CN101461804A - (+)-1-(3,4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其组合物与应用 - Google Patents
(+)-1-(3,4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其组合物与应用 Download PDFInfo
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- CN101461804A CN101461804A CNA200810185945XA CN200810185945A CN101461804A CN 101461804 A CN101461804 A CN 101461804A CN A200810185945X A CNA200810185945X A CN A200810185945XA CN 200810185945 A CN200810185945 A CN 200810185945A CN 101461804 A CN101461804 A CN 101461804A
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- depression
- hexane
- azabicyclic
- dichlorobenzene base
- disease
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Abstract
本发明涉及(+)－1－(3，4－二氯苯基)－3－氮杂二环[3.1.0]己烷及其可药用的盐、包含(+)－1－(3，4－二氯苯基)－3－氮杂二环[3.1.0]己烷或其可药用盐的组合物以及用于治疗或预防患者抑郁症、焦虑症、摄食障碍、或尿失禁的复发的方法，该方法包括使用(+)－1－(3，4－二氯苯基)－3－氮杂二环[3.1.0]己烷或其可药用的盐。该(+)－1－(3，4－二氯苯基)－3－氮杂二环[3.1.0]己烷或其可药用的盐优选地基本不含其相应的(－)－对映体。
Description
本申请是申请号为02806351.1申请日为2002年1月11日的发明专利申请的分案申请。
1.技术领域
本发明涉及(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其可药用的盐、包含(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用盐的组合物以及用于治疗或预防患者抑郁症、焦虑症、摄食障碍、或尿失禁的复发的方法，该方法包括给患者使用(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐。
2.背景技术
抑郁症是最常见的精神疾病之一，在普通人群中其具有10％以上的发病率。抑郁症的特征为感情的强烈悲伤、失望、精神弛缓、专心程度下降、悲观忧虑、激动、以及自我贬低(Harrison′s Principles ofInternal Medicine 2490-2497(Fauci等人编辑，第14版，1998年))。抑郁症可以有身体症状，包括失眠症、睡眠过度、厌食、体重下降、过度饱食、活力下降、性欲下降、和活动、体温、以及endosine功能正常24小时生理节奏的混乱。实际上，有多至10％至15％抑郁的个体表现自杀行为。R.J.Baldessarini，精神病学病症的药物和治疗：抑郁症和躁狂症，Goodman和Gilman′s The Pharmacological Basis ofTherapeutics 431(第9版，1996年)。
Epstein等在专利号为4,435,419的美国专利中公开了用作抗抑郁剂的外消旋的(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷。
将外消旋物质给药预患者可能有一些缺点，其中所说的外消旋物即任何药物50:50，(+)-和(-)-对映体的混合物，例如(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷。首先，该外消旋混合物的药理学活性可能低于其对映体中的一种，表现出外消旋药物固有的低效。第二，对于患者而言，该外消旋混合物的毒性比其对映体中的一种更高，从而使得外消旋混合物的给药可能会使患者出现不希望出现的副作用。
因此，在现有技术中显然需要一种可克服上述缺陷中的一种或两种的(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷的对映体，该对映体优选地基本不含相应的相反的对映体。
在本申请的第2部分中引用的用来进行鉴定的任何参考资料不能被认为是对该类参考是本申请的现有技术的认可。
发明内容
3.本发明的概述
在一个实施方案中，本发明提供了(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其可药用的盐。(+)-1-(3，4二氯苯基)-3-氮杂二环[3.1.0]己烷及其可药用的盐可用来治疗或预防患者抑郁症的复发。
本发明还提供了包含有效量的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其药用盐的组合物。本发明的组合物还可另外包含可药用的赋形剂。这些组合物可用来治疗或预防患者抑郁症的复发。
在另一个实施方案中，本发明提供了一种治疗或预防患者抑郁症复发的方法，该方法包括该需要进行该类治疗或预防的患者使用有效量的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐。
还是在本发明的另一个实施方案中，本发明提供了一种治疗或预防患者焦虑症、摄食障碍、或尿失禁的复发的方法，该方法包括给需要进行该类治疗或预防的患者使用有效量的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐。
优选地，(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐，特别是当用在本发明的方法或组合物中时，基本不含其相应的(-)-对映体，即(-)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷。这种对映异构的纯度可以通过使用色谱拆分技术如手性色谱法或模拟的移动床技术来获得，或者可以通过使用光学活性拆解试剂的化学分离来获得。
通过参考详细说明和实施例可以对本发明进行更充分的理解，这些实施例是用于举例说明本发明的非限制性的实施方案。
4.本发明的详细说明
申请人已经发现用于治疗或预防患者抑郁症复发的而言(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其可药用的盐令人吃惊并出乎意料地具有比(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷更高的活性。
4.1.定义
术语“基本不含其相应的(-)-对映体”的定义指的是包含至多约5％ w/w相应的(-)-对映体，优选至多约2％ w/w相应的(-)-对映体，更优选至多约1％ w/w相应的(-)-对映体。
当与(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐联用时，术语“相应的(-)-对映体”的定义指的是“(-)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷”或其可药用的盐。
“患者”指动物，非限制性地包括动物如牛、猴、马、羊、猪、鸡、火鸡、鹌鹑、猫、狗、小鼠、大鼠、兔、以及豚鼠，更优选地是哺乳动物，并且最优选地是人。
这里所用的“可药用的盐“的短语指的是酸和(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷的碱性氮基团所形成的盐。优选的盐非限制性地包括硫酸盐、枸橼酸盐、醋酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、醋酸盐、乳酸盐、水杨酸盐、枸橼酸盐、酸式枸橼酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、延胡索酸盐、葡萄糖酸盐、葡萄糖二酸盐(glucaronate)、蔗糖盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对-甲苯磺酸盐、以及双羟萘酸盐(即，1，1′-亚甲基-双-(2-羟基-3-萘甲酸盐))。
4.2 (+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷
(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷，优选地基本不含其相应的(-)-对映体，可以用手性色谱法由(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷获得，其中所说的手性色谱法如使用适宜柱，优选手性柱的高效液相色谱法(“HPLC”)。(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷可以用Epstein等人在专利号为4,435,419的美国专利中所公开的方法来获得。
在一个优选的实施方案中，(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷是通过用手性多糖固定相和有机洗脱剂对(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷进行拆分来获得的。优选地，该多糖是淀粉或淀粉衍生物。有利地，可以使用手性HPLC柱，例如由Daicel制造的并可购自Chiral Technologies，Inc.，Exton，宾夕法尼亚的CHIRALPAK AD柱，更优选地使用一种1cm×25cm的CHIRALPAK AD HPLC柱。优选的洗脱剂是一种用可混溶的极性有机溶剂来调节极性的烃类溶剂。优选地，该有机洗脱剂包含约95％至约99.5％(体积/体积)的非极性烃类溶剂和约5至约0.5％(体积/体积)的极性有机溶剂。在一个优选的实施方案中，该烃类溶剂是己烷并且该可混溶的极性有机溶剂是异丙胺。
在另一个优选的实施方案中，可以使用另一种已知的被称为模拟的移动床(SMB)色谱法的另一种供选择的色谱操作来对(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷进行拆分。在药学工业中，SMB逐渐变成大规模地对对映体进行分离时所选择的方法(见Chemical andEngineering News，2001，第79卷，第20期，第47页)。
还是在另一个实施方案中，可以通过使用光学活性的拆分酸，经形成所得的对映体的盐并随后将该盐分离出来而来对该外消旋的(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷进行拆分从而获得(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷。用于此目的常用手性酸包括：酒石酸和0-酰基酒石酸、扁桃酸和0-取代的扁桃酸、1，1′-联萘基-2，2′-二基磷酸氢酯、樟脑酸、樟脑磺酸、以及其它易于获得的光学活性的酸(既包括可以通过商业途径获得又包括易于合成的)。
对于立体异构体分离的一般讨论可参见Eliel和Wilen，有机化合物的立体化学；Wiley：纽约1994，第297-464、以及其中所引入的参考资料。
4.3.(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷的治疗应用
根据本发明，为了对病症进行治疗或预防，可以将(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐给药于患者，优选哺乳动物、更优选人，其中所说的病症非限制性地包括抑郁症、焦虑症、摄食障碍和尿失禁症。在一个实施方案中，“治疗”或“处理”指的是该类病症或其至少一种可识别症状的改善.在另一个实施方案中，“治疗”或“处理”指的是至少一种可测量的物理参数得到了改善，而不必是患者可意识到的。还是在另一个实施方案中，“治疗”或“处理”指的是在物理学上或生理上或同时在物理学上和生理上抑制了该类病症的进程，其中所说的在物理学上的抑制例如可识别症状的正常化，所说的在生理学上的抑制例如物理参数的正常化。还是在另一个实施方案中，“治疗”或“处理”指的是延迟了该类病症的发作。
4.3.1 用(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷对抑郁 症进行缓解
在某些实施方案中，作为对抗抑郁症复发的一种预防性措施而来给患者使用(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐，其中所说的患者优选地是一种哺乳动物，更优选地是人。正如这里所用的这样，“预防”或“阻止”指的是降低患有抑郁症的患者出现复发的危险。在一个实施方案中，将(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐作为一种对抗复发的预防性措施来给予患者。根据这一实施方案，该患者可具有抑郁症的遗传倾向，如有脑中生物化学失调的家族史，或者患有抑郁症的非遗传倾向。因此，(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其可药用的盐可用对抑郁症的一种表现进行治疗并可以对另一种进行预防。
(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其可药用的盐还可用来治疗或预防内因性抑郁症、单极性抑郁症、运动阻抑性抑郁症、激越性抑郁症、两极性抑郁症、产后抑郁症、伴有焦虑的抑郁症、伴有强迫症的抑郁症、伴有可引起癫痫发作的疾病的抑郁症、精神抑郁症、季节性情感病症、昼间心境变化、与绝经有关的抑郁症、以及与与医学疾病、酒精、或物质滥用有关的抑郁症的复发。
4.3.2 用(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷对焦虑 症进行缓解
(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其可药用的盐还可用来治疗或预防焦虑症的复发(焦虑症的综述可参见DerogatisL.R.& Wise，T.N.，“医学患者的焦虑症和抑郁症，”Washington，DC，American Psychiatric Press，1989，以及其中所引用的参考资料)。该类病症非限制性地包括惊恐性障碍；恐慌发作；恐旷症；广泛性焦虑症；强迫观念与行为症；恐怖症和创伤后应激障碍，其中一些可以进一步进行如下所列的亚分类。
与恐怖有关的病症非限制性地包括特定的恐怖症，如恐高症、疼痛恐怖症、恐蛛症、闪点恐怖症、恐鸟症(Aviaphobia)、幽闭恐怖症、恐犬病、恐魔症(Demophobia)、恐血症、孤居恐怖症、黑夜恐怖症、疾病恐怖症、火焰恐怖症、死亡恐怖症和动物恐怖症；泛化的社会恐怖症；特定性的社会恐怖症和非特定性的(NOS)恐怖症。
与强迫观念与行为有关的病症非限制性地包括拔毛癖、身体变形性精神障碍、癖好性病症、抽搐性病症；图雷特氏综合征和非特定性的(NOS)强迫观念与行为症。
与创伤后有关的病症非限制性地包括急性应激障碍；和非特定性的(NOS)创伤后病症。
4.3.3 用(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.01]己烷进行缓 解的其它病症
可以用(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷缓解的其它病症还包括摄食障碍和尿失禁并且并不限于这里所描述的特定性的病症，因为许多类型的病症可以由特定的原发性病症所表现出来。例如，正如Blum在专利号为6,132,724的美国专利中所公开的那样，注意涣散多动症可以以酒精滥用、药物滥用、强迫观念与行为、学习障碍、阅读问题、赌博、躁狂症状、恐怖、恐慌发作、反抗性的挑衅行为、指挥性行为、在学校中的学院问题、吸烟、变态的性行为、精神分裂行为、躯体化症状、抑郁症、睡眠障碍、广泛性焦虑、口吃、和抽搐性病症的形式将自身表现出来。此外，这里许多特定疾病所用的临床术语可以在得自DSM-IV(精神病的诊断和统计学手册，第四版)，The American Psychiatric Association，华盛顿，D.C.，1994，第358页，的诊断标准的快速参考中找到。在这种参考资料中也可以发现与所表明的病症相关的特定病症。此外，关于摄食障碍的详细讨论可以在...中找到。对于尿失禁及相关病症的进一步讨论，参见。
摄食障碍非限制性地包括神经性厌食；Binge-摄食障碍；非催泻型神经性贪食症；催泻型神经性贪食症；和非特定性的(NOS)摄食障碍。
尿失禁非限制性地包括欲望性尿失禁；压迫性失禁；溢流性失禁；功能性失禁；神经原性失禁和前列腺切除术后的失禁。
4.4.治疗/预防性给药和本发明的组合物
由于它们的活性，(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其可药用的盐可有利地用于兽医和人类医学中。正如上面所述的那样，(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其可药用的盐可用来治疗或预防患者抑郁症、焦虑症、摄食障碍和与尿失禁有关的病症的复发。
当被给药于患者时，(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐优选地作为一种组合物的组分来进行给药，其中所说的组合物可包含或不包含可药用赋形剂。本发明包含(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐的组合物优选地进行口服给药。本发明的组合物还可以通过任何其它常规途径进行给药，例如通过输注或推注(bolus injection)来进行给药，通过上皮或粘膜层(例如口腔粘膜、直肠、以及小肠粘膜等等)进行吸收并且可以与另一种生物学活性物质一起进行给药。可以进行全身给药或局部给药。各种传递系统都是已知的，例如包封于脂质体、微粒、微胶囊等等中并且可用所说的各种传递系统来对(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其可药用盐进行给药。
在某些实施方案中，本发明的组合物可以包含(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷和/或一种或多种其可药用的盐。
给药方法非限制性地包括真皮内给药、肌内给药、腹膜内给药、静脉内给药、皮下给药、鼻内给药、硬膜外给药、口服给药、舌下给药、鼻内给药、脑内给药、阴道内给药、经皮给药、直肠给药、通过吸入给药、或局部给药，特别是给药于耳、鼻、眼、或皮肤。医生有权决定给药方式。在大多数情况中，给药将使得(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐释放进入到血液中.
在特定的实施方案中，可能希望将(+)-1-(3，4二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐进行局部给药。这是可以做到的，例如非限制性地包括通过手术期间的局部输注、局部应用来进行给药，例如在手术后于创伤敷料合用、通过注射、导管、栓剂、或通过植入物来做到，所说的植入物是一种多孔的、无孔的、或凝胶状物质，包括膜如sialastic膜、或纤维。
在某些实施方案中，其需要将(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐通过任何适宜的途径来引入到中枢神经系统中，其中所说的适宜途径包括心室内注射、鞘内注射和硬膜外注射。通过使用与一种储库如Ommaya储库相连的心室内导管可以易化心室内的注射。
还可以使用肺部给药，例如通过使用吸入器或喷雾器并且与雾化剂一起进行制备、或通过灌注在碳氟化合物或合成的肺表面活性剂中来进行给药。在某些实施方案中，可以用常规的粘合剂和赋形剂如甘油三酯将(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其可药用的盐制备成栓剂。
在另一个实施方案中，(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其可药用的盐可以在囊(vesicle)中，特别是脂质体中进行传递(见Langer，1990，Science 249：1527-1533；Treat等人，感染性疾病和癌症的治疗中的脂质体，Lopez-Berestein和Fidler(编辑)，Liss，纽约，第353-365页(1989)；Lopez-Berestein，出处同上，第317-327页；一般见参见出处同上)。
还是在另一个实施方案中，(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其可药用的盐可以以控释系统的形式进行传递(见例如，Goodson，控释的医学应用，上述，第2卷，第115-138页(1984))。可以使用在综述中所讨论的其它控释系统，Langer，1990，Science249：1527-1533)。在一个实施方案中，可以使用一种泵(见Langer，同上；Sefton，1987，CRCCrit.Ref.Biomed.Eng.14：201；Buchwald等人，1980，Surgery 88：507 Saudek等人，1989，N.Engl.J.Med.321：574)。在另一个实施方案中，可以使用聚合物(见控释的医学应用，Langer和Wise(编辑)，CRC Pres.，Boca Raton，Florida(1974)；控释药物的生物利用度，药物产品的设计和性能，Smolen和Ball(编辑)，Wiley，纽约(1984)；Ranger和Peppas，1983，J.Macromol.Sci.Rev.Macromol.Chem.23：61；还可参见Levy等人，1985，Science 228：190；During等人，1989，Ann.Neurol.25：351；Howard等人，1989，JNeurosurg.71：105)。还是在另一个实施方案中，还可以将一种控释体系放置在靶向物质(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐的附近，例如使之靶向于脊柱或脑，从而仅需要小部分的全身给药。
本发明的组合物可以包含或不包含适宜数量的可药用赋形剂，以便为患者提供适宜的给药形式。
在特定的实施方案中，术语“可药用的”的定义指的是被联邦或州政府的权威机构批准用于动物、哺乳动物、并且更特别地是人或被列于美国药典或其它公认的药典中。术语“赋形剂”的定义指的是与本发明的化合物一起进行给药的稀释剂、辅剂、赋形剂、或载体。该类药用赋形剂可以是液体，如水和油，包括这些石油、动物、植物或合成来源的物质，如花生油、豆油、矿物油、芝麻油等等。药用赋形剂可以是盐水、阿拉伯胶、明胶、淀粉浆、滑石粉、角蛋白、胶质硅胶、脲等等。此外，还可以使用辅剂、稳定剂、增稠剂、润滑剂和着色剂。当给药于患者时，该可可药用的赋形剂优选地是无菌的。当将本发明的化合物进行静脉内给药时，水是一种优选的赋形剂。还可以用盐水溶液以及水性葡萄糖和甘油溶液作为液体赋形剂，特别是用作可注射溶液的赋形剂。适宜的药用赋形剂还包括赋形剂(excipients)如淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、稻、面粉、白垩、硅胶、硬脂酸钠、甘油单硬脂酸酯、滑石粉、氯化钠、干脱脂乳、甘油、丙二醇、乙二醇、水、乙醇等等。如果需要，本发明的组合物还可以包含少量的润湿剂或乳化剂、或pH缓冲剂。
本发明的组合物可以是溶液、混悬液、乳剂、片剂、丸剂、小丸、胶囊、包含液体的胶囊、粉末、缓释制剂、栓剂、乳剂、气雾剂、喷雾剂、混悬液的形式或任何其它适于应用的形式。在一个实施方案中，该可药用的赋形剂是一种胶囊(参见例如专利号为5,698,155的美国专利)。适宜的药物赋形剂的其他实施例在Remington′sPharmaceutical Sciences，Alfonso R.Gennaro编辑，Mack PublishingCo.Easton，pA，第19版，1995，第1447至1676页中进行了描述，其在这里被引入本文作为参考。
在一个优选的实施方案中，(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐被用常规方法制备成适于给人口服给药的药物组合物。用于口服传递的组合物可以是例如片剂、锭剂、水性或油性混悬液、颗粒剂、粉末、乳剂、胶囊、糖浆、或酏剂的形式。口服给药的组合物可以包含一种或多种药剂，以提供一种可口的药物制剂，其中所说的药剂为例如甜味剂如果糖、阿司帕坦或糖精；矫味剂如薄荷、冬青油、或樱桃；着色剂；以及防腐剂。此外，在片剂或丸剂形式的情况中，还可以对该组合物进行包衣以延迟其在胃肠道中的崩解和吸收，从而在延长的时间内提供一种缓释作用。在一种渗透性驱动活性作用的化合物周围的选择性的可渗透膜也适用于口服给药的组合物。在这些后面所述的平台中，得自环绕在胶囊周围的环境中的液体通过驱动化合物被吸收，其进行膨胀从而通过一种小孔替换了药剂或组合物。这种传递平台可以提供一种与立即释放制剂的峰形曲线相反的基本为零级的传递曲线。还可以使用一种延时物质如甘油单硬脂酸酯或甘油硬脂酸酯。口服组合物可以包括标准赋形剂如甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素和碳酸镁。该类赋形剂优选地是药用等级。用于静脉内给药的组合物一般包含无菌等渗的水性缓冲液。在需要的情况中，该组合物还可以包含增溶剂。
在另一个实施方案中，(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐可以被制备成用于静脉内给药的形式。用于静脉内给药的组合物可以包括或不包括一种局部麻醉剂如利多卡因以减少注射部位的疼痛感。一般而言，这些组分被分别供给或一起混在单位剂型中，例如在标明了活性物质数量的不漏气的密封容器如安瓿或小袋中的一种干的冷冻干燥粉末或不含水的浓缩物。例如，在(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐通过输注进行给药的情况中，其可以被分散于例如一个包含无菌的药用等级的水或盐水的输注小瓶中。在(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐通过注射进行给药的情况中，可以提供一种注射用无菌水或盐水的安瓿从而使该组分可以在给药前进行混合。
可有效治疗特定的抑郁症、焦虑症、摄食障碍或与尿失禁有关的病症的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐的数量将取决于该病症或情况的性质，并且可以通过标准的临床技术来进行决定。此外，可随意使用体内或体外实验以帮助确定最佳的剂量范围。所使用的精确剂量还将取决于给药途径以及疾病或病症的严重程度，并且应当根据医生的判断和各个患者的详细情况来决定。但是，用于口服给药的适宜剂量范围一般为每天每公斤体重约0.2毫克至约2.0毫克(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐。在本发明特定的优选实施方案中，该口服剂量为每天每公斤体重约0.01毫克至约100毫克，更优选每天每公斤体重约0.1毫克至约75毫克，更优选每天每公斤体重约0.5毫克至约50毫克，并且还更优选每天每公斤体重约1毫克至约30毫克。在另一个优选的实施方案中，该口服剂量为每天每公斤体重约1毫克至约3毫克本发明的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐。这里所述的剂量指的是给药的总量；即，如果(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷和/或其一种或多种可药用的盐被进行给药时，该优选的剂量相当于给药的总量。口服组合物优选地包含约10％至约95％重量的活性成分。
用于静脉内(i.v.)给药的适宜剂量范围为每天每公斤体重约0.01毫克至约100毫克、每天每公斤体重约0.1毫克至约35毫克、以及每天每公斤体重约1毫克至约10毫克。用于鼻内给药的适宜剂量范围一般为每天约0.01pg/kg体重至约每天1mg/kg体重。栓剂一般包含每天每公斤体重约0.01毫克至约50毫克的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐并且包含约0.5％至约10％重量范围的活性成分。
对于真皮内给药、肌内给药、腹膜内给药、皮下给药、硬膜外给药、舌下给药、脑内给药、阴道给药、经皮给药或吸入给药而言，推荐剂量在每天每公斤体重约0.001毫克至约200毫克的范围内。取决于给药的面积，局部给药的适宜剂量在约0.001毫克至约1毫克的范围内。用得自体外试验或动物模型实验系统的剂量-响应曲线可以外推出有效剂量。该类动物模型和系统在现有技术中是众所周知的。
本发明还提供了包含一种或多种含有(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐的容器的药物包装物或试剂盒.该类容器(容器们)可包含或不包含由管理药物或生物产品的制造、使用或销售的政府机构所规定的形式的通知书，该通知书反映了该机构对给药于人的物质的制造、使用或销售的批准。在某些实施方案中，该试剂盒包含(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷和/或一种或多种其可药用的盐。在另一个实施方案中，该试剂盒包含治疗剂和(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐。
在给人使用之前，优选地对(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其可药用的盐就所需的治疗或预防活性在体外或体内进行试验。例如，可以使用体外试验来决定其是否可优选地使用(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷、其可药用的盐、和/或另外的治疗剂来进行给药。可以用动物模型系统来证明安全性和有效性。
其它的方法对于本领域技术人员而言是公知的并且也属于本发明的范围。
4.5.联合治疗
在本发明的某些实施方案中，(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐可以与至少一种其它的治疗剂一起进行联合治疗。(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐和其它的治疗剂的作用可以加和地，更优选地是协同起效。在一个优选的实施方案中，将一种包含(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐的组合物与另一种治疗剂同时给药，它们可以同一种组合物的部分或是与包含(+)-1-(3，4二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐的组合物不同的组合物。在另一个实施方案中，包含(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐的组合物是在另外的治疗剂的给药之前或给药之后进行给药的。因为许多用(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷及其可药用的盐进行治疗的病症都是慢性的，所以在一个实施方案中联合治疗包括将包含(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐的组合物和包含另外的治疗剂的组合物交替进行给药。(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷、其可药用的盐、或其它的治疗剂给药的持续时间可以是例如一个月、三个月、六个月、一年、或更长的时间，如患者终身给药。在某些实施方案中，当本发明的组合物与可能会产生不良副作用的另外的治疗剂同时给药时，另外的治疗剂可以有利地以低于可引发不良副作用的阈值的剂量进行给药，其中所说的不良副作用非限制性地包括毒性。
其它的治疗剂可以是抗抑郁剂。有用的抗抑郁剂非限制性地包括阿米替林、氯米帕明、多塞平、丙咪嗪、曲米帕明、阿莫沙平、地昔帕明、马普替林、去甲替林、普罗替林、氟西汀、氟伏沙明、帕罗西汀、setraline、文拉法辛、安非他酮、萘发唑酮、曲唑酮、pheuelzine、反苯环丙胺和司来吉兰。
其它的治疗剂可以是抗焦虑剂。有用的抗焦虑剂非限制性地包括苯并二氮
类，如阿普唑仑、氯氮、氯硝西泮、氯氮、地西泮、哈拉西泮、劳拉西泮、奥沙西泮、和普拉西泮；非苯并二氮革类，如丁螺环酮；和镇定剂，如巴比妥类(barbituates)。
其它的治疗剂可以是抗精神病药。有用的抗精神病药非限制性地包括吩噻嗪类，如氯丙嗪、苯磺酸美索达嗪、硫利达嗪、马来酸醋奋乃静、氟奋乃静、奋乃静、和三氟拉嗪；噻吨类，如普氯噻吨、和替沃噻吨；和其它杂环化合物，如氯氮平、氟哌啶醇、洛沙平、吗茚酮、匹莫齐特、和利培酮。优选的抗精神病药包括氯丙嗪HCl、硫利达嗪HCl、氟奋乃静HCl、替沃噻吨HCl、和吗茚酮HCl。
其它的治疗剂可以是抗肥胖药。用于与本发明的化合物联合应用的抗肥胖药非限制性地包括β-肾上腺素能受体激动剂，优选β-3受体激动剂：芬氟拉明；右旋酚氟拉明；西布曲明；安非他酮；氟西汀；芬特明；苯丙胺；去氧麻黄碱；右旋苯丙胺；苄非他明；苯甲曲秦；芬美曲嗪；安非拉酮；马吲哚；和苯丙醇胺。
具体实施方式
5.实施例：(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.01己烷
5.1 用手性色谱法对外消旋物进行拆分
向用Epstein等人，J.Med.Chem.，24：481-490(1981)所述的方法获得的279mg(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷盐酸盐中加入7mL 9:1的己烷:异丙醇，然后再加入8滴二乙胺。向所得的混合物中滴加异丙醇直至获得一种溶液。用氦气流将该溶液浓缩至体积为6mL，将该浓缩物以6个1-mL的浓缩物形式用于高效液相色谱，该高效液相色谱使用配有1cm x 25cm Daicel CHIRALPAK AD柱(Chiral Technologies，Inc.，Exton，宾夕法尼亚)的HPLC仪器。在环境温度下用包含0.05％二乙胺的95:5(v/v)己烷:异丙醇溶液作为流动相来进行洗脱，流速为6mL/min。收集约21.5至26分钟的洗脱液并将其进行浓缩，得到第一种残余物，用最少数量的乙酸乙酯将其溶解。用氮气流将该乙酸乙酯溶液进行蒸发，得到第二种残余物，将其溶解于1mL二乙醚中。向该二乙醚溶液中加入1mL用气态盐酸进行了饱和的二乙醚。形成一种无色的沉淀，将其过滤出来，用2mL二乙醚进行洗涤并进行干燥，得到73.4mg(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷盐酸盐：在甲醇中在2mg/ml下旋光度[α]25 D＝+60°；99.7％对映体过量。
5.2 通过使用L-二-(O-苯甲酰基)酒石酸作为手性拆解试剂对外 消旋物进行拆分
将如Epstein等人，J.Med.Chem.，1981，24，第481-490页所述的2.68g(0.0101mol)(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷盐酸盐的样品溶解于50mL水中并将这种溶液用10N氢氧化钠溶液将其pH调至碱性，使其pH为11，将所沉淀出来的游离碱萃取到25mL二氯甲烷中。用硫酸钠对这种溶液进行干燥并进行过滤。向滤液中加入3.70g(0.1030mol)L-二-(O-苯甲酰基)酒石酸在25mL甲醇中的溶液，并将这种溶液煮沸至发生结晶。将该混合物冷却至室温并使之静置1小时。收集晶体，得到3.21g无色晶体，将该晶体在50mL甲醇中煮沸，然后将这种混合物用冰浴进行冷却，然后进行过滤，得到2.04g无色晶体，其是m.p.为185-187℃的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷与L-二-(O-苯甲酰基)酒石酸的单盐。将这种盐用5N水性氢氧化钠进行搅拌，将释放出来的游离碱萃取到乙酸乙酯中。用稀氢氧化钠水溶液对有机层进行洗涤，然后用水进行洗涤，并且然后用硫酸钠进行干燥。过滤，将滤液用在乙醚中的HCl溶液进行处理直至不再出现沉淀。通过过滤收集结晶并将其风干，得到0.748g(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷盐酸盐的无色结晶，m.p.173-173℃，(α)＝+64.2°，C＝6.7，MeOH，其基本不含相应的(-)-对映体。
6.实施例：(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷和 (±)-1-(3，4二氯苯基)-3-氮杂二环[3.1.0]己烷的活性比较
6.1.去甲肾上腺素转运蛋白结合试验
用标准的去甲肾上腺素转运蛋白结合试验对(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷盐酸盐的抗抑郁性和(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷盐酸盐的抗抑郁性进行了比较。
6.1.1.材料和方法
去甲肾上腺素结合试验是用Raisman等人，Eur.J.Pharmacol.78：345-351(1982)和Langer等人，Eur.J.Pharmacol.72：423(1981)所述的方法来进行的。受体来源是大鼠的前脑膜；放射性配体是具有1.0nM最终配体浓度的[3H]-愈苯丙胺(60-85Ci/mmol)；非特异性的定子[1.0μm]；参考化合物和阳性对照是(±)-脱甲基丙咪嗪HCl。(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷HCl是用上面实施例5的方法获得的。反应是在包含300mM NaCl和5mM KCl的50mMTRIS-HCl(pH7.4)中在0℃至4℃进行4小时来完成的。通过在玻璃纤维过滤器上快速进行真空过滤来终止该反应。测定滤器中所捕获的放射性并与对照值进行比较以确定试验化合物与去甲肾上腺素吸收部位的相互作用。数据如下面的表1所报告。
6.1.2.结果
表1：去甲肾上腺素转运蛋白结合试验
化合物 Ki
(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷HCl 1.42 x 10-7
(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷HCl 8.20 x 10-8
(±)-脱甲基丙咪嗪HCl 1.13 x 10-9
表1的数据表明(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷HCl与去甲肾上腺素吸收部位的亲和力远远高于(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷HCl与该部位的亲和力。已经将对去甲肾上腺素重吸收的成功抑制与一种或多种抑郁症症状的治疗联系了起来(R.J.Baldessarini，精神病症的药物和治疗：抑郁症和躁狂症，inGoodman & Gilman′s The Pharmacological Basis of Therapeutics431-459(第9版1996))。因此，对于患者抑郁症复发的治疗或预防而言，(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐的活性将远远高于(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐。
6.2.血清素转运蛋白结合试验
用标准的血清素转运蛋白结合试验对(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷盐酸盐的抗抑郁性和(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷盐酸盐的抗抑郁性进行了比较。
6.2.1.材料和方法
血清素结合试验是用D′Ama to等人，J.Pharmacol.Exp.Ther.242：364-371(1987)和Brown等人，Eur.J.Pharmac.123：161-165(1986)所述的方法来完成的。受体来源是大鼠的前脑膜；放射性配体是具有0.7nM最终配体浓度的[3H]-西酞普兰(70-87Ci/mmol)；非特定性的定子是氯米帕明[10μm]；并且参考化合物和阳性对照是(±)-脱甲基丙咪嗪。(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷HCl是用上面实施例5的方法获得的。反应是在包含120mM NaCl和5mM KCl的50mM TRIS-HCl(pH7.4)中在25℃下进行60分钟来完成的。通过在玻璃纤维滤器上快速进行真空过滤来终止该反应。用液体闪烁光谱测定法测定滤器中所捕获的放射性并将其与对照值进行比较以确定试验化合物与血清素转运蛋白结合部位的相互作用。数据如下面的表2所报告。
6.2.2结果
表2：血清素转运蛋白结合试验
化合物 Ki
(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷HCl 1.18 x 10-7
(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷HCl 5.08 x 10-8
(±)-脱甲基丙咪嗪HCl 2.64 x 10-8
表2的数据表明(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷HCl与血清素吸收部位的亲和力远远高于(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷HCl与该部位的亲和力。已经将对血清素重吸收的成功抑制与一种或多种抑郁症症状的治疗联系了起来(R.J.Baldessarini，精神病症的药物和治疗：抑郁症和躁狂症，在Goodman & Gilman′s The Pharmacological Basis of Therapeutics431-459(第9版1996))中。因此，对于患者抑郁症复发的治疗或预防而言，(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐的活性将远远高于(±)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐。
本发明范围并不受实施例中所公开的特定实施方案的限制，实施例中所公开的特定实施方案只是用来对本发明的一些方面进行举例说明并且任何功能相同的实施方案都在本发明的范围之内。实际上，除这里所表明和所述的这些变化外，本发明的各种变化对于本领域技术人员而言也是显而易见的并且也将落在所附权利要求的范围内。
在这里引用了许多参考资料，其全部公开内容都在这里被引入本文作为参考。
Claims (38)
1.(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐，其各自具有至多5％w/w的相应的(-)-对映体。
2.如权利要求1所述的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐，其具有至多2％w/w的相应的(-)-对映体。
3.如权利要求1所述的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐，其具有至多1％w/w的相应的(-)-对映体。
4.一种组合物，它包含有效量的(+)-1-(3，4二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐，其各自具有至多5％w/w的相应的(-)-对映体。
5.如权利要求4所述的组合物，其还进一步包含可药用的载体或赋形剂。
6.如权利要求4所述的组合物，其还进一步包含其他的治疗剂。
7.如权利要求6所述的组合物，其中所说的其它的治疗剂是一种抗抑郁剂。
8.如权利要求6所述的组合物，其中所说的其它的治疗剂是一种抗焦虑药。
9.如权利要求6所述的组合物，其中所说的其它的治疗剂是一种抗精神病药。
10.如权利要求6所述的组合物，其中所说的其它的治疗剂是一种抗肥胖药。
11.如权利要求7所述的组合物，其中所说的抗抑郁剂选自阿米替林、氯米帕明、多塞平、丙咪嗪、曲米帕明、阿莫沙平、地昔帕明、马普替林、去甲替林、普罗替林、氟西汀、氟伏沙明、帕罗西汀、setraline、文拉法辛、安非他酮、奈发唑酮、曲唑酮、pheuelzine、反苯环丙胺和司来吉兰。
12.如权利要求8所述的组合物，其中所说的抗焦虑药选自阿普唑仑、氯氮
、氯硝西泮、氯氮、地西泮、哈拉西泮、劳拉西泮、奥沙西泮、普拉西泮、和丁螺环酮。
13.如权利要求9所述的组合物，其中所说的抗精神病药选自氯丙嗪、苯磺酸美索达嗪、硫利达嗪、马来酸醋奋乃静、氟奋乃静、奋乃静、三氟拉嗪、氯普噻吨、替沃噻吨、氯氮平、氟哌啶醇、洛沙平、吗茚酮、匹莫齐特、和利培酮。
14.如权利要求10所述的组合物，其中所说的抗肥胖药选自芬氟拉明、右芬氟拉明、西布曲明、安非他酮、氟西汀、芬特明、苯丙胺、去氧麻黄碱、右苯丙胺、苄非他明、苯甲曲秦、芬美曲秦、安非拉酮、马吲哚和苯丙醇胺。
15.权利要求1的各自具有至多5％w/w的相应的(-)-对映体的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐在制备用于治疗或预防患者抑郁症复发的药物方面的用途。
16.如权利要求15所述的用途，其中所说的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐具有至多2％w/w的相应的(-)-对映体。
17.如权利要求15所述的用途，其中所说的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐具有至多1％w/w的相应的(-)-对映体。
18.如权利要求15所述的用途，其中所说的抑郁症选自内因性抑郁症、单极性抑郁症、运动阻抑性抑郁症、激越性抑郁症、两极性抑郁症、产后抑郁症、伴有焦虑的抑郁症、伴有强迫症的抑郁症、伴有可引起癫痫发作的疾病的抑郁症、精神抑郁症、季节性情感病症、昼间心境变化、与绝经有关的抑郁症、与医学疾病有关的抑郁症、与酒精有关的抑郁症、以及与物质滥用有关的抑郁症。
19.如权利要求16所述的用途，其中所说的抑郁症选自内因性抑郁症、单极性抑郁症、运动阻抑性抑郁症、激越性抑郁症、两极性抑郁症、产后抑郁症、伴有焦虑的抑郁症、伴有强迫症的抑郁症、伴有可引起癫痫发作的疾病的抑郁症、精神抑郁症、季节性情感病症、昼间心境变化、与绝经有关的抑郁症、与医学疾病有关的抑郁症、与酒精有关的抑郁症、以及与物质滥用有关的抑郁症。
20.如权利要求17所述的用途，其中所说的抑郁症选自内因性抑郁症、单极性抑郁症、运动阻抑性抑郁症、激越性抑郁症、两极性抑郁症、产后抑郁症、伴有焦虑的抑郁症、伴有强迫症的抑郁症、伴有可引起癫痫发作的疾病的抑郁症、精神抑郁症、季节性情感病症、昼间心境变化、与绝经有关的抑郁症、与医学疾病有关的抑郁症、与酒精有关的抑郁症、以及与物质滥用有关的抑郁症。
21.权利要求1的各自具有至多5％w/w的相应的(-)-对映体的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐在制备用于治疗或预防患者适于用血清素-去甲肾上腺素重吸收抑制剂治疗的焦虑症复发的药物方面的用途。
22.如权利要求21所述的用途，其中所说的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐具有至多2％w/w的相应的(-)-对映体。
23.如权利要求21所述的用途，其中所说的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐具有至多1％w/w的相应的(-)-对映体。
24.如权利要求21所述的用途，其中所说的焦虑症选自惊恐性障碍、恐慌发作、恐旷症、广泛性焦虑症、强迫观念与行为症、恐怖症和创伤后应激障碍。
25.如权利要求22所述的用途，其中所说的焦虑症选自惊恐性障碍、恐慌发作、恐旷症、广泛性焦虑症、强迫观念与行为症、恐怖症和创伤后应激障碍。
26.如权利要求23所述的用途，其中所说的焦虑症选自惊恐性障碍、恐慌发作、恐旷症、广泛性焦虑症、强迫观念与行为症、恐怖症和创伤后应激障碍。
27.权利要求1的各自具有至多5％w/w的相应的(-)-对映体的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐在制备用于治疗或预防患者适于用血清素-去甲肾上腺素重吸收抑制剂治疗的摄食障碍复发的药物方面的用途。
28.如权利要求27所述的用途，其中所说的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐具有至多2％w/w的相应的(-)-对映体。
29.如权利要求27所述的用途，其中所说的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐具有至多1％w/w的相应的(-)-对映体。
30.如权利要求27所述的用途，其中所说的摄食障碍选自神经性厌食、Binge-摄食障碍、非催泻型神经性贪食症和催泻型神经性贪食症。
31.如权利要求28所述的用途，其中所说的摄食障碍选自神经性厌食、Binge-摄食障碍；非催泻型神经性贪食症和催泻型神经性贪食症。
32.如权利要求29所述的用途，其中所说的摄食障碍选自神经性厌食、Binge-摄食障碍、非催泻型神经性贪食症和催泻型神经性贪食症。
33.权利要求1的各自具有至多5％w/w的相应的(-)-对映体的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐在制备用于治疗或预防患者适于用血清素-去甲肾上腺素重吸收抑制剂治疗的尿失禁病症复发的药物方面的用途。
34.如权利要求33所述的用途，其中所说的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐具有至多2％w/w的相应的(-)-对映体。
35.如权利要求33所述的用途，其中所说的(+)-1-(3，4-二氯苯基)-3-氮杂二环[3.1.0]己烷或其可药用的盐具有至多1％w/w的相应的(-)-对映体。
36.如权利要求33所述的用途，其中所说的尿失禁病症选自欲望性尿失禁；压迫性尿失禁、溢流性失禁、功能性失禁、神经原性失禁和前列腺切除术后的失禁。
37.如权利要求34所述的用途，其中所说的尿失禁病症选自欲望性尿失禁、压迫性失禁、溢流性失禁、功能性失禁、神经原性失禁和前列腺切除术后的失禁。
38.如权利要求35所述的用途，其中所说的尿失禁病症选自欲望性尿失禁、压迫性失禁、溢流性失禁、功能性失禁、神经原性失禁和前列腺切除术后的失禁。
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