CN113861064A - 一类神经保护剂及其药物用途 - Google Patents
一类神经保护剂及其药物用途 Download PDFInfo
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- CN113861064A CN113861064A CN202111197501.XA CN202111197501A CN113861064A CN 113861064 A CN113861064 A CN 113861064A CN 202111197501 A CN202111197501 A CN 202111197501A CN 113861064 A CN113861064 A CN 113861064A
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Abstract
一类神经保护剂及其药物用途，结构符合通式(I)，
其中：R1＝‑H或与R2连接形成环状结构，R2＝‑H、‑CH3或与R1连接形成环状结构，R3＝‑OH、‑NH2、‑NHCH3、‑CH2NH2、‑CH2NHCH3或‑COR4，R4＝‑OH、‑NH2、‑NHCH3或1‑3个碳原子的烷氧基。该类药物在脑卒中等动物模型中显示了良好的作用，可用于制备治疗脑卒中的药物。
Description
技术领域
本发明属于制药领域，提供一类神经保护剂及其药物用途。
背景技术
脑卒中后，谷氨酸激活NMDAR，通过NMDAR/突触后致密蛋白95(PSD95)/神经元型一氧化氮合酶(nNOS)复合物激活下游的nNOS，导致一氧化氮(NO)的病理性释放，和氧自由基结合，产生毒性更大的过氧硝基自由基，引发神经损伤。抑制NMDAR或该信号通路，能够减少脑卒中后神经损伤。NMDAR和nNOS具有重要的生理功能，直接抑制可能导致严重的中枢神经系统副作用。抑制其下游信号通路，特异性的抑制PSD95-nNOS相互作用，具有更好的安全性，研究显示：特异性的抑制PSD95-nNOS相互作用，能够抑制卒中后的神经损伤(naturemedicine，2010，16:1439-1443)，促进神经修复(Journal of Neuroscience，2014，34:13535-13548)，镇痛(Neuropharmacology 2018,141:238-248)等作用。ZL006(naturemedicine，2010)、SCR4026(Brain Research,2016:250-256.)是文献报导的PSD95-nNOS相互作用抑制剂。
中国专利CN101492384B公开了一类氨基水杨酸类衍生物及其作为神经保护剂的应用，其中：R1、R2、R3、R5中至少有一个为-OH；R1、R2、R3、R5不为-OH时，为-H、-OCH3、-F、-Cl、-Br、-CF3或-NO2；R4为-OCH3、-F、-Cl、-Br、-CF3或-NO2；R6、R7为-COOH或-OH；当R6为-COOH时，R7为-OH；当R6为-OH时，R7为-COOH。
ZL006代谢迅速，口服无效。ZL006的酯类衍生物，在体内能够代谢产生ZL006(Bioorg Med Chem Lett 2016)，中国专利CN103819354B公开了一类N-苄基取代的氨基水杨酸2-氨基乙醇酯衍生物及其药物用途(其中，R3、R4为分别独立的为乙基或者连接在一起形成环状结构)。该类药物既具有较好的中枢神经系统分布，而且具有较好的水溶性，有利于药物制剂。
发明内容
解决的技术问题：本发明提供一类神经保护剂及其药物用途，该类药物在体外显示了良好的神经保护作用，在脑卒中动物模型中显示了良好的作用，可用于制备治疗脑卒中的药物。
技术方案：结构符合通式(I)
优选结构为：
上述一类神经保护剂或其药学上可接受的盐在制备脑卒中所致缺血性神经功能缺失药物中的应用。
一种用于治疗脑卒中损伤药物，所述有效成分为上述神经保护剂或其药学上可接受的盐。
有益效果：该类药物在脑卒中等动物模型中显示了良好的作用，可用于制备治疗脑卒中的药物。
附图说明
图1为目标化合物9对光诱导血栓形成性脑缺血模型小鼠网格实验失足率的影响(％)；
图2为目标化合物9对光诱导血栓形成性脑缺血模型小鼠圆筒不对称指数的影响(％)。
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)4-((2-氨基-4,6-二氯苯氧基)甲基)-N-(2-氨基乙基)苯甲酰胺(目标化合物1)
合成路线：
将2,4-二氯苯酚(16.2g,0.1mol)加入到浓硫酸(60mL)溶液中，温度维持在0℃，在1小时内向溶液中缓慢滴加硝酸(13mL)，在0℃继续下搅拌3小时，TLC检测(石油醚：乙酸乙酯＝20:1)原料消失，缓慢向反应液中加入冰水，抽滤，用冰水冲洗滤饼，烘干得到19.5g黄色固体(1-1)，收率94％。
将化合物1-1(19.5g,95mmol)，4-(溴甲基)苯甲酸甲酯(26g,114mmol)，碳酸钾(15.8g,114mmol)加入到丙酮(200mL)溶液中，温度升高至65℃，反应8小时后，TLC检测(石油醚：乙酸乙酯＝20:1)原料消失，停止反应，缓慢向反应液中加入水(200mL)，抽滤，用水(100mL×2)冲洗滤饼，烘干得到31.5g灰白色固体(1-2)，收率93％。
将化合物1-2(31.5g,89mmol)和铁粉(24.8g 444mmol)加入乙酸(100mL)溶液中，温度升高至85℃，反应3小时后，TLC检测(石油醚:乙酸乙酯＝10:1)原料消失，停止反应，通过硅藻土抽滤，并用乙酸乙酯(100mL)冲洗滤渣，用乙酸乙酯(50mL×3)萃取，用饱和碳酸氢钠溶液(50mL×3)洗去过量的乙酸，收集有机相后用饱和氯化钠溶液(50mL×3)洗涤，有机相再用无水硫酸钠干燥，蒸除滤液并用无水乙醇打浆得到24.4g灰白色固体(1-3)，收率84％。
将化合物1-3(6.5g,20mmol)加入到甲醇(40mL)中，加入2M氢氧化钠的水溶液(15mL)，温度升至45℃搅拌3小时。TLC检测(石油醚:乙酸乙酯＝10:1)原料消失，停止反应，将甲醇蒸除后，用1M的稀盐酸调节pH至6左右，抽滤，干燥得到6.1g白色固体(1-4)，收率98％。
将化合物1-4(0.31g，1mmol)加入二氯甲烷(10mL)溶液中，加入氯化亚砜(3mL)后，温度升至65℃，搅拌3小时，待溶液澄清后，停止反应，将溶剂蒸去，得到黄色固体。将所得的黄色固体和N-叔丁氧羰基-1,2-乙二胺(0.24，1.5mmol)加入二氯甲烷(10mL)溶液中，在0℃下将三乙胺(0.15g,1.5mmol)缓慢滴加至上述反应液中，升高温度至室温，搅拌8小时后，TLC检测(石油醚:乙酸乙酯＝4:1)原料消失，将溶剂蒸除后，加入水(15mL)，用乙酸乙酯(10mL×3)萃取，合并有机层用饱和氯化钠溶液(10mL×3)洗涤，有机相用无水硫酸钠干燥，柱层析(石油醚：乙酸乙酯＝8:1)，分离得到0.39g类白色固体(1-5)，收率86％。
将化合物1-5(0.39g,0.86mmol)加入二氯甲烷(6mL)溶液，再将反应液中加入三氟乙酸(2mL)，常温搅拌5小时，TLC检测(石油醚:乙酸乙酯＝4:1)原料消失，停止反应，蒸除溶剂后得到浅褐色固体(1)0.24g，收率79％。m.p.136～138℃；MS(ESI):m/z＝354.3[M+H]+.1HNMR(400MHz,DMSO-d6)δ7.85(d,2H),7.56(d,2H),6.67(s,1H),6.61(s,1H),4.87(s,2H),3.30(q,2H),2.73(t,2H).13C NMR(101MHz,DMSO-d6)δ166.70,145.10,140.30,139.89,134.68,129.52,129.32,128.56,128.26,128.07,127.74,115.71,113.70,73.07,42.21,41.06ppm.
2)4-((2-氨基-4,6-二氯苯氧基)甲基)-N-(2-(甲基氨基)乙基)苯甲酰胺(目标化合物2)
参考目标化合物1的合成方法，以化合物1-4、1-N-叔丁氧羰基氨基2-甲基氨基乙胺为原料合成。m.p.158～160℃；MS(ESI):m/z＝368.3[M+H]+.1H NMR(400MHz,D2O)δ7.88-7.81(m,2H),7.45(dt,2H),7.22(d,1H),6.77(d,1H),4.86(s,2H),3.50(t,2H),2.83(t,2H),2.40(s,3H).13C NMR(101MHz,D2O)δ167.42,145.08,141.86,137.53,133.86,132.03,128.34,127.62,125.76,114.38,73.16,50.12,40.69,35.68.
3)(R)-4-((2-氨基-4,6-二氯苯氧基)甲基)-N-(2-氨基丙基)苯甲酰胺(目标化合物3)
参考目标化合物1的合成方法，以化合物1-4、2-N-叔丁氧羰基氨基丙胺为原料合成。m.p.132～134℃；MS(ESI):m/z＝368.3[M+H]+.1H NMR(400MHz,D2O)δ7.63-7.58(m,2H),7.37(d,2H),6.84(d,1H),6.76(d,1H),4.80(s,2H),3.50-3.41(m,3H),1.18(d,3H).13C NMR(101MHz,D2O)δ170.63,142.33,140.03,136.77,133.01,130.04,128.79,128.56,127.57,123.12,117.83,74.11,47.79,42.86,15.56ppm.
4)4-((2-氨基-4,6-二氯苯氧基)甲基)-N-(2-氨基苯基)苯甲酰胺(目标化合物4)
参考目标化合物1的合成方法，以化合物1-4、邻苯二胺为原料合成。m.p.88～90℃；MS(ESI):m/z＝402.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.66(d,2H),7.45(dd,1H),7.29(d,1H),7.24(td,2H),6.69(d,1H),6.63(d,1H),4.93(s,2H).13C NMR(101MHz,DMSO-d6)δ166.00,145.08,141.27,139.92,133.87,129.35,128.64,128.53,128.25,127.66,127.24,115.75,113.77,73.03ppm.
5)4-((2-氨基-4,6-二氯苯氧基)甲基)-N-((1S，2S)-2-氨基环己基)苯甲酰胺(目标化合物5)
参考目标化合物1的合成方法，以化合物1-4、N-((1S，2S)-2-N-叔丁氧羰基氨基环己基胺为原料合成。m.p.116～118℃；MS(ESI):m/z＝408.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.85(d,2H),7.59(d,2H),6.67(d,1H),6.61(d,1H),4.90(s,2H),3.92-3.83(m,1H),3.00(dt,1H),1.99(d,1H),1.87-1.80(m,1H),1.69(t,2H),1.36(t,2H),1.20(d,2H).13CNMR(101MHz,DMSO-d6)δ166.84,145.09,140.60,139.91,134.49,129.30,128.44,128.20,128.10,115.72,113.71,73.10,53.64,51.35,31.85,30.20,24.74,24.11ppm.
6)4-((2-氨基-4,6-二氯苯氧基)甲基)-N-((1R，2R)-2-氨基环己基)苯甲酰胺(目标化合物6)
参考目标化合物1的合成方法，以化合物1-4、N-((1R，2R)-2-N-叔丁氧羰基氨基环己基胺为原料合成。m.p.116～118℃；MS(ESI):m/z＝408.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.85(s,2H),7.59(d,2H),6.67(d,1H),6.61(d,1H),4.90(s,2H),3.90-3.81(m,1H),3.01(dt,1H),1.99(d,1H),1.86-1.78(m,1H),1.69(q,2H),1.41-1.31(m,2H),1.25-1.19(m,2H).13C NMR(101MHz,DMSO-d6)δ166.84,145.10,140.60,139.91,134.49,129.30,128.44,128.20,128.10,115.72,113.71,73.11,53.63,51.35,31.85,30.20,24.74,24.11ppm.
7)4-((2-氨基-4,6-二氯苯氧基)甲基)-N-(2-羟基乙基)苯甲酰胺(目标化合物7)
参考目标化合物1的合成方法，以化合物1-4、乙醇胺为原料合成。m.p.100～102℃；MS(ESI):m/z＝355.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.83(d,2H),7.56(d,2H),6.65(d,1H),6.62(d,1H),4.86(s,2H),3.47(q,2H),3.28(q,2H).13C NMR(101MHz,DMSO-d6)δ166.52,145.13,140.29,139.83,134.63,129.32,128.60,128.28,127.68,115.66,113.66,73.02,60.25,42.69ppm.
8)4-((2-氨基-4,6-二氯苯氧基)甲基)-N-(3-羟基丙基)苯甲酰胺(目标化合物8)
参考目标化合物1的合成方法，以化合物1-4、3-羟基丙胺为原料合成。MS(ESI):m/z＝369.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.83(d,2H),7.56(d,2H),6.65(d,1H),6.62(d,1H),4.86(s,2H),3.45(t,2H),3.26(t,2H),1.82(t,2H).
9)4-((2-氨基-4,6-二氯苯氧基)甲基)-N-(3-氨基丙基)苯甲酰胺(目标化合物9)
参考目标化合物1的合成方法，以化合物1-4、3-N-叔丁氧羰基氨基丙胺为原料合成。m.p.144～146℃；MS(ESI):m/z＝368.3[M+H]+.1H NMR(400MHz,D2O)δ7.56(d,2H),7.42(d,2H),6.89(d,1H),6.77(d,1H),4.88(s,2H),3.29(t,2H),2.86(t,2H),1.78(t,2H).13CNMR(101MHz,DMSO-d6)δ166.74,144.93,140.50,139.97,134.38,129.32,128.64,128.26,127.70,115.86,113.84,73.06,37.31,36.75,27.86ppm.
10)4-((2-氨基-4,6-二氯苯氧基)甲基)-N-(3-甲基氨基丙基)苯甲酰胺(目标化合物10)
参考目标化合物1的合成方法，以化合物1-4、3-N-叔丁氧羰基甲基氨基丙胺为原料合成。1H NMR(400MHz,D2O)δ7.56(d,2H),7.35(d,2H),6.74(dd,2H),4.78(s,2H),3.30(t,J＝6.6Hz,2H),2.92(t,2H),2.56(s,3H),1.84(p,2H).
11)(4-((2-氨基-4,6-二氯苯氧基)甲基)苯甲酰基)丙氨酸甲酯(目标化合物11)
参考目标化合物1的合成方法，以化合物1-4、丙氨酸甲酯为原料合成。1H NMR(400MHz,Chloroform-d)δ7.88–7.72(m,2H),7.53(d,2H),6.86(s,1H),6.75(d,1H),6.61(d,1H),4.99(s,2H),3.78–3.68(m,5H),2.74–2.62(m,2H).
12)(4-((2-氨基-4,6-二氯苯氧基)甲基)苯甲酰基)丙氨酸(目标化合物12)
将化合物9(0.21g,0.55mmol)加入到甲醇(10mL)中，在0℃下加入2M氢氧化钠的水溶液(3mL)，温度升至45℃搅拌3小时。TLC检测(石油醚:乙酸乙酯＝3:1)原料消失，停止反应，将甲醇蒸除后，用1M的稀盐酸调节pH至6.5左右，抽滤，干燥得到0.17g白色固体，收率84％。m.p.150～152℃；MS(ESI):m/z＝367.1[M-H]-.1H NMR(400MHz,DMSO-d6)δ7.84(d,2H),7.58(d,2H),6.65(d,1H),6.62(d,1H),4.87(s,2H),3.73(t,2H).2.59(t,2H)13C NMR(101MHz,DMSO-d6)δ166.06,145.14,140.38,139.82,134.47,129.32,128.67,128.28,127.62,115.64,113.66,73.02,43.22ppm.
13)(4-((2-氨基-4,6-二氯苯氧基)甲基)苯甲酰基)丙氨酸乙酯(目标化合物13)
参考目标化合物1的合成方法，以化合物1-4、丙氨酸乙酯为原料合成。1H NMR(400MHz,Chloroform-d)δ7.88–7.72(m,2H),7.53(d,2H),6.86(s,1H),6.61(d,1H),4.97(s,2H),4.13(q,2H)，3.85(t,2H)，2.75(t,3H)，1.29(t,3H)。
14)(4-((2-氨基-4,6-二氯苯氧基)甲基)苯甲酰基)丙氨酸异丙酯(目标化合物14)
参考目标化合物1的合成方法，以化合物1-4、丙氨酸异丙酯为原料合成。1H NMR(400MHz,Chloroform-d)7.83(d,2H),7.56(d,2H),6.67(d,1H),6.60(d,1H),4.91(s,2H),3.85(t,2H)，2.75(t,2H)，4.93(m,1H)，1.32(d,6H)。
15)(4-((2-氨基-4,6-二氯苯氧基)甲基)苯甲酰基)丙氨酰胺(目标化合物15)
参考目标化合物1的合成方法，以化合物1-4、丙氨酰胺为原料合成。1H NMR(400MHz,DMSO-d6)δ7.85(d,2H),7.57(d,2H),6.65(d,1H),6.62(d,1H),4.87(s,2H),3.75(t,2H).2.74(t,2H)
16)(4-((2-氨基-4,6-二氯苯氧基)甲基)苯甲酰基)丙氨酰甲胺(目标化合物16)
1H NMR(400MHz,DMSO-d6)δ7.84(d,2H),7.57(d,2H),6.66(d,1H),6.62(d,1H),4.86(s,2H),3.74(t,2H),3.05(s,3H).2.73(t,2H)
实施例2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
2.1原代神经元培养
胎龄16d的孕鼠颈椎脱臼处死，取胎鼠，置于冰盒上，依次用新洁尔灭溶液和75％乙醇溶液进行全身消毒，然后用碘伏对头部皮肤进行消毒。小心取出双侧皮层，置于预冷的D-Hank’s溶液(10mL)中，清洗后剥离脑膜，D-Hank’s溶液清洗两遍，吸干D-Hank’s，剪碎皮层组织，转移至37℃预热的0.125％胰酶消化液(4mL)中，37℃消化8min后取出，加入5mLDMEM/F12+10％FBS终止消化，轻柔吹打分散组织。2500rpm离心3分钟，弃去上清，加入含有2％B27的Neuralbasal培养基，混匀，400目筛网过滤，滤液进行细胞计数后，按1×105个/cm2接种于PORN包被的24孔板中，置37℃，95％空气+5％CO2的混合湿润气体的细胞孵箱中培养。在细胞培养第1、4天半量换液。
2.2谷氨酸造模
在神经元体外培养第8天，进行Glu和Gly造模，测试药物对损伤的保护作用。受试药物设置0.1μmol/L、1μmol/L、10μmol/L三个浓度(DMSO配制成1000×母液，用培养基稀释)，预先孵育30min；正常对照和模型对照加入等浓度的DMSO(0.1％)进行孵育。孵育结束后，模型对照组、受试药物组更换含Glu(终浓度10μmol/L)和Gly(终浓度50μmol/L)的培养基孵育30min，模拟缺血损伤造模；正常对照更换不含Glu和Gly的培养基孵育。造模结束后将24孔板中的培养基弃干净，每孔加300μL新培养基，收集漏出的LDH。6小时后，回收300μL培养基(即细胞外液)，各孔加300μL ddH2O，放入-80℃冰箱，反复冻融3次，回收300μL ddH2O(即细胞內液)。收集的细胞内、外液置-80℃保存，待测。
2.3 LDH测定
冻存细胞内、外液冰上解冻，使用LDH试剂盒(南京建成生物A020-2-2)，按照说明书测定吸光度。细胞内、外液OD值＝测定OD值-对照OD值，LDH漏出率＝细胞外液OD值/(细胞外液OD值+细胞内液OD值)。
细胞保护率＝(模型组LDH漏出率-样品组LDH漏出率)/(模型组LDH漏出率-正常组LDH漏出率)*100％
表1目标化合物对谷氨酸损伤神经元细胞保护率
由表1可见：目标化合物对OGD谷氨酸损伤神经元细胞保护率强于SCR4026。
实施例3目标化合物对光诱导血栓形成性脑缺血模型损伤的保护作用
3.1脑缺血模型制备
通过光诱导血栓形成性脑缺血模型模拟脑缺血。使用2％水合氯醛(0.02mL/g)麻醉小鼠后，固定小鼠于立体定位仪上，通过正中切口暴露头骨，清除结缔组织并吹干。用直径为2.5mm的冷光源垂直贴于颅骨上方，并使其圆心较前囟向右偏移1.5mm。静脉注射玫瑰红(50mg/kg)3min后进行冷光源照射10min，冷光源照射前用锡箔纸将小鼠尾部罩住避免损伤。照射结束后移除冷光源，缝合并消毒。在整个手术过程中，动物体温通过温控式红外灯调节，维持在(37±0.5)℃。手术结束后将动物放回各自饲养笼中，细心监护直至动物苏醒。造模成功的小鼠表现为前肢腕肘屈曲。
3.2网格实验方法
将小鼠放置在钢制网格(长与宽分别为32cm和20cm，其上网格边长为1.2cm×1.2cm)上，网格下方放置摄像头拍摄整个行走过程，让小鼠在网格上自由行走5min，记录四肢失足总数和总的步伐数。失足百分比(％)＝失足数/(失足数+未失足数)×100％。行走过程中如果小鼠足下没有支撑住而穿过网格即被认为是失足，如果小鼠仅仅是腕部靠在网格边缘亦认为是失足。
3.3圆筒实验
圆筒实验依据动物垂直贴壁向上探索的特性而设计，评判动物对某一侧肢体的依赖程度。小鼠被放在一个透明有机玻璃筒内，当小鼠在筒内站立时会用其某一侧前肢或者两侧前肢放在筒壁上来支撑身体。圆筒直径10cm，高15cm。在摄像头斜对侧放置一面镜子以记录另一侧的前肢贴壁情况。摄像头采集视频5min，播放时用1/5的正常速度播放，记录小鼠右肢、左肢单独以及左右肢同时放在筒壁上的时间。计算不对称指数＝(对照侧前肢贴壁时间患侧前肢贴壁时间)/左右肢贴壁总时间。
3.4实验结果
选取目标化合物9，于造模后第4天-第10天连续尾静脉给药，给药剂量3mg/kg。于第11天进行网格实验和圆筒实验，测定结果见图1、图2。
Claims (4)
1.一类神经保护剂，其特征在于，结构符合通式(I)：
2.根据权利要求1所述的一类神经保护剂，其特征在于，具体化合物结构如下所示：
3.权利要求1-2任一所述神经保护剂或其药学上可接受的盐在制备用于治疗脑卒中损伤药物中的应用。
4.一种用于治疗脑卒中损伤药物，其特征在于，所述有效成分为权利要求1-2任一所述神经保护剂或其药学上可接受的盐。
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