CN108586447B - 一种苯二氮杂卓化合物及其制备方法和应用 - Google Patents
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Abstract
本发明属于化学医药领域,具体涉及一种苯二氮杂卓化合物及其制备方法和应用。该苯二氮杂卓化合物在文献中未见报道,根据实验发现本发明的苯二氮杂卓化合物在改善脑缺血损伤后影响的运动功能和脑缺血损伤后神经可塑性方面有很好的效果;本发明提供的苯二氮杂卓化合物或含有该化合物的制剂,可以应用在治疗/预防脑缺血导致神经功能缺陷的药物中,能改善脑缺血导致神经功能缺陷、改善脑缺血导致运动协调和平衡控制功能障碍、改善脑缺血导致前肢技巧功能损伤、改善脑缺血损伤后神经可塑性和脑缺血损伤后神经可塑性。
Description
技术领域
本发明属于化学医药领域,具体涉及一种苯二氮杂卓化合物及其制备方法和应用。
背景技术
苯二氮卓类(benzodiazepines)多为1,4-苯并二氮卓的衍生物。临床常用的有20余种。苯并二氮杂卓类药物为苯环与含氮杂原子的七元环稠合而成的杂环化合物,主要药理作用是抑制中脑网状结构对皮层的激醒而有利于睡眠,抑制边缘系统神经元的活动,减弱其对网状结构的激活。虽然它们结构相似,但不同衍生物之间,抗焦虑、镇静催眠、抗惊厥、肌肉松弛和安定作用则各有侧重。该类药物为苯二氮卓受体激动剂,可引起中枢神经系统不同部位的抑制。
苯二氮卓类用于治疗焦虑症、亦能减轻短暂性情绪失控、功能或器质性疾病和神经性疾病所致的焦虑或紧张,非胃肠给药能减轻脑瘫患者的肌肉痉挛和手足徐动症,控制癫痫持续状态、破伤风和奇特癫痫发作的反复惊厥。
目前关于改善脑缺血引起的神经损伤的药物不多且效果不好,因此需要开发一种苯二氮杂卓化合物应用在治疗该方面疾病的药物中,这对临床治疗上有重要的意义。
发明内容
有鉴于此,本发明的目的在于提供一种苯二氮杂卓化合物,本发明的苯二氮杂卓化合物在改善脑缺血损伤后影响的运动功能和脑缺血损伤后神经可塑性方面有很好的效果,可以应用在治疗该方面疾病的药物中。
为实现上述目的,本发明的技术方案为:
一种苯二氮杂卓化合物,其结构如下式VI所示:
式VI所示化合物为5-(5-氯-2-甲养苯基)-7-氟-1-(噻唑-2-基甲基)-1,3-二氢-2H-苯并[e][1,4]二氮杂-2-酮,本发明的苯二氮杂卓化合物在文献中未见报道。
本发明的目的之二在于提供一种上述苯二氮杂卓化合物的制备方法,式V化合物与2-碘甲基噻唑反应得式VI化合物,合成路线反应如下:
进一步,式V化合物与2-碘甲基噻唑的摩尔比为1:1.2~1.5。
式V化合物为5-(5-氯-2-甲氧苯基)-7-氟-1,3-二氢-2H-苯并[e][1,4] 二氮杂-2-酮。
作为一种优选,式V化合物与2-碘甲基噻唑的摩尔比为1:1.2。
进一步,式V化合物是由式IV化合物、六亚甲基四胺和甲酸加入溶剂中混合反应后得到,合成路线反应如下:
进一步,式IV化合物与六亚甲基四胺的摩尔比为1:2.2~2.5;六亚甲基四胺与甲酸的质量体积比为100:40~50g/ml。
式IV化合物为2-溴-N-(2-(5-氯-2-甲氧基苯甲酰)-4-氟苯基) 乙酰胺。
作为一种优选,式IV化合物与六亚甲基四胺的摩尔比为1:2.2;六亚甲基四胺与甲酸的质量体积比为100:42g/ml。
作为一种优选,所述溶剂为无水乙醇,甲酸与无水乙醇的体积比为4.2:500。
作为一种优选,式IV化合物、六亚甲基四胺和99%甲酸加入到无水乙醇中,搅拌反应4小时,再经真空浓缩干燥、溶解分离、结晶得式V化合物。
进一步,式IV化合物是以式I化合物和式II化合物为原料在催化剂的存在下反应合成式III化合物,式III化合物再与溴乙酰溴反应生成式 IV化合物,合成路线反应如下:
进一步,式I化合物与式II化合物的摩尔比为2.7~3.5:0.8~2.5;式 III化合物与溴乙酰溴的摩尔比为0.1:0.12~0.15。
式I化合物为5-氯-2-甲氧基苯甲酰氯,式II化合物为4-氟苯胺,式 III化合物为(2-氨基-5-氟苯基)(5-氯-2-甲养苯基)甲酮。
作为一种优选,式I化合物与式II化合物的摩尔比为2.7~3.5: 1.3~2.5;式III化合物与溴乙酰溴的摩尔比为0.1:0.12~0.14。
作为一种优选,式I化合物与式II化合物的摩尔比为2.8:1.3;式 III化合物与溴乙酰溴的摩尔比为0.1:0.12。
进一步,所述催化剂为无水氯化锌;式I化合物与无水氯化锌的摩尔比为2.7~3.5:1.8~2.8。
作为一种优选,式I化合物与无水氯化锌的摩尔比为2.8:1.8。
作为一种优选,式I化合物先与无水氯化锌混合加热到130-140℃后缓慢加入式II化合物,完全混合后将混合物加热到200-205℃,搅拌 1小时反应,再经冷却、回流、萃取和干燥得式III化合物。将式III化合物加入到苯中后再加入溴乙酰溴,混合后在40℃反应2小时,再经真空下浓缩干燥得式IV化合物。
总的苯二氮杂卓化合物的制备方法的合成路线反应如下:
本发明的目的之三在于提供一种含有式VI化合物的组合物,所述组合物包括式VI化合物和药学上可接受的载体和/或助剂。
术语药学上可接受的载体和/或助剂的实例为:糖类,例如乳糖、蔗糖、甘露醇和山梨醇;淀粉类,例如玉米淀粉、木薯淀粉和土豆淀粉;纤维素及其衍生物,例如羧甲基纤维素钠,乙基纤维素和甲基纤维素;磷酸钙类,例如磷酸二钙和磷酸三钙;硫酸钠;硫酸钙;聚乙烯吡咯烷酮;聚乙烯醇;硬脂酸;硬脂酸碱土金属盐,例如硬脂酸镁和硬脂酸钙;植物油类,例如花生油、棉籽油、芝麻油、橄榄油和玉米油;非离子、阳离子和负离子表面活性剂;聚乙二醇;脂肪醇类;和谷物水解固形物以及其它无毒的可相容的填充剂、粘合剂、崩解剂、缓冲剂、防腐剂、抗氧剂、润滑剂、着色剂等在药物制剂中常用到的辅料。
本发明的目的还在于提供一种上述式VI化合物或上述组合物在治疗/预防脑缺血导致神经功能缺陷和改善脑缺血损伤后神经可塑性的药物中的应用。
所述脑缺血导致神经功能缺陷后会影响肢体运动及协调和平衡控制功能,本发明的含有VI化合物或组合物药物能改善脑缺血导致神经功能缺陷、改善脑缺血导致运动协调和平衡控制功能障碍、改善脑缺血导致前肢技巧功能损伤、改善脑缺血损伤后神经可塑性和脑缺血损伤后神经可塑性。
本发明的有益效果在于:
1)本发明提供的苯二氮杂卓化合物是一种新型的化合物,该苯二氮杂卓化合物在文献中未见报道,根据实验发现本发明的苯二氮杂卓化合物在改善脑缺血损伤后影响的运动功能和脑缺血损伤后神经可塑性方面有很好的效果。
2)本发明提供的苯二氮杂卓化合物或含有该化合物的制剂,可以应用在治疗/预防脑缺血导致神经功能缺陷的药物中,能改善脑缺血导致神经功能缺陷、改善脑缺血导致运动协调和平衡控制功能障碍、改善脑缺血导致前肢技巧功能损伤、改善脑缺血损伤后神经可塑性和脑缺血损伤后神经可塑性。
附图说明
图1为式VI化合物治疗改善缺血导致神经缺陷评分。(*:p<0.05, n=6,Kruskal–Wallis test followed by the Mann-Whitney U-test with the Bonferronicorrection)
图2为式VI化合物治疗改善缺血后平衡木实验得分。(*:p<0.05, n=6,Kruskal–Wallis test followed by the Mann-Whitney U-test with the Bonferronicorrection)
图3为式VI化合物治疗改善脑缺血导致前肢技巧功能损伤。(**: p<0.01,n=6,two-way ANOVA with Holm-Sidak correction)
图4为式VI化合物治疗上调缺血半暗区Gap-43 mRNA水平。(**: p<0.01,n=6,two-way ANOVA with Holm-Sidak correction)
图5为式VI化合物治疗上调缺血半暗区GAP-43蛋白水平。(**: p<0.01,n=6,two-way ANOVA with Holm-Sidak correction)
图6为式VI化合物治疗增加缺血半暗区GAP-43阳性细胞数量。 (**:p<0.01,n=6,two-way ANOVA with Holm-Sidak correction)
具体实施方式
以下将参照附图,对本发明的优选实施例进行详细描述。优选实施例中未注明具体条件的实验方法,通常按照常规条件,所举实施例是为了更好地对本发明的内容进行说明,但并不是本发明的内容仅限于所举实施例。所以熟悉本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整,仍属于本发明的保护范围。
实施例1 苯二氮杂卓化合物的制备方法
2.8mol式I化合物先与1.8mol无水氯化锌混合加热到130-140℃后缓慢加入1.8mol式II化合物,完全混合后将混合物加热到200-205℃,搅拌1小时反应,再经冷却、回流、萃取和干燥得式III化合物。将式 III化合物加入到3L苯中后再加入2.16mol溴乙酰溴,混合后在40℃反应2小时,再经真空下浓缩干燥得式IV化合物。0.36mol式IV化合物、0.792mol(111g)六亚甲基四胺和46.62mL99%甲酸加入到5.55L无水乙醇中,搅拌反应4小时,再经真空浓缩干燥、溶解分离、结晶得式V化合物。2mol式V化合物再与2.4mol 2-碘甲基噻唑在100~300℃发生取代反应得式VI化合物。
实施例2 苯二氮杂卓化合物的功能验证试验
1.实验方法
1.1实验动物分组及处理
SPF级C57成年雄性小鼠,18-22g,由第四军医大学实验动物中心提供,饮水饮食不限,12h交替照明,随机分为5组,假手术组,行假手术;脑缺血组(MCAO),行大脑中动脉栓塞术;低、中、高剂量组,脑缺血损伤24h后分别灌胃给与1mg/kg 2mg/kg和4mg/kg XXX,每天1次,连续给药14天。
1.2大脑中动脉栓塞(MCAO)模型的制备
小鼠麻醉,仰卧于手术台,沿劲中部剪开皮肤,分离右侧颈总动脉,自颈总动脉插入栓线,通过颈内动脉阻塞大脑中动脉,缺血60min 后拔出栓线进行再灌注,缝合手术伤口。
1.3运动功能评价
1.3.1神经缺陷评分
各组小鼠在脑缺血损伤前以及缺血后不同时间点进行神经缺陷评分,采用longa评分法将其分为5个等级,级别越高损伤越严重,0 分:正常无行为缺陷;1分:左侧前爪不能正常伸展;2分:中度神经功能缺损,行走时,大鼠向左侧转圈;3分:重度神经功能缺损,行走时,大鼠身体向左侧倾倒;4分:不能自发行走,有意识丧失
1.3.2平衡木行走实验
平衡木行走实验旨在评价脑缺血损伤后的运动协调和平衡控制功能,各组小鼠在脑缺血损伤前训练3天学会走平衡木。缺血损伤后,在各观察时间点再次评价小鼠平衡木得分,其评分标准如下,0分:小鼠四肢均置于平衡木并保持平衡;1分:一侧爪子握住平衡木或在木条上摇晃;2分:有一个或两个肢体滑下平衡木;3分:三个肢体滑下平衡木;4分:在平衡木上试图保持平衡失败滑下;5分:试图保持平衡失败,悬吊在平衡木上然后跌落;6分:无试图保持平衡的过程直接从木条上跌落。
1.3.3楼梯实验
楼梯实验旨在评价脑缺血损伤后受损前肢的运动技巧,楼梯装置由7节倾斜的楼梯组成,每节楼梯放置三个食物小球,评分结果为1h 小鼠从楼梯装置取出并吃掉的食物小球,该实验前12h小鼠禁食。
1.4神经可塑性检测
生长相关蛋白43(GAP43)是一种胞膜蛋白,是神经元可塑性的标志物。通过检测GAP43的表达能够反应脑缺血损伤后神经可塑性的变化。
1.4.1 RT-PCR实验
不同检测时间点过量麻醉处死小鼠,冰上断头取脑,提取缺血半暗区内脑组织,按照试剂盒说明提取RNA,逆转录为cDNA,采用两步扩增法进行PCR反应。
1.4.2 Westernblot实验
不同检测时间点过量麻醉处死小鼠,冰上断头取脑,提取缺血半暗区内脑组织,提取蛋白,BCA法蛋白定量,每孔加入等量的蛋白,200V电压跑浓缩胶45min,转膜60min,一抗孵育过夜,二抗孵育1h, ECL发光。
1.4.3免疫荧光实验
不同检测时间点麻醉小鼠,首先生理盐水灌注再4%多聚甲醛灌注,取脑,蔗糖脱水、多聚甲醛固定后冰冻切片,脑片加入一抗4℃孵育过夜,PBS洗去一抗,加入二抗孵育1h,荧光显微镜下观察。
2.实验结果:
2.1式VI化合物改善运动功能
2.1.1式VI化合物改善脑缺血导致神经功能缺陷
实验结果表明,手术前各组小鼠得分相同。脑缺血损伤24h后,各组小鼠均表现出明显的神经功能缺陷。式VI化合物(2mg/kg和4 mg/kg)治疗后,相比模型组,治疗7天后明显改善神经缺陷,治疗14 天后则是有了进一步的改善,见图1。
2.1.2式VI化合物改善脑缺血导致运动协调和平衡控制功能障碍
平衡木行走实验结果显示,脑缺血前,各组的实验结果评分无显著性差异,脑缺血损伤24h后,相比于对照组,各缺血损伤组得分均有显著增加,表现出明显的运动协调能力障碍,相比于模型组,式VI化合物(2mg/kg和4mg/kg)治疗7天后显著降低平衡木行走实验得分,治疗14天后则是有了进一步的降低,见图2,结果表明式VI化合物能够明显改善缺血导致的运动协调和平衡控制功能障碍。
2.1.3式VI化合物改善脑缺血导致前肢技巧功能损伤
楼梯实验结果表明,脑缺血损伤前,各组得分无显著性差异,脑缺血损伤24h后,相比于假手术组,各缺血损伤组得分均明显减少,表明脑缺血损伤导致了前肢运动技巧的损伤,相比于模型组,式VI 化合物(2mg/kg和4mg/kg)治疗7天后显著增加楼梯实验得分,治疗14天后则是有了进一步的改善,见图3,结果表明式VI化合物能够明显改善脑缺血导致前肢运动技巧的损伤。
2.2式VI化合物改善脑缺血损伤后神经可塑性
通过检测GAP-43水平评价脑缺血损伤后的神经可塑性,RT-PCR 实验结果表明,脑缺血损伤使用式VI化合物(2mg/kg和4mg/kg)治疗7天和14天后,治疗组缺血半暗区内gap-43 mRNA的水平明显高于模型组,见图4。Western blot实验结果表明,式VI化合物(2mg/kg和4mg/kg)治疗7天和14天后,治疗组缺血半暗区内GAP-43蛋白水平明显高于模型组,见图5。与RT-PCR和western blot结果一致,免疫荧光结果表明,式VI化合物(2mg/kg和4mg/kg)治疗7天和14天后,治疗组缺血半暗区内GAP-43阳性细胞的数量明显高于模型组,见图6。实验结果表明式VI化合物能够增加脑缺血后的神经可塑性。
最后说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的宗旨和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (10)
3.根据权利要求2所述的制备方法,其特征在于,式V化合物与2-碘甲基噻唑的摩尔比为1:1.2~1.5。
5.根据权利要求4所述的制备方法,其特征在于,式IV化合物与六亚甲基四胺的摩尔比为1:2.2~2.5;六亚甲基四胺与甲酸的质量体积比为100:40~50g/ml。
7.根据权利要求6所述的制备方法,其特征在于,式I化合物与式II化合物的摩尔比为2.7~3.5:0.8~2.5;式III化合物与溴乙酰溴的摩尔比为0.1:0.12~0.15。
8.根据权利要求6所述的制备方法,其特征在于,所述催化剂为无水氯化锌;式I化合物与无水氯化锌的摩尔比为2.7~3.5:1.8~2.8。
9.含有权利要求1中式VI化合物的组合物,其特征在于,所述组合物包括式VI化合物和药学上可接受的载体和/或助剂。
10.权利要求1中的式VI化合物或权利要求9的组合物在制备治疗/预防脑缺血导致神经功能缺陷和改善脑缺血损伤后神经可塑性的药物中的应用。
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Citations (5)
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CN1379764A (zh) * | 1999-10-15 | 2002-11-13 | 弗·哈夫曼-拉罗切有限公司 | 苯并二氮杂䓬衍生物 |
CN1535266A (zh) * | 2001-04-12 | 2004-10-06 | - | 用作mGluR2拮抗剂Ⅱ的二氢-苯并[b][1,4]二氮杂�-2-酮衍生物 |
JP2007137818A (ja) * | 2005-11-17 | 2007-06-07 | Taisho Pharmaceut Co Ltd | 8−ヒドロキシ−2,4(1h,3h)−キナゾリンジオン誘導体 |
WO2008011032A1 (en) * | 2006-07-17 | 2008-01-24 | Amgen Inc. | Quinazoline and pyridopyrimidine derivatives as p38 kinase inhibitors |
WO2012072620A1 (en) * | 2010-11-30 | 2012-06-07 | Giuseppe Pignataro | 7-nitro-5-phenyl-1-(pyrrolidin-1-ylmethyl)-1h-benzo[e][1,4]diazepin-2(3h)-one and other benzodiazepine derivatives |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1379764A (zh) * | 1999-10-15 | 2002-11-13 | 弗·哈夫曼-拉罗切有限公司 | 苯并二氮杂䓬衍生物 |
CN1535266A (zh) * | 2001-04-12 | 2004-10-06 | - | 用作mGluR2拮抗剂Ⅱ的二氢-苯并[b][1,4]二氮杂�-2-酮衍生物 |
JP2007137818A (ja) * | 2005-11-17 | 2007-06-07 | Taisho Pharmaceut Co Ltd | 8−ヒドロキシ−2,4(1h,3h)−キナゾリンジオン誘導体 |
WO2008011032A1 (en) * | 2006-07-17 | 2008-01-24 | Amgen Inc. | Quinazoline and pyridopyrimidine derivatives as p38 kinase inhibitors |
WO2012072620A1 (en) * | 2010-11-30 | 2012-06-07 | Giuseppe Pignataro | 7-nitro-5-phenyl-1-(pyrrolidin-1-ylmethyl)-1h-benzo[e][1,4]diazepin-2(3h)-one and other benzodiazepine derivatives |
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