CN103788143B - 1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷及其药物组合物和应用 - Google Patents
1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷及其药物组合物和应用 Download PDFInfo
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Abstract
本发明提供结构式(I)所示的化合物1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1-O-ethyl-6-O-caffeoyl-β-D-glucopyranose,1),以治疗有效量的化合物1及可药用载体或赋型剂组成的药物组合物,该化合物及其药物组合物的制备方法,以及它们在制备治疗人类疾病尤其是在制备抗乙型病毒性肝炎的药物中的应用。
Description
技术领域:
本发明属于药物技术领域。具体地,涉及一个新的葡萄糖基咖啡酸酯化合物,以其为活性成分的治疗乙型病毒性肝炎的药物组合物,它们的制备方法,以及它们在制药中的应用,特别是在制备抗乙型病毒性肝炎的药物中的应用。
背景技术:
乙型病毒性肝炎简称乙型肝炎,是由乙型肝炎病毒(hepatitis Bvirus,HBV)引起,一般通过血液和体液传播、呈慢性携带状态的传染病。其传染性比艾滋病强50~100倍,健康人群被感染后罹患肝硬化和肝细胞癌的风险增加1000倍,并最终导致死亡。据世界卫生组织(WHO)统计,全世界共有20亿HBV携带者,其中慢性乙型肝炎(chronic hepatitis B,CHB)患者3.5亿;仅在中国就有约1.2亿人携带HBV,其中CHB患者超过3000万,每年约35万例患者死于CHB相关疾病。现有的抗HBV药物(主要包括疫苗、干扰素和核苷类)的疗效已得到确认,但由于易产生耐药性、作用靶点单一、副作用明显等原因仍无法满足临床需要。迄今为止,乙型肝炎依旧是威胁全世界人类健康的重要问题,抗HBV药物仍然是全球药物研发的热点之一。
天然产物由于结构复杂多样,从中寻找高效低毒、作用靶点新颖的先导化合物已经成为新型抗HBV药物研发的重要组成部分。据统计,通过体内和体外活性筛选被证实具有潜在抗HBV活性的天然产物类型包括木脂素、萜类、生物碱、黄酮、香豆素、环肽等。茵陈为菊科植物滨蒿Artemisia scopariaWaldst.et Kit.或茵陈蒿ArtemisiacapillarisThunb.的干燥地上部分。春季幼苗高6~10cm时采收或秋季花蕾长成至花初开时采割,除去杂质和老茎,晒干。春季采收的习称“绵茵陈”,秋季采割的称“花茵陈”。本品味苦、辛,微寒。归脾、胃、肝、胆经。关于茵陈药理活性的记载最早见于《神农本草经》中,谓其能除“热结黄疸,久服轻身益气耐老”。中医认为其气芳香,有清湿热,退黄疸的功效,临床上主要用来治疗黄疸尿少、湿疮瘙痒、黄疸型传染性肝炎等症状。
茵陈广泛用于慢性乙型肝炎的治疗。《中国药典》中收录的多种治疗乙肝的中药制剂(乙肝宁颗粒、乙肝养阴活血颗粒、小儿肝炎颗粒、护肝片、利肝隆颗粒、肝炎康复丸、茵芪肝复颗粒、茵栀黄口服液、茵胆平肝胶囊、黄疸肝炎丸、清肝利胆胶囊等)中均以茵陈作为主要药效组分。为揭示茵陈蒿的活性成分,中外研究者其化学成分进行了大量的研究,结果表明茵陈中主要含有香豆素,黄酮,色原酮,三萜,甾体,烯炔,长链脂肪族化合物,嘧啶,挥发油等。然而,现有文献中对于这些化合物活性的报导主要集中在保肝利胆方面,其抗HBV活性物质仍然不清楚。
迄今,现有技术中无化合物1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1)的报道,也没有其作为有效成分的药物组合物的报道,也没有其药物组合物在制备或治疗乙型病毒性肝炎药物中的应用报道。
发明内容:
本发明的目的在于提供一类新的具有药用价值的式(I)所示的化合物1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1),含有治疗乙型病毒性肝炎有效量的化合物(1)及药用载体或赋形剂的药物组合物,化合物(1)及其药物组合物的制备方法,化合物1或其药物组合物在制备抗乙型病毒性肝炎药物中的应用。
为了实现本发明的上述目的,本发明提供了如下的技术方案:
结构式(I)所示的化合物1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1),
药物组合物,其中含有治疗有效量的式(I)化合物1和药学上可接受的载体。
用于治疗乙型病毒性肝炎的药物组合物,其中含有治疗有效量的式(I)化合物1和药学上可接受的载体。
如所述的药物组合物,为治疗乙型病毒性肝炎的药物组合物。
所述式(I)的化合物1在制备治疗人类疾病或病症的药物中的应用。
如所述的应用,所述的疾病是乙型病毒性肝炎。
所述药物组合物在制备治疗人类疾病或病症的药物中的应用。
如所述的应用,所述的疾病是乙型病毒性肝炎。
制备权利要求1所述式(I)化合物1的方法,取茵陈蒿(Artemisiacapillaris)全草,粉碎,用90%乙醇回流提取两次,每次3小时,合并乙醇提液,减压回收乙醇至无醇味,合并乙醇提取液,过滤,减压浓缩至无醇味,将该提取液悬浮于水溶液中,用乙酸乙酯萃取,乙酸乙酯部分用甲醇-氯仿溶解吸附于硅胶上,室温放置挥干溶剂,研碎后经硅胶柱层析,用甲醇-氯仿(0:100-60:40)洗脱,得到7个组分(A-G),组分F经过MCI CHP-20P gel柱中压制备,甲醇-水(30:70-100:0)洗脱,得到4个流份F-1~F-4.F-3再通过硅胶柱层析,以甲酸-甲醇-氯仿(0.1:10:90)洗脱,并经Sephadex LH-20柱(甲醇)纯化得到化合物1。
制备含1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1)的药物组合物的方法是以化合物1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1)为原料,加入可药用载体或赋形剂。
本发明化合物用作药物时,可以直接使用,或者以药物组合物的形式使用。该药物组合物含有0.1-99%,优选为0.5-90%的本发明化合物,其余为药物学上可接受的,对人和动物无毒和惰性的可药用载体和/或赋形剂。
所述的药用载体或赋形剂是一种或多种固体、半固体和液体稀释剂、填料以及药物制品辅剂。将本发明的药物组合物以单位体重服用量的形式使用。本发明的药物可经注射(静注、肌注)和口服两种形式给药。
具体实施方式:
为了更好地理解本发明的实质,下面将用本发明的试验例来说明本发明化合物1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1)的药理作用结果,但不以此试验例来限定本发明。
试验例1:
1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(I)对HBsAg和HBeAg的分泌以及HBV DNA复制的抑制作用以及对HepG2.2.15细胞的药物毒性。
1材料和方法
1.1材料:1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(I);泰诺福韦(江西晨阳药业有限公司);HepG2.2.15细胞(广州空军医院);高糖DMEM(GIBCO);G418(GIBICO);胎牛血清(GIBICO);L–谷氨酰胺(AMRESCO);青霉素,链霉素[石药集团中诺药业(石家庄)有限公司]。1.2仪器:酶标仪Bio-RAD680(美国);CO2培养箱Thermo Forma3310(美国);倒置生物显微镜XD-101型(南京);荧光定量PCR仪Mastercyclereprealplex型(德国eppendorf公司);低温高速离心机Centrifuge5415D型(德国eppendorf公司)。
1.3实验过程:HepG2.2.15细胞生长培养基组成为高糖DMEM,10%的胎牛血清,0.03%L–谷氨酰胺,100mg/L G418,100IU青霉素以及100IU链霉素。维持液组成为高糖DMEM,2%的胎牛血清,0.03%L–谷氨酰胺,100mg/L G418,100IU青霉素以及100IU链霉素。供试药物由维持液稀释配制成一定浓度的含药培养基。将胰酶消化后的单细胞悬液接种于细胞板上,于48h后换为含药培养基,每种药物用维持液四倍稀释为四个药物浓度,同时设置只加维持液的细胞对照组,并以泰诺福韦做阳性药物对照。用MTT法测定药物对细胞的毒性;用酶联免疫法测定HBsAg和HBeAg载量,用荧光定量PCR法检测HBV DNA载量。
1.3.1药物细胞毒性测定:
根据Mosmann建立的MTT法检测药物的细胞毒性。具体方法是:HepG2.2.15细胞接种于48孔板,3×104细胞每孔,加入生长培养基,于5%CO2,37℃培养箱中培养72h,吸除原培养基,加入不同浓度含药培养基,于5%CO2,37℃培养箱中继续培养72h后吸除培养基,按0.2mL每孔加入浓度为0.8mg/mL的MTT,于37℃5%CO2孵育4h后弃上清,每孔中加入0.2mL二甲基亚砜,于37℃孵育10min,至生成的蓝紫色结晶物完全溶解,在酶标仪上测定溶液在490nm下的吸光度值。根据结果计算药物对细胞的破坏百分率:
ηdestroy=(A细胞对照组–A供试样品组)/(A细胞对照组–A空白组)×100。
1.3.2抑制HBsAg和HBeAg分泌活性的测定:
利用ELISA(酶联免疫吸附试验)法,测定样品对HBsAg和HBeAg抑制活性。HepG2.2.15细胞接种于48孔板,3×104细胞每孔,加入生长培养基,于5%CO2,37℃培养箱中培养72h,吸除原培养基,加入不同浓度含药培养基,于5%CO2,37℃培养箱中培养72h。取上清液,分别利用HBsAg和HBeAg试剂盒检测。利用酶标仪测定溶液在的吸光度值(490nm)。
抑制率ηinhibitory=(A细胞对照组–A供试样品组)/(A细胞对照组–A空白组)×100
IC50=Anti lg[(50–<50%抑制率)/(>50%抑制率–<50%抑制率)×lg(稀释倍数)+lg(<50%抑制率的浓度)]
SI=CC50/IC50
1.3.3抑制HBV DNA复制活性的测定:
具体方法是:HepG2.2.15细胞按5×105个每孔接种于24孔细胞板,于5%CO2,37℃培养箱中用生长培养基培养,72h后更换为含药培养基,48h后继续以含药培养基更换原培养基,培养48h。使用血液/细胞/组织基因组DNA提取试剂盒(TIANampGemomic DNAKit,TIANGEN,China)提取细胞DNA。用HBV核酸定量检测试剂盒(QIAGEN,Co.,Ltd,Shenzhen)荧光定量PCR法定量检测HBVDNA载量。取2μL DNA样品,加入37.6μL HBV PCR反应液,0.4μL Taq酶,0.06μL UNG。PCR反应在Mastercycler Ep Realplex System定量PCR仪(Eppendorf,Masteraycler Eprealplex,German)上进行,扩增程序为:37℃:5min;94℃:1min;95℃:5sec,60℃:30sec,40个循环。根据结果计算药物的抑制百分率:
ηinhibition=(A细胞对照组–A供试样品组)/(A细胞对照组–A空白组)×100。
2.结果:
CC50为半数细胞致死浓度,根据破坏百分率ηdestroy计算得到。IC50为半数病毒抑制浓度,根据抑制百分率ηinhibition计算得到。最终结果以选择指数(SI=CC50/IC50)来评价。
CC50,IC50及SI的计算公式:
A=log(>50%时的ηdestroy/ηinhibition的药物浓度)
B=log(<50%时的ηdestroy/ηinhibition的药物浓度)
C=|A–B|
CC50=Anti log[(50–<50%时的ηdestroy)×C/(>50%时的ηdestroy–<50%时的ηdestroy)]+B
IC50=Antilog[(50–<50%时的ηinhibition)×C/(>50%时的ηinhibition–<50%时的ηinhibition)]+B
SI=CC50/IC50
具体结果见表1:
表11-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1)在HepG2.2.15细胞对HBV抑制活性和细胞毒性(单位μM)
3、结论:
实验结果显示,1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1)在体外对HBsAg和HBeAg的分泌以及HBV DNA复制都具有显著的抑制作用,其IC50值分别为28.08,126.70以及6.84μM,而且无明显细胞毒性,选择指数分别>37.7,>8.4以及>155.0。
以下通过本发明的实施例来进一步阐明本发明的制备方法及药物组成,便并不以此来限定本发明的实质性内容。
实施例1:
1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1)的制备:
1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1)的提取分离:
采集茵陈蒿全草(10kg),其学名经鉴定为ArtemisiacapillarisThunb.,用90%乙醇回流提取两次,每次3小时,合并乙醇提液,减压回收乙醇至无醇味。将该提取液悬浮于水溶液中,用乙酸乙酯萃取。乙酸乙酯部分用甲醇-氯仿溶解吸附于硅胶上,室温放置挥干溶剂,研碎后经硅胶柱层析,用甲醇-氯仿(0:100-60:40)洗脱,得到7个组分(A-G)。组分F经过MCI CHP-20P gel柱中压制备,甲醇-水(30:70-100:0)洗脱,得到4个流份F-1~F-4.F-3再通过硅胶柱层析,以甲酸-甲醇-氯仿(0.1:10:90)洗脱,并经Sephadex LH-20柱(甲醇)纯化得到化合物1(45mg)。化合物1的结构通过1H,13C-NMR,IR,UV,质谱,以及旋光数据得以确定。
1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1)的结构数据:
旋光由Jascomodel1020旋光仪(Horiba,Tokyo,Japan)测定;红外光谱(IR)采用KBr压片法,由Bio-Rad FTS-135型红外光谱仪(Hercules,California,USA)测定;紫外光谱由UV-2401PC型紫外光谱仪(Shimadzu,Kyoto,Japan)测定;核磁共振谱(1H-、13C-NMR、DEPT)用Brucker AM-400型超导核磁共振仪(Bruker,Bremerhaven,Germany)测定、二维核磁共振谱用DRX-500型超导核磁共振仪(Bruker,Bremerhaven,Germany)测定,以氘代丙酮作为溶剂,TMS(四甲基硅烷)作内标;质谱(MS)用LCMS-IT-TOF型质谱仪(Shimadzu,Kyoto,Japan)测定;薄层色谱硅胶、柱层析硅胶(200-300目)购自青岛美高及青岛海洋化工集团有限公司。
分子式:C17H22O9
分子量:370.35
性状:棕色胶状固体
旋光(c0.12,甲醇)
IR(KBr)vmax:3423,2977,2920,1692,1632,1605,1521,1446,1383,1284,1181,1053cm–1。
UV/Vis(甲醇)λmax(logε):329(4.26),216(4.27)nm。
HRESIMS(+)m/z:实验值393.1147,计算值393.1156(C17H22O9Na+,[M+Na]+)。
1H-NMR(400MHz,氘代丙酮)δ:7.56(1H,d,J=15.9Hz,H-3),7.17(1H,d,J=1.8Hz,H-5),7.05(1H,dd,J=8.1,1.8Hz,H-9),6.86(1H,d,J=8.1Hz,H-8),6.31(1H,d,J=15.9Hz,H-2),4.47(1H,dd,J=11.8,1.9Hz,H-6'a),4.30(2H,m,H-1',H-6'b),3.84(1H,m,H-1″a),3.54(2H,m,H-1″b,H-2'),3.41(1H,m,H-4'),3.39(1H,m,H-3'),3.19(1H,m,H-5'),1.14(3H,t,J=7.1Hz,H-2″).
13C-NMR(100MHz,氘代丙酮)δ:167.5(s,C-1),115.2(d,C-2),145.9(d,C-3),127.5(s,C-4),115.4(d,C-5),146.2(s,C-6),148.8(s,C-7),116.3(d,C-8),122.5(d,C-9),103.9(d,C-1'),74.8(d,C-2'),71.3(d,C-3'),77.8(d,C-4'),74.8(d,C-5'),64.3(t,C-6'),65.3(t,C-1″),15.5(q,C-2″).
实施例2:
按实施例1的方法先制得1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1),用少量的DMSO溶解后,按常规加注射用水,精滤,灌封灭菌制成注射液。
实施例3:
按实施例1的方法先制得1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1),用少量的DMSO溶解后,将其溶于无菌注射用水中,搅拌使溶解,用无菌抽滤漏斗过滤,再无菌精滤,分装于安瓿中,低温冷冻干燥后无菌熔封得粉针剂。
实施例4:
将所分离得到的1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1),按其与赋形剂重量比为9:1的比例加入赋形剂,制成粉剂。
实施例5:
按实施例1的方法先制得1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1),按其与赋形剂重量比为5:1的比例加入赋形剂,制粒压片。
实施例6:
按实施例1的方法先制得1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1),按常规口服液制法制成口服液。
实施例7:
按实施例1的方法先制得1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1),按其与赋形剂重量比为5:1的比例加入赋形剂,制成胶囊。
实施例8:
按实施例1的方法先制得1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1),按其与赋形剂重量比为3:1的比例加入赋形剂,制成胶囊。
实施例9:
按实施例1的方法先制得1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1),按其与赋形剂重量比为5:1的比例加入赋形剂,制成颗粒剂。
Claims (2)
1.结构式(I)所示的化合物1-O-乙基-6-O-咖啡酰基-β-D-葡萄糖吡喃苷(1)在制备治疗乙型病毒性肝炎的药物中的应用,
2.制备权利要求1所述式(I)化合物1的方法,取茵陈蒿(Artemisia capillaris)全草,粉碎,用90%乙醇回流提取两次,每次3小时,合并乙醇提液,减压回收乙醇至无醇味,合并乙醇提取液,过滤,减压浓缩至无醇味,将该提取液悬浮于水溶液中,用乙酸乙酯萃取,乙酸乙酯部分用甲醇-氯仿溶解吸附于硅胶上,室温放置挥干溶剂,研碎后经硅胶柱层析,用甲醇-氯仿0:100至60:40洗脱,得到7个组分A-G,组分F经过MCI CHP-20P gel柱中压制备,甲醇-水30:70至100:0洗脱,得到4个流份F-1~F-4,其中F-3再通过硅胶柱层析,以甲酸-甲醇-氯仿0.1:10:90洗脱,并经Sephadex LH-20柱甲醇洗脱,纯化得到化合物1。
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