CN103002893B - 神经障碍性疼痛的治疗药或预防药 - Google Patents
神经障碍性疼痛的治疗药或预防药 Download PDFInfo
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- CN103002893B CN103002893B CN201180037529.5A CN201180037529A CN103002893B CN 103002893 B CN103002893 B CN 103002893B CN 201180037529 A CN201180037529 A CN 201180037529A CN 103002893 B CN103002893 B CN 103002893B
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Abstract
本发明的目的在于提供神经障碍性疼痛的治疗药或预防药,该药物在不引起钙通道α2δ配体的副作用的用量下协同地提高镇痛作用,也不会产生新的中枢神经***的副作用。本发明提供神经障碍性疼痛的治疗药或预防药,该药物含有下式所代表的环己烷衍生物或其药理学上可接受的盐或其前体药物、和钙通道α2δ配体作为有效成分。
Description
技术领域
本发明涉及神经障碍性疼痛的治疗药或预防药。
背景技术
神经障碍性疼痛(也称作神经源性疼痛)是指,由末梢或中枢的体性感觉神经***的障碍或疾病引起的疼痛,是指虽然侵害接受器没有受到侵害刺激、但由于神经组织的直接的损伤或压迫等而产生的疼痛。
作为神经障碍性疼痛的治疗药,使用抗痉挛药、抗抑郁药、抗焦虑药、或作为钙通道α2δ配体的普瑞巴林、加巴喷丁等抗癫痫药(非专利文献1)。其中,已知普瑞巴林是神经障碍性疼痛的世界性的标准治疗药,但通过给予该药,经常出现头晕、嗜睡、运动失调、乏力感等认为是基于中枢神经***的抑制作用的副作用(非专利文献2)。
近年来,为了减少普瑞巴林或加巴喷丁的给药量,人们在研究上述的钙通道α2δ配体与各种药物的联用,例如,有报道称:通过将作为磷酸二酯酶5型抑制剂的西地那非、他达拉非、伐地那非(专利文献1)或其他药物(专利文献2~10和非专利文献8~12)与钙通道α2δ配体联用、或者将作为非阿片类镇痛药的对乙酰氨基酚(非专利文献3)或硝基对乙酰氨基酚(非专利文献4)、作为阿片类镇痛药的羟考酮(非专利文献5)或***(非专利文献13)、作为维生素B1衍生物的苯磷硫胺(非专利文献6)或作为维生素B12的氰钴胺(非专利文献6)与加巴喷丁联用,得到协同的镇痛作用。而且,还有报道称,通过将加巴喷丁、多奈哌齐(胆碱酯酶抑制剂)和度洛西汀(5-羟色胺和去甲肾上腺素再摄取抑制剂)这三种药物联用,得到协同的镇痛作用(非专利文献7)。
现有技术文献
专利文献
专利文献1:国际公开第04/016259号;
专利文献2:国际公开第10/025931号;
专利文献3:国际公开第09/021058号;
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专利文献10:国际公开第01/013904号;
专利文献11:国际公开第10/050577号;
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发明内容
发明所要解决的课题
但是,在钙通道α2δ配体的联合疗法中,现实状况是:为了降低钙通道α2δ配体自身的副作用,而减少钙通道α2δ配体的用量,由此导致无法发挥充分的镇痛作用;或者提高联用药物的用量,由此产生新的副作用。例如,有报道称:在加巴喷丁与***的联用中,在用于得到协同的镇痛作用的用量下出现运动协调障碍(非专利文献13),认为即使是使用其他药物作为联用药物的情况下,为了得到协同的镇痛作用,也难以避免产生中枢神经***的副作用。
因此,本发明的目的在于提供神经障碍性疼痛的治疗药或预防药,该药物在不引起钙通道α2δ配体的副作用的用量下协同地提高镇痛作用,也不会产生新的中枢神经***的副作用。
解决课题的方法
本发明人等为了解决上述课题反复进行了深入研究,结果发现:通过将钙通道α2δ配体和对神经障碍性疼痛显示出优异的镇痛效果的环己烷衍生物联用,协同地提高对神经障碍性疼痛的镇痛作用,并且不会使钙通道α2δ配体引起的中枢神经***的副作用加重。
即,本发明提供神经障碍性疼痛的治疗药或预防药,该药物含有下述通式(I)所示的环己烷衍生物或其药理学上可接受的盐或其前体药物、和钙通道α2δ配体作为有效成分:
[化学式1]
式中,A为通式(IIa)或(IIb)所表示的取代基;
[化学式2]
R1和R2各自独立表示氢原子、氯原子、碳原子数为1~3的卤烷基、碳原子数为1~4的烷基或碳原子数为1~4的烷氧基,R3为氢原子或氯原子,R4为氟原子、羟甲基或羟基,R5和R6各自独立表示氢原子、氟原子、碳原子数为1~3的卤烷基、羧基、甲氧基羰基、乙氧基羰基、碳原子数为1~4的烷氧基、羟基或碳原子数为2~5的烷基羰氧基,或者可以一起形成桥氧基;R7和R8各自独立表示氢原子或氟原子,Y为氧原子或硫原子,Z为氮原子或次甲基。
上述的环己烷衍生物或其药理学上可接受的盐或其前体药物优选:R1和R2各自独立表示三氟甲基、甲基或甲氧基,R3为氢原子,R4为羟甲基或羟基,R5和R6各自独立表示氢原子、氟原子、三氟甲基、羧基、甲氧基、羟基或乙酰氧基(可以一起形成桥氧基)。
另外,上述的钙通道α2δ配体优选普瑞巴林或加巴喷丁,更优选普瑞巴林。
发明效果
本发明的神经障碍性疼痛的治疗药或预防药,虽然减少了钙通道α2δ配体的给药量,但是可以协同地增强钙通道α2δ配体所具有的镇痛作用,可以大幅减少中枢神经***的副作用的发生。
附图说明
图1是显示在小鼠Seltzer模型中化合物3与普瑞巴林联用的效果的图(口服给药1小时后、2小时后和3小时后的经时性变化);
图2-A是显示在小鼠Seltzer模型中化合物3与普瑞巴林联用的效果的图(口服给药1小时后);
图2-B是显示在小鼠Seltzer模型中化合物3与普瑞巴林联用的效果的图(口服给药2小时后);
图3是显示在小鼠旋转笼试验中化合物3与普瑞巴林联用的效果的图(口服给药0.5~1.5小时后);
图4是显示在小鼠Seltzer模型中普瑞巴林单独给药的效果的图(口服给药1小时后);
图5是显示在小鼠旋转笼试验中普瑞巴林单独给药的效果的图(口服给药0.5~1.5小时后)。
具体实施方式
本发明的神经障碍性疼痛的治疗药或预防药,其特征在于:含有下述通式(I)所示的环己烷衍生物或其药理学上可接受的盐或其前体药物、和钙通道α2δ配体作为有效成分:
[化学式3]
式中,A为通式(IIa)或(IIb)所表示的取代基;
[化学式4]
R1和R2各自独立表示氢原子、氯原子、碳原子数为1~3的卤烷基、碳原子数为1~4的烷基或碳原子数为1~4的烷氧基,R3为氢原子或氯原子,R4为氟原子、羟甲基或羟基,R5和R6各自独立表示氢原子、氟原子、碳原子数为1~3的卤烷基、羧基、甲氧基羰基、乙氧基羰基、碳原子数为1~4的烷氧基、羟基或碳原子数为2~5的烷基羰氧基,或者可以一起形成桥氧基;R7和R8各自独立表示氢原子或氟原子,Y为氧原子或硫原子,Z为氮原子或次甲基。
“碳原子数为1~4的烷基”是指碳原子数为1~4的直链状、支链状、环状的烷基,例如可以列举:甲基、乙基、正丙基、异丙基、环丙基、环丙基甲基、正丁基、仲丁基、叔丁基。
“碳原子数为1~4的烷氧基”是指碳原子数为1~4的直链状、支链状、环状的烷基氧基,例如可以列举:甲氧基、乙氧基、正丙氧基、异丙氧基、环丙氧基、正丁氧基、仲丁氧基、叔丁氧基。
“碳原子数为1~3的卤烷基”是指碳原子数为1~3的直链状的烷基上的氢原子的一部分或全部被卤原子(卤原子是指氟原子、氯原子、溴原子、碘原子)取代的基团,例如可以列举:单氯甲基、单氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基。
“碳原子数为2~5的烷基羰氧基”例如可以列举:乙酰氧基(acetyloxy)、乙酰氧基(ethanoyloxy)、丙酰氧基、异丙酰氧基、丁酰氧基、异丁酰氧基或戊酰氧基。
通式(I)中,作为A,优选通式(IIa);作为Y,优选氧原子;作为Z,优选次甲基。
作为R1,优选氢原子、氯原子、三氟甲基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基,更优选三氟甲基、甲基、甲氧基,进一步优选甲基。
作为R2,优选氢原子、氯原子、三氟甲基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基,更优选甲氧基。
作为R3,优选氢原子;作为R4,优选羟甲基、羟基,更优选羟基。
作为R5,优选氢原子、氟原子、三氟甲基、羧基、甲氧基、乙氧基、正丙氧基、异丙氧基、羟基、乙酰氧基、丙酰氧基、丁酰氧基、异丁酰氧基,更优选氢原子、羟基、羧基,进一步优选羟基。
作为R6,优选氢原子、氟原子、三氟甲基、羧基、甲氧基、乙氧基、正丙氧基、异丙氧基、羟基、乙酰氧基、丙酰氧基、丁酰氧基、异丁酰氧基,更优选氢原子、羟基,进一步优选氢原子。另外,R5和R6可以一起形成桥氧基。
作为R7和R8,优选氢原子。
通式(I)所示的环己烷衍生物或其药理学上可接受的盐或其前体药物(以下记作化合物(I))中,优选的具体例子见表1,但这些例子并不限定本发明。
[表1-1]
[表1-2]
[表1-3]
[表1-4]
[表1-5]
需要说明的是,化合物(I)中存在不对称碳原子时的所有的对映异构体以及它们的混合物均包含在化合物(I)中。
而且,化合物(I)中存在立体异构体时的所有的立体异构体以及它们的混合物也均包含在化合物(I)中。
在本发明中,作为与化合物(I)联用的钙通道α2δ配体,例如可以列举:普瑞巴林(S-(+)-4-氨基-3-(2-甲基丙基)丁酸或(S)-3-(氨基甲基)-5-(甲基己酸))或加巴喷丁(1-(氨基甲基)-环己烷乙酸或2-[1-(氨基甲基)环己烷]乙酸)或其药理学上可接受的盐或其前体药物,但优选普瑞巴林或加巴喷丁,更优选普瑞巴林。
“药理学上可接受的盐”例如可以列举:盐酸盐、硫酸盐、磷酸盐、氢溴酸盐等无机酸盐;草酸盐、丙二酸盐、枸橼酸盐、富马酸盐、乳酸盐、苹果酸盐、琥珀酸盐、酒石酸盐、乙酸盐、三氟乙酸盐、马来酸盐、葡萄糖酸盐、苯甲酸盐、抗坏血酸盐、甲磺酸盐、对甲苯磺酸盐、肉桂酸盐等有机酸盐;钠盐、钾盐、钙盐、镁盐、铵盐等无机碱盐;甲胺盐、二乙胺盐、三甲胺盐、三乙胺盐、吡啶盐、三乙醇胺盐、乙二胺盐、胍盐等有机碱盐。而且,化合物(I)可以形成水合物、溶剂合物,多晶形也包含在其中。
化合物(I)例如可以按照公知文献(国际公开第10/050577号)中记载的方法来合成。
钙通道α2δ配体例如可以按照公知文献(日本特开昭51-88940号公报、日本特表平7-508288号公报或日本特表2004-536873号公报)中记载的方法来合成。
含有化合物(I)和钙通道α2δ配体作为有效成分的神经障碍性疼痛的治疗药或预防药,对人以外的哺乳类进行给药时也显示出优异的镇痛作用。这里,作为人以外的哺乳类,例如可以列举:小鼠、大鼠、仓鼠、兔、猫、狗、牛、绵羊、猴。
作为“神经障碍性疼痛”,例如可以列举:癌症性疼痛、带状疱疹痛、带状疱疹后神经痛、艾滋病相关性神经痛、三叉神经痛或糖尿病性神经障碍性疼痛。
作为含有化合物(I)和钙通道α2δ配体作为有效成分的神经障碍性疼痛的治疗药或预防药的给药形式,可以将两者的混合物即混合剂直接或者进一步混合医药上可接受的载体后进行口服或胃肠外给药。或者,还可以将两者不以混合剂的形式、而是各自单独即以单剂的形式准备好,再将它们直接或者进一步分别混合医药上可接受的载体后同时给药。而且,还可以将各自的单剂间隔适当的间隔彼此前后进行给药。在上述情况下,各自的单剂的剂型和给药途径不必相同,各自可以不同。需要说明的是,上述的“适当的间隔”可以通过临床上或动物实验来确认。
作为将化合物(I)和钙通道α2δ配体以单剂或混合剂的形式进行口服给药时的剂型,例如可以列举:片剂(包括糖衣片、薄膜包衣片)、丸剂、颗粒剂、散剂、胶囊剂(包括软胶囊剂、微囊剂)、糖浆剂、乳剂、悬浮剂;作为胃肠外给药时的剂型,例如可以列举:注射剂、注入剂、点滴剂、栓剂。而且,将其与适当的基质(例如丁酸的聚合物、羟基乙酸的聚合物、丁酸-羟基乙酸的共聚物、丁酸的聚合物与羟基乙酸的聚合物的混合物、聚甘油脂肪酸酯等)组合,制成缓释制剂也有效。
化合物(I)和钙通道α2δ配体的上述剂型的单剂或混合剂的制备,可以按照制剂领域通常采用的公知的制备方法来进行。此时,根据需要,可以含有制剂领域通常使用的赋形剂、粘合剂、润滑剂、崩解剂、甜味剂、表面活性剂、悬浮化剂、乳化剂等来制备。
作为化合物(I)和钙通道α2δ配体的单剂或混合剂的片剂的制备,可以含有赋形剂、粘合剂、崩解剂、润滑剂等来进行。作为丸剂和颗粒剂的制备,可以含有赋形剂、粘合剂、崩解剂等来进行。另外,作为散剂和胶囊剂的制备,可以含有赋形剂等来进行;作为糖浆剂的制备,可以含有甜味剂等来进行;作为乳剂和悬浮剂的制备,可以含有表面活性剂、悬浮化剂、乳化剂等来进行。
作为上述的赋形剂,例如可以列举:乳糖、葡萄糖、淀粉、蔗糖、微晶纤维素、甘草粉末、甘露醇、碳酸氢钠、磷酸钙、硫酸钙。
作为上述的粘合剂,例如可以列举:淀粉糊液、***胶溶液、明胶溶液、黄蓍胶溶液、羧甲基纤维素溶液、海藻酸钠溶液、甘油。
作为上述的崩解剂,例如可以列举:淀粉、碳酸钙。
作为上述的润滑剂,例如可以列举:硬脂酸镁、硬脂酸、硬脂酸钙、纯化滑石粉。
作为上述的甜味剂,例如可以列举:葡萄糖、果糖、转化糖、山梨醇、木糖醇、甘油、单糖浆。
作为上述的表面活性剂,例如可以列举:十二烷基硫酸钠、聚山梨酯80、脱水山梨糖醇单脂肪酸酯、聚乙二醇40硬脂酸酯。
作为上述的悬浮化剂,例如可以列举:***胶、海藻酸钠、羧甲基纤维素钠、甲基纤维素、膨润土。
作为上述的乳化剂,例如可以列举:***胶、黄蓍胶、明胶、聚山梨酯80。
而且,在化合物(I)和钙通道α2δ配体的上述剂型的单剂或混合剂的制备中,可以添加制剂领域通常使用的着色剂、保存剂、芳香剂、矫味剂、稳定剂、增稠剂等。
含有钙通道α2δ配体的制剂的每天的给药量根据患者的状态或体重、抑制剂的种类、给药途径等而不同,例如口服给予加巴喷丁时,成人(体重约60kg)优选按照10~3600mg的范围分1~3次进行给药;口服给予普瑞巴林时,成人(体重约60kg)优选按照5~600mg的范围分1~3次进行给药。另外,关于含有化合物(I)的制剂的每天的给药量,例如口服给药时,成人(体重约60kg)优选按照1~1000mg的范围分1~3次进行给药;进行胃肠外给药时,注射剂优选每1kg体重按照0.01~100mg的范围通过静脉注射进行给药。
实施例
以下,根据实施例来具体说明本发明,但本发明并不限于这些实施例。
(实施例1)在小鼠神经障碍性疼痛模型中化合物(I)与钙通道α2δ配体的联用效果:
在评价中,一组使用7~8例5周龄的ICR系雄性小鼠。小鼠神经障碍性疼痛模型按照Seltzer等人(Seltzer等人,Pain,1990年,第43卷,第205页;Malmberg等人,Pain,1998年,第76卷,第215页)的方法来制作。即,在麻醉下暴露小鼠的右侧后肢大腿部的坐骨神经,在显微镜下使用8-0的绢制缝合丝(夏目制作所)只对半周的坐骨神经高强度地进行三重结扎。
作为受检化合物,选择下式所示的、化合物(I)中所包含的1-(1-(4-甲氧基苯基)-5-(对甲苯基)-1H-吡唑-3-基)环己烷-顺式-1,4-二醇(以下记作化合物3)。
[化学式5]
另外,选择普瑞巴林作为钙通道α2δ配体。
小鼠神经障碍性疼痛模型分为以下4组:溶剂给药组(图1和图2的媒介物)、普瑞巴林的3mg/kg单独给药组(图1和图2的普瑞巴林)、化合物3的0.3mg/kg单独给药组(图1和图2的化合物3)、普瑞巴林的3mg/kg和化合物3的0.3mg/kg联合给药组(图1和图2的普瑞巴林+化合物3)。
使用0.5%的甲基纤维素作为溶剂,在上述的坐骨神经结扎手术7天后,对上述的各组给予溶剂、单独给予普瑞巴林悬浮液(3mg/kg)、单独给予化合物3悬浮液(0.3mg/kg)或给予普瑞巴林和化合物3的混合悬浮液(分别为3mg/kg、0.3mg/kg) (联合给药)。
在神经障碍性疼痛的评价(以下记作von Frey试验)中,将神经障碍性疼痛模型小鼠在设置于网上的测定用Acryl笼(夏目制作所)内驯化最低1小时,之后使用施加了0.16g的压力的长丝(North Coast Medical.Inc.),在两侧后肢的足底以3秒的间隔反复3次施加按压长丝3秒的机械性触刺激,对施加机械性触刺激时的逃避行为的强度进行打分(0:没有反应;1:对刺激作出缓慢且轻微的逃避行为;2:不伴有畏缩(敏捷且连续地摆足的行为)或舔足(舔足行为)、且对刺激作出快速的逃避行为;3:伴有畏缩或舔足的快速的逃避行为),以该3次分数的总和作为总分数。
在坐骨神经结扎手术7天后的受检化合物给药前、给药1小时后、2小时后和3小时后分别实施von Frey试验。作为从受检化合物给药前的总分数到受检化合物给药后的总分数变化,求出从受检化合物给药前的总分数中减去受检化合物给药后的各时刻的总分数而得到的值(以下记作ΔvF试验分数),以该值作为镇痛作用的指标。
另外,根据化合物3或普瑞巴林各自单独给药时的ΔvF试验分数,算出假定化合物3和普瑞巴林联用只显示出协同的镇痛作用时的理论上的ΔvF试验分数即理论总计值。即,将普瑞巴林单独给药组和化合物3单独给药组的各个体的ΔvF试验分数以每组按升序重新排列,将各组的相同顺序的分数彼此相加,以该值作为理论总计值。
评价结果见图1、图2-A和图2-B。各图的纵轴表示von Frey试验的ΔvF试验分数,数值越高则镇痛作用越强。图1中横轴表示受检化合物给药后的时间,图2中横轴表示各组的处置内容。
在各测定点的溶剂给药组与各给药组的比较中,通过双线配置分散分析(显著水平不足5%),组与时间的交替作用显著,因此通过Dunnett检验进行统计处理。图中的#号表示在与溶剂给药组的比较中在统计学上显著(###表示p<0.001)。另外,在普瑞巴林的3mg/kg和化合物3的0.3mg/kg联合给药组(图2的普瑞巴林+化合物3)与理论总计值的比较中,根据F检验(显著水平不足5%)分散均匀,因此通过Student’s t检验进行统计处理。图中的*号表示在与理论总计值的比较中在统计学上显著(*表示p<0.05、**表示p<0.01)。
在普瑞巴林的3mg/kg单独给药组(图1和图2的普瑞巴林)中,在给药1小时后、2小时后和3小时后均未确认到镇痛作用。另外,在化合物3的0.3mg/kg单独给药组(图1和图2的化合物3)中,在给药1小时后、2小时后和3小时后也均未确认到镇痛作用。
另一方面,在联合给药组(图1和图2的普瑞巴林+化合物3)中,给药1小时后和2小时后均确认到强的镇痛作用,与溶剂给药组(图1和图2的媒介物)相比,在统计学上显著。而且,将理论总计值(图2的理论总计值)与联合给药组(图2的普瑞巴林+化合物3)进行比较时,在给药1小时后和2小时后的任一个测定时间点均确认到统计学上显著的差异。由该结果可知:化合物(I)与钙通道α2δ配体的联用协同地增强彼此的镇痛作用。
(实施例2)小鼠旋转笼试验中化合物(I)与钙通道α2δ配体的联用效果:
在评价中,一组使用8例5周龄的ddY系雄性小鼠。受检化合物、小鼠的分组、所用溶剂和给药方法均与实施例1相同。
自受检化合物给药起0.5小时后,将小鼠移入旋转笼装置(夏目制作所)内,之后立即开始测定1小时的旋转笼的转数,评价运动抑制作用。
评价结果见图3。纵轴表示旋转笼试验的转数,数值越高则运动量越多。横轴表示各组的处置内容。
在溶剂给药组(图3的媒介物)与各给药组的比较中,根据F检验(显著水平不足5%)分散均匀,因此通过Student’s t检验进行统计处理。
在普瑞巴林的3mg/kg单独给药组(图3的普瑞巴林)和化合物3的0.3mg/kg单独给药组(图3的化合物3)中,均未确认到统计学上显著的运动抑制作用。而且,在普瑞巴林的3mg/kg和化合物3的0.3mg/kg联合给药组(图3的普瑞巴林+化合物3)中,也没有确认到统计学上显著的运动抑制作用。由该结果可知:将化合物(I)和钙通道α2δ配体以各自没有出现中枢神经***的副作用的用量彼此之间联用时,没有出现中枢神经***的副作用。
(比较例1)小鼠神经障碍性疼痛模型中钙通道α2δ配体的效果:
利用与实施例1相同的方法,评价在小鼠神经障碍性疼痛模型中普瑞巴林的1 mg/kg、3 mg/kg、10 mg/kg和30mg/kg的单独口服给药1小时后的作用。
评价结果见图4。在溶剂给药组(图4的媒介物)和普瑞巴林给药组(图4的普瑞巴林1mg/kg、普瑞巴林3mg/kg、普瑞巴林10mg/kg和普瑞巴林30mg/kg)的比较中,根据Bartlett检验(显著水平不足5%)分散均匀,因此通过Williams检验(单侧)进行统计处理。图中的*号表示在与溶剂给药组的比较中在统计学上显著(*表示p<0.025)。
在普瑞巴林的1mg/kg或3mg/kg单独口服给药时,没有确认到镇痛作用。另一方面,在普瑞巴林的10mg/kg或30mg/kg单独口服给药时,确认到统计学上显著的镇痛作用。另外,认为普瑞巴林的30mg/kg的镇痛作用、与普瑞巴林的3mg/kg和化合物3的0.3mg/kg联合给药时的程度相同。
(比较例2)小鼠旋转笼试验中钙通道α2δ配体的效果:
利用与实施例2相同的方法,评价普瑞巴林的30mg/kg和100mg/kg的单独口服给药所产生的运动抑制作用。
评价结果见图5。在溶剂给药组(图5的媒介物)与普瑞巴林的30mg/kg和100mg/kg给药组(分别是图5的普瑞巴林30mg/kg和普瑞巴林100mg/kg)的比较中,根据Bartlett检验(显著水平不足5%)分散均匀,因此通过Williams检验(单侧)进行统计处理。图中的*号表示在与溶剂给药组的比较中在统计学上显著(*表示p<0.025)。
在普瑞巴林的30mg/kg和100mg/kg单独口服给药时,转数在统计学上显著减少,确认到运动抑制作用。
产业实用性
本发明涉及是含有化合物(I)和钙通道α2δ配体作为有效成分的发明,可以用作药物、特别是神经障碍性疼痛的治疗药或预防药。
Claims (1)
1.神经障碍性疼痛的治疗药或预防药,该药物含有下述通式(I)所示的环己烷衍生物或其药理学上可接受的盐、和钙通道α2δ配体普瑞巴林作为有效成分:
式中,A为通式(IIa)所表示的取代基;
R1为甲基;
R2为甲氧基;
R3为氢原子;
R4为羟基;
R5为羟基;
R6为氢原子;
R7和R8为氢原子;
Z为次甲基。
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