5-acetylamino-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-[(2,2-dimethyl-[1,3]dioxolan-4-yl)-hydroxy-methyl]-5,6-dihydro-4H-pyran-2-carboxylic acid ethyl ester | 1333324-37-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 5-acetylamino-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-[(2,2-dimethyl-[1,3]dioxolan-4-yl)-hydroxy-methyl]-5,6-dihydro-4H-pyran-2-carboxylic acid ethyl ester
• 英文别名: ethyl (2R,3R,4S)-3-acetamido-4-[bis[(2-methylpropan-2-yl)oxycarbonylamino]methylideneamino]-2-[(S)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-hydroxymethyl]-3,4-dihydro-2H-pyran-6-carboxylate
• CAS: 1333324-37-0
• 化学式: C₂₇H₄₄N₄O₁₁
• 分子量: 600.667
• InChiKey: QILXLHDXQYRMFJ-CJSSEVFESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  42
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  192
• 氢给体数：
  4
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  5-acetylamino-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-[(2,2-dimethyl-[1,3]dioxolan-4-yl)-hydroxy-methyl]-5,6-dihydro-4H-pyran-2-carboxylic acid ethyl ester 在 吡啶 、 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 19.5h， 生成
  参考文献：
  名称：

  ENHANCED ANTI-INFLUENZA AGENTS CONJUGATED WITH ANTI-INFLAMMATORY ACTIVITY

  摘要：

  新型双靶向、双功能抗流感药物通过与抗炎药物结合形成。根据本发明的示例药物包括咖啡酸（CA）基底的扎那米韦（ZA）共轭物ZA-7-CA（1）、ZA-7-CA酰胺（7）和ZA-7-Nap（43），用于同时抑制流感病毒神经氨基酸酶和抑制促炎细胞因子。提供了用于制备这些增强型抗流感共轭药物的合成方法。合成的双功能ZA共轭物对保护由H1N1或H5N1流感病毒致命感染的小鼠具有协同作用。ZA-7-CA、ZA-7-CA酰胺和ZA-7-Nap共轭物的疗效远远优于ZA与抗炎药物的联合治疗。

  公开号：

  US20130274229A1
• 作为产物：
  描述：

  ethyl 4-acetamido-3-[2,3-bis(tert-butoxycarbonyl)guanidino]-5-(1,2,3-triacetoxy)propyl-(6-oxacyclohex-1-ene)carboxylate 在 sodium ethanolate 、 对甲苯磺酸 作用下， 以 乙醇 、 丙酮 为溶剂， 反应 13.0h， 以66%的产率得到5-acetylamino-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-[(2,2-dimethyl-[1,3]dioxolan-4-yl)-hydroxy-methyl]-5,6-dihydro-4H-pyran-2-carboxylic acid ethyl ester
  参考文献：
  名称：

  ENHANCED ANTI-INFLUENZA AGENTS CONJUGATED WITH ANTI-INFLAMMATORY ACTIVITY

  摘要：

  新型双靶向、双功能抗流感药物通过与抗炎药物结合形成。根据本发明的示例药物包括咖啡酸（CA）基底的扎那米韦（ZA）共轭物ZA-7-CA（1）、ZA-7-CA酰胺（7）和ZA-7-Nap（43），用于同时抑制流感病毒神经氨基酸酶和抑制促炎细胞因子。提供了用于制备这些增强型抗流感共轭药物的合成方法。合成的双功能ZA共轭物对保护由H1N1或H5N1流感病毒致命感染的小鼠具有协同作用。ZA-7-CA、ZA-7-CA酰胺和ZA-7-Nap共轭物的疗效远远优于ZA与抗炎药物的联合治疗。

  公开号：

  US20130274229A1

文献信息

• ENHANCED ANTI-INFLUENZA AGENTS CONJUGATED WITH ANTI-INFLAMMATORY ACTIVITY
  申请人：ACADEMIA SINICA

  公开号：US20130274229A1

  公开（公告）日：2013-10-17

  Novel dual-targeted, bifunctional anti-influenza drugs formed by conjugation with anti-inflammatory agents are disclosed. Exemplary drugs according to the invention include caffeic acid (CA)-bearing zanamivir (ZA) conjugates ZA-7-CA (1), ZA-7-CA-amide (7) and ZA-7-Nap (43) for simultaneous inhibition of influenza virus neuraminidase and suppression of proinflammatory cytokines. Synthetic methods for preparation of these enhanced anti-influenza conjugate drugs are provided. The synthetic bifunctional ZA conjugates act synergistically towards protection of mice lethally infected by H1N1 or H5N1 influenza viruses. The efficacy of ZA-7-CA, ZA-7-CA-amide and ZA-7-Nap conjugates is much greater than the combination therapy of ZA with anti-inflammatory agents.

  新型双靶向、双功能抗流感药物通过与抗炎药物结合形成。根据本发明的示例药物包括咖啡酸（CA）基底的扎那米韦（ZA）共轭物ZA-7-CA（1）、ZA-7-CA酰胺（7）和ZA-7-Nap（43），用于同时抑制流感病毒神经氨基酸酶和抑制促炎细胞因子。提供了用于制备这些增强型抗流感共轭药物的合成方法。合成的双功能ZA共轭物对保护由H1N1或H5N1流感病毒致命感染的小鼠具有协同作用。ZA-7-CA、ZA-7-CA酰胺和ZA-7-Nap共轭物的疗效远远优于ZA与抗炎药物的联合治疗。
• Intramolecular ion-pair prodrugs of zanamivir and guanidino-oseltamivir
  作者：Kung-Cheng Liu、Pei-Shan Lee、Shi-Yun Wang、Yih-Shyun E. Cheng、Jim-Min Fang、Chi-Huey Wong

  DOI：10.1016/j.bmc.2011.06.080

  日期：2011.8

  Zanamivir (ZA) is a potent anti-influenza drug, but it cannot be administrated orally because of the hydrophilic carboxylate and guanidinium groups. Guanidino-oseltamivir (GO) is another effective neuraminidase inhibitor with polar guanidinium group under physiological conditions. The ester prodrugs ZA-HNAP (5) and GO-HNAP (6) were prepared to incorporate a 1-hydroxy-2-naphthoic (HNAP) moiety to attain good lipophilicity in the intramolecular ion-pairing forms. ZA-HNAP resumed high anti-influenza activity (EC(50) = 48 nM), in cell-based anti-influenza assays, by releasing zanamivir along with nontoxic HNAP. Under similar conditions, the hydrolysis of the GO-HNAP ester was too sluggish to show the desired anti-influenza activity. (C) 2011 Elsevier Ltd. All rights reserved.
• Enhanced Anti-influenza Agents Conjugated with Anti-inflammatory Activity
  作者：Kung-Cheng Liu、Jim-Min Fang、Jia-Tsrong Jan、Ting-Jen R. Cheng、Shi-Yun Wang、Shi-Ting Yang、Yih-Shyun E. Cheng、Chi-Huey Wong

  DOI：10.1021/jm3009844

  日期：2012.10.11

  Influenza therapy with a single targeted compound is often limited in efficacy due to the rapidly developed drug resistance. Moreover, the uncontrolled virus-induced cytokines could cause the high mortality of human infected by H5N1 avian influenza virus. In this study, we explored the novel dual-targeted bifunctional anti-influenza drugs formed by conjugation with anti-inflammatory agents. In particular, the caffeic acid (CA)-bearing zanamivir (ZA) conjugates ZA-7-CA (1) and ZA-7-CA-amide (7) showed simultaneous inhibition of influenza virus neuraminidase and suppression of pro-inflammatory cytokines. These ZA conjugates provided remarkable protection of cells and mice against influenza infections. Intranasal administration of low dosage (<1.2 mu mol/kg/day) of ZA conjugates exhibited much greater effect than the combination therapy with ZA and the anti-inflammatory agents in protection of the lethally infected mice by H1N1 or H5N1 influenza viruses.