CN103420805B - 天麻中具有神经细胞保护活性的多聚苄类衍生物 - Google Patents
天麻中具有神经细胞保护活性的多聚苄类衍生物 Download PDFInfo
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Abstract
本发明公开了天麻中具有神经细胞保护活性的多聚苄类衍生物，具体涉及中药天麻中分离鉴定的一类新型化合物，所述新型化合物为多聚苄类衍生物，优选三聚苄和四聚苄衍生物。还公开了这类化合物在制备药物中的应用，这类化合物对去血清和鱼藤酮等化学试剂诱导的神经细胞损伤有保护活性，可用于治疗和辅助治疗各种神经系统疾病等，特别是帕金森氏病和老年痴呆。
Description
技术领域
本发明属于天然药物技术领域，具体地，本发明涉及从中药天麻中提取分离纯化得到的新型多聚苄类化合物，及其衍生物和药用盐类在制备预防和治疗各种神经系统疾病，特别是帕金森氏病和老年痴呆。
背景技术
天麻为兰科多年生寄生草本植物天麻Gastrodia elata Blume的块茎，生于湿润的林下，现多以栽培品应用，主要产于四川、云南、贵州、湖北和陕西等地。天麻药用首载于《神农本草经》，列为上品；《本草纲目》记载天麻乃肝经气分之药；《开宝本草》中称天麻主诸风湿痹，四肢拘挛，小儿风痫、惊气，利腰膝，强筋骨；《全国中草药汇编》中记载天麻主治高血压、眩晕、头痛、口眼歪斜、肢体麻木、小儿惊厥等症。现行《中华人民共和国药典》中对天麻的功效和作用描述为“具平肝熄风、祛风定惊的功效；用于头晕目眩，肢体麻木，小儿惊风，癫痫，高血压，耳源性眩晕”。
天麻化学成分的现代研究表明其中含有以下类型的成分：
简单的4-羟基苄醇衍生物，如4-羟基苄醇、4-羟基苄基甲基醚、4-羟基苄基乙基醚、4-羟基苯甲醛、4-羟基苯甲酸、3,4-二羟基苯甲醇、3-甲氧基-4-羟基苯甲醛、天麻素、4-（β-D-吡喃葡萄糖氧）苯甲醛、4-羟苄基-β-D-吡喃葡萄糖苷、3,5-二甲氧基苯甲酸-4-O-β-D-吡喃葡萄糖苷、4-甲基苯基-1-O-β-D-吡喃葡萄糖苷；
双4-羟基苄醚和多4-羟基苄基醚类，如4-(4′-羟基苄氧基)苄醇、4-(4′-羟基苄氧基)苄基甲基醚、4-(4′-羟基苄氧基)苄基乙基醚、双(4-羟基苄基)硫醚、双(4-羟基苄基)亚砜、双(4-羟基苄基)羟胺、双-4-羟基苄基醚单-O-β-D-吡喃葡萄糖苷、4-[4′-(4″-羟基苄氧基)苄氧基]苄醇、4-[4′-(4″-羟基苄氧基)苄氧基]苄基甲基醚；二聚和三聚苄衍生物，如3-(4-羟基苄基)-4- 羟基苄醇、4-羟基-3-(4-羟基苄基)苄基4-羟基苄基醚、2,4-双(4-羟基苄基)-苯酚；
柠檬酸及其简单酯和苄酯苷类，如柠檬酸、柠檬酸单甲酯、柠檬酸6-甲酯、柠檬酸1,5-二甲酯、派立辛（parishin）、派立辛B（parishin B）、派立辛C（parishin C）、1-[4-(β-D-吡喃葡萄糖氧基)苄基]柠檬酸酯、6-[4-(β-D-吡喃葡萄糖氧基)苄基]柠檬酸酯、1,5双-[4-(β-D-吡喃葡萄糖氧基)苄基]-6-[4-(β-D-吡喃葡萄糖基(1→6)-β-D-吡喃葡萄糖氧基)苄基]柠檬酸酯、1,6-双-[4-(β-D-吡喃葡萄糖氧基]-5-甲基柠檬酸酯；
其他有机酸及其衍生物类，如琥珀酸、棕榈酸(palmitic acid)、甘油-1-软脂酸单酯、硬脂酸、苯甲酸、二十二烷酸、三十一酸、阿魏酸β-D-吡喃葡萄糖酯苷；
植物中常见的甾醇类，如豆甾醇、β-谷甾醇、胡萝卜苷、3β-(4-羟基苄氧基)-谷甾烷；
核苷、碱基、氨基酸和三肽类，如腺嘌呤核苷、尿嘧啶核苷、尿嘧啶、腺嘌呤、N6-(4-羟基苄基)-腺嘌呤核苷、N2-(4-羟基苄基)-鸟嘌呤核苷、赖氨酸、焦谷氨酸、S-(4-羟基苄基)-谷胱甘肽；
糖类，如蔗糖、GE-Ⅰ(葡萄糖、甘露糖、木糖、阿拉伯糖)、GE-Ⅱ(葡萄糖、甘露糖)、GE-Ⅲ(葡萄糖及微量甘露糖)、TM1(L-鼠李糖、L-岩藻糖、D-木糖、D-甘露糖、D-葡萄糖)、TM2、TM3等；
其他成分，如cymbinodin A、维生素A、5-羟甲基呋喃甲醛、双-（5-羟甲基呋喃甲醛）醚、lycopene。
此外，天麻中含有大量微量元素，其中Cr含量最高，Fe、Zn、Mn、Cu、Se次之。
天麻提取物药理活性的现代研究表明，主要有作用包括对神经中枢系统的镇静、抗惊厥和镇痛作用，对心血管系统的强心降压作用，耐缺氧作用和增强免疫功能的作用。
天麻中分离鉴定化学成分药理活性的研究主要包括以下方面。
早期研究发现，天麻浸膏具有明显的对抗戊四氮诱导的阵挛性惊厥作用。而后，国内较早发现天麻对抗戊四氮作用的物质基础是天麻素及其苷元，后期有研究者通过LC-MS/MS动态监测小鼠脑和血液中的天麻素及对 羟基苄醇的含量研究其药代动力学，充分说明这两种物质可以较好的透过血脑屏障进入脑中发挥作用；进一步的研究发现天麻素及其苷元不能对抗士的宁所引起的惊厥，不能对抗吗啡引起小鼠的举尾反射，提示它们不作用于脊髓中枢，也不是抗精神失常药。国外的研究者进一步提出了天麻素是通过抑制GABA水解酶即琥珀酸半醛脱氢酶（SSADH），从而提高GABA在中枢神经系统含量的假说。台湾学者发现天麻水提物可经由c-Jun氨基末端激酶调节活化剂蛋白-1从而对抗由红藻氨酸所引起的惊厥作用。近几年的研究报道进一步证实了天麻水提物及天麻素可显著降低电致小鼠惊厥、戊四氮致小鼠的惊厥率。国外有研究者从天麻甲醇提取物的乙醚流份中发现水杨醛可通过清除氧自由基和调节GABA而起到对小鼠的抗惊厥作用。又有研究表明，天麻甲醇提取物可显著减少由可卡因所致小鼠惊厥的持续时间并延长发作周期，并提出至少部分与GABAA受体有关。除天麻素及其衍生物等，天麻中的香荚兰醛也具有抗惊厥作用，并已经商品化。
研究表明，天麻胶囊能提高血清中羟脯氨酸（HOP）含量，小鼠口服天麻粉后可明显提高RBC中SOD活力，天麻糖复合物能降低血清中过氧化脂质降解产物(MDA)含量，因此天麻具有明显的抗衰老作用。另外，研究发现天麻素对体外培养神经细胞的缺血再灌注损伤有保护作用，天麻微粉水溶液经造模小鼠腹腔注射后具有抗脑缺血再灌注后神经细胞凋亡的作用。
最新的研究表明，天麻的甲醇提取物是通过腺苷A2A受体/环磷酸腺苷/蛋白激酶A/反应结合蛋白途径来保护缺血性神经细胞，其乙醇提取物还可以通过显著的抗氧化和抗细胞凋亡方式，保护由MPP+所致损伤的多巴胺能神经细胞。研究发现天麻的甲醇提取物能够显著的保护受损的PC12细胞，表明其可治疗诸如老年痴呆等神经退行性疾病。且其甲醇提取物及香荚兰醇能够保护受损的多巴胺神经元，提示具有治疗和减缓帕金森病(Parkinson’s disease,PD)病程发展的作用。
老年痴呆（Alzheimer’s diseae,AD）和帕金森病（Parkinson’s diseases,PD）是发生在中老年期的常见的慢性神经退行性疾病，临床表现为学习记忆障碍和运动功能障碍等症状，病理变化为特定脑区神经元进行性死亡或缺失。国内外研究提示，目前治疗老年痴呆疾病主要应用的是胆碱能或胆 碱酯酶抑制剂类药物，如他克林，多奈哌齐，卡巴拉汀等，其通过增加乙酰胆碱的浓度来达到治疗目的。而已经上市的治疗帕金森病的有效药物并不多，如经典的左旋多巴用于治疗PD已有40余年历史，其他比较重要的治疗PD的药物有儿茶酚胺氧甲基转移酶(COMT)抑制剂和单胺氧化酶(MAO)抑制剂。这两类药物的使用可以减低左旋多巴的服药剂量。然而左旋多巴有明显的缺点：用药频繁，早期治疗效果明显，但效果一般只能维持1~5年。由于目前上市的治疗老年痴呆和帕金森病药物缺乏安全性，且需要联合多种药物进行治疗，明显不利于患者的长期使用。因此，兼具安全性和有效性的治疗药物成为现实需要，而不再只是简单缓解疾病症状的药物，因此对于治疗此类神经疾病的需求难以满足。
神经元的死亡与多种因素有关，主要包括环境因素和遗传因素。氧化应激是指机体高活性分子如活性氧自由基(reactive oxygen species,ROS)和活性氮自由基(reactive nitrogen species,RNS)产生与清除，即氧化系统和抗氧化系统之间失衡,从而导致组织损伤。氧化应激参与环境因素与遗传因素诱导的疾病，是多种损伤的最终共同通路，它能够直接导致DNA、蛋白质、脂肪等生物大分子的损伤，从而引发细胞功能紊乱，最终导致细胞死亡。由于脑组织耗氧量大，而脑细胞膜中存在大量的不饱和脂肪酸但内源性抗氧化酶却相对缺乏，因而更易受到氧化应激损伤。因而具有抗氧化应激能力的化合物在治疗神经退行性疾病方面很具潜力。因此，在新药研发中常通过检测氧化应激中活性氧的含量评价化合物的抗氧化能力，以此研究其神经保护的作用机制。
目前老年痴呆（Alzheimer’s diseae,AD）和帕金森病（Parkinson’sdiseases,PD）的发病机制尚不明确，但有研究表明，这两种疾病在发病机制上存在许多共性。主要表现为上述两类疾病均与线粒体损伤和氧化应激所导致的神经元损伤或细胞凋亡密切相关。
鱼藤酮（Rotenone）是一种实验室中常用的神经毒性剂，具有抑制线粒体复合物I的功能，同时也能够诱导氧化应激的产生，最终导致神经元的损伤，这些变化能够部分模拟神经退行性疾病的病理改变，因此被广泛应用于神经退行性疾病如PD和AD发病机制和药效学评价的研究中。有研究表明，神经退行性疾病AD和PD在发病过程中，尤其是脑缺血的发病，有营养物质缺乏的现象，因而通过去血清损伤细胞建立的模型，能够模拟神经系统中营养缺乏而造成的神经元的损伤等现象，可研究具有神经保护功能的化合物。
α-突触核蛋白（α-synuclein，α-syn）是与家族性PD关系非常密切的蛋白之一，该蛋白异常表达后能够导致多巴胺能神经元的死亡。因而针对α-突触核蛋白为靶点建立模型，被应用于与α-突触核蛋白相关疾病的研究。
PC-12细胞是来源于大鼠的嗜铬细胞瘤的细胞系，该细胞系具有神经元的某些特征，如形态、释放神经递质及表达蛋白，因而在神经系统疾病的研究中被广泛应用。本申请中即采用去血清、鱼藤酮及α-突触核蛋白损伤PC12细胞模拟神经系统疾病的变化，研究天麻提取物的神经保护作用。
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尽管通过半个多世纪的研究，文献报道从天麻中得到了如上所述多种多样的化学成分以及天麻提取物和部分天麻成分的药理活性，但是到目前为止，本发明涉及的新型多聚苄类及其衍生物，不但尚无人从天麻中得到，也无人通过分离纯化从其他植物分离得到或通过化学合成的方法制备得到；更无人报道这些化合物或其衍生物具有神经细胞的保护功能。
发明内容
本发明要解决技术问题是，提供一类新的具有神经细胞保护功能的药物。
本发明第一方面提供一种如通式（I）、（Ⅱ）和（Ⅲ）所示的新型三聚和四聚苄类化合物及其衍生物。
本发明第二方面提供一种如通式（I）、（Ⅱ）和（Ⅲ）所示化合物的制备方法。
本发明第三方面提供一种药物组合物，其中包括作为有效成分的如通式（I）、（Ⅱ）和（Ⅲ）所示的三聚和四聚苄类化合物，和制药领域中常用的载体。
本发明第四方面提供如通式（I）、（Ⅱ）和（Ⅲ）所示的三聚和四聚苄类化合物在制备用于治疗和辅助治疗各种神经系统疾病的药物中应用。
所述的各种神经系统疾病包括神经衰弱，帕金森氏病，老年痴呆、血管性痴呆，癫痫，抑郁，中风。本发明所述的化合物包括其衍生物和药效学上可接受的盐。
具体而言，本发明第一方面涉及如通式（I）所示的三聚苄类新型化合物，及其药效学上可接受的盐；
其中，R1和R2分别选自：
有并且只有一个选自
另外一个选自H、OMe、OH、C1-C6烷基（优选甲基，乙基，丙基，异丙基，丁基，异丁基）、乙酸酯、丙酸酯、C4-C16的长链脂肪酸酯、Glu、SO3H、PO3H2；
R、R3、R4、R5、R6和R7各自独立地选自：氢、C1-C6烷基（优选甲基，乙基，丙基，异丙基，丁基，异丁基）、乙酸酯、丙酸酯、C4-C16的长链脂肪酸酯、Glu、SO3H、PO3H2；
Glu表示β-D-吡喃葡萄糖基；SO3H表示硫酰基；PO3H2表示磷酰基。
如通式（II）所示的四聚苄类新型化合物，及其药效学上可接受的盐；
其中，R1、R2和R3分别选自：
有并且只有一个选自
另外两个各自独立地选自选自H、OMe、OH、C1-C6烷基（优选甲基，乙基，丙基，异丙基，丁基，异丁基）、乙酸酯、丙酸酯、C4-C16的长链脂肪酸酯、Glu、SO3H、PO3H2；
R、R4、R5、R6和R7、R8和R9各自独立地选自：氢、C1-C6烷基（优选甲基，乙基，丙基，异丙基，丁基，异丁基）、乙酸酯、丙酸酯、C4-C16的长链脂肪酸酯、Glu、SO3H、PO3H2；
Glu表示β-D-吡喃葡萄糖基；SO3H表示硫酰基；PO3H2表示磷酰基。
如通式（III）所示的四聚苄类新型化合物，及其药效学上可接受的盐；
其中，R1、R2和R3分别选自：
有并且只有一个选自
另外两个各自独立地选自H、OMe、OH、C1-C6烷基（优选甲基，乙基，丙基，异丙基，丁基，异丁基）、乙酸酯、丙酸酯、C4-C16的长链脂肪酸酯、Glu、SO3H、PO3H2；
R、R4、R5、R6和R7各自独立地选自：氢、C1-C6烷基（优选甲基，乙基，丙基，异丙基，丁基，异丁基）、乙酸酯、丙酸酯、C4-C16的长链脂肪酸酯、Glu、SO3H、PO3H2；
Glu表示β-D-吡喃葡萄糖基；SO3H表示硫酰基；PO3H2表示磷酰基。
本发明进一步优选的化合物选自如下群组：
本发明因此还涉及含有作为活性成分的本发明的化合物和常规药物赋形剂或辅剂的药物组合物。通常本发明药物组合物含有0.1-95%重量的本发明化合物。
本发明化合物的药物组合物可根据本领域公知的方法制备。用于此目的时，如果需要，可将本发明的化合物与一种或多种固体或液体药物赋形剂和/或辅剂结合，制成可作为人药或兽药使用的适当的施用形式或剂量形式。
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，给药途径可为肠道或非肠道，如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等，优选口服。
本发明化合物或含有它的药物组合物的给药途径可为注射给药。注射包括静脉注射、肌肉注射、皮下注射和皮内注射等。
给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明提取物或化合物可以制成普通制剂、也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将单位给药剂型制成片剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；湿润剂与粘合剂，如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等；崩解剂，例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；崩解抑制剂，例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；吸收促进剂，例如季铵盐、十二烷基硫酸钠等；润滑剂，例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、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。
例如为了将给药单元制成丸剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等；粘合剂，如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等；崩解剂，如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
例如为了将给药单元制成胶囊，将有效成分本发明提取物或化合物与上述的各种载体混合，并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分本发明化合物制成微囊剂，混悬于水性介质中形成混悬剂，亦可装入硬胶囊中或制成注射剂应用。
例如，将本发明提取物或化合物制成注射用制剂，如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂，这种制剂可以是含水或非水的，可含一种和／或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1，3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外，为了制备等渗注射液，可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油，此外，还可以添加常规的助溶剂、缓冲剂、pH调节剂等。这些辅料是本领域常用的。
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、甜味剂或其它材料。
去血清、鱼藤酮及α-突触核蛋白损伤神经细胞是能够模拟神经退行性疾病如AD和PD部分发病机制的模型。本发明化合物在上述模型中具有显著的保护作用，对鱼藤酮（Rot）诱导的PC12细胞凋亡具有抑制作用，对ROT导致的线粒体膜电位的降低具有改善作用，同时能够降低由鱼藤酮导致的ROS的产生。上述结果表明：本发明化合物及其药效学上可接 受的盐，在制备预防和/或治疗和/或缓解神经系统疾病的药物中的应用。所述的神经系统疾病包括但不限定于帕金森氏病，老年痴呆，血管性痴呆，癫痫，抑郁，神经衰弱或中风。
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。
本发明化合物、药物组合物的给药剂量取决于许多因素，例如所要预防或治疗疾病的性质和严重程度，患者或动物的性别、年龄、体重、性格及个体反应，给药途径、给药次数、治疗目的，因此本发明的治疗剂量可以有大范围的变化。一般来讲，本发明中药学成分的使用剂量是本领域技术人员公知的。可以根据本发明化合物组合物中最后的制剂中所含有的实际药物数量，加以适当的调整，以达到其治疗有效量的要求，完成本发明的预防或治疗目的。本发明化合物的每天的合适剂量范围本发明的提取物或化合物的用量为0.001—150mg/Kg体重，优选为0.01—100mg/Kg体重，更优选为0.01—60mg/Kg体重，最优选为0.1—10mg/Kg体重。上述剂量可以单一剂量形式或分成几个，例如二、三或四个剂量形式给药这受限于给药医生的临床经验以及包括运用其它治疗手段的给药方案。
每一种治疗所需总剂量可分成多次或按一次剂量给药。本发明的化合物、组合物可单独服用，或与其他治疗药物或对症药物合并使用并调整剂量。
本发明还涉及天麻提取物在制备预防或治疗各种神经系统疾病的药物中的应用。所述的各种神经系统疾病包括帕金森氏病、老年痴呆、血管性痴呆、癫痫、抑郁、神经衰弱或中风。天麻提取物含有药物有效剂量的上述本发明的任一化合物。
附图说明
图1：天麻联苄类化合物1，3，4，5，7，8对Rot损伤细胞的保护作用，且呈剂量依赖性。
图2：天麻联苄类化合物1，4，7，8对去血清造成的PC12细胞损伤 具有保护作用。
图3：天麻联苄类化合物1，8，9，11对α-突触核蛋白造成的PC12细胞损伤具有保护作用。
图4：天麻联苄类化合物7，8，对Rot造成的细胞凋亡具有抑制作用，且具有一定的剂量依赖性。图中数值为凋亡细胞的百分比。
图5：天麻联苄类化合物7，8能够抑制Rot所导致的ROS的产生，并具有剂量依赖性（浓度为10-5M，10-6M，10-7M）。图中绿色代表ROS。
图6：化合物7，8能够改善鱼藤酮（Rot）导致的线粒体膜电位的降低。
图7：天麻中新型三聚和四聚苄类化合物提取分离流程图。
具体实施方式
下面的实验实施例可进一步说明本发明，但不以任何方式限制本发明。
实施例1：化合物1-11为从天麻中提取分离纯化的新型三聚和四聚苄类化合物，它们的分离纯化过程和结构鉴定波谱数据如下：
干燥天麻(50kg)粉碎后在室温下用600L去离子水超声提取3次，每次200L，每次超声提取时间为1小时。水提取液减压浓缩至50L后，通过大孔吸附树脂(HPD-100,30Kg)吸附粗分离，用水、30%乙醇、50%乙醇和95%乙醇依次洗脱(分别为3个洗脱柱体积)，得到相应的4个组份Fr.1-Fr.4。50%乙醇洗脱组份Fr.3(1.9Kg)经MCI吸附树脂(CHP 20P,10Kg)吸附分离，以水、30%乙醇、50%乙醇、95%乙醇和丙酮依次洗脱(分别为3个洗脱柱体积)，得到5个组份Fr.3-1-Fr.3-5。水洗脱组份Fr.3-1(66g)用Sephadex LH-20(3Kg)柱色谱分离，以水、30%乙醇、50%乙醇、70%乙醇和95%乙醇依次洗脱(分别为2个洗脱柱体积)，得到5个组份Fr.3-1-1-Fr.3-1-5。30%乙醇洗脱组份Fr.3-1-2(16g)用中压RP-MPLC（ODS,50μm,YMC)分离，以甲醇-水(5-100%)梯度洗脱6个小时，根据薄层色谱检测合并相似的洗脱流份后得到4个亚组份Fr.3-1-2-1-Fr.3-1-2-4。亚组份Fr.3-1-2-3(9.3g)经硅胶柱色谱（200~300 目，150g）分离，以甲醇-氯仿（0-100%）梯度洗脱，薄层色谱检测合并相同洗脱流份后得到5个组份Fr.3-1-2-3-1-Fr.3-1-2-3-5。组份Fr.3-1-2-3-2(0.98g)进一步用Sephadex LH-20(300g)柱色谱分离，以甲醇为流动相，薄层色谱检测合并相同洗脱流份后得到3个组份Fr.3-1-2-3-2-1-Fr.3-1-2-3-2-3。组份Fr.3-1-2-3-2-2(0.31g)和组份Fr.3-1-2-3-2-3(0.26g)分别用高效液相色谱RP-HPLC（ODS,5μm,YMC)纯化分离，以甲醇:水(60:40)为流动相，得到化合物1(15.0mg)、3(8.6mg)、5(12.9mg)、8(5.1mg)和10(19.3mg)。组份Fr.3-1-2-3-4(0.61g)经Sephadex LH-20柱色谱(500g)分离，以甲醇:水(1:1)为流动相，再经制备硅胶薄层色谱PTLC纯化，以氯仿:甲醇(20:1)为展开溶剂得到化合物2(12.5mg)和9(26.8mg)。亚组份Fr.3-1-2-4(2.3g)经Sephadex LH-20柱色谱(500g)分离，用甲醇:水(1:1)为流动相，薄层色谱检测合并相同洗脱流份后得到4个组份Fr.3-1-2-4-1-Fr.3-1-2-4-4。组份Fr.3-1-2-4-2(0.62g)经硅胶柱色谱（300~400目，10g）分离，以甲醇:氯仿(0:1-1:0)梯度洗脱，再经高效液相色谱RP-HPLC（ODS,5μm,YMC)纯化，以甲醇:水(65:25)为流动相分别得到化合物4(12.0mg)、6(8.9mg)、7(9.2mg)和11(10.6mg)。
化合物1：白色无定型粉末；1H NMR(DMSO-d6,500MHz)δ：6.96(2H,d,J=8.0Hz,H-2″,6″),6.92(1H,brd,J=8.0Hz,H-6),6.88(1H,brs,H-2'),6.86(1H,brs,H-2),6.80(1H,brd,J=8.0Hz,H-6'),6.74(1H,d,J=8.0Hz,H-5),6.67(1H,d,J=8.0Hz,H-5'),6.62(2H,d,J=8.0Hz,H-3″,5″),4.18(2H,s,H-7),3.67(2H,s,H-7'),3.16(3H,s,OMe);13C NMR(DMSO-d6,150MHz);(+)-ESIMS m/z 373[M+Na]+,389[M+K]+;(-)-ESIMS m/z 385[M+Cl]-;(+)-HRESIMS m/z 373.1397[M+Na]+(calcd for C22H22O4Na,373.1416).
化合物2：白色无定型粉末;1H NMR(DMSO-d6,500MHz)δ：6.98(4H,d,J=8.0Hz,H-2',6',2″,6″),6.75(2H,brs,H-2,6),6.65(4H,d,J=8.0Hz,H-3',5',3″,5″),4.14(2H,s,H-7),3.80(4H,s,H-7',7″),3.16(3H,s,OMe);(+)-ESIMS m/z 389[M+K]+;(-)-ESIMS m/z 385[M+Cl]-;(+)-HRESIMSm/z 373.1410[M+Na]+(calcd for C22H22O4Na,373.1416).
化合物3：白色无定型粉末;1H NMR(DMSO-d6,500MHz)δ：6.96(2H, d,J=8.4Hz,H-2″′,6″′),6.92(1H,dd,J=8.4,2.4Hz,H-6),6.87(1H,d,J=2.4Hz,H-2″),6.86(1H,d,J=2.4Hz,H-2),6.84(1H,d,J=2.4Hz,H-2'),6.78(1H,dd,J=8.4,2.4Hz,H-6'),6.76(1H,dd,J=8.4,2.4Hz,H-6″),6.74(1H,d,J=8.4Hz,H-5),6.65(1H,d,J=8.4Hz,H-5″),6.64(1H,d,J=8.4Hz,H-5'),6.62(2H,d,J=8.4Hz,H-3″′,5″′),4.18(2H,s,H-7),3.67(4H,s,H-7',7″′),3.63(2H,s,H-7″),3.17(3H,s,OMe);(-)-ESIMS m/z 455[M-H]-,491[M+Cl]-;(+)-HRESIMSm/z 479.1831[M+Na]+(calcd for C29H28O5Na,479.1829).
化合物4：白色无定型粉末；1H NMR(DMSO-d6,500MHz)δ：6.98(2H,d,J=8.0Hz,H-2″′,6″′),6.97(1H,d,J=8.0Hz,H-2″,6″),6.86(1H,d,J=2.0Hz,H-2'),6.78(1H,dd,J=8.0,2.0Hz,H-6'),6.73(1H,d,J=1.5Hz,H-6),6.68(1H,brs,H-2),6.67(1H,d,J=8.0Hz,H-5'),6.65(2H,d,J=8.5Hz,H-3″′,5″′),6.62(2H,d,J=8.5Hz,H-3″,5″),4.12(2H,s,H-7),3.79(2H,s,H-7″′),3.75(2H,s,H-7'),3.67(2H,s,H-7″),3.14(3H,s,OMe);(+)-ESIMSm/z 479[M+Na]+;(-)-ESIMS m/z 455[M-H]-,491[M+Cl]-;(+)-HRESIMS m/z 479.1846[M+Na]+(calcd for C29H28O5Na,479.1829).
化合物5：白色无定型粉末;1H NMR(DMSO-d6,500MHz)δ:6.94(4H,d,J=7.5Hz,H-2″,6″,2″′,6″′),6.90(1H,brd,J=8.0Hz,H-6),6.80(1H,brs,H-2),6.72(1H,d,J=8.0Hz,H-5),6.70(2H,s,H-2',6'),6.62(4H,d,J=7.5Hz,H-3″,5″,3″′,5″′),4.16(2H,s,H-7),3.74(4H,s,H-7″,7″′),3.62(2H,s,H-7'),3.15(3H,s,OMe);(-)-ESIMS m/z 455[M-H]-,491[M+Cl]-;(+)-HRESIMS m/z 455.1847[M-H]-(calcd for C29H27O5,479.1864).
化合物6：白色无定型粉末;1H NMR(DMSO-d6,500MHz)δ:6.96(4H,d,J=8.5Hz，H-2″,6″,2″′,6″′),6.80(2H,d,J=2.0Hz,H-3,3'),6.73(2H,dd,J=8.0,2.0Hz,H-5,5'),6.65(2H,d,J=8.0Hz,H-6,6'),6.62(4H,d,J=8.5Hz,H-3″,5″,3″′,5″′),3.67(4H,s,H-7″,7″′),3.58(2H,s,H-7);(-)-ESIMS m/z 411[M-H]-,447[M+Cl]-;(-)-HRESIMS m/z 411.1604[M-H]-(calcd forC27H23O4,411.1602).
化合物7：白色无定型粉末;1H NMR(DMSO-d6,500MHz)δ:6.94(4H,d,J=8.0Hz,H-2″,6″,2″′,6″′),6.88(2H,d,J=8.5Hz,H-2',6'),6.66(2H,brs,H-3,5),6.63(4H,d,J=8.0Hz,H-3″,5″,3″′,5″′),6.60(2H,d,J=8.0Hz,H-3',5'),3.75(4H,s,H-7″,7″′),3.57(2H,s,H-7');(-)-ESIMS m/z 411[M-H]-,447[M+Cl]-;(+)-HRESIMS m/z 411.1582[M-H]-(calcdfor C27H23O4, 411.1602).
化合物8：白色无定型粉末;1H NMR(DMSO-d6,500MHz)δ:6.96(2H,d,J=8.5Hz,H-2″′,6″′),6.91(2H,d,J=8.5Hz,H-2″,6″),6.85(1H,d,J=2.0Hz,H-3'),6.78(1H,brs,H-3),6.76(1H,brd,J=7.5Hz,H-5'),6.74(1H,dd,J=8.5,2.0Hz,H-5),6.66(1H,d,J=8.0Hz,H-6),6.65(1H,d,J=7.5Hz,H-6'),6.64(2H,d,J=8.5Hz,H-3″,5″),6.63(1H,d,J=8.5Hz,H-3″′,5″′),3.66(2H,s,H-7″′),3.62(2H,s,H-7'),3.61(2H,s,H-7″);(-)-ESIMS m/z 411[M-H]-,447[M+Cl]-;(-)-HRESIMS m/z 411.1604[M-H]-(calcd forC27H23O4,411.1602).
化合物9：白色无定型粉末;1H NMR(DMSO-d6,300MHz)δ:7.12(4H,d,J=8.5Hz,H-2,2',6,6'),6.72(4H,d,J=8.5Hz,H-3,3',5,5'),4.32(4H,s,H-7,7');(+)-ESIMS m/z 253[M+Na]+;(-)-ESIMS m/z 230[M-H]-.
化合物10：白色无定型粉末;1H NMR(DMSO-d6,300MHz)δ:6.97(4H,d,J=8.4Hz,H-2,2',6,6'),6.64(4H,d,J=8.4Hz,H-3,3',5,5'),3.67(2H,s,H-7);(-)-ESIMS m/z 199[M-H]-;(-)-ESIMS m/z 399[M-H]-.
化合物11：白色无定型粉末;1H NMR(DMSO-d6,300MHz)δ:7.69(2H,d,J=8.7Hz,H-2',6'),6.93(2H,d,J=8.4Hz,H-2″,6″),6.83(1H,d,J=3.0Hz,H-3),6.78(1H,dd,J=3.0,8.4Hz,H-5),6.68(1H,d,J=8.1Hz,H-6),6.63(2H,d,J=8.4Hz,H-3″,5″),6.62(2H,d,J=8.7Hz,H-3',5'),3.67(2H,s,H-7'),3.62(2H,s,H-7″);(-)-ESIMS m/z 305[M-H]-.
本发明的化合物（见下表）。
天麻中提取分离纯化得到的本发明化合物
药理实验：
本发明化合物对去血清、鱼藤酮及α-突触核蛋白诱发的神经损伤模型具有保护作用。
实验例1：天麻联苄类化合物对鱼藤酮损伤模型的保护作用：将PC12细胞分为对照组、鱼藤酮组和鱼藤酮+化合物组，给药后细胞细胞置于细胞培养箱继续培养24小时，MTT法（570nM）测定细胞存活率。以对照组吸光度为100%，计算各组吸光度与对照组的比值。
实验结果：具体结果见图1。结果表明：本发明中发现天麻联苄类化合物1，3，4，5，7，8对Rot损伤的细胞具有保护作用，且呈剂量依赖性，显示出较好的神经保护功能。由此提示，上述化合物对与线粒体功能障碍相关的疾病方面具有潜在的治疗或预防作用，同时提示其它具有相似结构的化合物可能具有相同的神经保护功能。
实验例2：天麻联苄类化合物对去血清损伤模型的保护作用：将PC12细胞分为对照组、去血清组和去血清+化合物组，给药后细胞细胞置于细胞培养箱继续培养24小时，MTT法（570nM）测定细胞存活率。以对照组吸光度为100%，计算各组吸光度与对照组的比值。
实验结果：具体结果见图2。在本发明中发现：PC12细胞去血清后，细胞存活率与对照组比显著减少，而给予浓度为10-6M，10-7M天麻联苄类化合物1，4，7，8时细胞存活率显著增加，表明化合物1，4，7，8对去血清造成的PC12细胞损伤具有保护作用。由此提示，上述化合物可能对与脑缺血相关的疾病和神经退行性疾病具有治疗或保护作用，同时也提示其它具有相似结构的化合物可能具有相同的神经保护功能。
实验例3：天麻联苄类化合物对α-突触核蛋白伤模型的保护作用：将PC12细胞分为对照组、α-突触核蛋白组和α-突触核蛋白+化合物组，给药后细胞细胞置于细胞培养箱继续培养24小时，MTT法（570nM）测定细胞存活率。以对照组吸光度为100%，计算各组吸光度与对照组的比值。
实验结果：具体结果见图3。本发明发现，α-突触核蛋白刺激PC12细胞24小时后，细胞存活率显著降低，表明α-突触核蛋白能够导致PC12损伤，而给予10-5M浓度的化合物1，8，9，11细胞存活率显著增加，表明化合物1，8，9，11具有抗α-突触核蛋白损伤的作用，同时也提示该系列化合物可能成为治疗与α-突触核蛋白有关的疾病。
实验例4：天麻联苄类化合物抑制鱼藤酮（Rot）诱导的PC12细胞的凋亡：本部分实验采用Annexin V-FITC/PI染色流式细胞仪检测细胞凋亡评价化合物抗细胞凋亡的作用，图4为细胞凋亡分析的二维散点图，其中左下象限Annexin V-/PI-为正常细胞，右下象限Annexin V+/PI-为早期凋亡细胞，右上象限Annexin V+/PI+为晚期凋亡细胞，左上象限Annexin V-/PI+为死亡或坏死细胞。
实验结果：结果发现7，8，11号化合物能够抑制Rot导致的细胞凋亡（图4），图中数据为早期凋亡和晚期凋亡在总细胞中所占的百分率。神经退行性病变AD和PD表现为特定区域的神经元进行性丢失，这种丢失与神经元凋亡关系密切。本研究发现天麻联苄类化合物7，8，11对Rot造成的细胞凋亡具有抑制作用，且具有一定的剂量依赖性。该结果提示：上述化合物对与神经元凋亡关系密切的疾病具有一定的治疗或预防作用。
实验例5：天麻联苄类化合物抑制鱼藤酮（Rot）诱导的ROS的增加：本部分实验利用荧光探针DCFH-DA进行活性氧检测。DCFH-DA本身没有荧光，可以自由穿过细胞膜，进入细胞内后，可以被细胞内的酯酶水解生成DCFH。而DCFH不能通透细胞膜，从而使探针很容易被装载到细胞内。细胞内的活性氧可以氧化无荧光的DCFH生成有荧光的DCF。检测DCF的荧光就可以知道细胞内活性氧的水平，绿色荧光增强表明细胞内ROS增加。通过研究发现7和8号化合物具有降低细胞内ROS的功能，化合物在10-5-10-7M降低ROS的作用具有一定的剂量依赖性。
实验结果：具体结果见图5。本研究发现：天麻联苄类化合物7，8能够抑制Rot所导致的ROS的产生增加，并具有剂量依赖性。此结果表明上述天麻类化合物的神经保护作用可能与抗氧化应激有关，同时也表明上述天麻类化合物针对与氧化应激相关的疾病方面可能具有治疗作用。
实验例6：天麻联苄类化合物改善鱼藤酮（Rot）导致的线粒体膜电位的降低：JC-1是一种广泛用于检测线粒体膜电位(mitochondrial membrane potential)△Ψm的理想荧光探针，可以检测细胞、组织或纯 化的线粒体膜电位。在线粒体膜电位较高时，JC-1聚集在线粒体的基质(matrix)中，形成聚合物(J-aggregates)，可以产生红色荧光；在线粒体膜电位较低时，JC-1不能聚集在线粒体的基质中，此时JC-1为单体(monomer)，可以产生绿色荧光。这样就可以非常方便地通过荧光颜色的转变来检测线粒体膜电位的变化。
实验结果：具体结果见图6。本发明发现，鱼藤酮作用PC12细胞后，能够导致绿色荧光增强，表明线粒体膜电位降低，给予7和8后，绿色荧光降低，红色荧光增强，且呈剂量依赖性，表明这两种化合物具有改善线粒体膜电位的功能。由此提示这类化合物发挥神经保护作用的机制可能与改善线粒体功能有关。
结论：去血清、鱼藤酮及α-突触核蛋白损伤神经模型是能够模拟神经退行性系统疾病如AD和PD部分发病机制的模型，从天麻提取的联苄类化合物1，7，8等共6种单体化合物在上述模型中具有显著的保护作用，对鱼藤酮（Rot）诱导的PC12细胞凋亡具有抑制作用，对ROT导致的线粒体膜电位的降低具有改善作用，同时能够降低由鱼藤酮导致的ROS的产生。上述结果提示，从天麻提取的联苄类化合物的神经保护机制与抗氧化应激有关，是具有治疗AD和PD功能的先导化合物。
Claims (9)
1.如通式(I)所示的三聚苄类化合物，及其药效学上可接受的盐；
其中，R1和R2中有并且只有一个选自
另外一个选自H、OMe、OH；
R、R3、R4、R6和R7各自独立地选自：氢、甲基；
R5选自：乙基、丙基、丁基。
2.如通式(II)所示的四聚苄类化合物，及其药效学上可接受的盐；
其中，R1、R2和R3中有并且只有一个选自
另外两个各自独立地选自选自H、OMe、OH；
R、R4、R5、R6、R8和R9各自独立地选自：氢、甲基；
R7选自：氢、乙基、丙基、丁基。
3.如通式(III)所示的四聚苄类化合物，及其药效学上可接受的盐；
其中，R1、R2和R3中有并且只有一个选自
另外两个各自独立地选自H、OMe、OH；
R4、R5、R6各自独立地选自：氢、甲基；
R选自：乙基、丙基、丁基。
4.如下式所示的化合物，及其药效学上可接受的盐，其特征在于，所述的化合物选自如下群组
5.一种药物组合物，其特征在于，含有药物有效剂量的如权利要求1-4任一项所述的任一化合物或药效学上可接受的盐，及药学上可接受的载体。
6.权利要求1-4任一所述的化合物及其药效学上可接受的盐在制备预防和/或治疗和/或缓解神经系统疾病的药物中的应用。
7.根据权利要求6的应用，其特征在于，所述的神经系统疾病选自帕金森氏病，老年痴呆，血管性痴呆，癫痫，抑郁，神经衰弱或中风。
8.如下式所示化合物及其药效学上可接受的盐在制备预防和/或治疗和/或缓解神经系统疾病的药物中的应用：
9.根据权利要求8的应用，其特征在于，所述的神经系统疾病选自帕金森氏病，老年痴呆，血管性痴呆，癫痫，抑郁，神经衰弱或中风。
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