CN112566917B - 新型镁-丝氨酸盐化合物及其用途 - Google Patents
新型镁-丝氨酸盐化合物及其用途 Download PDFInfo
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- CN112566917B CN112566917B CN201980053116.2A CN201980053116A CN112566917B CN 112566917 B CN112566917 B CN 112566917B CN 201980053116 A CN201980053116 A CN 201980053116A CN 112566917 B CN112566917 B CN 112566917B
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Abstract
本发明涉及新型镁‑丝氨酸盐（magnesium‑serinate）化合物及其用途，更具体地，涉及L‑丝氨酸（serine）与镁原子形成螯合键的新型镁‑丝氨酸盐化合物和中枢神经系统疾病（centralnervous system diseases）等相关的其医药用途等。根据设备分析的结果，确认到通过本发明的制备方法获取的新型镁‑丝氨酸盐化合物由～10％的镁和～90％的丝氨酸形成，在常温的水中，在pH6.0～pH10.0范围内以～500mg/ml浓度进行增溶，以水溶液状态在未生成沉淀物的情况下维持，并且，在生理盐水（phosphate‑buffered saline，PBS）溶液中也是在常温下未生成沉淀物的情况下，以～500mg/ml的浓度进行增溶，从而确认到具有适合以口服及注射剂给药到人体的性质，上述化合物提高线粒体的耗氧率使线粒体功能及神经细胞的增殖激活，呈现抑制氧化应激引起的线粒体膜电位受损和/或内质网应激引起的神经细胞凋亡的神经细胞保护效果，呈现得到改善的血脑屏障的透过效率，从而认知障碍、智力障碍、小脑症、癫痫、神经发育障碍、痴呆、自闭症谱系障碍、唐氏综合征、雷特综合征、脆性X综合征、阿尔茨海默病、帕金森病、亨廷顿病及肌萎缩侧索硬化症等中枢神经系统疾病的预防、治疗及改善效果优秀，故而是非常有用于医药产业等的发明。
Description
技术领域
本发明涉及新型镁-丝氨酸盐(magnesium-serinate)化合物及其用途，更具体地，涉及L-丝氨酸(serine)与镁原子形成螯合键的新型镁-丝氨酸盐化合物和中枢神经系统疾病(centralnervous system diseases)等相关的其医药用途等。
背景技术
镁是人体中第四个丰富的无机盐类。约50％储存于骨头中，反而，剩余50％主要存在于身体组织和脏器的细胞内部[Jahnen-Dechent and Ketteler,2012；Farruggia etal.,2014]。在细胞内，镁起到几百种酶的辅因子(cofactor)作用，因而镁与主要的细胞反应相关。尤其，镁被与ATP-生成反应相关的多种酶的稳定化所需而与能量代谢相关[Swaminathan,2003；Saris et al.,2000；Romani,2013]。尤其，近期报告，在作为细胞内镁的主要储存处的线粒体中，镁稳态通过作为线粒体内膜的mg2+转运体的MRS2的作用被调节，此时，当MRS2的缺陷导致维持镁稳态失败时，随着线粒体的能量代谢及形态发生变化，ATP生产被抑制，细胞对应激的抵抗性减少[Yamanaka et al.,2016]。这种研究结果启示了线粒体内的镁稳态调节在确定细胞内能量代谢与细胞对应激的抵抗性时起到重要的作用。
并且，在过去的30年基本认知到改善及缓解神经系统疾病的镁的潜在神经保护作用，但在临床领域中，仍然缺乏与镁的治疗效果相关的准确解释。最近出现的研究结果不断启示镁与包括头痛、应激、酒精/药物中毒、急性脑损伤、发作、帕金森病及阿尔茨海默病的多种神经疾病状态相关地起到重要的作用[Vink,2016]。
不仅如此，据最近多个研究报告，通过口服供给镁，增加人体的脑可塑性(brainplasticity)，提高学习(learning)、记忆(memory)及认知功能(cognitive function)[Slutsky et al.,2010]。有关脑的老化恢复，摄取镁的人使脑老化逆转至9～14年左右，恢复脑功能[Liu et al.,2015]。
但是，人体内镁的脑吸收率及细胞内透过率低的问题仍然成为需要改善的研究对象。麻省理工学院(MIT)的研究人员通过测试L-苏糖酸镁(magnesium-L-threonate)化合物，发现L-苏糖酸镁具有高于无机镁盐(inorganic magnesium salts)的生物利用率和脑镁增强功能，可将脑镁数值增加约15％[Mickley et al.,2013]。这种研究结果启示相比于无机金属盐形态的镁，与作为糖酸(sugar acid)之一的苏糖酸(threonic acid)形成有机键的镁的细胞内透过率及向中枢神经系统的吸收率更高。
另一方面，氨基酸之一的L-丝氨酸在生物体内不仅是蛋白质的成员，还与甘氨酸和半胱氨酸等氨基酸的生物合成、作为DNA前体的嘌呤及嘧啶的生物合成、作为细胞膜磷脂质的磷脂酰丝氨酸(phosphatidylserine)的生物合成及脑中鞘磷脂(sphingomyeline)、脑苷脂(cerebrosides)及D-丝氨酸(D-serine)等的生物合成重要相关。因此，细胞内L-丝氨酸的浓度直接贡献于根据细胞的分裂增殖的生长，并且，来源于L-丝氨酸的甘氨酸及半胱氨酸是众所周知为细胞内主要抗氧化物质的谷胱甘肽(glutathione，GSH)的成员[Pompella et al.,2003]，因而L-丝氨酸通过作为细胞内谷胱甘肽生成所需的前体的供给源的作用，还可重要贡献于从活性氧簇(reactive oxygen radicals，ROS)导致的受损中保护细胞的防御机制[Aoyama et al.,2008；Zhou et al.,2017]。
像这样，人体细胞所需的L-丝氨酸可通过在细胞质内发生的磷酸化途径(phosphorylatedpathway)进行生物合成。但是，在疾病或应激条件下，在细胞内生物合成的L-丝氨酸，其生成量相比于细胞所需的L-丝氨酸的量不充分，因而分类为需要通过饮食的体外供给的条件必需氨基酸(conditionally essential amino acid)。尤其，据悉，先天性L-丝氨酸生物合成代谢的遗传缺陷符合血脑屏障(blood-brainbarrier，BBB)的透过效率比较低的L-丝氨酸的特性，诱发脑中的L-丝氨酸缺乏症，引起小脑症、严重的癫痫、智力障碍等疾病[Smith et al.,1987；Boado et al.,1999；De Koning et al,2002]。
作为先天性丝氨酸生物合成代谢的遗传缺陷引起脑中的L-丝氨酸缺乏导致中枢神经系统的严重疾病的理由，可例举L-丝氨酸不仅起到神经细胞的神经营养因子(neurotrophic factor)的作用[Furuya et al.,2000]，还用作与谷氨酸一同针对N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptor，NMDAR)起到协同激动剂(co-agonist)作用的甘氨酸及D-丝氨酸的供给源，重要贡献于脑神经发育、突触精细化(synapserefinement)、神经可塑性(neuronal plasticity)及兴奋细胞毒性(excitotoxicity)等[De Miranda et la.,2000]。
作为先天性L-丝氨酸生物合成代谢的缺陷，诊断L-丝氨酸生物合成酶基因，即，3-磷酸甘油酸脱氢酶(3-phosphoglycerate dehydrogenase，PHGDH)、磷酸丝氨酸转氨酶(phosphoserine aminotransferase，PSAT)和磷酸丝氨酸磷酸酶(phosphoserinephosphatase，PSP)的突变，据报告，针对患有L-丝氨酸生物合成代谢缺陷的婴儿，以100～600mg/kg/天给药L-丝氨酸，或给药L-丝氨酸200～700mg/kg和甘氨酸200～300mg/kg，如此同时长期口服给药时，在无副作用的情况下，癫痫和神经发育障碍好转，脑白质体积和髓鞘化恢复[Pineda et al.,2000；De Koning et al.,2002；ElHattab,2016]。并且，以100～150mg/kg/天将L-丝氨酸给药到患有3-磷酸甘油酸脱氢酶变异导致的L-丝氨酸生物合成代谢缺陷的青少年时，癫痫、行动障碍、基本障碍好转[Tabatabaie et al.,2011]。因此，以中枢神经系统所需的水平从体外供给因先天性L-丝氨酸生物合成代谢缺陷而缺乏的L-丝氨酸，这被揭示为相关疾病的有效治疗方案。
最近，作为成为大幅扩大L-丝氨酸用作成人神经疾病的治疗剂的原因的临床研究结果，据报告，在利用β-N-甲基氨基-L-丙氨酸(β-N-methylamino-L-alanine，L-BMAA)的关岛型肌萎缩侧索硬化症(Guamanian amyotrophic lateral sclerosis，ALS)/帕金森综合征-痴呆复合征(Parkinsonism dementia complex，PDC)治疗和肌萎缩侧索硬化症(Amyotrophic lateral sclerosis)治疗中，L-丝氨酸具有积极效果[Dunlop et al.,2018]。
另一方面，L-丝氨酸和镁在维持线粒体功能时起到必要作用[Lucas et al.,2018；Yamanaka et al.,2016]。线粒体的生成与调节在神经发生和神经可塑性起到主要作用，是自闭症谱系障碍、唐氏综合征、雷特综合征、脆性X综合征等认知及适应障碍相关多种神经发育障碍的核心病因，这揭示线粒体功能激活可成为新的治疗法[Valenti et al.,2014]。大部分唐氏综合征患者的脑部呈现与阿尔茨海默患者相似的病理学见解，当50岁以上时，75％患上痴呆，这与线粒体功能障碍密切相关，因而揭示早期开始线粒体功能活性相关治疗时，可降低痴呆发生率[Pinar et al.,2012]。并且，据报告，阿尔茨海默病(Alzheimer)[Wang et al.,2014]、帕金森病(Parkinson's Disease)[Franco-Iborra etal.,2018]、亨廷顿病(Huntington's disease)[Jodriri et al.,2017]、肌萎缩侧索硬化症(amyotropic lateral sclerosis，ALS)[Cozzolino and Carri,2012]之类的退行性神经疾病的发病原因为线粒体受损引起的氧化应激导致的神经细胞凋亡。线粒体是细胞的凋亡(apoptosis)或坏死(necrosis)的执行机构，为了从外部环境应激中维持细胞稳态，通过如线粒体的分裂及融合一样的线粒体数的量化调节来保护细胞或者恢复或去除受损的细胞[Youle andvan der Bliek,2012；Ni et al.,2014]。
尤其，神经细胞是需要高于其他组织的细胞的能量代谢，容易过氧化(peroxidation)的脂肪酸和金属离子比率高且细胞抗氧化系统水平比较低的分裂后非增殖细胞(post-mitotic non-proliferating cell)，其非常弱于活性氧簇或活性氮簇引起的氧化应激[Ogawa et al.,2007；Bhat et al.,2015]。据报告，基于这种神经细胞的特征，主要发病原因互不相同，但是，自闭症谱系障碍、唐氏综合征、雷特综合征、脆性X综合征之类的神经发育障碍、阿尔茨海默病、帕金森病、亨廷顿病、肌萎缩侧索硬化症之类的退行性神经疾病的共同症状为氧化应激引起的线粒体功能障碍(mitochondrial dysfunction)。
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发明内容
技术问题
本发明要解决的问题在于，提供根据需要向人体内同时传递镁和L-丝氨酸，呈现增加镁和L-丝氨酸的细胞内透过率、脑中的镁和L-丝氨酸的浓度的效果，有利于线粒体功能活性的新型镁-丝氨酸盐化合物及其制备方法。
本发明要解决的另一问题在于，提供包含上述镁-丝氨酸盐化合物或其药学上可接受的盐作为有效成分的用于预防或治疗认知障碍、智力障碍、小脑症、癫痫、神经发育障碍、痴呆、自闭症谱系障碍、唐氏综合征、雷特综合征、脆性X综合征、阿尔茨海默病、帕金森病、亨廷顿病及肌萎缩侧索硬化症等线粒体功能障碍引起的中枢神经系统疾病的药学组合物等。
解决问题的方案
为了解决如上所述的问题，本发明提供以下化学式(Ⅰ)的化合物、上述化合物的药剂学上可接受的盐、溶剂化物、水合物或异构体：
并且，本发明提供使L-丝氨酸与MgO进行反应来制备的上述化学式(Ⅰ)的化合物的制备方法。
优选地，上述反应在70～80℃下进行。
并且，本发明提供使L-丝氨酸与MgH2进行反应来制备的上述化学式(Ⅰ)的化合物的制备方法。
优选地，上述反应在常温下进行。
优选地，上述反应在70～80℃下进行。
并且，本发明提供包含上述化学式(Ⅰ)的化合物或其药学上可接受的盐作为有效成分的中枢神经系统疾病的预防或治疗用药学组合物。
优选地，上述中枢神经系统疾病选自由认知障碍、智力障碍、小脑症、癫痫、神经发育障碍、痴呆、自闭症谱系障碍、唐氏综合征、雷特综合征、脆性X综合征、阿尔茨海默病、帕金森病、亨廷顿病及肌萎缩侧索硬化症组成的组中。
优选地，上述中枢神经系统疾病选自由认知障碍、智力障碍、小脑症、癫痫、神经发育障碍、痴呆、自闭症谱系障碍、唐氏综合征、雷特综合征、脆性X综合征、阿尔茨海默病、帕金森病、亨廷顿病及肌萎缩侧索硬化症组成的组中。
并且，本发明提供包含上述化学式(Ⅰ)的化合物或其药学上可接受的盐的饲料添加用组合物。
并且，本发明提供包含上述化学式(Ⅰ)的化合物或其药学上可接受的盐的神经细胞凋亡抑制用试剂组合物。
并且，本发明提供包括在体外(in vitro)将上述化学式(Ⅰ)的化合物或其药学上可接受的盐处理于神经细胞的步骤的神经细胞的细胞凋亡抑制方法。
发明的效果
根据设备分析的结果，确认到通过本发明的制备方法获取的新型镁-丝氨酸盐化合物由～10％的镁和～90％的丝氨酸形成，在常温的水中，在pH6.0～pH10.0范围内以～500mg/ml的浓度进行增溶，以水溶液状态在未生成沉淀物的情况下维持，并且，在生理盐水(phosphate-buffered saline，PBS)溶液中也是在常温下未生成沉淀物的情况下，以～500mg/ml的浓度进行增溶，从而确认到具有适合以口服及注射剂给药到人体的性质，上述化合物提高线粒体的耗氧率使线粒体功能及神经细胞的增殖激活，呈现抑制氧化应激引起的线粒体膜电位受损和/或内质网应激引起的神经细胞凋亡的神经细胞保护效果，呈现得到改善的血脑屏障的透过效率，从而认知障碍、智力障碍、小脑症、癫痫、神经发育障碍、痴呆、自闭症谱系障碍、唐氏综合征、雷特综合征、脆性X综合征、阿尔茨海默病、帕金森病、亨廷顿病及肌萎缩侧索硬化症等中枢神经系统疾病的预防、治疗及改善效果优秀，故而是非常有用于医药产业等的发明。
附图说明
图1表示L-丝氨酸的1H-NMR分析结果。
图2表示本发明的镁-丝氨酸盐(是根据以下实施例1的合成法获取的化合物，以下，命名为“AST-011”)的1H-NMR分析结果。
图3表示本发明的镁-丝氨酸盐(是根据以下实施例2的合成法获取的化合物，命名为“AST-014”)的1H-NMR分析结果。
图4表示L-丝氨酸的13C-NMR分析结果。
图5表示本发明的镁-丝氨酸盐(AST-011)的13C-NMR分析结果。
图6表示本发明的镁-丝氨酸盐(AST-014)的13C-NMR分析结果。
图7表示L-丝氨酸的FT-IR分析结果。
图8表示本发明的镁-丝氨酸盐(AST-011)的FT-IR分析结果。
图9表示本发明的镁-丝氨酸盐(AST-014)的FT-IR分析结果。
图10表示本发明的镁-丝氨酸盐(是根据以下实施例3的合成法获取的化合物，命名为“AST-016”)的FT-IR分析结果。
图11表示根据本发明的镁-丝氨酸盐(AST-011)的处理浓度的小鼠海马神经元HT-22细胞(mouse hippocampal neuronal HT-22cells)的细胞激活。(A)表示丝氨酸/甘氨酸缺乏培养基中的细胞活力(cell viability)，(B)表示完全培养基中的细胞活力。
图12表示利用海马细胞外通量(XF)分析仪(Seahorse ExtracellularFlux(XF)analyzer)分析本发明的镁-丝氨酸盐(AST-011)的小鼠海马神经元HT-22细胞中对线粒体能量生成系统和呼吸系统的代谢能力(metabolic capacity)的影响的结果。
图13表示根据本发明的镁-丝氨酸盐(AST-011)的处理浓度的由2,3-二甲氧基-1,4-萘醌(DMNQ，2,3-dimethoxy-1,4-napthoquinone)处理的小鼠海马神经元HT-22细胞的细胞保护效果。
图14将本发明的镁-丝氨酸盐(AST-011)给药到ICR小鼠之后，对分布于血液和脑部的浓度进行定量，求出脑/血中比率表示药物的血脑屏障透过力。
具体实施方式
以下，详细说明本发明。
本发明的发明人的目的在于，开发一种根据需要向人体内同时传递镁和L-丝氨酸，可呈现镁和L-丝氨酸的细胞内透过率、脑中的镁和L-丝氨酸的浓度增加效果的新的化合物，对作为氨基酸的L-丝氨酸处理镁盐(MgO或MgH2)以氨基酸L-丝氨酸结合镁的金属氨基酸螯合物形态制备镁-丝氨酸盐。制备的镁-丝氨酸盐在常温的水中在pH6.0～pH10.0范围内以～500mg/ml的浓度进行增溶，以水溶液状态在未生成沉淀物的情况下维持。并且，制备的镁-丝氨酸盐在包含氯化钠(NaCl)和磷酸盐(phosphate)的常温的生理盐水溶液中也在未生成沉淀物的情况下以～500mg/ml浓度进行增溶。
因此，本发明提供以下化学式(Ⅰ)的化合物、上述化合物的药剂学上可接受的盐、溶剂化物、水合物或异构体：
上述化学式(I)的化合物如以下结构式，是双分子的丝氨酸与单分子的镁形成离子键及配位键的结构。
上述化学式(I)的化合物能够以碱-加成盐或酸-加成盐的形态存在。上述加成盐包含在本发明的一部分。上述盐有利地利用药学上可接受的酸制备，但是例如，对纯化或分离化学式(I)的化合物有用的其他酸的盐也包含在本发明的一部分。上述酸例如可以为苦味酸、草酸或光学活性酸、例如，酒石酸、二苯甲酰基酒石酸、扁桃酸或樟脑磺酸及形成生理学上可接受的盐，例如，盐酸盐、氢溴酸盐、硫酸盐、硫酸氢盐、磷酸二氢盐、苹果酸盐、富马酸盐、2-萘磺酸盐或对甲苯磺酸盐的酸。有关生理学上可接受的盐，可参照文献[Handbookof Pharmaceutical Salts:Properties,Selection and Use by Stahl andWermuth(Wiley-VCH,2002)]。
上述溶剂化物或水合物可在合成过程之后直接获取，化合物(I)能够以水合物，例如，一水合物或半水合物的形态分离，或以反应或纯化溶剂的溶剂化物的形态分离。
并且，上述化学式(I)的化合物能够以异构体例如以旋转异构体的形态存在。上述化学式(I)的化合物的旋转异构体包含在本发明的一部分。
本发明的上述化学式(I)的化合物可通过如下所述的制备方法以高的收率和纯度合成。
因此，本发明提供使L-丝氨酸与MgO进行反应来制备的上述化学式(Ⅰ)的化合物的制备方法。
优选地，上述化学式(I)的化合物根据以下化学反应式合成，合成反应在70～80℃下进行。
2L-丝氨酸+MgO→丝氨酸-Mg-丝氨酸+H2O
具体地，在装有蒸馏水的反应容器中投入L-丝氨酸溶解，一次性添加粉碎的MgO一边搅拌一边使其反应约2小时，可获取上述化学式(I)的化合物。回收及纯化反应容器内的上述化学式(I)的化合物的方法可依据常规的有机合成反应之后的分离及纯化方法。
并且，本发明提供使L-丝氨酸与MgH2进行反应来制备的上述化学式(Ⅰ)的化合物的制备方法。
优选地，上述化学式(I)的化合物根据以下化学反应式合成，合成反应在常温或70～80℃下进行。
2L-丝氨酸+MgH2→丝氨酸-Mg-丝氨酸+2H2
具体地，在装有蒸馏水的反应容器中投入L-丝氨酸，在常温(常温反应)下或升温(加热反应)至70～80℃，一边少量添加MgH2搅拌一边在常温反应中反应约14小时，在加热反应中反应约6小时，直到不产生H2气体，可获取上述化学式(I)的化合物。回收及纯化反应容器内的上述化学式(I)的化合物的方法可依据常规的有机合成反应之后的分离及纯化方法。
本发明的上述镁-丝氨酸盐化合物可应用为如下医药用途，可根据需要向人体内同时传递镁和L-丝氨酸，改善镁和L-丝氨酸的低血脑屏障透过力，对先天性神经疾病及退行性神经疾病等中枢神经系统相关疾病呈现效果。
因此，本发明提供包含上述化学式(Ⅰ)的化合物或其药学上可接受的盐作为有效成分的中枢神经系统疾病的预防或治疗用药学组合物。
本发明的有效成分能够以医药用途应用于中枢神经系统相关疾病，优选地，上述中枢神经系统疾病选自由认知障碍、智力障碍、小脑症、癫痫、神经发育障碍、痴呆、自闭症谱系障碍、唐氏综合征、雷特综合征、脆性X综合征、阿尔茨海默病、帕金森病、亨廷顿病及肌萎缩侧索硬化症组成的组中。
优选地，上述有效成分诱导神经细胞增殖激活。上述术语“神经细胞增殖激活”可理解为均包括促进神经细胞的细胞分裂的作用、可抑制神经细胞的凋亡或坏死的作用。
上述神经细胞增殖激活优选为根据线粒体的耗氧率增加的效果。
优选地，上述有效成分具有神经细胞保护活性。上述术语“神经细胞保护”意味着可抑制神经细胞因外部因素或细胞内部因素而发生细胞凋亡或坏死的作用。
优选地，上述神经细胞保护从氧化应激中保护。上述术语“氧化应激”意味着细胞因活性氧簇而处于异常状态。
优选地，通过抑制线粒体膜电位受损引起的细胞凋亡，从上述氧化应激中保护。
优选地，通过抑制内质网应激引起的细胞凋亡，从上述氧化应激中保护。
优选地，上述有效成分具有对血脑屏障的透过力。本发明的有效成分显著改善L-丝氨酸所具有的低的血脑屏障透过度，具有给药到患有L-丝氨酸生物合成缺陷的患者时，可有效传递到脑部的效果。
本发明的药学组合物可按各个使用目的根据常规方法以散剂、颗粒剂、片剂、胶囊剂、悬浮剂、乳液、糖浆、气溶胶等口服剂型、灭菌注射溶液的注射剂等多种形态剂型化来使用，可口服给药，或可通过包括静脉内、腹腔内、皮下、直肠、局部给药等的多种途径给药。
这种药学组合物还可包含载体、赋形剂或稀释剂等，作为可包含的适当的载体、赋形剂或稀释剂的例，可例举乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、非晶质纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油等。
并且，本发明的药学组合物还可包含填充剂、抗凝集剂、润滑剂、湿润剂、香料、乳化剂、防腐剂等。
本发明的药学组合物以药剂学上有效的量给药。在本发明中，“药剂学上有效的量”是指以可应用于医学治疗的合理受益/危险比率治疗疾病的充分量，有效容量水平可根据包括患者的疾病的种类、重症度、药物的活性、对于药物的敏感度、给药时间、给药途径及排出比率、治疗期间、同时使用的药物的因素及其他医学领域中知悉的因素而确定。
本发明的药学组合物能够以个别治疗剂给药或与其他治疗剂并用给药，可与以往的治疗剂依次或同时给药，可单次或多次给药。重要的是，将均考虑上述因素而可在无副作用的情况下以最小限度的量获得最大效果的量给药，这可由本发明所属技术领域的普通技术人员容易确定。
作为优选的具体例，本发明药学组合物的有效成分的有效量可根据患者的年龄、性别、体重而不同，通常，每体重可给药1至5000mg，优选地，可每天或隔天给药100至3000mg或一天分1至3次给药。但是，可根据给药途径、疾病的重症度、性别、体重、年龄等而增减，因而上述给药量以任何方法也不限制本发明的范围。
本发明的药学组合物可通过多种途径给药到对象。给药的所有方式可预测，例如，可通过口服、直肠或静脉、肌肉、皮下、子宫内硬膜或脑血管内(intracerebroventricular)注射给药。
在本发明中，“给药”意味着以任意适当的方法向患者提供规定的物质，本发明的药学组合物的给药途径只要可达到目的组织，就可通过常规的所有途径口服或非口服给药。并且，本发明的组合物还可利用可向靶细胞传递有效成分的任意装置给药。
在本发明中，“对象”不受特别限制，但例如，包括人、猴、牛、马、羊、猪、鸡、火鸡、鹌鹑、猫、狗、小鼠、老鼠、兔或豚鼠，优选地，意味着哺乳类，更优选地，意味着人。
优选地，上述中枢神经系统疾病选自由认知障碍、智力障碍、小脑症、癫痫、神经发育障碍、痴呆、自闭症谱系障碍、唐氏综合征、雷特综合征、脆性X综合征、阿尔茨海默病、帕金森病、亨廷顿病及肌萎缩侧索硬化症组成的组中。
本发明的镁-丝氨酸盐化合物可向生物体内有效供给镁和丝氨酸，因而可将其应用于饲料中。
因此，本发明提供包含上述化学式(Ⅰ)的化合物或其药学上可接受的盐的饲料添加用组合物。
上述饲料添加用组合物可以为动物用。上述“动物”作为与植物相对应的生物群，主要将有机物作为营养成分摄取，其消化或排泄及呼吸器官分化，具体地，可以为棘皮动物、甲壳类、软体动物、鱼类、两栖类、爬虫类、鸟类、哺乳类，优选地，可以为海胆类或海参类之类的棘皮动物、包括螃蟹、虾、大虾等甲壳类的节肢动物、头足类、腹足类或双壳类等软体动物、真鲷、鲷鱼、鳕鱼、鲽鱼、偏口鱼等鱼类、包括野鸡或鸡等家禽类的鸟类或猪、牛、羊、马、山羊、狗、猫等哺乳类。
上述饲料添加用组合物在本发明的有效成分中还可包含谷物、植物性蛋白质饲料、动物性蛋白质饲料、糖分或乳制品。上述谷物具体地可以为粉碎或破碎的小麦、燕麦、大麦、玉米及大米，上述植物性蛋白质饲料具体地能够以油菜、大豆及向日葵为主要成分，上述动物性蛋白质饲料具体地可以为血粉、肉粉、骨粉及海鲜粉，上述糖分或乳制品具体地可以为由各种奶粉及乳浆粉末形成的干燥成分。
上述饲料添加用组合物还可一同使用营养补充剂、消化及吸收提高剂、生长促进剂或疾病预防剂之类的成分。
本发明的饲料添加用组合物可根据饲料的使用目的及使用条件而不同，作为一例，以1kg的最终生产的饲料为基准，可包含0.1至100g的上述饲料添加用组合物。
并且，上述饲料添加用组合物可根据成分的粉碎程度而制备成硬粘性的粗粒或颗粒物质，上述组合物能够以网孔供给，或为了追加加工及包装而以所需的分离的形状形成，为了储存，可经过颗粒化、膨胀化或挤压工序，为了容易储存，优选地，过多的水被干燥去除。
另一方面，本发明的镁-丝氨酸盐有效抑制神经细胞凋亡，因而还可作为诱导细胞凋亡的试剂应用于细胞中，优选地应用于神经细胞。
因此，本发明提供包含上述化学式(Ⅰ)的化合物或其药学上可接受的盐的研究用试剂组合物，优选地提供神经细胞凋亡抑制用试剂组合物。
上述神经细胞可以为原发神经细胞、转化神经细胞或神经细胞株。
上述试剂能够以神经细胞增殖激活、根据线粒体的耗氧率增加的神经细胞增殖激活、神经细胞保护、抑制氧化应激引起的神经细胞受损、抑制氧化应激引起的线粒体膜电位受损导致的神经细胞凋亡、抑制氧化应激引起的内质网应激导致的神经细胞凋亡的用途应用。
并且，本发明提供神经细胞的细胞凋亡抑制方法，该方法包括将包含上述化学式(Ⅰ)的化合物或其药学上可接受的盐的本发明的试剂处理于神经细胞的步骤。
可通过上述方法获得神经细胞的增殖、根据线粒体的耗氧率增加的神经细胞增殖激活、神经细胞保护、抑制氧化应激引起的神经细胞受损、抑制氧化应激引起的线粒体膜电位受损导致的神经细胞凋亡、抑制氧化应激引起的内质网应激导致的神经细胞凋亡的效果。
在上述方法中，细胞培养法、试剂处理法等对本发明所属技术领域的普通技术人员来说是显而易见的，尤其，试剂的处理浓度等可在不改变本说明书中记载的事项的范围内或其效果的范围内适当地变形。
优选地，上述方法在体外(in vitro)进行。
以下，通过具体的实施例更详细说明本发明。以下实施例记载本发明的优选的一具体例，要明确的是，本发明的权利范围并不限定于以下实施例中记载的内容而被解释。
实施例
1.镁-丝氨酸盐(Mg-Serinate)的制备
1.1.镁-丝氨酸盐(Mg-Serinate，AST-011)的制备
在500ml的三角烧瓶中放入蒸馏水100ml，升温至70～80℃的温度之后，在该蒸馏水中，称取50g(～0.48moles)的L-丝氨酸(MW 105.1)一边利用磁力搅拌器(magneticstirrer)搅拌一边使其溶解。在研钵中，将MgO(MW 40.3)粉碎成小粒子之后，称取9.7g(～0.24moles)在L-丝氨酸水溶液中一边以70～80℃的温度搅拌一边少量添加放入，在三角烧瓶中附着回流冷却装置，在相同的条件下反应2小时。
在未冷却的状态下，直接在6000rpm下离心分离10分钟，回收130ml的上清液。在上清液中添加乙醇，使最终浓度成为75v/v％之后，利用磁力搅拌器在常温下搅拌14小时使其沉淀。上清液倒出来去除，仅回收沉淀物来冷冻干燥，获得镁-丝氨酸盐的固体物。
利用研钵将通过冷冻干燥回收的镁-丝氨酸盐固体物粉碎成小粒子，最终获得镁-丝氨酸盐粉末(AST-011)。此时回收的镁-丝氨酸盐粉末为53.1g，回收率为～89％左右。
1.2.基于常温反应的镁-丝氨酸盐(Mg-Serinate，AST-014)制备
在三角烧瓶(2000ml)中放入500ml的蒸馏水，在该蒸馏水中，称取75g(～0.71moles)的L-丝氨酸(MW 105.1)一边在常温下搅拌一边使其溶解。称取9.5g(～0.36moles)的MgH2(MW 26.3)在常温下一边搅拌一边少量添加放入L-丝氨酸水溶液中，在常温下一边利用磁力搅拌器搅拌14小时一边反应，直至不产生H2气体。
利用滤纸(Whatmann 3MM滤纸，GE Healthcare，生命科学，USA(Whatmann 3MMFilter Paper,GE Heathcare,Life Sciences,USA))过滤反应液之后，利用减压浓缩器(Heidolph LR 4000，Germany)将滤液浓缩成～200ml。在浓缩液(～200ml)中添加600ml的乙醇，使最终浓度成为75v/v％，利用磁力搅拌器搅拌沉淀14小时。接着，上清液倒出来去除，回收镁-丝氨酸盐沉淀物来冷冻干燥。
利用研钵将通过冷冻干燥回收的镁-丝氨酸盐固体粉碎成小粒子，最终获得镁-丝氨酸盐粉末(AST-014)。此时回收的镁-丝氨酸盐粉末为48.3g，回收率为～57.3％。
1.3.基于加热反应的镁-丝氨酸盐(Mg-serinate，AST-016)制备
在三角烧瓶(1000ml)中放入蒸馏水200ml，以70～80℃预先加热。在该加热的蒸馏水中，称取60g(～0.57moles)的L-丝氨酸(MW 105.1)一边搅拌一边使其溶解。称取7.5g(～0.285moles)的MgH2(MW 26.3)一边利用磁力搅拌器搅拌一边少量添加放入L-丝氨酸水溶液中，然后在三角烧瓶附着回流冷却装置，在相同的70～80℃下一边利用磁力搅拌器搅拌一边反应6小时，直至不产生H2气体。
利用滤纸(Whatmann 3MM滤纸，GE Healthcare，生命科学，USA(Whatmann 3MMFilter Paper,GE Heathcare,Life Sciences,USA))过滤反应液之后，利用减压浓缩器(Heidolph LR 4000，Germany)将滤液～220ml浓缩成～100ml。在浓缩液(～100ml)中添加乙醇，使最终浓度成为75v/v％，利用磁力搅拌器一边搅拌14小时一边使其沉淀。接着，上清液倒出来去除，在300ml的75v/v％乙醇中将沉淀物浸泡8小时洗涤之后，冷冻干燥沉淀物来回收镁-丝氨酸盐。
利用研钵将通过冷冻干燥回收的镁-丝氨酸盐固体粉碎成小粒子，最终获得镁-丝氨酸盐粉末(AST-016)。此时回收的镁-丝氨酸盐粉末为62.6g，回收率为～92.8％。
2.合成的镁-丝氨酸盐的设备分析
2.1.镁-丝氨酸盐内的镁含量分析
利用电感耦合等离子体质谱仪(Inductively coupled plasma-opticalemission spectrometry，ICP-OES)(Optima 7300DV,PerkinElmer,USA)分析各个螯合金属的镁含量。实验条件为频率40MHz，使用于无机物分析的波长为285.213nm。
(1)分别取约0.1～0.2g的试样准确测定重量之后，添加25～30g的硝酸。
(2)利用UltraWAVE(Milestone，Italy)装置在220℃下处理25分钟之后，利用2％硝酸稀释并分析。
将与此相关的分析平均值示于表1中。
表1镁-丝氨酸盐AST-011、AST-014及AST-016的镁含量
2.2.镁-丝氨酸盐内的构成氨基酸含量分析
使用氨基酸自动分析装置(L-8900,Hitachi,Japan)确认各个镁-丝氨酸盐内的构成氨基酸含量。
(1)在0.05g的试样中放入2ml的6N HCl充氮，在110℃下水解24小时。
(2)酸水解之后，以80℃加热24小时左右，干燥。
(3)利用0.02N HCl将酸水解溶液稀释1000倍之后，利用氨基酸自动分析仪分析。
将与此相关的分析值示于表2中。
表2镁-丝氨酸盐AST-011、AST-014及AST-016的丝氨酸含量
ND：未检测(Non-detect)
2.3.基于核磁共振(NMR，Nuclear Magnetic Resonance)的镁-丝氨酸盐的分析
利用1H NMR及13C NMR分析各个镁-丝氨酸盐(AST-011、AST-014及AST-016)及正宗的L-丝氨酸(authentic L-Serine)(ICN Biomedicals，OH，USA)。将各个100mg的试样溶解于0.7ml的D2O中，在24.85℃(298K)下使用核磁共振波谱法(NMR spectroscopy)(BrukerAvance II 500MHz with CyroBBO probe,Bruker,germany)测定。
2.3.1.1H NMR分析
如图1至图3所示，通过1H NMR分析法分析的结果如下：就正宗的L-丝氨酸而言，判断为具有羧基(carboxyl group)和氨基(amino group)的α碳(αcarbon)的峰值(peak)出现在3.7～3.8ppm范围内，判断为具有羟基(hydroxyl group)的β碳(βcarbon)的峰值出现在3.6～3.7ppm范围内。此时，就AST-011而言，判断为具有羧基和氨基的α碳的峰值出现在3.5～3.6ppm范围内，判断为具有羟基的β碳的峰值出现在3.2ppm范围内，就AST-014而言，判断为具有羧基和氨基的α碳的峰值也出现在3.5～3.6ppm范围内，判断为具有羟基的β碳的峰值出现在3.2ppm范围内。
最终，在AST-011及AST-014这两种试样中均共同确认到具有与正宗的L-丝氨酸非常类似的化学位移(chemical shift)的1H NMR峰值。此时，与正宗的L-丝氨酸的1H NMR峰值不同，就AST-011及AST-014而言，在3.4～3.5ppm范围内确认到乙醇(ethanol)的CH2峰值，在1.00ppm范围内确认到乙醇的CH3峰值，判断这是因为在AST-011和AST-014的制备工序中用于乙醇沉淀(ethanol precipitation)步骤的乙醇在冷冻干燥之后也少量残留于固体试样中。
2.3.2.13C NMR分析
如图4至图6所示，通过13C NMR分析法分析的结果如下：就AST-011而言，判断为正宗的L-丝氨酸内的α碳的羧基的C＝O峰值出现在177.885ppm范围内，β碳的羟基的C-O峰值出现在62.607ppm范围内，α碳和β碳的C-C峰值出现在56.151ppm范围内。并且，就AST-014而言，判断为α碳的羧基的C＝O峰值出现在179.838ppm范围内，β碳的羟基的C-O峰值出现在63.784ppm范围内，α碳和β碳的C-C峰值出现在56.892ppm范围内。
最终，在AST-011及AST-014这两种试样中均共同确认到与正宗的L-丝氨酸非常类似的13C NMR峰值。另一方面，AST-011在56.391ppm范围内和15.732ppm范围内且AST-014在57.334ppm范围内和16.692ppm范围内出现的小高度的峰值确认为在1H NMR分析中检测到的乙醇峰值。
2.3.3.NMR分析结果
综合利用以上1H NMR及13C NMR的两种分析结果，确认在制备的镁-丝氨酸盐试样AST-011及AST-014内包含L-丝氨酸。
2.4.基于傅里叶变换红外光谱(FT-IR，Fourier transforminfrared)的镁-丝氨酸盐的分析
利用FT-UV-VIS-IR光谱成像显微镜(FT-UV-VIS-IR Spectroscopic ImagingMicroscope)(Vertex 80,Bruker,Germany)分析各个镁-丝氨酸盐(AST-011、AST-014及AST-016)及正宗的L-丝氨酸(ICN Biomedicals,OH,USA)。通过这种分析结果调查制备的镁-丝氨酸盐的螯合物的合成与否。
此时，对于各30～40mg的试样，利用衰减全反射(ATR，Attenuated TotalReflectance)技术以分辨率(Resolution)4cm-1每个样品测定3次来分析。光谱(Spectral)范围为600-4000cm-1，使用DLaTGS检测器。
图7为单独仅测定作为对照组的L-丝氨酸的IR分析结果，确认到因两性离子的影响而呈现-COO-的指纹(fingerprint)出现在800～1400cm-1、1600cm-1，-NH3+的特性带形成在～2100cm-1。将其与图8至图10相比较时，可确认形成在800～1400cm-1的-COO-指纹发生变化而简化为几个峰值，尤其，形成在呈现-NH3+的特性带的～2100cm-1的峰值完全消失。
像这样，根据FT-IR分析结果，间接确认到通过L-丝氨酸的胺基和羧基的峰值变化，两种官能团均与镁的有机结合相关。
3.镁-丝氨酸盐的神经细胞增殖活性评价
3.1.细胞活力测定(Cell viability assay)
达尔伯克改良伊格尔培养基(Dulbecco's Modified Eagle Medium，DMEM)、胎牛血清(fetal bovine serum，FBS)、4-(2-羟乙基)哌嗪-1-乙磺酸(HEPES，4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid)和链霉素-青霉素(streptomycin-penicillin)等细胞培养用试剂购买于Gibco BRL公司(Grand Island,USA)。
在DMEM内添加10％FBS和100μg/ml的正泰霉素(gentamycin)的培养基中，在37℃、5％CO2大气(atmosphere)环境下培养小鼠海马神经元细胞系(Murine hippocampalneuronal cell line)HT-22。在本实施例中，使用细胞继代回收15次以下的细胞。
通过测定细胞活力的MTT assay调查细胞增殖活性。首先，在96-孔板(wellplates)中，将海马神经元细胞(hippocampal neuronal cell)HT-22(1×104cells)与按步骤稀释的试样溶液一同培养(incubation)16小时之后，与50μl的3-(4，5-二甲基噻唑基)2，5-二苯基四氮唑溴盐(3-(4,5-dimethyl thiazolyl)2,5-diphenyl tetrazoliumbromide，MTT)溶液(1.1mg/ml)混合之后，进一步培养4小时。利用150μl的二甲基亚砜(DMSO)溶液使形成的甲臜晶体(formazan crystal)溶解，利用酶标仪(plate reader)在540nm下测定光密度(OD)。
3.2.神经细胞增殖活性评价结果
为了评价筛选的本发明的镁-丝氨酸盐(AST-011)的神经细胞增殖活性，与AST-011一同将L-丝氨酸作为对照组以(25～10000μg)添加细胞增殖相关的各个物质来比较。其结果，如图11所示，在完全培养基中，L-丝氨酸未大大激活细胞增殖，相反，AST-011在处理浓度1mg/ml中呈现最大112％的细胞生存率(图11的B)。并且，在丝氨酸和甘氨酸缺乏的培养基中，当添加500μg/ml的L-丝氨酸时，也呈现125％的生存率，此时，AST-011呈现129％(图11的A)，确认到AST-011药物使海马(hippocampal)HT-22细胞增殖激活。
4.镁-丝氨酸盐的线粒体耗氧率评价
4.1.海马XF细胞线粒体应激测试(Seahorse XF Cell Mito Stress test)
在作为丝氨酸和镁-丝氨酸盐(AST-011)的海马神经元细胞系(hippocampalneuron cell line)的HT-22中，利用海马XF细胞线粒体应激测试(海马，安捷伦科技公司，Santa Clara，CA(Seahorse,Agilent Technologies,Santa Clara,CA))检验对线粒体的耗氧率(OCR)的影响。根据线粒体应激测试测试盒(Mito Stress TestKit)的方案进行所有过程。首先，以8×103/well的浓度将海马神经元(hippocampal neuronal)HT-22细胞接种(seeding)于XP-96细胞培养板(cell culture plate)之后，在DMEM培养基中，在37℃、CO2培养箱内培养12小时，之后，按浓度处理丝氨酸和AST-011药物。处理药物4小时之后，更换为新的培养基，在37℃、CO2培养箱中追加培养12小时。利用分析培养基(assay medium)(10mM的葡萄糖(glucose)、1mM的丙酮酸(pyruvate)、2mM的谷氨酰胺(glutamine)，pH7.4)将结束12小时培养的细胞清洗2次之后，添加180μl的培养基(medium)，之后，在37℃、非-CO2培养箱中培养1小时，利用海马细胞外通量(XF)分析仪分析。与1μM的寡霉素(oligomycin)、0.5μM的氟羰基氰化物苯腙(fluoro-carbonyl cyanide phenylhydrazone，FCCP)及0.5μM的鱼藤酮/抗霉素A(rotenone/antimycin A)反应来分析OCR值，各个试样在3个相同的孔(well)中实验，作为平均值导出结果。
4.2.线粒体耗氧率评价结果
为了调查L-丝氨酸和镁-丝氨酸盐(AST-011)的细胞增殖激活是否与线粒体功能提高相关，通过材料及方法中描述的方法调查耗氧率(oxygen consumption rate)。其结果，如图12所示，可确认L-丝氨酸和AST-011这两种药物增加OCR值，提高线粒体的功能，L-丝氨酸的OCR值增加，直至处理浓度为100μg/ml，在500μg/ml中稍微减少(图12的A)，相反，AST-011的OCR值增加，直至处理浓度为500μg/ml(图12的B)，确认到与图11的细胞增殖活性实验结果相一致。
5.镁-丝氨酸盐的神经细胞保护活性
5.1.流式细胞技术(Flow cytometry)分析
首先，利用包含2％FBS的PBS溶液将1×106细胞水洗3次之后，将水洗的细胞悬浊于70％乙醇中，在4℃下固定1小时。重新利用相同的溶液将固定的细胞洗涤2次之后，悬浊于浓度为50μg/ml的250μl的RNase A溶液中，在37℃下处理30分钟去除细胞内核糖核酸(RNA)，添加50μg/ml的碘化丙啶(propidium iodide)/1.12％柠檬酸钠缓冲液(sodiumcitrate buffer)(pH8.45)溶液250μl在37℃下将细胞内DNA染色20分钟。利用流式细胞仪(flow cytometer)(FACS Calibur)对其进行分析，以各个细胞内染色的DNA的含量为基准调查细胞周期的分布。
5.2.神经细胞保护活性评价结果
通过DiOC6染色法比较对由镁-丝氨酸盐(AST-011)的DMNQ诱导的氧化应激(oxidative stress)的细胞保护活性，其结果，确认到如图13所示，当单独处理DMNQ(10μM)时，细胞受损率为77.8％，相反，当以0.5、1、5mg/ml的浓度处理AST-011时，细胞受损率为66.5％、65.9％和64.6％，线粒体膜电位受损得到保护。从以上结果可知AST-011药物相比于L-丝氨酸可使细胞增殖激活，从氧化应激中保护神经细胞的活性也优秀。
6.镁-丝氨酸盐的血脑屏障(BBB)透过力检验
6.1.血脑屏障(Blood-Brain Barrier，BBB)透过力检验
以600mg/kg将L-丝氨酸和AST-011给药到7周龄的ICR小鼠(n＝3)之后，采集脑组织和血液，利用LC/Ms对分布于血液和脑部的L-丝氨酸的浓度定量，得出脑/血中比率，比较药物的BBB透过力。
6.2.镁-丝氨酸盐的BBB透过力评价结果
与L-丝氨酸比较是否过渡到AST-011的脑部，将其结果示于图14及表3中。如图14和表3所示，AST-011药物的Cbrain/Cplasm数值呈现21.85±4.28，其高于L-丝氨酸的18.29±2.43。这与脑组织中L-丝氨酸呈现11410±1299且AST-011呈现12296±610的结果和血浆中L-丝氨酸呈现636±55.2且AST-011呈现578±103的结果相一致，确认到本发明的镁-丝氨酸盐相比于L-丝氨酸，其BBB透过力大大提高。
表3雄性ICR小鼠(male ICR mice)中的脑/血浆比例(Brain/plasma ratio)(600mg/kg，P.O.，mean±SD，n＝4)
【支援本发明的韩国研究开发事业】
【课题固有号】S2611222
【部门名】中小风险企业部
【研究管理专门机构】中小企业技术信息振兴院
【研究事业名】创业成长-技术开发事业
【研究课题名】自闭症谱系障碍改善功能性食品开发【贡献率】1/1
【主管机构】Astrogen株式会社
【研究期间】2018.06.29～2019.06.28。
Claims (6)
1.一种用于预防或治疗中枢神经系统疾病的药学组合物，其中，所述药学组合物包含以下化学式（Ⅰ）的化合物或其药学上可接受的盐作为有效成分，
（Ⅰ）。
2.根据权利要求1所述的药学组合物，其特征在于，所述中枢神经系统疾病选自由认知障碍、智力障碍、小脑症、癫痫、神经发育障碍、痴呆、自闭症谱系障碍、唐氏综合征、雷特综合征、脆性X综合征、阿尔茨海默病、帕金森病、亨廷顿病及肌萎缩侧索硬化症组成的组中。
3.一种饲料添加用组合物，其特征在于，包含以下化学式（Ⅰ）的化合物或其药学上可接受的盐作为有效成分：
（Ⅰ）。
4.一种神经细胞凋亡抑制用试剂组合物，其特征在于，包含以下化学式（Ⅰ）的化合物或其药学上可接受的盐：
（Ⅰ）。
5.组合物的用于制造用于预防或治疗中枢神经系统疾病的药物的用途，其中所述组合物包含以下化学式（I）的化合物或其药学上可接受的盐作为有效成分，
（Ⅰ）。
6.根据权利要求5所述的用途，其中，所述中枢神经系统疾病选自由认知障碍、智力障碍、小脑症、癫痫、神经发育障碍、痴呆、自闭症谱系障碍、唐氏综合征、雷特综合征、脆性X综合征、阿尔茨海默病、帕金森病、亨廷顿病及肌萎缩侧索硬化症组成的组中。
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