CN117567450A - 噁唑酮类化合物及其药物组合物和应用 - Google Patents
噁唑酮类化合物及其药物组合物和应用 Download PDFInfo
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- CN117567450A CN117567450A CN202311551687.3A CN202311551687A CN117567450A CN 117567450 A CN117567450 A CN 117567450A CN 202311551687 A CN202311551687 A CN 202311551687A CN 117567450 A CN117567450 A CN 117567450A
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- acid
- compound
- iii
- oxazolone compound
- oxazolone
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- 206010008635 Cholestasis Diseases 0.000 claims abstract description 3
- 208000004930 Fatty Liver Diseases 0.000 claims abstract description 3
- 206010019708 Hepatic steatosis Diseases 0.000 claims abstract description 3
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Abstract
本发明公开了一种噁唑酮类化合及其药物组合物和应用。该类化合物结构如式I，还包含其顺反异构体、药学上可接受的盐或它们的混合物。本发明设计的化合物对单酰基甘油酯酶具有优异的抑制活性，在微摩尔浓度水平的酶抑制率达到50％以上；酶抑制IC50值达到纳摩尔浓度水平。可制备为治疗抑郁症、焦虑症、帕金森病、阿尔兹海默症、肌萎缩性侧索硬化、多发性硬化、神经疼痛、炎性疼痛、癌性疼痛、癫痫、癌症、脂肪肝、非酒精性脂肪肝炎、胆汁淤积、炎性肠病的药物，应用广泛。
Description
技术领域
本发明涉及一种噁唑酮类化合物及其药物组合物和应用，尤其涉及一种具有单酰基甘油酯酶抑制活性的噁唑酮类化合物及其药物组合物和应用。
背景技术
内源性大麻素系统(ECS)是一种存在于大多数脊椎动物中枢神经系统以及外周组织中的生物调节系统。其参与调节细胞、组织、器官和机体的平衡、大脑发育、神经递质释放和突触可塑性，以及小胶质细胞的细胞因子释放等许多生理过程，被认为是治疗多种疾病的潜在策略，包括中枢神经系统疾病、疼痛、癌症以及代谢性疾病等。研究发现：内源性大麻素系统主要由大麻素受体(CB1、CB2)、内源性大麻素(AEA、2-AG)以及负责合成和降解内源性大麻素的酶以及相关内源性大麻素转运体组成。
单酰基甘油酯酶(MAGL)是一种膜结合型丝氨酸水解酶，存在于中枢神经系统以及肝、肾、睾丸、肺、前列腺和小肠等周围组织中。MAGL活性在各种生物系统中具有核心功能，特别是内源性大麻素信号和AA代谢。MAGL是内源性大麻素2-AG水解的关键酶，在调节体内2-AG水平发挥着主导作用，其参与调节内源性大麻素的信号网络系统，与多种生理过程有关，如疼痛、炎症、摄食认知、抑郁症以及阿尔茨海默病和帕金森病等神经退行性疾病。MAGL还是一种代谢关键酶，被发现通过不同机制参与了肝病的发生发展，还以非常复杂的方式参与了脂肪和葡萄糖代谢等外周疾病。内源性大麻素信号在中枢及外周组织部位发挥着重要作用。因此，抑制MAGL有希望作为中枢神经系统疾病、疼痛或者肝部疾病的靶点。
迄今为止，MAGL抑制剂多数都是不可逆的，这些不可逆抑制剂虽然具有高效的抑制活性及较高的选择性，但由于其不可逆的作用机制导致CB受体的长期激活，产生CB1脱敏、强直性昏厥、运动减弱等副作用，不利于临床应用。
发明内容
发明目的：本发明的第一目的是提供一种噁唑酮类化合物，第二目的是提供一种包含所述化合物的药物组合物，第三目的是提供一种所述化合物及其药物组合物在制备药物中的应用。
技术方案：本发明所述的噁唑酮类化合物具有式I的结构，还包含其顺反异构体、药学上可接受的盐或它们的混合物：
其中：
R1、R2选自氢、卤素；
X1、X2选自碳、氮；
L选自化学键、5-7元含有氮、氧、硫的不饱和杂环；
Y选自被如下取代基取代的苯环、吡啶环：
卤素、C1-C4烷氧基、C1-C4酰氧基，或者双取代基与所连接的碳形成5-7元含有N、O的杂环基。
优选，所述结构中：
R1、R2选自氢、氟、氯；
L选自化学键、5元含有氮、氧、硫的芳杂环；
Y选自被如下取代基取代的苯环、吡啶环：
氟、氯、C1-C4烷氧基、C1-C4酰氧基，或者双取代基与所连接的碳形成6元含有N、O的杂环基。
进一步优选，所述结构中：
R1、R2不同为氟、氯；
X1、X2不同为氮；
L选自化学键、呋喃环；
Y选自被如下取代基取代的苯环、吡啶环：
氟、氯、C1-C4烷氧基、C1-C4酰氧基，或者双取代基与所连接的苯环形成6元含有N、O的杂环基。
更进一步优选，所述结构中：
L选自化学键、
Y选自被如下取代基取代的苯环、吡啶环：
氟、氯、甲氧基、乙氧基、甲酰氧基、乙酰氧基，或者双取代基与所连接的苯环形成
再进一步优选，所述结构中：
Y选自邻位单取代吡啶环，或者邻位、间位、对位上的单取代或双取代的苯环。
具体地，选自如下：
-Y-L选自如下：
更具体地，当选自/>时，-Y-L选自/>
当选自/>时，-Y-L选自/>
当选自/>时，-Y-L选自/>
最优选地，所述的噁唑酮类化合物选自如下任一的化合物：
本发明所述的药学上可接受的盐为所述化合物与选自如下任一的酸形成的盐：
盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸、阿魏酸。
“药学上可接受的盐”是指化合物的盐，由具有特定取代基的化合物与相对无毒的酸或碱制备。当化合物中含有相对酸性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的游离体形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的游离体形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸(形成碳酸盐或碳酸氢盐)、磷酸(形成磷酸盐、磷酸一氢盐、磷酸二氢盐、硫酸(形成硫酸盐或硫酸氢盐)、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；有机酸盐还包括氨基酸(如精氨酸等)、葡糖醛酸等有机酸的盐。当某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的游离体形式。化合物的游离体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
“药学上可接受的盐”可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
本发明所述的药物组合物包含所述噁唑酮类化合物以及药学上可接受的载体。
所述药物组合物中还含有药学上可接受的载体。
“药学上可接受的载体”可为药物生产领域中广泛采用的辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望的速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
本发明所述的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明所述的药物组合物可以任何形式给药，包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或缓释剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干粉制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂；气雾剂，如鼻腔喷雾剂或吸入剂；适于胃肠外给药的液体剂型；栓剂以及锭剂。
本发明所述的噁唑酮类化合物或其药物组合应用于制备单酰基甘油酯酶抑制剂药物。
优选，所述药物为治疗抑郁症、焦虑症、帕金森病、阿尔兹海默症、肌萎缩性侧索硬化、多发性硬化、神经疼痛、炎性疼痛、癌性疼痛、癫痫、癌症、脂肪肝、非酒精性脂肪肝炎、胆汁淤积、炎性肠病的药物。
有益效果：与现有技术相比，本发明具有如下显著优点：
本发明设计的化合物对单酰基甘油酯酶具有优异的抑制活性，在微摩尔浓度水平的酶抑制率达到50％以上，最优达到100％；酶抑制IC50值达到纳摩尔浓度水平，最优低于5nM。
附图说明
图1为现有化合物1的分子对接模拟图；
图2为现有化合物2的分子对接模拟图；
图3为现有化合物3的分子对接模拟图；
图4为现有化合物4的分子对接模拟图；
图5本发明的化合物III-11的分子对接模拟图。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1：2-(2-氯吡啶-4-基)-4-(3-苯氧基亚苄基)恶唑-5(4H)-酮(Ⅲ-1)的合成
(2-氯异烟酰基)甘氨酸(2)
将甘氨酸(150mg，2.0mmol)溶于1mL 10％的氢氧化钠溶液，冰浴下缓慢滴加2-氯异烟酰氯(385mg，1.1mmol)，撤去冰浴，将反应置于室温下搅拌反应约4小时。TLC监测反应完毕后，在冰浴下将反应液用2N稀盐酸调PH至2-3，析出黄色固体，抽滤干燥后得到黄色固体粉末239mg，产率：56.0％。1HNMR(400MHz,DMSO-d6)δ13.13(s,1H),8.60(t,J＝5.6Hz,1H),7.90-7.76(m,3H),3.96(d,J＝5.9Hz,2H).
2-(2-氯吡啶-4-基)-4-(3-苯氧基亚苄基)恶唑-5(4H)-酮(Ⅲ-1)
将中间体2(395mg，1.84mmol)和原料3(401mg，2.02mmol)溶于醋酸酐中，再加入乙酸钠(408mg，3.0mmol)后将反应置于110℃下搅拌反应2.5h。TLC监测反应完毕后，用10mL饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯(10mL×3)萃取水相，合并有机相后用饱和食盐水(10mL×2)洗涤，然后用无水硫酸钠干燥2小时以上。抽滤，将滤液减压浓缩后，进行柱层析分离纯化(石油醚：乙酸乙酯＝2：1)得到黄色固体粉末305mg，产率：44.3％。1HNMR(400MHz,DMSO-d6)δ8.71(d,J＝5.1Hz,1H),8.04(s,1H),7.83(d,J＝7.7Hz,1H),7.78(s,1H),7.75-7.70(m,1H),7.57-7.48(m,4H),7.36(t,J＝7.4Hz,1H),7.28(dd,J＝8.1,2.1Hz,1H),7.18(d,J＝7.7Hz,2H).
实施例2：2-(2-甲氧基吡啶-4-基)-4-(3-苯氧基亚苄基)恶唑-5(4H)-酮(Ⅲ-2)的合成(2-甲氧基异烟酰基)甘氨酸(5)
采用与中间体2相同的合成方法，以2-甲氧基异烟酰氯为原料，得到橙色固体397mg，收率：94.0％。1HNMR(400MHz,DMSO-d6)δ13.03(s,1H),9.16(t,J＝5.9Hz,1H),8.37(dd,J＝5.3,0.8Hz,1H),7.42(dd,J＝5.3,1.4Hz,1H),7.26(q,J＝2.6,1.8Hz,1H),3.99(d,J＝5.9Hz,2H),3.95(s,3H).
2-(2-甲氧基吡啶-4-基)-4-(3-苯氧基亚苄基)恶唑-5(4H)-酮(Ⅲ-2)
采用与Ⅲ-1相同的合成方法，以中间体5和化合物3为原料，得到黄色粉末状固体38.4mg，收率：43％。1H NMR(400MHz,DMSO-d6)δ8.43(dd,J＝5.3,0.8Hz,1H),8.07(dd,J＝2.6,1.5Hz,1H),7.79(dt,J＝7.8,1.3Hz,1H),7.56-7.49(m,3H),7.43(s,1H),7.38-7.32(m,1H),7.30-7.24(m,2H),7.19-7.13(m,3H),3.95(s,3H).
实施例3：2-氯-4-(5-氧代-4-(3-苯氧基亚苄基)-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-3)的合成
(3-氯-4-羟基苯甲酰基)甘氨酸乙酯(6)
将3-氯-4-羟基苯甲酸(517.7mg，3.0mmol)、HOBT(445.8mg，3.3mmol)、EDCI(632.6mg，3.3mmol)、TEA(758.9mg，7.5mmol)溶于N,N-二甲基甲酰胺中，加入分子筛。冰浴下加入甘氨酸乙酯盐酸盐(460.6mg，3.3mmol)的DMF溶液。撤去冰浴后Ar保护下室温搅拌约5h。TLC检测反应完毕后。用10mL水稀释反应液，用乙酸乙酯(8mL×3)萃取水相，合并有机相后用饱和食盐水(10mL×2)洗涤，然后用无水硫酸钠干燥2小时以上。抽滤，将滤液减压浓缩后，进行柱层析分离纯化(石油醚：乙酸乙酯＝1：1)得到白色粉絮状固体485mg，收率：62.7％。1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.89(t,J＝5.9Hz,1H),7.95(d,J＝2.1Hz,1H),7.75(dd,J＝8.5,2.2Hz,1H),7.09(d,J＝8.5Hz,1H),4.17(q,J＝7.1Hz,2H),4.01(d,J＝5.8Hz,2H),1.26(t,J＝7.1Hz,3H).
(3-氯-4-羟基苯甲酰基)甘氨酸(7)
将中间体6(485mg，1.88mmol)溶于四氢呋喃中，再加入10％氢氧化钠(226mg，5.65mmol)溶液，置于50℃下搅拌反应2h，TLC监测反应完毕后，将反应液冷却至室温，减压浓缩除去四氢呋喃，加入适量水。冰浴下用稀盐酸调PH至2-3后抽滤，干燥后得到367mg白色固体，收率：85.0％。1H NMR(300MHz,DMSO-d6)δ12.58(s,1H),10.88(s,1H),8.74(t,J＝5.9Hz,1H),7.89(d,J＝2.2Hz,1H),7.69(dd,J＝8.5,2.2Hz,1H),7.02(d,J＝8.5Hz,1H),3.88(d,J＝5.8Hz,2H).
2-氯-4-(5-氧代-4-(3-苯氧基亚苄基)-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-3)
采用与Ⅲ-1相同的合成方法，以中间体7和化合物3为原料，得到黄色粉末状固体51mg，收率：26.0％。1H NMR(400MHz,DMSO-d6)δ8.12(dd,J＝2.6,1.5Hz,1H),8.04(d,J＝2.0Hz,1H),7.91(dd,J＝8.5,2.1Hz,1H),7.86(dt,J＝7.8,1.2Hz,1H),7.68(d,J＝8.5Hz,1H),7.63-7.53(m,3H),7.44-7.36(m,2H),7.31(ddd,J＝8.2,2.5,1.0Hz,1H),7.27-7.20(m,2H),2.46(s,3H).
实施例4：2-氟-4-(5-氧代-4-(3-苯氧基亚苄基)-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-4)的合成
(3-氟-4-羟基苯甲酰基)甘氨酸乙酯(8)
采用与中间体6相同的合成方法，以3-氟-4-羟基苯甲酸和甘氨酸乙酯盐酸盐为原料，得到白色絮状固体480mg，收率：50％。1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),8.80(t,J＝5.9Hz,1H),7.65(dd,J＝12.3,2.1Hz,1H),7.57(dd,J＝8.4,2.1Hz,1H),7.01(t,J＝8.6Hz,1H),4.10(q,J＝7.1Hz,2H),3.95(d,J＝5.8Hz,2H),1.19(t,J＝7.1Hz,3H).
(3-氟-4-羟基苯甲酰基)甘氨酸(9)
采用与中间体7相同的合成方法，以中间体8为原料，得到白色固体62mg，收率：82.6％。1H NMR(300MHz,DMSO-d6)δ12.57(s,1H),10.57(s,1H),8.71(t,J＝5.9Hz,1H),7.73-7.50(m,2H),7.01(t,J＝8.6Hz,1H),3.88(d,J＝5.8Hz,2H).
2-氟-4-(5-氧代-4-(3-苯氧基亚苄基)-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-4)
采用与Ⅲ-1相同的合成方法，以中间体9和化合物3为原料，得到黄色粉末状固体90mg，收率：41.0％。1H NMR(400MHz,DMSO-d6)δ8.09(dd,J＝2.7,1.5Hz,1H),7.79(dt,J＝7.8,1.2Hz,1H),7.77-7.71(m,2H),7.60(dd,J＝8.7,7.6Hz,1H),7.55-7.49(m,3H),7.37-7.29(m,2H),7.25(ddd,J＝8.3,2.6,1.0Hz,1H),7.21-7.15(m,2H),2.40(s,3H).
实施例5：4-氯-3-(5-氧代-4-(3-苯氧基亚苄基)-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-5)的合成
(2-氯-5-羟基苯甲酰基)甘氨酸乙酯(10)
采用与中间体6相同的合成方法，以2-氯-5-羟基苯甲酸和甘氨酸乙酯盐酸盐为原料，得到白色絮状固体56mg，收率：50.4％。1HNMR(300MHz,DMSO-d6)δ9.96(s,1H),8.79(t,J＝6.0Hz,1H),7.30-7.24(m,1H),6.83(dt,J＝4.7,2.6Hz,2H),4.13(q,J＝7.1Hz,2H),3.94(d,J＝6.0Hz,2H),1.22(t,J＝7.1Hz,3H).
(2-氯-5-羟基苯甲酰基)甘氨酸(11)
采用与中间体7相同的合成方法，以中间体10为原料，得到白色固体89mg，收率：98.0％。1H NMR(400MHz,DMSO-d6)δ12.73(s,1H),10.02(s,1H),8.74(t,J＝5.8Hz,1H),7.33(dd,J＝9.5,3.5Hz,1H),6.94-6.86(m,2H),3.93(d,J＝6.1Hz,2H).
4-氯-3-(5-氧代-4-(3-苯氧基亚苄基)-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-5)
采用与Ⅲ-1相同的合成方法，以中间体11和化合物3为原料，得到黄色粉末状固体38mg，收率：29.6％。1H NMR(400MHz,DMSO-d6)δ8.18-8.15(m,1H),7.93(dt,J＝7.8,1.2Hz,1H),7.77(d,J＝2.8Hz,1H),7.73(d,J＝8.7Hz,1H),7.56(t,J＝7.9Hz,1H),7.50-7.45(m,2H),7.45-7.40(m,2H),7.23(dd,J＝7.7,2.1Hz,1H),7.18(td,J＝7.4,1.2Hz,1H),7.08(dt,J＝8.6,1.5Hz,2H),2.33(s,3H).
实施例6：4-氟-3-(5-氧代-4-(3-苯氧基亚苄基)-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-6)的合成
(2-氟-5-羟基苯甲酰基)甘氨酸乙酯(12)
采用与中间体6相同的合成方法，以2-氟-5-羟基苯甲酸和甘氨酸乙酯盐酸盐为原料，得到白色絮状固体160mg，收率：66.3％。1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.54(q,J＝5.5Hz,1H),7.11(dd,J＝10.4,8.9Hz,1H),7.03(dd,J＝5.9,3.1Hz,1H),6.89(ddd,J＝8.9,4.0,3.1Hz,1H),4.12(q,J＝7.1Hz,2H),3.97(d,J＝5.9Hz,2H),1.21(t,J＝7.1Hz,3H).
(2-氟-5-羟基苯甲酰基)甘氨酸(13)
采用与中间体7相同的合成方法，以中间体12为原料，得到白色固体104mg，收率：97.0％。1H NMR(300MHz,DMSO-d6)δ12.89(s,1H),12.66(s,1H),9.67(s,1H),8.41(q,J＝5.5Hz,1H),7.15-7.01(m,2H),6.88(dt,J＝7.4,3.6Hz,1H),3.91(d,J＝5.8Hz,2H).
4-氟-3-(5-氧代-4-(3-苯氧基亚苄基)-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-6)
采用与Ⅲ-1相同的合成方法，以中间体13和化合物3为原料，得到黄色粉末状固体54mg，收率：41.8％。1HNMR(400MHz,DMSO-d6)δ8.06-8.03(m,1H),7.93(dt,J＝7.8,1.2Hz,1H),7.70-7.65(m,1H),7.58-7.52(m,3H),7.49-7.41(m,3H),7.24-7.17(m,2H),7.14-7.08(m,2H),2.36(s,3H).
实施例7：4-氯-2-(5-氧代-4-(3-苯氧基亚苄基)-4,5-二氢噁唑-2-基)苯乙酸酯(Ⅲ-7)的合成
(5-氯-2-羟基苯甲酰基)甘氨酸乙酯(14)
采用与中间体6相同的合成方法，以5-氯水杨酸和甘氨酸乙酯盐酸盐为原料，得到白色絮状固体1305mg，收率：84.4％。1H NMR(300MHz,DMSO-d6)δ12.13(s,1H),9.21(t,J＝5.7Hz,1H),7.92(d,J＝2.7Hz,1H),7.46(dd,J＝8.8,2.7Hz,1H),6.98(d,J＝8.8Hz,1H),4.14(t,J＝7.1Hz,2H),4.10-4.04(m,2H),1.20(t,J＝7.1Hz,3H).
(5-氯-2-羟基苯甲酰基)甘氨酸(15)
采用与中间体7相同的合成方法，以中间体14为原料，得到白色固体1465mg，收率：100.0％。1H NMR(300MHz,DMSO-d6)δ12.81(s,1H),12.26(s,1H),9.17(t,J＝5.7Hz,1H),7.94(d,J＝2.7Hz,1H),7.46(dd,J＝8.8,2.7Hz,1H),6.98(d,J＝8.8Hz,1H),4.00(d,J＝5.6Hz,2H).
4-氯-2-(5-氧代-4-(3-苯氧基亚苄基)-4,5-二氢噁唑-2-基)苯乙酸酯(Ⅲ-7)
采用与Ⅲ-1相同的合成方法，以中间体15和化合物3为原料，得到黄色粉末状固体100mg，收率：35.0％。1H NMR(300MHz,DMSO-d6)δ8.04-7.88(m,3H),7.88-7.80(m,1H),7.55(t,J＝8.1Hz,1H),7.44(dd,J＝9.4,4.8Hz,4H),7.21(d,J＝9.7Hz,2H),7.08(d,J＝7.9Hz,2H),2.32(s,3H).
实施例8：2-(5-(3-氯苯基)呋喃-2-基)-4-(3-苯氧基亚苄基)恶唑-5(4H)-酮(Ⅲ-8)的合成
(5-(3-氯苯基)呋喃-2-羰基)甘氨酸乙酯(17)
采用与中间体6相同的合成方法，以5-(3-氯苯基)呋喃-2-羧酸和甘氨酸乙酯盐酸盐为原料，得到白色絮状固体50mg，收率：51.0％。1H NMR(400MHz,DMSO-d6)δ9.08(t,J＝6.0Hz,1H),8.11(t,J＝1.7Hz,1H),7.95-7.90(m,1H),7.55(t,J＝7.9Hz,1H),7.48(ddd,J＝8.0,1.9,0.9Hz,1H),7.31-7.25(m,2H),4.18(q,J＝7.1Hz,2H),4.07(d,J＝6.0Hz,2H),1.26(t,J＝7.1Hz,3H).
(5-(3-氯苯基)呋喃-2-羰基)甘氨酸(18)
采用与中间体7相同的合成方法，以中间体17为原料，得到白色固体30mg，收率：66.7％。1H NMR(400MHz,DMSO-d6)δ12.71(s,1H),8.98(dt,J＝7.1,3.7Hz,1H),8.08(q,J＝2.0Hz,1H),7.93-7.86(m,1H),7.51(td,J＝7.9,1.8Hz,1H),7.44(dt,J＝8.0,2.4Hz,1H),7.26(dd,J＝3.7,1.6Hz,1H),7.22(dd,J＝3.7,1.7Hz,1H),3.95(dd,J＝6.1,1.9Hz,2H).
2-(5-(3-氯苯基)呋喃-2-基)-4-(3-苯氧基亚苄基)恶唑-5(4H)-酮(Ⅲ-8)
采用与Ⅲ-1相同的合成方法，以中间体18和化合物3为原料，得到黄色粉末状固体24.3mg，收率：27.0％。1H NMR(400MHz,DMSO-d6)δ8.08-8.02(m,1H),7.96-7.90(m,2H),7.79(dt,J＝7.8,1.3Hz,1H),7.63-7.49(m,5H),7.49-7.44(m,2H),7.32(s,1H),7.23-7.16(m,2H),7.15-7.10(m,2H).
实施例9：6-(5-氧代-4-(3-苯氧基亚苄基)-4,5-二氢噁唑-2-基)-2H-苯并[b][1,4]恶嗪-3(4H)-酮(Ⅲ-9)的合成
(3-氧代-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-羰基)甘氨酸乙酯(20)
采用与中间体6相同的合成方法，以3-氧代-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-羧酸和甘氨酸乙酯盐酸盐为原料，得到白色固体135mg，收率：75.0％。1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),8.80(d,J＝6.1Hz,1H),7.45(d,J＝8.7Hz,1H),7.42(s,1H),7.02(d,J＝8.3Hz,1H),4.64(s,2H),4.11(q,J＝7.1Hz,2H),3.95(d,J＝5.8Hz,2H),1.20(t,J＝7.2Hz,3H).
(3-氧代-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-羰基)甘氨酸(21)
采用与中间体7相同的合成方法，以中间体20为原料，得到浅橙色固体112mg，收率：88.5％。1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),10.86(s,1H),8.71(t,J＝5.9Hz,1H),7.45(dd,J＝8.3,2.1Hz,1H),7.42(d,J＝2.0Hz,1H),7.01(d,J＝8.3Hz,1H),4.64(s,2H),3.88(d,J＝5.8Hz,2H).
6-(5-氧代-4-(3-苯氧基亚苄基)-4,5-二氢噁唑-2-基)-2H-苯并[b][1,4]恶嗪-3(4H)-酮(Ⅲ-9)
采用与Ⅲ-1相同的合成方法，以中间体21和化合物3为原料，得到黄色粉末状固体11mg，收率：12.0％。1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),8.11-8.07(m,1H),7.85(d,J＝7.7Hz,1H),7.54(d,J＝2.2Hz,1H),7.51(d,J＝3.0Hz,1H),7.49(d,J＝2.6Hz,2H),7.47(d,J＝2.2Hz,1H),7.33-7.29(m,1H),7.27(s,1H),7.20(s,1H),7.18(d,J＝2.6Hz,1H),7.16(t,J＝1.8Hz,2H),7.14-7.12(m,1H),4.76(s,2H).
实施例10：2-氯-4-(4-(3-(4-氯苯氧基)亚苄基)-5-氧代-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-10)的合成
采用与Ⅲ-1相同的合成方法，以中间体7和3-(4-氯苯氧基)苯甲醛为原料，得到黄色粉末状固体30mg，收率：16.3％。1HNMR(400MHz,DMSO-d6)δ8.38-8.12(m,1H),8.11-8.02(m,1H),7.93(t,J＝8.5Hz,1H),7.67-7.49(m,4H),7.43(dd,J＝24.3,7.9Hz,2H),7.33-7.16(m,2H),7.07(t,J＝5.7Hz,1H),2.11(d,J＝2.7Hz,3H).
实施例11：2-氯-4-(4-(3-(4-氟苯氧基)亚苄基)-5-氧代-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-11)的合成
采用与Ⅲ-1相同的合成方法，以中间体7和3-(4-氟苯氧基)苯甲醛为原料，得到黄色粉末状固体11mg，收率：6.2％。1H NMR(300MHz,DMSO-d6)δ8.05-7.97(m,2H),7.88(dd,J＝8.5,2.1Hz,1H),7.80(d,J＝7.7Hz,1H),7.59-7.48(m,2H),7.38-7.29(m,3H),7.26-7.17(m,3H),2.39(s,3H).
实施例12：4-氯-2-(4-(3-(4-氯苯氧基)亚苄基)-5-氧代-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-12)的合成
采用与Ⅲ-1相同的合成方法，以中间体15和化合物22为原料，得到黄色粉末状固体427mg，收率：55.0％。1H NMR(300MHz,DMSO-d6)δ7.99(dd,J＝7.2,2.2Hz,3H),7.84(dd,J＝8.7,2.7Hz,1H),7.57(t,J＝8.1Hz,1H),7.46(dt,J＝8.6,3.8Hz,4H),7.24-7.17(m,1H),7.14-7.07(m,2H),2.32(s,3H).
实施例13：4-氯-2-(4-(3-(4-氟苯氧基)亚苄基)-5-氧代-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-13)的合成
采用与Ⅲ-1相同的合成方法，以中间体15和化合物23为原料，得到黄色粉末状固体7mg，收率：11.2％。1H NMR(300MHz,DMSO-d6)δ8.08-8.03(m,1H),7.79(ddd,J＝9.7,8.0,2.2Hz,3H),7.61-7.50(m,2H),7.40-7.31(m,3H),7.29-7.21(m,3H),2.41(s,3H).
实施例14：4-(4-(3-(4-氯苯氧基)亚苄基)-5-氧代-4,5-二氢噁唑-2-基)-2-氟苯乙酸酯(Ⅲ-14)的合成
采用与Ⅲ-1相同的合成方法，以中间体9和化合物22为原料，得到黄色粉末状固体10mg，收率：10.0％。1H NMR(300MHz,DMSO-d6)δ8.05(t,J＝2.1Hz,1H),7.94-7.85(m,2H),7.85-7.78(m,1H),7.64-7.57(m,1H),7.57-7.51(m,3H),7.39(s,1H),7.25(dd,J＝8.0,2.5Hz,1H),7.22-7.15(m,2H),2.40(s,3H).
实施例15：2-氟-4-(4-(3-(4-氟苯氧基)亚苄基)-5-氧代-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-15)的合成
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采用与Ⅲ-1相同的合成方法，以中间体9和化合物23为原料，得到黄色粉末状固体20.7mg，收率：5.2％。1H NMR(300MHz,DMSO-d6)δ8.08-8.03(m,1H),7.79(ddd,J＝9.7,8.0,2.2Hz,3H),7.61-7.50(m,2H),7.40-7.31(m,3H),7.29-7.21(m,3H),2.41(s,3H).
实施例16：4-氯-3-(4-(3-(4-氯苯氧基)亚苄基)-5-氧代-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-16)的合成
采用与Ⅲ-1相同的合成方法，以中间体11和化合物22为原料，得到黄色粉末状固体6.6mg，收率：3.6％。1H NMR(300MHz,DMSO-d6)δ8.18(s,1H),7.96(d,J＝7.7Hz,1H),7.81(s,1H),7.73(d,J＝8.6Hz,1H),7.60-7.43(m,5H),7.26(d,J＝9.2Hz,1H),7.11(d,J＝8.4Hz,2H),2.32(s,3H).
实施例17：4-氯-3-(4-(3-(4-氟苯氧基)亚苄基)-5-氧代-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-17)的合成
采用与Ⅲ-1相同的合成方法，以中间体11和化合物23为原料，得到白色粉末状固体11.8mg，收率：3.7％。1H NMR(300MHz,DMSO-d6)δ8.14-8.10(m,1H),7.90(d,J＝7.7Hz,1H),7.78(d,J＝2.8Hz,1H),7.73(d,J＝8.7Hz,1H),7.54(t,J＝8.0Hz,1H),7.50-7.43(m,2H),7.30-7.19(m,3H),7.17-7.10(m,2H),2.31(s,3H).
实施例18：4-氟-3-(4-(3-(4-氟苯氧基)亚苄基)-5-氧代-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-18)的合成
采用与Ⅲ-1相同的合成方法，以中间体13和化合物23为原料，得到黄色粉末状固体9.9mg，收率：6.0％。1H NMR(300MHz,DMSO-d6)δ8.02(t,J＝1.9Hz,1H),7.91(d,J＝7.7Hz,1H),7.70(dd,J＝5.9,2.6Hz,1H),7.58-7.50(m,3H),7.42(s,1H),7.33-7.25(m,2H),7.22-7.14(m,3H),2.34(s,3H).
实施例19：4-氯-2-(5-氧代-4-(3-(吡啶-3-基氧基)亚苄基)-4,5-二氢噁唑-2-基)乙酸苯酯的合成(Ⅲ-19)的合成
3-(吡啶-3-基氧基)苯甲醛(25)
将3-羟基苯甲醛(936mg，7.67mmol)和3-溴吡啶(1817mg，11.50mmol)溶于无水二氧六环中，依次加入碳酸铯(3749mg，11.50mmol)，N,N-二甲基甘氨酸盐酸盐(214mg，1.53mmol)，氧化亚铜(146mg，0.77mmol)，将反应置于120℃下氩气保护回流反应约48h。TLC监测反应完毕后，加硅藻土抽滤，收集滤液减压浓缩除去二氧六环，然后用20mL水稀释反应液，用乙酸乙酯(15mL×3)萃取水相，合并有机相后用饱和食盐水(15mL×2)洗涤，然后用无水硫酸钠干燥2小时以上。抽滤，将滤液减压浓缩后，进行柱层析分离纯化(石油醚：乙酸乙酯＝6：1)得到淡黄色油916mg，产率：60％。1HNMR(300MHz,DMSO-d6)δ9.99(s,1H),8.48-8.42(m,2H),7.74(dt,J＝7.5,1.3Hz,1H),7.66(t,J＝7.7Hz,1H),7.55(ddd,J＝8.4,2.8,1.5Hz,1H),7.51-7.42(m,3H).
4-氯-2-(5-氧代-4-(3-(吡啶-3-基氧基)亚苄基)-4,5-二氢噁唑-2-基)乙酸苯酯的合成(Ⅲ-19)
采用与Ⅲ-1相同的合成方法，以中间体15和中间体25为原料，得到黄色粉末状固体100mg，收率：31.4％。1H NMR(300MHz,DMSO-d6)δ8.48-8.40(m,2H),8.03-7.96(m,2H),7.94(d,J＝2.6Hz,1H),7.84(dd,J＝8.7,2.6Hz,1H),7.63-7.50(m,2H),7.50-7.42(m,3H),7.24(ddd,J＝8.2,2.5,1.1Hz,1H),2.32(s,3H).
实施例20：4-氯-2-(4-(3-((5-氯吡啶-3-基)氧基)亚苄基)-5-氧代-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-20)的合成
3-((5-氯吡啶-3-基)氧基)苯甲醛(26)
采用与中间体25相同的合成方法，以化合物24为原料，得到黄色透明油470mg，收率：66.3％。1HNMR(300MHz,DMSO-d6)δ10.00(s,1H),8.49(dd,J＝2.0,0.5Hz,1H),8.42(dd,J＝2.5,0.5Hz,1H),7.82-7.73(m,2H),7.68(t,J＝7.8Hz,1H),7.58(dd,J＝2.6,1.4Hz,1H),7.50(ddd,J＝8.0,2.6,1.1Hz,1H).
4-氯-2-(4-(3-((5-氯吡啶-3-基)氧基)亚苄基)-5-氧代-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-20)
采用与Ⅲ-1相同的合成方法，以中间体15和中间体26为原料，得到黄色粉末状固体15mg，收率：9.6％。1H NMR(300MHz,DMSO-d6)δ8.49(d,J＝2.0Hz,1H),8.42(d,J＝2.5Hz,1H),8.09-8.02(m,2H),7.96(d,J＝2.6Hz,1H),7.85(dt,J＝8.7,2.6Hz,1H),7.75(t,J＝2.3Hz,1H),7.61(t,J＝8.0Hz,1H),7.50-7.43(m,2H),7.33-7.28(m,1H),2.32(s,3H).
实施例21：4-氯-2-(4-(3-((6-氯吡啶-3-基)氧基)亚苄基)-5-氧代-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-21)的合成
3-((6-氯吡啶-3-基)氧基)苯甲醛(27)
采用与中间体25相同的合成方法，以化合物24为原料，得到黄色透明油933mg，收率：65.6％。1HNMR(300MHz,DMSO-d6)δ9.99(s,1H),8.31(dd,J＝3.0,0.7Hz,1H),7.78-7.72(m,1H),7.70-7.65(m,1H),7.64…7.62(m,1H),7.59(d,J＝0.7Hz,1H),7.57…7.53(m,1H),7.48(ddd,J＝8.0,2.6,1.2Hz,1H).
4-氯-2-(4-(3-((6-氯吡啶-3-基)氧基)亚苄基)-5-氧代-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-21)
采用与Ⅲ-1相同的合成方法，以中间体15和中间体27为原料，得到黄色粉末状固体70mg，收率：36.0％。1H NMR(300MHz,DMSO-d6)δ8.30(dd,J＝3.0,0.7Hz,1H),8.06(d,J＝7.8Hz,1H),8.00(dd,J＝4.2,2.4Hz,2H),7.85(dd,J＝8.7,2.7Hz,1H),7.66-7.59(m,2H),7.59-7.54(m,1H),7.50-7.43(m,2H),7.28(ddd,J＝8.2,2.6,0.9Hz,1H),2.32(s,3H).
实施例22：4-氯-2-(4-((5-(4-氯苯氧基)吡啶-3-基)亚甲基)-5-氧代-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-22)的合成
5-(4-氯苯氧基)烟醛(29)
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将4-氯苯酚(510mg，44mmol)，5-溴烟醛(660mg，4.4mmol)溶于20mL无水二氯甲烷中，再依次加入无水醋酸铜(726mg，4mmol)、吡啶(316mg，4mmol)，将反应置于室温下搅拌反应约12小时。TLC检测反应完毕后，减压浓缩除去二氯甲烷。用10mL水稀释反应液，用乙酸乙酯(8mL×3)萃取水相，合并有机相后用饱和食盐水(10mL×2)洗涤，然后用无水硫酸钠干燥2小时以上。抽滤，将滤液减压浓缩后，进行柱层析分离纯化(石油醚：乙酸乙酯＝50：1)得到无色透明油50mg，收率：11.0％。1H NMR(300MHz,DMSO-d6)δ10.09(s,1H),8.88(d,J＝1.6Hz,1H),8.72(d,J＝2.9Hz,1H),7.74(dd,J＝2.9,1.7Hz,1H),7.55-7.48(m,2H),7.23…7.19(m,2H).
4-氯-2-(4-((5-(4-氯苯氧基)吡啶-3-基)亚甲基)-5-氧代-4,5-二氢噁唑-2-基)乙酸苯酯(Ⅲ-22)
采用与Ⅲ-1相同的合成方法，以中间体15和中间体29为原料，得到黄色粉末状固体10mg，收率：9.5％。1H NMR(300MHz,DMSO-d6)δ8.61(d,J＝1.7Hz,1H),8.42(d,J＝2.7Hz,1H),7.82(d,J＝2.7Hz,1H),7.60(t,J＝2.3Hz,1H),7.52(dd,J＝8.8,2.7Hz,1H),7.46(s,1H),7.28…7.21(m,2H),7.08…6.98(m,3H),3.76(s,3H).
实施例23：3-(4-亚苄基-5-氧代-4,5-二氢噁唑-2-基)-4-氟苯乙酸酯(Ⅲ-23)的合成
采用与Ⅲ-1相同的合成方法，以中间体13和中间体22为原料，得到黄色粉末状固体25mg，收率：36.0％。1H NMR(300MHz,DMSO-d6)δ8.05(t,J＝1.9Hz,1H),7.97(d,J＝7.8Hz,1H),7.75(dd,J＝6.4,2.4Hz,1H),7.54(dd,J＝4.9,2.8Hz,3H),7.50…7.46(m,2H),7.43(d,J＝4.0Hz,1H),7.22(dd,J＝7.9,2.5Hz,1H),7.16…7.10(m,2H).
实施例24：体外MAGL酶抑制活性评价
1、实验方法
MAGL可在细胞中水解2-AG生成花生四烯酸和甘油，针对一定量的反应底物，不同的酶活性催化生成不同量的产物，通过检测产物的量可以考察酶活性的高低。采用Cayman的MAGL抑制剂筛选试剂盒，根据其说明书，稀释一定浓度的MAGL，加入Buffer缓冲液，然后加入各浓度的化合物，同时设置空白对照组、酶初始活性组、JZL-195阳性对照组，孵育5分钟后，加入底物4-硝基苯乙酸酯(4-NPA)引发反应，再孵育10分钟后，通过酶标仪测定水解前后吸光度的变化，间接测得MAGL酶的活性，最后计算化合物的抑制率。IC50值可根据不同浓度下的抑制率，采用Graphpadprism 5.0软件进行非线性拟合计算得到IC50值。
2、实验结果
具体结果如表1～表2所示。
表1.MAGL抑制率结果(％)
表2.MAGL抑制IC50结果
| 化合物编号 | IC50(nM) |
| III-12 | 4.6 |
由上可见，本发明设计的化合物抑制活性得到进一步优化，微摩尔浓度水平的酶抑制率达到50％以上，酶抑制IC50值达到纳摩尔浓度水平。
实施例25：分子对接模拟评价
分子对接是一种预测配体分子与特定受体结合的计算方法，用于预测不同蛋白质-配体体系的结合模式以及结合亲和力。选取现有的4个化合物(化合物1～化合物4)和本发明的化合物III-11分别进行分子对接模拟。
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由图1～图5可见，现有的4个化合物和混合Ⅲ-11有着共同的结合作用力：ALA51和MET123的氢键作用，结构中的二苯醚部分均进入大疏水空腔中。而当将小疏水空腔中尾部芳环上的氯原子或者甲氧基替换成乙酰氧基后，化合物III-11的取代苯环部分相比现有的4个化合物更加深入占据小疏水空腔末端，与TYR194形成π-π堆积作用及更为稳定的关键氢键作用，因此酶抑制活性获得显著升高。
Claims (10)
1.一种噁唑酮类化合物，其特征在于，具有式I的结构，还包含其顺反异构体、药学上可接受的盐或它们的混合物：
其中：
R1、R2选自氢、卤素；
X1、X2选自碳、氮；
L选自化学键、5-7元含有氮、氧、硫的不饱和杂环；
Y选自被如下取代基取代的苯环、吡啶环：
卤素、C1-C4烷氧基、C1-C4酰氧基，或者双取代基与所连接的碳形成5-7元含有N、O的杂环基。
2.根据权利要求1所述的噁唑酮类化合物，其特征在于，所述结构中：
R1、R2选自氢、氟、氯；
L选自化学键、5元含有氮、氧、硫的芳杂环；
Y选自被如下取代基取代的苯环、吡啶环：
氟、氯、C1-C4烷氧基、C1-C4酰氧基，或者双取代基与所连接的碳形成6元含有N、O的杂环基。
3.根据权利要求2所述的噁唑酮类化合物，其特征在于，所述结构中：
R1、R2不同为氟、氯；
X1、X2不同为氮；
L选自化学键、呋喃环；
Y选自被如下取代基取代的苯环、吡啶环：
氟、氯、C1-C4烷氧基、C1-C4酰氧基，或者双取代基与所连接的苯环形成6元含有N、O的杂环基。
4.根据权利要求3所述的噁唑酮类化合物，其特征在于，所述结构中：
L选自化学键、
Y选自被如下取代基取代的苯环、吡啶环：
氟、氯、甲氧基、乙氧基、甲酰氧基、乙酰氧基，或者双取代基与所连接的苯环形成
5.根据权利要求4所述的噁唑酮类化合物，其特征在于，所述结构中：
Y选自邻位单取代吡啶环，或者邻位、间位、对位上的单取代或双取代的苯环。
6.根据权利要求1所述的噁唑酮类化合物，其特征在于，选自如下任一化合物：
7.根据权利要求1所述的噁唑酮类化合物，其特征在于，所述药学上可接受的盐为所述化合物与选自如下任一的酸形成的盐：
盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸、阿魏酸。
8.一种药物组合物，其特征在于，所述药物组合物包含权利要求1所述噁唑酮类化合物以及药学上可接受的载体。
9.一种权利要求1所述的噁唑酮类化合物或权利要求8所述的药物组合在制备单酰基甘油酯酶抑制剂药物中的应用。
10.根据权利要求9所述的应用，其特征在于，所述药物为治疗抑郁症、焦虑症、帕金森病、阿尔兹海默症、肌萎缩性侧索硬化、多发性硬化、神经疼痛、炎性疼痛、癌性疼痛、癫痫、癌症、脂肪肝、非酒精性脂肪肝炎、胆汁淤积、炎性肠病的药物。
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