CN1704064A - 多羟基棓酰基-β-D-葡萄糖衍生物的新用途 - Google Patents
多羟基棓酰基-β-D-葡萄糖衍生物的新用途 Download PDFInfo
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- CN1704064A CN1704064A CN 200410042882 CN200410042882A CN1704064A CN 1704064 A CN1704064 A CN 1704064A CN 200410042882 CN200410042882 CN 200410042882 CN 200410042882 A CN200410042882 A CN 200410042882A CN 1704064 A CN1704064 A CN 1704064A
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- glucose
- galloyl
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Abstract
本发明涉及多羟基棓酰基-β-D-葡萄糖衍生物或含至少一种多羟基棓酰基-β-D-葡萄糖的提取物在制备用于预防或治疗丙型肝炎产品中的用途。
Description
发明领域
本发明涉及多羟基棓酰基-β-D-葡萄糖衍生物或含至少一种多羟基棓酰基-β-D-葡萄糖的提取物在制备用于预防或治疗丙型肝炎产品中的用途。
背景技术
下面通式1-9代表的多羟基-β-D-葡萄糖衍生物是已知化合物,但有关通式1-9针对丙肝生物活性至今未见报道。
丙型肝炎病毒(Hepatitis C Virus,HCV)是一种导致丙型肝炎的病毒,目前对HCV的治疗还没有很好的方法或药物。由于HCV的组织培养和方便的动物模型目前还没有得到解决,因此,目前人们对拮抗HCV产品的寻找可通过确定是否对HCV基因组编码的蛋白NS3或称NS3丝氨酸蛋白酶产生抑制来进行。即人们选择HCV SN3丝氨酸蛋白酶作为靶酶进行抗丙肝产品的研究和确定。
发明内容
本发明人经研究现已发现通式1-9的多羟基-β-D-葡萄糖衍生物或含至少一个通式1-9化合物的提取物在HCV NS3丝氨酸蛋白酶上显示出拮抗活性。
因此,本发明涉及至少一个通式1-9化合物或其药用盐在制备用于预
防和/或治疗和/或缓解丙型肝炎的产品中用途。
本发明还涉及含至少一个通式1-9或其药用盐的提取物在制备用于
预防和/或缓解和/或治疗丙型肝炎的产品中用途。
本发明还涉及用于预防或治疗丙型肝炎的组合物或产品,其包括至少一种通式1-9化合物或其药用盐和载体或赋形剂。
本发明还涉及用于预防或治疗丙型肝炎的组合物或产品,其包括含至少一种通式1-9化合物或其药用盐的提取物和载体或赋形剂。
本发明还涉及预防或治疗丙型肝炎的方法,其包括给予需要预防或治疗的患者预防或治疗有效量的至少一种通式1-9的化合物或药用盐或含至少一种通式1-9化合物的提取物。
本发明进一步涉及至少一种通式1-9化合物或含至少一种通式1-9化合物的提取物在制备用于抑制HCV NS3丝氨酸蛋白酶的产品中用途。
根据本发明,本发明中所述的药用盐并不加以特别限定,举例讲,例如盐酸盐、硫酸盐、碳酸盐、碳酸氢盐、氢溴酸盐、氢碘酸盐等无机盐的加成盐;醋酸盐、马来酸盐、乳酸盐、酒石酸盐、三氟代醋酸盐等有机羧酸的加成盐;甲磺酸盐、羟基甲磺酸盐、羟基乙磺酸盐、苯磺酸盐、甲苯磺酸盐、牛磺酸等有机磺酸加成盐;三甲胺盐、三乙胺盐、吡啶盐、普鲁卡因盐、吡啶甲基盐、二环己胺盐、N,N,-二苄基乙二胺盐、N-甲基葡糖胺盐、二乙醇胺盐、三乙醇胺盐、三(羟基甲氨基)甲烷盐、苯乙基苄胺盐等胺的加成盐;精氨酸盐、赖氨酸盐、丝氨酸盐、甘氨酸盐、天门冬氨酸盐、谷氨酸盐等氨基酸的加成盐。
本发明的式1-9化合物或其药用盐也包括它们的对映异构体和/或几何的异构体等立体异构体。
化合物1-9一般的制备方法是:使用水、低级脂肪醇类、含水的低级脂肪醇类、芳香族醇类、低级酮类(丙酮等),含卤素溶剂溶剂以及它们的混合溶剂在0℃左右至沸点范围内,在减压、常压或加压下对含有式1-9化合物的植物的全草或其部位如根、茎、叶、花等进行提取,可得到含至少一种通式1-9化合物的提取物。对提取物进行各种分离精制法就可得到作为活性物质的通式1-9化合物。
本发明中的通式1-9化合物广泛存在于许多植物中,举例讲,例如五倍子(Chinese galla)、诃子(Terminalia chebula Retz.)、黑蕊虎耳草(Saxifraga melanocentra Franch.,藏文音译为:贞色达俄,达鄂),狭叶红景天(Rhodiolakirilowii,藏文音译为:索罗玛保)。进一步讲,通式1-9化合物为已知化合物,其可通过本领域已知方法或文献中公开的方法制备。举例讲,化合物1-9一般的制备方法是:使用水、低级脂肪醇类、含水的低级脂肪醇类、芳香族醇类、低级酮类(丙酮等),含卤素溶剂溶剂以及它们的混合溶剂在0℃左右至沸点范围内,在减压、常压或加压下对含有式1-9化合物的植物的全草或其部位如根、茎、叶、花等进行提取,可得到含至少一种通式1-9化合物的提取物。对提取物进行各种分离精制法就可得到作为活性物质式1-9化合物。
具体实施方式
下面实施例用于进一步说明本发明,但其不意味着对本发明的任何限制。
实施例1
由五倍子制备式3、6和9化合物
五倍子500g粉碎后,用50%乙醇-水室温三次冷浸提取,每次浸泡24小时,提取三次,提取的滤液浓缩,将得到的提取物旋干,回收溶剂得到粗提物,得到262g。用极性由小到大的溶剂对粗提物进行萃取分成多个部分。将乙酸乙酯部分分批上凝胶柱(Sephadex LH-20)层析,以水~甲醇∶水2∶8~甲醇∶水4∶6~甲醇∶水6∶4~甲醇∶水8∶2~甲醇~丙酮洗脱,以薄层层析检测,得6个组分。
将6个组分分别用聚酰胺柱减压柱层析,乙酸乙酯~乙酸乙酯∶甲醇10∶1~乙酸乙酯∶甲醇∶水10∶1∶0.5~乙醇∶水6∶4~乙醇∶水8∶2~乙醇~丙酮∶水6∶4~丙酮∶水8∶2~丙酮洗脱,以薄层层析检测,结合凝胶柱(Sephadex LH-20)层析,以水~甲醇∶水2∶8~甲醇∶水4∶6~甲醇∶水6∶4~甲醇∶水8∶2~甲醇~丙酮洗脱层析纯化,得到纯化的式3、6、9化合物。
五倍子粗提物:NS3蛋白酶抑制活性IC50(0.005mg/mL),主要成分为1,2,6-三棓酰基-β-D-葡萄糖(3)、1,2,3,4,6-五棓酰基-β-D-葡萄糖(6)、1,2,3,6-四棓酰基-β-D-葡萄糖(9)、1,6-二棓酰基-β-D-葡萄糖、六到十二棓酰基葡萄糖、没食子酸、没食子酸甲酯。这些主要成分化合物占乙酸乙酯部分80%以上。
实施例2
由诃子制备式7和8化合物
诃子果实2Kg粉碎后,用80%乙醇-水室温5000mL冷浸提取,每次浸泡一周,提取三次,提取的滤液浓缩,将得到的提取物旋干,回收溶剂得到粗提物552g。用极性由小到大的溶剂对粗提物进行萃取分成多个部分,石油醚部分15g、氯仿部分30g、乙酸乙酯部分53g、正丁醇部分234g和水部分220g。正丁醇部分分批(每批20g)上聚酰胺柱,湿法上柱。溶剂为:氯仿∶甲醇∶甲酸100∶10∶1~氯仿∶甲醇∶甲酸100∶15∶1~氯仿∶甲醇∶甲酸60∶40∶1~氯仿∶甲醇∶甲酸50∶50∶1,50mL/份。以薄层层析检测,得14组分。将所得流分继续通过凝胶柱层析等手段纯化得到7、8。
乙酸乙酯部分:NS3蛋白酶抑制活性IC50(0.04mg/mL),正丁醇部分:NS3蛋白酶抑制活性IC50(0.06mg/mL),主要成分为1,3,6-三棓酰基-β-D-葡萄糖(7)、诃黎勒酸(8,Chebulagic acid)、诃子酸(chebulinicacid)、诃子次酸(chebulic acid)、1,2,3,4,6-五没食子酰葡萄糖(1,2,3,4,,6-pentagalloyl glucose)、鞣云实精(corilagin)、原诃子酸(terchubin)、1-棓酰基-β-D-葡萄糖、诃子素(chebulin)、诃子次酸三乙酯(triethyl chebulate)、榄仁黄素(terflavin)、诃子鞣质(terchebulin)、2,3-O-连二没食子酰石榴皮鞣质(punicalagin)、榄仁酸(terninalic acid)、没食子酸。
这些主要成分化合物占乙酸乙酯部分60%以上。这些主要成分化合物占正丁醇部分60%以上。
实施例3
由黑蕊虎耳草制备式1,2和4化合物
黑蕊虎耳草1kg粉碎,用4000ml 80%乙醇浸泡一星期后,粗提液减压浓缩,蒸出溶剂再倒入容器中浸泡,共提取3次。粗提液减压浓缩,蒸去乙醇后,得浸膏205g。依次用石油醚(200ml×5),氯仿(200ml×6),乙酸乙酯(300ml×6),正丁醇(250ml×6)萃取。油层各自减压蒸干,得石油醚部分16g,氯仿部分3g,乙酸乙酯部分24g,正丁醇部分45g。正丁醇部分上聚酰胺柱,将所得流分继续通过凝胶柱层析等手段纯化得到纯化的化合物1、2、4。
乙酸乙酯部分:NS3蛋白酶抑制活性IC50(0.0044mg/mL),正丁醇部分:NS3蛋白酶抑制活性IC50(0.034mg/mL),主要成分为1,3,4-三棓酰基-β-D-葡萄糖(1)、1-O-二棓酰基-2,3,4-三棓酰基-β-D-葡萄糖(2)、3,6-六羟基联苯二甲酰基1,2,4-三棓酰基-β-D-葡萄糖(3)、1-棓酰基-β-D-葡萄糖、3,6-二棓酰基-β-D-葡萄糖,2,3-六羟基联苯二甲酰基1,6-二棓酰基-β-D-葡萄糖、岩白菜素(Bergenin)、山奈酚(kaempferol)、山奈酚-3-O-β-D-葡萄糖苷、山奈酚-3-O-芦丁糖苷、槲皮素(Quercetin)、芦丁(Rutin)、槲皮素-3-O-(2”-O-没食子酰)-芦丁糖苷和没食子酸(Gallic acid)。
这些主要成分化合物占乙酸乙酯部分60%以上。这些主要成分化合物占正丁醇部分60%以上。
实施例4
由狭叶红景天制备化合物5
狭叶红景天6kg粉碎,用20000ml 80%乙醇浸泡一星期后,粗提液减压浓缩,蒸出溶剂再倒入容器中浸泡,共提取3次。粗提液减压浓缩,蒸去乙醇后,得浸膏600g。取300g依次用石油醚(600ml×5),氯仿(600ml×5),乙酸乙酯(600ml×5),正丁醇(600ml×5)萃取。有机层各自减压蒸干,得石油醚部分23g,氯仿部分17g,乙酸乙酯部分48g,正丁醇部分100g,水部分100g。乙酸乙酯和正丁醇部分上聚酰胺柱,将所得流分继续通过凝胶柱层析等手段纯化得到纯化的化合物5。
乙酸乙酯部分:NS3蛋白酶抑制活性IC50(0.05mg/mL),正丁醇部分:NS3蛋白酶抑制活性IC50(0.07mg/mL),主要成分为2-O-二棓酰基-1,3,4-三棓酰基-β-D-葡萄糖(5)、3-O-棓酰-表棓儿茶素、3-O-棓酰-表儿茶素-(4→8)3-O-棓酰-表儿茶素、3-O-棓酰-表棓儿茶素-(4→8)3-O-棓酰-表棓儿茶素、木犀草素、槲皮素、红景天苷、红景天苷元、没食子酸。
这些主要成分化合物占乙酸乙酯部分60%以上。这些主要成分化合物占正丁醇部分60%以上。
化合物1-9的波谱数据:
化合物1浅黄色无定形粉末,负离子电喷雾飞行时间质谱ESI-TOF-MS获得准分子离子峰m/z:635[(C27H24O18)-H]-,13C NMR和1H NMR数据见表1和2。鉴定为1,3,4-三棓酰基-β-D-葡萄糖。
化合物2浅黄色无定形粉末,负离子电喷雾飞行时间质谱ESI-TOF-MS获得准分子离子峰m/z:939[(C41H32O26)-H]-,13C NMR和1H NMR数据见表1和2。鉴定为1-O-二棓酰基-2,3,4-三棓酰基-β-D-葡萄糖。
化合物3白色无定形粉末,负离子电喷雾飞行时间质谱ESI-TOF-MS获得准分子离子峰m/z:635[(C27H24O18)-H]-,13C NMR和1H NMR数据见表1和2。鉴定为1,2,6-三棓酰基-β-D-葡萄糖[12,13]。
化合物4浅黄色无定形粉末,负离子电喷雾飞行时间质谱ESI-TOF-MS获得准分子离子峰m/z:937[(C41H30O26)-H]-,13C NMR和1H NMR数据见表1和2。鉴定为3,6-六羟基联苯二甲酰基1,2,4-三棓酰基-β-D-葡萄糖。
化合物5浅黄色无定形粉末,负离子电喷雾飞行时间质谱ESI-TOF-MS获得准分子离子峰m/z:939[(C41H32O26)-H]-,13C NMR和1H NMR数据见表1和2。鉴定为2-O-二棓酰基-1,3,4-三棓酰基-β-D-葡萄糖。
化合物6白色无定形粉末,负离子电喷雾飞行时间质谱ESI-TOF-MS获得准分子离子峰m/z:939[(C41H32O26)-H]-,13C NMR和1H NMR见表1和2。数据鉴定为1,2,3,4,6-五棓酰基-β-D-葡萄糖[12]。
化合物7浅黄色无定形粉末,负离子电喷雾飞行时间质谱ESI-TOF-MS获得准分子离子峰m/z:635[(C27H24O18)-H]-,13C NMR和1H NMR数据见表1和2。鉴定为1,3,6-三棓酰基-β-D-葡萄糖。
化合物8浅黄色无定形粉末,负离子电喷雾飞行时间质谱ESI-TOF-MS获得准分子离子峰m/z:953[(C41H30O27)-H]-,13C NMR和1H NMR数据见表1和2。鉴定为诃黎勒酸(Chebulagic acid)[14,15]。
化合物9白色无定形粉末,负离子电喷雾飞行时间质谱ESI-TOF-MS获得准分子离子峰m/z:787[(C34H28O22)-H]-,红外光谱I.R.spectral(KBr)cm-1:3394,1701,1615,1536,1450,1321,1213,1209,1033,960,872,805。13C NMR和1H NMR数据见表1和2。鉴定为1,2,3,6-四棓酰基-β-D-葡萄糖[12,13]。
表1化合物13C NMR数据(δc,ppm)
Compound 1(CD3OD) 2(CD3)2CO) 5((CD3)2CO)
Glucose
1 94.1 93.2 93.8
2 74.3 71.7 72.2
3 76.6 73.2 74.1
4 71.4 69.2 69.8
5 75.9 73.9 74.4
6 64.2 62.7 63.1
Galloyl
1 120.0 121.1 121.3 119.8 120.4 120.5 120.6 121.4 119.7 120.2 120.2 120.4 121.0
2 110.2 110.4 110.6 110.0 110.0 110.1 110.2 110.3 110.4 110.5 110.6
3 146.4 146.5 146.5 145.7 145.7 145.8 145.9 146.0 146.3 146.4 146.4 146.4 146.5
4 139.9 140.0 140.6 138.8 139.0 139.1 139.2 139.6 140.0 140.1 140.3 140.3 140.7
5 146.4 146.5 146.5 145.7 145.7 145.8 145.9 146.6 146.3 146.4 146.4 146.4 146.5
6 110.2 110.4 110.6 110.0 110.0 110.1 110.2 110.3 110.4 110.5 110.6
C=O 166.5 167.6 168.3 164.9 165.6 165.6 165.8 166.3 166.2 166.9 167.0 167.3 167.9
Glucose:葡萄糖基;Galloyl:棓酰基
续表1化合物13C NMR数据(δc,ppm)
Compound 6(CD3)2CO 7(CD3OD) 8(CD3OD) 9(CD3)2CO)
Glucose
1 93.4 95.9 92.5 93.5
2 71.7 72.6 67.0 71.8
3 75.5 76.4 71.0 75.9
4 69.3 69.7 64.7 69.3
5 76.0 78.9 74.2 76.0
6 63.6 64.2 62.4 63.6
Galloyl
1 120.0 120.7 121.2 121.4 121.5 120.4 121.2 121.6 120.0 120.0 120.7 121.3 121.5
2 110.0 110.1 110.1 110.1 110.2 110.2 110.4 110.6 110.9 110.0 110.1 110.2 110.3
3 145.9 145.9 146.0 146.0 146.0 146.4 146.5 146.6 146.5 145.9 146.0 146.0 146.1
4 139.0 139.0 139.1 139.5 139.7 139.8 139.9 140.5 140.8 139.0 139.0 139.2 139.7
5 145.8 145.9 146.0 146.0 146.0 146.4 146.5 146.6 146.5 145.9 146.0 146.0 146.1
6 110.0 110.1 110.1 110.1 110.2 110.2 110.4 110.6 110.9 110.0 110.1 110.2 110.3
C=O 165.0 165.6 166.2 166.6 166.6 166.8 168.1 168.2 166.4 165.0 165.8 166.2 166.6
HHDP
1,1’ 115.9 117.6
2,2’ 124.5 125.6
3,3’ 108.2 110.4
4,4’ 145.3 145.6
5,5’ 137.5 138.6
6,6’ 145.5 146.1
C=O 167.4 170.1
Chebuloyl
1’ 170.7
2’ 66.7
3’ 41.7
4’ 39.9
5’ 30.7
6’ 174.4
7’ 174.9
8’ 166.2
1” 119.0
2” 120.0
3” 117.6
4” 147.3
5” 140.3
6” 141.3
HHDP:六羟基联苯二甲酰基;Chebuloyl:诃子酰基;Glucose:葡萄糖基;Galloyl:棓酰基
表2化合物1H NMR数据(δc,ppm)
Compound 1(CD3OD) 2(CD3)2CO 3(CD3)2CO 4(CD3)2CO 5(CD3)2CO
Galloyl 7.00,s 6.99,s 7.06,s 6.56,s 6.90,s
7.04,s 7.02,s 7.09,s 6.84,s 6.95,s
7.10,s 7.08,s 7.16,s 6.87,s 6.97,s
7.12,s 6.92,s 7.05,s
7.19,s 6.99,s 7.11,s
HHDP 6.45,s
6.08,s
Glucose
1 5.92,d 6.35,d 6.00,d 6.39,s 6.24,d
2 4.86,s 5.65,m 4.99,s 5.73,m 5.49,m
3 5.21,t 6.03,t 5.27,t 6.07,s 5.90,t
4 3.66,t 3.60,dd 3.75,m 3.54,m 3.34,d
5 3.83,t 3.60,dd 3.79,m 3.85,d 3.59,s
6 4.55,d 4.58,d 4.50,m 4.48,br 4.51,d
4.47,m 4.43,m 4.48,m 4.41,m
HHDP:六羟基联苯二甲酰基;Glucose:葡萄糖基;Galloyl:棓酰基
续表2化合物1H NMR数据(δc,ppm)
Compound 6(CD3)2CO 7(CD3OD) 8(CD3OD) 9(CD3)2CO
Galloyl 6.99,s 7.09,s 7.07(2H,s)
7.01,s 7.12,s 7.02,s
7.06,s 7.15,s 7.09,s
7.11,s 7.11,s
7.19,s 7.19,s
HHDP 6.84,s
6.50,s
Glucose
1 6.20,d 6.98,s 6.83,s 6.19,d,
2 5.49,t 5.42,t 5.39,s 5.49,dd,
3 5.70,t 5.82,d 5.82,s 5.70,t,
4 4.07,dd 5.28,t 5.22,d 4.12,t
5 4.18,m 4.45,dd 4.36,dd 4.16,m,
6 4.65,m 458,m 4.95,br 4.82,t 4.62,dd,
4.58,dd,
Chebutoyl
2’ 4.87,br
3’ 5.05,dd
4’ 3.81,m
5’ 2.13,d
3” 7.47,s
HHDP:六羟基联苯二甲酰基;Chebuloyl:诃子酰基;Glucose:葡萄糖基;Galloyl:棓酰基
实施例5
式1-9化合物拮抗HCV NS3丝氨酸蛋白酶的活性
抗HCV NS3丝氨酸蛋白酶活性测定是本领域用来判断拮抗丙型肝炎的常规实验,该方法是将包含了NS3蛋白酶基因质粒pMANS34NsH克隆进入JM109细胞,然后进行扩大培养、收集细胞、破碎、离心、收集上清液。通过直链淀粉亲和柱及金属螯合柱分离纯化得到NS3蛋白酶[11a]。NS3蛋白酶抑制活性测定方法是采用了ELISA方法[11b]。化合物1-9对NS3蛋白酶的活性测定结果如表3所示:
表3.抗HCV NS3丝氨酸蛋白酶活性
化合物 | IC50(ug/mL)(μM) | 植物来源 |
1 | 0.64(1.0) | 黑蕊虎耳草 |
2 | 0.64(0.68) | 黑蕊虎耳草 |
3 | 1.2(1.9) | 五倍子 |
4 | 0.80(0.85) | 黑蕊虎耳草 |
5 | 0.62(0.66) | 索罗玛保 |
6 | 1.5(1.6) | 五倍子 |
7 | 0.12(0.19) | 诃子 |
8 | 0.49(0.51) | 诃子 |
9 | 0.59(0.75) | 五倍子 |
由表3可看到,式1-9化合物分别对NS3蛋白酶有良好的抑制活性。
参考文献:
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(b)Yu-Lin Huang et al.,Two tannins from phyllanthus tenellus,J.Nat.Prod.,1998,61,523-524;
(c)Ohtani I.I.et al.,Thonningianins A and B,New antioxidants from the African Medicinal Herb Thonningia sanguinea,J.Nat.Prod.,2000,63,676-679.
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CN101209271B (zh) * | 2006-12-29 | 2011-06-22 | 江苏正大天晴药业股份有限公司 | 一种抗幽门螺杆菌的药物组合物 |
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