CN1635888A - 用于治疗神经退行性疾病的2－甲基四氢噻唑－2,4－二羧酸及其盐 - Google Patents
用于治疗神经退行性疾病的2－甲基四氢噻唑－2,4－二羧酸及其盐 Download PDFInfo
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- CN1635888A CN1635888A CNA038043505A CN03804350A CN1635888A CN 1635888 A CN1635888 A CN 1635888A CN A038043505 A CNA038043505 A CN A038043505A CN 03804350 A CN03804350 A CN 03804350A CN 1635888 A CN1635888 A CN 1635888A
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- thiazoles
- dicarboxylic acids
- methyl tetrahydro
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- neurodegenerative diseases
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Abstract
本发明涉及化合物(2R，4R)－、(2S，4R)－2－甲基四氢噻唑－2，4－二羧酸和(2RS，4R)－2－甲基四氢噻唑－2，4－二羧酸及所述化合物的盐；它们在预防和/或治疗神经退行性疾病中的应用；预防和/或治疗神经退行性疾病的方法；和含有所述化合物及生理相容性的载体、辅料和/或溶剂的药物组合物。
Description
技术领域
本发明涉及化合物(2R，4R)-、(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸和(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸及这些化合物的盐；它们在预防和/或治疗神经退行性疾病中的应用；预防和/或治疗神经退行性疾病的方法；和药物制剂，所述药物制剂含有所述化合物和/或其盐，也可选择性地含有其他添加剂。
背景技术
神经退行性疾病的例子有脑循环障碍、缺血、脑缺血、卒中、脑卒中、脑功能缺陷、老年性痴呆、阿尔茨海默病、亨廷顿舞蹈病和帕金森病。
帕金森病属于年老者高发的神经退行性疾病。
帕金森病(或特发性帕金森综合症)是一种进行性疾病，其特征是具有静息震颤、运动减少/运动徐缓和肌肉强直等症状。以神经病理学的观点来看，黑质中的伸向纹状体的多巴胺能神经元发生变性，并伴有纹状体多巴胺浓度下降和残存神经元内玻璃样包涵体(路易(Lewy)小体)的形成。人们对该疾病的病因及病理生理过程所知甚少。特发性帕金森综合症是年老者高发的神经疾病。其首次症状通常在50岁以后发生，年轻人极少罹患此病。60岁以后，发病率呈指数级增长，以至在60岁以上的人中，大约有1％～1.5％的人患有此病。
通过对多巴胺缺乏采取替代疗法来进行对症治疗，对该症状的治疗在5～10年内是可行的。但是，目前并不能影响疾病的进展，即不能影响多巴胺能神经元的变性速度。最初报道不可逆单胺氧化酶B抑制剂司来吉兰的神经保护作用的积极疗效时，并未证实其在治疗远期变性方面的作用。
目前，有3类药物可用于帕金森病的药物疗法。
多巴胺能药
左旋多巴(L-DOPA)加脱羧酶抑制剂(如，Madopar，Nacom)；
多巴胺激动剂：溴隐亭(Pravidel)、麦角乙脲(Dopergin)、培高利特(Parkotil)、二氢麦角隐亭(dihydrocryptine；Almirid)、卡麦角林、普拉克索、罗匹尼罗；
单胺氧化酶B抑制剂：司来吉兰(如，Deprenyl)。
抗胆碱能药
苯扎托品(Cogentinol)、苯海索(如Artane)、比哌立登(如Akineton)
谷氨酸盐/N-甲基-D-天冬氨酸(NMDA)受体拮抗剂
金刚烷胺(如PK-Merz)、美金刚胺。
多巴胺的前体物质L-DOPA是第一个已知的多巴胺能药。与多巴胺不同，L-DOPA可以通过血脑屏障，进而被多巴胺能神经细胞吸收，并被细胞溶质中的脱羧酶转化为多巴胺。L-DOPA总是与脱羧酶抑制剂结合，以防止在外周就被转化为多巴胺，所述脱羧酶抑制剂例如苄丝肼(商品名为Madopar)或甲基多巴肼(如Nacom)不会渗入脑内。在上述结合状态下，L-DOPA仍被认为是最有效的和最可配伍的拟多巴胺物质。
可直接影响纹状体多巴胺受体的多巴胺激动剂是另一类多巴胺能药。这类激动剂的效能均低于L-DOPA，然而，除了L-DOPA已知的副作用外，这类药物会引起更多的并发症，如心血管并发症、精神异常和幻觉。因此，在给年老的、患有多种疾病的患者施用这类药物时，需谨慎小心。
司来吉兰(如Movergan、Deprenyl)不可逆地抑制具有多巴胺降解功能的单胺氧化酶B，从而导致纹状体中多巴胺浓度的升高。但是它的这种作用是微弱的。在第一年治疗中，可以发现其具有神经保护作用，然而在远期治疗中，却无法检测到所述作用。
抗胆碱能药可以减轻静息震颤和强直的症状，但是对运动减少却没有显著作用。由于其具有多种副作用(精神异常乃至精神病、青光眼、无尿、眩晕和疲乏)，所以抗胆碱能药只能施用于具有严重症候的65岁以上的患者，同时所述患者还应完全没有认知障碍。
金刚烷胺(如PK-Merz)和仅具有轻微疗效的美金刚胺都属于市售的谷氨酸盐/NMDA受体拮抗剂。与上述多巴胺能药相比，这两种物质的作用是微弱的。
在长期施用上述的多巴胺能药后，许多患者出现迟发性运动障碍并发症。可以采用稳定血液中L-DOPA水平的方法(如，施用缓释剂)来治疗这类副作用。其次，可以减少L-DOPA的剂量率和使用更高剂量的多巴胺激动剂，所述激动剂优选半衰期长的药物(如，培高利特)。偶尔也可以使用一种激动剂(也可与金刚烷胺联合使用)来尝试进行单一治疗。在伴有疼痛性肌张力障碍的应激后长时间衰竭期中，对一些患者皮下施用多巴胺激动剂阿朴吗啡是不应放弃的。很多时候，治疗这些迟发性并发症的疗效总体上不令人满意，因此需要患者和医生之间的密切合作。作为最后一个选择，可以考虑实施立体定位手术。
在采用多巴胺能药的治疗过程中，精神病是另一类并发症。这一并发症的发生率和严重程度除受多巴胺药的每日剂量率影响外，还受年龄以及可能受脑部其他病变(如血管性脑病)的影响。这些药物引起的精神病开始表现为异常活跃的梦和幻觉认知，继而出现幻视、幻听(罕见)和妄想(Dr.med.A.Storch，Dr.med.J.Schwarz，″Geriatrie Praxis″，MMVMedizin Verlag GmbH München，Jahrgang 9(1997)4，24-28)。
此外，也有人寻求手术(将合成多巴胺的细胞移植到纹状体中；鞘内施用神经营养因子；对基底神经节中的过活跃核心区域实施结构或功能上的损伤)来治疗帕金森病。然而，部分由于会出现严重的副作用，所以这并不能作为药物治疗之外的一种替代疗法。
发明内容
本发明旨在提供具有良好生理相容性的物质，所述物质可用于预防/治疗神经退行性疾病，而且可以避免或至少减轻已知药物的副作用。
通过本发明的独立权利要求1的技术教导和权利要求5、6、9和11的主题，可达到上述目的。由本发明的从属权利要求、说明书和实施例可清楚地看出其他合适的实施方案、方面和细节。
发明人惊奇地发现，可以采用本发明的(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸和(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸及这些化合物的盐来预防和/或治疗神经性退行性疾病。作为神经退行性疾病的例子有帕金森病、亨廷顿舞蹈病、脑循环障碍、缺血、脑缺血、卒中、脑卒中、脑功能缺陷、老年性痴呆或阿尔茨海默病。
上述化合物的盐可以通过加入碱性溶液而制得。合适的碱有例如碱金属和碱土金属的氢氧化物、碳酸盐、碳酸氢盐、磷酸盐或胺。
尤其合适的是(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸和/或(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸与氨基酸形成的盐。
可用的氨基酸包括丙氨酸、天冬酰胺、半胱氨酸、谷氨酰胺、苯丙氨酸、甘氨酸、组氨酸、异亮氨酸、赖氨酸、亮氨酸、蛋氨酸、精氨酸、丝氨酸、鸟氨酸、苏氨酸、缬氨酸、色氨酸、酪氨酸或这些氨基酸的衍生物。优选碱性氨基酸如赖氨酸、精氨酸或组氨酸。进一步优选氨基酸的碱性盐，如氨基酸的钠盐、钾盐或锂盐，或谷氨酸或天门冬氨酸的二钠盐、二钾盐或二锂盐。
除了氨基酸以外，本发明所述的盐也可由碱金属和碱土金属阳离子或过渡金属离子形成。可以使用Li+、Na+、K+、Rb+、Cs+、Be2+、Mg2+、Ca2+、Sc3+、Mn2+、Fe3+、Cu+、Cu2+、Ag+和Zn2+，优选Li+、Na+、K+、Cs+、Mg2+、Ca2+和Zn2+，尤其优选Li+和Na+。
尤其优选的是(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸和/或(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸的赖氨酸盐。
名词“(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸”(2-MTDC)是指由(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸和(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸组成的非对映体混合物。
DE-A-21 16 629公开了对映体纯的2-甲基四氢噻唑-2，4-二羧酸(2-MTDC)的合成及其作为护肝剂的应用，还公开了对映体纯的2-甲基四氢噻唑-2，4-二羧酸的制剂，其中该对映体纯的2-甲基四氢噻唑-2，4-二羧酸包含在包衣片剂或膏剂形式的药品中。对映体纯的2-MTDC已作为药物而用于一些用途中。在欧洲专利申请号为989 16 811的文献中，将对映体纯的2-MTDC作为一种粘液溶解剂；欧洲专利申请号为989 16 809的文献描述了由对映体纯的2-MTDC和扑热息痛制得的一种复合制剂。
优选将2-MTDC的盐特别是2-MTDC与氨基酸形成的盐用于预防和/或治疗神经退行性疾病，而且所述盐优选是赖氨酸盐。同样优选采用非对映体纯的(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸或(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸的盐，特别是它们与氨基酸形成的盐。
于是根据本发明，可以采用2-MTDC的盐、(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸的盐和/或(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸的盐来制备用于预防和/或治疗神经退行性疾病的药物制剂，所述疾病尤其是帕金森病、亨廷顿舞蹈病、脑循环障碍、缺血、脑缺血、卒中、脑卒中、脑功能缺陷、老年性痴呆或阿尔茨海默病。除了盐的形式以外，(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸和(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸的非盐形式化合物也适合于上述用途。
实施多项试验来验证2-MTDC、(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸和/或(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸的盐和非盐化合物的活性，所述试验能够确定赖氨酸盐对黑质和纹状体中多巴胺及其代谢产物3，4-二羟基苯乙酸(DOPAC)和高香草酸(HVA)的浓度的影响，以及对5-羟色胺(5-HT)及其代谢产物5-羟基吲哚乙酸(5-HIAA)的影响。
此外，还检测了3-甲氧酪胺的浓度，其为多巴胺能神经元体内活性的指示物。3-甲氧酪胺在神经元外由多巴胺转化而来，所述过程由苯邻二酚-O-甲基转移酶(COMT)将3位的羟基甲基化完成。这就是说，只有被多巴胺能神经细胞活动时释放出来的多巴胺，才可成为该酶的底物。因此，多巴胺能神经元活性越高，3-甲氧酪胺的浓度就越高。在检测3-甲氧酪胺之前4～5天，腹膜内注射2-MTDC的赖氨酸盐。
可以证明，2-MTDC的赖氨酸盐导致了多巴胺能神经元的强烈激活。丙二酸盐的灭活作用被此作用过度补偿。这一观察结果令人兴奋，因为2-MTDC赖氨酸盐的作用是持久的。
为了研究已知对神经毒素反应敏感的多巴胺神经元，选择了左右纹状体作为脑部的目标区域，所述神经毒素可以引起例如帕金森病。多巴胺细胞体位于黑质内，其轴突伸进背侧的纹状体。下述试验可以分别研究通常首先变性的细胞附属物区域内的退行性变化过程，以及在比病原更具有抵抗性的多巴胺神经元的细胞体内的退行性变化过程。
选择丙二酸钠作为神经毒性物质，因为这种线粒体毒素可引起大鼠纹状体多巴胺急性释放。已证明，注射这种丙二酸盐7天后，一侧纹状体中多巴胺的浓度降至同一动物对侧纹状体的6％。丙二酸盐对多巴胺浓度的这种作用依赖于时间和剂量率。
丙二酸盐是琥珀酸脱氢酶(SDH)的竞争性抑制剂。这种线粒体酶在神经元的能量供给中起决定性作用。它还参与了三羧酸循环和氧化磷酸化。在纹状体内注射丙二酸盐可以引起表现为兴奋性毒性的损伤，通过施用NMDA受体的竞争性和非竞争性拮抗剂能够防止该损伤。在纹状体内注射更高剂量率的丙二酸盐可以引起多巴胺能和谷氨酸能细胞末端的损伤，也可以引起纹状体内ATP(三磷酸腺苷)浓度和多巴胺浓度的显著降低。所述兴奋性毒性过程由可导致细胞死亡的丙二酸盐所激发，并与生物能缺乏相联系。上述两个过程可能参与了许多神经退行性疾病的病理过程，如阿尔茨海默病、亨廷顿舞蹈病和帕金森病。
根据本发明，2-MTDC、(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸和/或(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸的非盐化合物和盐，可以分别以非盐和盐的形式直接使用，或将其制备为药物制剂。通过给适于进行预防和/或治疗特定神经退行性疾病的个体分别施用有效治疗剂量的相应的非盐或盐化合物，可以预防和/或治疗神经退行性疾病，尤其是帕金森病、亨廷顿舞蹈病、脑循环障碍、缺血、脑缺血、卒中、脑卒中、脑功能缺陷、老年性痴呆或阿尔茨海默病。
缺血一词指，由于动脉血供应不足(如，血栓形成、栓塞、闭塞性动脉内膜炎、血管痉挛或肿瘤)，导致器官、部分器官或组织的血液循环的减少或中断。由此，脑缺血即意味着脑部血液循环的减少或中断。缺血的结果是缺氧、梗塞和坏死。
本发明的另一个目的是提供一种药物制剂，所述制剂含有(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸和/或这些化合物的盐类作为药物活性成分；所述制剂还选择性地含有生理相容性载体、辅料、填料、矫味剂或着色剂和/或溶剂和稀释剂。
本发明所述的可应用的化合物和药物制剂适于静脉、腹膜、肌肉、皮下、直肠、透皮、口服、鼻腔、含服、舌下或任何其他给药方式。本发明的化合物特别优选通过口服和肠道外给药。
本发明所述化合物的用药剂量率为1～10,000mg，优选为10～5,000mg，特别优选为50～1,000mg。
根据所需的给药方式的不同，可以通过已知的方法制备适当剂量的本发明的药物，制备中采用常规固体或液体载体、稀释剂以及常规使用的药用辅料。这类药物的剂型有例如片剂、膜衣片剂、包衣片剂、胶囊、丸剂、粉剂、溶液、分散液、悬浮液、贮库制剂形式或吸入溶液。
当然也可以考虑例如注射或输注溶液的肠道外给药剂型。此外也可以采用例如栓剂等剂型。
例如可以通过混合本发明所述化合物和已知辅料来制备相应片剂，所述辅料可以是：例如，惰性稀释剂，如右旋糖、蔗糖(sugar)、山梨醇、甘露醇、聚乙烯吡咯烷酮；崩解剂，如玉米淀粉或藻酸；粘合剂，如淀粉或明胶；润滑剂，如硬脂酸镁或滑石；和/或一些能够起长效作用的辅料，如羧聚乙烯、羧甲基纤维素、邻苯二甲酸乙酸纤维素或聚乙酸乙烯酯。
于是，包衣片剂的制备方法可以是，采用包衣片剂包衣时常用的试剂给制成类似于片剂的片核包衣，所述试剂有例如聚乙烯吡咯烷酮或虫胶、阿拉伯橡胶、滑石、二氧化钛或糖。包衣片剂的包衣也可由数层组成，而辅料可采用上述片剂中提到的辅料。
此外，含有本发明可以采用的活性成分的溶液或悬浮液还可以含有改善口味的试剂，如糖精、环己氨基磺酸盐或糖，也可以含有香料，如香草醛或柑橙香精。而且，还可以含有如羧甲基纤维素钠等悬浮辅料或例如对羟基苯甲酸等防腐剂。含有活性成分的胶囊的制备方法可以是，例如，混合活性成分和惰性基底如乳糖或山梨醇，而后将其装入明胶胶囊。
合适的栓剂的制备方法可以是，例如，将活性成分与为其提供的基底物质混合，所述基底物质为例如中性油脂或聚乙二醇及其各自的衍生物。
本领域的技术人员知晓制备各种制剂的方法以及不同的施用方法，这些方法均详细描述于例如《雷氏药学大全》(Remington′sPharmaceutical Sciences，Mack publishing Co.，Easton PA)。
具体实施方式
“2-MTDC”指(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸和(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸以及(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸。然而在优选的情况下，2-MTDC是指外消旋化合物。
实施例1：
2-MTDC赖氨酸盐的制备
1.预先准备4N的乙酸钾溶液
294.45g(3mol)乙酸钾(纯，DAB)溶于约400ml软化水中，而后将变热的溶液冷却至25℃(±5℃)，在1L的量筒中定容至750ml。
2.反应
在一个4L的圆底烧瓶中，搅拌下将394.03g(2.5mol)盐酸半胱氨酸(cys*HCl)混悬于545ml甲醇中，再加入1.2L异丙醇。先加入约125ml4N乙酸钾溶液。形成大量白色沉淀。在该悬浮液中加入243ml(±2.5ml)丙酮酸。用总量75ml的异丙醇润洗上述使用过的量筒。在加入丙酮酸之后立即加入剩余的4N乙酸钾溶液。经充分搅拌后，悬浮液温度达到约40℃。4小时后，其温度缓慢降至室温。停止搅拌，将反应混合物于4℃放置16小时(即过夜)。经过这些步骤，得到了沉淀和浅黄色上层清液。
3.纯化
使用布氏漏斗以抽吸的方式过滤沉淀，而后压干，再用约150ml软化水溶解2次，抽吸过滤并压干。然后在约40℃的高真空烘箱内干燥。
在剧烈搅拌(勿用磁性搅拌器！)下，将得到的粗制产物加入到约900ml的沸腾的软化水中。小心加热约10分钟，此过程中仍剧烈搅拌粘稠的浆液。随后将该悬浮液冷却，静置3小时后抽滤，压干，再用约150ml冰冷的软化水溶解，抽滤并压干。然后在约40℃的高真空烘箱内干燥，直至质量恒定(冷阱替换)。将获得的产物研碎。
产量：354g(理论产量的74％)。
4.赖氨酸盐
室温下，在20ml水中溶解10mmol MTDC和20mmol左旋赖氨酸碱。然后将所得的透明溶液冻干。在所述溶液中，无法检测到丙酮酸或游离半胱氨酸。
实施例2
动物实验：
在一个实验系列中，12小时和48小时后分别给大鼠腹膜内注射0.8mmol/kg 2-MTDC赖氨酸盐(2-MTDC-lys)。在末次用药后30分钟，对一半大鼠的左侧纹状体注射2μmol丙二酸钠，所述操作通过前向定位植入的导向套管完成。右侧纹状体用作个体内对照组织。末次用药后4天，检测递质及其代谢产物的浓度。
对另一组大鼠的左侧纹状体注射溶剂，对第三组大鼠的左侧纹状体注射2μmol丙二酸钠。
实验描述：
在一个由6只Wistar大鼠(Charles River，Sulzbach Rosenberg)组成的实验组中，48小时内两次腹膜内注射0.8mmol/5ml/kg体重的2-MTDC-lys。第二次用药后30分钟，在全身麻醉下(肌肉注射80mg/kg氯胺酮和6～10mg/kg赛拉嗪)，使用装有精确泵的注射器，将2μmol溶于普通生理盐水的丙二酸钠(Sigma)定向直接注射进左侧纹状体(流速为0.5μl/min，总量为2μl)。
末次用药后4天，将每只大鼠处理侧及另一侧的纹状体和黑质分别摘除。摘除的纹状体和黑质经称重后，在0.1mol高氯酸中均质化(1只纹状体用500μl高氯酸，1只黑质用150μl高氯酸)，然后以13,000rpm(转每分钟)的速度离心5分钟(Biofuge 13，Heraeus)。所得的上清液以10,000rpm的速度过滤10分钟(Millipore，0.22μm孔径)。将洗脱液的等分试样直接注入HPLC(高效液相色谱)设备中。通过HPLC-ELCD(高效液相色谱与电导检测器联用)将多巴胺、DOPAC、HVA、5-HT、5HIAA和3-甲氧酪胺分离开，并且用比色分析的方法将其定量。由于在纹状体中，多巴胺的浓度高于代谢产物的浓度，所以纹状体中的多巴胺浓度是单独检测的(条件：注射量2μl，检测器调至20nAmp)。
检测其他物质和黑质的实验条件为：注射量为5μl，检测器调至5nAmp。
另一组大鼠于48小时内腹膜内注射溶剂(4次50％丙二醇和2次普通生理盐水，各5ml/kg)，最后一次用药后30分钟在其左侧纹状体内注射2μmol丙二酸纳。第二个实验步骤同上。
第三组大鼠于48小时内腹膜内注射溶剂(4次50％丙二醇和2次普通生理盐水，各5ml/kg)，最后一次用药后30分钟在其左侧纹状体内注射2μl普通生理盐水。其余实验步骤同上。
结果：
单独应用2-MTDC赖氨酸盐(2-MTDC-lys)对多巴胺、DOPAC和HVA的浓度没有影响。然而，用2-MTDC-lys的预处理防止了丙二酸盐的毒性作用。由于2-MTDC-lys分别防止了丙二酸盐降低多巴胺和多巴胺代谢产物浓度的作用，因此该物质具有神经保护作用。
在所选择的剂量率的条件下和从末次用药算起4天的检测期间，2-MTDC-lys明显影响了多巴胺能神经元，而非血清素能神经元。对多巴胺能神经元的作用包括长效激活作用，这可能也是起到神经保护作用的原因之一。采用2-MTDC-lys的处理能够防止纹状体中的神经末梢和黑质中的细胞体发生神经退行性病变(预防性的神经保护作用)。
对实施例2中的实验系列进行重复，其中，用2-MTDC的钠盐代替2-MTDC赖氨酸盐。结果显示，2-MTDC钠盐也得到了相似的结果。
实施例3：2-MTDC及其盐的治疗效果
在另一个动物实验模型(卒中模型)中，发现2-MTDC和2-MTDC的盐均具有大脑保护作用(实施例3和4)。2-MTDC[(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸和(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸]的游离酸形式和盐形式例如2-MTDC赖氨酸盐，均能减轻小鼠(MNRI小鼠)的由脑动脉阻塞引起的梗死的程度。其结果在下文2-MTDC钠盐的实施例中描述。
2-MTDC的钠盐(2-MTDC-Na)
下列实验系列用于检测2-MTDC-Na于缺血后使用时所表现出的神经保护作用。
实验描述
每个实验组有13～16只MNRI小鼠。根据Welsh法(F.A.Welsh，T.Sakamoto，A.E.McKee，R.E.Sims，J.Neurochem.1987，49，846-851)，将小鼠的大脑中动脉阻塞。为此，使用三溴乙醇(600mg/kg体重，腹膜内注射)将小鼠麻醉。麻醉后立即在小鼠的颅骨上钻出一个小孔，以暴露大脑中动脉。采用电凝法将大脑中动脉的主干和两个侧支阻塞。同时，用取暖灯维持小鼠的血温于37℃±1℃。随后，将小鼠在30℃的环境温度下放置2小时。
在大脑中动脉阻塞后15分钟给一组小鼠腹膜内注射2-MTDC-Na(200mg/kg 2-MTDC-Na溶于0.9％NaCl溶液)，而在大脑中动脉阻塞后60分钟给另一组小鼠腹膜内注射该2-MTDC-Na。第三组仅注射溶剂(0.9％NaCl溶液，不含2-MTDC-Na)。
大脑中动脉阻塞后2天，为了进行如下的组织学检查，用三溴乙醇将小鼠再次麻醉，腹膜内再注射0.5ml 1.5％中性红溶液(二苯乙烯红，Acros Chimica)。然后摘除小鼠的脑，在固定液(pH7.4的磷酸盐缓冲液配制的4％福尔马林)中放置24小时。
采用一种颜色分析系统(Kontron，Eching，Germany)来检测脑表面未被中性红染色的组织，该表面区域即为梗死区域(C.Backhauβ，C.Karkoutly，M.Welsh，J.Krieglstein，J.Pharmacol Toxicol Methods，1992，27(2)，27-32)。
结果
只在脑皮层组织中发现梗死形成。而且，梗死区域的体积和表面积相关。2-MTDC-Na能够显著缩小脑梗死区域，所以，在大脑中动脉阻塞后尽快使用2-MTDC-Na似乎非常重要。在本实验系列中，大脑中动脉阻塞后1小时注射2-MTDC-Na时，只对梗死有明显的减弱作用。
因此，缺血后施用的2-MTDC-Na表现出超过神经保护作用之外的功能，而大脑中动脉阻塞至施用2-MTDC-Na的治疗有效时间约为60分钟。
实施例4：2-MTDC及其盐的保护作用
重复实施例3的实验过程，但是，在大脑中动脉阻塞(MCA-O)前1小时施用2-MTDC-Na。
如果在大脑中动脉阻塞前1小时腹膜内注射2-MTDC-Na(浓度为200mg/kg受试动物体重)，则其表现出对脑缺血引起的动物脑损伤的保护作用。
重复实施例3和4的实验系列，但是，用2-MTDC-lys和2-MTDC的游离酸形式代替2-MTDC-Na。使用2-MTDC-lys和2-MTDC游离酸的实验结果与使用2-MTDC-Na的实验结果类似。
Claims (12)
1、(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸和(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸以及这些化合物的盐。
2、如权利要求1所述的盐，其特征为，所述的盐为生理相容性物质，尤其是所述化合物与氨基酸形成的盐。
3、如权利要求2所述的盐，其特征为，所述的盐为赖氨酸盐。
4、如权利要求1或2所述的盐，其特征为，所述的盐为Li+、Na+、K+、Cs+、Mg2+、Ca2+和/或Zn2+盐。
5、(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸和/或(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸以及这些化合物的盐在预防和/或治疗神经退行性疾病中的用途。
6、(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸和/或(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸以及这些化合物的盐在制备用于预防和/或治疗神经退行性疾病的药物制剂中的用途。
7、如权利要求5或6所述的用途，其特征为，所述神经退行性疾病为帕金森病、亨廷顿舞蹈病、脑循环障碍、缺血、脑缺血、卒中、脑卒中、脑功能缺陷、老年性痴呆或阿尔茨海默病。
8、如权利要求5至7任一项所述的用途，其特征为，所用的(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸以及(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸的盐、(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸的盐和/或(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸的盐的剂量率为1～10,000mg，尤其为10～5,000mg。
9、预防和/或治疗神经退行性疾病的方法，其特征为，将适于预防和/或治疗神经退行性疾病的有效治疗剂量的(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸和/或它们的盐施用于个体。
10、如权利要求9所述的方法，其特征为，所述神经退行性疾病为帕金森病、亨廷顿舞蹈病、脑循环障碍、缺血、脑缺血、卒中、脑卒中、脑功能缺陷、老年性痴呆或阿尔茨海默病。
11、含有如下物质的药物制剂：作为药物活性成分的(2R，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2S，4R)-2-甲基四氢噻唑-2，4-二羧酸、(2RS，4R)-2-甲基四氢噻唑-2，4-二羧酸和/或它们的盐，以及生理相容性的载体、辅料和/或溶剂。
12、如权利要求10所述的药物制剂，其特征为，所述药物制剂适于静脉、腹膜、肌肉、皮下、直肠、透皮、口服、鼻腔、含服或舌下给药，尤其适于口服给药和肠道外给药。
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| US3730724A (en) * | 1971-06-03 | 1973-05-01 | Eastman Kodak Co | Silver halide color photographic element containing a magenta color coupler and a carboxy substituted thiazoline compound |
| DE19711053C2 (de) * | 1997-03-03 | 1999-09-02 | Rommelspacher | Kombinationspräparat aus 2-Methyl-thiazolidin-2,4-dicarbonsäure und Paracetamol |
| DE19857690A1 (de) * | 1998-12-14 | 2000-06-15 | Consortium Elektrochem Ind | Verfahren zur Isolierung oder Reinigung von 2-Methyl-thiazolidin-2,4-dicarbonsäure |
| JP2005518436A (ja) * | 2002-02-22 | 2005-06-23 | ルディ・スシロ | 神経変性疾患の治療用の２−メチルチアゾリジン−２，４−ジカルボン酸およびその塩 |
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- 2003-02-24 AT AT03742914T patent/ATE321554T1/de not_active IP Right Cessation
- 2003-02-24 DE DE10390702T patent/DE10390702D2/de not_active Withdrawn - After Issue
- 2003-02-24 EP EP03742914A patent/EP1482934B1/de not_active Expired - Lifetime
- 2003-02-24 US US10/504,069 patent/US7101901B2/en not_active Expired - Fee Related
- 2003-02-24 ES ES03742914T patent/ES2261953T3/es not_active Expired - Lifetime
- 2003-02-24 CN CNB038043505A patent/CN1289083C/zh not_active Expired - Fee Related
- 2003-02-24 DE DE50302825T patent/DE50302825D1/de not_active Expired - Lifetime
- 2003-02-24 WO PCT/DE2003/000573 patent/WO2003072101A1/de active IP Right Grant
- 2003-02-24 CA CA002474793A patent/CA2474793A1/en not_active Abandoned
-
2006
- 2006-04-21 US US11/408,356 patent/US7244754B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1289083C (zh) | 2006-12-13 |
| DE10390702D2 (de) | 2005-01-27 |
| EP1482934A1 (de) | 2004-12-08 |
| AU2003227008A1 (en) | 2003-09-09 |
| WO2003072101A1 (de) | 2003-09-04 |
| US20050148641A1 (en) | 2005-07-07 |
| US20060189589A1 (en) | 2006-08-24 |
| JP2005518436A (ja) | 2005-06-23 |
| EP1482934B1 (de) | 2006-03-29 |
| DE50302825D1 (de) | 2006-05-18 |
| ES2261953T3 (es) | 2006-11-16 |
| US7101901B2 (en) | 2006-09-05 |
| US7244754B2 (en) | 2007-07-17 |
| ATE321554T1 (de) | 2006-04-15 |
| CA2474793A1 (en) | 2003-09-04 |
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