CN111801096A - 癫痫治疗剂 - Google Patents
癫痫治疗剂 Download PDFInfo
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- CN111801096A CN111801096A CN201980016269.XA CN201980016269A CN111801096A CN 111801096 A CN111801096 A CN 111801096A CN 201980016269 A CN201980016269 A CN 201980016269A CN 111801096 A CN111801096 A CN 111801096A
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- bipyridinyl
- pyrano
- dihydro
- oxo
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Abstract
本发明提供了一种组合药剂,该组合药剂组合N‑[(1S)‑2,2,5,7‑四氟‑2,3‑二氢‑1H‑茚‑1‑基]磺酰胺与AMPA型谷氨酸受体拮抗剂,如3‑(2‑氰基苯基)‑5‑(2‑吡啶基)‑1‑苯基‑1,2‑二氢吡啶‑2‑酮或2‑氟‑6‑(3‑氟‑8‑氧代‑7‑(吡啶‑3‑基)‑7,8‑二氢‑6H‑吡喃并[3,2‑b:5,4‑b']联吡啶‑9‑基)苯甲腈,并且该组合药剂具有用作用于癫痫的治疗剂的潜力。
Description
技术领域
本发明涉及用于癫痫的治疗剂,该治疗剂组合茚满-1-基磺酰胺衍生物和AMPA型谷氨酸受体拮抗剂。更具体地说,本发明涉及用于癫痫的治疗剂,该治疗剂组合N-[(1S)-2,2,5,7-四氟-2,3-二氢-1H-茚-1-基]磺酰胺(或其药学上可接受的盐)和AMPA型谷氨酸受体拮抗剂。
背景技术
癫痫是最常见的中枢神经系统疾病之一,影响了全世界超过50000000或更多的人。WHO将癫痫定义为“其特征是由于脑神经元的过度放电的反复发作(癫痫发作),伴随高度变化的临床和实验室检查结果的多病因慢性脑部疾病”。
癫痫发作的已知类型的实例包括部分性发作,如简单部分性发作、复杂部分性发作、和继发性全身性发作;以及无发作、肌阵挛性发作、阵挛性发作、强直性发作、强直性阵挛性发作、和猝倒。难治性癫痫的已知类型包括West综合征、兰诺克斯综合征、结节性硬化症、Dravet综合征、和脆性X综合征。癫痫治疗的重点是用抗癫痫药物(AED)的药物治疗。癫痫药物的目标是消除癫痫发作,同时避免治疗的副作用。使用抗癫痫药物的治疗通常从单药剂开始。单药治疗将通常使用2或3种不同类型的药物进行,且如果发现没有效果,随后可能会进行组合疗法。约70%的新诊断的癫痫患者可以期待用抗癫痫药物治疗缓解发作。而对于剩下的30%的患者,即使使用现有药物进行组合疗法,癫痫发作也很难抑制。因此,需要开发高效的组合疗法。
用于治疗癫痫的市售的药物的实例包括卡马西平、乙琥胺、苯巴比妥、苯妥英、扑痫酮、丙戊酸钠、唑尼沙胺、非尔氨酯、加巴喷丁、拉莫三嗪、托吡酯、噻加宾、左乙拉西坦、奥卡西平、艾司利卡西平、普瑞巴林、拉科酰胺、卢非酰胺、三甲双酮、舒噻美、乙酰唑胺、氨己烯酸、苯二氮类药物(如氯硝西泮、氯巴占、硝西泮、和地西泮)、吡仑帕奈、和瑞替加滨(NPL 1)。这些现有抗癫痫药物通过抑制神经元的过度兴奋来显示其效果。
用抗癫痫药物的药物疗法中的主要问题之一是由于神经功能的抑制引起的中毒症状(症状包括头晕、眼球震颤、复视、嗜睡、呕吐、共济失调、神经症状、萎靡不振、和意志丧失)。对大多数常规的抗癫痫药物,这些副作用表现为剂量依赖方式,且其组构成了限制治疗剂的选择和剂量的主要问题。其也显著地降低需要长期使用这些药物的癫痫患者的生活质量。降低组合药剂中单个活性成分的剂量可能会在有效剂量和神经毒性剂量之间产生差异,因此允许不仅为对药物治疗产生耐药性的病例,而且也为一般的癫痫病例提供更安全和更有效的治疗。
据报道,茚满-1-基磺酰胺衍生物如N-[(1S)-2,2,5,7-四氟-2,3-二氢-1H-茚-1-基]磺酰胺(在下文中也被称为“化合物(Ia)”)、N-[(1S)-2,2,4,7-四氟-2,3-二氢-1H-茚-1-基]磺酰胺(在下文中也被称为“化合物(Ib)”)、和(+)N-(2,2,4,6,7-五氟-2,3-二氢-1H-茚-1-基)磺酰胺(在下文中也被称为“化合物(Ic)”)(分别用式(Ia)、(Ib)、和(Ic)表示)在小鼠点燃模型(癫痫模型)中显示癫痫发作严重程度(评分)的改善效果,且作为癫痫治疗剂是有用的(PTL 1)。
AMPA型谷氨酸受体在癫痫波的产生和其通过突触的传播中起到了重要作用。AMPA型谷氨酸受体拮抗剂抑制通过谷氨酸盐的突触后的AMPA型谷氨酸受体的活性,抑制神经的过度兴奋并降低癫痫发作。到目前为止,大量的AMPA型谷氨酸受体拮抗剂已经被报道。之前提到的,已经被市售的用于癫痫治疗的药物吡仑帕奈(3-(2-氰基苯基)-5-(2-吡啶基)-1-苯基-1,2-二氢吡啶-2-酮)(由化学式(II)表示,在下文中也被称为“化合物(II)”)是AMPA型谷氨酸受体拮抗剂。
包括由化学式(III)表示的化合物(在下文中也被称为“化合物(III)”)的吡喃二吡啶化合物也对AMPA型谷氨酸受体显示拮抗作用,并且据报道,该吡喃二吡啶类化合物作为癫痫治疗剂(PTL 2)是非常有用的。
引证文献清单
专利文献
[PTL 1]国际专利公开号WO 2013/191144
[PTL 2]国际专利公开号WO 2017/82288
非专利文献
[NPL 1]Shrivastava等人,“An overview on antiepileptic drugs”[抗癫痫药概述],Drug Discoveries&Therapeutics.[药物发现与治疗],第6卷,第4期,第178-193页,2012
发明内容
技术问题
本发明的目的是提供显示强大的抗惊厥作用并且具有用作用于癫痫的治疗剂的潜力的组合药剂。
问题的解决方案
为了解决这个问题,诸位发明人已经使用小鼠声音诱导的惊厥模型和大鼠锂-毛果芸香碱癫痫持续状态模型进行了认真的调查。结果发现,茚满-1-基磺酰胺衍生物和AMPA型谷氨酸受体拮抗剂的组合显著地抑制小鼠声音诱导的惊厥模型中的声音诱导的惊厥。使用大鼠锂-毛果芸香碱癫痫持续状态模型进行进一步的研究后,发现茚满-1-基磺酰胺衍生物和AMPA型谷氨酸受体拮抗剂的组合显著地抑制癫痫持续状态发作,于是完成了本发明。
具体地,本发明涉及以下<1>至<14>。
<1>一种用于癫痫的治疗剂,其组合使用N-[(1S)-2,2,5,7-四氟-2,3-二氢-1H-茚-1-基]磺酰胺
或其药学上可接受的盐,和AMPA型谷氨酸受体拮抗剂。
<2>一种用于癫痫的治疗剂,其同时或分开施用N-[(1S)-2,2,5,7-四氟-2,3-二氢-1H-茚-1-基]磺酰胺
或其药学上可接受的盐,和AMPA型谷氨酸受体拮抗剂。
<3>一种用于癫痫的治疗剂,该治疗剂包含N-[(1S)-2,2,5,7-四氟-2,3-二氢-1H-茚-1-基]磺酰胺
或其药学上可接受的盐,和AMPA型谷氨酸受体拮抗剂。
<4>根据上述<1>至<3>中任一项所述的治疗剂,其中该AMPA型谷氨酸受体拮抗剂是选自由以下组成的组的化合物或其药学上可接受的盐:
3-(2-氰基苯基)-5-(2-吡啶基)-1-苯基-1,2-二氢吡啶-2-酮、
9-(2-氯苯基)-7-(吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
2-氟-6-(7-(5-甲氧基吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-氟-6-(7-(6-甲基吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
9-(2-氯-3-氟苯基)-7-(6-甲基吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
2-氟-6-(7-(2-甲氧嘧啶-5-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
7-(吡啶-3-基)-9-(2,3,5,6-四氟苯基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
3-(8-氧代-7-(噻吩-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
3-(8-氧代-7-(噻吩-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡嗪-2-甲腈、
9-(2-氟苯基)-7-苯基-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
2-(7-(4-氟苯基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
3-(7-(4-氟苯基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
3-(7-(2-氟苯基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
3-(3-氟-8-氧代-7-苯基-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
2-氟-6-(3-氟-8-氧代-7-(吡啶-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-氟-6-(7-(5-氟吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-氟-6-(10-氟-3-氧代-4-(吡啶-3-基)-4,5-二氢-3H-苯并吡喃[3,4-b]吡啶-2-基)苯甲腈、
9-(2-氯-3-氟苯基)-7-(5-氟吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
2-氟-6-(8-氧代-7-(嘧啶-5-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
3,6-二氟-2-(8-氧代-7-(吡啶-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-(7-(5-氯吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)-6-氟苯甲腈、
2-氟-6-(7-(2-甲基嘧啶-5-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、和
9-(3-氟-2-甲苯基)-7-(吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮,
<5>根据上述<1>至<3>中任一项所述的治疗剂,其中AMPA型谷氨酸受体拮抗剂是3-(2-氰基苯基)-5-(2-吡啶基)-1-苯基-1,2-二氢吡啶-2-酮
或其药学上可接受的盐。
<6>根据上述<1>至<3>中任一项所述的治疗剂,其中该AMPA型谷氨酸受体拮抗剂是选自由以下组成的组的化合物或其药学上可接受的盐:
9-(2-氯苯基)-7-(吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
2-氟-6-(7-(5-甲氧基吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-氟-6-(7-(6-甲基吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
9-(2-氯-3-氟苯基)-7-(6-甲基吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
2-氟-6-(7-(2-甲氧嘧啶-5-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
7-(吡啶-3-基)-9-(2,3,5,6-四氟苯基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
3-(8-氧代-7-(噻吩-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
3-(8-氧代-7-(噻吩-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡嗪-2-甲腈、
9-(2-氟苯基)-7-苯基-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
2-(7-(4-氟苯基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
3-(7-(4-氟苯基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
3-(7-(2-氟苯基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
3-(3-氟-8-氧代-7-苯基-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
2-氟-6-(3-氟-8-氧代-7-(吡啶-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-氟-6-(7-(5-氟吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-氟-6-(10-氟-3-氧代-4-(吡啶-3-基)-4,5-二氢-3H-苯并吡喃[3,4-b]吡啶-2-基)苯甲腈、
9-(2-氯-3-氟苯基)-7-(5-氟吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
3,6-二氟-2-(8-氧代-7-(吡啶-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-(7-(5-氯吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)-6-氟苯甲腈、
2-氟-6-(7-(2-甲基嘧啶-5-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
和9-(3-氟-2-甲苯基)-7-(吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮,
<7>根据上述<1>至<3>中任一项所述的治疗剂,其中该AMPA型谷氨酸受体拮抗剂是2-氟-6-(3-氟-8-氧代-7-(吡啶-3-基)-7,8-二氢-6H-吡喃酮[3,2-b:5,4-b']联吡啶-9-基)苯甲腈
或其药学上可接受的盐。
<8>一种通过与N-[(1S)-2,25,7-四氟-2,3-二氢-1H-茚-1-基]磺酰胺
或其药学上可接受的盐组合使用的用于治疗癫痫的AMPA型谷氨酸受体拮抗剂。
或其药学上可接受的盐,通过与AMPA型谷氨酸受体拮抗剂组合使用来治疗癫痫。
<10>一种用于治疗癫痫的方法,该方法组合使用N-[(1S)-2,2,5,7-四氟-2,3-二氢-1H-茚-1-基]磺酰胺
或其药学上可接受的盐,和AMPA型谷氨酸受体拮抗剂。
<11>一种药物组合物,该药物组合物包含N-[(1S)-2,2,5,7-四氟-2,3-二氢-1H-茚-1-基]磺酰胺
或其药学上可接受的盐、AMPA型谷氨酸受体拮抗剂、和赋形剂。
<12>一种试剂盒,该试剂盒包含:
药物组合物,该药物组合物包含N-[(1S)-2,2,5,7-四氟-2,3-二氢-1H-茚-1-基]磺酰胺
或其药学上可接受的盐和赋形剂,以及
药物组合物,该药物组合物包含AMPA型谷氨酸受体拮抗剂和赋形剂。
或其药学上可接受的盐组合使用。
<14>N-[(1S)-2,2,5,7-四氟-2,3-二氢-1H-茚-1-基]磺酰胺
或其药学上可接受的盐用于产生用于癫痫的治疗剂的用途,通过与AMPA型谷氨酸受体拮抗剂组合使用。
由式(III)至(XXIV)表示的化合物将在下文中统称为“化合物(III)至(XXIV)”。
发明的有利效果
本发明提供将茚满-1-基磺酰胺衍生物和AMPA型谷氨酸受体拮抗剂组合的药物。该药物展示出比当每个组分单独使用时更显著的抗癫痫效果,并且其具有用作用于癫痫的治疗剂的潜力。
附图说明
图1显示了对于测试实例2,在大鼠锂-毛果芸香碱癫痫持续状态模型中的化合物(Ia)和化合物(II)的组合的效果。
图2显示了对于测试实例3,在大鼠锂-毛果芸香碱癫痫持续状态模型中的化合物(Ia)和化合物(XVI)的组合的效果。
具体实施方式
现在将详细解释本发明。
例如,化合物(Ia)、(Ib)、或(Ic),或其药学上可接受的盐可以通过PTL 1中描述的方法产生。例如,化合物(II)或其药学上可接受的盐可以通过国际专利公开号WO 2006/004100中描述的方法产生。例如,化合物(III)至(XXIV)或其药学上可接受的盐可以通过PTL 2中描述的方法产生。
“药学上可接受的盐”没有特别的限制,只要其是与本发明的化合物形成,并且具体实例包括酸加成盐,例如无机酸盐、有机酸盐、或酸性氨基酸盐。
无机酸盐的实例包括盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、或磷酸盐。有机酸的盐的实例包括乙酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、乳酸盐、硬脂酸盐、苯甲酸盐、甲基磺酸盐、乙基磺酸盐、和对甲苯磺酸盐。
酸性氨基酸盐的实例包括天冬氨酸盐和谷氨酸盐。
本发明的治疗剂可以含有化合物(Ia)、(Ib)、或(Ic),或其药学上可接受的盐,和AMPA型谷氨酸受体拮抗剂(即选自由化合物(II)和化合物(III)至(XXIV),或其药学上可接受的盐(分别用公式表示)组成的组),并且两者同时或分开施用。这两种制剂也可以放在单独的包装中作为试剂盒配制品。两个化合物也可以被包括在单个配制品中。
本发明的治疗剂能通过混合药学上可接受的添加剂和化合物(Ia)、(Ib)、或(Ic)或其药学上可接受的盐,和/或选自由化合物(II)和化合物(III)至(XXIV)或其药学上可接受的盐组成的组的化合物。本发明的癫痫治疗剂可通过已知的方法产生,例如GeneralRules for Preparations of the Japanese Pharmacopoeia[日本药典的制备通则],第16版中描述的方法。
本发明的治疗剂可用适当的剂型适当地施用至患者。
在本发明的治疗剂中,化合物(Ia)、(Ib)、或(Ic)或其药学上可接受的盐的剂量将根据症状的严重程度、患者的年龄、性别、体重、和敏感性、施用的时间和方法、和医药配制品的类型而不同,但通常对于成年人(60kg体重)的每日口服剂量为100μg至5g,或可替代地300μg至3g、或又可替代地1mg至1g,或注射施用剂量为30μg至1g、可替代地30μg至500mg、或又可替代地50μg至300mg,一次性或分批的给予。
在本发明的治疗剂中,选自由化合物(II)和化合物(III)至(XXIV)或其药学上可接受的盐组成的组的化合物的剂量可按上述方式适当选择。用于成年人(60kg体重)的口服,每日施用通常为10μg至500mg、可替代地30μg至300mg、或又可替代地50μg至100mg,或对于注射施用为3μg至100mg、可替代地10μg至100mg、或又可替代地10μg至50mg,一次性或分批的给予。
化合物(Ia)、(Ib)、或(Ic)或其药学上可接受的盐的剂量(在本发明的治疗剂中)和选自由化合物(II)和化合物(III)至(XXIV)或其药学上可接受的盐组成的组的化合物剂量,将根据症状的严重程度、患者的年龄、性别、体重、和敏感性、施用的时间和方法、和医药配制品的类型而不同。通常,对成年人(60kg体重)的口服,化合物(Ia)、(Ib)、或(Ic)或其药学上可接受的盐的每日施用为100μg至5g,并且选自由化合物(II)和化合物(III)至(XXIV)或其药学上可接受的盐组成的组的化合物的每日施用为10μg至500mg,一次性或分批的给予。可替代地,对成年人(60kg体重)的口服,化合物(Ia)、(Ib)、或(Ic)或其药学上可接受的盐的每日施用为300μg至3g,并且选自由化合物(II)和化合物(III)至(XXIV)或其药学上可接受的盐组成的组的化合物的每日施用为30μg至300mg,一次性或分批的给予。又可替代地,对成年人(60kg体重)的口服,化合物(Ia)、(Ib)、或(Ic)或其药学上可接受的盐的每日施用为1mg至1g,并且选自由化合物(II)和化合物(III)至(XXIV)或其药学上可接受的盐组成的组的化合物的每日施用为50μg至100mg,一次性或分批的给予。通常,对成年人(60kg体重)的注射施用,化合物(Ia)、(Ib)、或(Ic)或其药学上可接受的盐的每日施用将为30μg至1g,并且选自由化合物(II)和化合物(III)至(XXIV)或其药学上可接受的盐组成的组的化合物的每日施用将为3μg至100mg,一次性或分批的给予。可替代地,对成年人(60kg体重)的注射施用,化合物(Ia)、(Ib)、或(Ic)或其药学上可接受的盐的每日施用可为30μg至500mg,并且选自由化合物(II)和化合物(III)至(XXIV)或其药学上可接受的盐组成的组的化合物的每日施用将为10μg至100mg,一次性或分批的给予。又可替代地,对成年人(60kg体重)的注射施用,化合物(Ia)、(Ib)、或(Ic)或其药学上可接受的盐的每日施用可为50μg至300mg,并且选自由化合物(II)和化合物(III)至(XXIV)或其药学上可接受的盐组成的组的化合物的每日施用将为10μg至50mg,一次性或分批的给予。实例
[药理学测试实例]
诸位发明人使用小鼠声音诱导的惊厥模型进行研究以确认对发作的抑制作用。我们也使用大鼠锂-毛果芸香碱癫痫持续状态模型进行了研究以证实对癫痫持续状态发作的抑制作用。
[测试实例1]使用小鼠声音诱导的惊厥模型针对惊厥的抑制效果的确认测试
进行小鼠声音诱导的惊厥模型测试以确认对惊厥的抑制效果。在这个模型中使用声音刺激诱导的强直性惊厥作为评价指标(European Journal of Pharmacology[欧洲药理学杂志],222,第193-203页(1992))。
<方法>
为测试提供了三周龄的雄性DBA/2JJcl小鼠(Clea日本公司)(每次处理n=5,共两次)。使用声音刺激诱导的强直性惊厥作为评价指标(见上述出版物)。
将化合物(Ia)和/或化合物(II)溶解在0.4%甲基纤维素/5%氢化蓖麻油/5%1N盐酸/10%二甲亚砜溶液中(各自20mL/kg的施用剂量)以制备用于口服施用的样品。使用不含化合物(媒介物)的混合溶液来作为阴性对照。组的组成如表1所示。在施用样品后进行声音刺激(11kHz,115dB,持续时间:30秒)30分钟,以诱发惊厥。在声音刺激停止后,立即通过观察后肢伸展是否存在来评估强直性惊厥。计算每个施用组中显示强直性惊厥的百分比(%强直性惊厥)。
基于计算的%强直性惊厥,通过回归分析计算单独施用化合物(Ia)的组、单独施用化合物(II)的组、和施用化合物(Ia)和化合物(II)(分别为化合物(Ia)ED50、化合物(II)ED50、和ED50 mix)的组合的组的50%有效剂量。按照文献中描述的方法(Epilepsia,44,第1003-1013页(2003)),计算理论添加ED50值(ED50 add),并且使用等压图法进行评价,当ED50 mix/ED50 add比率低于0.7时具有协同作用,当它是0.7至1.3时具有加成作用,并且当它大于1.3时具有拮抗作用。
<结果>
小鼠声音诱导的惊厥模型中的每个施用组的ED50如表2所示。计算的理论添加ED50值(ED50 add)为26mg/kg。因为ED50mix/ED50 add比率结果是0.58(表3),因此证明了化合物(Ia)和化合物(II)的组合显示协同抗惊厥效果。结果表明本发明的药物对惊厥显示显著的抑制效果。
[表1]
组号 | 处理 |
1 | 媒介物 |
2 | 25mg/kg化合物(Ia) |
3 | 50mg/kg化合物(Ia) |
4 | 100mg/kg化合物(Ia) |
5 | 200mg/kg化合物(Ia) |
6 | 0.125mg/kg化合物(II) |
7 | 0.25mg/kg化合物(II) |
8 | 0.5mg/kg化合物(II) |
9 | 1mg/kg化合物(II) |
10 | 7.5mg/kg化合物(Ia)+0.05mg/kg化合物(II) |
11 | 15mg/kg化合物(Ia)+0.1mg/kg化合物(II) |
12 | 30mg/kg化合物(Ia)+0.2mg/kg化合物(II) |
13 | 60mg/kg化合物(Ia)+0.4mg/kg化合物(II) |
[表2]
化合物 | ED50 |
(Ia) | 53mg/kg |
(II) | 0.33mg/kg |
(Ia)+(II) | 15mg/kg |
[表3]
ED50mix | 15mg/kg |
ED50add | 26mg/kg |
比率(ED50mix/ED50add) | 0.58 |
评估 | 协同作用 |
[测试实例2]使用大鼠锂-毛果芸香碱癫痫持续状态模型对癫痫持续状态发作的抑制作用的确认测试(1)
进行大鼠锂-毛果芸香碱癫痫持续状态模型测试以证实对癫痫持续状态发作的抑制作用。在这个模型中,使用药物诱发的脑波峰值等级来作为评价指标(Journal ofNeuroscience Methods[神经科学方法杂志],172,第143-157页(2008))。
<方法>
在三组分混合物(2mg/kg咪达唑仑、0.15mg/kg盐酸美托咪啶、2.5mg/kg酒石酸布托啡诺,皮下施用)麻醉下,将EEG电极被嵌入进颅骨。在手术后至少恢复两天,腹膜内施用氯化锂(127mg/kg的剂量,1mL/kg的施用体积)。一天后,以连续方式腹膜内施用毛果云香碱盐酸盐(30mg/kg的剂量,5mL/kg的施用体积)和(-)-东莨菪碱甲基溴(5mg/kg剂量,1mL/kg体积)以诱导发作。只有展示4或更高的发作得分的发作的动物才被用于实验。表4显示了发作得分和症状之间的关系。视觉上确认4或更高的发作得分后30分钟,将媒介物或样品施用至尾静脉(施用体积:1mL/kg,注射速率:冲洗)。组的组成如表5所示。连续记录脑波,直到媒介物或样品施用后1h。使用脑波分析软件(Kissei Comtec有限公司的SleepSign,长野县(Nagano Prefecture))计算每个设定时期(4秒/时期)的每个单个的脑波数据(分析目标频率:≥5Hz,<100Hz)的总功率(μV2)。在排除包含由于动物移动而产生噪声的时期后,施用前10分钟时期是有针对性的且计算每个时期每个频率的平均功率(μV2),在此之后总和所有的频带以获得每个单个的前总功率(μV2)。在以同样的方式施用1小时时间后进行FFT分析,以计算每个单个的后总功率(μV2)。计算每个单个的后总功率相对于前总功率的百分比((后总功率/前总功率)×100),并进行统计分析。通过未配对的t检验确定媒介物组和施用化合物(Ia)和化合物(II)的组合的组之间的统计显著性。在单因素方差分析以确定单独施用化合物(Ia)的组和单独施用化合物(II)的组,和施用化合物(Ia)和化合物(II)的组合的组之间的统计显著性后,对重要的实例进行Fisher LSD检测。在两种情况下,显著性水平均被认为是5%。
<结果>
图1显示了在大鼠锂-毛果芸香碱癫痫持续状态模型中化合物(Ia)和化合物(II)的组合的效果。与媒介物组比较,给予化合物(Ia)和化合物(II)的组合的组展示出显著的发作抑制效果。甚至与单独给予化合物(Ia)的组和单独给予化合物(II)的组相比,给予化合物(Ia)和化合物(II)的组合的组展示出发作抑制效果的显著增加。这个结果表明本发明的药物对癫痫持续状态发作有显著发作抑制效果。
[测试实例3]使用大鼠锂-毛果芸香碱癫痫持续状态模型对癫痫持续状态发作的抑制作用的确认测试(2)
进行大鼠锂-毛果芸香碱癫痫持续状态模型测试以证实对癫痫持续状态发作的抑制作用。
<方法>
提供六周龄的雄性SD大鼠(查尔斯河实验室(Charles River Laboratories),日本)用于测试。腹膜内施用氯化锂(127mg/kg剂量,1mL/kg施用体积)。一天后,以连续方式的腹膜内施用毛果云香碱盐酸盐(30mg/kg的剂量,5mL/kg的施用体积)和(-)-东莨菪碱甲基溴(5mg/kg剂量,1mL/kg体积)以诱导发作。只有展示发作得分为4或更高的发作的动物才被用于实验。表4显示了发作得分和症状之间的关系。视觉上确认4或更高的发作得分后30分钟,将媒介物或样品被注射入尾静脉(施用体积:1-4mL/kg,注射速率:冲洗)。组的组成如表6所示。如表4所示,施用化合物后1小时,对发作进行评分。由Holm-Sidak统计测试确定媒介物组与单独给予化合物(Ia)的组、单独给予化合物(XVI)的组、以及给予化合物(Ia)和化合物(XVI)的组合的组之间的统计显著性。由Holm-Sidak统计测试也确定了单独给予化合物(Ia)的组和单独给予化合物(XVI)的组,以及给予化合物(Ia)和化合物(XVI)的组合的组之间的统计显著性。在两种情况下,显著性水平均被认为是5%。
<结果>
图2显示在大鼠锂-毛果芸香碱癫痫持续状态模型中化合物(Ia)和化合物(XVI)的组合的效果。与媒介物组相比,给予化合物(Ia)和化合物(XVI)的组合的组展示出显著的发作抑制效果。甚至与单独给予化合物(Ia)的组和单独给予化合物(XVI)的组相比,给予化合物(Ia)和化合物(XVI)的组合的组展示发作抑制效果的显著增加。这个结果表明本发明的药物对癫痫持续状态发作有显著发作抑制效果。
[表4]
发作得分 | 症状 |
0 | 无发作 |
1 | 轻微面部阵挛和眨眼 |
2 | 严重面部阵挛、摇头、咀嚼 |
3 | 单边或交替的前肢阵挛 |
4 | 双侧前肢阵挛和站立 |
5 | 伴随站立和跌倒的双侧前肢阵挛 |
[表5]
组号 | 处理 |
1 | 媒介物 |
2 | 75mg/kg化合物(Ia) |
3 | 1mg/kg化合物(II) |
4 | 75mg/kg化合物(Ia)+1mg/kg化合物(II) |
[表6]
组号 | 处理 |
1 | 媒介物 |
2 | 75mg/kg化合物(Ia) |
3 | 2mg/kg化合物(XVI) |
4 | 75mg/kg化合物(Ia)+2mg/kg化合物(XVI) |
Claims (7)
4.根据权利要求1至3中任一项所述的治疗剂,其中该AMPA型谷氨酸受体拮抗剂是选自由以下组成的组的化合物或其药学上可接受的盐:
3-(2-氰基苯基)-5-(2-吡啶基)-1-苯基-1,2-二氢吡啶-2-酮、
9-(2-氯苯基)-7-(吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
2-氟-6-(7-(5-甲氧基吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-氟-6-(7-(6-甲基吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
9-(2-氯-3-氟苯基)-7-(6-甲基吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
2-氟-6-(7-(2-甲氧嘧啶-5-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
7-(吡啶-3-基)-9-(2,3,5,6-四氟苯基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
3-(8-氧代-7-(噻吩-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
3-(8-氧代-7-(噻吩-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡嗪-2-甲腈、
9-(2-氟苯基)-7-苯基-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
2-(7-(4-氟苯基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
3-(7-(4-氟苯基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
3-(7-(2-氟苯基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
3-(3-氟-8-氧代-7-苯基-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
2-氟-6-(3-氟-8-氧代-7-(吡啶-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-氟-6-(7-(5-氟吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-氟-6-(10-氟-3-氧代-4-(吡啶-3-基)-4,5-二氢-3H-苯并吡喃[3,4-b]吡啶-2-基)苯甲腈、
9-(2-氯-3-氟苯基)-7-(5-氟吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
2-氟-6-(8-氧代-7-(嘧啶-5-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
3,6-二氟-2-(8-氧代-7-(吡啶-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-(7-(5-氯吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)-6-氟苯甲腈、
2-氟-6-(7-(2-甲基嘧啶-5-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、和
9-(3-氟-2-甲苯基)-7-(吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮,
6.根据权利要求1至3中任一项所述的治疗剂,其中该AMPA型谷氨酸受体拮抗剂是选自由以下组成的组的化合物或其药学上可接受的盐:
9-(2-氯苯基)-7-(吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
2-氟-6-(7-(5-甲氧基吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-氟-6-(7-(6-甲基吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
9-(2-氯-3-氟苯基)-7-(6-甲基吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
2-氟-6-(7-(2-甲氧嘧啶-5-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
7-(吡啶-3-基)-9-(2,3,5,6-四氟苯基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
3-(8-氧代-7-(噻吩-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
3-(8-氧代-7-(噻吩-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡嗪-2-甲腈、
9-(2-氟苯基)-7-苯基-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
2-(7-(4-氟苯基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
3-(7-(4-氟苯基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
3-(7-(2-氟苯基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
3-(3-氟-8-氧代-7-苯基-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)吡啶甲腈、
2-氟-6-(3-氟-8-氧代-7-(吡啶-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-氟-6-(7-(5-氟吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-氟-6-(10-氟-3-氧代-4-(吡啶-3-基)-4,5-二氢-3H-苯并吡喃[3,4-b]吡啶-2-基)苯甲腈、
9-(2-氯-3-氟苯基)-7-(5-氟吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮、
2-氟-6-(8-氧代-7-(嘧啶-5-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
3,6-二氟-2-(8-氧代-7-(吡啶-3-基)-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
2-(7-(5-氯吡啶-3-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)-6-氟苯甲腈、
2-氟-6-(7-(2-甲基嘧啶-5-基)-8-氧代-7,8-二氢-6H-吡喃并[3,2-b:5,4-b']联吡啶-9-基)苯甲腈、
和9-(3-氟-2-甲苯基)-7-(吡啶-3-基)-6H-吡喃并[3,2-b:5,4-b']联吡啶-8(7H)-酮,
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