CN111320650B - Remdesivir的衍生物及其药物用途 - Google Patents
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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Abstract
Remdesivir的衍生物及其药物用途，结构符合通式(I)
Description
技术领域
本发明属于制药领域，提供一种Remdesivir的衍生物及其药物用途。
背景技术
Remdesivir是一种核苷类抗病毒药物，对于多种冠状病毒感染有效。Remdesivir作用机制是抑制病毒RNA依赖的RNA聚合酶，在体内，Remdesivir首先转化为Remdesivir-A，Remdesivir-A在磷酰化酶的作用下代谢为Remdesivir-B，Remdesivir-B进一步代谢为三磷酸物，产生作用。由于核苷类药物大多存在比较大的毒副作用，作为核苷类药物的一员，Remdesivir的安全性受到关注。
Remdesivir水溶性较差并且不稳定，注射用Remdesivir需要采用磺丁基β环糊精进行包合形成非共价复合物，从而提高药物的稳定性、水溶性、安全性，降低肾毒性。
被病毒感染的细胞会产生大量的自由基，因此，如果将药物设计成稳定的前药，在自由基富集区域释放出活性成分，就能够实现药物对感染部位的靶向作用，从而减少全身性的毒副作用，获得更安全有效的药物。
发明内容
解决的技术问题：本发明提供一种Remdesivir的衍生物及其药物用途，该类药物在自由基富集环境中能够迅速释放出活性成分，可用于制备治疗冠状病毒性感染的药物。
技术方案：Remdesivir的衍生物，结构符合通式(I)
上述Remdesivir的衍生物在制备治疗冠状病毒性感染药物中的应用。
制备治疗冠状病毒性感染的药物，有效成分为上述Remdesivir的衍生物或其药学上可接受的盐。
有益效果：该类药物在自由基富集环境中能够迅速释放出活性成分，能够实现药物对感染部位的靶向作用，从而减少全身性的毒副作用。可用于制备治疗冠状病毒性感染的药物。
具体实施方式
下面的实施例可使本专业技术人员可全面的理解本发明，但不以任何方式限制本发明。
实施例1目标化合物的合成:
1.1目标化合物1的合成:
合成路线:
操作：
室温下，100mL茄形瓶中加入16mL乙腈，1.1g化合物2(3.32mmol)，1.79g化合物3(3.98mmol)，31.6mg氯化镁(3.32mmol)，加热到50℃，加入1.45mLN,N-二异丙基乙胺(3.32mmol)，反应1小时以后，冷却到室温，用100mL乙酸乙酯稀释，分别用5％柠檬酸水、5％碳酸氢钠水、饱和氯化钠水、蒸馏水洗，无水硫酸钠干燥。蒸除溶剂，硅胶柱层析(石油醚-乙酸乙酯)，得1.45g化合物4。
室温下，100mL茄形瓶中加入10mL四氢呋喃，1.3g化合物4(2.0mmol)，于0℃下滴加37％浓盐酸2mL，升温到室温反应5小时，加入N,N-二异丙基乙胺(3.32mmol)，反应1小时以后，冷却到室温，加入100mL乙酸乙酯，分别用5％柠檬酸洗，5％碳酸氢钠洗，饱和氯化钠水洗，无水硫酸钠干燥。蒸除溶剂，得3.0g无色粘稠液体。硅胶柱层析(石油醚-乙酸乙酯)，得0.8g化合物1。
目标化合物：1H NMR(400MHz,DMSO-d6)δ(ppm)7.87(s,1H),7.74-7.26(m,2H),7.23-7.12(m,3H),6.92·(d,1H),6.88·(d,1H),4.97-4.95(m,1H),4.79(d,1H),4.43-4.34(m,2H),4.30-4.26(m,1H),4.00–3.85(m,2H),4.17(t,3H),3.45–3.30(m,2H),1.12(dd,3H).31P NMR(162MHz,DMSO-d6)δ(ppm)3.66(s).
实施例2：目标化合物在肝匀浆中的稳定性考察
NADPH启动系统制备：精密称取NADPNa2，G-6-P-Na，G-6-PDH和MgCl2适量，加水溶解并定容，体系含有2mmol L-1NADPNa2，40mmol L-1G-6-P-Na，4U L-1G-6-PDH，40mmol L- 1MgCl2，-20℃保存。
样品制备：首先在EP管中加入适量的样品甲醇溶液，水浴挥干溶剂，加入Tris缓冲溶液，大鼠肝匀浆，涡旋混匀。恒温振荡水槽37℃预温孵5min。加入NADPH启动系统200μL，涡旋混合均匀以启动反应。反应终体积为400μL，含1.0mmol·L-1 1NADPNa2，20mmol L-1G-6-P-Na，2U L-1G-6-PDH，20mmol L-1MgCl2，肝匀浆蛋白质量浓度为2.0mg mL-1，底物终浓度为0.5μmoL L-1。37℃水浴温孵。于温孵120min后分别加入乙腈0.4mL终止反应。平行5份。
样品处理：乙腈终止反应后，涡旋并超声5min使混合均匀，高速离心(13000r min-1，20min，4℃)，取上清，37℃水浴氮气流下挥干。残渣用400μL甲醇复溶，超声使溶解完全，高速离心(13 000r min-1，20min，4℃)，上清供31P NMR分析，测定目标化合物和Remdesivir-A峰面积，计算目标化合物转化为Remdesivir-A的百分比。Remdesivir-a31PNMR(162MHz,DMSO-d6)：δ(ppm)6.80，同法测定Remdesivir转化为Remdesivir-a的百分比。
加H2O2组样品制备：首先在EP管中加入适量的样品甲醇溶液，水浴挥干溶剂，加入Tris缓冲溶液，大鼠肝匀浆，涡旋混匀。恒温振荡水槽37℃预温孵5min。加入NADPH启动系统200μL，涡旋混合均匀以启动反应，加入0.1moLL-1的H2O2。反应终体积为400μL，含1.0mmol·L-1 1NADPNa2，20mmol L-1G-6-P-Na，2U L-1G-6-PDH，20mmol L-1MgCl2，肝匀浆蛋白质量浓度为2.0mg mL-1，底物终浓度为0.5μmoL L-1，H2O2浓度为1mmoL L-1。37℃水浴温孵。于温孵120min后分别加入乙腈0.4mL终止反应。平行5份。样品处理同上。
表1目标化合物在肝匀浆中转变为Remdesivir-A的百分比
| 化合物编号 | 正常 | H<sub>2</sub>O<sub>2</sub>(1mmol/l) |
| 目标化合物1 | 5％ | 89％ |
| Remdesivir | 95％ | 96％ |
以上实验结果显示：在正常条件下，目标化合物1释放活性代谢物Remdesivir-A的速度显著小于Remdesivir。在高自由基条件下，目标化合物1释放活性代谢物Remdesivir-A的速度显著增加，Remdesivir的释放速度没有明显变化。提示目标化合物1释放活性代谢物Remdesivir-a的速度和自由基浓度相关，能够靶向自由基浓度较大的区域释放活性代谢物Remdesivir-a。
Claims (3)
1.Remdesivir的衍生物，其特征在于结构符合通式(I)
2.权利要求1所述Remdesivir的衍生物在制备治疗冠状病毒性感染药物中的应用。
3.治疗冠状病毒性感染的药物，其特征在于有效成分为权利要求1所述的Remdesivir的衍生物或其药学上可接受的盐。
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Non-Patent Citations (2)
| Title |
|---|
| Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir;Egor P. Tchesnokov等;《Viruses》;20190404;第11卷;全文 * |
| 瑞德西韦的合成、作用机制与应用;陆泓雨等;《生物技术通讯》;20200130;第31卷(第1期);全文 * |
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| CN111320650A (zh) | 2020-06-23 |
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