Coumarin-chalcone hybrid derivatives as phosphodiesterase 2 inhibitors and their applications

Abstract

The present invention belongs to the field of medicinal chemistry, and specifically relates to coumarin-chalcone hybrid derivatives as phosphodiesterase 2 inhibitors and their applications. The present invention expands hybrid derivatives based on the structures of coumarin and chalcone, provides novel small molecule compounds that are inhibitors of PDE2, and the obtained compounds have good PDE2 inhibitory activity. These compounds have the potential to treat central nervous system diseases such as memory defects, cognitive impairments, anxiety, and depression, and can be used as active ingredients to prepare drugs that inhibit the activity of PDE2. Moreover, the preparation is easy, the reaction is rapid, the yield is high, the post-treatment is simple, and the solid acid catalyst left after post-treatment filtration can still be recycled, greatly reducing the reaction time and experimental cost.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to coumarin-chalcone hybrid derivatives as inhibitors of phosphodiesterase 2 (PDE2). Background Art

[0002] 3,5-cyclic adenosine monophosphate (cAMP) and 3,5-cyclic guanosine monophosphate (cGMP) are key second messengers ubiquitously present in intracellular signaling pathways and are involved in the regulation of various physiological activities in the body. Phosphodiesterases (PDEs) are a class of enzymes that inactivate second messengers (cAMP and cGMP) through metabolism, thereby regulating the levels of second messengers in cells to achieve the regulation of different physiological activities. Phosphodiesterase II (PDE2) is considered a dual-substrate specific enzyme that can hydrolyze both cGMP and cAMP simultaneously. PDE2 is most highly expressed in regions of the brain related to cognitive processes, such as the cortex, hippocampus, and striatum. Therefore, PDE2 inhibitors can improve cognitive dysfunction associated with neurodegenerative diseases such as Alzheimer's disease by regulating the intracellular cAMP and / or cGMP levels in brain regions crucial for cognitive function and memory.

[0003] Coumarin is a natural heterocyclic compound composed of a fused benzene ring and an α-pyrone ring, and has various biological activities. It has been widely studied because it can inhibit the activity of MAO in the brain and reduce the decomposition of dopamine to produce a central nervous system protective effect. Chalcone is a class of natural compounds composed of two aromatic rings connected by a three-carbon α,β-unsaturated ketone, and has potential medicinal value due to its free radical scavenging, anti-inflammatory, and neuroprotective properties, thus attracting extensive attention. However, the research and development of derivatives based on coumarin and chalcone targeting PDE2 small molecules for the treatment of neurodegenerative diseases such as Alzheimer's disease are still insufficient, which has hindered the commercialization process of drugs based on coumarin and chalcone. Summary of the Invention

[0004] Aiming at the insufficient research on derivatives based on coumarin and chalcone targeting PDE2 small molecules, the purpose of the present invention is to expand coumarin-chalcone hybrid derivatives and provide novel small molecule compounds that are inhibitors of PDE2.

[0005] In order to achieve the purpose of the present invention, the technical solutions adopted by the present invention are as follows:

[0006] A PDE2 inhibitor coumarin-chalcone hybrid derivative, with the general formula as compound I below:

[0007]

[0008] Among them, R is one of C2-C6 alkyl, cycloalkyl-substituted C1-C3 alkyl, heterocyclic-substituted C2-C3 alkyl, and aryl-substituted C1-C3 alkyl; the "cycloalkyl-substituted C1-C3 alkyl" means that R is C1-C3 alkyl, but the end of the C1-C3 alkyl is substituted by a cycloalkyl group.

[0009] The compound I is selected from the compounds shown in 1a-1j and 2a-2m:

[0010]

[0011] A preparation method of a PDE2 inhibitor coumarin-chalcone hybrid derivative, the steps are as follows:

[0012] (1) Pechmann condensation: Add the raw materials 4-acetoxybenzaldehyde, methyl acrylate, and the catalyst dirhodium diacetate to the solvent formic acid, and react at 100 °C for 4-6 h. Monitor the reaction by TLC. After the reaction is completed, after the reaction is complete, dilute the reaction solution with ethyl acetate, and wash the organic layer with water, 5% sodium bicarbonate solution, and saturated brine in sequence. Combine the organic layers, dry over anhydrous sodium sulfate and concentrate in vacuo to obtain a crude product, and recrystallize with ethanol to obtain 6-formylcoumarin.

[0013] (2) Preparation of sulfonated silica gel (SSA): Add 200-300 mesh silica gel to a three-necked flask, set up a tail gas absorption device with saturated Ca(OH)2 solution as the absorption liquid, add chlorosulfonic acid to a constant pressure funnel, and add chlorosulfonic acid dropwise with stirring, controlling the dropping time to be 0.5-1 h. After the dropping is completed, ultrasonicate for 20-30 min to obtain sulfonated silica gel (SSA).

[0014] (3) Claisen-Schmidt condensation: Add 6-formylcoumarin, 4-hydroxyacetophenone, and the catalyst SSA to a flask, heat up to 75 °C, and stir and react for 1-2 h. Monitor the reaction by TLC. After the reaction is complete. Dissolve the reactants completely with DMSO, filter off the sulfonated silica gel, drop the DMSO solution containing the product into water, a large amount of precipitate will precipitate, filter by suction and wash the filter cake with ethanol, and dry and then subject to column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain the product (E)-6-(3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one.

[0015] (4) Williamson ether synthesis: (E)-6-(3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one and potassium iodide were added to the solvent DMF, and the temperature was raised to 60 - 80 °C. Halide R-Br / Cl was added dropwise, and after stirring for 4 h, the reaction was monitored by TLC. After the reaction was completed, the reaction solution was poured into water, and a large amount of precipitate was precipitated. The obtained precipitate was dried by suction filtration and then purified by column chromatography (petroleum ether: ethyl acetate) to obtain a solid product.

[0016] The synthetic route is shown as follows:

[0017]

[0018] Among them, R is one of C2-C6 alkyl, C1-C3 alkyl substituted by cycloalkyl, C2-C3 alkyl substituted by heterocyclic group, and C1-C3 alkyl substituted by aromatic group; X is Cl or Br;

[0019] Among them, the molar ratio of 4-acetoxybenzaldehyde, methyl acrylate, and rhodium(II) acetate dimer is 1:1 - 1.5:0.025 - 0.05, the molar ratio of chlorosulfonic acid and silica gel is 1:2 - 2.5, the molar ratio of 6-formylcoumarin, 4-hydroxyacetophenone, and catalyst SSA is 1:1.1 - 1.2:1.5 - 2.0, and the molar ratio of (E)-6-(3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one, potassium iodide, and halide R-Br / Cl is 1:1.5 - 2.0:1.2 - 1.5;

[0020] Advantages of the present invention: The present invention provides novel PDE2 inhibitor compounds, mainly including 23 (E)-6-(3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one derivatives, all of which have good PDE2 inhibitory activity. These compounds have the potential to treat central nervous system diseases such as memory defects, cognitive impairment, anxiety, and depression, and can be used as active ingredients to prepare drugs that inhibit PDE2 activity. In addition, for the provided compound structures, corresponding synthetic methods are given. The synthetic methods are simple and have high yields. Among them, the Pechmann condensation reaction is carried out under the catalysis of a trace amount of catalyst rhodium(II) acetate dimer, the reaction is rapid and the yield is high. At the same time, the solid acid catalyst acylsulfonated silica gel (SSA) is prepared, and the Claisen-Schmidt condensation reaction under the acid catalysis mechanism is completed using the solid acid under solvent-free conditions. The reaction is rapid, the yield is high, the post-treatment is simple, and the solid acid catalyst left after post-treatment filtration can still be recycled, greatly reducing the reaction time and experimental cost. Description of the Drawings

[0021] Figure 1It is the infrared characterization diagrams of sulfonated silica gel and silica gel. Specific Embodiments

[0022] The present invention will be further described below in conjunction with the embodiments. The following embodiments are only used to more clearly illustrate the technical solutions of the present invention and cannot be used to limit the protection scope of the present invention.

[0023] Example 1

[0024] Preparation of compound 6 - aldehyde coumarin:

[0025]

[0026] 4 - Acetoxybenzaldehyde (10 mmol) and methyl acrylate (10 mmol) were added to the solvent formic acid (10 mL), and the catalyst rhodium (II) acetate dimer (2.5 mol%) was added. After heating to 100 °C, the mixture was stirred and reacted for 4 h. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was diluted with 50 mL of ethyl acetate, and the organic layer was washed successively with 50 mL of water, 75 mL of 5% sodium bicarbonate solution, and 50 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a light yellow solid 6 - aldehyde coumarin. After recrystallization from ethanol, a pale yellow solid was obtained (yield 87%).

[0027] 6 - Aldehyde coumarin: Pale yellow solid (yield 87%), m.p. 193.7 - 194.2 °C. 1 H NMR (300 MHz, DMSO - d6) δ 10.04 (s, 1H), 8.36 - 8.29 (d, J = 2.01 Hz, 1H), 8.27 - 8.17 (dd, J = 0.65, 9.72 Hz, 1H), 8.17 - 8.08 (dd, J = 2.02, 8.57 Hz, 1H), 7.65 - 7.56 (d, J = 8.52 Hz, 1H), 6.68 - 6.58 (d, J = 9.62 Hz, 1H). 13 C NMR (75 MHz, DMSO - d6) δ 192.12, 159.80, 157.66, 144.45, 133.03, 132.79, 131.10, 119.63, 117.94, 117.79.

[0028] Example 2

[0029] Preparation of sulfonated silica gel (SSA):

[0030] Add 50 g of 200 - 300 mesh silica gel into a three - necked flask, set up a tail gas absorption device with 100 mL of saturated Ca(OH)₂ solution as the absorption liquid. Add 25 mL of chlorosulfonic acid into a constant - pressure funnel, and dropwise add chlorosulfonic acid under stirring, controlling the dropping time to be 0.5 h. After the dropping is completed, ultrasonicate for 30 min to obtain white sulfonated silica gel (SSA), and store it sealed in the refrigerator. The infrared spectrum shows that the hydroxyl absorption peak of silica gel at 3448 cm -1 is significantly weakened after sulfonation, and a characteristic absorption peak of sulfonic acid group appears at 1186 cm -1 , proving that after sulfonation with chlorosulfonic acid, the sulfonic acid group replaces the hydroxyl group of silica gel.

[0031] Example 3

[0032] Preparation of compound (E) - 6 - (3 - (4 - hydroxyphenyl) - 3 - oxoprop - 1 - en - 1 - yl) - 2H - chromen - 2 - one:

[0033]

[0034] Add 6 - formylcoumarin (10 mmol) and 4 - hydroxyacetophenone (10 mmol) into a flask, and add catalyst SSA (1 g). Heat up to 75 °C and stir the reaction for 1 h. Monitor the reaction by TLC. After the reaction is complete, dissolve the reactants completely with 50 mL of DMSO, filter off the sulfonated silica gel, and drop the DMSO solution containing the product into 50 mL of water. A large amount of precipitate will precipitate out. Filter by suction and wash the filter cake with ethanol. After drying, obtain the white solid product (E) - 6 - (3 - (4 - hydroxyphenyl) - 3 - oxoprop - 1 - en - 1 - yl) - 2H - chromen - 2 - one by column chromatography (petroleum ether: ethyl acetate = 4:1).

[0035] (E) - 6 - (3 - (4 - hydroxyphenyl) - 3 - oxoprop - 1 - en - 1 - yl) - 2H - chromen - 2 - one: white solid (yield 81%), m.p. 298.1 - 298.8 °C, 1 ¹H NMR (300 MHz, DMSO - d₆) δ 10.98 (s, 1H), 8.25 - 8.18 (d, J = 2.1 Hz, 1H), 8.18 - 8.12 (dd, J = 2.1, 8.7 Hz, 1H), 8.12 - 8.00 (t, J = 9.6, 9.6 Hz, 3H), 8.00 - 7.90 (d, J = 15.6 Hz, 1H), 7.79 - 7.65 (d, J = 15.6 Hz, 1H), 7.53 - 7.42 (d, J = 8.6 Hz, 1H), 6.98 - 6.86 (d, J = 8.5 Hz, 2H), 6.62 - 6.50 (d, J = 9.6 Hz, 1H). 1313C NMR (75 MHz, DMSO-d6) δ 187.43, 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.

[0036] Example 4

[0037] (E)-6-(3-(4-Hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one (10 mmol) and potassium iodide (15 mmol) were added to a flask, and the solvent DMF (15 mL) was added. The temperature was raised to 75 °C. After dissolution, the halide R-Br / Cl (12 mmol) was added dropwise. After stirring and reacting for 4 h, the reaction was monitored by TLC. After the reaction was completed, the reaction solution was poured into water (30 mL), and a large amount of precipitate was precipitated. The obtained precipitate was dried by suction filtration and then purified by column chromatography (petroleum ether: ethyl acetate) to obtain solid products 1a-1j, 2a-2m. The selection of the halide R-Br / Cl is shown in detail in Table 1.

[0038] 1a: 1 1H NMR (400 MHz, CDCl3-d6) δ 8.09 - 8.00 (m, 2H), 7.87 - 7.77 (m, 2H), 7.77 - 7.70 (m, 2H), 7.60 - 7.52 (d, J = 15.61 Hz, 1H), 7.42 - 7.35 (d, J = 8.62 Hz, 1H), 7.02 - 6.94 (m, 2H), 6.52 - 6.45 (d, J = 9.58 Hz, 1H), 4.18 - 4.09 (m, 2H), 1.51 - 1.43 (t, J = 7.00, 7.00 Hz, 3H). 13 13C NMR (100 MHz, CDCl3-d6) δ 188.23, 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.

[0039] 1b: 11H NMR (400 MHz, CDCl3-d6)) δ 8.15 (m, 2H), 7.92 - 7.85 (m, 2H), 7.81 - 7.73 (m, 2H), 7.62 - 7.54 (d, J = 15.7 Hz, 1H), 7.42 - 7.35 (d, J = 8.6 Hz, 1H), 7.03 - 6.94 (m, 2H), 6.5 - 6.5 (d, J = 9.6 Hz, 1H), 4.1 - 4.0 (t, J = 6.5, 6.5 Hz, 2H), 1.9 - 1.8 (m, 2H), 1.13 - 1.06 (t, J = 7.4, 7.4 Hz, 3H). 13 13C NMR (100 MHz, CDCl3-d6) δ 188.15, 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: 1 1H NMR (400 MHz, CDCl3-d6) δ 8.08 - 8.00 (m, 2H), 7.87 - 7.77 (m, 2H), 7.77 - 7.70 (m, 2H), 7.60 - 7.52 (d, J = 15.63 Hz, 1H), 7.41 - 7.35 (d, J = 8.58 Hz, 1H), 7.03 - 6.94 (m, 2H), 6.52 - 6.45 (d, J = 9.55 Hz, 1H), 4.10 - 4.02 (t, J = 6.50, 6.50 Hz, 2H), 1.87 - 1.75 (m, 2H), 1.59 - 1.45 (m, 2H), 1.04 - 0.96 (t, J = 7.40, 7.40 Hz, 3H). 13 13C NMR (100 MHz, CDCl3-d6) δ 188.16, 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.

[0040] 1d: 11H NMR (400 MHz, CDCl3-d6) δ 8.08 - 8.00 (m, 2H), 7.87 - 7.77 (m, 2H), 7.77 - 7.69 (m, 2H), 7.60 - 7.52 (d, J = 15.58 Hz, 1H), 7.41 - 7.34 (d, J = 8.62 Hz, 1H), 7.02 - 6.94 (m, 2H), 6.52 - 6.45 (d, J = 9.53 Hz, 1H), 4.09 - 4.01 (t, J = 6.54, 6.54 Hz, 2H), 1.89 - 1.77 (dt, J = 6.48, 6.48, 8.13 Hz, 2H), 1.53 - 1.34 (m, 4H), 0.99 - 0.91 (t, J = 7.06, 7.06 Hz, 3H). 13 13C NMR (100 MHz, CDCl3-d6) δ 188.29, 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.

[0041] 1e: 1 1H NMR (400 MHz, CDCl3-d6) δ 8.08 - 8.00 (m, 2H), 7.87 - 7.77 (m, 2H), 7.77 - 7.70 (m, 2H), 7.60 - 7.52 (d, J = 15.58 Hz, 1H), 7.41 - 7.35 (d, J = 8.61 Hz, 1H), 7.01 - 6.93 (m, 2H), 6.52 - 6.45 (d, J = 9.60 Hz, 1H), 4.74 - 4.63 (m, 1H), 1.42 - 1.36 (d, J = 6.04 Hz, 6H). 13 13C NMR (100 MHz, CDCl3-d6) δ 188.12, 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.

[0042] 1f: 11H NMR (400 MHz, CDCl3-d6) δ 8.08 - 8.00 (m, 2H), 7.87 - 7.70 (m, 4H), 7.60 - 7.52 (d, J = 15.66 Hz, 1H), 7.41 - 7.34 (d, J = 8.62 Hz, 1H), 7.01 - 6.93 (m, 2H), 6.52 - 6.45 (d, J = 9.53 Hz, 1H), 4.50 - 4.38 (m, 1H), 1.85 - 1.61 (m, 3H), 1.38 - 1.32 (d, J = 6.08 Hz, 3H), 1.04 - 0.94 (t, J = 7.46, 7.46 Hz, 3H). 13 13C NMR (100 MHz, CDCl3-d6) δ 188.12, 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.

[0043] 1g: 1 1H NMR (400 MHz, CDCl3-d6) δ 8.18 - 8.10 (dt, J = 2.42, 2.42, 9.03 Hz, 2H), 7.98 - 7.79 (m, 4H), 7.71 - 7.62 (dd, J = 2.62, 15.59 Hz, 1H), 7.52 - 7.44 (dd, J = 2.62, 8.62 Hz, 1H), 7.39 - 7.34 (d, J = 2.59 Hz, 1H), 7.12 - 7.04 (dt, J = 2.44, 2.44, 9.05 Hz, 2H), 6.62 - 6.54 (dd, J = 2.67, 9.44 Hz, 1H), 4.22 - 4.14 (dt, J = 4.32, 4.32, 8.88 Hz, 2H), 2.01 - 1.92 (m,, 1H), 1.86 - 1.77 (m, 2H), 1.12 - 1.04 (dd, J = 2.62, 6.69 Hz, 6H). 13 13C NMR (100 MHz, CDCl3-d6) δ 188.32, 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.

[0044] 1h: 11H NMR (400 MHz, CDCl₃-d₆) δ 8.01 - 7.93 (m, 2H), 7.80 - 7.70 (m, 2H), 7.70 - 7.63 (m, 2H), 7.53 - 7.45 (d, J = 15.63 Hz, 1H), 7.34 - 7.28 (d, J = 8.64 Hz, 1H), 6.96 - 6.88 (m, 2H), 6.45 - 6.38 (d, J = 9.53 Hz, 1H), 3.86 - 3.80 (d, J = 6.96 Hz, 2H), 1.20 - 1.16 (m, 1H), 0.66 - 0.58 (m, 2H), 0.36 - 0.28 (dt, J = 4.75, 4.75, 6.25 Hz, 2H). 13 ¹³C NMR (100 MHz, CDCl₃-d₆) δ 163.20, 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.

[0045] 1i: 1 1H NMR (400 MHz, CDCl₃-d₆) δ 8.08 - 8.00 (m, 2H), 7.88 - 7.78 (m, 2H), 7.78 - 7.70 (m, 2H), 7.61 - 7.52 (d, J = 15.63 Hz, 1H), 7.42 - 7.35 (d, J = 8.57 Hz, 1H), 7.03 - 6.95 (m, 2H), 6.52 - 6.45 (d, J = 9.59 Hz, 1H), 3.96 - 3.89 (d, J = 6.95 Hz, 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). 13 ¹³C NMR (100 MHz, CDCl₃-d₆) δ 188.17, 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.

[0046] 1j: 11H NMR (300 MHz, CDCl3-d6) δ 8.02 - 7.93 (d, J = 8.57 Hz, 2H), 7.82 - 7.73 (m, 2H), 7.73 - 7.62 (m, 3H), 7.55 - 7.44 (d, J = 15.56 Hz, 1H), 7.36 - 7.30 (s, 1H), 7.22 - 7.16 (s, 2H), 6.96 - 6.87 (d, J = 8.73 Hz, 2H), 6.47 - 6.38 (d, J = 9.58 Hz, 1H), 3.81 - 3.73 (d, J = 5.98 Hz, 2H), 1.87 - 1.72 (t, J = 14.66, 14.66 Hz, 4H), 1.35 - 1.09 (m, 5H), 1.07 - 0.94 (m, 2H). 13 13C NMR (100 MHz, CDCl3-d6) δ 188.23, 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.

[0047] 2a: 1 1H NMR (300 MHz, CDCl3-d6) δ 8.10 - 8.00 (d, J = 8.90 Hz, 2H), 7.89 - 7.70 (m, 4H), 7.68 - 7.51 (s, 1H), 7.43 - 7.34 (d, J = 8.58 Hz, 1H), 7.29 - 7.17 (s, 1H), 7.07 - 6.89 (d, J = 8.62 Hz, 2H), 6.54 - 6.45 (d, J = 9.61 Hz, 1H), 4.39 - 4.25 (m, 1H), 4.10 - 3.99 (m, 2H), 3.99 - 3.91 (t, J = 6.76, 6.76 Hz, 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). 13 13C NMR (100 MHz, CDCl3-d6) δ 188.14, 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.

[0048] 2b:1 1H NMR (300 MHz, CDCl3-d6) δ 8.03 - 7.93 (d, J = 8.51 Hz, 2H), 7.82 - 7.62 (m, 4H), 7.53 - 7.45 (d, J = 15.61 Hz, 1H), 7.36 - 7.27 (d, J = 8.63 Hz, 1H), 7.00 - 6.92 (d, J = 8.56 Hz, 2H), 6.47 - 6.38 (d, J = 9.57 Hz, 1H), 5.31 - 5.18 (t, J = 3.97, 3.97 Hz, 1H), 4.09 - 4.04 (d, J = 3.98 Hz, 2H), 4.03 - 3.89 (m, 4H). 13 13C NMR (100 MHz, CDCl3) δ 187.11, 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.

[0049] 2c: 1 1H NMR (300 MHz, CDCl3-d6) δ 8.09 - 8.00 (d, J = 8.54 Hz, 2H), 7.89 - 7.70 (m, 4H), 7.62 - 7.51 (s, 1H), 7.43 - 7.34 (d, J = 8.60 Hz, 1H), 7.05 - 6.96 (d, J = 8.53 Hz, 2H), 6.54 - 6.45 (d, J = 9.51 Hz, 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). 13 13C NMR (100 MHz, CDCl3-d6) δ 187.05, 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.

[0050] 2d: 11H NMR (300 MHz, CDCl3-d6) δ 8.01 - 7.92 (d, J = 8.58 Hz, 2H), 7.82 - 7.73 (m, 1H), 7.73 - 7.68 (d, J = 2.71 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.55 - 7.44 (d, J = 15.58 Hz, 1H), 7.36 - 7.27 (s, 1H), 7.00 - 6.91 (d, J = 8.50 Hz, 2H), 6.47 - 6.37 (d, J = 9.54 Hz, 1H), 4.06 - 3.95 (dd, J = 6.44, 9.93 Hz, 2H), 3.95 - 3.87 (dd, J = 3.83, 9.98 Hz, 1H), 3.76 - 3.62 (q, J = 4.07, 6.98, 6.98 Hz, 1H), 3.52 - 3.37 (m, 1H), 1.92 - 1.82 (m, 1H), 1.66 - 1.57 (d, J = 12.04 Hz, 2H), 1.49 - 1.33 (m, 2H), 1.21 - 1.15 (s, 1H). 13 13C NMR (100 MHz, CDCl3-d6) δ 188.15, 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.

[0051] 2e: 1 1H NMR (400 MHz, CDCl3-d6) δ 8.02 - 7.94 (m, 2H), 7.81 - 7.71 (m, 2H), 7.71 - 7.63 (m, 2H), 7.53 - 7.45 (d, J = 15.62 Hz, 1H), 7.35 - 7.29 (d, J = 8.65 Hz, 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 = 6.41 Hz, 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). 1313C NMR (100 MHz, CDCl3-d6) δ 188.12, 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.

[0052] 2f: 1 1H NMR (400 MHz, CDCl3-d6) δ 8.09 - 8.01 (m, 2H), 7.88 - 7.78 (m, 2H), 7.78 - 7.70 (m, 2H), 7.60 - 7.52 (d, J = 15.62 Hz, 1H), 7.42 - 7.35 (d, J = 8.61 Hz, 1H), 7.04 - 6.96 (m, 2H), 6.52 - 6.46 (d, J = 9.58 Hz, 1H), 4.17 - 4.09 (t, J = 6.29, 6.29 Hz, 2H), 3.78 - 3.71 (t, J = 4.68, 4.68 Hz, 4H), 2.60 - 2.54 (t, J = 7.25, 7.25 Hz, 2H), 2.54 - 2.43 (d, J = 4.76 Hz, 4H), 2.07 - 2.00 (m, 2H). 13 13C NMR (100 MHz, CDCl3-d6) δ 188.11, 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.

[0053] 2g: 1 1H NMR (400 MHz, CDCl3-d6) δ 8.08 - 8.00 (m, 2H), 7.88 - 7.78 (m, 2H), 7.78 - 7.70 (m, 2H), 7.60 - 7.52 (d, J = 15.64 Hz, 1H), 7.42 - 7.35 (d, J = 8.59 Hz, 1H), 7.04 - 6.96 (m, 2H), 6.52 - 6.46 (d, J = 9.53 Hz, 1H), 4.84 - 4.74 (t, J = 5.16, 5.16 Hz, 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). 1313C NMR (100 MHz, CDCl3-d6) δ 188.15, 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.

[0054] 2h: 1 1H NMR (400 MHz, CDCl3-d6) δ 8.27 - 8.22 (d, J = 2.14 Hz, 1H), 8.22 - 8.15 (m, 3H), 8.09 - 7.97 (m, 2H), 7.80 - 7.71 (d, J = 15.56 Hz, 1H), 7.53 - 7.46 (d, J = 8.58 Hz, 1H), 7.18 - 7.11 (dd, J = 2.22, 9.08 Hz, 2H), 6.61 - 6.54 (d, J = 9.58 Hz, 1H), 4.53 - 4.41 (dd, J = 2.58, 11.44 Hz, 1H), 4.01 - 3.92 (dd, J = 6.63, 11.42 Hz, 1H), 3.41 - 3.37 (dd, J = 2.97, 5.64 Hz, 1H), 2.92 - 2.85 (t, J = 4.66, 4.66 Hz, 1H), 2.79 - 2.72 (dd, J = 2.64, 5.13 Hz, 1H). 13 13C NMR (100 MHz, CDCl3-d6) δ 187.14, 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.

[0055] 2i: 11H NMR (400 MHz, CDCl3-d6) δ 8.09 - 8.00 (m, 2H), 7.88 - 7.68 (m, 4H), 7.62 - 7.52 (m, 1H), 7.42 - 7.31 (d, J = 8.66 Hz, 1H), 7.12 - 6.98 (m, 2H), 6.53 - 6.46 (d, J = 9.59 Hz, 1H), 4.91 - 4.84 (d, J = 5.15 Hz, 1H), 4.16 - 4.04 (d, J = 5.19 Hz, 2H), 3.85 - 3.73 (m, 2H), 3.71 - 3.61 (m, 2H), 1.29 - 1.24 (t, J = 7.04, 7.04 Hz, 6H). 13 13C NMR (100 MHz, CDCl3-d6) δ 188.15, 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.

[0056] 2j: 1 1H NMR (400 MHz, CDCl3-d6) δ 8.73 - 8.66 (d, J = 4.84 Hz, 2H), 8.30 - 8.24 (m, 3H), 8.24 - 8.18 (dd, J = 2.10, 8.69 Hz, 1H), 8.10 - 8.00 (m, 2H), 7.86 - 7.78 (d, J = 15.57 Hz, 1H), 7.55 - 7.48 (d, J = 8.65 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.38 - 7.31 (t, J = 4.81, 4.81 Hz, 1H), 6.62 - 6.55 (d, J = 9.57 Hz, 1H).

[0057] 2k: 11H NMR (400 MHz, CDCl3-d6) δ 8.08 - 8.01 (m, 2H), 7.88 - 7.78 (m, 2H), 7.78 - 7.70 (m, 2H), 7.60 - 7.52 (d, J = 15.62 Hz, 1H), 7.42 - 7.35 (d, J = 8.63 Hz, 1H), 7.04 - 6.97 (m, 2H), 6.52 - 6.46 (d, J = 9.56 Hz, 1H), 4.25 - 4.18 (t, J = 5.99, 5.99 Hz, 2H), 2.87 - 2.77 (t, J = 5.98, 5.98 Hz, 2H), 2.62 - 2.48 (d, J = 6.76 Hz, 4H), 1.68 - 1.60 (t, J = 5.73, 5.73 Hz, 4H), 1.52 - 1.43 (m, 2H). 13 13C NMR (100 MHz, CDCl3-d6) δ 188.14, 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, 21: 1 1H NMR (400 MHz, CDCl3-d6) δ 8.11 - 8.03 (m, 2H), 7.88 - 7.78 (m, 2H), 7.78 - 7.70 (m, 2H), 7.62 - 7.53 (d, J = 15.62 Hz, 1H), 7.47 - 7.42 (d, J = 1.87 Hz, 1H), 7.42 - 7.35 (d, J = 8.66 Hz, 1H), 7.32 - 7.27 (d, J = 1.80 Hz, 2H), 7.15 - 7.07 (m, 2H), 6.52 - 6.46 (d, J = 9.57 Hz, 1H), 5.15 - 5.10 (s, 2H), 1.37 - 1.31 (s, 18H). 13 13C NMR (100 MHz, CDCl3-d6) δ 188.18, 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.

[0058] 2m: 11H NMR (400 MHz, CDCl3-d6) δ 10.52 - 10.47 (s, 1H), 8.25 - 8.20 (d, J = 2.10 Hz, 1H), 8.20 - 8.13 (dd, J = 2.09, 8.69 Hz, 1H), 8.13 - 8.06 (m, 3H), 8.06 - 8.02 (s, 1H), 8.01 - 7.93 (d, J = 15.61 Hz, 1H), 7.77 - 7.68 (d, J = 15.55 Hz, 1H), 7.52 - 7.46 (d, J = 8.62 Hz, 1H), 6.96 - 6.88 (m, 2H), 6.61 - 6.54 (d, J = 9.58 Hz, 1H). 13 13C NMR (100 MHz, CDCl3-d6) δ 186.91, 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

[0059]

[0060]

[0061]

[0062] Effect Example

[0063] The PDE2 enzyme inhibitory activity of the products 1a - 1j and 2a - 2m obtained in Example 4 was studied

[0064] The recombinant plasmid pET15b - PDE2A was transformed into Escherichia coli for expression. Through cultivation, the PDE2 protein was purified by nickel column affinity chromatography. The AlphaScreen kit was used to measure the inhibitory effect of the compound on PDE2. When PDE2 is present, it hydrolyzes Biotinylated cAMP, making it difficult for the receptor beads and donor beads to approach, resulting in a decrease in the signal value. If a PDE2 inhibitor is present in the system, it will inhibit PDE2 so that Biotinylated cAMP cannot be hydrolyzed, and finally the signal value level increases.

[0065] Take 2 μL of the compound dilution and 4 μL of the PDE2 protein dilution, react them at a constant temperature (25 °C) for 0.5 h, then add 4 μL of Biotinylated cAMP, centrifuge (1000 r / min) for 1 minute, react again at a constant temperature (25 °C) for 1 h, then add 15 μL of the Acceptor and Donor Bead suspension, centrifuge (1000 r / min) for 1 minute, react at a constant temperature (25 °C) for 1 h under light-proof conditions, and finally read the values with a multi-functional microplate reader. Positive controls (without the compound and PDE2 protein) and negative controls (without the compound) need to be configured for the experiment. The parts not added are supplemented with an equal amount of 1×Reaction buffer. This experiment is carried out in a 384-well white plate, and 3 parallel wells are set for each group.

[0066] Further determine the IC50 value of the synthesized compound. Dilute the potential compound to 7 final concentrations of 200 μM, 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, and 3.125 μM with 1×Reaction buffer. The specific experimental steps refer to the IC of BAY60-7550 above. 50 Determination method.

[0067] Table 2 IC of (E)-6-(3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one derivatives 50 Value

[0068]

[0069]

[0070]

[0071] The present invention provides 23 compounds of (E)-6-(3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one, all of which have good PDE2 inhibitory activity and have the potential to treat central nervous system diseases such as memory defects, cognitive disorders, anxiety, and depression. They can be used as active ingredients to prepare drugs that inhibit PDE2 activity. Among them, the IC50 of 1b, 1i, 2a, 2e, 2f, 2g, 2h, 2i, and 2m against the PDE2 protein is less than 50 μM. Among them, 1b, 2a, 2i, and 2m have better activity, and the IC50 of 2a is the best, which is 16.82 μM.

Claims

1. A class of coumarin-chalcone hybrid derivatives as phosphodiesterase 2 inhibitors, characterized in that: The structural formula of the coumarin-chalcone hybrid derivative is as follows: 、 、 、 、 、 。 2. Use of the coumarin-chalcone hybrid derivative according to claim 1 in the preparation of a PDE2 inhibitor drug.

Images