CN103260619A - 利用某些α-7烟酸受体激动剂与乙酰胆碱酯酶抑制剂的组合治疗认知障碍 - Google Patents
利用某些α-7烟酸受体激动剂与乙酰胆碱酯酶抑制剂的组合治疗认知障碍 Download PDFInfo
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- CN103260619A CN103260619A CN2011800463455A CN201180046345A CN103260619A CN 103260619 A CN103260619 A CN 103260619A CN 2011800463455 A CN2011800463455 A CN 2011800463455A CN 201180046345 A CN201180046345 A CN 201180046345A CN 103260619 A CN103260619 A CN 103260619A
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- quinuclidine
- donepezil
- acetylcholinesteraseinhibitors inhibitors
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Abstract
本发明描述了一种改善认知的方法以及相关组合物,该方法包括向患者给药某些α-7受体激动剂和乙酰胆碱酯酶抑制剂。
Description
相关申请
本申请要求2010年7月26日提交的美国临时申请No.61/367,672;2010年11月9日提交的美国临时申请No.61/411,911;和2010年11月10日提交的美国临时申请No.61/412,353的权益,将这些申请的全部内容明确地并入本文作为参考。
背景技术
烟碱乙酰胆碱受体(nAChR)形成被乙酰胆碱活化的离子通道家族。功能性受体含有五个亚基并且存在大量受体亚型。研究表明,中枢烟碱乙酰胆碱受体与学习和记忆有关。α-7亚型的烟碱乙酰胆碱受体(“α-7受体”)普遍存在于海马和大脑皮层中。
一些人将在阿尔茨海默病患者中观察到的认知和功能衰退归因于中枢神经***中胆碱能缺乏。已经用于治疗阿尔茨海默病的至少四种药物:他克林、多奈哌齐(多奈哌齐HCl;1-苄基-4-[(5,6-二甲氧基-1-茚酮)-2-基]甲基哌啶一盐酸盐)、利斯的明((S)-N-乙基-N-甲基-3-[1-(二甲基氨基)乙基]-苯基氨基甲酸酯)和加兰他敏(氢溴酸加兰他敏;
(4aS,6R,8aS)-4a,5,9,10,11,12-六氢-3-甲氧基-11-甲基-6H-苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇氢溴酸盐)显现出作为增加中枢神经***中的乙酰胆碱的乙酰胆碱酯酶抑制剂的作用。
据报道,N-[2-(吡啶-3-基甲基)-1-氮杂二环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺(TC-5619)以非常高的亲和力结合α-7受体,并且起到该受体的完全激动剂的作用,而在其他烟碱样受体中却几乎没有活性。在表现出许多发育、解剖、和多递质生物化学方面精神***症的鼠类模型中,TC-5619单独和与氯氮平组合起纠正分别模拟阳性和阴性症状的受损前脉冲抑制(PPI)和社会行为的作用(Hauser et al.2009Biochemical Pharmacology78:803)。
发明内容
本文描述了通过给药乙酰胆碱酯酶抑制剂(例如多奈哌齐或利斯的明)与某些α-7烟碱乙酰胆碱受体激动剂(“α-7激动剂”)的组合来改善阿尔茨海默病患者的认知的方法。有用的α-7受体激动剂包括∶N-[2-(吡啶-3-基甲基)-1-氮杂二环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺(TC-5619,式IVA-IVD)、(S)-N-(奎宁环-3-基)-1H-吲唑-3-甲酰胺(式II)、(R)-3-(6-(1H-吲哚-5-基)哒嗪-3-基氧基)奎宁环(式I)和(S)-1-(2-氟苯基)乙基(S)-奎宁环-3-基氨基甲酸酯(式III)以及它们的对映异构体和可药用盐。该方能够改善已经受益于由于给药乙酰胆碱酯酶抑制剂而提高一个或多个方面认知的患者的认知。因此,已经由于给药乙酰胆碱酯酶抑制剂而使一个或多个方面认知得益的患者可以由给药本文描述的α-7激动剂在一个或多个方面认知进一步获益。这样的α-7激动剂包括:
式I
(R)-3-(6-(1H-吲哚-5-基)哒嗪-3-基氧基)奎宁环;
式II
(S)-N-(奎宁环-3-基)-1H-吲唑-3-甲酰胺或包含(S)-N-(奎宁环-3-基)-1H-吲唑-3-甲酰胺和(R)-N-(奎宁环-3-基)-1H-吲唑-3-甲酰胺的混合物;
式III
(S)-1-(2-氟苯基)乙基(S)-奎宁环-3-基氨基甲酸酯;
式IV
N-[2-(吡啶-3-基甲基)-1-氮杂二环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺,其中包含该结构式描述的四种非对映异构体的对映异构体对如以下式IVA-IVB所示,意欲将其各自涵盖在本发明范围之内:
或(2S,3R)-N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺、(2R,3S)-N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺、(2S,3S)-N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺、和(2R,3R)-N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺。
本发明的某些实施方式中,α-7受体激动剂选自下述化合物之一:式I、II、III、IVA、IVB、IVC、IVD、它们的可药用盐、它们的多晶型物、它们的水合物、它们的溶剂化物、它们的一氢氯化物、或它们的一氢氯化物的溶剂化物或水合物。在一种特定实施方式中,α-7受体激动剂为(2S,3R)-N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺或其可药用盐或多晶型物。
本发明的化合物可以是可药用盐的形式。短语“可药用”是公知的技术术语,其是指由可药用无毒的碱和酸(包括无机碱和有机碱以无机酸和有机酸)制备的盐。衍生自无机碱的盐包括锂盐、钠盐、钾盐、镁盐、钙盐和锌盐。衍生自有机碱的盐包括氨盐(ammonia)、伯胺(例如氨基丁三醇)、仲夏胺和叔胺盐、以及氨基酸(例如赖氨酸)盐。衍生自无机酸的盐包括硫酸盐、盐酸盐、磷酸盐、甲烷基磺酸盐、氢溴酸盐。衍生自有机酸的盐包括C1-6烷基羧酸、二羧酸和三羧酸(如乙酸、丙酸、富马酸、马来酸、琥珀酸、酒石酸、己二酸和柠檬酸)和烷基磺酸如甲烷基磺酸、以及芳基磺酸如对甲苯磺酸和苯磺酸。盐的详细列表参见P.H.Stahl和C.G.Wermuth(编著)“Handbook of Pharmaceutical Salts,Properties,Selection and Use”Wiley-VCH(ISBN3-906390-26-8)。
化合物及其可药用盐可以是溶剂化物的形式。当本发明的化合物与一个或多个溶剂分子形成复合物(例如结晶)时产生溶剂化物。形成溶剂化物的溶剂的实例为水(水合物)、MeOH、EtOH、iPrOH和丙酮。本文描述的本发明的化合物涵盖描述化合物的所有溶剂化物。
本发明的化合物可以以被称为多晶型物的不同晶体形式存在。
在某些情况下,在没有其他化合物的存在下,乙酰胆碱酯酶抑制剂和α-7激动剂之一或两者都可以以亚临床剂量给药,即在该剂量下化合物(在没有其他化合物的存在下给药)对认知不会具有临床可测量益处(例如,不会测量到改善记忆的剂量)。因此,患者可以以非常低、副作用减少或无副作用的剂量给药的药物组合受益(例如改善记忆或认知)。而且,药物组合可以为较宽范围的患者和/或经较长治疗时期提供益处。例如,虽然在几个月治疗之后某些乙酰胆碱酯酶抑制剂会显示出功效降低,但该组合可以提供较长时期的功效。
患者可以在下述一个或多个方面受益:加工速度、注意力/警惕性、工作记忆、视觉学习、语言学习、视觉学习、推理/问题解决、执行功能和社会认知。重要的是,可以在这样的已接受治疗的患者中以低剂量使用α-7激动剂来改善认知,例如(或低于)以下每日口服剂量:3mg、2.70mg、2.50mg、2.25mg、2mg、1.75mg、1.50mg、1.25mg、1mg、0.7、0.5、0.3mg或者甚至0.1mg。因此,例如,它们可以以0.05-1.5mg日剂量给药,例如1mg/每日或0.5mg/每日的剂量。对于多奈哌齐,与α-7激动剂使用的日剂量可以为10mg、5mg、4.5mg、4mg、3.5mg、3mg、2.5mg、2mg、1mg或0.5mg。日剂量可以在5mg至0.5mg之间(例如,4.5-1.0mg/天、4.5-2.0mg/天、4.0-2.0或2.5mg/天)。对于利斯的明,组合中使用的日剂量可以为11mg、10mg、9mg、8mg、7mg、6mg或5mg。对于加兰他敏,组合中使用的日剂量可以为20mg、15mg、13mg、12mg、11mg、10mg、9mg、8mg、7mg、6mg或5mg。对于乙酰胆碱酯酶抑制剂,应当理解,对于改善记忆或认知的功效,它们必须给药以便获得至少65%的红细胞乙酰胆碱酯酶抑制。在本文描述的方法中,在没有α-7激动剂存在下,乙酰胆碱酯酶抑制剂可以以仅仅实现60%、55%(50%、45%、40%、35%或30%抑制)的较低剂量给药。
本文描述了一种用于改善认知的方法,所述方法包括向患者给药α-7激动剂和乙酰胆碱酯酶抑制剂,其中以亚临床剂量(即,在没有其他化合物存在下的亚临床的剂量)给药一种或两种化合物。在各种情形中:患者已被诊断为患有阿尔茨海默病或前期阿尔茨海默病,患者已被诊断为患有轻度至中度阿尔茨海默病,患者已被诊断为患有中度至重度阿尔茨海默病,乙酰胆碱酯酶抑制剂选自:他克林、多奈哌齐、利斯的明和加兰他敏,乙酰胆碱酯酶抑制剂选自:多奈哌齐、利斯的明和加兰他敏,乙酰胆碱酯酶抑制剂选自:多奈哌齐和利斯的明,患者在给药α-7激动剂之前已经给药一段时间的乙酰胆碱酯酶抑制剂,患者在给药乙酰胆碱酯酶抑制剂之前已经给药一段时间的α-7激动剂,之前给药至少一个月,之前给药至少三个月和之前给药至少六个月。在某些情况下∶所述方法改善学习、延迟记忆、注意力、工作记忆、视觉学习、加工速度、警惕性、语言学习、视运动功能、社会认知、长期记忆或执行功能中的一种或多种。
本文还描述了一种用于改善认知的方法,包括向患者给药亚临床剂量(当在没有乙酰胆碱酯酶抑制剂存在下给药时不会改善记忆的剂量)的α-7激动剂和同样为亚临床剂量(当在没有α-7激动剂存在下给药时不会改善记忆的剂量)的乙酰胆碱酯酶抑制剂。在不同情形中:以3.0mg/天、1.0mg/天;0.5mg/天;0.3mg/天;或0.1mg/天口服给药α-7激动剂。在不同情况中:乙酰胆碱酯酶抑制剂为多奈哌齐,且以5mg/天;4.5mg/天;4.0mg/天;2.5mg/天;1.5mg/天以下;1.0mg/天口服给药;和以获得10-65%稳态红细胞乙酰胆碱酯酶抑制的剂量给药乙酰胆碱酯酶抑制剂。
本文还描述了一种药物组合物,其包含乙酰胆碱酯酶抑制剂和α-7激动剂,例如:N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺(TC-5619)(例如(2S,3R)-N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺、(2R,3S)-N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺、(2S,3S)-N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺和(2R,3R)-N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺)、(S)-1-(2-氟苯基)乙基(S)-奎宁环-3-基氨基甲酸酯、(S)-N-(奎宁环-3-基)-1H-吲唑-3-甲酰胺和(R)-3-(6-(1H-吲哚-5-基)哒嗪-3-基氧基)奎宁环),以及可药用载体。
α-7激动剂也可以选自在下述专利申请和专利的任一篇中描述的那些:WO2004/029050、WO2006/065233、US2005/0245531、WO2005/092890、WO2007/038367、WO2005/092890、WO2002/7038367、US6,780,861和US6,953,855。
在不同情况中:乙酰胆碱酯酶抑制剂选自他克林、多奈哌齐、利斯的明和加兰他敏;乙酰胆碱酯酶抑制剂选自多奈哌齐、利斯的明和加兰他敏;乙酰胆碱酯酶抑制剂选自多奈哌齐和利斯的明;和乙酰胆碱酯酶抑制剂为多奈哌齐。
本文还描述了一种日单位剂量药物组合物,其包含不超过3.0mg、1.0mg或0.5mg的α-7激动剂、乙酰胆碱酯酶抑制剂和可药用载体。在不同情况中,该日单位剂量药物组合物包含不超过1.0mg、0.5(0.3或0.1)mg的α-7激动剂。在不同情况中,该日单位剂量药物组合物包括不超过5mg、4mg、3mg、2mg、1mg或0.5mg的多奈哌齐。
本文还描述了一种包装药物组合,其包括含有第一单位剂量的α-7激动剂和包含乙酰胆碱酯酶抑制剂的第二单位剂量药物组合物的包装。
本文描述了通过给药药物组合物治疗患者的方法,所述药物组合物包含α-7激动剂(例如日剂量为:3mg、2.70mg、2.50mg、2.25mg、2mg、1.75mg、1.50mg、1.25mg、1mg、0.7mg、0.5mg、0.3mg、0.1mg、0.03mg或0.01mg)与一种或多种乙酰胆碱酯酶抑制剂的组合。该治疗能够改善一个或多个方面的认知(例如视觉运动技能、学习、延迟记忆、注意力、工作记忆、视觉学习、加工速度、警惕性、语言学习、视运动功能、社会认知、长期记忆、执行功能等)。在给药α-7激动剂之前,患者已经采用乙酰胆碱酯酶抑制剂治疗一段时间,或者在给药抑制剂之前,患者已经采用α-7激动剂治疗一段时间。例如,患者可以已经用一种或另一种药物治疗至少一周、至少一个月、至少两个月、至少三个月、至少四个月、至少6个月或至少一年。这两种药剂可以同时以相同组合物或以两种不同组合物给药。另外,所述药剂可以在不同时间给药。
本文还描述了一种药物组合物,其包含α-7激动剂和乙酰胆碱酯酶抑制剂(例如他克林、多奈哌齐、利斯的明或加兰他敏)和可药用载体。
对于口服给药,药物组合物可以采取溶液、混悬剂、片剂、丸剂、胶囊剂、粉剂等形式。使用包含各种赋形剂(如柠檬酸钠、碳酸钙和磷酸钙)与各种崩解剂(如淀粉,且优选马铃薯淀粉或木薯淀粉及某些复合硅酸盐)一起,连同粘合剂(如聚乙烯吡咯烷酮、蔗糖、明胶和***胶)的片剂。另外,润滑剂如硬脂酸镁、十二烷基硫酸钠和滑石粉通常对于压片目的非常有用。类似类型的固体组合物也用作软和硬填充明胶胶囊中的填充剂;在特定实施方式中,这样的物质也包括乳糖(lactose或milk sugar)以及高分子量聚乙二醇。当需要口服给药水性混悬剂和/或酏剂时,本发明的化合物/组分可以与多种甜味剂、调味剂、着色剂、乳化剂和/或助悬剂、以及这样的稀释剂如水、乙醇、丙二醇、甘油及其各种类似组合来组合。
对于肠胃外给药而言,可以采用在芝麻油或花生油或在水性丙二醇中的溶液,以及相应水溶性盐的无菌水溶液。如有必要,这样的水溶液可以适当地缓冲,且首先用足够的盐水或葡萄糖使该液体稀释剂等渗。这些水溶液特别地适于静脉内、肌内、皮下和腹膜内注射目的。在这方面,所采用的无菌水介质全部都可以容易地通过本领域技术人员公知的标准技术获得。
对于透皮(例如局部)给药而言,可以制备稀释无菌水性或部分水性溶液(通常为约0.1%至5%浓度),其它类似于上述非肠道溶液的溶液。
用一定量活性成分制备各种药物组合物的方法是本领域普通技术人员已知的,或者根据本发明显而易见的。制备药物组合物的方法的实例参见Remington's Pharmaceutical Sciences,Mack Publishing Company,Easter,Pa.,第15版,(1975)。在将药物组合物在可接受的载体中配制之后,将其置于合适的容器中,并标记用于治疗指示病症。对于给药本发明的化合物而言,这样的标记将包括关于给药数量、频率和方法的说明。
“剂量”为向患者给药的活性药物组分(API)的量。例如,1mg是指每天向每名患者口服给药1mg的API。
“活性药物组分”包括本文描述的α-7激动剂和乙酰胆碱酯酶抑制剂。
具体实施方式
本文描述的药物组合对人类患者认知的作用可以使用CogState计算机化认知测试和/或通过使用所有的或一个NTB量表的子集(例如分类流畅性、轨迹A和B)来测量。
本文描述的药物组合对短时记忆的作用可以在鼠类模型中通过检查对于由在5个月大雄性Wistar大鼠的物体识别任务中毒蕈碱拮抗剂东莨菪碱诱导的缺陷的作用来测量。物体识别任务允许对(物体或对象)信息巩固进入记忆的评价(Ennaceur和Delacour,1988;Prickaerts et al.,1997)。在该任务中,对大鼠进行两个试验。在第一个试验中,将大鼠放置于其中放置两个相同物体的场地中。通常,大鼠将观察两个物体一定的时间。在一定延迟之后,对大鼠进行第二次试验。在该试验中,将大鼠再放入相同的场地中,但物体之一被新物体替换。类似于第一次试验,大鼠再次探究两个物体。记录探究每个物体的时间,以测定大鼠是否花费不同时间量来探究两个物体。可以测定基于该得分的记忆表现。
若干研究显示出当在第一次试验和第二次试验之间***一小时延迟时,Wistar大鼠显示出良好的物体记忆表现。然而,当使用二十四小时延迟时,在第二个试验中,大鼠却不能辨别新物体和熟悉的物体,这表明大鼠不记得熟悉的物体(即,在第一次试验和第二次试验中都存在的物体)。使用六小时延迟,辨别表现处于一小时和二十四小时延迟的表现之间,表明在此任务中的延迟依赖性遗忘。
简而言之,在学习试验前30分钟,大鼠接受注射毒蕈碱性受体拮抗剂东莨菪碱(0.1mg/kg,i.p.给药)。在用东莨菪碱治疗之后,大鼠在学习试验一小之后会表现出对物体没有记忆。在第一次试验前30分钟,即刚刚给药东莨菪碱之后,给予试验药物。
将动物分别圈养在空调室(约20℃)内锯屑床上标准3型Makrolon笼中。将它们保持在12/12-小时光/暗循环(自19.00至7.00h开灯),且自由取食和饮水。将大鼠圈养在对其进行试验的相同室内。
如在别处(Ennaceur和Delacour,1988)描述的进行物体识别试验。所述装置由直径83cm的圆形场地组成。40cm高壁的一半由灰色聚氯乙烯制成,另一半由透明聚氯乙烯制成。在装置的不同部分,光强度相同。将两个物体置于距离灰色壁约10cm的对称位置。每个物体可一式三份获得。物体为:1)在顶部具有由黄铜制成的领部(collar)的由灰色聚氯乙烯基座(最大直径18cm)构成的锥体(总高度16cm),2)装有水的标准1升棕色透明玻璃瓶(10cm,高度22cm),3)具有两个孔(直径1.9cm)的大块金属立方体(10.0×5.0×7.5cm),和4)具有锥形顶部的大块铝立方体(13.0×8.0×8.0cm)。大鼠不能转移物体。荧光红色管和灯泡在装置地板上提供约20lux的恒定照明。
测试时段包括两个试验。每个试验的持续时间为3分钟。在第一次试验(T1)期间,装置包含两个相同物体(样品)。大鼠总是在前(透明)部分中间面向壁置于装置中。在第一次探究时期之后,将大鼠放回其饲养笼中。随后,在预定延迟间隔之后,将大鼠放回装置中进行第二次试验(T2),但此时有两个不同的物体,一个熟悉物体(样品)和一个新物体。用个人计算机人工记录在T1和T2期间探究每个物体花费的时间。
探究定义如下:鼻子在不超过2cm的距离指向物体,和/或用鼻子触碰物体。坐在物体上不被认为是探究行为。为了避免存在嗅觉试验,总是彻底清洁物体。以均衡方式使用所有物体组合及位置,以减少由于特定位置或物体的偏爱而潜在的偏向。
一些研究已经显示,当在第一次试验和第二次试验之间***一小时延迟时,Wistar大鼠显示出良好的物体记忆表现。然而,当使用24小时延迟时,在第二次试验中,大鼠不能辨别新物体和熟悉物体,表明在大鼠不记得在第一次试验中出现的物体。使用六小时延迟,辨别表现处于一小时和二十四小时延迟的表现之间,表明在此任务中的延迟依赖性遗忘。
在测试之前两周,每日操控动物,且在两天之内使其适应程序,即每天允许其探究装置(没有任何物体)两次各3分钟。然后,使大鼠适应测试,且在第一次试验之前30分钟通过盐水注射剂腹腔注射和p.o.注射(分别1.0ml/kg和2.0ml/kg)直到它们显示出稳定辨别表现,即在1小时的间隔有良好的辨别而在24小时间隔没有辨别。
基本量度为大鼠在T1和T2期间用来探究物体所花费的时间。在探究两个相同样品所花费时间由‘a1’和‘a2’表示。在T2中用来探究样品和新物体所花费的时间分别由‘a’和‘b’表示。计算下述变量∶e1=a1+a2、e2=a+b和d2=(b–a)/e2。e1和e2为分别在T1和T2对两个物体的总探究时间的量度。D2为校正探究活性(e2)的辨别的相对量度。因此,以类似的间隔用类似处理的试验之间的d2指数应当没有任何差异。
并入作为参考
将本文引用的所有专利、公布的专利申请及其它参考文献的全部内容都明确地在此全部并入本文。
等同物
本领域技术人员将认识到或能仅仅使用常规实验来确定,许多的本文中描述的特定程序的许多等同物。这样的等同物被认为在本发明的范围内且背下述权利要求所涵盖。此外,本文提供的任何数值或字母的范围意欲包括那些范围的上限值和下限值。另外,至少在一种实施方式中,任何列表或分组意欲表示所列独立实施方式的简写或方便方式;因而,应认为列表的每个成员为单独的实施方式。
Claims (38)
1.一种用于改善认知的方法,包括向患者给药选自下述的化合物:(S)-1-(2-氟苯基)乙基(S)-奎宁环-3-基氨基甲酸酯、N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺(TC-5619)、(S)-N-(奎宁环-3-基)-1H-吲唑-3-甲酰胺和(R)-3-(6-(1H-吲哚-5-基)哒嗪-3-基氧基)奎宁环或它们的可药用盐,以及乙酰胆碱酯酶抑制剂。
2.根据权利要求1所述的方法,其中,所述患者已被诊断为患有阿尔茨海默病或前期阿尔茨海默病。
3.根据权利要求1所述的方法,其中,所述患者已被诊断为患有轻度至中度阿尔茨海默病。
4.根据权利要求1所述的方法,其中,所述患者已被诊断为患有中度至重度阿尔茨海默病。
5.根据前述权利要求中任一项所述的方法,其中,所述乙酰胆碱酯酶抑制剂选自他克林、多奈哌齐、利斯的明和加兰他敏。
6.根据权利要求5所述的方法,其中,所述乙酰胆碱酯酶抑制剂选自多奈哌齐、利斯的明和加兰他敏。
7.根据权利要求5所述的方法,其中,所述乙酰胆碱酯酶抑制剂选自多奈哌齐和利斯的明。
8.根据前述权利要求中任一项所述的方法,其中,在向所述患者给药选自下述化合物之前已经给药一段时间的乙酰胆碱酯酶抑制剂:(S)-1-(2-氟苯基)乙基(S)-奎宁环-3-基氨基甲酸酯、(2S,3R)-N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺、(S)-N-(奎宁环-3-基)-1H-吲唑-3-甲酰胺和(R)-3-(6-(1H-吲哚-5-基)哒嗪-3-基氧基)奎宁环或它们的可药用盐。
9.根据权利要求8所述的方法,其中,之前已经给药持续至少一个月。
10.根据权利要求9所述的方法,其中,之前已经给药持续至少三个月。
11.根据权利要求10所述的方法,其中,之前已经给药持续至少六个月。
12.根据前述权利要求中任一项所述的方法,其中,所述方法改善学习、延迟记忆、注意力、工作记忆、视觉学习、加工速度、警惕性、语言学习、视运动功能、社会认知、长期记忆或执行功能中的一种或多种。
13.根据权利要求1所述的方法,其中,所述α-7激动剂和所述乙酰胆碱酯酶抑制剂之一或两者以亚临床剂量给药。
14.根据权利要求13所述的方法,其中,所述α-7受体激动剂以少于1.0mg/天口服给药。
15.根据权利要求13所述的方法,其中,所述α-7受体激动剂以少于0.5mg/天口服给药。
16.根据权利要求13所述的方法,其中,所述α-7受体激动剂以少于0.3mg/天口服给药。
17.根据权利要求13所述的方法,其中,所述α-7受体激动剂以少于0.1mg/天口服给药。
18.根据权利要求13所述的方法,其中,所述乙酰胆碱酯酶抑制剂为多奈哌齐,且以少于5mg/天口服给药。
19.根据权利要求13所述的方法,其中,所述乙酰胆碱酯酶抑制剂为多奈哌齐,且以4.5mg/天或更少口服给药。
20.根据权利要求13所述的方法,其中,所述乙酰胆碱酯酶抑制剂为多奈哌齐,且以4.0mg/天或更少口服给药。
21.根据权利要求13所述的方法,其中,所述乙酰胆碱酯酶抑制剂为多奈哌齐,且以2.5mg/天或更少口服给药。
22.根据权利要求13所述的方法,其中,所述乙酰胆碱酯酶抑制剂为多奈哌齐,且以1.5mg/天或更少口服给药。
23.根据权利要求13所述的方法,其中,所述乙酰胆碱酯酶抑制剂为多奈哌齐,且以1.0mg/天或更少口服给药。
24.根据权利要求1所述的方法,其中,所述乙酰胆碱酯酶抑制剂以达到10-65%稳态红细胞乙酰胆碱酯酶抑制的剂量给药。
25.一种药物组合物,包含选自下述的化合物:(S)-1-(2-氟苯基)乙基(S)-奎宁环-3-基氨基甲酸酯、N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺(TC-5619)、(S)-N-(奎宁环-3-基)-1H-吲唑-3-甲酰胺和(R)-3-(6-(1H-吲哚-5-基)哒嗪-3-基氧基)奎宁环或它们的可药用盐,乙酰胆碱酯酶抑制剂,和可药用载体。
26.根据权利要求25所述的药物组合物,其中,所述乙酰胆碱酯酶抑制剂选自他克林、多奈哌齐、利斯的明和加兰他敏。
27.根据权利要求25所述的药物组合物,其中,所述乙酰胆碱酯酶抑制剂选自多奈哌齐、利斯的明和加兰他敏。
28.根据权利要求25所述的药物组合物,其中,所述乙酰胆碱酯酶抑制剂选自多奈哌齐和利斯的明。
29.根据权利要求25所述的药物组合物,其中,所述乙酰胆碱酯酶抑制剂为多奈哌齐。
30.一种日单位剂量药物组合物,包含不超过1.0mg选自下述的化合物∶(S)-1-(2-氟苯基)乙基(S)-奎宁环-3-基氨基甲酸酯、N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺(TC-5619)、(S)-N-(奎宁环-3-基)-1H-吲唑-3-甲酰胺和(R)-3-(6-(1H-吲哚-5-基)哒嗪-3-基氧基)奎宁环或它们的可药用盐,乙酰胆碱酯酶抑制剂,以及可药用载体。
31.根据权利要求30所述的日单位剂量药物组合物,包含不超过0.5mg选自下述的化合物:(S)-1-(2-氟苯基)乙基(S)-奎宁环-3-基氨基甲酸酯、N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺(TC-5619)、(S)-N-(奎宁环-3-基)-1H-吲唑-3-甲酰胺和(R)-3-(6-(1H-吲哚-5-基)哒嗪-3-基氧基)奎宁环或它们的可药用盐。
32.根据权利要求31所述的日单位剂量药物组合物,包含不超过0.3mg选自下述的化合物:(S)-1-(2-氟苯基)乙基(S)-奎宁环-3-基氨基甲酸酯、N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺(TC-5619)、(S)-N-(奎宁环-3-基)-1H-吲唑-3-甲酰胺和(R)-3-(6-(1H-吲哚-5-基)哒嗪-3-基氧基)奎宁环或它们的可药用盐。
33.根据权利要求31所述的日单位剂量药物组合物,包含不超过0.1mg选自下述的化合物:(S)-1-(2-氟苯基)乙基(S)-奎宁环-3-基氨基甲酸酯、N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺(TC-5619)、(S)-N-(奎宁环-3-基)-1H-吲唑-3-甲酰胺和(R)-3-(6-(1H-吲哚-5-基)哒嗪-3-基氧基)奎宁环或它们的可药用盐。
34.根据权利要求31所述的日单位剂量药物组合物,包含不超过5mg的多奈哌齐。
35.根据权利要求31所述的日单位剂量药物组合物,包含不超过4mg的多奈哌齐。
36.根据权利要求31所述的日单位剂量药物组合物,包含不超过2.5mg的多奈哌齐。
37.根据权利要求31所述的日单位剂量药物组合物,含不超过1mg的多奈哌齐。
38.一种包装药物,包括含有第一单位剂量药物组合物和第二单位剂量药物组合物的包装,所述第一单位剂量药物组合物包含选自下述的化合物∶(S)-1-(2-氟苯基)乙基(S)-奎宁环-3-基氨基甲酸酯、N-[2-(吡啶-3-基甲基)-1-氮杂双环[2.2.2]辛-3-基]-1-苯并呋喃-2-甲酰胺(TC-5619)、(S)-N-(奎宁环-3-基)-1H-吲唑-3-甲酰胺和(R)-3-(6-(1H-吲哚-5-基)哒嗪-3-基氧基)奎宁环或它们的可药用盐,而所述第二单位剂量药物组合物包含乙酰胆碱酯酶抑制剂。
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PCT/US2011/045206 WO2012015749A1 (en) | 2010-07-26 | 2011-07-25 | Treatment of cognitive disorders with certain alpha-7 nicotinic acid receptor agonists in combination with acetylcholinesterase inhibitors |
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US20050245531A1 (en) | 2003-12-22 | 2005-11-03 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
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