cyclopropavir | 632325-71-4

• 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: cyclopropavir
• 英文别名: filociclovir；ZSM-I-62；(Z)-9-{[2,2-bis-(hydroxymethyl)cyclopropylidene]methyl}guanine；Filociclovir；2-amino-9-[(Z)-[2,2-bis(hydroxymethyl)cyclopropylidene]methyl]-1H-purin-6-one
• CAS: 632325-71-4
• 化学式: C₁₁H₁₃N₅O₃
• 分子量: 263.256
• InChiKey: KMUNHOKTIVSFRA-KXFIGUGUSA-N

物化性质

• 沸点：
  628.1±65.0 °C(Predicted)
• 密度：
  1.83±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  -2.3
• 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：
  126
• 氢给体数：
  4
• 氢受体数：
  5

制备方法与用途

Cyclopropavir（又名Filociclovir或ZSM-I-62，MBX-400）是一种广谱抗疱疹病毒的化合物。它对巨细胞病毒、单纯性疱疹病毒HHV-6和HHV-8展现出良好的抗病毒活性，EC50值范围从0.7 μM到8 μM。

反应信息

• 作为反应物：
  描述：

  cyclopropavir 在 碘 吡啶 、 咪唑 、 N,N'-二环己基-4-吗啉脒 、 三甲基氯硅烷 、 甲烷磺酸 、 diphenyl phosphite 、 溶剂黄146 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 25.17h， 生成 Cyclovir monophosphate
  参考文献：
  名称：

  Nucleotides and Pronucleotides of 2,2-Bis(hydroxymethyl)methylenecyclopropane Analogues of Purine Nucleosides:  Synthesis and Antiviral Activity

  摘要：

  Phenylmethylphosphor-L-alaninate pronucleotides 7a, 7b, 8a, and 8b, cyclic phosphates 10a and 10b, and phosphates 11a and 11b derived from 2,2-bis(hydroxymethyl)methylenecyclopropane analogues 1a, 1b, 2a, and 2b were synthesized and evaluated for their antiviral activity. An improved protocol for the synthesis of analogues 1a, 1b, 2a, and 2b is also described. Phosphate 11a was the most effective agent against human and murine cytomegalovirus (EC50 0.25-1.1 muM). The Z-pronucleotides 7a and 7b had EC50 3.6-25.2 and 3-18.4 muM, respectively. The EC50 of cyclic phosphate 10a was 6.0-20 muM. The activity against Epstein-Barr (EBV) was assay-dependent. Pronucleotides 7a and 7b and phosphate 11a had EC50 2.3-3.4 muM against EBV/H-1, but 7b was cytotoxic (CC50 3.8 muM). Cyclic phosphate 10a was the only compound effective against EBV/Daudi (EC50 0.96 muM). but it was inactive in H-1 cells. Pronucleotide 7a was active against varicella zoster virus with EC50 6.3 and 7.3 muM, respectively. and hepatitis B virus (HBV, EC50 4.1 muM). Cyclic phosphate 10a was the most effective analogue against HBV (EC50 0.8 muM).

  DOI：

  10.1021/jm040149b
• 作为产物：
  描述：

  在 氨 作用下， 以 甲醇 为溶剂， 反应 4.0h， 以83 mg的产率得到cyclopropavir
  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 pyrmindines as antiviral agents
  申请人：Zemlicka Jiri

  公开号：US20050113393A1

  公开（公告）日：2005-05-26

  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。
• Synthesis and Enantioselectivity of Cyclopropavir Phosphates for Cellular GMP Kinase
  作者：Chengwei Li、Brian G. Gentry、John C. Drach、Jiri Zemlicka

  DOI：10.1080/15257770903172720

  日期：2009.9.17

  Enantiomeric cyclopropavir phosphates (+)-9 and (−)-9 were synthesized and investigated as substrates for GMP kinase. N2-Isobutyryl-di-O-acetylcyclopropavir (11) was converted to (+)-monoacetate 12 using hydrolysis catalyzed by porcine liver esterase. Phosphorylation via phosphite 13 gave after deacylation, phosphate (+)-9. Acid-catalyzed tetrahydropyranylation of (+)-monoacetate 12 gave, after deacylation

  合成了对映体环丙吡韦磷酸酯 (+)- 9和 (-)- 9作为 GMP 激酶的底物进行研究。使用由猪肝酯酶催化的水解，N 2 -异丁酰基-二-O-乙酰基环丙那韦( 11 )被转化为(+)-单乙酸酯12。脱酰后通过亚磷酸酯13磷酸化得到磷酸 (+)- 9。(+)-单乙酸酯12的酸催化四氢吡喃基化，在脱酰后得到四氢吡喃基衍生物14。通过亚磷酸酯15进行磷酸化，脱保护后得到对映体磷酸酯 (-) -9。外消旋二磷酸还合成了16。磷酸盐 (+)- 9是 GMP 激酶的相对较好的底物，其 K M值为 57 μM，与天然底物 GMP (61 μM) 和 dGMP (82 μM)的 K M值相似。相比之下，对映异构体 (-)- 9不是一个好的底物 (K M 1200 μM)，表明 GMP 激酶催化的单磷酸盐到二磷酸盐的反应具有显着的对映选择性。
• 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。
• WO2019172835A5
  申请人：——

  公开号：WO2019172835A5

  公开（公告）日：2022-03-16