CN117534661A - 甲基麦冬黄酮a类衍生物及其制备和应用 - Google Patents
甲基麦冬黄酮a类衍生物及其制备和应用 Download PDFInfo
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- CN117534661A CN117534661A CN202210919793.1A CN202210919793A CN117534661A CN 117534661 A CN117534661 A CN 117534661A CN 202210919793 A CN202210919793 A CN 202210919793A CN 117534661 A CN117534661 A CN 117534661A
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- methylophiopogon
- flavone
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Abstract
本发明属于药物化学领域，具体涉及三种甲基麦冬黄酮A的衍生物，其化学结构为式I，式II，式III，以及该类衍生物的制备方法、及衍生物在制备预防和/或治疗心血管疾病等方面药物中的应用。
Description
技术领域
本发明属于药物化学领域，具体涉及三种甲基麦冬黄酮A类衍生物式I、式II、式III及其制备和应用，尤其是在治疗和/或预防心血管疾病以及相关疾病方面的用途。
背景技术
心血管疾病(CVD)是全球导致死亡的主要原因，占全世界死亡的31.5％，占非传染性疾病致死人数的45.0％，高于肿瘤及其他疾病，且患病率处于持续上升态势。根据《中国心血管健康与疾病报告2021》，推算我国心血管病现患人数3.3亿，占总人口的约23％，其中冠心病1139万，心力衰竭890万，高血压2.45亿，肺源性心脏病500万，房颤487万，风湿性心脏病250万。同时发病年龄逐渐年轻化。心脑血管疾病住院总费用逐年增加，平均增速远高于国民生产总值增速。
近40年来，心血管疾病治疗药物有了很大进展，包括β受体阻滞剂、钙通道阻滞剂、利尿剂、肾素-血管紧张素-醛固酮系统药物、调脂药、血管扩张剂、窦房结通道阻滞剂、改善心肌代谢药及丹参片、速效救心丸、银杏叶制剂等中成药。但近年来，该领域治疗药物研发遇到瓶颈，除了在老药新用(如钠-葡萄糖协同转运蛋白2抑制剂恩格列净、达格列净)和少数的新作用靶点候选药物(Vericiguat和Omecamtiv Mecarbil)取得一定进展，整体研发明显落后于肿瘤药物和自身免疫性疾病药物，现有药物不能满足临床治疗的需要，迫切需要开发新的药物疗法。同时目前的标准治疗仍然存在心血管风险，接受二级预防的患者，仍会存在相当大的残留心血管风险，主要不良心血管事件的风险仍有4～12％。
以中药与天然产物为资源发现和研发创新药物，一直是新药创制的重要途径，中国原创并得到国际认可的创新药物如青蒿素、二氢青蒿素、石杉碱甲、双环醇、丁苯酞等都来源于中药。甲基麦冬黄酮A是中药麦冬中含有的成分，有研究显示其具有抗非酒精性脂肪肝及保肝活性，我们的研究发现其具有心血管疾病防治活性。在本发明中我们以甲基麦冬黄酮A为先导化合物，发现了具有更优活性的一类甲基麦冬黄酮A类衍生物，并进行了药效学评价。
发明内容
本发明解决的技术问题是提供三种甲基麦冬黄酮A类衍生物、其制备方法以及在制备预防和/或治疗与心血管有关疾病的药物中的应用。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供了三种甲基麦冬黄酮A类衍生物式I，式II，式III，及其药学上可接受的盐，具有如下的结构式：
本发明技术方案的第二方面是提供了第一方面所述三种甲基麦冬黄酮A类衍生物式I，式II，式III及其药学上可接受盐的制备方法。
本发明的甲基麦冬黄酮A类衍生物I可通过如下方法获得，该方法包括以下步骤：
在碱性的条件下，将2,4,6-三羟基苯乙酮(1)与卤代甲氧基甲基醚反应制得式(2)结构的化合物；在碱性的条件下，式(2)结构的化合物与胡椒醛反应制得式(3)结构的化合物；将式(3)结构的化合物的双键还原制得式(4)结构的化合物；式(4)结构的化合物与三氯氧磷、N,N-二甲基甲酰胺反应制得式I结构的化合物：
优选地，在步骤一中，所述碱为三乙胺或N,N-二异丙基乙胺，所述的卤代甲氧基甲基醚为溴代甲氧基甲基醚。在步骤二中，所述碱为氢化钠或醇钠，KOH/EtOH等。在步骤三中，所述还原剂为钯碳/氢气或二氯亚锡等。
更优选地，在步骤一中，所述碱为N,N-二异丙基乙胺。在步骤二中，所述碱为氢化钠，反应在溶剂如四氢呋喃、N,N-二甲基甲酰胺等的存在下进行。在步骤三中，所述还原剂为钯碳/氢气。
本发明的甲基麦冬黄酮A类衍生物II和III可通过如下方法获得，该方法包括以下步骤：
将2,4,6-三羟基苯甲醛还原为2,4,6-三羟基甲苯，与醋酐反应制得式(5)结构的化合物；在碱性条件下式(5)与卤代甲氧基甲基醚反应制得式(6)结构的化合物；在碱性的条件下，式(6)结构的化合物与胡椒醛反应制得式(7)结构的化合物；将式(7)结构的化合物的双键还原制得式(8)结构的化合物；式(8)结构的化合物与三氯氧磷、N,N-二甲基甲酰胺反应制得式Ⅱ和式Ⅲ结构的化合物：
优选地，在步骤一中，所述还原剂为金属还原剂或金属硼氢化物。在步骤三中，所述碱为三乙胺或N,N-二异丙基乙胺。在步骤四中，所述碱为氢化钠或醇钠，KOH/EtOH。在步骤五中，所述还原剂为钯碳/氢气或二氯亚锡等。
更优选地，在步骤一中，所述还原剂为金属还原剂。在步骤三中，所述碱为N,N-二异丙基乙胺。在步骤四中，所述碱为氢化钠，反应在四氢呋喃的存在下进行。在步骤五中，所述还原剂为钯碳/氢气。
本发明技术方案的第三方面提供了一种药物组合物，其包含治疗和/或预防有效量的本发明第一方面所述甲基麦冬黄酮A类衍生物及其药学上可接受的盐，以及任选的一种或多种药学可接受的载体或赋形剂。
该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助溶剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助溶剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助溶剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助溶剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-5mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
本发明技术方案的第四方面是提供了第一方面所述甲基麦冬黄酮A类衍生物
及其药
学上可接受的盐以及第三方面所述药物组合物在制备预防和/或治疗与心血管有关疾病的药物中的应用。其中所述的与心血管有关疾病选自选自以下中的一种或多种：心肌缺血、心肌损伤、心肌肥厚、冠心病、高血压、心力衰竭、心肌病、心率失常、心肌梗死、心绞痛。
有益技术效果
本发明的甲基麦冬黄酮A类衍生物，在异丙肾上腺素诱导的心肌细胞损伤模型、缺氧复氧诱导的心肌细胞损伤模型、血管紧张素II诱导的心肌细胞损伤模型，均表现显著的心肌细胞损伤保护活性，能够显著提高心肌细胞存活率，0.1μM即显示良好药效。在血管紧张素II诱导的心肌细胞肥大模型，亦表现显著的抑制心肌细胞肥大活性，0.1μM即显示良好药效。心肌损伤伴随在心血管疾病发生发展当中，心肌肥大是高血压等导致心力衰竭重要的病理过程。多个实验结果均表明，本发明的化合物具有良好的心肌细胞保护和抑制心肌肥大活性，且在本实验条件下，多数活性结果优于甲基麦冬黄酮A和地尔硫卓。
附图说明
图1.甲基麦冬黄酮A类衍生物式I和式II对血管紧张素II(AngII)引起心肌细胞肥大损伤改善作用的图。
具体实施方式
本发明提供了三种治疗心血管疾病的甲基麦冬黄酮A类衍生物及其制备和应用。下面列举实施例进一步对本发明予以说明，实施例仅为解释和说明性的，绝不意味着以任何方式限制本发明的范围。
化合物的结构是通过核磁共振氢谱(1H NMR)和/或质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AV400型核磁共振波谱仪。MS的测定是用Thermo scientific(ESI)质谱仪进行的。
柱层析一般使用200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于偶合科技、百灵威科技、安耐吉化学等公司。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
下列药理研究实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
下述实施例中，部分物质或缩写相应的中文名称如下：
Control：空白对照
Model：模型对照
ISO：异丙肾上腺素
H/R：缺氧复氧
AngⅡ：血管紧张素Ⅱ
DMSO：二甲基亚砜
NaH：氢化钠
Na2SO4：硫酸钠
NaCl：氯化钠
SFC：超临界液相色谱
DEA：二乙胺
实施例1甲基麦冬黄酮A类衍生物式I的制备
1、式(2)结构的化合物的制备(1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)ethan-1-one)
将2,4,6-三羟基苯乙酮(10.0g,59.5mmol)与N,N-二异丙基乙胺(23.1g,178.5mmol)溶于200mL二氯甲烷中，在冰浴下缓慢加入溴代甲氧基甲基醚(10.7mL,130.9mmol)，2h内加毕，UPLC-MS监测反应进程，待原料消失后，加甲醇淬灭反应，反应液减压浓缩，残余物经硅胶柱层析纯化，洗脱剂石油醚/乙酸乙酯＝10:1，得标题化合物8.0g，收率52％。
1H NMR(400MHz,CDCl3)δ13.72(s,1H),6.26(dd,J＝9.3,2.3Hz,2H),5.26(s,2H),5.17(s,2H),3.52(s,3H),3.47(s,3H),2.66(s,3H).
2、式(3)结构的化合物的制备(3-(benzo[d][1,3]dioxol-5-yl)-1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)prop-2-en-1-one)
将式(2)结构的化合物(8.0g,31.2mmol)溶于N,N-二甲基甲酰胺中，冰浴下缓慢加入NaH(1.1g,46.8mmol),然后加入胡椒醛(4.7g,31.2mmol)，反应液在冰浴下继续搅拌反应30min，UPLC-MS监测反应进程，待原料消失后，加水，再加乙酸乙酯萃取，有机相用水和饱和NaCl水溶液洗涤，减压浓缩后，残余物经硅胶柱层析纯化，洗脱剂石油醚/乙酸乙酯＝5:1，得标题化合物9.0g，收率74％。
1H NMR(400MHz,CDCl3)δ13.89(s,1H),7.82–7.69(m,2H),7.12–7.07(m,2H),6.84(d,J＝7.9Hz,1H),6.28(dd,J＝28.0,2.3Hz,2H),6.03(s,2H),5.29(s,2H),5.19(s,2H),3.54(s,3H),3.49(s,3H).
3、式(4)结构的化合物的制备(3-(benzo[d][1,3]dioxol-5-yl)-1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)propan-1-one)
将式(3)结构的化合物(9g,23.2mmol)溶于150ml四氢呋喃中，加入Pd/C(0.9g)，在室温下通入氢气16h，UPLC-MS监测反应进程，待原料消失后，过滤除去固体，液体减压浓缩，得到标题化合物7.2g，收率:79％。
1H NMR(400MHz,CDCl3)δ13.68(s,1H),7.26(s,1H),6.77–6.65(m,3H),6.27(dd,J＝11.6,2.3Hz,2H),5.93(s,2H),5.24(s,2H),5.17(s,2H),3.48(d,J＝3.1Hz,7H),3.35–3.29(m,2H),2.94(t,J＝7.6Hz,2H)。
4、式I的制备(3-(benzo[d][1,3]dioxol-5-yl)-1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)propan-1-one)
将式(4)结构的化合物(300mg,0.76mmol)溶于5mL乙酸乙酯，氮气氛下，缓慢滴加N,N-二甲基甲酰胺(224mg,3.06mmol)和三氯氧磷(470mg,3.06mmol)，反应液在室温下继续搅拌5h，UPLC-MS监测反应进程，待原料消失后，加水淬灭反应，再加乙酸乙酯萃取(3×25mL)，有机相用水和饱和NaCl水溶液洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析纯化，洗脱剂正己烷/乙酸乙酯＝1:1，得标题化合物34mg，收率24.5％。
1H NMR(400MHz,DMSO-d6)δ12.70(s,1H),11.36–11.08(m,1H),8.19(s,1H),6.90–6.73(m,3H),6.31-6.30(m,1H),6.16-6.15(m,1H),5.95(s,2H),3.57(s,2H).
MS(ESI-):[(M-H)-]311.0.
HPLC纯度:99.34％(254nm),99.13％(214nm)。
实施例2：甲基麦冬黄酮A类衍生物式Ⅱ和式Ⅲ的制备
1、式(5)结构的化合物的制备(1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)ethan-1-one)
将2,4,6-三羟基甲苯(5g,35.70mmol)溶于100mL冰醋酸中，室温下加入三氟化硼乙醚(6.08g,42.80mmol)和醋酐(4.37g,42.80mmol)，N2下100℃反应5h，冷却后，减压除去乙酸，加入乙酸乙酯，有机相再用水和饱和NaCl水溶液洗涤，无水Na2SO4干燥，过滤，滤液减压浓缩后，残余物经硅胶柱层析纯化，洗脱剂为石油醚/乙酸乙酯＝5:1，得标题化合物4.0g，收率62％。MS(ESI+):[(M+H)+]183.1.
2、式(6)结构的化合物的制备(1-(2,4,6-tris(methoxymethoxy)-3-methylphenyl)ethan-1-one)
将式(5)结构的化合物(4.0g,22.0mmol)溶于60mL THF中，在冰浴下缓慢加入NaH(3.70g,154.0mmol)，然后滴加溴代甲氧基甲基醚(16.50g,132.0mmol)，反应液冰浴下继续搅拌反应3h，缓慢加入水和乙酸乙酯淬灭反应，再加乙酸乙酯萃取(3x 20mL)，有机相用水和饱和NaCl水溶液洗涤，减压浓缩后，残余物经硅胶柱层析纯化，洗脱剂为石油醚/乙酸乙酯＝5:1，得标题化合物1.13g，收率16％。
1H NMR(400MHz,DMSO-d6)δ6.72(s,1H),5.23(s,2H),5.18(s,2H),4.86(s,2H),3.40(s,3H),3.39(s,3H),3.36(s,3H),2.42(s,3H),2.04(s,3H).
MS(ESI+):[(M+H)+]315.1.
3、式(7)结构的化合物的制备(E)-4-(benzo[d][1,3]dioxol-5-yl)-1-(2,4,6-tris(methoxymethoxy)-3-methylphenyl)but-2-en-1-one
将式(6)结构的化合物(1.13g,3.6mmol)溶于20mL四氢呋喃中，冰浴下缓慢加入NaH(130mg,5.4mmol)和胡椒醛(0.54g,3.6mmol)，反应液在冰浴下继续搅拌反应1h，缓慢加入水和乙酸乙酯淬灭反应，再加乙酸乙酯萃取(3x 20mL)，有机相用水和饱和NaCl水溶液洗涤，减压浓缩后残余物经硅胶柱层析纯化，洗脱剂为PE/EA＝5:1，得标题化合物1.1g，收率58％。
1H NMR(400MHz,DMSO-d6)δ7.41(s,1H),7.22(d,J＝16.0Hz,1H),7.16(d,J＝8.1Hz,1H),6.94(dd,J＝11.9,9.6Hz,2H),6.76(s,1H),6.08(s,2H),5.26(s,2H),5.13(s,2H),4.85(s,2H),3.48(s,1H),3.43(s,3H),3.39(d,J＝5.3Hz,1H),3.33(s,3H),3.27(s,3H),2.08(s,3H).
MS(ESI+):[(M-13)+]447.3.
4、式(8)结构的化合物的制备(4-(benzo[d][1,3]dioxol-5-yl)-1-(2,4,6-tris(methoxymethoxy)-3-methylphenyl)butan-1-one)
将式(7)结构的化合物(400mg,0.87mmol)溶于10mL四氢呋喃，加入Pd/C(462mg,4.34mmol)，室温下通入氢气8h，UPLC-MS监测反应进程，待原料消失后，过滤除去固体，液体减压浓缩，残余物经硅胶柱层析纯化，洗脱剂为石油醚/乙酸乙酯＝10:1，得标题化合物得到200mg，收率50％。
1H NMR(400MHz,DMSO-d6)δ6.83–6.79(m,2H),6.71-6.68(m,2H),5.95(s,2H),5.23(s,2H),5.13(s,2H),4.80(s,2H),3.40-3.39(m,5H),3.36(s,3H),3.32(s,3H),3.02(t,J＝7.4Hz,2H),2.82(t,J＝7.4Hz,2H),2.03(s,3H).MS(ESI+):[(M-13)+]449.2.
5、式Ⅱ和式Ⅲ的制备
(3-(benzo[d][1,3]dioxol-5-ylmethyl)-5,7-dihydroxy-8-methyl-4H-chromen-4-one(Ⅱ)and 3-(benzo[d][1,3]dioxol-5-ylmethyl)-5,7-dihydroxy-6-methyl-4H-chromen-4-one(Ⅲ))
将式(8)结构的化合物(200mg,0.43mmol)溶于10mL乙酸乙酯，氮气氛下，在冰浴下缓慢滴加N,N-二甲基甲酰胺(70mg,0.95mmol)和三氯氧磷(663mg,4.32mmol)，反应液升至室温继续搅拌反应5h，UPLC-MS监测反应进程，待原料消失后，加水淬灭反应，再加乙酸乙酯萃取(3x 10mL)，滤液减压浓缩后，残余物经制备型HPLC纯化，得式Ⅱ和式Ⅲ的混合物，进一步经SFC纯化(流动相:CO2/MeOH(0.1％DEA)＝65/35)分别得到式Ⅱ(tR＝1.073min，20mg,收率14％)和式Ⅲ(tR＝0.903min，9mg，收率6％)的化合物。
Ⅱ:1H NMR(400MHz,DMSO-d6)δ12.62(s,1H),10.79(s,1H),8.27(s,1H),6.87(d,J＝1.2Hz,1H),6.82-6.80(m,1H),6.77–6.73(m,1H),6.29(s,1H),5.95(s,2H),3.58(s,2H),2.06(s,3H).
MS(ESI+):[(M+H)+]327.0.
HPLC纯度:99.71％(254nm),99.33％(214nm)。
Ⅲ:1H NMR(400MHz,DMSO-d6)δ12.96(s,1H),10.86(s,1H),8.19(s,1H),6.87(d,J＝1.4Hz,1H),6.82-6.80(m,1H),6.76-6.74(m,1H),6.42(s,1H),5.95(s,2H),3.59(s,2H),1.96(s,3H).
MS(ESI+):[(M+H)+]327.0.
HPLC纯度:99.48％(254nm),98.77％(214nm)。
药理实验
实施例4：利用异丙肾上腺素(ISO)诱导的心肌细胞损伤模型对实施例化合物检测
实验方法：
对数生长期的大鼠H9C2心肌细胞，将7×104个/mL细胞接种于96孔板中，每孔100μL，分为空白对照组、ISO模型组、ISO+地尔硫卓10μM组、ISO+式I 0.1μM组、ISO+式I 0.3μM组、ISO+式I1μM组、ISO+式I 3μM组、ISO+式I 5μM组、ISO+式I10μM组、ISO+式II 0.1μM组、ISO+式II 0.3μM组、ISO+式II 1μM组、ISO+式II 3μM组、ISO+式II 5μM组、ISO+式II 10μM组、ISO+式III 1μM组、ISO+式III5μM组、ISO+式III 10μM组、ISO+甲基麦冬黄酮A1μM组、ISO+甲基麦冬黄酮A 5μM组、ISO+甲基麦冬黄酮A10μM组。培养24小时后，给药组分别加入800μMISO和相应浓度的药物，ISO模型组加入800μM ISO和等体积DMSO，空白对照组加入等体积DMSO，继续培养24h。去除上清液后每孔加入100μL MTT溶液(0.5mg/mL)，放入细胞培养箱中培养4h，去除上清液后每孔加入150μL DMSO，震荡混匀10min，置于酶标仪570nm处测定吸光度，计算细胞存活率。细胞存活率(％)＝[(As-Ab)/(Ac-Ab)]×100％。As：实验孔(含有细胞的培养基、MTT、ISO)；Ac：对照孔(含有细胞的培养基、MTT、不含ISO)；Ab：空白孔(不含细胞的培养基、MTT、不含ISO)。
实验结果：
结果见表1。与空白对照组相比，ISO作用H9C2心肌细胞24h，心肌细胞存活率显著降低(54.71％)，OD值与空白对照组比较有统计学差异。与ISO模型组比较，式I化合物0.1-10μM，式II化合物0.1-10μM及式III化合物1-10μM剂量，对ISO诱导的心肌细胞损伤均表现显著保护活性，能够显著提高细胞存活率，OD值与模型组比较有统计学差异。甲基麦冬黄酮A1μM与5μM剂量对ISO损伤心肌细胞亦表现显著保护作用。与同剂量的甲基麦冬黄酮A比较，式I,式II化合物表现更优活性，式III化合物活性与甲基麦冬黄酮A相当。地尔硫卓10μM对ISO诱导的心肌细胞损伤亦具有保护活性，式I,式II化合物对ISO损伤心肌细胞的保护活性优于地尔硫卓，式III化合物1μM活性优于地尔硫卓10μM。
表1实施例化合物对异丙肾上腺素(ISO)引起心肌细胞损伤的保护作用
***P<0.001与空白对照组比较；#P<0.05,##P<0.01,###P<0.001与模型组比较；&P<0.05,&&P<0.01与同剂量甲基麦冬黄酮A组比较。
注：药物所用剂量对H9C2心肌细胞无毒性，数据未展示，下同。
实施例5：利用缺氧复氧(H/R)诱导的心肌细胞损伤模型对实施例化合物检测
实验方法：
取对数生长期H9C2心肌细胞，7×104个/mL接种于96孔板中，每孔100μL，分为空白对照组、H/R模型组、H/R+地尔硫卓10μM组、H/R+式I 0.1μM组、H/R+式I 0.3μM组、H/R+式I1μM组、H/R+式I 3μM组、H/R+式I 5μM组、H/R+式I10μM组、H/R+式II 0.1μM组、H/R+式II 0.3μM组、H/R+式II 1μM组、H/R+式II 3μM组、H/R+式II 5μM组、H/R+式II 10μM组、H/R+式III 0.1μM组、H/R+式III 0.3μM组、H/R+式III 1μM组、H/R+式III 3μM组、H/R+式III 5μM组、H/R+式III 10μM组、H/R+甲基麦冬黄酮A 1μM组、H/R+甲基麦冬黄酮A 5μM组、H/R+甲基麦冬黄酮A10μM组。培养24h后，将H/R组、给药组的H9C2心肌细胞培养液更换为不含血清的无糖DMEM培养基，每孔100μL，放入缺氧孵化器后，37℃细胞培养箱进行缺氧培养。6h后，将H/R组、给药组的上清液弃掉，加入含10％胎牛血清的高糖培养基，每孔100μL，各给药组分别加入相应浓度的药物，H/R模型组和空白对照组加入等体积DMSO，在37℃，95％O2，5％CO2细胞培养箱中复氧培养12h。去除上清液后每孔加入100μL CCK溶液(CCK体积占DMEM培养液体积的10％)，放入细胞培养箱中培养1h，置于酶标仪450nm处测定吸光度，计算细胞存活率。细胞存活率＝(实验孔-空白孔)/(对照孔-空白孔)×100％。
实验结果：
结果见表2。与空白对照组相比，糖氧剥夺后复氧，导致心肌细胞显著损伤，细胞存活率仅为50.80％。式I化合物(0.1、0.3、1、3、10μM)、式II化合物(0.1、0.3、3μM)及式III化合物(3μM)对缺氧复氧诱导的心肌细胞损伤表现显著保护活性，显著提高缺氧复氧损伤心肌细胞的存活率，OD值与模型组比较有统计学差异。甲基麦冬黄酮A10μM浓度对缺氧复氧诱导的心肌损伤亦表现显著保护活性，甲基麦冬黄酮A 1μM与5μM对缺氧复氧诱导的心肌损伤未表现显著保护活性。地尔硫卓10μM对缺氧复氧诱导的心肌损伤未表现显著保护作用。在该模型，式I、式II化合物活性优于甲基麦冬黄酮A，且低剂量起效。式I、式II和式III化合物活性优于地尔硫卓。式I、式II和式III化合物表现抗缺血再灌注诱导的心肌细胞损伤活性，式I和式II化合物活性优于式III化合物。
表2实施例化合物对缺氧复氧(H/R)引起心肌细胞损伤的保护作用
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***P<0.001与空白对照组比较；#P<0.05,##P<0.01,###P<0.001与模型组比较。
实施例6：利用血管紧张素Ⅱ(AngⅡ)诱导的心肌细胞损伤模型对实施例化合物检测
实验方法：
对数生长期的大鼠H9C2心肌细胞，将7×104个/mL个细胞接种于96孔板中，每孔100μL，分为空白对照组、AngⅡ模型组、AngⅡ+地尔硫卓10μM组、AngⅡ+式I0.1μM组、AngⅡ+式I 0.3μM组、AngⅡ+式I1μM组、AngⅡ+式I 3μM组、AngⅡ+式I 10μM组、AngⅡ+式II 0.1μM组、AngⅡ+式II 0.3μM组、AngⅡ+式II 1μM组、AngⅡ+式II 3μM组、AngⅡ+式II 10μM组、AngⅡ+甲基麦冬黄酮A 10μM组。培养24小时后，给药组分别加入50μM AngⅡ和相应浓度的药物，AngⅡ模型组加入50μM AngⅡ和等体积DMSO，空白对照组加入等体积DMSO，继续培养24h。去除上清液后每孔加入100μL MTT溶液(0.5mg/mL)，放入细胞培养箱中培养4h，去除上清液后每孔加入150μL DMSO，震荡混匀10min，置于酶标仪570nm处测定吸光度，计算细胞存活率。细胞存活率(％)＝[(As-Ab)/(Ac-Ab)]×100％。As：实验孔(含有细胞的培养基、MTT、AngⅡ)；Ac：对照孔(含有细胞的培养基、MTT、不含AngⅡ)；Ab：空白孔(不含细胞的培养基、MTT、不含AngⅡ)。
实验结果：
结果见表3。与空白对照组相比，50μM AngⅡ引起心肌细胞显著损伤，细胞存活率仅70.81％，OD值与空白对照组比较有显著性差异。与模型组比较，式I化合物(3、10μM)和式II化合物(0.1、1、10μM)对AngⅡ引起的心肌细胞损伤均表现显著保护活性，显著提高细胞存活率，OD值与模型组比较有统计学差异。式I和式II化合物其他剂量组亦有改善AngⅡ引起心肌细胞损伤的趋势。10μM甲基麦冬黄酮A和10μM地尔硫卓对AngⅡ引起的心肌细胞损伤亦表现显著保护活性。在AngⅡ引起的心肌细胞损伤模型上，式I、式II化合物活性与甲基麦冬黄酮A和地尔硫卓相当，式II化合物0.1μM剂量活性略优于甲基麦冬黄酮A10μM。
表3实施例化合物对血管紧张素Ⅱ(AngⅡ)引起心肌细胞损伤的保护作用
***P<0.001与空白对照组比较；#P<0.05，##P<0.01，###P<0.001与模型组比较。
实施例7：利用血管紧张素Ⅱ(AngⅡ)诱导的心肌细胞肥大模型对实施例化合物检测
实验方法：
将对数生长期的H9C2心肌细胞调整为1.2×105/孔的密度接种于六孔板，分为空白对照组、AngⅡ模型组、AngⅡ+地尔硫卓10μM组、AngⅡ+式I 0.1μM组、AngⅡ+式I 0.5μM组、AngⅡ+式I1μM组、AngⅡ+式II 0.1μM组、AngⅡ+式II 0.5μM组、AngⅡ+式II 1μM组。培养24小时后，各给药组加入40μM AngⅡ和相应浓度的药物，AngⅡ+地尔硫卓10μM组加入40μMAngⅡ和10μM地尔硫卓，AngⅡ模型组加入40μM AngⅡ和等体积的DMSO，空白对照组加入等体积DMSO，继续培养24h。弃掉培养液，用PBS洗3次，每孔加入1mL甲醇于-20℃固定20分钟后放置至常温，弃去甲醇后每孔添加1mL 0.5％结晶紫染液染色10min，清水洗净后于倒置显微镜下拍照，随机选取视野拍照。采用Image J软件测量视野内所有心肌细胞的表面积和，同时计数视野内细胞数，获得每一个心肌细胞表面积。
单个心肌细胞表面积＝视野内所有心肌细胞表面积和/视野内心肌细胞数。
实验结果：
结果见图1与表4。AngⅡ40μM作用H9C2细胞24h，与空白对照组相比，模型组心肌细胞数量显著减少，心肌细胞体积显著增大，式I化合物0.1μM、0.5μM、1μM，式II化合物0.1μM、0.5μM、1μM，均能显著改善AngⅡ引起的细胞数量下降情况，细胞数明显增多。单个心肌细胞表面积的结果见表4，模型组单个心肌细胞表面积与空白对照组比较显著增加，有统计学差异。式I化合物0.1μM、0.5μM、1μM和式II化合物0.1μM、0.5μM、1μM均能显著抑制AngⅡ引起的心肌细胞肥大现象，单个心肌细胞表面积与模型组相比显著降低。地尔硫卓10μM亦显著降低AngⅡ引起的心肌细胞肥大。式I和式II化合物在0.1μM、0.5μM、1μM剂量对心肌细胞肥大的抑制活性优于阳性药地尔硫卓10μM。
表4实施例化合物对心肌细胞肥大的作用-单个心肌细胞表面积(μM2)
***P<0.01与空白对照组比较；###P<0.01与模型组比较。
Claims (8)
1.三种甲基麦冬黄酮A类衍生物或其药学上可接受的盐，其特征在于，该三种甲基麦冬黄酮A类衍生物具有式I，式Ⅱ，式Ⅲ所述的结构式：
2.权利要求1所述的甲基麦冬黄酮A类衍生物I的制备方法，其特征在于，包括以下步骤：
在碱性的条件下，将2,4,6-三羟基苯乙酮(1)与卤代甲氧基甲基醚反应制得式(2)结构的化合物；在碱性的条件下，式(2)结构的化合物与胡椒醛反应制得式(3)结构的化合物；将式(3)结构的化合物的双键还原制得式(4)结构的化合物；式(4)结构的化合物与三氯氧磷、N,N-二甲基甲酰胺反应制得式I结构的化合物：
3.如权利要求2所述的甲基麦冬黄酮A类衍生物I的制备方法，其特征在于，在步骤一中，所述碱为三乙胺或N,N-二异丙基乙胺，所述的卤代甲氧基甲基醚为溴代甲氧基甲基醚；在步骤二中，所述碱为氢化钠或醇钠，KOH/EtOH；在步骤三中，所述还原剂为钯碳/氢气或二氯亚锡。
4.权利要求1所述的甲基麦冬黄酮A类衍生物Ⅱ和Ⅲ的制备方法，其特征在于，包括以下步骤：
将2,4,6-三羟基苯甲醛还原为2,4,6-三羟基甲苯，与醋酐反应制得式(5)结构的化合物；在碱性条件下与式(5)与卤代甲氧基甲基醚反应制得式(6)结构的化合物；在碱性的条件下，式(6)结构的化合物与胡椒醛反应制得式(7)结构的化合物；将式(7)结构的化合物的双键还原制得式(8)结构的化合物；式(8)结构的化合物与三氯氧磷、N,N-二甲基甲酰胺反应制得式Ⅱ和式Ⅲ结构的化合物；
5.根据权利要求4所述的甲基麦冬黄酮A类衍生物Ⅱ和Ⅲ的制备方法，其特征在于，在步骤一中，所述还原剂为金属还原剂或金属硼氢化物。在步骤三中，所述碱为三乙胺或N,N-二异丙基乙胺，所述的卤代甲氧基甲基醚为溴代甲氧基甲基醚；在步骤四中，所述碱为氢化钠或醇钠，KOH/EtOH；在步骤五中，所述还原剂为钯碳/氢气或二氯亚锡等。
6.一种药物组合物，其特征在于，包含预防和/或治疗有效量的权利要求1所述的甲基麦冬黄酮A类衍生物或其药学上可接受的盐，以及任选的一种或多种药学上可接受的载体或赋形剂。
7.权利要求1所述甲基麦冬黄酮A类衍生物或其药学上可接受的盐或者权利要求6所述药物组合物在制备预防和/或治疗与心血管有关疾病的药物中的应用。
8.根据权利要求7的应用，其特征在于，所述的与心血管有关疾病选自以下中的一种或多种：心肌缺血、心肌损伤、心肌肥厚、冠心病、高血压、心力衰竭、心肌病、心率失常、心肌梗死、心绞痛。
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