CN101143192B - 治疗性天麻萃取物 - Google Patents
治疗性天麻萃取物 Download PDFInfo
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- CN101143192B CN101143192B CN2007100910948A CN200710091094A CN101143192B CN 101143192 B CN101143192 B CN 101143192B CN 2007100910948 A CN2007100910948 A CN 2007100910948A CN 200710091094 A CN200710091094 A CN 200710091094A CN 101143192 B CN101143192 B CN 101143192B
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Abstract
本发明提供了天麻相关的化合物、萃取物和医药组合物,以及治疗具有代谢失调或例如亨丁顿舞蹈症、三核苷重复症或血糖浓度异常症的医疗疾病的方法。
Description
技术领域
本发明提供一种天麻属(Gastrodia spp.)相关化合物、萃取物和医药组合物,以及用于治疗具有代谢失调或如亨丁顿舞蹈症(Huntington’s disease)的疾病的患者的方法。
背景技术
亨丁顿舞蹈症(Huntington’s disease,HD)为一种非性联显性神经退化疾病,其特征为舞蹈症、痴呆及精神症状。当疾病发作时,集中注意力与短期记忆力会降低,且头部、躯干及肢臂的不自主运动会增加。步行、言语及吞咽能力恶化。最终会死于窒息、感染或心脏衰竭导致的并发症。
病变的成因为位于亨丁顿(Huntingtin,Htt)基因(Huntington’s DiseaseCollaborative Research Group)上CAG三核苷的延伸。正常的染色体在其N端具有35次或较少次的CAG重复,而HD为36次或以上的重复。多余的CAG重复转译成Htt蛋白质的聚谷胺酰胺片段。当CAG重复超过36次时,几个大脑区域(特别是在纹状体(striatum))发生特殊的退化。神经末梢组织,包含血液细胞、肝脏及肾脏中Htt集合体(aggregate)的形成以及全体基因表现态样的改变也曾被报导(Borovecki,F.et al.(2005);Panov,et al.(2005):Ishiguro,et al.(2001))。由不同研究室的收集证据联想到突变的Htt形成聚集并且造成畸变的蛋白质-蛋白质交互作用(Bate,G.(2003))。尽管一些具有普通效果的治疗剂已经被报导,在本领域中对于HD的有效治疗仍有持续需求。
发明内容
申请人发现某些天麻(Gastrodia elata)(一传统中药)萃取物及相关化合物在治疗亨丁顿舞蹈症及血糖过高症上具有令人惊异的效果。例如,施用天麻萃取物延迟亨丁顿舞蹈症基因转殖鼠的运动表现的进一步恶化,以及延长亨丁顿舞蹈症基因转殖鼠的生命期(如实施例2)。同样地,以天麻萃取物处理可保护细胞免于因血清缺乏诱发的细胞凋亡(如实施例1)。更进一步地,以天麻萃取物投与R6/2老鼠降低了升高的血中葡萄糖浓度(如实施例4),并且降低了肝脏中突变的Htt的聚集(如实施例5)。更进一步地,这些由萃取物分离的化合物减缓了这些老鼠的亨丁顿舞蹈症的几个主要症状(包含运动退化、体重减轻及缩短生命期)(如实施例6)及防止PC12细胞因血清缺乏导致的程序性死亡(如实施例5)。
为达到上述目的,本发明提供了一种医药组合物,包含医药可接受的载体和医药可接受的天麻的水/乙醇萃取物,或利用以下结构式表示的化合物:
及医药可接受盐类或溶剂化物,其中,
环A除R3外为选择性地取代;
取代基B为选择性取代的芳香基或杂芳香基;
取代基C为-键结或选择性取代的环脂肪基、杂环基、芳香基或杂芳香基;
R1与R2独立为一键结或选择性取代的C1-C4烯烃基;
取代基X为-O-、-S-、-S-S-、-S(O)-、-SO2-、-NRa-、-C(O)NRa-、-NRaC(O)-、-NRaSO2-或-SO2NRa-;
R3和R4独立地为-OH、卤素、-CN、-NO2、-ORa、-RbORa、-C(O)Ra、-OC(O)Ra、-C(O)ORa、-SRa、-RbSRa、-C(S)Ra、-OC(S)Ra、-C(S)ORa、-C(O)SRa、-C(S)SRa、-B(ORa)2、-S(O)Ra、-SO2Ra、-SO3Ra、-OSO2Ra、-OSO3Ra、-PO2RaRb、-OPO2RaRb、-PO3RaRb、-OPO3RaRb、-N(RaRb)、-C(O)N(RaRb)、-C(O)NRaNRbSO2Rc、-C(O)NRaSO2Rc、-C(O)NRaCN、-SO2N(RaRb)、-NRaC(O)Ra或-NRcC(O)ORa;及
Ra-Rd各自独立为-H或选择性取代的脂肪基、环脂肪、杂环基、苯甲基、芳香基、杂芳香基;或-N(RaRb),同时为选择性取代的杂环基。
上述“环A除R3外为选择性地取代”其意为“ring A is optionallysubstituted in addition to R3”。
在各种实施态样中,本发明提供一个以下结构式所示的化合物:
及其医药可接受盐类及其溶剂化物。
环A除R3外可选择性地被取代;
取代基B为选择性取代的芳香基或杂芳香基;
取代基C为一键结或选择性取代的环脂肪基、杂环基、芳香基或杂芳香基;
R1与R2分别为一键结或选择性取代的烯烃基,例如C1-C4烯烃基;
取代基X为-O-、-S-、-S-S-、-S(O)-、-SO2-、-NRa-、-C(O)NRa、-NRaC(O)-、-NRaSO2-或-SO2NRa-;
R3及R4分别为-OH、卤素、-CN、-NO2、-ORa、-RbORa、-C(O)Ra、-OC(O)Ra、-C(O)ORa、-SRa、-RbSRa、-C(S)Ra、-OC(S)Ra、-C(S)ORa、-C(O)SRa、-C(S)SRa、-B(ORa)2、-S(O)Ra、-SO2Ra、-SO3Ra、-OSO2Ra、-OSO3Ra、-PO2RaRb、-OPO2RaRb、-PO3RaRb、-OPO3RaRb、-N(RaRb)、-C(O)N(RaRb)、-C(O)NRaNRbSO2Rc、-C(O)NRaSO2Rc、-C(O)NRaCN、-SO2N(RaRb)、-NRcC(O)Ra或-NRC(O)ORa;及
Ra-Rd各自分别为-H或一选择性取代的脂肪基、环脂肪、杂环基、苯甲基、芳香基、杂芳香基;或-N(RaRb)同时为选择性取代的杂环基。
上述环A“除R3外为选择性地取代”其意为环A“is optionally substitutedin addition to R3”。
在各种实施态样中,至少一个R1以及R2可为选择性取代的烯烃基(alkylene),例如C1-C4烯烃基。在部分实施态样中,R1及R2各自分别为C1-C4烯烃基。
当R1及R2同时为甲基、B为苯基、取代基C为一键结,且R3及R4同时为位于相对于R1及R2对位的羟基时,X不为-O-、-S-或-S(O)-;
该化合物不为天麻素、天麻醚苷或派立辛;且当该化合物为天麻的制品时,该化合物是被单离的;所述的单离(isolated),其为单独分离、分离或者提纯的含义。
在各种实施态样中,X可为-NRa-、-C(O)NRa、-NRaC(O)-、-NRaSO2-或-SO2NRa-,例如,-NH-。在部分实施态样中,X可为-O-或-C(O)-。在某些实施态样中,X可为-S-,-S(O)-或-SO2,例如,-S-。
在各种实施态样中,R3以及R4独立为卤素-OH、C1-C4烷醇、-SH、C1-C4烷硫醇、-CO2H、-NO2、-B(OH)2、-SO3H、-OSO3H、-PO3H2或-OPO3H2。
在部分实施态样中,R3及R4为相同官能基,例如-OH。
在各种实施态样中,环B(即B)为选择性取代的苯基、双苯基、萘基、芘基、蒽基、咪唑基、异咪唑基、噻吩基、呋喃基、茀基、吡啶基、嘧啶基(pyrimidyl)、吡喃基、吡唑基、吡咯基、吡嗪基、噻唑基、异噻唑基、噁唑基(oxazolyl)、异噁唑基(isoxazolyl)、1,2,3-三唑基、1,2,4-三唑基、喹唑啉基、吲哚基、四唑基、苯并噻吩基(benzothienyl)、苯并呋喃基、喹啉基、苯并噻唑基、苯并异噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、异喹啉基、嘌呤基或异吲哚基。
在各种实施态样中,环C(即C)为选择性取代:C3-C8环烷基、噁唑啉基、四氢噻唑基、噁唑烷基、噻唑烷基、四氢呋喃基、四氢硫苯基、吗啉基、硫吗啉基、吡咯烷基、哌嗪基、哌啶基、四氢噻唑基,呋喃糖基形式的葡萄糖、甘露糖、半乳糖、阿洛糖、阿卓糖、异葡萄糖、艾杜糖或太洛糖;或吡喃糖基形式的葡萄糖、甘露糖、半乳糖、阿洛糖、阿卓糖、异葡萄糖、艾杜糖或太洛糖。
在各种实施态样中,该化合物由以下结构式所表示:
其中环D选择性被取代或与另-环融合。
在部分实施态样中,该化合物可表示为:
在某些实施态样中,该化合物可表示为:
在特别的实施态样中,该化合物可表示为:
在部分实施态样中,该化合物为:
在各种实施态样中,该化合物可表示为以下结构式:
其中B’为选择性取代的杂芳香基,且C’为选择性的杂环基。
在各种实施态样中,B’为选择性取代的嘧啶基或嘌呤基。
在各种实施态样中C’与R4同为选择性取代的由葡萄糖、甘露糖、半乳糖、阿洛糖、阿卓糖、异葡萄糖、艾杜糖或太洛糖而来的呋喃糖或吡喃糖。
在部分实施态样中,该化合物可由以下结构式所表示:
在部分实施态样中,-NH-B’-C’-R4可同为选择性取代的核糖核苷或去氧核糖核苷。
在部分实施态样中,该化合物为:
在部分实施态样中,R1与R2均为一选择性取代的烯烃基,例如,C1-C4烯烃基。
在部分实施态样中,X不为-O-。在部分实施态样中,X不为-S-。在部分实施态样中,X不为-S-S-。在部分实施态样中,X不为-S(O)-或-SO2-。在部分实施态样中,X不为-NRa-。在部分实施态样中,X不为-C(O)NRa-或-NRaC(O)-。在部分实施态样中,X不为-NRaSO2-或-SO2NRa-。
在部分实施态样中,X为-O-。在部分实施态样中,X为-S-。在部分实施态样中,X为-S-S-。在部分实施态样中,X为-S(O)-或-SO2-。在部分实施态样中,X为-NRa-。在部分实施态样中,X为-C(O)NRa-或-NRaC(O)-。在部分实施态样中,X为-NRaSO2-或-SO2NRa-。
在部分实施态样中,R3及R4至少一个为-OH。
在部分实施态样中,R3及R4相同。
在部分实施态样中,R3及R4至少一个不为卤素。在部分实施态样中,R3及R4至少一个不为-OH。在部分实施态样中,R3及R4至少一个不为-CN或-NO2。在部分实施态样中,R3及R4至少一个不为-ORa、-RbORa、-C(O)Ra、-OC(O)Ra或-C(O)ORa。在部分实施态样中,R3及R4至少一个不为-SRa、-RbSRa、-C(S)Ra、-OC(S)Ra、-C(S)ORa、-C(O)SRa或-C(S)SRa。在部分实施态样中,R3及R4至少一个不为-B(ORa)2。在部分实施态样中,R3及R4至少一个不为-S(O)Ra、-SO2Ra、-SO3Ra、-OSO2Ra或-OSO3Ra。在部分实施态样中,R3及R4至少一个不为-PO2RaRb、-OPO2RaRb、-PO3RaRb或-OPO3RaRb。在部分实施态样中,R3及R4至少一个不为-N(RaRb)、-C(O)N(RaRb)、-C(O)NRaNRbSO2Rc、-C(O)NRaSO2Rc或-C(O)NRaCN。在部分实施态样中,R3及R4至少一个不为-SO2N(RaRb)。在部分实施态样中,R3及R4至少一个不为-NRaC(O)Ra或-NRcC(O)ORa。
在部分实施态样中,R3及R4至少一个为卤素。在部分实施态样中,R3及R4至少一个为-CN或-NO2。在部分实施态样中,R3及R4至少一个为-ORa、-RbORa、-C(O)Ra、-OC(O)Ra或-C(O)ORa。在部分实施态样中,R3及R4至少一个为-SRa、-RbSRa、-C(S)Ra、-OC(S)Ra、-C(S)ORa、-C(O)SRa或-C(S)SRa。在部分实施态样中,R3及R4至少一个为-B(ORa)2。在部分实施态样中,R3及R4至少一个为-S(O)Ra、-SO2Ra、-SO3Ra、-OSO2Ra或-OSO3Ra。在部分实施态样中,R3及R4至少一个为-PO2RaRb、-OPO2RaRb、-PO3RaRb或-OPO3RaRb。在部分实施态样中,R3及R4至少一个为-N(RaRb)、-C(O)N(RaRb)、-C(O)NRaNRbSO2Rc、-C(O)NRaSO2Rc或-C(O)NRaCN。在部分实施态样中,R3及R4至少一个为-SO2N(RaRb)。在部分实施态样中,R3及R4至少一个为-NRcC(O)Ra或-NRcC(O)ORa。
在部分实施态样中,该化合物为一被分离的化合物,例如,该化合物为纯的化合物,化合物可被包含于医药组合物中,化合物可被包含于天麻属(Gastrodia spp.),例如:天麻(Gastrodia elata)或类似萃取物中。
在部分实施态样中,当R1与R2同为甲基,B为苯基、C为一键结,且R3与R4同时为位于相对于R1及R2对位的羟基时,X不为-O-,-S-、或-S(O)-。例如,在部分实施态样中,该化合物不为双(4-羟基苯甲基)醚、双(4-羟基苯甲基)硫或双(4-羟基苯甲基)亚砜。
在部分实施态样中,该化合物不为天麻素(gastrodin)、天麻醚苷(gastrodioside)或派立辛(parishin)。
本发明还提供一种医药可接受的天麻属(Gastrodia spp.),例如:天麻(Gastrodia elata)萃取物,该萃取物可以本技术领域已知的任何方法制备,例如以有机溶剂萃取(例如:甲醇、乙醇、水/乙醇、水/甲醇、丙酮、丁酮、乙腈或其它类似溶剂)。本发明还提供了这些萃取物的萃取分层物及其萃取分层方法。天麻属可为天麻属任何一物种,包含Gastrodia elata、Gastrodiacunninghamil、Gastrodia aff.sesamoides、Gastrodia sesamoides及其它,但不限于上述物种。
一种医药组合物包含医药可接受载体或赋形剂。在部分实施态样中,该医药组合物包含该化合物。在部分实施态样中,该医药组合物包含医药可接受天麻属(例如:天麻(Gastrodia elata))萃取物。
一种治疗具有亨丁顿舞蹈症的患者的方法,在各种实施态样中,其包含对该受试者施以有效剂量的化合物及/或医药可接受天麻属(例如:天麻(Gastrodia elata))萃取物,或其医药组合物。
一种治疗患有血糖浓度异常症的受试者的方法,在各种实施态样中,其包含对该受试者施以有效剂量的化合物及/或医药可接受天麻属(例如:天麻(Gastrodia elata))萃取物,或其医药组合物。受试者的血糖浓度异常程度而呈现出血糖过高症,且在各种实施态样中,其具有一种或多种疾病如亨丁顿舞蹈症、三核苷重复症(包含SCA1、SCA2、SCA3、SCA6、SCA7、SCA17、dentatorubralpallidoluysian萎缩症及脊髓性肌肉萎缩症)、第一型(I型)糖尿病、第二型(II型)糖尿病、心血管疾病、X症候群,肥胖相关血糖过高症、食欲过盛相关血糖过高症或类固醇诱发的血糖过高症或其它。
一种控制受试者中A2A受体活性的方法,在各种实施态样中,其包含对该受试者施以有效剂量的化合物及/或医药可接受天麻属(例如:天麻(Gastrodiaelata)萃取物,或其医药组合物。在部分实施态样中,施用于受试者的化合物、萃取物或医药组合物的剂量可有效地治疗由A2A受体调控的疾病。例如,提高A2A受体的活性。这些疾病包含例如慢性心脏衰竭、末稍组织(包含肝脏、肾脏及心脏)缺血及败血症。
一种控制受试者体内环腺苷单磷酸浓度的方法,在各种实施态样中,其包含对该受试者施以有效剂量的化合物及/或医药可接受天麻属(例如:天麻(Gastrodia elata))萃取物,或其医药组合物。在部分实施态样中,施用于受试者的化合物剂量可有效地增加受试者体内的环腺苷单磷酸浓度,例如:广泛地或在局部的细胞或组织中。在部分实施态样中,施用于受试者的化合物、萃取物或医药组合物的剂量可有效地治疗受试者的由环腺苷单磷酸调控的疾病,例如藉由增加受试者体内环腺苷单磷酸的浓度。此类疾病包含慢性心脏衰竭、末稍组织(包含肝脏、肾脏及心脏)缺血和败血症。
在各种实施态样中,该医药组合物包含医药可接受载体与医药可接受天麻的水/乙醇萃取物或本发明所述的化合物。
在包含治疗受试者疾病的方法的各种实施态样中,其包含对受试者施用有效剂量的化合物、萃取物或医药组合物,例如医药组合物,其中,疾病包含亨丁顿舞蹈症、三核苷重复症或血中葡萄糖浓度异常或可藉由控制受试者体内A2A受体活性或控制受试者体内环腺苷单磷酸浓度的疾病。在部分实施态样中,该疾病为亨丁顿舞蹈症、三核苷重复症或血中葡萄糖浓度异常。在部分实施态样中,该疾病为亨丁顿舞蹈症。在部分实施态样中,该疾病为第一型糖尿病、第二型糖尿病、心血管疾病、X症候群,肥胖相关血糖过高症、食欲过盛相关血糖过高症或类固醇诱发的血糖过高症。在部分实施态样中,该疾病为选自包含SCA1、SCA2、SCA3、SCA6、SCA7、SCA17、dentatorubralpallidoluysian萎缩症及脊髓性肌肉萎缩症的群组的三核苷重复症。在部分实施态样中,该疾病选自包含慢性心脏衰竭、末稍组织(包含肝脏、肾脏及心脏)缺血及败血症的群组,其中该化合物、萃取物或医药组合物有效地增加受试者A2A受体活性或增加受试者环腺苷单磷酸浓度。
本发明的一个或多个实施态样的细节将在附图和实施方式中共同提出。本发明的其它特征、目的及优点可在实施方式、附图或权利要求的范围中被清楚地理解。
附图说明
图1:为条形图,呈现了PC12细胞生存能力,其表示以含血清对照组的MTT代谢量测(最左边条形)为百分之百的值;缺乏血清的群组为由左算起的第二个条形;缺乏血清的PC12细胞被施以含有不同剂量的天麻萃取物的不同甲醇萃取物(T1-1、T1-2及T1-3)24小时;相对于含血清对照组,*p<0.05;
图2A:为小鼠平衡测试图表,是四周大开始的R6/2鼠的对照组(CON=11)或饮用水中含天麻萃取物(5mg/ml,n=12)组的时间与年龄的关系;
图2B:为存活百分比的图表,是四周大开始的R6/2鼠的对照组(CON=11)或饮用水中含天麻萃取物(5mg/ml,n=12)其存活比例与年龄的关系;
图3A:在12周大R6/2鼠的纹状体标示亨丁顿突变蛋白颗粒的代表图,其于鼠四周大开始给予控制饮用水;比例尺:25μm;
图3B:在12周大R6/2鼠的纹状体标示亨丁顿突变蛋白颗粒的代表图,其于四周大开始给予含天麻萃取物(5mg/ml)饮用水;比例尺:25μm;
图3C:为12周大R6/2鼠的纹状体细胞表现神经元细胞亨丁顿突变蛋白核内聚集(NIIs)的百分比,其于四周大开始给予对照组或含天麻萃取物饮用水,定量方法描述于“材料与方法”中;比例尺:25μm;Student’s t-test与在指示年龄施以展色剂的R6/2鼠比较,**p<0.01;
图4:为原生鼠、R6/2鼠对照组及四周大开始施以含天麻萃取物(5mg/ml)饮用水的R6/2鼠的血中葡萄糖浓度(mg/ml)对年龄比较图;于指示时期收集血液样品并以于“方法”中的描述内容来进行检测;
图5A:为四周大开始给予控制饮用水的12周大R6/2鼠肝脏标示亨丁顿突变蛋白颗粒的代表图;比例尺:25μm;
图5B:为四周大开始给予含有天麻萃取物(5mg/ml)饮用水的12周大R6/2鼠肝脏标示亨丁顿突变蛋白颗粒的代表图;比例尺:25μm;
图5C:为四周大开始给予含有天麻萃取物(5mg/ml)饮用水的12周大的R6/2鼠肝脏细胞表现Htt聚集的比例条形图,其定量方法于“材料与方法”中予以描述;通过Student’s t-test与在指示年龄施以展色剂的R6/2鼠比较,**p<0.01;
图6:为天麻萃取物的活性层析层的层析图;其中,HPLC的条件包含:色谱柱为Merck RP-18e(250×4.6mm)管柱,流动相梯度洗脱是由70%-40%的水/甲醇洗40分钟、以及由40%至20%水/甲醇洗5分钟,在流速0.5ml/min与侦测(检测)波长270nm;其中两活性组成(T1-C与T1-11)的位置的标示参见该图所示的箭头处;
图7A:血清抽离后的PC12细胞施以T1-C或T1-11的细胞存活率的百分比;其中以含有血清的PC12细胞对照组的MTT代谢作为百分之百来表示,并藉以量化其它各血清抽离的实验组;其中数据点代表至少三个独立实验的means±SEM(n=3-6);
图7B:为ST14细胞在室温下分别先给予或未给予CSC前处理后,再施以CGS21680(CGS,10μM)、T1-C(10μM)或T1-11(26.8μM)20分钟后,细胞的cAMP的形成量;
图8A:为呈现由四周大开始在饮用水中给予控制(CON,1%DMSO,n=8)、T1-C(0.5mg/ml in 1%DMSO,n=7)或T1-11(0.05mg/ml in 1%DMSO,n=8)的R6/2鼠旋转轴测试图;
图8B:为呈现由四周大开始在饮用水中给予控制(CON,1%DMSO,n=8)、T1-C(0.5mg/ml in 1%DMSO,n=7)或T1-11(0.05mg/ml in 1%DMSO,n=8)的R6/2鼠体重图;
图8C:为呈现由四周大开始在饮用水中给予控制(CON,1%DMSO,n=8)、T1-C(0.5mg/ml in 1%DMSO,n=7)或T1-11(0.05mg/ml in 1%DMSO,n=8)的R6/2鼠存活比例图。
具体实施方式
以下结合附图详细说明本发明,但不限定本发明的实施范围。
天麻(Gastrodia elata)在亚洲是被广泛使用了至少1500年的中药,传统医学用来治疗头痛、头晕、肢体麻木和痉挛,尤其是抽筋等疾病,例如癫痫和肌强直(tetanus)。基于其主要用来治疗癫痫疾病的有效医疗用途,许多的研究被用来探讨其在预防神经伤害方面的作用。例如,天麻素,一种天麻中的组成成分,被发现会改变沙鼠海马区(gerbil hippocampus)中的GABA代谢(An,et al.(2003))。更进一步地,天麻的甲醇萃取物的乙醚分划层(萃取层)在对抗沙鼠局部缺血模型和施以藻氨酸(kainic-acid)处理的老鼠模型中的海马区神经伤害具有保护效果(Kim,et al.(2001);Kim,et al.(2003))。天麻的甲醇萃取物的乙醚分划层能显著地降低对β-淀粉样蛋白诱发的神经细胞死亡。同样地,藉由利用施以藻氨酸处理的老鼠模型,Hsieh与其同事证明投予天麻萃取物不仅可显著地降低了抽筋的次数,并且也延迟了开始的时间(Hsieh,etal(2001))。天麻出现这种抗抽筋的效果是藉由其自由基清除活性的调节(Hsieh,et al.(2000))。此外,一种天麻的甲醇萃取物藉由抑制JNK活性来防止PC12细胞因血清抽离的细胞凋亡(Huang,et al.(2004))。在本研究中,发明人证明,于老鼠的饮用水添加天麻的部分纯化物或由天麻纯化的两个新的化合物可以显著地改善有亨丁顿舞蹈症基因转殖的R6/2基因转殖鼠(Mangiarini,et.Al.(1996))的几个亨丁顿舞蹈症的主要症状。
申请人也发现在某些天麻(一种传统中药)萃取物及其相关化合物在治疗如亨丁顿舞蹈症和血糖过高症方面具有令人讶异的效果。举例来说,施用天麻萃取物延迟亨丁顿舞蹈症的基因转殖鼠的运动表现的进一步恶化并改善亨丁顿舞蹈症基因转殖鼠的生命期(如实施例2)。同样地,以天麻萃取物治疗可保护细胞免于因血清缺乏诱发的细胞凋亡(如实施例1)。更进一步地,以天麻萃取物治疗R6/2基因转殖鼠降低了升高的血中葡萄糖浓度(如实施例4),并降低其肝脏中突变的Htt的聚集(如实施例5)。更进一步地,由这些萃取物分离的化合物减缓了这些老鼠的亨丁顿式舞蹈症的几个主要症状(包含运动退化、体重消瘦及缩短生命)(如实施例6)以及防止PC12细胞因血清抽离导致的细胞凋亡(如实施例5)。
本发明所使用的合适的保护基是在合成和反应条件中用来提供保护与去保护,其为本技术领域所熟知的,例如,在Greene及Wuts(1991)。举例来说,特殊实施例的合适的羟基保护基包含:烷基醚类(例如:甲基、乙基),烷氧基烷基醚类(例如:甲氧基甲烷基),硅烷醚类(例如:三甲基硅烷基)及其它类似保护基,但不限于此。
本发明所使用的“被单离(isolated)”是指一化合物由一反应混合物或生物资源(例如:天麻)中至少经部分纯化而得到,即分离、精制或纯化的意思。举例来说,一部份纯化或分离的化合物是由一反应混合物或由天麻中通过一个或多个步骤的萃取、层析分离、再结晶、亲和纯化或其它本技术领域知悉的手段所纯化。例如,在特别的实施态样中,其披露的化合物利用高效液相色谱仪来分离纯化。
本发明所使用的脂肪基为一直链状、分支状或环状无芳香碳氢化合物,其为完全饱和或者包含一个或多个不饱和单元。烷基官能基为一饱和脂肪官能基。一般来说,直链或分支脂肪官能基具有1至10个碳原子,优选为1至约4个,及环状脂肪基(例如以B或C表示的环脂肪基)具有3至约10个碳原子,优选为3至约8个。一脂肪基优选为一直链或分支烷基,例如:甲基、乙基、正丙基、异丙基、正丁基、第二丁基(仲丁基)、第三丁基(叔丁基)、戊基、己基或辛基,或具有3至8个碳原子的环烷基。C1-C4直链或分支烷基或烷氧基或C3-C8环烷基或环烷氧基也被称为“较低级烷基”或“较低级烷氧基”。此类官能基以-F、-Cl、-Br或-I取代为“较低级卤烷基”或“较低级卤烷氧基”官能基;“较低级羟基烷基”为较低级烷基以-OH取代;或其它类似物。
本发明所使用的“烯烃基(alkylene)”(例如,以R1及R2表示的烯烃基),其为以-(CH2)n-表示的连结烷基链,其中n为1至10的整数,优选为1至4。
本发明所使用术语“芳香基”(例如以B或C表示的芳香基)表示C6-C14碳环芳香基,例如苯基、双苯基及其它类似物。芳香基也包含融合的聚环芳香基系,其中碳环芳香环与其它芳香基、环烷基或环脂肪环融合,例如萘基、芘基、蒽基及其它类似物。
本发明所使用的术语“杂芳香基”(例如以B或C表示的杂芳香基)是指5-14元的杂芳香环,其具有一个或多个O、S或N杂原子。杂芳香基的实施例包含咪唑基、异咪唑基、噻吩基、呋喃基、茀基、吡啶基、嘧啶基、吡喃基、吡唑基、吡咯基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、1,2,3-三唑基、1,2,4-三唑基、咪唑基、噻吩基、嘧啶基、喹唑啉基、吲哚基、四唑基或其它类似物。杂芳香基也包含融合的聚环芳香环系统,其为一碳环芳香环或杂芳香环与一个或多个其它芳香环融合。实施例包含苯并噻吩基、苯并呋喃基、吲哚基、喹啉基、苯并噻唑基、苯并异噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、喹啉基、异喹啉基、嘌呤基及异吲哚基。杂环官能基的特别实施例包含杂环芳香核碱,例如嘌呤基衍生物(例如:2-氨基-1H-嘌呤-6(9)H-酮)及嘧啶基衍生物(例如4-氨基嘧啶-2(1H)-酮或其它类似物)、5-甲基嘧啶-2,4(1H,3H)-双酮、嘧啶-2,4(1H,3H)-双酮,或其它类似物)。
本发明所使用的非芳香杂环官能基(例如:以B或C表示的杂环基)为非芳香碳环,其包含一个或多个例如N、O或S杂原子在环中。这些环可以是五、六、七或八元环,实施例包含:噁唑啉基、四氢噻唑基、噁唑烷基、噻唑烷基、四氢呋喃基、四氢硫苯基、吗啉基、硫吗啉基、吡咯烷基、哌嗪基、哌啶基、四氢噻唑基,环糖类(例如:在呋喃糖形式或吡喃糖形式的葡萄糖、甘露糖、半乳糖、阿洛糖、阿卓糖、异葡萄糖、艾杜糖或太洛糖或其它类似物)及其它类似物。
在烷基、环烷基、脂肪基、环脂肪基、杂环基、苯甲基、芳香基或杂芳香基中,合适的选择性取代的取代基是指那些取代基并不会实质上影响被披露的化合物的医药活性。“可取代原子”指原子具有一价或多价或电荷可与取代基形成一个或多个对应共价或离子键。例如,碳原子具有一价(例如-C(-H)=)可用于与烷基形成一键结(例如-C(-烷基)=),具有二价的碳原子(例如:-C(H2))可用于-形成一键或二个单键接至一或二个取代基(例如:-C(烷基)(H)-,-C(烷基)(Br)-),或一双键接到一取代原子(例如-C(=O)-),及其类似物。本发明考虑的取代基只包含那些可形成稳定化合物的取代基。
例如:对合适的选择性取代基(例如:对R1、R2、B的合适取代表示的取代基)的可取代碳原子包含-F、-Cl、-Br、-I、-CN、-NO2、-ORa、-C(O)Ra、-OC(O)Ra、-C(O)ORa、-SRa、-C(S)Ra、-OC(S)Ra、-C(S)ORa、-C(O)SRa、-C(S)SRa、-B(ORa)2、-S(O)Ra、-SO2Ra、-SO3Ra、-OSO2Ra、-OSO3Ra、-PO2RaRb、-OPO2RaRb、-PO3RaRb、-OPO3RaRb、-N(RaRb)、-C(O)N(RaRb)、-C(O)NRaNRbSO2Rc、-C(O)NRaSO2Rc、-C(O)NRaCN、-SO2N(RaRb)、-NRcC(O)Ra、-NRcC(O)ORa、-NRcC(O)N(RaRb)、-C(NRc)-N(RaRb)、-NRd-C(NRc)-N(RaRb)、-NRaN(RaRb)、-CRc=CRaRb、-C≡CRa、=O、=S、=CRaRb、=NRa、=NORa、=NNRa、选择性取代的烷基、选择性取代的环烷基、选择性取代的脂肪基、选择性取代的环脂肪基、选择性取代的杂环基、选择性取代的苯甲基、选择性取代的芳香基,及选择性取代的杂芳香基,其中Ra-Rd各自独立为-H或一选择性取代的脂肪基、选择性取代的环脂肪基、选择性取代的杂环基、选择性取代的苯甲基、选择性取代的芳香基或选择性取代的杂芳香基或-N(RaRb)中两者同时为选择性取代的杂环基。
适合氮原子的取代基(例如以R3、R4及X表示的官能基中的氮原子,或以B及C表示的杂芳香基或杂环基中的氮原子)与其它原子具有两共价键,其它原子包含,例如:选择性取代的烷基、选择性取代的环烷基、选择性取代的脂肪基、选择性取代的环脂肪基、选择性取代的杂环基、选择性取代的苯甲基、选择性取代的芳香基、选择性取代的杂芳香基、-CN、-NO2、-ORa、-C(O)Ra、-OC(O)Ra、-C(O)ORa、-SRa、-C(S)Ra、-OC(S)Ra、-C(S)ORa、-C(O)SRa、-C(S)SRa、-B(ORa)2、-S(O)Ra、-SO2Ra、-SO3Ra、-OSO2Ra、-OSO3Ra、-PO2RaRb、-OPO2RaRb、-PO3RaRb、-OPO3RaRb、-N(RaRb)、-C(O)N(RaRb)、-C(O)NRaNRbSO2Rc、-C(O)NRaSO2Rc、-C(O)NRaCN、-SO2N(RaRb)、-NRcC(O)Ra、-NRcC(O)ORa、-NRcC(O)N(RaRb)及其它类似物。
含氮杂芳香基或非芳香杂环基可以氧取代形成N-氧化物(N-oxide)。例如:N-氧化吡啶基、N-氧化六氢吡啶基或其它类似物。举例来说:在各种实施态样中,在含氮杂环或杂芳香基中的环氮原子可被取代以形成N-oxide。
本发明也包含该揭露化合物的医药可接受的盐类。这些化合物可具有一个或多个足够酸性的质子,使其可与合适的有机或无机碱反应形成碱加成的盐类。举例来说,当一化合物具有一氢原子键结至一氧原子、氮原子或硫原子时,当此氢原子与合适的有机或无机碱反应形成碱加成的盐时,其可预期该化合物也包含其盐类。碱加成盐类包含那些衍生自无机碱、例如铵或碱金或碱土金属氢氧化物、碳酸盐、碳酸氢盐及其它类似物,而有机碱例如烷氧化物、烷酰胺、烷基与芳香基胺及其它类似物。于制备本发明的盐类有用的此类碱包含氢氧化钠、氢氧化钾、氢氧化铵、碳酸钾及其它类似物。
举例来说,医药可接受盐类包含那些揭露的化合物与一当量的合适碱的反应所形成的单价盐(意即化合物具有单一负电荷可与医药可接受相对阳离子,例如:单价阳离子平衡)或与二当量的合适碱反应形成二价盐(意即化合物具有二个负电荷电子可与两医药可接受相对阳离子,例如两医药可接受单价阳离子或单一医药可接受二价阳离子)平衡。实施例包含Li+、Na+、K+、Mg2+、Ca2+及NR4 +,其中每个R个别为氢、选择性取代的脂肪基(例如:羟基烷基、氨基烷基或铵基烷基)或选择性取代芳香基,或二R基同时形成选择性取代非芳香杂环,其选择性与芳香环融合。一般来说,医药可接受阳离子为Li+、Na+、K+、NH3(C2H5OH)+或N(CH3)3(C2H5OH)+。
被揭示的化合物具有充分的碱基,例如氨基的医药可接受盐类,其由被揭示的化合物与有机或无机酸反应形成酸加成盐类来形成。一般由具有碱基的化合物形成酸加成盐类,酸包含无机酸,例如盐酸、溴酸、碘酸、硫酸、磷酸或其它类似物,以及有机酸例如对甲苯磺酸、甲烷磺酸、草酸、对溴苯磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸、醋酸或其它类似物。此类盐类的实施例包含硫酸盐类、焦硫酸盐类、双硫酸盐类、亚硫酸盐类、双亚硫酸盐类、磷酸盐类、单氢磷酸盐类、双氢磷酸盐类、间磷酸盐类、焦磷酸盐类(pyrophosphate)、氯酸盐类、溴酸盐类、碘酸盐类、醋酸盐类、丙酸盐类、癸酸盐类、辛酸盐类、丙烯酸盐类、甲酸盐类、异丁酸盐类、己酸盐类、庚酸盐类、丙炔酸盐类、草酸盐类、丙二酸盐类、琥珀酸盐类、辛二酸盐类、泌酸盐类、焦磷酸盐类(fumarate)、缩水苹果酸盐类、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯基醋酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、γ-羟基丁酸盐、甘醇酸盐、酒石酸盐、甲烷磺酸盐、丙烷磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐或其它类似物。
本发明也包含医药可接受溶剂化物(solvates,助溶剂)。本发明所使用术语“溶剂化物”是指本发明的化合物或其盐类可进一步包含化学计量或非化学计量的溶剂,例如藉由非共价分子间的力所结合的水或有机溶剂。
本发明也包括,包含所揭示的化合物的医药组合物。“医药组合物”包含揭示的化合物与可接受医药载体结合成为施用于受试者的医药组合物的一部分。被施用的化合物的配方会根据施用途径的选择而改变(例如:口服(例如药片、胶囊、锭剂、溶液或其它类似物))、血管内的、腹腔内、肌肉内、皮下、肠胃外的、口颊的、头盖骨内或脑脊髓的、眼球的(例如:溶液、软膏或包含一植入物或隐形镜片)、鼻腔的(例如:溶液、喷雾、气溶胶或其它类似物),咽喉的、肺的(例如:气溶胶)、阴道内的、肛门的、作为植入物或储备制备用、在植入接口装置表面披覆层中、作为局部施用的(例如:溶液、乳胶、胶囊、乳膏、软膏或其它类似物)。
合适的医药载体可包含不与该化合物反应的惰性组成。例如可使用于Remington’s Pharmaceutical Science(2005)描述的标准的医药配方技术。作为肠胃施用的合适医药载体包含,例如:无菌水、生理实验水、抗菌食盐水(食盐水中含有大约0.9%(mg/ml)苯甲醇)、磷酸缓冲食盐水、Hank’ssolution,Ringer’s-lactate及其它类似物。将组合物装入胶囊的方法(例如包在硬明胶或环葡萄聚糖衣内)为本技术领域所知悉(Baker,et al.(1986))。
当可轻易理解的是,部分被揭露的化合物可以不同的立体异构物(例如:非手性异构物及手性异构物)形式获得,而本发明包含所有被揭示化合物的异构物形式以及变旋(旋构)混合物,以及施以纯异构物及其混合物两者来治疗受试者的方法,也包含变旋混合物。立体异构物可利用任何合适的方法来分离与分隔,例如柱层析法。
在各种实施态样中,治疗具有亨丁顿舞蹈症受试者的方法,包含施用该受试者有效量的化合物及/或医药可接受天麻属(例如:天麻(Gastrodia elata))的萃取物,或其医药可接受组合物。
在各种实施态样中,治疗具有血中葡萄糖浓度异常受试者的方法,包含施用该受试者有效量的化合物及/或医药可接受天麻属(例如:天麻(Gastrodiaelata))的萃取物,或其医药可接受组合物。具有血中葡萄糖糖浓度异常的受试者可表现出血糖过高症,以及在各种实施态样中可具有一种或多种疾病,例如亨丁顿舞蹈症、第一型糖尿病、第二型糖尿病、心血管疾病、X症候群,肥胖相关血糖过高症、食欲过盛相关血糖过高症或类固醇诱发的血糖过高症或其它类似病症。
在各种实施态样中,控制受试者A2A受体活性的方法,包含施用该受试者有效量的化合物及/或医药可接受天麻属(例如:天麻(Gastrodia elata))的萃取物,或其医药可接受组合物。在部分实施态样中,施用于受试者的化合物、萃取物或医药组合物的剂量可有效地治疗受试者由A2A受体调控的疾病,例如,增加A2A受体的活性。
在各种实施态样中,调控受试者环单磷酸腺苷浓度的方法,包含施用该受试者有效量的化合物及/或医药可接受天麻属(例如:天麻(Gastrodia elata))的萃取物,或其医药可接受组合物。在部分实施态样中,施用于受试者的化合物剂量,广泛地或局部地在特殊细胞或组织有效地增加受试者环单磷酸腺苷的浓度。在部分实施态样中,施用于受试者的化合物、萃取物或医药组合物的剂量可有效地治疗受试者环单磷酸腺苷所致的疾病,例如,增加受试者环单磷酸腺苷的浓度。
实施例
材料与方法
制备天麻萃取物
天麻(Gastrodia elata B1.)的地下茎是由台北当地的中药店购买。将天麻薄片以乙醇水溶液萃取隔夜(60℃)。粗萃取物以真空回旋减压浓缩机浓缩。干燥的样品导入离子柱层析仪(DIAION HP20,HP21、Mitsubishi Chemical,Tokyo,Japan)并以水转换至甲醇的梯度洗脱。筛选各洗脱物(fractions)以保护PC12细胞因缺乏血清诱发的程序性死亡中的活性。具有此活性的洗脱物被结合后以SEPHADEX LH-20柱(Pharmacia LKB,Biotechnology AB,UppsalaSweden)纯化。以甲醇重复洗脱以获得两个记为T1-C及T1-11的活性成分。使用Merck PUROSPHER RP-18e(Merck KGaA Life Science&Analytics,Darmstadt,Germany),(250×4.6mm)柱的高效液相色谱仪,配合UV 270-nm检测器,以流速0.5ml/min,70%至40%水/甲醇的流动相梯度洗脱40分钟,再以40%至20%水/甲醇洗脱5分钟,观察不同批次的化学层析结果。
细胞培养
PC12细胞由American Type Culture Collection(ATCC,Manassas,VA,USA)订购,在补充了10%马血清及5%胎儿血清的Dulbecco’s Modified EagleMedium(DMEM)中存活,并且在37℃的二氧化碳培养箱中(5%)培养。StriatalProgenitor细胞株(ST14A)由Dr.E.Cattaneo(University of Milano,Italy)取得,并于33℃、10%二氧化碳-90%空气的前述培养槽中培养(Ehrlich,et al.(2001))。
MTT分析
PC12细胞以磷酸缓冲溶液(PBS)清洗三次后使其血清分离,之后重新悬浮于DMEM中,悬浮的细胞置入96-多孔板(每孔104个细胞),而后施以不同的萃取物或纯化物,在施以21小时后,取溴化3-(4,5-二甲基-噻唑-2-基)-2,5-二苯基四唑(MTT)加入培养基(0,5mg/ml)中,再于37℃中培养3小时。将培养基移除后,在每个孔中加入100μl二甲基亚砜(DMSO)来溶解甲臜(formazan)结晶,之后以微型酶联免疫吸收分析仪(micro-enzyme linked immunosorbentassay,ELISA)量测每个孔的570nm及630nm吸收值。
动物与药物施用
雄性R6/2鼠及同窝出生的对照组与雌性对照鼠(B6CBAF1/J)交配。实验鼠由Jackson Laboratories,Bar Harbor,ME,USA购入。其后代的鉴定通过遗传基因组的PCR遗传型技术。该遗传基因组是由尾部组织利用位于转基因(5’-CCGCTCAGGTTCTGCTTTTA-3’及5’-GGCTGAGGAAGCTGAGGAG-3’)的引子来确认CAG,重复的次数保持在约150。全部共有67只R6/2转基因鼠被用于本研究。这些动物以12小时日照/黑暗的周期储养于Institute of BiomedicalScience Animal Care Facility中。指示剂的日间注射为13:00至18:00间,老鼠体重的量测于每天喂食前记录一次,动物实验的操作参照Academia SinicaInstitutional Animal Care and Utilization Committee,Taiwan。
滚动轴测试
运动协调利用滚动轴装置(UGO BASILE,Comerio,Italy)在一恒定速度(12rpm)下超过2分钟(Carter,et al.(1999))来评估。所有的老鼠在六周大的时候训练两天,使其变为知悉该滚动轴装置。这些动物在7-12周大时每周测试三次。每次测试中,在激活转动前动物先置于装置中。因延迟而落下会被自动地记录。每只老鼠在每次测试中给予最多两分钟的三次测试。
免疫化学计量及定量:
含有纹状体的大脑(双耳5.34mm/前囱1.54mm至双耳3.7mm/前囱-0.1mm)切片(30μm)与肝切片(20μm)用来进行化学计量分析。使用先前技术(Wu,et al.(1998))中所描述的卵白素-生物素-过氧化酶错合物(ABC法)来操作单一抗原免疫染色。一般来说,稀释1∶2000时可用于多株抗体的抗泛素抗血清(DakoCytomation Denmark A/s,Glostrup,Denmark)。以抗泛素抗血清标示并以甲基绿复染的大脑的三种不同的切片定量。总计每个测试里的六只老鼠在12周时进行分析,每只老鼠至少1200和300个细胞被估算,以确定纹状体细胞和肝细胞表现泛素化Htt聚集。各别地,图3A为一代表性标示有泛素的纹状体的影像。其为一12周大的R6/2老鼠于四周大开始给予对照组的饮用水。比例尺为25微米。图3B为一代表性标示有泛素的纹状体的影像,其为一12周大的R6/2老鼠在四周大开始给予含有天麻萃取物(5mg/ml)的饮用水。比例尺为25微米。图3C为在第四周大开始给予控制或天麻萃取物(5mg/ml)饮用水的12周大R6/2鼠,其纹状体细胞所表现的神经元细胞核内含物(NIIs)条状图,其定量方法描述于“材料与方法”中。比例尺为25μm。在Student’s t-test中,在指示周数施以展色剂的R6/2老鼠比较时,**p<0.01。
血中葡萄糖浓度量测:
老鼠断颈方式处死,血液以EDTA血液试管收集血液样品(1-1.5ml),血糖浓度即利用ABBOTT Alcyon 300i分析仪(ABBOTT Labs,Abbott Park,IL,USA)进行量测。
串接质谱仪筛选血液中氨基酸:
通过使10.5周大的R6/2老鼠的尾巴静脉的血液(25μl)渗入滤纸中(S&S903;Schleicher&Shuell,Dassel,Germany)来进行样品的搜集。在进行分析前,血液先由滤纸层析,然后氨基酸的浓度利用一串接质谱仪(Qyatro Micro;Micromass,Beverly,MA,USA)以先前文献中的描述(Wu,et al.(2004))来检测。
实施例1:施用天麻萃取物保护细胞免于缺乏血清诱发的细胞凋亡
发明人先前发现A2A-R-特有致效剂特别改善几个HD的主要症状(Chou,et al.(2005))。此外,天麻萃取物不但呈现防止PC12细胞因血清分离所诱发的细胞凋亡,而且可活化A2A-R(Huang,et al.(2004))。在本研究中,发明人首先操作描述于“方法”中的天麻的不同色谱层析层的部分纯化。天麻萃取物的水/乙醇萃取物接着导入DIAION HP-20柱层析,并以水至甲醇的梯度洗脱。如图1所示,甲醇萃取的数个层析层(T1-1,T1-2及T1-3)呈现保护PC12免于血清抽离所诱发细胞凋亡的活性。最有效的层析层是T1-3层析(流析)层。
实施例2:施以天麻萃取物促进R6/2老鼠的运动协调与生命期
在此讨论T1-3层析层对R6/2老鼠的治疗效果。老鼠在4周至12周间被施以T1-3层析层(加入饮用水5mg/ml)。如图2A所示,R6/2HD鼠完成滚动轴测试全部流程(120s)的能力在10周大时显示降低。在饮用水中施以T1-3层析层减少R6/2老鼠以滚动轴测试其运动协调上的进一步恶化。图2B呈现R6/2老鼠的生命周期因慢性地施以T1-3层析层而适度地延长。由观测到的一般动物的行为或表现来推测在本研究中施用的T1-3层析层并无毒性影响。
实施例3:施以天麻萃取物降低R6/2老鼠神经元细胞核内聚集
T1-3层析层被用来讨论其对神经元细胞核内聚集(NIIs)形成的效应。由于在R6/2老鼠的大脑中观测到的NII2均泛素化(ubiquitinated)(Meade,etal.(2002)),被施以T1-3治疗的12周大R6/2老鼠的脑部切片被以抗泛素抗体染色,之后再以甲基绿复染。图3A-3C呈现出补充T1-3的R6/2老鼠其纹状体细胞表现NIIs明显地降低。推测天麻的施用延迟了HD鼠中NIIs的形成。而原生种老鼠的大脑中并未发现NII(Chou,et al.(2005)J Neurochem 93,310-20)。
实施例4:施以天麻萃取物降低R6/2鼠血中葡萄糖的升高
由各个实验室,包过发明人自己所展示的研究,HD病患与HD鼠存在血糖过高症(Chou,et al.(2005);Podolsky,et al.(1972);Duan,et al.(2003))。因为血糖过高的降低已经被联想到与HD受试者的神经元不足的促进有关(Duanet al.),发明人讨论是否慢性地施以T1-3可使R6/2老鼠的血中葡萄糖浓度正常。与早期文献(Hurlbert,et al.(1999))符合,R6/2老鼠与原生种老鼠相较,在六周大时其血中葡萄糖浓度约增加一倍。此增加的血中葡萄糖浓度比观察到移动协同缺陷的HD最终期(图2A)要更为明显。图4呈现出施以T1-3层析层降低了R6/2鼠中异常过高的血中葡萄糖浓度,展示了T1-3层析层促进葡萄糖调控与能量代谢。
表1、R6/2鼠与原生鼠的血中氨基酸浓度
Bloodcomponent | WT(CON)N=20 | R6/2(CON)N=24 | R6/2(RG)N=14 |
Arg | 31.30±3.24** | 78.60±6.41 | 49.87±9.96 |
Ala | 258.39±25.76* | 383.30±24.23 | 303.75±54.31 |
Cit | 22.51±3.48* | 41.38±4.79 | 37.49±8.70 |
Om | 12.02±2.05* | 24.25±5.02 | 27.88±4.99 |
Gln | 253.92±29.10* | 471.71±70.86 | 570.44±110.31 |
Glu | 153.24±15.22* | 230.80±17.18 | 164.92±28.22* |
Gly | 187.99±14.54* | 309.86±20.52 | 274.04±45.02 |
His | 4.23±0.66 | 3.27±0.38 | 3.36±0.64 |
Met | 13.79±1.33* | 28.55±1.79 | 26.92±5.04 |
Phe | 75.09±6.63* | 97.28±3.03 | 70.40±10.03* |
Pro | 738.22±99.42 | 812.81±52.68 | 546.90±87.47* |
Ser | 30.87±2.75** | 60.31±3.60 | 41.20±4.62** |
Thr | 65.38±7.00 | 74.07±5.27 | 53.45±6.77* |
Trp | 32.65±3.18* | 46.49±4.35 | 31.46±5.68* |
Tyr | 47.09±4.12** | 75.82±4.82 | 48.85±7.01** |
Val | 153.54±16.43 | 192.61±13.99 | 131.33±20.17* |
Asp | 72.81±23.06 | 54.95±6.99 | 141.04±26.00* |
实施例5:施以天麻萃取物降低HD鼠肝脏中的Htt聚集
由于代谢的不正常可能促成HD的病变,发明人进一步分析了血中氨基酸的浓度。如表1所示,在R6/2鼠中的17个被讨论的氨基酸中有12个显著地高于原生种。补充T1-3层析层将R6/2鼠中增高浓度氨基酸中的7个正常化。由于不正常氨基酸代谢可能造成肝脏官能障碍(Holm,et al.(1999)),发明人研究肝脏中Htt聚集的形成。与先前报导(Tanaka,et al.2004)符合,在R6/2鼠中可观察到Htt聚集(图5A)。慢性补充可降低HD鼠肝脏中的Htt聚集(图5B和图5C)。此保护效果与包含于局部缺血诱发的神经伤害与阿兹罕墨症(Kim,et al.(2001);Kim,et al.(2003)Phytother Res;Kim,et al.(2003)JEthnopharmacol;Hsieh,et al.(2001))的天麻的神经保护效果一致。
实施例6:活性天麻萃取物的分离组成保护PC12细胞免于细胞凋亡与其作用可能如A2A-R的致效剂
活性T1-3溶离层混合后经Sephadex LH-20柱层析(图6)分离与纯化。14个已知的化合物(包含天麻素、派立辛、4-羟基苯甲醇、4,4’-二羟基苯甲基亚砜、4-羟基苯基甲烷、双(4-羟基苯甲基)醚、4-羟基苯甲基乙醚、四羟基苯甲基-甲醚、柠檬酸三甲酯、4-羟基苯甲醛、尿苷、腺苷、5-(羟基甲基)-2-呋喃甲醛及T1-C(Taguchi,et al.(1981);Lin,et al(1996)Phytochemistry42,549-551;Hayashi,et al.(2002);Huang,et al.(2005),Xiao,et al.(2002))),及一先前未曾被分离的组成(T1-11)被鉴定出来。这些分离层析层测试其防止缺乏血清诱发细胞凋亡的能力。在15个组成中,两个组成(T1-C及T1-11)在保护PC12细胞免于程序性死亡具有活性(图7A)。T1-C及T1-11在T1-3层析层中大约分别占5%及0.2%。尽管其为一相对少量的组成,T1-11在保护PC12细胞免于细胞凋亡上比T1-C更具潜力。有趣的是,对于ST14A细胞(Ehrlich,et al.(2001))不论施以T1-C或T1-11,都显示增高细胞内cAMP的量,如同A2A-R选择性致效剂,CGS2168。此外,cAMP的反应可被A2A-R-依赖性拮抗剂(CSC,图7B)抑制。因此,相信T1-C与T1-11的功能应该如同A2A-R的致效剂。
实施例7:活性天麻萃取物的分离组成保持R6/2鼠的运动表现、降低体重减轻及延长生命期
由四周大开始,不论在饮用水中施以T1-C(0.5gm/ml)或T1-11(0.05mg/ml),都使R6/2鼠由滚动轴测试所估计的运动协同显著地延缓进一步恶化(见图8A)。此外,两种化合物改善了R6/2鼠的体重下降图(图8B)及并延长了生命期。对照组、T1-C及T1-11治疗鼠的平均存活时间为94.9±2.5、106.7±4.6及104.9±5.2天(mean±SEM,n=7-8;图8C)。
实施例8:活性天麻萃取物的分离组成的结构与性质
此二活性组成(T1-C及T1-11)的构造由光谱数据,特别是1D及2D核磁共振光谱数据解析。高效液相色谱仪用来监测不同批次活性层析层的化学剖面。活性层析层的层析图谱显示活性组成分的滞留时间为40.91分,其为T1-C,以及22.3分,其为T1-11。
T1-C为无色针状,由高解析离子化质谱(HREIMS)在m/z 247.0751(M++H)及13C的NMR光谱数据获得其分子式为C14H14O2S,有八个氢不足度(eight-hydrogendeficiency,IHD)。红外光谱图呈现羟基(3285cm-1)及芳香基(1604及1600cm-1)吸收。核磁共振光谱与质谱分析揭示了T1-C的结构为一对称化合物,1H NMR光谱指出一1,4-二取代苯基[δ7.09及6.72(4H each,d,J=8.5Hz)]以及二苯甲基硫烯烃基质子[δ3.53(4H,s)]。13C NMR的DEPT及HMQC分析揭示两个氧化合的sp2芳香碳原子[δ157.4(s)],六个芳香碳原子中两个完全取代sp2碳原子,以及两个硫烯烃基碳原子。T1-C的HMBC光谱揭示了由H-7至C-1,C-2(6)、由H-2(6)至C-1,C-3(5)与C-4的交叠波峰。由上述结果推测T1-C化合物应建构为4,4’-二羟基苯甲基硫:
T1-C:mp 126-128℃;IR(KBr)max:3285,1604,1600,1509,1214,1089,841,815cm-1;1H NMR(CD3OD)δ3.53(4H,s,H-7),6.72and 7.09(4H each,d,J=8.5Hz,H-3(5)and H-2(6));13C NMR(CD3OD)δ35.9(t,C-7),116.1(d,C-3(5)),130.5(s,C-1),131.1(d,C-2(6)),157.4(s,C-4);EIMS m/z(%)246(M+,35),200(15),107(100)HREIMS m/z 246.0717(calcd for C14H14O2S:246.0715).
与T1-C具有相同结构的化合物已经在较早的天麻萃取物的化学分析文献揭露(Xiao,et al.(2002)),相反地,T1-11在以前并未被鉴定出来,由其HRFABMS在m/z 374.1361(M++H)及13C NMR图谱数据鉴定为具有分子式C17H19O5N5的无色无晶型粉末。其IR图谱指出其羟基(3327、1125、1065cm-1),及一芳香系统(1630、1610、1585cm-1)。1H及13C NMR光谱呈现类似腺苷的图案,除了因对-羟基苯甲基氨基基团取代T-11氨基产生的讯号[δH4.60(2H,t,J=6.0Hz),6.65及7.12(2H each,d,J=8.5Hz,H-3”(5”)及H-2”(6”));δc 42.4(t,H-7”),114.9(d,C-3”(5”)),128.6(d,C-2”(6”)),130.8(s,C-1”)]。对-羟基苯甲氨基的连结可进一步由HMBC的H-7”及C-1”,C-2”(6”)及C-6的相关来确定。T1-11的结构((2-(6-(4-羟基苯甲氨基)-9H-嘌呤-9-基)-5-羟甲基)四氢呋喃-3,4-双醇)结构如下:
T1-11:mp 216~218℃;IR(KBr)max:3327,3164,2927,1630,1514,1125,1065,815cm-1;1H NMR(DMSO-d6)δ3.54and 3.64(1Heach,m,H-5’),3.95(1H,t,J=1.8Hz,H-4’),4.13(1H,m,H-3’),4.60(3H,m,H-2’,-7”),5.87(1H,d,J=5.5Hz,H-1’),6.65and 7.12(2H each,d,J=85Hz,H-3”(5”)and H-2”(6”)),8.19and 8.33(1Heach,s,H-2 and H-8),8.28,9.19(1H each,br s,OH and NH);13CNMR(DMSO-d6)δ42.4(t,C-7”),61.7(t,C-5’),70.7(d,C-3’),73.5(d,C-2’),85.9(d,C-4’),88.0(d,C-1’),114.9(d,C-3”(5”)),120.4(s,C-5),128.6(d,C-2”(6”)),130.8(s,C-1”),139.8(d,C-8),148.4(s C-4),152.3(d,C-2),154.5(s,C-6),156.1(s,C-4”);FABMS m/z(%)374(M++1,28),242(15),154(95),136(83),56(100);HRFABMS m/z 374.1361(calcd forC17H19O5N5:374.1388).
实施例9:化合物的合成流程
本发明所描述的化合物也可通过标准化学合成方法,或由手边容易获得的起始材料来获得。作为实施例的合成流程呈现如下。在一耦合步骤中,起始物与前驱官能基X1及X2耦合形成连结X:
举例来说,化合物的X为-O-时,其可选择一对等价的X1/X2,例如羟基与卤素或金属氧化物与卤素,在合适的反应条件下形成醚类(例如:Larock,R.C.(1999,page 890-895)。类似的,化合物的X为-S-时可藉由选择X1/X2价数例如硫醇或硫酯与一离去基例如卤素获得;此化合物可进一步氧化转换-S-成为-S(O)-或-SO2-。X为-C(O)NRa-、-NRaC(O)-、-NRaSO2-或-SO2NRa-的化合物,其可由X1与X2其中之一为氨基的起始材料以及另一为氨基反应羰基或磺酰基的衍生物来制备。举例来说,酸化卤、磺酰卤或其它类似物在合适条件下反应成酰胺或磺酰胺(例如:Larock,R.C.(1999,page 1953-1954))。X为双硫化物可在当X1/X2皆为-SH时经由还原与纯化制备。X为-NRa-时可藉由选择X1/X2价数如氨基与卤素在合适的反应条件下反应形成氨基的烷基化或芳香化(例如:Larock,R.C.(1999,page 779-784)。
依据反应条件,R3与R4基可藉由未经修饰的反应制得,或可选择性地被保护形成PG-R3与PG-R4,其中每个PG为一适当的保护基。例如,当R3与R4为-OH时,保护基包含烷基醚、烷氧基烷基醚、硅烷基醚或其它类似物。可用来由容易且手边等价物例如卤素、羟基或其它类似物转换成取代基,例如R3及R4或其它等价物的标准反应,其可参考Larock,1999做为例子。
实施例10:T1-C的合成途径
(4-甲氧基苯基)甲烷硫醇在乙醇中与氢氧化钠搅拌形成(4-甲氧基苯基)甲烷硫酯。将一当量的1-(氯甲基)-4-甲氧基苯加入混合物中搅拌隔夜。之后于此反应混合物加入稀酸来终止反应,所得产物双(4-甲氧基苯甲基)硫。接着将双(4-甲氧基苯甲基)硫与溴化氢在乙腈中反应移除甲氧基保护基,接着中和与纯化产物双(4-甲氧基苯甲基)硫。
实施例11:T1-11的合成途径
腺嘌呤核糖核苷(2-(6-氨基-9H-嘌呤-9-基)-5-(羟基甲基)四氢呋喃基-3,4-双醇)与4-甲氧基苯甲酰氯在二氯甲烷中反应隔夜。接着反应完成后使苯甲酰酮的部分在微过量的LiA1H4的乙醇中还原成亚烯基。所得化合物以溴化氢在乙腈中去保护以形成产物2-(6-(4-羟基苯甲基氨基)-9H-嘌呤-9-基)-5-(羟基甲基)四氢呋喃基-3,4-双醇(T1-11)。
本发明中所记载的每份文件均全文整合为参考文献。
本发明一系列的实施态样已揭示如上,然而当可轻易理解的是可在不背离本发明的精神与范围内进行各种修饰。其它实施态样由权利要求书的范围所界定。
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