CN107108603B - 芒果苷-6-o-小檗碱盐及其制备方法与用途 - Google Patents
芒果苷-6-o-小檗碱盐及其制备方法与用途 Download PDFInfo
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- CN107108603B CN107108603B CN201680003926.3A CN201680003926A CN107108603B CN 107108603 B CN107108603 B CN 107108603B CN 201680003926 A CN201680003926 A CN 201680003926A CN 107108603 B CN107108603 B CN 107108603B
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- mangiferin
- salt
- berberine
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Abstract
本发明提供了一种芒果苷‑6‑O‑小檗碱盐及其制备方法。另外亦提供该芒果苷‑6‑O‑小檗碱盐用作AMPK激活剂治疗糖尿病等的用途。
Description
技术领域
本发明涉及芒果苷-6-O-小檗碱盐及其制备方法及作为AMPK激活剂等的用途。
背景技术
芒果苷(mangiferin)是天然多酚类化合物,分子式:C19H18O11,分子量:422。其化学结构如下:
小檗碱(berberine)为异喹啉类生物碱。分子式:[C20H18NO4]+,分子量:336.37。其化学结构如下:
我们已公开一种将芒果苷与小檗碱以离子键结合的芒果苷小檗碱盐【国际公布号:WO2010/145192A1;发明名称:一种芒果苷小檗碱盐及其制备方法及用途】。
首先,该专利说明书第5页-第7页第2段对所述芒果苷小檗碱盐的碳核磁数据、氢核磁数据与芒果苷、小檗碱原型化合物的相应数据进行了比较,从而得出结论:芒果苷基团与小檗碱基团中各原子的化学环境发生了变化,说明小檗碱基团与芒果苷基团结合形成了芒果苷小檗碱盐。
分析芒果苷的结构可知,芒果苷分子结构中有4个酚羟基,所以芒果苷成盐位点存在着多种可能性,这使得获得单一成盐位点的芒果苷盐的技术难度大大增加。
根据WO2010/145192A1所披露的芒果苷小檗碱盐的核磁数据分析可知,其所述芒果苷小檗碱盐应为芒果苷-3-O-小檗碱盐与芒果苷-7-O-小檗碱盐的组合物。但关于芒果苷-3-O-小檗碱盐与芒果苷-7-O-小檗碱盐的具体情况,如二者比例如何,WO2010/145192A1并未予以阐述。
磷酸腺苷(AMP)激活的蛋白激酶(AMP-activated protein kinase,AMPK)是一种在细胞内行使能量代谢调节的蛋白激酶。随着对AMPK研究的日益深入,AMPK在代谢性疾病、心血管疾病、神经系统疾病、炎症性疾病、肿瘤、肌肉系统疾病的发病中发挥至关重要的作用,AMPK正成为疾病治疗新靶点,但目前尚未有上市的AMPK激活剂,故研究开发AMPK激活剂具有重要的临床意义【李忌.AMPK:糖尿病与心血管疾病治疗新靶点.中国医学论坛报,2009,(1149);任俊芳.AMPK与心血管重构.国际病理科学与临床杂志,2008,28(1):33-36;Ricardo Lage,Carlos Dieguez,Antonio Vidal-Puig.et al.AMPK:a metabolic gaugeregulating whole-body energy homeostasis.Trends Mol Med,2008,14(12):539-49;符庆瑛,高钰琪.蛋白激酶AMPK的研究进展.生命科学,17(2):147-152;陈奇,梁后杰,邹岚,等.一磷酸腺苷活化蛋白激酶对环氧合酶-2表达与5-氟尿嘧啶治疗结肠癌敏感性的关系.实用医院临床杂志,2008,5(3):56-58等】。
技术问题
按照药物注册的要求,上市药物所提供的原料药结构必须是明确的,如果原料药是组合物,其比例也必须是确定的,才能符合药物质量可控的要求。因此获得单一成盐位点的芒果苷小檗碱盐对于该化合物做为原料药而言,是必须解决的技术问题。
其次,WO2010/145192A1专利说明书第4页第3段至倒数第3段及实施例1-6对所述芒果苷小檗碱盐的制备方法给予详细论述,如下:
①在反应器中加入反应溶媒和芒果苷混悬得混悬液,将碱性钠(钾)盐水溶液加入混悬液中,反应至澄清,滤过,得溶液A。
②将小檗碱加入水中溶解,滤过,得溶液B。
③将溶液A滴加入搅拌状态下的溶液B中,滴加完毕继续搅拌,使反应完全,产生大量沉淀,过滤,固体物干燥,得芒果苷小檗碱盐。
所述反应溶媒为水与乙醇、甲醇、丙酮等可与水混溶的有机溶剂中一种或两种以上的混合物,其中水的体积比10-90%(v/v)。
从上述WO2010/145192A1所披露的制备方法中可以看出:芒果苷小檗碱盐在制备过程中需要较大量的乙醇、甲醇、丙酮等有机溶剂,这些有机溶剂不仅成本高,而且在工业生产中会带来沉重的环保压力。
技术解决方案
本发明提供一种芒果苷-6-O-小檗碱盐,其特征在于:所述芒果苷-6-O-小檗碱盐具有下式(Ⅰ)的结构。
其中0≤x≤4。
本发明所述的芒果苷-6-O-小檗碱盐,其特征在于:所述x=2。
本发明提供所述的芒果苷-6-O-小檗碱盐的制备方法,其特征在于:
①将碱性钠盐或碱性钾盐加入水中,制备碱性钠盐溶液或碱性钾盐溶液,浓度为0.1%-2%(w/v);
②将芒果苷加入二甲基亚枫中溶解,制成芒果苷溶液;
③将芒果苷溶液缓慢加入碱性钠盐溶液或碱性钾盐溶液中,充分搅拌,50℃-100℃反应完全,得芒果苷-6-O-钠盐溶液或芒果苷-6-O-钾盐溶液;
④取盐酸小檗碱加50℃-100℃水溶解,制成盐酸小檗碱溶液;
⑤将盐酸小檗碱溶液与芒果苷-6-O-钠盐溶液或芒果苷-6-O-钾盐溶液充分混合,反应完全,析出沉淀,过滤,得固体物;
⑥固体物干燥,得芒果苷-6-O-小檗碱盐。
本发明所述的芒果苷-6-O-小檗碱盐的制备方法,其特征在于:所述芒果苷与二甲基亚砜的配比为1:0.2-5(w/v)。
本发明所述的芒果苷-6-O-小檗碱盐的制备方法,其特征在于:所述芒果苷与碱性钠盐或碱性钾盐的摩尔配比为1:0.5-1。
本发明所述的芒果苷-6-O-小檗碱盐的制备方法,其特征在于:所述芒果苷-6-O-钠盐或芒果苷-6-O-钾盐与盐酸小檗碱摩尔比为1:1。
本发明所述的芒果苷-6-O-小檗碱盐的制备方法,其特征在于:所述碱性钠盐或碱性钾盐选自碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾中的一种或两种以上的混合物,所述盐酸小檗碱可由硫酸小檗碱或其它小檗碱医学上可接受的盐替代。
本发明提供一种药物,其特征在于:所述药物由上述的芒果苷-6-O-小檗碱盐与可药用辅料组成,并按相应制药方法,即可制成临床适用的片剂、胶囊剂、颗粒剂、口服溶液剂、口服混悬剂、糖浆剂、丸剂等任何一种口服制剂;凝胶剂、软膏剂、霜剂等外用制剂;冻干粉针等注射剂。
本发明提供所述的芒果苷-6-O-小檗碱盐在制备AMPK激活剂的用途。
本发明提供以所述的芒果苷-6-O-小檗碱盐为活性成分制备的药物在制备AMPK激活剂的用途。
鉴于现代医学对AMPK在疾病发生发展中所起重要作用的揭示,本发明提供一种芒果苷-6-O-小檗碱盐在制备AMPK激活剂的用途,其特征在于:所述AMPK激活剂可用于预防或治疗下述疾病中的任何一种或几种:糖尿病、糖尿病各种慢性并发症(包括冠心病、动脉粥样硬化、脑血管病、糖尿病肾病、糖尿病性视网膜病变、神经病变、糖尿病足、黄斑病、白内障、青光眼、屈光改变、虹膜睫状体病变等)、肥胖、高脂血症、胰岛素抵抗、高胰岛素血症、代谢综合征、高血压、动脉粥样硬化、缺血性心脏病、心肌肥大、心律失常、心力衰竭、上呼吸道感染、慢性支气管炎、慢性阻塞性肺病、哮喘、肺纤维化、肝炎、单纯性脂肪肝、非酒精性脂肪性肝病、非酒精性脂肪性肝炎、酒精性肝病、酒精性肝炎、肝纤维化、肝硬化、前列腺炎、胰腺炎、肾炎、肾病综合征、高血压肾病、慢性肾功能不全、前列腺炎、风湿性关节炎、类风湿性关节炎、骨性关节炎、炎症性肠病、脑梗塞、记忆障碍、阿尔茨海默氏病、梗塞性痴呆、帕金森氏症、肿瘤、肌肉萎缩、肌肉无力症。
本发明还提供一种芒果苷-6-O-小檗碱盐在制备乳腺增生、子宫息肉、前列腺增生、性功能障碍、不孕、湿疹、疲劳治疗药物中的应用。
本发明提供的芒果苷-6-O-小檗碱盐用作上述疾病治疗的有效剂量范围为37.5-600mg/日/人,优选75-300mg/日/人,每日给药1-3次,优选每日2次。用法可根据具体疾病进行选择,以口服为优选。
芒果苷-6-O-小檗碱盐的理化性质:
芒果苷-6-O-小檗碱盐,分子式:C20H18NO4·C19H17O11·xH2O,橙黄色粉末状物,熔点:177-179℃,几乎不溶于水,微溶于甲醇,在稀盐酸溶液中略溶。结构式如下:
芒果苷-6-O-小檗碱盐的波谱数据:ESI-MS(-)m/z 756(M-),421;ESI-MS(+)m/z336,
423;芒果苷基团1HNMR(400MHz,DMSO-d6)δ:4.56(H-1’),6.01(H-5),6.15(H-4),6.88(H-8)。13CNMR(400MHz,DMSO-d6)δ:161.51(C-1),106.58(C-2),163.06(C-3),92.77(C-4),155.55(C-4a),103.74(C-4b),98.64(C-5),166.93(C-6),147.03(C-7),100.47(C-8),100.53(C-8a),154.37(C-8b),176.73(C-9),73.51(C-1’),70.34(C-2’),79.14(C-3’),70.34(C-4’),81.37(C-5’),61.27(C-6’)。小檗碱基团1HNMR(400MHz,DMSO-d6)δ:3.2(H-5),4.03(-OCH3),4.07(-OCH3),4.89(H-6),6.13(-O-CH2-O-),7.01(H-4),7.69(H-1),7.86(H-12),8.07(H-11),8.78(H-13),9.78(H-8)。13CNMR(400MHz,DMSO-d6)δ:105.33(C-1),120.29(C-1a),147.56(C-2),149.71(C-3),108.22(C-4),130.45(C-4a),26.28(C-5),55.07(C-6),145.06(C-8),121.24(C-8a),143.51(C-9),150.15(C-10),126.55(C-11),123.33(C-12),132.87(C-12a),120.08(C-13),137.3(C-13a),56.93(C10(-OCH3)),61.74(C9(-OCH3)),101.96(-O-CH2-O-)。
附:芒果苷的波谱数据:ESI-MS m/z 421(M-);1HNMR(400MHz,DMSO-d6)δ:4.60(H-1’),6.37(H-5),6.86(H-4),7.39(H-8)。3CNMR(400MHz,DMSO-d6)δ:161.68(C-1),107.54(C-2),163.73(C-3),93.27(C-4),156.15(C-4a),101.25(C-4b),102.54(C-5),153.91(C-6),143.63(C-7),108.05(C-8),111.68(C-8a),150.7(C-8b),179.02(C-9),73.04(C-1’),70.24(C-2’),78.9(C-3’),70.56(C-4’),81.44(C-5’),61.41(C-6’)。
小檗碱的波谱数据:ESI-MS m/z 336(M);1HNMR(400MHz,DMSO-d6)δ:3.26(H-5),4.11(-OCH3),4.21(-OCH3),4.92(H-6),6.11(-O-CH2-O-),6.96(H-4),7.66(H-1),8.0(H-12),8.11(H-11),8.7(H-13),9.76(H-8)。13CNMR(400MHz,DMSO-d6)δ:106.54(C-1),121.49(C-1a),149.92(C-2),152.17(C-3),109.40(C-4),131.90(C-4a),28.24(C-5),57.20(C-6),145.73(C-8),123.33(C-8a),146.42(C-9),152.02(C-10),128.04(C-11),124.55(C-12),135.13(C-12a),121.86(C-13),139.65(C-13a),57.61(C10(-OCH3)),62.56(C9(-OCH3)),103.68(-O-CH2-O-)。
结构分析如下:
与小檗碱原型化合物比较,芒果苷-6-O-小檗碱盐中小檗碱基团碳谱数据各碳原子的化学位移由于屏蔽作用均发生明显改变。
与芒果苷原型化合物比较,芒果苷-6-O-小檗碱盐中芒果苷基团碳谱数据中C6,C7,C8b碳原子的化学位移由于去屏蔽作用而发生显著改变,C6化学位移变化最大;C5、C8、C8a碳原子的化学位移由于屏蔽作用均有不同程度的改变,其中处于C6原子间位的C8和对位的C8a化学位移变化较大。
根据以上波谱数据分析显示:芒果苷-6-O-与小檗碱-N+结合,形成了芒果苷-6-O-小檗碱盐。
芒果苷-6-O-小檗碱盐及其水合物的元素分析数据:
芒果苷-6-O-小檗碱盐及其水合物的元素分析数据
有益效果
我们通过多年的研究,终于成功获得了一种新的单一成盐位点的芒果苷小檗碱盐,即芒果苷-6-O-小檗碱盐。该芒果苷-6-O-小檗碱盐不但解决了芒果苷小檗碱盐做为原料药必须结构明确的问题,而且,相较于WO2010/145192A1所公开的芒果苷小檗碱盐,本发明化合物芒果苷-6-O-小檗碱盐取得以下意想不到的技术效果:
1、本发明的芒果苷-6-O-小檗碱盐在盐酸溶液中的溶解度较WO2010/145192A1所公开芒果苷小檗碱盐显著提高,从而更有利于其在胃中的溶解,从而增加吸收。在pH值1的盐酸溶液中,芒果苷-6-O-小檗碱盐最大溶解度为12mg/ml,而WO2010/145192A1所公开的芒果苷小檗碱盐为4mg/ml,芒果苷-6-O-小檗碱盐在pH值1的盐酸溶液中的溶解度是WO2010/145192A1所公开的芒果苷小檗碱盐的3倍,且芒果苷-6-O-小檗碱盐溶液的稳定性远好于WO2010/145192A1所公开的芒果苷小檗碱盐。
2、本发明的芒果苷-6-O-小檗碱盐在高湿环境下,吸湿增重比远小于WO2010/145192A1所公开的芒果苷小檗碱盐。这种在高湿环境下的稳定性有利于药物的贮藏,减少制剂过程中的水分吸收,提高药物质量。
3、意外发现本发明的芒果苷-6-O-小檗碱盐对乳腺增生、子宫息肉、性功能障碍、前列腺增生、不孕、疲劳、湿疹具有治疗作用。这些治疗作用是无法根据WO2010/145192A1所公开的芒果苷小檗碱盐的活性预测与获知的。
我们还获得一种芒果苷-6-O-小檗碱盐的制备方法,相较于WO2010/145192A1所公开的芒果苷小檗碱盐的制备方法,本发明的制备方法不但解决大量有机溶剂的使用带来的环保压力与成本问题,从而更适合工业化生产,而且还取得以下意想不到的技术效果:即获得了一种新的单一成盐位点的芒果苷小檗碱盐,即芒果苷-6-O-小檗碱盐。
试验例1:两种芒果苷小檗碱盐在pH值1的酸水溶解情况比较
1.供试样品:
样品A:芒果苷-6-O-小檗碱盐2水合物
样品B:按WO2010/145192A1所公开的芒果苷小檗碱盐制备方法制备的芒果苷小檗碱盐。
2.仪器:PHS-3C微机型pH计(上海康仪)
3.试验方法与结果:
取纯净水,加盐酸调pH值为1的溶液(25℃±2℃)备用;分别量取该溶液各50ml置三角瓶中,分别精密称取研成细粉的芒果苷小檗碱盐样品A和样品B各200mg加入三角瓶中,振摇;观察溶解情况。
样品A在数秒钟内迅速溶解,溶液为澄明状。
样品B在1分钟内能溶解,但溶液迅速呈浑浊状态,表明有沉淀物析出。
另取溶液各50ml置三角瓶中,分别精密称取研成细粉的芒果苷小檗碱盐样品A400mg和600mg,分别加入三角瓶中,振摇;观察溶解情况。
400mg样品A在50ml酸水溶液中迅速溶解,溶液为澄明状,放置24小时未见沉淀物析出。
600mg样品A在50ml酸水溶液中完全溶解,溶液为澄明状,约30分钟有少量沉淀析出,溶液呈微浊状态。
上述试验结果显示样品A在pH值1的盐酸液中最大溶解度约为12mg/ml,样品B在pH值1的酸液中最大溶解度约为4mg/ml。芒果苷-6-O-小檗碱盐溶液的稳定性远好于WO2010/145192A1所公开的芒果苷小檗碱盐。
4.结论
芒果苷-6-O-小檗碱盐在pH值1的盐酸液中最大溶解度为WO2010/145192A1所公开的芒果苷小檗碱盐的3倍。
试验例2:两种芒果苷小檗碱盐高湿环境稳定性比较
1.供试样品:
样品A:芒果苷-6-O-小檗碱盐2水合物
样品B:按WO2010/145192A1所公开的芒果苷小檗碱盐制备方法制备的芒果苷小檗碱盐
2.仪器:万分之一电子天平(Sartorius,德国)。
3.考察方法:
分别取样品A和样品B适量各三份,分别置平面皿内,精密称定,供试品置恒湿密闭容器中,于25℃、RH90%±5%条件下放置10天,分别于第5天和第10天精密称定,记录称定结果。计算吸湿增重比。
4.结果:如下表:
5.结论
芒果苷-6-O-小檗碱盐2水合物在高湿环境下,吸湿增重比远小于WO2010/145192A1所公开的芒果苷小檗碱盐。
试验例3:芒果苷-6-O-小檗碱盐对AMPK激活作用
1、材料
按上述实施例制备芒果苷-6-O-小檗碱盐2水合物,以DMSO溶解。临用前以培养基或HBS缓冲液稀释。DMSO终浓度≤0.2%。
L6细胞购自ATCC。高糖DMEM培养基购自GIBCO公司;胎牛血清购自Hyclone公司。抗AMPK兔源多克隆抗体、抗ACC兔源多克隆抗体、抗AMPK苏氨酸172位点磷酸化兔源多克隆抗体、抗ACC丝氨酸79位点磷酸化兔源多克隆抗体购自Cell Signal Technology公司。
2、实验方法
2.1细胞培养与分化:
分化前的L6细胞用高糖DMEM培养基,含10%胎牛血清,100U/ml青霉素、100U/ml链霉素,置于含有的5%CO2的培养箱内37℃培养。L6细胞的分化是在细胞长满60%左右时,换成含2%胎牛血清的高糖DMEM培养基,每两天更换一次培养基,直到L6细胞分化至90%左右。
2.2化合物处理及样品收集:
先将6孔板中的细胞在无血清的高糖DMEM培养基中饥饿。受试物以不同的浓度梯度加到无血清的高糖DMEM培养基中,DMSO含量0.2%。受试物与细胞孵育3h,然后,用冰冷的1×PBS洗2次,加入200μl 1×SDS电泳缓冲液(50mM Tris·HCL,100mM DTT,2%电泳级SDS,0.1%溴酚蓝,10%甘油)裂解细胞10min。收集裂解液,超声15秒钟,在100℃煮样品10min。
2.3免疫印迹检测:
裂解液经10%SDS聚丙烯酰胺凝胶电泳分析,再在转膜仪中以100V,1-2h转移到PVDF膜上。将凝胶中的蛋白质半干转移到硝酸纤维薄膜上,丽春红S(Ponceau S)确定条带。在封闭液(3%脱脂奶粉,0.1%Tween,TBS溶解)中封闭1小时,加入1:1000稀释一抗4℃过夜,TBS洗涤3×15min,加入1:1000稀释二抗,室温孵育1小时,TBS洗涤3×15min,置于ECL中冲洗5-10min,用X光片压片显影。
3、结果
结果表明:1.25-5μmol/L芒果苷-6-O-小檗碱盐2水合物呈剂量依赖性地显著增强了AMPK磷酸化水平,同时显著增强ACC磷酸化水平。
试验例4:芒果苷-6-O-小檗碱盐对代谢紊乱各项指标的改善作用
符合2型糖尿病并非酒精性脂肪性肝病诊断标准的患者,给予芒果苷-6-O-小檗碱盐片75mg(制备方法见实施例7),每日2次,口服。6月后,患者肝酶(ALT、AST)、肝彩超脂肪变、APRI指数(反映肝纤维化)、糖化血红蛋白(HbA1C)、血清胰岛素(INS)、胰岛素敏感指数(ISI)、血脂(TG)、血压(收缩压、舒张压)、尿微量白蛋白、体重皆明显改善。
结果表明:芒果苷-6-O-小檗碱盐具有降肝酶、改善肝脂肪变、改善肝纤维化、降糖、降胰岛素、增加胰岛素敏感性、降脂、降血压、降尿蛋白、降体重的作用。
具体如下表:
芒果苷-6-O-小檗碱盐给药前后各项指标情况表(n=8,均数±标准差)
注:*P<0.05。
试验例5:芒果苷-6-O-小檗碱盐对人体的各种治疗作用
给予芒果苷-6-O-小檗碱盐片(简称A,制备方法见实施例7),口服。在人体中发现芒果苷-6-O-小檗碱盐对类风湿性关节炎、乳腺增生、子宫息肉、前列腺增生、痴呆、性功能障碍、不孕、心律失常、心力衰竭、疲劳具有改善作用。给予芒果苷-6-O-小檗碱盐凝胶(简称B,制备方法见实施例10),涂患处,具有治疗湿疹作用。具体如下:
芒果苷-6-O-小檗碱盐对各疾病治疗作用情况(均数±标准差)
注:*P<0.05,#10对夫妻。
试验例6:芒果苷-6-O-小檗碱盐与芒果苷小檗碱盐的药代比较
1.试验方案
样品A:芒果苷-6-O-小檗碱盐2水合物
样品B:按WO2010/145192A1所公开的芒果苷小檗碱盐制备方法制备的芒果苷小檗碱盐
一次性灌胃给予SD大鼠受试样品A或样品B 100mg/kg,于0,0.083,0.25,0.5,1,1.5,2,3,4,5,6,7,8,12and 24h经颈静脉采血。
芒果苷对照品溶液的配制:精密称取芒果苷对照品,置25ml容量瓶中,加甲醇溶解并稀释至刻度,制得对照品母液,备用。精密量取对照品母液适量稀释成含芒果苷2、5、10、50、100、200ng/ml的对照品溶液。
盐酸小檗碱对照品溶液的配制:精密称取盐酸小檗碱对照品,置25ml容量瓶中,加甲醇溶解并稀释至刻度,制得对照品母液,备用。精密量取对照品母液适量稀释成含小檗碱0.2、0.5、2、10、20、50ng/ml的对照品溶液。
内标物溶液的配制:精密称取格列本脲,置25ml容量瓶中,加乙腈溶解并稀释至刻度,制得格列本脲50ng/ml的内标物溶液。
血样处理方法:取大鼠血液置肝素抗凝离心管中,6000rpm离心10min,取血浆,-20℃冷冻备用。
空白血浆的处理:取血浆100ul,加入乙腈-乙酸(9∶1)溶液500ul涡旋5min,,6000rpm离心10min,取上清,50℃真空干燥,残留物加流动相溶液100ul,涡旋3min,6000rpm离心10min,得空白血浆样品,取上清进样10ul。
给药血浆样品的预处理:取给药各采血点血浆100ul,加入乙腈-乙酸(9∶1)溶液500ul涡旋5min,6000rpm离心10min,取上清,50℃真空干燥,残留物加流动相溶液100ul,涡旋3min,6000rpm离心10min,得空白血浆样品,取上清进样10ul。
色谱条件:A相:0.1%甲酸溶液,B相:甲醇;色谱柱:Waters Xbridge C18(50×2.1mm,5μm);流速:0.40mL·min-1。
梯度洗脱程序:
Time(min) | Mobile phase B(%) |
0.50 | 18 |
1.20 | 98 |
2.50 | 98 |
2.51 | 18 |
4.00 | Stop |
质谱条件:离子检测方式:多离子检测(MRM);离子极性:正离子;芒果苷:m/z422.9/327.1,小檗碱:m/z 337.3/321.3,内标:m/z 494.2/369.1。
2.试验结果
采用Pharsight Phoenix 6.3中的非房室模型计算药代动力学参数。
芒果苷-6-O-小檗碱盐与芒果苷小檗碱盐的AUC比较(均数±标准差)
上述结果显示:口服芒果苷-6-O-小檗碱盐AUC是芒果苷小檗碱盐的2倍,表明芒果苷-6-O-小檗碱盐的吸收较芒果苷小檗碱盐有所提高。
本发明的最佳实施方式
芒果苷-6-O-小檗碱盐2水合物的制备
在反应器中加水670ml,将碳酸氢钾0.1mol加入水中制成浓度为1.5%(w/v)的碳酸氢钾溶液;将0.1mol芒果苷(42.2g)加入21ml DMSO(芒果苷与DMSO的配比为1:0.5(w/v))加热溶解,制成芒果苷溶液;将芒果苷溶液缓慢加入碳酸氢钾溶液中,充分搅拌,70℃保温反应完全,滤过,得芒果苷-6-O-钾盐溶液,60℃保温备用;取盐酸小檗碱0.1mol加70℃水3700ml溶解,得盐酸小檗碱溶液,80℃保温备用。将芒果苷-6-O-钾盐溶液缓慢加入盐酸小檗碱溶液中,充分搅拌,反应完全,静置析出沉淀,过滤,固体物45℃真空干燥,得橙黄色固体芒果苷-6-O-小檗碱盐2水合物65.7g,收率为82.8%。样品纯度经HPLC测定为97.6%。
本发明的实施方式
本发明所述的芒果苷采用市售品(西安杨凌东科药业有限公司,具有相应提取设备的厂家均可以生产,含量98%)。盐酸小檗碱、硫酸小檗碱等均为市售品(西安小草植物科技有限公司)。碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钾、二甲基亚砜(DMSO)等试剂均采用市售品。
制备例1:芒果苷-6-O-钠盐的制备
在反应器中加水1700ml,将碳酸氢钠0.1mol加入水中制成浓度为0.5%(w/v)的碳酸氢钠溶液;将0.1mol芒果苷(42.2g)加入85ml DMSO(芒果苷与DMSO的配比为1:2(w/v))加热溶解,制成芒果苷溶液;将芒果苷溶液缓慢加入碳酸氢钠溶液中,充分搅拌,85℃保温反应完全,滤过,反应液降至室温,加入反应液体积2倍量的丙酮,充分搅拌,析出大量沉淀,过滤,沉淀物无水乙醇充分洗涤,沉淀物40℃真空干燥,粉碎,得淡黄色粉末芒果苷-6-O-钠盐21.3g,收率为50.5%,样品纯度经HPLC测定为98.6%。
芒果苷6-O-钠盐:1HNMR(400MHz,DMSO-d6)δ:4.60(H-1’),6.01(H-5),6.10(H-4),6.96(H-8)。13CNMR(400MHz,DMSO-d6)(δppm):162.43(C-1),106.82(C-2),161.56(C-3),93.50(C-4),157.12(C-4a),101.06(C-4b),99.53C-5),161.56(C-6),147.08(C-7),103.75(C-8),106.83(C-8a),154.28(C-8b),176.63(C-9),73.67(C-1’),70.24(C-2’),79.19(C-3’),70.24(C-4’),81.05(C-5’),60.97(C-6’)。
制备例2:芒果苷-6-O-钾盐的制备
在反应器中加水1700ml,将碳酸钾0.05mol加入水中制成浓度为0.8%(w/v)的碳酸钾溶液;将0.1mol芒果苷(42.2g)加入42ml DMSO(芒果苷与DMSO的配比为1:1(w/v))加热溶解,制成芒果苷溶液;将芒果苷溶液缓慢加入碳酸钾溶液中,充分搅拌,60℃保温反应完全,滤过,反应液降温至40℃,加入反应液体积2倍量的丙酮,充分搅拌,析出大量沉淀,过滤,沉淀物无水乙醇充分洗涤,沉淀物50℃真空干燥,粉碎,得淡黄色粉末芒果苷-6-O-钾盐25.3g,收率为60.2%,样品纯度经HPLC测定为98.3%。
实施例1:芒果苷-6-O-小檗碱盐的制备
在反应器中加水2000ml,将碳酸氢钠0.1mol加入水中制成浓度为0.4%(w/v)的碳酸氢钠溶液;将0.1mol芒果苷(42.2g)加入127ml DMSO(芒果苷与DMSO的配比为1:3(w/v))加热溶解,制成芒果苷溶液;将芒果苷溶液缓慢加入碳酸氢钠溶液中,充分搅拌,80℃保温反应完全,滤过,得芒果苷-6-O-钠盐溶液,60℃保温备用;取0.1mol盐酸小檗碱加60℃水2000ml溶解,得盐酸小檗碱溶液,60℃保温备用。将芒果苷-6-O-钠盐溶液缓慢加入盐酸小檗碱溶液中,充分搅拌,反应完全,静置析出沉淀,过滤,固体物60℃真空干燥,将所得干燥物加入适量DMSO中溶解,将DMSO溶液缓慢滴加入适量丙酮中,充分搅拌均匀,静置,析出沉淀,过滤,沉淀物用适量无水乙醇洗涤,固体物55℃真空干燥,得橙黄色固体芒果苷-6-O-小檗碱盐52.0g,收率为65.6%。样品纯度经HPLC测定为95.6%。
实施例2:芒果苷-6-O-小檗碱盐2水合物的制备
在反应器中加水3500ml,将碳酸钠0.05mol加入水中制成浓度为0.3%(w/v)的碳酸钠溶液;将0.1mol芒果苷(42.2g)加入169ml DMSO(芒果苷与DMSO的配比为1:4(w/v))溶解,制成芒果苷溶液;将芒果苷溶液缓慢加入碳酸钠溶液中,充分搅拌,100℃保温反应完全,得芒果苷-6-O-钠盐溶液,80℃保温备用;取0.1mol盐酸小檗碱加90℃水3700ml溶解,得盐酸小檗碱溶液,80℃保温备用。将盐酸小檗碱溶液缓慢加入中芒果苷-6-O-钠盐溶液,充分搅拌,反应完全,静置析出沉淀,过滤,固体物干燥,得橙黄色固体芒果苷-6-O-小檗碱盐2水合物57.0g,收率为71.8%。样品纯度经HPLC测定为94.5%。
实施例3:芒果苷-6-O-小檗碱盐2水合物的制备
在反应器中加水13800ml,将碳酸钾0.06mol加入水中制成浓度为0.1%(w/v)的碳酸钾溶液;将0.1mol芒果苷(42.2g)加入210ml DMSO(芒果苷与DMSO的配比为1:5(w/v))溶解,制成芒果苷溶液;将芒果苷溶液缓慢加入碳酸钾溶液中,充分搅拌,50℃保温反应完全,得芒果苷-6-O-钾盐溶液,40℃保温备用;取0.1mol硫酸小檗碱加50℃水870ml溶解,滤过,得硫酸小檗碱溶液,40℃保温备用。将硫酸小檗碱溶液缓慢加入芒果苷-6-O-钾盐溶液中,充分搅拌,反应完全,静置析出沉淀,过滤,固体物50℃真空干燥,得橙黄色固体芒果苷-6-O-小檗碱盐2水合物48.2g,收率为57.6%。样品纯度经HPLC测定为95.5%。
实施例4:芒果苷-6-O-小檗碱盐4水合物的制备
在反应器中加水800ml,将碳酸氢钠0.1mol加入水中制成浓度为1%(w/v)的碳酸氢钠溶液;将0.1mol芒果苷(42.2g)加入8.5ml DMSO(芒果苷与DMSO的配比为1:0.2(w/v))加热溶解,制成芒果苷溶液;将芒果苷溶液缓慢加入碳酸氢钠溶液中,充分搅拌,90℃保温反应完全,滤过,得芒果苷-6-O-钠盐溶液,80℃保温备用;取盐酸小檗碱0.1mol加80℃水37000ml溶解,得盐酸小檗碱溶液,70℃保温备用。将芒果苷-6-O-钠盐溶液加入得盐酸小檗碱溶液中,充分搅拌,反应完全,析出沉淀,过滤,沉淀物用纯水充分洗涤,固体物干燥,得干燥物56.2g,收率为70.8%;将所得干燥物用适量甲醇中进行重结晶,得橙黄色芒果苷-6-O-小檗碱盐4水合物35.9g,收率为44.3%。样品纯度经HPLC测定为97.5%。
实施例5:芒果苷-6-O-小檗碱盐2水合物的制备
在反应器中加水380ml,将碳酸钠0.04mol和0.04mol碳酸氢钠加入水中制成浓度为2%(w/v)的碱性钠盐溶液;将0.1mol芒果苷(42.2g)加入50ml DMSO(芒果苷与DMSO的配比为1:1.2(w/v))加热溶解,制成芒果苷溶液;将芒果苷溶液缓慢加入碱性钠盐溶液中,充分搅拌,95℃保温反应完全,滤过,得芒果苷-6-O-钠盐溶液,90℃保温备用;取0.1mol盐酸小檗碱加100℃水3700ml溶解,滤过,得盐酸小檗碱溶液,90℃保温备用。将盐酸小檗碱溶液缓慢加入中芒果苷-6-O-钠盐溶液,充分搅拌,反应完全,降温,静置析出沉淀,过滤,沉淀物用纯水充分洗涤,固体物55℃真空干燥,得橙黄色固体芒果苷-6-O-小檗碱盐2水合物64.9g,收率为81.8%。样品纯度经HPLC测定为96.5%。
实施例6:芒果苷-6-O-小檗碱盐片剂的制备
将按实施例方法制备的芒果苷-6-O-小檗碱盐2水合物粉碎过160目筛,称取粉末37.5g,加入微晶纤维素50g、预胶化淀粉45g作为稀释剂组成制剂配方,混匀,以10%聚维酮K30乙醇溶液为粘合剂制软材,24目筛制粒,干燥后整粒,加入0.5%硬脂酸和2%的微粉硅胶为润滑剂,混匀,压片,制成1000片,包薄膜衣,即得,含药量为37.5mg/片。
实施例7:芒果苷-6-O-小檗碱盐颗粒的制备
将按实施例方法制备的芒果苷-6-O-小檗碱盐粉碎过160目筛,称取粉末103g,加入预胶化淀粉150g作为稀释剂,加入100g木糖为矫味剂组成制剂配方,混匀,以1%羧甲基纤维素钠溶液为粘合剂制软材,24目筛制粒,干燥后整粒,分装,即得,含药量为42mg/g。
实施例8:芒果苷-6-O-小檗碱盐胶囊的制备
将按实施例方法制备的芒果苷-6-O-小檗碱盐2水合物粉碎过160目筛,称取粉末75g,加入微晶纤维素20g、药用淀粉25g作为稀释剂组成制剂配方,混匀,以10%聚维酮K30乙醇溶液为粘合剂制软材,24目筛制粒,干燥后整粒,分装胶囊,制成1000粒,即得,含药量为75mg/粒。
实施例9:芒果苷-6-O-小檗碱盐凝胶剂的制备
取羟丙基甲基纤维素15g、海藻酸钠10g,加适量水,搅拌溶解,制成基质,取芒果苷-6-O-小檗碱盐4水合物5g加100ml二甲基亚砜溶解,与基质混合均匀,制成1000ml均匀液体,即芒果苷-6-O-小檗碱盐凝胶。
实施例10:芒果苷-6-O-小檗碱盐冻干粉针的制备
称取40g甘露醇,置于适当容器内,加入200ml注射用水,加针用炭0.2g(0.1%w/v),加热至80℃,搅拌30min,0.22μm微孔滤膜过滤,滤液备用。称取10g芒果苷-6-O-小檗碱盐2水合物,加叔丁醇100ml,搅拌使芒果苷-6-O-小檗碱盐完全溶解。混合芒果苷-6-O-小檗碱盐溶液及甘露醇溶液,补加注射用水至1000ml,用0.22μm微孔滤膜过滤,分装,装量为每支含芒果苷-6-O-小檗碱盐10mg,冷冻干燥。真空压塞,轧盖,贴签,包装即得。
上述具体实施方式对本发明作进一步说明,但不限于此。
工业实用性
本发明的化合物的制备方法解决大量有机溶剂的使用带来的环保压力与成本问题,从而更适合工业化生产。
Claims (13)
1.一种芒果苷-6-O-小檗碱盐,其特征在于:所述芒果苷-6-O-小檗碱盐具有下式(Ⅰ)的结构。
其中x=0,或2,或4。
2.根据权利要求1所述的芒果苷-6-O-小檗碱盐,其特征在于:所述x=2。
3.权利要求1-2任一所述的芒果苷-6-O-小檗碱盐的制备方法,其特征在于:
①将碱性钠盐或碱性钾盐加入水中,制备碱性钠盐溶液或碱性钾盐溶液,浓度为0.1%-2%(w/v);
②将芒果苷加入二甲基亚枫中溶解,制成芒果苷溶液;
③将芒果苷溶液缓慢加入碱性钠盐溶液或碱性钾盐溶液中,充分搅拌,50℃-100℃反应完全,得芒果苷-6-O-钠盐溶液或芒果苷-6-O-钾盐溶液;
④取盐酸小檗碱加50℃-100℃水溶解,制成盐酸小檗碱溶液;
⑤将盐酸小檗碱溶液与芒果苷-6-O-钠盐溶液或芒果苷-6-O-钾盐溶液充分混合,反应完全,析出沉淀,过滤,得固体物;
⑥固体物干燥,得芒果苷-6-O-小檗碱盐。
4.根据权利要求3所述的芒果苷-6-O-小檗碱盐的制备方法,其特征在于:所述芒果苷与二甲基亚砜的配比为1:0.2-5(w/v)。
5.根据权利要求3所述的芒果苷-6-O-小檗碱盐的制备方法,其特征在于:所述芒果苷与碱性钠盐或碱性钾盐的摩尔配比为1:0.5-1。
6.根据权利要求3所述的芒果苷-6-O-小檗碱盐的制备方法,其特征在于:所述芒果苷-6-O-钠盐或芒果苷-6-O-钾盐与盐酸小檗碱摩尔比为1:1。
7.根据权利要求3所述的芒果苷-6-O-小檗碱盐的制备方法,其特征在于:所述碱性钠盐或碱性钾盐选自碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾中的一种或两种以上的混合物,所述盐酸小檗碱可由硫酸小檗碱或其它小檗碱医学上可接受的盐替代。
8.一种药物,其特征在于:所述药物由权利要求1-2任一所述的芒果苷-6-O-小檗碱盐与可药用辅料组成。
9.权利要求8所述的药物,其特征在于:所述药物制成临床适用的片剂、胶囊剂、颗粒剂、口服溶液剂、口服混悬剂、糖浆剂、丸剂、外用制剂、注射剂。
10.权利要求1-2任一所述的芒果苷-6-O-小檗碱盐在制备AMPK激活剂的用途。
11.根据权利要求10所述的应用,其特征在于:所述AMPK激活剂可用于预防或治疗下述疾病中的任何一种或几种:糖尿病、糖尿病各种慢性并发症、肥胖、高脂血症、胰岛素抵抗、高胰岛素血症、代谢综合征、高血压、动脉粥样硬化、缺血性心脏病、心肌肥大、心律失常、心力衰竭、上呼吸道感染、慢性支气管炎、慢性阻塞性肺病、哮喘、肺纤维化、肝炎、单纯性脂肪肝、非酒精性脂肪性肝病、酒精性肝病、肝纤维化、肝硬化、前列腺炎、胰腺炎、肾炎、肾病综合征、高血压肾病、慢性肾功能不全、风湿性关节炎、类风湿性关节炎、骨性关节炎、炎症性肠病、脑梗塞、记忆障碍、阿尔茨海默氏病、梗塞性痴呆、帕金森氏症、肿瘤、肌肉萎缩、肌肉无力症。
12.根据权利要求11所述的应用,其特征在于:所述糖尿病各种慢性并发症具体指糖尿病并发冠心病、动脉粥样硬化、脑血管病、糖尿病肾病、糖尿病性视网膜病变、神经病变、糖尿病足、黄斑病、白内障、青光眼、屈光改变、虹膜睫状体病变中的一种或几种。
13.权利要求1-2任一所述的芒果苷-6-O-小檗碱盐在制备用于治疗乳腺增生、子宫息肉、前列腺增生、性功能障碍、不孕、疲劳、湿疹的药物中的应用。
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