CN104224796A - 齐墩果烷型三萜类酯衍生物抗神经退行性药物用途 - Google Patents
齐墩果烷型三萜类酯衍生物抗神经退行性药物用途 Download PDFInfo
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Abstract
本发明提供齐墩果烷型五环三萜类酯衍生物在制备防治老年痴呆症药物中的应用,所述老年痴呆症包括神经退行性疾病。所述药物是齐墩果烷型五环三萜类酯衍生物与药学上可接受的载体或赋形剂制成。本发明所述的齐墩果烷型五环三萜类酯衍生物具有显著的类似神经生长因子的活性,可以在制备预防及治疗老年痴呆症等神经退行性疾病药物中应用。本发明的齐墩果烷型五环三萜类酯衍生物的结构式:
Description
技术领域
本发明属医药技术领域,具体涉及齐墩果烷型五环三萜类酯衍生物及其在预防及治疗老年性痴呆等神经退行性疾病中的应用。
背景技术
老年人口的快速增长,使得人们更加关心该群体的健康状况,而老年痴呆症则严重影响老年人身体健康,其已成为成年人死亡的四位主要病因之一。在国际阿尔茨海默症协会2009年报告中指出:2010年,全世界约有3600万人患有痴呆症,且将会以每20年增长一倍的速度,在2030年达到6600万人,而2050年将达到1亿1540万人,中低收入国家患者数量将占到全球总数的71%。在2010年报告中,全球由于老年痴呆症导致的社会总成本大约为6040亿美元,超过全球GDP的1.0%。
我国老年痴呆患者估计超过500万, 约占世界总病例数的1/4;而且,随着我国人口老龄化进程的加快,这个数字将更为庞大,给社会稳定与发展带来重大的影响。据统计,中国老年性痴呆症的发病率65岁以上是5%,70岁以上是10%,80岁以上是30%,到了85岁以上则高达40%。再过20年,如今的中年人都将步入老年人的行列,痴呆症患者数量将急剧增加,老年人的健康也必将关系到整个社会的稳定与发展。因此,研究和开发有效的预防治疗老年痴呆等神经退行性疾病的药物已成为全世界迫切需要解决的医学问题。
在老年痴呆症三大分类中,AD是发病率最高,也是最重要的一种痴呆型疾病。AD是由神经退行性病变、脑血管病变、感染、外伤、肿瘤、营养代谢障碍等多种原因引起的一组症候群,是病人在意识清醒的状态下出现的持久的全面的智能减退,表现为记忆力、计算力、判断力、注意力、抽象思维能力、语言功能减退,情感障碍,日常生活能力和工作能力进行性减退直至丧失,并有各种神经精神症状和行为障碍。AD的确切病理机制尚不清楚,目前主要学术观点有以下几种:1.β淀粉样多肽(Aβ)毒性及沉积;2.胆碱能缺失学说;3.神经退行性病变(Neurodegeneration);4.其它多种因素,如基因突变学说、氧化应激学说。
研究表明,神经营养因子对神经发育和成年神经系统的疾病过程都有重要的影响。在神经退行性变动物模型中,发现神经生长因子(nerve growth factor,NGF)能阻止或减少神经元的退变。NGF是人类发现的第一个神经营养因子,也是最重要的神经营养因子;是一种对神经细胞的生长、发育、分化和功能保持等方面有重要调控作用的生物活性多肽;对神经萎缩、神经变性、外伤修复等神经疾病的治疗有显著效果。研究发现,NGF一定程度可阻止AD进展,其促进神经生长和神经保护作用是长期的研究热点。然而,它是一个由100多个氨基酸组成的多肽;由于分子量大和极性强等原因,不能通过血脑屏障(Blood Brain Barrier),并且难以大规模制备等诸多因素,局限了它的实际临床应用,NGF除脑内手术直接投药之外还没有找到更好的治疗方法。因此,寻找具有类似NGF活性(NGF mimics)或能增强其活性(NGF enhancer)并且能通过血脑屏障的低分子化合物就自然成为了研究热点。由于PC12细胞(Pheochromocytoma cells,从大鼠肾上腺嗜铬细胞克隆得到),具有神经细胞的一般特征和可传代特点,在NGF的作用下细胞会停止分裂,长出突起,转化成神经元样细胞。因此,在细胞分子水平研究NGF的功能PC12细胞是一个很好的模型。目前,已经有NGF mimics在三期临床试验阶段。
近来,本研究组从中药饿蚂蝗中分离纯化得到齐墩果烷型五环三萜类酯化合物,且发现其具有显著地拟神经生长因子活性。迄今为止,尚未有此类化合物具有类似NGF活性的相关报道。以齐墩果烷型五环三萜类酯化合物作为先导物,设计并合成一系列衍生物,广泛开展其体外活性研究,寻找该类物质的构效关系。如果能找到具有潜在的更优异活性和/或更低毒性的化合物,并能用于预防及治疗老年痴呆症等神经退行性疾病,将具有重要的现实意义。
发明内容
本发明的目的是提供齐墩果烷型五环三萜类酯衍生物式(Ⅰ)在制备防治老年痴呆症药物中的应用,所述老年痴呆症包括神经退行性疾病。
本发明提出的齐墩果烷型五环三萜类酯衍生物的结构式如下:
式中:
R1和R2不同,分别选自羟基或R,在R中:A1~A5可分别选自氢、羟基、酯基、氟、氯、溴、碘、巯基、氨基、氰基、硝基、磺酸基、三氟甲基、丙烯基、烷基、烷氧基、取代苯基;A6可为氧、硫、氮;A7可选自氧、硫;A8-A9可为碳原子数从1至20的直链或支链饱和烷基或不饱和烷基;
R3可选自羟基、酯基、氟、氯、溴、碘、巯基、氨基、氰基、硝基、磺酸基、三氟甲基、丙烯基、烷基、烷氧基、取代苯基。
本发明进一步还提供一种预防老年痴呆症等神经退行性疾病的药物组合物,该药物组合物含有生理有效量的(Ⅰ)所示的齐墩果烷型五环三萜类酯化合物及其衍生物和药学上可接受的载体或稀释剂。
这里所述的药学上可接受的载体是指药学领域常规的药物载体,例如稀释剂、赋形剂如是等,填充剂如淀粉、蔗糖、微晶纤维素等;粘合剂如淀粉浆、羟丙纤维素、明胶、聚乙二醇等;湿润剂如硬脂酸镁、微粉硅胶、聚乙二醇类等;吸收促进剂聚山梨脂、卵磷脂等,表面活性剂伯洛沙姆、脂肪酸山梨坦、聚山梨脂等等,另外还可以在组合物中加入其它辅剂如香味剂、甜味剂等。
本发明所述的齐墩果烷型五环三萜类酯化合物及其衍生物可以以单位剂量形式给药,给药途径可为肠道和非肠道,包括口服、肌肉、皮下和鼻腔。
本发明所述的化合物给药途径可为静脉给药。注射包括静脉注射、肌肉注射、皮下注射和穴位注射。
本发明的药物组合物的各种剂型可以按照药学领域的常规生产方法制备,例如使活性成分与一种或多种载体混合,然后将其制成所需的剂型。
给药剂型可以是片剂、胶囊剂、分散片、口服液、大输液、小针、冻干粉针、软膏、搽剂或栓剂。
本发明所述的齐墩果烷型五环三萜类酯衍生物具有显著的类似神经生长因子的活性,可以在制备预防及治疗老年痴呆症等神经退行性疾病药物中获得应用。
附图说明
图1是齐墩果烷五环三萜类酯衍生物经48小时后PC12细胞神经突起分化率。
图2是饿蚂蝗酯层活性组分(A)延长酵母细胞的复制性寿命。
图3是饿蚂蝗活性组分(B)延长酵母细胞的复制性寿命。
图4是饿蚂蝗活性组分(C)延长酵母细胞的复制性寿命。
图5是化合物(1)延长酵母细胞的复制性寿命。
图6是化合物(2)的衍生物延长酵母细胞的复制性寿命。
图7是化合物(3)的衍生物延长酵母细胞的复制性寿命。
具体实施方式
本发明通过实施例和附图作进一步的详细说明,但不应将此理解为本发明上述主题的范围仅限于下述的实例,凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1
化合物I-1a和I-1b的制备方法:
25 ml茄型瓶中用 2 ml 二氯甲烷和2 ml吡啶溶解化合物(1)[3,23,28-三羟基-12-齐墩果烯-3-咖啡酸酯(3,23,28-trihydroxy-12-oleanene-3-caffeate)](10 mg),加入0.5 mg DMAP(4-二甲氨基吡啶),搅拌,加入100 μl 乙酸酐,旋干反应液,用水和乙酸乙酯进行溶剂分配,回收酯层,并用PTLC以及HPLC纯化酯层样品,得到化合物I-1a和I-1b。
化合物I-1a的理化性质:白色固体,高分辨质谱显示出其分子式为C47H64O10(HR ESI-TOF-MS m/z (M+Na)+ Calcd. for C47H64O10Na: 811.4392, Found: 811.4422);1H NMR (500 MHz, CDCl3) 7.57 (d, J = 16.0 Hz, 1H), 7.39 (dd, J = 1.88, 8.34 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.34 (d, J = 16.0 Hz, 1H), 5.21 (brt, 1H), 4.94 (dd, J = 11.7, 4.7 Hz, 1H), 4.00 (dd, J = 25.5, 11.3 Hz, 2H), 3.68 (dd, J = 11.3, 8.3 Hz, 2H), 2.30 (s, 3H), 2.30 (s, 3H), 2.07 (s, 6H), 2.06 (s, 6H), 1.15 (s, 3H), 1.01 (s, 3H), 0.95 (s, 3H), 0.91 (s, 3H), 0.89 (s, 3H), 0.87 (s, 3H)。
13C NMR (125 MHz, CDCl3) 171.56, 171.12, 168.23, 168.16, 166.21, 143.76, 143.53, 142.81, 142.50, 133.42, 126.54, 124.02, 122.83, 122.81, 119.77, 77.41, 77.36, 77.16, 76.91, 75.04, 70.90, 65.82, 51.04, 47.97, 47.77, 46.27, 42.63, 41.68, 40.82, 39.85, 38.00, 36.74, 35.88, 34.07, 33.28, 32.27, 31.49, 31.02, 25.97, 25.60, 23.66, 23.20, 22.24, 22.14, 21.15, 21.12, 20.82, 20.78, 18.09, 16.81, 16.10, 13.37。
化合物I-1b的理化性质:白色固体,高分辨质谱显示出其分子式为C43H60O8(HR ESI-TOF-MS m/z (M+Na)+ Calcd. for C39H61O6Na: 727.4195, Found: 727.4212); 1H NMR (500 MHz, CDCl3) 7.49 (d, J = 15.9 Hz, 1H), 7.04 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.18 (d, J = 15.9 Hz, 1H), 5.20 (s, 1H), 4.93 (dd, J = 11.3, 5.0 Hz, 1H), 3.98 (dd, J = 11.6 , 57.7 Hz, 2H), 3.72 (dd, J = 23.5, 11.3 Hz, 2H), 2.08 (s, 3H), 2.07 (s, 3H), 1.15 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.91 (s, 3H), 0.89 (s, 3H), 0.87 (s, 3H)。
13C NMR (125 MHz, CDCl3) 171.87, 171.81, 167.43, 146.76, 145.21, 144.34, 143.72, 127.35, 122.84, 122.41, 115.58, 115.46, 114.29, 74.65, 71.06, 66.02, 51.01, 47.96, 47.76, 46.27, 42.63, 41.68, 40.88, 39.86, 38.01, 36.77, 35.88, 34.07, 33.28, 32.26, 31.50, 31.02, 25.99, 25.62, 23.66, 23.28, 22.24, 21.17, 18.05, 16.81, 16.12, 14.28, 13.39。
化合物 I-1c的制备方法:
将10 mg 化合物(1),5 mg碳酸锂溶于2 mL干燥的DMF (N,N-二甲基甲酰胺)中,搅拌下滴加0.6 mL 碘甲烷。室温反应4天。将反应液倾倒入5 mL水中,加入10%盐酸溶液中和,无水乙醚萃取(3 × 4 mL)。合并有机相,依次用水(2 × 5 mL)、饱和食盐水(5 mL)洗涤,无水硫酸钠干燥,浓缩,用制备薄层及高效液相色谱分离得到化合物I-1c。
化合物 I-1c的理化性质:白色固体,高分辨质谱显示出其分子式为C40H58O6(HR ESI-TOF-MS m/z (M+Na)+ Calcd. for C40H59O6: 635.4306, Found: 635.4307)。1H NMR (500 MHz, CDCl3) 7.61 (d, J = 15.9 Hz, 1H), 7.15 (s, 1H), 7.04 (d, J = 9.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 15.9 Hz, 1H), 5.19 (s, 1H), 5.01 (dd, J = 12.1, 4.5 Hz, 1H), 3.93 (s, 3H), 3.55 (d, J = 11.0 Hz, 1H), 3.40 (d, J = 12.6 Hz, 1H), 3.22 (d, J = 11.0 Hz, 1H), 2.94 (d, J = 12.7 Hz, 1H), 1.18 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.89 (s, 3H), 0.87 (s, 3H), 0.73 (s, 3H)。
13C NMR (125 MHz, CDCl3) 168.52, 148.79, 146.04, 145.49, 144.51, 128.07, 122.35, 122.16, 116.04, 113.20, 110.65, 74.68, 69.90, 64.64, 56.16, 47.60, 46.81, 46.58, 42.83, 42.48, 41.94, 39.95, 38.41, 37.09, 36.80, 34.22, 33.33, 32.35, 31.17, 31.11, 26.20, 25.67, 23.74, 22.17, 21.21, 17.84, 16.88, 16.39, 14.35, 13.11。
化合物I-2a和I-2b的制备方法:
25 mL茄型瓶中用2 mL二氯甲烷和2 mL吡啶溶解化合物( 2)[3,23,28-三羟基-12-齐墩果烯-23-咖啡酸酯(3,23,28-trihydroxy-12-oleanene-23-caffeate)](10 mg),加入0.5 mg DMAP(4-二甲氨基吡啶),搅拌,加入100 乙酸酐,旋干反应液,用水和乙酸乙酯进行溶剂分配,回收酯层,并用PTLC以及HPLC纯化酯层样品,得到化合物I-2a和I-2b。
化合物I-2a的理化性质:白色固体,高分辨质谱显示出其分子式为C47H64O10(HR ESI-TOF-MS m/z (M+Na)+ Calcd. for C47H64O10Na: 811.4392, Found: 811.4432);1H NMR (500 MHz, CDCl3) 7.61 (d, J = 16.0 Hz, 1H), 7.41 (dd, J = 8.4, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 16.0 Hz, 1H), 5.20 (s, 1H), 4.84 (dd, J = 11.6, 4.7 Hz, 1H), 4.09 (d, J = 11.6 Hz, 1H), 4.01 (d, J = 11.0 Hz, 1H), 3.78 (d, J = 11.7 Hz, 1H), 3.69 (d, J = 11.0 Hz, 1H), 2.31 (s, 3H), 2.30 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H), 1.12 (s, 3H), 1.00 (s, 3H), 0.95 (s, 3H), 0.88 (s, 6H), 0.87 (s, 3H)。
13C NMR (125 MHz, CDCl3) 171.54, 170.85, 168.19, 168.15, 166.45, 143.86, 143.66, 143.13, 142.56, 133.41, 126.56, 124.08, 123.03, 122.76, 119.28, 74.81, 70.92, 65.65, 48.12, 47.86, 46.27, 42.68, 41.73, 40.93, 39.89, 38.10, 36.81, 35.91, 34.08, 33.28, 32.31, 31.51, 31.03, 26.09, 25.56, 23.68, 23.10, 22.25, 21.43, 21.14, 20.83, 20.77, 18.15, 16.84, 16.16, 14.35, 13.21。
化合物I-2b的理化性质:白色固体,高分辨质谱显示出其分子式为C43H60O8(HR ESI-TOF-MS m/z (M+Na)+ Calcd. for C43H60O8Na: 727.4195, Found: 727.4201);1H NMR (500 MHz, CDCl3) 7.51 (d, J = 15.8 Hz, 1H), 7.04 (d, J = 4.4 Hz, 1H), 6.85 (d, J = 15.2 Hz, 2H), 6.21 (d, J = 15.8 Hz, 1H), 5.20 (s, 1H), 4.85 (s, 1H), 4.00 (dd, J = 19.0, 11.4 Hz, 2H), 3.88 (d, J = 11.3 Hz, 1H), 3.68 (d, J = 14.6 Hz, 1H), 2.08 (s, 3H), 2.05 (s, 3H), 1.14 (s, 3H), 1.00 (s, 3H), 0.95 (s, 3H), 0.91 – 0.85 (m, 9H)。
13C NMR (125 MHz, CDCl3) 171.83, 171.65, 167.46, 146.61, 145.28, 144.22, 143.82, 127.51, 122.78, 122.62, 115.57, 115.30, 114.44, 75.25, 70.96, 65.32, 48.07, 47.86, 46.30, 42.67, 41.73, 40.98, 39.89, 38.10, 36.79, 35.91, 34.08, 33.28, 32.31, 31.51, 31.02, 26.04, 25.59, 23.68, 23.12, 22.27, 21.51, 21.14, 18.11, 16.84, 16.16, 13.31, 13.27。
实施例2
在神经退行性病变动物模型中,研究发现NGF能阻止或减少神经元的退变,一定程度可阻止AD进展,具有促进神经生长和神经保护作用。由于PC12细胞具有神经细胞的一般特征,在NGF的作用下PC12细胞会停止分裂,长出突起,转化成神经元样细胞。因此,采用PC 12细胞作为有效的活性鉴定系统,筛选具有活性的有效成分,将成为治疗老年性痴呆的有效药物。
实验方法:
1)PC 12细胞的培养:接20×104个PC 12细胞于100 mm的培养皿中,含10 mL DMEM培养基(其中含10%马血清、5%胎牛血清),两天后更换一次培养基,再过三天继代。先用PBS将细胞洗两次,再加入10 mLPBS于培养皿中,在37 ℃,5% CO2的培养箱内培养10分钟,吹洗,转移到15 mL的一次性离心管,离心后血球计数板上计数。24孔细胞培养板每孔先加入1 mL含血清的DMEM培养基,细胞计数后,每孔接2×104个细胞,CO2培养箱培养24小时后加样。
2)活性测试:以DMSO为阴性对照,NGF 40 ng为阳性对照,将所合成的衍生物配置成不同浓度的DMSO溶液。用1 mL含1% DMSO和样品的DMEM溶液(不含血清)将24孔细胞板的每孔原培养基取代后,放入37 ℃,5% CO2的培养箱中培养。倒置显微镜下每隔24小时、连续6天观察细胞形态变化,记录细胞的神经突起分化率 (神经突起长于胞体直径一倍的细胞数目与视野下总细胞数目的比值),每个视野下约100个细胞,随机选取3处,并统计作图分析。
3)实验结果:
在一定浓度下,加入化合物I-1a, I-1b, I-1c, I-2a和I-2b后48小时,所有样品均具有促进PC 12细胞突起伸长的作用,显示出显著的拟神经生长因子活性,参见图1,图中DMSO为阴性对照;NGF :40 ng/mL,阳性对照;浓度单位:;** P<0.01, *** P<0.001。
Claims (3)
1.一种齐墩果烷型五环三萜类酯衍生物在制备防治老年痴呆症药物中的应用,所述老年痴呆症包括神经退行性疾病,所述齐墩果烷型五环三萜类酯衍生物的结构式:
式中:
R1和R2不同,分别选自羟基或R,在R中:A1~A5可分别选自氢、羟基、酯基、氟、氯、溴、碘、巯基、氨基、氰基、硝基、磺酸基、三氟甲基、丙烯基、烷基、烷氧基、取代苯基;A6可为氧、硫、氮;A7可选自氧、硫;A8-A9可为碳原子数从1至20的直链或支链饱和烷基或不饱和烷基;
R3可选自羟基、酯基、氟、氯、溴、碘、巯基、氨基、氰基、硝基、磺酸基、三氟甲基、丙烯基、烷基、烷氧基、取代苯基。
2.根据权利要求1所述的一种齐墩果烷型五环三萜类酯衍生物在制备防治老年痴呆症药物中的应用,其特征在于,所述药物是齐墩果烷型五环三萜类酯衍生物与药学上可接受的载体或赋形剂制成。
3.根据权利要求2所述的应用,其特征在于,所述药物的制剂形式为液体制剂或固体制剂,给药途径为肠道和非肠道。
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CN115246868A (zh) * | 2021-04-27 | 2022-10-28 | 中国医学科学院药物研究所 | 一类五环三萜类化合物在治疗神经退行性疾病中的用途 |
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CN108840899B (zh) * | 2018-07-25 | 2020-11-10 | 浙江大学 | 一种五环三萜类化合物及其衍生物和应用 |
CN115246868A (zh) * | 2021-04-27 | 2022-10-28 | 中国医学科学院药物研究所 | 一类五环三萜类化合物在治疗神经退行性疾病中的用途 |
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