CN116253736A - 一种吡唑β-内酰胺类衍生物及其制备方法和应用 - Google Patents
一种吡唑β-内酰胺类衍生物及其制备方法和应用 Download PDFInfo
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- CN116253736A CN116253736A CN202310017751.3A CN202310017751A CN116253736A CN 116253736 A CN116253736 A CN 116253736A CN 202310017751 A CN202310017751 A CN 202310017751A CN 116253736 A CN116253736 A CN 116253736A
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- pyrazole
- lactam derivative
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- cancer cells
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Abstract
本发明属于医药化学技术领域,具体涉及一种吡唑β‑内酰胺类衍生物及其制备方法和应用。本发明提供的吡唑β‑内酰胺类衍生物具有如式(Ⅰ)所示的结构,该衍生物结构新颖,具有较好的抗肿瘤作用,对人结肠癌细胞、人乳腺癌细胞、人非小细胞肺癌细胞均具有较好的抑制作用,在抗肿瘤作用方面具有很大的应用价值,有望制备成抗肿瘤药物或抑制肿瘤细胞增殖的药物,尤其是抗人结肠癌、人乳腺癌和人非小细胞肺癌的药物;同时,本发明方法的原料廉价易得,反应步骤少,操作简单安全,成本低,产生废物少,具有高原子经济性,高选择性,高收率的优势。
Description
技术领域
本发明属于医药化学技术领域,具体涉及一种吡唑β-内酰胺类衍生物及其制备方法和应用。
背景技术
癌症,亦称恶性肿瘤,是严重危害人类健康的常见病和多发病,具有发病率高、死亡率高、复发率高、治疗难等特点。进入21世纪,恶性肿瘤仍然是极大危害人类生命健康的严重疾病,是继心血管疾病后威胁人类健康的第二大杀手。因此,对癌症的治疗显得尤其紧迫。目前对于肿瘤的治疗主要有药物疗法、手术疗法和放射疗法。其中,药物治疗已经成为当今临床肿瘤治疗的重要手段。根据作用方式和化学机理的不同,抗癌药物可以分为直接作用于DNA的药物、干扰DNA合成的药物、以有丝分裂为靶点的药物、针对与肿瘤各个生长阶段相关的酶的抑制剂、免疫治疗药物以及中药治疗药物等。尽管目前为止已有数十种化疗和辅助抗癌药物运用于临床,而且对其中的一些肿瘤已取得一定的治愈率,但大多数药物仅仅只能起到缓解病情的作用。因此,寻找新型高效的肿瘤治疗药物依然是抗肿瘤药物研究的主要方向。
β-内酰胺结构单元是天然产物和药物分子中常见的“优势骨架”,在新药的发现中起到了极其重要的作用。众所周知,植物、动物或微生物源是发现具有生物活性的天然产物的重要宝库,从天然产物中寻求新的化学模型以开发新药一直是医药及农药工作者所追求的目标。而β-内酰胺结构及其衍生物广泛存在于天然产物中,并且有大量的数据表明其有很好的活性作用。当前,合成β-内酰胺结构的报道虽然不少,但是如何高效合成具有β-内酰胺结构的化合物,如何高效控制非对映选择性,以合成具有两个手性中心的β-内酰胺类化合物仍具有一定的挑战性。而且,目前关于具有抗肿瘤活性的β-内酰胺类化合物的报道非常少。因此,开发选择性好且具有良好抗肿瘤活性的β-内酰胺类化合物具有重要的应用价值。
发明内容
为了克服上述现有技术的不足,本发明提供了一种吡唑β-内酰胺类衍生物,该衍生物结构新颖,同时还具有较好的抗肿瘤作用,对人结肠癌细胞、人乳腺癌细胞、人非小细胞肺癌细胞均具有较好的抑制作用,在抗肿瘤作用方面具有很大的应用价值。
为实现上述目的,本发明是通过以下技术方案来实现的:
本发明第一方面提供了一种吡唑β-内酰胺类衍生物,所述吡唑β-内酰胺类衍生物的结构如式(Ⅰ)所示:
式(Ⅰ)中,所述R1选自苯、取代苯基、氢、C1-C6烷基或环烷烃;
R2选自苯、烷基、氢、卤素、甲氧基;
R3选自C1-C6烷基或环烷烃、苄基、酰基;
R4选自1-C6烷基或环烷烃、烷氧基、卤素;
Ar选自苯、联苯、取代苯。
优选地,所述R1选自氢、甲基、乙基、苯;R2选自氢,甲基;R3选自甲基、苄基;R4选自氢、氟、氯、三氟甲基、甲氧基。
优选地,所述吡唑β-内酰胺类衍生物选自下列结构式中的至少一种:
本发明第二方面提供了第一方面所述的吡唑β-内酰胺类衍生物的制备方法,具体为:根据下列反应式,将式1和式2所示的原料混溶于有机溶剂中,然后在金属催化剂存在的条件下经反应后制备得到式(Ⅰ)所示的衍生物:
其中,R1、R2、R3、R4和Ar的取值同第一方面所述的R1、R2、R3、R4、Ar。
本发明制备吡唑β-内酰胺类衍生物的方法,原料廉价易得,反应步骤少,操作简单安全,成本低,产生废物少,具有高原子经济性,高选择性,高收率的优势。
优选地,式1所示原料、式2所示原料和金属催化剂的反应摩尔比为(1.5~3.0):(1):(0.15~0.2)。
优选地,式2所示原料在有机溶剂中的浓度为(0.05~50.5)mol/L。
优选地,所述反应的温度为室温,时间为5~8h。
优选地,所述有机溶剂包括但不限于二氯甲烷、1,2二氯乙烷、氯仿、四氢呋喃、甲基叔丁基醚、甲苯、二甲苯和乙酸乙酯。
优选地,所述金属催化剂包括但不限于AgOTf、Rh2(OAc)4、[Pd(C3H5)Cl]2、Cu(CH3CN)4PF6、AgSbF6、AgPF4。更优选地,所述金属催化剂为AgOTf。
本发明第三方面提供了第一方面所述的吡唑β-内酰胺类衍生物在制备抗结肠癌的药物或抑制结肠癌细胞增殖的药物中的应用。
本发明第四方面提供了第一方面所述的吡唑β-内酰胺类衍生物在制备抗乳腺癌的药物或抑制乳腺癌细胞增殖的药物中的应用。
本发明第五方面提供了第一方面所述的吡唑β-内酰胺类衍生物在制备抗非小细胞肺癌的药物或抑制非小细胞肺癌细胞增殖的药物中的应用。
本发明的吡唑β-内酰胺类衍生物结构新颖,具有较好的抗肿瘤作用,对人结肠癌细胞、人乳腺癌细胞、人非小细胞肺癌细胞均具有较好的抑制作用,在抗肿瘤作用方面具有很大的应用价值,有望制备成抗肿瘤药物或抑制肿瘤细胞增殖的药物,尤其是抗人结肠癌、人乳腺癌和人非小细胞肺癌的药物。
优选地,所述结肠癌细胞为HCT116细胞,所述吡唑β-内酰胺类衍生物选自下列结构式中的至少一种:
优选地,所述乳腺癌细胞为MCF-7细胞,所述吡唑β-内酰胺类衍生物选自下列结构式中的至少一种:
优选地,所述非小细胞肺癌细胞为A549细胞,所述吡唑β-内酰胺类衍生物选自下列结构式中的至少一种:
本发明第六方面提供了一种抗肿瘤药物,所述药物以第一方面所述的吡唑β-内酰胺类衍生物作为主要活性成分。
优选地,所述肿瘤包括但不限于结肠癌、乳腺癌和非小细胞肺癌。
优选地,所述肿瘤细胞包括但不限于人结肠癌细胞、人乳腺癌细胞、人非小细胞肺癌细胞。
优选地,上述的抗肿瘤药物还包括药学上可接受的载体和/或赋形剂。即上述的抗肿瘤药物以吡唑β-内酰胺类衍生物作为主要活性成分,与药学上可接受的载体和/或赋形剂混合制备成组合物,并制备成临床上可接受的剂型。所述剂型是指临床上常用的注射剂、片剂、胶囊剂等。药物制剂可以经口服或胃肠外方式(例如静脉、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的,可将其制备成肠衣片剂。
进一步地,所述赋形剂是指可用于药学领域的稀释剂、黏合剂、润滑剂、崩解剂、助溶剂、稳定剂以及其他一些药用基质。
进一步地,所述载体是药物领域中可接受的功能性药用辅料,包括表面活性剂、助悬剂、乳化剂以及一些新型药用高分子材料,如环糊精、壳聚糖、聚乳酸(PLA)、聚乙醇酸聚乳酸共聚物(PLGA)、透明质酸等。
与现有技术相比,本发明的有益效果是:
本发明公开了一种β-内酰胺类衍生物,该衍生物结构新颖,同时还具有较好的抗肿瘤作用,对人结肠癌细胞、人乳腺癌细胞、人非小细胞肺癌细胞均具有较好的抑制作用,在抗肿瘤作用方面具有很大的应用价值,有望制备成抗肿瘤药物或抑制肿瘤细胞增殖的药物,尤其是抗人结肠癌、人乳腺癌、人非小细胞肺癌的药物。
同时,本发明的衍生物以酰胺重氮化合物、靛红亚胺为原料,以金属为催化剂,在有机溶剂中经过一步反应即可制备得到;所用的原料廉价易得,反应步骤少,操作简单安全,成本低,产生废物少,具有高原子经济性,高选择性,高收率的优势。
具体实施方式
下面对本发明的具体实施方式作进一步说明。在此需要说明的是,对于这些实施方式的说明用于帮助理解本发明,但并不构成对本发明的限定。此外,下面所描述的本发明各个实施方式中所涉及的技术特征只要彼此之间未构成冲突就可以相互组合。
下述实施例中的实验方法,如无特殊说明,均为常规方法,下述实施例中所用的试验材料,如无特殊说明,均为可通过常规的商业途径购买得到。
实施例1吡唑β-内酰胺类衍生物的制备
根据以下的反应式,将式II所示的靛红亚胺(0.20mmol),三氟甲磺酸银(0.03mmol,金属催化剂),分子筛(200mg)溶于2.0mL有机溶剂二氯甲烷中,配置成混合溶液1;另将式Ⅰ所示的重氮化合物(0.3mmol)溶于2.0mL有机溶剂二氯甲烷中,配置成溶液2;然后在室温于搅拌状态下将溶液2在1h内用注射泵加入到搅拌中的混合溶液1中,;滴加完毕后,室温条件下剧烈搅拌5~8h,直到重氮化合物消耗完全;将反应液过滤,柱层析分离纯化,得到纯的产品,即目标产物吡唑β-内酰胺类衍生物。
上述制备过程的化学反应式如下:
其中,R1选自苯、取代苯基、氢、C1-C6烷基或环烷烃;R2选自苯、烷基、氢、卤素、甲氧基;R3选自C1-C6烷基或环烷烃、苄基、酰基;R4选自1-C6烷基或环烷烃、烷氧基、卤素,Ar选自苯、联苯、取代苯。
制备所得的β-内酰胺类衍生物一共有45个产物,命名为化合物1至45,化合物1至45的结构如表1所示,具体的核磁氢谱数据如下:
化合物1的谱图数据:1H NMR(400MHz,Chloroform-d)δ7.43(t,J=7.8Hz,1H),7.27(d,J=7.0Hz,1H),7.20(t,J=7.9Hz,2H),7.10–7.04(m,4H),6.97(d,J=7.8Hz,1H),5.76(s,1H),3.12(s,3H),2.52(s,3H),2.10(s,3H),1.99(s,3H);
化合物2的谱图数据:1H NMR(400MHz,Chloroform-d)δ7.41(td,J=7.8,1.0Hz,1H),7.27(d,J=7.9Hz,1H),7.24–7.15(m,2H),7.14–7.01(m,4H),6.98(d,J=7.9Hz,1H),5.75(s,1H),3.85(dq,J=14.5,7.3Hz,1H),3.46(dq,J=14.2,7.1Hz,1H),2.54(s,3H),2.08(s,3H),2.01(s,3H),1.16(t,J=7.2Hz,3H);
化合物3的谱图数据:1H NMR(400MHz,Chloroform-d)δ7.35–7.26(m,7H),7.20(t,J=7.8Hz,2H),7.12–7.01(m,4H),6.79(d,J=8.0Hz,1H),5.78(s,1H),5.05(d,J=15.8Hz,1H),4.62(d,J=15.8Hz,1H),2.58(s,3H),2.13(s,3H),2.08(s,3H);
化合物4的谱图数据:1H NMR(500MHz,Chloroform-d)δ7.35–7.26(m,7H),7.16(d,J=8.7Hz,2H),7.06–7.01(m,3H),6.80(d,J=7.9Hz,1H),5.77(s,1H),5.02(d,J=15.7Hz,1H),4.61(d,J=15.8Hz,1H),2.54(s,3H),2.12(s,3H),2.06(s,3H);
化合物5的谱图数据:1H NMR(500MHz,Chloroform-d)δ7.35–7.31(m,2H),7.29–7.26(m,5H),7.04–6.97(m,5H),6.77(d,J=8.1Hz,1H),5.76(s,1H),5.03(d,J=15.8Hz,1H),4.60(d,J=15.8Hz,1H),2.57(s,3H),2.25(s,3H),2.12(s,3H),2.06(s,3H);
化合物6的谱图数据:1H NMR(500MHz,Chloroform-d)δ7.34–7.26(m,7H),7.06–7.02(m,3H),6.75(dd,J=20.4,8.4Hz,3H),5.77(s,1H),5.05(d,J=15.8Hz,1H),4.59(d,J=15.8Hz,1H),3.73(s,3H),2.58(s,3H),2.13(s,3H),2.06(s,3H);
化合物7的谱图数据:1H NMR(400MHz,Chloroform-d)δ8.03–7.95(m,1H),7.34–7.28(m,2H),7.26–7.17(m,5H),7.14–7.07(m,2H),6.98–6.89(m,2H),6.64(d,J=7.8Hz,1H),5.77(s,1H),5.09(d,J=15.9Hz,1H),4.42(d,J=16.0Hz,1H),2.57(s,3H),2.12(s,3H),2.05(s,3H);
化合物8的谱图数据:1H NMR(500MHz,Chloroform-d)δ7.41(d,J=7.4Hz,1H),7.32–7.27(m,3H),7.23–7.15(m,5H),7.10(d,J=7.8Hz,1H),7.06–7.02(m,2H),6.64(d,J=7.8Hz,1H),5.79(s,1H),5.09(d,J=15.9Hz,1H),4.49(d,J=15.9Hz,1H),2.62(s,3H),2.55(s,3H),2.15(d,J=10.7Hz,6H);
化合物9谱图数据:1H NMR(500MHz,Chloroform-d)δ7.73–7.67(m,2H),7.51(d,J=7.3Hz,1H),7.41–7.29(m,11H),7.02(t,J=7.6Hz,1H),6.84(d,J=8.2Hz,1H),5.79(s,1H),4.99(d,J=15.7Hz,1H),4.73(d,J=15.7Hz,1H),2.60(s,3H),2.14(s,3H),2.11(s,3H);
化合物10谱图数据:1H NMR(400MHz,Chloroform-d)δ7.30–7.27(m,1H),7.26–7.12(m,7H),7.08–7.07(m,1H),7.03–6.98(m,2H),6.50(d,J=8.0Hz,1H),5.76(s,1H),5.03(d,J=15.9Hz,1H),4.46(d,J=15.9Hz,1H),2.59–2.54(m,6H),2.29(s,3H),2.14(s,3H),2.11(s,3H);
化合物11谱图数据:1H NMR(400MHz,Chloroform-d)δ7.36–7.26(m,5H),7.23–7.18(m,2H),7.17–7.03(m,6H),6.81(d,J=7.9Hz,1H),6.00(s,1H),5.84(s,1H),5.12(d,J=15.7Hz,1H),4.66(d,J=15.7Hz,1H),2.45(s,3H),2.17(s,3H);
化合物12谱图数据:1H NMR(500MHz,Chloroform-d)δ7.34–7.27(m,7H),7.18(t,J=7.8Hz,2H),7.08–7.01(m,4H),6.76(d,J=7.9Hz,1H),5.75(s,1H),5.05(d,J=15.9Hz,1H),4.60(d,J=15.9Hz,1H),2.60–2.53(m,4H),2.41(dt,J=13.7,6.9Hz,1H),2.12(s,3H),0.98(t,J=7.2Hz,3H);
化合物13谱图数据:1H NMR(400MHz,Chloroform-d)δ7.55–7.51(m,2H),7.40–7.36(m,2H),7.35–7.27(m,4H),7.25–7.18(m,3H),7.15–7.08(m,4H),7.06–6.94(m,2H),6.76(td,J=7.6,0.6Hz,1H),6.35–6.30(m,1H),5.63(s,1H),5.10(d,J=15.2Hz,1H),4.90(d,J=15.2Hz,1H),2.16(s,3H),1.38(s,3H);
化合物14谱图数据:1H NMR(500MHz,Chloroform-d)δ7.74–7.70(m,2H),7.56–7.52(m,2H),7.37–7.28(m,9H),7.19–7.14(m,4H),7.09–7.05(m,1H),7.01(d,J=7.9Hz,1H),6.75(t,J=7.6Hz,1H),6.62(d,J=7.4Hz,1H),6.21–6.17(m,1H),4.92(d,J=15.3Hz,1H),4.87(d,J=15.2Hz,1H);
化合物15谱图数据:1H NMR(500MHz,Chloroform-d)δ7.69(d,J=7.3Hz,2H),7.38–7.29(m,10H),7.18–7.13(m,4H),7.08–7.04(m,1H),7.01(d,J=7.9Hz,1H),6.78(t,J=7.6Hz,1H),6.70(d,J=7.4Hz,1H),4.93–4.85(m,2H),1.94(s,3H);
化合物16谱图数据:1H NMR(500MHz,Chloroform-d)δ7.56(d,J=7.8Hz,2H),7.47(s,1H),7.44–7.40(m,2H),7.38–7.28(m,5H),7.26–7.22(m,2H),7.16–7.12(m,4H),7.07–7.02(m,2H),6.77(t,J=7.6Hz,1H),6.23(d,J=7.5Hz,1H),5.88(s,1H),5.15(d,J=15.1Hz,1H),4.94(d,J=15.1Hz,1H),1.44(s,3H);
化合物17谱图数据:1H NMR(400MHz,Chloroform-d)δ7.71–7.61(m,2H),7.51(d,J=12.6Hz,2H),7.43–7.28(m,9H),7.20–7.01(m,6H),6.86–6.79(m,1H),6.75–6.65(m,1H),4.95–4.82(m,2H);
化合物18谱图数据:1H NMR(400MHz,Chloroform-d)δ7.71–7.64(m,2H),7.38–7.27(m,10H),7.19–7.12(m,5H),7.08–7.03(m,1H),7.03–6.98(m,1H),6.83–6.78(m,1H),6.76–6.69(m,1H),4.93–4.83(m,2H),3.60(s,3H);
化合物19谱图数据:1H NMR(500MHz,Chloroform-d)δ8.61(s,1H),7.69(d,J=8.4Hz,1H),7.58(d,J=8.8Hz,1H),7.42(d,J=7.4Hz,1H),7.36–7.31(m,3H),7.30–7.27(m,3H),7.25–7.23(m,1H),7.21–7.17(m,2H),7.11–7.02(m,5H),6.86(d,J=7.9Hz,1H),4.94(d,J=15.7Hz,1H),4.50(d,J=15.7Hz,1H),2.15(s,3H);
化合物20谱图数据:1H NMR(400MHz,Chloroform-d)δ7.55–7.49(m,2H),7.39–7.30(m,5H),7.25–7.18(m,4H),7.04–6.98(m,2H),6.96–6.89(m,3H),6.75(t,J=7.5Hz,1H),6.33(d,J=7.4Hz,1H),5.62(s,1H),5.07(d,J=15.2Hz,1H),4.90(d,J=15.2Hz,1H),2.21(s,3H),2.14(s,3H),1.42(s,3H);
化合物21谱图数据:1H NMR(400MHz,Chloroform-d)δ7.56–7.52(m,2H),7.38–7.23(m,9H),7.14–7.09(m,2H),7.02(d,J=7.9Hz,1H),6.86–6.79(m,3H),6.34(dd,J=7.6,1.2Hz,1H),5.67(s,1H),5.12(d,J=15.2Hz,1H),4.92(d,J=15.2Hz,1H),2.20(s,3H),1.38(s,3H);
化合物22谱图数据:1H NMR(500MHz,Chloroform-d)δ7.55(d,J=7.4Hz,2H),7.38–7.32(m,5H),7.30–7.24(m,3H),7.17–7.10(m,4H),7.05(t,J=7.1Hz,1H),6.98(td,J=8.7,2.5Hz,1H),6.90(dd,J=8.6,4.0Hz,1H),6.11(dd,J=8.0,2.4Hz,1H),5.70(s,1H),5.11(d,J=15.3Hz,1H),4.89(d,J=15.3Hz,1H),2.17(s,3H),1.49(s,3H);
化合物23谱图数据:1H NMR(500MHz,Chloroform-d)δ7.47(d,J=7.3Hz,2H),7.44–7.37(m,4H),7.35–7.28(m,8H),7.16(d,J=8.6Hz,2H),7.06(t,J=7.5Hz,1H),6.81(d,J=7.9Hz,1H),5.78(s,1H),5.05(d,J=15.8Hz,1H),4.63(d,J=15.8Hz,1H),2.59(s,3H),2.13(s,3H),2.09(s,3H);
化合物24谱图数据:1H NMR(500MHz,Chloroform-d)δ7.34–7.26(m,7H),7.09–7.02(m,3H),6.92–6.86(m,2H),6.80(d,J=7.8Hz,1H),5.77(s,1H),5.03(d,J=15.8Hz,1H),4.60(d,J=15.8Hz,1H),2.55(s,3H),2.12(s,3H),2.06(s,3H);
化合物25谱图数据:1H NMR(500MHz,Chloroform-d)δ7.34–7.27(m,7H),7.15(s,1H),7.03(t,J=7.7Hz,2H),6.89(d,J=7.5Hz,1H),6.79(d,J=8.1Hz,1H),6.65(d,J=7.9Hz,1H),5.77(s,1H),4.98(d,J=15.8Hz,1H),4.65(d,J=15.8Hz,1H),2.57(s,3H),2.22(s,3H),2.13(s,3H),2.06(s,3H);
化合物26谱图数据:1H NMR(500MHz,Chloroform-d)δ7.35–7.26(m,7H),7.13(td,J=8.2,6.4Hz,1H),7.06(t,J=7.6Hz,1H),6.96(dt,J=10.0,2.1Hz,1H),6.81–6.72(m,3H),5.77(s,1H),5.03(d,J=15.8Hz,1H),4.62(d,J=15.8Hz,1H),2.55(s,3H),2.12(s,3H),2.06(s,3H);
化合物27谱图数据:1H NMR(500MHz,Chloroform-d)δ7.31–7.27(m,3H),7.25–7.22(m,1H),7.21–7.12(m,4H),7.07–7.00(m,2H),6.52(dd,J=8.4,2.2Hz,1H),6.21(d,J=1.8Hz,1H),5.77(s,1H),5.02(d,J=15.9Hz,1H),4.46(d,J=15.9Hz,1H),3.69(s,3H),2.60(s,3H),2.52(s,3H),2.12(s,6H);
化合物28谱图数据:1H NMR(500MHz,Chloroform-d)δ7.33(d,J=1.8Hz,1H),7.30–7.28(m,2H),7.25–7.22(m,2H),7.20–7.14(m,4H),7.04(d,J=3.9Hz,2H),6.53(d,J=8.4Hz,1H),5.76(s,1H),5.03(d,J=16.0Hz,1H),4.47(d,J=16.0Hz,1H),2.58(s,3H),2.52(s,3H),2.14(s,3H),2.10(s,3H);
化合物29谱图数据:1H NMR(500MHz,Chloroform-d)δ7.35–7.27(m,3H),7.25–7.22(m,2H),7.21–7.16(m,3H),7.08–6.99(m,4H),6.76(s,1H),5.74(s,1H),4.97(d,J=15.8Hz,1H),4.57(d,J=15.8Hz,1H),2.53(s,3H),2.10(s,3H),2.02(s,3H);
化合物30谱图数据:1H NMR(500MHz,Chloroform-d)δ7.32–7.28(m,2H),7.25–7.16(m,7H),7.09–7.01(m,3H),6.67(d,J=8.2Hz,1H),5.73(s,1H),4.96(d,J=15.8Hz,1H),4.58(d,J=15.8Hz,1H),2.51(s,3H),2.08(s,3H),2.04(s,3H);
化合物31谱图数据:1H NMR(500MHz,Chloroform-d)δ7.31–7.28(m,2H),7.25–7.21(m,3H),7.19–7.16(m,2H),7.08–7.00(m,4H),6.99–6.92(m,1H),6.67(dd,J=8.5,3.9Hz,1H),5.73(s,1H),4.99(d,J=15.8Hz,1H),4.56(d,J=15.8Hz,1H),2.52(s,3H),2.09(s,3H),2.04(s,3H);
化合物32谱图数据:1H NMR(500MHz,Chloroform-d)δ7.34–7.30(m,2H),7.27–7.26(m,3H),7.22–7.19(m,2H),7.11–7.06(m,7.6Hz,5H),6.67(d,J=7.9Hz,1H),5.76(s,1H),5.01(d,J=15.8Hz,1H),4.60(d,J=15.8Hz,1H),2.56(s,3H),2.27(s,3H),2.12(s,3H),2.07(s,3H);
化合物33谱图数据:1H NMR(500MHz,Chloroform-d)δ7.32–7.28(m,2H),7.26–7.21(m,3H),7.19–7.15(m,3H),7.08–7.03(m,3H),6.49(d,J=8.2Hz,1H),6.35(s,1H),5.74(s,1H),4.96(d,J=15.7Hz,1H),4.58(d,J=15.8Hz,1H),3.72(s,3H),2.53(s,3H),2.10(s,3H),2.03(s,3H);
化合物34谱图数据:1H NMR(400MHz,Chloroform-d)δ7.37–7.29(m,5H),7.25–7.21(m,2H),7.19–7.17(m,1H),7.14–7.10(m,3H),6.94(d,J=8.2Hz,1H),6.67(d,J=7.9Hz,1H),5.77(s,1H),5.02(d,J=15.8Hz,1H),4.56(d,J=15.8Hz,1H),2.56(s,3H),2.18(s,3H),2.12(s,3H);
化合物35谱图数据:1H NMR(400MHz,Chloroform-d)δ7.29(s,5H),7.19–7.15(m,2H),7.12–7.06(m,3H),7.04–6.96(m,3H),5.77(s,1H),4.97(d,J=15.4Hz,1H),4.89(d,J=15.4Hz,1H),2.55(s,3H),2.12(s,3H),2.04(s,3H);
化合物36谱图数据:1H NMR(500MHz,Chloroform-d)δ7.70(d,J=8.1Hz,1H),7.49(d,J=7.4Hz,1H),7.25–7.15(m,6H),7.13–7.03(m,5H),5.74(s,1H),5.17(d,J=16.9Hz,1H),4.89(d,J=16.9Hz,1H),2.52(s,3H),2.14(s,3H),2.03(s,3H);
化合物37谱图数据:1H NMR(400MHz,Chloroform-d)δ7.36–7.26(m,5H),7.23–7.18(m,2H),7.17–7.03(m,6H),6.81(d,J=7.9Hz,1H),6.00(s,1H),5.84(s,1H),5.12(d,J=15.7Hz,1H),4.66(d,J=15.7Hz,1H),2.45(s,3H),2.17(s,3H);
化合物38谱图数据:1H NMR(400MHz,Chloroform-d)δ7.51–7.48(m,2H),7.39–7.28(m,6H),7.25–7.18(m,3H),7.08–6.97(m,3H),6.79–6.69(m,3H),6.29(d,J=7.0Hz,1H),5.63(s,1H),5.11(d,J=15.2Hz,1H),4.91(d,J=15.2Hz,1H),2.17(s,3H),1.31(s,3H);
化合物39谱图数据:1H NMR(500MHz,Chloroform-d),δ7.60–7.56(m,2H),7.30–7.27(m,4H),7.25–7.17(m,6H),7.15–7.11(m,1H),6.99–6.96(m,1H),6.94–6.90(m,1H),6.86–6.79(m,2H),6.36(d,J=7.4Hz,1H),5.71–5.66(m,1H),4.99(d,J=15.5Hz,1H),4.93(d,J=15.5Hz,1H),2.60(s,3H),2.25(s,3H),1.36(s,3H);
化合物40谱图数据:1H NMR(400MHz,Chloroform-d)δ7.55–7.50(m,2H),7.36–7.19(m,10H),6.96–6.90(m,2H),6.85–6.80(m,1H),6.77–6.71(m,1H),6.63–6.57(m,1H),6.31(d,J=7.4Hz,1H),5.62(s,1H),5.12(d,J=15.2Hz,1H),4.86(d,J=15.2Hz,1H),2.15(d,J=6.2Hz,6H),1.38(s,3H);
化合物41谱图数据:1H NMR(400MHz,Chloroform-d)δ8.04(s,1H),7.53–7.48(m,2H),7.32–7.27(m,5H),7.21–7.13(m,4H),7.06–7.02(m,2H),6.87–6.80(m,2H),6.73–6.69(m,1H),6.35(d,J=7.2Hz,1H),5.60(s,1H),5.00(d,J=15.4Hz,1H),4.81(d,J=15.5Hz,1H),2.13(s,3H),1.36(s,3H);
化合物42谱图数据:1H NMR(500MHz,Chloroform-d)δ7.53(d,J=7.5Hz,2H),7.40–7.35(m,5H),7.30(t,J=7.3Hz,1H),7.26–7.22(m,2H),7.18–7.14(m,2H),7.13–7.09(m,2H),7.08–7.04(m,1H),6.99(d,J=1.3Hz,1H),6.79–6.75(m,1H),6.28(d,J=8.0Hz,1H),5.70–5.66(m,1H),5.07(d,J=15.3Hz,1H),4.90(d,J=15.3Hz,1H),2.16(s,3H),1.51(s,3H);
化合物43谱图数据:1H NMR(500MHz,Chloroform-d)δ7.64(d,J=8.0Hz,1H),7.48–7.43(m,2H),7.27–7.23(m,6H),7.21–7.16(m,4H),7.16–7.12(m,2H),7.10–7.05(m,1H),6.88(t,J=7.8Hz,1H),6.76(d,J=7.3Hz,1H),5.66(s,1H),5.27–5.20(m,2H),2.09(s,3H),1.69(s,3H);
化合物44谱图数据:1H NMR(500MHz,Chloroform-d)δ7.47–7.43(m,2H),7.43–7.39(m,2H),7.38–7.33(m,3H),7.32–7.28(m,1H),7.16–7.12(m,4H),7.07–7.02(m,3H),6.99(d,J=7.9Hz,1H),6.78(t,J=7.5Hz,1H),6.35(d,J=7.3Hz,1H),5.66(s,1H),5.14(d,J=15.2Hz,1H),4.93(d,J=15.2Hz,1H),2.30(s,3H),2.19(s,3H),1.42(s,3H);
化合物45谱图数据:1H NMR(500MHz,Chloroform-d)δ7.57–7.53(m,2H),7.41–7.30(m,6H),7.17–7.12(m,4H),7.07–7.00(m,2H),6.91(t,J=8.6Hz,2H),6.79(t,J=7.6Hz,1H),6.37(d,J=7.4Hz,1H),5.68(s,1H),5.10(d,J=15.2Hz,1H),4.93(d,J=15.2Hz,1H),2.15(s,3H),1.51(s,3H)。
表1化合物1至45的结构及分子量
实施例2吡唑β-内酰胺类衍生物对肿瘤细胞的抑制活性
1、测试采用的肿瘤细胞:人结肠癌细胞(HCT116)、人乳腺癌细胞(MCF-7)、人非小细胞肺癌细胞(A549)。其中,HCT116用1640培养基培养,MCF-7用DMEM培养基培养,A549用F-12K培养基培养。
2、测试方法:
(1)对肿瘤细胞的抑制率测定实验方法:
1)于96孔板中配制100uL细胞悬液(细胞接种量为5000个/孔),同时向空白孔中加入不含细胞的100uL细胞培养液,将接种好的96孔培养板放在培养箱中预培养24小时(37℃,5%CO2)。
2)向培养板中加入1μL最终浓度为20μM的待测化合物溶液(化合物1-45的溶液),其中对照孔和空白孔中加入1μL DMSO溶液。
3)加入待测化合物48小时后,将96孔培养板从培养箱中取出并观察细胞生长状态。向每孔中加入10μL CCK-8溶液(Cell Counting Kits-8),将培养板放置于培养箱中孵育2小时;
4)用Gen5酶标仪测定96孔培养板中各个孔在450nm处的吸光度,然后根据下列公式测得化合物对肿瘤细胞的抑制活性。
抑制率=【(Ac-As)/(Ac-Ab)】×100%,其中,As为样品孔;Ab为空白孔;Ac为对照孔。
(2)对肿瘤细胞的IC50测定实验方法:
1)于96孔板中配制100uL细胞悬液(细胞接种量为5000个/孔),同时向空白孔中加入不含细胞的100uL细胞培养液,将接种好的96孔培养板放在培养箱中预培养24小时(37℃,5%CO2).
2)向培养板中加入1μL 8个梯度浓度(50μmol/L、16.7μmol/L、5.6μmol/L、1.8μmol/L、0.62μmol/L、0.20μmol/L、0.07μmol/L、0.02μmol/L)的待测化合物溶液(化合物1-45的溶液),其中于对照孔和空白孔中加入1μL DMSO溶液。
3)加入待测化合物48小时后,将96孔培养板从培养箱中取出并观察细胞生长状态。向每孔中加入10μL CCK-8溶液(Cell Counting Kits-8),将培养板放置培养箱中孵育2小时;
4)用Gen5酶标仪测定96孔培养板中各个孔在450nm处的吸光度,然后根据下列公式计算肿瘤细胞在不同浓度的化合物溶液下的存活率。
细胞存活率=【(As-Ab)/(Ac-Ab)】×100%,其中,As为样品孔;Ab为空白孔;Ac为对照孔。
从表2可知,本发明的吡唑β-内酰胺类衍生物3种肿瘤细胞(HCT116、MCF-7、A549)均表现出一定的抑制作用,其中化合物3、11、12、16、24、25、26、28、29、31、33、34、35、36、37、45对三种肿瘤细胞表现出较好的抑制作用,尤其是化合物34和36对于3种肿瘤细胞均表现出明显的抑制作用。可见,本发明的吡唑β-内酰胺类衍生物可制备成为抗3种肿瘤细胞(HCT116、MCF-7、A549)的药物进行应用。
表2β-内酰胺类衍生物对多种癌细胞系的抑制作用
以上对本发明的实施方式作了详细说明,但本发明不限于所描述的实施方式。对于本领域的技术人员而言,在不脱离本发明原理和精神的情况下,对这些实施方式进行多种变化、修改、替换和变型,仍落入本发明的保护范围内。
Claims (10)
4.权利要求1或2所述的吡唑β-内酰胺类衍生物在制备抗结肠癌的药物或抑制结肠癌细胞增殖的药物中的应用。
5.权利要求1或2所述的吡唑β-内酰胺类衍生物在制备抗乳腺癌的药物或抑制乳腺癌细胞增殖的药物中的应用。
6.权利要求1或2所述的吡唑β-内酰胺类衍生物在制备抗非小细胞肺癌的药物或抑制非小细胞肺癌细胞增殖的药物中的应用。
10.一种抗肿瘤药物,其特征在于,所述药物以权利要求1或2所述的吡唑β-内酰胺类衍生物作为主要活性成分。
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