CN115634227A - 一种n-羟基吡啶酮类化合物在制备抗冠状病毒药物中的用途 - Google Patents
一种n-羟基吡啶酮类化合物在制备抗冠状病毒药物中的用途 Download PDFInfo
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- CN115634227A CN115634227A CN202210974348.5A CN202210974348A CN115634227A CN 115634227 A CN115634227 A CN 115634227A CN 202210974348 A CN202210974348 A CN 202210974348A CN 115634227 A CN115634227 A CN 115634227A
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Abstract
本发明公开了一种N‑羟基吡啶酮类化合物在制备抗冠状病毒药物中的应用。具体地,本发明涉及式I所示的化合物,或其药学上可接受的盐。本发明发现该化合物能在体外有效抑制α冠状病毒HCoV‑229E的复制,对HCoV‑229E的IC50为0.76μg/ml,显示该化合物具有抗冠状病毒活性,可用于治疗冠状病毒引起的感染。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种N-羟基吡啶酮类化合物及其药学上可接受的盐和含有该化合物或其药学上可接受的盐的组合物在制备抗冠状病毒药物 中的用途。
背景技术
冠状病毒(Coronavirus,CoV)广泛存在于自然界,是一类具有囊膜、基因组 为线性单股正链的RNA病毒,冠状病毒仅感染脊椎动物,与人类和动物的多种疾 病有关,可引起人和动物呼吸道、消化道和神经系统疾病。
目前,已知感染人的冠状病毒有7种分别是人冠状病毒HCoV-229E、 HCoV-OC43、HCoV-NL63和HCoV-HKU1,以及严重急性呼吸系统综合征冠状病 毒SARS-CoV、中东呼吸综合症冠状病毒MERS-CoV和SARS-CoV-2。以上冠状 病毒中,前4种冠状病毒会引发较轻微症状的普通感冒,而后3种则会导致严重 症状且传染性强,甚至引发致死的病毒性肺炎。寻找能够有效抗冠状病毒的药物 已经迫在眉睫。
N-羟基吡啶酮类化合物(N-hydroxypyridone)是一类主要由真菌产生的次级 代谢产物,其结构特征是分子中具有N-羟基吡啶酮母核。Militarinone A是Hamburger 等从真菌Paecilomyces militaris发酵提取物中首次分离得到的一个新N-羟基吡啶酮类 化合物[参见,Organic Lettters(有机化学快报杂志).2002,2,197-199],并报道了该化 合物具有神经营养活性。Kuenzi等报道了该化合物既可以促进神经突生长,也能够诱 导肿瘤细胞凋亡[参见,Apoptosis(细胞凋亡杂志),2008,13,364–376]。随后,本课题 组从一株冬虫夏草定殖真菌Isaria farinosa的发酵产物中分离得到该化合物[参见, Journal ofNatural Products(天然产物杂志).2011,74,32-37],同时报道了该化合物具 有明显的抑制肿瘤细胞增殖活性,结构式如式I所示。但是,目前尚未见该化合物作 为制备抗冠状病毒的药物报道。
发明内容
本发明的目的是提供一种N-羟基吡啶酮类化合物在制备抗冠状病毒药物中的新用途。药效学试验证实了该化合物在体外细胞模型中能有效抑制α群冠状病毒 HCoV-229E的复制,具有用于制备抗冠状病毒药物的潜力。
所述N-羟基吡啶酮类化合物的结构式如式I所示。
本发明所提供的式I所示化合物或其药学上可接受的盐的应用为下述(a)和/或(b) 和/或(c):
(a)式I所示化合物或其药学上可接受的盐在制备治疗冠状病毒所致疾病或冠状病毒感染的产品中的应用;
(b)式I所示化合物或其药学上可接受的盐在制备预防冠状病毒所致疾病或冠状病毒感染的产品中的应用;
(c)式I所示化合物或其药学上可接受的盐在制备冠状病毒抑制剂中的应用。
所述产品可为药物或药物制剂。
所述冠状病毒抑制剂能够抑制冠状病毒的复制。
所述冠状病毒可为α属冠状病毒和/或β属冠状病毒,具体的选自人冠状病毒2019-nCoV、HCoV-229E、HCoV-OC43、SARS-CoV和MERS-CoV中的至少一种。
上述应用中,“式I所示化合物药学上可接受的盐”指在可靠的医学判断范围内,适合用于与人类和低等动物的组织接触而不出现过度的毒性、刺激、过敏反应等, 且与合理的效果/风险比相称的盐。式I所示化合物药学上可接受的盐是本领域公知 的,包括但不限于钠盐、钾盐、钙盐、盐酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷 酸盐、磷酸氢盐、乙酸盐、草酸盐、乳酸盐、柠檬酸盐、酒石酸盐和马来酸盐等。
上述应用中,制备药物或药物制剂时,式I所示化合物或其药学上可接受的盐可作为有效成分之一,也可作为唯一有效成分。
上述应用中,制备药物或药物制剂时,式I所示化合物或其药学上可接受的盐可作为活性成分之一,也可作为唯一活性成分。
上述应用中,制备药物时,还可加入载体材料。
载体材料包括但不限于水溶性载体材料(如聚乙二醇、聚乙烯吡咯烷酮、有机酸等)、难溶性载体材料(如乙基纤维素、胆固醇硬脂酸酯等)、肠溶性载体材料(如醋 酸纤维素酞酸酯和羧甲乙纤维素等)。使用这些材料可以制成多种剂型,包括但不限于 片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、 透皮剂、口含片、栓剂、冻干粉针剂等。可以是普通制剂、缓释制剂、控释制剂及各 种微粒给药系统。为了将单位给药剂型制成片剂,可以广泛使用本领域公知的各种载 体。关于载体的例子是,例如稀释剂与吸收剂,如淀粉、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、硅酸铝等;湿润 剂与粘合剂,如水、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 乙烯吡咯烷酮等;崩解剂,例如干燥淀粉、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、 乙基纤维素等;崩解抑制剂,例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等;吸收 促进剂,例如季铵盐、十二烷基硫酸钠等;润滑剂,例如滑石粉、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。为了将单位给药剂型制 成丸剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸 收剂,如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、高岭土、滑 石粉等;粘合剂如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等;崩 解剂,如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素 等。为了将单位给药剂型制成栓剂,可以广泛使用本领域公知的各种载体。关于载体 的例子是,例如聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酯、明胶、半合成甘 油酯等。为了将单位给药剂型制成注射用制剂,如溶液剂、乳剂、冻干粉针剂和混悬 剂,可以使用本领域常用的所有稀释剂,例如,水、乙醇、聚乙二醇、1,3-丙二醇、 乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外,为了 制备等渗注射液,可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油,此外,还 可以添加常规的助溶剂、缓冲剂、pH调节剂等。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、甜味剂或其它材料。使用上述剂型可以经注射 给药,包括皮下注射、静脉注射、肌肉注射和腔内注射等;腔道给药,如经直肠和阴 道;呼吸道给药,如经鼻腔;粘膜给药。
本发明还提供了一种药物或药物组合物,其活性成分为式I所示化合物或其药 学上可接受的盐。
所述药物或药物组合物具有下述至少一种功效:
1)治疗冠状病毒所致疾病或冠状病毒感染;
2)预防冠状病毒所致疾病或冠状病毒感染;
3)抑制冠状病毒。
上述药物或药物组合物可以按照本领域技术人员已知的常规方法制成溶液剂、片剂、胶囊或注射剂等剂型。
利用本发明提供的式I所示化合物或其药学上可接受的盐预防和/或治疗冠状病毒引起的感染时,给予受试者生物体有效量的式I化合物或其药学上可接受的盐。
本发明化合物的使用剂量和使用方法取决于诸多因素,包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的 严重程度以及诊治医生的主观判断。优选的使用剂量介于0.01~100mg/kg体重/天,其 中最优剂量在0.1~10mg/kg体重/天。
本发明中,术语“有效量”是指可在受试者中实现治疗、预防、减轻和/或缓解 本发明所述疾病或病症的剂量。
本发明中,术语“受试者”可以指患者或者其它接受本发明组合物以治疗、预防、减轻和/或缓解本发明所述疾病或病症的动物,特别是哺乳动物,例如人、狗、猴、牛、 马等。
本发明中,所述冠状病毒所致疾病可为呼吸系统感染和/或消化系统感染。
所述呼吸系统感染为呼吸道感染和/或肺部感染;所述呼吸道感染可为鼻咽炎、鼻炎、咽喉炎、气管炎和/或支气管炎;所述肺部感染可为肺炎;所述消化系统感 染可为腹泻。
本发明中,所述冠状病毒所致疾病通常包括病毒性肺炎、严重急性呼吸综合征等。
本发明中,所述冠状病毒感染通常引起病毒性肺炎、严重急性呼吸综合征等疾病。
本发明选择α群冠状病毒HCoV-229E,探讨上述式I所示的N-羟基吡啶酮类化合 物在制备抗冠状病毒药物中应用的可能性,通过实验研究,发现该化合物能在体外显 著抑制α群冠状病毒HCoV-229E的复制,具有用于制备抗冠状病毒药物的潜力。
附图说明
图1为式I所示化合物的核磁共振1H-NMR谱图。
图2为式I所示化合物的核磁共振13C-NMR谱图。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下面的实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未 注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生 产厂商者,均为可以通过市购获得的常规产品。
实施例中所用的冠状病毒HCoV-229E为人冠状病毒229E株(Human coronavirus229E(VR-740TM));文献:Hamre D,Procknow JJ.A new virus isolated from thehuman respiratory tract.Proc.Soc.Exp.Biol.Med.121,190-193,1966.PubMed:4285768。
实施例中所述N-羟基吡啶酮类化合物的结构式如式I所示。
表1.式I所示化合物的氢谱(1H NMR)和碳谱(13C NMR)数据
a在400MHz以CD3OD为溶剂测试。
b在100MHz以CD3OD为溶剂测试。
通过将上述式I所示化合物核磁共振氢谱、碳谱与文献中所报道的“MilitarinoneA,a neurotrophic pyridone alkaloid from Paecilomyces militaris”[参见,OrganicLettters(有机化学快报杂志).2002,2,197-199]中化合物militarinone A的数据相同。
实施例1、式I化合物体外抗HCoV-229E活性效果检测
1.实验目的
为研究式I化合物在体外抗冠状病毒的药效,拟用细胞病变效应(CPE)实验测 定化合物在Huh7.5细胞中对冠状病毒(HCoV-229E)的半数抑制浓度(IC50)及SI。 采用利巴韦林(RBV)作为阳性对照药物。
实验在中国医学科学院医药生物技术研究所病毒室BSL-2生物安全实验室(实验楼329房间)进行。
2.材料
供试品:
式I化合物,为本实验室制备分离(分离方法参见文献:Journal of NaturalProducts (天然产物杂志).2011,74,32-37),黄色固体,纯度大于98%;结构鉴定图谱见图1、2;
阳性对照药利巴韦林注射液(RBV),购自天津金耀集团湖北天药药业股份有限公司,规格为100mg/ml,用时稀释至所需浓度,4℃冰箱保存。
细胞
传代人肝癌细胞Huh7.5细胞为中国医学科学院医药生物技术研究所传代保存,在含10%胎牛血清(inactivated fetal bovine serum)和1%双抗(青霉素和链霉素)的DMEM或1640培养基中,37℃,5%CO2培养箱中培养,2-3天传代一次。
毒株
HCoV-229E于Huh7.5细胞中传代,保存于-80℃冰箱。
3.实验方法
细胞培养
以Huh7.5细胞为例:在长满Huh7.5细胞的培养瓶内加0.25%Trypsin-EDTA(胰 酶细胞消化液)3ml,37℃消化1~2分钟,弃消化液,加培养液吹打,1:4传代,2-3 天传代一次,种板时配制成每毫升20万个细胞,接种96孔细胞培养板,每孔0.1ml, 37℃,5%CO2培养过夜,细胞长成单层后进行实验。
抗HCoV-229E的活性测定(CPE法)
实验在传代Huh7.5细胞中进行,Huh7.5细胞1×104个/孔接种于96孔板中,过 夜培养后将100μl HCoV-229E病毒液(100TCID50)感染96孔板内Huh7.5细胞,待测 药物用维持液稀释,分别于感染同时给药和感染后2h给药两种给药方案进行测定,待 测药物以三倍稀释8个剂量的样品进行实验,每个剂量设2个平行孔,同时设物无药 物的病毒对照组。以观察细胞病变为指标,显微镜下观察细胞病变,以细胞死亡比例 分别标记为4+(细胞死亡比例75%~100%)、3+(细胞死亡比例50%~75%)、2+(细 胞死亡比例25%~50%)、1+(细胞死亡比例0~25%)、0+(细胞全部存活)。待病毒 对照组病变达4+号时观察结果,记录并用Reed-Muench法计算药物对病毒的半数抑制 浓度(公式如下)及选择指数(SI=TC50/IC50)。
其中:A=累积抑制率<50%的药物浓度,B=累积抑制率>50%的抑制率,C=累 积抑制率<50%的抑制率,D=log稀释倍数
细胞毒性测定方法(CPE法)
细胞按1.5×104个/孔接种于96孔板中,过夜培养后加入含待测药物的维持液,待测药物以三倍稀释8个剂量的样品进行实验,继续培养。给药2天后倒置显微镜下 药物对细胞的毒性,并用Reed-Muench法计算半数有毒浓度TC50,计算公式如下:
其中:A=累积抑制率<50%的药物浓度,B=累积抑制率>50%的抑制率,C=累积抑制 率<50%的抑制率,D=log稀释倍数
4.实验结果
药物在Huh7.5细胞内对HCoV-229E的抑制作用
如表1所示,CPE法测定式I化合物对HCoV-229E毒株的IC50为0.76μg/ml,选 择指数SI为30.40;RBV对HCoV-229E的IC50为5.94μg/ml,选择指数SI为18.52。
表1.化合物在Huh7.5细胞内对HCoV-229E的抑制作用(IC50)(CPE法)
5.结论
本实验条件下,式I化合物对HCoV-229E毒株具有抑制作用;RBV对HCoV-229E 毒株具有抑制作用,并且RBV的抗冠状病毒HCoV-229E活性与文献和本实验之前的 结果相当,说明实验系统成立。
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解: 根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在 本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。 下面结合具体实施例对本发明作进一步阐述,但本发明并不限于以下实施例。所述方 法如无特别说明均为常规方法。所述原材料如无特别说明均能从公开商业途径获得。
Claims (8)
2.根据权利要求1所述的应用,其特征在于:所述产品为药物或药物制剂。
3.根据权利要求1或2所述的应用,其特征在于:所述冠状病毒为α属冠状病毒和/或β属冠状病毒;所述冠状病毒抑制剂能够抑制冠状病毒的复制。
4.根据权利要求3所述的应用,其特征在于:所述冠状病毒选自人冠状病毒2019-nCoV、HCoV-229E、HCoV-OC43、SARS-CoV和MERS-CoV中的至少一种。
6.根据权利要求5所述的药物或药物组合物,其特征在于:所述冠状病毒为α属冠状病毒和/或β属冠状病毒;
所述冠状病毒抑制剂能够抑制冠状病毒的复制。
7.根据权利要求6所述的药物或药物组合物,其特征在于:所述冠状病毒选自人冠状病毒2019-nCoV、HCoV-229E、HCoV-OC43、SARS-CoV和MERS-CoV中的至少一种。
8.根据权利要求5-7中任一项所述的药物或药物组合物,其特征在于:所述药物或药物组合物为药学上可接受的任意剂型,包括片剂、胶囊剂、注射剂、颗粒剂、混悬剂和溶液剂中的至少一种。
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