CN100506797C - 用于制备治疗情感和注意障碍以及神经性疼痛的药物的单羟基卡马西平 - Google Patents

用于制备治疗情感和注意障碍以及神经性疼痛的药物的单羟基卡马西平 Download PDF

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CN100506797C
CN100506797C CNB028224442A CN02822444A CN100506797C CN 100506797 C CN100506797 C CN 100506797C CN B028224442 A CNB028224442 A CN B028224442A CN 02822444 A CN02822444 A CN 02822444A CN 100506797 C CN100506797 C CN 100506797C
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M·施穆茨
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Abstract

本发明涉及式(I)的卡马西平衍生物用于治疗情感和注意障碍、神经性疼痛以及与神经性疼痛相关的疾病的用途。

Description

用于制备治疗情感和注意障碍以及神经性疼痛的药物的单羟基卡马西平
本发明涉及卡马西平衍生物的新药学用途。
更具体而言，本发明涉及式I的单羟基卡马西平的新药学用途，
单羟基卡马西平(10-羟基-10，11-二氢-卡马西平)自文献中熟知[参见例如Schuetz H.等人，Xenobiotica(GB)，16(8)，769-778(1986)]，其为抗癫痫药奥卡西平
Figure C02822444D00042
的主要代谢物且可根据常规方法由奥卡西平开始合成制备。单羟基卡马西平已首次公开于GB 1310120。据称，该化合物适合于治疗身心失调、癫痫、三叉神经痛和脑性痉挛。
根据本发明，现已令人惊讶地发现：式I化合物可用于治疗情感和注意障碍，包括例如抑郁症和双相性心境障碍，以及神经性疼痛和相关疾病。
例如式I化合物抑制γ-氨基丁酸(GABA)周转的能力证明了其在治疗情感和注意障碍以及神经性疼痛中的活性。这是由于这些化合物对GABA传导的活化作用引起的反馈抑制所致。
GABA在双相性和其它心境障碍中的作用是毋庸置疑的，且是多篇综述(例如Emrich等人，“丙戊酸钠对躁狂症的作用”，“情感障碍的GABA-假设”，Arch.Psychiatr.Nervenkr.1980；229：1-16；Petty.“GABA和心境障碍：简要综述和假设”，J.Affect.Disord.1995；34：275-81)的论题。已知对(双相性)心境障碍以及焦虑症和抑郁症有效的药物，例如锂、丙戊酸钠和地西泮可抑制GABA的周转率。这是由于这些化合物对GABA传导的活化作用引起的反馈抑制所致。
同样，GABA在慢性疼痛中的作用也是毋庸置疑的，且是多篇综述(例如Stamford.“疼痛的下行控制”，Br.J.Anaesth.1995；75：217-21)的论题。已知对慢性疼痛有效的药物如丙戊酸钠可抑制GABA的周转率。这是由于这些化合物对GABA传导的活化作用引起的反馈抑制所致。
以下实验证明了式I化合物对GABA周转的活性：
GABA周转的测定是基于在γ-氨基丁酸转氨酶(GABA-T)最大抑制后所观察到的GABA水平的线性增加。用该方法获得的GABA合成速率的数值与所使用的抑制剂无关，且处于GABA旁路中所涉及的酶的催化容量之内。
在这些条件下，式I化合物在30至约300mg/kg的口服剂量下剂量依赖性地抑制GABA的周转率。
式I化合物在治疗情感和注意障碍中的活性在例如适用于检测具有潜在解除行为抑制和/或社会取向作用的药物的试验中也得到了证明，所述药物被认为与抑郁症和相关精神病症的主要特征即社交退缩的康复相关。例如，使用Triangle，1982，21：95-105和J.Clin.Psychiatry，1994，55：9(增刊B)4-7中所述的基本方法可评价药物对闯入小鼠社交退缩的作用。
在1至约100mg/kg的口服剂量范围内，式I化合物在所述实验条件下可增加被治疗小鼠的社交探察。
由于其对GABA传导的抗焦虑-/抗抑郁样刺激作用和社会取向活性，式I化合物可用于治疗情感障碍，包括抑郁症和双相性精神障碍例如躁狂抑郁性精神病，极端精神状态例如躁狂症、精神分裂症，以及需要稳定行为的过度情绪摆动。另外，该化合物适用于ADHD(注意缺陷多动症)和其它注意障碍，例如孤独症，(且)适用于焦虑状态、广泛性焦虑症和广场恐怖症，以及那些以社交退缩为特征的行为状态例如负性症状(negativesymptom)。
式I化合物在治疗神经性疼痛中的直接活性例如在以下豚鼠神经性疼痛模型中得到证明：
用恩氟烷(对于豚鼠而言，处于N2O:O2中)麻醉Dunkin Hartley豚鼠，暴露左侧坐骨神经并用线部分结扎。该操作造成机械性痛觉过敏，其于2-3天内形成并保持至少4周。使用疼痛测定仪(analgesymeter)测量对压力刺激的缩足阈值。在施用药物或赋形剂之前和之后达6小时记录同侧(结扎的)和对侧(未结扎的)足的机械阈值。计算每个时间点的痛觉过敏逆转值。使用了6组动物。使用ANOVA、然后用Tukey’s HSD检验对缩足阈值读数进行统计学分析。
在该模型中，式I化合物在10至约100mg/kg的口服剂量下和3至约100mg/kg的皮下注射剂量下显著且剂量依赖性地逆转了神经性机械痛觉过敏。
式I化合物在治疗神经性疼痛和相关疾病中的活性可在临床试验中证实，该临床试验评价化合物治疗糖尿病性神经病变患者的慢性疼痛的功效。
在所述研究中发现：式I化合物相对安慰剂可以以统计学显著方式降低维持期和随访期的疼痛严重性等级。
因此，式I化合物可用于治疗神经性疼痛和相关的痛觉过敏，包括三叉神经痛和疱疹性神经痛、糖尿病性神经性疼痛、偏头痛、灼痛和传入神经阻滞综合征如臂丛撕脱，以及用于治疗痉挛和相关疾病。
对于以上提及的适应症，适合的剂量当然将根据例如所用的化合物、宿主、施用方式以及所治疗病症的性质和严重性而改变。但是，通常显示在动物中获得满意结果的日剂量为约0.05至约150、优选约0.1至约100mg/kg动物体重。在较大的哺乳动物例如人中，适用的日剂量是约0.5至约5000、优选约1至约500mg本发明的活性剂，所述剂量例如以每天不超过4次的分剂量或以缓释形式、例如每天一次方便地施用。
本发明的活性剂可通过任何常规途径施用，特别是经肠、优选口服施用，例如以片剂或胶囊剂形式施用，或经胃肠外施用，例如以注射溶液或混悬剂形式施用。
本发明的活性剂可单独或与其它药物活性剂组合施用于体内，例如对治疗其中人VR1活化发挥作用或被牵涉其中的疾病和病症有效的活性剂，包括环加氧酶-2(COX-2)抑制剂如特异性COX-2抑制剂(例如塞来昔布、COX189和洛芬昔布)或常见的非甾类抗炎药(NSAID)(例如乙酰水杨酸、丙酸衍生物)、三环类抗抑郁药(例如氯丙咪嗪
Figure C02822444D00071
阿莫沙平去甲替林
Figure C02822444D00073
阿米替林
Figure C02822444D00074
盐酸去甲丙咪嗪
Figure C02822444D00076
盐酸去甲替林
Figure C02822444D00077
多塞平
Figure C02822444D00078
曲米帕明
Figure C02822444D00079
丙咪嗪
Figure C02822444D000711
普罗替林
Figure C02822444D000712
双羟萘酸丙咪嗪
Figure C02822444D000713
抗惊厥药(例如加巴喷丁)、GABAB激动剂(例如L-巴氯芬)、阿片类、香草酸(Vanniloid)受体拮抗剂和大麻碱(Cannabinoid，CB)受体激动剂，例如CB1受体激动剂。
本发明的用于分别施用组合伙伴的药物组合物和用于施用固定组合的药物组合物，即包含至少两种组合伙伴的单一盖伦组合物可按照本身已知的方法制备，从而适于经肠如口服或直肠和胃肠外施用于哺乳动物、包括人，其包含治疗有效量的至少一种单独或与一种或多种可药用载体混合的药理学活性组合伙伴，尤其适于经肠或经胃肠外施用。
本发明还提供了式I化合物在制备用于治疗情感和注意障碍、神经性疼痛以及与神经性疼痛相关的疾病的药物组合物中的用途。
此外，本发明提供了在需要该治疗的对象中治疗情感和注意障碍、神经性疼痛以及与神经性疼痛相关的疾病的方法，其包括向所述对象施用治疗有效量的式I化合物。

Claims (19)

1.式I化合物在制备药物中的用途，
Figure C02822444C00021
所述药物用于治疗选自下组的疾病：情感障碍和注意障碍。
2.权利要求1的用途，其特征在于所述的疾病选自情感障碍。
3.权利要求2的用途，其特征在于所述的疾病是抑郁症。
4.权利要求2的用途，其特征在于所述的疾病选自双相性精神障碍。
5.权利要求2的用途，其特征在于所述的疾病选自双相性心境障碍。
6.权利要求2的用途，其特征在于所述的疾病选自躁狂抑郁性精神病。
7.权利要求2的用途，其特征在于所述的疾病选自极端精神状态。
8.权利要求2的用途，其特征在于所述的疾病是躁狂症。
9.权利要求2的用途，其特征在于所述的疾病是精神分裂症。
10.权利要求2的用途，其特征在于所述的疾病选自需要稳定行为的过度情绪摆动。
11.权利要求1的用途，其特征在于所述的疾病选自注意障碍。
12.权利要求11的用途，其特征在于所述的疾病选自注意缺陷多动症。
13.权利要求11的用途，其特征在于所述的疾病是孤独症。
14.权利要求1的用途，其特征在于所述的疾病选自焦虑状态。
15.权利要求1的用途，其特征在于所述的疾病是广泛性焦虑症。
16.权利要求1的用途，其特征在于所述的疾病是广场恐怖症。
17.权利要求1的用途，其特征在于所述的疾病选自以社交退缩为特征的行为状态。
18.权利要求17的用途，其特征在于所述的疾病选自负性症状。
19.制备药物的方法，所述药物用于治疗选自下组的疾病：情感障碍和注意障碍，该方法的特征在于将作为药理学活性化合物的式I化合物
Figure C02822444C00031
与至少一种可药用载体联用。
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PT101732B (pt) * 1995-06-30 1997-12-31 Portela & Ca Sa Novas di-hidrodibenzo<b,f>azepinas substituidas processo para a sua preparacao composicoes farmaceuticas que as contem e utilizacao dos novos compostos na preparacao de composicoes farmaceuticas empregues em doencas do sistema nervoso

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HUP0402381A2 (hu) 2005-03-29
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CN1585753A (zh) 2005-02-23
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