CN111349230A - 一种含peg查尔酮衍生物前药和合成方法及其在制备抗非酒精性脂肪肝炎药物中的应用 - Google Patents
一种含peg查尔酮衍生物前药和合成方法及其在制备抗非酒精性脂肪肝炎药物中的应用 Download PDFInfo
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Abstract
本发明涉及一种含PEG查尔酮衍生物,通过查尔酮衍生物1与4‑硝基苯基氯甲酸酯反应得到氨基甲酸酯,再与PEG偶联生成含PEG查尔酮衍生物Compound A。本发明含PEG查尔酮衍生物Compound A具有抗非酒精性脂肪肝炎活性,可以用于非酒精性脂肪肝炎治疗,可应用于制备抗非酒精性脂肪肝炎药物中。
Description
技术领域
本发明属于新化合物制备和药物技术领域,一种含PEG查尔酮衍生物前药和合成方法及其在制备抗非酒精性脂肪肝炎药物中的应用。
背景技术
查尔酮类化合物存在于自然界中,蔬菜,水果,茶和其他植物中均有广泛分布。查尔酮类化合物具有生物药理活性明显,活性较高,具有良好的可塑性结构,可以与不同的药物中间体及生物体内的受体结合,表现出其独特的生物活性。例如:抗肿瘤、抗疟疾、抗菌、抗过敏、抗艾滋病、抗炎、抗糖尿病、抗脱发及触发毛发生长、抗氧化、降血脂、降血压、抗非酒精性脂肪肝炎等作用。
我们前期申请专利(申请号:CN201910505831.7)的一个治疗非酒精性脂肪肝炎的药物,其化学结构式为该化合物在细胞水平和动物水平都表现出了良好的抗非酒精性脂肪肝炎的活性。但是,我们发现由于该化合物水溶性不足,导致生物利用度不高。为了提高化合物的水溶性,我们对其进行了结构改造,将N上引入长链PEG制成前药。该设计的优点是PEG部分能在体内水解,释放出原药分子,以提高该化合物的活性及水溶性,找到更好的抗非酒精性脂肪肝炎的药物。
通过检索,尚未发现与本发明专利申请相关的文献与专利公开文献。
发明内容
本发明目的在于克服现有技术的不足之处,提供一种含PEG查尔酮衍生物和合成方法及其在制备抗非酒精性脂肪肝炎药物中的应用,该查尔酮衍生物Compound A具有抗非酒精性脂肪肝炎活性,可以用于非酒精性脂肪肝炎治疗,可应用于制备抗非酒精性脂肪肝炎药物中。
本发明解决其技术问题所采用的技术方案是:
一种含PEG查尔酮衍生物前药,所述含PEG查尔酮衍生物前药为查尔酮衍生物Compound A,该Compound A的结构式如下:
而且,所述含PEG查尔酮衍生物前药在细胞水平对非酒精性脂肪肝炎活性进行评价,结果表明该化合物在体外水平有抗非酒精性脂肪肝炎活性。
如上所述的含PEG查尔酮衍生物前药的合成方法,合成路线如下:
而且,具体步骤如下:
在圆底烧瓶中将化合物1(1.4g 3.31mmol)溶解于二氯甲烷(10mL)中,然后加入4-硝基苯基氯甲酸酯(799.48mg,3.97mmol),加料完毕后在30℃反应4h,将反应液加入水与二氯甲烷萃取(3×100mL),合并有机相,经饱和食盐水洗涤,无水硫酸钠干燥,用展开剂石油醚∶乙酸乙酯=10∶1,200-300目硅胶柱层析纯化,得化合物21.12g,产率57%;
将聚乙二醇单甲醚2000(1.16g,0.58mmol)溶解于N,N-二甲基甲酰胺(10mL)中搅拌15分钟,然后缓慢加入化合物2(680mg,1.16mmol),加料完毕后在25℃搅拌2h,将反应液加入水与二氯甲烷萃取(3×100mL),合并有机相,经饱和食盐水洗涤,无水硫酸钠干燥,用展开剂二氯甲烷∶甲醇=20∶1,200-300目硅胶柱层析纯化,得Compound A 900mg,产率51%。
1H NMR(400MHz,CDCl3)δ7.99(d,J=8.8Hz,2H),7.70(d,J=15.6Hz,1H),7.43-7.38(m,3H),7.27(s,2H),4.30(t,J=4.8Hz,1H),3.81-3.36(m,168H),3.37(s,3H),3.36(s,3H),2.26(s,6H),1.51(s,9H),1.45(s,6H).
如上所述的查尔酮衍生物在制备抗非酒精性脂肪肝炎药物中的应用。
本发明取得的优点和积极效果为:
1、本发明含PEG查尔酮衍生物前药Compound A具有抗非酒精性脂肪肝炎活性,可以用于非酒精性脂肪肝炎治疗,可应用于制备抗非酒精性脂肪肝炎药物中。
2、本发明含PEG查尔酮衍生物前药Compound A的合成、纯化方法简单,这类衍生物具有抗非酒精性脂肪肝炎活性,开拓了一类新型抗非酒精性脂肪肝炎药物的研究方向。
附图说明
图1为本发明中含PEG查尔酮衍生物前药Compound A的核磁共振氢谱图;
图2为本发明中含PEG查尔酮衍生物前药Compound A及原药Compound 1对FFA诱导HepG2细胞非酒精性脂肪肝模型的保护作用的形态学结果图(400×);
图3为本发明中含PEG查尔酮衍生物前药Compound A及原药Compound 1 40μM刺激下HepG2细胞非酒精性脂肪肝模型细胞内甘油三酯(TG)测试结果图(**p<0.01);
图4为本发明中含PEG查尔酮衍生物前药Compound A及原药Compound 1 40μM刺激下HepG2细胞非酒精性脂肪肝模型细胞内谷草转氨酶(AST)活性测试结果图(**p<0.01)
具体实施方式
下面详细叙述本发明的实施例,需要说明的是,本实施例是叙述性的,不是限定性的,不能以此限定本发明的保护范围。
本发明中所使用的原料,如无特殊说明,均为常规的市售产品;本发明中所使用的方法,如无特殊说明,均为本领域的常规方法。
一种含PEG查尔酮衍生物前药,所述含PEG查尔酮衍生物前药为查尔酮衍生物Compound A,该Compound A的结构式如下:
较优地,所述含PEG查尔酮衍生物前药在细胞水平对非酒精性脂肪肝炎活性进行评价,结果表明该化合物在体外水平有抗非酒精性脂肪肝炎活性。
如上所述的含PEG查尔酮衍生物前药Compound A的合成方法,合成路线如下:
较优地,具体步骤如下:
在圆底烧瓶中将化合物1(1.4g 3.31mmol)溶解于二氯甲烷(10mL)中,然后加入4-硝基苯基氯甲酸酯(799.48mg,3.97mmol),加料完毕后在30℃反应4h,将反应液加入水与二氯甲烷萃取(3×100mL),合并有机相,经饱和食盐水洗涤,无水硫酸钠干燥,用展开剂石油醚∶乙酸乙酯=10∶1,200-300目硅胶柱层析纯化,得化合物2 1.12g,产率57%;
将聚乙二醇单甲醚2000(1.16g,0.58mmol)溶解于N,N-二甲基甲酰胺(10mL)中搅拌15分钟,然后缓慢加入化合物2(680mg,1.16mmol),加料完毕后在25℃搅拌2h,将反应液加入水与二氯甲烷萃取(3×100mL),合并有机相,经饱和食盐水洗涤,无水硫酸钠干燥,用展开剂二氯甲烷∶甲醇=20∶1,200-300目硅胶柱层析纯化,得Compound A 900mg,产率51%。
1H NMR(400MHz,CDCl3)δ7.99(d,J=8.8Hz,2H),7.70(d,J=15.6Hz,1H),7.43-7.38(m,3H),7.27(s,2H),4.30(t,J=4.8Hz,1H),3.81-3.36(m,168H),3.37(s,3H),3.36(s,3H),2.26(s,6H),1.51(s,9H),1.45(s,6H).
本发明含PEG查尔酮衍生物的相关检测如下:
本发明首次合成出含PEG查尔酮衍生物前药Compound A,并首次利用FFA诱导HepG2肝癌细胞的非酒精性脂肪肝炎模型评价了Compound A的抗非酒精性脂肪肝炎活性。
细胞培养使用的培养液为含1%的青霉素-链霉素溶液,10%的胎牛血清的DMEM细胞培养液,培养条件为37℃,含5%CO2的恒温培养箱。根据实验FFA诱导HepG2肝癌细胞非酒精性脂肪肝模型实验条件,对化合物进行测试。根据化合物溶解度及细胞活性测试常用浓度,用DMEM细胞培养液作为溶剂将化合物稀释为不同浓度梯度,在实验体系中,采用临床药物非诺贝特(Fenofibrate)作为阳性对照。根据构建的非酒精性脂肪肝炎模型,对CompoundA的细胞水平对非酒精性脂肪肝模型的保护作用进行了测试,进行三次平行实验,其实验结果见图2和图3。
利用游离脂肪酸(FFA)诱导HepG2肝癌细胞建立经典的非酒精性脂肪肝炎模型测试Compound A抗非酒精性脂肪肝炎的活性。实验结果显示:与模型组相比,40μM的CompoundA能显著降低由游离脂肪酸(FFA)引起的细胞内脂质的累积,并且能降低细胞内甘油三酯(TG)的含量(从0.099mmol/mg prot下降到0.043mmol/mg prot)和谷草转氨酶(AST)的活性(从33.27U/mg prot下降到29.42U/mg prot)。同时,Compound A的表现出的结果与Compound 1相一致,说明Compound A的PEG部分可以在实验系统中解离,释放出Compound1,从而发挥作用。以上结果说明:Compound A可以作为Compound 1的前药并且具有良好的体外水平抗非酒精性脂肪肝炎的活性。
本发明基于查尔酮类化合物有很好的生物活性,首次合成出含PEG查尔酮衍生物Compound A,这中类似物具有较好的抗非酒精性脂肪肝炎活性。其具有良好的细胞水平非酒精性脂肪肝炎活性,显著降低细胞内TG的含量和AST的活性。
含PEG查尔酮衍生物Compound A合成、纯化方法简单并具有较好的抗非酒精性脂肪肝炎的活性,在抗非酒精性脂肪肝炎药物的开发与应用方面具有广阔的前景。本发明查尔酮衍生物能够应用在制备抗非酒精性脂肪肝炎药物中,包括但不限于在治疗非酒精性脂肪肝炎中的应用。
尽管为说明目的公开了本发明的实施例,但是本领域的技术人员可以理解:在不脱离本发明及所附权利要求的精神和范围内,各种替换、变化和修改都是可能的,因此,本发明的范围不局限于实施例和附图所公开的内容。
Claims (5)
2.根据权利要求1所述的含PEG的查尔酮衍生物,其特征在于:所述含PEG的查尔酮衍生物在细胞水平对非酒精性脂肪肝炎活性进行评价,结果表明该化合物在体外水平有抗非酒精性脂肪肝炎活性。
4.根据权利要求3所述的含PEG的查尔酮衍生物的合成方法,其特征在于:具体步骤如下:
在圆底烧瓶中将化合物1(1.4g 3.31mmol)溶解于二氯甲烷(10mL)中,然后加入4-硝基苯基氯甲酸酯(799.48mg,3.97mmol),加料完毕后在30℃反应4h,将反应液加入水与二氯甲烷萃取(3×100mL),合并有机相,经饱和食盐水洗涤,无水硫酸钠干燥,用展开剂石油醚∶乙酸乙酯=10∶1,200-300目硅胶柱层析纯化,得化合物2 1.12g,产率57%;
将聚乙二醇单甲醚2000(1.16g,0.58mmol)溶解于N,N-二甲基甲酰胺(10mL)中搅拌15分钟,然后缓慢加入化合物2(680mg,1.16mmol),加料完毕后在25℃搅拌2h,将反应液加入水与二氯甲烷萃取(3×100mL),合并有机相,经饱和食盐水洗涤,无水硫酸钠干燥,用展开剂二氯甲烷∶甲醇=20∶1,200-300目硅胶柱层析纯化,得Compound A 900mg,产率51%。
5.如权利要求1或2所述的含PEG的查尔酮衍生物在制备抗非酒精性脂肪肝炎药物中的应用。
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