Alpha-p-amino benzylidene-5,6-dimethoxy-1-indenone derivatives, processes for their preparation and use

Abstract

The present application relates to the fields of pharmaceutical chemistry and biological medicine technology, in particular to a kind of alpha-p-amino benzylidene-5,6-dimethoxy-1-indanone derivative and its preparation method and application.The alpha-p-amino benzylidene-5,6-dimethoxy-1-indanone derivative, characterized in that, it has the structure general formula as shown in general formula I.The alpha-p-amino benzylidene-5,6-dimethoxy-1-indanone derivative prepared in the present application can be used for preparing the drug for preventing or treating Alzheimer's disease, and has important medicinal value and wide application prospect in Alzheimer's disease drug research and development.

Description

TECHNICAL FIELD

[0001] The present application relates to the fields of pharmaceutical chemistry and biological medicine, in particular to a kind of α-para-amino benzylidene-5,6-dimethoxy-1-indanone derivative and its preparation method and application. BACKGROUND

[0002] Alzheimer's disease (AD) is a multi-factorial neurodegenerative disease, the main pathogenic features include memory impairment, cognitive impairment and impaired motor and behavioral ability. Acetylcholinesterase (AChE) hypothesis believes that AD is related to the decreased level of ACh in cerebral cortex and hippocampus. AChE is an important central nervous excitatory neurotransmitter, which ensures the normal transmission of nerve signals. The special structure of AChE determines its diversity in binding with substrates, agonists and inhibitors. At present, the U.S. Food and Drug Administration (FDA) has approved four acetylcholinesterase inhibitors, including donepezil, rivastigmine, galantamine and tacrine. These drugs slow down the degradation rate of acetylcholine, prolong the action time of acetylcholine in synaptic cleft, enhance the function of central cholinergic system, and improve the cognitive function, memory and behavioral symptoms of patients with Alzheimer's disease. The design and synthesis of acetylcholinesterase inhibitors provide research ideas for the development of potential drugs for the treatment of AD. At present, among the anti-AD drugs approved by the U.S. FDA, there are acetylcholinesterase inhibitors such as donepezil, rivastigmine, galantamine and tacrine, but their side effects are large, for example, tacrine was withdrawn from the market soon after its listing due to serious liver toxicity and other side effects. Therefore, it is of great significance for the treatment of AD to develop new acetylcholinesterase inhibitors with good therapeutic effect and low toxicity. Therefore, it is necessary to explore and develop new acetylcholinesterase inhibitors. SUMMARY

[0003] The present application aims at the above-mentioned problems, and provides a kind of α-para-amino benzylidene-5,6-dimethoxy-1-indanone derivative and its preparation method and application.

[0004] In order to achieve the above-mentioned purpose, the present application adopts the following technical solutions:

[0005] The present application provides a kind of α-para-amino benzylidene-5,6-dimethoxy-1-indanone derivative, which has the structure general formula as shown in general formula I:

[0006]

[0007] Among them, R is selected from one of structures 1-7 as follows:

[0008]

[0009] Further, the α-p-amino benzylidene-5,6-dimethoxy-1-indanone derivative is compound I-1 to I-7 and pharmaceutically acceptable salts thereof, and the structural formula of compound I-1 to I-7 is as follows:

[0010]

[0011] Further, the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, hydrobromide, maleate, citrate, succinate, methanesulfonate, toluenesulfonate, xinafoate, pamoate or tartrate.

[0012] The application also provides a preparation method of the α-p-amino benzylidene-5,6-dimethoxy-1-indanone derivative, comprising the following steps:

[0013] a, taking compound and compound dissolved in solvent anhydrous ethanol, adding catalyst sodium hydroxide, and reacting to obtain compound

[0014] b, taking compound dissolved in anhydrous ethanol, adding stannous chloride dihydrate, and heating to react under nitrogen atmosphere, adding dichloromethane and water to extract, and obtaining compound crude product, and then purifying by elution with flash chromatography to obtain compound pure product;

[0015] c, taking one of structures 1-7 and 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, dissolving in N,N-dimethylformamide, adding catalyst triethylamine, stirring uniformly, and adding compound heating to react, and after the reaction is completed, extracting with ethyl acetate, and purifying the organic phase by silica gel column chromatography to obtain the target compound.

[0016] Preferably, in the above preparation method, the molar ratio of compound and compound in step a is 1:1; the molar ratio of compound and stannous chloride in step b is 1:5; and the molar ratio of R and compound in step c is 5:4.

[0017] Preferably, in the above preparation method, the reaction temperature in step a is 25°C, and the reaction time is 4-6 hours; the reaction temperature in step b is 80°C; and the reaction time is 5.5-6.5 hours; the reaction temperature in step c is 60°C; and the reaction time is 12-15 hours.

[0018] The application also provides application of the alpha-p-amino benzylidene-5,6-dimethoxy-1-indanone derivative in preparation of a drug for preventing or treating neurodegenerative diseases.

[0019] The application also provides application of the alpha-p-amino benzylidene-5,6-dimethoxy-1-indanone derivative in preparation of a drug for preventing or treating Alzheimer's disease.

[0020] In addition, the application further provides a pharmaceutical composition containing the alpha-p-amino benzylidene-5,6-dimethoxy-1-indanone derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0021] Further, the pharmaceutical composition is a tablet, a capsule, a powder, a syrup, a liquid, a suspension or a needle.

[0022] According to the above technical scheme, the application has the following beneficial effects:

[0023] 1. The alpha-p-amino benzylidene-5,6-dimethoxy-1-indanone derivative provided by the application has a novel structure and good in-vitro activity, and has an inhibitory activity on acetylcholinesterase, so it has a good application prospect in preparation of a drug for preventing or treating diseases caused by acetylcholinesterase, especially in preparation of a drug for treating Alzheimer's disease. That is, the alpha-p-amino benzylidene-5,6-dimethoxy-1-indanone derivative prepared by the application can be used for preparing a drug for preventing or treating Alzheimer's disease, and has important medicinal value and a wide application prospect in research and development of a drug for treating Alzheimer's disease.

[0024] 2. The application further provides a preparation method of the alpha-p-amino benzylidene-5,6-dimethoxy-1-indanone derivative, which has the advantages of low cost, simple operation, safety, low cost, less waste, high economy and high yield. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 The compound I-1 to I-7 contain the structure of the general formula I.

[0026] Figure 2 The IC value of the compound I-1 for acetylcholinesterase. 50 The numerical value.

[0027] Figure 3 The IC value of the compound I-2 for acetylcholinesterase. 50 The numerical value.

[0028] Figure 4 The IC value of the compound I-3 for acetylcholinesterase.50 Values.

[0029] Figure 5 IC for compound I-4 against acetylcholinesterase 50 Values.

[0030] Figure 6 IC for compound I-5 against acetylcholinesterase 50 Values.

[0031] Figure 7 IC for compound I-6 against acetylcholinesterase 50 Values.

[0032] Figure 8 IC for compound I-7 against acetylcholinesterase 50 Values.

[0033] Figure 9 Percent inhibition and IC50 values for compounds I-1 to I-7 at 50 μM 50 Values DETAILED DESCRIPTION

[0034] In order to better understand the technical scheme of the present application, the technical scheme in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work should belong to the scope of protection of the present application.

[0035] The present application provides an α-p-aminobenzylidene-5,6-dimethoxy-1-indenone derivative, which has a structure as shown in general formula I:

[0036]

[0037] wherein R is selected from any one of the following structures 1-7:

[0038]

[0039] Preferably, the α-p-aminobenzylidene-5,6-dimethoxy-1-indenone derivative is the following compounds I-1 to I-7 and pharmaceutically acceptable salts thereof, and the structural formulae of the compounds I-1 to I-7 are as follows:

[0040]

[0041] Preferably, the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, hydrobromide, maleate, citrate, succinate, mesylate, tosylate, xinafoate, pamoate or tartrate.

[0042] The synthetic route of the general formula I is shown below, and compounds I-1 to I-7 will be prepared according to the following synthetic route

[0043]

[0044] In step (a), the solvent used in the reaction is anhydrous ethanol, and the catalyst is inorganic strong base sodium hydroxide; the reaction temperature is 25°C, and the reaction time is 4 hours; in step (b), the solvent used in the reaction is anhydrous ethanol, and the reducing agent is stannous chloride; the reaction temperature is 80°C; and the reaction time is 5.5 hours; in step (c), the R used in the reaction includes any one of the structures of 1-7 (the selection of R and the corresponding synthesized compound is as shown in the following table) ; the reaction solvent is N,N-dimethylformamide; the basic catalyst is triethylamine; the carboxyl activator is 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate; the reaction temperature is 60°C, and the reaction time is 12-15 hours. Figure 1

[0045] In order to more clearly express the present application, the following further describes the present application through specific examples.

[0046] I. Preparation Examples

[0047] Example 1: Preparation of compound I-1

[0048] a. Preparation of compound of formula 3 according to the following synthetic route

[0049]

[0050] The specific operation is as follows:

[0051] Take compound of formula 1 (1.92g, 10mmol) and compound of formula 2 ​(1.52g, 10mmol) in a round bottom flask, 50 mL of anhydrous ethanol was ultrasonically dissolved, and a magnetic stirrer was used for uniform stirring. A constant pressure dropping funnel was used to add 20 mL of 10% NaOH, and the dropwise addition time was 10 minutes. During the dropwise addition of NaOH, the color of the solution gradually deepened, and then gradually changed from light yellow to dark red. The stirring reaction was continued for 4 hours, and the temperature was maintained at 25°C. During the reaction, thin plate chromatography (TLC) was used to track the reaction. After the reaction was completed, the reaction was stopped, at which time there was a large amount of precipitate in the solution. Filtration was performed, the filtrate was dark red, and the filter cake was green. The filter cake was repeatedly washed with ethanol several times, and the color of the solid changed to yellow-green. It was placed in a freeze dryer for 5 hours to dry, and finally the compound of formula 3 was obtained The compound of formula 3 was a yellow-green powder, 2.82 g, with a yield of 86.8%.

[0052] The structure of the compound of formula 3 was characterized by nuclear magnetic resonance, and the results are as follows:

[0053] 1 HNMR (400 MHz, DMSO) δ 8.31 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.9 Hz, 2H), 7.53 (s, 1H), 7.24 (s, 1H), 7.22 (s, 1H), 4.07 (s, 2H), 3.92 (s, 3H), 3.85 (s, 3H). 13 CNMR (100 MHz, DMSO) δ 191.9, 156.2, 149.9, 147.6, 145.9, 142.2, 140.3, 131.8, 131.8, 130.2, 128.9, 124.4, 124.4, 108.5, 105.2, 56.6, 56.2, 32.0. ESI-MS m / z: 326 [M+H] + .

[0054] b. The compound of formula 4 was prepared according to the following synthetic route

[0055]

[0056] The specific operation is as follows:

[0057] The compound of formula 3 (1.305 g, 4 mmol) was dissolved in 55 mL of ethanol in a three-necked flask by sonication. The solution turned yellow-green. Nitrogen gas was introduced, and the mixture was stirred with a magnetic stirrer. Stannous chloride (4.5 g, 20 mmol) was added, and the temperature was raised to 80 °C. The ethanol was refluxed at 80 °C, and the reaction was maintained at this temperature for 5.5 hours. The reaction was monitored by thin-plate chromatography (TLC). After the reaction was stopped, the solution was transferred to a single-necked round-bottom flask, and the pH was adjusted to 8.0 with 10% NaOH solution. The ethanol was evaporated to dryness. Then, dichloromethane and water were added for extraction. The organic phase was collected, and the aqueous phase was extracted twice more with dichloromethane. The organic phases were combined and washed with saturated brine. Finally, anhydrous sodium sulfate was added for drying, and the supernatant was filtered. The dichloromethane was evaporated to dryness to obtain compound of formula 4. The crude product was then subjected to gradient elution using rapid chromatography with petroleum ether / ethyl acetate as the eluent. The fractions were collected and characterized to obtain compound formula 4. Pure product; this compound of formula 4 is a brown powder, 0.92 g, yield 78.0%.

[0058] The structure of compound 4 was characterized using nuclear magnetic resonance, and the results are as follows:

[0059] 1 HNMR (400MHz, DMSO) δ7.45(d,J=8.6Hz,2H),7.29(s,1H),7.19(s,1H),7.19(s,1H),6.65(d,J=8.6Hz,2H),5.84(s,2H),3.89(s,5H),3.83(s,3H). 13 CNMR(100MHz,DMSO)δ192.3,155.1,151.3,149.6,144.7,133.1,133.1,133.1,131.1 ,130.1,122.8,114.3,114.3,108.5,104.9,56.4,56.1,32.3.ESI-MSm / z:318[M+Na] + .

[0060] c. Synthesis of compound I-1 The specific steps are as follows:

[0061] Pick 0.5 mmol of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.6 mmol) was added to N,N-dimethylformamide (6 mL), and stirred at room temperature for 10 min. Then, triethylamine was added as a catalyst, and the mixture was stirred at room temperature for another 10 min. Finally, compound 4 was added. (0.4 mmol) and the reaction mixture was stirred at 60 °C for 12 h, the reaction was followed by TLC during the reaction. After completion, the mixture was treated with 10 volumes of water and extracted with ethyl acetate, the combined organic layer was washed with brine, dried over anhydrous Na2S04, filtered and concentrated, then purified on a silica gel column eluted with petroleum ether / ethyl acetate to get the desired compound I-1 Yield 49.14 %.

[0062] The structure of compound I-1 was characterized by nuclear magnetic resonance, and the results are as follows:

[0063] 1 HNMR (400 MHz, DMSO) δ 10.67 (s, 1H), 7.94 (dd, J = 7.9, 1.7 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.47 - 7.40 (m, 2H), 7.23 (d, J = 1.8 Hz, 2H), 7.02 - 6.93 (m, 2H), 4.03 (d, J = 2.1 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H).13C NMR (100 MHz, DMSO) δ 192.3, 166.9, 158.6, 155.7, 149.8, 145.5, 140.0, 135.2, 134.2, 131.8, 131.8, 131.2, 131.2, 130.6, 129.8, 121.1, 121.1, 119.6, 118.5, 117.7, 108.6, 105.1, 56.5, 56.2, 32.1. ESI-MS m / z: 416 [M+H] + .

[0064] Example 2: Preparation of compound I-2

[0065] a. The compound of formula 3 was prepared according to the following synthetic route

[0066]

[0067] The specific operation is as follows:

[0068] The compound of formula 1 (1.92 g, 10 mmol) and the compound of formula 2 (1.52g, 10mmol) in a round bottom flask, 50 mL of anhydrous ethanol was ultrasonically dissolved, and a magnetic stirrer was used for uniform stirring. 10% NaOH 20 mL was added dropwise using a constant pressure dropping funnel, and the dropwise addition time was 10 minutes. During the dropwise addition of NaOH, the color of the solution gradually deepened, and then gradually changed from light yellow to dark red. The stirring reaction was continued for 6 hours, and the temperature was maintained at 25°C. During the reaction, thin plate chromatography (TLC) was used to track the reaction. After the reaction was completed, the reaction was stopped at this time, and there was a large amount of precipitate in the solution. Filtration, the filtrate was dark red, and the filter cake was green. It was repeatedly washed with ethanol several times, and the color of the solid changed to yellow-green. It was placed in a fume hood to dry for 6 hours, and finally the compound of formula 3 was obtained The compound of formula 3 was a yellow-green powder, 2.82g, with a yield of 86.8%.

[0069] The structure of the compound of formula 3 was characterized by nuclear magnetic resonance, and the results are as follows:

[0070] 1 HNMR (400MHz, DMSO) δ 8.31 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.9 Hz, 2H), 7.53 (s, 1H), 7.24 (s, 1H), 7.22 (s, 1H), 4.07 (s, 2H), 3.92 (s, 3H), 3.85 (s, 3H). 13 CNMR (100MHz, DMSO) δ 191.9, 156.2, 149.9, 147.6, 145.9, 142.2, 140.3, 131.8, 131.8, 130.2, 128.9, 124.4, 124.4, 108.5, 105.2, 56.6, 56.2, 32.0. ESI-MS m / z: 326 [M+H] + .

[0071] b. The compound of formula 4 was prepared according to the following synthetic route

[0072]

[0073] The specific operation is as follows:

[0074] The compound of formula 3 (1.305 g, 4 mmol) was dissolved in 55 mL of ethanol in a three-necked flask by sonication. The solution turned yellow-green. Nitrogen gas was introduced, and the mixture was stirred with a magnetic stirrer. Stannous chloride (4.5 g, 20 mmol) was added, and the temperature was raised to 80 °C. The ethanol was refluxed at 80 °C, and the reaction was maintained at this temperature for 6.5 hours. The reaction was monitored by thin-plate chromatography (TLC). After the reaction was stopped, the solution was transferred to a single-necked round-bottom flask, and the pH was adjusted to 8.0 with 10% NaOH solution. The ethanol was evaporated to dryness. Then, dichloromethane and water were added for extraction. The organic phase was collected, and the aqueous phase was extracted twice more with dichloromethane. The organic phases were combined and washed with saturated brine. Finally, the solution was dried with anhydrous sodium sulfate, filtered to obtain a supernatant, and the dichloromethane was evaporated to dryness to obtain compound of formula 4. The crude product was then subjected to rapid chromatography with a gradient elution using petroleum ether / ethyl acetate as the eluent. The fractions were collected and analyzed to obtain compound formula 4. Pure product; this compound of formula 4 is a brown powder, 0.92 g, yield 78.0%.

[0075] The structure of compound 4 was characterized using nuclear magnetic resonance, and the results are as follows:

[0076] 1 HNMR (400MHz, DMSO) δ7.45(d,J=8.6Hz,2H),7.29(s,1H),7.19(s,1H),7.19(s,1H),6.65(d,J=8.6Hz,2H),5.84(s,2H),3.89(s,5H),3.83(s,3H). 13 CNMR(100MHz,DMSO)δ192.3,155.1,151.3,149.6,144.7,133.1,133.1,133.1,131.1 ,130.1,122.8,114.3,114.3,108.5,104.9,56.4,56.1,32.3.ESI-MSm / z:318[M+Na] + .

[0077] c. Synthesis of compound I-2 The specific steps are as follows:

[0078] Pick 0.5 mmol of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.6 mmol) was added to N,N-dimethylformamide (6 mL), and stirred at room temperature for 10 min. Then, triethylamine was added as a catalyst, and the mixture was stirred at room temperature for another 10 min. Finally, compound 4 was added. (0.4 mmol), and the reaction was stirred at 60 °C for 15 h, during which the reaction was tracked by thin plate chromatography (TLC). After completion, the mixture was treated with 10 times the volume of water and extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered, and concentrated, then purified on a silica gel column eluted with petroleum ether / ethyl acetate to obtain the target compound I-2 Yield 50.7%.

[0079] The structure of compound I-2 was characterized by nuclear magnetic resonance, and the results are as follows:

[0080] 1 HNMR (400 MHz, DMSO) δ 11.81 (s, 1H), 10.61 (s, 1H), 8.08 (d, J = 1.9 Hz, 1H), 7.90-7.85 (m, 2H), 7.78 (d, J = 8.6 Hz, 2H), 7.62 (tt, J = 6.2, 2.4 Hz, 2H), 7.43 (d, J = 2.2 Hz, 1H), 7.38 (ddd, J = 11.5, 9.3, 2.6 Hz, 1H), 7.26-7.19 (m, 3H), 7.12 (d, J = 8.6 Hz, 1H), 4.03 (d, J = 2.1 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H). 13 CNMR (100 MHz, DMSO) δ 192.34, 166.54, 160.82, 158.13, 155.72, 149.81, 145.50, 140.89, 139.87, 135.25, 134.39, 132.22, 132.12, 131.82, 131.82, 131.31, 131.18, 130.57, 130.01, 125.71, 122.88, 121.22, 121.22, 118.97, 117.98, 112.63, 108.57, 105.08, 56.49, 56.16, 32.11. ESI-MS m / z: 528 [M+H] + .

[0081] Example 3: Preparation of compound I-3

[0082] The difference between this example and Example 1 is in step c, specifically, the R3 structure is used in the step c of this example instead of the R1 structure in Example 1 The other operations are consistent with Example 1, and the yield is 63.96%.

[0083] The structure of compound I-3 was characterized by nuclear magnetic resonance, and the results are as follows:​

[0084] 1H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 8.99 (s, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.79 - 7.70 (m, 3H), 7.51 - 7.42 (m, 2H), 7.42 - 7.35 (m, 4H), 7.22 (d, J = 5.4 Hz, 2H), 7.18 (d, J = 7.6 Hz, 1H), 7.12 - 7.05 (m, 1H), 4.05 - 3.98 (m, 2H), 3.91 (s, 3H), 3.84 (s, 3H).13C NMR (100 MHz, DMSO) δ 192.3, 167.7, 155.6, 149.8, 145.4, 144.1, 142.3, 140.6, 135.0, 132.6, 131.6, 131.6, 131.3, 130.8, 130.7, 130.6, 130.4, 130.1, 126.0, 124.5, 121.6, 121.1, 120.7, 120.7, 118.8, 117.2, 114.2, 108.6, 105.0, 56.3, 56.1, 32.1. ESI-MS m / z: 581 [M+Na]+.

[0085] Example 4: Preparation of compound I-4

[0086] The difference between this example and Example 1 is in step c, specifically, the use of compound in the step c of this example instead of the compound of in Example 1, and the other operations are consistent with Example 1, and the yield is 61.62%.

[0087] The structure of compound I-4 was characterized by nuclear magnetic resonance, and the results are as follows:

[0088] ​1H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 9.13 (s, 1H), 7.90 - 7.85 (m, 2H), 7.83 (dd, J = 7.9, 1.5 Hz, 1H), 7.80 - 7.73 (m, 2H), 7.44 - 7.36 (m, 2H), 7.27 - 7.20 (m, 3H), 7.20 - 7.12 (m, 2H), 7.01 (dd, J = 8.5, 1.1 Hz, 1H), 6.98 - 6.90 (m, 1H), 4.04 - 3.99 (m, 2H), 3.92 (s, 3H), 3.84 (s, 3H), 2.28 (s, 3H).13C NMR (100 MHz, DMSO) δ 192.3, 168.4, 155.7, 149.8, 145.5, 145.2, 141.9, 140.5, 135.1, 134.8, 133.1, 131.7, 131.7, 131.3, 130.9, 130.6, 130.0, 128.4, 127.9, 124.1, 121.1, 121.1, 119.9, 119.8, 118.9, 115.9, 108.6, 105.1, 56.5, 56.1, 32.1, 14.9. ESI-MS m / z: 540 [M+H]+.

[0089] Example 5: Preparation of compound I-5

[0090] The difference between this example and Example 1 is in step c, specifically, the compound of is used in place of the compound of in Example 1, and the other operations are consistent with Example 1, and the yield is 60.06%.

[0091] The structure of compound I-5 is characterized by nuclear magnetic resonance, and the results are as follows:

[0092] ​1H NMR (400 MHz, DMSO) δ 10.28 (s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.9 Hz, 2H), 7.37 (d, J = 2.1 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.21 (d, J = 2.8 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 3.99 - 3.94 (m, 2H), 3.90 (s, 3H), 3.83 (s, 4H), 2.41 (d, J = 7.1 Hz, 2H), 1.79 (dq, J = 13.5, 6.8 Hz, 1H), 1.42 (d, J = 7.0 Hz, 3H), 0.85 (d, J = 6.6 Hz, 6H).13C NMR (100 MHz, DMSO) δ 192.3, 173.2, 155.6, 149.8, 145.4, 140.9, 140.1, 139.4, 134.7, 131.8, 131.8, 131.3, 130.6, 130.4, 129.5, 129.5, 127.5, 127.5, 119.7, 119.7, 108.5, 105.0, 56.5, 56.1, 46.2, 44.7, 32.1, 30.1, 22.7, 22.7, 19.1. ESI-MS m / z: 506 [M+Na]+.

[0093] Example 6: Preparation of compound I-6

[0094] The difference between this example and Example 1 is in step c, specifically, the compound of structure is used in place of in Example 1, and the other operations are consistent with Example 1, with a yield of 57.72%.

[0095] The structure of compound I-6 is characterized by nuclear magnetic resonance, and the results are as follows:

[0096] 1 1H NMR (400 MHz, DMSO) δ 10.36 (s, 1H), 7.75 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H), 7.59 - 7.54 (m, 2H), 7.54 - 7.50 (m, 2H), 7.45 - 7.42 (m, 2H), 7.40 (dq, J = 8.1, 2.2 Hz, 4H), 7.37 - 7.33 (m, 1H), 7.21 (d, J = 6.4 Hz, 2H), 4.01 - 3.95 (m, 2H), 3.91 (s, 3H), 3.84 (s, 3H), 3.18 (t, J = 7.2 Hz, 2H), 2.95 (t, J = 7.2 Hz, 2H).​13 CNMR (100 MHz, DMSO) δ 192.3, 170.5, 163.1, 155.6, 149.8, 145.4, 145.1, 140.8, 134.8, 134.7, 132.5, 131.9, 131.9, 131.3, 130.6, 130.3, 130.1, 129.4, 129.4, 129.3, 129.1, 129.1, 128.9, 128.7, 127.8, 127.8, 126.8, 126.8, 119.5, 108.5, 105.0, 56.4, 56.1, 31.6, 30.3, 23.4. ESI-MS m / z: 593 [M+Na] + .

[0097] Example 7: Preparation of compound I-7

[0098] The difference between this example and Example 1 is in step c, specifically, the compound of structure is used in the step c of this example instead of in Example 1, and the other operations are consistent with Example 1, and the yield is 59.28%.

[0099] The structure of compound I-7 is characterized by nuclear magnetic resonance, and the results are as follows:

[0100] 1 HNMR (400 MHz, DMSO) δ 10.48 (s, 1H), 7.79 - 7.69 (m, 4H), 7.70 (d, J = 4.5 Hz, 2H), 7.69 - 7.62 (m, 2H), 7.38 (t, J = 2.0 Hz, 1H), 7.24 - 7.17 (m, 3H), 6.94 (d, J = 9.0 Hz, 1H), 6.72 (dd, J = 9.0, 2.6 Hz, 1H), 4.01 - 3.96 (m, 2H), 3.90 (s, 3H), 3.82 (d, J = 12.8 Hz, 5H), 3.76 (s, 3H), 2.30 (s, 3H). 13 ​CNMR (100 MHz, DMSO) δ 192.3, 169.3, 168.4, 156.1, 155.7, 149.7, 145.4, 140.7, 138.1, 135.9, 134.8, 134.7, 131.9, 131.9, 131.6, 131.6, 131.6, 131.4, 131.3, 130.8, 130.6, 130.5, 129.6, 129.6, 119.7, 115.1, 114.4, 111.7, 108.5, 105.1, 102.5, 56.5, 56.1, 55.9, 32.6, 32.1, 13.8. ESI-MS m / z: 636 [M+H] + .

[0101] II. Performance Test

[0102] Acetylcholinesterase (AChE) Inhibition Activity Test and Activity Results

[0103] Experimental Principle: AChE catalyzes the hydrolysis of Ach to produce choline, and choline reacts with dithio p-nitrobenzoic acid (DTNB) to produce 5-thio-nitrobenzoic acid (TNB); TNB has an absorption peak at 412 nm, and the IC value is calculated by measuring the absorbance at 412 nm. 50

[0104] Experimental Materials: Bovine serum albumin, iodothioacetylcholine (ACTI), 5,5'-dithiobis (2-nitrobenzoic acid) (DTNB), acetylcholinesterase (electric eel) (AChE), PBS buffer (0.05 mol / L, pH 7.4, sterile), dimethyl sulfoxide (DMSO) biotechnology grade, 96-well plate (sterile).

[0105] Experimental Instruments: Electronic analytical balance, constant temperature water bath shaker, full wavelength full-automatic enzyme marker.

[0106] Experimental Steps:

[0107] 1) Preparation of Solution

[0108] Buffer A: PBS solution with a pH of 7.4 and a concentration of 0.05 mol / L, stored at 4°C;

[0109] Buffer B: Buffer A containing 0.1% (w / v) bovine serum albumin, stored at 4°C;

[0110] Substrate ACTI: Prepared from buffer A with a concentration of 3 mmol / L;

[0111] Color reagent DTNB: Prepared from buffer A with a concentration of 0.6 mmol / L;

[0112] ​Enzyme solution: The lyophilized electric eel AChE powder was prepared into a 0.5 U / ml working solution using buffer B, aliquoted, and stored at -20℃; when using, it should be slowly dissolved in an ice-water mixture.

[0113] 2) The in vitro inhibitory effect of the samples on AChE was tested using the Ellman spectrophotometric method. The specific method is as follows: During the experiment, the microplate reader was preheated for 15 min. Blank group, negative control group, control group with single test compound, and experimental group with different concentration gradients of test compounds were set up in 96-well plates. The ratio of each well was 160 μL of PBS buffer, 40 μL of PBS buffer and 40 μL of AChE enzyme solution, 40 μL of test compound solution of different concentrations and 120 μL of PBS buffer, and 40 μL of test compound solution of different concentrations and 40 μL of AChE solution. Then, the plates were incubated in a shaker at 37°C for 30 min. Add 40 μL of chromogenic reagent 5,5-dithiobis(2-nitrobenzoic acid) solution and 40 μL of substrate thioacetylcholine iodide to three replicates of the negative control and experimental groups. Incubate at 37°C in the dark for 20 min on a shaker. Measure the absorbance (A) at 412 nm using a microplate reader. Perform the experiment three times for each compound at different concentrations and calculate the inhibition rate I. I = [1 - (Atest - Acompound) / (Anegative - Ablank)] × 100. Process the data using GraphPadPrism software to obtain the IC50 value for each test compound against acetylcholinesterase, as shown below. Figures 2-8 As shown; activity data are as follows Figure 9 As shown.

[0114] The results above show that the α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives (i.e., compounds I-1 to I-7) with general structural formula I provided by this invention have good acetylcholinesterase inhibitory activity, especially the IC50 of acetylcholinesterase inhibition of compounds I-3, I-4, and I-7. 50 Values ​​below or near 10 μM indicate that α-p-aminobenzyl-5,6-dimethoxy-1-indanone derivatives with general structural formula I are a class of drugs with the potential to treat diseases mediated by abnormal cholinesterase activity. These derivatives have broad application prospects in the preparation of Alzheimer's disease treatments. The series of compounds described in this invention, as active ingredients, combined with conventional pharmaceutical excipients, can be used to prepare anti-Alzheimer's disease drugs, with the potential to be formulated into any of the conventional pharmaceutical dosage forms such as tablets, granules, capsules, or oral liquids.

[0115] The above description is for the preferred embodiment of the present application, but the embodiment is not intended to limit the scope of the patent application of the present application. Any equivalent changes or modifications made under the technical spirit of the present application should be covered by the patent scope of the present application.

Claims

1. An α-p-aminobenzal-5,6-dimethoxy-1-indenone derivative, characterized in that, The α-p-aminobenzylidene-5,6-dimethoxy-1-indenone derivative is compound I-1 to I-7 and pharmaceutically acceptable salts thereof, and the structural formula of compound I-1 to I-7 is as follows: 。 2. The α-p-aminobenzaldehyde-5,6-dimethoxy-l-indenone derivative according to claim 1, characterized by The pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, hydrobromide, maleate, citrate, succinate, methanesulfonate, toluenesulfonate or tartrate.

3. Process for the preparation of a-para-amino-benzylidene-5,6-dimethoxy-l- indenone derivatives according to any one of claims 1-2, characterized in that, The method comprises the following steps: a, compound and compound dissolved in solvent absolute ethanol, adding catalyst sodium hydroxide, reaction to obtain compound ; b, taking the compound dissolved in anhydrous ethanol, stannous chloride was added, the reaction was heated under a nitrogen atmosphere, dichloromethane and water were added to extract, and the compound crude product, which was then purified by flash chromatography to obtain the compound pure product; c. one of the compounds of , , , , , and and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, dissolved in N,N-dimethylformamide, a catalyst triethylamine was added, stirred uniformly, the compound was added, heated to react, after the reaction was completed, extracted with ethyl acetate, the organic phase was purified by silica gel column chromatography to obtain the target compound.

4. The process for the preparation of α-p-aminobenzylidene-5,6-dimethoxy-1-indenone derivatives according to claim 3, characterized in that, Compound in step a and compounds The molar ratio is 1:1; in step b, the compound The molar ratio of stannous chloride to stannous chloride is 1:5; in step c , , , , , , and compounds The molar ratio is 5:

4.

5. The process for the preparation of α-p-aminobenzylidene-5,6-dimethoxy-l- indenone derivatives according to claim 3, characterized in that, The reaction temperature in step a is 25℃, and the reaction time is 4-6 hours; the reaction temperature in step b is 80℃, and the reaction time is 5.5-6.5 hours; the reaction temperature in step c is 60℃, and the reaction time is 12-15 hours.

6. Use of the α-p-aminobenzylidene-5,6-dimethoxy-1-indenone derivative according to any one of claims 1-2 in the preparation of a drug for preventing or treating neurodegenerative diseases.

7. Use of the α-p-aminobenzylidene-5,6-dimethoxy-1-indenone derivative according to any one of claims 1-2 in the preparation of a drug for preventing or treating Alzheimer's disease.

8. A pharmaceutical composition, characterized by, The pharmaceutical composition contains the α-p-aminobenzylidene-5,6-dimethoxy-1-indenone derivative or pharmaceutically acceptable salt thereof according to any one of claims 1-2, and comprises a pharmaceutically acceptable carrier or excipient.

9. The pharmaceutical composition of claim 8, wherein: The pharmaceutical composition is a tablet, capsule, powder, syrup, suspension or injection.

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