CN116253700A - 一种***二酚衍生物及其制备方法和应用 - Google Patents
一种***二酚衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种***二酚衍生物及其制备方法和应用,特别是神经***疾病(例如帕金森病)的预防和治疗中的应用。上述***二酚衍生物是从一系列合成衍生物中筛选得到的,动物试验结果显示,上述***二酚衍生物可以降低帕金森模型动物的平衡木评分,提高多巴胺水平和脑黑质(SubN)中酪氨酸羟化酶(TH)细胞阳性率,可用于癫痫、帕金森病等多种疾病的药物开发和研究,具有较佳的应用价值。
Description
技术领域
本发明涉及化学医药技术领域,具体涉及一种***二酚衍生物及其制备方法和应用,特别是神经***疾病(例如帕金森病)的预防和治疗中的应用。
背景技术
***二酚,简称CBD,是从***花叶中萃取的一种无毒的可用于药品、化妆品、保健食品的高附加值的酚类物质。其化学名称为2-[(1R,6R)-3-甲基-6-(1-甲基乙烯基)-2-环己烯-1-基]-5-戊基-1,3-苯二酚,CAS登记号:13956-29-1,化学结构如下所示:
现代医学研究表明,CBD在抗癫痫、抗应激、消炎等方面具有显著疗效,CBD获得了美国食药管理局批准,用于癫痫治疗,还可以作为改善情绪、抗焦虑的膳食补充剂。
但***素水溶性差,口服生物利用度低,不利于药物的开发利用。因此,需要提供一种新的***二酚衍生物及其制备方法和应用,在保证CBD纯度较高的同时具备较佳的水溶性,进一步提高其生物利用度,扩展其在医药领域的应用。
发明内容
为克服现有技术的不足,本发明提供一种***二酚衍生物及其制备方法和应用,特别是神经***疾病(例如帕金森病)的预防和治疗中的应用。
在本发明第一方面,提供一种化合物,其具有如下结构:
其中,
R8选自:-NH2、-H;优选地,R8为-NH2;
X1和X2独立地选自:单键、亚烷基(例如C1-15亚烷基、C1-10亚烷基、C1-5亚烷基)、被一个或多个取代基取代的亚烷基、被一个或多个-C(=O)O-间隔的亚烷基、被一个或多个-OC(=O)-间隔的亚烷基、被一个或多个烷基亚氨基间隔的亚烷基、被一个或多个-OC(=O)O-间隔的亚烷基、被以上间隔基团组合间隔的亚烷基;所述的取代基选自:烷基、羟基、卤素、芳基、环烷基、硫代烷氧基、硝基、氰基、氨基、杂芳基、杂环烷基,其中C原子上的H可被卤素、-OC0-10烷基、C1-10直链/支链烷基、硝基、氰基、氨基取代;
进一步地,X1和X2独立地选自:C1-5亚烷基、被一个或多个取代基取代的亚烷基、所述的取代基选自:烷基、羟基、卤素、芳基、环烷基、硫代烷氧基、硝基、氰基、氨基、杂芳基、杂环烷基,其中C原子上的H可被卤素、-OC0-10烷基、C1-10直链/支链烷基、硝基、氰基、氨基取代;
进一步地,X1和X2独立地选自:-CH2-、-CH2CH2-、-(CH2)2CH2-、-(CH2)3CH2-、-CH2CH(CH3)2-、-(CH2)4CH2-、-CH(CH3)CH2CH2-、-CH(OH)CH2-;
优选地,X1和X2均为-(CH2)3CH2-;
R3和R4各自独立地选自:-H、卤素、烷基、环烷基、芳基、杂芳基、杂环烷基;优选地,R3和R4均为-H;
R5、R6、R7各自独立地选自:-H、-OH、卤素、-NO2、-CN、烷基、环烷基;优选地,R5选自:-H或-OH,R6和R7均为-H。
在本发明的一个实施例中,R1和R2均为-NH2。
任选地,通式(I)可以被1个或者多个D原子取代。
在本发明的一个实施例中,上述化合物具有如下结构:
在本发明第二方面,提供第一方面所述化合物的立体异构体,其具有如下结构:
其中,X1、X2、R1、R2、R3、R4、R5、R6、R7、R8具有本发明第一方面所述相应定义。
进一步地,所述立体异构体具有如下结构:
在本发明的一些实施例中,上述立体异构体具有如下结构:
在本发明第三方面,提供第一方面所述化合物或第二方面所述立体异构体的盐或共晶,特别是药学上可接受的盐或共晶。
进一步地,该盐为碱加成盐或酸加成盐,所述的碱加成盐可以由金属或胺与化合物形成,特别是碱金属盐、碱土金属盐,例如钠盐、钾盐、镁盐、钙盐,特别是钠盐;所述的酸加成盐可以由无机酸或有机酸与化合物形成,例如盐酸盐、硝酸盐、硫酸盐、磷酸盐、柠檬酸盐、甲酸盐、富马酸盐、马来酸盐、乙酸盐、琥珀酸盐、酒石酸盐、甲磺酸盐、对甲苯磺酸盐,特别是甲磺酸盐。在本发明第四方面,提供第一方面所述化合物的前药、溶剂化物、代谢产物。在本发明第五方面,提供第一方面所述化合物的制备方法。
进一步地,该制备方法可以包括如下反应步骤:
进一步地,R'、R”为氨基保护基团,例如烷氧羰基类(例如-Boc)、酰基类、烷基类。
进一步地,上述反应的温度为20-30℃,例如室温。
在本发明第六方面,提供一种药物组合物,其包含本发明第一方面所述的化合物,或其药学上可接受的盐、共晶、立体异构体、前药、溶剂化物、代谢产物,以及一种或多种药学上可接受的辅料。
进一步地,药学上可接受的辅料可以选自:填充剂、粘合剂、润滑剂、崩解剂、抗氧化剂、缓冲剂、助悬剂、增溶剂、增稠剂、稳定剂和防腐剂等中的一种或多种。
进一步地,该药物组合物可通过胃肠给药或非胃肠给药,如通过静脉内、肌内、皮内和皮下途径给药。
进一步地,该药物组合物可以制备成以下剂型:片剂、丸剂、粉剂、颗粒剂、胶囊剂、锭剂、糖浆剂、凝胶剂、乳剂、混悬剂、控制释放制剂、气雾剂、粉雾剂、膜剂、注射剂、静脉滴注剂、透皮吸收制剂、软膏剂、洗剂、粘附制剂、栓剂、鼻制剂、肺制剂等。
进一步地,上述药物组合物的各种剂型可以按照药学领域的常规生产方法制备。
进一步地,该药物组合物还可以包含一种或多种其他针对相同或不同适应症的活性成分。
在本发明第七方面,提供本发明第一方面所述的化合物,或其药学上可接受的盐、共晶、立体异构体、前药、溶剂化物、代谢产物、第六方面所述的药物组合物在制备预防和/或治疗疾病的药物中的应用。
进一步地,上述疾病选自:神经***疾病、癌症、自身免疫性疾病、心血管疾病、疼痛、炎症、肝损伤中的一种或多种,优选地,所述疾病为神经***疾病;
进一步地,所述神经***疾病为神经退行性疾病或癫痫,所述神经退行性疾病选自:帕金森氏病、阿尔茨海默症、克雅二氏病、亨廷顿病、多发性硬化症;优选地,所述神经退行性疾病为帕金森氏病。
进一步地,癌症包括,但不限于,乳腺癌、肺癌、结直肠癌、肝癌、胰腺癌、胃癌、胃食管腺癌、食管癌、小肠癌、贲门癌、子宫内膜癌、卵巢癌、输卵管癌、外阴癌、睾丸癌、***癌、白血病、神经胶质瘤等。
进一步地,自身免疫性疾病包括,但不限于,***性红斑狼疮、类风湿关节炎、多发性硬化症、溃疡性结肠炎、克罗恩氏病、自身免疫性肝炎等。
在本发明第八方面,提供一种预防和/或治疗疾病的方法,其包括向有此需求的受试者施用本发明第一方面所述的化合物,或其药学上可接受的盐、共晶、立体异构体、前药、溶剂化物、代谢产物,或第六方面所述的药物组合物的步骤。
进一步地,上述疾病选自:神经***疾病、癌症、自身免疫性疾病、心血管疾病、疼痛、炎症、肝损伤中的一种或多种,优选地,所述疾病为神经***疾病。
进一步地,所述神经***疾病为神经退行性疾病或癫痫,所述神经退行性疾病选自:帕金森氏病、阿尔茨海默症、克雅二氏病、亨廷顿病、多发性硬化症;优选地,所述神经退行性疾病为帕金森氏病。
进一步地,癌症包括,但不限于,乳腺癌、肺癌、结直肠癌、肝癌、胰腺癌、胃癌、胃食管腺癌、食管癌、小肠癌、贲门癌、子宫内膜癌、卵巢癌、输卵管癌、外阴癌、睾丸癌、***癌、白血病、神经胶质瘤等。
进一步地,自身免疫性疾病包括,但不限于,***性红斑狼疮、类风湿关节炎、多发性硬化症、溃疡性结肠炎、克罗恩氏病、自身免疫性肝炎等。
进一步地,受试者可以为哺乳动物,例如,人类、猩猩、猴、犬、兔、鼠等,特别是人类。
本发明的发明人在***二酚的基础上进行结构修饰改造,在一系列合成衍生物中筛选得到本发明的化合物,动物试验结果显示,可以降低帕金森模型动物的平衡木评分,提高多巴胺水平和脑黑质(SubN)中酪氨酸羟化酶(TH)细胞阳性率,可用于帕金森病等多种疾病的药物开发和研究,具有较佳的应用价值。
附图说明
图1所示为帕金森模型行为学平衡木评分结果。
图2所示为帕金森模型治疗后纹状体多巴胺含量检测结果。
图3所示为脑黑质(SubN)中酪氨酸羟化酶(TH)细胞阳性率。
图4所示为脑黑质(SubN)中酪氨酸羟化酶(TH)细胞的显微镜图像。
具体实施方式
除非另有定义,本发明中所使用的所有科学和技术术语具有与本发明涉及技术领域的技术人员通常理解的相同的含义,例如:
术语“烷基”指的是直链或支链的且不含不饱和键的烃基,且该烃基以单键与分子其它部分连接。在本文中所使用的烷基通常含有1至12(例如1、2、3、4、5、6、7、8、9、10、11、12)个碳原子,优选含有1至6个碳原子(即,C1-6烷基)。所述烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、正己基、异己基等。
术语“亚烷基”指的是烷烃分子失去两个氢原子而成的烃基(二价烷基),其可以是直链或支链且其以单键与分子其它部分连接。在本文中典型的亚烷基1至12(例如1、2、3、4、5、6、7、8、9、10、11、12)个碳原子,优选含有1至6个碳原子,亚烷基的实例如亚甲基(-CH2-)、亚乙基、亚丙基、亚丁基等。
术语“烷氧基”指的是羟基中的氢被烷基取代后形成的取代基。本文中所使用的烷氧基通常含有1至12(例如1、2、3、4、5、6、7、8、9、10、11、12)个碳原子,优选含有1至6个碳原子(即,C1-6烷氧基)。所述烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基等。
术语“环烷基”指的是脂环烃,如含1至4个单环和/或稠环、含3-18个碳原子,优选3-10(例如3、4、5、6、7、8、9、10)个碳原子,如环丙基、环丁基、环戊基、环己基或金刚烷基等。
术语“芳基”指的是任何从简单芳香环衍生出的官能团或取代基,包括单环的芳基基团和/或稠环的芳基基团,如包含1-3个环的、单环或稠环的且具有6-18(例如6、8、10、12、14、16、18)个碳环原子。本文中所使用的芳基通常为包含1-2个环的、单环或稠环的且具有6-12个碳环原子的芳基(即,C6-12芳基),其中碳原子上的H可以被取代,例如被烷基、卤素等基团取代。所述芳基的实例包括但不限于苯基、对羟基苯基等。
术语“药学上可接受的盐”包括酸加成盐和碱加成盐。
术语“共晶”是指本发明的化合物与其他生理上可接受的酸、碱、非离子化合物,通过氢键、范德华力、π-π堆积作用、卤键等非共价键作用下结合而成的晶体。
术语“立体异构体”包括对映体、非对映体和几何异构体的形式存在。
术语“溶剂化物”是指本发明的化合物与一种或多种溶剂分子的物理结合。该物理结合包括各种程度的离子和共价键合,包括氢键合。在某些情况下,溶剂化物可被分离出来,例如当一个或多个溶剂分子掺入到结晶固体的晶格中。溶剂化物包括溶液相和可分离的溶剂化物。代表性的溶剂化物包括乙醇化物、甲醇化物等。
术语“代谢产物”是指本发明的化合物在体内生理条件下使其发生化学降解所得产物。
术语“前药”指适于对患者给药的无过分毒性、刺激性和***反应等的并且对其应用目的有效的式Ⅰ化合物形式,包括缩醛、酯和两性离子形式。前药在体内转化,如通过在血液中水解,得到母体化合物。
在本发明中,“D”指氘;“被氘取代”指的是用相应数量的氘原子取代一个或多个氢原子。
术语“受试者”是指接受本文所述的方法的任何动物或其细胞,不论是体外或原位。进一步地,前述动物包括哺乳动物,例如,大鼠、小鼠、豚鼠、兔、犬、猴、猩猩或人类,特别是人类。
术语“治疗”是指在疾病发作之后预防、治愈、逆转、减弱、减轻、最小化、抑制、制止和/或停止疾病的一种或多种临床症状。
术语“预防”指在疾病发作之前,通过治疗以避免、最小化或令疾病难于发作或发展。
本文所引用的各种出版物、专利和公开的专利说明书,其公开内容通过引用整体并入本文。
下面将结合本发明实施例,对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例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作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。
实施例1化合物3的制备
1、合成路线
2、合成方法
(1)化合物2的制备
1000mL单口烧瓶中加入化合物1(CBD,10g,31.85mmol)和二氯甲烷(500mL),搅拌溶解,然后加入Nα,Nε-双(Boc)-L-赖氨酸(23.14g,66.88mmol)、二环己基碳二亚胺(13.78g,66.88mmol)和4-二甲氨基吡啶(8.16g,66.88mmol),室温搅拌过夜。将反应中生成的不溶物过滤掉,滤液用饱和食盐水洗涤,有机相经无水硫酸钠干燥、过滤、减压浓缩后得到41g油状粗品。粗品经硅胶柱层析(正己烷:乙酸乙酯=5:1~3:1)得到泡沫状固体化合物2(13.5g)。MS(ESI):988[M+NH4]+。
(2)化合物3的制备
250mL单口烧瓶中加入化合物2(5.7g,5.88mmol)和1,4-二氧六环(60mL),搅拌溶解,在氮气保护下向反应烧瓶中加入甲基磺酸(3.8ml,58.8mmol),加料结束后,室温搅拌过夜。反应瓶中生成粘稠状固体,清液倒出,剩余固体经真空干燥得到6.8g粗品。粗品C18柱层析纯化(乙腈:水=2:100~4:100),HPLC检测层析液,收集并冻干得到白色泡沫状固体化合物3(2.5g),纯度92%。MS(ESI):286[(M+2H)/2]+。
实施例2对帕金森的治疗研究
1、实验动物和部分试剂
C57/BL6小鼠,SPF级别,体重18-20g,周龄6-8,雄性,购自上海斯莱克实验动物有限责任公司。饲养环境温度保持在22±1℃,湿度保持在65-70%,12小时明/暗光照周期,可自由饮水。
MPTP,购自Sigma公司;金刚烷胺,购自Sigma公司;无水乙醇,购自国药集团化学试剂有限公司。
2、实验分组
将实验动物随机分为4组:空白组、模型组、阳性药物组、化合物组,每组8只。
3、实验方法
(1)购买6-8周龄SPF级的C57小鼠32只,适应性饲养一周,开始造模。
(2)每天腹腔注射MPTP(25mg/kg)每天1次,连续7天。空白组不做处理。
(3)造模完成后,开始给药。阳性药物组灌胃金刚烷胺(40mg/kg),化合物组(100mg/kg)灌胃化合物3(实施例1制备)确定好的药物剂量,每天灌胃1次,连续14天。
(4)先进行行为学检测:平衡木检测评分
一根长为80cm、宽为2.5cm的木条,水平固定在离台面10cm高度的地方,然后让动物在木条上行走。
能跳上平衡木条,可以自由行走但不跌倒:0分;能跳上平衡木条,动物在上面行走会跌下,但跌下的机会小于50%:1分;能跳上平衡木条,动物在上面行走会跌下,但跌下的机会大于50%:2分;动物在正常侧身体的帮助下可以跳上平衡木条;但是瘫痪侧的后肢不能够帮助身体向前移动:3分;动物无法在平衡木条上行走,但是可以坐在木条上:4分;将动物放在木条上,动物很快会掉落下来:5分。
(5)评分结束后,开始取材
迅速处死小鼠后,取小鼠大脑,分离小鼠大脑皮质(CP)。暴露小鼠大脑纹状体后,取纹状体进行称量后,按照比例添加PBS后,进行研磨匀浆。然后分离上清检测脑纹状体中多巴胺含量。
4、试剂盒法检测检测脑纹状体中多巴胺含量
4.1试剂盒和部分仪器如下表所示。
表1试剂盒信息
表2主要仪器及耗材
4.2蛋白定量
(1)标准曲线的绘制:取一块酶标板,按照下表加入试剂;
表3试剂
孔号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
蛋白标准液(μl) | 0 | 2 | 4 | 6 | 8 | 12 | 16 | 20 |
去离子水(μl) | 20 | 18 | 16 | 14 | 12 | 8 | 4 | 0 |
蛋白浓度(μg/μl) | 0 | 0.05 | 0.1 | 0.15 | 0.2 | 0.3 | 0.4 | 0.5 |
(2)根据样品数量,将BCA试剂A与试剂B按体积比为50:1配制适量BCA工作液,充分混匀;
(3)各孔加入160μl BCA工作液;
(4)把酶标板放在振荡器上振荡30sec,37℃放置30分钟,然后在562nm下测定吸光度。以吸光值为横坐标,蛋白浓度(μg/μl)为纵坐标,绘出标准曲线;
(5)在酶标板中加入2μl待测蛋白和18μl PBS(稀释10倍),加入160μl BCA工作液,把酶标板放在振荡器上振荡30sec,37℃放置30分钟,然后在562nm下测定吸光度;
(6)根据所测样品的吸光值,在标准曲线上即可查得相应的蛋白浓度(μg/μl),乘以样品稀释倍数(10)即为样品实际浓度(单位:μg/μl);
(7)小鼠多巴胺检测实验操作及方法参考试剂盒说明书。
5、免疫组化测定脑黑质(SubN)中酪氨酸羟化酶(TH)细胞
5.1实验材料
表4主要试剂
表5主要仪器及耗材
溶液配制
(1)PBS溶液
600ml的ddH2O中溶解8g NaCl、0.2g KCl、1.44g Na2HPO4和0.24g KH2PO4,用HCl调节溶液pH至7.4,定容至1L,滤器过滤后,高压灭菌,室温保存。
(2)0.1mol/L枸橼酸酸钠缓冲溶液
0.1mol/L柠檬酸3.8ml、0.1mol/L柠檬酸钠16.2ml。
柠檬酸C6H8O7·H2O:分子量210.14;0.1mol/L溶液为21.01克/升。
柠檬酸钠Na3C6H5O7·2H2O:分子量294.12;0.1mol/L溶液为29.41克/毫升。
5.2实验方法
5.2.1样本包埋与固定
(1)取材和固定
切取组织时应使用锋利的刀、剪,切取组织块时,从刀的根部开始向后拉动切开组织。组织块的厚度约为0.2~0.3cm,大小为1.5cm×1.5cm×0.3cm为宜。取好的组织块置于10%***中固定48小时。
(2)洗涤和脱水
将固定后的组织用流水冲洗,去除残留的固定液和杂质。不同浓度的乙醇逐级脱水,50%、70%、85%、95%直至纯酒精(无水乙醇),每级2小时。脱水必须在有盖的瓶中进行,以防止高浓度乙醇吸收空气中水分导致浓度降低而使脱水不彻底。需要保存的材料可脱水至70%乙醇时停留其中,如需长期保存,可加入等量的甘油。
(3)透明
将组织块置入纯乙醇和二甲苯的等体积混合液中2小时,再进入纯二甲苯两小时,再一次纯二甲苯两小时;材料经过透明,会显示出前一步脱水的效果如何,若脱水彻底,组织则显现透明状态,如组织中有白色云雾状,说明脱水不净,须返工处理,但返工的效果往往不好。使用二甲苯透明时,应避免其挥发和吸收空气中的水分,并保持其无水状态。
(4)浸蜡
浸蜡须在恒温箱中进行。先把组织材料块放在熔化的石蜡和二甲苯的等量混合液浸渍1-2小时,再先后移入2个熔化的石蜡液中浸渍各3小时左右。
(5)包埋
包埋是使浸透蜡的组织块包裹在石蜡中。具体做法是:先准备好纸盒,将熔蜡倒入盒内,迅速用预温的镊子夹取组织块平放在纸盒底部,切面朝下,再轻轻提起纸盒,平放在冷水中,待表面石蜡凝固后立即将纸盒按入水中,使其迅速冷却凝固,30min后取出。
(6)切片
切片前将蜡块在-20℃冰箱中至少放置30min,以增加硬度。将切片刀装在刀片机的刀架上并固定紧,固定蜡块底座或蜡块,调整蜡块与刀至合适位置,刀刃与蜡块表面呈5度角。调整切片机上的切片厚度为4-7μm,然后切片。
5.2.2免疫组化染色
(1)烤片和脱蜡
将玻片置于65℃恒温烘箱中烤片30min;置于二甲苯I中浸泡15min,再置于二甲苯II中浸泡15min。
(2)水化
将脱蜡后的切片经100%酒精、95%酒精、85%酒精、75%酒精分别浸泡5min,自来水冲洗10min。
(3)抗原修复
采用0.01M柠檬酸钠缓冲溶液中高压修复15min,自然冷却后,0.02M PBS洗3min×3次。
(4)阻断
将玻片置于3%H2O2中,湿盒孵育10min,以消除内源性过氧化物酶的活性。0.02MPBS冲洗3min×3次。
(5)一抗孵育
滴加一抗(1:2000稀释),湿盒孵育,室温下放置1h(或者4℃孵育过夜)。0.02M PBS冲洗3min×3次。
(6)二抗孵育
滴加HRP标记广谱二抗,湿盒孵育,室温下放置20min-30min。0.02M PBS冲洗3min×3次。
(7)显色
DAB染色,观察到切片有颜色改变时,立即用自来水洗去染色液。
(8)苏木素染色
苏木素复染3min,1%盐酸酒精分化,显微镜下观察,控制染色程度。自来水冲洗10min,放入65℃烘箱中烘干水分。
(9)透明和封片
将玻片置于二甲苯中透明3min×2次,中性树胶封片,放入65℃烘箱中15min。
5.2.3图像采集和分析
通过显微镜拍照,采集分析样本相关部位,计算阳性面积。
6、实验结果
(1)帕金森模型行为学平衡木评分结果如下表及图1所示。
表6帕金森模型行为学平衡木评分结果
小鼠通过腹腔注射MPTP进行帕金森模型制备,通过平衡木评分进行行为学评价,MPTP腹腔注射7天后,进行平衡木评分,除空白组不进行造模,平衡木评分为0,其他各组小鼠的评分均在5-6分,各组对比空白组P≤0.05,具有统计学意义,证明模型成功。
后续通过阳性药物和化合物组进行治疗后,模型组的平衡木评分4-5分,阳性药物平衡木评分在2-3分之间。化合物组平衡木评分是3-4分。阳性药物组和化合物组对比模型组出现明显下降趋势,P≤0.05,具有统计学意义。
治疗后各组评分为空白组<阳性药物组<化合物组<模型组。
(2)帕金森模型治疗后纹状体多巴胺含量如下表所示及图2所示。
表7帕金森模型治疗后纹状体多巴胺含量
分组 | DA(ng/mg) |
空白组 | 0.71±0.16 |
模型组 | 0.30±0.07*** |
阳性药物组 | 0.61±0.12### |
化合物组(实施例1制备所得的化合物3) | 0.45±0.10## |
多巴胺作为神经递质调控中枢神经***的多种生理功能,通过检测治疗小鼠帕金森模型纹状体中多巴胺含量。判断药物治疗帕金森模型效果。
通过各组和空白组多巴胺含量进行对比判断模型中多巴胺下降程度,其中除阳性药物组外,化合物组的多巴胺含量出现明显下降,P≤0.05,具有统计学意义。
再通过化合物组对比模型组多巴胺含量,多巴胺含量对比模型组出现增高,P≤0.01,具有统计学意义,表明化合物组具有升高脑内多巴胺含量的作用。
纹状体多巴胺含量是空白组>阳性药物组>化合物组>模型组。
(3)免疫组化测定脑黑质(SubN)中酪氨酸羟化酶(TH)细胞的实验结果如下表及图3和图4所示。
表8免疫组化测定脑黑质(SubN)中酪氨酸羟化酶(TH)细胞的实验结果
分组 | TH细胞阳性率(%) |
空白组 | 34.27±5.08 |
模型组 | 12.74±1.71*** |
阳性药物组 | 20.82±5.77## |
化合物组(实施例1制备所得的化合物3) | 14.59±2.60 |
酪氨酸羟化酶(TH)是一种单加氧酶,它是催化生物体自身合成左旋多巴胺(L-Dopamine,DA)系列反应的第一步反应的限速酶,仅在胞浆表达。神经元中TH含量丰富,因中脑缺乏多巴胺-β-羟化酶,故中脑TH免疫反应阳性神经元为DA神经元,可作为脑内多巴胺神经元的标志。机体利用左旋酪氨酸,在酪氨酸羟化酶的催化下生存左旋多巴,左旋多巴在芳香族脱羧酶的催化下脱去羧基最后生成左旋多巴胺。由于酪氨酸羟化酶在多巴胺合成中的重要地位,其功能的缺失或表达不足直接影响多巴胺的合成与分泌。多巴胺是一种重要的神经递质,多巴胺能神经元对多巴胺不能合成或分泌不足会导致帕金森氏病。
本实验结果显示,通过腹腔注射MPTP造成的小鼠帕金森模型中,小鼠的脑黑质(SubN)中酪氨酸羟化酶(TH)细胞阳性率出现降低,P≤0.05,具有统计学意义。阳性药物组对比模型组的脑黑质(SubN)中酪氨酸羟化酶(TH)细胞阳性率,出现明显升高现象,表明造模成功。
对比化合物组对小鼠帕金森模型治疗后,通过化合物组对比模型组的脑黑质(SubN)中酪氨酸羟化酶(TH)细胞阳性率,出现升高现象。其中化合物组的脑黑质(SubN)中酪氨酸羟化酶(TH)细胞阳性率对比模型组,P≤0.01,且具有统计学意义。
通过对比各组的治疗后的脑黑质(SubN)中酪氨酸羟化酶(TH)细胞阳性率,空白组>阳性药物组>化合物组>模型组。
7、实验总结
本次实验通过腹腔注射MPTP(25mg/kg)每天1次,连续7天,造模成小鼠帕金森模型,通过平衡木评分对小鼠帕金森模型进行筛选。
后续通过阳性药物和化合物组对模型小鼠进行灌胃治疗,连续灌胃治疗14天后,通过分析治疗后各组的平衡木评分,ELISA检测纹状体中多巴胺含量,免疫组化检测脑黑质(SubN)中酪氨酸羟化酶(TH)细胞阳性率等检测方法,鉴定化合物组和空白组,模型组差别,再进行统计学分析,对化合物3的有效性进行分析。
通过治疗后平衡木评分鉴定,阳性药物组和化合物组对比模型组出现明显下降趋势,P≤0.05,具有统计学意义。
再通过化合物组对比模型组多巴胺含量,化合物组的多巴胺含量对比模型组都出现增高,P≤0.01,具有统计学意义。
对比化合物组和阳性药物对小鼠帕金森模型治疗后,阳性药物组和化合物组对比模型组的阳性率,其中化合物组的脑黑质(SubN)中酪氨酸羟化酶(TH)细胞阳性率对比模型组,P≤0.01,且具有统计学意义。
通过整体分析化合物组对比模型组,具有一定的治疗效果,对比各检测指标,化合物3具有较佳的治疗效果。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换等,均应包含在本发明的保护范围之内。
本发明中描述的前述实施例和方法可以基于本领域技术人员的能力、经验和偏好而有所不同。
本发明中仅按一定顺序列出方法的步骤并不构成对方法步骤顺序的任何限制。
Claims (11)
1.一种化合物或其药学上可接受的盐、共晶、立体异构体、前药、溶剂化物、代谢产物,所述化合物具有如下结构:
其中,
R8选自:-NH2、-H;
X1和X2独立地选自:单键、亚烷基、被一个或多个取代基取代的亚烷基、被一个或多个-C(=O)O-间隔的亚烷基、被一个或多个-OC(=O)-间隔的亚烷基、被一个或多个烷基亚氨基间隔的亚烷基、被一个或多个-OC(=O)O-间隔的亚烷基、被以上间隔基团组合间隔的亚烷基;所述的取代基选自:烷基、羟基、卤素、芳基、环烷基、硫代烷氧基、硝基、氰基、氨基、杂芳基、杂环烷基,其中C原子上的H可被卤素、-OC0-10烷基、C1-10直链/支链烷基、硝基、氰基、氨基取代;
R3和R4各自独立地选自:-H、卤素、烷基、环烷基、芳基、杂芳基、杂环烷基;
R5、R6、R7各自独立地选自:-H、-OH、卤素、-NO2、-CN、烷基、环烷基;
或者,通式(I)任选地被1个或者多个D原子取代。
5.如权利要求1所述的化合物,其特征在于,所述R1和R2均为-NH2。
6.如权利要求1所述的化合物,其特征在于,所述X1和X2选自:-CH2-、-CH2CH2-、-(CH2)2CH2-、-(CH2)3CH2-、-CH2CH(CH3)2-、-(CH2)4CH2-、-CH(CH3)CH2CH2-、-CH(OH)CH2-。
7.如权利要求1所述的化合物,其特征在于,所述X1和X2均为-(CH2)3CH2-。
9.一种药物组合物,其包含权利要求1-8任一项所述的化合物或其药学上可接受的盐、共晶、立体异构体、前药、溶剂化物、代谢产物,以及一种或多种药学上可接受的辅料。
10.权利要求1-7任一项所述的化合物或其药学上可接受的盐、共晶、立体异构体、前药、溶剂化物、代谢产物在制备预防和/或治疗疾病的药物中的应用,其中,所述疾病选自:神经***疾病、癌症、自身免疫性疾病、心血管疾病、疼痛、炎症、肝损伤中的一种或多种;优选地,所述疾病为神经***疾病。
11.如权利要求10所述的应用,其特征在于,所述神经***疾病为神经退行性疾病或癫痫,所述神经退行性疾病选自:帕金森氏病、阿尔茨海默症、克雅二氏病、亨廷顿病、多发性硬化症;优选地,所述神经退行性疾病为帕金森氏病;
所述癌症选自:乳腺癌、肺癌、结直肠癌、肝癌、胰腺癌、胃癌、胃食管腺癌、食管癌、小肠癌、贲门癌、子宫内膜癌、卵巢癌、输卵管癌、外阴癌、睾丸癌、***癌、白血病、神经胶质瘤;
所述自身免疫性疾病选自:***性红斑狼疮、类风湿关节炎、多发性硬化症、溃疡性结肠炎、克罗恩氏病、自身免疫性肝炎。
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