CN113968795A - 一种化合物、组合物及其在制备具有治疗心肌炎作用的药物中的应用 - Google Patents
一种化合物、组合物及其在制备具有治疗心肌炎作用的药物中的应用 Download PDFInfo
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Abstract
本发明涉及生物医学技术领域,具体公开了一种化合物、组合物及其在制备具有治疗心肌炎作用的药物中的应用。所述的化合物,具有式Ⅰ或式Ⅱ所示的结构;所述的组合物,包含式Ⅰ和式Ⅱ所示结构的化合物。研究表明,所述的化合物和组合物显示出来优异的治疗心肌炎活性;因此可以将其作为活性成分用于制备具有治疗心肌炎作用的药物。
Description
技术领域
本发明涉及生物医学技术领域,具体涉及一种化合物、组合物及其在制备具有治疗心肌炎作用的药物中的应用。
背景技术
心肌炎是指以心肌的局限性或弥漫性炎性病变为主要表现的疾病,心肌炎临床表现多样,可从无症状至出现严重心律失常、急性心功能不全、心源性休克甚至死亡。普通病毒感染或病毒感染后的免疫反应是导致心肌炎的常见方式之一,其中以引起肠道和上呼吸道感染的病毒最多见;如艾可病毒、脊髓灰质炎病毒、柯萨奇病毒A组以及柯萨奇病毒B组;这些病毒中以柯萨奇B组病毒是最主要的致病病毒。
因此,提供一种具有治疗心肌炎作用的化合物,尤其是具有治疗病毒性心肌炎作用的化合物;对于开发治疗心肌炎的药物,尤其是治疗病毒性心肌炎的药物具有重要的意义。
发明内容
鉴于此,本发明首先提供一种全新结构的化合物,经进一步研究表明,所述的化合物具有治疗心肌炎作用,尤其是具有治疗病毒性心肌炎作用。
本发明的详细技术方案如下:
本发明首先提供一种化合物,其具有式Ⅰ或式Ⅱ所示的结构:
本发明还提供一种组合物,其包含式Ⅰ和式Ⅱ所示结构的化合物。
优选地,式Ⅰ和式Ⅱ所示结构的化合物的质量比为3~6:1~3。
最优选地,式Ⅰ和式Ⅱ所示结构的化合物的质量比为5:2。
本发明还提供了一种上述式Ⅰ所示结构的化合物具体通过如下方法制备得到:
将3-甲氧基苯甲酸与缬氨酸进行缩合反应即得式Ⅰ所示结构的化合物。
优选地,式Ⅰ所示结构的化合物具体通过如下方法制备得到:
将3-甲氧基苯甲酸加入到无水二氯甲烷中,然后加入缬氨酸和缩合试剂,在室温下进行缩合反应5~8h,即得式Ⅰ所示结构的化合物。
本发明还提供了一种上述式Ⅱ所示结构的化合物具体通过如下方法制备得到:
将(E)-3-(3,4-dihydroxyphenyl)acrylic acid与methyl glycinate进行缩合反应即得式Ⅱ所示结构的化合物。
优选地,式Ⅱ所示结构的化合物具体通过如下方法制备得到:
将(E)-3-(3,4-dihydroxyphenyl)acrylic acid加入到无水二氯甲烷中,然后加入methyl glycinate和缩合试剂,在室温下进行缩合反应5~8h,即得式Ⅰ所示结构的化合物。
优选地,所述的缩合试剂为HATU。
本发明还提供了一种上述化合物或组合物在制备具有治疗心肌炎作用的药物中的应用。
优选地,所述的心肌炎为病毒性心肌炎。
最优选地,所述的病毒性心肌炎为柯萨奇病毒所致的心肌炎。
有益效果:本发明提供了一种全新式Ⅰ或式Ⅱ所示结构的化合物,并且首次提供了式Ⅰ或式Ⅱ所示结构的化合物在制备具有治疗心肌炎作用的药物中的应用;尤其是首次提供了其在制备具有治疗病毒性心肌炎作用的药物中的应用。进一步研究表明,将式Ⅰ或式Ⅱ所示结构的化合物组合后,其治疗心肌炎的作用要好于单独使用式Ⅰ或式Ⅱ所示结构的化合物;这表明,式Ⅰ或式Ⅱ所示结构的化合物组合后,产生了一定的协同治疗心肌炎的作用。此外,本发明还提供一种式Ⅰ或式Ⅱ所示结构的化合物的制备方法;所述的制备方法合成工序简单、步骤少,有利于降低式Ⅰ或式Ⅱ所示结构的化合物的制备成本。
附图说明
图1是式Ⅰ所示结构的化合物的质谱图。
图2是式Ⅰ所示结构的化合物的NMR图。
图3是式Ⅱ所示结构的化合物的质谱图。
图4是式Ⅱ所示结构的化合物的NMR图。
具体实施方式
以下结合具体实施例来进一步解释本发明,但实施例对本发明不做任何形式的限定。
实施例1式Ⅰ所示结构的化合物的制备
制备方法:称取反应底物3-甲氧基苯甲酸(1.0g)于100mL干净的圆底烧瓶中,放入磁子,加入50mL无水二氯甲烷,搅拌下加入缬氨酸(1.50g),三乙胺(3.9mL),5分钟后加入HATU(4.90g)。加料结束后,于室温下继续反应6小时,TLC监测反应原料消失。停止搅拌,将反应体系减压蒸除溶剂,残留物经硅胶柱层析(200-300目),纯化得白色固体,即式Ⅰ所示结构的化合物。
将式Ⅰ所示结构的化合物利用质谱和NMR对其进行测定(质谱和NMR图见图1和图2);结果如下:式Ⅰ所示结构的化合物:黄色粉末。ESI-MS显示离子峰m/z 251.9[M]+,确定分子式为C13H17NO4。式Ⅰ所示结构的化合物的1HNMR(600MHz,DMSO)δ8.03(s,1H),7.37(m,3H),7.10(m,1H),4.15(m,1H),3.81(s,3H),2.18(m,1H),0.92(d,6H);13C NMR(150MHz,DMSO)δ129.89,119.89,117.37,113.02,55.72,31.62,30.29,20.06,19.14。最终,将式Ⅰ所示结构的化合物鉴定为(3-methoxybenzoyl)valine。
实施例2式Ⅱ所示结构的化合物的制备
制备方法:称取反应底物(E)-3-(3,4-dihydroxyphenyl)acrylic acid(1.32g)于100mL干净的圆底烧瓶中,放入磁子,加入50mL无水二氯甲烷,搅拌下加入methylglycinate(1.14g),三乙胺(3.32mL),6分钟后加入HATU(4.90g)。加料结束后,于室温下继续反应4小时,TLC监测反应原料消失。停止搅拌,将反应体系减压蒸除溶剂,残留物经硅胶柱层析(200-300目),纯化得白色固体,即式Ⅱ所示结构的化合物。
将式Ⅱ所示结构的化合物利用质谱和NMR对其进行测定(质谱和NMR图见图3和图4);结果如下:式Ⅱ所示结构的化合物:白色粉末;ESI-MS显示离子峰m/z 250.1[M]+,离子峰m/z 274.1[M+Na]+,确定其分子式为C12H13NO5。人参酚酰胺衍生物-2(RSDF-2)的1H NMR(600MHz,DMSO)δ9.39(s,1H),9.15(s,1H),8.42(t,2H),7.26(d,1H),6.97(d,1H),6.86(dd,1H),6.76(d,1H),6.42(d,1H),3.96(d,2H),3.65(s,3H);13C NMR(151MHz,DMSO)δ171.01,166.35,147.95,146.00,140.43,126.63,121.07,118.06,116.21,114.33,52.16,41.19。最终,将式Ⅰ所示结构的化合物鉴定为methyl(E)-(3-(3,4-dihydroxyphenyl)acryloyl)glycinate。
实验例1本发明化合物治疗病毒性心肌炎实验
取昆明种小白鼠腹腔注射0.2mL含有100TCID50柯萨奇病毒B3(CVB3)的Eagle培养液,制备病毒性心肌炎小鼠模型;建模后选取血清心肌肌钙蛋白I(cTnI)浓度相当的小鼠分成实验组1~3和对照组,每组20只;其中,实验组1按1mg/kg/d的剂量注射式Ⅰ所示结构的化合物;实验组2按1mg/kg/d的剂量注射式Ⅱ所示结构的化合物;实验组3按1mg/kg/d的剂量注射由式Ⅰ和式Ⅱ所示结构的化合物组成的组合物(式Ⅰ和式Ⅱ所示结构的化合物的质量比为5:2);对照组每天注射等体积的生理盐水;同时设置正常组,正常组每天注射等体积的生理盐水;连续给药2周后,最后一次给药后2小时,取各组小鼠外周血提取血清,用于测定各组小鼠血清心肌肌钙蛋白I(cTnI)的浓度,测试结果显示模型组与正常组相比具有显著性差异(P<0.05),实验组1~3与模型组相比具有显著性差异(P<0.05),具体结果见表1。其中,血清心肌肌钙蛋白I(cTnI)浓度采用cTnI检测试剂盒(ELISA)测试得到。
表1.本发明化合物对血清心肌肌钙蛋白I(cTnI)浓度的影响
血清心肌肌钙蛋白I(cTnI)浓度是目前诊性心肌炎最敏感和最特异的检测指标。由表1数据可以看出,模型组的cTnI浓度显著高于正常组的cTnI浓度;这说明本发明小鼠心肌炎模型建模成功。
由表1数据还可以看出,实验组1和2的cTnI浓度显著低于模型组;这说明式Ⅰ和式Ⅱ所示结构的化合物能够显著降低小鼠的血清心肌肌钙蛋白I(cTnI)浓度;进一步说明式Ⅰ和式Ⅱ所示结构的化合物对心肌炎具有很好的治疗作用。
由表1数据还可以看出,实验组3的cTnI浓度要小于实验组1和2;这说明将式Ⅰ和式Ⅱ所示结构的化合物组合后其对心肌炎的治疗作用要好于单独使用式Ⅰ或式Ⅱ所示结构的化合物;式Ⅰ和式Ⅱ所示结构的化合物组合后产生了协同的治疗心肌炎作用。
Claims (10)
2.一种组合物,其特征在于,包含式Ⅰ和式Ⅱ所示结构的化合物。
3.根据权利要求1所述的组合物,其特征在于,式Ⅰ和式Ⅱ所示结构的化合物的质量比为3~6:1~3。
4.根据权利要求1所述的组合物,其特征在于,式Ⅰ和式Ⅱ所示结构的化合物的质量比为5:2。
5.根据权利要求1所述的制备方法,其特征在于,式Ⅰ所示结构的化合物具体通过如下方法制备得到:
将3-甲氧基苯甲酸与缬氨酸进行缩合反应即得式Ⅰ所示结构的化合物。
6.根据权利要求5所述的制备方法,其特征在于,式Ⅰ所示结构的化合物具体通过如下方法制备得到:
将3-甲氧基苯甲酸加入到无水二氯甲烷中,然后加入缬氨酸和缩合试剂,在室温下进行缩合反应5~8h,即得式Ⅰ所示结构的化合物。
7.根据权利要求1所述的制备方法,其特征在于,式Ⅱ所示结构的化合物具体通过如下方法制备得到:
将(E)-3-(3,4-dihydroxyphenyl)acrylic acid与methyl glycinate进行缩合反应即得式Ⅱ所示结构的化合物。
8.根据权利要求7所述的制备方法,其特征在于,式Ⅱ所示结构的化合物具体通过如下方法制备得到:
将(E)-3-(3,4-dihydroxyphenyl)acrylic acid加入到无水二氯甲烷中,然后加入methyl glycinate和缩合试剂,在室温下进行缩合反应5~8h,即得式Ⅰ所示结构的化合物。
9.根据权利要求6或8所述的制备方法,其特征在于,所述的缩合试剂为HATU。
10.权利要求1~4任一项所述的化合物或组合物在制备具有治疗心肌炎作用的药物中的应用。
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