CN105832735A - 用于治疗认知障碍的5-ht4受体促效剂化合物 - Google Patents
用于治疗认知障碍的5-ht4受体促效剂化合物 Download PDFInfo
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- CN105832735A CN105832735A CN201610257689.5A CN201610257689A CN105832735A CN 105832735 A CN105832735 A CN 105832735A CN 201610257689 A CN201610257689 A CN 201610257689A CN 105832735 A CN105832735 A CN 105832735A
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Abstract
本发明涉及用于治疗认知障碍的5‑HT4受体促效剂化合物。本发明还涉及特异性5‑HT4受体促效剂化合物用于治疗认知障碍的用途，具体来说，涉及这些化合物与其它药剂(明确地说是乙酰胆碱酯酶抑制剂)组合用于治疗阿尔茨海默氏病(Alzheimer's disease)和其它认知障碍的用途。
Description
本发明是申请号为201080016497.6、申请日为2010年4月12日、发明名称为“用于治疗认知障碍的5-HT4受体促效剂化合物”的发明专利申请的分案申请。
技术领域
本发明涉及特异性5-HT4受体促效剂化合物用于治疗认知障碍的用途，具体来说涉及这些化合物与其它药剂(明确地说是乙酰胆碱酯酶抑制剂)组合用于治疗阿尔茨海默氏病(Alzheimer's disease)和其它认知障碍的用途。
背景技术
在全世界范围内，随着预期寿命提高，具有患上痴呆风险的老年人数目迅速增长。根据一些专家所言，阿尔茨海默氏病是老年人中痴呆的最常见病因，占所有病例的50-60％。2008年，仅在美国就有估计520万人正忍受着阿尔茨海默氏病，占65岁以上美国人口的13％。
阿尔茨海默氏病定义为与正常衰老不一致的进行性认知下降和功能状态受损。认为胆碱能系统不足是造成与阿尔茨海默氏病有关的认知症状的主要促因。因此，对于阿尔茨海默氏病的主要药物治疗通过使用乙酰胆碱酯酶抑制剂来使症状适度减轻。这些药剂据信是通过降低乙酰胆碱降解的速率从而使大脑中的乙酰胆碱浓度增加来起作用。
血清素(5-羟基色胺，5-HT)是广泛分布于整个身体内的中枢神经系统和周围神经系统中的神经传递素。已鉴别出血清素受体的至少7种亚型并且血清素与这些不同受体之间的相互作用与多种生理功能有关联。大脑中的血清素能系统(serotonergic system)已显示与认知过程有关。具体来说，已证明5-HT4受体在记忆增强的神经元机制和动物模型中的认知过程中起作用。5-HT4受体活化增强乙酰胆碱从胆碱能神经元的释放，因此提供另一种可有利地增加脑内突触处乙酰胆碱浓度的药理学干预的潜在方法(梅耶(Maillet)等人,(2004),当今阿尔茨海默氏病研究(Current Alzheimer Research),1:79-85)。此外，已表明一些5-HT4受体促效剂化合物可用于治疗中枢神经系统病症，包括认知障碍、行为障碍、情绪障碍(例如抑郁症和焦虑症)和自主功能控制障碍。
5-HT4受体活化还刺激α分泌酶活性，导致可溶性淀粉样前体蛋白α(soluble amyloidprecursor protein alpha，sAPPα)(其具有神经营养和神经保护性质)的含量增加，并且还与临床前认知增强有关。β淀粉样蛋白(Aβ)是一种具有39-43个氨基酸的肽，其似乎是阿尔茨海默氏病患者脑中淀粉样蛋白斑块的主要成分。Aβ是在淀粉样前体蛋白经β分泌酶和γ分泌酶裂解后形成。在临床前研究中，5-HT4受体促效剂诱导的α分泌酶活化以及sAPPα产生使Aβ的含量降低。预期这种Aβ含量降低是有益的。因此，5-HT4受体促效剂呈现出提供症状益处与疾病改善益处的潜力(莱佐茨(Lezoualc'h),(2007)实验神经学(Experimental Neurology),205:325-329)。
迄今为止，尚未批准利用5-HT4机制用于治疗认知障碍的潜在效用进行的治疗。因此，仍需要利用通过使用5-HT4受体促效剂所预期的乙酰胆碱浓度增加和其它潜在益处来治疗罹患阿尔茨海默氏病的人的记忆功能障碍。
发明内容
本发明涉及特异性5-HT4受体促效剂化合物的用途并且涉及特异性5-HT4受体促效剂化合物与乙酰胆碱酯酶抑制剂组合用于治疗阿尔茨海默氏病或认知障碍的用途。具体来说，本发明涉及5-HT4受体促效剂化合物与乙酰胆碱酯酶抑制剂的用途，其中各药剂的使用浓度低于其单独使用时可观测到显著作用时的浓度。
5-HT4受体促效剂1-异丙基-2-氧代-1,2-二氢喹啉-3-甲酸{(1S,3R,5R)-8-[(R)-2-羟基-3-(甲烷磺酰基-甲基-氨基)丙基]-8-氮杂双环[3.2.1]辛-3-基}酰胺(1)和其医药学上可接受的盐
揭示于US 7,375,114 B2中。化合物1可替代地表示为1,2-二氢-N-[(3-内桥)-8-[(2R)-2-羟基-3-[甲基(甲基磺酰基)氨基]丙基]-8-氮杂双环[3.2.1]辛-3-基]-1-(1-甲基乙基)-2-氧代-3-喹啉甲酰胺。
5-HT4受体促效剂4-(4-{[(2-异丙基-1H-苯并咪唑-4-羰基)氨基]甲基}-哌啶-1-基甲基)哌啶-1-甲酸甲酯(2)和其医药学上可接受的盐
揭示于US 7,256,294 B2和US2006/0270652 A1中。化合物2可替代地表示为4-[[4-[[[[2-(1-甲基乙基)-1H-苯并咪唑-7-基]羰基]氨基]甲基]-1-哌啶基]甲基]-1-哌啶甲酸甲酯。
化合物1和化合物2是有效的选择性5-HT4受体促效剂，其在活体外分析中显示中度至高度固有活性。化合物1和化合物2已各自证明在大鼠莫里斯水迷宫(Morris watermaze)临床前认知模型中减弱由蕈毒碱拮抗剂(muscarinic antagonist)诱导的记忆缺失。在单独使用时具有极少作用或无作用的剂量下在化合物1与乙酰胆碱酯酶抑制剂多奈哌齐(donepezil)之间以及化合物2与多奈哌齐之间观测到与加和或协同效应一致的结果。化合物1和化合物2也已显示在活体外分析中引起随浓度变化的sAPPα增加。因此预期化合物1和化合物2可有益于治疗记忆功能障碍。
在一方面中，本发明可用于治疗患者的阿尔茨海默氏病或认知障碍的方法中，所述方法包含向患者投与5-HT4受体促效剂化合物，其中所述化合物选自1-异丙基-2-氧代-1,2-二氢喹啉-3-甲酸{(1S,3R,5R)-8-[(R)-2-羟基-3-(甲烷磺酰基-甲基-氨基)丙基]-8-氮杂双环[3.2.1]辛-3-基}酰胺和4-(4-{[(2-异丙基-1H-苯并咪唑-4-羰基)氨基]甲基}-哌啶-1-基甲基)哌啶-1-甲酸甲酯和其医药学上可接受的盐。因此，在一方面中，本发明提供用于治疗阿尔茨海默氏病或认知障碍的如上所述的5-HT4受体促效剂化合物。
本发明的5-HT4促效剂化合物可有利地与用于抑制体内乙酰胆碱酯酶作用的药剂组合使用。适用抑制剂包括(但不限于)盐酸多奈哌齐(购得)、氢溴酸加兰他敏(galantamine hydrobromide，或者写成galanthamine hydrobromide)( 酒石酸利斯的明(rivastigmine tartrate)和盐酸他克林(tacrine hydrochloride)
本发明可用于治疗患者的阿尔茨海默氏病或认知障碍的方法中，所述方法包含向患者投与5-HT4受体促效剂化合物与乙酰胆碱酯酶抑制剂，其中所述化合物选自1-异丙基-2-氧代-1,2-二氢喹啉-3-甲酸{(1S,3R,5R)-8-[(R)-2-羟基-3-(甲烷磺酰基-甲基-氨基)丙基]-8-氮杂双环[3.2.1]辛-3-基}酰胺和4-(4-{[(2-异丙基-1H-苯并咪唑-4-羰基)氨基]甲基}-哌啶-1-基甲基)哌啶-1-甲酸甲酯和其医药学上可接受的盐。
因此，在另一方面中，本发明提供与乙酰胆碱酯酶抑制剂组合用于治疗阿尔茨海默氏病或认知障碍的本发明5-HT4受体促效剂化合物。本发明进一步提供用于增强乙酰胆碱酯酶抑制剂用于治疗阿尔茨海默氏病或认知障碍的效力的本发明5-HT4受体促效剂化合物。
在本发明的一方面中，在上述方法中，5-HT4促效剂化合物和乙酰胆碱酯酶抑制剂各自以低于在单独投与时有效治疗阿尔茨海默氏病或认知障碍的剂量的剂量投与。
在一特定方面中，5-HT4受体促效剂化合物是1-异丙基-2-氧代-1,2-二氢喹啉-3-甲酸{(1S,3R,5R)-8-[(R)-2-羟基-3-(甲烷磺酰基-甲基-氨基)丙基]-8-氮杂双环[3.2.1]辛-3-基}酰胺盐酸盐并且乙酰胆碱酯酶抑制剂是多奈哌齐。
在另一特定方面中，5-HT4受体促效剂化合物是4-(4-{[(2-异丙基-1H-苯并咪唑-4-羰基)氨基]甲基}-哌啶-1-基甲基)哌啶-1-甲酸甲酯并且乙酰胆碱酯酶抑制剂是多奈哌齐。
本发明另外可用于增强经受记忆缺失的患者的记忆力的方法中，所述方法包含向患者投与5-HT4受体促效剂化合物与乙酰胆碱酯酶抑制剂，其中所述化合物选自1-异丙基-2-氧代-1,2-二氢喹啉-3-甲酸{(1S,3R,5R)-8-[(R)-2-羟基-3-(甲烷磺酰基-甲基-氨基)丙基]-8-氮杂双环[3.2.1]辛-3-基}酰胺和4-(4-{[(2-异丙基-1H-苯并咪唑-4-羰基)氨基]甲基}-哌啶-1-基甲基)哌啶-1-甲酸甲酯和其医药学上可接受的盐。
在一方面中，5-HT4促效剂化合物和乙酰胆碱酯酶抑制剂各自以低于在单独投与时有效增强经受记忆缺失的患者的记忆力的剂量的剂量投与。
因为sAPPα含量增加与认知增强有关，所以在另一方面中，本发明可用于增加患者的sAPPα含量的方法中，所述方法包含：(a)鉴别需要增加sAPPα产生的患者，即罹患认知损伤的患者；和(b)向患者投与治疗有效量的5-HT4受体促效剂化合物，其中所述化合物选自1-异丙基-2-氧代-1,2-二氢喹啉-3-甲酸{(1S,3R,5R)-8-[(R)-2-羟基-3-(甲烷磺酰基-甲基-氨基)丙基]-8-氮杂双环[3.2.1]辛-3-基}酰胺和4-(4-{[(2-异丙基-1H-苯并咪唑-4-羰基)氨基]甲基}-哌啶-1-基甲基)哌啶-1-甲酸甲酯和其医药学上可接受的盐。
本发明进一步提供包含医药学上可接受的载剂、5-HT4受体促效剂化合物与乙酰胆碱酯酶抑制剂的医药组合物，其中所述化合物选自1-异丙基-2-氧代-1,2-二氢喹啉-3-甲酸{(1S,3R,5R)-8-[(R)-2-羟基-3-(甲烷磺酰基-甲基-氨基)丙基]-8-氮杂双环[3.2.1]辛-3-基}酰胺和4-(4-{[(2-异丙基-1H-苯并咪唑-4-羰基)氨基]甲基}-哌啶-1-基甲基)哌啶-1-甲酸甲酯和其医药学上可接受的盐。
附图说明
通过参考随附图式来说明本发明的各个方面。
图1到图6显示在大鼠莫里斯水迷宫认知功能模型中测试的动物在测试第三天的平均逃离潜伏期(escape latency)(以秒计)。
图1显示投与媒剂、东莨菪碱(scopolamine)(Scop)(0.5mg/kg)、多奈哌齐(0.3mg/kg)+东莨菪碱(0.5mg/kg)、多奈哌齐(1mg/kg)+东莨菪碱(0.5mg/kg)以及多奈哌齐(3mg/kg)+东莨菪碱(0.5mg/kg)的结果。*关于媒剂在统计上显著(具有邦弗朗尼调整的学生t检验(student t-test with Bonferroni adjustment)，p<0.025)；#关于东莨菪碱(0.5mg/kg)在统计上显著(关于东莨菪碱(0.5mg/kg)和所有剂量的多奈哌齐+东莨菪碱(0.5mg/kg)的单因素方差分析(one-way ANOVA)，事后杜奈特检验(post-hocDunnett's test)，p<0.05)。
图2显示投与媒剂、东莨菪碱(Scop)(0.5mg/kg)、多奈哌齐(3mg/kg)+东莨菪碱(0.5mg/kg)、化合物1(0.01mg/kg)+东莨菪碱(0.5mg/kg)、化合物1(0.03mg/kg)+东莨菪碱(0.5mg/kg)、化合物1(0.1mg/kg)+东莨菪碱(0.5mg/kg)以及化合物1(0.1mg/kg)+东莨菪碱(0.5mg/kg)的结果。***关于媒剂在统计上显著(具有邦弗朗尼调整的学生t检验，p<0.0005)；#关于东莨菪碱(0.5mg/kg)在统计上显著(关于东莨菪碱(0.5mg/kg)和所有剂量的化合物1+东莨菪碱(0.5mg/kg)的单因素方差分析，事后杜奈特检验，p<0.05)。
图3显示投与媒剂、东莨菪碱(Scop)(0.5mg/kg)、GR125487(1mg/kg)、化合物1(0.1mg/kg)+GR125487(1mg/kg)和东莨菪碱(0.5mg/kg)以及化合物1(0.1mg/kg)+东莨菪碱(0.5mg/kg)的结果。*关于媒剂在统计上显著(具有邦弗朗尼调整的学生t检验，p<0.025)；关于化合物1(0.1mg/kg)+GR125487(1mg/kg)和东莨菪碱(0.5mg/kg)在统计上显著(具有邦弗朗尼调整的学生t检验，p<0.005)；#关于东莨菪碱(0.5mg/kg)在统计上显著(具有邦弗朗尼调整的学生t检验，p<0.025)。
图4显示投与媒剂、东莨菪碱(Scop)(0.5mg/kg)、多奈哌齐(0.1mg/kg)+东莨菪碱(0.5mg/kg)、化合物1(0.01mg/kg)+东莨菪碱(0.5mg/kg)以及化合物1(0.01mg/kg)+多奈哌齐(0.1mg/kg)和东莨菪碱(0.5mg/kg)的结果。*关于媒剂在统计上显著(学生t检验，p<0.05)。
图5显示投与媒剂、东莨菪碱(Scop)(0.5mg/kg)、多奈哌齐(3mg/kg)+东莨菪碱(0.5mg/kg)、化合物2(0.01mg/kg)+东莨菪碱(0.5mg/kg)、化合物2(0.03mg/kg)+东莨菪碱(0.5mg/kg)、化合物2(0.1mg/kg)+东莨菪碱(0.5mg/kg)以及化合物2(1mg/kg)+东莨菪碱(0.5mg/kg)的结果。***关于媒剂在统计上显著(具有邦弗朗尼调整的学生t检验，p<0.0005)；#关于东莨菪碱(0.5mg/kg)在统计上显著(关于东莨菪碱(0.5mg/kg)和所有剂量的化合物2+东莨菪碱(0.5mg/kg)的单因素方差分析，p＝0.0096；事后杜奈特检验，p<0.05)。
图6显示投与媒剂、东莨菪碱(Scop)(0.5mg/kg)、多奈哌齐(0.1mg/kg)+东莨菪碱(0.5mg/kg)、化合物2(0.01mg/kg)+东莨菪碱(0.5mg/kg)以及化合物2(0.01mg/kg)+多奈哌齐(0.1mg/kg)和东莨菪碱(0.5mg/kg)的结果。**关于媒剂在统计上显著(具有邦弗朗尼调整的学生t检验，p<0.005)；#关于东莨菪碱(0.5mg/kg)在统计上显著(具有邦弗朗尼调整的学生t检验，p<0.025)。
具体实施方式
定义
当描述本发明的组合物和方法时，除非另外说明，否则以下术语具有以下含义。
术语“治疗有效量”意谓在投与到需要治疗的患者时足以实现治疗的量。
术语“低于有效量的量”或等效地“低于有效剂量的剂量”意谓低于治疗有效量或剂量的量或剂量。
如本文中所用的术语“治疗”意谓治疗患者(例如哺乳动物(尤其是人类))的疾病、病症或医学病状，其包括一种或一种以上下列情形：
(a)预防疾病、病症或医学病状发生，即患者的预防性治疗；
(b)改善疾病、病症或医学病状，即消除患者的疾病、病症或医学病状或使患者的疾病、病症或医学病状消退，包括抵消其它治疗剂的作用；
(c)抑制疾病、病症或医学病状，即减缓或阻止患者的疾病、病症或医学病状发展；或
(d)减轻患者的疾病、病症或医学病状的症状。
如本文中所用的术语“组合疗法”意谓投与两种或两种以上治疗剂作为预期由所述治疗剂的组合作用提供有益效果的治疗方案的一部分。
如本文中所用的术语“乙酰胆碱酯酶抑制剂”意谓具有抑制乙酰胆碱酯酶作用的效应的任何药剂。所述术语包括称为胆碱酯酶抑制剂的药剂，其除了例如作为丁酰胆碱酯酶抑制剂以外，还可能具有其它活性。
术语“多奈哌齐”在本文中使用时与盐酸多奈哌齐相等。
活体内认知增强的证明
如以下实例中进一步描述，在莫里斯水迷宫模型中评估5-HT4促效剂1-异丙基-2-氧代-1,2-二氢喹啉-3-甲酸{(1S,3R,5R)-8-[(R)-2-羟基-3-(甲烷磺酰基-甲基-氨基)丙基]-8-氮杂双环[3.2.1]辛-3-基}酰胺(1)和4-(4-{[(2-异丙基-1H-苯并咪唑-4-羰基)氨基]甲基}-哌啶-1-基甲基)哌啶-1-甲酸甲酯(2)在大鼠中逆转蕈毒碱拮抗剂诱导的记忆损伤的功效。
剂量为0.03mg/kg、0.1mg/kg和1mg/kg的化合物1和剂量为0.03mg/kg和0.1mg/kg的化合物2减弱大鼠中由注射东莨菪碱所诱导的记忆损伤。对于这两种化合物，在0.1mg/kg下观测到统计上显著的反应。两种5-HT4促效剂化合物的效力和/或功效似乎与多奈哌齐(销售用于阿尔茨海默氏病的对症治疗的乙酰胆碱酯酶抑制剂)类似。通过共同投与各化合物与选择性5-HT4拮抗剂阻止了化合物1和化合物2的认知增强效应，证实在所观测的反应中涉及5-HT4受体。
在剂量分别为0.01mg/kg和0.1mg/kg的化合物1与多奈哌齐之间以及剂量分别为0.01mg/kg和0.1mg/kg的化合物2与多奈哌齐之间明显注意到加和或协同效应，所述剂量在单独投与时不能有效逆转东莨菪碱诱导的认知下降。
活体外sAPPα释放的证明
在经人类5-HT4(d)受体和人类APP695(淀粉样前体蛋白)稳定转染的HEK293细胞中研究了化合物1和化合物2对sAPPα的细胞外释放的影响。两种化合物都引起随浓度变化的sAPPα释放增加。5-HT4受体选择性拮抗剂GR113808可阻断释放，表明所观测到的效应与5-HT4受体的促效作用有关。
治疗方法
预期本发明的5-HT4促效剂化合物1和化合物2适用于治疗阿尔茨海默氏病或认知障碍，包括治疗轻度认知损伤，和治疗与阿尔茨海默氏病有关的记忆功能障碍和阿尔茨海默型痴呆(dementia of Alzheimer's type)。所述化合物可进一步用于治疗其它中枢神经系统病症，包括行为障碍、情绪障碍(例如抑郁症和焦虑症)，和自主功能控制障碍。另外，表明增强乙酰胆碱浓度的化合物也可用于治疗其它形式的痴呆，例如与帕金森氏病(Parkinson's disease)有关的痴呆、由于血管机制而引起的痴呆和路易体痴呆(Lewybody dementia)。
当本发明的5-HT4化合物与乙酰胆碱酯酶抑制剂在以各化合物单独投与时无效的剂量下共同投与时，在大鼠水迷宫实验中注意到加和或协同效应。因此，当本发明化合物与乙酰胆碱酯酶抑制剂(例如盐酸多奈哌齐氢溴酸加兰他敏 酒石酸利斯的明或盐酸他克林组合投与时，预期本发明化合物适用于治疗阿尔茨海默氏病或认知障碍。除了提供通过不同的互补作用机制作用的药剂的益处以外，组合疗法还提供允许使用较低剂量的各药剂，由此限制暴露于任何不良副作用的其它潜在益处。
此外，当与经设计以通过其它作用机制对阿尔茨海默氏病患者进行对症治疗的药剂组合投与时，化合物1和化合物2可为适用的。举例来说，本发明化合物可用于与NMDA受体拮抗剂美金刚(memantine)组合。可组合用于治疗阿尔茨海默氏病的其它药剂包括5-HT6拮抗剂，例如DMXB-阿那巴辛(anabaseine)、GSK-742457、SUVN-502、PRX-07034和SAM-531(WAY-262531)；烟碱受体促效剂，例如ABT-089、SSR-180711、AZD-0328和EVP-6124；蕈毒碱M1促效剂，例如NGX-267、AF-102B(西维美林(Cevimeline))和WAL 2014FU(他沙利定(talsaclidine))；组胺H3拮抗剂，例如GSK-189254和PF-365474；和狄梦邦(dimebon)。此外，5-HT4促效剂与其它建议疾病改善疗法(例如淀粉样蛋白β和τ聚集抑制剂)和β分泌酶抑制剂或γ分泌酶抑制剂(例如BMS-708163)组合可为有益的。
当用于组合疗法中时，本发明的5-HT4化合物与其它治疗剂物理混合以形成含有两种药剂的组合物；或各药剂存在于独立而不同的组合物中，这些组合物同时或以任何顺序依序投与到患者。当分别调配时，组合疗法包括实质上同时投与两种药剂，以及在不同时间投与各药剂。
举例来说，可使用常规程序和设备将本发明的5-HT4化合物与第二治疗剂组合以形成包含化合物1或化合物2与第二治疗剂的组合物。另外，治疗剂可与医药学上可接受的载剂组合以形成包含化合物1或化合物2、第二治疗剂和医药学上可接受的载剂的医药组合物。在这个实施例中，组合物的组分通常经混合或掺合以产生物理混合物。随后使用下文所述的任何途径以治疗有效量投与物理混合物。
或者，治疗剂在投与患者之前可保持独立而且不同。在这个实施例中，药剂在投与之前并未物理混合在一起，而是以独立组合物形式同时投与或在独立时间投与。所述组合物可独立包装或可以试剂盒形式包装在一起。试剂盒中的两种治疗剂可通过相同投药途径或通过不同投药途径投与。
当用于治疗阿尔茨海默氏病或认知障碍时，化合物1或化合物2通常将以单次日剂量或以每天多次剂量经口投与，但也可使用其它投药形式。在某些情形下，经皮或不经肠投与本发明5-HT4化合物可为有利的。每个剂量所投与的活性剂的量或每天所投与的总量通常将由医师根据相关情形确定，包括所欲治疗病状的严重程度、所选投药途径、所投与的特定化合物和其相对活性、个别患者的年龄、体重和反应等。
对于平均70kg的人来说，适用于治疗阿尔茨海默氏病或认知障碍的剂量范围将为每天约0.1mg到约90mg的5-HT4促效剂，包括例如每天约1mg到约50mg化合物1，和每天约0.5mg到约20mg化合物2。
当本发明5-HT4化合物与乙酰胆碱酯酶抑制剂用于组合疗法中时，以治疗有效量，即当与化合物1或化合物2共同投与时产生治疗有益效果的任何量，投与乙酰胆碱酯酶抑制剂。与本发明化合物组合投与的乙酰胆碱酯酶抑制剂的适合剂量通常在每天约1mg到每天约30mg的范围内。如先前所述，当用作组合疗法的一部分时，各个别药剂的有效剂量可能低于所述药剂独立使用时的有效剂量。
医药组合物
本发明的5-HT4促效剂和其它治疗剂(例如乙酰胆碱酯酶抑制剂)通常以医药组合物或调配物形式投与患者。所述医药组合物可通过任何可接受的投药途径投与患者，包括(但不限于)经口、经直肠、经阴道、经鼻、吸入、局部(包括经皮)和不经肠投药模式。
医药组合物通常含有治疗有效量的活性剂。但是，所属领域的技术人员应认识到，医药组合物可含有大于治疗有效量(即散装组合物)或小于治疗有效量(即设计成多次投药来获得治疗有效量的个别单位剂量)的量。
通常，所述医药组合物将含有约0.1重量％到约95重量％的活性剂；优选约5重量％到约70重量％的活性剂。
任何常规载剂或赋形剂都可用于本发明的医药组合物中。特定载剂或赋形剂或者载剂或赋形剂的组合的选择将取决于用于治疗特定患者的投药模式，或医学病状或疾病病况的类型。就此来说，适用于特定投药模式的医药组合物的制备完全属于制药领域技术人员的技能范围之内。另外，本发明的医药组合物中所用的载剂或赋形剂可购得。作为进一步说明，常规调配技术描述于以下文献中：雷明顿：药学技术与实践(Remington:TheScience and Practice of Pharmacy),第20版,利平科特·威廉斯·怀特出版公司(Lippincott Williams&White),巴尔的摩(Baltimore),马里兰州(Maryland)(2000)；和安塞尔(H.C.Ansel)等人,医药剂型和药物递送系统(Pharmaceutical Dosage Formsand Drug Delivery Systems),第7版,利平科特·威廉斯·怀特出版公司(LippincottWilliams&White),巴尔的摩(Baltimore),马里兰州(Maryland)(1999)。
可用作医药学上可接受的载剂的材料的代表性实例包括(但不限于)以下：糖，例如乳糖、葡萄糖和蔗糖；淀粉，例如玉米淀粉和马铃薯淀粉；纤维素，例如微晶纤维素，和其衍生物，例如羧甲基纤维素钠、乙基纤维素和乙酸纤维素；粉末状黄芪胶；麦芽；明胶；滑石；赋形剂，例如可可脂和栓剂蜡；油，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油；二醇，例如丙二醇；多元醇，例如甘油、山梨糖醇、甘露糖醇和聚乙二醇；酯，例如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，例如氢氧化镁和氢氧化铝；海藻酸；无热原质水；等渗盐水；林格氏溶液(Ringer's solution)；乙醇；磷酸盐缓冲溶液；和用于医药组合物中的其它无毒相容性物质。
通常通过充分而紧密地混合或掺合活性剂与医药学上可接受的载剂和一种或一种以上任选成分来制备医药组合物。随后可使用常规程序和设备使所得均匀掺合的混合物成形为片剂、胶囊、丸剂等或装入片剂、胶囊、丸剂等中。
医药组合物优选包装成单位剂型。术语“单位剂型”是指适用于向患者给药的物理个别单元，即，各单元含有预定量的活性剂，所述量是经过计算而单独或与一个或一个以上其它单元组合产生所要治疗作用。举例来说，这些单位剂型可为胶囊、片剂、丸剂等，或者适用于不经肠投与的单位包装。
在一实施例中，本发明的医药组合物适于经口投与。适用于经口投与的医药组合物可呈胶囊、片剂、丸剂、糖锭、扁胶剂、糖衣药丸、散剂、颗粒剂形式；或呈于水性或非水性液体中的溶液或悬浮液形式；或呈水包油或油包水液体乳液形式；或呈酏剂或糖浆形式；等；各剂型含有预定量的治疗化合物作为活性成分。
当打算以固体剂型(即呈胶囊、片剂、丸剂等形式)经口投与时，医药组合物通常将包含活性剂和一种或一种以上医药学上可接受的载剂，例如柠檬酸钠或磷酸二钙。或者或任选地，所述固体剂型还可包含：填充剂或增量剂，例如淀粉、微晶纤维素、乳糖、蔗糖、葡萄糖、甘露糖醇和/或硅酸；粘合剂，例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶；保湿剂，例如甘油；崩解剂，例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和/或碳酸钠；溶解延迟剂，例如石蜡；吸收促进剂，例如季铵化合物；润湿剂，例如鲸蜡醇和/或单硬脂酸甘油酯；吸收剂，例如高岭土和/或膨润土；润滑剂，例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠和/或其混合物；着色剂；和缓冲剂。
脱模剂、润湿剂、包衣剂、甜味剂、调味剂和加香剂、防腐剂和抗氧化剂也可存在于本发明的医药组合物中。医药学上可接受的抗氧化剂的实例包括：水溶性抗氧化剂，例如抗坏血酸、半胱氨酸盐酸盐、硫酸氢钠、焦亚硫酸钠、亚硫酸钠等；油溶性抗氧化剂，例如抗坏血酸棕榈酸酯、丁基化羟基茴香醚、丁基化羟基甲苯、卵磷脂、没食子酸丙酯、α-生育酚等；和金属螯合剂，例如柠檬酸、乙二胺四乙酸、山梨糖醇、酒石酸、磷酸等。用于片剂、胶囊、丸剂等的包衣剂包括用于肠溶衣的那些包衣剂，例如乙酸邻苯二甲酸纤维素、聚乙酸乙烯酯邻苯二甲酸酯、邻苯二甲酸羟丙基甲基纤维素、甲基丙烯酸-甲基丙烯酸酯共聚物、乙酸偏苯三酸纤维素、羧甲基乙基纤维素、乙酸丁二酸羟丙基甲基纤维素等。包衣剂还包括滑石、聚乙二醇、羟丙甲纤维素(hypomellose)和二氧化钛。
还可使用例如不同比例的羟丙基甲基纤维素；或其它聚合物基质、脂质体和/或微球体来调配医药组合物以提供活性剂的缓慢或控制释放。另外，医药组合物可任选含有遮光剂并且可经调配以使得其仅在或优先在胃肠道的某一部分中任选以延迟方式释放活性成分。可使用的包埋组合物的实例包括聚合物质和蜡。活性剂还可呈微囊封形式，适当时具有一种或一种以上上述赋形剂。
适用于经口投与的液体剂型包括例如医药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。液体剂型通常包含活性剂；和惰性稀释剂，例如水或其它溶剂；增溶剂和乳化剂，例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(尤其是棉籽油、落花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨糖醇脂肪酸酯和其混合物。除活性成分以外，悬浮液还可含有悬浮剂，例如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇和脱水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄芪胶，和其混合物。
本发明的活性剂还可不经肠投与(例如通过静脉内、皮下、肌肉内或腹膜内注射)。对于不经肠投与，通常将活性剂与适用于不经肠投与的媒剂混合，所述媒剂包括例如无菌水溶液、盐水、低分子量醇(例如丙二醇、聚乙二醇)、植物油、明胶、脂肪酸酯(例如油酸乙酯)等。不经肠调配物还可含有一种或一种以上抗氧化剂、增溶剂、稳定剂、防腐剂、润湿剂、乳化剂、缓冲剂或分散剂。通过使用无菌可注射介质、杀菌剂、过滤、辐照或加热可使这些调配物无菌。
或者，药剂经调配以通过吸入投与。适用于通过吸入投与的医药组合物通常呈气雾剂或粉末的形式。所述组合物一般使用众所周知的递送装置(例如计量吸入器、干粉吸入器、喷雾器或类似递送装置)投与。
当使用加压容器通过吸入投与时，本发明的医药组合物通常包含活性成分和合适推进剂，例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适气体。另外，医药组合物可呈胶囊或药筒(例如由明胶制成)的形式，其包含本发明化合物和适用于粉末吸入器的粉末。合适的粉末基质包括例如乳糖或淀粉。
最后，还可使用已知的经皮递送系统和赋形剂来经皮投与活性剂。举例来说，可将活性剂与渗透增强剂(例如丙二醇、聚乙二醇单月桂酸酯、氮杂环烷-2-酮等)混合，并且并入贴片或类似递送系统中。必要时，所述经皮组合物中也可使用其它赋形剂，包括胶凝剂、乳化剂和缓冲剂。
适用于治疗阿尔茨海默氏病或认知障碍的代表性医药组合物包括(但不限于)以下实例，其中‘本发明化合物’表示化合物1或化合物2。化合物1通常以盐酸盐形式供应，而化合物2通常以游离碱形式供应，但应了解，适用于特定投药模式的任何形式的化合物(即游离碱或医药盐)均可用于以下医药组合物中。
调配物实例A：用于经口投与的硬明胶胶囊
将本发明化合物(20mg)、淀粉(89mg)、微晶纤维素(89mg)和硬脂酸镁(2mg)充分掺合并且随后通过第45号筛目美国筛(U.S.sieve)。将所得组合物装入硬明胶胶囊中(每个胶囊200mg组合物)。
调配物实例B：用于经口投与的明胶胶囊
将本发明化合物(10mg)、聚氧乙烯脱水山梨糖醇单油酸酯(50mg)和淀粉粉末(250mg)充分掺合并且随后装入明胶胶囊中(每个胶囊310mg组合物)。
调配物实例C：用于经口投与的片剂
将本发明化合物(5mg)、微晶纤维素(400mg)、气相二氧化硅(fumed silicon dioxide)(10mg)和硬脂酸(5mg)充分掺合并且随后压制形成片剂(每个片剂420mg组合物)。
调配物实例D：用于经口投与的片剂
将本发明化合物(2mg)、微晶纤维素(400mg)、气相二氧化硅(10mg)和硬脂酸(5mg)充分掺合并且随后压制形成片剂(每个片剂417mg组合物)。
调配物实例E：用于经口投与的片剂
将本发明化合物(20mg)、微晶纤维素(400mg)、气相二氧化硅(10mg)和硬脂酸(5mg)充分掺合并且随后压制形成片剂(每个片剂435mg组合物)。
调配物实例F：用于经口投与的单刻痕片剂(Single-scored Tablet)
将本发明化合物(15mg)、玉米淀粉(50mg)、交联羧甲基纤维素钠(25mg)、乳糖(120mg)和硬脂酸镁(5mg)充分掺合并且随后压制形成单刻痕片剂(每个片剂215mg组合物)。
调配物实例G：用于经口投与的悬浮液
将以下成分充分混合以形成每10mL悬浮液含有20mg活性成分的用于经口投与的悬浮液：本发明化合物(200mg)、苯甲酸钠、柠檬酸钠、纯化水(补足到100mL)。
调配物实例H：可注射调配物
将本发明化合物(20mg)与0.1M柠檬酸钠缓冲溶液(15mL)掺合。使用1N盐酸水溶液或1N氢氧化钠水溶液将所得溶液的pH值调节到pH 6。随后添加于柠檬酸盐缓冲液中的无菌生理盐水，得到20mL的总体积。
调配物实例I：用于经口投与的单刻痕片剂
将本发明化合物(5mg)、盐酸多奈哌齐(5mg)、玉米淀粉(50mg)、微晶纤维素(15mg)、羟丙基纤维素(10mg)、乳糖(120mg)和硬脂酸镁(5mg)充分掺合并且随后压制形成单刻痕片剂(每个片剂210mg组合物)。
调配物实例J：用于经口投与的悬浮液
将以下成分充分混合以形成每10mL悬浮液含有5mg各药剂的用于经口投与的悬浮液：本发明化合物(50mg)、酒石酸利斯的明(50mg)、苯甲酸钠、柠檬酸钠、纯化水(补足到100mL)。
实例
在大鼠莫里斯水迷宫动物模型中评估单独或与乙酰胆碱酯酶抑制剂多奈哌齐组合使用的5-HT4促效剂1-异丙基-2-氧代-1,2-二氢喹啉-3-甲酸{(1S,3R,5R)-8-[(R)-2-羟基-3-(甲烷磺酰基-甲基-氨基)丙基]-8-氮杂双环[3.2.1]辛-3-基}酰胺(1)和4-(4-{[(2-异丙基-1H-苯并咪唑-4-羰基)氨基]甲基}-哌啶-1-基甲基)哌啶-1-甲酸甲酯(2)防止由蕈毒碱受体拮抗剂东莨菪碱诱导的空间记忆损伤的能力(莫里斯(Morris),(1984)神经科学方法杂志(Journal of Neuroscience Methods),11:47-60.)。在所有实验中都使用化合物1的盐酸盐。
莫里斯水迷宫模型方法
在各研究前一天由研究人员处理成年的雄性史泊格-多利大鼠(Sprague-Dawley rat)(体重范围为275-400g)约5分钟。在研究第一天，经腹膜内(i.p.)对各大鼠给药，首先给与测试化合物或媒剂，随后立即给与蕈毒碱受体拮抗剂东莨菪碱(0.5mg/kg)(所述剂量先前经鉴别以在这个模型中提供接近最大认知下降)或媒剂。给药后30分钟，将大鼠个别地放在填充有水(保持在23℃±1℃)的深蓝色圆形聚乙烯槽(直径为6英尺)中。将透明的平台定位在距水表面下方1cm并且距槽壁34cm的固定位置中。将四个视觉线索(A4纸大小的具有不同黑色与白色符号的图片)等距安置在槽壁上，紧邻水表面上方。将黑色窗帘安置在槽周围并且在整个测试期间产生白色噪音。将各大鼠释放到水中，在指定起始点(即在槽北边)面向槽壁，并且在各安置后允许定位浸没的平台60秒。借助于摄影机(加利福尼亚州圣地亚哥仪器公司(SanDiego Instrument,CA))和跟踪软件(SMART软件，加利福尼亚州圣地亚哥仪器公司(SanDiego Instrument,CA))自动记录将大鼠释放到水中与其定位平台之间的逃离潜伏期(以秒计)。当大鼠不能在60秒内找到平台时，将其引导到平台并且随后安置于其上(面向特定视觉线索)。允许大鼠在平台上停留30秒以观测外部视觉线索并且将其与平台的相对位置进行配对。随后使大鼠离开平台并且用纸巾轻轻擦干，随后再重复测试三次(从南边、接着东边并且最后西边起始位置)。在第四次测试后，将各大鼠放在加热灯下5分钟，随后返回其居住笼中。在第2天和第3天重复整个程序。在测试的三天内，大鼠学会将浸没平台的位置(和其逃离水的唯一方式)与视觉线索相关联。
评估测试药剂抑制东莨菪碱诱导的认知损伤的能力。在第4天，如前述对各大鼠给药并且进行2分钟“探针试验”，其中已从槽中移走平台。记录各象限中先前平台位置的穿过次数与大鼠所花费的时间。已了解平台位置的动物在适当象限中花费较多时间并且重复穿过所述象限。通过进行探针测试，可根据分析来排除假阳性(即，先前已通过与视觉线索无关的策略(例如随机游泳直到腿碰到平台)定位平台的大鼠)。没能根据三天测试与探针测试之间相矛盾的数据排除动物。
数据分析
对个别大鼠计算同一测试日的四次试验各自的平均逃离潜伏期，并且随后将这些数据组合以确定第1天、第2天和第3天的各治疗组的平均逃离潜伏期。对数据进行以下统计测试：
学生t检验比较媒剂/媒剂和媒剂/东莨菪碱组的逃离潜伏期。因为媒剂/东莨菪碱组进行学生t检验和单因素方差分析检验两者，所以α值进行邦弗朗尼调整到0.025。
使用单因素方差分析、接着杜奈特事后检验来比较媒剂/东莨菪碱和测试化合物/东莨菪碱组的逃离潜伏期，其中p<0.05，表明统计上显著的差异。
使用双因素重复测量方差分析(two-way repeated-measures ANOVA)、接着邦弗朗尼事后检验来比较连续三个测试日各自的平均逃离潜伏期，其中p<0.05，表明统计上显著的差异。
材料
分别根据US 7,375,114B2和US 7,256,294B2中所述的程序来制备5-HT4促效剂化合物1和化合物2，所述专利的揭示内容以引用的方式并入本文中。盐酸多奈哌齐购自常州大华进出口有限公司(Changzhou Dahua Imp.and Exp.Corp.Ltd.)(中国江苏省常州市(Changzhou,Jiangsu,China))，而盐酸东莨菪碱购自西格玛奥德里奇(Sigma Aldrich)(密苏里州圣路易斯市(St.Louis,MO))或美国斯百全化工有限公司(Spectrum ChemicalMfg.Corp.)(加利福尼亚州加迪纳市(Gardena,CA))。GR125487氨基磺酸盐购自托克利斯(Tocris)(密苏里州埃利斯维尔(Ellisville,MO))。将化合物1和化合物2与多奈哌齐调配于5％二甲亚砜和95％无菌盐水中，而东莨菪碱和GR125487是在100％无菌盐水中制备。剂量是关于各化合物的游离碱重量进行表示。
模型验证
在各研究中，在测试前30分钟向大鼠给与(腹膜内)媒剂导致逃离潜伏期的进行性缩减。第1天，经媒剂处理的大鼠通常定位在隐藏的平台上，其中四次试验的平均潜伏期在40-50秒的范围内，而第3天，平均潜伏期已缩短到10-25秒。与经媒剂处理的动物相比，东莨菪碱(0.5mg/kg，腹膜内)产生学习能力的统计上显著的减弱(p<0.025，具有邦弗朗尼调整的学生t检验)。乙酰胆碱酯酶抑制剂多奈哌齐(3mg/kg，腹膜内)与5-HT4受体促效剂化合物1(1mg/kg，腹膜内)和化合物2(1mg/kg，腹膜内)在单独投与时(即当投与未暴露于东莨菪碱的动物时)对大鼠获悉浸没平台位置的能力无正面或负面影响。多奈哌齐(0.3-3mg/kg，腹膜内)以剂量依赖性方式逆转东莨菪碱(0.5mg/kg，腹膜内)诱导的认知缺失，如显示第三测试日的平均逃离潜伏期的图1中所示。剂量为3mg/kg的多奈哌齐产生统计上显著的逆转。
实例1：化合物1对东莨菪碱诱导的认知损伤的影响
在大鼠莫里斯水迷宫模型中测试剂量为0.01mg/kg、0.03mg/kg、0.1mg/kg和1mg/kg的化合物1。如显示第三测试日的平均逃离潜伏期的图2中所示，化合物1与由0.5mg/kg东莨菪碱产生的记忆损伤的逆转有关。剂量为0.1mg/kg的化合物1的作用关于东莨菪碱(0.5mg/kg)达到统计上显著。剂量反应曲线明显呈“U形”；与0.1mg/kg剂量不同，最高剂量的化合物1(1mg/kg)对东莨菪碱诱导的反应无影响。在第3天化合物1(0.1mg/kg，腹膜内)产生与多奈哌齐(3mg/kg，腹膜内)类似的逆转(即在50-60％的范围内，参看图1)。
实例2：化合物1与5-HT4受体拮抗剂一起对东莨菪碱诱导的认知损伤的影响
为了探查所观测到的化合物1的作用是否可归因于对5-HT4受体的促效作用，将化合物1与选择性5-HT4受体拮抗剂化合物GR125487一起进行测试。如图3中所示，GR125487(1mg/kg，腹膜内)在单独投与时无作用。然而，共同投与拮抗剂GR125487(1mg/kg，腹膜内)消除了化合物1(0.1mg/kg，腹膜内)逆转东莨菪碱诱导的认知损伤的能力。因此，合理地推断出所观测到的化合物1的作用是归因于5-HT4受体促效作用。
实例3：共同投与化合物1与乙酰胆碱酯酶抑制剂多奈哌齐对东莨菪碱诱导的认知损伤的影响
在图4中说明共同投与化合物1与多奈哌齐的作用。剂量为0.01mg/kg的化合物1和剂量为0.1mg/kg的多奈哌齐在单独投与时均未发现具有显著作用。然而，同样剂量的化合物1和多奈哌齐在一起调配于5％DMSO和95％无菌盐水中时，导致东莨菪碱诱导的认知下降显著减弱。
实例4：化合物2对东莨菪碱诱导的认知损伤的影响
如实例1中所述测试化合物2。如图5中所示，剂量为0.1mg/kg的化合物2的作用关于东莨菪碱达到统计上显著。剂量反应曲线明显呈“U形”；与0.03mg/kg和0.1mg/kg剂量不同，最高剂量的化合物2(1mg/kg)对东莨菪碱诱导的反应无影响。在第3天化合物2(0.1mg/kg，腹膜内)产生与多奈哌齐(3mg/kg，腹膜内)类似的逆转(即在50-60％的范围内，参看图1)。
实例5：化合物2与5-HT4受体拮抗剂一起对东莨菪碱诱导的认知损伤的影响
如实例2中所述探查共同投与化合物2与5-HT4受体拮抗剂GR125487的作用。添加GR125487(1mg/kg，腹膜内)消除了化合物2(0.1mg/kg，腹膜内)逆转东莨菪碱诱导的认知损伤的能力，表明所观测到的化合物2的作用是归因于5-HT4受体促效作用。
实例6：共同投与化合物2与乙酰胆碱酯酶抑制剂多奈哌齐对东莨菪碱诱导的认知损伤的影响
在图6中说明共同投与化合物2与多奈哌齐的作用。剂量为0.01mg/kg的化合物2和剂量为0.1mg/kg的多奈哌齐在单独投与时均未发现具有显著作用。然而，同样剂量的化合物2和多奈哌齐在一起调配于5％DMSO和95％无菌盐水中时，导致东莨菪碱诱导的认知下降在统计上显著逆转(具有邦弗朗尼调整的学生t检验，p<0.025)。
实例7：化合物1和化合物2对HEK293-5-HT4(d)-APP695细胞中sAPPα的细胞外释放的影响的活体外研究
细胞培养
使经人类5-HT4(d)受体cDNA和人类APP695cDNA稳定转染的HEK-293(人类胚胎肾)细胞(HEK293-5-HT4(d)-APP695)在37℃下在5％CO2加湿培育箱中于补充有10％胎牛血清、2mM GlutaMax-1和100单位青霉素(penicillin)(100μg)和100μg/mL链霉素(streptomycin)的含有D-葡萄糖的杜贝卡氏改良伊格尔培养基(Dulbecco's ModifiedEagles Medium，DMEM)中生长。通过添加G418(500μg/mL)抗生素使细胞在连续选择压力下生长。
sAPPα释放
使HEK293-5-HT4(d)-APP695细胞(3×105个细胞/孔)血清饥饿4小时，随后在37℃下用促效剂培育30分钟(除非另外说明)。吸出培养基，离心以去除细胞碎片并且利用西方印迹法(Western blot)测定sAPPα含量。使用抗体6E10(希格耐特(Signet)/科文斯(Covance))和山羊抗小鼠HRP结合2°抗体检测sAPPα。利用ECL底物(皮尔斯(Pierce))和FluorChem HD2影像系统(阿尔法创新技术公司(Alpha Innotech))观测和定量对应于sAPPα的免疫反应性条带。一式两份进行样品的西方印迹分析。
结果
以pEC50值(EC50值的以10为底的负对数)报导效能数据，其中EC50为达到50％最大反应的有效浓度。在这个分析中展现较高pEC50值的测试化合物具有刺激sAPPα释放的较高效能。为测定EC50值，使用Graph Pad Prism软件将来自独立实验的数据同时拟合成S形浓度反应曲线(斜率限制为一)。下文给出化合物1和化合物2的效能数据，连同相对于浓度为1μM的内源性配体5-HT的作用的反应百分比：
通过用1μM GR113808培育细胞10分钟，随后用浓度为100nM(化合物在所述浓度下引起接近最大或最大反应)的化合物1或化合物2培育细胞来探查5-HT4受体选择性拮抗剂GR113808的作用。拮抗剂完全阻断化合物1和化合物2的作用，表明所观测到的sAPPα释放与5-HT4受体的促效作用有关。
尽管已参考本发明的具体实施例描述本发明，但所属领域的技术人员应了解，可在不偏离本发明的真实精神和范围的情况下进行各种改变并且可进行等效内容的替代。另外，可进行许多修改以使特定情形、材料、物质组合物、方法、方法步骤与本发明的目的、精神和范围相适应。预期所有所述修改都在随附权利要求书的范围内。另外，上文中所引用的所有公开案、专利和专利文献都是以全文引用的方式并入本文中，其并入程度如同以引用的方式单独并入一般。
Claims (6)
1.一种5-HT4促效剂化合物与盐酸多奈哌齐的用途，其用于制造一种药物，所述药物是用于治疗患者的阿尔茨海默氏病(Alzheimer's disease)或认知障碍，
其中所述5-HT4促效剂化合物是1-异丙基-2-氧代-1,2-二氢喹啉-3-甲酸{(1S,3R,5R)-8-[(R)-2-羟基-3-(甲烷磺酰基-甲基-氨基)丙基]-8-氮杂双环[3.2.1]辛-3-基}酰胺的盐酸盐，且
其中在剂量分别为0.01mg/kg和0.1mg/kg时，所述5-HT4促效剂化合物和盐酸多奈哌齐化合物在大鼠莫里斯水迷宫认知功能模型中呈现加和或协同效应。
2.一种5-HT4受体促效剂化合物与盐酸多奈哌齐的用途，其用于制造一种药物，所述药物是用于增强经受记忆缺失的患者的记忆力，
其中所述5-HT4受体促效剂化合物是1-异丙基-2-氧代-1,2-二氢喹啉-3-甲酸{(1S,3R,5R)-8-[(R)-2-羟基-3-(甲烷磺酰基-甲基-氨基)丙基]-8-氮杂双环[3.2.1]辛-3-基}酰胺的盐酸盐，且
其中在剂量分别为0.01mg/kg和0.1mg/kg时，所述5-HT4促效剂化合物和盐酸多奈哌齐化合物在大鼠莫里斯水迷宫认知功能模型中呈现加和或协同效应。
3.一种5-HT4促效剂化合物与盐酸多奈哌齐的组合，其用于治疗患者的阿尔茨海默氏病或认知障碍，
其中所述5-HT4促效剂化合物是1-异丙基-2-氧代-1,2-二氢喹啉-3-甲酸{(1S,3R,5R)-8-[(R)-2-羟基-3-(甲烷磺酰基-甲基-氨基)丙基]-8-氮杂双环[3.2.1]辛-3-基}酰胺的盐酸盐，且
其中在剂量分别为0.01mg/kg和0.1mg/kg时，所述5-HT4促效剂化合物和盐酸多奈哌齐化合物在大鼠莫里斯水迷宫认知功能模型中呈现加和或协同效应。
4.根据权利要求3所述的组合，其中所述1-异丙基-2-氧代-1,2-二氢喹啉-3-甲酸{(1S,3R,5R)-8-[(R)-2-羟基-3-(甲烷磺酰基-甲基-氨基)丙基]-8-氮杂双环[3.2.1]辛-3-基}酰胺的盐酸盐，是用于增强所述盐酸多奈哌齐的效力。
5.一种5-HT4促效剂化合物与盐酸多奈哌齐的组合，其用于增强经受记忆缺失的患者的记忆力，
其中所述5-HT4促效剂化合物是1-异丙基-2-氧代-1,2-二氢喹啉-3-甲酸{(1S,3R,5R)-8-[(R)-2-羟基-3-(甲烷磺酰基-甲基-氨基)丙基]-8-氮杂双环[3.2.1]辛-3-基}酰胺的盐酸盐，且
其中在剂量分别为0.01mg/kg和0.1mg/kg时，所述5-HT4促效剂化合物和盐酸多奈哌齐化合物在大鼠莫里斯水迷宫认知功能模型中呈现加和或协同效应。
6.一种医药组合物，其包含盐酸多奈哌齐、5-HT4受体促效剂化合物和医药学上可接受的载剂，
其中所述5-HT4受体促效剂化合物是1-异丙基-2-氧代-1,2-二氢喹啉-3-甲酸{(1S,3R,5R)-8-[(R)-2-羟基-3-(甲烷磺酰基-甲基-氨基)丙基]-8-氮杂双环[3.2.1]辛-3-基}酰胺的盐酸盐，且
其中在剂量分别为0.01mg/kg和0.1mg/kg时，所述5-HT4促效剂化合物和盐酸多奈哌齐化合物在大鼠莫里斯水迷宫认知功能模型中呈现加和或协同效应。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10164139A1 (de) | 2001-12-27 | 2003-07-10 | Bayer Ag | 2-Heteroarylcarbonsäureamide |
| US8642638B2 (en) | 2008-11-19 | 2014-02-04 | Envivo Pharmaceuticals, Inc. | Treatment of cognitive disorders with (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof |
| WO2010132423A1 (en) * | 2009-05-11 | 2010-11-18 | Envivo Pharmaceuticals, Inc. | Treatment of cognitive disorders with certain alpha-7 nicotinic acid receptors in combination with acetylcholinesterase inhibitors |
| KR101898107B1 (ko) | 2010-05-17 | 2018-09-12 | 포럼 파마슈티칼즈 인크. | (R)-7-클로로-N-(퀴누클리딘-3-일)벤조[b]티오펜-2-카르복사미드 히드로클로리드 모노히드레이트의 결정질 형태 |
| AU2013259871A1 (en) | 2012-05-08 | 2014-11-20 | Forum Pharmaceuticals Inc. | Methods of maintaining, treating or improving cognitive function |
| KR101476236B1 (ko) | 2012-08-16 | 2014-12-24 | 경희대학교 산학협력단 | 노화 및 치매의 예방 및/또는 치료 활성을 갖는 유산균 |
| US10874701B2 (en) | 2012-08-16 | 2020-12-29 | University-Industry Cooperation Group Of Kyung Hee University | Lactic acid bacteria capable of preventing and/or treating senescence and dementia |
| SMT202100240T1 (it) | 2017-05-24 | 2021-05-07 | H Lundbeck As | Combinazione di un antagonista del recettore di 5-ht6 e un inibitore della acetilcolinesterasi per l'uso nel trattamento della malattia di alzheimer in una sottopopolazione di pazienti portatori di alleli apoe4 |
| KR20200010211A (ko) | 2017-06-01 | 2020-01-30 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | Pde9 저해제를 포함하는 약제학적 조성물 |
| WO2018221729A1 (ja) | 2017-06-02 | 2018-12-06 | 富山化学工業株式会社 | 脳萎縮予防または治療剤 |
| US11642339B2 (en) * | 2017-07-31 | 2023-05-09 | Theravance Biopharma R&D Ip, Llc | Methods of treating symptoms of gastroparesis using velusetrag |
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| CN101151264A (zh) * | 2005-04-06 | 2008-03-26 | 施万制药 | 喹啉酮甲酰胺化合物的结晶形式 |
| US7375114B2 (en) * | 2004-04-07 | 2008-05-20 | Theravance, Inc. | Quinolinone-carboxamide compounds as 5-HT4 receptor agonists |
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| EP2130538A1 (en) * | 2000-03-03 | 2009-12-09 | Eisai R&D Management Co., Ltd. | Use of a cholinesterase inhibitor for the delaying the onset of Alzheimer's disease |
| US7598265B2 (en) | 2004-09-30 | 2009-10-06 | Epix Delaware, Inc. | Compositions and methods for treating CNS disorders |
| MY147756A (en) | 2005-05-25 | 2013-01-15 | Theravance Inc | Benzimidazole-carboxamide compounds as 5-ht4 receptor agonists |
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| US7375114B2 (en) * | 2004-04-07 | 2008-05-20 | Theravance, Inc. | Quinolinone-carboxamide compounds as 5-HT4 receptor agonists |
| CN101151264A (zh) * | 2005-04-06 | 2008-03-26 | 施万制药 | 喹啉酮甲酰胺化合物的结晶形式 |
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| ZA201107490B (en) | 2012-06-27 |
| US20140057939A1 (en) | 2014-02-27 |
| EP2419104B1 (en) | 2017-11-08 |
| PT2419104T (pt) | 2018-01-31 |
| RU2569056C2 (ru) | 2015-11-20 |
| WO2010120695A2 (en) | 2010-10-21 |
| MX2011010782A (es) | 2012-01-20 |
| BRPI1013777A8 (pt) | 2017-09-19 |
| US20100261752A1 (en) | 2010-10-14 |
| LT2419104T (lt) | 2018-02-12 |
| SMT201800036T1 (it) | 2018-03-08 |
| SI2419104T1 (en) | 2018-03-30 |
| CY1119800T1 (el) | 2018-06-27 |
| CN102395371A (zh) | 2012-03-28 |
| WO2010120695A3 (en) | 2010-12-02 |
| JP2012523437A (ja) | 2012-10-04 |
| AU2010236734A1 (en) | 2011-11-03 |
| PL2419104T3 (pl) | 2018-04-30 |
| HUE038141T2 (hu) | 2018-10-29 |
| DK2419104T3 (en) | 2018-02-05 |
| CA2758321A1 (en) | 2010-10-21 |
| AU2010236734B2 (en) | 2015-06-11 |
| IL215660A0 (en) | 2012-01-31 |
| ES2654930T3 (es) | 2018-02-15 |
| NO2419104T3 (zh) | 2018-04-07 |
| US8404711B2 (en) | 2013-03-26 |
| RU2011146032A (ru) | 2013-05-20 |
| EP2419104A2 (en) | 2012-02-22 |
| HRP20180018T1 (hr) | 2018-02-09 |
| KR20120017421A (ko) | 2012-02-28 |
| BRPI1013777A2 (pt) | 2016-04-05 |
| AU2010236734A8 (en) | 2012-02-16 |
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