CN110776504B - 一种苯异噁唑乙氧基环丁胺衍生物及其制备方法与应用 - Google Patents
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Abstract
本发明涉及一种苯异噁唑乙氧基环丁胺衍生物及其制备方法与应用，所述卤代苯异噁唑衍生物具有式I结构：
Description
技术领域
本发明属于药物合成领域，具体涉及一种苯异噁唑乙氧基环丁胺衍生物及其制备方法与应用。
背景技术
糖尿病是一种代谢性疾病，患者体内通常会出现高血糖，对人体的眼、心脏、肾脏、神经等组织和器官产生功能性障碍。蛋白酪氨酸磯酸酶1B(PTP1B)通过与蛋白酪氨酸磷酸激酶的共同作用来调节细胞内底物酪氨酸的磷酸化水平，来完成细胞内信号的转导。PTP1B过表达会使胰岛素及其受体过度去磷酸化，进而使胰岛素与胰岛素受体的结合过程受阻，进而使生物体内发生胰岛素抵抗。因此，开发一种新型PTP1B抑制剂有望用于治疗糖尿病。申请人近期发现两种卤代苯并异噁唑环己烷胺衍生物具有很强的PTP1B抑制活性，为了进一步研究基团环己烷胺基是否为药效团，采用氮杂环丁烷基对其进行替换，设计合成式I化合物。
发明内容
本发明提供一种式I结构的苯异噁唑乙氧基环丁胺衍生物或其药学上可接受的盐，其特征在于式I结构如下：
本发明的另一实施方案提供上述式I结构的苯异噁唑乙氧基环丁胺衍生物的制备方法，其特征在于包括如下步骤：
(1)有机溶剂中，式II化合物与式III化合物在氧化银作用下反应得到式IV化合物；
(2)式IV化合物于碱性条件下脱除甲基后，调pH至5-6即可得到式I化合物。
步骤(1)中有机溶剂优选乙腈、甲苯、二氧六环中的一种或几种。式II化合物：式III化合物＝1:1.2-1.5(摩尔比)，氧化银的摩尔用量为式III化合物的2倍，反应温度优选为70℃至回流温度；反应中优选加入式III化合物摩尔量4％-5％的AgOTf。
步骤(2)中碱性条件优选NaOH/MeOH或KOH/MeOH，pH为9-10。
本发明的另一实施方案提供一种制备式I化合物的式V中间体，其特征在于式V结构如下：
本发明的另一实施方案提供上述式V中间体(优选式IV)在制备式I化合物中的应用。
本发明的另一实施方案提供一种式IV中间体的制备方法，其特征在于包括如下步骤：
有机溶剂中，式II化合物与式III化合物在氧化银作用下反应得到式IV化合物。
有机溶剂优选乙腈、甲苯、二氧六环中的一种或几种。式II化合物：式III化合物＝1:1.2-1.5(摩尔比)，氧化银的摩尔用量为式III化合物的2倍，反应温度优选为70℃至回流温度；反应中优选加入式III化合物摩尔量4％-5％的AgOTf。
本发明的另一实施方案提供上述式I结构的苯异噁唑乙氧基环丁胺衍生物或其药学上可接受的盐在制备PTP1B抑制剂中的应用。
本发明的另一实施方案提供上述式I结构的苯异噁唑乙氧基环丁胺衍生物或其药学上可接受的盐在制备治疗糖尿病的药物中的应用。
本发明的另一实施方案提供一种药物组合物，其特征在于该药物组合物以上述式I结构的苯异噁唑乙氧基环丁胺衍生物或其药学上可接受的盐作为有效成分。该药物组合物还可包括其他治疗糖尿病的药物。该药物组合物还可包括药学上可接受的辅料。该药物组合物的剂型选自固体制剂、液体制剂或半固体制剂。优选片剂、胶囊或注射剂。
本发明使用的式II化合物、式III化合物均通过商业购买获得(本领域的技术人员也可根据现有技术自行制备)。例如式II化合物可由
与
在缩合剂作用下制备得到。
具体实施方式
为了便于对本发明的进一步理解，下面提供的实施例对其做了更详细的说明。但是这些实施例仅供更好的理解发明而并非用来限定本发明的范围或实施原则，本发明的实施方式不限于以下内容。
实施例1
取
(10mmol)溶于甲苯中，加入DCC(10mmol)、DMAP(1mmol)，搅拌30min后，加入
(1mmol)，升温至50℃反应24小时后，过滤，滤液浓缩后经硅胶柱层析(石油醚/乙酸乙酯＝10/1-5/1)，得到式II化合物，收率42.3％，ESI-MS(m/z):250.1[M+H]+。
实施例2
取式II化合物(1.0mmol)、式III化合物(1.5mmol)，溶于12mL甲苯中，加入Ag2O(3.0mmol)，升温至回流温度反应过夜，TLC检测式II化合物消失，停止加热恢复至室温后，过滤、滤液浓缩后经硅胶柱层析(乙酸乙酯/石油醚＝1/8-1/5)得到淡黄色固体166.1mg，即为式IV化合物，收率约为32.1％。结构确证数据：mp：111-113℃，ESI-MS m/z 517.1[M+H]+。
取式IV化合物(50mg)溶于NaOH/MeOH溶液(10mL，pH 9-10)，室温下反应5小时后，加入稀盐酸(1mol/L)调pH至5-6，减压浓缩后，用乙酸乙酯萃取、水洗，有机相浓缩后经硅胶柱层析(乙酸乙酯/石油醚＝1/4-1/3)得淡黄色固体36.7mg，即为式I化合物，收率约为75.5％，结构确证数据：mp：116-118℃，ESI-MS m/z 501.1[M-H]-，1H NMR(DMSO-d6,400MHz)δ:7.99(d,1H),7.93(s，1H),7.52(d,1H),7.44-7.31(m,4H),4.18-4.10(m,4H),4.02-3.98(m,1H),3.80-3.77(m,1H),3.62(dd,1H),3.47(s,2H),3.28-3.24(m,1H),1.46-1.38(d,6H).
实施例3
取式II化合物(1.0mmol)、式III化合物(1.2mmol)，溶于12mL乙腈中，加入Ag2O(2.4mmol)和AgOTf(0.048mmol,约12.3mg)，升温至70℃反应过夜，TLC检测式II化合物消失，停止加热恢复至室温后，过滤、滤液浓缩后经硅胶柱层析(乙酸乙酯/石油醚＝1/8-1/5)得到淡黄色固体403.2mg，TLC比对与实施例2制备的式IV化合物相同，收率约为77.9％，ESI-MS m/z 517.1[M+H]+。
实施例4
按照本领域的常规方法测试本发明化合物的酪氨酸磷酸酯酶1B(PTP1B)的抑制活性。反应体系的酶活缓冲液：甘油10％、HEPES 50mM pH7.2、NaCl 10mM、BSA 0.10％；反应在96孔板中进行，总反应体系为100μL，分为三组，实验组，阴性对照组和阳性对照组。实验组每孔依次加入48μL 100nM PTP1B(由人工提纯获得)，2μL 50mM式I化合物(溶于DMSO中)，振荡30s混匀，32℃条件下孵育10min，然后加入50μL 50mM pNPP，振荡30s混匀后，405nm测OD值，计算抑制率，抑制率＝[1-(OD样品-OD空白)/(OD阴性-OD空白)]×100％。利用软件并计算得出IC50，结果见下表。阴性对照组采用2μL DMSO替代实验组中的“2μL 50mM式I化合物(溶于DMSO中)”；阳性对照组采用2μL 50mM的钒酸钠替代实验组中的“2μL 50mM式I化合物(溶于DMSO中)”。
| 组别 | IC<sub>50</sub>(μM) |
| 实验组 | 0.83±0.12 |
| 阳性对照组 | 7.92±0.65 |
Claims (10)
1.一种作为PTP1B抑制剂的式I结构的苯异噁唑乙氧基环丁胺衍生物或其药学上可接受的盐，其特征在于式I结构如下：
2.权利要求1所述的式I结构的苯异噁唑乙氧基环丁胺衍生物的制备方法，其特征在于包括如下步骤：
(1)有机溶剂中，式II化合物与式III化合物在氧化银作用下反应得到式IV化合物；
(2)式IV化合物于碱性条件下脱除甲基后，调pH至5-6即可得到式I化合物。
3.权利要求2所述的制备方法，其特征在于步骤(1)中有机溶剂选自乙腈、甲苯、二氧六环中的一种或几种；式II化合物和式III化合物的摩尔比为1:1.2-1.5，氧化银的摩尔用量为式III化合物的2倍，反应温度为70℃至回流温度。
4.权利要求2-3任一项所述的制备方法，其特征在于步骤(1)反应中加入式III化合物摩尔量4％-5％的AgOTf。
5.权利要求2所述的制备方法，其特征在于步骤(2)中碱性条件选自NaOH/MeOH或KOH/MeOH，pH为9-10。
6.一种制备式I化合物的式V中间体，其特征在于式V结构如下：
R选自C1-C6烷基、苄基。
7.一种式IV中间体的制备方法，其特征在于包括如下步骤：
有机溶剂中，式II化合物与式III化合物在氧化银作用下反应得到式IV化合物。
8.权利要求1所述的式I结构的苯异噁唑乙氧基环丁胺衍生物或其药学上可接受的盐在制备PTP1B抑制剂中的应用。
9.一种药物组合物，其特征在于该药物组合物以权利要求1所述的式I结构的苯异噁唑乙氧基环丁胺衍生物或其药学上可接受的盐作为有效成分。
10.权利要求9所述的药物组合物，其特征在于该药物组合物还可包括其他治疗糖尿病的药物。
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