CN115073463B - 一类苦参碱型二聚体生物碱类化合物、其药物组合物及其应用 - Google Patents
一类苦参碱型二聚体生物碱类化合物、其药物组合物及其应用 Download PDFInfo
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- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
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- A—HUMAN NECESSITIES
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
本发明属于医药技术领域，具体公开了一类苦参碱型二聚体生物碱类化合物及其制备方法、药物组合物和用途，具体而言，本发明涉及式(I)所示的生物碱化合物或其药学上可接受的盐或其立体异构体及其制备方法，含有一个或多个该类化合物的组合物，和该类化合物在制备预防和/或治疗肝损伤相关的疾病药物中的用途。
Description
技术领域
本发明属于医药领域，涉及药物纯化鉴定和药理学领域，具体而言，涉及一类从苦豆子中分离得到的苦参碱型二聚体生物碱类新骨架化合物或其药学上可接受的盐及其在制备预防、缓解和/或治疗肝损伤药物中的应用。
背景技术
肝脏是人类与动物最重要的器官之一，是内源性和外源性物质代谢清除最主要的场所，在药物代谢和外源性毒性物质解毒过程中肝脏扮演着最重要的角色，但它极容易遭受到多种因素的损伤，如：肝炎病毒、药物毒性、食物发霉或酒精等。由这些因素引发的急性肝损伤(Acute liver failure，ALF)会导致肝细胞大面积坏死或凋亡、肝细胞脂肪变性、炎症反应以及氧化应激，甚至肝功能损害，严重的肝脏损伤导致肝脏功能的丧失并进展成为肝衰竭，进而可能引发肝纤维化、肝硬化或者肝癌。因此，采取有效改善肝脏损伤的措施，可能对肝脏疾病的防治起到至关重要作用
苦豆子(Sophora alopecuroides)是豆科(Leguminosae)槐属多年生草本或矮灌木植物，其全草、根及种子均可入药，具有清热解毒、抗菌消炎的作用。化学成分研究结果表明，苦豆子含有生物碱类、黄酮类、挥发油、多糖等多种成分，其中生物碱类是苦豆子的主要活性成分。现代药理研究结果表明，苦豆子生物碱具有抗肿瘤、抑菌、抗病毒、抗肝纤维化、抗肝损伤等药理作用。
发明内容
本发明解决的技术问题是提供一类苦豆子中的新骨架生物碱，及其制备方法、药物组合物和制备预防、缓解和/或治疗肝损伤药物中的应用。
申请者研究发现苦豆子生物碱具有抗肝损伤的功效，并从苦豆子中分离得到了一类具有11个连续手性中心的6/6/6/6/4/6/6/6/6九环结构的新骨架生物碱，化学结构如下。经药理学实验证明，化合物1能够有效缓解对乙酰氨基酚(APAP)诱导的肝细胞毒性、减少肝细胞凋亡。体内试验结果表明，在APAP诱导的小鼠急性肝损伤(ALF)模型中，化合物1能够降低APAP的毒性，减轻肝脏组织病理学改变；降低丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)水平；超氧化物歧化酶(SOD)和谷胱甘肽(GSH)的耗竭、肝细胞坏死以及肝脏出血均被明显抑制。
为解决本发明的技术问题，本发明提供了如下技术方案：
本发明技术方案的第一方面提供了一种式(I)所示的化合物或其药学上可接受的盐或其立体异构体，其特征在于，该化合物的结构如下：
其中：
R选自氧或无。
上述的药学上可接受的盐是指为药学上可接受的并且具有母体化合物所需的药理活性的盐，选自化合物与相应的有机酸、无机酸反应形成的药学上可接受的盐。所述的有机酸盐包括，但并不限于丙二酸盐、酒石酸盐、枸橼酸盐、马来酸盐、乳酸盐、水杨酸盐、苹果酸盐、苯甲酸盐、己二酸盐、富马酸盐或琥珀酸盐，所述的无机酸盐包括盐酸盐、硫酸盐、磷酸盐或氢溴酸盐。
进一步的，所述的化合物选自：
本发明技术方案的第二方面提供了第一方面所述化合物或其药学上可接受的盐的制备方法，其制备方法如下：苦豆子粉碎后使用去离子水提取，浓缩液加1％盐酸调至PH＝3.0左右，用二氯甲烷连续萃取苦豆子浓缩液，取酸性部位浓缩后使用氨水调至PH＝10.0左右，以上述同样条件使用二氯甲烷连续萃取，将碱性部位减压浓缩后获得苦豆子总生物碱，取苦豆子总生物碱进行大孔吸附树脂层析、MCI、硅胶柱层析及半制备型HPLC分离纯化，得到化合物经UV、IR、NMR、MS及CD等谱学手段分析鉴定化合物结构，目前未有该骨架类型的报道。
本发明技术方案的第三方面提供了一种药物组合物，所述的药物组合物包括本发明第一方面所述有效剂量的一种或多种化合物或其药学上可接受的盐或其立体异构体和药学上可接受的载体或赋形剂。
根据本发明的实施例，所述的药物组合物的给药途径为口服剂或注射剂。
根据本发明的实施例，所述的药物组合物的给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型，其他剂型例如片剂、胶囊、滴丸、丸剂、粉剂、颗粒剂、栓剂、冻干粉针剂等。
根据本发明的实施例，所述的药物组合物的口服剂包括片剂、胶囊剂、丸剂、颗粒剂、散剂、滴丸剂、口服液或混悬剂，所述的药物组合物的注射剂包括溶液剂、混悬剂或乳剂。
根据本发明的实施例，所述的药物组合物可以制成普通制剂、也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
通常本发明药物组合物含有0.1～95重量％的本发明化合物。在单元剂型中本发明化合物一般含量为0.1～100mg，优选的单元剂型含有4～50mg。
本发明技术方案的第四方面是提供本发明第一方面所述化合物或其药学上可接受的盐或其立体异构体在制备预防、缓解和/或治疗肝损伤药物中的应用。所述的肝损伤选自药物性肝损伤、酒精性肝损伤、脂肪性肝损伤或病毒性肝损伤。
有益技术效果：
1、本发明的一类苦豆子中的新骨架生物碱具有明显的防治肝损伤的作用，经药理学实验证明化合物1能够有效缓解APAP诱导的肝细胞毒性、减少肝细胞凋亡。体内试验结果表明，在APAP诱导的ALF小鼠模型中，化合物1能够降低APAP的毒性，减轻肝脏组织病理学改变，降低ALT和AST水平，SOD和GSH的耗竭、肝细胞坏死以及肝脏出血均被明显抑制。
2、本发明的一类具有11个连续手性中心的6/6/6/6/4/6/6/6/6九环结构的新骨架生物碱，未有文献报道，具有进一步开发成防治肝损伤方面药物的潜力。
附图说明
图1是根据本发明实施例的化合物1对APAP诱导的HepG2细胞毒性作用的影响结果示意图；
图2是根据本发明实施例的化合物1对APAP诱导的HepG2细胞凋亡的影响结果示意图；
图3是根据本发明实施例的化合物1对APAP诱导的ALF小鼠血清中ALT和AST水平的影响结果示意图；
图4是根据本发明实施例的化合物1对APAP诱导的ALF小鼠肝组织病理学的影响结果示意图；
图5是根据本发明实施例的化合物1对APAP诱导的ALF小鼠肝组织氧化损伤的影响结果示意图。
具体实施方式
下面的实施例及药理活性实验用于进一步说明本发明，但这并不意味着对本发明的任何限制。
实施例1苦豆子中单体化合物的制备及鉴定
干燥的苦豆子(50kg)粉碎后过60目筛，使用去离子水提取，提取温度80℃，每次3h，共3次。提取液浓缩后加1％盐酸调至PH＝3.0左右，用二氯甲烷连续萃取。取酸性部位浓缩后使用氨水调至PH＝10.0左右，使用二氯甲烷连续萃取，将碱性部位减压浓缩后获得苦豆子总生物碱。取苦豆子总生物碱(500g)上样HP-20大孔吸附树脂层析柱，使用乙醇-水梯度洗脱(0、20％、40％、60％、95％)，共获得21个馏分(Fr.A～U)。馏分Fr.T(12g)继续使用MCI微孔树脂层析分离，65％乙醇-水等度洗脱分离得到18个亚馏分(Fr.T1～T18)，亚馏分Fr.T16(2g)通过乙醇-水梯度洗脱的MCI微孔树脂柱色谱分离得到12个馏分(Fr.T16.1～T16.12)。Fr.T16.8(86.5mg)通过半制备HPLC(甲醇/水，含0.1‰二乙胺，60:40，v：v；流速3mL/min；检测波长254nm)纯化后得到化合物1。Fr.T16.11(11mg)通过半制备HPLC(甲醇/水，含0.1‰二乙胺，62:38，v：v；流速3mL/min；检测波长254nm)纯化后得到化合物2和化合物3。化合物结构经UV、IR、NMR、MS、X-ray及CD等谱学手段分析鉴定。
上述新骨架化合物的波谱信息及核磁信号归属如下：
化合物1
无色晶体(甲醇)；+35.0(c 1.0,CH3OH)；UV(CH3OH)λmax(logε):204(3.27)；IRνmax:2927、2858、1666、1616、1424、1292、1125、981和824cm-1；1H NMR(CD3OD,500MHz)δH:2.89(1H,overlapped,H-2a),3.00(1H,overlapped,H-2b),1.31(1H,m,H-3a),1.85(1H,m,H-3b),1.16(1H,m,H-4a),1.59(1H,m,H-4b),2.06(1H,m,H-5),3.58(1H,overlapped,H-6),1.89(1H,m,H-7),1.53(1H,m,H-8a),1.16(1H,m,H-8b),1.76(1H,m,H-9a),1.55(1H,m,H-9b),2.41(1H,brd,H-10a),3.02(1H,overlapped,H-10b),3.25(1H,overlapped,H-12),6.36(1H,dd,J＝10.0,5.5Hz,H-13),5.80(1H,d,J＝10.0Hz,H-14),2.65(1H,overlapped,H-17a),4.06(1H,dd,J＝13.5,4.5Hz,H-17b),1.97(1H,m,H-2′a),2.78(1H,m,H-2′b),1.45(1H,m,H-3′a),1.70(1H,m,H-3′b),1.51(1H,m,H-4′a),1.62(1H,m,H-4′b),1.65(1H,m,H-5′),2.11(1H,m,H-6′),1.38(1H,m,H-7′),1.45(1H,m,H-8′a),1.83(1H,m,H-8′b),1.45(1H,m,H-9′a),1.61(1H,m,H-9′b),1.97(1H,m,H-10′a),2.79(1H,m,H-10′b),3.67(1H,td,J＝11.0,3.0Hz,H-11′),2.16(1H,m,H-12′a),1.62(1H,m,H-12′b),2.67(1H,m,H-13′),3.23(1H,overlapped,H-14′),3.07(1H,overlapped,H-17′a),4.25(1H,dd,J＝13.5,4.5Hz,H-17′b)；13C NMR(CD3OD,125MHz)δC:54.8(C-2),19.8(C-3),29.5(C-4),27.6(C-5),58.9(C-6),51.6(C-7),19.9(C-8),25.9(C-9),45.5(C-10),71.0(C-11),39.6(C-12),138.7(C-13),125.6(C-14),165.7(C-15),42.2(C-17),58.3(C-2′),22.0(C-3′),28.7(C-4′),35.7(C-5′),64.1(C-6′),44.9(C-7′),27.4(C-8′),21.7(C-9′),58.2(C-10′),53.2(C-11′),29.4(C-12′),32.8(C-13′),51.3(C-14′),170.8(C-15′),42.2(C-17′)；HRESIMSm/z 491.3382[M+H]+(calcd for 491.3380)。
化合物2
+75.0(c 1.0,CH3OH)；UV(CH3OH)λmax(logε):209(3.41)nm；IRνmax:2939,2514,1686,1615,1440,1291,1200,1127,826,799,720cm-1；1H NMR(CD3OD,500MHz)δH:3.41(1H,dd,J＝13.5,3.5Hz,H-2a),3.51(1H,d,J＝13.5Hz,H-2b),1.85(1H,m,H-3a),1.93(1H,m,H-3b),1.24(1H,m,H-4a),1.58(1H,m,H-4b),2.23(1H,m,H-5),3.91(1H,dd,J＝12.0,3.5Hz,H-6),2.82(1H,m,H-7),1.57(1H,m,H-8a),1.28(1H,m,H-8b),2.26(1H,m,H-9a),1.70(1H,m,H-9b),2.77(1H,m,H-10a),3.83(1H,td,J＝13.0,3.5Hz,H-10b),3.34(1H,overlapped,H-12),6.40(1H,dd,J＝10.0,5.5Hz,H-13),5.84(1H,d,J＝10.0Hz,H-14),2.79(1H,m,H-17a),4.27(1H,dd,J＝13.5,5.0Hz,H-17b),2.33(1H,m,H-2′a),3.01(1H,m,H-2′b),1.54(1H,m,H-3′a),1.71(1H,m,H-3′b),1.54(1H,m,H-4′a),1.67(1H,m,H-4′b),1.79(1H,m,H-5′),2.57(1H,brs,H-6′),1.51(1H,m,H-7′),1.53(1H,m,H-8′a),1.91(1H,m,H-8′b),1.54(1H,m,H-9′a),1.71(1H,m,H-9′b),2.33(1H,m,H-10′a),3.01(1H,m,H-10′b),3.64(1H,td,J＝10.5,2.5Hz,H-11′),2.19(1H,m,H-12′a),1.55(1H,m,H-12′b),2.73(1H,m,H-13′),3.36(1H,overlapped,H-14′),3.02(1H,overlapped,H-17′a),4.33(1H,dd,J＝13.5,4.5Hz,H-17′b)；13C NMR(CD3OD,125MHz)δC:71.5(C-2),22.9(C-3),27.2(C-4),32.9(C-5),73.7(C-6),45.3(C-7),17.9(C-8),21.0(C-9),57.8(C-10),70.2(C-11),39.6(C-12),139.0(C-13),125.5(C-14),165.5(C-15),41.3(C-17),57.7(C-2′),21.3(C-3′),27.9(C-4′),34.9(C-5′),64.0(C-6′),43.9(C-7′),26.6(C-8′),20.7(C-9′),57.7(C-10′),52.8(C-11′),29.6(C-12′),32.9(C-13′),50.4(C-14′),170.7(C-15′),41.5(C-17′)；HRESIMS m/z:507.3326[M+H]+(calcd for 507.3329)。
化合物3
+45.0(c 1.0,methanol)；UV(methanol)λmax(logε):207(3.38)nm；IRνmax:2931,2759,1637,1443,1410,1350,1207,1128,871cm-1；1H NMR(CD3OD,500MHz)δH:1.91(1H,dd,J＝13.5,3.5Hz,H-2a),2.71(1H,d,J＝13.5Hz,H-2b),1.43(1H,m,H-3a),1.70(1H,m,H-3b),1.53(1H,m,H-4a),1.62(1H,m,H-4b),2.69(1H,m,H-5),2.51(1H,overlapped,H-6),2.38(1H,m,H-7),1.47(1H,m,H-8a),1.28(1H,m,H-8b),1.91(1H,m,H-9a),1.53(1H,m,H-9b),2.07(1H,m,H-10a),2.64(1H,td,J＝16.5,6.5Hz,H-10b),2.56(1H,m,H-12),1.61(1H,m,H-13a),1.78(1H,m,H-13b),2.08(1H,m,H-14a),2.26(1H,m,H-14b),3.32(1H,overlapped,H-17a),3.66(1H,t,J＝13.0Hz,H-17b),1.94(1H,m,H-2′a),2.78(1H,m,H-2′b),1.46(1H,m,H-3′a),1.66(1H,m,H-3′b),1.53(1H,m,H-4′a),1.61(1H,m,H-4′b),1.78(1H,m,H-5′),2.07(1H,brs,H-6′),1.53(1H,m,H-7′),1.54(1H,m,H-8′a),1.78(1H,m,H-8′b),1.48(1H,m,H-9′a),1.71(1H,m,H-9′b),1.93(1H,m,H-10′a),2.78(1H,m,H-10′b),3.30(1H,overlapped,H-11′),2.21(1H,m,H-12′a),1.33(1H,m,H-12′b),2.91(1H,m,H-13′),2.99(1H,overlapped,H-14′),3.05(1H,overlapped,H-17′a),3.83(1H,dd,J＝13.5,5.5Hz,H-17′b)；13C NMR(CD3OD,125MHz)δC:56.8(C-2),22.4(C-3),27.6(C-4),29.5(C-5),61.9(C-6),43.8(C-7),19.2(C-8),21.8(C-9),52.8(C-10),61.9(C-11),41.9(C-12),22.4(C-13),31.1(C-14),173.0(C-15),45.7(C-17),58.2(C-2′),21.7(C-3′),28.5(C-4′),34.0(C-5′),63.4(C-6′),42.3(C-7′),27.6(C-8′),21.7(C-9′),58.1(C-10′),51.4(C-11′),30.0(C-12′),27.4(C-13′),49.0(C-14′),174.7(C-15′),42.1(C-17′)；HRESIMS m/z:493.3526[M+H]+(calcd for 493.3537)。
药理实验
实验例1化合物1对APAP诱导的药物性肝细胞损伤的保护作用
化合物1缓解APAP对肝细胞的毒性作用
MTT法检测(图1)
取对数生长期的HepG2细胞，分别接种于96孔细胞培养板中，接种密度为5×103个/孔，在37℃、5％CO2恒温培养箱中培养。细胞贴壁后，每孔加入100μL不同浓度的化合物1(5、10、20μM)，2h后加入终浓度为10mM的APAP，继续孵育24h，使用双环醇(BD)作为阳性药。培养结束前4h，吸弃上清，每孔加入含MTT的培养基溶液(0.5mg/mL，100μL/孔)，继续培养4h后。小心吸弃上清液，每孔加入150μL的DMSO，在微型振荡器上震荡5min后，用酶标仪测定OD570nm值，并计算抑制率。抑制率(％)＝1-[(空白对照组OD值-实验组OD值)/空白对照组OD值]×100％。
细胞凋亡检测(图2)
取对数生长期的HepG2细胞，以1×106个/孔的密度接种于6孔板中，在37℃、5％CO2恒温培养箱中培养过夜，待细胞贴壁后加入不同浓度的化合物1(5、10、20μM)，2h后加入终浓度为10mM的APAP，继续孵育24h。培养结束后用胰酶消化细胞，收集细胞，1000r/min离心5min，用预冷的PBS洗涤3次，1000r/min离心5min，弃上清，将细胞用100μL的1×bindingbuffer重新混悬，加入5μL的Annexin V-FITC染色液，室温避光孵育15min，随后加入10μL20μg/mL的PI溶液，轻轻混匀，室温避光孵育15min，再加入400μL的1×binding buffer，在1h内使用流式细胞仪检测。
实验例2化合物1对APAP诱导的小鼠急性肝损伤的保护作用
60只六周龄18～22g的雄性Bal/bc小鼠购自北京维通利华有限公司，所有的动物饲养在22±2℃、相对湿度为40～50％的SPF级动物房。随机将小鼠分为六组，分别空白组、模型组(350mg/kg，APAP)、阳性药组(150mg/kg，BD)、低中高剂量组(10、20、30mg/kg，化合物1)，每组10只。适应两周后，给药组连续两次灌胃给药，每次间隔12h，阳性药组以同样条件灌胃双环醇，模型组和空白组给予同等体积的生理盐水。在最后一次给药1h后，模型组、给药组和阳性药组进行APAP(350mg/kg)腹腔注射造模小鼠急性肝损伤，空白组注射同等体积的生理盐水。12h后，小鼠麻醉取血取材，做进一步的分析。
血清中ALT和AST的检测(图3)
小鼠取血后，4℃ 4000rpm离心10min，取上清即为血清，使用全自动生化仪检测ALT和AST的含量。
肝脏组织病理学检查(图4)
小鼠取材后，取部分肝脏组织置于4％多聚甲醛溶液中固定48h，再进行乙醇脱水后，将其包埋在石蜡中，凝固后进行切片(5μm)。最后，进行脱蜡、HE染色后使用显微镜进行肝组织病理改变观察。
GSH和SOD的含量测定(图5)
小鼠取材后，取部分肝脏组织，使用电动匀浆器对肝脏进行匀浆，制备成匀浆。然后使用测试试剂盒对匀浆中GSH和SOD的含量进行测定，计算结果。
Claims (9)
1.一种式1所示的苦参碱型二聚体生物碱类化合物或其药学上可接受的盐或其立体异构体，
2.根据权利要求1的化合物或其药学上可接受的盐或其立体异构体，其特征在于，所述的药学上可接受的盐选自化合物与无机酸、有机酸反应形成的盐。
3.根据权利要求2的化合物或其药学上可接受的盐或其立体异构体，其特征在于，所述的有机酸盐包括丙二酸盐、酒石酸盐、枸橼酸盐、马来酸盐、乳酸盐、水杨酸盐、苹果酸盐、苯甲酸盐、己二酸盐、富马酸盐或琥珀酸盐，所述的无机酸盐包括盐酸盐、硫酸盐、磷酸盐或氢溴酸盐。
4.权利要求1-3任一项化合物的制备方法，其特征在于，所述的制备方法如下：苦豆子粉碎后使用去离子水提取，浓缩液加1％盐酸调至PH＝3.0，用二氯甲烷连续萃取苦豆子浓缩液，取酸性部位浓缩后使用氨水调至PH＝10.0，以上述同样条件使用二氯甲烷连续萃取，将碱性部位减压浓缩后获得苦豆子总生物碱，取苦豆子总生物碱上样HP-20大孔吸附树脂层析柱，依次使用水、20％、40％、60％、95％的乙醇梯度洗脱，共获得21个馏分Fr.A～U；馏分Fr.T继续使用MCI微孔树脂层析分离，65％乙醇-水等度洗脱分离得到18个亚馏分Fr.T1～T18，亚馏分Fr.T16通过乙醇-水梯度洗脱的MCI微孔树脂柱色谱分离得到12个馏分Fr.T16.1～T16.12；Fr.T16.8通过半制备HPLC纯化后得到化合物。
5.一种药物组合物，其特征在于，所述的药物组合物包括有效剂量的权利要求1-3任一项的化合物或其药学上可接受的盐或其立体异构体和药学上可接受的载体或赋形剂。
6.根据权利要求5所述的药物组合物，其特征在于，所述的药物组合物为口服剂或注射剂。
7.根据权利要求6所述的药物组合物，其特征在于，所述的药物组合物的口服剂包括片剂、胶囊剂、丸剂、颗粒剂、散剂、滴丸剂、口服液或混悬剂；所述的药物组合物的注射剂包括溶液剂、混悬剂或乳剂。
8.权利要求1-3任一项的化合物或其药学上可接受的盐或其立体异构体或权利要求5-7的药物组合物在制备预防、缓解和/或治疗肝损伤药物中的应用。
9.根据权利要求8的应用，其特征在于，所述的肝损伤选自药物性肝损伤、酒精性肝损伤、脂肪性肝损伤或病毒性肝损伤。
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| CN106822116A (zh) * | 2016-11-30 | 2017-06-13 | 南方医科大学 | 苦参碱二聚体a和b在制备抗炎或抗肿瘤药物制剂中的应用 |
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| CN106822116A (zh) * | 2016-11-30 | 2017-06-13 | 南方医科大学 | 苦参碱二聚体a和b在制备抗炎或抗肿瘤药物制剂中的应用 |
| CN107021970A (zh) * | 2017-03-21 | 2017-08-08 | 南方医科大学 | 苦豆子碱二聚体a～d在制备抗炎或抗肿瘤药物制剂中的应用 |
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