CN1812778A - 双环[2.2.1]庚烷衍生物用于制备神经保护药物组合物的用途 - Google Patents
双环[2.2.1]庚烷衍生物用于制备神经保护药物组合物的用途 Download PDFInfo
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- CN1812778A CN1812778A CNA2004800177453A CN200480017745A CN1812778A CN 1812778 A CN1812778 A CN 1812778A CN A2004800177453 A CNA2004800177453 A CN A2004800177453A CN 200480017745 A CN200480017745 A CN 200480017745A CN 1812778 A CN1812778 A CN 1812778A
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Abstract
本发明涉及通式(I)化合物及其药学上可接受的酸加成盐用于制备具有神经保护作用的药物组合物的用途,其中R3表示氢或羟基;R1表示氢或烷基;以及R2表示烷基。
Description
发明领域
本发明涉及双环[2.2.1]庚烷衍生物的新治疗用途。更特别的是,本发明涉及双环[2.2.1]庚烷衍生物用于制备具有神经保护作用的药物组合物的用途。
背景技术
已知,在2位包含苯基、苯基烷基或噻吩基侧链的1,1,7-三甲基-双环[2.2.1]庚烷衍生物具有抗惊厥、运动力抑制、环己烯巴比妥麻醉加强和止痛作用(GB 2,065,122)。HU 212,547公开了所述化合物组中的一个优秀成员游离碱形式的(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基-双环[2.2.1]庚烷及其药学上可接受的盐,尤其是延胡索酸盐。德伦环烷在不同的焦虑和应激动物模型中显示了相当大的作用。在Vogel惩处饮水试验(punished drinking test)中,德伦环烷在口服给予1和10mg/kg后是有活性的[Gacsalyi等,德伦环烷(EGIS-3886)在动物模型中的受体结合图和抗焦虑活性,Drug Dev.Res.40:第338-348页,(1997)]。在群聚相互接触模型中,单剂0.7mg/kg口服治疗后,化合物增加了群聚相互接触所花费的时间。在明-暗实验中,[Crawley,J.N.地西泮对简单焦虑模型的行为作用的神经药理学特异性,Pharmacol.Biochem.Behavior,15:第695-699页(1981)],德伦环烷被证明在单一口服剂量3mg/kg皮下注射时是有活性的。在大理石掩埋实验,[Broekkamp,C.L.等,在小鼠对大理石掩埋和游泳诱导理毛行为作用的基础上能区分强安定剂和弱安定剂。Eur.J.Pharmacol.126:p.223-229,(1986)],口服治疗后,分子在10和30mg/kg下是有活性的。
德伦环烷在提高的阳性迷津实验中(elevated plus maze test)是无效的,但是它在这个实验中能对抗由CCK引起的焦虑[Gacs ályi等,德伦环烷在动物模型中的受体结合图和抗焦虑活性,Drug Dev.Res.40:p.338-348,(1997)]。
除了这些抗焦虑作用外,德伦烷环在获得性无能实验中,在1和10mg/kg腹膜下注射剂量下能产生抗抑郁活性,该实验是已知的抑郁动物模型[Grial等,Biol.Psychiatry,23,237-242(1988)]。
根据其受体图,德伦环烷主要与中枢5-HT2C和5-HT2A受体结合。德伦环烷的抗焦虑和抗抑郁作用能通过其与这些5-HT受体的亲合力得以解释。
EP1,052,245记载了下式高纯度的德伦环烷
其含有小于0.2%的下式(1R,3S,4R)-3-[2-(N,N-二甲基氨基乙基)]-1,7,7-三甲基-双环[2.2.1]庚烷-2-酮。
式II德伦环烷的N-甲基衍生物记载于WO 98/17230中。这个化合物具有有价值的抗焦虑作用。
根据本发明的一个方面,在此提供了通式I的双环[2.2.1]庚烷衍生物
其中
R3表示氢或羟基;
R1表示氢或烷基;和
R2表示烷基
及药学上可接受的酸加成盐用于制备具有神经保护作用的药物组合物的用途。
本发明所基于的认识是通式I化合物对由全脑缺血所导致的神经损伤和随后的行为参数(自主运动)的病理变化产生了保护作用。这个作用不依赖于其已知的作用方式以及其抗焦虑和降低应激的作用,因为利坦色林,一种5-HT2A/2c拮抗剂,例如,具有能与德伦环烷相比拟的作用方式的化合物,在同样的局部缺血模型中没有显示神经保护活性(Piera,M.J.,等,5-HT2A受体拮抗剂对降低沙鼠暂时性全脑缺血3分钟后脑损伤没有效果,Fundana.Clin.Pharmacol,9:第562-568页,1995)。通式I化合物的这个作用使它们适于治疗由急性脑损伤和脊髓损伤例如中风、脑血管痉挛引起的疾病,以及由意外导致的头和脊髓损伤引起的神经元死亡疾病,同时也使它们适于改善由神经元损耗导致的行为参数并且也能治疗慢性神经变性疾病例如多发性硬化、运动神经元疾病(amyoptrophic侧索硬化,ALS,)Creutzfeld-Jakob疾病等。
除非另有指明,本专利说明书对术语的定义如下。
术语“低级烷基”指的是包含1-4个碳原子的直链或支链饱和脂肪烃基团例如甲基、乙基、n-丙基、异丙基、n-丁基、二级丁基等。
术语“药学上可接受的酸加成盐”指的是与药学上可接受的无毒无机或有机酸形成的盐。就盐的构成来说,能被使用的例如有盐酸、氢溴酸、硫酸、磷酸、醋酸、蚁酸、乳酸、酒石酸、马来酸、苹果酸、杏仁酸、延胡羧酸、苯磺酸、p-甲苯磺酸等。特别优选与延胡羧酸形成的盐。
我们的发明的一个优选实施方案是使用通式I化合物或其酸加成盐来制备适合减小急性局部缺血或创伤性头和脊髓损伤后果,尤其是各种类型的中风或脑血管痉挛、严重的脑血管闭塞、神经元损耗以及在由意外导致的头和脊髓损伤中的机能性后果的药物组合物。
我们的发明的另一个优选实施方案是使用通式I化合物或其酸加成盐来制备适合治疗神经变性疾病的药物组合物。
我们的发明的另一个优选实施方案是使用通式I化合物或其酸加成盐来制备适合治疗运动神经元疾病(ALS)、多发性硬化或Creutzfeld-Jakob疾病的药物组合物。
我们的发明的另一个优选实施方案是使用通式I化合物或其酸加成盐来制备适合预防中风,在首次中风事件后就能开始预防性治疗的药物组合物。
通式I化合物的神经保护性剂量能在很宽的范围内变化,并取决于多种因素例如所给活性成分的活性、受治患者的体重、年龄和状况、受治疾病的严重度,给药形式,这些始终由大夫决定。日神经保护剂量优选在约0.1mg/kg到150mg/kg之间,特别优选在约1mg/kg到约150mg/kg之间,特别有利的是在约10mg/kg到约150mg/kg之间。
至于通式I化合物,优选被使用的是(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基-双环[2.2.1]庚烷或其药学上可接受的酸加成盐,尤其是(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基-双环[2.2.1]庚烷-延胡索酸盐。
根据本发明能被优选使用的其它通式I化合物是以下物质:
(1R,2S,4R)-(-)-2-(2-甲基氨基乙氧基)-2-苯基-1,7,7三甲基-双环[2.2.1]庚烷;
(1R,2S,7R)-2-苯基-2-(2-甲基氨基乙氧基)-7-羟甲基-1,7-二甲基-双环[2.2.1]庚烷;或
(1R,2S,7R)-2-苯基-2-(2-乙基氨基乙氧基)-7-羟甲基-1,7-二甲基-双环[2.2.1]庚烷或以上化合物的药学上可接受的酸加成盐。
根据本发明最优选的实施方案,式II的(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基-双环[2.2.1]庚烷或其药学上可接受的酸加成盐,尤其是(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基-双环[2.2.1]庚烷-延胡索酸盐能被用于制备神经保护药物组合物。
根据本发明特别优选的实施方案,对于通式I化合物,使用了式II的(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基-双环[2.2.1]庚烷或其药学上可接受的酸加成盐,其中包含了不超过0.2%的式III的(IR,3S,4R)-3-[2-(N,N-二甲基氨基乙基)]-1,7,7-三甲基-双环[2.2.1]庚烷-2-酮或其药学上可接受的酸加成盐。
根据本发明以上实施方案的非常优选的变体,对于通式I化合物,使用了(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7三甲基-双环[2.2.1]庚烷-延胡索酸盐,其中包含了不超过0.2%的(1R,3S,4R)-3-[2-(N,N-二甲基氨基乙基)]-1,7,7-三甲基-双环[2.2.1]庚烷-2-酮-延胡索酸盐。
根据本发明的另一个方面,在此提供了包含作为活性成分的通式I化合物(其中R1、R2和R3如上所述)或其药学上可接受的酸加成盐与药学上可接受的固体或液体药物载体和/或赋形剂混合的神经保护药物组合物。
本发明的药物组合物能通过制药工业已知的方法制备。这样,可以通过混合通式I化合物或其药学上可接受的酸加成盐以及惰性固体或液体药物载体和/或赋形剂并将该混合物形成盖伦制剂形式来制备。
根据本发明的神经保护药物组合物能通过口服给予(片剂、包衣片、硬或软明胶胶囊、溶液、混悬液等)、非胃肠道给予(例如皮下、肌肉、静脉注射)、直肠给予(例如栓剂)或鼻腔给予(例如气雾剂)。活性成分能从药物组合物中快速输送,这种情况下的治疗效果的持续时间由活性成分本身的持续时间来决定。然而,本发明的神经保护药物组合物也能被制成缓释形式,其中治疗效果的持续时间也受组合物的形式所影响(调节、持续或延缓活性成分输送的药物组合物)。
本发明的药物组合物能通过制药领域的常规方法制备。
片剂和胶囊能包含乳糖(一水合物、无水、粉末、干燥态等)、甘露醇、纤维素类(粉末、微晶等)作为填充剂。明胶、聚乙烯吡咯烷酮(具有不同的分子量)、纤维素醚类(羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、乙基纤维素等)、水解淀粉、植物胶(阿拉伯胶、瓜耳胶等)能被用于水溶液中或与具有1-4个碳原子的脂族醇形成的溶液中与所述溶剂混合作为粘合剂。使用的崩解剂能是淀粉(土豆淀粉、玉米淀粉、小麦淀粉等)或所谓的优级崩解剂例如羧甲基纤维素(商品名为Ac-di-sol)、羧甲基淀粉钠(商品名为Primojel、Ultraamilopektin、Explo-Tab)、聚乙烯吡咯烷酮(商品名为Poliplasdone)等。至于润滑剂,能被使用的有例如碱性硬脂酸盐(例如硬脂酸镁、硬脂酸钙)、脂肪酸(例如硬脂酸)、甘油酯(商品名为Precirol,Cutina H)、石蜡油、硅油、硅油emergents(滑石粉、硅石等)。可以制备活性成分和赋形剂以用在液体或干燥制粒过程的压制和抗胶囊化步骤或滤过粉末匀化中。
调节或延缓释放的固体药物组合物能通过制药领域已知的方法制备。这种组合物可以是包含各种缓释成分[例如亲水聚合物如羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素、聚丙烯酸衍生物、多糖(例如瓜耳胶、黄原胶)等及其混合物]或疏水聚合物(例如乙基纤维素、甲基丙烯酸酯共聚物、聚醋酸乙烯酯、聚乙烯醇缩丁醛等)及其混合物的片剂。在本发明的其它神经保护药物组合物中,缓释效果通过使用含有亲水和疏水聚合物的混合物或聚合物与脂肪物质的混合物的基质来实现的。片剂也能被制成多层的形式,其中活性成分被混合到单独的层中,这样活性成分的溶解性就能被更好地调节到其特定的药动学特征。
本发明的缓释神经保护药物组合物也能被制成包衣小片的形式。小片的制备能独立于活性成分或活性成分的混合物而进行。小片的制备能通过挤出或片状槽制粒或轮转制粒(spheronificationrotogranulating)法或在安慰剂小片上包层衣来进行。小片的包衣能在旋转液化装置中进行。能使用水不溶性聚合物与有机溶剂(优选包含1-3个碳原子的脂族醇和/或包含1-2个碳原子的氯化烃和/或丙酮和/或乙酸乙酯或其混合物)形成的包衣剂溶液或分散剂(dispersents)。
根据本发明的神经保护药物组合物也能被制成渗透性或扩散-渗透组合物的形式并以该形式使用。能制备包含活性成分和亲水聚合物(例如羟丙甲基纤维素)的片剂,其中活性成分被半透性(例如醋酸纤维素)或渗透性(例如氨基甲基丙烯酸酯共聚物)膜层包被,此后,在所述层上形成孔口,活性成分通过该孔被光学地(optically)推出进入水性介质中。
根据本发明的另一个方面,在此提供了通式化合物及其药学上可接受的酸加成盐作为神经保护药学活性成分的用途。
通式化合物及其药学上可接受的酸加成盐能被特别用于降低急性局部缺血或创伤性头和脊髓损伤的后果,尤其是各种类型的中风或脑血管痉挛、严重的脑血管闭塞、神经元损耗以及在由意外导致的头和脊髓损伤中的机能性后果;或用于治疗神经变性疾病;或用于治疗运动神经元疾病(ALS)、多发性硬化或Creutzfeld-Jakob疾病;或用于预防中风;由此在首次中风事件后就能开始预防性治疗。
根据本发明的另一个方面,在此提供了神经保护的治疗方法,其包含给予需要这种治疗的患者药学上可接受量的通式I化合物或其药学上可接受的盐,优选式II(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基-双环[2.2.1]庚烷或其药学上可接受的酸加成盐。
通式I化合物的神经保护作用通过以下实验显示。对于通式化合物,使用的是(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基-双环[2.2.1]庚烷-延胡索酸盐(德伦环烷延胡索酸盐)。
德伦环烷的神经保护作用在由双侧颈动脉闭塞导致的全脑缺血模型中予以证明。在我们的实验中,使用了体重为50-80g的雄性蒙古沙鼠。德伦环烷在手术前60分钟、术后30和90分钟时以3×30mg/kg的量经腹膜内给予。德伦环烷被混悬在0.4%的甲基纤维素溶液中。在醚麻醉中,通过前中线颈切口暴露右和左侧颈总动脉并从迷走神经和周围组织中分离。颈动脉血流的完全停止通过紧固动脉瘤夹3分钟来实现。手术期间,在加热毯和加热灯的帮助下将动物的体温保持在个体术前的水平上(37.5±0.5℃)。
由于已知全脑缺血能引起动物过度兴奋,其被发现与海马损伤的严重度密切相关(Gerhardt,S.C.等,沙鼠脑缺血后运动活性的变化与海马中神经元变性的程度有关,Behav.Neurosci.102.第301-303页,1988),因此在术后四天,在对称的Y-迷宫(臂长40cm宽10cm高21.5cm)中测定动物的运动力。将蒙古沙鼠置于迷宫的中央然后记录5分钟内进入三个臂中的次数。我们定义,当动物进入臂内并前进至少为其身体长度的距离时,就为完成了臂进入。当沙鼠完全离开臂时就认为其退出了臂。组间的差别通过Kruskal-WallisANOVA进行统计学评价。在p<0.05显著性的情况下,使用Mann-Whitney U-检验进行配对比较。
行为实验后,用60mg/kg i.p.的戊巴比妥(10ml/kg)对动物进行麻醉并先用盐水通过心脏灌注然后用固定液灌注30分钟,其中固定液包含存在于0.1M磷酸盐缓冲液pH 7.4中的0.1%戊二醛、4%多聚甲醛和0.2%苦味酸。从颅骨中除去脑并于4℃下在相同的固定液中后固定至少1周。
用microtone从不同水平的背海马中切取另外60μm厚的冠状缝切片。不断用0.1M的磷酸盐缓冲液洗涤该切片然后通过银渗透染色。
在光学显微镜下对切片进行检测,并以6-点量度对两侧海马中海马CA1子域中所有的神经元损伤进行评分:(0)未损伤,(1)<10%,(2)10-30%,(3)30-50%,(4)50-70%,(5)70-90%和(6)90-100%细胞损失。药物治疗组和赋形剂治疗组之间的差异通过Mann-Whitney U-检验进行统计学分析。我们的结果汇总在表1中。
表1
德伦环烷对海马CA1锥体细胞死亡以及由双侧颈动脉闭塞(BCO)3分钟导致的全脑缺血后动物运动亢进的影响
治疗 | 剂量mg/kg i.p. | CA1细胞死亡(得分) | 作用% | 臂进入数 | 作用% |
假 | - | - | - | 40.25 | - |
BCO | - | 4.90 | - | 65.44++ | - |
BCO+德伦环烷 | 3×30 | 0.89** | -82% | 38.78** | -100 |
++p<0.01统计学显著性,与假手术组相比(Mann-Whitney U-检验,在Kruskal-Wallis ANOVA后)
**p<0.01统计学显著性,与BCO组相比(Mann-Whitney U-检验,在Kruskal-Wallis ANOVA后)。
以上结果证明了所用剂量下的德伦环烷能显著降低海马CA1区域中细胞死亡的比例并使动物的活动力降低到正常范围内,同时改善组织学得分。德伦环烷不仅能保护神经元细胞免于死亡而且还能使临床重要的行为异常有效地正常化。
基于我们对动物实验的观察,德伦环烷保护了由全脑缺血导致的神经元损耗以及在神经元死亡后发展的行为异常。德伦环烷这个令人惊奇的作用是不能被预测的,因为利坦色林,也具有5-HT2A/2C作用模式并在动物实验中显示抗焦虑作用,但它不能在这个模型中产生神经保护作用。
概括地说,根据本发明描述的认识,德伦环烷具有神经保护活性,因为该化合物显著降低了海马CA1区域的神经元细胞死亡并降低了过度活动,这是由蒙古沙鼠双侧颈动脉闭塞导致的全脑缺血后四天所观察到的神经元死亡的后果。基于前述的所有内容,德伦环烷的治疗性应用能用于治疗急性局部缺血或创伤性头和脊髓损伤,例如各种形式的中风、脑血管痉挛、严重的脑血管闭塞、与意外有关的头和脊髓损伤等,其能降低神经元破坏的程度从而降低由神经元损失引起的功能缺陷的危险性,此外,还能治疗慢性神经变性疾病例如侧索硬化(ALS)、多发性硬化和Creutzfeld-Jakob疾病等,就是说能减慢或停止神经元死亡的速度,由此减慢在所有疾病状态或状况(其中一些或所有神经元或它们的一部分都被损害或杀灭)中的疾病进展。
本发明的其它细节将能在以下实施例中找到,但所述实施例并不对保护范围构成限制。
实施例1
具有以下组成的片剂能通过制药领域已知的方法制备:
成分 量,mg/片
德伦环烷 20
玉米淀粉 90
聚乙烯吡咯烷酮 68
硬酯酸镁 2
总重 180
实施例2
具有以下组成的明胶胶囊能通过制药领域已知的方法制备:
成分 量,mg/胶囊
德伦环烷 20
玉米淀粉 212
Aerosil 5
硬酯酸镁 3
总重 240
Claims (22)
1.通式化合物
其中
R3表示氢或羟基;
R1表示氢或烷基;和
R2表示烷基
以及药学上可接受的酸加成盐用于制备具有神经保护作用的药物组合物的用途。
2.根据权利要求1的用途,用于制备适于降低急性局部缺血或创伤性头和脊髓损伤后果,尤其是各种类型的中风或脑血管痉挛、严重的脑血管闭塞、神经元损耗以及在由意外导致的头和脊髓损伤情况中的功能性后果的药物组合物。
3.根据权利要求1的用途,用于制备具有慢性神经变性作用的药物组合物。
4.根据权利要求3的用途,用于制备适于治疗运动神经元疾病(ALS)、硬化多发性或Creutzfeld-Jakob疾病的药物组合物。
5.根据权利要求1-4任一项的用途,其中使用(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基双环[2.2.1]庚烷(德伦环烷)或药学上可接受的酸加成盐作为通式I化合物。
6.根据权利要求5的用途,其中使用(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基双环[2.2.1]庚烷-延胡索酸盐(德伦环烷-延胡索酸盐)作为通式I化合物。
8.根据权利要求7的用途,其中使用包含不超过0.2%的(1R,3S,4R)-3-[2-(N,N-二甲基氨基乙基)]-1,7,7-三甲基双环[2.2.1]庚烷-2-酮-延胡索酸盐的(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基双环[2.2.1]庚烷-延胡索酸盐作为通式I的化合物。
9.根据权利要求1-4任一项的用途,其中使用(1R,2S,4R)-(-)-2-(2-甲基氨基乙氧基)-2-苯基-1,7,7三甲基-双环[2.2.1]庚烷、(1R,2S,7R)-2-苯基-2-(2-甲基氨基乙氧基)-7-羟甲基-1,7-二甲基-双环[2.2.1]庚烷或(1R,2S,7R)-2-苯基-2-(2-乙基氨基乙氧基)-7-羟甲基-1,7-二甲基-双环[2.2.1]庚烷或其药学上可接受的酸加成盐作为通式I的化合物。
10.神经保护药物组合物,含有作为活性成分的通式I化合物,其中R1、R2和R3如权利要求1所述,或其药学上可接受的酸加成盐与惰性药学上可接受的固体或液体药物活性成分和/或辅形剂混合。
11.根据权利要求10的药物组合物,适于降低急性局部缺血或创伤性头和脊髓损伤的后果,尤其是各种类型的中风或脑血管痉挛、严重的脑血管闭塞、神经元损耗以及在由意外导致的头和脊髓损伤情况中的功能性后果。
12.根据权利要求10的药物组合物适于治疗神经变性疾病。
13.根据权利要求11的药物组合物适于治疗运动神经元疾病(ALS)、硬化多发性或Creutzfeld-Jakob疾病。
14.根据权利要求10-13任一项的药物组合物,其含有式II的(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基-双环[2.2.1]庚烷或药学上可接受的酸加成盐作为通式I化合物。
15.根据权利要求14的药物组合物,其含有(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基-双环[2.2.1]庚烷-延胡索酸盐作为通式I化合物。
16.其中R1、R2和R3如权利要求1所述的通式I化合物及其药学上可接受的酸加成盐作为神经保护药物活性成份的用途。
17.根据权利要求16的用途,用于降低急性局部缺血或创伤性头和脊髓损伤的后果,尤其是各种类型的中风或脑血管痉挛、严重的脑血管闭塞、神经元损耗以及在由意外导致的头和脊髓损伤情况中的功能性后果。
18.根据权利要求16的用途,用于治疗慢性神经变性疾病。
19.根据权利要求16的用途,用于治疗运动神经元疾病(ALS)、硬化多发性或Creutzfeld-Jakob疾病。
20.式II的(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基-双环[2.2.1]庚烷及其药学上可接受的酸加成盐在根据权利要求16-19的适应症中的用途。
21.(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基-双环[2.2.1]庚烷-延胡索酸盐在根据权利要求16-19的适应症中的用途。
22.神经保护的治疗性方法,其包含给予需要这种治疗的患者治疗有效量的通式I化合物或其药学上可接受的酸加成盐,优选式II的(1R,2S,4R)-(-)-2-(2-二甲基氨基乙氧基)-2-苯基-1,7,7-三甲基-双环[2.2.1]庚烷或其药学上可接受的酸加成盐。
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