WO2013138964A1 - 异瑞香新素化合物在制备抗糖尿病药物中的应用 - Google Patents

异瑞香新素化合物在制备抗糖尿病药物中的应用 Download PDF

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WO2013138964A1
WO2013138964A1 PCT/CN2012/001297 CN2012001297W WO2013138964A1 WO 2013138964 A1 WO2013138964 A1 WO 2013138964A1 CN 2012001297 W CN2012001297 W CN 2012001297W WO 2013138964 A1 WO2013138964 A1 WO 2013138964A1
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daphnetin
rats
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张卫东
单磊
苏娟
李慧梁
柳润辉
沈云亨
徐希科
张寿德
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中国人民解放军第二军医大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

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  • the invention relates to drugs. Specifically, it relates to the use of iso-rhimelin compounds in the preparation of anti-diabetic drugs. Background technique
  • Oral anti-hyperglycemic drugs commonly used in clinical practice include: PPAR Y agonists, sulfonylureas that promote insulin secretion, Lenin, and biguanides.
  • the above drugs are only effective within a certain range, can not effectively control the development of diabetes, and have limited tolerance or varying degrees of adverse reactions, such as: glucose intolerance, hypoglycemia, weight gain, lactic acidosis and edema.
  • Isoflavin is from the Daphne plant of Phylaceae (Daphne), Phnom Penh (Daphne)
  • Source s Phnom Penh Daphne odora Thunb. var. marginata There are about 44 species of Chinese genus, which are rich in resources. Its roots, stems, leaves and flowers can be used as medicines. It is sweet and non-toxic. It has the functions of clearing heat and reducing fire, reducing inflammation, swelling, promoting blood circulation, and relieving pain. According to the "Chinese Medicine Dictionary", Ruixiang leaves can cure sore and wind pain; flowers can cure sore and swollen teeth; roots can cure snake bites, bruises and other diseases. In recent years, there have been many studies on the pharmacological activities of the extracts of Rhizoma rugulosa.
  • Jinbian Ruixiang is small. The cellular immunity, non-specific immunity and erythrocyte immune function of the mouse are promoted. The inventors conducted a systematic chemical composition study on Jinbian Ruixiang, and found that the chemical component of ruthenium has a good anti-diabetic effect. So far, there has been no report on the anti-diabetic effect of Phnom Penh. Summary of the invention
  • the technical problem to be solved by the present invention is to overcome the above-mentioned deficiencies, to study the new use of the sirolimus, and to design an effective anti-diabetic drug.
  • the present invention provides the use of isolisin in the preparation of an antidiabetic drug.
  • the ruthenium sulphate provided by the invention is obtained by the following method - the medicinal material of Phnom Penh is extracted by 75% ethanol, and the extract is concentrated under reduced pressure to obtain an extract, and the obtained crude extract is extracted with petroleum ether, chloroform and ethyl acetate respectively. , the ethyl acetate fraction was subjected to repeated silica gel H (200 to 300 mesh) column chromatography, chloroform: acetone (10: 1-1: 1), chloroform: methanol (50: 1-1: 1) gradient elution, Sephadex LH -20 column chromatography and reverse phase silica gel (Merck), the compound was obtained.
  • the invention adopts a high-sugar and high-fat diet combined with a low-dose streptozotocin (STZ) type 2 diabetic rat model, which is in line with the pathogenesis of human common type 2 diabetes, and is beneficial for the discovery of therapeutic drugs for type 2 diabetes.
  • STZ streptozotocin
  • the results of the experiment showed that the blood glucose level and glucagon level of type 2 diabetic rats decreased significantly after treatment with iso-rhimexin (P ⁇ 0.01), while insulin increased significantly, and there was no significant difference in blood glucose between the groups. (P>0.05). Therefore, isorubicin can be used to prepare an anti-diabetic drug.
  • the oral hypoglycemic agent metformin was used as a positive control, and the results showed that the isoxanthin and the positive drug metformin have considerable activity and have the functions of protecting and repairing islet cells.
  • the pharmaceutical composition of the present invention comprises a pharmaceutical composition comprising isosericin as an active ingredient and a pharmaceutically acceptable carrier.
  • the invention has good anti-diabetic effect, and has the functions of protecting and repairing islet cells.
  • the active ingredient isorubicin is derived from an extract of natural products, and is superior to chemical drugs and hypoglycemic agents in side effects and the like. Large clinical application value. detailed description
  • Phnom Penh fragrant herbs (commercially available) were pulverized and extracted with 150L 75% ethanol. The extract was concentrated under reduced pressure to obtain 8L extract. After the extract was diluted with 10L of water, 100L petroleum ether and 100L chloroform were used. 100 L of ethyl acetate was extracted, and the ethyl acetate fraction was collected and weighed to 125 g. The ethyl acetate fraction was subjected to two times of silica gel H (200 to 300 mesh) column chromatography, chloroform:acetone (10 : 1 to 1 : 1), chloroform. : Methanol (50: 1 ⁇ 1: 1) gradient elution, Sephadex LH-20 column chromatography and reversed-phase silica gel (Merck), to obtain 108 mg of the compound isotretin.
  • Example 2 The isoericin prepared in Example 1 was used in the following experiment.
  • Example 2 The isoericin prepared in Example 1 was used in the following experiment.
  • Material Irradix is prepared by the preparation of Example 1.
  • Model establishment 60 healthy Wi star rats, 10 randomly selected as normal control group (I), fed with conventional diet. 50 rats of the model were replicated. After 8 weeks of high-calorie diet, a small dose of 35 mg I kg STZ was intraperitoneally injected (STZ was diluted to 1 with 0.1 mol of sodium citrate-sodium citrate solution (pH 4.0). % of the solution), 72 h after the determination of fasting blood glucose stable at 11 mmol I blood glucose 29 ramol IL for the type 2 diabetes model required for this trial.
  • the diabetic model rats were randomly divided into 5 groups according to the blood glucose level, and 10 rats in each group were: normal control group (1), diabetes model group (11), low-dose group of different components (111), medium dose Group (IV), high dose group (V) (dissolved in a solution of 0.5% sodium carboxymethylcellulose (CMC-Na)) and metformin positive control (VI). 5% ⁇ carboxymethylcellulose was administered to groups I and II, respectively.
  • the above experiments show that the isoforms of the present invention are related to the type 2 sugar established by streptozotocin (STZ) combined with high fat diet.
  • STZ streptozotocin
  • the urinary rat model has better glycemic inhibitory activity and is equivalent to the positive drug metformin.
  • the changes of serum insulin and glucagon levels in this experiment indicate that isorubicin has the function of protecting and repairing islet cells, and can reduce the level of glucagon in serum and inhibit the possible pathogenesis of diabetes. . Therefore, isorubicin can be developed as a drug for treating diabetes.

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Abstract

本发明提供了异瑞香新素在制备抗糖尿病药物中的应用，其特征在于，所述异瑞香新素结构式（I）。本发明应用高糖高脂饲料结合小剂量链脲佐菌素（STZ）2型糖尿病大鼠模型，将雄性SD成年大鼠高糖高脂饲料喂养1个月，诱发出胰岛素抵抗，给予小剂量链脲佐菌素（STZ）25mg/kg，腹腔注射，建立2型糖尿病大鼠模型。然后腹腔注射给予药物，将老鼠的血糖、血清胰岛素、胰高血糖素、精神状态、体重、饮水量、食量等作为检测指标。实验结果显示，用异瑞香新素治疗后，2型糖尿病大鼠的血糖值和血清胰岛素水平明显的下降（P<0.01），而胰岛素明显升高各剂量组间血糖值无显著差异（P>0.05）。因此，异瑞香新素可以用于制备抗糖尿病药物。本发明所述药物由异瑞香新素作为活性成分与药用载体组成的药物组合物。

Description

异瑞香新素化合物在制备抗糖尿病药物中的应用 技术领域
本发明涉及药物。 具体涉及异瑞香新素化合物在制备抗糖尿病药物中的应 用。 背景技术
近年来， 2型糖尿病的发病率逐年攀升，严重威胁着人类健康。 目前研究表明， 2型糖尿病患者主要有三方面的缺陷:胰岛素抵抗、 β细胞功能障碍和肝葡萄糖过 度产生 。 临床常用的口服抗高血糖药包括： PPAR Y激动剂、 促进胰岛素分泌药 物磺酰脲类，列奈类以及双胍类等。以上药物仅在一定范围内有效,不能有效控制 糖尿病的发展,而且耐受性有限或有不同程度的不良反应，如:葡萄糖耐受不良、 低血糖症、 体重增加、 乳酸中毒和水肿等。
异瑞香新素来自瑞香科（Thymelaeaceae)瑞香属（Daphne)植物金边瑞香（Daphne
异瑞香新素结构：
Figure imgf000003_0001
来源 s 金边瑞香 Daphne odora Thunb. var. marginata 在中国瑞香属植物约有 44种，资源丰富。 其根、 茎、 叶、 花均可入药， 性甘 无毒， 具有清热降火、 消炎去肿活血化瘀、 散结止痛之功能。 据 《中药大辞典》 汇辑， 瑞香叶能治疮疡、风痛； 花可治咽喉牙齿肿痛； 根茎能治毒蛇咬伤、跌打 损伤等疾病。近几年对金边瑞香总提物的药理活性研究较多，但未见有化学研究 的报道， 具有镇痛作用、耐缺氧作用、抗脂质过氧化和抗衰老作用， 此外金边瑞 香对小鼠的细胞免疫、非特异性免疫和红细胞免疫功能有促进作用。本发明人对 金边瑞香进行了***的化学成分研究，经筛选发现了化学成分异瑞香新素具有较 好的抗糖尿病药效， 至今尚未见金边瑞香抗糖尿病药效的报道。 发明内容
本发明所要解决的技术问题在于克服上述不足之处，研究异瑞香新素的新用 途， 设计有效的抗糖尿病药物。 本发明提供了异瑞香新素在制备抗糖尿病药物中的应用。
本发明提供的异瑞香新素通过下列方法制得- 金边瑞香药材以 75%乙醇渗漉提取， 提取液减压浓缩得浸膏， 得到的粗提物 分别用石油醚、 氯仿、 乙酸乙酯萃取， 乙酸乙酯部分别经反复硅胶 H(200〜300 目)柱色谱， 氯仿： 丙酮 (10: 1-1： 1), 氯仿： 甲醇 (50:1-1:1)梯度洗脱， Sephadex LH-20柱色谱以及反相硅胶 (Merck), 分离得到化合物异瑞香新素。
本发明应用高糖高脂饲料结合小剂量链脲佐菌素 (STZ) 2型糖尿病大鼠模型， 此模型较符合人类普通型 2型糖尿病发病机制，有利于进行 2型糖尿病治疗药物的 发现。 我们将雄性 SD成年大鼠高糖高脂饲料喂养 1个月，诱发出胰岛素抵抗，给予 小剂量链脲佐菌素（ STZ) 25 mg/kg，腹腔注射，建立 2型糖尿病大鼠模型。然后腹腔 注射给予药物， 将老鼠的血糖、 血清胰岛素、 胰高血糖素、 精神状态、 体重、饮 水量、 食量、 大小便做为检测指标。 实验结果显示， 经过异瑞香新素治疗后， 2 型糖尿病大鼠的血糖值和胰高血糖素水平明显的下降 (P<0.01)， 而胰岛素明显升 高， 各剂量组间血糖值无显著差异 (P>0.05)。 因此， 异瑞香新素可以用于制备抗 糖尿病药物。本发明实验中， 以口服类降糖药二甲双胍作为阳性对照， 结果表明 异瑞香新素和阳性药二甲双胍具有相当的活性，并且具有保护和修复胰岛细胞的 作用。
本发明所述药物由异瑞香新素作为活性成分与药用载体组成的药物组合物。 本发明具有较好的抗糖尿病药效， 并且具有保护和修复胰岛细胞的作用，另 外，活性成分异瑞香新素来自天然产物的提取物，在副作用等方面优于化学药类 降糖药， 有较大的临床应用价值。 具体实施方式
实施例 1
异瑞香新素制备
7. 5kg金边瑞香药材 (市售)经粉碎后以 150L 75%乙醇渗漉提取， 提取液减压浓縮 得 8L浸膏， 浸膏加 10L水稀释后， 依次用 100L石油醚、 100L氯仿、 100L乙酸乙酯 萃取， 收集乙酸乙酯部位， 称重为 125g， 乙酸乙酯部分别经 2次硅胶 H(200〜300 目）柱色谱，氯仿：丙酮（10: 1〜1 : 1)，氯仿：甲醇 (50: 1〜1 : 1)梯度洗脱， Sephadex LH- 20柱色谱以及反相硅胶 (Merck)， 分离得到化合物异瑞香新素 108mg。
实施例 1制备的异瑞香新素用于下列实验。 实施例 2
异瑞香新素对大鼠血清胰岛素及胰高血糖素的影响 实验方法 本实验应用高糖高脂饲料结合小剂量链脲佐菌素 (STZ) 2型糖尿病大鼠模型， 此模型较符合人类普通型 2型糖尿病发病机制，有利于进行 2型糖尿病治疗药物 的发现。 将雄性 SD成年大鼠高糖高脂饲料喂养 1个月，诱发出胰岛素抵抗,给予 小剂量链脲佐菌素（ STZ) 25 mg/kg，腹腔注射，建立 2型糖尿病大鼠模型。 然后 腹腔注射给予药物，将老鼠的血糖、血清胰岛素、胰高血糖素、精神状态、体重、 饮水量、 食量、 大小便做为检测指标 （Pharmacological Research. 2005, 52 : 313 - 320)。 实验步骤-
1. 材料 异瑞香新素由实施例 1制备得到
1. 1实验动物和主要试剂： 清洁级健康雄性 Wistar大鼠 60只， 体重（180±20) g， 由上海 Slac实验动物有限公司提供。 链脲佐菌素 (美国 Sigma公司）； 盐酸二甲双 胍片 (北京市永康药业有限公司）； 生理盐水、 柠檬酸钠、 柠檬酸、 苦味酸、 乌拉 坦、 蒸馏水均为市售产品。
1. 2 主要仪器： TP-5000A 电子天平（分度值 0. 5 g， 湘仪天平仪器厂）； GT-1640 京都血糖仪（SUPER GLUCOCARD II)及试纸（日本 ARKRAY, Inct)； 可见〜紫外分光 光度计（日本岛津)； SHA— B—电热恒温水浴箱 (常州国华电器有限公司）。
2. 模型建立： 健康 Wi star大鼠 60只， 随机选取 10只作为正常对照组 (I)， 常规饲 料喂养。 复制模型的 50只大鼠， 给予高热量饲料 8周后， 一次性腹腔注射小剂量 35 mg I kg STZ (STZ用 0. 1 mol I L柠檬酸一柠檬酸钠溶液 (pH4. 0)稀释成 1%的溶 液）， 72 h后， 测定空腹血糖稳定在 11 mmol I 血糖 29 ramol I L者为本试验 所需的 2型糖尿病模型。 将糖尿病模型鼠按血糖值编号后随机分为 5组， 每组 10 只， 分别为： 正常对照组 (1)、 糖尿病模型组 (11)、 异瑞香新素低剂量组 （111)、 中剂量组 (IV)、高剂量组 (V) (将异瑞香新素溶解在 0. 5%羧甲基纤维素钠 (CMC- Na) 溶液中） 和二甲双胍阳性对照组 (VI)。 I组和 II组分别灌服 0. 5%的羧甲基纤维素 钠溶液； III、 IV、 V组分别每天给予异瑞香新素 20、 40、 60mg/kg (将异瑞香新 素溶解在 0.5%羧甲基纤维素钠 （CMC-Na) 溶液中的异瑞香新素含量为 5mg/ml); VI 组灌 ^服 m ^ m w w Π Π V V I I 100 mg/ kg的二甲双胍。 灌胃给药时间固定在每天上午 9: 00， 试验为 期 4周。
3. 样本的采集与处理： 分别于试验前、 试验第 3、 6、 9、 12周周末的同一时间， 各组大鼠均禁食 16 h， 第 2天分别断尾取血， 用血糖测定仪测定空腹血糖值； 4 周灌胃试验结束后， 腹主动脉取血， 分离血清， 放免法检测血清胰岛素及胰高血 糖素。
4. 数据处理： 数据用 SPSS16. 0软件包中 one— wayANOVA进行统计分析， 计量资 料以均数士标准差（X土 s ；)表示， 组间进行 DUNCAN多重比较 a =0. 05。
5. 结果与分析： 由下表可以看出， 与复制模型前及灌胃治疗前相比， 经过异瑞 香新素治疗后，2型糖尿病大鼠的血糖值和血清胰岛素水平明显的下降 (P<0.01)， 而胰岛素明显升高各剂量组间血糖值无显著差异 (P〉0.05)。
表 1 异瑞香新素对大鼠空腹血糖的影响
血糖 / (mmol/L)
复制模型前 SI 灌胃结束后
6.12±0.5 6.65±1.3 6.68±0.9 6.44±0.6 16. 33土 0. 9 15·21±0.6 6.52土 0.7 16. 54±1. 1 9.12±0.6 6.66±0.6 16. 62 ±0. 8 8.99±0.7 6.34±0.9 16. 50±1. 2 9.03±0.9 6.47士 1.0 16. 59±1. 3 8.89±1.1 注： 表中数据为 x±5, n=10, (P<0.01) 表 2 异瑞香新素对大鼠血清胰岛素及胰高血糖素的影响
处理 胰岛素 (pmol/L) 胰高血糖素 (pg/mL)
48.66 ±10.55 301.12±51.44
24.56 ±9.88 438.22±61.77
42.55±9.63 341.22±55.23
43.12±11.23 332.45±40.23
43.56 ±12.33 312.22±30.69
24.12±16.54 446.23 ±54, 63
注： 表中数据为 x±5， n=10, (P<0.01) 结论
以上实验表明，本发明异瑞香新素对链脲佐菌素 (STZ)配合高脂饲料建立的 2型糖 尿病大鼠模型具有较好的血糖抑制活性， 和阳性药二甲双胍活性相当。 同时，本 试验中血清胰岛素和胰高血糖素水平的变化结果表明，异瑞香新素具有保护和修 复胰岛细胞的作用， 同时能够降低血清中的胰高血糖素水平，抑制了糖尿病可能 的发病机制。 因此， 可以将异瑞香新素作为治疗糖尿病的药物进行开发。

Claims

权利要求
1、 异瑞香新素在制备抗糖尿病药物中的应用， 其特征在于， 所述异瑞香新素结 构式如下：
Figure imgf000008_0001
2、根据权利要求 1所述应用， 其特征在于，所述异瑞香新素通过下列方法制 得： 金边瑞香药材以 75%乙醇渗漉提取， 提取液减压浓缩得浸膏， 得到的粗提物 分别用石油醚、 氯仿、 乙酸乙酯萃取， 乙酸乙酯部分别经反复硅胶 H 200〜300 目柱色谱，氯仿：丙酮 10: 1-1： 1，氯仿：甲醇 50: 1-1 : 1梯度洗脱， Sephadex LH-20 柱色谱以及反相硅胶， 分离得到化合物异瑞香新素。
3、根据权利要求 1所述应用， 其特征在于，所述药物为由异瑞香新素作为活 性成分与药用载体组成的药物组合物。
PCT/CN2012/001297 2012-03-19 2012-09-24 异瑞香新素化合物在制备抗糖尿病药物中的应用 WO2013138964A1 (zh)

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CN114225012A (zh) * 2021-12-16 2022-03-25 浙江湃肽生物有限公司 一种测定索玛鲁肽生物活性的方法

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CN111925349A (zh) * 2020-09-03 2020-11-13 上海海洋大学 抑制剂瑞香素衍生物及其应用和药物组合物
CN111925349B (zh) * 2020-09-03 2022-08-26 上海海洋大学 抑制剂瑞香素衍生物及其应用和药物组合物
CN114225012A (zh) * 2021-12-16 2022-03-25 浙江湃肽生物有限公司 一种测定索玛鲁肽生物活性的方法
CN114225012B (zh) * 2021-12-16 2022-10-25 浙江湃肽生物股份有限公司 一种测定索玛鲁肽生物活性的方法

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