CN1726022A - 用于治疗纤维肌痛及其相关疾病的普加巴林及其衍生物 - Google Patents
用于治疗纤维肌痛及其相关疾病的普加巴林及其衍生物 Download PDFInfo
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Abstract
本发明涉及治疗哺乳动物纤维肌痛和其它疾病的方法，通过给予通式化合物或其药物上可接受的盐来进行，在所述的通式化合物中，R1为1－5个碳原子的直链或支链未被取代的烷基、未被取代的苯基或3－6个碳原子的未被取代的环烷基；R2为氢或甲基；且R3为氢、甲基或羧基。
Description
本发明涉及治疗各种中枢神经系统和其它疾病的方法，通过给予表现出作为钙通道α2δ配体(″α2δ配体″或″α2δ配体″)活性的某些化合物来进行。这类化合物在文献中也称作γ-氨基丁酸(GABA)类似物。
发明背景
已知几种α2δ配体。环α2δ配体加巴喷丁目前是商购可得的(Neurontin，Warner-Lambert Company)，在临床广泛用于治疗癫痫和神经病性疼痛。这类环α2δ配体描述在1977年5月17日授权的美国专利US4,024,175和1978年5月2日授权的美国专利US 4,087,544中。其它系列的α2δ配体描述在下列文献中：1996年10月8日授权的美国专利US 5,563,175；2001年11月13日授权的美国专利US 6,316,638；2002年1月31日提交的美国临时专利申请US60/353,632；2002年11月2日提交的美国临时专利申请US60/248,630；2002年10月28日提交的美国临时专利申请US60/421,868；2002年10月28日提交的美国临时专利申请US60/421,867；2002年9月25日提交的美国临时专利申请US60/413,856；2002年9月16日提交的美国临时专利申请US60/411,493；2002年10月28日提交的美国临时专利申请US60/421,866；2003年1月22日提交的美国临时专利申请US60/441,825；2003年3月7日提交的美国临时专利申请US60/452,871；2001年7月4日公开的欧洲专利申请EP 1112253；1999年2月25日公开的PCT专利申请WO 99/08671；和1999年12月2日公开的PCT专利申请WO 99/61424。将这些专利和授权的全部内容引入本文作为参考。
下文定义的α2δ配体、包括通式I化合物的其它应用在2002年12月13日提交的美国临时专利申请US 60/433,491中涉及。将该申请的全部内容引入本文作为参考。
发明概述
本发明涉及治疗哺乳动物、优选人的纤维肌痛的方法，包括对需要这类治疗的哺乳动物给予治疗有效量的通式I的化合物或其药物上可接受的盐的步骤：
其中：
R1为1-5个碳原子的直链或支链未被取代的烷基、未被取代的苯基或3-6个碳原子的未被取代的环烷基；
R2为氢或甲基；且
R3为氢、甲基或羧基。
纤维肌痛(FM)是一种慢性综合征，其特征主要在于广泛扩散的疼痛、精神不振性睡眠、情绪障碍和疲劳。通常与纤维肌痛合并的其它综合征包括过敏性肠综合征、偏头痛、抑郁症和失眠症等。将使用单一药物活性剂治疗纤维肌痛的成功描述为适当的，而临床试验结果则令人失望。基于目前对纤维肌痛涉及的机制和途经的理解，认为需要多种活性剂，目的在于疼痛、睡眠紊乱、情绪障碍和疲劳的主要症状。纤维肌痛患者通常对药物的副作用敏感，这是一种可能涉及该病的病理生理学的特征(Barkhuizen A，“纤维肌痛合理和靶向的药物疗法”(Rational and Targeted pharmacologic treatment offibromyalgia.)-《美国国家临床风湿病》(Rheum Dis Clin NAm)2002；28：261-290；Leventhal LJ.“纤维肌痛的控制”(Management of fibromyalgia.)-《国际药物年鉴》(Ann InternMed)1999；131：850-8)。
尽管纤维肌痛是具有多个方面的复杂疾病，但是这种复杂性可以得到充分评价(Yunus MB，“纤维肌痛综合征患者的综合医疗评价”(Acomprehensive medical evaluation of patients with fibromyalgiasyndrome)-《美国国家临床风湿病》(Rheum Dis Clin N Am)2002；28：201-217)。FM的诊断通常基于1990年美国风湿病学会分类标准的建议(Bennett RM，“纤维肌痛患者的合理控制”(The rationalmanagement of fibromyalgia patients.)-《美国国家临床风湿病》(Rheum Dis Clin N Am)2002；28：181-199；Wolfe F，Smythe HA，YunusMB，Bennett RM，Bombardier C，Goldenberg DL等“美国风湿病学会对纤维肌痛分类的1990年标准：多中心标准委员会报告”(TheAmerican College of Rheumatology 1990 criteria for the classifi阳离子of fibromyalgia：Report of the Multicenter CriteriaCommittee.)-《风湿性关节炎》(Arthritis Rheum)1990；33：160-72)。已经综述了对纤维肌痛的评价、控制和药物疗法(BarkhuizenA，“纤维肌痛合理和靶向的药物疗法”(Rational and Targetedpharmacologic treatment of fibromyalgia.)-《美国国家临床风湿病》(Rheum Dis Clin N Am)2002；Buskila D，“纤维肌痛、慢性疲劳综合征和肌筋膜痛综合征”(Fibromyalgia，chronic fatiguesyndrome and myofacial pain syndrome)-《最新风湿病学观点》(Current opinions in Rheumatology)2001；13：117-127；LeventhalLJ.“纤维肌痛的控制”(Management of fibromyalgia.)-《国际药物年鉴》(Ann Intern Med)1999；131：850-8；Bennett RM，“纤维肌痛患者的合理控制”(The rational management of fibromyalgiapatients.)-《美国国家临床风湿病》(Rheum Dis Clin N Am)2002；28：181-199；Yunus MB，“纤维肌痛综合征患者的综合医疗评价”(A comprehensive medical evaluation of patients withfibromyalgia syndrome)-《美国国家临床风湿病》(Rheum Dis ClinN Am)2002；28：201-217)。
本发明的一个更具体的方法上述治疗纤维肌痛的方法，其中对人给予通式I的化合物或其药物上可接受的盐以治疗伴随有一种或多种躯体症状的纤维肌痛，所述的躯体症状选自疲劳、头痛、颈痛、背痛、肢体痛关节痛、腹痛、腹胀、咕噜声(gargling)、腹泻神经质和与一般焦虑症相关的症状(例如发生多日而不是至少6个月的有关的大量情况和活动的过度焦虑和烦恼(忧虑的期待)、难以控制烦恼等)。参见《精神病诊断和统计指南》(Diagnostic and Statistical manualof Mental Disorders)第4版(DSM-IV)，American PsychiatricAssociation，Washington，D.C.，May 1194，pp.435-436和445-469。
本发明还涉及治疗哺乳动物疾病或病症的方法，所述的疾病或病症选自：睡眠障碍，诸如失眠症(例如：原发性失眠症，包括精神生理性和特发性失眠症；继发性失眠症，包括继发于不宁腿综合征、帕金森病或另一种慢性疾病的失眠症；和暂时性失眠症)；梦行症、睡眠剥夺、REM睡眠障碍、睡眠性呼吸暂停、睡眠过度、深眠状态、睡醒周期障碍、飞行时差、发作性睡病、与轮班工作或不规则工作时间表相关的睡眠障碍、因药物或其它原因导致的慢波睡眠减少所致缺乏睡眠质量；和其它睡眠障碍；该方法包括给予需要这类治疗的哺乳动物治疗有效量的通式I的化合物或其药物上可接受的盐的步骤。
本发明还涉及增加人体受试者慢波睡眠的方法，包括给予需要这类治疗的人体受试者治疗有效量的通式I化合物或其药物上可接受的盐的步骤。
本发明还涉及增加人体受试者的人生长激素分泌的方法，该方法包括给予需要这类治疗的人体受试者治疗有效量的通式I化合物或其药物上可接受的盐的步骤。
本发明还涉及增加人体受试者慢波睡眠的方法，包括给予需要这类治疗的人体受试者：
(a)通式I的化合物或其药物上可接受的盐；和
(b)人生长激素或人生长激素促分泌素或其药物上可接受的盐；
其中选择活性剂″a″和″b″的用量，使得该组合可有效增加慢波睡眠。
本发明的更具体的实施方案涉及上述方法，其中所用的人生长激素促分泌素为2-氨基-N-[2-(3a-苄基-2-甲基-3-氧代-2，3，3a，4，6，7-六氢-吡唑并[4，3-c]吡啶-5-基)-1-苄氧基甲基-2-氧代-乙基]-2-甲基-丙酰胺。
本发明还涉及增加用减少慢波睡眠的药物活性剂治疗的人体受试者慢波睡眠的方法，所述的减少慢波睡眠的药物活性剂诸如吗啡或另一种阿片类镇痛药或苯二氮杂，该方法包括给予需要这类治疗的人体受试者给予：
(a)通式I的化合物或其药物上可接受的盐；和
(b)人生长激素或人生长激素促分泌素或其药物上可接受的盐；
其中选择活性剂″a″和″b″的用量，使得该组合可有效增加慢波睡眠。
本发明的更具体的实施方案涉及上述方法，其中所用的人生长激素促分泌素为2-氨基-N-[2-(3a-苄基-2-甲基-3-氧代-2，3，3a，4，6，7-六氢-吡唑并[4，3-c]吡啶-5-基)-1-苄氧基甲基-2-氧代-乙基]-2-甲基-丙酰胺。
本发明还涉及增加用减少慢波睡眠的药物活性剂治疗的人体受试者慢波睡眠的方法，所述的减少慢波睡眠的药物活性剂诸如吗啡或另一种阿片类镇痛药，该方法包括给予这类人体受试者有效增加慢波睡眠的用量的如上所述的通式I的化合物或其药物上可接受的盐的步骤。
本发明还涉及治疗哺乳动物过敏性肠综合征的方法，包括给予需要这类治疗的哺乳动物治疗有效量的通式I的化合物或其药物上可接受的盐的步骤。
本发明还涉及治疗哺乳动物疾病或病症的方法，所述的疾病或病症选自：带有或不带有旷野恐怖的惊恐性障碍；无惊恐性障碍史的旷野恐怖；特异恐怖(例如特定动物恐怖症)；社交焦虑症；社交恐怖症；强迫行为与观念障碍(OCD)；和精神紧张性障碍，包括创伤后精神紧张性障碍和急性精神紧张性障碍；该方法包括给予需要这类治疗的哺乳动物通式I的化合物或其药物上可接受的盐的步骤。
本发明的更具体的实施方案涉及上述方法，其中所治疗的障碍或病症为创伤后精神紧张性障碍。
本发明的另一个更具体的实施方案涉及上述方法，其中所治疗的疾病或病症为社交恐怖症或社交焦虑症。
本发明的另一个更具体的实施方案涉及上述方法，其中所治疗的疾病或病症为OCD。
可以理解的是为了治疗惊恐性障碍、恐怖症、OCD和精神紧张性障碍，可以将通式I的化合物与其它抗抑郁药或抗焦虑药联用。
合适类型的抗抑郁药包括去甲肾上腺素再摄取抑制剂、选择性5-羟色胺再摄取抑制药(SSRIs)、单胺氧化酶抑制剂(MAOIs)、单胺氧化酶的可逆抑制剂(RIMAs)、5-羟色胺和去甲肾上腺素再摄取抑制剂(SNRIs)、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和非典型抗抑郁药。合适的去甲肾上腺素再摄取抑制剂包括叔胺三环类和仲胺三环类。合适的叔胺三环类的实例包括阿米替林、氯米帕明、多塞平、丙米嗪和曲米帕明及其药物上可接受的盐。合适的仲胺三环类的实例包括阿莫沙平、地昔帕明、马普替林、去甲替林和普罗替林及其药物上可接受的盐。合适的选择性5-羟色胺再摄取抑制药包括氟西汀、氟伏沙明、帕罗西汀和舍曲林及其药物上可接受的盐。合适的单胺氧化酶抑制剂包括异卡波肼、苯乙肼、反苯环丙胺和司来吉兰及其药物上可接受的盐。合适的单胺氧化酶可逆抑制剂包括吗氯贝胺及其药物上可接受的盐。本发明中所用的合适的5-羟色胺和去甲肾上腺素再摄取抑制剂包括文拉法辛及其药物上可接受的盐。合适的CRF拮抗剂包括那些描述在国际专利申请WO 94/13643、WO 94/13644、WO 94/13661、WO 94/13676和WO 94/13677中的化合物。合适的非典型抗抑郁药包括安非他酮、锂、奈法唑酮、曲唑酮和维洛沙秦及其药物上可接受的盐。合适类型的抗焦虑药包括苯二氮类和5-HTIA激动剂或拮抗剂，尤其是5-HTIA部分激动药和促肾上腺皮质激素释放因子(CRF)拮抗剂。合适的苯二氮类包括阿普唑仑、氯氮、氯硝西泮、氯氮盐(chorazepate)、地西泮、哈拉西泮、劳拉西泮、奥沙西泮和普拉西泮及其药物上可接受的盐。合适的5-HTIA受体激动剂或拮抗剂特别包括5-HTIA受体部分激动药丁螺环酮、氟辛克生、吉哌隆和依沙匹隆及其药物上可接受的盐。
本发明还涉及治疗哺乳动物、优选人的疾病或病症的方法，所述的疾病或病症选自下列疾病或病症：带有或不带有旷野恐怖的惊恐性障碍；无惊恐性障碍史的旷野恐怖；特异恐怖(例如特定动物恐怖症)；社交焦虑症；社交恐怖症；强迫观念与行为障碍；和精神紧张性障碍，包括创伤后精神紧张性障碍和急性精神紧张性障碍；该方法包括给予需要这类治疗的哺乳动物下列化合物的步骤：
(a)通式I的化合物或其药物上可接受的盐：
(b)为抗抑郁药或抗焦虑药的另一种化合物或其药物上可接受的盐；
其中选择活性剂″a″和″b″的用量，使得该组合在治疗上有效。
本发明的更具体的实施方案涉及任意上述方法，其中对人给予通式I的化合物或其药物上可接受的盐以治疗选自其治疗涉及任意上述方法的那些疾病和病症的任意两种或多种合并的疾病或病症。该方法在下文中也称作″治疗伴随疾病的方法″。
本发明的另一个更具体的实施方案涉及上述治疗伴随疾病的方法，其中对人给予通式I的化合物或其药物上可接受的盐以治疗纤维肌痛和伴随的惊恐性障碍。
本发明的另一个更具体的实施方案涉及上述治疗伴随疾病的方法，其中对人给予通式I的化合物或其药物上可接受的盐以治疗纤维肌痛和伴随的过敏性肠综合征。
本发明的另一个更具体的实施方案涉及上述治疗伴随疾病的方法，其中对人给予通式I的化合物或其药物上可接受的盐以治疗纤维肌痛和伴随的功能性腹痛。
本发明的另一个更具体的实施方案涉及上述治疗伴随疾病的方法，其中对人给予通式I的化合物或其药物上可接受的盐以治疗纤维肌痛和伴随的神经病性疼痛。
将神经病性疼痛定义为因神经系统中的原发性损害或机能障碍引发或导致的疼痛(“国际疼痛研究协会”(InternationalAssociation for the Study of Pain))。神经损伤可以因创伤和疾病导致且由此术语′神经病性疼痛′包括许多具有不同病因学的疾病。它们包括、但不限于糖尿病性神经病、带状疱疹神经痛、背痛、宫颈神经根病、癌性神经病、化疗诱发的神经病、HIV神经病、假性肢痛、腕管综合征、慢性酒精中毒、甲状腺机能减退、三叉神经痛、尿毒症、创伤诱发的神经病或维生素缺乏。神经病性疼痛是在它没有保护作用时的病理情况。它通常刚好在最初原因消散后出现、通常持续多年、显著降低患者的生活质量(Woolf和Mannion 1999《柳叶刀》(Lancet)353：1959-1964)。神经病性疼痛的症状难以治疗，因为通常它们甚至在患有相同疾病的两个患者之间也不同(Woolf&Decosterd 1999《疼痛增刊》(Pain Supp.)6：S141-S147；Woolf和Mannion 1999《柳叶刀》(Lancet)353：1959-1964)。它们包括：自发性疼痛，可以为持续或阵发性的和异常引起的疼痛，诸如痛觉过敏(对有害刺激物的敏感性增加)；和异常性疼痛(对一般无害的刺激物敏感)。
本发明的另一个更具体的实施方案涉及上述治疗伴随疾病的方法，其中对人给予通式I的化合物或其药物上可接受的盐以治疗纤维肌痛和伴随的月经前期焦虑症或月经前期综合征。
本发明的另一个更具体的实施方案涉及上述治疗伴随疾病的方法，其中对人给予通式I的化合物或其药物上可接受的盐以治疗纤维肌痛和伴随的严重的抑郁性障碍。
本发明的另一个更具体的实施方案涉及上述治疗伴随疾病的方法，其中对人给予通式I的化合物或其药物上可接受的盐以治疗纤维肌痛和伴随的心境恶劣。
本发明的另一个更具体的实施方案涉及上述治疗伴随疾病的方法，其中对人给予通式I的化合物或其药物上可接受的盐以治疗纤维肌痛和伴随的躯体形式障碍，所述的躯体形式障碍选自躯体化障碍、转换形式障碍、身体变形性精神障碍、疑病、躯体病样疼痛症、未分化的躯体形式障碍和未另外具体说明的躯体形式障碍。参见《精神病诊断和统计指南》(Diagnostic and Statistical manual of MentalDisorders)第4版(DSM-IV)，American Psychiatric Association，Washington，D.C.，May 1194，pp.435-436。
本发明的另一个更具体的实施方案涉及上述治疗纤维肌痛的方法，其中对人给予通式I的化合物或其药物上可接受的盐以治疗伴随有一种或多种躯体症状的纤维肌痛，所述的躯体症状选自食欲不振、睡眠失调(例如失眠症、中断性睡眠、很早觉醒、疲劳性唤醒)、性欲不振、坐立不安、疲劳、便秘、消化不良、心悸、疼痛和痛(例如头痛、颈痛、背痛、肢体痛、关节痛、腹痛)、头晕、恶心、胃灼热、神经质、震颤、灼觉和麻刺感、晨僵、腹部症状(例如腹痛、腹胀、咕噜声、腹泻)和与严重的焦虑障碍相关的症状(例如悲哀、流泪、兴趣缺失、害怕、无助、绝望、疲劳、自尊低下、强迫观念、自杀想法、疲劳、记忆力和集中力缺损、动力丧失、意志麻痹、食欲下降、食欲增加)。
上述方法在本文中也共同称作“本发明方法”或“本发明的方法”。
本发明的优选实施方案使用通式I的化合物，其为3-氨基甲基-5-甲基-己酸或尤其是一般称作普加巴林的(S)-3-(氨基甲基)-5-甲基己酸。
除非另有说明，本文所用的术语″烷基″包括带有直链、支链或环状部分或其组合的饱和一价烃基。″烷基″的实例包括、但不限于甲基、乙基、丙基、异丙基、丁基、异-、仲-和叔-丁基、戊基、己基、庚基、3-乙基丁基、环丙基、环丁基、环戊基、环己基、环庚基、降冰片基等。
除非另有说明，本文所用的术语环烷基指的是含有3-8个碳的饱和一价碳环基且选自环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
本文所用的术语″治疗(treating)″指的是这类术语所应用的疾病或病症逆转、缓解、抑制其发展或预防这类疾病或病症的一种或多种症状。本文所用的术语″治疗(treatment)″指的是作为上述定义的″治疗(treating)″的治疗作用。
通式I的化合物可以含有手性中心且由此可以以不同对映体和非对映体形式存在。可以在制备终产物或其中间体的过程中通过公知方法获得各异构体，诸如旋光拆分、旋光选择性反应或色谱分离。本发明涉及通式I化合物的所有旋光异构体和所有立体异构体，既包括这类化合物的外消旋混合物、又包括各异构体和非对映体及其混合物，本发明还涉及如上定义的分别含有或使用它们的所有药物组合物和治疗方法。通式I化合物的各对映体在治疗不同疾病或病症中与这些化合物的外消旋混合物相比具有优势。
就本发明通式I的化合物为碱性化合物的情况而言，它们能够与各种无机酸和有机酸形成各种不同的盐。尽管这类盐对动物给药而言必须是药物上可接受的，但是在实际操作中理想的通常是最初从反应混合物中分离碱性化合物作为药物上不可接受的盐，然后单纯通过用碱性试剂处理将其转化成游离碱化合物，此后将该游离碱转化成药物上可接受的酸加成盐。可以通过使由此形成的酸加成的盐与碱接触并按照常规方式分离化合物的游离碱形式使化合物的游离碱形式再生。按照本发明制备的通式I化合物的游离碱形式在某些物理特性方面不同于其相应的酸加成的盐形式，诸如溶解度、晶体结构、吸湿性等，但是，这类化合物的游离碱形式及其相应的酸加成的盐形式对本发明的目的而言是等同的。
用于本发明方法的碱性化合物的药物上可接受的酸加成的盐包括来源于无机酸和有机酸的无毒性盐，所述的无机酸诸如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、氢氟酸、磷酸等，且上的有机酸诸如脂族一-和二羧酸、苯基取代的链烷酸、羟基链烷酸、烷二酸、芳香酸、脂族和芳族磺酸等。这类盐包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、三氟乙酸盐、丙酸盐、辛酸盐、异丁酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、扁桃酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、邻苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、苯乙酸盐、柠檬酸盐、乳酸盐、苹果酸盐、酒石酸盐、甲磺酸盐等。还关注氨基酸盐，诸如精氨酸盐等和葡糖酸盐、半乳糖醛酸盐(例如，参见Berge S.M.等“药用盐”(″Pharmaceutical Salts″)-《药物科学杂志》(J.of Pharma.Sci.)，1977；66：1)。
就通式I的化合物为酸性化合物的情况而言，它们能够与各种无机碱和有机碱形成各种不同的盐。可以通过常规方式使化合物的游离酸形式与足量的所需碱接触而生成盐来制备用于本发明方法的酸性化合物的碱加成的盐。通过使化合物的游离酸形式与无毒性的金属离子、诸如碱金属或碱土金属阳离子或胺、尤其是有机胺接触制备用于上述本发明方法的酸性化合物的药物上可接受的碱加成的盐。合适的金属阳离子的实例包括钠阳离子(Na+)、钾阳离子(K+)、镁阳离子(Mg2+)、钙阳离子(Ca2+)等。合适的胺类的实例为N，N′-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、二环己胺、乙二胺、N-甲基葡糖胺和普鲁卡因(例如，参见Berge，文献同上，1977)。可以通过使由此形成的碱加成的盐与酸接触并按照常规方式分离化合物的游离酸形式使化合物的游离酸形式再生。用于上述本发明方法的化合物的游离酸形式在某些物理特性方面不同于其相应的盐形式，诸如溶解度、晶体结构、吸湿性等，但是，它们与其游离酸形式对本发明的目的而言是等同的。
用于本发明方法的某些化合物可以以非溶剂化形式和溶剂化形式存在，包括水合形式。一般来说，溶剂合物形式、包括水合形式与非溶剂化形式等同且包括在本发明范围内。
用于本发明方法的某些化合物可以作为两种或多种互变异构形式存在。例如，化合物的互变异构形式可以通过烯醇化/去烯醇化等互换。本发明的方法可以使用任意α2δ配体的互变异构形式或其药物上可接受的盐及其混合物。
本发明还包括同位素标记的化合物的上述本发明方法，所述的同位素标记的化合物与通式I中所述的化合物相同，但实际上一个或多个原子被具有原子量或原子数不同于通常实际发现的原子量或原子数的原子取代。可以引入本发明化合物的同位素实例分别包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，诸如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。含有上述同位素和/或其它原子同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药物上可接受的盐属于本发明的范围。某些同位素标记的本发明化合物、例如引入了诸如3H和14C这类放射性同位素的那些化合物用于药物和/或底物组织分布试验。含氚、
即 3H和碳-14、
即 14C同位素特别优选易于制备和可检测性。此外，诸如氘、
即 2H这类重同位素取代可以提供因代谢稳定性较高而产生的治疗优势，例如体内半衰期增加或剂量需求下降且由此在某些情况中优选。
口服给药的有效性取决于药物通过粘膜上皮的有效递送及其在肝肠循环中的稳定性。可以将非肠道给药后有效、而口服给药疗效较低或认为其血浆半衰期过短的药物通过化学方式修饰成前体药物形式。
前体药物是这样一种药物，它已经通过化学方式得到修饰且在其作用部位上无生物活性，但在体内过程中可以被一种或多种酶等降解或修饰成母体生物活性形式。
这种化学修饰的药物或前体药物应具有不同于母体药物的药动学特性，从而能够易于通过粘膜上皮吸收、配制的盐更好和/或溶解度、改善的全身稳定性(例如，血浆半衰期增加)。例如，这些化学修饰可以为：
1)例如，可以被酯酶或脂酶裂解的酯或酰胺衍生物。就酯衍生物而言，可以通过公知方式由药物分子的羧酸部分衍生酯。就酰胺衍生物而言，可以通过公知方式由药物分子的羧酸或胺部分衍生酰胺；
2)可以由特异性或非特异性蛋白酶识别的肽类(肽可以通过与通过公知方式与药物分子的胺或羧酸部分形成酰胺键与药物分子偶联)；
3)通过前体药物形式或修饰前体药物修饰的膜选择累积在作用部位的衍生物；或
4)1-3的任意组合。
目前在动物实验中进行的研究已经证实可以通过制备″软″季铵盐增加某些药物的口服吸收。季铵盐称作″软″季铵盐，这是因为它不同于一般季铵盐、例如R-N+(CH3)3而可以在水解时释放活性药物。
″软″季铵盐与碱性药物或其盐相比具有用于的物理特性。水溶性与其它盐、诸如盐酸盐相比得到增加，而更重要的是药物从肠中的吸收增加。吸收性增加可能是因如下事实所致：即″软″季铵盐具有表面活性剂特性且能够与胆汁酸等形成胶束和未电离离子对，由此能够更有效地透入肠上皮。吸收后，前体药物快速水解而释放活性母体药物。
使用通式I化合物前体药物的上述本发明方法包括在本发明范围内。前体药物和软药物是本领域中公知的(Palomino E.，《未来药物》(Drugs of the Future)，1990；15(4)：361-368)。将这最新两篇文献引入本文作为参考。
发明详述
具有通式I的α2δ配体描述在美国专利US 5,563,175和US6,197,819中，将这些文献的全部内容引入本文作为参考。
实施本发明方法的全部特征在于给予通式I的化合物或其药物上可接受的盐，其用量在治疗上可有效治疗一种或多种上述涉及的疾病或病症。这类治疗有效量一般约1-约300mg/kg体重所治疗的患者。对正常体重的成年患者而言，典型剂量约为10-约5000mg/天。在临床环境中，管理机构、诸如美国食品与药品监督管理局(″FDA″)可以要求特定的治疗有效量。
在测定构成α2δ配体或其药物上可接受的盐在治疗一种或多种上述本发明方法涉及的疾病或病患的有效量或治疗有效量的过程中，医务工作者或兽医一般要考虑到许多因素，如哺乳动物的年龄、性别、体重和一般情况以及所治疗疾病的类型和程度和接受治疗的哺乳动物使用的其它药物(如果有的话)。照此，给药剂量可以在上述范围或浓度或可以在其外、即低于或高于上述范围或浓度的范围改变，这取决于个体受试者的需要、所治疗疾病的严重程度和所用的特定治疗制剂。测定特定情况的合适剂量属于医学或兽医领域技术人员的范围。一般来说，开始可以使用低于最适合于特定受试者的较小剂量的活性化合物或多种化合物进行治疗。此后可以通过小剂量增加来增加剂量，直到达到该情况中的最佳作用为止。为方便起见，如果需要，可以将总每日剂量分隔并在当天分次给药。
可以通过口服、非肠道(诸如皮下、静脉内、肌内、胸骨内和输注技术)、直肠、口含、局部或鼻内途经给予通式I的化合物及其药物上可接受的盐。优选的给药途径为口服和非肠道。优选以单位剂型给药。用于本发明方法的通式I化合物或其药物上可接受的盐的单位剂型还可以包括用于其它成分，它们用于给予通式I化合物或其药物上可接受的盐所针对的疾病或病症或给予通式I化合物或其药物上可接受的盐所针对的疾病继发的疾病或病症。
通过用药用载体将活性化合物配制成单位剂型生产含有通式I化合物或其药物上可接受的盐的药物组合物。某些单位剂型的实例为片剂、胶囊、丸剂、扁囊剂、锭剂、霜剂、粉剂、口服水溶液和非水溶液和混悬液和包装在容器内的非肠道用溶液，其中含有一个或一定大量剂量单位且能够被再分成各个剂量。
合适的药用载体、包括药物稀释剂的某些实例为：胶囊；糖类，诸如乳糖和蔗糖；淀粉，诸如玉米淀粉和马铃薯淀粉；纤维素衍生物，诸如羧甲基纤维素钠、乙基纤维素、甲基纤维素和乙酸邻苯二甲酸纤维素；明胶；滑石；硬脂酸；硬脂酸镁；植物油，诸如花生油、棉子油、芝麻油、橄榄油、玉米油和可可油；丙二醇、甘油；山梨醇；聚乙二醇；水；琼脂；藻酸；等渗盐水；和磷酸盐缓冲溶液；以及常用于药物制剂的其它相容物质。
本发明方法中所用的组合物还可以含有其它成分，诸如着色剂、增香剂和/或防腐剂。如果存在，通常可以使用相对少量的这些物质常用量。如果需要，这些组合物还可以含有其它常用于治疗所治疗的疾病或病患的治疗剂。
上述组合物中活性组分的百分比可以在宽限内改变，但为了实际目的，优选在固体组合物中所含浓度至少为10％，而在原始液体组合物中的所含浓度至少为2％。最令人满意的组合物是含极高比例的活性组分、例如约达95％的那些组合物。
在片剂中，将活性成分与适当比例的具有必需粘合特性的载体混合并压制成所需性状和大小。粉剂和片剂优选含有5或10-约70％的活性化合物。合适的载体为碳酸镁、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、可可脂等。术语″制备″用于包括用作为制成胶囊的包囊材料配制活性化合物，其中用载体与或不与其它载体一起将活性成分包裹在中心。
为了制备栓剂，首先熔化诸如脂肪酸甘油酯类或可可脂的混合物这类低熔点蜡并通过搅拌使活性成分均匀分散于其中。然后将熔化的均匀混合物倾入常用大小的塑膜中、使之冷却且由此固化。
液体制剂包括溶液、混悬液和乳剂，例如水或水丙二醇溶液。为了进行非肠道注射，可以将液体制剂配制成含水的聚乙二醇溶液形式的溶液。可以通过将活性成分溶于水并根据需要添加合适的着色剂、增香剂、稳定剂和增稠剂来制备适合于口服应用的水溶液。可以通过将活性成分细粉分散于含有粘性物质的水中制备适合于口服应用的含水混悬液，所述的粘性物质诸如天然或合成树胶、树脂、甲基纤维素、羧甲基纤维素钠和其它众所周知的悬浮剂。
还包括在使用前立即转化成口服给药用的液体剂型的固体剂型。这类液体剂型包括溶液、混悬液和乳剂。这些制剂可以包括活性成分和着色剂、增香剂、稳定剂、缓冲剂、人工和天然增甜剂、分散剂、增稠剂、增溶剂等。
如N.S.Gee等在《病毒学化学杂志》(J.Viol.Chem.)，1996，271：5879-5776中所述，可以使用应用[3H]加巴喷丁和来源于猪脑组织的α2δ亚单位的放射性配体结合试验测定通式I化合物或其药物上可接受的盐与钙通道的α2δ亚单位的结合程度。
在下列体内实验中证实了普加巴林在治疗纤维肌痛中的功效，概括如下。
概述：
在第1天和第5天腓肠肌内经肌内(IM)注射100μL无菌无致热原的pH 4盐水的Sprague-Dawley雄性大鼠在第二次注射后约1周发生慢性机械性异常性疼痛(静态异常性疼痛)。(Sluka KA，Kalra A，MooreSA.“肌内注射酸性盐水产生了双侧长期持续性的痛觉过敏”(Intramuscular injections of acidic saline produce a bilateral，long-lasting hyperalgesia.)-《肌肉与神经》(Muscle&Nerve)2001；24：37-46)。通过将不同弯曲力(0.41-29g)的von Frey丝施加在注射后肢足底表面以测定爪退缩阈值(PWT)来确定异常性疼痛。以盲方式进行评价，其中动物和治疗均是随机的。第二次酸性盐水注射后1-2周的PWL通常低于5g(在酸性盐水注射前从22减少至28g)，表示触觉异常性疼痛。异常性疼痛持续3周。注射了pH 7.2的盐水的大鼠没有表现出异常性疼痛。在酸性盐水注射后，没有证据显示后肢之间的动态异常性疼痛(通过爪退缩至棉签敲击测定)或对重量承受的偏好。最后一次酸性盐水注射后2周使用10或30mg/kg普加巴林通过口腔管饲法(PO)治疗使机械性异常性疼痛逆转。普加巴林的镇痛样作用显著高于治疗后2-3小时使用载体的治疗。皮下(SC)给予3和10mg/kg吗啡减轻了异常性疼痛，而6mg/kg阿米替林皮下给药没有改变异常性疼痛。美国风湿病学会将纤维肌痛分类为压迫在大部分特定触痛点上的慢性一般性肌肉骨骼疼痛。使用盐水注射大鼠的结果证实普加巴林在大鼠模型中对异常性疼痛的减轻与人纤维肌痛疾病具有一定程度的相似性。
方法：
酸性盐水诱发的异常性疼痛：使约350g的雄性Sprague-Dawley大鼠(Harlan)圈养在带有有机纤维素垫的塑料隔离室内。动物可随意获得食物和水并将动物维持在12小时/12小时光照/黑暗循环中，其中在光照期中进行测试。在测试的当天，将大鼠放在金属室内升高的金属网底部上并使其适应至少20分钟。在第1天时，获得了右侧后爪的基线von Frey丝退缩阈值。然后，在第1天，将pH 4的酸性盐水(100uL)注入右侧腓肠肌并在第5天的相同位置上再次进行类似的注射。在后续的天中，对两侧后爪测定疼痛反应(von Frey丝退缩阈值、对使用棉签轻度敲击反应的退缩和2后爪之间重量承受(bearing)的改变)。评价实验药物治疗对静态异常性疼痛和其它疼痛终点的抑制作用。使用在药物测试当天(14-18天)爪退缩阈值(PWT)为6g或6g以下的大鼠。在接受药物或载体治疗1、2和3小时后估计大鼠的PWT。
与疼痛相关的行为反应的测定
静态异常性疼痛：使用具有不同弯曲力的Von Frey丝测定PWT(0.41、0.69、1.2、2.0、3.6、5.5、8.5、15.1和28.8g，StoeltingCorp，Wood Dale，IL)。以单侧缓慢施加方式将压力施加在后爪的足底表面达6秒，直到开始的施加在足底表面2.0-g丝。如果未获得退缩，则接下来施加更高的弯曲力，或如果退缩，则接下来施加更低力的丝。将这种情况持续至获得至少6次反应，包括至少1次退缩。然后使用Dixon起伏法(Dixon W.“对实验观察结果的有效分析”(Efficientanalysis of experimental observations.)-《药物毒理学综述年鉴》(Ann Rev Pharma col Toxicol)1980；20：441-62)测定每一时间点处的退缩阈值(对每只大鼠)。如果使用28.8g丝没有获得退缩，那么将退缩阈值定为29g。
动态异常性疼痛：用从金属丝网下施加的棉签缓慢敲击注射和对侧后爪的足底表面达15秒。报导退缩时间(一式三份的平均值)，如果没有观察到退缩，则最大值为15秒。
自发性疼痛：将大鼠放入带有升高平台和截去角的方形的底部的致密清洁的丙烯酸塑料盒内，使前爪置于升高平台上，而使后爪置于截去角的方形的底部。将该盒用于使后爪与失能检测器(LintonInstruments，Norfolk，England)的2个力传感器板中的每一个接触，所述的检测器可以测定室底部上的每只后爪施加的力。在4秒的期限内用该装置求得施加在每只后爪上的重量(按克计)并记录。报导的值为施加在2只后爪上的重量之差(对侧爪减去注射的后爪)的一式三份读数的平均值。
结果
模型的表征：反复两次肌内注射酸性盐水导致预先注射的后肢足底(planter)表面的von Frey退缩阈值持续下降。这些结果与上述公开的结果相似。(Sluka KA，Kalra A，Moore SA.“肌内注射酸性盐水产生了双侧长期持续性的痛觉过敏”(Intramuscular injectionsof acidic saline produce a bilateral，long-lastinghyperalgesia.)-《肌肉与神经》(Muscle&Nerve)2001；24：37-46)。然而，与上述公开的发现相反，在对侧接受酸性盐水注射的后肢中观察到退缩阈值几乎没有或没有改变，但不包括测试的最近时间点(表1)。在对棉签刺激物反应的退缩或后爪维持重量终点中没有观察到改变。有代表性的实验如表2中所示。
普加巴林在酸性盐水诱发的异常性疼痛模型中的药理学评价：在最近一次注射酸性盐水后的第14天开始，对第1天和第5天时注射酸性盐水的大鼠评价在可选的天数时疼痛反应的改变。在指定天时，仅将表现出异常性疼痛(对6g或6g以下von Frey丝反应的退缩)和纯粹接受上述药物治疗的大鼠用于评价测试化合物。在读取基线爪退缩后30分钟口服给予普加巴林或载体(水)。在药物或载体治疗后1、2和3小时时评价大鼠。当在药物治疗后2或3小时测试时，10或30mg/kg PO的普加巴林抑制静态的异常性疼痛(通过von Frey丝测定)(表3)。3mg/kg PO的普加巴林治疗对异常性疼痛没有作用。
基线测定后30分钟给予的10mg/kg SC吗啡抑制治疗后1和2小时时的静态异常性疼痛(表4)。使用3mg/kg吗啡进行的类似治疗增加了PWT，但仅在治疗后1小时时(非2或3小时)。6mg/kg SC阿米替林在治疗后1、2或3小时时未改变PWT(表5)。
预先在腓肠肌中反复注射pH 4的盐水对后肢同侧足底表面诱发几周期限的机械性异常性疼痛(使用von Frey丝测定)。相同的大鼠没有动态的后爪异常性疼痛(对棉签敲打的反应)或自发的疼痛行为(a后爪之间维持重量的优先性)。10和30mg/kg PO普加巴林减轻了因预先注射酸性盐水产生的静态异常性疼痛。3和10mg/kg SC吗啡使因预先注射酸性盐水的静态异常性疼痛减轻。6mg/kg PO阿米替林对异常性疼痛没有抑制作用。这些结果阈上述对吗啡公开的结果一致。(Sluka，KA，Rohling JJ，Bussey RA，Eikenberry SA，Wilken JM.《药理学实验疗法杂志》(J Pharmacol.Exp.Ther.)2002，302：1146-50)。尽管阿米替林在本研究中没有作用，但是开据它的处方通常是因纤维肌痛的疼痛且临床研究已经证实它是有效的。5，6可能的情况是阿米替林在这种动物模型(因反复注射酸性盐水导致的异常性疼痛)中有效，条件是在反复给药几天后对其进行测试。持续测试这种可能性。未研究较高剂量的阿米替林，因为在6mg/kg PO剂量剂量下观察到心动过速且10mg/kg PO剂量在部分注射大鼠中致死。
预先将酸性盐水反复注入腓肠肌产生大鼠后爪静态异常性疼痛可以提供评价治疗慢性肌肉骨骼疼痛的新活性剂的方法。动物模型可以用于评价治疗诸如纤维肌痛这类综合征中的慢性异常性疼痛的实验性镇痛化合物。
表1.对左侧腓肠肌注射100μL pH 4.2的酸性盐水前后左(同侧)和右
(对侧)侧足底后爪表面的大鼠爪退缩阈值
| 后肢 | 注射前第1天 | 开始注射后第5天 | 开始注射后第12天 | 开始注射后第16天 | 开始注射后第26天 |
| 同侧PWTSEM对侧PWTSEM | 27.471.1128.840.00 | 28.840.0025.642.48 | 13.19a，b3.6428.840.00 | 7.86a，b2.0728.840.00 | 10.93a，b2.8017.58b3.61 |
N＝9，数据为按克计的平均值。
ap＜0.05，注射后肢与对侧后肢相比，单相ANOVA并列(on ranks with)Tukey检验。
bp＜0.05，与第一次注射前第1天时的基线相比，单相ANOVA并列Tukey检验。
表2.对腓肠肌2次注射酸性盐水前(第1天)和后(第5和第8天)的不同时间时的爪退缩阈值(同侧)、爪退缩潜伏期(同侧)和重量承受测定值
| 注射前第1天 | 开始注射后第5天 | 开始注射后第18天 |
| 对von Frey丝的爪退缩阈值(g)pH 7.4 25.59SEM 2.28pH 4.2 27.47SEM 1.11对棉签敲打的爪退缩潜伏期(秒)pH 7.4 9.39SEM 0.65pH 4.2 9.17SEM 0.40重量承受：对侧力-同侧力(g)pH 7.4 -3.0SEM 5.0pH 4.2 7.0SEM 5.0 | 20.153.6512.42a3.17510.830.346.331.34-2.06.05.05.0 | 23.503.949.89a2.489.110.939.781.96-10.04.0-13.014.0 |
ap＜0.05，与第1天相比，单相ANOVA并列Tukey检验，n＝6/组。数据为平均值。
表3.对腓肠肌预先反复注射酸性盐水后用普加巴林PO治疗前后的爪
退缩阈值
| 第1天 | 基线 | Rx后1小时 | Rx后2小时 | Rx后3小时 | |
| 载体SE3mg/kg PO普加巴林SEMN＝6/组载体SEM10mg/kg PO普加巴林SEMN＝4/组载体SEM30mg/kg PO普加巴林SEM | 27.751.0927.371.0818.652.5024.903.9428.840.0026.071.81 | 3.520.355.320.514.720.903.550.144.570.734.740.75 | 9.874.057.922.9911.705.782.280.6812.954.4718.154.20 | 7.072.244.531.164.170.7028.84b0.003.610.6225.11b2.65 | 12.135.046.071.133.741.4222.23b6.625.052.1923.74b4.67 |
N＝6/组
a通过von Frey丝测定的爪退缩阈值，所有测定值均按克计；在基线测定后30分钟给予所有药物治疗。
b与载体组相比具有显著性差异(p＜0.05，单相ANOVA，然后进行Tukey检验，均采用配对比较程序)。数据为平均值。
表4.用吗啡SCa治疗前后大鼠的静态异常性疼痛
| 第1天 | 基线 | Rx后1小时 | Rx后2小时 | Rx后3小时 | |
| 载体SEM(n＝11)3mg/kg SC吗啡SEM(n＝10)载体SEM(n＝6)10mg/kg SC吗啡SEM(n＝6) | 28.240.6024.271.5428.840.0026.632.21 | 4.110.392.890.413.330.413.090.60 | 4.070.6520.52b3.334.560.9128.840b0.00 | 9.993.329.933.235.471.9822.05b4.32 | 9.742.707.092.254.670.7516.914.58 |
a通过von Frey丝测定的爪退缩阈值，所有测定值均按克计；在基线测定后30分钟给予所有药物治疗。
b与基线测定值相比p＜0.05，单相ANOVA并列Tukey检验。数据为平均值。
表5.用阿米替林SCa治疗前后大鼠的静态异常性疼痛
| 第1天 | 基线 | Rx后1小时 | Rx后2小时 | Rx后3小时 | |
| 载体SEM6mg/kg阿米替林SEM | 28.840.0024.442.21 | 3.060.282.360.40 | 8.644.2712.014.55 | 8.642.027.382.74 | 11.505.527.204.03 |
N＝6/组。组间没有显著性差异(单相ANOVA并列Tukey检验)。
a基线测定后30分钟给药。
还对普加巴林对患有纤维肌痛的人体患者的作用进行临床研究。进行本研究以评价普加巴林(150、300和450mg/天)与安慰剂相比在缓解患有纤维肌痛的患者的疼痛和改善其功能状态中的功效。参与本研究的患者必须满足纤维肌痛的美国风湿病学会标准(广泛扩散的疼痛存在至少3个月且在18个触痛点部位中至少有11个存在疼痛)。
方法
1周的基线期后，按照8周、双盲、多中心研究设计使有资格的患者随机接受150、300或450mg/天普加巴林或安慰剂。目的治疗(ITT)人群由总计529位患者组成：132位患者接受450mg/天，134位患者接受300mg/天，132位患者接受150mg/天的普加巴林，而131位患者接受安慰剂。8周双盲期的第一期由1周滴定期组成。随机进入安慰剂、150和300mg/天普加巴林治疗组的患者在第1天开始使用其固定剂量。随机进入450mg/天普加巴林治疗组的患者300mg/天开始并在第4天时滴定至450mg/天的靶向剂量并在双盲期的剩余时间保持该固定剂量。双盲期的第8周后，患者可以选择进入开放式标记的继续研究(方案1008-033)。
评价标准
初步功效测定值来源于每日来自患者日记的自我评价疼痛得分。次级测定值来源于SF-MPQ、手触痛点检查、来自每天日记的睡眠质量得分、疲劳的多维评价(MAF)、改变的临床综合印象(CGIC)和改变的患者综合印象(PGIC)、SF-36健康检查(SF-36)、医院焦虑和抑郁症等级(HADS)以及药效研究(MOS)睡眠评分。
结果
所有分析均对ITT人群进行，将ITT人群定义为接受至少一种研究药物剂量的所有随机化患者。450mg/天普加巴林的初步功效测定值、即终点平均疼痛得分显著优于安慰剂。在使用450mg/天普加巴林的组的第1周时观察到平均疼痛得分与安慰剂相比有显著性差异且持续至第7周。在使用450mg/天普加巴林的组的大部分其它次级参数中观察到了类似的结果，包括：每周和终点时的平均睡眠质量；SF-MPQ感觉；情感；和终点时的总得分和终点时的VAS；CGIC；PGIC；和MAF综合疲劳指数。在社交功能作用、身体疼痛、活力和SF-36健康检查的一般健康知觉域中观察到450mg/天普加巴林优于安慰剂的显著性差异。对患者而言，450mg/天普加巴林组中反应者的状态(定义为在终点时报告至少缓解50％的患者数量与基线之比)显著优于安慰剂组(分别为28.9％和13.2％；p＝0.003)。300和150mg/天普加巴林组中的患者在初步功效参数方面与安慰剂之间没有显著性差异。300和150mg/天普加巴林在许多次级参数中表现出与安慰剂的显著性差异。
结论
发现普加巴林在缓解与纤维肌痛相关的疼痛中的有效剂量为450mg/天。在150-和300-mg/天剂量下对疼痛没有显著作用。300和450mg/天普加巴林治疗臂对疲劳的改善、临床和患者改变的综合评价和睡眠质量的改善优于安慰剂。
Claims (15)
1.治疗哺乳动物纤维肌痛的方法，包括给予需要这类治疗的哺乳动物治疗有效量的通式I的化合物或其药物上可接受的盐的步骤：
其中：
R1为1-5个碳原子的直链或支链未被取代的烷基、未被取代的苯基或3-6个碳原子的未被取代的环烷基；
R2为氢或甲基；且
R3为氢、甲基或羧基。
2.治疗哺乳动物疾病或病症的方法，所述的疾病或病症选自：睡眠障碍，诸如失眠症(例如：原发性失眠症，包括精神生理性和特发性失眠症；继发性失眠症，包括继发于不宁腿综合征、帕金森病或另一种慢性疾病的失眠症；和暂时性失眠症)；梦行症、睡眠剥夺、REM睡眠障碍、睡眠性呼吸暂停、睡眠过度、深眠状态、睡醒周期障碍、飞行时差、发作性睡病、与轮班工作或不规则工作时间表相关的睡眠障碍、因药物或其它原因导致的慢波睡眠减少所致缺乏睡眠质量；和其它睡眠障碍；该方法包括给予需要这类治疗的哺乳动物治疗有效量的通式I的化合物或其药物上可接受的盐的步骤，其中通式I化合物的结构式如下：
其中：
R1为1-6个碳原子的直链或支链未被取代的烷基、未被取代的苯基或3-6个碳原子的未被取代的环烷基；
R2为氢或甲基；且
R3为氢、甲基或羧基。
3.增加人体受试者慢波睡眠的方法，包括给予需要这类治疗的人体受试者有效增加慢波睡眠用量的通式I化合物或其药物上可接受的盐的步骤，其中通式I化合物的结构式如下：
其中：
R1为1-5个碳原子的直链或支链未被取代的烷基、未被取代的苯基或3-6个碳原子的未被取代的环烷基；
R2为氢或甲基；且
R3为氢、甲基或羧基。
4.增加人体受试者的人生长激素分泌的方法，该方法包括给予需要这类治疗的人体受试者有效增加人生长激素分泌用量的通式I化合物或其药物上可接受的盐的步骤，其中通式I化合物的结构式如下：
其中：
R1为1-5个碳原子的直链或支链未被取代的烷基、未被取代的苯基或3-6个碳原子的未被取代的环烷基；
R2为氢或甲基；且
R3为氢、甲基或羧基。
5.治疗哺乳动物优选人的过敏性肠综合征的方法，包括给予需要这类治疗的哺乳动物治疗有效量的通式I的化合物或其药物上可接受的盐的步骤：
其中：
R1为1-5个碳原子的直链或支链未被取代的烷基、未被取代的苯基或3-6个碳原子的未被取代的环烷基；
R2为氢或甲基；且
R3为氢、甲基或羧基。
6.治疗哺乳动物疾病或病症的方法，所述的疾病或病症选自：带有或不带有旷野恐怖的惊恐性障碍；无惊恐性障碍史的旷野恐怖；特异恐怖；社交焦虑症；社交恐怖症；强迫观念与行为障碍；和精神紧张性障碍，包括创伤后精神紧张性障碍和急性精神紧张性障碍；该方法包括给予需要这类治疗的哺乳动物治疗有效量的通式I的化合物或其药物上可接受的盐的步骤，其中通式I化合物的结构式如下：
其中：
R1为1-5个碳原子的直链或支链未被取代的烷基、未被取代的苯基或3-6个碳原子的未被取代的环烷基；
R2为氢或甲基；且
R3为氢、甲基或羧基。
7.治疗哺乳动物疾病或病症的方法，所述的疾病或病症选自：带有或不带有旷野恐怖的惊恐性障碍；无惊恐性障碍史的旷野恐怖；特异恐怖；社交焦虑症；社交恐怖症；强迫性观念与行为障碍；和精神紧张性障碍，包括创伤后精神紧张性障碍和急性精神紧张性障碍；该方法包括给予需要这类治疗的哺乳动物下列化合物的步骤：
(a)通式I的化合物或其药物上可接受的盐：
其中：
R1为1-5个碳原子的直链或支链未被取代的烷基、未被取代的苯基或3-6个碳原子的未被取代的环烷基；
R2为氢或甲基；且
R3为氢、甲基或羧基；和
(b)为抗抑郁药或抗焦虑药的另一种化合物或其药物上可接受的盐；
其中选择活性剂″a″和″b″的用量，使得该组合在治疗上有效。
8.权利要求7的方法，其中所治疗的疾病或病症为创伤后精神紧张性障碍、社交恐怖症或社交焦虑症。
9.治疗哺乳动物两种或多种疾病或病症的方法，所述的疾病或病症各自独立地选自：过敏性肠综合征；纤维肌痛；神经病性疼痛；睡眠障碍，诸如失眠症(例如：原发性失眠症，包括精神生理性和特发性失眠症；继发性失眠症，包括继发于不宁腿综合征、帕金森病或另一种慢性疾病的失眠症；和暂时性失眠症)；梦行症、睡眠剥夺、REM睡眠障碍、睡眠性呼吸暂停、睡眠过度、深眠状态、睡醒周期障碍、飞行时差、发作性睡病、与轮班工作或不规则工作时间表相关的睡眠障碍、因药物或其它原因导致的慢波睡眠减少所致缺乏睡眠质量；其它睡眠障碍；带有或不带有旷野恐怖的惊恐性障碍；无惊恐性障碍史的旷野恐怖；特异恐怖；社交焦虑症；社交恐怖症；强迫性观念与行为障碍；和精神紧张性障碍，包括创伤后精神紧张性障碍和急性精神紧张性障碍；包括给予需要这类治疗的哺乳动物治疗有效量的通式I的化合物或其药物上可接受的盐的步骤：
其中：
R1为1-5个碳原子的直链或支链未被取代的烷基、未被取代的苯基或3-6个碳原子的未被取代的环烷基；
R2为氢或甲基；且
R3为氢、甲基或羧基。
10.权利要求1的方法，其中对人给予通式I的化合物或其药物上可接受的盐以治疗纤维肌痛和伴随疾病或病症，所述的伴随疾病或病症选自惊恐性障碍、过敏性肠综合征、功能性腹痛、神经病性疼痛、严重的抑郁性障碍和心境恶劣。
11.权利要求1的方法，其中对人给予通式I的化合物或其药物上可接受的盐以治疗纤维肌痛和伴随的躯体形式障碍，所述的躯体形式障碍选自躯体化障碍、转换形式障碍、身体变形性精神障碍、疑病、躯体病样疼痛症、未分化的躯体形式障碍和未另外具体说明的躯体形式障碍。
12.增加用减少慢波睡眠的药物活性剂治疗的人体受试者慢波睡眠的方法，包括给予这类人体受试者治疗有效量的通式I的化合物或其药物上可接受的盐的步骤。
13.增加人体受试者慢波睡眠的方法，包括给予需要这类治疗的人体受试者：
(a)通式I的化合物或其药物上可接受的盐；和
(b)人生长激素或人生长激素促分泌素或其药物上可接受的盐；
其中选择活性剂″a″和″b″的用量，使得该组合可有效增加慢波睡眠。
14.增加用减少慢波睡眠的药物活性剂治疗的人体受试者慢波睡眠的方法，包括给予需要这类治疗的人体受试者：
(a)通式I的化合物或其药物上可接受的盐；和
(b)人生长激素或人生长激素促分泌素或其药物上可接受的盐；
其中选择活性剂″a″和″b ″的用量，使得该组合可有效增加慢波睡眠。
15.权利要求1-14任一项的方法，其中给予的通式I的化合物为普加巴林。
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