CN1082895A - 治疗乙型肝炎病毒(hbv)感染的药用组合物 - Google Patents
治疗乙型肝炎病毒(hbv)感染的药用组合物 Download PDFInfo
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- CN1082895A CN1082895A CN93108597A CN93108597A CN1082895A CN 1082895 A CN1082895 A CN 1082895A CN 93108597 A CN93108597 A CN 93108597A CN 93108597 A CN93108597 A CN 93108597A CN 1082895 A CN1082895 A CN 1082895A
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- glucose
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Abstract
治疗乙型肝炎病毒对人体或动物感染的药用组
合物,它包括有效量的式(1)化合物(或其医药上可接
受的盐)及医药用载体的复合。
式(I)代表的这类环烯醚萜类化合物的特殊例
子是桃叶珊瑚苷、梓醇、京尼平苷、地黄苷、哈帕甙、哈
帕苷和京尼平。按照本发明,环烯醚萜类化合物被
β-糖苷酶水解成糖苷配基,糖苷配基有生物活性,对
HBV DNA的复制有抑制作用。
Description
本发明涉及治疗乙型肝炎病毒感染的药用组合物,它包括由如下结构式(1)代表的环烯醚萜苷及它们的糖苷配基,
其中R1是H或OH,R2是H或COOR6(R6是H或低级烷基),R3是H或β-D-葡萄糖,R4是OH、CH2OH或3-苯基丙烯酰氧基,R5是H、OH、O-β-D-葡萄糖或O-β-D-葡萄糖-(2→1)-β-D-葡萄糖,C7-C8表示一个单键、双键(△7)或
(环氧键),或其医药上可接受的盐作为活性组分。
在上式中:
若R1是OH,R2是H,R2是3-D-葡萄糖,R4是CH2OH,R5是H,C7-C8是双键,则该结构式(1)所确定的化合物是由结构式(A)所代表的桃叶珊瑚苷(Aucubin)。
若R1是OH,R2是H,R3是β-D-葡萄糖,R4是CH2OH,R5是H,C7-C8是环氧基,则该结构式(1)所确定的化合物是由结构式B所代表的梓醇[Catalpol]。
若R1是H,R2是COOR6(R6是CH3),R3是β-D-葡萄糖,R4是CH2OH,R5是H,C7-C8是双键,则结构式(1)所确定的化合物是由结构式C所代表的京尼平苷(Geniposide)。
若R1是OH,R2是H,R3是β-D-葡萄糖,R4是CH2OH,R5是O-β-D-葡萄糖,C7-C8是双键,则结构式(1)所确定的化合物是由结构式D所代表的地黄苷(Rehmannioside)。
若R1是OH,R2是H,R3是β-D-葡萄糖,R4是3-苯基丙烯酰氧基(3-phenylpropenoyloxy group),R5是OH,C7-C8是单键,则结构式(1)所确定的化合物是由结构式E所代表的哈帕苷(Harpagoside)。
若R1是OH,R2是H,R3是β-D-葡萄糖,R4是OH,R5是OH,C7-C8是单键,则结构式(1)所确定的化合物是由结构式F所代表的哈帕甙(Harpagide)。
若R1是H,R2是COOR6(R6是CH3),R3是H,R4是CH2OH,R5是H,C7-C8是双键,则结构式(1)所确定的化合物是由结构式G所代表的京尼平(Genipin)。
另外,结构式H所代表的羟异栀子甙(Gardenoside)和结构式(I)所代表的獐牙菜苦甙(Swertiamarin)也都属于这一组环烯醚萜类化合物。这些化合物呈现出与其他环烯醚萜类化合物类似的化学和药理特性,诸如桃叶珊瑚苷所表现的保护肝的活性和对于HBV感染的抗病毒活性。
附图的简要说明
图1是乙型肝炎病毒DNA在真核生物中复制的表达。
环烯醚萜类代表了一组单萜类化合物,通常以配糖物在自然界存在。当它们被糖水解酶,诸如β-糖苷酶,进行酶水解时,就形成了葡萄糖分子及糖苷配基作为水解产物。糖苷配基形式很容易转化成它的二醛产物并可进行进一步聚合[张等人:临床毒理(Clinical Toxicol)1984年22期77页]
人们已经认识到,配质的形成是呈现环烯醚萜类化合物抑制RNA和蛋白质生物合成作用之生物活性的一个前提步骤,这一类已由S.O.Hub等人在Korean Journal of Phermacognosy,1985年第16期第99页中以题为“环烯醚萜类化合物对肉瘤180细胞中RNA及蛋白质生物合成的作用”一文中作了报导。
桃叶珊瑚属日本山茶(山茱萸科)的叶子是桃叶珊瑚苷,一种环烯醚萜类化合物的主要来源。桃叶珊瑚苷[1,4α,5,7α-四氢-5-羟基-7-(羟甲基)环戊[C]吡喃基-β-D-吡喃糖苷]是由A.R.Trim和R.Hill第一次在“生物化学杂志”(Biochem.J.)1952年50期310页中报导的。
本发明者也报告了这一化合物[I.M.Chang,H.S.Yun(choi)中药材研究进展(Advances in Clinese Medicinal Materials Research),H.M.Chang等人编辑,世界科学出版公司(World Scienific Publishing Company),新加坡,1985年第269页]。
本发明先前报告的重要的生物活性归纳如下:
1)、抗菌活性
抗菌活性主要是对***[I.M.Chang等人第二届韩国和台湾关于天然产物的科学报告会文集,1985年第94页,汉城国立大学出版社(Seoul National University Press)]
2)、保护肝的活性
从试验室动物试验得出结论:包括桃叶珊瑚苷在内的环烯醚萜类化合物保护肝不受四氯化碳中毒引起的肝损害[I.M.Chang等人:“药物化学毒理”(Drug Chem.Toxicol.,1983年第5期第443页]。桃叶珊瑚苷也保护肝不受α-鹅膏菌素中毒在鼠中引起的损害[I.M.Chang等人,“临床毒理(Clinical Toxicol)”,1984年,22期,77页]。
3)、对RNA及蛋白质生物合成的抑制作用
环烯醚萜类化合物,包括桃叶珊瑚苷,可对肉瘤180细胞的RNA和蛋白质生物合成产生抑制作用[I.M.Chang等人“韩国生药学杂志”(Korean Journal of Pharmacognosy)1985年16期第99页,以及I.M.Chang和H.S.Yun“中药材研究进展”(Advances in Chinese Medicinal Maternials Research)H.M.Chang等人编辑,新加坡,1985年,第269页]。
4)解毒活性
桃叶珊瑚苷能将有毒的鹅膏蘑菇毒物(Amanitamushrooms′poisoning)解毒(韩国专利92-2290,由本发明人申请)。
桃叶珊瑚苷对毒性蘑菇萃取物中毒的警犬表现出有效的解毒活性[I.M.Chang和Y.Yamaure植物疗法综述(Phytotherapy Res.)1993年,7期53页]
HBV属于hepadnaviridae家族中hepadnavirus属。HBV基因组是由d-s-DNA(共价闭环DNA)构成的,病毒粒子大小为42毫微米的球形。主要感染黑猩猩、长臂猿、大猩猩、土拨鼠和人类[C.R.Howard及J.L.Melnick“肝炎病毒的分类和分类学”(Classification and Taxonomy of Hepatitis Viruse),载于F.B.Hollinger等人编辑的“病毒性肝炎和肝病国际研讨会论文集”(Proceedings of International Symposium on Viral Hepatitis and Liver Disease),Williams and Wilkins,Baltimore,1990年,第890页]。尽管HBV是一种DNA病毒,它在其复制过程中要求反转录,通过形成一个(+)股RNA中间体。图1中画出了HBV DNA复制过程的概况。
图1为hepadnavirus复制模型。在感染时病毒进入细胞并转入脱壳的核中。病毒DNA转化成ccc DNA,它成为病毒m-RNA包括前基因组转录的模板。随后前基因组RNA反转录成病毒DNA,再通过通路1循环,或作为病毒粒分泌(通路2)。本模型摘自题为“hepadnavirus DNA的合成”(T.T.Wu等“病毒性肝炎的肝病”一书,F.B.Hoillinger等人编,Williams and Wilkins,Beltimore,U.S.A出版,1991年,第114页)并稍稍加以改进。
由HBV在人体中的感染引起的乙型肝炎是全世界的一个主要健康问题,它不仅引起急、慢性肝炎,而且也会形成肝细胞癌。从这方面,已付出了巨大的努力来发展临床上有用的乙型肝炎的治疗方法。举例说,据报导干扰素和几种核苷类物可作为抗病毒剂,但对人类乙型肝炎的治愈率不高,并且它们经常产生严重的副作用。一种新发展的核苷类似物2′,3′-双脱氧胞苷(dideoxycylidine,ddC),其临床***的效果由于其对中枢和外周神经的高毒性而被要求索赔(Feldman等,实验室研究(Lab-Invest.)1992年,66(1)期,75页],对生血细胞也有毒性[Mencoboni等“在体内”(In-Vivo)1990年,4(3)期,171页]。另一种核苷类似物ara-AMP,虽在临床上用了很长时间并能瞬时地抑制HBV感染,却呈现出严重的毒性,因而应避免长期用ara-AMP治疗[J.L.Gerin.“肝脏学”(Hepatology)1991年,14期,198页]。
旨在开发一种新的乙肝抗病毒治疗方法,本发明者研究了几种从上几页叙述的药用植物中得到的环烯醚萜类化合物(结构式A-I)。据发现这些环烯醚萜类化合物呈现出对于肝毒性化学品例如CCl4和α-鹅膏菌素的保肝活性并具有RNA和蛋白质合成中的生物活性。
为了评价环烯醚萜类化合物在它们的生物特性,例如对RNA及蛋白质生物合成的抑制等方面的抗病毒活性,选择了使用2,2,15细胞(Hep G2细胞)的体内细胞培养体系(M.A.Sells等Proc.Natl.Acad.Sci.(U.S.A)1987年,84期,1005页]。使用了在其他地方报导的[B.E.Korba和G.Milman“抑制乙肝病毒复制的化合物的细胞培养检验”(A cell culture assay for compounds which inhibit hepatitis B virusreplication)刊于“抗病毒研究”(Antiviral Research)1991年,15期,217页]用这种细胞检验抗病毒活性的方法。
已发现,如上所述产生如此药理活性的环烯醚萜苷类是非常有效的抑制HBV DNA复制的天然产物,并发现它们是有用的潜在的治疗药物,在治疗HBV感染引起的肝炎方面具有相对低的细胞毒性及急性毒性,见表1-3。当用β-糖苷酶预处理环烯醚萜苷并加到感染有HBV DNA的2,2,15细胞中时,HBV DNA的复制被地抑制了。只用β-糖苷酶处理而不加环烯醚萜苷的话,就没有抑制作用。因而用糖水解酶从苷制造环烯醚萜糖苷配基(糖苷配基形式)是如上所述呈现抗病毒活性的先决过程。
正如试验结果表明的,桃叶珊瑚苷对HBV DNA生物合成产生明显的抑制作用。考虑到这种化合物的低毒性和生产用的丰富的植物资源,本发明开发一种新的***感染的抗病毒剂,可用下列实施例来证明。
采用2,2,15细胞培养评价桃叶珊瑚苷的抗病毒活性按下述进行。
实施例1:桃叶珊瑚苷在抑制乙肝病毒复制方面的作用。
检验方法的细节可在Korba和Milmann报告“抗病毒研究”(Antiviral Res.)1991年,第15期,第217页中找到。简言之,其试验步骤如下:
1)细胞培养
抗病毒评价在细胞(2,2,15细胞)的两个相互分离的通路中进行。所有微板的全部槽均在同时以相同的密度置种,将细胞系保存在含5%胎牛血清(FBS),2微摩尔(μM)谷氨酰胺和50微克/毫升硫酸庆大霉素的RPMI 1640培养介质中。检查细胞培养液对G418***污染的阻力。将1×104/厘米2的细胞放入一个多槽培养板(96个槽)中汇合培养七天,再在汇合条件下保持二至三天以稳定HBV DNA的水平,然后在将细胞暴露于试样前24小时更换培养介质。在该九天期间,更换培养介质,并每24小时将环烯醚萜类样品加入到有新培养介质的培养液中。在正好第一次样品化合物加入前,以及第3、6、9天处理后,收集培养介质并贮存于-70℃下待DNA病毒分析,然后测量这些细胞的细胞内HBV DNA含量。
2)DNA和RNA的萃取
为测量细胞外HBV DNA的含量,将0.2毫升培养介质在25℃下在1M NaOH/10xSSC/1SSC=0.15M NaCl/0.015M柠檬酸钠,pH7.2)中孵化20分钟,并用条形吸墨仪(slot blot apparatus)将其置入一个用20xSSC予浸的硝化纤维膜中,样品在0.5毫升1M Tris/2M NaCl(pH7.2)中洗两次,在0.5毫升20xSSC中洗一次,然后将膜过滤器在2xSSC中清洗并于80℃真空干燥一小时。
为分析细胞内HBV DNA,将细胞溶于槽0.5毫升溶胞缓冲液(lysis buffer)中(4M异硫氰酸胍,7%,2-巯基乙醇及2%肌氨酸(sarkosil)),并用微渗析器向6升50mM Tris,pH8.0-1mM Na2EDTA中渗析1小时。溶胞产物再用蛋白酶K消化,用酚及氯仿萃取,用乙醇沉淀并再悬浮于10mM Tris pH8.0-1.0mM Na2EDTA中。将保存在10cm盘中的培养细胞溶于6ml溶胞缓冲液中,按Korba等人的方法(肝脏学(Hepatology),1989年,9期,461页)制备RNA和DNA细胞。
3)在凝胶中电泳
将细胞DNA样品(10μg/泳道)用HindⅢ酶消化,并用于在1%琼脂糖凝胶中电泳,转到硝化纤维膜中,将未分级的细胞RNA(30μg/泳道)改性,并在带有6%甲醛/Na3PO4(pH6.5)的1%琼脂糖凝胶中电泳,并再转入硝化纤维素膜。
4)乙肝病毒DNA的杂化分析
将用(32P)dCTP标记的纯3.2kb EcoRI HBV DNA碎片用于刻痕转化的杂化探针。用Korba等人的方法作为杂化和后洗条件[“肝脏学”(Hematology)1989年,9期,461页]。用Ambis β-扫描器(Ambis beta scanner)测定HBV核酸的含量。将32P杂化的放射活性的相对量与用于每个硝化纤维素膜过滤器(凝胶或吸墨纸条)的已知量的HBV DNA量相比较。用标准曲线将相对放射活性与HBV DNA的量关联起来。
由于细胞内外HBV DNA含量的固有波动,只有比未处理细胞中HBV DNA形式的平均水平大3.5倍(对于HBV病毒粒DNA)或大3.0倍(对于复制中间体RI,见表1)的抑制作用才被认为在本试验中从统计上来说是重要的(P<0.05)。在每份细胞DNA制备(在本试验中以每个细胞为基础时它是恒定的)中,整个HBV DNA的水平被用作计算细胞内HBV DNA形式的水平,固而消除了吸墨杂化分析中固有的技术偏差。典型的未处理的细胞之细胞外HBV病毒粒DNA的值从50~150pg/ml培养介质(平均约76pg/ml)。在未处理的细胞中细胞内HBV DNA复制中间体(RI)的范围从50~100pg/μg细胞DNA(平均约74pg/μg细胞DNA)。一般说,用抗病毒剂处理后细胞内HBV水平上的抑制作用是意义不大的,且比HBV病毒粒DNA水平上的抑制作用更慢。
以进行的杂化分析的结果为基础,1.0pg细胞内HBV DNA/μg细胞DNA相当于每细胞2~3基因组复制,1.0pg细胞外HBV DNA/ml培养介质相当于3×105病毒粒/ml。
表1:桃叶珊瑚苷对HBV DNA在2,5,15细胞培养液中的复制的作用
细胞内HBV DNA* HBV病毒粒DNA**
(pg/μg细胞DNA) (pg/ml培养介质)
试验编号 处理 单 RI1)0天 3天 6天 9天
118AA (未处理细胞) 2.8 78 61 83 110 110
118AB 2.9 73 70 55 85 81
118BA 2.5 56 88 100 92 88
118BB 2.4 69 69 64 52 74
118AE ddC25μM2)1.1 1 65 41 15 0.3
118AF 1.2 1 70 33 13 0.0
118BE 0.8 1 78 31 10 0.0
118BF 1.0 1 60 40 12 0.0
123AA 桃叶珊瑚苷,1000μM+Gly3)2.2 3 64 84 25 1
123AB 2.1 2 81 79 18 1
123BA 2.3 3 69 70 22 1
123BB 2.6 2 80 67 20 1
123AC 桃叶珊瑚苷,300μM+Gly 2.0 7 54 66 54 9
123AD 2.0 6 59 89 48 7
123BC 2.4 5 77 98 44 5
123BD 2.5 9 66 84 51 6
123AE 桃叶珊瑚苷,100μM+Gly 2.6 21 52 59 40 15
123AF 2.8 27 76 77 48 22
123BE 2.4 22 55 79 66 20
123BF 2.1 26 62 51 59 17
续表1:
细胞内HBV DNA* HBV病毒粒DNA**
(pg/μg细胞DNA) (pg/ml培养介质)
试验编号 处理 单 RI2)0天 3天 6天 9天
试验编号 处理 单 RIU 0天 3天 6天 9天
123AG 桃叶珊瑚苷,30μM+Gly 2.6 70 62 94 49 55
123AH 2.8 75 67 82 58 72
123BG 2.4 63 60 97 61 70
123BH 2.1 68 71 62 69 67
123AI 桃叶珊瑚苷,1000μM+30'Gly4)2.3 3 84 67 20 2
123AJ 2.0 2 70 79 17 2
123BI 2.0 4 79 66 16 2
123BJ 2.1 4 59 78 24 3
123AK 桃叶珊瑚苷,300μM+30'Gly 2.4 11 88 80 54 9
123AL 2.6 10 51 55 39 7
123BK 1.9 7 50 54 44 6
123BL 2.0 9 59 61 49 8
123AM 桃叶珊瑚苷,100μM+30'Gly 2.5 33 55 80 50 20
123AN 2.4 32 51 49 66 17
123BM 2.3 27 69 50 41 16
123BN 2.7 26 86 57 45 21
123AN 桃叶珊瑚苷,30μM+30'Gly 2.5 92 57 85 70 80
123AO 2.4 68 61 94 62 48
123BN 2.3 59 79 51 55 87
123BO 2.7 68 68 75 75 91
*:细胞内HBV DNA的分析在第9天处理后24小时进行。
**:病毒粒HBV DNA的中止灵敏度是0.1pg/ml
1):RI:复制中间体。
2):ddC:2′,3′-双脱氧胞苷,一种作为已知抗病毒剂的阳性对比。
3):GLY:将桃叶珊瑚苷与β-糖苷酶按下述混合,但在加入培养细胞前不进行孵化。
4):30′GLY:将桃叶珊瑚苷在2.5mg/ml β-糖苷酶存在下在0.1M乙酸/钠(pH5)中于37℃孵化30分钟再加入培养介质中。将贮备液稀释100倍,β-糖苷酶在培养介质中的终浓度是25μg/ml。
正如上述试验所表明的,按照本发明环烯醚萜类化合物对HBV DNA的复制产生有效的抑制作用,因而能把本发明的药物用作防止和***病毒引起的肝炎。
实施例2:细胞毒性试验
毒性试验是在96槽平底组织培养板中进行的。细胞的培养和处理均按与抗病毒评价试验相同的程序进行(见实施例1)。每组四个浓度在三重培养液中试验,对中性红染料的吸收用于相对毒性水平的测量。将内部化染料(Internaliged dye)在510nm的吸光度(A510)用作定量分析。与用于试验化合物的方法相同,将保持在同一96槽板上的9个未处理细胞之培养液的A510、平均值(平均值±标准偏差)的百分数作为试验值。9个对比培养液在板23上的染料吸收的百分数是100±4,试验结果表明,在试验化合物浓度范围内未呈现出明显的细胞毒性(表2)。
表2细胞毒性试验
染料吸收量
(相对于对比物的浓度%)
板 处理剂 10,000 3000 1000 300
M M M M -
23 桃叶珊瑚苷 45±3 85±3 100±1 99±1
23 桃叶珊瑚苷 67±3 82±2 99±2 99±2
+30'GLY*
23 桃叶珊瑚苷 63±6 93±5 99±1 99±2
+GLY**
染料吸收量
(相对于对比物的浓度%)
板 处理剂 250 83 25 8.3
(μg/ml)
23 仅GLY***72±2 82±2 99±5 100±2
*:30′GLY:用β-糖苷酶将桃叶珊瑚苷在0.1M乙酸钠(pH5)中于37℃孵化30分钟再加入到培养介质中。(将贮备液稀释100倍,β-糖苷酶在培养介质中的最终浓度是25μg/ml)。
**:GLY:将桃叶珊瑚苷如上所述混合而无β-糖苷酶的予孵化。
***:仅GLY:只用β-糖苷酶处理而不加桃叶珊瑚苷。
实施例3:小鼠急性中毒试验
为检验桃叶珊瑚苷的可能存在的急性毒性,将100、300、600和900mg/kg的剂量分别施予每只小鼠的腹膜内,记录24小时内的死亡速率。
表3 小鼠急性中毒试验
施用 剂量 死亡数 SGOT 碱性磷 甘油
药物 (mg/ No.) (IU/L) 酸酶 三酯
kg) (IU/L) (mg/dL)
桃叶 100 0 261 236
珊瑚 300 0 194 157 35
苷 600 0 179 135 39
900 0 162 51
*每试验组包括10只小鼠。在施用桃叶珊瑚苷后24小时采集血清。
表3结果显示无死亡,说明其最低致死量大于900mg/kg。当施以高剂量时,SGOT及碱性磷酸酶的活性稍稍降低而甘油三酯含量则稍有升高,说明不呈现严重的毒性作用。
按照本发明,环烯醚萜类化合物能以药制剂的形式口服或胃肠外施药。该制药过程要在一容器或一辅助模内混合,这是制药领域中通用的。
以下是本发明制剂的实例。
制剂1(片剂)
桃叶珊瑚苷(每片) 500mg
乳糖 80mg
蔗糖 80mg
金合欢胶(Acacia rubber) 10mg
滑石粉 10mg
硬脂酸镁 1mg
纯化水 适量
将桃叶珊瑚苷、乳糖、蔗糖和金合欢胶混合,加入适量水,煮沸,通过8号筛选粒,再将湿粒在40℃烘干,然后通过10号筛制成小颗粒,再加入滑石粉和硬脂酸镁并压片。
制剂2(胶丸)
京尼平苷 500mg
乳糖 80mg
硬脂酸镁 适量
将这些组份混合并装入硬胶囊中。
制剂3(注射液)
将50毫克桃叶珊瑚苷溶于5毫升消毒的加热到60℃的生理盐水溶液中,灌入无菌瓶并封闭之。
Claims (12)
2、按权利要求1的组合物,其中的化合物(1)是桃叶珊瑚苷及其糖苷配基(或其医药上可接受的盐)。
3、按权利要求1的组合物,其中的化合物(1)是京尼平苷及其糖苷配基(或其医药上可接受的盐)。
4、按权利要求1的组合物,其中的化合物(1)是选自含梓醇、地黄苷、京尼平、哈帕苷、哈帕甙或它们的糖苷配基(或其医药上可接受的盐)的化合物。
6、按权利要求5的方法,其中化合物(1)是桃叶珊瑚苷及其糖苷配基(或其医药上可接受的盐)。
7、按权利要求5的方法,其中化合物(1)是京尼平苷及其糖苷配基(或其医药上可接受的盐)。
8、按权利要求5的方法,其中化合物(1)是选自梓醇、地黄苷、就尼平、哈帕甙、哈帕苷或它们的糖苷配基(或其医药上可接受的盐)类化合物。
10、按权利要求9的应用,其中化合物(1)是桃叶珊瑚苷及其糖苷配基(或其医药上可接受的盐)。
11、按权利要求9的应用,其中化合物(1)是尼片平苷及其糖苷配基(或其医药上可接受的盐)。
12、按权利要求9的应用,其中化合物(1)是选自梓醇、地黄苷、京尼平、哈帕苷、哈帕甙或它们的糖苷配基(或其医药上可接受的盐)的化合物。
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- 1992-07-15 KR KR1019920012600A patent/KR100218052B1/ko not_active IP Right Cessation
-
1993
- 1993-06-01 JP JP13051593A patent/JP3571061B2/ja not_active Expired - Fee Related
- 1993-07-12 IT IT93MI001522A patent/IT1264923B1/it active IP Right Grant
- 1993-07-14 DE DE4323567A patent/DE4323567B4/de not_active Expired - Fee Related
- 1993-07-15 CN CN93108597A patent/CN1047307C/zh not_active Expired - Fee Related
-
1995
- 1995-10-16 US US08/543,828 patent/US5929038A/en not_active Expired - Fee Related
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101486743B (zh) * | 2008-01-18 | 2012-07-18 | 北京卓凯生物技术有限公司 | 具有抗老年痴呆症作用的新环烯醚萜类化合物 |
CN102875617A (zh) * | 2012-09-12 | 2013-01-16 | 安徽医科大学 | 栀子苷衍生物及其制备方法及其在抗炎中的用途 |
CN102872067A (zh) * | 2012-10-25 | 2013-01-16 | 广西中医药大学 | 一种抗肝炎的药物制剂 |
CN104490907A (zh) * | 2014-11-11 | 2015-04-08 | 济南星懿医药技术有限公司 | 一种抗病毒的药物组合物 |
CN104510754A (zh) * | 2014-11-11 | 2015-04-15 | 济南星懿医药技术有限公司 | 一种抗病毒的药物组合物 |
Also Published As
Publication number | Publication date |
---|---|
JP3571061B2 (ja) | 2004-09-29 |
IT1264923B1 (it) | 1996-10-17 |
US5929038A (en) | 1999-07-27 |
DE4323567A1 (de) | 1994-01-20 |
ITMI931522A0 (it) | 1993-07-12 |
CN1047307C (zh) | 1999-12-15 |
DE4323567B4 (de) | 2006-12-07 |
ITMI931522A1 (it) | 1995-01-12 |
JPH0687740A (ja) | 1994-03-29 |
KR940001886A (ko) | 1994-02-16 |
KR100218052B1 (ko) | 1999-09-01 |
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