CN103429221A - 作为认知和运动功能增强剂的a2a拮抗剂 - Google Patents
作为认知和运动功能增强剂的a2a拮抗剂 Download PDFInfo
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Abstract
本发明描述了通过施用有效量的腺苷2a拮抗剂在患有帕金森氏病的患者中诱导认知和运动功能增强的方法。所述腺苷2a拮抗剂可任选地与多巴胺前体(例如左旋多巴)或多巴胺受体激动剂组合施用。
Description
技术领域
本公开涉及用于治疗与神经退行性疾病(例如帕金森氏病)相关的症状的方法和药物组合物。特别地,本公开涉及4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺及其可药用盐,以及它们在治疗帕金森氏病和其它相关疾病中的用途。
背景技术
帕金森氏病是通常发生于50岁以上人群的失能的进行性疾病。帕金森氏病的发生率随年龄而增加,并且个体发生该疾病的累积终生风险为约四十分之一。虽然帕金森氏病主要通过其运动症状(包括显著的四肢震颤、运动迟缓、强直和姿态变化)来定义,但是还有可严重影响患者生活质量的显著的行为改变(Jankovic,2008,J NeurolNeurosurg Psychiatry 79368-376)。帕金森氏病的非运动症状包括睡眠障碍、抑郁、焦虑、精神病和认知衰退。患有帕金森氏病的患者脑中的神经递质多巴胺不足。已将黑质的退行及后来黑质纹状体通路的破坏与运动症状相关联,而且已将基底神经节中多巴胺的损失和纹状体黑质区的退行与认知衰退及其他非运动症状相关联。可能额叶中的若干其他神经递质系统也被破坏,引起帕金森氏病中所述的总体范围的认知损伤。
左旋多巴(L-多巴或L-3,4-二羟基苯丙氨酸)是多巴胺的直接前体,是治疗帕金森氏病最常用的药物。由于主动运输通路的饱和度,左旋多巴的生物利用度是剂量依赖的。必须为每名患者仔细滴定左旋多巴的血浆水平以得到最佳治疗活性。如果血浆中(因此在脑中)左旋多巴的浓度过低,则患者可经历帕金森氏病症状(例如,强直、震颤和运动迟缓)的复发。另一方面,如果血浆药物水平过高,则运动波动可成为显著的副作用。血浆左旋多巴水平的失控波动可极大促使“开-关”波动(运动障碍)的发生。
另外,在外周组织中,左旋多巴被L-芳香氨基酸脱羧酶(AADC)迅速脱羧为多巴胺。左旋多巴的肠代谢是药物首次通过损失(first passloss)的主要来源,并且只有1%的施用剂量能够运输通过血脑屏障。因此,通常将左旋多巴与设计用以抑制其外周脱羧作用的药物(例如卡比多巴或苄丝肼)一起施用。卡比多巴和苄丝肼本身不以显著程度通过血脑屏障,因此不抑制所需的脑中左旋多巴到多巴胺的转化。
仍然持续需要用于治疗患有帕金森氏病和相关疾病(包括与这样的神经退行性疾病相关的症状)患者的新疗法。特别地,目前越来越认识到非运动症状(其可影响>50%的帕金森氏病患者)的治疗是高度未被满足的医疗需要领域。本公开满足了这些需要。
发明概述
本公开提供了作为A2a拮抗剂的化合物、包含所述化合物的组合物,及使用所述化合物的方法,包括治疗和/或预防由腺苷受体介导的疾病。特别地,本公开提供了通过施用任选地与多巴胺前体或多巴胺受体激动剂组合的A2a拮抗剂来治疗与神经退行性疾病相关的症状的方法和组合物。
因此,在一方面,本公开提供了抑制腺苷受体的方法,其包括使腺苷受体与有效量的对于抑制有效的本公开化合物或组合物接触。所述方法可以在体外或在体内实施,并且可用作治疗和/或预防与腺苷受体相关的疾病的治疗方法。
在另一方面,本公开涉及用于在患者中治疗与神经退行性疾病相关的症状的方法。本公开的方法包括向患者同时施用治疗有效量的至少一种A2a拮抗剂和治疗有效量的多巴胺前体或治疗有效量的多巴胺受体激动剂。A2a拮抗剂可以是4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺,多巴胺前体可以是左旋多巴,多巴胺受体激动剂可以是阿朴吗啡、普拉克索、溴麦角环肽、卡麦角林、罗匹尼罗或罗替戈汀。
本公开还涉及用于治疗与神经退行性疾病相关的症状的药物组合物和用于治疗与神经退行性疾病相关的症状的组合物。组合物包含治疗有效量的4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺和治疗有效量的多巴胺前体或治疗有效量的多巴胺受体激动剂。
本公开还涉及组合物在制备用于治疗与神经退行性疾病相关的症状的药物中的用途,其中所述组合物包含治疗有效量的4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺和治疗有效量的多巴胺前体或治疗有效量的多巴胺受体激动剂。
本公开还涉及组合物在治疗与神经退行性疾病相关的症状中的用途,其中所述组合物包含治疗有效量的4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺和治疗有效量的多巴胺前体或治疗有效量的多巴胺受体激动剂。
还提供了治疗与帕金森氏病相关的至少一种症状的方法,其中所述至少一种症状可以是认知损伤或衰退、运动症状例如震颤、肌僵硬、关节僵硬、痉挛、低肌肉控制、运动困难、臂强直、腿强直、自主活动(locomotoractivity)减少和运动协调,或其任意组合。所述方法包括向患者施用治疗有效量的4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺,任选地与多巴胺前体(例如左旋多巴)或多巴胺受体激动剂组合。
还提供了治疗与帕金森症相关的至少一种症状的方法,其中所述至少一种症状可以是认知损伤或衰退、运动症状例如震颤、肌僵硬、关节僵硬、痉挛、低肌肉控制、运动困难、同侧旋转、臂强直、腿强直、减少的自发活动和运动协调,或其任意组合。所述方法包括向患者施用治疗有效量的4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺,任选地与多巴胺前体(例如左旋多巴)或多巴胺受体激动剂组合。
附图说明
图1说明了与安慰剂(浅色线条)相比,A2a拮抗剂(深色线条)对Go/No-Go任务反应时间的影响,并且示出对于经4-羟基-4-甲基-哌啶-1-羧酸(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺处理的患者而言,反应时间更快,错误更少。
发明详述
本发明多种实施方案的描述仅出于说明的目的示出,并且不旨在完全是或者将本发明限于所公开的形式。相关领域技术人员可理解,根据所述实施方案教导可以有许多修改和变化。
除非另有指明,否则在本申请(包括说明书和权利要求书)中所使用的下述术语具有下文中给出的定义。必须注意,如本说明书和所附权利要求书中所使用的,除非上下文中清楚地另有规定,否则不使用数量词时包括复数指称。标准化学术语的定义可见于参考书目中,包括Carey和Sundberg(1992),“Advanced Organic Chemistry,第三版.”,卷A和B,Plenum Press,New York。除非另有指明,否则本公开的实施将采用质谱、蛋白质化学、生物化学、重组DNA技术和药理学中的常规方法,其全部在本领域技术范围内。
术语“可药用酸加成盐”包括无机酸盐和有机酸盐,例如盐酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸、对甲苯磺酸等。
术语“可药用载剂”指与本公开的化合物一起施用的稀释剂、辅药、赋形剂或载体。
术语“保护基团”指当与分子中的反应性官能团连接时,掩蔽、降低或阻止官能团的反应活性的一组原子。通常而言,在合成过程中,可根据期望选择性地除去保护基团。保护基团的实例可见于Greene和Wuts,Protective Groups in Organic Chemistry,第3版, 1999,John Wiley&Sons,NY和Harrison等,Compendium of Synthetic Organic Methods, 卷1-8,1971-1996,John Wiley&Sons,NY中。有代表性的氨基保护基团包括但不限于甲酰基、乙酰基、三氟乙酰基、苄基、苄基氧基羰基(“CBZ”)、叔丁氧基羰基(“Boc”)、三甲基甲硅烷基(“TMS”)、2-三甲基甲硅烷基-乙磺酰基(“SES”)、三苯甲基和取代的三苯甲基、烯丙基氧基羰基、9芴基甲基氧基羰基(“FMOC”)、硝基藜芦基氧基羰基(“NVOC”)等。有代表性的羟基保护基团包括但不限于其中羟基被酰化的那些(例如甲酯和乙酯、醋酸酯或丙酸酯基团或乙二醇酯)或被烷基化的那些,例如苄醚和三苯甲醚及烷基醚、四氢吡喃醚、三烷基甲硅烷基醚(例如TMS或TIPPS基团)和烯丙基醚。
如本文所使用的,术语“对象”和“患者”可互换使用,并且均涵盖哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物类的任何成员:人、非人灵长类例如黑猩猩,和其它猿和猴物种;农场动物例如牛、马、绵羊、山羊、猪;家养动物例如兔、狗和猫;实验室动物包括啮齿类动物,例如大鼠、小鼠和豚鼠等。非哺乳动物的实例包括但不限于鸟、鱼等。术语“对象”和“患者”不意指特定年龄或性别。
如本文所使用的,术语“处理”或“治疗”可互换使用,并且指(i)延缓疾病的发生和/或减轻将产生或预期产生的这样的症状的严重程度,或(ii)改善现有症状、预防其他症状,及改善或预防症状的潜在代谢原因。治疗可以是预防性的(预防或延迟疾病的发作,或者预防其临床或亚临床症状的表现)或者在疾病表现之后症状的治疗性抑制或缓解。
多巴胺(D2)受体与腺苷2a(A2a)受体在条纹体和丘脑中共定位。A2a受体被内源腺苷活化导致D2受体的活性下调和运动功能下降。A2a受体的拮抗剂防止该下调从而增强多巴胺对D2受体的活性并提高运动功能。
腺苷拮抗剂还刺激中枢神经系统(CNS)的活性,并且已被证实作为认知增强剂有效(Shen&Chen,2009,Current Neuropharmacology7195-206)。选择性A2a拮抗剂在多种形式的痴呆(例如阿尔茨海默病)的治疗中具有治疗潜力并且可用作神经保护剂。
本公开的化合物可用于抑制或降低A2a受体的活性。在这些上下文中,A2a受体活性的抑制和降低指与其中细胞或对象未经测试化合物处理的对照实验相比较低水平的测量活性。在一些特定方面中,测量活性的抑制或降低为至少10%的降低或抑制。本领域技术人员将理解对于特定应用可优选测量活性的降低或抑制为至少20%、50%、75%、90%或100%或者之间的任意数字。
本公开提供了用于治疗或缓解与神经退行性疾病相关的症状的方法。本公开的神经退行性疾病可以是引起神经元(例如产生多巴胺的神经元)的任何退行性、病变、损伤、退化或破坏的任何疾病、障碍、病症。所述神经退行性疾病包括任何帕金森氏病(PD)、阿尔茨海默氏病(AD)、路易体变体阿尔茨海默氏病、肌萎缩性侧索硬化症、痴呆、多系统萎缩症、神经元核内包涵体病和图雷特综合征。在本公开的某些方面中,疾病是帕金森氏病。
治疗神经退行性疾病的症状意指用于缓解、解除、治疗、治愈、减轻或改善与神经退行性疾病相关的症状的任何方式,并且不应限于症状的总体或完全消失。为本公开目的,症状为一般与神经退行性疾病相关的那些,并且包括认知损伤或衰退、震颤、肌僵硬、关节僵硬、痉挛、低肌肉控制、运动困难、同侧旋转、臂强直、腿强直、自主活动减少、运动协调或这些症状的组合。例如,使用本公开的方法和药物组合物支持这样的理念:4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺显著提高左旋多巴诱导的自主活动。
在本公开的一个方面中,本公开的方法和药物组合物包括用于在患有帕金森病的患者中增强认知的A2a拮抗剂。A2a拮抗剂可以是本领域中已知的任意一种,例如,在Flohr等的美国专利号7,368,446中所公开的4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺。
在许多方面中,用于本公开目的的多巴胺前体可以是左旋多巴(也称为L-3,4-二氢苯丙氨酸、L-多巴)或其任意衍生物。这样的左旋多巴衍生物包括左旋多巴甲酯(LDME,如美国专利号4,826,875中所述)或L-间酪氨酸(如美国专利号3,838,008中所述)、左旋多巴乙酯(LDEE,如美国专利号6,696,600中所述)或其盐。左旋多巴衍生盐包括但不限于以下:富马酸盐、二水合富马酸盐、盐酸盐、氢溴酸盐、硝酸盐、高氯酸盐、磷酸盐、硫酸盐、甲酸盐、乙酸盐、乌头酸盐、抗坏血酸盐、苯并磺酸盐、苯甲酸盐、肉桂酸盐、柠檬酸盐、双羟萘酸盐、enantate盐、富马酸盐、谷氨酸盐、乙醇酸盐、乳酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐盐、肉豆蔻酸盐、辛酸盐、邻苯二甲酸盐、水杨酸盐、山梨酸盐、硬脂酸盐、琥珀酸盐、二水合琥珀酸盐、酒石酸盐等。这些盐可根据本领域中已知的方法得到。
在许多方面中,用于本公开目的的多巴胺受体激动剂可以是阿朴吗啡、普拉克索、溴麦角环肽、卡麦角林、罗匹尼罗或罗替戈汀,或其组合。
A2a拮抗剂可与多巴胺前体或多巴胺受体激动剂同时施用。同时施用意指可用于使得多巴胺前体诱导的与神经退行性病症相关的症状的治疗增强的任何施用形式。这样的同时施用可包括其中4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺和/或多巴胺前体一起(例如在药物组合物中联合)或分开施用的任何施用形式。A2a拮抗剂与多巴胺前体或多巴胺受体激动剂分开施用优选地在使得每种这些化合物或这些化合物的组合进入血液循环、通过血脑屏障并对脑发挥其作用的时间范围内进行,其中一种化合物的作用增强其它化合物的作用。去氢表雄酮硫酸盐和去氢表雄酮的至少一种与治疗有效量的多巴胺前体的同时施用可通过本领域中已知的任何施用途径来进行,所述途径包括但不限于静脉内、皮下、皮内、经皮、腹膜内、经口、肠胃外、直肠、颊、舌下和局部施用。
用途和施用
A2a拮抗剂及其可药用盐(任选地与多巴胺前体或多巴胺受体激动剂一起)可用作药物,例如以药物制剂的形式。药物制剂可经口施用,例如以片剂、包衣片剂、糖衣丸、硬和软明胶胶囊、溶液剂、乳剂或混悬剂的形式。但是,施用还可经直肠(例如以栓剂的形式)、经肠胃外(例如,以注射液的形式)实施。
可以使用药用惰性的无机或有机载体来加工用于治疗的化合物以生产药物制剂。可以使用乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等,例如作为片剂、包衣片剂、糖衣丸和硬明胶胶囊的载体。软明胶胶囊的合适载体是例如植物油、蜡、脂肪、半固体和液体多元醇等。根据活性物质的性质,在软明胶胶囊的情况下可需要或不需要载体。用于生产溶液和糖浆的合适载体是例如水、多元醇、甘油、植物油等。栓剂的合适载体是例如天然油或硬化油、蜡、脂肪、半液体或液体多元醇等。
此外,药物制剂可包含防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、调味剂、用于改变渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们仍然还可包含其它有治疗价值的物质。
包含所述化合物或其可药用盐和治疗惰性载体的药物也是本公开的一个目的,它们的生产方法同样如此,所述方法包括将一种或更多种所述化合物和/或可药用酸加成盐以及(如果期望)一种或更多种有治疗价值的其它物质与一种或更多种治疗惰性载体一起制成盖伦施用(galenicaladminstration)形式。
根据本公开,作为A2a拮抗剂的化合物及其可药用盐可用于控制或预防基于腺苷受体拮抗活性的疾病,例如阿尔茨海默氏病、帕金森氏病、精神分裂症、神经保护、焦虑、疼痛、呼吸缺陷、抑郁、哮喘、变态反应、缺氧、缺血、癫痫、物质滥用、睡眠障碍和认知障碍。此外,本公开的化合物可用作镇静剂、肌肉松弛剂、抗精神病剂、抗癫痫剂、抗惊厥剂和心脏保护剂并且可用于生产相应药物。
在某些方面中,本公开涉及中枢神经系统障碍的治疗。例如某些抑郁障碍、神经保护、帕金森氏病、阿尔茨海默氏病、睡眠障碍、认知损伤和运动障碍的治疗或预防。
剂量可在广泛限度内改变,并且当然在每个特定情况下,将需要根据个体需求进行调节。在经口施用的情况下,成人剂量为约0.01mg至约1000mg/天的A2a拮抗剂化合物或相应量的其可药用盐。日剂量可以以单剂量或分开剂量施用,另外,也可超出上限(当发现其有所指示时)。
神经退行性疾病中的认知增强。
在本公开的一个方面中,提供了治疗对象的方法,其中A2a拮抗剂或其盐或溶剂化物与多巴胺前体或多巴胺受体激动剂组合施用治疗所必需的足够时间段。
当受损区神经功能的变化导致行为或行为能力变化时发生认知增强。
例如,可以通过使用功能/行为测试来评估由实施根据本公开的方法和组合物引起的患者运动技能(例如姿态、平衡、抓握或步态)的感觉运动和反射功能;认知技能;语言;和/或感官知觉(包括视觉能力、味觉、嗅觉),和本体感受增强从而评估患有神经退行性疾病的患者的认知增强。
可测试经本公开的方法和组合物处理的患者的认知增强。用于测量认知的测试实例包括以下:简明精神病等级量表、临床总体印象、阳性和阴性症状量表、用于评估阴性症状的量表、杨氏躁狂等级量表、阿尔茨海默氏病评估量表的认知分量表、临床医生的基于访谈的印象变化、短的便携式精神状况问卷调查、Folstein迷你精神状况检查、临床痴呆等级量表、剑桥神经心理测试自动套系(Cambridge Neuropsychological TestAutomated Battery)、威斯康辛卡片分类测试、N-回溯工作记忆测试(N-back working memory test)、天气预测概率学习测试、重复性成套神经心理状态评估(Repeatable Battery for Assessment ofNeuropsychological Status)或连续操作测试警戒(ContinuousPerformance Test Vigillance)。
任选地,还可使用神经成像工具(例如功能性磁共振成像(fMRI))或采用放射性药物(例如[18F]氟多巴)的PET扫描仪或旨在针对帕金森氏病的任意其它市售单光子发射计算机断层扫描(SPECT)配体来同时评价脑活性以提供患者的多巴胺能状态。
多种形式的连续操作测试已成为标准临床方法。一般而言,连续操作测试通过显示指导对象对其响应的一系列视觉刺激来评价对象的视觉注意力。在通常情况下,常常称为“Go-No Go”测试,刺激为两种类型(“Go”和”No Go”刺激);指导对象只响应“Go”刺激,而在示出“No Go”刺激时不响应或者“放弃(pass)”;无论对象是否响应,针对所示出的各刺激收集的数据都是由刺激类型组成;并且如果这样,它们用了多长时间响应。连续操作测试自1950年就已开始使用。
可提供本公开的组合物用于一种或更多种方法中。对于使用包含改善认知损伤症状的A2a拮抗剂和多巴胺前体或多巴胺受体激活剂的药物组合物的处理而言,本公开的组合物可提供为以一种或更多种剂量使用的药盒。所述药盒包括含有作为浓缩物(包括冻干组合物)的试剂的组合物,所述组合物可在使用前进一步稀释或者他们可以以使用浓度提供,其中瓶可包括一种或更多种剂量。方便地,在药盒中,可将单剂量提供于灭菌瓶中使得医师可直接使用瓶,其中所述瓶将具有期望的量和浓度的试剂。当瓶包含直接施用的制剂时,通常将无需其它试剂用于本方法。药盒也可以是用于单次施用或多次施用的经皮或经黏膜系统的形式。对象组合物可包含于包装材料中,所述包装材料包括示出对象组合物可用于治疗人认知障碍的标签。
实施例
下文是用于实施本公开的特定实施方案的实施例。这些实施例仅出于说明的目的提供,并不旨在以任何方式限制本公开的范围。已作出努力以确保所使用数字(例如,量、温度等)的准确性,但当然应允许一些实验误差和偏差。
实施例1
使用A2a拮抗剂和多巴胺前体的组合治疗帕金森氏病患者
帕金森氏病(PD)患者参与双盲、交叉研究以评估A2a拮抗剂与多巴胺前体的共同施用对认知和运功功能的影响。A2a拮抗剂是4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺,多巴胺前体是左旋多巴。
随机分配给患者1周的4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺和左旋多巴、1周洗出剂(只有左旋多巴),及1周安慰剂加左旋多巴或者顺序反之。根据常规临床实践,为每名患者建立最佳的左旋多巴剂量。以60mg1天2次(N=14)或20mgbid(N=12)的4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺施用活性药物。在每个治疗周结束时,参与者在过夜回收左旋多巴之后及再次在静脉内(IV)输注次优水平的左旋多巴之后完成运动评估、连续操作测试(CPT)、Go/No-Go(GNG)测试和2-回溯测试。
用4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺和左旋多巴处理的患者示出更快的GNG反应时间(60mgbid:p<0.01;20mgbid:p=0.05),准确性未下降(ps>0.25)(图1)。图1示出L-多巴治疗前后反应时间(mS)的平均变化(±SE)。对象监视视觉显示器,其每次显示一个单个大写字母,其间间插数字“5”。指导参与者在每个字母出现时按目标响应按钮(即,“Go”响应),但对数字5不作出响应(即,“No-Go”响应)。目标频率以具有两个水平目标频率(83%字母:17%“5”;50%字母:50%“5”)的分区方式(blocked fashion)操作。
各剂量的4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺和多巴胺对2-回溯或CPT测试没有显著影响(所有p值>0.05)。与安慰剂相比,在左旋多巴之前和之后,使用4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺60mg bid,参与者报告较少的睡眠(p<0.05),但用4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺20mgbid没有显著差异(p>0.05)。在左旋多巴之前和之后,4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺60mg bid对拍的速度有显著的运动益处(p≤0.05),4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺60mg bid和左旋多巴对UPDRS的迅速交换手运动项目有显著影响(p=0.03)。
这些结果与在PD的运动和认知上A2a拮抗剂和多巴胺之间有益的相互作用的剂量响应曲线相一致。因此,A2a拮抗剂和多巴胺前体可用于在患有神经退行性疾病的患者中增强认知和运功功能。
对于相关领域的普通技术人员而言明显的是,本文所述的方法和应用的其它合适的修改和变化是合适的,并且可以进行这些修改和变化而不脱离本发明或其任意实施方案的范围。虽然已与某些实施方案相关联地描述了本发明,但是其不旨在将本发明限于所给出的特定形式,而相反,其旨在包括如可包括在由所附权利要求书所限定的本发明的精神和范围内的这样的替换、修改和等同变体。
本说明书的正文中所引用的全部参考文献、授权专利和专利申请出于所有目的而通过引用整体并入本文作为参考。
Claims (30)
1.用于在患有帕金森氏病的患者中治疗与帕金森氏病相关的症状的方法,所述方法包括:
向所述患者施用与治疗有效量的多巴胺前体或治疗有效量的多巴胺受体激动剂相组合的治疗有效量的A2a拮抗剂。
2.根据权利要求1所述的方法,其中所述A2a拮抗剂是4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺。
3.根据权利要求1所述的方法,其中所述多巴胺前体包括左旋多巴或其衍生物。
4.根据权利要求1所述的方法,其中所述多巴胺受体激动剂是阿朴吗啡、普拉克索、溴麦角环肽、卡麦角林、罗匹尼罗、罗替戈汀或其组合。
5.根据权利要求3所述的方法,其中左旋多巴或所述衍生物与所述A2a拮抗剂同时使用。
6.根据权利要求1所述的方法,其中所述A2a拮抗剂与所述多巴胺前体或多巴胺受体激动剂分开施用。
7.根据权利要求1所述的方法,其中所述患者是人。
8.根据权利要求1所述的方法,其中所述与帕金森氏病相关的症状是认知损伤。
9.根据权利要求1所述的方法,其中所述与帕金森氏病相关的症状是运动症状。
10.根据权利要求9所述的方法,其中所述运动症状是震颤、肌僵硬、关节僵硬、痉挛、低肌肉控制、运动困难、臂强直、腿强直、自主活动减少、运动协调,或其组合。
11.治疗患有认知损伤或衰退的患者的方法,其包括向所述患者施用有效量的4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺。
12.根据权利要求11所述的方法,其中所述患者是人。
13.根据权利要求11所述的方法,其中所述患者因阿尔茨海默氏病、帕金森氏病、抑郁、衰老或其组合而患有认知损伤。
14.根据权利要求11所述的方法,其还包括治疗有效量的多巴胺前体或治疗有效量的多巴胺受体激动剂。
15.根据权利要求14所述的方法,其中所述多巴胺前体包括左旋多巴或其衍生物。
16.根据权利要求15所述的方法,其中左旋多巴或所述衍生物与4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺同时使用。
17.根据权利要求14所述的方法,其中所述多巴胺受体激动剂是阿朴吗啡、普拉克索、溴麦角环肽、卡麦角林、罗匹尼罗、罗替戈汀或其组合。
18.用于在患者中增强认知的方法,其包括向所述患者施用治疗有效量的4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺和治疗有效量的左旋多巴。
19.根据权利要求18所述的方法,其中所述患者是人。
20.用于在患有帕金森症的患者中治疗与帕金森症相关的症状的方法,所述方法包括:
向所述患者施用与治疗有效量的多巴胺前体或治疗有效量的多巴胺受体激动剂相组合的治疗有效量的A2a拮抗剂。
21.根据权利要求20所述的方法,其中所述A2a拮抗剂是4-羟基-4-甲基-哌啶-1-羧酸-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-酰胺。
22.根据权利要求20所述的方法,其中所述多巴胺前体包括左旋多巴或其衍生物。
23.根据权利要求20所述的方法,其中所述多巴胺受体激动剂是阿朴吗啡、普拉克索、溴麦角环肽、卡麦角林、罗匹尼罗、罗替戈汀或其组合。
24.根据权利要求22所述的方法,其中左旋多巴或所述衍生物与所述A2a拮抗剂同时使用。
25.根据权利要求20所述的方法,其中所述A2a拮抗剂与所述多巴胺前体或多巴胺受体激动剂分开施用。
26.根据权利要求20所述的方法,其中所述患者是哺乳动物。
27.根据权利要求26所述的方法,其中所述哺乳动物是人、猿、猫、犬或小鼠。
28.根据权利要求20所述的方法,其中所述与帕金森症相关的症状是运动症状。
29.根据权利要求28所述的方法,其中所述运动症状是震颤、肌僵硬、关节僵硬、痉挛、低肌肉控制、运动困难、同侧旋转、臂强直、腿强直、自主活动减少、运动协调,或其组合。
30.根据权利要求20所述的方法,其中所述与帕金森症相关的症状是认知损伤。
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