CN112370455A - 一种磺酰胺衍生物作为α-葡萄糖苷酶抑制剂及其应用 - Google Patents
一种磺酰胺衍生物作为α-葡萄糖苷酶抑制剂及其应用 Download PDFInfo
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Abstract
本发明涉及药物化学领域，具体涉及一种具有抑制α‑葡萄糖苷酶活性的2‑甲基‑3‑氧代‑N‑(5,6,7,8‑四氢萘‑2‑基)‑3,4‑二氢‑2H‑苯并[b][1,4]恶嗪‑6‑磺酰胺类衍生物，其结构通式如下所示：
Description
技术领域
本发明涉及一种α-葡萄糖苷酶抑制剂及其应用，2-甲基-3-氧代-N-(5,6,7,8-四氢萘-2-基)-3,4-二氢-2H-苯并[b] [1,4]恶嗪-6-磺酰胺作为新型α-葡萄糖苷酶抑制剂的应用。
背景技术
糖尿病（Diabetes Mellitus, DM）是由一组因胰岛素绝对或相对分泌不足和（或）胰岛素利用障碍引起的碳水化合物、蛋白质、脂肪代谢紊乱性疾病，以高血糖为主要标志。临床表现为“三多一少”，即多饮、多尿、多食和体重下降，以及血糖高、尿液中含有葡萄糖等，病程久可引起多系统损坏，组织器官进行缓慢性病变、功能衰退及衰竭，严重时引起急性严重代谢紊乱。目前在全球范围内，糖尿病的患病率和发病率急剧攀升。
糖尿病的病因尚未系统阐明。研究证明，α-葡萄糖苷酶是寡糖和二糖分解为葡糖糖的关键水解酶之一，而α-葡萄糖苷酶抑制剂在降低餐后血糖和治疗糖尿病上有显著效果。α-葡萄糖苷酶抑制剂在小肠上皮刷状缘与糖类竞争水解酶进而α-葡萄糖苷酶的活性，从而减慢碳水化合物水解生成单糖的速度，并且在降血脂和延缓冠心病的发生等方面有显著作用。目前国内上市的α-糖苷酶抑制剂有阿卡波糖、伏格列波糖和米格列醇，广泛用于2型糖尿病的治疗。
在新药开发过程中，我们课题组对商业化合物库（SPECS）进行了α-葡萄糖苷酶抑制剂虚拟筛选，后期通过酶水平活性筛选从中得到了一种磺酰胺衍生物，该化合物能抑制α-葡萄糖苷酶，可作为一种新型α-葡萄糖苷酶抑制剂，在治疗糖尿病方面的开发研究具有广阔的前景。
发明内容
本发明的目的是提供一种新型α-葡萄糖苷酶抑制剂。
本发明的第一方面，提供了一种如式Ⅰ所示的化合物，或其药学上可接受的盐、水合物、溶剂化物、或前药：
该化合物为2-甲基-3-氧代-N-(5,6,7,8-四氢萘-2-基)-3,4-二氢-2H-苯并[b] [1,4]恶嗪-6-磺酰胺；
本发明的第二方面，一种药物组合物，所述药物组合物包含第一方面所述的式I所示的化合物或其药学上可接受的盐、水合物、溶剂化物或前药；和药学上可接受的载体。
本发明的第三方面，提供了第一方面所述的式I所示的化合物或其药学上可接受的盐、水合物、溶剂化物或前药用途，用于：
（i）制备α-葡萄糖苷酶抑制剂；
（ii）制备预防和/或治疗与α-葡萄糖苷酶相关的疾病的药物。
药学上可接受的载体必须可与配方的其他成分兼容，且不会对其接受者有害，一般为适当载剂、稀释剂及赋形剂是为本领域技术人员所公知且包括诸如碳水化合物、蜡、水溶性及/或泡胀性聚合物、亲水性或疏水性材料、明胶、油、溶剂、水及类似物。所使用的特定载剂、稀释剂或赋形剂将取决于给予本发明化合物的方式及目的。溶剂通常是基于本领域技术人员所认为安全给予哺乳动物的溶剂(GRAS)而选择。通常，安全溶剂为无毒水性溶剂(诸如水)及其他可溶于水或与水可混溶的无毒溶剂。适当水性溶剂包括水、乙醇、丙二醇、聚乙二醇(例如PEG400或PEG300)等及其混合物。还可包括一或多种缓冲剂、稳定剂、表面活性剂、湿润剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、不透明剂、助滑剂、加工助剂、着色剂、甜味剂、香料、调味剂及其他提供药物(即本发明化合物或其医学组合物)精美外观或有助于制造药物产品(即用于制备药剂)的已知添加剂。
有益效果
本发明的化合物，能够显著抑制α-葡萄糖苷酶，并能够用于制备预防和/或治疗与α-葡萄糖苷酶相关的疾病的药物。
下面对本发明的实施例作详细说明，本实施例在以本发明技术方案为前提下进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于下述的实施例。
本申请的发明人经过对商业化合物库的虚拟筛选及活性研究，发现了一种α-葡萄糖苷酶抑制剂，能够有效抑制α-葡萄糖苷酶活性，活性明显优于对照药物。在此基础上，完成了本发明。
本发明中，式I化合物是指具有如下式I所示的化合物：
实施例1 化合物对α-葡萄糖苷酶活性的影响
α-葡萄糖苷酶购买自Sigma，作为底物的对硝基苯基-α-D-葡萄糖苷（PNPG）购自Aladdin，配置缓冲液以及猝灭剂所需要的钠盐、磷酸盐均购自上海麦克林生化科技有限公司。α-糖苷酶抑制活性测定参考已发表的报道方法进行。96孔板每孔加入99 μL的PBS磷酸缓冲液(pH＝6.8)，然后将20 mmol的1 μL待测化合物溶液或空白对照加入到对应的孔中，随后加入25 μL的α糖苷酶溶液，置于37℃摇床孵育15 min。加入25 μL的PNPG溶液，再置于37℃摇床孵育15 min，随后加入50 μL的0.2 M碳酸钠溶液，酶标仪测定405 nm处的吸光度，计算待测化合物对α-糖苷酶的抑制率。然后将该化合物配置出10种不同的梯度浓度进行再一次测定，根据抑制曲线求得化合物的IC50值(抑制酶活力50％时的抑制剂浓度)，实验结果如表1所示。
表1. 化合物对α-葡萄糖苷酶的抑制活性
| 化合物 | 抑制率（100 μM） | IC<sub>50</sub>（μM） |
| Ⅰ | 88.21% | 16.03 |
| 阳性对照 野尻霉素 | 66.54% | 52.02 |
实验结果表明，化合物Ⅰ对α-葡萄糖苷酶具有显著的抑制作用，其作用效果优于阳性对照药物野尻霉素。
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。
Claims (3)
1.式I所示α-葡萄糖苷酶抑制剂
或其药学上可接受的盐在制备预防和/或治疗与α-葡萄糖苷酶相关的疾病的药物中的应用。
2.根据权利要求1所述的应用，其特征在于，预防和/或治疗α-葡萄糖苷酶相关的疾病的药物为α-葡萄糖苷酶抑制剂的药物。
3.式I所示乙酰胆碱酯酶抑制剂
或其药学上可接受的盐在制备预防和/或治疗糖尿病相关的药物中的应用。
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