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CN116903569B - Coumarin-chalcone hybrid derivatives as phosphodiesterase 2 inhibitors and application thereof - Google Patents

Coumarin-chalcone hybrid derivatives as phosphodiesterase 2 inhibitors and application thereof 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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chalcone
pde2
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CN116903569A (en
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宋国强
范家如
冯筱晴
唐龙
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Changzhou University
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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。The present invention belongs to the field of medicinal chemistry, and in particular to coumarin-chalcone hybrid derivatives and applications as phosphodiesterase 2 inhibitors. The present invention expands hybrid derivatives based on coumarin and chalcone, provides novel PDE2 inhibitor small molecule compounds, and the obtained compounds have good PDE2 inhibitory activity. These compounds have the potential to treat central nervous system diseases, such as memory deficits, cognitive impairment, anxiety and depression, etc., and can be used as active ingredients to prepare drugs that inhibit PDE2 activity. And it is easy to prepare, reacts quickly, has a high yield, is simple to post-process, and the solid acid catalyst left by post-processing filtration can still be recycled, greatly reducing reaction time and experimental costs.

Description

Coumarin-chalcone hybrid derivatives as phosphodiesterase 2 inhibitors and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to coumarin-chalcone hybrid derivatives serving as inhibitors of phosphodiesterase 2 (PDE 2).
Background
Adenosine 3, 5-cyclic phosphate (cAMP) and guanosine 3, 5-cyclic phosphate (cGMP) are key secondary signalling pathways that are ubiquitous in cells, involved in the regulation of various physiological activities in the body. Phosphodiesterases (PDEs) are a class of enzymes that metabolize and inactivate second messengers (cAMP and cGMP) and thereby regulate the level of second messengers in cells to regulate diverse physiological activities. Phosphodiesterase II (PDE 2) is considered a dual substrate specific enzyme capable of hydrolyzing cGMP and cAMP simultaneously. PDE2 is expressed most in areas of the brain associated with cognitive processes, such as the cortex, hippocampus and striatum. PDE2 inhibitors can therefore ameliorate cognitive dysfunction associated with neurodegenerative diseases such as alzheimer's disease by modulating intracellular cAMP and/or cGMP levels in brain regions critical to cognitive function and memory.
Coumarin is a natural heterocyclic compound consisting of a fused benzene ring and an alpha-pyrone ring, has various biological activities, and is widely studied because of its ability to inhibit MAO activity in the brain and reduce dopamine decomposition to produce central nervous system protection. Chalcones are a class of natural compounds consisting of two aromatic rings linked by a three-carbon α, β -unsaturated ketone, and have great interest because of their potent medicinal value in scavenging free radicals, anti-inflammatory and neuroprotective properties. However, the derivatives based on coumarin and chalcone are targeted to PDE2 small molecules, and are still insufficient in research and development for treating neurodegenerative diseases such as Alzheimer's disease, which hinders the commercialization process of drugs based on coumarin and chalcone.
Disclosure of Invention
Aiming at the defect of research on targeting of derivatives based on coumarin and chalcone to PDE2 small molecules, the invention aims to expand hybrid derivatives based on coumarin and chalcone and provide novel PDE2 inhibitor small molecule compounds.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
a PDE2 inhibitor coumarin-chalcone hybrid derivative, of the general formula:
Wherein R is one of C 2-C6 alkyl, cycloalkyl substituted C 1-C3 alkyl, heterocyclyl substituted C 2-C3 alkyl, aryl substituted C 1-C3 alkyl, wherein "cycloalkyl substituted C 1-C3 alkyl" means that R is C 1-C3 alkyl, but the C 1-C3 alkyl end is substituted with cycloalkyl.
The compound I is selected from compounds shown as 1a-1j and 2a-2 m:
a preparation method of PDE2 inhibitor coumarin-chalcone hybrid derivatives comprises the following steps:
(1) Pechmann condensation, namely adding raw material 4-acetoxybenzaldehyde, methyl acrylate and catalyst dimerization rhodium acetate into solvent formic acid, and reacting for 4-6h at 100 ℃. The reaction was monitored by TLC. After the reaction is completed, diluting the reaction solution with ethyl acetate, washing the organic layer by using water, 5% sodium bicarbonate solution and saturated saline water in sequence, combining the organic layers, drying the organic layers by using anhydrous sodium sulfate, concentrating the organic layers in vacuum to obtain a crude product, and recrystallizing the crude product by using ethanol to obtain the 6-aldehyde coumarin.
(2) The preparation of sulfonated silica gel (SSA) comprises adding 200-300 mesh silica gel into a three-mouth bottle, placing a tail gas absorption device with saturated Ca (OH) 2 solution as absorption liquid, adding chlorosulfonic acid into a constant pressure funnel, dropwise adding chlorosulfonic acid under stirring, controlling the dropwise adding time to be 0.5-1h, and performing ultrasonic treatment for 20-30min after the dropwise adding is completed to obtain the sulfonated silica gel (SSA).
(3) Claisen-Schmidt condensation, namely adding 6-aldehyde coumarin, 4-hydroxyacetophenone and a catalyst SSA into a flask, heating to 75 ℃, and stirring and reacting for 1-2h. TLC monitored the reaction and after completion of the reaction. The reaction was completely dissolved in DMSO, sulfonated silica gel was removed by suction filtration, DMSO solution containing the product was added dropwise to water with a large amount of precipitate separated out, suction filtration and washing of the filter cake with ethanol, and column chromatography (petroleum ether: ethyl acetate=4:1) after drying gave the product (E) -6- (3- (4-hydroxyphenyl) -3-oxoprop-1-en-1-yl) -2H-chromen-2-one.
(4) Williamson ether is carried out by adding (E) -6- (3- (4-hydroxy phenyl) -3-oxo-prop-1-ene-1-yl) -2H-chromen-2-one and potassium iodide into solvent DMF, heating to 60-80 ℃, dropping halogenated compound R-Br/Cl, stirring and reacting for 4H. TLC monitored the reaction and after completion of the reaction. Pouring the reaction solution into water, precipitating a large amount of precipitate, filtering the precipitate, drying the precipitate, and performing column chromatography (petroleum ether: ethyl acetate) to obtain a solid product.
The synthetic route is shown in the following formula:
wherein R is one of C 2-C6 alkyl, cycloalkyl substituted C 1-C3 alkyl, heterocyclyl substituted C 2-C3 alkyl and aryl substituted C 1-C3 alkyl, X is Cl or Br;
Wherein, the mol ratio of the 4-acetoxybenzaldehyde to the methyl acrylate to the rhodium diacetate is 1:1-1.5:0.025-0.05, the mol ratio of the chlorosulfonic acid to the silica gel is 1:2-2.5, the mol ratio of the 6-aldehyde coumarin, the 4-hydroxyacetophenone and the catalyst SSA is 1:1.1-1.2:1.5-2.0, and the mol ratio of the (E) -6- (3- (4-hydroxyphenyl) -3-oxo-1-en-1-yl) -2H-chromen-2-one, the mol ratio of the potassium iodide to the halogenated R-Br/Cl is 1:1.5-2.0:1.2-1.5;
The invention has the beneficial effects that the invention provides novel PDE2 inhibitor compounds, which mainly comprise 23 compounds of (E) -6- (3- (4-hydroxyphenyl) -3-oxo-prop-1-en-1-yl) -2H-chromen-2-one derivatives, and all have good PDE2 inhibition activity. The compounds have the potential to treat central nervous system diseases, such as memory deficiency, cognitive dysfunction, anxiety, depression and the like, and can be used as active ingredients for preparing medicines for inhibiting PDE2 activity. In addition, a corresponding synthetic method is provided for the structure of the provided compound, the synthetic method is simple, and the yield is high. The Pechmann condensation reaction is carried out under the catalysis of a trace amount of catalyst rhodium diacetate, the reaction is rapid, the yield is higher, meanwhile, solid acid catalyst acyl sulfonated silica gel (SSA) is prepared, the Claisen-Schmidt condensation reaction under an acid catalysis mechanism is completed by using solid acid under the condition of no solvent, the reaction is rapid, the yield is higher, the post-treatment is simple, and the solid acid catalyst remained by the post-treatment filtration can be recycled, so that the reaction time and the experiment cost are greatly reduced.
Drawings
FIG. 1 is a graph of infrared characterization of sulfonated silica gel and silica gel.
Detailed Description
The invention is further described below in connection with embodiments. The following embodiments are only for more clearly illustrating the technical aspects of the present invention, and should not be used to limit the scope of the present invention.
Example 1
Preparation of compound 6-aldehyde coumarin:
4-Acetoxybenzaldehyde (10 mmol) and methyl acrylate (10 mmol) were added to solvent formic acid (10 mL), and rhodium acetate (2.5 mol%) was added as a catalyst, after heating to 100℃and stirring for 4h, TLC detection was performed, after completion of the reaction, the reaction solution was diluted with 50mL of ethyl acetate and, in turn, 50mL of water, 75mL of a 5% sodium bicarbonate solution were used, 50mL of saturated saline water was used to wash the organic layer, and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give 6-aldehyde coumarin as a pale yellow solid, which was recrystallized from ethanol (yield 87%).
6-Aldehyde coumarin pale yellow solid (yield 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.
Example 2
Preparation of sulfonated silica gel (SSA):
Adding 50g of 200-300 mesh silica gel into a three-mouth bottle, placing a tail gas absorption device which takes 100mL of saturated Ca (OH) 2 solution as absorption liquid, adding 25mL of chlorosulfonic acid into a constant pressure funnel, dropwise adding chlorosulfonic acid under stirring, controlling the dropwise adding time to be 0.5h, and performing ultrasonic treatment for 30min after the dropwise adding is finished to obtain white sulfonated silica gel (SSA), and sealing, refrigerating and preserving. The infrared spectrogram shows that the absorption peak of hydroxyl at 3448cm -1 of the silica gel is obviously weakened after sulfonation, and the characteristic absorption peak of sulfonic acid group at 1186cm -1 appears, which proves that the sulfonic acid group replaces the hydroxyl of the silica gel after chlorosulfonic acid sulfonation.
Example 3
Preparation of compound (E) -6- (3- (4-hydroxyphenyl) -3-oxoprop-1-en-1-yl) -2H-chromen-2-one:
6-aldehyde coumarin (10 mmol) and 4-hydroxyacetophenone (10 mmol) are added into a flask, a catalyst SSA (1 g) is added, the temperature is raised to 75 ℃ and the mixture is stirred for reaction for 1H, TLC monitors the reaction, 50mL of DMSO is used for completely dissolving reactants after the reaction is completed, sulfonated silica gel is removed by suction filtration, a DMSO solution containing the product is dripped into 50mL of water, a large amount of precipitate is separated out, suction filtration and ethanol are used for washing a filter cake, and a white solid product (E) -6- (3- (4-hydroxyphenyl) -3-oxo-prop-1-en-1-yl) -2H-chromen-2-one is obtained after drying and column chromatography (petroleum ether: ethyl acetate=4:1).
(E) -6- (3- (4-hydroxyphenyl) -3-oxoprop-1-en-1-yl) -2H-chromen-2-one as a white solid (yield) 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.
Example 4
(E) -6- (3- (4-hydroxyphenyl) -3-oxo-prop-1-enyl-1-yl) -2H-chromen-2-one (10 mmol) and potassium iodide (15 mmol) were added to a flask, solvent DMF (15 mL) was added, the temperature was raised to 75 ℃, halogenide R-Br/Cl (12 mmol) was added dropwise after dissolution, after stirring for 4H, TLC monitored the reaction, after completion of the reaction, the reaction solution was poured into water (30 mL) with a large amount of precipitate precipitated out, the precipitate obtained by suction filtration was dried and then column chromatography (petroleum ether: ethyl acetate) was used to obtain solid products 1a-1j, 2a-2m, wherein the choice of halogenide R-Br/Cl was detailed in Table 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).13C NMR(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. TABLE 1 (E) -6- (3- (4-hydroxyphenyl) -3-oxoprop-1-en-1-yl) -2H-chromen-2-one derivatives
Effect example
PDE2 enzyme inhibition Activity Studies were performed on the 1a-1j, 2a-2m products obtained in example 4
The recombinant plasmid pET15b-PDE2A is transformed into escherichia coli to be expressed, and PDE2 protein is obtained through culture and nickel column affinity chromatography purification. Inhibition of PDE2 by compounds measured using the AlphaScreen kit hydrolyzes Biotinylated cAMP in the presence of PDE2, rendering the acceptor microbead and donor microbead difficult to pull up, resulting in a decrease in signal value, and inhibits PDE2 in the presence of PDE2 inhibitor in the system, rendering Biotinylated cAMP non-hydrolyzable, ultimately exhibiting an increase in signal value.
Taking 2 mu L of compound diluent and 4 mu L of PDE2 protein diluent, reacting for 0.5h at constant temperature (25 ℃), adding Biotinylated cAMP mu L of the compound diluent, centrifuging (1000 r/min) for 1 min, reacting for 1h at constant temperature (25 ℃) again, adding Acceptor and 15 mu L of Donor Bead suspension, centrifuging (1000 r/min) for 1 min, reacting for 1h at constant temperature (25 ℃) in the dark, and finally reading the value by using a multifunctional enzyme-labeled instrument. The experiments were performed in 384 white plates with 3 parallel wells, with positive control (no compound and PDE2 protein added) and negative control (no compound added) and 1 x Reaction buffer in equal amounts in each group.
The IC50 values were further determined for the synthesized compounds and the potential compounds were diluted with 1 Xreaction buffer to 7 final concentrations of 200. Mu.M, 100. Mu.M, 50. Mu.M, 25. Mu.M, 12.5. Mu.M, 6.25. Mu.M, 3.125. Mu.M, for specific experimental procedures, reference was made to the IC 50 assay method for BAY60-7550 described above.
TABLE 2 IC 50 values for (E) -6- (3- (4-hydroxyphenyl) -3-oxoprop-1-en-1-yl) -2H-chromen-2-one derivatives
The invention provides 23 compounds of (E) -6- (3- (4-hydroxyphenyl) -3-oxo-prop-1-ene-1-yl) -2H-chromen-2-one, which have good PDE2 inhibition activity, have the potential of treating central nervous system diseases, such as memory deficiency, cognitive dysfunction, anxiety, depression and the like, and can be used as active ingredients for preparing medicines for inhibiting PDE2 activity. Wherein 1b,1i,2a,2e,2f,2g,2h,2i,2M pair PDE the IC50 of the 2 protein is less than 50 mu M, of these, 1b,2a,2i,2M are more active, and the IC50 of 2a is optimal at 16.82. Mu.M.

Claims (2)

1. The coumarin-chalcone hybrid derivatives serving as phosphodiesterase 2 inhibitors are characterized by having the structural formula:
、、、、、。
2. use of a coumarin-chalcone hybrid derivative according to claim 1 in the preparation of a PDE2 inhibitor drug.
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CN103459395A (en) * 2011-01-31 2013-12-18 勃林格殷格翰国际有限公司 (1,2,4)triazolo[4,3-a]quinoxaline derivatives as inhibitors of phosphodiesterases
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