CN112912102A - 6-磷酸甘露糖及其修饰物用于增强记忆和减少记忆受损的用途 - Google Patents
6-磷酸甘露糖及其修饰物用于增强记忆和减少记忆受损的用途 Download PDFInfo
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- CN112912102A CN112912102A CN201980066502.5A CN201980066502A CN112912102A CN 112912102 A CN112912102 A CN 112912102A CN 201980066502 A CN201980066502 A CN 201980066502A CN 112912102 A CN112912102 A CN 112912102A
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Abstract
提供了用于增强记忆,包括恢复记忆受损的组合物和方法。该组合物和方法涉及6‑磷酸甘露糖和6‑磷酸甘露糖的衍生物。所述方法涉及向需要增强记忆的个体给予M6P或其衍生物。
Description
关于联邦资助研究或开发的声明
本发明是基于美国国立卫生研究院(National Institutes of Health)授予的授权号MH065635和MH074736的政府支持下完成的。政府对本发明享有某些权利。
相关申请的交叉引用
本申请要求2018年8月10日提交的美国临时专利申请62/717,405和2019年7月8日提交的美国临时专利申请62/871,453的优先权,其各自内容通过引用全文纳入本文。
发明背景
在记忆保留和回忆受到不利影响的病原性情况以及非病态情况下可能需要增强记忆。可能发生记忆丧失的疾病的例子包括:神经变性疾病,轻度认知受损,脑血管疾病,路易体病,额颞变性,发育性认知障碍,创伤性脑损伤,谵妄,感染,酗酒或癌症。在缺乏用于增强记忆的有效手段的情况下,仍然需要开发用于增强记忆的方法。
发明内容
本公开提供了用于增强记忆和恢复记忆受损的方法。该方法包括向需要增强记忆或恢复记忆受损的对象,或寻求增强记忆或恢复记忆受损的对象,给予包含治疗有效量的除了IGF-2之外的IGF-2受体的激动剂或活化剂或基本上由其组成的组合物。在一个实施方案中,激动剂是6-磷酸甘露糖(M6P)或6-磷酸甘露糖的衍生物(在本文中也称为“修饰物”),或IGF-2的衍生物或修饰物(例如,IGF-2类似物)。在一个实施方案中,包含M6P或M6P衍生物或基本上由其组成的组合物可以用于治疗其中存在蛋白质聚集(导致突触病(synaptopathies))的任何神经变性疾病,包括诸如阿尔茨海默病,帕金森病,路易体病等。在一个实施方案中,包含M6P或M6P衍生物或基本上由其组成的组合物可用于减少记忆受损。在一个实施方案中,IGF-2修饰物(例如,IGF-2类似物)可用于增强记忆或减少记忆受损。
附图说明
图1:正常(野生型,WT)小鼠中M6P(也称为IGF2R.L1(L1))对nOR影响的剂量反应曲线。实验时间表显示在图表上方。所有数据均表示为平均值±s.e.m.。N=4/组。单向方差分析(ANOVA),然后进行Bonferroni事后检验。*P<0.05,**P<0.01。在进行nOR训练前20分钟,WT小鼠经皮下注射载剂或不同剂量的IGF2R.L1(L1)。图表显示,在训练后4小时和24小时进行的测试中,与熟悉的物体相比,对新物体的探索偏好百分比。
图2:M6P在安格曼综合征的小鼠模型中逆转了物体识别记忆缺陷并增强了WT小鼠的记忆。实验时间表显示在图表上方。在所有实验中,在nOR训练或测试前20分钟,小鼠均接受皮下注射载剂或M6P(↑)。训练后4小时和24小时进行测试,训练前20分钟注射载剂或M6P(标签为IGF-2R.L1)的WT(对照)和Ube3a-/+(AS)小鼠的新物体识别期间,与熟悉的物体相比,对新物体的探索偏好百分比。N=4/组。所有数据表示为平均值(±s.e.m.)。双向方差分析(ANOVA),然后进行Tukey事后检验。*P<0.05,**P<0.01,***P<0.001。
图3:注射到大鼠海马中的M6P增强记忆:剂量反应曲线。实验时间表显示在图表上方。在进行情境恐惧记忆任务抑制回避(IA)训练后,大鼠立即接受了双侧海马内注射载剂或不同剂量的IGF-2R.L1(M6P)(↑)。然后在训练后的24小时(T1)和7天(T2)测试记忆保留。测试测量了进入训练期间动物受到足部冲击的隔室的潜伏期。N=12/组。所有数据表示为平均值(±s.e.m.)。双向重复测量方差分析(ANOVA),然后进行Bonferroni事后检验。*P<0.05,**P<0.01,***P<0.001。
图4:M6P衍生物膦酸酯M6P(PnM6P)增强了小鼠的记忆力。实验时间表显示在图表上方。在训练前20分钟,小鼠接受皮下注射载剂或850μg/Kg的膦酸酯-M6P(PnM6P),称为IGF-2R.L2(或L2)(↑)。(A)训练后24小时(测试1)、5天(测试2)和14天(测试3)进行测试,训练前20分钟注射载剂或L2的小鼠的nOR范例期间,与熟悉的物体相比,对新物体的探索偏好百分比。N=8-10/组。数据表示为%平均值±s.e.m.。(B)在训练前20分钟,在注射载剂或L2的小鼠的nOR训练期间,探索两个物体所花费的总时间。N=4/组。相似的探索时间表明,物体探索/兴趣没有基础偏差,从而确认A的变化是由于记忆保留的变化引起的。数据以秒为单位表示。双向方差分析(ANOVA),然后进行Bonferroni事后检验。*P<0.05,**P<0.01,***P<0.001。
图5:比较M6P(L1)和PnM6P(L2)对记忆保留的影响:L1和L2相似地增强了小鼠的nOR。实验时间表显示在图表上方。在训练前20分钟,小鼠接受皮下注射载剂或850μg/Kg的膦酸酯-M6P(PnM6P),称为IGF-2R.L2(或L2),或850μg/Kg的M6P(IGF-2R.L1或L1)(↑)。(A)训练后24小时(测试1)、5天(测试2)和14天(测试3)进行测试,训练前20分钟注射载剂、L2或L1的小鼠的nOR范例期间,与熟悉的物体相比,对新物体的探索偏好百分比。N=4-10/组。数据表示为%平均值±s.e.m.。(B)在训练前20分钟,在注射载剂、L2或L1的小鼠的nOR训练期间,探索两个物体所花费的总时间。N=2-4/组。相似的总探索时间表明,偏好数据不是由于物体探索/兴趣行为的变化,而是由于记忆的变化。数据以秒为单位表示。双向方差分析(ANOVA),然后进行Bonferroni事后检验。*P<0.05,**P<0.01,***P<0.001。
图6:PnM6P(L2)逆转了安格曼综合征小鼠模型中的物体识别记忆缺陷。实验时间表显示在图表上方。在训练或测试前20分钟,小鼠接受皮下注射载剂或850μg/Kg的膦酸酯-M6P(PnM6P),称为IGF-2R.L2(或L2)(↑)。(A)训练后4小时、24小时和5天(5d)进行测试,训练前20分钟注射载剂或L2的野生型(WT,用作对照小鼠)和Ube3a-/+(AS)小鼠的nOR范例期间,与熟悉的物体相比,对新物体的探索偏好百分比。N=4/组。数据表示为%平均值±s.e.m.。(B)在训练前20分钟,在注射载剂或L2的WT和AS小鼠的nOR训练期间,探索两个物体所花费的总时间。N=4/组。相似的总探索时间表明,偏好数据不是由于物体探索/兴趣行为的变化,而是由于记忆的变化。数据以秒为单位表示。双向方差分析(ANOVA),然后进行Bonferroni事后检验。*P<0.05,**P<0.01,***P<0.001。
发明详述
本公开提供了使用除IGF-2之外的IGF-2受体的激动剂或活化剂来增强记忆或治疗记忆受损的组合物和方法。例如,可以使用M6P或其衍生物。
如本文所用,术语“治疗”是指与正在治疗的特定病症的存在相关的一种或多种症状或特征的减少或延迟。治疗并不意味着完全治愈。关于记忆增强的治疗意味着增加的记忆保留,增加的记忆强度和/或减少的记忆衰退。
本文所用的术语“治疗有效量”是足以以单次或多次剂量达到预期治疗目的的量。例如,实现记忆增强的有效量是足以实现记忆的可测量增加的量(可以通过例如测试学习和记忆性能的标准测试来测试)。期望或需要的确切量将根据给药方式,患者的具体情况等而变化。受益于本公开,本领域普通技术人员(例如临床医生)可以确定适当的有效量。
如本文所用,术语“记忆丧失”是指记忆的全部或部分丧失。
术语“记忆保留”是记忆强度的量度。因此,“增强记忆强度”可以通过对象保留特定记忆的能力来衡量。
如本文所用,术语“短期记忆”是持续数秒或数分钟的记忆。
如本文所用,术语“工作记忆”是指负责临时保存可用于处理的信息的记忆。工作记忆对于推理以及决策和行为的指导很重要。
如本文所用,术语“长期记忆”是指可以持续至少几个小时,至少一天,至少一年,至少十年或终生的记忆。
在本公开中提供值的范围的情况下,应理解,除非文中另有明确说明,各中间值到该范围上下限之间的下限单位的十分之一,以及在所述范围内的任何其他中间值均包括在本发明范围内。这些较小范围的上限和下限可以独立地包括在本公开内容所涵盖的较小范围中。
如本公开中所使用的,除非文本中另有明确说明,单数形式包括复数形式,反之亦然。
本公开描述了M6P和M6P衍生物对记忆增强的影响。在一个方面,本公开提供了一种增强记忆的方法,该方法包括向需要治疗或需要增强记忆的对象(例如寻求增强记忆的个体)给予包含M6P或其修饰物、或基本上由M6P或其修饰物组成的组合物。M6P的膦酸酯和磺酸酯衍生物在本领域中是已知的(授予Ferguson的美国专利6,140,307,其描述通过引用并入本文)。记忆增强可以是记忆召回和保留(短期或长期)和/或记忆强度的形式。在一个实施方案中,可以使用IGF-2修饰物(例如,IGF-2类似物)。例如,可以使用具有氨基酸取代的IGF-2(Armitaj等人,Neuroscience,2010年10月27日;170(3):722-30)。
本公开的分子(在本文中也称为试剂)包括M6P(在本文中称为L1)。可以通过对甘露糖的碳1和/或碳6进行修饰来制备M6P的衍生物(在本文中也称为修饰物)。在碳1和碳6上进行化学反应的方法是本领域已知的。衍生物的实例包括其中碳1被烷氧基(例如,甲氧基,乙氧基等)或炔烃官能化并且碳6被膦酸酯,乙酯,丙二酸甲酯,膦酸,羧酸盐或丙二酸酯官能化的例子。在各种实例中,碳1被烷氧基(例如甲氧基)官能化并且碳6被以下基团官能化:膦酸酯(在本文中称为L2),乙酯(在本文中称为L3),丙二酸甲酯(在本文中称为L4),膦酸(在本文中称为L5),羧酸盐(例如,羧酸的钠盐)(在本文中称为L6),或丙二酸酯(在本文中称为L7),以及碳1被炔烃官能化并且碳6被以下基团官能化:膦酸(称为L8)或膦酸酯(称为L9)。上面列出的M6P及其衍生物的结构如下所示:
如本文所述的M6P的制剂、剂量和用途也适用于任何修饰物(衍生物)。M6P或M6P衍生物的用量可以为约1-2,000μg/kg体重及其间的所有值和范围。例如,M6P和/或其衍生物的用量可以为1-2,000μg/kg,1-1,500μg/kg,1-1,000μg/kg,1-500μg/kg,1-100μg/kg,10-2,000μg/kg,10-1,500μg/kg,10-1,000μg/kg,10-500μg/kg,10-100μg/kg,50-2,000μg/kg,50-1,500μg/kg,50-1,000μg/kg,50-500μg/kg和50-100μg/kg体重,以及上述范围内的所有值。在一个实施方案中,M6P和/或其衍生物可以以850μg/kg皮下给予。在一个实施方案中,M6P和/或其衍生物的用量可以为100-1,000μg/kg。在特定的实施方案中,M6P和/或其衍生物的用量可以为50、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1,250、1,500、1,750和2,000μg/kg体重。此外,基于本文提供的关于动物的数据,本领域技术人员可以获得相关人剂量。这种转化的指导是本领域已知的(参见,例如,Nair等人Nair et al.,J.Basic Clin.Pharma.,v 7(2),2016年3月-2016年5月;27-31,通过引用并入本文)。
M6P可以以游离磷酸或其药学上可接受的单盐或二盐的形式存在,例如钠盐,钙盐,镁盐或钡盐。它也可以以可以在体内从中释放M6P的含M6P的化合物的形式提供,也可以以可以在体内从中产生M6P的前体的形式提供。M6P衍生物(在适用的情况下(例如,L3,L7和L8))也可以以游离酸或其盐(例如,其单钠盐或二钠盐)的形式存在。
在一个方面,本公开提供了一种在需要或期望增强记忆的对象中增强记忆的方法,其包括向对象给予包含M6P或其衍生物或基本上由M6P或其衍生物组成的组合物。对象可以是人。对象可以是任何年龄或性别。对象可能已经或可能没有被诊断出与记忆有关的病症。在一个实施方案中,本发明提供了包含M6P或其衍生物或基本上由M6P或其衍生物组成的组合物,用于改善记忆疾病或记忆受损,或用于增强正常记忆。在一个实施方案中,M6P或其衍生物是组合物中唯一与IGF-2受体特异性结合的试剂。本公开的组合物和方法可用于增强记忆,或预防、延迟发作或治疗记忆受损。本方法可以增加对以前的经验、知识、想法、感觉、思想或印象的心理登记、保留或回忆。在一个实施方案中,包含M6P或其衍生物的本发明组合物增加了短期和/或长期信息保留、工作记忆、具有空间关系的便利、记忆(排演)策略以及言语检索和制作。在一个实施方案中,包含M6P或其衍生物或基本上由M6P或其衍生物组成的本发明组合物可以改善海马依赖性学习、联想学习、短期记忆、工作记忆和/或空间记忆。这些反应可以通过本领域已知的标准记忆和/或认知测试来测量。
在一个实施方案中,本公开提供了一种治疗脑中有蛋白质聚集的疾病的方法,例如神经变性疾病,例如阿尔茨海默病,帕金森病,路易体病等。该方法包括向需要治疗的对象给予包含M6P或其衍生物或基本上由M6P或其衍生物组成的组合物。在一个实施方案中,本公开提供了一种治疗神经变性疾病的方法,所述神经变性疾病包括亨廷顿病,帕金森病,肌萎缩性侧索硬化症(ALS)和由于衰老引起的神经变性,所述方法包括向需要治疗的对象给予包含M6P或其衍生物或基本上由M6P或其衍生物组成的组合物。在一个实施方案中,本公开提供了一种治疗与头部损伤,脊髓损伤,发作,中风,癫痫,局部缺血,神经精神性综合征,病毒性脑炎引起的CNS损伤,脑膜炎引起的CNS损伤,或肿瘤引起的CNS损伤有关的记忆受损的方法,所述方法包括向需要治疗的对象给予包含M6P或基本上由M6P组成的组合物。在一个实施方案中,本公开提供了一种增强正常对象中记忆保留的方法,所述正常对象不患有影响神经功能的神经变性疾病或病理状况,所述方法包括向需要治疗的对象给予包含M6P或其衍生物或基本上由M6P或其衍生物组成的组合物。
可以通过与合适的药学上可接受的载体、赋形剂和/或稳定剂组合,以药物组合物的形式提供本发明的试剂。药学上可接受的载体、赋形剂和稳定剂的实例可参见《雷明顿:科学与药学实践》(Remington:The Science and Practice of Pharmacy)(2005)第21版,宾夕法尼亚州费城,Lippincott Williams&Wilkins。M6P可以悬浮液,溶液,凝胶或固体形式使用。合适的载体包括在使用的剂量和浓度下对接受者无毒的赋形剂或稳定剂,包括:缓冲剂,例如乙酸盐,Tris,磷酸盐,柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂,例如十八烷基二甲基苄基氯化铵;氯化六甲铵;苯扎氯铵,苄索氯铵;苯酚,丁醇或苯甲醇;对羟基苯甲酸烷基酯,例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;邻苯二酚;间苯二酚;环己醇;3-戊醇;和间甲酚;氨基酸,例如甘氨酸,谷氨酰胺,天冬酰胺,组氨酸,精氨酸或赖氨酸;单糖,二糖和其他碳水化合物,包括葡萄糖,甘露糖或糊精;螯合剂,如EDTA;渗透压调节剂(tonicifier),例如海藻糖和氯化钠;糖,例如蔗糖,甘露醇,海藻糖或山梨糖醇;表面活性剂,例如聚山梨酯;成盐的抗衡离子,例如钠;和/或非离子表面活性剂,例如吐温或聚乙二醇(PEG)。药物组合物可以包含0.01-99重量/体积%或重量/重量%的活性物质(例如,M6P,M6P衍生物或IGF-2修饰物(例如,IGF-2类似物))。
可以使用本领域已知的任何合适的给药途径给予本发明组合物。例如,可以通过静脉内,肌内,腹膜内,脑脊髓内,皮下,关节内,滑膜内,口服,局部或吸入途径给予组合物。该组合物可以胃肠外或肠内给药。在一个实施方案中,本发明的组合物可以口服给药,例如是片剂,胶囊剂,丸剂,粉末剂,糊剂,颗粒剂,酏剂,溶液剂,混悬剂,分散剂,凝胶剂,糖浆剂或任何其他可摄取形式。M6P或其衍生物可以通过脂质体,微粒,微胶囊递送。组合物可以以单次给药或多次给药的形式引入,或者可以在一段时间内以连续的方式引入。例如,给药可以是预定的给药次数或每日、每周或每月给药,其可以是连续的或间歇性的,如临床需要和/或治疗上所指示的那样。
在一个实施方案中,组合物中的M6P或M6P衍生物不连接(例如,不直接或通过接头共价结合)任何其他部分,并且不充当任何其他部分或试剂的载体。
一方面,本公开提供了M6P衍生物和包含甘露糖衍生物的组合物。M6P的衍生物可以通过在M6P的碳1和/或碳6上进行化学反应来制备。在己糖的碳1和/或碳6上进行化学反应的各种方法是本领域已知的。M6P衍生物的实例包括但不限于:膦酸酯(L2),乙酯(L3),丙二酸甲酯(L4),膦酸(L5),羧酸盐(L6),丙二酸酯(L7),炔烃(L8),和炔烃前药(L9)。在一个实施方案中,本公开提供选自L2,L3,L4,L5,L6,L7,L8和L9的化合物。在一个实施方案中,本公开提供了包含L1,L2,L3,L4,L5,L6,L7,L8和L9中的一个或多个的组合物。
下述实施例作为说明性实施例提供,并不旨在以任何方式进行限制。
实施例1
该实施例证实了全身给予6-磷酸甘露糖(M6P)可增强正常啮齿动物的记忆并逆转小鼠模型中的记忆缺陷。我们测试了不同浓度的M6P用于增强记忆。结果如图1所示。
我们发现在模拟安格曼综合征的小鼠(Ube3a-/+小鼠,AS小鼠)中全身给予M6P可以逆转其记忆受损(图2)。我们还证实了该配体在全身和脑内注射的小鼠和大鼠中均充当认知增强剂(图2和3)。
具体来说,我们在小鼠中使用了新物体识别(nOR)范例来评估非厌恶性情节记忆。在这项任务中,利用啮齿动物对新事物的天生偏好。在训练期间,允许小鼠探索2个相同的物体。在测试日,将训练物体之一替换为新物体。因为小鼠天生喜欢新事物,所以如果小鼠识别出熟悉的物体,它将在新物体上花费更多的时间。
皮下注射M6P可逆转AS小鼠的记忆受损。如图2所示,nOR训练后4小时的测试显示,注射了对照溶液(载剂)的对照组(野生型同窝仔,WT)小鼠具有较强的记忆力,而注射载剂的AS小鼠表现出明显的记忆受损,证实了它们已建立的记忆缺陷。训练前进行M6P注射可逆转AS小鼠的记忆缺陷,事实上其记忆保留水平与对照组WT小鼠相似。
此外,与注射载剂的小鼠相比,注射M6P的对照小鼠显示出显著的记忆增强,表明M6P在正常动物中是强效的记忆增强剂。在训练后24小时进行测试时,注射载剂的对照组和AS小鼠均对旧物体几乎没有或没有记忆。然而,注射M6P在两组中均显著增强了记忆保留,进一步证明了在学习过程中通过M6P激活IGF-2受体对增强记忆保留和持久性非常有效。
我们还发现,将M6P双侧注射到大鼠海马中后,可显著增强大鼠的记忆保留。在这些实验中,对成年大鼠进行了抑制回避(IA)范例训练。在这种范例中,动物学会避免与足部冲击相关的隔室。如图3所示,与接受载剂注射的大鼠相比,训练后立即接受向海马内的M6P双侧注射的大鼠在训练后1天测试的回避记忆显著提高。在6天后重复进行的另一项测试中,这种效果持续存在。M6P的记忆增强作用是剂量依赖性的。
我们发现,M6P衍生物膦酸酯M6P,PnM6P(也称为IGF-2R.L2或L2)在皮下注射(s.c.)小鼠时显著增强记忆。具体来说,我们在小鼠中使用了新物体识别(nOR)范例。与注射载剂的小鼠相比,注射PnM6P(L2)的小鼠显示出显著的记忆增强,表明L2在正常动物中是强效的记忆增强剂(图4)。在训练后24小时和5天进行测试时,注射载剂的小鼠对旧物体几乎没有或没有记忆。然而,在训练后的这两个时间点注射L2可以显著增加记忆保留,表明L2可以显著增加记忆保留和持久性。9天后(训练后14天)再次测试小鼠时,不再看到记忆增强。在这个时间点,注射载剂的小鼠和注射L2的小鼠均表现出机会偏爱(无记忆)。
在训练后24小时、5天或14天,将L2(PnM6P)与L1(M6P)的效果进行比较时,记忆增强效果没有发现差异(图5)。在训练后24小时和5天,L1和L2注射导致相似的显著的记忆增强。训练后第14天,两者的效果均恢复到基线。
L2可以显著逆转安格曼综合征(AS)小鼠模型中的记忆缺陷。如图6所示,皮下注射PnM6P可以逆转AS小鼠的记忆受损。训练后4小时测试的NOR记忆显示,注射了对照溶液(载剂)的对照组(野生型同窝仔,WT)小鼠具有较强的记忆力,而注射载剂的AS小鼠表现出明显的记忆受损,证实了它们已建立的记忆缺陷。训练前进行L2注射可逆转AS小鼠的记忆缺陷,事实上,在训练后4小时其记忆保留水平与对照WT小鼠相似。此外,如第0034段和第0035段中所述,在训练后4小时,注射L2的WT小鼠显示增强的记忆。训练后24小时进行再次测试,结果表明,注射载剂的对照(WT)和AS小鼠均无记忆,但是注射L2在两组中均具有显著的记忆。
实施例2
本实施例描述了M6P衍生物的合成和表征。
一般合成方法
除非另有说明,所有反应均在进行磁力搅拌的同时,在氮气或氩气正压下,在火焰干燥或烘箱干燥的玻璃器皿中进行。通过使溶剂通过活性氧化铝柱进入火焰干燥的玻璃器皿,获得无水二氯甲烷(CH2Cl2),乙醚(Et2O),1,4-二噁烷,四氢呋喃(THF),甲苯(PhMe)和N,N-二甲基甲酰胺(DMF)。除非另外说明,否则使用从商业供应商(Acros Organics,AKScientific,Alfa Aesar,Chem-Impex International,Combi-Blocks,Sigma-Aldrich,Strem Chemicals,Synthonix,Tokyo Chemical Industry Co.)获得的其他溶剂和试剂。薄层色谱(TLC)使用预先涂有F254荧光指示剂(Millipore Sigma)的硅胶60玻璃板进行反应监测,通过阻挡紫外线(λ=254nm)可视化,或通过用高锰酸钾(KMnO4)水溶液,酸性钼酸铵铈(IV)(CAM)水溶液,酸性对茴香醛乙醇溶液,或茚三酮丁醇溶液染色,然后用热风枪轻轻加热。使用玻璃柱或Teledyne Isco MPLCRf+,用硅胶(40-63μm,Silicycle或Merck),在氮气压力下于室温进行快速柱色谱。在25℃,在配备有CryoProbeTM的Bruker Avance III HD 400MHz光谱仪上,记录质子核磁共振(1H NMR)谱,表示为百万分之一(ppm,δ量级),相对于四甲基硅烷的低场(TMS,δ=0ppm),内部参比NMR溶剂的残余质子离子(protium)共振(CDCl3:7.26[CHCl3],CD3OD:4.87[MeOH],D2O:3.31[H2O],C6D6:7.16[C6H6],(CD3)2SO:2.50[(CH3)2SO])。在25℃,在配备有CryoProbeTM的Bruker Avance III HD400MHz光谱仪上记录质子解耦的碳-13核磁共振(13C{1H}NMR)谱,表示为百万分之一(ppm,δ量级),相对于四甲基硅烷的低场(TMS,δ=0ppm),内部参比NMR溶剂的C-13共振的中心线(CDCl3:77.36[CHCl3],CD3OD:49.00[MeOH],(CD3)2SO:39.52[(CH3)2SO])。在25℃,在配备有CryoProbeTM的Bruker Avance III HD 400MHz光谱仪上记录质子解耦的磷-31核磁共振(31P{1H}NMR)谱,表示为百万分之一(ppm,δ量级),相对于磷酸的低场(H3PO4,δ=0ppm),外部参比三苯基磷酸酯标准溶液(0.0485M在CDCl3中,δ=-17.7ppm)。报告的数据表示为:化学位移(百万分之一,ppm,δ量级)(积分,多重性,以Hz为单位的偶合常数J,原子分配)。多重性缩写为:s,单峰;d,双重峰;t,三重峰;q,四重峰;quint,五重峰;sext,六重峰;hept,七重峰;br,宽峰;m,多重峰;或其组合。高分辨率质谱(HRMS)使用Agilent 6224精确质量飞行时间(TOF)液相色谱质谱仪(LC/MS)结合常压化学电离(APCI)或电喷雾电离(ESI)方法进行。参比聚苯乙烯标准品,在Thermo Scientific Nicolet 6700FT-IR光谱仪上记录傅立叶变换红外(FT-IR)光谱。信号以波数(cm-1)表示为吸收频率,描述符缩写为:w,弱;m,中等;s,强,br,宽。在具有反相(RP)Phenomenex半制备柱(00D-4439-E0 Gemini,C18相,粒径3μm,孔径)的Agilent 1260Infinity II液相色谱仪上进行高效液相色谱(HPLC)纯化,流速为8mL/分钟,溶剂混合物为在(A)乙腈(HPLC级)和(B)水(HPLC级)中的0.1%甲酸(FA)。在具有Flint Glass Faraday电池调制器、钠灯光源和光电倍增管(PMT)检测器的Jasco P-2000旋光仪上记录旋光度测量值。根据公式[α]=(100·α)/(l·c)计算比旋光度,其中浓度c以g/100mL为单位,光程长度l以分米为单位。计算的比旋光度报告为无单位值,并表示为:[α]D T比旋光度(c浓度,溶剂),其中温度T以℃为单位,D代表钠D-线监测仪的波长(589nm)。
化合物的合成与表征
合成L2
甲基6-O-三苯甲基-α-D-甘露吡喃糖苷(2)
三苯甲基醚2根据改进的公开方法(Traboni等人,ChemistrySelect 2017,2,4906-4911;Tennant-Eyles等人,J.Tetrahedron:Asymmetry 2000,11,231-243)进行制备。向甲基-α-D-甘露吡喃糖苷(5.02g,25.8mmol,1.0当量)和三苯甲基氯(7.91g,28.4mmol,1.1当量)的混合物中加入吡啶(5.2mL,64.6mmol,2.5当量)。将反应混合物加热至100℃,并搅拌30分钟。30分钟后,将所得粘稠的糊状物通过在40℃超声溶解在CH2Cl2中。将溶液用饱和氯化铵水溶液(2×)洗涤,用无水硫酸钠干燥,过滤,并在减压下浓缩。粗残余物通过快速柱色谱法纯化(50%至100%乙酸乙酯/己烷),得到为白色泡沫状的2(11.0g,25.2mmol,98%)。NMR光谱与文献报道的那些相匹配(Traboni等人,ChemistrySelect 2017,2,4906-4911;Tennant-Eyles等人,J.Tetrahedron:Asymmetry 2000,11,231-243)。1H NMR(400MHz,CDCl3)δ7.48-7.28(15H,m),4.72(1H,d,J=1.6Hz),3.92(1H,m),3.82-3.63(3H,m),3.50-3.39(2H,m),3.38(3H,s),2.73(1H,m),2.54(1H,m),2.27(1H,m)。13C NMR(101MHz,CDCl3)δ143.9,128.9,128.3,127.5,100.9,87.7,72.0,70.64,70.59,70.1,65.2,55.3。
甲基2,3,4-三-O-苯甲基-α-D-甘露吡喃糖苷(4)
苯甲基醚3根据改进的公开方法(Hofmann等人,Carbohydr.Res.2015,412,34-42)进行制备。将三苯甲基醚2(2.01g,4.61mmol)溶解在无水DMF(115mL)中,并在0℃,向该溶液分批加入NaH(60%,在矿物油中,14.8g,371mmol,7.2当量)的悬浮液。将反应混合物在0℃下搅拌10分钟,并向该混合物中缓慢加入苯甲基氯(39.1g,309mmol,6.0当量),将悬浮液在0℃下搅拌5分钟,然后温热至室温并搅拌16小时。将反应混合物用水淬灭,并用乙酸乙酯萃取。有机层用无水硫酸钠干燥,并减压浓缩,得到3,为粘稠的黄色油,将其直接用于以下过程。
醇4根据改进的公开方法(Jaramillo等人,J.Org.Chem.1994,59,3135-3141)进行制备。将苯甲基醚3溶解在MeOH-CH2Cl2(2:1,6mL)中,并添加p-TsOH直至pH<4。将反应混合物在室温搅拌20小时,然后用Et3N中和并在减压下浓缩。将残余物溶于CH2Cl2中,并用蒸馏水和盐水洗涤。有机层经无水硫酸钠干燥并在减压下浓缩。粗残余物通过快速柱色谱法(30%至60%乙酸乙酯/己烷)纯化,得到浅黄色浆状的醇4(0.90g,1.94mmol,42%)。NMR光谱与文献报道的那些光谱相匹配(Norberg等人,Carbohydr.Res.2017,452,35-42)。1H NMR(CDCl3,400MHz)δ7.41-7.30(15H,m),4.97(1H,d,J=10.9Hz),4.81(1H,d,J=12.3Hz),4.75-4.65(5H,m),3.99(1H,app.t,J=9.4Hz),3.92(1H,dd,J=9.4,2.9Hz),3.90-3.84(1H,m),3.83-3.76(2H,m),3.68-3.62(1H,m),3.33(3H,s),2.00(1H,app.t,J=6.4Hz)。13C NMR(101MHz,CDCl3)δ138.8,138.7,138.6,128.70,128.68,128.67,128.3,128.1,128.0,127.9,99.6,80.5,75.5,75.2,75.0,73.2,72.5,72.4,62.7,55.1.HRMS(APCI/LC-TOF)m/z:[M+NH4]+计算值482.2537;实测值482.2533。
甲基2,3,4-三-O-苯甲基-6-脱氧-6-二乙氧基氧膦基亚甲基-α-D-甘露吡喃糖苷(7)
醛5根据伯醇氧化的一般方法(Tojo等人,醇氧化为醛和酮的方法:当前常用方法指南(Oxidation of alcohols to aldehydes and ketones:a guide to current commonpractice).Springer Science&Business Media:2006)进行制备。在氮气下在无水DMSO(1.8mL)中制备4的溶液(0.334g,0.72mmol,0.4M)。向该溶液中加入Et3N(1.0mL,7.2mmol,10当量),并将反应混合物在冰水浴中冷却至0℃并搅拌。在0℃下,向该溶液中滴加三氧化硫-吡啶配合物(0.347g,2.2mmol,3.0当量)的DMSO(1mL)溶液。将反应混合物温热至室温,并搅拌20小时。溶液用CH2Cl2稀释并用蒸馏水洗涤,用无水硫酸钠干燥,并在减压下浓缩,得到5,为黄色油。将该油通过二氧化硅短柱过滤,并直接用于以下过程。
膦酸酯7根据改进的公开方法(Vidil等人,Eur.J.Org.Chem.1999,447-450)进行制备。向NaH(60%,在矿物油中,37.8mg,0.945mmol,2.2当量)在无水甲苯(2mL)中的悬浮液滴加亚甲基二膦酸四乙酯(0.27mL,1.08mmol,2.5当量),并在室温下搅拌30分钟。在氮气下将5的无水甲苯溶液(5mL)滴加到该混合物中,并在室温搅拌2小时。反应混合物用CH2Cl2稀释,并用蒸馏水淬灭。有机层用CH2Cl2(3×)萃取,用无水硫酸钠干燥,并在减压下浓缩。粗残余物通过快速柱色谱法纯化(40%至100%乙酸乙酯/己烷),得到7,为无色浆液(162mg,0.272mmol,62%)。NMR谱与文献报道的那些相匹配(Vidil等人,Eur.J.Org.Chem.1999,447-450).[α]D 20=+40.4(c=1.01,CHCl3)。1H NMR(CDCl3,400MHz)δ7.39-7.27(15H,m),6.96(1H,ddd,J=22.1,17.2,4.3Hz),6.12(1H,ddd,J=21.2,17.5,1.8Hz),4.88and 4.59(2H,AMq,J=10.6Hz),4.77和4.70(2H,ABq,J=12.4Hz),4.73(1H,s),4.63(2H,s),4.14-4.03(5H,m),3.90(1H,dd,J=9.3,3.0Hz),3.81-3.77(1H,m),3.72(1H,t,J=9.5Hz),3.29(3H,s),1.31(6H,t,J=7.1Hz)。13C NMR(CDCl3,101MHz)δ148.4(d,J=5.8Hz),138.7,138.5,138.3,128.7,128.4,128.14,128.05,127.9,118.3(d,J=188.2Hz),99.6,80.4,78.5(d,J=1.9Hz),75.7,75.0,73.2,72.7,71.5(d,J=21.5Hz),62.1(dd,J=5.8,1.3Hz),55.3,16.7.31PNMR(162MHz,CDCl3)δ18.3.FT-IR(净,cm-1):ν(C-H)=2982(m),ν(P=O)=1253(s),ν(P-O-C)=1024(s),ν(P-O-C)=969(m)。
甲基2,3,4-三-O-苯甲基-6-脱氧-6-二异丙氧基羰基氧基-甲基-氧膦基亚甲基-α-D-甘露吡喃糖苷(10)
膦酸8根据公开方法(Vidil等人,Eur.J.Org.Chem.1999,447-450)进行制备。在氮气下向7(0.146g,0.245mmol,1当量)的无水CH3CN(5.6mL)溶液中添加吡啶(31μL,0.392mmol,1.6当量)和三甲基甲硅烷基溴化物(0.32mL,2.45mmol,10当量),并在室温下搅拌。2小时后,将反应混合物冷却至0℃,并加入吡啶(51μL,0.634mmol,2.6当量)和H2O(185μL,10.3mmol,42当量),然后温热至室温并搅拌。2小时后,将反应混合物用CH2Cl2和2M HCl(4mL)和H2O(4mL)稀释。有机层用CH2Cl2萃取,经无水硫酸钠干燥,并在减压下浓缩,得到8,为棕色油。粗残余物直接用于以下过程。
膦酸酯10根据改进方法(Graham等人,(2017).国际专利申请公开号WO2017/87256)进行制备。在氮气下8在无水CH3CN中的混合物用DIPEA(0.480mL,2.76mmol,9.9当量),TBAB(93.1mg,0.289mmol,1.0当量)和碳酸氯甲基异丙酯(0.30mL,2.24mmol,8.1当量)处理,然后加热至60℃。搅拌16小时后,将反应混合物在减压下浓缩。粗残余物通过快速柱色谱法纯化(30%至100%乙酸乙酯/己烷),得到10,为无色油(116mg,0.150mmol,54%)。TLC(EtOH/EtOAc/己烷1.5:1.5:7):Rf=0.49。1H NMR(CDCl3,400MHz)δ7.40–7.29(15H,m),7.10(1H,ddd,J=24.5,17.2,3.8Hz),6.40–6.17(1H,m),5.80–5.65(6H,m),4.81–4.59(7H,m),4.22–4.14(1H,m),3.91(1H,dd,J=9.3,3.1Hz),3.83–3.78(1H,m),3.74(1H,t,J=9.5Hz),3.30(3H,s),1.32–1.29(12H,m)。13C NMR(CDCl3,101MHz)δ153.5,138.7,138.5,138.3,128.8,128.7,128.6,128.2,128.1,127.9,99.7,84.5(d,J=5.7Hz),84.4(d,J=6.8Hz),80.5,78.3(d,J=2.1Hz),75.8,75.0,73.5(d,J=3.5Hz),73.3,72.7,71.3(d,J=22.3Hz),55.3.31P NMR(162MHz,CDCl3)δ26.3。
甲基6-脱氧-6-二异丙氧基羰基氧基-甲基-氧膦基甲基-α-D-甘露吡喃糖苷(L2)
合成L2的最后步骤根据公开的氢化方法(Jeanjean等人,Bioorg.Med.Chem.Lett.2008,18,6240-6243)进行。在烘箱干燥的小瓶中,将10(36.0mg,0.047,1当量)干燥并在高真空下脱气。向其中加入10%Pd/C(36.6mg,0.344mmol,7.4当量),并用CH2Cl2(2mL)和EtOH(2mL)冲洗。将反应混合物在表面下用N2鼓泡1分钟。然后将反应混合物在减压下脱气,并用H2(5×)替换环境气体。将反应混合物在H2下剧烈搅拌4小时,之后,将反应混合物在减压下脱气并重新填充N2(5×)。将反应混合物用CH2Cl2(2mL)稀释,并通过湿硅藻土短柱过滤。将过滤的有机层在减压下浓缩,并将粗残余物通过HPLC纯化(40%至85%[H2O+0.1%FA]:[CH3CN+0.1%FA],tR(L2)=7.00分钟),得到L2(10.1mg,0.020mmol,43%),为白色固体。所有13C-31P耦合常数均在标准值范围内(Buchanan等人,Can.J.Chem.1976,54,231-237)。1H NMR(400MHz,CDCl3)δ5.68(2H,dd,J=20.5Hz,J=5.3Hz,H8),5.65(2H,dd,J=18.3Hz,J=5.4Hz,H8’),4.93(2H,hept,J=6.3Hz,H10),4.68(1H,s,H1),3.95-3.86(1H,br,H5),3.74(1H,m,H2),3.58(2H,m,H3,H4),3.35(3H,s,OCH 3 ),3.22-3.07(1H,m,OH),2.95(2H,m,2×OH),2.27-2.07(2H,m),2.06-1.86(2H,m,H6,H6’,H7,H7’),1.32(12H,d,J=6.2Hz,H11).13C NMR(101MHz,CDCl3)δ153.6(d,J=3.7Hz,C9),101.2(s,C1),84.5(d,J=6.3Hz,C8),84.3(d,J=6.3Hz,C8’),73.7(d,J=3.2Hz,C10),72.0(s,C2),70.9(d,J=16.1Hz,C5),70.6(s),70.5(s,C3,C4),55.3(s,OCH3),23.8(d,J=4.5Hz,C6),22.4(s,C11),21.7(d,J=142.3Hz,C7).31P NMR(162MHz,CDCl3)δ34.4.FT-IR(净,cm-1):ν(O-H)=3409(br),ν(C-H)=2923(m),ν(C=O)=1760(s),ν(P=O)=1269(s).LR-MS(ESI-)[M+HCOO]-计算值:549.2;实测值549.2。
虽然已经通过各种实施方式描述了本公开,但是常规修饰对于本领域技术人员而言将是显而易见的,因此这类修改意图在包括在本公开的范围内。
Claims (12)
1.一种用于在对象中增强记忆的方法,包括向需要增强记忆的对象给予包含治疗有效量的6-磷酸甘露糖(M6P)和/或其衍生物的组合物。
2.如权利要求1所述的方法,其中,增强记忆根据记忆保留和/或记忆持续时间测量。
3.如权利要求1所述的方法,其中,给予所述M6P或其衍生物的量为1-2,000μg/kg体重。
4.如权利要求2所述的方法,其中,给予所述M6P或其衍生物的量为100-1,000μg/kg体重。
5.如权利要求1所述的方法,其中,所述M6P或其衍生物不与另一部分偶联。
6.如前述权利要求中任一项所述的方法,其中,所述M6P或其衍生物是所述组合物中唯一与IGF-2受体特异性结合的试剂。
7.如权利要求1所述的方法,其中,所述对象不具有记忆受损。
8.如权利要求1所述的方法,其中,所述对象具有记忆受损。
9.如权利要求8所述的方法,其中,所述记忆受损与神经变性疾病或衰老相关。
10.如权利要求9所述的方法,其中,所述神经变性疾病选自:阿尔茨海默病,亨廷顿病,帕金森病和肌萎缩性侧索硬化症(ALS)。
11.如权利要求8所述的方法,其中,所述记忆受损与头部损伤,脊髓损伤,发作,中风,癫痫,局部缺血,神经精神性综合征,病毒性脑炎引起的CNS损伤,脑膜炎引起的CNS损伤,或肿瘤引起的CNS损伤有关。
12.如权利要求1所述的方法,其中,所述记忆是短期记忆或长期记忆。
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