CN110066273A - 一种含三氮唑环的单芳基嘧啶类hiv-1逆转录酶抑制剂及其制备方法与应用 - Google Patents
一种含三氮唑环的单芳基嘧啶类hiv-1逆转录酶抑制剂及其制备方法与应用 Download PDFInfo
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- CN110066273A CN110066273A CN201910486939.6A CN201910486939A CN110066273A CN 110066273 A CN110066273 A CN 110066273A CN 201910486939 A CN201910486939 A CN 201910486939A CN 110066273 A CN110066273 A CN 110066273A
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- Prior art keywords
- azide
- solution
- reverse transcriptase
- hiv
- reaction
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Abstract
本发明涉及含三氮唑环的单芳基嘧啶类HIV‑1逆转录酶抑制剂及其制备方法和应用。所述化合物具有式I或II所示的结构。本发明还涉及含有式I或II结构化合物的药物组合物。本发明还提供上述化合物以及含有一个或多个此类化合物的组合物在制备抗艾滋病药物中的应用。
Description
技术领域
本发明属于有机化合物合成与医药应用技术领域，具体涉及一种含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂及其制备方法与应用。
背景技术
艾滋病(Acquired Immune Deficiency Syndrome，AIDS)，全称为获得性免疫缺陷综合症，是由人免疫缺陷病毒(Human Immunodeficiency Virus，HIV)引起的一种破坏人体免疫系统的慢性传染病。自1981年艾滋病被发现以来，人们积极探索相关治疗方法，多种上市的抗艾滋病药物的联合应用可以将艾滋病患者的HIV-1病毒载量控制在检测限以下。即便如此，全球艾滋病防治形势依然严峻。据2018年世界卫生组织(WHO)数据统计显示，截至2017年底，全球约有3690万HIV病毒携带者，2017年新增感染者180万，2017年艾滋病患者死亡人数高达94万。此外，我国用于临床治疗艾滋病的药物品种较少，多为国外药物专利过期后的仿制药，毒副作用较大，难以满足大部分患者终生服药的需求。
逆转录酶在HIV-1病毒复制周期中起着至关重要的作用，并且人体内不存在其同源酶，因而以逆转录酶为靶点的抗HIV-1药物具备选择特异性，在临床上具备巨大的开发价值。按照作用机制不同，以逆转录酶为靶点的抗HIV-1药物可分为核苷类逆转录酶抑制剂(NRTIs)和非核苷类逆转录酶抑制剂(NNRTIs)。其中，NNRTIs作为一类非竞争性抑制剂，能够特异性识别NNRTIs疏水结合口袋(NNRTIs binding pocket，NNIBP)并与之结合，所以该类抑制剂具备较好的选择性，使得其成为临床上高效抗逆转录疗法(Highly ActiveAntiretroviral Therapy，HAART)的重要组成部分。但是，随着NNRTIs的临床应用，该类抑制剂出现的耐药性、溶解度差、毒副作用等问题也逐渐引发人们关注。
因此，聚焦HIV-1逆转录酶，研发高效低毒抗耐药的NNRTIs在当前艾滋病研发领域仍具有重要意义。
发明内容
针对现有技术的不足，本发明提供了一种含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂及其制备方法，本发明还提供上述化合物作为HIV-1逆转录酶抑制剂的活性筛选结果及其应用。
本发明的技术方案如下：
1.含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂
一种含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂，或其药学上可接受的盐或酯，具有通式I或II所示的结构：
其中，
n为1或者2；
X为：O或者NH；
R为：CH3，CN或者CH＝CHCN；
R1为：苯基或吡啶基；或卤素、CH3、SO2NH2、SO2CH3、CONH2、NO2、CN、NH2、CF3、NHCH3、OH、COOH、CH2OH、CO2Me、OCH3、B(OH)2、NHCOCH3取代的苯基，取代基为邻、间、对位单取代或多取代；或COOR2；或CONR2；或(CH2)nCOOR2,或(CH2)nCONR2,五元杂环、六元杂环；
R2为：CH3，CH2CH3，环丙基，五元杂环、六元杂环。
根据本发明优选的，n为2，所述的五元杂环、六元杂环优选为吡咯、呋喃、噻吩、四氢呋喃、吡唑、咪唑、噁唑、噻唑、异噁唑、吡啶、哒嗪、嘧啶、吡嗪、哌嗪和吗啉环。
根据本发明进一步优选的，含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂是下列化合物之一：
本发明中所述的“药学上可接受的盐”是指在可靠的医药评价范围内，化合物的盐类适于与人或较低等动物的组织相接触而无不适当的毒性、刺激及过敏反应等，具有相当合理的收益与风险比例，通常是水或油可溶的或可分散的，并可有效地用于其预期的用途。包括药学上可接受的酸加成盐和药学上可接受的碱加成盐，在这里是可做预期的用途并与式I化合物的化学性质相容的。适宜的盐的列表参见S.M.Birge等，J.Pharm.Sci.,1977,66,1-19页。
2.含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂的制备方法
含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂的制备方法，步骤包括：以2,4-二氯嘧啶为初始原料，首先在碱性条件下分别与取代苯酚或苯胺经亲核取代反应生成中间体2；然后中间体2与N-Boc-4-氨基哌啶或氨基丁炔盐酸盐经亲核取代反应生成中间体3或6；随后，中间体3在三氟乙酸中脱去Boc保护得到中间体4；然后4与溴丙炔反应生成中间体5；最后中间体5和6分别与叠氮取代基发生一价铜催化的叠氮-末端炔环加成反应(CuAACClick)得到目标产物I或II；合成路线如下：
试剂及条件:(i)取代苯酚或苯胺，N,N-二甲基甲酰胺，碳酸钾，室温；(ii)N-Boc-4-氨基哌啶或氨基丁炔盐酸盐，N,N-二甲基甲酰胺，碳酸钾，110℃；(iii)二氯甲烷，三氟乙酸，室温；(iv)溴丙炔，N,N-二甲基甲酰胺，碳酸钾，室温；(v)维生素C钠，五水硫酸铜，体积比1:1的四氢呋喃/水，叠氮取代基，室温；
n、X、R、R1同上述通式I或II所示；
所述的取代苯酚或苯胺为：均三甲基苯酚、2,6-二甲基-4-氰基苯酚、2,6-二甲基-4-(E)-氰基乙烯基苯酚、均三甲基苯胺、2,6-二甲基-4-氰基苯胺、2,6-二甲基-4-(E)-氰基乙烯基苯胺；
所述的叠氮取代基为：邻甲基苄基叠氮、间甲基苄基叠氮、对甲基苄基叠氮、邻氯苄基叠氮、间氯苄基叠氮、对氯苄基叠氮、邻溴苄基叠氮、间溴苄基叠氮、对溴苄基叠氮、邻氟苄基叠氮、间氟苄基叠氮、对氟苄基叠氮、2,4-二氟苄基叠氮、3,4-二氟苄基叠氮、邻氰基苄基叠氮、间氰基苄基叠氮、对氰基苄基叠氮、邻硝基苄基叠氮、间硝基苄基叠氮、对硝基苄基叠氮、邻甲氧基苄基叠氮、间甲氧基苄基叠氮、对甲氧基苄基叠氮、对甲磺酰基苄基叠氮、间甲磺酰基苄基叠氮、邻甲磺酰基苄基叠氮、对磺酰胺基苄基叠氮、间磺酰胺基苄基叠氮、邻磺酰胺基苄基叠氮、对甲酰胺基苄基叠氮、间甲酰胺基苄基叠氮、邻甲酰胺基苄基叠氮、2-叠氮基-1-(吡咯烷-1-基)乙-1-酮、2-叠氮基-N-环丙基乙酰胺、2-叠氮基-1-吗啉-1-酮，2-叠氮基乙酸乙酯，2-叠氮基乙酸甲酯，4-叠氮基丁酸甲酯，(4-(叠氮甲基)苯基)硼酸。
根据本发明优选的，含有三唑的单芳基嘧啶类的化合物Ⅰ或II制备方法，步骤如下：
(1)将初始原料2,4-二氯嘧啶1、取代苯酚或苯胺、与碳酸钾加入到20mL N,N-二甲基甲酰胺溶液中，室温条件下搅拌，反应8～12h；TLC监测反应，待反应完成后，向反应溶液中加入40mL水溶液并继续搅拌20～30min，过滤得白色固体，即中间体2；
(2)将中间体2、N-Boc-4-氨基哌啶或氨基丁炔盐酸盐和碳酸钾充分混合于20mLDMF溶液中，120℃油浴条件下搅拌，溶液呈黄色，TLC检测反应24-27h；加入100mL水溶液淬灭反应，乙酸乙酯萃取3次，每次20mL，合并有机层，饱和氯化钠溶液洗涤(3×50mL)，无水硫酸钠干燥，过滤，浓缩；硅胶柱色谱分离；乙酸乙酯/石油醚或者二氯甲烷/正己烷重结晶得到中间体3和6；
(3)将中间体3加入到15mL二氯甲烷溶液中，充分搅拌，然后加入三氟乙酸，室温搅拌，反应6-8h；然后用饱和碳酸氢钠溶液调节反应液的pH＝9，加入二氯甲烷溶液萃取；合并有机层，饱和食盐水洗涤3次，每次50mL；无水硫酸钠干燥；过滤，减压浓缩，硅胶柱色谱分离得到中间体4；
(4)将中间体4、溴丙炔与碳酸钾混合于10mL DMF中，室温反应；TLC检测，待反应完毕，加60mL水稀释反应液，乙酸乙酯萃取3次，每次20mL，合并有机层，加饱和食盐水洗涤3次，每次50mL，有机相用无水硫酸钠干燥；过滤，减压蒸干溶剂；硅胶柱色谱分离得到中间体5；
(5)将炔基片段5和6分别与不同的叠氮取代基加入到体积比1:1的THF/H2O混合溶液中，然后向此混合溶液中加入VcNa和CuSO4.5H2O，室温搅拌6-12h，TLC检测；随后，向反应液中加入适量的水，用乙酸乙酯萃取3次，每次10mL；合并有机层，饱和氯化钠溶液洗涤3次，每次30mL，无水硫酸钠干燥；过滤，减压蒸干溶剂；硅胶柱色谱分离；乙酸乙酯/石油醚或者二氯甲烷/正己烷重结晶得到目标化合物含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂I或II。
本发明所述的室温为20-30℃。
3.含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂的抗HIV-1活性及应用
通过酶联免疫吸附法测定目标化合物I和II对重组逆转录酶的抑制活性，以依曲韦林(ETV)和HIV-1抑制剂K-5a2为阳性对照。
目标化合物A1-A10的HIV-1逆转录酶水平的活性抑制结果如表1和表2所示。可以发现，10个目标化合物的酶活水平的抑制效果均与K-5a2和ETV相当或较好。其中，化合物A2(IC50＝0.02μM)活性较为突出。
本发明的含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂可作为非核苷类HIV-1抑制剂应用。具体地说，作为HIV-1抑制剂用于制备抗艾滋病药物。
一种抗HIV-1药物组合物，包括本发明的含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂和一种或多种药学上可接受载体或赋形剂。
本发明提供了结构全新的含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂及其制备方法，本发明还提供了化合物抗HIV-1酶活水平的活性筛选结果及其在抗病毒领域中的首次应用。总之，本发明的含三氮唑环的单芳基嘧啶类衍生物可作为HIV-1逆转录酶抑制剂应用并具有很高的应用价值。具体地说，作为HIV-1抑制剂用于制备抗艾滋病药物。
具体实施方式
通过下述实施例有助于理解本发明，但是不能限制本发明的内容。
实施例中所涉及的合成路线如下：
实施例1：4-((2-氯嘧啶-4-基)氧基)-3,5-二甲基苄腈(7)的制备
将初始原料2,4-二氯嘧啶(13.42mmol，2.00g)、3,5-二甲基-4-羟基苯腈(14.76mmol，2.18g)与碳酸钾(16.10mmol，2.22g)加入到20mL N,N-二甲基甲酰胺(DMF)溶液中，室温条件下搅拌，反应8～12h。TLC监测反应，待反应完成后，向反应溶液中加入40mL水溶液并继续搅拌20～30min，过滤得白色固体，即中间体7。1H NMR(400MHz,DMSO-d6)δ8.70(d,J＝5.7Hz,1H),7.75(s,2H),7.32(d,J＝5.7Hz,1H),2.10(s,6H)；ESI-MS:m/z 259.97(M+H)+,C13H10ClN3O(259.05).
实施例2：4-((2-氯嘧啶-4-基)氨基)-3,5-二甲基苯甲醛(11)的制备
操作步骤同中间体7的制备，所不同的是用3,5-二甲基-4-羟基-苯甲醛代替7制备过程中的3,5-二甲基-4-羟基苯腈，得到白色固体。1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.70(d,J＝5.7Hz,1H),7.77(s,2H),7.30(d,J＝5.7Hz,1H),2.15(s,6H)；ESI-MS:m/z263.10(M+H)+,C13H11ClN2O2(262.05).
实施例3：(E)-3-(4-((2-氯嘧啶-4-基)氨基)-3,5-二甲基苯基)丙烯腈(12)的制备
冰浴条件下，将氰甲基磷酸二乙酯(11.40mmol，2.02g)加入到10mL四氢呋喃和二氯甲烷的混合溶液(v:v＝1:1)中，充分混合后，向上述溶液中加入叔丁醇钾(11.40mmol，1.28g)。然后，将溶解于5mL四氢呋喃的中间体11(3.81mmol，1.00g)缓慢滴加到上述混合溶液中，滴加完毕，撤去冰浴，室温反应。待反应完成，减压除掉溶剂，用20mL DMF溶解，随后加入60～80mL水溶液，析出白色固体。过滤，水洗滤饼，氯仿重结晶得中间体(E)-3-(4-((2-氯嘧啶-4-基)氨基)-3,5-二甲基苯基)丙烯腈(12)。收率64％，白色固体，1H NMR(400MHz,DMSO-d6)δ8.67(d,J＝5.7Hz,1H),7.62(d,J＝16.7Hz,1H),7.52(s,2H),7.25(d,J＝5.7Hz,1H),6.45(d,J＝16.7Hz,1H),2.07(s,6H)，ESI-MS:m/z 286.2(M+H)+,C15H12ClN3O(285.07).
实施例4：(E)-3-(4-((2-(丁-3-炔-1-基氨基)嘧啶-4-基)氨基)-3,5-二甲基苯基)丙烯腈(13)的制备
将中间体12(3.50mmol，1.00g)、氨基丁炔盐酸盐(4.62mmol，487.7mg)和碳酸钾(7.70mmol，1.06g)充分混合于20mLDMF溶液中，120℃油浴条件下搅拌，溶液呈黄色，反应24-27h(TLC检测)。加入大量水溶液(100mL)淬灭反应，乙酸乙酯萃取(3×20mL)，合并有机层，饱和氯化钠溶液洗涤(3×50mL)，无水硫酸钠干燥，过滤，浓缩。硅胶柱色谱分离；乙酸乙酯/石油醚或者二氯甲烷/正己烷重结晶得到(E)-3-(4-((2-(丁-3-炔-1-基氨基)嘧啶-4-基)氨基)-3,5-二甲基苯基)丙烯腈(13)。1H NMR(400MHz,DMSO-d6)δ8.19(s,1H),7.58(d,J＝16.7Hz,1H),7.45(s,2H),7.29–7.07(m,1H),6.40(d,J＝16.7Hz,1H),6.22(s,1H),3.34(s,1H),3.31(s,1H),3.02(s,1H),2.77(s,1H),2.34(s,1H),2.06(s,6H).13C NMR(100MHz,DMSO)δ168.70,151.98,150.49,131.67,131.52,128.57,119.39,96.65,82.85,72.42,18.79,16.55.ESI-MS:m/z 319.3(M+H)+,C19H18N4O(318.15).
实施例5：4-((4-(4-氰基-2,6-二甲基苯氧基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁酯(8-1)的制备
操作步骤同炔基片段13的制备，所不同的是用N-Boc-4-氨基哌啶(4.23mmol，0.85g)代替取代基氨基丁炔盐酸盐。1H NMR(400MHz,DMSO-d6)δ8.20(d,J＝5.5Hz,1H),7.68(s,2H),6.39–6.01(m,1H),3.85(s,3H),2.81(dd,J＝63.9,1.4Hz,3H),2.08(s,6H),1.64(d,J＝80.2Hz,2H),1.38(d,J＝1.5Hz,9H),1.23(s,2H).ESI-MS:m/z 446.06(M+Na)+,C23H29N5O3(423.23).
实施例6：(E)-4-((4-(4-(2-氰基乙烯基)-2,6-二甲基苯氨基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁酯(8-2)的制备
操作步骤同炔基片段13的制备，所不同的是用N-Boc-4-氨基哌啶(4.23mmol，0.85g)代替取代基氨基丁炔盐酸盐。1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝5.6Hz,1H),7.68–7.51(m,1H),7.46(d,J＝4.5Hz,2H),6.40(d,J＝16.6Hz,1H),6.17(s,1H),3.85(s,3H),2.81(d,J＝63.8Hz,2H),2.06(s,6H),1.91–1.52(m,3H),1.41(d,J＝6.0Hz,3H),1.38(s,6H),1.31–0.99(m,2H).ESI-MS:m/z 472.02(M+Na)+,C25H31N5O3(449.24).
实施例7：3,5-二甲基-4-((2-(哌啶-4-基氨基)嘧啶-4-基)氧基)苄腈(9-1)的制备
将中间体8-1(3.16mmol，1.34g)加入到15mL二氯甲烷溶液中，充分搅拌，然后加入三氟乙酸(15.82mmol，1.80g)，室温搅拌，反应6-8h。然后用饱和碳酸氢钠溶液调节反应液的pH＝9，加入二氯甲烷溶液萃取；合并有机层，饱和食盐水洗涤(3×50mL)；无水硫酸钠干燥；过滤，减压浓缩，硅胶柱色谱分离得到关键中间体3,5-二甲基-4-((2-(哌啶-4-基氨基)嘧啶-4-基)氧基)苄腈(9-1)。1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝5.6Hz,1H),7.67(s,2H),7.13(d,J＝101.9Hz,1H),6.22(d,J＝5.6Hz,1H),3.75(s,2H),2.92(s,3H),2.08(s,6H),1.63(d,J＝82.6Hz,2H),1.45–1.03(m,3H).ESI-MS:m/z 324.11(M+H)+,C18H21N5O(323.17).
实施例8：(E)-3-(3,5-二甲基-4-((2-(哌啶-4-基氨基)嘧啶-4-基)氨基)苯基)丙烯腈(9-2)的制备
操作步骤同中间体9-1的制备，所不同的是用中间体8-2(3.16mmol，1.42g)代替中间体8-1。1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝5.6Hz,1H),7.59(d,J＝16.4Hz,1H),7.46(s,1H),7.33–6.95(m,1H),6.41(d,J＝16.8Hz,1H),6.17(s,1H),3.02(s,2H),2.47(dd,J＝7.1,1.3Hz,2H),2.06(s,6H),1.91–1.52(m,3H),1.54–1.09(m,4H).ESI-MS:m/z 350.12(M+H)+,C20H23N5O(349.19).
实施例9：3,5-二甲基-4-((2-((1-(丙-2-炔-1-基)哌啶-4-基)氨基)嘧啶-4-基)氧基)苄腈(10-1)的制备
将中间体9-1(0.65mmol，0.21g)、溴丙炔(0.779mmol，0.093g)、碳酸钾(1.30mmol，0.179g)混合于10mL DMF中，室温反应。TLC检测，待反应完毕，加大量水(60mL)稀释反应液，乙酸乙酯萃取(3×20mL)，合并有机层，加饱和食盐水洗涤(3×50mL)，有机相用无水硫酸钠干燥；过滤，减压蒸干溶剂；硅胶柱色谱分离得到炔基片段3,5-二甲基-4-((2-((1-(丙-2-炔-1-基)哌啶-4-基)氨基)嘧啶-4-基)氧基)苄腈(10-1)。白色固体，收率65％。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝5.6Hz,1H),7.66(s,2H),7.08(d,J＝113.6Hz,1H),6.23(d,J＝5.5Hz,1H),3.63(s,1H),3.20(s,2H),3.10(s,1H),2.71(t,J＝15.8Hz,2H),2.08(s,7H),1.80(d,J＝34.3Hz,2H),1.64–1.14(m,3H).13C NMR(100MHz,DMSO)δ168.28,133.13,119.07,108.61,75.82,46.65,31.50,31.47,16.30.ESI-MS:m/z 362.4(M+H)+,C21H23N5O(361.45).
实施例10：(E)-3-(3,5-二甲基-4-((2-((1-(丙-2-炔-1-基)哌啶-4-基)氨基)嘧啶-4-基)氨基)苯基)丙烯腈(10-2)的制备
操作步骤同炔基片段10-1的制备，所不同的是用中间体9-2代替中间体IIIA-9-1。淡黄色固体，收率63％。1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝5.7Hz,1H),7.58(d,J＝16.3Hz,1H),7.44(s,2H),7.05(d,J＝92.4Hz,1H),6.39(d,J＝16.7Hz,1H),6.16(d,J＝5.7Hz,1H),3.14(d,J＝37.2Hz,3H),2.67(d,J＝43.4Hz,2H),2.07(d,J＝9.6Hz,7H),1.76(s,3H),1.33(dd,J＝45.6,30.9Hz,3H).13C NMR(100MHz,DMSO)δ168.67,150.49,131.72,131.50,119.38,96.59,75.83,51.47,51.19,46.65,31.53,16.58.ESI-MS:m/z 388.4(M+H)+,C23H25N5O(387.49).
实施例11：目标化合物A1及A2-A10的制备
将炔基片段10-1，10-2或13(1.0eq)与不同的叠氮取代基(1.2eq)加入到8mL的THF/H2O(v:v＝1:1)混合溶液中，然后向此混合溶液中加入VcNa(0.3eq)和CuSO4.5H2O(0.1eq.)，室温搅拌6-12h，TLC检测。随后，向反应液中加入适量的水，用乙酸乙酯萃取(3×10mL)；合并有机层，饱和氯化钠溶液洗涤(3×30mL)，无水硫酸钠干燥；过滤，减压蒸干溶剂；硅胶柱色谱分离；乙酸乙酯/石油醚或者二氯甲烷/正己烷重结晶得到目标化合物A1及A2-A10。
甲基(E)-2-(4-(2-((4-(4-(2-氰基乙烯基)-2,6-二甲基苯氨基)嘧啶-2-基)氨基)乙基)-1H-1,2,3(甲基)-三唑-1-基)乙酸甲酯(A1)
白色晶体，84mg，收率：62％，mp:137-139℃。1H NMR(400MHz,DMSO-d6)δ8.21(s,1H),7.88(s,1H),7.58(d,J＝16.7Hz,1H),7.46(s,2H),7.30–7.04(m,1H),6.39(d,J＝16.7Hz,1H),6.21(s,1H),5.35(s,2H,CH3OC＝OCH2),3.72(s,3H,OCH3),3.47(s,1H),3.14(s,1H),2.75(d,J＝85.9Hz,2H，triazole-CH2),2.08(s,6H,2×CH3).13C NMR(100MHz,DMSO)δ168.69,168.20,160.42,152.04,150.45,144.97,131.73,131.46,128.56,123.98,119.37,96.63,55.37,52.94,50.58,41.10,25.46,16.56.
4-((4-((4-((4-(4-氰基-2,6-二甲基苯氧基)嘧啶-2-基)氨基)哌啶-1-基)甲基)-1H-1,2,3-三唑-1-基)甲基)苯甲酰胺(A2)
白色粉末，75mg，收率：50％，mp:143-145℃。1H NMR(400MHz,DMSO-d6)δ8.27–8.13(m,1H),8.01(d,J＝24.8Hz,2H),7.87(d,J＝7.8Hz,2H),7.66(s,2H),7.40(s,1H),7.35(d,J＝7.9Hz,2H),7.10(d,J＝113.8Hz,1H),6.22(d,J＝5.6Hz,1H),5.64(s,2H,NH2COPhCH2),3.57–3.44(m,2H,triazole-CH2),2.74(d,J＝30.7Hz,2H),2.08(s,6H,2×CH3),2.00–1.85(m,1H),1.63(d,J＝72.1Hz,3H),1.48–1.17(m,2H),1.01(d,J＝6.3Hz,1H).13C NMR(100MHz,DMSO)δ168.28,167.89,139.68,134.46,133.12,128.37,128.05,124.40,119.11,108.58,67.73,67.66,53.10,52.78,52.33,31.55,20.46,16.29.ESI-MS:m/z 538.25(M+H)+,C29H31N9O2(537.26).
2-(4-((4-((4-(4-氰基-2,6-二甲基苯氧基)嘧啶-2-基)氨基)哌啶-1-基)甲基)-1H-1,2,3-三唑环丁烷-1-基)-N-环丙基乙酰胺(A3)
白色粉末，84mg，收率：60％，mp:109-111℃。1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.19(s,1H),7.89(s,1H),7.67(s,2H),7.10(d,J＝110.8Hz,1H),6.40–6.07(m,1H),5.00(s,2H),3.53(s,2H),2.73(d,J＝52.7Hz,3H),2.09(s,7H),1.65(d,J＝74.1Hz,3H),1.48–1.06(m,3H),0.66(d,J＝7.4Hz,2H),0.46(s,2H).13C NMR(100MHz,DMSO)δ168.28,166.89,133.12,125.64,119.10,108.59,55.37,53.01,52.33,51.88,31.53,22.82,16.30,6.06.ESI-MS:m/z502.29(M+H)+,C26H31N9O2(501.26).
4-(4-((4-((4-(4-氰基-2,6-二甲基苯氧基)嘧啶-2-基)氨基)哌啶-1-基)甲基)-1H-1,2,3-三唑-1-基)丁酸乙酯(A4)
白色固体，99mg，收率：70％，mp:144-146℃。1H NMR(400MHz,DMSO-d6)δ8.19(s,1H),7.97(s,1H),7.67(s,2H),7.09(d,J＝109.9Hz,1H),6.23(s,1H),4.37(s,2H),3.59(s,4H),2.78(s,2H),2.32(s,2H),2.09(s,9H),1.88–0.50(m,7H).13C NMR(100MHz,DMSO)δ172.95,168.28,144.05,133.12,124.11,119.10,108.59,53.11,52.32,48.89,31.54,30.61,25.59,16.31.ESI-MS:m/z 505.18(M+H)+,C26H32N8O3(504.26).
(E)-3-(3,5-二甲基-4-((2-((1-((1-(2-吗啉代-2-氧代乙基)-1H-1,2,3-三唑-4-基)甲基)哌啶-4-基)氨基)嘧啶-4-基)氨基)苯基)丙烯腈(A5)
淡黄色固体，81mg，收率：56％，mp:145-147℃。1H NMR(400MHz,DMSO-d6)δ8.27–8.05(m,1H),7.83(s,1H),7.71–7.52(m,1H),7.44(s,2H),7.07(d,J＝94.1Hz,1H),6.40(d,J＝16.7Hz,1H),6.16(s,1H),5.43(s,2H),3.93–3.39(m,11H),2.79(s,2H),2.08(s,2H),2.06(s,5H),1.66(d,J＝55.4Hz,3H),1.32(d,J＝68.9Hz,2H).13C NMR(100MHz,DMSO)δ168.68,165.01,150.51,131.71,128.56,125.82,119.41,96.60,66.41,53.08,52.35,50.90,45.19,42.37,31.59,16.59.
(E)-2-(4-((4-((4-(4-(2-氰基乙烯基)-2,6-二甲基苯基)氨基)嘧啶-2-基)氨基)哌啶-1-基)甲基)-1H--1,2,3-三唑-1-基)-N-环丙基乙酰胺(A6)
淡黄色粉末，90mg，收率：66％，mp:113-115℃。1H NMR(400MHz,DMSO-d6)δ8.46(d,J＝4.1Hz,1H),8.16(s,1H),7.89(s,1H),7.69–7.52(m,1H),7.45(s,2H),7.07(d,J＝94.7Hz,1H),6.40(d,J＝16.7Hz,1H),6.16(s,1H),5.00(s,2H),3.53(s,2H),2.92–2.58(m,3H),2.07(d,J＝9.7Hz,8H),1.66(d,J＝55.8Hz,3H),1.47–1.19(m,3H),0.65(d,J＝6.9Hz,2H),0.45(d,J＝4.2Hz,2H).13C NMR(100MHz,DMSO)δ168.68,166.90,162.12,160.35,152.07,150.49,148.59,143.68,131.71,131.52,131.50,128.58,125.66,119.39,118.35,96.61,95.42,53.02,52.33,51.88,48.41,41.80,40.61,40.40,40.20,39.99,39.88,39.78,39.57,39.36,31.56,26.92,22.82,16.58,7.79,6.06.
乙基(E)-2-(4-((4-((4-(4-(2-氰基乙烯基)-2,6-二甲基苯基)氨基)嘧啶-2-基)氨基)哌啶-1-基)甲基)-1H-1,2,3-三唑-1-基)乙酸甲酯(A7)
淡黄色粉末，57mg，收率：43％，mp:87-89℃。1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.95(s,1H),7.72–7.51(m,1H),7.45(s,2H),7.05(d,J＝89.5Hz,1H),6.40(d,J＝16.6Hz,1H),6.16(s,1H),5.36(s,2H),4.18(d,J＝7.2Hz,2H),3.53(s,2H),2.78(s,2H),2.08(d,J＝9.9Hz,7H),1.66(d,J＝55.8Hz,3H),1.51–0.98(m,6H).13C NMR(100MHz,DMSO)δ168.68,167.74,150.49,148.58,144.17,131.49,128.63,125.53,119.39,96.61,61.90,53.02,52.32,50.74,31.61,16.58,14.41.
甲基(E)-2-(4-((4-((4-(4-(2-氰基乙烯基)-2,6-二甲基苯基)氨基)嘧啶-2-基)氨基)哌啶-1-基)甲基)-1H-1,2,3-三唑-1-基)乙酸甲酯(A8)
白色粉末，63mg，收率：49％，mp:85-87℃。1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.96(s,1H),7.59(d,J＝14.1Hz,1H),7.45(s,2H),7.07(d,J＝92.9Hz,1H),6.40(d,J＝16.6Hz,1H),6.16(s,1H),5.38(s,2H),3.72(s,3H),3.51(d,J＝20.3Hz,2H),2.75(d,J＝29.1Hz,2H),2.07(s,7H),1.67(d,J＝53.6Hz,3H),1.32(d,J＝65.1Hz,3H).13C NMR(100MHz,DMSO)δ168.69,168.26,150.49,144.21,131.71,131.49,128.53,125.51,119.39,96.61,53.02,52.96,52.35,50.63,31.63,16.58.
甲基(E)-4-(4-((4-((4-(4-(2-氰基乙烯基)-2,6-二甲基苯基)氨基)嘧啶-2-基)氨基)哌啶-1-基)甲基)-1H-1,2,3-三唑-1-基)丁酸乙酯(A9)
淡黄色粉末，101mg，收率：74％，mp:87-89℃。1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝5.6Hz,1H),8.05(s,1H),7.70–7.51(m,1H),7.45(s,2H),7.13(d,J＝91.2Hz,1H),6.41(d,J＝16.6Hz,1H),6.18(s,1H),4.38(t,J＝7.0Hz,2H),3.83–3.67(m,1H),3.59(s,3H),3.06(d,J＝7.3Hz,1H),2.92(d,J＝17.1Hz,2H),2.74(s,1H),2.33(t,J＝7.3Hz,3H),2.07(d,J＝10.4Hz,8H),1.64(d,J＝123.7Hz,4H),1.21(dd,J＝14.5,7.3Hz,1H).13C NMR(100MHz,DMSO)δ172.95,168.68,150.48,144.12,131.71,128.62,124.06,119.39,96.61,53.14,52.40,51.86,48.89,31.60,30.61,25.59,16.57.
(E)-(4-((4-((4-((4-(4-(2-氰基乙烯基)-2,6-二甲基苯基)氨基)嘧啶-2-基)氨基)哌啶-1-基)甲基)-1H-1,2,3-三唑-1-基)甲基)苯基)硼酸(A10)
淡黄色粉末，105mg，收率：72％，mp:153-155℃.1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),8.07(d,J＝14.1Hz,2H),7.78(d,J＝7.7Hz,2H),7.66–7.51(m,1H),7.44(s,2H),7.25(d,J＝7.6Hz,2H),7.08–6.67(m,1H),6.40(d,J＝16.7Hz,1H),6.17(s,1H),5.59(s,2H),3.63(s,3H),3.00–2.62(m,2H),2.07(d,J＝10.3Hz,7H),1.88–1.56(m,3H),1.53–1.24(m,3H).13C NMR(100MHz,DMSO)δ172.95,168.68,150.48,144.12,131.71,128.62,124.06,119.39,96.61,53.14,52.40,51.86,48.89,31.60,30.61,25.59,16.57.
实施例12：目标化合物的体外抗HIV-1逆转录酶活性水平抑制实验
实验原理：待测化合物对重组逆转录酶的抑制活性通过酶联免疫吸附法进行测定。首先，逆转录酶(RT)以地高辛(Digoxin，DIG)和生物素(Biotin)标记的dNTPs为底物，oligo(dT)15为引物，Poly(A)为模板完成引物延伸过程。待逆转录完成，生物素和地高辛双标记的DNA结合到含有链霉亲和素的96孔板上。然后加入连接有过氧化物酶(Peroxidase，POD)的地高辛抗体，使之与DNA结合。最后加入过氧化物酶底物2'-联氨-双-3-乙基苯并噻唑啉-6-磺酸(ABTS)，其与过氧化物酶相互作用，产生不同颜色。随即用酶标仪检测其吸光度，得到抑制活性。
实验材料：不同规格的微量加样器(10μL、20μL、100μL、200μL、1000μL)、EP管(0.5mL、1.5mL、5mL)、待测化合物、HIV-1逆转录酶试剂盒(Recombinant HIV-1RT kit,Roche)、三蒸水、阳性对照依曲韦林和K-5a2(结构式如下)。
实验步骤：按照Roche逆转录酶试剂盒中说明书的操作步骤，进行待测化合物的逆转录酶的活性测试。首先，用裂解缓冲液和三蒸水将500ng HIV-1RT冷冻干燥物配制成0.1ng/μL的酶溶液，取20μL置于0.5mL的EP管中；然后，向EP管中加入同样用裂解缓冲液稀释得到的待测化合物20μL和反应混合液(模板、dNTP、引物)20μL，37℃下孵育2h。待第一次孵育完毕，用微量加样器转移EP管中的60μL反应液至涂有链霉亲和素的微孔中，封口膜封闭，37℃下继续孵育1h。待第二次孵育完毕，除去反应液，用250μL的洗液对各加样微孔清洗5次，除去洗液，每孔中加入连有过氧化物酶的地高辛抗体溶液200μL，37℃下继续孵育1h。待第三次孵育完毕，除去反应液，接着同样用250μL的洗液对各加样微孔清洗5次，除去洗液，向各孔中加入ABTS溶液200μL。随即以405nm为测量波长，490nm为参比波长，用酶标仪测定各孔吸光度值。值得注意的是，每次测试都需设置空白组(无逆转录酶，无抑制剂)和阴性对照组(无抑制剂、有逆转录酶)。
结果计算：
根据上述公式计算出单个浓度下待测化合物对逆转录酶的抑制率。而不同浓度下的待测化合物对逆转录酶的抑制率结合GraphPad Prism 5软件处理得到IC50值。
按照上述实验方法对合成的部分含三氮唑环的单芳基嘧啶类衍生物进行了体外抗逆转录酶水平的活性筛选，活性结果如表1、表2所示。
表1部分目标产物对HIV-1RT的抑制作用
表2部分目标产物对HIV-1RT的抑制作用
Claims (7)
1.一种含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂，或其药学上可接受的盐或酯，其特征在于，具有通式I或II所示的结构：
其中，
n为1或者2；
X为：O或者NH；
R为：CH3，CN或者CH＝CHCN；
R1为：苯基或吡啶基；或卤素、CH3、SO2NH2、SO2CH3、CONH2、NO2、CN、NH2、CF3、NHCH3、OH、COOH、CH2OH、CO2Me、OCH3、B(OH)2、NHCOCH3取代的苯基，取代基为邻、间、对位单取代或多取代；或COOR2；或CONR2；或(CH2)nCOOR2,或(CH2)nCONR2,五元杂环、六元杂环；
R2为：CH3，CH2CH3，环丙基，五元杂环、六元杂环。
2.如权利要求1所述的含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂，其特征在于，n为2，所述的五元杂环、六元杂环为吡咯、呋喃、噻吩、四氢呋喃、吡唑、咪唑、噁唑、噻唑、异噁唑、吡啶、哒嗪、嘧啶、吡嗪、哌嗪和吗啉环。
3.如权利要求1或2所述的含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂，其特征在于是下列化合物之一：
4.如权利要求1所述的含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂的制备方法，步骤包括：以2,4-二氯嘧啶为初始原料，首先在碱性条件下分别与取代苯酚或苯胺经亲核取代反应生成中间体2；然后中间体2与N-Boc-4-氨基哌啶或氨基丁炔盐酸盐经亲核取代反应生成中间体3或6；随后，中间体3在三氟乙酸中脱去Boc保护得到中间体4；然后4与溴丙炔反应生成中间体5；最后中间体5和6分别与叠氮取代基发生一价铜催化的叠氮-末端炔环加成反应(CuAAC Click)得到目标产物I或II；合成路线如下：
试剂及条件:(i)取代苯酚或苯胺，N,N-二甲基甲酰胺，碳酸钾，室温；(ii)N-Boc-4-氨基哌啶或氨基丁炔盐酸盐，N,N-二甲基甲酰胺，碳酸钾，110℃；(iii)二氯甲烷，三氟乙酸，室温；(iv)溴丙炔，N,N-二甲基甲酰胺，碳酸钾，室温；(v)维生素C钠，五水硫酸铜，体积比1:1的四氢呋喃/水，叠氮取代基，室温；
n、X、R、R1同上述通式I或II所示；
所述的取代苯酚或苯胺为：均三甲基苯酚、2,6-二甲基-4-氰基苯酚、2,6-二甲基-4-(E)-氰基乙烯基苯酚、均三甲基苯胺、2,6-二甲基-4-氰基苯胺、2,6-二甲基-4-(E)-氰基乙烯基苯胺；
所述的叠氮取代基为：邻甲基苄基叠氮、间甲基苄基叠氮、对甲基苄基叠氮、邻氯苄基叠氮、间氯苄基叠氮、对氯苄基叠氮、邻溴苄基叠氮、间溴苄基叠氮、对溴苄基叠氮、邻氟苄基叠氮、间氟苄基叠氮、对氟苄基叠氮、2,4-二氟苄基叠氮、3,4-二氟苄基叠氮、邻氰基苄基叠氮、间氰基苄基叠氮、对氰基苄基叠氮、邻硝基苄基叠氮、间硝基苄基叠氮、对硝基苄基叠氮、邻甲氧基苄基叠氮、间甲氧基苄基叠氮、对甲氧基苄基叠氮、对甲磺酰基苄基叠氮、间甲磺酰基苄基叠氮、邻甲磺酰基苄基叠氮、对磺酰胺基苄基叠氮、间磺酰胺基苄基叠氮、邻磺酰胺基苄基叠氮、对甲酰胺基苄基叠氮、间甲酰胺基苄基叠氮、邻甲酰胺基苄基叠氮、2-叠氮基-1-(吡咯烷-1-基)乙-1-酮、2-叠氮基-N-环丙基乙酰胺、2-叠氮基-1-吗啉-1-酮，2-叠氮基乙酸乙酯，2-叠氮基乙酸甲酯，4-叠氮基丁酸甲酯，(4-(叠氮甲基)苯基)硼酸。
5.如权利要求4所述的含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂的制备方法，步骤如下：
(1)将初始原料2,4-二氯嘧啶1、取代苯酚或苯胺、与碳酸钾加入到20mL N,N-二甲基甲酰胺溶液中，室温条件下搅拌，反应8～12h；TLC监测反应，待反应完成后，向反应溶液中加入40mL水溶液并继续搅拌20～30min，过滤得白色固体，即中间体2；
(2)将中间体2、N-Boc-4-氨基哌啶或氨基丁炔盐酸盐和碳酸钾充分混合于20mL DMF溶液中，120℃油浴条件下搅拌，溶液呈黄色，TLC检测反应24-27h；加入100mL水溶液淬灭反应，乙酸乙酯萃取3次，每次20mL，合并有机层，饱和氯化钠溶液洗涤(3×50mL)，无水硫酸钠干燥，过滤，浓缩；硅胶柱色谱分离；乙酸乙酯/石油醚或者二氯甲烷/正己烷重结晶得到中间体3和6；
(3)将中间体3加入到15mL二氯甲烷溶液中，充分搅拌，然后加入三氟乙酸，室温搅拌，反应6-8h；然后用饱和碳酸氢钠溶液调节反应液的pH＝9，加入二氯甲烷溶液萃取；合并有机层，饱和食盐水洗涤3次，每次50mL；无水硫酸钠干燥；过滤，减压浓缩，硅胶柱色谱分离得到中间体4；
(4)将中间体4、溴丙炔与碳酸钾混合于10mL DMF中，室温反应；TLC检测，待反应完毕，加60mL水稀释反应液，乙酸乙酯萃取3次，每次20mL，合并有机层，加饱和食盐水洗涤3次，每次50mL，有机相用无水硫酸钠干燥；过滤，减压蒸干溶剂；硅胶柱色谱分离得到中间体5；
(5)将炔基片段5和6分别与不同的叠氮取代基加入到体积比1:1的THF/H2O混合溶液中，然后向此混合溶液中加入VcNa和CuSO4·5H2O，室温搅拌6-12h，TLC检测；随后，向反应液中加入适量的水，用乙酸乙酯萃取3次，每次10mL；合并有机层，饱和氯化钠溶液洗涤3次，每次30mL，无水硫酸钠干燥；过滤，减压蒸干溶剂；硅胶柱色谱分离；乙酸乙酯/石油醚或者二氯甲烷/正己烷重结晶得到目标化合物含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂I或II。
6.如权利要求1-3任一项所述含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂在制备抗艾滋病药物中的应用。
7.一种药物组合物，包含权利要求1-3任一项所述含三氮唑环的单芳基嘧啶类HIV-1逆转录酶抑制剂和一种或多种药学上可接受的载体或赋形剂。
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| CN115636817A (zh) * | 2022-06-20 | 2023-01-24 | 山东大学 | 含三唑环的靛红类衍生物及其制备方法与应用 |
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