CN115154447A - 一种2,6-二(2-(三氟甲基)苯亚甲基)环己酮在炎症性肠病药物制备中的应用 - Google Patents
一种2,6-二(2-(三氟甲基)苯亚甲基)环己酮在炎症性肠病药物制备中的应用 Download PDFInfo
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Abstract
本发明公开了一种2,6‑二(2‑(三氟甲基)苯亚甲基)环己酮在药物制备中的应用,所述的药物用于治疗或者预防化学物质葡聚糖硫酸钠(DSS)引起的机体局部免疫器官对肠道内抗原的高敏状态而引起的非特异性炎症,但是不局限于这种诱导物,具体的,该药物可以抑制或改善结肠组织的病理损伤、纤维化、炎症反应和细胞凋亡。
Description
技术领域
本发明属于医药技术领域,具体涉及一种式(I)的化合物(代号C66)或其药学上可接受的盐在制备用于治疗或预防炎症性肠病药物中的用途。
背景技术
近年来,炎症性肠病(IBD)的发病率持续上升,并已成为一种全球性疾病。IBD的发病机制非常复杂,包括个体遗传差异,肠道菌群的变化,炎症免疫反应和外部环境变化。IBD的特征是腹痛,腹泻,血便,体重减轻以及产生细胞因子,蛋白水解酶和自由基的中性粒细胞和巨噬细胞的浸润,最终导致炎症和溃疡。
本发明人在多年的工作基础上,发现了式(I)的化合物(C66)能够有效治疗多种因素诱发的炎症性肠病,尤其是机体器官局部免疫对肠道内抗原的高敏状态而引起的非特异性炎症,能够抑制化学物质葡聚糖硫酸钠(DSS)的结肠损伤。
发明内容
本发明的目的在于提供了2,6-二(2-(三氟甲基)苯亚甲基)环己酮(式(I)的化合物,代号C66)的新的用途。
具体而言,本发明提供了式(I)的化合物(C66)或其药学上可接受的盐在制备用于治疗或预防炎症性结肠炎的药物中的用途。
优选本发明的用途是在制备用于治疗或预防炎症性结肠炎的药物中的用途。
本发明还提供了式(I)的化合物(C66)或其药学上可接受的盐在制备用于改善炎症性结肠炎的药物中的用途。
优选本发明的用途是在制备用于改善炎症性结肠炎的药物中的用途。
炎症性肠病是由多种因素引起的,炎症性肠病包括溃疡性结肠炎和克罗恩病等。炎症性肠病发病机制非常复杂,包括个体遗传差异、肠道菌群的变化、炎症免疫反应和外部环境变化。不同的原因导致的炎症性肠病的症状以及治疗方式都有所不同,作为优选,本发明所针对的炎症性肠病主要是由化学物质葡聚糖硫酸钠(DSS)引起的机体器官局部免疫对肠道内抗原的高敏状态而引起的非特异性炎症,但不限于这种致病因素诱发的。
优选在本发明的用途中,炎症性肠病的主要症状是腹泻,黏液脓血便,体重下降以及结肠组织炎症和凋亡。
优选在本发明的用途中,式(I)的化合物(C66)或其药学上可接受的盐是不在统计学上显著降低体重的。
本发明的用途中的药物含有有效剂量的式(I)的化合物(C66)。有效剂量可以是单位给药剂量形式(如,一片、一针、一丸或一剂)的药物中的含量,也可以是所需治疗/预防的患者的单位剂量(如,单位体重剂量)。药物制造商能够很容易地通过所需治疗/预防的患者群体的平均体重将所需治疗/预防的患者的单位体重剂量换算成单位给药剂量形式的药物中的含量,例如,成人患者的平均体重可以是60kg,因此通过平均体重乘以成人的单位体重剂量,即可得到用于成人的单位给药剂量形式的药物中的含量。在本发明中,患者可以是哺乳动物,如人、兔、狗或鼠。根据本领域普通技术人员所公知的实验动物与人的等效剂量换算关系(通常可参见FDA、SFDA等药品管理机构的指导意见,也可参见“黄继汉等.药理试验中动物间和动物与人体间的等效剂量换算.中国临床药理学与治疗学,2004,9(9):1069-1072”)可从实验动物的剂量推导出人的单位体重剂量。例如,对于常用的实验动物小鼠而言,根据上述文献,其与成人的换算关系约为12:1;对于常用的实验动物大鼠而言,根据上述文献,其与成人的换算关系约为6:1。在本发明中,有效剂量(以含量计)可以是10μg-1g优选是0.1mg-500mg,更优选是1mg-100mg。
本发明的用途中的药物通常还含有药学上可接受的载体。本文中使用的药学上可接受的载体指无毒的填充剂、稳定剂、稀释剂、佐剂或其他制剂辅料。例如,稀释剂、赋形剂,如水、生理盐水等;填充剂,如淀粉、蔗糖等;粘合剂,如纤维素衍生物、藻酸盐、明胶和/或聚乙烯吡咯烷酮;湿润剂,如甘油;崩解剂,如琼脂、碳酸钙和/或碳酸氢钠;吸收促进剂,如季铵化合物;表面活性剂,如十六烷醇;吸附载体,如高岭土和/或皂粘土;润滑剂,如滑石粉、硬脂酸钙/镁、聚乙二醇等。另外,本发明的药物组合物还可以进一步含有其它辅料,如香味剂、甜味剂等。根据本领域的公知技术,可以根据治疗目的、给药途径的需要将药物组合物制成各种剂型,优选该组合物为单位给药剂量形式,如冻干剂、片剂、胶囊、粉剂、乳液剂、水针剂或喷雾剂,更优选该药物组合物为注射剂型(如,冻干粉针剂)或口服剂型(如,片剂、胶囊)。药物可以通过常规途径施用,特别是肠内,例如口服,例如以片剂或胶囊剂形式,或非肠道施用,例如以可注射溶液剂或混悬剂形式,局部施用,例如以洗剂或凝胶剂,或以鼻剂或检剂形式。
为了便于理解,本发明引用了公开文献,这些文献是为了更清楚地描述本发明,其全文内容均纳入本文进行参考。以下将通过具体的实施例和附图对本发明进行详细地描述。需要特别指出的是,这些描述仅仅是部分示例性的描述,并不构成对本发明范围的限制。依据本说明书的论述,本发明的许多变化、改变对所属领域技术人员来说都是显而易见了。
附图说明:
图1式(I)的化合物(C66)对炎症性结肠炎小鼠体重、脾脏指数、DAI值和结肠长度的影响。
图2式(I)的化合物(C66)对炎症性结肠炎小鼠结肠病理损伤的改善效果。
图3式(I)的化合物(C66)对炎症性结肠炎小鼠结肠纤维化的改善效果。
图4式(I)的化合物(C66)对炎症性结肠炎小鼠结肠中炎症的改善效果。
图5式(I)的化合物(C66)对炎症性结肠炎小鼠结肠中细胞凋亡的改善效果。
具体实施方式:
本发明在以下的实施例中进一步说明。这些实施例只是为了说明的目的,而不是用来限制本发明的范围。
实施例1本发明的化合物缓解炎症性结肠炎诱导后小鼠体重减轻、DAI值升高和结肠长度缩短。
将C57L/B6小鼠随机分为3组,每组6只,分别为:
空白对照组(Con组):健康C57L/B6小鼠,正常饮食正常饮水10天;
DSS造模组(DSS组):正常饮食喂养小鼠,2.5%DSS饮水7天后给正常水3天共10天,不给药;
化合物治疗组(DSS+C66 5mg/kg):正常饮食喂养小鼠,2.5%DSS喂养7天后给予正常饮水3天,同时每天以5mg/kg/day的剂量给小鼠灌胃给药方式(I)的化合物(C66),连续给药10天。
期间测定各组鼠的体重(Body weight),记录粪便稠度、血便的存在和体重减轻情况并打分,将个体评分合并取平均值以生成疾病活动指数(DAI),该指数每天为每只小鼠计算。结果如图1A,B所示,化合物治疗组小鼠相比于DSS造模组体重下降有所缓解,DAI值评分较低,这表明,式(I)的化合物(C66)缓解DSS诱导引起的小鼠体重减轻和DAI值升高。
在给药10天后,处死小鼠,称重,用4%水合氯醛溶液麻醉小鼠,腹腔打开,取出脾脏,测量脾脏的重量,用脾脏重量除以第10天的体重计算脾脏指数,单位用‰表示。将肛门到盲肠区的结肠取肠系膜纵向部分,整理并固定,测量结肠长度。结果如图1C-E显示,给予式(I)的化合物(C66)后对DSS诱导引起的脾脏指数增加和结肠长度缩短有明显的缓解作用。
这表明,式(I)的化合物(C66)对DSS诱导的体重减轻、脾脏指数升高和结肠长度缩短有缓解作用。
实施例2本发明的化合物明显改善炎症性结肠炎小鼠结肠组织的病理损伤。
按照实施例1分组并进行试验,给药10天后,处死各组小鼠,取结肠组织,以4%福尔马林液固定、石蜡包埋、5μm切片后进行苏木素&伊红(H&E)染色并镜检。结果如图2A,B所示,与空白对照组相比,DSS造模组结肠远端炎症细胞浸润,隐窝组织丢失和上皮细胞破坏;而同时给予式(I)的化合物后,明显改善了各治疗组的小鼠结肠组织的损伤、炎症细胞浸润和隐窝组织丢失和上皮细胞破坏等症状。这表明,式(I)的化合物(C66)能够阻止由于炎症性结肠炎而引起的结肠组织的病理损伤。
实施例3本发明的化合物明显改善炎症性结肠炎小鼠结肠的纤维化。
按照实施例1分组并进行试验,给药10天后,处死各组小鼠,取结肠组织,以4%福尔马林液固定、石蜡包埋、5μm切片后进行胶原纤维(MASSON)染色并镜检。结果如图3A所示
取结肠组织匀浆后,采用Trizol试剂提取总mRNA,并且用RT-qPCR实验进行检测发现,DSS诱导结肠组织纤维化相关指标COL-1(图3B)、TGF-β(图3C)、Timp-1(图3D)的mRNA转录增加,而给予式(I)的化合物后,显著抑制了DSS诱导结肠组织纤维化相关指标COL-1、TGF-β和Timp-1的基因转录。这表明,式(I)的化合物(C66)能够阻止由于化学物质DSS诱导结肠组织的纤维化,从而缓解结肠损伤。
实施例4本发明的化合物明显改善炎症性结肠炎小鼠结肠中的炎症升高。
按照实施例1分组并进行试验,给药10天后,处死各组小鼠,收集血液,同时取结肠组织匀浆后,用特定的ELISA试剂盒(Thermo Scientific,USA)检测血清和组织裂解液中IL-6、TNF-α和IL-1β的含量。IL-6、TNF-α和IL-1β参与炎症性结肠炎的发病过程,可作为临床判断疾病严重程度的重要指标。图4A-F显示,与空白对照组相比,化学物质葡聚糖硫酸钠(DSS)明显上调IL-6、TNF-α和IL-1β的含量,而在治疗组中,化合物(I)可以显著地抑制IL-6、TNF-α和IL-1β的升高(p<0.05)。
取结肠组织匀浆后,采用Trizol试剂提取总mRNA,并且用RT-qPCR实验进行检测发现,化学物质葡聚糖硫酸钠(DSS)显著升高结肠组织中炎症相关指标IL-6(图4G)、TNF-α(图4H)和IL-1β(图4I)的mRNA转录,而给予式(I)的化合物后,显著抑制了化学物质葡聚糖硫酸钠(DSS)引起的结肠组织中IL-6、TNF-α和IL-1β的基因转录。这表明,式(I)的化合物(C66)能够阻止由于化学物质葡聚糖硫酸钠(DSS)而引起的结肠组织中的炎症,从而缓解结肠损伤。
实施例5本发明的化合物明显改善炎症性结肠炎小鼠结肠中的细胞凋亡。
按照实施例1分组并进行试验,给药10天后,处死各组鼠,取结肠组织,以4%福尔马林液固定、石蜡包埋、5μm切片后进行TUNEL免疫组化染色并镜检。结果如图5A所示,与空白对照组相比,DSS造模组小鼠结肠组织有明显的细胞凋亡,而同时给予式(I)的化合物后,明显改善了DSS造模组的小鼠结肠组织的细胞凋亡。取结肠组织匀浆后,样品加入到相应比例的SDS凝胶上样体系中。SDS-PAGE电泳并转移膜后,将膜5%脱脂牛奶封闭,室温下1.5小时并用TBST洗涤3次。然后加入Bcl-2(1:1000)、Bax(1:1000)和Cleaved-Caspase3(1:1000)一抗,膜在4℃下孵育过夜,用TBST洗涤3次,用与辣根过氧化物酶偶联的二抗在室温下孵育1小时,膜洗涤3次,检测免疫反应条带在超敏ECL化学发光试剂盒显现。用凝胶成像系统进行拍照。结果如图5B所示,与空白对照组相比,DSS造模组的Bcl-2蛋白含量降低,Bax和Cleaved-Caspase3蛋白含量增加,给予式(I)的化合物(C66)后,Bcl-2蛋白含量增加,Bax和Cleaved-Caspase3蛋白含量减少,这表明,式(I)的化合物(C66)能够阻止由于化学物质葡聚糖硫酸钠(DSS)而引起的结肠中的细胞凋亡。
Claims (7)
2.根据权利要求1所述的2,6-二(2-(三氟甲基)苯亚甲基)环己酮或其药学上可接受的盐在药物制备中的应用,其特征在于,所述的与结肠有关的疾病为机体器官局部免疫对肠道内抗原的高敏状态而引起的疾病。
3.根据权利要求1~2任一项所述的2,6-二(2-(三氟甲基)苯亚甲基)环己酮或其药学上可接受的盐在药物制备中的应用,其特征在于,所述与结肠有关的疾病的症状为体重减轻、DAI值升高和结肠长度缩短。
4.根据权利要求1~2任一项所述的2,6-二(2-(三氟甲基)苯亚甲基)环己酮或其药学上可接受的盐在药物制备中的应用,其特征在于,所述的与结肠有关的疾病为结肠组织功能和病理损伤。
5.根据权利要求4所述的2,6-二(2-(三氟甲基)苯亚甲基)环己酮或其药学上可接受的盐在药物制备中的应用,其特征在于,所述的结肠组织功能和病理损伤的症状包括结肠组织中的纤维化。
6.根据权利要求1~2任一项所述的2,6-二(2-(三氟甲基)苯亚甲基)环己酮或其药学上可接受的盐在药物制备中的应用,其特征在于,所述的与结肠有关的疾病为结肠组织的炎症。
7.根据权利要求1~2任一项所述的2,6-二(2-(三氟甲基)苯亚甲基)环己酮或其药学上可接受的盐在药物制备中的应用,其特征在于,所述的与结肠有关的疾病为结肠组织中的细胞凋亡。
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