CN1279673A - (环)烷基取代的)－γ－氨基丁酸衍生物(=GABA类似物),其制备和在治疗神经病中的用途 - Google Patents

(环)烷基取代的)－γ－氨基丁酸衍生物(=GABA类似物),其制备和在治疗神经病中的用途 Download PDF

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CN1279673A
CN1279673A CN98811474A CN98811474A CN1279673A CN 1279673 A CN1279673 A CN 1279673A CN 98811474 A CN98811474 A CN 98811474A CN 98811474 A CN98811474 A CN 98811474A CN 1279673 A CN1279673 A CN 1279673A
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treatment
compound
methyl
significant quantity
needs
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CN1210268C (zh
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T·R·贝里奥蒂
J·S·布莱恩斯
T·卡皮利斯
D·C·霍维尔
C·O·尼恩
D·J·乌斯特罗
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Warner Lambert Co LLC
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Abstract

公开了式(1A)和(1B)的新的胺或其药用盐,其中:n是0—2的整数;R是磺酰胺,酰胺,膦酸,杂环,磺酸,异羟肟酸;A是氢或甲基;而B是(a),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是－O－,－S－,－NR’3,其中R’3是1—6个碳的烷基,3—8个碳的环烷基,苄基或苯基,其中的苄基或苯基是未取代的或被1—3个取代基取代,该取代基各自选自烷基,烷氧基,卤素,羟基,羧基,烷氧羰基,三氟甲基和硝基以及其用作癫痫、晕厥发作、少动症、颅疾病、神经变性疾病、抑郁、焦虑、恐慌、疼痛、神经病理紊乱、炎症以及胃肠道紊乱,特别是IBS的治疗剂。也公开了其制备方法和用于该制备的中间体。

Description

((环)烷基取代的)-γ-氨基丁酸衍生物(=GABA类似物)， 其制备和在治疗神经病中的用途
发明背景
下式的化合物
Figure 9881147400051
其中R1是氢或低级烷基而n是4、5或6，已知于美国专利号4024175及其分案的美国专利号4087544。公开的用途是：对氨基硫脲引起的痉挛的保护作用；对卡地阿唑痉挛的保护作用；脑疾病、癫痫、晕厥发作、少动症及颅外伤；并改善脑功能。这些化合物有用于老年病患者。将上述专用引入作为参考。下式的化合物
Figure 9881147400052
其中R1是含1至6个碳原子的直链或支链烷基、苯基或含3至6个碳原子的环烷基；R2是氢或甲基；而R3是氢、甲基或羧基，已知于美国专利号5563175及其多个分案申请。将这些专利引入作为参考。
发明概述
本发明的化合物是用于多种疾病的新的胺及其药用盐。这些疾病包括：癫痫、晕厥发作、少动症、颅部疾病、神经变性疾病、抑郁、焦虑、恐慌、疼痛、神经病理性疾病、炎症及胃肠疾病。
本发明的化合物为下式1A和1B的化合物。
优选的化合物是如下的式1A和1B的化合物，其中R是选自-NHSO2R15或-SO2NHR15的磺酰胺，其中R15是直链或支链烷基或三氟甲基。
特别优选的是：
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，HCl；
3-(2-氨基甲基-4-甲基-戊基)-4H-[1，2，4]噁二唑-5-酮，HCl；
(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]氧杂噻二唑-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]氧杂噻二唑-4-基)丙胺。
其它优选的化合物是如下的式1A和1B的化合物，其中R是膦酸，-PO3H2。
其它优选的化合物是如下的式1A和1B的化合物，其中：
Figure 9881147400061
特别优选的是
发明详述
本发明的胺是式1A和1B及其药用盐。
本发明的化合物是下式的化合物及其药用盐：
Figure 9881147400072
其中：
N是0-2的整数；
R是磺酰胺，酰胺，膦酸，杂环，磺酸，异羟肟酸；
A是氢或甲基；而
B是
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是-O-，-S-，-NR’3，其中R’3是1-6个碳的烷基，3-8个碳的环烷基，苄基或苯基，其中苄基或苯基可是未取代的或被1-3个取代基取代的，该取代基各自选自烷基，烷氧基，卤素，羟基，羧基，烷氧羰基，三氟甲基和硝基。
因为氨基是两性的，故药用盐可以是适当的无机酸或有机酸的盐，例如，盐酸、硫酸、磷酸、乙酸、草酸、乳酸、枸橼酸、苹果酸、水杨酸、丙二酸、马来酸、琥珀酸、甲磺酸和抗坏血酸。从相应的氢氧化物或碳酸盐开始，可以制备与碱金属或碱土金属的盐，例如，形成钠、钾、镁或钙盐，还可以用如四甲基铵离子制备季铵盐。氨基酸的羧基可以通过已知方法酯化。
本发明的某些化合物可以以非溶剂化及溶剂化的形式存在，包括水合物形式。一般来说，溶剂化形式，包括水合物形式，与非溶剂化形式是等价的，并包括在本发明的范围内。
用于限定本发明的术语描述如下。
磺酰胺是-NHSO2R15或-SO2NHR15的磺酰胺，其中R15是含1至6个碳原子的直链或支链烷基，或三氟甲基。
酰胺是式-NHCOR12的化合物，其中R12是含1至6个碳原子的直链或支链烷基、苄基和苯基。
膦酸是-PO3H2。
磺酸是-SO3H。
异羟肟酸是
杂环为1至2个环基，其中含1至6个杂原子，其选自氧原子、
氮原子和硫原子。
优选的杂环为
Figure 9881147400082
术语烷基除非另外说明，指含1至11个碳原子的直链或支链烷基，包括但不限于甲基、乙基、丙基、正丙基、异丙基、丁基、2-丁基、叔丁基、戊基、己基、正己基、庚基、辛基、壬基、癸基和十一烷基。
环烷基除非另外说明，含3至8个碳原子，并且是环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
苄基和苯基可以无取代或被1至3个选自羟基、羧基、烷氧羰基、卤素、CF3、硝基、烷基和烷氧基的取代基取代。优选是卤素。
烷氧基中的烷基定义如上所述。
卤素是氟、氯和溴，并优选氟和氯。
烷氧羰基是-COO烷基，其中烷基定义如上。优选甲氧羰基和乙氧羰基。
本发明的某些化合物可以以非溶剂化及溶剂化的形式存在，包括水合物形式。一般来说，溶剂化形式，包括水合物形式，与非溶剂化形式是等价的，并包括在本发明的范围内。
本发明的某些化合物具有一个或多个手性中心，并且每个中心可存在R(D)或S(L)构型。本发明包括了所有对映体和差向异构体以及其适当的混合物。
采用[3H]加巴喷丁和得自猪脑组织的α2δ亚单位进行放射性配体结合检测(“新的结合到钙通道的α2δ亚单位的抗惊厥药物，加巴喷丁”，Gee N．S．等，J．Bio Chem，1996；271(10)：5768-5776)。
本发明的化合物对α2δ亚单位显示出了良好的结合亲和力。在此检测中加巴喷丁(Neutontin)的浓度约为0．10至0．12μM。由于本发明的化合物也结合此亚单位，预计它们会发挥与加巴喷丁可比的药理性质。例如，作为治疗惊厥、焦虑和疼痛的药剂。表1
Figure 9881147400101
本发明的化合物还涉及有效用于治疗癫痫的一种市售的药物Neutontin。Neutontin是1-(氨基甲基)-环己烷乙酸，其结构式如下：
Figure 9881147400102
优选的新的加巴喷丁和异丁基-GABA类似物，其衍生物和药用盐用于治疗各种疾病，包括癫痫、晕厥发作、少动症、颅部疾病、神经变性疾病、抑郁、焦虑、恐慌、疼痛、和神经病理性疾病。该化合物是以下通式的化合物：
其药用盐和前药，其中n=0，1，2，m=0，1，2，3，而R是选自-NHSO2R1或-SO2NHR1的磺酰胺，其中R1是H或直链或支链烷基或三氟甲基。R也可为通式-NHCOR1的酰胺。或者R也可是膦酸-PO3H2(Lipinski C．A．，Ann．Rep．Med．Chem．，21：283(1986))。
本发明的化合物还预计用于治疗癫痫。
本发明还涉及模拟的化合物作为治疗神经变性疾病的药剂的治疗用途。
这些神经变性疾病为，例如，早老性痴呆、杭廷顿氏舞蹈病、帕金森氏病、肌萎缩性侧硬化(Amyotrophic Lateral Sclerosis)和癫痫。
本发明还涉及治疗称为急性脑损伤的神经变性疾病。其中包括但不限于中风、脑外伤和窒息。
中风指脑血管疾病，并还可以指脑血管事件(CVA)，并包括急性血栓栓塞中风。中风包括病灶和系统局部缺血。还包括暂时脑局部缺血发作及其它伴随脑局部缺血的脑血管问题，如特别是进行颈动脉动脉内膜切除术，或其它一般的脑血管或血管手术方法的患者，或者进行包括脑血管造影术等的诊断血管方法的患者。
疼痛指急性及慢性疼痛。
急性疼痛通常时间短并与交感神经系统的机能亢进有关。实例为手术后和异常性疼痛。
慢性疼痛通常定义为持续3至6个月的疼痛，并包括躯体原性的疼痛和精神性的疼痛。其它疼痛是感受伤害。
其它疼痛由外周感觉神经损伤或感染。它包括但不限于由外周神经外伤、疱疹病毒感染、糖尿病、灼痛、血管或神经丛撕脱、神经瘤、截肢和脉管炎引起的疼痛。神经性疼痛还由慢性酒精中毒、人免疫缺陷病毒感染、甲状腺功能减退、尿毒症或维生素缺乏造成的神经损伤引起。神经性疼痛包括但不限于由神经损伤引起的疼痛，如糖尿病患者的疼痛。
精神性疼痛是无器质性原由而发生的，如腰痛、非典型面部疼痛和慢性头痛。
其它类型的疼痛为：炎症疼痛、骨关节疼痛、三叉神经痛、癌症疼痛、糖尿病神经病、腿多动综合征、急性疱疹和疱疹后神经痛、灼痛、臂血管神经丛撕脱、枕部神经痛、痛风、幻肢、烧伤及其它形式的神经痛、神经性和自发性疼痛综合征。
其它事件为头外伤、脊髓外伤或由普通缺氧症、低氧症、低血糖和低血压引起的损伤，以及在关节复位、高融合术和低氧症过程中观察到的类似损伤。
本发明将有利于各种突发事件，例如，在心脏分流术中，在颅内出血中，在产期窒息中，在心搏停止和癫痫持续状态中。
通过本发明的方法，熟练的医师将能确定给药的适宜状态，其中患者易于患有或有患有例如中风的危险以及患有中风。
还预计本发明的化合物用于治疗抑郁。抑郁可以是器质性病的结果、继发于个人损失有关的紧张状态后或是自发的。一些形式的抑郁存在很强家族发病倾向，这暗示了至少一些形式的抑郁的发病机理。抑郁的诊断主要是通过对患者情绪改变的定量测定。情绪的评价一般由医生进行或由神经心理学医生用验证的检定标度，如Hamilton抑郁检定程序表或简要精神病学检定标度进行定量。其它一些标度已被开发用于定量和检测抑郁患者情绪的改变程度，如失眠、注意力难于集中、乏力、无用感及内疚感。抑郁的诊断标准以及精神病诊断标准收集于精神病诊断和标准手册(Diagnostic and Statistical Manual of Mental Disorders)(第5版)，称为DSM-IV-R手册，由美国精神病协会(AmericanPsychiatric Association)在1994年出版。
GABA是中枢神经系统的抑制性神经递质。就抑制的总概念而言，似乎GABA-模拟物可降低或抑制脑功能并因此可使功能减慢并降低心境，其导致抑郁。
本发明的化合物可以通过在突触接点增加新产生的GABA来造成抗惊厥作用。如果加巴喷丁确实在突触接点增加了GABA水平或增加了GABA的作用，则可将其分类为GABA-模拟物，并可能降低或抑制脑功能，并因此可使功能减慢并降低心境，其导致抑郁。
本发明的化合物可用于治疗胃肠紊乱，特别是应激性肠综合征。
GABA激动剂或GABA-模拟物可能就通过提高心境的相反的方式起作用，并因此可作为抗抑郁剂的事实是一个新概念，与以前流行的GABA活性不同。
通过标准的药理学方法证明，本发明的化合物还预计可用来治疗焦虑和恐慌。
材料和方法
角叉菜胶引起的痛觉过敏
在大鼠爪压力实验中用疼痛检测器(Randall-Sellito法：Randall L．O．，Sellitto J．J．，对发炎组织止痛活性的检测方法，Arch．Int．Pharmacodyn．，4：409-419(1957))检测感受伤害压力阈。实验目前在此仪器上训练雄性Sprague-Dawley鼠(70-90g)。给每只鼠的后爪逐渐施加压力并将感受伤害阈确定为引起爪缩回需要的压力(g)。截止点为250g，以防止对爪造成的任何组织损伤。在实验的当天，在给动物右后爪足底内注射100μL2％角叉菜胶前检测两至三个基线值。角叉菜胶给药后3小时再测定感受伤害阈，以确定这些动物表现了痛觉过敏。在注射角叉菜胶后3．5小时给动物施用加巴喷丁(3-300mg／kg，s．c．)、吗啡(3mg／kg，s．c．)或盐水，并在注射角叉菜胶后4、4．5和5小时检测感受伤害阈值。
氨基脲引起的强直癫痫发作
由皮下施用氨基脲(750mg／kg)引起小鼠强直癫痫发作。注意前爪强直延伸的潜伏期。将使用氨基脲后2．0小时不产生惊厥的任何小鼠视为受到了保护，并给出最大潜伏期记录为120分钟。
动物
雄性Hooded Lister大鼠(200-250g)得自Interfauna(Huntingdon，UK)，而雄性T0小鼠(20-25g)得自Bantin和Kingman(Hull，UK)。这两种啮齿类每六只一组被关在笼中。重280至360g的普通狨(Callithrix Jacchus)在Manchester大学医学院(Manchester，UK)饲养，成对关在茏中。将所有动物关在12小时亮／暗循环的环境(在07．00小时照明)中，并任意食用食物和水。
给药
在实验前40分钟，腹膜内(IP)或皮下(SC)给药，对于大鼠和狨为1ml／kg，而对于小鼠为10ml／kg。
小鼠亮／暗箱
此仪器是顶部开口的箱，长45厘米、宽27厘米、高27厘米，通过延伸在墙的20厘米上方的分隔将其分为小区域(2／5)和大区域(3／5)(Costall B．等，在黑和白箱中探查小鼠：确定为焦虑的模型，Pharmacol．Biochem．Behav．，32：777-785(1989))。
在分隔中央地板上有7．5×7．5厘米的开口。小室被漆为黑色而大室被漆为白色。白色室用60 W钨灯照明。实验室用红灯照明。将每只小鼠放置在白色区域的中央并允许其探查新环境5分钟。检测在照明一侧花费的时间(Kilfoil T．等，在小鼠焦虑的简单模型中抗焦虑药和焦虑产生药对探查活性的作用，Neuropharmacol．28：901-905(1989))。
大鼠升高的X-迷宫
将标准升高的迷宫(Handley S．L．等，α-肾上腺素受体激动剂和拮抗剂在“恐惧”激发的行为的迷宫研究模型中的效果，Naunyn-Schiedeberg′s Arch．Pharmacol．，327：1-5(1984))按照以前的描述自动化(Field等，大鼠升高的X-迷宫焦虑测试的自动化，Br．J．Pharmacol．，102(suppl)：304P(1991))。将动物置于X-迷宫的中央，面对一个开口的狭长弯道。为了检测抗焦虑作用，在5分钟实验期间检测最后在开放狭长弯道的一半通过的次数和花费的时间(Costall等，用高标准迷宫评价焦虑剂在大鼠中的效能，Br．J．Pharmacol．，96(Suppl)：312P(1989))。
狨被人威胁实验
在2分钟的实验期间内记录动物对威胁刺激(人站立在离狨笼0．5m处并凝视狨的眼睛)表现出的体态的总次数。记录的体态为缝凝视、尾部姿势、嗅笼／杆的气味、立毛、退避和弓背。在药物处理前和后，在实验的当天每只动物接触威胁刺激2次。通过Dunnett′s t检验用变量单侧分析法分析两组评分的差异。所有的药物处理在第一次(对照)威胁后至少2小时SC进行。每个化合物的预处理时间为40分钟。大鼠冲突实验
在操作室内训练大鼠压杆来获取食物。此方案由通过开室内灯为信号的30秒的可变间隔4个4分钟无处罚期以及以室内灯关掉为信号的固定的变换系数5(通过给食物时伴随爪电击)的3个3分钟处罚期的改变组成。调整对每只鼠的爪电击程度，让其与无处罚的响应相比获得约80％至90％的响应抑制。在训练期鼠接受盐水载体。
本发明的化合物也预计可用于治疗疼痛和恐怖紊乱(Am．J．Pain Manag．，5：7-9(1995))。
本发明的化合物还预计可用于治疗躁狂、急慢性、单侧或复发抑郁的症状。它们还预计用于治疗和／或预防两极紊乱(美国专利5510381)。
TNBS诱导的大鼠慢性内脏异常性疼痛(Allodynia)
已发现给结肠注射三硝基苯磺酸(TNBS)引起慢性结肠炎。在人中，消化紊乱经常与内脏疼痛有关。在这些疾病中，内脏疼痛阈值降低表明内脏超敏。结果，设计此实验来评价在结肠扩张实验模型中给经肠注射TNBS对内脏疼痛阈值的作用。
动物和手术
使用重340-400g雄性的Sprague-Dawley大鼠(Janvier，LeGenest-St-Ilse，法国)。在调节的环境(20±1℃，50±5％温度，早8：00至晚8：00光照)每个笼中关3只动物。麻醉下(氯胺酮80mg／kgi．p．；乙酰丙嗪12mg／kg ip)，给结肠的近端(距盲肠1厘米)进行TNBS(50mg／kg)或盐水(1．5ml／kg)注射。手术后，将动物单独关在聚丙烯笼中，并在调节的环境(20±1℃，50+5％湿度，早8：00至晚8：00光照)中关7天。
实验方法
TNBS给药后第7天，通过肛门插入气球(5-6厘米长)并通过轻击插管至尾部根部保持在此位置(气球尖端距肛门5厘米)。逐渐给此气球充气，每次5mmHg，从0至75mmHg，每次充气持续30秒。通过标准气压补偿器(ABS，St-Die，法国)控制结肠扩张的每个循环。阈值相应于产生第一次腹部收缩并停止扩张循环的压力。对同一动物进行4个循环的扩张后确定此结肠阈值(以mmHg表示的压力)。
化合物活性的检测
通过比较被测化合物治疗组与TNBS治疗组及对照组来分析数据。计算每组的平均值和SEM。化合物的抗异常活性计算如下：
活性(％)=(组C-组T)／(组A-组T)
组C：对照组结肠阈值的平均值
组T：TNBS治疗组的结肠阈值的平均值
组A：被测化合物治疗组的结肠阈值的平均值
统计分析
用单侧ANOVA再用Student不成对t检验确定每组之间的统计学显著性。在p＜0．05下认为差异是统计学显著性的。
化合物
TNBS溶解于30％乙醇中，并以0．5ml／大鼠的体积注射。TNBS购自Fluka。
在结肠扩张循环前1小时进行被测化合物或其载体的口服给药。
在结肠扩张循环前30分钟进行被测化合物或其载体的皮下给药。
本发明的化合物可以以多种口服和非肠道给药剂型制备并给药。因此，本发明的化合物可以通过注射给药，即静脉内、肌肉内、皮内、皮下、十二指肠内或腹膜内给药。本发明的化合物还可以通过吸入给药，例如，鼻内吸入。此外，本发明的化合物可以透皮给药。本领域技术人员显而易见下列剂型可以含有式Ⅰ的化合物或式Ⅰ化合物的相应药用盐作为活性组分。
为了由本发明的化合物制备药物组合物，药用载体可以是固体或液体。固体制剂包括散剂、片剂、丸剂、胶囊、扁囊剂、栓剂和可分散颗粒剂。固体载体可以是一种或多种物质，它们也可以作为稀释剂、矫味剂、粘合剂、防腐剂、片剂崩解剂或包囊材料。
在散剂中，载体是细分的固体，其与细分的活性组分存在于混合物中。
在片剂中，此活性组分与具有需要的粘合性质的载体以适当比例混合，并压制为所需的形状和大小。
散剂和片剂优选含有5或10至约70％活性化合物。适宜的载体是碳酸镁、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“制剂”旨在包括以包囊材料为载体提供胶囊的活性化合物的制剂，其中活性化合物与其它载体或无其它载体被包在载体中，该化合物于是与该载体联合。同样，包括扁囊剂和锭剂。片剂、散剂、胶囊、丸剂、扁囊剂和锭剂可以是适于口服给药的固体剂型。
为了制备栓剂，先将低熔点蜡如脂肪酸甘油酯或可可脂的混合物熔化，并通过搅拌将此活性组分均匀地分散在其中。然后，将熔化的均匀混合物倒入大小合适的模中，让其冷却，并由此固化。
液体形式的制剂包括溶液剂、混悬剂和乳剂，例如，水或含水丙二醇溶液。对于非肠道注射液体制剂，可以在含水聚乙二醇溶液中制备。
适于口服的含水溶液剂可以通过将活性组分溶解于水中，并按照需要加入适宜的着色剂、矫味剂、稳定和增稠剂制备。
适于口服的含水混悬剂可以通过将细分的活性组分分散于含水粘性物质中制备，如天然或合成胶、树脂、甲基纤维素、羧甲基纤维素钠及其它熟知的混悬剂。
还包括在使用前短不久转变为口服给药的液体制剂的固体形式的制剂。这些液体形式包括溶液剂、混悬剂和乳剂。除活性组分外这些制剂可含有着色剂、矫味剂、稳定剂、缓冲剂、合成或天然甜味剂、分散剂、增稠剂、助溶剂等。
此药物制剂优选是单位剂型。在此剂型中，此制剂被再分为含适量活性组分的单位剂量。此单位剂量可以是包装的制剂，该包装含可分量的制剂，如包装的片剂、胶囊和在小瓶或安瓿中的散剂。此单位剂型还可以是胶囊、片剂、扁囊剂或锭剂本身，或其可以是存在于包装形式中的适当数量的任何这些剂型。
单位剂量制剂中活性组分的量可根据具体的应用和活性组分的效力而变化或调节自0．1mg至约1g。在医药用途中，该药物以例如100或300mg的胶囊每天给药三次。必要时，该组合物还可含其他相容的治疗剂。
在治疗用途中，用于本发明药学方法的化合物以起始剂量每天约0．01mg至约100mg／kg给药。日剂量范围优选约0．01mg至约100mg／kg。但是，这些剂量可以根据患者的需要、被治疗病症的严重性以及使用的化合物变化。对特定情况下适当剂量的确定是本领域技术人员的一般知识。一般来说，开始以小于该化合物最佳剂量的较小剂量治疗。此后，小量增加此剂量直到达到在此环境下的最佳效果。方便起见，如果需要可将总日剂量再细分并在该天内分次给药。
R也可是杂环如四唑
Figure 9881147400191
或其它已用作CO2H取代的杂环，如(Kohara Y．，Imamiya E．，Wada T．，Inada Y．，和Naka T．，J．Med．Chem．，39：5228(1996))。
也优选磺酸和异羟肟酸。
式1A的四唑可通过方案1所示的路径合成。方案1
以下实施例是本发明的例举说明，其并非限制本发明的范围。
实施例1
4-甲基-2-(1H-四唑-5-基甲基)-戊胺
方案1的化合物3{2-[(2-氰基-乙基氨基甲酰基)-甲基]-4-甲基-戊基}-氨基甲酸-丁酯
将化合物2的溶液(8．0g，0．03mmol)(以常规方法制备于(BOC)2和pregabalin)置于250 ml无水THF中并在冰水浴中冷却。加入三乙胺(4．62 mL，0．033mol)并随后加入氯甲酸异丁酯(4mL，0．031mol)。在0℃下搅拌该反应物约15分钟，在此期间形成沉淀。在分液瓶中放入在35 ml 1M NaOH和300 ml THF中的3-氨基丙腈富马酸(3．95g，0．03mmol)。冷却此混合物到0℃并用上述形成的混合酐分四次处理。在加入每部分前，加入35 ml 1M NaOH到该混合物中。搅拌该反应物24小时并浓缩除去THF。用乙酸乙酯萃取所得的水相。用盐水洗涤该合并的有机萃取液，硫酸镁干燥。减压除去溶剂得到6．6g绿色油。MS(APCI)m／z312(M+1)。
方案1的化合物4[4-甲基-2-(1-(2-氰基-乙基)-四唑-5-基甲基)-戊基]-氨基甲酸叔丁酯和化合物5[4-甲基-2-(1H四唑-5-基甲基)-戊基]-氨基甲酸叔-丁酯。
将氰酰胺(6．5g，0．0209mol)和三苯膦(11．06g，0．042mol)溶解在300 ml无水THF中。用DEAD(6．7mL，0．0425mol)和TMSN3(5．75mL，0．043mol)处理该溶液。搅拌该反应物24小时并冷却此混合物到0℃，用900ml含46．9(NH4)2Ce(IV)NO3的水溶液。浓缩该反应混合物除去THF并用三部分CH2Cl2萃取。用盐水和Na2SO4干燥合并的有机层，减压除去溶剂得到透明油，通过硅胶塞得到混有氧化三苯膦的产物。将此混合物溶于200ml THF和50 ml 2N NaOH中。加热混合物回流2小时，然后在室温下搅拌过夜。减压除去THF并用水稀释所得的残留物。用乙醚萃取后，酸化水相到pH 7并用21 ml 4N HCl萃取。然后用固体KH2PO4饱和水相。用CH2Cl2萃取水性混合物。用盐水洗涤有机相萃取液并用Na2SO4干燥。减压蒸发有机溶剂导致分离3．4g琥珀色油。
4-甲基-2-(1H-四唑-5-基甲基)-戊胺
将前步骤所得的材料(0．9g，3．18mmol)溶于20 ml 4M HCl的二噁烷溶液。让该反应物静置1小时。形成固体，加入10 ml乙醚，过滤该反应物得到780mg白色固体。MS(APCI)m／z184(M+1)。
实施例2
异丁基GABA噁二唑酮硫酮(G)也称为3-(2-氨基甲基-4-甲基-戊基)-4H-[1，2，4]噁二唑-5-硫酮；HClBOC-异丁基GABA(B)
在十分钟内，加入二碳酸二-叔-丁酯(13．1g，0．06mol)的THF(200ml)溶液到冰浴冷却的异丁基GABA(9．95g，0．056mol)的1NNaOH(125ml)和THF(50ml)溶液中。在室温下搅拌该反应混合物3小时，浓缩除去THF，用饱和的KH2PO4饱和并用3X Et2O萃取。2X盐水洗涤萃取液，硫酸镁干燥。蒸干得到白色固体，17．9g(65％)；mp 84-88℃。MS(APCI)m／z 260(M+1)。BOC-异丁基GABA酰胺(C)
将BOC-异丁基GABA(6．78g，0．026mol)和三乙胺(3．0g，0．030mol)冷却至0℃并缓慢加入氯甲酸异丁酯(3．9g，0．029mol)。在0℃下搅拌20分钟，将氨气通入反应混合物30分钟，然后在室温下搅拌18小时。浓缩混合物除去THF，悬浮于水，用3X Et2OAc萃取。用1X10％Na2CO3，2X盐水洗涤萃取液，硫酸钠干燥。蒸干得到油，4．9 g(73％)；无须进一步纯化即可使用。MS(APCI)m／z 259(M+1)。
BOC-异丁基GABA腈(D)
立即加入BOC-异丁基GABA酰胺(4．6g，0．0178mol)的DMF(15ml)到氰尿酰氯(1．66g，0．009mol)中，在室温下搅拌30分钟。将反应混合物注入NaHCO3(4．2g，0．05mol)的冷水(15ml)溶液。加入固体K2CO3使其pH到9。2XCH2Cl2萃取该混合物，用1X盐水洗涤和Na2SO4干燥。蒸干得到油状物，硅胶过滤，以CH2Cl2-EtOAc洗脱得到3．8g油状物(73％)；无须进一步纯化即可使用。MS(APCI)m／z 240(M+1)；IR(膜)2215cm-1。
BOC-异丁基GABA偕胺肟(E)
通过加入三乙胺(7．62g，0．075mol)到盐酸羟胺(5．21g，0．075mol)的DMSO(25ml)悬浮液中制备羟胺溶液。15分钟后，滤去盐酸三乙胺，加入BOC-异丁基GABA腈(3．61g，0．015mol)到滤液中。在75℃加热该混合物17小时。用水稀释该混合物，并用3X EtOAc萃取。用2X盐水洗涤，硫酸钠干燥。蒸干得到油状物通过用CH2Cl2-EtOAc洗脱的短硅胶柱过滤得到3．2 g(78％)油。1HNMR(CDCl3)δ0．84(d，6H，J=6．35 Hz)，1．11(m，2H)，1．40(s，9H)，1．63(m，1H)，3．05(m，1H)，3．15(m，1H)，4．85(m，1H)，5．43(m1，H)；MS(APCI)274(M+1)．
BOC-异丁基GABA噁二唑酮硫酮(F)
在室温下搅拌含BOC-异丁基GABA偕胺肟(0．5g，0．00183mol)，DBU(1．12g，0．00736mol)和90％1，1’-硫代羰基二咪唑(0．398g，0．002mol)的MeCN(12ml)溶液16小时。蒸干该反应混合物，溶于EtOAc，并用KHSO4溶液洗涤。用1N NaOH(100ml)萃取EtOAc层。用Et2O洗涤该碱性萃取液，并用饱和的KH2PO4酸化并用3X Et2O萃取。用1X水，1X盐水洗涤，硫酸镁干燥。蒸干得到油，0．25g(43％)。1H NMR(CDCl3)δ0．84(d，6H，J=6．59 Hz)，1．1(m，2H)，1．41(s，9H)，1．65(m，1H)，1．85(m，1H)，2．60(m，2H)，3．1(m，2H)，4．94(m，1H)，12．8(s，1H)．MS(APCI)316(M+1)．
异丁基GABA噁二唑酮硫酮(G)也称为3-(2-氨基甲基-4-甲基-戊基)-4H-[1，2，4]噁二唑-5-硫酮；HCl
在室温下将BOC-异丁基GABA噁二唑酮硫酮(0．25g，0．79mmol)置于在二噁烷中的4M HCl(10ml)中1小时。蒸发，随后在MeCN中重结晶该残余物得到奶油色晶体，0．108g，mp 183-185℃。
1H NMR(DMSO-d6)δ0．84(d，6H，
J=6．59 Hz)，1．1(m，2H)，1．41(s，9H)，1．65(m，1H)，0．80(d，6H，J=6．59 Hz)，
1．06(m，1H)，1．25(m，1H)，1．55(m，1H)，2．1(m，1H)，2．7(m，4H)，7．95(s，3H)；
MS(APCI)216(M+1)．计算分析C9H17N3OS·HCl：C，42．93；H，7．21；
N，16．69；Cl，14．08．测定值：C，43．38；H，7．24；N，16．29；Cl，14．17．
实施例3
异丁基GABA噁二唑酮(J)也称为3-(2-氨基甲基-4-甲基-戊基)-4H-[1，2，4]噁二唑-5-酮；HCl
Figure 9881147400241
BOC-异丁基GABA偕胺肟氨基甲酸酯(H)
在0℃下将氯甲酸异丁酯(0．253g，0．00185mol)滴加到BOC-异丁基GABA偕胺肟(0．5g，0．00183mol)和吡啶(0．158g，0．002mol)的DMF(10ml)溶液中。在此温度下30分钟后，用水稀释该反应混合物并用3X EtOAc萃取。用1X水，1X盐水洗涤萃取液并MgSO4干燥。蒸干得到油状物，0．7g(100％)；无须进一步纯化即可使用。MS(APCI)m／z 374(M+1)。
BOC-异丁基GABA噁二唑酮(I)
将BOC-异丁基GABA偕胺肟氨基甲酸酯(0．7g，0．00183mol)置于在二甲苯(20ml)中并回流加热2小时。蒸发得到暗色透明油，将其溶于Et2O中并用1N NaOH萃取。用饱和的KH2PO4酸化该碱性萃取液并用3X Et2O萃取。用盐水洗涤，硫酸钠干燥。蒸干得到棕色油，0．25g(46％)，无须进一步纯化即可使用。MS(APCI)m／z 300(M+1)。异丁基GABA噁二唑酮(J)也称为3-(2-氨基甲基-4-甲基-戊基)-4H-[1，2，4]噁二唑-5-酮；HCl
将BOC-异丁基GABA噁二唑酮(0．25g，0．835mmol)置于在二噁烷中的4M HCl中并让其静置2．5小时。蒸发，随后在MeCN-Et2O中重结晶该残余物得到褐色固体，53mg，(27％)；mp 181-184℃。
1H NMR(DMSO-d6)δ0．80(d，6H，J-6．35Hz)，1．1(m，
2H)，1．25(s，9H)，1．60(m，1H)，2．10(m，1H)，2．5-2．8(m，4H)，7．95(s，3H)，
12．39(s，1H)．MS(APCI)216(M+1)．计算分析C9H17N3O2·HC1：
C，45．86；H，7．70；N，17．83；Cl，15．04．测定值：C，45．40；H，7．55；N，16．79；
Cl．15．81．
实施例4制备(2-氨基甲基-4-甲基-戊基)-膦酸(9)
Figure 9881147400261
1．制备2-异丁基-丁二酸-4-叔丁酯-1-甲酯(2)
在-78℃和氩气下加入4-甲基戊酸甲酯(10．0g，76．8mmol)到LDA的150 mlTHF溶液中。15分钟后，在-78℃通过套管将该阴离子溶液加到溴乙酸叔丁酯(22．5g，115．2mmol)的50 ml THF溶液中，并搅拌该溶液45分钟。然后将该反应混合物温至室温，用100 ml饱和的KH2PO4处理。蒸发THF，将有机物萃取入Et2O(3X50ml)。用10％Na2S2O3洗涤Et2O，并用硫酸镁干燥。蒸发溶剂，并真空(0．1mmHg)下蒸馏残留的油得到11．1g(收率59％)在65-72℃沸腾的2-异丁基-丁二酸-4-叔丁酯-1-甲酯。NMR(H1，400MHz，CDCl3)
δ0．9(6H，m)；δ1．2(1H，m)；δ1．4(9H，s)；δ1．5(2H，m)；δ2．3(1H，dd)；
δ2．5(1H，dd)；δ2．8(1H，m)；δ3．6(3H，s)．
2．制备2-异丁基-丁二酸-4-叔丁酯(3)：
在室温下于180ml 3∶1 IPA／H2O中搅拌2-异丁基－丁二酸-4-叔丁酯-1-甲酯(11．1g，45．4mmol)和LiOH·H2O过夜。用Et2O(3X25 ml)萃取反应混合物。用饱和的KH2PO4酸化该水相到Ph=4并用Et2O(3X50ml)萃取。硫酸镁干燥Et2O，并蒸发得到8．0g(收率77％)油状的2-异丁基-丁二酸-4-叔丁酯。
NMR(H1，400 MHz，CDCl3)
δ0．9(6H，m)；δ1．3(1H，m)；δ1．4(9H，s)；δ1．6(2H，m)；δ2．3(1H，dd)；
δ2．6(1H，dd)；δ2．8(1H，m)．
3．制备4-异丁基-二氢-呋喃-2-酮(4)：
在氩气下冷却2-异丁基-丁二酸-4-叔丁酯(8．0g，34．7mmol)的100ml THF溶液并加入硼烷二甲基硫复合物(2．6g，34．7mmol)。在0℃下搅拌该反应混合物10分钟，并在室温下过夜。冷却该溶液至0℃并加入100ml MeOH。蒸发溶剂，并真空下干燥残留的油2小时。将残留的油溶于100 ml THF，并加入催化量的对甲苯磺酸。加温该溶液至回流过夜。冷至室温后，蒸发溶剂，将油溶于Et2O(100ml)。用2．0N Na2CO3(3X50ml)随后用盐水萃取Et2O溶液，并用硫酸镁干燥。蒸发Et2O，随后在20％ EtOAc／己烷中压色谱(MPLC)残留的油得到4．4g(收率89％)油状的4-异丁基-二氢-呋喃-2-酮。
NMR(H1，400 MHz，CDCl3)δ0．9(6H，m)；
δ1．3(2H，dd)；δ1．5(1H，m)；δ2．1(1H，m)；δ2．6(2H，m)；δ3．6(1H，m)；
δ4．4(1H，m)．
4．制备3-溴甲基-3-异丁基-丙酸乙酯(5)：
冷却4-异丁基-二氢-呋喃-2-酮(4．4g，30．9mmol)的无水EtOH(50ml)溶液到0℃并通过通HBr气10分钟用HBr饱和。升温该溶液到室温并搅拌2．5小时。用150 ml盐水稀释并用Et2O(3X100 ml)萃取。用硫酸镁干燥，蒸发溶剂得到4．9g(收率63％)油状的3-溴甲基-3-异丁基-丙酸乙酯。
NMR(H1，300 MHz，CDCl3)δ0．9(6H，d)；δ1．3(5H，m)；δ1．6(1H，m)；
δ2．3(1H，m)；δ2．5(1H，dd)；δ3．2(1H，dd)；δ3．6(1H，dd)；δ4．1(2H，q)．
5．制备3-(二乙氧基-磷酰基甲基)-5-甲基-己酸乙酯(5)：
在氩气下于170℃的油浴中升温3-溴甲基-3-异丁基-丙酸乙酯(4．6g，18．3mmol)。在2小时内滴加亚磷酸三乙酯(3．6g，22mmol)。加完时，将油浴温度升至190℃ 4小时。冷却该反应混合物至室温，并在EtOAc中MPLC纯化该产物得到2．7 g(收率48％)3-(二乙氧基-磷酰基甲基)-5-甲基-己酸乙酯。
NMR(H1，400 MHz，CDCl3)δ0．8(6H，d)；δ1．2(5H，m)；δ1．3(6H，m)；
δ1．6(1H，m)；δ1．7(1H，d)；δ1．8(1H，d)；2．3(2H，m)；δ 2．5(1H，dd)；δ4．1(6H，
m)．
6．制备3-(二乙氧基-磷酰基甲基)-5-甲基-己酸(7)：
在0℃下的10 ml的EtOH中反应3-(二乙氧基-磷酰基甲基)-5-甲基-己酸乙酯(1．0g，3．2mmol)和NaOH(1．8ml，2．0M)。15分钟后，升温该反应混合物至室温并搅拌过夜。蒸发EtOH，并加入50ml的2．0M NaOH。用Et2O(3X50 ml)萃取该溶液，然后用浓HCl酸化至pH=1。用EtOAc(3X50ml)萃取该酸性溶液，硫酸镁干燥该合并的萃取液，蒸发得到0．65g(收率72％)油状的3-(二乙氧基-磷酰基甲基)-5-甲基-己酸。    NMR
(H1，400 MHz，CDCl3)δ0．9(6H，d)；δ1．3(8H，m)；δ1．6(1H，m)；δ 1．8(2H，m)；
δ2．3(1H，m)；δ2．5(2H，m)；δ4．1(4H，m)．
7．制备[2-(苄基氧羰基氨基-甲基)-4-甲基-戊基]膦酸二乙酯(8)：
在100 ml甲苯中将3-(二乙氧基-磷酰基甲基)-5-甲基-己酸(0．65g，2．3mmol)，二苯基-二-磷酰-叠氮(0．76g，2．8mmol)，三乙胺(0．47g，4．6mmol)，和苄醇(0．5g，4．6mmol)升温至回流过夜。蒸发甲苯，并将残留油溶于50 ml EtOAc。用1．0N HCl(2X50 ml)，饱和NaHCO3(2X50 ml)和50 ml盐水洗涤该EtOAc溶液。硫酸钠干燥。蒸发溶剂得到油，在EtOAc中MPLC纯化。[2-(苄基氧羰基氨基-甲基)-4-甲基-戊基]膦酸二乙酯的产量=0．46g(52％)。
NMR(H1，400 MHz，CDCl3)δ0．9(6H，m)；δ1．1-1．4(9H，
m)；1．7(2H，m)；δ2．0(1H，m)；δ3．1(1H，m)；δ3．3(1H，m)；δ4．1(4H，q)；
δ5．0(2H，s)；δ5．7(1H，bs)；δ7．3(5H，m)．
8．制备[2-氨基甲基-4-甲基-戊基]-膦酸(9)：
在20 ml 47％的含水HBr中将[2-(苄基氧羰基氨基-甲基)-4-甲基-戊基]膦酸二乙酯(0．46g，1．2mmol)升温至回流过夜。冷却该溶液至室温，并蒸发水。将残留固体溶于10 ml的水中，滤过Celite545，并通过Dowex50离子交换柱(床体积=30 ml)。用200ml水，150 ml 3％NH4OH，和150 ml 10％6NH4OH洗脱该柱。合并碱性洗脱液并蒸发得到0．14g白色固体。60℃下用P2O2真空干燥后，[2-氨基甲基-4-甲基-戊基]-膦酸的产量=0．11g(47％)。
NMR(H1，400 MHz，CD3OD)δ0．9(6H，m)；δ1．2(2H，t)；
δ1．4(1H，m)；δ1．7(2H，m)；δ2．1(1H，m)；δ2．7(1H，dd)；δ3．0(1H，dd)．MS
(m／e)196(M+1，100％)．分析  C7H18NO3P：计算值：C-43．07，
H-9．29，N-7．18，测定值 C-43．08，H-8．62，N-6．89．

Claims (18)

1．本发明的化合物是下式的化合物及其药用盐：
Figure 9881147400021
其中：n是0-2的整数；R是磺酰胺，酰胺，膦酸，杂环，磺酸，异羟肟酸；A是氢或甲基；而B是
Figure 9881147400022
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是-O-，-S-，-NR’3，其中R’3是1-6个碳的烷基，3-8个碳的环烷基，苄基或苯基，其中的苄基或苯基是未取代的或被1-3个取代基取代，该取代基各自选自烷基，烷氧基，卤素，羟基，羧基，烷氧羰基，三氟甲基和硝基。
2．权利要求1的化合物，其中n是1，m是2，而R是
Figure 9881147400023
3．权利要求1的化合物，其中R是磺酰胺，选自-NHSO2R15或-SO2NHR15，其中R15是直链或支链烷基或三氟甲基。
4．权利要求1的化合物，名称为：
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，HCl；
3-(2-氨基甲基-4-甲基-戊基)-4H-[1，2，4]噁二唑-5-酮，HCl；
(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]氧杂噻二唑-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]氧杂噻二唑-4-基)丙胺。
5．权利要求1的化合物，其中R是膦酸，-PO3H2。
6．权利要求1的化合物，其中R是选自如下的杂环：
Figure 9881147400031
7．一种药物组合物，其中含有治疗有效量的权利要求1所述的化合物和药用载体。
8．治疗癫痫的方法，包括给需要所述治疗的哺乳动物给药治疗有效量的权利要求1所述的化合物。
9．治疗晕厥发作、少动症和颅疾病的方法，包括给需要所述治疗的哺乳动物给药治疗有效量的权利要求1所述的化合物。
10．治疗神经变性疾病的方法，包括给需要所述治疗的哺乳动物给药治疗有效量的权利要求1所述的化合物。
11．治疗抑郁的方法，包括给需要所述治疗的哺乳动物给药治疗有效量的权利要求1所述的化合物。
12．治疗焦虑的方法，包括给需要所述治疗的哺乳动物给药治疗有效量的权利要求1所述的化合物。
13．治疗恐慌的方法，包括给需要所述治疗的哺乳动物给药治疗有效量的权利要求1所述的化合物。
14．治疗疼痛的方法，包括给需要所述治疗的哺乳动物给药治疗有效量的权利要求1所述的化合物。
15．治疗神经病理紊乱的方法，包括给需要所述治疗的哺乳动物给药治疗有效量的权利要求1所述的化合物。
16．治疗胃肠道损伤的方法，包括给需要所述治疗的哺乳动物给药治疗有效量的权利要求1所述的化合物。
17．治疗炎症的方法，包括给需要所述治疗的哺乳动物给药治疗有效量的权利要求1所述的化合物。
18．治疗胃肠紊乱特别是应激性肠综合征的方法，包括给需要所述治疗的哺乳动物给药治疗有效量的权利要求1所述的化合物。
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