CN117982522A - 核苷类化合物的制药用途 - Google Patents
核苷类化合物的制药用途 Download PDFInfo
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- CN117982522A CN117982522A CN202211367238.9A CN202211367238A CN117982522A CN 117982522 A CN117982522 A CN 117982522A CN 202211367238 A CN202211367238 A CN 202211367238A CN 117982522 A CN117982522 A CN 117982522A
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Abstract
一种核苷类化合物的制药用途，具体为式(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正痘病毒属病毒感染性疾病的药物中的用途，所述式(I)化合物对痘苗病毒、猴痘病毒、牛痘病毒和天花病毒等有明显的抑制作用；
Description
技术领域
本发明涉及核苷类化合物在制备预防或治疗正痘病毒属病毒感染性疾病的药物中的用途。
背景技术
痘病毒科正痘病毒属病毒多数引起全身性疹病。
天花病毒是人类天花的病原体。感染天花病毒后初期症状包括高烧、疲累、头疼、心跳加速及背痛，之后会有典型的天花红疹明显地分布在脸部、手臂和腿部。在发疹的初期，还会有淡红色的块状面积伴随疹子而出现。病灶在几天之后开始化脓、结痂，接下来慢慢发展成疥癣，然后慢慢剥落。
猴痘病毒感染的人类出现的症状与过去在天花病毒等感染患者身上所看到的症状相似。这种病毒可以通过直接密切接触由动物传染给人，也可以在人与人之间传播。传染途径主要包括血液和体液。2022年5月20日，欧洲确诊和疑似猴痘病例超过100例。2022年5月29日，世卫组织发布疾病信息通报，并将猴痘的全球公共卫生风险评估为中等。2022年6月24日，全世界猴痘确诊病例数已超过3200例。2022年7月23日，世界卫生组织将猴痘疫情列为“国际关注突发公共卫生事件”。到2022年9月，美国疾病控制和预防中心公布的数据显示，美国的确诊病例已经超过2万5千例。猴痘病毒具有发病快、传染性强和致死率高的严重危害性。
牛痘病毒是一种可引起牛产生轻微牛痘病灶的病毒。人若感染该病毒，会产生轻微不适，并产生抗牛痘病毒的抵抗力。
痘苗病毒致病力弱，但足以诱导机体产生抵制疾病的抗体，其在血清学和免疫学上与天花病毒有密切关系，被用作天花预防疫苗的抗原。
发明内容
化合物1(阿兹夫定)已经作为治疗艾滋病药和新型冠状病毒感染药批准上市，其安全性得到保障。
发明人测试了化合物I抑制猴痘病毒(Monkeypox virus)、天花病毒(Smallpoxvirus)、牛痘病毒(cowpox virus)和痘苗病毒(vaccinia virus)的活性，结果表明，化合物I对这些病毒均有明显的抑制作用。
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正痘病毒属病毒感染性疾病的药物中的用途；本文另一方面，提供一种预防或治疗正痘病毒属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；本文另一方面，提供一种药物组合物，包括式(I)所示的化合物或其药学上可接受的盐和任选的辅料，所述药物组合物用于预防或治疗正痘病毒属病毒感染性疾病。
其中式(I)结构式如下：
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：
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。
优选地，式(I)中，
R1为H、或R5-CO-；
R2为叠氮基；
R3为H、或R-CO-，其中R为C1-C6烷基；
R4为卤素；
B为：
其中，X1为-NH2；
Y为CH；
Z为H；
R5选自H、和C1-C6烷基。
优选如下化合物或其药学上可接受的盐：
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。
本文中正痘病毒属病毒感染性疾病，是由正痘病毒属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。特别是感染人类所引发的疾病。所述正痘病毒属病毒包括例如猴痘病毒、牛痘病毒或天花病毒等。
式(I)化合物的治疗和预防正痘病毒属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。
实施例：化合物抗病毒活性测试
1.1.细胞株和病毒株
人包皮成纤维细胞HFF-1和Vaccinia VP13、Monkeypox virus、Cowpox
virus以及Smallpox virus病毒株分别来自美国典型培养物保藏中心(ATCC)和中国典型培养物保藏中心(CCTCC)。实验培养液为添加了2％胎牛血清和2mM L-谷氨酰胺、1％非必需氨基酸、1％双抗、1％丙酮酸钠的DMEM培养液。
1.2.化合物
受试化合物是由河南真实生物医药科技有限公司提供的化合物1固体粉末，用100％DMSO配制成20mM储存溶液。对照化合物ST-246(MedChemExpress，货号HY-14805)由药明康德提供。化合物测试8个浓度，3倍系列稀释，三复孔。受试化合物起始测试浓度为10μM。最高测试浓度见表1。
表1.化合物信息
| 化合物 | 分子量 | 最高测试浓度 | 备注 |
| 化合物1 | 286.22 | 10μM | 受试化合物 |
| ST-246 | 376.33 | 1μM和100μM* | 对照化合物 |
*注：ST-246抗病毒活性和细胞毒性测试最高测试浓度分别是1μM和100μM。
1.3.主要试剂和仪器
(1)主要仪器：酶标仪(Molecule Devices，型号SpectraMax340PC384)。
(2)主要试剂：细胞活力检测试剂CCK-8(上海李记生物科技有限公司，货号AC11L057)。
2.实验方法
ST-246为活性测试的对照化合物。化合物测试8个浓度，三复孔。
表2.抗病毒活性实验方法
第一天：HFF-1细胞以每孔6,000个细胞，每孔100μL的密度接种到96孔测试板中并于5％ CO2、37℃培养箱中培养过夜。
第二天：每孔分别加入50μL倍比稀释后的化合物(8个浓度，3倍稀释，三复孔)和50μL病毒(病毒接种量为MOI＝0.1)。设置细胞对照(细胞，无化合物处理和病毒感染)，病毒对照(细胞感染病毒，无化合物处理)和培养液对照(只有培养液)。细胞培养液总体积为每孔200μL。培养液中DMSO的终浓度分别为0.5％。细胞于5％ CO2、37℃培养箱中培养4天。
第六天：使用细胞活力检测试剂盒CCK8检测细胞活力。受试样品的抗病毒活性和细胞毒性分别由不同浓度下的样品对病毒引起的细胞病变效应的抑制率(％)和细胞的活率(％)表示。计算公式如下：
抑制率(％)＝(测试孔读值-病毒对照平均值)/(细胞对照平均值-病毒对照平均值)×100
细胞活率(％)＝(测试孔读值-培养基对照平均值)/(细胞对照平均值-培养基对照平均值)×100
EC50和CC50值通过Prism软件(version 7)计算，抑制曲线拟合方法为log(inhibitor)vs.response--Variable slope of GraphPad Prism。
3.结果和讨论
在细胞病变实验中，阳性对照化合物ST-246表现出预期的抗病毒活性和细胞毒性，表明了实验的可信性。受试化合物和对照化合物抗病毒活性和细胞毒性结果总结在表3。
表3.化合物抗病毒活性结果
结果表明，化合物1对痘苗病毒(Vaccinia virus)、猴痘病毒(Monkeypox virus)、牛痘病毒(Cowpox virus)和天花病毒(Smallpox virus)都有明显的抑制作用，EC50分别为0.57、0.32、0.75和1.20μM。虽然化合物1的抗病毒活性较ST-246弱,由于化合物1已经作为治疗艾滋病药和新型冠状病毒感染药批准上市，其安全性得到保障，所以，化合物1更有临床应用潜力。
Claims (6)
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正痘病毒属病毒感染性疾病的药物中的用途，
式(I)中，
R1为H、R5-CO-、或其中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：
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所述的用途，其中式(I)中，
R1为H、或R5-CO-；
R2为叠氮基；
R3为H、或R-CO-，其中R为C1-C6烷基；
R4为卤素；
B为：
其中，X1为-NH2；
Y为CH；
Z为H；
R5选自H、和C1-C6烷基。
3.根据权利要求1所述的用途，其中式(I)所示化合物为下列化合物：
或者
4.根据权利要求1-3任一项所述的用途，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。
5.根据权利要求1-4任一项所述的用途，其中所述正痘病毒属病毒为猴痘病毒、牛痘病毒或天花病毒，所述正痘病毒属病毒感染性疾病包括感染人或其他动物所引起的疾病。
6.根据权利要求1-5任一项所述的用途，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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| CN202211367238.9A CN117982522A (zh) | 2022-11-02 | 2022-11-02 | 核苷类化合物的制药用途 |
| PCT/CN2023/127028 WO2024093813A1 (zh) | 2022-11-02 | 2023-10-27 | 核苷类化合物的制药用途 |
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| WO2003059334A2 (en) * | 2001-10-25 | 2003-07-24 | Eli Lilly And Company | Gemcitabine in the treatment of smallpox |
| US8642577B2 (en) * | 2005-04-08 | 2014-02-04 | Chimerix, Inc. | Compounds, compositions and methods for the treatment of poxvirus infections |
| CN100532388C (zh) * | 2007-07-16 | 2009-08-26 | 郑州大学 | 2’-氟-4’-取代-核苷类似物、其制备方法及应用 |
| US20230151048A1 (en) * | 2018-07-02 | 2023-05-18 | Henan Genuine Biotech Co., Ltd. | Crystal form, preparation method, and application of 4′-substituted nucleoside |
| CN116098917A (zh) * | 2020-02-27 | 2023-05-12 | 河南真实生物科技有限公司 | 核苷类化合物在治疗冠状病毒感染性疾病中的用途 |
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