CN106659762A - Nmdar调节化合物的组合 - Google Patents
Nmdar调节化合物的组合 Download PDFInfo
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- CN106659762A CN106659762A CN201580031430.2A CN201580031430A CN106659762A CN 106659762 A CN106659762 A CN 106659762A CN 201580031430 A CN201580031430 A CN 201580031430A CN 106659762 A CN106659762 A CN 106659762A
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- nmdar
- glyx
- nmdar antagonists
- antagonists
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Abstract
本公开的特征在于NMDAR调节化合物的组合。本公开的特征在于包含一种或多种NMDAR拮抗剂和GLYX‑13(其每一种在本文中有时称为“组分”)的组合。所述组合的有益作用部分基于以下发现:施用GLYX‑13(例如,单剂量)可以逆转和/或预防NMDAR拮抗剂诱导的认知损伤(例如,NMDAR拮抗剂诱导的新物体识别中的损伤;例如,通过所述NMDAR拮抗剂的重复给药而被诱导)。
Description
相关申请的交叉引用
本申请要求于2014年5月6日提交的美国临时申请No.61/989,183的权益,该美国临时申请通过引用整体并入本文。
发明背景
N-甲基-d-天冬氨酸(NMDA)受体(NMDAR)是突触后离子型受体,其尤其响应于兴奋性氨基酸谷氨酸和甘氨酸以及合成的化合物NMDA。NMDA受体控制二价和一价离子通过受体相关通道流入突触后神经细胞中(Foster等人,Nature 1987,329:395-396;Mayer等人,Trends in Pharmacol.Sci.1990,11:254-260)。NMDA受体在特定神经元建构和突触连接性的发展期间有涉及,并且可以参与经验依赖性突触修饰。另外,NMDA受体也被认为参与长时程增强和中枢神经系统障碍。
NMDA受体在成为许多较高认知功能如记忆获得、保持和学习的基础的突触可塑性中以及在某些认知途径和痛觉中发挥主要作用(Collingridge等人,The NMDA Receptor,Oxford University Press,1994)。另外,NMDA受体的某些性质表明它们可能参与脑中成为意识本身的基础的信息处理。
NMDA受体特别引人关注,因为其似乎参与广泛的CNS障碍。例如,在由中风或创伤性损伤引起的脑缺血期间,从受损或缺氧的神经元释放过量的兴奋性氨基酸谷氨酸。这一过量的谷氨酸结合到NMDA受体,这打开了它们的配体-门控离子通道;钙内流进而产生高水平的细胞内钙,所述细胞内钙活化生物化学级联,导致蛋白质降解和细胞死亡。该现象,称为兴奋性中毒,也被认为引起与低血糖症和心脏停搏到癫痫的范围的其它障碍相关的神经损害。另外,有初步报告指出在亨廷顿氏病(Huntington′s disease)、帕金森氏病(Parkinson′s disease)、阿尔茨海默氏病(Alzheimer′s disease)的慢性神经变性中存在类似参与。NMDA受体的活化已显示引起中风后惊厥并且在某些癫痫模型中,NMDA受体的活化已显示为产生癫痫发作所必需的。NMDA受体的神经精神参与也已被认识,因为动物麻醉剂PCP(苯环利定(phencyclidine))阻断NMDA受体Ca++通道在人类中产生类似于精神分裂症的精神病状态(综述于Johnson,K和Jones,S.,1990中)。此外,NMDA受体也牵涉于某些类型的空间学习中。
NMDA受体被认为由嵌入突触后膜中的若干蛋白质链组成。到目前为止发现的前两种类型的亚单位形成大的细胞外区,所述细胞外区可能包含大多数变构结合位点,若干跨膜区成环并折叠以便形成孔或通道,所述孔或通道可渗透Ca++和羧基末端区域。通过各种配体与驻留在细胞外表面上的蛋白质的结构域(变构位点)的结合来调节所述通道的打开和关闭。所述配体的结合被认为影响蛋白质总体结构的构象变化,所述构象变化最终反映为通道打开、部分打开、部分关闭或关闭。
NMDA受体拮抗剂用于拮抗或抑制N-甲基-D-天冬氨酸受体(NMDAR)的作用。然而,受阻抑的NMDA受体功能可能与负面副作用相关,包括影响认知能力的副作用。
最近,已报道称为GLYX-13的改善的NMDAR部分激动剂。GLYX-13由以下结构例示:
其具有分子量:413.47,和化学式:C18H31N5O6。GLYX-13展示益智、神经保护和抗伤害感受的活性,并增强体内的学习、记忆和认知。
发明概要
本公开的特征在于包含一种或多种NMDAR拮抗剂和GLYX-13(其每一种在本文中有时称为“组分”)的组合。所述组合的有益作用部分基于以下发现:施用GLYX-13(例如,单剂量)可以逆转和/或预防NMDAR拮抗剂诱导的认知损伤(例如,NMDAR拮抗剂诱导的新物体识别中的损伤;例如,通过NMDAR拮抗剂的重复给药而被诱导)。所述组合可以进一步包含一种或多种其它生物活性成分(例如一种或多种其它抗抑郁化合物)和/或一种或多种药学上可接受的赋形剂和/或载体。可以以依序方式(在不同时间施用每种组分)或以基本同时的方式向患者施用所述组合的组分(在本文中有时也称为化学实体或化学化合物)。应当理解,所述组分可以存在于相同的药学上可接受的载体中,因此,可以被同时施用。或者,每种组分可以存在于可以同时或依序施用的单独的药物载体中,例如常规口服剂型或胃肠外形式(或一种组分可以是口服的且另一种可以是肠胃外的)。在一些实施方案中,用GLYX-13预处理(即,在施用一种或多种NMDAR拮抗剂之前给予)可以是特别有益的。
因此,在一个方面,提供了基本上逆转或预防急性施用NMDAR拮抗剂的患者的认知损伤的方法,其包括施用有效量的GLYX-13。
在另一方面,提供了治疗有需要的患者的认知损伤障碍的方法,其包括施用有效量的GLYX-13和一种或多种NMDAR拮抗剂。认知损伤障碍可以归因于以下中的一种或多种:认知能力的缺陷、先天性缺陷、环境因素或药物诱导,且包括但不限于学习障碍和/或诵读困难。在一些实施方案中,施用有效量的GLYX-13在急性施用一种或多种NMDAR拮抗剂之前或之后发生。在其它实施方案中,施用有效量的GLYX-13基本上与急性施用一种或多种NMDAR拮抗剂同时发生。
在又一方面,提供了治疗包括但不限于以下的障碍、病状或疾病的方法:神经性障碍或其它障碍(例如,中风、精神病性障碍、疼痛(神经性疼痛)、抑郁症(重性抑郁症)、帕金森氏病和阿尔茨海默氏病);中枢神经系统疾病(例如,神经变性疾病、中风、创伤性脑损伤和脊髓损伤);精神分裂症和/或抑郁症(例如难治性抑郁症),其包括施用有效量的GLYX-13和一种或多种NMDAR拮抗剂。在一些实施方案中,基本上同时施用GLYX-13和一种或多种NMDAR拮抗剂。在其它实施方案中,依序施用GLYX-13和一种或多种NMDAR拮抗剂,例如,在一种或多种NMDAR拮抗剂之前或之后施用GLYX-13。
在一个方面,提供了药学上可接受的组合物,其包含GLYX-13、一种或多种NMDAR拮抗剂和一种或多种药学上可接受的赋形剂和/或载体。
附图简述
图1是显示新物体识别模型的概况的图。
图2显示在用每天两次注射氯胺酮(30mg/kg,腹膜内)连续7天并随后在测试前1小时注射无菌盐水媒介物(氯胺酮组)、在测试前1小时注射GLYX-13(1mg/kg,静脉内)(GLYX-13+氯胺酮组),或每天两次注射无菌盐水持续7天并在测试前1小时注射媒介物预处理的成年雄性C57BL/6雄性小鼠中的新物体识别试验中的平均值±SEM辨别指数得分。使用下式计算辨别指数:(探索新物体所耗费的时间-探索熟悉物体所耗费的时间)/(探索新物体和熟悉物体两者所耗费的总时间)。N=8-10只/组。*p<.001,与媒介物组相比DI显著降低,#p<0.001,与氯胺酮组相比DI显著逆转(费雪氏PLSD事后检验(Fisher′s PLSD post hoctest))。图2中的数据证实GLYX-13(1mg/kg,静脉内)逆转在小鼠中新物体识别中慢性氯胺酮诱导的损伤。
图3显示在用每天两次注射PCP(10mg/kg,腹膜内)连续7天并随后在测试前1小时注射无菌盐水媒介物(PCP组)、在测试前1小时注射GLYX-13(1mg/kg,静脉内)(GLYX-13+PCP组),或每天两次注射无菌盐水持续7天并在测试前1小时注射媒介物预处理的成年雄性C57BL/6雄性小鼠中的新物体识别试验中的平均值±SEM辨别指数得分。使用下式计算辨别指数:(探索新物体所耗费的时间-探索熟悉物体所耗费的时间)/(探索新物体和熟悉物体两者所耗费的总时间)。N=8-10只/组。*p<.001,与媒介物组相比DI显著降低,#p<0.001,与PCP组相比DI显著逆转(费雪氏PLSD事后检验)。图3中的数据证实GLYX-13(1mg/kg,静脉内)逆转在小鼠中新物体识别中慢性苯环利定诱导的损伤。
图4显示在躯体感觉皮质中用3mpk和30mpk的GLYX-13、随后用氯胺酮预处理的显著减毒。
图5显示在氯胺酮(10mg/kg,皮下)前30min用GLYX-13(3mg/kg,静脉内)预处理并在20min后测试的成年雄性C57BL/6雄性小鼠的新物体识别试验中的平均值±SEM辨别指数得分。使用下式计算辨别指数:(探索新物体所耗费的时间-探索熟悉物体所耗费的时间)/(探索新物体和熟悉物体两者所耗费的总时间)。N=8-11只/组。***p<.0001,与媒介物组相比DI显著降低,##p<0.01,与氯胺酮组相比DI显著逆转(费雪氏PLSD事后检验)。图5中的数据证实GLYX-13(3mg/kg,静脉内)逆转在小鼠中新物体识别中急性氯胺酮(10mg/kg,皮下)诱导的损伤。
图6显示在氯胺酮(10mg/kg,静脉内)前30min用GLYX-13(3mg/kg,静脉内)预处理的2-3月龄雄性Sprague Dawley大鼠中在旷场中的刻板性行为(转圈和头部晃动(headweaving))的平均(±SEM)数。媒介物处理的动物接受盐水媒介物注射而不是GLYX-13和氯胺酮注射。在最终剂量后立即将动物置于旷场中,并分析行为20min。N=8-12只。图6中的数据证实GLYX-13(3mg/kg,静脉内)抑制在大鼠中氯胺酮(10mg/kg,静脉内)诱导的刻板性。
具体实施方式
本公开的特征在于包含一种或多种NMDAR拮抗剂和GLYX-13(其每一种在本文中有时称为“组分”)的组合。所述组合的有益作用部分基于以下发现:施用GLYX-13(例如,单剂量)可以逆转和/或预防NMDAR拮抗剂诱导的认知损伤(例如,NMDAR拮抗剂诱导的新物体识别中的损伤;例如,通过NMDAR拮抗剂的重复给药而被诱导)。所述组合可以进一步包含一种或多种其它生物活性成分(例如一种或多种其它抗抑郁化合物)和/或一种或多种药学上可接受的赋形剂和/或载体。可以以依序方式(在不同时间施用每种组分)或以基本同时的方式向患者施用所述组合的组分(在本文中有时也称为化学实体或化学化合物)。应当理解,所述组分可以存在于相同的药学上可接受的载体中,因此,可以被同时施用。或者,每种组分可以存在于可以同时或依序施用的单独的药物载体中,例如常规口服剂型或胃肠外形式(或一种组分可以是口服的且另一种可以是肠胃外的)。在一些实施方案中,用GLYX-13预处理(即,在施用一种或多种NMDAR拮抗剂之前给予)可以是特别有益的。
“GLYX-13”由下式表示:
并且包括上述化合物的多晶型物、水合物、溶剂合物、游离碱和/或合适的盐形式。
“治疗”包括使病状、疾病、障碍等改善的任何效应,例如减轻、降低、调节或消除。
如本文所用的术语“烷氧基”是指连接至氧的直链或支链烷基(烷基-O-)。示例性的烷氧基包括但不限于具有1-6或2-6个碳原子的烷氧基,在本文中分别称为C1-C6烷氧基和C2-C6烷氧基。示例性的烷氧基包括但不限于甲氧基、乙氧基、异丙氧基等。
如本文所用的术语“烷基”是指饱和的直链或支链烃,如具有1-6、1-4或1-3个碳原子的直链或支链基团,在本文中分别称为C1-C6烷基、C1-C4烷基和C1-C3烷基。示例性的烷基包括但不限于甲基、乙基、丙基、异丙基、2-甲基-1-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-1-丁基、3-甲基-2-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、丁基、异丁基、叔丁基、戊基、异戊基、新戊基、己基等。如本文所用的术语“卤代烷基”是指饱和的直链或支链烷基,其中所述烷基的一个或多个氢原子被一个或多个独立选择的卤素取代。术语“卤代烷基”涵盖其中烷基的所有氢原子被独立选择的卤素取代的烷基(有时称为”全卤代”烷基。示例性的卤代烷基包括但不限于CH2F、CH2CH2Cl、CF3、CHFCH2Cl。
如本文所用的术语“卤代”或”卤素”是指F、Cl、Br或I。
如本文所用的术语“氧代”是指基团=O。
如本文所用,术语“NMDA受体拮抗剂”和“NMDAR拮抗剂”通常都是指能够结合至NMDA受体的甘氨酸结合位点并且用于拮抗或抑制N-甲基-D-天冬氨酸受体(NMDAR)的作用的化学实体。
“药学上或药理学上可接受的”包括当视情况向动物或人施用时不产生不利的、过敏的或其它不良反应的分子实体和组合物。对于人施用来说,制剂应当满足FDA生物制品标准局(FDA Office of Biologics standards)所要求的对无菌性、致热原性、一般安全性和纯度的标准。
如本文所用的术语“药学上可接受的载体”或“药学上可接受的赋形剂”是指与药物施用相容的任何和所有的溶剂、分散介质、包衣、等渗剂和吸收延迟剂等。此类介质和试剂用于药物活性物质的用途是本领域熟知的。本文所述的组合还可以含有提供补充的、额外的或增强的治疗功能的其它活性化合物。
如本文使用的术语“药物组合物”是指包含与一种或多种药学上可接受的载体和/或赋形剂一起配制的本文公开的组合的至少一种组分的组合物。
“个体”、“患者”或“受试者”可互换使用,并且包括任何动物,包括哺乳动物,优选小鼠、大鼠、其它啮齿动物、兔、犬、猫、猪、牛、绵羊、马或灵长类动物,且最优选人。本发明的组合可以如本文所述被施用于哺乳动物,如人,但还可以被施用于其它哺乳动物,如需要兽医治疗的动物,例如,家养动物(例如,犬、猫等)、农场动物(例如,奶牛、绵羊、猪、马等)和实验室动物(例如,大鼠、小鼠、豚鼠等)。在一些实施方案中,在本发明的方法中治疗的哺乳动物是期望治疗例如疼痛或抑郁症的哺乳动物。
术语“有效量”是指研究人员、兽医、内科医生或其他临床医师正在寻求的将会诱发组织、系统、动物或人的生物或医学响应的所述主题组分的量。举例来说,有效量可以是有效治疗本文所述的任何疾病、障碍和病状的量。或者,有效量可以指实现期望的治疗和/或预防效果所需的量,如使NMDAR拮抗剂诱导的认知损伤(例如,NMDAR拮抗剂诱导的新物体识别中的损伤;例如,通过NMDAR拮抗剂的重复给药诱导)逆转和/或预防的GLYX-13的量。
如本文所用的术语“药学上可接受的盐”是指可以存在于本组合中所用的化合物中的酸性基团或碱性基团的盐。包含在本组合中的性质上为碱性的化合物能够与各种无机酸和有机酸形成各种各样的盐。可以用于制备此类碱性化合物的药学上可接受的酸加成盐的酸是形成无毒酸加成盐的那些,所述无毒酸加成盐即含有药理学上可接受的阴离子的盐,包括但不限于苹果酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乙酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖二酸盐(glucaronate)、糖二酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即,1,1′-亚甲基-双-(2-羟基-3-萘甲酸盐))。包含在本组合中的性质上为酸性的化合物能够与各种药理学上可接受的阳离子形成碱盐。此类盐的实例包括碱金属盐或碱土金属盐,且特别是钙盐、镁盐、钠盐、锂盐、锌盐、钾盐和铁盐。包含在本组合中的包含碱性部分或酸性部分的化合物还可以与各种氨基酸形成药学上可接受的盐。包含在本组合中的化合物可以含有酸性基团和碱性基团两者;例如,一个氨基和一个羧酸基。在这种情况下,所述化合物可以作为酸加成盐、两性离子或碱盐存在。
包含在本组合中的化合物可以含有一个或多个手性中心和/或双键,因此作为几何异构体、对映异构体或非对映异构体存在。对映异构体和非对映异构体可以由符号“(+)”、“(-)”指定。“R”或“S”,取决于立构碳原子周围的取代基的构型,但本领域技术人员将认识到结构可以隐含地表示手性中心。由碳-碳双键周围的取代基排列或环烷基或杂环周围的取代基排列产生的几何异构体也可以存在于本发明的化合物中。碳-碳双键周围的取代基被指定为处于“Z”或“E”构型,其中术语“Z”和“E”根据IUPAC标准使用。除非另有说明,否则描绘双键的结构涵盖“E”和“Z”两种异构体。碳-碳双键周围的取代基或者可以称为“顺式”或“反式”,其中“顺式”表示双键的同侧的取代基,而“反式”表示双键的对侧的取代基。碳环周围的取代基排列也可以被指定为“顺式”或“反式”。术语“顺式”表示环的平面的同侧的取代基,而术语“反式”表示环的平面的对侧的取代基。其中取代基布置在环的平面的相同侧和对侧的化合物的混合物被指定为“顺式/反式”。
包含在本组合中的化合物可以与药学上可接受的溶剂如水、乙醇等以溶剂化形式以及非溶剂化形式存在,并且本发明旨在涵盖溶剂化形式和非溶剂化形式两者。在一个实施方案中,所述化合物是无定形的。在一个实施方案中,所述化合物是单一多晶型物。在另一实施方案中,所述化合物是多晶型物的混合物。在另一实施方案中,所述化合物呈结晶形式。
术语“前药”是指在体内转化以产生所公开的化合物或该化合物的药学上可接受的盐、水合物或溶剂合物的化合物。转化可以在各种位置(如在肠腔中或在肠、血液或肝脏转运时)通过各种机制(如通过酯酶、酰胺酶、磷酸酶、氧化和/或还原性代谢)发生。前药是本领域熟知的(例如,参见Rautio,Kumpulainen等人,Nature Reviews Drug Discovery2008,7,255)。例如,如果本发明的化合物或该化合物的药学上可接受的盐、水合物或溶剂合物含有羧酸官能团,则前药可以包括通过用诸如以下的基团替代酸基的氢原子而形成的酯:(C1-C8)烷基、(C2-C12)烷酰氧基甲基、具有4至9个碳原子的1-(烷酰氧基)乙基、具有5至10个碳原子的1-甲基-1-(烷酰氧基)-乙基、具有3至6个碳原子的烷氧基羰氧基甲基、具有4至7个碳原子的1-(烷氧基羰氧基)乙基、具有5至8个碳原子的1-甲基-1-(烷氧基羰氧基)乙基、具有3至9个碳原子的N-(烷氧基羰基)氨基甲基、具有4至10个碳原子的1-(N-(烷氧基羰基)氨基)乙基、3-酞基、4-巴豆酸内酯基(4-crotonolactonyl)、γ-丁内酯-4-基、二-N,N-(C1-C2)烷基氨基(C2-C3)烷基(如β-二甲基氨基乙基)、氨基甲酰基-(C1-C2)烷基、N,N-二(C1-C2)烷基氨基甲酰基-(C1-C2)烷基和哌啶基-、吡咯烷基-或吗啉基(C2-C3)烷基。
组合组分
GLYX-13可以通过熟知的重组或合成方法获得,所述方法如美国专利5,763,393和4,086,196中描述的那些,所述美国专利通过引用并入本文。还涵盖GLYX 13的多晶型物、水合物、同系物、溶剂合物、游离碱和/或合适的盐形式,例如但不限于乙酸盐。肽可以是环化形式或非环化形式,如US 5,763,393中进一步所描述。在一些实施方案中,GLYX-13类似物可以包含在一个或多个Thr或Pro基团上的部分的插入或缺失,如CH2、OH或NH2部分的缺失。在其它实施方案中,GLYX-13可以任选地被一个或多个卤素、C1-C3烷基(任选地被卤素或氨基取代)、羟基和/或氨基取代。涵盖用于本文的其它化合物包括US 5,763,393、US 6,107,271和Wood等人,Neuro.Report,19,1059-1061,2008中所公开的NMDAR的甘氨酸位点部分激动剂,所述文献的全部内容通过引用并入本文。
可以理解,本文所公开的肽可以包括天然氨基酸和非天然氨基酸两者,例如,所有天然氨基酸(或其衍生物)、所有非天然氨基酸(或其衍生物),或天然氨基酸和非天然氨基酸的混合物。例如,GLYX-13中的一个、两个、三个或更多个氨基酸可以各自独立地具有d-构型或l-构型。
在一些实施方案中,NMDAR拮抗剂选自由以下组成的组:氯胺酮、美金刚(memantine)、拉尼西明(lanicemine)(AZD6765)、CERC-301、右美沙芬(dextromethorphan)、右啡烷(dextrorphan)、苯环利定、地佐环平(dizocilpine)(MK-801)、金刚烷胺、艾芬地尔(ifenprodil)、AV-101、AZD 6423和利鲁唑(riluzole),或其药学上可接受的盐或前药。还涵盖上述NMDAR拮抗剂的衍生物。
在某些实施方案中,NMDAR拮抗剂具有式(I):
其中:
R1是苯基、噻吩基或苯并噻吩基,其每一个任选地被1-3个独立地选自由以下组成的组的取代基取代:卤代;-OH;NRaRb,其中Ra和Rb中的每一个独立地选自H和C1-C3烷基;C1-C3烷基;和C1-C3烷氧基;
R2是-NRcRd,其中Rc和Rd中的每一个独立地选自H和C1-C6烷基,所述C1-C6烷基任选地被-OH或C1-C3烷氧基取代;或Rc和Rd连同各自所连接的氮原子一起形成任选地被1-2个独立地选择的C1-C3烷基取代的5-7元环;并且
R3是H、氧代或C1-C3烷基;或其药学上可接受的盐或前药。
在某些实施方案中,R1是苯基,其任选地被1-3个独立地选自由以下组成的组的取代基取代:卤代;-OH;NRaRb,其中Ra和Rb中的每一个独立地选自H和C1-C3烷基;C1-C3烷基;和C1-C3烷氧基。例如,R1可以是苯基、3-羟基苯基、3-甲氧基苯基、3-氨基苯基、3-甲基苯基、4-氟苯基、4-羟基苯基、3-甲氧基苯基或2-氯苯基。在其它实施方案中,R1是任选取代的噻吩基或任选取代的苯并噻吩基。
在某些实施方案中,R2是-NRcRd,其中Rc和Rd中的每一个独立地选自H和任选地被-OH或C1-C3烷氧基取代的C1-C6烷基,例如,H和C1-C6烷基,例如,H和C1-C3烷基,例如,Rc和Rd中的一个是H,并且另一个是C1-C3烷基。例如,R2可以是-NH(C1-C3烷基),如-NH(CH3)。在其它实施方案中,R2是-NRcRd,其中Rc和Rd连同各自所连接的氮原子一起形成任选地被1-2个独立地选择的C1-C3烷基取代的5-7元环,如哌啶基。
在某些实施方案中,R3是H或氧代。
在某些实施方案中:
R1是苯基,其任选地被1-3个独立地选自由以下组成的组的取代基取代:卤代;-OH;NRaRb,其中Ra和Rb中的每一个独立地选自H和C1-C3烷基;C1-C3烷基;和C1-C3烷氧基(例如,R1是苯基、3-羟基苯基、3-甲氧基苯基、3-氨基苯基、3-甲基苯基、4-氟苯基、4-羟基苯基、3-甲氧基苯基或2-氯苯基);
R2是-NRcRd,其中Rc和Rd中的每一个独立地选自H和任选地被-OH或C1-C3烷氧基取代的C1-C6烷基;例如,H和C1-C6烷基,例如,H和C1-C3烷基;例如,Rc和Rd中的一个是H,并且另一个是C1-C3烷基;例如,R2可以是-NH(C1-C3烷基),如-NH(CH3);并且
R3是H或氧代(例如,氧代)。
在某些实施方案中:
R1是苯基,其任选地被1-3个独立地选自由以下组成的组的取代基取代:卤代;-OH;NRaRb,其中Ra和Rb中的每一个独立地选自H和C1-C3烷基;C1-C3烷基;和C1-C3烷氧基(例如,R1是苯基、3-羟基苯基、3-甲氧基苯基、3-氨基苯基、3-甲基苯基、4-氟苯基、4-羟基苯基、3-甲氧基苯基或2-氯苯基);
R2是-NRcRd,其中Rc和Rd连同各自所连接的氮原子一起形成任选地被1-2个独立地选择的C1-C3烷基取代的5-7元环,如哌啶基;并且R3是H或氧代(例如,H)。
在某些实施方案中,R1是苯基,R2是哌啶基,并且R3是H。例如,所述化合物可以是苯西克定。
在某些实施方案中,R1是2-氯苯基,R2是-NH(CH3),并且R3是氧代。例如,所述化合物可以是氯胺酮,例如,(S)-氯胺酮。
在某些实施方案中,NMDAR拮抗剂是美金刚或金刚烷胺。在某些实施方案中,NMDAR拮抗剂是地佐环平(MK-801)。在某些实施方案中,NMDAR拮抗剂是右美沙芬或右啡烷。在某些实施方案中,NMDAR拮抗剂是拉尼西明(AZD6765)、CERC-301或艾芬地尔。在某些实施方案中,NMDAR拮抗剂是AV-101或AZD 6423。
在一些实施方案中,NMDAR拮抗剂选自由以下组成的组:一氧化二氮、托莫西汀(atomoxetine)、dextrallorphan、diphenidine、乙环利定(eticyclidine)、加环利定(gacyclidine)、伊波加因(ibogaine)、methoxetamine、硝基美金刚(nitromemantine)、咯环利定(rolicyclidine)、替诺环定(tenocyclidine)、methoxydine、替来他明(tiletamine)、奈拉美生(neramexane)、依利罗地(eliprodil)、乙苯噁啶(etoxadrol)、右奥沙屈(dexoxadrol)、美沙酮(methadone)、WMS-2539、NEFA、瑞马西胺(remacemide)、德芦西明(delucemine)、8A-PDHQ、阿替加奈(aptiganel)(Cerestat,CNS-1102)、HU-211、瑞马西胺、钩藤碱、TK-40、曲索罗地(Traxoprodil)(CP-101,606)、1-氨基环丙烷羧酸(ACPC)、犬尿喹啉酸或其衍生物、2-羧基四氢喹啉或其衍生物、2-羧基吲哚或其衍生物、4-羟基-2-喹啉或其衍生物、4-羟基喹啉或其衍生物、喹噁啉-2,3-二酮或其衍生物、三环拮抗剂(trycyclic antagonist)、拉考沙胺(lacosamide)、L-苯丙氨酸、米达福太(midafotel)和阿替加奈或其药学上可接受的盐或前药。
还参见例如Kvist等人,J.Biol.Chem.2013 288:33124-33135中所描述的那些,该文献通过引用整体并入本文。还参见例如Traynelis等人,Pharmacological Reviews2010,62,405中所描述的那些,该文献通过引用整体并入本文(例如,CGP-61594;CGP-58411;ACEA-1011和1021;L-701,324;(R)-AP5;(R)-AP7;PMPA;(R)-CPP;NVP-AAM077;PPDA;(R)-a-AA;PBPD;UBP141;CGS-19755(基福太(selfotel));CGP-43487;CGP-40116;芋螺睡眠肽(Conantokin),例如,Br、G、Pr1、Pr2、Pr3、R和T;雷迪普洛迪尔(radiprodil);和MK-0657)。
在某些实施方案中,NMDAR拮抗剂是犬尿喹啉酸或其衍生物、2-羧基四氢喹啉或其衍生物、2-羧基吲哚或其衍生物、4-羟基-2-喹啉或其衍生物、4-羟基喹啉或其衍生物、喹噁啉-2,3-二酮或其衍生物或三环拮抗剂。此类化合物的实例描述于本文以及例如Danysz等人,Pharmacological Reviews 1998,50,597中,该文献通过引用整体并入本文。
方法
在一个方面,提供了基本上逆转或预防急性施用NMDAR拮抗剂的患者的认知损伤的方法,其包括施用有效量的GLYX-13。
在另一方面,提供了治疗有需要的患者的认知损伤障碍的方法,其包括施用有效量的GLYX-13和一种或多种NMDAR拮抗剂。认知损伤障碍可以归因于以下中的一种或多种:认知能力的缺陷、先天性缺陷、环境因素或药物诱导,且包括但不限于学习障碍和/或诵读困难。在一些实施方案中,有效量的GLYX-13在急性施用一种或多种NMDAR拮抗剂之前或之后发生。在其它实施方案中,有效量的GLYX-13基本上与急性施用一种或多种NMDAR拮抗剂同时发生。
在又一方面,提供了治疗包括但不限于以下的障碍、病状或疾病的方法:神经性障碍或其它障碍(例如,中风、精神病性障碍、疼痛(例如,神经性疼痛)、抑郁症(例如,重性抑郁症)、帕金森氏病和阿尔茨海默氏病);中枢神经系统疾病(例如,神经变性疾病、中风、创伤性脑损伤和脊髓损伤);精神分裂症和/或抑郁症(例如难治性抑郁症),所述方法包括施用本文所述的组合,例如有效量的GLYX-13和一种或多种NMDAR拮抗剂。其它示例性病状包括但不限于学习障碍、孤独性障碍、注意缺陷多动障碍、焦虑症、偏头痛、图雷特氏综合征(Tourette′s syndrome)、恐惧症、创伤后应激障碍、痴呆症、与衰老相关的记忆缺陷、AIDS痴呆症、亨廷顿氏病、痉挛状态、肌阵挛、肌肉痉挛、双相型障碍、神经性疼痛、物质滥用障碍、尿失禁、缺血、特殊学习障碍、癫痫发作、中风后惊厥、脑缺血、低血糖症、心脏停搏和癫痫。在一些实施方案中,基本上同时施用GLYX-13和一种或多种NMDAR拮抗剂。在其它实施方案中,依序施用GLYX-13和一种或多种NMDAR拮抗剂,例如,在一种或多种NMDAR拮抗剂之前或之后施用GLYX-13。
涵盖的方法包括治疗有需要的患者的孤独症和/或孤独症谱系障碍的方法,其包括施用本文所述的组合,例如有效量的GLYX-13和一种或多种NMDAR拮抗剂。在一个实施方案中,涵盖用于降低有需要的患者的孤独症症状的方法,其包括施用本文所述的组合,例如有效量的GLYX-13和一种或多种NMDAR拮抗剂。例如,在施用后,所述组合可以降低孤独症的一种或多种症状的发生率,所述病症如目光接触回避、不能社交、注意缺陷、不良心情、多动、异常声音敏感性、不适当的言语、中断睡眠和持续动作。这种降低的发生率可以相对于所述未治疗个体或一个或多个未治疗个体的发生率来测量。
在一些实施方案中,患有孤独症的患者还患有另一医学病状,如脆性X综合征、结节性硬化症、先天性风疹综合征和未治疗的苯丙酮尿症。
在一些实施方案中,涵盖治疗有需要的患者的障碍的方法,其中所述障碍选自由以下组成的组:脑缺血、中风、脑创伤、脑肿瘤、急性神经性疼痛、慢性神经性疼痛、睡眠障碍、药物成瘾、抑郁症、某些视觉障碍、酒精戒断、焦虑症、记忆和学习失能、孤独症、癫痫、AIDS痴呆症、多系统萎缩、进行性核上麻痹、弗里德里希共济失调(Friedrich′s ataxia)、唐氏综合征(Down’s syndrome)、脆性X综合征、结节性硬化症、橄榄体-脑桥性小脑萎缩、大脑性麻痹、药物诱导的视神经炎、周围神经病变、骨髓病变、缺血性视网膜病变、糖尿病性视网膜病变、青光眼、心脏停搏、行为障碍、冲动控制障碍、阿尔茨海默氏病、伴随早期阿尔茨海默氏病的记忆丧失、注意缺陷障碍、ADHD、精神分裂症、阿片制剂(opiate)、尼古丁成瘾、酒精成瘾的改善、创伤性脑损伤、脊髓损伤、创伤后应激综合征和亨廷顿氏舞蹈症(Huntington’s chorea),所述方法包括施用本文所述的组合,例如有效量的GLYX-13和一种或多种NMDAR拮抗剂。
在一些实施方案中,本文涵盖治疗有此需要的患者的注意缺陷障碍、ADHD(注意缺陷多动障碍)、精神分裂症、焦虑症、阿片制剂、尼古丁和/或酒精成瘾的改善(例如治疗此类成瘾或改善来自此类成瘾的戒断副作用的方法)、脊髓损伤、糖尿病性视网膜病变、创伤性脑损伤、创伤后应激综合征和/或亨廷顿氏舞蹈症的方法,其包括施用本文所述的组合,例如有效量的GLYX-13和一种或多种NMDAR拮抗剂。例如,患有精神分裂症、成瘾(例如酒精或阿片制剂)、孤独症、亨廷顿氏舞蹈症、创伤性脑损伤、脊髓损伤、创伤后应激综合征和糖尿病性视网膜病变的患者可能全部遭受改变的NMDA受体表达或功能。
例如,本文提供治疗有需要的患者的抑郁症的方法,其包括施用本文所述的组合,例如有效量的GLYX-13和一种或多种NMDAR拮抗剂。在某些实施方案中,耐受治疗的患者被鉴别为在施用本文所述的组合之前已经用至少两种类型的抗抑郁治疗进行治疗的患者。在其它实施方案中,耐受治疗的患者是被鉴别为不愿或不能耐受至少一种类型的抗抑郁治疗的副作用的患者。
最常见的抑郁病状包括重性抑郁障碍和心境恶劣障碍。其它抑郁病状在独特的情况下发生。此类抑郁病状包括但不限于精神病性抑郁症、产后抑郁症、季节性情感障碍(SAD)、情绪障碍、由慢性医学病状如癌症或慢性疼痛、化疗、慢性应激引起的抑郁症、创伤后应激障碍和双极障碍(或躁狂抑郁障碍)。
难治性抑郁症发生在对标准药理学治疗有抗性的患有抑郁症的患者中,所述标准药理学治疗包括三环抗抑郁剂、MAOI、SSRI、及双重和三重摄取抑制剂和/或抗焦虑药、以及非药理学治疗如心理疗法、电惊厥疗法、迷走神经刺激和/或经颅磁刺激。耐受治疗的患者可以被鉴别为尽管经受一种或多种标准药理学或非药理学治疗,但未能经历抑郁症的一种或多种症状(例如,持续的焦虑感或悲伤感、无助感、绝望感、悲观感)缓和的患者。在某些实施方案中,耐受治疗的患者是即使经受用两种不同的抗抑郁药治疗也未能经历抑郁症的一种或多种症状缓和的患者。在其它实施方案中,耐受治疗的患者是即使经受用四种不同的抗抑郁药治疗也未能经历抑郁症的一种或多种症状缓和的患者。耐受治疗的患者还可以被鉴别为不愿或不能耐受一种或多种标准药理学或非药理学治疗的副作用的患者。
在另一方面,提供了用于增强动物的疼痛缓解和用于向动物提供镇痛的方法。在一些实施方案中,提供了用于治疗神经性疼痛的方法。神经性疼痛可以是急性或慢性的。在一些情况下,神经性疼痛可以与诸如以下的病状相关:疱疹、HIV、创伤性神经损伤、中风、缺血后、纤维肌痛、反射性交感神经营养不良、复杂性局部疼痛综合征、脊髓损伤、坐骨神经痛、幻肢痛、糖尿病性神经病变和癌症化疗诱导的神经性疼痛。还涵盖用于增强患者的疼痛缓解和用于向患者提供镇痛的方法。
在某些实施方案中,提供了用于治疗精神分裂症的方法。例如,可以使用本文所涵盖的方法和组合物治疗偏执型精神分裂症、错乱型精神分裂症(即,青春型精神分裂症)、紧张型精神分裂症、未分化型精神分裂症、残余型精神分裂症、精神分裂症后抑郁症和单纯型精神分裂症。还可以使用本文所涵盖的组合物治疗精神病性障碍,如分裂情感性障碍、妄想性障碍、短时精神病性障碍、共有型精神病性障碍和具有妄想或幻觉的精神病性障碍。
偏执型精神分裂症的特征可以在于其中存在妄想或幻听,但不存在思维障碍、错乱行为(disorganized behavior)或情感冷淡。妄想可以是迫害和/或夸大的,但除了这些之外,还可以存在其它主题如嫉妒、宗教性或躯体化。
错乱型精神分裂症的特征可以在于其中思维障碍和情感冷淡一起存在。
紧张型精神分裂症的特征可以在于其中受试者可以几乎不动或表现出激动的无目的运动。症状可以包括紧张性木僵和蜡样屈曲。
未分化型精神分裂症的特征可以在于其中存在精神病性症状,但尚未满足偏执型、错乱型或紧张型的准则。
残余型精神分裂症的特征可以在于其中阳性症状仅以低强度存在。
精神分裂症后抑郁症的特征可以在于其中在精神分裂症疾患之后出现抑郁发作,其中一些低水平的精神分裂症症状可能仍然存在。
单纯型精神分裂症的特征可以在于显著阴性症状的隐袭的和进行性的发展,且没有精神病发作史。
在一些实施方案中,提供了用于治疗可以存在于其它精神障碍中的精神病性症状的方法,所述其它精神障碍包括但不限于双相型障碍、边缘型人格障碍、药物中毒和药物诱发的精神病。
在另一实施方案中,提供了用于治疗可以存在于例如妄想性障碍中的妄想(例如,“非古怪型”)的方法。
还提供了用于治疗包括但不限于社交焦虑症、回避型人格障碍和精神分裂型人格障碍的病状中的回避社交的方法。
另外,提供了用于治疗强迫性障碍(OCD)的方法。
本文还提供了调节细胞中孤独症靶基因表达的方法,其包括使细胞与本文所述的组合,例如有效量的GLYX-13和一种或多种NMDAR拮抗剂接触。孤独症基因表达可以例如选自ABAT、APOE、CHRNA4、GABRA5、GFAP、GRIN2A、PDYN和PENK。在另一实施方案中,提供了调节患有突触可塑性相关障碍的患者的突触可塑性的方法,其包括施用本文所述的组合,例如有效量的GLYX-13和一种或多种NMDAR拮抗剂。
在另一实施方案中,提供了治疗有此需要的患者的阿尔茨海默氏病或例如治疗例如伴随早期阿尔茨海默氏病的记忆丧失的方法,其包括施用本文所述的组合,例如有效量的GLYX-13和一种或多种NMDAR拮抗剂。本文还提供了在体外或体内(例如,在细胞中)调节阿尔茨海默氏淀粉样蛋白质(例如,β淀粉样肽,例如同种型Aβ1-42)的方法,其包括使所述蛋白质与本文所述的组合,例如有效量的GLYX-13和一种或多种NMDAR拮抗剂接触。例如,在一些实施方案中,GLYX-13或另一种公开的化合物可以阻断此类淀粉样蛋白质抑制海马脑片中的长时程增强以及凋亡性神经元细胞死亡的能力。在一些实施方案中,所公开的化合物(例如GLYX-13)可以向有需要的阿尔茨海默氏病患者提供神经保护性质,例如,可以对晚期阿尔茨海默氏病相关的神经元细胞死亡提供治疗作用。
在一些实施方案中,患者是人,例如人儿科患者。
本公开涵盖“组合疗法”,其包括(但不限于)共同施用有效量的GLYX-13和一种或多种NMDAR拮抗剂,作为特定治疗方案的一部分,意在提供来自这些治疗剂的共同作用的有益效果。所述组合的有益效果包括但不限于由治疗剂的组合产生的药代动力学或药效动力学共同作用。这些治疗剂的组合施用通常在限定的时间段(通常是数天、数周、数月或数年,这取决于所选择的组合)内实施。组合疗法意在涵盖以依序方式施用多种治疗剂,即其中在不同的时间施用每种治疗剂,以及以基本上同时的方式施用这些治疗剂或至少两种治疗剂。基本上同时施用可以例如通过向受试者施用具有固定比率的每种治疗剂的单个片剂或胶囊或在用于每种治疗剂的多个单一胶囊中实现。每种治疗剂的依序或基本上同时施用可以通过任何适当的途径来实现,所述途径包括但不限于口服途径、静脉内途径、肌肉内途径和通过粘膜组织直接吸收。治疗剂可以通过相同的途径或通过不同的途径施用。例如,所选择的组合的第一治疗剂可以通过静脉内注射施用,而所述组合的其它治疗剂可以口服施用。或者,例如,所有治疗剂可以口服施用或所有治疗剂可以通过静脉内注射施用。
组合疗法还可以涵盖如上所述的治疗剂与其它生物活性成分和非药物疗法进一步组合施用。当组合疗法进一步包括非药物治疗时,非药物治疗可以在任何合适的时间进行,只要实现来自治疗剂和非药物治疗的组合的共同作用的有益效果即可。例如,在适当情况下,当暂时从治疗剂的施用中去除非药物治疗可能达到数天或甚至数周时,仍然实现有益效果。
在一些实施方案中,本文所述组合的一种或多种组分可以经胃肠外向患者施用,包括但不限于皮下和静脉内。在一些实施方案中,本文所述组合的一种或多种组分还可以通过缓慢控制的静脉内输注或通过从植入装置释放来施用。在一些实施方案中,在一次(单次)剂量施用GLYX-13的1小时后、2小时后、4小时后、8小时后、12小时后、1天后、1周后、2天后、3天后、4天后、5天后、6天后,或甚至8天后,患者具有例如认知损伤的实质性改善。
用于疗法所需的所公开化合物的治疗有效量随着所治疗的孤独症病状的性质、期望的治疗时间长度、患者的年龄和状况而变化,并且最终由主治医师确定。然而,一般来说,用于成人治疗的剂量通常在每天约0.01mg/kg至约1000mg/kg(例如,每天约0.01mg/kg至约100mg/kg、每天约0.01mg/kg至约10mg/kg、每天约0.1mg/kg至约100mg/kg、每天约0.1mg/kg至约50mg/kg、每天约0.1mg/kg至约10mg/kg)的本文所述的组合的每种组分的范围。在某些实施方案中,用于成人治疗的GLYX-13的剂量通常在每天约0.01mg/kg至约100mg/kg(例如,每天约0.01mg/kg至约10mg/kg、每天约0.1mg/kg至约100mg/kg、每天约0.1mg/kg至约50mg/kg、每天约0.1mg/kg至约10mg/kg、每天约0.1mg/kg至约1mg/kg)的范围。在某些实施方案中,用于成人治疗的NMDAR拮抗剂的剂量通常在每天约0.01mg/kg至约100mg/kg(例如,每天约0.1mg/kg至约100mg/kg、每天约0.1mg/kg至约50mg/kg、每天约10mg/kg或每天约30mg/kg)的范围。期望的剂量可以方便地以单剂量施用,或作为以适当间隔施用的多次剂量施用,例如作为每天两次、三次、四次或更多次子剂量(sub-dose)施用。
许多因素可以导致本文所述的组合的每种组分在宽剂量范围内施用。当与其它治疗剂组合给予时,本发明化合物的剂量可以以相对较低的剂量给予。在某些实施方案中,GLYX-13的剂量可以是约1ng/kg至约100mg/kg。GLYX-13的剂量可以是任何剂量,包括但不限于约1ug/kg、25ug/kg、50ug/kg、75ug/kg、100u ug/kg、125ug/kg、150ug/kg、175ug/kg、200ug/kg、225ug/kg、250ug/kg、275ug/kg、300ug/kg、325ug/kg、350ug/kg、375ug/kg、400ug/kg、425ug/kg、450ug/kg、475ug/kg、500ug/kg、525ug/kg、550ug/kg、575ug/kg、600ug/kg、625ug/kg、650ug/kg、675ug/kg、700ug/kg、725ug/kg、750ug/kg、775ug/kg、800ug/kg、825ug/kg、850ug/kg、875ug/kg、900ug/kg、925ug/kg、950ug/kg、975ug/kg、1mg/kg、2.5mg/kg、5mg/kg、10mg/kg、15mg/kg、20mg/kg、25mg/kg、30mg/kg、35mg/kg、40mg/kg、45mg/kg、50mg/kg、60mg/kg、70mg/kg、80mg/kg、90mg/kg或100mg/kg。
在一些实施方案中,所公开的化合物,例如GLYX-13,可以以逆转或预防认知损伤的量给药。
所公开的化合物可以作为液体或固体配制物的一部分提供,所述配制物例如水性或油性悬浮液、溶液、乳液、糖浆和/或酏剂。所述组合物还可以被配制成干产品,以供在使用前用水或其它合适的载体构造。此类液体制剂可以含有添加剂,包括但不限于悬浮剂、乳化剂、非水性媒介物和防腐剂。悬浮剂包括但不限于山梨醇糖浆、甲基纤维素、葡萄糖/糖浆、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶和氢化食用脂肪。乳化剂包括但不限于卵磷脂、脱水山梨糖醇单油酸酯和阿拉伯胶。非水性媒介物包括但不限于食用油、杏仁油、分馏的椰子油、油性酯、丙二醇和乙醇。防腐剂包括但不限于羟基苯甲酸甲酯或羟基苯甲酸丙酯和山梨酸。所涵盖的化合物还可以被配制用于肠胃外施用,包括但不限于通过注射或连续输注。注射用配制物可以呈油性或水性媒介物中的悬浮液、溶液或乳液的形式,并且可以含有配制剂,包括但不限于悬浮剂、稳定剂和分散剂。所述组合物还可以以粉末形式提供,以供用合适的媒介物重构,所述媒介物包括但不限于无菌的无热原水(例如,注射用水)。
在一些实施方案中,所公开的化合物,例如GLYX-13,可以作为适于静脉内注射的水性组合物的一部分提供。在某些实施方案中,此类组合物可以包含:(i)60mg/mL至约200mg/mL(例如,约125mg/mL至约175mg/mL;例如,约150mg/mL或约75mg/mL)的具有下式的药物活性化合物:
或其药学上可接受的盐;(ii)水(例如,注射用水);和(iii)酸;其中稳定的水性组合物在25℃下具有约3.9至约5.5(例如,约4.0至约5.0、约4.2至约5.0、约4.1至约4.7、约4.2至约4.8、约4.0、约4.5)的pH。在某些实施方案中,此类组合物可以被布置在容器(例如,预填充的注射器或小瓶)内,其中所述化合物的量可作为至少一个单剂量推断。在某些实施方案中,单剂量可以具有约1mL至约4mL(例如,3mL)的体积。
在某些实施方案中,水性组合物可以包含约200mg至约500mg(例如,约450mg;约375mg或约225mg)的药物活性化合物。
在某些实施方案中,酸可以选自由以下组成的组:富马酸、苹果酸、乳酸、盐酸、氢溴酸、乙酸、柠檬酸、磷酸、硝酸、硫酸和抗坏血酸。在某些实施方案中,酸提供水性组合物中的氯离子(例如,盐酸)。
在某些实施方案中,在向患者施用一定剂量的包含约150mg/mL药物活性化合物并且具有约3mL的体积的水性液体组合物后,在该患者中获得约800mOsmol/kg至约900mOsmol/kg的生理渗透压。在其它实施方案中,在向患者施用一定剂量的包含约75mg/mL药物活性化合物并且具有约3mL的体积的稳定的水性液体组合物后,在该患者中获得约375mOsmol/kg至约475mOsmol/kg的生理渗透压。
实施例
小鼠中的新物体识别试验(“NOR”)测试改编自(Hashimoto K,Fujita Y,ShimizuE,Iyo M(2005).Phencyclidine-induced cognitive deficits in mice are improvedby subsequent subchronic administration of clozapine,but nothaloperidol.European journal of pharmacology519(1-2):114-117)。还参见例如Rajagopal等人,Current Pharmaceutical Design 2014,20,1。NOR箱是由Plexiglas制成的开放箱(52cm L;52cm W;31cm H)。我们针对小鼠使用的箱的尺寸与用于大鼠的箱相同。所述箱被放置在地板上方约30cm处。与大鼠NOR研究中的黑色背景相反,所述箱的壁具有白色背景。我们发现,当与黑色背景比较时,C57BL/6小鼠在白色背景中探索得更多。在测试前三天,使小鼠适应于空的NOR场地1小时。小鼠中的NOR测试类似于先前用于研究大鼠NOR的NOR测试,只是获得和保持测试的持续时间为10min,然后是24小时的试验间间隔(ITI),在此期间,使小鼠返回它们的居住笼,而在大鼠中,获得和保持测试的持续时间为3min,间隔1min ITI(Horiguchi M,Meltzer HY(2012).The role of 5-HT1A receptors inphencyclidine(PCP)-induced novel object recognition(NOR)deficit inrats.Psychopharmacology 221(2):205-215)。我们针对获得和保持测试探索比较了3min、5min和10min,并且发现10分钟对于可靠的数据收集是最佳的。两种测试均被记录用于随后的盲法评分。
所有数据均表示为平均值±S.E.M。通过双因素方差分析(ANOVA)来分探索数据。这检测了药物治疗的主要效果、任务的主要效果以及药物治疗与物体探索之间的相互作用。当发现显著效果时,进行通过事后学生t检验的进一步分析以比较探索新物体和熟悉物体所耗费的时间。主要端点是辨别指数(DI)。当通过ANOVA检测到显著效果时,使用单因素ANOVA,随后使用Bonferroni检验分析DI(新-熟悉/新+熟悉)数据。
图2中的数据证实GLYX-13(1mg/kg,静脉内)逆转在小鼠中新物体识别中慢性氯胺酮诱导的损伤。图3中的数据证实GLYX-13(1mg/kg,静脉内)逆转在小鼠中新物体识别中慢性苯环利定诱导的损伤。图4显示在躯体感觉皮质中用3mpk和30mpk的GLYX-13、随后用氯胺酮预处理的显著减毒。图5中的数据证实GLYX-13(3mg/kg,静脉内)预处理逆转在小鼠中新物体识别中急性氯胺酮(10mg/kg,皮下)诱导的损伤。图6中的数据证实GLYX-13(3mg/kg,静脉内)抑制在大鼠中氯胺酮(10mg/kg,静脉内)诱导的刻板性。
本领域技术人员仅使用常规实验即可识别或能够确定本文所述的本发明具体实施方案的许多等同物。所述等同物意在被所附权利要求涵盖。
本文引用的所有专利、公开的专利申请、网站和其它参考文献的全部内容在此通过引用整体明确并入本文。
Claims (47)
1.一种基本上逆转或预防急性施用NMDAR拮抗剂的患者的认知损伤的方法,其包括施用有效量的GLYX-13。
2.根据权利要求1所述的方法,其中所述施用有效量的GLYX-13在急性施用所述NMDAR拮抗剂之前发生。
3.根据权利要求1所述的方法,其中所述施用有效量的GLYX-13在急性施用所述NMDAR拮抗剂之后发生。
4.根据权利要求1所述的方法,其中所述施用有效量的GLYX-13基本上与急性施用所述NMDAR拮抗剂同时发生。
5.一种治疗有需要的患者的认知损伤障碍的方法,其包括施用GLYX-13和NMDAR拮抗剂。
6.根据权利要求5所述的方法,其中所述认知损伤障碍归因于以下中的一种或多种:认知能力的缺陷、先天性缺陷、环境因素或药物诱导。
7.根据权利要求5所述的方法,其中所述认知损伤障碍是学习障碍和/或诵读困难。
8.一种治疗神经性障碍或其它障碍的方法,其包括施用GLYX-13和NMDAR拮抗剂。
9.根据权利要求8所述的方法,其中所述障碍选自由以下组成的组:中风、精神病性障碍、疼痛(神经性疼痛)、抑郁症(重性抑郁症)、帕金森氏病和阿尔茨海默氏病。
10.一种治疗有需要的患者的中枢神经系统疾病的方法,其包括施用GLYX-13和NMDAR拮抗剂。
11.根据权利要求10所述的方法,其中所述中枢神经系统疾病选自由以下组成的组:神经变性疾病、中风、创伤性脑损伤和脊髓损伤。
12.一种治疗有需要的患者的精神分裂症的方法,其包括施用GLYX-13和NMDAR拮抗剂。
13.一种治疗有需要的患者的抑郁症的方法,其包括施用GLYX-13和NMDAR拮抗剂。
14.根据权利要求13所述的方法,其中所述抑郁症是难治性抑郁症。
15.根据权利要求5-14中任一项所述的方法,其中基本上同时施用所述GLYX-13和所述NMDAR拮抗剂。
16.根据权利要求5-14中任一项所述的方法,其中依序施用所述GLYX-13和所述NMDAR拮抗剂。
17.根据权利要求16所述的方法,其中在所述NMDAR拮抗剂之前施用所述GLYX-13。
18.根据权利要求16所述的方法,其中在所述NMDAR拮抗剂之后施用所述GLYX-13。
19.一种药学上可接受的组合物,其包含GLYX-13和NMDAR拮抗剂。
20.根据权利要求1-18中任一项所述的方法或根据权利要求19所述的药物组合物,其中所述NMDAR拮抗剂具有式(I):
其中:
R1是苯基、噻吩基或苯并噻吩基,其每一个任选地被1-3个独立地选自由以下组成的组的取代基取代:卤代;-OH;NRaRb,其中Ra和Rb中的每一个独立地选自H和C1-C3烷基;C1-C3烷基;和C1-C3烷氧基;
R2是-NRcRd,其中Rc和Rd中的每一个独立地选自H和C1-C6烷基,所述C1-C6烷基任选地被-OH或C1-C3烷氧基取代;或Rc和Rd连同各自所连接的氮原子一起形成任选地被1-2个独立地选择的C1-C3烷基取代的5-7元环;并且
R3是H、氧代或C1-C3烷基;
或其药学上可接受的盐或前药。
21.根据权利要求20所述的方法,其中R1是苯基,其任选地被1-3个独立地选自由以下组成的组的取代基取代:卤代;-OH;NRaRb,其中Ra和Rb中的每一个独立地选自H和C1-C3烷基;C1-C3烷基;和C1-C3烷氧基。
22.根据权利要求21所述的方法,其中R1是苯基、3-羟基苯基、3-甲氧基苯基、3-氨基苯基、3-甲基苯基、4-氟苯基、4-羟基苯基、3-甲氧基苯基或2-氯苯基。
23.根据权利要求20所述的方法,其中R2是-NH(C1-C3烷基)或哌啶基。
24.根据权利要求20所述的方法,其中R3是H或氧代。
25.根据权利要求20所述的方法,其中R1是苯基,R2是哌啶基,并且R3是H。
26.根据权利要求20所述的方法,其中R1是2-氯苯基,R2是-NH(CH3),并且R3是氧代。
27.根据权利要求1-18中任一项所述的方法或根据权利要求19所述的药物组合物,其中所述NMDAR拮抗剂选自由以下组成的组:氯胺酮、美金刚、拉尼西明(AZD6765)、CERC-301、右美沙芬、右啡烷、苯环利定、地佐环平(MK-801)、金刚烷胺、艾芬地尔、AV-101、AZD6423和利鲁唑,或其药学上可接受的盐或前药。
28.根据权利要求27所述的方法,其中所述NMDAR拮抗剂是氯胺酮。
29.根据权利要求28所述的方法,其中所述NMDAR拮抗剂是(S)-氯胺酮。
30.根据权利要求27所述的方法,其中所述NMDAR拮抗剂是苯环利定。
31.根据权利要求27所述的方法,其中所述NMDAR拮抗剂是美金刚或金刚烷胺。
32.根据权利要求27所述的方法,其中所述NMDAR拮抗剂是地佐环平(MK-801)。
33.根据权利要求27所述的方法,其中所述NMDAR拮抗剂是右美沙芬或右啡烷。
34.根据权利要求27所述的方法,其中所述NMDAR拮抗剂是拉尼西明(AZD6765)、CERC-301、AV-101、AZD 6423或艾芬地尔。
35.根据权利要求1-18中任一项的所述方法或根据权利要求19所述的药物组合物,其中所述NMDAR拮抗剂选自由以下组成的组:一氧化二氮、托莫西汀、dextrallorphan、diphenidine、乙环利定、加环利定、伊波加因、methoxetamine、硝基美金刚、咯环利定、替诺环定、methoxydine、替来他明、奈拉美生、依利罗地、乙苯噁啶、右奥沙屈、美沙酮、WMS-2539、NEFA、瑞马西胺、德芦西明、8A-PDHQ、阿替加奈(Cerestat,CNS-1102)、HU-211、瑞马西胺、钩藤碱、TK-40、曲索罗地(CP-101,606)、1-氨基环丙烷羧酸(ACPC)、犬尿喹啉酸或其衍生物、2-羧基四氢喹啉或其衍生物、2-羧基吲哚或其衍生物、4-羟基-2-喹啉或其衍生物、4-羟基喹啉或其衍生物、喹喔啉-2,3-二酮或其衍生物、三环拮抗剂、拉考沙胺、L-苯丙氨酸、米达福太和阿替加奈,或其药学上可接受的盐或前药。
36.根据权利要求35所述的方法,其中所述NMDAR拮抗剂是2-羧基四氢喹啉或其衍生物。
37.根据权利要求36所述的方法,其中所述NMDAR拮抗剂选自由以下组成的组:
或其药学上可接受的盐或前药。
38.根据权利要求35所述的方法,其中所述NMDAR拮抗剂是2-羧基吲哚或其衍生物。
39.根据权利要求38所述的方法,其中所述NMDAR拮抗剂选自由以下组成的组:
或其药学上可接受的盐或前药。
40.根据权利要求35所述的方法,其中所述NMDAR拮抗剂是犬尿喹啉酸或其衍生物。
41.根据权利要求40所述的方法,其中所述NMDAR拮抗剂选自由以下组成的组:
或其药学上可接受的盐或前药。
42.根据权利要求35所述的方法,其中所述NMDAR拮抗剂是4-羟基喹啉或其衍生物。
43.根据权利要求42所述的方法,其中所述NMDAR拮抗剂选自由以下组成的组:
或其药学上可接受的盐或前药。
44.根据权利要求35所述的方法,其中所述NMDAR拮抗剂是喹噁啉-2,3-二酮或其衍生物。
45.根据权利要求44所述的方法,其中所述NMDAR拮抗剂选自由以下组成的组:
或其药学上可接受的盐或前药。
46.根据权利要求35所述的方法,其中所述NMDAR拮抗剂是三环拮抗剂。
47.根据权利要求46所述的方法,其中所述NMDAR拮抗剂选自由以下组成的组:
或其药学上可接受的盐或前药。
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CN107550907A (zh) * | 2017-08-29 | 2018-01-09 | 昆明医科大学 | 治疗精神分裂症的药物及验证药物的动物模型构建方法 |
WO2020088270A1 (zh) * | 2018-10-29 | 2020-05-07 | 中国药科大学 | 犬尿喹啉酸或其衍生物在制备改善慢性精神应激相关病理损伤药物中的应用 |
CN111670041A (zh) * | 2017-12-05 | 2020-09-15 | 诺雷克斯股份有限公司 | 用在组合疗法(睡眠障碍或中枢神经系统障碍)中的nmda受体调节剂(拉帕斯汀)组合 |
CN113234036A (zh) * | 2021-05-12 | 2021-08-10 | 中国科学院上海有机化学研究所 | Nmda受体拮抗剂及其用途 |
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CA2957898C (en) | 2014-09-15 | 2023-02-21 | Rugen Holdings (Cayman) Limited | Pyrrolopyrimidine derivatives as nr2b nmda receptor antagonists |
US20180271869A1 (en) * | 2014-09-22 | 2018-09-27 | Jie Liu | Treatment of anxiety disorders and autism spectrum disorders |
US10221182B2 (en) | 2015-02-04 | 2019-03-05 | Rugen Holdings (Cayman) Limited | 3,3-difluoro-piperidine derivatives as NR2B NMDA receptor antagonists |
JP6876625B2 (ja) | 2015-06-01 | 2021-05-26 | リューゲン ホールディングス (ケイマン) リミテッド | Nr2bnmdaレセプターアンタゴニストとしての3,3−ジフルオロピペリジンカルバメート複素環式化合物 |
EP3362067A4 (en) * | 2015-10-16 | 2019-07-17 | Impact Biosciences Corp. | METHOD AND COMPOSITIONS FOR TREATING TRAUMATIC BRAIN DAMAGE |
US20180325893A1 (en) * | 2015-10-16 | 2018-11-15 | Northwestern University | Subacute administration of nmda modulators alone or in combination |
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WO2018098128A1 (en) | 2016-11-22 | 2018-05-31 | Rugen Holdings (Cayman) Limited | Treatment of autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders |
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KR20230056971A (ko) * | 2021-10-21 | 2023-04-28 | 삼육대학교산학협력단 | 신규 케타민 유도체를 포함하는 우울증 예방 또는 치료용 약학적 조성물 |
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- 2015-05-06 US US15/309,390 patent/US20170072005A1/en not_active Abandoned
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CN107550907A (zh) * | 2017-08-29 | 2018-01-09 | 昆明医科大学 | 治疗精神分裂症的药物及验证药物的动物模型构建方法 |
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CN113234036A (zh) * | 2021-05-12 | 2021-08-10 | 中国科学院上海有机化学研究所 | Nmda受体拮抗剂及其用途 |
WO2022237849A1 (zh) * | 2021-05-12 | 2022-11-17 | 中国科学院上海有机化学研究所 | Nmda受体拮抗剂及其用途 |
Also Published As
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AU2015256075A1 (en) | 2016-11-24 |
JP2022159322A (ja) | 2022-10-17 |
KR20170013890A (ko) | 2017-02-07 |
MX2016014581A (es) | 2018-02-16 |
RU2016146714A (ru) | 2018-06-06 |
CA2947976A1 (en) | 2015-11-12 |
BR112016025910A8 (pt) | 2021-07-13 |
KR20220102662A (ko) | 2022-07-20 |
JP2020138973A (ja) | 2020-09-03 |
EP3139943A4 (en) | 2018-07-18 |
JP2017514871A (ja) | 2017-06-08 |
WO2015171770A1 (en) | 2015-11-12 |
BR112016025910A2 (pt) | 2017-08-15 |
RU2721948C2 (ru) | 2020-05-25 |
RU2016146714A3 (zh) | 2018-10-08 |
AU2015256075B2 (en) | 2021-02-25 |
US20170072005A1 (en) | 2017-03-16 |
EP3139943A1 (en) | 2017-03-15 |
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