CN111568896A - 14-取代穿心莲内酯在制备治疗抗病毒药物中的应用 - Google Patents
14-取代穿心莲内酯在制备治疗抗病毒药物中的应用 Download PDFInfo
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Abstract
本发明公开了14‑取代穿心莲内酯在制备治疗抗病毒药物中的应用。本发明提供的14‑芳基醚穿心莲内酯衍生物抗病毒活性高，能够用于制备登革病毒和寨卡病毒及其类似病毒(包括但不限于西尼罗河病毒、基孔肯雅病毒、乙脑病毒)引起的疾病、引起手足口病(hand‑foot‑and‑mouth disease,HFMD)的肠道病毒感染的疾病、以及HIV引起的艾滋病的药物。
Description
技术领域
本发明属于抗病毒药物技术领域，具体涉及14-取代穿心莲内酯在制备治疗抗病毒药物中的应用。
背景技术
登革病毒(DENV)、寨卡病毒(ZIKV)、西尼罗河病毒、乙脑病毒(JEV)属于黄病毒科，而基孔肯雅病毒(CHIKV)属于被膜病毒科第IV类甲病毒，它们之间由许多相似之处，包括在病毒结构、组织构架以及引起的临床症状上均非常相似，由于此，这些病毒感染导致的发热症状在临床早期难以准确判断感染源。它们引起的感染的区别主要在不良的预后，DENV的感染者会出现严重的出血症状，JEV感染者出现神经性不稳定的脑炎，ZIKV感染孕期母亲会引起认知缺陷的小头症婴儿，而CHIKV感染者则可能引起长期和严重的关节痛。这些病毒感染引起的疾病目前均没有特效药物，乙脑有疫苗，但登革病毒感染疫苗Dengvaxia(CYD-TDV)还存在不确定性，因此这类疾病主要是在辅助治疗下依靠人体的免疫系统完成对病毒感染的抵抗。
引发手足口病的肠道病毒有20多种亚型，其中以柯萨奇病毒A16型(Cox A16)和肠道病毒71型(EV 71)最为常见。患者表现口痛、厌食、低热、手、足、口腔等部位出现小疱疹或小溃疡，多数患儿一周左右自愈，少数患儿可引起不良后果的心肌炎、肺水肿、无菌性脑膜脑炎等并发症。个别重症患儿病情发展快，可能会导致死亡。由于引起手足口病有可能是多种肠道病毒共同感染所致，因此具有广谱效果的药物可能更有效治疗这类疾病。
发明内容
本部分的目的在于概述本发明的实施例的一些方面以及简要介绍一些较佳实施例。在本部分以及本申请的说明书摘要和发明名称中可能会做些简化或省略以避免使本部分、说明书摘要和发明名称的目的模糊，而这种简化或省略不能用于限制本发明的范围。
本发明克服现有技术的不足，提供14-取代穿心莲内酯在制备治疗抗病毒药物中的应用。本发明提供一类14-芳基醚穿心莲内酯衍生物的新应用，特别是用于制备登革病毒和寨卡病毒及其类似病毒(包括但不限于西尼罗病毒、基孔肯雅病毒、乙脑病毒)引起的疾病的治疗药物，用于治疗引起手足口病(hand-foot-and-mouth disease,HFMD)的肠道病毒感染的疾病的药物。
式(I)所示的化合物或其药学上可接受的盐在制备抑制登革病毒复制和繁殖、制备治疗登革病毒引起的登革疾病的药物中的作用，
其中，Ar是任意取代的苯环、萘环、吡咯环、呋喃环、噻吩环、喹啉环、异喹啉环、吡啶环、嘧啶环、苯并恶唑环、苯并噻唑、吲哚环、嘌呤、喋啶环中的一种或几种；X1-R1、X2-R2、X3-R3可以相同或不同，包括H、OH、OR4、SH、S(R4)、SO3H、NH(R4)、N(R4R5)、NO2、F、CH2F、CHF2、CF3、OSi(R4R5R6)、C(R4R5R6)中的一种或几种；X2-R2、X3-R3包括羰基、肟、腙中的一种或几种；Y包括O、S、S(O)、S(O2)、N(R4)、C(R5R6)、CF2、CHF中的一种或几种；R1-R6包括取代或未取代的烷基、烯基、芳香基中的一种或几种；*表示手性中心，包括R构型和/或S构型。
作为本申请的第二个目，式(I)所示的化合物或其药学上可接受的盐在制备抑制寨卡病毒复制、繁殖、感染、制备治疗寨卡病毒引起的寨卡疾病的药物中的应用。
作为本申请的第三个目，式(I)所示的化合物或其药学上可接受的盐在制备治疗登革病毒、复制、繁殖、感染、制备治疗登革病毒引起的疾病的药物中的应用。
作为本申请的第四个目，式(I)所示的化合物或其药学上可接受的盐在制备治疗登革病毒和/或寨卡病毒相关病毒的复制、繁殖、感染、制备治疗登革病毒引起的疾病的药物中的应用。
优选的，本发明所述的应用，其中：所述类似病毒包括但不限于西尼罗河病毒、基孔肯雅病毒、乙脑病毒中的一种或几种。
作为本申请的第五个目，式(I)所示的化合物或其药学上可接受的盐在制备治疗引起手足口病的肠道病毒感染的疾病的药物中的应用。
优选的，本发明所述的化合物包括，
本发明的有益效果：本发明14-芳基醚穿心莲内酯衍生物抗病毒活性高，能够用于制备登革病毒和寨卡病毒及其类似病毒(包括但不限于西尼罗河病毒、基孔肯雅病毒、乙脑病毒)引起的疾病、引起手足口病(hand-foot-and-mouth disease,HFMD)的肠道病毒感染的疾病、以及HIV引起的艾滋病的药物。
具体实施方式
为使本发明的上述目的、特征和优点能够更加明显易懂，下面结合具体实施例对本发明的具体实施方式做详细的说明。
在下面的描述中阐述了很多具体细节以便于充分理解本发明，但是本发明还可以采用其他不同于在此描述的其它方式来实施，本领域技术人员可以在不违背本发明内涵的情况下做类似推广，因此本发明不受下面公开的具体实施例的限制。
其次，此处所称的“一个实施例”或“实施例”是指可包含于本发明至少一个实现方式中的特定特征、结构或特性。在本说明书中不同地方出现的“在一个实施例中”并非均指同一个实施例，也不是单独的或选择性的与其他实施例互相排斥的实施例。
本发明提供14-芳基醚穿心莲内酯衍生物的新应用，特别是用于制备登革病毒和寨卡病毒及其类似病毒(包括但不限于西尼罗河病毒、基孔肯雅病毒、乙脑病毒)引起的疾病的治疗药物，用于治疗引起手足口病(hand-foot-and-mouth disease,HFMD)的肠道病毒感染的疾病的药物，以及用于治疗HIV引起的艾滋病的药物。
具体化合物如下(表格中EC50是指测得的化合物抗病毒感染活性，其中登革病毒：DENV；寨卡病毒:ZIKV)：
应说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围当中。
Claims (7)
1.式(I)所示的化合物或其药学上可接受的盐在制备抑制登革病毒复制和繁殖、制备治疗登革病毒引起的登革疾病的药物中的作用，
其中，Ar是任意取代的苯环、萘环、吡咯环、呋喃环、噻吩环、喹啉环、异喹啉环、吡啶环、嘧啶环、苯并恶唑环、苯并噻唑、吲哚环、嘌呤、喋啶环中的一种或几种；
X1-R1、X2-R2、X3-R3可以相同或不同，包括H、OH、OR4、SH、S(R4)、SO3H、NH(R4)、N(R4R5)、NO2、F、CH2F、CHF2、CF3、OSi(R4R5R6)、C(R4R5R6)中的一种或几种；
X2-R2、X3-R3包括羰基、肟、腙中的一种或几种；
Y包括O、S、S(O)、S(O2)、N(R4)、C(R5R6)、CF2、CHF中的一种或几种；
R1-R6包括取代或未取代的烷基、烯基、芳香基中的一种或几种；
*表示手性中心，包括R构型和/或S构型。
2.式(I)所示的化合物或其药学上可接受的盐在制备抑制寨卡病毒复制、繁殖、感染、制备治疗寨卡病毒引起的寨卡疾病的药物中的应用。
3.式(I)所示的化合物或其药学上可接受的盐在制备治疗登革病毒、复制、繁殖、感染、制备治疗登革病毒引起的疾病的药物中的应用。
4.式(I)所示的化合物或其药学上可接受的盐在制备治疗登革病毒和/或寨卡病毒相关病毒的复制、繁殖、感染、制备治疗登革病毒引起的疾病的药物中的应用。
5.根据权利要求4所述的应用，其特征在于：所述类似病毒包括但不限于西尼罗河病毒、基孔肯雅病毒、乙脑病毒中的一种或几种。
6.式(I)所示的化合物或其药学上可接受的盐在制备治疗引起手足口病的肠道病毒感染的疾病的药物中的应用。
7.根据权利要求1～6任一所述的应用，其特征在于：所述化合物包括，
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