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CN116903569B - 作为磷酸二酯酶2抑制剂的香豆素-查尔酮杂合类衍生物及其应用 - Google Patents

作为磷酸二酯酶2抑制剂的香豆素-查尔酮杂合类衍生物及其应用 Download PDF

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CN116903569B
CN116903569B CN202310823447.8A CN202310823447A CN116903569B CN 116903569 B CN116903569 B CN 116903569B CN 202310823447 A CN202310823447 A CN 202310823447A CN 116903569 B CN116903569 B CN 116903569B
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coumarin
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pde2
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宋国强
范家如
冯筱晴
唐龙
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Abstract

本发明属于药物化学领域，具体涉及作为磷酸二酯酶2抑制剂的香豆素‑查尔酮杂合类衍生物以及应用。本发明拓展以香豆素和查尔酮为结构基础的杂合衍生物，提供新颖的PDE2的抑制剂小分子化合物，得到的化合物有良好的PDE2抑制活性。这些化合物具有治疗中枢神经系统疾病的潜力，如记忆缺陷、认知障碍、焦虑和抑郁症等，可作为活性成分制备抑制PDE2活性的药物。并且制备容易，反应迅速，产率较高，后处理简单，且后处理过滤留下的固体酸催化剂仍可回收利用，大大降低了反应时间和实验成本。

Description

作为磷酸二酯酶2抑制剂的香豆素-查尔酮杂合类衍生物及其 应用
技术领域
本发明属于药物化学领域，具体涉及作为磷酸二酯酶2(PDE2)的抑制剂香豆素-查尔酮杂合类衍生物。
背景技术
3,5-环磷酸腺苷(cAMP)和3,5-环磷酸鸟苷(cGMP)是普遍存在于细胞内信号通路的关键第二信使，参与体内多种生理活动的调节。磷酸二酯酶(PDEs)是一类通过代谢使第二信使(cAMP和cGMP)失活，从而调节第二信使在细胞内的水平，以达到调控不同的生理活动的酶。磷酸二酯酶Ⅱ(PDE2)被认为是一种双底物特异性酶，能同时水解cGMP和cAMP。PDE2在大脑中与认知过程相关的区域，如皮质、海马体和纹状体中的表达量最高。因此PDE2抑制剂可通过调节对认知功能和记忆至关重要的大脑区域的细胞内cAMP和/或cGMP水平来改善阿尔茨海默病等神经退行性疾病相关的认知功能障碍。
香豆素是由稠合的苯环和α-吡喃酮环组成的天然杂环化合物，具有多种生物活性，因其能抑制脑内MAO活性，降低多巴胺分解产生中枢神经系统保护作用，而受到广泛的研究。查尔酮是由三个碳的α,β-不饱和酮连接的两个芳香环组成的一类天然化合物，因其具有清除自由基、抗炎和神经保护特性而具有潜在的药用价值，因此引起了广泛的关注。但以香豆素和查尔酮为结构基础的衍生物靶向到PDE2小分子，用于治疗阿兹海默病等神经退行性疾病研究和开发仍显不足，这便阻碍了以香豆素和查尔酮为结构基础的药物的商品化进程。
发明内容
针对以香豆素和查尔酮为结构基础的衍生物靶向到PDE2小分子的研究不足，本发明的目的是拓展以香豆素和查尔酮为结构基础的杂合衍生物，提供新颖的PDE2的抑制剂小分子化合物。
为了实现本发明目的，本发明所采用的技术方案如下：
一种PDE2抑制剂香豆素-查尔酮杂合衍生物，通式如下化合物I：
其中，R为C2-C6烷基、环烷基取代的C1-C3烷基、杂环基取代的C2-C3烷基、芳香基取代的C1-C3烷基中的一种；其中“环烷基取代的C1-C3烷基”是指R为C1-C3烷基，但是C1-C3烷基末端被环烷基所取代。
所述化合物Ⅰ选自1a-1j、2a-2m所示的化合物：
一种PDE2抑制剂香豆素-查尔酮杂合衍生物的制备方法，步骤如下：
(1)Pechmann缩合：将原料4-乙酰氧基苯甲醛和丙烯酸甲酯、催化剂二聚醋酸铑加入到溶剂甲酸中，在100℃下，反应4-6h。通过TLC监测反应。反应结束后，反应完全后，用乙酸乙酯稀释反应液，并依次使用水、5％碳酸氢钠溶液、饱和食盐水洗涤有机层，合并有机层，经无水硫酸钠干燥并真空浓缩得粗品，经乙醇重结晶得6-醛基香豆素。
(2)磺化硅胶(SSA)的制备：在三口瓶中加入的200-300目硅胶，搭置以饱和Ca(OH)2溶液为吸收液的尾气吸收装置，将氯磺酸加入恒压漏斗中，在搅拌下逐滴加入氯磺酸，控制滴加时间为0.5-1h，滴加完成后超声20-30min，即得磺化硅胶(SSA)。
(3)Claisen-Schmidt缩合：将6-醛基香豆素、4-羟基苯乙酮和催化剂SSA，加入烧瓶，升温至75℃，搅拌反应1-2h。TLC监测反应，反应完全后。用DMSO将反应物完全溶解，抽滤除去磺化硅胶，将含有产物的DMSO溶液，滴加至水中，有大量沉淀析出，抽滤并用乙醇洗涤滤饼，干燥后经柱层析(石油醚:乙酸乙酯＝4:1)得产物(E)-6-(3-(4-羟基苯基)-3-氧代丙-1-烯-1-基)-2H-色烯-2-酮。
(4)Williamson醚合：将(E)-6-(3-(4-羟基苯基)-3-氧代丙-1-烯-1-基)-2H-色烯-2-酮和碘化钾加入溶剂DMF中，升温至60-80℃，滴加卤代物R-Br/Cl,搅拌反应4h后。TLC监测反应，反应完成后。将反应液倾入水中，有大量沉淀析出，抽滤所得沉淀干燥后经柱层析(石油醚:乙酸乙酯)得固体产物。
合成路线如下式所示：
其中，R为C2-C6烷基、环烷基取代的C1-C3烷基、杂环基取代的C2-C3烷基、芳香基取代的C1-C3烷基中的一种；X为Cl或Br；
其中，所述4-乙酰氧基苯甲醛、丙烯酸甲酯、二聚醋酸铑的摩尔比为1:1-1.5:0.025-0.05，氯磺酸和硅胶的摩尔比为1:2-2.5，6-醛基香豆素、4-羟基苯乙酮和催化剂SSA的摩尔比为1:1.1-1.2:1.5-2.0,(E)-6-(3-(4-羟基苯基)-3-氧代丙-1-烯-1-基)-2H-色烯-2-酮、碘化钾和卤代物R-Br/Cl的摩尔比为1:1.5-2.0:1.2-1.5；
本发明的有益效果：本发明提供了新颖的PDE2的抑制剂化合物，主要包括(E)-6-(3-(4-羟基苯基)-3-氧代丙-1-烯-1-基)-2H-色烯-2-酮衍生物23个化合物，均有良好的PDE2抑制活性。这些化合物具有治疗中枢神经系统疾病的潜力，如记忆缺陷、认知障碍、焦虑和抑郁症等，可作为活性成分制备抑制PDE2活性的药物。另外，针对所提供的化合物结构，给出了相应的合成方法，合成方法简单，收率较高。其中，Pechmann缩合反应是在微量的催化剂二聚醋酸铑的催化下进行，反应迅速，且产率较高，同时制备了固体酸催化剂酰磺化硅胶(SSA)，并使用固体酸在无溶剂的条件下完成了酸催化机理下的Claisen-Schmidt缩合反应，反应迅速，产率较高，后处理简单，且后处理过滤留下的固体酸催化剂仍可回收利用，大大降低了反应时间和实验成本。
附图说明
图1为磺化硅胶和硅胶的红外表征图。
具体实施方式
下面结合实施方式对本发明作进一步描述。以下实施方式仅用于更加清楚地说明本发明的技术方案，而不能以此来限制本发明的保护范围。
实施例1
化合物6-醛基香豆素制备：
将4-乙酰氧基苯甲醛(10mmol)和丙烯酸甲酯(10mmol)，加入到溶剂甲酸(10mL)中，并加入催化剂二聚醋酸铑(2.5mol％)，升温至100℃后，搅拌反应4h，TLC检测反应，反应完全后，用50mL的乙酸乙酯稀释反应液，并依次使用50mL的水，75mL的5％碳酸氢钠溶液，50mL饱和食盐水洗涤有机层，有机层经无水硫酸钠干燥并真空浓缩得浅黄色固体6-醛基香豆素，经乙醇重结晶后淡黄色固体(产率87％)。
6-醛基香豆素:淡黄色固体(产率87％),m.p.193.7-194.2℃。1H NMR(300MHz,DMSO-d6)δ10.04(s,1H),8.36-8.29(d,J＝2.01Hz,1H),8.27-8.17(dd,J＝0.65,9.72Hz,1H),8.17-8.08(dd,J＝2.02,8.57Hz,1H),7.65-7.56(d,J＝8.52Hz,1H),6.68-6.58(d,J＝9.62Hz,1H).13CNMR(75MHz,DMSO-d6)δ192.12,159.80,157.66,144.45,133.03,132.79,131.10,119.63,117.94,117.79.
实施例2
磺化硅胶(SSA)的制备：
在三口瓶中加入50g的200-300目硅胶，搭置以100mL饱和Ca(OH)2溶液为吸收液的尾气吸收装置，将25mL氯磺酸加入恒压漏斗中，在搅拌下逐滴加入氯磺酸，控制滴加时间为0.5h，滴加完成后超声30min，即得白色的磺化硅胶(SSA)，密封冷藏保存。红外谱图显示硅胶在3448cm-1处的羟基吸收峰，经磺化后明显减弱,并且在1186cm-1处出现了磺酸基的特征吸收峰，证明经氯磺酸磺化后，磺酸基取代了硅胶的羟基。
实施例3
化合物(E)-6-(3-(4-羟基苯基)-3-氧代丙-1-烯-1-基)-2H-色烯-2-酮的制备：
将6-醛基香豆素(10mmol)与4-羟基苯乙酮(10mmol)加入到烧瓶中，并加入催化剂SSA(1g)，升温至75℃搅拌反应1h，TLC监测反应，反应完全后，用50mL的DMSO将反应物完全溶解，抽滤除去磺化硅胶，将含有产物的DMSO溶液，滴加至50mL水中，有大量沉淀析出，抽滤并用乙醇洗涤滤饼，干燥后经柱层析(石油醚：乙酸乙酯＝4:1)得白色固体产物(E)-6-(3-(4-羟基苯基)-3-氧代丙-1-烯-1-基)-2H-色烯-2-酮。
(E)-6-(3-(4-羟基苯基)-3-氧代丙-1-烯-1-基)-2H-色烯-2-酮:白色固体(产率81％),m.p.298.1-298.8℃，1HNMR(300MHz,DMSO-d6)δ10.98(s,1H),8.25-8.18(d,J＝2.1Hz,1H),8.18-8.12(dd,J＝2.1,8.7Hz,1H),8.12-8.00(t,J＝9.6,9.6Hz,3H),8.00-7.90(d,J＝15.6Hz,1H),7.79-7.65(d,J＝15.6Hz,1H),7.53-7.42(d,J＝8.6Hz,1H),6.98-6.86(d,J＝8.5Hz,2H),6.62-6.50(d,J＝9.6Hz,1H).13C NMR(75MHz,DMSO-d6)δ187.43,162.79,160.18,154.97,144.46,141.57,132.37,131.86,131.70,129.49,129.34,123.07,119.53,117.48,117.36,115.91.
实施例4
将(E)-6-(3-(4-羟基苯基)-3-氧代丙-1-烯-1-基)-2H-色烯-2-酮(10mmol)和碘化钾(15mmol)加入烧瓶中,并加入溶剂DMF(15mL)，升温至75℃，溶解后滴加卤代物R-Br/Cl(12mmol),搅拌反应4h后，TLC监测反应，反应完成后，将反应液倾入水中(30mL),有大量沉淀析出，抽滤所得沉淀干燥后经柱层析(石油醚：乙酸乙酯)得固体产物1a-1j、2a-2m，其中卤代物R-Br/Cl的选择详细见表1。
1a:1H NMR(400MHz,CDCl3-d6)δ8.09-8.00(m,2H),7.87-7.77(m,2H),7.77-7.70(m,2H),7.60-7.52(d,J＝15.61Hz,1H),7.42-7.35(d,J＝8.62Hz,1H),7.02-6.94(m,2H),6.52-6.45(d,J＝9.58Hz,1H),4.18-4.09(m,2H),1.51-1.43(t,J＝7.00,7.00Hz,3H).13CNMR(100MHz,CDCl3-d6)δ188.23,163.23,160.26,155.14,143.14,141.76,131.85,131.10,130.99,130.73,128.21,122.68,119.29,117.79,117.60,114.50,77.34,63.96,14.80.
1b:1H NMR(400MHz,CDCl3-d6))δ8.15(m,2H),7.92-7.85(m,2H),7.81-7.73(m,2H),7.62-7.54(d,J＝15.7Hz,1H),7.42-7.35(d,J＝8.6Hz,1H),7.03-6.94(m,2H),6.5-6.5(d,J＝9.6Hz,1H),4.1-4.0(t,J＝6.5,6.5Hz,2H),1.9-1.8(m,,2H),1.13-1.06(t,J＝7.4,7.4Hz,3H).13C NMR(100MHz,CDCl3-d6)δ188.15,163.37,160.21,155.07,143.10,141.68,131.78,131.05,130.92,130.60,128.16,122.60,119.22,117.72,117.52,114.46,77.29,69.86,22.51,10.54.1c:1H NMR(400MHz,CDCl3-d6)δ8.08-8.00(m,2H),7.87-7.77(m,2H),7.77-7.70(m,2H),7.60-7.52(d,J＝15.63Hz,1H),7.41-7.35(d,J＝8.58Hz,1H),7.03-6.94(m,2H),6.52-6.45(d,J＝9.55Hz,1H),4.10-4.02(t,J＝6.50,6.50Hz,2H),1.87-1.75(m,2H),1.59-1.45(m,2H),1.04-0.96(t,J＝7.40,7.40Hz,3H).13C NMR(100MHz,CDCl3-d6)δ188.16,163.38,143.09,141.68,131.04,130.92,130.60,128.15,122.61,119.22,117.74,117.54,114.46,77.28,68.09,31.19,19.25,13.88.
1d:1H NMR(400MHz,CDCl3-d6)δ8.08-8.00(m,2H),7.87-7.77(m,2H),7.77-7.69(m,2H),7.60-7.52(d,J＝15.58Hz,1H),7.41-7.34(d,J＝8.62Hz,1H),7.02-6.94(m,2H),6.52-6.45(d,J＝9.53Hz,1H),4.09-4.01(t,J＝6.54,6.54Hz,2H),1.89-1.77(dt,J＝6.48,6.48,8.13Hz,2H),1.53-1.34(m,4H),0.99-0.91(t,J＝7.06,7.06Hz,3H).13C NMR(100MHz,CDCl3-d6)δ188.29,163.51,160.40,155.32,143.26,141.87,131.94,131.18,131.08,130.72,128.32,122.75,119.38,117.89,117.64,114.61,68.53,29.01,28.32,22.61,14.21.
1e:1H NMR(400MHz,CDCl3-d6)δ8.08-8.00(m,2H),7.87-7.77(m,2H),7.77-7.70(m,2H),7.60-7.52(d,J＝15.58Hz,1H),7.41-7.35(d,J＝8.61Hz,1H),7.01-6.93(m,2H),6.52-6.45(d,J＝9.60Hz,1H),4.74-4.63(m,1H),1.42-1.36(d,J＝6.04Hz,6H).13C NMR(100MHz,CDCl3-d6)δ188.12,162.26,160.21,143.09,141.64,131.80,131.04,130.97,130.40,128.14,122.63,119.22,117.73,117.53,115.36,77.28,70.26,21.98.
1f:1H NMR(400MHz,CDCl3-d6)δ8.08-8.00(m,2H),7.87-7.70(m,4H),7.60-7.52(d,J＝15.66Hz,1H),7.41-7.34(d,J＝8.62Hz,1H),7.01-6.93(m,2H),6.52-6.45(d,J＝9.53Hz,1H),4.50-4.38(m,1H),1.85-1.61(m,3H),1.38-1.32(d,J＝6.08Hz,3H),1.04-0.94(t,J＝7.46,7.46Hz,3H).13C NMR(100MHz,CDCl3-d6)δ188.12,162.62,160.22,143.10,141.64,131.81,131.04,130.98,130.37,128.14,122.64,119.22,117.73,117.53,115.38,77.28,75.34,29.14,19.19,9.78.
1g:1H NMR(400MHz,CDCl3-d6)δ8.18-8.10(dt,J＝2.42,2.42,9.03Hz,2H),7.98-7.79(m,4H),7.71-7.62(dd,J＝2.62,15.59Hz,1H),7.52-7.44(dd,J＝2.62,8.62Hz,1H),7.39-7.34(d,J＝2.59Hz,1H),7.12-7.04(dt,J＝2.44,2.44,9.05Hz,2H),6.62-6.54(dd,J＝2.67,9.44Hz,1H),4.22-4.14(dt,J＝4.32,4.32,8.88Hz,2H),2.01-1.92(m,,1H),1.86-1.77(m,2H),1.12-1.04(dd,J＝2.62,6.69Hz,6H).13C NMR(100MHz,CDCl3-d6)δ188.32,160.40,155.22,143.27,141.85,131.93,131.21,131.08,130.72,128.32,122.77,119.35,117.88,117.63,114.60,67.00,37.97,25.20,22.75.
1h:1H NMR(400MHz,CDCl3-d6)δ8.01-7.93(m,2H),7.80-7.70(m,2H),7.70-7.63(m,2H),7.53-7.45(d,J＝15.63Hz,1H),7.34-7.28(d,J＝8.64Hz,1H),6.96-6.88(m,2H),6.45-6.38(d,J＝9.53Hz,1H),3.86-3.80(d,J＝6.96Hz,2H),1.20-1.16(m,1H),0.66-0.58(m,2H),0.36-0.28(dt,J＝4.75,4.75,6.25Hz,2H).13C NMR(100MHz,CDCl3-d6)δ163.20,160.21,143.09,141.73,131.78,131.05,130.93,130.70,128.16,122.60,119.23,117.74,117.55,114.52,77.28,73.11,10.15,3.33.
1i:1H NMR(400MHz,CDCl3-d6)δ8.08-8.00(m,2H),7.88-7.78(m,2H),7.78-7.70(m,2H),7.61-7.52(d,J＝15.63Hz,1H),7.42-7.35(d,J＝8.57Hz,1H),7.03-6.95(m,2H),6.52-6.45(d,J＝9.59Hz,1H),3.96-3.89(d,J＝6.95Hz,2H),2.48-2.32(m,1H),1.93-1.81(m,2H),1.72-1.63(m,3H),1.62-1.56(m,1H),1.47-1.31(m,2H).13C NMR(100MHz,CDCl3-d6)δ188.17,163.53,155.08,143.10,141.69,131.81,131.06,130.92,128.16,122.63,119.23,117.75,117.55,114.50,77.29,72.56,39.02,29.52,25.49.
1j:1H NMR(300MHz,CDCl3-d6)δ8.02-7.93(d,J＝8.57Hz,2H),7.82-7.73(m,2H),7.73-7.62(m,3H),7.55-7.44(d,J＝15.56Hz,1H),7.36-7.30(s,1H),7.22-7.16(s,2H),6.96-6.87(d,J＝8.73Hz,2H),6.47-6.38(d,J＝9.58Hz,1H),3.81-3.73(d,J＝5.98Hz,2H),1.87-1.72(t,J＝14.66,14.66Hz,4H),1.35-1.09(m,5H),1.07-0.94(m,2H).13C NMR(100MHz,CDCl3-d6)δ188.23,155.14,143.16,141.74,131.86,131.11,130.98,130.60,128.22,122.69,119.29,117.80,117.60,114.54,77.35,73.86,37.73,29.95,26.57,25.88.
2a:，1H NMR(300MHz,CDCl3-d6)δ8.10-8.00(d,J＝8.90Hz,2H),7.89-7.70(m,4H),7.68-7.51(s,1H),7.43-7.34(d,J＝8.58Hz,1H),7.29-7.17(s,1H),7.07-6.89(d,J＝8.62Hz,2H),6.54-6.45(d,J＝9.61Hz,1H),4.39-4.25(m,1H),4.10-3.99(m,2H),3.99-3.91(t,J＝6.76,6.76Hz,1H),3.91-3.80(m,1H),2.23-2.08(m,1H),2.08-1.89(m,2H),1.88-1.70(m,1H).13C NMR(100MHz,CDCl3-d6)δ188.14,162.94,160.19,155.07,143.07,141.76,131.73,131.04,130.88,130.83,128.14,122.54,119.20,117.72,117.52,114.56,66.28,57.73,55.13,25.86,24.10.
2b:1H NMR(300MHz,CDCl3-d6)δ8.03-7.93(d,J＝8.51Hz,2H),7.82-7.62(m,4H),7.53-7.45(d,J＝15.61Hz,1H),7.36-7.27(d,J＝8.63Hz,1H),7.00-6.92(d,J＝8.56Hz,2H),6.47-6.38(d,J＝9.57Hz,1H),5.31-5.18(t,J＝3.97,3.97Hz,1H),4.09-4.04(d,J＝3.98Hz,2H),4.03-3.89(m,4H).13C NMR(100MHz,CDCl3)δ187.11,161.46,154.03,142.02,140.84,130.63,130.00,129.83,127.11,121.42,118.15,116.67,116.47,113.53,100.65,67.80,64.38.
2c:1H NMR(300MHz,CDCl3-d6)δ8.09-8.00(d,J＝8.54Hz,2H),7.89-7.70(m,4H),7.62-7.51(s,1H),7.43-7.34(d,J＝8.60Hz,1H),7.05-6.96(d,J＝8.53Hz,2H),6.54-6.45(d,J＝9.51Hz,1H),5.16-5.05(m,1H),4.28-4.12(m,2H),4.10-3.83(m,4H),2.27-2.14(m,2H).13C NMR(100MHz,CDCl3-d6)δ187.05,161.89,159.17,153.97,142.08,140.69,130.63,130.00,129.83,129.71,127.13,121.41,116.62,116.39,113.39,100.78,63.96,62.89,32.55.
2d:1H NMR(300MHz,CDCl3-d6)δ8.01-7.92(d,J＝8.58Hz,2H),7.82-7.73(m,1H),7.73-7.68(d,J＝2.71Hz,1H),7.68-7.62(m,2H),7.55-7.44(d,J＝15.58Hz,1H),7.36-7.27(s,1H),7.00-6.91(d,J＝8.50Hz,2H),6.47-6.37(d,J＝9.54Hz,1H),4.06-3.95(dd,J＝6.44,9.93Hz,2H),3.95-3.87(dd,J＝3.83,9.98Hz,1H),3.76-3.62(q,J＝4.07,6.98,6.98Hz,1H),3.52-3.37(m,1H),1.92-1.82(m,1H),1.66-1.57(d,J＝12.04Hz,2H),1.49-1.33(m,2H),1.21-1.15(s,1H).13C NMR(100MHz,CDCl3-d6)δ188.15,163.03,155.04,143.12,141.74,131.71,131.07,130.84,128.16,122.51,119.19,117.70,117.48,114.59,75.78,71.68,68.66,28.16,25.84,23.05.
2e:1H NMR(400MHz,CDCl3-d6)δ8.02-7.94(m,2H),7.81-7.71(m,2H),7.71-7.63(m,2H),7.53-7.45(d,J＝15.62Hz,1H),7.35-7.29(d,J＝8.65Hz,1H),6.96-6.88(m,2H),6.46-6.41(s,1H),4.01-3.93(m,2H),3.86-3.80(d,J＝6.41Hz,2H),3.45-3.34(m,2H),2.19-1.92(m,1H),1.76-1.65(m,2H),1.54-1.49(s,3H),1.49-1.36(m,2H),1.21-1.16(s,1H).13C NMR(100MHz,CDCl3-d6)δ188.12,163.15,160.18,155.08,143.05,141.79,131.72,131.01,130.92,128.17,122.52,119.21,117.73,117.54,114.41,72.80,67.61,35.10,29.68.
2f:1H NMR(400MHz,CDCl3-d6)δ8.09-8.01(m,2H),7.88-7.78(m,2H),7.78-7.70(m,2H),7.60-7.52(d,J＝15.62Hz,1H),7.42-7.35(d,J＝8.61Hz,1H),7.04-6.96(m,2H),6.52-6.46(d,J＝9.58Hz,1H),4.17-4.09(t,J＝6.29,6.29Hz,2H),3.78-3.71(t,J＝4.68,4.68Hz,4H),2.60-2.54(t,J＝7.25,7.25Hz,2H),2.54-2.43(d,J＝4.76Hz,4H),2.07-2.00(m,2H).13C NMR(100MHz,CDCl3-d6)δ188.11,163.13,160.17,155.07,143.06,141.76,131.01,130.90,130.75,128.17,122.51,119.21,117.72,117.52,114.44,66.91,66.40,55.41,53.74,26.24.
2g:1H NMR(400MHz,CDCl3-d6)δ8.08-8.00(m,2H),7.88-7.78(m,2H),7.78-7.70(m,2H),7.60-7.52(d,J＝15.64Hz,1H),7.42-7.35(d,J＝8.59Hz,1H),7.04-6.96(m,2H),6.52-6.46(d,J＝9.53Hz,1H),4.84-4.74(t,J＝5.16,5.16Hz,1H),4.21-4.08(m,4H),3.86-3.75(m,2H),2.19-2.04(m,3H),1.42-1.34(m,1H).13C NMR(100MHz,CDCl3-d6)δ188.15,163.08,160.19,155.06,143.07,141.73,131.74,131.04,130.88,130.74,128.14,122.56,119.20,117.72,117.51,114.49,99.32,66.98,63.68,34.93,25.80.
2h:1H NMR(400MHz,CDCl3-d6)δ8.27-8.22(d,J＝2.14Hz,1H),8.22-8.15(m,3H),8.09-7.97(m,2H),7.80-7.71(d,J＝15.56Hz,1H),7.53-7.46(d,J＝8.58Hz,1H),7.18-7.11(dd,J＝2.22,9.08Hz,2H),6.61-6.54(d,J＝9.58Hz,1H),4.53-4.41(dd,J＝2.58,11.44Hz,1H),4.01-3.92(dd,J＝6.63,11.42Hz,1H),3.41-3.37(dd,J＝2.97,5.64Hz,1H),2.92-2.85(t,J＝4.66,4.66Hz,1H),2.79-2.72(dd,J＝2.64,5.13Hz,1H).13C NMR(100MHz,CDCl3-d6)δ187.14,162.28,159.66,154.59,143.95,141.59,131.99,131.30,130.97,130.61,129.04,122.45,119.06,117.02,116.93,114.58,69.32,49.53,43.76.
2i:1H NMR(400MHz,CDCl3-d6)δ8.09-8.00(m,2H),7.88-7.68(m,4H),7.62-7.52(m,1H),7.42-7.31(d,J＝8.66Hz,1H),7.12-6.98(m,2H),6.53-6.46(d,J＝9.59Hz,1H),4.91-4.84(d,J＝5.15Hz,1H),4.16-4.04(d,J＝5.19Hz,2H),3.85-3.73(m,2H),3.71-3.61(m,2H),1.29-1.24(t,J＝7.04,7.04Hz,6H).13C NMR(100MHz,CDCl3-d6)δ188.15,162.68,160.18,155.08,143.06,141.83,131.71,131.09,131.05,130.86,130.51,128.15,122.52,119.21,117.72,117.53,114.62,114.41,100.39,68.72,62.97,62.92,15.37,15.33.
2j:1H NMR(400MHz,CDCl3-d6)δ8.73-8.66(d,J＝4.84Hz,2H),8.30-8.24(m,3H),8.24-8.18(dd,J＝2.10,8.69Hz,1H),8.10-8.00(m,2H),7.86-7.78(d,J＝15.57Hz,1H),7.55-7.48(d,J＝8.65Hz,1H),7.46-7.39(m,2H),7.38-7.31(t,J＝4.81,4.81Hz,1H),6.62-6.55(d,J＝9.57Hz,1H).
2k:1H NMR(400MHz,CDCl3-d6)δ8.08-8.01(m,2H),7.88-7.78(m,2H),7.78-7.70(m,2H),7.60-7.52(d,J＝15.62Hz,1H),7.42-7.35(d,J＝8.63Hz,1H),7.04-6.97(m,2H),6.52-6.46(d,J＝9.56Hz,1H),4.25-4.18(t,J＝5.99,5.99Hz,2H),2.87-2.77(t,J＝5.98,5.98Hz,2H),2.62-2.48(d,J＝6.76Hz,4H),1.68-1.60(t,J＝5.73,5.73Hz,4H),1.52-1.43(m,2H).13CNMR(100MHz,CDCl3-d6)δ188.14,162.94,160.19,155.07,143.07,141.76,131.73,131.04,130.88,130.83,128.14,122.54,119.20,117.72,117.52,114.56,66.28,57.73,55.13,25.86,24.10.2l:1H NMR(400MHz,CDCl3-d6)δ8.11-8.03(m,2H),7.88-7.78(m,2H),7.78-7.70(m,2H),7.62-7.53(d,J＝15.62Hz,1H),7.47-7.42(d,J＝1.87Hz,1H),7.42-7.35(d,J＝8.66Hz,1H),7.32-7.27(d,J＝1.80Hz,2H),7.15-7.07(m,2H),6.52-6.46(d,J＝9.57Hz,1H),5.15-5.10(s,2H),1.37-1.31(s,18H).13C NMR(100MHz,CDCl3-d6)δ188.18,163.14,160.19,155.08,151.32,143.07,141.76,135.03,131.75,131.05,130.91,130.89,128.15,122.60,122.57,122.24,119.21,117.73,117.53,114.83,71.16,34.94,31.49.
2m:1H NMR(400MHz,CDCl3-d6)δ10.52-10.47(s,1H),8.25-8.20(d,J＝2.10Hz,1H),8.20-8.13(dd,J＝2.09,8.69Hz,1H),8.13-8.06(m,3H),8.06-8.02(s,1H),8.01-7.93(d,J＝15.61Hz,1H),7.77-7.68(d,J＝15.55Hz,1H),7.52-7.46(d,J＝8.62Hz,1H),6.96-6.88(m,2H),6.61-6.54(d,J＝9.58Hz,1H).13C NMR(100MHz,CDCl3-d6)δ186.91,162.32,159.67,154.50,143.96,141.07,131.91,131.38,131.22,129.01,128.87,122.60,119.05,116.99,116.90,115.42.表1(E)-6-(3-(4-羟基苯基)-3-氧代丙-1-烯-1-基)-2H-色烯-2-酮衍生物
效果例
对实施例4得到的1a-1j、2a-2m产品进行PDE2酶抑制活性研究
将重组质粒pET15b-PDE2A转化到大肠杆菌中表达，通过培养，镍柱亲和层析纯化得到PDE2蛋白。使用AlphaScreen试剂盒测量化合物对PDE2的抑制作用，当PDE2存在时，会水解Biotinylated cAMP使受体微珠与供体微珠难以拉近，而导致信号值降低，若体系中存在PDE2抑制剂时，就会通过抑制PDE2使Biotinylated cAMP无法被水解，最终表现为信号值水平升高。
取化合物稀释液2μL与PDE2蛋白稀释液4μL，将其恒温(25℃)反应0.5h，后加入Biotinylated cAMP 4μL离心(1000r/min)1分钟，再次于恒温(25℃)反应1h，后加入Acceptor和Donor Bead混悬液15μL，离心(1000r/min)1分钟，于避光的条件下恒温(25℃)反应1h，最后用多功能酶标仪读取数值。实验需配置阳性对照(未加化合物和PDE2蛋白)和阴性对照(未加化合物)，未加的部分均用1×Reaction buffer等量补充，该实验在384白孔板中进行，每组设置平行孔3个。
对所合成的化合物进一步测定IC50值，用1×Reaction buffer将潜力化合物稀释7个终浓度分为是200μM、100μM、50μM、25μM、12.5μM、6.25μM、3.125μM，具体实验步骤参照上述BAY60-7550的IC50测定方法。
表2(E)-6-(3-(4-羟基苯基)-3-氧代丙-1-烯-1-基)-2H-色烯-2-酮衍生物的IC50值
本发明提供了(E)-6-(3-(4-羟基苯基)-3-氧代丙-1-烯-1-基)-2H-色烯-2-酮类23个化合物，均有良好的PDE2抑制活性，具有治疗中枢神经系统疾病的潜力，如记忆缺陷、认知障碍、焦虑和抑郁症等，可作为活性成分制备抑制PDE2活性的药物。其中1b，1i，2a，2e，2f，2g，2h，2i，2m对PDE2蛋白的IC50小于50μM，其中1b，2a，2i，2m的活性较好，2a的IC50最优，为16.82μM。

Claims (2)

1.一类作为磷酸二酯酶2抑制剂的香豆素-查尔酮杂合类衍生物，其特征在于：所述香豆素-查尔酮杂合类衍生物的结构式为：
、、、、、。
2.根据权利要求1所述的香豆素-查尔酮杂合类衍生物在制备PDE2抑制剂药物中的应用。
CN202310823447.8A 2023-07-06 2023-07-06 作为磷酸二酯酶2抑制剂的香豆素-查尔酮杂合类衍生物及其应用 Active CN116903569B (zh)

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CN103459395A (zh) * 2011-01-31 2013-12-18 勃林格殷格翰国际有限公司 作为磷酸二酯酶抑制剂的(1,2,4)三唑并[4,3-a]喹喔啉衍生物
CN113336735A (zh) * 2021-06-08 2021-09-03 常州大学 一种尿石素类化合物、制备方法、药物组合物及用途

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US8815940B2 (en) * 2010-08-05 2014-08-26 Council Of Scientific & Industrial Research Coumarin-chalcones as anticancer agents
CN113387916A (zh) * 2021-07-15 2021-09-14 常州大学 一种尿石素类pde2抑制剂化合物及其制备方法

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CN103459395A (zh) * 2011-01-31 2013-12-18 勃林格殷格翰国际有限公司 作为磷酸二酯酶抑制剂的(1,2,4)三唑并[4,3-a]喹喔啉衍生物
CN113336735A (zh) * 2021-06-08 2021-09-03 常州大学 一种尿石素类化合物、制备方法、药物组合物及用途

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