CN114642659A - 香青兰中一个咖啡酸衍生物的制备方法及其用途 - Google Patents
香青兰中一个咖啡酸衍生物的制备方法及其用途 Download PDFInfo
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- CN114642659A CN114642659A CN202210182432.3A CN202210182432A CN114642659A CN 114642659 A CN114642659 A CN 114642659A CN 202210182432 A CN202210182432 A CN 202210182432A CN 114642659 A CN114642659 A CN 114642659A
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- dibenzo
- ethanol
- oxepin
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Abstract
本发明公开了式Ⅱ所示的二苯并[b,f]噁庚英环类化合物或其药用盐在制备上调KLF2表达药物中的用途。本发明还公开了式Ⅱ所示的二苯并[b,f]噁庚英环类化合物或其药用盐在制备治疗心血管疾病或抗炎药物中的用途。发明人采用KLF2筛选模型对其进行心血管方面活性评价：以KLF2‑COS7细胞为实验对象，首次发现二苯并[b,f]噁庚英环类化合物或其药用盐具有显著上调与动脉粥样硬化、抗炎等相关的靶点KLF2表达的活性，在治疗动脉粥样硬化相关疾病方面具有较好的应用前景。本发明还公开了所述的二苯并[b,f]噁庚英环类化合物的制备方法。
Description
技术领域
本发明属于天然药物技术领域，涉及从植物特别是唇形科植物包括香青兰，但不仅限于香青兰中制备咖啡酸衍生物—二苯并[b,f]噁庚英环类化合物moldavica acid A的方法，二苯并[b,f]噁庚英环类化合物moldavica acid A或其药用盐在制备心血管疾病如动脉粥样硬化、血栓、冠心病、心绞痛、心肌梗塞或脑卒中等药物中的用途。
背景技术
近年来，随着人们物质生活水平的提高，心脑血管疾病的发病率呈明显上升趋势，心脑血管疾病死亡人数占全球人口死亡数的1/3，心血管疾病已成为我国城乡居民首要死亡原因，给社会和居民带来了很大的经济负担。其中，动脉粥样硬化性疾病已成为人类的第一“杀手”。动脉粥样硬化(atherosclerosis,AS)是一种慢性炎性疾病，是缺血性心脑血管疾病(如冠心病、心绞痛、心肌梗塞、脑卒中等)共同的病理生理基础。目前我国动脉粥样硬化呈现高发病率、年轻化趋势。
尽管目前针对AS治疗药物多种多样，但每种药物均有一定的局限性，使得药物的临床应用受到了一定程度的限制。KLF2(Krueppel-like factor 2)属于锌指家族DNA结合转录因子的成员，因在肺高表达，故又被称为肺kruupel样转录因子2(LKLF2)，其C端为高度保守的锌指结构域，便于结合到特定的DNA序列和核内定位，N端为高度分散的非DNA结合区，发挥转录激活或转录抑制作用。KLF2在血管功能和疾病中作为一关键的“分子开关”，起着非常重要的调节作用。KLF2具有多项机能负向调控炎症因子的表达从而发挥抗炎作用，同时也有维持内皮细胞结构及功能、防止血栓形成和抗氧化等作用，与动脉粥样硬化有着密切关系。
天然产物一直是创新药物的重要源泉。唇形科青兰属植物香青兰(DracocephalumMoldavica L.)是维吾尔族民族习用药物，具有益心护脑，保肝健胃，开通脑中闭塞的功效，用于治疗心脏病、高血压及头痛等疾病，历史悠久，疗效确切。近年来，随着对香青兰研究的不断推进，其对冠心病、动脉粥样硬化、心肌缺血等疾病的作用逐步受到关注。
发明内容
本发明目的在于首次从植物特别是唇形科植物香青兰中分离纯化得到二苯并[b,f]噁庚英环类化合物，拓宽了其获取渠道；发明人采用KLF2筛选模型对其进行心血管方面活性评价：以KLF2-COS7细胞为实验对象，筛选香青兰提取物、提取馏分及二苯并[b,f]噁庚英环类化合物上调KLF2的表达活性，首次发现二苯并[b,f]噁庚英环类化合物或其药用盐具有显著上调与动脉粥样硬化、抗炎等相关的靶点KLF2表达的活性，在治疗动脉粥样硬化相关疾病方面具有较好的应用前景，有望成为新一代临床治疗心血管疾病药物。
本发明的目的在于提供式Ⅱ所示的二苯并[b,f]噁庚英环类化合物或其药用盐在制备上调 KLF2表达药物中的用途，
化合物moldavica acid A的分子式为：C17H12O6，分子量为：312。
本发明的另一个目的在于提供式Ⅱ所示的二苯并[b,f]噁庚英环类化合物(记为moldavica acid A)或其药用盐在制备治疗心血管疾病或抗炎药物中的用途。
所述的心血管疾病为动脉粥样硬化、血栓、冠心病、心绞痛、心肌梗塞或脑卒中等。
所述的二苯并[b,f]噁庚英环类化合物的药用盐包括二苯并[b,f]噁庚英环类化合物与无机酸、有机酸、氨基酸或磺酸形成的盐。
所述的无机酸为盐酸或硫酸；所述的有机酸为乙酸、三氟乙酸、柠檬酸、马来酸、草酸、琥珀酸、苯甲酸、酒石酸、富马酸、扁桃酸、抗坏血酸或苹果酸；所述的氨基酸为丙氨酸、天冬氨酸或赖氨酸；所述的磺酸为甲磺酸或对甲苯磺酸。
本发明的另一个目的是提供一种药物组合物，它是以式Ⅱ所示的二苯并[b,f]噁庚英环类化合物或其药用盐作为活性成分或主要有效成分，与药学上可接受的一种或多种载体制成的。
本发明的另一个目的是提供所述的药用组合物在制备上调KLF2表达药物中的用途。
本发明的另一个目的是提供所述的药用组合物在制备治疗心血管疾病或抗炎的药物中的用途。
式Ⅱ所示的二苯并[b,f]噁庚英环类化合物或其药用盐也可与已知用于上调KLF2表达或治疗心血管疾病的药物组成复方制剂。
所述的药物组合物中，含有的式Ⅱ所示的二苯并[b,f]噁庚英环类化合物或其药用盐的重量百分比为0.1～99.9％，药学上可接受的载体的重量百分比为0.1～99.9％。
所述的药物组合物以适合药用的制剂形式存在。
所述的制剂为片剂、胶囊剂、颗粒剂、丸剂、散剂、膏剂、混悬剂、注射剂、粉针剂、栓剂、霜剂、滴剂或贴剂。其中，所述的片剂为糖衣片剂、薄膜衣片剂、肠溶衣片剂或缓释片剂；所述的胶囊剂为硬胶囊剂、软胶囊剂、缓释胶囊剂；所述的粉针剂为冻干粉针剂。
本发明的药物组合物，作为制剂形式，每剂中含有的式Ⅱ所示的二苯并[b,f]噁庚英环类化合物或其药用盐的有效量为0.1～1000mg。虽然剂量单位形式中所含活性成分的量可以变化，但一般根据所选择活性成分的效力，调节在1～800mg范围内。本领域技术人员可按常规方法确定适于某种情况的优选剂量。一般，开始治疗的量低于活性成分的最佳剂量，然后逐渐增加给药剂量，直到达到最佳治疗效果。为治疗需要，总的日剂量可一次给药或分数次给药。
每剂指的是每一制剂单位，如片剂的每片，胶囊的每粒，也可指每次服用剂量，如每次服用100mg。
本发明的药物组合物在制备成粉剂、片剂、可分散粉剂、胶囊、扁囊剂、栓剂和软膏形式的固体或半固体药物制剂时，可使用固体载体。所述的固体载体选自稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、膨胀剂等中的一种或多种物质，或可为包封物质。在粉状制剂中，在载体中含有5～70％的微粒化活性成分。所述的固体载体包括碳酸镁、硬脂酸镁、滑石粉、蔗糖、乳糖、果胶、糊精、淀粉、明胶、甲基纤维素、羧甲基纤维素钠、低沸点蜡、可可脂等。由于它们易于给药，片剂，粉剂、扁囊剂和胶囊等代表最有利的口服固体制剂。
本发明的液体制剂包括溶液、悬液和乳液。例如，非胃肠道给药的注射制剂可为水或水 -丙二醇溶液形式，调节其等渗度，pH等使适于活体的生理条件。液体制剂还可制成在聚乙二醇、水溶液中的溶液形式。可通过将活性成分溶解在水中，再加入适量的着色剂、调味剂、稳定剂和增稠剂，来制备口服水溶液。可将微粒化的活性成分分散在粘性物质如天然和合成胶、甲基纤维素、羧甲基纤维素钠和其它已知悬浮剂中制备适于口服的水悬液。
为了易于给药及剂量均一，将上述药物制剂配制成剂量单位形式是特别有利的。制剂的剂量单位形式指适于作为单一剂量的物理分离单位，每个单位含有产生所期望的治疗效果的计算好的预定量的活性成分。这种剂量单位形式可为包装形式，如片剂、胶囊或装在小管或小瓶中的粉剂，或装在管或瓶中的软膏、凝胶或霜剂。
本发明的另一个目的是提供所述的二苯并[b,f]噁庚英环类化合物的制备方法，包括：取干燥香青兰全草，按照干燥香青兰全草和0～60％乙醇的重量体积比1:3(kg/L或g/mL)加入0～60％乙醇，回流提取2～3次，得到提取液；提取液浓缩至无醇味，得到混悬液，加入蒸馏水得到澄清溶液；将澄清溶液进行大孔吸附树脂柱层析，采用水、30％乙醇、50％乙醇和95％乙醇梯度洗脱，得到4个洗脱部位：水洗脱部位、30％乙醇洗脱部位、50％乙醇洗脱部位、95％乙醇洗脱部位；取50％乙醇洗脱部位，用乙酸乙酯萃取3次，得到乙酸乙酯部位；将乙酸乙酯萃取部位经硅胶柱色谱、Sephadex LH-20柱色谱、半制备HPLC，纯化得到式Ⅱ所示的化合物。
优选的，取干燥香青兰全草，按照干燥香青兰全草和40％乙醇的重量体积比1:3(kg/L 或g/mL)加入40％乙醇，回流提取3次。
所述的混悬液和蒸馏水的体积比为1:2。
所述的大孔吸附树脂为HP20大孔吸附树脂。
所述的硅胶柱色谱的填料为200～300目硅胶，洗脱剂为二氯甲烷:甲醇＝100∶0～0∶ 100V∶V，得到15个流分，记为：XQL-1～XQL-15。流分XQL-8上Sephadex LH-20柱色谱。
所述的Sephadex LH-20柱色谱的洗脱剂为二氯甲烷:甲醇＝1∶1V∶V，得到11个亚流分，记为XQL-8-1～XQL-8-11。亚留分XQL-8-10进行半制备HPLC。
所述的半制备HPLC的色谱柱为：CAPCELL PAK PFP(粒径5μm,内径10mm×长度250mm)，流动相为乙腈:0.1％三氟醋酸水溶液＝33∶67V∶V，流速为1.5ml/min。
具体实施方式
本发明实施方案适用于从植物，而不限于香青兰中制备式Ⅱ化合物。以下实施例用于帮助本领域技术人员更好地理解本发明的技术方案，但不以任何方式限制本发明。
实施例1
提取：取干燥香青兰全草40kg，经3倍量(120L)40％乙醇回流提取3次，得到提取液，提取液浓缩至无醇味，得到20L混悬液；加40L蒸馏水至混悬液中，得到60L澄清溶液；
式II化合物的分离纯化：澄清溶液上HP-20大孔吸附树脂柱，弃去未吸附溶液，采用水、30％乙醇、50％乙醇和95％乙醇梯度洗脱，得到4个洗脱部位：水洗脱部位、30％乙醇洗脱部位、50％乙醇洗脱部位、95％乙醇洗脱部位；取50％乙醇洗脱部位，用乙酸乙酯萃取3次，得到乙酸乙酯部位(41.1g)；将乙酸乙酯萃取部位上硅胶(200～300目)柱，以二氯甲烷:甲醇＝100∶0～0∶100(V∶V)为洗脱剂进行梯度洗脱，得到15个流分(记为XQL-1～XQL-15)；XQL-8上Sephadex LH-20柱，以二氯甲烷:甲醇＝1∶1(V∶V)为洗脱剂，得到11 个亚流分(记为XQL-8-1～XQL-8-11)；亚流分XQL-8-10以乙腈:0.1％三氟醋酸水溶液＝ 33∶67(V∶V)为流动相进行半制备HPLC(色谱柱：CAPCELL PAK PFP(5μm,10mm×250 mm)；流速为1.5ml/min)，纯化得到化合物2，为黄色无定形粉末。
ESI-MS给出准分子离子峰m/z 311.1[M–H]–，HRESIMS m/z 311.0568，提示其分子组成为C17H12O6(calcd for C17H11O6 311.0556)，不饱和度为12。IR光谱提示化合物2含有羟基 (3250cm-1)、羧酸(3000-2500cm-1,强而宽的吸收峰)、共轭羰基(1670cm-1)、碳碳双键(1650cm-1)、苯环(1600，1494，1451cm-1)的特征吸收峰。化合物2的1H NMR谱中显示一个1,3,4,5-四取代的苯环[δH 7.08(d,J＝1.8Hz,H-5)和6.96(d,J＝1.8Hz,H-9)]、一个1,2,4,5-四取代的苯环[δH 6.83(s,H-7')和6.96(d,J＝1.8Hz,H-4')]、一个二取代的反式双键 [δH6.30(d,J＝16.2Hz,H-2)和7.39(d,J＝16.2Hz,H-3)]和一个二取代的顺式双键[δH 6.58(d, J＝11.4Hz,H-2')和6.50(d,J＝11.4Hz,H-1')]的质子共振信号；另外还有3个活泼[δH9.56(s, OH-6)、9.39(s,OH-6')和8.89(s,OH-7')]质子的共振信号。13C NMR谱显示17个碳原子，除了上述氢谱显示的4个单元的碳数据外，还有一个羰基共振信号(δC 167.6)。为了准确确定化合物2的化学结构，进行了2D NMR实验。通过HSQC谱解析，化合物2中的1H及其对应的13C共振信号得到了一一对应归属(见表1)。化合物2的1H-1H COSY谱显示H- 2/H-3的双键质子偶合相关信号，HMBC谱中显示H-2与C-1和C-4，H-3与C-4、C-5和C- 9，H-5与C-3、C-6、C-7和C-9，H-9与C-3、C-5和C-7，以及OH-6与C-5、C-6和C-7 的异核远程相关信号，并结合这些质子、碳的化学位移和分子组成，说明该化合物中含有一个6-OH,7-O,8-二取代的咖啡酸单元。同时1H-1H COSY谱显示H-1'/H-2'的双键质子偶合相关信号，HMBC谱中显示H-2'与C-3'、C-4'和C-8'，H-5'与C-3'、C-4'、C-6'和C-7'，H-8'与 C-2'、C-4'、C-6'和C-7'，OH-6'与C-5'、C-6'和C-7'，以及OH-7'与C-6'的异核远程相关信号，结合这些碳和质子的化学位移表明该化合物中含有一个4'-O,6',7'-二羟基取代的苯乙烯单元。此外，在HMBC谱中，H-1'与C-7、C-8和C-9，H-2'与C-8，以及H-9与C-1'的相关信号，显示上述两个单元通过C-8–C-1'键相连。最后结合化合物2的分子组成中只有6个氧原子以及不饱和度12，表明该化合物还有一个环的存在。因此，化合物2中的7-O和4'-O 取代应该共用一个氧原子，C-7和C-4'之间形成一个醚键，确定了该化合物中含有一个二苯并[b,f]噁庚英环系，从而确定了化合物2为(E)-3-(4,7,8-三羟基二苯并[b,f]噁庚英环-2)-丙烯酸，并将其命名为moldavica acidA。经scifinder数据库检索，化合物2在中国专利 CN107936034A中已被合成出来，但并未对该化合物进行解析归属，也未对该化合物进行药理活性评价。因此，化合物2为一个新的天然产物，首次从自然界中获得，结构如式Ⅱ所示：
表1.化合物2的1H NMR和13C NMR数据(DMSO-d6,600MHz)
实施例2化合物2上调KLF2的表达能力测试
采用KLF2筛选模型，以转染KLF2质粒的COS7细胞(KLF2-COS7)为实验对象，以荧光素酶(Bright-Lite Luciferase Assay System，南京诺唯赞生物科技股份有限公司，批号：7E512L1)为报告基因，使用EnVision多功能酶标仪检测荧光素酶与底物反应的发光强度，用相对发光单位(Relative Luminescence Unit,RLU)的数值来表示。实验过程中设置空白对照孔(不加测试样品)，加药孔与空白对照孔荧光强度的比值就是药物上调KLF2的倍数值。
具体实验方法如下：消化对数生长期的COS7细胞，10％胎牛血清DMEM培养基稀释并细胞计数5×105个/ml，同时瞬时转染KLF2质粒，96孔板接种，150μL/孔，4-6h待细胞贴壁后，更换为5％胎牛血清DMEM培养基200μL/孔，再加入1μL溶解于DMSO中的化合物2，加药孔中化合物2浓度为100μM，18-24h后检测。上调倍数大于1.5的化合物被认定为具有上调KLF2的活性，化合物2上调倍数大于2。继续测定其EC50：用5％胎牛血清DMEM培养基稀释至100、50、25、12.5、6.25、3.125、1.56、0.78和0.078μM的梯度浓度，200μL/孔，检测后用GraphPadPrism 8软件制作EC50曲线。
实验结果：在KLF2筛选模型上，化合物2对KLF2具有显著的上调作用，在浓度为100μM时，能够上调KLF2的表达10.6倍，其EC50为23.0μM。
Claims (10)
1.式Ⅱ所示的二苯并[b,f]噁庚英环类化合物或其药用盐在制备上调KLF2表达药物中的用途，
2.式Ⅱ所示的二苯并[b,f]噁庚英环类化合物或其药用盐在制备治疗心血管疾病或抗炎药物中的用途，
3.根据权利要求2所述的用途，其特征在于：所述的心血管疾病为动脉粥样硬化、血栓、冠心病、心绞痛、心肌梗塞或脑卒中。
4.根据权利要求1或2所述的用途，其特征在于：二苯并[b,f]噁庚英环类化合物的药用盐包括二苯并[b,f]噁庚英环类化合物与无机酸、有机酸、氨基酸或磺酸形成的盐。
5.根据权利要求4所述的用途，其特征在于：所述的无机酸为盐酸或硫酸；所述的有机酸为乙酸、三氟乙酸、柠檬酸、马来酸、草酸、琥珀酸、苯甲酸、酒石酸、富马酸、扁桃酸、抗坏血酸或苹果酸；所述的氨基酸为丙氨酸、天冬氨酸或赖氨酸；所述的磺酸为甲磺酸或对甲苯磺酸。
6.一种药物组合物，其特征在于：它是以式Ⅱ所示的二苯并[b,f]噁庚英环类化合物或其药用盐作为活性成分或主要有效成分，与药学上可接受的一种或多种载体制成的。
7.权利要求6所述的药用组合物在制备上调KLF2表达药物中的用途。
8.权利要求6所述的药用组合物在制备治疗心血管疾病或抗炎药物中的用途。
9.一种式Ⅱ所示的二苯并[b,f]噁庚英环类化合物的制备方法，其特征在于：包括：取干燥香青兰全草，按照干燥香青兰全草和0～60％乙醇的重量体积比1:3加入0～60％乙醇，回流提取2～3次，得到提取液；提取液浓缩至无醇味，得到混悬液，加入蒸馏水得到澄清溶液；将澄清溶液进行大孔吸附树脂柱层析，采用水、30％乙醇、50％乙醇和95％乙醇梯度洗脱，得到4个洗脱部位：水洗脱部位、30％乙醇洗脱部位、50％乙醇洗脱部位、95％乙醇洗脱部位；取50％乙醇洗脱部位，用乙酸乙酯萃取3次，得到乙酸乙酯部位；将乙酸乙酯萃取部位经硅胶柱色谱、Sephadex LH-20柱色谱、半制备HPLC，纯化得到式Ⅱ所示的化合物。
10.根据权利要求9所述的二苯并[b,f]噁庚英环类化合物的制备方法，其特征在于：硅胶柱色谱的洗脱剂为二氯甲烷:甲醇＝100∶0～0∶100 V∶V；所述的Sephadex LH-20柱色谱的洗脱剂为二氯甲烷:甲醇＝1∶1V∶V；所述的半制备HPLC的色谱柱为：CAPCELL PAK PFP(5μm,10mm×250mm)，流动相为乙腈:0.1％三氟醋酸水＝33∶67V∶V，流速为1.5ml/min。
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| CN107936034A (zh) * | 2017-12-22 | 2018-04-20 | 浙江工业大学 | 苄氧基二苯并[b,f]噁庚英环丙烯酸类化合物与中间体及其应用 |
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| CN107936034A (zh) * | 2017-12-22 | 2018-04-20 | 浙江工业大学 | 苄氧基二苯并[b,f]噁庚英环丙烯酸类化合物与中间体及其应用 |
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