CN1170536C - 四氢苯并[cd]吲哚-6-甲酰胺类化合物在制备用于预防呕吐的药物中的用途 - Google Patents
四氢苯并[cd]吲哚-6-甲酰胺类化合物在制备用于预防呕吐的药物中的用途 Download PDFInfo
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- CN1170536C CN1170536C CNB00132828XA CN00132828A CN1170536C CN 1170536 C CN1170536 C CN 1170536C CN B00132828X A CNB00132828X A CN B00132828XA CN 00132828 A CN00132828 A CN 00132828A CN 1170536 C CN1170536 C CN 1170536C
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- Prior art keywords
- indole
- methanamide
- compound
- tetrahydro benzo
- test
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Abstract
本发明提供了利用某些四氢苯并[cd]吲哚类化合物或其可药用的酸加成盐在制备用于预防哺乳动物呕吐的药物中的用途。
Description
本发明涉及哺乳动物中预防呕吐和治疗性机能障碍的方法以及涉及适用于该方法的药物组合物。
针对研制能够预防哺乳动物呕吐和治疗哺乳动物性机能障碍的化合物，已经进行了许多年的广泛研究。例如，已评价了丁螺旋酮、8-羟基-二丙氨基四氢萘、育亨宾、东莨菪碱和各种5-羟色胺-3-拮抗剂的预防呕吐作用。然而，迄今为止，这些化合物由于各种原因，包括缺乏使用安全性、功效不足、存在不良副作用以及缺乏广谱抗呕吐活性，因此作为抗呕吐剂并不令人满意。同样，也已评价了溴麦角环肽、育亨宾、丁氨苯丙酮、环丙甲羟二羟吗啡酮、二甲麦角新碱、丁螺旋酮和释放激素的促性腺激素的治疗性机能障碍的作用。同样地，迄今为止，由于许多上述相同的原因，已证明这些化合物在治疗性机能障碍方面并不令人满意。
本发明的一个目的在于提供预防哺乳动物呕吐和治疗哺乳动物性机能障碍的新方法，该方法包括施用选自于下列通式的某些四氢苯并[cd]吲哚中的一个化合物。
确信本发明方法中使用的四氢苯并[cd]吲哚化合物能提供安全而广谱的预防呕吐和治疗性机能障碍的方法，同时具有最小的副作用。因此，深信本发明方法克服了用先前已试验的化合物在治疗性机能障碍和预防呕吐中所观察到的许多缺陷。
由于本发明提供了预防哺乳动物呕吐和治疗哺乳动物性机能障碍的新方法，因此需要适用于该新方法的药物组合物。因此，本发明的另一目的是要提供适用于本发明方法的药物组合物。
本发明的上述目的采用下列通式的某些四氢苯并[cd]吲哚化合物：
如下文所述，这些化合物在本领域是公知的，并且已经发现具有多种用途。
Flaugh在美国专利4,576,959中公开了在本发明中采用的伯氨基羧酰胺化合物(即其中R3和R4都为氢的那些化合物)是中枢5-羟色胺拮抗剂。因此，所述化合物被认为可用于治疗抑郁症、肥胖、酒精中毒、吸烟和老年性痴呆。事实上，Flaugh专利中公开的化合物之一，即(±)-4-二丙氨基-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，目前正在进行用于治疗人类抑郁症的临床试用。
Leander在美国专利4,745,126中公开了在上述Flaugh的专利中公开的伯氨基羧酰胺化合物也可用于治疗焦虑。事实上，在Leander的专利中公开的化合物之一，即上述的6-甲酰胺化合物，目前也正在进行用于治疗人类焦虑的临床试用。
最后，欧洲专利申请392768公开了在本发明中采用的取代的氨基羧酰胺化合物(即其中R3和/或R4不是氢的那些化合物)可用于治疗需要加强体内5-羟色胺功能的病症。所述病症包括抑郁症、焦虑、酒精中毒、肥胖、吸烟、性机能障碍和老年性痴呆。
本发明方法中采用的伯氨基酰胺化合物在此之前并没有作为可用于哺乳动物预防呕吐或治疗性机能障碍而被公开。另外，本发明方法中采用的取代的氨基羧酰胺化合物在此之前也没有作为可用于预防呕吐而被公开。如上文所述的这些化合物的公知活性没有建议本发明的方法。因此，本发明的一个目的是要提供某些已知的四氢苯并[cd]吲哚类化合物的新的药理用途以及用于该用途的合适的形式。
本发明的其它目的、特征和优点为从下面的描述和附加的权利要求书中将变得显而易见。
正如上文所述，本发明提供了预防哺乳动物呕吐和治疗哺乳动物性机能障碍的方法，包括给易感于或正患有呕吐或性机能障碍的哺乳动物施用有效量的式I化合物或其可药用的酸加成盐：
其中
R1为氢、C1-C4烷基或烯丙基；
R2为氢、C1-C4烷基或烯丙基。
本发明还提供了预防哺乳动物呕吐的方法，包括给易感于或正患有呕吐的哺乳动物施用有效量的式II化合物或其可药用的酸加成盐：
R1为氢、C1-C4烷基或烯丙基；
R2为氢、C1-C4烷基或烯丙基。
R3和R4各自独立地是氢、C1-C4烷基、被苯基取代的C1-C4烷基、苯基，或者R3和R4和与其连接的氮原子一起形成一个C3-C5杂环，条件是R3和R4中仅有一个可为氢，而R3和R4的另一个必须不是氢。
最后，由于本发明提供了预防哺乳动物呕吐和治疗哺乳动物性机能障碍的新方法，因此需要适用于所述新方法的药物组合物。因此，本发明还提供了可用于预防呕吐和治疗性机能障碍的药物组合物，它包括将式I或II化合物或者其可药用的酸加成盐与一种或多种可药用的载体、稀释剂或赋形剂混合。
本文所用术语“C1-C4烷基”代表具有1～4个碳原子的直链或支链烷基。典型的C1-C4烷基包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基等。
术语“C3-C5杂环”包括吡咯烷、哌啶、吗啉等。
尽管式I和II的所有化合物均可用于本发明的治疗呕吐和性机能障碍的方法中，然而对于该用途，式I和II的某些化合物是优选的。优选式I和II中R1和R2均为C1-C4烷基(尤其是正丙基)以及式II中R3和R4或者均为甲基或者R3为甲基而R4为氢。下文描述本发明的其它优选的方面。
式I和II化合物的可药用的酸加成盐也可用于本发明公开的预防呕吐和治疗性机能障碍的方法。因此，这些盐也包括在本发明方法范围内。
在此使用的术语“可药用的酸加成盐”是指对活体有机体基本无毒的式I和II化合物的酸加成盐。典型的可药用的酸加成盐包括通过将式I或II的游离碱形式的化合物与可药用的无机或有机酸反应而制备的那些盐。通常用于制备该盐的可药用的无机或有机酸包括：无机酸，例如盐酸、氢溴酸、氢碘酸、硝酸、硫酸和磷酸；以及有机酸，例如对甲苯磺酸、甲磺酸、马尿酸、草酸、对溴苯磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸、乙酸；以及其它有关的无机和有机酸。因此所述可药用的盐包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、乙酸盐、硝酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、内炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1，4-二酸盐、己炔-1，6-二酸盐、苯甲酸盐、氯代苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、对苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、β-羟基丁酸盐、乙醇酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-2-磺酸盐、对甲苯磺酸盐、扁桃酸盐、马尿酸盐等等。用于本发明方法中的优选的可药用的酸加成盐是马尿酸盐。在欧洲专利申请444852中公开了这些盐形式及其制备方法，该专利的内容作为参考文献并入本文。
在本发明方法中采用的化合物在其四氢苯并[cd]吲哚环的4-位碳原子上具有不对称中心。因此，化合物可以其外消旋混合物或单个的立体异构体存在。所有这些类型的化合物都可考虑用于本发明的方法中。
以下说明适于在本发明使用的代表性的化合物：
(±)-4-(二正丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺草酸盐，
(+)-4-氨基-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺马来酸盐，
(-)-4-(甲氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺甲酸盐，
(-)-4-(二乙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(+)-4-(二甲基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺草酸盐，
(+)-4-(乙氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺磷酸盐，
(±)-4-氨基-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺盐酸盐，
(±)-4-(正丙氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺草酸盐，
(±)-4-(甲氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺甲苯磺酸盐，
(-)-4-氨基-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(+)-4-(甲基乙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺硫酸盐，
(-)-4-(二乙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(-)-4-氨基-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺丙酸盐，
(+)-4-(二甲基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(±)-4-(二乙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺氢碘酸盐，
(±)-4-氨基-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(±)-4-(乙基-正丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(±)-4-(二正丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺琥珀酸盐，
(-)-4-(甲基-正丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(+)-4-(二甲基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺硫酸盐，
(-)-4-氨基-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺马来酸盐，
(+)-4-(二乙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(±)-4-(二正丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺马尿酸盐，
(+)-4-(二甲基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(-)-4-(二正丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺乙酸盐，
(±)-4-氨基-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺琥珀酸盐，
(±)-4-(二甲基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺柠檬酸盐，
(±)-4-(二正丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺氢溴酸盐，
(-)-4-(乙基-正丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺苯甲酸盐，
(+)-4-(甲基-正丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺邻苯二甲酸盐，
(+)-4-(甲基乙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(+)-4-(甲基烯丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺甲磺酸盐，
(-)-4-(二正丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺马来酸盐，
(+)-4-(二烯丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺琥珀酸盐，
(-)-4-氨基-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺富马酸盐，
(+)-4-(二正丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(+)-4-(二乙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺乙酸盐，
(±)-4-(乙氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(-)-4-氨基-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(+)-4-(甲氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(+)-4-(正丙氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺氢溴酸盐，
(+)-4-(二正丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(±)-4-(甲基乙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺氢碘酸盐，
(+)-4-(烯丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺丙二酸盐，
(±)-4-(二乙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(±)-N，N-二甲基-4-(二正丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(±)-N-甲基-4-(二正丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
(±)-N，N-二乙基-4-(二正丙基氨基)-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺，
正如上述所述，本发明方法中采用的化合物是已知的。例如，在美国专利4576959和4745126中讲述了制备式I化合物的方法，而在美国专利5204340中讲述了制备式II化合物的方法。在美国专利申请07/799924及其相关的欧洲专利申请EP444851中讲述了制备式I和II化合物(并且尤其是这些化合物的立体异构体)的优选方法。所有这些专利和专利申请均作为参考文献并入本文。
本发明提供了预防哺乳动物呕吐和治疗哺乳动物性机能障碍的方法。在以下试验体系中证实了这些活性。
呕吐
获取混合种的成年雌性猫作为实验动物，房养之，使之除了在试验期间之外能自由进食和进水。将猫置于例如描述于Crampton等人的文章(Aviat.Space Environ.Med.，56，pp.462-465(1985))中的运动装置上测定猫对30分钟旋转(0.28Hz，17rpm)的反应，基于该试验，选择在5次试验中至少有2次呕吐发作的猫用于呕吐研究实验。每次呕吐反应试验的间隔期最少为两周，以防止猫对运动刺激的习惯形成。在评估受试化合物之前和之后，测定在用盐水预处理后猫对运动刺激的基准反应(发生干呕和呕吐)。在运动试验前10分钟，对实验动物皮下注射体积为0.1mg/kg的在无菌盐水中的受试化合物或载体。试验顺序为盐水，0.02、0.05、0.01、0.0075、0.0025mg/kg受试化合物以及盐水。使用Cochrane′s Q试验方法并用McNewmar′s试验方法作重复测定，分析干呕/呕吐的二项式实验数据。试验结果报告于下列表I中。
表I
猫的运动病的抑制
处理* 受试化合物剂量 呕吐次数/ 试验中观察到的
(mg/kg) 试验次数 实验动物的行为改变
盐水 - 7/13 没有
受试化合物 0.0025 6/13 没有
受试化合物 0.005 5/13 没有
受试化合物 0.0075 1/13+ 没有
受试化合物 0.010 0/11+ 没有
受试化合物 0.020 0/11+ 没有
盐水 - 13/13 没有
采用的受试化合物为(-)-4-二丙基氨基-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺
+与对照组有明显差异(P＜0.05)
用一组16只雄性White Carneaux鸽也进行了试验，其体重为约460至650g(自由进食后体重的85-90％)。除了在试验期间以外，让动物自由进水和贝壳硬渣并每天一次喂约20g谷基饲料(PurinaPigeon Checkers)。每天上午6点至下午6点光照其集居室。所有试验均在光照期间进行。
首先在其家笼中给鸽喂饲20g Purina Pigeon Checkers。5分钟后，将其称重并静脉内注射10或13mg/kg顺氯氨铂(二氯化二氨顺铂II；Signma Chemical.Co.，ST.Louis，Mo)，然后置于有机玻璃观察笼内。45分钟后，肌内注射给予载体或者给予0.08或0.32mg/kg受试化合物。借助几滴乳酸使受试化合物溶解在蒸馏水中。在以后的4.5小时内观察动物干呕和呕吐次数。呕吐被视为实际排出了流体或固体物质，而干呕视视为是没有排出物质的呕吐动作。每只鸽只使用一次，并在4.5小时观察期后立即终止。该试验结果示于下列表II中。
表II
顺氯氨铂诱发的鸽呕吐的抑制
处理* 顺氯氨铂 受试化合物 鸽的
的剂量 的剂量 数目 干呕次数 呕吐次数
(mg/kg) (mg/kg)
载体 10 - 4 2.0±0.73 4.8±1.59
受试化合物 10 0.08 4 3.25±1.65 3.0±1.22
受试化合物 10 0.32 4 0 0
载体 13 - 2 1.5 6
受试化合物 13 0.32 2 0 0
*采用的受试化合物为(-)-4-二丙基氨基-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺。
用二甲苯基胍(DTG)代替顺氯氨铂诱发呕吐，对另外一组20只体重约为460至650g(其自由进食后体重的85～90％)的雄性White Carneaux鸽也进行了试验。让动物在除了试验期间以外自由进水和贝壳硬渣并每天一次喂约20g谷基饲料(Purina pigeoncheckers)。每天上午6点至下午6点光照集居室。所有试验均在光照期进行。
首先在其家笼中给鸽喂饲20g Purina Pigeon Checkers。5分钟后，将其称重，注射不同剂量的受试化合物并使之返回其家笼。借助几滴乳酸使受试化合物溶解在蒸馏水中。均以1ml/kg的体积进行胸肌注射。15分钟后，给予5.6mg/kg剂量的DTG并将鸽置于有机玻璃观察室内。1小时后，将其从观察室移至其家笼，检查观察笼底板排出物的存在。本研究中的应变数是在显现出排出物的各个剂量时鸟的百分数。该研究的结果示于下列表III中。
表III
二甲苯基胍诱发的鸽呕吐的抑制
受试化合物剂量* 鸽呕吐的百分数
(mg/kg)
0.01 100
0.02 75
0.04 50
0.08 25
0.16 0
*采用的受试化合物为(-)-4-二丙基氨基-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺。
表I、II和III中的数据证实，式I和II的化合物可用以预防呕吐。为本发明目的而使用的术语“呕吐”是指呕吐(实际排出胃容物)、干呕(没有排出物质的呕吐动作)和与该症状有关的伴随的恶心。因此，式I和II化合物能用以抑制由刺激动作(运动病)和各种化学刺激例如肿瘤药物(如顺氯氨铂)或精神性药物(如甲苯噻嗪、止痛药、麻醉药和多巴胺能药物)等引起的呕吐反应。
性机能障碍
在该研究中，使用从Charles River实验室(Portage，MI)购买的雄性Sprague-Dawley大鼠和已切除卵巢的Long-Evans大鼠。将全部的大鼠在温控室中房养，其中在10点至20点将灯熄灭。对用作受试雄鼠性伙伴的已切除卵巢的大鼠在试验前48小时皮下给予在丙二醇中的400μg雌甾酮并在试验前4小时皮下给予在丙二醇中的2.5mg孕酮，使之成为性接受者。在试验前的开始4周，将雄性大鼠分别单只房养，从6月龄鼠开始试验，至12月龄结束，试验间隔期为2周，所使用的方法已公布于Foreman等人的文章(J.Neural.Trans.，68，pp 153-170(1987))中。交配试验在12点至17点光照循环的黑暗期进行。每次行为试验时，将性接受的雌性大鼠引入交配场所内进而开始试验，试验或者结束于30分钟之后，或者在首次攀骑(mount)射精后立即结束。在用药物溶液处理之前，每只雄性大鼠需要进行至少两次连续的载体试验，伴随有相似的性行为。在每次药物试验之后，进行附加的载体试验。为消除药物处理后的行为反应(该行为反应可能是由于基准交配行为的自发变化)，将用随后的载体处理的行为反应的可逆性作为标准。因此，将对药物处理的有效行为反应规定为一种反应，该反应或者并不改变先前的对照反应或者在随后的用载体的对照试验中逆转。使用Wilcoxon成对样品试验方法，进行每只动物对载体处理和药物处理的性反应间的统计学比较。这些试验的结果报告在下列表IV中。
在表IV中，第1栏是对每只试验动物给药的试验化合物的剂量；第2栏和第3栏分别是每一试验剂量与对照比较，其射精潜伏期和为射精所需要的攀骑总次数的百分数变化；最后，第4栏和第5栏分别是每一试验剂量与对照比较，其交配效率和交配率的百分数和变化。
表IV
大鼠性机能障碍的治疗
| 给药的试验化合物剂量*(μg/kg，s.c.) | 与对照比较的百分数变化 | 与对照比较的百分数变化 | ||
| 射精潜伏期 | 为射精所需要的攀骑总次数 | 交配效率** | 交配率 | |
| 0(载体对照) | +0.4±2.7 | +20.5±8.4 | +7.0±6.2 | +23.4±9.1 |
| 1.0 | -20.6±8.3+ | -7.2±10.3 | +7.4±14.6 | +11.8±9.4 |
| 10 | -27.9±3.6+ | -20.9±7.8+ | +21.9±15.8 | +9.9±9.0 |
| 100 | -55.7±4.8+ | -34.1±6.5+ | +36.4±11.4+ | +62.2±17.7 |
*所采用的试验化合物为(-)-4-二丙氨基-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺
**定义为：插入次数/攀骑总次数
+与对照比较有明显差异；
表IV中的数据证实了式I化合物可用作治疗性机能障碍。在此使用的术语“性机能障碍”是指与雄性哺乳动物的勃起反应和雄性或雌性哺乳动物的性冲动和性(激醒的和机能的)反射有关的任何病症，因此，式I化合物可用于治疗勃起障碍、延迟射精和性感缺乏。该化合物还可进一步用于增强哺乳动物两性的性欲。
正如上述讨论，式I和II化合物具有生理活性因而提供了本文要求权利的有价值的治疗方法。这些方法包括给需要预防呕吐或治疗性机能障碍的哺乳动物(优选人类)施用有效量的足以取得预期治疗或预防效果的一种或多种式I化合物(预防呕吐和治疗性机能障碍)或式II化合物(仅预防呕吐)。可通过各种途径施用该化合物，包括口服、直肠、皮肤、皮下、静脉、肌内或鼻内等途径。优选口服和经皮肤途径给药。不管选用哪种给药途径，所述给药过程均通过按药剂学上公知的技术制备的药物组合物完成。
本发明方法包括以预防的方式防止呕吐和治疗性机能障碍(即，对敏感于所述病症的哺乳动物，在这些病症实际发生或再次发生之前，使用式I和II化合物防止呕吐或治疗性机能障碍)。这种预防性的给药方法尤其可适于下述情况，即：患者对运动病敏感并即将上船、车或飞机旅行，而这种旅行通常会导致患者发生运动病；患者即将经受用已知能导致呕吐的各种化学刺激(癌症化疗和放射疗法、止痛剂和麻醉剂等)进行的治疗；患者即将经受或正在经受已知导致性机能障碍的用抗焦虑药(如苯并二氮类)或抗抑郁药(如5-HT重摄取抑制剂或三环类抗抑郁药)进行的治疗；患者过去经历过性机能障碍并即将进行性交，并希望能防止性机能障碍的再次发生；或者患者希望增强其性冲动。
如上文所述，本发明方法利用药物组合物。在配制这些组合物过程中，通常将一种或多种活性成分与载体混合，或用载体稀释，或包裹于可为胶囊、香囊、纸或其它容器的载体中。当载体用作稀释剂时，载体可以是固体、半固体或液体物质，其作为活性成分的载体、赋形剂或介质。因此，组合物的形式可以是片剂、丸剂、粉剂、锭剂、香囊剂、扁囊剂、酏剂、悬浮液、乳化液、溶液、糖浆、气雾剂(作为固体或在液体介质中)、含有例如至多10％(重量)活性化合物的软膏剂、软和硬明胶胶囊剂、栓剂、无菌注射溶液和无菌包装的粉剂。
合适的载体、赋形剂和稀释剂的一些实例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯树胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、盐水溶液、糖浆、甲基纤维素、羟基苯甲酸甲酯和丙酯、滑石、硬脂酸镁和矿物油。制剂中另外可包括润滑剂、湿润剂、乳化剂和悬浮剂、防腐剂、甜味剂或调味剂。可以将组合物进行调剂，通过使用本领域公知的方法制剂本发明组合物，以便对患者给药后能提供活性成分的快速、持久或延迟释放。
将组合物优选配制成单位剂量形式，使得每剂量含有约5至约500mg更通常约25至约300mg的活性化合物。术语“单位剂量形式”是指适于对人类接受者和其它哺乳动物作为单位剂量的物理上分离的单位，每单位含有经计算能产生预期治疗或预防效果的预定量的活性物质和一种或多种可药用的稀释剂、赋形剂或载体。
本发明所采用的化合物可在很宽的剂量范围内有效预防呕吐和治疗性机能障碍。因此，在此使用的术语“有效量”是指约0.5至500mg/kg体重/每天的剂量范围。在治疗成年人时，优选的剂量范围为约1至约100mg/kg，单次给药或分多次给药。然而，应当明白，实际给予的化合物的剂量应由医生根据有关情况决定，它们包括待治疗的症状、所给化合物的选用、预期的预防效果或预期的治疗效果、所选择的给药途径，个体患者的年龄、体重以及对药物的反应、以及患者症状的严重性。因此，上述剂量范围并不意味着以任何方式限制本发明的范围。
下列制剂实施例可采用任何式I或II化合物作为活性成分。实施例仅是说明性的，并不是以任何方式限制本发明的范围。
实施例1
用下列成分制备适于预防呕吐的硬明胶胶囊：
数量(mg/胶囊)
(±)-4-二丙基氨基-1，3，4，5-四氢苯
并[cd]吲哚-6-甲酰胺马尿酸盐 250
干燥的淀粉 200
硬脂酸镁 10
将上述成分混合，并以460mg的数量装入硬明胶胶囊中。
实施例2
用下列成分制备适于预防呕吐的片剂：
数量(mg/片)
(±)-N-甲基-4-二丙基氨基-1，3，4，5-
四氢苯并[cd]吲哚-6-甲酰胺盐酸盐 250
微晶纤维素 400
二氧化硅 10
硬脂酸 5
将所述成分混合，并以每片重665mg压制成片剂。
实施例3
制备含有下列成分的适于治疗性机能障碍的气雾剂溶液：
重量
(±)-4-二乙基氨基-1，3，4，5-四氢苯
并[cd]吲哚-6-甲酰胺 0.25
乙醇 29.75
推进剂22(氯二氟代甲烷) 70.00
将活性化合物与乙醇混合，并将混合物加至一定比例的推进剂22中，冷却至-30℃并转移至填充装置中。然后将预定量的混合物装入不锈钢容器中并以剩余的推进剂稀释。然后将阀门单元装配在容器上。
实施例4
如下制备每片含有60mg活性成分的适于治疗性机能障碍的片剂：
(+)-4-二乙基氨基-1，3，4，5-四氢苯
并[cd]吲哚-6-甲酰胺 60mg
淀粉 45mg
微晶纤维素 35mg
聚乙烯吡咯烷酮(作为10％水溶液) 4mg
羧甲基淀粉钠 4.5mg
硬脂酸镁 0.5mg
滑石粉 1mg
总计 150mg
将活性成分、淀粉和纤维素过第45目美国筛并充分混合。将聚乙烯吡咯烷酮的溶液与所得粉末混合，然后过第14目美国筛。将如此制备的颗粒于50-60℃干燥并过第18目美国筛。然后将已过了第60目美国筛的羧甲基淀粉钠、硬脂酸镁和滑石粉加到所述颗粒中，混合后，用压片机压制得到每片重150mg的片剂。
实施例5
如下制备每粒含有80mg药物的适于预防呕吐的胶囊：
(±)-N-甲基-4-二乙基氨基-1，3，4，5-四
氢苯并[cd]吲哚-6-甲酰胺马尿酸盐 80mg
淀粉 59mg
微晶纤维素 59mg
硬脂酸镁 2mg
总计 200mg
将活性成分、纤维素、淀粉和硬脂酸镁混合，过第45目美国筛，并以200mg的数量充入硬明胶胶囊中。
实施例6
如下制备每粒含有225mg活性成分的适于治疗性机能障碍的栓剂：
(±)-4-二烯丙基氨基-1，3，4，5-四氢苯
并[cd]吲哚-6-甲酰胺 225mg
饱和脂肪酸甘油酯 加至2000mg
将活性成分过第60目美国筛并悬浮在用最少必需热量熔化的饱和脂肪酸甘油酯中。然后将混合物倒入公称2g容量的栓剂模型中并使之冷却。
实施例7
如下制备每5ml剂量含有50mg药物的适于预防呕吐的悬浮液：
(-)-N，N-二乙基-4-二丙基氨基-1，3，
4，5-四氢苯并[cd]-吲哚-6-甲酰胺 50mg
羧甲基纤维素钠 50mg
糖浆 1.25ml
苯甲酸溶液 0.10ml
调味剂 适量
色素 适量
纯水 加至 5ml
将药物过第45目美国筛并与羧甲基纤维素钠和糖浆混合以形成平滑的糊状物。将苯甲酸溶液、调味剂和色素用一些水稀释，并在搅拌的同时加入。然后加入足量水至预期的体积。
实施例8
如下制备每粒含有150mg药物的适于用作治疗性机能障碍的胶囊：
(-)-4-二丙基氨基-1，3，4，5-四氢苯并
[cd]吲哚-6-甲酰胺马尿酸盐 150mg
淀粉 164mg
微晶纤维素 164mg
硬脂酸镁 22mg
总计 500mg
将活性成分、纤维素、淀粉和硬脂酸镁混合，过第45目美国筛，并以500mg的数量装入硬明胶胶囊中。
Claims (3)
1.下式化合物或其可药用的酸加成盐在制备用于预防哺乳动物呕吐的药物中的用途：
其中
R1为氢、C1-C4烷基或烯丙基；
R2为氢、C1-C4烷基或烯丙基。
2.权利要求1的用途，其中在所采用的化合物中，R1和R2各自独立地是C1-C4烷基。
3.权利要求1或2的用途，其中所采用的化合物是(-)-4-二丙基氨基-1，3，4，5-四氢苯并[cd]吲哚-6-甲酰胺或其立体异构体或其可药用的酸加成盐。
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| KR0151699B1 (ko) * | 1989-07-13 | 1998-10-15 | 로버트 에이. 아미테이지 | (1,2n) 및 (3,2n)-카보사이클릭-2-아미노테트랄린 유도체 |
| IL97308A (en) * | 1990-02-26 | 1996-10-31 | Lilly Co Eli | Xahydrobenz [DC] Induced indoles in position 6, their preparation process and pharmaceutical preparations containing them |
| US5302612A (en) * | 1990-02-26 | 1994-04-12 | Eli Lilly And Company | 6-substituted-hexahydrobenz[cd]indoles |
| WO1991013872A1 (en) * | 1990-03-15 | 1991-09-19 | The Upjohn Company | Therapeutically useful heterocyclic indole compounds |
| US5258379A (en) * | 1990-05-04 | 1993-11-02 | Eli Lilly And Company | Method of inhibiting gastric acid secretion with n-arylpiperazines |
| US5096908A (en) * | 1990-05-04 | 1992-03-17 | Eli Lilly And Company | Method of inhibiting gastric acid secretion |
| US5229409A (en) * | 1990-08-15 | 1993-07-20 | Eli Lilly And Company | 6-substituted-tetrahydrobenz[cd]indoles |
| US5244912A (en) * | 1991-03-28 | 1993-09-14 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,3,4,5-tetrahydrobenz(cd)indoles and pharmaceutical use thereof |
-
1994
- 1994-06-02 NZ NZ260667A patent/NZ260667A/en unknown
- 1994-06-02 CZ CZ941354A patent/CZ285762B6/cs not_active IP Right Cessation
- 1994-06-02 NZ NZ314570A patent/NZ314570A/xx unknown
- 1994-06-02 IL IL10987294A patent/IL109872A/xx not_active IP Right Cessation
- 1994-06-02 ZA ZA943862A patent/ZA943862B/xx unknown
- 1994-06-02 CZ CZ982818A patent/CZ285829B6/cs not_active IP Right Cessation
- 1994-06-03 CA CA002125088A patent/CA2125088A1/en not_active Abandoned
- 1994-06-04 TW TW083105103A patent/TW258660B/zh active
- 1994-06-06 UA UA94005243A patent/UA29415C2/uk unknown
- 1994-06-07 EP EP01201582A patent/EP1166783A3/en not_active Withdrawn
- 1994-06-07 EP EP94304103A patent/EP0633023A3/en not_active Withdrawn
- 1994-06-08 AU AU64607/94A patent/AU677317B2/en not_active Ceased
- 1994-06-08 KR KR1019940012778A patent/KR100367792B1/ko not_active IP Right Cessation
- 1994-06-09 CN CN94106467A patent/CN1072932C/zh not_active Expired - Fee Related
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1995
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1999
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2000
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- 2000-10-31 CN CNB00132828XA patent/CN1170536C/zh not_active Expired - Fee Related
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2001
- 2001-11-28 NO NO20015806A patent/NO20015806D0/no unknown
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2002
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- 2002-08-31 KR KR1020020052257A patent/KR100367791B1/ko not_active IP Right Cessation
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