CN106967147B - C27螺甾烷型甾体皂苷化合物与其药物组合物和其应用 - Google Patents
C27螺甾烷型甾体皂苷化合物与其药物组合物和其应用 Download PDFInfo
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- CN106967147B CN106967147B CN201710220703.9A CN201710220703A CN106967147B CN 106967147 B CN106967147 B CN 106967147B CN 201710220703 A CN201710220703 A CN 201710220703A CN 106967147 B CN106967147 B CN 106967147B
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Abstract
本发明涉及从百合科丫蕊花属(Ypsilandra)、延龄草属(Trillium)及重楼属(Paris)植物中分离得到的C27螺甾烷型甾体皂苷及其制备方法,以及其在制备治疗出血性疾病的药物中的应用,和其在制备治疗功能失调性子宫出血药物,以及在制备功能性日化品和保健品中的应用。本发明的方法原料易得,方法简单,易操作,所得化合物通过生物实验证明本发明的化合物具有显著的诱导血小板聚集活性,及止血活性。
Description
技术领域:
本发明属于药物领域,具体的涉及从丫蕊花属(Ypsilandra)、延龄草属(Trillium)和重楼属(Paris)植物中分离得到C27螺甾烷型甾体皂苷及其药物组合物,它们在制备治疗出血性疾病的药物,包括治疗功能失调性子宫出血的药物中的应用,以及它们在制备功能性日化品和保健品中的应用。
背景技术:
目前临床常用的止血药物很多,止血机制也很复杂,对止血药物的研究一直是个热门话题。出血诱因较多,某些疾病并发症也多伴随出血,故在应用止血药同时需要对症治疗,根据不同的出血原因、出血症状及止血药作用机制选择相应止血药物。凝血为多系统参与的复杂过程,内源性、外源性凝血途径及纤溶系统均参与该过程。血管收缩性能、血小板、血液黏稠度、凝血因子及纤溶等因素均影响止血过程。而止血药或促凝血药是能促进血液凝固而使出血停止的药物,其临床应用广泛,同时有着重要的临床价值。传统中药和药用植物来源的天然化合物具有毒性较低、来源广泛等特点,在止血方面有着独特的优势和巨大的潜力。
丫蕊花属(Ypsilandra)为百合科植物,共有5个种,主要分布于我国的西南部,全草具有清热解毒,利湿消肿,止血,用于崩漏、外伤出血等特点。我们前期的研究发现该属植物的提取物具有治疗出血性疾病活性(ZL03117694.1),在此基础上我们明确了其活性成分。延龄草属(Trillium)为百合科植物,我国有3种,分别是延龄草(T.tschonoskii)、吉林延龄草(T.kamtschaticum)和西藏延龄草(T.govanianum),主要分布于西南、西北和东北地区,具有止血、镇痛、消肿、除风湿之功效,用于治疗外伤出血、头痛、神经衰弱及无名肿毒等疾病。重楼属(Paris)为百合科植物,全属共27种,我国有21种,18种为特有种,主要分布于西南各省区,具有较强的生理活性,如止血、抗癌、抗炎、消肿、清热解毒、凉肝定惊等功效。
现有技术中未有式(Ⅰ)的C27螺甾烷甾体皂苷及其药物组合物,它们在制备治疗出血性疾病药物,包括治疗功能失调性子宫出血药物中的应用,以及它们在制备功能性日化、保健品中的应用的报道。
发明内容:
本发明的目的在于提供从丫蕊花属(Ypsilandra)、延龄草属(Trillium)和重楼属(Paris)植物中分离得到C27螺甾烷型甾体皂苷化合物,其为药物活性成分的药物组合物,其制备方法,它们在制备治疗出血性疾病的药物,包括治疗功能失调性子宫出血的药物中的应用。本发明从丫蕊花属、延龄草属和重楼属植物中分离得到C27螺甾烷型甾体皂苷,经过多次药理试验研究表明,该类化合物具有显著的诱导血小板聚聚活性,从而具有止血功效。
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:
具有下述通式(I)表示的C27螺甾烷型甾体皂苷化合物:
式I中,R1‐R3为氢、或氧、或羟基;R4为包含内侧糖为葡萄糖,2‐位连接鼠李糖基,3‐位或4‐位连接鼠李糖基或阿拉伯糖基的2‐4个糖基组成的糖链。
具体的化合物为:
式(I)中R1=H,R2=O,R3=H,R4=S1时的化合物为:小果丫蕊花皂苷D(ypsiparosideD:gentrogenin3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside);
式(I)中R1=R2=H,R3=OH,R4=S1时的化合物为:皂苷Tb(pennogenin3-O-α-L-rhanmopyranosyl-(1→2)-β-D-glucopyranoside);
式(I)中R1=R2=H,R3=OH,R4=S2时的化合物为:皂苷Tc(pennogenin3‐O‐α‐L‐rhanmopyranosyl‐(1→4)‐[α‐L‐rhanmopyranosyl‐(1→2)]‐β‐D‐glucopyranoside);
式(I)中R1=OH,R2=O,R3=H,R4=S6时的化合物为:丫蕊花皂苷M(ypsilandrosideM:(25R)‐spirost‐3β,11α‐diol‐5‐en‐12‐one‐3‐O‐α‐L‐rhanmopyranosyl‐(1→4)‐α‐L‐rhanmopyranosyl‐(1→4)‐[α‐L‐rhanmopyranosyl‐(1→2)]‐β‐D‐glucopyranoside);
式(I)中R1=R2=R3=H,R4=S6时的化合物为:重楼皂苷II(diosgenin3‐O‐α‐L‐rhanmopyranosyl‐(1→4)‐α‐L‐rhanmopyranosyl‐(1→4)‐[α‐L‐rhanmopyranosyl‐(1→2)]‐β‐D‐glucopyranoside);
式(I)中R1=R2=H,R3=OH,R4=S6时的化合物为:皂苷Tg (pennogenin3‐O‐α‐L‐rhanmopyranosyl‐(1→4)‐α‐L‐rhanmopyranosyl‐(1→4)‐[α‐L‐rhanmopyranosyl‐(1→2)]‐β‐D‐glucopyranoside);
式(I)中R1=R2=H,R3=OH,R4=S3时的化合物为:Spiroconazole A(pennogenin3‐O‐α‐L‐rhanmopyranosyl‐(1→3)‐[α‐L‐rhanmopyranosyl‐(1→2)]‐β‐D‐glucopyranoside);
式(I)中R1=R2=H,R3=OH,R4=S5时的化合物为:17‐羟基纤细薯蓣皂苷(17‐hydroxygracillin:pennogenin3‐O‐β‐D‐glucopyranosyl‐(1→3)‐[α‐L‐rhanmopyranosyl‐(1→2)]‐β‐D‐glucopyranoside);
式(I)中R1=R2=H,R3=OH,R4=S4时的化合物为:重楼皂苷H(pennogenin3‐O‐α‐L‐arabinofuranosyl‐(1→4)‐[α‐L‐rhanmopyranosyl‐(1→2)]‐β‐D‐glucopyranoside)。
本发明同时提供了上述化合物的制备方法,包括用50‐80%的甲醇或乙醇溶剂,冷浸或热回流提取丫蕊花属植物全草、延龄草属植物根茎或全草、重楼属植物根茎部分得到总浸膏,总浸膏用水分散后用有机溶剂正丁醇萃取得到萃取物或通过大孔吸附树脂得到70%乙醇或甲醇洗脱物,正丁醇萃取物或洗脱物经过各种正反相柱层析、制备及半制备HPLC分离得到所述化合物。
更具体的方法是:取干燥丫蕊花(Ypsilandra thibetica Franch.)全株,粉碎后,用75%乙醇‐水回流提取3次,每次2小时,合并提取液,减压回收溶剂得到浸膏,将浸膏分散于水,通过D‐101大孔树脂,依次用水、30%乙醇、70%乙醇、95%乙醇洗脱;回收70%乙醇洗脱物,用80‐100目硅胶拌样,经200‐300目硅胶柱层析,洗脱剂用氯仿‐甲醇‐水(10:1:0→8:2:0.2→7:3:0.5)梯度洗脱,TLC检测合并得到5部分Fr.1‐5。Fr.3(氯仿‐甲醇‐水8:2:0.2)洗脱部分经MCI Gel CHP20P柱层(甲醇‐水9:1)和反相柱层析(甲醇‐水8:2)分离得到皂苷Tb、小果丫蕊花皂苷D(ypsiparosideD)和皂苷Tc。Fr.4(氯仿‐甲醇‐水7:3:0.5)洗脱部分经MCI Gel CHP20P柱层(甲醇‐水8:2)和反相柱层析(甲醇‐水7:3)分离得到皂苷Tg、重楼皂苷Ⅱ和丫蕊花皂苷M(ypsilandroside M)。
更具体的方法为:取吉林延龄草(Trilliumkamtschaticum)全株,粉碎后,用75%乙醇回流提取3次,每次2小时,合并提取液,减压回收溶剂得到浸膏,将浸膏分散于水,通过D‐101大孔树脂,依次用水、30%乙醇、70%乙醇、95%乙醇洗脱;回收70%乙醇洗脱物,用80‐100目硅胶拌样,经200‐300目硅胶柱层析,洗脱剂用氯仿‐甲醇‐水(10:1:0→8:2:0.2→7:3:0.5→2:1:0.5)梯度洗脱,TLC检测合并得到4部分Fr.1‐4。Fr.2反相柱层析(甲醇‐水5:5→7:3)分离得到皂苷Tb;Fr.3部分通过反相柱层析(甲醇‐水6:4→1:0)和重结晶得到皂苷Tc和皂苷Tg。
本发明还提供了用于治疗出血性疾病的药物,包括治疗功能失调性子宫出血的药物组合物,其中含有治疗有效量的权利要求1化合物和药学上可接受的载体。
本发明提供本发明任意一项的化合物在制备治疗出血性疾病的药物,包括治疗功能失调性子宫出血的药物中的应用。
以及,本发明任意一项的化合物在制备功能性日化品、保健品中的应用。
本发明选择丫蕊花(Ypsilandra thibetica)、吉林延龄草(Trilliumkamtschaticum)和云南重楼(Paris polyphylla var.yunnanensis)全株或根茎为材料,进行提取、分离、结构鉴定和活性筛选等系统研究工作,从中得到9个C27螺甾烷型甾体皂苷。
本发明选择性的化合物小果丫蕊花皂苷D、丫蕊花皂苷M、重楼皂苷II、皂苷Tb、皂苷Tc、皂苷Tg、重楼皂苷H、17‐羟基纤细薯蓣皂苷和Spiroconazole A进行了体外对兔血小板聚集的活性实验,发现9个化合物均能显著诱导兔血小板聚集,具有止血功效,其EC50值从94.0到873.5μM;化合物重楼皂苷II诱导血小板聚集活性最强,其EC50值为94.0±21.0μM。
本发明的化合物和药物组合物可用于制备治疗出血性疾病药物,包括治疗功能失调性子宫出血疾病药物,以及用于制备功能性日化产品、保健品。
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。式(I)化合物为有效成分组成的药物组合物采用制药和功能性日化产品、保健品领域公认的方法制备成各种剂型、如液体制剂(注射剂、混悬剂、乳剂、溶液剂、糖浆剂等)、固体制剂(片剂、胶囊剂、颗粒剂,冲剂等)、喷剂、气雾剂等。本发明的药物可经注射(静脉注射、静脉滴注、肌肉注射、腹腔注射、皮下注射)和口服、舌下给药、粘膜透析等给药途径进行止血,包括功能失调性子宫出血等疾病的治疗。
附图说明:
图1为重楼皂苷II诱导家兔血小板聚集的药效实验结果图
图中a:Con.(DMSO,1%); b:18.75μg/mL; c:37.5μg/mL;
d:75μg/mL; e:150μg/mL; f:300μg/mL
图2为皂苷Tg诱导家兔血小板聚集的药效实验结果图
图中a:Con.(DMSO,1%); b:37.5μg/mL; c:75μg/mL;
d:150μg/mL; e:300μg/mL; f:600μg/mL
具体实施方式:
下面结合附图,本发明实施例来进一步说明本发明的实质内容,但本发明的内容并不局限于此。
下述试验中,1H‐NMR和13C‐NMR的1D、2D NMR谱由Bruker AM‐400、DRX‐500和AvanceIII600MHz超导核磁共振仪测定(TMS为内标,化学位移δ用ppm表示,耦合常数J用Hz表示);MS在甲醇中用UPLC‐IT‐TOF液相‐离子阱飞行时间质谱仪,Waters AutoSpec Premier P776三扇型双聚焦质谱仪仪器或Xevo TQ‐S超高压液相色谱三重四极杆串联质谱联用仪测定;HR‐ESI‐MS在甲醇中用6200series TOF/6500series或Agilent G6230TOF‐MS飞行时间质谱仪测定;红外光谱(IR)在Bruker Tensor‐27红外光谱仪上测定(KBr压片);紫外光谱(UV)在甲醇中用Shimazu UV‐2401PC紫外光谱仪测定;旋光在甲醇中用JASCO P‐1020DIP型数字式旋光仪测定;柱层析用硅胶G(200‐300目)或硅胶H(10‐40μ)及薄层层析均为青岛海洋华工工厂产品。反相材料分离材料(Rp‐8及Rp‐18)和反相薄层板为Merck公司产品。分析和半制备用Agilent 1260型高效液相色谱仪,半制备色谱柱为Agilent公司的ZORBAX‐SB‐C18column(5μm;25×9.4mm)。薄层层析通过5%硫酸‐乙醇溶液加热观察其斑点。
实施例1:
小果丫蕊花皂苷D、丫蕊花皂苷M、皂苷Tb、皂苷Tc、皂苷Tg及重楼皂苷II六个化合物的制备:
丫蕊花干燥全草30kg,粉碎后用75%乙醇回流提取3次(每次2小时),合并提取液,减压回收乙醇,得到水溶液。然后将水溶液通过大孔树脂(型号:YWD‐03F;用量:12L)柱,分别用水、30%EtOH、70%EtOH、95%EtOH洗脱。将70%乙醇洗脱部分的溶剂分别回收干,得到70%EtOH洗脱物1.5kg,用3kg硅胶(80‐100目)拌样,经15kg硅胶(200‐300目)湿法柱层析,用氯仿‐甲醇‐水(10:1:0→8:2:0.2→7:3:0.5)梯度洗脱,最后用甲醇洗柱,TLC检测合并后得到5个组份(Fr.1‐Fr.5)。Fr.3(氯仿‐甲醇‐水8:2:0.2)洗脱部分经MCI Gel CHP20P柱层析(甲醇‐水9:1)、反相柱层析(甲醇‐水8:2)和半制备HPLC(甲醇‐水60:40和65:35)分离得到小果丫蕊花皂苷D(1,20mg)、皂苷Tb(2,35mg)和皂苷Tc(3,40mg)。Fr.4(氯仿‐甲醇‐水7:3:0.5)洗脱部分经MCI Gel CHP20P柱层析(甲醇‐水8:2)和反相柱层析(甲醇‐水7:3)分离得到丫蕊花皂苷M(4,120mg)、重楼皂苷Ⅱ(5,200mg)和皂苷Tg(6,3 00mg)。
实施例2:
皂苷Tb、皂苷Tc和皂苷Tg三个化合物的制备:
干燥吉林延龄草(Trilliumkamtschaticum)全草(10kg)粉碎后分别用75%乙醇回流提取3次,每次2h,合并提取液,减压回收乙醇。用正丁醇对回收液萃取三次,减压浓缩回收,得到正丁醇萃取物839.4g。正丁醇萃取物溶解后,经大孔吸附树脂柱,分别用水、30%EtOH、70%EtOH、95%EtOH洗脱。将70%EtOH洗脱部分的溶剂分别回收干,得到70%EtOH洗脱物170.2g。70%乙醇洗脱部位经过MCI脱色后,用1700g硅胶(300‐400目)进行干法装柱上样,用氯仿‐甲醇‐水(8:2:0.2,7:3:0.5)梯度洗脱,TLC检测后合并得到4个部分Fr.1‐4。Fr.2通过反相柱层析(甲醇‐水5:5→7:3)分离得到皂苷Tb(2,209.0mg);Fr.3(86.3g)经硅胶柱层析,氯仿‐甲醇‐水(8:2:0.2,7:3:0.5)梯度洗脱细分为5个部分Fr.2.1(6.4g),Fr.2.2(13.8g),Fr.2.3(9.6g),Fr.2.4(7.8g),Fr.2.5(26.4g);分别将这五部分,反复使用硅胶柱层析(氯仿‐乙醇‐水8:2:0.2→7:3:0.5v/v),Sephadex LH‐20(氯仿‐甲醇1:1),和进一步使用高效液相半制备(乙腈‐水30%→60%v/v)分离纯化得到化合物皂苷Tc(3,100.8mg)和皂苷Tg(6,200.0mg)。
实施例3:
皂苷Tb、皂苷Tg、重楼皂苷II、17‐羟基纤细薯蓣皂苷、Spiroconazole A和重楼皂苷H、六个化合物的制备:
云南重楼(Paris polyphylla var.yunnanensis)干燥根茎5kg,粉碎后用75%乙醇回流提取3次(每次2小时),合并提取液,减压回收乙醇,得到水溶液。然后将水溶液通过大孔树脂(型号:D‐101)柱,分别用水、30%EtOH、70%EtOH、95%EtOH洗脱。将70%洗脱部分的溶剂分别回收干,得到70%EtOH洗脱物225g,用450g硅胶(80‐100目)拌样,经2200g硅胶(200‐300目)湿法柱层析,用氯仿‐甲醇‐水(10:1:0→8:2:0.2→7:3:0.5)梯度洗脱,最后用甲醇洗柱,TLC检测合并后得到4个组份(Fr.1‐Fr.5)。Fr.3(氯仿‐甲醇‐水8:2:0.2)部分经硅胶柱层(氯仿‐甲醇‐水10:1:0→8:2:0.2)、反相柱层析(甲醇‐水8:2→9:1)和半制备HPLC(甲醇‐水60:40和65:35)分离得到皂苷Tb(2,22mg)、Spiroconazole A(7,16mg)、重楼皂苷H(8,18mg)和17‐羟基纤细薯蓣皂苷(9,14mg)。Fr.4部分经过硅胶柱层(氯仿‐甲醇‐水8:2:0.2→7:3:0.5)和反相柱层析(甲醇‐水7:3→8:2)分离得到重楼皂苷Ⅱ(5,120mg)和皂苷Tg(6,50mg)。
小果丫蕊花皂苷D(1)的物理常数和波谱数据:白色无定形粉末;[α]2 D 1–80.4(c0.7,MeOH);IR(KBr)νmax(cm-1):3428,2930,2909,1707,1637,1454,1381,1048,981,919,899,868(intensity:899>919cm-1);positive ESI‐MS:m/z 759[M+Na]+;HR‐ESI‐MS:m/z759.3929[M+Na]+(calcd for C39H60O13Na,759.3932);1H NMR(C5D5N,400MHz)和13C NMRdata(C5D5N,100MHz)见表1。
表1.化合物1的1H‐和13C‐NMR数据(in C5D5N,δin ppm,J in Hz)a.
表2.化合物2‐6的13CNMR数据(in C5D5N;δin ppmz).
皂苷Tb(2)的物理常数和波谱数据:C39H62O13;白色无定形粉末;ESI‐MS m/z 761[M+Na]+;1H NMR date(C5D5N,500MHz):δH5.28(1H,d,4.4,H‐6),0.95(3H,s,Me‐18),1.08(3H,s,Me‐19),0.67(3H,d,J=7.2Hz,H‐21),1.23(3H,d,J=7.2Hz,H‐27),6.40(1H,br s,H‐1”),5.04(1H,br s,H‐1'),1.77(3H,d,J=6.2Hz,H‐6”);13C NMR date(C5D5N,125MHz)见表2。
皂苷Tc(3)的物理常数和波谱数据:C45H72O17;白色无定形粉末;ESI‐MS m/z 907[M+Na]+;1H NMR date(C5D5N,500MHz):δH5.26(1H,br d,H‐6),0.94(3H,s,Me‐18),1.07(3H,s,Me‐19),0.66(3H,d,J=7.2Hz,H‐21),1.22(3H,d,J=7.2Hz,H‐27),6.42(1H,br s,H‐1”),5.87(1H,br s,H‐1”'),4.82(1H,br d,H‐1'),1.76(3H,d,J=6.2Hz,H‐6”),1.62(3H,d,J=6.2Hz,H‐6”');13C NMR date(C5D5N,125MHz)见表2。
丫蕊花皂苷M(4)的物理常数和波谱数据:白色无定形粉末;(c 0.1,MeOH);IR(KBr)νmax cm‐1:3441,2932,2875,1710,1638,1456,1383,1051,981,919,899,and866(intensity:899>919);ESI‐MS(negative ion mode)m/z:1043[M‐H]‐;HR‐ESI‐MS(negative)m/z:1043.5057([M‐H]‐,C51H79O22;calc.1043.5063);1H NMR(C5D5N,500MHz):δH1.87(m,H‐1a)1.23(m,H‐1b),2.04(m,H‐2a)1.92(m,H‐2b),3.88(m,H‐3),2.83(m,H‐4a),2.77(t,J=11.8Hz,H‐4b),5.33(d,J=3.9Hz,H‐6),1.80(m,H‐7a),1.49(m,H‐7b),1.46(m,H‐8),1.40(m,H‐9),4.72(d,J=9.9Hz,H‐11),1.41(m,H‐14),2.09(m,H‐15a),1.80(m,H‐15b),4.44(m,H‐16),2.87(m,H‐17),1.11(s,Me‐18),1.36(s,Me‐19),1.85(m,H‐20),1.29(d,J=6.9Hz,Me‐21),1.65(m,H‐23a),1.61(m,H‐23b),1.52(m,H2‐24),1.57(m,H‐25),3.56(m,H‐26a),3.45(t,J=10.5Hz,H‐26b),0.68(d,J=5.5Hz,Me‐27),4.97(d,J=7.0Hz,H‐1'),4.15(d,J=11.6Hz,H‐6'a),4.02(d,J=11.1Hz,H‐6'b),6.41(br s,H‐1”),1.59(d,J=5.8Hz,Me‐6”),5.85(br s H‐1”'),1.59(d,J=5.8Hz,Me‐6”'),6.29(br s H‐1””),1.77(d,J=6.2Hz,Me‐6””);13C NMR(C5D5N,125MHz)见表2。
重楼皂苷II(5)的物理常数和波谱数据:白色针晶(甲醇);positive ESI‐MS:m/z1037[M+Na]+;1H NMR(500MHz,C5D5N):δH6.41(brs,H‐1”),6.29(brs,H‐1””),5.85(brs,H‐1”'),5.30(brs,H‐6),4.95(d,J=7.2Hz,H‐1'),1.76(d,J=5.8Hz,H‐6”),1.59(d,J=5.5Hz,H‐6”'),1.59(d,J=5.5Hz,H‐6””),1.12(d,J=6.6Hz,Me‐21),1.04(s,Me‐19),0.81(s,Me‐18),0.67(brs,Me‐27);13C NMR(C5D5N,125MHz)见表2。
皂苷Tg(重楼皂苷VII,6)的物理常数和波谱数据:C45H72O17;无色针晶;(c=0.08MeOH);ESI‐MS m/z 1053[M+Na]+;1H NMR date(C5D5N,500MHz):δH5.28(1H,br d,H‐6),0.95(3H,s,Me‐18),1.07(3H,s,Me‐19),0.67(3H,d,,J=7.2Hz,H‐21),1.22(3H,d,J=7.2Hz,H‐27),6.39(1H,br s,H‐1”),6.29(1H,br s,H‐1”'),5.84(1H,br s,H‐1””),4.92(1H,br d,H‐1'),1.76(3H,d,J=6.2Hz,H‐6”),1.59(3H,d,J=6.2Hz,H‐6”'),1.59(3H,d,J=6.2Hz,H‐6””);13C NMR date(C5D5N,125MHz)见表2。
Spiroconazole A(7)的物理常数和波谱数据:C45H72O17;白色无定形粉末;1H‐NMR(500MHz,C5D5N):δH 5.10(1H,overlap,H‐6),4.47(1H,m,H‐16),0.67(3H,s,H‐18),0.94(3H,s,H‐19),1.22(3H,d,J=7.1Hz, H‐21),1.53(3H,m,H‐27),3‐Glc:4.87(1H,d,J=8.0Hz,H‐1′),2‐Rha:5.85(1H,s,H‐1″),1.74(3H,d,J=6.2Hz,H‐6″),3‐Rha 5.76(1H,s,H‐1″′),1.64(3H,d,J=6.1Hz,H‐6″′);13C‐NMR(125MHz,C5D5N):δC 37.5(t,C‐1),30.1(t,C‐2),78.5(d,C‐3),38.8(t,C‐4),140.7(s,C‐5),121.9(d,C‐6),31.9(t,C‐7),32.4(d,C‐8),50.2(d,C‐9),37.1(s,C‐10),19.5(t,C‐11),32.5(t,C‐12),45.2(s,C‐13),53.1(d,C‐14),31.9(t,C‐15),90.2(d,C‐16),90.0(s,C‐17),17.4(q,C‐18),19.5(q,C‐19),44.8(d,C‐20),9.9(q,C‐21),109.9(s,C‐22),28.9(t,C‐23),32.2(t,C‐24),30.5(d,C‐25),66.7(t,C‐26),17.2(q,C‐27);糖基部分3‐Glc:99.9(d,C‐1′),78.2(d,C‐2′),87.2(d,C‐3′),70.7(d,C‐4′),77.8(d,C‐5′),62.3(t,C‐6′);2′‐Rha:102.7(d,C‐1″),72.5(d,C‐2″),72.8(d,C‐3″),73.9(d,C‐4″),69.9(d,C‐5″),18.8(q,C‐6″);3′‐Rha:103.9(d,C‐1″′),72.6(d,C‐2″′),72.7(d,C‐3″′),73.6(d,C‐4″′),70.0(d,C‐5″′),18.5(q,C‐6″′)。
重楼皂苷H(8)的物理常数和波谱数据:C44H70O17;白色无定形粉末;FAB‐MS m/z:869[M‐H]‐;1H‐NMR(C5D5N,600MHz):δH0.92(3H,s,Me‐18),0.99(3H,s,Me‐19),1.23(3H,d,J=6.7Hz,Me‐21),0.76(3H,d,J=4.9Hz,Me‐27),1.79(1H,d,J=6.1Hz,Rha‐H‐6”),3.86(1H,m,H‐3),5.88(1H,br s,H‐6),4.94(1H,d,J=7.3Hz,H‐1'),6.28(1H,br s,H‐1”),和5.92(1H,br s,H‐1”');13C‐NMR(C5D5N,150MHz):δC37.6(t,C‐1),30.3(t,C‐2),78.2(d,C‐3),39.4(t,C‐4),141.0(s,C‐5),121.1(d,C‐6),32.6(t,C‐7),32.5(d,C‐8),50.5(d,C‐9),37.6(s,C‐10),21.1(t,C‐11),32.2(t,C‐12),45.2(s,C‐13),53.2(d,C‐14),32.3(t,C‐15),90.1(d,C‐16),90.2(d,C‐17),17.3(q,Me‐18),19.7(q,Me‐19),45.0(d,C‐20),9.6(q,Me‐21),110.6(s,C‐22),32.5(d,C‐23),29.5(t,C‐24),40.4(d,C‐25),63.1(t,C‐26),19.6(q,Me‐27);糖基部分3‐Glc:100.2(d,C‐1'),78.2(d,C‐2'),77.6(d,C‐3'),77.0(d,C‐4'),77.4(d,C‐5'),62.8(t,C‐6');2′‐Rha:102.2(d,C‐1”),73.2(d,C‐2”),72.5(d,C‐3”),74.4(d,C‐4”),69.9(d,C‐5”),19.2(q,C‐6”);4′‐Ara:109.9(d,C‐1”'),83.2(d,C‐2”'),78.2(d,C‐3”'),87.1(d,C‐4”'),61.9(t,C‐5”')。
17‐羟基纤细薯蓣皂苷(9)的物理常数和波谱数据:C45H72O18;白色无定形粉末;1H‐NMR(C5D5N,500MHz):δH 0.96(3H,s,Me‐18),1.08(3H,s,Me‐19),0.67(3H,d,J=7.2Hz,H‐21),1.24(3H,d,J=7.2Hz,H‐27),1.74(d,J=6.2Hz,H‐6”),5.28(1H,d,J=4.1Hz,H‐6),4.93(d,J=7.2Hz,H‐1'),6.38(br s,H‐1”),5.09(d,J=7.7Hz,H‐1”');13C‐NMR(C5D5N,125MHz):δC37.5(t,C‐1),30.0(t,C‐2),77.7(d,C‐3),38.6(t,C‐4),140.6(s,C‐5),121.6(d,C‐6),32.1(t,C‐7),31.6(d,C‐8),50.0(d,C‐9),37.0(s,C‐10),21.1(t,C‐11),32.4(t,C‐12),44.7(s,C‐13),53.2(d,C‐14),32.1(t,C‐15),90.1(d,C‐16),90.2(d,C‐17),17.3(q,Me‐18),19.6(q,Me‐19),45.0(d,C‐20),9.5(q,Me‐21),109.7(s,C‐22),31.8(d,C‐23),28.7(t,C‐24),30.3(d,C‐25),66.7(t,C‐26),17.2(q,Me‐27);糖基部分3‐Glc:99.7(d,C‐1'),77.2(d,C‐2'),89.0(d,C‐3'),69.2(d,C‐4'),77.9(d, C‐5'),62.1(t,C‐6');2′‐Rha:101.8(d,C‐1”),72.3(d,C‐2”),72.3(d,C‐3”),73.5(d,C‐4”),69.3(d,C‐5”),18.4(q,C‐6”);3'‐Glc:104.1(d,C‐1”'),74.5(d,C‐2”'),78.2(d,C‐3”'),71.1(d,C‐4”'),77.9(d,C‐5”'),62.1(t,C‐6”')。
实施例4:
将实施例1所制得的小果丫蕊花皂苷D(1)、丫蕊花皂苷M(4)、皂苷Tb(2)、皂苷Tc(3)、重楼皂苷II(5)及皂苷Tg(6)六个化合物与赋形剂重量比为9:1的比例加入赋形剂,制成粉剂。
实施例5:
按实施2的方法制得的皂苷Tb(2)、皂苷Tc(3)及皂苷Tg(6)三个化合物与赋形剂重量比为9:1的比例加入赋形剂,制成粉剂。
实施例6:
按实施3的方法制得的皂苷Tb(2)、17‐羟基纤细薯蓣皂苷(9)、Spiroconazole A(7)、重楼皂苷H(8)、重楼皂苷II(5)和皂苷Tg(6)六个化合物的与赋形剂重量比为9:1的比例加入赋形剂,制成粉剂。
实施例7:
按实施例1的方法制得的小果丫蕊花皂苷D(1)、丫蕊花皂苷M(4)、皂苷Tb(2)、皂苷Tc(3)、重楼皂苷II(5)及皂苷Tg(6)六个化合物,按其与赋形剂重量比为1:5‐1:10的比例加入赋形剂,制粒压片。
实施例8:
按实施2的方法制得的皂苷Tb(2)、皂苷Tc(3)及皂苷Tg(6)三个化合物,按其与赋形剂重量比为1:5‐1:10的比例加入赋形剂,制粒压片。
实施例9:
按实施例1、2的方法制得的小果丫蕊花皂苷D(1)、丫蕊花皂苷M(4)、皂苷Tb(2)、皂苷Tc(3)、重楼皂苷II(5)及皂苷Tg(6)六个化合物,按其与赋形剂重量比为5:1的比例加入赋形剂,制成胶囊或颗粒剂或冲剂。
实施例10:
按实施例1、2的方法制得的小果丫蕊花皂苷D(1)、丫蕊花皂苷M(4)、皂苷Tb(2)、皂苷Tc(3)、重楼皂苷II(5)及皂苷Tg(6)六个化合物,按其1加入,N‐月桂酰肌氨酸钠5,月桂醇硫酸钠0.5,磷酸氢钙二水合物5,海藻胶0.9,二氧化钛0.4,苯甲酸钠0.5,香精适量,精制加水至100。制成膏状,作为牙膏等功能性日化品。
实施例11:
为了更好地说明本发明的药理活性试验结果和本发明的优异性,下面将用本发明的化合物小果丫蕊花皂苷D(1)、皂苷Tb(2)、皂苷Tc(3)、丫蕊花皂苷M(4)、重楼皂苷II(5)、皂苷Tg(6)、Spiroconazole A(7)、重楼皂苷H(8)和17‐羟基纤细薯蓣皂苷(9)诱导兔血小板聚集活性试验来说明,但并不以此来限定本发明。
日本大耳白兔耳中央用乙醇消毒液擦拭后,用医用一次性采血针经耳中央动脉抽取血液(枸橼酸钠真空抗凝采血管,全血:枸橼酸钠为9:1),轻轻颠倒采血管次使血液和抗凝剂混合均匀。所得抗凝血离心(200×g,10min),收集上清液为富血小板血浆(PRP);剩余血液再次离心(2400×g,20min),收集上清液为贫血小板血浆(PPP),以PPP调PRP血小板计数为500×109个/L(参考文献:Küster LJ,Filep J,JC.Mechanism of PAF‐inducedplatelet aggregation in man.Thromb.Res.1986,43(4):425‐33;Born,G.V.R.Aggregation of blood platelets by adenosine diphosphate and itsreversal.Nature 1962,194:927–929;Yin H,Litvinov RI,Vilaire G,Zhu H,Li W,Caputo GA,Moore DT,Lear JD,Weisel JW,Degrado WF,Bennett JS.Activation ofplatelet αIIbβ3 by an exogenouspeptide corresponding to thetransmembranedomain ofαIIb.J.Biol.Chem.2006,281:36732–41)。将带搅拌子的比色杯与不带搅拌子的比色杯分别置于血小板聚集仪预温孔,37℃预温10min。向预温好的带搅拌子的比色杯中加入250μL PRP,不带搅拌子的比色杯中加入250μL PPP,同时加入2.5μL溶解样品所用的溶媒。然后继续预温5min后,将两比色杯分别放入PRP测试位和PPP测试位。
调整记录曲线的基线,首先按照单体化合物300μg/mL剂量向PRP测试杯中加入受试样品,记录血小板聚集曲线并计算最大聚集率。在此浓度下具有显著诱导血小板聚集活性的化合物,按表3所示剂量向PRP测试杯中加入诱导剂或受试样品,记录血小板聚集曲线并计算最大聚集率,并计算EC50。阳性对照药ADP试剂配制按照说明书配制成1mM溶液分装成100μL/管,‐80℃冻存备用。
结果表明这9个化合物在300μg/mL的浓度下,均有明显诱导兔血小板聚集的作用。进而测定这9个化合物诱导兔血小板聚集的EC50值,结果如表3所示;其中化合物5(重楼皂苷II)诱导兔血小板聚集的活性最强,其EC50值为94.0±21.0μM。
表3.发明化合物诱导兔血小板聚集量效关系的实验结果(n=3)
综上,对本发明化合物小果丫蕊花皂苷D、丫蕊花皂苷M、重楼皂苷II、皂苷Tb、皂苷Tc、皂苷Tg、重楼皂苷H、17‐羟基纤细薯蓣皂苷和Spiroconazole A进行了体外对兔血小板聚集的活性实验,发现9个化合物均能显著诱导兔血小板聚集,具有止血功效,其EC50值从94.0到873.5μM;化合物重楼皂苷II诱导血小板聚集活性最强,其EC50值为94.0±21.0μM。
Claims (7)
1.C27螺甾烷型甾体皂苷类化合物的制备方法,其特征在于:取干燥丫蕊花全草粉碎,用75%乙醇回流提取3次,每次2小时,合并提取液,减压回收乙醇,得到水溶液,然后将水溶液通过大孔树脂柱,分别用水、30%EtOH、70%EtOH、95%EtOH洗脱,将70%EtOH洗脱部分的溶剂回收干,得到70%EtOH洗脱物,用80-100目硅胶拌样,经200-300目硅胶湿法柱层析,用10:1:0→8:2:0.2→7:3:0.5的氯仿-甲醇-水梯度洗脱,TLC检测合并后得到5个组份Fr.1-Fr.5;Fr.3部分经MCI Gel CHP20P柱层用甲醇-水9:1、反相柱层析甲醇-水8:2和半制备HPLC甲醇-水60:40和65:35分离得到小果丫蕊花皂苷D、皂苷Tb和皂苷Tc;Fr.4部分经MCIGel CHP20P柱层用甲醇-水8:2和反相柱层析甲醇-水7:3分离得到丫蕊花皂苷M、重楼皂苷Ⅱ和皂苷Tg。
2.C27螺甾烷型甾体皂苷类化合物的制备方法,其特征在于:取干燥吉林延龄草根茎或全株粉碎,用75%乙醇回流提取3次,每次2h,合并提取液,减压回收乙醇,用正丁醇对回收液萃取三次,减压浓缩回收,得到正丁醇萃取物,正丁醇萃取物溶解后,经大孔吸附树脂柱,分别用水、30%EtOH、70%EtOH、95%EtOH洗脱,将70%EtOH洗脱部分的溶剂分别回收干,得到70%EtOH洗脱物,70%乙醇洗脱部位经过MCI脱色后,硅胶拌样,用300-400目硅胶进行干法装柱上样,用8:2:0.2,7:3:0.5氯仿-甲醇-水梯度洗脱,TLC检测后合并得到4个部分Fr.1-4,Fr.2通过反相柱层析甲醇-水5:5→7:3分离得到皂苷Tb;Fr.3反复使用硅胶柱层析氯仿-乙醇-水8:2:0.2→7:3:0.5v/v和高效液相半制备乙腈-水30%→60%v/v分离纯化得到化合物皂苷Tc和皂苷Tg。
3.C27螺甾烷型甾体皂苷类化合物的制备方法,其特征在于:取云南重楼干燥根茎粉碎,用75%乙醇回流提取3次,每次2小时,合并提取液,减压回收乙醇,得到水溶液,然后将水溶液通过大孔树脂柱,分别用水、30%EtOH、70%EtOH、95%EtOH洗脱,将70%EtOH洗脱部分的溶剂分别回收干,得到70%EtOH洗脱物,用80-100目硅胶拌样,经200-300目硅胶湿法柱层析,用10:1:0→8:2:0.2→7:3:0.5的氯仿-甲醇-水梯度洗脱,TLC检测合并后得到5个组份Fr.1-Fr.5;Fr.3部分经硅胶柱层、洗脱剂氯仿-甲醇-水10:1:0→8:2:0.2、反相柱层析甲醇-水8:2→9:1和半制备HPLC甲醇-水60:40和65:35分离得到皂苷Tb、Spiroconazole A、重楼皂苷H和17-羟基纤细薯蓣皂苷;Fr.4部分经硅胶柱8:2:0.2→7:3:0.5的氯仿-甲醇-水和反相柱层析甲醇-水7:3→8:2分离得到重楼皂苷Ⅱ和皂苷Tg。
4.权利要求1所述C27螺甾烷型甾体皂苷类化合物的制备方法,其特征在于,制备得到的化合物小果丫蕊花皂苷D的结构如下图所示:
式(I)中,R1=H,R2=O,R3=H,R4=S1。
5.权利要求1-3任一所述C27螺甾烷型甾体皂苷类化合物的制备方法,其特征在于,制备得到的小果丫蕊花皂苷D、丫蕊花皂苷M、重楼皂苷II、Spiroconazole A、17-羟基纤细薯蓣皂苷或重楼皂苷H可用于制备治疗出血性疾病的药物。
6.权利要求5所述的制备方法,其特征在于,所述出血性疾病为功能失调性子宫出血。
7.权利要求5所述的制备方法,其特征在于,用于制备功能性日用化妆品或保健品中。
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