TWI805952B - 取代氨基丙酸酯類化合物在治療SARS-CoV-2感染中的應用 - Google Patents
取代氨基丙酸酯類化合物在治療SARS-CoV-2感染中的應用 Download PDFInfo
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Abstract
本申請涉及式I所示取代氨基丙酸酯類化合物,及其藥學上可接受的鹽和/或其溶劑化物和/或其水合物,及含有此化合物的藥物組合物,用於治療 SARS-CoV-2引起的疾病或感染。
Description
本申請是以CN申請號為202010071087.7,申請日為2020年1月21日的申請為基礎,並主張其優先權,該CN申請的揭露內容在此作為整體引入本申請中。
取代氨基丙酸酯類化合物(式I化合物),化學名為2-乙基丁基(2S)-2-[[(2R,3S,4R,5R)-5-(4-氨基吡咯[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羥氧環烷-2-基]甲氧基苯氧磷醯基]氨基]丙酸酯(2-ethylbutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate),又名Remdesivir(GS-5734),是一種病毒RNA聚合酶抑制劑,其體內活性形式為母體藥物的核苷三磷酸酸(NTP)。該藥化合物目前已完成臨床治療伊波拉病毒感染的III期臨床試驗,對伊波拉病毒感染顯示出良好的治療效果。
Remdesivir在基於細胞的測定中表現出針對EBOV和其它絲狀病毒的多種變體的抗病毒活性。在伊波拉病毒感染的恆河猴模型中,即使在病毒暴露後三天開始治療(在六隻處理的動物中的兩隻中檢測到全身病毒RNA),每天靜脈內施用10mg / kg的GS-5734,持續給藥12 天,可非常明顯的抑制EBOV的複製,100%的保護EBOV 感染的動物免受於死亡,並改善臨床疾病徵象和病理生理標誌物。除了伊波拉病毒外,GS-5734還具有廣譜的抗病毒活性,比如尼帕病毒(Nipah virus)、中東呼吸症候群冠狀病毒(MERS-CoV)、馬堡病毒(Marburg virus)等。
2019新型冠狀病毒(2019-nCoV)是以前從未在人類中發現的冠狀病毒新毒株。2020年2月11日,國際病毒分類委員會(ICTV)宣佈,2019新型冠狀病毒(2019-nCoV)的正式分類名為嚴重急性呼吸症候群冠狀病毒2(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)。同日,世界衛生組織(WHO)宣佈,由這一病毒導致的疾病的正式名稱為COVID-19。SARS-CoV-2病毒感染的症狀主要以肺炎為主,依據病情的輕重程度可分為單純性感染、輕症肺炎、重症肺炎、急性呼吸窘迫症候群、膿毒症、膿毒症休克等。單純性感染的患者可能有非特異性症狀,例如發熱、咳嗽、咽痛、鼻塞、乏力、頭痛、肌肉疼痛或不適,老年人和免疫抑制者可能會出現非典型症狀。輕症肺炎的患者主要以咳嗽、呼吸困難+呼吸急促為主。重症肺炎可見於青少年、成人或兒童,主要症狀為呼吸頻率增加,嚴重的呼吸衰竭或呼吸困難,中心型發紺、嗜睡、意識不清或驚厥、抽氣等。急性呼吸窘迫症候群的肺部影像為雙側磨玻璃影,但不能完全由積液、大葉滲出或者肺不張或者肺部塊影解釋,以肺水腫為主要症狀。膿毒症患者往往有致命的器官功能障礙,膿毒性休克是最為危重的患者,死亡可能性較高。
目前,針對SARS-CoV-2病毒感染,臨床上以支持治療為主,無抗病毒藥物可用。
本申請目的是發現對SARS-CoV-2有抗病毒活性的藥物,可用於其感染引起相關疾病的救治。本申請通過創造性的研究發現式I 化合物具有抑制SARS-CoV-2複製方面的功能,在治療SARS-CoV-2引起的疾病方面具有很好的潛在的治療效果。
在某些實施方案中,本申請所述式I所示化合物的藥學上可接受的鹽包括其無機或有機酸鹽,以及無機或有機鹼鹽,本申請涉及上述鹽的所有形式,其中包括但不限於:鈉鹽、鉀鹽、鈣鹽、鋰鹽、葡甲胺鹽、鹽酸鹽,氫溴酸鹽,氫碘酸鹽,硝酸鹽,硫酸鹽,硫酸氫鹽,磷酸鹽,磷酸氫鹽,乙酸鹽,丙酸鹽,丁酸鹽,草酸鹽,三甲基乙酸鹽,己二酸鹽,藻酸鹽,乳酸鹽,檸檬酸鹽,酒石酸鹽,琥珀酸鹽,馬來酸鹽,富馬酸鹽,苦味酸鹽,天冬氨酸鹽,葡糖酸鹽,苯甲酸鹽,甲磺酸鹽,乙磺酸鹽,苯磺酸鹽,對甲苯磺酸鹽和雙羥萘酸鹽等。
式I所示化合物可在細胞上抑制SARS-CoV-2病毒複製,減少細胞培養物中SARS-CoV-2病毒核酸載量。
本申請的發明人在經過創造性發明研究後,發現了式I所示化合物在細胞內的新作用特點:式I所示化合物可以在微摩爾級濃度下降低SARS-CoV-2感染的細胞病毒核酸載量水準。
本申請還涉及式I所示的化合物,其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物在製備用於治療 SARS-CoV-2引起的疾病或感染(例如呼吸系統疾病(例如單純性感染(如發熱、咳嗽和咽痛等)、肺炎、急性呼吸道感染、嚴重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫症候群、 膿毒症和膿毒性休克等))的藥物中的用途,
I。
本申請還涉及式I所示的化合物,其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物在製備作為 SARS-CoV-2抑制劑的藥物中的用途。
本申請還涉及式I所示的化合物,其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物在製備用於抑制 SARS-CoV-2在細胞(例如哺乳動物細胞)中複製或繁殖的藥物中的用途。
本申請還涉及一種藥物組合物,其包含式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物,
較佳地,所述的藥物組合物還包含藥學上可接受的載體或輔料,具體地,該藥物組合物為固體製劑、注射劑、外用製劑、噴劑、液體製劑、或複方製劑。
在某些實施方案中,所述的藥物組合物中含有有效量的式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物。
本申請還涉及該包含式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物的藥物組合物或式I所示化合物化合物、其幾何異構體及其藥學上可接受的鹽和/或其溶劑化物和/或其水合物在製備用於治療呼吸系統疾病但不限於呼吸系統疾病(單純性感染(如發熱、咳嗽和咽痛等)、肺炎、急性呼吸道感染、嚴重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫症候群、膿毒症和膿毒性休克等)的藥物中的用途。
本申請還涉及該包含式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物的藥物組合物在製備用於治療SARS-CoV-2引起的疾病或感染(例如呼吸系統疾病(例如單純性感染(如發熱、咳嗽和咽痛等)、肺炎、急性呼吸道感染、嚴重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫症候群、 膿毒症和膿毒性休克等))的藥物中的用途。
本申請還涉及該包含式I化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物的藥物組合物在製備作為 SARS-CoV-2抑制劑的藥物中的用途。
本申請還涉及該包含式I化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物的藥物組合物在製備用於抑制 SARS-CoV-2在細胞(例如哺乳動物細胞)中複製或繁殖的藥物中的用途。
本申請還涉及一種在有需要的哺乳動物中治療和/或預防疾病的方法或者在有需要的哺乳動物中抑制SARS-CoV-2複製或繁殖的方法,該方法包括給有需要的哺乳動物施用治療和/或預防有效量的該包含式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物的藥物組合物或該式I化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物,其中所述的疾病包括SARS-CoV-2引起的疾病,例如SARS-CoV-2引起的病毒感染性疾病(例如呼吸系統疾病,包括單純性感染(如發熱、咳嗽和咽痛等)、肺炎、急性呼吸道感染、嚴重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫症候群、 膿毒症和膿毒性休克等)。
本申請還涉及式I所示的化合物,其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物,其用於治療 SARS-CoV-2引起的疾病或感染(例如呼吸系統疾病(包括單純性感染(如發熱、咳嗽和咽痛等)、肺炎、急性呼吸道感染、嚴重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫症候群、膿毒症和膿毒性休克等))。
本申請還涉及式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物,其作為 SARS-CoV-2抑制劑。
本申請還涉及式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物,其用於抑制 SARS-CoV-2在細胞(例如哺乳動物細胞)中複製或繁殖。
本申請還涉及該包含式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物的藥物組合物,其用於治療SARS-CoV-2引起的疾病或感染(例如呼吸系統疾病(例如單純性感染(如發熱、咳嗽和咽痛等)、肺炎、急性呼吸道感染、嚴重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫症候群、 膿毒症和膿毒性休克等))。
本申請還涉及該包含式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物的藥物組合物,其作為 SARS-CoV-2抑制劑。
本申請還涉及該包含式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物的藥物組合物,用於抑制 SARS-CoV-2在細胞(例如哺乳動物細胞)中複製或繁殖。
在某些實施方案中,本申請所述的SARS-CoV-2引起的疾病包括但不限於呼吸系統疾病,例如單純性感染如發熱、咳嗽和咽痛等、肺炎、急性呼吸道感染、嚴重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫症候群、膿毒症和膿毒性休克等。
在某些實施方案中,本申請所述的SARS-CoV-2引起的疾病為COVID-19。
本申請中,所用術語“2019新型冠狀病毒(2019-nCoV)”的正式分類名為嚴重急性呼吸症候群冠狀病毒2(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)。
本申請中,所用術語“2019新型冠狀病毒 (2019-nCoV)引起的疾病”的正式名稱為COVID-19。
在某些實施方案中,該哺乳動物包括牛科動物、馬科動物、羊科動物、豬科動物、犬科動物、貓科動物、齧齒類動物、靈長類動物,其中較佳的哺乳動物為人、貓、狗或豬。
本申請所述藥物組合物可以根據不同給藥途徑而製備成各種形式。
根據本申請,所述的藥物組合物可以以下面的任意方式施用:口服、噴霧吸入、直腸用藥、鼻腔用藥、頰部用藥、陰道用藥、局部用藥、非腸道用藥如皮下、靜脈、肌內、腹膜內、鞘內、心室內、胸骨內和顱內注射或輸入、或借助一種外植儲器用藥。其中較佳口服、腹膜內或靜脈內用藥方式。
當口服用藥時,該式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物可製成任意口服可接受的製劑形式,包括但不限於片劑、膠囊、水溶液或水懸浮液。其中,片劑一般使用的載體包括乳糖和玉米澱粉,另外也可加入潤滑劑如硬質酸鎂。膠囊製劑一般使用的稀釋劑包括乳糖和乾燥玉米澱粉。水懸浮液製劑則通常是將活性成分與適宜的乳化劑和懸浮劑混合使用。如果需要,以上口服製劑形式中還可加入一些甜味劑、芳香劑或著色劑。
當直腸用藥時,該式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物一般可製成栓劑的形式,其通過將藥物與一種適宜的非刺激性賦形劑混合而制得。該賦形劑在室溫下呈現固體狀態,而在直腸溫度下熔化釋出藥物。該類賦形劑包括可哥脂、蜂蠟和聚乙二醇。
當局部用藥時,特別是治療局部外敷容易達到的患面或器官,如眼睛、皮膚或下腸道神經性疾病時,該式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物可根據不同的患面或器官製成不同的局部用藥製劑形式,具體說明如下:
當眼部局部施用時,該式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物可配製成一種微粉化懸浮液或溶液的製劑形式,所使用載體為等滲的一定pH的無菌鹽水,其中可加入也可不加防腐劑如氯化苄基烷醇鹽。此外對於眼用,也可將化合物製成膏劑形式如凡士林膏。
當皮膚局部施用時,該式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物可製成適當的軟膏、洗劑或霜劑製劑形式,其中活性成分懸浮或溶解於一種或多種載體中。這裡軟膏即可使用的載體包括但不限於:礦物油、液體凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蠟和水;洗劑或霜劑可使用的載體包括但不限於:礦物油、脫水山梨糖醇單硬脂酸酯、吐溫60、十六烷酯蠟、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
當下腸道局部施用時,該式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物可製成如上所述的直腸栓劑製劑或適宜的灌腸製劑形式,另外也可使用局部透皮貼劑。
該式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物還可以無菌注射製劑形式用藥,包括無菌注射水或油懸浮液,或無菌注射溶液。其中,可使用的載體和溶劑包括水,林格氏溶液和等滲氯化鈉溶液。另外,滅菌的非揮發油也可用作溶劑或懸浮介質,如單甘油酯或二甘油酯。
上述各種劑型的藥物均可以按照藥學領域的常規方法製備。
本申請中,術語“治療有效量”或“預防有效量”是指在合理的醫學判斷範圍內,足以治療或預防患者疾病但足夠低地避免嚴重副作用(在合理的利益/風險比)的量。化合物的治療有效量將根據所選擇的具體化合物(例如考慮化合物的效力、有效性和半衰期)、所選擇的給藥途徑、所治療的疾病、所治療的疾病的嚴重性、所治療的患者的年齡、大小、體重和身體疾病、所治療的患者的醫療史、治療持續時間、並行療法的性質、所需的治療效果等因素發生變化,但仍可以由本領域技術人員常規確定。
另外需要指出,該式I所示化合物、其幾何異構體或其藥學上可接受的鹽和/或其溶劑化物和/或其水合物針對不同患者的特定使用劑量和使用方法決定於諸多因素,包括患者的年齡,體重,性別,自然健康狀況,營養狀況,藥物的活性強度,服用時間,代謝速率,病症的嚴重程度以及診治醫師的主觀判斷。這裡較佳使用劑量介於0.001-1000mg/kg體重/天。
下面的實施例是本申請說明性較佳實施方案,對本申請不構成任何限制。
實施例1:Remdesivir降低SARS-CoV-2病毒感染的細胞病毒核酸載量實驗
(1)藥物處理感染病毒的細胞
將Vero E6細胞(購自ATCC,貨號1586)接種至24孔板,培養24h;然後進行病毒感染,具體的,用2%細胞維持液(配方為:將FBS(購自Gibco公司,貨號16000044)按照2%的體積比加入MEM(購自Gibco公司,貨號10370021),即為2%細胞維持液)將SARS-CoV-2(2019-nCoV)病毒(nCoV-2019BetaCoV/Wuhan/WIV04/2019株,由中國科學院武漢病毒研究所提供)稀釋成相應濃度,然後加入24孔板中使每孔含有病毒量為100TCID50
。接下來,再用2%細胞維持液將Remdesivir(購自MedChemExpress,貨號HY-104077)分別稀釋成相應濃度,加入到對應的孔中,使藥物最終濃度分別為100μM、33 μM、11μM、3.7μM、1.23μM、0.41μM、0.14μM,然後放37℃、5% CO2
孵箱繼續培養48h,細胞對照組只加不含有任何受試藥物的2%細胞維持液。
(2)RNA提取
RNA提取試劑盒購自Qiagen公司,貨號74106。下述RNA提取步驟中所涉及的耗材(離心柱、無RNA酶的2ml收集管等)及試劑(RLT、RW1、RPE、無RNA酶水等)均為試劑盒的組成部分。下述提取步驟均為試劑盒說明書所推薦的步驟。
1)取受試培養板的上清液100μL,加入無核酸酶EP管中,然後每孔加入350μL Buffer RLT,用移液槍吹吸混勻使其充分裂解後,離心取上清;
2)向1)中所得上清液加入等體積的70%乙醇,混勻;
3)將上述2)中所得混合液轉入無RNA酶的離心柱中,12000 rpm離心15s,棄廢液;
4)加入700μL Buffer RW1,12000 rpm離心15s清洗離心柱,棄廢液;
5)加入500μL Buffer RPE,12000 rpm離心15s清洗離心柱,棄廢液;
6)加入500μL Buffer RPE,12000 rpm離心2min清洗離心柱,棄廢液;
7)換新的無RNA酶的2ml收集管,12000 rpm離心1min,乾燥離心柱,然後將離心柱整體轉移至步驟8)的1.5ml收集管中;
8)換上新的1.5ml收集管,放入步驟7)中乾燥後的離心柱,並向離心柱中加入30μl不含RNA酶的水,12000 rpm離心2min,洗脫液即含有相應的RNA,加入RNA酶抑制劑(購自NEB公司,貨號M0314L),用Nano Drop(購自Thermo scientific,型號Nano Drop One)檢測各RNA濃度。
(3)RNA反轉錄
實驗採用TaKaRa公司生產的反轉錄試劑盒(PrimeScript™ RT reagent Kit with gDNA Eraser,貨號RR047Q)進行RNA反轉錄,步驟如下。
①gDNA去除:收集各實驗組RNA樣品,分別取1 μg進行反轉錄。首先,向各實驗組RNA中加入2μl 5× gDNA Eraser Buffer,用 RNase Free 水補足反應體系至 10μl,充分混勻, 42℃水浴 2 min 去除樣品中可能存在的g DNA;
②逆轉錄:向①所得樣品中加入適量的酶和引物 Mix 及反應緩衝液,用 RNase Free 水補足體積至 20 μl,37℃水浴反應 15 min,之後投入 85℃水中 5 sec,既可轉錄得到 cDNA。
(4)Real-time PCR
採用螢光定量PCR檢測原病毒液每毫升所含拷貝數。
採用TB Green Premix (Takara,Cat#RR820A)混好反應體系,在StepOne Plus Real-time PCR儀 (品牌:ABI)進行擴增反應和讀數。計算原病毒液每毫升所含拷貝數。步驟如下:
①首先建立標準品:將質粒pMT-RBD(質粒由中國科學院武漢病毒研究所提供)稀釋成5×108
copies/μL, 5×107
copies/μL, 5×106
copies/μL, 5×105
copies/μL, 5×104
copies/μL, 5×103
copies/μL, 5×102
copies/μL。取2 μL標準品或cDNA範本用於qPCR反應。
②實驗過程中所用引物序列如下(均為5’-3’方向表示):
RBD-qF: CAATGGTTTAACAGGCACAGG
RBD-qR: CTCAAGTGTCTGTGGATCACG
③反應程式如下:
預變性:95℃ 5分鐘;
迴圈參數:95℃ 15秒,54℃ 15秒,72℃30秒,共40個迴圈。
(5)藥物對細胞毒性測試
藥物對細胞毒性的檢測利用CCK-8試劑盒(Beoytime)測定。具體步驟如下:
①96孔板中接種1×104
個Vero E6 (ATCC)細胞,37℃培養8小時。
②將藥物用DMSO稀釋到合適的母液濃度,再用含2%FBS(購自Gibco公司,貨號16000044)的MEM培養基(購自Gibco公司,貨號10370021)稀釋到與藥物處理同樣的濃度,棄96孔板中原培養基,取100 μL含藥物的MEM培養基加入到細胞中,每個濃度做三個複孔。設置陰性對照(細胞孔中加DMSO和培養基,而不加藥物)和空白對照(不含細胞,加DMSO和培養基)。加藥完畢,細胞37℃培養48小時。
③向待測孔中加入20 μL CCK-8溶液(Beoytime),輕輕混勻,不要產生氣泡,37℃繼續培養2小時。在酶標儀(購自Molecular Devices公司,型號SpectraMax M5)上讀取OD450
,計算細胞活性:
細胞活性(%)=(A(藥物處理組)
-A(空白對照)
)/ (A(陰性對照)
-A(空白對照)
) ×100%
其中A為酶標儀讀數。
(6) 實驗結果
病毒增殖抑制實驗的結果顯示,受試化合物在100μM,33μM,11.1μM以及3.7μM的濃度下,均能夠有效抑制感染上清中SARS-CoV-2病毒基因組的複製(表1和圖1)
表1. 受試化合物(Remdesivir)的體外抗病毒實驗
濃度(μM) | 100 | 33.33 | 11.11 | 3.70 | 1.23 | 0.41 | 0.14 | Vehicle |
病毒基因組拷貝數 | 9010444.5±2282239.02 | 12429732±1812581.22 | 16308516.5±1475181.58 | 20287512.5±13084251.56 | 879273650.5±189609425.32 | 1751863138.5±1115069812.46 | 6120820311.5±2886728551.13 | 510815026±180518414.22 |
細胞毒性結果顯示,在所有受試濃度下,受試化合物(Remdesivir)的處理均未改變細胞活力,即受試化合物在所有濃度下對細胞均無毒性作用(表2和圖1)。
表2. 受試化合物(Remdesivir)的細胞毒性實驗
濃度(μM) | 100 | 33.33 | 11.11 | 3.70 | 1.23 | 0.41 | 0.14 | Vehicle |
細胞活力(陰性對照%) | 97.70± 0.76 | 99.06± 0.41 | 97.05± 1.12 | 97.40± 0.41 | 97.88± 1.12 | 100.76±1.17 | 100.97±2.61 | 100.19±2.62 |
無。
圖1. 顯示Remdesivir有效降低SARS-CoV-2病毒感染的veroE6細胞上病毒核酸載量。其中(a)Remdesivir在細胞感染SARS-CoV-2病毒48h後能夠抑制細胞上的病毒RNA載量,其中33μM的藥物濃度可使得病毒的核酸載量降低一個數量級。縱坐標為樣品中病毒RNA的拷貝數,橫坐標為藥物濃度;(b)Remdesivir在受試濃度下對受試細胞處理48h,觀察不到細胞毒性。縱坐標為相對於陰性對照組(只有細胞,未加藥物)的細胞活力百分比,橫坐標為藥物濃度。
Claims (14)
- 如請求項1或請求項2所述的用途,其中該SARS-CoV-2引起的疾病為呼吸系統疾病。
- 如請求項1或請求項2所述的用途,其中該SARS-CoV-2引起的疾病為單純性感染、肺炎、急性呼吸道感染、嚴重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫症後群、膿毒症或膿毒性休克。
- 如請求項4所述的用途,其中該單純性感染為發熱、咳嗽和/或咽痛。
- 如請求項2所述的用途,其中該藥物組合物為固體製劑、注射劑、外用藥劑、噴劑、液體製劑或複方製劑。
- 如請求項9或請求項10所述的用途,其中該藥物組合物為固體製劑、注射劑、外用製劑、噴劑、液體製劑或複方製劑。
- 如請求項1或請求項2所述的用途,其中該SARS-CoV-2引起的疾病為COVID-19。
- 如請求項8或請求項10所述的用途,其中該細胞為哺乳動物細胞,該哺乳動物為牛科動物、馬科動物、羊科動物、豬科動物、犬科動物、貓科動物、齧齒類動物、靈長類動物。
- 如請求項13所述的用途,其中該哺乳動物為人、貓、狗或豬。
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UY39029A (es) | 2021-03-26 |
CN111494396A (zh) | 2020-08-07 |
EA202092169A1 (ru) | 2021-07-30 |
CN111265532A (zh) | 2020-06-12 |
CN111494396B (zh) | 2021-06-15 |
US20210220377A1 (en) | 2021-07-22 |
EP3854403A1 (en) | 2021-07-28 |
WO2021147236A9 (zh) | 2021-09-16 |
TW202128186A (zh) | 2021-08-01 |
JP2021116295A (ja) | 2021-08-10 |
JP2024020274A (ja) | 2024-02-14 |
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