CN103339131B - 含有吡啶酮衍生物的药物组合物 - Google Patents
含有吡啶酮衍生物的药物组合物 Download PDFInfo
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- CN103339131B CN103339131B CN201280006755.1A CN201280006755A CN103339131B CN 103339131 B CN103339131 B CN 103339131B CN 201280006755 A CN201280006755 A CN 201280006755A CN 103339131 B CN103339131 B CN 103339131B
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- oxo
- azabicyclic
- oct
- niacinamide
- thiazolyl
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Abstract
一种吡啶酮衍生物及其药学上可接受的盐、同分异构体、溶剂合物、水合物，以及一种用于认知障碍的预防性或治疗性药物组合物，该组合物包括所述吡啶酮衍生物或其药学上可接受的盐、同分异构体、溶剂合物、水合物。
Description
技术领域
本发明提供了一种作为α7-烟碱型乙酰胆碱受体(nAChR)激动剂或部分激动剂的氮杂二环烷烃取代的吡啶酮衍生物，及其药学上可接受的盐、同分异构体、溶剂合物或水合物。
背景技术
属于配体门控性离子通道家族的烟碱型乙酰胆碱受体(nAChR)普遍存在于中枢神经系统(CNS)和周围神经系统(PNS)中，并与多种生理功能相关。这些受体作为重要因子通过控制多种神经递质如乙酰胆碱、去甲肾上腺素、多巴胺、血清素和γ-氨基丁酸(GABA)的释放来控制CNS的生理功能。因此，通过控制这类神经递质和细胞信号传递系统，AChR可用于治疗与认知功能、学习和记忆、神经变性、疼痛和炎症、神经精神病和情绪失调、以及强迫性和上瘾行为有关的疾病，控制和治疗炎症或炎症性疾病，以及缓解疼痛。
在CNS和PNS中存在不同的nAChR的亚型。通常，nAChR是能够选择性传输各种阳离子的离子通道，其有5个单体围绕着该离子通道中央的离子传导孔。在人类中，表达了至少12个单体即α2～α10和β2～β4，其中这些单体通过彼此组合而形成各种同聚的或异聚的复合体。与烟碱结合亲和力高的异聚α4β2nAChR和与烟碱结合亲和力低的同聚α7nAChR，已知主要表达于CNS中[Gotti C,Zoli M,Clementi F(2006)Trends in Pharmacol.Sci.27;482-491]。
烟碱型α7受体表达于负责大脑的认知和感觉功能的大脑皮层和海马体中，并被发现存在于突触前和突触后末梢中，因而被认为是突触传递中的重要因子[Burghaus L,Schutz U,Krempel U,de Vos RAI,Jansen Steur ENH,Wevers A,Lindstrom J,Schroder H(2000),Mol.Brain Res.76;385-388;Banerjee C,Nyengaard RJ,Wevers A,de Vos RAI,Jansen Steur ENH,Lindstrom J,Pilz K,Nowacki S,Bloch W,Schroder H(2000),Neurobiol.Disease,7;666-672]。烟碱型α7受体天生对于钙离子有高渗透性，因此被认为是各种钙-依赖性神经传递系统的重要因子[Oshikawa J,Toya Y,Fujita T,Egawa M,Kawabe J,Umemura S,Ishikawa Y(2003)Am.J.Physiol.Cell Physiol.285;567-574;MarreroMB,Bencherif M(2009)Brain Res.1256;1-7;Ospina JA,Broide RS,Acevedo D,Robertson RT,Leslie FM(1998)J.Neurochem.70;1061-1068]。
由于烟碱型乙酰胆碱受体与包括认知功能和注意力的各种大脑功能控制有关，因此预计能够直接或间接激活该烟碱型乙酰胆碱受体的物质基本上有益于缓解认知障碍，如阿尔茨海默型痴呆症、精神分裂症有关的认知障碍，以及注意力缺陷如注意缺陷多动障碍(ADHD)[Levin ED,McClernon FJ,Rezvani AH(2006)Psychopharmacology184;523-539]。
发明详述
技术问题
本发明提供了一种作为α7-烟碱型乙酰胆碱受体(nAChR)激动剂或部分激动剂的氮杂二环烷烃取代的吡啶酮衍生物，及其药学上可接受的盐、同分异构体、溶剂合物或水合物。
技术方案
根据本发明多个方面，提供了一种由下述式I表示的吡啶衍生物及其药学上可接受的盐、同分异构体、溶剂合物或水合物，其中，在式I中，A是可由选自下组中至少一种基团取代的C1-C10杂芳基：卤素、C1-C6烷基、C3-C7环烷基、C6-C12芳烷基、C1-C6烷氧基和C6-C12芳基；且B是O或NH。
在一些实施方案中，B可为NH。
本文所用术语“杂芳基”是指具有至少一个包括至少一个选自N、O和P的杂原子的芳环体系，其中所述环的其他为碳，也可考虑包括一个稠合环(二环杂芳基)。在一些实施方案中，所述C1-C10杂芳基可选自下组：噻唑基、苯并噻唑基、吡啶基、异噁唑基、异喹啉基、喹啉基、苯并噻二唑基、噻二唑基、吡唑基和吡嗪基。
在一些实施方案中，所述芳烷基和芳基可被其他卤素或烷基取代。
在一些实施方案中，式I的所述吡啶酮衍生物可由本领域技术人员通过任何已知化合物或容易由其获得的任何化合物来制备。因此，下述与制备所述吡啶酮衍生物的方法有关的描述仅用于说明的目的，而非旨在限制本发明的范围。例如，所述单元操作的顺序可根据需要改变。
反应路线1
在以上描述的反应路线中，R可为杂芳基。在以上反应路线中描述的通用合成方法中，由香豆基酸1作为起始原料合成中间体2后，中间体2可与氨基杂芳基化合物(R-NH2)和二甲基甲酰胺(DMF)在约150℃反应，以获得6-吡啶酮化合物3，然后其可被水解为6-吡啶酮-3-甲酸4，然后可通过引入奎宁环来获得最终化合物5。
反应路线2
在以上描述的反应路线中，R可为杂芳基。由6-吡啶酮-3-甲酸(4)合成6-氧代-3-甲酰氯(6)以后，可通过引入奎宁醇来获得最终化合物(7)。
所述吡啶衍生物的实例为：由式I表示的化合物、其药学上可接受的盐，如其加成酸或碱盐和任何立体化学同分异构体，其中这些盐没有特别限定，且可为能够在目标对象中保留母体化合物活性而不产生任何不良作用的任何盐。这些盐的实例有：无机盐和有机盐，如乙酸、硝酸、天冬氨酸、磺酸、硫酸、马来酸、谷氨酸、甲酸、琥珀酸、磷酸、邻苯二甲酸、丹宁酸、酒石酸、氢溴酸、丙酸、苯磺酸、苯甲酸、硬脂酸、甲苯基酸、乳酸、重碳酸、重硫酸、重酒石酸、草酸、丁酸、依地酸钙、樟脑磺酸、碳酸、氯苯甲酸、柠檬酸、乙二胺四乙酸、甲苯磺酸、edicylinic酸、ecylinic酸、富马酸、葡庚糖酸(glucepticacid)、双羟萘酸、葡萄糖酸、乙二醇对氨基苯胂酸(glycollarsanylicacid)、硝酸甲酯、聚半乳糖醛酸、hexyllisorcynonic酸、丙二酸、异羟肟酸(hydrobamic acid)、盐酸、氢碘酸、羟萘酸、羟乙磺酸、乳糖酸、扁桃酸、estolinic酸、粘液酸、粘康酸、p-硝基甲烷磺酸、环己胺磺酸、泛酸、单氢磷酸、磷酸二氢、水杨酸、磺酰胺酸、对氨基苯磺酸、甲磺酸和硫辛酸(theoclic acid)。碱盐的实例有：铵盐，碱或碱土金属如锂、钠、钾、镁或钙的盐，含有有机碱如苄星青霉素、N甲基-D-葡糖胺或海巴明青霉素的盐，以及含有氨基酸如精氨酸或赖氨酸的盐。通过用合适的酸或碱处理可将这些盐转化为游离形式。术语“加成盐”可理解为包括由任何式I的化合物和其盐获得的溶剂合物。这些溶剂合物的实例有水合物和醇合物。
在一些实施方案中，所述吡啶酮衍生物的立体化学同分异构体可为衍生自式I所示化合物的任何化合物。除非另有提及或说明，化合物的化学名称涵盖该化合物可能具有的任何可能的立体化学同分异构体形式的混合物，其中所述混合物可含有该化合物的基本分子结构的任何非对映异构体和/或对映异构体。具体地，所述立构中心可为R或S-构型，二价环状(部分)饱和基团的取代基可为顺式-或反式-构型。具有双键的化合物在所述双键中可具有E-或Z-立体化学。式I或式II的化合物的任何立体化学同分异构体也落入本发明公开的范围。
在一些实施方案中，所述吡啶衍生物可选自下组：N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(2-噻唑基)-3-吡啶甲酰胺、N-[(3R)-1-氮杂二环[2.2.2]辛-3-基]-6-氧代-1-(2-噻唑基)-3-吡啶甲酰胺、N-[(3S)-1-氮杂二环[2.2.2]辛-3-基]-6-氧代-1-(2-噻唑基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(2-吡啶基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(3-吡啶基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-氯-2-吡啶基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-苯基-2-吡啶-1-基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(3-异噁唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(3-苯基-5-异噁唑基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-甲基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3R)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-甲基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3S)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-甲基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-乙基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3R)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-乙基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3S)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-乙基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-丙基-2-噻唑基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-丙-2-基-2-噻唑基)-3-吡啶甲酰胺、N-[(3R)-1-氮杂二环[2.2.2]辛-3-基]-6-氧代-1-(5-丙-2-基-2-噻唑基)-3-吡啶甲酰胺、N-[(3S)-1-氮杂二环[2.2.2]辛-3-基]-6-氧代-1-(5-丙-2-基-2-噻唑基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-叔丁基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3R)-1-氮杂二环[2.2.2]辛-3-基)]-1-(5-叔丁基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3S)-1-氮杂二环[2.2.2]辛-3-基)]-1-(5-叔丁基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-环戊基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-环己基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-苯基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-氯-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3R)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-氯-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3S)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-氯-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-[5-(苯甲基)-2-噻唑基]-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(4-甲基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-[4-(4-氯苯基)-2-噻唑基]-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(4,5-二甲基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(1,3-苯并噻唑-2-基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(4-甲氧基-1,3-苯并噻唑-2-基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5,6-二甲基-1,3-苯并噻唑-2-基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(2,1,3-苯并噻二唑-4-基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(1,3-苯并噻唑-6-基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-甲基-2-苯基-3-吡唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(1-异喹啉基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-异喹啉基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-喹啉基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-甲基-1,3,4-噻二唑-2-基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-苯基-1,3,4-噻二唑-2-基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(2-吡嗪基)-3-吡啶甲酰胺、(1-氮杂二环[2.2.2]辛-3-基)-1-(5-甲基-1,3-噻唑-2-基)-6-氧代-3-吡啶甲酸酯，以及(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-丙-2-基-1,3-噻唑-2-基)-3-吡啶甲酸酯。
在一些实施方案中，所述吡啶酮衍生物可为α7烟碱型乙酰胆碱受体的激动剂或部分激动剂。
本文所用术语“激动剂”应理解为赋予了其最宽泛的含义，即，作为部分或全部地激活目标材料(例如，α7烟碱型乙酰胆碱受体)至少一种生物活性的任何分子。例如，术语“激动剂”化合物是指能提高或诱导激动剂化合物所结合的蛋白质(例如，α7烟碱型乙酰胆碱受体c-Met)的生物活性的化合物。例如，所述吡啶衍生物可特异性结合至α7烟碱型乙酰胆碱受体的胞外结构域以诱导胞内信号传递，从而证明其在预防或治疗认知障碍和在神经性康复中的功效。
烟碱型α7受体已知在提高例如，学习、记忆和注意力方面的认知功能上很重要。例如，烟碱型α7受体与下述疾病有关：轻度认知障碍、阿尔茨海默症、与年龄相关的和其他认知障碍、精神分裂症、注意力缺陷障碍、注意缺陷多动障碍（ADHD）、注射或代谢失调引起的痴呆症、路易体痴呆症、抽搐如癫痫、多发性脑梗塞、情绪失调、强迫性和上瘾行为、炎性疾病，以及与控制由这些失调导致的疼痛有关的疾病和病症。烟碱型α7受体的活性可通过施用α7受体配体来改变或调节，所述α7受体配体的非限制性实例有：拮抗剂、激动剂、部分激动剂和反向激动剂。α7受体配体可用于治疗和预防这些和各种类型的认知障碍和其他病症和疾病，而其激动剂和部分激动剂已知能在啮齿动物、非人类灵长类和人类中改善认知功能和注意力[Gotti C andClementi F(2004)Prog.Neurobiol.74;363-396;Jones HE,Garrett BE,Griffiths,RR(1999)J.Pharmacol.Exp.Ther.288;188-197;Castner SA,Smagin GN,Piser TM,Wang Y,Smith JS,Christian EP,Mrzljak L,Williams GV(2011)Biol.Psychiatry69;12-18;Wallace TL,Callahan PM,Tehim A,Bertrand D,Tombaugh G,Wang S,Xie W,Rowe WB,Ong V,Graham E,Terry AV Jr,Rodefer JS,Herbert B,Murray M,Porter R,Santarelli L,Lowe DA.(2011)J.Pharmacol.Exp.Ther.336;242-253;Bitner RS,Bunnelle WH,Decker MW,Drescher KU,Kohlhaas KL,Markosyan S,Marsh KC,Nikkel AL,Browman K,Radek R,AndersonDJ,Buccafusco J,Gopalakrishnan M.(2010)J.Pharmacol.Exp.Ther.334;875-886;Woodruff-Pak,DS,Santos IS(2000)Behav.Brain Res.113;11-19;Spinelli S,Ballard T,Feldon J,Higgins GA,Pryce CR(2006)Neuropharmacology51;238-250]。
根据本发明另一个方面，提供了一种用于预防或治疗认知障碍的药物组合物，其包括治疗上有效量的上述吡啶酮衍生物或其药学上可接受的盐、同分异构体、溶剂合物或水合物；以及药学上可接受的载体。
在一些实施方案中，所述认知障碍可选自下组：早老年性痴呆症、早发性阿尔茨海默病、老年性痴呆症、阿尔茨海默型痴呆症、路易体小体性痴呆症、微小梗塞性痴呆症、AIDS(艾滋病)相关痴呆症、HIV痴呆症、路易体相关痴呆症、唐氏综合征相关痴呆症、皮克氏病、轻度认知功能障碍、与年龄相关的记忆障碍、最近短期记忆障碍、年龄相关认知障碍、药物相关的认知障碍、免疫缺陷综合征相关的认知障碍、血管疾病相关的认知功能障碍、精神分裂症、注意力缺陷障碍、注意缺陷多动障碍（ADHD），以及学习缺陷障碍。所述药物组合物在预防或治疗例如，阿尔茨海默症、帕金森氏症、肌肉萎缩性侧索硬化症(ALS)或亨廷顿氏症方面具有神经保护性作用。
本文所用术语“认知障碍”是指动物在认知功能或认知领域方面大范围的退化，例如，在工作记忆、注意力和警觉、语言学习和记忆、视觉学习和记忆、推理和解决问题方面，尤其是，例如，在执行能力、任务处理速度和/或社会认知方面。认知障碍已知表现出注意力缺陷、思维紊乱、思维反应迟钝、理解困难、注意力差、失去解决问题能力、记忆不准确、表达思想和/或综合思维以及感觉和行为上有困难或在消除不合理思维上有困难。术语“认知障碍”和“认知缺陷”可互换使用。
术语“治疗”可认为是包括预防、抑制和减缓(消退)动物的与认知障碍相关的疾病、失调或病症，该动物过去从未诊断为患有由认知障碍导致的这类疾病、失调或病症，但其易于患上这类疾病、失调或病症。相应地，术语“治疗上有效量”是指用于缓解、减轻或预防待治疗疾病的症状所需有效剂量的临床指标，或用于降低或延迟这类症状发作的有效活性化合物的有效剂量，其可在待治疗疾病的体内和/或体外模型中通过实验根据经验来确定。
在一些实施方案中，所述药物组合物可配制为以任何合适途径施用的任何形式，例如，通过口服、直肠、鼻、肺、局部、透皮、脑池内、腹膜内、阴道和肠胃外(包括经皮下、肌肉内、鞘内、静脉内和真皮内)的途径，优选口服施用。对于口服施用，所述药物组合物可包括本领域常用的药学上可接受的载体(vehicle)。在一些实施方案中，对于口服液体制剂如混悬剂、糖浆剂、酏剂和溶液，载体的实例有：水、乙二醇、油和乙醇。对于固体制剂如丸剂、胶囊剂、糖锭剂，载体的实例有：淀粉、糖、高岭土、润滑剂、粘合剂和崩解剂。但是应理解，优选的途径取决于总体条件、待治疗对象的年龄、待治疗病症的特性和所选活性成分。在一些实施方案中，所述药物组合物可根据便利施用和剂量一致性而制备成单位剂量的形式。
在一些实施方案中，所述药物组合物可通过任何合适途径施用，例如，以注射形式通过肠胃外施用，或以以下形式通过口服途径施用：例如，片剂、胶囊剂、粉剂、颗粒剂、锭剂、糖衣丸、丸剂、糖锭剂、含水或无水溶液、混悬剂、油包水或水包油乳剂、酏剂或糖浆剂。对于肠胃外施用，所述药物组合物可制备成分散剂、混悬剂、乳剂、无菌注射溶液或含无菌粉的分散剂。所述药物组合物也作为长效注射剂(depot injection)提供。所述药物组合物的其他合适施用形式为：栓剂、喷雾剂、膏剂、霜剂（cream）、凝胶剂、吸入剂和皮肤贴剂。所述药物组合物可使用本领域任何已知方法来制备成上述所列举的任何形式。可使用本领域常用的任何药学上可接受的载体稀释剂、赋形剂或其他添加剂。
在一些实施方案中，出于临床目的，所述药物组合物可以约0.001～100mg/kg的单位剂量形式或以多剂量形式施用。本申请公开的活性化合物每日总剂量可为约0.001mg/kg体重至约100mg/kg体重，在一些实施方案中按体重计可为约0.01mg/kg至约10mg/kg，但不限于此，其取决于患者的总体状况和所施用的活性化合物的活性。在一些实施方案中，所述药物组合物一天可施用约1-3次。在一些情况下，式I和式II的吡啶酮衍生物可配制前药型有效药物组合物。
在一些实施方案中，所述药物组合物可进一步包括其他不抑制或有助于所述活性成分功能的辅助成分，并可配制成本领域已知的任何各种形式。
根据本发明另一个方面，提供了治疗认知障碍的方法，所述方法包括使待治疗的对象接触以上描述的药物组合物。所述接触可以在体内或体外进行。所述体内接触包括将所述药物组合物施用于所述对象。所述对象可为细胞、组织、器官或个体。在一些实施方案中，可将所述药物组合物溶解于合适的缓冲溶液中后通过直接接触来施用于细胞、组织或器官，或者以肠胃外方式施用于个体。由于以上的描述，所述药物组合物和治疗中的施用方法此处不再详述。所述药物组合物施用的对象可为任何动物，例如，人类或非人类，如狗、猫和小鼠。
本发明的有益效果
在一些实施方案中，本发明的药物组合物可有效预防或治疗认知受损有关的认知障碍。
具体实施方式
现在将参照以下实施例详细描述本发明的一个或多个实施方案。但是，这些实施例仅用于说明的目的，而非旨在限制本发明一个或多个实施方案的范围。
实施例1：合成N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(2-噻唑基)-3-吡啶甲酰胺
实施例1-1:合成4-(甲氧基亚甲基)-2-戊二酸二甲酯
于约0℃，用约10min将52mL(0.73mmol)乙酰氯缓慢滴加至500mL甲醇和50g(0.36mol)香豆酸的混合溶液中，同时搅拌。所得反应溶液在回流下搅拌约10h(小时)。通过液相层析来确定所述反应终止后，使用甲醇减压蒸馏反应产物得到化合物。所述化合物用水和乙酸乙酯提取3次，在减压下用柱层析(己烷:乙酸乙酯=1:5)纯化有机相，从而获得目标化合物(实际产量:38g,百分产率:53%)。
(主要/次要比=5.8:1)
1H-NMR(CDCl3,200MHz,主要)δ7.64(s,1H),7.58(d,1H),6.62(d,1H),4.02(s,3H),3.73(m,6H)。
1H-NMR(CDCl3,200MHz,次要)δ8.87(s,1H),8.31(d,1H),6.34(d,1H),3.89(s,3H),3.73(m,6H)。
实施例1-2:合成6-氧代-1-(2-噻唑基)-1,6-二氢-3-吡啶甲酸甲酯
将2g(9.9mmol)由实施例1-1获得的4-(甲氧基亚甲基)2-戊二酸二甲酯溶解于10mL DMF以后，将1g(9.9mmol)2-氨基噻唑加入至所述溶液。然后，将所得反应溶液在回流下于约150℃搅拌6h。通过液相层析来确定所述反应结束后，在真空下去除所述溶剂，然后用盐水洗涤，再用硫酸镁干燥，过滤。减压蒸馏后，所得产物用柱层析(己烷:乙酸乙酯=1:3)纯化，从而获得目标化合物(实际产量：1g,百分产率：43%)。
1H-NMR(CDCl3,500MHz)δ9.65(s,1H),7.99(d,1H),7.75(s,1H),7.34(s,1H),6.79(d,1H),3.95(s,3H)。
实施例1-3:合成6-氧代-1-(2-噻唑基)-1,6-二氢-3-吡啶甲酸甲酯
将680mg(2.88mmol)6-氧代-1-(2-噻唑基)-1,6-二氢-3-吡啶甲酸甲酯溶解于12mL甲醇和4mL水以后，将207mg(8.64mmol)氢氧化锂加入至所述溶液。然后，将所得反应溶液于约75℃搅拌5h。通过液相层析来确定所述反应结束后，在真空下去除所述溶剂，再将HCl水溶液加入至该反应溶液以滴定，直到pH为2。过滤所得固体化合物，从而获得目标化合物(实际产量：466mg,百分产率：73%)。
1H-NMR(DMSO-d6,500MHz)δ13.29(s,br,1H),9.40(s,1H),7.92(d,1H),7.81(s,1H),7.69(s,1H),6.76(d,2H)。
实施例1-4：合成N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(2-噻唑基)-3-吡啶甲酰胺
使用下述方法之一合成N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(2-噻唑基)-3-吡啶甲酰胺。
方法1：将720mg(3.15mmol)6-氧代-1-(2-噻唑基)-1,6-二氢-3-吡啶甲酸溶解于20mL四氢呋喃和2mL DMF以后，将450mg(3.78mmol)奎宁环二盐酸盐和1.28g(9.43mmol)二乙基异丙基酰胺加入至所述溶液。将该反应溶液在室温下搅拌约30min以后，将1.4g(3.78mmol)O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)加入至该反应溶液，将该反应溶液在室温下搅拌约24h。通过液相层析来确定所述反应结束后，在真空下去除所述溶剂，然后用氯仿和NaOH水溶液(pH12)提取3次，并用液相层析(氯仿:甲醇:氨水=10:1:0.1)纯化，从而获得目标化合物(实际产量：676mg,百分产率:67%)。
方法2：将200mg(0.90mmol)6-氧代-1-(2-噻唑基)-1,6-二氢-3-吡啶甲酸溶解于10mL二氯甲烷以后，将363mg(2.86mmol)草酰氯加入至所述溶液，再向其中加入催化量的DMF。在室温下搅拌约2h以后，在真空下去除所述溶剂。将220mg(1.36mmol)奎宁环二盐酸盐加入至10mL乙腈以后，将445mg(3.45mmol)二乙基异丙基酰胺加入至所述溶液。将该反应溶液在室温下搅拌约1h。将减压蒸馏的反应混合物加入至乙腈以后，向其中缓慢加入奎宁环二盐酸盐反应溶液，然后于室温下搅拌约24h，并在真空下去除所述溶剂。所得化合物用氯仿和NaOH水溶液(pH12)提取3次，并用液相层析(氯仿:甲醇:氨水=10:1:0.1)纯化，从而获得目标化合物(实际产量：95mg,百分产率:32%)。
1H-NMR(CDCl3,500MHz)δ9.26(s,1H),7.86(d,1H),7.55(d,1H),7.24(d,1H),7.19(br,1H),6.65(d,1H),4.13(m,1H),3.39(m,1H),3.01(m,1H),2.80(m,4H),2.05(m,1H),1.86(m,1H),1.71(m,2H),1.50(m,1H)。
实施例2:合成N-[(3R)-1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(2-噻唑基)-3-吡啶甲酰胺
以与实施例1-2和实施例1-3相同方式合成6-氧代-1-(2-噻唑基)-1,6-二氢-3-吡啶甲酸的。以与实施例1-4和方法1相同的方式，由合成的6-氧代-1-(2-噻唑基)-1,6-二氢-3-吡啶甲酸和3R-奎宁环二盐酸盐获得目标化合物。
1H-NMR(CDCl3,500MHz)δ9.26(s,1H),7.86(d,1H),7.55(d,1H),7.24(d,1H),7.19(br,1H),6.65(d,1H),4.13(m,1H),3.39(m,1H),3.01(m,1H),2.80(m,4H),2.05(m,1H),1.86(m,1H),1.71(m,2H),1.50(m,1H)。
实施例3:合成N-[(3S)-1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(2-噻唑基)-3-吡啶甲酰胺
以与实施例1-2和实施例1-3相同的方式合成6-氧代-1-(2-噻唑基)-1,6-二氢-3-吡啶甲酸的。以与实施例1-4和方法1相同的方式，由合成的6-氧代-1-(2-噻唑基)-1,6-二氢-3-吡啶甲酸和3S-奎宁环二盐酸盐获得目标化合物。
1H-NMR(CDCl3,500MHz)δ9.26(s,1H),7.86(d,1H),7.55(d,1H),7.24(d,1H),7.19(br,1H),6.65(d,1H),4.13(m,1H),3.39(m,1H),3.01(m,1H),2.80(m,4H),2.05(m,1H),1.86(m,1H),1.71(m,2H),1.50(m,1H)。
实施例4:合成N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(2-吡啶基)-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基吡啶被用作起始原料。
1H-NMR(CDCl3,500MHz)δ8.61(s,1H),8.51(s,1H),7.89(m,2H),7.78(d,1H),7.40(m,1H),6.67(d,1H),6.18(br,d,1H),4.12(m,1H),3.44(m,1H),2,86(m,4H),2.60(m,1H),2.04(m,1H),1.72(m,3H),1.54(m,1H)。
实施例5:合成N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(3-吡啶基)-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：3-氨基吡啶被用作起始原料。
1H-NMR(CDCl3,500MHz)δ8.75(s,1H),8.69(m,1H),8.11(m,1H),7.85(m,1H),7.52(m,1H),7.49(m,1H),6.72(m,1H),6.03(br,1H),4.14(m,1H),3.49(m,1H),2.89(m,4H),2.61(m,1H),2.05(m,1H),1.75(m,3H),1.58(m,1H)。
实施例6：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-氯-2-吡啶基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-5-氯吡啶被用作起始原料。
1H-NMR(CDCl3,500MHz)δ8.47(s,1H),8.08(m,1H),7.81(d,1H),7.74(d,1H),7.52(d,1H),6.70(d,1H),6.05(br,1H),4.13(m,1H),3.48(m,1H),2.84(m,4H),2.57(m,1H),2.03(m,1H),1.73(m,3H),1.57(m,1H)
实施例7:合成N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-苯基-2-吡啶-1-基)-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-5-苯基吡啶被用作起始原料。
1H-NMR(CDCl3,500MHz)δ8.80(s,1H),8.59(m,1H),8.01(m,2H),7.84(m,1H),7.57(m,2H),7.47(m,3H),6.68(d,1H),6.43(br,1H),4.19(m,1H),3.42(m,1H),3.08(m,1H),2.84(m,4H),2.10(m,1H),1.77(m,3H),1.58(m,1H)。
实施例8：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(3-异噁唑基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：3-氨基异噁唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ8.58(s,1H),8.48(s,1H),7.90(m,1H),7.17(s,1H),6.95(br,1H),6.63(d,1H),4.25(m,1H),3.48(m,1H),3.25(m,1H),2.91(m,4H),2.14(m,1H),1.78(m,3H),1.58(m,1H)。
实施例9：合成N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-[3-苯基-5-异噁唑基)-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：5-氨基-3-苯基异噁唑被用作起始原料。
1H-NMR(DMSO-d6,500MHz)δ8.66(s,1H),8.33(m,1H),8.02(d,1H),7.95(m,2H),7.57(m,3H),7.50(s,1H),6.70(d,1H),3.96(m,1H),3.19(m,1H),2,89(m,1H),2.70(m,4H),1.81(m,2H),1.61(m,2H),1.34(m,1H)。
实施例10：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-甲基-2-噻唑基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-5-甲基噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.23(s,1H),7.85(d,1H),7.33(s,1H),6.73(d,1H),6.56(br,1H),4.14(m,1H),3.42(m,1H),2.82(m,4H),2.65(m,1H),2.48(s,3H),2.04(m,1H),1.74(m,3H),1.56(m,1H)。
实施例11：合成N-[(3R)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-甲基-2-噻唑基)-6-氧代-3-吡啶甲酰胺
以与实施例1-2和实施例1-3相同的方式合成6-氧代-1-(5-甲基-2-噻唑基)-1,6-二氢-3-吡啶甲酸，不同之处在于：2-氨基-5-甲基噻唑被用作起始原料。以与实施例1-4和方法1相同的方式，由合成的6-氧代-1-(5-甲基-2-噻唑基)-1,6-二氢-3-吡啶甲酸和3R-奎宁环二盐酸盐获得目标化合物。
1H-NMR(CDCl3,500MHz)δ9.23(s,1H),7.85(d,1H),7.33(s,1H),6.73(d,1H),6.56(br,1H),4.14(m,1H),3.42(m,1H),2.82(m,4H),2.65(m,1H),2.48(s,3H),2.04(m,1H),1.74(m,3H),1.56(m,1H)。
实施例12：合成N-[(3S)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-甲基-2-噻唑基)-6-氧代-3-吡啶甲酰胺
以与实施例1-2和实施例1-3相同的方式合成6-氧代-1-(5-甲基-2-噻唑基)-1,6-二氢-3-吡啶甲酸，不同之处在于：2-氨基-5-甲基噻唑被用作起始原料。以与实施例1-4和方法1相同的方式，由合成的6-氧代-1-(5-甲基-2-噻唑基)-1,6-二氢-3-吡啶甲酸和3S-奎宁环二盐酸盐获得目标化合物。
1H-NMR(CDCl3,500MHz)δ9.23(s,1H),7.85(d,1H),7.33(s,1H),6.73(d,1H),6.56(br,1H),4.14(m,1H),3.42(m,1H),2.82(m,4H),2.65(m,1H),2.48(s,3H),2.04(m,1H),1.74(m,3H),1.56(m,1H)。
实施例13：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-乙基-2-噻唑基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-5-乙基噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.30(s,1H),7.96(d,1H),7.30(s,1H),7.18(br,d,1H),6.72(d,1H),4.24(m,1H),3.45(m,1H),3.21(m,1H),3.02(m,1H),2.88(m,5H),2.16(m,1H),1.93(m,1H),1.80(m,2H),1.58(m,1H),1.34(t,3H)。
实施例14：合成N-[(3R)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-乙基-2-噻唑基)-6-氧代-3-吡啶甲酰胺
以与实施例1-2和实施例1-3相同的方式合成6-氧代-1-(5-乙基-2-噻唑基)-1,6-二氢-3-吡啶甲酸，不同之处在于：2-氨基-5-乙基噻唑被用作起始原料。以与实施例1-4和方法1相同的方式，由合成的6-氧代-1-(5-乙基-2-噻唑基)-1,6-二氢-3-吡啶甲酸和3R-奎宁环二盐酸盐获得目标化合物。
1H-NMR(CDCl3,500MHz)δ9.30(s,1H),7.96(d,1H),7.30(s,1H),7.18(br,d,1H),6.72(d,1H),4.24(m,1H),3.45(m,1H),3.21(m,1H),3.02(m,1H),2.88(m,5H),2.16(m,1H),1.93(m,1H),1.80(m,2H),1.58(m,1H),1.34(t,3H)。
实施例15：合成N-[(3S)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-乙基-2-噻唑基)-6-氧代-3-吡啶甲酰胺
以与实施例1-2和实施例1-3相同的方式合成6-氧代-1-(5-乙基-2-噻唑基)-1,6-二氢-3-吡啶甲酸，不同之处在于：2-氨基-5-乙基噻唑被用作起始原料。以与实施例1-4和方法1相同的方式，由合成的6-氧代-1-(5-乙基-2-噻唑基)-1,6-二氢-3-吡啶甲酸和3S-奎宁环二盐酸盐获得目标化合物。
1H-NMR(CDCl3,500MHz)δ9.30(s,1H),7.96(d,1H),7.30(s,1H),7.18(br,d,1H),6.72(d,1H),4.24(m,1H),3.45(m,1H),3.21(m,1H),3.02(m,1H),2.88(m,5H),2.16(m,1H),1.93(m,1H),1.80(m,2H),1.58(m,1H),1.34(t,3H)。
实施例16：合成N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-丙基-2-噻唑基)-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-5-丙基噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.27(s,1H),7.90(d,1H),7.31(s,1H),6.84(br,1H),6.72(d,1H),4.18(m,1H),3.43(m,1H),3.09(m,1H),2.88(m,4H),2.80(t,2H),2.11(m,1H),1.86(m,1H),1.73(m,4H),1.56(m,1H),1.00(t,3H)。
实施例17：合成N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-丙-2-基-2-噻唑基)-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-5-异丙基噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.28(s,1H),7.96(d,1H),7.29(br,d,1H),6.71(d,1H),4.23(m,1H),3.42(m,1H),3.22(m,2H),2.93(m,4H),2.16(m,1H),1.94(m,1H),1.80(m,2H),1.53(m,1H),1.35(d,6H)。
实施例18：合成N-[(3R)-1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-丙-2-基-2-噻唑基)-3-吡啶甲酰胺
以与实施例1-2和实施例1-3相同的方式合成6-氧代-1-(5-丙-2-基-2-噻唑基)-1,6-二氢-3-吡啶甲酸，不同之处在于：2-氨基-5-异丙基噻唑被用作起始原料。以与实施例1-4和方法1相同的方式，由合成的6-氧代-1-(5-丙-2-基-2-噻唑基)-1,6-二氢-3-吡啶甲酸和3R-奎宁环二盐酸盐获得目标化合物。
1H-NMR(CDCl3,500MHz)δ9.28(s,1H),7.96(d,1H),7.29(br,d,1H),6.71(d,1H),4.23(m,1H),3.42(m,1H),3.22(m,2H),2.93(m,4H),2.16(m,1H),1.94(m,1H),1.80(m,2H),1.53(m,1H),1.35(d,6H)。
实施例19：合成N-[(3S)-1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-丙-2-基-2-噻唑基)-3-吡啶甲酰胺
以与实施例1-2和实施例1-3相同的方式合成6-氧代-1-(5-丙-2-基-2-噻唑基)-1,6-二氢-3-吡啶甲酸，不同之处在于：2-氨基-5-异丙基噻唑被用作起始原料。以与实施例1-4和方法1相同的方式，由合成的6-氧代-1-(5-丙-2-基-2-噻唑基)-1,6-二氢-3-吡啶甲酸和3S-奎宁环二盐酸盐获得目标化合物。
1H-NMR(CDCl3,500MHz)δ9.28(s,1H),7.96(d,1H),7.29(br,d,1H),6.71(d,1H),4.23(m,1H),3.42(m,1H),3.22(m,2H),2.93(m,4H),2.16(m,1H),1.94(m,1H),1.80(m,2H),1.53(m,1H),1.35(d,6H)。
实施例20:合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-叔丁基-2-噻唑基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-5-叔丁基噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.25(s,1H),7.86(d,1H),7.27(s,1H),6.87(br,1H),6.70(d,1H),4.19(m,1H),3.45(m,1H),3.08(m,1H),2.89(m,4H),2.11(m,1H),1.90(m,1H),1.76(m,2H),1.57(m,1H),1.42(s,9H)。
实施例21:合成N-[(3R)-1-氮杂二环[2.2.2]辛-3-基]-1-[5-叔丁基-2-噻唑基]-6-氧代-3-吡啶甲酰胺
以与实施例1-2和实施例1-3相同的方式合成6-氧代-1-(5-叔丁基-2-噻唑基)-1,6-二氢-3-吡啶甲酸，不同之处在于：2-氨基-5-叔丁基噻唑被用作起始原料。
以与实施例1-4和方法1相同的方式，由合成的6-氧代-1-(5-叔丁基-2-噻唑基)-1,6-二氢-3-吡啶甲酸和3R-奎宁环二盐酸盐获得目标化合物。
1H-NMR(CDCl3,500MHz)δ9.25(s,1H),7.86(d,1H),7.27(s,1H),6.87(br,1H),6.70(d,1H),4.19(m,1H),3.45(m,1H),3.08(m,1H),2.89(m,4H),2.11(m,1H),1.90(m,1H),1.76(m,2H),1.57(m,1H),1.42(s,9H)。
实施例22:合成N-[(3S)-1-氮杂二环[2.2.2]辛-3-基]-1-[5-叔丁基-2-噻唑基]-6-氧代-3-吡啶甲酰胺
以与实施例1-2和实施例1-3相同的方式合成6-氧代-1-(5-叔丁基-2-噻唑基)-1,6-二氢-3-吡啶甲酸，不同之处在于：2-氨基-5-叔丁基噻唑被用作起始原料。以与实施例1-4和方法1相同的方式，由合成的6-氧代-1-(5-叔丁基-2-噻唑基)-1,6-二氢-3-吡啶甲酸和3S-奎宁环二盐酸盐获得目标化合物。
1H-NMR(CDCl3,500MHz)δ9.25(s,1H),7.86(d,1H),7.27(s,1H),6.87(br,1H),6.70(d,1H),4.19(m,1H),3.45(m,1H),3.08(m,1H),2.89(m,4H),2.11(m,1H),1.90(m,1H),1.76(m,2H),1.57(m,1H),1.42(s,9H)。
实施例23：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-环戊基-2-噻唑基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-5-环戊基噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.17(s,1H),7.80(d,1H),7.21(s,1H),6.95(br,1H),6.64(d,1H),4.10(m,1H),3.37(m,1H),3.19(m,1H),2.99(m,1H),2.81(m,4H),2.12(m,2H),2.04(m,1H),1.78(m,3H),1.66(m,6H),1.50(m,1H)
实施例24：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-环己基-2-噻唑基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-5-环己基噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.33(s,1H),8.01(d,1H),7.52(br,1H),7.26(s,1H),6.68(d,1H),4.32(m,1H),3.47(m,1H),3.39(m,1H),3.32(m,1H),3.05(m,3H),2.83(m,1H),2.24(m,1H),2.04(m,3H),1.87(m,4H),1.74(m,1H),1.65(m,1H),1.49(m,4H),1.23(m,1H)。
实施例25：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-苯基-2-噻唑基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-5-苯基噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.53(s,1H),7.93(d,2H),7.85(d,1H),7.45(m,4H),6.79(d,1H),6.63(br,1H),4.21(m,1H),3.46(m,1H),3.06(m,1H),2.92(m,4H),2.06(m,1H),1.84(m,3H),1.68(m,1H)。
实施例26：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-氯-2-噻唑基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-5-氯噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.13(s,1H),7.85(d,1H),7.44(s,1H),6.92(br,1H),6.69(d,1H),4.13(m,1H),3.41(m,1H),3.00(m,1H),2.28(m,4H),2.06(m,1H),1.84(m,1H),1.71(m,2H),1.52(m,1H)。
实施例27：合成N-[(3R)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-氯-2-噻唑基)-6-氧代-3-吡啶甲酰胺
以与实施例1-2和实施例1-3相同的方式合成6-氧代-1-(5-氯-2-噻唑基)-1,6-二氢-3-吡啶甲酸，不同之处在于：2-氨基-5-氯噻唑被用作起始原料。以与实施例1-4和方法1相同的方式，由合成的6-氧代-1-(5-氯-2-噻唑基)-1,6-二氢-3-吡啶甲酸和3R-奎宁环二盐酸盐获得目标化合物。
1H-NMR(CDCl3,500MHz)δ9.13(s,1H),7.85(d,1H),7.44(s,1H),6.92(br,1H),6.69(d,1H),4.13(m,1H),3.41(m,1H),3.00(m,1H),2.28(m,4H),2.06(m,1H),1.84(m,1H),1.71(m,2H),1.52(m,1H)。
实施例28：合成N-[(3S)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-氯-2-噻唑基)-6-氧代-3-吡啶甲酰胺
以与实施例1-2和实施例1-3相同的方式合成6-氧代-1-(5-氯-2-噻唑基)-1,6-二氢-3-吡啶甲酸，不同之处在于：2-氨基-5-氯噻唑被用作起始原料。以与实施例1-4和方法1相同的方式，由合成的6-氧代-1-(5-氯-2-噻唑基)-1,6-二氢-3-吡啶甲酸和3S-奎宁环二盐酸盐获得目标化合物。
1H-NMR(CDCl3,500MHz)δ9.13(s,1H),7.85(d,1H),7.44(s,1H),6.92(br,1H),6.69(d,1H),4.13(m,1H),3.41(m,1H),3.00(m,1H),2.28(m,4H),2.06(m,1H),1.84(m,1H),1.71(m,2H),1.52(m,1H)。
实施例29：合成N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-[5-(苯甲基)-2-噻唑基)]-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：5-苄基-1,3-噻唑基-2-苯胺被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.23(s,1H),7.82(d,1H),7.32(m,6H),6.72(d,1H),6.36(br,1H),4.16(s,2H),4.12(m,1H),3.44(m,1H),2.89(m,4H),2.62(m,1H),2.04(m,1H),1.72(m,3H),1.52(m,1H)。
实施例30：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(4-甲基-2-噻唑基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-4-甲基噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.34(s,1H),7.83(d,1H),6.87(s,1H),6.78(d,1H),6.40(br,1H),4.18(m,1H),3.42(m,1H),2.84(m,4H),2.65(m,1H),2.51(s,3H),2.08(m,1H),1.78(m,3H),1.58(m,1H)。
实施例31：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-[4-(4-氯苯基)-2-噻唑基]-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-4-氯苯基噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.52(s,1H),7.87(m,2H),7.81(m,1H),7.45(s,1H),7.41(m,2H),6.80(m,1H),6.38(br,1H),4.13(m,1H),3.47(m,1H),3.03(m,1H),2.83(m,3H),2.77(m,1H),2.11(m,1H),1.86(m,3H),1.69(m,1H)。
实施例32：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(4,5-二甲基-2-噻唑基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法2相同的方式获得目标化合物，不同之处在于：2-氨基-4,5-二甲基噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.18(s,1H),7.80(d,1H),7.19(br,d,1H),6.60(d,1H),4.12(m,1H),3.35(m,1H),3.02(m,1H),2.84(m,4H),2.29(s,3H),2.08(s,3H),2.06(m,1H),1.87(m,1H),1.72(m,2H),1.50(m,1H)。
实施例33：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(1,3-苯并噻唑-2-基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-1,3-苯并噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.45(s,1H),7.98(m,3H),7.56(m,1H),7.52(m,1H),6.84(m,1H),6.32(br,1H),4.17(m,1H),3.44(m,1H),3.04(m,1H),2.94(m,3H),2.65(m,1H),2.01(m,1H),1.84(m,3H),1.60(m,1H)。
实施例34：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(4-甲氧基-1,3-苯并噻唑-2-基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-4-甲氧基-1,3-苯并噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.50(s,1H),7.97(d,1H),7.54(d,1H),7.38(m,1H),6.84(d,1H),6.69(d,1H),6.53(br,1H),4.14(m,1H),4.08(m,3H),3.43(m,1H),2.71(m,4H),2.68(m,1H),2.08(m,1H),1.73(m,3H),1.58(m,1H)。
实施例35：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-[5,6-二甲基-1,3-苯并噻唑-2-基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-5,6-二甲氧基-1,3-苯并噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.46(s,1H),8.65(d,1H),8.09(d,1H),7.84(d,2H),6.80(d,1H),4.14(m,1H),3.46(m,1H),2.89(m,4H),2.49(m,6H),2.38(m,1H),2.07(m,1H),1.79(m,3H),1.62(m,1H)。
实施例36：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(2,1,3-苯并噻唑-4-基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法4相同的方式获得目标化合物，不同之处在于：4-氨基-2,1,3-苯并噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ8.18(s,1H),8.16(d,1H),7.80(m,1H),7.78(m,1H),7.68(m,1H),6.66(d,1H),6.42(br,d,1H),4.05(m,1H),3.33(m,1H),2,84(m,4H),2.54(m,1H),1.95(m,1H),1.67(m,3H),1.46(m,1H)。
实施例37：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(1,3-苯并噻唑-6-基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：6-氨基-1,3-苯并噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ8.93(s,1H),8.23(m,1H),8.20(s,1H),8.02(s,1H),7.79(d,1H),7.57(d,1H),6.65(d,1H),6.56(br,d,1H),4.15(m,1H),3.39(m,1H),2,88(m,4H),2.72(m,1H),2.01(m,1H),1.76(m,3H),1.53(m,1H)。
实施例38：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-甲基-2-苯基-3-吡唑基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：3-氨基-5-甲基-2-苯基吡唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ8.97(s,1H),8.51(s,1H),8.23(d,2H),7.52(m,3H),7.33(m,2H),6.44(br,1H),4.23(m,1H),3.48(m,1H),2.91(m,3H),2.86(m,2H),2.67(m,3H),1.98(m,1H),1.75(m,3H),1.59(m,1H)。
实施例39：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(1-异喹啉基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：1-氨基异喹啉被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.10(d,1H),8.92(d,1H),8.50(s,1H),7.80(m,3H),7.61(d,1H),7.43(m,2H),5.98(br,1H),4.13(m,1H),3.63(m,1H),2.87(m,4H),2.58(d,1H),2.07(m,1H),1.93(m,2H),1.52(1H),1.43(s,1H)。
实施例40：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-异喹啉基)-6-氧代-3-吡啶甲酰胺
按照与实施例5和方法1相同的方式获得目标化合物，不同之处在于：1-氨基异喹啉被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.38(m,1H),8.59(m,1H),8.18(m,1H),8.05(m,1H),7.82(m,1H),7.78(m,2H),7.23(m,1H),6.77(d,1H),6.30(br,1H),4.11(m,1H),3.41(m,1H),2.85(m,4H),2.61(m,1H),2.05(m,1H),1.78(m,3H),1.49(m,1H)。
实施例41:合成N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-喹啉基)-3-吡啶甲酰胺
按照与实施例5和方法1相同的方式获得目标化合物，不同之处在于：1-氨基喹啉被用作起始原料。
1H-NMR(CDCl3,500MHz)δ8.90(d,1H),8.23(s,1H),8.12(s,1H),7.80(t,3H),7.51(m,2H),6.78(d,1H),6.23(br,1H),4.04(m,1H),3.48(m,1H),2.81(m,4H),2.59(m,1H),1.93(m,1H),1.87(m,2H),1.64(m,1H),1.45(m,1H)。
实施例42：合成N-(1-氮杂二环[2.2.2]辛-3-基)-1-[5-甲基-1,3,4-噻二唑-2-基)-6-氧代-3-吡啶甲酰胺
按照与实施例1和方法2相同的方式获得目标化合物，不同之处在于：2-氨基-5-甲基-1,3,4-噻二唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.31(s,1H),8.03(d,1H),7.24(br,s,1H),6.78(d,1H),4.21(m,1H),3.39(m,1H),3.12(m,1H),2.91(m,4H),2.77(s,3H),2.12(m,1H),1.91(m,1H),1.78(m,2H),1.57(m,1H)。
实施例43：合成N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-苯基-1,3,4-噻二唑-2-基)-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基-5-苯基-1,3,4-噻二唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ8.14(s,1H),7.97(m,2H),7.59(m,3H),7.47(m,1H),7.41(m,1H),5.99(br,1H),4.11(m,1H),3.42(m,1H),2.82(m,4H),2.54(m,1H),2.01(m,1H),1.83(m,3H),1.66(m,1H)。
实施例44:合成N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(2-吡嗪基)-3-吡啶甲酰胺
按照与实施例1和方法1相同的方式获得目标化合物，不同之处在于：2-氨基吡嗪被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.31(s,1H),8.62(m,3H),7.78(m,1H),6.68(d,1H),6.31(br,1H),4.09(m,1H),3.41(m,1H),2.87(m,4H),2.65(m,1H),2.17(m,1H),1.75(m,3H),1.58(m,1H)。
实施例45：合成(1-氮杂二环[2.2.2]辛-3-基)-1-[5-甲基-1,3-噻二唑-2-基)-6-氧代-3-吡啶甲酸酯
实施例45-1：合成1-(5-甲基-1,3-噻唑-2-基)-1,6-二氢-6-氧代-3-吡啶甲酸甲酯
使用2-氨基-5-甲基噻唑，按照与实施例1-2相同的方式合成目标化合物。
实施例45-2：合成1-(5-甲基-1,3-噻唑-2-基)-1,6-二氢-6-氧代-3-吡啶甲酸
使用1-(5-甲基-1,3-噻唑-2-基)-1,6-二氢-6-氧代-3-吡啶甲酸甲酯和LiOH，按照与实施例1-3相同的方式获得目标化合物。
实施例45-3：合成6-氧代-1-苯基-1,6-二氢-吡啶-3-甲酰氯
将510mg由实施例45-2获得的(2.15mmol)1-(5-甲基-1,3-噻唑-2-基)-1,6-二氢-6-氧代-3-吡啶甲酸溶解于10mL甲苯以后，将522mg(4.30mmol)氯化亚砜加入至所述溶液。然后，将所得反应溶液在回流下于约100℃搅拌2h。通过液相层析来确定所述反应结束后，在真空下去除所述溶剂。所得固体化合物不经另外的纯化工序而用于实施例45-4中。
实施例45-4：合成(1-氮杂二环[2.2.2]辛-3-基)-1-[5-甲基-1,3-噻二唑-2-基)-6-氧代-3-吡啶甲酸酯
将由实施例45-3获得的6-氧代-1-苯基-1,6-二氢吡啶-3-甲酰氯的混合溶液溶解于5mL吡啶以后，向其中加入547mg(4.30mmol)3-羟基奎宁环。然后，将所得反应溶液在室温下搅拌约3d(天)。通过液相层析来确定所述反应结束后，在真空下去除所述溶剂。所得化合物用水和氯仿提取3次，所述有机相用液相层析(氯仿:甲醇:氨水=10:1:0.1)纯化，从而获得目标化合物(实际产量：357mg,百分产率:48%)。
1H-NMR(CDCl3,500MHz)δ9.52(s,1H),7.92(d,1H),7.35(s,1H),6.72(d,1H),5.01(m,1H),3.33(m,1H),2.89(m,5H),2.46(s,3H),2.14(m,1H),1.94(m,1H),1.72(m,1H),1.60(m,1H),1.48(m,1H)。
实施例46：合成(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-丙-2-基-1,3-噻唑-2-基)-3-吡啶甲酸酯
按照与实施例45相同的方式获得目标化合物，不同之处在于：2-氨基-5-异丙基噻唑被用作起始原料。
1H-NMR(CDCl3,500MHz)δ9.58(s,1H),7.95(d,1H),7.42(s,1H),6.77(d,1H),5.07(m,1H),3.38(m,1H),3.26(m,1H),2.87(m,5H),2.21(m,1H),2.02(m,1H),1.79(m,1H),1.67(m,1H),1.54(m,1H),1.40(d,6H)。
实施例47：测量人的α7烟碱型乙酰胆碱受体(nAChR)的活性
通过FlexStation-Ca2+流入检测来测量异聚体α7nAChR的活性。在本实施例中，考虑到α7nAChR为Ca2+-可渗透的非选择性阳离子通道，用荧光染料钙-3(Molecular Devices公司提供)和FlexStationⅡ检测仪(Molecular Devices公司提供)来测量细胞内的Ca2+浓度变化。
将人的CHRNA7(NM_000746)cDNA ORF克隆(C/N RC221382;Origene)和人的RIC(NM_024557)cDNA ORF克隆(C/N RC205179;Origene)亚克隆到pcDNA2.1/Zeo(+)载体(Invitrogen,Co.公司提供)以构建用人的α7nAChR转染的HEK293T/17细胞(ATCC,CRL-11268)。然后，将这些细胞悬浮于生长培养基(其组成如下：杜尔伯克氏改良伊格尔培养基(DMEM，Invitrogen公司提供)、10%热灭活胎牛血清(FBS,Invitrogen公司提供)、300μg/ml遗传霉素(Geneticin)(Invitrogen公司提供)、250μg/ml博莱霉素(Zeocin)(Invitrogen公司提供)以及1x青霉素/链霉素(Invitrogen公司提供))，然后接种到Ф150mm的培养皿。开始该检测24h以前，收集生长于所述悬浮液中的细胞，进行离心，然后再次以5x105个细胞/mL的浓度悬浮于生长培养基中。将该细胞悬浮液分配至具有由聚-D-赖氨酸包被的透明底(Biocoat公司提供,BD)的96-孔黑色平板(5x104细胞/孔)的每个孔内。将带有所述细胞的平板于约37℃、5%CO2下孵育约24h。
在进行检测的当天，将生长培养基去除后，用检测缓冲液(7mMTris-Cl,20mM HEPES,20mM NaCl,5mM KCl,0.8mM MgSO4,4mM CaCl2,120mM NMDG,5mM D-葡萄糖,pH7.4)洗涤所述细胞一次，再向每个孔内加入约100ul用检测缓冲液稀释的钙-3染料，室温贮存约1h。将测试化合物(100%二甲基亚砜(DMSO)中的10mM储备液)用检测缓冲液稀释为各种浓度，从最高约40μM至低于1/3，并将用于放大Ca2+通透性信号转导的PNU-120596(Sigma公司提供)用检测缓冲液稀释至约30μM。将终浓度为约1μM的地棘蛙素(Epibatidine)(Sigma公司提供)用作阳性对照组。
为测量细胞内Ca2+浓度的变化，将该平板于室温储存约1h后，将测试化合物稀释平板放入FlexStation||检测仪，在加入药物(所述化合物)前测量细胞的荧光约30s(秒)，然后加入PNU-120596并测量荧光变化约120s。将细胞暴露于测试化合物以后，测量荧光变化约90s(于485nm激发/于525nm发射)。记录每个浓度的最大荧光值，使用非线性回归分析，以相对于阳性对照组的相对荧光值来确定测试化合物的EC50。
结果以EC50值表示。在测试的化合物中，对于浓度缺少依赖关系的那些化合物，在测试的化合物具有最高荧光值的浓度下记录相对荧光值读数。该测试进行一次或多次。用与上述同样的方法测试一些实施例中合成的所述化合物的功效，结果如下述表1和表2所示。在表1中+表示1000nM以上的EC50，++表示500nM至1000nM的EC50，+++表示100nM至约500nM的EC50，以及++++表示100nM以下的EC50。
【表1】
| 实施例 | 人α7nAChR的EC50(nM) |
| 1 | +++ |
| 2 | +++ |
| 3 | +++ |
| 6 | + |
| 7 | +++ |
| 9 | + |
| 10 | +++ |
| 11 | ++++ |
| 12 | ++ |
| 13 | +++ |
| 14 | ++++ |
| 15 | +++ |
| 16 | +++ |
| 17 | +++ |
| 18 | ++++ |
| 19 | +++ |
| 20 | +++ |
| 21 | +++ |
| 22 | ++ |
| 23 | +++ |
| 24 | +++ |
| 25 | ++ |
| 26 | ++++ |
| 27 | +++ |
| 28 | + |
| 29 | +++ |
| 30 | + |
| 33 | +++ |
| 42 | + |
| 45 | + |
| 46 | + |
+，1000nM以上；++，500nm至1000nM；+++，100mM至500nM；++++，100nM以下。
实施例48：对施用含有吡啶衍生物的组合物的小鼠进行新物体认知测试(NORT)
NORT是首先由Ennaceu和Delacour引入的一种认知记忆测试，用于测量基于大鼠的本性其是否能够记住之前经历过的物体，即倾向于探索新物体[Ennaceur A and Delacour J(1988)A new one-trial test forneurobiological studies of memory in rats.1;Behavioral data.BehavioralBrain Res.31;47-59]。该NOR测试是一种通用实验方法，用于测试施用健忘症诱导药物或其他常规药物的啮齿类动物对物体记忆的变化，通过其探讨测试药物对于施用健忘症诱导药物的啮齿类动物的记忆恢复功效。在本实施例中，按照Bevins和Besheer的描述来进行测试[Bevins,R.A.&Besheer,J.Object recognition in rats and mice;aone-trial non-matching-to-sample learning task to study'recognitionmemory'.Nat Protoc.2006;1(3);1306-11.(2006)]。以0.03～3mg/kg和10ml/kg体重的剂量，给重量约20g至约32g的雄性ICR小鼠(OrientBio Inc.公司提供，韩国)口服施用溶解于30%PEG中的测试化合物。施用30min后，将溶于生理盐水的MK-801(Sigma公司提供)以0.1mg/kg和10ml/kg体重的剂量皮下施用以诱导健忘症。施用MK-801约30min后，让小鼠探索之前放置于盒子中约5min的方形不锈钢柱或圆形塑料柱。探索后约24h，将之前出现过的两个物体之一替换为新物体(即，包括一个方形不锈钢柱和一个圆形塑料柱)，测量其试图探索的次数约5min。认知指数(RI)定义为：
[(测试化合物组中对新物体的探索时间/测试化合物组中对所有物体的探索时间)/(MK801组中对新物体的探索时间/MK801组中对所有物体的探索时间)x100]。
下述表2所示为所述化合物在产生半数最大激活(EC50)的最小剂量时的相对RI值。
【表2】
| 实施例 | NORT相对RI(%)MED |
| 1 | 114.8%0.03po |
| 2 | 116.4%0.01po |
| 10 | 114.8%0.3po |
| 11 | 111.8%0.03po |
| 13 | 116.7%0.3po |
| 14 | 109.6%0.03po |
| 17 | 112.0%0.3po |
| 20 | 117.0%0.3po |
| 24 | 121.6%0.03po |
| 26 | 110.4%0.3po |
| 33 | 118.3%0.01po |
Claims (6)
1.一种下述式I表示的吡啶酮衍生物或其药学上可接受的盐或R或S异构体：
式I
其中，在式I中，A是可由选自下组中至少一种基团取代的C1-C10杂芳基：卤素、C1-C6烷基、C3-C7环烷基、C6-C12芳烷基、C1-C6烷氧基和C6-C12芳基；
B是O或NH；且
其中所述C1-C10杂芳基选自下组：噻唑基、苯并噻唑基、吡啶基、异噁唑基、异喹啉基、喹啉基、苯并噻二唑基、噻二唑基、吡唑基和吡嗪基。
2.根据权利要求1所述的吡啶酮衍生物或其药学上可接受的盐或R或S异构体，其中B是NH。
3.一种吡啶酮衍生物、其药学上可接受的盐或R或S异构体，所述吡啶酮衍生物选自下组：N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(2-噻唑基)-3-吡啶甲酰胺、N-[(3R)-1-氮杂二环[2.2.2]辛-3-基]-6-氧代-1-(2-噻唑基)-3-吡啶甲酰胺、N-[(3S)-1-氮杂二环[2.2.2]辛-3-基]-6-氧代-1-(2-噻唑基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(2-吡啶基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(3-吡啶基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-氯-2-吡啶基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-苯基-2-吡啶-1-基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(3-异噁唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(3-苯基-5-异噁唑基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-甲基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3R)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-甲基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3S)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-甲基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-乙基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3R)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-乙基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3S)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-乙基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-丙基-2-噻唑基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-丙-2-基-2-噻唑基)-3-吡啶甲酰胺、N-[(3R)-1-氮杂二环[2.2.2]辛-3-基]-6-氧代-1-(5-丙-2-基-2-噻唑基)-3-吡啶甲酰胺、N-[(3S)-1-氮杂二环[2.2.2]辛-3-基]-6-氧代-1-(5-丙-2-基-2-噻唑基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-叔丁基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3R)-1-氮杂二环[2.2.2]辛-3-基)]-1-(5-叔丁基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3S)-1-氮杂二环[2.2.2]辛-3-基)]-1-(5-叔丁基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-环戊基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-环己基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-苯基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-氯-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3R)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-氯-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-[(3S)-1-氮杂二环[2.2.2]辛-3-基]-1-(5-氯-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-[5-(苯甲基)-2-噻唑基]-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(4-甲基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-[4-(4-氯苯基)-2-噻唑基]-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(4,5-二甲基-2-噻唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(1,3-苯并噻唑-2-基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(4-甲氧基-1,3-苯并噻唑-2-基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5,6-二甲基-1,3-苯并噻唑-2-基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(2,1,3-苯并噻二唑-4-基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(1,3-苯并噻唑-6-基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-甲基-2-苯基-3-吡唑基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(1-异喹啉基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-异喹啉基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-喹啉基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-1-(5-甲基-1,3,4-噻二唑-2-基)-6-氧代-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-苯基-1,3,4-噻二唑-2-基)-3-吡啶甲酰胺、N-(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(2-吡嗪基)-3-吡啶甲酰胺、(1-氮杂二环[2.2.2]辛-3-基)-1-(5-甲基-1,3-噻唑-2-基)-6-氧代--3-吡啶甲酸酯，以及(1-氮杂二环[2.2.2]辛-3-基)-6-氧代-1-(5-丙-2-基-1,3-噻唑-2-基)-3-吡啶甲酸酯。
4.根据权利要求1所述的吡啶酮衍生物或其药学上可接受的盐或R或S异构体，其中所述吡啶酮衍生物是α7烟碱型乙酰胆碱受体的激动剂或部分激动剂。
5.用于预防或治疗认知障碍的药物组合物，所述组合物包含治疗上有效量的权利要求1-4中任一项所述的吡啶酮衍生物、其药学上可接受的盐或R或S异构体；以及药学上可接受的载体。
6.根据权利要求5所述的药物组合物，其中所述认知障碍选自下组：早老年性痴呆症、早发性阿尔茨海默病、老年性痴呆症、阿尔茨海默型痴呆症、路易体小体性痴呆症、微小梗塞性痴呆症、AIDS相关痴呆症、HIV痴呆症、路易体相关痴呆症、唐氏综合征相关痴呆症、皮克氏病、轻度认知功能障碍、与年龄相关的记忆障碍、最近短期记忆障碍、年龄相关认知障碍、药物相关的认知障碍、免疫缺陷综合征相关的认知障碍、血管疾病相关的认知功能障碍、精神分裂症、注意力缺陷障碍、注意缺陷多动障碍(ADHD)，以及学习缺陷障碍。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2011-0008962 | 2011-01-28 | ||
| KR20110008962 | 2011-01-28 | ||
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| KR101928505B1 (ko) * | 2011-01-28 | 2018-12-12 | 에스케이바이오팜 주식회사 | 피리돈 유도체 및 이를 포함하는 약학적 조성물 |
| KR101925971B1 (ko) * | 2011-01-28 | 2018-12-06 | 에스케이바이오팜 주식회사 | 피리돈 유도체 및 이를 포함하는 약학적 조성물 |
| AR092742A1 (es) | 2012-10-02 | 2015-04-29 | Intermune Inc | Piridinonas antifibroticas |
| KR102373700B1 (ko) | 2014-04-02 | 2022-03-11 | 인터뮨, 인크. | 항섬유성 피리디논 |
| CN109293507B (zh) * | 2018-10-12 | 2020-12-18 | 河北科技大学 | 4-甲氧基甲烯基-2-烯戊二酸二甲酯的合成方法及其应用 |
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| CN1612876A (zh) * | 2002-01-07 | 2005-05-04 | 法商沙诺费-辛芷拉保公司 | 5－(吡啶－3－基)－1－氮杂二环[3.2.1]辛烷衍生物,其制备及其治疗应用 |
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| US4404138A (en) * | 1982-06-22 | 1983-09-13 | Warner-Lambert Company | 3-[2-(Azabicyclo) ethyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-ones |
| SE0000540D0 (sv) * | 2000-02-18 | 2000-02-18 | Astrazeneca Ab | New compounds |
| US6492385B2 (en) * | 2000-08-18 | 2002-12-10 | Pharmacia & Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease |
| JP4445704B2 (ja) * | 2000-12-22 | 2010-04-07 | アルミラル・ソシエダッド・アノニマ | キヌクリジンカルバメート誘導体およびｍ３アンダゴニストとしてのそれらの使用 |
| US6569865B2 (en) * | 2001-06-01 | 2003-05-27 | Astrazeneca Ab | Spiro 1-azabicyclo[2.2.2]octane-3,2′(3′h)-furo[2,3-b]pyridine |
| AR036040A1 (es) * | 2001-06-12 | 2004-08-04 | Upjohn Co | Compuestos de heteroarilo multiciclicos sustituidos con quinuclidinas y composiciones farmaceuticas que los contienen |
| EP1419161A1 (en) * | 2001-08-24 | 2004-05-19 | PHARMACIA & UPJOHN COMPANY | Substituted-heteroaryl-7-aza 2.2.1]bicycloheptanes for the treatment of disease |
| DE10156719A1 (de) * | 2001-11-19 | 2003-05-28 | Bayer Ag | Heteroarylcarbonsäureamide |
| BR0307874A (pt) * | 2002-02-20 | 2004-12-28 | Upjohn Co | Atividade de compostos azabicìclicos com receptor de acetilcolina nicotìnica alfa7 |
| MXPA04012439A (es) * | 2002-06-10 | 2005-04-19 | Bayer Healthcare Ag | Amidas de acidos 2-heteroarilcarboxilicos. |
| WO2004013137A1 (en) * | 2002-08-01 | 2004-02-12 | Pharmacia & Upjohn Company Llc | 1h-pyrazole and 1h-pyrrole-azabicyclic compounds with alfa-7 nachr activity |
| KR101129933B1 (ko) * | 2002-09-25 | 2012-03-23 | 메모리 파마슈티칼스 코포레이션 | 인다졸, 벤조티아졸 및 벤조이소티아졸 및 그의 제조 및용도 |
| BRPI0417933A (pt) * | 2003-12-22 | 2007-04-17 | Astrazeneca Ab | composto, métodos para o tratamento ou a profilaxia de uma doença ou condição, e de distúrbios, e para a indução da cessação do hábito de fumar, composição farmacêutica, e, uso de um composto |
| US20050234095A1 (en) * | 2004-03-25 | 2005-10-20 | Wenge Xie | Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, and preparation and uses thereof |
| CA2591817A1 (en) * | 2004-12-22 | 2006-06-29 | Memory Pharmaceuticals Corporation | Nicotinic alpha-7 receptor ligands and preparation and uses thereof |
| US8106066B2 (en) * | 2005-09-23 | 2012-01-31 | Memory Pharmaceuticals Corporation | Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, pyrazolopyridines, isothiazolopyridines, and preparation and uses thereof |
| WO2010042799A2 (en) * | 2008-10-09 | 2010-04-15 | Howard Hughes Medical Institute | Novel chimeric ligand-gated ion channels and methods of use thereof |
| KR101928505B1 (ko) * | 2011-01-28 | 2018-12-12 | 에스케이바이오팜 주식회사 | 피리돈 유도체 및 이를 포함하는 약학적 조성물 |
| KR101925971B1 (ko) * | 2011-01-28 | 2018-12-06 | 에스케이바이오팜 주식회사 | 피리돈 유도체 및 이를 포함하는 약학적 조성물 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1612876A (zh) * | 2002-01-07 | 2005-05-04 | 法商沙诺费-辛芷拉保公司 | 5－(吡啶－3－基)－1－氮杂二环[3.2.1]辛烷衍生物,其制备及其治疗应用 |
Non-Patent Citations (1)
| Title |
|---|
| Anilinoquinazoline Inhibitors of Fructose 1,6-Bisphosphatase Bind at a Novel Allosteric Site: Synthesis, In Vitro Characterization, and X-ray Crystallography;Stephen W. Wright,等;《J. Med. Chem.》;20020726;第45卷(第18期);3865-3877 * |
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