CN101410118A - 疼痛的治疗 - Google Patents
疼痛的治疗 Download PDFInfo
- Publication number
- CN101410118A CN101410118A CNA2007800105001A CN200780010500A CN101410118A CN 101410118 A CN101410118 A CN 101410118A CN A2007800105001 A CNA2007800105001 A CN A2007800105001A CN 200780010500 A CN200780010500 A CN 200780010500A CN 101410118 A CN101410118 A CN 101410118A
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- Prior art keywords
- pain
- diaza
- pentamethylene
- indole
- octahydro
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Abstract
本发明提供了治疗哺乳动物疼痛的方法,其包括给需要该类治疗的哺乳动物施用治疗疼痛有效量的式(Ⅰ)化合物或其可药用的盐,式(Ⅰ)化合物中R1、R2、R3、R4、R5、R6、n和m各自如本文所定义和描述。本发明还提供了用于治疗疼痛的药物组合物,其包含治疗疼痛有效量的式(Ⅰ)化合物。
Description
相关申请的交叉参考
本申请要求了于2006年3月24日提交的序号为60/785,633的美国临时专利申请的优先权,将其特此全文引入本文作为参考。
发明背景
在文献中已经以各种不同的方式对疼痛进行了表征和描述。例如,疼痛在性质上可以是剧烈的、局部的、锐痛或刺痛性的和/或钝性的、痛苦的、扩散或灼烧性的。疼痛也可以是中枢性的(即,发生于脊髓背侧角、脑干和脑)或外周性的(即,发生于损伤部位和周围组织)。发生很长一段时间的(即,持续的)疼痛通常被称为慢性疼痛。慢性疼痛的实例包括神经性疼痛、炎性痛和癌症疼痛。这些疼痛可能与痛觉过敏和/或异常性疼痛有关,其中痛觉过敏是指对典型有害的刺激敏感性增加,异常性疼痛是指对典型无害的刺激敏感性增加。
目前缺乏足够的药理学治疗的一类慢性疼痛是神经性疼痛。神经性疼痛通常被认为是由外周或中枢神经系统的损伤或病理学变化造成的慢性疼痛。与神经性疼痛有关的病理学变化的实例包括延长的外周或中枢神经原敏化作用、与中枢敏化作用有关的神经系统抑制和/或兴奋功能的损害和副交感神经和交感神经系统之间的相互作用异常。许多临床病症与神经性疼痛有关或者形成了神经性疼痛的基础,所述病症包括例如糖尿病、切断术的创伤后疼痛、下背痛、癌症、化学损伤或毒素、其它大外科手术、由创伤性损伤压迫造成的外周神经损害、营养缺乏或感染如带状疱疹或HIV。
目前多种类型的试剂被用来治疗疼痛,例如,非麻醉性镇痛剂如阿司匹林、对乙酰氨基酚或布洛芬;非甾体抗炎药(NSAIDs);麻醉性镇痛剂如吗啡、氢吗啡酮、芬太尼、可待因或哌替啶;甾族化合物如泼尼松或地塞米松;三环抗抑郁药如阿米替林、地昔帕明或丙咪嗪;抗癫痫药如加巴喷丁、卡马西平、托吡酯、丙戊酸钠或苯妥英;或这些不同物质的组合。但是,对于慢性疼痛的治疗而言,这些物质通常不令人满意,并且可能具有副作用如困倦、头晕、口干、体重增加、记忆力受损和/或直立性低血压。
最近,令人感兴趣的是用N-甲基-D-天冬氨酸(“NMDA”)受体抑制剂(在下文被称为“NMDA受体拮抗剂”)来治疗疼痛。虽然一些该类化合物表现出前景,但是由于一些不利作用如头痛、心率增加、血压升高;运动功能紊乱如共济失调或镇静;和/或拟精神病作用如头晕、幻觉、烦躁不安、或当以镇静剂量施用时观察到的认识功能紊乱,其临床应用一直受限。因此,仍然需要治疗疼痛的改善的疗法。
发明概述
本发明提供了治疗哺乳动物的疼痛的方法,其包括给需要该类治疗的哺乳动物施用治疗疼痛有效量的至少一种具有式I的化合物:
或其可药用的盐,其中:
表示单键或双键;
n是1或2;
m是0或1;
R1和R2各自独立地是卤素、-CN、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
各R独立地是氢或C1-6烷基;
R3和R4与它们所键合的碳原子一起形成饱和或不饱和的4-8元环,其中所述环任选地被1-3个独立地选自卤素、-R或OR的基团取代;且
R5和R6各自独立地是-R。
本发明还提供了包含治疗疼痛有效量的式I化合物或其可药用的盐和至少一种药用载体或其它成分的药物组合物。
在本发明的一些实施方案中,式I化合物与其它疼痛缓解剂和/或一种或多种减少疼痛缓解剂副作用的物质组合施用。
本发明还提供了被配制用于施用于哺乳动物来治疗疼痛的包含一种或多种式I化合物的药物组合物。在一些实施方案中,该药物组合物是单位剂型的形式。本发明进一步提供了用于治疗哺乳动物疼痛的单位剂型形式的包含一种或多种式I化合物的治疗包装。
众所周知的是,神经递质5-HT在伤害感受传递的抑制中起着重要作用。许多研究已经证明,在疼痛处理途径中存在至少4族5-HT受体,包括5-HT1、5-HT2、5-HT3和5-HT4(1-2)。此外,虽然对其精确机理仍然知之甚少,但是表明5-HT2C受体对神经性疼痛有抑制作用(3-5)。总之,5-HT2C激动剂可有效治疗糖尿病性神经病、疱疹后神经痛、下背痛、幻肢痛、内脏痛(慢性的和急性的)、肠易激惹综合征痛、易激惹性肠病痛(irritablebowel disease pain)、纤维肌痛和复杂性区域疼痛综合征。
附图简要说明
图1表示化合物1在触觉异常性疼痛模型中的效力。
图2表示化合物2在机械痛觉过敏模型中的效力。
本发明某些实施方案的详细描述
1.化合物
本发明利用式I的5-HT2c受体激动剂或部分激动剂:
或其可药用的盐,其中:
表示单键或双键;
n是1或2;
m是0或1;
R1和R2各自独立地是卤素、-CN、-R、-OR、-C1-6全氟代烷基或-OC1-6全氟代烷基;
各R独立地是氢或C1-6烷基;
R3和R4与它们所键合的碳原子一起形成饱和或不饱和的4-8元环,其中所述环任选地被1-3个独立地选自卤素、-R或OR的基团取代;且
R5和R6各自独立地是-R。
本文所用的术语“烷基”包括但不限于直链和支链,如甲基、乙基、正-丙基、异丙基、正-丁基、异丁基、仲-丁基或叔-丁基。
本文所用的术语“卤素”或“卤代”是指氯、溴、氟或碘。
本文所用的术语“全氟代烷基”是指其中所述烷基上的每一个氢原子均被氟原子代替的本文所定义的烷基。该类全氟代烷基包括-CF3。
本文所用的术语“有效量”和“治疗有效量”是指当施用于个体时可有效治疗、预防、延迟患者所患病症或降低患者所患病症的严重程度的化合物或组合的量。具体而言,本发明的治疗有效量是足以治疗、预防精神病性精神障碍的至少一种症状或发作或者延迟精神病性精神障碍的至少一种症状或发作的开始或者改善精神病性精神障碍的至少一种症状或发作的量。
术语“可药用的盐”是指用有机酸或无机酸例如乙酸、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、羟基乙酸、丙酮酸、甲磺酸、乙磺酸、甲苯磺酸、水杨酸、苯甲酸或类似的已知的可接受的酸处理式I化合物得到的盐。在某些实施方案中,本发明提供了式I化合物的盐酸盐。
本文所用的术语“患者”是指哺乳动物。在某些实施方案中,术语“患者”是指人。
本文所用的术语“施用”是指向患者直接施用化合物或组合物或者向患者施用化合物的前药衍生物或类似物,其将在患者体内形成等价量的活性化合物或物质。
上文所定义的或在本文所述的类或亚类中定义的式I化合物对脑血清素受体的2C亚型具有亲和性和激动剂或部分激动剂活性。
2.举例性化合物的描述:
在某些实施方案中,式I中的R1基团是R、OR、卤素、氰基或-C1-3全氟代烷基。在另一些实施方案中,式I中的R1基团是氢、卤素、氰基、-OR,其中R是C1-3烷基或三氟甲基。根据另一个实施方案,式I中的R1基团是氢。
在某些实施方案中,式I中的R2基团是R、OR、卤素、氰基或-C1-3全氟代烷基。在另一些实施方案中,式I中的R2基团是氢、卤素、氰基、-OR,其中R是氢、C1-3烷基或三氟甲基。根据另一个实施方案,式I中的R2基团是氢。
根据本发明的一个方面,式I中的R1和R2基团中至少一个是-OH。根据本发明的另一个方面,式I中的R1和R2基团均是-OH。
根据另一个实施方案,式I中的R1和R2基团各自是氢。根据又一个实施方案,式I中的R5和R6基团各自是氢。
如上面一般性定义的那样,式I中的R3和R4基团一起形成饱和或不饱和的4-8元环,其中所述环任选地被1-3个独立地选自卤素、-R或OR的基团取代。根据一个实施方案,式I中的R3和R4基团一起形成饱和或不饱和的5-8元环,其中所述环任选地被1-3个独立地选自卤素、-R或OR的基团取代。在某些实施方案中,式I中的R3和R4基团一起形成饱和或不饱和的5-6元环,其中所述环任选地被1-3个独立地选自卤素、-R或OR的基团取代。该4-8元(优选5-8元,更优选5-6元)环优选地是碳环。该4-8元(优选5-8元,更优选5-6元)环优选地是饱和的。但是,如果该4-8元(优选5-8元,更优选5-6元)环是不饱和的,则其不饱和度可以是烯烃性的或芳族的。
如上面一般性定义的那样,n是1或2。因此,本发明提供了式I-a和I-b的化合物:
或其可药用的盐,其中m、R1、R2、R3、R4、R5和R6各自如上文式I化合物中所定义和如上文和本文的类和亚类中所述。
如上面一般性定义的那样,m是0或1。因此,本发明提供了式I-c和I-d的化合物:
或其可药用的盐,其中n、R1、R2、R3、R4、R5和R6各自如上文式I化合物中所定义和如上文和本文的类和亚类中所述。
在另一些实施方案中,n是1,m是1,式I中的R3和R4基团一起形成饱和的5-元环,并且所述化合物是式II的化合物:
或其可药用的盐,其中R1、R2、R5和R6各自如上文式I化合物中所定义和如上文和本文的类和亚类中所述。
根据本发明的另一个方面,提供了其中n是1、m是0且式I中的R3和R4基团一起形成饱和的5-元环的化合物,并且所述化合物是式III的化合物:
或其可药用的盐,其中R1、R2、R5和R6各自如上文式I化合物中所定义和如上文和本文的类和亚类中所述。
本发明的化合物含有不对称碳原子,从而产生立体异构体,包括对映异构体和非对映异构体。因此,本发明涉及所有这些立体异构体,并且涉及立体异构体的混合物。在本申请的各处,在没有给出不对称中心的绝对构型的情况下,本发明的产物名称涵盖各个立体异构体以及立体异构体的混合物。
根据另一个方面,本发明提供了式I-e或I-f的化合物:
或其可药用的盐,其中n、m、R1、R2、R3、R4、R5和R6各自如上文式I化合物中所定义和如上文和本文的类和亚类中所述。
在某些实施方案中,本发明提供了式IV或V的化合物:
或其可药用的盐,其中R1、R2、R5和R6各自如上文式I化合物中和如上文和本文所述的类和亚类中所定义。
在优选对映异构体的情况下,在一些实施方案中其可以被以基本上不含相应对映异构体的形式被提供。因此,基本上不含相应对映异构体的对映异构体是指通过分离技术分开的或分离的或者以不含相应对映异构体的形式制备的化合物。本文所用的“基本上不含”意指化合物由显著更高比例的一种对映异构体组成。在某些实施方案中,化合物由至少约90重量%的优选的对映异构体组成。在本发明的另一些实施方案中,化合物由至少约99重量%的优选的对映异构体组成。优选的对映异构体可以通过本领域技术人员已知的任何方法(包括手性高压液相色谱法(HPLC)以及手性盐的形成和结晶)从外消旋混合物中分离出或者可以通过本文所述的方法制备。参见例如Jacques等人,Enantiomers,Racemates and Resolutions(WileyInterscience,New York,1981);Wilen,S.H.等人,Tetrahedron 33:2725(1977);Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962);Wilen,S.H.Tables of Resolving Agents and Optical Resolutions第268页(E.L.Eliel编辑,Univ.of Notre Dame Press,Notre Dame,IN1972)。
在下面的表1中列出了可用于本发明的方法的举例性化合物。
表1.式I的举例性化合物
1-氟-2-甲氧基-4,5,6,7,9,9a,10,11,12,12a-十氢环戊烷并[c][1,4]二氮杂并[6,7,1-ij]喹啉;
1-氟-2-甲氧基-4,5,6,7,9,9a,10,11,12,13,14,14a-十二氢环庚烷并[c][1,4]二氮杂并[6,7,1-ij]喹啉;
(7bR,10aR)-1,2,3,4,8,9,10,10a-八氢-7bH-环戊烷并-[b][1,4]二氮杂并[6,7,1-hi]吲哚;
(2S)-(rel-7bR,10aR)-2-甲基-1,2,3,4,8,9,10,10a-八氢-7bH-环戊烷并[b][1,4]二氮杂并[6,7,1-hi]吲哚;
(2R)-(rel-7bR,10aR)-2-甲基-1,2,3,4,8,9,10,10a-八氢-7bH-环戊烷并[b][1,4]二氮杂并[6,7,1-hi]吲哚;
rel-(4S,7bS,10aS)-4-甲基-1,2,3,4,8,9,10,10a-八氢-7bH-环戊烷并[b][1,4]二氮杂并[6,7,1-hi]吲哚;
(7bR,10aR)-9,9-二甲基-1,2,3,4,8,9,10,10a-八氢-7bH-环戊烷并[b][1,4]二氮杂并[6,7,1-hi]吲哚;和
或其可药用的盐。本发明的另一个方面提供了上面各化合物的盐酸盐。
而且,本领域普通技术人员应当理解的是本文中对化合物的提及旨在包括提及任何相关的形式如多晶型物、水合物等。而且,化合物可以以前药形式或以在制备、处理、配制、递送过程中或在体内转化为活性剂的其它形式被提供。
还应当理解的是本发明的各原则可应用本文所述的化合物的所有放射性标记形式,包括例如其中放射性标记选自3H、11C、14C、18F、123I和125I的那些。这类放射性标记的化合物在代谢药动学研究中和在动物和人的结合测定中可用作研究和诊断工具。
用于本发明的式I化合物可以按照任何可使用的方法来获得或制备,所述方法包括在美国专利7,129,237(于2003年4月24日提交的序号为10/422,524的美国专利申请)和WO2006/052768(要求了于2004年11月5日提交的序号为60/625,300的美国临时专利申请的优先权)中详细描述的方法,将它们各自全文特此引入本文作为参考。
不希望受任何特定理论的束缚,本发明的发明人注意到式I化合物是5HT2c受体的高特异性激动剂。具体而言,本发明将神经递质5-HT在伤害感受传递的抑制中起重要作用的观察结果与多种研究证明在疼痛处理途径中存在至少四族5-HT受体(包括5-HT1、5-HT2、5-HT3和5-HT4)的观察结果(Doly等人,J Comp Neurol.476(4):316-329,2004;Ridet等人,J.Neurosc.Res 38(1):109-21,1994)联系了起来。此外,虽然仍然对其精确机理知之甚少,但是表明5-HT2C受体在神经性疼痛中具有抑制作用(Obata等人,Pain 108(1-2):163-9,2004;Sasaki等人,Anesthesia & Analgesia,Baltimore,MD,96(4):1072-1078,2003;Obata等人,Brain Research965(1-2):114-20,2003)。因此,根据本发明,5-HT2c激动剂可有效治疗糖尿病性神经病、疱疹后神经痛、下背痛(low back pain)、幻肢痛、内脏痛(慢性的和急性的)、肠易激惹综合征痛、易激惹性肠病痛、纤维肌痛和复杂性区域疼痛综合征。此外,本发明还包括式I化合物所表现出来的独特亲合力和选择性可为疼痛提供有效治疗的认识。此外,本发明还认识到式I化合物可在较低剂量下和/或在比其它可用治疗副作用更少的情况下治疗疼痛。
2.药物组合物
根据本发明,式I化合物可以以其自身的形式被施用来治疗疼痛。但是,其更常见地是在药物组合物中被施用,所述药物组合物除了包含治疗疼痛有效量的一种或多种式I化合物外还可包含一种或多种本领域技术人员已知的用于配制药物组合物的成分。该类成分包括例如载体(例如,固体或液体形式的载体)、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、包封材料、乳化剂、缓冲剂、防腐剂、甜味剂、增稠剂、着色剂、粘度调节剂、稳定剂或渗透压调节剂或它们的组合。
固体药物组合物优选包含一种或多种固体载体,并任选地包含一种或多种其它添加剂如矫味剂、润滑剂、增溶剂、助悬剂、填充剂、助流剂、压缩助剂、粘合剂或片剂崩解剂或包封材料。合适的固体载体包括例如磷酸钙、硬脂酸镁、滑石粉、糖类、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、低熔点蜡或离子交换树脂或它们的组合。在散剂药物组合物中,载体优选是与微细分割的活性成分混合的微细分割的固体。在片剂中,一般将活性成分与具有所需压缩性的载体以合适的比例混合,并任选地混入其它添加剂,然后将其压缩成所需形状和大小。固体药物组合物如散剂和片剂优选包含不超过99%的活性成分。
液体药物组合物优选包含一种或多种式I化合物和一种或多种用于形成溶液剂、混悬剂、乳剂、糖浆剂、酏剂或加压组合物的液体载体。可药用的液体载体包括例如水、有机溶剂、可药用的油类或脂肪类或它们的组合。液体载体可包含其它合适的添加剂如增溶剂、乳化剂、缓冲剂、防腐剂、甜味剂、矫味剂、助悬剂、增稠剂、着色剂、粘度调节剂、稳定剂或渗透压调节剂或它们的组合。如果该液体制剂用于儿科使用,则其一般需要避免包含醇。
适于口服或胃肠外施用的液体载体的实例包括水(优选包含添加剂如纤维素衍生物如羧甲基纤维素钠)、醇类或其衍生物(包括单羟基醇或多羟基醇如二醇类)或油类(例如分馏椰子油和花生油)。对于胃肠外施用而言,载体还可以是油性酯如油酸乙酯和肉豆蔻酸异丙酯。用于加压组合物的液体载体可以是卤化烃类或其它可药用的抛射剂。
为无菌溶液剂或混悬剂的液体药物组合物可以被胃肠外施用,例如通过肌内、腹膜内、硬膜外、鞘内、静脉内或皮下注射施用。用于口服或透粘膜施用的药物组合物可以是液体或固体组合物的形式。
在本发明的某些实施方案中,药物组合物除包含式I化合物外还可以包含治疗有效量的一种或多种其它疼痛缓解剂和/或一种或多种其它药学活性剂(参见下面的进一步讨论)。因此,本发明还提供了用于治疗疼痛的药物组合物,其包含治疗疼痛有效量的至少两种各自单独具有疼痛治疗活性的不同的活性剂,至少一种活性剂是式I化合物。本领域普通技术人员应当理解的是,在该类组合中提供“治疗疼痛有效量”所需的每种活性剂的量可能与各活性剂单独使用时提供治疗疼痛有效量所需的量不同。在某些实施方案中,在组合中至少一种疼痛治疗剂的量比单独使用时更低。在本发明的一些实施方案中,用式I化合物和阿片类镇痛剂的组合来治疗疼痛。
在本发明的一些实施方案中,药物组合物以单位剂型如片剂或胶囊剂的形式被提供。对于该类形式而言,组合物被细分为包含适宜量活性成分的单位剂量。单位剂型可以是包装的组合物,例如包装的散剂、小瓶、安瓿、预填充的注射器或包含液体的小药囊。单位剂型可以是例如胶囊剂或片剂本身,或者其可以是包装形式的适宜数目的任何该类组合物。
因此,本发明还提供了用于治疗哺乳动物疼痛的单位剂型的药物组合物,其包含可有效治疗疼痛的单位剂量的至少一种式I化合物。正如本领域技术人员将意识到的那样,优选的可有效治疗疼痛的单位剂量将取决于例如施用方法。式I化合物的典型剂量通常为约0.5mg至约500mg,在一些实施方案中为约1mg或约10mg至约500mg。
本发明还提供了用于将式I化合物给予待治疗疼痛的哺乳动物的治疗包装。在一些实施方案中,该治疗包装包含一个或多个单位剂量的式I化合物、含有该一个或多个单位剂量的容器和指导用该包装治疗哺乳动物疼痛的标签。在某些实施方案中,单位剂量是片剂或胶囊剂的形式。在一些情况下,每个单位剂量是治疗疼痛的有效量。
3.其它活性剂
式I化合物可单独施用来根据本发明治疗疼痛,或者可以与一种或多种其它药学活性剂组合使用。在本发明的一些实施方案中,所述其它药学活性剂也具有疼痛缓解活性。作为替代选择或者另外地,所述其它活性剂可缓解与疼痛缓解剂有关的一种或多种副作用,或者可缓解与疼痛有关的或者患有疼痛或易于罹患疼痛的个体关注的一种或多种其它症状或病症。
因此,根据本发明,术语“疼痛缓解剂”是指直接或间接治疗疼痛或疼痛症状的任何物质。间接疼痛缓解剂的实例包括例如抗炎药如抗类风湿药。
在本发明涉及两种或更多种药学活性剂例如两种或更多种疼痛缓解剂的施用的情况下,可以将两种或更多种活性剂彼此同时施用(如在相同的时间单独施用或者在一个药物组合物中一起施用)和/或相继施用。一般而言,式I化合物和其它药学活性剂以使得二者在治疗疼痛的某一时期内均存在于哺乳动物体内的方式被施用。
而且,据信两种或更多种药学活性剂可以通过相同的施用途径或通过不同的途径进行递送。合乎需要的施用途径可能在很大程度上取决于所选择的特定活性剂,其中许多活性剂具有本领域技术人员已知的推荐施用途径。例如,阿片类物质一般通过口服、静脉内或肌内施用途径被施用。类似地,如本领域中已知的那样,组合物中药学活性剂的剂量可能受施用途径影响。一般而言,药学活性剂可以根据本领域技术人员已知的实践来确定剂量和施用,所述实践例如在参考资料如Physicians′Desk Reference,第55版,2001,出版商Medical Economics Co.,Inc.,Montvale,NJ中所公开的那些。
可以与本发明的式I化合物一起施用的疼痛缓解剂的实例包括但不限于镇痛剂如非麻醉性镇痛剂或麻醉性镇痛剂;抗炎药如非甾体抗炎药(NSAIDs)、甾族化合物或抗风湿药;偏头痛制剂如β肾上腺素能阻滞剂、麦角衍生物或异美汀;三环抗抑郁药如阿米替林、地昔帕明或丙咪嗪;抗癫痫药如加巴喷丁、卡马西平、托吡酯、丙戊酸钠或苯妥英;α2激动剂;或选择性血清素再摄取抑制剂/选择性去甲肾上腺素摄取抑制剂或它们的组合。
本领域技术人员将意识到,本文所述的一些活性剂发挥缓解多种病症如疼痛和炎症的作用,而另一些活性剂仅能缓解一种症状如疼痛。具有多种性质的活性剂的一个具体实例是阿司匹林,当以高剂量被给予时,阿司匹林是一种抗炎剂,但是在以较低剂量给予时,其仅仅是一种镇痛剂。疼痛缓解剂可以包括上述活性剂的任何组合,例如疼痛缓解剂可以是非麻醉性镇痛剂与麻醉性镇痛剂的组合。
可用于实施本发明的非麻醉性镇痛剂包括例如水杨酸类如阿司匹林、布洛芬酮洛芬萘普生对乙酰氨基酚、吲哚美辛或它们的组合。可以与式I化合物组合使用的麻醉性镇痛剂的实例包括阿片类镇痛剂如芬太尼、舒芬太尼、吗啡、氢吗啡酮、可待因、羟考酮、丁丙诺啡或其可药用的盐或它们的组合。可以与式I化合物组合使用的抗炎药的实例包括但不限于阿司匹林;布洛芬;酮洛芬;萘普生;依托度酸COX-2抑制剂如塞来考昔罗非考昔伐地考昔帕瑞考昔、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-2,3-二氢噁唑-4-基)苯磺酰胺、达布非酮、氟舒胺、4-(4-环己基-2-甲基-5-噁唑基)-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-甲基磺酰基)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-酮或它们的生理学可接受的盐、酯或溶剂化物;舒林酸双氯芬酸吡罗昔康二氟尼柳萘丁美酮噁丙嗪吲哚美辛或甾族化合物如泼尼松龙磷酸钠口服溶液、SOLU-注射用甲泼尼龙琥珀酸钠、商标的泼尼松龙糖浆。
根据本发明,可用于治疗疼痛、例如与类风湿性关节炎有关的疼痛的抗炎药的另一些实例包括萘普生(其可以以EC-NAPROS延迟释放片剂、 和DS片剂和混悬剂的形式由罗氏公司(Roche Labs)商业获得)、商标的塞来考昔片剂、商标的罗非考昔、商标的倍他米松、商标的青霉胺胶囊剂、商标的可滴定青霉胺片剂、DEPO-MEDROL商标的醋酸甲泼尼龙可注射混悬剂、ARAVATM商标的来氟米特片剂、AZULFIDIINE EN-商标的柳氮磺吡啶延迟释放片剂、商标的吡罗昔康胶囊剂、商标的双氯芬酸钾片剂、商标的双氯芬酸钠延迟释放片剂、-XR双氯芬酸钠延长释放片剂或etanerecept产品。
用于治疗炎症、尤其是类风湿性关节炎的另一些活性剂的实例包括免疫抑制剂如GENGRATM商标的环孢菌素胶囊剂、商标的环孢菌素胶囊剂或口服溶液或商标的硫唑嘌呤片剂或静脉内注射剂;商标的吲哚美辛胶囊剂、口服混悬剂或栓剂;商标的硫酸羟氯喹;或静脉内注射用英夫利昔单抗重组物;或金化合物如金诺芬或硫代苹果酸金钠注射剂。
本发明提供了疼痛治疗,其中将式I化合物与一种或多种不是疼痛缓解剂的其它药学活性剂一起施用。例如,根据本发明,式I化合物可以与一种或多种治疗哺乳动物中存在的与哺乳动物所经历的疼痛有关或无关的任何其它症状或医学病症的其它药学活性剂一起施用。该类药学活性剂的实例包括例如抗血管生成药、抗肿瘤药、抗糖尿病药、抗感染药或胃肠道药或它们的组合。
在Physicians′Desk Reference,第55版,2001,出版商MedicalEconomics Co.,Inc.,Montvale,NJ中可以找到包括疼痛缓解剂在内的药学活性剂的更完整的列表。这些物质各自可以与一种或多种本发明的式I化合物联合施用。对于大多数或者所有这些活性剂而言,推荐的有效剂量和给药方案在本领域中是已知的;其中的许多可以在上面提及的Physicians′Desk Reference,第55版,2001,出版商Medical Economics Co.,Inc.,Montvale,NJ中找到。
4.用途
根据本发明,式I化合物可用于治疗哺乳动物的疼痛或延迟其发作。本文所用术语“治疗”是指部分或完全减轻、抑制、改善和/或缓解疼痛。例如,本文所用的“治疗”包括部分或完全减轻、抑制或缓解疼痛达一段时间。“治疗”还包括完全改善疼痛。术语“延迟......的发作”是指在触发后疼痛的开始延迟。在一些情况中,还可以降低最后所遭受的疼痛的程度;在一些情况中,疼痛可以被完全避免。
因此,在本发明的一些实施方案中,式I化合物在疼痛发作后被施用;在另一些实施方案中,该化合物在疼痛发作前、例如在与预期或认为可能诱发疼痛的刺激接触后被施用。
根据本发明,式I化合物可用于治疗哺乳动物如人所经历的许多不同类型的疼痛中的任何一种。例如,式I化合物可用于治疗急性疼痛(持续时间短的疼痛)或慢性疼痛(有规律地复发或持续性的疼痛),无论其是中枢性的还是外周性的。
可能是急性的或慢性的并且可以用本发明的方法治疗的疼痛的实例包括炎性痛、肌肉骨骼痛、骨痛、腰骶痛、颈或上背痛、内脏痛、躯体痛、神经性疼痛、癌症疼痛、由损伤或手术造成的疼痛如烧伤痛或头痛如偏头痛或紧张性头痛或这些疼痛的组合。本领域技术人员应当意识到这些疼痛可以彼此重叠。例如,由炎症造成的疼痛在性质上也可以是内脏痛或肌肉骨骼痛。
在本发明的一个实施方案中,将一种或多种式I化合物施用于哺乳动物来治疗慢性疼痛,如神经性疼痛,例如与外周或中枢神经系统的损害或病理学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痛;与例如下背部或上背部、脊柱、纤维肌痛、颞下颌关节或肌筋膜疼痛综合征有关的肌肉骨骼痛;与例如骨或关节变性障碍如骨关节炎、类风湿性关节炎或椎管狭窄有关的骨痛;头痛如偏头痛或紧张性头痛;或与感染如HIV、镰状细胞贫血、自身免疫性障碍、多发性硬化或炎症如骨关节炎或类风湿性关节炎有关的疼痛。
在一些实施方案中,根据本文所述的方法,用式I化合物治疗慢性疼痛,其是神经性疼痛、内脏痛、肌肉骨骼痛、骨痛、头痛、癌症疼痛或炎性痛或它们的组合。炎性痛可能与许多医学病症如骨关节炎、类风湿性关节炎、手术或损伤有关。神经性疼痛可能与例如糖尿病性神经病、外周神经病、疱疹后神经痛、三叉神经痛、腰或颈的神经根病、纤维肌痛、舌咽神经痛、反射交感性营养不良、灼痛(casualgia)、丘脑综合征、神经根撕脱或导致外周和/或中枢敏化的损伤造成的神经损害如幻肢痛、反射交感性营养不良或开胸术后的疼痛、癌症、化学损伤、毒素、营养缺乏或病毒或细菌感染如带状疱疹或HIV或它们的组合有关。本发明的治疗方法进一步包括其中神经性疼痛是转移性浸润、痛性肥胖症、烧伤或与丘脑病症有关的中枢疼痛病症所继发的病症的治疗。
在一些情况下,上述神经性疼痛可以被归类为“疼痛性细纤维神经病”如特发性疼痛性细纤维感觉神经病或“疼痛性大纤维神经病”如脱髓鞘神经病或轴突神经病或它们的组合。该类神经病在例如J.Mendell等人,N.Engl.J.Med.2003,348:1243-1255中有更详细的描述,将其全文特此引入作为参考。
在另一个实施方案中,用于本发明的化合物可被施用以完全或部分抑制神经性疼痛病症的发生。例如,本发明的化合物可被施用于有发生神经性疼痛病症风险的哺乳动物,如感染带状疱疹的哺乳动物或进行癌症治疗的哺乳动物。
在一个实施方案中,用于本发明的化合物可以在手术操作前或手术操作期间被施用以部分或完全抑制与手术操作有关的疼痛的发生。
如前面所述,本发明的方法可用于治疗在性质上是躯体性和/或内脏性的疼痛。例如,能按照本发明的方法治疗的躯体痛包括与手术期间经历的结构或软组织损伤、牙科操作、烧伤或创伤的机体损伤有关的疼痛。能按照本发明的方法治疗的内脏痛的实例包括与内脏器官的疾患如溃疡性结肠炎、肠易激惹综合征、刺激性膀胱(irritable bladder)、克隆病、风湿病(rheumatologic)(关节痛)、肿瘤、胃炎、胰腺炎、器官感染或胆道病症或它们的组合有关的或者由其导致的那些类型的疼痛。本领域技术人员还将意识到,按照本发明的方法治疗的疼痛也可以与痛觉过敏、异常性疼痛或这二者有关。此外,按照本发明治疗的慢性疼痛可伴有或不伴有外周或中枢敏化。
本发明还提供了式I化合物用于治疗与女性病症有关的急性和/或慢性疼痛(其也可被称为女性特有的疼痛)。该类疼痛包括仅女性遇到或主要是女性遇到的那些,包括与月经、排卵、怀孕或分娩、流产、宫外孕、逆行月经、卵泡破裂或黄体囊肿、骨盆脏器的刺激、子宫平滑肌瘤、子宫腺肌病、子宫内膜异位症、感染和炎症、骨盆器官局部缺血、梗阻、腹腔内粘连、骨盆脏器的解剖学畸变、卵巢脓肿、骨盆托的丧失、肿瘤、盆腔充血症有关的疼痛或由非妇科学原因引起的所述疼痛。
根据本发明,式I化合物可以以各种方式施用,包括例如通过口服、肌内、腹膜内、硬膜外、鞘内、静脉内、皮下、粘膜内如舌下或鼻内或透皮施用来进行施用。在本发明的某些实施方案中,式I化合物被口服、粘膜内或静脉内施用。
本发明提供了治疗方法,其中式I化合物被以治疗疼痛有效量施用于需要治疗疼痛的哺乳动物。本文所用的“治疗疼痛有效量”至少是减轻、缓解、延迟和/或消除所讨论的疼痛的式I化合物或其可药用盐形式的最小量。
为了确定在特定情况下治疗疼痛所施用的化合物的治疗疼痛有效量,医师可以例如通过逐渐增加剂量、例如从0.5mg增加至约1000mg直至达到所需的症状缓解水平来评价给定的式I化合物在患者中的作用。然后,可以改变调整继续给药方案以达到所需的结果。可以通过类似的技术确定不同施用途径的有效剂量范围。
实施例
实施例1
疼痛治疗效力评估
可以按照本发明对式I化合物进行评估以确定其治疗疼痛的效力的程度,并且可任选地将其与其它疼痛治疗相比较。
在本领域中已经建立了许多评价化合物缓解疼痛的效力的方法。参见例如Bennett等人,Pain 33:87-107,1988;Chaplan等人,J.Neurosci.Methods 53:55-63,1994;和Mosconi等人,Pain 64:37-57,1996。下面是对可以使用的一种策略的具体说明。
操作
使单独饲养的Spraque-Dawley大鼠自由进食鼠料和水。使用12小时光照/12小时黑暗循环(从6:00am至6:00pm光照)。按照国立卫生研究院实验室动物资源委员会(the National Institutes of Health Committee onLaboratory Animal Resources)所提供的指导原则进行动物饲养和研究。这些个体被用于下述试验中。
试验方法1:前列腺素E
2
-诱导的热超敏性
将其尾巴末端10cm置于包含加温至38、42、46、50、54或58℃的水的热水瓶中。用动物从水中抽出尾巴的潜伏期(以秒为单位)作为伤害感受性的量度。如果动物在20秒内没有抽出尾巴,则实验人员将其尾巴从水中抽出并记录20秒的最大潜伏期。
在评估基线热敏感性之后,通过将体积为50μL的0.1mg前列腺素E2(PGE2)注射至尾巴末端1cm来产生热超敏性。在PGE2注射前(基线)和注射后(15、30、60、90和120分钟)产生温度-作用曲线。以前用其它种属进行的研究(例如猴;Brandt等人,J.Pharmacol.Exper.Ther.296:939,2001)已经表明PGE2产生剂量-和时间-依赖性的热超敏性,其在注射后15分钟达到峰值并且在2小时后消失。
单一化合物研究。用单剂量时间-过程操作来对药物逆转PGE2-诱导的热超敏性的能力进行评估。在这种操作中,在注射PGE2前30分钟,将供试化合物的单剂量腹膜内(IP)施用、口服(PO)施用或鼻内(IN)施用。在PGE2注射后30分钟,对触觉敏感性进行评估。
组合化合物研究。可以进行两种或多种可能的疼痛治疗剂的组合研究。在热温水尾巴撤回试验中,将第一种活性剂例如吗啡的最小有效剂量单独施用以及与一种或多种式I化合物的无效剂量组合施用。在试验前30分钟,将化合物同时IP施用。
也可以在PGE2-诱导的热超敏性试验中进行组合研究。例如,在PGE2-诱导的热温水尾巴撤回试验中,可以将完全逆转热超敏性(即回复至基线)的吗啡剂量单独施用以及与一种或多种式I化合物的剂量组合施用。将化合物与PGE2(其在试验前30分钟被施用)同时IP施用。
试验方法1数据分析-由各温度-作用曲线计算在尾巴撤回潜伏期方面产生半数最大增加的温度(即,T10)。该T10是由温度-作用曲线上上面和下面10秒的点之间划出的线通过内插法来确定的。对于这些研究而言,热超敏性被定义为温度-作用曲线向左移动和T10值降低。热超敏性的逆转被定义为回复至温度-作用曲线的基线和T10值并且是根据下面的方程式来进行计算:
其中T10 药物+PGE2是药物与PGE2组合后的T10,T10 PGE2是PGE2单独使用后的T10,T10 基线是对照条件下的T10。100%的MPE值表示完全回复至未注射PGE2时观察到的基线热敏感性。大于100%的值表示供试化合物将热敏感性降低至低于未注射PGE2时的基线热敏感性。
试验方法2:慢性缩窄性损伤
将大鼠用3.5%位于O2中的氟烷以1 L/min的速度麻醉和在手术期间用1.5%位于O2中的氟烷维持麻醉。通过皮肤切口和通过股二头肌钝性分离暴露坐骨神经来产生改进的慢性坐骨神经缩窄性损伤(Mosconi &Kruger,1996;Bennett & Xie,1988)。将一根PE 90聚乙烯管(Intramedic,Clay Adams;Becton Dickinson Co.)套囊(cuff)(长度为2mm)在大腿中部水平上放到坐骨神经周围。用4-0丝质缝线和创伤夹将伤口分层闭合。在手术后6-10天进行试验。
将动物放到升高的金属丝笼子中并使其对试验场所适应45-60分钟。在手术前0-3天,用一系列校准的von Frey单丝(Stoelting;Wood Dale,IL)对基线触觉敏感性进行评估。以连续的升序或降序将Von Frey单丝应用到后爪足底中部,根据需要,使其尽可能地接近响应阈值。该阈值是用引起对刺激的强烈撤回响应的最低力来表示的。因此,撤回响应导致接下来给予较轻的刺激,缺乏撤回响应导致接下来给予更强的刺激。将基础阈值<4g力的大鼠从该研究中剔除。在CCI手术后大约1周,重新对触觉敏感性进行评估并进一步将表现出运动缺陷(即爪拖动)或随后不能表现出触觉超敏性(阈值≥10g)的动物从试验中剔除。在累积给药情况下,将化合物以1/2log单位增量用累积剂量每30分钟IP施用。在每次药物施用后20-30分钟评估触觉超敏性。
试验方法2数据分析。计算用Dixon非参数检验(Chaplan等人,1994)估算的50%阈值(以gm力为单位)并用15克力作为最大力。制备各大鼠各实验条件的剂量-作用曲线。将各触觉超敏性阈值平均以提供平均值(±1SEM)。将触觉超敏性的逆转定义为回复至基线触觉敏感性并根据下面的方程式进行计算:
其中50%药物+CCI是在CCI手术后化合物在动物体内大约1周后的50%值,50%CCI是仅进行CCI手术后大约1周的50%值,50%基线是在CCI手术前的50%值。100%逆转的最大作用表示处于该实验条件中的个体回复至手术前的平均阈值。
试验方法3:预定的受控的响应
在每周进行五天的试验期间,在多周期操作下对大鼠进行训练。各训练周期由10分钟的预处理期和随后10分钟的响应期所组成。在预处理期期间,不照射刺激光线,响应没有预定结果。在响应期期间,照射左或右刺激光(在个体间平衡),响应水平被延长,个体可在食物给予的固定比30方案下响应。训练期由3个连续周期所组成。除了在第一个周期开始时施用单剂量的药物之外,试验期与训练期相同。
试验方法3数据分析。将试验期各动物三个周期的动作响应速度平均并用得自之前训练日的平均速度作为对照值(即三个周期的平均值)将其转化成对照响应的百分比。将数据表示为对照百分比形式的平均(±1 SEM)响应速度。因此,例如,100%的试验值将表示施用供试化合物后的响应速度与对照响应速度相同并且供试化合物没有不良作用。
实施例2
在慢性神经性疼痛模型中的效力评估
化合物:
化合物1得自惠氏(Wyeth)化合物库,加巴喷丁购自多伦多研究化学试剂公司(Toronto Research Chemicals)(Ontario,加拿大)和购自西格玛化学试剂公司(Sigma Chemical Company)(St.Louis,MO)。将化合物1溶解于无菌盐水中,将加巴喷丁混悬于2%吐温80在0.5%甲基纤维素和无菌水中的溶液中。所有化合物均被腹膜内(i.p.)施用。
个体:将雄性Sprague-Dawley大鼠(125-150g,Harlan;Indianapolis,IN)在垫料上单独饲养。对于所有的研究而言,将动物维持在处于12小时光照/黑暗循环(在0630下照明)下的气候受控的房间中,使其自由进食和饮水。
手术:所有手术操作均在4%异氟烷/O2麻醉下进行,经由鼻锥体递送麻醉剂并在手术持续期间将麻醉剂维持在2.5%的水平上。
L5脊神经结扎(SNL):除了通过将左侧L5脊神经紧紧结扎来产生神经损伤外,如之前所述的那样(Kim和Chung,XXX)进行手术。
触觉异常性疼痛(触觉敏感性)评估:用一系列校准的von Frey单丝(Stoelting;Wood Dale,IL)对触觉阈值进行评估。如之前所述的那样(Chaplan等人,1994),用上下(up-down)法测定产生50%撤回可能性的阈值。将动物放到升高的金属丝笼子中并使其适应试验场所45-60分钟。以连续的升序或降序将Von Frey单丝应用到左后爪足底中部,根据需要,使其尽可能地接近响应阈值。该阈值是用引起对刺激的强烈撤回响应的最低力来表示的。引起对刺激的强烈撤回响应的最低力决定疼痛阈值。在手术前一天测定触觉阈值并将基线阈值<10g力的大鼠从研究中剔除。在SNL手术后三周,重新对触觉阈值进行评估并将不能表现出随后的触觉异常性疼痛(阈值≥5g)的动物从进一步的试验中剔除。将个体伪随机分成试验组(n=8-10),使得组间的平均基线和手术后敏感性相似。给大鼠施用化合物1(3、10或17.8,i.p.)、加巴喷丁(100mg/kg,i.p.,阳性对照)或基质,在施用后至多60、180和300分钟对触觉阈值进行评估。
结果分析:利用定制的SAS-excel应用程序(SAS Institute,Cary,NC)使用重复测量方差分析进行统计学分析。随后用最小显著差异分析来进一步对显著的主要作用进行分析。显著差异的标准是p<0.05。根据下面的方程式来计算触觉异常性疼痛的逆转:
其中50%阈值药物+手术后是在神经损伤个体中施用药物后50%阈值(以g力为单位),50%阈值手术后是在神经损伤个体中的50%阈值(以g力为单位),50%阈值手术前是神经损伤前的50%阈值(以g力为单位)。100%逆转的最大作用表示在试验条件下回复至个体的平均手术前阈值。参见图1。
实施例3
在慢性炎性痛中的效力评估
化合物:
化合物2得自惠氏化合物库,塞来考昔购自多伦多研究化学试剂公司(Ontario,加拿大)。将化合物2溶解于无菌盐水中并腹膜内(i.p.)施用。用塞来考昔作为阳性对照,将其混悬于2%吐温80在0.5%甲基纤维素中的溶液中并口服(p.o.)施用。
个体:将雄性Sprague-Dawley大鼠(125-150g,Harlan;Indianapolis,IN)在垫料上3只/每笼地饲养,将动物维持在处于12小时光照/黑暗循环(在0630下照明)下的气候受控的房间中,使其自由进食和饮水。
机械痛觉过敏的弗氏完全佐剂(FCA)模型:用痛觉测量计(7200型;UgoBasile)测定后爪对有害机械刺激的撤回阈值(PWTs)。将截止值设定为250g,所取终点为完全撤爪。在每个时间点对每只大鼠测定一次PWT(n=10/组)。测定基线PWT,用异氟烷(2%,位于氧中)将大鼠麻醉,向其左后爪跖内注射50%FCA(50μl,用盐水稀释)。在FCA注射后24小时,测量给药前PWTs,给大鼠施用基质或化合物,在给药后1、3、5和24小时对PWTs进行评估。
结果分析:利用定制的SAS-excel应用程序(SAS Institute,Cary,NC)用单因素方差分析(ANOVA)进行统计学分析。随后用最小显著差异分析来进一步对显著的主要作用进行分析。显著差异的标准是与基质处理的FCA大鼠相比p<0.05。根据下面的方程式将数据表示为逆转百分比:逆转百分比=[(给药后阈值)-给药前阈值])/(基线阈值-给药前阈值)]×100。参见图2。
将本文中所引用的或所述的各专利、专利申请和公开物的全部内容特此引入作为参考。
虽然已经给出了许多本发明的实施方案,但显然我们的基础构思可以被改变以提供利用本发明的化合物和方法的其它实施方案。因此,应当理解的是,本发明的范围是由所附权利要求书、而不是由作为实例给出的具体实施方案来定义的。
Claims (23)
2.根据权利要求1所述的方法,其中表示单键。
3.根据权利要求2所述的方法,其中:
R1是R、OR、卤素、氰基或-C1-3全氟代烷基;且
R2是R、OR、卤素、氰基或-C1-3全氟代烷基。
4.根据权利要求3所述的方法,其中R1和R2中至少一个是-OH。
5.根据权利要求3所述的方法,其中R3和R4与它们所键合的碳原子一起形成饱和或不饱和的5-8元环,其中所述环任选地被1-3个独立地选自卤素、-R或OR的基团取代。
7.根据权利要求1所述的方法,其中所述化合物是式I-c或I-d的化合物:
或其可药用的盐。
11.根据权利要求1所述的方法,其中所述化合物选自:
1-氟-4,5,6,7,9,9a,10,11,12,12a-十氢环戊烷并[c][1,4]二氮杂并[6,7,1-ij]喹啉;
1-氟-2-甲氧基-4,5,6,7,9,9a,10,11,12,12a-十氢环戊烷并[c][1,4]二氮杂并[6,7,1-ij]喹啉;
4,5,6,7,9,9a,10,11,12,13,14,14a-十二氢环庚烷并[c][1,4]二氮杂并[6,7,1-ij]喹啉;
(9aS,14aR)-4,5,6,7,9,9a,10,11,12,13,14,14a-十二氢环庚烷并[c][1,4]二氮杂并[6,7,1-ij]喹啉;
4,5,6,7,9a,10,11,12,13,13a-十氢-9H-[1,4]二氮杂并[6,7,1-de]菲啶;
1,2,3,4,9,10-六氢-8H-环戊烷并[b][1,4]二氮杂并[6,7,-hi]吲哚;
(7bR,10aR)-1,2,3,4,8,9,10,10a-八氢-7bH-环戊烷并[b][1,4]二氮杂并[6,7,1-hi]吲哚;
(2S)-(rel-7bR,10aR)-2-甲基-1,2,3,4,8,9,10,10a-八氢-7bH-环戊烷并[b][1,4]二氮杂并[6,7,1-hi]吲哚;
rel-(4S,7bS,10aS)-4-甲基-1,2,3,4,8,9,10,10a-八氢-7bH-环戊烷并[b][1,4]二氮杂并[6,7,1-hi]吲哚;
或其可药用的盐。
12.根据权利要求11所述的方法,其中所述化合物是盐酸盐。
13.根据权利要求1所述的方法,其中所述疼痛是急性疼痛或慢性疼痛。
14.根据权利要求15所述的方法,其中所述疼痛是炎性痛、肌肉骨骼痛、骨痛、腰骶痛、颈或上背痛、内脏痛、躯体痛、神经性疼痛、癌症疼痛、由损伤或手术造成的疼痛或头痛或它们的组合。
15.根据权利要求13所述的方法,其中所述疼痛是慢性疼痛。
16.根据权利要求15所述的方法,其中所述慢性疼痛与异常性疼痛、痛觉过敏或这二者有关。
17.根据权利要求15所述的方法,其中所述慢性疼痛是神经性疼痛;癌症疼痛;内脏痛;肌肉骨骼痛;骨痛;头痛;或与感染、镰状细胞贫血、自身免疫性障碍、多发性硬化或炎症有关的疼痛,或它们的组合。
18.根据权利要求1所述的方法,其中所述疼痛包括神经性疼痛。
19.根据权利要求18所述的方法,其中所述神经性疼痛与糖尿病性神经病、外周神经病、疱疹后神经痛、三叉神经痛、腰或颈的神经根病、纤维肌痛、舌咽神经痛、反射交感性营养不良、灼痛、丘脑综合征、神经根撕脱、幻肢痛、反射交感性营养不良、开胸术后的疼痛、癌症、化学损伤、毒素、营养缺乏或病毒或细菌感染或它们的组合有关。
20.根据权利要求1所述的方法,其进一步包括施用药学有效量的至少一种疼痛缓解剂。
21.根据权利要求20所述的方法,其中所述疼痛缓解剂包括一种或多种镇痛剂;抗炎药;偏头痛制剂;三环抗抑郁药;抗癫痫药;α2激动剂;或选择性血清素再摄取抑制剂/选择性去甲肾上腺素摄取抑制剂;或它们的组合。
22.根据权利要求21所述的方法,其中所述疼痛缓解剂包括阿片类镇痛剂。
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- 2007-03-23 EP EP07753842A patent/EP1998781A2/en not_active Withdrawn
- 2007-03-23 PE PE2007000327A patent/PE20081192A1/es not_active Application Discontinuation
- 2007-03-23 CA CA002644656A patent/CA2644656A1/en not_active Abandoned
- 2007-03-23 AU AU2007230997A patent/AU2007230997A1/en not_active Abandoned
- 2007-03-23 PA PA20078720901A patent/PA8720901A1/es unknown
- 2007-03-23 KR KR1020087023340A patent/KR20080110759A/ko not_active Application Discontinuation
- 2007-03-23 BR BRPI0709163-0A patent/BRPI0709163A2/pt not_active Application Discontinuation
- 2007-03-23 AR ARP070101211A patent/AR060089A1/es unknown
- 2007-03-23 CN CNA2007800105001A patent/CN101410118A/zh active Pending
- 2007-03-23 JP JP2009502886A patent/JP2009531434A/ja not_active Withdrawn
- 2007-03-23 WO PCT/US2007/007246 patent/WO2007112000A2/en active Application Filing
- 2007-03-23 US US11/726,850 patent/US20070225277A1/en not_active Abandoned
- 2007-03-23 TW TW096110146A patent/TW200806299A/zh unknown
- 2007-03-23 MX MX2008012092A patent/MX2008012092A/es not_active Application Discontinuation
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2008
- 2008-08-28 IL IL193748A patent/IL193748A0/en unknown
- 2008-09-23 EC EC2008008762A patent/ECSP088762A/es unknown
Also Published As
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KR20080110759A (ko) | 2008-12-19 |
IL193748A0 (en) | 2009-08-03 |
PE20081192A1 (es) | 2008-10-07 |
MX2008012092A (es) | 2008-10-03 |
ECSP088762A (es) | 2008-10-31 |
WO2007112000A2 (en) | 2007-10-04 |
US20070225277A1 (en) | 2007-09-27 |
AU2007230997A1 (en) | 2007-10-04 |
TW200806299A (en) | 2008-02-01 |
EP1998781A2 (en) | 2008-12-10 |
WO2007112000A3 (en) | 2008-01-17 |
AR060089A1 (es) | 2008-05-21 |
CA2644656A1 (en) | 2007-10-04 |
JP2009531434A (ja) | 2009-09-03 |
PA8720901A1 (es) | 2008-11-19 |
BRPI0709163A2 (pt) | 2011-06-28 |
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