CN106083875A - 联苯苄唑的药物组合物及其保肝作用 - Google Patents
联苯苄唑的药物组合物及其保肝作用 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
- A61K36/8966—Fritillaria, e.g. checker lily or mission bells
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
本发明公开了联苯苄唑的药物组合物及其保肝作用,本发明提供的联苯苄唑的药物组合物中含有联苯苄唑和一种从浙贝母的干燥鳞茎中分离得到的结构新颖的天然产物化合物(Ⅰ),联苯苄唑、化合物(Ⅰ)可以提高小鼠肝组织中GSH含量,降低MDA含量,抑制TG的积累,具有一定的保肝作用;联苯苄唑和化合物(Ⅰ)联合使用时,治疗效果更好,可开发成保肝药物,与现有技术相比具有突出的实质性特点和显著的进步。
Description
技术领域
本发明属于生物医药领域,涉及联苯苄唑的新用途,具体涉及联苯苄唑的药物组合物及其保肝的医药用途。
背景技术
联苯苄唑为咪唑类抗真菌剂,具有广谱抗真菌作用,对皮肤真菌、酵母菌、霉菌及其它真菌,如秕糠状鳞斑霉菌,微小棒状杆菌有效。体外试验表明本药对皮肤真菌(如发癣菌)的作用主要是杀菌,而对酵母菌的作用主要是抑菌。本药能很好地透过被感染的皮肤,作用迅速并持续时间长,维持时间超过48hr。
适应症:急性及慢性皮肤真菌病,特别是皮肤毛癣菌属,小孢子菌属,絮状表皮癣菌;酵母菌,如白色念珠菌及其它种类的酵母菌;霉菌,如曲霉菌所致的皮肤真菌病;秕糠状鳞斑霉所引起的花斑糠疹;棒状杆菌所致的红癣;上述真菌所致皮肤浅表感染。
目前尚未见联苯苄唑与保肝的相关性报道。
发明内容
本发明的目的在于提供一种联苯苄唑的药物组合物,该药物组合物中含有联苯苄唑和一种从草本中分离得到的结构新颖的天然产物,联苯苄唑和该天然产物可以协同保肝。
本发明的上述目的是通过下面的技术方案得以实现的:
一种具有下述结构式的化合物(Ⅰ),
一种联苯苄唑的药物组合物,包括联苯苄唑、如上所述的化合物(Ⅰ)和药学上可以接受的载体。
如上所述的化合物(Ⅰ)的制备方法,包含以下操作步骤:(a)将浙贝母的干燥鳞茎粉碎,用85~95%乙醇热回流提取,合并提取液,浓缩至无醇味,依次用石油醚、乙酸乙酯和水饱和的正丁醇萃取,分别得到石油醚萃取物、乙酸乙酯萃取物和正丁醇萃取物;(b)步骤(a)中正丁醇取物用大孔树脂除杂,先用35%乙醇洗脱8个柱体积,再用90%乙醇洗脱12个柱体积,收集90%洗脱液,减压浓缩得90%乙醇洗脱浓缩物;(c)步骤(b)中90%乙醇洗脱浓缩物用正相硅胶分离,依次用体积比为120:1、60:1、30:1和15:1的二氯甲烷-甲醇梯度洗脱得到4个组分;(d)步骤(c)中组分3用正相硅胶进一步分离,依次用体积比为40:1、30:1和10:1的二氯甲烷-甲醇梯度洗脱得到3个组分;(e)步骤(d)中组分2用十八烷基硅烷键合的反相硅胶分离,用体积百分浓度为85%的甲醇水溶液等度洗脱,收集14~18个柱体积洗脱液,洗脱液减压浓缩得到化合物(Ⅰ)。
进一步地,步骤(a)用90%乙醇热回流提取,合并提取液。
进一步地,所述大孔树脂为D101型大孔吸附树脂。
如上所述的化合物(Ⅰ)在制备保肝的药物中的应用。
如上所述的联苯苄唑的药物组合物在制备保肝的药物中的应用。
本发明的优点:
本发明提供的联苯苄唑的药物组合物中含有联苯苄唑和一种从浙贝母的干燥鳞茎中分离得到的结构新颖的天然产物,联苯苄唑和该天然产物单独作用时,具有保肝作用;二者联合作用时,保肝效果进一步提高,可以开发成保肝的药物。本发明与现有技术相比具有突出的实质性特点和显著的进步。
具体实施方式
下面结合实施例进一步说明本发明的实质性内容,但并不以此限定本发明保护范围。尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和范围。
实施例1:化合物(Ⅰ)分离制备及结构确证
分离方法:(a)将浙贝母的干燥鳞茎(2kg)粉碎,用90%乙醇热回流提取(15L×3次),合并提取液,浓缩至无醇味(3L),依次用石油醚(3L×3次)、乙酸乙酯(3L×3次)和水饱和的正丁醇(3L×3次)萃取,分别得到石油醚萃取物、乙酸乙酯萃取物和正丁醇萃取物;(b)步骤(a)中乙酸乙酯萃取物用D101型大孔树脂除杂,先用35%乙醇洗脱8个柱体积,再用90%乙醇洗脱12个柱体积,收集90%洗脱液,减压浓缩得90%乙醇洗脱浓缩物;(c)步骤(b)中90%乙醇洗脱浓缩物用正相硅胶分离,依次用体积比为120:1(11个柱体积)、60:1(9个柱体积)、30:1(9个柱体积)和15:1(8个柱体积)的二氯甲烷-甲醇梯度洗脱得到4个组分;(d)步骤(c)中组分3用正相硅胶进一步分离,依次用体积比为40:1(6个柱体积)、30:1(8个柱体积)和10:1(6个柱体积)的二氯甲烷-甲醇梯度洗脱得到3个组分;(e)步骤(d)中组分2用十八烷基硅烷键合的反相硅胶分离,用体积百分浓度为85%的甲醇水溶液等度洗脱,收集14~18个柱体积洗脱液,洗脱液减压浓缩得到化合物(Ⅰ)(553mg,HPLC归一化纯度大于98%)。
结构确证:HR-ESI-MS显示[M+H]+为m/z 467.2378,结合核磁特征可得分子式为C28H34O6,不饱和度为12。核磁共振氢谱数据δH(ppm,CD3OD,500MHz):H-1(6.81,s),H-4(6.05,s),H-5(5.38,s),H-8(3.79,m),H-9(1.36,m),H-10(2.91,d,J=12.4Hz),H-11(2.08,m),H-12(6.32,dd,J=11.9,7.7Hz),H-13(6.53,m),H-14(2.37,m),H-14(2.59,m),H-16(1.02,d,J=6.5Hz),H-18(4.07,dd,J=12.7Hz),H-20(3.24,dqd,J=13.2,7.4,6.5Hz),H-21(1.34,m),H-21(1.77,m),H-22(1.20,m),H-22(1.26,m),H-23(1.24,m,2H),H-24(1.24,m,2H),H-25(1.25,m,2H),H-26(0.88,t,J=7.2Hz),H-27(1.21,d,J=7.2Hz);核磁共振碳谱数据δC(ppm,CD3OD,125MHz):143.3(CH,1-C),156.6(C,3-C),110.8(CH,4-C),144.2(C,4a-C),107.3(CH,5-C),190.8(C,6-C),82.4(C,7-C),43.5(CH,8-C),116.3(C,8a-C),19.2(CH3,9-C),62.1(CH,10-C),21.1(CH,11-C),133.6(CH,12-C),123.2(CH,13-C),43.3(CH2,14-C),206.5(C,15-C),19.5(CH3,16-C),169.3(C,17-C),51.1(CH,18-C),206.3(C,19-C),46.3(CH,20-C),32.7(CH2,21-C),27.6(CH2,22-C),29.0(CH2,23-C),31.3(CH2,24-C),22.2(CH2,25-C),14.2(CH3,26-C),16.6(CH3,27-C)。红外波谱中的1710cm-1吸收带与UV谱中的224nm吸收带表明该化合物含有α,β-不饱和羰基结构。13C NMR、DEPT和HSQC谱中显示有28个碳信号,包括四个甲基,六个亚甲基,十个次甲基(五个烯烃碳),以及八个季碳(一个连氧碳,四个羰基碳和三个烯烃碳),以上功能结构再结合不饱和数表明该化合物为四环结构。核磁数据表明该化合物含有一个α,β-不饱和羰基结构[δH5.38(1H,s,H-5);δC144.2(C-4a),107.3(C-5),190.8(C-6)],一个五元内酯环[δH3.79(1H,m,H-8),4.07(1H,dd,J=12.7Hz,H-18);δC82.4(C-7),43.5(C-8),169.3(C-17),51.1(C-18)],一个2-甲基辛酰基片段[δH3.24(1H,dqd,J=13.2,7.4,6.5Hz,H-20),1.34(1H,m,H-21),1.77(1H,m,H-21),1.20(1H,m,H-22),1.26(1H,m,H-22),1.24(2H,m,H-23),1.24(2H,m,H-24),1.25(2H,m,H-25),0.88(3H,t,J=7.2Hz,H-26),1.21(3H,d,J=7.2Hz,H-27);δC206.3(C-19),46.3(C-20),32.7(C-21),27.6(C-22),29.0(C-23),31.3(C-24),22.2(C-25),14.2(C-26),16.6(C-27)]。1H-1H COSY谱中显示的H3-27/H-20/H2-21/H2-22/H2-23/H2-24/H2-25/H3-26相关信号与HMBC谱中显示的H-18与C-8和C-19,H-20与C-19的相关性以及相关碳化学位移表明该化合物含有一个2-甲基辛酰基片段。另1H-1H COSY谱中存在H-4/H-10/H-11/H-12/H-13/H2-14相关信号结合HMBC谱中显示的H-1与C-4a、C-8a和C-8,H-4与C-3、C-4a和C-8a,H-5与C-4、C-4a和C-6,H-8与C-7、C-8a和C-18,H-10与C-3、C-11、C-15和C-16,H-12与C-11、C-13、C-14和C-16,H2-14与C-12、C-13和C-15,H-18与C-8和C-17相关信号,可以推测azaphilone骨架结构存,因此,根据上述结构片段构建化合物可以确认为Cohaerin衍生物。综合氢谱、碳谱、HMBC谱和ROESY谱,以及文献关于相关类型核磁数据,可基本确定该化合物如下所示,立体构型进一步通过ECD试验确定,理论值与实验值基本一致。
该化合物化学式及碳原子编号如下:
实施例2:药理作用
1、材料与方法
1.1材料与仪器
联苯苄唑购自中国药品生物制品检定所。化合物(Ⅰ)自制,制备方法见实施例1。ICR雌性小白鼠体重(25±5)g,上海斯莱克实验动物责任有限公司;考马斯亮蓝G-250、甘油三脂试剂盒、丙二醛测试盒、谷胱甘肽过氧化物试剂盒、乙醇脱氢酶测定试剂盒南京建成生物工程研究所;海王金樽,广东深圳海王药业有限公司;56°红星二锅头白酒,北京红星酿酒厂。Alpha-D2冻干机德国Christ公司;电子天平,上海天平仪器厂;UV752N紫外可见分光光度计,上海仪电分析仪器有限公司。
1.2动物分组
将72只ICR小鼠在(22±1)℃,湿度40%~60%,12h日夜交替,自由进食、进水的条件下适应性喂养一周后,随机分为六组。空白对照组12只:实验过程中不做任何处理,自由喂养;模型组12只:0.9%的生理盐水;联苯苄唑组12只:浓度为100mg/mL;化合物(Ⅰ)组12只:浓度为100mg/mL;联苯苄唑与化合物(Ⅰ)组合物组12只:浓度为50mg/mL联苯苄唑+50mg/mL化合物(Ⅰ);阳性对照组12只:浓度为25mg/mL的海王金樽溶液。
1.3给药
每日经口灌胃给予20mL/kg·BW受试样品。空白对照组不做任何灌胃,自由进食、进水;模型对照组按体重给予生理盐水,连续给药30d。每周称重一次,根据体重调整用药量。给予受试样品结束时,将模型对照组及各样品组一次灌胃给予白酒5mL/kg·BW,空白对照组给蒸馏水。
1.4肝脏样品制备
末次给药后,禁食不禁水12h,将小鼠颈椎脱臼处死,解剖取出完整肝脏,预冷生理盐水清洗至洗液无血色后,吸干肝脏表面水分。剪取0.1g肝脏组织置于小烧杯中(于冰水),准备9倍(0.9mL)于肝脏组织重量的0.9%的生理盐水,转移总量2/3的生理盐水于烧杯中,尽快剪碎组织块,倒入玻璃匀浆器,再将剩余的1/3生理盐水冲洗残留在烧杯中的碎组织块,一起倒入匀浆管进行匀浆,充分研磨后制成10%的组织匀浆,于离心机中以2000r/min离心15min,取上清液备用。
1.5检测指标
小鼠体重:每周称量一次小鼠体重,直到实验结束,以考察受试样品对各组小鼠体重的影响。肝组织指标测定:各组肝组织中GSH、MDA和TG含量,ADH活性测定根据各试剂盒说明书操作步骤进行。
1.3数据统计
数据均以(平均值±标准偏差)表示,组间差异采用SPSS16.0进行单因素分析(ANOVA),以P<0.05或P<0.01确定差异是否有统计学意义。
2、实验结果
2.1对谷胱甘肽、丙二醛含量的影响
肝脏谷胱甘肽(GSH)的总含量是评价药物醒酒保肝功能的一个重要指标。由表1可知,与空白组比较,模型组小鼠经白酒灌胃后,肝脏GSH含量极显著降低(P<0.01),说明该模型造模成功。阳性对照组和联苯苄唑与化合物(Ⅰ)组合物组小鼠肝匀浆中GSH含量与模型组相比极显著升高(P<0.01),联苯苄唑组、化合物(Ⅰ)组小鼠肝匀浆中GSH含量也明显升高(P<0.05)。组合物能够维持肝脏GSH含量,对抗乙醇损伤引起的肝脏GSH耗竭,提高机体清除自由基的能力,从而对小鼠肝脏起到保护作用。由于GSH能在一定程度上阻止肝组织中脂质过氧化反应,而丙二醛(MDA)是脂质过氧化反应的产物之一,因此GSH浓度的降低会间接导致肝脏MDA含量的增加。由表1可知,与空白组比较,模型组小鼠灌胃后,肝脏MDA含量极显著升高(P<0.01),说明该模型造模成功。阳性对照组和联苯苄唑与化合物(Ⅰ)组合物组小鼠肝匀浆中MDA含量与模型组相比显著下降P(<0.01),联苯苄唑组、化合物(Ⅰ)组也表现出MDA含量明显下降,显著性水平(P<0.05)。
表1受试样品对小鼠肝组织中GSH、MDA含量的影响
组别 | GSH(mmol/L) | MDA(nmol/mgprot) |
空白组 | 27 | 5.2 |
模型组 | 17 | 11.7 |
阳性对照组 | 26 | 6.2 |
联苯苄唑组 | 24 | 8.7 |
化合物(Ⅰ)组 | 24 | 8.9 |
联苯苄唑与化合物(Ⅰ)组合物组 | 29 | 5.4 |
2.2对甘油三酯含量的影响
当机体摄入大量乙醇时,乙醇在乙醇脱氢酶的作用下大量氧化,使得三羧酸循环和脂肪代谢受阻,使得甘油三酯(TG)在肝脏中不断堆积,不但会诱发较为严重的心血管疾病,还会引发脂肪肝。由表2可知,与空白组比较,模型组小鼠肝脏组织TG含量极显著升高(P<0.01),说明该模型造模成功。与模型组比较,联苯苄唑与化合物(Ⅰ)组合物组和阳性对照组小鼠肝匀浆中TG含量极显著降低(P<0.01)。本实验中,各药物组都表现出降低醉酒小鼠肝脏TG含量,并且组合物组都达到极显著水平(P<0.01),说明此组合物可降低醉酒小鼠肝脏组织TG含量,减轻肝脏脂肪堆积,起到保护肝脏的作用。
表2受试样品对小鼠肝组织中TG含量的影响
组别 | TG(mmol/L) |
空白组 | 0.6±0.02 |
模型组 | 1.4±0.14 |
阳性对照组 | 0.7±0.01 |
联苯苄唑组 | 0.9±0.03 |
化合物(Ⅰ)组 | 0.9±0.02 |
联苯苄唑与化合物(Ⅰ)组合物组 | 0.7±0.02 |
上述试验表明,联苯苄唑、化合物(Ⅰ)可以提高小鼠肝组织中GSH含量,降低MDA含量,抑制TG的积累,具有一定的保肝作用;联苯苄唑和化合物(Ⅰ)联合使用时,治疗效果更好,可开发成保肝药物。
上述实施例的作用在于说明本发明的实质性内容,但并不以此限定本发明的保护范围。本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和保护范围。
Claims (7)
1.一种具有下述结构式的化合物(Ⅰ),
2.一种联苯苄唑的药物组合物,其特征在于:包括联苯苄唑、如权利要求1所述的化合物(Ⅰ)和药学上可以接受的载体。
3.权利要求1所述的化合物(Ⅰ)的制备方法,其特征在于,包含以下操作步骤:(a)将浙贝母的干燥鳞茎粉碎,用85~95%乙醇热回流提取,合并提取液,浓缩至无醇味,依次用石油醚、乙酸乙酯和水饱和的正丁醇萃取,分别得到石油醚萃取物、乙酸乙酯萃取物和正丁醇萃取物;(b)步骤(a)中正丁醇取物用大孔树脂除杂,先用35%乙醇洗脱8个柱体积,再用90%乙醇洗脱12个柱体积,收集90%洗脱液,减压浓缩得90%乙醇洗脱浓缩物;(c)步骤(b)中90%乙醇洗脱浓缩物用正相硅胶分离,依次用体积比为120:1、60:1、30:1和15:1的二氯甲烷-甲醇梯度洗脱得到4个组分;(d)步骤(c)中组分3用正相硅胶进一步分离,依次用体积比为40:1、30:1和10:1的二氯甲烷-甲醇梯度洗脱得到3个组分;(e)步骤(d)中组分2用十八烷基硅烷键合的反相硅胶分离,用体积百分浓度为85%的甲醇水溶液等度洗脱,收集14~18个柱体积洗脱液,洗脱液减压浓缩得到化合物(Ⅰ)。
4.根据权利要求3所述的化合物(Ⅰ)的制备方法,其特征在于:步骤(a)用90%乙醇热回流提取,合并提取液。
5.根据权利要求3所述的化合物(Ⅰ)的制备方法,其特征在于:所述大孔树脂为D101型大孔吸附树脂。
6.权利要求1所述的化合物(Ⅰ)在制备保肝的药物中的应用。
7.权利要求2所述的联苯苄唑的药物组合物在制备保肝的药物中的应用。
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