CN112168831A - 一个雷公藤内酯醇衍生物在防治炎症性肠病中的用途 - Google Patents
一个雷公藤内酯醇衍生物在防治炎症性肠病中的用途 Download PDFInfo
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- CN112168831A CN112168831A CN201910583248.8A CN201910583248A CN112168831A CN 112168831 A CN112168831 A CN 112168831A CN 201910583248 A CN201910583248 A CN 201910583248A CN 112168831 A CN112168831 A CN 112168831A
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Abstract
本发明公开了一个雷公藤内酯醇衍生物在防治炎症性肠病中的用途，属于医药技术领域。具体公开了如下化合物I及其药学上可接受的盐，体内外实验结果表明化合物Ⅰ毒性较低，具有明显的抗炎以及治疗炎症性肠病的药理活性，有望成为治疗炎症性肠病相关疾病的药物。
Description
技术领域
本发明涉及天然药物、药物化学以及药理学领域，具体涉及一个雷公藤内酯醇衍生物，并公开了其在制备预防和/或治疗炎症性肠病药物方面的用途。
背景技术
炎症性肠病(Inflammatory bowel disease,IBD)是一种比较常见的自身免疫性疾病，主要包括克罗恩病(CD)和溃疡性结肠炎(UC)，临床表现为长期慢性的肠道炎症[1,2]。IBD的病因和发病机制尚未完全明确，已知肠道黏膜免疫系统异常反应所导致的炎症反应在IBD发病中起重要作用，认为是由多因素相互作用所致，主要包括环境、遗传、感染和免疫因素。近年来，在全世界范围内IBD的发病率在发展中和发达国家均在逐年上升，其中儿童IBD的发病率增加更明显[3]。由于溃疡性结肠炎的发病机制并不确切,目前所有的药物只能控制症状而不能彻底治愈，给全社会和患者带来了沉重的经济和心理负担。更值得关注的是，长时间不愈的结肠炎最后发展为结肠癌的概率很大，所以深入研究溃疡性结肠炎的发病机理，寻找新的药物治疗靶点对于溃疡性结肠炎的治疗具有至关重要的意义。
基因学和免疫学研究发现炎性因子在炎症性肠病的发生发展过程中占有重要地位，当机体接触到IBD的诱发因素，会使肠上皮屏障作用发生破坏，使原本不能进入机体的抗原，如细菌等进入肠壁诱发异常的炎症反应[4]。研究表明，在IBD 病人以及IBD动物模型中上述免疫细胞分泌的促炎性细胞因子和抑炎性细胞因子的平衡对于炎症性肠病的恢复至关重要。在参与炎症性肠病的免疫细胞中巨噬细胞作为重要的先天免疫防御细胞介导和参与了机体各个器官与组织中的炎症反应。巨噬细胞作为重要的固有免疫细胞，广泛分布于机体的多种组织中，尤其存在于肺脏，肠道以及皮肤这类直接与抗原接触组织中，是机体抵御外源入侵的第一道防线，在维护机体内环境稳态方面具有十分重要的作用[5]。
IBD由于其发病的复杂性，没有特效药完全治愈，目前的治疗药物类型包括非甾体抗炎药、非受体酪氨酸激酶抑制剂，基于炎性因子的生物抗体药物，以及传统中药。雷公藤作为我国传统中草药，已有上千年的药用历史，现已明确它具有多种药理作用，其最主要的药理活性即是抗炎、抗肿瘤和免疫抑制作用[6,7]，曾经是治疗类风湿性关节炎、炎症性肠病、肾小球肾炎、红斑狼疮等自身免疫性疾病的首选中药[8]，其抗炎作用肯定、疗效确切，但存在副作用。其中雷公藤内酯醇(Triptolide,TP)是雷公藤最主要的活性物质，但它的毒性同样十分明显，由于其治疗窗口非常窄，所以不能成为临床治疗药物。确是众多科学家们关注的焦点和热点，大家试图通过结构改造获得毒性明显降低而保证其活性的新衍生物，但迄今为止仍然没有成功上市的先例。
化合物I我们已经申请了申请号为2018104648420的化合物及其制备方法和其药物组合物与用途的发明专利，用途为抗肿瘤疾病作用。
我们的研究是在雷公藤内酯醇的基础上衍生得到的化合物，其在保持雷公藤内酯醇活性的同时明显降低了毒性，是一个非常有前景的抗炎症性肠病的的化合物。
参考文献：
[1]Y.Q.YANG,Y.F.WU,F.F.XU,et al.Tripterygium glycoside fraction n2:Alleviation of DSS-induced colitis by modulating immune homeostasis in mice[J].Phytomedicine,2019,58: 152855.
[2]G.LOPEZ-GARCIA,A.CILLA,R.BARBERA,et al.Effect of a Milk-BasedFruit Beverage Enriched with Plant Sterols and/or Galactooligosaccharides ina Murine Chronic Colitis Model[J].Foods,2019,8.
[3]I.GUERRA,L.BUJANDA,J.CASTRO,et al.Clinical characteristics,associated malignancies and management of primary sclerosing cholangitis ininflammatory bowel disease patients:A multicenter retrospective cohort study[J].J Crohns Colitis,2019.
[4]J.M.PELOQUIN,G.GOEL,E.J.VILLABLANCA,et al.Mechanisms of PediatricInflammatory Bowel Disease[J].Annu Rev Immunol,2016,34:31-64.
[5]J.BONNARDEL,M.GUILLIAMS.Developmental control of macrophagefunction[J].Curr Opin Immunol,2018,50:64-74.
[6]C.XI,S.PENG,Z.WU,et al.Toxicity of triptolide and the molecularmechanisms involved[J]. Biomed Pharmacother,2017,90:531-541.
[7]J.WEI,Y.YAN,X.CHEN,et al.The roles of plant-derived Triptolide onnon-small cell lung cancer[J].Oncol Res,2019.
[8]M.CHEN,J.M.WANG,D.WANG,et al.Triptolide inhibits migration andproliferation of fibroblasts from ileocolonic anastomosis of patients withCrohn's disease via regulating the miR161/HSP70pathway[J].Molecular medicinereports,2019.
发明内容
本发明的技术方案在于通过将雷公藤内酯醇14位羟基通过酯键或醚键偶联苯磺酰基呋咱氮氧化物，以得到安全窗扩大的抗炎免疫药物。
本发明拟解决的另一个问题是化合物Ⅰ(中国专利申请号为2018104648420 中化合物)或其药学上可接受的盐可应用于制药领域，具体为化合物Ⅰ或其药学上可接受的盐与其药物组合物在制备调控巨噬细胞及预防和/或治疗炎症性肠病药物中的应用，所述的炎症性肠病包括溃疡性结肠炎和克罗恩病。
本发明的目的可通过以下措施达到：
一种具有化合物14-O-(3-苯磺酰基-2-氧-呋咱-4-氧)-雷公藤内酯醇(Ⅰ)或其药学上可接受的盐，
其中，Ph表示苯基
化合物Ⅰ的一种制备方法为：将雷公藤内酯醇在碱性条件下与苯磺酰基呋咱氮氧化物反应得到所述化合物。其反应方程式如下：
上述反应中反应溶剂为四氢呋喃或N,N-二甲基甲酰胺；碱为氢化钠或氢氧化钠；反应温度为0℃。
本发明另一方面还涉及以本发明化合物作为活性成分的药物组合物。该药物组合物根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔黏膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂 (包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛应用本领域公知的各种赋形剂，包括稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露糖、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片、或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、粘合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各种稀释剂、粘合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等。pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-150mg/kg体重，优选0.1-100 mg/kg体重，更优选为1-60mg/kg体重，最优选为2-30mg/kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
附图说明
图1、化合物Ⅰ对LPS刺激的Ana-1细胞中炎性因子释放的抑制；###p<0.001,和对照组比较,***p<0.001,和模型组比较.
图2、化合物Ⅰ对DSS模型小鼠体重的影响；#p<0.05,###p<0.001,和对照组比较；*p<0.05,***p<0.001,和模型组比较.
图3、化合物Ⅰ对DSS模型小鼠结肠长度的影响；###p<0.001,和对照组比较；**p <0.01,和模型组比较.
图4、化合物Ⅰ对DSS模型小鼠肠炎活动指数的影响；###p<0.001,和对照组比较；*p<0.05,**p<0.01,***p<0.001,和模型组比较.
具体实施方式
实施例1、化合物Ⅰ的合成
化合物Ⅰ同中国专利申请号为2018104648420中化合物LA-67为同一化合物，其制备方法亦一致。
将500mg雷公藤内酯醇完全溶解于10ml四氢呋喃中。冰水浴冷却至0℃，向其中缓慢分批加入111mg氢化钠，搅拌10分钟。然后将苯磺酰基呋咱氮氧化物的四氢呋喃溶液(1.02g溶于10ml四氢呋喃)滴入反应瓶中，继续搅拌2小时。停止反应，向其中加入二氯甲烷稀释，然后用少量水及饱和氯化钠溶液各洗涤一次，再用无水硫酸钠干燥、抽滤，滤液旋干得粗品。通过硅胶柱层析(氯仿：甲醇＝20:1)进行纯化得白色固体，再通过甲醇重结晶得纯品511mg，产率63％。H1 NMR(400MHz,CDCl3)δ8.23-8.21(d,J＝7.8Hz,2H),7.75-7.72(t,1H),7.62-7.59(t, 2H),5.05(s,1H),4.72-4.63(q,2H),3.95-3.94(d,J＝2.2Hz,1H),3.69(s,1H), 3.48-3.47(d,J＝5.4Hz,1H),2.75-2.72(m,1H),2.39-2.35(m,1H),2.22-2.17(m,2H), 2.10-2.05(m,1H),1.91-1.85(t,1H),1.68-1.65(m,1H),1.31-1.25(m,1H),1.09(s,3H), 1.04-1.02(d,J＝6.80Hz,3H),0.94-0.93(d,J＝6.80Hz,3H)。HRESIMS m/z ＝585.1521[M+H]+(calcd for C28H28O10N2S,584.1465)。
药理实验：
实验例1、化合物Ⅰ抑制巨噬细胞(Ana-1)中炎性因子的释放
1.抑制炎性因子释放检测原理
以Ana-1细胞为实验对象，通过ELISA法检测化合物Ⅰ对LPS(脂多糖)刺激后的Ana-1细胞中炎性因子释放的影响。ELISA法是1971年瑞典学者Engvail 和Perlmann,荷兰学者Van Weerman和Schuurs分别报道的将免疫技术发展为检测体液中微量物质的固相免疫测定方法，其主要的测定原理是采用抗原与抗体的特异反应将待测物与酶连接，然后通过酶与底物产生颜色反应，用于定量测定。
2.实验方法
(1)10％胎牛血清的1640培养基、37℃、5％CO2以及饱和湿度环境下培养Ana-1 细胞，当细胞呈对数增长时，处理，接种于96孔板中，接种密度为2.5×105个/mL， 100μL/孔，培养12-14h后进行后续实验。
(2)当细胞密度达到75％～80％，弃去10％胎牛血清的1640培养基,改为2％胎牛血清的1640培养基，饥饿4h，随后分为：①正常对照组(Control)：终体积为 100μL；②模型组(Model)：每孔加10μL LPS，终体积为100μL。③化合物Ⅰ组 (Sample1)和雷公藤甲素(Triptolide,TP)组每孔加待检测化合物10μL，1h以后加10μL LPS，终体积为100μL，化合物终浓度0.3μM，0.1μM。化合物Ⅰ与 Ana-1细胞共同孵育24h后收样，ELISA法进行检测，操作步骤按说明书所示。
3.实验结果
由实验结果可以看出，在不影响Ana-1细胞增殖的情况下，化合物Ⅰ可明显抑制LPS刺激的Ana-1细胞中IL-6、TNF-α炎性因子的释放，结果见表1及图1。
表1、化合物Ⅰ对LPS刺激的Ana-1细胞中炎性因子释放的抑制作用(mean±SD)
###p<0.001,和对照组比较；***p<0.001,和模型组比较.
实验例2、化合物Ⅰ对DSS诱导的UC动物模型的药效学评价
1.实验原理
葡聚糖硫酸钠(DSS)是由蔗糖合成的一种硫酸多糖体，可通过抑制DNA合成，破坏肠道粘膜屏障系统使肠道菌群失调、巨噬细胞功能失调，肠道抗原进入粘膜层诱发UC，也可通过上调TNF-α、IFN-γ、IL-10等因子的表达及影响嗜酸性粒细胞脱颗粒干预UC发展的进程。可根据公式DSS(mg/g)＝总饮水量(mL) ×[DSS(mg)/100mL]/鼠的初始体重(g)计算DSS的摄取量，并根据小鼠的体重、大便性状和隐血、便血情况及组织学观察来评价化合物Ⅰ对小鼠UC模型的改善情况。
该模型制作简便、经济，重复性好，其组织病理改变与人类的溃疡性结肠炎的临床表现极为相似，被广泛用于UC发病机制、病理变化和药物疗效评估的研究。
2.实验方法
(1)动物购置后适应性饲养一周，按体重随机分为4组：对照组，模型组，化合物Ⅰ(0.3、1.0mg/kg,p.o.)，模型组给予等剂量的溶媒，每组6只；让小鼠自由饮用3％DSS溶液，连续7d，构建急性UC模型。
(2)自开始给与小鼠饮用DSS之日起，不同组别小鼠给与不同剂量的化合物Ⅰ(0.3、1.0mg/kg,p.o.)治疗，每天记录各组小鼠体重及稀血便情况，直至取材。
(4)待模型组出现明显的便血，表明造模成功，开始取材。
(4)取各组小鼠结肠，测量结肠长度，观察血便、稀便情况，拍照。
3.实验结果
由实验结果可以看出，与模型组相比，化合物Ⅰ可以明显改善小鼠生存状态，缓解DSS模型小鼠体重减轻的症状,结果见表2及图2。与正常组相比，模型组小鼠结肠明显缩短，给药组小鼠结肠长度更接近正常组，结果见表3及图3。同时，与模型组相比，化合物Ⅰ可明显降低DSS模型小鼠的DAI评分，结果见表4及图 4。以上结果说明化合物Ⅰ对溃疡性结肠炎有明显的改善作用。
表2、化合物Ⅰ对DSS小鼠模型体重的影响(mean±SD)
#p<0.05,###p<0.001,和对照组比较；*p<0.05,***p<0.001,和模型组比较.
表3、化合物Ⅰ对DSS小鼠模型结肠长度的影响(mean±SD)
###p<0.001,和对照组比较；**p<0.01,和模型组比较.
表4、化合物Ⅰ对DSS小鼠模型DAI评分的影响(mean±SEM)
###p<0.001,和对照组比较；*p<0.05,**p<0.01,***p<0.001,和模型组比较。
Claims (3)
1.式I所示化合物或其药学上可接受的盐在制备预防和/或治疗炎症性肠病药物中的应用，
其中，Ph表示苯基。
2.一种药物组合物在制备预防和/或治疗炎症性肠病药物中的应用，其包含作为有效成分的式I所示化合物或其药学上可接受的盐以及药效学上可接受的载体或赋形剂
其中，Ph表示苯基。
3.根据权利1-2任一项的应用，所述的炎症性肠病选自溃疡性结肠炎或克罗恩病。
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