CN105693813A - 一种甘草酸类小檗碱偶合物的制备及医药用途 - Google Patents
一种甘草酸类小檗碱偶合物的制备及医药用途 Download PDFInfo
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Abstract
本发明提供式(I)的衍生物制备方法和其作为治疗高血脂、降血脂药物中应用。通过药理学方面实验发现，该类衍生物具有多种价值的药物活性，特别是其容易吸收的性能是甘草酸类药物所不具备的，具体地该类衍生物在动物实验中显示出优异调节高血脂大鼠血脂作用。其主要作用促使胆固醇含量降低，磷脂质明显下降，抑制机体和血管壁的炎症反应，防止动脉粥样硬化的发生及发展。
Description
技术领域
本发明涉及食品制药技术领域，具体涉及一种甘草酸类小檗碱偶合物在治疗高血脂、降低血脂产品中的应用。
背景技术
过去20年间，人们的食物消费和膳食结构发生了很大改变，由此带来的最显著效应就是高血脂症的发病率不断提升。日前召开的血液安全研讨会上，专家估计，全国30岁以上的成年人中间，高血脂症的发病率在10％-20％左右，高血脂症患者人数高达9000万。卫生部有关统计也显示，去年每3个死亡的中国人中间就有一个死于心脑血管疾病，而高血脂症导致动脉粥样硬化是心脑血管疾病的罪魁祸首。国外学者早在70年代即证明,甘草酸具有降低动物血脂作用,并在临床用于高胆固醇血症治疗。
小檗碱BBR(Berberine,BBR)是黄连的主要活性成分，黄连中BBR含量最高，占5.2-7.69％。黄连味苦，具有清热、解毒、泻火和治消渴症的功效。以往多认为口服后不易吸收，对痢疾杆菌、大肠杆菌、金黄色葡萄球菌引起的肠道感染、眼结膜炎、化脓性中耳炎等有效，临床主要用于肠道感染的治疗。随着研究的深入，近年来陆续发现其具有抗心律失常、舒张血管、保护心肌、抗血小板聚集、降血糖、降血脂、抗炎、抗病毒、抗肿瘤等药理作用。
然而由于甘草酸类的水溶性较差，口服生物利用度低，限制了其药效的充分发挥。而盐酸小檗碱水溶性很小，脂溶性更小，胃肠道吸收不良，导致其口服生物利用度低，影响了它的全身治疗作用。尽管，甘草酸类药物，小檗碱具有许多相似的药理活性，但都因生物利用度低一定程度上限制了在临床上的使用，因此寻找一种提高甘草酸类药物和小檗碱的生物利用度并发挥两者的协同作用的方法在临床上将有非常重要的意义。
发明内容：
本发明提供式(I)的衍生物制备方法和其作为治疗高血脂、降低血脂的药物中应用。通过药理学方面实验发现，该类衍生物具有多种价值的药物活性，特别是其容易吸收的性能是甘草酸类药物所不具备的，具体地该类衍生物在动物实验中显示出优异调节高血脂大鼠血脂作用。其主要作用体现在促使胆固醇含量降低，磷脂质明显下降，抑制机体和血管壁的炎症反应，防止动脉粥样硬化的发生及发展。
本发明提供式(I)的衍生物，结构如下：
式(I)中，R为
R1＝H或C1～C18直链或支链烷烃。
1.式(I)的衍生物制备方法，包括以下步骤：
(1)将盐酸小檗碱溶于0.01～5mol/L无机碱溶液中；
(2)向步骤(1)所得的溶液中加入式(I)所述相应酸化合物溶液，60-70℃加热搅拌1-8h；
(3)将反应产物进行趁热抽滤、滤液回收至原体积1/3、冷却析晶、过滤、干燥即得式(I)所述化合物；
2.步骤(1)中的无机碱溶液：其特征在于盐酸小檗碱与无机碱摩尔比为1:1～1:3，优选1:1.0～1.05；其中无机碱为氢氧化钠、氢氧化钾、氢氧化钙中的一种或两种以上；溶液为0-100％(体积比)甲醇、乙醇、异丙醇溶液，优选70％乙醇溶液；
3.步骤(2)中相应酸化合物溶液是指，是指相应酸化合物溶于0-100％(体积比)甲醇、乙醇、异丙醇溶液，优选70％乙醇溶液；
本发明提供式(I)的衍生物经过常规工艺或间接加入药学上可接受赋形剂制成临床上可接受剂型，临床上用于治疗高血脂、降低血脂。
具体实施例
通过以下实施例以更好的说明本发明。但本发明不受下述实施例的限制。
实施例1
甘草酸小檗碱偶合物的合成
取盐酸小檗碱3.7g，加入250ml三口烧瓶中，加入100ml乙醇，用3mol/l的氢氧化钠调节pH至7-8，升温至60-70℃，搅拌溶解，再加入8.2g甘草酸，保持此温度搅拌1-2h，趁热过滤，滤液浓缩至原体积三分之一，冷却析晶、过滤、干燥即得甘草酸小檗碱偶合物9.3g，收率80％。
实施例2
甘草酸小檗碱偶合物的合成
取盐酸小檗碱3.7g，加入250ml三口烧瓶中，加入100ml乙醇，用3mol/l的氢氧化钠调节pH至7-8，升温至60-70℃，搅拌溶解，再加入8.9g甘草酸，保持此温度搅拌1-2h，趁热过滤，滤液浓缩至原体积三分之一，冷却析晶、过滤、干燥即得甘草酸小檗碱偶合物9.7g，收率84％。
实施例3
甘草酸小檗碱偶合物的合成
取盐酸小檗碱3.7g，加入250ml三口烧瓶中，加入150ml乙醇，用3mol/l的氢氧化钠调节pH至7-8，升温至60-70℃，搅拌溶解，再加入9.5g甘草酸，保持此温度搅拌1-2h，趁热过滤，滤液浓缩至原体积三分之一，冷却析晶、过滤、干燥即得甘草酸小檗碱偶合物10.2g，收率92％。ESI-MS(M++H)m/zcalcdforC20H18NO4 +337.12found337.26；ESI-MS(M++H)m/zcalcdforC42H62O16823.40found823.34。
实施例4
甘草次酸小檗碱偶合物的合成
取盐酸小檗碱3.7g，加入250ml三口烧瓶中，加入100ml乙醇，用3mol/l的氢氧化钠调节pH至7-8，升温至60-70℃，搅拌溶解，再加入4.7g甘草次酸，保持此温度搅拌1-2h，趁热过滤，滤液浓缩至原体积三分之一，冷却析晶、过滤、干燥即得甘草次酸小檗碱偶合物6.5g，收率81％。
实施例5
甘草次酸小檗碱偶合物的合成
取盐酸小檗碱3.7g，加入250ml三口烧瓶中，加入100ml乙醇，用3mol/l的氢氧化钠调节pH至7-8，升温至60-70℃，搅拌溶解，再加入5.2g甘草次酸，保持此温度搅拌1-2h，趁热过滤，滤液浓缩至原体积三分之一，冷却析晶、过滤、干燥即得甘草次酸小檗碱偶合物6.9g，收率86％。ESI-MS(M++H)m/zcalcdforC20H18NO4 +337.12found337.26；ESI-MS(M++H)m/zcalcdforC30H46O4471.34found471.38。
实施例6甘草酸类小檗碱偶合物的降血脂作用
降血脂实验：选取仓鼠喂以高脂高胆固醇(HFHC)食物10天后，口服给予实施例所述化合物，25天后测定血中总胆固醇、甘油三酷和低密度脂蛋白-C的水平。表中为平均值±标准差。给药方式：每日口服，共25天；每组动物数:n＝7。取血测定胆固醇，甘油三酷和低密度脂蛋白的水平，并进行统计学处理，结果见表1
表1实施例化合物在仓鼠联合使用的降血脂作用
实验结果显示，甘草酸类小檗碱偶合物降脂效果明显优于甘草酸和小檗碱单体。
Claims (6)
1.本发明提供式(I)的衍生物，结构如下：
其特征在于式(I)中，R为
R1＝H或C1～C18支链或支链烷烃。
2.权利要求1所述的式(I)化合物的制备方法，包括以下步骤：
(1)将盐酸小檗碱溶于0.01～5mol/L无机碱溶液中；
(2)向步骤(1)所得的溶液中加入式(I)所述相应酸化合物溶液，60-70℃加热搅拌1-8h；
(3)将反应产物进行趁热抽滤、滤液回收至原体积1/3、冷却析晶、过滤、干燥即得式(I)所述化合物。
3.权利要求2所述的步骤(1)中的无机碱溶液：其特征在于盐酸小檗碱与无机碱摩尔比为1:1～1:3，优选1:1.0～1.05；其中无机碱为氢氧化钠、氢氧化钾、氢氧化钙中的一种或两种以上；溶液为0-100％(体积比)甲醇、乙醇、异丙醇溶液，优选70％乙醇溶液。
4.权利要求2所述的步骤(2)中所述相应酸化合物溶液，是指相应酸化合物溶于0-100％(体积比)甲醇、乙醇、异丙醇溶液，优选70％乙醇溶液。
5.权利要求1所述的式(I)化合物经过常规工艺或间接加入药学上可接受赋形剂制成临床上可接受剂型，包括注射剂、口服剂，优选口服制剂。
6.权利要求1所述的式(I)化合物经过常规工艺或间接加入药学上可接受赋形剂制成临床上可接受剂型，临床上用于预防和治疗高血脂、降低血脂。
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| CN106146489A (zh) * | 2016-06-30 | 2016-11-23 | 合肥华方医药科技有限公司 | 9‑位取代的双功能团小檗碱衍生物的制备方法及用途 |
| CN114306640A (zh) * | 2022-01-27 | 2022-04-12 | 南方医科大学南方医院 | 一种增加小檗碱溶解度的方法 |
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| CN1563073A (zh) * | 2004-04-06 | 2005-01-12 | 南开大学 | 甘草次酸的制备方法 |
| CN103319479A (zh) * | 2012-03-20 | 2013-09-25 | 王从品 | 大黄酸小檗碱离子对化合物、制备方法及应用 |
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| CN1563073A (zh) * | 2004-04-06 | 2005-01-12 | 南开大学 | 甘草次酸的制备方法 |
| CN103319479A (zh) * | 2012-03-20 | 2013-09-25 | 王从品 | 大黄酸小檗碱离子对化合物、制备方法及应用 |
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| CN106146489A (zh) * | 2016-06-30 | 2016-11-23 | 合肥华方医药科技有限公司 | 9‑位取代的双功能团小檗碱衍生物的制备方法及用途 |
| CN106146489B (zh) * | 2016-06-30 | 2019-02-05 | 合肥华方医药科技有限公司 | 9-位取代的双功能团小檗碱衍生物的制备方法及用途 |
| CN114306640A (zh) * | 2022-01-27 | 2022-04-12 | 南方医科大学南方医院 | 一种增加小檗碱溶解度的方法 |
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