CN115768415A - 新型冠状病毒感染症(covid-19)的治疗和/或预防剂 - Google Patents
新型冠状病毒感染症(covid-19)的治疗和/或预防剂 Download PDFInfo
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- CN115768415A CN115768415A CN202180029760.3A CN202180029760A CN115768415A CN 115768415 A CN115768415 A CN 115768415A CN 202180029760 A CN202180029760 A CN 202180029760A CN 115768415 A CN115768415 A CN 115768415A
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Abstract
本发明提供包含5‑氨基乙酰丙酸(ALA)或其衍生物或者它们的盐的新型冠状病毒感染症(COVID‑19)的治疗和/或预防剂、以及使用了该治疗和/或预防剂的新型冠状病毒感染症(COVID‑19)的治疗和/或预防方法。
Description
技术领域
本发明涉及新型冠状病毒感染症(COVID-19)的治疗和/或预防剂，更详细地说，涉及包含5-氨基乙酰丙酸(5-ALA)或其衍生物或者它们的盐的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂、以及使用该治疗和/或预防剂的新型冠状病毒感染症(COVID-19)的治疗和/或预防。
背景技术
新型冠状病毒感染症(COVID-19)是由新型冠状病毒(SARS-CoV-2)引起的新型肺炎。新型冠状病毒(SARS-CoV-2)是与引起重症急性呼吸综合征(SARS：severe acuterespiratory syndrome)的SARS-CoV具有相似性的、经鉴定为新型的病毒。新型冠状病毒感染症(COVID-19)除了引起肺炎症状以外，已知其还会引起发热、咳嗽、气喘、呼吸困难、恶寒、伴有恶寒的颤栗、肌肉痛、头痛、咽痛、味觉障碍或嗅觉障碍等广泛的症状。新型冠状病毒感染症(COVID-19)患者在世界各地迅速增加。
目前尚不存在针对新型冠状病毒(SARS-CoV-2)的特异性治疗方法，虽进行了针对其他病毒的现有药物的效果试验，但对新型冠状病毒(SARS-CoV-2)显示出效果的现有抗病毒药剂有限(非专利文献1)。因此，开发出对新型冠状病毒(SARS-CoV-2)有效的其他治疗药成为当务之急。
此外，最近检出了新型冠状病毒(SARS-CoV-2)的多种突变株，这些突变株被指出与现有株相比感染力强的可能性、病原性高的可能性、和/或与现有株相比使免疫或疫苗的效果降低的可能性，成为临床上的新问题(非专利文献3和4)，因此迫切希望开发出对这些突变株也有效的其他治疗药。
5-ALA是在细胞内的线粒体内产生的血红素系化合物的共同前体，已知最终由原卟啉(PPIX)转换成血红素(Heme)的5-ALA对特定的炎症性疾病显示出抗炎作用。另外还已知在一部分癌细胞中，通过抑制由PPIX向血红素的转换而使PPIX蓄积，进行了利用蓄积的PPIX使癌细胞可视化的研究(非专利文献2)。但是，尚未已知5-ALA及其衍生物可抑制新型冠状病毒(SARS-CoV-2)的感染、增殖和/或病毒蛋白表达从而治疗或预防新型冠状病毒感染症(COVID-19)；以及PPIX外排抑制剂的合用增强该治疗或预防效果。
现有技术文献
非专利文献
非专利文献1：Cell Research,2020,Vol.30,pp.269-271
非专利文献2：Scientific Reports,2019,Vol.9,pp.no.8666,doi：https://doi.org/10.1038/s41598-019-44981-y
非专利文献3：Review in Medical Virology.2021Mar 16.Doi：10.1002/rmv.2231
非专利文献4：“新型コロナウイルス感染症(変異株)へ的対応(新型冠状病毒感染症(突变株)的应对)”厚生劳动省(URL：https://www.mhlw.go.jp/content/10900000/000766545.pdf、访问日期：2021年4月20日)
发明内容
发明所要解决的课题
本发明的课题在于提供新型冠状病毒感染症(COVID-19)的治疗和/或预防剂。更详细地说，提供包含5-ALA或其衍生物或者它们的盐的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂。另外，在其他方式中，提供使用了5-ALA或其衍生物或者它们的盐的新型冠状病毒感染症(COVID-19)的治疗和/或预防方法。在其他方式中，本发明的课题在于提供将5-ALA或其衍生物或者它们的盐与PPIX外排抑制剂合用的新型冠状病毒感染症(COVID-19)的治疗和/或预防方法、以及用于该治疗和/或预防的药物。另外，在其他方式中，本发明提供通过将5-ALA或其衍生物或者它们的盐优选与PPIX外排抑制剂合用来使用而抑制新型冠状病毒(SARS-CoV-2)的感染、增殖和/或病毒核酸或蛋白质的表达的方法、以及用于该方法的药物。
用于解决课题的手段
本发明人为了解决上述课题反复进行了深入研究，结果完全出乎意料地发现，5-ALA抑制作为新型冠状病毒感染症(COVID-19)的致病病毒的新型冠状病毒(SARS-CoV-2)的感染、增殖和/或病毒蛋白表达，从而治疗或预防COVID-19，进一步发现，通过合用PPIX外排抑制剂，具有协同性的优异效果，从而完成了本发明。
5-ALA是在细胞内的线粒体内产生的血红素系化合物的共同前体。已知5-ALA对特定的炎症性疾病显示出抗炎作用，但尚未已知5-ALA及其衍生物可抑制新型冠状病毒(SARS-CoV-2)的感染、增殖和/或病毒蛋白表达从而治疗或预防新型冠状病毒感染症(COVID-19)。本发明新提供了用于治疗或预防新型冠状病毒感染症(COVID-19)的、含有5-ALA及其衍生物的药物及其用途。
此外，本发明人还发现了，通过将5-ALA与柠檬酸亚铁钠(Sodium FerrousCitrate、SFC)等含金属化合物组合使用，可得到极其优异的新型冠状病毒感染症(COVID-19)的治疗或预防效果。
即，本发明提供以下方案。
[项目1]
一种新型冠状病毒感染症(COVID-19)的治疗和/或预防剂，其含有下述式(I)所表示的化合物或其盐：
[化1]
(式中，R1表示氢原子或酰基，R2表示氢原子、直链或支链状烷基、环烷基、芳基或芳烷基)。
[项目2]
如项目1所述的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂，其特征在于，R1和R2为氢原子。
3.如项目1或2所述的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂，其特征在于，进一步含有一种或两种以上的含金属化合物。
4.如项目3所述的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂，其特征在于，含金属化合物为含有铁、镁、锌、镍、钒、铜、铬、钼或钴的化合物。
5.如项目3所述的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂，其特征在于，含金属化合物为含有铁、镁或锌的化合物。
6.如项目3所述的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂，其特征在于，含金属化合物为含有铁的化合物。
7.如项目1～6中任一项所述的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂，其用于与PPIX外排抑制剂合用。
8.如项目7所述的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂，其中，PPIX外排抑制剂为转运体抑制剂或胞吐抑制剂。
9.如项目7或8所述的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂，其中，PPIX外排抑制剂为ABCG2抑制剂或发动蛋白(Dynamin)抑制剂。
10.如项目7～9中任一项所述的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂，其中，PPIX外排抑制剂为ABCG2抑制剂。
[项目11]
一种新型冠状病毒感染症(COVID-19)的治疗和/或预防方法，其包括将下述式(I)所表示的化合物或其盐与药学上允许的赋形剂一同给药，
[化2]
式中，R1表示氢原子或酰基，R2表示氢原子、直链或支链状烷基、环烷基、芳基或芳烷基)。
[项目12]
下述式(I)所表示的化合物或其盐在新型冠状病毒感染症(COVID-19)的治疗和/或预防中的用途：
[化3]
(式中，R1表示氢原子或酰基，R2表示氢原子、直链或支链状烷基、环烷基、芳基或芳烷基)。
发明的效果
本发明的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂特别是强力地抑制病毒的细胞感染或增殖、病毒衣壳蛋白的表达或集合、和/或病毒粒子的释放等，由此抑制感染细胞的增加，发挥出优异的新型冠状病毒感染症(COVID-19)治疗和/或预防效果。另外，在其他方式中，本发明的将5-氨基乙酰丙酸(5-ALA)或其衍生物或者它们的盐与PPIX外排抑制剂合用的新型冠状病毒感染症(COVID-19)的治疗和/或预防方法、以及用于该治疗和/或预防的药物具有提供新型冠状病毒感染症(COVID-19)的治疗和/或预防的效果。
附图说明
图1是示出5-ALA和FTC对于VeroE6细胞中的SARS-CoV-2感染的效果的图。
图2是示出5-ALA和FTC对于VeroE6细胞中的SARS-CoV-2感染的效果的图。
图3是示出5-ALA或者5-ALA和SFC对于Caco-2细胞中的SARS-CoV-2感染的效果的图。
图4是示出5-ALA或者5-ALA和SFC对于Caco-2细胞中的SARS-CoV-2感染的效果的图。
图5是示出5-ALA、5-ALA和SFC、以及SFC单独应用对于VeroE6细胞中的SARS-CoV-2感染的浓度依赖性感染抑制效果和细胞毒性效果的图。
图6是示出5-ALA、5-ALA和SFC、以及SFC单独应用对于Caco-2细胞中的SARS-CoV-2感染的浓度依赖性感染抑制效果和细胞毒性效果的图。
具体实施方式
(定义)
本说明书中，在示出复数个数值范围的情况下，由这些复数个范围的任意的下限值和上限值的组合构成的范围也同样有意义。
(新型冠状病毒(SARS-CoV-2))
作为本发明的对象的新型冠状病毒(SARS-CoV-2)不仅包括现有株，而且还包括突变株(参照非专利文献3、4等)。例如，作为“具有N501Y突变的突变株”，可以举出在英国确认的突变株(VOC-202012/01)、在南非确认的突变株(501Y.V2)、在巴西确认的突变株(501Y.V3)、以及在菲律宾确认的突变株，另外，作为“具有E484K突变的突变株”，可以举出在南非确认的突变株(501Y.V2)、在巴西确认的突变株(501Y.V3)、以及在菲律宾确认的突变株，但并不限于这些。
(本发明的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂、以及新型冠状病毒(SARS-CoV-2)蛋白表达抑制剂的有效成分)
作为本发明的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂、以及新型冠状病毒(SARS-CoV-2)蛋白表达抑制剂的有效成分使用的化合物，可以例示出式(I)所表示的化合物或其盐(以下有时也将它们统称为“ALA类”)。也被称为δ-氨基乙酰丙酸的5-ALA是式(I)的R1和R2均为氢原子的情况，是氨基酸中的1种。作为5-ALA衍生物，可以举出式(I)的R1为氢原子或酰基、式(I)的R2为氢原子、直链或支链状烷基、环烷基、芳基或芳烷基的、除5-ALA以外的化合物。
作为式(I)中的酰基，可以举出甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、己酰基、辛酰基、苄基羰基等直链或支链状的碳原子数1～8的烷酰基、苯甲酰基、1-萘甲酰基、2-萘甲酰基等碳原子数7～14的芳酰基。
作为式(I)中的烷基，可以举出甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、庚基、辛基等直链或支链状的碳原子数1～8的烷基。
作为式(I)中的环烷基，可以举出环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环十二烷基、1-环己烯基等饱和或者可以存在一部分不饱和键的碳原子数3～8的环烷基。
作为式(I)中的芳基，可以举出苯基、萘基、蒽基、菲基等碳原子数6～14的芳基。
作为式(I)中的芳烷基，芳基部分可与上述芳基相同地例示，烷基部分可与上述烷基相同地例示，具体地说，可以举出苄基、苯乙基、苯丙基、苯丁基、二苯甲基、三苯甲基、萘甲基、萘乙基等碳原子数7～15的芳烷基。
作为上述5-ALA衍生物，优选R1为甲酰基、乙酰基、丙酰基、丁酰基等的化合物、上述R2为甲基、乙基、丙基、丁基、戊基等的化合物，优选可以举出上述R1与R2的组合为甲酰基与甲基、乙酰基与甲基、丙酰基与甲基、丁酰基与甲基、甲酰基与乙基、乙酰基与乙基、丙酰基与乙基、丁酰基与乙基的组合的化合物等。
5-ALA类只要在生物体内以式(I)的5-ALA或其衍生物的状态作为有效成分起作用即可，根据给药的形态，可以以用于提高溶解性的各种盐、酯或者被生物体内的酶分解的前药(前体)的形式进行给药。例如，作为5-ALA及其衍生物的盐，可以举出药理学上允许的酸加成盐、金属盐、铵盐、有机胺加成盐等。作为酸加成盐，可例示出例如盐酸盐、氢溴酸盐、氢碘酸、磷酸盐、硝酸盐、硫酸盐等各无机酸盐、甲酸盐、乙酸盐、丙酸盐、甲苯磺酸盐、琥珀酸盐、草酸盐、乳酸盐、酒石酸盐、乙醇酸盐、甲磺酸盐、丁酸盐、戊酸盐、柠檬酸盐、富马酸盐、马来酸盐、苹果酸盐等各有机酸加成盐。作为金属盐，可例示出锂盐、钠盐、钾盐等各碱金属盐、镁盐、钙盐等各碱土金属盐、铝、锌等各金属盐。作为铵盐，可例示出铵盐、四甲基铵盐等烷基铵盐等。作为有机胺盐，可例示出三乙胺盐、哌啶盐、吗啉盐、甲苯胺盐等各盐。另外，这些盐在使用时也可以以溶液的形式使用。
以上的ALA类中，优选为5-ALA及5-ALA甲酯、5-ALA乙酯、5-ALA丙酯、5-ALA丁酯、5-ALA戊酯等各种酯类、以及它们的盐酸盐、磷酸盐、硫酸盐，特别优选可例示出ALA盐酸盐、5-ALA磷酸盐。
上述ALA类可以通过化学合成、利用微生物进行生产、利用酶进行生产中的任一种公知的方法来制造。另外，上述ALA类可以形成水合物或溶剂化物，并且可以单独使用任一种或将2种以上适当组合使用。
本发明的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂、以及新型冠状病毒(SARS-CoV-2)蛋白表达抑制剂优选在不产生过量症的范围内进一步含有含金属化合物，作为该含金属化合物的金属部分，可以举出铁、镁、锌、镍、钒、钴、铜、铬、钼，优选铁、镁、锌，其中优选可例示出铁。
通过将上述ALA类与含金属化合物合用，即使使用更低浓度的ALA类，也能够得到新型冠状病毒(SARS-CoV-2)感染、增殖和/或病毒蛋白表达抑制效果、以及优异的新型冠状病毒感染症(COVID-19)的治疗和/或预防效果。
作为上述铁化合物，可以为有机盐也可以为无机盐，作为无机盐，可以举出氯化铁、三氧化二铁、硫酸铁、焦磷酸亚铁，作为有机盐，可以举出羧酸盐、例如作为羟基羧酸盐的柠檬酸亚铁、柠檬酸铁钠、柠檬酸亚铁钠(Sodium Ferrous Citrate、SFC)、柠檬酸铁铵等柠檬酸盐、焦磷酸铁、血红素铁、右旋糖苷铁、乳酸铁、葡萄糖酸亚铁、二乙三胺五乙酸铁钠、二乙三胺五乙酸铁铵、乙二胺四乙酸铁钠、乙二胺五乙酸铁铵、二羧甲基谷氨酸铁钠、二羧甲基谷氨酸铁铵、富马酸亚铁、乙酸铁、草酸铁、琥珀酸亚铁、琥珀酸柠檬酸铁钠等有机酸盐、三亚乙基四胺铁、乳铁蛋白铁、转铁蛋白铁、叶绿酸铁钠、铁蛋白铁、含糖氧化铁、甘氨酸亚铁硫酸盐。
作为上述镁化合物，可以举出柠檬酸镁、苯甲酸镁、乙酸镁、氧化镁、氯化镁、氢氧化镁、碳酸镁、硫酸镁、硅酸镁、硝酸镁、二乙三胺五乙酸镁二铵、乙二胺四乙酸镁二钠、镁原卟啉。
作为上述锌化合物，可以举出氯化锌、氧化锌、硝酸锌、碳酸锌、硫酸锌、二乙三胺五乙酸锌二铵、乙二胺四乙酸锌二钠、锌原卟啉、含锌酵母。
上述含金属化合物分别可以使用一种或两种以上，作为含金属化合物的给药量，相对于5-ALA的给药量以摩尔比计为0～100倍即可，优选为0.01倍～10倍、更优选为0.1倍～8倍。
本发明的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂可以在不产生过量症的范围内进一步与其他抗病毒剂、其他疾病治疗药合用。这些其他药剂的给药量以及与5-ALA的给药量之比可以由本领域技术人员适当地调整。
本发明的ALA类优选与PPIX外排抑制剂合用。作为PPIX外排抑制剂，可以使用转运体抑制剂或胞吐抑制剂，作为这些抑制剂，例如可以使用ABCG2抑制剂等多药耐性转运体抑制剂、发动蛋白抑制剂、螯合剂、维生素D的活化体。
本发明中使用的具体的PPIX外排抑制剂没有特别限定。例如可以举出ABCG2抑制剂、螯合剂、维生素D的活化体。螯合剂可用于增加细胞内的PpIX的累积量例如记载于WO2014/2023833、Photochem Photobiol.2010,Vol.86,no.2,pp.471-475中。另外，维生素D的活化体可用于增加细胞内的PpIX的累积量例如记载于Cancer Res,2011,Vol,71,no.18,pp.6040-6050中。
本发明中可任选地使用的ABCG2抑制剂例如可以使用：Int J Biochem Mol Biol,2012,Vol.3,no.1,pp.1-27的表3和表4中记载的化合物、Chin J Cancer,2012,Vol.31,no.2,p75-99的表2中记载的化合物、拓扑异构酶II抑制剂(米托蒽醌、比生群、依托泊苷、贝特卡令(Becatecarin)、NB-506、J-107088等)；蒽环类(柔红比星、多柔比星、表柔比星、吡柔比星等)；喜树碱类似物(拓扑异构酶I抑制剂)(拓扑替康、SN-38、CPT-11、9-氨基喜树碱、NX211、DX-8951f、高喜树碱、BN80915(二氟替康)、吉马替康、贝洛替康等)；酪氨酸激酶抑制剂(达沙替尼、凡德他尼、尼洛替尼、索拉非尼、坦度替尼、CI1033(Pan-HER TKI)、CP-724,714(HER2 TKI)、Symadex(fms样酪氨酸激酶3抑制剂)等)；抗代谢物(MTX、MTX二谷氨酸盐、MTX三谷氨酸盐(叶酸拮抗剂)、GW1843、拓优得(Tomudex)(叶酸拮抗剂)、三甲曲沙、吡曲克辛、美托普林(metoprine)、乙胺嘧啶(亲脂性叶酸拮抗剂)、5-氟尿嘧啶(嘧啶类似物)、CdAMP(核苷酸)、克拉屈滨(核苷)等)；周期蛋白依赖性激酶抑制剂(夫拉平度等)；CDK和极光激酶抑制剂(JNJ-7706621等)；非甾体类抗雄激素药(比卡鲁胺等)；PEITC(异硫氰酸苯乙酯等)；吲唑系微管蛋白抑制剂(TH-337等)；外源化学物(xenobiotics)的硫酸盐和葡糖苷酸缀合物(雌酮3-硫酸盐(E1S)、17β-雌二醇硫酸盐、DHEAS、4[35S]-甲基伞形酮硫酸盐、E3040硫酸盐、曲格列酮硫酸盐、17α-乙炔雌二醇的3-O-硫酸盐缀合物、SN-38-葡糖酸苷、[3Η]17β-雌二醇-17β-葡糖酸苷、[14C]4-甲基伞形酮葡糖酸苷、BP-3-硫酸盐、BP-3-葡糖酸苷、酚化葡萄糖醛麦考酚酸等)；天然化合物和毒素(叶酸、尿酸盐、染料木素(Genistein)、核黄素(维生素B2)、白花丹素(维生素K3)、谷胱甘肽(GSH)、1-磷酸鞘氨醇、PhIP(致癌物)等)；以及([(125)I]碘芳基叠氮基哌唑嗪(IAAP)、[(3)H]叠氮平(azidopine)；柳氮磺吡啶(抗炎)；红霉素(大环内脂类抗菌素)；环丙沙星、氧氟沙星、诺氟沙星、恩氟沙星、格雷沙星、尤利沙星(氟喹诺酮类抗生素)；呋喃妥因(尿道抗生素)；莫昔克丁(驱虫剂)；阿苯达唑亚砜和奥芬达唑(驱肠虫剂)；更昔洛韦(抗病毒药物)；齐多夫定、拉米夫定(NRTI)；来氟米特、A771726(抗风湿药物)；双氯芬酸(止痛和抗炎药物)；西咪替丁(Cimetidine)(组胺H2-受体拮抗剂)；ME3277(亲水性糖蛋白IIb/IIIa拮抗剂)；匹伐他汀、瑞舒伐他汀(HMG-CoA还原酶抑制剂)；双嘧达莫(血栓素合酶抑制剂)；格列本脲(降血糖药)；尼卡地平、硝苯地平、尼群地平(Ca2+通道阻滞剂)；奥美沙坦酯(血管紧张素II AT1-R拮抗剂)；贝氟沙通(选择性单胺氧化酶抑制剂)；哌唑嗪(Prazosin)(α-1-肾上腺素能受体拮抗剂)；利鲁唑(Na+通道阻滞剂)；β-淀粉样蛋白唑来膦酸(促骨化合物)；橙皮素缀合物、山奈酚(类黄酮、也参见WO2004/069233)；FTC(烟曲霉毒素C)及其衍生物(参见Mol.Cancer Ther.,2002,1:417-425)；雌激素和抗雌激素(参见Mol.Cancer Ther.,2003,2:105-112)；新生霉素(参见Int.J.Cancer,2004,108:146-151)；二苯基丙烯腈衍生物(参见WO2004/069243)；具有杂环的丙烯腈衍生物(参见WO2006/106778、WO2009/072267)等。
上述PPIX外排抑制剂分别可以使用一种或两种以上，PPIX外排抑制剂的给药量可以根据所期望的治疗效果适当地选择，例如，相对于5-ALA的给药量，以摩尔比计，可以使用0～10000倍、优选0.0倍～1000倍、更优选1倍～300倍、进一步优选10～100倍的给药量。
(本发明的治疗和/或预防剂的给药方法)
本发明的新型冠状病毒感染症(COVID-19)的治疗和/或预防方法或者用于在这些方法中使用的药物中，ALA类、PPIX外排抑制剂、含金属化合物或其他药剂可以以包含这些全部成分的组合物的形式给药，或者也可以分别单独或以仅含有其中一部分成分的组合物的形式给药。在一个方式中，在使用分别单独含有ALA类和其他药剂或仅含有其中一部分成分的组合物的情况下，可以将它们同时给药，另外也可以分开给药。优选可以按照ALA类与其他药剂的给药能够发挥出累加效果或协同效果的方式进行组合给药。在将分别单独含有ALA类和其他药剂或仅含有其中一部分成分的组合物分开给药的情况下，它们的给药间隔可以设定为5分钟、10分钟、15分钟、20分钟、30分钟、45分钟、1小时、2小时、3小时、4小时、5小时、6小时、7小时、8小时、9小时、10小时、11小时、12小时等，但并不限于这些。
作为本发明的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂的给药途径没有特别限定，可以使用口服给药、吸入给药、注射、通过点滴等的静脉内给药、经皮给药、栓剂、或者通过使用鼻胃管、鼻肠管、胃瘘管或肠瘘管的强制性经肠营养法的给药等非口服给药等。
(本发明的治疗和/或预防剂的剂型)
作为本发明的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂的剂型，可以根据上述给药途径适当地决定，可以举出注射剂、点滴剂、片剂、胶囊剂、细颗粒剂、散剂、液剂、溶解于糖浆等中的水剂、贴膏剂、栓剂等。
为了制备本发明的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂，可以根据需要添加药理学上可允许的载体、赋形剂、稀释剂、添加剂、崩解剂、粘结剂、包覆剂、润滑剂(潤滑剤)、增滑剂(滑走剤)、光滑剂(滑沢剤)、风味剂、甜味剂、增溶剂、溶剂、胶凝剂、营养剂等，本领域技术人员可以根据目的选择各具体成分。
(本发明的治疗和/或预防剂的给药量)
作为本发明的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂的给药量、频率、期间，根据希望进行新型冠状病毒感染症(COVID-19)的治疗或预防的动物的种类、年龄、体重、症状等而不同，例如在对人给药的情况下，作为ALA类的给药量，以5-ALA重量换算计，可以举出0.01-200mg/体重kg/天、优选0.5-100mg/体重kg/天、更优选1-50mg/体重kg/天、进一步优选5-30mg/体重kg/天，特别是在作为预防剂使用的情况下，优选持续摄取低用量。例如在作为预防剂补充剂给药的情况下，可以以0.1-30mg/体重kg/天、优选0.3～10mg/体重kg/天、更优选1.0～5mg/体重kg/天等的给药量进行给药。作为给药频率，可例示出一天一次至多次的给药或通过点滴等的连续给药。作为治疗剂或预防剂的给药期间可以由医师等本技术领域的专业人士通过已知的方法来确定。
(本发明的治疗和/或预防剂的适用症状)
本发明的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂可适用于以新型冠状病毒(SARS-CoV-2)的感染和/或新型冠状病毒感染症(COVID-19)发病为原因而产生的各种症状的治疗和预防。作为这样的症状，可例示出肺炎、发热、咳嗽、气喘、呼吸困难、恶寒、伴有恶寒的颤栗、肌肉痛、头痛、咽痛、味觉障碍或嗅觉障碍，但并不限于这些。
(本发明的治疗和/或预防剂的适用动物)
本发明的新型冠状病毒感染症(COVID-19)的治疗和/或预防剂可给药于人、猴、狗、猫、貂、牛、猪和它们的亲缘动物、其他哺乳类、鸟类等。
以下通过实施例更详细地说明本发明，但本发明并不限于这些实施例。
[实施例1]
(治疗例)
1.患者：53岁男性1名
2.治疗经过
从2020年2月28日星期五晚上开始感觉到平常未感觉过的强烈的倦怠感和恶寒、流涕、咽痛、胸痛，有干咳，夜间醒来，测体温，结果为37.5℃。为了缓解嗓子干渴，饮用了橙汁，但感觉不到味道。
难以忍受的倦怠感造成难以入眠，在2月29日星期六开始摄取含有5-ALA磷酸盐50mg和SFC 28.7mg的补充剂(胶囊)，观察到以下的经过。
2月29日星期六
2:00摄取了4粒胶囊，结果恶寒得到改善，体温为37.5℃
4:00再次感到恶寒，因此摄取2粒胶囊，体温为37.2℃
5:00持续咳嗽、打喷嚏，但咽痛减轻，体温为36.8℃
8:00体温上升至37.9℃，因此再次摄取4粒胶囊，体温降低至37.2
10:00体温37.5℃，摄取2粒胶囊，体温降低至37.1℃
12:00体温37.4℃，摄取2粒胶囊，体温降低至37.0℃
15:00体温37.2℃，摄取2粒胶囊，体温36.8℃，变为正常，倦怠感开始改善。
19:00体温36.9℃，可以吃晚餐，味觉变得正常，摄取2粒胶囊，就寝
3月1日星期日
5:00体温36.8℃，摄取4粒胶囊，感冒症状缓解
10:00体温36.9℃，摄取4粒胶囊，无症状
12:00体温36.8℃，摄取4粒胶囊，无症状
16:00体温36.8℃，感觉轻微的肌肉痛，摄取4粒胶囊
17:30肌肉痛缓解，体温36.9℃，无症状
之后在4月17日使用新型冠状病毒(SARS-CoV-2)抗体检查试剂盒(仓敷纺织株式会社制品，编号RF-NC002)调查男性患者的抗新型冠状病毒抗体，结果为阳性。
3.结果
根据以上经过可知，通过5-ALA的摄取，能够在短时间内显著改善新型冠状病毒感染症(COVID-19)的各种症状。
[实施例2]
(细胞试验)
(方法)
实验材料
非洲绿猴肾脏来源的VeroE6由北海道大学的高田博士处获得。人结肠癌来源的Caco-2细胞由大阪大学的饭田博士处获得。
非洲绿猴肾脏来源的VeroE6细胞利用添加有10％胎牛血清(FBS)和1％青霉素/链霉素溶液的杜氏改良伊格尔培养基(DMEM))进行培养。
Caco-2细胞也利用相同的方法进行培养。
将5-氨基乙酰丙酸(5-ALA)盐酸盐用纯水制备成100mM溶液，将柠檬酸亚铁钠(SFC)用纯水和1N HCl制备成25mM溶液，将烟曲霉毒素C(FTC)用DMSO制备成5mM，在每个实验中将它们用DMEM稀释后使用。在免疫染色法中，使用山羊血清、兔抗SARS-CoV N抗体(NOVUS公司)、Alexa Fluor 488山羊抗兔(Thermo Fisher Scientific公司)、Hoechst33342(Thermo Fisher Scientific公司)。
病毒
本实验中使用的SARS-CoV-2由日本国内的感染者分离得到(AJPN/NGS/IA-1/2020、GISAID登录号EPI-ISL-481251)。另外，作为SARS-CoV-2的突变株，使用下述6株突变株：由国立感染症研究所获得的英国株QK002(hCoV-19/Japan/QK002/2020、GISAID ID：EPI＿ISL＿768526)、英国株QHN001(hCoV-19/Japan/QHN001/2020、GISAID ID：EPI＿ISL＿804007)、英国株QHN002(hCoV-19/Japan/QHN002/2020、GISAID ID：EPI＿ISL＿804008)、巴西株TY7-501(hCoV-19/Japan/TY7-501/2021、GISAID ID：EPI＿ISL＿833366)、巴西株TY7-503(hCoV-19/Japan/TY7-503/2021、GISAID ID：EPI＿ISL＿877769)、南非株TY8-612(hCoV-19/Japan/TY8-612/2021、GISAID ID：EPI＿ISL＿1123289)。病毒使用VeroE6细胞进行传代，培养3～4天后回收培养上清，以2000xg离心15分钟后，将上清保存于-80℃，每次实验时解冻后使用。使用了该病毒的感染实验全部在长崎大学具有的BSL3实验室中进行。
药效评价试验
(a)使用VeroE6细胞的试验
将VeroE6细胞以0.5x104细胞/孔的密度接种在96孔板中，细胞贴附于板底后，向培养基中添加各药剂。作为试验药剂，使用5-ALA(1000uM)、5-ALA(1000uM)+FTC(10uM)、5-ALA(1000uM)+SFC(250uM)、5-ALA(1000uM)+SFC(250uM)+FTC(10uM)、FTC(10uM)。添加药剂后，将细胞在37℃培养48小时或72小时。之后在BSL3实验室中感染SARS-CoV-2。感染开始48小时后，将感染细胞在4％多聚甲醛(PFA)中浸渍一夜，进行细胞的固定和病毒的灭活。进一步将细胞用0.2％ TritonX-100进行透过处理后，用10％山羊血清进行封闭，利用兔抗SARS-CoV N抗体进行一次抗体处理，用Alexa Fluor 488山羊抗兔进行二次抗体处理，利用Hoechst 33342进行细胞核的染色。之后使用Cytation 5细胞成像微孔板检测仪(BioTek公司)进行感染细胞的图像拍摄。这些图像的解析使用CellProfiler图像解析软件(博德研究所、MIT)进行，计算出感染细胞数和总细胞数，使用GraphPad Prism(MDF公司)进行图的制作和统计处理。
在利用各药剂进行了48小时的前处理的条件下，通过5-ALA和FTC的共添加，显著抑制了SARS-CoV-2的感染。在添加其他药剂的条件下未确认到效果(图1)。在利用各药剂进行了72小时的前处理的条件下，通过5-ALA和FTC的共添加、或者5-ALA和SFC与FTC的共添加，强烈抑制了SARS-CoV-2的感染(图2)。
根据以上的结果，通过5-ALA和FTC的共添加、或者5-ALA和SFC与FTC的共添加确认到抗病毒活性的增强。
另外，使接种细胞数为1x104细胞/孔时，通过5-ALA的单独添加或者5-ALA和SFC的添加显著抑制了SARS-CoV-2的感染。
(b)使用Caco-2细胞的试验
在使用Caco-2细胞的药物评价试验中，将从SARS-CoV-2感染到灭活为止的时间变更为72小时；并且感染的病毒量在VeroE6细胞中为0.002MOI、而在Caco-2细胞中为0.02MOI，除此以外，同样地进行。
在药剂添加后培养72小时后感染SARS-CoV-2的情况下，在5-ALA单独处理或者5ALA与SFC合用处理后的细胞中，SARS-CoV-2的感染和/或增殖受到强力抑制(图3)。在Caco-2细胞中，在药剂添加后培养48小时后感染SARS-CoV-2的情况下，也得到了同样的SARS-CoV-2感染和/或增殖抑制作用(图4)。
另外，在同样地使突变株感染的情况下，在5-ALA单独处理或5ALA与SFC合用处理后的细胞中，也可期待对SARS-CoV-2的感染和/或增殖抑制效果。
本结果证实了，5-ALA在人类细胞中显示出SARS-CoV-2感染和/或增殖抑制效果。
需要说明的是，已知Caco-2细胞进行从细胞外供给的5-ALA的代谢(Biochem.Biophys.Rep.,2017.Vol/11,pp.105-111)。
(c)用量依赖性的感染和/或增殖抑制效果
为了确认SARS-CoV-2感染和/或增殖抑制效果中的用量依赖性，对各浓度的药剂进行了试验。
其结果，对于VeroE6细胞，5-ALA单独的IC50为570uM，5-ALA与SFC的联合应用的IC50为695uM。另一方面，SFC的单独应用未显示出SARS-CoV-2感染和/或增殖抑制效果(图5)。
另外，对于Caco-2细胞，5-ALA单独的IC50为39uM，5-ALA与SFC联合应用的IC50为63uM。另一方面，SFC的单独应用未显示出SARS-CoV-2感染和/或增殖抑制效果(图6)。
需要说明的是，在进行了试验的全部浓度范围(最大2000uM)内，5-ALA未显示出显著的细胞毒性。
以上结果显示出，5-ALA在各种细胞类型中具有特异性且强力的SARS-CoV-2感染和/或增殖抑制效果。
Claims (10)
1.一种新型冠状病毒感染症COVID-19的治疗和/或预防剂，其含有下述式(I)所表示的化合物或其盐：
[化1]
式中，R1表示氢原子或酰基，R2表示氢原子、直链或支链状烷基、环烷基、芳基或芳烷基。
2.如权利要求1所述的新型冠状病毒感染症COVID-19的治疗和/或预防剂，其特征在于，R1和R2为氢原子。
3.如权利要求1或2所述的新型冠状病毒感染症COVID-19的治疗和/或预防剂，其特征在于，进一步含有一种或两种以上的含金属化合物。
4.如权利要求3所述的新型冠状病毒感染症COVID-19的治疗和/或预防剂，其特征在于，含金属化合物为含有铁、镁、锌、镍、钒、铜、铬、钼或钴的化合物。
5.如权利要求3所述的新型冠状病毒感染症COVID-19的治疗和/或预防剂，其特征在于，含金属化合物为含有铁、镁或锌的化合物。
6.如权利要求3所述的新型冠状病毒感染症COVID-19的治疗和/或预防剂，其特征在于，含金属化合物为含有铁的化合物。
7.如权利要求1～6中任一项所述的新型冠状病毒感染症COVID-19的治疗和/或预防剂，其中，所述治疗和/或预防剂用于与PPIX外排抑制剂合用。
8.如权利要求7所述的新型冠状病毒感染症COVID-19的治疗和/或预防剂，其中，PPIX外排抑制剂为转运体抑制剂或胞吐抑制剂。
9.如权利要求7或8所述的新型冠状病毒感染症COVID-19的治疗和/或预防剂，其中，PPIX外排抑制剂为ABCG2抑制剂或发动蛋白抑制剂。
10.如权利要求7～9中任一项所述的新型冠状病毒感染症COVID-19的治疗和/或预防剂，其中，PPIX外排抑制剂为ABCG2抑制剂。
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| PCT/JP2021/016372 WO2021215517A1 (ja) | 2020-04-22 | 2021-04-22 | 新型コロナウイルス感染症（ｃｏｖｉｄ－１９）の治療及び／又は予防剤 |
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| US5895786A (en) * | 1996-05-08 | 1999-04-20 | New York Blood Center, Inc. | Method for treating viral infections |
| MXPA05008298A (es) | 2003-02-04 | 2005-09-20 | Yakult Honsha Kk | Inhibidor de la proteina de resistencia a cancer de mama. |
| EP1591112A4 (en) | 2003-02-04 | 2006-06-14 | Yakult Honsha Kk | INHIBITOR OF BREAST CANCER RESISTANT PROTEIN |
| UA105162C2 (uk) | 2005-03-30 | 2014-04-25 | Кабусики Кайся Якулт Хонса | Похідне акрилонітрилу та його застосування як інгібітору bcrp/abcg2 |
| EP2218719A4 (en) | 2007-12-03 | 2012-01-11 | Yakult Honsha Kk | INHIBITOR OF ABCG2 |
| AU2013291455B2 (en) | 2012-07-19 | 2016-07-21 | Sbi Pharmaceuticals Co., Ltd. | Prophylactic/therapeutic agent for influenza virus infection |
| EP3010356B1 (en) | 2013-06-18 | 2017-03-15 | Nestec S.A. | Filter unit for a capsule |
| CN107405323A (zh) * | 2015-04-10 | 2017-11-28 | 思佰益药业股份有限公司 | 含有ala类的病毒感染症预防/治疗剂 |
| TW202106293A (zh) | 2019-04-26 | 2021-02-16 | 日商日本紐翱醫藥股份有限公司 | 黃病毒（ｆｌａｖｉｖｉｒｕｓ）感染症治療劑 |
| US11883376B2 (en) | 2020-04-22 | 2024-01-30 | Nadimpally Satyavarahala Raju | Viral infection treatment with 5-aminolevulinic acid |
| US10987329B1 (en) | 2020-04-22 | 2021-04-27 | Nadimpally Satyavarahala Raju | Combination therapy for coronavirus infections including the novel corona virus (COVID-19) |
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| JPWO2021215517A1 (zh) | 2021-10-28 |
| WO2021215517A1 (ja) | 2021-10-28 |
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