CN106905281A - 厚果崖豆藤中抑制乙酰和丁酰胆碱酯酶的黄酮类化合物及其用途 - Google Patents
厚果崖豆藤中抑制乙酰和丁酰胆碱酯酶的黄酮类化合物及其用途 Download PDFInfo
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Abstract
本发明属于医药技术领域,具体涉及从豆科植物厚果崖豆藤中分离得到的具有抑制乙酰和丁酰胆碱酯酶活性的黄酮类化合物及其可药用盐,以及含有这些化合物的药物组合物。本发明的三个黄酮类化合物对乙酰和丁酰胆碱酯酶具有显著的抑制作用,显示出在预防和治疗学习记忆障碍和老年性痴呆疾病中的独特优势。
Description
技术领域
本发明涉及医药技术领域。具体而言,本发明涉及从豆科植物厚果崖豆藤中分离得到的3种具有较强乙酰和丁酰胆碱酯酶抑制活性的黄酮类化合物及其可药用盐,以及含有这些化合物的药物组合物。可以预期其用于学习记忆障碍和老年性痴呆症的预防和治疗。
背景技术
阿尔茨海默病(Alzheimer's disease,AD)是一种渐进性神经退化性失调症,临床表现为认知和记忆功能不断恶化,日常生活能力进行性减退,并有各种神经精神症状和行为障碍。该病多为大脑原发性疾病,起病缓慢,病程呈进行性,多有家族史,是老年人群中引起痴呆的最常见的疾病。AD最显著的神经病理组织学特征是老年斑、淀粉状蛋白沉积物和神经纤维缠结,主要发生在前脑基底、海马组织和大脑皮层。
关于AD发病机制,目前有多种不同的假说,其中中枢胆碱能神经功能失调被认为是最为重要的一种。乙酰胆碱(acetylcholine,ACh)为促进学习记忆的神经递质,其在脑内被两种胆碱酯酶水解,即乙酰胆碱酯酶(Acetylcholinesterase,AChE)和丁酰胆碱酯酶(Butyrveholinesterase,BuChE)。胆碱酯酶抑制剂能延缓乙酰胆碱的水解,因此胆碱酯酶抑制剂能够提高AD患者乙酰胆碱在突触间隙的含量而产生疗效,是目前惟一被普遍认可的药物治疗手段。
目前临床应用的大部分胆碱酯酶抑制剂都是选择性的AChE抑制剂,如他克林(tacrine)、加兰他敏(galanthamine)、多奈哌齐(donepezil)、利伐司替明(rivastigmine)等。我国学者从蕨类植物蛇足石杉中发现并开发的AChE抑制剂石杉碱甲(huperzine A)也显示了良好的临床应用前景。但因其外周副作用较大,长期治疗效果不理想。Mesulam等研究发现,尽管脑内AChE较BuChE浓度高许多,但当AD患者脑中AChE活性下降时,BuChE的活性却逐渐增加,这充分表明当AChE被AChE抑制剂所抑制时,BuChE起到一定补偿作用。此外BuChE在晚期AD病人大脑中的含量很高,其在晚期AD患者脑中乙酰胆碱的水解过程中起到更为突出的作用。故建议开发AChE- BuChE双重抑制剂或选择性BuChE抑制剂。
厚果崖豆藤Millettia pachycarpa为豆科崖豆藤属植物,其种子味苦,辛,有毒,具有杀虫、攻毒和止痛的功效,主治疥癣疮癞、痧气腹痛和小儿疳积,分布于我国的浙江、四川、江西、湖南、广东、广西、贵州、云南、福建等地,为广西和贵州部分地区民间用药材。对其化学成分的研究表明,该植物中次生代谢产物主要为结构新颖的黄酮、异黄酮、二氢黄酮、查耳酮和鱼藤酮类化合物。并且其中的部分异黄酮类化合物具有较好的抗雌性激素样作用、细胞毒和诱导肿瘤细胞凋亡的活性,但是有关该植物和分离化合物的胆碱酯酶抑制活性及其在抗老年痴呆疾病中的应用尚未见报告。
发明内容:
本发明的目的是提供了一种从豆科植物厚果崖豆藤中得到有效抑制乙酰及丁酰胆碱酯酶单体化合物的方法和应用。这3个黄酮类化合物均具有明显的乙酰胆碱酯酶和丁酰胆碱酯酶抑制作用,显示出在预防和治疗学习记忆障碍和老年痴呆疾病中的独特优势。
本发明的再一目的是提供了含有本发明的化合物和制药学上可用的载体的药物组合物。
本发明的又一目的是提供了将本发明化合物用于制备预防和治疗学习记忆障碍和老年痴呆药物及与上述疾病有关的医药或保健品用途。
本发明的化合物结构式如下所示:
本发明的3个黄酮类化合物,来自豆科植物厚果鸡血藤的根、茎、叶、皮和种子中,经过提取、分离、纯化得到。也可通过半合成或全合成得到。
本发明的化合物具有较高的乙酰胆碱酯酶和丁酰胆碱酯酶抑制活性,进一步的实验结果表明本发明的化合物对两种胆碱酯酶具有双重抑制活性或选择性抑制活性。
本发明还涉及以本发明化合物作为活性成分的药物组合物。该药物组合物可根据本领域公知的方法进行制备。通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形物和/或辅剂结合,制成适于人使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.01-95重量%。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径包括口服、静脉注射、肌肉注射、皮下注鼻腔、口腔黏膜、呼吸道、皮肤、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括O/W、W/O型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴鼻剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊和肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂是以淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、磷酸氢钙、碳酸钙等;润湿剂可以是水、乙醇、异丙醇等、粘合剂可以是淀粉浆、糊精、糖浆、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羟甲基淀粉钠、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片或双层片和多层片。
为了将本发明化合物制成胶囊剂,可以将本发明化合物与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可以将本发明化合物先与稀释剂、粘合剂、润湿剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各种稀释剂、黏合剂、润湿剂、崩解剂和助流剂等可用于制备本发明化合物的胶囊剂。
为将本发明化合物制备成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调节剂可以是磷酸盐、醋酸盐、盐酸盐、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖磷酸盐、醋酸盐等。如制备冻干粉针剂,还可以加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其他添加剂。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明的化合物或组合物可单独服用,或与其它治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
具体实施例:
下面结合具体实施例对本发明作进一步阐述,但不限制本发明。
实施例1:本发明3个化合物的提取、分离、纯化的方法:
(1)取厚果鸡血藤种子4.5kg,粉碎后置于热回流装置中,用95%的乙醇浸没药材,用电热套加热回流提取,每次3小时,提取3次。
(2)将乙醇提取液真空浓缩,回收乙醇,得到乙醇浓缩液。
(3)用适量的水稀释乙醇浓缩液,得到的混悬液用石油醚进行萃取。萃取采取少量多次的原则,第一次采用水溶液一半体积的石油醚,进行萃取,以后逐步减少石油醚用量,直到石油醚层颜色非常浅为止,萃取过程中的乳化层归于水层。
(4)上层为石油醚层,将石油醚层真空浓缩回收石油醚后得到石油醚浸膏。
(5)下层为水层,水层同法用乙酸乙酯萃取,萃取过程中的乳化层归于水层。
(6)上层为乙酸乙酯层,乙酸乙酯层真空浓缩回收乙酸乙酯后得到乙酸乙酯浸膏。
(7)下层为水层,水层同法用水饱和的正丁醇萃取,萃取过程中的乳化层归于正丁醇层。
(8)上层为正丁醇层,正丁醇层真空浓缩回收正丁醇后得到正丁醇浸膏。
(9)乙酸乙酯浸膏137 g进行硅胶柱层析(8 cm柱子)分离,用石油醚-乙酸乙酯混合溶液进行梯度洗脱,将收集到的流分按照TLC检测结果、用显色剂显色后的颜色以及放置后析出沉淀等性质进行合并浓缩,得到6个流份(流份A~F)。
(10)流份B 4 g,用硅胶柱分离(2.5 cm柱子)。用石油醚-乙酸乙酯的混和溶液梯度洗脱(从10∶1,8:1到6∶1,体积比,每个梯度400 mL)。其中流份B-3~11中有橙色针晶析出,抽滤后重结晶得化合物1。
化合物1为4-methoxylonchocarpin,其结构鉴定如下:
橙色针晶,1H-NMR (400 MHz, CDCl3):δ13.79 (1H, brs, -OH), 7.85 (1H, d, J =15.2 Hz, H-α), 7.72 (1H, d, J = 9.6 Hz, H-2'), 7.61 (2H, d, J = 8.4 Hz, H-2),7.44 (1H, d, J = 15.2 Hz, H-β), 6.94 (2H, d, J = 8.8 Hz, H-3), 6.75 (1H, d, J= 10 Hz, H-4''), 6.38 (1H, d, J =9.2 Hz, H-3'), 5.59 (1H, d, J = 10 Hz, H-3''), 3.86 (3H, s, OMe), 1.47 (6H, s, 2×Me); 13C-NMR (100.0 MHz, CDCl3):δ191.9 (C-O), 161.8 (C-4'), 160.9 (C-2') , 159.9 (C-4), 144.1 (C-β), 130.5 (C-6'), 130.3 (C-2, 6), 128.1(C-2''), 127.5 (C-1), 117.8 (C-α), 115.9 (C-11''),114.4 (C-3,5), 114.1 (C-1'), 109.4 (C-3'), 108.2 (C-5'), 77.7 (C-3''), 55.4(OMe), 28.3 (2×Me)。以上光谱数据与文献(Singhal AK, Barua NC, Sharma RP, et al. Phytochemistry, 1983, 22(4): 1005-1006.)报道相符,故该化合物鉴定为4-methoxylonchocarpin。
(11)流份 D 4.8g, 用硅胶柱分离(2.5 cm柱子)。用石油醚-乙酸乙酯的混和溶液梯度洗脱(从,8:1,6:1, 4:1,2:1到 1∶1,体积比,每个梯度400 mL)。其中流份D-111~141中有白色粉末析出,抽滤后进一步纯化后得化合物2。其中流份D-216~228中有白色粉末析出,进一步纯化后得化合物3。
化合物2为barbigerone,其结构鉴定如下:
白色无定形粉末,1H-NMR (CDCl3, 400 MHz): δ 8.06 (1H, d, J = 8.4 Hz, H-4''), 7.96 (1H, s, H-2), 7.20 (1H, d, J = 2.0 Hz, H-6'), 7.04 (1H, dd, J =2.0, 8.4 Hz, H-2'), 6.92 (1H, d, J = 8.0 Hz, H-3'), 6.86 (1H, d, J = 8.8 Hz,H-5''), 6.81 (1H, d, J = 10.4 Hz, H-4''), 3.91 (6H, s, 2 × OCH3), 1.50 (6H,s, 2 × CH3). 13C-NMR (CDCl3, 100 MHz): δ175.9 (C-4), 157.3 (C-7), 152.3 (C-10), 151.9 (C-2), 149.1 (C-4'), 148.8 (C-3'), 130.3 (C-5''), 126.7 (C-5),124.7 (C-1'), 121.1 (C-6'), 118.3 (C-10), 115.3 (C-6), 114.9 (C-4''), 112.6(C-2'), 111.2 (C-5'), 109.2 (C-8), 77.7 (C-6''), 56.0 (2 × OCH3), 28.1 (2×CH3)。以上光谱数据与文献(Ye H, Chen L, Li Y, et al. Journal of ChromatographyA, 2008, 1178(1): 101-107)报道相符,故该化合物鉴定为barbigerone。
化合物3为4',5'-dimethoxy-6,6- dimethylpyrano isoflavone,其结构鉴定如下:
白色无定形粉末,1H-NMR (CDCl3, 400 MHz): δ 8.06 (1H, d, J= 8.4 Hz, H-4''),7.96 (1H, s, H-2), 7.20 (1H, d, J = 2.0 Hz, H-6'), 7.04 (1H, dd, J = 2.0, 8.4Hz, H-2'), 6.92 (1H, d, J = 8.0 Hz, H-3'), 6.86 (1H, d, J = 8.8 Hz, H-5''),6.81 (1H, d, J = 10.4 Hz, H-4''), 3.91 (6H, s, 2 × OCH3), 1.50 (6H, s, 2 ×CH3). 13C-NMR (CDCl3, 100 MHz): δ175.9 (C-4), 157.3 (C-7), 152.3 (C-10), 151.9(C-2), 149.1 (C-4'), 148.8 (C-3'), 130.3 (C-5''), 126.7 (C-5), 124.7 (C-1'),121.1 (C-6'), 118.3 (C-10), 115.3 (C-6), 114.9 (C-4''), 112.6 (C-2'), 111.2(C-5'), 109.2 (C-8), 77.7 (C-6''), 56.0 (2 × OCH3), 28.1 (2×CH3)。以上光谱数据与文献(Ye H, Chen L, Li Y, et al. Journal of Chromatography A, 2008, 1178(1): 101-107)报道相符,故该化合物鉴定为4',5'-dimethoxy-6,6- dimethylpyranoisoflavone。
实施例2 化合物对胆碱酯酶的体外抑制活性
根据文献并优化的胆碱酯酶抑制剂筛选模型,对苦檀子中分离得到的化合物进行了活性检测,发现化合物具有较高的抑制活性,其活性见表1。
表1 化合物体外抑制AChE和BChE的活性
化合物编号 | |||
1 | 17.14 ± 2.25 | 5.68 ± 0.39 | 3.03 |
2 | 121.60 ± 4.68 | 21.77 ± 1.06 | 5.63 |
3 | 131.17 ± 13.77 | 2.34 ± 0.05 | 55.98 |
加兰他敏 | 1.60 ± 0.02 | 13.18 ± 0.77 | 0.12 |
Claims (4)
1.具有下列结构的黄酮类化合物及其可药用盐或溶剂化物。
。
2.权利要求1所述之化合物,其名称分别为:
化合物1 为 4-methoxylonchocarpin;
化合物2 为barbigerone;
化合物3为4',5'-dimethoxy-6,6- dimethylpyrano isoflavone。
3.根据权利要求1或2所述化合物的制备途径,其主要来源于任意一种中国产的崖豆藤属植物任一部位,即可以是中国药品市场上常见的崖豆藤药材;可以是干品或鲜品;也可以是药材植物的根、茎、叶、花、种子、皮、果实,也可以是它们的混合物。
4.根据权利要求1和2所述的化合物在制备抗老年痴呆和学习记忆障碍药物中的应用。
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---|---|---|---|---|
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-
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---|---|---|---|---|
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Title |
---|
HAOYU YE, ET AL.: "Cytotoxic and apoptotic effects of constituents from Millettia pachycarpa Benth", 《FITOTERAPIA》 * |
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