CN115177613A - 含木脂素类化合物futoenone的药物组合物和其应用 - Google Patents
含木脂素类化合物futoenone的药物组合物和其应用 Download PDFInfo
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Abstract
本发明公开了如结构式(1)所示的螺环二烯酮型木脂素类化合物futoenone在制备治疗或预防帕金森病和阿尔兹海默病的药物或提高学习记忆功能保健品中的应用。同时公开了以futoenone为有效成分的药物组合物,和其制备方法。属于药物技术领域。药理活性试验证明:本发明的化合物futoenone具备促进神经生长因子(Nerve growth factor,NGF)诱导大鼠肾上腺髓质嗜铬瘤分化细胞(PC12细胞)分化的作用,可用于预防和治疗帕金森病或阿尔兹海默病或用于提高学习记忆。
Description
技术领域:
本发明属于药物技术领域,具体涉及螺环二烯酮型木脂素类化合物futoenone在制备治疗或预防帕金森病和阿尔兹海默病相关药物或提高学习记忆功能保健品中的应用,同时涉及以其为有效成分的药物组合物,和其制备方法。
背景技术:
神经退行性疾病是神经元或髓鞘减少所致的神经系统疾病,随着年龄的增加,患者表现为选择性神经元功能障碍。其中,最常见的神经退行性疾病是阿尔茨海默病(Alzheimer's disease,AD)和帕金森病(Parkinson's disease,PD)。根据国际阿尔茨海默病协会报告,目前全球约有痴呆患者5500万人;据世界卫生组织(WHO)统计,全球现有580万帕金森病,我国患者人数约260万,居世界第一。随着世界人口老龄化加剧,神经退行性疾病的患病人数将持续增加,神经退行性疾病已成为全球迫切解决的问题。
天然产物是自然界的生物历经千百万年进化并通过自然选择保留下来的代谢产物,具有化学结构多样性和生物活性多样性的特点,是创新药物发现的重要来源。据Newman最新统计,在1981-2019年间上市的小分子药物中,有1/3直接或间接来源于天然产物(Journal of Natural Products,2020,83,770-803)。从天然产物中也发现众多神经营养活性成分,具有治疗帕金森病或阿尔兹海默症的潜能。如:从木兰属植物厚朴中发现的厚朴酚(Magnolol)及和厚朴酚(honokiol)、八角属植物假地枫皮中发现的假地枫皮内酯(jiadifenolide)、荚蒾属植物中发现的vibsane二萜类化合物neovibsanin A和neovibsanin B都具有神经营养活性(Journal of Natural Medicines,2020,74,648-671)。
紫玉兰(Magnolia liliflora)为木兰科(Magnoliaceae)木兰属(Magnolia)落叶灌木。紫玉兰与玉兰(Magnolia denudata)同为我国两千多年的传统花卉,在我国大部分城市均有栽培,并已被引种至欧美各国,其树皮、叶和花蕾均可入药,常用作镇痛消炎剂。据《新华本草纲要》记载,紫玉兰具有祛风散寒,通鼻窍的功效,用于治疗鼻塞、鼻渊、风寒头痛、浊涕等症,是民间药材辛夷的重要来源之一(《新华本草纲要》,上海科学技术出版社,1990,468-469.)。紫玉兰化学成分研究较少,仅见少量木脂素类成分报道(Phytochemistry,1983,22,763-766;Phytochemistry,1982,21,747–750)并发现部分化合物具有抗炎和抗氧化活性(Industrial Crops and Products,2018,125,416-424)。
迄今为止,未发现螺环二烯酮型木脂素类化合物futoenone的药理活性的报道。
发明内容:
针对现有技术存在的上述不足之处,本发明的目的在于:提供螺环二烯酮型木脂素类化合物futoenone,以其为活性成分的药物组合物,其制备方法,以及该类化合物及药物组合物在制备治疗或预防帕金森病和阿尔兹海默病相关药物或提高学习记忆功能保健品中的应用。药理活性试验证明本发明的化合物futoenone促进神经生长因子(Nervegrowth factor,NGF)诱导大鼠肾上腺髓质嗜铬瘤分化细胞(PC12细胞)分化的作用。
为了实现本发明的上述目的,本发明提供了如下的技术方案:
如下结构式所示的螺环二烯酮型木脂素类化合物futoenone在制备治疗或预防帕金森病和阿尔兹海默病的药物中的应用,
螺环二烯酮型木脂素类化合物futoenone在制备提高学习记忆功能保健品中的应用。
螺环二烯酮型木脂素类化合物futoenone的制备方法,包括以下工艺步骤:取晒干后的紫玉兰叶,粉碎并用95%乙醇冷浸提取三次,合并三次提取液,减压浓缩,得到总浸膏,该浸膏分散于水中用于乙酸乙酯萃取,萃取物经反相中压液相色谱MCI树脂进行分离,用甲醇/水体积比为30:70、40:60、50:50、60:40、70:30、80:20、90:10和100:0梯度洗脱,经检测合并成13个组份Fr.1~Fr.13;组份6经硅胶柱层析,用石油醚/乙酸乙酯4:1洗脱,得到6个亚组分Fr.6.1~Fr.6.6,其中组分Fr.6.3经硅胶柱层析,石油醚/丙酮7:3和凝胶SephdexLH-20柱层析,氯仿/甲醇1:1洗脱,分离得到化合物futoenone。
螺环二烯酮型木脂素类化合物futoenone通过促进神经生长因子诱导PC12细胞的分化从而实现神经营养作用。
本发明此外还提供了包含螺环二烯酮型木脂素类化合物futoenone和至少一种药学上可接受的载体的药物组合物。
上面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,水、葡萄糖、乳糖、阿拉伯胶等和适合在制备固体、半固体、液体或气溶胶形式的制剂中使用的其他载体。组合物可以另外含有稳定剂,增稠剂,和/或着色剂和香料。
本发明的螺环二烯酮型木脂素类化合物futoenone及其药学上可接受的载体制备而成的组合物可经口或不经过口给药,给药量因药物不同而各有不同,对成人来说,每天1-100mg较合适。
经口服给药时,首先使化合物与常规的药用辅剂如赋形剂、解剂、黏合剂、润滑剂、抗氧化剂、包衣剂、着色剂、芳香剂、表面活性剂等混合,将其制成颗粒剂、胶囊、片剂等形式给药:非经口给药时可以栓剂、经皮吸收制剂等形式给药。制备上述制剂时,可使用常规的制剂技术。
与现有技术相比,本发明具备如下的优益性:
1.本发明提供了螺环二烯酮型木脂素类化合物futoenone在药学上的新的用途。
2.本发明提供的螺环二烯酮型木脂素类化合物futoenone的制备方法不需要化学合成,以紫玉兰叶为原料进行提取得到,原料来源广泛、成本较低,避免使用大量的有机原料以及复杂的制备过程,绿色环保,操作简单,得率高。
3.本发明的螺环二烯酮型木脂素类化合物futoenone,在10μM浓度下化合物futoenone对NGF诱导PC12细胞的分化率为11.98%。在相同浓度下,阳性对照组(NGF终浓度为50ng/mL)对NGF诱导PC12细胞的分化率为18.49%。该结果提示,化合物futoenone对PC12细胞分化具有显著促进作用,具有治疗帕金森病和阿尔兹海默病的作用。
4.本发明还提供了所述螺环二烯酮型木脂素类化合物futoenone或其药学上可接受的盐或其药物组合物在制备治疗或预防帕金森病和阿尔兹海默病相关药物或提高学习记忆功能保健品中的应用。
附图说明:
图1为本发明的螺环二烯酮型木脂素类化合物的结构示意图;
图2为化合物futoenone对NGF诱导PC12细胞的神经分化作用,其中,Blank:空白对照组;Negative:阴性对照组;Positive:阳性对照组。
具体实施方式:
下面结合附图,用本发明的实施例来进一步说明本发明的实质性内容,但并不以此来限定本发明。根据本发明的实质对本发明进行的改进都属于本发明的范围。
实施例1:
螺环二烯酮型木脂素类化合物futoenone的制备及结构鉴定:
制备方法:取晒干后的紫玉兰叶,粉碎并用95%乙醇冷浸提取三次,合并三次提取液,减压浓缩,得到总浸膏,该浸膏分散于水中用于乙酸乙酯萃取,萃取物经反相中压液相色谱MCI树脂进行分离,用甲醇/水体积比为30:70、40:60、50:50、60:40、70:30、80:20、90:10和100:0梯度洗脱,经检测合并成13个组份Fr.1~Fr.13;组份6经硅胶柱层析,用石油醚/乙酸乙酯4:1洗脱,得到6个亚组分Fr.6.1~Fr.6.6,其中组分Fr.6.3经硅胶柱层析,石油醚/丙酮7:3和凝胶Sephdex LH-20柱层析,氯仿/甲醇1:1洗脱,分离得到化合物futoenone。
结构鉴定:本发明所述化合物分子结构式(1)分别对应化合物futoenone:
化合物futoenone:白色无定型粉末;C20H20O5;ESI-MS m/z:363[M+Na]+。1H-NMR(500MHz,CDCl3)δ:6.65(1H,d,J=1.6Hz,H-2),6.61(1H,dd,J=8.0,1.7Hz,H-5),6.72(1H,d,J=8.0Hz,H-6),2.52(1H,m,H-7),2.02(1H,m,H-8),0.55(1H,d,J=6.5Hz,H-9),5.76(1H,s,H-3'),5.45(1H,s,H-6'),2.36(1H,m,H-7'a),2.15(1H,d,J=11.4Hz,H-7'b),5.01(1H,t,J=5.7Hz,H-8'),2.26(1H,m,H-9'a),1.69(1H,dd,J=13.7,12.0Hz,H-9'b),3.64(3H,s,5'-OCH3),5.90(2H,s,-OCH2O-);13C-NMR(125MHz,CDCl3)δ:137.2(C-1),107.6(C-2),147.8(C-3),146.3(C-4),108.3(C-5),121.0(C-6),46.1(C-7),45.4(C-8),14.3(C-9),50.2(C-1'),180.1(C-2'),101.3(C-3'),183.1(C-4'),153.2(C-5'),109.0(C-6'),43.5(C-7'),81.8(C-8'),37.9(C-9'),101.0(-OCH2O-),55.2(5'-OCH3)。经与文献报道futoenone(Tetrahedron Letters 1968,9,2003-2008;中药材,2012,35,53-56.)的1H和13C核磁数据比对,鉴定为同一个化合物。
实施例2:
螺环二烯酮型木脂素类化合物futoenone对NGF诱导PC12细胞的神经分化作用:
(1)实验方法:
PC12细胞采用Ham's F12K+12.5%HS+2.5%FBS+100U/mL双抗培养基进行培养,取对数生长期PC12细胞,胰酶消化,制备细胞悬液。将细胞悬液离心5min弃上清液,加入新的培养基使细胞浓度调至5×104cells/ml。接种PC12细胞于48孔板,放入细胞培养箱培养。吸出原培养基,加入含Ham's F12K+2.5%FBS的培养基,5ng/mL的NGF和待测化合物。设置空白对照组(不加NGF),阳性对照组(NGF终浓度为50ng/mL),阴性对照组(NGF终浓度为5ng/mL),化合物组(终浓度为10μM),同时加入终浓度为5ng/mL的NGF诱导72h。之后每天观察细胞分化情况,统计细胞分化比例。
(2)实验结果:
实验表明与阴性对照组相比(4.58%),在10μM浓度下化合物futoenone对NGF诱导PC12细胞的分化率为11.98%。在相同浓度下,阳性对照组(NGF终浓度为50ng/mL)对NGF诱导PC12细胞的分化率为20.49%。该结果提示,化合物futoenone对PC12细胞分化具有显著促进作用,具有治疗帕金森病和阿尔兹海默病的作用。
实施例3
取螺环二烯酮型木脂素类化合物futoenone,和赋形剂,按照质量比分别为1:5、1:5.5、1:6、1:6.5、1:7、1:7.5、、1:8、1:8.5、1:9、1:9.5、1:10混合均匀,制粒压片。
实施例4
取螺环二烯酮型木脂素类化合物futoenone,和赋形剂按照质量比为5:1混合均匀,分别采用常规的胶囊剂、颗粒剂和冲剂的制备方法,制备得到化合物胶囊、颗粒剂和冲剂。
实施例5
取螺环二烯酮型木脂素类化合物futoenone,和赋形剂按照质量比为3:1混合均匀,分别采用常规的胶囊剂、颗粒剂和冲剂的制备方法,制备得到胶囊、颗粒剂和冲剂。
实施例6
本发明的螺环二烯酮型木脂素类化合物futoenone可用于制作功能保健品,用作保健品时,可直接食用,或配以保健品常规辅料制作而成。
颗粒剂的制备工艺采用:螺环二烯酮型木脂素类化合物futoenone 3份,糊精2份,适量50%乙醇。将上述原辅料按照常规制备颗粒剂的工艺制备,即先对原辅料进行检验称重—制软材—制粒—干燥—整粒—成品分装。颗粒剂规格:20g/袋。为便携式制剂,配料简单,最大限度保持了营养成分,可增强免疫力,提高学习记忆等,老少皆宜,适合各类人群使用。
虽然本发明已以较佳实施例公开如上,但其并非用以限定本发明,任何熟悉此技术的人,在不脱离本发明的精神和范围内,都可做各种的改动与修饰,因此本发明的保护范围不局限于申请文件所界定的内容。
Claims (9)
2.权利要求1中结构式所示的螺环二烯酮型木脂素类化合物futoenone在制备提高学习记忆功能保健品中的应用。
3.药物组合物,其中含有权利要求1中结构式所示的螺环二烯酮型木脂素类化合物futoenone和药学上可接受的载体。
4.根据权利要求3所述的药物组合物,其特征在于,所述的药物组合物为微粒给药系统,剂型为片剂、胶囊、丸剂、颗粒剂、缓释制剂、控释制剂。
5.权利要求3所述的药物组合物在制备治疗或预防帕金森病或阿尔兹海默病的药物中的应用。
6.权利要求3所述的药物组合物在制备提高学习记忆功能保健品中的应用。
7.根据权利要求1或5所述的应用,其特征在于,所述的螺环二烯酮型木脂素类化合物futoenone是通过促进神经生长因子诱导PC12细胞的分化从而实现神经营养作用。
8.权利要求1中结构式所示的螺环二烯酮型木脂素类化合物futoenone的制备方法,其特征在于,该方法包括下述步骤:取晒干后的紫玉兰叶,粉碎并用95%乙醇冷浸提取三次,合并三次提取液,减压浓缩,得到总浸膏,该浸膏分散于水中用于乙酸乙酯萃取,萃取物经反相中压液相色谱MCI树脂进行分离,用甲醇/水体积比为30:70、40:60、50:50、60:40、70:30、80:20、90:10和100:0进行梯度洗脱,经检测合并成13个组份Fr.1~Fr.13;组份6经硅胶柱层析,用石油醚/乙酸乙酯4:1洗脱,得到6个亚组分Fr.6.1~Fr.6.6,其中组分Fr.6.3经硅胶柱层析,石油醚/丙酮7:3和凝胶Sephdex LH-20柱层析,氯仿/甲醇1:1洗脱,分离得到化合物futoenone。
9.权利要求3所述的药物组合物的制备方法,其特征在于,该方法包括下述步骤:取晒干后的紫玉兰叶,粉碎并用95%乙醇冷浸提取三次,合并三次提取液,减压浓缩,得到总浸膏,该浸膏分散于水中用于乙酸乙酯萃取,萃取物经反相中压液相色谱MCI树脂进行分离,用甲醇/水体积比为30:70、40:60、50:50、60:40、70:30、80:20、90:10和100:0进行梯度洗脱,经检测合并成13个组份Fr.1~Fr.13;组份6经硅胶柱层析,用石油醚/乙酸乙酯4:1洗脱,得到6个亚组分Fr.6.1~Fr.6.6,其中组分Fr.6.3经硅胶柱层析,石油醚/丙酮7:3和凝胶Sephdex LH-20柱层析,氯仿/甲醇1:1洗脱,分离得到化合物futoenone;然后再加入药学上可接受的载体。
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