CN116693520A - 一种色酮噻唑二酮类化合物及其制备方法、药物组合物和应用 - Google Patents
一种色酮噻唑二酮类化合物及其制备方法、药物组合物和应用 Download PDFInfo
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Abstract
本发明公开了一种色酮噻唑二酮类化合物及其制备方法、药物组合物和应用，所述色酮噻唑二酮类化合物具有如式(Ⅰ)所示的化合物：其中，R选自取代或未取代的C6～12的芳基。本发明设计并合成了一系列色酮噻唑二酮类化合物，这些化合物表现出强的PTP1B抑制作用，能够作为PTP1B酶抑制剂用于治疗或预防糖尿病。
Description
技术领域
本发明涉及有机合成技术领域，尤其是涉及一种色酮噻唑二酮类化合物及其制备方法、药物组合物和应用。
背景技术
2021年12月6日，国际糖尿病联盟(IDF)发布了《IDF世界糖尿病地图(第10版)》，其中包括2021年全球糖尿病的九大数据：每10个20～79岁的成年人中就有1名糖尿病患者，总数达5.37亿人；每2名糖尿病患者中有1名未被确诊，总数达2.40亿人；每4名糖尿病患者中有3名生活在中低收入国家或地区；每18个20～79岁的成年人中就有1名空腹血糖受损，总数达3.19亿；每6个活产儿中有1个受妊娠期高血糖的影响，总数达2100万，80％孩子的母亲有妊娠期糖尿病；120万20岁以下的儿童青少年患有1型糖尿病；每9个20～79岁的成年人中就有1名糖耐量受损，总数达5.41亿人；全世界9％的健康支出花在了糖尿病上，总额达9.66亿美元；670万人死于糖尿病。
糖尿病是一种由于胰岛素分泌不足，或者胰岛β细胞损害，致使血糖水平升高的慢性代谢紊乱疾病。糖尿病导致的患者体内长期血糖浓度过高，可能引起一系类并发症，例如，血糖水平的增加可能会导致许多微血管和大血管的并发症。其中，微血管并发症包括视网膜病变、白内障、肾病、神经病，而大血管并发症包括中风、心血管疾病、冠状动脉疾病、脑血管疾病和糖尿病足，糖尿病足严重时可能导致截肢。目前临床上应用的降糖药物主要有磺脲类、双胍类、α-葡萄糖苷酶抑制剂、噻唑烷二酮类和非磺脲类胰岛素促分泌剂等。
在PTP家族成员中，蛋白酪氨酸磷酸酯酶1B(PTP1B)在胰岛素和瘦素信号系统具有负调节作用，已被证明是潜在治疗II型糖尿病的重要分子靶点。在人类和动物模型中的大量研究表明，在II型糖尿病中，胰岛素抵抗是通过PTP活性以及PTP家族成员表达水平的增加来实现的。胰岛素与胰岛素受体(IR)结合会引起构象变化，从而激活受体酪氨酸激酶结构，进而引发细胞质内的胰岛素信号转导。在多个酪氨酸残基上的激活的受体会发生自磷酸化，自磷酸化后产生的胰岛素受体底物1(IRS1)进而激活PI3K和Akt通路。随后，4型葡萄糖转运蛋白(GLUT4)被转运到细胞表面并摄取细胞葡萄糖。PTP1B催化酪氨酸残基(pY1162/pY1163)，使磷酸化的IR和IRS1去磷酸化，从而使IR信号失活并终止。根据Johnson的研究，瘦素与其受体结合会导致Janus激酶2(JAK2)磷酸化，从而激活JAK2信号转换器和转录3(STAT3)。通过STAT3诱导基因调节来减少乙酰辅酶A羧化酶的转录和丙二酰辅酶A和脂肪酸合成，同时增加脂肪酸氧化。因此，蛋白酪氨酸磷酸酯酶1B(PTP1B)被认为是治疗糖尿病和肥胖症的重要靶点之一，可以作为药物治疗的靶点。
因此，有必要开发一种作用于蛋白酪氨酸磷酸酯酶1B的治疗糖尿病的化合物。
发明内容
本发明旨在至少解决现有技术中存在的技术问题之一。为此，本发明第一方面提出一种色酮噻唑二酮类化合物，本发明的提供的色酮噻唑二酮类化合物具有PTP1B抑制活性，能够通过抑制PTP1B从而治疗和/或预防糖尿病。
本发明第二方面还提供一种色酮噻唑二酮类化合物的制备方法。
本发明第三方面还提供一种药物组合物。
本发明第四方面还提供一种蛋白酪氨酸磷酸酯酶1B抑制剂。
本发明第五方面还提供一种色酮噻唑二酮类化合物的应用。
根据本发明的第一方面实施例提供的一种色酮噻唑二酮类化合物或其药学上可接受的盐，所述色酮噻唑二酮类化合物具有如式(Ⅰ)所示的化合物：
其中，R选自取代或未取代的C6～12的芳基。
根据本发明实施例的色酮噻唑二酮类化合物或其药学上可接受的盐，至少具有如下有益效果：
本发明设计并合成了一系列色酮噻唑二酮类化合物，这些化合物表现出强的PTP1B抑制作用，能够作为PTP1B酶抑制剂用于治疗或预防糖尿病。
根据本发明的一些实施例，所述R选自取代或未取代的苯基，所述取代为单取代或多取代，所述取代的基团选自卤素、C1～6的烷基、C1～6的烷氧基、C1～6的卤代烷基、C1～6的卤代烷氧基、硝基、氰基或苯基。
根据本发明的一些实施例，所述R选自如下所示的基团：
根据本发明的第二方面实施例提供上述所述的色酮噻唑二酮类化合物的制备方法，包括如下步骤：
将中间体3、铜催化剂和还原剂发生环加成反应，得到色酮噻唑二酮类化合物；
其中，中间体3的结构式如下：
根据本发明的一些实施例，所述环加成反应的反应温度为室温。
根据本发明的一些实施例，所述环加成反应的反应时间为8～16h。
根据本发明的一些实施例，所述铜催化剂为五水硫酸铜、碘化铜或溴化铜中的至少一种。
根据本发明的一些实施例，所述还原剂包括抗坏血酸钠或金属铜中的至少一种。
根据本发明的一些实施例，所述中间体3通过如下方法制备：
将中间体2和噻唑烷二酮发生羟醛缩合反应生成中间体3；
所述中间体2的结构式如下：
根据本发明的一些实施例，所述中间体2通过如下方法制备：
将中间体1进行Vilsmeier–Haack反应得到中间体2；
所述中间体1的结构式如下：
根据本发明的一些实施例，所述中间体1通过如下方法制备：
将2,4-二羟基苯乙酮、炔丙基溴、碱和有机溶剂混合发生反应生成中间体1。
根据本发明的一些实施例，所述碱为碳酸钾、碳酸钠、碳酸铯或氢氧化钠中的至少一种。
根据本发明的一些实施例，所述有机溶剂为丙酮、二氯甲烷或乙腈。
本发明第三方面提供一种药物组合物，包括上述所述的色酮噻唑二酮类化合物或其药学上可接受的盐；和药学上可接受的辅料。
本发明第四方面提供一种蛋白酪氨酸磷酸酯酶1B抑制剂，包括上述所述的色酮噻唑二酮类化合物或其药学上可接受的盐。
本发明第五方面提供上述所述的色酮噻唑二酮类化合物在制备治疗和/或预防糖尿病产品中的应用。
根据本发明的一些实施例，所述产品包括药品或保健品。
定义和一般术语
“取代或未取代的C6～12的芳基”表示全碳单环或稠合多环基团，具有完全共轭的π电子系统；且碳原子总数为6～12个。并且芳基中任选有至少一个H被本文定义的相应基团所取代。
“C1～6的烷基”表示碳原子总数为1-6的烷基，包括C1-6的直链烷基、C1-6的支链烷基和C3-6的环烷基，例如可以为碳原子总数为1、2、3、4、5或6的直链烷基、碳原子总数为1、2、3、4、5或6的支链烷基或者碳原子总数为3、4、5或6的环烷基，例如可以为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、环丙基、甲基环丙基、乙基环丙基、环戊基、甲基环戊基、环己基等。
“C1～6的烷氧基”表示碳原子总数为1-6的烷氧基，包括C1-6的直链烷氧基、C1-6的支链烷氧基和C2-6的环烷氧基，例如可以为碳原子总数为1、2、3、4、5或6的直链烷氧基、碳原子总数为1、2、3、4、5或6的支链烷氧基或者碳原子总数为2、3、4、5或6的环烷氧基，例如可以为甲氧基、乙氧基、正丙氧基、异丙氧基等。
“C1～6的卤代烷基”表示碳原子总数为1～6的烷基，优选如上所定义的烷基，它被一个或多个相同或不同的卤原子取代，例如-CH2Cl、-CF3、-CCl3、-CH2CF3、-CH2CCl3等。
“C1～6的卤代烷氧基”表示碳原子总数为1～6的烷氧基，优选如上所定义的烷氧基，它被一个或多个相同或不同的卤原子取代。
本发明中结构式出现的表示基团的连接位点。
本发明中室温的含义是指温度为20～28℃之间。
本发明使用的术语“药学上可接受”是指从毒理学观点来看可接受用于制药应用且不会与活性成分发生不利地相互作用的物质。
本发明使用的药学上可接受的辅料包括任何溶剂、固体赋形剂、稀释剂、粘合剂、崩解剂、或其他液体赋形剂、分散剂、矫味剂或悬浮剂、表面活性剂、等渗剂、增稠剂、乳化剂、防腐剂、固体粘合剂、助流剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia ofPharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,MarcelDekker,New York,综合此处文献的内容，表明不同的辅料可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的辅料与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。
作为药学上可接受辅料的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯-聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇；磷酸缓冲溶液；和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁；着色剂；释放剂；包衣衣料；甜味剂；调味剂；香料；防腐剂和抗氧化剂。
本发明化合物的药物组合物可以是以单位剂量形式给药。给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
口服片剂和胶囊可以含有赋形剂如粘合剂，如糖浆、阿拉伯胶、山梨醇、黄芪胶或聚乙烯吡咯烷酮；填充剂，如乳糖、蔗糖、玉米淀粉、磷酸钙、山梨醇、氨基乙酸；润滑剂，如硬脂酸镁、滑石、聚乙二醇、硅土；崩解剂，如马铃薯淀粉；或可接受的增润剂如月桂醇钠硫酸盐。片剂可以用制药学上公知的方法包衣。
口服液可以制成水合油的悬浮液、溶液、乳浊液、糖浆或酏剂，也可以制成干品，用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂，如悬浮剂、山梨醇、纤维素甲醚、葡萄糖糖浆、凝胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶、氢化的食用油脂、乳化剂，如卵磷脂、山梨聚醣单油酸盐、阿拉伯胶；或非水载体(可能包含可食用油)，如杏仁油，油脂如甘油、乙二醇、或乙醇；防腐剂，如对羟基苯甲酸甲酯或丙酯、山梨酸。如需要可添加调味剂或着色剂。
本发明的其它特征和优点将在随后的说明书中阐述，并且，部分地从说明书中变得显而易见，或者通过实施本发明而了解。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1为本发明实施例31提供一种色酮噻唑二酮类化合物Ⅰ-18作为PTP1B抑制剂在体外对PTP1B的半数抑制浓度图
图2为本发明实施例32中色酮噻唑二酮类化合物Ⅰ-18作为PTP1B酶抑制剂在体外对PTP1B的酶动力学图；
图3为本发明实施例33中色酮噻唑二酮类化合物Ⅰ-18作为PTP1B抑制剂在体外对PTP1B酶的底物动力学图。
具体实施方式
以下是本发明的具体实施例，并结合实施例对本发明的技术方案作进一步的描述，但本发明并不限于这些实施例。
本发明所采用的试剂、方法和设备，如无特殊说明，均为本技术领域常规试剂、方法和设备。
本发明提供一种色酮噻唑二酮类化合物的通用制备方法，其通用制备方法如下：
以2,4-二羟基苯乙酮为原料，其与炔丙基溴反应生成中间体1，接着中间体1进行Vilsmeier–Haack反应制备中间体2。中间体2再与噻唑烷二酮发生羟醛缩合生成中间体3，最后中间体3与发生环加成反应得到目标产物；其反应方程式如下所示：
具体的操作步骤如下：
将2,4-二羟基苯乙酮(1.0g，6.6mmol)、炔丙基溴(515μL，6.6mmol)和碳酸钾(0.91g，6.6mmol)的混合物加入15mL丙酮溶液中，在60℃下加热回流6h。通过TLC监测反应过程，反应完成后热过滤混合物，在减压下蒸发溶剂，所得粗产物中间体1不需要纯化直接进行下一步反应。
在无水无氧的条件下，将三氯氧磷(1.9mL，20.4mmol)滴加到搅拌并冷却(0～5℃)的干燥DMF溶液(5mL)中，使反应混合物升温至室温继续搅拌30min。在冰浴条件下，溶解于DMF中的中间体1(1.9g，10.0mmol)缓慢滴入反应液里，搅拌30min后逐渐恢复室温保持4h。反应完全后将混合物倒入碎冰后搅拌4小时。抽滤红色固体沉淀，用水和少量乙酸乙酯溶液清洗混合物后即可得中间体2。
依次将中间体2(5.8g，2 5.2mmol)、噻唑烷二酮(3.0g，25.2mmol)和乙酸钠(2g，25.2mmol)加入50mL冰醋酸中。接着在100℃下搅拌，观察到固体逐步溶解至反应体系变红。反应4h左右有固体析出。点板监测反应确认反应完全后，冷却至室温并抽滤固体沉淀，用少量冰乙醇洗涤粗产物，得到红色固体中间体3。
向15mL反应管加入中间体3(150.0mg，0.5mmol)、(130.0mg，0.75mmol)、五水硫酸铜(15.0mg，0.06mmol)、三[(1-苄基-1H-1,2,3-三唑-4-基)甲基]胺(26.0mg，0.05mmol)和抗坏血酸钠(53.0mg，0.28mmol)，加入四氢呋喃/水(2.5:1，4mL)的混合溶液作溶剂，在避光的条件下室温搅拌过夜。反应完成后，抽滤出固体并用DMF进行重结晶，得到终产物。
实施例1～30
实施例1～30提供一系列色酮噻唑二酮类化合物，其制备方法采用上述通用的制备方法制备即可，结构通式和R基如下：
表1.R基团的结构式
通过NMR，MS和熔点表征实施例1～30制备的化合物的结构，以下为各化合物的性状、产率、核磁和质谱结果表征：
(Ⅰ-1,C23H16N4O5S).White sold；Yield 77％；m.p.277.3–280.8℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.74(s,1H),8.36(s,1H),8.01(d,J＝8.8 Hz,1H),7.64(s,1H),7.43–7.29(m,6H),7.17(dd,J＝8.9,2.3Hz,1H),5.63(s,2H),5.33(s,2H).13C NMR(126MHz,DMSO)δ173.97,163.04,157.14,142.03,135.95,128.80,128.21,128.01,127.06,125.17,116.92,115.93,101.98,61.98,52.89.HRMS(ESI)[M+H]+calcd.for C23H16N4O5S:461.0912；found:461.0914.
(Ⅰ-2,C23H15FN4O5S).White sold；Yield 65％；m.p.265.3–268.8℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.75(s,1H),8.36(s,1H),8.01(d,J＝8.9 Hz,1H),7.60(s,1H),7.41(dd,J＝8.2,5.0 Hz,3H),7.25–7.13(m,3H),5.62(s,2H),5.32(s,2H).13C NMR(126 MHz,DMSO)δ174.00,163.05,162.90,160.96,160.54,157.14,142.05,132.22,132.20,130.43,130.36,129.86,127.08,125.09,116.90,115.95,115.74,115.57,101.98,61.98,52.09.HRMS(ESI)[M+H]+calcd.for C23H15FN4O5S:479.0820；found:479.0821.
(Ⅰ-3,C23H15FN4O5S).White sold；Yield 70％；m.p.276.2–279.1℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.73(s,1H),8.40(s,1H),8.01(d,J＝8.9Hz,1H),7.65(s,1H),7.47–7.37(m,2H),7.22–7.12(m,4H),5.66(s,2H),5.34(s,2H).13C NMR(126MHz,DMSO)δ173.95,163.09,163.00,161.15,157.13,142.13,138.61,138.55,130.93,130.86,127.05,125.33,124.10,124.08,116.93,115.92,115.16,114.99,114.94,114.77,101.97,61.94,52.19.HRMS(ESI)[M+H]+calcd.for C23H15FN4O5S:479.0820；found:479.0817.
(Ⅰ-4,C23H15FN4O5S).White sold；Yield 67％；m.p.251.3–253.3℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.71(s,1H),8.35(s,1H),8.00(d,J＝8.9Hz,1H),7.64(s,1H),7.46–7.34(m,3H),7.24(dt,J＝15.2,8.4Hz,2H),7.15(dd,J＝8.9,2.3Hz,1H),5.69(s,2H),5.32(s,2H).13C NMR(126 MHz,DMSO)δ173.89,162.96,161.06,159.10,157.09,141.97,130.83,130.79,130.76,127.00,125.36,124.85,124.82,122.74,122.62,116.89,115.85,115.71,115.54,101.90,61.85,46.99,46.96.HRMS(ESI)[M+H]+calcd.forC23H15FN4O5S:479.0820；found:479.0819.
(Ⅰ-5,C23H15ClN4O5S).White sold；Yield 68％；m.p.280.7–283.2℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.76(s,1H),8.37(s,1H),8.01(d,J＝8.9 Hz,1H),7.60(s,1H),7.45(d,J＝8.1 Hz,2H),7.40(d,J＝2.4 Hz,1H),7.35(d,J＝8.2 Hz,2H),7.17(dd,J＝8.9,2.4 Hz,1H),5.63(s,2H),5.33(s,2H).13C NMR(126 MHz,DMSO)δ173.98,163.04,160.56,157.13,142.07,134.93,132.94,129.99,128.81,127.08,125.21,116.90,115.94,101.99,61.97,52.08.HRMS(ESI)[M+H]+calcd.for C23H15ClN4O5S:495.0524；found:495.0523.
(Ⅰ-6,C23H15ClN4O5S).White sold；Yield 62％；m.p.275.7–279.2℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.73(s,1H),8.40(s,1H),8.01(d,J＝8.9 Hz,1H),7.62(s,1H),7.45–7.36(m,4H),7.32–7.25(m,1H),7.16(dd,J＝9.0,2.4 Hz,1H),5.65(s,2H),5.34(s,2H).13C NMR(126 MHz,DMSO)δ173.95,162.98,157.12,138.31,133.29,130.74,128.20,127.86,127.06,126.74,125.35,116.92,115.92,101.97,61.93,52.10.HRMS(ESI)[M+H]+calcd.forC23H15ClN4O5S:495.0524；found:495.0522.
(Ⅰ-7,C23H15ClN4O5S).White sold；Yield 67％；m.p.223.8–227.3℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.63(d,J＝21.5 Hz,1H),8.35(s,1H),8.02(d,J＝8.9 Hz,1H),7.83(s,1H),7.53(dd,J＝7.7,1.5 Hz,1H),7.45–7.34(m,3H),7.26(dd,J＝7.4,1.9 Hz,1H),7.17(dd,J＝8.9,2.3Hz,1H),5.74(s,2H),5.34(s,2H).13C NMR(126 MHz,DMSO)δ173.93,162.94,157.17,133.14,132.66,130.59,130.32,129.65,127.74,127.03,125.62,117.01,115.87,101.95,61.88,50.68.HRMS(ESI)[M+H]+calcd.for C23H15ClN4O5S:495.0524；found:495.0525.
(Ⅰ-8,C23H15BrN4O5S).White sold；Yield 71％；m.p.286.6–289.4℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.71(s,1H),8.36(s,1H),8.02(d,J＝8.9 Hz,1H),7.67(s,1H),7.58(d,J＝8.3 Hz,2H),7.39(d,J＝2.3 Hz,1H),7.29(d,J＝8.1 Hz,2H),7.16(dd,J＝8.9,2.4 Hz,1H),5.62(s,2H),5.33(s,2H).13C NMR(126 MHz,DMSO)δ173.95,162.98,157.18,135.34,131.72,130.28,127.06,125.23,121.49,115.88,101.95,67.01,61.94,52.13.HRMS(ESI)[M+H]+calcd.forC23H15BrN4O5S:536.9874；found:536.9876.
(Ⅰ-9,C23H15BrN4O5S).White sold；Yield 75％；m.p.264.4–267.1℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.72(s,1H),8.40(s,1H),8.01(d,J＝8.9 Hz,1H),7.87–7.55(m,1H),7.53(d,J＝1.8 Hz,2H),7.39(d,J＝2.3 Hz,1H),7.37–7.29(m,2H),7.17(dd,J＝8.9,2.3 Hz,1H),5.64(s,2H),5.34(s,2H).13C NMR(126 MHz,DMSO)δ173.94,162.98,157.13,138.55,131.09,131.01,130.73,127.13,127.06,125.34,121.85,116.95,115.91,101.97,61.93,52.03.HRMS(ESI)[M+H]+calcd.for C23H15BrN4O5S:536.9874；found:536.9877.
(Ⅰ-10,C23H15BrN4O5S).White sold；Yield 70％；m.p.270.1–272.4℃；1H NMR(500MHz,DMSO)δ12.63–12.23(m,1H),8.70(s,1H),8.33(s,1H),8.00(d,J＝8.8 Hz,1H),7.68(d,J＝7.9Hz,2H),7.46–7.35(m,2H),7.31(t,J＝7.5 Hz,1H),7.24–7.11(m,2H),5.71(s,2H),5.34(s,2H).13C NMR(126 MHz,DMSO)δ173.86,162.93,157.12,134.71,132.89,130.49,130.44,128.25,126.99,125.63,122.88,115.87,101.93,61.85,52.96.HRMS(ESI)[M+H]+calcd.forC23H15BrN4O5S:536.9874；found:536.9875.
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(Ⅰ-11,C24H18N4O5S).White sold；Yield 73％；m.p.273.2–276.7℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.74(s,1H),8.32(s,1H),8.01(d,J＝8.9 Hz,1H),7.61(s,1H),7.39(d,J＝2.4 Hz,1H),7.22(d,J＝7.8 Hz,2H),7.20–7.13(m,3H),5.56(s,2H),5.31(s,2H),2.27(s,3H).13C NMR(126 MHz,DMSO)δ173.97,163.04,157.13,137.57,132.94,129.31,128.06,127.06,125.02,116.89,115.94,101.98,61.98,52.70,20.70.HRMS(ESI)[M+H]+calcd.for C24H18N4O5S:473.0925；found:473.0927.
(Ⅰ-12,C24H18N4O5S).White sold；Yield 77％；m.p.250.6–253.4℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.71(s,1H),8.35(s,1H),8.01(d,J＝8.8 Hz,1H),7.77(d,J＝74.1 Hz,1H),7.38(d,J＝2.3 Hz,1H),7.25(t,J＝7.6 Hz,1H),7.19–7.07(m,4H),5.57(s,2H),5.32(s,2H),2.27(s,3H).13C NMR(126 MHz,DMSO)δ173.90,162.97,157.12,137.99,135.79,128.80,128.67,128.52,127.02,125.15,125.09,116.93,115.88,101.93,61.93,52.86,20.88.HRMS(ESI)[M+H]+calcd.for C24H18N4O5S:473.0925；found:473.0925.
(Ⅰ-13,C24H18N4O5S).White sold；Yield 73％；m.p.234.3–236.8℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.68(s,1H),8.26(s,1H),8.01(d,J＝8.9 Hz,1H),7.71(s,1H),7.38(s,1H),7.27–7.14(m,4H),7.09(d,J＝7.5 Hz,1H),5.63(s,2H),5.32(s,2H),2.30(s,3H).13C NMR(126MHz,DMSO)δ173.92,162.96,157.16,136.32,134.04,130.44,128.68,128.37,127.03,126.26,125.27,116.99,115.89,101.96,61.92,51.00,18.62.HRMS(ESI)[M+H]+calcd.for C24H18N4O5S:473.0925；found:473.0926.
(Ⅰ-14,C24H18N4O6S).White sold；Yield 66％；m.p.248.8–250.5℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.68(s,1H),8.30(s,1H),8.01(d,J＝8.9 Hz,1H),7.71(d,J＝7.6 Hz,1H),7.38(d,J＝2.3 Hz,1H),7.30(d,J＝8.3 Hz,2H),7.15(dd,J＝8.9,2.3 Hz,1H),6.95–6.89(m,2H),5.53(s,2H),5.31(s,2H),3.73(s,3H).13C NMR(126 MHz,DMSO)δ173.92,162.99,159.15,157.17,129.66,127.82,127.03,124.85,117.00,115.86,114.12,101.92,61.95,55.12,52.43.HRMS(ESI)[M+H]+calcd.for C24H18N4O6S:489.0874；found:489.0877.
(Ⅰ-15,C24H18N4O6S).White sold；Yield 66％；m.p.247.9–251.9℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.72(s,1H),8.36(s,1H),8.01(d,J＝8.9 Hz,1H),7.72(s,1H),7.39(s,1H),7.28(t,J＝8.2 Hz,1H),7.16(d,J＝8.9 Hz,1H),6.88(dd,J＝15.6,6.4 Hz,3H),5.58(s,2H),5.33(s,2H),3.72(s,3H).13C NMR(126 MHz,DMSO)δ173.94,162.98,159.42,157.17,137.35,129.94,127.04,125.21,120.04,117.00,115.90,113.75,113.48,101.95,67.00,61.94,55.08,52.78,25.11.HRMS(ESI)[M+H]+calcd.for C24H18N4O6S:489.0874；found:489.0872.
(Ⅰ-16,C24H15F3N4O5S).White sold；Yield 67％；m.p.262.7–265.5℃；1H NMR(500MHz,DMSO)δ12.44(s,1H),8.63(s,1H),8.41(s,1H),8.02(d,J＝8.8 Hz,1H),7.76(d,J＝8.0 Hz,2H),7.52(d,J＝8.0 Hz,2H),7.39(d,J＝2.3 Hz,1H),7.17(dd,J＝8.9,2.3 Hz,1H),5.76(d,J＝1.7 Hz,2H),5.34(s,2H).13C NMR(126 MHz,DMSO)δ173.90,162.94,157.24,140.57,128.70,128.57,127.06,125.76,125.73,125.70,125.48,115.84,101.93,61.92,52.20.HRMS(ESI)[M+H]+calcd.for C24H15F3N4O6S:527.0642；found:527.0639.
(Ⅰ-17,C24H15F3N4O5S).White sold；Yield 63％；m.p.241.3–244.4℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.71(s,1H),8.43(s,1H),8.01(d,J＝8.9 Hz,1H),7.74–7.69(m,2H),7.62(dd,J＝4.9,1.7 Hz,2H),7.38(d,J＝2.4 Hz,1H),7.16(dd,J＝9.0,2.4 Hz,1H),5.75(s,2H),5.34(s,2H).13C NMR(126 MHz,DMSO)δ173.93,162.96,157.12,137.31,132.23,129.99,129.51,129.26,127.04,125.38,125.05,125.02,124.99,124.96,124.71,124.68,124.65,124.61,122.89,116.94,115.90,101.94,61.91,52.13.HRMS(ESI)[M+H]+calcd.for C24H15F3N4O6S:527.0642；found:527.0645.
(Ⅰ-18,C24H15F3N4O5S).White sold；Yield 67％；m.p.271.3–273.0℃；1H NMR(500MHz,DMSO)δ12.44(s,1H),8.76(s,1H),8.36(s,1H),8.03(d,J＝8.9 Hz,1H),7.82(d,J＝7.8 Hz,1H),7.70(t,J＝7.6 Hz,1H),7.60(q,J＝6.2 Hz,2H),7.41(d,J＝2.4 Hz,1H),7.24–7.15(m,2H),5.83(s,2H),5.36(s,2H).13C NMR(126 MHz,DMSO)δ173.99,163.03,157.14,141.99,133.54,133.22,130.42,129.01,127.07,126.76,126.52,126.31,126.27,125.84,125.22,123.04,116.92,115.99,102.03,61.92,49.67.HRMS(ESI)[M+H]+calcd.for C24H15F3N4O6S:527.0642；found:527.0644.
(Ⅰ-19,C24H15F3N4O6S).White sold；Yield 64％；m.p.253.4–255.6℃；1H NMR(500MHz,DMSO)δ12.44(s,1H),8.69(s,1H),8.40(s,1H),8.02(d,J＝8.9 Hz,1H),7.71(s,1H),7.47(d,J＝8.5 Hz,2H),7.39(d,J＝7.9 Hz,3H),7.17(dd,J＝8.9,2.3 Hz,1H),5.68(s,2H),5.34(s,2H).13CNMR(126 MHz,DMSO)δ174.40,163.46,157.67,148.56,135.87,130.55,127.54,125.77,121.88,116.35,102.43,62.42,52.45.HRMS(ESI)[M+H]+calcd.forC24H15F3N4O6S:543.0592；found:543.0594.
(Ⅰ-20,C24H15F3N4O6S).White sold；Yield 69％；m.p.242.6–244.8℃；FC 1H NMR(500MHz,DMSO)δ12.44(s,1H),8.74(s,1H),8.42(s,1H),8.02(d,J＝8.9 Hz,1H),7.64(s,1H),7.53(t,J＝8.0Hz,1H),7.40(d,J＝2.4Hz,1H),7.35(q,J＝5.0Hz,3H),7.17(dd,J＝8.9,2.4Hz,1H),5.71(s,2H),5.35(s,2H).13C NMR(126MHz,DMSO)δ174.42,163.46,157.60,148.93,142.63,139.06,131.37,127.56,127.53,125.85,121.48,121.18,120.94,119.44,117.39,116.39,102.43,62.39,52.51.HRMS(ESI)[M+H]+calcd.for C24H15F3N4O6S:543.0592；found:543.0594.
(Ⅰ-21,C24H15F3N4O6S).White sold；Yield 61％；m.p.245.3–246.7℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.75(s,1H),8.32(s,1H),8.01(d,J＝9.0 Hz,1H),7.64(s,1H),7.52(td,J＝7.8,1.9Hz,1H),7.46–7.34(m,4H),7.16(dd,J＝8.9,2.4Hz,1H),5.71(s,2H),5.34(s,2H).13C NMR(126MHz,DMSO)δ173.97,163.01,157.14,146.42,141.93,130.94,130.61,127.99,127.80,127.05,125.48,121.08,120.48,119.03,116.92,115.98,101.99,61.90,47.76,29.00.HRMS(ESI)[M+H]+calcd.for C24H15F3N4O6S:543.0592；found:543.0593.
(Ⅰ-22,C23H15N5O7S).White sold；Yield 62％；m.p.247.3–249.8℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.66(d,J＝13.4Hz,1H),8.44(s,1H),8.24(d,J＝8.4Hz,2H),8.01(d,J＝8.9Hz,1H),7.93–7.60(m,1H),7.54(d,J＝8.3Hz,2H),7.39(d,J＝2.3Hz,1H),7.16(dd,J＝8.8,2.2Hz,1H),5.82(s,2H),5.35(s,2H).13C NMR(126MHz,DMSO)δ174.41,163.42,157.65,147.73,143.78,129.57,127.55,126.10,124.43,117.50,116.33,102.42,62.40,52.45.HRMS(ESI)[M+H]+calcd.for C23H15N5O7S:504.0619；found:504.0620.
(Ⅰ-23,C23H15N5O7S).White sold；Yield 67％；m.p.252.4–255.5℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.70(s,1H),8.45(s,1H),8.25–8.18(m,2H),8.01(d,J＝8.9Hz,1H),7.79(d,J＝7.6Hz,1H),7.69(t,J＝7.9Hz,1H),7.38(s,1H),7.24–7.06(m,1H),5.81(s,2H),5.34(s,2H).13C NMR(126MHz,DMSO)δ173.92,162.95,157.13,147.86,137.98,134.80,130.45,127.05,125.46,123.19,122.84,116.97,115.88,101.93,61.91,51.81.HRMS(ESI)[M+H]+calcd.for C23H15N5O7S:504.0619；found:504.0620.
(Ⅰ-24,C23H15N5O7S).White sold；Yield 58％；m.p.265.3–267.4℃；1H NMR(500MHz,DMSO)δ12.45(s,1H),8.78(s,1H),8.36(s,1H),8.16(d,J＝8.1Hz,1H),8.04(d,J＝8.9Hz,1H),7.76(t,J＝7.6Hz,1H),7.65(t,J＝7.8Hz,1H),7.60(s,1H),7.43(d,J＝2.3Hz,1H),7.19(d,J＝9.0Hz,1H),7.10(d,J＝7.8Hz,1H),6.00(s,2H),5.38(s,2H).HRMS(ESI)[M+H]+calcd.forC23H15N5O7S:504.0619；found:504.0622.
(Ⅰ-25,C24H15N5O5S).White sold；Yield 56％；m.p.253.4–257.3℃；1H NMR(500MHz,DMSO)δ12.42(s,1H),8.55(s,1H),8.44(s,1H),8.00(d,J＝8.7Hz,1H),7.86(d,J＝7.8Hz,2H),7.47(d,J＝7.9Hz,2H),7.35(s,1H),7.14(d,J＝8.7Hz,1H),5.76(s,2H),5.33(s,2H).13C NMR(126MHz,DMSO)δ173.70,162.74,157.02,141.15,132.61,128.61,126.91,118.35,115.63,110.83,101.73,61.72,52.15.HRMS(ESI)[M+H]+calcd.forC24H15N5O5S:484.0721；found:484.0722.
(Ⅰ-26,C24H15N5O5S).White sold；Yield 57％；m.p.275.9–278.3℃；1H NMR(500MHz,DMSO)δ12.69–12.17(m,1H),8.73(s,1H),8.42(s,1H),8.01(d,J＝8.9 Hz,1H),7.83(dd,J＝4.6,2.6 Hz,2H),7.77–7.52(m,3H),7.38(d,J＝2.4 Hz,1H),7.16(dd,J＝8.9,2.4Hz,1H),5.71(s,2H),5.34(s,2H).13C NMR(126 MHz,DMSO)δ173.94,162.99,157.11,137.43,133.02,132.06,131.74,130.13,127.06,125.39,118.40,116.93,115.90,111.70,101.94,61.94,51.93.HRMS(ESI)[M+H]+calcd.for C24H15N5O5S:484.0721；found:484.0722.
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(Ⅰ-27,C24H15N5O5S).Whitesold；Yield 63％；m.p.261.7–262.9℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.61(s,1H),8.41(s,1H),8.01(d,J＝8.8 Hz,1H),7.92(d,J＝7.6 Hz,1H),7.73(t,J＝7.7 Hz,1H),7.57(t,J＝7.6 Hz,1H),7.44–7.36(m,2H),7.19–7.13(m,1H),5.84(s,2H),5.35(s,2H).13C NMR(126 MHz,DMSO)δ174.36,163.42,157.75,139.14,134.34,133.89,129.98,129.76,127.53,126.20,117.45,116.34,111.75,102.44,62.34,51.57.HRMS(ESI)[M+H]+calcd.for C24H15N5O5S:484.0721；found:484.0721.
(Ⅰ-28,C29H20N4O5S).White sold；Yield 67％；m.p.272.3–274.5℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.70(s,1H),8.40(s,1H),8.01(d,J＝8.9 Hz,1H),7.65(dd,J＝11.6,7.7 Hz,4H),7.46(t,J＝7.6 Hz,2H),7.43–7.33(m,4H),7.17(dd,J＝9.0,2.3 Hz,1H),5.68(s,2H),5.34(s,2H).13C NMR(126 MHz,DMSO)δ173.93,162.99,157.15,140.06,139.51,135.07,128.94,128.61,127.62,127.07,127.04,126.68,125.24,116.98,115.92,101.98,61.97,52.55.HRMS(ESI)[M+H]+calcd.for C29H20N4O5S:535.1082；found:535.1081.
(Ⅰ-29,C29H20N4O5S).White sold；Yield 67％；m.p.224.1–225.6℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.67(s,1H),8.43(s,1H),8.00(d,J＝8.9Hz,1H),7.67–7.59(m,4H),7.46(td,J＝7.7,2.9Hz,3H),7.42–7.29(m,3H),7.15(dd,J＝8.8,2.3Hz,1H),5.70(s,2H),5.33(s,2H).13C NMR(126MHz,DMSO)δ173.87,162.94,157.11,140.64,139.56,136.57,129.42,128.94,127.67,127.05,127.00,126.65,126.51,126.49,115.84,101.89,61.91,52.87.HRMS(ESI)[M+H]+calcd.for C29H20N4O5S:535.1082；found:535.1082.
(Ⅰ-30,C29H20N4O5S).White sold；Yield 67％；m.p.261.5–262.7℃；1H NMR(500MHz,DMSO)δ12.43(s,1H),8.72(s,1H),8.07–7.99(m,2H),7.67(s,1H),7.41(dq,J＝15.5,8.0Hz,6H),7.34(d,J＝7.2Hz,2H),7.29(d,J＝7.4Hz,1H),7.16(d,J＝7.1Hz,2H),5.56(s,2H),5.29(s,2H).13C NMR(126MHz,DMSO)δ141.26,132.81,130.26,129.00,128.73,128.48,128.39,127.96,127.52,127.07,125.39,101.97,61.89,50.89.HRMS(ESI)[M+H]+calcd.for C29H20N4O5S:535.1082；found:535.1083.
实施例31：将上述实施例制备的色酮噻唑二酮类化合物的PTP1B酶抑制活性测试
实验步骤：
将待测溶液溶于二甲亚砜(DMSO)中，均配成10个梯度浓度，分别为32μM，16μM，8μM，4μM，2μM，1μM，0.5μM，0.25μM，0.125μM，0.625μM。在384孔黑底板中每个孔加入20μL含有酶(0.29μg/mL PTP1B)和缓冲液(50mM MOPS，2mM DTT和1mM EDTA：PH＝6.5)的混合物，然后再往各个孔中加入10μL预先配好的化合物母液(每组平行四孔)。加完母液后，将384孔板放在37℃恒温培养箱中孵育15min，向每孔中加入20μL底物(DiFMUP，20mM)。最后使用酶标仪检测荧光信号强度值(RFU)。
抑制率计算公式：
RFU样品：384孔板中加了化合物与蛋白反应后加入底物DiMUP所测得的RFU值；
RFU空白：384孔板中加入DMSO与蛋白，再加入底物DiMUP所测得的RFU值。
结果分析
应用体外酶学实验对合成得到的化合物进行PTP1B酶抑制活性评价，其测定结果如表2所示：
表2.化合物与PTP1B酶的体外抑制活性评价
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a值为三次独立实验结果的mean±S。
从表2可以看出，本发明提供的这些小分子化合物在与PTP1B酶相互作用时表现出较强的结合亲和力。含有本发明结构的化合物具有较好的PTP1B酶抑制活性，其中，实施例18制备的化合物具有最强的PTP1B酶抑制活性，抑制率是0.10μM；阳性对照药齐墩果酸的IC50为5.33μM。约是齐墩果酸的53倍。
实施例32：酶动力学实验
采用体外酶动力学实验对合成得到的活性化合物进行PTP1B酶抑制活性动力学评价：
1、实验步骤
酶动力学实验需要数种不同的PTP1B酶浓度。因此，本文使用五种不同浓度的PTP1B蛋白(终浓度为0.29，0.58，0.87，1.16μg/mL)对实施例18制备的活性最好的化合物Ⅰ-18进行后续的实验。首先，在384孔黑底板中每个孔加入20μL含有酶(0.29，0.58，0.87，1.16μg/mL PTP1B)和缓冲液(50mM MOPS，2mM DTT和1mM EDTA，PH＝6.5)的混合物，接着往各个孔中分别加入10μL准备好的化合物母液(每组平行四孔)。然后将384孔板放在37℃恒温条件下振动孵育15min，孵育完成后马上加入20μL底物(DiFMUP，20μM)。最后使用酶标仪检测荧光信号强度值(RFU)。测定不同浓度的化合物对PTP1B(0.29，0.58，0.87，1.16μg/mL)的荧光强度，根据不同酶浓度及其荧光强度的变化率作图。
2、结果分析
酶动力学抑制类型评价实验测定结果如图2所示。由图2可以看出，抑制剂以非共价键与酶结合阻遏酶的活性，是一种可逆抑制作用。
实施例33：底物动力学实验
采用体外底物动力学实验对合成得到的活性化合物进行PTP1B酶抑制活性动力学评价：
1、实验步骤
使用五种不同浓度的DiMUP底物(终浓度为20，40，60，80μM)对实施例18制备的活性最好的化合物Ⅰ-18进行后续的实验。首先，在384孔黑底板中每个孔加入20μL含有酶(0.29μg/mL PTP1B)和缓冲液(50mM MOPS,2mM DTT和1mM EDTA:PH＝6.5)的混合物，接着往各个孔中加入10μL预先准备好的化合物母液(每组平行四孔)。加完母液后，将384孔板放在37℃恒温条件下振动孵育15min，孵育完成后马上加入20μL DiFMUP底物(20，40，60，80μM)。最后使用酶标仪检测荧光信号强度值(RFU)。测定不同浓度的化合物存在下的荧光强度变化，根据不同底物浓度及其荧光强度变化率作Lineweaver-Burk双倒数图。
2、结果分析
底物动力学抑制类型评价实验测定结果如图3所示，图3对应色酮噻唑二酮类化合物Ⅰ-18的在体外对PTP1B酶的底物动力学图，图3中的为双倒数作图法作出的底物动力学图。由图3可以看出，筛选得到的抑制剂为混合型抑制剂。
上面结合本发明实施例作了详细说明，但本发明不限于上述实施例，在所属技术领域普通技术人员所具备的知识范围内，还可以在不脱离本发明宗旨的前提下作出各种变化。
Claims (10)
1.一种色酮噻唑二酮类化合物或其药学上可接受的盐，其特征在于，所述色酮噻唑二酮类化合物具有如式(Ⅰ)所示的化合物：
其中，R选自取代或未取代的C6～12的芳基。
2.根据权利要求1所述的色酮噻唑二酮类化合物或其药学上可接受的盐，其特征在于，所述R选自取代或未取代的苯基，所述取代为单取代或多取代，所述取代的基团选自卤素、C1～6的烷基、C1～6的烷氧基、C1～6的卤代烷基、C1～6的卤代烷氧基、硝基、氰基或苯基。
3.根据权利要求1所述的色酮噻唑二酮类化合物或其药学上可接受的盐，其特征在于，所述R选自如下所示的基团：
4.根据权利要求1～3任一项所述的色酮噻唑二酮类化合物的制备方法，其特征在于，包括如下步骤：
将中间体3、铜催化剂和还原剂发生环加成反应，得到色酮噻唑二酮类化合物；
其中，中间体3的结构式如下：
5.根据权利要求4所述的制备方法，其特征在于，所述环加成反应的反应温度为室温；
优选地，所述环加成反应的反应时间为8～16h。
6.根据权利要求4所述的制备方法，其特征在于，所述中间体3通过如下方法制备：
将中间体2和噻唑烷二酮发生羟醛缩合生成中间体3；
所述中间体2的结构式如下：
7.一种药物组合物，其特征在于，包括权利要求1～3任一项所述的色酮噻唑二酮类化合物或其药学上可接受的盐；和药学上可接受的辅料。
8.一种蛋白酪氨酸磷酸酯酶1B抑制剂，其特征在于，包括权利要求1～3任一项所述的色酮噻唑二酮类化合物或其药学上可接受的盐。
9.根据权利要求1～3任一项所述的色酮噻唑二酮类化合物在制备治疗和/或预防糖尿病产品中的应用。
10.根据权利要求9所述的应用，其特征在于，所述产品包括药品或保健品。
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