CN115990178B - 一种化合物在制备抗凝药物中的用途 - Google Patents
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Abstract
本发明公开了一种化合物在制备抗凝药物中的用途,属于制药领域。所述化合物的结构如示(Ⅰ)所示,采用动物体外试验研究方法,以候选药物为研究对象,考察了其对体外二磷酸腺苷诱导的血小板聚集的抑制作用。鉴于抑制血小板聚集是药物发挥抗凝作用的重要表现,因此该化合物有望作为抗凝血药物在血栓或栓塞性疾病的治疗中发挥一定作用。
Description
技术领域
本发明属于制药领域,涉及一种化合物在制备抗凝药物中的新用途。
背景技术
人体中存在着血液凝固与血液溶解的动态平衡,如果血液凝固的功能增强,就会导致血栓或栓塞性疾病从而需要进行抗凝治疗。临床上常用的抗凝药物主要有阿司匹林、肝素类、华法林等,其中,阿司匹林能抑制花生四烯酸来减少血小板聚集,是公认的一线抗凝药物。肝素能促使凝血酶失活,华法林能抑制维生素K的吸收,减少与维生素K相关凝血因子的活性,从而发挥抗凝作用。另外,波立维能够抑制ADP从而减少血小板聚集,也常应于心脏瓣膜术后的抗凝治疗。
香青兰(Dracocephalum moldavica L),在新疆地区被称作巴迪然吉布亚,是唇形科青兰属的植物香青兰干燥地上部分。益心巴迪然吉布亚颗粒(以下简称益心颗粒)由香青兰单味药材制备而成,是一种已被批准在我国上市使用的中成药,收载于中华人民共和国卫生部药品标准维吾尔药分册。益心颗粒具有补益心脑,利尿,止喘之功效,临床上可用于神疲失眠,心烦气喘,神经衰弱等病症,疗效确切,功能显著。
目前对益心颗粒和香青兰的研究主要集中于心血管疾病方面。萨迪克·司依提等以56例冠心病及心绞痛患者为研究对象,考察益心颗粒治疗心血管疾病的疗效,发现其能够抗血小板聚集,显著改善心肌缺血状况,缓解冠心病、心绞痛。田友清等对香青兰修复心脏缺血再灌注损伤进行研究,并深入考察香青兰对于血流动力学指标影响,研究表明,香青兰能够显著调节心脏血液供应和氧气平衡,减轻心肌缺血过程中血小板聚集和抗血栓形成。
为了探明中药作用机理,揭示其治疗疾病的效应物质基础,申请人采用现代中药提取技术,结合气相、液相、质谱、核磁共振等检测鉴定手段,对益心颗粒和香青兰中的化学成份,以及药物经口服后进入动物体内的血清化学成分及其代谢产物进行了系统研究,最终鉴定出多种化合物,申请人对这些化合物进行高通量活性筛选,发现了大量具有药理活性的成分,其中很多活性都与益心颗粒的药理作用相关,推断这些成分是益心颗粒的药效活性成分。
在此过程中,申请人从香青兰中鉴定到一种黄酮类化合物,具有抗血小板聚集的活性,与香青兰的药理活性相关,于是完成本发明。
发明内容
本发明的目的是提供一种化合物在制备抗凝药物中的新用途。该化合物的结构式如下:
式(Ⅰ)中,R为H或单糖。
当R为H时,该化合物名称为Takakin,CAS:51876-19-8;分子式C16H12O6;分子量300。Takakin的8位羟基可与单糖的半缩醛羟基反应生成糖苷。例如,将Takakin与葡萄糖醛酸反应,便可得到以下化合物:
Takakin-8-Glucuronide
而将Takakin与吡喃葡萄糖反应,可得到以下化合物:
takakin-8-O-β-D-glucopyranoside
以上Takakin-8-Glucuronide与takakin-8-O-β-D-glucopyranoside两种化合物中的葡萄糖均为己糖,按碳原子数目,所述单糖还可以包括丙糖、丁糖、戊糖等,能够与Takakin反应生成糖苷的单糖均在本发明的保护范围内。
研究式(Ⅰ)化合物是否与益心颗粒的药理作用(抑制血小板聚集)相关。首先考察阳性药物阿司匹林对ADP诱导的血小板聚集抑制情况,以确保试验可行性,结果表明阿司匹林的血小板聚集抑制率高达38.54%,该试验方法可用于血小板聚集抑制率考察。进而考察候选化合物的血小板聚集抑制率,试验表明Takakin及其糖苷对ADP诱导的血小板聚集有明显抑制作用,且Takakin的8位糖苷是重要活性基团。
本试验验证了Takakin及其糖苷是益心颗粒的活性成份,在体内发挥抑制血小板聚集作用,该作用与益心颗粒的药理作用密切相关,因此可将其作为益心颗粒的质量标志物之一进行检测。鉴于抑制血小板聚集是药物发挥抗凝作用的重要表现,因此Takakin及其糖苷也有望作为抗凝血药物在血栓或栓塞性疾病的治疗中发挥重要作用。
更详尽的技术方案参见具体实施例。
具体实施方式
下面通过具体实施例对本发明进行详细说明。试验中所使用的化合物均为已知化合物,既能通过商业途径获得,也能从天然植物中提取分离得到,例如,从香青兰中提取Takakin糖苷,然后使用酸碱催化的化学方法使糖苷裂解得到苷元,再将苷元与不同单糖反应,即可得到试验所需的化合物。
实施例1化合物抗血小板聚集药效研究
本试验采用动物体外试验研究方法,以候选化合物为研究对象,考察其对体外二磷酸腺苷诱导的血小板聚集的抑制作用。
1.试验方法
1.1实验试剂配制
12%水合氯醛溶液:精密称取12g水合氯醛,加入100ml生理盐水,搅拌使完全溶解,即得。
二磷酸腺苷溶液(ADP):精密称取8.54mg二磷酸腺苷,置200ml容量瓶中,加入生理盐水,配制为浓度42.7μg/ml(0.1μmol/ml)的ADP试液,-20℃保存。
阳性对照品制备:精密称取10mg阿司匹林,置10ml容量瓶加生理盐水稀释为浓度1mg/ml的对照品溶液,备用。
供试品制备:精密称取Takakin 10mg、Takakin-8-Glucuronide 10mg,置10ml容量瓶加生理盐水至刻度,分别配制成浓度为1mg/ml的供试品溶液,备用。
1.2药效实验方法
准备10只SPF级成年健康大鼠,体质量为230~270g,适应性喂养3d后,腹腔注射12%水合氯醛溶液麻醉,将大鼠固定后切开颈部动脉采血,各只大鼠采血约5ml,按体积比10:1加入2.5%枸橼酸钠溶液抗凝,离心5min(1000rpm),分离上部血浆即富血小板血浆(PRP),其余部分继续离心10min(3000rpm),取上清液即贫血小板血浆(PPP)。用血小板计数仪计数PRP血小板数,用PPP调整PRP的血小板数约在1×108/mL。在测试管中加入PRP0.2ml,然后加入受试品溶液(供试品溶液或阳性对照品溶液)至终浓度0.1mg/ml,以等体积生理盐水为空白对照。37℃温育5min后加入诱导剂ADP溶液至终浓度10μmol/L,诱导5min后记录浊度变化,计算血小板聚集率,计算公式如下。
血小板聚集抑制率(%)=[空白对照组聚集率-试验组聚集率]/空白对照组聚集率
2.实验结果
首先考察阳性对照药阿司匹林对ADP诱导的血小板聚集抑制情况,以确保试验可行性。结果表明阿司匹林对血小板聚集抑制率高达38.54%。进而考察候选化合物的血小板聚集抑制率,试验表明Takakin的血小板聚集抑制率为7%,聚集率与空白组相比有显著性差异(P<0.05),Takakin-8-Glucuronide的聚集抑制率为12.45%,聚集率与空白组相比有极显著性差异(P<0.01)。另外,Takakin-8-Glucuronide对血小板聚集的抑制率高于Takakin,其血小板聚集率与Takakin组相比有显著性差异(P<0.05),说明Takakin的8位糖苷是重要活性基团。结果见表1。
表1化合物的血小板聚集抑制率(n=10)
与空白组比较,*P<0.05,**P<0.01;与Takakin组比较,#P<0.05。
本试验验证了Takakin及其糖苷具有抑制血小板聚集的作用,与益心颗粒的药理作用密切相关,可用于制备抑制血小板聚集的药物用于血栓或栓塞性疾病的治疗。
Claims (1)
1.一种化合物在制备抗凝药物中的用途,所述化合物的结构如式(Ⅰ)所示:
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新疆香青兰活血化瘀作用及其化学成分的研究;阿迪拉木·阿比利米提;硕士论文 医药卫生科技专辑(第3期);16-26 * |
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