CN118047828A - 甘草次酸-小檗碱衍生物及其在制备治疗代谢性疾病药物中的应用 - Google Patents
甘草次酸-小檗碱衍生物及其在制备治疗代谢性疾病药物中的应用 Download PDFInfo
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- CN118047828A CN118047828A CN202410203756.XA CN202410203756A CN118047828A CN 118047828 A CN118047828 A CN 118047828A CN 202410203756 A CN202410203756 A CN 202410203756A CN 118047828 A CN118047828 A CN 118047828A
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- glycyrrhetinic acid
- berberine
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Abstract
本发明属于生物医药技术领域,涉及用于治疗代谢性疾病的化学药物,具体涉及甘草次酸‑小檗碱衍生物及其在制备治疗代谢性疾病药物中的应用。其化学结构如式I所示,其中,n为1~6,为单键或双键,R为O、羟基或
Description
技术领域
本发明属于生物医药技术领域,涉及用于治疗代谢性疾病的化学药物,具体涉及甘草次酸-小檗碱衍生物及其在制备治疗代谢性疾病药物中的应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
目前代谢性疾病的治疗包括生活方式干预、均衡饮食、适当运动和使用药物。近年来,在使用双胍类药物、磺脲类药物、他汀类药物和糖皮质激素治疗代谢性疾病方面取得了相当大的进展。然而,由于这些药物的不良反应,如胃肠道不适、低血糖、肝功能障碍、肌痛、体重增加、心血管损害等,仍有一定的局限性。
小檗碱是一种重要的四元苄基异喹啉类生物碱,由于其副作用(例如胃肠道不适,恶心呕吐等)和较差的生物利用度限制了其在治疗代谢性疾病中的临床应用。
发明内容
为了解决现有技术的不足,本发明的目的是提供,甘草次酸-小檗碱衍生物及其在制备治疗代谢性疾病药物中的应用,本发明将具有广泛生物活性的甘草次酸与小檗碱结合起来,显著提高了小檗碱和甘草次酸单独使用时的生物利用度和活性,并对代谢性疾病尤其是糖尿病、高脂血症的治疗效果,从mmol级提升到nmol级,大大提高了小檗碱的临床用药的安全性。
为了实现上述目的,本发明的技术方案为:
第一方面,一种甘草次酸-小檗碱衍生物,其化学结构如式I所示,
其中,n为1~6,为单键或双键,R为O、羟基或/>R’为C1-C5的烷基。
在一些实施例中,为单键,R为羟基或/>R’为C1-C5的烷基。
在一些实施例中,为双键,R为O。
为单键时,可以为/>也可以为/>在一些实施例中,结构式为:
在一些实施例中,R’为C1-C5的直链烷基。
在一些实施例中,R’为C1-C3的直链烷基。
在一些实施例中,R’为甲基。
在一些实施例中,n为1、3、4或6。
第二方面,一种甘草次酸-小檗碱衍生物的制备方法,包括按照如下反应路线获得式I所示化合物的步骤;
其中,R、n分别如上所述。
在一些实施例中,檗碱(BBR)在强碱环境(如氢氧化钠、氢氧化钾等强碱的溶液)中与丙酮加成得到化合物1,化合物1与二碘代烷(I-CH2-(CH2)n-CH2-I,或I-CH2-CH2-(CH2)n-I)经亲核取代得到化合物2,化合物2与甘草次酸或其衍生物经亲核取代反应获得式I所示化合物。
在一种或多种实施例中,化合物1制备化合物2的亲核取代反应的条件为加热回流。具体地,采用的有机溶剂为乙腈。
在一种或多种实施例中,化合物2与甘草次酸或其衍生物制备式I所示化合物的亲核取代反应的条件为:在碱性条件下,室温搅拌反应。具体地,所述碱性条件可以由碳酸钾、碳酸铯等碱性化合物调节。具体地,采用的溶剂为N,N-二甲基甲酰胺。
在一些实施例中,具体反应路线如下:
步骤a中,小檗碱(BBR)在强碱环境中与丙酮加成得到化合物1;所述强碱环境为氢氧化钠水溶液(5N)。
步骤b中,化合物1与相应的二碘代烷经亲核取代得到化合物2a-d;亲核取代反应在有机溶剂中进行;所述有机溶剂为乙腈;所述二碘代烷为1,3二碘丙烷,1,5二碘戊烷,1,6二碘己烷,1,8二碘辛烷等;所述反应条件为加热回流。
步骤c中,甘草次酸经乙酰化反应得到化合物3;乙酰化反应在乙酰化试剂、碱性条件下、有机溶剂中进行;所述乙酰化试剂为乙酸酐;所述碱性条件、有机溶剂为吡啶。
步骤d中,甘草次酸经氧化反应得到化合物4;氧化反应在有机溶剂中,氧化剂条件的存在下进行;所述有机溶剂为N,N二甲基甲酰胺;所述氧化剂为重铬酸吡啶、氯铬酸吡啶盐。
步骤e中,化合物2与甘草次酸或其衍生物经亲核取代反应得到化合物5a-d,6a-d,7a-d;亲核取代反应在碱性条件下、有机溶剂中进行;所述碱性条件为过量碳酸钾,碳酸铯等;所述有机溶剂为N,N二甲基甲酰胺;所述化合物2为步骤b中所述的2a-d;所述的甘草次酸或其衍生物为步骤(c)和(d)中所述的化合物3和4。
第三方面,一种药物组合物,包括上述甘草次酸-小檗碱衍生物或其药学上可接受的盐、溶剂化物、水合物。
本发明所述的药学上可接受的盐可以为化合物与无机酸(例如盐酸、硫酸、硝酸等)形成的盐,也可以为化合物与有机酸(例如乙酸、草酸、丙二酸、乳酸、柠檬酸、苹果酸、酒石酸、对苯甲磺酸、富马酸、马来酸等)形成的盐。
本发明所述的溶剂化物是指在有机溶剂中形成的化合物,例如甘草次酸-小檗碱衍生物的乙醇化物、乙醚化物、丙酮化合物等。
本发明所述的水合物是指带有结晶水的化合物,可以为半水合物、一水合物、二水合物等。
在一些实施例中,还包括药用载体。所述药用载体例如硬脂酸铝、卵磷脂、血清蛋白、聚乙二醇、胶态氧化硅、羧甲基纤维素钠、蜂蜡、微晶蜡、棕榈酸异丙酯等。
在一些实施例中,还包括赋形剂。所述赋形剂包括粘合剂、填充剂、润滑剂、崩解剂、稳定剂、抗氧化剂等。
第四方面,一种药物制剂,给药剂型为液体剂型或固体剂型。
具体地,所述液体剂型可以为口服液、注射液、酊剂、汤剂、酒剂、糖浆剂、露剂等。所述固体剂型可以为片剂、颗粒剂、胶囊剂、滴丸剂、散剂、膜剂等。
第五方面,一种上述甘草次酸-小檗碱衍生物、药物组合物或药物制剂在制备SCD1蛋白抑制剂、SREBP-1蛋白抑制剂、SREBP-1c磷酸化促进剂、AMPK激活剂或胆固醇抑制剂中的应用。
第六方面,一种上述甘草次酸-小檗碱衍生物、药物组合物或药物制剂在制备治疗代谢性疾病药物中的应用。
具体地,所述代谢性疾病包括糖尿病和/或高脂血症等。
本发明的有益效果:
通过药理学方面实验发现,本发明提供的甘草次酸-小檗碱衍生物对能够调节代谢性疾病相关通路上的蛋白表达含量,起到治疗的效果。其主要作用体现在,在胰岛素和高糖诱导细胞模型当中,这些化合物能够激活代谢性疾病的AMPK-SREBP-1c-SCD1通路,促进AMPK和SREBP-1c的磷酸化,进而降低SCD1的表达,从而调节脂质代谢,降低胆固醇含量,抑制磷脂质的生成,抑制机体和血管壁的炎症反应,在糖尿病及其并发症、高血脂症等重大的代谢异常的慢性疾病中发挥显著的治疗作用。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。
图1为本发明实施例中经化合物处理后HepG2(A)和HL7702(B)细胞中的代谢通路的相关蛋白的表达量结果图;
图2为本发明实施例中经不同浓度化合物7c处理后HepG2细胞中的代谢通路的相关蛋白的表达量结果图,A为蛋白印迹图,B为m-SREBP1的柱状图,C为SCD1的柱状图;
图3为本发明实施例中化合物7c通过激活AMPK抑制SREBP1通路结果图;
图4为本发明实施例中化合物7c下调成熟形式SREBP1的表达的免疫荧光结果图,A为空白,B为胰岛素+葡萄糖,C为化合物7c,D为小檗碱+甘草次酸;
图5为本发明实施例中化合物7c下降低细胞胆固醇含量的荧光显微镜图片,A为模型,B为阳性药(25-HC),C为0.4μM化合物7c,D为0.8μM化合物7c;
图6为本发明实施例中体内实验的结果图,A为体重曲线,B为脂肪与体重的比例柱状图,C为肝重柱状图,D为脂肪(WAT)重量柱状图,E为胰岛素抵抗曲线,F为葡萄糖耐量曲线,化合物7c体内活性评价#P<0.05,##P<0.01,###P<0.001,与模型组相比较有统计学差异,*P<0.05,**P<0.01,***P<0.001,与对照组相比较有统计学差异,ns无统计学差异;
图7为本发明实施例中小鼠的肝脏代表性照片(A)及对脂肪、肝组织学改变的影响结果图(B)。
具体实施方式
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案,以下将结合具体的实施例详细说明本发明的技术方案。
以下实施例中各化合物的反应路线如下所示。
实施例一:小檗碱衍生物2a-d的制备
精密称取盐酸小檗碱(BBR)(1.0g,2.7mmol)溶于5N NaOH(10mL)溶液中。一边搅拌一边缓滴入丙酮(0.8mL)。室温搅拌1h后,过滤反应混合物,用80%的MeOH洗涤至中性,得到中间体1,无需纯化直接进行下一部反应。然后,在化合物1(1mmol)的干燥MeCN溶液中加入二碘代烷(10mmol),并将混合物加热至82℃,加热6-12h。在TLC监控下,反应完成后,将溶剂减压蒸发得到粗产物,在硅胶上进行柱层析(DCM/MeOH,100/1-50/1,v/v)纯化,得到中间体2a-d为黄色粉末。
化合物2a:黄色粉末,收率54%.1H NMR(400MHz,CDCl3)δ10.40(s,1H),8.01(d,J=9.3Hz,1H),7.91(d,J=9.3Hz,1H),7.13(s,1H),6.93(s,1H),6.14(s,2H),5.15(s,2H),4.42(s,3H),4.12(s,3H),3.62-3.52(m,2H),3.34(t,J=6.1Hz,2H),3.25(t,J=5.7Hz,2H),2.37-2.25(m,2H).13C NMR(101MHz,CDCl3)δ150.3,149.9,147.4,145.8,145.1,136.6,133.6,132.9,132.5,125.6,121.8,120.1,119.9,109.1,108.6,102.1,62.9,58.0,56.9,33.5,30.7,28.3,5.1.ESI-MS m/z 504.4[M-I]+.
化合物2b:黄色粉末,收率43%.1H NMR(400MHz,CDCl3)δ10.24(s,1H),7.91(q,J=9.4Hz,2H),7.08(s,1H),6.89(s,1H),6.11(s,2H),5.09(s,2H),4.35(s,3H),4.07(s,3H),3.31(t,J=8.1Hz,2H),3.20(q,J=6.8,5.9Hz,4H),1.92-1.82(m,4H),1.65-1.56(m,2H).13C NMR(101MHz,CDCl3)δ150.4,149.8,147.3,146.0,145.1,136.1,133.9,133.5,133.0,125.6,121.8,120.2,120.1,109.0,108.6,102.2,63.1,58.1,57.0,32.4,30.2,29.9,29.8,28.5,6.6.ESI-MS m/z 532.4[M-I]+.
化合物2c:黄色粉末,收率47%.1H NMR(400MHz,CDCl3)δ10.29(s,1H),7.89(q,J=9.6Hz,2H),7.09(s,1H),6.89(s,1H),6.11(s,2H),5.11(s,2H),4.37(s,3H),4.08(s,3H),3.29(t,J=8.8Hz,2H),3.21(td,J=6.5,3.8Hz,4H),1.94-1.79(m,4H),1.60-1.43(m,4H).13C NMR(101MHz,CDCl3)δ150.2,149.7,147.2,145.5,144.4,136.0,134.3,133.3,132.9,125.6,121.6,120.3,120.0,108.9,108.4,102.1,62.7,58.0,56.9,33.0,30.7,29.7,28.3,28.2,6.8.ESI-MS m/z 546.4[M-I]+.
化合物2d:黄色粉末,收率55%.1H NMR(400MHz,CDCl3)δ10.25(s,1H),7.89(d,J=10.0Hz,2H),7.10(s,1H),6.89(s,1H),6.12(s,2H),5.09(s,2H),4.39(s,3H),4.08(s,3H),3.31-3.25(m,2H),3.25-3.16(m,4H),1.92-1.81(m,4H),1.56-1.49(m,2H),1.43-1.35(m,6H).13C NMR(101MHz,CDCl3)δ150.3,149.7,147.2,146.1,145.2,136.1,134.3,133.6,133.1,125.4,122.0,120.2,120.1,109.1,108.6,102.2,63.2,58.2,57.0,33.3,31.1,30.3,30.0,29.4,28.8,28.5,28.3,7.3.ESI-MS m/z 574.5[M-I]+.
实施例二:甘草次酸衍生物3的制备
在0℃冰浴条件下,在18β-甘草次酸(GA)(400mg,0.86mmol)的吡啶(4mL)溶液中加入乙酸酐(8mL)。将混合物升温至室温后搅拌16h至反应结束后,用饱和NH4Cl淬火,用DCM(20ml×3)提取。有机相用盐水洗涤,Na2SO4干燥,旋转蒸发除去溶剂后得到的粗产物经柱层析(己烷/乙酸乙酯,10/1-2/1,v/v)纯化,得到化合物3为白色粉末(400mg,92%)。1H NMR(400MHz,CDCl3)δ5.70(s,1H),4.52(dd,J=11.6,4.8Hz,1H),2.80(dt,J=13.6,3.3Hz,1H),2.37(s,1H),2.19(dd,J=14.1,3.5Hz,1H),2.05(s,3H),2.04-1.91(m,3H),1.89-1.79(m,1H),1.73-1.65(m,3H),1.63-1.56(m,3H),1.45-1.39(m,4H),1.37(s,3H),1.23(s,3H),1.21-1.19(m,1H),1.17(s,3H),1.13(s,3H),1.10-1.01(m,2H),0.88(s,6H),0.83(s,3H),0.82-0.78(m,1H).13C NMR(101MHz,CDCl3)δ200.4,181.6,171.1,169.5,128.4,80.6,61.7,55.0,48.2,45.5,43.8,43.2,40.8,38.8,38.0,37.7,36.9,32.7,31.9,30.9,28.5,28.4,28.0,26.4,26.4,23.6,23.3,21.3,18.7,17.4,16.7,16.4.ESI-MS m/z 513.8[M+H]+.
实施例三:甘草次酸衍生物4的制备
在干燥的DMF溶液(20mL)中加入GA(1g,2.1mmol),PDC(3.2g,3.15mmol)。室温搅拌过夜,TLC监测反应结束后,用水淬灭,经乙酸乙酯提取,盐水洗涤,Na2SO4干燥后,旋转蒸发除去溶剂后得到的粗产物经柱层析(DCM/MeOH,20/1,v/v)纯化,得到化合物4为白色粉末(820mg,83%)。1H NMR(400MHz,CDCl3)δ5.74(s,1H),2.97(ddd,J=13.3,7.1,4.0Hz,1H),2.64(ddd,J=16.1,11.3,7.1Hz,1H),2.45(s,1H),2.36(ddd,J=15.8,6.2,4.0Hz,1H),2.22(dd,J=13.4,4.4Hz,1H),2.10-1.99(m,2H),1.98-1.91(m,1H),1.89-1.81(m,1H),1.73-1.60(m,3H),1.57-1.52(m,2H),1.48-1.41(m,3H),1.38(s,3H),1.33-1.26(m,2H),1.28(s,3H),1.23(s,3H),1.18(s,3H),1.11(s,3H),1.07(s,3H),1.03(s,1H),0.91-0.86(m,1H),0.86(s,3H).13C NMR(101MHz,CDCl3)δ217.4,199.7,182.0,170.0,128.3,61.0,55.3,48.2,47.7,45.2,43.8,43.3,40.8,39.6,37.6,36.6,34.2,32.0,31.8,30.8,28.5,28.4,26.5,26.3,26.3,23.3,21.4,18.7,18.5,15.6.ESI-MS m/z 469.7[M+H]+.
实施例四:目标产物甘草次酸-小檗碱衍生物的制备
将GA(0.5mmol)和K2CO3(2.0mmol)加入干燥的DMF溶液中,加入相应的小檗碱中间体2a-d(0.75mmol)。室温搅拌过夜,TLC监测后,用水淬灭,有机溶剂二氯甲烷(DCM)提取,经盐水洗涤,Na2SO4干燥后,旋转蒸发除去溶剂后得到的粗产物经柱层析经柱层析(DCM/MeOH,50/1-10/1,v/v)纯化,得到化合物5a-d,6a-d,7a-d为黄色粉末。
化合物5a:黄色粉末,收率47%.1H NMR(400MHz,CDCl3)δ10.27(s,1H),8.07-7.89(m,2H),7.09(s,1H),6.84(s,1H),6.08(d,J=3.6Hz,2H),5.49(s,1H),5.24-5.10(m,1H),5.10-4.90(m,1H),4.34(s,3H),4.26(t,J=5.9Hz,2H),4.08(s,3H),3.41(t,J=7.3Hz,2H),3.30-3.09(m,3H),2.72(d,J=13.4Hz,1H),2.32-2.16(m,3H),2.06-1.95(m,3H),1.89(d,J=13.3Hz,1H),1.82-1.75(m,1H),1.68-1.55(m,5H),1.45-1.37(m,3H),1.34(s,3H),1.32-1.28(m,1H),1.24(d,J=7.0Hz,2H),1.20-1.14(m,1H),1.16(s,3H),1.07(s,3H),1.06(s,3H),1.03-0.93(m,2H),0.98(s,3H),0.77(s,3H),0.76(s,3H),0.67(d,J=11.6Hz,1H).13C NMR(101MHz,CDCl3)δ199.9,176.2,169.3,150.4,149.7,147.2,146.1,145.4,136.4,133.8,132.8,132.6,128.2,126.0,121.8,120.0,119.8,109.0,108.6,102.1,78.5,63.6,63.1,61.8,58.1,57.0,54.8,48.6,45.4,44.1,43.2,41.1,39.1,39.0,37.6,37.0,32.6,31.8,31.0,29.9,28.5,28.4,28.3,28.0,27.2,26.9,26.4,26.3,23.4,18.6,17.4,16.2,15.5.HR-ESI-MS m/z calculated for C53H68NO8 +[M-I]+846.4939,found 846.4935.
化合物5b:黄色粉末,收率46%.1H NMR(400MHz,CDCl3)δ10.26(s,1H),7.97(q,J=7.8Hz,2H),7.08(s,1H),6.88(s,1H),6.09(s,2H),5.62(s,1H),5.11(s,2H),4.36(s,3H),4.19(dt,J=12.6,6.4Hz,1H),4.11-4.05(m,1H),4.07(s,3H),3.31(t,J=7.8Hz,2H),3.26-3.15(m,3H),2.74(d,J=13.4Hz,1H),2.33(s,1H),2.05-1.98(m,2H),1.96-1.90(m,2H),1.78-1.70(m,4H),1.65-1.59(m,6H),1.43-1.38(m,3H),1.36(s,3H),1.34-1.30(m,3H),1.27-1.23(m,3H),1.20(s,1H),1.15(s,3H),1.11(s,3H),1.10(s,3H),1.06-1.02(m,1H),0.99(s,3H),0.97-0.91(m,1H),0.79(s,6H),0.69(d,J=11.5Hz,1H).13C NMR(101MHz,CDCl3)δ200.2,176.4,169.5,150.4,149.7,147.2,146.0,145.2,136.0,133.9,133.6,133.0,128.4,125.7,121.9,120.3,120.2,109.0,108.6,102.1,78.6,64.0,63.1,61.8,58.1,56.9,54.9,48.6,45.4,44.0,43.2,41.1,39.1,39.1,37.7,37.1,32.7,31.8,31.1,30.8,29.9,29.6,28.6,28.5,28.4,28.1,27.2,26.4,26.3,26.2,23.4,18.7,17.4,16.3,15.5.HR-ESI-MS m/z calculated for C55H72NO8 +[M-I]+874.5252,found 874.5250.
化合物5c:黄色粉末,收率39%.1H NMR(400MHz,CDCl3)δ10.18(s,1H),7.93(q,J=9.3Hz,2H),7.08(s,1H),6.87(s,1H),6.08(s,2H),5.56(s,1H),5.07(s,2H),4.32(s,3H),4.13(dt,J=12.9,6.6Hz,1H),4.06(s,3H),4.08-4.01(m,1H),3.27(t,J=7.4Hz,2H),3.22-3.15(m,3H),2.66(d,J=13.5Hz,1H),2.29(s,1H),2.02-1.96(m,2H),1.91-1.87(m,2H),1.71-1.62(m,4H),1.59-1.55(m,5H),1.48-1.44(m,2H),1.40-1.35(m,3H),1.33(s,3H),1.28(d,J=9.6Hz,3H),1.22(s,3H),1.17(s,1H),1.11(s,3H),1.06(s,3H),1.06(s,3H),1.03-0.99(m,1H),0.96(s,3H),0.90(s,1H),0.76(s,3H),0.75(s,3H),0.65(d,J=11.6Hz,1H).13C NMR(101MHz,CDCl3)δ200.2,176.5,169.5,150.4,149.8,147.3,145.9,145.0,136.2,134.3,133.5,133.2,128.4,125.7,121.9,120.4,120.3,109.1,108.6,102.2,78.6,64.2,63.1,61.8,58.2,57.1,54.9,48.6,45.4,44.0,43.3,41.1,39.1,37.7,37.1,32.7,31.8,31.1,31.0,30.0,29.7,29.2,28.7,28.6,28.5,28.4,28.1,27.3,26.5,26.4,25.6,23.4,18.7,17.5,16.4,15.6.HR-ESI-MS m/z calculated for C56H74NO8 +[M-I]+888.5409,found 888.5404.
化合物5d:黄色粉末,收率32%.1H NMR(400MHz,CDCl3)δ10.61(s,1H),7.89(q,J=9.5Hz,2H),7.09(s,1H),6.87(s,1H),6.08(s,2H),5.59(s,1H),5.25(s,2H),4.32(s,3H),4.13-4.02(m,2H),4.06(s,3H),3.27(dq,J=16.8,8.1Hz,2H),3.20-3.10(m,3H),2.60(d,J=13.2Hz,1H),2.27(s,1H),2.05-1.96(m,2H),1.92-1.83(m,3H),1.82-1.71(m,2H),1.66-1.58(m,4H),1.57-1.48(m,4H),1.44-1.36(m,8H),1.33(s,3H),1.31-1.26(m,2H),1.23(s,2H),1.17(s,1H),1.11(d,J=11.4Hz,4H),1.07(s,3H),1.02(s,3H),0.96(s,3H),0.87-0.83(m,1H),0.77(s,3H),0.74(s,3H),0.63(d,J=11.8Hz,1H).13C NMR(101MHz,CDCl3)δ200.1,176.4,169.3,150.4,149.6,147.2,146.5,146.1,135.9,134.1,133.9,133.0,128.4,125.4,122.2,120.3,120.2,109.0,108.5,102.1,78.4,64.4,63.1,61.8,57.4,57.0,54.9,48.5,45.4,44.0,43.2,41.1,39.1,39.0,37.7,37.0,32.7,31.8,31.1,29.8,29.6,29.5,29.2,28.9,28.7,28.5,28.4,28.1,27.2,26.4,26.3,26.0,23.3,18.6,17.4,16.2,15.6.HR-ESI-MS m/z calculated for C58H78NO8 +[M-I]+916.5722,found 916.5720.
化合物6a:黄色粉末,收率55%.1H NMR(400MHz,CDCl3)δ10.30(s,1H),7.95(q,J=8.8Hz,2H),7.09(s,1H),6.85(s,1H),6.08(s,2H),5.50(s,1H),5.23-4.96(m,2H),4.50(d,J=11.0Hz,1H),4.35(s,3H),4.30-4.20(m,2H),4.07(s,3H),3.41(d,J=10.9Hz,2H),3.27-3.08(m,2H),2.74(d,J=12.4Hz,1H),2.30(s,1H),2.26-2.15(m,2H),2.03(s,3H),2.02-1.96(m,3H),1.90(d,J=13.7Hz,1H),1.85-1.71(m,2H),1.66-1.56(m,4H),1.46-1.36(m,3H),1.34(s,3H),1.31-1.28(m,1H),1.26-1.22(m,2H),1.16(s,3H),1.11(s,3H),1.07(s,3H),1.01(d,J=13.4Hz,2H),0.86(s,6H),0.79(d,J=11.5Hz,1H),0.76(s,3H).13CNMR(101MHz,CDCl3)δ199.8,176.3,170.9,169.3,150.5,149.7,147.2,146.1,145.5,136.3,133.8,132.8,132.5,128.2,125.9,121.8,120.0,119.8,108.9,108.6,102.1,80.4,63.6,63.1,61.7,58.1,57.0,54.9,48.5,45.4,44.1,43.2,41.0,38.8,37.9,37.6,36.9,32.6,31.8,31.0,29.9,28.5,28.4,28.3,27.9,26.9,26.3,26.3,23.5,23.3,21.2,18.6,17.3,16.6,16.3.HR-ESI-MS m/z calculated for C55H70NO9 +[M-I]+888.5045,found888.5041.
化合物6b:黄色粉末,收率53%.1H NMR(400MHz,CDCl3)δ10.27(s,1H),8.07-7.87(m,2H),7.09(s,1H),6.88(s,1H),6.09(s,2H),5.63(s,1H),5.11(s,2H),4.50(dd,J=11.5,4.7Hz,1H),4.38(s,3H),4.19(dt,J=12.8,6.5Hz,1H),4.13-4.06(m,1H),4.08(s,3H),3.37-3.27(m,2H),3.21(t,J=5.5Hz,2H),2.76(d,J=13.6Hz,1H),2.36(s,1H),2.10-2.05(m,1H),2.04(s,3H),2.02-1.97(m,2H),1.96-1.91(m,2H),1.83-1.72(m,3H),1.68-1.60(m,6H),1.45-1.39(m,2H),1.37(s,3H),1.35-1.30(m,3H),1.27-1.24(m,2H),1.21(s,1H),1.15(s,3H),1.14(s,3H),1.11(s,3H),1.06-1.00(m,2H),0.87(s,6H),0.79(s,3H),0.82-0.75(m,1H).13C NMR(101MHz,CDCl3)δ200.0,176.4,170.9,169.5,150.4,149.8,147.3,146.1,145.3,136.1,134.0,133.6,133.1,128.4,125.7,122.0,120.3,120.3,109.0,108.6,102.1,80.5,64.0,63.2,61.8,58.1,56.9,55.0,48.6,45.4,44.0,43.3,41.1,38.8,38.0,37.7,37.0,32.7,31.9,31.1,30.8,30.0,29.3,28.6,28.5,28.4,28.0,26.5,26.4,26.3,23.5,23.3,21.3,18.7,17.3,16.6,16.4.HR-ESI-MS m/z calculatedfor C57H74NO8 +[M-I]+916.5358,found 916.5355.
化合物6c:黄色粉末,收率60%.1H NMR(400MHz,CDCl3)δ10.58(s,1H),7.89(q,J=8.9Hz,2H),7.07(s,1H),6.87(s,1H),6.09(s,2H),5.59(s,1H),5.23(s,2H),4.48(dd,J=11.0,3.6Hz,1H),4.32(s,3H),4.19-4.10(m,1H),4.06(s,3H),4.08-4.01(m,1H),3.27(d,J=6.4Hz,2H),3.20-3.12(m,2H),2.72(d,J=13.1Hz,1H),2.33(s,1H),2.03(s,3H),2.08-1.94(m,2H),1.93-1.84(m,3H),1.81-1.74(m,1H),1.71-1.64(m,3H),1.62-1.53(m,5H),1.52-1.42(m,3H),1.38(d,J=13.1Hz,2H),1.34(s,3H),1.29(d,J=9.7Hz,2H),1.23(s,2H),1.18(s,1H),1.12(s,3H),1.11(s,3H),1.07(s,3H),1.00(d,J=12.9Hz,2H),0.86(s,6H),0.80-0.73(m,1H),0.75(s,3H).13C NMR(101MHz,CDCl3)δ200.0,176.5,171.0,169.4,150.4,149.7,147.2,146.5,146.1,136.0,134.0,133.9,133.0,128.3,125.5,122.2,120.3,120.1,109.0,108.6,102.1,80.5,64.2,63.1,61.7,57.4,57.0,55.0,48.6,45.4,44.0,43.2,41.0,38.8,38.0,37.7,36.9,32.6,31.8,31.1,31.0,29.8,29.6,29.2,28.7,28.5,28.4,28.0,26.4,26.3,25.6,23.5,23.3,21.3,18.6,17.3,16.6,16.4.HR-ESI-MS m/z calculated for C58H76NO9 +[M-I]+930.5515,found 930.5515.
化合物6d:黄色粉末,收率80%.1H NMR(400MHz,CDCl3)δ10.43(s,1H),7.88(q,J=9.6Hz,2H),7.06(s,1H),6.84(s,1H),6.06(s,2H),5.57(s,1H),5.16(s,2H),4.43(dd,J=11.5,4.4Hz,1H),4.28(s,3H),4.04(d,J=8.1Hz,5H),3.28-3.18(m,2H),3.12(s,2H),2.69(d,J=13.7Hz,1H),2.29(s,1H),2.08-2.01(m,1H),1.99(s,3H),1.96-1.92(m,1H),1.89-1.78(m,3H),1.77-1.70(m,1H),
1.65-1.56(m,4H),1.54-1.45(m,4H),1.42-1.33(m,8H),1.31(s,3H),1.29-1.23(m,3H),1.21-1.19(m,2H),1.15(s,1H),1.09(s,3H),1.07(s,3H),1.05(s,3H),1.02-0.93(m,2H),0.82(s,6H),0.74(s,3H),0.78-0.68(m,1H).13C NMR(101MHz,CDCl3)δ199.9,176.4,170.8,169.3,150.3,149.6,147.1,146.1,145.4,135.8,134.2,133.6,132.9,128.2,125.5,121.9,120.1,108.9,108.4,102.0,80.4,64.2,62.9,61.6,57.6,57.0,54.9,48.4,45.3,43.9,43.1,40.9,38.6,37.9,37.6,36.8,32.5,32.3,31.7,31.0,31.0,29.8,29.5,29.4,28.9,28.8,28.5,28.4,28.3,27.9,26.3,26.2,25.8,23.4,23.2,21.1,18.5,17.2,16.5,16.2.HR-ESI-MS m/z calculated for C60H80NO9 +[M-I]+958.5828,found958.5828.
化合物7a:黄色粉末,收率90%.1H NMR(400MHz,CDCl3)δ10.30(s,1H),8.03-7.86(m,2H),7.10(s,1H),6.86(s,1H),6.09(s,2H),5.59(s,1H),5.29(s,
1H),5.20-4.98(m,2H),4.37(s,3H),4.27(t,J=5.2Hz,2H),4.09(s,3H),3.41(t,J=7.8Hz,2H),3.29-3.14(m,2H),2.96-2.86(m,1H),2.67-2.55(m,1H),2.44-2.32(m,2H),2.28-2.18(m,2H),2.10-1.98(m,3H),1.92(d,J=13.5Hz,1H),1.83(dd,J=12.1,3.9Hz,1H),1.72-1.59(m,3H),1.57-1.50(m,2H),1.47-
1.41(m,2H),1.37(s,3H),1.33-1.30(m,2H),1.23(s,3H),1.17(s,3H),1.13(s,3H),1.09(s,3H),1.05(s,3H),1.04-1.00(m,1H),0.90-0.82(m,1H),0.79(s,3H).13C NMR(101MHz,CDCl3)δ216.9,199.2,176.3,169.8,150.5,149.8,147.3,146.2,145.6,136.4,133.8,132.8,132.6,128.3,125.9,121.9,120.1,119.7,109.0,108.6,102.1,63.6,63.1,61.1,58.1,57.0,55.3,48.6,47.7,45.2,44.1,43.3,41.2,39.8,37.7,36.7,34.1,32.0,31.9,31.0,30.0,28.6,28.5,28.3,26.9,26.4,26.4,26.3,23.3,21.3,18.7,18.5,15.7.HR-ESI-MS m/z calculated for C53H66NO8 +[M-I]+844.4783,found 844.4781.
化合物7b:黄色粉末,收率94%.1H NMR(400MHz,CDCl3)δ10.23(s,1H),7.99-7.91(m,2H),7.07(s,1H),6.87(s,1H),6.08(s,2H),5.64(s,1H),5.08(s,2H),4.33(s,3H),4.20-4.08(m,2H),4.06(s,3H),3.30(t,J=8.1Hz,2H),3.22-3.14(m,2H),2.88(dt,J=12.2,5.9Hz,1H),2.62-2.52(m,1H),2.42(s,1H),2.33(dt,J=13.0,3.9Hz,1H),2.22-2.14(m,1H),2.09(d,J=13.1Hz,1H),2.03-1.96(m,2H),1.95-1.87(m,3H),1.85-1.78(m,1H),1.75-1.71(m,1H),1.65-1.57(m,3H),1.55-1.49(m,2H),1.46-1.38(m,3H),1.36(s,3H),1.31-1.27(m,3H),1.22(s,3H),1.18(s,1H),1.13(s,6H),1.07(s,3H),1.03(s,3H),1.01(s,1H),0.88-0.81(m,1H),0.79(s,3H).13C NMR(101MHz,CDCl3)δ216.9,199.3,176.3,169.9,150.3,149.7,147.2,145.9,145.0,136.0,134.0,133.5,133.0,128.2,125.7,121.8,120.3,120.1,108.9,108.5,102.1,63.9,63.0,61.0,58.1,57.0,55.2,48.5,47.6,45.1,43.9,43.3,41.1,39.7,37.6,36.6,34.1,32.0,31.8,31.0,30.7,29.9,28.6,28.4,28.3,26.4,26.4,26.3,26.1,23.3,21.3,18.7,18.4,15.6.HR-ESI-MS m/z calculatedfor C55H70NO8 +[M-I]+872.5096,found 872.5093.
化合物7c:黄色粉末,收率92%.1H NMR(400MHz,CDCl3)δ10.24(s,1H),7.91(q,J=9.3Hz,2H),7.08(s,1H),6.87(s,1H),6.09(s,2H),5.62(s,1H),5.09(s,2H),4.34(s,3H),4.14-4.02(m,2H),4.06(s,3H),3.31-3.23(m,2H),3.19(s,2H),2.92-2.82(m,1H),2.63-2.53(m,1H),2.41(s,1H),2.37-2.29(m,1H),2.11-2.05(m,1H),2.01-1.95(m,2H),1.93-1.86(m,3H),1.82-1.76(m,1H),1.72-1.63(m,3H),1.60-1.53(m,3H),1.48-1.38(m,4H),1.35(s,3H),1.30-1.26(m,3H),1.23(s,2H),1.21(s,3H),1.17(s,1H),1.12(s,3H),1.11(s,3H),1.07(s,3H),1.04(s,3H),0.99(s,1H),0.85(t,J=6.4Hz,1H),0.77(s,3H).13C NMR(101MHz,CDCl3)δ217.0,199.4,176.4,169.9,150.4,149.7,147.2,146.1,145.8,136.1,134.2,133.6,133.1,128.3,125.7,122.0,120.3,109.1,108.6,102.2,64.2,63.4,61.0,58.2,57.1,55.3,48.5,47.7,45.2,43.9,43.3,41.1,39.7,37.7,36.6,34.1,32.0,31.8,31.1,31.0,30.0,29.6,29.2,28.8,28.6,28.6,28.4,26.5,26.4,26.3,25.5,23.3,21.3,18.7,18.5,15.7.HR-ESI-MS m/z calculated for C56H72NO8 +[M-I]+886.5252,found886.5251.
化合物7d:黄色粉末,收率68%.1H NMR(400MHz,CDCl3)δ10.57(s,1H),7.88(t,J=9.7Hz,2H),7.08(s,1H),6.87(s,1H),6.09(s,2H),5.65(s,1H),5.23(s,2H),4.33(s,3H),4.12-4.01(m,2H),4.06(s,3H),3.31-3.21(m,2H),3.15(s,2H),2.93-2.85(m,1H),2.62-2.52(m,1H),2.41(s,1H),2.36-2.29(m,1H),2.13-2.07(m,1H),2.03-1.98(m,3H),1.92-1.81(m,4H),1.68-1.58(m,5H),1.56-1.49(m,5H),1.45-1.41(m,3H),1.35(s,3H),1.31-1.26(m,6H),1.21(s,3H),1.18(s,1H),1.12(s,6H),1.07(s,3H),1.03(s,3H),1.00(s,1H),0.87-0.84(m,1H),0.79(s,3H).13C NMR(101MHz,CDCl3)δ217.0,199.4,176.4,169.8,150.4,149.7,147.2,146.4,146.0,135.9,134.0,133.9,133.0,128.3,125.4,122.1,120.3,120.0,109.0,108.5,102.1,64.3,63.1,61.0,57.5,57.0,55.3,48.4,47.7,45.2,43.9,43.3,41.1,39.7,37.7,36.6,34.1,32.0,31.8,31.1,29.9,29.6,29.5,29.0,28.9,28.6,28.6,28.6,28.4,26.5,26.4,26.3,25.8,23.3,21.3,18.7,18.4,15.6.HR-ESI-MS m/z calculated for C58H76NO8 +[M-I]+914.5565,found 914.5568.
实施例六:化合物的免疫印迹(western blot)实验
(a)人肝癌细胞HepG2和人正常肝细胞HL7702细胞分别在含有5.5mM葡萄糖(Glucose)的无血清DMEM培养基中孵育过夜,并在Glucose(30mM)和胰岛素(Insulin)(100nM)存在下,用0.8μM的甘草次酸-小檗碱衍生物处理24小时后。
(b)细胞经药物处理后,PBS洗涤细胞两遍。加入预冷的1X细胞裂解液(蛋白酶抑制剂PMSF现用现加),冰上裂解20min后用细胞刮刀将细胞刮下,转移至EP管。
(c)4℃,12000rpm,离心20min。收集上清,95℃,5min加热变性。
(d)BCA法测蛋白浓度。
(e)SDS-PAGE电泳。根据目的蛋白选择分离胶的浓度。待分离胶凝固以后,配置5%的浓缩胶。待胶凝固后,拔掉上样梳子,安置于电泳槽内,加入电泳缓冲液。
(f)上样:按照标准蛋白曲线计算蛋白浓度,取出30-80μg的蛋白,加入4x SDS上样缓冲液,双蒸水补齐至同一体积。95℃加热5min。处理好的样品蛋白和标准蛋白Marker上样过后,连接电泳仪,恒压90V 30min,120V使溴酚蓝跑到电泳槽的底部,停止电泳。转膜:胶取出,裁剪出合适的分离胶和NC膜。按照负极-海绵-滤纸-分离胶-NC膜-滤纸-海绵的顺序组装,轻轻赶走气泡,安装到电转槽中。恒流280mA,3h。封闭、免疫反应:NC膜取出后,放在TBS配制的5%的脱脂奶粉中,水平摇床缓慢摇动1h。TBST洗涤一次。按照抗体说明书配制一抗工作液,NC膜加上一抗工作液,摇床孵育,4℃过夜。取出膜,回收一抗,TBST快速洗涤5min 3次,TBS洗涤5min。常温孵育二抗1h,TBST快速洗涤5min 3次,TBS洗涤5min。显色:预先配制ECL发光液,A:B=1:1配成工作液,均匀滴在NC膜上,迅速放在凝胶成像仪中成像,结果用Image Lab软件处理分析。
结果如图1所示,表明本发明的甘草次酸-小檗碱衍生物降低了SCD1和SREBP-1的蛋白表达,并增加了SREBP-1c(Ser372)的磷酸化,抑制了胆固醇的从头合成。这说明本发明的甘草次酸-小檗碱衍生物在浓度为nM的水平下就可以明显调控代谢性疾病相关通路上的关键酶,比原型药提高了两个数量级,用药量极小就能达到同等的治疗效果,避免了小檗碱在治疗代谢性疾病中用量大带来的胃肠道不适等副作用,安全系数高。
选择活性比较好的化合物7c,进行不同浓度的免疫印迹实验,如图2所示。同时加入小檗碱(1μM),甘草次酸(1μM),小檗碱+甘草次酸(1μM+1μM)做对比。结果表明,发现1μM相应剂量的小檗碱与甘草次酸均没有活性,而化合物7c在0.3μM时就能激活AMPK的磷酸化,激活效果随浓度增强,在0.8μM时效果十分明显。此外,AMPK已知位于SREBP-1c的上游,可以直接磷酸化SREBP-1c(Ser372)。SREBP-1c(Ser372)的磷酸化抑制其裂解和核易位,从而降低其靶基因SREBP-1c和SCD1的表达。因此,本发明的化合物可能是通过AMPK-SREBP-1c通路介导,来降低肝细胞SCD1表达。Western blot实验表明本发明的化合物使AMPK(Thr172)的磷酸化水平升高,导致SREBP-1和SCD1的表达受到抑制,抑制效果随浓度升高而增强,在0.8μM时几乎恢复至正常细胞的表达水平。
化合物7c处理后,AMPK总量无明显变化,磷酸化AMPK剂量依赖上调,使用AMPK抑制剂Cpd.C,可以阻碍化合物7c引起的m-SREBP1下调,说明7c号化合物通过激活AMPK抑制SREBP1通路,如图3所示。
实施例七:化合物的免疫荧光实验
将HepG2细胞经高糖,胰岛素诱导得到细胞模型。药物处理细胞后,弃培养基,PBS洗涤两次,固定液(甲醇:丙酮=1:1)固定5min。PBS洗涤5min后,3%BSA(TritonX-100)浸泡20min,PBS-Tx洗涤5min。加入一抗封闭液,4℃过夜封闭。PBS-Tx洗涤5min 3次。加入二抗封闭液,37℃封闭1h。PBS-Tx洗涤5min 3次。弃PBS-Tx,DAPI染色20min,PBS-Tx洗涤5min 3次。激光共聚焦显微镜观察。
免疫荧光如图4所示,结果表明,正常情况下,SREBP1主要分布在细胞质中;在高糖和胰岛素诱导的细胞模型中,可以观察到SREBP1入核,小檗碱和甘草次酸联用的效果也微乎其微,而经本发明的化合物7c作用后,SREBP1核内荧光强度减弱,说明其能够显著下调成熟形式SREBP1的表达。
实施例八:Fillipin III染色——检测胆固醇含量
首先,使用4%的多聚甲醛将经高糖,胰岛素诱导的HepG2细胞进行固定处理,接下来,将固定的细胞用Fillipin III荧光染色剂进行染色处理。Fillipin III是一种荧光染色剂,它与胆固醇结合并产生荧光信号。染色后,用PBS洗涤细胞3次。最后,使用荧光显微镜观察染色后的细胞。结果表明,在荧光显微镜下,经0.8μM的7c处理后的细胞荧光强度明显下降,说明其能降低胆固醇含量,如图5所示。
实施例九:体内实验
8周龄雄性C57小鼠共24只,随机分为4组,即对照组(chow),高脂肪饮食模型组(HFD),低剂量组(7c,1mg/kg),高剂量组(7c,2mg/kg),每组6只。对照组小鼠饲喂正常鼠粮(碳水化合物73.4%,脂肪4.0%,蛋白质22.6%),HFD组和给药组均喂食高脂饲料(HFD;40.0%碳水化合物、39.9%脂肪和20.0%蛋白质),持续12周构建肥胖小鼠模型。造模成功后,给药组腹腔注射化合物7c,每两天1次,连续6周。6周后,测试各组小鼠胰岛素抵抗和葡萄糖抵抗的能力。随后收集小鼠眼球静脉血,解剖小鼠取肝部组织。
实验结果表明,经本发明化合物7c处理后的小鼠体重明显减轻,尤其是在给药剂量为2mg/kg时效果最为显著,如图6A所示。此外,脂肪与体重的比例有所改善,而且肝重也明显下降,如图6B、C和D所示。胰岛素抵抗实验和葡萄糖抵抗实验表明,HFD可促进小鼠胰岛素抵抗,降低葡萄糖耐量;然而,7c治疗后改善了HFD诱导的胰岛素抵抗(图6E)和葡萄糖耐量的增加(图6F)。从图7的肝脏的外观和H&E染色显示,给药剂量为2mg/kg的7c时,减少了HFD小鼠肝小叶中的脂肪变性,并能显著抑制高脂饮食诱导的脂肪沉积和脂肪细胞变大。HFD组小鼠的肝脏结构受到严重损害,肝细胞中含有大量空泡。然而,与HFD组相比,7c的摄入显著降低了肝脂肪变性的程度,肝小叶中的脂肪空泡数量减少。这些结果表明化合物7c减轻了高脂饮食对肝脏和皮下脂肪组织的损伤,表明了其对高脂饮食诱导的肥胖小鼠代谢功能障碍具有改善作用。
实施例十:药代动力学参数评价
标准曲线的绘制:取一定量的化合物7c,准确称量,以甲醇为溶剂溶解,溶剂体积低于100mL,之后将该溶液转移至100mL的容量瓶中,并将溶液定容至相应的刻度,摇匀溶液使化合物与溶剂充分混合,从而制得1μmol/ml的储备液。从该储备液中取出部分,用甲醇稀释并定容,从而制成浓度为10-1、10-2、10-3、10-4、10-5、10-6μmol/ml的一系列标准溶液,置于4℃的冰箱中保存。准确量取大鼠空白血浆,即未给药的大鼠血浆90μl,加入标准系列溶液10μl及含有2nmol/ml的内标对照品溶液300μl,涡旋混匀10min,离心(13000rpm)10min,取上清200μl,进行HPLC-HR-MS分析。求得直线回归方程可视为化合物7c在血清中浓度的标准曲线。
血浆样品采集:取化合物BBR和7c适量,加入DMSO,PEG,生理盐水溶解,制成澄清的溶液。
选取健康的雌性SD大鼠共12只,随机平均分成4组(BBR灌胃组、BBR静脉组,7c灌胃组、7c静脉组),每组3只。为确保实验准确性,实验大鼠在实验前12小时内不可进食,一般给与适量饮用水。灌胃组直接灌胃给药,受试药物为15μmol/kg,每隔一定时间由大鼠眼眶静脉取血,时间间隔一般为给药前取血,标记为0min,给药后5min、15min、30min、1h、2h、4h、8h、12h、24h、48h和72h取血,取血量1mL左右的静脉血至布满肝素钠的离心管中。离心管在离心机中快速离心10min左右,将上层血清取出并于-80℃冰箱保存待测。
静脉组大鼠通过尾静脉注射给与受试药物,浓度为15μmol/kg,每隔一定时间由大鼠眼眶静脉取血,标记为0min,给药后5min、15min、30min、1h、2h、4h、8h、12h、24h、48h和72h取血,取血量1mL左右的静脉血至布满肝素钠的离心管中。离心管在离心机中快速离心10min左右,将上层血清取出并于-80℃冰箱保存待测。
取大鼠血浆样品100μl,加入300μl内标溶液,涡旋混匀10min,离心(13000rpm)10min,取上清200μl,进行HPLC-HR-MS分析。上述生物利用度实验的血药浓度相应数据的计算是基于非房室模型。通过DAD2.0软件可以计算得到药代动力学相关参数。
通过生物利用度公式F=(AUC_ext*Dose_iv)/(AUC_iv*Dose_ext)*100%,可以计算得到化合物BBR和7c的生物利用度。
从表1和表2可以看出,化合物BBR和7c灌胃给药后,全血暴露量AUC较BBR大,口服相对生物利用度为21.2%,而BBR口服相对生物利用度仅为9.08%,并且7c的半衰期明显增长。
表1.化合物BBR的药代动力学参数
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表2.化合物7c的药代动力学参数
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种甘草次酸-小檗碱衍生物,其特征是,其化学结构如式I所示,
其中,n为1~6,为单键或双键,R为O、羟基或/>R’为C1-C5的烷基。
2.如权利要求1所述的甘草次酸-小檗碱衍生物,其特征是,为单键,R为羟基或R’为C1-C5的烷基;
或,为双键,R为O;
为单键时,可以为/>也可以为/>在一些实施例中,结构式为:
或,R’为C1-C5的直链烷基;
或,R’为C1-C3的直链烷基;
或,R’为甲基;
或,n为1、3、4或6。
3.一种甘草次酸-小檗碱衍生物的制备方法,其特征是,包括按照如下反应路线获得式I所示化合物的步骤;
其中,R、n分别如权利要求1所述。
4.如权利要求3所述的甘草次酸-小檗碱衍生物的制备方法,其特征是,小檗碱在强碱环境中与丙酮加成得到化合物1,化合物1与二碘代烷经亲核取代得到化合物2,化合物2与甘草次酸或其衍生物经亲核取代反应获得式I所示化合物;
或,化合物1制备化合物2的亲核取代反应的条件为加热回流;或,采用的有机溶剂为乙腈;
或,化合物2与甘草次酸或其衍生物制备式I所示化合物的亲核取代反应的条件为:在碱性条件下,室温搅拌反应;或,所述碱性条件可以由碳酸钾或碳酸铯调节;或,采用的溶剂为N,N-二甲基甲酰胺。
5.一种药物组合物,其特征是,包括权利要求1或2所述的甘草次酸-小檗碱衍生物或其药学上可接受的盐、溶剂化物、水合物。
6.如权利要求5所述的药物组合物,其特征是,还包括药用载体;
或,还包括赋形剂。
7.一种药物制剂,其特征是,给药剂型为液体剂型或固体剂型。
8.一种权利要求1或2所述的甘草次酸-小檗碱衍生物、权利要求5或6所述的药物组合物或权利要求7所述的药物制剂在制备SCD1蛋白抑制剂、SREBP-1蛋白抑制剂、SREBP-1c磷酸化促进剂、AMPK激活剂或胆固醇抑制剂中的应用。
9.一种权利要求1或2所述的甘草次酸-小檗碱衍生物、权利要求5或6所述的药物组合物或权利要求7所述的药物制剂在制备治疗代谢性疾病药物中的应用。
10.如权利要求9所述的应用,其特征是,所述代谢性疾病包括糖尿病和/或高脂血症。
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