CN116947832B - 一种川芎嗪衍生物、其制备方法及医药用途 - Google Patents
一种川芎嗪衍生物、其制备方法及医药用途 Download PDFInfo
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
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Abstract
本发明涉及一种川芎嗪衍生物、其制备方法及医药用途,本发明化合物以取代的苯并呋喃酮或取代茚酮为起始原料,经缩合反应制备,得到的化合物能够在缺氧缺糖的条件下显著提高大脑皮层神经元细胞的存活率,而且能够显著改善缺血/再灌注大鼠模型的脑梗死面积和神经功能。本发明化合物合成方法简单,原料廉价易得,因此适合产业化应用。
Description
技术领域
本发明属于医药技术领域,具体为一种川芎嗪衍生物、其制备方法及医药用途。
背景技术
苯并呋喃酮类化合物和茚酮类化合物是非常重要的天然活性化合物,具有较好的神经保护活性。川芎嗪(四甲基吡嗪,tettramethylpyrazine,TMP)是中药川芎中所含的有效成分之一,药理研究表明川芎嗪具有清除自由基、抑制血小板聚集、拮抗钙离子和促进内皮细胞修复等作用。对心脑血管的治疗作用与其抗氧化、抗炎、钙稳态作用等有关。
但是现有的川芎嗪或其衍生物对心脑血管治疗或预防效果、以及神经保护作用不够,影响了该类化合物的应用研究进展,因此如何设计另外一种川芎嗪衍生物,使其具有更好的心脑血管治疗或预防效果、以及神经保护作用,是目前急需解决的问题。
发明内容
本发明的目的在于为了解决如上问题,而提供一种具有较好的心脑血管治疗或预防效果、以及神经保护作用的川芎嗪类衍生物。本发明获得的这几类化合物结构简单,分子大小适中,可作为结构修饰及筛选神经保护剂的先导化合物。
本发明通过如下技术方案方式实现:
一种川芎嗪衍生物,结构通式如下式I-1或式I-2:
;
其中,X选自-O-或者-CH2-;
R选自卤素或者三氟甲基。
所述川芎嗪衍生物选自但不限于以下结构:
。
本发明还提供了所述的川芎嗪衍生物在制备药物中的应用,所述药物包括神经保护剂、血小板聚集抑制剂、自由基清除药物、血管舒张剂或抗氧化剂。
本发明还提供了所述川芎嗪衍生物在制备药物中的应用,所述药物包括预防或治疗神经退化性疾病、缺血性疾病或者血管性痴呆的药物。进一步地,所述神经退化性疾病为阿尔兹海默病、帕金森病、亨廷顿病或者肌萎缩性侧索硬化,所述缺血性疾病为心肌缺血或者脑卒中。
本发明还提供了一种药物组合物,其包含至少一种所述川芎嗪衍生物或其药学上可接受的盐、前药、溶剂化物以及立体异构体。
本发明还提供了一种所述川芎嗪衍生物的制备方法:
所述式I-1结构的制备方法包括以下步骤:以取代的苯并呋喃酮为起始原料,经缩合反应制备;或以取代茚酮为起始原料,经缩合反应制备;
所述I-2结构的制备方法包括以下步骤:以I-1衍生物为起始原料,经还原反应制备。
包括以下合成路径:
,
或者
。
本发明的有益效果在于:本发明的川芎嗪衍生物具有较好的神经保护作用,能够在缺氧缺糖的条件下显著提高大脑皮层神经元细胞的存活率,而且能够显著改善缺血/再灌注大鼠模型的脑梗死面积和神经功能。本发明的川芎嗪衍生物结构简单,分子大小适中,可作为结构修饰及筛选神经保护剂的先导化合物。且合成方法简单,原料廉价易得,因此适合产业化应用。
附图说明
图1为验证本发明化合物的体内脑保护作用的治疗性给药过程示意图;
图2为验证本发明化合物的体内脑保护作用的治疗性给药的脑梗死情况;
图3为验证本发明化合物的体内脑保护作用的预防性给药过程示意图;
图4 为验证本发明化合物的体内脑保护作用的预防性给药的脑梗死情况。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
一、本发明川芎嗪衍生物的合成
(一)化合物1-化合物4的通用合成路径如下:
。
实施例1 化合物1的合成
在反应瓶中依次加入6-氟-苯并呋喃酮6.5mmol,三氧化二铝247mmol,3,5,6-三甲基吡嗪-2-甲醛6.5mmol和二氯甲烷50 ml,搅拌使其使充分溶解,在40℃的惰性气体保护条件下回流反应两小时,待反应完全后停止反应。反应液使用真空泵、定性滤纸,布氏漏斗进行抽滤,滤液用旋蒸仪旋蒸干。反应液粗品使用硅胶柱色谱层析纯化(PE:EA=4:1),得淡黄色固体1.54g,收率为78%。
化合物1结构式如下:
。
1H NMR (400 MHz, Chloroform-d) δ 7.80 (dd, J = 8.5, 5.7 Hz, 1H), 7.06– 7.02 (m, 1H), 7.01 (s, 1H), 6.94 (td, J = 8.8, 2.1 Hz, 1H), 2.66 (s, 3H),2.62 (s, 3H), 2.56 (s, 3H).13C NMR (100 MHz, Chloroform-d) δ 182.32, 167.44(d, J = 258.4 Hz), 167.35 (d, J = 14.6 Hz), 150.50, 149.79, 149.17, 148.07,141.38, 125.68 (d, J = 11.8 Hz), 116.68 (d, J = 2.0 Hz), 111.24 (d, J = 24.0Hz), 106.41,100.36 (d, J = 26.7 Hz), 21.03, 20.96, 20.44.HRMS-TOF (m/z) calcdfor C16H13FN2O2[M+H]+:285.1039,found 285.1018。
参照实施例1的方法分别合成以下化合物2~化合物4。
实施例2 化合物2
化合物2的起始原料为6-氯-苯并呋喃酮,其结构式如下:
。
1H NMR (400 MHz, Chloroform-d) δ 7.72 (d, J = 8.2 Hz, 1H), 7.36 (d, J= 1.5 Hz, 1H), 7.20 (dd, J = 8.2, 1.6 Hz, 1H), 7.02 (s, 1H), 2.65 (s, 3H),2.61 (s, 3H), 2.55 (s, 3H)。
13C NMR (100 MHz, Chloroform-d) δ 182.67, 166.18, 150.56, 149.87,149.17, 147.78, 142.36, 141.34, 124.50, 123.58, 118.69, 113.04, 106.85,21.06, 20.95, 20.45.HRMS-TOF (m/z) calcd for C16H13ClN2O2[M+H]+:301.0774,found301.0721。
实施例3 化合物3
化合物3的起始原料为5-氟-3-苯并呋喃酮,其结构式如下:
。
淡黄色固体,收率为77.9%。1H NMR (600 MHz, Chloroform-d) δ 7.45 (dd, J =6.6, 2.7 Hz, 1H), 7.38 (td, J = 8.7, 2.8 Hz, 1H), 7.31 (dd, J = 8.9, 3.6 Hz,1H), 7.03 (s, 1H), 2.65 (s, 3H), 2.62 (s, 3H), 2.55 (s, 3H)。
13C NMR (150 MHz, CDCl3) δ 184.71, 163.25, 159.01 (d, J = 244.8 Hz),151.76, 151.15, 150.26, 149.37, 142.52, 124.85 (d, J = 25.9 Hz), 121.88 (d, J= 8.2 Hz), 114.80 (d, J = 7.9 Hz), 110.44 (d, J = 24.3 Hz), 108.10, 22.25,22.12, 21.66。
实施例4 化合物4
化合物4的起始原料为5-氯-3-苯并呋喃酮,其结构式如下:
。
淡黄色固体,收率为90%。1H NMR (600 MHz, Chloroform-d) δ 7.75 (d, J =1.9 Hz, 1H), 7.60 (dd, J = 8.7, 2.0 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.03(s, 1H), 2.65 (s, 3H), 2.61 (s, 3H), 2.55 (s, 3H)。
13C NMR (150 MHz, CDCl3) δ 184.04, 165.43, 151.83, 151.20, 150.28,148.92, 142.43, 137.19, 129.53, 124.46, 122.37, 114.92, 108.23, 22.25, 22.11,21.65。
(二)化合物5-化合物7的通用合成路径如下:
。
实施例5 化合物5的制备
将6-氟-1-茚酮150mg与20mg氢氧化钠置于烧瓶中,充入氩气保护。加入12.5ml甲醇,置于冰水浴冷却中反应,反应1.5h,期间逐渐升温至室温。将150mg 3,5,6-三甲基吡嗪-2-甲醛溶解在2ml甲醇中,加入到反应液中,维持室温继续反应30min,用TLC监控反应。反应结束,用150ml乙酸乙酯稀释反应液,用20%氯化钠溶液洗涤有机相,无水硫酸镁干燥乙酸乙酯溶液,过滤除去硫酸镁。减压浓缩后经硅胶柱色谱纯化(石油醚:乙酸乙酯=2:1)得到类白色固体产物,收率56.23%。
化合物5结构式如下:
。
1H NMR (600 MHz, Chloroform-d) δ 7.77 (t, J = 2.2 Hz, 1H), 7.58 –7.50 (m, 2H), 7.33 (td, J = 8.6, 2.6 Hz, 1H), 4.24 (s, 2H), 2.72 (s, 3H),2.60 (s, 3H), 2.57 (s, 3H)。
13C NMR (100 MHz, Chloroform-d) δ 192.82 (d, J = 3.0 Hz), 161.26 (J =247.6 Hz), 150.41, 149.91, 148.57, 145.70 (d, J = 2.1 Hz), 143.80, 139.28,138.53 (d, J = 7.4 Hz), 126.65 (d, J = 7.8 Hz), 125.90, 121.37 (d, J = 23.6Hz), 109.25 (d, J = 21.9 Hz), 31.93, 20.93, 20.87, 20. 17.HRMS-TOF (m/z)calcd for C17H15FN2O [M+H]+: 283.1247,found 283.1223。
参照实施例5的方法分别合成以下化合物6~化合物7。
实施例6 化合物6
化合物6的起始原料为5-氟-1-茚酮,其结构式如下:
。
类白色固体产物,收率61.2%。1H NMR (600 MHz, Chloroform-d) δ7.90 (dd, J= 8.4, 5.3 Hz, 1H), 7.73 (t, J = 2.3 Hz, 1H), 7.22 (dd, J = 8.6, 2.2 Hz, 1H),7.10 (td, J = 8.7, 2.3 Hz, 1H), 4.25 (d, J = 2.3 Hz, 2H), 2.69 (s, 3H), 2.58(s, 3H), 2.54 (s, 3H)。
13C NMR (100 MHz, Chloroform-d) δ 193.04, 167.27 (d, J = 255.9 Hz),154.31 (d, J = 10.2 Hz), 151.43, 150.91, 149.71, 145.04, 139.91, 134.44 (d, J= 1.8 Hz), 126.88 (d, J = 10.4 Hz), 126.42, 115.76 (d, J = 23.7 Hz), 113.12(d, J = 22.3 Hz), 33.63 (d, J = 2.2 Hz), 22.05, 22.02, 21.29.HRMS-TOF (m/z)calcd for C17H15FN2O [M+H]+:283.1247,found 283.1224。
实施例7 化合物7
化合物7的起始原料为6-三氟甲基-1-茚酮,其结构式如下:
。
类白色固体产物,收率45.3%。1H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J= 1.7 Hz, 1H), 7.85 (dd, J = 8.0, 1.8 Hz, 1H), 7.81 (t, J = 2.3 Hz, 1H), 7.70(d, J = 8.0 Hz, 1H), 4.33 (s, 2H), 2.70 (s, 3H), 2.59 (s, 3H), 2.55 (s, 3H)。
13C NMR (100 MHz, CDCl3) δ 193.61, 154.53, 151.74, 151.30, 149.82,144.78, 139.27, 138.34, 131.23 (dd, J = 3.5 Hz), 130.28 (dd, J = 32.9 Hz),127.62, 127.13, 123.98(dd,J=272), 121.71 (dd, J = 3.9 Hz), 33.78, 22.10,22.03, 21.30.HRMS-TOF (m/z) calcd for C18H15F3N2O [M+H]+:333.1215, found:333.1207。
(三)化合物8、化合物9的通用合成路径如下:
。
实施例8 化合物8的制备
将化合物1(500mg,1.76mmol)置于反应瓶中,加入20ml的乙酸乙酯充分溶解,再加入75mg钯碳(0.7mmol),通入氢气,使之在氢气环境常温条件下反应30min,用TLC监控反应。反应结束,对反应液进行过滤,滤液浓缩得到粗品。使用柱层析PE:EA(4:1)进行纯化得淡黄色固体156mg,收率为31.2%。
化合物8结构式如下:
。
1H NMR (400 MHz, Chloroform-d) δ 7.71 (dd, J = 8.5, 5.8 Hz, 1H), 6.82(td, J = 8.7, 2.1 Hz, 1H), 6.73 (dd, J = 9.2, 2.1 Hz, 1H), 5.20 (dd, J = 7.5,3.8 Hz, 1H), 3.48 (dd, J = 16.5, 3.8 Hz, 1H), 3.26 (dd, J = 16.3, 7.6 Hz,1H), 2.47 (s, 3H), 2.44 (s, 3H), 2.25 (s, 3H).13C NMR (100 MHz, CDCl3) δ199.59, 173.82 (d, J = 14.8 Hz), 169.17 (d, J = 257.2 Hz), 149.44, 148.60,148.15, 145.60, 125.97 (d, J = 12.1 Hz), 118.64 (d, J = 1.7 Hz), 110.67 (d, J= 24.3 Hz), 100.84 (d, J = 25.9 Hz), 84.74, 35.24, 21.41, 21.08, 20.97.HRMS-TOF (m/z) calcd for C16H15FN2O2[M+H]+: 287.1196, found 287.1171。
实施例9 化合物9的制备
其结构式如下:
。
参照实施例8的方法,以化合物2为起始原料,通过还原反应合成化合物9,得淡黄色固体132mg,收率为26.4%。1H NMR (400 MHz, Chloroform-d) δ 7.67 – 7.62 (m, 1H),7.11 – 7.05 (m, 2H), 5.17 (dd, J = 7.2, 3.9 Hz, 1H), 3.49 (dd, J = 16.5, 3.8Hz, 1H), 3.29 (dd, J = 16.4, 7.3 Hz, 1H), 2.47 (s, 3H), 2.43 (s, 3H), 2.22(s, 3H)。
13C NMR (100 MHz, Chloroform-d) δ 200.04, 172.56, 149.46, 148.59,148.12, 145.48, 143.69, 124.85, 122.89, 120.79, 113.88, 84.35, 35.23, 21.37,21.00, 20.93.HRMS-TOF (m/z) calcd for C16H15ClN2O2[M+H]+:303.0900,found303.0870。
二、本发明的川芎嗪衍生物对神经元的保护作用
使用CCK8法,测试了化合物1-化合物9在OGD(oxygen-glucose deprivation/reoxygenation,体外氧糖剥夺/复氧)模型中的大鼠大脑原代皮层神经保护作用。依达拉奉为阳性对照药,按照表1浓度给药,测试了化合物在6个不同浓度下对大鼠神经元保护作用。
选取生长到第7 d左右的大鼠脑原代皮层神经元细胞进行OGD/R模型。使用4×104的细胞密度接种于12孔培养板中,空白组使用1%FBS的EMEM培养基5%CO2、37℃培养箱常规培养,OGD/R模型组和给药组分别含有1%FBS以及对应浓度的含药EMEM培养基常规培养24 h后开始制备OGD/R模型:首先将培养基更换为不含葡萄糖与血清的EMEM培养基,同时将细胞置于含有5%CO2、95%N2三气培养箱中培养2 h,完成缺氧过程;随后将细胞培养基更换为完全DMEM培养基,同时将细胞置于含有5% CO2培养箱中培养24 h完成复氧过程。孵育结束前4h,每孔加入20 μL MTT溶液(5 mg/mL)。孵育结束后,弃去各孔上清液,每孔加入150μLDMSO,细胞振荡仪上振荡10 min,待结晶物充分溶解后用酶标仪测定OD570。结果采用mean±SD形式表示。数据组间统计学差异采用one-way ANOVA和Sidak's检验,P值小于0.05认为有显著性差异。公式:生存率= (实验组OD值/对照组OD值)×100%。
测试结果如下表1-1和表1-2所示。
表1-1
表1-2
实验结果表明,本申请化合物能够显著提高大鼠脑原代皮层神经元细胞OGD/R造模后的存活率,并且大部分化合物与阳性药依达拉奉相比,显示出强效的神经元保护作用,显著优于阳性对照药。
三、本发明的川芎嗪衍生物对体内脑的保护作用
采用MCAO法建立大鼠脑缺血再灌注模型,通过检测造模后大鼠的脑梗死面积,验证化合物的体内脑保护作用。
模型建立方法:大鼠用3%异氟烷1.5 L/min流量进行麻醉,用动物剃毛器去除颈部毛发,碘伏和酒精消毒,颈部正中切开皮肤,钝性分离皮下组织,然后沿右侧胸锁乳突肌腱向下寻找颈动脉,小心地分离动脉鞘,勿伤及迷走神经,随后分离颈总、颈外和颈内动脉,并结扎颈总、颈外动脉,使用动脉夹夹闭颈内动脉,并在颈总动脉处用眼科剪剪一小口,插入预先准备好的线栓,栓线正好插至颃内的大脑前动脉,堵住大脑中动脉的开口。用线结扎好线栓并缝合肌肉和皮肤,缝好后的大鼠放入笼中,加强术后保温。
1、治疗性给药
使用雄性大鼠,体重(260±10) g,随机分组:假手术组,模型组,阳性药组(丁苯酞,40mg/kg),目标化合物1(40mg/kg)组。实验前禁食12 h,自由饮水。给药过程见图1,造模前1h(注射)给药1次,造模后第二天开始连续给药6天。假手术组的动物仅进行相同的麻醉和手术过程,但不栓塞大脑中动脉造成脑缺血模型。采用TTC染色法检测脑梗死面积。染色之后,白色为脑梗死区域,红色为正常组织。按照记录,用Image-Proplus(Version 6.0)分析软件计算脑梗死面积。脑梗死面积(%)=脑梗死面积5片之和/总面积5片之和×100%。
脑梗死情况见图2,具体的脑梗死面积百分比情况见表2。
表2
由以上结果可知,丁苯酞组在给药剂量40 mg/kg下脑梗死面积比例从56.76%下降到36.52%,而化合物1组下降到27.04%,明显优于阳性药组。
2、预防性给药:
使用雄性大鼠,体重(260±10) g,随机分组:假手术组,模型组,阳性药组(丁苯酞,80mg/kg),目标化合物1分为高剂量组(80mg/kg)和低剂量组(40mg/kg)。实验前禁食12h,自由饮水。给药过程见图3,造模前五天每天(口服)给药1次,造模当天且手术前给药1次,再灌注24 h后给药1次。假手术组的动物仅进行相同的麻醉和手术过程,但不栓塞大脑中动脉造成脑缺血模型。采用TTC染色法检测脑梗死面积,具体方法参考前述治疗性给药部分。
脑梗死情况见图4,具体的脑梗死面积百分比情况见表3。
表3
由以上结果可知,化合物1(40 mg/kg)与丁苯酞 (80 mg/kg)的脑保护作用相当,而化合物1 (80 mg/kg)显著改善脑梗死面积比例从42.8%下降到23.6%,表现出最优的脑保护作用。
四、本发明的川芎嗪衍生物的安全性实验
1、体外急性毒性实验(大鼠原代神经元)
使用CCK8法(具体实验操作参照前述第二部分神经元保护作用的实验,差别在于不建立OGD/R模型),测试化合物1-化合物9的大鼠大脑原代皮层神经元的急性毒性作用。依达拉奉为阳性对照药,测试了化合物在6个不同浓度下的大鼠神经元的存活率。结果见下表4-1和表4-2。
表4-1
表4-2
实验结果表明,本发明化合物在浓度范围3.75 μM- 100 μM下,没有显示出细胞毒性作用,表明化合物的安全性好。
2、体内急性毒性实验
使用雄性小鼠,体重(25±5) g,随机分组:空白组和目标化合物1组,每组设6只老鼠。化合物组每天给药3.2g/kg,给药剂量是药物有效剂量的80倍,连续给药7天,观察老鼠的死亡情况和体重变化。结果见下表5。
表5
实验结果表明,化合物1在每天给药3.2 g/kg的给药剂量,连续给药7天后,体重稳定增加,与空白组体重相差较小。表明化合物1的体内安全性好。
最后应说明的是,以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (6)
1.一种川芎嗪衍生物,其特征在于:所述川芎嗪衍生物选自以下结构式:
。
2.一种根据权利要求1所述的川芎嗪衍生物在制备预防或治疗神经退化性疾病、缺血性疾病或者血管性痴呆的药物中的应用,其特征在于:所述神经退化性疾病为阿尔兹海默病、帕金森病、亨廷顿病或者肌萎缩性侧索硬化,所述缺血性疾病为心肌缺血或者脑卒中。
3.一种药物组合物,其特征在于:其包含至少一种如权利要求1所述的川芎嗪衍生物或其药学上可接受的盐。
4.一种根据权利要求 1所述的川芎嗪衍生物的制备方法,其特征在于:
所述化合物1的制备方法包括以下步骤:在反应瓶中依次加入6-氟-苯并呋喃酮6.5mmol,三氧化二铝247mmol,3,5,6-三甲基吡嗪-2-甲醛6.5mmol和二氯甲烷50 ml,搅拌使其充分溶解,在40℃的惰性气体保护条件下回流反应两小时,待反应完全后停止反应,反应液使用真空泵、定性滤纸,布氏漏斗进行抽滤,滤液用旋蒸仪旋蒸干得反应液粗品,反应液粗品使用硅胶柱色谱层析PE:EA=4:1纯化,得化合物1。
5.一种根据权利要求 1所述的川芎嗪衍生物的制备方法,其特征在于:
所述化合物5的制备方法包括以下步骤:将6-氟-1-茚酮150mg与20mg氢氧化钠置于烧瓶中,充入氩气保护,加入12.5ml甲醇,置于冰水浴冷却中反应,反应1.5h,期间逐渐升温至室温,将150mg 3,5,6-三甲基吡嗪-2-甲醛溶解在2ml甲醇中,加入到反应液中,维持室温继续反应30min,用TLC监控反应,反应结束,用150ml乙酸乙酯稀释反应液,用20%氯化钠溶液洗涤有机相,无水硫酸镁干燥乙酸乙酯溶液,过滤除去硫酸镁,减压浓缩后经硅胶柱色谱石油醚:乙酸乙酯=2:1纯化得化合物5。
6.一种根据权利要求 1所述的川芎嗪衍生物的制备方法,其特征在于:
所述化合物8的制备方法包括以下步骤:将化合物1 1.76mmol置于反应瓶中,加入20ml的乙酸乙酯充分溶解,再加入钯碳0.7mmol,通入氢气,使之在氢气环境常温条件下反应30min,用TLC监控反应,反应结束,对反应液进行过滤,滤液浓缩得到粗品,使用柱层析PE:EA=4:1进行纯化得化合物8。
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