CN103664926A - 一类二氢吡唑噻唑衍生物的合成及在抗癌药物中的应用 - Google Patents
一类二氢吡唑噻唑衍生物的合成及在抗癌药物中的应用 Download PDFInfo
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本发明的目的在于提供一类二氢吡唑噻唑衍生物的合成及在抗癌药物中的应用
背景技术
近年来,含噻唑环化合物在药物研究和生物学等方面显示出越来越重要的作用,其中氨基噻唑类化合物具有较强生理活性,尤其受到研究者的重视。
吡唑是一类重要的杂环化合物,广泛分布在自然界中。自从含吡唑环的安替吡啉具有镇痛消炎及退热作用被发现以来,该类化合物因其具有高效、低毒,以及其环上取代基的多方位变换而在药物领域中得到广泛应用。研究发现吡唑类化合物具有消炎、止痛、抑菌、杀菌、抗高血糖、抗癌、抗凝血剂等药理活性。近年来,许多新型吡唑类医药相继商品化,对吡唑类化合物的深入研究已成为当今药物设计合成研究的热点之一。
2H吡唑是极为重要的含氮的五元杂环化合物,它具有较强的生物活性,比如抗肿瘤、抗菌、抗病毒、抗真菌、抗结核、杀虫等活性。它是一个具有各种药理特性的结构性存在亚基,存在普遍药用生物活性的活性化合物先导。更为重要的是:因为2H吡唑多是手性的,导致环上的取代及分子的构象具有更大的多变性,具有更好的生物活性潜质!2H吡唑类化合物在有机合成和其他领域中的应用越来越广泛,且手性2H吡唑类化合物具有诸多生物及药理性能,促进了药物的巨大发展,为以后的药物开发研究提供了很大的研究空间,发展前景非常广阔,因此构建具有2H吡唑结构的杂环体系具有重要的意义,是近几年被关注的热点。
基于此,本发明将不同噻唑引入到二氢吡唑衍生物中,设计合成了一系列结构新颖的二氢吡唑噻唑衍生物,期望具有更好的生物活性、更高的选择性、更低的毒性、更长或更短的残效期等.
发明内容
本发明的技术方案如下:
1.一类二氢吡唑噻唑衍生物的合成及制备,其特征是它有如下通式:
R1:H,F,CH3O;R2:H,CH3O,Br;R3:H,Br,CH3O,CF3
一种上述的二氢吡唑噻唑衍生物的合成,它由下列步骤组成:
步骤1.在搅拌下,依次向反应容器中加入适量的水杨醛、不同取代基的苯乙酮、碱溶液、有机溶剂,适当的温度下继续搅拌反应适当的时间后,过滤,洗涤,干燥得中间体2。
步骤2.在反应容器中加入适量的查尔酮的衍生物2、氨基硫脲、碱、适量的有机溶剂,在适当的温度下搅拌反应一段时间(TLC跟踪反应,直至至少一种原料很少甚至没有),过滤得粗产品,粗品经柱层析或采用适当的有机溶剂重结晶提纯得化合物3.
步骤3.在适量的反应容器中加入适量的化合物3和不同取代基的α-溴苯乙酮,有机溶剂,置于一定的条件下反应,采取一定的条件处理得本发明的目标化合物。
本发明的二氢吡唑噻唑衍生物对人乳腺癌细胞(MCF-7)、宫颈癌细胞(Hela)以及肝癌细胞(Hepg2)有明显的抑制作用,因此本发明的二氢吡唑噻唑衍生物可以应用于制备抗肿瘤药物。
具体实施方式
实施例一:2-(3-苯基-1-(4-苯噻唑基)-4,5-二氢吡唑)苯酚(化合物1)的制备
在搅拌下依次将合成的中间体3(0.5g,1.3mmol)、DMF(15mL)、α-溴代苯乙酮(0.26g,1.3mmol)加入到25mL的圆底烧瓶中,室温下搅拌反应6h,TLC跟踪反应(展开剂VAcOEt:V正己烷=1:2),反应结束后,将反应液直接倒入冰水中,过滤,固体用蒸馏水洗涤,最后真空干燥,将得到的固体溶于无水乙醇重结晶提纯得到晶体状目标化合物。
白色晶体,产率89.2%.m.p.212~214℃;1H NMR(DMSO-d6,300MHz)δ:9.72(s,1H),7.77(dd,J1=7.8,J2=6.8Hz,2H),7.70(d,J=7.2Hz,2H),7.45(t,J=2.8Hz, 3H),7.35~7.20(m,4H),7.09(dd,J1=16.4,J2=16.1Hz,2H),6.84(d,J=7.8Hz,1H),6.74(t,J=3.7Hz,1H),5.81(dd,J1=12.1,J2=12.2Hz,1H),3.97(dd,J1=17.7,J2=17.6Hz,1H),3.27(q,J=10.7Hz,1H).
实施例二:2-(1-(4-(4-溴苯基)噻唑)-3-苯基-4,5-二氢吡唑)苯酚(化合物2)的制备
制备方法同实施例一得白色晶体,产率94.1%.m.p.238~240℃;1H NMR(DMSO-d6,300MHz)δ:9.73(s,1H),7.77(dd,J1=7.7,J2=6.7Hz,2H),7.67(d,J=8.5Hz,2H),7.53~7.45(m,5H),7.36(s,1H),7.10(dd,J1=13.3,J2=13.7Hz,2H),6.85(d,J=7.8Hz,1H),6.75(t,J=3.7Hz,1H),5.81(dd,J1=12.0,J2=12.1Hz,1H),3.97(dd,J1=17.7,J2=17.6Hz,1H),3.29(dd,J1=17.7,J2=17.6Hz,1H).
实施例三:2-(1-(4-(3-溴苯基)噻唑)-3-苯基-4,5-二氢吡唑)苯酚(化合物3)的制备
制备方法同实施例一得白色晶体,产率88.3%.m.p.193~195℃;1H NMR(DMSO-d6,300MHz)δ:9.71(s,1H),7.88(s,1H),7.75(dd,J1=16.2,J2=18.9Hz,3H),7.46(t,J=2.8Hz,5H),7.30(t,J=3.9Hz,1H),7.17~7.07(m,2H),6.85(d,J=7.8Hz,1H),6.76(t,J=3.6Hz,1H),5.80(dd,J1=11.9,J2=11.9Hz,1H),3.96(dd,J1=17.7,J2=17.5Hz,1H),3.31(dd,J1=17.9,J2=17.7Hz,1H).
实施例四:2-(1-(4-(4-甲氧基苯基)噻唑)-3-苯基-4,5-二氢吡唑)苯酚(化合物4)的制备
制备方法同实施例一得白色晶体,产率91.5%.m.p.207~209℃;1H NMR(DMSO-d6,300MHz)δ:9.72(s,1H),7.74~7.70(m,4H),7.35~7.22(m,5H),7.11~6.98(m,5H),6.85(d,J=4.3Hz,1H),6.74(t,J=2.2Hz,1H),5.79(dd,J1=7.1,J2=7.1Hz,1H),3.95(dd,J1=10.5,J2=10.4Hz,1H),3.81(s,3H),3.25(dd,J1=10.5,J2=10.5Hz,1H).
实施例五:2-(1-(4-(3-甲氧基苯基)噻唑)-3-苯基-4,5-二氢吡唑)苯酚(化合物5)的制备
制备方法同实施例一得白色晶体,产率90.4%.m.p.196~197℃;1H NMR(DMSO-d6,300MHz)δ:9.71(s,1H),7.85~7.76(m,3H),7.46(d,J=6.0Hz,3H),7.36(s,1H),7.23(t,J=3.9Hz,1H),7.14~7.03(m,3H),6.92(t,J=3.7Hz,1H),6.85(d,J=7.9Hz,1H),6.75(t,J=3.7Hz,1H),5.81(dd,J1=11.9,J2=12.0Hz,1H),3.97(dd,J1=17.7,J2=17.6Hz,1H),3.87(s,3H),3.28(dd,J1=17.6,J2=17.6Hz,1H).
实施例六:2-(1-(4-(4-三氟苯基)噻唑)-3-苯基-4,5-二氢吡唑)苯酚(化合物6)的制备
制备方法同实施例一得白色晶体,产率89.7%.m.p.236~238℃;1H NMR(DMSO-d6,300MHz)δ:9.73(s,1H),7.92(d,J=8.1Hz,2H),7.78(dd,J1=7.7,J2=6.5Hz,2H),7.69(d,J=8.3Hz,2H),7.52(s,1H),7.51~7.45(m,3H),7.15~7.06(m,2H),6.85(d,J=7.8Hz,1H),6.76(t,J=3.6Hz,1H),5.83(dd,J1=11.9,J2=12.1Hz,1H),3.98(dd,J1=17.7,J2=17.6Hz,1H),3.30(dd,J1=17.8,J2=17.7Hz,1H).
实施例七:2-(3-(4-氟苯基)-1-(4-苯噻唑)-3-苯基-4,5-二氢吡唑)苯酚(化合物7)的制备
制备方法同实施例一得白色晶体,产率88.7%.m.p.236~238℃;1H NMR(DMSO-d6,300MHz)δ:9.73(s,1H),7.83(dd,J1=8.3,J2=8.1Hz,2H),7.71(d,J=7.5Hz,2H),7.34~7.22(m,6H),7.10(dd,J1=18.0,J2=17.9Hz,2H),6.85(d,J=7.9Hz,1H),6.75(t,J=3.7Hz,1H),5.81(dd,J1=11.9,J2=12.1Hz,1H),3.97(dd,J1=17.7,J2=17.7Hz,1H),3.29(q,J=10.7Hz,1H).
实施例八:2-(1-(4-(4-溴苯基)噻唑)-3-(4-氟苯基)-4,5-二氢吡唑)苯酚(化合物8)的制备
制备方法同实施例一得白色晶体,产率87.8%.m.p.248~250℃;1H NMR(DMSO-d6,300MHz)δ:9.72(s,1H),7.83(dd,J1=5.1,J2=5.1Hz,2H),7.66(d,J=5.1Hz,2H),7.53(d,J=5.1Hz,2H),7.36(s,1H),7.31(t,J=2.6Hz,2H),7.13~7.07(m,2H),6.84(d,J=4.8Hz,1H),6.75(t,J=2.2Hz,1H),5.80(dd,J1=7.2,J2=7.2Hz,1H),3.96(dd,J1=10.6,J2=10.5Hz,1H),3.28(dd,J1=10.6,J2=10.6Hz,1H).
实施例九:2-(1-(4-(3-溴苯基)噻唑)-3-(4-氟苯基)-4,5-二氢吡唑)苯酚(化合物9)的制备
制备方法同实施例一得白色晶体,产率90.4%.m.p.199~201℃;1H NMR(DMSO-d6,300MHz)δ:9.72(s,1H),7.88~7.80(m,3H),7.71(d,J=7.7Hz,1H),7.42(t,J=2.9Hz,2H),7.34~7.27(m,3H),7.17~7.07(m,2H),6.85(d,J=8.2Hz,1H),6.76(t,J=3.6Hz,1H),5.79(dd,J1=11.9,J2=12.2Hz,1H),3.95(dd,J1=17.6,J2=17.6Hz,1H),3.31(dd,J1=17.6,J2=17.9Hz,1H).
实施例十:2-(3-(4-氟苯基)-1-(4-(4-甲氧基苯基)噻唑)-4,5-二氢吡唑)苯酚(化合物10)的制备
制备方法同实施例一得白色晶体,产率94.6%.m.p.239~241℃;1H NMR(DMSO-d6,300MHz)δ:9.73(s,1H),7.82(dd,J1=4.7,J2=4.6Hz,2H),7.64(d,J=5.0Hz,2H),7.31(t,J=2.6Hz,2H),7.13~7.07(m,3H),6.90~6.84(m,3H),6.75(t,J=2.2Hz,1H),5.80(dd,J1=7.2,J2=7.2Hz,1H),3.96(dd,J1=10.6,J2=10.5Hz,1H),3.75(s,3H),3.28(dd,J1=10.6,J2=10.6Hz,1H).
实施例十一:2-(3-(4-氟苯基)-1-(4-(3-甲氧基苯基)噻唑)-4,5-二氢吡唑)苯酚(化合物11)的制备
制备方法同实施例一得白色晶体,产率93.6%.m.p.205~207℃;1H NMR(DMSO-d6,300MHz)δ:9.73(s,1H),7.85~7.80(m,3H),7.32(dd,J1=15.5,J2=17.6Hz,3H),7.26~7.20(m,1H),7.14~7.03(m,3H),6.92(t,J=3.8Hz,1H),6.85(d,J=7.8Hz,1H),6.75(t,J=3.6Hz,1H),5.81(dd,J1=11.9,J2=12.0Hz,1H),3.96(dd,J1=17.7,J2=17.6Hz,1H),3.87(s,3H),3.28(dd,J1=17.7,J2=17.6Hz,1H).
实施例十二:2-(3-(4-氟苯基)-1-(4-(4-三氟甲基苯基)噻唑)-4,5-二氢吡唑)苯酚(化合物12)的制备
制备方法同实施例一得白色晶体,产率90.4%.m.p.216~218℃;1H NMR(DMSO-d6,300MHz)δ:9.73(s,1H),7.92(d,J=8.1Hz,2H),7.83(dd,J1=8.7,J2=8.6Hz,2H),7.69(d,J=8.3Hz,2H),7.52(s,1H),7.30(t,J=4.4Hz,2H),7.12~7.06(m,2H),6.85(d,J=7.8Hz,1H),6.76(t,J=3.7Hz,1H),5.82(dd,J1=12.0,J2=12.1Hz,1H),3.97(dd,J1=17.8,J2=17.6Hz,1H),3.28(dd,J1=17.6,J2=17.5Hz,1H).
实施例十三:2-(3-(4-甲氧基苯基)-1-(4-苯噻唑)-3-苯基-4,5-二氢吡唑)苯酚(化合物13)的制备
制备方法同实施例一得白色晶体,产率90.5%.m.p.234~236℃;1H NMR(DMSO-d6,300MHz)δ:9.72(s,1H),7.77(d,J=4.3Hz,2H),7.64(d,J=5.1Hz,2H),7.48~7.43(m,3H),7.13~7.07(m,3H),6.87(dd,J1=12.9,J2=12.7Hz,3H),6.75(t,J=2.2Hz,1H),5.81(dd,J1=7.2,J2=7.2Hz,1H),3.97(dd,J1=10.5,J2=10.4Hz,1H),3.75(s,3H),3.28(q,J=10.6Hz,1H).
实施例十四:2-(1-(4-(4-溴苯基)噻唑)-3-(4-甲氧基苯基)-4,5-二氢吡唑)苯酚(化合物14)的制备
制备方法同实施例一得白色晶体,产率91.3%.m.p.250~252℃;1H NMR(DMSO-d6,300MHz)δ:7.69(dd,J1=18.0,J2=17.8Hz,5H),7.52(d,J=8.6Hz,2H),7.34(s,1H),7.10~7.01(m,4H),6.85(d,J=7.9Hz,1H),6.74(t,J=3.8Hz,1H),5.78(dd,J1=11.8,J2=11.9Hz,1H),3.95(dd,J1=17.7,J2=17.5Hz,1H),3.19(s,3H),3.25(dd,J1=17.6,J2=17.6Hz,1H).
实施例十五:2-(1-(4-(3-溴苯基)噻唑)-3-(4-甲氧基苯基)-4,5-二氢吡唑)苯酚(化合物15)的制备
制备方法同实施例一得白色晶体,产率90.1%.m.p.189~191℃;1H NMR(DMSO-d6,300MHz)δ:7.87(s,1H),7.72(d,J=8.7Hz,3H),7.42(t,J=4.0Hz,2H),7.30(t,J=3.9Hz,1H),7.14~7.01(m,5H),6.85(d,J=7.7Hz,1H),6.75(t,J=3.7Hz,1H),5.77(dd,J1=11.7,J2=11.6Hz,1H),3.94(dd,J1=17.5,J2=17.4Hz,1H),3.81(s,3H),3.27(dd,J1=17.6,J2=17.5Hz,1H).
实施例十六:2-(3-(4-甲氧基苯基)-1-(4-(4-甲氧基苯基)噻唑)-4,5-二氢吡唑)苯酚(化合物16)的制备
制备方法同实施例一得白色晶体,产率93.4%.m.p.198~200℃;1H NMR(DMSO-d6,300MHz)δ:7.72(d,J=8.7Hz,2H),7.64(d,J=8.7Hz,2H),7.11~6.96(m,6H),6.87(dd,J1=11.2,J2=10.6Hz,3H),6.74(t,J=3.8Hz,1H),5.77(dd,J1=11.8,J2=12.0Hz,1H),3.94(dd,J1=17.6,J2=17.6Hz,1H),3.81(s,3H),3.75(s,3H),3.24(dd,J1=17.6,J2=17.5Hz,1H).
实施例十七:2-(3-(4-甲氧基苯基)-1-(4-(3-甲氧基苯基)噻唑)-4,5-二氢吡唑)苯酚(化合物17)的制备
制备方法同实施例一得白色晶体,产率92.8%.m.p.93~95℃;1H NMR(DMSO-d6,300MHz)δ:7.82(dd,J1=7.9,J2=7.7Hz,1H),7.72(d,J=8.7Hz,2H),7.33(s,1H),7.26~7.20(m,1H),7.12~7.01(m,6H),6.94~6.84(m,2H),6.74(t,J=3.8Hz,1H),5.78(dd,J1=11.8,J2=11.9Hz,1H),3.95(dd,J1=17.6,J2=17.5Hz,1H),3.87(s,3H),3.81(s,3H),3.24(dd,J1=17.7,J2=17.6Hz,1H).
实施例十八:2-(3-(4-甲氧基苯基)-1-(4-(4-三氟甲基苯基)噻唑)-4,5-二氢吡唑)苯酚(化合物18)的制备
制备方法同实施例一得白色晶体,产率92.7%.m.p.95~97℃;1H NMR(DMSO-d6,300MHz)δ:9.73(s,1H),7.92(d,J=8.1Hz,2H),7.71(t,J=4.5Hz,4H),7.51(s,1H),7.12~7.01(m,4H),6.86(d,J=7.8Hz,1H),6.75(t,J=3.7Hz,1H),5.80(dd,J1=11.8,J2=11.9Hz,1H),3.96(dd,J1=17.6,J2=17.6Hz,1H),3.81(s,3H),3.27(dd,J1=17.6,J2=17.5Hz,1H).
实施例十九:二氢吡唑噻唑衍生物体外抗肿瘤活性研究
采用MTT[3-(4,5)-双甲基-2-噻唑-(2,5)-苯基溴化四氮唑蓝]法来测定二氢吡唑磺胺衍生物对人乳腺癌细胞(MCF-7)、宫颈癌细胞(Hela)、肺癌细胞(A549)以及肝癌细胞(Hepg2)的半数抑制浓度(IC50)。
(1)培养液(每升)的配制:①悬浮细胞:RPMI-1640培养粉一袋(10.4g),新生牛血清100mL,青霉素溶液(20万U/mL)0.5mL,链霉素溶液(20万U/mL)0.5mL,加三蒸水溶解后,用5.6%的NaHCO3溶液调PH值至7.2-7.4,最后定容至1000mL。过滤灭菌。②贴壁细胞:同上,再加入NaHCO32.00g,HEPES2.38g。
(2)D-Hanks缓冲液(每升)的配制:NaCl8.00g,KCl0.40g,Na2HPO4·12H2O0.06g,KH2PO40.06g,NaHCO30.35g。高压灭菌。
(3)胰蛋白酶液的配制:利用D-Hanks缓冲液配成浓度为0.5%胰蛋白酶液。过滤除菌。
(4)实验药液的配制:将测试样品用少量的三蒸水溶解配成储备液,一般按实验最高浓度的10倍配制储备液。根据化合物溶解性不同,可用三蒸水直接溶解,或用少量DMSO助溶,再加三蒸水溶解。DMSO在培养液中的浓度不宜 过大,加药后的每孔细胞悬液中DMSO的终浓度一般不超过0.05%-0.1%。储备液保存于-20℃冰箱中备用。
(5)人乳腺癌细胞(MCF-7)、宫颈癌细胞(Hela)、肺癌细胞(A549)以及肝癌细胞(Hepg2)的培养:为悬浮生长细胞,常规培养于RPMI-1640培养液内(含10%小牛血清、100U/mL链霉素),置于37℃、5%CO2培养箱中培养,每隔3-4天传代一次。传代时将原瓶中培养液转移至离心管中,1000rpm离心5min,弃去原培养液,加入等量新鲜培养液,吹打均匀,移取适量至新鲜培养瓶中,再补充新鲜培养液至原体积(培养液体积约为培养瓶容量的1/10)。
(6)细胞孵育:取对数生长期的肿瘤细胞,调细胞悬液浓度为1-1.5×105个mL-1。在96孔培养板中每孔加细胞悬液100μL,置37℃,5%CO2培养箱中培养24h。培养24h后,分别按设计加入药液。
(8)加药:将测试药液按照最终浓度的浓度梯度分别加入到各个孔中,每个浓度设6个平行孔。实验分为药物试验组(分别加入不同浓度的测试药)、对照组(只加培养液和细胞,不加测试药)和空白组(只加培养液,不加细胞和测试药)。将加药后的96孔板置于37℃,5%CO2培养箱中培养48h。阳性对照药物的活性按照测试样品的方法测定。
(9)存活细胞的测定:在培养了48h后的96孔板中,每孔加MTT40μL(用D-Hanks缓冲液配成4mg/mL)。在37℃放置4h后,移去上清液。每孔加150μLDMSO,振荡5min,使formazan结晶溶解。最后,利用自动酶标仪在570nm波长处检测各孔的光密度(OD值)。
半数抑制浓度(IC50)定义为当50%的肿瘤细胞存活时的药物浓度。根据测定的光密度(OD值),制作细胞生长抑制率的标准曲线,在标准曲线上求得其对应的药物浓度。
测得的IC50见表1所示。
表1本发明所列二氢吡唑噻唑衍生物对肿瘤细胞的抑制IC50值(μg/mL)
Claims (2)
1.一类二氢吡唑噻唑衍生物的合成及制备,其特征是它有如下通式:
一种上述的二氢吡唑噻唑衍生物的合成,它由下列步骤组成:
步骤1.在搅拌下,依次向反应容器中加入适量的水杨醛、不同取代基的苯乙酮、碱溶液、有机溶剂,适当的温度下继续搅拌反应适当的时间后,过滤,洗涤,干燥得中间体2。
步骤2.在反应容器中加入适量的查尔酮的衍生物2、氨基硫脲、碱、适量的有机溶剂,在适当的温度下搅拌反应一段时间(TLC跟踪反应,直至至少一种原料很少甚至没有),过滤得粗产品,粗品经柱层析或采用适当的有机溶剂重结晶提纯得化合物3.
步骤3.在适量的反应容器中加入适量的化合物3和不同取代基的α-溴苯乙酮,有机溶剂,置于一定的条件下反应,采取一定的条件处理得本发明的目标化合物。
2.根据权利要求所述的二氢吡唑噻唑衍生物在制备抗肿瘤药物中的应用。
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