CN105384696A - 多取代1,6-二氢嘧啶类化合物、其合成方法及用途 - Google Patents
多取代1,6-二氢嘧啶类化合物、其合成方法及用途 Download PDFInfo
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- C07D239/56—One oxygen atom and one sulfur atom
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Abstract
多取代1,6-二氢嘧啶类化合物、其合成方法及用途,属药物技术领域。产品为一种2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(取代苯基)乙酰胺类化合物,结构通式:其中,R2为3’,5’-2Me、2’,4’-2F、2’-CF3、3’,5’-2F、2’-F’、4’-F、2’,5’-2Cl、4’-Br、2’-Br、4’-CF3、PhCONHSO2-、4’-OMe、3’,4’-2OMe、4-SO2NH2、3’-CF3-4’-Cl。同时公开了产品的制备方法。产品用途是作为制备抗丙型肝炎病毒药物的活性成分候选物。产品合成便利,对HCV病毒具有明显的抑制作用。
Description
技术领域
本发明属药物技术领域,具体涉及2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(取代苯基)乙酰胺类化合物、其合成方法及用途。
背景技术
丙型肝炎病毒(HepatitisCVirus,HCV)是于1989年由Choo等首次成功克隆非肠道传播的非甲非乙型肝炎病。研究表明HCV是引起慢性肝炎的主要病原体之一,一般为血液传播。丙型肝炎是继乙型肝炎、艾滋病之后又一引起全球关注的重要传染病。全球有1.2~1.8亿人为HCV感染者,占总人口的2~3%,且每年有300万~400万新增病例,70%~90%成为慢性感染,约30%发展为进展性肝病,包括肝硬化或肝癌。我国普通人群中的HCV感染率为2.5-4.9%,估计感染人数超过4000万人。
由于HCV病毒自身的生物学特征,目前临床上尚无有效疫苗来预防。国内治疗慢性丙型肝炎(CHC)主要采用干扰素类药物与广谱抗病毒药物利巴韦林联合治疗的策略,但该疗法有一定的毒副作用,抗病毒疗效受到基因型、病毒载量等多种因素的影响,治疗有效率不到50%。直接抗病毒药物(DAA)的出现为慢性丙型肝炎的治疗提供了更多选择。但DAA的临床使用经验有限,一些问题如对药物的耐受性、联合使用及耐药、价格昂贵等使其不能立即广泛应用于临床。目前已发现的DAA靶点主要有内源性核糖体进入位点(IRES)、结构蛋白(E1、E2)和非结构蛋白NS2、NS3、NS5A和NS5B等。其中,NS5B蛋白是基因编码的RNA依赖性RNA聚合酶(RdRp),其对HCV病毒的复制起关键性作用,未被HCV感染的细胞不会表达NS5B,因此NS5B抑制剂在阻断HCV复制的同时不会带来其他毒副作用,是目前抗HCV药物研究的重要靶点。
本专利申请的发明人长期从事抗病毒药物的研发,前期工作在非核苷类HIV逆转录酶抑制剂(NNRTIs)的研究中,采用计算辅助药物设计的方法,设计合成了系列结构新颖的5-烷基-2-[2-羟基-2-取代苯乙基硫]-6-取代苄基/环己甲基-3H-嘧啶-4-酮类化合物(ZL201110358811.5)。这些化合物具有较好的抗HIV活性,其中有的还可抑制HCV病毒的复制,但对于抗HCV病毒,还需在此基础上进一步研究开发出活性更显著的化合物。
发明内容
本发明旨在提供一种2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(取代苯基)乙酰胺类化合物,其抗HCV病毒的活性优于ZL201110358811.5公布的化合物。本发明的目的还在于获得所述化合物的制备方法及其用途。
本发明产品为一种2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(取代苯基)乙酰胺类化合物,结构通式如下:
其中:R2为:3’,5’-2Me、2’,4’-2F、2’-CF3、3’,5’-2F、2’-F’、4’-F、2’,5’-2Cl、4’-Br、2’-Br、4’-CF3、PhCONHSO2-、4’-OMe、3’,4’-2OMe、4-SO2NH2、3’-CF3-4’-Cl。
本发明产品的制备方法为:以6-环己基-5-乙基-2-硫基-2,3-二氢嘧啶-4(1H)-酮为原料,在溶剂A中与各2-溴代取代苯乙酰胺经N-氮烷基化反应制备目标化合物,其中以6-环己基-5-乙基-2-硫基-2,3-二氢嘧啶-4(1H)-酮与各2-溴代取代苯乙酰胺的摩尔比为1:1~1.5,反应溶剂A为吡啶、DMF、二氯甲烷其中的一种或它们的混合物,反应温度为25~80℃,反应时间为5~12小时。
换言之,本发明产品的制备方法是从环己基甲酸和乙基丙二酸二乙酯出发,经缩合、关环、烷基化反应制得2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(取代苯基)乙酰胺类化合物,其反应式如下所示:
试剂与反应条件:(a)CDI,CH3CN,rt,1h;(b)KOH,EtOH,rt,12h;(c)(i)MgCl2,Et3N,CH3CN,室温过夜,回流6h;(ii)13%HCl;(d)硫脲,EtONa,EtOH,回流5-7h;(e)R2PhNHCOCH2Br,K2CO3,溶剂A;
其反应式中:1为环己基甲酸,2为乙基丙二酸二乙酯,3为2-环己甲酰丁酸乙酯,4为6-环己基-5-乙基-2-硫基-2,3-二氢嘧啶-4(1H)-酮,5为2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(取代苯基)乙酰胺;
R2为:3’,5’-2Me、2’,4’-2F、2’-CF3、3’,5’-2F、2’-F’、4’-F、2’,5’-2Cl、4’-Br、2’-Br、4’-CF3、PhCONHSO2-、4’-OMe、3’,4’-2OMe、4-SO2NH2、3’-CF3-4’-Cl;
6-环己基-5-乙基-2-硫基-2,3-二氢嘧啶-4(1H)-酮和各2-溴代取代苯乙酰胺反应的摩尔比为1:1~1.5,反应溶剂A为吡啶、DMF、二氯甲烷其中的一种或它们的混合物,反应温度为25~80℃,反应时间为5~12小时。
中间体6-环己基-5-乙基-2-硫基-2,3-二氢嘧啶-4(1H)-酮4的制备是现有技术,例如可参照以下文献的方法制备:HeYan-Pinget.al.Bioorg.Med.Chem.Lett.2011,21:694-697;WuDao-chunetal.Lett.Drug.Des.Discov.2013,10(3):271-276。
所得目标化合物5a-5l,结构见表1。
表1目标化合物5a-5l的结构式
本发明产品的用途是作为制备抗丙型肝炎病毒药物的活性成分候选物,也就是作为不同剂型的抗HCV药物组合物的活性成分。
本发明的有益效果:化合物合成便利;对HCV病毒具有明显的抑制作用,抗HCV病毒的活性不但优于ZL201110358811.5公布的化合物,而且其治疗指数高于现临床药物干扰素α-1b(IFNα-1b)和利巴韦林(Ribavirin);可作为抗HCV药物候选物。
具体实施方式
通过下述实施例将有助于理解本发明,但不能限制本发明的范围。所有目标物的编号与表1相同,所述百分比数均为质量百分比。
实施例1:中间体2-环己甲酰丁酸乙酯(反应式中的3)的制备方法
将0.1mol的乙基丙二酸二乙酯(2)置于150mL无水乙醇中,加入0.1mol的KOH的乙醇溶液,室温搅拌12小时,减压蒸去溶剂,用乙醚或乙酸乙酯洗两次,再次减压蒸去溶剂,制得乙基丙二酸二乙酯单钾盐,直接用于下步反应。
将0.1mol的取代丙二酸二乙酯单钾盐置于150mL无水乙腈中,依次加入0.18mol的无水MgCl2,0.15molEt3N,室温搅拌2个小时;将0.048mol的环己甲酸(1)置于100mL的无水乙腈中,逐批加入0.05mol的N,N-羰基二咪唑,反应一个小时,然后将反应混合液加入乙基丙二酸二乙酯单钾盐、无水MgCl2和Et3N的混合液中,室温搅拌过夜,加热回流3-5小时,TLC追踪至反应完全;冷却反应液,用13%的盐酸调pH值为6左右,分层,取有机层减压蒸去溶剂,水层用乙酸乙酯萃取3次,合并有机层,依次用饱和NaHCO3溶液、饱和NaCl溶液洗涤,无水Na2SO4干燥过夜,减压蒸去溶剂,制得β-酮酸酯(3),可不经纯化直接用于下一步。
实施例2:中间体6-环己基-5-乙基-2-硫基-2,3-二氢嘧啶-4(1H)-酮(反应式中的4)的制备方法
在干燥的反应瓶中,将10g(0.43mol)金属钠分批加入300mL无水乙醇中,待钠溶解冷却后,一次性加入24g(0.315mol)硫脲,然后滴加β-酮酸酯(3)(0.27mol)的乙醇溶液20mL,将混合物加热回流5—7个小时,TLC追踪至β-酮酸酯原料点消失后停止加热,冷却,减压蒸去溶剂,将残余物溶于300mL水中,用浓盐酸调pH值为6左右,有大量白色沉淀产生,抽滤,用水洗涤滤饼,烘干得6-环己基-5-乙基-2-硫基-2,3-二氢嘧啶-4(1H)-酮(4),可不经纯化直接用于下一步目标化合物的合成。
6-环己基-5-乙基-2-硫基-2,3-二氢嘧啶-4(1H)-酮:白色粉末,产率57%。
实施例3:2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(取代苯基)乙酰胺类化合物(反应式中的5)的制备
反应的一般操作:
将6-环己基-5-乙基-2-硫基-2,3-二氢嘧啶-4(1H)-酮(4)0.477g(2mmol)和K2CO30.276g(2mmol)置于反应瓶中,加入溶剂A(吡啶、DMF、二氯甲烷其中的一种或它们的混合物)10mL,于室温下搅拌30min后,加入各2-溴代取代苯乙酰胺2.2mmol,室温搅拌5—12小时,TLC追踪至原料点消失,停止反应,将反应液倾入100mL冰水混合液中,有白色沉淀生成,抽滤,用乙醇重结晶或柱层析得2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(取代苯基)乙酰胺的白色固体纯品。
以6-环己基-5-乙基-2-硫基-2,3-二氢嘧啶-4(1H)-酮(4)出发,按照上述方法操作,与不同的2-溴代取代苯乙酰胺发生烷基化反应,得目标化合物5a-5o,其结构如表1所示,理化常数及光谱数据如下:
2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(3,5-二甲氧基苯基)乙酰胺5a,白色晶体,产率:26%,mp:249.4-249.9℃。1HNMR(DMSO,300MHz),δ(ppm):0.91-0.96(t,3H,J=7.2Hz,CH3),1.14-1.25(m,3H,cyclohexyl),1.36-1.86(m,7H,cyclohexyl),2.32-2.36(q,2H,J1=6.6Hz,J2=7.5Hz,CH2CH3),2.81(s,6H,CH3),3.96(s,2H,SCH2),6.84-6.87(s,1H,Ph),7.49-7.52(d,2H,Ph),10.13(s,1H,NH),12.52(brs,1H,NH);MS(ESI):m/z400.3(M++1).
2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(2,4-二氟苯基)乙酰胺5b,白色晶体,产率:27%,mp:207.1-207.8℃。1HNMR(DMSO,300MHz),δ(ppm):0.89-0.92(t,3H,J=9.9Hz,CH3),1.20-1.57(m,10H,cyclohexyl),2.32-2.39(q,2H,J1=7.2Hz,J2=7.2Hz,CH2CH3),2.51-2.59(m,1H,cyclohexyl),4.08(s,2H,SCH2),7.01-7.08(m,1H,Ph),7.27-7.35(m,1H,Ph),7.93-8.03(m,1H,Ph),10.07(s,1H,NH),12.51(brs,1H,NH);MS(ESI):m/z408.0(M++1).
2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(2-(三氟甲基)苯基)乙酰胺5c,白色晶体,产率:31%,mp:188.2-190.1℃。1HNMR(DMSO,300MHz),δ(ppm):0.92-0.97(t,3H,J=7.2Hz,CH3),1.05-1.29(m,3H,cyclohexyl),1.47-1.64(m,7H,cyclohexyl),2.35-2.38(q,2H,J1=7.2Hz,J2=7.5Hz,CH2CH3),2.61(brs,1H,cyclohexyl),4.08(s,2H,SCH2),7.40-7.42(d,1H,Ph),7.64-7.71(m,3H,Ph),9.67(s,1H,NH),12.52(brs,1H,NH);MS(ESI):m/z439.9(M++1).
2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(3,5-二氟苯基)乙酰胺5d,白色晶体,产率:26%,mp:219.2-219.8℃。1HNMR(DMSO,300MHz),δ(ppm):0.90-0.95(t,3H,J=7.2Hz,CH3),1.16-1.46(m,10H,cyclohexyl),2.30-2.38(q,2H,J1=6.9Hz,J2=7.5Hz,CH2CH3),2.54-2.57(m,1H,cyclohexyl),3.99(s,2H,SCH2),6.84-6.91(t,1H,J=9.3Hz,Ph),7.31-7.33(d,2H,Ph),10.66(s,1H,NH),12.54(brs,1H,NH);MS(ESI):m/z408.0(M++1).
2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(2-氟苯基)乙酰胺5e,白色粉末,产率:32%,mp:198.1-199.2℃。1HNMR(DMSO,300MHz),δ(ppm):0.91-0.96(t,3H,J=7.2Hz,CH3),1.14-1.26(m,3H,cyclohexyl),1.37-1.62(m,7H,cyclohexyl),2.32-2.39(q,2H,J1=7.2Hz,J2=7.5Hz,CH2CH3),4.09(s,2H,SCH2),7.06-7.15(m,2H,Ph),7.23-7.27(m,1H,Ph),8.02-8.08(m,1H,Ph),10.04(s,1H,NH),12.50(brs,1H,NH);MS(ESI):m/z390.1(M++1).
2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(2,5-二氯苯基)乙酰胺5f,白色晶体,产率:31%,mp:191.8-192.6℃。1HNMR(DMSO,300MHz),δ(ppm):0.91-0.97(t,3H,J=7.2Hz,CH3),1.16-1.29(m,3H,cyclohexyl),1.39-1.58(m,7H,cyclohexyl),2.32-2.40(q,2H,J1=7.2Hz,J2=7.5Hz,CH2CH3),2.54-2.60(m,1H,cyclohexyl)3.96(s,2H,SCH2),7.19-7.23(q,1H,J1=2.4Hz,J2=2.7Hz,Ph),7.50-7.53(d,1H,Ph),8.07-8.08(d,1H,Ph),9.76(s,1H,NH),12.54(brs,1H,NH);MS(ESI):m/z440.9(M++1).
N-(4-溴苯基)-2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)乙酰胺5g,白色粉末,产率:32%,mp:236.4-237.6℃。1HNMR(DMSO,300MHz),δ(ppm):0.90-0.95(t,3H,J=6.9Hz,CH3),1.16-1.58(m,10H,cyclohexyl),2.31-2.36(q,2H,J1=6.6Hz,J2=7.5Hz,CH2CH3),3.98(s,2H,SCH2),7.45-7.48(d,2H,Ph),7.57-7.59(d,2H,Ph),10.41(s,1H,NH),12.50(brs,1H,NH);MS(ESI):m/z451.1(M++1).
N-(2-溴苯基)-2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)乙酰胺5h,白色粉末,产率:33%,mp:186.2-187.8℃。1HNMR(CDCl3,300MHz),δ(ppm):.91-0.96(t,3H,J=7.2Hz,CH3),1.02-1.29(m,3H,cyclohexyl),1.40-1.54(m,7H,cyclohexyl),2.32-2.39(q,2H,J1=6.9Hz,J2=7.5Hz,CH2CH3),2.48-2.58(m,1H,cyclohexyl),4.07(s,2H,SCH2),7.05-7.10(t,1H,J=7.2Hz,Ph),7.31-7.36(t,1H,J=7.5Hz,Ph),7.60-7.63(d,1H,Ph),7.79-7.81(d,1H,Ph),9.48(s,1H,NH),12.52(brs,1H,NH);MS(ESI):m/z451.0(M++1).
2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(4-(三氟甲基)苯基)乙酰胺5i,白色粉末,产率:36%,mp:217.4-218.5℃。1HNMR(DMSO,300MHz),δ(ppm):0.88-0.93(t,3H,J=6.9Hz,CH3),1.12-1.20(m,3H,cyclohexyl),1.30-1.53(m,7H,cyclohexyl),2.31-2.33(q,2H,J1=6.9Hz,J2=7.2Hz,CH2CH3),2.56-2.59(m,1H,cyclohexyl),3.97(s,2H,SCH2),7.26-7.29(d,2H,Ph),7.68-7.71(d,2H,Ph),10.46(s,1H,NH),12.51(s,1H,NH);MS(ESI):m/z440.2(M++1).
N-((4-(2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)乙酰基)苯基)磺酰基)苯甲酰胺5j,白色粉末,产率:19%,mp:210.2-211.3℃。1HNMR(DMSO,300MHz),δ(ppm):0.90-0.94(t,3H,J=7.4Hz,CH3),1.04-1.14(m,3H,cyclohexyl),1.56-1.21(m,7H,cyclohexyl),2.29-2.36(q,2H,J1=7.2Hz,J2=7.4Hz,CH2CH3),2.46(s,1H,cyclohexyl),4.65(s,2H,SCH2),7.08-7.11(d,2H,Ph),7.46-7.59(m,3H,Ph),7.85-7.93(m,2H,Ph),8.05-8.08(d,2H,Ph),12.53(brs,1H,NH);MS(ESI):m/z540.4(M++1).
2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(4-甲氧基苯基)乙酰胺5k,白色粉末,产率:31%,mp:233.4-234.2℃。1HNMR(DMSO,300MHz),δ(ppm):0.91-0.96(t,3H,J=7.2Hz,CH3),1.14-1.25(m,2H,cyclohexyl),1.36-1.86(m,8H,cyclohexyl),2.32-2.36(q,2H,J1=6.6Hz,J2=7.5Hz,CH2CH3),3.69(s,3H,OCH3),3.96(s,2H,SCH2),6.84-6.87(d,2H,Ph),7.49-7.52(d,2H,Ph),10.13(s,1H,NH),12.52(brs,1H,NH);MS(ESI):m/z402.3(M++1).
N-(4-氯-3-(三氟甲基)苯基)-2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)乙酰胺5l,白色粉末,产率:33%,mp:189.7-190.8℃。1HNMR(DMSO,300MHz),δ(ppm):1.08-1.13(t,3H,J=7.2Hz,CH3),1.17-1.35(m,3H,cyclohexyl),1.66-1.98(m,7H,cyclohexyl),2.51-2.56(q,2H,J1=6.6Hz,J2=7.5Hz,CH2CH3),2.75-2.87(m,1H,cyclohexyl),4.06(s,2H,SCH2),7.36(s,1H,Ph),7.40-7.43(d,1H,Ph),7.76-7.79(d,1H,Ph),7.91(s,1H,NH),9.52(s,1H,NH);MS(ESI):m/z474(M++1).
2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(4-磺酰胺苯基)乙酰胺5m,白色粉末,产率:32%,mp:204.6-205.5℃。1HNMR(DMSO,300MHz),δ(ppm):0.94(t,3H,J=6.8Hz,CH3),1.16-1.55(m,10H,cyclohexyl),2.35(q,2H,J=7.0Hz,CH2CH3),4.04(s,2H,SCH2),7.24(s,2H,NH2),7.76(s,4H,Ph),10.61(s,1H,NH),12.51(brs,1H,NH);MS(ESI):m/z451.2(M++1).
2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(3,4-二甲氧基苯基)乙酰胺5n:白色粉末,产率:24%,mp:209.3-209.8℃。1HNMR(DMSO,300MHz),δ(ppm):0.94(d,3H,J=6.6Hz,CH3),1.18-1.86(m,10H,cyclohexyl),2.35(d,2H,J=6.6Hz,CH2CH3),2.57(s,1H,cyclohexyl),3.69(s,6H,OCH3),3.96(s,2H,SCH2),6.87(d,1H,J=8.4Hz,Ph),7.10(d,1H,J=8.1Hz,Ph),7.31(s,1H,Ph),10.12(s,1H,NH),12.52(brs,1H,NH);m/z432.2(M++1).
2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(4-氟苯基)乙酰胺5o:白色粉末,产率:34%,mp:231.1-232.4℃。1HNMR(DMSO,300MHz),δ(ppm):0.92(t,3H,J=6.9Hz,CH3),1.15-1.60(m,10H,cyclohexyl),2.34(q,2H,J=7.2Hz,CH2CH3),2.53(s,1H,cyclohexyl),3.97(s,2H,SCH2),7.12(t,2H,J=8.7Hz,Ph),7.60-7.64(m,2H,Ph),10.35(s,1H,NH),12.51(brs,1H,NH);m/z390.2(M++1).
实施例4:体外抗HCV活性实验
采用人肝癌细胞株Huh7.5.1进行体外细胞水平抗HCV活性评价。方法描述如下:
MTT法检测药物细胞毒性:取对数生长期的Huh7.5.1细胞,以9×103cells/well细胞铺于96孔板,贴壁5小时后,加入2μLDMSO梯度稀释药物,5倍稀释,5个稀释度,每个梯度设有三个重复孔,同时设置空白对照(只含培养基)、细胞对照、药物颜色对照、DMSO对照及抗HCV阳性药物利巴韦林对照,终体积200μL/well。将培养板置于37℃、5%CO2培养箱进行培养。第三天于实验孔加入20μL的5mg/mLMTT溶液,37℃、5%CO2孵育4小时。弃去上清,加入150μL/well的DMSO,振荡溶解10分钟后,于酶标仪上测定OD490的值,并以GraphadPrism5.0计算药物IC50(IC50:半数抑制浓度,将细胞生长抑制50%所需的浓度)的值。计算公式:细胞生长抑制率(%)=(1–试验孔OD值/对照孔OD值)×100%。
HCV复制抑制试验:取对数生长期的Huh7.5.1细胞,以9×103cells/well细胞铺于96孔板,贴壁5小时后,加入2μLDMSO梯度稀释药物,5倍稀释,5个稀释度,每个梯度设有三个重复孔,同时加入病毒,设细胞对照、病毒对照、抗HCV阳性对照(IFNα-1b及利巴韦林)、DMSO对照,终体积200μL/well。将培养板置于37℃、5%CO2培养箱进行培养,3天后收集上清3000rpm/min离心10min,取澄清上清进行RNA载量检测。以GraphadPrism5.0计算HCV复制抑制率及EC50(EC50:半数效应浓度,引起受试对象50%个体产生一种特定效应的药物剂量)。计算公式:HCV复制抑制率(%)=(1–试验孔HCVRNA载量/对照孔HCVRNA载量)×100%
抗HCV药效评价:治疗指数(Therapeuticindex,TI)为药物对细胞的半数抑制浓度IC50和对病毒的半数效应浓度的比值,代表药物的安全性,此数值越大越安全。
以抗HCV临床治疗药物Ribavirin和IFNα-1b(IU/ml)作为阳性对照。按上述方法对合成的化合物(5a-o)进行了药物细胞毒性和抗HCV病毒活性筛选,具体测试数据(IC50、EC50及TI值)参见表2,从表中可见,所测化合物中有11个化合物治疗指数高于Ribavirin,其中5a、5b、5d、5e等四个化合物的治疗指数比Ribavirin高59-198倍,可作为抗HCV的候选物进一步研究开发。
表2化合物5a-l的EC50、IC50及TI值
Claims (3)
1.多取代6-二氢嘧啶类化合物,其特征在于为2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(取代苯基)乙酰胺类化合物,结构通式为:
其中:R2为:3’,5’-2Me、2’,4’-2F、2’-CF3、3’,5’-2F、2’-F’、4’-F、2’,5’-2Cl、4’-Br、2’-Br、4’-CF3、PhCONHSO2-、4’-OMe、3’,4’-2OMe、4-SO2NH2、3’-CF3-4’-Cl。
2.如权利要求1所述的2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(取代苯基)乙酰胺类化合物的制备方法,其特征在于:以6-环己基-5-乙基-2-硫基-2,3-二氢嘧啶-4(1H)-酮为原料,在溶剂A中与各2-溴代取代苯乙酰胺经N-氮烷基化反应制备目标化合物,其中以6-环己基-5-乙基-2-硫基-2,3-二氢嘧啶-4(1H)-酮与各2-溴代取代苯乙酰胺的摩尔比为1:1~1.5,反应溶剂A为吡啶、DMF、二氯甲烷其中的一种或它们的混合物,反应温度为25~80℃,反应时间为5~12小时。
3.如权利要求1所述的2-((4-环己基-5-乙基-6-羰基-1,6-二氢嘧啶)-2-巯基)-N-(取代苯基)乙酰胺类化合物的用途,其特征在于作为制备抗丙型肝炎病毒药物的活性成分候选物。
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