CN113929581A - 一种丹参素衍生物丹参素酯及其制备方法与应用 - Google Patents
一种丹参素衍生物丹参素酯及其制备方法与应用 Download PDFInfo
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- CN113929581A CN113929581A CN202111207160.XA CN202111207160A CN113929581A CN 113929581 A CN113929581 A CN 113929581A CN 202111207160 A CN202111207160 A CN 202111207160A CN 113929581 A CN113929581 A CN 113929581A
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- C07C68/06—Preparation of esters of carbonic or haloformic acids from organic carbonates
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及一种丹参素衍生物丹参素酯及其制备方法与应用。本发明中的丹参素衍生物丹参素酯,是由丹参素与丹皮酚以酯键结合,与现有技术中将丹参素和丹皮酚简单复配使用相比,本发明采用化学杂交的策略,将丹参素和丹皮酚进行结合,合成一种新的活性成分‑丹参素酯,改善了丹参素的成药性同时增加了丹参素的稳定性,使其更好地发挥作用。丹参素酯进入体内可以直接作用于靶点发挥作用,进一步在体内被代谢,酯键断裂,释放出一分子丹参素与一分子丹皮酚,代谢产物也发挥作用,因而疗效更佳,可有效促进血管再生。丹参素酯在体内的代谢产物丹参素和丹皮酚都是已知中药的活性成分,不产生未知的代谢产物,安全性更高。
Description
技术领域
本发明属于医药技术领域,具体涉及一种丹参素衍生物丹参素酯及其制备方法与应用。
背景技术
冠心病(Coronary Heart Disease,CHD)亦称缺血性心脏病或冠状动脉心脏病,是指因冠状动脉狭窄、供血不足而引起的心肌机能障碍和(或)器质性病变,现代医学研究表明其主要病因是冠状动脉病变,包括冠状动脉粥样硬化和冠状动脉痉挛,其中绝大多数是由冠状动脉粥样硬化所致。CHD发病机理是一个复杂的漫长过程,现代医学认为主要由心血管内皮细胞损害、平滑肌细胞增生、血小板粘附、脂代谢异常等多个发病环节组成,其主要病理学基础为动脉粥样硬化和血脂代谢异常。我国传统中药干预冠心病的发生、发展已经具有高效、低毒的特点,大量的中药制剂已经在冠心病临床的防治中发挥了很大作用。然而,传统中药的服用方式、以及多成分的特点,对于现代药物研发而言,存在巨大的障碍。但是从传统中药中获得灵感,发现新的药用物质,也是冠心病药物研发的一个重要途径。
丹参素(danshensu,DSS)是从中药丹参中分离得到的主要生物活性物质。丹参素化学名为D(+)-β-(3,4-二羟基苯基)乳酸,分子式为C9H10O5,丹参素在体内体外实验中均显示出良好的心肌保护能力。冠脉结扎致实验性心肌缺血大鼠经丹参素预处理后,血清心肌酶水平显著降低,心肌梗死面积和程度均显著减小,而血清中超氧化物歧化酶的活力、丙二醛的含量分别明显升高或降低,脂质过氧化所造成的损伤得到显著改善。采用膜片钳技术记录心肌细胞动作电位的体外实验则表明,丹参素能够调控心肌细胞胞内电流状态,同时缩短心肌细胞动作电位时程,从而改善心肌异常放电状态。但丹参素水溶性极强、不稳定、易氧化、不易穿过血脑屏障进入脑中发挥作用,限制其作为冠心病的药物在临床上的应用。因此,开发脂溶性强、稳定性好、可用于治疗冠心病的丹参素衍生物已成为该领域的研究热点。中国专利文献CN105085264A(申请号201410186652.9)公开了一种丹参素酯衍生物的不对称合成方法,所述方法包括:(R)-或(S)-丹参素钠和卤代烃、磺酸酯、硫酸酯或碳酸酯直接反应得到高光学活性的(R)-或(S)-丹参素酯衍生物。
丹皮酚是中药牡丹皮的主要化学活性成分,化学名称为2-羟基-4-甲氧基苯乙酮,分子式为C9H10O3,具有易挥发、在水中溶解度差等特性,对多种心血管疾病模型均具有显著的保护作用。丹皮酚对垂体后叶素所致豚鼠心梗模型发挥明显的心肌保护功效。丹皮酚可通过抗氧化作用降低心梗模型体内脂质过氧化水平,使缺血的心肌细胞膜免受氧自由基损伤,维持并保护了细胞膜功能与结构的完整性。丹皮酚在多种实验性动脉粥样硬化动物模型中亦显示出其显著的自由基清除能力及抗脂质过氧化功效。现有的研究结果显示丹参素和丹皮酚均对冠心病具有良好的治疗效果,现有技术中有关于丹参素和丹皮酚复配使用的报道,如,中国专利文献CN102379864A(申请号201110332983.5)提供了一种以丹参素和丹皮酚为主要成分的复方丹参素注射剂,丹皮酚用2-羟丙基-β-环糊精包合,再将丹参素、丹皮酚包合物和赋形剂混合,即得;中国专利文献CN101623276A(申请号200910022908.1)公开了一种治疗中风的复方丹参素胶囊,主要是将丹参素微囊和丹皮酚包合物混合,装入胶囊即得;但是尚未见关于丹皮酚修饰的丹参素衍生物的报道。
为了改善丹参素的成药性同时增加丹参素稳定性使其更好地发挥作用,本发明将丹参素与丹皮酚利用化学杂交策略拼合,制备得到一种新的化合物,用于改善或治疗冠心病。
发明内容
针对现有技术的不足,本发明提供了一种丹参素衍生物丹参素酯及其制备方法与应用。
本发明涉及一种新的丹参素衍生物-丹参素酯(Pae-DSS),主要是将丹参素和丹皮酚拼合,以及该丹参素酯的制备方法;还包括丹参素酯在制备预防或治疗冠心病的药物中的应用。
术语说明:
(Boc)2O:二碳酸二叔丁酯;Et3N:三乙胺;DCM:二氯甲烷;DCC:二环己基碳二亚胺;DMAP:4-二甲氨基吡啶;TFA:三氟乙酸。
室温:具有本领域公知的含义,一般是指25±2℃。
本发明的技术方案如下:
一种丹参素衍生物丹参素酯(Pae-DSS),是由丹参素与丹皮酚以酯键结合,结构式如式Ⅰ所示:
本发明的参素衍生物丹参素酯具有较强的促血管再生作用,可显著缓解冠心病症状。
上述丹参素衍生物丹参素酯(Pae-DSS)的制备方法,反应式如下:
具体步骤如下:
(1)(R)-3-(3,4-双((叔丁氧基羰基)氧基)苯基)-2-((叔丁氧基羰基)氧基)丙酸(化合物2)的合成:
将化合物1与(Boc)2O溶解于二氯甲烷中,加入三乙胺,室温下反应20-30h,反应完成后,经洗涤、干燥、纯化后得化合物2;
(2)2-乙酰基-5-甲氧基苯基(R)-3-(3,4-双((叔丁氧基羰基)氧基)苯基)-2-((叔丁氧基羰基)氧基)丙酸酯(化合物4)的合成:
将化合物2和化合物3与DCC以及DMAP溶解于二氯甲烷中,室温下反应20-30h,反应完成后,经洗涤、干燥、纯化后得化合物4;
(3)丹参素酯(化合物5)的合成:
将化合物4溶解于二氯甲烷中,加入TFA,室温下反应20-30h,反应完成后,经洗涤、干燥、纯化后得化合物5,即丹参素酯。
根据本发明优选的,步骤(1)中所述化合物1与(Boc)2O的摩尔比为1:3~5;进一步优选为1:3。
根据本发明优选的,步骤(1)中所述化合物1与三乙胺的摩尔比为1:0.09~0.5;进一步优选为1:0.1。
根据本发明优选的,步骤(2)中所述化合物2、化合物3、DCC、DMAP的摩尔比为1:1~2:1~2:0.1~0.5;进一步优选为1:1.1:1:0.1。
根据本发明优选的,步骤(3)中所述化合物4和TFA的摩尔比为1:3~5;进一步优选为1:3。
根据本发明优选的,步骤(1)、(2)、(3)中所述洗涤、干燥、纯化的步骤为:所得反应液依次用水、饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压蒸馏除去溶剂,再用硅胶柱层析分离纯化。
上述丹参素衍生物丹参素酯在制备治疗冠心病的药物中的应用。
一种治疗冠心病的药物,含有药学上有效剂量的上述丹参素衍生物丹参素酯。
根据本发明优选的,所述药物还含有药学上可接受的载体。
根据本发明优选的,所述药物的剂型包括片剂、丸剂、注射剂、胶囊剂、滴丸剂。
有益效果:
与现有技术中将丹参素和丹皮酚简单复配使用相比,本发明采用化学杂交的策略,将丹参素和丹皮酚进行结合,合成一种新的活性成分-丹参素酯,脂溶性好、稳定性高,改善了丹参素的成药性同时增加了丹参素的稳定性,使其更好地发挥作用。丹参素酯进入体内可以直接作用于靶点发挥作用,进一步在体内被代谢,酯键断裂,释放出一分子丹参素与一分子丹皮酚,代谢产物也发挥作用,因而疗效更佳,可有效促进血管再生。丹参素酯在体内的代谢产物丹参素和丹皮酚都是已知中药的活性成分,因此使用丹参素酯不产生未知的代谢产物,安全性更高。本发明的合成工艺简单,步骤少,收率高,成本更低,工业化前景更好。
附图说明
图1为不同给药组斑马鱼的节间血管生长情况。
具体实施方式
下面结合实施例和试验例对本发明作进一步说明,但本发明的保护范围不限于此。
实施例中涉及的药品及试剂,若无特殊说明,均为普通市售产品。实施例中未详加说明的内容均按本领域现有技术。
实施例1:
丹参素衍生物丹参素酯的制备方法,反应式如下:
具体步骤如下:
(1)(R)-3-(3,4-双((叔丁氧基羰基)氧基)苯基)-2-((叔丁氧基羰基)氧基)丙酸(化合物2)的合成:
将化合物1(丹参素,198mg,1mmol),(Boc)2O(654mg,3mmol)溶解于二氯甲烷中,加入三乙胺(10mg,0.1eq),室温搅拌反应24h,TLC检测(展开剂:二氯甲烷-甲醇=20:1,v/v)反应完成;反应液用乙酸乙酯稀释,有机相依次用水、饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压蒸馏除去溶剂得粗品,粗品用硅胶柱层析分离纯化(流动相:二氯甲烷-甲醇=50:1,v/v),得白色固体状化合物2(448mg,90%)。LRMS:C24H35O11(M+H)+m/z=499.2,分子量=498.5250,准确质量=498.2101。
(2)2-乙酰基-5-甲氧基苯基(R)-3-(3,4-双((叔丁氧基羰基)氧基)苯基)-2-((叔丁氧基羰基)氧基)丙酸酯(化合物4)的合成:
将化合物2(498mg,1mmol),化合物3(丹皮酚,182mg,1.1mmol),DCC(206mg,1mmol)以及DMAP(12mg,0.1mmol)溶解于二氯甲烷(10mL)中,室温下反应24h,TLC检测(展开剂:二氯甲烷-甲醇=20:1,v/v)反应完成;有机相依次用水、饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压蒸馏除去溶剂得粗品,粗品用硅胶柱层析分离纯化(流动相:二氯甲烷-甲醇=20:1,v/v),得浅灰色固体状化合物4(516mg,80%)。LRMS:C33H43O13(M+H)+m/z=647.3,分子量=646.6860,准确质量=646.2625。
(3)丹参素酯(Pae-DSS)(化合物5)的合成:
将化合物4(646mg,1mmol)溶于二氯甲烷(10mL)中,室温搅拌下加入TFA(342mg,3mmol),反应24h,TLC检测(展开剂:二氯甲烷-甲醇=20:1,v/v)反应完成;有机相依次用水、饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压蒸馏除去溶剂得粗品,粗品用硅胶柱层析分离(流动相:二氯甲烷-甲醇=20:1,v/v),得到化合物5,即丹参素酯(276mg,80%),为白色固体。
丹参素酯(化合物5)的结构表征:ESI-HRMS m/z:C18H19O7(M+H)+,计算值347.1131,实测值347.1128,分子量=346.3350,准确质量=346.1053;1H NMR(600MHz,CDCl3)δ7.63(dd,J=8.4,1.8Hz,1H),7.50(d,J=1.8Hz,1H),7.24(d,J=8.4Hz,1H),6.69–6.60(m,3H),6.55(s,1H),6.24(s,1H),4.34(td,J=7.2,6.0Hz,1H),4.17(d,J=6.0Hz,1H),3.88(s,3H),3.06(dd,J=13.8,7.2Hz,1H),2.95(dd,J=13.8,7.2Hz,1H),2.60(s,3H)。
实施例2:丹参素酯舌下滴丸制剂的制备
取实施例1制备的丹参素酯40mg,PEG4000 5g,PEG6000 15g,泊洛沙姆F68 15g,滴距为15cm,冷凝液的温度为7℃,制得滴丸。所得滴丸圆整度较好,色泽均匀,溶散时限平均为210.8s,每丸重25mg,丸重差异平均为2.22%。
实施例3:丹参素酯对斑马鱼促血管生成活性评价
选择发育良好的成熟斑马鱼(血管绿色荧光转基因斑马鱼Tg(flia:EGFP),按照雌:雄=2:2配对产卵,第2天抽去隔板,使斑马鱼交配产卵,将获得的鱼卵收集到培养皿中,在培养皿中滴入几滴稀释过的亚甲基蓝,备用。
称量实施例1制备的丹参素酯10mg,用DMSO配成50mg/mL的母液,备用;并用DMSO配制100μg/mL的PTK787(血管生成抑制剂)溶液备用。选择发育至24hpf的斑马鱼受精卵,用1mg/mL的脱膜剂链霉蛋白酶进行脱膜处理。实验共分为实验组、模型组和空白对照组,模型组PTK787终浓度的0.2μg/mL,实验组在加入终浓度0.2μg/mL PTK787构建血管损伤模型后再加入丹参素酯,并设置不同浓度的丹参素酯组(1、5、10μM);空白对照组仅加入DMSO(DMSO限量最高浓度0.5%);每组10条,平行3次。24h后荧光显微镜下观察斑马鱼的节间血管情况并进行拍照,结果如图1,用Image Pro测量血管长度,统计不同组别的节间血管总长度(ISV),统计结果用GraphPad软件进行组间分析(单因素方差分析),若P<0.05则说明组间有统计学差异。
结果显示:PTK787能明显抑制模型组斑马鱼的血管生长(节间血管总长度为663.5±264.6μm),且无畸形或死亡出现,说明血管损伤模型建立成功;实验组结果显示,丹参素酯能够逆转PTK787造成的斑马鱼血管损伤,证明丹参素酯具有促进血管再生的作用,且随着丹参素酯剂量的增加(1、5、10μM),节间血管总长度分别增长至1485.9±773.0μm、2032.8±578.2μm、3250.1±507.5μm,表明其具有较强的促血管再生作用。
实施例4:丹参素酯与单药使用的比较实验
选择发育良好的成熟斑马鱼(血管绿色荧光转基因斑马鱼Tg(flia:EGFP)产卵,收集受精卵备用。选择发育至24hpf的斑马鱼受精卵用1mg/mL的脱膜剂链霉蛋白酶进行脱膜处理。实验设置模型组(PTK787,0.2μg/mL),以及采用PTK787构建血管损伤模型后分别设置丹参素酯组(化合物5,10μM)、丹参素组(化合物1,10μM)、丹皮酚组(化合物3,10μM),最后设置空白对照组(仅含DMSO,限量最高浓度0.5%);每组10条,平行3次。24h后荧光显微镜下观察斑马鱼的节间血管情况并进行拍照,用Image Pro测量血管长度,统计不同组别的节间血管总长度(ISV),统计结果用GraphPad软件进行组间分析(单因素方差分析),若P<0.05则说明组间有统计学差异,结果见表1。
表1不同给药组斑马鱼节间血管生长情况
实验组别 | ISV(μm) |
空白对照组 | 5320±140 |
模型组 | 235±29## |
丹参素酯组 | 4901±56** |
丹参素组 | 3210±62* |
丹皮酚组 | 901±55* |
结果显示:模型组斑马鱼节间血管出现明显抑制,给药组尤其是丹参素酯给药组斑马鱼被抑制的血管出现明显生长,且组间分析表明P<0.05,即模型组与空白对照组有统计学差异,给药组与模型组有统计学差异,可初步认为PTK787能明显抑制斑马鱼血管生长,且无畸形或死亡出现,说明血管损伤模型建立成功,丹参素酯、丹参素和丹皮酚均有助于血管再生,其中,丹参素酯给药组比单体给药组对斑马鱼被抑制的血管出现再生更明显,说明丹参素酯对于斑马鱼被抑制血管的再生产生的效果更好。
实施例5:丹参素酯滴丸对冠心病患者症状的缓解作用
资料来源:全部病人来源于调查医院住院病人及门诊病人。选择心绞痛发作频率为每周5次-24次,40例病人,随机分为两组,每组各20例。所有病人均签署知情同意书。
分组:①治疗组:男15例,女5例,年龄46岁~67岁,平均56.4岁,合并高血压病8例,高脂血症6例,Ⅱ型糖尿病2例。②对照组:男13例,女7例,年龄48岁~72岁平均59.2岁:合并高血压病6例,高脂血症8例,Ⅱ型糖尿病3例。两组情况相似,具有可比性。
诊断标准:(1)以发作性胸痛心绞痛为主要临床表现:①疼痛发作一般都有诱因,②疼痛部位主要在胸骨后、心前区、左上腹疼痛等,③疼痛性质为压迫、发闷或紧缩感,④疼痛持续时间每次3min~5min,休息或舌下含用硝酸甘油后缓解,(2)发作时心电图出现暂性心肌缺血引起的呈组合导联的ST段移位(下降>0.05mv,或抬高>0.1mv)或心电图负荷试验阳性。
疗效判定:①治愈标准:症状被控制,心电图或负荷心电图恢复正常;②好转标准:心绞痛发作次数明显减少或程度减轻,心电图明显好转;③未愈标准:症状未减轻或恶化,心电图未见好转或缺血加重。
治疗方法:所有患者在治疗开始前3d停用所有原先所用之抗心绞痛之药物,两组病人在治疗期间心绞痛发作时含用硝酸甘油0.3mg,观察时间均为1周。治疗组:口服实施例2制备的丹参素酯舌下滴丸,每日三次,一次4粒;对照组:盛元堂丹参(破壁超微粉)饮片1.5g*20袋,(北京深港药业有限公司,货号:Y00506)10mg,每日三次,一次一袋。
结果:
症状疗效:治疗组20例,症状控制8例(40%),发作明显减少10例(50%),无效2例(10%),缓解率90%。对照组20例,症状控制6例(30%),发作明显减少10例(50%),无效4例(20%),缓解率80%。
心电图疗效:治疗组20例,心电图恢复正常6例(30%),心电图好转10例(50%),心电图无好转4例(20%),缓解率80%。对照组20例,心电图恢复正常5例(25%),心电图好转7例(35%),心电图无好转8例(40%),缓解率60%。
两组对照,无论在症状改善和心电图变化上,治疗组都优于对照组(P<0.05)。
在治疗过程中,治疗组患者中未出现任何副作用,而对照组有3例患者在服用盛元堂丹参后出现头痛轻微发热,继续服用后减轻。
结果显示:相较于其他药品,本发明丹参素酯滴丸对冠心病患者症状的缓解有显著作用,且无其他副作用产生。
Claims (10)
2.权利要求1所述的丹参素衍生物丹参素酯(Pae-DSS)的制备方法,其特征在于,反应式如下:
具体步骤如下:
(1)(R)-3-(3,4-双((叔丁氧基羰基)氧基)苯基)-2-((叔丁氧基羰基)氧基)丙酸(化合物2)的合成:
将化合物1与(Boc)2O溶解于二氯甲烷中,加入三乙胺,室温下反应20-30h,反应完成后,经洗涤、干燥、纯化后得化合物2;
(2)2-乙酰基-5-甲氧基苯基(R)-3-(3,4-双((叔丁氧基羰基)氧基)苯基)-2-((叔丁氧基羰基)氧基)丙酸酯(化合物4)的合成:
将化合物2和化合物3与DCC以及DMAP溶解于二氯甲烷中,室温下反应20-30h,反应完成后,经洗涤、干燥、纯化后得化合物4;
(3)丹参素酯(化合物5)的合成:
将化合物4溶解于二氯甲烷中,加入TFA,室温下反应20-30h,反应完成后,经洗涤、干燥、纯化后得化合物5,即丹参素酯。
3.如权利要求2所述的制备方法,其特征在于,步骤(1)中所述化合物1与(Boc)2O的摩尔比为1:3~5;进一步优选为1:3。
4.如权利要求2所述的制备方法,其特征在于,步骤(1)中所述化合物1与三乙胺的摩尔比为1:0.09~0.5;进一步优选为1:0.1。
5.如权利要求2所述的制备方法,其特征在于,步骤(2)中所述化合物2、化合物3、DCC、DMAP的摩尔比为1:1~2:1~2:0.1~0.5;进一步优选为1:1.1:1:0.1。
6.如权利要求2所述的制备方法,其特征在于,步骤(3)中所述化合物4和TFA的摩尔比为1:3~5;进一步优选为1:3。
7.如权利要求2所述的制备方法,其特征在于,步骤(1)、(2)、(3)中所述洗涤、干燥、纯化的步骤为:所得反应液依次用水、饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压蒸馏除去溶剂,再用硅胶柱层析分离纯化。
8.权利要求1所述的丹参素衍生物丹参素酯在制备治疗冠心病的药物中的应用。
9.一种治疗冠心病的药物,其特征在于,含有药学上有效剂量的权利要求1所述的丹参素衍生物丹参素酯。
10.如权利要求9所述的药物,其特征在于,所述药物还含有药学上可接受的载体;
优选的,所述药物的剂型包括片剂、丸剂、注射剂、胶囊剂、滴丸剂。
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Non-Patent Citations (1)
Title |
---|
李骅: "双丹方成分分析及其主要成分丹参素配伍丹皮酚对心肌损伤的保护作用及机制研究", 中国博士学位论文全文数据库医药卫生科技辑 * |
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