CN103058938A - 4-苯胺喹唑啉类和取代肉桂酸的复合物及其制备方法与用途 - Google Patents
4-苯胺喹唑啉类和取代肉桂酸的复合物及其制备方法与用途 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及4-苯胺喹唑啉类和取代肉桂酸的复合物及其制备方法与作为抗癌药物的用途。
背景技术
蛋白酪氨酸激酶(PTK)是一类具有酪氨酸激酶活性的蛋白质,可分为受体型和非受体型两种,它们能催化ATP上的磷酸基团转移到许多重要蛋白质的酪氨酸残基上,使其发生磷酸化。蛋白酪氨酸激酶在细胞内的信号转导通路中占据了十分重要的地位,调节着细胞体内生长、分化、死亡等一系列生理过程。蛋白酪氨酸激酶功能的失调则会引发生物体内的一系列疾病。已有的资料表明,超过50%的原癌基因和癌基因产物都具有蛋白酪氨酸激酶活性,酪氨酸蛋白激酶过度表达时,会阻碍细胞程序死亡,使细胞的生长调控失控,始终处于增生状态,发展成为恶性肿瘤。此外,酪氨酸基酶的异常表达还与肿瘤的侵袭和转移,肿瘤新生血管的生成,肿瘤的化疗抗性密切相关。因此,以酪氨酸激酶为靶点进行药物研发成为国际上抗肿瘤药物研究的热点。
不同配体与酪氨酸激酶结合,导致受体发生多聚化,并进一步使受体胞内区特异的受体酪氨酸残基发生自身磷酸化或交叉磷酸化,从而激活下游的信号转导通路。许多肿瘤的发生、发展都与酪氨酸激酶的异常表达有着极其密切的联系。其中与肿瘤的发生、发展最为密切,最引人注目的受体型酪氨酸激酶为表皮生长因子受体(EGFR)家族、血管内皮细胞生长因子受体(VEGFR)家族。
表皮生长因子受体(EGFR)家族广泛分布于哺乳动物的上皮细胞。临床研究表明,许多类型的实质性肿瘤都有高水平的EGFR的表达。EGFR的高度表达可以促进肿瘤细胞的增殖、血管生成、黏附、侵袭和转移,抑制肿瘤细胞的凋亡,导致肿瘤患者存活率低,预后差,疗效差,肿瘤转移可能性大,容易引起肿瘤细胞对各种细胞毒性药物的耐药性。
大多数标准的化疗药物同时杀死癌细胞和正常细胞,而表皮生长因子受体抑制剂能够针对性地附着并摧毁癌细胞,进行癌症的靶向治疗。正因为如此,EGFR抑制剂治疗方法有更少的副作用。EGFR酪氨酸磷酸化的选择性抑制剂已成为一类重要的潜在抗癌药物。4-苯胺喹唑啉类小分子化合物是目前世界上最令人感兴趣的EGFR和VEGFR信号传递阻断试剂,也是极具潜力的抗癌新药。
取代肉桂酸广泛分布于植物界中,在咖啡豆、橄榄、蜂胶、水果和蔬菜中均有发现,通常以简单的衍生物形式存在,包括酰胺,酯,糖酯,和糖苷。羟基肉桂酸酯类广泛分布于植物界,作为细胞的抗氧化剂、消炎药或参与细胞增殖或具有其他生物活性的酶的抑制剂。许多研究小组研究过各种肉桂酸衍生物的抗肿瘤活性,特别是肉桂酸酯衍生物表现出潜在的抗肿瘤活性。
由于肿瘤复杂的形成机理,分子组合旨在阻止肿瘤的形成引起关注。一个常见的策略是将作用于不同靶点的两个具有抗癌活性的化合物通过酯键或者酰胺键组合在一起,作为一种前体药物,进入体内分解后分别作用于不同靶点。因此将4-苯胺喹唑啉类与肉桂酸以酰胺键相连,增强其抗癌活性,是很好的课题。
发明内容
本发明的目的在于提供一类4-苯胺喹唑啉类和取代肉桂酸的复合物以及它们的制备方法与用途。
本发明的技术方案如下:
一类4-苯胺喹唑啉类和取代肉桂酸的复合物,其特征是它有如下通式:
式中:X为Cl或Br;
R为
一种制备上述的4-苯胺喹唑啉类和取代肉桂酸的复合物的方法,其特征是它由下列步骤组成:
步骤1.将0.1mol 2-氰基-4-硝基苯胺缓慢加入50mlN,N-二甲基甲酰胺二甲基缩醛,在70-75℃下反应2h。反应结束后冷却至室温,析出红色固体,抽滤,乙醚洗涤。
步骤2.将0.1mol卤代苯胺加入50ml乙酸,然后缓慢加入步骤1所得产物,在70-75℃下反应1-2h,析出大量黄色固体,抽滤,先用乙酸洗涤,然后再用乙醚洗涤,烘干。
步骤3.取步骤2所得化合物2g,与140ml无水乙醇,40ml水,6ml醋酸,3g铁粉加入于500ml的烧瓶中,然后加热60-80℃回流搅拌反应5-6小时,反应结束后,将反应液全部倒入500ml烧杯中,然后冷却至室温,加入40ml浓氨水搅拌。减压蒸馏除去乙醇,用乙酸乙酯萃取。萃取液拌入适量硅胶,旋干,干法上柱,乙酸乙酯∶石油醚=4∶1,柱层析,得深黄色产物。
步骤4.将10mmol取代苯甲醛与等物质的量的丙二酸加入嘧啶和哌啶的混合溶液,80℃回流,反应24h,反应混合物冷却后倒入50ml 3mol/L的盐酸,析出白色沉淀,过滤,冰水洗涤至滤液呈中性,重结晶白色晶体。
步骤5.取步骤4合成的取代肉桂酸1mmol加到二氯亚砜中,80℃回流4h,减压蒸干。乙酸乙酯溶解,加入步骤3制得的深黄色化合物1mmol,加入少量碳酸钾,冰浴,过夜。反应结束后,过滤除去碳酸钾,柱层析,乙酸乙酯∶石油醚=3∶1,得目标化合物。
实验结果表明,本发明的新型4-苯胺喹唑啉类和取代肉桂酸的复合物对细菌具有明显的抑制作用。因此本发明的4-苯胺喹唑啉类和取代肉桂酸的复合物可以应用于制备抗癌药物。
具体实施方式
通过以下实施例进一步详细说明本发明,但本发明的范围并不受这些实施例的任何限制。
实施例一:(E)-N-(4-(3-溴苯基)氨基)喹唑啉-6-基)肉桂酰胺的制备
取1mmol肉桂酸,加到3ml二氯亚砜中,80℃回流4h,减压蒸干。乙酸乙酯溶解,加入1mmol深黄色化合物N4-(3-溴苯基)喹唑啉-4,6-二胺,加入少量碳酸钾,冰浴,过夜。反应结束后,过滤除去碳酸钾,柱层析,乙酸乙酯∶石油醚=3∶1,得目标化合物。白色粉末,产率90%,Mp 265-266℃;1H NMR(300MHz,DMSO-d6,δppm):6.92(d,J=15.72Hz,1H),7.27-7.37(m,2H),7.42-7.48(m,3H),7.66(t,J=7.7Hz,3H),7.79-7.87(m,2H),7.94(dd,J1=8.97Hz,J2=8.97Hz,1H),8.17(s,1H,NH),8.59(s,1H),8.83(s,1H),9.97(s,1H),10.55(s,1H,NHCO).ESI-MS:445.1(C23H17BrN4O,[M+H]+).Anal.Calcd for C23H16BrN4O:C,62.03%;H,3.85%;N,12.58%.Found:C,61.99%;H,4.16%;N,13.01%.
实施例二:(E)-N-(4-((3-溴苯基)氨基)喹唑啉-6-基)-3-(4-氯苯基)丙烯酰胺的制备
制备方法同实施例一。以4-氯肉桂酸代替肉桂酸,得到目标化合物。白色粉末,产率93%,Mp 283-285℃;1H NMR(300MHz,DMSO-d6,δppm):6.93(d,J=15.7Hz,1H),7.3(d,J=7.95Hz,1H),7.35(t,J=8.02Hz,1H),7.54(d,J=8.55Hz,2H),7.65-7.70(m,3H),7.82(d,J=8.85Hz,1H),7.88(d,J=8.1Hz,1H),7.96(dd,J1=9Hz,J2=8.85Hz,1H),8.19(s,1H,NH),8.6(s,1H),8.83(s,1H),9.95(s,1H,OH),10.56(s,1H,NHCO).ESI-MS:479.0(C23H16BrClN4O,[M+H]+).Anal.Calcdfor C23H15BrClN4O:C,57.58%;H,3.36%;N,11.68%.Found:C,57.87%;H,3.12%;N,11.57%.
实施例三:(E)-N-(4-((3-溴苯基)氨基)喹唑啉-6-基)-3-(2-氯苯基)丙烯酰胺的制备
制备方法同实施例一。以2-氯肉桂酸代替肉桂酸,得到目标化合物。白色粉末,产率92%,Mp 287-288℃;1H NMR(300MHz,DMSO-d6,δppm):6.97(d,J=15.54Hz,1H),7.27-7.37(m,2H),7.44-7.47(m,2H),7.59(t,J=4.67Hz,1H),7.79-8.00(m,5H),8.17(s,1H,NH),8.59(s,1H),8.88(s,1H),9.97(s,1H),10.66(s,1H,NHCO).ESI-MS:479.0(C23H16BrClN4O,[M+H]+).Anal.Calcd forC23H15BrClN4O:C,57.58%;H,3.08%;N,10.69%.Found:C,58.03%;H,3.36%;N,9.87%.
实施例四:(E)-N-(4-((3-溴苯基)氨基)喹唑啉-6-基)-3-(4-溴苯基)丙烯酰胺的制备
制备方法同实施例一。以4-溴肉桂酸代替肉桂酸,得到目标化合物。淡黄色粉末,产率88%,Mp 295-296℃;1H NMR(300MHz,DMSO-d6,δppm):6.95(d,J=15.72Hz,1H),7.29-7.39(m,2H),7.61-7.75(m,5H),7.84(t,J=10.52Hz,2H),7.96(d,J=8.94Hz,1H),8.18(s,1H,NH),8.6(s,1H),8.84(s,1H),10(s,1H),10.59(s,1H,NHCO).ESI-MS:523.0(C23H16Br2N4O,[M+H]+).Anal.Calcd forC23H15Br2N4O:C,52.70%;H,3.08%;N,10.69%.Found:C,52.43%;H,3.36%;N,10.89%.
实施例五:(E)-N-(4-((3-溴苯基)氨基)喹唑啉-6-基)-3-(2-溴苯基)丙烯酰胺的制备
制备方法同实施例一。以2-溴肉桂酸代替肉桂酸,得到目标化合物。淡黄色粉末,产率94%,Mp 293-294℃;1H NMR(300MHz,DMSO-d6,δppm):6.94(d,J=15.54Hz,1H),7.37(t,J=8.69Hz,3H),7.52(t,J=7.5Hz,1H),7.74-7.85(m,4H),7.96(t,J=7.86Hz,2H),8.16(s,1H,NH),8.64(s,1H),8.95(s,1H),10.16(bs,1H),10.72(s,1H,NHCO).ESI-MS:523.0(C23H16Br2N4O,[M+H]+).Anal.Calcd forC23H15Br2N4O:C,52.70%;H,3.08%;N,10.69%.Found:C,52.83%;H,3.23%;N,10.33%.
实施例六:(E)-N-(4-((3-溴苯基)氨基)喹唑啉-6-基)-3-(4-甲氧基苯基)丙烯酰胺的制备
制备方法同实施例一。以4-甲氧基肉桂酸代替肉桂酸,得到目标化合物。白色粉末,产率93%,Mp 239-240℃;1H NMR(300MHz,DMSO-d6,δppm):3.83(s,3H,OCH3),7.02-7.10(m,2H),7.29-7.39(m,2H),7.63(t,J=7.49Hz,1H),7.82-7.94(m,5H),8.03(dd,J1=8.97Hz,J2=8.97Hz,1H),8.2(s,1H,NH),8.63(s,1H),8.79(s,1H),9.98(s,1H),10.51(s,1H,NHCO).ESI-MS:475.0(C24H19BrN4O2,[M+H]+).Anal.Calcd for C24H18BrN4O2:C,60.64%;H,4.03%;N,11.79%.Found:C,60.85%;H,4.23%;N,11.43%.
实施例七:(E)-N-(4-((3-溴苯基)氨基)喹唑啉-6-基)-3-(2-甲氧基苯基)丙烯酰胺的制备
制备方法同实施例一。以2-甲氧基肉桂酸代替肉桂酸,得到目标化合物。
白色粉末,产率91%,Mp 307-308℃;1HNMR(300MHz,DMSO-d6,δppm):3.89(s,3H,OCH3),6.93-7.05(m,2H),7.11(d,J=8.04Hz,1H),7.28-7.38(m,2H),7.42(d,J=7.14Hz,1H),7.59(d,J=7.68Hz,1H),7.79-7.86(m,3H),7.91-7.96(m,1H),8.16(s,1H,NH),8.6(s,1H),8.85(s,1H),10.01(bs,1H),10.54(s,1H,NHCO).ESI-MS:475.0(C24H19BrN4O2,[M+H]+).Anal.Calcd for C24H18BrN4O2:C,60.64%;H,4.03%;N,11.79%.Found:C,60.94%;H,4.31%;N,11.40%.
实施例八:(E)-N-(4-((3-溴苯基)氨基)喹唑啉-6-基)-3-(3-甲氧基苯基)丙烯酰胺的制备
制备方法同实施例一。以3-甲氧基肉桂酸代替肉桂酸,得到目标化合物。白色粉末,产率90%,Mp 303-305℃;1H NMR(300MHz,DMSO-d6,δppm):3.83(s,3H,OCH3),6.88-7.07(m,2H),7.20-7.37(m,4H),7.47(d,J=8.79Hz,1H),7.80-7.93(m,4H),8.17(s,1H,NH),8.58(s,1H),8.9(s,1H),9.94(bs,1H),10.64(s,1H,NHCO).ESI-MS:475.0(C24H19BrN4O2,[M+H]+).Anal.Calcd forC24H18BrN4O2:C,60.64%;H,4.03%;N,11.79%.Found:C,60.34%;H,3.98%;N,11.66%.
实施例九:(E)-N-(4-((3-溴苯基)氨基)喹唑啉-6-基)-3-(噻吩-2-基)丙烯酰胺的制备
制备方法同实施例一。以噻吩-2-丙烯酸代替肉桂酸,得到目标化合物。淡黄色粉末,产率89%,Mp 244-246℃;1H NMR(300MHz,DMSO-d6,δppm):7.28(dd,J1=5.13Hz,J2=5.13Hz,1H),7.33(d,J=4.59Hz,1H),7.38(d,J=7.86Hz,1H),7.76(d,J=2.91Hz,1H),7.86(t,J=7.88Hz,2H),7.95(d,J=5.1Hz,1H),8.04(dd,J1=8.97Hz,J2=8.97Hz,1H),7.74-7.85(m,4H),7.96(t,J=7.86Hz,2H),8.19(s,1H,NH),8.32(s,1H),8.64(s,1H),8.79(s,1H),10.04(bs,1H),10.54(s,1H,NHCO).ESI-MS:451.0(C21H15BrN4OS,[M+H]+).Anal.Calcd for C21H14BrN4OS:C,55.88%;H,3.35%;N,12.41%.Found:C,55.83%;H,3.24%;N,12.63%.
实施例十:(E)-N-(4-((3-溴苯基)氨基)喹唑啉-6-基)-3-(4-甲苯基)丙烯酰胺的制备
制备方法同实施例一。以4-甲基肉桂酸代替肉桂酸,得到目标化合物。白色粉末,产率87%,Mp 248-249℃;1H NMR(300MHz,DMSO-d6,δppm):2.37(s,3H,CH3),7.32-7.39(m,5H),7.81-7.85(m,3H),7.9(d,J=7.86Hz,2H),8.02(d,J=10.98Hz,1H),8.21(s,1H,NH),8.63(s,1H),8.79(s,1H),9.93(s,1H),10.57(s,1H,NHCO).ESI-MS:459.0(C24H19BrN4O,[M+H]+).Anal.Calcd for C24H18BrN4O:C,62.75%;H,4.17%;N,12.20%.Found:C,63.03%;H,4.17%;N,11.83%.
实施例十一:(E)-N-(4-((3-溴苯基)氨基)喹唑啉-6-基)-3-(4-硝基苯基)丙烯酰胺的制备
制备方法同实施例一。以4-硝基肉桂酸代替肉桂酸,得到目标化合物。黄色粉末,产率92%,Mp 300-302℃;1H NMR(300MHz,DMSO-d6,δppm):7.11(d,J=15.93Hz,1H),7.29-7.39(m,2H),7.75-7.99(m,6H),8.18(s,1H,NH),8.32(d,J=8.79Hz,2H),8.61(s,1H),8.85(s,1H),10(s,1H),10.71(s,1H,NHCO).ESI-MS:490.0(C23H16BrN5O3,[M+H]+).Anal.Calcd for C23H15BrN5O3:C,56.34%;H,3.29%;N,14.28%.Found:C,56.44%;H,3.38%;N,14.11%.
实施例十二:(E)-N-(4-((3-溴苯基)氨基)喹唑啉-6-基)-3-(2-硝基苯基)丙烯酰胺的制备
制备方法同实施例一。以2-硝基肉桂酸代替肉桂酸,得到目标化合物。黄色粉末,产率93%,ESI-MS:490.0(C23H16BrN5O3,[M+H]+).Anal.Calcd forC23H15BrN5O3:C,56.34%;H,3.29%;N,14.28%.Found:C,56.22%;H,3.18%;N,14.53%.
实施例十三:(E)-N-(4-((3-氯苯基)氨基)喹唑啉-6-基)肉桂酰胺-3-(2-硝基苯基)的制备
取1mmol肉桂酸,加到3ml二氯亚砜中,80℃回流4h,减压蒸干。乙酸乙酯溶解,加入1mmol深黄色化合物N4-(3-氯苯基)喹唑啉-4,6-二胺,加入少量碳酸钾,冰浴,过夜。反应结束后,过滤除去碳酸钾,柱层析得目标化合物。淡黄色化合物,产率90%,Mp 294-295℃;1H NMR(500MHz,DMSO-d6,δppm):6.93(d,J=15.75Hz,1H),7.16(d,J=7.8Hz,1H),7.40-7.49(m,4H),7.67(t,J=8.1Hz,3H),7.82(d,J=8.65Hz,2H),7.96(d,J=9Hz,1H),8.07(s,1H,NH),8.6(s,1H),8.84(s,1H),9.96(s,1H),10.55(s,1H,NHCO).ESI-MS:401.1(C23H17ClN4O,[M+H]+).Anal.Calcd for C23H16ClN4O:C,68.91%;H,4.27%;N,13.98%.Found:C,68.99%;H,4.16%;N,13.91%.
实施例十四:(E)-N-(4-((3-氯苯基)氨基)喹唑啉-6-基)-3-(4-氯苯基)丙烯酰胺的制备
制备方法同实施例十三。以4-氯肉桂酸代替肉桂酸,得到目标化合物。白色粉末,产率93%,Mp 306-307℃;1H NMR(500MHz,DMSO-d6,δppm):6.93(d,J=15.75Hz,1H),7.17(d,J=8.1Hz,1H),7.17(d,J=8.1Hz,1H),7.42(t,J=8.07Hz,1H),7.54(d,J=8.4Hz,2H),7.83(d,J=8.4Hz,2H),7.65-7.70(m,3H),7.97(dd,J1=9Hz,J2=9Hz,1H),8.06(s,1H,NH),8.6(s,1H),8.83(s,1H),9.99(s,1H,OH),10.57(s,1H,NHCO).ESI-MS:435.1(C23H16Cl2N4O,[M+H]+).Anal.Calcd forC23H15Cl2N4O:C,63.46%;H,3.70%;N,12.87%.Found:C,63.05%;H,3.93%;N,13.01%.
实施例十五:(E)-N-(4-((3-氯苯基)氨基)喹唑啉-6-基)-3-(2-氯苯基)丙烯酰胺的制备
制备方法同实施例十三。以2-氯肉桂酸代替肉桂酸,得到目标化合物。淡黄色粉末,产率87%,Mp 292-294℃;1H NMR(500MHz,DMSO-d6,δppm):6.98(d,J=15.7Hz,1H),7.17(d,J=7.9Hz,1H),7.41(t,J=8.08Hz,1H),7.47(t,J=3.65Hz,2H),7.58(t,J=4.58Hz,1H),7.82(t,J=8.77Hz,3H),7.94(d,J=8.85Hz,1H),7.99(d,J=5.75Hz,1H),8.07(s,1H,NH),8.6(s,1H),8.89(s,1H),9.95(s,1H),10.65(s,1H,NHCO).ESI-MS:435.1(C23H16Cl2N4O,[M+H]+).Anal.Calcd forC23H15Cl2N4O:C,63.46%;H,3.70%;N,12.87%.Found:C,63.75%;H,3.45%;N,13.01%.
实施例十六:(E)-N-(4-((3-氯苯基)氨基)喹唑啉-6-基)-3-(4-溴苯基)丙烯酰胺
制备方法同实施例十三。以4-溴肉桂酸代替肉桂酸,得到目标化合物。淡黄色粉末,产率90%,Mp 289-291℃;1H NMR(500MHz,DMSO-d6,δppm):6.95(d,J=15.75Hz,1H),7.16(d,J=8.1Hz,1H),7.41(t,J=8.18Hz,1H),7.62(d,J=8.55Hz,2H),7.67(t,J=5.65Hz,3H),7.82(d,J=8.85Hz,2H),7.96(dd,J1=9Hz,J2=9Hz,1H),8.07(s,1H,NH),8.6(s,1H),8.82(s,1H),9.95(s,1H),10.56(s,1H,NHCO).ESI-MS:478.1(C23H16BrClN4O,[M+H]+).Anal.Calcd for C23H15BrClN4O:C,57.58%;H,3.36%;N,11.68%.Found:C,57.23%;H,3.36%;N,11.89%.
实施例十七:(E)-N-(4-((3-氯苯基)氨基)喹唑啉-6-基)-3-(2-溴苯基)丙烯酰胺
制备方法同实施例十三。以2-溴肉桂酸代替肉桂酸,得到目标化合物。淡黄色粉末,产率90%,Mp 292-293℃;1H NMR(500MHz,DMSO-d6,δppm):7.38-7.43(m,2H),7.51(d,J=7.5Hz,1H),7.75(d,J=8.05Hz,1H),7.79-7.84(m,3H),7.94(t,J=11.98Hz,2H),8.06(s,1H,NH),8.61(s,1H),8.91(s,1H),9.98(s,1H),10.67(s,1H,NHCO).ESI-MS:479.0(C23H16BrClN4O,[M+H]+).Anal.Calcdfor C23H15BrClN4O:C,57.58%;H,3.36%;N,11.68%.Found:C,57.83%;H,3.21%;N,11.33%.
实施例十八:(E)-N-(4-((3-氯苯基)氨基)喹唑啉-6-基)-3-(3-甲氧基苯基)丙烯酰胺
制备方法同实施例十三。以3-甲氧基肉桂酸代替肉桂酸,得到目标化合物。白色粉末,产率93%,Mp 284-285℃;1H NMR(500MHz,DMSO-d6,δppm):3.82(s,3H,OCH3),6.93(d,J=15.55Hz,1H),7.01(dd,J1=8.25Hz,J2=8.25Hz,1H),7.17(d,J=7.45Hz,1H),7.64(d,J=15.7Hz,1H),7.82(d,J=8.85Hz,2H),7.37-7.43(m,2H),7.24(t,J=9.3Hz,2H),7.95(t,J=5.5Hz,1H),8.06(s,1H,NH),8.6(s,1H),8.85(s,1H),9.97(s,1H),10.54(s,1H,NHCO).ESI-MS:431.1(C24H19ClN4O2,[M+H]+).Anal.Calcd for C24H18ClN4O2:C,66.90%;H,4.44%;N,13.00%.Found:C,66.84%;H,3.99%;N,13.16%.
实施例十九:(E)-N-(4-((3-氯苯基)氨基)喹唑啉-6-基)-3-(噻吩-2-基)丙烯酰胺
制备方法同实施例十三。以噻吩-2-丙烯酸代替肉桂酸,得到目标化合物。黄色粉末,产率90%,Mp 241-243℃;1H NMR(500MHz,DMSO-d6,δppm):6.69(d,J=8.5Hz,1H),7.16-7.17(m,2H),7.41(t,J=8.1Hz,1H),7.49(d,J=3.35Hz,1H),7.69(d,J=5Hz,1H),7.82(d,J=7.62Hz,3H),7.92(dd,J1=9Hz,J2=8.85Hz,1H),8.06(s,1H,NH),8.59(s,1H),8.84(s,1H),9.97(s,1H),10.52(s,1H,NHCO).ESI-MS:451.0(C21H15ClN4OS,[M+H]+).Anal.Calcd for C21H14ClN4OS:C,61.99%;H,3.72%;N,13.77%.Found:C,61.83%;H,3.94%;N,13.63%.
实施例二十:(E)-N-(4-((3-氯苯基)氨基)喹唑啉-6-基)-3-(4-甲基苯基)丙烯酰胺
制备方法同实施例十三。以4-甲基肉桂酸代替肉桂酸,得到目标化合物。白色粉末,产率89%,Mp 277-279℃;1H NMR(500MHz,DMSO-d6,δppm):2.35(s,3H,CH3),6.87(d,J=15.75Hz,1H),7.16(d,J=8.05Hz,1H),7.28(d,J=7.9Hz,2H),7.41(t,J=8.15Hz,1H),7.55(d,J=8.1Hz,2H),7.64(d,J=15.7Hz,1H),7.82(d,J=8.7Hz,2H),7.95(dd,J1=9Hz,J2=8.85Hz,1H),8.06(s,1H,NH),8.6(s,1H),8.83(s,1H),9.95(s,1H),10.5(s,1H,NHCO).ESI-MS:415.1(C24H19ClN4O,[M+H]+).Anal.Calcd for C24H18ClN4O:C,69.48%;H,4.62%;N,13.50%.Found:C,69.03%;H,4.57%;N,13.83%
实施例二十一:(E)-N-(4-((3-氯苯基)氨基)喹唑啉-6-基)-3-(萘-1-基)丙烯酰胺
制备方法同实施例十三。以萘-1-丙烯酸代替肉桂酸,得到目标化合物。黄色粉末,产率90%,Mp 293-294℃;1H NMR(500MHz,DMSO-d6,δppm):7.01(d,J=15.4Hz,1H),7.17(d,J=9.15Hz,1H),7.42(t,J=8.1Hz,1H),7.60-7.69(m,3H),7.85(d,J=9Hz,2H),7.9(d,J=7.15Hz,1H),7.99-8.05(m,3H),8.26(d,J=8.4Hz,1H),8.46(d,J=15.55Hz,1H),8.08(s,1H,NH),8.62(s,1H),8.9(s,lH),10(s,1H),10.65(s,1H,NHCO).ESI-MS:495.0(C27H19ClN4O,[M+H]+).Anal.Calcd forC27H18ClN4O:C,71.92%;H,4.25%;N,12.43%.Found:C,71.99%;H,4.16%;N,12.51%.
实施例二十二:(E)-N-(4-((3-氯苯基)氨基)喹唑啉-6-基)-3-(4-硝基苯基)丙烯酰胺
制备方法同实施例十三。以4-硝基肉桂酸代替肉桂酸,得到目标化合物。黄色粉末,产率94%,Mp 280-282℃;1H NMR(300MHz,DMSO-d6,δppm):7.42(t,J=8.06Hz,1H),7.08-7.18(m,2H),7.75-7.85(m,3H),7.92-8.06(m,4H),8.31(d,J=8.4Hz,1H),8.61(s,1H),8.84(s,1H),10(s,1H),10.7(s,1H,NHCO).ESI-MS:446.1(C23H16ClN5O3,[M+H]+).Anal.Calcd for C23H15ClN5O3:C,61.96%;H,3.62%;N,15.71%.Found:C,61.64%;H,3.38%;N,15.91%.
实施例二十三:(E)-N-(4-((3-氯苯基)氨基)喹唑啉-6-基)-3-(2-硝基苯基)丙烯酰胺
制备方法同实施例十三。以2-硝基肉桂酸代替肉桂酸,得到目标化合物。色黄粉末,产率91%,Mp 287-289℃;1H NMR(500MHz,DMSO-d6,δppm):6.91(d,J=15.4Hz,1H),7.17(d,J=7.9Hz,1H),7.42(t,J=8.07Hz,1H),7.68-7.72(m,1H),7.82-7.88(m,4H),7.93(d,J=9Hz,1H),7.97(d,J=15.55Hz,1H),8.07(s,1H,NH),8.11(d,J=10Hz,1H),8.6(s,1H),8.9(s,1H),9.96(s,1H),10.68(s,1H,NHCO).ESI-MS:446.1(C23H16ClN5O3,[M+H]+).Anal.Calcd for C23H15ClN5O3:C,61.96%;H,3.62%;N,15.71%.Found:C,61.65%;H,3.38%;N,15.93%.
实施例二十四:新型肉桂酸4-苯胺喹唑啉酰胺衍生物的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]法来测定肉桂酸4-苯胺喹唑啉酰胺衍生物对人体肺癌细胞株(A549)和黑色素瘤细胞(F10)的抑制率,计算IC50值(μM)。
(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NaHCO3 2.00g,HEPES 2.38g。
(2)D-Hanks缓冲液(每升)的配制:NaCl 8.00g,KCl 0.40g,Na2HPO4·12H2O 0.06g,KH2PO4 0.06g,NaHCO3 0.35g。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-般不超过0.05%-0.1%。储备液保存于-20℃冰箱中备用。
(5)人肺癌细胞A549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)人体口腔上表皮癌细胞KB的培养:为贴壁生长细胞,常规培养于RPMI-1640培养液内(含10%小牛血清、100U/ml链霉素),置37℃、5%CO2培养箱中培养,每隔3-4天传代一次。传代时先弃去原培养液,再用D-Hanks缓冲液洗涤;然后用0.5%胰蛋白酶消化30秒左右,加入少量新鲜培养液终止消化;吹打,使贴壁细胞从培养瓶壁上脱落下来;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)。
(7)细胞孵育:取对数生长期的2种肿瘤细胞,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MTT 40μl(用D-Hanks缓冲液配成4mg/ml)。在37℃放置4h后,移去上清液。每孔加150μl DMSO,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)。
抑制率的计算:细胞生长的抑制率按照下列公式计算:
生长抑制率=(1-存活率)×100%=[1-(OD实验-OD空白)/(OD对照-OD空 白)]×100%(OD实验表示测试药物组的平均光密度,OD对照表示对照组的平均光密度,OD空白表示对照组的平均光密度)。
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
表格1本发明所列肉桂酸4-苯胺喹唑啉酰胺衍生物对肿瘤细胞的抑制IC50值
Claims (3)
2.一种制备上述的4-苯胺喹唑啉类和取代肉桂酸的复合物的方法,其特征是它由下列步骤组成:
步骤1.将0.1mol 2-氰基-4-硝基苯胺缓慢加入50mlN,N-二甲基甲酰胺二甲基缩醛,在70-75℃下反应2h。反应结束后冷却至室温,析出红色固体,抽滤,乙醚洗涤。
步骤2.将0.1mol卤代苯胺加入50ml乙酸,然后缓慢加入步骤1所得产物,在70-75℃下反应1-2h,析出大量黄色固体,抽滤,先用乙酸洗涤,然后再用乙醚洗涤,烘干。
步骤3.取步骤2所得化合物2g,与140ml无水乙醇,40ml水,6ml醋酸,3g铁粉加入于500ml的烧瓶中,然后加热60-80℃回流搅拌反应5-6小时,反应结束后,将反应液全部倒入500ml烧杯中,然后冷却至室温,加入40ml浓氨水搅拌。减压蒸馏除去乙醇,用乙酸乙酯萃取。萃取液拌入适量硅胶,旋干,柱层析,干法上柱,乙酸乙酯∶石油醚=4∶1,得深黄色产物。
步骤4.将10mmol取代苯甲醛与等物质的量的丙二酸加入嘧啶和哌啶的混合溶液,80℃回流,反应24h,反应混合物冷却后倒入50ml 3mol/L的盐酸,析出白色沉淀,过滤,冰水洗涤至滤液呈中性,重结晶白色晶体。
步骤5.取步骤4合成的取代肉桂酸1mmol加到二氯亚砜中,80℃回流4h,减压蒸干。乙酸乙酯溶解,加入步骤3制得的深黄色化合物1mmol,加入少量碳酸钾,冰浴,过夜。反应结束后,水洗除去碳酸钾,重结晶得目标化合物。
3.权利要求1所述的4-苯胺喹唑啉类和取代肉桂酸的复合物在制备抗癌药物中的应用。
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CN106632287A (zh) * | 2016-12-19 | 2017-05-10 | 陕西师范大学 | 靛红杂合喹唑啉类化合物合成的靛红衍生物及其在制备抗肿瘤药物中的应用 |
CN106632287B (zh) * | 2016-12-19 | 2019-08-20 | 陕西师范大学 | 靛红杂合喹唑啉类化合物合成的靛红衍生物及其在制备抗肿瘤药物中的应用 |
CN107903248A (zh) * | 2017-11-14 | 2018-04-13 | 陕西师范大学 | N‑取代靛红杂合喹唑啉类化合物合成的靛红衍生物及在制备抗肿瘤药物中的应用 |
CN110092781A (zh) * | 2018-01-31 | 2019-08-06 | 河南省医药科学研究院 | 一种新型喹唑啉类egfr抑制剂及其制备和应用 |
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