Alpha-p-aminobenzal-5, 6-dimethoxy-1-indanone derivative as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicinal chemistry and biological medicine, in particular to an alpha-p-aminobenzal-5, 6-dimethoxy-1-indanone derivative as well as a preparation method and application of the alpha-p-aminobenzal-5, 6-dimethoxy-1-indanone derivative. The alpha-p-aminobenzylidene-5, 6-dimethoxy-1-indanone derivative is characterized in that the alpha-p-aminobenzylidene-5, 6-dimethoxy-1-indanone derivative has a structural general formula as shown in a general formula I in the specification. The alpha-p-aminobenzylidene-5, 6-dimethoxy-1-indanone derivative prepared by the invention can be used for preparing a medicine for preventing or treating the Alzheimer's disease, and has an important medicinal value and a wide application prospect in research and development of the medicine for treating the Alzheimer's disease.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry and biomedicine technology, and in particular to an α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivative and a preparation method and application thereof. Background Art

[0002] Alzheimer's disease (AD) is a neurodegenerative disease with multiple etiologies. Its main features include memory impairment, cognitive impairment, and impaired motor and behavioral abilities. The acetylcholinesterase (AChE) hypothesis believes that AD is related to decreased levels of ACh in the cerebral cortex and hippocampus. AChE is an important excitatory neurotransmitter in the central nervous system, ensuring the normal transmission of nerve signals. The three-dimensional structure of AChE is a deep and narrow canyon. Its special structure determines its diversity in binding with substrates, agonists and inhibitors. Currently, 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 the synaptic cleft, enhance the function of the 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 and development ideas for the development of potential drugs for the treatment of AD. At present, the anti-AD drugs approved by the US FDA include acetylcholinesterase inhibitors such as donepezil, rivastigmine, galantamine and tacrine, but their side effects are large. For example, tacrine was withdrawn due to severe liver toxicity and other side effects shortly after it was launched on the market. Therefore, the development of new acetylcholinesterase inhibitors with good therapeutic effects and low toxicity is of great significance for the treatment of AD. Therefore, it is necessary to explore and develop new acetylcholinesterase inhibitors. Summary of the invention

[0003] The object of the present invention is to provide an α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivative and a preparation method and application thereof in view of the above-mentioned problems.

[0004] In order to achieve the above object, the present invention adopts the following technical solutions:

[0005] The present invention provides an α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivative having a general structural formula as shown in general formula I:

[0006]

[0007] Wherein, R is selected from one of the structures 1-7 shown below:

[0008]

[0009] Furthermore, the α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives are compounds I-1 to I-7 and pharmaceutically acceptable salts thereof. The structural formulas of compounds I-1 to I-7 are as follows:

[0010]

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

[0012] The present invention also provides a method for preparing the α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives, comprising the following steps:

[0013] a. Take the compound and compounds Dissolved in anhydrous ethanol, added with sodium hydroxide as a catalyst, the reaction yielded the compound

[0014] b. Take the compound Dissolve in anhydrous ethanol, add stannous chloride dihydrate, heat to react under nitrogen atmosphere, add dichloromethane and water to extract, and obtain compound The crude product was then purified by flash chromatography to give the compound Pure product;

[0015] c. Take one of the structures 1-7 and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, dissolve them in N,N-dimethylformamide, add the catalyst triethylamine, stir evenly, and add the compound The reaction was heated, and after the reaction was completed, the mixture was extracted with ethyl acetate and the organic phase was purified by silica gel column chromatography to obtain the target compound.

[0016] Preferably, in the above preparation method, the compound in step a and compounds The molar ratio of the compound in step b is 1:1; The molar ratio of R and compound is 1:5; The molar ratio 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 present invention also provides the use of the α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives in the preparation of drugs for preventing or treating neurodegenerative diseases.

[0019] The present invention also provides the use of the α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives in the preparation of drugs for preventing or treating Alzheimer's disease.

[0020] In addition, the present invention also provides a pharmaceutical composition, which contains the α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or excipient.

[0021] Furthermore, the pharmaceutical composition is in the form of tablets, capsules, powders, syrups, liquids, suspensions or injections.

[0022] In summary, due to the adoption of the above technical solution, the present invention has the following beneficial effects:

[0023] 1. The α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives provided by the present invention have novel structures, good in vitro activity, and inhibitory activity against acetylcholinesterase, and have good application prospects in the preparation of drugs for preventing or treating diseases caused by acetylcholinesterase, especially in the preparation of drugs for treating Alzheimer's disease. That is to say, the α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives prepared by the present invention can be used to prepare drugs for preventing or treating Alzheimer's disease, and have important medicinal value and broad application prospects in the research and development of Alzheimer's disease drugs.

[0024] 2. The present invention also provides a method for preparing the α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives. The raw materials used in the preparation process are cheap and easily available, the reaction steps are few, the operation is simple and safe, the cost is low, and less waste is generated. It has the advantages of high economy and high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The structures of compounds I-1 to I-7 containing the general formula I are shown in FIG.

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

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

[0028] Figure 4 is the IC of compound I-3 for acetylcholinesterase50 Numeric value.

[0029] Figure 5 is the IC of compound I-4 for acetylcholinesterase 50 Numeric value.

[0030] Figure 6 is the IC of compound I-5 for acetylcholinesterase 50 Numeric value.

[0031] Figure 7 is the IC of compound I-6 for acetylcholinesterase 50 Numeric value.

[0032] Figure 8 is the IC of compound I-7 for acetylcholinesterase 50 Numeric value.

[0033] Fig. 9 The percentage inhibition rate and IC of compounds I-1 to I-7 at 50 μM 50 value DETAILED DESCRIPTION

[0034] In order to enable those skilled in the art to better understand the present application, the technical solutions in the embodiments of the present application are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field without creative work should fall within the scope of protection of the present application.

[0035] The present invention provides an α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivative having a general structural formula 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-indanone derivatives are the following compounds I-1 to I-7 and pharmaceutically acceptable salts thereof, and the structural formulas of 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, methanesulfonate, toluenesulfonate, xinafoate, pamoate or tartrate.

[0042] The synthetic route of the general formula I is as follows. Compounds I-1 to I-7 are prepared according to the following synthetic route:

[0043]

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

[0045] In order to express the present invention more clearly, the present invention is further described below through specific examples.

[0046] 1. Preparation Example

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

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

[0049]

[0050] The specific operations are:

[0051] Take the compound of formula 1 (1.92 g, 10 mmol) and the compound of formula 2 (1.52g, 10mmol) was placed in a round-bottom flask, 50mL of anhydrous ethanol was added for ultrasonic dissolution, a magnetic stirrer was added, 20mL of 10% NaOH was added dropwise with a constant pressure dropping funnel, and the addition time was 10 minutes; during the addition of NaOH, the color of the solution gradually darkened, and then gradually changed from light yellow to dark red; the reaction was stirred for 4 hours, and the temperature was maintained at 25°C; the reaction was tracked by thin plate chromatography (TLC) during the reaction; the reaction was stopped after the reaction was completed. At this time, there was a large amount of precipitation in the solution, and the filtrate was dark red and the filter cake was green. After repeated washing with ethanol, the solid color changed to yellow-green. It was placed in a freeze dryer and dried for 5 hours to finally obtain the compound of formula 3 The compound of formula 3 is 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 H NMR (400MHz, DMSO) δ8.31(d,J=8.8Hz,2H),8.01(d,J=8.9Hz,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 C NMR (100MHz, DMSO) δ191.9,156.2,149.9,147.6,145.9,142.2,140.3,131.8 ,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. Prepare the compound of formula 4 according to the following synthetic route

[0055]

[0056] The specific operations are:

[0057] Take the compound of formula 3 (1.305g, 4mmol) was added to a three-necked flask, 55mL of ethanol was added for ultrasonic dissolution, the solution was yellow-green, nitrogen was introduced, magnetic stirring was added, stannous chloride (4.5g, 20mmol) was added, the temperature was raised to 80°C, ethanol was refluxed at 80°C, and the reaction was maintained at this temperature for 5.5 hours. During the reaction, the reaction was tracked by thin plate chromatography (TLC). After stopping the reaction, the solution was transferred to a single-mouth round-bottom flask, the pH was adjusted to 8.0 with 10% NaOH solution, and the ethanol was dried; then dichloromethane and water were added for extraction, the organic phase was taken, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and washed with saturated brine, and finally dried with anhydrous sodium sulfate, filtered to obtain a clear liquid, and dichloromethane was dried to finally obtain a compound of formula 4 The crude product was then subjected to flash chromatography with petroleum ether / ethyl acetate as the eluent for gradient elution, and the components were collected and characterized to obtain a compound of formula 4 Pure product; the compound of formula 4 is a brown powder, 0.92g, yield 78.0%.

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

[0059] 1 H NMR (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 C NMR(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-MS m / z:318[M+Na] + .

[0060] c. Synthesis of Compound I-1 The specific operations are:

[0061] Pick (0.5mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.6mmol) were added to N,N-dimethylformamide (6mL), stirred at room temperature for 10min, then the catalyst triethylamine was added, stirred at room temperature for another 10min, and then the compound of formula 4 was added (0.4 mmol), and stirred the reaction at 60 ° C for 12 h. The reaction was followed by thin plate chromatography (TLC). After completion, the mixture was treated with 10 volumes of water and extracted with ethyl acetate. The combined organic layers were washed with brine and anhydrous Na 2 SO 4 Dry, filter and concentrate, then purify on a silica gel column eluted with petroleum ether / ethyl acetate to obtain the target 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 H NMR (400MHz, DMSO) δ10.67(s,1H),7.94(dd,J=7.9,1.7Hz,1H),7.87(d,J=8.8Hz,2H),7.78(d,J=8.8Hz,2H),7. 47–7.40(m,2H),7.23(d,J=1.8Hz,2H),7.02–6.93(m,2H),4.03(d,J=2.1Hz,2H),3.92(s,3H),3.85(s,3H).13C NMR (100MHz, DMSO) δ192.3,166.9,158.6,155.7,149.8,145.5,140.0,135.2,134.2,131.8,131.8,131.2,13 1.2,130.6,129.8,121.1,121.1,119.6,118.5,117.7,108.6,105.1,56.5,56.2,32.1.ESI-MSm / z:416[M+H] + .

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

[0065] a. Prepare the compound of formula 3 according to the following synthetic route

[0066]

[0067] The specific operations are:

[0068] Take the compound of formula 1 (1.92 g, 10 mmol) and the compound of formula 2 (1.52g, 10mmol) was placed in a round-bottom flask, 50mL of anhydrous ethanol was added for ultrasonic dissolution, a magnetic stirrer was added, 20mL of 10% NaOH was added dropwise with a constant pressure dropping funnel, and the addition time was 10 minutes; during the addition of NaOH, the color of the solution gradually darkened, and then gradually changed from light yellow to dark red; the reaction was stirred for 6 hours, and the temperature was maintained at 25°C; the reaction was tracked by thin plate chromatography (TLC) during the reaction; the reaction was stopped after the reaction was completed. At this time, there was a large amount of precipitation in the solution, and the filtrate was dark red and the filter cake was green. After repeated washing with ethanol, the solid color changed to yellow-green. It was placed in a fume hood and dried for 6 hours to finally obtain the compound of formula 3 The compound of formula 3 is a yellow-green powder, 2.82 g, 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 H NMR (400MHz, DMSO) δ8.31(d,J=8.8Hz,2H),8.01(d,J=8.9Hz,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 C NMR (100MHz, DMSO) δ191.9,156.2,149.9,147.6,145.9,142.2,140.3,131.8 ,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. Prepare the compound of formula 4 according to the following synthetic route

[0072]

[0073] The specific operations are:

[0074] Take the compound of formula 3 (1.305g, 4mmol) was added to a three-necked flask, 55mL of ethanol was added for ultrasonic dissolution, the solution was yellow-green, nitrogen was introduced, magnetic stirring was added, stannous chloride (4.5g, 20mmol) was added, the temperature was raised to 80°C, ethanol was refluxed at 80°C, and the temperature was maintained for 6.5 hours. During the reaction, the reaction was tracked by thin plate chromatography (TLC). After stopping the reaction, the solution was transferred to a single-mouth round-bottom flask, the pH was adjusted to 8.0 with 10% NaOH solution, and the ethanol was dried; then dichloromethane and water were added for extraction, the organic phase was taken, the aqueous phase was extracted twice with dichloromethane, the organic phase was combined, and washed with saturated brine, and finally dried with anhydrous sodium sulfate, filtered to obtain a clear liquid, and dichloromethane was dried to finally obtain a compound of formula 4 The crude product was then subjected to flash chromatography with petroleum ether / ethyl acetate as the eluent for gradient elution, and the various components were collected and tested to obtain a compound of formula 4 Pure product; the compound of formula 4 is a brown powder, 0.92g, yield 78.0%.

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

[0076] 1 H NMR (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 C NMR(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-MS m / z:318[M+Na] + .

[0077] c. Synthesis of Compound I-2 The specific operations are:

[0078] Pick (0.5mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.6mmol) were added to N,N-dimethylformamide (6mL), stirred at room temperature for 10min, then the catalyst triethylamine was added, stirred at room temperature for another 10min, and then the compound of formula 4 was added (0.4mmol), and stirred at 60°C for 15h. The reaction was tracked by thin plate chromatography (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 Na2SO4, filtered and concentrated, and 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 H NMR (400MHz, DMSO) δ11.81(s,1H),10.61(s,1H),8.08(d,J=1.9Hz,1H),7.90–7.85(m,2H),7.78(d,J=8.6Hz,2H),7.62(tt,J=6.2,2.4Hz,2H),7.4 3(d,J=2.2Hz,1H),7.38(ddd,J=11.5,9.3,2.6Hz,1H),7.26–7.19(m,3H) ,7.12(d,J=8.6Hz,1H),4.03(d,J=2.1Hz,2H),3.92(s,3H),3.85(s,3H). 13 C NMR (100MHz, DMSO) δ192.34,166.54,160.82,158.13,155.72,149.81,145.50,140.89,139.87,135.25,134.39,132.22,132.12,131.82,131 .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: Compound I-3 Preparation

[0082] The difference between this embodiment and embodiment 1 is that in step c, specifically, in step c of this embodiment, the R3 structure is used. Replace the R1 structure in Example 1 The other operations were consistent with those in Example 1, with a yield of 63.96%.

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

[0084] 1H NMR (400MHz, DMSO) δ10.57(s,1H),8.99(s,1H),7.85(d,J=8.5Hz,2H),7.79–7.70(m,3H),7.51–7.42(m,2H),7.42–7.35( m,4H),7.22(d,J=5.4Hz,2H),7.18(d,J=7.6Hz,1H),7.12–7.05(m,1H),4.05–3.98(m,2H),3.91(s,3H),3.84(s,3H).13C NMR (100MHz, DMSO) δ192.3,167.7,155.6,149.8,145.4,144.1,142.3,140.6,135.0,132.6,131.6,131.6,131.3,130.8,130.7 ,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: Compound I-4 Preparation

[0086] The difference between this embodiment and embodiment 1 is that in step c, the The compound replaces the one in Example 1 The other operations were consistent with those in Example 1, with a yield of 61.62%.

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

[0088] 1H NMR (400MHz, DMSO) δ10.57(s,1H),9.13(s,1H),7.90–7.85(m,2H),7.83(dd,J=7.9,1.5Hz,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=8.5,1.1Hz,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 (100MHz, DMSO) δ192.3,168.4,155.7,149.8,145.5,145.2,141.9,140.5,135.1,134.8,133.1,131.7,131.7,131.3,130. 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: Compound I-5 Preparation

[0090] The difference between this embodiment and embodiment 1 is that in step c, the Instead of the The other operations were consistent with those in Example 1, with a yield of 60.06%.

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

[0092] 1H NMR (400MHz, DMSO) δ10.28(s,1H),7.74(d,J=8.8Hz,2H),7.68(d,J=8.9Hz,2H ),7.37(d,J=2.1Hz,1H),7.32–7.27(m,2H),7.21(d,J=2.8Hz,2H),7.12(d,J=8 .0Hz,2H),3.99–3.94(m,2H),3.90(s,3H),3.83(s,4H),2.41(d,J=7.1Hz,2H), 1.79(dq,J=13.5,6.8Hz,1H),1.42(d,J=7.0Hz,3H),0.85(d,J=6.6Hz,6H).13C NMR (100MHz, DMSO) δ192.3,173.2,155.6,149.8,145.4,140.9,140.1,139.4,134.7,131.8,131.8,131.3,130.6,130.4 ,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: Compound I-6 Preparation

[0094] The difference between this embodiment and embodiment 1 lies in step c. Specifically, in step c of this embodiment, the structure Instead of the The other operations were the same as those in Example 1, and the yield was 57.72%.

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

[0096] 1 H NMR(400MHz,DMSO)δ10.36(s,1H),7.75(d,J=8.9Hz,2H),7.71(d,J=8.9Hz ,2H),7.59–7.54(m,2H),7.54–7.50(m,2H),7.45–7.42(m,2H),7.40(dq,J= 8.1,2.2Hz,4H),7.37–7.33(m,1H),7.21(d,J=6.4Hz,2H),4.01–3.95(m,2 H), 3.91 (s, 3H), 3.84 (s, 3H), 3.18 (t, J = 7.2Hz, 2H), 2.95 (t, J = 7.2Hz, 2H).13 C NMR (100MHz, DMSO) δ192.3,170.5,163.1,155.6,149.8,145.4,145.1,140.8,134.8,134.7,132.5,131.9,131.9,131.3,130.6,130.3,130. 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: Compound I-7 Preparation

[0098] The difference between this embodiment and embodiment 1 lies in step c. Specifically, in step c of this embodiment, the structure Instead of The other operations were the same as those in Example 1, and the yield was 59.28%.

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

[0100] 1 H NMR (400MHz, DMSO) δ10.48(s,1H),7.79–7.69(m,4H),7.70(d,J=4.5Hz,2H),7.69–7.62(m,2H),7.38(t,J=2.0Hz,1H),7.24–7.17(m,3H ),6.94(d,J=9.0Hz,1H),6.72(dd,J=9.0,2.6Hz,1H),4.01–3.96(m,2H),3.90(s,3H),3.82(d,J=12.8Hz,5H),3.76(s,3H),2.30(s,3H). 13C NMR (100MHz, DMSO) δ192.3,169.3,168.4,156.1,155.7,149.7,145.4,140.7,138.1,135.9,134.8,134.7,131.9,131.9,131.6,131.6,131.6, 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] 2. Performance Test

[0102] Acetylcholinesterase (AChE) inhibition activity test and activity results

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

[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 automatic microplate reader.

[0106] Experimental steps:

[0107] 1) Solution preparation

[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 in buffer A at a concentration of 3 mmol / L;

[0111] Color developing agent DTNB: prepared with buffer A to a concentration of 0.6 mmol / L;

[0112] Enzyme solution: Electric eel AChE freeze-dried powder is prepared into 0.5U / ml working solution with buffer B, divided into aliquots, and stored at -20℃; when used, slowly melted in an ice-water mixture;

[0113] 2) The in vitro inhibitory effect of the samples on AChE was tested by Ellman spectrophotometry, and the specific method was as follows: during the experiment, the microplate reader was preheated for 15 minutes, and a blank group, a negative control group, a control group of a single test compound, and an experimental group of test compounds with different concentration gradients were set up on a 96-well plate; the ratio of each well was 160 μL PBS buffer, 40 μL PBS buffer and 40 μL AChE enzyme solution, 40 μL of a mixture of test compound solutions of different concentrations and 120 μL PBS buffer, and 40 μL of a mixture of test compound solutions of different concentrations and 40 μL AChE; then the plates were incubated at 37°C in a shaker for 30 minutes. Continue to add 40 μL of the colorimetric reagent 5,5-dithiobis(2-nitrobenzoic acid) solution and 40 μL of the substrate iodinated thioacetylcholine to the three replicate wells of the negative control group and the experimental group, and incubate in a 37°C shaker in the dark for 20 minutes. Then place the 96-well plate in a microplate reader to measure the absorbance value (A) at a wavelength of 412 nm. Each compound under different concentration conditions was tested 3 times, and the inhibition rate I was calculated. I = [1-(A test-A compound) / (A negative-A empty)] × 100. The data was processed using GraphPad Prism software, and the IC50 value of each test compound for acetylcholinesterase was finally obtained, as shown in the figure. Figure 2-8 As shown; activity data as Fig. 9 shown.

[0114] From the above results, it can be seen that the α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives with the general structural formula I provided by the present invention (i.e., compounds I-1 to I-7) have good acetylcholinesterase inhibitory activity, especially the acetylcholinesterase inhibitory IC values ​​of I-3, I-4, and I-7 are 50 The value is lower than or near 10 μM, indicating that the α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives with the general structural formula I are a class of drugs with the potential to treat diseases mediated by abnormal cholinesterase activity, and such derivatives have broad application prospects in the preparation of drugs for treating Alzheimer's disease. The series of compounds described in the present invention are used as active ingredients and then added with conventional pharmaceutical excipients to prepare anti-Alzheimer's disease drugs, which have the potential to be prepared into any dosage form such as tablets, granules, capsules, oral liquids, etc. in conventional pharmacy.

[0115] The above description is a detailed description of the preferred feasible embodiments of the present invention, but the embodiments are not intended to limit the scope of the patent application of the present invention. All equivalent changes or modified changes completed under the technical spirit suggested by the present invention should fall within the patent scope covered by the present invention.

Claims

1. α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives, characterized in that: It has a general structural formula as shown in Formula I: Wherein, R is selected from one of the structures 1-7 shown below:

2. The α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivative according to claim 1, characterized in that: The α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives are compounds I-1 to I-7 and pharmaceutically acceptable salts thereof. The structural formulas of compounds I-1 to I-7 are as follows:

3. The α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivative according to claim 2, characterized in that: The pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, hydrobromide, maleate, citrate, succinate, methanesulfonate, toluenesulfonate, xinafoate, pamoate or tartrate.

4. The method for preparing α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives according to any one of claims 1 to 3, characterized in that: The following steps are involved: a. Take the compound and compounds Dissolved in anhydrous ethanol, added with sodium hydroxide as a catalyst, the reaction yielded the compound b. Take the compound Dissolve in anhydrous ethanol, add stannous chloride, heat to react under nitrogen atmosphere, add dichloromethane and water to extract, and obtain compound The crude product was then purified by flash chromatography to give the compound Pure product; c. Take one of the structures 1-7 and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, dissolve them in N,N-dimethylformamide, add the catalyst triethylamine, stir evenly, and add the compound The reaction was heated, and after the reaction was completed, the mixture was extracted with ethyl acetate and the organic phase was purified by silica gel column chromatography to obtain the target compound.

5. The method for preparing α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives according to claim 4, characterized in that: Compound in step a and compounds The molar ratio of the compound in step b is 1:1; The molar ratio of R and compound is 1:5; The molar ratio is 5:

4.

6. The method for preparing α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives according to claim 4, characterized in that: In step a, the reaction temperature is 25° C. and the reaction time is 4-6 hours; in step b, the reaction temperature is 80° C. and the reaction time is 5.5-6.5 hours; in step c, the reaction temperature is 60° C. and the reaction time is 12-15 hours.

7. Use of the α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives according to any one of claims 1 to 3 in the preparation of drugs for preventing or treating neurodegenerative diseases.

8. Use of the α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivatives according to any one of claims 1 to 3 in the preparation of a drug for preventing or treating Alzheimer's disease.

9. A pharmaceutical composition, characterized in that The pharmaceutical composition contains the α-p-aminobenzylidene-5,6-dimethoxy-1-indanone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, and contains a pharmaceutically acceptable carrier or excipient.

10. The pharmaceutical composition according to claim 9, characterized in that: The pharmaceutical composition is in the form of tablets, capsules, powders, syrups, liquids, suspensions or injections.

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