A novel zaltopiprofen derivative, its preparation method and application

Abstract

This invention discloses a novel zaltoibuprofen derivative, its preparation method, and its applications. The derivative is 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one. The preparation method involves heating zaltoibuprofen, dimethyl sulfoxide, and potassium fluoride in an oil bath. After the reaction is complete, the mixture is separated and purified to obtain 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one. This preparation method has the advantages of simple operation, low cost, and high yield. The obtained derivative, 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one, exhibits neuroprotective activity against nerve cell damage and can be used in the preparation of neuroprotective agents for the treatment of neurodegenerative diseases.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis and application technology, specifically relating to a new zaltopiprofen derivative, its preparation method and application. Background Technology

[0002] Neurodegenerative diseases are a class of diseases characterized by the progressive loss of specific subtypes of neurons, leading to functional impairment. Genetic and environmental factors are believed to jointly contribute to the disease process. With the increasing aging of society, the incidence of neurodegenerative diseases is rising year by year, mainly including Alzheimer's disease, Parkinson's syndrome, and Huntington's disease, becoming the fourth leading cause of death and health threats to the elderly after cardiovascular disease, cancer, and stroke. Besides severely impacting patients' quality of life, neurodegenerative diseases also impose enormous medical and economic burdens on society. Despite this, most neurodegenerative diseases still lack effective treatments in clinical practice due to unclear pathogenic mechanisms, making the development of effective drugs for the prevention and treatment of neurodegenerative diseases particularly urgent.

[0003] Among the numerous hypotheses regarding the etiology and pathogenesis of neurodegenerative diseases, excitotoxicity, apoptosis, and oxidative stress have received widespread attention. The excitotoxicity hypothesis posits that activated glutamate receptors, in addition to participating in rapid excitatory synaptic transmission, can regulate normal central nervous system physiological functions such as neurotransmitter release, synaptic plasticity, learning and memory, and long-term potentiation and inhibition of synapses. However, excessively high glutamate concentrations in the intercellular space can excite glutamate receptors, including the N-methyl-D-aspartate receptor (NMDAR), leading to a surge in calcium and sodium glutamate. 2+ Influx, intracellular Ca 2+ Overload can cause excitotoxicity in neurons, leading to neuronal degeneration, aging, and death. This excitotoxic effect of glutamate is closely related to the occurrence and development of various neurodegenerative diseases and is one of the important mechanisms leading to neuronal death in neurodegenerative diseases.

[0004] Neurodegenerative diseases pose a serious threat to human life and health, but effective drugs and treatments are still lacking. NMDAR is an important target for neuroprotective agents, and antagonists developed targeting this target can effectively inhibit calcium channel blockade. 2+Influx of NMDAR can protect nerve cells and may be used to prevent and treat neurodegenerative diseases. NMDAR is generally believed to be mainly distributed on the postsynaptic membrane of nerve cells. PC12 cells, with morphology and physiological function similar to normal nerve cells, are widely used in neurodegenerative disease research. NMDA is an exogenous agonist of NMDAR; high concentrations of NMDA can induce excitatory damage in PC12 cells, and this damage model can be used for screening drugs for neurodegenerative diseases. Therefore, it is necessary to develop new compounds that can be used to prepare effective drugs for treating neurodegenerative diseases.

[0005] In the prior art, reference document 1, patent application number 00808431.9, patent title: Tricyclic Fused Heterocyclic Compounds and Their Preparation Methods and Uses, discloses a preparation method that typically requires multiple steps to prepare zatobuprofen derivatives. However, this invention provides a novel method for preparing the zatobuprofen derivative 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one in one step using zatobuprofen KF catalysis. This preparation method has the advantages of being simple, green, low-cost, and having a high yield. Summary of the Invention

[0006] The purpose of this invention is to provide a novel zaltopiprofen derivative. This novel derivative is 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one.

[0007] Another object of the present invention is to provide a novel method for preparing zaltoibuprofen derivatives. This method has the advantages of being simple, green, low-cost, and having a high yield (up to 80% or more).

[0008] Another object of the present invention is to provide the use of a novel zaltopibuprofen derivative (2-ethyl-11-methyldibenzo[b,f]thiophene-10-one) in the preparation of a neuroprotective medicament for the treatment of neurodegenerative diseases.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0010] The novel zaltopibuprofen derivative of this invention is 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one, the structure of which is shown in general formula 1 below:

[0011]

[0012] The method for preparing the novel zaltobuprofen derivative of the present invention is as follows: zaltobuprofen, dimethyl sulfoxide (DMSO) and potassium fluoride (KF) are added to a pressure-resistant reaction flask, and the mixture is heated in an oil bath at 170-190℃ for 3.5-4.5 h; after the reaction is completed, the mixture is separated and purified to obtain 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one.

[0013] Preferably, the preparation method of the present invention is as follows: add zaltopiprofen, dimethyl sulfoxide (DMSO) and potassium fluoride (KF) to a pressure-resistant reaction flask, and heat in an oil bath at 180°C for 4 hours; after the reaction is completed, separate and purify to obtain 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one.

[0014] The synthetic route for the derivative 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one described in this invention is as follows:

[0015]

[0016] The ratio of zaltoibuprofen, dimethyl sulfoxide, and potassium fluoride described in this invention is: n (扎托布洛芬) V (DMSO) :n (KF) =0.3mmol: 1mL: 0.09mmol.

[0017] The separation and purification described in this invention are as follows: the substance obtained after the ethyl acetate extraction reaction is completed is extracted 1-3 times, the organic layer is washed with water 1-3 times in sequence, the washed organic layer is dried with anhydrous sodium sulfate and filtered; the mixture is concentrated under reduced pressure, and the residue after concentration is further separated and purified by silica gel column chromatography to obtain 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one.

[0018] Preferably, the separation and purification described in this invention is as follows: the substance obtained after the ethyl acetate extraction reaction is completed is washed twice with water, the washed organic layer is dried with anhydrous sodium sulfate and filtered; the mixture is concentrated under reduced pressure, and the residue after concentration is further separated and purified by silica gel column chromatography to obtain 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one.

[0019] The eluent for silica gel column chromatography described in this invention is petroleum ether / ethyl acetate, with a volume ratio of 20-30:1.

[0020] Preferably, the eluent for silica gel column chromatography of the present invention is petroleum ether / ethyl acetate, with a volume ratio of 25:1.

[0021] The application of 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one or 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one prepared by the above preparation method in the preparation of neuroprotective drugs for treating neurodegenerative diseases.

[0022] Beneficial effects:

[0023] 1. This invention discloses for the first time a novel zaltopiprofen derivative, 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one, and its preparation method. This method has the advantages of simple operation, low cost, and high yield (up to 80% or more).

[0024] 2. This invention employs a screening experiment to protect against NMDA-induced PC12 cell damage, revealing that 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one can reverse NMDA-induced excitatory damage to PC12 cells, demonstrating its neuroprotective activity and potential for development into a neuroprotective agent. This agent could be used to treat neurodegenerative diseases. Attached Figure Description

[0025] Figure 1 2-Ethyl-11-methyldibenzo[b,f]thiophene-10-one 1 H NMR spectrum.

[0026] Figure 2 2-Ethyl-11-methyldibenzo[b,f]thiophene-10-one 13 C10 NMR spectrum.

[0027] Figure 3 The protective activity of different concentrations of 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one against NMDA-induced PC12 cell damage. Detailed Implementation

[0028] The technical solution of the present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0029] Example 1: A novel zaltopiprofen derivative and its preparation method

[0030] Add 0.3 mmol of zaltopiprofen, 1 mL of DMSO, and 0.09 mmol of KF to a 5 mL pressure-resistant reaction flask, and react in an oil bath at 180 °C for 4 h. After the reaction, extract twice with 200 mL of ethyl acetate, then wash the organic layer twice with tap water, and dry the washed organic layer with anhydrous sodium sulfate. Filter the solution. Concentrate the filtrate under reduced pressure, and then purify the residue by silica gel column chromatography (25:1) to obtain 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one; yield 81%.

[0031] Nuclear magnetic resonance (NMR) of the prepared 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one 1 H NMR and 13 The CNMR detection data are as follows: 1 H NMR (600MHz, CDCl3) δ8.21(dd,J=8.0,1.4Hz,1H),7.60(dd,J=11.0,7.9Hz,2H),7.47–7.40(m,1H),7.35–7.30(m,1H),7.26(s ,1H),7.04(dd,J=7.8,1.3Hz,1H),4.95(q,J=6.7Hz,1H),2.68(q,J=7.6Hz,2H),1.73(d,J=6.7Hz,3H),1.25(t,J=7.6Hz,3H). 13 C NMR (151MHz, CDCl3) δ193.59,146.71,141.26,140.49,136.14,132.06,131.52 ,131.05,130.26,126.39,126.25,126.25,125.66,48.78,28.87,15.54,12.95.

[0032] The structural formula is:

[0033]

[0034] Example 2: A novel zaltopiprofen derivative and its preparation method

[0035] Add 0.3 mmol of zaltopiprofen, 1 mL of DMSO, and 0.09 mmol of KF to a 5 mL pressure-resistant reaction flask, and react in an oil bath at 170 °C for 4.5 h. After the reaction, extract once with 200 mL of ethyl acetate, then wash the organic layer once with tap water, and dry the washed organic layer with anhydrous sodium sulfate. Filter the solution. Concentrate the filtrate under reduced pressure, and then purify the residue by silica gel column chromatography (20:1) to obtain 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one; yield 72%.

[0036] Example 3: A novel zaltopiprofen derivative and its preparation method

[0037] Add 0.3 mmol of zaltopiprofen, 1 mL of DMSO, and 0.09 mmol of KF to a 5 mL pressure-resistant reaction flask, and react in an oil bath at 190 °C for 3.5 h. After the reaction, extract three times with 200 mL of ethyl acetate, then wash the organic layer three times with tap water, and dry the washed organic layer with anhydrous sodium sulfate. Filter the solution. Concentrate the filtrate under reduced pressure, and then purify the residue by silica gel column chromatography (30:1) to obtain 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one; yield 78%.

[0038] To further verify the feasibility and effectiveness of the present invention and to select the optimal solution, the inventors conducted a series of experiments, as follows:

[0039] 1. Main Instruments and Materials

[0040] INOVA 600MHz NMR spectrometer (TMS internal standard), Varian Technologies China Co., Ltd.;

[0041] DMSO, Bailingwei Reagent Co., Ltd.; Zaltoibuprofen, Anaiji Chemical; Potassium fluoride (KF), Anaiji Chemical; Anhydrous sodium sulfate, Anaiji Chemical; Ethyl acetate, Anaiji Chemical; Silicone oil, Bailingwei Reagent Co., Ltd.; Thin-layer chromatography silica gel plate, Qingdao Ocean Chemical Plant.

[0042] 2. Experiment

[0043] 2.1 Preparation method:

[0044] Add 0.3 mmol of zaltopiprofen, 1 mL of DMSO, and 0.09 mmol of KF to a 5 mL pressure-resistant reaction flask, and react in an oil bath at 180 °C for 4 h. After the reaction, extract twice with 200 mL of ethyl acetate, then wash the organic layer twice with tap water, and dry the washed organic layer with anhydrous sodium sulfate. Filter the solution. Concentrate the filtrate under reduced pressure, and then purify the residue by silica gel column chromatography (25:1) to obtain 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one; yield 81%.

[0045] 2.2 Nuclear Magnetic Resonance Imaging (NMR) Detection:

[0046] The prepared 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one was subjected to nuclear magnetic resonance (NMR) to obtain... 1 HNMR and 13 The C NMR detection data are as follows: 1H NMR (600MHz, CDCl3) δ8.21(dd,J=8.0,1.4Hz,1H),7.60(dd,J=11.0,7.9Hz,2H),7.47–7.40(m,1H),7.35–7.30(m,1H),7.26(s ,1H),7.04(dd,J=7.8,1.3Hz,1H),4.95(q,J=6.7Hz,1H),2.68(q,J=7.6Hz,2H),1.73(d,J=6.7Hz,3H),1.25(t,J=7.6Hz,3H). 13 C NMR (151MHz, CDCl3) δ193.59,146.71,141.26,140.49,136.14,132.06,131.52 ,131.05,130.26,126.39,126.25,126.25,125.66,48.78,28.87,15.54,12.95.

[0047] The structural formula is:

[0048]

[0049] 2.3 Screening of the protective activity of 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one against NMDA-induced PC12 cell damage:

[0050] 1) Activity testing steps:

[0051] Logarithmic growth phase cells were seeded at a density of 4000 cells / well in 96-well plates (200 μL per well) and incubated in a 5% CO2 incubator for 96 h. Cells were then washed twice with PBS and divided into four groups: a control group (Control), a model group (Model), a positive control group (MK-801), and a drug-treated group (Compound), with five replicates per group. The control and model groups received only DMEM medium, the positive control group received 20 μM MK-801, and the drug-treated groups received 5-40 μM 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one. All groups were incubated for another 24 h. After 24 h, the model, positive control, and drug-treated groups received NMDA (final concentration 2 mM), while the control group received an equal volume of sterile deionized water. All groups were then incubated for another 6 h. After 6 h, MTT assay was performed for 4 h, and cell viability was assessed using the MTT assay. The absorbance of cells in each group was measured at 490 nm using an ELISA reader. The calculation formula was: Viability = OD value of treatment group / OD value of blank control group × 100%.

[0052] 2) Results:

[0053] like Figure 3 As shown, compared with the model group (NMDA), the cell viability of 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one increased at a concentration of 20 μM, exhibiting significant neuroprotective activity. The protective effect was best at a concentration of 30 μM, comparable to the positive control drug MK-801, indicating that it has significant neuroprotective activity and has the potential to be developed into a neuroprotective agent.

[0054] Although the present invention has been described in detail above with general descriptions, specific embodiments, and experiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A method for preparing a novel zaltoibuprofen derivative, wherein the derivative is 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one, and its structure is shown in general formula 1 below: ； characterized in that The preparation method includes: adding zaltoibuprofen, DMSO and KF to a pressure-resistant reaction flask, wherein the ratio of zaltoibuprofen, DMSO and KF is: n(zaltoibuprofen):V(DMSO):n(KF) = 0.3mmol:1mL:0.09mmol, and reacting in an oil bath at 180℃ for 4 h; after the reaction is completed, separation and purification are performed to obtain 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one; The separation and purification in the preparation method are as follows: the substance obtained after the reaction is extracted with ethyl acetate 1-3 times, the organic layer is washed with water 1-3 times in sequence, the washed organic layer is dried with anhydrous sodium sulfate and filtered; the concentration is carried out under reduced pressure, and the residue after concentration is further separated and purified by silica gel column chromatography to obtain 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one. The eluent for the silica gel column chromatography is petroleum ether / ethyl acetate, with a volume ratio of 20-30:

1.

2. The process for the preparation of novel zaltoprofen derivatives according to claim 1, characterized in that, The separation and purification in the preparation method are as follows: the substance obtained after the reaction is extracted with ethyl acetate is washed twice with water, the organic layer is dried with anhydrous sodium sulfate and filtered; the mixture is concentrated under reduced pressure, and the residue after concentration is further separated and purified by silica gel column chromatography to obtain 2-ethyl-11-methyldibenzo[b,f]thiophene-10-one. The eluent for the silica gel column chromatography was petroleum ether / ethyl acetate, with a volume ratio of 25:1.

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