CN1704051A - 苯并吡喃化合物的新用途 - Google Patents
苯并吡喃化合物的新用途 Download PDFInfo
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Abstract
本发明涉及苯并吡喃化合物或含至少一种苯并吡喃化合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
本发明涉及苯并吡喃化合物或含至少一种苯并吡喃化合物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1-4代表的苯并吡喃化合物是已知化合物，但有关通式1-4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NS3丝氨酸蛋白酶产生抑制来进行。即人们选择HCV NS3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1-4的多羟基-β-D-葡萄糖衍生物或含至少一个通式1-4化合物的提取物在丙肝(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1-4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1-4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1-4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1-4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1-4的化合物或药用盐或含至少一种通式1-4化合物的提取物。
本发明进一步涉及至少一种通式1-4化合物或含至少一种通式1-4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1-4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1-4一般的制备方法是：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1-4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1-4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1-4化合物。
本发明中的通式1-4化合物广泛存在于许多植物中，举例讲，例如狭叶红景天(Rhodiolakirilowii，藏文音译为：索罗玛保)，绿茶。进一步讲，通式1-4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1-4一般的制备方法是：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1-4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1-4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1-4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
索罗玛保干燥粗粉3300g用80％的乙醇在室温下进行渗漉，将渗漉液合并，40℃下减压回收溶剂，得到浸膏630g。将浸膏分散在2000ml水中，用石油醚萃取脱脂后，水相依次用氯仿、乙酸乙酯萃取(600ml×5次)，将合并后的乙酸乙酯萃取相40℃下减压回收溶剂后得到48g萃取物。将此萃取物用柱层析的方法分离精制得到化合物1-4依次为120、150、50、30mg。
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3-O-棓酰-表棓儿茶素(2)、3-O-棓酰-表儿茶素-(4→8)3-O-棓酰-表儿茶素(3)、3-O-棓酰-表棓儿茶素-(4→8)3-O-棓酰-表棓儿茶素(4)、2-O-二棓酰基-1，3，4-三棓酰基-β-D-葡萄糖、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。
实施例2
绿茶干燥粗粉1000g用80％的乙醇在室温下进行渗漉，将渗漉液合并，40℃下减压回收溶剂，得到浸膏。将浸膏分散在水中，用石油醚萃取脱脂后，水相依次用氯仿、乙酸乙酯萃取(600ml×5次)，将合并后的乙酸乙酯萃取相40℃下减压回收溶剂后得到150g萃取物。将此萃取物用柱层析的方法分离精制得到化合物1。
乙酸乙酯部分主要成分为：3-O-棓酰-表儿茶素(1)、3-O-棓酰-儿茶素、儿茶素、1，3，6-三棓酰基-β-D-葡萄糖。
这些主要成分化合物占乙酸乙酯部分50％以上。
化合物1-4的波谱数据：
化合物1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：441[(C22H18O10)-H]-，13C NMR和1H NMR数据见表1和2。鉴定为3-O-棓酰-表儿茶素[13-15]。
化合物2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：457[(C22H18O11)-H]-，13C NMR和1H NMR数据见表1和2。鉴定为3-O-棓酰-表棓儿茶素[13-15]。
化合物3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：881[(C44H34O20)-H]-，13C NMR和1H NMR数据见表1和2。鉴定为3-O-棓酰-表儿茶素-(4→8)3-O-棓酰-表儿茶素[13-15]。
化合物4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：913[(C44H36O20)-H]-，13C NMR和1H NMR数据见表1和2。鉴定为3-O-棓酰-表棓儿茶素-(4→8)3-O-棓酰-表棓儿茶素[13-15]。
表1化合物1-3 13C NMR数据(δc，CD3OD，ppm，参见式(III))
Compound 1 2 3
C环 c-2 78.6 78.6 76.4
c-3 70.0 70.0 69.8
c-4 30.7 30.7 34.6
A环 c-4a 99.4 99.5 97.1
c-5 157.9 157.9 156.2
c-6 96.6 96.6 96.3
c-7 157.7 157.2 156.2
c-8 95.9 95.9 96.0
c-8a 157.3 157.2 156.2
B环 c-1’ 131.5 130.8 131.8
c-2’ 115.1 106.9 115.0
c-3’ 145.9 146.3 145.8
c-4’ 145.9 133.8 145.5
c-5’ 116.0 146.3 116.0
c-6’ 119.4 106.9 119.8
棓酰基 c-1” 121.4 121.6 121.6
c-2” 110.2 110.3 110.3
c-3” 146.3 146.7 146.2
c-4” 139.8 139.8 139.8
c-5” 146.3 146.7 146.2
c-6” 110.2 110.3 110.3
C＝O 167.6 167.7 167.7
表2化合物1-4 1H NMR数据(δc，CD3OD，ppm，参见式(III))
Compound 1 2 3 4
C环 H-2 4.95，s 4.85，s 4.87，s 4.86，s
H-3 5.51，s 5.51，s 5.45，m 5.54，s
H-4 2.82-3.00，m 2.80-3.00，m 3.59，m 3.30，m 3.59，m 330，m
A环 H-6 5.95，s 5.95，s 5.83，s 5.95，s
H-8 5.95，s 5.95，s 6.03，s 6.05，s
B环 H-2’ 6.68，d 6.49，s 6.53，d 6.39，s
H-3’ 6.79.d 6.73，d
H-6’ 6.81，d 6.49，s 6.92，m 6.52，s
棓酰基 H-2”，6” 6.93，s 6.94，s 6.98，s 6.98，s
式(III)
实施例3
式1-4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1-4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 | 8.3(18.8) | 绿茶 |
| 2 | 40.0(87.3) | 索罗玛保 |
| 3 | 0.76(0.86) | 索罗玛保 |
| 4 | 7.0(7.6) | 索罗玛保 |
由表3可看到，式1-4化合物分别对NS3蛋白酶有良好的抑制活性。
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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 AfricanMedicinal Herb Thonningia sanguinea，J.Nat.Prod.，2000，63，676-679.
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11.(a)Kakiuchi N.，Hijikata M.，Komoda Y.，Tani T.，Hirowatan Y.，Shimotohno K.，Bacterial expression and analysis of cleavage activity of HCV serine proteinaseusing recombinant and synthetic substrate，BBRC，1995，210(3)，1059-1065.
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Claims (4)
1.至少一种下面通式1-4的化合物或其药用盐或其立体异构体在制
备用于预防和/或治疗丙型肝炎的产品中用途。
2.至少一种下面通式1-4的化合物或其药用盐或其立体异构体在制
备用于抑制HCV NS3丝氨酸蛋白酶的产品中用途。
3.含至少一种通式1-4化合物或其药用盐或其立体异构体的提取物在制备用于预防和/或治疗丙型肝炎的产品中用途。
4.用于预防和/或治疗丙型肝炎的产品，其包括至少一种通式1-4化合物或含至少一种通式1-4化合物的提取物，及载体或赋形剂。
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