CN1193973A - [1,2,4]三唑并[4,3-α]喹喔啉酮衍生物,其制备和用途 - Google Patents
[1,2,4]三唑并[4,3-α]喹喔啉酮衍生物,其制备和用途 Download PDFInfo
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- CN1193973A CN1193973A CN95195697A CN95195697A CN1193973A CN 1193973 A CN1193973 A CN 1193973A CN 95195697 A CN95195697 A CN 95195697A CN 95195697 A CN95195697 A CN 95195697A CN 1193973 A CN1193973 A CN 1193973A
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Abstract
下列通式(Ⅰ)的[1,2,4]三唑并[4,3-a]喹喔啉酮化合物可用于治疗由兴奋性神经传递质机能亢进引起的适应症,式中,R1是POX’X”或者是用COX’或POX’X”取代的烷基,X’和X”独立地为羟基或烷氧基,R6、R7、R8和R9独立地为氢、烷基、卤素、NH2、NO2、CN、CF3、SO2NY’Y”或COZ’(其中Z’是NY’Y”或烷基,Y’和Y”独立地为氢或烷基)、三唑基、咪唑基或用苯基或烷基取代的咪唑基。
Description
本发明涉及治疗活性的杂环化合物,其制备方法,含有该化合物的药物组合物以及用其治疗的方法。
更具体地说,本发明涉及[1,2,4]三唑并[4,3-a]喹喔啉酮衍生物,其可用于治疗任何由于兴奋性氨基酸机能亢进引起的适应症。
现有技术已知了各种相关的化合物。
因此,EP-A-0040401在属类上描述了在三唑并环上用诸如烷基、酰基或烷氧羰基取代的三唑并喹喔啉-4-酮。文称这些化合物具有有用的抗高血压活性。
在美国专利5153196中公开了某些兴奋性氨基酸受体拮抗剂及其使用方法。该化合物与在三唑并环上具有一个H、烷基、芳基或CF3取代基的三唑并喹喔啉酮一致。
另外,国际专利申请WO93/20077描述了在三唑并环上选择性用低级烷基(其可以被一或二(低级烷基)氨基取代)取代的稠合喹喔啉酮衍生物。
L-谷氨酸、L-天冬氨酸和许多其它密切相关的氨基酸都可激活中枢神经系统(CNS)的神经元。生物化学、电生理和药理学研究证实了这一点,并且确实了酸性氨基酸是哺乳动物CNS中大多数兴奋性神经元的传递质。
与谷氨酸介导的神经传导相互作用被认为是治疗神经和精神病的有用方法。因此,已知的兴奋性氨基酸拮抗剂具有强抗焦虑作用(Stephens等,精神药理学(Psychopharmacology)90,143-147,1985)、抗惊厥性(Croucher等,科学(Science)216,899-901,1982)和肌肉松弛特性(Turski等,神经学快报(Neurosci,Lett.)53,321-326,1985)。
已表明,细胞外兴奋性氨基酸的聚集,随后神经元的过度刺激可解释神经障碍(例如肌萎缩性脊髓侧索硬化、帕金森氏症、早老性痴呆、亨廷顿舞蹈病、癫痫病)中观察到的神经元变性,以及在脑缺血、缺氧和低血糖或者头部及脊髓创伤后观察到的精神和运动障碍(McGeer等,自然(Nature)263,517-519,1976;Simon等,Science 226,850-852 1984;Wieloch,Science 230,681-683,1985;Faden等,Science 244,798-800,1989;Turski等,Nature 349,414-418,1991)。其它可能的适应症有精神病、肌强直、呕吐和痛觉缺失。
兴奋性氨基酸通过突触前或突触后定位的特殊受体发挥其作用。基于电生理和神经化学证据,目前将这些受体便利地细分成三组:1.NMDA(N-甲基-D-天冬氨酸)受体,2.AMPA受体,和3.红藻氨酸受体。L-谷氨酸和L-天冬氨酸可能激活以上所有的兴奋性氨基酸受体以及其它类型的受体。
将兴奋性氨基酸受体如上分类为NMDA、AMPA和红藻氨酸受体主要基于以下电生理和神经化学发现。
1)N-甲基-D-天冬氨酸(NMDA)受体对兴奋性NMDA表现出高度的选择性。鹅膏蕈氨酸、L-高半胱氨酸、D-谷氨酸和反式-2,3-哌啶二羧酸(反式-2,3-PDA)对这些受体表现出强至中度的激动活性。最强的选择性拮抗剂是2-氨基-5-膦酰基羧酸的D-异构体,例如2-氨基-5-膦酰基戊酸(D-APV)和3-[(±)-2-羧基哌嗪-4-基]-丙基-1-膦酸(CPP),而长链2-氨基二羧酸的D-异构体(例如D-2-氨基己二酸)和长链二氨基二羧酸(例如二氨基庚二酸)表现出中度拮抗活性。在哺乳动物中枢神经系统中,特别是脊髓中已充分研究了NMDA诱导的突触反应(J.Davies等,生理学杂志(J.Physiol.)297,621-635,1979),该反应可被Mg2+强烈抑制。
2)AMPA受体可选择性被AMPA(2-氨基-3-羟基-5-甲基-4-异噁唑丙酸)激活,其它强的激动剂为使君子氨酸和L-谷氨酸。谷氨酸二乙酯(GDEE)是该位点的选择性但极弱的拮抗剂。AMPA受体对Mg2+相对不敏感。
谷氨酸的释放长期以来被认为在脑缺血导致的神经元死亡中发挥主要作用(Benveniste,H.等,神经化学杂志(J.Neurochem.)43,1369-1374,1984)。众所周知,NMDA受体引起的Ca2+流入是缺血性神经元细胞损失中的一个重要机制。非NMDA受体偶联的离子载体不能渗透钙。但是,由CA1区中的Scaffer侧突引起的兴奋通过非NMDA受体发挥作用,这一事实对缺血后期中的活动很重要。近期的研究表明,选择性AMPA拮抗剂对沙土鼠中普遍缺血具有神经保护作用,甚至在再输注后数小时(Sheardown等,Science 247,571-574,1990)。
因此,AMPA拮抗剂可用于治疗脑缺血。
3)红藻氨酸受体。对红藻氨酸的兴奋性反应对NMDA拮抗剂及GDEE的拮抗作用相对不敏感,且已提出红藻氨酸激活了酸性氨基酸受体的第三亚类。红藻氨酸的某些内酯化衍生物是选择性拮抗剂(O.Goldberg等,神经科学快报(Neurosci.Lett.)23,187-191,1981),3-谷氨酰基-甘氨酸二肽也表现出对红藻氨酸受体的某些选择性。Ca2+而不是Mg2+是红藻氨酸结合的强抑制剂。
一种物质对一种或多种不同类型兴奋性氨基酸受体的亲合力可以在简单的结合实验中研究。实质上,该方法包括培养特殊选择的放射性标记的配基,并且用含有该受体的脑组织匀浆研究这种特殊物质。通过测定与组织匀浆结合的放射活性并减去非特异性结合即可测得受体的占位。
AMPA受体的结合可用3H-AMPA作为放射性配基进行研究。
体外通过鸡视网膜播散性抑郁(spreading depression)现象研究谷氨酸类似物对谷氨酸受体相互作用的继发性效应的影响。这种实验可提供试验物的效力(激动剂/拮抗剂)信息。这是结合研究的对照,结合研究仅提供化合物对受体的亲合力信息。
已发现,本发明化合物对AMPA受体具有亲合力,并且是这一类型受体的拮抗剂,这使其可用于治疗由兴奋性氨基酸机能亢进引起的许多适应症,特别是在肌萎缩性脊髓侧索硬化、亨廷顿舞蹈病、帕金森氏症、癫痫病和老年痴呆中观察到的神经元变性,以及在脑缺血、缺氧、低血糖和头部及脊髓创伤后观察到的精神和运动障碍。其它可能的适应症有精神病、肌强直、呕吐、急慢性炎症疾病和痛觉缺失。
R1是POX’X”或者是用COX’或POX’X”取代的直链或支链C1-6-烷基,X’和X”独立地为羟基或C1-6-烷氧基,和
R6、R7、R8和R9独立地为氢;C1-6-烷基;卤素;NH2;NO2;CN;CF3;SO2NY’Y”或COZ’(其中Z’是NY’Y”或C1-6-烷基,Y’和Y”独立地为氢或C1-6-烷基);三唑基;咪唑基或用苯基或C1-6-烷基取代的咪唑基。
本文所用术语“C1-6-烷基”是指具有1-6个碳原子的直链或支链的饱和烃链,例如甲基、乙基、正丙基、异丙基、正丁基、2-丁基、叔丁基、3-戊基、新戊基或正己基。
本文所用术语“C1-6-烷氧基”(单独或结合)是指含有通过醚氧连接的C1-6-烷基且其自由价键来自醚氧的单价取代基,例如甲氧基、乙氧基、丙氧基、异丙氧基、环丙基甲氧基、丁氧基、苯氧基。
本文所用术语“卤素”是指氟、氯、溴和碘。
本发明一个优选的实例是R1为POX’X”取代的C1-6-烷基。
本发明另一优选的实例是R6、R7、R8和R9独立地为氢、氯、NO2、CN、CF3、三唑基、咪唑基或用苯基或C1-6-烷基取代的咪唑基。
本发明另一优选的实例是R6和R9为氢。
本发明优选的化合物有:
1-(乙氧基-羟基-磷酰基甲基)-8-(1H-咪唑-1-基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
8-(1H-咪唑-1-基)-1-膦酰基甲基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
1-(乙氧基-羟基-磷酰基甲基)-8-(2-异丙基-1H-咪唑-1-基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
8-(2-异丙基-1H-咪唑-1-基)-1-膦酰基甲基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮。
本发明另外优选的化合物有:
1-膦酰基甲基-8-(1H-1,2,4-三唑-1-基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
8-(4-甲基-1H-咪唑-1-基)-1-膦酰基甲基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
8-(2-甲基-1H-咪唑-1-基)-1-膦酰基甲基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
8-(2-苯基-1H-咪唑-1-基)-1-膦酰基甲基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
7-氰基-8-(1H-咪唑-1-基)-1-膦酰基甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
8-(1H-咪唑-1-基)-1-(1-膦酰基乙基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
8-(2-乙基-1H-咪唑-1-基)-1-膦酰基甲基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
1-膦酰基甲基-8-(2-正丙基-1H-咪唑-1-基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
8-(1H-咪唑-1-基)-7-硝基-1-膦酰基甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
8-(1H-咪唑-1-基)-7-硝基-1-(1-膦酰基乙基)[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
8-(2-甲基-1H-咪唑-1-基)-7-硝基-1-膦酰基甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
7-氰基-8-(2-甲基-1H-咪唑-1-基)-1-膦酰基甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
7-氰基-8-(2-苯基-1H-咪唑-1-基)-膦酰基甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
8-(4-苯基-1H-咪唑-1-基)-1-膦酰基甲基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
7-氰基-8-(2-异丙基-1H-咪唑-1-基)-1-膦酰基甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
7-氰基-8-(2-乙基-1H-咪唑-1-基)-1-膦酰基甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
7-氰基-8-(1H-咪唑-1-基)-1-(1-膦酰基乙基)[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
7-(1H-咪唑-1-基)-1-膦酰基甲基-8-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
7-(2-甲基-1H-咪唑-1-基)-1-膦酰基甲基-8-三氟甲基[1,2,4]三唑并[4,3-a ]喹喔啉-4(5H)-酮;
8-氰基-7-(1H-咪唑-1-基)-1-膦酰基甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
7-(1H-咪唑-1-基)-8-硝基-1-膦酰基甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
1-膦酰基甲基-7-(1H-1,2,4-三唑-1-基)-8-三氟甲基[1,2,4]三唑并[4,3-a ]喹喔啉-4(5H)-酮;
7-(1H-咪唑-1-基)-1-(1-膦酰基乙基)-8-三氟甲基[ 1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
7-氰基-8-(4-甲基-1H-咪唑-1-基)-1-膦酰基甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
7-氰基-8-(2-正丙基-1H-咪唑-1-基)-1-膦酰基甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
7-氰基-8-(4-苯基-1H-咪唑-1-基)-1-膦酰基甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
7-氰基-1-膦酰基甲基-8-(1H-1,2,4-三唑-1-基)[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
7-硝基-1-膦酰基甲基-8-(1H-1,2,4-三唑-1-基)[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
7-氯-8-(1H-咪唑-1-基)-1-膦酰基甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
8-氯-7-(1H-咪唑-1-基)-1-膦酰基甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮。
本发明的化合物可以以不同互变异构体形式存在。因此,本发明包括所有这些互变异构体形式。
本发明的另一实例是通式I的[1,2,4]三唑并[4,3-a]喹喔啉酮衍生物的可药用盐。这些盐包括从无机酸和有机酸衍生出的盐,酸例如有盐酸、氢溴酸、醋酸、硫酸、硝酸、草酸、富马酸、酒石酸等。其它盐包括碱金属盐,例如钠盐或钾盐;碱土金属盐,例如钙盐或镁盐;以及铵盐。
另外,本发明的另一方面涉及通式(I)化合物或其可药用盐用作一种药物,优选用作治疗与兴奋性神经传递质,特别是AMPA受体机能亢进相关的适应症的药物。
本发明也涉及制备上述化合物的方法。本发明的式I化合物通过以下制备而得:
a)将通式II化合物,式中R6、R7、R8和R9如上定义,用苄基卤化物烷基化形成通式III化合物式中R6、R7、R8和R9如上定义,然后将该化合物卤化形成通式IV化合物式中R6、R7、R8和R9如上定义,Q是Br、Cl或I;将该化合物与肼反应形成通式V化合物式中R6、R7、R8和R9如上定义,将该化合物用通式VI:R1-COCl(其中R1如上通式I化合物所定义,其中X’和X”是C1-6烷氧基)的酰氯酰基化形成通式VII化合物式中R1、R6、R7、R8和R9如上定义,将该化合物氢解形成通式VIII化合物式中R1、R6、R7、R8和R9如上定义,然后通过热环化作用同时脱氧合而形成其中X’和X”独立地为羟基或C1-6烷氧基的通式I化合物,或者
b)将通式IX化合物式中R6、R7、R8和R9如上定义,Q是Br、Cl或I,与通式VI:R1-COCl(其中R1如上通式I化合物所定义,其中X’和X”是C1-6烷氧基)的化合物反应形成通式XI化合物式中R1、R6、R7、R8和R9如上定义,Q是Br、Cl或I,然后先环化后水解或者同时环化和水解而形成其中X’和X”独立地为羟基或C1-6烷氧基的通式I化合物,或者
c)将通式XII化合物式中R6、R7、R8和R9如上定义,Z是卤素或C1-6烷氧基,用一、二或三甲氧基取代的苄胺取代而形成通式XIII化合物式中R6、R7、R8和R9如上定义,V’和V”独立地为氢或甲氧基,然后将该化合物与乙基草酰氯反应形成通式XIV化合物式中R6、R7、R8和R9如上定义,V’和V”独立地为氢或甲氧基,然后先氢化形成中间体环化的N-羟基化合物后脱氧合,或者通过氢化作用环化形成通式XV化合物式中R6、R7、R8和R9如上定义,V’和V”独立地为氢或甲氧基,将通式XV化合物卤化,将所得化合物与肼反应,然后与上述定义的通式VI酰氯进行酰化作用,接着环化形成通式XVI化合物式中R1、R6、R7、R8和R9如上定义,V’和V”独立地为氢或甲氧基,水解形成其中X’和X”独立地为氢或C1-6烷氧基的通式I化合物,或者
d)用含水碱将其中X’和X”为C1-6烷氧基的通式I化合物水解形成其中X’是羟基、X”是C1-6烷氧基的通式I化合物,或者
e)将其中X’是羟基或C1-6烷氧基、X”是C1-6烷氧基的通式I化合物与卤代三甲基硅烷反应形成其中X’和X”是羟基的通式I化合物。
按照标准方法用适当酸或碱处理通式I化合物即可制备可药用盐。
本文未描述其制备的起始物都是已知化合物(例如国际申请PCT-DK94/00170中的)或者可用类似于已知化合物的制备方法或类似于已知方法制备的化合物。
本发明化合物的药理特性可以通过测定其将放射性标记的2-氨基-3-羟基-5-甲基-4-异噁唑丙酸(AMPA)从AMPA型受体置换的能力来阐明。这些化合物的拮抗特性可通过其拮抗使君子氨酸刺激的鸡视网膜播散性抑郁的能力来证实。
这些化合物的置换活性可通过测定IC50值来表示,该值代表置换50%3H-AMPA特异性结合的浓度(μM)。
通过测定IC50值测量拮抗作用,该值表示产生50%最大抑制使君子氨酸刺激的鸡视网膜播散性抑郁的浓度。
3H-AMPA结合(试验1)
将500μl解冻大鼠大脑皮层膜组织匀浆的Tris-HCl(30mM)、氯化钙(2.5mM)和KSCN(100mM)pH 7.1溶液于0℃与25μl3H-AMPA(5nM终浓度)和测试化合物及缓冲液孵育30分钟。与L-谷氨酸(600μM终浓度)孵育后测定非特异性结合。加入5毫升冰冷却的缓冲液终止结合反应,然后通过Whatman GF/C玻璃纤维滤器过滤并用2×5毫升冰冷却的缓冲液洗涤。通过闪烁计数测定结合放射性。通过Hill分析至少四种浓度的测试化合物而计算IC50。
播散性抑郁(试验2)
断头处死鸡(3-10天大),摘出眼睛并沿中纬面切片。除去前室和玻璃体后,将每只眼的后室置于含有如下组成(mM)的生理盐水溶液(P.S.S.)的小培替氏皿中:NaCl(100)、KCl(6.0)、CaCl2(1.0)、MgSO4(1.0)、NaHCO3(30)、NaH2PO4(1.0)、葡萄糖(20)。
将该溶液用100%O2饱和,保持在26℃的温度。
首先将眼睛在普通P.S.S.中孵育15-30分钟,然后转移到含有使君子氨酸(1μg/ml)的P.S.S.中。在这种“刺激溶液”中,S.D.一般自发地从视网膜边缘开始,并且易于用眼睛观察到。测定每只眼中S.D.开始所需的时间。
在普通P.S.S.中再孵育15分钟后,将眼转移至含有测试化合物的普通P.S.S.中并孵育15分钟。然后将眼转移至含有相同浓度测试化合物的“刺激溶液”中。再次测量每只眼中S.D.开始所需的时间。然后将眼放回普通P.S.S.中,15分钟后,再次测量每只眼中S.D.开始所需的时间以评价从任意药物作用中恢复的程度。
S.D.开始所需时间比对照时间增加30秒钟则被认为是100%抑制S.D.。因此,用给定剂量获得的最大反应百分数来表示药物的作用。因此测定值为产生50%最大抑制作用(IC50)的测试物浓度(μM)。
测试本发明某些化合物所得的测试结果如下表1所示。表1
试验1 | 试验2 | |
实施例化合物 | IC50μM | IC50μM |
1 | 0.24 | 1.31 |
含有本发明化合物的组合物药物制剂可通过口服、直肠或非肠道途径给予人或动物。
活性化合物或其可药用盐的有效量可按照常规因素确定,例如病情的性质和严重性以及需要治疗的哺乳动物的体重。
常规赋形剂为可药用的适于非肠道或肠道用药并不与活性化合物发生有害反应的有机或无机载体。
这些载体的实例有水、盐溶液、醇类、聚乙二醇、多羟基乙氧基化的蓖麻油、明胶、乳糖、直链淀粉、硬脂酸镁、滑石、硅酸、脂肪酸甘油单酯和甘油二酯、季戊四醇脂肪酸酯、羟甲基纤维素和聚乙烯吡咯烷酮。
可以将药物制剂灭菌,如果需要,可与辅助剂如润滑剂、防腐剂、稳定剂、湿润剂、乳化剂、影响渗透压的盐、缓冲剂和/或着色剂等混合,这些物质不能与活性化合物发生有害反应。
注射用溶液或悬浮液,优选将活性化合物溶于多羟基化蓖麻油的水溶液特别适用于非肠道给药。
安瓿是便利的单位剂量形式。
含有滑石和/或载体或粘合剂等的片剂、糖锭剂或胶囊特别适用于口服给药。载体优选为乳糖和/或玉米淀粉和/或马铃薯淀粉。
当使用甜味赋形剂或者需要时,可使用糖浆剂、酏剂等。
一般地,将本发明化合物分配在单位剂量形式中,该单位剂量形式每单位剂量含有0.5-1000毫克活性成分(在可药用载体中或与可药用载体一起)。
当将其作为药物给予患者例如人时,本发明化合物的剂量为每日1-500毫克,例如每剂量约50-100毫克。
通过常规成片技术制备的典型片剂含有:
片芯:
活性化合物(游离化合物或其盐) 100mg
胶态二氧化硅(Aerosil) 1.5mg
微晶纤维素(Avicel) 70mg
改性纤维素胶(Ac-Di-Sol) 7.5mg
硬脂酸镁 1mg
包衣:
HPMC 约9mg
*Mywacett9-40T 约0.9mg
*薄膜包衣中用作增塑剂的酰化甘油单酯。
形成碱金属盐或碱土金属盐的本发明游离化合物可以以这种盐形式使用。通过将该化合物与等量或过量的选定的碱金属或碱土金属的氢氧化物反应即可形成这种碱金属盐或碱土金属盐,该反应经常且适当地在中性溶剂存在下混合,盐可以从中性溶剂中沉淀出或者以其它常规方式如蒸发来回收。优选将本发明化合物以其可药用水溶性碱金属盐或碱土金属盐的形式并以药物组合物形式口服、直肠或非肠道给药,在药物组合物中还含有可药用液体或固体载体或稀释剂。
可将本发明的化合物与常规辅助剂、载体或稀释剂一起置于药物组合物形式及其单位剂量中,可使用的这种形式有固体,例如片剂或填充胶囊,或者液体,例如溶液剂、悬浮剂、乳剂、酏剂,或者填充相同物质的胶囊,这些都是口服使用;可以直肠给药的栓剂形式;或者非肠道(包括皮下)使用的灭菌注射用溶液形式。这些药物组合物及其单位剂量形式可按常规比例含有常规的组分,含有或不含另外的活性化合物或主药,并且这些单位剂量形式可以含有任何适当有效的AMPA拮抗量的活性成分,其与所用的每日预计剂量范围相当。因此每片含有1-500毫克活性成分或者更具体为10-200毫克的片剂是适当的代表性单位剂量形式。
由于它们高度的AMPA拮抗活性以及其低毒性,并且表现出最好的治疗指标,因此本发明化合物可给予需要这种治疗并消除、减轻或改善对AMPA受体状况的变化敏感的适应症(例如硬化症、帕金森氏症、早老性痴呆、亨廷顿舞蹈病、癫痫病、在缺血、缺氧、低血糖、头部及脊髓创伤后观察到的缺陷、精神病、肌强直、呕吐和痛觉缺失)的受者,例如活动物体,通常优选将该化合物以其碱金属或碱土金属盐的形式,同时或与可药用载体或稀释剂一起,特别优选以其药物组合物的的形式通过口服、直肠或非肠道(包括皮下)的途径以有效量给予受者。
适宜的剂量范围是每日1-500毫克,优选每日10-200毫克,特别是每日50-100毫克,通常取决于给药的确定模式、给药形式、给药的适应症、患者及患者体重、主治医师或兽医师的爱好及经验。
这种治疗方法可描述为治疗由需要这种治疗的患者中兴奋性神经传递质,特别是AMPA受体机能亢进引起或与之相关的适应症,该治疗包括给予所述患者神经病学上有效量的本发明AMPA拮抗化合物或者其可药用盐。
另外,本发明涉及将本发明化合物用于制备治疗由需要治疗的患者中兴奋性神经传递质,特别是AMPA受体机能亢进引起或与之相关适应症的药物。
通过以下实施例更详细描述本发明:
实施例1
1-(乙氧基-羟基-磷酰基甲基)-8-(1H-咪唑-1-基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
步骤a.1-苄氧基-3-[2-[(二乙氧基磷酰基)乙酰基]肼基]-6-(1H-咪唑-1-基)-7-三氟甲基喹喔啉-2(1H)-酮
将(二乙氧基磷酰基)乙酰氯(2.4克,11毫摩尔)在20毫升无水四氢呋喃中的溶液滴加到搅拌下的1-苄氧基-3-肼基-6-(1H-咪唑-1-基)-7-三氟甲基喹喔啉-2(1H)-酮(4.16克,10毫摩尔)和无水三乙胺(1.53毫升,11毫摩尔)在150毫升无水四氢呋喃中的溶液中。
室温下搅拌化合物2小时,真空中蒸发至干。将残余物悬浮在100毫升水中,用饱和碳酸氢钠水溶液调节pH值至约7。
将粗产物通过过滤并从乙酸乙酯/乙醚中重结晶而分离得4.7克(79%)标题化合物。熔点:159-161℃。1H-NMR(DMSO-d6):δ1.23(t,6H),3.04(d,2H),4.06(五重峰,4H),5.39(s,2H),7.08(s,1H),7.34-7.68(m,8H),7.81(s,1H),10.33(br.s,2H,可互换).
步骤b.3-[2-[(二乙氧基磷酰基)乙酰基]肼基]-1-羟基-6-(1H-咪唑-1-基)-7-三氟甲基喹喔啉-2(1H)-酮
将1-苄氧基-3-[2-[(二乙氧基磷酰基)乙酰基]肼基]-6-(1H-咪唑-1-基)-7-三氟甲基喹喔啉-2(1H)-酮(3.86克,6.5毫摩尔)和500毫克10%披钯碳在250毫升乙醇中的悬浮液在大气压下于室温氢化3小时。滤除催化剂,用少量乙醇洗涤。将合并的滤液及洗涤液于真空中蒸发至干,残余物用乙醚研制而得2.80克(86%)标题化合物。1H-NMR(DMSO-d6):δ1.23(t,6H),3.03(d,2H),4.08(五重峰,4H),7.07(s,1H),7.40(s,1H),7.41(s,1H),7.83(s,1H),7.90(s,1H),10.1-10.3(2H),12.5(very br.s,1H).
步骤c.1-(乙氧基-羟基-磷酰基甲基)-8-(1H-咪唑-1-基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
120℃下将3-[2-[(二乙氧基磷酰基)乙酰基]肼基]-1-羟基-6-(1H-咪唑-1-基)-7-三氟甲基喹喔啉-2(1H)-酮(2.52克,5毫摩尔)和三苯膦(2.62克,10毫摩尔)在100毫升冰醋酸中的溶液搅拌23小时。在冷却后的混合物中加入150毫升乙醚。过滤分离沉淀下来的固体,用乙醚和丙酮洗涤而得1.09克(43%)标题化合物。熔点324-328℃。1H-NMR(DMSO-d6):δ1.10(t,3H),1.91(s,3H),3.88(五重峰,2H),4.05(d,2H),7.21(s,1H),7.50(s,1H),7.82(s,1H),8.06(s,1H),8.50(s,1H),12.49(s,1H).
实施例2
8-(1H-咪唑-1-基)-1-膦酰基甲基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
将溴代三甲基硅烷(2毫升,14毫摩尔)滴加到搅拌下的1-(乙氧基-羟基-磷酰基甲基)-8-(1H-咪唑-1-基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮(450毫克)在20毫升无水N,N-二甲基甲酰胺中的溶液中。将该溶液于室温搅拌3天,加入25毫升水并于真空中蒸发至干。将油状残余物用少量水研制,过滤分离所得沉淀物并用少量冷水、乙醇和乙醚洗涤而得210毫克标题化合物。熔点349-350℃。1H-NMR(DMSO-d6):δ3.98(d,2H),7.20(s,1H),7.48(s,1H),7.83(s,1H),8.05(s,1H),8.50(s,1H),12.4(br.s,1H).(C14H10N6F3O4P·1.5H2O)计算值:C38.11,H2.97,N19.05实测值:C38.21,H3.02,N18.75
实施例3
1-(乙氧基-羟基-磷酰基甲基)-8-(2-异丙基-1H-咪唑-1-基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
步骤a.1-苄氧基-3-氯-6-(2-异丙基-1H-咪唑-1-基)-7-三氟甲基喹喔啉-2(1H)-酮
0℃下将20%碳酰氯在甲苯中的溶液(18毫升,34.7毫摩尔)滴加到搅拌下的5.04克(11.3毫摩尔)1-苄氧基-6-(2-异丙基-1H-咪唑-1-基)-7-三氟甲基喹喔啉-2,3(1H,4H)-二酮在50毫升无水N,N-二甲基甲酰胺中的溶液中。将混合物于25℃搅拌过夜,过滤分离沉淀下来的固体,用乙醚洗涤而得4.81克(85%)标题化合物盐酸盐。1H-NMR(DMSO-d6):δ1.33(畸变的t,6H),2.65-2.80(m,1H),5.87(s,2H),7.40-7.67(m,5H),7.77(s,1H),7.92(s,1H),7.96(s,1H),8.62(s,1H).
步骤b.1-苄氧基-3-肼基-6-(2-异丙基-1H-咪唑-1-基)-7-三氟甲基喹喔啉-2(1H)-酮
将1-苄氧基-3-氯-6-(2-异丙基-1H-咪唑-1-基)-7-三氟甲基喹喔啉-2(1H)-酮盐酸盐(4.8克,9.6毫摩尔)和水合肼(2.0毫升,41毫摩尔)在100毫升二氯甲烷中的混合物于0℃搅拌2小时。将混合物于真空中蒸发至干,残余物用水研制而得4.1克(93%)标题化合物。1H-NMR(DMSO-d6):δ1.10 (d,6H),2.42-2.65(m,1H),5.32(s,2H),6.91(s,1H),7.07(s,1H),7.28(s,1H),7.37-7.47(m,3H),7.50(s,1H),7.52-7.60(m,2H).
步骤c.1-苄氧基-3-[2-[(二乙氧基磷酰基)乙酰基]肼基]-6-(2-异丙基-1H-咪唑-1-基)-7-三氟甲基喹喔啉-2(1H)-酮
将(二乙氧基磷酰基)乙酰氯(1.93克,9毫摩尔)在25毫升无水四氢呋喃中的溶液滴加到搅拌下的1-苄氧基-3-肼基-6-(2-异丙基-1H-咪唑-1-基)-7-三氟甲基喹喔啉-2(1H)-酮(4.0克,8.7毫摩尔)和无水三乙胺(1.25毫升,9毫摩尔)在75毫升无水四氢呋喃中的溶液中。
将混合物于室温搅拌过夜并蒸发至干。残余物用500毫升水溶解并过滤。用饱和碳酸氢钠水溶液将滤液pH值调节至8,用乙酸乙酯(5×50毫升)萃取。干燥(无水硫酸钠)合并的有机萃取物,过滤,真空中蒸发至干而得4.3克(78%)粗标题化合物。1H-NMR(DMSO-d6):δ1.25(t,12H),2.63-2.77(m,1H),3.03(d,2H),4.07(五重峰,4H),5.40(s,2H),7.38-7.48(m,3H),7.55-7.63(m,2H),7.68(s,1H),7.79(s,2H),7.87(s,1H),10.4(br.s,1H),10.5(br.s,1H).
步骤d.3-[2-[(二乙氧基磷酰基)乙酰基]肼基]-1-羟基-6-(2-异丙基-1H-咪唑-1-基)-7-三氟甲基喹喔啉-2(1H)-酮
将1-苄氧基-3-[2-[(二乙氧基磷酰基)乙酰基]肼基]-6-(2-异丙基-1H-咪唑-1-基)-7-三氟甲基喹喔啉-2(1H)-酮(4.3克,6.6毫摩尔)和100毫克5%披钯碳在100毫升乙醇中的悬浮液氢化2小时。滤除催化剂并用乙醇洗涤。于真空中将合并的滤液蒸发至干,残余物用乙醚研制而得3.0克(83%)标题化合物。熔点>190℃,分解。1H-NMR(DMSO-d6):δ≈1.09(两个d,6H),1.22(t,6H),2.46-2.69(m,1H),3.02(d,2H),4.05(五重峰,4H),6.94(s,1H),7.15(s,1H),7.38(s,1H),7.94(s,1H).
步骤e.1-(乙氧基-羟基-磷酰基甲基)-8-(2-异丙基-1H-咪唑-1-基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
将3-[2-[(二乙氧基磷酰基)乙酰基]肼基]-1-羟基-6-(2-异丙基-1H-咪唑-1-基)-7-三氟甲基喹喔啉-2(1H)-酮(3.0克,5.5毫摩尔)和三苯膦(2.9克,11毫摩尔)在50毫升冰醋酸中的溶液于120℃搅拌23小时。将混合物冷却至室温,过滤分离沉淀下来的固体,用乙醚洗涤而得1.84克标题化合物。熔点335-338℃。1H-NMR(CF3COOD):δ1.68(t,3H),1.82(畸变的t,6H),3.37-3.57(m,1H),4.62(五重峰,2H),4.78-5.00(m,2H),7.88(s,2H),8.69(s,1H),9.35(s,1H).
实施例4
8-(2-异丙基-1H-咪唑-1-基)-1-膦酰基甲基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
将溴代三甲基硅烷(2.5毫升,17.5毫摩尔)滴加到搅拌下的1-(乙氧基-羟基-磷酰基甲基)-8-(2-异丙基-1H-咪唑-1-基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮(1.5克,2.7毫摩尔)在10毫升无水N,N-二甲基甲酰胺中的溶液中。将该溶液于室温搅拌3天,于真空中蒸发至干。将油状残余物用20毫升水研制,过滤分离所得沉淀物并用水洗涤。用50毫升1M磷酸二氢钾缓冲液(pH7.4)处理粗产物,滤出所得钾盐,然后将其溶于50毫升水,用脱色炭处理,过滤,最后用浓盐酸再沉淀。过滤分离产物,用水洗涤并干燥而得0.76克(54%)标题化合物。熔点>325℃1H-NMR(DMSO-d6):δ1.07(d,3H),1.19(d,3H),2.79(五重峰,1H),3.57-4.01(m,2H),7.04(s,1H),7.17(s,1H),7.88(s,1H),8.48(s,1H).
Claims (14)
2.根据权利要求1的化合物,其中R1是用POX’X”取代的C1-6-烷基,X’和X”独立地为羟基或C1-6-烷氧基。
3.根据权利要求1或2的化合物,其中R6、R7、R8和R9独立地为氢、氯、NO2、CN、CF3、三唑基、咪唑基或用苯基或C1-6-烷基取代的咪唑基。
4.根据前述权利要求的化合物,其中R6和R9为氢。
5.根据权利要求1-4任一项的化合物,其为
1-(乙氧基-羟基-磷酰基甲基)-8-(1H-咪唑-1-基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
8-(1H-咪唑-1-基)-1-膦酰基甲基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
1-(乙氧基-羟基-磷酰基甲基)-8-(2-异丙基-1H-咪唑-1-基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;
8-(2-异丙基-1H-咪唑-1-基)-1-膦酰基甲基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮。
6.一种药物组合物,含有根据权利要求1-5任一项的化合物或其可药用盐作为活性成分以及可药用载体或稀释剂。
7.根据权利要求6的药物组合物,为含有约10-200毫克活性化合物的剂量单位形式。
8.根据权利要求1-5任一项的化合物或其可药用盐作为药物的用途。
9.根据权利要求1-5任一项的化合物或其可药用盐在制备用于治疗与兴奋性神经传递质机能亢进相关的适应症的药物中的用途。
10.一种适用于治疗与兴奋性神经传递质机能亢进相关的适应症的药物组合物,该药物组合物含有根据权利要求1-5任一项的化合物或其可药用盐作为活性成分以及可药用载体或稀释剂。
11.一种治疗与需要治疗的患者中兴奋性神经传递质机能亢进相关的适应症的方法,包括给予所述患者神经病学上有效的AMPA拮抗量的权利要求1-5任一项的化合物或其可药用盐。
12.根据权利要求11的方法,其中的适应症涉及脑缺血。
13.一种制备根据权利要求1-5任一项的通式I化合物的方法,该方法包括
a)将通式II化合物,式中R6、R7、R8和R9如上定义,用苄基卤化物烷基化形成通式III化合物式中R6、R7、R8和R9如上定义,然后将该化合物卤化形成通式IV化合物式中R6、R7、R8和R9如上定义,Q是Br、Cl或I;将该化合物与肼反应形成通式V化合物式中R6、R7、R8和R9如上定义,将该化合物用通式VI:R1-COCl(其中R1如上通式I化合物所定义,其中X’和X”是C1-6烷氧基)的酰氯酰基化形成通式VII化合物式中R1、R6、R7、R8和R9如上定义,将该化合物氢解形成通式VIII化合物式中R1、R6、R7、R8和R9如上定义,然后通过热环化作用同时脱氧合而形成其中X’和X”独立地为羟基或C1-6烷氧基的通式I化合物,或者
b)将通式IX化合物式中R6、R7、R8和R9如上定义,Q是Br、Cl或I,与通式VI:R1-COCl(其中R1如上通式I化合物所定义,其中X’和X”是C1-6烷氧基)的化合物反应形成通式XI化合物式中R1、R6、R7、R8和R9如上定义,Q是Br、Cl或I,然后先环化后水解或者同时环化和水解而形成其中X’和X”独立地为羟基或C1-6烷氧基的通式I化合物,或者
c)将通式XII化合物式中R6、R7、R8和R9如上定义,Z是卤素或C1-6烷氧基,用一、二或三甲氧基取代的苄胺取代而形成通式XIII化合物式中R6、R7、R8和R9如上定义,V’和V”独立地为氢或甲氧基,然后将该化合物与乙基草酰氯反应形成通式XIV化合物式中R6、R7、R8和R9如上定义,V’和V”独立地为氢或甲氧基,然后先氢化形成中间体环化的N-羟基化合物后脱氧合,或者通过氢化作用环化形成通式XV化合物式中R6、R7、R8和R9如上定义,V’和V”独立地为氢或甲氧基,将通式XV化合物卤化,将所得化合物与肼反应,然后与上述定义的通式VI酰氯进行酰化作用,接着环化形成通式XVI化合物式中R1、R6、R7、R8和R9如上定义,V’和V”独立地为氢或甲氧基,水解形成其中X’和X”独立地为氢或C1-6烷氧基的通式I化合物,或者
d)用含水碱将其中X’和X”为C1-6烷氧基的通式I化合物水解形成其中X’是羟基、X”是C1-6烷氧基的通式I化合物,或者
e)将其中X’是羟基或C1-6烷氧基、X”是C1-6烷氧基的通式I化合物与卤代三甲基硅烷反应形成其中X’和X”是羟基的通式I化合物。
14.一种生产用于治疗与兴奋性神经传递质机能亢进相关的适应症的药物组合物的方法,该方法包括将权利要求1的通式I化合物或其可药用盐制成盖仑制剂剂形。
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DK162491D0 (da) * | 1991-09-20 | 1991-09-20 | Novo Nordisk As | Heterocycliske forbindelser, deres fremstilling og farmaceutiske praeparater indeholdende forbindelserne |
WO1993020077A1 (en) * | 1992-04-03 | 1993-10-14 | Yamanouchi Pharmaceutical Co., Ltd. | Fused quinoxalinone derivative and pharmaceutical composition containing the same |
DK31093D0 (zh) * | 1993-03-19 | 1993-03-19 | Novo Nordisk As | |
KR100304177B1 (ko) * | 1993-05-06 | 2001-11-22 | 한센 핀 베네드, 안네 제헤르, 웨이콥 마리안느 | (1,2,4)트리아졸로(4,3-a)퀴녹살린화합물,이의제조방법및이를함유하는약제학적조성물_ |
-
1995
- 1995-09-12 CN CN95195697A patent/CN1193973A/zh active Pending
- 1995-09-12 DK DK95930410T patent/DK0781282T3/da active
- 1995-09-12 CA CA002200056A patent/CA2200056A1/en not_active Abandoned
- 1995-09-12 TW TW084109492A patent/TW397835B/zh not_active IP Right Cessation
- 1995-09-12 DE DE69511420T patent/DE69511420T2/de not_active Expired - Fee Related
- 1995-09-12 KR KR1019970701669A patent/KR970706285A/ko not_active Application Discontinuation
- 1995-09-12 WO PCT/DK1995/000365 patent/WO1996008493A1/en not_active Application Discontinuation
- 1995-09-12 SK SK334-97A patent/SK282457B6/sk unknown
- 1995-09-12 AU AU33808/95A patent/AU694554B2/en not_active Ceased
- 1995-09-12 EP EP95930410A patent/EP0781282B1/en not_active Expired - Lifetime
- 1995-09-12 HU HU9701241A patent/HUT76802A/hu unknown
- 1995-09-12 PL PL95319175A patent/PL319175A1/xx unknown
- 1995-09-12 ES ES95930410T patent/ES2138233T3/es not_active Expired - Lifetime
- 1995-09-12 AT AT95930410T patent/ATE183186T1/de not_active IP Right Cessation
- 1995-09-12 JP JP8509828A patent/JPH10506620A/ja active Pending
- 1995-09-12 CZ CZ97753A patent/CZ284930B6/cs not_active IP Right Cessation
- 1995-09-12 NZ NZ292108A patent/NZ292108A/xx unknown
- 1995-09-14 IL IL11529995A patent/IL115299A0/xx unknown
- 1995-09-15 ZA ZA957794A patent/ZA957794B/xx unknown
-
1997
- 1997-03-14 FI FI971076A patent/FI971076A/fi unknown
- 1997-03-14 NO NO971187A patent/NO308797B1/no not_active IP Right Cessation
-
1999
- 1999-11-09 GR GR990402881T patent/GR3031788T3/el unknown
Also Published As
Publication number | Publication date |
---|---|
NO971187D0 (no) | 1997-03-14 |
NZ292108A (en) | 1999-02-25 |
DK0781282T3 (da) | 2000-02-28 |
CZ284930B6 (cs) | 1999-04-14 |
SK33497A3 (en) | 1998-02-04 |
CZ75397A3 (en) | 1997-08-13 |
NO308797B1 (no) | 2000-10-30 |
HUT76802A (en) | 1997-11-28 |
DE69511420T2 (de) | 2000-03-30 |
KR970706285A (ko) | 1997-11-03 |
ZA957794B (en) | 1996-05-14 |
ATE183186T1 (de) | 1999-08-15 |
FI971076A0 (fi) | 1997-03-14 |
SK282457B6 (sk) | 2002-02-05 |
IL115299A0 (en) | 1995-12-31 |
AU3380895A (en) | 1996-03-29 |
PL319175A1 (en) | 1997-08-04 |
TW397835B (en) | 2000-07-11 |
EP0781282A1 (en) | 1997-07-02 |
WO1996008493A1 (en) | 1996-03-21 |
GR3031788T3 (en) | 2000-02-29 |
EP0781282B1 (en) | 1999-08-11 |
NO971187L (no) | 1997-05-15 |
AU694554B2 (en) | 1998-07-23 |
ES2138233T3 (es) | 2000-01-01 |
JPH10506620A (ja) | 1998-06-30 |
FI971076A (fi) | 1997-05-13 |
DE69511420D1 (de) | 1999-09-16 |
CA2200056A1 (en) | 1996-03-21 |
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