CN1291893A - D1/d5拮抗剂用于治疗强迫观念与行为失调、体型失调、分离失调、吃喝失调、冲动控制失调与孤独症的用途 - Google Patents
D1/d5拮抗剂用于治疗强迫观念与行为失调、体型失调、分离失调、吃喝失调、冲动控制失调与孤独症的用途 Download PDFInfo
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Abstract
公开了强迫观念与行为失调、体型失调、分离失调、吃喝失调、冲动控制失调、和孤独症的一种治疗方法。这些病症是通过给药某一有效量的一种D1/D5拮抗剂治疗的。
Description
发明背景
本发明涉及一群以反复、侵入式思维和/或仪式般行为为标志的病症即强迫观念与行为失调、体型失调、分离失调、吃喝失调、冲动控制失调、和孤独症的治疗。
强迫观念与行为失调(“OCD”)被公认是所有精神病学病症中最常见的,在美国人口中的发生率为2~3%。OCD的特征在于引起焦虑的和侵入式的思维(例如,害怕沾污和病菌、怀疑和不能肯定未来的危害,需要对称等),从而导致仪式般和/或不合理的行为(例如不断检查、洗涤、触摸、计数等)。见Hollander等人,J.Clin Psychiatry57(Suppl.8),pp.3-6(1996)。
体型失调(例如身体畸形症和疑病症)的特征在于对某人外貌和身体条件的一种异常偏见。例如,身体畸形症是对凭想像或轻微的外貌缺陷的一种偏见。很多有身体畸形症的患者因其异常偏见而严重衰弱,在日常生活的社会方面、职业方面或其它重要方面有显著损害。见Phillips,J.Clin Psychiatry 57(Suppl.8),pp.61-64(1996)。疑病症的特征在于持久地坚信某人有病或可能要生病。很多疑病症患者因其病态性偏见而不能工作或从事正常活动。
分离失调(例如人格解体)的特征在于同一性、记忆、或意识上的突然暂时性改变,使来自该个体的占主导同一性的个性(人格)的正常一体化记忆或组成部分割裂开。人格解体症是一种分离失调,其特征在于人格解体的一个或多个事件(某人对自身或某个身体形象的知觉上的不真实感或陌生感)。
饮食失调(例如厌食性神经过敏、食欲过盛、和狂饮狂食)的特征在于异常强制,以避免消费异常大量食物的饮食冲动或不可控制冲动。这些病症不仅影响社会健康,而且也影响患者的身体健康。
冲动控制失调(例如病理性赌博、冲动性购买、性冲动和偷窃狂)的特征在于一种偏见,而且忍不住反复从事各种要么是社会上不可接受的要么用社会标准衡量时异常过度的行为。
孤独症是一种失调,其特征是对某人自身的一种偏见,和对正常形式外界刺激的感知能力或反应能力的严重损害。很多孤独症患者甚至不能与其它人沟通。
鉴于这些病症的悲剧性效果和衰弱效果,对可以有效治疗此类病症的药物疗法有强烈需要。
已经有一些报告说,某些D1拮抗剂:能抑制新生-6-羟基propamine损害的大鼠中L-DOPA诱发的self-mutilatory行为;能阻止大鼠中苯丙胺诱发的运动性活动和阿扑吗啡诱发的刻板动作;能抑制对狨给药D1拮抗剂诱发的自我打扮活动和口头活动;能抑制小鼠中阿扑吗啡诱发的刻板动作;和能扭转用氟哌啶醇处理的猴子中的锥体束外副作用。见Criswell等人,Neuropsychopharmacology(神经精神药理学),7(2)pp.95-103(1992);Kerkman等人,European Journal ofPharmacology(欧洲药理学杂志),166(3)481-91(1989);Gnanalingham等人,Psychophamacology(精神药理学),117(4),pp.403-12(1995);Acri等人,Drug Dev.Res(药物进展评论),37(1),pp.39-47(1996);McHugh等人,European Journalof Pharmacologu(欧洲药理学杂志)202,pp.133-134(1991);Coffin等人,Neurochem.Int.(国际神经化学),Vol.20.Suppl.,pp.141S-145S(1992);waddington,Gen.Pharmac.(药学)Vol.19,No.1,pp.55-60(1988);和Beaulieu,Can.J.Neurol,Sci.(神经科学),14:402-406(1987)。
发明概要
本发明提供一种通过给药某一有效量的一种D1/D5拮抗剂来治疗患有强迫观念与行为失调、体型失调、分离失调、饮食失调、冲动控制失调或孤独症的人的方法。
本发明的详细说明
本文中使用的下列术语具有以下提到的含义。
“D1/D5拮抗剂”是一种能选择性地结合脑中的D1受体和/或D5受体,从而减少或防止多巴胺进入这些部位的化合物。一种化合物当它显示出要么对D1受体要么对D5受体比它对D2受体有更大的结合时“选择性结合”D1和/或D5受体。D1/D5拮抗剂包括只结合D1受体的化合物(纯D1拮抗剂)、只结合D5受体的化合物(D5拮抗剂)、以及能同时结合D1和D5受体的化合物。
D1/D5拮抗剂的非限制性实例包括:SCH 39166[(-)-反式-6,7,7a,8,9,13b-六氢-3-氯-2-羟基-N-甲基-5-H-苯并[d]萘并{2,1-b}吖庚因·HCl];SCH 23390[(R)-(+)-8-氯-2,3,4,5-四氢-3-甲基-5-苯基-1H-3-苯并吖庚因-7-醇·马来酸盐];BTS-73-947[(S)-1-(1-(2-氯苯基)环丙基)-7-羟基-6-甲氧基-2-甲基-1,2,3,4-四氢异喹啉];A-69024[1-(2-溴-4,5-二甲氧基苄基)-7-羟基-6-甲氧基-2-甲基-1,2,3,4-四氢异喹啉];JHS-271[8-氯-3-[6-(二甲胺基)己基]-2,3,4,5-四氢-5-苯基-1H-3-苯并吖庚因-7-醇];JHS-198[8-氯-3-[6-(二甲胺基)己基]-2,3,4,5-四氢-5-苯基-1H-3-苯并吖庚因-7-醇与氰基硼烷的1∶1配合物];JHS-136[8-氯-3-[4-(二甲胺基)丁基]-2,3,4,5-四氢-5-苯基-1H-3-苯并吖庚因-7-醇];和NNC-22-0010[S(+)-8-氯-5-(5-溴-2,3-二氢苯并呋喃-7-基)-7-羟基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因]。上述D1/D5拮抗剂可以用已知方法制备,例如用U.S.5,302,716、WO 93/13073、WO93/1702、WO 95/25102、和J.Med.Chem.(药物化学杂志)38(21)pp.4284-93(1995)中所述方法制备,其内容列为本文参考文献。SCH 39166和SCH 23390是特别好的,而SCH 39166是最好的。
熟悉本门技术的人员将知道,强迫观念与行为失调、体型失调、分离失调、吃喝失调、冲动控制失调、和孤独症治疗的有效剂量将因所治疗的特定个体和该病症的相对严重性而异。D1/D5拮抗剂的日给药剂量较好的是0.01~500mg/kg体重,更好的是0.01~150mg/kg,最好的是0.01~10mg/kg。该日剂量可以以单一剂量给药,也可以等分成若干个剂量给药。
为了制备有本发明中使用的D1/D5拮抗剂的医药组合物;惰性、医药上可接受的载体可以要么是固体要么是液体。固体形式制剂包括散剂、片剂、可分散颗粒剂、胶囊剂、扁囊剂和栓剂。散剂和片剂可以包含约5%~约70%有效成分。适用的固体载体是技术上已知的,例如碳酸镁、硬脂酸镁、滑石、糖、乳糖。片剂、散剂、扁囊剂和胶囊剂可以用来作为适合于经口给药的固体剂型。
为了制备栓剂,先将低熔点蜡例如脂肪酸甘油酯或可可脂的混合物熔融,用搅拌法将有效成分均匀分散于其中。然后,把熔融的均匀混合物倾入尺寸适中的模具中,使之冷却、凝固。
液体形式制剂包括溶液剂、悬浮液剂和乳液剂。作为一个实例,可以列举非经肠注射用水溶液剂或水-丙二醇溶液剂。
液体形式制剂也可以包括经鼻内给药用溶液剂。
适合于吸入的气雾剂制剂包括溶液剂和呈粉末形式的固体剂,它们可以与医药上可接受的载体例如惰性压缩气体组合。
还包括那些打算在临使用前转化成要么经口给药要么非经肠给药用液体形式制剂的固体形式制剂。这样的液体形式包括溶液剂、悬浮液剂和乳液剂。
D1/D5拮抗剂也可以是可经皮给药的。经皮给药用组合物可以呈霜剂、洗剂、气雾剂和/或乳液剂的形式,而且可以包括在基体型或贮器型经皮贴剂中,这也是本用途技术上常用的。
较好的是,D1/D5拮抗剂是经口给药的。
实例1
制备含有SCH 39166作为有效成分的医药组合物:
No. | 成分 | 胶囊 | 胶囊 |
1 | SCH 39166 | 5.0 | 25.0 |
2 | 乳糖(美国药典) | 114.0 | 94.0 |
3 | 淀粉乙醇酸钠(国家药典) | 6.0 | 6.0 |
4 | 吡咯烷酮(美国药典)(K29/32) | 4.0 | 4.0 |
5 | 硬脂酸镁(国家药典) | 1.0 | 1.0 |
合计 | 130.0mg | 130.0mg |
表中1~4项在一台适用掺合机中混合10~15分钟。添加第5项,混合1~3分钟。用一台适用的胶囊灌装机把混合物灌装到适用的两件式硬明胶胶囊中。
实例2
对诊断为强迫观念与行为失调的患者在六个月内一天一次给药实例1胶囊(含5.0mg SCH 39166),从而减少或消除该失调的可观察症状。
实例3
对诊断为孤独症的患者在六个月内一天一次给药实例1胶囊(含25.0mg SCH 39166),从而减少或消除该失调的可观察症状。
虽然本发明给含以上列举的具体实施方案加以说明,但对于有本门技术一般技能的人员来说,它的很多替代物、改良和变异将是显而易见的。所有这样的替代物、改良和变异都属于本发明的精神和范围之内。
Claims (20)
1.患有从强迫观念与行为失调、体型失调、分离失调、吃喝失调、冲动控制失调、和孤独症组成的一组中选择的病症的人的治疗方法,所述方法包含给药某一有效量的一种D1/D5拮抗剂。
2.权利要求1的方法,其中,D1/D5拮抗剂的日给药剂量为0.01~500mg/kg。
3.权利要求2的方法,其中,D1/D5拮抗剂的日给药剂量为0.01~150mg/kg。
4.权利要求3的方法,其中,D1/D5拮抗剂的日给药剂量为0.01~10mg/kg。
5.权利要求1的方法,其中,D1/D5拮抗剂选自如下一组:(-)-反式-6,7,7a,8,9,13b-六氢-3-氯-2-羟基-N-甲基-5-H-苯并[d]萘并{2,1-b}吖庚因·HCl;(R)-(+)-8-氯-2,3,4,5-四氢-3-甲基-5-苯基-1H-3-苯并吖庚因-7-醇·马来酸盐;(S)-1-(1-(2-氯苯基)环丙基)-7-羟基-6-甲氧基-2-甲基-1,2,3,4-四氢异喹啉;1-(2-溴-4,5-二甲氧基苄基)-7-羟基-6-甲氧基-2-甲基-1,2,3,4-四氢异喹啉;8-氯-3-[6-(二甲胺基)己基]-2,3,4,5-四氢-5-苯基-1H-3-苯并吖庚因-7-醇;8-氯-3-[6-(二甲胺基)己基]-2,3,4,5-四氢-5-苯基-1H-3-苯并吖庚因-7-醇与氰基硼烷的1∶1配合物;8-氯-3-[4-(二甲胺基)丁基]-2,3,4,5-四氢-5-苯基-1H-3-苯并吖庚因-7-醇;和S(+)-8-氯-5-(5-溴-2,3-二氢苯并呋喃-7-基)-7-羟基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因。
6.权利要求5的方法,其中,D1/D5拮抗剂的日给药剂量为0.01~500mg/kg。
7.权利要求6的方法,其中,D1/D5拮抗剂的日给药剂量为0.01~150mg/kg。
8.权利要求7的方法,其中,D1/D5拮抗剂的日给药剂量为0.01~10mg/kg。
9.权利要求1的方法,其中,该病症是强迫观念与行为失调。
10.权利要求9的方法,其中,D1/D5拮抗剂选自如下一组:(-)-反式-6,7,7a,8,9,13b-六氢-3-氯-2-羟基-N-甲基-5-H-苯并[d]萘并{2,1-b}吖庚因·HCl;(R)-(+)-8-氯-2,3,4,5-四氢-3-甲基-5-苯基-1H-3-苯并吖庚因-7-醇·马来酸盐;(S)-1-(1-(2-氯苯基)环丙基)-7-羟基-6-甲氧基-2-甲基-1,2,3,4-四氢异喹啉;1-(2-溴-4,5-二甲氧基苄基)-7-羟基-6-甲氧基-2-甲基-1,2,3,4-四氢异喹啉;8-氯-3-[6-(二甲胺基)己基]-2,3,4,5-四氢-5-苯基-1H-3-苯并吖庚因-7-醇;8-氯-3-[6-(二甲胺基)己基]-2,3,4,5-四氢-5-苯基-1H-3-苯并吖庚因-7-醇与氰基硼烷的1∶1配合物;8-氯-3-[4-(二甲胺基)丁基]-2,3,4,5-四氢-5-苯基-1H-3-苯并吖庚因-7-醇;和S(+)-8-氯-5-(5-溴-2,3-二氢苯并呋喃-7-基)-7-羟基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因。
11.权利要求10的方法,其中,D1/D5拮抗剂是(-)-反式-6,7,7a,8,9,13b-六氢-3-氯-2-羟基-N-甲基-5-H-苯并[d]萘并{2,1-b}吖庚因·HCl。
12.权利要求11的方法,其中,D1/D5拮抗剂的日给药剂量为0.01~500mg/kg。
13.权利要求12的方法,其中,D1/D5拮抗剂的日给药剂量为0.01~150mg/kg。
14.权利要求1的方法,其中,该病症选自厌食性神经过敏、食欲过盛、和狂饮狂食组成的一组。
15.权利要求14的方法,其中,D1/D5拮抗剂选自如下一组:(-)-反式-6,7,7a,8,9,13b-六氢-3-氯-2-羟基-N-甲基-5-H-苯并[d]萘并{2,1-b}吖庚因·HCl;(R)-(+)-8-氯-2,3,4,5-四氢-3-甲基-5-苯基-1H-3-苯并吖庚因-7-醇·马来酸盐;(S)-1-(1-(2-氯苯基)环丙基)-7-羟基-6-甲氧基-2-甲基-1,2,3,4-四氢异喹啉;1-(2-溴-4,5-二甲氧基苄基)-7-羟基-6-甲氧基-2-甲基-1,2,3,4-四氢异喹啉;8-氯-3-[6-(二甲胺基)己基]-2,3,4,5-四氢-5-苯基-1H-3-苯并吖庚因-7-醇;8-氯-3-[6-(二甲胺基)己基]-2,3,4,5-四氢-5-苯基-1H-3-苯并吖庚因-7-醇与氰基硼烷的1∶1配合物;8-氯-3-[4-(二甲胺基)丁基]-2,3,4,5-四氢-5-苯基-1H-3-苯并吖庚因-7-醇;和S(+)-8-氯-5-(5-溴-2,3-二氢苯并呋喃-7-基)-7-羟基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因。
16.权利要求15的方法,其中,D1/D5拮抗剂选自(-)-反式-6,7,7a,8,9,13b-六氢-3-氯-2-羟基-N-甲基-5-H-苯并[d]萘并{2,1-b}吖庚因·HCl或(R)-(+)-8-氯-2,3,4,5-四氢-3-甲基-5-苯基-1H-3-苯并吖庚因-7-醇·马来酸盐,且日给药剂量为0.01~500mg/kg。
17.权利要求1的方法,其中,该病症的孤独症。
18.权利要求17的方法,其中,D1/D5拮抗剂选自(-)-反式-6,7,7a,8,9,13b-六氢-3-氯-2-羟基-N-甲基-5-H-苯并[d]萘并{2,1-b}吖庚因·HCl或(R)-(+)-8-氯-2,3,4,5-四氢-3-甲基-5-苯基-1H-3-苯并吖庚因-7-醇·马来酸盐,且日给药剂量为0.01~500mg/kg。
19.权利要求1的方法,其中,该病症是从病理性赌博、冲动性购买、和性冲动组成的一组中选择的一种冲动控制失调。
20.权利要求19的方法,其中,D1/D5拮抗剂选自(-)-反式-6,7,7a,8,9,13b-六氢-3-氯-2-羟基-N-甲基-5-H-苯并[d]萘并{2,1-b}吖庚因·HCl或(R)-(+)-8-氯-2,3,4,5-四氢-3-甲基-5-苯基-1H-3-苯并吖庚因-7-醇·马来酸盐,且日给药剂量为0.01~500mg/kg。
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NO20004363L (no) | 2000-10-31 |
BR9908392A (pt) | 2000-10-31 |
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