CN111201219A - 用于治疗癫痫的吡哆醇衍生物 - Google Patents
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Abstract
本发明涉及有机杂环化合物化学，即基于吡哆醇的新化合物式1：
要求保护的化合物表现出高水平的抗癫痫活性。在25、50和100mg/kg的剂量下，化合物1在对使用青霉素癫痫模型的大鼠腹膜内施用后一小时内完全抑制大脑的癫痫电活动。大鼠的可拉佐癫痫模型显示，腹膜内施用25和100mg/kg的剂量以及口服100和200mg/kg的剂量的化合物1时，癫痫发作的强度降低且持续时间减少，并且在口服施用剂量为250mg/kg的某些情况下完全预防了癫痫发作。在这种情况下，化合物1是低毒性的，因为大鼠的LD50参数在腹膜内和口服施用时分别超过2000和5000mg/kg体重。通常，要求保护的技术解决方案允许创建一种用于治疗癫痫的新型高效和安全的药物，这可能会显著改善患者的质量和预期寿命。
Description
本发明涉及生理些活性物质-吡哆醇衍生物，即式1的化合物，其具有抗癫痫活性。
癫痫是世界上最常见的神经系统慢性疾病之一，其影响儿童和成人。根据WHO的数据，约有五千万人患有癫痫，或约占世界人口的0.5-1％。每年全世界诊断出约250万新病例。30％的癫痫患者对药物有抗药性。
从所研究的现有技术中，申请人尚未鉴定出一种技术方案，其在化学结构方面类似于要求保护的技术方案。
从所研究的现有技术中，申请人确定了已知的技术方案，该技术方案根据预期的目的为要求保护的技术方案的类似物，即抗癫痫药。
根据现代国际惯例，将所有当前可利用的抗癫痫药(AED)分为：
-老的(苯巴比妥和diphenine)；
-中间的(琥珀酰亚胺和苯二氮杂卓)；
-基础的(丙戊酸盐和卡马西平)；
-新的(拉莫三嗪，托吡酯，奥卡西平，左乙拉西坦，替加宾，加巴喷丁(gabapentinum)，非尔氨酯(felbamate)，普瑞巴林(pregabalinum)，唑尼沙胺)。
在上述药物中，丙戊酸制剂(丙戊酸盐)和卡马西平类药物目前最常使用，并且被视为“首选”药物(基础药物)。
药物德巴金(Depakine)(Sanofi-Aventis,France)是已知的。活性物质：丙戊酸。使用适应症：全身性癫痫发作-阵挛性(clonic)、强直性(tonic)、强直性-阵挛性(tonic-clonic)、失神性(absences)、肌阵挛性(myoclonic)、失语性(atonic)；Lennox-Gastaut综合征；伴或不伴继发性全身发作的部分癫痫发作(单一疗法或与其他抗癫痫药联用)。允许用于儿科。
已知药物的缺陷在于具有以下副作用：嗜睡，胃肠道紊乱，肝毒性，胰腺毒性，恶心，体重增加。[Stevens G.M.Pharmacology/G.M.Stevens,C.W.Brenner-Philadelphia:Elsevier/Saunders,2013.-519c.(https://books.google.ru/books？id＝Cd39SN6OBiMC& pg＝PA204&redir_esc＝y#v＝onepage&q&f＝false)]。口服施用(丙戊酸钠)对小鼠的急性毒性LD50：977mg/kg，腹膜内施用LD50 470mg/kg(http://datasheets.scbt.com/sc- 202378.pdf)。
药物Finlepsin(AWD.pharma,Germany)是已知的。活性物质：卡马西平。使用适应症：癫痫病-具有基本症状的部分癫痫发作(局灶性癫痫发作)，具有复杂症状的部分癫痫发作，精神运动性癫痫发作，主要为病源性的大惊厥性癫痫病(grands convulsive mals ofmainly focal origin)(睡眠中的大发作(grands mals during sleep)，弥漫性大发作(diffuse grands mals))，混合性癫痫；三叉神经痛；舌咽神经特发性神经痛；糖尿病多发性神经病的疼痛；多发性硬化症的癫痫样抽搐，三叉神经痛的面部痉挛，强直性抽搐，阵发性构音障碍和共济失调，阵发性感觉异常和疼痛发作；戒酒综合症(焦虑，惊厥，过度兴奋，睡眠障碍)；精神障碍(情感障碍和情感分裂性障碍，精神病，边缘系统功能障碍)。允许它用于儿科。
已知药物的缺陷在于具有以下副作用：嗜睡，昏睡和中枢神经系统抑郁的其他迹象，共济失调，恶心，很少出现再生障碍性贫血。[Stevens G.M.Pharmacology/G.M.Stevens,C.W.Brenner-Philadelphia:Elsevier/Saunders,2013.-519c.(https:// books.google.ru/books？id＝Cd39SN6OBiMC&pg＝PA204&redir_esc＝y#v＝onepage&q&f ＝false)]。口服施用对小鼠(卡马西平)的急性毒性LD50：529mg/kg，而腹膜内施用LD50:114mg/kg(http://datasheets.scbt.com/sc-202518.pdf)。
药物苯巴比妥(JSC Dalhimpharm,Russia)是已知的。活性物质：苯巴比妥。使用适应症：癫痫-全身性强直-阵挛性癫痫发作，成人和儿童的局部性癫痫发作；舞蹈症；痉挛性麻痹；各种惊厥反应；作为小剂量的镇静剂与其他药物(解痉药，血管扩张剂)联合用于神经营养性疾病；作为安眠药。允许它用于儿科。
已知药物的缺陷在于以下副作用：共济失调，智力下降，嗜睡，头晕，成瘾发生，皮疹，呼吸抑制。[Stevens G.M.Pharmacology/G.M.Stevens,C.W.Brenner-Philadelphia:Elsevier/Saunders,2013.-519c.(https://books.google.ru/books？id＝Cd39SN6OBiMC& pg＝PA204&redir_esc＝y#v＝onepage&q&f＝false)].对大鼠口服施用(苯巴比妥)的急性毒性LD50:163mg/kg(http://www.sciencelab.com/msds.php？msdsId＝9926461)。
药物Diphenine(Usolye-Siberian CPP，俄罗斯)是已知的。活性物质：苯妥英钠。使用适应症：癫痫病(大发作(grands mals))；患有强直-阵挛性癫痫的癫痫状态；神经外科中的癫痫发作(预防和治疗)；心律失常(包括糖苷中毒或与中毒相关的三环类抗抑郁药)；三叉神经痛(作为二线药物或与卡马西平联用)。允许它用于儿科。
已知药物的缺点是以下副作用：消化系统障碍，牙龈增生，巨幼红细胞性贫血和其他红细胞缺乏症表现，骨软化症，精神病表现。[Stevens G.M.Pharmacology/G.M.Stevens,C.W.Brenner-Philadelphia:Elsevier/Saunders,2013.-519c.(https:// books.google.ru/books？id＝Cd39SN6OBiMC&pg＝PA204&redir_esc＝y#v＝onepage&q&f ＝false)]。口服施用对小鼠(苯妥英钠)的急性毒性LD50:165mg/kg(http:// www.pfizer.com/system/files/products/material_safety_data/PHENYTOIN％ 20SODIUM％20SOLN.pdf)。
药物Suxilep(Delpharm Lille S.a.S.,France)是已知的。活性物质：乙琥胺。使用适应症：嗜睡性失神发作(seizures of pycnoleptic absences)；复杂和非典型的惊厥发作；肌阵挛性-静止性小发作(myoclonic-astatic petits mals)；幼年性肌阵挛性癫痫发作(冲动性小发作(impulsive petits mals)。不建议用于6岁以下的儿童。
已知药物的缺陷在于以下副作用：嗜睡，头晕，消化系统障碍，昏睡和恶心。[Stevens G.M.Pharmacology/G.M.Stevens,C.W.Brenner-Philadelphia:Elsevier/Saunders,2013.-519c.(https://books.google.ru/books？id＝Cd39SN6OBiMC&pg＝PA204&redir_esc＝y#v＝onepage&q&f＝false)].对小鼠口服施用(乙琥胺)的急性毒性LD50:1530mg/kg(http://www.pfizer.com/files/products/material_safety_data/ ETHOSUXIMIDE％20CAPSULES.pdf)。
药物Lamitor(Torrent Pharmaceuticals,India)是已知的。活性物质：拉莫三嗪。使用适应症：癫痫病-部分和全身性癫痫发作，包括强直性阵挛性癫痫发作，以及作为联合疗法或单一疗法组成部分的具有Lennox-Gastaut综合征的癫痫发作。允许用于儿科。
已知药物的缺陷在于以下副作用：共济失调，复视，头晕，嗜睡，头痛，恶心，皮疹，Stevens-Johnson综合症。[Stevens G.M.Pharmacology/G.M.Stevens,C.W.Brenner-Philadelphia:Elsevier/Saunders,2013.-519c.(https://books.google.ru/books？id＝Cd39SN6OBiMC&pg＝PA204&redir_esc＝y#v＝onepage&q&f＝false)].对小鼠口服施用(拉莫三嗪)的急性毒性LD50:269mg/kg(http://www.msds-gsk.com/GetSdsFile.ashx？fileId ＝5508)。
药物托吡酯(Topiramate)(ALSI Pharma,Russia)是众所周知的。活性物质：托吡酯。使用的适应症：在部分(有或没有继发性全身发作(secondary generalization))或原发性全身性强直-阵挛性癫痫发作的成人和6岁以上儿童中的单一疗法；在部分具有或没有继发性全身发作或全身性强直-阵挛性癫痫发作的成人和3岁以上儿童中的联合疗法，以及因Lennox-Gastaut综合征引起的癫痫发作的治疗；成人偏头痛发作的预防。
已知药物的缺陷碍于以下副作用：共济失调，头昏，嗜睡，眼球震颤，感觉异常，精神运动障碍。[Stevens G.M.Pharmacology/G.M.Stevens,C.W.Brenner-Philadelphia:Elsevier/Saunders,2013.-519c.(https://books.google.ru/books？id＝Cd39SN6OBiMC&pg＝PA204&redir_esc＝y#v＝onepage&q&f＝false)].对大鼠口服施用(托吡酯)的急性毒性LD50:3570mg/kg(https://fagron.com/sites/default/files/document/msds_coa/ 97240-79-4_(USA).pdf)。
药物Levetinol(Actavis hf.,Iceland)是已知的。活性物质：左乙拉西坦。使用适应症：新诊断为癫痫的16岁以上患者中有或没有继发性全身发作的部分惊厥；12岁以上的青少年肌阵挛性癫痫患者中的肌阵挛性抽搐；12岁以上的具有特发性全身性癫痫的患者中的原发性全身性强直-阵挛性惊厥。
已知药物的缺陷碍于以下副作用：嗜睡，虚弱和头晕。[StevensG.M.Pharmacology/G.M.Stevens,C.W.Brenner-Philadelphia:Elsevier/Saunders,2013.-519c.(https://books.google.ru/books？id＝Cd39SN6OBiMC&pg＝ PA204&redir_esc＝y#v＝onepage&q&f＝false)]。对小鼠口服施用(左乙拉西坦)的急性毒性LD50:>5000mg/kg(http://www.akorn.com/documents/catalog/msds/50383-241- 16.pdf)，而静脉内注射LD50:1081mg/kg(https://www.caymanchem.com/msdss/ 9001820m.pdf)。
药物Tebantin(Gedeon Richter,Hungary)是已知的。活性物质：加巴喷丁。使用适应症：作为单一疗法或辅助疗法在有或没有继发性全身发作的成人和12岁以上儿童中的部分惊厥；作为附加疗法在有或没有继发性全身发作的3-12岁的儿童中的部分惊厥；18岁以上患者的神经性疼痛。
已知药物的缺陷碍于以下副作用：共济失调，嗜睡，头晕，眼球震颤和四肢发抖。[Stevens G.M.Pharmacology/G.M.Stevens,C.W.Brenner-Philadelphia:Elsevier/Saunders,2013.-519c.(https://books.google.ru/books？id＝Cd39SN6OBiMC&pg＝ PA204&redir_esc＝y#v＝onepage&q&f＝false)]。对小鼠口服施用(加巴喷丁)的急性毒性LD50:>5000mg/kg；而静脉内注射LD50:1000-2000mg/kg(http://www.pfizer.com/system/ files/products/material_safety_data/PZ01158.pdf)。
药品Lyric(Pfizer Manufacturing Deutschland,Germany)是已知的。活性物质：普瑞巴林。使用适应症：成人神经性疼痛；癫痫病(作为成人部分惊厥发作的辅助疗法，无论是否伴有继发性全身发作)；成人广泛性焦虑症；成人纤维肌痛。它不用于儿科。
已知药物的缺陷碍于以下副作用：嗜睡，视觉障碍，体重增加，动作协调受损。[Stevens G.M.Pharmacology/G.M.Stevens,C.W.Brenner-Philadelphia:Elsevier/Saunders,2013.-519c.(https://books.google.ru/books？id＝Cd39SN6OBiMC&pg＝PA204&redir_esc＝y#v＝onepage&q&f＝false)].对大鼠口服施用(加巴喷丁)的急性毒性LD50:>5000mg/kg；而静脉内注射LD50:>300mg/kg(http://www.pfizer.com/system/files/ products/material_safety_data/PZ01158.pdf)。
药物Zonegran(Eisai Co.Ltd.,Japan)是已知的。活性物质：唑尼沙胺。使用适应症：具有部分癫痫发作的患者中的单一疗法，伴或不伴继发性全身发作，首先诊断为癫痫；作为辅助疗法的组成部分，适用于存在部分癫痫发作的成人、青少年和6岁以上儿童，无论是否伴有继发性全身发作。
已知药物的缺陷碍于以下副作用：头痛，头晕，嗜睡，厌食，恶心，在幼年时期-代谢性酸中毒。[Stevens G.M.Pharmacology/G.M.Stevens,C.W.Brenner-Philadelphia:Elsevier/Saunders,2013.-519c.(https://books.google.ru/books？id＝Cd39SN6OBiMC&pg＝PA204&redir_esc＝y#v＝onepage&q&f＝false)].对小鼠口服施用(唑尼沙胺)的急性毒性LD50:1829mg/kg，而腹膜内施用LD50:699mg/kg(http://datasheets.scbt.com/sc- 203316.pdf)。
因此，已知药物的一般缺陷在于：存在明显的副作用、疾病症状对治疗的免疫性以及高昂的治疗费用。当今，迫切需要创建新的、有效且安全的用于治疗癫痫的药物并将其引入临床实践。
要求保护技术方案的目的在于获得一种具有高度抗癫痫活性并且在化学结构上在世界上没有类似物的新化合物。
提出的发明的技术效果在于基于吡哆醇的新型抗癫痫化合物，其具有有效终止癫痫发作的能力。
该技术问题得以解决，并且通过获得具有式1的要求保护的新化合物并具有有效降低大脑的癫痫活动的能力，可以实现特定的技术效果。
要求保护的化合物通过三步合成法从起始的吡哆醇2的6-羟基甲基衍生物按照以下方案获得：
所得化合物的结构通过质谱法、1H和13C NMR光谱法证实。用Bruker AVANCE-400装置记录NMR光谱。化学位移根据氘代溶剂的残留质子信号确定(1H和13C)。熔点温度使用Stanford Research Systems MPA-100OptiMelt确定。通过TLC方法在Sorbfil板上进行反应过程和化合物纯度的控制。使用TripleTOF 5600质谱仪AB Sciex(Germany)进行超高分辨率HPLC/MS实验。
如从现有技术中已知的，青霉素和可拉佐(corazol)在它们进入中枢神经系统时能够引起癫痫发作，它们被视为引起癫痫性癫痫发作的药物。[Mironov A.N.,BunatyanN.D.等人Rukovodstvo po provedeniyu doklinicheskikh issledovaniylekarstvennykh sredstv.[Guidelines for Pre-clinical Drug Research]。
要求保护的技术方案示例在图1和图2中。
图1提供表1，其显示有关化合物1在青霉素大鼠癫痫模型中的抗癫痫特性的数据。
图2提供表2，其显示有关化合物1在可拉佐大鼠癫痫模型中的抗癫痫特性的数据。
要求保护的技术方案通过下列具有特定性能的实施例示例。
实施例1.(5-羟基-3,4-双(羟基甲基)-6-甲基吡啶-2-基)甲磺酸(1)的合成.
按照3步由起始化合物(2)得到化合物1。
步骤1.将部分100.0g(0.418mol)6-(羟基甲基)-3,3,8-三甲基-1,5-二氢-[1,3]二噁庚因并(dioxepino)[5,6-c]吡啶-9-醇(2)混悬于1000ml二氯甲烷[ShtyrlinN.V.Novyy metod sinteza6-metil-2,3,4-tris(gidroksimetil)piridin-5-ola[A newmethod for the synthesis of 6-methyl-2,3,4-tris(hydroxymethyl)pyridin-5-ol]/N.V.Shtyrlin,A.D.Strelnik,L.P.Sysoeva,O.A.Lodochnikova,E.N.Klimovitsky,Y.G.Shtyrlin//Zhurn.org.khimii.[Journal of organic chemistry]2009.-Vol.45,Publ.8.-P.1274-1275.]。在搅拌时，向得到的混悬液中一次加入145.0ml(1.045mol)三乙胺，然后滴加74.2ml(1.045mol)乙酰氯。将该反应混合物在室温搅拌2小时。此后，用500ml水将该溶液洗涤3次。用硫酸镁干燥有机部分，过滤，用旋转蒸发器蒸发，得到132.0g(98％)(9-乙酰氧基-3,3,8-三甲基-1,5-二氢-[1,3]二噁庚因并[5,6-c]吡啶-6-基)甲基乙酸酯(3)。
步骤2.将来自上述步骤的部分(9-乙酰氧基-3,3,8-三甲基-1,5-二氢[1,3]二噁庚因并[5,6-c]吡啶-6-基)甲基乙酸酯(3)(132.0g,0.408mol)溶于700ml甲醇。单独制备127.0g(1.225mol)亚硫酸钠在900ml水中的溶液。一起倾倒得到的溶液，在室温搅拌4小时。然后用盐酸将该混合物中和至pH＝7.0，用旋转蒸发器蒸发。用600ml热正丙醇萃取干馏残余物，过滤。冷却时，从滤液中过滤出沉淀，用50ml冷正丙醇洗涤3次，干燥，得到75.9g(57％)甲磺酸(9-羟基-3,3,8-三甲基-1,5-二氢-[1,3]二噁庚因并[5,6-c]吡啶-6-基)钠(4)。熔点为197℃，伴随分解。NMR光谱1H(400MHz,DMSO-d6),δ,ppm:1.38(s,6H,C(CH3)2)；2.30(s,3H,CH3)；3.82(s,2H,CH2—S)；4.79(s,2H,CH2)；4.90(s,2H,CH2).NMR 13C{1H}(100MHz,DMSO-d6),δ,ppm:19.28；23.73；57.47；59.11；60.97；101.45；132.07；134.18；140.97；143.25；146.78.HRMS-ESI:测定值[М+Н]+326.0669,[М+Na]+348.0488,C12H16NNaO6S,计算值[М+Н]+326.0669,[М+Na]+348.0488。
步骤3.将来自上述步骤的部分甲磺酸(9-羟基-3,3,8-三甲基-1,5-二氢[1,3]二噁庚因并[5,6-c]吡啶-6-基)钠(4)(75.9g 0.233mol)溶于500ml水。用浓盐酸使得到的溶于达到pH＝1。将该反应混合物在室温静置3小时，然后用旋转蒸发器蒸发。用200ml冷盐酸萃取干残余物并且过滤。将700ml异丙醇加入到滤液中。在冷条件下结晶从该混合物中沉淀，过滤，用30ml冷异丙醇洗涤3次，得到期望的产物-60.8g(95％)(5-羟基-3,4-双(羟基甲基)-6-甲基吡啶-2-基)甲磺酸(1)。T.分解为250℃。NMR 1H(400MHz,DMSO-d6),δ,ppm:2.56(s,3H,CH3)；4.27(s,2H,CH2—S)；4.70(s,2H,CH2)；4.90(s,2H,CH2).NMR 13C{1H}(100MHz,DMSO-d6),δ,ppm:14.74；51.57；55.52；56.19；136.44；138.79；141.50；142.95；151.62.HRMS-ESI:测定值[М+Н]+264.0536,C9H13NO6S,计算值[М+Н]+264.0536。
实施例2.化合物1对癫痫发作中脑电活动的影响研究(使用癫痫的青霉素模型作为实例)
实验使用体重为180-250g的雄性Wistar大鼠进行。
在异氟烷麻醉下(1.5％)，进行用于实验的手术准备。在本实验过程中使用氨基甲酸乙酯(Urethane)(1.5mg/kg)进行麻醉。接下来，将动物固定在立体定向装置中。在动物的头骨中的大脑感觉运动皮层的对称区域上钻2×2mm的孔，并在记录电极之间安装一个16-通道基于硅的探头(Neuronexus)，步长为100μm，以便从这些区域转移电活动。将用作组合的接地电极和参比电极的氯化银电极导入小脑或视觉皮层至深度为2-3mm。
为了建立与体感区平行的癫痫活动焦点，在视觉皮层区域钻2×2mm的孔，在其中以40,000IU/ml的浓度施加10μl苄青霉素钠盐溶液。
在青霉素施用后30分钟，在稳定的癫痫样活动存在下，通过腹膜内(ip)施用100mg/kg、50mg/kg、25mg/kg剂量的化合物1。评价癫痫样活动的振幅-频率特征。
作为对比物质，使用丙戊酸钠600mg/kg，在稳定的癫痫样活动存在下将其ip施用。
为了对实验数据进行统计处理，使用统计程序Origin 8.5和IBM SPSSStatistics。
群体间差异的显著性通过Mann-Whitney U检验进行评价。
如实施例2中的申请人的实验结果显示如下。
颅内施用青霉素后2-3分钟，以20-70min-1的频率在脑电图上观察到尖锐的高振幅波(1000-20000μV)出现。在登记的三个小时内观察到由青霉素引起的高振幅放电(HAED)。它们的存在、频率和幅度是脑癫痫活动的特征指标。
30分钟的作用后，青霉素的作用相当于100％，被称为“参比点”，从此开始施用测试化合物(要求保护的化合物和参比药物-丙戊酸钠)。
参比点后5分钟、30分钟和60分钟的HAED特性如图1的表1所示。
从表1的数据可以看出，要求保护的化合物1的导入导致HAED的振幅和频率降低，从而在施用后60分钟完全抑制动物中的HAED。
丙戊酸钠的施用无法完全抑制HAED。
如上所述，我们可以得出结论，剂量为25、50、100mg/kg的要求保护化合物1的抗癫痫作用比对比药物丙戊酸钠要显著得多，因为丙戊酸钠的施用甚至可以在600mg/kg剂量下也不能完全抑制HAED。因此，与丙戊酸钠相比，要求保护化合物的抗癫痫作用更高，不低于6-24倍。
实施例3.化合物1对癫痫发作的影响研究(使用癫痫的可拉佐(corazol)模型作为实例)
实验使用体重为180-250g的雄性Wistar大鼠进行。
在背部的颈部区域皮下施用剂量为80mg/kg的可拉佐。注射可拉佐后，观察动物60min，并登记主要指标-首次全身性阵挛性癫痫发作，且翻转反射消失。
以6-点等级对惊厥性癫痫发作的强度进行研究：
·0-缺乏抽搐活动；
·1-运动亢进；
·2-颤抖，抽搐，过度修饰，刻板动作；
·3-前腿阵挛性抽搐，后腿抬高；
·4-明显的强直-阵挛性抽搐，动物跌倒至一侧，存在强直性扩张期；
·5-反复的强直-阵挛性抽搐，失去姿势；
·6-完全强直性发作伴有呼吸暂停，动物死亡。
为了研究要求保护的化合物1对可拉佐引起的惊厥发展的影响，将化合物1溶于生理盐水中并按以下方式施用：
-在用可拉佐诱发惊厥前30分钟腹膜内(ip)剂量为25mg/kg；100mg/kg；
-在用可拉佐诱发惊厥前1小时胃内(ip)剂量为100mg/kg、200mg/kg、250mg/kg。
惊厥障碍的发生由以下指标评价：
-癫痫发作开始前的时间(min)；
-癫痫发作持续时间(秒)；
-使用6-点等级的癫痫发作强度；
-反复惊厥的动物数量；
-组中死亡动物的数量。
为了对实验数据进行统计处理，使用统计程序Origin 8.5和IBM SPSSStatistics。
群体间差异的显著性通过Mann-Whitney U检验进行评价。
图2中的表2显示了化合物1对可拉佐引起的惊厥发展的影响的研究结果。
正如从表2中的数据可以看出的，如实施例3中的实验结果显示化合物1在大鼠癫痫的可拉佐模型中以口服和静脉内施用方式均具有明显的抗癫痫活性，其以剂量依赖性方式表现为减少癫痫发作的持续时间和强度。
此外，在所有剂量下，化合物1均显著地降低了癫痫发作复发的可能性，也完全防止了死亡。
通过口服施用剂量为250mg/kg的化合物1，可以观察到在施用可拉佐后减少癫痫发作的最佳结果。在100和200mg/kg的浓度下，要求保护的化合物1的作用稍不显著。
实施例4.口服施用对小鼠的急性毒性测定
本研究对CD-1(ICR)品系小鼠(6-8周，体重不低于18g，雌性)进行。使用胃管以两倍于胃内(口服)施用化合物1，其体积不超过0.5ml/30g小鼠体重。
对剥夺食物(不少于8小时的时间期限)、但可自由取水的动物给予。基于给予该物质之前即刻记录的体重，对每只动物分别计算施用体积。施用后一小时，重新获得水和饲料。
为了制备向小鼠施用的5000mg/kg剂量，在Vibra天平(Shinko Denshi,Japan)的聚苯乙烯舟皿(boat)中称重一部分1.5g化合物1，转移到每10ml体积A级精度的容量瓶中，溶于蒸馏水并调节至刻度。由于化合物1的溶解度不足，因此再将10ml蒸馏水添加到所得体积的溶液中。
施用30分钟后，分别对动物进行临床检查，然后每小时至少一次进行4小时，然后每天一次进行14天。在施用制剂前即刻记录体重，以计算施用体积，然后每两天一次。
基于进行的研究，发现化合物1是低毒性的，因为对大鼠口服施用的参数LD50超过5000mg/kg体重。
实施例5.腹膜内施用对小鼠的急性毒性测定
本研究对雄雌两性的CD-1(ICR)品系小鼠(6-8周，体重不低于18g)进行。使用胰岛素注射器以每40g小鼠体重1ml的体积在1000mg/kg和2000mg/kg的剂量腹膜内注射化合物1。基于导入该物质之前即刻记录的体重，对每只动物分别计算施用体积。
为了制备向小鼠施用的2000mg/kg剂量，在Vibra天平(Shinko Denshi,Japan)的聚苯乙烯舟皿(boat)中称重一部分800mg化合物1，并转移到每10ml体积A级精度的容量瓶中，溶于生理盐水，并调整到刻度。用0.22μm注射器喷嘴(Jet Biofil)过滤该溶液。
为了制备向小鼠施用的1000mg/kg剂量，在Vibra天平(Shinko Denshi,Japan)的聚苯乙烯舟皿中称重一部分400mg化合物1，并转移到每10ml体积A级精度的容量瓶中，溶于生理盐水，并调整到刻度。用0.22μm注射器喷嘴(Jet Biofil)过滤该溶液。
施用30分钟后，分别对动物进行临床检查，然后每小时至少一次进行4小时，然后每天一次进行14天。在制剂施用前即刻记录体重，以计算施用体积，然后每两天一次。
基于进行的研究，发现化合物1是低毒性的，因为用于大鼠腹膜内施用的参数LD50超过2000mg/kg体重。
因此，从以上可以得出结论，要求保护的化合物表现出高水平的抗癫痫活性。
因此，在25、50和100mg/kg的剂量下，化合物1对大鼠癫痫的青霉素模型的腹膜内施用后一小时内完全抑制大脑的癫痫电活动。
大鼠的可拉佐癫痫模型显示，腹膜内施用25和100mg/kg以及口服100和200mg/kg剂量的化合物1时，癫痫发作的强度降低且持续时间减少，并且在某些情况下，使用口服施用剂量为250mg/kg完全预防了癫痫发作。
在这种情况下，化合物1是低毒性的，因为大鼠的LD50参数在腹膜内和口服施用时分别超过2000和5000mg/kg体重。
通常，我们可以认为申请人完成了任务并达到了要求保护的技术效果，即，获得了一种具有高度抗癫痫活性并且在化学结构上在世界上没有类似物的新化合物。所得的制剂将潜在地显著改善患者的质量和预期寿命。
要求保护的技术方案满足适用于发明的“新颖性”标准，因为所研究的技术水平并未曾确定过具有所陈述的一系列鲜明特征的技术方案，这些特征可以确保实现所陈述的技术效果。
要求保护的技术方案满足适用于本发明的“创造性”的标准，因为对于本领域的技术人员而言这是非显而易见的。
要求保护的技术方案满足“工业适用性”的标准，因为它可以在使用标准设备、众所周知的国内材料和技术的任何专业企业中实施。
Claims (2)
1.基于吡哆醇的化合物式1：
2.权利要求1的化合物，具有抗癫痫活性。
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| RU2650523C1 (ru) | 2018-04-16 |
| EA039617B1 (ru) | 2022-02-17 |
| US20200157051A1 (en) | 2020-05-21 |
| EA202000011A1 (ru) | 2020-04-08 |
| US10844018B2 (en) | 2020-11-24 |
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