CN115536653A - 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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- CN115536653A CN115536653A CN202211210834.6A CN202211210834A CN115536653A CN 115536653 A CN115536653 A CN 115536653A CN 202211210834 A CN202211210834 A CN 202211210834A CN 115536653 A CN115536653 A CN 115536653A
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- chromone
- thiazole
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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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。其色酮噻唑二酮类化合物具有如式I所示的结构：
其中，R为取代或未取代的芳香基、取代或未取代的C1～10的烷基、取代或未取代的杂环基。本发明设计并合成了一系列色酮噻唑二酮类化合物，这些化合物表现出最强的α‑葡萄糖苷酶抑制作用，其IC50值低，能够作为α‑葡萄糖苷酶抑制剂用于治疗或预防糖尿病。
Description
技术领域
本发明涉及药物化学技术领域，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
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。
α-葡萄糖苷酶抑制剂通过抑制小肠黏膜刷状缘的α-葡萄糖苷酶以延缓碳水化合物的吸收，降低餐后高血糖。主要特点包括平稳降糖、安全性高，以及可降低心血管并发症的发生率，是少数可干预糖耐量受损的口服降糖药之一。α-葡萄糖苷酶抑制剂的降糖机制是通过抑制肠黏膜上的α-葡萄糖苷酶，使淀粉分解为葡萄糖的速度减缓，减少和延缓小肠对葡萄糖的吸收，以降低血糖，对餐后高血糖的作用比较明显。葡萄糖苷酶抑制剂不刺激胰岛素的分泌，单独使用本类药物通常不会引发低血糖，因此可帮助减少血糖的波动。可以明显降低糖尿病患者发生心血管病变的概率，对心肌梗死的改善作用最为显著。
因此，有必要开发一种新的对α-葡萄糖苷酶抑制的化合物。
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，本发明提出一种色酮噻唑二酮类化合物，能够有效降低半数抑制浓度。
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色酮噻唑二酮类化合物的应用。
本发明第四方面还提供一种药物组合物。
根据本发明的第一方面实施例的色酮噻唑二酮类化合物，所述色酮噻唑二酮类化合物具有如式I所示的结构：
其中，R为取代或未取代的芳香基、取代或未取代的C1～10的烷基、取代或未取代的杂环基。
根据本发明实施例的色酮噻唑二酮类化合物，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，这些化合物表现出最强的α-葡萄糖苷酶抑制作用，其IC50值低，能够作为α-葡萄糖苷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，R选自C1～5的烷基、和如下结构式中的至少一种：
其中，n为0～5，R1为一个或多个基团，独立地选自H、C1～10的烷基、卤素、C1～10的卤代烷基、C1～10的烷氧基、硝基、氰基。
根据本发明的一些实施例，所述R选自如下结构式中的一种：
本发明的第二方面实施例提供一种色酮噻唑二酮类化合物的制备方法，包括如下步骤：S4、化合物3与R-NH2进行酰胺缩合反应得到色酮噻唑二酮类化合物；
其中，化合物3的结构式如下：
根据本发明的一些实施例，所述化合物3通过如下方法制备：
S1、以2,4-噻唑二酮与溴乙酸乙酯进行亲核取代反应得到取代化合物1；
S2、将化合物1与色酮-3-甲醛在乙酸钠和乙酸条件下反应生成化合物2；
S3、将化合物2进行水解得到化合物3；
其中，化合物1、化合物2的结构式如下：
根据本发明的一些实施例，步骤S3中，所述水解在酸性条件下进行。
本发明第三方面提供上述所述的色酮噻唑二酮类化合物在制备预防和/或治疗糖尿病产品中的应用。
根据本发明的一些实施例，所述产品为药物、保健品种的至少一种。
本发明第四方面提供一种药物组合物，包括药物活性成分和药学上可接受的辅料，所述药物活性成分包括上述所述的色酮噻唑二酮类化合物。
根据本发明的一些实施例，药物活性成分占总质量的0.1％～35％。
定义和一般术语
“C1～10的烷基”表示碳原子总数为1～10的烷基，包括C1～10的直链烷基、C1-10的支链烷基和C3-10的环烷基，例如可以为碳原子总数为1、2、3、4、5、6、7、8、9、10的直链烷基、碳原子总数为1、2、3、4、5、6、7、8、9、10的支链烷基或者碳原子总数为3、4、5、6、7、8、9、10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。针对“C1-5的烷基”具有与此相似的解释，所不同的是，碳原子数不同。
“取代或未取代的C1～10的烷基”与“C1～10的烷基”的定义相似，所不同的是，该烷基中有至少一个H被本文所定义的相应基团所取代。
“芳香基”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。例如，苯、萘、茚、芴等。
“取代或未取代的芳香基”具有相似的定义，芳香基中任选有至少一个H被本文所定义的相应基团所取代。
“取代或未取代的杂环基”表示碳原子总数为2-12的杂环基团，该杂环中成环原子中含有杂原子，并且任选该基团中有至少一个H被本文定义的相应基团所取代。
杂芳基的例子，包括但不限于，吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、三氮唑、嘧啶、吡啶、吡啶酮、咪啶、吡嗪、哒嗪、吲哚、氮杂吲哚、苯并咪唑、苯并三氮唑、吲哚啉、吲哚酮、喹啉、异喹啉、喹唑啉、噻吩并吡啶、噻吩并嘧啶等。此类基团的优选实施例为吡咯基、吡唑基、咪唑基、三氮唑基、呋喃基、噁唑基、噻吩基、噻唑基、苯并咪唑基、苯并三氮唑。杂芳基中的一个或全部氢原子可被下列基团取代：氢、羟基、硝基、氰基、氧代、低级烷基、低级烷氧基、低级环烷基、低级杂脂环基、低级卤代烷氧基、烷硫基、卤素、低级卤代烷基、低级羟烷基、低级环烷基亚烷基、低级杂脂环基亚烷、芳基、杂芳基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨基羰基、烷基羰基氨基、芳基羰基氨基。
“卤素”包括氟、氯、溴、碘中的任意一个或两个以上。
本发明中“取代或未取代的”是指基团可以被或可以不被一个或更多个选自以下的基团进一步取代：C1～10的烷基、卤素、C1～10的卤代烷基、C1～10的烷氧基或苄氧基。
本发明所述的药物组合物
像本发明所描述的，本发明所述的药物组合物进一步包含药学上可接受的辅料，这些辅料，例如像本发明所应用的，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：InRemington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of PharmaceuticalTechnology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,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。
可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。
本发明的药物组合物，可以用以下所述的任意方式给与：口服给药、喷雾吸入法、局部给药、经直肠给药、经鼻给药、局部给药、阴道给药、非肠道给药如皮下、静脉、肌内、腹腔内、鞘内、心室内、胸骨内、或颅内注射或输液，或借助一种外植的储器用药。优选的方式为口服给药、肌注、向腹膜内给药或静脉注射。
本发明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。
栓剂可包含常规的栓剂基质，如可可黄油或其他甘油酯。
对胃外投药，液态剂型通常由化合物和一种消毒的载体制成。载体首选水。依照所选载体和药物浓度的不同，化合物既可溶于载体中也可制成悬浮溶液，在制成注射用溶液时先将化合物溶于水中，过滤消毒后装入封口瓶或安瓿中。
当皮肤局部施用时，本发明化合物可以制成适当的软膏，洗剂，或霜剂的形式，其中活性成分悬浮或溶解于一种或多种的载体中，其中软膏制剂可以使用的载体包括但不局限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水；洗剂和霜剂可使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
本发明的前述制备方法中还可以涉及本领域已知的各种后处理操作，例如萃取、洗涤、过滤、柱层析、重结晶等，本发明对此没有特别的限制，本领域技术人员不应理解为对本发明的限制。
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为本发明提供一种色酮噻唑二酮类化合物作为α-葡萄糖苷酶抑制剂在体外对α-葡萄糖苷酶的半数抑制浓度图；(a)为12的半数抑制浓度图；(b)为27的半数抑制浓度图；(c)为28的半数抑制浓度图；
图2为本发明色酮噻唑二酮类化合物28作为α-葡萄糖苷酶抑制剂在体外对α-葡萄糖苷酶的酶动力学图；
图3为本发明色酮噻唑二酮类化合物28作为α-葡萄糖苷酶抑制剂在体外对α-葡萄糖苷酶的底物动力学图。
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。
实施例1～35
实施例1～35提供一系列色酮噻唑二酮类化合物，其反应方程式如下，制备方法如下：
S1、将噻唑二酮(3mmol,351.4mg)和碳酸钾(6mmol,829.2mg)加入丙酮(3mL)中。向该混合物中加入溴乙酸乙酯(3mmol，335μL)。回流2小时后，过滤除去K2CO3并用大量乙酸乙酯彻底洗涤。最后，减压蒸发溶剂，得到黄色油状产物，即化合物1。
S2、将化合物1(2mmol,406.5mg)、色酮-3-甲醛(2mmol,348.3mg)和乙酸钠(2mmol,165.6mg)在2mL冰醋酸的溶液回流搅拌5h。反应完成后，将反应体系冷却至室温。接着过滤固体并用尽可能少的乙酸乙酯洗涤固体。最后将所得混合物在室温下干燥，得到化合物2。
S3、将化合物2(1mmol,400.7mg)加入到12N HCl(1mL)和冰醋酸(4mL)的混合物中。将反应溶液在100℃搅拌。反应完成后，过滤固体。最后，白色固体用水洗涤3次(3×100mL)，在真空烘箱(40℃)中干燥24h，得到化合物3。
S4、将化合物3(2mmol,662.6mg)、取代的胺(2mmol)和EDCI(2mmol,310.5mg)在2mL吡啶的混合物在室温下搅过夜。用水淬灭后，然后过滤以获得粗产物。最后，用DMF和水重结晶，得到最终产物(1～35)。制备得到的产物(1～35)为：
通过NMR，MS和熔点表征实施例1～35制备的色酮噻唑二酮化合物的结构，以下为各化合物的性状、产率、核磁和质谱结果表征：
(1,C21H14N2O5S).White sold；Yield 65％；1H NMR(500MHz,DMSO)δ10.39(s,1H),8.98(s,1H),8.15(dd,J＝8.0,1.6Hz,1H),7.93–7.86(m,1H),7.76(t,J＝4.3Hz,2H),7.57(dd,J＝17.3,8.0Hz,3H),7.32(t,J＝7.7Hz,2H),7.08(t,J＝7.4Hz,1H),4.49(s,2H)；13CNMR(126MHz,DMSO)δ174.96,168.64,165.78,163.90,162.25,155.41,138.46,135.21,128.91,126.71,126.55,125.60,123.69,123.06,122.61,119.13,118.68,117.80,43.87.HRMS(ESI)[M+H]+calcd.for C21H14N2O5S:425.0517；found:425.0516.
(2,C21H13FN2O5S).White sold；Yield 67％；1H NMR(500MHz,DMSO)δ10.44(s,1H),8.96(s,1H),8.17–8.12(m,1H),7.92–7.85(m,1H),7.75(d,J＝7.2Hz,2H),7.61–7.54(m,3H),7.17(t,J＝8.6Hz,2H),4.48(s,2H)；13C NMR(126MHz,DMSO)δ174.94,168.62,165.75,163.87,162.23,159.14,157.23,155.40,135.20,134.85,134.83,126.71,126.53,125.58,123.04,122.58,120.98,120.92,118.66,117.78,115.58,115.41,43.79.HRMS(ESI)[M+H]+calcd.for C21H13FN2O5S:447.0422；found:447.0421.
(3,C21H13ClN2O5S).White sold；Yield 67％；1H NMR(500MHz,DMSO)δ10.54(s,1H),8.98(s,1H),8.15(dd,J＝8.0,1.6Hz,1H),7.93–7.87(m,1H),7.76(t,J＝4.3Hz,2H),7.63–7.55(m,3H),7.39(d,J＝8.5Hz,2H),4.49(s,2H)；13C NMR(126MHz,DMSO)δ174.97,168.65,165.77,164.15,162.30,155.41,137.40,135.22,128.85,127.27,126.79,126.56,125.60,123.06,122.56,120.73,118.69,117.78,43.88.HRMS(ESI)[M+H]+calcd.forC21H13ClN2O5S:463.0126；found:463.0126.
(4,C21H13BrN2O5S).White sold；Yield 71％；1H NMR(500MHz,DMSO)δ10.54(s,1H),8.97(s,1H),8.15(d,J＝7.9Hz,1H),7.89(t,J＝7.9Hz,1H),7.75(t,J＝4.3Hz,2H),7.58(t,J＝7.6Hz,1H),7.56–7.48(m,4H),4.49(s,2H)；13C NMR(126MHz,DMSO)δ174.96,168.64,165.76,164.16,162.30,155.41,137.81,135.22,131.75,126.79,126.55,125.59,123.05,122.55,121.10,118.68,117.77,115.32,43.90.HRMS(ESI)[M+H]+calcd.forC21H13BrN2O5S:506.9623；found:506.9621.
(5,C22H16N2O5S).White sold；Yield 54％；1H NMR(500MHz,DMSO)δ10.29(s,1H),8.97(s,1H),8.15(dd,J＝8.1,1.7Hz,1H),7.89(ddd,J＝8.6,7.2,1.7Hz,1H),7.75(t,J＝4.2Hz,2H),7.58(t,J＝7.5Hz,1H),7.44(d,J＝8.4Hz,2H),7.12(d,J＝8.1Hz,2H),4.47(s,2H),2.25(s,3H)；13C NMR(126MHz,DMSO)δ174.96,168.64,165.78,163.63,162.22,155.41,135.96,135.21,132.63,129.27,126.66,126.54,125.60,123.05,122.64,119.15,118.68,117.80,43.83,20.46.HRMS(ESI)[M+H]+calcd.for C22H16N2O5S:443.0674；found:443.0672.
(6,C22H16N2O6S).White sold；Yield 63％；1H NMR(500MHz,DMSO)δ10.24(s,1H),8.97(s,1H),8.15(dd,J＝8.0,1.7Hz,1H),7.89(ddd,J＝8.6,7.2,1.7Hz,1H),7.75(t,J＝4.3Hz,2H),7.58(t,J＝7.6Hz,1H),7.50–7.43(m,2H),6.93–6.86(m,2H),4.45(s,2H),3.72(s,3H)；13C NMR(126MHz,DMSO)δ175.40,169.10,166.24,163.82,162.66,155.90,155.86,135.65,132.04,127.08,126.99,126.05,123.50,123.09,121.13,119.13,118.25,114.44,55.62,44.21.HRMS(ESI)[M+H]+calcd.for C22H16N2O6S:459.0621；found:459.0621.
(7,C22H13F3N2O5S).White sold；Yield 68％；1H NMR(500MHz,DMSO)δ10.78(s,1H),8.98(s,1H),8.15(d,J＝7.9Hz,1H),7.89(t,J＝7.9Hz,1H),7.77(d,J＝8.3Hz,4H),7.70(d,J＝8.5Hz,2H),7.58(t,J＝7.6Hz,1H),4.54(s,2H)；13C NMR(126MHz,DMSO)δ175.43,169.10,166.21,165.15,162.81,155.86,142.42,135.68,127.33,127.01,126.74,126.71,126.05,123.51,122.96,119.58,119.14,118.22,44.42.HRMS(ESI)[M+H]+calcd.forC22H13F3N2O5S:497.0391；found:497.0389.
(8,C22H13N3O5S).White sold；Yield 59％；1H NMR(500MHz,DMSO)δ10.85(s,1H),8.97(s,1H),8.14(d,J＝7.9Hz,1H),7.89(t,J＝8.0Hz,1H),7.84–7.66(m,6H),7.58(t,J＝7.7Hz,1H),4.54(s,2H)；13C NMR(126MHz,DMSO)δ174.98,168.64,165.73,164.91,162.38,155.41,142.58,135.23,133.49,126.94,126.56,125.60,123.05,122.47,119.26,118.96,118.69,117.76,105.53,44.02.HRMS(ESI)[M+H]+calcd.for C22H13N3O5S:470.0212；found:470.0207.
(9,C21H13N3O7S).White sold；Yield 61％；1H NMR(500MHz,DMSO)δ11.04(s,1H),8.98(s,1H),8.24(d,J＝9.1Hz,2H),8.15(dd,J＝7.9,1.6Hz,1H),7.90(td,J＝7.7,1.7Hz,1H),7.81(d,J＝8.8Hz,2H),7.78–7.73(m,2H),7.58(q,J＝7.4Hz,1H),4.57(s,2H)；13C NMR(126MHz,DMSO)δ175.43,169.09,166.18,165.55,162.85,155.86,144.94,143.02,135.69,127.42,127.02,126.05,125.60,123.50,122.91,119.46,119.14,118.20,44.52.HRMS(ESI)[M+H]+calcd.forC21H13N3O7S:452.0547；found:452.0547.
(10,C21H13FN2O5S).White sold；Yield 67％；1H NMR(500MHz,DMSO)δ10.63(s,1H),8.97(s,1H),8.15(dd,J＝7.9,1.7Hz,1H),7.93–7.86(m,1H),7.78–7.72(m,2H),7.58(t,J＝7.6Hz,1H),7.53(dt,J＝11.6,2.3Hz,1H),7.37(q,J＝8.1Hz,1H),7.28(dd,J＝8.2,1.9Hz,1H),6.92(td,J＝8.5,2.6Hz,1H),4.50(s,2H)；13C NMR(126MHz,DMSO)δ174.98,168.65,165.76,164.39,163.12,162.32,161.20,155.42,140.17,140.08,135.23,130.68,130.60,126.83,126.56,125.61,123.06,122.54,118.69,117.78,114.94,114.92,110.32,110.15,106.11,105.90,43.90.HRMS(ESI)[M+H]+calcd.for C21H13FN2O5S:447.0422；found:447.0421.
(11,C21H13ClN2O5S).White sold；Yield 70％；1H NMR(500MHz,DMSO)δ10.60(s,1H),8.98(s,1H),8.15(d,J＝7.9Hz,1H),7.89(t,J＝7.9Hz,1H),7.75(d,J＝6.8Hz,3H),7.57(s,1H),7.48–7.31(m,2H),7.14(d,J＝7.9Hz,1H),4.50(s,2H)；13C NMR(126MHz,DMSO)δ174.97,168.65,165.75,164.42,162.33,155.41,139.84,135.22,133.20,130.67,126.83,126.55,125.60,123.46,123.05,122.52,118.68,117.77,117.57,43.91.HRMS(ESI)[M+H]+calcd.forC21H13ClN2O5S:463.0126；found:463.0126.
(12,C21H13BrN2O5S).White sold；Yield 73％；1H NMR(500MHz,DMSO)δ10.58(s,1H),8.97(s,1H),8.18–8.12(m,1H),7.89(dt,J＝8.6,4.5Hz,2H),7.75(d,J＝7.3Hz,2H),7.58(t,J＝7.5Hz,1H),7.49–7.44(m,1H),7.33–7.25(m,2H),4.50(s,2H)；13C NMR(126MHz,DMSO)δ174.97,168.64,165.75,164.40,162.32,155.41,139.97,135.21,130.96,126.82,126.55,126.36,125.60,123.05,122.52,121.66,121.53,118.68,117.95,117.77,43.90.HRMS(ESI)[M+H]+calcd.for C21H13BrN2O5S:506.9624；found:506.9621.
(13,C22H16N2O5S).White sold；Yield 65％；1H NMR(500MHz,DMSO)δ10.31(s,1H),8.97(s,1H),8.15(d,J＝7.9Hz,1H),7.89(t,J＝8.0Hz,1H),7.75(t,J＝4.2Hz,2H),7.58(t,J＝7.5Hz,1H),7.41(s,1H),7.33(d,J＝8.1Hz,1H),7.20(t,J＝7.8Hz,1H),6.89(d,J＝7.5Hz,1H),4.47(s,2H),2.27(s,3H)；13C NMR(126MHz,DMSO)δ175.41,169.10,166.23,164.27,162.68,155.86,138.83,138.57,135.66,129.18,127.12,126.99,126.05,124.83,123.50,123.07,120.15,119.13,118.24,116.78,44.33,21.63.HRMS(ESI)[M+H]+calcd.for C22H16N2O5S:443.0674；found:443.0672.
(14,C22H16N2O6S).White sold；Yield 66％；1H NMR(500MHz,DMSO)δ10.39(s,1H),8.97(s,1H),8.20–8.10(m,1H),7.93–7.84(m,1H),7.75(t,J＝4.3Hz,2H),7.58(t,J＝7.5Hz,1H),7.30–7.18(m,2H),7.07(d,J＝8.5Hz,1H),6.66(dd,J＝8.3,2.5Hz,1H),4.48(s,2H),3.72(s,3H)；13C NMR(126MHz,DMSO)δ174.96,168.65,165.77,163.96,162.26,159.58,155.41,139.64,135.21,129.73,126.74,126.54,125.60,123.05,122.58,118.68,117.79,111.33,109.25,104.78,54.99,43.89.HRMS(ESI)[M+H]+calcd.for C22H16N2O6S:459.0621；found:459.0621.
(15,C22H13F3N2O5S).White sold；Yield 52％；m.p.244-245℃；1H NMR(500MHz,DMSO)δ9.92(s,1H),8.14(s,1H),7.31(d,J＝7.9Hz,1H),7.21(s,1H),7.05(t,J＝7.9Hz,1H),6.93–6.87(m,3H),6.74(t,J＝7.7Hz,2H),6.60(d,J＝7.7Hz,1H),3.68(s,2H)；13C NMR(126MHz,DMSO)δ175.42,169.11,166.21,165.13,162.79,155.86,139.61,135.67,130.70,130.15,129.90,127.31,127.00,126.05,125.57,123.50,123.40,123.21,122.96,120.56,119.13,118.22,115.68,44.36.HRMS(ESI)[M+H]+calcd.for C22H13F3N2O5S:497.0389；found:497.0389.
(16,C22H13N3O5S).White sold；Yield 67％；1H NMR(500MHz,DMSO)δ10.77(s,1H),8.97(s,1H),8.15(d,J＝8.0Hz,1H),8.03(s,1H),7.89(s,1H),7.77(d,J＝14.3Hz,3H),7.56(s,3H),4.52(s,2H)；13C NMR(126MHz,DMSO)δ175.41,169.09,166.19,165.18,162.80,155.85,139.63,135.66,130.92,127.79,127.33,126.99,126.04,124.21,123.49,122.93,122.30,119.12,119.03,118.20,112.19,44.35.HRMS(ESI)[M+H]+calcd.for C22H13N3O5S:454.0468；found:454.0468.
(17,C21H13N3O7S).White sold；Yield 77％；m.p.244-245℃；1H NMR(500MHz,DMSO)δ11.04(s,1H),8.98(s,1H),8.24(d,J＝9.3Hz,2H),8.15(dd,J＝8.0,1.6Hz,1H),7.90(t,J＝7.8Hz,1H),7.81(d,J＝8.8Hz,2H),7.77–7.74(m,2H),7.58(t,J＝7.6Hz,1H),4.57(s,2H)；13C NMR(126MHz,DMSO)δ174.99,168.64,165.73,165.10,162.41,155.42,144.50,142.58,135.24,126.97,126.57,125.60,125.15,123.05,122.46,119.01,118.69,117.76,44.07.HRMS(ESI)[M+H]+calcd.for C21H13N3O7S:474,0368；found:474,0366.
(18,C21H13FN2O5S).White sold；Yield 54％；1H NMR(500MHz,DMSO)δ10.27(s,1H),8.97(s,1H),8.18–8.12(m,1H),7.89(t,J＝8.2Hz,2H),7.75(t,J＝4.1Hz,2H),7.58(t,J＝7.5Hz,1H),7.33–7.25(m,1H),7.17(dt,J＝6.4,3.1Hz,2H),4.57(s,2H)；13C NMR(126MHz,DMSO)δ175.42,169.08,166.21,164.98,162.73,155.86,154.80,152.86,135.67,127.18,127.00,126.10,126.05,124.98,124.96,124.19,123.50,123.04,119.14,118.24,116.16,116.00,44.16.HRMS(ESI)[M+H]+calcd.for C21H13FN2O5S:447.0424；found:447.0421.
(19,C21H13ClN2O5S).White sold；Yield 67％；1H NMR(500MHz,DMSO)δ10.07(s,1H),8.98(s,1H),8.15(s,1H),7.96–7.47(m,6H),7.40–7.16(m,2H),4.58(s,2H).HRMS(ESI)[M+H]+calcd.for C21H13ClN2O5S:463.0128；found:463.0126.
(20,C21H13BrN2O5S).White sold；Yield 69％；m.p.244-245℃；1H NMR(500MHz,DMSO)δ10.01(s,1H),8.97(s,1H),8.15(d,J＝8.0Hz,1H),7.89(t,J＝7.9Hz,1H),7.75(d,J＝7.1Hz,2H),7.68(d,J＝8.0Hz,1H),7.58(dd,J＝8.2,5.1Hz,2H),7.38(t,J＝7.8Hz,1H),7.16(t,J＝7.8Hz,1H),4.55(s,2H).HRMS(ESI)[M+H]+calcd.for C21H13BrN2O5S:506.9623；found:506.9621.
(21,C22H16N2O5S).White sold；Yield 63％；1H NMR(500MHz,DMSO)δ9.76(s,1H),8.98(s,1H),8.15(s,1H),8.01–7.51(m,4H),7.43–6.99(m,4H),4.52(s,2H),2.22(s,3H).HRMS(ESI)[M+H]+calcd.for C22H16N2O5S:443.0675；found:443.0672.
(22,C22H16N2O6S).White sold；Yield 57％；1H NMR(500MHz,DMSO)δ9.74(s,1H),8.97(s,1H),8.15(d,J＝7.9Hz,1H),7.96–7.84(m,2H),7.75(d,J＝6.2Hz,2H),7.58(t,J＝7.6Hz,1H),7.08(d,J＝9.0Hz,2H),6.90(t,J＝7.5Hz,1H),4.58(s,2H),3.87(s,3H)；13CNMR(126MHz,DMSO)δ175.40,169.09,166.24,164.56,162.65,155.85,149.90,135.65,127.13,127.08,126.98,126.04,125.19,123.50,123.06,122.11,120.75,119.12,118.25,111.73,56.17,44.33.HRMS(ESI)[M+H]+calcd.for C22H16N2O6S:459.0621；found:459.0621.
(23,C22H13F3N2O5S).White sold；Yield 67％；1H NMR(500MHz,DMSO)δ10.11(s,1H),8.98(s,1H),8.16(s,1H),7.90(s,1H),7.76(s,3H),7.64–7.37(m,3H),4.51(s,2H).HRMS(ESI)[M+H]+calcd.for C22H13F3N2O5S:497.0389；found:497.0389.
(24,C22H13N3O5S).White sold；Yield 54％；1H NMR(500MHz,DMSO)δ10.68(s,1H),8.99(s,1H),8.16(d,J＝8.0Hz,1H),7.93–7.83(m,2H),7.78–7.69(m,3H),7.65(d,J＝8.2Hz,1H),7.59(t,J＝7.6Hz,1H),7.39(t,J＝7.6Hz,1H),4.57(s,2H)；13C NMR(126MHz,DMSO)δ174.97,168.56,165.68,164.90,162.30,155.40,139.38,135.21,134.00,133.50,126.78,126.54,126.07,125.59,125.22,123.05,122.57,118.68,117.77,116.60,106.70,43.62.HRMS(ESI)[M+H]+calcd.for C22H13N3O5S:454.0468；found:454.0468.
(25,C21H13N3O7S).White sold；Yield 67％；1H NMR(500MHz,DMSO)δ10.72(s,1H),8.98(s,1H),8.15(d,J＝8.0Hz,1H),8.02–7.85(m,2H),7.82–7.53(m,5H),7.42(t,J＝8.1Hz,1H),4.53(s,2H).HRMS(ESI)[M+H]+calcd.for C21H13N3O7S:474,0368；found:474,0366.
(26,C21H12F2N2O5S).White sold；Yield 57％；1H NMR(500MHz,DMSO)δ10.65(s,1H),8.97(s,1H),8.14(d,J＝7.9Hz,1H),7.92–7.85(m,1H),7.78–7.68(m,3H),7.58(t,J＝7.5Hz,1H),7.41(q,J＝9.6Hz,1H),7.30–7.24(m,1H),4.49(s,2H)；13C NMR(126MHz,DMSO)δ174.97,168.64,165.74,164.33,162.33,155.41,135.47,135.41,135.22,126.85,126.56,125.60,123.05,122.51,118.68,117.77,117.63,115.55,108.35,108.17,43.83.HRMS(ESI)[M+H]+calcd.for C21H13F2N2O5S:465.0327；found:465.0327.
(27,C21H12Cl2N2OS).White sold；Yield 62％；1H NMR(500MHz,DMSO)δ10.71(s,1H),8.98(s,1H),8.15(d,J＝7.9Hz,1H),7.95–7.83(m,2H),7.75(t,J＝4.2Hz,2H),7.59(dd,J＝8.4,3.4Hz,2H),7.46(dd,J＝8.8,2.5Hz,1H),4.50(s,2H)；13C NMR(126MHz,DMSO)δ174.98,168.64,165.74,164.60,162.37,155.41,138.47,135.23,131.15,130.91,126.89,126.56,125.60,125.22,123.05,122.49,120.43,119.26,118.69,117.76,43.92.HRMS(ESI)[M+H]+calcd.forC21H13Cl2N2O5S:496.9739；found:496.9736.
(28,C21H12Br2N2OS).White sold；Yield 70％；1H NMR(500MHz,DMSO)δ10.68(s,1H),8.98(s,1H),8.22–8.01(m,2H),7.89(t,J＝7.9Hz,1H),7.83–7.65(m,3H),7.58(t,J＝7.7Hz,1H),7.42(d,J＝8.8Hz,1H),4.50(s,2H).13C NMR(126MHz,DMSO)δ174.97,168.64,165.74,164.58,162.36,155.41,138.94,135.22,133.96,126.88,126.56,125.60,123.87,123.55,123.05,122.49,119.92,118.68,117.76,117.40,43.93.HRMS(ESI)[M+H]+calcd.for C21H13Br2N2O5S:600.8467；found:600.8465.
(29,C18H16N2O5S).White sold；Yield 50％；1H NMR(500MHz,DMSO)δ8.95(s,1H),8.24(t,J＝5.5Hz,1H),8.14(d,J＝7.9Hz,1H),7.89(t,J＝7.9Hz,1H),7.79–7.68(m,2H),7.58(t,J＝7.6Hz,1H),4.22(s,2H),3.03(q,J＝6.6Hz,2H),1.41(q,J＝7.2Hz,2H),0.84(t,J＝7.4Hz,3H)；13C NMR(126MHz,DMSO)δ174.98,168.61,165.80,164.94,162.07,155.44,135.24,126.57,126.30,125.62,123.07,122.87,118.71,117.85,43.31,40.56,22.29,11.39.HRMS(ESI)[M+H]+calcd.for C18H16N2O5S:411.0411；found:411.0412.
(30,C19H16N2O6S).White sold；Yield 67％；1H NMR(500MHz,DMSO)δ8.96(s,1H),8.14(d,J＝7.9Hz,1H),7.89(t,J＝7.8Hz,1H),7.77–7.71(m,2H),7.57(t,J＝7.5Hz,1H),4.59(s,2H),3.64(t,J＝4.7Hz,2H),3.59–3.51(m,4H),3.43(t,J＝4.9Hz,2H)；13C NMR(126MHz,DMSO)δ174.93,168.56,165.76,163.51,162.15,155.40,135.20,126.55,126.53,125.59,123.04,122.60,118.67,117.78,65.95,44.54,42.41,41.95.HRMS(ESI)[M+H]+calcd.for C19H16N2O6S:439.0361；found:439.0361.
(31,C19H16N2O5S).White sold；Yield 52％；1H NMR(500MHz,DMSO)δ8.96(s,1H),8.14(dd,J＝8.0,1.6Hz,1H),7.88(d,J＝7.0Hz,1H),7.83–7.68(m,2H),7.58(t,J＝7.5Hz,1H),4.46(s,2H),3.53(t,J＝6.8Hz,2H),3.30(t,J＝7.0Hz,2H),1.92(p,J＝6.8Hz,2H),1.79(p,J＝6.9Hz,2H).13C NMR(126MHz,DMSO)δ174.94,168.52,165.74,162.80,162.11,155.41,135.20,126.53,126.48,125.60,123.05,122.68,118.68,117.81,45.86,45.06,43.09,25.60,23.70.HRMS(ESI)[M+H]+calcd.for C19H16N2O5S:423.0411；found:423.04122.
(32,C24H25N3O7S).White sold；Yield 49％；1H NMR(500MHz,DMSO)δ8.96(d,J＝0.6Hz,1H),8.14(dd,J＝8.0,1.7Hz,1H),7.89(ddd,J＝8.7,7.1,1.7Hz,1H),7.78–7.70(m,2H),7.58(ddd,J＝8.1,7.2,1.1Hz,1H),4.60(s,2H),3.52(dd,J＝6.8,3.8Hz,2H),3.46–3.37(m,4H),3.34–3.29(m,2H),1.42(s,9H)；13C NMR(126MHz,DMSO)δ174.93,168.55,165.74,163.51,162.14,155.40,153.76,135.20,126.56,126.53,125.59,123.04,122.61,118.67,117.78,79.27,43.83,42.51,41.42,28.05.HRMS(ESI)[M+H]+calcd.forC24H25N3O7S:522.1305；found:522.1305.
(33 C18H11N3O5S2).White sold；Yield 57％；1H NMR(500MHz,DMSO)δ12.63(s,1H),8.99(s,1H),8.16(dd,J＝7.9,1.7Hz,1H),7.90(ddd,J＝8.7,7.1,1.7Hz,1H),7.76(s,2H),7.59(t,J＝7.3Hz,1H),7.51(d,J＝3.6Hz,1H),7.28(d,J＝3.6Hz,1H),4.61(s,2H)；13C NMR(126MHz,DMSO)δ175.43,169.09,166.14,165.00,162.84,157.98,155.86,138.22,135.68,127.37,127.01,126.05,123.50,122.98,119.14,118.20,114.51,43.65.HRMS(ESI)[M+H]+calcd.forC18H11N3O5S2:436.0033；found:436.0032.
(34 C24H15N3O5S).White sold；Yield 67％；1H NMR(500MHz,DMSO)δ10.80(s,1H),8.99(d,J＝4.3Hz,2H),8.55(d,J＝7.7Hz,1H),8.44(d,J＝8.3Hz,1H),8.16(d,J＝7.9Hz,1H),7.90(t,J＝7.9Hz,1H),7.81–7.75(m,2H),7.72(d,J＝8.1Hz,1H),7.67(dd,J＝8.3,4.1Hz,1H),7.59(d,J＝8.1Hz,2H),4.82(s,2H)；13C NMR(126MHz,DMSO)δ174.96,168.71,165.83,164.65,162.27,155.40,149.03,138.33,136.65,135.21,134.21,127.97,126.92,126.78,126.54,125.60,123.05,122.59,122.56,122.24,118.67,117.80,117.40,44.34.HRMS(ESI)[M+H]+calcd.for C24H15N3O5S:480.0627；found:480.0625.
(35,C22H15BrN2O5S).White sold；Yield 64％；1H NMR(500MHz,DMSO)δ8.96(s,1H),8.84(t,J＝6.0Hz,1H),8.14(dd,J＝8.0,1.6Hz,1H),7.92–7.85(m,1H),7.74(d,J＝9.9Hz,2H),7.57(t,J＝7.5Hz,1H),7.45(d,J＝8.1Hz,2H),7.29(dt,J＝16.2,7.6Hz,2H),4.37–4.26(m,4H).13C NMR(126MHz,DMSO)δ174.93,168.64,165.78,165.48,162.10,155.40,141.81,135.20,130.54,129.89,129.78,126.52,126.38,126.23,125.59,123.03,122.82,121.71,118.67,117.81,43.38,41.67.HRMS(ESI)[M+H]+calcd.for C22H15BrN2O5S:520.9779；found:520.9777.
通过该方法能够成功制备得到一系列的以2,4-噻唑二酮结构为母核的色酮噻唑二酮类化合物，该制备方法具有产率高和操作简单的优点。
性能测试
色酮噻唑二酮类化合物的α-葡萄糖苷酶抑制活性测试
1、试剂与标准溶液的配制
(1)100mM磷酸缓冲液(PBS，pH 6.8)：称取一定质量的磷酸二氢钾与磷酸氢二钠，用超纯水溶解，用于溶解稀释试剂。
(2)α-葡萄糖苷酶溶液配制：将酶活力为100U的酶加适量100mM PBS配成工作浓度为0.05U/mL，并分装冷冻。
(3)底物配制：准确称取适量4-硝基苯基-D-吡喃葡糖苷(PNPG)，加入100mM PBS溶液溶解，配制成浓度为0.25mM的底物工作液，涡旋混匀，每次实验前新鲜配制。
供试药物配制:准确称取待测药物适量，用DMSO溶解配制为10mM的储备液，于-20℃避光保存。实验前用DMSO稀释至不同所需浓度(0～200μM)，DMSO含量等于5％。
2、实验步骤
(1)在96孔板上依次加入10μL工作浓度为0.05U/mL的α-葡萄糖苷酶，130μL(pH6.8)浓度为100mM的磷酸缓冲液，10μL不同浓度的化合物(实施例1中制备得到的吲哚酮类衍生物3a～3v)，空白对照组用10μL含量等于5％的DMSO来替换10μL化合物，用阿卡波糖作为阳性对照，每组平行设置4个复孔，将酶反应体系置于酶标仪上37℃孵育10min。
(2)随后，向酶反应体系中加入50μL的底物PNPG以启动酶反应，将微孔板置于酶标仪上37℃继续孵育15min，在孵育的过程中平均分配3次时间，每段时间于波长405nm读数一次，读数记为OD1、OD2、OD3。
(3)待测化合物的α-葡萄糖苷酶抑制活性根据如下公式计算：
抑制率(％)＝[(OD3-OD)-(OD1-OD)]/OD3-OD×100％
其中OD代表空白对照组的吸光度值，数据处理：使用MS Excel分析处理数据，并用Origin 9.1计算得到半数抑制浓度(IC50)，IC50代表在所述实验条件下，α-葡萄糖苷酶的活性被抑制50％时所需待测化合物的浓度。
3、结果分析
应用体外酶学实验对合成得到的化合物进行α-葡萄糖苷酶抑制活性评价，其测定结果如表2所示：
表2.实施例1～35的化合物与α-葡萄糖苷酶的体外抑制活性评价
a值为三次独立实验结果的mean±S。
其中的阳性对照药阿卡波糖(Acarbose)的IC50为640.57μM。从图1可以看出，(a)为12的半数抑制浓度图；(b)为27的半数抑制浓度图；(c)为28的半数抑制浓度图；本申请的实施例12、27和28有较好的α-葡萄糖苷酶抑制活性的衍生物，实施例12、27和28的抑制率分别是2.79μM、2.95μM和2.40μM，为阿卡波糖的100～150倍。结果表明这些小分子化合物在与α-葡萄糖苷酶相互作用时表现出较强的结合亲和力。由此可以推知，色酮和噻唑二酮骨架结构对此类型化合物具有较好的α-葡萄糖苷酶抑制活性有着非常重要作用。
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α-葡萄糖苷酶抑制活性动力学评价：
1、试剂与标准溶液的配制
(1)100mM磷酸缓冲液(PBS，pH 6.8)：称取一定质量的磷酸二氢钾与磷酸氢二钠，用超纯水溶解，用于溶解稀释试剂。
(2)α-葡萄糖苷酶溶液配制：将酶活力为100U的酶加适量100mM PBS配成工作浓度分别为0.0375U/mL、0.05U/mL、0.0625U/mL、0.075U/mL并分装冷冻。
(3)底物配制：准确称取适量4-硝基苯基-D-吡喃葡糖苷(PNPG)，加入100mM PBS溶液溶解，配制成浓度为0.25mM的底物工作液，涡旋混匀，每次实验前新鲜配制。
供试药物配制:准确称取待测药物适量，用DMSO溶解配制为10mM的储备液，于-20℃避光保存。实验前用DMSO稀释至不同所需浓度(0～200μM)，DMSO含量等于5％。
2、实验步骤
(1)在96孔板上依次加入10μL浓度分别为0.0375U/mL、0.05U/mL、0.0625U/mL、0.075U/mL的α-葡萄糖苷酶，130μL(PH 6.8)浓度为100mM的磷酸缓冲液，10μL不同浓度的化合物(实施例1中制备得到的色酮噻唑二酮类化合物28)，空白对照组用10μL含量等于5％的DMSO来替换10μL化合物，用阿卡波糖作为阳性对照，每组平行设置4个复孔，将酶反应体系置于酶标仪上37℃孵育10min。
(2)随后，向酶反应体系中加入50μL浓度为0.25mM的底物PNPG以启动酶反应，将微孔板置于酶标仪上37℃继续孵育15min，在孵育的过程中平均分配3次时间，每段时间于波长405nm读数一次，读数记为OD1、OD2、OD3。
(3)数据处理：使用MS Excel分析处理数据，酶反应体系的反应速率为△OD/min。
3、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。
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α-葡萄糖苷酶抑制活性动力学评价：
1、试剂与标准溶液的配制
(1)100mM磷酸缓冲液(PBS，pH 6.8)：称取一定质量的磷酸二氢钾与磷酸氢二钠，用超纯水溶解，用于溶解稀释试剂。
(2)α-葡萄糖苷酶溶液配制：将酶活力为100U的酶加适量100mM PBS配成工作浓度为0.05U/mL，并分装冷冻。
(3)底物配制：准确称取适量4-硝基苯基-D-吡喃葡糖苷(PNPG)，加入100mM PBS溶液溶解，配制成浓度为(0.25mM、0.5mM、0.75mM、1mM)的底物工作液，涡旋混匀，每次实验前新鲜配制。
供试药物配制:准确称取待测药物适量，用DMSO溶解配制为10mM的储备液，于-20℃避光保存。实验前用DMSO稀释至不同所需浓度(0～200μM)，DMSO含量等于5％。
2、实验步骤
(1)在96孔板上依次加入10μL浓度为0.5U/mL的α-葡萄糖苷酶，130μL(pH 6.8)浓度为100mM的磷酸缓冲液，10μL不同浓度的化合物(实施例1中制备得到的色酮噻唑二酮类化合物28)，空白对照组用10μL含量等于5％的DMSO来替换10μL化合物，用阿卡波糖作为阳性对照，每组平行设置4个复孔，将酶反应体系置于酶标仪上37℃孵育10min。
(2)随后，向酶反应体系中加入50μL不同浓度的底物PNPG以启动酶反应，将微孔板置于酶标仪上37℃继续孵育15min，在孵育的过程中平均分配3次时间，每段时间于波长405nm读数一次，读数记为OD1、OD2、OD3。
(3)数据处理：使用MS Excel分析处理数据，酶反应体系的反应速率为△OD/min。
3、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28的在体外对α-葡萄糖苷酶的底物动力学图，由图3可以看出，筛选得到的抑制剂为非竞争性抑制剂。表明它只与α-葡萄糖苷酶结合。
综上所述，本发明提供的一系列实施例，并确定了它们对α-葡萄糖苷酶的活性。结果表明，大多数合成的衍生物对α-葡萄糖苷酶表现出显著的抑制活性，特别是化合物28表现出最强的α-葡萄糖苷酶抑制作用，IC50值为2.40μM，是阿卡波糖的100～150倍，能够作为α-葡萄糖苷酶抑制剂用于治疗或预防糖尿病。
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，其特征在于，所述色酮噻唑二酮类化合物具有如式I所示的结构：
其中，R为取代或未取代的芳香基、取代或未取代的C1～10的烷基、取代或未取代的杂环基。
2.根据权利要求1所述的色酮噻唑二酮类化合物，其特征在于，R选自C1～5的烷基、和如下结构式中的至少一种：
其中，n为0～5，R1为一个或多个基团，独立地选自H、C1～10的烷基、卤素、C1～10的卤代烷基、C1～10的烷氧基、硝基、氰基。
3.根据权利要求2所述的色酮噻唑二酮类化合物，其特征在于，所述R选自如下结构式中的一种：
4.根据权利要求1～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：
S4、化合物3与R-NH2进行酰胺缩合反应得到色酮噻唑二酮类化合物；
其中，化合物3的结构式如下：
5.根据权利要求4所述的色酮噻唑二酮类化合物的制备方法，其特征在于，所述化合物3通过如下方法制备：
S1、以2,4-噻唑二酮与溴乙酸乙酯进行亲核取代反应得到取代化合物1；
S2、将化合物1与色酮-3-甲醛在乙酸钠和乙酸条件下反应生成化合物2；
S3、将化合物2进行水解得到化合物3；
其中，化合物1、化合物2的结构式如下：
6.根据权利要求5所述的色酮噻唑二酮类化合物的制备方法，其特征在于，步骤S3中，所述水解在酸性条件下进行。
7.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预防和/或治疗糖尿病产品中的应用。
8.根据权利要求7所述的应用，其特征在于，所述产品为药物、保健品种的至少一种。
9.一种药物组合物，其特征在于，包括药物活性成分和药学上可接受的辅料，所述药物活性成分包括权利要求1～3任一项所述的色酮噻唑二酮类化合物。
10.根据权利要求9所述的药物组合物，其特征在于，药物活性成分占总质量的0.1％～35％。
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