CN106377526A - 一种促进脑卒中患者神经再生的药物组合物及其应用 - Google Patents
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Abstract
本发明公开了一种促进脑卒中患者神经再生的药物组合物及其应用,该药物组合物为口服制剂,由活性成分和药用辅料制备而成,其特征在于:所述的活性成分包括下式所示的N’‑(2‑(1H‑吲哚‑3‑基)乙酰基)芳酰肼类化合物。本发明的药物组合物可通过增加神经生长正性调控因子的表达,抑制神经生长负性调控因子的表达,促进脑卒中后的神经再生过程,进而促进运动功能康复。
Description
技术领域
本发明属于医药技术领域,具体而言,尤其涉及一种促进脑卒中患者神经再生的药物组合物及其应用。
背景技术
脑卒中是由于颅内外血管阻塞或破裂而造成的急性脑功能损伤,严重危害中老年人的生命健康,也是造成中老年人致死、致残的主要原因之一。脑卒中患者约有1/3在发病不久后死亡,幸存者由于偏瘫、失语等后遗症致残丧失工作甚至生活自理能力。目前通常治疗脑卒中有两种方法:一种是通过增加血流量改善动脉中氧和葡萄糖不足;另一种是保护神经元,减少脑组织缺血可能性,降低神经元的兴奋毒性死亡。用于临床治疗的神经元保护剂有钙离子通道阻断剂,谷氨酸受体拮抗剂,NMDA拮抗剂等。与脑卒中的高发病率、高致死率及高致残率相比,目前用于预防治疗脑卒中的药物品种较少,远远不能满足临床需要。
研究表明,人体的大多数组织在损伤后具有再生和修复能力,但成年哺乳动物中枢神经系统损伤后却存在再生与修复困难,在脑缺血性损伤相关疾病、脊髓损伤、以及许多神经病变的情况下,中枢神经系统功能恢复非常有限,并且容易发生肢体运动和感觉障碍等严重影响个人生活质量的病症。因此,中枢神经系统再生问题一直是医学界和神经科学界在理论研究和临床实践中亟待解决的重大难题。近二十年来的研究已有突破性进展,目前认为中枢神经系统损伤后的神经再生与后期康复效果密切相关,但受内在因素和外部环境的限制。内在因素包括生长相关基因、蛋白,外部环境包括神经营养因子、神经生长抑制因子、胶质瘢痕等。trk-B是脑源性神经生长因子的高亲和力受体,主要集中于中枢神经系统内表达,是脑内分布最为广泛、也是不可缺少的神经营养因子受体。nogo-A是目前发现的最为强烈的神经纤维再生抑制物质,抑制损伤神经再生,尤其是再生神经纤维的长距离生长,它在体内和体外都显示出了抑制神经轴突生长的作用。而拮抗nogo-A后所获得的神经纤维再生是有功能性的,并能形成具有功能的突触联系。Trk-B和nogo-A分别代表了神经再生微环境的神经生长营养因子和抑制因子两个方面。因此,寻找影响此二者表达的药物,比较其活性的强弱,可了解中药对中枢神经再生微环境的作用,对临床治疗中枢神经损伤非常重要。CN105732468A公开了一种N′-(2-(1H-吲哚-3-基)乙酰基)芳酰肼类化合物,并披露了该类化合物对HCV病毒具有明显的抑制作用,制备方法包括如下步骤:包括以下步骤:(1)吲哚乙酸与C1-C5醇发生酯化反应得到吲哚乙酸酯;(2)式II所示吲哚乙酸酯与水合肼反应得到吲哚乙酰肼;(3)由式IV所示芳香羧酸与氯化试剂反应制备得到芳基酰氯;(4)由式III所示吲哚乙酰肼与式V所示芳基酰氯反应得到N′-(2-(1H-吲哚-3-基)乙酰基)芳酰肼类化合物。然而,现有技术并没有披露该类化合物可用于治疗脑卒中等脑神经损伤性疾病。
发明内容
本发明的目的在于提供一种促进缺血性脑卒中患者神经再生的药物组合物及其应用。为了实现本发明的目的,发明人通过大量试验研究并不懈努力,最终获得了如下技术方案:
一种促进脑卒中患者神经再生的药物组合物,该药物组合物为口服制剂,由活性成分和药用辅料制备而成,所述的活性成分包括式(I)所示的N’-(2-(1H-吲哚-3-基)乙酰基)芳酰肼类化合物(N′-(2-(1H-吲哚-3-基)乙酰基)-2-羟基苯甲酰肼):
优选地,如上所述促进脑卒中患者神经再生的药物组合物,其中的活性成分由所述式(I)所示的N’-(2-(1H-吲哚-3-基)乙酰基)芳酰肼类化合物组成。
进一步优选地,如上所述促进脑卒中患者神经再生的药物组合物,其中所述的药物组合物为口服制剂,所述的口服制剂包括片剂、胶囊剂、颗粒剂。
本发明通过用电凝法制备大脑中动脉闭塞大鼠模型试验研究了N’-(2-(1H-吲哚-3-基)乙酰基)芳酰肼类化合物对脑卒中模型大鼠运动功能以及脑组织酪氨酸受体激酶B(trk-B)和勿动蛋白A(Nogo-A)表达的影响,结果发现该化合物可显著增强trk-B并抑制Nogo-A的表达,从而改善神经再生微环境,促进脑卒中大鼠运动功能康复。因此,本发明还提供一种制药用途,即:N′-(2-(1H-吲哚-3-基)乙酰基)-2-羟基苯甲酰肼在制备促进脑卒中患者神经再生的药物中的应用;或者:N′-(2-(1H-吲哚-3-基)乙酰基)-2-羟基苯甲酰肼在制备预防或治疗脑卒中的药物中的应用。
与现有技术相比,本发明的药物组合物可通过增加神经生长正性调控因子的表达,抑制神经生长负性调控因子的表达,充分调动卒中后对神经系统损伤的各种修复机制,促进脑卒中后的神经再生过程,进而促进运动功能康复。
具体实施方式
以下是本发明的具体实施例,对本发明的技术方案做进一步作描述,但是本发明的保护范围并不限于这些实施例。凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
实施例1:N′-(2-(1H-吲哚-3-基)乙酰基)-2-羟基苯甲酰肼的制备
(1)在500毫升圆底烧瓶中加入吲哚乙酸8.8g(50mmol),甲醇(60mL),浓硫酸(3mL),70℃反应1-3小时,TLC检测反应完毕后,蒸出甲醇,加入水(50mL),分离有机相,水相用乙酸乙酯(3×20mL)萃取,合并有机相,依次用饱和碳酸氢钠溶液和水洗涤,无水硫酸钠干燥,减压浓缩后得到吲哚乙酸甲酯粗产物,本品无需纯化直接用于下一步反应。
(2)在500毫升圆底烧瓶中加入吲哚乙酸甲酯946g(48mmol),乙二醇甲醚(40mL),水合肼5mL,115℃加热回流反应约20小时,薄层色谱(TLC)检测原料点消火,停止反应,冷却到室温,加入水(50mL),静置析出白色固体,抽滤得到粗产物,用乙醇重结晶得吲哚乙酰肼白色固体9.2克。
(3)在100毫升圆底烧瓶中加入芳香羧酸1.6mmol,无水四氢呋喃10mL,滴加一滴DMF,加入0.5mL氯化亚砜,油浴,70℃加热反应约10小时,TLC检测反应完毕后,蒸出溶剂,得芳酰氯粗产物直接用于下一步反应。
(4)在100毫升圆底烧瓶中加入3-吲哚乙酰肼(300mg,1.59mmol),无水四氢呋喃10毫升,Et3N(3mL,1.59mmol),滴加芳酰氯(1.59mmol)的四氢呋喃溶液,产生沉淀,继续室温(25℃)搅拌12小时,TLC检测反应完毕后,减压除去溶剂得橙黄色固体,分别用乙酸乙酯、水洗涤,抽滤得到淡黄色粗产物,用适当溶剂重结晶得白色固体纯品,产率:76.1%,mp:189.2-190.0℃;1H-NMR(500MHz,DMSO-d6),δ(ppm):3.82(s,2H,CH2),6.92(s,1H,Ar-H),7.04-7.07(m,1H,Ar-H),7.11-7.14(m,1H,Ar-H),7.29-7.42(m,4H,Ar-H),7.66-7.67(m,1H,Ar-H),7.82-7.84(m,1H,Ar-H),10.13(1H,NH),10.41(s,1H,NH);10.88(1H,NH-吲哚);m/z 308.1[M+-1]。
实施例2:化合物对大脑中动脉闭塞模型的影响试验
成年SD大鼠55只,雄性,健康清洁级,体质量280~320g,随机取出15只大鼠作为假手术组,其余大鼠按下述方法制作大脑中动脉闭塞模型:用0.4%戊巴比妥钠10mL/kg腹腔注射麻醉大鼠,侧卧位固定于手术台上,沿右外耳道与右眼外眦连线中点,垂直于连线切开皮肤约2cm,然后在手术显微镜下沿颞肌中线,依次切断颞肌和咬肌,并向两侧分开,暴露出颧弓。用咬骨钳除去颧弓并沿颅骨剪开筋膜,暴露出颞前窝,用小牵张器将颧弓和下颌骨的距离撑大,暴露鳞状骨的大部分,然后在颧骨和鳞状骨前联合的前下方约2mm处钻孔,开一直径约2mm小颅窗,刺破硬脑膜,分离血管周围的软脑膜和蛛网膜组织,使之游离。然后在嗅束与大脑中动脉交界处轻挑起大脑中动脉,将电刀置双极电凝位置,选择3-4档电凝开关,电凝烧灼嗅束内2mm至大脑下静脉之间的一段大脑中动脉,血管阻断后于远侧切断以防止再灌流,逐层缝合伤口,术后苏醒送回原笼饲养。以上过程均在室温恒定(24-25℃)情况下进行,以利于评价脑缺血程度。麻醉醒后24h内出现左侧肢体痛刺激收缩现象消失,向左侧倾倒或转圈,提尾时左上肢不能向前伸直为模型复制成功,造模成功的大鼠分为模型对照组(18只)、化合物治疗组(18只)。假手术组大鼠行同样开颅术,但不凝闭大脑中动脉,其余操作同模型对照组。
以大鼠重量为基准,化合物治疗组灌胃给予N′-(2-(1H-吲哚-3-基)乙酰基)-2-羟基苯甲酰肼60mg/kg/次,模型对照组和假手术组分别灌胃给予等量生理盐水,每天早九点点和晚六点各1次,共2周。于造模成功后6h给药,固体饲料和水自由摄取。实验过程中模型对照组大鼠有1只死亡。试验结束后,采用前肢放置检测法(HuaY,SchallertT,KeepRF,elal.Behavioral tests after intracerebral hemorrhage in therat[J].Stroke,2002,33:2478.)测定大鼠运动功能。检查者手持大鼠背部皮肤使四肢悬空,将一侧胡须刷触桌面角边缘,测试同侧前肢的活动隋况,未受损者可将前肢迅速放到桌面,脑损伤时此动作有不同程度的损害。大鼠每侧受测10次,前肢触及桌面角边缘次数的百分率即为该侧得分。注意:抓握大鼠要轻柔,前肢自由悬垂,试验前轻轻活动大鼠,尽量让其放松,如大鼠挣扎,肌肉紧张或肢体放在试验者手上不计在内。分别于造模成功后24h、3d、1、2周进行评分。另外,采用免疫组织化学法、原位杂交法检测trk-B、nogo-A的表达情况。试验统计结果参见表1、表2。
表1各组大鼠运动功能评分比较
注:与模型对照组比较,#P<0.05;##P<0.01。
表2各组大鼠trk-B、nogo-A平均灰度比较
注:与模型对照组比较,#P<0.05;##P<0.01。
通过表1的试验结果可以看出,术后24h模型对照组与化合物治疗组的评分均显著低于假手术组;以后各时间点模型对照组和化合物治疗组评分均有提高,且化合物治疗组更为明显,与模型对照组比较有显著性差异(P<0.05或P<0.01)。通过表2的试验结果可以看出,2周后模型对照组和化合物治疗组的trk-B染色平均灰度较假手术组均显著降低,但化合物治疗组降低更为明显,与模型对照组相比有极显著差异(P<0.01);模型对照组nogo-A染色平均灰度较假手术组显著降低,化合物治疗组则接近假手术组,与模型对照组比较有极显著差异(P<0.01)。
Claims (5)
1.一种促进脑卒中患者神经再生的药物组合物,该药物组合物为口服制剂,由活性成分和药用辅料制备而成,其特征在于:所述的活性成分包括下式所示的N’-(2-(1H-吲哚-3-基)乙酰基)芳酰肼类化合物:
2.根据权利要求1所述促进脑卒中患者神经再生的药物组合物,其特征在于:所述的活性成分由所述的N’-(2-(1H-吲哚-3-基)乙酰基)芳酰肼类化合物作为唯一组分组成。
3.根据权利要求1或2所述促进脑卒中患者神经再生的药物组合物,其特征在于:所述的口服制剂包括片剂、胶囊剂、颗粒剂。
4.N′-(2-(1H-吲哚-3-基)乙酰基)-2-羟基苯甲酰肼在制备促进脑卒中患者神经再生的药物中的应用。
5.N′-(2-(1H-吲哚-3-基)乙酰基)-2-羟基苯甲酰肼在制备预防或治疗脑卒中的药物中的应用。
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