CN113105504B - Remdesivir衍生物、其类似物及其制备方法与应用 - Google Patents
Remdesivir衍生物、其类似物及其制备方法与应用 Download PDFInfo
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- CN113105504B CN113105504B CN202110339904.7A CN202110339904A CN113105504B CN 113105504 B CN113105504 B CN 113105504B CN 202110339904 A CN202110339904 A CN 202110339904A CN 113105504 B CN113105504 B CN 113105504B
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- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical class NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 claims abstract description 38
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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Abstract
本发明公开了Remdesivir衍生物、其类似物及其制备方法与应用。如下式所示的Remdesivir衍生物及其类似物,所述类似物包括其药学上可接受的盐、酯、水合物、溶剂化物、结晶形式、立体异构体、醚、代谢物或前药:
Description
技术领域
本发明属于药物技术领域,具体涉及Remdesivir衍生物、其类似物及其制备方法与应用。
背景技术
新型冠状病毒肺炎(corona virus disease 2019,covid-19)自爆发以来已经肆虐全球,逾千万人感染,死亡人数也将近百万,在全世界范围造成了严重的社会危害和经济损失。由于没有针对性的药物和疫苗,新型冠状病毒的新药研发意义重大。
Remdesivir是一种核苷类抗病毒药物,对于多种冠状病毒感染有效,包括非典型肺炎冠状病毒(SARS-CoV)和中东呼吸综合症相关冠状病毒(MERS-CoV),在世界多个国家用于治疗新型冠状病毒肺炎(covid-19)的临床实验,并已在美国,日本和欧洲等地获紧急使用授权用于新型冠状病毒治疗。由于核苷类药物大多存在比较大的毒副作用,Remdesivir的安全性也受到关注。因此,对Remdesivir进行结构改造,制备出新型抗新冠病毒药物具有重要的意义。
本背景技术中所陈述内容并不代表承认其属于已公开的现有技术。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此,本发明提出一类新的Remdesivir衍生物及其类似物,该类衍生物结构新颖,且具有较好的安全性。
本发明还提出Remdesivir衍生物的制备方法。
本发明还提出上述物质的应用。
根据本发明的一个方面,提出了如下式所示的Remdesivir衍生物及其类似物,所述类似物包括其药学上可接受的盐、酯、水合物、溶剂化物、结晶形式、立体异构体、醚、代谢物或前药:
其中,X选自H、卤素或乙烯基,R选自H或氯,X、R其中之一为H。
根据本发明的一种优选的实施方式,至少具有以下有益效果:本发明方案提供了一系列新型结构的衍生物及其类似物,结构新颖且这些物质效能相当,部分还具有较低的tPSA,可较好地改善现有的Remdesivir利用度问题,具有良好的工业应用前景。
在本发明的一些实施方式中,所述药学上可接受的盐包括但不仅限于无机酸盐、有机酸盐、烷基磺酸盐和芳基磺酸盐中的至少一种;优选地,所述无机酸盐包括但不仅限于盐酸盐、氢溴酸盐、硝酸盐、硫酸盐和磷酸盐中的至少一种;优选地,所述有机酸盐包括但不仅限于甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐和柠檬酸盐中的至少一种;优选地,所述烷基磺酸盐包括但不仅限于甲基磺酸盐和乙基磺酸盐中的至少一种;所述芳基磺酸盐包括但不仅限于苯磺酸盐和对甲苯磺酸盐中的至少一种。
在本发明的一些优选的实施方式中,所述Remdesivir衍生物选自如下化合物中的至少一种:
根据本发明的再一个方面,提出了Remdesivir卤代衍生物的制备方法,包括如下步骤:将Remdesivir在卤代试剂的作用下发生卤代,制备所述Remdesivir卤代衍生物;其中,所述卤代试剂包括1-氟-4-甲基-1,4二氮杂双环[2,2,2]辛烷四氟硼酸盐(Selectfluor)、1-氯1λ3,2-苯碘酰-3-酮、N-溴代丁二酰亚胺(NBS)、N-碘代丁二酰亚胺(NIS)、N-氯代丁二酰亚胺(NCS)中的至少一种。
根据本发明的一种优选的实施方式的Remdesivir卤代衍生物的制备方法,至少具有以下有益效果:本发明方案的衍生物制备步骤简单,一步即可高效合成卤代衍生物,生产成本低,适宜于工业化大规模化生产。在Remdesivir的结构中,由于羟基、胺基的存在,限制了常用的氟化试剂如HF、DAST、BAST、NFSI等、常用的氯化试剂氯化亚砜、HCl等、常用的溴化试剂如单质溴、过溴化吡啶氢溴酸盐(PHP)或者HBr等或常用的碘化试剂碘或NH4I等的应用,这些试剂无法得到目标产物。本申请方案所选用的(X=F、Cl、Br或I)亲电子卤代试剂,具有更高的选择性。
上述反应的机理如下:
在本发明的一些优选实施方式中,所述卤代试剂为1-氟-4-甲基-1,4二氮杂双环[2,2,2]辛烷四氟硼酸盐(Selectfluor)、1-氯1λ3,2-苯碘酰-3-酮、N-氯代丁二酰亚胺、N-溴代丁二酰亚胺或N-碘代丁二酰亚胺中的至少一种。选用N-氯代丁二酰亚胺(NCS)时,选择性的高收率获得碱基环外N上的氢被氯取代产物。而将氯化试剂选为1-氯1λ3,2-苯碘酰-3-酮时,高收率得到5-氯代Remdesivir。
在本发明的一些实施方式中,所述卤代试剂与Remdesivir的摩尔当量之比为1:1~3:1;优选为2:1。在该摩尔当量范围内,反应产率更高。
在本发明的一些实施方式中,所述合成过程在溶剂中进行,所述溶剂包括N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMAc)、二甲亚砜(DMSO)、氯仿、N-甲基吡咯烷酮(NMP)中的至少一种。
根据本发明的再一个方面,提出了Remdesivir烯基化衍生物的制备方法,包括如下步骤:通过上述方法制备Remdesivir卤代衍生物,将所述Remdesivir卤代衍生物通过金属催化偶联反应制得所述Remdesivir烯基化衍生物。
根据本发明的一种优选的实施方式的Remdesivir烯基化衍生物的制备方法,至少具有以下有益效果:本发明方案的烯基化衍生物制备步骤简单,操作简便,生产成本低,适宜于工业化大规模化生产。
在本发明的一些实施方式中,所述金属催化偶联反应包括Suzuki偶联反应或Sonogashira反应;优选地,所述Suzuki偶联反应为在碱性试剂且钯配合物存在下,Remdesivir卤代衍生物与有机硼化合物反应。
在本发明的一些实施方式中,所述碱性试剂选自碳酸氢钠、碳酸钠、磷酸钾中的至少一种;优选为碳酸氢钠。
在本发明的一些实施方式中,所述钯配合物选自双(三苯基膦)氯化钯、四三苯基钯、醋酸钯中的至少一种;优选为双(三苯基膦)氯化钯。
在本发明的一些实施方式中,所述有机硼化合物选自乙烯三氟硼酸钾、乙烯硼酸酯中的至少一种;优选为乙烯三氟硼酸钾。
根据本发明的再一个方面,提出了Remdesivir衍生物及其类似物在制备预防或治疗covid-19的药物中的应用。
根据本发明的再一个方面,提出了一种药物,所述药物的活性成分包括上述Remdesivir衍生物及其类似物。
根据本发明的一种优选的实施方式的应用,至少具有以下有益效果:由于上述Remdesivir衍生物及其类似物具有更高的安全性且效能相当,新型结构的成分还可避免新型冠状病毒的耐药性,其在抗新型冠状病毒药物制备领域具有良好的应用前景。
在本发明的一些实施方式中,所述药物还包括药学上可接受的载体或辅料;优选为包括稀释剂、吸收剂、湿润剂崩解剂、润滑剂、崩解抑制剂和粘合剂中的至少一种;更优选为包括淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝、水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮、干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯、山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素、蔗糖、三硬脂酸甘油酯、可可脂、氢化油、滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇中的至少一种。可根据需要添加药学上可接受的载体或辅料。关于药学上可接受的载体或辅料未一一例举,本领域普通技术人员可根据所掌握的公知常识进行具体选择。
在本发明的一些实施方式中,所述药物的剂型选自口服剂型;优选为片剂、胶囊剂、颗粒剂、滴丸剂等中的至少一种。根据需要可制备成药学上可接受的剂型。
根据本发明一些实施方式,所述药物中还包含其他治疗成分,如包括干扰素、抗炎药巴瑞替尼等。Remdesivir衍生物可作为唯一活性成分,也可和其他药用许可的物质组合。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述,以充分地理解本发明的目的、特征和效果。显然,所描述的实施例只是本发明的一部分实施例,而不是全部实施例,基于本发明的实施例,本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例,均属于本发明保护的范围。实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的材料、试剂等,如无特殊说明,均可从商业途径得到的试剂和材料。
本发明的描述中,参考术语“一个实施例”、“一些实施例”、“示意性实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不一定指的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。
下述实施例中,所有有机试剂均购自上海的九鼎化学。运行XWINNMR软件包的Bruker Ascend 600NMR光谱仪(1H NMR为600MHz,13C NMR为150MHz)用于NMR实验。在正离子或负离子模式下在质谱仪上采集高分辨率MS质谱图配备电喷雾离子源(ESI)的Agilent6230精确质量飞行时间质谱仪(美国)。用硅胶60(200-300目,Bio-Gene TechnologyLtd.Hong Kong)进行柱色谱法(CC)分离。
实施例1:本实施例制备了一种Remdesivir衍生物(后称“化合物RDV-1”),其制备路线如下:
具体包括如下步骤:
将RDV(瑞德西韦,12.6mg,0.021mmol)溶于无水DMF(N,N-二甲基甲酰胺,1mL)中,加入NCS(N-氯代丁二酰亚胺,14.0mg,0.105mmol),混合物在室温搅拌过夜,反应用乙酸乙酯萃取,干燥,柱层析分离得到(RDV-1)11.8mg,产率89%,白色粉末。测得氢核磁共振谱数据如下:1H NMR(600MHz,CDCl3)δ9.79(s,1H),7.58(s,1H),7.23-7.25(m,2H),7.14(d,J=8.0Hz,2H),7.08(t,J=7.4Hz,1H),6.72(d,J=4.2Hz,1H),6.62(d,J=4.2Hz,1H),4.65-4.67(m,1H),4.42-4.45(m,1H),4.33-4.37(m,1H),4.28-4.30(m,2H),4.15-4.20(m,1H),4.03-4.05(m,1H),3.89-3.95(m,2H),1.44-1.48(m,1H),1.31(d,J=7.0Hz,3H),1.31-1.26(m,4H),0.84(t,J=7.5Hz,6H);13C NMR(150MHz,CDCl3)δ173.73,173.68,150.34,150.30,148.24,135.66,129.81,125.23,124.99,120.00,119.96,118.43,116.54,110.91,105.09,83.42,83.38,79.34,75.44,70.45,67.83,60.00,50.18,40.16,23.12,23.09,20.82,20.79,10.96,10.91;采用ESI(电喷雾电离)源的高分辨质谱测定C27H34ClN6O8P的质荷比结果如下:理论值为636.1864,实测值为637.1919。由此表明,本实施例方案制得了结构式正确的目标产物。实施例2:本实施例制备了一种Remdesivir衍生物(后称“化合物RDV-F”),其制备路线如下:
具体包括如下步骤:
将RDV(12.5mg,0.021mmol)溶于无水DMF(1mL)中,加入SelectFlour(29.4mg,0.083mmol),混合物在室温搅拌过夜,反应用乙酸乙酯萃取,干燥,柱层析分离得到(RDV-F)3.5mg,产率27%,白色粉末。测得氢核磁共振谱数据如下:1H NMR(600MHz,CDCl3)δ7.89(s,1H),7.19-7.22(m,2H),7.10(d,J=8.0Hz,2H),7.06(t,J=7.4Hz,1H),6.58(s,1H),4.57-4.58(m,1H),4.31-4.37(m,3H),4.23-4.26(m,1H),4.07-4.10(m,1H),3.98-4.01(m,1H),3.90-3.91(m,1H),3.73-3.76(m,1H),1.49-1.53(m,1H),1.37(d,J=7.0Hz,3H),1.30-1.34(m,4H),0.88(t,J=7.5Hz,6H);13C NMR(150MHz,CDCl3)δ173.53,173.48,154.33,150.41,150.36,148.42,144.09,142.44,129.55,124.95,121.73,121.71,120.00,119.97,115.41,102.26,102.11,97.58,97.48,85.24,85.19,78.82,76.28,71.86,67.79,65.79,65.72,50.27,40.23,23.18,23.15,21.12,21.09,10.97,10.93;采用ESI(电喷雾电离)源的高分辨质谱测定C27H34FN6O8P的质荷比结果如下:理论值为620.2160,实测值为621.2216。由此表明,本实施例方案制得了结构式正确的目标产物。实施例3:本实施例制备了一种Remdesivir衍生物(后称“化合物RDV-Cl”),其制备路线如下:
具体包括如下步骤:
将RDV(14.7mg,0.024mmol)溶于无水DMF(1mL)中,加入氯化试剂(8.5mg,0.03mmol),混合物在室温搅拌过夜,反应用乙酸乙酯萃取,干燥,柱层析分离得到(RDV-Cl)12.0mg,产率77%,白色粉末。测得氢核磁共振谱数据如下:1H NMR(600MHz,CDCl3)δ7.93(s,1H),7.19(d,J=8.0Hz,2H),7.10(d,J=8.0Hz,2H),7.05(t,J=7.4Hz,1H),6.82(s,1H),4.57-4.59(m,1H),4.37-4.36(m,1H),4.35-4.31(m,1H),4.29(d,J=5.8Hz,1H),4.23-4.26(m,1H),4.07-4.10(m,1H),3.98-4.00(m,1H),3.90-3.94(m,1H),3.64-3.67(m,1H),1.49-1.53(m,1H),1.37(d,J=7.0Hz,3H),1.30-1.34(m,4H),0.87(t,J=7.5Hz,6H);13C NMR(150MHz,CDCl3)δ173.47,173.42,155.36,150.38,150.34,148.47,129.52,124.91,124.72,120.00,119.96,115.33,111.77,110.64,105.43,85.31,85.26,78.79,76.35,71.94,67.77,65.74,65.71,50.27,40.23,23.17,23.14,21.13,21.10,10.97,10.92;采用ESI(电喷雾电离)源的高分辨质谱测定C27H34ClN6O8P的质荷比结果如下:理论值为636.1864,实测值为637.1867。由此表明,本实施例方案制得了结构式正确的目标产物。
实施例4:本实施例制备了一种Remdesivir衍生物(后称“化合物RDV-Br”),其制备路线如下:
具体包括如下步骤:
将RDV(10.2mg,0.017mmol)溶于无水DMF(1mL)中,加入NBS(10.6mg,0.06mmol),混合物在室温搅拌过夜,反应用乙酸乙酯萃取,干燥,柱层析分离得到(RDV-Br)7.7mg,产率67%,白色粉末。测得氢核磁共振谱数据如下:1H NMR(600MHz,CDCl3)δ7.93(s,1H),7.20-7.23(m,2H),7.11(d,J=8.0Hz,2H),7.06(t,J=7.4Hz,1H),6.91(s,1H),4.55-4.57(m,1H),4.38(d,J=5.8Hz,1H),4.36-4.33(m,2H),4.25-4.28(m,1H),4.06-4.09(m,1H),3.91-3.99(m,3H),1.52-1.48(m,1H),1.36(d,J=6.8Hz,3H),1.30-1.34(m,4H),0.87(t,J=7.5Hz,6H);13C NMR(150MHz,CDCl3)δ173.60,173.55,155.50,150.40,150.36,148.27,129.57,125.47,124.95,120.03,120.00,115.53,113.33,113.12,88.96,78.94,76.03,71.63,67.76,65.76,65.73,50.27,40.22,23.17,23.14,21.11,21.08,10.98,10.94;采用ESI(电喷雾电离)源的高分辨质谱测定C27H34BrN6O8P的质荷比结果如下:理论值为680.1359,实际测得[M+H]+为683.1410。由此表明,本实施例方案制得了结构式正确的目标产物。
实施例5:本实施例制备了一种Remdesivir衍生物(后称“化合物RDV-I”),其制备路线如下:
具体包括如下步骤:
将RDV(69.6mg,0.116mmol)溶于无水DMF(2mL)中,加入NIS(39.0mg,0.173mmol),混合物在室温搅拌过夜,反应用乙酸乙酯萃取,干燥,柱层析分离得到(RDV-I)72.4mg,产率86%,白色粉末。测得氢核磁共振谱数据如下:1H NMR(600MHz,CDCl3)δ7.94(s,1H),7.20-7.23(m,2H),7.12(d,J=8.0Hz,2H),7.06(t,J=7.4Hz,1H),7.02(s,1H),4.55-4.56(m,1H),4.40(d,J=5.5Hz,1H),4.33-4.37(m,2H),4.25-4.29(m,1H),4.03-4.08(m,2H),3.91-3.98(m,2H),1.47-1.52(m,1H),1.36(d,J=7.0Hz,3H),1.30-1.34(m,4H),0.87(t,J=7.5Hz,6H);13C NMR(150MHz,CDCl3)δ173.63,173.58,155.57,150.41,150.36,147.90,129.61,126.93,124.96,120.06,120.03,118.78,115.63,115.46,84.79,84.74,79.00,75.88,71.50,67.75,65.78,65.74,52.07,50.26,40.21,23.17,23.14,21.13,21.10,10.99,10.95;采用ESI(电喷雾电离)源的高分辨质谱测定C27H34IN6O8P的质荷比结果如下:理论值为728.1220,实测值为729.1285。由此表明,本实施例方案制得了结构式正确的目标产物。
实施例6:本实施例制备了一种Remdesivir衍生物(后称“化合物RDV-EN”),其制备路线如下:
具体包括如下步骤:
在氮气保护下,将RDV-I(13.8mg,0.019mmol)溶于THF/H2O(1.0mL,9/1,v/v)的混合溶液中,加入Pd(PPh3)2Cl2(0.5mg,0.0007mmol),碳酸氢钠(6.4mg,0.075mmol),和乙烯基三硼酸钾(5.1mg,0.038mmol),于50℃下搅拌过夜。然后冷却,过滤,滤液浓缩,残余液经过柱层析分离纯化得到(RDV-EN)6.1mg,产率51%,白色粉末。测得氢核磁共振谱数据如下:1HNMR(600MHz,CDCl3)δ7.92(s,1H),7.17-7.20(m,2H),7.09(d,J=8.0Hz,2H),7.05(t,J=8.2Hz,1H),6.94(s,1H),6.81(dd,J=17.0,10.8Hz,1H),5.60(d,J=17.0Hz,1H),5.39(d,J=10.8Hz,1H),4.56-4.58(m,1H),4.38-4.39(d,J=5.8Hz,1H),4.33-4.36(m,2H),4.25-4.29(m,1H),4.05-4.08(m,1H),3.92-3.9 8(m,2H),3.86-3.90(m,1H),1.48-1.50(m,1H),1.35(d,J=7.0Hz,3H),1.30-1.34(m,4H),0.87(t,J=7.5Hz,6H);13C NMR(150MHz,CDCl3)δ173.60,173.55,156.15,150.44,150.40,147.46,129.55,128.17,125.35,124.91,120.05,120.01,118.48,117.24,115.81,112.19,109.63,84.97,84.92,79.13,75.96,71.74,67.74,65.84,65.81,50.25,40.21,23.16,23.13,21.12,21.09,10.96,10.92;采用ESI(电喷雾电离)源的高分辨质谱测定C27H34ClN6O8P的质荷比结果如下:理论值为628.2410,实测值为629.2474。由此表明,本实施例方案制得了结构式正确的目标产物。
对比例1为市购Remdesivir(后文简称RDV),也可参照如下路线制备而得:
即:先对核苷进行修饰,然后再磷酸化,但这种方法通常会增加合成步骤和操作,限制了Remdesivir的进一步开发利用。
对比例2
本对比例拟采用液溴作为溴代试剂来制备RDV-Br,但是实验结果与实施例4相比,反应结果是很复杂的混合物,并没有得到纯的单一物质。具体过程为:将RDV(10.0mg,0.017mmol)溶于无水DMF(1mL)中,加入Br2(2μL,0.036mmol),混合物在室温搅拌过夜,LC-MS和TLC检测都未检测到RDV-Br。
对比例3
本对比实验拟采用单质碘来制备RDV-I,与实施例5相比并没有得到RDV-I,具体过程为:将RDV(10.0mg,0.017mmol)溶于无水DMF(1mL)中,加入I2(8.6mg,0.034mmol),混合物在室温搅拌过夜,LC-MS和TLC检测都未检测到RDV-I。
试验例
本试验例测试了实施例1~6制备的Remdesivir衍生物和对比例1中的Remdesivir的药物毒性、对SARS-CoV-2病毒的抑制效果并计算各物质对CPE的半数抑制浓度(IC50),结果如下表1所示。
具体的,药物毒性评价实验如下:
(1)实验材料
Vero E6(非洲绿猴肾细胞)细胞购自美国ATCC。
(2)药物的细胞的无毒浓度
Remdesivir及衍生物用DMSO(二甲亚砜)溶解,超声过滤后,加入培养液稀释至5mg/mL,经0.22μm滤膜过滤后置4℃保存,96孔板单层Vero E6细胞弃去培养液,加入不同稀释度的药物100μL/孔,正常细胞对照孔加入等体积DMEM培养基,37℃、5%CO2继续培养72小时后,观察药物引起细胞病变(CPE),明确CC0(药物对细胞的最大无毒浓度)。
药物对SARS-CoV-2病毒的抑制效果实验如下:
(1)实验材料
Vero E6(非洲绿猴肾细胞)细胞购自美国ATCC,SARS-CoV-2(Genebank accessionno.MT123290.1)为临床分离株。
(2)实验方法
96孔板单层Vero-E6细胞每孔加入100个TCID50病毒液100μL,37℃孵育2小时,弃病毒液后加入100μL两倍梯度稀释的药物,4℃、5%CO2条件下培养72小时,记录CPE。CPE程度按以下6级标准记录:-为细胞生长正常,无病变出现;±为细胞病变少于整个单层细胞的10%;+为细胞病变约占整个单层细胞的25%;++为细胞病变约占整个单层细胞的50%;+++为细胞病变约占整个单层细胞的75%:++++为细胞病变约占整个单层细胞的75%以上。计算药物对CPE的半数抑制浓度(IC50)。
表1
由上表1可以看出,本发明方案制得的衍生物的性能与瑞德西韦接近,但毒性有不同程度的降低,大部分化合物有明显降低,RDV-Br的CC0略低于RDV的CC0。
此外,还通过chemdraw计算上述各化合物的tPSA及cLogP等参数,结果发现,RDV的tPSA及cLogP分别为201.32和1.249,而化合物RDV-1的tPSA及cLogP分别为187.33和1.219,由此可见,将RDV制备成RDV-1降低了tPSA和cLogP,不仅降低了毒性,同时还提高了其溶解性和体内利用度。RDV的tPSA高达200以上,只能通过注射用药,无法通过口服吸收;而本发明实施例方案的衍生物大幅降低了tPSA和cLogP,还可能通过口服使用。因此,采用本发明方案的衍生物可以较好的改善现有技术中瑞德西韦的利用问题。
上面对本发明实施例作了详细说明,但是本发明不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。此外,在不冲突的情况下,本发明的实施例及实施例中的特征可以相互组合。
Claims (19)
1.Remdesivir衍生物及其类似物,其特征在于:所述类似物为其药学上可接受的盐,所述Remdesivir衍生物如下式所示:
其中,X选自H,R选自氯。
2.根据权利要求1所述的Remdesivir衍生物及其类似物,其特征在于:所述药学上可接受的盐包括但不仅限于无机酸盐、有机酸盐、烷基磺酸盐和芳基磺酸盐中的至少一种。
3.根据权利要求2所述的Remdesivir衍生物及其类似物,其特征在于:所述无机酸盐包括但不仅限于盐酸盐、氢溴酸盐、硝酸盐、硫酸盐和磷酸盐中的至少一种。
4.根据权利要求2所述的Remdesivir衍生物及其类似物,其特征在于:所述有机酸盐包括但不仅限于甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐和柠檬酸盐中的至少一种。
5.根据权利要求2所述的Remdesivir衍生物及其类似物,其特征在于:所述烷基磺酸盐包括但不仅限于甲基磺酸盐和乙基磺酸盐中的至少一种;所述芳基磺酸盐包括但不仅限于苯磺酸盐和对甲苯磺酸盐中的至少一种。
6.如权利要求1所述的Remdesivir衍生物及其类似物的制备方法,其特征在于:包括如下步骤:将Remdesivir在卤代试剂的作用下发生卤代,制备所述Remdesivir衍生物;所述卤代试剂为N-氯代丁二酰亚胺。
7.根据权利要求6所述的制备方法,其特征在于:所述合成过程在溶剂中进行,所述溶剂包括N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、氯仿、N-甲基吡咯烷酮中的至少一种。
8.根据权利要求6所述的制备方法,其特征在于:所述卤代试剂与Remdesivir的摩尔当量之比为1:1~3:1。
9.根据权利要求6所述的制备方法,其特征在于:所述卤代试剂与Remdesivir的摩尔当量之比为2:1。
10.根据权利要求1至5任一项所述的Remdesivir衍生物及其类似物在制备预防或治疗covid-19的药物中的应用。
11.一种药物,其特征在于:所述药物的活性成分包括如权利要求1至5任一项所述衍生物及其类似物。
12.根据权利要求11所述的药物,其特征在于:所述药物还包括药学上可接受的载体或辅料。
13.根据权利要求12所述的药物,其特征在于:药学上可接受的载体或辅料包括稀释剂、吸收剂、湿润剂、崩解剂、润滑剂、崩解抑制剂和粘合剂中的至少一种。
14.根据权利要求13所述的药物,其特征在于:药学上可接受的载体或辅料包括淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、白陶土、微晶纤维素、硅酸铝、水、甘油、聚乙二醇、乙醇、丙醇、羧甲基纤维素钠、紫胶、甲基纤维素、乙基纤维素、磷酸钾、聚乙烯吡咯烷酮、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯、山梨糖醇脂肪酸酯、十二烷基磺酸钠、三硬脂酸甘油酯、可可脂、氢化油、滑石粉、二氧化硅、硬脂酸盐、海藻酸盐、硼酸、液体石蜡中的至少一种。
15.根据权利要求13所述的药物,其特征在于:药学上可接受的载体或辅料包括糖浆、蜂蜜、淀粉浆、阿拉伯胶浆、明胶浆、琼脂粉、干燥淀粉、褐藻淀粉、玉米淀粉中的至少一种。
16.根据权利要求13所述的药物,其特征在于:药学上可接受的载体或辅料包括葡萄糖溶液。
17.根据权利要求11所述的药物,其特征在于:所述药物的剂型选自口服剂型。
18.根据权利要求17所述的药物,其特征在于:所述口服剂型为片剂、胶囊剂、颗粒剂、滴丸剂中的至少一种。
19.根据权利要求11所述的药物,其特征在于:所述药物中还包含其他治疗成分。
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