CN116672337A - 甘松新酮在制备抗流感病毒药物中的应用 - Google Patents
甘松新酮在制备抗流感病毒药物中的应用 Download PDFInfo
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Abstract
本发明属于医药技术领域,公开了甘松新酮在制备抗流感病毒药物中的应用。具体公开了如结构式(I)所示的甘松新酮或其药学上可接受的盐在制备预防或治疗流感病毒感染的药物中的应用。以及含有如结构式(I)所示的甘松新酮或其药学上可接受盐的药物组合物在制备预防或治疗流感病毒感染的药物中的应用,进一步,所述的药物组合物还含有其他抗病毒药物。
Description
技术领域
本发明属于医药技术领域,具体涉及甘松新酮(CAS:23720-80-1)制备预防或治疗流感病毒感染的药物中的应用。本发明包含甘松新酮(CAS:23720-80-1) 在流感病毒感染预防或治疗中的单独或联合应用。
背景技术
流感病毒(Influenza virus)是对全球公共卫生安全的重要威胁,据世界卫生组织(WHO)统计,每年约有5-10%成人和20-30%的儿童感染流感病毒,其中300-500万为重症患者,死亡人数约25-50万人[Ziegler T,Mamahit A,Cox NJ:65years of influenzasurveillance by a world health organization-coordinat ed globalnetwork.Influenza and other respiratory viruses(2018)12(5):558-56 5.]。流感病毒属于正粘病毒科(Orthomyxoviridae),分甲、乙、丙和丁共四型,其中甲、乙和丙型流感病毒可感染人并引起呼吸道疾病。甲型流感病毒流行范围最广,危害最大。
流感病毒呈球形,直径约80-120nm,是包膜病毒,其基因组是单链分节段 RNA。甲型流感病毒共有8条RNA,编码至少10种病毒蛋白[David M Knipe P,Peter M Howley,MD:Fields virology,6th edition.2.Lippincott Williams& Wilkins(LWW),(2013)]。流感病毒包膜来自宿主细胞膜,上面嵌有三种病毒蛋白:血凝素蛋白(Hemagglutinin,HA)、神经氨酸酶(Neuraminidase,NA)和M 2离子通道。甲型流感病毒根据HA和NA血清学分类,已知有18种HA和10 种NA,故理论上共有180种亚型。
除流感大流行外,季节性流感每年都会出现,主要发生在冬季,最常由甲型或乙型流感病毒引起,其中以H1N1和H3N2较为常见。患季节性流感后的症状包括突然发热、咳嗽(通常是干咳)、头痛、肌肉和关节疼痛、喉咙痛和流鼻涕。咳嗽可能很严重,可持续2周或更长时间。大多数人在一周内从发烧和其它症状中恢复,不需要进行医疗。然而,流感可导致高危群体的严重疾病或死亡。[Ho w can I avoid getting the flu?World HealthOrganization website:https://www. who.int/news-room/q-a-detail/how-can-i-avoid-getting-the-flu]
现有抗流感病毒药物包括三类共7个[Amarelle L,Lecuona E,Sznajder JI:Anti-influenza treatment:Drugs currently used and under development.Archiv osde bronconeumologia(2017)53(1):19-26.]:M2离子通道抑制剂金刚烷胺和金刚乙胺;神经氨酸酶抑制剂奥司他韦、扎那米韦、帕拉米韦和拉尼米韦;CAP 依赖核酸内切酶抑制剂巴洛沙韦玛波西酯(baloxavirmarboxil)。这7个抗流感病毒药物有一个共性:它们都是以流感病毒蛋白为靶点的药物,所以,当靶点变异时,药物亲和力下降,流感病毒逃逸,成为耐药病毒。例如流感病毒M2离子通道抑制剂金刚烷胺和金刚乙胺经过长期使用,病毒已产生稳定耐药突变,WHO 已不推荐金刚烷胺和金刚乙胺用于甲型流感病毒的治疗[Summary ofinfluenza antiviral susceptibility surveillance findings,September 2010-march2011:(20 11).https://www.who.int/influenza/gisrs_laboratory/updates/antiviral_susceptibility/e n/]。
虽然有7个曾经或正在使用的抗流感病毒药物,但全球每年仍有5-15亿人次流感病毒感染并患病。在有抗流感病毒药物供应及注射流感病毒疫苗后,全部人口中仍有5%-20%感染患病,究其原因,主要由于流感病毒本身性质和变异和其RNA基因组的重组(Reassortment)引起的。例如,神经氨酸酶抑制剂是临床最常用的抗甲型流感病毒药物,其中以奥司他韦(达菲) 应用最广,临床数据显示,患者只有在感染病毒48小时内服药才可获得较好疗效[Summary of influenza antiviral susceptibility surveillancefindings,September 2010-March 2011:(2011).https://www.who.int/influenza/gisrs_laboratory/updat es/antiviral_susceptibility/en/]。
人工智能是近年来快速发展的前沿技术,可对高维度、大量级的数据进行高效分析及有效抽提,该技术为疾病大数据和化合物大数据的特征信息抽提和凝练提供了可能[Y.Peng,M.Yuan,J.Xin,et al.,Screening novel drug candidates for Alzheimer’sdisease by an integrated network and transcriptomeanalysis.Bioi nformatics 36(2020)4626-4632.],为多环节干预流感病毒感染的药物研发提供了途径。化合物细胞文库是化合物扰动细胞的转录组学大数据,包含化合物在不同浓度、不同时间处理细胞后的全基因表达谱。本发明应用转录组特征反向匹配 (Transcriptome signature reversion,TSR)策略[Koudijs KKM,et al.Transcripto me Signature Reversion as a Method toReposition Drugs Against Cancer for Precision Oncology.Cancer J.2019,25(2):116-120],将流感病毒感染致细胞病变的转录组特征基因集与20,000余个化合物扰动细胞的转录组特征基因集反向匹配,发现多环节反向干预流感病毒感染特征基因的活性化合物。
研究显示,甘松新酮(Nardosinone,CAS:23720-80-1)具有抗心律失常作用 [简鹏,李庆海,范立华.甘松新酮对快速性心律失常大鼠心肌细胞抑制作用的实验研宄.中国临床药理学杂志,2015,31(22):2240-2242]、神经保护作用[Ko W,et al.Nardosinone-typesesquiterpenes from the hexane fraction of Nardostach ysjatamansiattenuate NFkappaB and MAPK signaling pathways in lipopolysacc haride-stimulated BV2microglial cells.Inflammation 2018,41:1215-1228]、抗肿瘤、抗抑郁和抗菌作用[Wen J,et al.A review of nardosinone for pharmacologi calactivities.European Journal of Pharmacology.2021,908:174343]。经文献检索,未见关于甘松新酮抗流感病毒活性的报道。
本发明将首先提取流感病毒感染致细胞病变的特征基因集,并将其与化合物扰动细胞特征基因集反向匹配,发现化合物甘松新酮可反向调节流感病毒感染致细胞病变特征基因的表达。随后,应用流感病毒感染模型进行化合物抗病毒活性评价,发现甘松新酮具有广谱抗流感病毒活性,对甲型和乙型流感病毒感染有较强抑制活性。数据显示甘松新酮抗流感病毒活性与一线抗病毒药物利巴韦林相当,其中抗甲型H1N1流感病毒活性强于利巴韦林,且甘松新酮安全性良好。我们认为甘松新酮抗流感病毒新用途价值较高,具有应用前景。本发明是关于已知化合物新用途的发明专利。
发明内容
本发明解决的技术问题是,提供甘松新酮及其药学上可接受的盐在制备预防或治疗流感病毒感染的药物中的应用。
具体而言,为解决本发明的技术问题,采用如下技术方案:
本发明技术方案的第一方面是提供了如结构式(I)所示的甘松新酮及其药学上可接受的盐在制备预防或治疗流感病毒药物中的应用,
所述甘松新酮药学上可接受的盐,包括药学上可接受的有机盐或无机盐,其中,所述的有机盐包括磺酸盐、羧酸盐、氨基酸盐以及脂肪酸盐,无机盐包括盐酸盐、溴酸盐、碘酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐和硝酸盐。优选为硫酸氢盐,硫酸盐,盐酸盐和碘酸盐。
所述的磺酸盐包括含1-15个碳原子的烷基磺酸盐及苯磺酸盐、对甲苯磺酸盐、邻甲苯磺酸盐、间甲苯磺酸盐;羧酸盐包括酒石酸盐、马来酸盐、富马酸盐、枸橼酸盐、苹果酸盐、肉桂酸盐、苯甲酸盐、丙二酸盐、丁二酸盐、戊二酸盐、己二酸盐、双羟萘酸盐及乳酸盐;氨基酸盐包括谷氨酸盐、天冬氨酸盐;脂肪酸盐包括含2-18个碳原子的长链脂肪酸盐。
其中,所述的流感病毒包括甲型流感病毒、乙型流感病毒、丙型流感病毒和丁型流感病毒。
所述的甲型流感病毒包括H1N1亚型、H1N2亚型、H2N2亚型、H2N3亚型、 H3N1亚型、H3N2亚型、H3N8亚型、H5N1亚型、H5N2亚型、H5N3亚型、H 5N6亚型、H5N8亚型、H5N9亚型、H6N1亚型、H6N2亚型、H7N1亚型、H7 N2亚型、H7N3亚型、H7N4亚型、H7N7亚型、H7N9亚型、H9N2亚型、H10 N3亚型、H10N7亚型、H10N8亚型、H11N2亚型、H11N9亚型、H17N10亚型、 H18N11亚型。
本发明技术方案的第二方面提供了一种药物组合物在制备抗流感病毒药物中的应用,其特征在于,所述的药物组合物包含结构式(I)所示的甘松新酮及其药学上可接受的盐以及药学上可接受的载体或赋形剂;所述的药物组合物还可以含有其它的抗病毒药
其中,所述的流感病毒包括甲型流感病毒、乙型流感病毒、丙型流感病毒和丁型流感病毒。
所述的甲型流感病毒包括H1N1亚型、H1N2亚型、H2N2亚型、H2N3亚型、 H3N1亚型、H3N2亚型、H3N8亚型、H5N1亚型、H5N2亚型、H5N3亚型、H 5N6亚型、H5N8亚型、H5N9亚型、H6N1亚型、H6N2亚型、H7N1亚型、H7 N2亚型、H7N3亚型、H7N4亚型、H7N7亚型、H7N9亚型、H9N2亚型、H10 N3亚型、H10N7亚型、H10N8亚型、H11N2亚型、H11N9亚型、H17N10亚型、 H18N11亚型。
该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂 (包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明化合物与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
本发明的发明人发现甘松新酮可阻断流感病毒感染宿主细胞。还可以和其他的抗病毒药物进行联合用药。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。
本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
有益技术效果
本发明的发明人通过提取流感病毒感染致细胞病变的特征基因集,并将其与化合物扰动细胞特征基因集反向匹配,得到可干预流感病毒感染致细胞病变特征基因的化合物甘松新酮。随后应用抗流感病毒活性评价模型,发现甘松新酮对甲型和乙型流感病毒感染有较强抑制活性,数据显示甘松新酮抗流感病毒活性与一线抗病毒药物利巴韦林相当,其中抗甲型H1N1流感病毒活性强于利巴韦林,且甘松新酮的安全性良好。我们认为甘松新酮抗流感病毒新用途价值较高,具有应用前景。
附图说明
图1.甘松新酮阻断甲型流感病毒H1N1亚型感染MDCK细胞的活性评价结果。
图2.甘松新酮阻断甲型流感病毒H3N2亚型感染MDCK细胞的活性评价结果。
图3.甘松新酮阻断乙型流感病毒感染MDCK细胞的活性评价结果。
图4.甘松新酮对MDCK细胞活力的影响
具体实施方式
实施例1.提取流感病毒感染致细胞病变的特征基因集
以“Influenza”、“lung”和“homo sapiens”为关键词,从GEO数据库(Gene Expression Omnibus,https://www.ncbi.nlm.nih.gov/geo/)中检索获得流感感染细胞的高通量测序数据集(GSE61517、GSE104168)和DNA微阵列数据集(GSE1062 79、GSE32139、GSE71766、GSE37571)。首先分别对3个数据集的9种不同流感病毒株感染6组不同细胞24小时后的转录组学数据进行差异表达分析,计算获得基因表达变化倍数(Log2Foldchange值);然后应用基于秩聚合方法分析工具RobustRankAggregation软件包[Kolde R,Laur S,Adler P,Vilo J.Robust ran k aggregation for gene list integration and meta-analysis.Bioinformatics.2012, 28(4):573-580]对差异基因汇总分析,确定111个蛋白编码基因作为流感病毒感染致细胞病变的特征基因集(表1),用于转录组特征基因反向匹配计算。
表1流感病毒感染肺细胞的特征基因集
实施例2.应用转录组特征基因反向匹配获得干预流感病毒感染致细胞病变特征基因的化合物
应用基因集富集分析方法(Gene Set Enrichment Analysis,GSEA),将流感病毒感染致细胞病变的特征基因集与化合物细胞文库数据应用fgsea[Subramanian A, TamayoP,Mootha VK,et al.Gene set enrichment analysis:a knowledge-based approach forinterpreting genome-wide expression profiles.ProcNatlAcadSci U S A. 2005;102(43):15545-15550]R包进行特征反向匹配,结果显示化合物甘松新酮的富集分数为-0.0423,提示甘松新酮可反向调节流感病毒感染致细胞病变的特征基因集,该化合物将用于抗流感病毒活性评价。
实施例3.检测流感病毒感染模型的原理
甲型流感病毒H1N1亚型,甲型流感病毒H3N2亚型和乙型流感病毒为经典的季节性流感亚型。本检测模型主要检测化合物对甲型流感病毒H1N1亚型和H 3N2亚型感染MDCK细胞的抑制效果,以及化合物对乙型流感病毒感染MDCK 细胞的抑制效果。
本检测模型在感染前将化合物与细胞预孵育20h,随后将细胞感染病毒,并在感染后48h检测MDCK细胞活力,通过与溶剂对照组细胞和未感染病毒的正常细胞的细胞活力进行对比,计算化合物对病毒感染的抑制率。
实施例4.甲型流感病毒H1N1亚型感染MDCK细胞模型的实验方法和结果
将MDCK细胞以每孔4×104个细胞接种于96孔板,4小时后加入甘松新酮,终浓度分别为100μM、30μM、10μM、3μM和1μM,正常细胞对照组和溶剂对照组加入等体积DMSO,继续培养20小时。吸弃培养板中的培养基,用PBS 润洗细胞一次,加入甲型流感病毒H1N1亚型感染(100*TCID50),37℃孵育1 小时。吸弃培养基,PBS润洗一次,加入含受试化合物的培养基,正常细胞对照组和溶剂对照组加入含等量DMSO的培养基。48小时后使用发光法细胞活力检测试剂盒(Promega公司)检测细胞活力,即测定细胞裂解液中的相对荧光素酶活性(relativeluminescence units,RLUs)。按公式(1)和(2)计算各个实验组的细胞病变率和病毒抑制率。采用GraphPad Prism软件分析实验数据,以浓度-抑制率作散点图并用非线性拟合得到量效曲线,计算待测化合物的半数有效浓度EC50。
(1)细胞病变率%=(100-RLUs给药组(或RLUs溶剂对照组)/RLUs正常细胞对照组)×100%
(2)病毒抑制率%=(溶剂对照组细胞病变率-给药组细胞病变率)/溶剂对照组细胞病变率×100%
结果显示,甘松新酮可阻断甲型流感病毒H1N1亚型感染MDCK细胞,抗病毒活性优于一线抗病毒药物利巴韦林(结果见表2、量效曲线见附图1)。
表2化合物对甲型流感病毒H1N1亚型感染MDCK细胞的活性评价结果
实施例5.甲型流感病毒H3N2亚型感染MDCK细胞模型的实验方法和结果
将MDCK细胞以每孔4×104个细胞接种于96孔板,4小时后加入甘松新酮,终浓度分别为300μM、100μM、30μM和10μM,正常细胞对照组不加入任何化合物,溶剂对照组加入等体积DMSO,继续培养20小时。吸弃培养板中的培养基,用PBS润洗细胞一次,加入甲型流感病毒H3N2亚型感染(100*TCID50), 37℃孵育1小时。吸弃培养基,PBS润洗一次,加入含受试化合物的培养基,正常细胞对照组加入培养基,溶剂对照组加入含等量DMSO的培养基。48小时后使用发光法细胞活力检测试剂盒(Promega公司)检测细胞活力,即测定细胞裂解液中的相对荧光素酶活性(relativeluminescence units,RLUs)。按公式(1)和(2)计算各个实验组的细胞病变率和病毒抑制率。采用GraphPad Pris m软件分析实验数据,以浓度-抑制率作散点图并用非线性拟合得到量效曲线,计算待测化合物的半数有效浓度EC50。
(1)细胞病变率%=(100-RLUs给药组(或RLUs溶剂对照组)/RLUs正常细胞对照组)×100%
(2)病毒抑制率%=(溶剂对照组细胞病变率-给药组细胞病变率)/溶剂对照组细胞病变率×100%
结果显示,甘松新酮可阻断甲型流感病毒H3N2亚型感染MDCK细胞,抑制活性与一线抗病毒药物利巴韦林相当(结果见表3、量效曲线见附图2)。
表3化合物对甲型流感病毒H3N2亚型感染MDCK细胞的活性评价结果
实施例6.乙型流感病毒感染MDCK细胞模型的实验方法和结果
将MDCK细胞以每孔4×104个细胞接种于96孔板,4小时后加入甘松新酮,终浓度分别为300μM、100μM、30μM和10μM,正常细胞对照组不加入任何化合物,溶剂对照组加入等体积DMSO,继续培养20小时。吸弃培养板中的培养基,用PBS润洗细胞一次,加入乙型流感病毒感染(100*TCID50),37℃孵育1 小时。吸弃培养基,PBS润洗一次,加入含受试化合物的培养基,正常细胞对照组加入培养基,溶剂对照组加入含等量DMSO的培养基。48小时后使用 发光法细胞活力检测试剂盒(Promega公司)检测细胞活力,即测定细胞裂解液中的相对荧光素酶活性(relativeluminescence units,RLUs)。按公式(1) 和(2)计算各个实验组的细胞病变率和病毒抑制率。采用GraphPad Prism软件分析实验数据,以浓度-抑制率作散点图并用非线性拟合得到量效曲线,计算待测化合物的半数有效浓度EC50。
(1)细胞病变率%=(100-RLUs给药组(或RLUs溶剂对照组)/RLUs正常细胞对照组)×100%
(2)病毒抑制率%=(溶剂对照组细胞病变率-给药组细胞病变率)/溶剂对照组细胞病变率×100%
结果显示,甘松新酮可阻断乙型流感病毒感染MDCK细胞,抑制活性与一线抗病毒药物利巴韦林相当(结果见表4、量效曲线见附图3)。
表4化合物对乙型流感病毒感染MDCK活性评价结果
实施例7.检测化合物对细胞活力的影响
原理:ATP在细胞的各项生理过程中起着重要作用,为机体直接提供能量,是反映细胞活力的重要指标与活细胞数目成正相关。因此,通过定量检测细胞裂解液中ATP反映待测样本中活细胞数目。
本模型采用Luminescent Cell Viability Assay发光法细胞活力检测试剂盒(Promega公司),通过检测ATP定量MDCK细胞活力,评价化合物对MDCK细胞活力的影响。
将MDCK细胞按8000个/孔密度接种至96孔板,每孔100μL细胞液,37℃, 5%CO2培养24h。次日将不同浓度的受试化合物加至细胞,以等量DMSO(0.1% v/v)作为溶剂对照。继续培养48h后,每孔加入CellTiter-Glo试剂100μL,振荡混匀2min,室温孵育10min,测定各孔中的RLUs[Tang K,He S,Zhang X,et al. Tangeretin,an extract from Citruspeels,blocks cellular entry of arenaviruses that cause viral hemorrhagicfever.Antiviral Res.2018,160:87-93.]。以DMSO溶剂孔 RLUs值为100%,计算加药孔的细胞存活率。
细胞存活率%=荧光强度给药组/荧光强度溶剂对照组×100%。
实验结果表明化合物甘松新酮在其半数有效浓度下对MDCK细胞活力没有影响(结果见表5、量效曲线见附图4)。
表5甘松新酮对MDCK细胞活力的影响
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Claims (6)
1.如结构式(I)所示的甘松新酮或其药学上可接受的盐在制备预防或治疗流感病毒感染的药物中的应用;
2.根据权利要求1的应用,其特征在于,所述的药学上可接受的盐,包括药学上可接受的有机盐或无机盐,其中,所述的有机盐包括磺酸盐、羧酸盐、氨基酸盐以及脂肪酸盐,无机盐包括盐酸盐、溴酸盐、碘酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐和硝酸盐。
3.根据权利要求2的应用,其特征在于,所述的磺酸盐包括含1-15个碳原子的烷基磺酸盐、苯磺酸盐、对甲苯磺酸盐、邻甲苯磺酸盐、间甲苯磺酸盐;羧酸盐包括酒石酸盐、马来酸盐、富马酸盐、枸橼酸盐、苹果酸盐、肉桂酸盐、苯甲酸盐、丙二酸盐、丁二酸盐、戊二酸盐、己二酸盐、双羟萘酸盐及乳酸盐;氨基酸盐包括谷氨酸盐、天冬氨酸盐;脂肪酸盐包括含2-18个碳原子的长链脂肪酸盐。
4.一种药物组合物在制备预防或治疗流感病毒感染的药物中的应用,其特征在于,所述的药物组合物包含结构式(I)所示的甘松新酮或其药学上可接受的盐,以及药学上可接受的载体或赋形剂,
5.根据权利要求4的应用,其特征在于,所述的药物组合物还含有其它的抗病毒药。
6.根据权利要求1-4任一项的应用,其特征在于,所述的流感病毒包括甲型流感病毒、乙型流感病毒、丙型流感病毒或丁型流感病毒。
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