CN1342082A - 替安乃亭在制取治疗神经变性病变的药物中的应用 - Google Patents
替安乃亭在制取治疗神经变性病变的药物中的应用 Download PDFInfo
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Abstract
本发明涉及替安乃亭或其对映异构体在制取用作于治疗神经变性病变的药物中的用途。
Description
本发明涉及替安乃亭、其异构体和其盐在制取治疗神经变性病变的药物中的应用。
式(I)的化合物替安乃亭(Tianeptine)：
作为治疗精神性神经失调、疼痛和咳嗽的新药在法国专利说明书FR2 104 728中进行了描述。
此外，法国专利说明书FR2 635 461中描述了替安乃亭和其化合物用于治疗紧张。
近期的研究显示替安乃亭对于记忆有显著的作用。这些在以下文献中有描述：
-S.E.FILE等人：药物开发研究(Drug Development Research)，1991，23.47-56；
-R.Jaffard等人：精神病生物学和治疗学月报1989.3.特刊(Journal dePsychiatrie Biologique et Thérapeutique)，1989，March special edition；37-39；
-R.Jaffard等人：第十六届CINP会议文摘(Abstracts of the XVIIth.CINPConggress)，慕尼黑(德国)15-19，1988年8月；精神药理学增刊(Psychopharmacology)，1988，96(suppl)，31 02.32，275页；
-R.Jaffard等人：行为药理学(Behavioural Pharmacology)，1991，2，37-46；
-C.Lebrun等人：欧洲精神病学增刊2(European Psychiatry)，1993，8(suppl.2)81s-88s；
-R.Jaffard等人：医学快报(Press Médicale)，1991，20，37，1812-1816。
最后，法国专利FR2 716 723描述了在制取用于记忆-认知失调的药物中使用替安乃亭(+)异构体。
本申请人已经令人惊异地发现，替安乃亭是AMPA/红藻氨酸(AMPA/kainatetype)型的谷氨酸盐受体的调节剂因而可以用于治疗神经变性的病变。
L-谷氨酸和L-天门冬氨酸能够激活中枢神经系统的神经元，很多研究表明，这些兴奋氨基酸(EAAs)满足神经递质的限定标准；由于这个原因，与这些EAAs相关的神经过程的调节作用似乎就是一个治疗神经病的有希望的目标。
实际上，已经证实EAAs的过量释放及其受体的过度刺激是在癫痫症、老年性痴呆或脑血管突发急病中观察到的神经变性的原因之一。当前，与EAAs紧密相关的神经变性的疾病的数量持续不断地增长(亨廷顿氏舞蹈病、精神分裂症、肌萎缩性侧索硬化)(Mc GEER E.G.等人，自然(Nature)，263，517-519，1976；SIMON R等人，科学(Science)，226，850-852，1984)。
此外，尽管EAA神经递质的过度激活确实产生神经中毒的作用，但其正常的激活作用却便于记忆和认知的施行(LYNCH G.& BAUDRY M.，科学(Science)，224，1057-1063，1984；ROTHMAN S.M.& OLNEY J.W.，神经科学的动向(Trendsin Neuro Sci)，10 299-302，1987)。因此，从药理学和治疗学的观点来看，只消除病理刺激而同时保持生理激活水平是合适的。
具有后-和前-突触位置的EAA受体按照具体配体的亲和性和电生理学和/或神经化学作用被分类为4组：
·NMDA(N-甲基-右型-天门冬氨酸盐)受体，它与可透过一和二-价阳离子(包括钙)但被镁阻断的一个离子通道相关。钙和锌在细胞中的积累可能是神经元死亡的一个原因。NMDA通道的开启通过与该受体相关的几个位置(site)来调节，而尤其便于被甘氨酸调节，这种作用是士的宁不敏感的。甘氨酸的位置代表NMDA受体调节激活作用的一个重要目标。
·AMPA(α-氨基-3-羟基-5-甲基-4-异噁唑-丙酸)受体，它与可透过一价阳离子(包括钠)的一个离子通道相关。这个通道的激活会导致膜的去极化作用。
·红藻氨酸受体，其离子特征与AMPA受体相似但导电性和脱敏的水平不同。然而很多研究趋于认同AMPA受体和红藻氨酸受体具有接近的结构和官能相似性并且构成单一的受体族。(KEINANEN K.等人，科学(Science)，249，556-560，1990)。
·ACPD(反式-1-氨基环戊烷-1，3-二羧酸)受体，它被称为代谢(metabotropic)受体因为它不与离子通道偶合。
EAAs的离子化(ionotropic)受体的激活开启离子通道尤其允许钠进入，后者将细胞去极化。这个第一阶段，涉及AMPA受体，导致抑制解除，然后是NMDA受体的过度激活和钙的大量积累(BLAKE J.F等人，神经科学通讯(Neurosci.Letters)，89，182-186，1988；BASHIR Z.I.等人，自然(Nature)，349，156-158，1991)。
尤其是显示出，替安乃亭以一种新的方式调节AMPA/红藻氨酸型的谷氨酸能(glutamatergic)受体并因此而能够用于治疗神经变性病变。
更具体地说，本发明涉及替安乃亭、其对映异构体和其可药用的盐在制取治疗神经变性病变(neuodegenerative pathologies)，例如脑局部缺血、脑外伤病、脑老化、阿耳茨海默氏病、多发硬化症、肌萎缩性侧索硬化、脱髓鞘性病变、脑病、慢性疲劳综合征、肌痛性脑脊髓炎、后-病毒疲劳综合症(post-viralfatigue syndrome)、伴随细菌或病毒感染的疲劳和抑郁状态，和AIDS的痴呆综合症的药物组合物中的应用。
可以呈现或不呈现可药用盐的形式的替安乃亭和其对映异构体应该以适于通过口服、非肠道、经皮肤或透过皮肤、鼻、直肠、经舌、眼睛或呼吸道给药的药物剂型存在，尤其是可注射制剂、气雾剂、眼或鼻滴剂、舌下含片、glossette、软明胶胶囊、硬明胶胶囊、糖锭、栓剂、乳膏、油膏、皮肤凝胶等，这些形式允许活性成分立即释放或延迟释放和受控释放。
剂量依病人的年龄和体重、给药途径、治疗医嘱和相关的治疗而变化，范围为每剂或每次12.5mg-300mg。
作为可以将替安乃亭和其对映异构体转化为盐的碱。可使用但不限于氢氧化钠、氢氧化钾、氢氧化钙或氢氧化铝、碱金属或碱土金属碳酸盐，或有机碱如三乙胺、苄胺、二乙醇胺、叔丁胺、二环已胺、精氨酸等。
作为可以将替安乃亭和其对映异构体转化为盐的酸，可以使用但不限于盐酸、硫酸、磷酸、酒石酸、苹果酸、马来酸、富马酸、草酸、甲磺酸、乙磺酸、樟脑酸、柠檬酸等。
替安乃亭优选的盐是钠盐。
A-替安乃亭对AMPA/红藻氨酸受体的作用
该试验显示浓度为4、10和25μM的替安乃亭影响原始培养的端脑细胞中红藻氨酸(kainate)(250μM)诱导的电流。
试验方案
将16.5天龄的Wistar大鼠胚胎的端脑细胞培养12天。膜片钳试验(patchclamp experiments)在以下的介质中于环境温度下进行：5mM KCl、140mM NaCl、10mM Hepes、2mM MgCl2、2mM CaCl2和10mM D-葡萄糖(pH＝7.3)，微型吸移管吸入140mM KCl、4mM NaCl、10mM Hepes、5mM EGTA和0.5mM CaCl2(pH＝7.2)。替安乃亭(呈现钠盐的形式)以4、10和25mM的浓度试验。
结果
在这个实验中，端脑细胞的培养物中的红藻氨酸(AMPA/红藻氨酸型的谷氨酸能受体的激动剂)，增大进入细胞的电流。这个作用通过膜片钳技术测量。在这些条件下替安乃亭(10μM)本身没有作用；因此它不是直接的激动剂。不过替安乃亭(4、10和25μM)却增大由红藻氨酸(250μM)诱导的电流，如上图所示。
因此替安乃亭是AMPA/红藻氨酸受体的调节剂。
B-替安乃亭于体外在预示神经毒性的两种模型中对神经毒性的影响
这些试验显示替安乃亭在神经毒性模型中的作用，这些模型预示在局部缺血、脑创伤病和神经变性中活性成分的神经保护作用。谷氨酸盐神经毒性在许多病态中所遇到的神经元损失发病中起主要作用(Choi，D.W.神经科学的动向(Trends Neurosci)，11，465，1988)。
B-1替安乃亭对于因低氧症引起的神经毒性的作用
试验方案
从Sprague-Dawley大鼠的胚胎中提取皮层细胞并在含有5％马血清和5％胎牛血清的MEM(最低必要培养基)中培养。培养保持在37℃温度和93％空气和7％二氧化碳气氛下。就在缺氧症之前，将培养基用HEPES(HCSS)缓冲的300μl生理盐水溶液替换。细胞在这些条件和环境温度下培养10分钟。替安乃亭(呈钠盐形式)和MK-801以不同的浓度加入并将细胞培养10分钟。然后用300μlpH7.4的去氧PIPES缓冲液替换培养基。
然后将细胞在37℃和含95％氮气和5％氧气的缺氧气氛下培养3小时。培养基然后用200μ1没有血清的MEM替换并将细胞在标准条件下于37℃再培育24小时。在细胞的形态检验之后，收集培养基上层清液并测量其中的乳酸脱氢酶(LDH)活性。
结果
如下图所示，替安乃亭在1、10和100μM浓度下显著地降低了因缺氧引起的神经中毒。活性的减少分别为98.8、91.7和91.4％。在这些条件下，用作参照的神经保护剂的MK-801(20μM)，产生大约几乎完全(86.3％)的抗缺氧保护作用。
结论
微摩尔浓度的替安乃亭完全保护了在培养基中的皮层神经元不受缺氧引起的细胞损害。在这些条件下，其作用与参照的NMDA受体拮抗药MK-801的相同。
B-2替安乃亭时于因谷氨酸盐引起的神经毒性的作用
试验方案
从Sprague-Dawley大鼠的胚胎中提取皮层细胞在含有5％马血清和5％胎牛血清的MEM(最低必要培养基)中培养。培养保持在37℃和93％空气和7％二氧化碳气氛下。就在用谷氨酸盐(glutamate)处理之前，将培养基用HEPES缓冲的300μl生理盐水溶液替换。细胞与1mM谷氨酸盐一起培养15分钟。培养基然后用200μl没有血清的MEM替换并将细胞在37℃培育24小时。在细胞的形态检验之后，收集培养基上层清液并测量其中的乳酸脱氢酶(LDH)活性。
结果
如下图所示，替安乃亭在1、10和100nM和1、10和100μM浓度下显著地降低了谷氨酸盐引起的毒性。活性的减少在59和94％之间。在这些条件下，用作参照的神经保护剂MK-801(20μM)，产生大约完全的抗缺氧保护作用。
结论
纳摩尔浓度的替安乃亭能够保护在培养基中的皮层神经元抵抗由谷氨酸盐引起的变性作用。这些结果表明替安乃亭可以直接作用于神经元以减少它们因退化病理引起的损害的易损性。
C-替安乃亭对于在培养物中保存的星形细胞中与缺氧相关的三磷酸腺苷(ATP)的水平的作用
试验方案
按照Booher J.和Sensenbrenner M描述的技术(神经生物学(Neurobiology)2，97-105，1992)，用新生大鼠制取星形细胞的培养物。在被放置于培养物中三周后使用它们。在加入已经除氧并含有各种浓度的替安乃亭培养基(DMEM)之后，在厌氧室中造成缺氧24小时。APT的浓度通过冷光测来定并表达为每mg细胞蛋白中APT的皮摩尔数。试验一式三份地进行。
结果
替安乃亭(0.1-1-10μM)以剂量-依赖的方式保护在培养物中的星形细胞。保护作用的百分比在10μM的剂量时达到最大且为68％。
结论
微摩尔浓度的替安乃亭能够保护在培养物中的星形细胞对抗由缺氧引起变性的作用。
D-替安乃亭对于失去生长因子的运动神经元死亡的作用
试验方案
将胚胎寿命14天的孕期Sprague-Dawley大鼠杀死。胚胎的运动神经元按照C.E.Henderson(在“神经细胞培养”中的“纯化的胚胎运动神经元”：一种实用的方法(Purified embryonic mtoneurons”in“Nerve cell culture：apractical approach”)，J.Cohen和G.Wilkn，Eds，1995，p69-81)和V.Aree(神经科学研究期刊(J.Neurosci.Res)，1999，55，p.119-126)等人公布的方法来纯化。
神经细胞元以为每16-mm孔眼约1000个细胞的密度接种，并且在补充了B27和马血清的神经基(Neurobasal)中培养。当运动神经元附着后，细胞自身，与脑衍生的神经营养因子(BDNF)，1ng/ml或与替安乃亭一起，在37.2℃培养两天半。直接计数存活的运动神经元。
结果
生长因子对运动神经元是至关重要的因为缺少BDNF细胞即死亡。BDNF保护运动神经元不死亡。依照浓度-依赖的方式，替安乃亭防止运动神经元死亡(如下图所示)。培养2.5天后，运动神经元在各4个孔中的2个区域中的计数，给出了每区的绝对值(均值±s.e.m.，n＝8)
结论
Duong等人(英国药物期刊(Br.J.Pharmaco1.)，128，1385-1392)使用类似的模型显示，一种以其神经保护作用著称的产品，SR57746A，是有效力的。作者肯定地说“SR57746A是已知体外对存活运动神经元有活性的唯一的合成化合物，因而是肌萎缩性侧索硬化症良好的候选化合物”。
在这个实验中我们显示替安乃亭具有完全出人意外的神经保护作用，表明替安乃亭在肌萎缩性侧索硬化的治疗中同样是一种潜在的有用化合物。
E-替安乃亭体内对于牵连于氧化应力(oxidative stress)的基因表达的作用
通过逆转录(reverse transcription)然后进行链式聚合反应扩增(RT-PCR)的差示分析的近代分子生物学技术，已经能够研究用替安乃亭在中枢水平上(central level)遗传调控大鼠扁桃体而以慢性基础的(chronic basis)的体内治疗作用。
设备和方法
两组大鼠(n＝6)用替安乃亭钠盐(15mg/kg；i.p.)或生理血清处理21天。将大鼠杀死并除去脑之后，提取扁桃体区的全部RNA然后进行RT-PCR试验。简言之，对提取的RNA进行逆转录，然后将转录的产物用链式聚合反应(PCR)扩增进行高分辨(high-resolution)聚丙烯酰胺凝胶电泳。从凝胶中取出有关的区带、再扩增、并测序和分析。
结果
这些结果表明，替安乃亭的主要目标是线粒体基因组，它由16000碱基的成环的DNA分子构成。编码呼吸链的酶复合体的13个亚单位(sub-unit)以及全系列核糖体RNA和转移RNA。事实上，以慢性基础施用替安乃亭，引起NADH泛醌还原酶的线粒体基因(亚单位2和5)以及16SrRNA、1eu-tRNA和val-tRNA编码基因的过度表达。
NADH泛醌还原酶是粒线体呼吸链中三种酶能转移络合物中的第一种并且代表穿过这个链的主电子流的进入点。此外，线粒体DNA的突变与总名称为线粒体脑肌病的某些神经变性疾病相关(K.Chandrasekaran等人，分子脑研究(Mol.Brain Res)，1994.24：336-340；S.J.Kish等人，神经化学期刊(J.Neurochem)，1992，59：776-779；E.M.Mutisaya等人，神经化学期刊(J.Neurochem)，1994，63：2179-2184。
此外，使用成纤维细胞的培养还显示，紧张引起NADH的亚单位4、细胞色素b和rRNA的亚单位165S的基因的转录水平下调(D.R.Crawford等人，自由基生物医学(Free Radic Bio1.Med.)，1997，22(3)：551-559)。
结论
通过在慢性基础上给予替安乃亭引起的扁桃体线粒体基因的过度表达，表明这种化合物增加了细胞呼吸和中枢(central)氧化新陈代谢的水平。这样一种中枢作用意味着替安乃亭的体内神经保护活性。
Claims (6)
1.替安乃亭或其对映异构体，可以呈现或不呈现与可药用酸或碱的加成的盐的形式，在制取用作治疗神经变性的病变中的AMPA/红藻氨酸型谷氨酸盐受体调节剂的药物的用途。
2.根据权利要求1的应用，其特征在于，这些药物用于治疗脑局部出血、脑外伤病、脑老化、阿耳茨海默氏病、多发硬化症、肌萎缩性侧索硬化、脱髓鞘性病变、脑病、慢性疲劳综合征、肌痛性脑脊髓炎、后-病毒疲劳综合症、伴随细菌或病毒感染的疲劳和抑郁状态，和AIDS的痴呆综合症。
3.根据权利要求2的应用，其特征在于，这种药物用于治疗肌萎缩性侧索硬化症。
4.根据权利要求1、2或3中任一权利要求的应用，其特征在于，替安乃亭呈现纳盐的形式。
5.根据权利要求1、2、3或4中任一权利要求的应用的药物组合物，含有作为活性成分的替安乃亭或其对映异构体，可以呈现或不呈现与可药用的酸或碱的加成盐的形式，以及一种或多种可药用赋形剂。
6.根据权利要求5的药物组合物，其特征在于，活性成分是呈钠盐形式的替安乃亭。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9904313A FR2791891A1 (fr) | 1999-04-07 | 1999-04-07 | Utilisation de la tianeptine pour l'obtention de medicaments destines au traitement des pathologies de la neurodegenerescence |
| FR99/04313 | 1999-04-07 |
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| CN1342082A true CN1342082A (zh) | 2002-03-27 |
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| CN00804470A Pending CN1342082A (zh) | 1999-04-07 | 2000-04-06 | 替安乃亭在制取治疗神经变性病变的药物中的应用 |
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| US (1) | US6599896B1 (zh) |
| EP (1) | EP1165089A1 (zh) |
| JP (1) | JP2002541110A (zh) |
| KR (1) | KR20010102463A (zh) |
| CN (1) | CN1342082A (zh) |
| AU (1) | AU3824800A (zh) |
| BR (1) | BR0008703A (zh) |
| CA (1) | CA2361988A1 (zh) |
| EA (1) | EA200100802A1 (zh) |
| FR (1) | FR2791891A1 (zh) |
| HK (1) | HK1042053A1 (zh) |
| HU (1) | HUP0200145A3 (zh) |
| NO (1) | NO20014081D0 (zh) |
| NZ (1) | NZ513565A (zh) |
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| US20030045449A1 (en) * | 2001-08-15 | 2003-03-06 | Pfizer, Inc. | Pharmaceutical combinations for the treatment of neurodegenerative diseases |
| EP1755614A4 (en) * | 2004-04-08 | 2009-06-10 | Vela Pharmaceuticals Inc | COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROPATHIC PAIN, FIBROMYALGIA AND CHRONIC FATIGUE SYNDROME |
| EP1752143A1 (en) * | 2005-08-08 | 2007-02-14 | NewThera | Novel uses for drugs targeting glutamine synthetase |
| US9314469B2 (en) * | 2008-05-05 | 2016-04-19 | Tonix Pharma Holdings Limited | Method for treating neurocognitive dysfunction |
| JO2844B1 (en) * | 2008-10-31 | 2014-09-15 | ترانسفورم فارماسيتيكالز، انك. | Forms of Tyapentin sulfate salt and methods of its manufacture and use |
| US8198268B2 (en) | 2008-10-31 | 2012-06-12 | Janssen Biotech, Inc. | Tianeptine sulfate salt forms and methods of making and using the same |
| KR20120092993A (ko) * | 2011-02-14 | 2012-08-22 | 지엘팜텍 주식회사 | 티아넵틴 또는 이의 약제학적으로 허용되는 염을 포함하는 경구투여용 서방성 정제 |
| KR101136976B1 (ko) * | 2011-09-06 | 2012-05-30 | 건일제약 주식회사 | 티아넵틴 또는 그의 염을 포함하는 탈모증의 예방 또는 치료용 약학 조성물 |
| BR112019013244A2 (pt) | 2016-12-28 | 2019-12-24 | Tonix Pharma Holdings Ltd | sais e polimorfos de oxalato de tianeptina |
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| FR2635461B1 (fr) * | 1988-08-18 | 1992-01-17 | Adir | Utilisation de derives tricycliques pour l'obtention de medicaments destines au traitement du stress |
| FR2716623B1 (fr) * | 1994-02-25 | 1996-08-23 | Adir | Utilisation d'un dérivé tricyclique pour l'obtention de médicaments destinés au traitement des troubles mnémo-cognitifs. |
| FR2747921B1 (fr) * | 1996-04-24 | 1998-10-30 | Adir | Comprime matriciel permettant la liberation prolongee du sel de sodium de tianeptine apres administration par voie orale |
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1999
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- 2000-04-06 EP EP00917135A patent/EP1165089A1/fr not_active Withdrawn
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| Publication number | Publication date |
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| NO20014081L (no) | 2001-08-22 |
| ZA200106690B (en) | 2002-11-14 |
| KR20010102463A (ko) | 2001-11-15 |
| AU3824800A (en) | 2000-10-23 |
| BR0008703A (pt) | 2002-02-13 |
| JP2002541110A (ja) | 2002-12-03 |
| PL356739A1 (en) | 2004-06-28 |
| HUP0200145A2 (hu) | 2002-05-29 |
| HUP0200145A3 (en) | 2004-07-28 |
| WO2000059511A1 (fr) | 2000-10-12 |
| NO20014081D0 (no) | 2001-08-22 |
| HK1042053A1 (zh) | 2002-08-02 |
| EP1165089A1 (fr) | 2002-01-02 |
| NZ513565A (en) | 2004-04-30 |
| CA2361988A1 (fr) | 2000-10-12 |
| FR2791891A1 (fr) | 2000-10-13 |
| EA200100802A1 (ru) | 2002-04-25 |
| US6599896B1 (en) | 2003-07-29 |
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