CN1431901A - 用于治疗精神病和眼科疾病的s-甲基-二氢一齐拉昔酮 - Google Patents
用于治疗精神病和眼科疾病的s-甲基-二氢一齐拉昔酮 Download PDFInfo
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Abstract
本发明涉及含有S-甲基-二氢-齐拉昔酮的药物组合物和该化合物及其药学可接受盐在治疗精神病和眼科疾病中的应用。更加具体地,它涉及所述化合物及其药学可接受盐在治疗选自下列障碍或病症中的应用:精神分裂症、焦虑症如广泛性焦虑症、恐慌症、创伤后紧张症和恐怖症(例如社会恐怖症、广场恐怖症);焦虑的精神病发作:焦虑、激动、过度侵略性、紧张,或精神病相关性社交或情感回避;精神病性情感障碍如严重重性抑郁症,精神障碍相关性情感障碍,例如急性躁狂和两极性障碍相关性抑郁,和精神分裂症相关性情感障碍;智力低下相关性行为紊乱、孤独性障碍和品行障碍;痴呆,例如阿耳茨海默氏病相关性痴呆;药物引起的和基于神经变性的运动障碍;强迫观念与行为障碍、图雷特氏综合征;青光眼、缺血性视网膜病。
Description
发明背景
本发明涉及含有S-甲基-二氢-齐拉昔酮(ziprasidone)的药物组合物和该化合物及其药学可接受盐在治疗精神病和眼科疾病中的应用。更加具体地,本发明涉及所述化合物及其药学可接受盐在治疗选自下列的障碍和病症中的应用:精神分裂症、焦虑症如广泛性焦虑症、恐慌症、创伤后紧张症和恐怖症(例如社会恐怖症、广场恐怖症);焦虑的精神病发作:焦虑、激动、过度侵略性、紧张,或精神病相关性社交或情感回避;精神病性情感障碍如严重重性抑郁症,精神障碍相关性情感障碍,例如急性躁狂和两极性障碍相关性抑郁,和精神分裂症相关性情感障碍;智力低下相关性行为紊乱、孤独症和品行障碍;痴呆,例如阿耳茨海默氏病相关性痴呆;药物引起的和基于神经变性的运动障碍;强迫观念与行为障碍、图雷特氏综合征;青光眼、缺血性视网膜病。
S-甲基-二氢-齐拉昔酮,其具有下面的结构:并且化学名为6-氯-5-(2-{4-[亚氨基-(2-甲硫基苯基)-甲基]-哌嗪-1-基}-乙基)-1,3-二氢-吲哚-2-酮,是抗精神病药物齐拉昔酮的活性代谢物质,其具有下面的结构:
齐拉昔酮和有关的芳基哌嗪基-(C2-C4)亚烷基-杂环化合物、其合成方法及其在精神分裂症类的精神病治疗中的应用并且用于消除或减轻精神病患者中的症状例如焦虑、激动、过度侵略性、紧张和社交或情感回避可以参见美国专利4,831,031(其在1989年5月16日授权)、美国专利5,206,366(1993年4月27日授权)、美国专利4,833,795(1989年11月28日授权)、美国专利5,312,925(1994年5月17日)和美国专利5,338,846(1994年8月16日授权)。齐拉昔酮和此类相关化合物在治疗强迫观念与行为障碍和图雷特氏综合征中的应用参考美国专利申请09/146,289,该申请提交于1998年9月3日。齐拉昔酮及其相关化合物在与精神病有关的行为症状的治疗中的应用参见美国专利申请09/216,344,该申请提交于1998年12月8日。齐拉昔酮及其相关化合物在治疗青光眼和缺血性视网膜病中的应用参见美国专利申请09/314,792,其提交于1999年5月18日。上述专利、专利申请和杂志文献全部在此全文引入作为参考。
发明概述
本发明涉及用于治疗包括人在内的哺乳动物中选自下列的障碍或病症的药物组合物:精神分裂症、焦虑症如广泛性焦虑症、恐慌症、创伤后紧张症和恐怖症(例如社会恐怖症、广场恐怖症);焦虑的精神病发作:焦虑、激动、过度侵略性、紧张,或精神病相关性社交或情感回避;精神病性情感障碍如严重重性抑郁症,精神障碍相关性情感障碍,例如急性躁狂和两极性障碍相关性抑郁,和精神分裂症相关性情感障碍;智力低下相关性行为紊乱、孤独症和品行障碍;痴呆,例如阿耳茨海默氏病相关性痴呆;药物引起的和基于神经变性的运动障碍;强迫观念与行为障碍、图雷特氏综合征;青光眼、缺血性视网膜病;该组合物含有治疗上述障碍或病症有效量的S-甲基-二氢-齐拉昔酮或其药学可接受盐,和药学可接受载体。
本发明涉及一种治疗包括人在内的哺乳动物中选自下列障碍或病症的方法:精神分裂症、焦虑症如广泛性焦虑症、恐慌症、创伤后紧张症和恐怖症(例如社会恐怖症、广场恐怖症);焦虑的精神病发作:焦虑、激动、过度侵略性、紧张,或精神病相关性社交或情感回避;精神病性情感障碍如严重重性抑郁,精神障碍相关性情感障碍,例如急性躁狂和两极性障碍相关性抑郁,和精神分裂症相关性情感障碍;智力低下相关性行为紊乱、孤独症和品行障碍;痴呆,例如阿耳茨海默氏病相关性痴呆;药物引起的和基于神经变性的运动障碍;强迫观念与行为障碍、图雷特氏综合征;青光眼、缺血性视网膜病;该方法包括给该哺乳动物施用治疗所述障碍或病症有效量的S-甲基-二氢-齐拉昔酮或其药学可接受盐。这种方法此后也称作“本发明的方法”。
在此所用的术语“治疗”是指逆转、减轻、抑制所述障碍或病症的进程,或者预防所述的障碍或病症,该术语适用于此类障碍或病症的一种或多种症状。在此所用的术语“疗法”是指起治疗的作用,如同上面“治疗”定义。
本发明还涉及上述本发明方法,其中用S-甲基-二氢-齐拉昔酮的放射性标记形式代替S-甲基-二氢-齐拉昔酮。优选的S-甲基-二氢-齐拉昔酮的放射性标记化合物是那些其中放射性标记选自3H、11C、2H、13C、14C、18F、123I和125I的化合物。此类放射性标记的化合物在动物和人的代谢药代动力学研究和结合实验中用作研究和诊断工具。
式I化合物的药学可接受酸加成盐的实例是盐酸、对甲苯磺酸、富马酸、柠檬酸、琥珀酸、水杨酸、草酸、氢溴酸、磷酸、甲磺酸、酒石酸、马来酸、二对甲苯甲酰基酒石酸、乙酸、硫酸、氢碘酸和苦杏仁酸的盐。
本发明的一个具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症是精神分裂症。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症选自焦虑症如广泛性焦虑症、恐慌症、创伤后紧张症和恐怖症。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症是强迫观念与行为障碍。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症是青光眼。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症是缺血性视网膜病。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症是两极性障碍。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症是图雷特氏综合征。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症是药物引起的运动障碍。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症是基于神经变性的运动障碍。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症是精神障碍相关性情感障碍,例如急性躁狂和两极性障碍相关性抑郁,或精神分裂相关性情感障碍。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症是智力低下相关性行为紊乱、孤独性障碍和品行障碍。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症选自血管性痴呆、由HIV疾病引起的痴呆、由头部创伤引起的痴呆、由帕金森氏病引起的痴呆、由杭廷顿氏舞蹈病引起的疾病、由皮克氏病引起的痴呆、由Creutzfeldt-Jakob病引起的痴呆、物质引起的持久性痴呆、由多种病因引起的痴呆和无他规定(NOS)的痴呆。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症是阿尔茨海默氏病型的痴呆并且选自具有非并发性早期发作的阿尔茨海默氏病型的痴呆、具有妄想的早期发作的阿尔茨海默氏病型的痴呆。具有抑郁情感早期发作的阿尔茨海默氏病型的痴呆、具有非并发性晚期发作的阿尔茨海默氏病型的痴呆、具有妄想的晚期发作的阿尔茨海默氏病型的痴呆和具有抑郁情感的晚期发作的阿尔茨海默氏病型的痴呆。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症选自:不具有广场恐怖症的恐怖性障碍、具有广场恐怖症的恐怖性障碍、没有恐怖性障碍病史的广场恐怖症、社交恐怖症、创伤后紧张症、急性紧张症、广泛性焦虑症、物质引起的焦虑症和无他规定(NOS)的焦虑。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症选自抑郁性障碍、两极性障碍、具有抑郁特征的情感障碍、具有大抑郁样发作的器官障碍、具有躁狂特征的情感障碍、具有混和特征的情感障碍、物质引起的情感障碍和无他规定(NOS)的情感障碍。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症选自重性抑郁症(一次性发作)和重性抑郁症(复发性)。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症选自两极性I或II障碍(一次性躁狂发作)、两极性I或II障碍(常复发性轻躁狂发作)、两极性I或II障碍(常复发性躁狂发作,两极性I或II障碍常复发性混和发作,两极性I或II障碍常复发性抑郁发作)、躁郁循环性精神障碍和无他规定(NOS)的两极性障碍。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症是妄想型、组织破坏型、紧张症型、未分化型或其余类型的精神分裂症。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症是智力低下的行为表现。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症是品行障碍的行为表现。
本发明的另一具体实施方式涉及上述本发明方法,其中被治疗的障碍或病症是孤独性障碍的行为表现。
在此所述的所有精神病障碍和病症是所属领域技术人员已知的并且在Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition,American Psychiatric Association,1994(DMS IV)中定义,其在此全文引入作为参考。
发明详述
S-甲基-二氢-齐拉昔酮可以通过二氢-齐拉昔酮与甲基化试剂(例如碘甲烷或二偶氮甲烷)反应制备,优选与碘甲烷反应。该反应适宜在氮气氛下进行。通常该反应是在低级链烷醇例如甲醇、乙醇或丙醇、优选甲醇中,在约0℃至约溶剂的回流温度下进行,优选在约室温下,该反应是在强碱如氢氧化钾、氢氧化钠、叔丁醇钾或钠,或者碳酸钾或碳酸钠的存在下进行。
二氢-齐拉昔酮可以按照美国专利5,935,960所述方案制备,该专利在1999年8月10日授权。该专利在此全文引入作为参考。
以常规方式通过用约一个化学当量的药学可接受酸处理游离碱(I)的溶液或混悬液来制备S-甲基-二氢-齐拉昔酮的药学可接受酸加成盐。在盐的分离中采用常规浓缩和重结晶技术。适用酸的示例是乙酸、盐酸、氢溴酸、氢碘酸、硝酸、磺酸、硫酸、异烟酸、乳酸、水杨酸、柠檬酸、酒石酸、泛酸、重酒石酸、抗坏血酸、琥珀酸、马来酸、富马酸、葡糖二酸(glucaronic)、糖质酸、甲酸、苯甲酸、谷氨酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸和葡糖酸。
S-甲基-二氢-齐拉昔酮及其药学可接受盐(此后总称为“本发明的活性化合物”)在实践中可以单独给予人体对象,或者,更加可取地,与药学可接受载体或稀释剂组合。此类化合物可以经口服或非肠道给药。非肠道给药尤其包括静脉内和肌肉内给药。此外,在含有本发明活性化合物的药物组合物中,活性成分与载体的重量比一般是在1∶6-2∶1的范围内,并且优选1∶4-1∶1内。然而,在任何具体情况中,所选择的比例取决于多种因素,例如活性成分的溶解度、所考虑的剂量和给药的确切途径。
本发明的活性化合物可以经口服、非肠道(例如皮下、静脉内、肌肉内、胸骨内和灌注技术)、直肠、鼻内或局部途径给予哺乳动物。通常,这些化合物最理想地是以约0.5-约500mg/天的剂量一次性或分多次给药(即每天给药1-4次),虽然根据物种、被治疗对象的体重和状况以及所选择的具体给药途径必然会出现变化。然而,最希望采用在约10mg-约80mg/kg体重/天内的剂量水平。但是,根据被治疗动物的物种及其个体对该药物的反应,以及所选药物制剂的类型和进行给药的时间长短和间隔可能出现变化。在一些情况中,低于上述范围的下限的剂量水平可能更加适当,而其他情况是使用较大剂量不会引起任何有害副作用,条件是这样的较高剂量水平首先被分为多个小剂量用于在全天内给药。
本发明的活性化合物可以单独或者与药学可接受载体或稀释剂组合通过上述途径给药,并且这样的给药可以以一个或多个剂量进行。更加具体地,本发明的新的治疗剂可以以多种不同的剂型给药,即,它们可以与多种药学可接受惰性载体组合为片剂、胶囊、锭剂、糖锭剂、硬糖、散剂、喷雾剂、霜剂、油膏、栓剂、胶冻、凝胶、糊剂、洗剂、软膏、水混悬剂、可注射溶液、酏剂、糖浆剂等。此类载体包括固体稀释剂或填充剂、灭菌水介质和多种无毒有机溶剂等。此外,口服药物组合物可以适当地增甜和/或矫味。通常,本发明的治疗上有效的化合物是以约5.0%-约70%(重量)的浓度水平存在于所述剂型中。
为了口服用于治疗上述各种障碍和病症,可以以例如片剂或胶囊的形式,或者作为水溶液或混悬液给药。含有多种赋形剂例如微晶纤维素、柠檬酸钠、碳酸钙、磷酸氢二钙和甘氨酸的片剂可以与各种崩解剂例如淀粉(并且优选玉米、土豆或木薯淀粉)、藻酸和某些复合硅酸盐,以及制粒粘合剂例如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶一起使用。另外,润滑剂例如硬脂酸镁、十二烷基硫酸钠和滑石常常非常适用于制片目的。相似类型的固体组合物还可以用作明胶胶囊中的填充剂;有关的优选物质还包括乳糖或奶糖以及高分子量聚乙二醇。当希望用水混悬剂和/或酏剂来口服给药时,活性成分可以与多种甜味剂或矫味剂、着色物质或染料,并且如果需要与乳化剂和/或助悬剂,与上述稀释剂如水、乙醇、丙二醇、甘油及其多种联合形式合用。
为了非肠道给药,可以使用本发明的化合物在芝麻油或花生油或在含水丙二醇中的溶液。如果需要含水溶液应当被适当缓冲(优选pH大于8)并且液体稀释剂首先提供等渗。这些含水溶液适合静脉内注射目的。油溶液适合于关节内、肌肉内和皮下注射目的。所有这些溶液在灭菌条件下的制备很容易通过所属领域技术人员熟知的标准制药技术来完成。
为了肌肉内、非肠道和静脉内使用,可以制备活性成分的灭菌溶液,并且溶液的pH应该被适当调节且缓冲。为了静脉内使用,溶质的总浓度应当控制在使该制剂等渗。
而且,当治疗眼科疾病如青光眼和缺血性视网膜病时也可以局部施用本发明的化合物,并且这可以通过霜剂、胶冻、凝胶、糊剂、贴剂、软膏等按照标准药学实践来实施。
下列实施例举例说明S-甲基-二氢-齐拉昔酮的合成。
实施例1
6-氯-5(2-{4-[亚氨基-(2-甲硫基苯基)-甲基]哌嗪-1-基}-乙
基)-1,3-二氢-吲哚-2-酮
在氮气氛下将氢氧化钾(1.82g)加入到甲醇(1300ml)且在21℃下搅拌15分钟。加入二氢-齐拉昔酮(13.0g,31.3mmol)且在21℃下搅拌该混合物直至形成溶液为止。加入碘甲烷(2.34ml,37.7mmol,1.2当量)且将该溶液在21℃下搅拌过夜。利用薄层层析(硅胶,用4∶1二氯甲烷∶异丙醇洗脱,在254nm的uV灯下显色)监测反应的进程。将该反应混合物真空浓缩且向残余固体加入2.0L的二氯甲烷和500ml水。搅拌该混浊混合物15分钟,此后弃去水层(pH=9.8)。呈淡粉色的二氯甲烷用硫酸镁干燥且加入Darco G60使固体脱色。将该混合物继续在21℃下搅拌15分钟且经硅藻土过滤。硅藻土滤垫用50ml二氯甲烷洗涤,并且合并的滤液真空浓缩得到固体(13.05g),其为浅粉色。利用硅胶和二氯甲烷洗脱剂的快速色谱进一步纯化得到7.38g的标题化合物。M.P.103-106℃(生成气体)。质谱(m/e,%强度):429(100,M+1),236,194.13C NMR(CDCl3)177.70,166.83,142.36,136.94,136.17,133.10,131.30,129.51,126.86,125.27,124.46,111.06,58.84,53.11,36.09,30.95和15.87。
Claims (13)
1.一种治疗哺乳动物中选自下列障碍或病症的方法:精神分裂症、焦虑症如广泛性焦虑症、恐慌症、创伤后紧张症和恐怖症;焦虑的精神病发作:焦虑、激动、过度侵略性、紧张,或精神病相关性社交或情感回避;精神病性情感障碍如严重重性抑郁症;精神障碍相关性情感障碍,例如急性躁狂和两极性障碍相关性抑郁,和精神分裂症相关性情感障碍;智力低下相关性行为紊乱、孤独性障碍和品行障碍;痴呆,例如阿耳茨海默氏病相关性痴呆;药物引起的和基于神经变性的运动障碍;强迫观念与行为障碍、图雷特氏综合征;青光眼、缺血性视网膜病,该方法包括给哺乳动物施用有效治疗上述障碍或病症量的6-氯-5(2-{4-[亚氨基-(2-甲硫基苯基)-甲基]哌嗪-1-基}-乙基)-1,3-二氢-吲哚-2-酮或其药学可接受盐。
2.按照权利要求1所述的方法,其中被治疗的障碍或病症是精神分裂症。
3.按照权利要求1所述的方法,其中被治疗的障碍或病症是广泛性焦虑症。
4.按照权利要求1所述的方法,其中被治疗的障碍或病症是恐怖症。
5.按照权利要求1所述的方法,其中被治疗的障碍或病症是两极性障碍。
6.按照权利要求1所述的方法,其中被治疗的障碍或病症是创伤后紧张症。
7.按照权利要求1所述的方法,其中被治疗的障碍或病症是痴呆。
8.按照权利要求1所述的方法,其中被治疗的障碍或病症是智力低下的行为表现。
9.按照权利要求1所述的方法,其中被治疗的障碍或病症是品行障碍的行为表现。
10.按照权利要求1所述的方法,其中被治疗的障碍或病症是孤独性障碍的行为表现。
11.按照权利要求1所述的方法,其中被治疗的障碍或病症是青光眼。
12.按照权利要求1所述的方法,其中被治疗的障碍或病症是缺血性视网膜病。
13.一种用于治疗哺乳动物中选自下列障碍或病症的药物组合物:精神分裂症、焦虑性障碍如广泛性焦虑症、恐慌症、创伤后紧张症和恐怖症;焦虑的精神病发作:焦虑、激动、过度侵略性、紧张,或精神病相关性社交或情感回避;精神病性情感障碍如严重重性抑郁症;精神障碍相关性情感障碍,例如急性躁狂和两极性障碍相关性抑郁,和精神分裂症相关性情感障碍;智力低下相关性行为紊乱、孤独症和品行障碍;痴呆,例如阿耳茨海默氏病相关性痴呆;药物引起的和基于神经变性的运动障碍;强迫观念与行为障碍、图雷特氏综合征;青光眼、缺血性视网膜病,其中含有有效治疗上述障碍或病症量的6-氯-5(2-{4-[亚氨基-(2-甲硫基苯基)-甲基]哌嗪-1-基}-乙基)-1,3-二氢-吲哚-2-酮或其药学可接受盐,和药学可接受载体。
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2002
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- 2002-11-29 MA MA26927A patent/MA26908A1/fr unknown
- 2002-12-02 HR HR20020953A patent/HRP20020953A2/hr not_active Application Discontinuation
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2007
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