CN1108306C - 一种新皂甙化合物及其制备方法和用途 - Google Patents
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Abstract
本发明涉及一种通式为(I)的新皂甙化合物，该新皂甙化合物具有降糖、降脂或抗血小板凝聚的作用。此外本发明还涉及该新皂甙化合物的制备方法及其在制药方面的用途，尤其是在制备治疗糖尿病药物方面的用途。
Description
本发明涉及一种新皂甙化合物，该化合物具有降糖、降脂和抗血小板凝聚作用，本发明还涉及该化合物的制备方法及其用途，尤其是在制备治疗糖尿病药物方面的用途。
匙羹藤为萝摩科植物Gymnema sylvestre R.Br。由于它在印度民间用来抗肿毒、蛇伤、解疟、利尿和降血糖等，所以人们对它所含的成分进行了许多研究和报导，发现其中所含的匙羹藤酸具有降糖活性。发明人在前人研究的基础上进一步研究，发现在匙羹藤中还有一种新皂甙化合物，到目前为止，尚没有发现有文献报导。这种新皂甙化合物也具有降糖活性。
本发明的目的是提供一种新皂甙化合物。
本发明的另一目的是提供该皂甙化合物的制备方法。
本发明的又一目的是提供该皂甙化合物的用途。
本发明所述的新皂甙化合物具有下列通式(I)：或
当R1为
时，R2为氢原子或
本发明新皂甙化合物可通过下列方法得到：
a)匙羹藤干叶，粉碎，用60-95％的乙醇回流提取3次，每次2小时，合并提取液，减压回收至无醇味，得到浓缩液，备用；
b)把所得到的浓缩液用环己烷萃取3-6次，然后再用正丁醇萃取，把正丁醇部分减压回收至干浸膏，备用；
c)将步骤b)得到的干浸膏中拌入粗硅胶，处理后待上柱；使用硅胶H的薄层层析分离，用氯仿—甲醇比例为90∶10-50∶50的混合液在样品上样后加压柱层析，分别得到式(I)的新皂甙化合物。其中当R1为氢原子并且R2为
时，这种新皂甙化合物(下称化合物A)具有下列理化数据：
无定形粉末；mp206-209℃；[α]20 D-16.0°(c0.11，MeOH)；IRνmax3424(OH)，1735(COOR)，1636(C＝C)，1457，1034cm-1，1H NMR(400MHz，pyridine-d5)δ0.82(3H，s，Me)，0.87(3H，s，Me)，0.91(3H，s，Me)，0.97(3H，s，Me)，1.07(3H，s，Me)，1.20(3H，s，Me)，1.23(3H，s，Me)，3.17(1H，dd，J＝3.5和10.2Hz，H-18)，3.30(1H，dd，J＝3.9和11.7Hz，H-3α)，5.37(1H，brs，H-12)；13C NMR(100 MHz，pyridine-d5)见表1与表2；FABMS m/z 943[M+H]+。当R1为
R2为氢原子时，这种新皂甙化合物(下称化合物B)具有下列理化数据：
无定形粉末；mp202-204℃；[α]20 D-3.2°(c0.15，MeOH)；IRνmax3410(OH)，1710(COOH)，1638(C＝C)，1458，1036cm-1，1H NMR(400MHz，pyridine-d5)δ0.87(3H，s，Me)，0.91(3H，s，Me)，0.96(3H，s，Me)，1.02(3H，s，Me)，1.10(3H，s，Me)，1.24(3H，s，Me)，1.29(3H，s，Me)，3.30(1H，dd，J＝4.5和11.5Hz，H-3α)，5.38(1H，br s，H-12)；13C NMR(100MHz，pyridine-d5)见表1与表2；FABMS m/z 935[M+Na]+。当R1为
R2为
时，这种新皂甙化合物(下称化合物C)具有下列理化数据：
无定形粉末；mp212-215℃；[α]20 D-9.6°(c0.20，MeOH)；IRνmax3414(OH)，1740(COOR)，1636(C＝C)，1460，1364，1044，896cm-1，1H NMR(500MHz，pyridine-d5)δ0.85(3H，s，Me)，0.90(3H，s，Me)，0.94(3H，s，Me)，1.00(3H，s，Me)，3.19(1H，dd，J＝4.0和13.7Hz，H-18)，3.32(1H，dd，J＝4.4和11.7Hz，H-3α)，5.40(1H，br s，H-12)；13C NMR(125MHz，pyridine-d5)见表1与表2；FABMS m/z 1097[M+Na]+。当R1为氢原子，R2 时，这种新皂甙化合物(下称化合物D)具有下列理化数据：
无定形粉末；mp 209-211℃；[α]20 D-12.1°(c0.12，MeOH)；IRνmax3424(OH)，1734(COOR)，1636(C＝C)，1458，1074cm-1，1HNMR(500MHz，pyridine-d5)δ0.87(3H，s，Me)，0.90(3H，s，Me)，0.92(3H，s，Me)，1.00(3H，s，Me)，1.09(3H，s，Me)，1.22(3H，s，Me)，1.26(3H，s，Me)，3.20(1H，dd，J＝3.5和13.6Hz，H-18)，3.33(1H，dd，J＝4.4和11.5Hz，H-3α)，5.39(1H，br s，H-12)；13C NMR(125MHz，pyridine-d5)见表1与表2；FABMS m/z 1127[M+Na]+。
表1：化合物A-D的糖甙配基部分的13C NMR的数据
| 碳原子 | 化合物A | 化合物B | 化合物C | 化合物D |
| 1 | 38.8 | 38.7 | 38.7 | 38.7 |
| 2 | 26.6 | 26.7 | 26.7 | 26.7 |
| 3 | 88.9 | 89.0 | 89.0 | 89.0 |
| 4 | 39.4 | 39.5 | 39.5 | 39.5 |
| 5 | 55.7 | 55.8 | 55.8 | 55.8 |
| 6 | 18.4 | 18.3 | 18.5 | 18.5 |
| 7 | 33.0 | 33.1 | 33.1 | 33.1 |
| 8 | 39.8 | 39.9 | 39.9 | 39.9 |
| 9 | 47.9 | 48.0 | 48.0 | 48.0 |
| 10 | 36.9 | 37.0 | 37.0 | 37.0 |
| 11 | 23.7 | 23.7 | 23.8 | 23.7 |
| 12 | 122.9 | 122.8 | 123.0 | 122.9 |
| 13 | 144.0 | 144.4 | 144.0 | 144.1 |
| 14 | 42.0 | 42.1 | 42.1 | 42.1 |
| 15 | 28.2 | 28.2 | 28.2 | 28.2 |
| 16 | 23.3 | 23.4 | 23.4 | 23.4 |
| 17 | 46.9 | 46.5 | 47.0 | 47.0 |
| 18 | 41.6 | 41.9 | 41.7 | 41.7 |
| 19 | 46.2 | 46.1 | 46.2 | 46.3 |
| 20 | 30.7 | 30.9 | 30.8 | 30.8 |
| 21 | 33.9 | 34.4 | 34.0 | 34.0 |
| 22 | 32.5 | 33.1 | 32.5 | 32.5 |
| 23 | 28.1 | 28.2 | 28.2 | 28.3 |
| 24 | 17.0 | 17.0 | 17.0 | 17.0 |
| 25 | 15.5 | 15.8 | 15.6 | 15.6 |
| 26 | 17.4 | 17.3 | 17.5 | 17.5 |
| 27 | 26.0 | 26.1 | 26.1 | 26.1 |
| 28 | 176.4 | 180.2 | 176.5 | 176.5 |
| 29 | 33.1 | 33.2 | 33.2 | 33.2 |
| 30 | 23.6 | 23.7 | 23.7 | 23.7 |
表2：化合物A-D的糖部分的13C NMR数据
| C-3 | 化合物A | 化合物B | 化合物C | 化合物D |
| Glc 1 | 106.9 | 107.0 | 107.0 | 106.9 |
| Glc 2 | 75.1 | 75.0 | 75.0 | 75.2 |
| Glc 3 | 78.4 | 78.3 | 78.3 | 78.4 |
| Glc 4 | 71.6 | 71.5 | 71.5 | 71.5 |
| Glc 5 | 77.0 | 77.0 | 77.0 | 77.0 |
| Glc 6 | 70.4 | 70.4 | 70.4 | 70.5 |
| Glc’1 | 105.4 | 105.4 | 105.4 | 105.4 |
| Glc’2 | 75.5 | 75.6 | 75.6 | 75.6 |
| Glc’3 | 78.5 | 78.5 | 78.5 | 78.6 |
| Glc’4 | 71.7 | 71.6 | 71.6 | 71.7 |
| Glc’5 | 78.4 | 76.9 | 76.9 | 78.5 |
| Glc’6 | 62.7 | 69.8 | 69.8 | 62.6 |
| Xyl 1 | 106.0 | 106.0 | ||
| Xyl 2 | 74.9 | 74.9 |
| Xyl 3 | 78.0 | 78.1 | ||
| Xyl 4 | 71.1 | 71.1 | ||
| Xyl 5 | 67.0 | 67.1 | ||
| C-28 | ||||
| Glc”1 | 95.7 | 95.8 | 95.7 | |
| Glc”2 | 74.1 | 74.1 | 73.9 | |
| Glc”3 | 78.8 | 78.9 | 78.7 | |
| Glc”4 | 71.0 | 71.1 | 70.9 | |
| Glc”5 | 79.3 | 79.3 | 78.0 | |
| Glc”6 | 62.1 | 62.2 | 69.3 | |
| Glc1 | 105.3 | |||
| Glc2 | 75.2 | |||
| Glc3 | 78.5 | |||
| Glc4 | 71.7 | |||
| Glc5 | 78.4 | |||
| Glc6 | 62.7 |
试验证明，含有通式(I)的新皂甙化合物具有降糖、降脂和抗血小板凝聚的作用。
以下通过实施例和试验例对本发明新皂甙化合物作详细说明。
实施例1
匙羹藤叶粗粉1000g，用75％的乙醇回流提取三次，每次体积为6.0L，时间各2小时，合并乙醇提取液，把该乙醇提取液减压回收至无醇味，把浓缩液用0.5L的环己烷丁醇萃取3次，合并正丁醇萃取液，减压回收，得到干浸膏状物72.0g。取36.0g干浸膏状物，拌入60-100目的粗硅胶60g，用水浴锅蒸发至干，待上样。用400g薄层层析用的200-400目的硅胶H，湿法装柱，样品上样后，用90∶10-50∶50的氯仿-甲醇混合液进行加压柱层析，分别得到新皂甙化合物A(130mg)、化合物B(115mg)、化合物C(160mg)和化合物D(195mg)。试验例1
本发明新皂甙化合物对小鼠血糖升高的影响
雄性昆明种小鼠，随机分成实验组，分别口服本发明新皂甙化合物50，100，200mg/kg，阳性对照组分别口服优降糖50mg/kg，空白对照组及正常对照组口服等量蒸馏水，给药体积为20ml/kg，连续7天，末次给药前禁食10h，除正常对照组外，各组口服给予葡糖溶液2.5g/kg(10ml/kg)，分别于葡糖前和葡糖后30min，由眼眶采血100ul，按葡糖氧化酶法，测定血清中的葡糖含量。
结果，小鼠口服葡糖30min，血糖明显升高，本发明新皂甙化合物100，200mg/kg及优降糖50mg/kg均显著抑制小鼠血糖升高，本发明新皂甙化合物200mg/kg的降糖作用与优降糖50mg/kg相近，见下表3。
表3
| 组别 | 剂量(mg/kg) | 血糖值(mmol/L) | |
| 0(min) | 30(min) | ||
| 正常组 | 6.20±1.01 | 6.64±1.04 | |
| 对照组 | 6.55±1.16 | 13.94±3.22ΔΔ | |
| 本发明新皂甙化合物 | 50 | 6.79±1.16 | 12.01±1.88 |
| 100 | 6.09±1.34 | 9.59±2.25** | |
| 200 | 6.42±0.99 | 9.16±1.08** | |
| 优降糖 | 50 | 4.48±0.83** | 8.18±1.72** |
ΔΔP＜0.01，与正常组比较；**P＜0.01，与对照组比较。试验例2
本发明新皂甙化合物对高脂血症大鼠血清甘油三酯、胆固醇含量的影响
雄性SD大鼠，体重130-170g，正常组给予普通饲料，其它各组给予高脂饲料(1％胆固醇、10％猪油、0.3％胆酸、0.2％甲硫基咪唑和88.5％普通饲料，自制成块状饲料)。连续14天，大鼠禁食12小时后，按试剂盒法测定大鼠血清甘油三酯及胆固醇含量，然后，按血脂值进行随机分组。实验组口服给予50、100、200mg/kg，阳性对照组分别口服安妥明100mg/kg，对照组给予蒸馏水，给药体积为10ml/kg，连续10天，各组在给药前5天仍饲以高脂饲料，后5天饲以普通饲料，末次给药前禁食11小时，给药后1小时采血测血清中甘油三酯及胆固醇含量。
结果，大鼠给予高脂饲料10天后，血清甘油三酯及胆固醇含量明显升高，本发明新皂甙化合物50、100、200mg/kg及安妥明100mg/kg均使高脂血症大鼠血清甘油三酯及胆固醇水平明显下降，本发明新皂甙化合物200mg/kg的降血脂作用与安妥明100mg/kg相近，见表4。表4：本发明化合物对高脂血症大鼠血脂含量的影响(X±SD，
n＝9-10)
| 组别 | 剂量(mg/kg) | 甘油三酯(mmol/L) | 总胆固醇(mmol/L) | ||
| 给药前 | 给药后 | 给药前 | 给药后 | ||
| 正常组 | 1.02±0.22 | 1.04±0.15 | 2.43±0.41 | 1.99±0.47 | |
| 对照组 | 2.64±0.82 | 3.04±0.93 | 4.10±0.51ΔΔ | 4.77±0.63ΔΔ | |
| 本发明新皂甙化合物 | 50 | 2.72±0.61 | 2.41±0.44 | 4.29±0.60 | 3.92±0.58** |
| 100 | 2.54±0.90 | 1.75±0.53** | 4.02±0.59 | 2.94±0.66** | |
| 200 | 2.72±0.76 | 1.37±0.40** | 4.18±0.61 | 2.31±0.74** | |
| 安妥明 | 100 | 2.51±0.77 | 2.72±0.74 | 4.33±0.51 | 2.15±0.76** |
ΔΔP＜0.01，与正常组比较；**P＜0.01，与对照组比较试验例3
本发明新皂甙化合物对体外家兔血小板聚集的影响
家兔心脏穿刺取血，3.8％枸橼酸钾抗凝(1∶9)1000rpm离心5min，取上层作为富血小板血浆(PRP)，再以4000rpm离心10min，上清夜为贫血小板血浆(PPP)。将终浓度分别为250，500，1000ug/ml，阳性对照管加入阿斯匹林生理盐水溶液10ul，终浓度为250ug/ml，空白对照管加入生理盐水10ul，终浓度为1.0×10-5M，在PAM-1型血小板聚集仪上观察3min内的最大聚集率。
结果，本发明新皂甙化合物500，1000ug/ml，阿斯匹林250ug/ml显著抑制家兔血小板聚集，结果见表5。表5：本发明新皂甙化合物对体外家兔血小板聚集的影响(X±SD，
n＝8)
| 组别 | 终浓度(ug/ml) | 最大聚集率(％) | 抑制率(％) |
| 对照组 | 47.9±5.2 | ||
| 250 | 43.6±7.0 | 9.0 | |
| 500 | 35.9±4.5** | 25.1 | |
| 1000 | 27.8±4.8** | 42.0 | |
| 阿斯匹林 | 250 | 23.7±6.0** | 50.3 |
**P＜0.01，与对照组比较。
Claims (5)
- 或
当R1为 时，R2为氢原子
- 2.权利要求1的新皂甙化合物的制备方法，包括下列步骤：a)匙羹藤干叶，粉碎，用60-95％的乙醇回流提取三次，每次2小时，合并提取液，减压回收至无醇味，得到浓缩液，备用；b)把所得到的浓缩液用环己烷萃取3-6次，然后再用正丁醇萃取，把正丁醇部分减压回收至干浸膏，备用；c)将步骤b)得到的干浸膏中拌入粗硅胶，处理后待上柱；使用硅胶H的薄层层析分离，用氯仿—甲醇比例为90∶10-50∶50的混合液在样品上样后加压柱层析，分别得到式(I)的新皂甙化合物。
- 3.权利要求1的新皂甙化合物在制备药物方面的用途。
- 4.根据权利要求3，其中所述的药物具有降糖、降脂或抗血小板聚集的功效。
- 5.根据权利要求3，其中所述的药物能够治疗糖尿病。
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
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| CN99100721A CN1108306C (zh) | 1999-02-11 | 1999-02-11 | 一种新皂甙化合物及其制备方法和用途 |
| AU20909/00A AU2090900A (en) | 1999-02-11 | 2000-01-21 | Novel gymnemic acid derivatives, process for the preparation thereof and use thereof as medicine |
| JP2000598513A JP4903309B2 (ja) | 1999-02-11 | 2000-01-21 | 新規ギムネマ酸誘導体、その製造、それらを含む医薬組成物、およびそれらの医薬的使用 |
| US09/913,322 US6833443B1 (en) | 1999-02-11 | 2000-01-21 | Gymnemic acid derivatives, process for the preparation thereof and use thereof as medicine |
| KR1020017010217A KR100625222B1 (ko) | 1999-02-11 | 2000-01-21 | 신규 짐넴산 유도체, 그 제조 방법, 및 그의 약학적 용도 |
| PCT/CN2000/000010 WO2000047594A1 (fr) | 1999-02-11 | 2000-01-21 | Nouveau derives d'acide gymnemique, leur procede de preparation et leur application comme medicaments |
| EP00901035A EP1176149B1 (en) | 1999-02-11 | 2000-01-21 | Novel gymnemic acid derivatives, process for the preparation thereof and use thereof as medicine |
| CA2362864A CA2362864C (en) | 1999-02-11 | 2000-01-21 | New gymnemic acid derivatives, their preparation, pharmaceutical composition containing them and their medical use |
| DE60004353T DE60004353T2 (de) | 1999-02-11 | 2000-01-21 | Derivate der gymnemischen säure, verfahren zu ihrer herstellung und ihre verwendung als medikamente |
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| US5843909A (en) * | 1997-06-13 | 1998-12-01 | Kowa Chemical Industries Co., Ltd. | (3-β), 4-α, 16-β)-16, -23, 28-trihdroxyolean-12-ene-3-yl-β-D-glucopyranuronic acid derivatives, as glucose absorption inhibiting agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5843909A (en) * | 1997-06-13 | 1998-12-01 | Kowa Chemical Industries Co., Ltd. | (3-β), 4-α, 16-β)-16, -23, 28-trihdroxyolean-12-ene-3-yl-β-D-glucopyranuronic acid derivatives, as glucose absorption inhibiting agents |
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