CN101260063B - γ-氨基丁酸衍生物及其制备方法 - Google Patents
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Abstract
本发明提供式I所示的γ-氨基丁酸衍生物、光学异构体或其药学上可接受的药用盐，及其在制备神经病理性疼痛、癫痫药物中的用途。其中R1＝H，R2＝CH2CH(CH3)2或R1，R2＝环己基，R为碳原子数1～6的烷基、取代烷基或环烷基、含羟基的氨基酸残基，包括丝氨酸残基、苏氨酸残基，可以是D、L或DL构型。
Description
技术领域
本发明涉及γ-氨基丁酸衍生物、光学异构体或其药学上可接受的药用盐及其在制备神经病理性疼痛、癫痫药物中的用途。
背景技术
神经性疼痛是指由中枢或外周神经系统原发性病变或功能障碍而引起的疼痛综合征。可由外伤或/和疾病致末梢神经、脊髓后根、脊髓及其以上中枢神经某些部位损伤而引发。根据神经损伤的病因、性质和程度不同，在临床上分为中枢神经疼痛和外周神经损伤所致的周围神经疼痛两大类。中枢神经疼痛简称中枢痛，为中枢神经系统的疼痛传导通路发生损害或功能障碍而引起的原发性疼痛，常见于脊髓的创伤或脑血管疾病，多发性硬化症和肿瘤等。周围神经疼痛系外伤、缺血、压迫、感染、炎症、代谢等因素损伤外周神经所致，如幻肢痛，带状疱疹后神经痛，多发性神经炎，糖尿病性周围神经痛等。
神经性疼痛一直是困扰医学界的难题：发病机理尚不清楚，。治疗神经性疼痛的药物和非药物方法很多，但常规的止痛药、阿片类麻醉药物及非甾体抗炎药的治疗效果不佳，只有不超过50％患者疼痛缓解，而且均有不同程度的毒副作用，加上慢性疼痛治疗的长期性，大大限制了这些药物的应用。有关神经性疼痛的外周和中枢敏感性增强的过程非常复杂，单一种类、单一作用模式的药物去逆转这些过程，由此缓解疼痛是不可能的，除非可以逆转在这些”瀑布”事件中的一个关键的步骤。神经性疼痛的病人通常需要多种具有不同作用模式和作用机制的药物联合治疗。目前，大多数治疗神经性疼痛的药物是辅助性镇痛药，如抗癫痫药物和抗抑郁药物，但疗效仍然有限，不能达到理想的治疗效果。
癫痫是由多种原因引起的慢性脑功能障碍临床综合征，是大脑神经细胞群反复超同步放电所引起的发作性、突然性、反复性、短暂性脑神经系统功能紊乱。根据大脑异常放电的部位和扩散的范围不同，其临床发作表现症状各异。临床上可有短暂的运动、感觉、意识、行为、植物神经系统等不同障碍，或兼而有之。脑电图呈痫样放电和实验室检查异样。癫痫具有发作性、复发性和自然缓解性的特点，是一种慢性、反复发作性的脑功能失常性疾患。与神经性疼痛相似，癫痫病的发病机理也很复杂，尚不完全清楚，其治疗也是当今医学急需解决的难题。
发明内容
本发明发现，上市的γ-氨基丁酸衍生物主要有普瑞巴林、加巴喷丁，它们均含有游离的氨基、羧基，将其转化为酯的形式，能够增加亲脂性，增加对血脑屏障的穿透性，提高在脑组织中的分布，减少用药量，降低副反应。同时，可以避免现有γ-氨基丁酸衍生物存放过程中容易产生的内酰胺化杂质，增加药物的稳定性。
本发明提供式I所示的γ-氨基丁酸衍生物、光学异构体或其药学上可接受的药用盐。
其中：R1＝H，R2＝CH2CH(CH3)2或R1，R2＝环己基；R为碳原子数1～6的烷基、取代烷基或环烷基、含羟基的氨基酸残基，包括丝氨酸残基、苏氨酸残基，可以是D、L或DL构型。
本发明优选的化合物为：
普瑞巴林-L-丝氨酸酯二盐酸盐(I1)
普瑞巴林-D-丝氨酸酯二盐酸盐(I2)
普瑞巴林-L-苏氨酸酯二盐酸盐(I3)
加巴喷丁-L-苏氨酸酯二盐酸盐(I4)
本发明还提供式I所示的γ-氨基丁酸衍生物、光学异构体或其药学上可接受的药用盐与一种或多种药用载体或赋形剂的药用组合物。本发明的组合物，在制成药剂时可以制成任何可药用的剂型，其中优选片剂和注射剂。
本发明的药物组合物，在制成药剂时，单位剂量的制剂可含有本发明的化合物10-1000mg，其余为药学上可接受的载体。药学上可接受的载体以重量计可以是制剂总重量的0.1-99.9％。
本发明还涉及式I所示的γ-氨基丁酸衍生物、光学异构体或其药学上可接受的药用盐用于制备神经病理性疼痛、癫痫药物的用途。其日用量为150～600mg，分2～3次用，可根据具体情况和需要选择适当的给药量和给药方式。
具体实施方式
通过下面的实施例可以对本发明进行进一步的描述，然而，本发明的发明并不限于下面的实施例，这些实施例不以任何方式限制本发明的范围。本领域的技术人员在权利要求的范围内所作出的某些改变和调整也应认为属于本发明的范围。
实施例1 化合物I1的制备
在反应瓶中加入8gNaOH、150ml水，搅拌使溶解，冰浴冷却，加入普瑞巴林31.8g，完全溶解后同时滴加52.4g BOC酸酐-250ml二氧六环溶液、8.8gNaOH-220ml水溶液，控制滴加速率使反应液PH控制在9左右，约1h加毕。然后继续反应2h，升至室温反应2h。停止反应，用乙醚提取反应液中过量的BOC酸酐，提取4次，每次耗乙醚250ml，弃去。水相用5％柠檬酸溶液调PH为3左右，乙酸乙酯提取3次，每次600ml，合并有机相，水洗3次，饱和盐水洗涤3次，无水硫酸镁干燥4h以上。过滤，浓缩，得到BOC-普瑞巴林44.5g，收率86％。Mp：70～72℃。1H-NMR(CDCl3)：0.85～0.88(dd，6H)，1.16～1.19(t，2H)，1.45(s，9H)，1.60～1.64(m，1H)，2.09～2.15(m，1H)，2.17～2.30(m，2H)，2.86～2.98(m，2H)。
在反应瓶中加入BOC-普瑞巴林10g、无水二氯甲烷80ml，搅拌使固体溶解，冷却至0℃，再加BOC-L-丝氨酸7.9g-40ml无水DMF，滴加DCC8.3g-20ml无水二氯甲烷溶液，反应1h后加入1gDMAP，室温反应12h以上，过滤，减压浓缩至干，乙酸乙酯400ml溶解，过滤，分别用5％NaHCO3100ml×3次、5％柠檬酸80ml×3次、5％NaHCO3100ml×3次、饱和NaCl溶液100ml×3次洗涤，无水硫酸镁干燥4h以上。过滤，浓缩。过硅胶层析柱纯化。得到BOC保护的普瑞巴林-L-丝氨酸酯15.7g，收率91％。
将上述所得的BOC保护的普瑞巴林-L-丝氨酸酯溶于200ml乙酸乙酯，加入4NHCl/EtOAc溶液200ml，室温搅拌反应1h，过滤，依次用冷的乙酸乙酯、无水乙醚洗涤，干燥，得到化合物I111.0g，收率98％。元素分析C11H24N2O4Cl2：计算值(，％)：C 41.38，H 7.52，N 8.78；测定值(，％)：C 41.54，H 7.45，N 8.62。MS(ESI，m/e)：247.2(M+1)。
实施例2 化合物I2的制备
参照实施例1的方法，BOC-D-丝氨酸代替BOC-L-丝氨酸，得到化合物I2。元素分析C11H24N2O4Cl2：计算值(，％)：C 41.38，H 7.52，N 8.78；测定值(，％)：C 41.62，H 7.54，N 8.56。MS(ESI，m/e)：247.1(M+1)。
实施例3 化合物I3的制备
参照实施例1的方法，BOC-L-苏氨酸代替BOC-L-丝氨酸，得到化合物I3。元素分析C12H26N2O4Cl2：计算值(，％)：C 43.24，H 7.81，N 8.41；测定值(，％)：C 43.02，H 7.70，N 8.38。MS(ESI，m/e)：260.9(M+1)。
实施例4 化合物I4的制备
参照实施例1的方法，加巴喷丁代替普瑞巴林，BOC-L-苏氨酸代替BOC-L-丝氨酸，得到化合物I4。元素分析C13H26N2O4Cl2：计算值(，％)：C 45.22，H 7.54，N 8.12；测定值(，％)：C 45.43，H 7.66，N 8.17。MS(ESI，m/e)：273.1(M+1)。
实施例5 含有化合物I1的片剂的制备
将20克化合物I1用适量水使溶解，备用；将500克微晶纤维素、220克淀粉混合均匀，用前述溶液作为粘合剂制软材，24目筛制粒，60～70℃干燥，20目筛整粒，加入28克微粉硅胶、50克羧甲基淀粉钠，混合均匀后采用适宜冲模压制片剂，即得，每片含有20mg化合物I1。
实施例6 含有化合物I1的注射剂的制备
将200ml氨丁三醇、100g亚硫酸钠溶解于约17000ml注射用水中，加入600g化合物I1，搅拌使溶解完全，加入0.1％活性炭吸附60℃吸附30min，，0.22um微孔滤膜过滤，灌装，每支20ml，高压灭菌，即得。每支含有600mg化合物I1。
生物学实验
实验1 抗神经病理性疼痛活性
1.1鞘内置管和慢性病理性疼痛模型的建立：雄性SD大鼠，体质量220～260g，用10％水合氯醛300mg/kg腹腔注射麻醉后，按改良的Yaksh法鞘内置入Microspinal导管至脊髓腰段(置入长度约8.5cm)。参考Bennett等方法，切开右下肢股骨中段皮肤，分离肌肉在股骨后找到坐骨神经主干，用4-0铬制的羊肠线轻轻结扎四道，以神经外膜轻轻受压为宜，制成坐骨神经松弛结扎模型(CCI模型)。手术操作均在无菌条件下进行，术毕肌注青霉素3×10～4×10U预防感染。术后观察3d，大鼠出现肢体感觉和运动丧失以及导管脱出者不作为观察对象。
1.2分组与给药：术后第4天将大鼠随机分为6组，分别为空白对照组，普瑞巴林对照组，及4种新化合物组，每日给药1次，连续6d。各组均腹腔注射标准治疗量的实验药物，其中空白对照组只注射0.9％等量生理盐水。
1.3疼痛行为学的测试：采用BME-410A型热痛刺激仪，测试前10min将大鼠置于检测盒内，检测盒的底面为2mm厚的普通玻璃板，四周为透明的有机玻璃(22mm×22mm×28mm)，中间有隔板，可同时测量两只大鼠，顶端敞开使大鼠在盒内一定范围内自由活动，待动物适应环境，安静后将辐射灯以一定强度照射足跖部中后1/3处，同时按下控制手柄，记录从光照到发生缩腿的时间作为大鼠热痛缩腿反应潜伏期(PWL)。整个测试过程中保持安静，室温为20～25℃。设定切断时间为25S防止大鼠组织热灼伤。每一侧足部测定3次取其平均值。
结果见表1
表1 各组药物对CCI大鼠热刺激缩爪潜伏期的影响(
n＝8)
实验2：抗癫痫活性
2.1方法：遗传性自发性癫痫大鼠(SER)模型36只，分组与给药同实验1。
2.2脑电图的测定与指标评价：大鼠称重，3％的戊巴比妥钠40mg·kg-1ip麻醉，腹位固定于立体定位仪上。切开眼一耳间中线皮肤，刮净颅骨外肌肉及骨膜，彻底止血、消毒。用骨钻在距前囟(-3mm，3mm)、(3mm，3mm)、(-2mm，-4mm)3点处钻透颅骨及硬脑膜，前两孔插入螺丝钉分别作为皮质电极及参考电极，第3孔插入4mm深由不锈钢针制成，外涂绝缘漆的海马电极，502胶封闭海马电极钻孔。将四联微型插座矢状位置于中线处，由头端至尾端依次焊接参考电极、皮质电极、海马电极，尾端电极丝埋人皮下作为机体地线。用牙托粉包埋和固定电极。待术后7d测脑电图。大鼠置于40cm×40cm×40cm的箱内，导线焊有微型插座的一端通过箱顶的导线孔与箱内大鼠头顶外置的插座相连，另一端通过生物电输入盒与多导生理记录仪的生物电放大器插件相连。大鼠安静30min后连续记录脑电图30min，纸速为10mm·s-1。试验记录期间每5min向大鼠后背吹气1次以保持动物清醒和持续癫痫发作。持续时间＞1S的5～7Hz高尖棘慢综合波被认为是1次癫痫小发作，如果两个5～7Hz的棘慢综合波间隔时间＜1S，则认为是1次癫痫大发作。记录脑电图时间分别为给药前，给药后1、2、4、6h，1、2d。记录30min内SER自发性和由每5min吹气刺激引发的癫痫大发作和小发作出现频率。
结果见表2
表2 各组药物对癫痫发作频率的影响(n＝6)
Claims (7)
1.式1所示的γ-氨基丁酸衍生物、光学异构体或其药学上可接受的药用盐：
其中：R1＝H，R2＝CH2CH(CH3)2或R1，R2＝环己基；
R为含羟基的氨基酸残基，由丝氨酸残基、苏氨酸残基组成，可以是D、L或DL构型。
2.权利要求1的化合物，优选化合物I1：
3.权利要求1的化合物，优选化合物I2：
4.权利要求1的化合物，优选化合物I3：
5.权利要求1的化合物，优选化合物I4：
6.权利要求1～5中任一化合物与一种或多种药用载体或赋形剂的药用组合物。
7.权利要求1～5中任一化合物用于制备神经病理性疼痛、癫痫药物的用途。
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| Effect of gabapentin derivates on mechanical allodynia-like behaviour in a rat model of chronic sciatic constriction injury;Yang Hong-Ju, et al;《Bioorganic & Medicinal Chemistry Letters》;20041231;第14卷;2537-2541 * |
| ect of gabapentin derivates on mechanical allodynia-like behaviour in a rat model of chronic sciatic constriction injury.《Bioorganic & Medicinal Chemistry Letters》.2004,第14卷2537-2541. |
| Yang Hong-Ju, et al.Eff |
| 史卫国 等.神经病理性疼痛互联体前药的设计和合成(II).《中国新药杂志》.2007,第16卷(第20期),1689-1692. |
| 神经病理性疼痛互联体前药的设计和合成(II);史卫国 等;《中国新药杂志》;20071231;第16卷(第20期);1689-1692 * |
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