CN108409686A - 一种可用于制备治疗呼吸道合胞体病毒感染的药物及其制备方法 - Google Patents
一种可用于制备治疗呼吸道合胞体病毒感染的药物及其制备方法 Download PDFInfo
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- CN108409686A CN108409686A CN201810304839.2A CN201810304839A CN108409686A CN 108409686 A CN108409686 A CN 108409686A CN 201810304839 A CN201810304839 A CN 201810304839A CN 108409686 A CN108409686 A CN 108409686A
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Abstract
本发明提供一种可用于制备治疗呼吸道合胞体病毒感染药物的苯并噻唑类化合物及其制备方法及其医药用途，体外药理活性实验显示：将RSV接种在人喉癌上皮细胞(Hep‑2)上后，采用细胞病变效应(CPE)和MTT法，以利巴韦林作为阳性对照药物，观察加入相应目标合成化合物后的细胞存活率。结果表明与RSV组相比，本发明提供的苯并噻唑类化合物样品组对病毒的抑制率较高，表明其对RSV具有一定的体外抑制作用，因此有望进一步开发成为药物，用于治疗呼吸道合胞体病毒感染的疾病。
Description
技术领域
本发明涉及式I所示的苯并噻唑类化合物或其可药用盐及其制备方法，含有一个或多个相关化合物的组合物和该类化合物在治疗呼吸道合胞体病毒感染疾病方面的用途。
背景技术
人呼吸道合胞病毒(Human respiratory syncytial virus，RSV)最早在1956年被Morris从患鼻伤风的黑猩猩体内分离到，后发现其能使病变细胞融合成多核巨细胞，因此称为呼吸道合胞病毒。RSV为单股负链RNA病毒，隶属副黏液病毒科、肺病毒属，有1个血清型，分为A、B 2个亚型。目前，流行区域最广泛、研究最多的RSV毒株主要有3种:A2、Long和Line19，3株病毒分别于1961年的澳大利亚、1956年的巴尔的摩和1967年的密西根大学被首次分离。
RSV病毒由病毒粒子和脂质包膜构成，其基因组由约15kb核苷酸组成，可转录产生10种蛋白，包括2种基质蛋(M1、M2)、3种核衣壳蛋白(N、P、L)、2种非结构蛋白NS1、NS2)和3种跨膜蛋白(主要粘附蛋白G、融合蛋白小疏水蛋白SH)。病毒的负链RNA被包裹在由N核糖核白螺旋而成的核衣壳中，N蛋白介导RNA和RNA聚合酶的相互作用，该聚合酶主要由磷蛋白P和蛋白L构成。基蛋白M1、M2在核衣壳和脂质包膜之间形成1个基质层结构蛋白NS1、NS2的含量很少，主要参与调节病毒RNA合成。
RSV病毒在温带地区的春、冬季和热带地区的雨季极为易发，流行地域广，爆发时间长，主要感染对象为5岁以下的儿童以及婴幼儿，据报道每年有超过3300万5岁以下的儿童感染RSV病毒。出生6个月以下的婴儿免疫功能尚不成熟，是严重感染和死亡的高发期。RSV传播的方式主要是通过飞沫传播，其次是污染的手指直接将病毒接种到鼻粘膜和眼粘膜而引起感染。RSV自然感染产生的免疫不充分，使机体可以再次感染，但往往不如原发感染严重，即使发生多次RSV自然感染也不能诱导上呼吸道对病毒感染产生终身的免疫保护。
RSV是导致婴幼儿和2岁以下儿童严重的下呼吸道感染的最重要的病原体,同时也是致使某些免疫抑制人群和年老人群发病和死亡的重要的原因。目前唯一允许用于化学疗法的药物是利巴韦林(ribavirin),它严格用于高危和病情严重的患儿。人类单克隆抗体palivizumab(Synagis)和静脉用免疫球蛋白(RSV-IGIV)已经注册使用,疗效较好,但是其治疗一个周期所需的费用很高,不能普遍应用于临床。迄今临床还没有疫苗用于预防RSV感染。因此,迫切需要高效廉价的防治RSV感染的药物。
发明内容
本发明提供一种可用于制备治疗呼吸道合胞体病毒感染药物的化合物或其药学上可接受的盐，其特征在于所述化合物具有式I的结构：
其中R1选自氢、氟、氯、溴、甲基、乙基、正丙基、氰基、异丙基、正丁基、叔丁基、异丙氧基、异丁氧基、异戊氧基、异己氧基、叔丁氧基等；
R2选自甲基、乙基、丙基、异丙基、异丁基、异戊基、异己基、叔丁基、 等。
优选地，所述化合物选自下列化合物或其药学上可接受的盐：
优选地，所述的可药用盐包括但不限于以下几种：盐酸盐，磷酸盐，硫酸盐，对甲苯磺酸盐，乙酸盐，三氟乙酸盐，马来酸盐，酒石酸盐，富马酸盐，柠檬酸盐，乳酸盐。
此外，本发明还提供一种制备可用于制备治疗呼吸道合胞体病毒感染药物的化合物的方法，其特征在于合成路线如下：
第一步：4-氟-3-三氟甲基苯甲酸与草酰氯反应制备成4-氟-3-三氟甲基苯甲酰氯；
第二步：4-氟-3-三氟甲基苯甲酰氯与相应的邻氨基苯硫酚合环生成苯并噻唑化合物；
第三步：苯并噻唑化合物在碳酸铯碱性条件下，与不同的醇发生取代反应，生成目标化合物；
另外，上述反应中的起始原料及中间体容易得到，或对本领域熟练技术人员来说可以用有机合成中的常规方法很容易合成。
本发明还涉及以本发明化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等途径。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。
当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
本发明的技术方案包括了所述的化合物在制备预防和治疗呼吸道合胞体病毒感染疾病的药物中的应用。
附图说明
图1显示为本发明的目标化合物对感染RSV的Hep-2的治疗作用示意图。
图中横坐标为不同组别，纵坐标为相应组别的细胞OD值。
具体实施方式
以下由特定的具体实施例说明本发明的实施方式，熟悉此技术的人士可由本说明书所揭露的内容轻易地了解本发明的其他优点及功效。
实施例1
2-(4-氟-3-三氟甲基苯基)苯并噻唑的合成：将4-氟-3-三氟甲基苯甲酸(20mmol)溶于50mL干燥的DCM中，加催化量的DMF，冰水浴下滴加草酰氯(3.4mL,40mmol),搅拌30min后，移至室温下搅拌2h。旋干反应液，加入40mL干燥的甲苯，制成酰氯溶液，密封待用。将邻氨基苯硫酚(2.5g,20mmol)溶于20mL干燥的甲苯中，搅拌下滴加制备好的酰氯溶液，N2保护下110℃反应3h。冷却至室温，反应液用乙酸乙酯(100ml)和饱和碳酸氢钠溶液(50mL)稀释,萃取，分离有机相，水相用乙酸乙酯(2×50ml)，收集有机相水洗，无水硫酸钠干燥，过滤、浓缩后硅胶柱层析，得2-(4-氟-3-三氟甲基苯基)苯并噻唑(淡黄色固体)。
2-(4-甲氧基-3-三氟甲基苯基)苯并噻唑的合成：2-(4-氟-3-三氟甲基苯基)苯并噻唑(3mmol)溶于10mL干燥的DMF中，加入甲醇(9mmol)和Cs2CO3(9mmol)，25℃下反应过夜。用乙酸乙酯(50mL)稀释，加入水(25mL)萃取，水层用乙酸乙酯(2×25mL)萃取两次，收集乙酸乙酯层，水洗，无水硫酸钠干燥。过滤，减压旋去溶剂，得目标化合物1，核磁和质谱数据见表1。
实施例2
2-(4-氟-3-三氟甲基苯基)苯并噻唑的合成(步骤同实施例1)
2-(4-乙氧基-3-三氟甲基苯基)苯并噻唑的合成：2-(4-氟-3-三氟甲基苯基)苯并噻唑(3mmol)溶于10mL干燥的DMF中，加入乙醇(9mmol)和Cs2CO3(9mmol)，25℃下反应过夜。用乙酸乙酯(50mL)稀释，加入水(25mL)萃取，水层用乙酸乙酯(2×25mL)萃取两次，收集乙酸乙酯层，水洗，无水硫酸钠干燥。过滤，减压旋去溶剂，得目标化合物2，核磁和质谱数据见表1。
实施例3
2-(4-氟-3-三氟甲基苯基)苯并噻唑的合成(步骤同实施例1)
2-(4-丙氧基-3-三氟甲基苯基)苯并噻唑的合成：2-(4-氟-3-三氟甲基苯基)苯并噻唑(3mmol)溶于10mL干燥的DMF中，加入丙醇(9mmol)和Cs2CO3(9mmol)，25℃下反应过夜。用乙酸乙酯(50mL)稀释，加入水(25mL)萃取，水层用乙酸乙酯(2×25mL)萃取两次，收集乙酸乙酯层，水洗，无水硫酸钠干燥。过滤，减压旋去溶剂，得目标化合物3，核磁和质谱数据见表1。
实施例4-8
按照实施例1的方法，用不同取代基的醇与2-(4-氟-3-三氟甲基苯基)苯并噻唑在Cs2CO3碱性条件反应，同理制备得到化合物4-8，核磁和质谱数据见表1。
表1化合物1-8的核磁共振氢谱数据和质谱数据
实施例9
试剂：利巴韦林注射液，上海现代哈森药业有限公司生产，批号：h19993528；DMEM培养液、胎牛血清、胰酶(均为WISENT公司产品)；MTT(凯基生物)；DMSO(Solarbio公司)。
毒株与细胞：呼吸道合胞病毒A亚型(Long株)由武汉国家典型培养物保藏中心提供。人喉癌上皮细胞(Hep-2)，由南京基天生物有限公司提供。
仪器：EXL800型酶联免疫检测仪(美国BioTek)；倒置显微镜DMIL(德国LEICA)。
方法：1.RSV扩增及组织培养半数感染量(TCID50)的测定Hep-2细胞(人喉癌上皮细胞)以1×105/mL接种24孔板。待细胞长成单层时弃培养液，接种病毒液200μL/孔，置37℃、5％CO2培养箱中吸附1.5h后，补充含2％胎牛血清的维持液至1mL/孔，继续培养3-5d。逐日观察细胞病变(cytopathic effect，CPE)，典型病变是融合的大泡，病变达75％以上时，置-70℃(至少2h)和37℃反复冻融3次。收集病毒液，2500r/min离心10min。弃沉淀，收集病毒上清液，分装后于-70℃保存备用。将Hep-2细胞以1×105/mL，每孔0.1mL接种96孔细胞培养板，置37℃、5％CO2培养箱中培养。将病毒液用维持液10倍递次稀释成8个浓度。细胞长成单层时吸弃培养液，磷酸盐缓冲溶液洗细胞面，接种各稀释度的病毒液，每个稀释度设6孔，并设正常细胞对照组。置35℃、5％CO2培养箱中吸附1.5h，30min轻轻摇晃1次，使病毒均匀吸附。吸弃病毒液，每孔加维持液100μL，置培养箱中继续培养。每日在倒置显微镜下观察细胞病变效应(CPE)。CPE记录方法为：无CPE为“-”，25％以下细胞病变为“+”，25％-50％细胞病变为“++”，50％-75％细胞病变为“+++”，75％-100％的细胞病变为“++++”。用Reed-Muench公式计算病毒液的TCID50。
2.细胞的毒性试验Hep-2细胞以1×105/mL浓度加入96孔细胞板，每孔100μL，待长成单层后，加入用细胞维持液稀释每个样品(化合物1-8)200、100、50、25、12.5、6.25ug/mL6个浓度，每孔100μL，空白对照和正常细胞对照孔加入100μL/孔维持液。置37℃、5％CO2培养箱中培养，观察细胞病变至72h。弃去上清液，每孔加入MTT(1mg/mL)100μL。置孵箱孵育4h。吸弃孔内上清液，每孔加100μL DMSO，低速振荡10min，使结晶物充分溶解。选择490nm波长，用酶标仪测定各孔光吸收值，确定药物的最大无毒浓度。
3.体外抗RSV实验
治疗作用实验(RSV感染后药物干预)：细胞在培养板中长成单层后，以100TCID50RSV液每孔50μL吸附2h，弃去病毒液，然后加入含药200μg/mL(目标化合物1-8)维持液，设3个复孔。同时设RSV组、利巴韦林(200μg/mL)组和正常细胞组，置37℃、5％CO2培养箱。每日观察CPE，持续3-5d。当RSV组细胞病变达75％以上，再12h后，MTT法检测细胞存活率。实验重复3次。
结果显示：将RSV接种在人喉癌上皮细胞(Hep-2)上，采用细胞病变效应(CPE)，通过计算，RSVLong株TCID50为10-3.85/50μL；在Hep-2细胞中，化合物1-8在200ug/mL浓度时依旧对细胞无明显毒性；体外抗RSV实验结果见图1。使用化合物1-8进行干预前均出现典型的CPE，使用化合物1-8进行干预后对RSV引起的CPE有明显的抑制作用(P<0.05)。
上述实施例仅例示性说明本发明的原理及其功效，而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下，对上述实施例进行修饰或改变。因此，举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变，仍应由本发明的权利要求所涵盖。
Claims (6)
1.一种可用于制备治疗呼吸道合胞体病毒感染药物的化合物或其药学上可接受的盐，其特征在于所述化合物具有式I的结构：
其中R1选自氢、氟、氯、溴、甲基、乙基、异丙基、氰基、甲氧基、叔丁基、异丙氧基、异丁氧基、异戊氧基、异己氧基、叔丁氧基；
R2选自甲基、乙基、丙基、异丙基、正丁基、异丁基、正戊基、异戊基、异己基、叔丁基、
2.根据权利要求1所述的可用于制备治疗呼吸道合胞体病毒感染药物的化合物，其特征在于所述化合物选自下列化合物或其药学上可接受的盐：
3.根据权利要求1所述的可用于制备治疗呼吸道合胞体病毒感染药物的化合物，其特征在于所述的药学上可接受的盐包括：盐酸盐，磷酸盐，硫酸盐，对甲苯磺酸盐，乙酸盐，三氟乙酸盐，马来酸盐，酒石酸盐，富马酸盐，柠檬酸盐，乳酸盐。
4.一种制备权利要求1所述的可用于制备治疗呼吸道合胞体病毒感染药物的化合物的方法，其特征在于合成路线如下：
第一步：4-氟-3-三氟甲基苯甲酸与草酰氯反应制备成4-氟-3-三氟甲基苯甲酰氯；
第二步：4-氟-3-三氟甲基苯甲酰氯与相应的邻氨基苯硫酚合环生成苯并噻唑化合物；
第三步：苯并噻唑化合物在碳酸铯碱性条件下，与不同的醇反应生成目标化合物；
5.一种药物的组合物，其特征在于含有权利要求1的化合物和制剂学可接受的载体。
6.权利要求1所述的化合物在制备预防和治疗呼吸道合胞体病毒感染疾病的药物中的应用。
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