Analogues of Acyclovir and Guanosine
  作者：Tomasz Ostrowski、Joanna Zeidler、Tomasz Goslinski、Bozenna Golankiewicz

  DOI：10.1080/15257770008045468

  日期：2000.10

  Abstract Aryl or tert-butyl substituent in the 6 position of 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-6-R-5H-imidazo[1,2-α]purine (6-R-TACV)1 1 partly directs aralkylation reactions into unusual positions: N-4 to give 3 and C-7 to give N-5, 7-disubstituted or N-4, 7-disubstituted derivatives. In the case of alkylation the effect is limited to aryl substituent and position N-4. Replacement of acyclic

  摘要3,9-二氢-3-[（2-羟基乙氧基）甲基] -9-氧代-6-R-5H-咪唑并[1,2-α]嘌呤的6位上的芳基或叔丁基取代基（6 -R-TACV）1 1部分将芳烷基化反应引导到不同的位置：N-4生成3，C-7生成N-5，7-二取代或N-4，7-二取代的衍生物。在烷基化的情况下，该作用限于芳基取代基和位置N-4。用7中的核糖基取代1的无环部分可防止N-4取代。切割3b的第三个环以得到3-苄基阿昔洛韦10是制备3-芳烷基-9-取代的鸟嘌呤的新捷径的一个实例。
• Ester Groups as Carriers of Antivirally Active Tricyclic Analogue of Acyclovir in Prodrugs Designing: Synthesis, Lipophilicity – Comparative Statistical Study of the Chromatographic and Theoretical Methods, Validation of the HPLC Method
  作者：Monika Lesniewska、Tomasz Ostrowski、Joanna Zeidler、Izabela Muszalska

  DOI：10.2174/1386207317666140526100532

  日期：2014.7.16

  Knowledge of the lipophilicity of candidate compounds for prodrugs may predict their predetermined course/effect in the body. Acyclovir (ACV) belongs to a class of drugs with low bioavailability. Its tricyclic analogues, the derivatives of 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-5H-imidazo[1,2-a]purine (TACV) exhibit similar antiviral activities and are more lipophilic as compared with acyclovir itself. In the search for new antiviral prodrugs 6-(4- methoxyphenyl) tricyclic compound (6-(4-MeOPh)-TACV) was modified by esterification of a hydroxyl group in the aliphatic chain. Selected esters (acetyl, isobutyryl, pivaloyl, ethoxycarbonyl and nicotinoyl) were synthesized and their lipophilicity was determined by the HPLC-RP method. The study compared the log kw calculated from the linear and quadratic equations and proved the correctness of the application of the linear relationship log k as a function of the concentration of ACN in the mobile phase (30-60%). Statistical analyses of the comparative values of log kw and clogP were carried out using computational methods. It was proved that the AC logP algorithm can be useful for the analysis of these compounds, which can have a statistically justified application in the assessment of the quantitative structure– activity relationship (QSAR). The lipophilicity determined by the HPLC method appears as follows: 6-(4-MeOPh)-TACV < Ac- < Nic- < Etc- < iBut- < Piv- (log kw = 0.65-2.26). Finally, the HPLC-RP method was developed and validated for simultaneous determination of synthesized esters.

  了解候选原药化合物的亲脂性可以预测它们在体内的预定疗程/效果。阿昔洛韦（ACV）属于生物利用度较低的一类药物。其三环类似物、3,9-二氢-3-[(2-羟基乙氧基)甲基]-9-氧代-5H-咪唑并[1,2-a]嘌呤（TACV）的衍生物具有类似的抗病毒活性，而且与阿昔洛韦本身相比更具亲脂性。为了寻找新的抗病毒原药，6-(4-甲氧基苯基)三环化合物（6-(4-MeOPh)-TACV）通过脂肪链中的羟基进行酯化改性。合成了一些酯（乙酰基、异丁酰基、新戊酰基、乙氧基羰基和烟酰基），并通过 HPLC-RP 方法测定了它们的亲脂性。研究比较了线性方程和二次方程计算出的 log kw，证明了应用 log k 作为流动相中 ACN 浓度（30%-60%）函数的线性关系的正确性。使用计算方法对 log kw 和 clogP 的比较值进行了统计分析。结果证明，AC logP 算法可用于分析这些化合物，在定量结构-活性关系（QSAR）评估中具有统计学上的合理应用。用高效液相色谱法测定的亲脂性如下：6-(4-MeOPh)-TACV < Ac- < Nic- < Etc- < iBut- < Piv- （log kw = 0.65-2.26）。最后，建立并验证了同时测定合成酯的 HPLC-RP 方法。
• Unusual Tritylation Reactions of Tricyclic Analogues of Acyclovir and an Attempt to Elucidate Their Mechanism
  作者：Tomasz Goslinski、Joanna Zeidler、Bozenna Golankiewicz

  DOI：10.1002/(sici)1522-2675(20000216)83:2<373::aid-hlca373>3.0.co;2-n

  日期：2000.2.16

  In reference to our earlier observation that the 3,9-dihydro-3-[ (2-hydroxyethoxy)methyl]-6-methyl-9-oxo-5H-imidazo[1,2-a]purine (6-Me-TACV) tricyclic antiviral agent derived from acyclovir undergoes unusual C-tritylation to 7-trityl and 7-[4-(benzhydryl)phenyl] derivatives enforced by a 6-Mc substituent, we studied tritylation of 6-Ph (1a) and 6-(4-MeOPh) (1b) TACV derivatives. The treatment of 1a and 1b with TrCl in K2CO3/DMF resulted exclusively in the formation of 7-[4-(benzhydryl)phenyl] derivatives 2a, 2b, 3a, 3b, and 4a. inhibition experiments with radical scavengers DNB and DBNO indicated a single-electron-transfer (SET) mechanism for this reaction. Analogous experiments with unsubstituted TACV and 6-Me-TACV suggest that the nature of the substituent at C(6) determines the reaction mechanism. The presence of a 6-aryl substituent results in the exclusive formation of 4-(benzhydryl)phenyl derivatives via a SET mechanism. On the contrary, when C(6) is unsubstituted, trityl derivatives are the only products of the S-N reaction. In the case of 6-Me-TACV, concomitant SET and S-N mechanisms direct the reaction towards 4-(benzhydryl)phenyl and trityl products.
• A Convenient Approach to N-3 Alkylation of 9-Substituted Guanines
  作者：Tomasz Ostrowski、Joanna Zeidler、Tomasz Goelizski、Bozenna Golankiewicz

  DOI：10.1080/15257779908041495

  日期：1999.4

  Aryl or tert-butyl substituent in the 6 position of 3,9-dihydro-3-[(2-hydroxy-ethoxy)methyl]-9-oxo-6-R-5H-imid 1 directs the benzylation reaction partly into N-4 position to give 3. Cleavage of the third ring of 3 gives 3-benzylacycloguanosine 5, a first 3-aralkilo-9-substituted guanine.
• Synthesis, antiviral activity, and stability of nucleoside analogs containing tricyclic bases
  作者：Franck Amblard、Emilie Fromentin、Mervi Detorio、Alexander Obikhod、Kimberly L. Rapp、Tamara R. McBrayer、Tony Whitaker、Steven J. Coats、Raymond F. Schinazi

  DOI：10.1016/j.ejmech.2009.04.003

  日期：2009.10

  A series of 3,9-dihydro-9-oxo-5H-imidazo[1,2-A]purine nucleosides (tricylic nucleosides) were synthesized from 9-[4-α-(hydroxymethyl)cyclopent-2-ene-1-α-yl]guanine (CBV) 5, (−)-β-D-(2R,4R)-1,3-dioxolane-guanosine (DXG) 6, 3′-azido-3′-deoxy-guanosine (AZG) 7, and 2′-C-methylguanosine 8. Their in vitro activity against HIV and HCV was evaluated and correlated to their ability to degrade to their purine

  以9-[4-α-(羟甲基)环戊-2-烯-1为原料合成了一系列3,9-dihydro-9-oxo-5 H - imidazo [1,2- A ]嘌呤核苷(三环核苷) -α-基]鸟嘌呤 (CBV) 5 , (-)-β-D-(2 R ,4 R )-1,3-二氧戊环-鸟苷 (DXG) 6 , 3'-叠氮基-3'-脱氧-鸟苷(AZG) 7和 2'- C-甲基鸟苷8。他们对 HIV 和 HCV 的体外活性进行了评估，并与它们降解为嘌呤对应物的能力相关联。