CN114195850A - 一种用于防治肝病的化合物及其制药用途 - Google Patents
一种用于防治肝病的化合物及其制药用途 Download PDFInfo
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Abstract
Description
技术领域
本发明属于医药技术领域,具体涉及一种用于防治肝病的化合物及其制药用途。
背景技术
脂肪肝是一种常见肝病变,是指各种原因引起的肝细胞内脂肪堆积,当脂肪含量超过肝重量(湿重)的5%,或在组织学上超过肝实质30%时,称为脂肪肝。脂肪肝又可细分为酒精性脂肪肝或非酒精性脂肪肝。后者又包含如肥胖型脂肪肝、营养失调性脂肪肝、药物性脂肪肝、妊娠急性脂肪肝、糖尿病性脂肪肝等等。从进程上可以将脂肪肝分为3期,第I期为单纯性脂肪肝,第II期为脂肪性肝炎,约有10%转化为III期,第III期则为脂肪性肝纤维化和肝硬化。脂肪肝在我国是仅次于肝炎的第二大肝病,并且发病率还在稳步提高;在欧美脂肪肝病人多于肝炎病人,也是十大常见死因之一。总之脂肪肝已经成为威胁人类生命健康的严重问题,但是防治脂肪肝的药物还不能满足临床的需求。
胆酸类衍生物被报道在治疗脂肪肝中具有一定的效果。失碳熊去氧胆酸(norursodeoxycholic acid,简写norUDCA)被报道具有防治非酒精性脂肪肝的效果(Journal of hepatology,2010,52:S304),在胆淤型肝硬化中具有较好治疗效果(Journalof hepatology,2017,67:549),还在硫代乙酰胺诱导的肝纤维化模型中表现出具有较好的保护作用。HTD1801是一种针对酒精性脂肪肝和原发性硬化性胆管炎的候选药物分子,其结构如下所示,该化合物由熊去氧胆酸与小檗碱复合而成。但是,这些化合物对脂肪肝的治疗效果还有待进一步提高。
总之,开发出安全有效的脂肪肝治疗新药仍然是未满足的临床需求。
发明内容
本发明的目的在于提供一种新的用于防治肝病(比如脂肪肝、肝硬化、肝纤维化等)的化合物及其制药用途。
本发明提供了一种式I-1所示的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物:
本发明还提供了式I-1所示的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物在制备预防和/或治疗肝病的药物中的用途。
进一步地,所述肝病为脂肪肝、肝纤维化或肝硬化。
进一步地,所述脂肪肝为酒精性脂肪肝或非酒精性脂肪肝。
进一步地,所述药物能够降低ALT、AST、ALP。
本发明还提供了一种预防和/或治疗肝病的药物,所述药物是以式I-1所示化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物为活性成分,加上药学上可接受的辅料制得的制剂。
进一步地,所述药学上可接受的辅料选自稀释剂、填充剂、着色剂、助流剂、润滑剂、粘合剂、稳定剂、助悬剂或缓冲剂的任一种或多种;
和/或,所述制剂是片剂、胶囊剂、口服液、注射剂、透皮剂、气雾剂固体制剂、脂质体制剂或缓控释制剂;
和/或,所述制剂中每单位制剂含权利要求1所述化合物5-2500mg。
本发明还提供了式I-1所示化合物的制备方法,所述方法包括以下步骤:以盐酸小檗碱与失碳熊去氧胆酸为原料,反应制得。
进一步地,所述盐酸小檗碱与失碳熊去氧胆酸的摩尔比为1:(0.8~1.2);所述反应的溶剂为醇类溶剂,所述反应的温度为室温。
进一步地,所述盐酸小檗碱与失碳熊去氧胆酸的摩尔比为1:1;所述醇类溶剂为甲醇或乙醇。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
本发明中,失碳熊去氧胆酸,其英文名称为norursodeoxycholic acid,简写为norUDCA,特指在熊去氧胆酸侧链上少一个亚甲基,总碳数从24个变为23个;
本发明的血清生化指标中,ALT表示谷丙转氨酶、AST表示谷草转氨酶、ALP表示碱性磷酸酶。
室温指25±2℃。
本发明所述的溶剂合物是指化合物与溶剂形成溶剂合物,其中溶剂并非以游离状态存在,而是参与并存在于晶体中形成溶剂合物。所述溶剂包括(但并不限于):水、乙醇、甲醇、异丙醇、丙二醇、四氢呋喃、二氯甲烷。
实验结果表明,本发明化合物不仅可显著降低ALT、AST、ALP,而且针对肝脏病理损伤(例如肝细胞脂肪变性)具有明显的改善作用。本发明化合物I-1对脂肪肝、肝纤维化和肝硬化的治疗效果优于nor-UDCA与盐酸小檗碱的治疗效果之和;本发明化合物I-1对脂肪肝、肝纤维化和肝硬化的治疗效果显著优于HTD1801。因此,本发明化合物在制备预防和/或治疗脂肪肝、肝纤维化和肝硬化等肝病的药物中具有广泛的应用前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为实验例1中各组小鼠血浆中谷草转氨酶AST指标。
图2为实验例1中各组小鼠血浆中谷丙转氨酶ALT指标。
图3为实验例1中各组小鼠血浆中碱性磷酸酶ALP指标。
具体实施方式
本发明具体实施方式中使用的化学试剂购自成都市科龙化工试剂厂。
按照文献(Journal of Medicinal Chemistry,2014:57:7687)公开的方法,制得失碳熊去氧胆酸(norUDCA),分析核磁等数据与文献一致,HPLC鉴定纯度99.0%。
下面实施例中若无特殊说明,采用的方法为本领域常规方法。
实施例1本发明化合物I-1的制备
0.79克盐酸小檗碱(2.12mmol)溶于4毫升甲醇中,加入硫酸钠干燥60分钟,过滤,再加入硫酸钠备用。另取0.80克norUDCA(S-1,2.11mmol)溶于4毫升乙醇中,加入0.15克乙醇钠(2.20mmol),室温下搅拌10分钟后,浓缩至干。所得固体用4毫升甲醇溶解,将溶液滴入盐酸小檗碱的甲醇溶液中,室温下搅拌1小时,过滤,滤液浓缩至干,所得粗品用乙酸乙酯分散结晶,烘干得化合物I-1共计1.18克,收率78.1%。
1HNMR(DMSO-d6,400MHz):δppm:9.88(s,1H),8.92(s,1H),8.20(d,J=9.1Hz,1H),8.00(d,J=9.1Hz,1H),7.79(s,1H),7.08(s,1H),4.96-4.88(m,2H),4.09(s,3H),4.06(s,3H),3.79(s,1H),3.33-3.23(m,2H),3.23-3.16(m,2H),2.09-2.00(m,1H),1.96-1.88(m,1H),1.84-1.54(m,6H),1.58-1.25(m,9H),1.25-0.91(m,7H),0.91-0.88(m,3H),0.88-0.82(m,6H),0.61(s,3H)。
实施例2制备本发明化合物的药用片剂组合物
化合物I-1的药用片剂组合物,其组成为:I-1化合物1重量份,乳糖0.1-0.5重量份,羟丙纤维素0.05-0.08重量份,羧甲基淀粉钠0.008-0.014重量份,聚维酮K30 0.01-0.02重量份,硬脂酸镁0.01-0.05重量份。按照上述配方制备成片剂,每片含50毫克化合物I-1。
实施例3制备本发明化合物的药用胶囊剂组合物
化合物I-1的药用胶囊剂组合物,制备材料包括100克化合物I-1、146克乳糖、4克微粉硅胶,及2号空心胶囊。制备方法为:
a.使用常规方法混合化合物I-1,乳糖和微粉硅胶,粉碎,得混合物粉末;
b.将混合粉末过120目筛后装填入2号胶囊并封口,共制1000粒。
其中,每粒胶囊含100毫克化合物I-1。
以下通过实验例证明本发明的有益效果。
实验例1本发明化合物防治脂肪肝的动物实验研究
1、实验方法
选取C57BL/6N雄性、8周龄小鼠,48只,随机挑选8只为空白组,正常饲料喂养,其余40只统一建模。建模之前6天为适应期,MCD:MCS配比饲养(江苏南通特洛菲饲料科技有限公司,TP3005GS,高脂饲料)按1:2、1:1、2:1的顺序各两天。之后给予小鼠28天的MCD饲料(江苏南通特洛菲饲料科技有限公司,TP3005G,蛋氨酸和胆碱缺乏饲料),第28天随机分为5组,每组8只,分别为模型组、化合物I-1组、norUDCA组、盐酸小檗碱组和HTD1801组。各给药组分组后再给予20天含有药物的订制MCD饲料,模型组与前期相同。各组按照等热量饲养给予饲料。小鼠于第21天末次给药后禁食16小时(不禁水),动物称重,股动脉取血,离心并分离血清,-30℃低温保存,待测血清中的生化指标。另摘取肝脏,每只取肝左叶2块分别放于10%中性福尔马林溶液,待处理后作肝组织病理学检查。
2、实验结果
各组大鼠生化指标记录如表1、图1、图2、图3:
表1各组小鼠血清生化指标
注:和HTD1801比较:***P<0.01,**P<0.05,*P<0.5。
肝组织病理学检查分析结果如下表2:
表2各组小鼠肝组织病理学检查
肝脂肪染色评价结果如下表3:
表3各组小鼠肝脂肪染色结果
组别 | 给药剂量(mg/kg) | 评分 |
空白组 | N/A | 0.1 |
模型组 | N/A | 2.8 |
I-1 | 300 | 1.0 |
nor-UDCA | 150 | 1.7 |
盐酸小檗碱 | 150 | 1.9 |
HTD1801 | 300 | 1.1 |
上述实验表明,本发明化合物I-1不仅可显著降低ALT、AST、ALP,而且针对肝脏病理损伤(例如肝细胞脂肪变性)具有明显的改善作用。
而且,化合物I-1组对脂肪肝的治疗作用明显优于失碳熊去氧胆酸组、盐酸小檗碱组和HTD1801组。从表1可知看出,与模型组相比,nor-UDCA组对ALT、AST、ALP的降低率分别为21.82%、20.67%、12.95%,盐酸小檗碱组对ALT、AST、ALP的降低率分别为12.09%、1.86%、15.10%;但是,I-1组对ALT、AST、ALP的降低率分别为59.67%、84.04%、32.40%,高于nor-UDCA组与盐酸小檗碱组的降低率之和。另外,与HTD1801组相比,相同给药剂量的I-1组对ALT、AST、ALP的降低效果也显著提高。
上述实验结果表明,本发明化合物I-1对脂肪肝的治疗效果优于nor-UDCA与盐酸小檗碱的治疗效果之和;本发明化合物I-1对脂肪肝的治疗效果显著优于HTD1801。
实验例2本发明化合物防治硫代乙酰胺诱导的肝硬化动物模型试验
1、实验方法
Wistar大鼠,体重180~220g,雄性,60只,每组10只大鼠,由成都达硕实验动物有限公司提供。本发明化合物及阳性对照药物失碳熊去氧胆酸(norUDCA)实验时先用适量吐温研磨,再用0.5%的羧甲基纤维素钠(CMC)按设计浓度配制。
大鼠肝纤维化模型建立的制作应用硫代乙酰胺诱导法,腹腔注射硫代乙酰胺,剂量为200mg/kg,一周3次,连续12周。在硫代乙酰胺诱导4周后,给药组口服灌胃本发明化合物,空白组及模型组给予等量CMC混悬液。其中,每天上午各给药组大鼠给予160mg/kg的化合物I-1、80mg/kg的失碳熊去氧胆酸、80mg/kg的盐酸小檗碱、160mg/kg的阳性对照HTD1801,试验结束后,所有大鼠实施安乐死并取出肝脏。
肝组织经10%甲醛溶液固定后,并包埋在石蜡中。对固定肝脏组织进行切片处理,厚度约5mm,然后对其进行苏木素-伊红染色以及天狼星红染色。天狼星红染色用于形态分析并确定受其纤维化影响的肝组织百分比。利用显微摄像系统对切片进行图像采集。为了使结果更加准确,每张切片随机选取15个天狼星红染色阳性视野用于计算肝纤维化面积比例用于统计分析。
2、实验结果
实验结果如下表4:
表4各组大鼠肝纤维化面积
组别 | 给药剂量(mg/kg) | 肝纤维化面积(%) |
空白组 | N/A | 0.0±0.0 |
模型组 | N/A | 17.80±4.15 |
I-1 | 160 | 8.72±1.06* |
nor-UDCA | 80 | 16.79±5.48 |
盐酸小檗碱 | 80 | 15.14±3.67 |
HTD1801 | 160 | 9.39±1.45 |
注:和HTD1801相比较,**P<0.05,*P<0.5
结果显示,本发明化合物能显著抑制硫代乙酰胺诱导的肝纤维化。此外,从表4可以看出,与肝硬化动物模型组相比,nor-UDCA组的纤维化面积降低率为6.18%,盐酸小檗碱组的纤维化面积降低率为15.17%,而化合物I-1组的纤维化面积降低率为50.90%,降低效果优于nor-UDCA组和盐酸小檗碱组之和。与HTD1801组相比,相同给药剂量的I-1组的纤维化面积也显著降低。
上述实验结果表明,本发明化合物I-1抗肝脏纤维化的效果优于nor-UDCA与盐酸小檗碱的治疗效果之和;本发明化合物I-1抗肝脏纤维化的效果显著优于HTD1801。
综上,本发明提供了一种失碳熊去氧胆酸的离子盐化合物。实验结果表明,本发明化合物不仅可显著降低ALT、AST、ALP,而且针对肝脏病理损伤(例如肝细胞脂肪变性)具有明显的改善作用。本发明化合物I-1对脂肪肝、肝纤维化和肝硬化的治疗效果优于nor-UDCA与盐酸小檗碱的治疗效果之和;本发明化合物I-1对脂肪肝、肝纤维化和肝硬化的治疗效果显著优于HTD1801。因此,本发明化合物在制备预防和/或治疗脂肪肝、肝纤维化和肝硬化等肝病的药物中具有广泛的应用前景。
Claims (10)
2.权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物在制备预防和/或治疗肝病的药物中的用途。
3.根据权利要求2所述的用途,其特征在于:所述肝病为脂肪肝、肝纤维化或肝硬化。
4.根据权利要求3所述的用途,其特征在于:所述脂肪肝为酒精性脂肪肝或非酒精性脂肪肝。
5.根据权利要求2~4任一项所述的用途,其特征在于:所述药物能够降低ALT、AST、ALP。
6.一种预防和/或治疗肝病的药物,其特征在于:所述药物是以权利要求1所述化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物为活性成分,加上药学上可接受的辅料制得的制剂。
7.根据权利要求6所述的药物,其特征在于:所述药学上可接受的辅料选自稀释剂、填充剂、着色剂、助流剂、润滑剂、粘合剂、稳定剂、助悬剂或缓冲剂的任一种或多种;
和/或,所述制剂是片剂、胶囊剂、口服液、注射剂、透皮剂、气雾剂固体制剂、脂质体制剂或缓控释制剂;
和/或,所述制剂中每单位制剂含权利要求1所述化合物5-2500mg。
8.权利要求1所述的化合物的制备方法,其特征在于:所述方法包括以下步骤:以盐酸小檗碱与失碳熊去氧胆酸为原料,反应制得。
9.根据权利要求8所述的方法,其特征在于:所述盐酸小檗碱与失碳熊去氧胆酸的摩尔比为1:(0.8~1.2);所述反应的溶剂为醇类溶剂,所述反应的温度为室温。
10.根据权利要求9所述的方法,其特征在于:所述盐酸小檗碱与失碳熊去氧胆酸的摩尔比为1:1;所述醇类溶剂为甲醇或乙醇。
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CN114716498B (zh) * | 2022-01-20 | 2024-01-23 | 成都贝诺科成生物科技有限公司 | 一种高稳定性的失碳熊去氧胆酸小檗碱盐晶型及其制备方法 |
CN117398395A (zh) * | 2023-12-14 | 2024-01-16 | 成都贝诺科成生物科技有限公司 | 失碳熊去氧胆酸小檗碱盐在制备预防和/或治疗消化道炎症的药物中的用途 |
CN117398395B (zh) * | 2023-12-14 | 2024-02-09 | 成都贝诺科成生物科技有限公司 | 失碳熊去氧胆酸小檗碱盐在制备预防和/或治疗消化道炎症的药物中的用途 |
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US20230330109A1 (en) | 2023-10-19 |
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