CN101061117A - 新的萘基取代的氮杂双环衍生物和它们作为单胺神经递质再摄取抑制剂的用途 - Google Patents
新的萘基取代的氮杂双环衍生物和它们作为单胺神经递质再摄取抑制剂的用途 Download PDFInfo
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Abstract
本发明涉及用作单胺神经递质再摄取抑制剂的新的萘基取代的氮杂双环衍生物。在其它方面,本发明涉及这些化合物在治疗方法中的用途以及含有本发明化合物的药物组合物。
Description
技术领域
本发明涉及用作单胺神经递质再摄取抑制剂的新的萘基取代的氮杂双环衍生物。
在其它方面,本发明涉及这些化合物在治疗方法中的用途以及含有本发明化合物的药物组合物。
背景技术
5-羟色胺选择性再摄取抑制剂(SSRI)目前可有效治疗多种CNS障碍,包括抑郁和惊恐性障碍。SSRI通常被精神科医师和初级护理医师认为是有效、耐受良好且方便给药。然而,它们与很多不理想特性有关。
因此,仍然强烈需要对于单胺神经递质5-羟色胺、多巴胺和去甲肾上腺素再摄取活性具有最佳药理特性(例如5-羟色胺再摄取与去甲肾上腺素和多巴胺再摄取活性的比例)的化合物。
WO 02/44176(NeuroSearch A/S)描述了3-取代的奎宁环和它们作为烟碱激动剂的用途。
发明概述
在第一方面,本发明提供了式I化合物,
在第二方面,本发明提供了药物组合物,其含有治疗有效量的本发明化合物、或其任何异构体或其异构体的任何混合物、或其可药用盐,以及至少一种可药用载体、赋型剂或稀释剂。
在另一方面,本发明提供了本发明化合物、或其任何异构体或其异构体的任何混合物、或其可药用盐在制备用于治疗、预防或缓解哺乳动物(包括人)的疾病、障碍或病症的药物组合物的应用,所述疾病、障碍或病症对抑制中枢神经系统中的单胺神经递质再摄取具有应答。
在又一方面,本发明涉及治疗、预防或缓解活的动物体(包括人)的疾病或障碍或病症的方法,所述障碍、疾病或病症对抑制中枢神经系统中的单胺神经递质再摄取具有应答,所述方法包括向有该需要的活动物体施用治疗有效量的本发明化合物、或其任何异构体或其异构体的任何混合物、或其可药用盐的步骤。
根据下面的详细描述和实施例,本发明其它目的对于本领域技术人员而言是显而易见的。
发明详述
萘基取代的氮杂双环衍生物
在第一方面,本发明提供了式I化合物,
或其任何异构体或其异构体的任何混合物,
或其可药用盐,
其中
Q代表萘基;
该萘基被一个或多个独立地选自下述的取代基取代:
卤素,三氟甲基,三氟甲氧基,氰基,硝基,羟基,烷氧基,环烷氧基,烷氧基烷基,环烷氧基烷基,烷基,环烷基,环烷基烷基,链烯基,炔基,-NR′R″,-(C=O)NR′R″或-NR′(C=O)R″;其中R′和R″彼此独立地是氢或烷基。
在另一个实施方案中,Q代表
其中各个R5、R6、R7和R8彼此独立地代表氢,卤素,三氟甲基,三氟甲氧基,氰基,硝基,羟基,烷氧基,环烷氧基,烷氧基烷基,环烷氧基烷基,烷基,环烷基,环烷基烷基,链烯基,炔基,-NR′R″,-(C=O)NR′R″或-NR′(C=O)R″;其中R′和R″彼此独立地是氢或烷基;条件是,至少一个R5、R6、R7和R8不代表氢。
在一个具体的实施方案中,各个R5、R6、R7和R8彼此独立地代表氢,烷基,烷氧基,环烷氧基,烷氧基烷基或环烷氧基烷基;条件是,至少一个R5、R6、R7和R8不代表氢。
在另一个具体的实施方案中,R5、R6、R7和R8之一代表烷氧基;且R5、R6、R7和R8中其余的3个代表氢。在另一个实施方案中,R6代表烷氧基,且各个R5、R7和R8代表氢。
在另一个实施方案中,R5、R6、R7和R8之一代表羟基;且R5、R6、R7和R8中其余的3个代表氢。在另一个实施方案中,R6代表羟基,且每个R5、R7和R8代表氢。
在另一个实施方案中,R6代表羟基或烷氧基。
在另一个实施方案中,Q代表6-甲氧基-萘-2-基。在另一个实施方案中,Q代表6-羟基-萘-2-基。
在一个具体的实施方案中,本发明的化合物是3-(6-甲氧基-萘-2-基)-1-氮杂-双环[2.2.2]辛-2-烯;6-(1-氮杂-双环[2.2.2]辛-2-烯-3-基)-萘-2-酚;或其可药用盐。
两个或多个上述实施方案的任意组合被认为落入本发明范围之内。
取代基的定义
在本发明上下文中,卤素代表氟、氯、溴或碘。
在本发明上下文中,烷基指一价饱和的直链或支链烃链。该烃链优选包含1-6个碳原子(C1-6-烷基),包括戊基、异戊基、新戊基、叔戊基、己基和异己基。在一个优选的实施方案中,烷基表示C1-4-烷基,包括丁基、异丁基、仲丁基和叔丁基。在本发明另一优选实施方案中,烷基表示C1-3-烷基,所述基团可以具体为甲基、乙基、丙基或异丙基。
在本发明上下文中,链烯基指包含一个或多个双键的碳链,包括二烯、三烯和多烯。在一个优选的实施方案中,本发明的链烯基包含2-6个碳原子(C2-6-链烯基),包括至少一个双键。在最优选实施方案中,本发明的链烯基为乙烯基;1-或2-丙烯基;1-、2-或3-丁烯基,或1,3-丁二烯基;1-、2-、3-、4-或5-己烯基,或1,3-己二烯基,或1,3,5-己三烯基。
在本发明上下文中,炔基指包含一个或多个叁键的碳链,包括二炔、三炔和多炔。在一个优选的实施方案中,本发明的炔基包含2-6个碳原子(C2-6-炔基),包括至少一个叁键。在其最优选实施方案中,本发明的炔基为乙炔基;1-或2-丙炔基;1-、2-或3-丁炔基,或1,3-丁二炔基;1-、2-、3-、4-戊炔基,或1,3-戊二炔基;1-、2-、3-、4-或5-己炔基,或1,3-己二炔基或1,3,5-己三炔基。
在本发明上下文中,环烷基指环状烷基,优选包含3-7个碳原子(C3-7-环烷基),包括环丙基、环丁基、环戊基、环己基和环庚基。
烷氧基为O-烷基,其中烷基定义同上。
环烷氧基意指O-环烷基,其中环烷基定义同上。
环烷基烷基意指上述的环烷基和上述的烷基,例如意指环丙基甲基。
氨基为NH2或NH-烷基或N-(烷基)2,其中烷基定义同上。
可药用盐
本发明化合物可以以任何适于目标给药的形式提供。适宜的形式包括本发明化合物的药学上(即生理学上)可接受的盐和前药形式。
可药用加成盐的实例包括但不限于,无毒无机和有机酸加成盐,例如盐酸盐、氢溴酸盐、硝酸盐、高氯酸盐、磷酸盐、硫酸盐、甲酸盐、乙酸盐、阿康酸盐、抗坏血酸盐、苯磺酸盐、苯甲酸盐、肉桂酸盐、柠檬酸盐、双羟萘酸盐、庚酸盐、富马酸盐、葡萄糖酸盐、羟基乙酸盐、乳酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、萘-2-磺酸衍生盐、邻苯二甲酸盐、水杨酸盐、山梨酸盐、硬脂酸盐、琥珀酸盐、酒石酸盐、对甲苯磺酸盐等。上述盐可以通过本领域众所周知和已记载过的方法制备。
可能未被认为可药用的其它酸,例如草酸可以用于制备用作得到本发明化合物的中间体的盐和它的可药用酸加成盐。
本发明化合物的可药用阳离子盐的实例非限制性地包括,含有阴离子基团的本发明化合物的钠盐、钾盐、钙盐、镁盐、锌盐、铝盐、锂盐、胆碱、赖氨酸和铵盐等。上述阳离子盐可以通过本领域众所周知和已记载过的方法制备。
在本发明上下文中,含氮化合物的“鎓盐”也被认为是可药用盐。优选的“鎓盐”包括烷基-鎓盐、环烷基-鎓盐和环烷基烷基-鎓盐。
本发明化合物的前药形式(pre or prodrug)的实例包括本发明物质的适宜前药的实例,包括在母体化合物的一个或多个反应性或可衍生基团上进行修饰的化合物。特别感兴趣的化合物是在羧基、羟基或氨基上进行修饰的化合物。适宜衍生物的实例为酯或酰胺。
本发明化合物可以以可溶或不溶形式与可药用溶剂(例如水、乙醇等)一起提供。可溶形式还可以包括水合形式,例如一水合物、二水合物、半水合物、三水合物、四水合物等。通常认为可溶形式对于本发明目的而言等同于不溶形式。
立体异构体
本领域技术人员应该理解,本发明化合物可以包含一个或多个手性中心,且这些化合物可以以异构体形式存在。
同样,具有-C=C-双键的部分本发明化合物可以以两种形式存在:顺式-和反式-形式(Z-和E-形式),这取决于双键周围取代基的排列。因此,本发明化合物可以为顺式-或反式形式,或可以是它们的混合物。
此外,本发明化合物可以以(+)和(-)形式的对映异构体以及外消旋形式(±)存在。
本发明包括所有这些异构体及其任意混合物,包括外消旋混合物。
外消旋形式可以用已知的方法和技术拆分成光学对映体。一种分离异构盐的方法是使用光学活性酸,并通过用碱处理释放出光学活性的胺化合物。另一种将外消旋体拆分成光学对映体的方法基于在光学活性基质上进行色谱处理。因此,例如通过分步结晶d-或1-盐(酒石酸盐、扁桃酸盐或樟脑磺酸盐),可以将本发明的外消旋化合物拆分成它们的光学对映体。
本发明化合物还可以通过以下方法拆分:使本发明化合物与光学活性活化的羧酸(如由(+)或(-)苯基丙氨酸、(+)或(-)苯基甘氨酸、(+)或(-)樟脑酸衍生的羧酸)反应形成非对映的酰胺,或使本发明化合物与光学活性的氯甲酸酯等反应形成非对映的氨基甲酸酯。
用于拆分光学异构体的其它方法在本领域中是已知的。这些方法包括Jaques J,Collet A,& Wilen S in“
Enantiomers,Racemates, and Resolutions”,John Wiley and Sons,New York(1981)中描述的方法。
光学活性化合物还可以由光学活性原料制备。
标记的化合物
本发明化合物可以其标记或未标记形式使用。在本发明上下文中,标记的化合物的一个或多个原子被具有不同于自然界通常发现的原子量或原子数的原子所替代。标记可以方便所述化合物的定量检测。
本发明的标记的化合物可以用作多种诊断方法中的诊断工具、放射示踪剂或监测剂,还可以用于体内受体成像。
本发明的标记的异构体优选包含至少一个放射性核素作为标记。发射正电子的放射性核素是所有用途的候选物。在本发明上下文中,放射性核素优选选自2H(氘)、3H(氚)、13C、14C、131I、125I、123I和18F。
用于检测本发明标记的异构体的物理方法可以选自正电子发射断层摄影(PET)、单光子成像计算机断层成像(SPECT)、磁共振光谱(MRS)、磁共振成像(MRI)和计算机辅助轴向X射线断层摄影术(CAT)或它们的组合。
制备方法
本发明化合物可以通过用于化学合成的常规方法、例如实施例中所述的方法制备。用于本申请所述方法的原料是已知的,或可以方便地通过常规方法由可商购得到的化学物质制备得到。
还可以使用常规方法将一种本发明化合物转化为另一种本发明化合物。
本文所述反应的终产物可以通过常规技术(例如萃取、结晶、蒸馏、色谱处理等)进行分离。
生物活性
如WO 97/30997(NeuroSearch A/S)所述,可以测试本发明化合物抑制再摄取突触体中单胺多巴胺、去甲肾上腺素和5-羟色胺的能力。根据在这些测试中观察到的平衡活性,认为本发明化合物可用于治疗、预防或缓解哺乳动物(包括人)的疾病或障碍或病症,所述疾病、障碍或病症对抑制中枢神经系统中的单胺神经递质再摄取有应答。
在一个具体实施方案中,认为本发明化合物可用于治疗、预防或缓解:心境障碍、抑郁、非典型抑郁、继发于疼痛的抑郁、重度抑郁症、情绪恶劣性障碍、双相性精神障碍、I型双相性精神障碍、II型双相性精神障碍、循环情感障碍、由全身医学病症导致的心境障碍、物质诱导的心境障碍、假性痴呆、甘塞氏综合征、强迫观念与行为障碍、惊恐性障碍、无广场恐怖症的惊恐性障碍、有广场恐怖症的惊恐性障碍、无惊恐性障碍病史的广场恐怖症、惊恐发作、记忆缺陷、记忆丧失、注意力缺陷多动症、肥胖、焦虑、广泛性焦虑症、进食障碍、帕金森氏病、帕金森氏综合征、痴呆、老化性痴呆、老年性痴呆、阿尔茨海默氏病、获得性免疫缺陷综合征痴呆复征、老化性记忆机能障碍、特定恐怖症、社交恐怖症、创伤后精神紧张障碍、急性精神紧张障碍、药物成瘾、药物滥用、可卡因滥用、烟碱滥用、烟草滥用、酒精成瘾、酒精中毒、疼痛、慢性疼痛、炎性疼痛、神经病性疼痛、偏头痛、紧张型头痛、慢性紧张型头痛、与抑郁、纤维肌痛、关节炎、骨关节炎、类风湿性关节炎有关的疼痛、背部疼痛、癌痛、肠易激性疼痛、肠易激综合征、术后疼痛、乳房切除术后疼痛综合征(PMPS)、中风后疼痛、药物导致的神经病、糖尿病性神经病、交感神经维持性疼痛、三叉神经痛、牙痛、肌筋膜疼痛、幻肢痛、贪食症、月经前综合征、晚黄体期综合征、创伤后综合征、慢性疲劳综合征、尿失禁、压迫性尿失禁、欲望性尿失禁、夜间尿失禁、性功能障碍、早泄、勃起困难、勃起功能障碍、过早的女性性高潮、不宁腿综合征、进食障碍、神经性厌食、睡眠障碍、全身性发育迟缓、孤独症、阿斯波哥尔障碍、雷特障碍、童年瓦解性障碍、学习能力丧失、运动技能障碍、哑症、拔毛发癖、发作性睡眠、中风后抑郁、中风诱导的脑损害、中风诱导的神经元损害或吉勒德拉图雷综合征。在一个优选实施方案中,认为该化合物可用于治疗、预防或缓解抑郁。
目前预期上述活性药物成分(API)的适宜剂量范围为约0.1至约1000mgAPI/天,更优选约10至约500mgAPI/天,最优选约30至约100mgAPI/天,但这取决于确切的给药方式、其给药形式、考虑的适应症、受试者,特别是所涉及受试者的体重,以及进一步地,主管内科医师或兽医的其它偏好和经验。
优选的本发明化合物在亚微摩尔和微摩尔范围(即从低于1至约100μM)表现出生物活性。
药物组合物
在另一方面,本发明提供了新的药物组合物,其包含治疗有效量的本发明化合物。
虽然用于治疗的本发明化合物可以以原始化合物的形式给药,但是优选地,将任选为生理学上可接受盐形式的活性成分与一种或多种助剂、赋型剂、载体、缓冲剂、稀释剂和/或其它常规药物辅料引入药物组合物中。
在一个优选实施方案中,本发明提供了药物组合物,其同时包含本发明化合物或其可药用盐或其衍生物,和一种或多种可药用载体,以及任选的本领域已知和使用的其它治疗和/或预防成分。所述载体必须是“可接受的”,即与制剂中其它成分兼容且对其受者无害。
本发明的药物组合物可以是适合口、直肠、支气管、鼻、肺、局部(包括颊和舌下)、透皮、阴道或肠胃外(包括皮肤、皮下、肌内、腹膜内、静脉内、动脉内、大脑内、眼内注射或输注)给药的药物组合物,或是适合通过吸入或吹入给药(包括粉末和液体气溶胶给药)、或通过持续释放系统给药的形式。适宜的持续释放系统的实例包括,包含本发明化合物的固体疏水聚合物的半渗透性基质,所述基质可以是成形颗粒的形式,例如薄膜或微囊。
可以将本发明化合物与常规助剂、载体或稀释剂一起置于药物组合物或其单位剂量的剂型中。这些剂型包括固体特别是片剂、填充胶囊剂、散剂和丸剂,以及液体特别是含水或无水的溶液、混悬剂、乳剂、酏剂和填充有它们的胶囊剂(它们都可用于口服)、用于直肠给药的栓剂和用于肠胃外应用的无菌注射溶液。上述药物组合物及其单位剂型可以包含常规比例的常规成分,并含有或不含有附加的活性化合物或成分,而且所述单位剂型可以包含任何适宜的与期望使用的日剂量范围相当的有效量的活性成分。
本发明化合物可以多种口服和肠胃外剂型给药。本领域技术人员显然可以理解,下述剂型中可以包含本发明化合物或本发明化合物的可药用盐作为活性成分。
为了将本发明化合物制备成药物组合物,可药用载体可以是固体或液体。固体制剂包括散剂、片剂、丸剂、胶囊剂、锭剂、栓剂或可分散颗粒剂。固体载体可以是一种或多种物质,其还可以用作稀释剂、调味剂、稳定剂、润滑剂、助悬剂、粘合剂、防腐剂、片剂崩解剂或包囊材料。
在散剂中,载体可以是细分固体,其与细分的活性成分相混合。
在片剂中,活性成分以适当比例与具有必要粘合能力的载体混合,然后压制成所需的形状和大小。
散剂和片剂优选包含5或10%至约70%的活性化合物。适宜的载体为碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可油等。术语“制剂”意在包括带有包囊材料作为载体的活性化合物的制剂,由此提供胶囊,其中通过载体包围含或不含载体的所述活性成分,从而使载体与其结合。类似地,本发明包括扁囊剂和锭剂。片剂、散剂、胶囊剂、丸剂、扁囊剂和锭剂可以用作适合口服给药的固体剂型。
为了制备栓剂,首先将低熔点蜡(例如脂肪酸甘油或可可油的混合物)熔化,通过搅拌,将活性组分均匀分散于其中。然后将熔化的均匀混合物倾入常规大小的模具中,使其冷却,从而固化。
适合阴道给药的组合物可以以包含活性成分和本领域已知的适宜载体的阴道栓、棉塞、霜剂、凝胶剂、糊剂、泡沫剂或喷雾剂形式呈现。
液体制剂包括溶液、混悬剂和乳剂,例如水或水-丙二醇溶液。例如,可以将肠胃外注射液体制剂制备成在聚乙二醇水溶液中的溶液。
因此,可以将本发明化合物配制用于肠胃外给药(例如通过注射,如快速推注或连接输注),并可以以在安瓿、预填充的注射剂、含加入的防腐剂的小体积输液或多剂量容器中的单位剂型形式呈现。所述组合物可以是在油或水性赋型剂中的混悬液、溶液或乳剂形式,并可以包含制剂试剂,如助悬剂、稳定剂和/或分散剂。或者,活性成分可以是粉末形式,其通过无菌分离无菌固体或通过冻干溶液而获得,在使用前与适宜的赋型剂(如无菌、无热原分水)配制。
可以通过将活性成分溶解于水中,然后根据需要加入适宜的着色剂、调味剂、稳定剂和增稠剂,制备适合口服的水溶液。
可以通过将细分的活性组分分散于水中,所述水含有粘性物质,例如天然或合成树胶、树脂、甲基纤维素、羧甲基纤维素钠或其它的已知助悬剂,制备适合口服的水混悬剂。
还包括打算在使用前短时间内转化成口服液体形式制剂的固体剂型。所述液体形式包括溶液、悬浮液和乳液。除了活性组分之外,这些制剂中可以包含着色剂、调味剂、稳定剂、缓冲剂、人工和合成增甜剂、分散剂、增稠剂、增溶剂等。
为了局部施用至表皮,可以将本发明化合物配制成软膏剂、霜剂或洗液、或透皮贴剂形式。例如,软膏剂和霜剂可以使用水或油性基质,并加入适宜的增稠剂和/或胶凝剂制备。洗液可以使用水或油性基质制备,且一般还包含一种或多种乳化剂、稳定剂、分散剂、助悬剂、增稠剂或着色剂。
适合在口腔中进行局部给药的组合物包括,含有在调味基质(通常为蔗糖和阿拉伯胶或黄蓍胶)中的活性试剂的锭剂;包含在惰性基质(如明胶和甘油或蔗糖和阿拉伯胶)中的活性成分的软锭剂(pastilles);和包含在适宜的液体载体中的活性成分的嗽口水。
溶液或混悬剂可以通过常规方法,例如使用滴管、吸管或喷雾器直接应用于鼻腔。所述组合物可以单剂量或多剂量形式提供。
呼吸道给药还可以通过气溶胶制剂实现,其中将活性成分提供在压力包装中,后者含有适宜抛射剂,例如含氯氟烃(CFC)如二氯二氟甲烷、三氯氟甲烷或二氯四氟乙烷,二氧化碳或其它适宜气体。所述气溶胶还可以方便地包含表面活性剂,例如卵磷脂。药物的剂量可以通过提供的计量阀来控制。
或者,活性成分可以干燥散剂形式提供,例如化合物在适宜的粉末基质中的粉末混合物,所述基质例如乳糖、淀粉、淀粉衍生物如羟丙基甲基纤维素和聚乙烯吡咯烷酮(PVP)。散剂载体通常在鼻腔中形成凝胶。所述粉末组合物可以单位剂型提供,例如在明胶胶囊剂或药筒中,或在可通过吸入器施用粉末的泡罩包装中。
在打算用于向呼吸道给药的组合物(包括鼻内组合物)中,化合物一般具有小的粒径,例如数量级为5微米或更小。这种粒径可以通过本领域已知方法获得,例如通过微粉化。
如果需要的话,可以使用适合持续释出活性成分的组合物。
药物制剂优选为单位剂型。在这类剂型中,将制剂细分成包含适量活性组分的单位剂量。单位剂型可以是其中包含离散数量的制剂的包装制剂,例如包装片剂、胶囊剂和在小瓶或安瓿中的散剂。另外,单位剂型可以是胶囊剂、片剂、扁囊剂或锭剂本身,或是它们的适宜数量的包装形式。
用于口服的片剂或胶囊剂以及用于静脉内给药和连续输注的液体是优选的组合物。
关于制剂和给药技术的其它细节,可以参见
Remington’s Pharmaceutical Sciences(Maack Publishing Co.,Easton,PA)的最新版本。
治疗有效剂量指缓解病症或状况的活性成分的数量。通过标准的细胞培养物或实验动物药理学方法,可以确定治疗效力和毒性反应,例如ED50和LD50。治疗和毒性作用之间的剂量比是治疗指数,它可以使用比率LD50/ED50表示。优选表现出高治疗指数的药物组合物。
给药剂量当然必须根据待治疗个体的年龄、重量和病症、和给药途径、剂型和方案、以及期望的结果仔细调整,确切的剂量应该由执业医生确定。
实际剂量取决于待治疗疾病的性质和严重程度,且属于内科医师的判断范畴,并可以根据本发明的特定情形通过剂量滴定进行改变,以获得期望的治疗效果。但是,目前认为每个单独剂量包含约0.1至约500mg活性成分、优选约1至约100mg、最优选约1至约10mg的药物组合物适用于治疗性处理。
活性成分可以以每天一个或几个剂量给药。在某些情况下,可以在低至0.1μg/kgi.v.和1μg/kgp.o的剂量下获得满意的结果。目前剂量范围的上限为约10mg/kgi.v.和100mg/kgp.o。优选的范围为约0.1μg/kg至约10mg/kg/天i.v.,以及约1μg/kg至约100mg/kg/天p.o。
治疗方法
在另一方面,本发明提供了治疗、预防或缓解活的动物体(包括人)的疾病或障碍或病症的方法,所述疾病、障碍或病症对抑制中枢神经系统中的单胺神经递质再摄取有应答,所述方法包括向有该需要的活动物体(包括人)施用有效量的本发明化合物。
目前认为,适宜的剂量范围为0.1-1000毫克/天、10-500毫克/天、特别是30-100毫克/天,这通常取决于确切的给药方式、给药剂型、给药针对的适应症、涉及的受试者、涉及的受试者体重、以及主管内科医师或兽医的其它偏好与经验。
实施例
参考下面的实施例进一步解释本发明,这些实施例并不意味着以任何方式限制要求保护的本发明范围。
概况:全部涉及空气敏感试剂或中间体的反应都是在氮气下和无水溶剂中进行。在后处理中,使用硫酸镁作为干燥剂,然后减压蒸发溶剂。
实施例1
3-(6-甲氧基-萘-2-基)-1-氮杂-双环[2.2.2]辛-2-烯富马酸盐
在50℃搅拌3-(6-甲氧基-萘-2-基)-1-氮杂-双环[2.2.2]辛-3-醇(0.49g,1.72mmol)和盐酸(9ml,25%)的混合物15小时。在冰上冷却混合物,加入氢氧化钠水溶液(20ml,10M)。用二氯甲烷(2X25ml)萃取混合物。用硫酸镁干燥混合物,并蒸发。使用二氯甲烷:甲醇(9∶1)的混合物和1%氨作为洗脱剂,通过硅胶色谱纯化粗混合物。通过加入用富马酸饱和的二乙醚和甲醇混合物(9∶1),得到对应的盐。产率:190mg(34%)。熔点:226.9℃。
(+/-)-3-(6-甲氧基-萘-2-基)-1-氮杂-双环[2.2.2]辛-3-醇(中间体)
在20℃,将丁基锂(2.5M,1.86ml,4.64mmol)加入2-溴-6-甲氧基萘(1.0g,4.22mmol)和二乙醚(10ml)的混合物。将温度保持低于35℃30分钟。将混合物冷却至-70℃,在-70℃加入3-奎宁环酮(quinuclidinone)(0.53g,4.22mmol)。将混合物在-70℃搅拌1小时。使混合物达到室温。加入水(1ml),然后加入氢氧化钠水溶液(1M,10ml)。过滤晶体状产物,并用冷的二乙醚(2ml)洗涤。产率0.49g(41%)。熔点>330℃。
实施例2
6-(1-氮杂-双环[2.2.2]辛-2-烯-3-基)-萘-2-酚盐酸盐
将3-(6-甲氧基-萘-2-基)-1-氮杂-双环[2.2.2]辛-2-烯(0.80g,2.10mmol)和二氯甲烷(25ml)的混合物冷却至-10℃。在-10℃逐滴加入溶于二氯甲烷(21.0ml,21.0mmol)中的三溴化硼(10当量)。将混合物搅拌48小时。加入浓氨水(20ml)。分离相,并用二氯甲烷(2×20ml)萃取水相。干燥合并的有机相,并蒸发。通过加入溶于乙醇中的盐酸,将标题化合物的游离碱沉淀成盐酸盐。产率20mg(3%)。熔点:227-230℃。
Claims (14)
4.权利要求3的化合物,其中各个R5、R6、R7和R8彼此独立地代表氢,烷基,烷氧基,环烷氧基,烷氧基烷基或环烷氧基烷基;条件是,R5、R6、R7和R8中的至少一个不代表氢。
5.权利要求3的化合物,其中R5、R6、R7和R8之一代表烷氧基;且R5、R6、R7和R8中其余的3个代表氢。
6.权利要求3的化合物,其中R5、R6、R7和R8之一代表羟基;且R5、R6、R7和R8中其余的3个代表氢。
7.权利要求3的化合物,其中Q代表6-甲氧基-萘-2-基。
8.权利要求3的化合物,其中Q代表6-羟基-萘-2-基。
9.权利要求1的化合物,它是
3-(6-甲氧基-萘-2-基)-1-氮杂-双环[2.2.2]辛-2-烯;
6-(1-氮杂-双环[2.2.2]辛-2-烯-3-基)-萘-2-酚;
或其可药用盐。
10.药物组合物,其包含治疗有效量的权利要求1-9中任一项的化合物、或其任何异构体或其异构体的任何混合物、或其可药用盐,以及至少一种可药用载体、赋型剂或稀释剂。
11.权利要求1-9中任一项的化合物、或其任何异构体或其异构体的任何混合物、或其可药用盐在制备药物中的用途。
12.根据权利要求11的用途,用于制备治疗、预防或缓解哺乳动物,包括人的疾病、障碍或病症的药物组合物,所述疾病、障碍或病症对抑制中枢神经系统中的单胺神经递质再摄取有应答。
13.根据权利要求12的用途,其中所述疾病、障碍或病症是:心境障碍、抑郁、非典型抑郁、继发于疼痛的抑郁、重度抑郁症、情绪恶劣性障碍、双相性精神障碍、I型双相性精神障碍、II型双相性精神障碍、循环情感障碍、由全身医学病症导致的心境障碍、物质诱导的心境障碍、假性痴呆、甘塞氏综合征、强迫观念与行为障碍、惊恐性障碍、无广场恐怖症的惊恐性障碍、有广场恐怖症的惊恐性障碍、无惊恐性障碍病史的广场恐怖症、惊恐发作、记忆缺陷、记忆丧失、注意力缺陷多动症、肥胖、焦虑、广泛性焦虑症、进食障碍、帕金森氏病、帕金森氏综合征、痴呆、老化性痴呆、老年性痴呆、阿尔茨海默氏病、获得性免疫缺陷综合征痴呆复征、老化性记忆机能障碍、特定恐怖症、社交恐怖症、创伤后精神紧张障碍、急性精神紧张障碍、药物成瘾、药物滥用、可卡因滥用、烟碱滥用、烟草滥用、酒精成瘾、酒精中毒、疼痛、慢性疼痛、炎性疼痛、神经病性疼痛、偏头痛、紧张型头痛、慢性紧张型头痛、与抑郁、纤维肌痛、关节炎、骨关节炎、类风湿性关节炎有关的疼痛、背部疼痛、癌痛、肠易激性疼痛、肠易激综合征、术后疼痛、乳房切除术后疼痛综合征(PMPS)、中风后疼痛、药物导致的神经病、糖尿病性神经病、交感神经维持性疼痛、三叉神经痛、牙痛、肌筋膜疼痛、幻肢痛、贪食症、月经前综合征、晚黄体期综合征、创伤后综合征、慢性疲劳综合征、尿失禁、压迫性尿失禁、欲望性尿失禁、夜间尿失禁、性功能障碍、早泄、勃起困难、勃起功能障碍、过早的女性性高潮、不宁腿综合征、进食障碍、神经性厌食、睡眠障碍、全身性发育迟缓、孤独症、阿斯波哥尔障碍、雷特障碍、童年瓦解性障碍、学习能力丧失、运动技能障碍、哑症、拔毛发癖、发作性睡眠、中风后抑郁、中风诱导的脑损害、中风诱导的神经元损害或吉勒德拉图雷综合征。
14.治疗、预防或缓解活的动物体,包括人的疾病、障碍或病症的方法,所述疾病、障碍或病症对抑制中枢神经系统中的单胺神经递质再摄取有应答,所述方法包括向有该需要的活的动物体施用治疗有效量的根据权利要求1-9任一项的化合物、或其任何异构体或其异构体的任何混合物、或其可药用盐。
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EP (1) | EP1831213A1 (zh) |
JP (1) | JP2008524305A (zh) |
KR (1) | KR20070089945A (zh) |
CN (1) | CN101061117A (zh) |
AU (1) | AU2005318225A1 (zh) |
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KR20070089945A (ko) | 2007-09-04 |
US20070287728A1 (en) | 2007-12-13 |
NO20073840L (no) | 2007-07-20 |
BRPI0519382A2 (pt) | 2009-01-20 |
US8022081B2 (en) | 2011-09-20 |
AU2005318225A1 (en) | 2006-06-29 |
JP2008524305A (ja) | 2008-07-10 |
ZA200704471B (en) | 2009-02-25 |
RU2007115600A (ru) | 2009-01-27 |
CA2592130A1 (en) | 2006-06-29 |
WO2006067090A1 (en) | 2006-06-29 |
IL182268A0 (en) | 2007-07-24 |
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