CN110590785B - 一种氨基噻唑类化合物及其制备方法与抗肠道病毒71型的应用 - Google Patents
一种氨基噻唑类化合物及其制备方法与抗肠道病毒71型的应用 Download PDFInfo
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- CN110590785B CN110590785B CN201910897898.XA CN201910897898A CN110590785B CN 110590785 B CN110590785 B CN 110590785B CN 201910897898 A CN201910897898 A CN 201910897898A CN 110590785 B CN110590785 B CN 110590785B
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- imidazo
- pyrimidin
- amine
- nmr
- aminothiazole
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Abstract
本发明公开了一种氨基噻唑类化合物及其制备方法与抗肠道病毒71型的应用。属于医药技术领域。具体以2‑氯‑1‑（咪唑并[1,2‑a]嘧啶‑3‑基）乙‑1‑酮、2‑氯‑1‑（咪唑并[1,2‑a]吡啶‑3‑基）乙‑1‑酮或α‑溴代苯乙酮类化合物和芳香杂环硫脲衍生物为原料，通过成环反应制备了一系列氨基噻唑类化合物。所述的氨基噻唑类化合物具有抗肠道病毒71型的活性，其对细胞的毒性小，可以作为新的抗EV71药物进行开发，具有广泛的应用前景。
Description
技术领域
本发明属于医药技术领域，涉及一种氨基噻唑类化合物及其制备方法与抗肠道病毒71型的应用。
背景技术
肠道病毒是小核糖核酸病毒科的无包膜单链RNA病毒，突变性较高。肠道病毒包含人肠道病毒(A、B、C、D)和非人肠道病毒，而EV71则归属于人肠道病毒。EV71病毒可被划分为三种基因型(A、B、C)，这三种基因型根据结构蛋白VP1中的序列不同又可细分为十一种亚型。A基因型只包含原种菌株(BrCr)，B基因型和C基因型各包含五种亚型(B1-B5、C1-C5)。
对婴幼儿生命健康造成严重威胁的手足口病主要是由EV71和CA16引起的。手足口病能引起以发热和手、足、口腔等部位的皮疹、疱疹和疱疹性咽峡炎为主要特征的急性传染病，多发于5岁以下的婴幼儿。其中EV71引发的手足口病更为严重，往往与神经系统疾病有着密不可分的关系，如引起脑膜炎、乙型脑炎，甚至能够导致死亡。目前仍缺乏能够有效治疗手足口病的药物，临床上主要采用对症和支持疗法用于治疗手足口病。近年来关于手足口病的爆发也常有报道，尤其以亚太平洋地区最为频繁，因此设计、合成一系列新型有效的EV71抑制剂显得尤为迫切。
根据病毒的复制周期，目前用于治疗EV71的药物主要集中在以下靶点：1、衣壳蛋白抑制剂，普拉康纳利(Pleconaril)是一种衣壳蛋白结合分子，已显示出对鼻病毒和肠道病毒的广谱活性，它主要是通过干扰衣壳受体结合位点来抑制病毒附着于宿主细胞。2、3C蛋白酶抑制剂，对其基因组研究表明，编码3C蛋白酶的基因序列高度保守，如依据3C蛋白酶设计的潜力抗病毒抑制剂芦平曲韦在临床上具有很好的效果，基于此结构开发的抑制剂也多有报道。3、宿主因子抑制剂，如靶向PI4KB的PIK93、GW5074以及靶向OSBP的25-羟胆固醇等，此类抑制剂主要表现为更低的耐药性，拥有良好的应用前景。
虽然已有不同结构的EV71小分子抑制剂被报道，但是真正被应用于临床研究的治疗药物还是少之又少，所以合成一系列新型结构骨架的EV71小分子抑制剂是十分有必要的。
发明内容
本发明的首要目的在于克服现有技术存在的不足而提供下述通式(I)所示的氨基噻唑类化合物，所述的氨基噻唑类化合物具有抗肠道病毒71型的活性，可以作为新的抗EV71药物进行开发，具有广泛的应用前景。
本发明另一目的是提供下述通式(I)所示的氨基噻唑类化合物的制备方法。
为了实现上述目的，本发明所采取的技术方案如下：
第一方面，提供一种通式(I)所示的氨基噻唑类化合物或其药理或生理上可接受的盐，
其中，
R1为
R2为
优选地，本发明提供了如下表1所示的化合物：
表1
更进一步地，本发明提供以下化合物：N-(2-溴苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺(I-1)，N-(2-氟苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺(I-4)，N-([1,1'-联苯]-4-基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺(I-9)，N-(2-溴-4-甲基苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺(I-11)，4-(咪唑并[1,2-a]嘧啶-3-基)-N-苯乙基-2-胺(I-18)，4-(咪唑并[1,2-a]嘧啶-3-基)-N-(喹啉-2-基)噻唑-2-胺(I-20)。
本发明通过体外抗EV71活性实验，发现上述氨基噻唑类化合物可以用于制备抗肠道病毒71型的药物。
第二方面，本发明提供上述任意一种氨基噻唑类化合物或其药理或生理上可接受的盐在制备抗肠道病毒71型的药物中的应用。
第三方面，提供一种抗肠道病毒71型的药用组合物，包含上述氨基噻唑类化合物或其药理或生理上可接受的盐，以及药学上可接受的载体或赋形剂。
第四方面，提供通式(I)所示氨基噻唑类化合物的制备方法，该制备方法包括如下步骤：将芳香杂环硫脲类化合物与α-卤代芳香酮类化合物(如2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮、2-氯-1-(咪唑并[1,2-a]吡啶-3-基)乙-1-酮或α-溴代苯乙酮类化合物)在乙醇中回流过夜得到氨基噻唑类衍生物，
R1为取代的苯环、芳香杂环或取代的双苯环类基团中的任一种；R2为芳香杂环或者取代的苯环基团任一种。
优选的，上述通式(I)所示氨基噻唑类化合物的制备方法中芳香杂环硫脲类化合物与α-卤代芳香酮类化合物的物质的量之比为1:1。
本发明涉及的通式(I)所示氨基噻唑类化合物，可以有效抑制EV71的活性，其对细胞的毒性小，可用于制备抗EV71的药物。
具体实施方式
下面结合实施例对本发明做进一步详细的描述，所提供的实施例仅是对本发明方法的说明，而不以任何方式限制本发明揭示的其余内容。
【实施例1】带取代基R的芳香杂环硫脲类衍生物的制备
通过下式i所示反应合成得到带R的芳香杂环硫脲类衍生物。
以1-(2,6-二溴苯基)硫脲2m的制备为例，步骤如下：将硫氰酸铵(273.0mg,3.6mmol)溶解于15mL丙酮中，然后加入苯甲酰氯(460.2mg,3.38mmol)，回流15min。冷却至室温，加入2,6-二溴苯胺1m(600mg,2.4mmol)，回流30min。冷却至室温后，倒入冰水中，搅拌30min。静置两分钟，用抽滤漏斗过滤，沉淀用水洗，干燥后将固体溶于15mL10％NaOH溶液中，于80℃下加热搅拌30min，冷却至室温，缓慢滴加6N盐酸至溶液pH为1-2，搅拌30min，然后用氨水调pH至10，搅拌5分钟，抽滤，固体用水洗，干燥。用甲醇溶解以后加入硅胶拌样，旋干，用流动相比例为石油醚和乙酸乙酯(V/V＝3/1)过硅胶柱纯化，得到产物1-(2,6-二溴苯基)硫脲2m(550mg，白色固体)作为反应iv的原料。
其他带R的芳香杂环硫脲类衍生物(2a-2t)的制备方向同上。
【实施例2】带R2的α-氯代丙酮衍生物的制备
通过下式ii和iii所示反应合成得到带R2的α-氯代丙酮衍生物。
以2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a的制备为例，步骤如下：称取2-氨基嘧啶3a(1g，10.5mmol)溶解于20mL甲苯中，加入N,N-二甲基二甲缩醛(1.38g，11.6mmol)，回流6h。TLC点板监测反应完全后，旋干，得到粗产品N,N-二甲基-N'-(嘧啶-2-基)甲脒4a。将其溶解于15mL二氯甲烷中，加入1,3-二氯丙酮(2g，15.8mmol)，回流过夜。TLC监测反应完全后，浓缩并用流动相比例为石油醚和乙酸乙酯(V/V＝1/3)过硅胶柱纯化。最后得到黄色固体2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a 700mg。
化合物2-氯-1-(咪唑并[1,2-a]吡啶-3-基)乙-1-酮5b的制备方法同上。
α-溴代苯乙酮类化合物(5c-5d)通过购买得到。
【实施例3】本发明氨基噻唑类化合物的制备
通过下式iv和v所示反应合成得到氨基噻唑类化合物。
取1.0当量的实施例1制备的芳香杂环硫脲类衍生物置于25mL单口瓶中，加入8mL的无水乙醇，然后加入1.0当量的实施例2制备或购买得到的化合物，回流过夜。TLC监测反应，确认反应完全后，经硅胶柱层析分离纯化得到氨基噻唑类化合物。反应式如下式所示：
R1为
R2为
上述6a-6x对应于表1中的I-1至I-24。
(1)N-(2-溴苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺(I-1)的制备以化合物2a N-(2-溴苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺的制备为例，具体步骤如下：将1-(2-溴苯基)硫脲1a(240mg，1.0mmol，1.0eq)加入盛有8mL无水乙醇的25mL单口瓶中，加入2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a(204mg，1.0mmol，1.0eq)，回流过夜。TLC监测反应完全后，加入硅胶拌样，并用流动相比例为石油醚和乙酸乙酯(V/V＝1/3)过硅胶柱纯化，分离得到纯的黄色固体化合物I-1，产率为62％。
1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),9.45(d,J＝5.7Hz,1H),8.56(s,1H),8.19(s,1H),8.07(d,J＝7.6Hz,1H),7.68(d,J＝7.4Hz,1H),7.45-7.30(m,2H),7.18-6.98(m,2H).13C NMR(101MHz,DMSO-d6)δ165.86,150.08,148.45,139.82,139.26,134.93,133.99,133.60,128.95,125.79,123.87,119.62,115.54,109.68,105.00.
(2)N-(3-溴苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺(I-2)的制备
带R1的芳香杂环硫脲类衍生物为1-(3-溴苯基)硫脲1b，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为70％。
1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),9.53(d,J＝1.8Hz,1H),8.61(q,J＝4.0Hz,1H),8.22(s,1H),8.16(s,1H),7.45(d,J＝3.2Hz,2H),7.31(t,J＝8.0Hz,1H),7.26-7.10(m,2H).13C NMR(101MHz,DMSO-d6)δ163.94,150.23,148.56,142.75,139.99,134.75,134.22,131.49,124.39,122.47,119.95,119.63,116.44,109.77,104.61.
(3)N-(4-溴苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺(I-3)的制备
带R1的芳香杂环硫脲类衍生物为1-(4-溴苯基)硫脲1c，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为65％。
1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),9.46(d,J＝1.6Hz,1H),8.60(d,J＝2.1Hz,1H),8.22(s,1H),7.63(d,J＝8.8Hz,2H),7.53(d,J＝8.8Hz,2H),7.42(s,1H),7.27-7.23(m,1H).13C NMR(101MHz,DMSO-d6)δ164.07,150.19,148.57,140.64,140.03,134.79,134.29,132.32,119.66,119.51,113.22,109.93,104.44.
(4)N-(2-氟苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺(I-4)的制备
带R1的芳香杂环硫脲类衍生物为1-(2-氟苯基)硫脲1d，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为76％。
1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.47(d,J＝1.8Hz,1H),8.59(d,J＝2.1Hz,1H),8.32(t,J＝7.8Hz,1H),8.21(s,1H),7.41(s,1H),7.34–7.16(m,3H),7.10-7.02(m,1H).13C NMR(101MHz,DMSO-d6)δ164.79,153.87,151.44,150.12,148.53,139.75,134.78,134.13,129.19,125.25,123.41,120.98,119.71,115.86,109.77,105.09.
(5)N-(4-氟苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺(I-5)的制备
带R1的芳香杂环硫脲类衍生物为1-(4-氟苯基)硫脲1e，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为76％。
1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.48(d,J＝1.8Hz,1H),8.60(d,J＝2.1Hz,1H),8.21(s,1H),7.69-7.64(m,2H),7.38(s,1H),7.30–7.16(m,3H).13C NMR(101MHz,DMSO-d6)δ164.68,158.77,156.41,150.15,148.54,139.94,137.87,134.82,134.23,119.73,119.42,119.34,116.27,116.05,109.85,103.88.
(6)4-(咪唑并[1,2-a]嘧啶-3-基)-N-(4-甲氧基苯基)噻唑-2-胺(I-6)的制备
带R1的芳香杂环硫脲类衍生物为1-(4-甲氧基苯基)硫脲1f，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为50％。
1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.53(d,J＝1.8Hz,1H),8.60(d,J＝2.1Hz,1H),8.19(s,1H),7.54(d,J＝8.9Hz,2H),7.31(s,1H),7.25-7.21(m,1H),6.97(d,J＝9.0Hz,2H),3.75(s,3H).13C NMR(101MHz,DMSO-d6)δ165.40,154.98,150.10,148.49,140.03,134.89,134.77,134.04,119.78,114.87,109.79,103.11,55.71.
(7)4-(咪唑并[1,2-a]嘧啶-3-基)-N-(4-乙氧基苯基)噻唑-2-胺(I-7)的制备
带R1的芳香杂环硫脲类衍生物为1-(4-乙氧基苯基)硫脲1g，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为52％。
1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.53(d,J＝1.7Hz,1H),8.59(d,J＝2.1Hz,1H),8.19(s,1H),7.52(d,J＝8.9Hz,2H),7.30(s,1H),7.25-7.20(m,1H),6.95(d,J＝8.9Hz,2H),4.00(q,J＝6.9Hz,2H),1.32(t,J＝6.9Hz,3H).13C NMR(101MHz,DMSO-d6)δ165.44,154.27,150.08,148.49,140.04,134.89,134.68,134.02,119.82,115.42,109.77,103.07,63.65,15.20.
(8)4-(咪唑并[1,2-a]嘧啶-3-基)-N-(4-三氟甲基苯基)噻唑-2-胺(I-8)的制备
带R1的芳香杂环硫脲类衍生物为1-(4-三氟甲基苯基)硫脲1h，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为41％。
1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),9.46(d,J＝6.9Hz,1H),8.66–8.54(m,1H),8.25(d,J＝1.6Hz,1H),7.85(d,J＝7.9Hz,2H),7.73(d,J＝7.8Hz,2H),7.50(d,J＝1.6Hz,1H),7.29-7.24(m,1H).13C NMR(101MHz,DMSO-d6)δ163.68,150.24,148.63,144.58,140.10,134.78,134.47,127.03,127.00,126.96,126.93,119.58,117.17,110.00,105.21.
(9)N-([1,1'-联苯]-4-基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺(I-9)的制备
带R1的芳香杂环硫脲类衍生物为1-([1,1'-联苯]-4-基)硫脲1i，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为36％。
1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),9.54(d,J＝5.9Hz,1H),8.61(d,J＝1.8Hz,1H),8.24(s,1H),7.83–7.60(m,6H),7.47–7.40(m,3H),7.37–7.21(m,2H).13C NMR(101MHz,DMSO-d6)δ164.31,150.16,148.57,140.79,140.23,140.10,134.87,134.23,133.74,129.36,127.83,127.28,126.56,119.74,118.00,109.88,104.10.
(10)4-(咪唑并[1,2-a]嘧啶-3-基)-N-苯基噻唑-2-胺(I-10)的制备
带R1的芳香杂环硫脲类衍生物为苯基硫脲1j，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为69％。
1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),9.54–9.49(m,1H),8.62–8.58(m,1H),8.21(s,1H),7.64(d,J＝7.9Hz,2H),7.40–7.34(m,3H),7.25–7.20(m,1H),7.00(t,J＝7.3Hz,1H).13C NMR(101MHz,DMSO-d6)δ164.55,150.16,148.53,141.34,140.02,134.83,134.14,129.64,122.13,119.75,117.67,109.81,103.90.
(11)N-(2-溴-4-甲基苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺(I-11)的制备
带R1的芳香杂环硫脲类衍生物为1-(2-溴-4-甲基苯基)硫脲1k，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为78％。
1H NMR(400MHz,CDCl3)δ9.52–9.48(m,1H),8.84–8.44(m,1H),8.08(s,1H),7.85(d,J＝8.3Hz,1H),7.75(s,1H),7.42(s,1H),7.15(d,J＝8.3Hz,1H),6.99–6.84(m,2H),2.32(s,3H).13C NMR(101MHz,CDCl3)δ164.90,149.52,140.75,135.34,134.62,133.74,133.33,129.15,119.36,113.58,108.83,103.68,20.50.
(12)N-(2-溴-4-氟苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺(I-12)的制备
带R1的芳香杂环硫脲类衍生物为1-(2-溴-4-氟苯基)硫脲1l，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为48％。
1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),9.44–9.40(m,1H),8.58–8.54(m,1H),8.18(s,1H),8.06–8.01(m,1H),7.70–7.65(m,1H),7.46–7.27(m,2H),7.18–7.14(m,1H).13C NMR(101MHz,DMSO-d6)δ166.41,159.85,157.41,150.08,148.45,139.83,136.10,134.90,133.98,126.02,120.53,120.27,119.60,116.02,115.80,109.69,104.76.
(13)N-(2,6-二溴苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺(I-13)的制备
带R1的芳香杂环硫脲类衍生物为1-(2,6-二溴苯基)硫脲1m，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为52％。
1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),9.35(s,1H),8.53(s,1H),8.13(s,1H),7.82(d,J＝3.5Hz,2H),7.18(d,J＝66.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ167.55,150.10,148.38,140.21,138.22,134.68,133.82,133.45,130.80,125.04,119.54,109.52,104.23.
(14)4-(咪唑并[1,2-a]嘧啶-3-基)-N-(2,4,6-三溴苯基)噻唑-2-胺(I-14)的制备
带R1的芳香杂环硫脲类衍生物为1-(2,4,6-三溴苯基)硫脲1n，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为38％。
1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),9.32(d,J＝5.7Hz,1H),8.55(d,J＝1.9Hz,1H),8.21–8.03(m,3H),7.30(s,1H),7.16–7.10(m,1H).13C NMR(101MHz,DMSO-d6)δ166.98,150.11,148.41,135.45,134.61,133.88,125.61,121.32,119.46,109.58,104.62.
(15)N-(2,6-二氟-4-碘苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺(I-15)的制备
带R1的芳香杂环硫脲类衍生物为1-(2,6-二氟-4-碘苯基)硫脲1o，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为52％。
1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),9.33–9.30(m,1H),8.57–8.53(m,1H),8.13(s,1H),7.73(d,J＝7.4Hz,2H),7.36(s,1H),7.17–7.13(m,1H).13C NMR(101MHz,DMSO-d6)δ166.10,158.58,156.03,150.18,148.43,139.92,134.57,133.92,122.06,121.81,119.40,109.67,105.34.
(16)N-(2,6-二氯-4-甲基苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺(I-16)的制备
带R1的芳香杂环硫脲类衍生物为1-(2,6-二氯-4-甲基苯基)硫脲1p，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为45％。
1H NMR(400MHz,CDCl3)δ9.48–9.37(m,1H),8.59–8.44(m,1H),8.03(s,1H),7.82(s,1H),7.31(t,J＝8.5Hz,1H),7.17(d,J＝8.3Hz,1H),6.97–6.79(m,2H),2.41(s,3H).13CNMR(101MHz,CDCl3)δ167.96,149.50,148.59,140.61,136.90,134.65,134.57,133.60,133.43,130.45,129.82,128.04,119.24,108.69,104.94,20.58.
(17)4-(咪唑并[1,2-a]嘧啶-3-基)-N-(2,4,6-三氯苯基)噻唑-2-胺(I-17)的制备
带R1的芳香杂环硫脲类衍生物为1-(2,4,6-三氯苯基)硫脲1q，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为56％。
1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),9.32–9.26(m,1H),8.56–8.52(m,1H),8.13(s,1H),7.85(s,2H),7.32(s,1H),7.14–7.12(m,1H).13C NMR(101MHz,DMSO-d6)δ166.80,150.14,148.41,134.60,133.91,132.52,129.35,119.42,109.61,104.86.
(18)4-(咪唑并[1,2-a]嘧啶-3-基)-N-苯乙基-2-胺(I-18)的制备
带R1的芳香杂环硫脲类衍生物为1-苯乙基硫脲1r，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为29％。
1H NMR(400MHz,CDCl3)δ9.56–9.52(m,1H),8.54–8.51(m,1H),8.02(s,1H),7.39–7.32(m,2H),7.30–7.24(m,3H),6.92–6.88(m,1H),6.73(s,1H),5.79(s,1H).3.67(t,J＝6.9Hz,2H),3.04(t,J＝7.0Hz,2H).13C NMR(101MHz,CDCl3)δ169.75,149.42,148.53,140.65,138.47,134.90,133.19,128.80,126.76,119.68,108.71,102.02,46.94,35.44.
(19)4-(咪唑并[1,2-a]嘧啶-3-基)-N-(嘧啶-2-基)噻唑-2-胺(I-19)的制备带R1的芳香杂环硫脲类衍生物为1-(嘧啶-2-基)硫脲1s，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为39％。
1H NMR(400MHz,DMSO-d6)δ12.01(s,1H),9.83(d,J＝4.7Hz,1H),8.80–8.42(m,3H),8.24(s,1H),7.61(s,1H),7.15(d,J＝49.5Hz,2H).13C NMR(101MHz,DMSO-d6)δ160.41,158.65,157.38,150.15,148.51,139.57,135.50,133.82,119.63,114.70,109.63,107.72.
(20)4-(咪唑并[1,2-a]嘧啶-3-基)-N-(喹啉-2-基)噻唑-2-胺(I-20)的制备带R1的芳香杂环硫脲类衍生物为1-(喹啉-2-基)硫脲1t，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]嘧啶-3-基)乙-1-酮5a，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为39％。
1H NMR(400MHz,DMSO-d6)δ11.96(s,1H),9.75–9.72(m,1H),8.64–8.60(m,1H),8.33–8.20(m,2H),7.96–7.82(m,2H),7.71(t,J＝7.2Hz,1H),7.63(s,1H),7.43(t,J＝7.3Hz,1H),7.33–7.21(m,2H).13C NMR(101MHz,DMSO-d6)δ160.16,150.63,150.13,148.52,146.23,139.12,138.58,135.09,133.97,130.57,128.38,126.42,124.64,124.45,119.85,113.22,109.61,107.68.
(21)N-(2-溴苯基)-4-(咪唑并[1,2-a]吡啶-3-基)噻唑-2-胺(I-21)的制备带R1的芳香杂环硫脲类衍生物为1-(2-溴苯基)硫脲1b，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]吡啶-3-基)乙-1-酮5b，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为45％。
1H NMR(400MHz,CDCl3)δ9.08(d,J＝7.0Hz,1H),8.15–8.11(m,1H),7.94(s,2H),7.66(d,J＝9.1Hz,1H),7.61–7.57(m,1H),7.38–7.31(m,1H),7.24–7.16(m,1H),6.98–6.90(m,1H),6.89–6.81(m,2H).13C NMR(101MHz,CDCl3)δ163.82,146.08,141.47,137.92,132.88,128.56,126.49,124.64,123.84,120.63,118.73,117.70,112.84,112.59,103.64.
(22)N-(2-溴-4-甲基苯基)-4-(咪唑并[1,2-a]吡啶-3-基)噻唑-2-胺(I-22)的制备
带R1的芳香杂环硫脲类衍生物为1-(2-溴-4-甲基苯基)硫脲1k，R2取代的α-氯代丙酮衍生物为2-氯-1-(咪唑并[1,2-a]吡啶-3-基)乙-1-酮5b，参照(1)中的方法制备目标化合物，产物为黄色固体，产率为37％。
1H NMR(400MHz,CDCl3)δ9.09(d,J＝7.0Hz,1H),8.14–7.87(m,2H),7.79(s,1H),7.66(d,J＝9.0Hz,1H),7.42(s,1H),7.26–7.19(m,1H),7.15(d,J＝8.3Hz,1H),6.87–6.83(m,2H),2.32(s,3H).13C NMR(101MHz,CDCl3)δ164.51,146.06,141.48,135.47,134.25,133.24,132.79,129.16,126.53,124.58,120.69,119.18,117.69,113.27,112.54,103.25,20.49.
(23)4-(4-溴苯基)-N-(2,4,6-三氯苯基)噻唑-2-胺(I-23)的制备
带R1的芳香杂环硫脲类衍生物为1-(2,4,6-三氯苯基)硫脲1q，R2取代的α-溴代丙酮衍生物为2-溴-1-(4-溴苯基)乙-1-酮5c，参照(1)中的方法制备目标化合物，产物为白色固体，产率为56％。
1H NMR(400MHz,CDCl3)δ8.50(s,1H),7.58(d,J＝8.2Hz,2H),7.50–7.35(m,4H),6.78(s,1H).13C NMR(101MHz,CDCl3)δ170.68,139.36,138.75,136.93,136.68,134.00,132.84,125.79,109.70.
(24)4-(4-甲氧基苯基)-N-(2,4,6-三氯苯基)噻唑-2-胺(I-24)的制备
带R1的芳香杂环硫脲类衍生物为1-(2,4,6-三氯苯基)硫脲1q，R2取代的α-溴代丙酮衍生物为2-溴-1-(4-甲氧基苯基)乙-1-酮5d，参照(1)中的方法制备目标化合物，产物为白色固体，产率为52％。
1H NMR(400MHz,CDCl3)δ9.12(s,1H),7.59(d,J＝8.7Hz,2H),7.39(d,J＝6.5Hz,2H),6.76(d,J＝8.7Hz,2H),6.61(d,J＝6.5Hz,1H),3.81(s,3H).13C NMR(101MHz,CDCl3)δ167.48,159.29,151.05,134.87,134.76,132.91,128.81,127.38,113.64,101.04,55.25.
以上合成的本发明的目标化合物I-1至I-24的化学结构见表1。
【实施例4】氨基噻唑类化合物生物活性测试
(1)氨基噻唑类化合物体外抗EV71活性：
首先，向铺满RD细胞的96孔板中加入EV71病毒与不同稀释度的药物的混合物，面积比为80％，每个稀释度8个重复孔。37℃恒温条件下培养24–48小时病毒对照组细胞完全病变后，加入20μL MTS/PMS混合溶液，37℃恒温条件下继续培养4小时。用酶标仪测定490nm下的OD值。化合物的抑制率(％)＝[1-(E-N)/(P-N)]×100，其中“E”代表实验组的OD值，“P”代表阳性对照组的OD值，“N”代表阴性对照组的OD值。细胞病变程度可以体现药物对病毒的抑制程度。半数抑制浓度(EC50)是抗病毒活性的指标。
(2)氨基噻唑类化合物细胞毒性测定：
Cell Counting Kit-8简称CCK-8试剂盒，是一种基于WST-8(化学名：2-(2-甲氧基-4-硝苯基)-3-(4-硝苯基)-5-(2,4-二磺基苯)-2H-四唑单钠盐)的广泛应用于细胞增殖和细胞毒性的快速高灵敏度检测试剂盒。工作原理为：在电子耦合试剂存在的情况下，可以被线粒体内的脱氢酶还原生成高度水溶性的橙黄色的甲臜产物(formazan)。颜色的深浅与细胞的增殖成正比，与细胞毒性成反比。使用酶标仪在450nM波长处测定OD值，间接反映活细胞数量。
首先，向铺满RD细胞的96孔板中，24小时后加入不同稀释度的药物。37℃恒温条件下培养8-24小时后，加入20μL MTS/PMS混合溶液，37℃恒温条件下继续培养4小时。用酶标仪测定450nm下的OD值。化合物的抑制率(％)＝[1-(E-N)/(P-N)]×100，其中“E”代表实验组的OD值，“P”代表阳性对照组的OD值，“N”代表阴性对照组的OD值。半数抑制浓度(CC50)是化合物细胞毒性的指标。
本发明以恩韦肟对照，对合成的24个化合物进行细胞毒性和抗EV71活性检查，并计算了化合物的选择性指数SI，结果见表2。
表2 本发明合成的目标化合物I1-24抗EV71活性和细胞毒性的结果
| Compounds | EC<sub>50</sub>(μM) | CC<sub>50</sub>(μM) | SI(EC<sub>50</sub>/CC<sub>50</sub>) |
| I-1 | 11.194 | >89.548 | >8.0 |
| I-2 | NA | 167.902 | - |
| I-3 | 44.774 | 179.096 | 4.0 |
| I-4 | 3.346 | 60.224 | 18.0 |
| I-5 | NA | 535.320 | - |
| I-6 | 51.541 | >51.541 | >1.0 |
| I-7 | 37.048 | 268.464 | 7.2 |
| I-8 | 69.185 | >369.434 | >5.3 |
| I-9 | 5.322 | 56.182 | 10.6 |
| I-10 | NA | >568.150 | - |
| I-11 | 10.787 | 56.182 | 5.2 |
| I-12 | 42.710 | 170.839 | 4.0 |
| I-13 | 73.887 | 100.819 | 1.4 |
| I-14 | 15.722 | 314.442 | 20.0 |
| I-15 | 27.459 | >27.459 | >1 |
| I-16 | 33.222 | 177.183 | 5.3 |
| I-17 | 21.008 | >420.165 | 20.0 |
| I-18 | 6.482 | 122.303 | 18.9 |
| I-19 | NA | >564.360 | - |
| I-20 | 7.102 | >483.933 | >68.1 |
| I-21 | 22.446 | >448.937 | >20.0 |
| I-22 | 86.517 | >432.586 | >5.0 |
| I-23 | NA | >383.530 | - |
| I-24 | NA | >432.126 | - |
| 恩韦肟 | 0.140 | 28.000 | 200.0 |
上述实验结果表明：合成的大多数氨基噻唑类化合物都具有较好抗EV71活性，例如化合物I-1(EC50＝11.194μM,SI>8.0)、I-4(EC50＝3.346μM,SI＝18.0)、I-9(EC50＝5.322μM,SI＝10.6)、I-11(EC50＝10.787μM,SI＝5.2)、I-18(EC50＝6.482μM,SI＝18.9)和I-20(EC50＝7.102μM,SI>68.1)等，尤其是化合物I-4、I-18和I-20均显示了较低的微摩尔水平的抗流感病毒活性和较高的选择性。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (4)
1.一种氨基噻唑类化合物或其药理或生理上可接受的盐，其特征在于，结构如通式(I)所示：
其中，所述的氨基噻唑类化合物具体为表1所示的化合物：
表1
2.根据权利要求1所述的氨基噻唑类化合物或其药理或生理上可接受的盐，其特征在于，所述通式(I)所示的氨基噻唑类化合物为：N-(2-溴苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺，N-(2-氟苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺，N-([1,1'-联苯]-4-基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺，N-(2-溴-4-甲基苯基)-4-(咪唑并[1,2-a]嘧啶-3-基)噻唑-2-胺，4-(咪唑并[1,2-a]嘧啶-3-基)-N-苯乙基-2-胺，4-(咪唑并[1,2-a]嘧啶-3-基)-N-(喹啉-2-基)噻唑-2-胺。
3.权利要求1或2所述的氨基噻唑类化合物或其药理或生理上可接受的盐在制备抗肠道病毒71型的药物中的应用。
4.一种抗肠道病毒71型的药用组合物，其特征在于，包含权利要求1或2所述的氨基噻唑类化合物或其药理或生理上可接受的盐，以及药学上可接受的载体或赋形剂。
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