CN108440292B - 异序乌桕素a-h及其药物组合物和其应用 - Google Patents
异序乌桕素a-h及其药物组合物和其应用 Download PDFInfo
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Abstract
本发明提供结构式(I)所示的八个新的对映‑阿替烷型二萜,异序乌桕素A‑H(1‑8),含有化合物1‑8及可药用载体的药物组合物,化合物1‑8的制备方法,以及化合物1‑8在制药中的应用,特别是在制备α‑葡萄糖苷酶抑制剂药物中的应用,和在制备治疗或改善糖尿病及其相关疾病的药物中的应用。
Description
技术领域
本发明属于天然药物化学和医药技术领域,具体地说,涉及八个新的对映-阿替烷型二萜,异序乌桕素A-H(1-8),含有化合物1-8及可药用载体的药物组合物,化合物1-8的制备方法,以及化合物1-8在制药中的应用,特别是在制备α-葡萄糖苷酶抑制剂药物中的应用,和在制备治疗或改善糖尿病及其相关疾病的药物中的应用。
背景技术
糖尿病(Diabetes Mellitus)是由遗传或环境因素引起的发病率较高的一种代谢性疾病,主要是由于体内胰岛素分泌绝对不足或相对不足引发的,以高血糖为主要病理特征并伴随多种并发症的代谢性障碍疾病。糖尿病通常分为两大类:Ⅰ型糖尿病(胰岛素依赖型)是由于胰岛分泌细胞被破坏而导致的一种自身免疫性疾病;Ⅱ型糖尿病(非胰岛素依赖型)是由于患者不能有效利用自身分泌的胰岛素,而产生胰岛素抵抗,胰岛素分泌障碍以及肝糖原输出过多等各种代谢性障碍。世界卫生组织(WHO)公布的2016年全球糖尿病报告指出,2014年全球糖尿病患病人数达到4.22亿,2012年糖尿病导致了150万人死亡,并且其患病率和致死率正在逐年上升,预计到2030年糖尿病将成为第七位主要死因。由于长期的糖代谢紊乱,糖尿病患者通常会出现多种慢性或急性并发症,如由于神经系统损伤出现的神经病变、眼部的视网膜发生病变而导致的失明、心脑血管病变产生的脑血栓和高血压、肾脏排泄器官病变出现乳酸性酸中毒和酮症酸中毒、末端肢体病变出现的糖尿病足等,这些并发症给病人带来许多痛苦,造成了严重的身体伤害、经济损失及心理压力。目前,临床上常用的降血糖药物根据其不同的作用机制归纳为以下几类:①胰岛素及其类似物:临床上此类药物是I型和II型糖尿病晚期患者的主要治疗药物,主要是通过增加机体内胰岛素的含量来达到治疗糖尿病的目的,临床上主要通过注射给药来使用此类药物。②胰岛素促泌剂:是最早发现的治疗糖尿病的药物之一,主要是通过促进机体内源性胰岛素的分泌来调控血糖浓度,磺酰脲类是此类药物中最常用的,如格列美脲和格列吡嗪。③胰岛素增敏剂:此类药物临床常用的有噻唑烷二酮类和双胍类。噻唑烷二酮的代表药物有罗格列酮,它是高选择性的PPAR-γ强效激动剂,能有效改善血糖水平。双胍类药物主要是通过抑制肝糖原异生,减少葡萄糖生成,同时增加外周组织对葡萄糖的利用来提高胰岛素的敏感性,代表药物为二甲双胍。④α-葡萄糖苷酶抑制剂:此类药物通过与小肠黏膜上皮细胞分泌的α-糖苷酶结合,抑制其活性,从而延缓小肠内二糖和多糖的水解,减少对单糖的吸收来达到降低餐后血糖的目的。临床上常用的药物有阿卡波糖和米格列醇。
目前,有很多α-葡萄糖苷酶抑制剂来源于天然产物,如黄酮,木脂素,香豆素,萜类以及生物碱等。Milella等从茜草科植物Arcytophyllum thymifolium中分离得到的一个新的黄酮类化合物(2S)-7prenyloxyeriodictyol对α-糖苷酶具有较强的抑制活性,其IC50为28.1±2.6μM,其活性远超过阳性药物阿卡波糖(IC50=402.7±15.5μM)。Dang等从红豆杉属植物西藏红豆杉Taxus wallichiana的根中分离得到木脂素类化合物formosanol对α-葡萄糖苷酶具有较好的抑制作用,其IC50为35.3μM(阿卡波糖的IC50为215μM)。另外从该植物的枝干中分离得到的一个新的紫杉烷二萜类化合物wallitaxanes对α-糖苷酶表现出更强的抑制活性,其IC50为3.6μM。Wang等从猴头菇Hericium erinaceus中分离得到的一个生物碱erinacerin Q对α-糖苷酶表现出较好的抑制作用,其IC50为12.7μM(阿卡波糖的IC50为273μM)。此外,很多不同骨架类型的二萜成分,如贝壳杉烷型,紫杉烷型,松香烷型,半日花烷型及新克罗烷型等二萜化合物都被报道具有一定的α-糖苷酶抑制活性。
异序乌桕Sapium insigne是大戟科乌桕属植物,是一种落叶乔木,国内主要分布于云南、四川及海南,印度、不丹、缅甸、越南、柬埔寨也有分布。该属植物全球约有120种,主要分布于热带地区,南美洲最多,我国有9种,多分布于东南至西南部丘陵地区。该属植物在中国南方地区,马来西亚,非洲,玻利维亚等地区被广泛用作民间药材,叶子可以用来治疗皮肤相关疾病如湿疹,皮炎疱疹等;枝干和种子可以用来治疗消化道相关疾病,如便秘,腹水等;根皮可治毒蛇咬伤。该属植物的化学成分报道主要有黄酮类,萜类,甾体类以及酚类化合物等。二萜类成分为主要成分,其结构类型丰富多样,包括佛波酯类,半日花烷型二萜,对映-贝壳杉烷型二萜,以及海松烷型二萜等。该属植物药理活性方面的报道包括抗氧化,抗菌,抗炎,细胞毒活性以及抗肿瘤活性。
迄今,现有技术无异序乌桕素A-H的报道,也没有异序乌桕素A-H作为有效成分的药物组合物的报道,也没有异序乌桕素A-H及其药物组合物作为α-葡萄糖苷酶抑制剂,及在治疗或改善糖尿病及其相关疾病的药物中的应用的报道。
发明内容
本发明的目的在于提供一类具有药用价值的式(I)所示的八个新的对映-阿替烷型二萜,异序乌桕素A-H及其制备方法,有效剂量的异序乌桕素A-H作为α-葡萄糖苷酶抑制剂,异序乌桕素A-H及其药物组合物在制备治疗或改善糖尿病及其相关疾病的药物中的应用。
为了实现本发明的上述目的,本发明提供了如下技术方案:
结构式(I)所示的化合物异序乌桕素A-H(1-8),
式(I)中化合物1-8在制备α-葡萄糖苷酶抑制剂中的应用。
式(I)中化合物1-8在制备治疗或改善糖尿病及其相关疾病的药物中的应用。
如所述的应用,其中所述的疾病是与α-葡萄糖苷酶相关的糖尿病。
本发明同时还提供了含有治疗有效量的式(I)化合物1-8和药学上可接受的载体的药物组合物。
所述的药物组合物在制备α-葡萄糖苷酶抑制剂中的应用。
所述的药物组合物在制备治疗或改善糖尿病及其相关疾病的药物中的应用。
如所述的应用,其中所述的疾病是与α-葡萄糖苷酶相关的糖尿病。
制备所述的式(I)化合物1-8的方法,取异序乌桕Sapium insigne的干燥枝干,粉碎,用90%乙醇室温浸提3次,每次48小时,合并乙醇提取液,减压回收乙醇得浸膏。浸膏用甲醇溶解,吸附于硅胶上,室温放置挥干溶剂,利用硅胶柱层析,石油醚-乙酸乙酯(0:100~100:0)洗脱,得到7个流分Frs.1-7。其中流分Fr.3-7继续经MCI中压柱层析,硅胶柱层析,凝胶柱色谱及高效液相色谱半制备得到目标化合物1-8。
制备含化合物1-8的药物组合物的方法是,以化合物1-8为原料,加入可药用载体或赋形剂。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。
本发明化合物1-8用作α-葡萄糖苷酶抑制剂或药物时,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0.1~99.9%,优选为0.5~90%的化合物1-8,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。将本发明的药物组合物以单位体重服用量的形式使用。本发明的药物是临床上能够使用的各种剂型,如胶囊、颗粒剂、丸剂、片剂、注射剂、膏剂、酊剂、口服液;或已有的保健食品剂型,如胶囊、颗粒剂、片剂、饮料等。
附图说明:
图1为化合物异序乌桕素A-H(1-8)的结构示意图;
图2为本发明化合物1-8对α-葡萄糖苷酶的抑制率,以阿卡波糖为阳性对照,化合物的测试浓度为1.5mM,激动率为Mean±SD(n=3)。
具体实施方式:
为了更好地理解本发明的实质,下面结合附图,用本发明的试验例和实施例来进一步说明本发明化合物1-8的制备方法、结构鉴定、药理作用,以及本发明的制备方法及药物组成,但不以此试验例和实施例来限定本发明。
实施例1:
化合物1-8的制备方法:
取异序乌桕Sapium insigne的干燥枝干,粉碎,用90%乙醇室温浸提3次,每次48小时,合并乙醇提取液,减压回收乙醇得浸膏。浸膏用甲醇溶解,吸附于硅胶上,室温放置挥干溶剂,利用硅胶柱层析,石油醚-乙酸乙酯(0:100~100:0)洗脱,得到7个流分Frs.1-7。其中流分Fr.3-7继续经MCI中压柱层析,硅胶柱层析,凝胶柱色谱及高效液相色谱半制备得到目标化合物1-8。
化合物1-8的结构鉴定数据:
紫外图谱是用UV-2401PC(Shimadzu,Kyoto,Japan)测定。红外图谱用Bio-RadFTS-135(Hercules,California,USA)测定(KBr压片)。旋光数据采用旋光仪Jasco P-1020(Horiba,Tokyo,Japan)测定。核磁共振图谱用Bruker Avance III-600或800超导核磁共振仪(Bruker,Bremerhaven,Germany)测定,TMS(四甲基硅烷)作内标。薄层色谱硅胶板购买自青岛海洋化工有限公司(Qingdao Haiyang,Qingdao,China);柱色谱硅胶(200~300目)购买自青岛美高化工有限公司(Makall,Qingdao,China);凝胶Sephadex LH-20(20~50μm)购买自Pharmacia Fine Chemical Co.,Ltd.(Pharmacia,Uppsala,Sweden)。显色剂为H2SO4(10%)的乙醇溶液。高效液相色谱仪为岛津公司生产的,泵型号是LC-20AR,检测器型号为SPD-M20A,控制器型号是CBM-20A,柱温箱型号为AT-350,使用的色谱柱型号为YMC-Pack Ph(5μm,10×250mm)或者Agilent-ZORBAX SB-C18(5μm,10×250mm)。色谱甲醇和乙腈购买自默克公司。高分辨质谱用LC-MS-IT-TOF(Shimadzu,Kyoto,Japan)质谱仪测定。
化合物1
分子式:C21H32O4;分子量:348;性状:无色油状物;HRESIMS(+)m/z 349.2378([M+H]+计算值349.2373);(c 0.43,氯仿);IR(KBr)vmax:3496,3469,2951,2929,2877,1735,1717,1437,1373,1283,1201,1168,1099,890cm-1;UV/Vis(甲醇)λmax(logε):202(3.72)nm;1H-NMR和13C-NMR数据见表1和3。
化合物2
分子式:C22H34O4;分子量:362;性状:无色油状物;HRESIMS(+)m/z 385.2358([M+Na]+计算值385.2349);(c 0.31,CHCl3);IR(KBr)vmax:3493,2959,2921,2874,2851,1717,1371,1283,1162,1098,889cm-1;UV/Vis(甲醇)λmax(logε):202(3.65),219(3.12)nm;1H-NMR和13C-NMR数据见表1和3。
化合物3
分子式:C22H32O4;分子量:360;性状:无色油状物;HRESIMS(+)m/z 361.2377([M+H]+计算值361.2373);(c 0.14,CHCl3);IR(KBr)vmax:3435,2955,2926,2873,2855,1728,1635,1450,1387,1184,1028,894cm-1;UV/Vis(甲醇)λmax(logε):202(3.62),214(3.41)nm;1H-NMR和13C-NMR数据见表1和3。
化合物4
分子式:C20H30O2;分子量:302;性状:白色粉末;HRESIMS(+)m/z 303.2315([M+H]+计算值303.2319);(c 0.06,CHCl3);IR(KBr)vmax:3489,3446,2977,2922,2864,1696,1650,1462,1446,1012,884cm-1;UV/Vis(甲醇)λmax(logε):202(3.69)nm;1H-NMR和13C-NMR数据见表1和3。
化合物5
分子式:C20H26O2;分子量:298;性状:白色粉末;HRESIMS(+)m/z 299.2027([M+H]+计算值299.2006);(c 0.04,CHCl3);IR(KBr)vmax:3440,3427,2957,2922,2854,1632,1461,1097cm-1;UV/Vis(甲醇)λmax(logε):202(3.69),217(3.56)nm;1H-NMR和13C-NMR数据见表2和3。
化合物6
分子式:C20H28O4;分子量:332;性状:白色粉末;HRESIMS(+)m/z 333.2066([M+H]+计算值333.2060);(c 0.11,CHCl3);IR(KBr)vmax:3435,2966,2955,2934,2875,1719,1651,1396cm-1;UV/Vis(甲醇)λmax(logε):202(3.73)nm;1H-NMR和13C-NMR数据见表2和3。
化合物7
分子式:C20H32O4;分子量:336;性状:白色粉末;HRESIMS(+)m/z 359.2205([M+Na]+计算值359.2193);(c 0.13,CHCl3);IR(KBr)vmax:3423,2940,2874,1714,1632,1446,1393,1040cm-1;UV/Vis(甲醇)λmax(logε):202(3.34)nm;1H-NMR和13C-NMR数据见表2和3。
化合物8
分子式:C20H30O4;分子量:334;性状:白色粉末;HRESIMS(+)m/z 357.2037(M+Na]+计算值357.2036);(c 0.08,MeOH);IR(KBr)vmax:3429,2938,2875,1668,1648,1400,1228,1054cm-1;UV/Vis(甲醇)λmax(logε):270(4.01),200(3.53)nm;1H-NMR和13C-NMR数据见表2和3。
表1.化合物1-4的1H NMR数据(δin ppm,J in Hz,CDCl3)a
a测试仪器为600MHz
表2.化合物5-8的1H NMR数据(δin ppm,J in Hz)
a测试溶剂为CD3OD,b测试溶剂为CDCl3,c测试仪器为600MHz,d测试仪器为800MHz
表3.化合物1-8的13C NMR数据(δin ppm)
a测试溶剂为CDCl3,b测试溶剂为CD3OD,c测试仪器为600MHz,d测试仪器为800MHz
实施例2:
化合物1-8体外抑制α-葡萄糖苷酶实验:
称取实施例1所述的化合物1-8适量,用500μL磷酸盐缓冲液:甲醇(1:1)溶解,得到浓度为1.5mM的样品待测液。再根据情况稀释,得到不同浓度的待测样品溶液。
(1)配制磷酸盐缓冲液:0.1M Na2HPO4溶液与0.1M NaH2PO4溶液各取适量,混合至pH 7.40,过0.45μm滤膜,待用。(2)α-葡萄糖苷酶溶液:精密称取α-葡萄糖苷酶(SigmaAldrich,来源于酿酒酵母Saccharomyces cerevisiae)适量,加磷酸钾缓冲液配成浓度为0.2U/mL的溶液,过0.45μm滤膜,待用。(3)pNPG底物溶液:称取适量,加磷酸钾缓冲液配成浓度为2.5mM的溶液,过0.45μm滤膜,待用。(4)Na2CO3终止液:精密称取Na2CO3适量,加水配成浓度为0.1M的溶液,过0.45μm滤膜,待用。取化合物待测液30μL,加入到96孔板中;加入20μL0.2U/mL的酶溶液,震摇1min,37℃下孵育5min;加入20μL 2.5mM的pNPG底物溶液,震摇1min,37℃下反应15min;加入40μL 0.1M的Na2CO3溶液,震摇1min,37℃孵育5min终止反应,405nm处测定吸光度值。本实验设置阳性对照组,阳性对照药为阿卡波糖。α-葡萄糖苷酶抑制率计算公式:抑制率(%)=[(OD空白–OD空白背景)–(OD样品–OD样品背景)]/(OD空白–OD空白背景)×100%。
实验结果表明,化合物1,4,6-8均对α-葡萄糖苷酶表现出激动活性,在浓度为1.5mM时,激动率在24.1%~98.9%。进一步研究表明,化合物4和6对α-葡萄糖苷酶具有较好的抑制作用,其IC50值分别为340μM和587μΜ(阳性阿卡波糖IC50为149μM)。
实施例3
按实施例1的方式先获得化合物1-8,按它们与赋形剂重量比4:1的比例混合均匀,制粒,压片。治疗Ⅱ型糖尿病1~4片/次,3次/日。
实施例4:
按实施例1的方式先获得化合物1-8,按它们与赋形剂重量比8:1的比例混合均匀,制粒,压片。治疗Ⅱ型糖尿病1~3片/次,3次/日。
实施例5:
按实施例1的方式先获得化合物1-8,按它们与赋形剂重量比3:1的比例混合均匀,制粒,制成胶囊剂。治疗Ⅱ型糖尿病1~3粒/次,3次/日。
实施例6:
按实施例1的方式先获得化合物1-8,按它们与赋形剂重量比6:1的比例混合均匀,制粒,制成胶囊剂。治疗Ⅱ型糖尿病,1~3粒/次,3次/日。
实施例7:
按实施例1的方式先获得化合物1-8,按常规口服液的制法制成口服液。治疗Ⅱ型糖尿病,20~30mL瓶/次,3次/日。
Claims (8)
2.权利要求1所述的化合物1、3-4、6-8在制备α-葡萄糖苷酶抑制剂药物中的应用。
3.权利要求1所述化合物1、3-4、6-8在制备治疗或改善糖尿病及其相关疾病的药物中的应用。
4.制备权利要求1所述的化合物1、3-4、6-8的方法,取异序乌桕Sapium insigne的干燥枝干,粉碎,用90%乙醇室温浸提3次,每次48小时,合并乙醇提取液,减压回收乙醇得浸膏,浸膏用甲醇溶解,吸附于硅胶上,室温放置挥干溶剂,利用硅胶柱层析,石油醚-乙酸乙酯0:100~100:0洗脱,得到7个流分Frs.1-7,其中流分Fr.3-7继续经MCI中压柱层析,硅胶柱层析,凝胶柱色谱及高效液相色谱半制备得到目标化合物1、3-4、6-8。
5.含有治疗有效量的权利要求1所述的化合物1、3-4、6-8和药学上可接受的载体的药物组合物。
6.权利要求5所述的药物组合物在制备α-葡萄糖苷酶抑制剂药物中的应用。
7.权利要求5所述的药物组合物在制备治疗或改善糖尿病及其相关疾病的药物中的应用。
8.制备权利要求5所述的药物组合物的方法,取异序乌桕Sapiuminsigne的干燥枝干,粉碎,用90%乙醇室温浸提3次,每次48小时,合并乙醇提取液,减压回收乙醇得浸膏,浸膏用甲醇溶解,吸附于硅胶上,室温放置挥干溶剂,利用硅胶柱层析,石油醚-乙酸乙酯0:100~100:0洗脱,得到7个流分Frs.1-7,其中流分Fr.3-7继续经MCI中压柱层析,硅胶柱层析,凝胶柱色谱及高效液相色谱半制备得到目标化合物1、3-4、6-8,再以化合物1、3-4、6-8为原料加入可药用载体或赋形剂。
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