CN115677815A - 一种靶向降解ptp1b的protac化合物及其制备方法与应用 - Google Patents
一种靶向降解ptp1b的protac化合物及其制备方法与应用 Download PDFInfo
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- CN115677815A CN115677815A CN202211334968.9A CN202211334968A CN115677815A CN 115677815 A CN115677815 A CN 115677815A CN 202211334968 A CN202211334968 A CN 202211334968A CN 115677815 A CN115677815 A CN 115677815A
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Abstract
本发明属于化学药物技术领域，具体公开了一种靶向降解PTP1B的PROTAC化合物及其制备方法与应用，所述PROTAC化合物通过PTP1B抑制剂和E3泛素连接酶配体合理设计得到。本发明的化合物或药物组合物具有预防和/或治疗肿瘤和糖尿病的用途。
Description
技术领域
本发明属于化学药物技术领域，具体涉及一种靶向降解PTP1B的PROTAC化合物及其制备方法与应用。
背景技术
蛋白降解靶向嵌合体（Proteolysis Targeting Chimerias, PROTACs）是近些年人们利用泛素蛋白酶体通路具有特异性降解底物蛋白的特点，用一种双功能小分子将目标蛋白和细胞内的E3泛素连接酶拉近，从而选择性诱导蛋白降解的技术。PROTACs包含三部分功能结构：1）可与蛋白底物相结合部分；2）能与E3泛素连接酶相结合部分；3）前两部分相连接链。PROTACs不仅有极高的靶向性，还具有类似于催化反应的作用机制，能够以很小的剂量获得极高的活性。PROTAC分子并非直接对靶蛋白进行降解，它相当于一个媒介，利用E3泛素连接酶配体和靶蛋白配体将E3泛素连接酶和靶蛋白的距离减小，使得二者可以接触，E3泛素连接酶会给靶蛋白标记上泛素化标签，最终，带有标签的靶蛋白会被相应的酶进行降解掉，而PROTAC分子可以重新参与另一次的降解反应。
与传统小分子药物相比，PROTACs具有一下优势：首先，PROTACs可用于与疾病相关不可成药靶点。不管靶蛋白有无明显活性位点，只要PROTACs分子的靶蛋白配体能够与靶蛋白的任何一个位点结合，就可以诱导靶蛋白的降解。第二，PROTACs具有更高的选择性。第三，PROTACs无需与靶蛋白活性中心高强度的结合，可克服传统小分子抑制剂在治疗疾病过程中出现的耐药性问题。最后，PROTACs有较好的安全性和有效性。小分子抑制剂通常需要较高的药物浓度来对靶蛋白进行竞争性结合，容易产生脱靶效应进而引起副作用，而PROTACs作用过程类似催化反应，不需要等摩尔量的药物，可实现较高的分子活性。
蛋白酪氨酸磷酸酶1B（Protein tyrosine phosphatase 1B，PTP1B）能够使磷酸化的胰岛素受体去磷酸化，从而阻断下游PI3K-Akt通路的激活，抑制胰岛素敏感细胞中4型葡萄糖转运蛋白的转运和葡萄糖摄取。因此，作为胰岛素信号的负调节剂，PTP1B在胰岛素抵抗中发挥着重要作用，也成为了预防和治疗糖尿病的靶点之一。另外，许多蛋白酪氨酸激酶（RTKs）具有致癌作用，作为蛋白酪氨酸磷酸酶（PTPs）家族中的一员，PTP1B被认为在肿瘤中起到抑癌作用。
基于PROTACs作用的优势，本发明公开了一系列靶向PTP1B的PROTACs化合物及其制备方法和用途。
发明内容
本发明提供了一类PROTACs衍生物、其制备方法及含有该化合物的药物组合物以及在药学上可接受的盐作为治疗和/或预防癌症和糖尿病，尤其是2型糖尿病和代谢综合症的药物及其预防代谢失调和肥胖的药物。
本发明的技术方案如下：
一种靶向降解PTP1B的PROTAC化合物，所述化合物的结构式如下通式I或者通式II：
其中，Linker为连接分子，PTP1B Inhibitor为PTP1B抑制剂，所述PTP1B抑制剂选自以下化学结构式A～F：
优选的，所述Linker选自以下化学结构式a～n：
其中，X、Y为NH或CH2，n = 1～10。
本发明还提供了一种PROTAC化合物药学上可接受的盐，所述PROTAC化合物为所述的靶向降解PTP1B的PROTAC化合物。
优选的，所述PROTAC化合物或其药学上可接受的盐在其他药理学活性物质之前、之后或一起施用。
优选的，所述PROTAC化合物或其药学上可接受的盐与其他药理学活性物质组合施用。
本发明还提供了一种药物制剂，其包含所述的靶向降解PTP1B的PROTAC化合物或其药学上可接受的盐，以及一种或多种药理学活性物质。
本发明还提供了一种药物组合物，其包含所述的靶向降解PTP1B的PROTAC化合物或其药学上可接受的盐，以及一种或多种药学上可接受的载体或辅料。
所述靶向降解PTP1B的PROTAC化合物，其用于治疗和/或预防PTP1B蛋白相关疾病。与PTP1B蛋白相关的疾病可以是，但不限于：肺癌、肝癌、肾癌、非小细胞肺癌、前列腺癌、甲状腺癌、皮肤癌、胰腺癌、卵巢癌、乳腺癌、膀胱癌、骨质增生异常综合症、淋巴癌、食管癌、胃肠道癌、骨肉瘤、中枢或外周神经系统的肿瘤、代谢综合症、糖尿病、代谢失调和肥胖。
优选的，所述糖尿病为2型糖尿病。
有益效果：本发明靶向降解PTP1B的PROTAC化合物，对PTP1B的降解具有明显效果，可作为治疗和/或预防癌症和糖尿病，尤其是2型糖尿病和代谢综合症的药物及其预防代谢失调和肥胖的药物。
附图说明
图1为本发明化合物对PTP1B蛋白的降解效果图；
图2为本发明化合物在不同剂量下的口服葡萄糖耐量试验的血糖曲线图；
图3为本发明化合物在不同剂量下的口服葡萄糖耐量试验的2 h内的血糖曲线下面积（AUC）图；
图4为本发明化合物在最佳剂量下的口服葡萄糖耐量试验的血糖曲线图；
图5为本发明化合物在最佳剂量下的口服葡萄糖耐量试验的2 h内的血糖曲线下面积（AUC）图。
具体实施方式
为了进一步理解本发明，下面将结合本发明实施例，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
如无特殊说明，本发明实施例中所涉及的试剂均为市售产品，均可以通过商业渠道购买获得。
一、本发明化合物1～12的制备
1、化合物1～12的合成通用路线如下：
其中，不同化合物中PTP1B抑制剂的选择以及m、n的取值具体如下：
化合物1：PTP1B为结构式E，n=1，m=1；
化合物2：PTP1B为结构式E，n=2，m=1；
化合物3：PTP1B为结构式E，n=3，m=1；
化合物4：PTP1B为结构式E，n=1，m=5；
化合物5：PTP1B为结构式E，n=2，m=5；
化合物6：PTP1B为结构式E，n=3，m=5；
化合物7：PTP1B为结构式D，n=1，m=1；
化合物8：PTP1B为结构式D，n=2，m=1；
化合物9：PTP1B为结构式D，n=3，m=1；
化合物10：PTP1B为结构式D，n=1，m=5；
化合物11：PTP1B为结构式D，n=2，m=5；
化合物12：PTP1B为结构式D，n=3，m=5。
2、化合物1～12的具体合成步骤如下：
（1）中间体4a的合成（以n=3为例）：在两口烧瓶中加入NaH（100mg, 2.5mmol），氮气保护。注射DMF和THF溶液各3ml，冰浴环境下缓慢滴加三乙二醇（0.67ml, 5mmol)，搅拌40分钟后注射溴氯己烷（0.15ml, 1mmol），室温反应12 h，TLC跟踪反应，待反应完全后，加水淬灭，乙酸乙酯萃取三次，合并有机相，饱和食盐水多次洗涤，无水硫酸钠干燥，浓缩，粗产物经硅胶柱纯化（石油醚:乙酸乙酯=3:1）即得无色油状液体120mg，产率为45%。
（2）中间体4b的合成（以n=3, m=1为例）：在两口烧瓶中加入中间体4a（270mg, 1mmol），氮气保护下注射DMF和THF溶液各3ml，冰浴环境下快速加入NaH（48mg, 1.2mmol），搅拌30分钟后注射溴乙酸叔丁酯（0.29mg, 2mmol)，室温反应12 h，TLC跟踪反应，待反应完全后，加水淬灭，乙酸乙酯萃取三次，合并有机相，饱和食盐水多次洗涤，无水硫酸钠干燥，浓缩，粗产物经硅胶柱纯化（石油醚:乙酸乙酯=3:1）即得淡黄色油状液体162mg，产率为42%。
（3）中间体4c的合成（以n=3, m=1为例）：在单口烧瓶中加入中间体4b（383mg,1mmol），加入3ml甲酸，既做反应液又做溶剂，室温下搅拌3 h，TLC 跟踪反应，待反应完全后减压蒸馏掉多余的甲酸，然后抽真空，氮气保护下缓慢滴加5ml氯化亚砜，既做反应液又做溶剂，升温至回流，搅拌4 h后减压蒸馏掉多余的氯化亚砜，即得黄色液体293mg，产率为85%。
（4）中间体4d的合成（以n=3, m=1为例）：得到的中间体4c立即抽真空，氮气保护，注射溶剂四氢呋喃3ml，快速加入泊马度胺（137mg, 0.5mmol），升温至回流，搅拌6 h后TLC监测反应，待反应完全后，加少量水淬灭，用乙酸乙酯萃取三次，合并所有有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗产品经硅胶柱纯化（石油醚:乙酸乙酯=1:1）即得淡黄色固体198mg，产率为68%。
（5）中间体4e的合成（以n=3, m=1为例）：取中间体4d（58mg, 0.1mmol）溶于3ml的丙酮，加入NaI（75mg, 0.5mmol），氮气保护，升温至回流温度，搅拌24 h，待反应完全后，真空旋干溶剂，再溶于乙酸乙酯和Na2SO3（10%, 10%），萃取分层，饱和食盐水多次洗涤有机层，无水硫酸钠干燥，旋蒸，无需纯化方可进入下一步。
（6）中间体4f的合成（以n=3, m=1为例）：取中间体4e（58mg, 0.1mmol），加入叠氮化钠（26mg, 0.4mmol），乙腈2.5ml，水1ml，回流过夜，TLC 监测反应，待反应完全后，加少量水淬灭，乙酸乙酯萃取三次，合并所有有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到淡黄色固体47mg，产率为80%，不用纯化直接进行下一步。
（7）中间体4g的合成（以n=3, m=1为例）:取中间体4f（58mg, 0.1mmol）溶3ml的四氢呋喃，滴加0.5ml的纯净水，再加入三苯基膦（53mg, 0.2mmol），室温下反应过夜。氮气保护，升温至回流温度，搅拌24 h，待反应完全后，真空旋干溶剂，TLC监测反应，待反应完全后，加水淬灭，用3%的稀盐酸调节反应液的PH至酸性，使产物成盐溶于水，用乙酸乙酯洗去三苯基膦和三苯基氧膦，再用饱和的NaHCO3调节PH至碱性，游离出产物，用二氯甲烷萃取出目标产物，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到黄色固体25mg，产率为48%。
（8）将氨基中间体4g（0.1 mmol）溶于3 mL DMF溶液中，陆续加入HATU（53 mg,0.14 mmol），DIPEA（0.043 mL, 0.25 mmol），PTP1B Inhibitor（0.12 mmol），75℃下反应24h，TLC监测反应，待反应完全后，加少量水淬灭，用乙酸乙酯萃取三次，合并所有有机相，饱和食盐水多次洗涤，无水硫酸钠干燥，真空旋干多余的乙酸乙酯，粗产品经硅胶柱纯化（石油醚：乙酸乙酯= 1: 1）即得化合物产品。
实施例1：化合物1的合成
结构式如下：
白色固体，产率为25%。1H NMR (600 MHz, CDCl3) δ 10.49 (s, 1H, CONH), 8.88(d, J = 8.5 Hz, 1H, Ph), 8.70 (d, J = 11.4 Hz, 1H, CONH), 7.74 (t, J = 7.9Hz, 1H, Ph), 7.60 (d, J = 7.3 Hz, 1H, Ph), 5.96 (t, J = 5.6 Hz, 1H, CONH),5.38 (t, J = 3.6 Hz, 1H, CH=C), 4.98 (dd, J = 12.5, 5.1 Hz, 1H, Poma), 4.23(s, 2H, OCH2), 3.84-3.83 (m, 2H, OCH2), 3.75-3.73 (m, 2H, OCH2), 3.50 (t, J =6.6 Hz, 2H, OCH2), 3.39-3.36 (m, 1H, NHCH2 ), 3.23 (dd, J = 11.3, 4.2 Hz, 1H,CHOH), 3.00 – 2.97 (m, 1H, NHCH2 ), 1.17 (s, 3H, CH3), 1.00 (s, 3H, CH3), 0.92(s, 3H, CH3), 0.91 (s, 6H, CH3), 0.79 (s, 3H, CH3), 0.77 (s, 3H, CH3)。
13C NMR (150 MHz, CDCl3) δ 178.25, 170.97, 169.55, 168.40, 167.92,166.82, 145.13, 136.74, 136.27, 131.38, 125.25, 122.67, 118.78, 116.18,78.92, 71.65, 71.52, 71.11, 70.13, 55.07, 49.33, 47.52, 46.82, 46.23, 42.32,42.09, 39.35, 38.75, 38.62, 38.47, 36.95, 34.14, 32.99, 32.45, 32.33, 31.51,30.73, 29.70, 29.57, 29.32, 28.09, 27.27, 27.12, 26.88, 25.72, 23.78, 23.60,23.54, 22.57, 18.28, 16.91, 15.59, 15.37。
实施例2：化合物2的合成
结构式如下：
淡黄色固体，产率为27%。1H NMR (600 MHz, CDCl3) δ 10.50 (s, 1H, CONH),8.88 (d, J = 8.5 Hz, 1H, Ph), 8.61 (s, 1H, CONH), 7.74 (t, J = 7.9 Hz, 1H,Ph), 7.60 (d, J = 7.3 Hz, 1H, Ph), 5.95 (s, 1H, CONH), 5.38 (s, 1H, CH=C),4.97 (dd, J = 12.5, 5.3 Hz, 1H, Poma), 4.23 (s, 2H, OCH2), 3.84-3.80 (m, 4H,OCH2), 3.83-3.82 (m, 2H, OCH2), 3.69 (t, J = 4.9 Hz, 2H, OCH2), 3.60-3.58 (dd,J = 8.6, 4.7 Hz, 2H, OCH2), 3.45 (t, J = 6.7 Hz, 2H, OCH2), 3.37-3.33 (m, 1H,NHCH2 ), 3.23 (dd, J = 11.4, 4.3 Hz, 1H, CHOH), 3.03-2.98 (m, 1H, NHCH2 ), 1.11(s, 3H, CH3), 1.00 (s, 3H, CH3), 0.96 (s, 3H, CH3), 0.94 (s, 3H, CH3), 0.88(d, J = 6.4 Hz, 3H, CH3), 0.80 (s, 3H, CH3), 0.79 (s, 3H, CH3)。
13C NMR (150 MHz, CDCl3) δ 178.16, 170.89, 169.46, 168.42, 167.90,166.77, 145.15, 136.76, 136.30, 131.38, 125.23, 122.66, 118.78, 116.15,78.92, 71.53, 71.39, 71.05, 70.73, 70.66, 70.02, 55.08, 49.27, 47.53, 46.81,46.24, 42.34, 42.10, 39.38, 39.36, 38.76, 38.47, 36.96, 34.15, 33.00, 32.48,32.35, 31.42, 30.73, 29.70, 29.56, 29.30, 28.10, 27.28, 27.13, 26.95, 25.76,25.73, 23.78, 23.60, 22.66, 18.28, 16.92, 15.60, 15.38。
实施例3：化合物3的合成
结构式如下：
白色固体，产率为28%。1H NMR (600 MHz, CDCl3) δ 10.50 (s, 1H, CONH), 8.97(s, 1H, CONH), 8.86 (d, J = 8.5 Hz, 1H, Ph), 7.73 (t, J = 7.9 Hz, 1H, Ph),7.58 (d, J = 7.3 Hz, 1H, Ph), 5.94 (s, 1H, CONH), 5.37 (s, 1H, CH=C), 4.96(dd, J = 12.3, 5.3 Hz, 1H, Poma), 4.24-4.18 (m, 2H, OCH2), 3.82 (s, 4H, OCH2),3.72-3.70 (m, 2H, OCH2), 3.67-3.63 (m, 4H, OCH2), 3.59-3.57 (m, 2H, OCH2),3.45 (t, J = 6.7 Hz, 2H, OCH2), 3.36-3.33 (m, 1H, NHCH2 ), 3.22 (dd, J = 11.2,4.3 Hz, 1H, CHOH), 3.01-2.97 (m, 1H, NHCH2 ), 1.16 (s, 3H, CH3), 0.99 (s, 3H,CH3), 0.91 (s, 3H, CH3), 0.90 (s, 6H, CH3), 0.78 (s, 3H, CH3), 0.76 (s, 3H,CH3)。
13C NMR (150 MHz, CDCl3) δ 178.17, 171.18 , 169.41, 168.41 , 168.10 ,166.78 , 145.10, 136.71, 136.26, 131.38, 125.18, 122.66, 118.76, 116.16,78.88, 71.58, 71.28, 70.96, 70.65, 70.55, 70.48, 70.44, 70.01, 55.07, 49.27,47.51, 46.78, 46.22, 42.32, 42.08, 39.39, 39.34, 38.74, 38.47, 36.94, 34.13,32.99, 32.46, 32.34, 31.41, 30.71, 29.68, 29.44, 29.27, 28.09, 27.26, 27.09,26.95, 25.74, 23.76, 23.59, 23.53, 22.69, 18.27, 16.90, 15.60, 15.37。
实施例4：化合物4的合成
结构式如下：
白色固体，产率为30%。1H NMR (600 MHz, CDCl3) δ 9.44 (s, 1H, CONH), 8.85(d, J = 8.5 Hz, 1H, Ph), 8.29 (s, 1H, CONH), 7.73 (t, J = 7.9 Hz, 1H, Ph),7.57 (d, J = 7.4 Hz, 1H, Ph), 5.94 (s, 1H, CONH), 5.39 (s, 1H, CH=C), 4.98(dd, J = 12.4, 5.2 Hz, 1H, poma), 3.59 (s, 4H, OCH2), 3.51 – 3.46 (m, 4H,OCH2), 3.39 – 3.35 (m, 1H, NHCH2 ), 3.24 (dd, J = 11.3, 4.2 Hz, 1H, CHOH), 3.04– 3.00 (m, 1H, NHCH2 ), 1.18 (s, 3H, CH3), 1.01 (s, 3H, CH3), 0.93 (s, 3H,CH3), 0.92 (s, 6H, CH3), 0.80 (s, 3H, CH3), 0.78 (s, 3H, CH3)。
13C NMR (150 MHz, CDCl3) δ 178.16, 172.24, 170.85, 169.16, 167.94,166.70, 145.14, 137.85, 136.43, 131.10, 125.27, 122.67, 118.42, 115.30,78.92, 71.34, 71.07, 70.10, 70.07, 55.08, 49.29, 47.53, 46.81, 46.24, 42.37,42.10, 39.40, 39.36, 38.75, 38.48, 37.91, 36.96, 34.15, 32.99, 32.48, 32.36,31.40, 30.73, 29.70, 29.58, 29.29, 28.10, 27.28, 27.12, 27.01, 25.82, 25.73,25.72, 25.07, 23.79, 23.60, 23.55, 22.69, 18.28, 16.92, 15.60, 15.38。
实施例5：化合物5的合成
结构式如下：
白色固体，产率为26%。1H NMR (600 MHz, CDCl3) δ 9.44 (s, 1H, CONH), 8.85(d, J = 8.5 Hz, 1H, Ph), 8.41 (s, 1H, CONH), 7.73 (t, J = 7.9 Hz, 1H, Ph),7.57 (d, J = 7.3 Hz, 1H, Ph), 5.94 (s, 1H, CONH), 5.39 (s, 1H, CH=C), 4.98(dd, J = 12.3, 5.2 Hz, 1H, poma), 3.67 – 3.65 (m, 4H, OCH2), 3.61 – 3.60 (m,4H, OCH2), 3.50 – 3.45 (m, 4H, OCH2), 3.38 – 3.35 (m, 1H, NHCH2 ), 3.24 (dd, J= 11.4, 4.3 Hz, 1H, CHOH), 3.02 – 2.98 (m, 1H, NHCH2 ), 1.18 (s, 3H, CH3), 1.01(s, 3H, CH3), 0.93 (s, 3H, CH3), 0.92 (s, 6H, CH3), 0.80 (s, 3H, CH3), 0.78(s, 3H, CH3)。
13C NMR (150 MHz, CDCl3) δ 178.12, 172.22, 170.72, 169.16, 167.85,166.69, 145.17, 137.87, 136.44, 131.10, 125.28, 122.66, 118.43, 115.29,78.95, 71.34, 71.07, 70.60 (x2), 70.12, 70.10, 55.09, 49.29, 47.54, 46.82,46.24, 42.37, 42.11, 39.40, 39.36, 38.76, 38.48, 37.93, 36.97, 34.15, 33.00,32.49, 32.36, 31.41, 30.74, 29.71, 29.60, 29.32, 29.30, 28.10, 27.29, 27.15,27.02, 25.83, 25.73, 25.07, 23.80, 23.61, 23.56, 22.70, 18.29, 16.92, 15.59,15.38。
实施例6：化合物6的合成
结构式如下：
白色固体，产率为26%。1H NMR (600 MHz, CDCl3) δ 9.45 (s, 1H, CONH), 8.84(d, J = 8.4 Hz, 1H, Ph), 8.53 (s, 1H, CONH), 7.73 (t, J = 7.9 Hz, 1H, Ph),7.57 (d, J = 7.2 Hz, 1H, Ph), 5.96 (s, 1H, CONH), 5.39 (s, 1H, CH=C), 4.98(dd, J = 12.2, 5.1 Hz, 1H, poma), 3.67 – 3.65 (m, 8H, OCH2), 3.61 – 3.59 (m,4H, OCH2), 3.51 – 3.46 (m, 4H, OCH2), 3.39 – 3.34 (m, 1H, NHCH2 ), 3.24 (dd, J= 11.3, 4.5 Hz, 1H, CHOH), 3.01 – 2.98 (m, 1H, NHCH2 ), 1.17 (s, 3H, CH3), 1.00(s, 3H, CH3), 0.92 (s, 3H, CH3), 0.92 (s, 6H, CH3), 0.80 (s, 3H, CH3), 0.77(s, 3H, CH3)。
13C NMR (150 MHz, CDCl3) δ 178.20, 172.28, 170.82, 169.13, 167.94,166.70, 145.10, 137.82, 136.42, 131.12, 125.28, 122.70 , 118.44, 115.34,78.93, 71.38, 71.08, 70.42 (×2), 70.31 (×2), 69.88, 69.87, 55.09, 49.30 ,47.53, 46.81, 46.24, 42.34, 42.10, 39.36, 39.3, 38.76, 38.48, 37.85, 36.96,34.16, 33.00, 32.49, 32.36, 31.40, 30.73, 29.46, 29.26, 29.13, 28.10, 27.28,27.14, 26.88, 25.73, 25.68, 25.61, 25.00, 23.78, 23.60, 23.55, 22.68, 18.29,16.92, 15.59, 15.38。
实施例7：化合物7的合成
结构式如下：
白色固体，产率为35%。1H NMR (600 MHz, CDCl3) δ 10.49 (s, 1H, CONH), 8.88(d, J = 8.5 Hz, 1H, Ph), 8.64 (d, J = 13.8 Hz, 1H, CONH), 7.74 (t, J = 7.9Hz, 1H, Ph), 7.60 (d, J = 7.3 Hz, 1H, Ph), 5.94 (s, 1H, CONH), 5.31 (s, 1H,CH=C), 4.98 (dd, J = 12.6, 5.1 Hz, 1H, poma), 4.23 (s, 2H, OCH2), 3.84 – 3.83(m, 2H, OCH2), 3.75 – 3.73 (m, 2H, OCH2), 3.50 (t, J = 6.6 Hz, 2H, OCH2), 3.35– 3.31 (m, 1H, NHCH2 ), 3.23 (dd, J = 11.3, 4.3 Hz, 1H, CHOH), 3.01 – 2.99 (m,1H, NHCH2 ), 1.11 (s, 3H, CH3), 1.00 (s, 3H, CH3), 0.96 (s, 3H, CH3), 0.93 (s,3H, CH3), 0.88 (d, J = 6.0 Hz, 3H, CH3), 0.79 (s, 3H, CH3), 0.79 (s, 3H, CH3)。
13C NMR (150 MHz, CDCl3) δ 178.17, 170.95, 169.57, 168.42, 167.90,166.83, 140.08, 136.77, 136.29, 131.40, 125.53, 125.27, 118.80, 116.19,78.97, 71.65, 71.53, 71.12, 70.14, 55.12, 53.96, 49.34, 47.67, 42.53, 39.79,39.53, 39.36, 39.11, 38.75, 38.64, 37.15, 36.94, 32.74, 31.51, 30.91, 29.70,29.57, 29.26, 28.13, 27.84, 27.16, 26.89, 25.74, 24.87, 23.42, 23.24, 22.58,21.25, 18.27, 17.27, 16.92, 15.63, 15.51。
实施例8：化合物8的合成
结构式如下：
白色固体，产率为20%。1H NMR (600 MHz, CDCl3) δ 10.50 (s, 1H, CONH), 8.88(d, J = 8.4 Hz, 1H, Ph), 8.52 (s, 1H, CONH), 7.75 (t, J = 7.9 Hz, 1H, Ph),7.60 (d, J = 7.3 Hz, 1H, Ph), 5.93 (s, 1H, CONH), 5.32 (s, 1H， CH=C), 4.97(dd, J = 12.5, 5.4 Hz, 1H, poma), 4.23 (s, 2H, OCH2),3.86– 3.85 (m, 2H, OCH2),3.83– 3.82 (m, 2H, OCH2), 3.70 (t, J = 5.0 Hz, 2H, OCH2), 3.61 – 3.58 (m, 1H,OCH2), 3.45 (t, J = 6.7 Hz, 2H, OCH2), 3.34 – 3.30 (m, 1H, NHCH2 ), 3.24 (dd, J= 11.3, 4.4 Hz, 1H, CHOH), 3.03 – 2.98 (m, 1H, NHCH2 ), 1.11 (s, 3H, CH3), 1.00(s, 3H, CH3), 0.96 (s, 3H, CH3), 0.94 (s, 3H, CH3), 0.88 (d, J = 6.4 Hz, 3H,CH3), 0.80 (s, 3H, CH3), 0.79 (s, 3H, CH3)。
13C NMR (150 MHz, CDCl3) δ 178.06, 170.86, 169.46, 168.41, 167.88,166.77, 140.07, 136.77, 136.31, 131.37, 125.51, 125.24, 118.79, 116.15,78.96, 71.53, 71.39, 71.05, 70.73, 70.66, 70.01, 55.11, 53.97, 49.27, 47.67,42.53, 39.79, 39.53, 39.38, 39.11, 38.75, 38.63, 37.18, 36.94, 32.75, 31.41,30.91, 29.70, 29.55, 29.24, 28.13, 27.85, 27.16, 26.96, 25.79, 24.88, 23.42,23.24, 22.67, 21.24, 18.27, 17.27, 16.94, 15.64, 15.51。
实施例9：化合物9的合成
结构式如下：
白色固体，产率为37%。1H NMR (600 MHz, CDCl3) δ 10.52 (s, 1H, CONH), 8.87(d, J = 8.4 Hz, 2H, Ph), 7.74 (t, J = 7.9 Hz, 1H, Ph), 7.59 (d, J = 7.3 Hz,1H, Ph), 5.92 (s, 1H, CONH), 5.31 (s, 1H, CH=C), 4.97 (dd, J = 12.4, 5.4 Hz,1H, poma), 4.24 – 4.18 (m, 2H, OCH2), 3.83 (s, 4H, OCH2), 3.73– 3.71 (m, 2H,OCH2), 3.68 – 3.64 (m, 4H, OCH2), 3.60 – 3.58 (m, 2H, OCH2), 3.46 (t, J = 6.7Hz, 2H, OCH2), 3.33 – 3.29 (m, 1H, NHCH2 ), 3.24 (dd, J = 11.1, 4.0 Hz, 1H,CHOH), 3.01 – 2.98 (m, 1H, NHCH2 ), 1.10 (s, 3H, CH3), 1.00 (s, 3H, CH3), 0.96(s, 3H, CH3), 0.93 (s, 3H, CH3), 0.89 (d, J = 6.4 Hz, 3H, CH3), 0.79 (s, 3H,CH3), 0.78 (s, 3H, CH3).13C NMR (150 MHz, CDCl3) δ 178.08, 171.06, 169.40,168.42, 168.02, 166.78, 140.05, 136.74, 136.28, 131.39, 125.52, 125.20,118.78, 116.17, 78.95, 71.60, 71.30, 70.97, 70.66, 70.56, 70.49, 70.45,70.03, 55.11, 53.97, 49.27, 47.67, 47.52, 42.52, 39.78, 39.52, 39.39, 39.10,38.74, 38.63, 37.17, 36.93, 32.75, 30.90, 29.69, 29.44, 29.22, 28.13, 27.84,27.15, 26.98, 25.77, 24.87, 23.41, 23.23, 22.72, 21.24, 18.26, 17.26, 16.93,15.64, 15.51.
实施例10：化合物10的合成
结构式如下：
白色固体，产率为28%。1H NMR (600 MHz, CDCl3) δ 9.44 (s, 1H, CONH), 8.85(d, J = 8.5 Hz, 1H, Ph), 8.27 (d, J = 9.7 Hz, 1H, CONH), 7.73 (t, J = 7.9 Hz,1H, Ph), 7.57 (d, J = 7.3 Hz, 1H, Ph), 5.92 (s, 1H, CONH), 5.32 (s, 1H, CH=C), 4.98 (dd, J = 12.5, 5.2 Hz, 1H, poma), 3.59 (s, 4H, OCH2), 3.51 – 3.46(m, 4H, OCH2), 3.34 – 3.21 (m, 1H, NHCH2 ), 3.24 (dd, J = 11.2, 4.4 Hz, 1H,CHOH), 3.04 – 3.01 (m, 1H, NHCH2 ), 1.11 (s, 3H, CH3), 1.01 (s, 3H, CH3), 0.97(s, 3H, CH3), 0.94 (s, 3H, CH3), 0.88 (d, J = 6.4 Hz, 3H, CH3), 0.80 (s, 3H,CH3), 0.80 (s, 3H, CH3)。
13C NMR (150 MHz, CDCl3) δ 178.05, 172.22, 170.75, 169.16, 167.87,166.70, 140.09, 137.87, 136.44, 131.10, 125.52, 125.27, 118.43, 115.29,78.97, 71.35, 71.07, 70.12, 70.08, 55.12, 54.00, 49.29, 47.68, 42.54, 39.79,39.53, 39.40, 39.11, 38.75, 38.64, 38.62, 37.93, 37.18, 32.76, 31.40, 30.92,29.70, 29.58, 29.30, 29.23, 28.13, 27.85, 27.17, 27.03, 25.85, 25.72, 25.07,24.89, 23.42, 23.24, 22.69, 21.24, 18.27, 17.27, 16.94, 15.63, 15.51。
实施例11：化合物11的合成
结构式如下：
白色固体，产率为27%。1H NMR (600 MHz, CDCl3) δ 9.44 (s, 1H, CONH), 8.85(d, J = 8.5 Hz, 1H, Ph), 8.29 (s, 1H, CONH), 7.74 (t, J = 7.9 Hz, 1H, Ph),7.57 (d, J = 7.3 Hz, 1H, Ph), 5.91 (s, 1H, CONH), 5.32 (s, 1H, CH=C), 4.98(dd, J = 12.5, 5.3 Hz, 1H, poma), 3.67 – 3.65 (m, 4H, OCH2), 3.62 – 3.59 (m,4H, OCH2), 3.51 – 3.45 (m, 4H, OCH2), 3.35 – 3.31 (m, 1H, NHCH2 ), 3.24 (dd, J= 11.1, 4.0 Hz, 1H, CHOH), 3.03 – 3.00 (m, 1H, NHCH2 ), 1.11 (s, 3H, CH3), 1.01(s, 3H, CH3), 0.97 (s, 3H, CH3), 0.94 (s, 3H, CH3), 0.89 (d, J = 6.4 Hz, 3H,CH3), 0.80 (s, 3H, CH3), 0.80 (s, 3H, CH3)。
13C NMR (150 MHz, CDCl3) δ 178.03, 172.22, 170.70, 169.16, 167.84,166.70, 140.09, 137.87, 136.44, 131.10, 125.51, 125.28, 118.43, 115.29,78.98, 71.34, 71.07, 70.59, 70.11, 70.09, 55.12, 54.00, 49.29, 47.68, 47.53,42.54, 39.80, 39.53, 39.40, 39.12, 38.76, 38.64, 37.93, 37.18, 36.94, 32.76,31.41, 30.92, 29.71, 29.58, 29.30, 29.25, 28.14, 27.86, 27.18, 27.03, 25.85,25.73, 25.07, 24.89, 23.42, 23.24, 22.70, 21.25, 18.28, 17.27, 16.94, 15.63,15.52。
实施例12：化合物12的合成
结构式如下：
白色固体，产率为34%。1H NMR (600 MHz, CDCl3) δ 9.44 (s, 1H, CONH), 8.85(d, J = 8.5 Hz, 1H, Ph), 8.29 (d, J = 4.4 Hz, 1H, CONH), 7.73 (t, J = 7.9 Hz,1H, Ph), 7.57 (d, J = 7.2 Hz, 1H, Ph), 5.91 (s, 1H, CONH), 5.32 (s, 1H, CH=C), 4.98 (dd, J = 12.5, 5.3 Hz, 1H, poma), 3.68 (s, 4H, OCH2), 3.67 – 3.65(m, 4H, OCH2), 3.61 – 3.59 (m, 4H, OCH2), 3.51 – 3.45 (m, 4H, OCH2), 3.35 –3.31 (m, 1H, NHCH2 ), 3.24 (dd, J = 11.3, 4.5 Hz, 1H, CHOH), 3.03 – 3.00 (m,1H, NHCH2 ), 1.11 (s, 3H, CH3), 1.01 (s, 3H, CH3), 0.97 (s, 3H, CH3), 0.94 (s,3H, CH3), 0.89 (d, J = 6.4 Hz, 3H, CH3), 0.80 (s, 3H, CH3), 0.80 (s, 3H, CH3)。
13C NMR (150 MHz, CDCl3) δ 178.03, 172.24, 170.80, 169.16, 167.90,166.71, 140.08, 137.86, 136.43, 131.10, 125.52, 125.27, 118.42, 115.29,78.96, 71.34, 71.06, 70.57(x 4), 70.09, 70.06, 55.12, 53.99, 49.29, 47.67,47.53, 42.53, 39.79, 39.53, 39.40, 39.11, 38.75, 38.64, 37.91, 37.18, 36.94,32.76, 31.41, 30.91, 29.58, 29.28, 29.24, 28.13, 27.85, 27.17, 27.02, 25.84,25.71, 25.06, 24.88, 23.42, 23.24, 22.69, 21.25, 18.27, 17.27, 16.93, 15.64,15.51。
二、本发明化合物13～18的制备
1、化合物13～18的通用合成路线：
其中，化合物13、15、17中，PTP1B为结构式E。
化合物14、16、18中，PTP1B为结构式D。
2、化合物13～18的具体合成步骤如下：
（1）中间体的合成（以中间体8a为例）：将1,6-己烷二胺（18 mg, 0.15 mmol)溶于3ml DMF 溶液中，陆续加入HATU（57 mg, 0.15 mmol），DIPEA（0.052 ml, 0.3 mmol），PTP1BInhibitor（0.1 mmol)，40℃下反应过夜，TLC监测反应，待反应完全后，加少量水淬灭，用二氯甲烷萃取三次，合并所有有机相，饱和食盐水多次洗涤，无水硫酸钠干燥，真空旋干多余的二氯甲烷，粗产品经硅胶柱纯化（二氯甲烷：甲醇= 10: 1）即得到黄色固体20mg，产率为36%。
（2）目标化合物13～18的合成（以中间体8a为例）：将中间体8a（61mg, 0.11mmol)溶于3 ml NMP溶液中，陆续加入2-(2,6-二氧杂环哌啶-3-基)-4-氟异吲哚啉-1,3-二酮（28mg, 0.1 mmol），DIPEA（0.035 ml, 0.2 mmol）90℃下反应过夜，TLC监测反应，待反应完全后，加少量水水淬灭，用乙酸乙酯萃取三次，合并所有有机相，饱和食盐水洗涤，无水硫酸钠干燥，真空旋干多余的乙酸乙酯，粗产品经硅胶柱纯化（石油醚：乙酸乙酯= 1: 1）即得到目标化合物产品。
实施例13：化合物13的合成
结构式如下：
黄色固体，产率为38%。1H NMR (600 MHz, CDCl3) δ 8.40 (s, 1H, CONH), 7.50(t, J = 7.8 Hz, 1H, Ph), 7.10 (d, J = 7.1 Hz, 1H, Ph), 6.88 (d, J = 8.5 Hz,1H, Ph), 6.23 (s, 1H, NHPh), 5.95 (s, 1H, CONH), 5.39 (s, 1H, CH=C), 4.93(dd, J = 12.3, 5.3 Hz, 1H, poma), 3.39 – 3.35 (m, 1H, NHCH2 ), 3.27 (q, J =6.6 Hz, 2H, NHCH2 ), 3.23 (dd, J = 11.1, 3.6 Hz, 1H, CHOH), 3.04 – 3.01 (m,1H, NHCH2 ), 1.17 (s, 3H, CH3), 0.99 (s, 3H, CH3), 0.91 (s, 6H, CH3), 0.91 (s,3H, CH3), 0.78 (s, 3H, CH3), 0.77 (s, 3H, CH3)。
13C NMR (150 MHz, CDCl3) δ 178.24, 171.27, 169.50, 168.51, 167.62,146.92, 145.16, 136.11, 132.49, 122.67, 116.60, 111.41, 109.86, 78.89, 55.06,48.87, 47.48, 46.78, 46.26, 42.60, 42.38, 42.10, 39.35, 38.75, 38.45, 36.95,34.13, 32.99, 32.51, 32.35, 31.43, 30.73, 29.69, 29.26, 29.22, 28.11, 27.28,27.07, 26.88, 26.62, 25.71, 23.78, 23.60, 23.56, 22.81, 18.28, 16.96, 15.61,15.37。
实施例14：化合物14的合成
结构式如下：
黄色固体，产率为42% 。1H NMR (600 MHz, CDCl3) δ 8.41 (s, 1H, CONH), 7.50(t, J = 7.7 Hz, 1H, Ph), 7.10 (d, J = 6.5 Hz, 1H, Ph), 6.89 (d, J = 8.5 Hz,1H, Ph), 6.23 (s, 1H,NHPh), 5.92 (s, 1H, CONH), 5.32 (s, 1H, CH=C), 4.93 (dd,J = 12.3, 5.3 Hz, 1H, poma),3.35 – 3.31 (m, 1H, NHCH2 ), 3.27 (q, J = 6.6 Hz,2H, NHCH2 ), 3.23 (dd, J = 11.1, 3.6 Hz, 1H, CHOH), 3.05 – 3.02 (m, 1H, NHCH2 ),1.11 (s, 3H, CH3), 1.00 (s, 3H, CH3), 0.96 (s, 3H, CH3), 0.92 (s, 3H, CH3),0.88 (d, J = 6.0 Hz, 3H, CH3), 0.79 (s, 3H, CH3), 0.78 (s, 3H, CH3)。
13C NMR (150 MHz, CDCl3) δ 178.15, 171.22, 169.50, 168.48, 167.61,146.93, 140.14, 136.12, 132.50, 125.49, 116.60, 111.42, 109.87, 78.94, 55.09,54.03, 48.87, 47.71, 47.48, 42.61, 42.54, 39.79, 39.53, 39.35, 39.12, 38.75,38.61, 37.21, 32.75, 31.42, 30.90, 29.69, 29.25, 29.13, 28.14, 27.85, 27.09,26.88, 26.64, 24.87, 23.43, 23.22, 22.82, 21.23, 18.26, 17.27, 16.97, 15.64,15.50。
实施例15：化合物15的合成
结构式如下：
黄色固体，产率为35% 。1H NMR (600 MHz, CDCl3) δ 8.64 (s, 1H, CONH), 7.49(t, J = 7.8 Hz, 1H, Ph), 7.08 (d, J = 8.4 Hz, 1H, Ph), 6.93 (d, J = 8.5 Hz,1H, Ph), 6.44 (s, 1H, NHPh), 6.22 (s, 1H, CONH), 5.34 (s, 1H, CH=C), 4.91(dd, J = 12.3, 5.2 Hz, 1H, poma), 3.68 – 3.66 (m, 4.0 Hz, 4H, OCH2), 3.62 –3.59 (m, 6H, OCH2), 3.53 – 3.52 (m, 2H, OCH2), 3.45 – 3.40 (m, 3H,NHCH2 ), 3.21(d, J = 9.0 Hz, 1H, CHOH), 3.15 – 3.11 (m, 1H, NHCH2 ), 1.15 (s, 3H, CH3), 0.98(s, 3H, CH3), 0.90 (s, 9H, CH3), 0.77 (s, 3H, CH3), 0.75 (s, 3H, CH3)。
13C NMR (150 MHz, CDCl3) δ 178.06, 171.44, 169.37, 168.63, 167.66,146.97, 144.74, 136.09, 132.49, 122.64, 116.65, 111.34, 109.88, 78.87, 70.53(x2), 70.39, 70.25, 69.80, 68.78, 55.08, 48.85, 47.53, 46.70, 46.13, 42.06,41.97, 40.11, 39.34, 38.73, 38.45, 37.49, 36.95, 34.12, 33.02, 32.65, 32.38,31.43, 30.71, 29.67, 29.34, 29.23, 28.09, 27.29, 27.08, 25.79, 23.62, 23.50,22.80, 18.27, 16.94, 15.60, 15.34。
实施例16：化合物16的合成
结构式如下：
黄色固体，产率为33% 。1H NMR (600 MHz, CDCl3) δ 8.53 (d, J = 44.8 Hz,1H, CONH), 7.50 (t, J = 7.8 Hz, 1H, Ph), 7.09 (d, J = 7.1 Hz, 1H, Ph), 6.94(d, J = 8.5 Hz, 1H, Ph), 6.45 (s, 1H, NHPh), 6.19 (s, 1H, CONH), 5.29 (s, 1H,CH=C), 4.92 (dd, J = 12.3, 5.3 Hz, 1H, poma), 3.70 – 3.67 (m, 4H, OCH2), 3.63– 3.61 (m, 6H, OCH2), 3.54 – 3.51 (m, 2H,NHCH2 ), 3.43 – 3.39 (m, 2H, OCH2, 1H,NHCH2 ), 3.23 (dd, J = 11.0, 4.1 Hz, 1H, CHOH), 3.17 – 3.13 (m, 1H, NHCH2 ),1.09 (s, 3H, CH3), 0.99 (s, 3H, CH3), 0.95 (s, 3H, CH3), 0.92 (s, 3H, CH3),0.87 (s, 3H, CH3), 0.78 (d, J = 7.8 Hz, 3H, CH3), 0.78 (s, 3H, CH3).
13C NMR (150 MHz, CDCl3) δ 177.94, 171.30, 169.37, 168.54, 167.65,146.99, 139.55, 136.10, 132.50, 125.56, 116.66, 111.37, 109.89, 78.94, 70.54,70.52, 70.41, 70.26, 69.85, 68.80, 55.12, 53.72, 48.85, 47.55, 47.52, 42.39,40.13, 39.68, 39.53, 39.09, 38.73, 38.61, 37.50, 37.29, 36.93, 32.78, 31.43,30.90, 29.69, 29.35, 29.19, 28.13, 27.83, 27.14, 24.73, 23.33, 22.82, 21.25,18.27, 17.28, 16.96, 15.63, 15.48.
实施例17：化合物17的合成
结构式如下：
黄色固体，产率为37% 。1H NMR (600 MHz, CDCl3) δ 8.51 (d, J = 47.9 Hz,1H, CONH), 7.50 (t, J = 7.8 Hz, 1H, Ph), 7.10 (d, J = 7.1 Hz, 1H, Ph), 6.93(d, J = 8.5 Hz, 1H, Ph), 6.44 (s, 1H, NHPh), 6.25 (s, 1H, CONH), 5.35 (s, 1H,CH=C), 4.92 (dd, J = 12.3, 5.3 Hz, 1H, poma), 3.55 – 3.54 (m, 2H, OCH2), 3.50– 3.46 (m, 6H, OCH2, 1H, NHCH2 ), 3.42 – 3.39 (m, 2H, OCH2), 3.22 (dd, J =10.7, 3.8 Hz, 1H, CHOH),3.17 – 3.13 (m, 1H, NHCH2 ), 1.16 (s, 3H, CH3), 0.99(s, 3H, CH3), 0.91 (s, 9H, CH3), 0.78 (s, 3H, CH3), 0.77 (s, 3H, CH3)。
13C NMR (150 MHz, CDCl3) δ 178.00, 171.28, 169.37, 168.53, 167.65,146.97, 144.78, 136.06, 132.52, 122.62, 116.59, 111.36, 109.92, 78.91, 70.98,70.95, 69.40, 68.28, 55.09, 48.86, 47.54, 46.74, 46.14, 42.10, 41.98, 40.22,39.36, 38.74, 38.45, 37.74, 36.95, 34.11, 33.02, 32.67, 32.38, 31.42, 30.73,29.69, 29.45, 29.28, 28.09, 27.30, 27.10, 26.46, 26.38, 25.82, 23.62, 23.51,22.82, 18.29, 16.93, 15.59, 15.35。
实施例18：化合物18的合成
结构式如下：
黄色固体，产率为38% 。1H NMR (600 MHz, CDCl3) δ 8.52 (s, 1H, CONH), 7.49(t, J = 7.8 Hz, 1H, Ph), 7.09 (d, J = 7.1 Hz, 1H, Ph), 6.93 (d, J = 8.6 Hz,1H, Ph), 6.44 (s, 1H, NHPh), 6.25 (s, 1H, CONH), 5.29 (s, 1H, CH=C), 4.92(dd, J = 12.3, 5.3 Hz, 1H, poma), 3.54 (t, J = 5.7 Hz, 2H, NHCH2 ), 3.51 –3.46 (m, 6H, OCH2), 3.42 – 3.40 (m, 2H, OCH2,,1H, NHCH2 ), 3.22 (dd, J = 11.1,4.3 Hz, 1H, CHOH), 3.17 – 3.14 (m, 1H, NHCH2 ), 1.09 (m, 3H, CH3), 0.99 (m, 3H,CH3), 0.95 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.87 (d, J = 7.8 Hz, 3H, CH3),0.78 (m, 6H, CH3)。
13C NMR (150 MHz, CDCl3) δ 177.81, 171.29, 169.37, 168.53, 167.65,146.96, 139.52, 136.06, 132.51, 125.55, 116.58, 111.36, 109.91, 78.92, 70.97,70.95, 69.61, 68.28, 55.12, 53.75, 48.86, 47.53, 42.39, 40.22, 39.68, 39.54,39.11, 38.73, 38.62, 37.87, 37.30, 36.92, 32.78, 31.43, 30.89, 29.69, 29.45,29.18, 28.13, 27.83, 27.14, 26.55, 26.40, 24.71, 23.38, 23.35, 22.82, 21.25,18.28, 17.27, 16.93, 15.63, 15.48。
三、本发明化合物的应用
1、体外蛋白降解实验
使用HepG2细胞株，WesternBlot法分别测试化合物6，8，9，15和17在1nM、5nM、25nM、125nM、625nM、1250nM的水溶液浓度下，药物作用48 h或72 h对PTP1B蛋白的降解作用，选用GAPDH（甘油醛-3-磷酸脱氢酶）为参照物。其结果如附图1所示，化合物表现出良好的蛋白降解作用。
2、口服葡萄糖耐量试验（oGTT）
使用KM小鼠单剂量给药10 mg/kg、20 mg/kg和40 mg/kg来筛选化合物15的口服葡萄糖耐量试验的给药最佳剂量。化合物使用乙醇-水（4：1）溶液进行配比，测定给糖前、给糖后15min、30min、60min、90min和120 min时的血糖值，计算2 h内的血糖曲线下面积（AUC）。
结果如附图2、3所示，化合物15给药剂量为40 mg/kg在15min、30min、60min、90min时血糖值均明显低于空白组，在10 mg/kg、20 mg/kg和40 mg/kg 的剂量下，观察到0～2h内的血糖曲线下面积分别减少了8.6%、14.8%和21.8%，说明化合物15以剂量依赖的方式降低小鼠体内血糖浓度，最终选择给药剂量为40 mg/kg作为口服葡萄糖耐量试验的最佳剂量。
对化合物6、8、16和17进行口服葡萄糖耐量试验，给药剂量为40 mg/kg，测定给糖前、给糖后15min、30min、60min、90min和120 min时的血糖值，计算2 h内的血糖曲线下面积（AUC）。结果如附图4、5所示，化合物6的血糖值始终低于空白组，化合物8在60 min时降糖效果最佳，化合物16，17，8和6的血糖曲线下面积分别减少了6.7%、15.3%、18.3%和29%，化合物6具有显著的降糖效果（与空白组相比，P<0.05，n=6）。
最后应说明的是，以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种靶向降解PTP1B的PROTAC化合物，其特征在于：所述化合物的结构式如下通式I或者通式II：
其中，Linker为连接分子，PTP1B Inhibitor为PTP1B抑制剂，所述PTP1B抑制剂选自以下化学结构式A～F：
2.根据权利要求1所述的靶向降解PTP1B的PROTAC化合物，其特征在于：所述Linker选自以下化学结构式a～n：
其中，X、Y为NH或CH2，n = 1～10。
3.一种PROTAC化合物药学上可接受的盐，其特征在于：所述PROTAC化合物为权利要求1或2所述的靶向降解PTP1B的PROTAC化合物。
4.根据权利要求1或3所述的PROTAC化合物或其药学上可接受的盐，其特征在于：所述PROTAC化合物或其药学上可接受的盐在其他药理学活性物质之前、之后或一起施用。
5.一种药物制剂，其特征在于：其包含权利要求1或3所述的靶向降解PTP1B的PROTAC化合物或其药学上可接受的盐，以及一种或多种药理学活性物质。
6.一种药物组合物，其特征在于：其包含权利要求1或3所述的靶向降解PTP1B的PROTAC化合物或其药学上可接受的盐，以及一种或多种药学上可接受的载体或辅料。
7.一种如权利要求1或3所述的PROTAC化合物或其药学上可接受的盐在制备治疗和/或预防PTP1B蛋白相关疾病的药物中的应用。
8.根据权利要求7所述的应用，其特征在于：所述PTP1B蛋白相关疾病为癌症、骨质增生异常综合症、代谢综合症、糖尿病、代谢失调和肥胖中的一种。
9.根据权利要求7所述的应用，其特征在于：所述糖尿病为2型糖尿病。
10.根据权利要求7所述的应用，其特征在于：所述癌症包括肺癌、肝癌、肾癌、非小细胞肺癌、前列腺癌、甲状腺癌、皮肤癌、胰腺癌、卵巢癌、乳腺癌、膀胱癌、淋巴癌、食管癌、胃肠道癌、骨肉瘤、中枢神经系统的肿瘤以及外周神经系统的肿瘤中的一种。
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| WO2006069466A1 (fr) * | 2004-12-27 | 2006-07-06 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Serie d’inhibiteurs de ptp1b triterpenoides et leur procede de preparation et utilisation |
| WO2021180787A1 (en) * | 2020-03-12 | 2021-09-16 | Julius-Maximilians-Universitaet Wuerzburg | Proteolysis targeting chimera (protac) for degradation of aurora a-kinase |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2006069466A1 (fr) * | 2004-12-27 | 2006-07-06 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Serie d’inhibiteurs de ptp1b triterpenoides et leur procede de preparation et utilisation |
| WO2021180787A1 (en) * | 2020-03-12 | 2021-09-16 | Julius-Maximilians-Universitaet Wuerzburg | Proteolysis targeting chimera (protac) for degradation of aurora a-kinase |
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| Title |
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| RITA DE CÁSSIA LEMOS LIMA等: "High-Resolution PTP1B Inhibition Profiling Combined with HPLC-HRMS-SPE-NMR for Identification of PTP1B Inhibitors from Miconia albicans", 《MOLECULES》, vol. 23, no. 7, pages 6 - 1755 * |
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