CN1319013A - 治疗帕金森氏病、adhd和微腺瘤的药物试剂 - Google Patents
治疗帕金森氏病、adhd和微腺瘤的药物试剂 Download PDFInfo
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- CN1319013A CN1319013A CN99811132A CN99811132A CN1319013A CN 1319013 A CN1319013 A CN 1319013A CN 99811132 A CN99811132 A CN 99811132A CN 99811132 A CN99811132 A CN 99811132A CN 1319013 A CN1319013 A CN 1319013A
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Abstract
本发明涉及由式(Ⅰ)所定义的、也被描述为双氮杂二环化合物的某些吡啶并[1,2-a]吡嗪衍生物在哺乳动物帕金森氏病、注意短缺活动过强症和微腺瘤治疗中的用途,和有关组合物。
Description
发明领域
本发明涉及也被描述为双氮杂二环化合物的某些吡啶并[1,2-a]吡嗪衍生物在包括人类在内的哺乳动物的帕金森氏病、注意短缺活动过强症(“ADHD”)和微腺瘤治疗中的用途。还涉及多巴胺-2(D2)受体激动剂与血清素-1A(5HT1A)受体激动剂相结合在帕金森氏病治疗中的用途。还涉及阿尔法-2(α2)肾上腺素能受体配体与D2受体激动剂或5HT1A受体激动剂的组合在ADHD治疗中的用途。还涉及D2受体激动剂与5HT1A受体激动剂的组合在ADHD治疗中的用途。还涉及阿尔法-2(α2)肾上腺素能受体配体同时与D2受体激动剂和5HT1A受体激动剂的组合在ADHD治疗中的用途。
发明背景
血清素在若干精神病学病症中发挥作用,包括焦虑症、阿尔茨海默氏病、抑郁症、恶心和呕吐、饮食失调和偏头痛(见Rasmussen等,“第1章:血清素5HT1A受体调制剂的最新进展”(“Chapter 1.RecentProgress in Serotonin 5HT1A Receptor Modulators”)《药物化学年度报告》第Ⅰ部分(Annual Reports in Medicinal Chemistry,SectionⅠ),30,pp.1-9,1995,Academic Press,Inc;Antigas等《神经科学趋势》(Trends Neurosci.),19(9),1996,pp.378-383;Wolf等《药物开发研究》(Drug Development Research),40,1997,pp.17-34)。血清素也在精神***症的阳性和阴性症状中发挥作用(见Sharma等《精神病学年鉴》(Psychiatric Annals.),26(2),1996年2月,pp.88-92)。血清素1A受体激动剂已表现出可增加额叶前部皮质的多巴胺(DA)释放。见Wedzony等《欧洲药理学杂志》(Eur.J.Pharmacol.)305:73-78(1996)。丁螺环酮是一种5HT1A受体激动剂,已表现出对治疗各种与ADHD有关的症状有效。血清素1A受体激动剂也已表现出可逆转非人类灵长类动物的由神经安定剂诱发的张力障碍,这是一种模拟人类帕金森氏病症状的状态。见Casey,D.E.,《神经精神药理学》(Neuropsychopharmacol.),10:370S(1994)。
与ADHD有关的症状已表现出可用诸如哌醋甲酯等儿茶酚胺释放药和诸如可乐定等突触后α2肾上腺素能受体激动剂来缓解。同样,突触前α2肾上腺素能受体拮抗剂也已表现出可增加去甲肾上腺素(NE)的释放。
许多1-(2-嘧啶基)-4-[4-(环-亚氨基)丁基]哌啶衍生物已作为普遍缺乏镇静活性的抗焦虑药。其中有丁螺环酮,其环-亚氨基是4,4-四亚甲基-哌啶-2,6-二酮-1-基(wu等,美国专利3,717,634和3,907,801;Casten等,美国专利4,182,763);吉吡隆,其环-亚氨基是4,4-二甲基哌啶-2,6-二酮-1-基(Temple,Jr.,美国专利4,423,049);和伊沙匹降,其环-亚氨基是1,1-二氧苯并[d]异噻唑-3(2H)-酮-基(Dompert等,德国专利公报3,321,969-A1)。也参见Ishizumi等,美国专利4,507,303和4,543,55;Freed等,美国专利4,562,225;Stack等,美国专利4,732,983;New等,美国专利4,524,026;和Stack,美国专利4,788,290。
下列式(Ⅰ)化合物公开在美国专利5,122,525中,它们可用于焦虑症和抑郁症的治疗。这种化合物在成瘾治疗中的用途描述在美国专利5,616,885中。
发明概要
本发明涉及治疗包括人类在内的哺乳动物病症的方法,该病症选自帕金森氏病、ADHD和微腺瘤,该方法包括将治疗该病症有效量的下式化合物
或其药学上可接受的酸加成盐对需要接受治疗的哺乳动物给药,其中
X是N或CH;
特别优选的化合物是其中Z是Y1(CH2)n,Y1是CH2,n是1且X是N的那些。
式Ⅰ化合物是D2受体激动剂,可用于帕金森氏病的治疗。它们也表现出5HT1A受体激动剂的活性。
式Ⅰ化合物也表现出作为α2肾上腺素能受体拮抗剂的活性,可用于ADHD的治疗。该化合物增加海马体NE的释放,也增加额叶前部皮质DA的释放。
碱性式Ⅰ化合物能与各种有机酸和无机酸生成酸加成盐。可用于制备上述式Ⅰ碱化合物的药学上可接受的酸加成盐的酸是生成无毒的酸加成盐的那些,即含有药理学上可接受的阴离子的盐,例如盐酸盐、氢溴化物、氢碘化物、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐、酸式柠檬酸盐、酒石酸盐、酒石酸氢盐、琥珀酸盐、马来酸盐、富马酸盐、葡糖酸盐、糖二酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酰酸盐和扑酸盐(即1,1’-亚甲基-双-(2-羟基-3-萘甲酸盐))。
本文所用动词“治疗”是指逆转、缓解、抑制该术语所针对的病症或病情的进展,或预防该病症或病情,或者该病症或病情的一种或多种症状。本文所用名词“治疗”是指刚才所定义的动词“治疗”的动作。
本发明也涉及治疗包括人类在内的哺乳动物帕金森氏病的方法,该方法包括将D2受体激动剂与5HT1A受体激动剂联合对需要接受治疗的哺乳动物给药,其中前述两种活性试剂的含量使它们的组合对治疗帕金森氏病是有效的。
本发明也涉及用于治疗包括人类在内的哺乳动物帕金森氏病的药物组合物,该组合物包含(a)D2受体激动剂或其药学上可接受的盐;(b)5HT1A受体激动剂或其药学上可接受的盐;和(c)药学上可接受的载体;其中前述两种活性试剂在组合物中的量使它们的组合对治疗帕金森氏病是有效的。
本发明也涉及治疗包括人类在内的哺乳动物ADHD的方法,该方法包括将α2肾上腺素能受体配体或其药学上可接受的盐与D2受体激动剂或5HT1A受体激动剂或它们的药学上可接受的盐联合对需要接受治疗的哺乳动物给药,其中前述两种活性试剂的含量使它们的组合对ADHD是有效的。
本发明也涉及用于治疗包括人类在内的哺乳动物ADHD的药物组合物,该组合物包含(a)α2肾上腺素能受体配体或其药学上可接受的盐;(b)D2受体激动剂或5HT1A受体激动剂,或它们的药学上可接受的盐;和(c)药学上可接受的载体;其中前述两种活性试剂在组合物中的量使它们的组合对治疗ADHD是有效的。
本发明也涉及治疗包括人类在内的哺乳动物ADHD的方法,该方法包括将D2受体激动剂或其药学上可接受的盐与5HT1A受体激动剂或其药学上可接受的盐联合对需要接受治疗的哺乳动物给药,其中前述两种活性试剂的含量使它们的组合对治疗ADHD是有效的。
本发明也涉及用于治疗包括人类在内的哺乳动物ADHD的药物组合物,该组合物包含(a)D2受体激动剂或其药学上可接受的盐;(b)5HT1A受体激动剂或其药学上可接受的盐;和(c)药学上可接受的载体;其中前述两种活性试剂在组合物中的量使它们的组合对治疗ADHD是有效的。
本发明也涉及治疗包括人类在内的哺乳动物ADHD的方法,该方法包括将α2肾上腺素能受体配体或其药学上可接受的盐与D2受体激动剂或其药学上可接受的盐以及5HT1A受体激动剂或其药学上可接受的盐联合对需要接受治疗的哺乳动物给药,其中前述三种活性试剂的含量使它们的组合对ADHD是有效的。
本发明也涉及用于治疗包括人类在内的哺乳动物ADHD的药物组合物,该组合物包含(a)α2肾上腺素能受体配体或其药学上可接受的盐;(b)D2受体激动剂或其药学上可接受的盐;(c)5HT1A受体激动剂或其药学上可接受的盐;和(d)药学上可接受的载体;其中前述三种活性试剂在组合物中的量使它们的组合对治疗ADHD是有效的。
式Ⅰ化合物可以含有手性中心,因此可以以不同的对映异构和非对映异构形式存在。本文所用的术语“式Ⅰ化合物”是指如上所定义的式Ⅰ化合物的所有旋光异构体和所有其它立体异构体,指它们的所有外消旋的和其它混合物,和如上所定义的含有或采用这些异构体或混合物的所有药物组合物和治疗方法。
上式Ⅰ化合物包括等同于所描述的那些但只是一个或多个氢或碳原子被它们的同位素取代的化合物。这样的化合物在代谢药动学研究和结合测定法中可用作研究和诊断工具。研究中的具体应用包括放射性配体结合测定法、放射自显影法研究和体内结合研究。
可用在本发明方法中的D2受体激动剂的例子包括但不限于式Ⅰ化合物和药学上可接受的盐、培高利特、溴隐亭、罗平尼洛和普拉克索。
可用在本发明方法中的5HT1A受体激动剂的例子包括但不限于:(a)式Ⅰ化合物和其药学上可接受的盐,(b)丁螺环酮(美国专利3,717,638、3,907,801和4,182,763);(c)吉吡隆(美国专利4,423,049);(d)伊沙匹降(德国专利公报3,321969-A1);和(d)氟辛克生(flexinoxan)。
可用在本发明方法中的α2肾上腺素能受体拮抗剂的例子包括但不限于式Ⅰ化合物和其药学上可接受的盐、育亨宾和咪唑克生。
本发明更具体实施方式的例子是采用α2肾上腺素能受体配体的上述治疗ADHD的方法和用于ADHD治疗的药物组合物,其中该配体是突触前α2肾上腺素能受体拮抗剂或突触后α2肾上腺素能受体激动剂。
本发明的优选方法是治疗包括人类在内的哺乳动物帕金森氏病的方法,该方法包括将治疗帕金森氏病有效量的下示式Ⅰ化合物即其中X是氮,其中Y是下式基团(“萨尼彼彻(sunipetron)”)或其药学上可接受的盐对需要接受治疗的哺乳动物给药。
本发明的另一种优选实施方式是治疗包括人类在内的哺乳动物ADHD的方法,该方法包括将治疗ADHD有效量的萨尼彼彻或其药学上可接受的盐对需要接受治疗的哺乳动物给药。
本发明的另一种优选方法是治疗包括人类在内的哺乳动物微腺瘤的方法,该方法包括将治疗微腺瘤有效量的萨尼彼彻或其药学上可接受的盐对需要接受治疗的哺乳动物给药。
附图的简要说明
图1显示用0.5mg/kg或1.0mg/kg式Ⅰ化合物治疗猴子而达到的帕金森氏病分值。
发明的详细说明
本文列举的所有专利、专利申请和文章均全文引用在此作为参考文献。
式Ⅰ化合物和其药学上可接受的盐可按下述方法制备:美国专利5,122,525、美国专利5,185,449、美国专利5,455,350、1995年6月6日提交的美国专利申请08/470,377和1997年6月16日提交并指定美国的国际专利申请PCT/IB97/00704。
式Ⅰ化合物能够与不同无机酸和有机酸生成多种不同的盐。可用于制备本发明碱化合物的药学上可接受的酸加成盐的酸是生成无毒的酸加成盐的那些,即含有药学上可接受的阴离子的盐,例如盐酸盐、氢溴化物、氢碘化物、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐、酸式柠檬酸盐、酒石酸盐、酒石酸氢盐、琥珀酸盐、马来酸盐、富马酸盐、葡糖酸盐、糖二酸盐、苯甲酸盐、甲磺酸盐和扑酸盐(即1,1’-亚甲基-双-(2-羟基-3-萘甲酸盐))。尽管这样的盐在对动物给药时必须是药学上可接受的,但在实践中经常需要最初从反应混合物中分离到式Ⅰ化合物的药学上不可接受的盐,然后通过碱性试剂处理,使后者简单地转化为游离的碱化合物,随后将游离的碱转化为药学上可接受的酸加成盐。本发明碱化合物的酸加成盐易于这样制备,在水性溶剂介质或适当的有机溶剂中,例如甲醇或乙醇,将碱化合物用大致等量的选定无机酸或有机酸处理。小心地蒸发溶剂后,得到所需的固体盐。
在用于治疗人的帕金森氏病、ADHD或微腺瘤时,将约为2-300mg/天的式Ⅰ化合物或其药学上可接受的盐每日一次或分多次给药。在特定情况下,主治医师可自行指定超过该范围的剂量。优选的给药途径一般是口服,但是肠胃外给药(例如肌内、静脉内、真皮内)在特殊情况下也将是优选的,例如疾病减少了口服吸收,或者患者不能吞咽。在一种实施方式中,式Ⅰ化合物的单次给药剂量约为1.0mg/kg,给药频率约为每天三次。或者可以采用控释制剂,每天给药一次。在另一种实施方式中,特定给药途径所需化合物的给药量使血浆浓度在给药后2至3小时内达到100与500ng/ml之间,优选约为200ng/ml。
用在本发明中的化合物一般以药物组合物的形式给药,该组合物包含至少一种式(Ⅰ)化合物或其盐以及药学上可接受的载体或稀释剂。这样的组合物一般按常规方式加以配制,并根据所需给药方式采用固体或液体载体或稀释剂:口服给药为片剂、硬或软胶囊剂、悬浮液、颗粒剂、粉末等形式;肠胃外给药为可注射溶液或悬浮液等形式。
利用下列D2受体结合测定法能够测定化合物与D2受体的结合。
表达人D2长型(D2L)受体的LTK细胞生长在D-葡萄糖(T-175瓶)中,其中含有补充有10%胎牛血清(FBS)的最低必需培养基(DMEM,Gibco)。用5mM EDTA的PBS溶液移取细胞,利用Brinkman Polytron,并设置在6档,在含5mM MgSO4的50mM Tris HCl(pH 7.4)中匀化20秒。多重分离循环后,离心回收膜,再悬浮在新鲜的冰冷却的缓冲液中。将组织(~2mg组织,湿重)加入到试管中,试管内含有培养缓冲液(50mMTris HCl,120mM NaCl,2mM MgCl2,5mM KCl,5mM CaCl2,pH 7.2)、不同浓度的供试药物和[3H]-螺哌隆(最终浓度0.06nM,Amersham,Arlington Heights IL)。在2μM(+)-布他拉莫的存在下测定非特异性结合。在30℃下45分钟后,利用Brandel细胞收集器通过WhatmanGF/B滤器进行快速过滤,终止培养。膜用3×4ml冰冷却的培养缓冲液洗涤,在Ready-Safe闪烁混合液(用于滴定配体)中通过滤器的液体闪烁计数测定与膜结合的配体。预先用饱和分析法测定放射性配体的Kd(0.06nM),代入Cheng-Prusoff方程计算表观Ki。
利用下列三种测定法能够测定化合物对D2受体的激动或拮抗活性。
(1)GH4C1细胞内cAMP生成的人D2受体调节作用
在T-175瓶中,取自大鼠垂体的、表达长或短型人D2受体的GH4C1细胞生长融合在补充有10%FBS和2mM 1-谷氨酸盐与10 U/ml青霉素-链霉素的(HAM)F-10营养素混合物(Gibco)中。用5mM乙二胺四乙酸(EDTA)的磷酸盐缓冲盐水(PBS)溶液移取细胞,再悬浮在含有5mMMgCl2、30mM羟乙基哌嗪-N-乙磺酸(HEPES)和50mM异丁基甲基黄嘌呤(IBMX)的PBS中。细胞(~200,000/管)与5mM弗司扣林、100nM喹吡罗或弗司扣林加喹吡罗加拮抗剂接触11分钟。在与拮抗剂的实验中,细胞先于喹吡罗与拮抗剂接触11分钟。为了判断激动活性,在没有激动剂喹吡罗的存在下,测试化合物对弗司扣林刺激的cAMP蓄积的作用。加入6N高氯酸以终止反应,样本用5N氢氧化钾和2M Tris缓冲液中和。利用商业上可得到的竞争性结合试剂盒(Amersham)测量环AMP水平。通过浓度-响应曲线的线性回归分析计算IC50值。利用下列方程计算表观Ki值:Ki=IC50/(1+[激动剂]/[激动剂EC50])。
(2)大鼠脑切片的电生理学
用氟烷将雄性Sprague-Dawley大鼠(200-250gm,Charles RiverLaboratories,Wilmington,MA)轻微麻醉,斩首,迅速取出大脑置于冰冷却的氧化培养基(95%O2/5%CO2;124mM NaCl,2mM KCl,1.25mMNaH2PO4,26mM NaHCO3,10mM d-葡萄糖,2mM MgSO47H2O和2mM CaCl2,pH7.4)中。用氰基丙烯酸酯将腹侧被盖区封闭并粘合在充满冰冷却培养基的Lancer Vibratome(1000系列)的操作台上。切下冠状切片(350μ)并置于氧化培养基(22℃)内1小时,然后记录。在记录时,将切片置于记录腔内的尼龙网上,在那里切片完全浸没在不断流动着的35℃培养基(~1ml/min)内。从灌注培养基切换到含有药物的溶液,以施用所有药物。用装有0.9%生理盐水的玻璃吸移管(6-8MW)记录自发的细胞外作用电位。在箱内联机标绘发射速率10或20秒,施用药物前后2分钟内的平均速率被用来计算发射速率的变化。用线形回归法构建和分析浓度-响应曲线。
(3)微量透析
Ⅰ形同心微量透析探针由透析纤维(分子量截止于18,000,300umo.d.,Hospal,The Netherlands)构成,该透析纤维用环氧树脂封闭于一端,并连接在熔融石英微管上。将全长9mm、透析膜外露长度2mm的探针植入已被***(75mg/kg)和赛拉嗪(10mg/kg)麻醉的雄性Sprague-Dawley大鼠(300-350g)的听神经核(nueleus accumbens)(AP 1.7,ML-1.2,DV-8.0)。手术后,将大鼠置于绝缘箱中的有机玻璃笼内,将探针入口经由柔软的聚醚醚酮(PEEK)管通过双通道流体旋转***连接到CMA/100微量注入泵(CMA/Microdialysis,Acton,MA)上。向探针灌注人造脑脊髓液(147mM NaCl,2.7mM KCl,1.3mM CaCl2,1.0mM MgCl2和0.1mM抗坏血酸)过夜,流速为0.5ml/min。第二天,将流速增加到1.5ml/min,并将带有PEEK管的探针入口连接到DECADE电化学检测器(ANTEC,Leiden,The Netherlands)中的30ml样本环上,开始进行实验。联机收集微量透析样本(30ml),每20或25分钟自动注射到柱子上。在35℃下进行反相HPLC,通过BDS Hypersil C18 3m柱(150×3mm)分离被分析物,所用移动相为pH 5.0的75mM磷酸钾,其中含有0.8mM辛烷磺酸盐、8%甲醇、3mM三乙胺,再用ESA 580泵释放出来,流速为0.35ml/min。利用设置在550mV对Ag/AgCl的DECADE检测器的玻璃碳电极进行多巴胺的电流检测。通过比较样品峰高度与标准品峰高度,测量多巴胺的细胞外水平。
获得稳定的基线(每20或25分钟收集的5-7份样本)后给药,并监测DA的释放达4至7小时。透析液浓度以基线的百分率表示。DA的透析液浓度没有对穿过透析纤维的回收进行校正。为了测定每次给药是否都对听神经核的DA释放具有显著作用,利用SuperANova软件(Abacus Concepts,Inc.,Berkeley CA)进行方差的多元分析,并在一定时间内反复测量。
特定化合物对非人类的灵长类动物表现出抗帕金森氏病作用的能力可以采用Greenemyre等《神经病学年鉴》(Ann.Neurol.)35:655-661,1994和Klockgether等《神经病学年鉴》30:717-723,1991所述操作加以测定。
本发明的特定化合物对5HT1A受体的激动和拮抗活性可以按照下列操作,利用单一饱和浓度加以测定。将雄性Hartley豚鼠斩首,解剖海马中的5HT1A受体。利用手持型玻璃-聚四氟乙烯匀化器,在含有1mM EGTA的5mM HEPES缓冲液(pH 7.5)中匀化个体组织,在4℃以35,000xg离心10分钟。将颗粒状物再悬浮在含有1mM EGTA的100mMHEPES缓冲液(pH 7.5)中,每管的最终蛋白质浓度为20mg(海马体)或5mg(黑质)。加入下列试剂,使每管内的反应混合物含有2.0mMMgCl2、0.5mM ATP、1.0mM cAMP、0.5mM IBMX、10mM磷酸肌酸、0.31mg/ml肌酸磷酸激酶、100mM GTP和0.5-1微居里的[32P]-ATP(30Ci/mmol:NEG-003,New England Nuclear)。将组织加入到硅化处理的microfuge管中(一式三份),在30℃下培养15分钟。每管内加入20ml组织、10ml药物或缓冲液(在10X最终浓度下)、10ml 32nM激动剂或缓冲液(在10X最终浓度下)、20ml弗司扣林(最终浓度3mM)和40ml前述反应混合物。加入含有40,000dpm[3H]-cAMP(30Ci/mmol:NET-275,New England Nuclear)的100ml 2%SDS、1.3mM cAMP、45mM ATP溶液,以终止培养,监测从柱子回收的cAMP。利用Salomon等《分析生物化学》(Analytical Biochemistry)1974,58,541-548的方法完成[32]-ATP与[32P]-cAMP的分离。用液体闪烁计数法测量放射性。将10mM(R)-8-OH-DPAT对5HT1A受体的作用定义为最大抑制作用。然后计算供试化合物相对于(R)-8-OH-DPAT的抑制作用百分率。相对于32nM激动剂的作用计算由激动剂诱发的对弗司扣林刺激的腺苷酸环化酶活性的抑制作用的逆转。
本发明涉及治疗帕金森氏病和ADHD的方法,其中采用了两种或三种活性试剂一起给药,它们是同一药物组合物的组成部分,还涉及这样的治疗方法,其中将这些活性试剂单独给药,它们是适当的给药方案的组成部分,以获得联合疗法的有益效果。各活性试剂的适当的给药方案、每次给药量和两次给药之间的具体间隔将取决于所治疗的患者、对药物的耐受性如何和病情的严重性。一般来说,在进行上述本发明的联合方法时,5HT1A受体激动剂的给药量约为5-90mg每天,分一次或多次给药,α2肾上腺素能受体配体的给药量,在α2肾上腺素能受体拮抗剂的情况下,约为1.0-100mg每天,分一次或多次给药,在α2肾上腺素能受体激动剂的情况下,给药量约为0.1-100mg每天,分一次或多次给药,D2受体激动剂的给药量约为0.5mg-25mg每天,分一次或多次给药。(对用在本发明联合方法中的经过FDA许可的药物来说,《Physician’s Desk Reference》中具体说明的药物剂量范围对医师可起到指导作用。)虽然如此,仍然可能发生一些变化,这取决于所治疗动物的种类及其对所述药物的个体反应,以及所选择的药物制剂类型和给药进行的时间阶段与间隔。在某些情况下,低于上述范围下限的剂量水平可能是更适合的,而在其它情况下,即使采用更高的剂量,也不会引起任何有害的副作用,只要将这种更高的剂量首先分成若干小剂量,在一整天内给药即可。
本发明的联合方法包括这样的方法,其中所需的联合活性存在于一种化合物或药学上可接受的盐中。表现出一种以上药学活性(例如5HT1A激动性和D2激动性)的本发明药物组合物包括这样的药物组合物,其中所有所需的药学活性都存在于一种化合物或药学上可接受的盐中。
为本发明药物组合物和方法所采用的D2受体激动剂、5HT1A受体激动剂和α2受体拮抗剂以下也称为“治疗剂”。治疗剂能够通过口服或肠胃外途径给药。含有D2受体激动剂和5HT1A受体激动剂、或者含有D2受体激动剂、5HT1A受体激动剂和α2肾上腺素能受体拮抗剂的组合物一般是口服或肠胃外给药的,每日分一次或多次给药,使每种活性试剂的总给药量落在上述指标内。
治疗剂可以单独给药,或者与药学上可接受的载体或稀释剂结合给药,给药途径是前述之一,这种给药可以分一次或多次进行。更确切地说,本发明治疗剂可以以多种不同的剂型给药,也就是说,它们可以与各种药学上可接受的惰性载体混合制成片剂、胶囊剂、锭剂、糖锭剂、硬糖剂、栓剂、水悬液、可注射溶液、酏剂、糖浆剂等。这样的载体包括固体稀释剂或填充剂、无菌水性介质和多种无毒的有机溶剂等。而且,口服药物组合物可以适当加入甜味剂和/或矫味剂。一般来说,本发明的治疗组合物在单独给药时(即不在同一药物组合物中),在这些剂型中的浓度水平约为5.0至70重量%。
口服给药可以采用片剂,其中含有各种赋形剂,例如微晶纤维素、柠檬酸钠、碳酸钙、磷酸二钙和甘氨酸,以及各种崩解剂,例如淀粉(优选为玉米、马铃薯或木薯淀粉)、海藻酸和某些复合硅酸盐,以及造粒粘合剂,例如聚乙烯吡咯烷酮、蔗糖、明胶和***胶。另外,润滑剂对压片目的经常是非常有用的,例如硬脂酸镁、月桂基硫酸钠和滑石。相似类型的固体组合物也可用来作为明胶胶囊的填充剂;这方面优选的物质也包括乳糖或奶糖以及高分子聚乙二醇。当口服给药需要水悬液和/或酏剂时,活性成分可以与各种甜味剂或矫味剂、着色物质或染料混合,如果需要的话,还有乳化和/或悬浮剂以及稀释剂,例如水、乙醇、丙二醇、甘油及其各种组合。
肠胃外给药可以采用治疗剂在芝麻油或花生油中或在含水丙二醇中的溶液。如果必要的话,水溶液应当加以适当缓冲,首先赋予液体稀释剂以等渗性。这些水溶液适合于静脉内注射。油溶液适合于动脉内、肌内和皮下注射。按照本领域技术人员熟知的标准药学工艺,易于实现所有这些溶液在无菌条件下的制备。
下列实施例仅供阐述发明,不被解释为限制其范围。
实施例
测定萨尼彼彻给药对经过MPTP(1-甲基-4-苯基-1,2,3,6-四氢吡啶)处理的猴子帕金森氏病分值的行为作用。所用方法描述在Greenemyre等,出处同上和Klockgether等,出处同上。
简要地说,将0.5mg/kg或1.0mg/kg萨尼彼彻对帕金森氏病猴子给药,各在给药后4个时间点评估帕金森氏病症状的严重性,与对照溶液(“载体”)给药的效果进行比较。
从研究中获得的帕金森氏病分值显示在图1中。联系给药后化合物血浆水平的评估结果,数据证明在大约200ng/ml的血浆水平下,最大程度减少了帕金森氏病的分值。最低有效血浆水平大约为100ng/ml。
Claims (19)
2、根据权利要求1的方法,其中在所采用的式(Ⅰ)化合物或药学上可接受的盐中,Y是
Z是Y1(CH2)n,Y1是CH2,n是1且X是N。
3、治疗哺乳动物帕金森氏病的方法,该方法包括将D2受体激动剂或其药学上可接受的盐与5HT1A受体激动剂或其药学上可接受的盐联合对需要接受治疗的哺乳动物给药,其中前述两种活性试剂的含量使它们的组合对治疗帕金森氏病是有效的。
4、用于治疗哺乳动物帕金森氏病的药物组合物,该组合物包含(a)D2受体激动剂或其药学上可接受的盐;(b)5HT1A受体激动剂或其药学上可接受的盐;和(c)药学上可接受的载体;其中前述两种活性试剂在组合物中的量使它们的组合对治疗帕金森氏病是有效的。
5、治疗哺乳动物ADHD的方法,该方法包括将α2肾上腺素能受体配体或其药学上可接受的盐与D2受体激动剂或其药学上可接受的盐以及5HT1A受体激动剂或它们的药学上可接受的盐联合对需要接受治疗的哺乳动物给药,其中前述活性试剂的含量使它们的组合对ADHD是有效的。
6、用于治疗哺乳动物ADHD的药物组合物,该组合物包含(a)α2肾上腺素能受体配体或其药学上可接受的盐;(b)D2受体激动剂或其药学上可接受的盐;(c)5HT1A受体激动剂,或它们的药学上可接受的盐;和(d)药学上可接受的载体;其中前述三种活性试剂在组合物中的量使它们的组合对治疗ADHD是有效的。
7、治疗哺乳动物ADHD的方法,该方法包括将α-肾上腺素能受体配体或其药学上可接受的盐与D2受体激动剂或与5HT1A受体激动剂或它们的药学上可接受的盐联合对需要接受治疗的哺乳动物给药,其中前述两种活性试剂的含量使它们的组合对治疗ADHD是有效的。
8、用于治疗哺乳动物ADHD的药物组合物,该组合物包含(a)α2肾上腺素能受体配体或其药学上可接受的盐;(b)D2受体激动剂或5HT1A受体激动剂或它们的药学上可接受的盐;和(c)药学上可接受的载体;其中前述两种活性试剂在组合物中的量使它们的组合对治疗ADHD是有效的。
9、治疗哺乳动物ADHD的方法,该方法包括将D2受体激动剂或其药学上可接受的盐与5HT1A受体激动剂或其药学上可接受的盐联合对需要接受治疗的哺乳动物给药,其中前述二种活性试剂的含量使它们的组合对ADHD是有效的。
10、用于治疗哺乳动物ADHD的药物组合物,该组合物包含(a)D2受体激动剂或其药学上可接受的盐;(b)5HT1A受体激动剂或其药学上可接受的盐;和(c)药学上可接受的载体;其中前述二种活性试剂在组合物中的量使它们的组合对治疗ADHD是有效的。
11、根据权利要求1的治疗哺乳动物帕金森氏病的方法,该方法包括将治疗帕金森氏病有效量的萨尼彼彻或其药学上可接受的盐对需要接受治疗的哺乳动物给药。
12、根据权利要求1的治疗哺乳动物ADHD的方法,该方法包括将治疗ADHD有效量的萨尼彼彻或其药学上可接受的盐对需要接受治疗的哺乳动物给药。
13、根据权利要求1的治疗哺乳动物微腺瘤的方法,该方法包括将治疗微腺瘤有效量的萨尼彼彻或其药学上可接受的盐对需要接受治疗的哺乳动物给药。
14、根据权利要求5的方法,其中所采用的α2肾上腺素能受体配体是突触前α2肾上腺素能受体拮抗剂或突触后α2肾上腺素能受体激动剂。
15、根据权利要求7的方法,其中所采用的α2肾上腺素能受体配体是突触前α2肾上腺素能受体拮抗剂或突触后α2肾上腺素能受体激动剂。
16、根据权利要求6的药物组合物,其中所采用的α2肾上腺素能受体配体是突触前α2 肾上腺素能受体拮抗剂或突触后α2肾上腺素能受体激动剂。
17、根据权利要求8的药物组合物,其中所采用的α2肾上腺素能受体配体是突触前α2肾上腺素能受体拮抗剂或突触后α2肾上腺素能受体激动剂。
19、根据权利要求18的药物组合物,其中在所采用的式(Ⅰ)化合物或药学上可接受的盐中,Y是Z是Y1(CH2)n,Y1是CH2,n是1且X是N。
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CN101318020B (zh) * | 2007-06-06 | 2011-09-28 | 四川科瑞德制药有限公司 | 抗焦虑或/和抗抑郁的药物组合物及用途 |
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