CN115403545B - 愈创木烷类倍半萜前药及其用途 - Google Patents
愈创木烷类倍半萜前药及其用途 Download PDFInfo
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Abstract
本发明公开了一类愈创木烷类倍半萜前药及其用途，所述愈创木烷类倍半萜前药或药学上可接受的盐如式I所示。本申请以小白菊内酯、去氢木香烃内酯等量丰天然成分为原料，合成了通式I所示的愈创木烷类倍半萜前药，该类前药能够抑制NLRP3炎症小体活化，通过实验测试表明该类前药显著提高了其原药形式的口服吸收，具有较好临床应用前景。
Description
技术领域
本发明涉及一种前药及其用途，特别是涉及一类新愈创木烷类倍半萜前药及其医药用途。
背景技术
NLRP3炎性小体的过度活化与多种疾病的发生发展密切相关，包括免疫性疾病、自身免疫性疾病、恶性肿瘤、皮肤疾病、心血管疾病、肝脏相关疾病、肾脏系统相关疾病、胃肠道相关疾病、中枢神经系统疾病、代谢性疾病、内分泌相关疾病、呼吸道疾病、淋巴系统疾病、炎症、感染性疾病、眼病、心理障碍、疼痛等【Nat Med,2015,21:248-255；J ClinInvest,2020,130:1961-1976；Cell Metab,2020,31:580-591；Circ Res,2018,122:1722-1740；J Hepatol,2017,66:1037-1046；Ageing Res Rev,2020,64:101192；Autophagy,2019,15:1860-1881；Brain,2020,143:1414-1430；Mucosal Immunol,2019,12:1150-1163；J Clin Invest,2018,128:1793-1806；Immunology,2020,160:78-89；J Inflamm(Lond),2015,12:41；Nat Commun,2020,11:4243；Front Immunol,2020,11:570251；BiochemBiophys Res Commun,2016,477:329-335；Pharmaceutics,2020,12:867；Arthritis Rheumatol,2020,72:1192-1202；Food Chem Toxicol,2020,144:111588；EMBORep,2020,21:e49666；Int Immunopharmacol,2020,81:106257；Cells,2019,8:1389；CellProlif,2021,54:e12973.】。因此，可以通过抑制NLRP3炎症小体的活化来预防和/或治疗上述疾病。
Abderrazak A课题组研究发现愈创木烷类蓓半萜内酯阿格拉宾具有极强的抑制NLPR3炎症小体活化活性，其EC50为10nM，可减轻NLPR3炎症小体相关的炎症，保护胰腺β细胞免于凋亡，在长期高脂饮食的ApoE2Ki小鼠模型中可预防2型糖尿病的发展【Circulation,2015,131:1061-1070；J Pharmacol Exp Ther,2016,357:487-494】。阿格拉宾是从哈萨克斯坦产植物苦艾(蒿)中提取获得，含量较低，约为0.27％；化学稳定性差，在胃液环境下，8h之内会有50％发生降解，口服生物利用度仅为5％，这些缺点限制其进一步的临床应用。
发明内容
发明目的：本发明的目的在于提供一类新愈创木烷类倍半萜前药，以提高愈创木烷类倍半萜的口服生物利用度。本发明还有一个目的是提供所述新愈创木烷类倍半萜前药在制备NLRP3炎症小体活化抑制剂中的应用。
技术方案：如式I所示的愈创木烷类倍半萜前药或药学上可接受的盐，
式中：
R1为氢或不存在，与邻位的碳原子以双键形式存在。
R2为甲基，R3为羟基或氟；R2和R3也可共同构成双键；或R3不存在，分别与邻位的碳原子以双键形式存在；
R4为氢，或R4与R3成环氧键；
R5为甲基，R6为甲氧基；R5和R6也可共同构成双键；或R6不存在，分别与邻位的碳原子以双键形式存在；
R7为羟基或氢，或R7与R6成单键或环氧键。
优选的，式I所述的愈创木烷类倍半萜前药选自下列化合物，其与无机酸或有机酸形成在药学上可接受的盐，包括盐酸盐、富马酸等：
本申请还提供包含治疗有效量的选自本申请愈创木烷类倍半萜衍生物或其药学上可接受的盐中的一种或多种作为活性成分的药物组合物。所述药物组合物任选可以进一步包含药学上可接受的载体、佐剂或辅料。
本申请还提供上述愈创木烷类倍半萜衍生物或其药学上可接受的盐、和包含该衍生物的药物组合物在制备用于预防和或治疗NLPR3炎症小体相关疾病药物中的用途。
本申请还提供一种药物组合物，其包含治疗有效量的选自本申请愈创木烷类倍半萜衍生物或其药学上可接受的盐中的一种或多种作为活性成分以及其他药学上可接受的治疗剂，特别是其他NLRP3炎症小体抑制剂。所述药物组合物进一步包含药学上可接受的载体、佐剂或辅料。
本申请还提供一种预防和或治疗NLPR3炎症小体相关疾病的方法，所述方法包括给需要该治疗的患者给药治疗有效量的选自本申请愈创木烷类倍半萜衍生物或其药学上可接受的盐中的一种或多种，或根据本申请包含治疗有效量的选自根据本申请的愈创木烷类倍半萜衍生物或其药学上可接受的盐中的一种或多种作为活性成分的药物组合物。
进一步的NLPR3炎症小体相关疾病包括：免疫性疾病、自身免疫性疾病、恶性肿瘤、皮肤疾病、心血管疾病、肝脏相关疾病、肾脏系统相关疾病、胃肠道相关疾病、中枢神经系统疾病、代谢性疾病、内分泌相关疾病、呼吸道疾病、淋巴系统疾病、炎症、感染性疾病、眼病、心理障碍、疼痛等。
进一步的与NLRP3炎症小体相关的慢性炎症，包括Cryopyrin蛋白相关周期性综合征(CAPS)：穆克-韦尔斯综合症(MWS)、家族性冷性自身炎综合症(FCAS)和慢性婴儿皮肤神经关节综合征(NOMID)；同时包括自身炎症性疾病，包括：家族性地中海热(FMF)、TNF受体相关周期性综合征(TRAPS)、甲羟戊酸激酶缺乏症(MKD)、高免疫球蛋白D和周期性发热综合征(HIDS)、白细胞介素1受体(DIRA)缺乏、Majeed综合症、化脓性关节炎、脓疱病坏疽和痤疮(PAPA)、A20单倍体不足(HA20)、小儿肉芽肿性关节炎(PGA)、PLCG2相关的抗体缺乏和免疫失调(PLAID)、PLCG2相关的自发炎症、抗体缺乏和免疫失调(APLAID)与铁粒细胞性贫血伴B细胞免疫缺陷、周期性发烧和发育迟缓(SIFD)；同时包括Sweet's综合症，包括：慢性非细菌性骨髓炎(CNO)、慢性复发性多灶性骨髓炎(CRMO)和滑膜炎、痤疮、脓疱病、骨质增生，骨炎综合征(SAPHO)；同时包括自身免疫性疾病，包括多发性硬化症(MS)、1型糖尿病、银屑病、类风湿关节炎、Behcet's病、Sjogren's综合征和Schnitzler综合征；同时包括呼吸系统疾病，包括慢性阻塞性肺疾病(COPD)、类固醇抵抗性哮喘、石棉肺、矽肺和囊性纤维化；同时包括中枢神经系统疾病，包括帕金森症、阿尔茨海默症、运动神经元疾病、Huntington's病、脑疟疾和肺炎球菌性脑膜炎引起的脑损伤；同时包括代谢性疾病，包括2型糖尿病、动脉粥样硬化、肥胖症，痛风、假性痛风；同时包括眼疾病，包括眼上皮、年龄相关性黄斑变性(AMD)、角膜感染、葡萄膜炎和干眼症；同时包括肾脏相关疾病，包括慢性肾脏疾病、草酸肾病和糖尿病肾病；同时包括肝脏相关疾病，包括非酒精性脂肪性肝炎和酒精性肝病；同时包括皮肤相关的炎症反应，包括接触过敏和晒伤；同时包括关节相关的炎症反应，包括骨关节、系统性幼年特发性关节炎、成年性Still's病、复发性多软骨炎；同时包括病毒感染，包括登革热病毒和寨卡病毒、流感、艾滋病毒；同时包括化脓性汗腺炎(HS)和其他引起囊肿的皮肤疾病；同时包括癌症，包括肺癌、胰腺癌、胃癌，骨髓增生异常综合症，白血病；同时包括多发性肌炎；同时包括中风；同时包括心肌梗塞；同时包括高血压；同时包括结肠炎；同时包括蠕虫感染和细菌感染；同时包括腹主动脉瘤；同时包括伤口愈合；同时包括抑郁症；同时包括心包炎，包括Dressler's综合征、缺血再灌注损伤等疾病。
申请人采用巨噬细胞NLRP3炎症小体活化模型，研究木香抗溃疡性结肠炎的物质基础，意外发现去氢木香烃内酯(DCL)具有显著的抑制NLPR3炎症小体活化作用，并在此基础上开展进一步的前药及其用途研究。为提高该类倍半萜类成分的口服生物利用度和资源供应的经济性等，本申请以小白菊内酯、去氢木香烃内酯等量丰天然成分为原料，制备式I类愈创木烷类倍半萜前药，发现其显著提高原药形式的口服吸收，提高其临床应用前景。
有益效果：本申请以小白菊内酯、去氢木香烃内酯等量丰天然成分为原料，合成了通式I所示的愈创木烷类倍半萜前药，通过实验测试表明这些前药的成盐后能够显著提高水溶性、改善原药的口服吸收，具有更好的临床应用前景。
附图说明
图1是在小鼠血浆中化合物1及DCL浓度随时间的变化；
图2是DCL抑制小鼠来源巨噬细胞NLRP3/ASC/pro-caspase-1复合物形成；
图3是DCL抑制NLRP1、NLRC4、AIM2以及NLPR3炎症小体活化的测试；
图4是DCL对结肠组织病理学改变的影响。
具体实施方式
下面结合具体实施例对本申请作出详细说明。
实施例1：小白菊内酯、去氢木香烃内酯的制备
小白菊内酯(PTL)的制备。取山玉兰干燥根皮5kg粉碎成粗粉，以10倍量95％乙醇浸泡12h，加热回流提取两次，每次2h，过滤，合并滤液，减压浓缩，干燥即得山玉兰粗提物。再经硅胶柱层析精制，以石油醚-乙酸乙酯梯度洗脱，分段收集富含小白菊内酯、木香烃内酯流份，合并、浓缩，经重结晶获得小白菊内酯，制备得率为4.0％，纯度为96.3％。
小白菊内酯：1H NMR(500MHz,CDCl3):δ6.31(d,J＝2.9Hz,1H),5.62(d,J＝3.4Hz,1H),5.20(d,J＝11.8Hz,2H),3.85(t,J＝8.6Hz,1H),2.78(d,J＝8.9Hz,1H),2.45-2.32(m,2H),2.22-2.10(m,4H),1.70(s,3H),1.69-1.66(m,1H),1.29(s,3H),1.27-1.18(m,1H).ESI-MS(m/z):[M+H]+＝249.1(calcd:249.1).
去氢木香烃内酯(DCL)的制备。取云木香药材5kg粉碎成粗粉，以8倍量石油醚浸泡12h，加热回流提取两次，每次2h，过滤，合并滤液，减压浓缩，干燥即得云木香粗提物。再经硅胶柱层析精制，以石油醚-乙酸乙酯梯度洗脱，分段收集富含去氢木香烃内酯的流份，合并、浓缩，经重结晶获得去氢木香烃内酯(化合物1)，制备得率为1.0％，纯度为96.8％。1HNMR(500MHz，CDCl3):δ6.22(d,J＝3.3Hz,1H),5.49(d,J＝3.2Hz,1H),5.27(d,J＝2.0Hz,1H),5.07(d,J＝2.0Hz,1H),4.90(s,1H),4.82(s,1H),3.97-3.94(m,1H),2.95-2.88(m,2H),2.87(dd,J＝9.3,3.0Hz,1H),2.24-2.22(m,1H),2.16-2.13(m,1H),1.99-1.96(m,2H),1.88-1.86(m,2H),1.42-1.40(m,2H).ESI-MS(m/z):[M+H]+＝231.1(calcd:231.1)。
实施例2：化合物1～11盐酸盐的制备
化合物1的制备
圆底烧瓶中加入去氢木香烃内酯DCL(230mg，1.00mmol)、二氯甲烷(30mL)、盐酸二甲胺(815mg，10.00mmol)，碳酸钾(2764mg，20mmol)，搅拌反应4h。反应液过滤，依次用水(10mL×3)、饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥后减压浓缩，获得的中间体不经纯化，直接进行下一步反应。将上述中间体溶于二氯甲烷(2mL)中，室温搅拌2h，然后滴加盐酸溶液，至pH值4～5，过滤，所得固体用二氯甲烷洗涤，所得白色固体即为DCL的盐酸前药1，收率90％。1H NMR(500MHz,CD3OD):δ5.15(d,J＝3.3Hz,1H),5.05(d,J＝3.2Hz,1H),4.93(d,J＝2.0Hz,1H),4.83(d,J＝2.0Hz,1H),4.18(t,J＝10.0Hz,1H),3.57-3.52(m,1H),3.40-3.37(m,1H),3.11-3.06(m,1H),2.99(s,6H),2.92-2.88(m,1H),2.63-2.51(m,3H),2.39-2.32(m,1H),2.19-2.09(m,2H),2.02-1.97(m,1H),1.95-1.88(m,1H),1.53-1.45(m,1H),1.38-1.31(m,1H)。ESI-MS(m/z):[M+H]+＝312.2(calcd:312.2)。
化合物2的制备
圆底烧瓶中加入小白菊内酯(248mg，1.00mmol)、丙酮(9.5mL)、水(0.5mL)，搅拌均匀后加入amberlyst(3.22g)，反应8h后，将反应液浓缩，用乙酸乙酯(10mL×3)萃取，依次用水(10mL×3)、饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥后减压浓缩，经硅胶柱层析分离，得2-1，收率：27％。1H NMR(500MHz,CDCl3):δ6.26(d,J＝3.5Hz,1H),5.55(d,J＝3.5Hz,1H),5.01(d,J＝10.6Hz,2H),4.08(t,J＝10.5Hz,1H),3.08-3.02(m,1H),2.81-2.76(m,1H),2.73-2.68(m,1H),2.40(t,J＝12.0Hz,1H),2.30-2.26(m,1H),1.99-1.90(m,3H),1.86-1.81(m,3H),1.42-1.39(m,1H),1.34(s,3H)。ESI-MS(m/z):[M+Na]+＝271.1(calcd:271.1)。
以2-1为原料，参照DCL盐酸盐前药的制备方法可制备得到2-1的盐酸盐前药(化合物2)，收率81％。1H NMR(500MHz,CD3OD):δ5.02-4.99(m,2H),4.30(t,J＝10.6Hz,1H),3.55-3.49(m,1H),3.39-3.35(m,1H),3.12-3.04(m,2H),2.98(s,6H),2.66-2.62(m,1H),2.31(t,J＝12.0Hz,1H),2.24-2.12(m,2H),1.99-1.93(m,1H),1.87-1.81(m,3H),1.51-1.43(m,1H),1.34(s,3H),1.32-1.30(m,1H)。ESI-MS(m/z):[M+H]+＝330.2(calcd:330.2)。
化合物3的制备
圆底烧瓶中加入小白菊内酯(248mg，1.00mmol)、甲醇(10mL)，搅拌溶解后加入对甲苯磺酸(344mg，2.00mmol)，搅拌反应8h。反应液浓缩后，用乙酸乙酯(10mL×3)萃取，有机层依次用饱和碳酸氢钠(10mL×3)、水(10mL×3)、饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥后减压浓缩，经硅胶柱层析分离，得到3-1，收率：34％。1H NMR(500MHz,CDCl3):δ6.23(d,J＝3.5Hz,1H),5.53(d,J＝3.0Hz,1H),4.23(t,J＝10.5Hz,1H),3.21(s,3H),2.90-2.78(m,2H),2.38-2.33(m,2H),2.21-2.15(m,1H),2.02-1.97(m,1H),1.90-1.88(m,1H),1.86-1.84(m,1H,H5),1.82-1.80(m,1H),1.75-1.69(m,1H),1.60-1.52(m,1H),1.47-1.42(m,1H),1.40(s,3H),1.18(s,3H,H15)。ROESY谱显示H5和H15有信号相关，确定H15的甲基为α构型。ESI-MS(m/z):[M+Na]+＝303.2(calcd:303.2)。
以3-1为原料，参照DCL盐酸盐前药的制备方法可制备得到3-1的盐酸盐前药(化合物3)，收率80％。1H NMR(500MHz,CD3OD):δ4.42(t,J＝10.5Hz,1H),3.54-3.46(m,1H),3.39-3.37(m,1H),3.24(s,3H),3.23-3.21(m,1H),2.99(s,6H),2.48-2.40(m,1H),2.19-2.15(m,1H),2.02-1.98(m,1H),1.97-1.91(m,1H),1.86-1.82(m,2H),1.79-1.72(m,2H),1.63-1.54(m,2H),1.39(s,3H),1.35-1.32(m,1H),1.21(s,3H)。ESI-MS(m/z):[M+H]+＝362.2(calcd:362.2)。
化合物4的制备
150mL圆底烧瓶中依次加入二氯甲烷(50mL)、对甲苯磺酸(125mg，0.73mmol)和小白菊内酯(5g，20.16mmol)，室温下搅拌至TLC检测反应结束。反应液依次用水(10mL×3)、饱和食盐水(10mL×3)洗涤，有机相用无水硫酸钠干燥后减压浓缩，经硅胶柱层析分离，得到含笑内酯(MCL)，收率：90％。1H NMR(500MHz,CDCl3):δ6.21(d,J＝3.5Hz,1H),5.51(d,J＝3.0Hz,1H),3.81(t,J＝10.5Hz,1H),2.73(d,J＝10.5Hz,1H),2.68-2.64(m,2H),2.42-2.37(m,1H),2.26-2.16(m,3H),2.11-2.08(m,1H),1.83-1.75(m,2H),1.69(s,3H),1.31(s,3H),1.27-1.25(m,1H)。ESI-MS(m/z):[M+Na]+＝271.1(calcd:271.1)。
圆底烧瓶中依次加入间氯过氧苯甲酸(267.5mg，1.55mmol)、无水二氯甲烷(20mL)，将MCL(248mg，1.00mmol)的二氯甲烷溶液(5mL)缓慢加入后搅拌反应8h。饱和硫代硫酸钠溶液淬灭后，依次用饱和碳酸氢钠(10mL×3)、水(10mL×3)、饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥后减压浓缩，经硅胶柱层析分离，得到4-1，收率：85％。1H NMR(500MHz,CDCl3):δ6.21(d,J＝3.5Hz,1H),5.49(d,J＝3.0Hz,1H),4.05(t,J＝10.5Hz,1H),2.85(s,1H),2.36(d,J＝11Hz,1H),2.31-2.22(m,3H),2.03-1.99(m,2H),1.90-1.88(m,1H),1.85-1.83(m,1H,H5),1.80-1.76(m,1H),1.70-1.65(m,1H),1.48(s,3H),1.31(s,3H,H15)。ROESY谱显示H5和H15有信号相关，确定环氧丙烷为β构型。ESI-MS(m/z):[M+Na]+＝287.1(calcd:287.1)。
以4-1为原料，参照DCL盐酸盐前药的制备方法可制备得到4-1的盐酸盐前药(化合物4)，收率：87％。1H NMR(500MHz,CD3OD):δ4.95(t,J＝10.5Hz,1H),3.40-3.35(m,2H),3.11-3.03(m,1H),2.99(s,6H),2.90(d,J＝15.0Hz,1H,H5),2.56-2.46(m,1H,H11),2.30-2.21(m,2H),2.13-2.05(m,1H),1.90-1.86(m,1H),1.85-1.78(m,2H),1.77-1.73(m,1H),1.70-1.65(m,1H),1.37(s,3H),1.32(s,3H)。ESI-MS(m/z):[M+H]+＝360.2(calcd:360.2)。
化合物5的制备
圆底烧瓶中加入MCL(124mg，0.50mmol)，二氯甲烷(5mL)，氮气保护，置于-78℃搅拌溶解，缓慢滴加DAST试剂(161mg，1.00mmol)，滴加完成后继续搅拌10-15min。反应液加水淬灭，二氯甲烷稀释后依次用水(10mL×3)、饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥后减压浓缩，经硅胶柱层析分离，得到5-1，收率：57％。1H NMR(500MHz,CDCl3):δ6.19(d,J＝3.5Hz,1H),5.45(d,J＝3.0Hz,1H),3.96(t,J＝10.5Hz,1H),2.73-2.66(m,2H),2.45-2.40(m,2H),2.26-2.24(m,2H),2.13-2.06(m,3H),1.77(s,3H),1.72(d,J＝21.5Hz,3H),1.40-1.36(m,1H)。19F NMR(470MHz,CDCl3):δ-159.39。ESI-MS(m/z):[M+Na]+＝273.1(calcd:273.1)。
以5-1为原料，参照DCL盐酸盐前药的制备方法可制备得到5-1的盐酸盐前药(化合物5)，收率：80％。1H NMR(500MHz,CD3OD):δ4.14(t,J＝10.5Hz,1H),3.54-3.49(m,1H),3.44-3.40(m,1H),3.15-3.10(m,1H),2.99(s,6H),2.82-2.75(m,1H),2.7(d,J＝10.0Hz,2H),2.22-2.17(m,3H),2.07-2.00(m,1H),1.94-1.91(m,1H),1.79(s,3H),1.76-1.68(m,1H),1.64(d,J＝21.5Hz,3H),1.47-1.39(m,1H)。ESI-MS(m/z):[M+Na]+＝332.2(calcd:332.2)。
化合物6的制备
以4-1为原料，采用制备5-1的方法，可以制备得到6-1，收率：46％。1H NMR(500MHz,CDCl3):δ6.20(d,J＝3.5Hz,1H),5.47(d,J＝3.0Hz,1H),4.22(t,J＝10.5Hz,1H),2.31-2.18(m,4H),2.04-1.97(m,1H),1.93-1.82(m,3H),1.74(d,J＝21.0Hz,3H),1.55-1.46(m,1H),1.36(s,3H),1.31-1.29(m,1H)。19F NMR(470MHz,CDCl3):δ-156.9。ESI-MS(m/z):[M+Na]+＝289.1(calcd:289.1)。
以6-1为原料，参照DCL盐酸盐前药的制备方法可制备得到6-1的盐酸盐前药(化合物6)，收率：92％。1H NMR(500MHz,CD3OD):δ4.36(t,J＝10.5Hz,1H),3.48-3.43(m,1H),3.38-3.35(m,1H),3.08-3.03(m,1H),2.98(s,6H),2.42-2.34(m,1H),2.33-2.27(m,1H),2.20-2.15(m,2H),2.06-2.02(m,1H),1.86-1.78(m,3H),1.73-1.69(m,1H),1.65(d,J＝20.0Hz,3H),1.34(s,3H),1.33-1.30(m,1H)。ESI-MS(m/z):[M+Na]+＝348.2(calcd:348.2)。
化合物7的制备
圆底烧瓶中依次加入MCL(200mg,0.81mmol)、无水吡啶(10mL),氮气保护，冰水浴溶解，逐滴加入三氯氧磷(1242mg，8.10mmol)，滴加完成后移至室温反应2h。将反应液倾入冰水中，乙酸乙酯(10mL×3)萃取，有机层依次用饱和硫酸铜溶液(10mL×6)、水(10mL×3)、饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥后减压浓缩，经硅胶柱层析分离，得到7-1，收率：65％。1H NMR(500MHz,CDCl3):δ6.13(d,J＝3.5Hz,1H),5.40(d,J＝3.4Hz,1H),5.08(s,1H),4.93(s,1H),4.80(s,1H),4.70(s,1H),3.66(t,J＝10.5Hz,1H),3.41(d,J＝10.0Hz,1H),3.00-2.98(m,2H),2.83-2.77(m,1H),2.35-2.29(m,1H),2.21-2.16(m,1H),2.13-2.08(m,1H),1.96(s,3H),1.74(s,3H),1.42-1.35(m,1H)。ESI-MS(m/z):[M+Na]+＝253.1(calcd:253.1)。
以7-1为原料，参照DCL盐酸盐前药的制备方法可制备得到7-1的盐酸盐前药(化合物7)，收率：89％。1H NMR(500MHz,CD3OD):δ5.58-5.57(m,1H),3.89(t,J＝10.5Hz,1H),3.54-3.49(m,1H),3.45-3.41(m,2H),3.15-3.09(m,1H),3.01(s,6H),2.97-2.95(m,2H),2.40-2.32(m,1H),2.31-2.23(m,1H),2.18-2.14(m,1H),1.97-1.93(m,1H),1.90(s,3H),1.75(s,3H),1.50-1.43(m,1H)。ESI-MS(m/z):[M+H]+＝312.2(calcd:312.2)。
化合物8的制备
圆底烧瓶中加入Burgess Reagent(282mg，1.10mmol)、无水四氢呋喃(10mL)，氮气保护，冰浴。加入MCL(248mg，1.00mmol)，搅拌20min后移至室温，继续搅拌3h。反应液浓缩后，用乙酸乙酯(10mL×3)萃取，有机层依次用水(10mL×3)、饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥后减压浓缩，经硅胶柱层析分离，得到8-1，收率：67％。1H NMR(500MHz,CDCl3):δ6.24(d,J＝3.5Hz,1H),5.51(d,J＝3.0Hz,1H),5.13(d,J＝10.5Hz,1H),3.04-2.97(m,1H),2.57-2.45(m,3H),2.42-2.36(m,3H),2.08-2.05(m,1H),2.04(s,3H),1.75(s,3H),1.73-1.69(m,1H)。ESI-MS(m/z):[M+Na]+＝253.1(calcd:253.1)。
以8-1为原料，参照DCL盐酸盐前药的制备方法可制备得到8-1的盐酸盐前药(化合物8)，收率：85％。1H NMR(500MHz,CD3OD):δ5.22(d,J＝10.5Hz,1H),3.66-3.61(m,1H),3.39-3.35(m,1H),3.20-3.15(m,1H),2.99(s,6H),2.67-2.62(m,3H),2.41-2.35(m,3H),2.18-2.16(m,1H),2.07-2.06(m,1H),2.04(s,3H),1.80(s,3H),1.72-1.68(m,1H)。ESI-MS(m/z):[M+H]+＝312.2(calcd:312.2)。
化合物9的制备
圆底烧瓶中依次加入4-1(264mg，1.00mmol)，甲醇(10mL)，对甲苯磺酸(172mg，1.00mmol)，搅拌反应8h。反应液浓缩后，用乙酸乙酯(10mL×3)萃取，有机层依次用饱和碳酸氢钠(10mL×3)、水(10mL×3)、饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥后减压浓缩，经硅胶柱层析分离，得到9-1，收率：85％。1H NMR(500MHz,CDCl3):δ6.23(d,J＝3.5Hz,1H),5.53(d,J＝3.0Hz,1H),4.79(t,J＝10.5Hz,1H),3.37(s,3H),2.78-2.73(m,1H),2.50(d,J＝11.0Hz,1H),2.41-2.34(m,1H),2.07-1.99(m,2H),1.94-1.84(m,2H),1.81-1.78(m,1H,H5),1.68-1.59(m,1H),1.50-1.46(m,1H),1.41(s,3H),1.40-1.38(m,1H),1.30-1.26(m,1H),1.23(s,3H,H15)。ROESY显示H5和H15有信号相关，确定H15的甲基为α构型。ESI-MS(m/z):[M+Na]+＝285.1(calcd:285.1)。
以9-1为原料，参照DCL盐酸盐前药的制备方法可制备得到9-1的盐酸盐前药(化合物9)，收率：88％。1H NMR(500MHz,CD3OD):δ5.03(t,J＝10.5Hz,1H,H6),3.54-3.49(m,1H),3.38(s,3H,H16),3.23-3.18(m,1H),3.07-3.01(m,1H),2.98(s,6H),2.41(d,J＝11.0Hz,1H,H5),2.30-2.21(m,2H),2.13-2.03(m,2H),1.97-1.92(m,2H),1.88-1.81(m,1H),1.79-1.74(m,2H),1.40(s,3H,H15),1.16(s,3H,H14)。ROESY显示H6和H15有信号相关,而与H14无信号相关，以及H5和H16有信号相关。ESI-MS(m/z):[M+H]+＝378.2(calcd:378.2)。
化合物10的制备
在冰浴、氮气保护条件下，向无水二氯甲烷(67mL)中加入乙二醇二甲醚(1.67mL，21.26mmol),搅拌均匀后加入13.3mL二乙基锌溶液(1M正己烷溶液)，缓慢滴加二碘甲烷(2.67mL，3.11mmol)，搅拌10min，制成环丙烷化试剂。另取一圆底烧瓶，加入含笑内酯MCL(300mg，1.21mmol)、无水二氯甲烷(5mL)，搅拌溶解后氮气保护，置于冰浴。将上述环丙烷化试剂逐滴加入底物溶液中，滴加完成后继续反应1h，移至室温反应反应8h。反应液用饱和氯化铵淬灭，过滤后依次用水(10mL×3)、饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥后减压浓缩，经硅胶柱层析分离，得到10-1，收率：75％。10-1利用化合物7相同的合成方法，发生消除反应得到10-2，收率：78％。10-2利用化合物4相同的合成方法，发生环氧化反应可得到10-3，收率：83％。1H NMR(500MHz,CDCl3):δ6.18(d,J＝3.5Hz,1H),5.48(d,J＝3.0Hz,1H),3.79(t,J＝10.5Hz,1H,H6),2.53-2.48(m,1H),2.28-2.24(m,1H,H3),2.16-2.10(m,2H),2.04-2.01(m,1H,H5),1.73(s,3H),1.56-1.45(m,3H),1.12-1.09(m,1H),1.08(s,3H),0.57(d,J＝4.0Hz,1H,H16a),0.49(d,J＝4.0Hz,1H,H16b)。ROESY显示H5和H16a,以及H3和H6有信号相关，显示环丙烷和环氧丙烷均为α构型。ESI-MS(m/z):[M+Na]+＝283.1(calcd:283.1)。
以10-3为原料，参照DCL盐酸盐前药的制备方法可制备得到10-3的盐酸盐前药(化合物10)，收率：88％。1H NMR(500MHz,CD3OD):δ4.56(t,J＝10.5Hz,1H),4.21-4.18(m,1H),3.49-3.45(m,1H),3.39-3.35(m,1H),3.15-3.10(m,1H),2.99(s,6H),2.42-2.38(m,1H),2.25-2.19(m,3H),2.00-1.98(m,1H),1.93-1.91(m,1H),1.86-1.80(m,2H),1.62(s,3H),1.14(s,3H),0.80(d,J＝5.0Hz,1H),0.54(d,J＝5.0Hz,1H)。ESI-MS(m/z):[M+H]+＝342.2(calcd:342.2)。
化合物11的制备
以7-1为起始原料，制备方法同化合物4，可获得11-1,收率：71％。1H NMR(500MHz,CDCl3):δ6.17(d,J＝3.5Hz,1H),5.44(d,J＝3.0Hz,1H),4.13(t,J＝10.5Hz,1H),2.51(d,J＝10.5Hz,1H),2.36(d,J＝15.5Hz,1H),2.28-2.22(m,1H),2.21-2.16(m,1H),1.99-1.93(m,2H),1.85-1.81(m 1H),1.70(s,3H),1.67-1.65(m,1H),1.52-1.44(m,1H),1.31(s,3H)。ESI-MS(m/z):[M+Na]+＝285.1(calcd:285.1)。
以11-1为原料，参照DCL盐酸盐前药的制备方法可制备得到11-1的盐酸盐前药(化合物11)，收率：82％。1H NMR(500MHz,CD3OD):δ4.47(t,J＝10.5Hz,1H),4.26-4.24(m,1H),3.56-3.46(m,2H),3.18-3.12(m,2H),3.06(s,6H),2.68-2.64(m,1H),2.52-2.49(m,1H),2.26-2.23(m,1H),2.16-2.07(m,1H),1.95-1.89(m 1H),1.80-1.77(m,1H),1.70(s,3H),1.62-1.63(m,1H),1.40(s,3H)。ESI-MS(m/z):[M+H]+＝344.2(calcd:344.2)。
实施例3：DCL的盐酸盐前药(化合物1)在血浆中转化为DCL
实验方法
血浆制备：取小鼠血浆于预先装有肝素钠的EP管中，在4℃下8000rpm离心10min，取上清液。
样品分析：取0.6mg的DCL的盐酸盐前药(化合物1)溶于250μL去离子水中。样品中加入250μL小鼠血清中，37℃恒温孵育，分别于不同的时间点取样，取20μL样品于EP管中，加入60μL甲醇，涡旋混匀，在4℃下12000rpm离心10min。分别于1h、2h、4h、8h及12h时，取上清液，HPLC分析样品，进样量10μL，记录相应的峰面积。色谱条件如下：色谱柱为汉邦C18(4.6×250mm，5μm)；流动相为乙腈：10mmol/mL甲酸铵溶液＝60：40；流速1.0mL/min；检测波长210nm；柱温30℃。
实验结果
如图1所示，在1h、2h、4h、8h、12h时，在小鼠血浆中DCL的含量逐渐变多，含量分别为6.64％、14.13％、26.14％、40.83％、54.14％。该实验结果表明，在小鼠血浆中，化合物1的可作为前药转变为原药DCL。
同样的，其他前药在血浆中可转化为对应的原药。
实施例4：原型及其前药的水溶解度测试
精密称取原形化合物各5μg，以及前药1-11各10mg，加入1mL去离子水中，超声使其完全溶解。配制成饱和溶液过滤后用HPLC进样分析，进样量依次为1μL、3μL、5μL、10μL、15μL、20μL，绘制对应原形化合物以及前药的标准曲线。
配制上述化合物的不饱和溶液，超声辅助溶解4h，置于37℃水浴中静置1h，将所得不饱和溶液离心，移取30μL上清液，加入200μL去离子水稀释后，过滤后通过HPLC分析样品，将相关数据代入上述测得的标准曲线后，即可获得测试原形化合物以及前药的溶解度。
实验结果
表1.化合物的溶解度
如表1所示，与阿格拉宾以及相对应的原药相比，经过13,13-N,N-二甲基衍生物盐酸盐前药饰后，前药1-11的水溶性至少提高了100倍以上。
实施例5：化合物的原形及其前药抑制NLRP3炎症小体的活性测试
NLRP3是一种重要的模式识别受体，能够通过接头蛋白ASC与pro-caspase-1形成NLRP3炎症小体，NLRP3炎症小体活化之后可以介导caspase-1活化，进而促进IL-1β的成熟和分泌。为了确定制备的愈创木烷类倍半萜内酯衍生物的原形及其前药能否抑制NLRP3炎症小体活化，我们用LPS和ATP诱导NLRP3炎症小体活化，观察化合物的原药及其前药对NLRP3炎症小体活化导致的IL-1β水平的影响。
实验材料
实验试剂
药物按实施例1制备；脂多糖(Lipopolysaccharide,LPS)和三磷酸腺苷(Adenosine triphosphate,ATP)，Sigma公司；重组小鼠巨噬细胞集落刺激因子(recombinant mouse macrophage colony stimulating factor,rmM-CSF)，PeproTech公司；RPMI 1640培养基、DMEM培养基和胎牛血清(Fetal bovine serum,FBS)。
实验动物
C57BL/6小鼠，雌性，6-8周龄，体重18-20g，由南京市江宁区青龙山动物养殖场提供，生产许可证号：SCXK(苏)2017-0001。
实验方法
小鼠骨髓来源巨噬细胞(BMDMs)的分离与培养
取C57BL/6小鼠，采用颈椎脱臼法处死小鼠后将其用75％酒精浸泡5-10min后，用剪刀将小鼠两条后腿取下，然后除肉剩腿骨，用PBS将小鼠腿骨洗三次，将1mL注射器内吸满无血清RPMI 1640培养基，用镊子夹取骨头，用剪刀从两端剪开，然后用注射器将骨髓吹至15mL离心管中，反复多次，直至骨髓全部冲出，骨头由红变白。随后，1500rpm，离心5min，弃上清，用1mL红细胞裂解液重悬，并反复吹打，然后静置7min以裂解红细胞。1500rpm，离心5min后弃上清，用含有100ng/mLrmM-CSF的RPMI 1640培养基进行重悬，然后转移至6孔培养板中进行培养。6-7天后，可观察细胞状态，呈长梭形，说明状态良好，可用于后续实验。
NLRP3炎症小体活化模型建立
配制含1％FBS以及100ng/mL LPS的DMEM培养基，取上述6孔培养板中的BMDMs，加入配制好的培养基进行预刺激，刺激时间为3h。随后，加入阿格拉宾(1,3,10,30,60,120nM)孵育1h后，加入ATP(5mM)刺激1h。收集上清至1.5mL EP管中，后续用于IL-1β水平检测。
实验结果
表2.对NLRP3炎症小体活化的抑制作用
| 原药 | IC50(nM) | 前药 | IC50(nM) |
| 1-1(DCL) | +++ | 1 | ++ |
| 2-1 | +++ | 2 | ++ |
| 3-1 | +++ | 3 | ++ |
| 4-1 | +++ | 4 | ++ |
| 5-1 | +++ | 5 | ++ |
| 6-1 | +++ | 6 | ++ |
| 7-1 | +++ | 7 | ++ |
| 8-1 | +++ | 8 | ++ |
| 9-1 | +++ | 9 | ++ |
| 10-3 | +++ | 10 | + |
| 11-1 | +++ | 11 | ++ |
| 阿格拉宾 | +++ |
注：+代表80nM<IC50<100nM,++代表40nM<IC50<80nM，+++代表IC50<40nM
在BMDMs中采用LPS和ATP诱导NLRP3炎症小体活化模型，考察原药对IL-1β表达水平的影响。如表2所示，原药显示更强或相当的活性。
实施例6：DCL影响NLPR3/ASC/pro-caspase-1复合物形成
实验方法：
免疫共沉淀法检测NLRP3/ASC/pro-caspase-1复合物形成
取小鼠骨髓来源巨噬细胞(BMDMs)，加入含100ng/mL LPS的5％FBS DMEM培养基，预处理4h后，加入DCL(1,3,10,30nM)处理1h，再在实验孔中加入NLRP3炎症小体激活剂ATP(5mM)刺激1h。随后，取出细胞板，弃上清，预冷的PBS溶液洗涤3次。加入400μL RAPI强裂解液，冰上裂解10-15min，细胞刮刀刮下细胞后，12000rpm、4℃离心5min，吸取上清。采用BCA蛋白定量试剂盒测定蛋白浓度，并调整至相等。取出100μL上清蛋白，加入25μL 5×loadingbuffer，煮沸5min。其余的上清蛋白加入1μL ASC抗体，4℃摇匀过夜。次日，加入20μLProtein A+G agarose，室温摇匀4-5h，5000rpm、4℃离心5min，弃上清。加入500μL RAPI强裂解液洗涤沉淀3-4次，加入25μL 2×loading buffer，瞬时离心1min，煮沸5min。采用western blotting法测定ASC和pro-caspase-1蛋白水平。
实验结果：
如图2所示，DCL(3,10,30nM)能够浓度依赖性地减少NLRP3/ASC/pro-caspase-1复合物的形成，提示DCL能够阻断NLRP3/ASC/pro-caspase-1组装过程。
实施例7：DCL高选择性抑制NLRP3炎症小体活化
实验方法：
对巨噬细胞NLRP3、AIM2、NLRP1和NLRC4炎症小体活化模型的影响
取BMDMs，加入含100ng/mL LPS的5％FBS DMEM培养基，预处理4h后，加入DCL(1,3,10,30nM)处理1h，再在实验孔中分别加入NLPR3炎症小体激活剂ATP(5mM)作用1h、NLRP1炎症小体激活剂muramyldipeptide(MDP,200ng/mL)、NLRC4炎症小体激活剂flagellin(200ng/mL)和AIM2炎症小体激活剂poly dA:dT(500ng/mL)共同作用6h，刺激时间结束后收集细胞上清。采用ELISA方法检测IL-1β的释放。
实验结果：
如图3所示，DCL(1,3,10,30nM)对LPS+MDP诱导的NLRP1炎症小体活化、LPS+flagellin诱导的NLRC4炎症小体活化和LPS+polydA:dt诱导的AIM2炎症小体活化产生的IL-1β无明显作用，但却能呈浓度依赖性减少LPS+ATP诱导的NLRP3炎症小体活化导致的IL-1β释放。提示，DCL不影响NLRP1、NLRC4、AIM2炎症小体活化，而是选择性抑制NLRP3炎症小体活化。
实施例8：化合物DCL及其盐酸盐前药(化合物1)的等摩尔剂量的药代动力学性质比较
实验材料
实验试剂
药物按实施例1制备；甲苯磺丁脲(内标，internal standard，IS)，大连美仑生物技术有限公司；二甲基亚砜，上海泰坦科技股份有限公司；生理盐水，辰欣药业股份有限公司；吐温80，国药集团化学试剂有限公司；橄榄油，上海麦克林生化科技有限公司；甲醇、乙腈和甲酸，Merck公司；纯水，杭州娃哈哈集团有限公司。
实验仪器
冷冻离心机，eppendorf公司；涡旋振荡器，scientific industries公司；数控超声波清洗器，昆山市超声仪器有限公司；电子天平，sartorius公司；磁力搅拌器，IKA公司；电子天平，常州市幸运电子设备有限公司；H-Class/Xevo TQ-S micro液质联用仪，waters公司。
实验动物
SPF级雄性SD大鼠，体重200±20g，由南京市江宁区青龙山动物养殖场提供。购入后饲养于环境温度23～26℃，湿度40～60％条件下7天，期间自由进食饮水，动物生产许可证号：SCXK(浙)2019-0002。
实验方法
UPLC-MS/MS测定方法的建立
色谱条件：采用Waters Acquity BEH C18柱(2.1×50mm，1.7μm)；以0.1％甲酸水溶液为流动相A，乙腈为流动相B进行梯度洗脱(0-2.0min，20％-70％B；2.0-3.0min，70％-100％B；3.0-4.0min，100％-100％B；4.0-5.0min，100％-20％B；5.0-6.0min，20％-20％B)，总运行时间：6min；流速：0.4mL/min，柱温为30℃，进样量为4μL。
质谱条件：采用电喷雾离子源(ESI)，正离子监测模式，扫描方式为多反应检测(MRM)模式，用于检测的离子为：m/z 231.2→195.2(化合物1)，m/z271.2→91.1(IS)。MS工作参数设置为：毛细管电压为1000V，去溶剂温度600℃，去溶剂流速为1000L/Hr。化合物DCL和IS的锥孔电压分别为10V和28V，碰撞能量分别为8V和30V。使用Masslynx 4.2进行数据采集和分析。
血浆样品处理
经方放学考察后，以1:3蛋白沉淀法进行血浆样品前处理，选择甲醇作为蛋白沉淀剂。吸取50μL大鼠血浆样品，加入150μL内标甲醇溶液(20ng/mL)，于14000rpm/min、4℃条件下离心10min，取上清液，以4μL进样，进行LC-MS/MS分析。
药代动力学研究
SD大鼠(雄性)共6只，随机分为化合物1灌胃给药组和化合物24灌胃给药组，每组6只。大鼠分别灌胃等摩尔化合物DCL(0.413mmol/kg)和DCL的盐酸前药1(0.413mmol/kg)。化合物DCL以橄榄油(含5％DMSO及0.1％吐温80)为溶剂，经灌胃后的大鼠于给药后0.25、0.5、1、1.5、2、4、5、6、7、8、10、11、12和24小时进行眼眶采血。化合物1以生理盐水(含5％DMSO及0.1％吐温80)为溶剂，经灌胃后的大鼠于给药后0.083、0.167、0.25、0.5、0.75、1、1.5、2、4、6、8、10、12和24h进行眼眶采血。经眼眶静脉丛采取得全血置于用肝素钠溶液处理过的1.5mL EP管里，以于8000rpm/min、4℃条件下离心10min，得到血浆，-20℃贮存，备用。
数据分析
药代动力学参数包括浓度-时间曲线下面积(AUC)、最大血药浓度(Cmax)、平均滞留时间(MRT)、半衰期(t1/2)和达到最大血药浓度的时间(Tmax)通过DAS(药物与统计，2.0版)软件的非房室模型计算。所有数据均以均平均值±标准差(SD)表示。
实验结果
表3.灌胃给药化合物DCL及其盐酸盐前药(化合物1)后大鼠血液中DCL的主要药动学参数
如表3所示，灌胃同等摩尔数的化合物DCL和DCL的盐酸盐前药1，灌胃1后血液中化合物DCL的AUC值是直接灌胃DCL后血液中化合物DCL的AUC值的接近5倍。灌胃1后血液中化合物DCL的Cmax值是灌胃DCL后血液中化合物DCL的Cmax值的接近5倍，显示前药显著提高了化合物DCL的口服吸收。
实施例9：化合物DCL对DSS诱导急性小鼠结肠炎的影响
实验材料
实验试剂
本申请药物按实施例1制备；5-氨基水杨酸(5-aminosalicylic acid,5-ASA)，法国爱的发制药有限公司；DSS，美国MP Biomedicals公司；髓过氧化物酶(myeloperoxidase,MPO)试剂盒，南京建成生物工程研究所；羧甲基纤维素钠(sodium carboxyl methylcellulose,CMC-Na)、过氧化氢，国药集团化学试剂；邻甲苯胺，上海麦克林生化科技有限公司；冰乙酸，上海申博化工有限公司。
实验仪器
-80℃冰箱，Thermo Scientific公司；涡旋振荡器，scientific industries公司；电子分析天平，sartorius公司；磁力搅拌器，IKA公司。
实验动物
C57BL/6小鼠，雌性，18-22g，购于南京青龙山实验动物养殖场(生产许可证号：SCXK(浙)2019-0002)。实验动物均饲养于南京中医药大学实验动物中心无病原体的屏障环境内，自由饮食饮水，环境温度在22℃±2℃，湿度在45％±10％。适应性饲养一周后，用于实验。
实验方法
(1)小鼠结肠炎模型的建立与分组给药
结肠炎模型建立：选取36只6-8周龄，体重18-22g的雌性C57BL/6小鼠，根据体重随机分为6组：Normal组、DSS组、DCL(2.5,5,10μg/kg)组和5-ASA(200mg/kg)组。除Normal组外，其余小鼠自由饮用2.5％DSS溶液7天，随后换成蒸馏水再自由饮用3天。DCL和5-ASA组小鼠从造模当天起，分别接受腹腔或灌胃给药治疗，每日一次，给药体积为0.1mL/10g；Normal组和DSS组小鼠给予等体积溶媒。
(2)疾病活动指数评分
自造模第二天起，每日观察小鼠的体征、行为变化，检测小鼠体重、腹泻、便血情况，并根据评分准则进行评分，疾病活动指数(disease activity index,DAI)得分为体重减轻、腹泻、便血三项评分的平均值。隐血测定方法：收集小鼠粪便于48孔板中，先后加入邻甲苯胺-冰醋酸溶液200μL和3％过氧化氢溶液200μL，若溶液颜色迅速变蓝，则判定为有隐血。具体评分标准如下。
疾病活动指数评分
| 分数 | 体重降低(％) | 大便性状 | 大便出血 |
| 0 | 无 | 正常 | 阴性 |
| 1 | 1-5 | - | - |
| 2 | 6-10 | 松软 | 阳性 |
| 3 | 11-15 | - | - |
| 4 | >15 | 腹泻 | 肉眼可见出血 |
(3)标本采集
到达实验终点后，颈椎脱臼法处死小鼠，取小鼠完整结肠组织，量取结肠长度并拍照。接着用剪刀将结肠剪开，预冷的PBS反复清洗，去除肠内容物，取部分组织进行流式检测。取远心端约0.5cm结肠组织固定于4％甲醛溶液中，进行苏木精-伊红(H&E)染色和组织免疫荧光检测，其余部分-80℃冰箱保存备用。
(4)MPO活力测定
称取结肠组织约20mg，在预冷的PBS溶液中清洗后，加入500μL缓冲液，使用玻璃匀浆器轻轻碾磨，随后转移至1.5mL EP管中，3000rpm，4℃离心15min后取上清，制备组织匀浆悬液。根据试剂盒说明书依次添加相应试剂，并在相应的温度下孵育样品，最终在460nm处读取吸光度值。MPO活力(U/g组织湿重)＝(测定管OD-对照管OD值)/11.3×取样量(g)。
(5)组织病理学检查
取固定于4％甲醛中的结肠组织，转移至30％蔗糖溶液中4℃脱水处理24h，再经过石蜡包埋、切片后，进行H&E染色。使用倒置显微镜拍照观察结肠组织病理改变，根据粘膜损伤程度、炎性细胞浸润、隐窝损伤等指标并进行评分，具体评分细则如下：
结肠组织病理学评分
| 评分 | 肠壁炎症程度 | 病变严重程度 | 隐窝损害 |
| 0 | 正常 | 正常 | 正常 |
| 1 | 轻度 | 粘膜层 | 1/3隐窝损害 |
| 2 | 中度 | 粘膜和粘膜下层 | 2/3隐窝损害 |
| 3 | 重度 | 透壁性损伤 | 隐窝缺失、表面上皮完整 |
| 4 | - | - | 隐窝和表面上皮都缺失 |
(6)数据分析
所有数据均采用means±S.E.M.表示，采用Graphpad Prism 5.0软件进行统计和制图，使用IBM SPSS 19.0软件进行检验，多组数据之间采用单因素方差分析，P<0.05表示差异具有统计学意义。
实验结果
(1)对体征和DAI评分的影响
Normal组小鼠体重缓慢增长，粪便性状正常，精神状态活跃；而饮用DSS的小鼠出现了不同程度的体重下降、便溏、便血等结肠炎症状，出现厌食，精神状态萎靡，活动量减少等生理变化。而接受DCL(2.5,5,10μg/kg)和5-ASA(200mg/kg)治疗的小鼠体重减轻、腹泻、便血症状相对于DSS组小鼠有明显改善，具体表现为DAI评分显著低于DSS组小鼠(表4)。
表4：小鼠DAI评分
(2)对结肠形态和长度的影响
如表5所示，Normal组小鼠结肠表面光泽，富有韧性；DSS组小鼠结肠呈现水肿、充血的特点，肠壁变薄，黏膜溃疡，结肠长度明显缩短。接受DCL(2.5,5,10μg/kg)和5-ASA(200mg/kg)治疗的小鼠结肠水肿、充血、溃疡以及结肠缩短的情况得到明显改善。
表5：小鼠结肠长度
(3)对结肠组织MPO活力的影响
MPO是中性粒细胞所特有的酶，测定结肠部位MPO活力侧面反应中性粒细胞浸润情况和炎症严重程度。如表6所示，DSS组小鼠结肠MPO活力比Normal组提高2倍，而DCL(5,10μg/kg)降低UC小鼠结肠组织MPO活力。
表6：小鼠结肠MPO活力
(4)对结肠组织病理学改变的影响
如表7和图4所示，Normal组小鼠结肠粘膜完整，无明显损伤，上皮细胞排列紧密，而DSS组小鼠结肠组织损伤严重，腺体结构破坏或消失、杯状细胞减少、粘膜损坏、溃疡形成，有明显的炎性细胞浸润。DCL(2.5,5,10μg/kg)和5-ASA(200mg/kg)明显改善结肠组织病理损伤，表现为粘膜损伤程度、炎性浸润、隐窝损伤各项组织病理学评分降低。
表7：小鼠结肠病理评分
| 组别 | 只数 | 病理评分 |
| Normal | 6 | 0.62±0.05 |
| DSS | 6 | 10.17±0.95## |
| DCL(2.5μg/kg) | 6 | 7.50±0.76* |
| DCL(5μg/kg) | 6 | 4.17±0.60** |
| DCL(10μg/kg) | 6 | 3.17±0.48** |
| 5-ASA(200mg/kg) | 6 | 5.67±0.88** |
Claims (3)
1.一种愈创木烷类倍半萜前药在制备预防和治疗与NLRP3炎症小体相关疾病的药物中的应用；所述愈创木烷类倍半萜前药选自以下化合物：
；
所述与NLRP3炎症小体相关疾病，选自Cryopyrin蛋白相关周期性综合征、家族性地中海热、TNF受体相关周期性综合征、甲羟戊酸激酶缺乏症、高免疫球蛋白D和周期性发热综合征、白细胞介素1受体缺乏、Majeed综合症、化脓性关节炎、坏疽性脓皮病脓疱病坏疽和痤疮、A20单倍体不足、小儿肉芽肿性关节炎、PLCG2相关的自发炎症、抗体缺乏和免疫失调、铁粒细胞性贫血伴B细胞免疫缺陷-周期性发热和发育迟缓、慢性非细菌性骨髓炎、慢性复发性多灶性骨髓炎和滑膜炎、脓疱病、骨质增生、骨炎综合征、多发性硬化症、银屑病、Behcet's病、Sjogren's综合征、Schnitzler综合征、慢性阻塞性肺疾病、类固醇抵抗性哮喘、石棉肺、矽肺、囊性纤维化、帕金森症、阿尔茨海默症、运动神经元疾病、Huntington's病、脑疟疾、肺炎球菌性脑膜炎引起的脑损伤、肥胖症、痛风、假性痛风、年龄相关性黄斑变性、角膜感染、葡萄膜炎、干眼症、慢性肾脏疾病、草酸肾病、糖尿病肾病、非酒精性脂肪性肝炎、酒精性肝病、系统性幼年特发性关节炎、成年性Still's病、复发性多软骨炎、登革热病毒感染、寨卡病毒感染、流感病毒感染、艾滋病毒感染、化脓性汗腺炎、多发性肌炎、心包炎、蠕虫感染、细菌感染、抑郁症、中风、高血压、Dressler's综合征、缺血再灌注损伤。
2.权利要求1所述的愈创木烷类倍半萜前药的药学上可接受的盐在制备预防和治疗与NLRP3炎症小体相关疾病的药物中的应用；
所述与NLRP3炎症小体相关疾病，选自Cryopyrin蛋白相关周期性综合征、家族性地中海热、TNF受体相关周期性综合征、甲羟戊酸激酶缺乏症、高免疫球蛋白D和周期性发热综合征、白细胞介素1受体缺乏、Majeed综合症、化脓性关节炎、坏疽性脓皮病、A20单倍体不足、小儿肉芽肿性关节炎、PLCG2相关的自发炎症、抗体缺乏和免疫失调、铁粒细胞性贫血伴B细胞免疫缺陷-周期性发热和发育迟缓、慢性非细菌性骨髓炎、慢性复发性多灶性骨髓炎和滑膜炎、脓疱病、骨质增生、骨炎综合征、多发性硬化症、银屑病、Behcet's病、Sjogren's综合征、Schnitzler综合征、慢性阻塞性肺疾病、类固醇抵抗性哮喘、石棉肺、矽肺、囊性纤维化、帕金森症、阿尔茨海默症、运动神经元疾病、Huntington's病、脑疟疾、肺炎球菌性脑膜炎引起的脑损伤、肥胖症、痛风、假性痛风、年龄相关性黄斑变性、角膜感染、葡萄膜炎、干眼症、慢性肾脏疾病、草酸肾病、糖尿病肾病、非酒精性脂肪性肝炎、酒精性肝病、系统性幼年特发性关节炎、成年性Still's病、复发性多软骨炎、登革热病毒感染、寨卡病毒感染、流感病毒感染、艾滋病毒感染、化脓性汗腺炎、多发性肌炎、心包炎、蠕虫感染、细菌感染、抑郁症、中风、高血压、Dressler's综合征、缺血再灌注损伤。
3.一种药物组合物在制备预防和治疗与NLRP3炎症小体相关疾病的药物中的应用；
所述药物组合物是指权利要求1所述的愈创木烷类倍半萜前药或权利要求2所述的愈创木烷类倍半萜前药的药学上可接受的盐中的一种或多种作为活性成分，以及药物上可接受的载体、赋形剂、佐剂、辅料和/或稀释剂；
所述与NLRP3炎症小体相关疾病，选自Cryopyrin蛋白相关周期性综合征、家族性地中海热、TNF受体相关周期性综合征、甲羟戊酸激酶缺乏症、高免疫球蛋白D和周期性发热综合征、白细胞介素1受体缺乏、Majeed综合症、化脓性关节炎、坏疽性脓皮病、A20单倍体不足、小儿肉芽肿性关节炎、PLCG2相关的自发炎症、抗体缺乏和免疫失调、铁粒细胞性贫血伴B细胞免疫缺陷-周期性发热和发育迟缓、慢性非细菌性骨髓炎、慢性复发性多灶性骨髓炎和滑膜炎、脓疱病、骨质增生、骨炎综合征、多发性硬化症、银屑病、Behcet's病、Sjogren's综合征、Schnitzler综合征、慢性阻塞性肺疾病、类固醇抵抗性哮喘、石棉肺、矽肺、囊性纤维化、帕金森症、阿尔茨海默症、运动神经元疾病、Huntington's病、脑疟疾、肺炎球菌性脑膜炎引起的脑损伤、肥胖症、痛风、假性痛风、年龄相关性黄斑变性、角膜感染、葡萄膜炎、干眼症、慢性肾脏疾病、草酸肾病、糖尿病肾病、非酒精性脂肪性肝炎、酒精性肝病、系统性幼年特发性关节炎、成年性Still's病、复发性多软骨炎、登革热病毒感染、寨卡病毒感染、流感病毒感染、艾滋病毒感染、化脓性汗腺炎、多发性肌炎、心包炎、蠕虫感染、细菌感染、抑郁症、中风、高血压、Dressler's综合征、缺血再灌注损伤。
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Effective date of registration: 20240521 Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangning City, Lianyungang, Jiangsu Patentee after: JIANGSU KANION PHARMACEUTICAL Co.,Ltd. Country or region after: China Address before: No.138 Xianlin Avenue, Qixia District, Nanjing City, Jiangsu Province Patentee before: Nanjing University of Chinese Medicine Country or region before: China |
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