CN1296409A - 恐慌发作的治疗 - Google Patents
恐慌发作的治疗 Download PDFInfo
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- CN1296409A CN1296409A CN99804849A CN99804849A CN1296409A CN 1296409 A CN1296409 A CN 1296409A CN 99804849 A CN99804849 A CN 99804849A CN 99804849 A CN99804849 A CN 99804849A CN 1296409 A CN1296409 A CN 1296409A
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Abstract
化合物1’－[4－[1－(4－氟苯基)－1H－吲哚－3－基]－1－丁基]－螺[异苯并呋喃－1(3H),4’－哌啶]在预测对恐慌发作作用的模型中有效并用于制备治疗与恐慌发作有关的疾病药物中的用途。
Description
发明领域
本发明涉及化合物1′-[4-[1-(4-氟苯基)-1H-吲哚-3-基]-1-丁基]-螺[异苯并呋喃-1(3H)，4′-哌啶]或其药用盐制备治疗恐慌发作的药物的用途。
发明背景
国际专利申请WO92/22554描述了一系列σ受体配体，它们用于治疗一定范围内的精神及神经病。已对这些化合物的结构活性关系进行了进一步研究(Perregaard，J.等，J.Med.Chem.，1995，38，11，1988-2008页)。
在这些化合物中，国际专利申请WO92/22554描述的化合物1′-[4-[1-(4-氟苯基)-1H-吲哚-3-基]-1-丁基]-螺[异苯并呋喃-1(3H)，4′-哌啶]，是本发明的主题。Perregaard，J.等，J.Med.Chem.，1995，38，11，1988-2008页中指出此化合物是有效的和选择性的σ配体，特别是σ2配体。此外，在对大鼠的黑/白探察实验中检测了该化合物的抗焦虑潜力，其中用动物模型来预测在治疗一般性焦虑病的效果。发现在大剂量范围内有效。在一般性焦虑病模型中进一步的实验结果报告于J.Pharmacol.Exp.Ther.，1997，283，No.2。
待审的丹麦专利申请No.0071/98公开了该化合物在治疗药物成瘾性及其它物质滥用方面的作用。
对σ受体的生物学和功能研究给出了证据，即σ受体配体可以用于治疗一定范围的精神和神经病，包括精神病和运动机能紊乱，例如张力障碍和迟发运动障碍，以及与杭廷顿氏舞蹈病或图雷特氏综合征及在帕金森氏病中有关的运动障碍(Walker，J.M.等，Pharmacological Reviews，1990，42，355)。已知的σ受体配体林卡唑临床上显示了治疗精神病的作用(Snyder，S.H，Largent，B.L.J.Neuropsychiatry，1989，1，7)，还已描述了一组σ受体配体在动物模型中显示了抗幻觉作用(国际专利申请WO9103243)。
还报告了σ受体配体参与调节大脑中NMDA受体介导的过程并在体内实验中用作抗局部缺血剂(Rao，T.S.等，Molecular Pharmacology，1990，37，978)。除了局部缺血，σ受体配体还可以用于治疗其它NMDA受体受体介导的过程，例如，癫痫症和惊厥。
另外，已发现了一些σ受体配体在动物模型中显示了抗记忆缺失作用(Early等，Brain Research，1991，546，281-286)。已表明σ配体影响动物模型中中枢乙酰胆碱水平(Matsuno等，BrainResearch，1992，575，315-319；Junien等，Eur.J.Pharm.，1991，200，343-345)并因此可能在治疗阿耳茨海默型的早老性痴呆中具有潜力。
最后，已公开了具有σ受体活性的一些胍衍生物用作抗焦虑药(国际专利申请WO9014067)，还发现一些σ受体配体结合在多巴胺转运蛋白上的可卡因结合位点，还已发现另一些抑制多巴胺的摄入(Lzenwasser，S.等，Eur.J.Pharmacol.，243，201-205及Woodward，J.J.和Harms，J.，Eur.J.Pharmacol.，210，265-270)。
与恐慌发作作为主要因素的疾病包括恐慌病、特定恐惧症和广场恐怖症。特定恐惧症和广场恐怖症都出现或不出现恐慌。按照DSM IV恐慌病，特定恐惧症和广场恐怖症构成了精神病的不同亚类，且人们充分注意到根据诊断、遗传(Kendler K.S.等，Arch.Gen.Psychiatry，1995，52，347-383)和药学标准能区分一般性焦虑病和这些疾病。
用苯并二氮杂环庚三烯类如地西泮和咪达唑仑(其不用于治疗恐慌)和5HT1A受体激动剂如丁螺环酮(据报道其在治疗恐慌中无效(Fulton B.and Brogden R.N.Buspirone：CNS Drugs，1997，7(1)，68-88))治疗一般性焦虑。在恐慌及其它与恐慌有关的疾病中所选择的治疗包括高效苯并二氮杂环庚三烯类和一般与治疗抑郁有关的化合物。选择性5-羟色胺再吸收抑制剂显著降低了与恐慌有关症状的严重性并较其它治疗有更好的耐受性(Bertani A.等，Depression andAnxiety，1997，4，253；Sheehan and Harnett-Sheenan，J.Clin.Psychiatry，1996，57(suppl.10)，51-60)。于是，现在在恐慌病中它们变成了第一选择。5-羟色胺再吸收抑制剂不能用于治疗一般性焦虑病。
研究一表明患恐慌发作，特别是与广场恐怖症有关的患者，其生活质量的损害与在酗酒、精神分裂症及人格缺陷病患者中发现的劳动能力丧失相当或更大。
因此，需要用于治疗与恐慌发作有关的疾病的其它治疗手段。
现在，我们惊奇地发现本发明的化合物在治疗恐慌发作中显示了有利的作用。
发明描述
按照本发明，提供了1′-[4-[1-(4-氟苯基)-1H-吲哚-3-基]-1-丁基]-螺[异苯并呋喃-1(3H)，4′-哌啶]的新用途，即用来制备用于治疗恐慌发作的药物。
术语治疗恐慌发作包括对任何与恐慌发作有关疾病的治疗，包括恐慌病、特定恐惧症、社交恐惧症及广场恐怖症，其中发生恐慌发作。这些疾病在DSM IV中进一步限定。恐慌发作是不连续的阶段，其中强的忧惧、害怕或恐怖突然发作，常与即将发生厄运的感觉有关。在症状发作期间，存在症状如心悸、出汗、震颤、呼吸短促感、窒息感、胸痛或不适、恶心、感到头晕、不真实的感觉、担心失去控制或变疯，死亡恐惧、感觉异常和寒战或热潮红。
恐慌疾病特征在于对一直关心的问题周期性发生意外的恐慌发作。在恐慌发作时，广场恐怖症是对从其中逃避出来会很困难或得不到帮助的场合或情况的焦虑，或要避免上述情况。特定恐惧症和社交恐惧症(以前统称简单恐惧症)的特征在于显著和持续的恐惧，其是过度的或没有理由的，由特定目标或情形(飞行、高度、动物、看见血等)或社会行为环境的出现或预测所暗示。
通过对发作的出现的预测，将发生恐慌发作的疾病彼此区分，例如，在恐慌病中发作是不可预测的并且与任何特定的事件没有关系，而在特定恐惧症中发作是由特定的刺激诱发的。
术语“治疗恐慌病”指降低发作次数或防止发作和/或减轻发作的严重性。
按照本发明，化合物1′-[4-[1-(4-氟苯基)-1H-吲哚-3-基]-1-丁基]-螺[异苯并呋喃-1(3H)，4′-哌啶]可以以化合物的碱形式，或以其药用酸加成盐的形式，或此盐的脱水物或水合物的形式使用。用于本发明的化合物的盐是与无毒有机酸或无机酸形成的盐。这些有机盐的实例为与马来酸、富马酸、苯甲酸、抗坏血酸、琥珀酸、草酸、双亚甲基水杨酸、甲磺酸、乙二磺酸、乙酸、丙酸、酒石酸、水杨酸、枸橼酸、葡糖酸、乳酸、苹果酸、杏仁酸、柠康酸、天门冬氨酸、肉桂酸、硬脂酸、棕榈酸、衣康酸、乙醇酸、对氨基苯甲酸、谷氨酸、苯磺酸及茶碱乙酸以及8-卤代茶碱如8-溴-茶碱形成的盐。其中无机盐的实例为与氢氯酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸形成的盐。优选此化合物以碱或富马酸盐的形式使用。
已发现用于本发明方法中的化合物，在超声波诱发的Lister突冠大鼠的防卫行为的模型中抑制防卫跑动，所用模型是恐慌发作和潜在的抗恐慌药物的实验模型(Bechett等，Psychopharmacol.，1996，127，384-390)。
按照本发明，1′-[4-[1-(4-氟苯基)-1H-吲哚-3-基]-1-丁基]-螺[异苯并呋喃-1(3H)，4′-哌啶]或其药用盐可以以任何适宜的途径给药，例如，口服或非肠道给药，且其可以存在于任何适于此给药的剂型中，例如，片剂、胶囊、散剂、糖浆或者注射用溶液剂或分散剂。按照本发明的目的，优选本发明的化合物以固体药物实体的形式给药，该实体适宜作为片剂或胶囊或者注射用混悬剂、溶液剂或分散剂。
制备固体药物制剂的方法是本领域熟知的。通过将活性组份与常规辅剂和/或稀释剂混合，随后将此混合物在常规制片机中压制，可以制备片剂。辅剂或稀释剂的实例包括：玉米淀粉、乳糖、滑石、硬脂酸镁、明胶、乳糖、树胶等。只要与活性组份是相容的，就还可以其它辅剂或添加剂如着色剂、芳香剂、防腐剂等。
本发明的化合物最常以单位剂型如片剂或胶囊口服给药，其中活性组份的含量为约10μg/kg至10mg/kg体重，优选25μg/天/kg至1.0mg/天/kg，最优选0.1mg/天/kg至1.0mg/天/kg体重。
可以按照Perregaard，J.等，J.Med.Chem.，1995，38，11，1998-2008(化合物14f)的描述制备1′-[4-[1-(4-氟苯基)-1H-吲哚-3-基]-1-丁基]-螺[异苯并呋喃-1(3H)，4′-哌啶]的富马酸盐，而可以从其中的标准方法中获得碱或其它药用盐。
因此，本发明的酸加成盐可以通过用酸在惰性溶剂中处理1′-[4-[1-(4-氟苯基)-1H-吲哚-3-基]-1-丁基]-螺[异苯并呋喃-1(3H)，4′-哌啶]，接着沉淀、分离并通过已知方法重结晶(此步骤可有可无)进行制备，且如果需要，通过湿法或干法研磨或其它适当的方法制备微粉化的产品，或通过溶剂乳化方法制备颗粒。
优选在惰性溶剂，例如，惰性极性溶剂如醇(例如，乙醇、2-丙醇和正丙醇)中，进行该盐的沉淀。
药理实验
在Lister突冠大鼠中超声波诱发防卫行为的模型
在对Lister突冠大鼠超声波诱发防卫行为的模型中，检测本发明的化合物治疗恐慌病的作用。此模型已由Beckett等人给出(1996年，出处同上)，是基于观察接受其厌恶的刺激如捕食者放射的频率为18-27kHz的超声波声音。这些声音具有交往价值并给其它动物传递其所厌恶的刺激的信息。动物听到这些声音的反应包括自主激动、痛觉缺失和行为反射，其包括寒冷、逃跑和防卫性攻击。人们认为大鼠的此防卫状态类似于人的恐慌发作。
给幼鼠放人工产生的20kHz频率的超声波以影响其行为，让它们表现出与恐慌发作有关的防卫性奔跑。已表明用具有抗焦虑性质的试剂减弱了超声波诱发的防卫行为。此外，已知恐慌激发试剂育亨宾导致此超声波反应加强(Beckett等，1996，出处同上)。还观察到与厌恶反应调节有关的脑区的细胞活化。
实验方法
以前已详细描述过此方法(Beckett等，1996，出处同上)。简言之，用雄性Lister突冠大鼠(Charles River，250-300g)。在开始实验前30分钟用药物(或载体)预处理，并置于圆形开放实验场地(直径75cm，壁高46cm)，上部装有压电话筒。基线值观察2分钟后，让动物接受1分钟的20kHz方波超声波(85dB)，接着2分钟没有声音。用多功能信号发生器产生超声波。用头顶视频摄像机监控动物的行为并随后用计算机追踪系统(Ethovision，1.9版，Noldus InformationTechnology，The Netherlands)。将动物的行为评价为在每个两秒的时期内跑动的总距离。
计算所有基值检测(30×2s样本)的平均值，于是给出了每个动物的“基值”评分。将其作为比较所有后续数据点的参考。从放超声波的1分钟的每个2秒时间内移动的距离减去基值评分。得到30个数值，一些是阳性的而一些是阴性的，将所有的阳性值相加得到动物跑动高于基值的总评分，即，超声波诱发的活动过多的量。比较大鼠活动的基值以排除非特异性药物作用，并比较超声波诱发的跑动的增加。
每个实验包括两个对照组(每组用载体处理)，其中一个接受超声波而另一个只让其在实验期间在此场地共探察5分钟。此外，用药物处理的组进行接受超声波刺激的实验。
用非参数分析，Mann Whitney Rank总和检验分析数据，比较两个对照组(以确定超声波的作用)，并分析排列数据的差异以比较药物对超声波诱发反应的作用。如果适当的话，在方差分析后进行post-hoc比较(Mann Whitney排列总和检验)。
结果
本发明的化合物不影响动物探察的基值，这表明报告如下的作用不是由于本发明化合物对运动活力的非特异性作用。
在实验的第3分钟(在使用超声波期间)，较无超声波对照动物，对照-USV动物显示了明显较高的活力(两个实验中P＜0.01，MannWhitney Rank总和检验)。
剂量为0.63mg/kg的本发明化合物显著降低了防卫性跑动(P＜0.05：Mann Whitney Rank总和检验)。
为了比较，这些实验中包括了熟知的5-羟色胺再吸收抑制剂西酞普兰。
基于防卫性跑动反应被看作恐慌模型的事实，用发明化合物处理导致了防卫性跑动的降低，这与这些化合物抗恐慌作用相吻合。
Claims (9)
1．1′-[4-[4-(4-氟苯基)-1H-吲哚-3-基]-1-丁基]-螺[异苯并呋喃-1(3H)，4′-哌啶]或其药用盐在制备治疗恐慌发作药物中的用途。
2．权利要求1的用途，其特征在于所述化合物以碱或富马酸盐的形式使用。
3．权利要求1或2的用途，其特征在于所述药物以单位剂型给药。
4．权利要求3的用途，其特征在于所述单位剂型中活性组份的含量为约10μg/kg至10mg/kg体重，优选25μg/天/kg至1.0mg/天/kg，最优选0.1mg/天/kg至1.0mg/天/kg体重。
5．权利要求4的用途，其特征在于所述单位剂型中活性组份的含量为0.1mg/天/kg至1.0mg/天/kg体重。
6．权利要求1至5任一项的用途，其特征在于所述药物用于治疗恐慌病。
7．权利要求1至5任一项的用途，其特征在于所述药物用于治疗特定恐惧症。
8．权利要求1至5任一项的用途，其特征在于所述药物用于治疗社交恐惧症。
9．权利要求1至5任一项的用途，其特征在于所述药物用于治疗广场恐怖症。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK0501/1998 | 1998-04-07 | ||
| DK50198 | 1998-04-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1296409A true CN1296409A (zh) | 2001-05-23 |
Family
ID=8094284
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99804849A Pending CN1296409A (zh) | 1998-04-07 | 1999-03-30 | 恐慌发作的治疗 |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US6262061B1 (zh) |
| EP (1) | EP1069899A1 (zh) |
| JP (1) | JP2002510626A (zh) |
| KR (1) | KR20010042502A (zh) |
| CN (1) | CN1296409A (zh) |
| AR (1) | AR019023A1 (zh) |
| AU (1) | AU3025899A (zh) |
| BG (1) | BG104814A (zh) |
| BR (1) | BR9909598A (zh) |
| CA (1) | CA2325948A1 (zh) |
| EA (1) | EA200001032A1 (zh) |
| HR (1) | HRP20000659A2 (zh) |
| HU (1) | HUP0101706A3 (zh) |
| ID (1) | ID28335A (zh) |
| IL (1) | IL138484A0 (zh) |
| IS (1) | IS5636A (zh) |
| NO (1) | NO20005062L (zh) |
| PL (1) | PL342989A1 (zh) |
| SK (1) | SK14842000A3 (zh) |
| TR (1) | TR200002891T2 (zh) |
| WO (1) | WO1999051229A1 (zh) |
| YU (1) | YU58900A (zh) |
| ZA (1) | ZA200004856B (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002524515A (ja) * | 1998-09-15 | 2002-08-06 | ハー・ルンドベック・アクチエゼルスカベット | うつ病の治療方法 |
| AU2001279607A1 (en) * | 2000-08-15 | 2002-02-25 | H. Lundbeck, A/S | Pharmaceutical composition containing 1'-(4-(1-(4-fluorophenyl)-1h-indole-3-yl) -1-butyl)-spiro(isobenzofuran-1(3h),4'-piperidine) |
| US20050020483A1 (en) * | 2003-06-12 | 2005-01-27 | Donna Oksenberg | Sigma ligands for neuronal regeneration and functional recovery |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ243065A (en) * | 1991-06-13 | 1995-07-26 | Lundbeck & Co As H | Piperidine derivatives and pharmaceutical compositions |
-
1999
- 1999-03-30 PL PL99342989A patent/PL342989A1/xx unknown
- 1999-03-30 KR KR1020007011128A patent/KR20010042502A/ko not_active Application Discontinuation
- 1999-03-30 EP EP99911643A patent/EP1069899A1/en not_active Withdrawn
- 1999-03-30 SK SK1484-2000A patent/SK14842000A3/sk unknown
- 1999-03-30 YU YU58900A patent/YU58900A/sh unknown
- 1999-03-30 WO PCT/DK1999/000190 patent/WO1999051229A1/en not_active Application Discontinuation
- 1999-03-30 CA CA002325948A patent/CA2325948A1/en not_active Abandoned
- 1999-03-30 CN CN99804849A patent/CN1296409A/zh active Pending
- 1999-03-30 ID IDW20002279A patent/ID28335A/id unknown
- 1999-03-30 IL IL13848499A patent/IL138484A0/xx unknown
- 1999-03-30 JP JP2000542000A patent/JP2002510626A/ja not_active Withdrawn
- 1999-03-30 TR TR2000/02891T patent/TR200002891T2/xx unknown
- 1999-03-30 BR BR9909598-0A patent/BR9909598A/pt not_active IP Right Cessation
- 1999-03-30 EA EA200001032A patent/EA200001032A1/ru unknown
- 1999-03-30 HU HU0101706A patent/HUP0101706A3/hu unknown
- 1999-03-30 AU AU30258/99A patent/AU3025899A/en not_active Abandoned
- 1999-04-06 AR ARP990101556A patent/AR019023A1/es unknown
-
2000
- 2000-09-13 ZA ZA200004856A patent/ZA200004856B/xx unknown
- 2000-09-22 IS IS5636A patent/IS5636A/is unknown
- 2000-09-29 BG BG104814A patent/BG104814A/xx unknown
- 2000-10-06 US US09/685,016 patent/US6262061B1/en not_active Expired - Fee Related
- 2000-10-06 NO NO20005062A patent/NO20005062L/no not_active Application Discontinuation
- 2000-10-06 HR HR20000659A patent/HRP20000659A2/hr not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| BR9909598A (pt) | 2000-11-21 |
| WO1999051229A1 (en) | 1999-10-14 |
| YU58900A (sh) | 2002-11-15 |
| EP1069899A1 (en) | 2001-01-24 |
| NO20005062D0 (no) | 2000-10-06 |
| HUP0101706A3 (en) | 2003-03-28 |
| AU3025899A (en) | 1999-10-25 |
| NO20005062L (no) | 2000-11-30 |
| CA2325948A1 (en) | 1999-10-14 |
| ID28335A (id) | 2001-05-10 |
| EA200001032A1 (ru) | 2001-04-23 |
| SK14842000A3 (sk) | 2001-06-11 |
| HUP0101706A2 (hu) | 2001-11-28 |
| ZA200004856B (en) | 2001-08-29 |
| IS5636A (is) | 2000-09-22 |
| JP2002510626A (ja) | 2002-04-09 |
| PL342989A1 (en) | 2001-07-16 |
| TR200002891T2 (tr) | 2001-02-21 |
| IL138484A0 (en) | 2001-10-31 |
| AR019023A1 (es) | 2001-12-26 |
| KR20010042502A (ko) | 2001-05-25 |
| HRP20000659A2 (en) | 2001-04-30 |
| US6262061B1 (en) | 2001-07-17 |
| BG104814A (en) | 2001-04-30 |
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