CN101175740A - 二氢苯并呋喃衍生物和其用途 - Google Patents
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- CN101175740A CN101175740A CNA2006800167696A CN200680016769A CN101175740A CN 101175740 A CN101175740 A CN 101175740A CN A2006800167696 A CNA2006800167696 A CN A2006800167696A CN 200680016769 A CN200680016769 A CN 200680016769A CN 101175740 A CN101175740 A CN 101175740A
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Abstract
本发明涉及式(I)化合物,它们是脑5-羟色胺受体2C亚型的激动剂或部分激动剂。本发明公开式(I)或其药学上可接受的盐,在式(I)中,R1、R2、R3、R4、Rx、Ry和n如说明书中所定义。这些化合物和其组合物可用于治疗例如精神分裂症的多种中枢神经系统疾病。
Description
相关申请的交叉参考
本申请要求于2005年4月22日提交的美国临时专利申请序列号60/674150的优先权,该临时专利申请的全部内容在此引入作为参考。
技术领域
本发明涉及5-HT2C受体激动剂、制备它们的方法和它们的用途。
背景技术
精神分裂症困扰着约500万人。目前精神分裂症最普遍的治疗方法为采用非典型抗精神病药物进行治疗,它对多巴胺(D2)和5-羟色胺(5-HT2A)受体均具有拮抗作用。相对于典型抗精神病药物而言,尽管有报道称非典型抗精神病药物在疗效和副作用方面有改善,但这些化合物似乎不能充分治疗精神分裂症的所有症状并且伴有疑似的副作用,例如体重增加(Allison,D.B.等,Am.J.Psychiatry,156:1686-1696,1999;Masand,P.S.,Exp.Opin.Pharmacother.I:377-389,2000;Whitaker,R.,Spectrum Life Sciences.Decision Resources.2:1-9,2000)。
非典型抗精神病药物也能够以高亲和性与5-HT2C受体结合,并具有5-HT2C受体拮抗剂或反向激动剂的作用。体重增加为与非典型抗精神病药物(例如氯氮平和奥氮平)有关的疑似副作用,有报道5-HT2C的拮抗作用与体重增加有关。然而,众所周知的是5-HT2C受体的兴奋能够导致食物摄取和体重减少(Walsh等,Psychopharmacology 124:57-73,1996;Cowen,P.J.等,Human Psychopharmacology 10:385-391,1995;Rosenzweig-Lipson,S.等,ASPET abstract,2000)。
数个证据链都支持5-HT2C受体激动或部分激动在治疗精神分裂症中的作用。研究表明5-HT2C拮抗剂能够增加多巴胺的突触水平,因而在帕金森病动物模型中有效(Di Matteo,V.等,Neuropharmacology 37:265-272,1998;Fox,S.H.等,Experimental Neurology 151:35-49,1998)。因为精神分裂症的阳性症状与多巴胺的水平增加有关,因而与那些5-HT2C拮抗剂作用相反的化合物(例如5-HT2C激动剂和部分激动剂)应该可以降低突触多巴胺水平。最近的研究已经证明5-HT2C激动剂能够降低前额叶皮质和伏隔核中多巴胺的水平(Millan,M.J.等,Neuropharmacology 37:953-955,1998;Di Matteo,V.等,Neuropharmacology 38:1195-1205,1999;DiGiovanni,G.等,Synapse 35:53-61,2000),这些脑部区域被认为能够介导药物(如氯氮平)的重要的抗精神病作用。然而,5-HT2C激动剂不能降低纹状体中多巴胺的水平,该脑部区域与锥体外系副作用密切相关。另外,最近的研究证明5-HT2C激动剂能够降低腹侧被盖区(VTA)的放电,但在黑质区不会产生同样的情况。在与黑质纹状体通路相关的中脑边缘通路中5-HT2C激动剂的不同作用表明5-HT2C激动剂具有边缘选择性,因而可能不会产生与典型抗精神病药物相关的锥体外系副作用。
发明内容
本发明涉及5-HT2C激动剂和其用途。本发明化合物可用于,例如,治疗精神分裂症和并发的心境障碍以及精神分裂症的认知损伤。在某个具体实施方案中,本发明化合物几乎不引起与当前非典型抗精神病药物有关的体重增加。本发明化合物还用于治疗肥胖症和它的并存病(comorbidity)。
在某些具体实施方案中,本发明提供式I化合物或其药学上可接受的盐:
其中:
每个独立代表单键或双键,前提是两个基团不同时代表双键;
R1为氢、低级烷基或-C(O)R;
R为氢或低级烷基;
R2为氢、-OH或-OS(O)2OH;
R3为氢、卤素、甲基、甲氧基、-OH或-OS(O)2OH;
R4为氢、-OH或-OS(O)2OH;
Ra和Rb每个都为氢或两者一起形成氧代基团;
Rc和Rd每个都为氢或两者一起形成氧代基团;
每个Rx独立地为卤素或低级烷基;
每个Ry独立地为氢、-OH或-OS(O)2OH,其中至少R2、R4和Ry之一为-OH或-OS(O)2OH,且
n为1或2。
在某些其它具体实施方案中,本发明涉及治疗患有下列疾病的患者的方法,该方法包括给予所述患者治疗有效量的式I化合物或其药学上可接受的盐,所述疾病为:精神分裂症、精神分裂症样疾病、分裂情感性精神病、妄想症、物质诱导的精神病、L-DOPA-诱导的精神病、与阿尔茨海默氏痴呆有关的精神病、与帕金森病有关的精神病、与路易体有关的精神病、痴呆、记忆减退、与阿尔茨海默氏病有关的智力减退、双相情感障碍、抑郁症、情绪发作、焦虑症、适应障碍、进食障碍、癫痫、睡眠障碍、偏头痛、性机能失调、药物滥用、酒精和其它药物(包括咖啡因和尼古丁)成瘾、胃肠道疾病、肥胖或者与创伤、中风或脊索损伤有关的中枢神经系统缺陷。
在另外其它具体实施方案中,本发明涉及组合物,该组合物包含式I化合物或其药学上可接受的盐以及一种或多种药学上可接受的载体、赋形剂或稀释剂。
发明详述
1.化合物和定义
本发明涉及为脑5-羟色胺受体2C亚型的激动剂或部分激动剂的化合物。
文中所用的术语“低级烷基”指具有最多至4个碳原子、优选1-3个碳原子、更优选1-2个碳原子的烃链。术语“烷基”包括但不限于例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基的直链或支链烃链。
文中所用的术语“卤素”或“卤代”指氯、溴、氟或碘。
文中所用的“有效量”和“治疗有效量”指,当给予患者时,对治疗该患者患有的病症至少是部分有效的式I化合物的量。所述病症包括但不限于精神分裂症、分裂情感性精神病、精神分裂症样疾病、L-DOPA-诱导的精神病、双相情感障碍、肥胖症、强迫症、抑郁症、惊恐病、睡眼障碍、进食障碍和癫痫。
术语“药学上可接受的盐”指用有机或无机酸处理式I化合物而得到的盐,所述有机或无机酸例如为乙酸、乳酸、柠檬酸、肉桂酸、酒石酸、琥珀酸、富马酸、马来酸、丙二酸、扁桃酸、苹果酸、草酸、丙酸、盐酸、氢溴酸、磷酸、硝酸、硫酸、羟乙酸、丙酮酸、甲磺酸、乙磺酸、甲苯磺酸、水杨酸、苯甲酸或同样已知的可接受的酸。在某些具体实施方案中,本发明提供式I化合物的盐酸盐。
文中所用的术语“患者”指哺乳动物。在某些具体实施方案中,文中所用的术语“患者”指人类。
文中所用的术语“给药”指或者直接将化合物或组合物给药至患者,或者将化合物的前药衍生物或类似物给药至患者,该前药衍生物或类似物在患者体内生成等量的活性化合物或物质。
文中所用术语“治疗”指部分或完全减轻、抑制、预防、改善和/或缓解病症。
文中所用术语“患有”指患者被诊断或被怀疑带有的一种或多种病症。
2.示例化合物的描述:
在某些具体实施方案中,本发明涉及式I化合物和其药学上可接受的盐:
其中:
每个独立代表单键或双键,前提是两个基团不同时代表双键;
R1为氢、低级烷基或-C(O)R;
R为氢或低级烷基;
R2为氢、-OH或-OS(O)2OH;
R3为氢、卤素、甲基、甲氧基、-OH或-OS(O)2OH;
R4为氢、-OH或-OS(O)2OH;
Ra和Rb每个都为氢或两者一起形成氧代基团;
Rc和Rd每个都为氢或两者一起形成氧代基团;
每个Rx独立地为卤素或低级烷基;
每个Ry独立地为氢、-OH或-OS(O)2OH,其中至少R2、R4和Ry之一为-OH或-OS(O)2OH,且
n为1或2。
一般地,如上面所定义,每个独立代表单键或双键,前提是两个基团不同时代表双键。Ra和Rb每个都为氢或两者一起形成氧代基团;Rc和Rd每个都为氢或两者一起形成氧代基团。应当理解,当基团代表双键时,相应的Ra和Rb对,或Rc和Rd对必须代表单个氢。这是因为考虑到式I化合物的价键许可。
在某些具体实施方案中,式I中的n为1。
在某些具体实施方案中,式I中的n为2。
一般,如上面所定义,式I中的R1基团为氢、低级烷基或-C(O)R,其中R为氢或低级烷基。在某些具体实施方案中,式I中的R1基团为氢。在其它具体实施方案中,式I中的R1基团为低级烷基。在另外其它具体实施方案中,式I中的R1基团为甲基。根据另一方面,式I中的R1基团为-C(O)R,其中R为氢或甲基。
在某些具体实施方案中,式I中的R3基团为氟或氯。在其它具体实施方案中,式I中的R3基团为氟。
在某些具体实施方案中,式I中的R2基团为-OH,且R4基团为氢。在其它具体实施方案中,R2基团为氢,且式I中的R4基团为-OH。在另外其它具体实施方案中,式I中的R2和R4基团都为-OH。
在某些具体实施方案中,式I中的每个Rx基团独立地为卤素或甲基。在其它具体实施方案中,式I中的每个Rx基团独立地为卤素基团。在另外其它具体实施方案中,式I中的两个Rx基团都为氯。
在某些具体实施方案中,至少式I中的R2、R4和Ry基团之一为-OS(O)2OH。根据另一方面,本发明提供了式I-a、I-b、I-c、I-d和I-e中的任一式的化合物或其药学上可接受的盐:
其中,R2、R4、Rx和Ry中的每一个如上面以及在所述的类或亚类中所定义。
在某些具体实施方案中,式I中的基团为双键。在其它具体实施方案中,本发明提供了式I-f化合物或其药学上可接受的盐:
其中,R2、R3、R4、Rx和Ry中的每一个如上面以及在所述的类或亚类中所定义。
根据本发明的一个方面,Ra和Rb一起形成氧代基团。根据另一方面,Rc和Rd一起形成氧代基团。在某些具体实施方案中,本发明提供了式I-g和式I-h的化合物或其药学上可接受的盐:
其中,R2、R3、R4、Rx和Ry中的每一个如上面以及在所述的类或亚类中所定义。
在其它具体实施方案中,本发明提供了式I’化合物或其药学上可接受的盐:
其中,R1、n、R2、R3、R4、Rx和Ry中的每一个如上面以及在所述的类或亚类中所定义。
根据另一具体实施方案,本发明提供了式II化合物或其药学上可接受的盐:
其中,Rx、Ry和R4中的每一个如上面以及在所述的类或亚类中所定义。
根据另一具体实施方案,本发明提供了式III化合物或其药学上可接受的盐:
其中,Rx、Ry和R2中的每一个如上面以及在所述的类或亚类中所定义。
根据另一具体实施方案,本发明提供了式IV化合物或其药学上可接受的盐:
其中,Rx、R2和R4中的每一个如上面以及在所述的类或亚类中所定义。
根据另一具体实施方案,本发明提供了式V化合物或其药学上可接受的盐:
其中,Rx、R2和R4中的每一个如上面以及在所述的类或亚类中所定义。
根据另一具体实施方案,本发明提供了式VI化合物或其药学上可接受的盐:
其中,Rx、R2和R4中的每一个如上面以及在所述的类或亚类中所定义。
本发明的化合物包含不对称碳原子,因此会产生立体异构体,包括对映异构体和非对映异构体。因此,本发明还涉及所有这些立体异构体以及立体异构体的混合物。在整个本申请中,当没有指明不对称中心的绝对构型时,本发明的产物的名称将包括单独的立体异构体及立体异构体的混合物。在本发明的某些实施方案中,优选具有R绝对构型的化合物。
在某些具体实施方案中,本发明提供了式Ia或Ib化合物或其药学上可接受的盐:
其中,R1、R2、R3、R4、Rx和Ry中的每一个如上面对式I化合物以及所述的类或亚类中所定义的。
根据另一具体实施方案,本发明提供了式Ic或Id化合物或其药学上可接受的盐:
其中,R1、R2、R4、Rx和Ry中的每一个如上面对式I化合物以及所述的类或亚类中所定义的。
当优选一种对映异构体时,在一些具体实施方案中,可以以基本不含它的相应的对映异构体的形式提供该优选的对映异构体。因此,一种基本上不含相应的对映异构体的对映异构体指通过分离技术分离或者制备的不含相应的对映异构体的化合物。如文中所用,“基本上不含”指化合物主要由占据绝大比例的一种对映异构体构成。在某些具体实施方案中,该化合物由至少约90%(重量)的优选对映异构体构成。在本发明的其它具体实施方案中,该化合物由至少约99%(重量)的优选对映异构体构成。通过本领域技术人员公知的任何方法,可以从外消旋混合物中分离出优选的对映异构体,所述方法包括手性高效液相色谱(HPLC)及手性盐的形成或结晶,或者可以通过文中所述的方法制备优选对映异构体。见,例如Jacques等人,对映体、外消旋物和拆分(Enantiomers,Racemates andResolutions)(Wiley Interscience,New York,1981);Wilen,S.H.等人,四面体(Tetrahedron)33:2725(19777);Eliel,E.L.碳化合物的立体化学(Stereochemistry ofCarbon Compounds)(McGraw-Hill,NY,1962);Wilen,S.H.拆分试剂表和光学拆分(Tables of Resolving Agents and Optical Resolutions)p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)。
可以理解,本发明化合物可能存在阻转异构体。因此,本发明包括如吐面所定义的式I化合物以及所述的类和亚类的阻转异构体。
式I的示例化合物列在下面的表1中。
表1:式I的示例化合物:
除上面所述的化合物外,本发明还提供了作为如文中所定义的式I的5-HT2C激动剂或部分激动剂的前药的式VII化合物。这些化合物为通式VII的化合物或其药学上可接受的盐:
其中,每个独立代表单键或双键,前提是两个基团不同时代表双键;
R1为氢、-C(O)R、-Glu、-C(O)Glu或-C(O)OGlu;
R为氢或低级烷基;
R2为氢、-OH、-OS(O)2OH或-OGlu;
R3为氢、卤素、甲基、甲氧基、-OH、-OS(O)2OH或-OGlu;
R4为氢、-OH、-OS(O)2OH或-OGlu;
Ra和Rb每个都为氢或两者一起形成氧代基团;
Rc和Rd每个都为氢或两者一起形成氧代基团;
每个Rx独立地为卤素或低级烷基;
R5独立地为氢、-OH、-OS(O)2OH或-OGlu;
每个Glu为葡糖苷酸基;且
n为1或2;
前提是至少R1、R2、R4和R5之一包含葡糖苷酸基。
如上面一般定义的,每个独立代表单键或双键,前提是两基团不同时代表双键;Ra和Rb每个都为氢或两者一起形成氧代基团;且Rc和Rd每个都为氢或两者一起形成氧代基团;应当理解,当基团代表双键时,相应的Ra和Rb对,或Rc和Rd对,必须代表单个氢。这是因为考虑到式VII化合物的价键许可。
本发明化合物还用于研究生理和病理现象中的5-HT2C激动剂或部分激动剂,以及用于5-HT2C激动剂或部分激动剂的比较评价。
本发明化合物作为5-HT2C激动剂或部分激动剂的代谢研究结果而被发现。尽管不希望受任何理论的限制,但是认为本发明化合物为5-HT2C激动剂或部分激动剂的代谢产物,例如2004年10月21日提交的序列号10/970714的美国专利申请和PCT公开号WO2005/044812中所描述的,其全部内容在此引入作为参考。因此,本发明化合物还可用于评价这些5-HT2C激动剂或部分激动剂的体内或体外作用。
如文中所用,术语“前药”指需要在体内进行转化以释放活性药物的母药分子的衍生物,与母药分子相比,它有改善的物理和/或递送特性。前药被设计用于在药学上和/或药物代谢动力学上提高与母药分子相关的基本性质。前药的优势在于它的物理性质,例如,与母药相比,就胃肠外给药而言,可以提高生理pH下的水溶性;或提高消化道的吸收;或可以提高长期存放的药物稳定性。最近几年,人们已开发了用于设计前药的几种类型的生物可逆衍生物。对于含有羧基或羟基官能团的药物,用酯作为前药类型在本领域中是公知的,例如在“药物设计和药物相互作用的有机化学(The Organic Chemistry of Drug Design and DrugInteraction)”Richard Silverman,Academic Press出版(1992)中描述的。
如文中所用,术语“葡糖苷酸基”指具有下面结构的基团:
其中所绘的波浪线指与式VII化合物的连接位点。
在某些具体实施方案中,式VII中的n为1。
在其它具体实施方案中,式VII中的n为2。
如上面一般定义,式VII中的R1基团为氢、-Glu或-C(O)OGlu。在某些具体实施方案中,式VII中的R1基团为氢。在其它具体实施方案中,式VII中的R1基团为-Glu。在另外其它具体实施方案中,式VII中的R1基团为-C(O)OGlu。
在某些具体实施方案中,式VII中的R3基团为氟或氯。在其它具体实施方案中,式VII中的R3基团为氟。
在某些具体实施方案中,式VII中的R2基团为-OH且R4基团为氢。在其它具体实施方案中,R2基团为氢,并且式VII中的R4基团为-OH。在另外其它具体实施方案中,式VII中的R2和R4基团都为-OH。
在某些具体实施方案中,式VII中的R2基团为-OGlu且R4基团为氢。在其它具体实施方案中,R2基团为氢,并且式VII中的R4基团为-OGlu。
在某些具体实施方案中,式VII中的每个Rx独立地为卤素或甲基。在其它具体实施方案中,式VII中的每个Rx独立地为卤素基团。在另外其它具体实施方案中,两个Rx都为氯。
根据另一具体实施方案,本发明提供式VIII化合物或其药学上可接受的盐:
其中,Rx、R1和R5中的每一个如上面以及所述的类或亚类中所定义。
根据另一具体实施方案,本发明提供式IX、IXa或IXb的化合物或其药学上可接受的盐:
其中,Rx、R2、R4和R5中的每一个如上面以及所述的类或亚类中所定义。
根据另外的具体实施方案,本发明提供了式X化合物和其药学上可接受的盐:
其中,Rx、R1、R2和R4中的每一个如上面以及所述的类或亚类中所定义。
3.提供本发明化合物的通用方法:
可以根据2004年10月21日提交的序列号10/970714的美国专利申请(WO2005/044812)中详细描述的方法,制备本发明化合物,上述专利申请的全部内容在此引入作为参考。通过2004年10月21日提交的序列号为60/621023的美国临时专利申请和2004年10月21日提交的序列号为60/621024的美国临时专利申请中所描述的立体选择性方法,可以制备本发明的立体异构体,上述两临时专利申请的全部内容在此引入作为参考。
一般通过本领域普通技术人员公知的方法制备式VII化合物,例如,通过下面通用流程图中所描述的方法。
流程图1
上面的流程图1描述了制备式VIII化合物的通用方法。如上面所示,用适当保护的且具有能够发生所需偶联的适当的离去基团的Glururonidate化合物2处理羟基化合物1,形成3。就式2化合物而言,PG2、PG3和PG4为适当的羟基保护基。适当的羟基保护基在本领域中是公知的,包括在有机合成中的保护基(Protecting Groups in OrganicSynthesis),T.W.Greene和P.G.M.Wuts,第三版,John Wiley & Sons,1999中详细描述的羟基保护基,该书中的全部内容在此引入作为参考。适当的羟基保护基的示例另外包括但不限于酯、烯丙醚、硅醚、烷基醚、芳烷基醚和烷氧烷基醚。这些酯的示例包括甲酸酯、乙酸酯、碳酸酯和磺酸酯。具体示例包括甲酸酯、苯甲酰甲酸酯、氯乙酸酯、三氟乙酸酯、甲氧基乙酸酯、三苯甲氧基乙酸酯、对-氯苯氧基乙酸酯、3-苯基丙酸酯、4-氧代戊酸酯、4,4-(亚乙基二硫代)戊酸酯、新戊酸酯(三甲基乙酰基)、巴豆酸酯、4-甲氧基-巴豆酸酯、苯甲酸酯、对-苄基(benyl)苯甲酸酯、2,4,6-三甲基苯甲酸酯;碳酸酯,例如甲基、9-芴基甲基、乙基、2,2,2-三氯乙基、2-(三甲硅基)乙基、2-(苯磺酰基)乙基、乙烯基、烯丙基和对-硝基苄基的碳酯酯。所述硅醚的示例包括三甲基硅基、三乙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、三异丙基硅基和其它三烷基硅基醚。烷基醚包括甲基、苄基、对甲氧基苄基、3,4-二甲氧基苄基、三苯甲基、叔丁基、烯丙基和烯丙氧羰基醚或衍生物。烷氧基烷基醚包括缩醛,例如甲氧甲基、甲硫甲基、(2-甲氧乙氧)甲基、苄氧甲基、β-(三甲硅基)乙氧甲基和四氢吡喃基醚。芳基烷基醚的示例包括苄基、对-甲氧基苄基(MPM)、3,4-二甲氧基苄基、邻-硝基苄基、对硝基苄基、对卤代苄基、2,6-二氯苄基、对-氰基苄基、2-和4-吡啶甲基。
应当理解,PG2、PG3和PG4可以是不同的或者相同的。在某些具体实施方案中,PG2、PG3和PG4是相同的,因此它们可以用相同的条件脱除。这些保护基的脱除,也称为“脱保护”,可以用本领域公知的方法完成,包括有机合成中的保护基(Protecting Groups in Organic Synthesis),T.W.Greene和P.G.M.Wuts,第三版,John Wiley & Sons,1999中详细描述的方法。
就式2化合物而言,PG1基团是适当的羧基保护基。这些保护基在本领域是公知的,并且包括有机合成中的保护基(Protecting Groups inOrganic Synthesis),T.W.Greene和P.G.M.Wuts,第三版,John Wiley &Sons,1999中详细描述的羧基保护基,该书全部内容在此引入作为参考。适当的羧基保护基另外包括但不限于取代的C1-6脂肪族酯、任选取代的芳基酯、甲硅烷基酯、活化的酯、酰胺、酰肼等。这些酯基的示例包括甲基、乙基、丙基、异丙基丁基、异丁基、苄基和苯基,其中每个基团被任选取代。
将glucoronidate化合物2与化合物1偶联后,得到被保护的化合物3。然后,将该化合物脱保护,生成式VIII化合物。
应当明白,在某些情况下,最好同时脱除所有保护基。在这些情况下,应当对PG1、PG2、PG3和PG4作如此选择,即使每一保护基都在相同条件下脱除,例如通过酸或碱处理、还原或紫外线光照,仅举几例。这些保护基的选择对本领域的普通技术人员而言是公知的。
可以按与流程图1中描述的基本相似的方法、上述的方法和本领域普通技术人员公知的方法,制备式IX和X化合物。
4.用途、制剂和给药
本发明化合物对脑5-羟色胺受体的2C亚型有亲和性以及激动剂或部分激动剂活性,因此可以用于治疗多种病症和/或缓解一种或多种相关的症状。这些与调节脑5-羟色胺受体的2C亚型有关的病症在下面进行了详细描述。本发明认为,本发明化合物可以快速起作用。另外,本发明化合物没有性功能障碍副作用。
如文中所述,本发明化合物可用于治疗一种或多种精神病疾病,而不引起糖尿病病变。糖尿病病变是与非典型抗精神病药物相关的副作用。尽管不希望受任何理论的束缚,但是认为与非典型抗精神病药物相关的糖尿病病变,是由于这些药物是5-HT2C拮抗剂导致的。如文中所述,本发明化合物为5-HT2C激动剂,或部分激动剂,因此,本发明化合物与糖尿病病变无关。
本发明化合物用于治疗一种或多种精神病疾病,例如包括妄想型、错乱型、紧张型、未分化型的精神分裂症、精神分裂症样疾病、分裂情感性精神病、妄想症、物质诱导的精神病和其它没有特别指出的精神病;L-DOPA-诱导的精神病、与阿尔茨海默氏痴呆有关的精神病、与帕金森病有关的精神病、与路易体有关的精神病。
本发明化合物还用于治疗与精神分裂型精神病相关的症状,包括所谓的精神分裂症的 “阳性”和“阴性”症状。这些症状包括例如精神病人中的幻觉、妄想、偏执、焦虑、激动、过度攻击、紧张、思维障碍、感情迟钝、社交或情感退缩。通常与精神病相关的其它症状包括认知障碍或例如缺乏专注力和功能障碍的认知减退、抑郁、自杀、代谢综合征和药物滥用。因此,本发明的另一具体实施方案提供了治疗一种或多种与精神病相关的症状的方法。
在其它具体实施方案中,本发明化合物用于治疗焦虑症,例如恐慌发作、恐旷症、惊恐病、特定性恐惧症、社交恐惧症、社交焦虑症、强迫症、创伤后应激障碍、急性应激障碍、广泛性焦虑症、分离焦虑症、物质诱导的焦虑症和其它没有特别指出的焦虑症。
根据另一具体实施方案,本发明化合物可用于治疗双相情感障碍。所述双相情感障碍包括I型双相情感障碍、II型双相情感障碍和循环情感障碍(cyclothymic disorder);双相躁狂、痴呆和有精神病特征的抑郁。本发明化合物还用于治疗(包括预防)可能出现在双相抑郁和双相躁狂之间的循环。
前面所述的精神障碍的更加完整的描述见精神障碍的诊断和统计手册(Diagnostic and Statistical Manual of Mental Disorders)第四版,Washington,DC,American Psychiatric Association(1994),将其全部内容在此引入作为参考。
在某些具体实施方案中,本发明化合物与一种或多种抗精神病药物共同给药。所述抗精神病药物在本领域中是公知的,包括氯氮平(例如Clozaril)、利培酮(例如Risperidal)、奥氮平(例如Zyprexa)、喹硫平(例如Seroquel)、齐拉西平(例如Geodon)、阿立哌唑、氨磺必利、氯丙嗪、氟奋乃静、氟哌啶醇(例如Haldol)、洛沙平、美索达嗪、吗茚酮、奋乃静、匹莫齐特、思瑞康、舒必利、硫利哒嗪、替沃噻吨、三氟拉嗪和bifeprunox,在此仅指出几例。
本发明化合物与一种或多种抗精神病药物的组合产品可用于治疗例如包括妄想型、错乱型、紧张型、未分化型的精神分裂症、精神分裂症样疾病、分裂情感性精神病、妄想症、物质诱导的精神病和其它没有特别指出的精神病;L-DOPA-诱导的精神病;与阿尔茨海默氏痴呆有关的精神病;与帕金森病有关的精神病;与路易体有关的精神病;双相情感障碍,例如包括I型双相情感障碍、II型双相情感障碍和循环情感障碍;双相躁狂、痴呆和有精神病特征的抑郁。在一些具体实施方案中,这些组合物还用于治疗双相情感障碍,包括例如治疗在双相抑郁和双相躁狂之间的循环。
在其它具体实施方案中,本发明化合物与抗精神病药物一起给药提供了抗精神病药物的益处,同时消除或最小化某些副作用(例如静坐不能、张力障碍、帕金森病运动障碍和迟发性运动障碍等),当单独服用抗精神病药物时,通常可以观察到上述副作用。
在其它具体实施方案中,本发明化合物可用于治疗一种或多种抑郁症,例如重性抑郁障碍、季节性情感障碍、心境恶劣障碍、物质诱导的情绪障碍、其它没有特别指出的抑郁症并可治疗难治性抑郁症。
本发明的另一方面提供了用于治疗一种或多种例如重抑郁发作、躁狂发作、混合发作和轻躁狂发作的情绪发作;及适应障碍例如伴有焦虑和/或抑郁情绪的适应障碍的方法。
本发明化合物还用于治疗与抑郁症相关的症状,包括例如神经性疼痛和性功能障碍的躯体症状。其它躯体症状包括绝望、无助、焦虑和烦恼、有或无认知损伤客观征兆的记忆障碍、快感缺失(anhedonia)、行动迟缓、易怒、对个人生活自理缺少兴趣,例如不很好坚持医药和饮食方案。
在某些具体实施方案中,本发明提供了治疗与抑郁相关的性功能障碍的方法。在其它具体实施方案中,本发明提供了治疗与给药5-羟色胺重摄取抑制剂(SRI)(用于治疗抑郁和其它病症)相关的性功能障碍的方法。这些治疗性功能障碍的方法在下面进行了详细描述。
在某些具体实施方案中,本发明化合物与一种或多种抗抑郁药组合给药。适当的抗抑郁药包括,例如5-羟色胺重摄取抑制剂(SRIs)、去甲肾上腺素重摄取抑制剂(NRIs)、5-羟色胺和去甲肾上腺素重摄取的抑制剂(SNRIs)、单胺氧化酶抑制剂(MAOIs)、单胺氧化酶的可逆抑制剂(RIMAs)、磷酸二酯酶-4(PDE4)抑制剂、促肾上腺皮质激素释放因子(CRF)拮抗剂、α-肾上腺素受体拮抗剂或包括非典型抑郁药的其它化合物。与本发明化合物组合给药的另外的抑郁药包括三重摄取(triple uptake)抑制剂,例如DOV216303和DOV21947;褪黑激素激动剂,例如agomelotine;上神经递质阻滞剂(SNUBs;例如GlaxoSmithKline和Neurosearch的NS-2389;Sepracor的(R)-DDMA)和/或P物质/神经激肽受体拮抗剂(例如,Merck的aprepitant/MK-869;Novartis的NKP-608;Pfizer的CPI-122721;Roche的R673;Takeda的TAK637;和GlaxoSmithKline的GW-97599)。
与本发明化合物组合给药的另一类抗抑郁药为去甲肾上腺素能和特异性5-羟色胺能抗抑郁药(NaSSAs)。NaSSAs的适当的示例为mirtazepine。
与本发明化合物组合给药的适当的NRIs包括叔胺三环抗抑郁药和仲胺三环抗抑郁药。适当的叔胺三环抗抑郁药包括阿米替林、氯丙咪嗪、多塞平、丙咪嗪(见美国专利2554736,将其全部内容在此引入作为参考)和三甲丙咪嗪及它们的药学上可接受的盐。适当的仲胺三环抗抑郁药包括:阿莫沙平、地昔帕明、马普替林、去甲替林和普罗替林及它们的药学上可受的盐。
与本发明化合物组合给药的另外的NRI为瑞波西汀(EdronaxTM;2-[α-(2-乙氧基)苯氧基-苄基]吗啉,通常以外消旋物给药;见美国专利4229449,将其全部内容在此引入作为参考)。
与本发明化合物组合给药的适当的SSRIs包括:西酞普兰(1-[3-(二甲氨基)丙基]-(4-氟苯基)-1,3-二氢-o-5-异苯并呋喃甲腈;见美国专利4136193;Christensen等人,欧洲药理学杂志(Eur.J.Pharmacol.)41:153,1977;Dufour等人,国际临床精神药理学(Int.Clin.Psychopharmacol.)2:225,1987;Timmerman等人,ibid.,239,将上述所有文献的全部内容在此引入作为参考);氟西汀(N-甲基-3-(p-三氟甲基苯氧基)-3-苯基丙胺,以盐酸盐形式和它的两种异构体的外消旋混合物形式上市;见,例如美国专利4314081;Robertson等人,药物化学杂志(J.Med.Chem.),31:1412,1988,将上述文献在此引入作为参考);混合的氟西汀/奥氮平;氟伏沙明(5-甲氧基-1-[4-(三氟甲基)苯基]-1-戊酮O-(2-氨基乙基)肟;见美国专利4085225;Claassen等人,英国药理学杂志(Brit.J.Pharmacol)60:505,1977;De Wilde等人,情感障碍杂志(J.Affective Disord.)4:249,1982;Benfield等人,药物(Drugs)32:313,1986,将上述文献全部内容在此引入作为参考);帕罗西汀(反式-(-)-3-[(1,3-苯并间二氧杂环戊烯-5-基氧基)甲基]-4-(4-氟苯基)哌啶;见美国专利3912743;美国专利4007196;Lassen,欧洲药理学杂志,47:351,1978;Hassan等人,英国临床药理学杂志(Brit.J.Clin.Pharmacol.),19:705,1985;Laursen等人,Acta Psychiat.Scand.71:249,1985;Battegay等人,神经精神病(Neuropsychobiology),13:31,1985,将所有文献的全部内容在此引入作为参考);舍曲林,(1S-顺式)-4-(3,4-二氯苯基)-1,2,3,4-四氢-N-甲基-1-萘胺盐酸盐;见美国专利4536518,将其全部内容在此引入作为参考);依他普仑(见美国专利RE34712);和其药学上可接受的盐。
与本发明化合物组合给药的适当的MAOIs包括异卡波肼、苯乙肼、司来吉兰和反苯环丙胺及它们药学上可接受的盐。
与本发明化合物组合给药的适当的可逆MAOIs包括:吗氯贝胺(4-氯-N-[2-(4-吗啉基)-乙基]苯甲酰胺;见美国专利4210754,将其全部内容在此引入作为参考),司来吉兰和它们药学上可接受的盐。
与本发明化合物组合给药的适当的SNRIs包括文拉法辛(见美国专利4535186,将其全部内容在此引入作为参考;还见美国专利5916923、6274171、6403120、6419958、6444708,将上述所有文献的全部内容在此引入作为参考),和其药学上可接受的盐及类似物,包括O-脱甲基文拉法辛琥珀酸盐;米那普仑(N,N-二乙基-2-氨基甲基-1-苯基环丙烷甲酰胺;见美国专利4478836;Moret等人,神经药理学,24:1211-19,1985,将所有文献的全部内容在此引入作为参考);萘法唑酮(可从Bristol Myers Squibb和Dr.Reddy Labs Inc.得到);度洛西汀;和它们的药学上可接受的盐。
与本发明化合物组合给药的适当的CRF拮抗剂包括在序列号为WO94/13643、WO 94/13644、WO 94/13661、WO 94/13676和WO 94/13677的国际专利说明书中详细描述的那些化合物。
与本发明化合物组合给药的适当的非典型抗抑郁药包括丁氨苯丙酮(WellbutrinTM;(.+-.)-1-(3-氯苯)-2-[(1,1-二甲基乙基)氨基]-1-丙酮)、锂、萘法唑酮、曲唑酮和维络沙素,及它们的药学上可接受的盐。另一适当的非典型抗抑郁药为西布曲明。
与本发明化合物组合给药的具体抗抑郁药包括但不限于,阿地唑仑、阿拉丙酯、阿奈螺酮、阿米庚酸、阿米替林、阿米替林/氯氮混合物、阿莫沙平、阿瑞匹坦、阿替美唑、azamianserin、巴嗪普令、苯呋拉林、二苯美仑、binodaline、比培那醇、溴法罗明、buproprion、卡罗沙酮、西克拉明、氰帕明、西莫沙酮、西酞普兰、氯美醇、氯米帕明、氟伏胺、氮尼尔、丹醇、地美替林、地昔帕明、O-脱甲基文拉法辛、二苯西平、二苯噻庚英、多塞平、屈昔多巴、度洛西汀、elzasonan、乙非辛、依他匹隆、依他普仑、艾司唑仑、依托哌酮、非莫西汀、酚加宾、非唑拉明、氟曲辛、氟西汀、氟伏沙明、吉哌隆、咪唑克生、丙米嗪、吲达品、茚洛秦、依普吲哚、异卡波肼、左丙替林、利托西汀、洛非帕明、马普替林、美地沙明、美他帕明、美曲吲哚、米安色林、米那普仑、米那普令、米氮平、码氯贝酯、孟替瑞林、奈拉西坦、奈福泮、nefozodine、nemititide、尼亚拉胺、诺米芬辛、诺氟西汀、去甲替林、奥替瑞林、奥沙氟生、帕罗西汀、苯乙肼、匹那西泮、pirlindone、苯噻啶、普罗替林、瑞波西汀、利坦色林、罗巴佐坦、咯利普兰、司来吉兰、sercloremine、舍曲林、司普替林、西布曲明、舒布硫胺、舒必利、舒奈吡琼、替尼沙秦、托扎啉酮、thymoliberin、噻奈普汀、替氟卡宾、托芬那辛、托非索泮、托洛沙酮、托莫西汀、反苯环丙胺、曲唑酮、trimiprimine、文拉法辛、维拉必利、维拉佐酮、维洛沙嗪、维喹啉、齐美利定和zometrapine和它们的药学上可接受的盐,以及圣约翰草(John’s wort herb)或Hypencuin perforatum或它们的提取物。
与本发明化合物组合给药的适当类型的抗焦虑药包括5-HT1A激动剂或拮抗剂,特别是5-HT1A部分激动剂;神经激肽受体(NK)拮抗剂(例如沙瑞度坦和奥沙奈坦)和促肾上腺素皮质激素释放因子(CRF)拮抗剂。可以在本发明中使用的适当5-HT1A受体激动剂或部分激动剂包括,特别是5-HT1A受体部分激动剂的丁螺环酮、氟辛克生、吉哌隆和伊沙匹隆及它们的药学上可接受的盐。具有5-HT1A受体拮抗剂/部分激动剂活性的化合物的示例为吲哚洛尔。新的5-HT1A激动剂variza、阿奈螺酮、吉哌隆、舒奈吡琼、MKC242、维拉佐酮、依他匹隆和来自Organon的ORG12962;新的5-HT1A拮抗剂例如罗巴佐坦;新的5-HT1B激动剂例如elzasonan;新的5HT2拮抗剂例如YM-992(来自Yamanouchi Pharmaceuticals)和奈米非肽(nemifitide)。
根据本发明,本发明的组合产品可以与一种或多种用于治疗抑郁或其它情绪障碍的其它药物一起给药。或者,本发明的组合产品可以与一种或多种其它药物一起给药,所述药物有治疗哺乳动物存在的任何其它症状或病况的活性,不管该症状或病况与该哺乳动物患有的抑郁或情绪障碍相关或不相关。这些药物的示例包括,例如,抗血管生成药物、抗肿瘤药物、抗糖尿病药物、抗感染药物、止痛药物、抗精神病药物、胃肠药物等或它们的组合。
可用于本发明的实施的其它药物包括,例如,通常用于提高抗抑郁药的疗效的辅助治疗药物。这些辅助药物可以包括例如,情绪稳定剂(例如锂、丙戊酸、卡马西平等);吲哚咯尔、兴奋药(例如利他林、右苯丙胺等);或甲状腺增加药(例如T3);抗精神病药物、抗焦虑药物(例如苯并二氮杂类)和/或减轻性功能障碍的药物(例如丁螺环酮,其还有抗焦虑作用;多巴胺能药物,例如金刚烷胺、普拉克索、安非他酮等)。
作为5-HT2c调节剂,本发明化合物可用于治疗许多病症。这些病症包括月经前综合征(PMS)、月经前焦虑障碍(PMDD)、例如帕金森病的运动(motion or motor)障碍;慢性疲劳综合征;神经性厌食症、睡眠障碍(例如睡眠呼吸暂停)和缄默症。
月经前焦虑障碍或PMDD是一种严重形式的PMS。类似于PMS,PMDD通常在月经发生的前一星期中出现,并在几天后消失。PMDD的特征为严重的每月的情绪不稳和干扰日常生活(特别是女子与她的家人和朋友关系)的身体症状。PMDD症状远远超过被认为是易控制或正常的月经前症状。
PMDD是症状的组合,可能包括易怒、抑郁情绪、焦虑、睡眠障碍、精神集中困难、怒气爆发、乳房触痛和胃气胀。诊断标准重点在于抑郁情绪、焦虑、情绪不稳或易怒性。该病症影响高达20分之一的有规则月经周期的美国女性。根据另一具体实施方案,本发明提供治疗一种或多种与PMDD相关的症状的方法。
在当前,选择性5-羟色胺重摄取抑制剂(SSRIs)为治疗与PMDD相关的症状的优选方法。根据另一方面,本发明提供了通过将式I化合物与SSRI组合给药,治疗PMDD或与PMDD相关的一种或多种症状的方法。在某些具体实施方案中,SSRI为氟西汀、文拉法辛、帕罗西汀、度洛西汀或舍曲林。
根据另一具体实施方案,本发明化合物可用于治疗多种进食障碍。在某些具体实施方案中,进食障碍为饮食过量、贪食症或神经性厌食症。在某些具体实施方案中,本发明化合物可用于治疗胃肠病症,例如胃肠活力或肠推进障碍。本发明化合物还可以用于减肥或控制体重(例如减少卡路里或食物摄入,和/或抑制食欲)。这些方法对治疗肥胖和其引起的并存病特别有效,所述并存病包括糖尿病尿崩症、II型糖尿病、心血管疾病、高血压、高血脂症、中风、骨性关节炎、睡眠呼吸暂停、胆囊疾病、痛风、某些癌症、某些不育症和早期死亡。
在某些具体实施方案中,将本发明化合物与一种或多种抗肥胖药一起给药。这些抗肥胖药在本领域中是公知的,包括载脂蛋白-B分泌物/微粒体甘油三酯转运蛋白(apo-B/MTP)抑制剂、11β-羟基甾类化合物脱氢酶-1(11β-HSD 1型)抑制剂、PYY3.36和其类似物、MCR-4激动剂、胆囊收缩素-A(CCK-A)激动剂、单胺重摄取抑制剂(例如西布曲明)、拟交感神经药、R3肾上腺素能受体激动剂、多巴胺激动剂(例如溴隐停)、黑色素细胞-刺激激素受体类似物、大麻素受体1拮抗剂(例如利莫那班)、黑色素浓集激素拮抗剂、瘦蛋白(OB蛋白)、瘦蛋白类似物、瘦蛋白受体激动剂、甘丙肽拮抗剂、脂酶抑制剂(例如tetrahydrolipstatin,例如奥利司他)、厌食药(例如铃蟾肽激动剂)、神经肽Y受体拮抗剂、拟甲状腺药、脱氢表雄酮或其类似物、糖皮质激素受体激动剂或拮抗剂、orexin受体拮抗剂、urocortin结合蛋白拮抗剂、胰高血糖素样肽-1受体激动剂、睫状节神经营养因子(例如AxokineTA)、人类豚鼠相关蛋白(AGRP)、ghrelin受体拮抗剂、组胺3受体拮抗剂或逆激动剂以及神经介素U受体激动剂。
在其它具体实施方案中,将本发明化合物与抗肥胖药一起给药,所述抗肥胖药选自奥利司他、西布曲明、溴隐停、麻黄碱、瘦蛋白、利莫那班、伪麻黄碱、PYY3.36或其类似物、2-氧代-N-(5-苯基吡嗪基)螺-[异苯并呋喃-1(3H),4’-哌啶]-1’-甲酰胺。根据本发明的另一方面,将本发明化合物与抗肥胖药一起给药,同时用例如锻练和合理饮食的典型肥胖治疗法进行治疗。
根据另一具体实施方案,将本发明化合物与一种或多种用于治疗糖尿病或相关病症的药物组合给药。在某些具体实施方案中,将本发明化合物与一种或多种药物组合给药,所述药物包括胰岛素和胰岛素类似物(例如赖氨酸脯氨酸胰岛素);GLP-1(7-37)(insulinotropin)和GLP-1(7-36)-NH2;磺脲类和其类似物:氯磺丙脲、格列苯脲、甲苯磺丁脲、妥拉磺脲、醋磺己脲、Glypizide、格列美脲、瑞格列奈、美格列奈;双胍:二甲双胍、苯乙双胍、丁福明、<<2-拮抗剂和咪唑啉类:咪格列唑、伊格列哚、德格列哚、咪唑克生、依法克生、氟洛克生;胰岛素促分泌物:利诺格列、A-4166;格列酮类:环格列酮、Actos(匹格列酮)、恩格列酮、曲格列酮、达格列酮、Avandia(BRL49653);脂肪酸氧化抑制剂:氯莫克舍、乙莫克舍;葡糖苷酶抑制剂:阿卡波糖、米格列醇、乙格列醇、伏利波糖、MDL-25637、卡格列波糖、MDL-73,945;13-激动剂:BRL 35135、BRL 37344、RO16-8714、ICI D7114、CL 316243;或磷酸二酯酶抑制剂:L-386398。
在其它具体实施方案中,将本发明化合物与一种或多种降脂药物组合给药,所述降脂药物为:苯氟雷司:钒酸盐和钒络合物(例如,Nagiivan)和过氧化钒络合物;糊精拮抗剂;胰高血糖素拮抗剂;葡萄糖异生抑制剂;生长素释放肽类似物;抗脂解药物:烟酸、阿昔莫司、WAG 994、普兰林肽(“Symlin”)、AC 2993、那格列奈、醛糖还原酶抑制剂(例如唑泊司他)、糖原磷酸化酶抑制剂、山梨糖醇脱氢酶抑制剂、钠-氢交换泵1型(NNE-1)抑制剂和/或胆固醇生物合成抑制剂或胆固醇吸收抑制剂,特别是HMG-CoA还原酶抑制剂或HMG-CoA合成酶抑制剂;或HMG-CoA还原酶或合成酶基因表达抑制剂;CETP抑制剂;胆汁酸螯合剂(sequesterant)、贝特(fibrate)、ACAT抑制剂;角鲨烯合成酶抑制剂;或抗氧化剂。在其它具体实施方案中,将本发明化合物与一种或多种天然存在的降低血浆胆固醇水平的化合物组合给药。这些天然存在的化合物通常指营养品,例如大蒜提取物、Hoodia plant提取物和烟酸。
在某些具体实施方案中,本发明化合物用于诱导、协助或维持哺乳动物中所需的膀胱控制。该方法对治疗遭受或容易遭受膀胱不稳定或小便失禁的哺乳动物特别有益。本发明的方法包括预防、治疗或抑制膀胱相关的泌尿疾病和膀胱不稳定,包括原发性膀胱不稳定、夜遗尿、夜尿症、排空障碍和小便失禁(包括例如,压力性尿失禁、急迫性尿失禁和/或混合型尿失禁)。通过给药本发明化合物还可以治疗或可以预防由前列腺肥大继发的膀胱不稳定,这是甚至在其他健康人中,提高尿道张力和降低不希望的尿遗漏的方法。例如本发明方法用于缓解在处于生孩子后第一年中的妇女中经常出现的尿遗漏。
在其它具体实施方案中,本发明化合物用于治疗尿潴留或逼尿肌括约肌协同失调。患有尿潴留的患者包括患有脊髓损伤的患者或患有良性前列腺增生的男性患者。
根据本发明,本发明化合物还可用于提高临时延迟排尿(当其需要时)。根据本发明,需要时,这些化合物可以用于稳定膀胱。因此,可以将本发明方法用于受试者,以使其控制排尿的紧迫性和频率。
在本发明的一些具体实施方案中,将本发明化合物给药至需要它们的哺乳动物,用于治疗、预防、抑制和/或改善急迫性尿失禁(还称为膀胱不稳定、神经性膀胱、排空障碍、活动过度性膀胱、逼尿肌过度活性、逼尿肌反射亢进或无抑制性膀胱)或混合型尿失禁。本发明的用途包括但不限于,用于膀胱活性和不稳定性,其中尿急与前列腺炎、前列腺肥大、间质性膀胱炎、尿道感染或阴道炎相关。本发明的方法还可用于协助抑制或校正尿频-尿急综合征和懒惰膀胱(lazy bladder)(还称为排空频率稀少综合征(infrequent voiding syndrome))。
本发明化合物还用于治疗、预防、抑制或限制与使用其它药物相关或由其引起的尿失禁、尿不稳定或尿急,所述药物包括利尿药、加压素拮抗剂、抗胆碱能药、镇静药或安眠药、麻醉药、α-肾上腺素能激动剂、α-肾上腺素能拮抗剂或钙通道阻滞剂。
本发明化合物可用于诱导或协助泌尿膀胱控制或预防或治疗需要其缓解的人类中的文中所述疾病,包括成人和儿科使用。它们还可用于兽医进行的应用,特别是包括犬科和猫科动物膀胱控制方法。如果需要的话,所述方法还可用于农场动物,例如羊、马、猪和马科动物。
根据本发明,本发明化合物可以单独给药调节膀胱活性,或者可以与一种或多种其它用于调节膀胱活性的药物组合(同时或依次)给药。另外,本发明化合物可以与一种或多种其它药物组合给药,所述药物为用于治疗或预防一种或多种需要膀胱活性调节的个体所遭受的其它症状、病症或疾病。
用于调节膀胱活性,特别用于治疗、预防、抑制和/或缓解尿失禁的其它药物包括,例如,醋酸去氨加压素(以来自Aventis Pharmaceuticals的DDAVP鼻喷雾剂和DDAVP片剂形式使用)和醋酸去氨加压素鼻管(rhinal tube)(得自Ferring Pharmaceuticals Inc.)。其它产品包括,例如,酒石酸托特罗定(来自Pharmacia & Upjohn,以Detroltm片剂应用)、盐酸奥昔布宁(来自ALZA Pharmaceuticals,以Ditropan片剂和糖浆剂以及Ditropan XL缓释片剂形式应用)、氢溴酸propanthaline(以片剂形式,得自Roxane Laboratories,Inc.)、莨菪碱和硫酸莨菪碱(分别以Cystopaz片剂和Cystopaz-M定时释放胶囊形式应用,得自PolyMedicaPharmaceuticals(U.S.A.),Inc.)、氢溴酸莨菪碱、盐酸黄酮哌酯(以Urispas100mg片剂应用,来自ALZA Pharmaceuticals)、盐酸丙咪嗪(以10mg、25mg和50mg片剂应用,来自Geneva Pharmaceuticals,Inc.)、苯丙醇胺、盐酸米多君(以2.5mg和5mg Proamatine片剂形式应用,来自Shire USInc.)、盐酸酚苄明(以Dibenzyline胶囊应用,来自WellSpringPharmaceuticals Corporation)和盐酸哌唑嗪(以Minipress胶囊形式应用,来自Pfizer Inc.)。可以将这些药物中的每一种以本领域公知的药学有效量和方案给药,包括列在医师桌面参考(Physicians'Desk Reference),55版,2001,由Medical Economics Company,Inc在Monvale出版,NJ07645-1742,其相关部分在此引入作为参考。
另外其它能够调节膀胱活性的药物包括,例如,其它5HT2c受体调节剂。例如美国专利申请2004/0235856(在前面已将其全部内容引入作为参考)描述了许多可以用于实施本发明的5HT2c受体调节剂。另外的5HT2c激动剂在Bishop等人,Expert Opin.Ther.Patent 13:1691-1705,2003中进行了举例谫明,将该文献全部内容在此引入作为参考。
另外其它能够调节膀胱活性的药物包括,例如,一种或多种KCNQ钾通道调节剂。在本发明的一些具体实施方案中,将本发明化合物与一种或多种KCNQ2/3或KCNQ3/5激动剂共同给药。这些KCNQ调节剂包括,例如,美国专利5384330和美国专利5565483中所描述的化合物,以及美国专利申请2002/0183395和美国专利申请2004/0029949中所描述的化合物;这些专利和专利申请的全部内容在此引入作为参考。在本发明的一些具体实施方案中,将本发明化合物与瑞替加宾一起给药。
在本发明的一些具体实施方案中,本发明化合物与一种或多种化合物组合给药,所述化合物为加压素激动剂,包括但不限于U.S.专利6194407(Failli等人)、U.S.专利6090803(Failli等人)、U.S.专利6096736(Ogawa等人)和U.S.专利6096735(Ogawa等人)中描述的那些化合物。
一般而言,根据本发明,通常需要将一种或多种本发明化合物与一种或多种α-肾上腺素能受体激动剂和/或一种或多种其它拟交感神经药组合给药。
根据本发明,式I化合物可以用于治疗、预防或减轻对多种物质中任何一种的依赖、戒断或其症状,所述物质包括,例如,娱乐物质(例如,酒精、烟草[例如尼古丁])、具有药理作用的物质(例如镇痛药[例如Vicodin、Lortab、Lorcet、Percocet、Percodan、Tylox、氢可酮、OxyContin、美沙酮、曲马多等]、镇定剂、兴奋剂或镇静剂)和违禁药(例如大麻、海洛因、可卡因、ecstasy、LSD、PCP、氧麻黄碱等)。
如文中所用,术语“物质滥用”可以参照精神障碍的诊断和统计手册,第4版,(1994)(“DSM-IV”)中设定的标准进行定义,该手册由美国精神病协会的命名和统计小组(Task Force on Nomenclature and Statistics)制定。物质滥用的特征为不良适应模式的药物应用,显示出复发性和与这些物质重复使用相关的显著副作用。如在DSM-IV中所叙述的,物质滥用定义为导致显著临床损伤或不良应激的不良适应模式的物质滥用,所述损伤或不良应激显示为一种(或多种)下面情况,在12个月周期内出现:(1)导致未履行工作、学校或家庭中的主要职责的复发性物质使用;(2)对身体有危害性的复发性物质使用;(3)复发性物质相关的法律问题;和(4)尽管有持久性或复发性的由物质的作用引起或恶化的社会或人与人之间的问题,仍持续的物质使用。此外,DMS-IV要求,物质滥用的症状与物质依赖的标准不相符。
如文中所用,术语“物质依赖”,可以参照精神障碍的诊断和统计手册,第4版,(1994)(“DSM-IV”)中设定的标准进行定义,该手册由美国精神病协会的命名和统计小组制定。DSM-IV中设定的物质依赖的标准是一种物质使用的模式,该模式导致由至少三种下面所述情况所证明的显著临床损伤或不良应激,所述情况可在相同的12个月周期内任何时间点出现:(1)耐受性,其由下列特征进行定义:(a)为达到所需作用,需要大量增加物质的量;或(b)随着持续使用相同量的物质,作用大量减少,(2)戒断,其由下列特征证明:(a)对于特定物质的特征性戒断综合征;或(b)服用相同或密切相关的物质,以减轻或消除戒断综合征,(3)通常以比预期更大量或更长时间服用此物质;(4)持续需要或不能消除或控制物质使用;(5)大量时间被花费在获取物质、使用物质或从它的作用中恢复上;(6)由于物质使用,放弃或减少重要的社会、职业或娱乐活动;以及(7)继续物质使用,尽管对可能由这些物质引起或恶化的持久或复发性身体或心理问题了解。物质依赖可能伴有生理依赖性;这由耐受性和戒断存在所证明,或没有生理依赖性,此时没有耐受性和戒断存在的迹象。DSM-IV中设定的状况中的4种包括缓解(remission)。这些类型的缓解是基于由于依赖停止而消失的时间间隔,及是否持续存在一种或多种包括在依赖性标准中的症状。
在某些具体实施方案中,本发明化合物用于治疗酒精中毒(例如酒精滥用、上瘾和/或依赖,包括用于戒酒、降低上瘾性和预防酒精摄入复发的治疗)和/或烟草滥用(例如,吸烟成瘾、停止和/或依赖,包括用于降低上瘾性和预防吸烟复发的治疗)。
根据本发明,在评价物质滥用时,可以参考,例如,关于药物使用和健康的全国调查(National Survey on Drug Use and Health)(NSDUH),该文献从9种不同类别的违禁药品的使用中获取信息:大麻、可卡因、海洛因、致幻剂、吸入剂、处方型止痛药、镇定剂、兴奋剂、镇静剂的非医学使用。在这些类别中,大麻麻醉剂(hashish)包括在大麻中,将crack认为是可卡因的一种形式。将几种药物归类在致幻剂类别中,包括LSD、PCP、仙人球膏(peyote)、仙人球毒碱(mescaline)、蘑菇和“Esctasy”(MDMA)。吸入剂包括多种物质,例如亚硝酸异戊酯、清洗液、汽油、涂料和胶。四种类型的处方型药物(止痛药、镇定剂、兴奋剂、镇静剂)涵盖多数通过处方或有时“在街头”非法可获得的药物。去氧麻黄碱被认为是一类兴奋药。应答者被要求仅报告没有给他们开处方的药物,或他们仅根据他们的经验或感觉服用的药物的使用。不包括非处方药和处方药的合法使用。NSDUH报告将四种处方型的药物类别合并为一类,称为“任何心理治疗剂”。
利用与例如啤酒、葡萄酒、威士忌、白兰地和混合型酒精饮料的消费频率有关的问题调查,NSDUH将酒精滥用进行分类。在给予调查问卷之前,给予调查对象涵盖这些饮料种类的示例的广泛列表。将一份“饮品”定义为一罐或一瓶啤酒、一杯葡萄酒或a wine cooler、一小杯(shot)酒或一份含有酒的混合饮料。当调查对象仅啜饮少量饮品时,不将如此认为是在消费。对于此报告,最初在三个水平上对酒精使用的流行率进行评估,对于男性和女性及对所有年龄而言,这三个水平如下定义:
当前使用-在过去的30天中最少一份饮品(包括放纵使用和大量使用)。
放纵使用-在过去的30天中,至少有一次,在同一场合饮用五份或更多的饮品(包括大量使用)。
大量使用-在过去的30天中,至少有5天,在同一场合饮用五份或更多的饮品。
NSDUH还对烟草产品的使用进行分类,所述烟草产品包括香烟、嚼烟、鼻烟、雪茄和烟斗烟草(pipe tobacco)。为了分析的目的,嚼烟和鼻烟的数据合并为“无烟烟草”。将香烟使用定义为吸食“一支香烟的部分或全部”。NSDUH还进行了确定当前吸香烟者中的尼古丁依赖的调查。根据尼古丁依赖综合征标度(Nicotine Dependence Syndrome Scale(NDSS))或Fagerstrom尼古丁依赖性测试(Fagerstrom Test of Nicotine Dependence(FTND))中的标准对尼古丁依赖进行确定。
在其它具体实施方案中,本发明化合物用于治疗药物上瘾(包括尼古丁、酒精和其它物质滥用的上瘾)的戒断。个体通常遭受尼古丁戒断症状,该症状是任何形式烟草的不连续使用造成的,所述任何形式烟草使用包括但不限于吸食香烟、雪茄或烟斗烟草,或口腔或鼻内摄入烟草或嚼烟。这些口腔或鼻内摄入烟草包括但不限于鼻烟和嚼烟。尼古丁使用的停止或尼古丁使用量的减少,通常在24小时内出现下列症状,包括烦躁和低落的情绪;头晕;失眠;易怒、失意或发怒;焦虑;神经性震颤;精力难于集中;不安;心率减慢;食欲增加或体重增加;且渴求烟草或尼古丁。这些症状通常在社会、职业或其它重要的作用方面,引起临床上的不良应激或损伤。
阿片样物质一般是通过注射或口服,或者通过吸烟或鼻内摄入而自己给药,它的不连续服用或减用,通常导致出现特征性的阿片戒断状况。在阿片使用后,给药例如纳洛酮或纳曲酮的阿片拮抗剂也可引起上述戒断状况。阿片戒断具有一般与阿片激动剂效应相反的症状的特征。这些戒断症状可以包括焦虑;不安;肌肉疼痛,通常在背部和腿部;渴望阿片类物质;易怒并且对疼痛敏感性增加;情绪烦躁;恶心或呕吐;流泪;鼻溢;乳突扩张;毛发直立;出汗;腹泻;打呵欠;发烧;和失眠。当对例如海洛因的短作用型阿片类物质依赖时,在最近服用后的6-24小时内通常出现戒断症状,而对于例如美沙酮的较长效作用的阿片类物质,出现症状可能要花费2-4天。这些症状通常在社会、职业或其它重要的作用方面,引起临床上的不良应激或损伤。本发明最优选用于减轻一种或多种阿片戒断引起的症状,当这些症状不是由一般医疗情况引起,且不是更多由另外医学障碍引起时。
乙醇(含有乙醇的饮料)使用的减少或中断,导致了乙醇戒断病症的发作。乙醇戒断病症具有乙醇使用已经停止或减少后的4-12小时内,且乙醇血液浓度急剧下降时,开始出现症状的特征。这些乙醇戒断症状包括对乙醇的渴求;自发的机能亢进(例如出汗或脉搏速度超过100);手震颤;失眠、恶心、呕吐;暂时视觉、触觉或听觉出现幻觉或错觉;精神运动性激动;焦虑;癫痫大发作。这些症状通常在社会、职业或其它重要的作用方面,引起临床上的不良应激或损伤。本发明最优选用于减轻一种或多种乙醇戒断,当这些症状不是由一般医疗情况引起,且不是更多由另外医学障碍引起时。
根据另一具体实施方案,将本发明化合物与一种或多种治疗物质滥用的药物组合给药。在某些具体实施方案中,将本发明化合物与一种或多种治疗烟草滥用的药物组合给药。这些药物包括尼古丁部分激动剂盐酸安非他酮(ZybanTM)和尼古丁代替治疗品。
根据另一具体实施方案,本发明化合物与一种或多种治疗酒精中毒的药物组合给药。所述药物例如阿片拮抗剂(例如纳曲酮,ReViaTM)、纳美芬、双硫仑(AntabuseTM)和阿坎酸(CampralTM)。
在某些具体实施方案中,将化合物与一种或多种减轻酒精戒断症状的药物组合给药,所述药物例如苯并二氮杂类、β-阻滞剂、可乐定、卡马西平、普瑞巴林和加巴喷丁(NeurontinTM)。在本发明的其它具体实施方案中,使用本发明化合物的治疗,同时伴有和/或紧跟教育和/或行为改变方案,以提高持续的对物质依赖或滥用的戒瘾。本发明的方法可能对治疗在康复或其它治疗方案中经常观察到的戒断症状特别有效。因此,由于将注意力集中在教育和行为改变目标上,所以这些方案可能更加有效,从而减少方案无法完成的发生率。
在某些具体实施方案中,通过给药本发明药物,将本发明化合物用于治疗一种或多种智力减退疾病。在其它具体实施方案中,这些智力减退疾病包括痴呆,例如老年性痴呆、血管性痴呆、轻度认知损伤、年龄相关的认知减退、轻度神经性认知障碍、儿童和成人中的阿尔茨海默氏病和记忆减退、注意力减退疾病(ADD,还称为注意力减退活动过度疾病或ADHD)。在某些具体实施方案中,本发明提供了治疗儿科患者中的ADD和/或ADHD的方法,该方法包括给予上述患者式I化合物或其药学组合物。
在某些具体实施方案中,本发明提供了治疗一种或多种认知障碍的方法。根据另一方面,认知障碍为学习障碍。这些学习障碍在本领域中是公知的,包括孤独症、诵读困难、Asperger氏综合征、类似于孤独症且有严重社会和沟通技能减退特征的神经生理学障碍;特定学习能力丧失,即涉及理解或使用口头或书面语言的一种或多种基本心理过程障碍,其可能显示为在听、思考、说、读、写、拼读或做数学计算方面的能力有缺陷;书写困难,即在成形字母或在规定的空间内书写方面有困难的疾病;计算障碍,即致使人们在做算术和理解数学概念方面有问题的疾病;运动障碍,身体系统的运动问题,其干涉个人对给定情况的做出控制性或协调性身体响应;视觉知觉缺陷,接收和/或加工来自视觉的准确信息困难,尽管视力没有任何问题;和听觉知觉缺陷,通过听觉方式接收准确信息困难,尽管听力没有问题。
在某些具体实施方案中,本发明提供了治疗一种或多种冲动性疾病(例如边缘人格疾病)、分裂性行为疾病或冲动控制疾病的方法。在某些具体实施方案中,本发明提供了治疗Tourette氏综合征(TS)的方法,TS为遗传的神经性疾病,它具有重复和无意识地身体运动(抽搐)和/或不可控地发出声音的特征。
根据另一方面,本发明提供了治疗一种或多种行为成瘾和成瘾障碍的方法。行为成瘾和成瘾障碍是在某些活动中由脑化学物质(例如5-羟色胺、肾上腺素(adrenaline)、肾上腺素(epinephrine)等)释放引起的知觉中毒而导致的。这些障碍在本领域中是公知的,包括赌博、性成瘾、进食障碍、花费成瘾、暴怒/愤怒、工作狂、锻练成瘾、冒险成瘾和完美主义,在此仅举几例。
在某些具体实施方案中,将本发明化合物与一种或多种认知改善药物组合给药。这些药物在本领域中是公知的,包括盐酸多奈哌齐(AirceptTM)和其它乙酰胆碱酯酶抑制剂;加兰他敏、神经保护药物(例如美金刚);ADD/ADHD药物(例如哌甲酯(RitalinTn″)、阿托西汀(StratteraTM)、哌甲酯、缓释(ConcertaTM)和苯丙胺/右苯丙胺(AdderallTM))。
根据另一方面,本发明提供了治疗性功能障碍的方法,该方法包括给药本发明化合物。在某些具体实施方案中,性功能障碍与抑郁症相关。在其它具体实施方案中,性功能障碍与通过给药5-羟色胺重摄取抑制剂治疗疾病有关。本发明化合物可用于治疗男性和女性的性功能障碍。这些障碍包括男性勃起功能障碍(MED)和例如女性性唤起功能障碍(FSAD)的女性性功能障碍(FSD)。
在其它具体实施方案中,本发明提供了治疗一种或多种与性功能障碍相关的疾病的方法,所述性功能障碍包括:HSDD,特征为缺乏或缺失性幻想和对性活动的欲望;FASD,特征为持续或重发性的无力达到或维持直到性活动完成、对性刺激产生足够的润滑-膨胀响应;FOD特征为在正常性刺激状态后持续或重发性地延迟或缺失性高潮;性疼痛障碍,例如性交疼痛和阴道痉挛;和/或以没有或几乎没有性欲望以及没有或几乎没有性想法或幻想的女性为特征的HSDD。
根据另一具体实施方案,将本发明化合物与一种或多种治疗男性性功能障碍(男性勃起功能障碍)的药物组合给药。这些药物在本领域中是公知的,包括多巴胺能药物(例如D2、D3或D4激动剂和阿扑吗啡);NPY(神经肽Y)(优选NPY-I和/或NPY-5抑制剂);黑皮质素受体激动剂或调节剂或黑皮质素增强子;NEP抑制剂;PDE抑制剂(优选cGMP PDE-5抑制剂);铃蟾肽受体拮抗剂或调节剂和可溶性分泌内肽酶抑制剂(SEPi)。在某些具体实施方案中,将本发明化合物与一种或多种例如前列地尔或昔多芬的治疗男性性功能障碍的药物组合给药。
根据另一具体实施方案,将本发明化合物与一种或多种治疗女性性功能障碍的药物组合给药。这些药物在本领域中是公知的,包括雌激素受体调节剂(例如雌激素激动剂和/或雌激素拮抗剂);睾酮代替药物,睾酮(Tostrelle)、二氢睾酮、脱氢表雄酮(DHEA);睾酮植入片,例如脱氢雄酮、雌激素、雌激素、甲羟孕酮、酯酸甲羟孕酮(MPA);雌激素和甲基睾酮激素代替治疗药物的组合产品,倍美力(Premarin)、Cenestin、Oestrofeminal、Equin、Estrace、诺坤复(Estrofem)、Elleste Solo、Estring、Eastraderm TTS、Eastraderm Matrix、Dermestril、Premphase、Preempro、Prempak、Premique、Estratest、Estratest HS、替勃龙(Tibolone);多巴胺能药物,例如阿朴吗啡或选择性D2、D3或D2/D3激动剂,例如普拉克索和罗匹妥英;NPY(神经肽Y)抑制剂,例如NPY1或NPY5抑制剂的NPY(神经肽Y)抑制剂,优选NPY1抑制剂;黑皮质素受体调节剂或黑皮质素增强子,例如美拉诺坦II、PT-14、PT-141;NEP(中性内肽酶)抑制剂;PDE(磷酸二酯酶)抑制剂,例如昔多芬和/或铃蟾肽受体调节剂。
根据本发明,本发明化合物可用于治疗例如人类的哺乳动物所遭受的多种不同类型疼痛中的任何一种。例如,本发明化合物可以用于治疗急性疼痛(持续时间短)或慢性疼痛(定期复发或持久的),无论是中枢的或外周的。
可以是急性或慢性的且可以用本发明的方法进行治疗的疼痛示例包括炎性疼痛、肌肉骨骼疼痛、骨疼痛、腰骶疼痛、颈或上背疼痛、内脏疼痛、躯体疼痛、神经性疼痛、癌症疼痛、由损伤或手术引起的疼痛(例如灼伤疼痛)或例如偏头痛或紧张性头痛的头痛、或这些疼痛的组合。本领域的技术人员可知道,这些疼痛可能与另外的疼痛重叠。例如,由炎症引起的疼痛还可能是内脏或肌肉骨骼的疼痛。
在本发明的一具体实施方案中,将一种或多种本发明化合物给予哺乳动物,以治疗慢性疼痛,例如,与外周或中枢神经系统中的例如损伤或病理变化有关的神经性疼痛;癌症疼痛;与例如腹部、骨盆和/或会阴区域或胰腺炎有关的内脏疼痛;与例如下背或上背部、脊柱、纤维肌痛(fibromylagia)、颞下颌关节或肌筋膜疼痛综合征有关的肌肉骨骼疼痛;与例如骨或关节退行性疾病(例如骨性关节炎、类风湿性关节炎或脊柱狭窄)相关的骨疼痛;例如偏头痛或紧张性头痛的头痛;或与感染(例如HIV、镰刀形红细胞贫血症、自身免疫疾病、多发性硬化症或例如骨关节炎或类风湿性关节炎的炎症)相关的疼痛。
在一些具体实施方案中,按文中所述的方法,用本发明化合物治疗慢性疼痛,所述慢性疼痛为神经性疼痛、内脏疼痛、肌肉骨骼疼痛、骨疼痛、头痛、癌症疼痛或炎性疼痛或它们的组合。炎性疼痛可以与例如骨关节炎、类风湿性关节炎、手术或损伤的许多医学病症相关。神经性疼痛可以与例如糖尿病神经病变、外周神经病变、疱疹后神经痛、三叉神经痛、腰部或颈部神经根病、纤维肌痛、舌咽神经痛、反射性交感神经营养不良、casualgia、丘脑综合征、神经根性撕脱伤或由导致外周和/或中枢致敏的损伤引起的神经损伤(例如幻肢痛)、反射性交感营养不良或开胸术后疼痛、癌症、化学损伤、毒素、营养缺乏或例如带状疱疹或HIV的病毒或细菌感染或者它们的组合。本发明的治疗方法另外包括疗法,其中神经性疼痛是继发于转移渗入(metastatic infiltration)、痛性肥胖症、烧伤或与丘脑病症相关的中枢疼痛病症的病症。
在一些情况下,上面所述的神经性疼痛还可以分类为“疼痛性小纤维神经病变”,例如原发性小纤维疼痛感觉的神经病变;或“疼痛性大纤维神经病变”,例如demylinating神经病变或轴突神经病变;或它们的组合。例如在J.Mendell等人,新英格兰医学杂志(N.Engl.J.Med.)2003,348:1243-1255中对这些神经病变进行更加详细的描述,将其全部内容在此引入作为参考。
在另一具体实施方案中,可将本发明中的有效化合物给药,以完全地或部分地抑制神经性疼痛病症,阻止它的进展。例如可以将本发明化合物给药至处于神经性疼痛病症进展的危险下的哺乳动物,例如感染带状疱的哺乳动物或正在进行癌症治疗的哺乳动物。
在一具体实施方案中,可将本发明中的有效化合物在手术过程之前或之中给药,以部分地或完全地抑制与手术过程相关的疼痛的发展。
如前面提到的,本发明的方法可以用于治疗躯体和/或内脏性质的疼痛。例如,可以按本发明的方法治疗的躯体疼痛,包括与在手术期间遭受的结构或软组织损伤、牙科操作、烧伤或创伤性身体损伤相关的疼痛。可以按本发明的方法治疗的内脏疼痛,包括与内部器官疾病相关或由其引起的那些类型的疼痛,所述内部器官疾病例如溃疡性结肠炎、肠易激综合征、过敏性膀胱、Crohn氏病、风湿病(关节痛)、肿瘤、胃炎、胰腺炎、器官感染或胆道疾病或者它们的组合。本领域技术人员还将知道,根据本发明方法治疗的疼痛还可能与痛觉增敏、异常性疼痛疾病或它们两者相关。此外,根据本发明进行治疗的慢性疼痛可能伴有或不伴有外周或中枢增敏。
本发明还提供了本发明化合物治疗与女性病症相关的急性和/或慢性疼痛(还可称为女性特定疼痛)的用途。这些类型的疼痛包括由女性单独遇到或主要由女性遇到的疼痛,包括与月经、排卵、妊娠或分娩、流产、异位妊娠、逆行月经、卵泡或黄体囊肿破裂、骨盆内脏的刺激、子宫肌瘤、子宫内膜异位(adenomyosis)、子宫内膜异位(endometriosis)、感染和炎症、骨盆器官缺血、梗塞、腹内粘连、骨盆内脏的解剖学上的畸变、卵巢脓肿、骨盆托损失、肿瘤、骨盆充血相关的疼痛或非妇产科原因涉及到的疼痛。
在某些具体实施方案中,本发明的化合物与止痛药组合给药。可以与本发明组合给药的止痛药的示例包括但不限于镇痛药,例如非麻醉性镇痛药或麻醉性镇痛药;抗炎药,例如非甾体抗炎药(NSAIDs)、甾体药物或抗风湿药;偏头痛制剂,例如β-肾上腺素能阻滞剂、麦角衍生物或异美汀;三环抗抑郁药,例如阿米替林(amitryptyline)、地昔帕明或丙咪嗪;抗癫痫药,例如加巴喷丁、卡马西平、托吡酯、丙戊酸钠或苯妥英;α2激动剂或选择性5-羟色胺重摄取抑制剂/选择性去甲肾上腺素摄取抑制剂;或者它们的组合。
本领域技术人员将知道,文中描述的一些药物有减轻多重病症(例如疼痛和炎症)的作用,而其它药物可能只减轻一种症状(例如疼痛)。有多重特性的药物的具体示例为阿司匹林,当给予高剂量时,阿司匹林为抗炎药,但是在较低剂量时,仅为止痛药。止痛药可以包括任何前面提到的药物的组合,例如止痛药可以为混合有麻醉性镇痛药的非麻醉性镇痛药。
在本发明的实施中有用的非麻醉性镇痛药包括,例如阿司匹林的水杨酸类化合物、布洛芬(Motrin,Advil)、酮洛芬(Orudis)、萘普生(Naprosyn)、对乙酰氨基酚、吲哚美辛或它们的组合。可以与本发明化合物组合使用的麻醉性镇痛药的示例包括阿片类镇痛药,例如芬太尼(fentenyl)、舒芬太尼、吗啡、氢吗啡酮、可待因、羟考酮、丁丙诺啡或它们药学上可接受的盐或者上述物质的组合。可以与本发明化合物组合使用的抗炎药的示例包括但不限于阿司匹林;布洛芬;酮洛芬;萘普生;依托度酸(Lodine);COX-2抑制剂,例如塞来考昔(Celebrex)、罗非考昔(Vioxx)、伐地考昔(Bextra)、帕瑞考昔、艾托考昔(MK663)、地拉考昔、2-(4-乙氧基-苯基)-3-(4-甲磺酰基-苯基)-吡唑并[1,5-b]哒嗪、4-(2-氧代-3-苯基-2,3-二氢唑-4-基)苯磺酰胺、达布非酮、氟舒胺、4-(4-环己基-2-甲基-5-唑基)-2-氟苯磺酰胺)、美洛昔康、尼美舒利、1-甲磺酰基-4-(1,1-二甲基-4-(4-氟苯基)环戊-2,4-二烯-3-基)苯、4-(1,5-二氢-6-氟-7-甲氧基-3-(三氟甲基)-(2)-苯并噻喃并(4,3-c)吡唑-1-基)苯磺酰胺、4,4-二甲基-2-苯基-3-(4-甲磺酰基)苯基)环-丁烯酮、4-氨基-N-(4-(2-氟-5-三氟甲基)-噻唑-2-基)-苯磺酰胺、1-(7-叔丁基-2,3-二氢-3,3-二甲基-5-苯并-呋喃基)-4-环丙基丁-1-酮或它们的生理上可接受的盐、酯或溶剂合物;舒林酸(Clinoril);双氯芬酸(Voltaren);吡罗昔康(Feldene);二氟尼柳(Dolobid)、萘丁美酮(Relefen)、奥沙普秦(Daypro)、吲哚美辛(Indocin);或甾体类,例如Pediaped泼尼松龙磷酸钠口服液、Solu-Medrol注射用的甲泼尼龙琥珀酸钠、商标为Prelone的泼尼松龙糖浆。
此外,根据本发明,可以用于治疗例如与类风湿性关节炎相关的疼痛的抗炎药的示例包括得自商业的EC-Naprosyn缓释片剂、Naprosyn、出自Roche Labs的Anaprox和AnaproxDS片剂及Naprosyn混悬剂形式的萘普生;商标为Celebrex的塞来考昔片剂;商标为Vioxx的罗非考昔;商标为Celestone的倍他米松;商标为Cupramine的青霉胺胶囊;商标为Depen的可滴定的青霉胺片剂;商标为Depo-Medrol的醋酸甲泼尼龙可注射混悬剂;AravaTM来氟米特片剂;商标为Azulfidine EN-tabs的柳氮磺吡啶的缓释片剂;商标为Feldene的吡罗昔康胶囊;Cataflam双氯芬酸钾片剂;Voltaren双氯芬酸钠缓释片剂;Voltaren-XR双氟芬酸钠延长释放片剂;或Enbreletanerecept产品。
用于治疗炎症,特别是类风湿性关节的另外其它药物的示例包括免疫抑制剂,例如商标为GengrafTM的环孢菌素胶囊、商标为Neoral的环孢菌素胶囊或口服液或商标为Imuran的硫唑嘌呤片剂或IV注射剂;商标为Indocin的吲哚美辛胶囊、口服混悬剂或栓剂;商标为Plaquenil的硫酸羟氯喹;或Remicade用于IV注射的英夫利昔单抗重组体;或金化合物,例如金锘芬或Myochrisyine苹果酸金钠注射剂。
作为5-HT2C调节剂,本发明化合物可用于治疗多种疾病。这些疾病包括月经前综合征、例如帕金森病的运动(motion or motor)障碍和癫痫;偏头痛、慢性疲劳综合征、神经性厌食症、睡眠障碍(例如睡眠呼吸暂停)和缄默症。
在其它具体实施方案中,本发明化合物用于治疗一种或多种例如与创伤、中风和脊柱损伤、神经变性疾病、或毒性或感染性CNS疾病(例如脑炎或脑膜炎)、或帕金森病相关的中枢神经系统缺陷。因此,本发明化合物可以在所涉及的疾病或创伤期间或之后,用来改善或抑制中枢神经系统活性的进一步退化。这些改善包括维持或提高运动或活动技能、控制性、协调性和力量。
5.药学上可接受的组合物
在其它具体实施方案中,本发明涉及组合物,该组合物包括至少一种式I或式VII化合物或者它们的药学上可接受盐,和一种或多种药学上接受的载体、赋形剂或稀释剂。这些组合物包括治疗或控制中枢神经系统疾病状态或疾病的药物组合物。在某些具体实施方案中,组合物包含一种或多种式I或VII化合物的混合物。
在某些具体实施方案中,本发明涉及组合物,该组合物包括至少一种式I或VII化合物,或者它们的药学上可接受盐,和一种或多种药学上可接受的载体、赋形剂或稀释剂。根据可接受的药学方法制备这些组合物,所述药学方法例如在Remingtons Pharmaceutical Sciences,第17版,编者Alfonoso R.Gennaro,Mack Publishing Company,Easton,PA(1985)中所描述的方法,将此书的全部内容在此引入作为参考。药学上可接受的载体是那些与制剂中的其它成分可配伍的并且是生物可接受的载体。
可以将式I或VII化合物经口或胃肠外单独或与常规药学载体混合给药。可用的固体载体可以包括一种或多种物质,所述物质可以作为矫味剂、润滑剂、增溶剂、助悬剂、填充剂、助流剂、压缩助剂、粘合剂、片剂崩解剂或包封材料。在散剂中,载体为与微粒活性成分混合的微粒固体。在片剂中,活性成分与有适当比例的必需压缩特性的载体混合,并压成所需形状和大小。散剂和片剂优选含有高至99%的活性成分。适当的固体载体包括例如磷酸钙、硬脂酸镁、滑石粉、糖、乳糖、糊精、淀粉、明胶、纤维素、甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷、低熔点蜡和离子交换树脂。
液体载体可用于制备溶液剂、混悬剂、乳剂、糖浆和酏剂。可以将活性成分溶解或混悬在药学可接受的液体载体中,例如,水、有机溶剂、两者的混合物或药学上可接受的油或脂肪。液体载体可以包含其它适当的药学添加剂,例如增溶剂、乳化剂、缓冲剂、防腐剂、甜味剂、矫味剂、助悬剂、增稠剂、染料、粘性调节剂、稳定剂或渗透压调节剂。对于口服或胃肠外给药而言,适当的液体载体包括水(特别是包含例如纤维素衍生物的上述添加剂的水,优选羧甲基纤维素钠溶液)、醇(包括单羟基醇和多羟基醇,例如乙二醇)和它们的衍生物以及油(例如分馏的椰子油和花生油)。对于胃肠外给药而言,载体还可以是油酯,例如油酸乙酯和肉豆蔻酸异丙酯。将无菌液体载体用于形成胃肠外给药的组合物的无菌液体中。就加压组合物而言,液体载体可以为卤代烃或其它药学上可接受的抛射剂。
为无菌溶液或混悬液的液体药物组合物可以通过例如肌内、腹膜内或皮下注射给药。无菌溶液可以通过静脉注射给药。口服给药的组合物可以为液体或固体形式。
式I或VII化合物可以以常规栓剂形式经直肠或阴道给药。对于经鼻或支气管吸入或吹入给药而言,可以将式I或VII化合物制成水溶液或部分水溶液,然后这些溶液可以以气雾剂形式使用。通过使用经皮贴剂还以将式I化合物经皮给药,所述贴剂包含活性化合物和载体,该载体对活性化合物是惰性的,对皮肤没有毒性,并能使药物经皮系统性吸收至血流中,从而将药物递送。载体可以有许多形式,例如乳膏和软膏、糊剂、凝胶剂和闭合装置(occlusive devices)。乳膏和软膏可以为粘稠液体或水包油或油包水型的半固体乳剂。由分散在含有活性成分的石油或亲水性石油中的可吸收粉末组成的糊剂也可能是适当的。许多闭合装置可以用于将活性成分释放到血流中,例如覆盖含有活性成分且含有或不含载体的贮存库的半渗透性膜,或含有活性成分的基质。其它闭合装置可在文献中发现。
优选的药学组合物为单位剂量形式的,例如片剂、胶囊、散剂、溶液剂、混悬剂、乳剂、颗粒剂或栓剂。在这些形式中,将组合物分为含有适当量活性成分的单位剂量;单位剂量形式可以为经包装的组合物,例如包装的散剂、管形瓶、安瓿、预填装的注射器或包含液体的袋剂。单位剂量形可以为,例如,胶囊或片剂本身,或可以为包装形式的适当数量的任何上述组合物。
提供给患者的式I或VII化合物的量将根据所给药的物质、给药的目的(例如预防或治疗)、患者的状态、给药的方式等而变化。在治疗应用中,将足够量的式I化合物提供给患有病症的患者,以治疗或至少部分治疗病症和它的并发症的症状。完成上面情况的足够量为前面文中所述的“治疗有效量”。治疗具体案例所用的剂量必须由主治医师主观决定。涉及的变量包括具体的病症和患者的体积、年龄和响应模式。在主治医师的指导下,用自觉给药的相同方法治疗物质滥用。一般来讲,起始剂量为约5mg每天,日剂量逐渐增加到约150mg每天,以在患者中提供所需的剂量水平。
在某些具体实施方案中,本发明涉及式I化合物的前药。如文中所用,术语“前药”指化合物在体内通过代谢方法(例如水解)可转变为式I化合物。各种形式的前药在本领域中是公知的,例如在Bundgaard,(编者),前药的设计(Design of Prodrugs),Elsevier(1985);Widder等人(编者),酶学中的方法(Methods in Enzymology)vol.4,Academic Press(1985);Krogsgaard-Larsen等人,(编者)前药的设计和应用,药物设计和开发的教科书(Design and Application of Prodrugs,Textbook of Drug Design andDevelopment),第5章,113-191(1991),Bundgaard等人,药物递送综述杂志(Journal of Drug Delivery Reviews),8:1-38(1992),Bundgaard,药物科学杂志(J.of Pharmaceutical Sciences),77:285 et seq.(1988);和Higuchi和Stella(编者)作为新的药物递送体系的前药(Prodrugs as Novel DrugDelivery Systems),American Chemical Society(1975),将上述每份文献的全部内容在此引入作为参考。
实施例
生物学实验
用几种标准的药理学实验方法,对本发明化合物作为5-HT2C激动剂或部分激动剂的能力进行确定;这些方法提供在下面。在这些实验方法中,5-HT代表5-羟色胺,mCPP代表间-氯苯基哌嗪,DOI代表1-(2,5-二甲氧基-4-碘苯基)异丙胺。
为了评价各种式I化合物对5-HT2C受体的活性而言的亲和性,将用表达人5-羟色胺-2C(h5-HT2C)受体的cDNA转染的CHO(中国仓鼠卵巢)细胞系维持在加有胎牛血清、谷氨酰胺和标记鸟嘌呤磷酸核糖基转移酶(GTP)和次黄嘌呤胸苷(HT)的DMEM(Dulbecco氏改良的Eagle培养基)中。使细胞在大的培养皿中生长至汇合,中间更换培养基并分裂。一旦生长至汇合,用刮除法收获细胞。将收获的细胞混悬在半体积的新鲜的生理学的磷酸缓冲盐水(PBS)溶液中,并低速离心(900×g)。将此操作再重复一次。然后用设定(setting)为#7的polytron,将收集的细胞在10体积的50mM Tris.HCl(pH7.4)和0.5mM EDTA中匀浆15秒钟。将匀浆在900×g下离心15分钟,除去核粒子和其它细胞碎片。弃去沉淀物(pellet),将上清液在40000×g下再离心30分钟。将得到的沉淀物重新混悬在少量体积的Tris.HCl缓冲液中,确定10-25μL体积的等分试样中的组织蛋白质含量。根据Lowry等人(J.Biol.Chem.,193:265(1951))所述的方法进行蛋白含量测定,将牛血清白蛋白(BSA)用作标准品。用包含:0.1%抗坏血酸、10mM帕吉林和4mM CaCl2的50mM Tris.HCl缓冲液调整混悬的细胞膜的体积,以得到组织蛋白质浓度为1-2mg每ml的混悬液。将制备的膜混悬液(多倍浓缩液)分为1ml体积的等分试样,并在-70℃下贮存待在后面的结合实验中使用。
在96孔微滴定板中进行结合测定,总体积为200μL。向每一孔中加入:60μL由pH7.4的50mM Tris.HCl缓冲液组成且含有4mM CaCl2的孵育缓冲液;20μL[125I]DOI(S.A.,2200 Ci/mmol,NEN Life Science)。
解离常数,人类5-羟色胺5-HT2C受体的[125I]DOI的KD为0.4nM,这是用[125I]DOI浓度增加的饱和结合测定的。最后加入含有50μg受体蛋白的100μL的组织混悬液,开始反应。在加在20.0μL体积中的1μM未标记的DOI存在下,测定非特异性结合。将测试化合物加入到20.0μL中。将混合物在室温下孵育60分钟。通过快速过滤中止孵育。用PackardFiltermate 196捕获器,将结合的配体-受体复合物经96孔过滤器过滤。将捕获到过滤盘上的结合的复合物在真空干燥箱中加热到60℃干燥,在装有六(6)光电倍增管检测器的Packard TopCount中,用40μLMicroscint-20闪烁液,通过液体闪烁测定放射活性。
特异性结合定义为总的结合放射活性减去1μM未标记的DOI存在时的结合量。将各种浓度的测试药物存在时的结合,以无药物时的特异性结合的百分数表示。然后将这些结果以log%结合对log测试药物的浓度作图。数据点的非线性回归分析得到测试化合物的EC50和Ki值,置信区间为95%。或者,对数据点下倾的线性回归线作图,EC50值可以从曲线上读出,通过解下面的等式可以确定Ki值:
其中,L为所用的放射性配体的浓度,KD为配体与受体的解离常数,两者都以nM表示。
各种参考化合物的Ki值(95%置信区间)提供在表2中。
表2:各种参考化合物的Ki数据
化合物 | Ki |
利坦色林 | 2.0(1.3-3.1)nM |
酮色林 | 94.8(70.7-127.0)nM |
米安色林 | 2.7(1.9-3.8)nM |
氯氮平 | 23.2(16.0-34.0)nM |
美塞西平 | 4.6(4.0-6.0)nM |
美西麦角 | 6.3(4.6-8.6)nM |
洛沙平 | 33.0(24.0-47.0)nM |
mCPP | 6.5(4.8-9.0)nM |
DOI | 6.2(4.9-8.0)nM |
通过下面的方法测定式I化合物对钙动员的影响,从而估测它们对脑5-HT2C产生激动剂响应的能力,所述方法为:将稳定表达人5-HT2C受体的CHO细胞在添加10%胎牛血清和非必需氨基酸的Dulbecco改良的Eagle培养基中进行培养。在对5-HT2C受体刺激的钙动员进行评价的24小时之前,将细胞以40K细胞/孔浓度铺板在澄清见底黑色板壁的96孔板中。对于钙研究而言,在Hank氏缓冲的盐水(HBS)中及37℃下,将细胞加载钙指示剂染料Fluo-3-AM,处理60分钟。在室温下用HBS洗涤细胞,并转移到荧光成像读板仪中(FLIPR,Molecular Devices,Sunnyvale,CA),采集钙的影像。用氩离子激光器在488nm进行激发,并使用510-560nm的发射过滤器。以1秒时间间隔采集荧光影像和相对强度,用FLIPR的内部流控模块进行10次基线测量后,加入激动剂对细胞进行刺激。荧光量的增加与细胞内钙的增加相对应。
为了对激动剂的药理学进行评价,用原始荧光计数数据的最大量减去最小量计算,测定响应不同浓度激动剂的钙变化。然后,将钙变化用使用最大有效浓度5-HT时观察到的响应的百分比表示。通过使用4-参数对数函数的log浓度%最大量5-HT响应曲线的非线性回归分析,对EC50值进行估测。在某些具体实施方案中,本发明化合物提供了约≤1000nM的EC50值。在其它具体实施方案中,本发明化合物提供了约≤100nM的EC50值,在另外其它具体实施方案中,约≤20nM,在另外其它具体实施方案中,约≤5nM,且在某些具体实施方案中,约≤2nM。
各种参考化合物的EC50值提供在表3中。
表3:各种参考化合物的EC50数据:
化合物 | EC50 |
5-HT | 0.5nM |
DOI | 0.5nM |
mCPP | 5.4nM |
在该文中引用的或描述的每份专利、专利申请和出版物的全部内在此引入作为参考。
虽然申请人在此列举了许多本发明的具体实施方案,但是显而易见的是,可以改变所述的基本构思,以提供其它利用本发明化合物和方法的具体实施方案。因此,应当理解,本发明的范围用本申请的权利要求进行定义,而不是通过在此以举例的方式列举的具体实施方案进行定义。
Claims (34)
2.根据权利要求1的化合物,其中R1为氢。
3.根据权利要求1或权利要求2的化合物,其中R3为氯或氟。
4.根据权利要求1-3中任何一项的化合物,其中Rx独立地为卤素。
5.根据权利要求1-4中任何一项的化合物,其中R2为-OH或-OS(O)2OH。
6.根据权利要求1-5中任何一项的化合物,其中R4为-OH或-OS(O)2OH。
10.式VII化合物或其药学上可接受的盐:
其中:
每个独立代表单键或双键,前提是两个基团不同时代表双键;
R1为氢、-C(O)R、-Glu、-C(O)Glu或-C(O)OGlu;
R为氢或低级烷基;
R2为氢、-OH、-OS(O)2OH或-OGlu;
R3为氢、卤素、甲基、甲氧基、-OH、-OS(O)2OH或-OGlu;
R4为氢、-OH、-OS(O)2OH或-OGlu;
Ra和Rb每个都为氢或两者一起形成氧代基团;
Rc和Rd每个都为氢或两者一起形成氧代基团;
每个Rx独立地为卤素或低级烷基;
R5独立地为氢、-OH、-OS(O)2OH或-OGlu;
每个Glu为葡糖苷酸基;且
n为1或2;
前提是至少R1、R2、R4和R5之一包含葡糖苷酸基。
11.根据权利要求10的化合物,其中R1为-Glu、-C(O)Glu或-C(O)OGlu。
12.根据权利要求10或权利要求11的化合物,其中R2为-OH且R4为氢。
13.根据权利要求10或权利要求11的化合物,其中R4为-OH且R2为氢。
14.根据权利要求10或权利要求11的化合物,其中R2为-OGlu且R4为氢。
18.组合物,该组合物包含根据权利要求1-17中任何一项的化合物和一种或多种药学上可接受的载体、稀释剂或赋形剂。
19.权利要求18的组合物,该组合物还包含另外的药物,该药物选自抗精神病药物、抗抑郁药物、抗肥胖药物、用于调节膀胱活性的药物、阿片拮抗剂、治疗ADD或ADHD的药物、认知改善药物、治疗性功能障碍的药物或止痛药。
20.治疗患者疾病的方法,该方法包括给予患者治疗有效量的权利要求1-17中的任何一项的化合物或根据权利要求18或权利要求19的组合物,所述疾病选自至少下列疾病之一:精神疾病、焦虑症、双相情感障碍、抑郁症、月经前综合征(PMS)、月经前焦虑障碍(PMDD)、进食障碍、膀胱控制障碍、物质滥用或物质依赖、认知障碍、ADD或ADHD、冲动性疾病、上瘾性疾病、男性或女性性功能障碍、疼痛、运动障碍、帕金森病、癫痫、偏头痛、慢性疲劳综合征、神经性厌食症、睡眠障碍、缄默症、或一种或多种中枢神经系统缺陷。
21.权利要求20的方法,其中所述精神疾病为精神分裂症、妄想型精神分裂症、错乱型精神分裂症、紧张型精神分裂症、未分化型精神分裂症、精神分裂症样疾病、分裂情感性精神病、妄想症、物质诱导的精神病和其它没有特别指出的精神病;L-DOPA-诱导的精神病;与阿尔茨海默氏痴呆有关的精神病;与帕金森病有关的精神病;与路易体有关的精神病。
22.权利要求20的方法,其中所述疾病为双相情感障碍,并选自I型双相情感障碍、II型双相情感障碍和循环情感障碍;双相躁狂、痴呆和有精神病特征的抑郁症,或双相抑郁和双相躁狂之间的循环。
23.权利要求20的方法,其中所述抑郁症为重性抑郁障碍、季节性情感障碍、心境恶劣障碍、物质诱导的情绪障碍、其它没有特别指出的抑郁症、难治性抑郁症、重性抑郁发作。
24.权利要求23的方法,该方法还包括给予患者抗抑郁药物,所述抗抑郁药物选自5-羟色胺重摄取抑制剂(SRIs)、去甲肾上腺素重摄取抑制剂(NRIs)、5-羟色胺和去甲肾上腺素重摄取的抑制剂(SNRIs)、单胺氧化酶抑制剂(MAOIs)、单胺氧化酶的可逆抑制剂(RIMAs)、磷酸二酯酶-4(PDE4)抑制剂、促肾上腺皮质激素释放因子(CRF)拮抗剂、α-肾上腺素受体拮抗剂、三重摄取抑制剂、褪黑激素激动剂、上神经递质阻滞剂(SNUBs)、肾上腺素能和特异性5-羟色胺能抗抑郁药(NaSSAs)或物质P/神经激肽受体拮抗剂。
25.权利要求20的方法,其中所述认知障碍为学习障碍。
26.权利要求20的方法,其中所述患者为进行肥胖治疗的患者。
27.权利要求20的方法,其中患者为进行ADD或ADHD治疗的患者。
28.权利要求20的方法,其中所述物质滥用或物质依赖中的物质为娱乐物质、有药理作用的物质、镇定剂、兴奋剂、镇静剂、违禁药物。
29.权利要求20的方法,该方法还包括给予患者另外的药物,所述药物选自抗精神病药物、抗抑郁药物、抗肥胖药物、用于调节膀胱活性的药物、阿片拮抗剂、治疗ADD或ADHD的药物、认知改善药物、治疗性功能障碍的药物或止痛药。
30.治疗患者的精神分裂症的方法,该方法包括给予患者治疗有效量的根据权利要求18的组合物。
32.治疗患者的双相情感障碍的方法,该方法包括给予患者治疗有效量的根据权利要求18的组合物。
33.治疗患者的抑郁症的方法,该方法包括给予患者治疗有效量的根据权利要求18的组合物。
34.根据权利要求1-17中任何一项的化合物或根据权利要求18或权利要求19中的组合物在制备治疗患者疾病的药物中的用途,所述疾病选自至少下列疾病之一:精神疾病、焦虑症、双相情感障碍、抑郁症、月经前综合征(PMS)、月经前焦虑障碍(PMDD)、进食障碍、膀胱控制障碍、物质滥用或物质依赖、认知障碍、ADD或ADHD、冲动性疾病、上瘾性疾病、男性或女性性功能障碍、疼痛、运动障碍、帕金森病、癫痫、偏头痛、慢性疲劳综合征、神经性厌食症、睡眠障碍、缄默症、或一种或多种中枢神经系统缺陷。
35.产品,该产品包含权利要求1-17的任何一项中要求保护的化合物和选自抗精神病药物、抗抑郁药物、抗肥胖药物、用于调节膀胱活性的药物、阿片拮抗剂、治疗ADD或ADHD的药物、认知改善药物、治疗性功能障碍的药物或止痛药的另外的药物,将上述化合物和另外的药物作为组合的制剂同时、分开或相继使用,用于医治患有至少下列疾病之一的患者,所述疾病选自精神疾病、焦虑症、双相情感障碍、抑郁症、月经前综合征(PMS)、月经前焦虑障碍(PMDD)、进食障碍、膀胱控制障碍、物质滥用或物质依赖、认知障碍、ADD或ADHD、冲动性疾病、上瘾性疾病、男性或女性性功能障碍、疼痛、运动障碍、帕金森病、癫痫、偏头痛、慢性疲劳综合征、神经性厌食症、睡眠障碍、缄默症、或一种或多种中枢神经系统缺陷。
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MX2007013026A (es) * | 2005-04-22 | 2008-01-11 | Wyeth Corp | Combinaciones terapeuticas para el tratamiento o prevencion de trastornos psicoticos. |
WO2006116150A1 (en) | 2005-04-22 | 2006-11-02 | Wyeth | Dihydrobenzofuran derivatives and uses thereof |
AU2006239941A1 (en) * | 2005-04-24 | 2006-11-02 | Wyeth | Methods for modulating bladder function |
-
2006
- 2006-04-21 WO PCT/US2006/015192 patent/WO2006116150A1/en active Application Filing
- 2006-04-21 GT GT200600164A patent/GT200600164A/es unknown
- 2006-04-21 JP JP2008507944A patent/JP2008538572A/ja active Pending
- 2006-04-21 US US11/409,479 patent/US7402687B2/en not_active Expired - Fee Related
- 2006-04-21 BR BRPI0608475-3A patent/BRPI0608475A2/pt not_active Application Discontinuation
- 2006-04-21 EP EP06758483A patent/EP1871755A1/en not_active Withdrawn
- 2006-04-21 CN CNA2006800167696A patent/CN101175740A/zh active Pending
- 2006-04-21 TW TW095114317A patent/TW200718692A/zh unknown
- 2006-04-21 CA CA002604916A patent/CA2604916A1/en not_active Abandoned
- 2006-04-21 MX MX2007012883A patent/MX2007012883A/es not_active Application Discontinuation
- 2006-04-21 PE PE2006000419A patent/PE20061298A1/es not_active Application Discontinuation
- 2006-04-21 AU AU2006239920A patent/AU2006239920A1/en not_active Abandoned
- 2006-04-21 AR ARP060101593A patent/AR056980A1/es not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101712879B (zh) * | 2009-09-23 | 2013-03-20 | 中国科学技术大学 | 制备2,3-二氢苯并呋喃和生物油的方法及其专用装置 |
Also Published As
Publication number | Publication date |
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MX2007012883A (es) | 2007-12-10 |
JP2008538572A (ja) | 2008-10-30 |
AR056980A1 (es) | 2007-11-07 |
PE20061298A1 (es) | 2006-12-24 |
AU2006239920A1 (en) | 2006-11-02 |
GT200600164A (es) | 2007-03-14 |
US7402687B2 (en) | 2008-07-22 |
EP1871755A1 (en) | 2008-01-02 |
BRPI0608475A2 (pt) | 2010-01-05 |
CA2604916A1 (en) | 2006-11-02 |
US20060241176A1 (en) | 2006-10-26 |
WO2006116150A1 (en) | 2006-11-02 |
TW200718692A (en) | 2007-05-16 |
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