CN117700396A - 含吡啶-苯环结构的杂芳基嘧啶类衍生物及其制备方法和用途 - Google Patents
含吡啶-苯环结构的杂芳基嘧啶类衍生物及其制备方法和用途 Download PDFInfo
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Abstract
本发明属于医药技术领域，具体为含吡啶‑苯环结构的杂芳基嘧啶类衍生物及其制备方法和用途。本发明化合物结构为为含吡啶‑苯环结构的杂芳基嘧啶类衍生物，还包含其药用盐、水合物及溶剂化物，其多晶或共晶，其同样生物功能的前体和衍生物；该化合物或其组合物可用于制备预防或治疗艾滋病等相关药物。体外细胞水平抗HIV‑1活性实验结果显示，该类小分子具有较强的抗HIV‑1生物活性，显著抑制被HIV‑1病毒感染的MT‑4细胞内的病毒复制，并且具有较低细胞毒性。
Description
技术领域
本发明属于医药技术领域，具体涉及含吡啶-苯环结构的5位芳杂环取代的嘧啶衍生物化合物及其制备方法和用途。
背景技术
艾滋病目前仍是全球性的危害人类生命卫生健康的重大传染性疾病。其具有窗口期长、致死率高、一旦患病无法根治等特点，一直受到广泛的研究和持续关注。
HIV攻击人体T淋巴细胞，破坏细胞免疫和体液免疫过程，从而使免疫系统失去功能。HIV病毒的生命周期可以概括为：(1)与宿主T淋巴细胞吸附并逐步融合，将基因组RNA释放到宿主细胞内；(2)通过逆转录将遗传物质形成DNA并将其整合到宿主的基因组中；(3)借助宿主细胞内的酶和物质进行转录和翻译，合成出病毒所需的基因组和蛋白；(4)在宿主内完成组装，释放到宿主细胞外。这些病毒继续侵染新的宿主细胞，从而破坏宿主免疫系统。HIV-1逆转录酶在艾滋病毒生命周期中发挥着重要的作用，具有三大功能：(1)依赖RNA的DNA聚合功能；(2)依赖DNA的DNA聚合功能；(3)RNA水解即RNase H活性，是HIV-1抑制剂研发中的重要靶点之一。RT抑制剂可分为核苷类逆转录酶抑制剂(NRTIs)以及非核苷类逆转录酶抑制剂(NNRTIs)。核苷类逆转录酶抑制剂与底物竞争性的作用于RT活性位点，具有选择性差，毒性高等缺点。非核苷类逆转录酶抑制剂则是以非竞争性的方式结合于距逆转录酶活性位点约距离的变构结合口袋，即非核苷类逆转录酶抑制剂结合口袋(NNIBP)。NNRTIs具有选择型高，活性高等特点，目前临床上使用的NNRTIs主要是第二代抑制剂：二芳基嘧啶类化合物，利匹韦林(Rilpivirine,RPV)和依曲韦林(Etravirine,ETR)。然而，较差的水溶性(ETR,<<1μg/mL；RPV,20 ng/ml)，低的病人响应率(ETR,36.5％；RPV,27.3％)，以及在长期服用中产生的毒副作用限制了他们在临床上的使用。此外，耐药病毒株的产生大大降低了药物的疗效。因此开发具有广谱抗耐药性的新型高效非核苷类逆转录酶抑制剂成为药物化学家们研究的热点之一。
本发明旨在对RPV及ETR进行结构优化，通过引入芳杂环来增强化合物与周围氨基酸的相互作用，提高化合物对抗耐药病毒株的生物活性，同时改善其成药性。
发明内容
本发明的目的在于提供一种具有较强抗HIV-1生物活性，可以显著抑制被HIV-1病毒感染的MT-4细胞内的病毒复制，并且具有较低的细胞毒性的含吡啶-苯环结构的5位芳杂环取代的嘧啶衍生物及其制备方法和用途。
本发明提供的吡啶-苯环结构的5位芳杂环取代的嘧啶衍生物，其结构式为如下(Ⅰ)或(Ⅱ)所示：
其中，R选自但不限于取代或未取代的吡啶基、呋喃基、吡咯基、噻吩基、吡唑基。
本发明化合物中，在嘧啶母核5位碳上引入芳杂环，目的是通过增加化合物与周围氨基酸(特别是I180)的氢键或极性相互作用来提高目标化合物的抗病毒活性。同时，左翼上联芳基结构能深入结合口袋加强与高度保守氨基酸残基Phe227，Trp229之间的结合力，进一步提高目标化合物抗耐药病毒株的生物活性。
该类化合物为HIV-1非核苷类逆转录酶抑制剂(NNRTIs)，不仅具有较强的生物活性，还具有较小的细胞毒性和较高的选择系数。
本发明化合物，还包括衍生物的可药用盐、立体化学异构体、水合物或溶剂化物。
本发明中，所述可药用盐为盐酸盐、氢溴酸盐、甲酸盐、甲磺酸盐、三氟甲磺酸盐、硫酸盐、磷酸盐、醋酸盐、对甲苯磺酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、马来酸盐、富马酸盐或苹果酸盐。
本发明提供上述含吡啶-苯环结构的5位芳杂环取代的嘧啶衍生物化合物的制备方法，具体步骤如下：
以5-碘代嘧啶类衍生物Ⅲa或Ⅲb为原料与相应的芳香杂环反应得到化合物I或Ⅱ，其反应通式如下：
其中：
所述溶剂为二氧六环，丙酮、乙腈、四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺，乙醇，异丙醇，正丁醇，异丁醇中的一种或者多种与水的混合溶剂，体积比为1:1～10:1；
所述碱选自碳酸钠，碳酸钾，氢氧化钠，磷酸钾，LDA，LiHMDS，NaHMDS；
所述催化剂选自：Pd(dppf)Cl2，Pd(PPh4)3，Pd2(dba)3，PdCl2，Pd(OAc)2，Pd(dba)2；
所述的原料化合物IIIa或化合物IIIb与相应的芳杂环硼酸、催化剂、碱的摩尔比为1:(1.0～2.0):(0.005～0.2):(1～5)，最优摩尔比例为1:1.2:0.1:2；
反应温度为50～180℃；优选反应温度为100～120℃；
反应时间为2～24h，优选反应时间为16h。
本发明还提供一种药物组合物，该组合物含有有效剂量的上述化合物和相关的药用载体。
本发明还提供所述化合物或组合物在制备预防和治疗艾滋病药物中的应用。
本发明基于嘧啶类化合物与HIV逆转录酶的结合模式，结合计算机辅助药物设计，在嘧啶母核5位碳上引入芳杂环，目的是通过增加化合物与周围氨基酸(特别是I180)的氢键或极性相互作用来提高目标化合物的抗病毒活性。同时，左翼上联芳基结构能深入结合口袋加强与高度保守氨基酸残基Phe227，Trp229之间的结合力，进一步提高目标化合物抗耐药病毒株的生物活性。实验结果显示，该系列化合物具有较显著的抗HIV-1活性，并且具有较低的细胞毒性和较高的选择性。
具体实施方式
通过下述实施实例可以更好地理解本发明内容，但是不能限制本发明的内容。
实施例1：终产物Ⅰa的合成
将化合物Ⅲa(1mmol)，2-呋喃硼酸(1.3mmol)，碳酸铯(2mmol)加入到二氧六环(12mL)与水(3mL)的混合溶剂中搅拌10min后加入Pd(dppf)Cl2(0.1mmol)。将混合物脱气3次并置换氮气保护。反应液于120℃下搅拌6h。TLC监测示原料消耗完全。将反应液浓缩后硅胶柱层析(乙酸乙酯：石油醚(5％～100％)为洗脱剂)得到化合物Ⅰa。
收率:89％,黄色固体,mp:264.9-266.4℃.1H NMR(400MHz,DMSO-d6):δ10.00(s,1H),9.14-8.63(m,2H),8.60(s,1H),8.49(s,1H),8.06-7.89(m,2H),7.88-7.81(m,2H),7.81(s,1H),7.61-7.59(m,2H),7.37-7.35(m,2H),6.89(d,J＝4Hz,1H),6.67(d,J＝4Hz,1H).13C NMR(100MHz,DMSO-d6):δ159.74(dd,J1＝247Hz,J2＝6Hz),158.24,157.71,155.71,150.86,148.46,145.20,144.74,143.23,137.84(t,J＝9Hz),132.91,121.92,119.85,118.65,117.64(t,J＝17Hz),112.17,110.85(dd,J1＝18Hz,J2＝8Hz),107.47,102.97,102.56.19F NMR(376MHz,DMSO-d6):δ-116.26.HRMS calcd for C26H16F2N6O[M+Na]+:489.1246,found 489.1245.HPLC analysis:retention time＝10.68min；peak area,98.34％(λ＝254nm)。
实施例2：终产物Ⅰb的合成
操作同实施例1
黄色固体,收率:83％,mp:251.3-252.4℃.1H NMR(400MHz,DMSO-d6):δ9.88(s,1H),8.72-8.71(m,2H),8.45(s,1H),8.21(s,1H),7.89-7.88(m,2H),7.84-7.82(m,2H),7.74-7.73(m,2H),7.66-7.64(m,2H),7.40-7.38(m,3H).13C NMR(100MHz,DMSO-d6):δ159.73(dd,J1＝246Hz,J2＝6Hz),159.35,158.28,156.94,150.95,145.54,144.79,137.52(t,J＝9Hz),134.59,132.94,128.42,127.55,124.05,121.57,119.97,118.45,117.93(t,J＝17Hz),110.82(dd,J1＝19Hz,J2＝6Hz),108.19,102.21.19F NMR(376MHz,DMSO-d6):δ-116.34.
HRMS calcd for C26H16F2N6S[M+H]+:483.1198,found 483.1194.HPLC analysis:retention time＝10.56min；peak area,99.42％(λ＝254nm)。
实施例3：终产物Ⅰc的合成
操作同实施例1
收率:85％,黄色固体,mp:281.5-283.1℃.1H NMR(400MHz,DMSO-d6):δ9.95(s,1H),8.75-8.70(m,3H),8.39(s,1H),8.14-8.10(m,2H),7.88-7.87(m,2H),7.84-7.82(m,2H),7.69-7.67(m,2H),7.43-7.41(m,2H),7.34(d,J＝8Hz,1H).13C NMR(100MHz,DMSO-d6):δ163.07(d,J＝235Hz),159.77,159.49(dd,J1＝246Hz,J2＝5Hz),159.01,157.66,150.93,148.15(d,J＝16Hz),145.42,144.75,143.53(d,J＝8Hz),137.49(t,J＝9Hz),132.98,129.26(d,J＝4Hz),121.56,119.93,118.62,117.56(t,J＝17Hz),111.89(dd,J1＝19Hz,J2＝7Hz),110.30(d,J＝38Hz),108.67,102.47.19F NMR(376MHz,DMSO-d6):δ-70.41,-116.35.HRMS calcd for C27H16F3N7[M+H]+:496.1492,found 496.1496.HPLC analysis:retention time＝9.65min；peak area,98.17％(λ＝254nm)。
实施例4：终产物Ⅰd的合成
操作同实施例1
收率:59％,黄色固体,mp:>300℃.
1H NMR(400MHz,DMSO-d6):δ10.05(s,1H),8.92(s,1H),8.72-8.71(m,2H),8.50(d,J＝4Hz,1H),8.25(s,1H),7.89-7.84(m,4H),7.67-7.58(m,4H),7.41-7.39(m,2H).13C NMR(100MHz,DMSO-d6):δ159.44(dd,J1＝247Hz,J2＝6Hz),159.17,159.11,158.08,151.40,150.95,150.76,146.45,145.15,144.72,137.63(t,J＝9Hz),132.98,124.26,123.52,121.58,119.84,118.79,117.44(t,J＝17Hz),110.95(dd,J1＝19Hz,J2＝6Hz),109.14,102.77.19F NMR(376MHz,DMSO-d6):δ-116.43.HRMS calcd for C27H16ClF2N7[M+Na]+:534.1016,found 534.1018.HPLC analysis:retention time＝10.13min；peak area,94.83％(λ＝254nm)。
实施例5：终产物Ⅱa的合成
将化合物Ⅲb(1mmol)，2-呋喃硼酸(1.1mmol)，碳酸铯(2mmol)加入到二氧六环(12mL)与水(6mL)的混合溶剂中搅拌10min后加入Pd(dppf)Cl2(0.1mmol)。将混合物脱气3次并置换氮气保护。反应液于120℃下搅拌16h。将反应液浓缩后硅胶柱层析(乙酸乙酯：石油醚(5％～100％)为洗脱剂)得到化合物Ⅱa。
收率:78％,黄色固体,mp:282.1-283.7℃.1H NMR(400MHz,DMSO-d6):9.89(s,1H),8.68-8.67(m,2H),8.44-8.42(m,2H),7.81-7.79(m,3H),7.70(s,2H),7.54-7.52(m,2H),7.25-7.23(m,2H),6.93-6.92(d,J＝4Hz,1H),6.67-6.65(m,1H),2.25(s,6H).13C NMR(100MHz,DMSO-d6)δ:158.34,157.76,154.95,150.72,149.00,147.17,145.57,142.87,138.86,137.87,135.80,132.74,126.67,121.63,119.93,118.38,112.13,106.91,102.31,102.04,18.79.HRMS calcd for C28H22N6O[M+H]+:459.1928,found 459.1926.HPLCanalysis:retention time＝11.61min；peak area,99.23％(λ＝254nm)。
实施例6：终产物Ⅱb的合成
操作同实施例5
收率:77％,黄色固体,mp:269.5-271.6℃.
1H NMR(400MHz,DMSO-d6):δ9.82(s,1H),8.67-8.64(m,2H),8.51(s,1H),8.28-8.26(m,1H),8.09(s,1H),7.79-7.77(m,2H),7.66(s,2H),7.53-7.51(m,2H),7.24-7.19(m,3H),7.01(s,1H),3.90(s,3H),2.23(s,6H).13C NMR(100MHz,DMSO-d6):δ164.64,159.23,159.08,156.77,150.72,147.98,147.22,146.16,145.62,138.79,137.81,135.66,132.75,126.67,121.52,119.93,118.42,117.63,110.27,109.52,102.02,53.67,18.84.HRMScalcd for C30H25N7O[M+H]+:500.2193,found 500.2198.HPLC analysis:retention time＝11.43min；peak area,98.97％(λ＝254nm)。
实施例7：终产物Ⅱc的合成
操作同实施例5
收率:35％,黄色固体,mp:>300℃.1H NMR(400MHz,DMSO-d6):δ13.11(s,1H),9.65(s,1H),8.67-8.65(m,2H),8.10-8.07(m,3H),7.87(s,1H),7.80-7.79(m,2H),7.67(s,2H),7.53-7.51(m,2H),7.23-7.21(m,2H),2.23(s,6H).13C NMR(100MHz,DMSO-d6):δ159.47,158.10,155.53,150.74,147.26,145.98,139.20,137.93,135.52,132.72,126.61,121.51,120.05,118.09,113.71,104.22,101.45,18.85.HRMS calcd for C27H22N8[M+H]+:459.2040,found 459.2044.HPLCanalysis:retention time＝9.13min；peak area,99.41％(λ＝254nm)。
实施例8：终产物Ⅱd的合成
操作同实施例5
收率:56％,黄色固体,mp:>300℃.
1H NMR(400MHz,DMSO-d6):δ9.82(s,1H),8.65-8.66(m,2H),8.46(s,1H),8.42(d,J＝1Hz),8.15(dd,J1＝8Hz,J2＝4Hz,1H),8.04(s,1H),7.78-7.77(m,2H),7.65(s,2H),7.60-7.58(m,2H),7.33(dd,J1＝8Hz,J2＝1Hz,1H),7.29-7.27(m,2H),2.24(s,6H).13C NMR(100MHz,DMSO-d6):δ162.99(d,J＝234Hz),159.92,159.18,156.85,150.73,148.07(d,J＝15Hz),147.20,145.79,143.51,143.47(d,J＝8Hz),138.66,137.76,135.64,132.80,129.77(d,J＝5Hz),126.68,121.51,120.00,118.38,110.33(d,J＝38Hz),108.01,101.93,18.88.19F NMR(376MHz,DMSO-d6):δ-70.56.HRMS calcd for C29H22FN7[M+H]+:488.1993,found 488.1993.HPLC analysis:retentiontime＝9.87min；peak area,97.73％(λ＝254nm)。
实施例9：终产物Ⅱe的合成
操作同实施例5
收率:71％,黄色固体,mp:240.7-242.3℃.
1H NMR(400MHz,DMSO-d6):δ9.80(s,1H),8.67-8.65(m,2H),8.45(s,1H),8.41-8.40(m,1H),8.17-8.12(m,1H),8.03(s,1H),7.79-7.77(m,2H),7.66(s,2H),7.59-7.57(m,2H),7.35-7.32(m,1H),,7.28-7.26(m,2H),2.24(s,6H).13C NMR(100MHz,DMSO-d6):δ162.99(d,J＝234Hz),159.93,159.18,156.84,150.70,148.07(d,J＝15Hz),147.23,145.78,143.47(d,J＝9Hz),138.66,137.76,135.63,132.78,129.77(d,J＝5Hz),126.68,121.52,119.97,118.39,110.32(d,J＝38Hz),108.02,101.94,18.86.19F NMR(376MHz,DMSO-d6):δ-70.59.HRMS calcd for C29H22FN7
[M+H]+:488.1993,found 488.1993.HPLC analysis:retention time＝9.88min；peak area,99.40％(λ＝254nm)。
实施例10：终产物Ⅱf的合成
操作同实施例5
收率:77％,黄色固体,mp:277.6-279.5℃.
1H NMR(400MHz,DMSO-d6):δ9.71(s,1H),8.66-8.65(m,2H),8.21(s,1H),8.11(s,1H),7.79-7.78(m,2H),7.74-7.72(m,2H),7.66(s,2H),7.53-7.51(m,2H),7.42(d,J＝4Hz,1H),7.23-7.21(m,2H),2.23(s,6H).13C NMR(100MHz,DMSO-d6):δ159.45,158.37,156.19,150.72,147.26,145.83,139.08,137.91,135.56,135.12,132.73,128.32,127.50,126.63,123.52,121.52,120.01,118.20,107.50,101.66,18.87.HRMS calcd for C28H22N6S[M+H]+:475.1699,found
475.1696.HPLC analysis:retention time＝11.21min；peak area,99.60％(λ＝254nm)。
实施例11：终产物Ⅱg的合成
操作同实施例5
收率:73％,黄色固体,mp:269.1-270.6℃.
1H NMR(400MHz,DMSO-d6):δ9.83(s,1H),8.67-8.65(m,2H),8.53(d,J＝8Hz,1H),8.49(s,1H),8.10(s,1H),7.80-7.78(m,2H),7.67(s,2H),7.54-7.52(m,2H),7.46(s,1H),7.40(d,J＝8Hz,1H),7.24-7.22(m,2H),2.54(s,3H),2.24(s,6H).
13C NMR(100MHz,DMSO-d6):δ159.22,159.06,158.94,156.93,150.75,149.96,147.19,145.65,143.32,138.82,137.84,135.69,132.75,126.69,123.20,121.52,121.02,119.93,118.40,109.61,102.00,24.72,18.89.HRMS calcd for C30H25N7[M+H]+:484.2244,found 484.2243.HPLC analysis:retention time＝10.24min；peak area,99.95％(λ＝254nm)。
实施例12：终产物Ⅱh的合成
操作同实施例5
收率:68％,黄色固体,mp:190.5-192.1℃.
1H NMR(400MHz,DMSO-d6):δ9.77(s,1H),8.66-8.63(m,3H),8.44(s,1H),7.99(s,1H),7.86-7.84(m,1H),7.79-7.77(m,2H),7.65(s,2H),7.57-7.55(m,2H),7.38(d,J＝8Hz,1H),7.26-7.24(m,2H),2.53(s,3H),2.23(s,6H).13C NMR(100MHz,DMSO-d6):δ159.86,158.94,157.27,156.67,150.65,149.16,147.32,145.82,138.89,137.79,137.43,135.53,132.75,128.38,126.66,123.84,121.53,119.98,118.32,109.07,101.81,24.25,18.86.HRMS calcd for C30H25N7
[M+H]+:484.2244,found 484.2243.HPLC analysis:retention time＝9.38min；peak area,97.48％(λ＝254nm)。
实施例13：终产物Ⅱi的合成
操作同实施例5
收率:56％,黄色固体,mp:273.2-274.9℃.
1H NMR(400MHz,DMSO-d6):δ9.84(s,1H),8.71(s,1H),8.66-8.65(m,2H),8.64-8.60(m,2H),8.09-8.08(m,2H),7.79-7.77(m,2H),7.66(s,2H),7.57-7.55(m,2H),7.27-7.25(m,2H),2.24(s,6H).13C NMR(100MHz,DMSO-d6):δ159.67,159.22,157.25,150.73,148.38,147.30,147.18,145.66,138.57,137.72,136.80,135.65,132.98,132.79,131.71,126.69,121.52,119.93,118.44,107.60,102.04,18.87.HRMS calcd for C29H22ClN7[M+H]+:504.1698,found 504.1694.HPLCanalysis:retention time＝10.86min；peak area,97.28％(λ＝254nm)。
实施例14：终产物Ⅱj的合成
操作同实施例5
收率:70％,黄色固体,mp:269.6-271.4℃.
1H NMR(400MHz,DMSO-d6):δ9.72(s,1H),8.66-8.64(m,2H),8.36(s,1H),7.98-7.97(m,1H),7.96(s,1H),7.92-7.91(m,1H),7.78-7.77(m,2H),7.65(s,2H),7.55-7.53(m,2H),7.25-7.22(m,2H),7.10(t,J＝4Hz,1H),5.47(s,2H),2.23(s,6H).13C NMR(100MHz,DMSO-d6):δ159.79,158.82,156.21,150.71,147.27,145.84,145.41,138.99,137.84,137.15,136.01,135.52,132.75,131.14,126.62,121.51,120.56,120.01,118.28,109.66,101.73,18.88.HRMS calcd for C29H24N8
[M+H]+:485.2197,found 485.2202.HPLC analysis:retention time＝8.93min；peak area,97.88％(λ＝254nm)。
实施例15：终产物ⅠⅠk的合成
操作同实施例5
收率:75％,黄色固体,mp:166.6-168.1℃。
1H NMR(400MHz,DMSO-d6):δ9.69(s,1H),8.66-8.65(m,2H),8.25(s,1H),7.93(s,1H),7.78-7.77(m,2H),7.65(s,2H),7.58(s,1H),7,56-7.53(m,2H),7.26-7.24(m,2H),7.07(s,1H),5.10(s,2H),3.92(s,3H),2.24(s,6H).13C NMR(100MHz,DMSO-d6):160.06,158.68,155.86,152.05,150.70,147.30,145.95,139.06,137.84,135.47,133.02,132.75,132.51,126.59,124.96,121.50,120.04,119.88,118.23,109.96,101.62,53.41,18.88.HRMS calcd for C30H26N8O[M+H]+:515.2302,found 515.2308.HPLC analysis:retention time＝9.81min；peak area,98.29％(λ＝254nm)。
实施例16：终产物ⅠⅠl的合成
操作同实施例5
收率:80％,黄色固体,mp:>300℃.
1H NMR(400MHz,DMSO-d6):δ9.66(s,1H),8.66-8.64(m,2H),8.24(s,1H),8.10(d,J＝4Hz,1H),7.91(s,1H),7.78-7.76(m,2H),7.64(s,2H),7.57-7.54(m,3H),7.25-7.23(m,2H),6.60(d,J＝8Hz,1H),6.10(s,2H),2.22(s,6H).13C NMR(100MHz,DMSO-d6):δ160.11,159.69,158.46,155.87,150.72,148.13,147.29,146.00,139.13,138.30,137.82,135.44,132.74,126.59,121.50,120.06,118.79,118.17,110.18,108.66,101.52,18.89.HRMScalcd for C29H24N8[M+H]+:485.2197,found 485.2194.HPLC analysis:retention time＝7.10min；peak area,98.72％(λ＝254nm)。
实施例17：终产物ⅠⅠm的合成
操作同实施例5
收率:42％,黄色固体,mp:234.9-236.1℃.
1H NMR(400MHz,DMSO-d6):δ9.91(s,1H),8.67-8.66(m,3H),8.50(d,J＝4Hz,1H),8.15(s,1H),7.80-7.79(m,2H),7.70(s,1H),7.68(s,2H),7.64(d,J＝4Hz,1H),7.54-7.52(m,2H),7.26-7.23(m,2H),2.24(s,6H).13C NMR(100MHz,DMSO-d6):δ159.31,159.17,157.43,151.42,150.75,147.16,147.01,145.50,138.56,137.73,135.76,132.77,126.74,124.11,123.39,121.52,119.87,118.52,108.37,102.23,18.87.HRMS calcd forC29H22ClN7[M+H]+:504.1698,found504.1691.HPLC analysis:retention time＝10.66min；peak area,98.02％(λ＝254nm)。
抗HIV生物活性测试
比利时Katholleke大学的Rega药物研究所对体外细胞水平上的抗HIV病毒活性进行了测定，主要包括两个方面：对MT-4细胞感染HIV后的抑制活性以及对细胞的毒性。具体方法如下：将化合物加入到MT-4细胞中，在不同时间点感染HIV，并通过MTT法评估药物对HIV诱变引起的细胞损伤的保护作用，并计算出使50％细胞免受HIV诱导损伤所需浓度(EC50)。同时，在与抗HIV活性实验并行进行的毒性测试中，使用MTT法确定使50％未感染细胞发生损伤所需浓度(CC50)，并计算选择性指数SI＝EC50/CC50。
材料与方法：
各化合物的抗HIV活性由药物对HIV在细胞中引起的细胞病变的抑制作用效率来监控。采用MT-4细胞进行细胞培养。采用的病毒株有：HIV-1病毒株ⅢB及HIV-2病毒株ROD。
具体操作如下：将化合物用DMSO或水溶解后在磷酸盐缓冲食盐水溶液稀释，将3×105MT-4细胞用100μL各化合物不同浓度此溶液在37℃预培养1h，然后向该化合物中加入100μL适当的病毒稀释液，将细胞于37℃培养1h。洗涤三次后，将细胞再次分别悬浮于含有或不含有化合物的培养介质中。接着将细胞在5％CO2氛围中，于37℃下再培养7天，并于感染后第三天用含有或不含有化合物的培养介质替换补充培养液。每种培养液条件重复操作两次。对病毒的细胞病变作用每天都用反向光学显微镜监控。典型来讲，本实验中所用的病毒稀释液常常会在病毒感染后第五天导致细胞病变。药物抑制浓度以药物对病毒细胞病变作用产生50％抑制作用而同时对细胞无直接毒性的浓度(CC50)表示。需要强调的是，当化合物水溶性较差，需要DMSO才能溶解时，DMSO比浓度相对于水来讲，一般低于10％(DMSO在MT-4细胞培养介质中最终浓度小于2％)。因为DMSO能影响测试化合物的抗病毒活性，对含有相同浓度DMSO溶液抗病毒活性对比空白实验也应该平行进行。另外，DMSO最终浓度(1/1000)远远低于HIV-1在T细胞中复制所需的浓度。
本发明用药物奈维拉平(Nevirapine,NVP)、依非韦伦(Efavirenz,EFV)和ETR作对照品，部分目标化合物对HIV的抑制活性结果见表1，临床常见耐药株对HIV-1的抑制活性见表2。
表1:HIV-1对野性株的抑制活性
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表2:对HIV-1临床常见耐药株的抑制活性
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实验结果表明，实施例的目标产物I和Ⅱ具有较强的抗HIV-1病毒活性，可以显著地抑制被HIV-1病毒感染的MT-4细胞内的病毒复制，并且具有较小的细胞毒性和较高的选择性指数。
需要说明的是，尽管在本文中已经对上述各实施例进行了描述，但并非因此限制本发明的专利保护范围，其中未尽详细描述的技术参数和原料组分在本发明列举的参数范围内变化时，仍能够得到与上述实施例相同或相近的技术效果，仍属与本发明的保护范围。因此，基于本发明的创新理念，对本文所述实施例进行的变更和修改，或利用本发明说明书实施例内容所作的等效结构或等效流程变换，直接或间接地将以上技术方案运用在其他相关的技术领域，均包括在本发明的专利保护范围之内。
Claims (5)
1.一种含吡啶-苯环结构的杂芳基嘧啶类衍生物，其特征在于，结构式为如下(Ⅰ)或(Ⅱ)所示：
其中，R选自取代或未取代的吡啶基、呋喃基、吡咯基、噻吩基、吡唑基。
2.如权利要求1所述的含吡啶-苯环结构的杂芳基嘧啶类衍生物的制备方法，其特征在于，具体步骤如下：
以5-碘代嘧啶类衍生物Ⅲa或Ⅲb为原料，与相应的芳杂环硼酸反应得到化合物I或Ⅱ，其反应通式如下：
其中：
所述溶剂为二氧六环，丙酮、乙腈、四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺，乙醇，异丙醇，正丁醇，异丁醇中的一种或者多种与水的混合溶剂，体积比为1:1～10:1；
所述碱选自碳酸钠、碳酸钾、氢氧化钠、磷酸钾、LDA、LiHMDS、NaHMDS；
所述催化剂选自Pd(dppf)Cl2、Pd(PPh4)3、Pd2(dba)3、PdCl2、Pd(OAc)2、Pd(dba)2；
所述原料化合物IIIa或化合物IIIb、芳杂环硼酸、催化剂、碱的摩尔比为1:(1.0～2.0):(0.005～0.2):(1～5)；
反应温度为50～180℃；
反应时间为2～24h。
3.一种如权利要求1所述含吡啶-苯环结构的杂芳基嘧啶类衍生物的药用盐，其特征在于包括盐酸盐、氢溴酸盐、硫酸盐、甲酸盐、甲磺酸盐、三氟甲磺酸盐、磷酸盐、醋酸盐、对甲苯磺酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、马来酸盐、富马酸盐或苹果酸盐，以及药学上可接受的前体药物和衍生物。
4.一种药物组合物，其特征在于，含有有效剂量如权利要求1所述的含吡啶-苯环结构的杂芳基嘧啶类衍生物任一化合物及药用载体。
5.如权利要求1所述的含吡啶-苯环结构的杂芳基嘧啶类衍生物在制备预防和治疗艾滋病的药物中的应用。
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