CN104138375A - 苯并吡啶类衍生物在制备抗hiv药物中的用途 - Google Patents
苯并吡啶类衍生物在制备抗hiv药物中的用途 Download PDFInfo
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- CN104138375A CN104138375A CN201310167343.2A CN201310167343A CN104138375A CN 104138375 A CN104138375 A CN 104138375A CN 201310167343 A CN201310167343 A CN 201310167343A CN 104138375 A CN104138375 A CN 104138375A
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Abstract
本发明涉及苯并吡啶类衍生物在制备用于预防和/或治疗获得性免疫缺陷综合征的药物中的新用途。具体地，本发明涉及通式I的化合物或其药学可接受的盐在制备用于预防和/或治疗获得性免疫缺陷综合征(AIDS)的药物以及在制备ZAP抑制剂中的用途。
Description
技术领域
本发明涉及苯并吡啶类衍生物在制备用于预防和/或治疗获得性免疫缺陷综合征的药物中的新用途。本发明进一步涉及苯并吡啶类衍生物在制备ZAP抑制剂中的新用途。
背景技术
获得性免疫缺陷综合征(Acquired immunodeficiency syndrome,AIDS)又称为艾滋病，是一种由人类免疫缺陷病毒(Human immunodeficiency virus,HIV)感染导致人体免疫机能缺陷，而易于发生机会性感染和肿瘤的临床综合症。HIV攻击人体免疫系统中最重要的T4淋巴细胞，从而破坏人体的免疫系统并最终使其崩溃。当感染者的免疫功能受到病毒严重破坏而不能维持最低的抵抗能力时，则发展为艾滋病患者。迄今为止，全世界共有超过6000万人感染HIV，其中已有2200万人因发展艾滋病而死亡。
目前美国FDA批准用于临床的抗HIV药物及复方制剂主要分为三类。第一类是抑制HIV逆转录酶活性的药物，从结构上划分为糖苷类逆转录酶抑制剂和非糖苷类逆转率酶抑制剂；第二类是抑制病毒蛋白酶水解的蛋白酶抑制；第三类是阻止病毒进入的HIV进入抑制剂。目前临床上广泛使用的“鸡尾酒疗法”，即高效抗逆转录病毒疗法(HAART)，联合使用第一类和第二类药物的应用来治疗艾滋病。但是这两类药物或其联合使用易于诱导HIV的耐药性，使越来越多的患者无法长期接受这些抗HIV药物的治疗。
而且，虽然通过HAART治疗艾滋病能够明显降低病毒的复制，但只能将患者的血浆病毒载量降低到一般方法无法检测的水平却无法完全清除病毒。因此，病毒在感染者体内依然存在，并且形成了病毒潜伏库(latent viralreservoir)。单一的HAART治疗很难彻底清除病毒，必须长期服药。而且长期药物治疗的副作用给病人带来的痛苦使得很多人难以坚持治疗。因此，完全清除HIV的病毒潜伏库才是彻底治愈HIV的最佳选择。
“Shock and kill”是一种通过外界刺激，促使潜伏感染的病毒启动转录和复制，然后通过免疫反应和治疗来促进HIV病毒清除的治疗策略。“Shockand kill”策略能特异性地激活病毒库中病毒的复制表达，同时又不激起全局的免疫反应，只是仅仅清除潜伏的感染细胞，达到最终彻底清除病毒的目的。这种策略已成为当今抗HIV治疗的首要任务(见Deeks SG.HIV:Shockand kill.Nature.2012Jul25;487(7408):439-40.和Deeks SG,Autran B,Berkhout B.et al.Towards an HIV cure:a global scientific strategy.Nat RevImmunol 2012:12:607–14.CrossRef,CAS)。在长期的进化过程中，哺乳动物已经产生了各种机制来抑制HIV等逆转录病毒的感染和复制。锌指抗病毒蛋白(Zinc finger Antiviral Protein，ZAP)是一种宿主抗病毒因子，具有抗HIV等多种病毒的功能，广泛存在于鸟类和哺乳动物的多个组织中，在肝、肾和激活的T细胞中表达水平最高。ZAP通过抑制病毒mRNA的翻译并促进其降解来达到抗病毒功能：ZAP识别病毒RNA中的特定序列，并结合到靶RNA上，抑制病毒RNA的翻译，并且通过一系列细胞内RNA降解机制来启动病毒RNA的降解。研究发现，ZAP对HIV早期调控蛋白Tat、Nef等的翻译和mRNA的稳定性有显著的抑制活性(见Zinc-finger antiviralprotein inhibits HIV-1infection by selectively targeting multiply spliced viralmRNAs for degradation.Proc.Natl.Acad.Sci.USA2011,108,15834-15839和Zhu Y,Wang X,Goff SP,Gao G.Translational repression precedes and isrequired for ZAP-mediated mRNA decay.EMBO J.2012Nov5;31(21):4236-46)。HIV早期调控蛋白Tat、Nef能反式激活HIV的转录。这提示，在HIV感染机体的进程中，ZAP对Tat、Nef的抑制作用会使得病毒在细胞中保持长期的低水平潜伏复制，从而促进潜伏感染的发生，即形成病毒潜伏库。因此，抑制ZAP的活性会使得病毒早期蛋白Tat、Nef大量产生，使发生了潜伏感染的HIV病毒启动复制。当病毒复制到一定的水平时，就可以启动所谓的“Shock and kill”策略，进而完全清除HIV病毒潜伏库，最终实现治愈AIDS的目的。
由此，ZAP已经成为抗HIV治疗的潜在靶点。相应地，ZAP的小分子抑制剂可以发展成为抗HIV的新药物。
发明内容
本发明通过提供ZAP的抑制剂来解决上述问题。
在第一方面，本发明涉及通式I的化合物或其药学可接受的盐在制备用于预防和/或治疗获得性免疫缺陷综合征(AIDS)的药物中的用途，
其中
R1选自以下组中：H、C1-C6烷基、C1-C6烷氧基、-C1-C6烷基苯基、-C1-C6烷基硝基、-C1-C6烷基羧基、硝基、卤素、苯基、苯氧基以及-O-杂环基，所述苯基、苯氧基和杂环基各自任选地被选自羟基、氨基、卤素、硝基和C1-C6烷基的取代基取代；并且
R2选自以下组中：H、C1-C6烷基、C1-C6烷氧基、-C1-C6烷基苯基、-C1-C6烷基硝基、-C1-C6烷基羧基、硝基、卤素、苯基、苯氧基以及-O-杂环基，所述苯基、苯氧基和杂环基各自任选地被选自羟基、氨基、卤素、硝基和C1-C6烷基的取代基取代。
在优选的实施方案中，R1和R2各自独立地选自H、C1-C6烷基和卤素。
在特别优选的实施方案中，R1和R2均为H。
在第二方面，本发明涉及通式I的化合物或其药学可接受的盐在制备用作ZAP抑制剂的药物中的用途，
其中
R1选自以下组中：H、C1-C6烷基、C1-C6烷氧基、-C1-C6烷基苯基、-C1-C6烷基硝基、-C1-C6烷基羧基、硝基、卤素、苯基、苯氧基以及-O-杂环基，所述苯基、苯氧基和杂环基各自任选地被选自羟基、氨基、卤素、硝基和C1-C6烷基的取代基取代；并且
R2选自以下组中：H、C1-C6烷基、C1-C6烷氧基、-C1-C6烷基苯基、-C1-C6烷基硝基、-C1-C6烷基羧基、硝基、卤素、苯基、苯氧基以及-O-杂环基，所述苯基、苯氧基和杂环基各自任选地被选自羟基、氨基、卤素、硝基和C1-C6烷基的取代基取代。
在优选的实施方案中，R1和R2各自独立地选自H、C1-C6烷基和卤素。
在特别优选的实施方案中，R1和R2均为H。
在第三方面，本发明还涉及一种药物组合物，其包含本发明的通式I的化合物和/或其药学可接受的盐，和/或本发明的ZAP抑制剂作为活性成分，以及和药学可接受的赋形剂。
在第四方面，本发明涉及一种预防和/或获得性免疫缺陷综合征(AIDS)的方法，所述方法包括向有需要的个体给予本发明的通式I的化合物或其药学可接受的盐、本发明的ZAP抑制剂或本发明的药物组合物。
附图说明
图1示出在化合物HZC-010的存在下，ZAP对病毒的抑制倍数(FI)。
具体实施方式
下面对本发明的各个方面和特点作进一步的描述。
本发明使用的各种术语和短语具有本领域技术人员公知的一般含义，当提及的术语和短语如有与公知含义不一致时，以本文中所列的含义为准。本文所用的缩略语通常为本领域技术人员所熟知的，或者可以是根据基础知识易于理解的。
本文所用的术语“C1-C6烷基”指具有1-6个(包括1、2、3、4、5或6个)、优选1-4个碳原子(C1-C4烷基)、更优选1-3个碳原子(C1-C3烷基)碳原子的直链或支化的饱和烷基，其实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基和己基等。所述“C1-C6烷基”可以任选地被选自羟基、氨基、硝基、卤素和C1-C6烷基的取代基取代。
本文所用的术语“C1-C6烷氧基”指“C1-C6烷基-O-”基团，其通过氧原子连接至分子的其他部分，并且其中“C1-C6烷基”如上文所述。其实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、己氧基等。所述“C1-C6烷氧基”可以任选地被选自羟基、氨基、硝基、卤素和C1-C6烷基的取代基取代。
本文所用的术语“-C1-C6烷基苯基”指与苯环连接的上文所述的“C1-C6烷基”，并且通过所述烷基部分连接至分子的其他部分。其实例包括但不限于苯甲基和苯乙基等。所述“-C1-C6烷基苯基”可以任选地被选自羟基、氨基、硝基、卤素和C1-C6烷基的取代基取代，所述取代基可以位于其中的“C1-C6烷基”上，也可以位于“苯基”上。
类似地，本文所用的术语“-C1-C6烷基硝基”和“-C1-C6烷基羧基”分别指与硝基或羧基连接的上文所述的“C1-C6烷基”，并且通过所述烷基部分连接至分子的其他部分。
本文所用的术语“杂环基”指包含5个或6个环原子的非芳香杂环基团，其可以包含1、2或3个、优选1或2个选自N、O、S的杂原子。所述“杂环基”可以任选地被选自羟基、氨基、硝基、卤素和C1-C6烷基的取代基取代。
本文所用的术语“-O-杂环基”指通过氧原子与分子的其他部分相连的上文所述的“杂环基”，其中的“杂环基”可以任选地被选自羟基、氨基、硝基、卤素和C1-C6烷基的取代基取代。
本文所用的术语“卤素”包括氟(F)、氯(Cl)、溴(Br)和碘(I)，优选氯(Cl)和溴(Br)。
本文所用的术语“药学上可接受的盐”是指保持化合物的生物学有效性和性质的盐，且其不是生物学或其它方面上不利的。药学上可接受的酸加成盐可以通过无机酸和有机酸来形成。可以衍生得到盐的无机酸包括如盐酸、氢溴酸、硫酸、硝酸、磷酸等。可以衍生得到盐的有机酸包括如乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、对甲苯磺酸、水杨酸等。药学上可接受的碱加成盐可以通过无机和有机碱来形成。可以衍生得到盐的无机碱包括如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝的氢氧化物等。可以衍生得到盐的有机碱包括如伯、仲和叔胺、取代的胺(其包括天然存在的取代的胺)、环胺等，如异丙基胺、三甲基胺、二乙基胺、三乙基胺、三丙基胺和乙醇胺等。
本文所用的术语“药学可接受的赋形剂”涵盖各种药学可接受辅料，如填充剂、崩解剂、粘合剂、润湿剂、润滑剂、助流剂、致孔剂、骨架材料和包衣剂等。
本文所用的术语“任选(地)”指可以存在或不存在。例如，当指某基团可以任选地被取代时，其可以是未取代的，也可以被指定的取代基以任何合适的方式取代。
除非另有说明，本申请实施例中采用的化合物均购买于北京百灵威科技有限公司。除非另有说明，本文中所用的比例和百分比均按重量计。
实施例1：化合物的对ZAP的抑制活性
在本实施例中测试以下结构表示的化合物(即R1和R2为H)的ZAP抑制活性。该化合物编号为HZC-010，得自北京百灵威科技有限公司。
I.材料与方法
1.测试化合物配制：
将化合物HZC-010溶于二甲基亚砜(DMSO)，浓度为1mol/L。
2.细胞株：
293T细胞(来自ATCC：CRL-11268TM)
Jurkat细胞株(来自ATCC：ATCCTIB-152TM)
3.细胞培养液：
1640细胞培养液(90%的RPMI Medium1640,Gibico)
10%的胎牛血清(FBS,Gibico)
4.其他材料：
萤光素酶(Luciferase)酶活性测定系统：Assay System(Cat.#1500,Promega)
转染试剂：LipofectamineTM2000(Invitrogen)
5.实验方法：
将两种假病毒VSVG-NL4-3-luciferase和VSVG-pHR'-luciferase用作ZAP活性的检测系统。这两种假病毒含有水疱性口炎病毒(VesicularStomatitis Virus)的包膜蛋白和HIV病毒的RNA基因组(基因组中插入有荧光素酶表达基因)。ZAP能抑制VSVG-NL4-3-luciferase假病毒(NL4-3)，但是对VSVG-pHR'-luciferase假病毒(pHR')没有显著抑制效果，因此将其用作ZAP活性的检测系统。
假病毒包装用的质粒：pNL4-3-Luc(Catalog No.3418)和pVSVG(Catalog No.4693)购自National Institutes of Health,AIDS Research andReference Reagent Program；pHR'-luc和pCMV-Delta8.2由Naldini L博士提供(见Naldini L,et al.(1996)In vivo gene delivery and stable transduction ofnondividing cells by a lentiviral vector.Science272:263-267.和Zufferey R,Nagy D,Mandel RJ,Naldini L,Trono D(1997)Multiply attenuated lentiviralvector achieves efficient gene delivery in vivo.Nat Biotechnol15:871-875.)。
具体步骤如下：
1)病毒包装：在293T细胞中分别共转染表达VSV的包膜的质粒pVSVG和表达HIV突变基因组的质粒pNL4-3-luc(假病毒VSVG-NL4-3-luciferase)，或者pVSVG、pHR'-luc和pCMV-Delta8.2(假病毒VSVG-pHR'-luciferase)。根据生产商的说明书，使用LipofectamineTM2000进行转染。
2)病毒感染：转染48小时后，分别用0.45μm滤膜过滤上述两种被转染的细胞(分别对应VSVG-NL4-3-luciferase和VSVG-pHR'-luciferase)的培养基上清。将过滤的上清用1640细胞培养液分别稀释3倍后，取1ml稀释的上清直接加入两组各自含有500μl待测Jurkat细胞(密度为1×105/ml)的培养皿中(样品组)。温育4小时(37℃和5%CO2)后，向上述样品组中各自加入化合物HZC-010，使得培养基中化合物的最终浓度为100μM。各样品组的参照基准组中用等体积的DMSO代替测试化合物。
3)病毒复制效果检测：温育48小时后(37℃和5%CO2)，用离心管收集细胞与培养基的混合液(800rpm，离心3分钟)，用移液管吸去上清，向细胞沉淀中加入200μl细胞裂解液(来自Assay System)，然后用振荡器混匀2分钟使细胞裂解。放置15分钟后，以12000rpm将裂解混合物离心10分钟。然后取上清20μl，向其中加入50μl浓度为0.5mg/ml的发光底物Beetle luciferin(来自AssaySystem)，并且用荧光检测仪Luminometer TD-20/20检测萤光素酶值。该值代表病毒的复制滴度，萤光素酶值越高，则病毒的复制滴度越高。
化合物抑制ZAP的效果用抑制倍数(FI)表示。FI=感染病毒并加入测试化合物后检测的萤光素酶值/感染病毒并加入DMSO后检测的萤光素酶值。如果化合物有抑制ZAP的活性，则FI值大于1。FI值越高，表示化合物对ZAP的抑制活性越高。
将测试化合物的浓度调整为200μM和400μM，分别重复以上实验，从而得到不同浓度的测试化合物下的结果。
II.实验结果：
图1示出在各种浓度的测试化合物HZC-010的存在下测定的抑制倍数(FI)。当化合物浓度为100μM、200μM和400μM时，测试组中(△，NL4-3，对应VSVG-NL4-3-luciferase)的FI分别为6.91、4.89和3.35，而对照组(■，pHR'，对应VSVG-pHR'-luciferase)的FI则分别为1.79、1.56和1.76。
可见，该化合物能够使ZAP抑制的HIV病毒株NL4-3的萤光素酶值升高3-7倍，而对另一种非ZAP抑制的HIV病毒株pHR'的萤光素酶值无明显的影响，从而证实该化合物能够抑制ZAP的活性。
以上实验表明，本发明通式I的化合物对ZAP具有显著的抑制活性，因此可以用于制备ZAP抑制剂，并且可以用作预防和/或治疗获得性免疫缺陷综合征(AIDS)的药物。
上文描述了本发明的一些优选实施方案。应该理解，尽管本文为了说明的目的已经描述了本发明的具体实施方案，但在不背离本发明精神和范围的情况下可以进行各种修改。因此，本发明只受所附权利要求书的限制。可以根据本公开进行和执行本文公开和要求保护的所有实施方案而无需进行过度的实验。
Claims (6)
1.通式I的化合物或其药学可接受的盐在制备用于预防和/或治疗获得性免疫缺陷综合征(AIDS)的药物中的用途，
其中
R1选自以下组中：H、C1-C6烷基、C1-C6烷氧基、-C1-C6烷基苯基、-C1-C6烷基硝基、-C1-C6烷基羧基、硝基、卤素、苯基、苯氧基以及-O-杂环基，所述苯基、苯氧基和杂环基各自任选地被选自羟基、氨基、卤素、硝基和C1-C6烷基的取代基取代；并且
R2选自以下组中：H、C1-C6烷基、C1-C6烷氧基、-C1-C6烷基苯基、-C1-C6烷基硝基、-C1-C6烷基羧基、硝基、卤素、苯基、苯氧基以及-O-杂环基，所述苯基、苯氧基和杂环基各自任选地被选自羟基、氨基、卤素、硝基和C1-C6烷基的取代基取代。
2.权利要求1的用途，其中R1和R2各自独立地选自H、C1-C6烷基和卤素。
3.权利要求1或2的用途，其中R1和R2均为H。
4.通式I的化合物或其药学可接受的盐在制备用作ZAP抑制剂的药物中的用途，
其中
R1选自以下组中：H、C1-C6烷基、C1-C6烷氧基、-C1-C6烷基苯基、-C1-C6烷基硝基、-C1-C6烷基羧基、硝基、卤素、苯基、苯氧基以及-O-杂环基，所述苯基、苯氧基和杂环基各自任选地被选自羟基、氨基、卤素、硝基和C1-C6烷基的取代基取代；并且
R2选自以下组中：H、C1-C6烷基、C1-C6烷氧基、-C1-C6烷基苯基、-C1-C6烷基硝基、-C1-C6烷基羧基、硝基、卤素、苯基、苯氧基以及-O-杂环基，所述苯基、苯氧基和杂环基各自任选地被选自羟基、氨基、卤素、硝基和C1-C6烷基的取代基取代。
5.权利要求4的用途，其中R1和R2各自独立地选自H、C1-C6烷基和卤素。
6.权利要求4或5的用途，其中R1和R2均为H。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10517909B2 (en) | 2014-08-26 | 2019-12-31 | Guangzhou Virotech Pharmaceutical Co., Ltd | Use of alphavirus in preparation of antitumor drugs |
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2013
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10517909B2 (en) | 2014-08-26 | 2019-12-31 | Guangzhou Virotech Pharmaceutical Co., Ltd | Use of alphavirus in preparation of antitumor drugs |
| US11235011B2 (en) | 2014-08-26 | 2022-02-01 | Guangzhou Virotech Pharmaceutical Co., Ltd. | Use of alphavirus in preparation of antitumor drugs |
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Application publication date: 20141112 |