CN113440527A - 萘酚喹或含萘酚喹的组合制剂在抗冠状病毒中的应用 - Google Patents
萘酚喹或含萘酚喹的组合制剂在抗冠状病毒中的应用 Download PDFInfo
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- CN113440527A CN113440527A CN202010214507.2A CN202010214507A CN113440527A CN 113440527 A CN113440527 A CN 113440527A CN 202010214507 A CN202010214507 A CN 202010214507A CN 113440527 A CN113440527 A CN 113440527A
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Abstract
本发明涉及萘酚喹或含萘酚喹的组合制剂在抗冠状病毒中的应用。具体而言,本发明涉及萘酚喹类化合物及其药物组合物作为抑制冠状病毒复制的抑制剂;和/或(b)治疗和/或预防、缓解由冠状病毒感染引起的相关疾病的药物中的用途。本发明的萘酚喹类化合物可治疗和/或预防、缓解由2019新型冠状病毒感染引起的呼吸道感染、肺炎等相关疾病。
Description
技术领域
本发明涉及医药领域,具体地涉及萘酚喹或含萘酚喹的组合制剂在抗冠状病毒中的应用。
背景技术
在急性传染病中,绝大部分都是病毒性传染病,病毒性传染病的发病率高,死亡率也很高。由于检测和诊断手段有限,导致新病毒引发的新疫情爆发往往具有突发性、随机性和不可预测性等特点,一旦爆发,如无有效的防治手段,极易造成大规模流行,严重威胁人民健康生命安全。
新型冠状病毒(2019-nCoV或SARS-CoV-2)感染可引起严重肺炎。2019-nCoV病毒传播途径未完全掌握,已知能通过飞沫和接触传播,且存在人传人、医务人员感染,一定社区传播风险,且病毒存在变异的可能。目前对于新型冠状病毒所致疾病没有特异的预防和治疗方法。
2019-nCoV冠状病毒属于冠状病毒科冠状病毒属,为具有包膜的单链正义 RNA病毒。和其他已知冠状病毒类似,2019-nCoV冠状病毒也经过吸附、穿入、脱壳、生物合成、子代病毒的组装与释放等几个过程完成子代病毒的增殖。2019-nCoV冠状病毒感染宿主细胞起始于病毒包膜表面的刺突糖蛋白与宿主细胞表面的受体结合,随后发生膜融合,病毒进入宿主细胞,在细胞溶酶体等细胞器作用下,释放出病毒的遗传物质单链正义RNA,在宿主细胞的线粒体、核糖体等蛋白质合成元件以及必须的原料等作用下,翻译产生多聚蛋白,之后,2019-nCoV冠状病毒的两大必需半胱氨酸蛋白酶:木瓜样蛋白酶(papain-likeprotease,PLpro)和3C样蛋白酶(3C-like protease,3CLpro)在特定位点切割加工多聚蛋白前体,产生多个对病毒生命周期非常重要的非结构蛋白。在这些非结构蛋白的作用下,病毒RNA复制出子代病毒核酸物质,并大量翻译出所需的结构蛋白,完成子代病毒的组装和释放。2019-nCoV冠状病毒感染细胞的生命周期的任何环节或关键酶均可以作为抗病毒药物的研究靶点,如水解切割多聚蛋白前体的半胱氨酸蛋白酶PLpro和3CLpro,负责完成子代病毒遗传物质复制的 RNA聚合酶等。
目前,针对SARS-CoV-2冠状病毒导致的严重肺炎疾病尚无特效的疫苗和抗病毒药物。这些感染性疾病严重影响了人们的生命健康,研发效果好的抗病毒药物迫在眉睫。针对SARS-CoV-2冠状病毒开发出低毒高效的抗病毒药物,以满足国内外SARS-CoV-2冠状病毒感染患者的临床需求,具有重大的社会意义。
综上所述,本领域迫切需要开发针对SARS-CoV-2冠状病毒的抑制剂以用于治疗新型冠状病毒感染引起的肺炎。
发明内容
本发明的目的是提供一种可有效抑制冠状病毒复制的活性成分及其在新型冠状 病毒感染引起的肺炎等疾病中的新用途。
具体地,本发明提供了式I所示的萘酚喹类化合物及其组合物在抗冠状病毒尤其是新型冠状病毒(SARS-CoV-2)中的用途。
在本发明第一方面,提供了一种活性成分或含所述活性成分的制剂的用途,所述的活性成分为式I所示的萘酚喹类化合物或其药学上可接受的盐:
式中,
R1为H、C1-C6烷基或C3-C6环烷基;
R2为H、-CO-C1-C6烷基、-CO-C3-C6环烷基、C1-C6烷基或C3-C6环烷基;
并且,所述的化合物或含所述化合物的药物组合物的制剂被用于制备(a)抑制冠 状病毒复制的抑制剂;和/或(b)治疗和/或预防、缓解由冠状病毒感染引起的相关疾病的药物。
在另一优选例中,所述的抑制冠状病毒复制包括通过抑制SARS-CoV-2病毒刺突蛋白(2019nCov-S)的活性,进而抑制冠状病毒复制。
在另一优选例中,所述的活性成分或含所述活性成分的制剂被用于制备(a)抑制2019新型冠状病毒(SARS-CoV-2)复制的抑制剂;和/或(b)治疗和/或预防、缓解由2019新型冠状病毒(SARS-CoV-2)感染引起的相关疾病的药物。
在另一优选例中,所述冠状病毒选自下组:感染人类的冠状病毒,重症急性呼吸综合征冠状病毒SARS-CoV(Severe acute respiratory syndrome coronavirus,SARS-CoV)、2019新型冠状病毒(2019-nCoV或SARS-CoV-2)、中东呼吸综合征冠状病毒MERS-CoV(MiddleEast respiratory syndrome coronavirus,MERS-CoV)或致普通感冒的冠状病毒;所述的致普通感冒的冠状病毒优选人冠状病毒OC43(Human coronavirus OC43)、人冠状病毒229E(Human coronavirus 229E)、人冠状病毒NL63(Human coronavirus NL63)、人冠状病毒HKUl(Human coronavirus HKUl)。
在另一优选例中,所述冠状病毒引起的相关疾病选自下组:人冠状病毒引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症、SARS-CoV-2引起的新型冠状病毒肺炎(Corona Virus Disease 2019,COVID-19)或其组合。
在另一优选例中,所述由2019新型冠状病毒感染引起的相关疾病选自下组:呼吸道感染、肺炎及其并发症、或其组合。
在另一优选例中,所述的活性成分为(Z1)萘酚喹、或其药学上可接受的盐。
在另一优选例中,所述的活性成分为下式所示的萘酚喹:
在另一优选例中,含所述化合物的药物组合物还可以含有其他抗病毒药。
在另一优选例中,所述的药物还包括选自下组的额外组分:抗肺损伤的药物、抗炎药物或具有免疫调节作用的药物。
在另一优选例中,所述的药物还包括选自下组的额外组分:阿奇霉素(azitromycin)、青蒿素(artemisinin)、双氢青蒿素(dihydroartemisinin)、青蒿琥酯(Artesunate)、青蒿酮(Artemisone)中的一种或多种。
在另一优选例中,所述的组合物或药物包括:口服制剂和非口服制剂。
在另一优选例中,所述的制剂包括:粉剂、颗粒剂、胶囊剂、注射剂、酊剂、口服液、片剂、含片、或滴丸。
本发明第二方面提供了一种药物组合物,所述的药物组合物含有:
(a1)第一活性成分,所述的第一活性成分为式I所示的萘酚喹类化合物或其药学上可接受的盐:
式中,
R1为H、C1-C6烷基、C3-C6环烷基;
R2为H、-CO-C1-C6烷基、-CO-C3-C6环烷基、C1-C6烷基或C3-C6环烷基;
(a2)任选的第二活性成分,所述的第二活性成分为抗病毒药物,其选自下组:RNA依赖的RNA聚合酶抑制剂(如Remdesivir(瑞德西韦或GS-5734)、法匹拉韦(favipiravir)、Galidesivir、GS-441524);3CL蛋白酶抑制剂(如GC-376)、洛匹那韦(Lopinavir)、利托那韦(Ritonavir)、奈非那韦(Nelfinavir);氯喹(Chloroquine,Sigma-C6628)、羟氯喹(hydroxychloroquine)、黄芩苷(baicalin)、黄芩素(baicalein)、环索奈德(Ciclesonide)、利巴韦林(Ribavirin)、喷昔洛韦(Penciclovir)、来氟米特(Leflunomide)、特立氟胺(Teriflunomide)、萘莫司他(nafamostat)、硝唑尼特(nitazoxanide)、达芦那韦(Darunavir)、阿比多尔(Arbidol)、卡莫司他(Camostat)、氯硝柳胺(Niclosamide)、巴瑞替尼(baricitinib)、芦可替尼(Ruxolitinib)、达沙替尼(Dasatinib)、沙奎那韦(Saquinavir)、Beclabuvir、司美匹韦(Simeprevir)、或其药学上可接受的盐、或其组合;
和/或所述的第二活性成分选自下组:阿奇霉素(azitromycin)、青蒿素(artemisinin)、双氢青蒿素(dihydroartemisinin)、青蒿琥酯(Artesunate)、青蒿酮(Artemisone)中的一种或多种;
以及(b)药学上可接受的载体。
在另一优选例中,所述的第二活性成分选自下组:(Y1)RNA复制酶抑制剂(如Remdesivir(瑞德西韦或GS-5734));(Y2)洛匹那韦(Lopinavir);(Y3)利托那韦(Ritonavir);(Y4)法匹拉韦;(Y5)氯喹(Chloroquine,Sigma-C6628)、羟氯喹(hydroxychloroquine)、或其药学上可接受的盐(如磷酸氯喹)、(Y6)上述Y1~Y5的任意组合;
在另一优选例中,所述的药物组合物用于抑制冠状病毒复制。
在另一优选例中,所述药物组合物用于抑制2019新型冠状病毒(SARS-CoV-2)复制。
在另一优选例中,所述的药物组合物用于制备(a)抑制冠状病毒;和/或(b)治疗和/或预防、缓解由冠状病毒感染引起的相关疾病的药物
在另一优选例中,用于制备(a)抑制2019新型冠状病毒(SARS-CoV-2)复制的抑制剂;和/或(b)治疗和/或预防、缓解由2019新型冠状病毒(SARS-CoV-2)感染引起的相关疾病的药物。
本发明第三方面提供了一种抑制2019新型冠状病毒(SARS-CoV-2)复制或抑制SARS-CoV-2病毒刺突蛋白(2019nCov-S)的活性的方法,包括步骤:
将第一活性成分或含所述第一活性成分的制剂与2019新型冠状病毒(SARS-CoV-2)接触,从而抑制所述冠状病毒的复制;
或者,将第一活性成分或含所述第一活性成分的制剂与SARS-CoV-2病毒刺突蛋白(2019nCov-S)接触,从而抑制SARS-CoV-2病毒刺突蛋白(2019nCov-S)的活性;
其中,所述的第一活性成分为式I化合物或其药学上可接受的盐:
式中,
R1为H、C1-C6烷基、C3-C6环烷基;
R2为H、-CO-C1-C6烷基、-CO-C3-C6环烷基、C1-C6烷基或C3-C6环烷基。
在另一优选例中,所述的第一活性成分为萘酚喹、或其药学上可接受的盐。
在另一优选例中,所述方法是体外方法。
在另一优选例中,所述方法是非治疗性和非诊断性的。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
无。
具体实施方式
本发明人经过广泛而深入的研究,通过大量筛选,首次意外地开发了一类可有效抑制2019新型冠状病毒(SARS-CoV-2)等冠状病毒复制的活性成分。实验表明,本发明的活性成分(以萘酚喹为代表的式I化合物或其药学上可接受的盐)可高效地抑制2019新型冠状 病毒(SARS-CoV-2)等冠状病毒的复制和活力。在此基础上完成了本发明。
具体地,本发明揭示了萘酚喹及其组合物在抗冠状病毒的用途,尤其是在抗SARS-CoV-2病毒治疗中的用途。萘酚喹对冠状病毒复制具有优良的抑制作用,具有良好的临床应用前景。
术语
如本文所用,“本发明的活性化合物”、“本发明的活性成分”、“本发明的抑制冠状 病毒复制的活性化合物”可互换使用,指具有优异的抑制冠状病毒复制的活性的萘酚喹类化合物,包括式I所示的化合物,例如萘酚喹、或其药学上可接受的盐、或其组合。
如本文所用,“本发明的制剂”指含有本发明活性化合物的制剂。
如本文所用,术语“包括”或其变换形式如“包含”或“包括有”等等,被理解为包括所述的元件或组成部分,而并未排除其它元件或其它组成部分。
如本文所用,术语“新型冠状病毒”、“2019-nCov”或“SARS-CoV-2”可互换使用,该2019新型冠状病毒是已知感染人的第7种冠状病毒,并且造成新冠肺炎(COVID-19),是威胁全球人类健康的严重传染性疾病之一。
冠状病毒
冠状病毒(Coronavirus,CoV)属于套式病毒目(Nidovirales)冠状病毒科(Coronaviridae),是一种有包膜的正链RNA病毒,其亚科包含α、β、δ及γ四属。
目前已知的感染人的冠状病毒中,HCoV-229E和HCoV-NL63属于α属冠状病毒,HCoV-OC43、SARS-CoV、HCoV-HKU1、MERS-CoV和SARS-CoV-2均为β属冠状病毒。SARS-CoV-2也被称为2019-nCov。
2003年和2012年分别爆发的高致病性冠状病毒“非典”SARS-CoV和“中东呼吸综合征”MERS-CoV均属于β属冠状病毒。新型冠状病毒(SARS-CoV-2)与SARS-CoV有约80%相似性、与MERS-CoV有40%的相似性,也属于β属冠状病毒。
该类病毒的基因组是一条单股正链RNA,是基因组最大的RNA病毒之一,编码包括复制酶、刺突蛋白、囊膜蛋白、包膜蛋白和核壳蛋白等。在病毒复制的初始阶段,基因组被翻译成两条长达几千个氨基酸的肽链即前体多聚蛋白(Polyprotein),随后前体蛋白被蛋白酶切割生成非结构蛋白(如RNA聚合酶和解旋酶)和结构蛋白(如刺突蛋白)及辅助蛋白。
本发明的活性化合物和活性成分
在本发明中,提供了一种可有效抑制2019新型冠状病毒(SARS-CoV-2)等冠状病毒复制的活性成分,其为式I所示的萘酚喹类化合物或其药学上可接受的盐:
式中,
R1为H、C1-C6烷基、C3-C6环烷基;
R2为H、-CO-C1-C6烷基、-CO-C3-C6环烷基、C1-C6烷基或C3-C6环烷基。
优选地,R1为C3-C6烷基(优选C3、C4、C5烷基)、或C3-C4环烷基。
优选地,R2为H、-CO-C1-C3烷基、或C1-C3烷基。
在本发明中,所述活性成分包括式I所示的萘酚喹类化合物、或其药学上可接受的盐、或其组合、或其晶体、或其溶剂化物。
一种优选的化合物是萘酚喹,其结构式如下:
试验表明,本发明的活性成分可有效地抑制2019新型冠状病毒(SARS-CoV-2)的复制,从而预防、治疗和/或缓解SARS-CoV-2相关疾病。
如本文所用,“本发明的活性化合物”、“本发明的抑制冠状病毒复制的活性化合物”可互换使用,指具有优异的抑制冠状病毒复制的活性的式I的萘酚喹类化合物(包括萘酚喹)、或其药学上可接受的盐、或其晶体、或其溶剂化物。
应理解,本发明的活性成分包括式I化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体、或其前药。应理解,本发明的活性成分还包括本发明的活性化合物的晶型、无定形化合物、以及氘代化合物等形式。
所述“药学上可接受的盐”为本发明的活性化合物与无机酸或有机酸反应形成常规的无毒盐。例如,常规的无毒盐可通过本发明的活性化合物与无机酸或有机酸反应制得,所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等,所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等;或者本发明的活性化合物与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、天冬氨酸或谷氨酸形成酯后再与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐;或者本发明的活性化合物与赖氨酸、精氨酸、鸟氨酸形成酯后再与盐酸、氢溴酸、氢氟酸、硫酸、硝酸或磷酸形成的对应的无机酸盐或与甲酸、乙酸、苦味酸、甲磺酸或乙磺酸形成的对应的有机酸盐。
此外,本发明的活性成分还特别适合与其他抗冠状病毒的药物联用。代表性的其他的抗冠状病毒药物包括(但并不限于):RNA依赖的RNA聚合酶抑制剂(如Remdesivir(瑞德西韦或GS-5734)、法匹拉韦(favipiravir)、Galidesivir、 GS-441524);3CL蛋白酶抑制剂(如GC-376)、洛匹那韦(Lopinavir)、利托那韦(Ritonavir)、奈非那韦(Nelfinavir);氯喹(Chloroquine,Sigma-C6628)、羟氯喹、环索奈德(Ciclesonide)、利巴韦林(Ribavirin)、喷昔洛韦(Penciclovir)、来氟米特(Leflunomide)、特立氟胺(Teriflunomide)、萘莫司他(nafamostat)、硝唑尼特(nitazoxanide)、达芦那韦(Darunavir)、阿比多尔(Arbidol)、卡莫司他(Camostat)、氯硝柳胺(Niclosamide)、巴瑞替尼(baricitinib)、芦可替尼(Ruxolitinib)、达沙替尼(Dasatinib)、沙奎那韦(Saquinavir)、Beclabuvir、司美匹韦(Simeprevir)、或其药学上可接受的盐、或其组合。
另一类适合与本发明化合物联用的药物选自下组:阿奇霉素(azitromycin)、青蒿素(artemisinin)、双氢青蒿素(dihydroartemisinin)、青蒿琥酯(Artesunate)、青蒿酮(Artemisone)、或其组合。
此外,由于SARS-CoV-2)感染可引起急性肺损伤、炎症反应甚至细胞因子风暴,本发明的活性成分还特别适合与具有改善急性肺损伤、抗炎作用或调节免疫作用的药物联用。代表性的药物包括但不限于:锌(Zinc)、芬戈莫德(Fingolimod)、维生素C(Vitamin C)、奥美沙坦酯、缬沙坦、氯沙坦、沙利度胺(Thalidomide)、甘草酸(glycyrrhizic acid)、青蒿素(Artemisinin)、双氢青蒿素(dihydroartemisinin)、青蒿琥酯(Artesunate)、青蒿酮(Artemisone)、阿奇霉素(Azithromycin)。
优选地,本发明的活性成分与青蒿素类药物(青蒿素、双氢青蒿素、青蒿琥酯、青蒿酮中的一种或多种)联用。大量研究显示青蒿素类药物具有多重的抗炎、免疫调节机制,通过抑制T细胞增殖与活化,抑制B细胞活化和抗体产生,增加调节性T细胞以及减少致炎细胞因子的释放来实现抗炎、免疫调节功能,预期能够缓解新型冠状病毒(SARS-CoV-2)感染引起的免疫损伤症状。
优选地,本发明的活性成分与青蒿素类药物(青蒿素、双氢青蒿素、青蒿琥酯、青蒿酮中的一种或多种)、阿奇霉素联用。
本发明的活性成分可抑制SARS-CoV-2等新型冠状病毒的感染活性。因此,当在治疗上施用或给予本发明的的活性成分时,可抑制2019新型冠状病毒(SARS-CoV-2)的感染,进而达到抗病毒作用。
药物组合物和应用
本发明还提供了以本发明的抑制冠状病毒复制的活性化合物、或其药学上可接受的盐、或其前药的一种或多种的混合物为有效成分,在制备治疗和/或预防、缓解由2019新型冠状病毒等冠状病毒感染引起的呼吸道感染、肺炎等相关疾病的药物中的用途。
本发明所提供的药物组合物优选含有重量比为0.001-99wt%的活性成份,优选的比例是本发明的活性化合物作为活性成分占总重量的0.1wt%~90wt%或 1wt%~50wt%,其余部分为药学可接受的载体、稀释液或溶液或盐溶液。
需要的时候,在本发明药物中还可以加入一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
本发明所提供的化合物和药物组合物可以是多种形式,如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等,并可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位计量中通常包含0.05-400mg本发明的活性化合物,优选地,制剂配方的单位计量中包含1mg-500mg本发明的活性化合物。
本发明的化合物和药物组合物可对哺乳动物临床使用,包括人和动物,可以通过口、鼻、皮肤、肺或者胃肠道等的给药途径。最优选为口服。最优选日剂量为0.01-400mg/kg体重,一次性服用,或0.01-200mg/kg体重分次服用。不管用何种服用方法,个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始,逐渐增加剂量一直到找到最适合的剂量。
本发明的药物或抑制剂可通过各种不同方式施用,例如可通过注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉、粘膜组织;或是被其他物质混合或包裹导入机体。
典型地,本发明活性成分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。
本发明活性成分可以被制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明活性成分被制成片剂,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;润湿剂可以是水、乙醇、异丙醇等;黏合剂可以是淀粉浆、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活性成分与稀释剂、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的胶囊剂。
为将本发明活性成分制成注射剂,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、矫味剂或其他添加剂。
本发明的活性成分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。
当本发明的活性成分与其他治疗药物存在协同作用时,应根据实际情况调整它的剂量。
本发明的主要优点包括:
(a)本发明活性化合物可高效地抑制SARS-CoV-2复制,IC50值远小于10μM,针对SARS-CoV-2病毒刺突蛋白(2019nCov-S)具有高抑制活性,IC50高达0.95 μM。
(b)本发明活性化合物的毒副作用低,成药性好。这提示着本发明的萘酚喹类化合物在抗新冠肺炎领域有很好的药用前景。
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,否则百分比和份数按重量计算。
实施例1.磷酸萘酚喹对SARS-CoV-2病毒刺突蛋白抑制活性筛选(假病毒- 细胞水平模型)
测试原理:以Huh7细胞作为病毒宿主细胞(易感细胞),测试样品阻断 SARS-CoV-2病毒的刺突蛋白(S蛋白)修饰HIV假病毒感染Huh7细胞的活性,该抑制活性可反应样品干预SARS-CoV-2病毒感染关键靶点的活性。检测指标为报告基因萤火虫荧光素酶Luciferase活性水平。
测试方法:
Huh7细胞提前一天铺种于96孔培养板,分别设活性测定板和细胞毒性测定板,置于37℃培养箱,5%CO2培养。活性测定板和细胞毒性测定板按同样加样方式,加入不同稀释浓度的样品和SARS-CoV-2病毒S蛋白修饰假病毒悬液,设病毒对照、细胞对照和样品对照。继续培养3天后,细胞毒性测定板采用MTT法测定细胞存活率。活性测定板吸去细胞培养液后每孔加入100μL细胞裂解液,震荡裂解5分钟后,每孔再加入100μL的Luciferase反应检测液,震荡孵育5分钟后测定化学发光值。
评价方法:
细胞毒性(MTT法):通过比较病毒对照、细胞对照和样品对照的OD值,计算细胞的存活率,并进一步计算样品的细胞毒作用。
假病毒感染率:以细胞对照组读值为本底,将病毒对照和样品对照的化学发光值扣除本底后,计算相对病毒对照孔的相对感染率,进而计算样品对病毒感染细胞的保护活性。
表1萘酚喹对SARS-CoV-2病毒刺突蛋白(2019nCov-S)抑制活性筛选实验结果
从表1中可以看出,磷酸奈酚喹可以显著抑制SARS-CoV-2病毒的刺突蛋白(S蛋白)修饰的HIV假病毒复制,且具有较好的治疗指数,预计具有抑制新型冠状病毒复制的作用。
实施例2:磷酸萘酚喹(Naphthoquine phosphate)对新型冠状病毒复制的抑制作用研究
测定化合物对2019新型冠状病毒(SARS-CoV-2)复制抑制活性:Vero E6细胞购买自ATCC,SARS-CoV-2病毒来源于国家病毒资源库微生物菌毒种保藏中心。将Vero E6细胞在密度为5×104细胞/孔的48孔细胞培养皿中培养过夜,用不同浓度的磷酸萘酚喹预先处理细胞1小时,然后加入病毒(感染复数MOI 为0.05)使其感染1小时,然后取出病毒化合物混合物,用含磷酸萘酚喹的新鲜培养基进一步培养细胞。在24h p.i.时,收集细胞上清液并在裂解缓冲液中裂解,通过定量实时RT-PCR(qRT-PCR)对细胞上清液中的病毒拷贝数进行定量评估。
结果表明,在10μM下磷酸萘酚喹显著抑制SARS-CoV-2病毒复制,与药物未处理的对照组比较,对新型冠状病毒复制的抑制率>99%。
实施例3:磷酸萘酚喹的半数毒性浓度测定
在本实施例中,通过CCK8试剂盒分析确定磷酸萘酚喹对Vero E6细胞的半数毒性浓度(CC50)。
结果显示,磷酸萘酚喹在最高浓度10uM下对Vero E6细胞无细胞毒作用,这提示CC50远大于10μM。
讨论
萘酚喹为抗疟药,药理研究表明萘酚喹对各种疟原虫裂殖体及某些种株疟原虫配子体和组织期原虫有杀灭作用,临床上磷酸萘酚喹主要用于恶性疟、间日疟和抗药性疟疾的治疗。专利文献CN 104666300A还报道了磷酸萘酚喹的抗真菌和普通病原菌作用。由昆明药业研发的青蒿素/磷酸萘酚喹复方制剂,于 2006年在尼日利亚和乌干达获批上市,商品名为为口服片剂,每片含有50mg萘酚喹和125mg青蒿素,用于疟疾的治疗。另外, Naphthoquine/Azithromycin(复方萘酚阿奇片)用于治疗疟疾也已经完成III期临床试验,获得军队特需药品批件。复方萘酚阿奇片是一种50S核糖体亚基抑制剂(阿奇霉素)和磷酸萘酚喹、青蒿素组成的复方药物。
在本发明之前,萘酚喹或其药学上可接受的盐对2019新型冠状病毒(SARS-CoV-2)等冠状病毒的复制的抑制作用尚未见报道。
在本发明中,本发明人首次公开了萘酚喹或其药学上可接受的盐对 SARS-CoV-2的复制具有显著的抑制作用,对SARS-CoV-2病毒刺突蛋白(2019nCov-S)具有显著的抑制作用,IC50达到个位数微摩尔级别或更低。因此,萘酚喹或其药学上可接受的盐具有优异的抗2019新型冠状病毒(SARS-CoV-2)活性,具有良好的临床应用前景。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
2.如权利要求1所述的用途,其特征在于,所述冠状病毒选自下组:感染人类的冠状病毒,重症急性呼吸综合征冠状病毒SARS-CoV(Severe acute respiratory syndromecoronavirus,SARS-CoV)、2019新型冠状病毒(2019-nCoV或SARS-CoV-2)、中东呼吸综合征冠状病毒MERS-CoV(Middle East respiratory syndrome coronavirus,MERS-CoV)或致普通感冒的冠状病毒;所述的致普通感冒的冠状病毒优选人冠状病毒OC43(Humancoronavirus OC43)、人冠状病毒229E(Human coronavirus 229E)、人冠状病毒NL63(Humancoronavirus NL63)、人冠状病毒HKUl(Human coronavirus HKUl)。
3.如权利要求1所述的用途,其特征在于,所述冠状病毒引起的相关疾病选自下组:人冠状病毒引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症、SARS-CoV-2引起的新型冠状病毒肺炎(Corona Virus Disease 2019,COVID-19)或其组合。
4.如权利要求1所述的用途,其特征在于,所述的活性成分为(Z1)萘酚喹、或其药学上可接受的盐。
5.如权利要求1所述的用途,其特征在于,所述的组合物或药物包括:口服制剂和非口服制剂。
6.一种药物组合物,其特征在于,所述的药物组合物含有:
(a1)第一活性成分,所述的第一活性成分为式I所示的萘酚喹类化合物或其药学上可接受的盐:
式中,
R1为H、C1-C6烷基、C3-C6环烷基;
R2为H、-CO-C1-C6烷基、-CO-C3-C6环烷基、C1-C6烷基或C3-C6环烷基;
(a2)任选的第二活性成分,所述的第二活性成分为抗病毒药物,其选自下组:RNA依赖的RNA聚合酶抑制剂(如Remdesivir(瑞德西韦或GS-5734)、法匹拉韦(favipiravir)、Galidesivir、GS-441524);3CL蛋白酶抑制剂(如GC-376)、洛匹那韦(Lopinavir)、利托那韦(Ritonavir)、奈非那韦(Nelfinavir);氯喹(Chloroquine,Sigma-C6628)、羟氯喹(hydroxychloroquine)、黄芩苷(baicalin)、黄芩素(baicalein)、环索奈德(Ciclesonide)、利巴韦林(Ribavirin)、喷昔洛韦(Penciclovir)、来氟米特(Leflunomide)、特立氟胺(Teriflunomide)、萘莫司他(nafamostat)、硝唑尼特(nitazoxanide)、达芦那韦(Darunavir)、阿比多尔(Arbidol)、卡莫司他(Camostat)、氯硝柳胺(Niclosamide)、巴瑞替尼(baricitinib)、芦可替尼(Ruxolitinib)、达沙替尼(Dasatinib)、沙奎那韦(Saquinavir)、Beclabuvir、司美匹韦(Simeprevir)、或其药学上可接受的盐、或其组合;
和/或所述的第二活性成分选自下组:阿奇霉素(azitromycin)、青蒿素(artemisinin)、双氢青蒿素(dihydroartemisinin)、青蒿琥酯(Artesunate)、青蒿酮(Artemisone)中的一种或多种;
以及(b)药学上可接受的载体。
7.如权利要求6所述的药物组合物,其特征在于,所述的药物组合物用于抑制冠状病毒复制。
8.一种权利要求6所述的药物组合物的用途,其特征在于,用于制备(a)抑制冠状病毒;和/或(b)治疗和/或预防、缓解由冠状病毒感染引起的相关疾病的药物。
9.一种抑制2019新型冠状病毒(SARS-CoV-2)复制或抑制SARS-CoV-2病毒刺突蛋白(2019nCov-S)的活性的方法,其特征在于,包括步骤:
将第一活性成分或含所述第一活性成分的制剂与2019新型冠状病毒(SARS-CoV-2)接触,从而抑制所述冠状病毒的复制或抑制SARS-CoV-2病毒刺突蛋白(2019nCov-S)的活性;
或者,将第一活性成分或含所述第一活性成分的制剂与SARS-CoV-2病毒刺突蛋白(2019nCov-S)接触,从而抑制SARS-CoV-2病毒刺突蛋白(2019nCov-S)的活性;
其中,所述的第一活性成分为式I化合物或其药学上可接受的盐:
式中,
R1为H、C1-C6烷基、C3-C6环烷基;
R2为H、-CO-C1-C6烷基、-CO-C3-C6环烷基、C1-C6烷基或C3-C6环烷基。
10.如权利要求9所述的方法,其特征在于,所述的第一活性成分为萘酚喹、或其药学上可接受的盐。
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