CN1230174C - 治疗偏头痛的选择性iGluR5受体拮抗剂 - Google Patents
治疗偏头痛的选择性iGluR5受体拮抗剂 Download PDFInfo
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Abstract
本发明提供一种治疗或预防偏头痛的方法,包括对需此治疗的患者施用有效量的选择性iGluR5受体拮抗剂。本发明还提供用作选择性iGluR5受体拮抗剂的新化合物以及含有所述选择性iGluR5受体拮抗剂的组合物和制剂。
Description
发明背景
在哺乳动物的中枢神经系统(CNS)中,通过传送神经元释放的神经递质与接收神经元上的表面受体之间的相互作用调控神经冲动的传递,这种相互作用导致该接收神经元兴奋。在哺乳动物中,CNS中含量最高的神经递质-L-谷氨酸介导主要的兴奋性途径,因此被称为兴奋性氨基酸(EAA)。响应于谷氨酸的受体被称为兴奋性氨基酸受体(EAA受体)。参见Wakins & Evans,Ann.Rev.Pharmacol.Toxicol.,21,165(1981);Monaghan,Bridges和Cotman,Ann.Rev.Pharmacol.Toxicol.,29,365(1989);Watkins,Krogsgaard-Larsen和Honore,Trans.Pharm.Sci.,11,25(1990)。兴奋性氨基酸具有非常重要的生理学意义,它们在多种生理过程中起着作用,例如长期强化(学习和记忆)、突触塑性的发育、运动调节、呼吸、心血管调节和感知过程。
兴奋性氨基酸受体可划分为两大类。直接与神经元细胞膜中的开放性阳离子通道结合的受体被称为“离子移变性”受体。以选择性激动剂N-甲基-D-天冬氨酸(NMDA)、α-氨基-3-羟基-5-甲基异噁唑-4-丙酸(AMPA)和红藻氨酸(KA)的去极化作用来定义,该类受体可细分为至少三种亚型。分子生物学研究表明AMPA受体包括亚组(GluR1-GluR4),它们可装配成功能性离子通道。五种红藻氨酸受体已被鉴定,它们可分为高亲和性(KA1和KA2)或低亲和性(GluR5、GluR6和GluR7)两类。Bleakman等,Molecular Pharmacology,49,No.4,581(1996)。
第二大类受体是G-蛋白质或第二信使连接的“metabotropic”兴奋性氨基酸受体。这第二大类受体与多个第二信使系统结合,结果导致促进磷酸肌醇水解、磷脂酶D的活化、cAMP形成的增加或减少以及离子通道功能改变。Schoepp和Conn,Trends in Pharmacol.Sci.,14,13(1993)。这两类受体不仅介导正常突触沿兴奋性途径的传递,还与发育和整个生命过程的突触连接的改变有关。Schoepp,Bockaert和Sladeczek,Trends in Pharmacol.Sci.,11,508(1990);McDonald和Johnson,Brain Research Reviews,15,41(1990)。
过度或不适当地刺激兴奋性氨基酸受体会以已知称为兴奋毒性的机制方式致神经元细胞损伤或损失。据认为,该过程在多种神经病和神经病症中介导神经元变性。这种神经元变性的医学后果使得这些变性神经病的缓解具有重要的治疗意义。
兴奋性氨基酸的兴奋毒性与许多神经病的病理生理学有关。例如,兴奋毒性与心脏旁路手术和移植后脑缺血或缺氧(cerebraldeficit)、中风、脑缺血、创伤或炎症导致的脊髓损害、围产期缺氧、心脏停搏和降糖药性神经元损伤的病因学有关。此外,兴奋毒性还与慢性神经变性疾病,包括阿尔茨海默氏病、杭廷顿氏舞蹈病、遗传性共济失调、AIDS-引发的痴呆、肌萎缩性侧索硬化、特发症和药物引发的帕金森氏病以及眼部损伤和视网膜病。与兴奋毒性和/或谷氨酸机能障碍有关的其它神经病包括肌肉痉挛状态(包括震颤)、药物耐受和戒除、脑缺血、惊厥性病症(包括癫痫)、抑郁、焦虑和与焦虑有关的病症(例如创伤后紧张综合症)、迟缓型运动障碍、与抑郁有关的精神病、精神分裂症、两极神经障碍、躁狂症以及药物中毒或成瘾。另外,据报道兴奋性氨基酸的兴奋毒性与急慢性疼痛,包括严重疼痛、顽固性疼痛、神经病性疼痛和创伤后疼痛的病因有关。
据信,神经保护性药物,例如兴奋性氨基酸受体拮抗剂可用于治疗或预防这些病症和/或降低与这些病症有关的神经病性损伤的程度。兴奋性氨基酸受体拮抗剂还可用作镇痛剂。
由Graham和Wolff研究得出的有关偏头痛病生理学的早期理论(Arch.Neurol.Psychiatry,39,737-63(1938))自1938年至今一直占主导地位。他们认为偏头痛的原因是颅外血管舒张。对于麦角生物碱和舒马坦收缩颅内血管平滑肌并且可有效治疗偏头痛的认识支持了这种观点。舒马坦是一种亲水性5-HT1类受体激动剂并且不穿过血脑屏障(Humphrey等,Ann.NYAcad.Sci.,600,587600(1990))。因此,据述已开发数类可用于治疗偏头痛的化合物以优化舒马坦的5-HT1类受体介导的血管收缩活性。然而,舒马坦的禁忌症,包括冠状动脉血管痉挛、高血压和绞痛也都是血管收缩活性的产物(MacIntyre,P.D.等,British Journal of Clinical Pharmacology,34,541-546(1992);Chester,A.H.等,Cardiovascular Research,24,932-937(1990);Conner,H.E.等,European Journal ofPharmacology,161,91-94(1990)).
虽然偏头痛的血管性机理为人们广泛接受,但其正确性尚未被完全认同。例如,Moskowitz已经表明偏头痛的发生与血管的直径变化无关(Cephalalgia,12,5-7,(1992))。已知三叉神经的神经节及其相关性神经途径与面部,例如头部的疼痛感觉,尤其是偏头痛有关。Moskowitz认为未知性引发因素刺激使头部组织内的脉管系统受神经支配的三叉神经的神经节,导致使脉管系统受神经支配的轴突中血管活性神经肽的释放。这些神经肽引发一系列事件,导致脑脊膜的神经性炎症,其结果是疼痛。与治疗急性人偏头痛所需的相似剂量的舒马坦阻断这种神经性炎症。然而,如上所述,这种剂量的舒马坦与伴随舒马坦的血管收缩特性的禁忌症有关(见上)。
5-HT1D受体参与介导神经性蛋白质溢出的阻断(Neurology,43(suppl.3),S16-S20(1993))。此外,据报道,α2、H3、鸦片样物质和生长抑素受体也位于三叉神经血管纤维上,可阻断神经性血浆溢出(Matsubara等,Eur.J.Phannacol.,224,145-150(1992))。Weinshank等报道说舒马坦和数种麦角生物碱对血清素5-HT1F受体具有高度亲和性,因此认为他们对偏头痛中的5-HTlF受体具有作用(WO93/14201)。
欧洲专利申请590789A1以及美国专利US 5446051和5670516公开了某些十氢异喹啉衍生物化合物是AMPA受体拮抗剂,因此可用于治疗许多病症,包括疼痛和偏头痛。
最近,据报道,所有的五种红藻氨酸亚型受体、离子移变性谷氨酸受体都在大鼠的三叉神经的神经节上表达。特别是观察到了GluR5和KA2的高水平表达(Sahara等,The Journal of Neuroscience,17(17),6611(1997))。Simmons等报道,在持续疼痛的大鼠模型中,红藻氨酸GluR5受体亚型介导对福尔马林的伤害感受反应(Neuropharmacology,37,25(1998)。此外,WO 98/45270早先公开了对iGluR5受体具有选择性的拮抗剂可用于治疗疼痛,包括严重疼痛、慢性疼痛、顽固性疼痛和神经病性疼痛。值得注意的是,先前认为红藻氨酸受体与偏头痛的病因学无关的观察。特别是,以前没有选择性iGluR5受体拮抗剂可用于治疗偏头痛的报道。
出人意料地是,依据本发明,发明者发现iGluR5受体亚型的选择性拮抗剂在神经性炎症的动物模型中有效,因此可用于治疗偏头痛。这类拮抗剂可以满足对安全有效偏头痛药物的长久需求,而不具有伴随的副作用。另外还可治疗神经病病症。
发明概述
本发明提供一种治疗或预防偏头痛的方法,包括对需此治疗的患者施用有效量的选择性iGluR5受体拮抗剂或其可药用盐。
更具体地说,本发明提供一种治疗或预防硬脑膜蛋白质溢出的方法,包括对需此治疗的患者施用有效量的选择性iGluR5受体拮抗剂。
此外,本发明提供一种治疗或预防偏头痛的方法,包括向需此治疗的患者施用有效量的化合物或者联合给药的化合物,所述化合物具有选择性iGluR5受体拮抗剂的活性。
在另一实施方案中,本发明提供一种治疗或预防神经病或者神经变性疾病的方法,包括向需此治疗的患者施用治疗有效量的选择性iGluR5受体拮抗剂或其可药用盐。这类神经病或神经变性疾病的实例包括:心脏旁路手术和移植后脑缺乏、中风、脑缺血、创伤或炎症导致的脊髓损害、围产期缺氧、心脏停搏和降糖药性神经元损伤、阿尔茨海默氏病、杭廷顿氏舞蹈病、遗传性共济失调、AIDS-引发的痴呆、肌萎缩性侧索硬化、特发症和药物引发的帕金森氏病、眼部损伤和视网膜病、肌肉痉挛状态(包括震颤)、药物耐受和戒除、脑缺血、惊厥性病症(包括癫痫)、抑郁、焦虑和与焦虑有关的病症(例如创伤后紧张综合症)、迟缓型运动障碍、与抑郁有关的精神病、精神分裂症、两极神经障碍、躁狂症、药物中毒或成瘾、急性和慢性疼痛(包括严重疼痛、顽固性疼痛、神经病性疼痛和创伤后疼痛)。
另一方面,本发明提供式I化合物或其可药用盐,
其中R1和R2各自独立地是H、C1-C20烷基、C2-C6链烯基、C1-C6烷芳基、C1-C6烷基(C3-C10)环烷基、C1-C6烷基-N,N-C1-C6二烷基氨基、C1-C6烷基-吡咯烷、C1-C6烷基-哌啶或C1-C6烷基-吗啉。
另一方面,本发明提供一种治疗或预防偏头痛的方法,包括向需此治疗的患者施用有效量的式I化合物。
此外,本发明提供用于治疗或预防偏头痛的药物组合物,它含有选择性iGluR5受体拮抗剂与一种或多种可药用载体、稀释剂或赋形剂。
本发明还提供选择性iGluR5受体拮抗剂用于制备治疗或预防偏头痛的药物的用途。
发明详述
本发明提供一种治疗偏头痛的方法,这可以通过特定的作用机制,神经性硬脑膜蛋白质溢出的抑制得到证实.通过用相对于其它兴奋性氨基酸受体具有选择性的iGluR5受体拮抗剂的化合物或组合物治疗偏头痛,介导偏头痛的神经性溢出被抑制,而不具有特地优化舒马坦的5-HT1介导的血管收缩活性的药物伴生的副作用。此外,本发明提供用作选择性iGluR5受体拮抗剂的化合物及其可药用盐、前药和组合物。
本文采用的术语“可药用盐”是指本发明提供或使用的化合物的盐,它们对活的生物体基本上无毒。典型的盐包括通过本发明的化合物与可药用无机酸或有机酸或者有机碱或无机碱反应制备的那些盐。这类盐已知称为酸加成盐或碱加成盐。
本领域技术人员应该清楚,本发明中使用的大多数或所有化合物可形成盐,盐形式的药物是常用的,这通常是因为盐较游离碱更容易结晶和纯化。在所有的情况下,本说明书均包括使用盐形式的本发明药物,并且这种形式通常是优选的,它们的名称中均包括了使用化合物的可药用盐。
常用于形成酸加成盐的酸是无机酸,例如氢氯酸、氢溴酸、氢碘酸、硫酸、磷酸等;有机酸,例如对甲苯磺酸、甲磺酸、草酸、对溴苯磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸、乙酸等。这类可药用盐的实例是硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏鳞酸盐、焦磷酸盐、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、盐酸盐、二盐酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、丁二酸盐、辛二酸盐癸二酸盐、富马酸盐、马来酸盐、丁炔-l,4-酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯代苯甲酸盐、甲基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、二甲苯磺酸盐、苯乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、α-羟基丁酸盐、羟乙酸盐、酒石酸盐、甲磺酸盐、丙烷磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐等。优选的可药用酸加成盐是与无机酸,如氢氯酸和氢溴酸形成的那些盐,以及与有机酸,如马来酸和甲磺酸形成的那些盐。
碱加成盐包括用无机碱得到的盐,例如用铵盐或碱金属或碱土金属的氢氧化物、碳酸盐、碳酸氢盐等。用于制备本发明的盐的碱包括氢氧化钠、氢氧化钾、氢氧化铵、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钙、碳酸钙等。尤其优选形成钾盐和钠盐。
应该认识到,形成本发明的任何盐的抗衡离子一般没有决定性的性质,只要盐在整体上是药理学可接受的并且只要抗衡离子对盐整体不产生不希望得到的性质即可。
本文采用的术语“立体异构体”是指包含由相同的键连接但具有不同三维结构的同一原子的化合物,它们不发生互变。三维结构也称为构型。本文采用的术语“旋光对映体”是指其分子是彼此不可重叠的镜像的两种立体异构体。术语“手性中心”是指四个不同的基团与之相连的碳原子。本文采用的术语“非对映体”是指非旋光对映体的立体异构体。此外,在本文中仅有的一个手性中心具有不同构型的两种非对映体被称为“差向异构体”。术语“外消旋体”、“外消旋混合物”或“外消旋变体”是指等量旋光对映体的混合物。
本文采用的术语“对映体富集”是指提高相对于另一种对映体的对映体的量。表示所得对映体富集的简便方法是对映体过量的概念,或“ee”,它采用下式得出:
其中E1是第一种对映体的量,E2是第二种对映体的量。因此,如果两种对映体的起始比例为50∶50,例如以外消旋混合物形式存在,得到了最终为50∶30的比例的对映体富集,则第一种对映体的ee为25%。但是,如果最终比例为90∶10,则第一种对映体的ee为80%。ee优选高于90%,更优选高于95%,最优选高于99%。由本领域普通技术人员采用标准技术或方法,例如运用手性柱的气相或高效液相色谱很容易测定对映体富集。分离对映体对所需的适合手性柱、洗脱剂和条件的选择均是本领域普通技术人员熟知的知识。此外,式I化合物的对映体可由本领域普通技术人员采用本领域公知的标准技术,例如J.Jacques等在《对映体、外消旋体及拆分》(Enantiomers,Racemates,and Resolutions),John Wiley and Sons,Inc.,1981中描述的那些技术进行拆分。
本发明的化合物具有一个或多个手性中心,可以多种立体异构体构型存在。这些手性中心存在的结果是,本发明的化合物可形成外消旋体、对映体混合物和对映体单体以及非对映体和非对映体的混合物。所有这些外消旋体、对映体和非对映体均在本发明的范围之内。
如有机化学中常用的那样,本文采用的术语“R”和“S”是指手性中心的特定构型。术语“R”(右旋)是指当沿着指向最低优先次序基团的键观察时,具有顺时针方向关系基团优先次序(highest tosecond lowest)的手性中心的构型。术语“S”(左旋)是指当沿着指向最低优先次序基团的键观察时,具有逆时针方向关系基团优先次序的手性中心的构型。基团的优先次序基于它们的原子数量(以下降的原子数量为序)。《有机化合物的命名:原则和实践》(Nomenclatureof Organic Compounds:Principles and Practice,J.H.Fletcher等编辑,1974)的103-120页包括优先次序的部分排列和立体化学讨论。
式(I)化合物的特定立体异构体和对映体可由本领域普通专业技术人员采用公知技术和方法进行制备,例如Eliel和Wilen在《有机化合物的立体化学》(Stereochemistry of Organic Compounds),John Wiley & Sons,Inc.,1994,第7章,“立体异构体的分离、拆分和外消旋化”,以及Collet和Wilen在《对映体、外消旋体和拆分》(Enantiomers,Racemates,and Resolutions),John Wiley& Sons,Inc.,1981中公开的方法。例如,特定的立体异构体和对映体可使用对映体纯或几何异构体纯或者富含异构体或者几何异构体的原料通过立体特异性合成来制备。另外,对使用相应试剂形成的加成盐通过例如手性固定相色谱、酶拆分或分级重结晶技术也可制备特定的立体异构体和对映体。
本领域普通技术人员应该理解,用于本发明方法的所有化合物可以前药制剂形式利用。本文的“前药”是指本发明提供的或本发明方法中使用的功能酸化合物(药物)的容易代谢的酯或二酯衍生物。当施用于患者时,前药进行酶解和/或化学水解,由此释放出母体羧酸(药物)或者母体二羧酸。在所有情况下,均包括使用前药形式的本文所述化合物,并且这种形式通常是优选的,因此本文的化合物名称均包括使用的所有化合物的前药。
本文采用的术语“C1-C4烷基”是指1-4个碳原子的直链或支链的、一价饱和脂族链,包括,但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基等。
本文采用的术语“C1-C6烷基”是指1-6个碳原子的直链或支链的一价饱和脂族链,包括,但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、正己基等。
本文采用的术语“C1-C10烷基”是指1-10个碳原子的直链或支链的一价饱和脂族链,包括,但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、戊基、异戊基、己基、2,3-二甲基-2-丁基、庚基、2,2-二甲基-3-戊基、2-甲基-2-己基、辛基、4-甲基-3-庚基等。
本文采用的术语“C1-C20烷基”是指1-20个碳原子的直链或支链的一价饱和脂族链,包括,但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、己基、3-甲基戊基、2-乙基丁基、正庚基、正辛基、正壬基、正癸基、正十一烷基、月桂基、正十三烷基、正十四烷基、正十五烷基、正十六烷基、正十七烷基、正十九烷基、正二十烷基等。
本文采用的术语“Me”、“Et”、“Pr”、“iPr”、“Bu”和“t-Bu”分别指甲基、乙基、丙基、异丙基、丁基和叔丁基。
本文采用的术语“C2-C6链烯基”是指具有二至六个碳原子的直链或支链的、一价不饱和脂族链。典型的C2-C6链烯基包括乙烯基、1-甲基乙烯基、1-甲基-1-丙烯基、1-丁烯基、1-己烯基、2-甲基-2-丙烯基、1-丙烯基、2-丙烯基、2-丁烯基、2-戊烯基等。
本文采用的术语“芳基”是指含有一个或多个稠合或非稠合的苯环的一价碳环基团,包括,例如苯基1-或2-萘基、1,2-二氢萘基、1,2,3,4-四氢萘基等。
本文采用的术语“C1-C6烷芳基”是指有一个芳基与之相连的1-6个碳原子的直链或支链的、一价的饱和脂族链。术语“C1-C6烷芳基”包括下列基团:
等。
本文采用的术语“(C3-C10)环烷基”是指含有3-10个碳原子的饱和烃环结构。代表性的C3-C10环烷基包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。应该清楚,“(C3-C10)环烷基”包括“(C3-C8)环烷基”和“(C4-C6)环烷基”。
本文采用的术语“C1-C6烷基(C3-C10)环烷基”是指有(C3-C10)环烷基与之相连的1-6个碳原子的直链或支链的、一价饱和脂族链。术语“C1-C6烷基(C3-C10)环烷基”包括下列基团:
等。
本文采用的术语“N,N-C1-C6二烷基胺”是指被两个1-6个碳原子的直链或支链的一价饱和脂族链取代的氮原子。术语“N,N-C1-C6二烷基胺”包括-N(CH3)2、-N(CH2CH3)2、-N(CH2CH2CH3)2、-N(CH2CH2CH2CH3)2等。
本文采用的术语“C1-C6烷基-N,N-C1-C6二烷基胺”是指有N,N-C1-C6二烷基胺与之相连的1-6个碳原子的直链或支链的一价饱和脂族链。术语“C1-C6烷基-N,N-C1-C6二烷基胺”包括下列基团:
等。
本文采用的术语“C1-C6烷基-吡咯烷”是指有吡咯烷与之相连的1-6个碳原子的直链或支链的一价饱和脂族链。“C1-C6烷基-吡咯烷”包括下列基团:
等。
本文采用的术语“C1-C6烷基-哌啶”是指有哌啶与之相连的1-6个碳原子的直链或支链的一价饱和脂族链。“C1-C6烷基-哌啶”包括下列基团:
等。
本文采用的术语“C1-C6烷基-吗啉”是指有吗啉与之相连的1-6个碳原子的直链或支链的一价饱和脂族链。“C1-C6烷基-吗啉”包括下列基团:
等。
本文采用的术语“iGluR5”是指兴奋性氨基酸受体类的红藻氨酸离子移变性谷氨酸受体的第5亚型。
本文采用的术语“偏头痛”是指一种以下列症状复发为特征的神经系统障碍:头痛(不是由于脑结构异常,如由肿瘤或中风引起的)、胃肠道失调和可能有关的神经病症状,例如视觉失真。偏头痛的特征性头痛通常持续一天并且还经常伴随恶心、呕吐和畏光。
偏头痛是一种“慢性”病。本文中术语“慢性”是指缓慢发展和长期续存的病症。因此,在慢性病被确诊时应进行治疗并且这种治疗持续整个疾病过程。
相反,术语“急性”是指短时的剧烈症状或发作,随后是缓和期。因此,认为偏头痛的治疗包括急性病情和慢性病症。在急性病情中,在症状开始时施用化合物,当症状消失时则中止化合物的施用。如上所述,慢性病的治疗持续疾病的整个过程。
本文采用的术语“患者”是指哺乳动物,例如小鼠、沙土鼠、豚鼠、大鼠、狗和人。应该清楚,优选的患者是人。
本文采用的术语“选择性iGluR5受体拮抗剂”应理解为包括那些兴奋性氨基酸受体拮抗剂,它们相对于iGluR2 AMPA受体亚型而言选择性地与iGluR5红藻氨酸受体亚型结合。用于本发明方法的选择性iGluR5拮抗剂对于iGluR5的结合亲和性比对于iGluR2的结合亲和性高至少10倍,更优选高至少100倍。如本领域普通专业技术人员所知,本发明包括任何选择性iGluR5受体拮抗剂。这类选择性iGluR5受体拮抗剂很容易得到,或者很容易由本领域普通技术人员按照下面认知的方法制备。选择性iGluR5受体拮抗剂的实例包括,但不限于WO 98/45270中提供的化合物,该文献的全部内容并入本文以供参考。
还应该清楚选择性iGluR5受体拮抗剂可以以可药用盐的形式存在,因此本发明包括这类盐。
本文采用的术语“治疗”是指缓解所说病症的暂时性或持续性的症状、消除产生症状的原因,以及预防、减缓症状的出现或者逆转其发展或降低其严重程度。因此,本发明的方法包括治疗性和预防性给药。
本文采用的术语“有效量”是指在对患者单次或多次给药时化合物的量或剂量,该量的化合物对确诊或治疗的患者提供所需的作用。
有效量很容易由本领域的专业技术人员-参与诊断的医师利用已知技术并通过在类似情况下获得的观察结果来确定。在确定给药化合物的有效量或剂量中,参与诊断的医师应考虑多种因素,包括,但不限于哺乳动物的种类;其大小、年龄和健康状况;相关程度或有关偏头痛的严重程度;个体患者的反应;给药的特定化合物;给药方式;给药制剂的生物利用度性质;选择的剂量方案;同时使用的药物;和其它有关情况。
本发明治疗方法中使用的各种化合物的典型每日剂量为约0.01mg/kg-约100mg/kg。每日剂量优选为约0.05mg/kg-约50mg/kg,更优选为约0.1mg/kg-约25mg/kg。
根据本发明方法使用的选择性iGluR5拮抗剂可以是一种化合物或者可用作选择性iGluR5受体拮抗剂的多种化合物的联合形式。例如,可以是可用作选择性iGluR5受体拮抗剂的化合物与一种或多种其它谷氨酸受体的联合给药形式,与一种或多种可阻断其与iGluR2受体的作用的化合物的联合形式。但是应该理解,本发明方法中使用的选择性iGluR5拮抗剂优选是一种化合物。
无论是单独给药或者是以可用作选择性iGluR5受体拮抗剂的化合物的联合形式给药,本发明中使用的化合物的优选给药途径都是口服。口服给药不是唯一的给药途径,甚至不是唯一优选的给药途径。其它优选的给药途径包括透皮、皮下、静脉内、肌内、鼻内、颊或直肠内途径。在选择性iGluR5受体拮抗剂以化合物联合给药的情况下,当有特殊需要时,一种化合物可通过一种途径,例如口服给药,另一种化合物可通过透皮、皮下、静脉内、肌内、鼻内、颊或直肠内途径给药。给药途径可以以任何方式发生变化,但应受到化合物的物理性质以及方便患者和护理者的限制。
用于本发明的化合物可以以药物组合物形式给药,因此含有所述化合物的药物组合物是本发明的重要实施方案。这类组合物可以呈任何可药用的物理形式,但口服给药的药物组合物是特别优选的。这类药物组合物含有有效量的选择性iGluR5受体拮抗剂,该有效量与给药化合物的每日剂量有关。每个剂量单位可含有日剂量的给药化合物,或者可含有日剂量几分之一,例如二分之一或三分之一的化合物。每个剂量单位中包含的各种化合物的量取决于选择用于治疗的特定化合物的特性,和其它因素,例如其适用的适应症。本发明的药物组合物可采用公知的方法配制成对患者给药后速释、缓释或者延迟释放活性成分的形式。
组合物优选配制成单位剂量形式,每剂含有约1-约500mg的一种化合物,或者在单次单位剂量形式的情况下,更优选含有约5-约300mg(例如25mg)的一种化合物。术语“单位剂量形式”是指适宜作为患者用单元剂量的物理上的独立单位,各单位含有计算产生所需疗效的预定量的活性物质和适于药用的载体、稀释剂或赋形剂。
药物组合物的惰性成分和配制方式是常规性的。这里可采用制药科学中的一般性配制方法。可采用组合物的所有常见类型,包括片剂、口嚼片、胶囊、溶液、非胃肠溶液、鼻内喷雾剂或粉末、锭剂、栓剂、透皮贴剂和混悬剂。根据所需的剂量和采用的组合物类型,组合物通常含有占总重量约0.5%-约50%的化合物。但是,化合物的量最好定义为“有效量”,即向需此治疗的患者提供所需剂量的各种化合物的量。用于本发明化合物的活性不依赖于组合物的性质,因此仅以方便和经济目的来选择和配制组合物。
胶囊可通过化合物与适合的稀释剂并将该适量混合物填充到胶囊中来制备。常用的稀释剂包括惰性粉末物质,例如淀粉、粉末状纤维素(特别是结晶纤维素和微晶纤维素)、糖类(如果糖、甘露醇和蔗糖)、谷物粉和类似的可食用粉末。
片剂可通过直接压缩、湿法制粒或干法制粒来制备。制剂中通常掺入稀释剂、粘合剂、润滑剂和崩解剂以及化合物。典型的稀释剂包括各类淀粉、乳糖、甘露醇、高岭土、磷酸钙或硫酸钙、无机盐(如氯化钠)和糖粉。也可使用粉末纤维素衍生物。典型的片剂粘合剂是下列物质,例如淀粉、明胶和糖类,如乳糖、果糖、葡萄糖等。天然和合成的树胶也是适用的,包括阿拉伯胶、藻酸盐、甲基纤维素、聚乙烯吡咯烷酮等。聚乙二醇、乙基纤维素和蜡也可用作粘合剂。
片剂经常用作为芳香剂和密封剂的糖进行包衣。在制剂中也可使用大量的口味宜人的物质,如甘露醇,将化合物配制成口嚼片,这是已得到确认的实践。速溶片类剂型也常用于保证患者消费剂型,从而避免了烦扰某些患者的吞咽固体物品的困难。
为防止片剂粘着在冲压机冲膜中,片剂中经常需要加入润滑剂。润滑剂选自这类润滑性固体,例如滑石、硬脂酸镁和硬脂酸钙、硬脂酸和氢化植物油。
片剂崩解剂是当润湿时溶胀以使片剂崩裂并释放出化合物的物质。它们包括淀粉、粘土、纤维素、褐藻胶和树胶。更具体地,可使用,例如玉米和土豆淀粉、甲基纤维素、琼脂、膨润土、木质纤维素、天然海绵粉、阳离子交换树脂、海藻酸、瓜耳胶、柑橘属果浆和羧甲基纤维素以及十二烷基硫酸钠。
为避免活性成分与胃中强酸性内容物的接触,经常使用肠溶制剂。这类制剂可通过用不溶于酸性环境、但溶于碱性环境的聚合物膜包衣固体剂型得到。膜的实例是乙酸邻苯二甲酸纤维素、乙酸邻苯二甲酸聚乙烯、邻苯二甲酸羟丙甲基纤维素和乙酸琥珀酸羟丙甲基纤维素。
当需要以栓剂形式使用化合物时,可使用常用的基质。椰子油是一种传统栓剂基质,可通过加入蜡进行改性以使其熔点略为升高。水混溶性栓剂基质特别包括,广泛使用的各种分子量的聚乙二醇。
最近透皮贴剂变得流行。它们典型地包括药物溶解或部分溶于其中的树脂样组合物,通过一层保护该组合物的膜而与皮肤接触。最近出现了许多使用贴剂的患者。另外,也有人使用更为复杂的贴剂组合物,尤其是具有穿有无数微孔的膜,药物通过渗透作用由微孔泵释的那些贴剂。
下列片剂提供了适用于本发明使用的化合物的制剂实例。下列制剂仅用于举例说明本发明而不应解释为是以任何方式限制本发明。
制剂1
用下列成分制备硬明胶胶囊:
量(mg/胶囊)
活性成分 250
淀粉,干燥的 200
硬脂酸镁
10
总计 460mg
将上述成分混合并以460mg的量填充到硬明胶胶囊中。
制剂2
用下列成分制备片剂:
量(mg/片)
活性成分 250
纤维素,微晶的 400
二氧化硅,雾化的 10
硬脂酸
5
总计 665mg
将各成分混合并压成每片重665mg的片。
制剂3
制备含下列成分的气溶胶溶液:
重量%
活性成分 0.25
乙醇 29.75
抛射剂22
70.00
(一氯二氟甲烷)
总计 100.00
将活性化合物与乙醇混合,该混合物加到部分抛射剂22中,冷却到-30℃并转移到填充设备中。然后将需要量的混合物充入不锈钢容器中并用剩余的抛射剂稀释。再将阀门安装在该容器上。
制剂4
如下制备每片含60mg活性成分的片剂:
活性成分 60mg
淀粉 45mg
微晶纤维素 35mg
聚乙烯吡咯烷酮 4mg
羧甲基淀粉钠 4.5mg
硬脂酸镁 0.5mg
滑石
1mg
总计 150mg
将活性成分、淀粉和纤维素过No.45目U.S.筛并充分混合。将聚乙烯吡咯烷酮溶液与所得粉末混合,然后通过No.14目U.S.筛。在50℃下干燥如此得到的颗粒并使其通过No.18目U.S.筛。将预先通过No.60目U.S.筛的羧甲基淀粉钠、硬脂酸镁和滑石加到该颗粒中,混合后,在压片机上压缩得到每片重150mg的片。
制剂5
如下制备每粒胶囊含80mg药物的胶囊:
活性成分 80mg
淀粉 59mg
微晶纤维素 59mg
硬脂酸镁
2mg
总计 200mg
将活性成分、纤维素、淀粉和硬脂酸镁混合,通过No.45筛,然后以200mg的量填充到硬明胶胶囊中。
制剂6
如下制备每个栓中含225mg活性成分的栓剂:
活性成分 225mg
饱和脂肪酸甘油酯
2,000mg
总计 2,225mg
将活性成分过No.60目U.S.筛后,悬浮到预先用所需最小热量融化的饱和脂肪酸甘油酯中。然后将该混合物倾入标示2g容量的栓剂模具中并使其冷却。
制剂7
如下制备每5ml含50mg药物的混悬液:
活性成分 50mg
羧甲基纤维素钠 50mg
糖浆 1.25ml
苯甲酸溶液 0.10ml
芳香剂 适量
着色剂 适量
纯水加至 5ml
使药物过No.45目U.S.筛后,将其与羧甲基纤维素钠和糖浆混合形成一润滑的糊状物。苯甲酸溶液、芳香剂或着色剂用适量水稀释后,在搅拌下加入。然后再加入足量水至所需体积。
制剂8
如下制备静脉内给药的制剂:
活性成分 100mg
甘露醇 100mg
5N氢氧化钠 200ml
纯水加至 5ml
本领域普通技术人员应该清楚,上述方法也可应用于治疗偏头痛的方法,该方法包括对患者施用有效量的具有选择性iGluR5受体拮抗剂活性的化合物。
抑制硬脑膜的神经元蛋白质溢出是本发明方法的作用基质的一种实例。该方法还要求表现出这种抑制作用的化合物具有选择性结合和抑制iGluR5受体的作用。下面描述用于举例说明本发明原理的化合物和用于证明本发明机制有效性的药理分析。据信,先前没有关于代表新化合物的本文化合物III、IV(a)和IV(b)是选择性iGluR5受体拮抗剂的描述或者治疗偏头痛有效的报道。因此,本发明的另一类实施方案提供了化合物III、IV(a)和IV(b)。
下列实施例举例说明本发明的方法。对于本领域普通专业技术人员而言,很容易获得下列试剂和原料。这些实施例旨在举例说明,而不是以任何方式构成对本发明范围的限制。本文中,下列术语具有所示含义“i.v.”是指静脉内;“p.o.”是指口服;“i.p.”是指腹膜内;“eq”或“equiv.”是指当量;“g”是指克;“mg”是指毫克;“L”是指升;“mL”是指毫升;“μl”是指“微升”;“mol”是指摩尔;“mmol”是指毫摩尔;“psi”是指每平方英寸的磅数;“mmHg”是指毫米汞柱;“min”是指分;“h”或“hr”是指小时;“℃”是指摄氏度;“TLC”是指薄层色谱;“HPLC”是指高效液相色谱;“Rf”是指保留因子;“Rt”是指保留时间;“δ”是指距四甲基硅烷低场百万分子一的份数;“THF”是指四氢呋喃;“DMF”是指N,N-二甲基甲酰胺;“DMSO”是指二甲亚砜;“aq”是指水的或水性的;“EtOAc”是指乙酸乙酯;“iPrOAc”是指乙酸异丙酯;“MeOH”是指甲醇;“MTBE”是指叔丁基甲基醚;“RT”是指室温;“Ki”是指酶-拮抗剂配合物的解离常数,用作配体结合指数;“ID50”和“ID100”是指分别降低50%和100%生理反应所施用的治疗剂的剂量。
实施例1
化合物I
3S,4aR,6S,8aR-6-(((4-羧基)苯基)甲基)-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸
本领域普通专业技术人员将会认识到化合物I是一种对iGluR5受体亚型具有选择性的兴奋性氨基酸受体拮抗剂。在获知美国专利5446051,特别是最近出版的国际申请WO 98/45270(1998年10月15日出版)中描述的通用方法后,本领域普通专业技术人员很容易制备化合物I。
化合物II
3S,4aR,6S,8aR-6-((((1H-四唑-5-基)甲基)氧)甲基)-
1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸
本领域普通专业技术人员将会认识到兴奋性氨基酸受体拮抗剂化合物II对iGluR5受体亚型具有选择性。在获知美国专利5670516(见实施例11和化合物7),特别是最近出版的国际申请WO 98/45270(1998年10月15日出版)中描述的通用方法后,本领域普通专业技术人员很容易制备并且拆分化合物II。
化合物III
化合物III代表一种功能为选择性iGluR5受体拮抗剂的新化合物。化合物III很容易制备;可任选地拆分所需的对映体;并且基本上按照美国专利5670516的实施例8,化合物8所述的通用方法很容易制备含有化合物III的药物组合物,该文献的全部内容并入本文参考。
化合物IV(b)
3S,4aR,6S,8aR 6-(((2S)-2-(乙氧羰基)-4,4-二氟吡咯烷基)
甲基)-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸乙酯
A.3S,4aR,6S,8aR 6-((4-甲苯基)磺酰氧基)甲基)-2-甲氧羰基-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸乙酯的制备
往冷却到0℃的15.0g(50.1mmol)羟甲基中间体(参见美国专利5356902的第11-12栏的方案II,该文献的全部内容并入本文以供参考)在CH2Cl2(100mL)中的溶液中加入三乙胺(20.9mL,150.3mmol),然后加入溶于CH2Cl2(100ml)中的甲苯磺酰氯(19.1g,100.2mmol)。使该反应温热到室温并搅拌16小时,然后分配到CH2Cl2和10%NaHSO4水溶液中。水层用二氯甲烷萃取,合并的有机相经硫酸镁干燥、过滤并真空浓缩。经柱色谱(10-50%EtOAc/己烷)得到20.1g(89%)无色油状的所需的中间体标题化合物:
MS(m/e):451.5(M+)
C22H31NO7S 0.1CH2Cl2的计算理论值:C,57.45;H,6.81;N,3.03.实测值:C,57.76;H,6.93;N,3.35.
13C NMR(DMSO-d6):δ171.4,144.8,132.4,130.1,127.6,74.6,60.4,53.1,52.4,44.1,34.6,31.8,31.0,29.8,28.8,24.9,23.3,21.0,14.0.
B.3S,4aR,6S,8aR 6-(((3S,5S)-5-(乙氧羰基)-3-羟基吡咯烷基)甲基)-2-甲氧羰基-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸乙酯的制备
将反式4-羟基-L-脯氨酸乙酯(6.5g,33.1mmol),上步骤A的化合物(10.0g,22.0mmol)和碳酸钾(4.6g,33.1mmol)的混合物在乙腈(22mL)中加热回流60小时。将该反应混合物冷却到室温,然后分配到CH2Cl2和水中。水层用CH2Cl2萃取两次,合并的有机层经硫酸镁干燥、过滤并真空浓缩。经色谱(50%EtOAc/己烷,然后是5%MeOH/CH2Cl2)得到9.2g(95%)无色油状的所需的中间体标题化合物:
MS(m/e):441.3(M+)
C22H36N2O7S的计算理论值:C,59.98;H,8.24;N,6.36.实测值:C,60.17;H,8.23;N,6.42.
C.3S,4aR,6S,8aR 6-(((5S)-5-(乙氧羰基)-3-氧代吡咯烷基)甲基)-2-甲氧羰基-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸乙酯
往冷却到-78℃的DMSO(2.3mL,32.5mmol)的CH2Cl2(25mL)溶液中滴加草酰氯(1.4mL,16.3mmol)。将该反应混合物搅拌5分钟,然后加入溶于20ml CH2Cl2中的上步骤B的化合物(6.0g,13.6mmol)。在-78℃搅拌45分钟后,加入三乙胺(9.5mL,32.5mmol)。反应物经过大约2小时温热到室温,加入10%NaHSO4水溶液处理。水层用二氯甲烷萃取,合并的有机相经硫酸镁干燥、过滤并真空浓缩。经柱色谱(25-50%EtOAc/己烷)得到4.6g(78%)无色油状的所需的中间体标题化合物:
MS(m/e):439.1(M+)
D.3S,4aR,6S,8aR 6-(((2S)-2-(乙氧羰基)-4,4-二氟吡咯烷基)甲基)-2-甲氧羰基-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸乙酯
往冷却到-78℃的上步骤C的化合物(4.62g,10.5mmol)在二氯甲烷(50mL)中的混合物中滴加二乙氨基三氟化硫(3.5mL,26.3mmol)。使反应物温热到室温,再搅拌48小时,然后加入甲醇骤停。真空浓缩后,将残余物分配到二氯甲烷和饱和碳酸氢钠水溶液中。水层用二氯甲烷萃取,合并的有机层经硫酸镁干燥、过滤并真空浓缩。经柱色谱(25-50%EtOAc/己烷)得到3.3g(68%)无色油状的所需的中间体标题化合物:
MS(m/e):461.2(M+)
C22H34F2N2O6的计算理论值:C,57.38;H,7.44;N,6.08.实测值:C,57.28;H,7.52;N,6.13.
E.3S,4aR,6S,8aR 6-(((2S)-2-(乙氧羰基)-4,4-二氟吡咯烷基)甲基)-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸乙酯(化合物IV(b))
将上步骤D的化合物(3.3g,7.10mmol)溶于二氯甲烷(40mL)中并冷却到0℃,然后加入三甲基碘硅烷(3.0mL,21.3mmol)中。使反应物温热到室温,再搅拌4小时,然后加入饱和碳酸氢钠水溶液处理(50mL)。水层用二氯甲烷萃取,合并的有机相用1N硫代硫酸钠溶液洗涤,经硫酸镁干燥、过滤并真空浓缩。该粗品溶于20ml乙醚中经色谱(2%MeOH/二氯甲烷),然后往其中加入50mL HCl/Et2O溶液中。真空除去溶剂,得到2.6g(76%)白色固体的最终的标题化合物:
MS(m/e):403.4(M+)
C20H32Cl2F2N2O4的计算理论值:C,50.53;H,7.21;N,5.89.实测值:C,50.90;H,7.41;N,5.84.
13C NMR(D2O):δ170.3,167.7,125.1(t,JC-F=249.1Hz),65.9,65.0,64.1,63.4,60.1(t,JC-F=33.9Hz),57.6,52.8,42.9,37.2(t,JC-F=26.4Hz),34.5,31.7,31.3,30.5,28.4,26.9,24.3,13.6.
化合物IV(a)
3S,4aR,6S,8aR 6-(((2S)-2-(羧酸)-4,4-二氟吡咯烷基)甲基)-
1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸
将3S,4aR,6S,8aR 6-(((2S)-2-(乙氧羰基)-4,4-二氟吡咯烷基)甲基)-2-甲氧羰基-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸乙酯(3.3g,7.10mmol),上步骤D的化合物溶于5N HCl水溶液(15mL)中的溶液在90℃加热18小时。将反应混合物冷却到室温并真空浓缩。所得泡沫状粗品溶于水(75mL)中并在Dowex 50X8(100-200)离子交换树脂(10g)的存在下搅拌2小时。将树脂过滤,顺序用1∶1THF/H2O和水洗涤,然后在10%吡啶/水的存在下搅拌2小时。过滤后,树脂用水洗涤,滤液真空浓缩得到白色泡沫状的标题化合物(0.6g,97%)。
MS(m/e):374.2(M+)
C16H24F2N2O40.1H2O的计算理论值:C,55.19;H,7.01;N,8.05.实测值:C,54.81;H,6.82;N,8.13.
13C NMR(D2O):δ175.1,171.1,125.6(t,JC-F=249.4Hz),67.9,63.0,59.3(t,JC-F=34.0Hz),54.5,42.5,37.5(t,JC-F=24.9Hz),34.3,32.7,32.4,30.6,28.2,27.0,24.3.
实施例2
为确认iGluR5受体亚型介导神经性蛋白质溢出-一种偏头痛的功能性特征,首先用标准方法测定化合物与iGluR5受体的结合亲和性。例如,可通过在克隆或表达的人iGluR5受体上放射标记的配体结合研究(Korczak等,1994,Recept.Channels 3;41-49),以及通过快速分离的大鼠背底部神经节神经元的全细胞电压夹的电生理电流记录(Bleakman等,1996,Mol.Pharmacol.49;581-585)来测定化合物作为iGluR5受体拮抗剂的活性。化合物作用于iGluR5受体亚型的选择性可通过比较对iGluR5受体的拮抗剂活性与对其它AMPA和红藻氨酸受体的拮抗剂活性来测定。用于这种比较研究的方法包括:人GluR1、GluR2、GluR3和GluR4受体上功能性活性的受体-配体结合研究和全细胞电压夹的电生理记录(Fletcher等,1995,Recept.Channels 3;21-31);人GluR6受体功能性活性的受体-配体结合研究和全细胞电压夹的电生理记录(Hoo等,Recept.Channels 2;327-338);和快速分离的小脑浦肯野氏神经元中的AMPA受体功能性活性的全细胞电压夹的电生理记录(Bleakman等,1996,Mol.Pharmacol.49;581-585)和其它组织表达的AMPA受体(Fletcher和Lodge,1996,Pharmacol.Ther.70;65-89)。
iGluR5拮抗剂结合亲和性的简要描述
采用人iGluR受体稳定转染的细胞系(HEK293细胞)。在iGluR1、iGluR2、iGluR3和iGluR4表达细胞中测定由于拮抗剂浓度提高导致的3[H]AMPA置换,同时在iGluR5、iGluR6、iGluR7和KA2-表达细胞中测定3[H]红藻氨酸(KA)的置换。测定化合物I-IV的估算的拮抗剂亲和结合活性(Ki)(以μM表示)。还测定作为选择性标志的对iGluR2AMPA受体亚型的结合亲和性与对iGluR5红藻氨酸受体亚型的结合亲和性的比率。结果显示,本发明提供的化合物对iGluR5的结合亲和性比对iGluR2的结合亲和性高至少10倍,更优选高至少100倍。
实施例3
用下列动物模型测定本发明组的各种化合物抑制蛋白质溢出(一种偏头痛神经元机制的功能性分析实例)的能力。表I(在下)中概括了该模型中得到的本发明化合物组的结果。
硬脑膜蛋白质溢出的动物模型
用戊巴比妥钠经腹膜内给药(分别以65mg/kg或45mg/kg的量)麻醉Harlan Sprague-Dawley大鼠(225-325g)或得自Charles RiverLaboratories的豚鼠(225-325g)并以3.5mm(大鼠)或4.0mm(豚鼠)门牙棒放入趋实体性框架(David Kopf Instruments)中。作一中线前后向的头皮切口后,通过头盖骨钻两对两侧的洞(大鼠后侧6mm,侧向2.0和4.0mm;豚鼠后侧4mm,侧向3.2和5.2mm,所有坐标均以前囟为参考点)。通过两个半球的孔使插入的除末端在外的一对不锈钢刺激电极(Rhodes Medical Systems,Inc.)降低到距离硬脑膜9mm(大鼠)或10.5mm(豚鼠)的深度。
使股骨静脉暴露,以1ml/kg剂量体积静脉内注射(i.v.)一剂的试验化合物,或者以2.0ml/Kg剂量体积经管饲法口服(p.o.)给药试验化合物。静脉注射约7分钟后,再静脉注射50mg/Kg剂量的伊文思蓝(一种荧光染料)。伊文思蓝与血液中的蛋白质配合,作为蛋白质溢出的标志。试验化合物注射后10分钟,用Model273稳压器/恒电流(EG & G Princeton Applied Research)以1.0mA电流强度(5Hz,4毫秒延续时间)对左侧三叉神经的神经节刺激3分钟。
刺激15分钟后,处死动物并用20mL盐水放血。取下头盖骨顶部以助于收集硬脑膜。从两个半球取出膜样,用水漂洗并平铺在显微镜玻片上。干燥后,该组织用70%甘油/水溶液盖玻片。
用安装有光栅单色器和分光光度计的荧光显微镜(Zeiss)定量测定每种样品中的伊文思蓝染料的量。利用大约535nm的激发波长,在600nm下测定发射强度。显微镜安装有机动化镜台并与个人计算机相接。这有助于计算值控制镜台的运动,以在各硬脑膜样品的25点处(500mm间距)进行荧光测定。通过计算值确定测定的平均值和标准偏差。
由电刺激三叉神经的神经节引发的溢出是一种同侧效应(即,仅发生于其中三叉神经的神经节被刺激的硬脑膜一侧)。这使得另一半(未受刺激的)硬脑膜可作为对照。计算受刺激一侧的溢出量与未受刺激一侧的溢出量之比。对照动物仅给予盐水,大鼠中该比率约为2.0,豚鼠中该比率约为1.8。比较而言,可有效防止受刺激一侧的硬脑膜中溢出的化合物得出的比率约为1.0。
制作各化合物的剂量-反应曲线并估算抑制50%(ID50)或100%(ID100)溢出的剂量。下表I中概括了本发明中使用的各种化合物各自的ID50和/或ID100值。
表I
硬脑膜蛋白质溢出的抑制(ng/Kg)
化合物 | 给药途径 | ID50(ng/Kg) | ID100(ng/kg) |
IIIIIIIV(b) | i.v.i.v.i.v.p.o. | 6.5(大鼠)4.0(豚鼠)15(大鼠)0053(大鼠)-- | ------0.100.01 |
Claims (11)
2.权利要求1的用途,其中选择性iGluR5受体拮抗剂选自3S,4aR,6S,8aR乙基6-(((2S)-2-(乙氧羰基)-4,4-二氟吡咯烷基)甲基)-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸酯,或3S,4aR,6S,8aR 6-(((2S)-2-(羧酸)-4,4-二氟吡咯烷基)甲基)-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3羧酸。
4.权利要求3的化合物,其中R1和R2各自独立地是H或C1-C20烷基。
5.权利要求4的化合物,它是3S,4aR,6S,8aR乙基6-(((2S)-2-(乙氧羰基)-4,4-二氟吡咯烷基)甲基)-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸酯或其可药用盐。
6.权利要求4的化合物,它是3S,4aR,6S,8aR 6-(((2S)-2(羧酸)-4,4-二氟吡咯烷基)甲基)-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3羧酸或其可药用盐。
7.一种药物组合物,它含有权利要求3-6任一项的化合物和一种或多种可药用载体、稀释剂或赋形剂。
8.权利要求5的化合物,它是3S,4aR,6S,8aR乙基6-(((2S)-2-(乙氧羰基)-4,4-二氟吡咯烷基)甲基)-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸酯·扁桃酸盐。
9.权利要求2的用途,其中选择性iGluR5受体拮抗剂是3S,4aR,6S,8aR乙基6-(((2S)-2-(乙氧羰基)-4,4-二氟吡咯烷基)甲基)-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸酯或其可药用盐。
10.权利要求2的用途,其中选择性iGluR5受体拮抗剂是3S,4aR,6S,8aR 6-(((2S)-2(羧酸)-4,4-二氟吡咯烷基)甲基)-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3羧酸或其可药用盐。
11.权利要求9的用途,其中选择性iGluR5受体拮抗剂是3S,4aR,6S,8aR乙基6-(((2S)-2-(乙氧羰基)-4,4-二氟吡咯烷基)甲基)-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸酯·扁桃酸盐。
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US6579886B2 (en) | 1999-12-22 | 2003-06-17 | Eli Lilly And Company | Selective iglur5 receptor antagonists |
MXPA03005982A (es) * | 2001-01-05 | 2003-09-10 | Lilly Co Eli | Antagonistas de receptores de aminoacidos excitadores. |
US7205313B2 (en) | 2001-01-05 | 2007-04-17 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
PL361934A1 (en) * | 2001-01-05 | 2004-10-18 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
US6924294B2 (en) | 2001-01-05 | 2005-08-02 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
WO2002053555A2 (en) * | 2001-01-05 | 2002-07-11 | Eli Lilly And Company | Pyrrolidinylmethyl- and piperidinyl substituted decahydroisoquinolines as excitatory amino acid receptor antagonists |
WO2002053139A2 (en) * | 2001-01-05 | 2002-07-11 | Eli Lilly And Company | Excitatory amino acid receptor antagonist and 5-ht1f agonist combination: a method for the treatment of neurological disorders |
US6855725B2 (en) * | 2001-01-05 | 2005-02-15 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
GB0128996D0 (en) | 2001-12-04 | 2002-01-23 | Novartis Ag | Organic compounds |
US20040082606A1 (en) * | 2001-12-20 | 2004-04-29 | Khau Vien Van | Excitatory amino acid receptor antagonists |
JP2005529892A (ja) | 2002-04-26 | 2005-10-06 | イーライ・リリー・アンド・カンパニー | 鎮痛剤としてのデカヒドロイソキノリン−3−カルボン酸のエステルプロドラッグ |
US7960436B2 (en) | 2006-06-05 | 2011-06-14 | Valeant Pharmaceuticals International | Substituted arylamino-1,2,3,4-tetrahydro naphthalenes and-2,3-dihydro-1H-indenes as potassium channel modulators |
RU2009110172A (ru) | 2006-08-23 | 2010-09-27 | Валеант Фармасьютикалс Интернэшнл (Us) | Производные 4-(n-азациклоалкил)анилидов в качестве модуляторов калиевых каналов |
US8993593B2 (en) | 2006-08-23 | 2015-03-31 | Valeant Pharmaceuticals International | N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide as potassium channel modulators |
US8722929B2 (en) | 2006-10-10 | 2014-05-13 | Valeant Pharmaceuticals International | N-[2-amino-4-(phenylmethoxy)phenyl] amides and related compounds as potassium channel modulators |
ATE538084T1 (de) | 2006-11-28 | 2012-01-15 | Valeant Pharmaceuticals Int | Bicyclische 1,4-retigabin-analoga als kaliumkanalhemmer |
US8367684B2 (en) | 2007-06-13 | 2013-02-05 | Valeant Pharmaceuticals International | Derivatives of 4-(N-azacycloalkyl) anilides as potassium channel modulators |
US8563566B2 (en) | 2007-08-01 | 2013-10-22 | Valeant Pharmaceuticals International | Naphthyridine derivatives as potassium channel modulators |
US7786146B2 (en) | 2007-08-13 | 2010-08-31 | Valeant Pharmaceuticals International | Derivatives of 5-amino-4,6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators |
CA3066711A1 (en) | 2017-07-31 | 2019-02-07 | Novartis Ag | Use of mavoglurant in the reduction of cocaine use or in preventing relapse into cocaine use |
JP7399096B2 (ja) | 2018-03-05 | 2023-12-15 | ヤンセン ファーマシューティカ エヌ.ベー. | 神経変性を検出するためのアッセイ |
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US5284957A (en) * | 1992-09-03 | 1994-02-08 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
US5356902A (en) | 1992-11-06 | 1994-10-18 | Eli Lilly And Company | Decahydroisoquinoline compounds as excitatory amino acid receptor antagonists |
US5446051A (en) | 1994-05-31 | 1995-08-29 | Eli Lilly And Company | Aryl-spaced decahydroisoquinoline-3-carboxylic acids as excitatory amino acid receptor antagonists |
US5767117A (en) * | 1994-11-18 | 1998-06-16 | The General Hospital Corporation | Method for treating vascular headaches |
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