Deoxyvasicinone derivatives, processes for their preparation and use thereof

Abstract

The present application belongs to the technical field of pharmaceutical therapy, and particularly relates to a deoxyvibradbaccatin derivative, a preparation method and application thereof. The structural formula of the deoxyvibradbaccatin derivative is shown in formula (A): wherein R is any one of a phenyl group, a 4-methylphenyl group, a 4-ethylphenyl group, a 4-propylphenyl group, a 4-isopropylphenyl group, a 4-tert-butylphenyl group, a 2,4,6-triisopropylphenyl group, a 4-methoxyphenyl group, a 2,4-dimethoxyphenyl group, a 3,4-dimethoxyphenyl group, a 4-fluorophenyl group, a 3-fluorophenyl group, a 2-fluorophenyl group, a 2,6-difluorophenyl group, a 4-trifluoromethylphenyl group, a 3-trifluoromethylphenyl group, a 2-trifluoromethylphenyl group and the like. The deoxyvibradbaccatin derivative can selectively inhibit the activity of acetylcholinesterase, and has the ability of selectively chelating metal ions, and has the potential to develop into a drug for treating Alzheimer's disease.

Description

Technical Field

[0001] This invention belongs to the field of pharmacotherapeutic technology, specifically relating to a deoxydaunocarbazone derivative, its preparation method, and its application in treating Alzheimer's disease. Background Technology

[0002] Alzheimer's disease (AD) is a common neurodegenerative disease clinically characterized by cognitive impairment, particularly memory loss. In recent years, its prevalence has been increasing annually due to the aging of the global population. Currently, FDA-approved drugs for treating AD typically provide temporary or incomplete symptom relief and are accompanied by serious side effects. Therefore, there is an urgent need to develop more effective AD treatments.

[0003] The main pathological features of Alzheimer's disease (AD) are extracellular senile plaques (SP), intracellular neurofibrillary tangles (NFT), loss of synapses and dendritic spines, and neuronal loss. The pathogenesis of AD involves abnormalities in multiple pathways and processes, with interactions and mutual influences between different mechanisms. Currently, its pathogenesis is not fully understood, with several hypotheses existing, including the cholinergic hypothesis, the amyloid cascade hypothesis, the oxidative stress hypothesis, the tau protein hypothesis, the metal ion hypothesis, and the inflammation and mitochondrial dysfunction hypothesis.

[0004] The cholinergic hypothesis is a key hypothesis in the pathogenesis of Alzheimer's disease (AD). The cholinergic system plays a crucial role in cognitive function, particularly in brain regions associated with learning and memory, such as the hippocampus and cortex. The cholinergic hypothesis posits that cognitive loss is related to a decline in the function of the cholinergic nervous system in the hippocampus and cortex. In AD patients, extensive damage to cholinergic neurons leads to a decrease in the level of acetylcholine (ACh) released into the synaptic cleft, thereby affecting the transmission of neural signals and resulting in cognitive and memory impairments. Inhibiting acetylcholinesterase reduces ACh hydrolysis, increases ACh levels in the synaptic cleft, and counteracts the decline in ACh levels caused by cholinergic neuronal damage and loss, increasing signal transduction capacity and thus improving cognitive and memory function in AD patients. Most currently marketed AD treatments are acetylcholinesterase inhibitors developed based on this hypothesis, including tacrine, donepezil, galantamine, and rivastigmine. However, tacrine has been withdrawn from clinical use due to hepatotoxicity issues.

[0005] However, current medications cannot fundamentally improve the clinical condition of the disease or halt its progression. The development of drugs to treat Alzheimer's disease (AD) remains a key focus in the pharmaceutical and medical fields, and the research and development of more effective treatments is urgently needed. Seeking new drugs to treat AD is of positive significance. Summary of the Invention

[0006] To address the aforementioned technical problems, the present invention first provides a deoxydaunoside alkaloid derivative, the structural formula of which is shown in formula (A):

[0007]

[0008] Wherein, R is any one of phenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 2,4,6-triisopropylphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2,6-difluorophenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 3-bromo-5-trifluoromethyl, 5-bromo-2-methoxyphenyl, 5-chloro-4-fluorophenyl, and 5-chloro-2,4-difluorophenyl.

[0009] The preparation method of this deoxydextrin derivative includes the following steps:

[0010] S1. Using phosphorus oxychloride as a catalyst, 4-nitro-o-aminobenzoic acid and 2-pyrrolidone undergo a dehydration condensation reaction. Excess 4-nitro-o-aminobenzoic acid is neutralized by adding ammonia water, and the yellow solid reaction product 6-nitro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one is collected.

[0011] S2. Palladium on carbon is added as a catalyst and hydrazine hydrate is used as a reducing agent to reduce the yellow solid reaction product to the intermediate compound 6-amino-2,3-dihydropyrrolo[2,1-b]quinazoline-9(1H)-one;

[0012] S3. The intermediate compound undergoes a substitution reaction with chloroacetyl chloride, and the white solid reaction product 2-chloro-N-(9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-6-yl)acetamide is collected;

[0013] S4. Mix the white solid reaction product with ammonia water. After the ammoniation reaction, collect the ammoniation reaction product 2-amino-N-(9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-6-yl)acetamide.

[0014] S5. The product of the amination reaction is added to dichloromethane and reacted with benzenesulfonyl chloride with various substituents R (RT). The product is purified by column chromatography to obtain the deoxyduckbillone alkaloid derivative.

[0015] The preparation route can be represented as follows:

[0016]

[0017] The preparation route is primarily for illustrative purposes and not for limiting the invention.

[0018] Step i: Compound a (4-nitro-o-aminobenzoic acid) and compound b (2-pyrrolidone) were mixed in toluene, and phosphorus oxychloride was added as a catalyst. The mixture was then refluxed at 110°C for 4 hours. The toluene solution was discarded, and the reactants were poured into water. Concentrated ammonia was added to make the solution alkaline to remove excess 4-nitro-o-aminobenzoic acid. The yellow solid was collected by filtration and purified by silica gel column chromatography to obtain compound c (6-nitro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one).

[0019] Step ii: Compound c was completely dissolved in methanol, and then 10% palladium on carbon and hydrazine hydrate were added. The mixture was hydrogenated at 60°C for 4 hours. After the reaction was completed, the palladium on carbon was filtered off while hot, and the methanol and hydrazine hydrate were removed by rotary evaporation. The crude product was purified by silica gel column chromatography to obtain compound d (6-amino-2,3-dihydropyrrolo[2,1-b]quinazoline-9(1H)-one).

[0020] Step iii: The mixture of compound d, chloroacetyl chloride, acetone, and triethylamine was stirred overnight at room temperature. After the reaction was completed, petroleum ether was added to precipitate a white solid. The solid was filtered and dried, and purified by silica gel column chromatography to obtain compound e (2-chloro-N-(9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-6-yl)acetamide).

[0021] Step iv: Compound e (2.8 g, 10 mmol) was dissolved in 200 mL of methanol, 20 mL of ammonia and 5 mL of triethylamine were added, and the mixture was aminated at 60 °C for 4 h. The reaction was carried out in a closed environment. The solution was removed by rotary evaporation, and the crude product was collected and passed through a short silica gel column to remove inorganic salts. The organic phases were combined, concentrated, and then column chromatography was used to obtain compound f (2-amino-N-(9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-6-yl)acetamide).

[0022] Step v: Compound f was dissolved in dichloromethane, and benzenesulfonyl chloride containing various substituents R was added. The reaction was carried out at room temperature for 10 hours. The reaction progress was monitored by thin-layer chromatography. The crude product was purified by column chromatography using a mixture of dichloromethane and methanol to obtain deoxyduckbillone alkaloid derivatives g1-g32. Wherein the substituent R is any one of phenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 2,4,6-triisopropylphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2,6-difluorophenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 3-bromo-5-trifluoromethyl, 5-bromo-2-methoxyphenyl, 5-chloro-4-fluorophenyl, and 5-chloro-2,4-difluorophenyl.

[0023] The present invention further provides the use of the deoxydaunoside derivative described above in the preparation of a drug that inhibits acetylcholinesterase activity.

[0024] The present invention also provides the application of the deoxydaunoside derivative described above in the preparation of neuroprotective drugs.

[0025] The present invention also provides the use of the deoxydaunoside derivative described above in the preparation of a medicament for treating Alzheimer's disease.

[0026] The present invention also provides a drug for inhibiting acetylcholinesterase activity, which contains a pharmaceutically effective dose of the deoxyduckbillone alkaloid derivative as described above.

[0027] The present invention also provides a medicament for treating Alzheimer's disease, which contains a pharmaceutically effective dose of the deoxyduckbillone alkaloid derivative as described above.

[0028] Preferably, the drug further comprises a pharmaceutically acceptable carrier.

[0029] Preferably, the pharmaceutically acceptable carrier includes one or more excipients with functions such as excipients, stabilizers, antioxidants, colorants, diluents, and sustained-release agents; such as starch, lipids, waxes, dextrin, sucrose, lactose, microcrystalline cellulose, gelatin, citric acid, inorganic salts, hydroxypropyl methylcellulose, hydroxyethyl cellulose, etc.

[0030] Preferably, the drug is any one of injection, tablet, pill, capsule, suspension or emulsion.

[0031] The beneficial effects of this invention are as follows:

[0032] 1. The deoxydaunoside derivatives involved in this invention have a selective inhibitory effect on AChE activity, indicating that such compounds have the potential to be developed into effective AChE inhibitors.

[0033] 2. The deoxydaunoside derivatives involved in this invention have the effects of antioxidant and neuroprotective multi-target small molecule compounds, and have the potential to be developed into neuroprotective drugs.

[0034] 3. Through selective chelation of metal ions and the use of multi-target small molecule compounds with antioxidant and neuroprotective properties, the deoxydaunoside derivatives provided by this invention have the potential to be developed into effective Alzheimer's disease treatments. Attached Figure Description

[0035] Figure 1 This demonstrates the neuroprotective effect of compound g17 against H2O2-induced PC12 damage. ## p<0.01, * p<0.05, ** p<0.01 and *** p<0.001 compared to the model group.

[0036] Figure 2-6 The results of the Morris water maze test in mice induced by scopolamine using compound g17 are shown.

[0037] Figure 2 The time it took for the drug-treated and normal mice to find a plateau;

[0038] Figure 3 The results show the difference in swimming speed between the drug group and the normal group;

[0039] Figure 4 The results show the number of crossovers between the drug group and the normal group mice on the virtual platform after the platform was removed;

[0040] Figure 5 The results show the time spent in the target quadrant by mice in the drug group and the normal group after the platform was removed;

[0041] Figure 6 This is a representative trajectory diagram of mice in the Morris water maze test. As can be seen from the diagram, after the platform was removed, except for the normal group, the mice treated with a dose of 30 mg / kg took significantly less time to enter the platform quadrant and entered the area more frequently than the model group. Detailed Implementation

[0042] Unless otherwise stated, the terms used herein have the meanings commonly understood by those skilled in the art.

[0043] The technical solution of the present invention will be described in more detail below with reference to the embodiments.

[0044] Example 1

[0045] Synthesis of compound g1

[0046]

[0047] Compound f (258 mg, 1 mM) was dissolved in 20 mL of dichloromethane, followed by the addition of benzenesulfonyl chloride (846 mg, 4.8 mM), and the reaction was carried out at room temperature for 8–12 hours. The reaction progress was monitored by TLC. After the reaction was complete, insoluble impurities were removed by filtration, and the solvent was removed by rotary evaporation. Compound g1 was obtained by column chromatography with methanol:dichloromethane (1:9), as a white solid with a yield of 72%. 1 HNMR (500MHz, DMSO-d6) δ10.34(s,1H),8.17(s,1H),8.02(d,J=8.7Hz,1H),7.86(dd,J=3.2,1.6Hz,2H),7.84(d,J=1.8Hz,1H),7.65–7.61(m ,1H),7.58(dd,J=8.3,6.3Hz,2H),7.50(dd,J=8.7,2.1Hz,1H),4.02(t,J=7.2Hz,2H),3.76(s,2H),3.05(t,J=7.9Hz,2H),2.20–2.10(m,2H). 13 C NMR(126MHz,DMSO-d6)δ167.55,161.35,159.93,150.56,143.98,140.91,132.9 4,129.58,127.07,127.03,117.92,116.02,115.13,46.66,46.42,32.36,19.36.

[0048] Example 2

[0049] Synthesis of compound g2

[0050]

[0051] The method is the same as in Example 1, except that the R group is replaced with 4-toluenesulfonyl chloride, yielding a white solid with a yield of 68%. 1H NMR (500MHz, DMSO-d6) δ10.33(s,1H),8.02(d,J=8.7Hz,1H),7.97(t,J=6.2Hz,1H),7.84(d,J=2.0Hz,1H),7.78(d,J=8.9Hz,1H),7.50(dd ,J=8.7,2.1Hz,1H),7.08(d,J=8.9Hz,1H),4.03(t,J=7.3Hz,2H),3.79(s,3H),3.72(d,J=6.2Hz,2H),3.06(t,J=7.9Hz,2H),2.18–2.11(m 2H). 13 C NMR(126MHz,DMSO-d6)δ167.53,161.35,159.94,150.55,143.99,143.23,137.96,1 30.00,127.13,127.04,117.96,116.01,115.17,46.67,46.45,32.36,21.41,19.38.

[0052] Example 3

[0053] Synthesis of compound g3

[0054]

[0055] The method is the same as in Example 1, except that the R group is replaced with 4-ethylbenzenesulfonyl chloride, yielding a white solid with a yield of 55%. 1 H NMR(500MHz,DMSO-d6)δ10.33(s,1H),8.06(t,J=6.2Hz,1H),8.02(d,J=8.7H z,1H),7.84(d,J=2.0Hz,1H),7.76(d,J=8.3Hz,2H),7.50(dd,J=8.7,2.1Hz, 1H),7.40(d,J=8.3Hz,2H),4.03(t,J=7.2Hz,2H),3.74(d,J=6.1Hz,2H),3.0 6(t,J=7.9Hz,2H),2.70–2.60(m,2H),2.20–2.10(m,2H),1.15(t,J=7.6,3H). 13 C NMR (126MHz, DMSO-d6) δ167.57,161.39,159.99,150.48,149.32,143.95,138.07,128. 88,127.22,127.02,117.98,115.96,115.14,46.68,46.39,32.32,28.41,19.31,15.50.

[0056] Example 4

[0057] Synthesis of compound g4

[0058]

[0059] The method is the same as in Example 1, except that the R group is replaced with 4-propanesulfonyl chloride, yielding a white solid with a yield of 62%. 1 H NMR(500MHz,DMSO-d6)δ10.30(s,1H),8.05(t,J=6.2Hz,1H),8.02(d,J=8.7Hz,1H) ,7.83(d,J=2.0Hz,1H),7.74(d,J=8.3Hz,2H),7.49(dd,J=8.7,2.0Hz,1H),7.37(d, J=8.3Hz,2H),4.03(t,J=7.1Hz,2H),3.74(d,J=6.2Hz,2H),3.05(t,J=7.9Hz,2H), 2.58(t,J=7.7Hz,2H),2.20–2.10(m,2H),1.58–1.49(m,2H),0.84(t,J=7.3Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ167.54,161.33,159.95,150.52,147.70,143.96,138.15,129.40, 127.13,127.01,117.95,115.99,115.15,46.67,46.42,37.34,32.34,24.11,19.36,13.96.

[0060] Example 5

[0061] Synthesis of compound g5

[0062]

[0063] The method is the same as in Example 1, except that the R group is replaced with 4-isopropylbenzenesulfonyl chloride, yielding a white solid with a yield of 62%. 1H NMR(500MHz,DMSO-d6)δ10.31(s,1H),8.06(t,J=6.2Hz,1H),8.02(d,J=8.7H z,1H),7.84(d,J=2.0Hz,1H),7.76(d,J=8.4Hz,2H),7.50(dd,J=8.7,2.0Hz,1 H),7.44(d,J=8.3Hz,2H),4.03(t,J=7.0Hz,2H),3.74(d,J=6.2Hz,2H),3.06( t,J=7.9Hz,2H),2.98–2.87(m,1H),2.21–2.10(m,2H),1.17(d,J=6.9Hz,6H). 13 C NMR (126MHz, DMSO-d6) δ167.56,161.35,159.96,153.78,150.49,143.96,138.22,127. 49,127.26,127.03,117.96,115.98,115.14,46.67,46.42,33.81,32.33,23.87,19.34.

[0064] Example 6

[0065] Synthesis of compound g6

[0066]

[0067] The method is the same as in Example 1, except that the R group is replaced with 4-tert-butylbenzenesulfonyl chloride, yielding a white solid with a yield of 69%. 1 H NMR (500MHz, DMSO-d6) δ10.32(s,1H),8.08(s,1H),8.01(d,J=6.9Hz,1H),7.84(d,J=1.6Hz,1H),7.77(d,J=6.8Hz,1H),7.58(d,J= 6.9Hz,2H),7.50(dd,J=6.9,2.0Hz,1H),4.03(t,J=7.3Hz,2H),3.74(s,2H),3.05(t,J=7.9Hz,2H),2.20–2.10(m,2H),1.25(s,9H). 13 C NMR(126MHz,DMSO-d6)δ167.55,161.30,159.94,155.93,150.53,143.97,137.90,1 27.00,126.39,117.95,115.99,115.17,46.66,46.46,35.23,32.34,31.18,19.36.

[0068] Example 7

[0069] Synthesis of compound g7

[0070]

[0071] The method is the same as in Example 1, except that the R group is replaced with 2,4,6-triisopropylbenzenesulfonyl chloride to obtain a white solid with a yield of 66%. 1 H NMR (500MHz, DMSO-d6) δ10.32(s,1H),8.01(d,J=8.7Hz,1H),7.89(t,J=6.0Hz,1H),7.83(d,J=2.0Hz,1H),7.48(dd,J=8.7,2.0Hz,1H),7.21(s,2H), 4.15–4.05(m,2H),4.02(t,J=7.4Hz,2H),3.82(d,J=6.1Hz,2H),3.05(t,J =7.9Hz,2H),2.95–2.85(m,1H),2.20–2.10(m,2H),1.20(t,J=7.0Hz,18H). 13 C NMR(126MHz,DMSO-d6)δ167.73,161.38,159.93,152.39,150.51,150.03,144.05,134.12,127 .07,123.88,117.91,115.95,115.05,46.67,45.75,33.76,32.34,29.54,25.22,23.88,19.35.

[0072] Example 8

[0073] Synthesis of compound g8

[0074]

[0075] The method is the same as in Example 1, except that the R group is replaced with 4-methoxybenzenesulfonyl chloride, yielding a white solid with a yield of 68%. 1H NMR (500MHz, DMSO-d6) δ10.33(s,1H),8.02(d,J=8.7Hz,1H),7.97(t,J=6.2Hz,1H),7.84(d,J=2.0Hz,1H),7.79–7.76(m,2H),7.50(dd,J =8.7,2.1Hz,1H),7.10–7.07(m,2H),4.03(t,J=7.3Hz,2H),3.79(s,3H),3.72(d,J=6.2Hz,2H),3.06(t,J=7.9Hz,2H),2.21–2.10(m,2H). 13 C NMR(126MHz,DMSO-d6)δ167.61,162.68,161.41,159.97,150.43,143.97,132.36,1 29.30,127.03,117.99,115.96,115.12,114.69,56.04,46.69,46.42,32.32,19.32.

[0076] Example 9

[0077] Synthesis of compound g9

[0078]

[0079] The method is the same as in Example 1, except that the R group is replaced with 2,4-dimethoxybenzenesulfonyl chloride, yielding a white solid with a yield of 57%. 1 H NMR (500MHz, DMSO-d6) δ10.24(s,1H),8.02(d,J=8.6Hz,1H),7.83(d,J=2.0H z,1H),7.67(d,J=8.8Hz,1H),7.48(dd,J=8.7,2.1Hz,1H),7.35(t,J=6.1Hz,1 H),6.64(d,J=2.4Hz,1H),6.58(dd,J=8.8,2.3Hz,1H),4.02(t,J=7.4Hz,2H), 3.86(s,3H),3.78(d,J=3.7Hz,4H),3.05(t,J=7.9Hz,2H),2.20–2.10(m,2H). 13C NMR (126MHz, DMSO-d6) δ167.90,164.68,161.32,159.93,158.41,150.56,144.03,131.34,127. 04,120.71,117.89,115.96,115.09,105.13,99.63,56.67,56.14,46.74,46.65,32.35,19.37.

[0080] Example 10

[0081] Synthesis of compound g10

[0082]

[0083] The method is the same as in Example 1, except that the R group is replaced with 3,4-dimethoxybenzenesulfonyl chloride, yielding a white solid with a yield of 48%. 1 H NMR (500MHz, DMSO-d6) δ10.29(s,1H),8.02(d,J=8.6Hz,1H),7.95(t,J=6.2Hz,1 H),7.84(d,J=2.0Hz,1H),7.49(dd,J=8.7,2.1Hz,1H),7.41(dd,J=8.4,2.2Hz,1H ),7.36(d,J=2.1Hz,1H),7.09(d,J=8.5Hz,1H),4.02(t,J=7.2Hz,2H),3.81(s,3 H),3.79(s,3H),3.72(d,J=6.2Hz,2H),3.05(t,J=7.9Hz,2H),2.20–2.09(m,2H). 13 C NMR (126MHz, DMSO-d6) δ167.58,161.32,159.93,152.44,150.55,149.07,143.95,132.20,127. 03,120.84,117.91,116.02,115.15,111.50,110.05,56.23,56.14,46.65,46.55,32.35,19.36.

[0084] Example 11

[0085] Synthesis of compound g11

[0086]

[0087] The method is the same as in Example 1, except that the R group is replaced with 4-fluorobenzenesulfonyl chloride, yielding a white solid with a yield of 77%. 1H NMR (500MHz, DMSO-d6) δ10.36(s,1H),8.23(t,J=5.8Hz,1H),8.02(d,J=8.7Hz,1H),7.91(ddd,J=10.2,5.2,2.6Hz,3H),7.85(d,J=2.0H z,1H),7.50(dd,J=8.7,2.1Hz,1H),7.43(t,J=8.8Hz,3H),4.02(t,2H),3.79(d,J=5.7Hz,2H),3.05(t,J=7.9Hz,2H),2.20–2.08(m,2H). 13 C NMR (126MHz, DMSO-d6) δ167.47,164.62(d,J=250.8Hz),161.35,159.92,150.55,143.93,137.34(d,J=3.1Hz ),130.12(d,J=9.5Hz),127.07,117.89,116.66(d,J=22.7Hz).116.03,115.11,46.65,46.36,32.34,19.34.

[0088] Example 12

[0089] Synthesis of compound g12

[0090]

[0091] The method is the same as in Example 1, except that the R group is replaced with 3-fluorobenzenesulfonyl chloride, yielding a white solid with a yield of 78%. 1 H NMR (500MHz, DMSO-d6) δ10.38(s,1H),8.35(s,1H),8.03(d,J=8.7Hz,1H),7.85(d,J=2.0Hz,1H),7.72–7.69(m,1H), 7.68–7.62(m,2H),7.53–7.47(m,2H),4.02(t,J=7.2Hz,2H),3.83(s,2H),3.05(t,J=7.9Hz,2H),2.23–2.12(m,2H). 13C NMR (126MHz, DMSO-d6) δ167.41,162.15(d,J=247.9Hz),161.34,159.91,150.55,143.91,143.08(d,J=6.5Hz),131.95(d,J=8.0Hz ),127.09,123.28(d,J=3.1Hz),120.08(d,J=21.1Hz),117.87,116.04,115.10,114.14(d,J=24.4Hz),46.65,46.36,32.35,19.35.

[0092] Example 13

[0093] Synthesis of compound g13

[0094]

[0095] The method is the same as in Example 1, except that the R group is replaced with 2-fluorobenzenesulfonyl chloride, yielding a white solid with a yield of 51%. 1 H NMR (500MHz, DMSO-d6) δ10.37(s,1H),8.42(t,J=6.11Hz,1H),8.02(d,J=8.7Hz,1H),7.87–7.80(m,2H),7.70–7.64(m,1H),7.48(dd,J=8.7, 2.1Hz,1H),7.46–7.39(m,1H),7.35(t,J=7.6Hz,1H),4.02(t,J=7.2Hz,2H),3.93(d,J=6.1Hz,2H),3.05(t,J=7.9Hz,2H),2.21–2.12(m,2H). 13 C NMR (126MHz, DMSO-d6) δ167.64, 161.34, 159.91, 158.87 (d, J = 253.4Hz), 150.56, 144.00, 135.60 (d, J = 8.5Hz), 129.84, 129. 29(d,J=14.2Hz),127.10,125.08(d,J=3.5Hz),117.85,117.57(d,J=21.2Hz),115.98,115.03,46.65,46.22,32.35,19.36.

[0096] Example 14

[0097] Synthesis of compound g14

[0098]

[0099] The method is the same as in Example 1, except that the R group is replaced with 2,6-difluorobenzenesulfonyl chloride, yielding a white solid with a yield of 68%. 1 H NMR (500MHz, DMSO-d6) δ10.42(s,1H),8.76–8.68(m,1H),8.02(d,J=8.7Hz,1H),7.81(d,J=2.0Hz,1H),7.67(tt,J=8.4,6. 0Hz,1H),7.47(dd,J=8.7,2.1Hz,1H),7.25(t,J=8.9Hz,2H),4.04–3.98(m,4H),3.05(t,J=7.9Hz,2H),2.23–2.12(m,2H). 13 CNMR(126MHz,DMSO-d6)δ167.51,161.36,160.16(d,J=4.1Hz),159.91,158.12(d,J=4.3Hz),150.56,143.95,135.41(t,J= 11.1Hz), 127.11, 119.26 (t, J = 16.4Hz), 117.83, 116.01, 115.04, 113.65 (dd, J = 23.2, 3.4Hz), 46.65, 46.28, 32.35, 19.35.

[0100] Example 15

[0101] Synthesis of compound g15

[0102]

[0103] The method is the same as in Example 1, except that the R group is replaced with 4-trifluoromethylbenzenesulfonyl chloride, yielding a white solid with a yield of 69%. 1 H NMR (500MHz, DMSO-d6) δ10.37(s,1H),8.50(t,J=6.1Hz,1H),8.06(d,J=8.2Hz,2H),8.02(d,J=8.7Hz,1H),7.97(d,J=8.3Hz,2H),7.82 (d,J=2.1Hz,1H),7.47(dd,J=8.7,2.1Hz,1H),4.03(t,J=7.2Hz,2H),3.85(d,J=6.1Hz,2H),3.06(t,J=7.9Hz,2H),2.21–2.13(m,2H). 13C NMR(126MHz,DMSO-d6)δ167.33,161.32,159.91,150.54,144.92,143.87,128.07, 127.06,126.77(q,J=3.8Hz),117.84,116.05,115.09,46.65,46.33,32.34,19.35.

[0104] Example 16

[0105] Synthesis of compound g16

[0106]

[0107] The method is the same as in Example 1, except that the R group is replaced with 3-trifluoromethylbenzenesulfonyl chloride, yielding a white solid with a yield of 71%. 1 H NMR (500MHz, DMSO-d6) δ10.39(s,1H),8.49(s,1H),8.15(d,J=8.2Hz,2H),8.01(d,J=8.7Hz,2H),7.84(t,J=7.8Hz,1H),7.81 (d,J=2.0Hz,1H),7.46(dd,J=8.7,2.1Hz,1H),4.02(t,J=7.2Hz,2H),3.87(s,2H),3.06(t,J=7.9Hz,2H),2.21–2.10(m,2H). 13 C NMR (126MHz, DMSO-d6) δ167.33,161.34,159.92,150.54,143.86,142.29,131.14,130.16(d,J=32.6Hz),129.66( q,J=2.9Hz),127.05,125.00,123.68(q,J=4.0Hz),122.83,117.83,116.04,115.07,46.65,46.31,32.35,19.35.

[0108] Example 17

[0109] Synthesis of compound g17

[0110]

[0111] The method is the same as in Example 1, except that the R group is replaced with 2-trifluoromethylbenzenesulfonyl chloride, yielding a white solid with a yield of 53%. 1H NMR (500MHz, DMSO-d6) δ10.39(s,1H),8.40(t,J=6.1Hz,1H),8.21(dd,J=7.9,1.4Hz,1H),8.03(d,J=8.7Hz,1H),7.98(dd,J=7.8,1.4Hz,1H),7.88(td ,J=7.8,7.5,1.3Hz,1H),7.84–7.80(m,2H),7.49(dd,J=8.7,2.0Hz,1H),4. 02(t,2H),3.94(d,J=6.0Hz,2H),3.05(t,J=7.9Hz,2H),2.22–2.13(m,2H). 13 C NMR (126MHz, DMSO-d6) δ167.60,161.37,159.91,150.56,143.94,140.04,133.58,133.32,130.65,128.74(q,J=6. 2Hz), 127.13, 126.54 (q, J = 32.6Hz), 123.43 (d, J = 273.7Hz), 117.84, 116.01, 115.03, 46.65, 46.39, 32.34, 19.34.

[0112] Example 18

[0113] Synthesis of compound g18

[0114]

[0115] The method is the same as in Example 1, except that the R group is replaced with 4-trifluoromethoxybenzenesulfonyl chloride, yielding a white solid with a yield of 51%. 1 H NMR (500MHz, DMSO-d6) δ10.40(s,1H),8.35(t,J=6.1Hz,1H),8.02(d,J=8.7Hz,1H),8.00–7.96(m,2H),7.85(d,J=2.0Hz,1H),7.58 (dt,J=7.6,1.1Hz,2H),7.50(dd,J=8.7,2.1Hz,1H),4.03(t,2H),3.82(d,J=6.1Hz,2H),3.07(t,J=7.9Hz,2H),2.23–2.12(m,2H). 13C NMR(126MHz,DMSO-d6)δ167.43,161.44,159.88,151.28,150.29,143.97,139.96,129.70,1 27.09,121.79,120.31(d,J=257.9Hz),117.92,115.98,114.92,46.72,46.33,32.33,19.34.

[0116] Example 19

[0117] Synthesis of compound g19

[0118]

[0119] The method is the same as in Example 1, except that the R group is replaced with 3-trifluoromethoxybenzenesulfonyl chloride, yielding a white solid with a yield of 37%. 1 H NMR(500MHz,DMSO-d6)δ10.39(s,1H),8.46(t,J=6.1Hz,1H),8.02(d,J=8.7H z,1H),7.89(dt,J=7.8,1.4Hz,1H),7.84(d,J=2.0Hz,1H),7.79(s,1H),7.74 (t,J=8.0Hz,1H),7.67–7.64(m,1H),7.49(dd,J=8.7,2.1Hz,1H),4.03(t,J= 7.2Hz,2H),3.85(d,J=6.1Hz,2H),3.06(t,J=7.9Hz,2H),2.21–2.12(m,2H). 13 C NMR(126MHz,DMSO-d6)δ167.35,161.36,159.91,150.52,148.67(d,J=1.9Hz),143.92,143.21,132.00,127 .06,126.16,125.54,120.39(d,J=257.9Hz),119.46,117.86,116.03,115.06,46.66,46.30,32.35,19.35.

[0120] Example 20

[0121] Synthesis of compound g20

[0122]

[0123] The method is the same as in Example 1, except that the R group is replaced with 2-trifluoromethoxybenzenesulfonyl chloride, yielding a white solid with a yield of 31%. 1H NMR (500MHz, DMSO-d6) δ10.40(s,1H),8.32(t,J=6.1Hz,1H),8.03(d,J=8.6Hz,1H),7.99(dd,J=7.8,1.7Hz,1H),7.84(d,J=2.0Hz,1H),7.74(ddd,J=8.3 ,7.5,1.7Hz,1H),7.57–7.51(m,2H),7.49(dd,J=8.7,2.0Hz,1H),4.02(t,J= 7.2Hz, 2H), 3.94 (d, J = 6.1Hz, 2H), 3.05 (t, J = 7.9Hz, 2H), 2.22–2.10 (m, 2H). 13 C NMR (126MHz, DMSO-d6) δ167.69,161.36,159.92,150.56,145.68,144.01,135.13,133.78,130.37,127.6 8,127.09,127.09,121.18,120.38(d,J=258.9Hz),117.85,115.98,115.04,46.65,46.36,32.35,19.36.

[0124] Example 21

[0125] Synthesis of compound g21

[0126]

[0127] The method is the same as in Example 1, except that the R group is replaced with 4-chlorobenzenesulfonyl chloride, yielding a white solid with a yield of 77%. 1 H NMR (500MHz, DMSO-d6) δ10.70(s,1H),8.34(t,J=6.1Hz,1H),8.12(d,J=8.7Hz,1H),8.09(d,J=2.0Hz,1H),7.84(d,J=6.9Hz,2H), 7.65(d,J=8.7Hz,2H),7.60–7.58(m,2H),4.15(t,J=7.4Hz,2H),3.83(d,J=5.6Hz,2H),3.36(t,J=7.9Hz,2H),2.32–2.23(m,2H). 13 C NMR(126MHz,DMSO-d6)δ168.08,158.33,147.45,145.18,139.82,137.85,133.5 4,129.70,129.04,128.20,127.88,119.33,114.50,48.63,46.39,32.20,19.08.

[0128] Example 22

[0129] Synthesis of compound g22

[0130]

[0131] The method is the same as in Example 1, except that the R group is replaced with 3-chlorobenzenesulfonyl chloride, yielding a white solid with a yield of 59%. 1 H NMR (500MHz, DMSO-d6) δ10.38(s,1H),8.37(t,J=6.1Hz,1H),8.02(d,J=8.7Hz,1H) ,7.86(t,J=2.0Hz,1H),7.84(d,J=2.0Hz,1H),7.79(dt,J=7.8,1.4Hz,1H),7.70(d dd,J=8.1,2.1,1.0Hz,1H),7.61(t,J=7.9Hz,1H),7.49(dd,J=8.7,2.1Hz,1H),4.0 2(t,J=7.4Hz,2H),3.82(d,J=6.1Hz,2H),3.06(t,J=7.9Hz,2H),2.21–2.10(m,2H). 13 CNMR(126MHz,DMSO-d6)δ167.39,161.39,159.92,150.52,143.92,142.89,134.17,132.8 9,131.63,127.09,126.75,125.74,117.91,116.05,115.09,46.67,46.35,32.36,19.37.

[0132] Example 23

[0133] Synthesis of compound g23

[0134]

[0135] The method is the same as in Example 1, except that the R group is replaced with 2-chlorobenzenesulfonyl chloride, yielding a white solid with a yield of 73%. 1H NMR(500MHz,DMSO-d6)δ10.34(s,1H),8.31(t,J=6.1Hz,1H),8.03–8.01(m,1H), 8.01–8.00(m,1H),7.83(d,J=2.0Hz,1H),7.66(dd,J=7.9,1.3Hz,1H),7.61(td,J =7.8,1.7Hz,1H),7.51(dd,J=7.6,1.4Hz,1H),7.48(dd,J=8.7,2.1Hz,1H),4.02( t,J=7.2Hz,2H),3.90(d,J=6.1Hz,2H),3.05(t,J=7.9Hz,2H),2.21–2.12(m,2H). 13 C NMR (126MHz, DMSO-d6) δ167.68,161.37,159.91,150.52,143.99,138.77,134.34,132.1 5,131.36,130.59,127.91,127.11,117.85,115.98,115.00,46.67,46.40,32.36,19.36.

[0136] Example 24

[0137] Synthesis of compound g24

[0138]

[0139] The method is the same as in Example 1, except that the R group is replaced with 2-chlorobenzenesulfonyl chloride, yielding a white solid with a yield of 86%. 1 H NMR (500MHz, DMSO-d6) δ10.40(s,1H),8.47(t,J=6.1Hz,1H),8.01(d,J=8.7Hz,1H),7.79(d,J=2.0Hz,1H),7.60(dd,J=8.1,0.5Hz,3H),7.51 (dd,J=8.8,7.3Hz,1H),7.46(dd,J=8.7,2.1Hz,1H),4.02(t,J=7.4Hz,2H),3.96(d,J=6.1Hz,2H),3.05(t,J=7.9Hz,2H),2.20–2.11(m,2H). 13C NMR(126MHz,DMSO-d6)δ167.47,161.36,159.90,150.52,143.94,136.63,134.1 8,133.58,131.94,127.12,117.83,116.00,115.01,46.66,46.41,32.35,19.35.

[0140] Example 25

[0141] Synthesis of compound g25

[0142]

[0143] The method is the same as in Example 1, except that the R group is replaced with 3,5-dichlorobenzenesulfonyl chloride, yielding a white solid with a yield of 68%. 1 H NMR (500MHz, DMSO-d6) δ10.56(s,1H),9.82(s,1H),8.58(t,J=6.1Hz,1H),8.02(d,J=8.7Hz,1H),7.86(d,J=2.1Hz,1H),7.81( d,J=1.9Hz,2H),7.52(d,J=2.0Hz,1H),4.03(t,J=7.3Hz,2H),3.89(d,J=6.1Hz,2H),3.09(d,J=2.5Hz,2H),2.22–2.11(m,2H). 13 C NMR(126MHz,DMSO-d6)δ167.34,161.42,159.90,144.21,143.93,135.31,134.1 0,132.48,128.55,127.06,125.71,124.71,117.91,46.71,46.41,32.36,19.37.

[0144] Example 26

[0145] Synthesis of compound g26

[0146]

[0147] The method is the same as in Example 1, except that the R group is replaced with 4-bromobenzenesulfonyl chloride, yielding a white solid with a yield of 38%. 1H NMR (500MHz, DMSO-d6) δ10.35(s,1H),8.30(s,1H),8.02(d,J=8.7Hz,1H),7.83(d,J=2.1Hz,1H),7.80(d,J=8.8Hz,2H),7.77(d,J=8.8Hz,2H),7. 49(dd,J=8.7,2.1Hz,1H),4.02(t,J=7.5Hz,2H),3.79(s,2H),3.40(d,J= 1.4Hz,7H),3.06(t,J=7.9Hz,2H),2.58–2.49(m,1H),2.20–2.10(m,2H). 13 C NMR(126MHz,DMSO-d6)δ167.41,161.35,159.93,150.55,143.91,140.24,132.6 1,129.13,127.08,126.78,117.90,116.05,115.12,46.66,46.35,32.35,19.35.

[0148] Example 27

[0149] Synthesis of compound g27

[0150]

[0151] The method is the same as in Example 1, except that the R group is replaced with 3-bromobenzenesulfonyl chloride, yielding a white solid with a yield of 73%. 1 H NMR (500MHz, DMSO-d6) δ10.38(s,1H),8.36(s,1H),8.02(d,J=8.7Hz,1H),7.99(t,J=1.9Hz,1H),7.85–7.83(m,2H),7.83–7.82(m ,1H),7.55(t,J=7.9Hz,1H),7.49(dd,J=8.7,2.1Hz,1H),4.02(t,2H),3.82(s,2H),3.06(t,J=6.3,6.3Hz,2H),2.21–2.11(m,2H). 13 C NMR (126MHz, DMSO-d6) δ167.38,161.36,159.94,150.56,143.91,143.01,135.76,131.8 2,129.52,127.08,126.08,122.49,117.92,116.05,115.14,46.66,46.35,32.36,19.36.

[0152] Example 28

[0153] Synthesis of compound g28

[0154]

[0155] The method is the same as in Example 1, except that the R group is replaced with 2-bromobenzenesulfonyl chloride, yielding a white solid with a yield of 66%. 1 H NMR(500MHz,DMSO-d6)δ10.60(s,1H),8.24(t,J=6.1,6.1Hz,1H),8.04(dd,J=7 .8,1.7Hz,1H),8.01(d,J=8.7Hz,1H),7.86(d,J=2.0Hz,1H),7.82(dd,J=7.8,1. 3Hz,1H),7.54(qd,J=9.0,8.3,1.7Hz,2H),7.50(td,J=7.6,1.8Hz,1H),4.02(t ,J=7.2Hz,2H),3.90(d,J=6.0Hz,2H),3.06(t,J=7.9Hz,2H),2.21–2.12(m,2H). 13 C NMR (126MHz, DMSO-d6) δ167.71,161.34,159.94,150.55,144.07,140.42,135.67,134.2 8,130.74,128.45,127.04,119.84,117.89,115.96,115.04,46.66,46.50,32.37,19.37.

[0156] Example 29

[0157] Synthesis of compound g29

[0158]

[0159] The method was the same as in Example 1, except that the R group was replaced with 3-bromo,5-trifluoromethylbenzenesulfonyl chloride, yielding a white solid in 62% yield. ¹H NMR (500 MHz, DMSO-d6) δ 10.42 (s, ¹H), 8.62 (t, J = 6.1 Hz, ¹H), 8.28 (s, ¹H), 8.27 (s, ¹H), 8.10 (s, ¹H), 8.02 (d, J = 8.7 Hz, ¹H), 7.81 (d, J = 2.0 Hz, ¹H), 7.46 (dd, J = 8.7, 2.1 Hz, ¹H), 4.03 (t, 2H), 3.92 (d, J = 6.1 Hz, 2H), 3.06 (t, J = 7.9 Hz, 2H), 2.23–2.12 (m, 2H). ¹³C NMR (126MHz, DMSO-d6) δ167.26, 161.38, 159.91, 150.49, 144.15, 143.81, 133.71, 132.48 (d, J = 3.9Hz), 131.99 (q, J = 33. 3Hz), 127.07, 123.59, 122.94 (d, J = 273.6Hz), 122.79 (d, J = 3.8Hz), 117.83, 116.07, 115.04, 46.67, 46.33, 32.35, 19.36.

[0160] Example 30

[0161] Synthesis of compound g30

[0162]

[0163] The method is the same as in Example 1, except that the R group is replaced with 5-bromo,2-methoxybenzenesulfonyl chloride, yielding a white solid with a yield of 83%. 1 H NMR (500MHz, DMSO-d6) δ10.32(s,1H),8.02(d,J=8.6Hz,1H),7.90(t,J=6.1Hz,1H),7.85(d,J=2.0Hz,1H),7.81(d,J=2.6Hz,1H),7.72(dd,J=8.9,2.6 Hz,1H),7.48(dd,J=8.7,2.1Hz,1H),7.16(d,J=8.9Hz,1H),4.02(t,2H),3. 90(d,J=6.1Hz,2H),3.86(s,3H),3.06(t,J=7.9Hz,2H),2.20–2.11(m,2H). 13C NMR(126MHz,DMSO-d6)δ167.82,161.37,159.92,156.23,150.53,144.04,137.19,131.43,1 30.77,127.11,117.86,115.97,115.71,114.96,111.28,56.99,46.67,46.64,32.36,19.38.

[0164] Example 31

[0165] Synthesis of compound g31

[0166]

[0167] The method is the same as in Example 1, except that the R group is replaced with 3-chloro,4-fluorobenzenesulfonyl chloride, yielding a white solid with a yield of 61%. 1 H NMR (500MHz, DMSO-d6) δ10.42(s,1H),8.41(t,J=6.1Hz,1H),8.03(d,J=3.2Hz,1H),8.02(t,1H),7.88–7.84(m,1H),7.84(d,J=2.2Hz,1H), 7.64(t,J=8.9Hz,1H), 7.49(dd,J=8.7,2.1Hz,1H), 4.03(t,J=7.0Hz,2H), 3.85(d,J=6.1Hz,2H), 3.06(t,J=7.9Hz,2H), 2.20–2.12(m,2H). 13 C NMR (126MHz, DMSO-d6) δ167.38,161.36,160.84,159.90,158.82,150.50,143.88,138.57(d,J=3.6Hz),129.77,128.54( d,J=8.9Hz),127.07,120.94(d,J=18.8Hz),118.25(d,J=22.2Hz),117.86,116.04,115.06,46.66,46.38,32.35,19.35.

[0168] Example 32

[0169] Synthesis of compound g32

[0170]

[0171] The method is the same as in Example 1, except that the R group is replaced with 5-chloro,2,4-difluorobenzenesulfonyl chloride, yielding a white solid with a yield of 68%. 1H NMR (500MHz, DMSO-d6) δ10.42(s,1H),8.70(t,J=6.1Hz,1H),8.02(d,J=8.7Hz,1H),7.96(t,J=7.6Hz,1H),7.84(d,J=9.6Hz,1H),7.81 (d,J=1.9Hz,1H),7.46(dd,J=8.7,2.1Hz,1H),4.03(t,J=7.2Hz,2H),3.96(d,J=6.1Hz,2H),3.06(t,J=7.9Hz,2H),2.21–2.12(m,2H). 13 C NMR(126MHz, DMSO-d6)δ167.54,161.38,159.90,159.22(dd,J=14.7,12.1Hz),157.12(d,J=12.2Hz),150.54,143.88,131.01, 127.29(d,J=4.1Hz),127.12,117.80,116.04,115.89(d,J=4.1Hz),115.02,108.07(t,J=26.8Hz),46.67,46.20,32.35,19.36.

[0172] Example 33

[0173] Cholinesterase activity inhibition experiment

[0174] (1) Preparation of drug solution:

[0175] Weigh a certain amount of each sample to be analyzed and dissolve it in dimethyl sulfoxide (DMSO) to prepare a 10 mM concentration. Store it in a -20°C freezer. Before use, dilute it with phosphate buffer (0.1 mol / L, pH=8.0) to the required concentration so that the final concentration of DMSO is less than or equal to 0.5% (v / v).

[0176] (2) Preparation of enzyme stock solution:

[0177] Acetylcholinesterase and butyrylcholinesterase were purchased from Sigma-Aldrich; a certain amount of acetylcholinesterase or butyrylcholinesterase was weighed and diluted with deionized water to the appropriate activity range.

[0178] (3) Preparation of substrate stock solution:

[0179] Acetylthiocholine (ATCI) and butylthiocholine (BTCI) were purchased from Sigma-Aldrich. A certain amount of ATCI or BTCI was weighed and prepared into a 0.01 mol / L solution with phosphate buffer (0.1 mol / L, pH 8.0), and stored in the dark at 4°C.

[0180] (4) Preparation of the colorimetric reagent stock solution:

[0181] The colorimetric reagent 5,5-dithiobis(2-nitrobenzoic acid) (DTNB) was purchased from Sigma-Aldrich. A certain amount of DTNB was weighed and prepared into a 0.01 mol / L solution with phosphate buffer (0.1 mol / L, pH 8.0), and stored at 4°C in the dark.

[0182] (5) Enzyme inhibition test

[0183] The compound dissolved in DMSO was diluted to different concentrations with PB (phosphate buffer) solution and then added to 48-well plates (100 μL per well). The plates were then incubated with 100 μL of AChE or BuChE at 37°C. After 20 minutes, 100 μL of substrate (iodothioacetylcholine or S-iodide butyrylthiocholine) and 100 μL of PB solution were added to the 48-well plates. Then, 100 μL of chromogenic material (5,5-dithiobis-(2-nitrobenzoic acid, DTNB, Ellman's reagent) was added and incubated for 5 minutes. The absorbance was then measured at 410 nm using a multi-plate reader.

[0184] (6) Calculation of results:

[0185] IC 50 Value calculation: The change in absorbance (slope) measured without the addition of inhibitor is taken as 100 activity units (Acontrol). Relative enzyme activity = (absorbance change with inhibitor / absorbance change without inhibitor) × 100. When the relative enzyme activity reaches 50, it is the IC50 of the inhibitor. 50 value.

[0186] The experimental results are the average of three independent experiments.

[0187] (7) Experimental results:

[0188] Table 1. Inhibitory activities of compounds against acetylcholinesterase and butyrylcholinesterase

[0189]

[0190]

[0191] aSelectivity for acetylcholinesterase = IC 50 (Butyrylcholinesterase) / IC 50 (acetylcholinesterase)

[0192] Results and Discussion: The synthesized compounds exhibit some inhibitory activity against AChE, demonstrating that these compounds can selectively inhibit AChE activity and possess the potential to be developed into drugs for the treatment of Alzheimer's disease (AD). Among them, compound g17 showed the most significant inhibitory effect on AChE, with an IC50 value of [missing value]. 50 =0.24±0.04μM.

[0193] Example 34

[0194] Inhibition of H2O2-induced cytotoxicity

[0195] Mouse neuronal cell line PC12 was routinely cultured in DMEM complete medium containing 10% fetal bovine serum at 37°C, under saturated humidity, in a carbon dioxide incubator containing 5% CO2 and 95% air. Cells in the logarithmic growth phase were harvested, digested with 0.25% trypsin solution, and then resuspended in complete medium. Cells were counted using a cell counting chamber under a microscope, and the cell concentration was adjusted to 1 × 10⁻⁶ cells / mL. 5 Cells were seeded at 100 μL / well in 96-well cell culture plates and cultured overnight to allow cell adhesion. The experiment included a test sample group, a blank group, and a solvent control group. The culture medium in the 96-well cell culture plates was discarded, and the test sample group solution was added. The blank group received complete culture medium without the compound, and the solvent control group received the same concentration of DMSO. After pre-incubation for 30 min, 140 μM hydrogen peroxide was added. The model group did not receive the test compound; 250 μM hydrogen peroxide was added directly. After incubation for 24 h, the cells were protected from light, and 20 μL of 5 mg / mL MTT stock solution was added to each well, and the cells were cultured for 4 h. The culture medium in the 96-well cell culture plates was discarded, and 100 μL of DMSO was added to each well. The plates were shaken to completely dissolve the formazan in the DMSO, and the absorbance of each well was measured at 570 nm using a microplate reader.

[0196] G17 cells, which showed the best cholinesterase inhibition assay, were selected for neuroprotective experiments. Cells were pretreated with compounds at concentrations of 1 μM, 2.5 μM, 5 μM, 10 μM, and 20 μM. MTT assays were performed to compare cell viability after 24 hours of incubation with hydrogen peroxide (250 μM) with that of the hydrogen peroxide-induced control group. The cell survival rate promoted by the compounds was calculated using the following formula:

[0197] Cell survival rate (%) = 100% * (A) 待测化合物 -A 模型组 ) / (A 模型组 -A 空白组 ).

[0198] The results are as follows Figure 1 As shown, cell viability increases in a concentration-dependent manner after compound treatment. Specifically, g17 exhibits a more significant neuroprotective effect on hydrogen peroxide-induced PC12 cells compared to the positive control.

[0199] Example 35

[0200] Morris water maze experiment

[0201] 1) Male C57BL mice (18-23g), 8 weeks old, were purchased from the Experimental Center of Anhui University of Traditional Chinese Medicine. The mice were housed under standard conditions in a temperature and humidity controlled environment (23℃~25℃, 40%~60%, 12h).

[0202] 2) Treatment and modeling:

[0203] Thirty mice were randomly divided into five groups. The normal control group and the model group were administered 0.5% sodium carboxymethyl cellulose (CMC-Na) solution by gavage for 7 days. The drug group and the positive control group were administered different concentrations of g17 (30 mg / kg, 10 mg / kg) and donepezil (10 mg / kg) by gavage, respectively. On day 7, except for the normal control group (physiological saline), the mice in the other groups were injected with scopolamine to establish the AD model.

[0204] 3) Morris Water Maze Test

[0205] The MWM device mainly consists of a circular water tank (150 cm in diameter and 60 cm in height), a 10 cm diameter escape platform, a data acquisition system, and an analysis system. First, the circular water tank was filled with water (1.0 cm above the escape platform), and titanium dioxide (0.25 g / L) was added to make the water turbid. The platform was fixed in the third quadrant of the circular water tank (out of four quadrants). All mice were trained for four days, with four training trials per day.

[0206] A mouse (head facing the pool wall) was randomly placed in one of the four quadrants. If the mouse successfully found the platform within 60 seconds, it was allowed to stay on the platform for 15 seconds; otherwise, it was taken to the platform and allowed to stay there for 15 seconds. Four days later, the platform was removed from its position, and the mouse was placed in the first quadrant, the furthest from the platform, to search for the platform (60 seconds). The time spent in the platform quadrant and the number of times the mouse entered that area within 60 seconds were recorded.

[0207] The results are as follows Figure 2-6 As shown. By Figure 2 It can be seen that the drug group reduced the time for mice to find the platform in a dose-dependent manner, i.e., reduced the escape latency of the mice. Furthermore, compared with the model group (Model), the drug... Figure 3It can be seen that there was no significant difference in swimming speed between the drug group and the normal group. It can be seen that the drug group reduced the time for mice to find the platform in a dose-dependent manner, i.e., reduced the escape latency of the mice. On the fifth day, by Figure 4 and Figure 5 It can be seen that when the platform was removed, mice treated with a dose of 30 mg / kg had significantly better time spent in the target quadrant and more crossovers on the virtual platform via the space probe experiment than mice treated with a dose of 10 mg / kg. Figure 6 The figure shows the representative trajectory of mice in the Morris water maze test. As can be seen from the figure, after the platform was removed, except for the normal group, the mice treated with a dose of 30 mg / kg took significantly less time to enter the platform quadrant and entered the area more frequently than the other groups.

[0208] Experiments show that the compound g17 involved in this invention can significantly improve the learning and memory abilities and behaviors of AD animal models in terms of space and orientation, and its effect is superior to donepezil, a first-line clinical drug, indicating that the compound g17 has the potential to be developed into an effective treatment for Alzheimer's disease.

[0209] The above are merely preferred embodiments of the present invention and are not intended to limit the scope of the invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A deoxyvasicinone derivative, characterized by, The structural formula of the deoxy-duckbill ketone derivative is shown in formula (A): （A） Wherein, R is any one of 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, and 2-trifluoromethylphenyl.

2. A process for preparing the deoxyvasicinone derivative according to claim 1, characterized by, Includes the following steps: S1. Using phosphorus oxychloride as a catalyst, 4-nitro-o-aminobenzoic acid and 2-pyrrolidone undergo a dehydration condensation reaction. Excess 4-nitro-o-aminobenzoic acid is neutralized by adding ammonia water, and the yellow solid reaction product 6-nitro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one is collected. S2. Palladium on carbon is added as a catalyst and hydrazine hydrate is used as a reducing agent to reduce the yellow solid reaction product to the intermediate compound 6-amino-2,3-dihydropyrrolo[2,1-b]quinazoline-9(1H)-one; S3. The intermediate compound undergoes a substitution reaction with chloroacetyl chloride, and the white solid reaction product 2-chloro-N-(9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-6-yl)acetamide is collected; S4. Mix the white solid reaction product with ammonia water. After the ammoniation reaction, collect the ammoniation reaction product 2-amino-N-(9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-6-yl)acetamide. S5. The product of the amination reaction is added to dichloromethane and reacted with benzenesulfonyl chloride having various substituents R (RT). The product is purified by column chromatography to obtain the deoxydoxyduckbillone alkaloid derivative; wherein the substituent R is any one of 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, and 2-trifluoromethylphenyl.

3. The use of a deoxydaunoside derivative as described in claim 1 in the preparation of a drug that inhibits acetylcholinesterase activity.

4. The use of a deoxydaunoside derivative as described in claim 1 in the preparation of neuroprotective drugs.

5. The use of a deoxydaunoside derivative as described in claim 1 in the preparation of a medicament for treating Alzheimer's disease.

6. A drug for inhibiting acetylcholinesterase activity, comprising a pharmaceutically effective dose of the deoxydaunoside derivative as described in claim 1.

7. A medicament for treating Alzheimer's disease, comprising a pharmaceutically effective dose of the deoxyduckbillone alkaloid derivative as claimed in claim 1.

8. The medicament according to claim 6 or 7, characterized in that The drug also contains a pharmaceutically acceptable carrier.

9. The medicament according to claim 8, wherein The pharmaceutically acceptable carriers include carriers that function as one or more of the following: excipients, stabilizers, antioxidants, colorants, diluents, and sustained-release agents.

10. The medicament according to claim 9, wherein The drug is any one of the following: injection, tablet, pill, capsule, suspension, or emulsion.

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