CN112592328B - 草豆蔻中二芳基庚烷-查尔酮聚合物及其药物组合物与应用 - Google Patents
草豆蔻中二芳基庚烷-查尔酮聚合物及其药物组合物与应用 Download PDFInfo
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- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
本发明提供了一种草豆蔻中二芳基庚烷‑查尔酮聚合物及其药物组合物和其制备方法与应用,涉及药物技术领域。本发明提供的二芳基庚烷‑查尔酮聚合物,主要包括16种新结构化合物,草豆蔻醇A1–A16(katsumadainols A1–A16,1–16),该类化合物对α‑葡萄糖苷酶和蛋白质酪氨酸磷酸酶1B(PTP1B)具有明显的抑制活性,能够与可药用载体或赋型剂组成药物组合物,能够用于制备α‑葡萄糖苷酶和PTP1B抑制剂药物、降血糖药物或保健食品中。
Description
技术领域:
本发明属于药物技术领域。具体地,涉及16个新的二芳基庚烷-查尔酮聚合物,草豆蔻醇A1–A16(katsumadainols A1–A16,1–16),以化合物1–16为有效成分的药物组合物,化合物和其药物组合物在制备降血糖药物或保健食品中的应用。
背景技术:
2型糖尿病如今已是全球性的人类疾病,影响将近5亿人的身体健康。2型糖尿病是由胰腺β细胞功能障碍及胰岛素抵抗引起的,以不合适的快速或餐后高血糖为特征。许多口服降血糖药物如双胍类、α-葡萄糖苷酶抑制剂、胰岛素促泌剂、胰岛素增敏剂、胰高血糖素样肽-1受体激动剂、二肽基肽酶-4抑制剂、钠葡萄糖转运蛋白-2抑制剂,已被批准治疗2型糖尿病。然而由于上述药物呈现不可避免的低血糖症等副作用使具有多靶点新药的发现显得尤为迫切。
蛋白质酪氨酸磷酸酶1B(PTP1B)能够通过对胰岛素受体和下游底物蛋白的脱磷酸化来负向调控胰岛素信号。尽管这类抑制剂具有很好的抗糖尿病活性,但是由于其较差的膜通透性和对同源蛋白如T细胞蛋白质酪氨酸磷酸酶(TCPTP)的弱选择性,并没有临床应用,而寻找PTP1B选择性的抑制剂极具挑战性。此外,α-葡萄糖苷酶抑制剂在控制血糖浓度方面也具有重要作用,相关的一些合成药物如阿卡波糖、米格列醇和伏格列波糖已被用于治疗2型糖尿病,但是却带来了肝毒性和胃肠不适等副作用。因此,具有PTP1B和α-葡萄糖苷酶双重抑制活性的候选药物的将对治疗2型糖尿病有重要意义。
草豆蔻(Alpinia katsumadai Hayata)系姜科良姜属植物,主要分布于中国和东南亚一些国家。草豆蔻的干燥种子在中国是一种广为使用的食品香料,同时也作为一味传统中药用于治疗呕吐、胃病及炎症。我们的前期研究工作发现草豆蔻干燥种子的90%乙醇提取物在小鼠实验中具有降血糖活性,活性导向分离得到了一系列二芳基庚烷-查尔酮聚合物,包括16个结构首次发现且具有PTP1B及α-葡萄糖苷酶抑制活性的化合物,草豆蔻素草豆蔻醇A1–A16(katsumadainols A1–A16,1–16)。迄今为止,现有技术尚无草豆蔻醇A1–A16(katsumadainols A1–A16,1–16)的报道,也没有化合物1–16及其药物组合物作为PTP1B抑制剂、α-葡萄糖苷酶抑制剂,及在制备降血糖药物或保健食品中的应用报道。
发明内容:
本发明的目的在于提供一类新的具有药用价值如式(I)所示的化合物草豆蔻醇A1–A16(1–16)(katsumadainols A1–A16,1–16),以其为活性成分的药物组合物,化合物1–16及其药物组合物在制备PTP1B抑制剂、α-葡萄糖苷酶抑制剂,以及其在制备降血糖药物或保健食品中的应用。
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:
结构式(I)所示的草豆蔻醇A1–A16(1–16),
草豆蔻醇A1–A16(1–16)在制备α-葡萄糖苷酶抑制剂药物中的应用。
草豆蔻醇A1–A16(1–16)在制备蛋白质酪氨酸磷酸酶1B抑制剂药物中的应用。
草豆蔻醇A1–A16(1–16)在制备降血糖药物或保健食品中的应用。
制备式(I)的草豆蔻醇A1–A16(1–16)的方法,取草豆蔻Alpinia katsumadai的干燥种子,粉碎,用90%乙醇回流提取3次,每次2h,合并乙醇提液,减压回收乙醇得浸膏,浸膏分散在水中后用乙酸乙酯萃取,随后浓缩得到乙酸乙酯萃取部分,然后将乙酸乙酯萃取部分Fr.A过硅胶柱层析,以甲醇-氯仿(0:100、2:98、5:95、10:90、20:80和100:0,v/v)为洗脱剂梯度洗脱得到Fr.A-1~Fr.A-8八个流分;流分Fr.A-5经MCI CHP 20P gel柱层析(系统体系为甲醇-水,40:60、60:40、70:30、80:20、90:10和100:0)得到七个亚流分Fr.A-5-1~Fr.A-5-7;Fr.A-5-3经硅胶柱层析(MeOH-CHCl3,10:100)、Sephadex LH-20柱层析(氯仿-甲醇,50:50)和半制备高效液相色谱(MeCN-H2O,40:60,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物13,14,15和16;Fr.A-5-4经反相C18柱层析(甲醇-水,40:60、50:50、60:40、70:30和100:0)得到七个亚流分Fr.A-5-4-1~Fr.A-5-4-7;Fr.A-5-4-3经硅胶柱层析(MeOH-CHCl3,6:94)、Sephadex LH-20柱层析(氯仿-甲醇,50:50)和半制备高效液相色谱(MeCN-H2O,40:60,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物1,2,6和7;Fr.A-5-4-6经硅胶柱层析(MeOH-CHCl3,10:90)、Sephadex LH-20柱层析(氯仿-甲醇,50:50)和半制备高效液相色谱(MeCN-H2O,40:60,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物3,4和5;Fr.A-5-5经反相C18柱层析(甲醇-水,40:60、50:50、60:40和70:30)、硅胶柱层析(acetone-CHCl3,40:60;MeOH-CHCl3,8:92)、Sephadex LH-20柱层析(氯仿-甲醇,50:50)和半制备高效液相色谱(MeCN-H2O,35:65,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物11和12;Fr.A-5-6经反相C18柱层析(甲醇-水,40:60、50:50、60:40和70:30)、硅胶柱层析(MeOH-CHCl3,50:50)、Sephadex LH-20柱层析(氯仿-甲醇,50:50)和半制备高效液相色谱(MeCN-H2O,35:65,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物8,9和10。
本发明同时提供了包含上述的草豆蔻醇A1–A16(1–16)中的至少一种和药学上可接受的载体或赋型剂的药物组合物。
所述的药物组合物在制备α-葡萄糖苷酶抑制剂药物中的应用。
所述的药物组合物在制备PTP1B抑制剂药物中的应用。
所述的药物组合物在制备降血糖药物或保健食品中的应用。
此外,还提供了制备所述的药物组合物的方法,取草豆蔻Alpinia katsumadai的干燥种子,粉碎,用90%乙醇回流提取3次,每次2h,合并乙醇提液,减压回收乙醇得浸膏,浸膏分散在水中后用乙酸乙酯萃取,随后浓缩得到乙酸乙酯萃取部分,然后将乙酸乙酯萃取部分Fr.A过硅胶柱层析,以甲醇-氯仿(0:100、2:98、5:95、10:90、20:80和100:0,v/v)为洗脱剂梯度洗脱得到Fr.A-1~Fr.A-8八个流分;流分Fr.A-5经MCI CHP20P gel柱层析(系统体系为甲醇-水,40:60、60:40、70:30、80:20、90:10和100:0)得到七个亚流分Fr.A-5-1~Fr.A-5-7;Fr.A-5-3经硅胶柱层析(MeOH-CHCl3,10:100)、Sephadex LH-20柱层析(氯仿-甲醇,50:50)和半制备高效液相色谱(MeCN-H2O,40:60,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物13,14,15和16;Fr.A-5-4经反相C18柱层析(甲醇-水,40:60、50:50、60:40、70:30和100:0)得到七个亚流分Fr.A-5-4-1~Fr.A-5-4-7;Fr.A-5-4-3经硅胶柱层析(MeOH-CHCl3,6:94)、Sephadex LH-20柱层析(氯仿-甲醇,50:50)和半制备高效液相色谱(MeCN-H2O,40:60,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物1,2,6和7;Fr.A-5-4-6经硅胶柱层析(MeOH-CHCl3,10:90)、Sephadex LH-20柱层析(氯仿-甲醇,50:50)和半制备高效液相色谱(MeCN-H2O,40:60,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物3,4和5;Fr.A-5-5经反相C18柱层析(甲醇-水,40:60、50:50、60:40和70:30)、硅胶柱层析(acetone-CHCl3,40:60;MeOH-CHCl3,8:92)、Sephadex LH-20柱层析(氯仿-甲醇,50:50)和半制备高效液相色谱(MeCN-H2O,35:65,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物11和12;Fr.A-5-6经反相C18柱层析(甲醇-水,40:60、50:50、60:40和70:30)、硅胶柱层析(MeOH-CHCl3,50:50)、Sephadex LH-20柱层析(氯仿-甲醇,50:50)和半制备高效液相色谱(MeCN-H2O,35:65,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物8,9和10,再以化合物1–16为原料加入一定比例的可药用载体或赋形剂。
制备含化合物1–16的药物组合物的方法是,以化合物1–16的至少一种为原料,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1–16用作PTP1B及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%,优选为0.5~90%的化合物1–16的至少一种,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。本发明的药物可经注射(静注、肌注)和口服两种形式给药。
附图说明:
图1为本发明化合物1–16的结构式示意图。
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(katsumadainols A1–A16,1–16)的制备方法、结构鉴定、药理作用,以及组合物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1–16的制备:
取草豆蔻Alpinia katsumadai的干燥种子,粉碎,用90%乙醇回流提取3次,每次2h,合并乙醇提液,减压回收乙醇得浸膏。浸膏分散在水中后用乙酸乙酯萃取,随后浓缩得到乙酸乙酯萃取部分。然后将乙酸乙酯萃取部分(Fr.A)过硅胶柱层析,以甲醇-氯仿(0:100、2:98、5:95、10:90、20:80和100:0,v/v)为洗脱剂梯度洗脱得到Fr.A-1~Fr.A-8八个流分。流分Fr.A-5经MCI CHP 20P gel柱层析(系统体系为甲醇-水,40:60、60:40、70:30、80:20、90:10和100:0)得到七个亚流分Fr.A-5-1~Fr.A-5-7。Fr.A-5-3经硅胶柱层析(MeOH-CHCl3,10:100)、Sephadex LH-20柱层析(氯仿-甲醇,50:50)和半制备高效液相色谱(MeCN-H2O,40:60,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物13,14,15和16。Fr.A-5-4经反相C18柱层析(甲醇-水,40:60、50:50、60:40、70:30和100:0)得到七个亚流分Fr.A-5-4-1~Fr.A-5-4-7。Fr.A-5-4-3经硅胶柱层析(MeOH-CHCl3,6:94)、Sephadex LH-20柱层析(氯仿-甲醇,50:50)和半制备高效液相色谱(MeCN-H2O,40:60,3.0mL/min,AgilentXDB-C18柱,9.4×250mm,5μm)得到化合物1,2,6和7。Fr.A-5-4-6经硅胶柱层析(MeOH-CHCl3,10:90)、Sephadex LH-20柱层析(氯仿-甲醇,50:50)和半制备高效液相色谱(MeCN-H2O,40:60,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物3,4和5。Fr.A-5-5经反相C18柱层析(甲醇-水,40:60、50:50、60:40和70:30)、硅胶柱层析(acetone-CHCl3,40:60;MeOH-CHCl3,8:92)、Sephadex LH-20柱层析(氯仿-甲醇,50:50)和半制备高效液相色谱(MeCN-H2O,35:65,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物11和12。Fr.A-5-6经反相C18柱层析(甲醇-水,40:60、50:50、60:40和70:30)、硅胶柱层析(MeOH-CHCl3,50:50)、Sephadex LH-20柱层析(氯仿-甲醇,50:50)和半制备高效液相色谱(MeCN-H2O,35:65,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm)得到化合物8,9和10。
化合物1–16的波谱数据:
旋光由Jasco model 1020旋光仪(Horiba,Tokyo,Japan)测定;红外光谱(IR)采用KBr压片法,由Bio-Rad FTS-135型红外光谱仪(Hercules,California,USA)测定;紫外光谱由UV-2401PC型紫外光谱仪(Shimadzu,Kyoto,Japan)测定;ECD谱由Applied Photophysics圆二色谱仪(Agilent,Santa Clara,United States)测定;核磁共振谱(1D和2D NMR)用AV800或Avance III-600型超导核磁共振仪(Bruker,Bremerhaven,Germany)测定,以氘代甲醇作为溶剂;高分辨质谱(HRMS)用LCMS-IT-TOF型质谱仪(Shimadzu,Kyoto,Japan)测定;薄层色谱硅胶、柱层析硅胶(200-300目)购自青岛美高及青岛海洋化工集团有限公司,葡聚糖凝胶LH-20(Sephadex LH-20)购自Amersham Bioscience(瑞典)。CHP20P MCI凝胶购自Mitsubishi Chemical Corporation(Tokyo,Japan)。
草豆蔻醇A1(1)
分子式:C25H34O8
分子量:582
性状:黄色固体
HRESIMSm/z:583.2329[M+H]+(calcd.for C35H35O8,583.2326)
UV(MeOH)λmax(logε):226(3.51),266(3.36),303(3.22)nm
IR(KBr)vmax:3416,1709,1614,1596,1514,1469,1454,1437,1367,1239,1212,1111,1042cm–1
ECD(c 0.10,MeOH)λmax(Δε):226(–8.28),267(–11.97),303(+16.76)nm
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇A2(2)
分子式:C25H34O8
分子量:582
性状:黄色固体
HRESIMS m/z:583.2325[M+H]+(calcd.for C35H35O8,583.2326)
UV(MeOH)λmax(logε):225(3.48),265(3.31),290(3.22)nm
IR(KBr)vmax:3426,1708,1613,1514,1436,1365,1215,1171,1106cm–1
ECD(c 0.12,MeOH)λmax(Δε):219(+8.20),289(-4.86),336(+1.96)nm
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇A3(3)
分子式:C35H35O9
分子量:598
性状:黄色固体
HRESIMS m/z:599.2266[M+H]+(calcd.for C35H35O9,599.2276)
UV(MeOH)λmax(logε):225(3.52),366(3.49)nm
IR(KBr)vmax:3409,1627,1605,1514,1437,1343,1233,1170,1132,1106cm–1
ECD(c 0.12,MeOH)λmax(Δε):228(-3.18),251(+2.00),306(+0.11),3.58(-1.92)nm
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇A4(4)
分子式:C35H34O9
分子量:598
性状:黄色固体
HRESIMS m/z:599.2266[M+H]+(calcd.for C35H35O9,599.2276)
UV(MeOH)λmax(logε):225(3.86),363(3.43)nm
IR(KBr)vmax:3406,1626,1605,1514,1436,1343,1232,1170,1132,1106cm–1
ECD(c 0.12,MeOH)λmax(Δε):226(+3.00),252(+3.50),310(+2.01),360(-1.65)nm
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇A5(5)
分子式:C35H34O9
分子量:598
性状:黄色固体
HRESIMS m/z:599.2266[M+H]+(calcd.for C35H35O9,599.2276)
UV(MeOH)λmax(logε):227(4.63),370(4.59)nm
IR(KBr)vmax:3370,1628,1603,1514,1436,1343,1230,1204,1170,cm–1
ECD(c 0.12,MeOH)λmax(Δε):214(-0.52),230(+0.88),255(+1.08),361(-1.09)nm
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇A6(6)
分子式:C54H54O11
分子量:878
性状:黄色固体
HRESIMS m/z:877.3597[M-H]-(calcd.for C54H53O11,877.3593)
UV(MeOH)λmax(logε):225(3.67),286(2.98),335(3.28)nm
IR(KBr)vmax:3424,1599,1514,1446,1365,1233,1170,1145,1104cm–1
ECD(c 0.12,MeOH)λmax(Δε):238(-3.31),338(+0.73)nm
1H-NMR和13C-NMR(DEPT)数据见表4。
草豆蔻醇A7(7)
分子式:C54H54O11
分子量:878
性状:黄色固体
HRESIMS m/z:877.3592[M-H]-(calcd.for C54H53O11,877.3593)
UV(MeOH)λmax(logε):226(3.73),228(2.99),335(3.36)nm
IR(KBr)vmax:3428,1612,1600,1514,1446,1367,1330,1237,1171,1103cm–1
ECD(c 0.12,MeOH)λmax(Δε):220(+2.01),238(+1.24),298(-0.83),338(+1.03)nm
1H-NMR和13C-NMR(DEPT)数据见表4。
草豆蔻醇A8(8)
分子式:C35H34O9
分子量:598
性状:黄色固体
HRESIMS m/z:597.2132[M-H]-(calcd.for C35H33O9,597.2130)
UV(MeOH)λmax(logε):208(3.66),230(3.44),332(3.31)nm
IR(KBr)vmax:3443,1615,1602,1514,1447,1258,1170cm–1
ECD(c 0.12,MeOH)λmax(Δε):208(+2.87),226(-1.17),329(-1.31)nm
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇A9(9)
分子式:C35H34O9
分子量:598
性状:黄色固体
HRESIMS m/z:599.2271[M+H]+(calcd.for C35H35O9,599.2276)
UV(MeOH)λmax(logε):215(3.65),240(3.09),335(3.31)nm
IR(KBr)vmax:3442,1616,1602,1515,1448,1259,1125cm–1
ECD(c 0.10,MeOH)λmax(Δε):218(+2.24),236(+1.65),336(+3.25)nm
1H-NMR和13C-NMR(DEPT)数据见表1和2。
草豆蔻醇A10(10)
分子式:C35H32O7
分子量:564
性状:黄色固体
HRESIMS m/z:565.2217[M+H]+(calcd.for C35H33O7,565.2217)
UV(MeOH)λmax(logε):226(3.45),335(3.10)nm
IR(KBr)vmax:3419,1709,1600,1514,1438,1334,1228,1169,1147,1105cm–1
ECD(c 0.10,MeOH)λmax(Δε):224(+0.48),336(+0.61)nm
1H-NMR和13C-NMR(DEPT)数据见表1和3。
草豆蔻醇A11(11)
分子式:C37H36O9
分子量:624
性状:黄色固体
HRESIMS m/z:625.2437[M+H]+(calcd.for C37H37O9,625.2432)
UV(MeOH)λmax(logε):226(2.53),270(1.80),368(2.47)nm
IR(KBr)vmax:3391,1704,1605,1513,1441,1338,1229,1170,1142,1106cm–1
ECD(c 0.10,MeOH)λmax(Δε):224(+0.83),248(+0.91),367(+0.24)nm
1H-NMR和13C-NMR(DEPT)数据见表1和3。
草豆蔻醇A12(12)
分子式:C37H36O9
分子量:624
性状:黄色固体
HRESIMS m/z:625.2424[M+H]+(calcd.for C37H37O9,625.2432)
UV(MeOH)λmax(logε):226(2.53),268(1.84),367(2.45)nm
IR(KBr)vmax:3427,1704,1606,1513,1439,1339,1228,1170,1142,1105,1046cm–1
ECD(c 0.12,MeOH)λmax(Δε):238(-0.38),254(+0.18),358(-0.21)nm
1H-NMR和13C-NMR(DEPT)数据见表1和3。
草豆蔻醇A13(13)
分子式:C36H36O9
分子量:612
性状:黄色固体
HRESIMS m/z:613.2441[M+H]+(calcd.for C36H37O9,613.2432)
UV(MeOH)λmax(logε):225(2.59),368(2.40)nm
IR(KBr)vmax:3427,1705,1606,1513,1438,1347,1229,1169,1106,1044cm–1
ECD(c 0.12,MeOH)λmax(Δε):227(-0.89),247(+0.62),265(-0.25),366(+0.39)nm
1H-NMR和13C-NMR(DEPT)数据见表1和4。
草豆蔻醇A14(14)
分子式:C36H36O9
分子量:612
性状:黄色固体
HRESIMS m/z:613.2425[M+H]+(calcd.for C36H37O9,613.2432)
UV(MeOH)λmax(logε):226(2.58),368(2.48)nm
IR(KBr)vmax:3425,1712,1606,1513,1455,1436,1352,1228,1167,1106,1033cm–1
ECD(c 0.12,MeOH)λmax(Δε):247(-1.18),276(-0.31),365(-0.25)nm
1H-NMR和13C-NMR(DEPT)数据见表1和3。
草豆蔻醇A15(15)
分子式:C36H36O9
分子量:612
性状:黄色固体
HRESIMS m/z:613.2432[M+H]+(calcd.for C36H37O9,613.2432)
UV(MeOH)λmax(logε):225(3.60),368(3.51)nm
IR(KBr)vmax:3407,1605,1513,1437,1340,1229,1170,1143,1106cm–1
ECD(c 0.12,MeOH)λmax(Δε):224(-2.24),248(+0.38),368(+0.25)nm
1H-NMR和13C-NMR(DEPT)数据见表1和3。
草豆蔻醇A16(16)
分子式:C36H36O9
分子量:612
性状:黄色固体
HRESIMS m/z:613.2422[M+H]+(calcd..for C36H37O9,613.2432)
UV(MeOH)λmax(logε):225(3.66),362(3.58)nm
IR(KBr)vmax:3425,1605,1513,1436,1339,1228,1169,1142,1105cm–1
ECD(c 0.10,MeOH)λmax(Δε):224(-1.53),247(-1.52),368(-0.44)nm
1H-NMR和13C-NMR(DEPT)数据见表1和3。
表413C NMR(150MHz,CD3OD,δin ppm)data of compounds 6and 7
实施例2:
PTP1B和α-葡萄糖苷酶抑制活性。
1材料和方法
1.1材料
α-葡萄糖苷酶(Sigma Aldrich,St.Louis,MO,USA);磷酸盐缓冲液(≥99%,美仑生物,大连);对硝基苯基-α-D-吡喃葡萄糖(≥99%,源叶生物,上海);阿卡波糖(≥98%,拜耳医药,北京);PTP1B(10304-H07E,蛋白酪氨酸磷酸酶)和TCPTP(10570-HNCB)购自SinoBiological(Wayne,PA,USA);苏拉明钠购自ACROS(New Jersey USA)
1.2仪器
Flex Station 3台式多功能酶标仪(Bio-RAD 680,美国);分析天平(AG135,Metler Toledo,中国);恒温箱(DHP-9082,上海)。
1.3实验过程
PTP1B和TCPTP抑制活性是根据本发明人先前的研究进行的。简言之,工作缓冲液(working buffer,WB)是由3-(N-吗啉代)丙磺酸(MOPS,722.02mg)、二硫苏糖醇(DTT,30mg)、EDTA(25.7mg)、牛血清蛋白(BSA,200mg)和NaCl(12.1g)溶于100mL超纯水配制而成。溶解在1mL超纯水中p-硝基苯基磷酸盐(p-NPP,31mg)作为底物。将70μL WB、10μL PTP1B酶(5mg/L)和10μL溶解在DMSO中的待测样品依次添加到96孔板中,在37℃下孵育15min后,通过加入10μL 100mM p-NPP引发反应,之后孵育30min。在反应混合物中加入100μL 0.1MNa2CO3溶液终止反应,用酶标仪在405nm处测定吸光值,记录结果。阴性对照用DMSO代替待测溶液,阳性为苏拉明钠,其他方法相同。PTP1B/TCPTP抑制率计算公式为抑制率(%)=(△酶-△样/△酶-△阴)×100%。利用Graphpad prism 5软件对实验结果进行分析。
α-葡萄糖苷酶抑制活性测试采用文献报道的方法进行了轻微改良。阿卡波糖为阳性对照,硝基苯基-α-葡萄糖(PNPG)作为底物。将20μL溶解在磷酸盐缓冲液(PB,pH=7)中的0.2U/mLα-葡萄糖苷酶和30μL溶解在MeOH-PB(50:50)中的待测样品依次加入到96孔板中。实验的空白用相同的方法,只是将PB代替α-葡萄糖苷酶。混合液在37℃恒温箱中孵育5分钟后,将底物20μL 5.0mM PNPG依次加到96孔板引发反应,反应混合物在37℃恒温箱中孵育15分钟后,通过加入40μL 0.1M Na2CO3终止反应。用酶标仪在405nm处测定吸光值,记录结果。阴性对照用PB代替待测溶液,其他方法相同。α-葡萄糖苷酶抑制率计算公式为:抑制率(%)=(△酶-△样/△酶-△阴)×100%。利用Graphpad prism 5软件对实验结果进行分析。
2.结果:
化合物1–3、5–7和11–16对PTP1B酶抑制活性如表5所示,所有化合物均对PTP1B和TCPTP具有明显的选择性抑制活性,其IC50值在22.0到119.8μM之间。
化合物1–3、5–7和10–16对α-葡萄糖苷酶表现出明显的抑制活性,其IC50值在3.1到23.8μM之间,以上结果表明草豆蔻中所有被测化合物可作为新型的α-葡萄糖苷酶抑制剂,以及作为药物用于治疗糖尿病相关的疾病。
表5.化合物的PTP1B、TCPTP和α-葡萄糖苷酶抑制活性a
aIC50从三次独立的实验中得到.
由上述可知,化合物1–7、11–16对PTP1B显示显著抑制活性,所有化合物对α-葡萄糖苷酶显示显著抑制活性,具有降血糖作用。
制剂实施例:
1.按实施例1的方法制备得到化合物1–16,用少量的DMSO溶解后,按常规加注射用水,精滤,灌封灭菌制成注射液。
2.按实施例1的方法制备得到化合物1–16,用少量的DMSO溶解后,将其溶于无菌注射用水中,搅拌使溶解,用无菌抽滤漏斗过滤,再无菌精滤,分装于安瓿中,低温冷冻干燥后无菌熔封得粉针剂。
3.按实施例1的方法先制备得到化合物1–16,按其与赋形剂重量比为9:1的比例加入赋形剂,制成粉剂。
4.按实施例1的方法先制备得到化合物1–16,按其与赋形剂重量比为5:1的比例加入赋形剂,制粒压片。
5.按实施例1的方法先制备得到化合物1–16,按常规口服液制法制成口服液。
6.按实施例1的方法先制备得到化合物1–16,按其与赋形剂重量比为5:1的比例加入赋形剂,制成胶囊。
7.按实施例1的方法先制得化合物1–16,按其与赋形剂重量比为3:1的比例加入赋形剂,制成胶囊。
8.按实施例1的方法先制备得到化合物1–16,按其与赋形剂重量比为5:1的比例加入赋形剂,制成颗粒剂。
Claims (10)
3.权利要求2所述的式(I)中的化合物1-9、11-16在制备蛋白质酪氨酸磷酸酶1B(PTP1B)抑制剂药物中的应用。
4.权利要求2所述的式(I)中的化合物1–16在制备降血糖药物中的应用。
5.制备权利要求1所述的化合物1和2的方法,取草豆蔻Alpinia katsumadai的干燥种子,粉碎,用90%乙醇回流提取3次,每次2h,合并乙醇提液,减压回收乙醇得浸膏,浸膏分散在水中后用乙酸乙酯萃取,随后浓缩得到乙酸乙酯萃取部分,然后将乙酸乙酯萃取部分Fr.A过硅胶柱层析,以甲醇-氯仿为洗脱剂,以0:100、2:98、5:95、10:90、20:80和100:0v/v进行梯度洗脱,得到Fr.A-1~Fr.A-8八个流分;流分Fr.A-5经MCI CHP 20P gel柱层析,系统体系为甲醇-水,40:60、60:40、70:30、80:20、90:10和100:0进行洗脱,得到七个亚流分Fr.A-5-1~Fr.A-5-7;Fr.A-5-4经反相C18柱层析,以甲醇-水为洗脱剂,以40:60、50:50、60:40、70:30和100:0比例进行洗脱,得到七个亚流分Fr.A-5-4-1~Fr.A-5-4-7;Fr.A-5-4-3经硅胶柱层析,MeOH-CHCl3,6:94、Sephadex LH-20柱层析,氯仿-甲醇50:50和半制备高效液相色谱,MeCN-H2O,40:60,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm进行洗脱,得到化合物1,2。
6.包含权利要求1所述的化合物1或2中的至少一种和药学上可接受的载体的药物组合物。
7.权利要求6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。
8.权利要求6所述的药物组合物在制备蛋白质酪氨酸磷酸酶1B(PTP1B)抑制剂药物中的应用。
9.权利要求6所述的药物组合物在制备降血糖药物中的应用。
10.制备权利要求6所述的药物组合物的方法,取草豆蔻Alpinia katsumadai的干燥种子,粉碎,用90%乙醇回流提取3次,每次2h,合并乙醇提液,减压回收乙醇得浸膏,浸膏分散在水中后用乙酸乙酯萃取,随后浓缩得到乙酸乙酯萃取部分,然后将乙酸乙酯萃取部分Fr.A过硅胶柱层析,以甲醇-氯仿为洗脱剂,以0:100、2:98、5:95、10:90、20:80和100:0v/v进行梯度洗脱,得到Fr.A-1~Fr.A-8八个流分;流分Fr.A-5经MCI CHP 20P gel柱层析,系统体系为甲醇-水,40:60、60:40、70:30、80:20、90:10和100:0进行洗脱,得到七个亚流分Fr.A-5-1~Fr.A-5-7;Fr.A-5-4经反相C18柱层析,以甲醇-水为洗脱剂,以40:60、50:50、60:40、70:30和100:0比例进行洗脱,得到七个亚流分Fr.A-5-4-1~Fr.A-5-4-7;Fr.A-5-4-3经硅胶柱层析,MeOH-CHCl3,6:94、Sephadex LH-20柱层析,氯仿-甲醇50:50和半制备高效液相色谱,MeCN-H2O,40:60,3.0mL/min,Agilent XDB-C18柱,9.4×250mm,5μm进行洗脱,得到化合物1,2;再以化合物1–2为原料加入一定比例的可药用载体。
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