(Z)-2-amino-6-chloro-9-{[2,2-bis(hydroxymethyl)cyclopropylidene]methyl}purine | 632325-69-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: (Z)-2-amino-6-chloro-9-{[2,2-bis(hydroxymethyl)cyclopropylidene]methyl}purine
• 英文别名: [(2Z)-2-[(2-amino-6-chloropurin-9-yl)methylidene]-1-(hydroxymethyl)cyclopropyl]methanol
• CAS: 632325-69-0
• 化学式: C₁₁H₁₂ClN₅O₂
• 分子量: 281.702
• InChiKey: RVWFOZDLCFEUFR-KXFIGUGUSA-N

物化性质

• 沸点：
  626.7±65.0 °C(Predicted)
• 密度：
  1.81±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  110
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (Z)-2-amino-6-chloro-9-{[2,2-bis(hydroxymethyl)cyclopropylidene]methyl}purine 在 甲酸 、 氨 、 甲醇 作用下， 以 甲醇 为溶剂， 反应 10.0h， 以89%的产率得到cyclopropavir
  参考文献：
  名称：

  2,2-bis-(hydroxymethyl)cyclopropylidenemethyl-purines and pyrmindines as antiviral agents

  摘要：

  具有抗病毒活性的化合物具有以下公式：其中B是嘌呤或嘧啶杂环环或碱基。在一个首选实施例中，嘌呤包括6-氨基嘌呤（腺嘌呤）、6-羟基嘌呤（次黄嘌呤）、2-氨基-6-羟基嘌呤（鸟嘌呤）、2,6-二氨基嘌呤，2-氨基-6-叠氮基嘌呤，2-氨基-6-卤代嘌呤，例如2-氨基-6-氯嘌呤，2-氨基-6-氟嘌呤，2-氨基-6-烷氧基嘌呤，例如2-氨基-6-甲氧基嘌呤，2-氨基-6-环丙基氨基嘌呤，2-氨基-6-烷基氨基或2-氨基-6-二烷基氨基嘌呤，2-氨基-6-硫嘌呤，2-氨基-6-烷硫代嘌呤，3-脱氮嘌呤，7-脱氮嘌呤和8-氮嘌呤。嘧啶包括胞嘧啶、尿嘧啶和胸腺嘧啶，5-卤代胞嘧啶和尿嘧啶，5-烷基代胞嘧啶和尿嘧啶，包括具有饱和或不饱和烷基基团的衍生物和6-氮杂嘧啶。

  公开号：

  US20050113393A1
• 作为产物：
  描述：

  diethyl bromoisopropylidenemalonate 在 吡啶 、 lithium aluminium tetrahydride 、 potassium tert-butylate 、 溴 、 potassium carbonate 作用下， 以 甲醇 、 四氯化碳 、 乙醚 、 N,N-二甲基甲酰胺 、 叔丁醇 为溶剂， 反应 56.25h， 生成 (Z)-2-amino-6-chloro-9-{[2,2-bis(hydroxymethyl)cyclopropylidene]methyl}purine
  参考文献：
  名称：

  Synthesis and Antiviral Activity of (Z)- and (E)-2,2-[Bis(hydroxymethyl)cyclopropylidene]methylpurines and -pyrimidines:  Second-Generation Methylenecyclopropane Analogues of Nucleosides

  摘要：

  The second generation of methylenecyclopropane analogues of nucleosides 5a-5i and 6a-6i was synthesized and evaluated for antiviral activity. The 2,2-bis(hydroxymethyl)methylenecyclopropane (11) was converted to dibromo derivative 7 via acetate 12. Alkylation-elimination of adenine (16) with 7 afforded the Z/E mixture of acetates 17 + 18, which was deacetylated to give analogues 5a and 6a separated by chromatography. A similar reaction with 2-amino-6-chloropurine (19) afforded acetates 20 + 21 and, after deprotection and separation, isomers 5f and 6f. The latter served as starting materials for synthesis of analogues 5b, 5e, 5g-5i and 6b, 6e, 6g-6i. Alkylation-elimination of N(4)-acetylcytosine (22) with 7 afforded a mixture of isomers 5c + 6c which were separated via N(4)-benzoyl derivatives 23 and 24. Deprotection furnished analogues 5c and 6c. Alkylation of 2,4-bis(trimethylsilyloxy)-5-methylpyrimidine (25) with 7 led to bromo derivative 26. Elimination of HBr followed by deacetylation and separation gave thymine analogues 5d and 6d. The guanine Z-isomer 5b was the most effective against human and murine cytomegalovirus (HCMV and MCMV) with EC(50) = 0.27-0.49 muM and no cytotoxicity. The 6-methoxy analogue 5g was also active (EC(50) = 2.0-3.5 muM) whereas adenine Z-isomer 5a was less potent (EC(50) = 3.6-11.7 muM). Cytosine analogue 5c was moderately effective, but 2-amino-6-cyclopropylamino derivative 5e was inactive. All E-isomers were devoid of anti-CMV activity, and none of the analogues was significantly active against herpes simplex viruses (HSV-1 or HSV-2). The potency against Epstein-Barr virus (EBV) was assay-dependent. In Daudi cells, the E-isomers of 2-amino-6-cyclopropylamino- and 2,6-diaminopurine derivatives 6e and 6h were the most potent (EC(50) approximate to 0.3 muM), whereas only the thymine Z-isomer 5d was active (EC(50) = 4.6 muM). Guanine Z-derivative 5b was the most effective compound in H-1 cells (EC(50) = 7 muM). In the Z-series, the 2-amino-6-methoxypurine analogue 5g was the most effective against varicella zoster virus (VZV, EC(50) = 3.3 muM) and 2,6-diaminopurine 5h against hepatitis B virus (HBV, EC(50) = 4 muM). Adenine analogues 5a and 6a were moderately active as substrates for adenosine deaminase.

  DOI：

  10.1021/jm030316s

文献信息

• 2,2-Bis-(hydroxymethyl)cyclopropylidenemethyl-Purines and -Pyrimidines As Antiviral Agents
  申请人：Zemlicka Jiri

  公开号：US20090118308A1

  公开（公告）日：2009-05-07

  Compounds which are active against viruses have the following formulas: wherein B is a purine or pyrimidine heterocyclic ring or base. In a preferred embodiment, the purine include 6-aminopurine (adenine), 6-hydroxypurine (hypoxanthine), 2-amino-6-hydroxypurine (guanine), 2,6-diamino-purine, 2-amino-6-azidopurine, 2-amino-6-halo substituted purines such as 2-amino-6-chloropurine, 2-amino-6-fluoropurine, 2-amino-6-alkoxypurines such as 2-amino-6-methoxypurine, 2-amino-6-cyclopropylaminopurine, 2-amino-6-alkylamino or 2-amino-6-dialkylamino substituted purines, 2-amino-6-thiopurine, 2-amino-6-alkylthio substituted purines, 3-deazapurines, 7-deazapurines and 8-azapurines. The pyrimidine incorporates cytosine, uracil and thymine, 5-halo substituted cytosines and uracils, 5-alkyl substituted cytosines and uracils including derivatives with a saturated or unsaturated alkyl group and 6-azapyrimidines.

  对病毒具有活性的化合物具有以下公式：其中B是嘌呤或嘧啶杂环环或碱基。在优选实施例中，嘌呤包括6-氨基嘌呤（腺嘌呤），6-羟基嘌呤（次黄嘌呤），2-氨基-6-羟基嘌呤（鸟嘌呤），2,6-二氨基嘌呤，2-氨基-6-叠氮基嘌呤，2-氨基-6-卤代嘌呤，例如2-氨基-6-氯嘌呤，2-氨基-6-氟嘌呤，2-氨基-6-烷氧基嘌呤，例如2-氨基-6-甲氧基嘌呤，2-氨基-6-环丙基氨基嘌呤，2-氨基-6-烷基氨基或2-氨基-6-二烷基氨基取代的嘌呤，2-氨基-6-硫代嘌呤，2-氨基-6-烷基硫代取代嘌呤，3-去氮嘌呤，7-去氮嘌呤和8-氮杂嘧啶。嘧啶包括胞嘧啶，尿嘧啶和胸腺嘧啶，5-卤代胞嘧啶和尿嘧啶，5-烷基取代的胞嘧啶和尿嘧啶，包括具有饱和或不饱和烷基的衍生物和6-氮杂嘧啶。
• 2,2-BIS-(HYDROXYMETHYL)CYCLOPROPYLIDENEMETHYL-PURINES AND -PYRIMIDINES AS ANTIVIRAL AGENTS
  申请人：Zemlicka Jiri

  公开号：US20110275652A1

  公开（公告）日：2011-11-10

  Compounds which are active against viruses have the following formulas: wherein B is a purine or pyrimidine heterocyclic ring or base. In a preferred embodiment, the purine include 6-aminopurine (adenine), 6-hydroxypurine (hypoxanthine), 2-amino-6-hydroxypurine (guanine), 2,6-diamino-purine, 2-amino-6-azidopurine, 2-amino-6-halo substituted purines such as 2-amino-6-chloropurine, 2-amino-6-fluoropurine, 2-amino-6-alkoxypurines such as 2-amino-6-methoxypurine, 2-amino-6-cyclopropylaminopurine, 2-amino-6-alkylamino or 2-amino-6-dialkylamino substituted purines, 2-amino-6-thiopurine, 2-amino-6-alkylthio substituted purines, 3-deazapurines, 7-deazapurines and 8-azapurines. The pyrimidine incorporates cytosine, uracil and thymine, 5-halo substituted cytosines and uracils, 5-alkyl substituted cytosines and uracils including derivatives with a saturated or unsaturated alkyl group and 6-azapyrimidines.

  具有抗病毒活性的化合物具有以下公式：其中B是一种嘌呤或嘧啶杂环环或碱基。在优选实施例中，嘌呤包括6-氨基嘌呤（腺嘌呤）、6-羟基嘌呤（次黄嘌呤）、2-氨基-6-羟基嘌呤（鸟嘌呤）、2,6-二氨基嘌呤、2-氨基-6-叠氮基嘌呤、2-氨基-6-卤代嘌呤，例如2-氨基-6-氯嘌呤、2-氨基-6-氟嘌呤、2-氨基-6-烷氧基嘌呤，例如2-氨基-6-甲氧基嘌呤、2-氨基-6-环丙胺基嘌呤、2-氨基-6-烷基氨基或2-氨基-6-二烷基氨基取代的嘌呤，2-氨基-6-硫代嘌呤，2-氨基-6-烷基硫代取代的嘌呤，3-脱氮嘌呤，7-脱氮嘌呤和8-氮杂嘧啶。嘧啶包括胞嘧啶、尿嘧啶和胸腺嘧啶，5-卤代胞嘧啶和尿嘧啶，5-烷基取代的胞嘧啶和尿嘧啶，包括具有饱和或不饱和烷基的衍生物和6-氮杂嘧啶。
• Synthesis and antiviral activity of certain second generation methylenecyclopropane nucleosides
  作者：John D. Williams、Atiyya R. Khan、Emma A. Harden、Caroll B. Hartline、Geraldine M. Jefferson、Kathy A. Keith、Mark N. Prichard、Jiri Zemlicka、Norton P. Peet、Terry L. Bowlin

  DOI：10.1016/j.bmc.2012.04.049

  日期：2012.6

  A second-generation series of substituted methylenecyclopropane nucleosides (MCPNs) has been synthesized and evaluated for antiviral activity against a panel of human herpesviruses, and for cytotoxicity. Although alkylated 2,6-diaminopurine analogs showed little antiviral activity, the compounds containing ether and thioether substituents at the 6-position of the purine did demonstrate potent and selective antiviral activity against several different human herpesviruses. In the 6-alkoxy series, antiviral activity depended on the length of the ether carbon chain, with the optimum chain length being about four carbon units long. For the corresponding thioethers, compounds containing secondary thioethers were more potent than those with primary thioethers. (C) 2012 Elsevier Ltd. All rights reserved.
• Synthesis and antiviral activity of 6-deoxycyclopropavir, a new prodrug of cyclopropavir
  作者：Chengwei Li、Debra C. Quenelle、Mark N. Prichard、John C. Drach、Jiri Zemlicka

  DOI：10.1016/j.bmc.2012.02.031

  日期：2012.4

  Synthesis of 6-deoxycyclopropavir (10), a prodrug of cyclopropavir (1) and its in vitro and in vivo antiviral activity is described. 2-Amino-6-chloropurine methylenecyclopropane 13 was transformed to its 6-iodo derivative 14 which was reduced to prodrug 10. It is converted to cyclopropavir (1) by the action of xanthine oxidase and this reaction can also occur in vivo. Compound 10 lacked significant in vitro activity against human cytomegalovirus (HCMV), human herpes virus 1 and 2 (HSV-1 and HSV-2), human immunodeficiency virus type 1 (HIV-1), human hepatitis B virus (HBV), Epstein-Barr virus (EBV), vaccinia virus and cowpox virus. In contrast, prodrug 10 given orally was as active as cyclopropavir (1) reported previously [Kern, E. R.; Bidanset, D. J.; Hartline, C. B.; Yan, Z.; Zemlicka, J.; Quenelle, D. C. et al. Antimicrob. Agents Chemother. 2004, 48, 4745] against murine cytomegalovirus (MCMV) infection in mice and against HCMV in severe combined immunodeficient (SCID) mice. (C) 2012 Elsevier Ltd. All rights reserved.
• EP1490368A4
  申请人：——

  公开号：EP1490368A4

  公开（公告）日：2006-07-19