CN114835691B - 一种苯并咪唑衍生物及其用途 - Google Patents
一种苯并咪唑衍生物及其用途 Download PDFInfo
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- CN114835691B CN114835691B CN202110135739.3A CN202110135739A CN114835691B CN 114835691 B CN114835691 B CN 114835691B CN 202110135739 A CN202110135739 A CN 202110135739A CN 114835691 B CN114835691 B CN 114835691B
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- Veterinary Medicine (AREA)
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Abstract
本发明涉及一种苯并咪唑衍生物及其用途，所述苯并咪唑衍生物具有NS5A抑制活性并且可用于丙肝药物或缓解性药物的化合物，具体来说，本发明提供一种如式I所示的苯并咪唑衍生物或其药学上可接受的盐：L1a‑M1a‑C(＝O)‑Q1a‑T1a‑Q1b‑C(＝O)‑M1b‑L1b(I)。
Description
技术领域
本发明属于药物化学领域，具体涉及一类苯基咪唑衍生物及其用途，特别是作为通过抑制非结构蛋白5A复制发挥抑制HCV病毒复制的用途，所涉及的生物标志物包括但不限于NS5A(非结构蛋白5A)。
背景技术
据世界卫生组织(WHO)公布，全球约有8000万(6400万～1.3亿)慢性丙型肝炎患者，其病毒血症发病率(HCV RNA阳性)约为1.1％。全球抗-HCV流行率(提示既往病毒血症感染)为1.6％，对应人口为1.5亿(9200万-1.49亿)。每年约有70万人死于丙型肝炎相关并发症，包括肝硬化和肝癌等。HCV的高发区包括非洲西部、欧洲东部和亚洲中部。
新的直接抗病毒小分子药物(DAAs)的问世预示着消灭丙型肝炎的时代即将到来。然而，不同基因型HCV的分布各不相同，直接影响了治疗的决策。如基因1型和2型主要分布在北美、日本和欧洲，基因3型主要分布在非洲东南部和印度。在中东和非洲南部地区，最常见的分别是基因4型和5型。中国的HCV基因型主要包括4种基因型、9个亚型，其中最为常见的是基因1型(69.6％)，汉族感染基因6型的人群主要分布在我国南部和西部。治疗方面，随着治疗手段和药物的进展和开发，自上世纪八十年代至今，HCV的持续病毒学应答(SVR)率在不断上升。
NS5A也属于乙肝病毒的非结构蛋白，而且是一种高度磷酸化的非结构蛋白，不具备酶催化活性，其磷酸化水平在HCV基因组的复制和翻译过程中也起着调节的作用。NS5A非结构蛋白含有447个氨基酸，有3个不同的结构域。结构域I(氨基酸序列:1-213)由一个高度保守的两性α-螺旋和一个疏水的侧链及带电的侧链组成，是NS5A与RNA结合的重要区域。其晶体结构(图2)显示它是一个二聚体，有一个包含四个半胱氨酸残基(Cys39、Cys57、Cys59、Cys80)的锌结合区域，此区域对蛋白的稳定性起着重要作用。结构域II(氨基酸序列:250-342)和结构域III(氨基酸序列：356-447)也对病毒的复制和组装有着重要作用。
NS5A可以诱导白细胞介素-8(IL-8)的表达，从而使HCV对α-干扰素的抗病毒作用产生抑制。同时，NS5A蛋白上的干扰素敏感性决定位点(interferon sensitivitydeterminingregion，ISDR)可以通过与依赖RNA的蛋白激酶(PKR)结合抑制细胞对α-干扰素的应答过程，而且NS5A的磷酸化水平在HCV基因组的复制和翻译过程中也起着调节的作用，NS5A功能的重要性和多样性使它成为抗HCV的重要靶点。
目前随着泛基因型抗HCV药物进入临床和上市，针对抗HCV的药物研发进入快车道，提供高效、低毒全新结构的药物化合物是必要的。
发明内容
本发明提供了一类具有NS5A抑制活性并且可用于丙肝药物或缓解性药物的化合物。
具体来说，本发明提供一种如式I所示的苯并咪唑衍生物或其药学上可接受的盐：
L1a-M1a-C(＝O)-Q1a-T1a-Q1b-C(＝O)-M1b-L1b
(I)
其中：T1a为
或在任意一个位置被一个或多个卤素、烷基、卤代烷基的基团取代；
X是-CH＝CH-；
其中，Q1a是：
Q1b是
M1a是：
M1b是：
L1a是-N(H)(烷氧基羰基)、-N(H)C(＝O)CH3；
L1b是-N(H)(烷氧基羰基)、-N(H)C(＝O)CH3；
优选的，本发明所述的苯并咪唑衍生物或其药学上可接受的盐，具有通式(II)的结构：
优选的，本发明所述苯并咪唑衍生物选自以下化合物：
其中，本发明所述的苯并咪唑衍生物药学上可接受的盐，为本发明苯并咪唑衍生物与下列酸形成的盐：盐酸、对甲苯磺酸、酒石酸、马来酸、乳酸、甲磺酸、硫酸、磷酸、柠檬酸、乙酸或三氟乙酸。
优选的，所述的酸为对甲苯磺酸、盐酸、酒石酸或三氟乙酸。
本发明所述的苯并咪唑衍生物药学上可接受的盐进一步包括它们的溶剂化物，代谢物前药等。
本发明提供的苯并咪唑衍生物对HCV抑制活性进行评价，结果表明这类化合物具有很好的抗HCV活性。
本发明提供的苯并咪唑衍生物具有很好的抗HCV活性，开拓了一类新型丙肝药物的研究方向。
本发明还提供一种含有本发明所述衍生物或其药学上可接受的盐的药物组合物。
本发明的药物组合物，优选的是单位剂量的药物制剂形式，在制成药物制剂时可以制成任何可药用的剂型，这些剂型选自：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、混悬剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、贴剂。优选的是口服制剂形式，最佳优选的是片剂，胶囊剂。
进一步的，本发明所述药物组合物还含有药学上可接受的载体。
可以采用制剂学常规技术制备该药物制剂，所述药学上可接受的的载体包括但不限于：甘露醇、山梨醇、山梨酸或钾盐、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素A、维生素C、维生素E、维生素D、氮酮、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、丙二醇、乙醇、土温60-80、司班-80、蜂蜡、羊毛脂、液体石蜡、十六醇、没食子酸酯类、琼脂、三乙醇胺、碱性氨基酸、尿素、尿囊素、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β－环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本发明的药物组合物，在制成药剂时，单位剂量的药剂可含有本发明的药物活性物质0.1-1000mg，其余为药学上可接受的载体。药学上可接受的载体以重量计可以是制剂总重量的0.1-99.9％。
本发明的药物组合物在使用时根据病人的情况确定用法用量。
本发明还包括所述苯并咪唑衍生物、或其药学上可接受的盐在制备与NS5A相关的疾病的药物中的用途。所述与NS5A相关的疾病包括但不限于丙型肝炎。本发明所述的苯并咪唑衍生物，可以采用以下制备方法制备：
方案一：
方案一中，以左旋苯甘氨酸和L-缬氨酸为原料与3氯甲酸甲酯在碱性条件下反应，得到中间体1-1和1-2。
方案二：
方案二中，以1-3为起始原料，依次经过取代、还原、水解、环合，溴代、脱保护等反应得到关键这中间体1-10。
方案三：
方案三中，以(2S,5S)-N-Boc-5-甲基吡咯烷-2-甲酸为原料经过缩合、环合、Heck偶联、Suzuki偶联、氧化等反应，得到中间体1-16。
方案四：
方案四中，以1-19为原料经过缩合、Suzuki偶联等反应，得到目标化合物1、2、3、4。
有益效果：
本发明提供了结构新颖高效、低毒的新化合物。
本发明的新化合物的特点在于：(1)在细胞水平上的活性优异，其针对基因型1a和1b的IC50可以达到40pM以下；(2)所述化合物可以作为NS5A抑制剂用于丙肝药物。
附图说明
图1.化合物1的1H-NMR谱图
图2.化合物2的1H-NMR谱图
图3化合物3的1H-NMR谱图
图4.化合物4的1H-NMR谱图
具体实施方式
下面结合具体实施例对本发明作进一步的说明。
实施例1：中间体1-1和1-2的合成
中间体1-1的合成
将左旋苯甘氨酸5g(33mmol，1equiv)加入到圆底烧瓶中，然后加入30ml5％1,4-二氧六环氢氧化钠水溶液，再加入氯甲酸甲酯3.75g(39.7mmol，1.2equiv)。将反应液加热到60℃反应12h。反应在结束后将反应液倒入冰水中，滴加2M稀盐酸酸化至中性，乙酸乙酯萃取，静置后分取有机层，依次用水、饱和食盐水洗涤，无水硫酸钠干燥，然后浓缩；浓缩物用硅胶柱层析分离两次(PE，200-300目)，得到5.6g产品即1-1。MS(ESI):m/z＝210.12[M+1]+，1H NMR:400MHz DMSOδ12.85(s,1H),7.42(d,J＝8Hz,1H),7.41-7.28(m,5H),5.14-5.12(d,J＝8Hz,1H),3.55(s,3H).
中间体1-2的合成
将L-缬氨酸4g(34mmol，1equiv)加入到圆底烧瓶中，然后加入30ml 5％1,4-二氧六环氢氧化钠水溶液，再加入氯甲酸甲酯3.87g(40.9mmol，1.2equiv)。将反应液加热到60℃反应12h。反应在结束后将反应液倒入冰水中，滴加2M稀盐酸酸化至中性，乙酸乙酯萃取，静置后分取有机层，依次用水、饱和食盐水洗涤，无水硫酸钠干燥，然后浓缩；浓缩物用硅胶柱层析分离两次(PE，200-300目)，得到5.1g产品即1-1。MS(ESI):m/z＝176.222[M+1]+，1HNMR:400MHz CDCl3δ5.13-5.10(d,J＝12Hz,1H),4.27-4.24(m,1H),3.63(s,3H),2.19-2.12(m,1H),0.95-0.88(m,6H).
实施例2：中间体1-10的合成
化合物1-10的合成
将50g 1-3(182.9mmol，1equiv)加入到250ml圆底烧瓶中，然后加入100ml10％氢氧化锂水溶液，将反应液50℃反应6h，TLC检测反应完全后，将反应液倒入冰水混合物中，滴加2M稀盐酸至酸性，乙酸乙酯萃取，以饱和食盐水洗涤有机层，减压浓缩，浓缩物以硅胶柱层析分离(200-300，PE:EA＝5:1)，得到产品42g即为1-4。MS(ESI):m/z＝274.29[M+H]+.
将40g化合物1-4(154mmol，1equiv)加入到500ml三口瓶中，然后加入80ml无水四氢呋喃，冰浴下加入100ml 1.6mol/L而甲硫醚硼烷溶液，氩气保护下将反应液在80℃反应3h，将反应液在冰浴下淬灭，将混合物真空中减压浓缩，浓缩物以硅胶柱层析分离得到油状物29.6g即为化合物1-5。MS(ESI):m/z＝246.29[M+H]+.
将29g 1-5(118mmol，1equiv)加入到250ml圆底烧瓶中，然后加入21g TEA(142mmol，1.2equiv)，-70℃下加入15.7g草酰氯(124mmol，1.05equiv)，最后加入DMSO二氯甲烷溶液30ml(11.8mmol，0.1equiv)，将反应液-70℃下反应4h，TLC检测反应完全后，将反应液倒入冰水混合物中，饱和碳酸氢钠中和，乙酸乙酯萃取，以饱和食盐水洗涤有机层，减压浓缩，浓缩物以硅胶柱层析分离(200-300，PE:EA＝10:1)，得到油状物21g即为1-6。
将21g 1-6(86.3mmol，1equiv)加入到250ml圆底烧瓶中，然后加入40ml 7M NH3/MeOH溶液，冰浴下加入7.5g乙二醛(129mmol，1.5equiv)，将反应液0-25℃反应4h，TLC检测反应完全后，将反应液倒入冰水混合物中，乙酸乙酯萃取，以饱和食盐水洗涤有机层，减压浓缩，浓缩物以pre-HPLC分离，得到产品16g即为1-7。MS(ESI):m/z＝282.31[M+H]+.
将16g 1-7(56.9mmol，1equiv)加入到250ml圆底烧瓶中，然后加入80ml二氯甲烷，-15℃下加入11.1g NBS(62.6mmol，1.1equiv)，将反应液-15℃反应2h，TLC检测反应完全后，将反应液倒入冰水混合物中，二氯甲烷萃取，以饱和食盐水洗涤有机层，减压浓缩，浓缩物以pre-HPLC分离，得到产品10g即为1-8。MS(ESI):m/z＝439.05[M+H]+.
将16g 1-8(36.4mmol，1equiv)加入到100ml圆底烧瓶中，然后加入40ml Ethanol/H2O溶液(3:7)，然后加入6.89g亚硫酸钠(54.7mmol，1.5equiv)，将反应液80℃反应12h，TLC检测反应完全后，将反应液倒入冰水混合物中，乙酸乙酯萃取，以饱和食盐水洗涤有机层，减压浓缩，浓缩物以硅胶柱层析分离(200-300，PE:EA：DCM＝10:1:1)，得到油状物5.1g即为1-9。MS(ESI):m/z＝360.0[M+H]+.1H NMR:400MHz DMSO-d6 δ12.21-12.16(d,1H),7.12-7.09(d,1H),4.69-4.61(m,1H),3.64-3.56(m,1H),3.34-3.32(d,2H),3.23(s,3H),3.14-3.09(t,1H),2.46-2.40(m,2H),2.33-2.26(m,1H),1.28(s,9H).
将5g 1-9(13.9mmol，1equiv)加入到100ml圆底烧瓶中，然后加入30ml Ethanol/HCl溶液(1M)，将反应液60℃反应6h，TLC检测反应完全后，将反应液倒入冰水混合物中，乙酸乙酯萃取，以饱和食盐水洗涤有机层，减压浓缩，浓缩物以硅胶柱层析分离(200-300，PE:EA：DCM＝10:1:1)，得到油状物3.4g即为1-10。MS(ESI):m/z＝260.1[M+H]+.1H NMR:400MHzDMSO-d6 δ10.43(s,1H),9.37(s,1H),7.41-7.39(d,1H),4.74-4.70(m,1H),3.41-3.37(m,3H),3.27-3.26(d,3H),3.16(s,2H),3.06-3.01(m,1H),2.68-2.64(t,1H),2.47-2.42(m,1H),1.98-1.90(m,1H).
实施例3：中间体1-16的合成
将5g化合物1-11(21.8mmol，1equiv)、8.3g的HATU(21.8mmol，1equiv)、11.3gDIPEA(87.2mmol，4equiv)和10ml N,N-二甲基甲酰胺放入100ml圆底烧瓶中，然后再加入6.1g 4-溴邻苯二胺(32.7mmol，1.5equiv)，氩气保护下于室温下反应过夜，将反应液倒入冰水中，乙酸乙酯萃取，有机相减压浓缩，浓缩物以硅胶柱层析分离得到8g化合物1-12。直接进行下步反应。
将8g 1-12(20mmol，1equiv)加入100ml圆底烧瓶中，然后再加入40ml无水乙醇，氩气保护下于100℃下反应16h，将反应液倒入冰水中，乙酸乙酯萃取，有机相减压浓缩，浓缩物以硅胶柱层析分离得到5.2g化合物1-13。MS(ESI):m/z＝380.1[M+H]+，直接进行下步反应。
将5g 1-13(13.1mmol，1equiv)、0.24g的乙酸钯(1.05mmol，0.08equiv)、3.1gXPhos(6.6mmol，0.5equiv)、2.2g的4-氯苯乙烯(15.7mmol，1.2equiv)和15ml 1,4-二氧六环装入微波反应管中，氩气保护下于130℃下反应30min，将反应液倒入冰水中，乙酸乙酯萃取，有机相减压浓缩，浓缩物以硅胶柱层析分离得到3.6g 1-14，MS(ESI):m/z＝438.2[M+H]+。
将3.6g 1-14(8.2mmol，1equiv)、0.6g的Pd2(dba)3(0.65mmol，0.08equiv)、1.9gXPhos(4.1mmol，0.5equiv)、1.2g乙酸钾(12.3mmol，1.5equiv)、2.5g的联硼酸频那醇酯(9.9mmol，1.2equiv)和15ml 1,4-二氧六环装入微波反应管中，氩气保护下于130℃下反应30min，将反应液倒入冰水中，乙酸乙酯萃取，有机相减压浓缩，浓缩物以硅胶柱层析分离得到3.7g 1-15，MS(ESI):m/z＝530.4[M+H]+。
将3.7g 1-15(7mmol，1equiv)、3g的NaIO4(14mmol，2equiv)和30ml四氢呋喃水溶液加入100ml圆底烧瓶中，氩气保护下于室温下反应16h，将反应液倒入冰水中，乙酸乙酯萃取，有机相减压浓缩，浓缩物以硅胶柱层析分离得到2.4g 1-16，MS(ESI):m/z＝448.3[M+H]+，1H NMR:400MHz CD3OD δ7.73(s,1H),7.65-7.63(d,2H),7.59-7.56(d,4H),7.39-7.35(d,1H),7.22-7.18(d,1H),4.93(s,1H),4.13-4.06(m,1H),2.40-2.18(m,3H),1.76-1.72(m,1H),1.47(s,6H),1.20(s,6H).
实施例4：化合物1的合成
将0.2g中间体1-10溶于2ml N,N-二甲基甲酰胺中，然后加入0.1g DIPEA，再加入0.29g HATU，冰浴下加入0.19g中间体1-1，将反应液于室温下反应2h，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，萃取，加入约50ml乙酸乙酯，用水洗三次(水的总量约30ml)，有机相再用饱和NaCl溶液洗一次，有机相旋干，拌样，柱层析分离(二氯甲烷：甲醇＝60：1)，真空干燥30分钟，得到微黄色固体0.28g，即化合物1-18。MS(ESI):m/z＝451.14[M+H]+，1H NMR:400MHz CDCl3 δ7.40-7.37(m,5H),6.94(s,1H),6.00-5.96(d,1H),5.20-5.17(t,1H),3.66(s,3H),3.55-3.51(m,1H),3.43-3.39(m,1H),3.35-3.32(m,1H),3.25(s,3H),3.18-3.16(m,1H),2.61-2.58(m,1H),2.34-2.27(m,2H).
将0.6g中间体1-16加入到100ml圆底烧瓶中，然后加入15ml二氯甲烷，冰浴下滴加TFA的DCM溶液(7.5ml DCM和7.5ml TFA)，之后室温搅拌1h，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，将反应液倒入冰水中，NaHCO3中和至中性，乙酸乙酯萃取，然后有机相用饱和NaCl溶液反洗一次，有机相旋干，得到淡黄色固体450mg，即中间体1-19，直接下步反应。
将0.3g中间体1-19加入到50ml圆底烧瓶中，然后加入4ml N,N-二甲基甲酰胺，再加入0.11g DIPEA、0.33g HATU，冰浴下加入0.18g中间体1-2，将反应液于室温反应2小时，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，乙酸乙酯萃取，水洗三次，有机相再用饱和NaCl溶液洗一次，有机相旋干，拌样，柱层析分离(二氯甲烷：甲醇＝40：1)，真空干燥30分钟，得到白色固体164mg，即1-21。MS(ESI):m/z＝505.19[M+H]+，1H NMR:400MHzDMSO δ8.08(s,2H),7.80-7.78(d,2H),7.58-7.53(m,3H),7.44-7.40(d,1H),7.24-7.20(d,2H),5.10-5.06(t,1H),4.73-4.70(t,1H),3.55(s,3H),2.33(m,2H),1.86(m,2H),1.44(m,2H),1.35(s,3H),1.28-1.23(m,3H),0.87-0.86(d,3H),0.74-0.73(d,2H).
将49mg 1-18、60mg 1-21、4mg PdCl2(dppf)、15mg KOAc和2ml 1,4-dioxane放入微波反应管中，氮气保护，135℃微波反应30min，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，乙酸乙酯萃取，水洗三次，有机相再用饱和NaCl溶液洗一次，有机相旋干，拌样，柱层析分离(二氯甲烷：甲醇＝20：1)，得到褐色固体23mg，即化合物1。MS(ESI):m/z＝829.24[M-H]-，1H NMR:400MHz CDCl3 δ7.69-7.67(m,3H),7.55-7.39(m,9H),7.26-7.05(t,3H),5.97-5.93(d,1H),5.41-5.35(m,3H),4.68(s,1H),4.27-4.22(m,1H),3.81(s,1H),3.71-3.56(m,6H),3.42-3.37(m,1H),3.26-3.23(m,5H),2.43-1.99(m,8H),1.27-1.26(d,3H),1.18-1.16(d,1H),1.10-1.04(dd,2H),0.99-0.97(d,2H),0.82-0.80(d,2H).
实施例5：化合物2的合成
将0.2g中间体1-10溶于2ml N,N-二甲基甲酰胺中，然后加入0.1g DIPEA，再加入0.29g HATU，冰浴下加入0.16g中间体1-2，将反应液于室温下反应2h，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，乙酸乙酯萃取，用水洗三次，有机相再用饱和NaCl溶液洗一次，有机相旋干，拌样，柱层析分离(二氯甲烷：甲醇＝60：1)，真空干燥30分钟，得到微黄色固体0.26g，即化合物1-17。MS(ESI):m/z＝417.15[M+H]+，1H NMR:400MHz CDCl3 δ6.92(s,1H),4.39-4.35(m,1H),4.07-4.06(d,1H),3.75-3.68(m,1H),3.67(s,3H),3.56-3.52(m,1H),3.34(s,3H),3.29-3.24(m,1H),3.20-3.15(m,1H).
将0.6g中间体1-16加入到100ml圆底烧瓶中，然后加入15ml二氯甲烷，冰浴下滴加TFA的DCM溶液(7.5ml DCM和7.5ml TFA)，之后室温搅拌1h，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，将反应液倒入冰水中，NaHCO3中和至中性，乙酸乙酯萃取，然后有机相用饱和NaCl溶液反洗一次，有机相旋干，得到淡黄色固体450mg，即中间体1-19，直接下步反应。
将0.15g中间体1-19加入到25ml圆底烧瓶中，然后加入2ml N,N-二甲基甲酰胺，再加入56mg DIPEA、0.16g HATU，冰浴下加入0.1g中间体1-1，将反应液于室温反应2h，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，乙酸乙酯萃取，水洗三次，有机相再用饱和NaCl溶液洗一次，有机相旋干，拌样，柱层析分离(二氯甲烷：甲醇＝40：1)，真空干燥30分钟，得到白色固体120mg，即1-20。MS(ESI):m/z＝539.30[M+H]+，1H NMR:400MHz DMSO δ12.26(s,1H),8.21(s,1H),8.04(s,2H),7.86-7.79(m,2H),7.58-7.44(m,3H),7.41-7.36(m,5H),7.23-7.19(d,1H),6.97-6.93(d,1H),5.58-5.54(t,1H),4.17-4.02(m,1H),3.62-3.57(m,1H),3.53(s,3H),3.15-3.12(m,1H),2.34-2.27(m,2H),1.82-1.74(m,1H),1.47-1.45(d,2H),1.27-1.24(t,3H).
将42mg 1-17、60mg 1-20、4mg PdCl2(dppf)、14mg KOAc和2ml 1,4-dioxane放入微波反应管中，氮气保护，135℃微波反应30min，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，乙酸乙酯萃取，水洗三次，有机相再用饱和NaCl溶液洗一次，有机相旋干，柱层析分离(二氯甲烷：甲醇＝20：1)，得到深棕色固体20mg，即化合物2。MS(ESI):m/z＝829.51[M-H]-，1H NMR:400MHz CDCl3 δ7.64-7.61(m,2H),7.55-7.49(m,3H),7.44-7.39(m,6H),7.37-7.35(d,2H),7.25-7.21(d,1H),7.14-7.10(d,1H),5.92-5.90(d,1H),5.50-5.42(m,3H),4.11-4.07(m,2H),3.72(s,5H),3.27-3.22(m,1H),2.99(s,1H),2.48(s,1H),2.11-2.05(m,1H),1.84-1.43(m,9H),1.33-1.32(d,4H),1.25(s,4H).
实施例6：化合物3的合成
将38mg 1-18、50mg 1-20、3mg PdCl2(dppf)、12mg KOAc和2ml 1,4-dioxane放入微波反应管中，氮气保护，135℃微波反应30min，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，乙酸乙酯萃取，水洗三次，有机相再用饱和NaCl溶液洗一次，有机相旋干，柱层析分离(二氯甲烷：甲醇＝20：1)，得到深褐色固体20mg，即化合物3。MS(ESI):m/z＝863.45[M-H]-，1H NMR:400MHz CDCl3 δ7.71-7.69(m,2H),7.56-7.52(m,2H),7.48-7.40(m,10H),7.25-7.05(m,2H),5.99-5.92(m,1H),5.52-5.39(m,3H),4.06(s,1H),3.70-3.63(m,5H),3.57-3.53(m,2H),3.38(m,1H),3.24(m,4H),3.02(s,1H),2.64-2.40(m,4H),1.83(s,2H),1.33-1.31(d,2H),1.28-1.22(m,5H),0.88-0.86(d,1H).
实施例7：化合物4的合成
将38mg 1-17、50mg 1-21、3mg PdCl2(dppf)、12mg KOAc和2ml 1,4-dioxane放入微波反应管中，氮气保护，135℃微波反应30min，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，乙酸乙酯萃取，水洗三次，有机相再用饱和NaCl溶液洗一次，有机相旋干，柱层析分离(二氯甲烷：甲醇＝20：1)，得到棕色固体16mg，即化合物4。(MS：GQQ-19-1212，1H-NMR：GQQ-19-2)。MS(ESI):m/z＝795.16[M-H]-，1H NMR:400MHz CDCl3 δ10.67(s,1H),7.70-7.30(m,6H),7.14-7.12(m,1H),7.02-6.97(m,1H),6.92(d,1H),6.85-6.83(d,1H),5.43-5.35(m,2H),5.17-5.13(t,1H),5.02-4.92(m,2H),4.39-4.35(m,1H),4.06-4.04(m,1H),3.69(s,3H),3.56-3.52(m,1H),3.41-3.36(m,6H),3.28-3.23(m,2H),2.78-2.70(m,1H),2.61-2.56(m,2H),2.43-2.37(m,2H),2.07-1.87(m,5H),1.43(s,6H),1.33(s,3H),0.78-0.76(d,3H).
实施例8：化合物对Huh-7细胞和HCV-1a及1b抑制实验
方法过程：
(1)实验方案
应用HCV GT1b和GT1a稳定转染复制子细胞检测化合物对HCV GT1b和GT1a的抑制活性。
(2)方法与操作
(1)对化合物进行3倍系列稀释8个浓度点，双复孔，加入96孔板中。
(2)设置DMSO为无加化合物对照。
(3)将HCV GT1b或GT1a细胞悬浮在含10％FBS的培养液中。
(4)将培养液种到含有化合物的96孔板中。
(5)细胞在5％CO2、37℃条件下培养3天。
(6)然后用CellTiter-Fluor(Promega)测定化合物对HCV GT1b复制子细胞毒性。
(7)用Bright-Glo(Promega)检测荧光素酶测定化合物抗HCV GT1b和GT1a复制子活性。
(8)采用GraphPad Prism软件分析数据并计算EC50和CC50值。
表1所选化合物对对复制子GT1a的抑制活性
表2所选化合物对对复制子GT12的抑制活性
Claims (7)
1.苯并咪唑衍生物或其药学上可接受的盐，选自以下化合物：
2.根据权利要求1所述的苯并咪唑衍生物或其药学上可接受的盐，其中，所述药学上可接受的盐，为苯并咪唑衍生物与下列酸形成的盐：盐酸、对甲苯磺酸、酒石酸、马来酸、乳酸、甲磺酸、硫酸、磷酸、柠檬酸、乙酸或三氟乙酸。
3.根据权利要求2所述的苯并咪唑衍生物或其药学上可接受的盐，其中，所述药学上可接受的盐，为苯并咪唑衍生物与下列酸形成的盐：对甲苯磺酸、盐酸、酒石酸或三氟乙酸。
4.权利要求1所述的苯并咪唑衍生物或其药学上可接受的盐在制备抗HCV药物中的应用。
5.含有权利要求1所述的苯并咪唑衍生物或其药学上可接受的盐的药物组合物。
6.根据权利要求5所述的药物组合物，是单位剂量的药物制剂形式，在制成药物制剂时可以制成任何可药用的剂型。
7.根据权利要求6所述的药物组合物，所述剂型为片剂或胶囊剂。
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| CN102858157A (zh) * | 2010-03-04 | 2013-01-02 | 埃南塔制药公司 | 作为hcv复制的抑制剂的组合药物活性剂 |
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| CN102858157A (zh) * | 2010-03-04 | 2013-01-02 | 埃南塔制药公司 | 作为hcv复制的抑制剂的组合药物活性剂 |
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