CN113521289A - 15种药物有效成分在抗病毒感染中的应用 - Google Patents
15种药物有效成分在抗病毒感染中的应用 Download PDFInfo
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- CN113521289A CN113521289A CN202010301125.3A CN202010301125A CN113521289A CN 113521289 A CN113521289 A CN 113521289A CN 202010301125 A CN202010301125 A CN 202010301125A CN 113521289 A CN113521289 A CN 113521289A
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Abstract
本发明涉及15种药物有效成分在抗冠状病毒中的应用。具体而言,本发明涉及伯舒替尼,羟哌氯丙嗪,盐酸碘胺酮,盐酸氟哌噻吨,盐酸去甲替林,酒石酸异丁嗪,达泊西汀,盐酸氯丙噻烯,盐酸普罗替林,盐酸异丙嗪,吉非替尼,琥珀酸索利那新,盐酸氮卓斯汀,富马酸氯马斯汀和托瑞米芬或其组合物作为抑制冠状病毒刺突蛋白活性的抑制剂;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。
Description
技术领域
本发明涉及医药领域,具体地涉及15种药物有效成分在抗病毒感染中的应用,尤其是在抗冠状病毒感染中的应用。
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。
冠状病毒(Coronaviruses)是单股正链RNA病毒,属于巢病毒目(Nidovirales) 冠状病毒科(Coronaviridae)正冠状病毒亚科(Orthocoronavirinae),可以感染人、蝙蝠、猪、老鼠、牛、马、山羊、猴子等多种物种。已知感染人的冠状病毒(HCoV) 有6种,包括中东呼吸综合征相关冠状病毒(MERSr-CoV)和严重急性呼吸综合征相关冠状病毒(SARSr-CoV)。
新型冠状病毒2019-nCoV(SARS-CoV-2)是第7种感染人的冠状病毒,可以引起严重肺炎。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,PL pro)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15种可有效抑制冠状病毒刺突蛋白的药物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15种药物活性成分(以盐酸异丙嗪(Promethazinehydrochloride)、盐酸氟哌噻吨(Flupenthixol dihydrochloride)、盐酸碘胺酮(Amiodarone hydrochloride)为代表)及其药物组合物,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,所述的活性成分选自下组药物活性成分:伯舒替尼(Bosutinib)、羟哌氯丙嗪 (Perphenazine)、盐酸碘胺酮(Amiodarone hydrochloride)、盐酸氟哌噻吨 (Flupenthixoldihydrochloride)、盐酸去甲替林(Nortriptyline hydrochloride)、酒石酸异丁嗪(Trimeprazine tartrate)、达泊西汀 (Dapoxetine)、盐酸氯丙噻烯(Chlorprothixenehydrochloride)、盐酸普罗替林 (Protriptyline hydrochloride)、盐酸异丙嗪(Promethazine hydrochloride)、吉非替尼(Gefitinib)、琥珀酸索利那新(Solifenacinsuccinate)、盐酸氮卓斯汀 (Azelastine hydrochloride)、富马酸氯马斯汀(Clemastinefumarate)和托瑞米芬(Toremifene)或其药学上可接受的盐或其组合物。
并且,所述的活性成分或含所述活性成分的药物组合物的制剂被用于制备(a) 抑制冠状病毒刺突蛋白活性成分的抑制剂;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,所述冠状病毒为选自下组的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(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(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:人冠状病毒引起的感冒症状、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,所述的活性成分选自下组药物活性成分:盐酸异丙嗪(Promethazine hydrochloride)、盐酸氟哌噻吨(Flupenthixol dihydrochloride)、盐酸碘胺酮(Amiodarone hydrochloride)或其药物组合物。
在另一优选例中,含所述活性成分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:锌(Zinc)、芬戈莫德(Fingolimod)、维生素C(Vitamin C)、奥美沙坦酯(Olmesartan Medoxomil)、缬沙坦(valsartan)、氯沙坦(Losartan)、沙利度胺(Thalidomide)、甘草酸 (glycyrrhizicacid)、青蒿素(Artemisinin)、双氢青蒿素(dihydroartemisinin)、青蒿琥酯(Artesunate)、青蒿酮(Artemisone)、阿奇霉素(Azithromycin)、七叶皂苷(Escin)、萘普生(Naproxen)、或其组合。
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。
在本发明第二方面,提供一种药物组合物,所述的药物组合物含有:
(a1)选自下组的第一活性成分:伯舒替尼(Bosutinib)、羟哌氯丙嗪(Perphenazine)、盐酸碘胺酮(Amiodarone hydrochloride)、盐酸氟哌噻吨(Flupenthixol dihydrochloride)、盐酸去甲替林(Nortriptyline hydrochloride)、酒石酸异丁嗪(Trimeprazine tartrate)、达泊西汀 (Dapoxetine)、盐酸氯丙噻烯(Chlorprothixene hydrochloride)、盐酸普罗替林 (Protriptyline hydrochloride)、盐酸异丙嗪(Promethazine hydrochloride)、吉非替尼(Gefitinib)、琥珀酸索利那新(Solifenacin succinate)、盐酸氮卓斯汀 (Azelastine hydrochloride)、富马酸氯马斯汀(Clemastine fumarate)和托瑞米芬(Toremifene)或其药学上可接受的盐或其组合物。
(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:干扰素、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)、环孢菌素 (cyclosporine)、可利霉素(Carrimycin)、黄芩苷(baicalin)、黄芩素(baicalein)、萘酚喹(Naphthoquine)、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:锌(Zinc)、芬戈莫德(Fingolimod)、维生素C(Vitamin C)、奥美沙坦酯(Olmesartan Medoxomil)、缬沙坦(valsartan)、氯沙坦(Losartan)、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)、七叶皂苷(Escin)、萘普生 (Naproxen)、或其组合;
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)奈非那韦(Nelfinavir);(Y7)上述Y1~Y6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刺突蛋白活性。
在另一优选例中,所述药物组合物用于抑制严重急性呼吸综合征冠状病毒(SARS-CoV)刺突蛋白活性。
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(2019-nCoV) /(SARS-CoV-2)刺突蛋白活性。
在另一优选例中,所述药物组合物用于抑制中东呼吸综合征冠状病毒 (MERS-coV)刺突蛋白活性。
在本发明的第三方面,提供了一种本发明第二方面所述的药物组合物的用途,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)抑制急性呼吸综合征冠状病毒(SARS-CoV)刺突蛋白活性的抑制剂;和/或(b)治疗和/或预防、缓解由急性呼吸综合征冠状病毒 (SARS-CoV)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)/(2019-nCoV)刺突蛋白活性的抑制剂;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,用于制备(a)抑制中东呼吸综合征冠状病毒(MERS-coV)刺突蛋白活性的抑制剂;和/或(b)治疗和/或预防、缓解由2中东呼吸综合征冠状病毒 (MERS-coV)感染引起的相关疾病的药物。
在本发明第四方面,提供了一种抑制冠状病毒刺突蛋白的方法,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冠状病毒(SARS-CoV-2)接触,抑制所述冠状病毒刺突蛋白的活性,从而抑制冠状病毒的复制;
其中,所述的第一活性成分选自下组:伯舒替尼(Bosutinib)、羟哌氯丙嗪(Perphenazine)、盐酸碘胺酮(Amiodarone hydrochloride)、盐酸氟哌噻吨(Flupenthixoldihydrochloride)、盐酸去甲替林(Nortriptyline hydrochloride)、酒石酸异丁嗪(Trimeprazine tartrate)、达泊西汀 (Dapoxetine)、盐酸氯丙噻烯(Chlorprothixenehydrochloride)、盐酸普罗替林 (Protriptyline hydrochloride)、盐酸异丙嗪(Promethazine hydrochloride)、吉非替尼(Gefitinib)、琥珀酸索利那新(Solifenacinsuccinate)、盐酸氮卓斯汀 (Azelastine hydrochloride)、富马酸氯马斯汀(Clemastinefumarate)和托瑞米芬(Toremifene)或其药学上可接受的盐或其组合物。
在另一优选例中,所述的第一活性成分选自下组药物活性成分:盐酸异丙嗪(Promethazine hydrochloride)、盐酸氟哌噻吨(Flupenthixol dihydrochloride)、盐酸碘胺酮(Amiodarone hydrochloride)或其药学上可接受的盐、或其药物组合物。
在另一优选例中,所述第一活性成分下组药物活性成分:盐酸异丙嗪(Promethazine hydrochloride)、盐酸氟哌噻吨(Flupenthixol dihydrochloride)、盐酸碘胺酮(Amiodarone hydrochloride)或其药物组合物。
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。
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15种已上市药物活性成分可有效抑制冠状病毒刺突蛋白。实验表明,本发明的活性成分(以盐酸异丙嗪(Promethazine hydrochloride)、盐酸氟哌噻吨(Flupenthixol dihydrochloride)、盐酸碘胺酮(Amiodarone hydrochloride)为代表),可高效地抑冠状病毒刺突蛋白的活性。在此基础上完成了本发明。
具体地,本发明揭示了选自下组的药物性活性成分及其药物组合物:伯舒替尼(Bosutinib)、羟哌氯丙嗪(Perphenazine)、盐酸碘胺酮(Amiodarone hydrochloride)、盐酸氟哌噻吨(Flupenthixol dihydrochloride)、盐酸去甲替林 (Nortriptylinehydrochloride)、酒石酸异丁嗪(Trimeprazine tartrate)、达泊西汀(Dapoxetine)、盐酸氯丙噻烯(Chlorprothixene hydrochloride)、盐酸普罗替林(Protriptylinehydrochloride)、盐酸异丙嗪(Promethazine hydrochloride)、吉非替尼(Gefitinib)、琥珀酸索利那新(Solifenacin succinate)、盐酸氮卓斯汀(Azelastine hydrochloride)、富马酸氯马斯汀 (Clemastine fumarate)和托瑞米芬(Toremifene)在抗冠状病毒中的用途。本发明的药物活性成分具有优良的抑制冠状病毒刺突蛋白活性的作用从而抑制冠状病毒的复制,具有良好的临床应用前景。
术语
如本文所用,“本发明的药物活性成分”、“本发明的活性成分”、“本发明的抑制冠状病毒刺突蛋白的活性成分”、“15个已上市药物有效成分”、“本发明的有效成分”可互换使用,指具有优异的抑制冠状病毒刺突蛋白活性的药物活性成分,包括伯舒替尼(Bosutinib)、羟哌氯丙嗪(Perphenazine)、盐酸碘胺酮(Amiodarone hydrochloride)、盐酸氟哌噻吨(Flupenthixol dihydrochloride)、盐酸去甲替林(Nortriptylinehydrochloride)、酒石酸异丁嗪(Trimeprazine tartrate)、达泊西汀(Dapoxetine)、盐酸氯丙噻烯(Chlorprothixene hydrochloride)、盐酸普罗替林(Protriptylinehydrochloride)、盐酸异丙嗪 (Promethazine hydrochloride)、吉非替尼(Gefitinib)、琥珀酸索利那新 (Solifenacin succinate)、盐酸氮卓斯汀(Azelastine hydrochloride)、富马酸氯马斯汀(Clemastine fumarate)和托瑞米芬(Toremifene)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”指含有本发明活性成分的制剂。
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。2019年年底爆发的新型冠状病毒 (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,提供了可有效抑制冠状病毒刺突蛋白活性的活性成分。该活性成分选自下组:伯舒替尼(Bosutinib)、羟哌氯丙嗪(Perphenazine)、盐酸碘胺酮 (Amiodaronehydrochloride)、盐酸氟哌噻吨(Flupenthixol dihydrochloride)、盐酸去甲替林(Nortriptyline hydrochloride)、酒石酸异丁嗪(Trimeprazine tartrate)、达泊西汀(Dapoxetine)、盐酸氯丙噻烯(Chlorprothixene hydrochloride)、盐酸普罗替林(Protriptyline hydrochloride)、盐酸异丙嗪 (Promethazine hydrochloride)、吉非替尼(Gefitinib)、琥珀酸索利那新 (Solifenacin succinate)、盐酸氮卓斯汀(Azelastinehydrochloride)、富马酸氯马斯汀(Clemastine fumarate)和托瑞米芬(Toremifene)或其药学上可接受的盐、或其组合。
试验表明,本发明的活性成分可有效地抑制新型冠状病毒的刺突蛋白活性,从而预防、治疗和/或缓解新型冠状病毒的相关疾病。
如本文所用,“本发明的药物活性成分”“本发明的活性成分”“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化合物。
应理解,本发明的活性成分包括伯舒替尼(Bosutinib)、羟哌氯丙嗪(Perphenazine)、盐酸碘胺酮(Amiodarone hydrochloride)、盐酸氟哌噻吨(Flupenthixol dihydrochloride)、盐酸去甲替林(Nortriptyline hydrochloride)、酒石酸异丁嗪(Trimeprazine tartrate)、达泊西汀 (Dapoxetine)、盐酸氯丙噻烯(Chlorprothixene hydrochloride)、盐酸普罗替林 (Protriptyline hydrochloride)、盐酸异丙嗪(Promethazine hydrochloride)、吉非替尼(Gefitinib)、琥珀酸索利那新(Solifenacin succinate)、盐酸氮卓斯汀 (Azelastine hydrochloride)、富马酸氯马斯汀(Clemastine fumarate)和托瑞米芬(Toremifene)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、锌盐、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;或者本发明的活性化合物分子中的羧基/酚羟基与无机碱形成的钠盐、锌盐、钾盐、钙盐、铝盐或铵盐。
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):干扰素、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、环孢菌素(cyclosporine)、可利霉素(Carrimycin)、黄芩苷(baicalin)、黄芩素 (baicalein)、萘酚喹(Naphthoquine)、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。所述干扰素包括干扰素α-2a、干扰素α-2b、干扰素α-n1、干扰素α-n3、干扰素β-1a、干扰素β-1b中的一种或多种。
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(Olmesartan Medoxomil)、缬沙坦(valsartan)、氯沙坦(Losartan)、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)、七叶皂苷(Escin)、萘普生 (Naproxen)。
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严重急性呼吸综合征冠状病毒(SARS-CoV)和/或中东呼吸综合征冠状病毒(Middle East Respiratory Syndrome,MERS-CoV) 和/或SARS-CoV-2(新冠状病毒),具有明显的抗病毒效应。其中盐酸碘胺酮 (Amiodaronehydrochloride)抑制SARS-CoV的IC50值仅为0.39μM;盐酸碘胺酮 (Amiodaronehydrochloride)抑制SARS-CoV-2的IC50值仅为0.56μM;酒石酸异丁嗪(Trimeprazinetartrate)抑制MERS-CoV的IC50值仅为0.17μM。
(b)本发明活性化合物的毒副作用低,成药性好。盐酸异丙嗪(Promethazinehydrochloride)、盐酸普罗替林(Protriptyline hydrochloride)、盐酸氯丙噻烯(Chlorprothixene hydrochloride)、盐酸氮卓斯汀(Azelastine hydrochloride)、琥珀酸索利那新(Solifenacin succinate)、吉非替尼(Gefitinib)的CC50值均大于 20μM。提示着本发明活性成分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,例如Sambrook等人,分子克隆:实验室手册(New York: Cold Spring HarborLaboratory Press,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
实施例1.抗SARS-CoV假病毒侵入活性筛选(病毒表面刺突蛋白-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膜蛋白修饰HIV假病毒感染细胞的活性,该活性可反应样品干预SARS-CoV 感染关键靶点的抗病毒活性。检测指标为假病毒基因组上报告基因活性水平。
测试方法:
Huh7细胞提前一天接种于96孔培养板,分别设活性板和细胞毒性板,置 37℃,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,细胞毒性板采用MTT法测定细胞存活率。活性板吸去培养液后加入 100μL每孔细胞裂解液,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。
结果:15个已上市药物有效成分均对SARS-CoV病毒侵入宿主细胞具有抑制活性。
表1:15种有效成分对SARS-CoV病毒的抑制作用(IC50)、安全性(CC50)和SI
实施例2.抗2019-nCoV假病毒侵入活性筛选(病毒表面刺突蛋白-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 2019-nCoV膜蛋白修饰HIV假病毒感染细胞的活性,该活性可反应样品干预 2019-nCoV感染关键靶点的抗病毒活性。检测指标为假病毒基因组上报告基因活性水平。
测试方法:
Huh7细胞提前一天接种于96孔培养板,分别设活性板和细胞毒性板,置 37℃,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2019-nCoV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,细胞毒性板采用MTT法测定细胞存活率。活性板吸去培养液后加入100μL每孔细胞裂解液,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。
结果:15个已上市药物有效成分均对2019-nCoV病毒侵入宿主细胞具有抑制活性。
表2. 15种有效成分对2019-nCoV病毒的抑制作用(IC50)、安全性(CC50)和SI
实施例3.抗MERS-CoV假病毒侵入活性筛选(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 MERS-CoV膜蛋白修饰HIV假病毒感染细胞的活性,该活性可反应样品干预MERS-CoV 感染关键靶点的抗病毒活性。检测指标为假病毒基因组上报告基因活性水平。
测试方法:
Huh7细胞提前一天接种于96孔培养板,分别设活性板和细胞毒性板,置 37℃,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2019-nCoV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,细胞毒性板采用MTT法测定细胞存活率。活性板吸去培养液后加入 100μL每孔细胞裂解液,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。
结果:15个已上市药物有效成分均对MERS-CoV病毒侵入宿主细胞具有抑制活性。
表3:15种有效成分对MERS-CoV病毒的抑制作用(IC50)、安全性(CC50)和SI
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)
1.一种活性成分或含所述活性成分的制剂的用途,其特征在于,所述的活性成分选自下组药物活性成分:伯舒替尼(Bosutinib)、羟哌氯丙嗪(Perphenazine)、盐酸碘胺酮(Amiodarone hydrochloride)、盐酸氟哌噻吨(Flupenthixol dihydrochloride)、盐酸去甲替林(Nortriptyline hydrochloride)、酒石酸异丁嗪(Trimeprazine tartrate)、达泊西汀(Dapoxetine)、盐酸氯丙噻烯(Chlorprothixene hydrochloride)、盐酸普罗替林(Protriptyline hydrochloride)、盐酸异丙嗪(Promethazine hydrochloride)、吉非替尼(Gefitinib)、琥珀酸索利那新(Solifenacin succinate)、盐酸氮卓斯汀(Azelastinehydrochloride)、富马酸氯马斯汀(Clemastine fumarate)和托瑞米芬(Toremifene)或其药学上可接受的盐或其组合物;
并且,所述的活性成分或含所述活性成分的药物组合物的制剂被用于制备(a)抑制冠状病毒刺突蛋白活性成分的抑制剂;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。
2.如权利要求1所述的用途,其特征在于,所述冠状病毒为选自下组的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:人冠状病毒引起的感冒症状、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,所述的活性成分选自下组药物活性成分:盐酸异丙嗪(Promethazine hydrochloride)、盐酸氟哌噻吨(Flupenthixoldihydrochloride)、盐酸碘胺酮(Amiodarone hydrochloride)或其药物组合物。
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)选自下组的第一活性成分:伯舒替尼(Bosutinib)、羟哌氯丙嗪(Perphenazine)、盐酸碘胺酮(Amiodarone hydrochloride)、盐酸氟哌噻吨(Flupenthixoldihydrochloride)、盐酸去甲替林(Nortriptyline hydrochloride)、酒石酸异丁嗪(Trimeprazine tartrate)、达泊西汀(Dapoxetine)、盐酸氯丙噻烯(Chlorprothixenehydrochloride)、盐酸普罗替林(Protriptyline hydrochloride)、盐酸异丙嗪(Promethazine hydrochloride)、吉非替尼(Gefitinib)、琥珀酸索利那新(Solifenacinsuccinate)、盐酸氮卓斯汀(Azelastine hydrochloride)、富马酸氯马斯汀(Clemastinefumarate)和托瑞米芬(Toremifene)或其药学上可接受的盐或其组合物;
(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:干扰素、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)、环孢菌素(cyclosporine)、可利霉素(Carrimycin)、黄芩苷(baicalin)、黄芩素(baicalein)、萘酚喹(Naphthoquine)、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:锌(Zinc)、芬戈莫德(Fingolimod)、维生素C(Vitamin C)、奥美沙坦酯(Olmesartan Medoxomil)、缬沙坦(valsartan)、氯沙坦(Losartan)、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)、七叶皂苷(Escin)、萘普生(Naproxen)、或其组合;
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刺突蛋白活性。
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。
9.一种抑制冠状病毒刺突蛋白的方法,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冠状病毒(SARS-CoV-2)接触,抑制所述冠状病毒刺突蛋白的活性,从而抑制冠状病毒的复制;
其中,所述的第一活性成分选自下组:伯舒替尼(Bosutinib)、羟哌氯丙嗪(Perphenazine)、盐酸碘胺酮(Amiodarone hydrochloride)、盐酸氟哌噻吨(Flupenthixoldihydrochloride)、盐酸去甲替林(Nortriptyline hydrochloride)、酒石酸异丁嗪(Trimeprazine tartrate)、达泊西汀(Dapoxetine)、盐酸氯丙噻烯(Chlorprothixenehydrochloride)、盐酸普罗替林(Protriptyline hydrochloride)、盐酸异丙嗪(Promethazine hydrochloride)、吉非替尼(Gefitinib)、琥珀酸索利那新(Solifenacinsuccinate)、盐酸氮卓斯汀(Azelastine hydrochloride)、富马酸氯马斯汀(Clemastinefumarate)和托瑞米芬(Toremifene)或其药学上可接受的盐或其组合物。
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选自下组药物活性成分:盐酸异丙嗪(Promethazine hydrochloride)、盐酸氟哌噻吨(Flupenthixoldihydrochloride)、盐酸碘胺酮(Amiodarone hydrochloride)或其药学上可接受的盐、或其药物组合物。
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