CN110872240B - 全蝎中胍类生物碱钳蝎碱甲和/或钳蝎碱乙的提取方法及医药用途 - Google Patents
全蝎中胍类生物碱钳蝎碱甲和/或钳蝎碱乙的提取方法及医药用途 Download PDFInfo
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- CN110872240B CN110872240B CN201911232934.7A CN201911232934A CN110872240B CN 110872240 B CN110872240 B CN 110872240B CN 201911232934 A CN201911232934 A CN 201911232934A CN 110872240 B CN110872240 B CN 110872240B
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- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
Description
技术领域
本发明涉及中药提取制备领域,特别是全蝎中两种胍类生物碱的提取方法及医药用途。
背景技术
全蝎别名钳蝎、蝎子、全虫、虿、万尾虫、山蝎、东全蝎等,辛、平,有毒,为钳蝎科动物东亚钳蝎Buthus martensii Karsch的干燥体。全蝎主产于我国山东、河南等地,在中国、韩国、印度及非洲作为药物使用已经有2000多年的历史。在中国宋朝时期全蝎已经作为药物使用。全蝎具有镇痛、抗惊厥、抗癫痫、抗肿瘤等功效,临床用于治疗溃疡、白血病、哮喘、慢性肾炎等病症。目前没发现全蝎对阿尔茨海默病(Alzheimer’s Disease,AD)开展相关作用研究的文献报道。
全蝎在我国资源丰富,对其大分子以及蝎毒的科学研究较为广泛,但是目前对于它的一些小分子化学成分和活性方面研究相对较少,更未见从全蝎中提取得到胍类生物碱成分的相关文献。
阿尔茨海默病是一种常见于老年人的神经退行性疾病,其主要临床表现为记忆障碍、失用症、失认症、视空间损害、执行功能障碍、人格和行为异常,严重影响患者的日常生活能力。世界卫生组织声称全世界现已有4600万人患有阿尔茨海默病,根据最新的《世界阿尔茨海默病报告》,预计到2050年,每年新增阿尔茨海默病病例近100万例。目前阿尔茨海默病治疗仍然是世界性难题之一。
迄今阿尔茨海默病的确切发病机制还没有完全阐明,现在较为广泛认可的是胆碱能***假说、淀粉样蛋白假说和Tau蛋白假说。由于乙酰胆碱酯酶(AChE)广泛分布于人脑中的神经组织,它可以降解突触间隙的神经递质乙酰胆碱,所以通过抑制AChE活性,可维持乙酰胆碱在突触间隙的正常水平,使胆碱能神经信号传递正常,恢复AD患者的认知障碍。目前AChE抑制药是临床主要使用的抗AD药物,这包括AChE抑制剂卡巴拉汀和加兰他敏,在我国还有石杉碱甲。
这些乙酰胆碱酯酶抑制剂主要作用于乙酰胆碱酯酶底部的催化活性位点(CAS),可以缓解轻度至中度AD患者的症状。然而最近研究发现,其外周活性位点(PAS)也与水解乙酰胆碱有密切的关系,并可抑制β淀粉样蛋白聚集。因此,基于双活性中心位点(AChE的CAS和PAS)抑制的功能分子成为近年的研究热点。目前多奈哌齐是市场上唯一用于抗AD临床治疗的双位点AChE抑制药。
近年来,乙酰胆碱酯酶的同工酶---丁酰胆碱酯酶(BChE)的代偿作用日益引起人们的关注。研究发现,BChE在脑内也有分布,并能降解神经递质乙酰胆碱。有充分的证据表明,BChE在AD进展过程中补偿了AChE的损失,并在AChE产生不足或其活性受到抑制时补偿其功能。事实上,与正常大脑相比,晚期AD患者的AChE水平下降了90%,而BChE水平大约是正常水平的两倍,并有持续增加的趋势。这是AD患者对选择性AChE抑制剂产生耐药性的主要原因。因此对AD中后期来说BChE是相当重要的药物作用靶标。现在用于临床AD治疗的胆碱酯酶抑制药物中唯有卡巴拉汀为BChE和AChE双酯酶的强效抑制剂,这与长期对BChE作用的忽视有关;但卡巴拉汀只与AChE的CAS部位强势结合,不与其PAS部位产生相互作用。
目前研究发现,AD患者老年斑内含有过量Cu2+、Zn2+和Fe2+等金属离子,这些离子进而促进脑内β淀粉样蛋白聚集和tau蛋白聚集。因此,通过金属离子螯合作用降低脑内离子浓度也已成为AD治疗的重要策略之一,并也用于其它神经退行性疾病的治疗(参见雷鹏,等.过渡金属离子与神经退行性疾病.大学化学,2006,21(6):32-35;及参见Cristina Rodríguez-Rodríguez,et al.The art of building multifunctional metal-bindingagents from basic molecular scaffolds for the potential application inneurodegenerative diseases.Coordination Chemistry Reviews,2012,256:2308–2332)。
发明内容
本发明目的是提供全蝎中两种胍类生物碱,即钳蝎碱甲和/或钳蝎碱乙的提取方法。
本发明的第二个目的是提供钳蝎碱甲和/或钳蝎碱乙的医药用途。
本发明的第三个目的是提供包含钳蝎碱甲和钳蝎碱乙的全蝎提取物。
本发明的第四个目的是提供全蝎提取物的医药用途。
本发明的第五个目的是提供含钳蝎碱甲和/或钳蝎碱乙的药物组合物。
本发明的第六个目的是提供上述药物组合物的医药用途。
本发明的技术方案概述如下:
钳蝎碱甲,具有式(I)的结构:
钳蝎碱乙,具有式(II)的结构:
钳蝎碱甲和/或钳蝎碱乙的提取方法,包括以下步骤:
(1)以全蝎干燥体为原料,破碎后加入原料8-10质量倍的体积分数为50%-90%的乙醇水溶液(或甲醇水溶液),回流提取2-3次,每次提取2-3小时,合并得到提取液,减压回收溶剂,浓缩后得到总浸膏,即为全蝎提取物;
(2)将总浸膏分散到5-10质量倍的水中,用乙酸乙酯(或二氯甲烷,或三氯甲烷)进行萃取,乙酸乙酯(或二氯甲烷,或三氯甲烷)萃取液弃去,剩余水层减压浓缩得到剩余水层浸膏;
(3)将剩余水层浸膏经硅胶柱色谱分离,以体积比分别为20:1、10:1和1:1的二氯甲烷-甲醇为洗脱剂梯度洗脱,得到馏分Fr.1、Fr.2、Fr.3、Fr.4、Fr.5;
(4)馏分Fr.5经硅胶柱色谱分离,以体积比为10:1的二氯甲烷-甲醇为洗脱剂等度洗脱,得到馏分Fr.5-1、Fr.5-2、Fr.5-3、Fr.5-4、Fr.5-5、Fr.5-6;
(5)馏分Fr.5-5经ODS柱色谱分离,以体积比为1:9、2:8、4:6、5:5和9:1的甲醇-水为洗脱剂梯度洗脱,得到馏分Fr.5-5-1、Fr.5-5-2、Fr.5-5-3和Fr.5-5-4;
(6)馏分Fr.5-5-2经ODS柱色谱分离,以体积比为1:4的甲醇-水为洗脱剂等度洗脱,得到钳蝎碱甲,即N-(4-胍丁基)-4-羟基苯甲酰胺;
(7)馏分Fr.5-5-3经ODS柱色谱分离,以体积比为1:4的甲醇-水为洗脱剂等度洗脱,得到钳蝎碱乙,即N-(4-胍丁基)-2-吡啶甲酰胺。
钳蝎碱甲和/或钳蝎碱乙在制备抗阿尔茨海默病药物、抑制乙酰胆碱酯酶和丁酰胆碱酯酶的药物以及金属离子螯合药物中的应用。
包含钳蝎碱甲和钳蝎碱乙的全蝎提取物。
全蝎提取物在制备抗阿尔茨海默病药物、抑制乙酰胆碱酯酶和丁酰胆碱酯酶的药物以及金属离子螯合药物中的应用。
一种药物组合物,包含钳蝎碱甲和/或钳蝎碱乙或其药学上可接受的盐,以及药学上可接受的载体和/或赋形剂。
上述药物组合物在制备抗阿尔茨海默病药物、抑制乙酰胆碱酯酶和丁酰胆碱酯酶的药物以及金属离子螯合药物中的应用。
本发明的优点和有益效果:
本发明的钳蝎碱甲和钳蝎碱乙能有效地抑制乙酰胆碱酯酶和丁酰胆碱酯酶的活性,并以与乙酰胆碱酯酶的PAS位点结合为优势特征,同时具有金属离子螯合能力,本发明全蝎提取物可作为抗阿尔茨海默病的药物。
附图说明
图1是钳蝎碱甲与各金属离子螯合的吸收光谱图。
图2是钳蝎碱乙与各金属离子螯合的吸收光谱图。
具体实施方式
实施例1
钳蝎碱甲和钳蝎碱乙的提取方法,包括以下步骤:
(1)以全蝎(Buthus martensii Karsch)的干燥体(2.0kg)为原料,破碎后加入原料9质量倍的体积分数为85%的甲醇水溶液,回流提取3次,每次提取3小时,合并得到提取液,减压回收溶剂,浓缩后得到总浸膏(337g),即为全蝎提取物;
(2)将总浸膏分散到8质量倍的水中,用等体积乙酸乙酯进行萃取,乙酸乙酯萃取液弃去,剩余水层减压浓缩得到剩余水层浸膏(110g);
(3)将剩余水层浸膏经硅胶柱色谱分离,以体积比分别为20:1、10:1和1:1的二氯甲烷-甲醇为洗脱剂梯度洗脱,得到馏分Fr.1、Fr.2、Fr.3、Fr.4、Fr.5(41g);
(4)馏分Fr.5经硅胶柱色谱分离,以体积比为10:1的二氯甲烷-甲醇为洗脱剂等度洗脱,得到馏分Fr.5-1、Fr.5-2、Fr.5-3、Fr.5-4、Fr.5-5(6.6g)、Fr.5-6;
(5)馏分Fr.5-5经ODS柱色谱分离,以体积比为1:9、2:8、4:6、5:5和9:1的甲醇-水为洗脱剂梯度洗脱,得到馏分Fr.5-5-1、Fr.5-5-2(1.2g)、Fr.5-5-3(0.8g)和Fr.5-5-4;
(6)馏分Fr.5-5-2经ODS柱色谱分离,以体积比为1:4的甲醇-水为洗脱剂等度洗脱,得到淡黄色固体钳蝎碱甲(53mg);
(7)馏分Fr.5-5-3经ODS柱色谱分离,以体积比为1:4的甲醇-水为洗脱剂等度洗脱,得到黄白色固体钳蝎碱乙(18mg)。
钳蝎碱甲的谱图数据如下:
HR-ESI-MS(positive mode)m/z:251.1514[M+H]+(calculated for C12H19N4O2,251.1508)。1HNMR(400MHz,CD3OD)δ:1.64(2H,m,H-3'),1.65(2H,m,H-2'),3.22(2H,t,J=6.2Hz,H-4'),3.38(2H,t,J=6.2Hz,H-1'),6.87(2H,d,J=8.6Hz,H-3and H-5),7.71(2H,d,J=8.6Hz,H-2and H-6)。13C NMR(100MHz,CD3OD)δ:170.4(C-7),161.2(C-4),158.2(C-5'),130.3(C-2and C-6),126.4(C-1),116.3(C-3and C-5),42.1(C-4'),40.2(C-1'),27.5(C-2'),27.0(C-3')。通过现代波谱学技术(HR-MS、1D-NMR和2D-NMR),结合文献相关数据,鉴定它的结构为N-(4-胍丁基)-4-羟基苯甲酰胺,钳蝎碱甲为新发现的天然化合物,其化学结构如下所示:
钳蝎碱乙的谱图数据如下:
HR-ESI-MS(positive mode)m/z:236.1524[M+H]+(calculated for C11H18N5O,236.1511)。1HNMR(400MHz,CD3OD)δ:1.69(2H,m,H-3'),1.71(2H,m,H-2'),3.26(2H,t,J=6.9Hz,H-4'),3.49(2H,t,J=6.5Hz,H-1'),7.57(1H,dd-like,J=4.4,7.7Hz,H-5),7.98(1H,t,J=7.7Hz,H-4),8.11(1H,d,J=7.7Hz,H-3),8.66(1H,d,J=4.4Hz,H-6)。13C NMR(100MHz,CD3OD)δ:167.1(C-7),158.8(C-5'),151.1(C-2),150.0(C-6),139.0(C-4),127.9(C-5),123.2(C-3),42.3(C-4'),39.9(C-1'),27.9(C-2'),27.3(C-3')。通过现代波谱学技术(HR-MS、1D-NMR和2D-NMR)解析,鉴定它的结构为N-(4-胍丁基)-2-吡啶甲酰胺,钳蝎碱乙为未见文献报道的新化合物,其化学结构如下所示:
实施例2
钳蝎碱甲和钳蝎碱乙的提取方法,包括以下步骤:
(1)以全蝎干燥体为原料,破碎后加入原料8质量倍的体积分数为50%的乙醇水溶液,回流提取2次,每次提取3小时,合并得到提取液,减压回收溶剂,浓缩后得到总浸膏,即为全蝎提取物;
(2)将总浸膏分散到5质量倍的水中,用等体积二氯甲烷进行萃取,二氯甲烷萃取液弃去,剩余水层减压浓缩得到剩余水层浸膏;
步骤(3)-(8)同实施例1中步骤(3)-(8)。
实施例3
钳蝎碱甲和钳蝎碱乙的提取方法,包括以下步骤:
(1)以全蝎干燥体为原料,破碎后加入原料10质量倍的体积分数为90%的甲醇水溶液,回流提取3次,每次提取2小时,合并得到提取液,减压回收溶剂,浓缩后得到总浸膏,即为全蝎提取物;
(2)将总浸膏分散到10质量倍的水中,用等体积三氯甲烷进行萃取,三氯甲烷萃取液弃去,剩余水层减压浓缩得到剩余水层浸膏;
步骤(3)-(8)同实施例1中步骤(3)-(8)。
实施例4
钳蝎碱甲和钳蝎碱乙的胆碱酯酶抑制活性检测
采用改进的Ellman法,对钳蝎碱甲和钳蝎碱乙进行乙酰胆碱酯酶和丁酰胆碱酯酶抑制活性的测定。
在96孔板中依次加入140μL 100mM的磷酸盐缓冲液,20μL 0.05U/mL的AChE(或20μL 0.05U/mL BChE),待测化合物钳蝎碱甲或钳蝎碱乙20μL,混合均匀后放入25℃恒温箱中培养15分钟。然后加入10μL 10.0mM DNTB和10μL7.5 mM ATCI(或10μL 7.5mM BTCI),再放入恒温箱中,在37℃下培养30分钟后,测量96孔板中溶液在412nm下的吸光值大小。用20μL0.01mol/L的DMSO作为阴性对照,用20μL加兰他敏代替待测化合物作为阳性对照,空白组则是通过加入20μL100 mM的磷酸盐缓冲液代替待测化合物。每组数据平行做3次,取平均值。
抑制率的计算方法如下:
抑制率=(空白组-实验组)/空白组×100%
活性结果(IC50值)见表1。
结果表明钳蝎碱甲和钳蝎碱乙都能有效地抑制乙酰胆碱酯酶和丁酰胆碱酯酶的活性。从而说明本发明的钳蝎碱甲和/或钳蝎碱乙、含钳蝎碱甲和钳蝎碱乙的全蝎提取物、含钳蝎碱甲和/或钳蝎碱乙的组合物能制备成治疗乙酰胆碱不足相关联疾病的药物。乙酰胆碱不足相关联的疾病包括阿尔茨海默病、重症肌无力、青光眼等。
表1钳蝎碱甲和钳蝎碱乙对胆碱酯酶抑制的活性结果(IC50值)
实施例5
钳蝎碱甲和钳蝎碱乙的碘化丙啶置换检测
将5U的AChE和150μL的100μM钳蝎碱甲或钳蝎碱乙样品溶液在96孔板中25℃下培养6小时。然后加入50μL的1μM碘化丙啶溶液,室温培养10min。在激发波长(λex)为535nm和发射波长(λem)为595nm的条件下用酶标仪测试吸光度(OD)。其中空白组用Tris-HCl溶液代替,阳性对照组采用多奈哌齐标准品。每组数据平行做3次,取平均值。
根据下式计算碘化丙啶置换率:
置换率=(1-OD样品/OD空白)×100%
检测结果见表2。
结果表明钳蝎碱甲和钳蝎碱乙的碘化丙啶置换能力都与阳性对照药多奈哌齐相近,说明钳蝎碱甲和钳蝎碱乙的乙酰胆碱酯酶抑制都具有与其PAS位点强效抑制的作用特征。
表2钳蝎碱甲和钳蝎碱乙的碘化丙啶置换结果
实施例6
钳蝎碱甲和钳蝎碱乙对金属离子的螯合检测
步骤一、试样的制备:分别配置浓度为20μM的AlCl3,CuCl2,FeCl2,ZnCl2甲醇溶液;分别配置浓度为20μM的钳蝎碱甲样品溶液和钳蝎碱乙样品溶液。
步骤二、钳蝎碱甲和钳蝎碱乙对金属离子的螯合能力测定:
分别取2mL钳蝎碱甲或钳蝎碱乙样品溶液与2mL金属离子溶液混匀,置于比色皿中避光静置30min,然后使用紫外分光光度计测定波长范围为200-600nm的UV吸收光谱。检测结果见图1和图2。
结果显示钳蝎碱甲和钳蝎碱乙的样品溶液加入Al3+、Cu2+、Fe2+和Zn2+后UV光谱的吸收强度均明显降低,表明钳蝎碱甲和钳蝎碱乙对Al3+、Cu2+、Fe2+和Zn2+四种金属离子都有较强的螯合活性,从而说明本发明的钳蝎碱甲和/或钳蝎碱乙、含钳蝎碱甲和钳蝎碱乙的全蝎提取物、含钳蝎碱甲和/或钳蝎碱乙的组合物能制备成治疗Al3+、Cu2+、Fe2+和Zn2+四种金属离子过量相关联疾病的药物。Al3+、Cu2+、Fe2+和Zn2+四种金属离子过量相关联疾病包括阿尔茨海默病、帕金森氏病(Parkinson’s disease)、亨廷顿病(Huntington’sdisease)、朊病毒类疾病(Prion diseases)等。
含有本发明所述胍类生物碱钳蝎碱甲和/或钳蝎碱乙的组合物的医药用途,可以为适用于口服或注射等应用形式,例如,按常规技术,加入药物可接受的载体和/或赋形剂制成片剂、胶囊剂、粉剂、糖浆剂、针剂等。
本发明所述全蝎提取物具有药理活性,因此,含有该全蝎提取物的组合物也具有药理活性。
以上实施例的说明只是用于帮助理解本发明的方法及其中心思想。应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护。
Claims (6)
1.全蝎中胍类生物碱钳蝎碱甲和/或钳蝎碱乙的提取方法,其特征在于包括如下步骤:
(1)以全蝎干燥体为原料,破碎后加入原料8-10质量倍的体积分数为50%-90%的乙醇水溶液或甲醇水溶液,回流提取2-3次,每次提取2-3小时,合并得到提取液,减压回收溶剂,浓缩后得到总浸膏,即为全蝎提取物;
(2)将总浸膏分散到5-10质量倍的水中,用乙酸乙酯或二氯甲烷或三氯甲烷中的一种进行萃取,乙酸乙酯或二氯甲烷或三氯甲烷萃取液弃去,剩余水层减压浓缩得到剩余水层浸膏;
(3)将剩余水层浸膏经硅胶柱色谱分离,以体积比分别为20:1、10:1和1:1的二氯甲烷-甲醇为洗脱剂梯度洗脱,得到馏分Fr.1、Fr.2、Fr.3、Fr.4、Fr.5;
(4)馏分Fr.5经硅胶柱色谱分离,以体积比为10:1的二氯甲烷-甲醇为洗脱剂等度洗脱,得到馏分Fr.5-1、Fr.5-2、Fr.5-3、Fr.5-4、Fr.5-5、Fr.5-6;
(5)馏分Fr.5-5经ODS柱色谱分离,以体积比为1:9、2:8、4:6、5:5和9:1的甲醇-水为洗脱剂梯度洗脱,得到馏分Fr.5-5-1、Fr.5-5-2、Fr.5-5-3和Fr.5-5-4;
(6)馏分Fr.5-5-2经ODS柱色谱分离,以体积比为1:4的甲醇-水为洗脱剂等度洗脱,得到钳蝎碱甲,即N-(4-胍丁基)-4-羟基苯甲酰胺;
(7)馏分Fr.5-5-3经ODS柱色谱分离,以体积比为1:4的甲醇-水为洗脱剂等度洗脱,得到钳蝎碱乙,即N-(4-胍丁基)-2-吡啶甲酰胺。
3.权利要求1中所述方法提取的钳蝎碱甲和/或钳蝎碱乙在制备抗阿尔茨海默病药物、抑制乙酰胆碱酯酶和丁酰胆碱酯酶的药物以及金属离子螯合药物中的应用。
4.包含权利要求1所述方法提取的含钳蝎碱甲和钳蝎碱乙的全蝎提取物。
5.权利要求4所述的全蝎提取物在制备抗阿尔茨海默病药物、抑制乙酰胆碱酯酶和丁酰胆碱酯酶的药物以及金属离子螯合药物中的应用。
6.一种包含权利要求1所述方法提取的钳蝎碱甲和/或钳蝎碱乙或其药学上可接受的盐以及药学上可接受的载体和/或赋形剂构成的药物组合物的应用,用于制备抗阿尔茨海默病药物、抑制乙酰胆碱酯酶和丁酰胆碱酯酶的药物以及金属离子螯合药物。
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