CN106977504A - 一种1,2,4‑恶二唑衍生物、制备方法及其医药用途 - Google Patents
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明涉及药物化学领域，具体涉及一种1,2,4‑恶二唑衍生物（式I所示），
Description
技术领域
本发明涉及药物化学领域，具体涉及一种如式I所示的1,2,4-恶二唑衍生物，包括该化合物的制备方法和在治疗II型糖尿病、肥胖症及其并发症中的应用。
背景技术
II型糖尿病是一种常见的代谢性紊乱疾病，其患者体内产生胰岛素的能力并未丧失，甚至产生过多，但病人体内细胞上的胰岛素受体对胰岛素的敏感程度降低，导致糖尿病并引发肥胖症（The Lancet, 2014, 383, 1947）。
蛋白酪氨酸磷酸酯酶1B（protein tyrosine phosphatase 1B, PTP1B）是第一个被成功分离的蛋白酪氨酸磷酸酯酶，由435个氨基酸残基组成，属于典型的非受体型PTP酶家族（Proc. Natl. Acad. Sci USA, 1990, 87, 5148）。早期研究证明，PTP1B能在体外有效的将胰岛素受体去磷酸化（J. Cell. Biol. 1996, 134, 801；J. Biol. Chem., 1995,270, 20503）。敲除PTP1B基因或者运用反义核苷酸(AS0)抑制体内PTP1B蛋白及mRNA的表达不仅可以显著提高受试小鼠对胰岛素的敏感性，而且能明显降低肥胖症的患病机率（Mol. Cell. Biol. 2000, 20, 5479；Plos One, 2015, 10, e0126866；Drugs, 2003, 12,223）。近年来，越来越多的研究证明PTP1B是治疗II型糖尿病的一个有效药物作用靶点。
发明内容
本发明公开一种如式I所示的1,2,4-恶二唑衍生物，其制备方法及其医疗用途。初步活性测试证明本发明化合物具有良好的PTP1B抑制活性，可用于制备治疗II型糖尿病、肥胖症及其并发症的药物。
本发明的化合物：5-(5′-对二乙胺基苯基-1′,2′,4′-恶二唑)-1H-吲哚-3-甲醛，结构式（式I）如下：
。
本发明还公开了式I化合物的制备方法，如下：
。
式1化合物经甲酰化反应得到式I，所采用酰化试剂为草酰氯、三氯氧磷；所用溶剂为N,N-二甲基甲酰胺、二氯甲烷、水及其混合物；该反应温度为0 ℃～80 ℃，反应时间为1～24小时。
本发明所述式I化合物具有显著的PTP1B的抑制作用，可作为用于制备II型糖尿病、肥胖症及其并发症的药物或药物先导物。
具体实施方式
下面结合具体实施例对本发明做进一步的详细说明。
实施例1：式I化合物的制备
。
2mL 三氯氧磷冰浴滴入4ml DMF中，冷至0度，后加入60 mg 式1混合物，室温反应过夜。TLC检测显示反应完全后，缓慢加入10% NaOH溶液调pH值至9，乙酸乙酯萃取，无水硫酸钠干燥有机相，浓缩，残余物经柱层析纯化（DCM：MeOH=10：1）后得到15mg黄色固体式I，产率23%。1H NMR (600 MHz, CDCl3) δ 12.42 (1H, s), 10.00 (1H, s), 8.86 (1H, s),8.43 (1H, s), 7.98 (1H, d, J = 6 Hz), 7.96 (1H, d, J = 6 Hz), 7.68 (1H, d, J= 6 Hz), 6.83 (1H, d, J = 6 Hz), 3.43 (4H, t, J = 6 Hz), 1.14 (6H, t, J = 6Hz). 13C NMR (150 MHz, CDCl3) δ184.7, 175.1, 167.9, 150.1, 139.2, 138.8,129.1, 123.6, 121.8, 120.1, 119.7, 118.0, 112.6, 110.5, 108.4, 43.3, 11.7.ESI-MS m/z: 361.2 [M+H]+.
实施例2：蛋白酪氨酸磷酸酯酶1B（PTP1B）抑制活性测试
将上述实施例1中制备的式I化合物及齐墩果酸（对照化合物）用DMSO溶解，低温保存，DMSO在最终体系中的浓度控制在不影响检测活性的范围之内，即2% DMSO范围内。采用光吸收检测法，在96孔平底透明微孔板中检测酶活性。底物pNPP经PTP1B水解得到的游离产物在405nm处有很强的光吸收。通过酶标仪监测405nm处光吸收强度的变化，计算得到反应初速度。初筛选择单浓度条件下（20μg/mL），对样品的活性进行测试。对于在一定条件下表现出活性的样品，即抑制率大于50%，测试活性剂量依赖关系，通过样品活性对样品浓度进行非线性拟和得到IC50，计算所用软件为GraphpadPrism4，拟合所使用的模型为sigmoidaldose-response (varible slope)，对于大多数抑制剂筛选模型，将拟合曲线底部和顶部设定为0和100。一般情况下，每个样品在测试中均设置复孔(n≥3)，在结果中以标准误差(StandardError, SE)表示。结果如下：
实验表明，式I化合物可以抑制蛋白酪氨酸磷酸酯酶1B（PTP1B），其IC50值为1.3 μM，活性是阳性对照齐墩果酸活性的一倍。因此，本发明的式I化合物作为PTP1B抑制剂，可用于制备治疗II型糖尿病、肥胖症及其并发症的药物或是作为药物的先导化合物。
Claims (4)
1.一种1,2,4-恶二唑衍生物，其特征在于，它是5-(5′-对二乙胺基苯基-1′,2′,4′-恶二唑)-1H-吲哚-3-甲醛，其结构式为式I：。
2.一种权利要求1所述衍生物的制备方法：以式1化合物为原料，合成式I化合物；。
3.一种权利要求1所述的衍生物作为蛋白酪氨酸磷酸酯酶1B抑制剂在制备药物中的用途。
4.一种权利要求1所述的1,2,4-恶二唑衍生物在制备治疗II型糖尿病、肥胖症及其并发症的药物中的用途。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112336719A (zh) * | 2020-10-19 | 2021-02-09 | 济南大学 | 一种噻唑衍生物作为α-葡萄糖苷酶抑制剂及其应用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101415702A (zh) * | 2006-04-03 | 2009-04-22 | 安斯泰来制药有限公司 | 杂环化合物 |
| CN101611033A (zh) * | 2006-12-21 | 2009-12-23 | 葛兰素集团有限公司 | 作为s1p1受体激动剂的吲哚衍生物 |
| WO2009153307A1 (en) * | 2008-06-20 | 2009-12-23 | Glaxo Group Limited | Compounds |
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- 2017-04-06 CN CN201710219607.2A patent/CN106977504A/zh active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101415702A (zh) * | 2006-04-03 | 2009-04-22 | 安斯泰来制药有限公司 | 杂环化合物 |
| CN101611033A (zh) * | 2006-12-21 | 2009-12-23 | 葛兰素集团有限公司 | 作为s1p1受体激动剂的吲哚衍生物 |
| WO2009153307A1 (en) * | 2008-06-20 | 2009-12-23 | Glaxo Group Limited | Compounds |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112336719A (zh) * | 2020-10-19 | 2021-02-09 | 济南大学 | 一种噻唑衍生物作为α-葡萄糖苷酶抑制剂及其应用 |
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