CN1726015A - 不同药物用途的α2δ配体 - Google Patents
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- CN1726015A CN1726015A CNA2003801059680A CN200380105968A CN1726015A CN 1726015 A CN1726015 A CN 1726015A CN A2003801059680 A CNA2003801059680 A CN A2003801059680A CN 200380105968 A CN200380105968 A CN 200380105968A CN 1726015 A CN1726015 A CN 1726015A
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Abstract
本发明涉及治疗中枢神经系统疾病和其它疾病的方法,通过给药α2δ配体,例如通式(I)的化合物或其药物上可接受的盐来进行,其中R1为氢或直链或支链低级烷基且n为4-6的整数。
Description
本发明涉及治疗各种中枢神经系统疾病和其它疾病的方法,通过给药显示为α2δ配体(α2δ配体)的活性的化合物来进行。这类化合物具有对钙通道α2δ亚单位的亲和性。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
几种α2δ配体是已知的。环状α2δ配体加巴喷丁目前是商购的(Neurontin_,Warner-Lambert Company)和临床上广泛用于治疗癫痫和神经病性pain。这类环状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60/353,632;2001年7月4日公开的欧洲专利申请EP1112253;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疾病或疾患的方法,所述的疾病或疾患选自昏厥发作;癫痫;窒息;一般性缺氧;低氧;脊髓创伤;外伤性脑损伤;头部创伤;脑缺血;中风(包括血栓栓塞发作、局部缺血、全心缺血、暂时性脑缺血发作和诸如在一般进行颈动脉内膜切除术或其他血管外科手术或诸如血管造影术这类血管外科诊断方法的患者中伴随脑缺血的其它脑血管问题);氨基硫脲导致的痛性痉挛;戊四氮痛性痉挛;和因急性或慢性脑血管损害导致的脑血管疾病,诸如脑梗死、蛛网膜下出血或脑水肿;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自:神经心脏疾病,诸如神经心脏性晕厥、神经原性晕厥、颈动脉窦高度敏感、神经血管综合征和心律失常,包括心律失常继发性胃肠紊乱;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自:急性痛;慢性痛;软组织和外周损伤导致的疼痛,诸如急性创伤;带状疱疹神经痛、枕神经痛、三叉神经痛、节段或肋间神经痛和其它神经痛;与骨关节炎和类风湿性关节炎相关的疼痛;肌肉骨骼痛,诸如与劳损、扭伤和创伤相关的疼痛,诸如骨折;脊柱痛、中枢神经系统疼痛,诸如因脊髓或脑干损伤导致的疼痛;腰背痛、坐骨神经痛、牙痛、肌筋膜痛综合征、外阴切开术痛、痛风性痛和因灼伤导致的疼痛;深部痛和内脏痛,诸如心脏痛;肌肉痛、眼痛、炎性疼痛、口面疼痛,例如牙痛;腹痛;和妇科痛,例如痛经、分娩痛和与子宫内膜异位症相关的疼痛;躯体原性痛;与神经和神经根损伤相关的疼痛,诸如与外周神经障碍相关的疼痛,例如神经受累和臂丛撕脱;与截肢术相关的疼痛、三叉神经痛、神经瘤或脉管炎;糖尿病性神经病、化疗诱发的神经病、急性疱疹和带状疱疹神经痛;非典型颜面疼痛、神经病性腰背痛和蛛网膜炎、三叉神经痛、枕神经痛、节段或肋间神经痛、与HIV相关的神经痛和与AIDS相关的神经痛和其它神经痛;异常性疼痛、痛觉过敏、灼痛、特发性疼痛、化疗导致的疼痛;枕神经痛、精神性疼痛、臂神经丛撕脱、与下肢不宁综合征相关的疼痛;与胆石相关的疼痛;慢性醇中毒导致的疼痛或甲状腺功能减退症或尿毒症或维生素缺乏;与癌相关的神经病性和非神经病性疼痛、通常称作癌痛、假性肢痛、功能性腹痛、头痛,包括有先兆的偏头痛、无先兆的偏头痛和其它血管性头痛、急性或慢性紧张性头痛、窦性头痛和丛集性头痛;颞下颌痛和上颌窦痛;因强直性脊柱炎导致的疼痛;因膀胱收缩增加导致的疼痛;术后痛、瘢痕痛和慢性非神经病性疼痛诸如与HIV相关的疼痛、痈痛(anthralgia)、脉管炎和纤维肌痛;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自:情感障碍,诸如抑郁症,或更具体地说为抑郁性障碍,例如严重的抑郁性障碍、重度单相性复发性严重抑郁发作、心境恶劣障碍、抑郁性神经症和官能性抑郁症、忧郁症性抑郁症,包括食欲缺乏、体重减轻、失眠症、早晨很早步行或精神运动性阻抑、不典型抑郁症(或反应性抑郁症),包括食欲增加、睡眠过度、意识运动激越或应激性;抗治疗抑郁症;季节性情感障碍和儿科抑郁症;月经前期综合征、月经前期心境恶劣障碍、热潮红、双相性精神障碍或躁狂性抑郁症,例如双相性I型精神障碍、双相性II型精神障碍和环胸腺疾病;季节性情感障碍、品行障碍和分裂性行为障碍;与压力相关的躯体障碍和焦虑病,诸如具有或不具有旷野恐怖的惊恐性障碍,无惊恐性障碍史的旷野恐怖、特定的恐怖症(例如特定的动物恐怖症)、社交焦虑症、社交恐怖症、强迫性神经失调、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和一般焦虑症;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及哺乳动物治疗疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:边缘型人格障碍;精神分裂症和其它精神障碍,例如精神分裂症样精神障碍、情感分裂性精神障碍、妄想性障碍、短暂性精神障碍、分担类精神障碍、因一般性医学疾患导致的精神障碍、带有妄想或幻觉的精神障碍、物质引起的精神障碍、焦虑性精神病发作、与精神病相关的焦虑、精神病性情感障碍,诸如重度严重的抑郁性障碍;与精神病相关的情感障碍,诸如急性躁狂和与双相性精神障碍相关的抑郁症、与精神分裂症相关的情感障碍;和与智力低下相关的行为障碍;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组: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,包括下肢不宁综合征、帕金森病或另一种慢性疾病继发性失眠症;和暂时性失眠症);梦行病;睡眠丧失;REM睡眠障碍;睡眠性呼吸暂停;睡眠过度;深眠状态;睡眠-醒来循环障碍;时差综合症;发作性睡病;与工作改变或不规则的工作安排相关的睡眠障碍;因药物或其它原因导致的慢波睡眠减少所致睡眠情况不足;和其它睡眠障碍;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及增加人患者慢波睡眠并增加生长激素分泌的方法,该方法包括对需要这类治疗的人患者给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:呼吸性疾病,特别是与粘液分泌过度相关的那些呼吸性疾病,诸如慢性气道阻塞性疾病、支气管肺炎、慢性支气管炎、囊性纤维化、成人呼吸窘迫综合征和支气管痉挛;咳嗽、百日咳、血管紧张肽转化酶(ACE)诱发的咳嗽、肺结核、变态反应,诸如湿疹和鼻炎;接触性皮炎、特应性皮炎、荨麻疹和其他湿疹样皮炎;瘙痒、与血液透析相关的瘙痒;炎性疾病,诸如炎性肠病、银屑病、骨关节炎、软骨损伤(例如因身体活动或骨关节炎导致的软骨损伤)、类风湿性关节炎、牛皮癣性关节炎、哮喘、瘙痒症和晒斑;和超敏反应性疾病,诸如常春藤中毒;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:神经变性疾病,诸如帕金森病(PD)、亨廷顿舞蹈病(HD)和阿尔茨海默病(AD);谵妄(delerium)、痴呆(例如阿尔茨海默型老年性痴呆、老年性痴呆、血管性痴呆、与HIV-1相关的痴呆、艾滋病痴呆综合征(ADC)、因头部创伤导致的痴呆、帕金森病、亨廷顿舞蹈病、皮克病、克-雅病或因多发病因所致的病);遗忘症;其它认知或记忆障碍;和痴呆的行为症状;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:唐氏综合征;斯耶格伦综合征、高血压、血细胞生成、术后神经瘤、良性前列腺肥大、牙周病、痔和肛裂、不孕、交感反射性营养不良、肝炎、伴随高血脂的腱痛、血管舒张、纤维组织形成和胶原病,诸如硬皮病和嗜酸性片形吸虫病;和血管整复性疾病,诸如心绞痛、偏头痛和Reynaud病;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:眼病,诸如干眼综合征、结膜炎、春季结膜炎等;和与细胞增殖相关的眼病,诸如增生性玻璃体视网膜病变;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及哺乳动物治疗疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:孤独症、注意力不集中的过度反应症(ADHD)、血管发生(即用于抑制血管发生)、莱特尔综合征和anthropathies;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:因使用酒精、苯丙胺(或苯丙胺样物质)、咖啡因、大麻、可卡因、致幻药、吸入剂和气溶胶抛射剂、烟碱、阿片样物质、苯基甘氨酸(glycidine)衍生物、镇静药、催眠药和抗焦虑药导致的与物质相关的疾病这些与物质相关的疾病包括依赖和滥用、中毒、病理性退隐、中毒性谵妄(delerium)和脱瘾性谵妄;和成瘾疾病,包括成瘾行为(例如赌博成瘾和其它成瘾行为);该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:唐氏综合征;脱髓鞘病,诸如多发性硬化(MS)和前侧索硬化(ALS);该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:全身性发育迟缓、纤维肌痛、人免疫缺陷病毒(HIV)感染;HIV脑病;分离性障碍,诸如身体变形性精神障碍;进食障碍疾患,诸如食欲缺乏和食欲过盛;溃疡性结肠炎;克罗恩病;过敏性肠综合征;慢性胰腺炎;慢性疲劳综合征;婴儿猝死综合征(SIDS);膀胱活动过度;膀胱活动过度的下尿道症状;慢性膀胱炎;化疗诱发的膀胱炎;咳嗽、血管紧张肽转化酶(ACE)诱发的咳嗽;瘙痒;打呃;月经前期综合征、月经前期心境恶劣障碍、闭经病,诸如月经过少(desmenorrhea);交感反射性营养不良,诸如肩/手综合征;因细胞因子化疗导致的血浆外渗;膀胱功能障碍,诸如慢性膀胱炎、膀胱逼尿肌反射亢进、尿道和尿失禁的炎症,包括欲望性尿失禁、膀胱活动过度、压迫性尿失禁和混合性尿失禁;纤维组织形成和胶原病,诸如硬皮病和嗜酸性片形吸虫病;血管舒张导致的血流障碍和血管整复性疾病,诸如心绞痛和Reynaud病;性功能障碍,包括早泄和男性勃起功能障碍;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及治疗哺乳动物疾病或疾患的方法所述的疾病或疾患选自下列疾病或疾患组成的组:运动障碍,诸如原发性运动障碍、运动不能、运动障碍(例如家族性发作性运动障碍、迟发性运动障碍、震颤、舞蹈症、肌阵挛、抽搐和其它运动障碍)、痉挛状态、图雷特综合征、Scott综合征、麻痹(例如贝尔麻痹、大脑性瘫痪、产伤麻痹、上肢麻痹、消瘦性麻痹、局部缺血性麻痹、进行性延髓性麻痹和其它麻痹)、运动不能-强直综合征;锥体束外运动障碍,诸如药物诱发的运动障碍,例如精神安定药诱发的帕金森综合征、神经阻滞剂恶性综合征、精神安定药诱发的急性张力障碍、精神安定药诱发的急性静坐不能、精神安定药诱发的迟发性运动障碍和药物诱发的姿势性震颤;与帕金森病或亨廷顿舞蹈病相关的下肢不宁综合征和运动障碍;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:乳腺痛综合征、晕动病、系统性红斑狼疮和免疫功能障碍(例如压力诱发的免疫功能障碍诸如特发性免疫功能障碍、感染后免疫功能障碍、局部病灶切除术后免疫功能障碍、猪应激综合征、牛航运热、马阵发性肌纤维震颤、小鸡的分娩功能异常、绵羊的绝对应激和狗中的人-动物相互影响应激反应);该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:胃肠(GI)病,包括炎性胃肠病,诸如炎性肠病、幽门螺旋菌导致的疾病和胃肠道疾病,诸如胃炎、直肠炎、胃十二指肠溃疡、消化性溃疡、消化不良、与内脏的神经元控制相关的疾病、溃疡性结肠炎、克罗恩病、过敏性肠综合征和呕吐,包括术后恶心和术后呕吐且包括急性、延时或预感性呕吐(呕吐,包括化疗、放疗、毒素、病毒或细菌感染诱发的呕吐;前庭紊乱,例如运动病、眩晕、头晕和梅尼埃病、手术、偏头痛、颅内压改变、胃食管反流疾病、酸性消化不良、暴食或暴饮、胃酸过多、胃灼热或反胃、胃灼热,例如发作性、夜间或食物诱发的胃灼热和消化不良);该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
本发明还涉及治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:肿瘤,包括乳腺肿瘤、胃癌、胃淋巴瘤、神经节母细胞瘤和小细胞癌,诸如小细胞肺癌;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
上述方法在本文中共同称作″本发明的方法″。
本发明的优选实施方案使用α2δ配体,其为通式I的环氨基酸化合物及其药物上可接受的盐:
其中R1为氢或低级烷基且n为4-6的整数。尤其优选的实施方案使用通式I的化合物,其中R1为氢且n为5,该化合物为1-(氨基甲基)-环己烷乙酸,在类别上称作加巴喷丁。其它优选的α2δ配体或其药物上可接受的盐为通式I的化合物,其中环被例如烷基、诸如甲基或乙基取代。典型的这类化合物包括(1-氨基甲基-3-甲基环己基)乙酸、(1-氨基甲基-3-甲基环戊基)乙酸和(1-氨基甲基-3,4-二甲基环戊基)乙酸。
通式I的环氨基酸及其合成方法描述在美国专利US 4,024,175和US4,087,544中,将这两篇文献的全部内容引入本文作为参考。
在其它实施方案中,本发明的方法使用了通式II的α2δ配体或其药物上可接受的盐:
其中:
R1为1-6个碳原子的直链或支链未被取代的烷基、未被取代的苯基或未被取代的3-6个碳原子的环烷基;
R2为氢或甲基;且
R3为氢、甲基或羧基。
通式II化合物的非对映体和对映体可以用于本发明。
本发明方法的优选实施方案使用通式II的化合物,其为3-氨基甲基-5-甲基-己酸或尤其是(S)-3-(氨基甲基)-5-甲基己酸,在类别上称作普加巴林。
本发明方法的其他优选实施方案使用通式II的化合物,其为3-(1-氨基乙基)-5-甲基庚酸或3-(1-氨基乙基)-5-甲基己酸。
具有通式II的α2δ配体和这类化合物的合成方法描述在美国专利US5,563,175中,该文献的全部内容引入本文作为参考。
本发明方法的其他优选实施方案使用α2δ配体,其为通式III、IIIC、IIIF、IIIG或IIIH的化合物或其药物上可接受的盐:
其中:
n为0-2的整数;
m为0-3的整数;
R为:
磺酰胺;
酰胺;
膦酸;
杂环;
磺酸;或
异羟肟酸;
条件是当m为2且n为1时,R可以不为磺酸;
R1-R14各自独立地选自氢或1-6个碳的直链或支链烷基、未被取代或取代的苄基或苯基,其取代基选自卤素、烷基、烷氧基、羟基、羧基、烷氧羰基、羧基甲基和硝基;
A′为选自下列基团的桥环:
其中:
Z1-Z4各自独立地选自氢和甲基;
O为1-4的整数;且
P为0-2的整数。
本发明方法的其它优选实施方案使用了选自通式III、IIIC、IIIF、IIIG或IIIH的下列化合物及其药物上可接受的盐的化合物:
(1-氨基甲基-环己基甲基)-膦酸;
(1R-反式)(1-氨基甲基-3-甲基-环己基甲基)-膦酸;
(反式)(1-氨基甲基-3,4-二甲基-环戊基甲基)-膦酸;
(1R-反式)(1-氨基甲基-3-甲基-环戊基甲基)-膦酸;
(1S-顺式)(1-氨基甲基-3-甲基-环戊基甲基)-膦酸;
(1S-反式)(1-氨基甲基-3-甲基-环戊基甲基)-膦酸;
(1R-顺式)(1-氨基甲基-3-甲基-环戊基甲基)-膦酸;
(1a,3a,4a)(1-氨基甲基-3,4-二甲基-环戊基甲基)-膦酸;
(1a,3,4)(1-氨基甲基-3,4-二甲基-环戊基甲基)-膦酸;
(R)(1-氨基甲基-3,3-二甲基-环戊基甲基)-膦酸;
(S)(1-氨基甲基-3,3-二甲基-环戊基甲基)-膦酸;
(1-氨基甲基-3,3-二甲基-环丁基甲基)-膦酸;
2-(1-氨基甲基-环己基)-N-羟基-乙酰胺;
(1S-反式)2-(1-氨基甲基-3-甲基-环己基)-N-羟基-乙酰胺;
(反式)2-(1-氨基甲基-3,4-二甲基-环戊基)-N-羟基-乙酰胺;
(1S-顺式)2-(1-氨基甲基-3-甲基-环戊基)-N-羟基-乙酰胺;
(1R-反式)2-(1-氨基甲基-3-甲基-环戊基)-N-羟基-乙酰胺;
(1R-顺式)2-(1-氨基甲基-3-甲基-环戊基)-N-羟基-乙酰胺;
(1S-反式)2-(1-氨基甲基-3-甲基-环戊基)-N-羟基-乙酰胺;
(1α,3α,4α)2-(1-氨基甲基-3,4-二甲基-环戊基)-N-羟基-乙酰胺;
(1α,3β,4β)2-(1-氨基甲基-3,4-二甲基-环戊基)-N-羟基-乙酰胺;
(S)2-(1-氨基甲基-3,3-二甲基-环戊基)-N-羟基-乙酰胺;
(R)2-(1-氨基甲基-3,3-二甲基-环戊基)-N-羟基-乙酰胺;
2-(1-氨基甲基-3,3-二甲基-环丁基)-N-羟基-乙酰胺;
N-[2-(1-氨基甲基-环己基)-乙基]-甲磺酰胺;(1S-顺式)N-[2-(1-氨基甲基-3-甲基-环己基)-乙基]-甲磺酰胺;
(反式)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-甲磺酰胺;(1S-顺式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-甲磺酰胺;
(1R-反式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-甲磺酰胺;
(1R-顺式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-甲磺酰胺;
(1S-顺式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-甲磺酰胺;
(1α,3α,4α)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-甲磺酰胺;
(1α,3β,4β)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-甲磺酰胺;
(S)N-[2-(1-氨基甲基-3,3-二甲基-环戊基)-乙基]-甲磺酰胺;
(R)N-[2-(1-氨基甲基-3,3-二甲基-环戊基)-乙基]-甲磺酰胺;
N-[2-(1-氨基甲基-3,3-二甲基-环丁基)-乙基]-甲磺酰胺;
(1S-顺式)3-(1-氨基甲基-3-甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮;
(反式)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1S-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1R-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1R-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1S-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1α,3α,4α)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1α,3β,4β)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(S)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(R)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
3-(1-氨基甲基-3,3-二甲基-环丁基甲基)-4H-[1,2,4]噁二唑-5-酮;
3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1S-顺式)3-(1-氨基甲基-3-甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(反式)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1S-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1R-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1R-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1S-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1α,3α,4α)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1α,3β,4β)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(S)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(R)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
3-(1-氨基甲基-3,3-二甲基-环丁基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
C-[1-(1H-四唑-5-基甲基)-环己基]-甲胺;
(1S-顺式)C-[3-甲基-1-(1H-四唑-5-基甲基)-环己基]-甲胺;
(反式)C-[3,4-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1S-顺式)C-[3-甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1R-反式)C-[3-甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1R-顺式)C-[3-甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1S-反式)C-[3-甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1α,3α,4α)C-[3,4-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1α,3β,4β)C-[3,4-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(S)C-[3,3-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(R)C-[3,3-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
C-[3,3-二甲基-1-(1H-四唑-5-基甲基)-环丁基]-甲胺;
N-[2-(1-氨基甲基-环己基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1S-顺式)N-[2-(1-氨基甲基-3-甲基-环己基)-乙基]-C,C,C-三氟-甲磺酰胺;
(反式)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1R-顺式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1S-反式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1S-顺式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1R-反式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1α,3α,4α)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1α,3β,4β)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(S)N-[2-(1-氨基甲基-3,3-二甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(R)N-[2-(1-氨基甲基-3,3-二甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
N-[2-(1-氨基甲基-3,3-二甲基-环丁基)-乙基]-C,C,C-三氟-甲磺酰胺;
3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1S-顺式)3-(1-氨基甲基-3-甲基-环己基甲基)-4H-[1,2,4]噻二唑-5-酮;
(反式)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1R-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1S-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1S-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1R-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1α,3α,4α)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1α,3β,4β)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(S)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(R)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
3-(1-氨基甲基-3,3-二甲基-环丁基甲基)-4H-[1,2,4]噻二唑-5-酮;
C-[1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基甲基)-环己基]-甲胺;
(1S-顺式)C-[3-甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基甲基)-环己基]-甲胺;
(反式)C-[3,4-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基甲基)-环戊基]-甲胺;
(1S-顺式)C-[3-甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基甲基)-环戊基]-甲胺;
(1R-反式)C-[3-甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基甲基)-环戊基]-甲胺;
(1R-顺式)C-[3-甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基甲基)-环戊基]-甲胺;
(1S-反式)C-[3-甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基甲基)-环戊基]-甲胺;
(1α,3α,4α)C-[3,4-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基甲基)-环戊基]-甲胺;
(1α,3β,4β)C-[3,4-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基甲基)-环戊基]-甲胺;
(S)C-[3,3-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基甲基)-环戊基]-甲胺;
(R)C-[3,3-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基甲基)-环戊基]-甲胺;
C-[3,3-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基甲基)-环丁基]-甲胺;
(1-氨基甲基-环己基)-甲磺酰胺;
(1R-反式)(1-氨基甲基-3-甲基-环己基)-甲磺酰胺;
(反式)(1-氨基甲基-3,4-二甲基-环戊基)-甲磺酰胺;
(1S-反式)(1-氨基甲基-3-甲基-环戊基)-甲磺酰胺;
(1R-顺式)(1-氨基甲基-3-甲基-环戊基)-甲磺酰胺;
(1R-反式)(1-氨基甲基-3-甲基-环戊基)-甲磺酰胺;
(1S-顺式)(1-氨基甲基-3-甲基-环戊基)-甲磺酰胺;
(1α,3β,4β)(1-氨基甲基-3,4-二甲基-环戊基)-甲磺酰胺;
(1α,3α,4α)(1-氨基甲基-3,4-二甲基-环戊基)-甲磺酰胺;
(R)(1-氨基甲基-3,3-二甲基-环戊基)-甲磺酰胺;
(S)(1-氨基甲基-3,3-二甲基-环戊基)-甲磺酰胺;
(1-氨基甲基-3,3-二甲基-环丁基)-甲磺酰胺;
(1-氨基甲基-环己基)-甲磺酸;
(1R-反式)(1-氨基甲基-3-甲基-环己基)-甲磺酸;
(反式)(1-氨基甲基-3,4-二甲基-环戊基)-甲磺酸;
(1S-反式)(1-氨基甲基-3-甲基-环戊基)-甲磺酸;
(1S-顺式)(1-氨基甲基-3-甲基-环戊基)-甲磺酸;
(1R-反式)(1-氨基甲基-3-甲基-环戊基)-甲磺酸;
(1R-顺式)(1-氨基甲基-3-甲基-环戊基)-甲磺酸;
(1α,3β,4β)(1-氨基甲基-3,4-二甲基-环戊基)-甲磺酸;
(1α,3α,4α)(1-氨基甲基-3,4-二甲基-环戊基)-甲磺酸;
(R)(1-氨基甲基-3,3-二甲基-环戊基)-甲磺酸;
(S)(1-氨基甲基-3,3-二甲基-环戊基)-甲磺酸;
(1-氨基甲基-3,3-二甲基-环丁基)-甲磺酸;
(1-氨基甲基-环戊基甲基)-膦酸;
2-(1-氨基甲基-环戊基)-N-羟基-乙酰胺;
N-[2-(1-氨基甲基-环戊基)-乙基]-甲磺酰胺;
3-(1-氨基甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
3-(1-氨基甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
C-[1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
N-[2-(1-氨基甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
3-(1-氨基甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
C-[1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基甲基)-环戊基]-甲胺;
(1-氨基甲基-环戊基)-甲磺酰胺;
(1-氨基甲基-环戊基)-甲磺酸;
(9-氨基甲基-双环[3.3.1]壬-9-基甲基)-膦酸;
2-(9-氨基甲基-双环[3.3.1]壬-9-基)-N-羟基-乙酰胺;
N-[2-(9-氨基甲基-双环[3.3.1]壬-9-基)-乙基]-甲磺酰胺;
3-(9-氨基甲基-双环[3.3.1]壬-9-基甲基)-4H-[1,2,4]噁二唑-5-酮;
3-(9-氨基甲基-双环[3.3.1]壬-9-基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
C-[9-(1H-四唑-5-基甲基)-双环[3.3.1]壬-9-基]-甲胺;
N-[2-(9-氨基甲基-双环[3.3.1]壬-9-基)-乙基]-C,C,C-三氟-甲磺酰胺;
3-(9-氨基甲基-双环[3.3.1]壬-9-基甲基)-4H-[1,2,4]噻二唑-5-酮;
C-[9-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基甲基)-双环[3.3.1]壬-9-基]-甲胺;
(9-氨基甲基-双环[3.3.1]壬-9-基)-甲磺酰胺;
(9-氨基甲基-双环[3.3.1]壬-9-基)-甲磺酸;
(2-氨基甲基-金刚烷-2-基甲基)-膦酸;
2-(2-氨基甲基-金刚烷-2-基)-N-羟基-乙酰胺;
N-[2-(2-氨基甲基-金刚烷-2-基)-乙基]-甲磺酰胺;
3-(2-氨基甲基-金刚烷-2-基甲基)-4H-[1,2,4]噁二唑-5-酮;
3-(2-氨基甲基-金刚烷-2-基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
C-[2-(1H-四唑-5-基甲基)-金刚烷-2-基]-甲胺;
N-[2-(2-氨基甲基-金刚烷-2-基)-乙基]-C,C,C-三氟-甲磺酰胺;
3-(2-氨基甲基-金刚烷-2-基甲基)-4H-[1,2,4]噻二唑-5-酮;
C-[2-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基甲基)-金刚烷-2-基]-甲胺;
(2-氨基甲基-金刚烷-2-基)-甲磺酰胺;
(2-氨基甲基-金刚烷-2-基)-甲磺酸;
(1-氨基甲基-环庚基甲基)-膦酸;
2-(1-氨基甲基-环庚基)-N-羟基-乙酰胺;
N-[2-(1-氨基甲基-环庚基)-乙基]-甲磺酰胺;
3-(1-氨基甲基-环庚基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
N-[2-(1-氨基甲基-环庚基)-乙基]-C,C,C-三氟-甲磺酰胺;
C-[1-(2-氧代-2,3-二氢-2 14-[1,2,3,5]氧硫杂二唑-4-基甲基)-环庚基]-甲胺;
(1-氨基甲基-环庚基)-甲磺酰胺;
(1-氨基甲基-环庚基)-甲磺酸;
(1α,3α,4α)-(1-氨基甲基-3,4-二甲基-环戊基)-乙酸;
(1α,3α,4α)-(1-氨基甲基-3,4-二乙基-环戊基)-乙酸;
(1α,3α,4α)-(1-氨基甲基-3,4-二异丙基-环戊基)-乙酸;
[1S-(1α,3α,4α)]-(1-氨基甲基-3-乙基-4-甲基-环戊基)-乙酸;
[1R-(1α,3α,4α)]-(1-氨基甲基-3-乙基-4-甲基-环戊基)-乙酸;
[1S-(1α,3α,4α)]-(1-氨基甲基-3-异丙基-4-甲基-环戊基)-乙酸;
[1R-(1α,3α,4α)]-(1-氨基甲基-3-异丙基-4-甲基-环戊基)-乙酸;
[1S-(1α,3α,4α)]-(1-氨基甲基-3-乙基-4-异丙基-环戊基)-乙酸;
[1R-(1α,3α,4α)]-(1-氨基甲基-3-乙基-4-异丙基-环戊基)-乙酸;
[1S-(1α,3α,4α)]-(1-氨基甲基-3-叔丁基-4-甲基-环戊基)-乙酸;
[1R-(1α,3α,4α)]-(1-氨基甲基-3-叔丁基-4-甲基-环戊基)-乙酸;
[1S-(1α,3α,4α)]-(1-氨基甲基-3-叔丁基-4-乙基-环戊基)-乙酸;
[1R-(1α,3α,4α)]-(1-氨基甲基-3-叔丁基-4-乙基-环戊基)-乙酸;
[1S-(1α,3α,4α)]-(1-氨基甲基-3-叔丁基-4-异丙基-环戊基)-乙酸;
[1R-(1α,3α,4α)]-(1-氨基甲基-3-叔丁基-4-异丙基-环戊基)-乙酸;
(1α,3α,4α)-(1-氨基甲基-3,4-二叔丁基-环戊基)-乙酸;
[1S-(1α,3α,4α)]-(1-氨基甲基-3-甲基-4-苯基-环戊基)-乙酸;
[1R-(1α,3α,4α)]-(1-氨基甲基-3-甲基-4-苯基-环戊基)-乙酸;
[1S-(1α,3α,4α)]-(1-氨基甲基-3-苄基-4-甲基-环戊基)-乙酸;
[1R-(1α,3α,4α)]-(1-氨基甲基-3-苄基-4-甲基-环戊基)-乙酸;
(1S-顺式)(1-氨基甲基-3-甲基-环戊基)-乙酸;
(1S-顺式)(1-氨基甲基-3-乙基-环戊基)-乙酸;
(1S-顺式)(1-氨基甲基-3-异丙基-环戊基)-乙酸;
(1S-顺式)(1-氨基甲基-3-叔丁基-环戊基)-乙酸;
(1S-顺式)(1-氨基甲基-3-苯基-环戊基)-乙酸;
(1S-顺式)(1-氨基甲基-3-苄基-环戊基)-乙酸;
(1R-顺式)(1-氨基甲基-3-甲基-环戊基)-乙酸;
(1R-顺式)(1-氨基甲基-3-乙基-环戊基)-乙酸;
(1R-顺式)(1-氨基甲基-3-异丙基-环戊基)-乙酸;
(1R-顺式)(1-氨基甲基-3-叔丁基-环戊基)-乙酸;
(1R-顺式)(1-氨基甲基-3-苯基-环戊基)-乙酸;
(1R-顺式)(1-氨基甲基-3-苄基-环戊基)-乙酸;
(S)-(1-氨基甲基-3,3-二甲基-环戊基)-乙酸;
(S)-(1-氨基甲基-3,3-二乙基-环戊基)-乙酸;
(1-氨基甲基-3,3,4,4-四甲基-环戊基)-乙酸;
(1-氨基甲基-3,3,4,4-四乙基-环戊基)-乙酸;
(1α,3β,4β)-(1-氨基甲基-3,4-二甲基-环戊基)-乙酸;
(1α,3β,4β)-(1-氨基甲基-3,4-二乙基-环戊基)-乙酸;
(1α,3β,4β)-(1-氨基甲基-3,4-二异丙基-环戊基)-乙酸;
[1R-(1α,3β,4β)]-(1-氨基甲基-3-乙基-4-甲基-环戊基)-乙酸;
[1S-(1α,3β,4β)]-(1-氨基甲基-3-乙基-4-甲基-环戊基)-乙酸;
[1R-(1α,3β,4β)]-(1-氨基甲基-3-异丙基-4-甲基-环戊基)-乙酸;
[1S-(1α,3β,4β)]-(1-氨基甲基-3-异丙基-4-甲基-环戊基)-乙酸;
[1R-(1α,3β,4β)]-(1-氨基甲基-3-乙基-4-异丙基-环戊基)-乙酸;
[1S-(1α,3β,4β)]-(1-氨基甲基-3-乙基-4-异丙基-环戊基)-乙酸;
[1R-(1α,3β,4β)]-(1-氨基甲基-3-叔丁基-4-甲基-环戊基)-乙酸;
[1S-(1α,3β,4β)]-(1-氨基甲基-3-叔丁基-4-甲基-环戊基)-乙酸;
[1R-(1α,3β,4β)]-(1-氨基甲基-3-叔丁基-4-乙基-环戊基)-乙酸;
[1S-(1α,3β,4β)]-(1-氨基甲基-3-叔丁基-4-乙基-环戊基)-乙酸;
[1R-(1α,3β,4β)]-(1-氨基甲基-3-叔丁基-4-异丙基-环戊基)-乙酸;
[1S-(1α,3β,4β)]-(1-氨基甲基-3-叔丁基-4-异丙基-环戊基)-乙酸;
(1α,3β,4β)-(1-氨基甲基-3,4-二-叔丁基-环戊基)-乙酸;
[1R-(1α,3β,4β)]-(1-氨基甲基-3-甲基-4-苯基-环戊基)-乙酸;
[1S-(1α,3β,4β)]-(1-氨基甲基-3-甲基-4-苯基-环戊基)-乙酸;
[1R-(1α,3β,4β)]-(1-氨基甲基-3-苄基-4-甲基-环戊基)-乙酸,
[1S-(1α,3β,4β)]-(1-氨基甲基-3-苄基-4-甲基-环戊基)-乙酸;
(1R-反式)-(1-氨基甲基-3-甲基-环戊基)-乙酸;
(1R-反式)-(1-氨基甲基-3-乙基-环戊基)-乙酸;
(1R-反式)-(1-氨基甲基-3-异丙基-环戊基)-乙酸;
(1R-反式)-(1-氨基甲基-3-叔丁基-环戊基)-乙酸;
(1R-反式)-(1-氨基甲基-3-苯基-环戊基)-乙酸;
(1R-反式)-(1-氨基甲基-3-苄基-环戊基)-乙酸;
(1S-反式)-(1-氨基甲基-3-甲基-环戊基)-乙酸;
(1S-反式)-(1-氨基甲基-3-乙基-环戊基)-乙酸;
(1S-反式)-(1-氨基甲基-3-异丙基-环戊基)-乙酸;
(1S-反式)-(1-氨基甲基-3-叔丁基-环戊基)-乙酸;
(1S-反式)-(1-氨基甲基-3-苯基-环戊基)-乙酸;
(1S-反式)-(1-氨基甲基-3-苄基-环戊基)-乙酸;
(R)-(1-氨基甲基-3,3-二甲基-环戊基)-乙酸;
(R)-(1-氨基甲基-3,3-二乙基-环戊基)-乙酸;
顺式-(1-氨基甲基-3-甲基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-乙基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-异丙基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-叔丁基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-苯基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-苄基-环丁基)-乙酸;
反式-(氨基甲基-3-甲基-环丁基)-乙酸;
反式-(1-氨基甲基-3-乙基-环丁基)-乙酸;
反式-(1-氨基甲基-3-异丙基-环丁基)-乙酸;
反式-(1-氨基甲基-3-叔丁基-环丁基)-乙酸;
反式-(1-氨基甲基-3-苯基-环丁基)-乙酸;
反式-(I-氨基甲基-3-苄基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-乙基-3-甲基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-异丙基-3-甲基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-叔丁基-3-甲基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-甲基-3-苯基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-苄基-3-甲基-环丁基)-乙酸;
反式-(1-氨基甲基-3-乙基-3-甲基-环丁基)-乙酸;
反式-(1-氨基甲基-3-异丙基-3-甲基-环丁基)-乙酸;
反式-(1-氨基甲基-3-叔丁基-3-甲基-环丁基)-乙酸;
反式-(1-氨基甲基-3-甲基-3-苯基-环丁基)-乙酸;
反式-(1-氨基甲基-3-苄基-3-甲基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-乙基-3-异丙基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-叔丁基-3-乙基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-乙基-3-苯基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-苄基-3-乙基-环丁基)-乙酸;
反式-(1-氨基甲基-3-乙基-3-异丙基-环丁基)-乙酸;
反式-(1-氨基甲基-3-叔丁基-3-乙基-环丁基)-乙酸;
反式-(1-氨基甲基-3-乙基-3-苯基-环丁基)-乙酸;
反式-(1-氨基甲基-3-苄基-3-乙基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-叔丁基-3-异丙基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-异丙基-3-苯基-环丁基)-乙酸;
反式-(1-氨基甲基-3-苄基-3-异丙基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-叔丁基-3-苯基-环丁基)-乙酸;
反式-(1-氨基甲基-3-苄基-3-叔丁基-环丁基)-乙酸;
反式-(1-氨基甲基-3-叔丁基-3-异丙基-环丁基)-乙酸;
反式-(1-氨基甲基-3-异丙基-3-苯基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-苄基-3-异丙基-环丁基)-乙酸;
反式-(1-氨基甲基-3-叔丁基-3-苯基-环丁基)-乙酸;
顺式-(1-氨基甲基-3-苄基-3-叔丁基-环丁基)-乙酸;
(1-氨基甲基-3,3-二甲基-环丁基)-乙酸;
(1-氨基甲基-3,3-二乙基-环丁基)-乙酸;
(1-氨基甲基-3,3-二异丙基-环丁基)-乙酸;
(1-氨基甲基-3,3-二-叔丁基-环丁基)-乙酸;
(1-氨基甲基-3,3-二苯基-环丁基)-乙酸;
(1-氨基甲基-3,3-二苄基-环丁基)-乙酸;
(1-氨基甲基-2,2,4,4-四甲基-环丁基)-乙酸;
(1-氨基甲基-2,2,3,4,4-六甲基-环丁基)-乙酸;
(R)-(1-氨基甲基-2,2-二甲基-环丁基)-乙酸;
(S)-(1-氨基甲基-2,2-二甲基-环丁基)-乙酸;
(1R-顺式)-(1-氨基甲基-2-甲基-环丁基)-乙酸;
[1R-(1α,2α,3α)]-(1-氨基甲基-2,3-二甲基-环丁基)-乙酸;
(1α,2α,4α)-(1-氨基甲基-2,4-二甲基-环丁基)-乙酸;
[1R-(1α,2α,3α)]-(1-氨基甲基-2,3-二甲基-环丁基)-乙酸;
(1α,2α,4β)-(1-氨基甲基-2,4-二甲基-环丁基)-乙酸;
(1S-反式)-(1-氨基甲基-2-甲基-环丁基)-乙酸;
[1S-(1α,2β,3β)]-(1-氨基甲基-2,3-二甲基-环丁基)-乙酸;
(1α,2β,4β)-(1-氨基甲基-2,4-二甲基-环丁基)-乙酸;
[1S-(1α,2β,3α)]-(1-氨基甲基-2,3-二甲基-环丁基)-乙酸;
(1α,2β,4α)-(1-氨基甲基-2,4-二甲基-环丁基)-乙酸;
(1R-反式)-(1-氨基甲基-2-甲基-环丁基)-乙酸;
[1R-(1α,2β,3β)]-(1-氨基甲基-2,3-二甲基-环丁基)-乙酸;
[1R-(1α,2β,4β)]-(1-氨基甲基-2,4-二甲基-环丁基)-乙酸;
[1R-(1α,2β,3α)]-(1-氨基甲基-2-乙基-4-甲基-环丁基)-乙酸;
[1R-(1α,2β,3α)-(1-氨基甲基-2,3-二甲基-环丁基)-乙酸;
(1α,2β,4α)-(1-氨基甲基-2,4-二甲基-环丁基)-乙酸;
(1S-顺式)-(1-氨基甲基-2-甲基-环丁基)-乙酸;
[1S-(1α,2α,3α)]-(1-氨基甲基-2,3-二甲基-环丁基)-乙酸;
[1S-(1α,2α,4α)]-(1-氨基甲基-2,4-二甲基-环丁基)-乙酸;
[1S-(1α,2β,3α)]-(1-氨基甲基-2,3-二甲基-环丁基)-乙酸;
(3S,4S)-(1-氨基甲基-3,4-二甲基-环丁基)-乙酸;
(3R,4R)-(1-氨基甲基-3,4-二甲基-环丁基)-乙酸;
(3S,4S)-(1-氨基甲基-3,4-二乙基-环丁基)-乙酸;
(3R,4R)-(1-氨基甲基-3,4-二乙基-环丁基)-乙酸;
(3S,4S)-(1-氨基甲基-3,4-二异丙基-环丁基)-乙酸;
(3R,4R)-(1-氨基甲基-3,4-二异丙基-环丁基)-乙酸;
(3S,4S)-(1-氨基甲基-3,4-二叔丁基-环丁基)-乙酸;
(3R,4R)-(1-氨基甲基-3,4-二叔丁基-环丁基)-乙酸;
(3S,4S)-(1-氨基甲基-3,4-二苯基-环丁基)-乙酸;
(3R,4R)-(1-氨基甲基-3,4-二苯基-环丁基)-乙酸;
(3S,4S)-(1-氨基甲基-3,4-二苄基-环丁基)-乙酸;
(3R,4R)-(1-氨基甲基-3,4-二苄基-环丁基)-乙酸;
[1S-(1α,3α,4β)]-(1-氨基甲基-3-甲基-4-乙基-环戊基)-乙酸;
[1R-(1α,3β,4α)]-(1-氨基甲基-3-甲基-4-乙基-环戊基)-乙酸;
[1R-(1α,3α,4β)]-(1-氨基甲基-3-甲基-4-乙基-环戊基)-乙酸;
[1S-(1α,3β,4α)]-(1-氨基甲基-3-甲基-4-乙基-环戊基)-乙酸;
[1S-(1α,3α,4β)]-(1-氨基甲基-3-甲基-4-异丙基-环戊基)-乙酸;
[1R-(1α,3β,4α)]-(1-氨基甲基-3-甲基-4-异丙基-环戊基)-乙酸;
[1R-(1α,3α,4β)]-(1-氨基甲基-3-甲基-4-异丙基-环戊基)-乙酸;
[1S-(1α,3β,4α)]-(1-氨基甲基-3-甲基-4-异丙基-环戊基)-乙酸;
[1S-(1α,3α,4β)]-(1-氨基甲基-3-甲基-4-叔丁基-环戊基)-乙酸;
[1R-(1α,3β,4α)]-(1-氨基甲基-3-甲基-4-叔丁基-环戊基)-乙酸;
[1R-(1α,3α,4β)]-(1--氨基甲基-3-甲基-4-叔丁基-环戊基)-乙酸;
[1S-(1α,3β,4α)]-(1-氨基甲基-3-甲基-4-叔丁基-环戊基)-乙酸;
[1S-(1α,3α,4β)]-(1-氨基甲基-3-甲基-4-苯基-环戊基)-乙酸;
[1R-(1α,3β,4α)]-(1-氨基甲基-3-甲基-4-苯基-环戊基)-乙酸;
[1R-(1α,3α,4β)]-(1-氨基甲基-3-甲基-4-苯基-环戊基)-乙酸;
[1S-(1α,3β,4α)]-(1-氨基甲基-3-甲基-4-苯基-环戊基)-乙酸;
[1S-(1α,3α,4β)]-(1-氨基甲基-3-苄基-4-甲基-环戊基)-乙酸;
[1R-(1α,3β,4α)]-(1-氨基甲基-3-苄基-4-甲基-环戊基)-乙酸;
[1R-(1α,3α,4β)]-(1-氨基甲基-3-苄基-4-甲基-环戊基)-乙酸;
[1S-(1α,3β,4α)]-(1-氨基甲基-3-苄基-4-甲基-环戊基)-乙酸;
[1S-(1α,3α,4β)]-(1-氨基甲基-3-乙基-4-异丙基-环戊基)-乙酸;
[1R-(1α,3β,4α)]-(1-氨基甲基-3-乙基-4-异丙基-环戊基)-乙酸;
[1R-(1α,3α,4β)]-(1-氨基甲基-3-乙基-4-异丙基-环戊基)-乙酸;
[1S-(1α,3β,4α)]-(1-氨基甲基-3-乙基-4-异丙基-环戊基)-乙酸;
[1S-(1α,3α,4β)]-(1-氨基甲基-3-叔丁基-4-乙基-环戊基)-乙酸;
[1R-(1α,3β,4α)]-(1-氨基甲基-3-叔丁基-4-乙基-环戊基)-乙酸;
[1R-(1α,3α,4β)]-(1-氨基甲基-3-叔丁基-4-乙基-环戊基)-乙酸;
[1S-(1α,3β,4α)]-(1-氨基甲基-3-叔丁基-4-乙基-环戊基)-乙酸;
[1S-(1α,3α,4β)]-(1-氨基甲基-3-乙基-4-苯基-环戊基)-乙酸;
[1R-(1α,3β,4α)]-(1-氨基甲基-3-乙基-4-苯基-环戊基)-乙酸;
[1R-(1α,3α,4β)]-(1-氨基甲基-3-乙基-4-苯基-环戊基)-乙酸;
[1S-(1α,3β,4α)]-(1-氨基甲基-3-乙基-4-苯基-环戊基)-乙酸;
[1S-(1α,3α,4β)]-(1-氨基甲基-3-苄基-4-乙基-环戊基)-乙酸;
[1R-(1α,3β,4α)]-(1-氨基甲基-3-苄基-4-乙基-环戊基)-乙酸;
[1R-(1α,3α,4β)]-(1-氨基甲基-3-苄基-4-乙基-环戊基)-乙酸;
[1S-(1α,3β,4α)]-(1-氨基甲基-3-苄基-4-乙基-环戊基)-乙酸;
[1S-(1α,3α,4β)]-(1-氨基甲基-3-叔丁基-4-异丙基-环戊基)-乙酸;
[1R-(1α,3β,4α)]-(1-氨基甲基-3-叔丁基-4-异丙基-环戊基)-乙酸;
[1R-(1α,3α,4β)]-(1-氨基甲基-3-叔丁基-4-异丙基-环戊基)-乙酸;
[1S-(1α,3β,4α)]-(1-氨基甲基-3-叔丁基-4-异丙基-环戊基)-乙酸;
[1S-(1α,3α,4β)]-(1-氨基甲基-3-异丙基-4-苯基-环戊基)-乙酸;
[1R-(1α,3β,4α)]-(1-氨基甲基-3-异丙基-4-苯基-环戊基)-乙酸;
[1R-(1α,3α,4β)]-(1-氨基甲基-3-异丙基-4-苯基-环戊基)-乙酸;
[1S-(1α,3β,4α)]-(1-氨基甲基-3-异丙基-4-苯基-环戊基)-乙酸;
[1S-(1α,3α,4β)]-(1-氨基甲基-3-苄基-4-异丙基-环戊基)-乙酸;
[1R-(1α,3β,4α)]-(1-氨基甲基-3-苄基-4-异丙基-环戊基)-乙酸;
[1R-(1α,3α,4β)]-(1-氨基甲基-3-苄基-4-异丙基-环戊基)-乙酸;
[1S-(1α,3β,4α)]-(1-氨基甲基-3-苄基-4-异丙基-环戊基)-乙酸;
[1S-(1α,3α,4β)]-(1-氨基甲基-3-叔丁基-4-苯基-环戊基)-乙酸;
[1R-(1α,3β,4α)]-(1-氨基甲基-3-叔丁基-4-苯基-环戊基)-乙酸;
[1R-(1α,3α,4β)]-(1-氨基甲基-3-叔丁基-4-苯基-环戊基)-乙酸;
[1S-(1α,3β,4α)]-(1-氨基甲基-3-叔丁基-4-苯基-环戊基)-乙酸;
[1R-(1α,3α,4β)]-(1-氨基甲基-3-苄基-4-叔丁基-环戊基)-乙酸;
[1S-(1α,3β,4α)]-(1-氨基甲基-3-苄基-4-叔丁基-环戊基)-乙酸;
[1S-(1α,3α,4β)]-(1-氨基甲基-3-苄基-4-叔丁基-环戊基)-乙酸;
[1R-(1α,3β,4α)]-(1-氨基甲基-3-苄基-4-叔丁基-环戊基)-乙酸;
[1S-(1α,3α,4β)]-(1-氨基甲基-3-苄基-4-苯基-环戊基)-乙酸;
[1R-(1α,3β,4α)]-(1-氨基甲基-3-苄基-4-苯基-环戊基)-乙酸;
[1R-(1α,3α,4β)]-(1-氨基甲基-3-苄基-4-苯基-环戊基)-乙酸;
[1S-(1α,3β,4α)]-(1-氨基甲基-3-苄基-4-苯基-环戊基)-乙酸;
(1R-顺式)-(1-氨基甲基-2-甲基-环戊基)-乙酸;
(1S-顺式)-(1-氨基甲基-2-甲基-环戊基)-乙酸;
(1R-反式)-(1-氨基甲基-2-甲基-环戊基)-乙酸;
(1S-反式)-(1-氨基甲基-2-甲基-环戊基)-乙酸;
(R)-(1-氨基甲基-2,2-二甲基-环戊基)-乙酸;
(S)-(1-氨基甲基-2,2-二甲基-环戊基)-乙酸;
(1-氨基甲基-2,2,5,5-四甲基-环戊基)-乙酸;
(1α,2β,5β)-(1-氨基甲基-2,5-二甲基-环戊基)-乙酸;
(2R,5R)-(1-氨基甲基-2,5-二甲基-环戊基)-乙酸;
(2S,5S)-(1-氨基甲基-2,5-二甲基-环戊基)-乙酸;
(1α,2α,5α)-(1-氨基甲基-2,5-二甲基-环戊基)-乙酸;
[1R-(1α,2α,3α)]-(1-氨基甲基-2,3-二甲基-环戊基)-乙酸;
[1R-(1α,2β,3α)]-(1-氨基甲基-2,3-二甲基-环戊基)-乙酸;
[1R-(1α,2α,3β)]-(1-氨基甲基-2,3-二甲基-环戊基)-乙酸;
[1R-(1α,2β,3β)]-(1-氨基甲基-2,3-二甲基-环戊基)-乙酸;
[1S-(1α,2α,3α)]-(1-氨基甲基-2,3-二甲基-环戊基)-乙酸;
[1S-(1α,2β,3α)]-(1-氨基甲基-2,3-二甲基-环戊基)-乙酸;
[1S-(1α,2α,3β)]-(1-氨基甲基-2,3-二甲基-环戊基)-乙酸;
[1S-(1α,2β,3β)]-(1-氨基甲基-2,3-二甲基-环戊基)-乙酸;
[1R-(1α,2α,4α)]-(1-氨基甲基-2,4-二甲基-环戊基)-乙酸;
[1S-(1α,2α,4α)]-(1-氨基甲基-2,4-二甲基-环戊基)-乙酸;
[1R-(1α,2α,4β)]-(1-氨基甲基-2,4-二甲基-环戊基)-乙酸;
[1S-(1α,2α,4β)]-(1-氨基甲基-2,4-二甲基-环戊基)-乙酸;
[1R-(1α,2α,4α)]-(1-氨基甲基-2,4-二甲基-环戊基)-乙酸;
[1S-(1α,2β,4α)]-(1-氨基甲基-2,4-二甲基-环戊基)-乙酸;
[1R-(1α,2β,4β)]-(1-氨基甲基-2,4-二甲基-环戊基)-乙酸;和
[1S-(1α,2β,4β)]-(1-氨基甲基-2,4-二甲基-环戊基)-乙酸。
本发明方法其它优选的实施方案使用通式III、IIIC、IIIF、IIIG或IIIH的化合物,其中R为选自-NHSO2R15或-SO2NHR15的磺酰胺,其中R15为直链或支链烷基或三氟甲基。
本发明方法其它优选的实施方案使用通式III、IIIC、IIIF、IIIG或IIIH的化合物,其为N-[2-(1-氨基甲基-环己基)-乙基]-甲磺酰胺。
本发明方法其它优选的实施方案使用通式III、IIIC、IIIF、IIIG或IIIH的化合物,其中R为膦酸-PO3H2。
本发明方法其它优选的实施方案使用通式III、IIIC、IIIF、IIIG或IIIH的化合物,其为(1-氨基甲基-环己基甲基)-膦酸和(2-氨基甲基-4-甲基-戊基)-膦酸。
本发明方法其它优选的实施方案使用通式III、IIIC、IIIF、IIIG或IIIH的化合物,其中其它优选的化合物为这类化合物,其中R为选自下列基团的杂环:
本发明方法其它优选的实施方案为使用通式III、IIIC、IIIF、IIIG或IIIH的化合物的那些方法,所述的化合物为C-[1-(1H-四唑-5-基甲基)环己基]-甲胺或4-甲基-2-(1H-四唑-5-基甲基)-戊胺。
本发明方法尤其优选的实施方案使用通式III、IIIC、IIIF、IIIG或IIIH的化合物,其中:
m为0-2的整数;
p为整数2;且
本发明方法其它更优选的实施方案为使用通式III、IIIC、IIIF、IIIG或IIIH的化合物的那些方法,所述的化合物为3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮或其药物上可接受的盐。
本发明方法其它更优选的实施方案为使用通式III、IIIC、IIIF、IIIG或IIIH的化合物的那些方法,所述的化合物为3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮盐酸盐。
本发明方法其它更优选的实施方案为使用通式III、IIIC、IIIF、IIIG或IIIH的化合物的那些方法,所述的化合物为3-(1-氨基甲基-环庚基甲基)-4H-[1,2,4]噁二唑-5-酮或其药物上可接受的盐。
本发明方法其它更优选的实施方案为使用通式III、IIIC、IIIF、IIIG或IIIH的化合物的那些方法,所述的化合物为3-(1-氨基甲基-环庚基甲基)-4H-[1,2,4]噁二唑-5-酮盐酸盐。
本发明方法其它更优选的实施方案为使用通式III、IIIC、IIIF、IIIG或IIIH的化合物的那些方法,所述的化合物为C-[1-(1H-四唑-5-基甲基)-环庚基]-甲胺或其药物上可接受的盐。
通式III、IIIC、IIIF、IIIG或IIIH的α2δ配体及其合成方法描述在PCT专利申请WO 99/31075中,将该文献的全部内容引入本文作为参考。
本发明方法其它优选的实施方案使用通式IV化合物或其药物上可接受的盐的α2δ配体:
其中:
R1为氢、1-6个碳原子的直链或支链烷基或苯基;
R2为:1-8个碳原子的直链或支链烷基;
2-8个碳原子的直链或支链链烯基;
3-7个碳原子的环烷基;
1-6个碳原子的烷氧基;
-烷基环烷基;
-烷基烷氧基;
-烷基OH;
-烷基苯基;
-烷基苯氧基;
-苯基或取代的苯基;且
当R2为甲基时,R1为1-6个碳原子的直链或支链烷基。
本发明方法其它优选的实施方案为使用通式IV化合物的那些方法,其中R1为氢且R2为烷基。
本发明方法其它优选的实施方案为使用通式IV化合物的那些方法,其中R1为甲基且R2为烷基。
本发明方法其它优选的实施方案为使用通式IV化合物的那些方法,其中R1为甲基且R2为甲基或乙基。
本发明方法其它优选的实施方案为使用通式IV化合物的那些方法,所述的通式IV的化合物选自:
3-氨基甲基-5-甲基庚酸;
3-氨基甲基-5-甲基-辛酸;
3-氨基甲基-5-甲基-壬酸;
3-氨基甲基-5-甲基-癸酸;
3-氨基甲基-5-甲基-十一酸;
3-氨基甲基-5-甲基-十二酸;
3-氨基甲基-5-甲基-十三酸;
3-氨基甲基-5-环丙基-己酸;
3-氨基甲基-5-环丁基-己酸;
3-氨基甲基-5-环戊基-己酸;
3-氨基甲基-5-环己基-己酸;
3-氨基甲基-5-三氟甲基-己酸;
3-氨基甲基-5-苯基-己酸;
3-氨基甲基-5-(2-氯苯基)-己酸;
3-氨基甲基-5-(3-氯苯基)-己酸;
3-氨基甲基-5-(4-氯苯基)-己酸;
3-氨基甲基-5-(2-甲氧基苯基)-己酸;
3-氨基甲基-5-(3-甲氧基苯基)-己酸;
3-氨基甲基-5-(4-甲氧基苯基)-己酸;和
3-氨基甲基-5-(苯基甲基)-己酸。
(3R,4S)-3-氨基甲基-4,5-二甲基-己酸;
3-氨基甲基-4,5-二甲基-己酸;
(3R,4S)-3-氨基甲基-4,5-二甲基-己酸MP;
(3S,4S)-3-氨基甲基-4,5-二甲基-己酸;
(3R,4R)-3-氨基甲基-4,5-二甲基-己酸MP;
3-氨基甲基-4-异丙基-己酸;
3-氨基甲基-4-异丙基-庚酸;
3-氨基甲基-4-异丙基-辛酸;
3-氨基甲基-4-异丙基-壬酸;
3-氨基甲基-4-异丙基-癸酸;
3-氨基甲基-4-苯基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-5-甲氧基-己酸;
(3S,5S)-3-氨基甲基-5-乙氧基-己酸;
(3S,5S)-3-氨基甲基-5-丙氧基-己酸;
(3S,5S)-3-氨基甲基-5-异丙氧基-己酸;
(3S,5S)-3-氨基甲基-5-叔丁氧基-己酸;
(3S,5S)-3-氨基甲基-5-氟甲氧基-己酸;
(3S,5S)-3-氨基甲基-5-(2-氟-乙氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(3,3,3-三氟-丙氧基)-己酸;
(3S,5S)-3-氨基甲基-5-苯氧基-己酸;
(3S,5S)-3-氨基甲基-5-(4-氯-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(3-氯-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(2-氯-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(4-氟-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(3-氟-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(2-氟-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(4-甲氧基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(3-甲氧基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(2-甲氧基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(4-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(3-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(2-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-6-羟基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-甲氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-乙氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-丙氧基-己酸;
(3S,5S)-3-氨基甲基-6-异丙氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-叔丁氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-氟甲氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-氟-乙氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(3,3,3-三氟-丙氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-苯氧基-己酸;
(3S,5S)-3-氨基甲基-6-(4-氯-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-氯-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-氯-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(4-氟-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-氟-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-氟-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(4-甲氧基-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-甲氧基-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-甲氧基-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(4-三氟甲基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(3-三氟甲基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(2-三氟甲基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(4-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(3-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(2-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-6-苄氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-7-羟基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-甲氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-乙氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-丙氧基-庚酸;
(3S,5S)-3-氨基甲基-7-异丙氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-叔丁氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-氟甲氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(2-氟-乙氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(3,3,3-三氟-丙氧基)-庚酸;
(3S,5S)-3-氨基甲基-7-苄氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-苯氧基-庚酸;
(3S,5S)-3-氨基甲基-7-(4-氯-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(3-氯-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(2-氯-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(4-氟-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(3-氟-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(2-氟-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(4-甲氧基-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(3-甲氧基-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(2-甲氧基-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(4-三氟甲基-苯氧基)-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(3-三氟甲基-苯氧基)-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(2-三氟甲基-苯氧基)-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(4-硝基-苯氧基)-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(3-硝基-苯氧基)-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(2-硝基-苯氧基)-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-6-苯基-己酸;
(3S,5S)-3-氨基甲基-6-(4-氯-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-氯-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-氯-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(4-甲氧基-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-甲氧基-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-甲氧基-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(4-氟-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-氟-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-氟-苯基)-5-甲基-己酸;
(3S,5R)-3-氨基甲基-5-甲基-7-苯基-庚酸;
(3S,5R)-3-氨基甲基-7-(4-氯-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(3-氯-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(2-氯-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(4-甲氧基-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(3-甲氧基-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(2-甲氧基-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(4-氟-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(3-氟-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(2-氟-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-5-甲基-辛-7-烯酸;
(3S,5R)-3-氨基甲基-5-甲基-壬-8-烯酸;
(E)-(3S,5S)-3-氨基甲基-5-甲基-辛-6-烯酸;
(Z)-(3S,5S)-3-氨基甲基-5-甲基-辛-6-烯酸;
(Z)-(3S,5S)-3-氨基甲基-5-甲基-壬-6-烯酸;
(E)-(3S,5S)-3-氨基甲基-5-甲基-壬-6-烯酸;
(E)-(3S,5R)-3-氨基甲基-5-甲基-壬-7-烯酸;
(Z)-(3S,5R)-3-氨基甲基-5-甲基-壬-7-烯酸;
(Z)-(3S,5R)-3-氨基甲基-5-甲基-癸-7-烯酸;
(E)-(3S,5R)-3-氨基甲基-5-甲基-十一碳-7-烯酸;
(3S,5S)-3-氨基甲基-5,6,6-三甲基-庚酸;
(3S,5S)-3-氨基甲基-5,6-二甲基-庚酸;
(3S,5S)-3-氨基甲基-5-环丙基-己酸;
(3S,5S)-3-氨基甲基-5-环丁基-己酸;
(3S,5S)-3-氨基甲基-5-环戊基-己酸;
(3S,5S)-3-氨基甲基-5-环己基-己酸;
(3S,5R)-3-氨基甲基-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-5-甲基-壬酸;
(3S,5R)-3-氨基甲基-5-甲基-癸酸;
(3S,5R)-3-氨基甲基-5-甲基-十一酸;
(3S,5R)-3-氨基甲基-5-甲基-十二酸;
(3S,5R)-3-氨基甲基-5,9-二甲基-癸酸;
(3S,5R)-3-氨基甲基-5,7-二甲基-辛酸;
(3S,5R)-3-氨基甲基-5,8-二甲基-壬酸;
(3S,5R)-3-氨基甲基-6-环丙基-5-甲基-己酸;
(3S,5R)-3-氨基甲基-6-环丁基-5-甲基-己酸;
(3S,5R)-3-氨基甲基-6-环戊基-5-甲基-己酸;
(3S,5R)-3-氨基甲基-6-环己基-5-甲基-己酸;
(3S,5R)-3-氨基甲基-7-环丙基-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-环丁基-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-环戊基-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-环己基-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-8-环丙基-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-8-环丁基-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-8-环戊基-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-8-环己基-5-甲基-辛酸;
(3S,5S)-3-氨基甲基-6-氟-5-甲基-己酸;
(3S,5S)-3-氨基甲基-7-氟-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-8-氟-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-9-氟-5-甲基-壬酸;
(3S,5S)-3-氨基甲基-7,7,7-三氟-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-8,8,8-三氟-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-5-甲基-8-苯基-辛酸;
(3S,5S)-3-氨基甲基-5-甲基-6-苯基-己酸;和
(3S,5R)-3-氨基甲基-5-甲基-7-苯基-庚酸。
通式IV的α2δ配体及其合成方法描述在PCT专利申请WO 00/76958中,将该文献的全部内容引入本文作为参考。
本发明方法的其它优选实施方案使用通式(IXA)或(IXB)的化合物或其药物上可接受的盐的α2δ配体:
其中:
n为0-2的整数;
R为:
磺酰胺;
酰胺;
膦酸;
杂环;
磺酸;或
异羟肟酸;
A为氢或甲基;且
B为
1-11个碳的直链或支链烷基;或
-(CH2)1-4-Y-(CH2)0-4-苯基,其中Y为-O-、-S-、-NR′3,其中
R′3为1-6个碳的烷基、3-8个碳的环烷基、苄基或苯基,其中苄基或苯基可以未被取代或被1-3个取代基取代,所述的取代基各自独立地选自烷基、烷氧基、卤素、羟基、羧基、烷氧羰基、三氟甲基和硝基。
本发明方法的其它优选实施方案使用通式(IXA)或(IXB)化合物的α2δ配体,其中R选自-NHSO2R15或-SO2NHR15的磺酰胺,其中R15为直链或支链烷基或三氟甲基。
本发明方法的其它优选实施方案使用通式(IXA)或(IXB)的化合物,其选自:
4-甲基-2-(1H-四唑-5-基甲基)-戊胺;
3-(2-氨基甲基-4-甲基-戊基)-4H-[1,2,4]噁二唑-5-硫酮盐酸盐;
(2-氨基甲基-4-甲基-戊基)-膦酸;
3-(3-氨基-2-环戊基-丙基)-4H-[1,2,4]噁二唑-5-酮;
3-(3-氨基-2-环戊基-丙基)-4H-[1,2,4]噻二唑-5-酮;
2-环戊基-3-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基)-丙胺;
3-(3-氨基-2-环丁基-丙基)-4H-[1,2,4]噁二唑-5-酮;
3-(3-氨基-2-环丁基-丙基)-4H-[1,2,4]噻二唑-5-酮;和
2-环丁基-3-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]氧硫杂二唑-4-基)-丙胺。
本发明方法的其它优选实施方案使用通式(IXA)或(IXB)的化合物,其中R为膦酸,-PO3H2。
本发明方法的其它优选实施方案使用通式(IXA)或(IXB)的化合物,其中R为:
本发明方法的其它优选实施方案使用通式(IXA)或(IXB)的化合物,其中R为:
本发明方法的其它优选实施方案使用通式(IXA)或(IXB)的化合物,其为3-(2-氨基甲基-4-甲基-戊基)-4H-[1,3,4]噁二唑-5-酮或其药物上可接受的盐。
本发明方法的其它优选实施方案使用通式(IXA)或(IXB)的化合物,其为3-(2-氨基甲基-4-甲基-戊基)-4H-[1,2,4]噁二唑-5-酮盐酸盐。
通式(IXA)或(IXB)的α2δ配体及其合成方法描述在PCT专利申请WO99/31074中,将该文献的全部内容引入本文作为参考。
本发明方法的其它优选实施方案使用通式V、VI、VII或VIII的化合物或其药物上可接受的盐的α2δ配体:
其中n为1-4的整数,其中存在立体中心,各中心可以独立为R或S。
本发明方法的其它优选实施方案使用通式V、VI、VII或VIII的化合物或其药物上可接受的盐,其中n为2-4的整数。
本发明方法的其它优选实施方案使用通式V的化合物或其药物上可接受的盐。
本发明方法的其它优选实施方案使用通式V、VI、VII或VIII的化合物或其药物上可接受的盐,其选自下列化合物及其药物上可接受的盐:
(1α,6α,8β)(2-氨基甲基-八氢-茚-2-基)-乙酸;
(2-氨基甲基-八氢-茚-2-基)-乙酸;
(2-氨基甲基-八氢-环戊二烯-2-基)-乙酸;
(2-氨基甲基-八氢-环戊二烯-2-基)-乙酸;
(3-氨基甲基-双环[3.2.0]庚-3-基)-乙酸;
(3-氨基甲基-双环[3.2.0]庚-3-基)-乙酸;
(2-氨基甲基-八氢-茚-2-基)-乙酸;
(1α,5β)(3-氨基甲基-双环[3.1.0]己-3-基)-乙酸;
(1α,5β)(3-氨基甲基-双环[3.2.0]庚-3-基)-乙酸;
(1α,5β)(2-氨基甲基-八氢-环戊二烯-2-基)-乙酸;
(1α,6β)(2-氨基甲基-八氢-茚-2-基)-乙酸;
(1α,7β)(2-氨基甲基-十氢-薁-2-基)-乙酸;
(1α,5β)(3-氨基甲基-双环[3.1.0]己-3-基)-乙酸;
(1α,5β)(3-氨基甲基-双环[3.2.0]庚-3-基)-乙酸;
(1α,5β)(2-氨基甲基-八氢-环戊二烯-2-基)-乙酸;
(1α,6β)(2-氨基甲基-八氢-茚-2-基)-乙酸;
(1α,7β)(2-氨基甲基-十氢-薁-2-基)-乙酸;
(1α,3α,5α)(3-氨基甲基-双环[3.1.0]己-3-基)-乙酸;
(1α,3α,5α)(2-氨基甲基-八氢-环戊二烯-2-基)-乙酸;
(1α,6α,8α)(2-氨基甲基-八氢-茚-2-基)-乙酸;
(1α,7α,9α)(2-氨基甲基-十氢-薁-2-基)-乙酸;
(1α,3β,5α)(3-氨基甲基-双环[3.1.0]己-3-基)-乙酸;
(1α,3β,5α)(2-氨基甲基-双环[3.1.0]庚-3-基)-乙酸;
(1α,3β,5α)(2-氨基甲基-八氢-环戊二烯-2-基)-乙酸;
(1α,6β,8α)(2-氨基甲基-八氢-茚-2-基)-乙酸;
(1α,7α,9β)(2-氨基甲基-十氢-薁-2-基)-乙酸;
((1R,3R,6R)-3-氨基甲基-双环[4.1.0]庚-3-基)-乙酸;
((1R,3S,6R)-3-氨基甲基-双环[4.1.0]庚-3-基)-乙酸;
((1S,3S,6S)-3-氨基甲基-双环[4.1.0]庚-3-基)-乙酸;
((1S,3R,6S)-3-氨基甲基-双环[4.1.0]庚-3-基)-乙酸;
((1R,3R,6S)-3-氨基甲基-双环[4.2.0]辛-3-基)-乙酸;
((1R,3S,6S)-3-氨基甲基-双环[4.2.0]辛-3-基)-乙酸;
((1S,3S,6R)-3-氨基甲基-双环[4.2.0]辛-3-基)-乙酸;
((1S,3R,6R)-3-氨基甲基-双环[4.2.0]辛-3-基)-乙酸;
((3αR,5R,7αS)-5-氨基甲基-八氢-茚-5-基)-乙酸;
((3αR,5S,7αS)-5-氨基甲基-八氢-茚-5-基)-乙酸;
((3αS,5S,7αR)-5-氨基甲基-八氢-茚-5-基)-乙酸;
((3αS,5R,7αR)-5-氨基甲基-八氢-茚-5-基)-乙酸;
((2R,4αS,8αR)-2-氨基甲基-十氢-萘-2-基)-乙酸;
((2S,4αS,8αR)-2-氨基甲基-十氢-萘-2-基)-乙酸;
((2S,4αR,8αS)-2-氨基甲基-十氢-萘-2-基)-乙酸;
((2R,4αR,8αS)-2-氨基甲基-十氢-萘-2-基)-乙酸;
((2R,4αS,9αR)-2-氨基甲基-十氢-苯并环庚烯-2-基)-乙酸;
((2S,4αS,9αR)-2-氨基甲基-十氢-苯并环庚烯-2-基)-乙酸;
((2S,4αR,9αS)-2-氨基甲基-十氢-苯并环庚烯-2-基)-乙酸;
((2R,4αR,9αS)-2-氨基甲基-十氢-苯并环庚烯-2-基)-乙酸;
((1R,3R,6S)-3-氨基甲基-双环[4.1.0]庚-3-基)-乙酸;
((1R,3S,6S)-3-氨基甲基-双环[4.1.0]庚-3-基)-乙酸;
((1S,3S,6R)-3-氨基甲基-双环[4.1.0]庚-3-基)-乙酸;
((1S,3R,6R)-3-氨基甲基-双环[4.1.0]庚-3-基)-乙酸;
((1R,3R,6R)-3-氨基甲基-双环[4.2.0]辛-3-基)-乙酸;
((1R,3S,6R)-3-氨基甲基-双环[4.2.0]辛-3-基)-乙酸;
((1S,3S,6S)-3-氨基甲基-双环[4.2.0]辛-3-基)-乙酸;
((1S,3R,6S)-3-氨基甲基-双环[4.2.0]辛-3-基)-乙酸;
((3αR,5R,7αR)-5-氨基甲基-八氢-茚-5-基)-乙酸;
((3αR,5S,7αR)-5-氨基甲基-八氢-茚-5-基)-乙酸;
((3αS,5S,7αS)-5-氨基甲基-八氢-茚-5-基)-乙酸;
((3αS,5R,70αS)-5-氨基甲基-八氢-茚-5-基)-乙酸;
((2R,4αR,8αR)-2-氨基甲基-十氢-萘-2-基)-乙酸;
((2S,4αS,8αR)-2-氨基甲基-十氢-萘-2-基)-乙酸;
((2S,4αR,8αS)-2-氨基甲基-十氢-萘-2-基)-乙酸;
((3αS,4S,8αS)-2-氨基甲基-八氢-萘-5-基)-乙酸;
((2R,4αR,9αR)-2-氨基甲基-十氢-苯并环庚烯-2-基)-乙酸;
((2S,4αS,9αR)-2-氨基甲基-十氢-苯并环庚烯-2-基)-乙酸;
((2S,4αR,9αS)-2-氨基甲基-十氢-苯并环庚烯-2-基)-乙酸;和
((3αS,4S,9αS)-2-氨基甲基-八氢-苯并环庚烯-5-基)-乙酸。
本发明方法的其它优选实施方案使用通式V、VI、VII或VIII的α2δ配体,其为(1α,3α,5α)(3-氨基甲基-双环[3.1.0]庚-3-基)-乙酸或其药物上可接受的盐。
本发明方法的其它优选实施方案使用通式V、VI、VII或VIII的α2δ配体,其为(1α,3α,5α)(3-氨基甲基-双环[3.2.0]庚-3-基)-乙酸盐酸盐。
PCT专利申请WO 01/28978中描述了为通式V、VI、VII或VIII化合物的α2δ配体及其合成方法,将该文献的全部内容引入本文作为参考。
本发明方法的其它优选实施方案使用选自下列化合物及其药物上可接受的盐的α2δ配体:
3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮;
(S,S)-(1-氨基甲基-3,4-二甲基-环戊基)-乙酸;
(R,S)-3-氨基甲基-5-甲基-辛酸;
(S,R)-3-氨基甲基-5-甲基-辛酸;
(3-氨基甲基-双环[3.2.0]庚-3-基)-乙酸;
(3-氨基甲基-双环[3.2.0]庚-3-基)-乙酸,其中环丁基环对甲胺基而言是反式的;和
C-[1-(1H-四唑-5-基甲基)-环庚基]-甲胺。
如下所述或如1999年5月6日公开的PCT专利申请WO 99/21824,2000年12月21日公开的PCT专利申请WO 00/76958或2001年4月26日公开的PCT专利申请WO 01/28978中所述制备这些化合物。将这些申请的全部内容引入本文作为参考。
可以用于本发明方法的优选实施方案的其它α2δ配体描述在PCT专利申请WO 99/31057中,将该文献的全部内容引入本文作为参考。这类α2δ配体为通式(XII)和(XIII)的化合物或其药物上可接受的盐:
其中:
n为0-2的整数;
R为:
磺酰胺;
酰胺;
膦酸;
杂环;
磺酸;或
异羟肟酸;且
X为-O-、-S-、-S(O)-、-S(O)2-或NR′1,其中R′1为氢、1-6个碳的直链或支链烷基、苄基、-C(O)R′2,其中R′2为1-6个碳的直链或支链烷基、苄基或苯基或-CO2R′3,其中R′3为1-6个碳的直链或支链烷基或苄基,其中苄基或苯基可以未被取代或被1-3个取代基取代,所述的取代基选自卤素、三氟甲基和硝基。
可以用于本发明方法的优选实施方案的其它α2δ配体及其合成方法描述在PCT专利申请WO 98/17627中,将该文献的全部内容引入本文作为参考。这类α2δ配体为如下通式的化合物或其药物上可接受的盐:
其中:
R为氢或低级烷基;
R1为氢或低级烷基;
R2为
7-11个碳原子的直链或支链烷基;或
-(CH2)(1-4)-X-(CH2)(0-4)-苯基,其中:
X为-O-、-S-、-NR3-,其中:
R3为1-6个碳的烷基、3-8个碳的环烷基、苄基或苯基;其中苯基和苄基可以未被取代或被1-3个取代基取代,所述的取代基各自独立地选自烷基、烷氧基、卤素、羟基、羧基、烷氧羰基、三氟甲基、氨基和硝基。
可以用于本发明方法的优选实施方案的其它α2δ配体及其合成方法描述在PCT专利申请WO 99/61424中,将该文献的全部内容引入本文作为参考。这类α2δ配体为通式(1)、(2)、(3)、(4)、(5)、(6)、(7)和(8)的化合物和这类化合物的药物上可接受的盐和前体药物:
其中:
R1-R10各自独立地选自氢或1-6个碳的直链或支链烷基、苄基或苯基;
m为0-3的整数;
n为1-2的整数;
o为0-3的整数;
p为1-2的整数;
q为0-2的整数;
r为1-2的整数;
s为1-3的整数;
t为0-2的整数;且
u为0-1的整数。
可以用于本发明方法的优选实施方案的其它α2δ配体及其合成方法描述在2002年3月28日提交的美国临时专利申请60/368,413中,将该文献的全部内容引入本文作为参考。这类α2δ配体为如下所述的通式X、XA、XB、XI、XIA、XIB和XB-1的化合物及其药物上可接受的盐。
通式X的化合物具有如下通式:
其中:
R1为氢或任选被1-5个氟原子取代的(C1-C3)烷基;
R2为氢或任选被1-5个氟原子取代的(C1-C3)烷基;
R3为(C1-C6)烷基、(C3-C6)环烷基、(C3-C6)环烷基-(C1-C3)烷基、苯基、苯基-(C1-C3)烷基、吡啶基、吡啶基-(C1-C3)烷基、苯基-N(H)-或吡啶基-N(H)-,其中上述烷基部分可以各自任选被1-5个氟原子取代、优选被0-3个氟原子取代且其中所述的苯基和所述的比啶基和所述苯基-(C1-C3)烷基和所述吡啶基-(C1-C3)烷基的苯基和吡啶基部分可以分别任选被1-3个取代基、优选被0-2个取代基取代,所述的取代基独立地选自氯、氟、氨基、硝基、氰基、(C1-C3)烷氨基、任选被1-3个氟原子取代的(C1-C3)烷基和任选被1-3个氟原子取代的(C1-C3)烷氧基;
条件是当R1为氢时,R2不为氢。
通式XI的化合物具有如下通式:
其中R1、R2和R3如上述定义通式X化合物中所定义。
通式XA的化合物具有如下通式:
其中R3如上述定义通式X化合物中所定义。
通式XIA的化合物具有如下通式:
其中R3如上述定义通式X化合物中所定义。
通式XIB的化合物具有如下通式:
其中R1、R2和R3如上述定义通式X化合物中所定义。
通式XB的化合物具有如下通式:
其中R1、R2和R3如上述定义通式X化合物中所定义。
通式XB-1的化合物具有如下通式:
其中R3如上述定义通式X化合物中所定义。
将上面引述的所有美国专利和WO专利的全部内容引入本文作为参考。
应理解术语″使用(uses)″、″使用(utilizes)″和″使用(employs)″在描述本发明实施方案时可以互换使用。
术语″低级烷基″指的是带有1-6个碳原子的直链或支链烷基且包括甲基、乙基、正-丙基、异-丙基、正-丁基、异-丁基、仲-丁基、叔-丁基、正-戊基、正-己基等。
除非另有说明,这里使用的术语″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,环烷基为含有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。
苄基和苯基可以未被取代或被1-3个取代基取代,所述的取代基选自羟基、氨基、羧基、烷氧羰基、卤素、CF3、硝基、烷基和烷氧基。优选的取代基为氟和氯。
烷氧羰基为-COO烷基,其中烷基如上所述。优选的烷氧羰基为甲氧羰基和乙氧羰基。
除非另有说明,本文所用的术语″烷氧基″指的是″烷基-O-″,其中″烷基″如上述所定义。″烷氧基″的实例包括、但不限于甲氧基、乙氧基、丙氧基、丁氧基和戊氧基。
除非另有说明,本文所用的术语″链烯基″包括带有一个或多个连接两个碳原子的双键的不饱和烃基,其中所述的烃基可以具有直链、支链或环状基团或其组合。″链烯基″的实例包括、但不限于乙烯基、丙烯基、丁烯基、戊烯基和二甲基戊基且包括适用的E和Z型。
除非另有说明,本文所用的术语″芳基″包括不含杂原子的芳族环系,它可以未被取代或被1、2或3个取代基取代,所述的取代基选自卤素、任选被1-3个氟原子取代的(C1-C4)烷基和任选被1-3个氟原子取代的(C1-C4)烷氧基组成的组。
除非另有说明,本文所用的术语″芳氧基″指的是″芳基-O-″,其中″芳基″如上述所定义。
除非另有说明,本文所用的术语″杂芳基″包括含有5或6个环原子的芳族杂环,其中1-4个环原子可以为独立地选自N、S和O的杂原子且所述环可以未被取代、被取代基单取代或二取代,所述的取代基独立地选自卤素、任选被1-3个氟原子取代的(C1-C4)烷基和(C1-C4)烷氧基。
除非另有说明,本文所用的术语″杂芳氧基″指的是″杂芳基-O″,其中杂芳基如上述所定义。
本文所用的术语″一个或多个取代基″指的是等于基于可结合位置的数的1-最大数量的可能取代基的取代基数。
除非另有说明,本文所用的术语″卤代″和″卤素″包括氟、氯、溴和碘。
本文所用的术语″治疗(treating)″指的是这类术语所施用的疾病或疾患逆转、缓解、抑制其发展或预防这类疾病或疾患的一种或多种症状。本文所用的术语″治疗″指的是作为上述定义的″治疗″的治疗作用。
本文所用的术语″亚甲基″指的是-CH2-。
本文所用的术语″亚乙基″指的是-CH2CH2-。
本文所用的术语″亚丙基″指的是-CH2CH2CH2-。
″卤素″或″卤代″包括氟、氯、溴和碘。
磺酰胺类为通式-NHSO2R15或-SO2NHR15的那些化合物,其中R15为1-6个碳的直链或支链烷基或三氟甲基。
酰胺类为通式-NHCOR12的化合物,其中R12为1-6个碳的直链或支链烷基、苄基和苯基。
膦酸类为-PO3H2。
磺酸类为-SO3H。
异羟肟酸为:
杂环为1-2个环的基团、带有4-7个环原子的单环和带有7-12个环原子的双环,其中这类环含有1-6个选自氧、氮和硫的杂原子,条件是不存在两个为氧的相邻环原子。
优选的杂环为:
通式I-XI-B的化合物(即通式I、II、III、IV、V、VI、VII、VIII、IX、X、XA、XB、XB-1、XI、XIA和XIB的化合物)可以含有手性中心且由此可以以不同的对映体和非对映体形式存在。可以通过公知方法获得各异构体,诸如在制备终产物或其中间体的过程中进行旋光拆开、任选选择性反应或色谱分离。本发明涉及通式I-XIB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和各对映体和非对映体、也包括其混合物;且本发明涉及含有它们的所有药物组合物和使用它们的上述定义的治疗方法。通式I化合物的各对映体与这些化合物的外消旋混合物相比在治疗各种疾病或疾患中具有优势。
只要本发明通式I-XIB的化合物为碱性化合物,它们都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,但是经常理想的是在开始从反应混合物中作为药物上可接受的盐分离碱性化合物且然后通过用碱性试剂处理将其简单转化成游离碱化合物且此后将该游离碱转化成药物上可接受的酸加成盐。易于通过用基本上等量的选择的无机酸或有机酸在含水溶剂或适宜有机溶剂、诸如甲醇或乙醇中处理碱性化合物来制备本发明碱性化合物的酸加成盐。在谨慎蒸发溶剂后,易于得到所需固体盐。用于制备上述本发明的碱性化合物的药物上可接受的酸加成盐的酸是形成无毒性的酸加成盐的那些酸,所述的无毒性酸加成盐为含有可药用阴离子的盐,诸如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐或硫酸氢盐、磷酸盐或酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐或酸式柠檬酸盐、酒石酸盐或酒石酸氢盐、琥珀酸盐、马来酸盐、富马酸盐、葡糖酸盐、糖二酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1,1′-亚甲基-双-(2-羟基-3-萘酸))盐。
本发明还包括同位素标记的化合物,它们与通式I-XIB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。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,用诸如氘、
即 2H这类重同位素取代可以得到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。
发明详述
如N.S.Gee等在J.Biol.Chem.,1996,271:5879-5776中所述,可以使用来源于猪脑组织的[3H]加巴喷丁和α2δ亚单位的放射性配体结合试验测定与α2δ亚单位的结合程度。
实施本发明方法所需的是给药α2δ配体或其药物上可接受的盐,其用量可有效治疗一种或多种上述涉及的疾病或疾患。这类治疗有效量一般约为1-约300mg/kg患者体重。对一般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、诸如美国食品和药品管理局(″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疾患的有效量或治疗有效量的的过程中,医务工作者或兽医一般要考虑到许多因素,如医师或兽医的经验、公开的临床研究、患者的年龄、性别、体重和一般情况以及所治疗的疾病或疾患类型和患者使用的其它药物(如果有的话)。照此,给药剂量可以在上述范围或浓度内或可以在其外、即低于或高于上述范围或浓度,这取决于个体患者的需要、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,开始可以使用低于特定患者最佳剂量的较小剂量的α2δ配体进行治疗。此后可以通过小剂量增加来增加剂量,直到达到该情况下的最佳作用。为方便起见,如果需要,可以将总每日剂量分开并在当天分次给药。
通过用药用载体将活性化合物配制成单位剂型生产α2δ配体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、粉剂、包装在容器内的口服水溶液和非水溶液和混悬液和非肠道用溶液,其中含有一个或多个剂量单位且能够被再分成单个剂量。
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。
本发明中所用的组合物还可以含有其它成分,诸如着色剂、调味剂和/或防腐剂。如果存在,通常可以使用相对少量的这些物质。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疾患的治疗剂。
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。
α2δ配体或其药物上可接受的盐的优选给药途径为口服或非肠道。例如,有用的静脉内剂量为5-50mg且有用的口服剂量为20-800mg。
可以以任何形式给药α2δ配体或其药物上可接受的盐。优选以单位剂型给药。用于本发明的α2δ配体或其药物上可接受的盐的单位剂型还可以包括其它用于给药α2δ配体治疗的疾病或疾患或所述疾病继发性病变或疾患或给药α2δ配体的疗法的化合物。
用于本发明方法的某些化合物可以进一步形成药物上可接受的盐,包括、但不限于酸加成盐和/或碱盐。酸加成盐由碱性化合物形成,而碱加成盐由酸性化合物形成。所有这些形式均属于用于本发明方法的范围。
用于本发明方法的碱性化合物的药物上可接受的酸加成盐包括来源于无机酸和来源于有机酸的无毒性盐,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,所述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、芳族酸、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、苯基乙酸盐、柠檬酸盐、乳酸盐、苹果酸盐、酒石酸盐、甲磺酸盐。另外关注的有氨基酸盐、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″-J.of Pharma.Sci.,1977;66:1)。
通过将所述化合物的游离碱形式与足量的所需酸以常规方式接触生成无毒性盐来制备用于本发明方法的碱性化合物的酸加成盐。可以通过按照常规方式使如此形成的酸加成盐与碱接触并分离所述化合物的游离碱形式使该化合物的游离碱形式再生。按照本发明方法制备的化合物的游离碱形式在某些物理特性在一定程度上不同于其相应的酸加成盐形式,诸如溶解度、晶体结构、吸湿性等,然而在别的方面所述化合物的游离碱形式及其相应的酸加成盐形式对本发明的目的而言是等价的。
可以通过使所述化合物的游离酸形式与无毒性金属阳离子、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)。
通过将所述化合物的游离酸形式与足量的所需碱以常规方式接触生成盐来制备用于本发明方法的酸性化合物的碱加成盐。可以通过按照常规方式使如此形成的盐形式与酸接触并分离所述化合物的游离酸使该化合物的游离酸形式再生。用于本发明方法的化合物的游离酸形式在某些物理特性在一定程度上不同于其相应的盐形式,诸如溶解度、晶体结构、吸湿性等,然而在别的方面这些盐与相应的游离酸对本发明的目的而言是等价的。
用于本发明方法的某些化合物可以以非溶剂化形式以及溶剂合物形式存在,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价且包括在本发明范围内。
用于本发明方法的某些化合物具有一个或多个手性中心且每个中心可以以R或S构型存在。本发明方法可以使用任意的α2δ配体的非对映体、对映体或差向异构体形式或其药物上可接受的盐及其混合物。
另外,用于本发明方法的某些化合物可以以几何异构体存在,诸如链烯基的E型(entgegen)(E)和Z型(zusammen)(Z)异构体。本发明的方法可以使用α2δ配体的任意顺式、反式、顺、反、E型(E)或Z型(Z)异构体或其药物上可接受的盐及其混合物。
用于本发明方法的某些化合物可以以两种或多种互变体形式存在。例如,通过烯醇化/去-烯醇化等可以使所述化合物的互变体形式互变。本发明的方法可以使用α2δ配体的任意互变体形式或其药物上可接受的盐及其混合物。
下列实施例解释了含有α2δ配体和药物上可接受载体、稀释剂或赋形剂的本发明药物组合物。这些实施例仅是代表性的,但不在任何方面限定本发明。
制剂实施例1
片剂:
组分 量(mg)
3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮盐酸盐 25
乳糖 50
玉米淀粉(用于混合) 10
玉米淀粉(用于成糊) 10
硬脂酸镁(1%) 5
总计 100
将3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮盐酸盐、乳糖和玉米淀粉(用于混合)掺合均匀。将玉米淀粉(用于成糊)悬浮于200mL水中并在搅拌的同时加热成糊。将该糊用于使混合的粉末成粒。使湿颗粒通过8号手动筛并在80℃下干燥。用1%硬脂酸镁使干颗粒润滑并压制成片。将这类片剂每天对人给药1-4次治疗ADHD。
制剂实施例2
包衣片:
按照常规方式给制剂实施例1的片剂包蔗糖、马铃薯淀粉、滑石、黄耆胶和着色剂的包衣层。
制剂实施例3
注射小瓶:
使用2M盐酸将500g加巴喷丁和5g磷酸氢二钠溶液的pH在3L双蒸水调节至pH 6.5。将该溶液进行无菌过滤并将滤液灌入注射小瓶、在无菌条件下冻干并进行无菌密封。每支注射小瓶含有25mg加巴喷丁。
制剂实施例4
栓剂:
将25g(1α,3α,5α)(3-氨基甲基-双环[3.2.0]庚-3-基)-乙酸盐酸盐、100g大豆卵磷脂和1400g可可脂的混合物熔化、倾入塑模并冷却。每个栓剂含有25mg(1α,3α,5α)(3-氨基甲基-双环[3.2.0]庚-3-基)-乙酸盐酸盐。
制剂实施例5
溶液:
由1g 3-(2-氨基甲基-4-甲基-戊基)-4H-[1,2,4]-噁二唑-5-酮盐酸盐、9.38g NaH2PO4 12H2O、28.48g Na2HPO4-12H2O和0.1g苯扎氯铵在940mL双蒸水中制备溶液。使用2M盐酸将该溶液的pH调节至pH 6.8。用双蒸水将该溶液稀释至1.0L并通过照射灭菌。25mL体积的该溶液含有25mg 3-(2-氨基甲基-4-甲基-戊基)-4H-[1,2,4]-噁二唑-5-酮盐酸盐。
制剂实施例6
软膏:
将500mg 3-(1-氨基甲基-环庚基甲基)-4H-[1,2,4]噁二唑-5-酮盐酸盐与99.5g凡士林在无菌条件下混合。5g软膏部分含有25mg 3-(1-氨基甲基-环庚基甲基)-4H-[1,2,4]噁二唑-5-酮盐酸盐。
制剂实施例7
胶囊:
按照常规方式将2kg 3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮盐酸盐填充入硬明胶胶囊,使得每个胶囊含有25mg 3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮盐酸盐。
制剂实施例8
安瓿:
将2.5kg加巴喷丁溶液溶于60L双蒸水。将该溶液进行无菌过滤并将滤液灌入安瓿。在无菌条件下将安瓿冻干并在无菌条件下密封。每支安瓿含有25mg加巴喷丁。
由于说明了本发明的方法,所以要求保护有关本发明的各种实施方案。
Claims (14)
1.治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自:昏厥发作;癫痫;窒息;一般性缺氧;低氧;脊髓创伤;外伤性脑损伤;头部创伤;脑缺血;中风(包括血栓栓塞发作、局部缺血、全心缺血、暂时性脑缺血发作和诸如在一般进行颈动脉内膜切除术或其他血管外科手术或诸如血管造影术这类血管外科诊断方法的患者中伴随脑缺血的其它脑血管问题);氨基硫脲导致的痛性痉挛;戊四氮痛性痉挛;因急性或慢性脑血管损害导致的脑血管疾病,诸如脑梗死、蛛网膜下出血或脑水肿;神经心脏性晕厥;神经原性晕厥;颈动脉窦高度敏感;神经血管综合征;和心律失常,包括心律失常继发性胃肠紊乱;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
2.治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自:急性痛、慢性痛、软组织和外周损伤导致的疼痛,诸如急性创伤;带状疱疹神经痛、枕神经痛、三叉神经痛、节段或肋间神经痛和其它神经痛;与骨关节炎和类风湿性关节炎相关的疼痛;肌肉骨骼痛,诸如与劳损、扭伤和创伤相关的疼痛,诸如骨折;脊柱痛、中枢神经系统疼痛,诸如因脊髓或脑干损伤导致的疼痛;腰背痛、坐骨神经痛、牙痛、肌筋膜痛综合征、外阴切开术痛、痛风性痛和因灼伤导致的疼痛;深部痛和内脏痛,诸如心脏痛;肌肉痛;眼痛;炎性疼痛;口面疼痛,例如牙痛;腹痛;和妇科痛,例如痛经、分娩痛和与子宫内膜异位症相关的疼痛;躯体原性痛;与神经和神经根损伤相关的疼痛,诸如与外周神经障碍相关的疼痛,例如神经受累和臂丛撕脱;与截肢术相关的疼痛、三叉神经痛、神经瘤或脉管炎;糖尿病性神经病、化疗诱发的神经病、急性疱疹和带状疱疹神经痛;非典型颜面疼痛、神经病性腰背痛和蛛网膜炎、三叉神经痛、枕神经痛、节段或肋间神经痛、与HIV相关的神经痛和与AIDS相关的神经痛和其它神经痛;异常性疼痛、痛觉过敏、灼痛、特发性疼痛、化疗导致的疼痛;枕神经痛、精神性疼痛、臂神经丛撕脱、与下肢不宁综合征相关的疼痛;与胆石相关的疼痛;慢性醇中毒或甲状腺功能减退症或尿毒症或维生素缺乏导致的疼痛;通常称作癌痛的与癌相关的神经病性和非神经病性疼痛;假性肢痛、功能性腹痛、头痛,包括有先兆的偏头痛、无先兆的偏头痛和其它血管性头痛、急性或慢性紧张性头痛、窦性头痛和丛集性头痛;颞下颌痛和上颌窦痛;因强直性脊柱炎导致的疼痛;因膀胱收缩增加导致的疼痛;术后痛;瘢痕痛;和慢性非神经病性疼痛,诸如与HIV相关的疼痛、痈痛(anthralgia)、脉管炎和纤维肌痛;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
3.治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自:情感障碍,诸如抑郁症,或更具体地说为抑郁性障碍,例如严重的抑郁性障碍、重度单相性复发性严重抑郁发作、心境恶劣障碍、抑郁性神经症和官能性抑郁症、忧郁症性抑郁症,包括食欲缺乏、体重减轻、失眠症、早晨很早步行或精神运动性阻抑、不典型抑郁症(或反应性抑郁症),包括食欲增加、睡眠过度、意识运动激越或应激性;抗治疗抑郁症;季节性情感障碍和儿科抑郁症;月经前期综合征、月经前期心境恶劣障碍、热潮红、双相性精神障碍或躁狂性抑郁症,例如双相性I型精神障碍、双相性II型精神障碍和环胸腺疾病;季节性情感障碍、品行障碍和分裂性行为障碍;与压力相关的躯体障碍和焦虑病,诸如具有或不具有旷野恐怖的惊恐性障碍、无惊恐性障碍史的旷野恐怖、特定的恐怖症(例如特定的动物恐怖症)、社交焦虑症、社交恐怖症、强迫性神经失调、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和一般焦虑症;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
4.治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:边缘型人格障碍;精神分裂症和其它精神障碍,例如精神分裂症样精神障碍、情感分裂性精神障碍、妄想性障碍、短暂性精神障碍、分担类精神障碍、因一般性医学疾患导致的精神障碍、带有妄想或幻觉的精神障碍、物质引起的精神障碍、焦虑性精神病发作、与精神病相关的焦虑、精神病性情感障碍,诸如重度严重的抑郁性障碍;与精神病相关的情感障碍,诸如急性躁狂和与双相性精神障碍相关的抑郁症、与精神分裂症相关的情感障碍;和与智力低下相关的行为障碍;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
5.治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组: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,包括下肢不宁综合征、帕金森病或另一种慢性疾病继发性失眠症;和暂时性失眠症);梦行病、睡眠丧失、REM睡眠障碍、睡眠性呼吸暂停、睡眠过度、深眠状态、睡眠-醒来循环障碍、时差综合症、发作性睡病、与工作转换或不规则工作安排相关的睡眠障碍、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;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
6.治疗人患者慢波睡眠增加和生长激素分泌增加的方法,该方法包括对需要这类治疗的人患者给药治疗有效量的α2δ配体或其药物上可接受的盐。
7.治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:湿疹;接触性皮炎、特应性皮炎、荨麻疹和其他湿疹样皮炎;瘙痒、与血液透析相关的瘙痒;炎性疾病,诸如炎性肠病、银屑病、骨关节炎、软骨损伤(例如因身体活动或骨关节炎导致的软骨损伤)、类风湿性关节炎、牛皮癣性关节炎、瘙痒症和晒斑;和超敏反应性疾病,诸如常春藤中毒;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
8.治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:神经变性疾病,诸如帕金森病(PD);亨廷顿舞蹈病(HD)和阿尔茨海默病(AD);谵妄(delerium);痴呆(例如阿尔茨海默型老年性痴呆、老年性痴呆、血管性痴呆、与HIV-1相关的痴呆、艾滋病痴呆综合征(ADC)、因头部创伤导致的痴呆、帕金森病、亨廷顿舞蹈病、皮克病、克-雅病或因多发病因所致的病)、遗忘症、其它认知或记忆障碍;和痴呆的行为症状;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
9.治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:唐氏综合征;斯耶格伦综合征、高血压、血细胞生成、术后神经瘤、良性前列腺肥大、牙周病、痔和肛裂、不孕、交感反射性营养不良、肝炎、伴随高血脂的腱痛、血管舒张、纤维组织形成和胶原病,诸如硬皮病和嗜酸性姜片虫病;和血管整复性疾病,诸如心绞痛、偏头痛和Reynaud病;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
10.治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:唐氏综合征;脱髓鞘病,诸如多发性硬化(MS)和前侧索硬化(ALS);眼病,诸如干眼综合征、结膜炎、春季结膜炎等;与细胞增殖相关的眼病,诸如增生性玻璃体视网膜病变;因使用酒精、苯丙胺(或苯丙胺样物质)、咖啡因、大麻、可卡因、致幻药、吸入剂和气溶胶抛射剂、烟碱、阿片样物质、苯基甘氨酸(glycidine)衍生物、镇静药、催眠药和抗焦虑药导致的与物质相关的疾病,这些与物质相关的疾病包括依赖和滥用、中毒、病理性退隐、中毒性谵妄(delerium)和脱瘾性谵妄;和成瘾疾病,包括成瘾行为(例如赌博成瘾和其它成瘾行为);该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
11.治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:全身性发育迟缓、纤维肌痛、人免疫缺陷病毒(HIV)感染;HIV脑病;分离性障碍,诸如身体变形性精神障碍;进食障碍疾患,诸如食欲缺乏和食欲过盛;溃疡性结肠炎;克罗恩病;过敏性肠综合征;慢性疲劳综合征;婴儿猝死综合征(SIDS);膀胱活动过度;膀胱活动过度的下尿道症状;慢性膀胱炎;化疗诱发的膀胱炎;瘙痒、打呃、月经前期综合征、月经前期心境恶劣障碍、闭经病,诸如月经过少(desmenorrhea);孤独症、注意力不集中的过度反应症(ADHD)、血管发生(即用于抑制血管发生)、莱特尔综合征、anthropathies、交感反射性营养不良,诸如肩/手综合征;因细胞因子化疗导致的血浆外渗;膀胱功能障碍,诸如慢性膀胱炎、膀胱逼尿肌反射亢进、尿道和尿失禁,包括欲望性尿失禁、压迫性尿失禁和混合性尿失禁;纤维组织形成和胶原病,诸如硬皮病和嗜酸性片形吸虫病;血管舒张导致的血流障碍和血管整复性疾病,诸如心绞痛和Reynaud病;和男性勃起功能障碍;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
12.治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:运动障碍,诸如原发性运动障碍、运动不能、运动障碍(例如家族性发作性运动障碍、迟发性运动障碍、震颤、舞蹈症、肌阵挛、抽搐和其它运动障碍)、痉挛状态、图雷特综合征、Scott综合征、麻痹(例如贝尔麻痹、大脑性瘫痪、产伤麻痹、上肢麻痹、消瘦性麻痹、局部缺血性麻痹、进行性延髓性麻痹和其它麻痹)、运动不能-强直综合征;锥体束外运动障碍,诸如药物诱发的运动障碍,例如精神安定药诱发的帕金森综合征、神经阻滞剂恶性综合征、精神安定药诱发的急性张力障碍、精神安定药诱发的急性静坐不能、精神安定药诱发的迟发性运动障碍和药物诱发的姿势性震颤;与帕金森病或亨廷顿舞蹈病相关的下肢不宁综合征和运动障碍;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
13.治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:乳腺痛综合征、晕动病、系统性红斑狼疮、免疫功能障碍(例如压力诱发的免疫功能障碍,诸如特发性免疫功能障碍、感染后免疫功能障碍、局部病灶切除术后免疫功能障碍、猪应激综合征、牛航运热、马阵发性肌纤维震颤、小鸡的分娩功能异常、绵羊的绝对应激和狗中的人-动物相互影响应激反应)、肿瘤,包括乳腺肿瘤、胃癌、胃淋巴瘤、神经节母细胞瘤和小细胞癌,诸如小细胞肺癌;该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
14.治疗哺乳动物疾病或疾患的方法,所述的疾病或疾患选自下列疾病或疾患组成的组:胃肠(GI)病,包括炎性胃肠病,诸如炎性肠病、幽门螺旋菌导致的疾病和胃肠道疾病,诸如胃炎、直肠炎、胃十二指肠溃疡、消化性溃疡、消化不良、与内脏的神经元控制相关的疾病、溃疡性结肠炎、慢性胰腺炎、克罗恩病、过敏性肠综合征和呕吐,包括术后恶心和术后呕吐且包括急性、延时或预感性呕吐(呕吐,包括化疗、放疗、毒素、病毒或细菌感染诱发的呕吐;前庭紊乱,例如运动病、眩晕、头晕和梅尼埃病;手术;偏头痛;颅内压改变;食管反流疾病;酸性消化不良;暴食或暴饮;胃酸过多;胃灼热或反胃;胃灼热,例如发作性、夜间或食物诱发的胃灼热;和消化不良);该方法包括对需要这类治疗的哺乳动物给药治疗有效量的α2δ配体或其药物上可接受的盐。
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2007
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