CN112057440A - 1,4-萘醌类衍生物的医药用途 - Google Patents
1,4-萘醌类衍生物的医药用途 Download PDFInfo
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Abstract
本发明涉及药学领域,特别是涉及三种1,4‑萘醌类衍生物或其药学上可接受的盐在制备抑制新型冠状病毒3CL蛋白酶或SARS冠状病毒3CL蛋白酶的药物中的应用。本发明的三种1,4‑萘醌类衍生物可用于治疗新型冠状病毒或SARS冠状病毒感染。
Description
技术领域
本发明属于药学领域,特别是涉及一种1,4-萘醌类衍生物的医药用途。
背景技术
由新型冠状病毒(SARS-CoV-2)引起的病毒性肺炎(COVID-19)已成为国际关注的突发公共卫生事件。是继SARS冠状病毒(SARS-CoV)、MERS冠状病毒(MERS-CoV)之后发现的一种新型冠状病毒。该病毒一般通过呼吸道分泌物排出,可通过飞沫传播,也可通过接触传播等。目前暂时还没有有效防控冠状病毒的手段,市场上亦无高效、特异性阻断病毒传染的日常洗护用品。
在病毒感染宿主的过程中,冠状病毒中的3CL蛋白酶(又称为Mpro)是一类半胱氨酸水解酶,能够在病毒中11个不同的位点裂解多蛋白,生成多个有活性的功能蛋白,最近的研究结果表明SARS-CoV-2与SARS-CoV的3CL蛋白酶只差12个氨基酸,同源性>96%,两者结构基本一致。因此,3CL蛋白酶可作为抗冠状病毒的关键靶标,可通过开发其抑制剂,阻断冠状病毒复制过程,降低传染的风险,对于冠状病毒感染的防治具有重要价值与意义。目前,还没有可强效抑制3CL蛋白酶进而阻断冠状病毒的日常洗护产品。因此,有必要借助现代技术发现3CL蛋白酶的强效抑制剂,进而开发出能防治冠状病毒感染的日常洗护产品以满足大众需求,降低病毒感染的风险。
发明内容
本发明首先提供了下列式(Ⅰ)化合物或其药学上可接受的盐在制备抑制新型冠状病毒3CL蛋白酶或SARS冠状病毒3CL蛋白酶的药物中的应用:
在一优选例中,所述式(Ⅰ)化合物或其药学上可接受的盐是作为唯一的原料药应用于所述抑制新型冠状病毒3CL蛋白酶或SARS冠状病毒3CL蛋白酶的药物的制备中。
本发明的第二方面是提供了下列式(Ⅰ)化合物或其药学上可接受的盐在制备抑制新型冠状病毒3CL蛋白酶或SARS冠状病毒3CL蛋白酶的外用消毒洗液制品中的应用,所述外用消毒洗液制品选自漱口液、洗眼液、洗鼻液、洗耳液、洗手液、消毒液、洗衣液、沐浴液、洗发液、洗洁精、清洁剂、消毒凝胶或湿巾:
本发明的第三方面是提供了下列式(Ⅱ)化合物或其药学上可接受的盐在制备抑制新型冠状病毒3CL蛋白酶或SARS冠状病毒3CL蛋白酶的药物中的应用:
在一优选例中,所述式(Ⅱ)化合物或其药学上可接受的盐是作为唯一的原料药应用于所述抑制新型冠状病毒3CL蛋白酶或SARS冠状病毒3CL蛋白酶的药物的制备中。
本发明的第四方面是提供了下列式(Ⅱ)化合物或其药学上可接受的盐在制备抑制新型冠状病毒3CL蛋白酶或SARS冠状病毒3CL蛋白酶的外用消毒洗液制品中的应用,所述外用消毒洗液制品选自漱口液、洗眼液、洗鼻液、洗耳液、洗手液、消毒液、洗衣液、沐浴液、洗发液、洗洁精、清洁剂、消毒凝胶或湿巾:
本发明的第五方面是提供了下列式(Ⅲ)化合物或其药学上可接受的盐在制备抑制新型冠状病毒3CL蛋白酶或SARS冠状病毒3CL蛋白酶的药物中的应用:
在一优选例中,所述式(Ⅲ)化合物或其药学上可接受的盐是作为唯一的原料药应用于所述抑制新型冠状病毒3CL蛋白酶或SARS冠状病毒3CL蛋白酶的药物的制备中。
本发明还提供了下列式(Ⅲ)化合物或其药学上可接受的盐在制备抑制新型冠状病毒3CL蛋白酶或SARS冠状病毒3CL蛋白酶的外用消毒洗液制品中的应用,所述外用消毒洗液制品选自漱口液、洗眼液、洗鼻液、洗耳液、洗手液、消毒液、洗衣液、沐浴液、洗发液、洗洁精、清洁剂、消毒凝胶或湿巾:
本发明包括上述化合物相应的所有药学上可以接受的盐。这些盐可以由化合物中带正电荷的部分(例如,胺基)与具有相反电性的带负电荷(例如,三氟醋酸)形成;或者由化合物中带负电荷的部分(例如,羧基)与正电荷(例如,钠、钾、钙、镁)形成。化合物可以含有一个非芳香性的双键,具有一个或多个不对称中心。所以,这些化合物可以作为外消旋的混合物、单独的对映异构体、单独的非对映异构体、非对映异构体混合物、顺式或反式异构体存在。所有这些异构体都是可预期的。
本发明的化合物可通过商业途径购买或者利用市售原料,通过现有技术中传统的化合物合成方法合成获得。本领域的普通技术人员根据现有公知技术可以合成本发明的化合物。合成的化合物可以进一步通过柱色谱法、高效液相色谱法或结晶等方式进一步纯化。
合成化学改造、保护官能团方法学(保护或去保护)对合成应用化合物是很有帮助的,并且是现有技术中公知的技术,如R.Larock,Comprehensive OrganicTransformations,VCH Publishers(1989);T.W.Greene and P.G.M.Wuts,ProtectiveGroups in Organic Synthesis,3rd Ed.,John Wiley and Sons(1999);L.Fieser andM.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis,John Wiley andSons(1994);and L.Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis,John Wiley and Sons(1995)中都有公开。
本发明的化合物可以有效抑制新型冠状病毒3CL蛋白酶或SARS冠状病毒3CL蛋白酶,故而本发明的化合物可用于制备抑制新型冠状病毒3CL蛋白酶或SARS冠状病毒3CL蛋白酶的药物。
本发明的化合物可以制备成药物组合物,该组合物包括一种或几种本发明的化合物或其药学上可接受的盐,与药学上可接受的载体,该组合物可用于治疗新型冠状病毒或SARS冠状病毒感染;
本发明的化合物可以制备成药物制剂,该药物制剂包括一种或几种本发明的化合物或其药学上可接受的盐,该药物制剂可用于治疗新型冠状病毒或SARS冠状病毒感染。
所述化合物或其药学上可接受的盐在药物组合物或药物制剂中的含量例如0.0001-50wt%;较佳的0.001-30wt%;更佳的0.01-20wt%。
治疗有效量(即:可对人和/或动物产生功能或活性的且可被人和/或动物所接受的量)的本发明的化合物或其药学上可接受的盐与药学上可以接受的载体(用于治疗给药的载体,它们本身并不是必要的活性成分,且施用后没有过分的毒性)可以组成药物制剂,这些药物制剂可以制备成口服制剂、注射剂、片剂、粉制剂、胶囊剂、分散片、缓释制剂等。
治疗有效量的本发明的药物组合物的用量介于0.001-500mg/kg体重/天之间,任何介于上述范围之内的用量皆为本发明的药物组合物的有效量。优选的,本发明的药物组合物的用量介于0.005-300mg/kg体重/天之间;更优选的,本发明的组合物的用量介于0.0l-100mg/kg体重/天之间。所述的“治疗有效量”可用于相关疾病的单一用药或联合用药治疗。本领域的专业人员能够理解,在实际给药时的用量可高于或低于上述剂量范围。针对某一对象(如哺乳动物一人)的“治疗有效量”和具体治疗方案可受诸多因素的影响,包括所用化合物的药效活性、给药对象的年龄、体重、一般情况、性别、饮食、给药时间、疾病易感性、疾病进程以及收治医师的判断等。所述的“治疗”指的是给予机体(含有肿瘤、具有肿瘤的症状、或者具有肿瘤的前兆)一种或几种本发明的化合物或其药学上可接受的盐,以治疗、减轻、减缓、改变、治愈、影响、改善其新型冠状病毒或SARS冠状病毒感染的前兆。
本发明的化合物或其药学上可接受的盐或其组合物或其药物制剂可以通过口服、静脉内、肌肉内、皮下、鼻腔内、直肠内等途径给药。固体载体如:淀粉、乳糖、磷酸二醇、微晶纤维素、黑糖和白陶土,而液态载体如:无菌水、聚乙二醇、非离子型表面活性剂和食用油(如玉米油、花生油和芝麻油),只要适合活性成分的特性和所需要的特定给药方式。在制备药物组合物中通常使用的佐剂也可有利地被包括,如,调味剂、色素、防腐剂和抗氧化剂如维生素E、维生素C、BHT和BHA。
这些活性化合物或其药学上可接受的盐也可肠胃外或腹腔内给药。也可在适当混合有表面活性剂(如羟丙基纤维素)的水中制备这些活性化合物(作为游离碱或药学上可接受的盐)的溶液或悬浮液。还可在甘油、聚乙二醇及其在油中的混合物中制备分散液。在常规储存和使用条件下,这些制剂中含有防腐剂以防止微生物的生长。
适用于注射的药物形式包括:无菌水溶液或分散液和无菌粉(用于临时制备无菌注射液或分散液)。在所有情况中,这些形式必须是无菌的且必须是流体以易于注射器排出流体。在制造和储存条件下必须是稳定的,且必须能防止微生物如细菌和真菌的污染和影响。载体可以是溶剂或分散介质,其中含有如水、醇、它们的适当混合物和植物油。
本发明还提供一种抑制冠状病毒3CL蛋白酶的多种外用洗液的制备工艺。以本发明的化合物或其药学上可接受的盐为活性成分,有效浓度范围为0.1-100μM。添加辅料加以配制,灭菌,包装加工制成日常外用消毒洗液制品。
所述日常外用消毒洗液制品可分为药物洗剂和外用消杀用品两类,其中,药物洗剂包括但不限于漱口液,洗眼液,洗鼻洗耳剂等;所述外用消杀用品包括但不限于洗手液,消毒液,洗衣液,沐浴液,洗发液,洗洁精,清洁剂和湿巾等。
较为优选地,所述日常外用消毒洗液制品接受安全合适的添加剂,主要有效成分为本发明的化合物或其药学上可接受的盐的任意一种或多种的组合,其余部分为各种添加剂,如表面活性剂、保湿剂、螯合剂、pH调节剂、增稠剂、助溶剂、香料、起泡剂、荧光剂等。
本发明各个方面的细节将在随后的章节中得以详尽描述。通过下文以及权利要求的描述,本发明的特点、目的和优势将更为明显。
附图说明
图1为5,8-二羟基-1,4-萘醌对SARS-CoV-2 3CL蛋白酶时间及剂量依赖性抑制曲线,表明5,8-二羟基-1,4-萘醌可时间及剂量依赖性灭活SARS-CoV-2 3CL蛋白酶;
图2为5,8-二羟基-1,4-萘醌对SARS-CoV 3CL蛋白酶抑制曲线,表明5,8-二羟基-1,4-萘醌可剂量依赖性抑制SARS-CoV 3CL蛋白酶;
图3为5,8-二羟基-1,4-萘醌对SARS-CoV-2 3CL蛋白酶抑制的KI曲线,表明5,8-二羟基-1,4-萘醌可时间及剂量依赖性灭活SARS-CoV-2 3CL蛋白酶;
图4为5-羟基-1,4-萘醌对SARS-CoV-2 3CL蛋白酶抑制曲线;
图5为5-羟基-1,4-萘醌对SARS-CoV 3CL蛋白酶抑制曲线;
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。除非另外说明,否则所有的百分数、比率、比例、或份数按重量计。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明提到的上述特征,或实施例提到的特征可以任意组合。本专利说明书所揭示的所有特征可与任何组合物形式并用,说明书中所揭示的各个特征,可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明,所揭示的特征仅为均等或相似特征的一般性例子。
实施例1:1,4-萘醌衍生物抑制3CL蛋白酶的IC50测定
1.材料与方法
1.1材料
5-羟基-1,4-萘醌、5,8-二羟基-1,4-萘醌和2,3-二氯-5,8-二羟基-1,4-萘醌购自J&K公司;SARS-2 3CL蛋白酶及SARS 3CL蛋白酶由上海中医药大学交叉科学研究院葛广波课题组重组表达,作为体外3CL蛋白酶抑制实验的酶源;底物Dabcyl-KNSTLQSGLRKE-Edans由Sangon Biotech公司合成(上海);磷酸二氢钾、磷酸氢二钾、乙二胺四乙酸均购自美仑生物(纯度>98%);色谱级二甲基亚砜购自Tedia公司(美国);Milli-Q Direct 8纯水/超纯水一体化系统(Bedford,美国);2.5μL、10μL、20μL、100μL、200μL、1000μL移液器(德国Eppendorf);黑色96孔板;涡旋仪;恒温混匀仪(杭州奥盛);ID3多模式酶标仪(奥地利)。
1.2方法
向96孔板中加入90μL预孵液,预孵液由pH=7.4,含1mM乙二胺四乙酸(EDTA)的磷酸盐缓冲液78μL、不同浓度的抑制剂2μL、10μL新冠/SARS 3CL蛋白酶组成。将预孵液在37℃下预孵33分钟后,加入底物(Dabcyl-KNSTLQSGLRKE-Edans)起始反应,于多功能酶标仪下对底物的代谢水解产物连续检测20分钟(激发波长为340nm,发射波长为490nm)。随后以抑制剂浓度的对数值为横坐标,剩余酶活为纵坐标,绘制其抑制曲线,由Graph Pad Prism 7.0软件进行数据处理。
其中剩余酶活的计算公式为:
剩余酶活(%)=(F0-F1)/F0×100%
F0为预孵液中不加抑制剂时测得的荧光强度值,F1为预孵液中加入各浓度抑制剂时测得的荧光强度值。
注:表中所述浓度均为100μL体系中的终浓度。
2.结果
5-羟基-1,4-萘醌、5,8-二羟基-1,4-萘醌和2,3-二氯-5,8-二羟基-1,4-萘醌分别能够呈剂量依赖型强效抑制SARS-2 3CL蛋白酶和SARS 3CL蛋白酶,其IC50值如下表:
实施例2:5,8-二羟基-1,4-萘醌时间及剂量依赖性抑制SARS-CoV-2 3CL蛋白酶
1.材料与方法
1.1材料
5,8-二羟基-1,4-萘醌购自J&K公司;SARS-2 3CL蛋白酶及SARS 3CL蛋白酶由上海中医药大学交叉科学研究院葛广波课题组重组表达,作为体外3CL蛋白酶抑制实验的酶源;底物Dabcyl-KNSTLQSGLRKE-Edans由Sangon Biotech公司合成(上海);磷酸二氢钾、磷酸氢二钾、乙二胺四乙酸均购自美仑生物(纯度>98%);色谱级二甲基亚砜购自Tedia公司(美国);Milli-Q Direct 8纯水/超纯水一体化系统(Bedford,美国);2.5μL、10μL、20μL、100μL、200μL、1000μL移液器(德国Eppendorf);黑色96孔板;涡旋仪;恒温混匀仪(杭州奥盛);ID3多模式酶标仪(奥地利)。
1.2方法
反应体系体积为100μL,首先向96孔板中加入预孵液,预孵液由PBS-EDTA缓冲液(pH7.4)、终浓度为4μg/mL的3CL蛋白酶和不同浓度的5,8-二羟基-1,4-萘醌组成。将预孵液在37℃恒温金属浴震荡,分别孵育3min和33min。再向预孵液中加入终浓度为20μM的Dabcyl-KNSTLQSGLRKE-Edans荧光底物,起始反应,接着采用多模式酶标仪,检测水解产物(λex=340nm,λem=490nm)在采集波长处的荧光强度值。随后以抑制剂浓度的对数值为横坐标,剩余酶活为纵坐标,绘制其抑制曲线,由Graph Pad Prism 7.0软件进行数据处理。
其中剩余酶活的计算公式为:
剩余酶活(%)=(F0-F1)/F0×100%
F0为预孵液中不加5,8-二羟基-1,4-萘醌时测得的荧光强度值,F1为预孵液中加入各浓度5,8-二羟基-1,4-萘醌时测得的荧光强度值。
2.结果
如图1所示,5,8-二羟基-1,4-萘醌呈时间及剂量依赖性抑制SARS-CoV-2 3CL蛋白酶,其IC50值如下表:
实施例3:5,8-二羟基-1,4-萘醌灭活SARS-CoV-2 3CL蛋白酶的灭活常数KI测定
1.材料与方法
1.1材料
5,8-二羟基-1,4-萘醌购自J&K公司;SARS-2 3CL蛋白酶及SARS 3CL蛋白酶由上海中医药大学交叉科学研究院葛广波课题组重组表达,作为体外3CL蛋白酶抑制实验的酶源;底物Dabcyl-KNSTLQSGLRKE-Edans由Sangon Biotech公司合成(上海);磷酸二氢钾、磷酸氢二钾、乙二胺四乙酸均购自美仑生物(纯度>98%);色谱级二甲基亚砜购自Tedia公司(美国);Milli-Q Direct 8纯水/超纯水一体化系统(Bedford,美国);2.5μL、10μL、20μL、100μL、200μL、1000μL移液器(德国Eppendorf);黑色96孔板;涡旋仪;恒温混匀仪(杭州奥盛);ID3多模式酶标仪(奥地利)。
1.2方法
首先准备一系列失活孵育样品A(100μL)和3CL蛋白酶活性评价孵育样品B(90μL),失活孵育样品A由不同浓度的5,8-二羟基-1,4-萘醌和3CL蛋白酶组成。样品A按不同时间点在恒温孵育器上37℃分别预孵0,10,20,30后,各取出10μL,然后迅速加入3CL蛋白酶活性评价孵育样品B中起始反应,样品B包含80μL PBS-EDTA缓冲液(pH 7.4)及荧光底物Dabcyl-KNSTLQSGLRKE-Edans,反应20min后,加入等体积的冰乙腈终止反应,涡旋混匀。接着从终止反应后的样品B中取出100μL至96孔板中,采用多模式酶标仪,检测水解产物(λex=340nm,λem=490nm)在采集波长处的荧光强度值。3CL蛋白酶残余活性的计算公式:残余活性(%)=(抑制剂存在时测得的荧光强度值)/空白组测得的荧光强度值×100%,绘制抑制曲线,计算KI。
两个样品组:
A.失活孵育样品
B.SARS-2 3CL活性评价孵育样品
2.结果:5,8-二羟基-1,4-萘醌能够呈时间及剂量依赖性强效抑制SARS-2 3CL蛋白酶,其KI值为3.05μM,Kinact为0.05min-1,结果如图3所示。
实施例4:5,8-二羟基-1,4-萘醌抗病毒洗手液的制备
配方(质量比):5,8-二羟基-1,4-萘醌10%、烷基糖苷4%、乙二胺四乙酸0.2%、甜菜碱3%、乙醇2%、氯化钠适量,柠檬酸:pH值6.1、柠檬酸钠0.5%、水溶性薄荷香料0.5%和去离子水组成。制备工艺:在有加热装置的反应中加入水,再依次将溶剂、表面活性剂和其他助剂等以上组分缓慢依次加入纯净水中。边加热边搅拌,搅拌30分钟后加入香精。温度降至常温状态时,杀菌后瓶装。
实施例5:5,8-二羟基-1,4-萘醌抗病毒漱口液的制备
配方(质量比):5,8-二羟基-1,4-萘醌5%、甘油0.1%,辛甘醇0.5%、山梨醇2%、乙醇5%,柠檬酸0.5%、柠檬酸钠0.4%、水溶性薄荷香料0.5%和去离子水组成。制备工艺:在有加热装置的反应中加入水,再依次将溶剂、表面活性剂和其他助剂等缓慢依次加入纯净水中,柠檬酸调节pH值6.5。边加热边搅拌,搅拌加入水溶性薄荷香料。温度降至常温状态时,杀菌后瓶装。
实施例6:5,8-二羟基-1,4-萘醌抗病毒洗洁精的制备
配方(质量比):5,8-二羟基-1,4-萘醌10%、烯醚硫酸钠8%;起泡剂:烷基醇酰胺65012%、防腐剂0.08%、氢氧化钠1.3%、脂肪醇聚氧乙烯醚5%、直链烷基苯磺酸10%、乙二胺四乙酸二钠0.1%、氯化钠1%、香精和去离子水组成。制备工艺:将定量的去离子水投入配料锅中,在搅拌下加入固碱,待其溶解后缓缓加入直链烷基苯磺酸,搅拌中和pH 7~8,在温度60~70℃下加入表面活性剂等,溶解后加入其余助剂,澄清透明后加适量香精,补足去离子水即可,杀菌后瓶装。
实施例7:5,8-二羟基-1,4-萘醌抗病毒消毒液的制备
配方(质量比):5,8-二羟基-1,4-萘醌25%、乙醇30%、双氧水3%、甘油6%、香精1%和去离子水组成。制备工艺:先将酒精装入容器中,再去离子水和双氧水,最后加入甘油和5,8-二羟基-1,4-萘醌,搅拌容器使液体混合均匀,杀菌后瓶装。
实施例8:5,8-二羟基-1,4-萘醌抗病毒洗眼剂的制备
配方(质量比):5,8-二羟基-1,4-萘醌2%、牛磺酸0.02%、硼酸盐0.02%、维生素B6 0.05%、叶黄素0.05%、透明质酸0.05%、珍珠粉0.01%、茶多酚0.02%,薄荷醇0.05%、甘油3%和去离子水组成。制备工艺:先加入牛磺酸、珍珠粉和甘油,搅拌20-30分钟,后将剩余组分依次加入,检测相关指标后,灭菌装瓶。
实施例9:5,8-二羟基-1,4-萘醌抗病毒洗鼻洗耳剂的制备
配方(质量比):5,8-二羟基-1,4-萘醌5%、冰片5%、盐酸萘甲唑啉1%、氯化钠5%和去离子水组成。制备工艺:按照配方依次加入5,8-二羟基-1,4-萘醌、冰片以及其他助剂适量,在反应容器中搅拌20-30分钟使液体混合均匀,检测相关指标,合格后灭菌瓶装,即得抗病毒洗鼻洗耳剂。
实施例10:5,8-二羟基-1,4-萘醌抗病毒洗发液的制备
配方(质量比):5,8-二羟基-1,4-萘醌10%、柠檬酸5%、珠光浆1%、保湿柔亮剂2%、发泡剂2%、增稠剂3%、香精1%、色素1%、柠檬酸3%、防腐剂1%和去离子水组成。制作工艺:取以上组分连续搅拌25-30分钟混匀乳化,随后加入柠檬酸3%用于调节pH 6.5-7之间持续真空搅拌25-30分钟;最后加入香精、色素、防腐剂和发泡剂再真空搅拌25-30分钟,杀菌后瓶装。
实施例11:5,8-二羟基-1,4-萘醌抗病毒洗衣液制备
配方(质量比):5,8-二羟基-1,4-萘醌30%、纳米二氧化钛8%、椰子油脂肪酸甘氨酸钾10%、柠檬酸2%、氯化十二烷基二甲基苄基铵5%、羧甲基纤维素2%、硅酸钠3%。制作工艺:将以上组分加入搅拌罐中均匀搅20min后,加入、氯化十二烷基二甲基苄基铵、羧甲基纤维素和硅酸钠混合后加入加热罐中低温加热,加热温度为50℃,加热时间为20min,之后缓慢冷却至室温,静置5h后,杀菌后瓶装,即得到洗衣液。
实施例12:5,8-二羟基-1,4-萘醌抗病毒湿巾的制备
配方(质量比):5,8-二羟基-1,4-萘醌5%,30-40%的体积浓度的乙醇,十二烷基二甲基氧化胺0.1%、月桂醇聚氧乙烯醚0.1%、木糖醇2%和余量水。制作工艺:将以上组分和余量水混匀,通过预浸渍方法喷淋到基材上,经过湿巾机器裁切、包装获得抗病毒湿巾成品。
实施例13:5,8-二羟基-1,4-萘醌抗病毒沐浴露的制备
配方(质量比):脂肪醇聚氧乙烯醚硫酸铵70%、5,8-二羟基-1,4-萘醌10%、脂肪酸甲酯磺酸盐5%、乳化硅油3%、椰子油脂肪酸二乙醇酰胺3%、水杨酸0.1%、杏仁油2%、柠檬酸、香精和去离子水组成。制作工艺:将杏仁油和椰子油脂肪酸二乙醇酰胺混合为油相,加热到75℃融化成液体保温备用,其余佐剂加热后加入油相,搅拌混合,柠檬酸调pH值6,均质成稳定乳液。降温后加入香精,静置消泡,灭菌后瓶装。
实施例14:5,8-二羟基-1,4-萘醌抗病毒全能清洁剂的制备
配方(质量比):椰子油脂肪醇单乙醇酰胺50%、5,8-二羟基-1,4-萘醌25%、柠檬酸8%、烷基酚聚氧乙烯醚10%、氢氧化钠3.8%、二甲基苯磺酸钠6.2%、偏硅酸钠5%、香料6%和去离子水。制作工艺:将5,8-二羟基-1,4-萘醌、椰子油脂肪醇单乙醇酰胺、烷基酚聚氧乙烯醚、偏硅酸钠加入到反应釜中反应20-30分钟,把柠檬酸用水稀释加入,在搅拌中徐徐加入氢氧化钠,依次添加其余组分,搅拌均匀至透明,调节pH值,再进行自然消泡静止20-30分钟后除去沉淀,测定相关指标,合格后灌装,即得抗病毒全能清洁剂。
实施例15:5,8-二羟基-1,4-萘醌抗病毒消毒凝胶的制备
配方(质量比):5,8-二羟基-1,4-萘醌15%、三氯羟基二苯醚0.5%、乙醇55%、卡波姆940 10%、山梨醇3.8%、可食用色素6%和去离子水。制作工艺:将卡波姆940加入到有水的反应釜中静止溶胀30分钟,制备出A溶液;将可食用色素用水稀释,搅拌中缓缓加入其余组分,搅拌均匀,调节pH值,制备出B溶液;再将B溶液加入A溶液中,搅拌均匀灌装,即得免洗消毒凝胶。
本发明所涉及的多个方面已做如上阐述。然而,应理解的是,在不偏离本发明精神之前提下,本领域专业人员可对其进行等同改变和修饰,所述改变和修饰同样落入本专利申请之权利要求的覆盖范围。
Claims (9)
2.如权利要求1的用途,其特征在于,所述式(Ⅰ)化合物或其药学上可接受的盐是作为唯一的原料药应用于所述抑制新型冠状病毒3CL蛋白酶或SARS冠状病毒3CL蛋白酶的药物的制备中。
5.如权利要求4的用途,其特征在于,所述式(Ⅱ)化合物或其药学上可接受的盐是作为唯一的原料药应用于所述抑制新型冠状病毒3CL蛋白酶或SARS冠状病毒3CL蛋白酶的药物的制备中。
8.如权利要求7的用途,其特征在于,所述式(Ⅲ)化合物或其药学上可接受的盐是作为唯一的原料药应用于所述抑制新型冠状病毒3CL蛋白酶或SARS冠状病毒3CL蛋白酶的药物的制备中。
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WO2016112553A1 (zh) * | 2015-01-17 | 2016-07-21 | 广州自远生物科技有限公司 | 一种预防和/或治疗由冠状病毒属和/或轮状病毒属病毒引发的疾病的药物组合物 |
CN105832759A (zh) * | 2015-01-17 | 2016-08-10 | 广州自远生物科技有限公司 | 一种预防和/或治疗由冠状病毒属和/或轮状病毒属病毒引发的疾病的药物组合物 |
CN111233649A (zh) * | 2020-03-02 | 2020-06-05 | 上海交通大学 | 一种抗新型冠状病毒的萘醌类化合物及其医药用途 |
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