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CN116098917A - 核苷类化合物在治疗冠状病毒感染性疾病中的用途 - Google Patents

核苷类化合物在治疗冠状病毒感染性疾病中的用途 Download PDF

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CN116098917A
CN116098917A CN202211442145.8A CN202211442145A CN116098917A CN 116098917 A CN116098917 A CN 116098917A CN 202211442145 A CN202211442145 A CN 202211442145A CN 116098917 A CN116098917 A CN 116098917A
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常俊标
杜锦发
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Abstract

式(I)所示的化合物或其药学上可接受的盐在制备预防或治疗冠状病毒感染性疾病的药物中的用途，所述式(I)化合物用于治疗新冠状病毒肺炎病人，在病毒核酸试验转阴率、转阴疗程、治愈出院时间都显示明显优势。

Description

核苷类化合物在治疗冠状病毒感染性疾病中的用途
技术领域
本发明涉及核苷类化合物新的抗病毒用途。
背景技术
冠状病毒(Coronavirus,CoV)是一类有包膜的正向单链RNA病毒，在人类、其他哺乳动物和鸟类中广泛传播，并可导致呼吸道、肠道、肝脏和神经系统等疾病。目前已知有七种CoV可导致人类疾病，其中四种CoV-229E、-OC43、-NL63和-HKU1在人群中流行，并通常引起普通感冒症状。而其他三种SARS-CoV、MERS-CoV和新冠状病毒(2019-nCoV，或称COVID-19)都具有发病快、传染性强和致死率高的严重危害性。因此，快速研发直接抗病毒药物，治疗新冠状病毒感染，十分迫切。
发明内容
化合物1作为抗艾滋病药物已经完成II期临床试验，安全性良好。
Figure BDA0003948762180000011
发明人在新冠状病毒感染的MRC-5细胞内，测定了化合物1的体外抗病毒活性。结果表明，化合物1只有微弱的抑制新冠状病毒的活性(EC50为25μM)。
然而，发明人直接用式(1)化合物进行研究性临床试验，惊奇地发现，较对照性常规治疗，用式(1)化合物治疗新冠状病毒肺炎病人，在病毒核酸试验转阴率、转阴疗程、治愈出院时间都显示明显优势。发明人认为，化合物1没有显示明显抑制病毒作用，可能与其在体外中不能有效地磷酸酯化有关。
鉴于此，本文中一方面，提供式(I)所示的化合物、或其药学上可接受的盐在制备预防或治疗冠状病毒感染性疾病的药物中的用途，另一方面，本文中提供一种预防或治疗冠状病毒感染性疾病的方法，包括向有此需要的患者给予治疗或预防有效量的式(I)化合物或其药学上可接受的盐，
其中式(I)结构式如下：
Figure BDA0003948762180000021
式(I)中，
R1为OR1基团可以在体内代谢释放出羟基，或者形成O-磷酸基的任何基团；OR1优选为酯基，R1优选为H、R5-CO-、或
Figure BDA0003948762180000022
其中Ar是苯基和取代苯基，萘基和取代萘基，所述取代基选自C1-6烷基、F、Cl、Br、I、CN、N3、OH、NH2、OR5、NHR5；
R2选自:H、叠氮基、C1-C6烷基(例如甲基、乙基)、C1-C6烷氧基(例如甲氧基、乙氧基)、C2-C6炔基(例如乙炔基)、C2-C6烯基(例如乙烯基)、卤代C1-C6烷基(例如2-氯乙基、2-氟乙基、三氟乙基)；
R3选自H、任选被取代的R-CO-、任选被取代的R-O(C＝O)-、和任选被取代的RNH-CO-，其中R选自C1-C6烷基(例如甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、异戊基等)；其中，取代基选自C1-C6烷基、卤素(如F、Cl)、CN、N3、和OR5。
R4选自H、OH、卤素(例如F)、C1-C6烷基(例如甲基，乙基)、C1-C6烷氧基(例如甲氧基，乙氧基)；
B选自：
Figure BDA0003948762180000023
其中，X1选自-OH、-NH2、R5CONH-、R5COO-、R5O(C＝O)NH-；
X2选自-OH、-SH、-NH2、R5COO-、R5COS-、R5CONH2-、R5O(C＝O)NH-；X3选自H、F、-OH和-NH2；
Y选自CH和N；
Z为H、-OH或F；
R5选自H、C1-C6烷基(例如甲基、乙基、丙基、异丙基)、C2-C6炔基(例如乙炔基)、C2-C6烯基(例如乙烯基)、卤代C1-C6烷基(例如2-氯乙基、2-氟乙基、三氟乙基)、任选被C1-6烷基、C1-6烷氧基、CN、N3、OH、NH2、卤素(例如F、Cl、Br、I)取代的苯基、任选被C1-6烷基、C1-6烷氧基、CN、N3、OH、NH2、卤素(例如F、Cl、Br、I)取代的萘基。
优先如下化合物或其药学上可接受的盐：
Figure BDA0003948762180000031
Figure BDA0003948762180000041
式(I)化合物的药学上可接受的盐包括，但不限于，例如式(I)化合物与以下酸形成的盐：盐酸、氢溴酸、氨基磺酸、硫酸、磷酸、硝酸、甲酸、乙酸、丙酸、草酸、乙醇酸、丙二酸、苯甲酸、乳酸、葡糖酸、柠檬酸、酒石酸、琥珀酸、富马酸、马来酸、杏仁酸、苹果酸、甲磺酸、乙磺酸、羟乙基磺酸、苯磺酸、对甲苯磺酸、萘磺酸、萘二磺酸、樟脑磺酸、抗坏血酸棕榈酸、水杨酸、磺基水杨酸、2-羟基-3-萘甲酸、邻苯二甲酸、赖氨酸、精氨酸、谷氨酸、甘氨酸、丝氨酸、苏氨酸、丙氨酸、异亮氨酸、亮氨酸等。
式(I)化合物可通过商业渠道购买或者已知的方法制得。
本文中冠状病毒感染性疾病，是由冠状病毒科病毒感染所引发的疾病，包括感染人或其他动物所引起的疾病。特别是人冠状病毒感染人类所引发的疾病，包括但不限于CoV-229E、-OC43、-NL63、-HKU1、SARS-CoV、MERS-CoV和新冠状病毒(2019-nCoV，或称COVID-19)感染引起的疾病。
式(I)化合物的治疗和预防冠状病毒感染性疾病的有效量可由本领域技术人员根据本文提供的信息确定。例如，成年人用量可以为1-500mg/天，可选为1-50mg/天，可选为1-20mg/天；可选为1-10mg/天，可选为5mg/天。可以单次或分多次给药。
给药方式可以为口服或者胃肠外给药。可以是速释剂型，也可以是缓释剂型、控释剂型。具体剂型可是本领域的各种常规剂型。例如，口服制剂可以列举片剂、硬或软胶囊剂、水性或油性混悬剂、颗粒剂、乳剂、糖浆剂或酏剂等。注射剂可以列举注射液、粉针剂等。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是，此处所描述的具体实施方式仅用于示例性地对本发明进行说明，并不用于限制本发明。
试验例
临床试验验证化合物用于治疗新冠状病毒(COVID-19)肺炎的有效性和安全性。
选择20例通过核酸试剂测定确诊新冠状病毒感染的患者，分为阿兹夫定(化合物1)组和克力芝对照组，每组10例。阿兹夫定组治疗方案：每天服用5毫克(口服，5片，每片1毫克)；克力芝对照组治疗方案：克力芝(口服，2片/日，250mg/片)+阿比多尔片(口服200mg/次，3次/日)+干扰素(500万U，每日两次雾化吸入)。测定核酸变化，体温变化，观察各种症状。
结果如下表所示。
Figure BDA0003948762180000051
Figure BDA0003948762180000061
临床试验结果表明，10例新冠状病毒感染患者中，阿兹夫定组全部患者核酸检测转阴，其中7例第8天内出院。
上述临床试验结果表明，化合物1治疗新冠病毒肺炎在病人核酸转阴率、转阴疗程、治愈率和治愈疗程几个指标都显示显著临床治疗优势。
其中一例使用克力芝支持治疗20多天仍不能转阴的病人，采用化合物1治疗后3天转阴。治疗中，没有发现任何药物有关的毒副作用。

Claims (5)

1.式(I)所示的化合物或其药学上可接受的盐在制备预防或治疗冠状病毒感染性疾病的药物中的用途，
Figure FDA0003948762170000011
式(I)中，
R1为H、R5-CO-、或
Figure FDA0003948762170000012
其中Ar为苯基、取代苯基、萘基或取代萘基，其中取代基选自C1-6烷基、F、Cl、Br、I、CN、N3、OH、NH2、OR5、NHR5；
R2为:H、叠氮基、C1-C6烷基(例如甲基、乙基)、C1-C6烷氧基(如甲氧基、乙氧基)、C2-C6炔基(例如乙炔基)、C2-C6烯基(例如乙烯基)、或者卤代C1-C6烷基(例如2-氯乙基、2-氟乙基、三氟乙基)；
R3为H、任选被取代的R-CO-、任选被取代的R-O(C＝O)-、或任选被取代的RNH-CO-，其中R为C1-C6烷基(例如甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、异戊基等)，其中，取代基选自C1-C6烷基、卤素(如F、Cl)、CN、N3、和OR5；
R4为H、OH、卤素(例如F)、C1-C6烷基(例如甲基，乙基)、或C1-C6烷氧基(例如甲氧基，乙氧基)；
B选自：
Figure FDA0003948762170000013
其中，X1为-OH、-NH2、R5CONH-、R5COO-或R5O(C＝O)NH-；
X2为OH、SH、NH2、R5COO-、R5COS-、R5CONH2-、或R5O(C＝O)NH-；X3为H、F、OH或NH2；
Y为CH或N；
Z为H、OH或F；
R5选自H、C1-C6烷基(例如甲基、乙基、丙基、异丙基)、C2-C6炔基(例如乙炔基)、C2-C6烯基(例如乙烯基)、卤代C1-C6烷基(例如2-氯乙基、2-氟乙基、三氟乙基)、任选被C1-6烷基、C1-6烷氧基、CN、N3、OH、NH2、卤素(例如F、Cl、Br、I)取代的苯基、任选被C1-6烷基、C1-6烷氧基、CN、N3、OH、NH2、卤素(例如F、Cl、Br、I)取代的萘基。
2.根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐在制备预防或治疗冠状病毒感染性疾病的药物中的用途，其中式(I)所示化合物为下列化合物：
Figure FDA0003948762170000021
Figure FDA0003948762170000031
或者
Figure FDA0003948762170000032
。
3.根据权利要求1或2所述的式(I)所示化合物或其药学上可接受的盐在制备预防或治疗冠状病毒感染性疾病的药物中的用途，其中式(I)化合物的药学上可接受的盐包括式(I)化合物与以下酸形成的盐：盐酸、氢溴酸、氨基磺酸、硫酸、磷酸、硝酸、甲酸、乙酸、丙酸、草酸、乙醇酸、丙二酸、苯甲酸、乳酸、葡糖酸、柠檬酸、酒石酸、琥珀酸、富马酸、马来酸、杏仁酸、苹果酸、甲磺酸、乙磺酸、羟乙基磺酸、苯磺酸、对甲苯磺酸、萘磺酸、萘二磺酸、樟脑磺酸、抗坏血酸棕榈酸、水杨酸、磺基水杨酸、2-羟基-3-萘甲酸、邻苯二甲酸、赖氨酸、精氨酸、谷氨酸、甘氨酸、丝氨酸、苏氨酸、丙氨酸、异亮氨酸或亮氨酸。
4.根据权利要求1-3任一项所述的式(I)所示化合物或其药学上可接受的盐在制备预防或治疗冠状病毒感染性疾病的药物中的用途，其中所述冠状病毒感染性疾病是由冠状病毒科病毒感染所引发的疾病，包括感染人或其他动物所引起的疾病，尤其是人冠状病毒感染人类所引发的疾病，例如，CoV-229E、-OC43、-NL63、-HKU1、SARS-CoV、MERS-CoV或COVID-19感染引起的疾病。
5.根据权利要求1-3任一项所述的式(I)所示化合物或其药学上可接受的盐在制备预防或治疗冠状病毒感染性疾病的药物中的用途，其中所述药物剂型为速释剂型、缓释剂型、或控释剂型，例如片剂、硬、软胶囊剂、水性或油性混悬剂、颗粒剂、乳剂、糖浆剂、酏剂、注射液、或粉针剂。
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