CN111116608A - 一类具有自由基清除作用的n-苄基苯胺衍生物及其药物用途 - Google Patents
一类具有自由基清除作用的n-苄基苯胺衍生物及其药物用途 Download PDFInfo
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Abstract
Description
技术领域
本发明属于制药领域,提供一类具有自由基清除作用的N-苄基苯胺衍生物及其药物用途。
背景技术
缺血期间或再灌注后增加的有害活性氧(ROS)引起的细胞膜脂质过氧化损伤、蛋白质氧化及DNA损伤是脑缺血障碍的重要原因之一。依达拉奉(EDA)是一种自由基清除剂。临床研究提示N-乙酰门冬氨酸(NAA)是特异性的存活神经细胞的标志,脑梗塞发病初期含量急剧减少。脑梗塞急性期患者给予依达拉奉,可抑制梗塞周围局部脑血流量的减少,使发病后第28天脑中NAA含量较甘油对照组明显升高。临床前研究提示,大鼠在缺血/缺血再灌注后静脉给予依达拉奉,可阻止脑水肿和脑梗塞的进展,并缓解所伴随的神经症状,抑制迟发性神经元死亡。机理研究提示,依达拉奉可清除自由基,抑制脂质过氧化,从而抑制脑细胞、血管内皮细胞、神经细胞的氧化损伤。临床用于改善急性脑梗塞所致的神经症状、日常生活活动能力和功能障碍。
依达拉奉的三种互变结构
依达拉奉存在三种互变结构,其主要代谢物是其羟基的硫酸结合物和葡萄糖醛酸结合物。中国发明200910129816.3公开了依达拉奉环状衍生物泰瑞拉奉,由于其将依达拉奉的代谢部位的羟基进行了保护,预期具有更长的作用时间和体内活性,但由于在苯环上引入了吸电子的羰基,导致苯环上的电子云密度下降,其清除自由基的能力下降(附表1)。
N-甲基-D-天冬氨酸受体(NMDA)是中枢神经系统内一类重要的兴奋性氨基酸受体。脑卒中后,NMDA受体的过度激活是导致神经损伤的重要原因,因此,NMDA受体抑制剂具有一定的抗脑缺血作用。脑缺血后,NMDA受体过度激活,通过NMDA-PSD95-nNOS的通路过度释放NO,是卒中后神经损伤的重要原因,PSD95-nNOS蛋白相互作用抑制剂ZL006具有明确的抗缺血损伤作用(Nature Medicine,2010,1439-1443),并且能够促进神经恢复(Journalof Neuroscience,2014,34(40):13535-13548)。
发明内容
解决的技术问题:一类具有自由基清除作用的N-苄基苯胺衍生物及其药物用途,该类药物具有良好的减少卒中后神经损伤、促进功能恢复作用,可用于制备治疗脑卒中损伤及其所致缺血性神经功能缺失的药物。
技术方案:一类具有自由基清除作用的N-苄基苯胺衍生物,结构符合下述通式(I)
具体结构如式1-6所示:
上述一类具有自由基清除作用的N-苄基苯胺衍生物或其药学上可接受的盐在制备作为脑卒中损伤及其所致缺血性神经功能缺失药物中的应用。
脑卒中损伤及其所致缺血性神经功能缺失药物,有效成分为上述一类具有自由基清除作用的N-苄基苯胺衍生物或其药学上可接受的盐。
有益效果:体外实验表明,本发明化合物具有良好的清除自由基的活性。同时,本发明化合物仍然保持了抑制PSD95-nNOS蛋白相互作用、在谷氨酸刺激模型下的显示出细胞保护作用,在体内实验中显示了更好的减少卒中后神经损伤或更好的促进功能恢复作用,可用于制备治疗脑卒中损伤及其所致缺血性神经功能缺失的药物。
附图说明
图1为大鼠MCAO模型中化合物1的效果示意图,其中可以看出:目标化合物1能显著降低脑梗死面积,显著减轻神经缺陷症状,明显优于依达拉奉和ZL006。
具体实施方式
下面的实施例可使本专业技术人员可全面的理解本发明,但不以任何方式限制本发明。
实施例1目标化合物的合成:
1.1目标化合物1的合成:
合成路线:
在250mL的茄形瓶中加原料A(4.3g,20mmol)和3,5-二氯水杨醛(3.9g,20mmol),加入100mL甲醇,加热回流12h后,过滤,滤饼烘干,得到亚胺淡红色固体2.2g,在250mL的茄形瓶中加入50mL甲醇、亚胺(2.2g),分5批加入硼氢化钠(1.0g),TCL检测反应完全后,用浓HCl调节pH至7左右,加水100mL,有淡黄色固体析出,抽滤,取滤饼,烘干,得到淡黄色固体1.6g,产率72.4%。1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),7.62(s,1H),7.60(t,1H),7.46(d,1H),7.25(d,1H),6.70(s,1H),6.51(d,1H),5.55(s,1H),4.36(d,2H),2.39(s,3H).13C NMR(101MHz,DMSO-D6)δ160.65,156.98,155.80,150.86,150.24,141.64,129.97,128.11,127.19,126.88,123.88,122.40,107.88,103.94,41.89,12.57.
1.2目标化合物2的合成:
参考目标化合物1的合成方法,以原料A和3-氯-5-溴水杨醛为原料合成。
1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),7.64(t,1H),7.49(d,1H),7.46(d,1H),7.22(d,1H),6.69(s,1H),6.50(s,1H),5.55(s,1H),4.35(d,2H),2.39(s,3H).13C NMR(101MHz,DMSO-D6)δ160.65,156.99,155.79,150.87,150.67,130.81,130.40,129.76,127.20,122.73,111.17,107.88,103.95,41.82,12.57.
1.3目标化合物3的合成:
参考目标化合物1的合成方法,以原料A和3-氯-5-氟水杨醛为原料合成
1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),7.62(t,1H,,NH),7.48(d,1H),7.46(d,1H),7.21(d,1H),6.68(s,1H),6.51(s,1H),5.54(s,1H),4.34(d,2H),2.38(s,3H).
1.4目标化合物4的合成:
参考目标化合物1的合成方法,以原料A和3-氯-5-三氟甲基水杨醛为原料合成。
1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),7.64(s,1H),7.61(t,1H),7.47(d,1H),7.26(d,1H),6.71(s,1H),6.50(d,1H),5.54(s,1H),4.35(d,2H),2.38(s,3H)
1.5目标化合物5的合成:
参考目标化合物1的合成方法,以原料A和3-氯-5-特丁基水杨醛为原料合成。
1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),7.63(s,1H),7.60(t,1H),7.46(d,1H),7.25(d,1H),6.70(s,1H),6.49(d,1H),5.53(s,1H),4.34(d,2H),2.37(s,3H),1.17(s,9H).
1.6目标化合物6的合成:
在250mL的茄形瓶中加原料B(4.3g,2 0mmol)和3,5-二氯水杨醛(3.9g,2 0mmol),加入100mL甲醇,加热回流12h后,过滤,滤饼烘干,得到亚胺淡红色固体2.2g,在250mL的茄形瓶中加入50mL甲醇、亚胺(2.2g),分5批加入硼氢化钠(1.0g),TCL检测反应完全后,用浓HCl调节pH至7左右,加水100mL,有淡黄色固体析出,抽滤,取滤饼,烘干,得到淡黄色固体1.6g,产率72.4%。1HNMR(400MHz,DMSO-d6)δ13.27,9.74(s,1H),7.63(dd,2H),7.49(d,1H),7.27(d,1H),6.72(s,1H),6.54(d,1H),5.95(s,1H),4.37(d,2H),2.37(s,3H).
1.7化合物7的合成:
在25mL的茄形瓶中加入目标化合物1(77mg,0.2mmol),甲醇5mL,2N氢氧化钠水溶液5mL,室温搅拌30min后,调节pH至5-6,抽滤,收集滤饼,得到褐色固体50mg,产率61.7%。1H NMR(400MHz,DMSO-d6)δ7.68(d,1H),7.64(d,1H),7.30(d,1H),6.70(d,1H),6.67(dd,1H),5.52(s,1H),4.37(s,2H),2.19(s,3H).13C NMR(101MHz,DMSO-D6)δ165.76,156.14,152.58,151.59,147.75,133.45,132.94,131.01,130.25,114.04,113.08,111.88,111.53,89.18,41.95,13.42.
实施例2目标化合物抗DPPH自由基试验
二苯代苦味酰自由基(DPPH)是一种筛选抗氧化剂的简便方法。当有过量自由基清除剂存在时,其剩余浓度可以反映出目标物的自由基清除能力,剩余浓度越小,自由基清除能力越大。
精密称取DPPH 39.4mg,置于100mL容量瓶中,并用95%乙醇定容至100mL,即配成DPPH溶液(1.0mmol/L),目标化合物用DMF为溶剂,配制为1.0mmol/L的溶液。
DPPH溶液1.0mL,目标化合物溶液4.0mL置于10mL容量瓶中,并用水定容至10mL,放置3小时,采用高效液相法(检测波长517nm)测定剩余DPPH的浓度。
表1目标化合物的剩余DPPH的浓度(mmol/L)
化合物 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | ZL006 | 依达拉奉 | 泰瑞拉奉 |
浓度 | 0.01 | 0.02 | 0.02 | 0.02 | 0.02 | 0.02 | 0.02 | 0.1 | 0.03 | 0.05 |
从实验结果可见:ZL006对于DPPH没有明显清除作用,所有目标化合物对于DPPH的清除作用均强于依达拉奉和泰瑞拉奉,其中目标化合物1最好。
实施例3目标化合物对体外培养的原代皮层神经元损伤的保护作用(谷氨酸模型)
原代神经元培养9天后,预给药30分钟,谷氨酸50微摩尔+甘氨酸10微摩尔孵育45分钟。全量换液(药物和谷氨酸甘氨酸都撤除),8小时后测定LDH漏出率。
原代皮层神经元分别给予各种处理后,吸取六孔板中的神经元培养液于1.5mL塑料离心管中备用;用PBS溶液洗涤细胞3次,每孔加入PBS1000μL,将细胞反复冻融3次,于4℃12000′g离心5分钟,吸取上清备用。吸取50μL培养液和25μL上清进行LDH酶活性测定,使用乳酸脱氢酶试剂盒测定LDH活性。
表2目标化合物对谷氨酸损伤神经元释放LDH的抑制作用
由表2可见:所有目标化合物对谷氨酸损伤神经元释放LDH的抑制作用均强于依达拉奉或者泰瑞拉奉,与ZL006相当,其中目标化合物1最好。提示所有目标化合物对对体外培养的原代皮层神经元谷氨酸损伤的保护作用与ZL006相当。依达拉奉或者泰瑞拉奉对体外培养的原代皮层神经元谷氨酸损伤没有显示出明显的保护作用,目标化合物1的开环产物化合物7对于谷氨酸损伤神经元没有显示出明显的神经保护作用。
实施例4目标化合物对体外培养的原代皮层神经元损伤的保护作用(OGD模型)
原代神经元培养9天后,换含1%FBS的DMEM高糖培养基,血清饥饿过夜,然后用OGD培养液洗2次。这种OGD培养液含DMEM培养基、1%FBS、1%青霉素/链霉素和B27,无糖。而后,原代神经元与所试药物孵育30分钟,加入OGD培养液放入厌氧罐中缺氧2小时,弃OGD培养液,换氧饱和的DMEM培养基,内含1%FBS、1%青霉素/链霉素和B27。8小时后收集培养液测定LDH含量。
原代皮层神经元分别给予各种处理后,吸取六孔板中的神经元培养液于1.5mL塑料离心管中备用;用PBS溶液洗涤细胞3次,每孔加入PBS1000μL,将细胞反复冻融3次,于4℃12000g离心5分钟,吸取上清备用。吸取50μL培养液和25μL上清进行LDH酶活性测定,使用乳酸脱氢酶试剂盒测定LDH活性。
表3目标化合物对OGD损伤神经元释放LDH的抑制作用
由表3可见:所有目标化合物对OGD损伤神经元释放LDH的抑制作用均强于依达拉奉、泰瑞拉奉或者ZL006,其中目标化合物1最好。提示所有目标化合物对对体外培养的原代皮层神经元损伤的保护作用强于依达拉奉、泰瑞拉奉或者ZL006,其中目标化合物1最好。
实施例5目标化合物对局灶性脑缺血再灌注损伤的保护作用
5.1局灶性脑缺血再灌注模型的制备
采用大脑中动脉阻塞(MCAO)再灌注模型诱导脑缺血损伤。大鼠经2%水合氯醛(0.2mL/10g,i.p.)麻醉后,将动物仰卧固定于手术台上,沿颈正中切开皮肤,钝性分离颈部肌肉组织,暴露右侧颈总动脉(CCA)并小心游离;轻轻剥离伴行的迷走神经,结扎并剪断向内及浅表走向的颈外动脉分支(ECA);循颈内动脉(ICA)向前,在颅底附近有向外侧的分支动脉—翼腭动脉,将其分离结扎。CCA近心端以手术线结扎;结扎线的远端用眼科剪剪开小口,将商业化用于手术用MCAO模型制备的尼龙线(4/0号)沿该小口处插入,插入约20mm感觉有轻微阻力时为止,提示线栓前端已经达到大脑前动脉。至此,大脑中动脉(MCA)的血液供应包括颈动脉和大脑韦氏环前交通支来源的血供均已阻断。根据标记判断插入线拴的深度。线拴的血管外部分结扎固定,防止线栓的滑脱。右侧脑缺血120分钟后,小心拔除线栓,结扎断端,实现缺血后的再灌注。缝合皮肤,回笼精心喂养。手术过程中保持动物体温恒定在37±0.5℃。
5.2局灶性脑缺血再灌注损伤大鼠的神经缺陷症状评价
采用改良Bederson 5分制法进行神经缺陷症状评价。采用单盲法评价脑缺血后大鼠的神经缺陷症状,即由试验设计者将动物按组标记,对神经缺陷症状进行评分的试验者不知道动物的分组情况,评分结束后,评分者将各种标记的评分结果呈交设计者,由设计者揭盲,获得各试验组每只动物的评分。
5.3脑梗死面积测定
动物用10%的水合氯醛3.5mL/kg麻醉,断头取脑,去除嗅球、小脑和低位脑干,用生理盐水冲洗大脑表面血迹,吸去表面残留水迹,于-80℃放置7min,取出后立即于视线交叉平面垂直向下作冠状切面,并向后每隔2mm切一片,将脑片置于用0.2mol/L pH 7.4~7.8PBS新鲜配制的20g/L TTC染液中水浴(37℃90min),正常脑组织染成深红色,缺血脑组织则呈苍白色,用生理盐水冲洗后,迅速将脑片从前向后按顺序排成一排,吸干表面残留水迹,拍照。用图像分析软件对照片进行统计,圈定右侧缺血面积(白色区域)和右侧总面积,用如下公式计算脑梗死面积的百分比。
5.4目标化合物1,2,3对于大鼠急性局灶性脑缺血再灌注损伤的保护作用
大鼠MCAO 120分钟,再灌注后1小时尾静脉注射不同剂量的目标化合物1或等体积的溶剂,目标化合物1的剂量为2.0mg/kg(第2组)、1.5mg/kg(第3组)、1.0mg/kg(第4组),ZL006 1.5mg/kg(第5组)、依达拉奉1.5mg/kg(第6组),注射药物的体积为0.1mL/100g体重,于脑缺血后48小时评价神经缺陷症状,而后处死动物,取脑,TTC染色,测定染色后脑片的梗死面积。结果如图1所示:与溶剂对照组相比,目标化合物依赖性显著降低脑梗死面积,显著减轻神经缺陷症状。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005343789A (ja) * | 2002-03-15 | 2005-12-15 | Mitsubishi Pharma Corp | 低酸素性虚血性脳障害予防・治療剤 |
CN101318968A (zh) * | 2008-07-18 | 2008-12-10 | 青岛黄海制药有限责任公司 | 一种苯并噁嗪并吡唑类及开环化合物 |
CN106491624A (zh) * | 2016-11-02 | 2017-03-15 | 南京医科大学附属儿童医院 | 一种治疗脑卒中的药用组合物及其应用 |
CN106880631A (zh) * | 2015-12-15 | 2017-06-23 | 烟台益诺依生物医药科技有限公司 | 一种含有苯并噁嗪吡唑类化合物和冰片的组合物 |
CN106963768A (zh) * | 2017-04-01 | 2017-07-21 | 南京中瑞药业有限公司 | 一种药物组合物及用途 |
-
2020
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005343789A (ja) * | 2002-03-15 | 2005-12-15 | Mitsubishi Pharma Corp | 低酸素性虚血性脳障害予防・治療剤 |
CN101318968A (zh) * | 2008-07-18 | 2008-12-10 | 青岛黄海制药有限责任公司 | 一种苯并噁嗪并吡唑类及开环化合物 |
CN101508696A (zh) * | 2008-07-18 | 2009-08-19 | 青岛黄海制药有限责任公司 | 2-甲基-5-亚胺基-苯并[d][1,3]噁嗪[5-b]吡唑化合物及其制备方法和用途 |
CN106880631A (zh) * | 2015-12-15 | 2017-06-23 | 烟台益诺依生物医药科技有限公司 | 一种含有苯并噁嗪吡唑类化合物和冰片的组合物 |
CN106491624A (zh) * | 2016-11-02 | 2017-03-15 | 南京医科大学附属儿童医院 | 一种治疗脑卒中的药用组合物及其应用 |
CN106963768A (zh) * | 2017-04-01 | 2017-07-21 | 南京中瑞药业有限公司 | 一种药物组合物及用途 |
Non-Patent Citations (1)
Title |
---|
戴鹏 等: "基于 NMDAR 信号通路的神经保护剂的研究进展", 《中国新药杂志》 * |
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