Benzo-aza-ligand-containing Alzheimer's disease prevention and treatment medicine and application thereof

Abstract

The invention discloses an Alzheimer's disease prevention and treatment medicine containing a benzaza # imgabs0 # ligand and application thereof.The adopted benzazepine ligand is a compound SOMCL-668, the compound SOMCL-668 is adopted for activating an ERK1 / 2 signal channel in the brain of an Alzheimer's disease transgenic model 3 * Tg-AD mouse, apoptosis of nerve cells is reduced, and the Alzheimer's disease is prevented and treated. The deposition of amyloid plaques, the entanglement of nerve fibers and the loss of neurons are reduced, and the learning and memory ability of 3 * Tg-AD mice is improved. Therefore, the benzaza # imgabs 1 # ligand can be used as a pharmaceutical active ingredient for preparing a medicine for preventing or treating the Alzheimer's disease.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical compounds, and in particular to a compound containing benzazepine Ligand-based Alzheimer's disease prevention and treatment drugs and their applications. Background Art

[0002] Alzheimer's disease (AD) is rapidly becoming one of the most expensive, deadly and burdensome diseases of this century, and is the main cause of senile dementia. Clinically, AD is characterized by memory impairment, aphasia, apraxia, cognitive impairment, impaired visual and spatial skills, executive dysfunction, personality and behavioral disorders. The incidence of AD increases significantly after the age of 65, and the average time from onset to death is 3 to 9 years. With the aging of the population, it has brought a heavy family and economic burden to society. The cause of AD is complex. Despite the tremendous efforts made by medical and scientific professionals around the world in the past two decades, AD remains an incurable and irreversible disease.

[0003] Sigma-1 receptors are very abundant in the body and are highly expressed in both the central and peripheral nervous systems. They are mainly distributed in the mitochondria-associated endoplasmic reticulum membrane (MAM). Sigma-1 receptors have long been identified as pathophysiological targets of neuropsychiatric diseases. However, there is currently little preclinical and clinical research evidence on Sigma-1 receptors in Alzheimer's disease. The synthesis method of SOMCL-668 has been reported in an article published in 2018. The compound SOMCL-668 can allosterically activate the Sigma-1 receptor, achieve the same therapeutic effect as the orthosteric ligand, while avoiding the adverse reactions of the orthosteric ligand and achieving precise regulation of the target protein, thus providing a new strategy for the drug treatment of Alzheimer's disease.

[0004] In view of this, the present invention is proposed. Summary of the invention

[0005] The object of the present invention is to provide a Ligand-based Alzheimer's disease prevention and treatment drugs and their applications, including benzazepine The ligand is SOMCL-668, which activates the ERK1 / 2 signaling pathway in the brain of the Alzheimer's disease transgenic model 3×Tg-AD mice, reduces the apoptosis of nerve cells, reduces the deposition of amyloid plaques, neurofibrillary tangles and neuron loss, and improves the learning and memory ability of 3×Tg-AD mice.

[0006] The present invention is implemented as follows:

[0007] The present invention provides a drug for preventing and treating Alzheimer's disease containing a benzazepine ligand, and the benzazepine ligand is SOMCL-668, and its structural formula is shown in formula (I):

[0008]

[0009] In some preferred embodiments, the Alzheimer's disease is caused by abnormal protein expressions of APP / β-Amyloid, p-Tau (Thr 181), p-Tau (Thr 396), p-ERK1 / 2, and p-CREB.

[0010] In some preferred embodiments, the drug is prepared by adding SOMCL-668 as an active ingredient to a pharmaceutically acceptable carrier and / or excipient to form a pharmaceutically acceptable dosage form.

[0011] In some preferred embodiments, the dosage form of the drug includes an injection preparation or an oral preparation.

[0012] The present invention also provides an application of a drug for preventing and treating Alzheimer's disease containing a benzazepine ligand in preventing or treating Alzheimer's disease.

[0013] In some preferred embodiments, the application of the drug in alleviating the decline of learning and memory ability in Alzheimer's disease.

[0014] In some preferred embodiments, the application of the drug in anti-oxidative stress injury in Alzheimer's disease.

[0015] In some preferred embodiments, the application of the drug in inhibiting neuronal apoptosis in Alzheimer's disease.

[0016] In some preferred embodiments, the application of the drug in improving amyloid plaque deposition or / and reducing neurofibrillary tangles.

[0017] In some preferred embodiments, the application of the drug in alleviating β-Amyloid-induced neuronal cytotoxicity.

[0018] The present invention has the following beneficial effects:

[0019] The benzazepine ligand shows the improvement of learning and memory ability in transgenic Alzheimer's disease model 3×Tg-AD mice, the improvement of oxidative stress injury in transgenic Alzheimer's disease model mice, the inhibition of apoptosis of Alzheimer's disease neurons and their related proteins, the reduction of amyloid plaque deposition and neurofibrillary tangles, providing a new idea for the current prevention and treatment of Alzheimer's disease. Brief Description of the Drawings

[0020] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for the embodiments will be briefly introduced below. It should be understood that the following accompanying drawings only show some embodiments of the present invention and should not be regarded as limiting the scope. For those of ordinary skill in the art, other related accompanying drawings can be obtained based on these drawings without creative efforts.

[0021] Figure 1 Compound SOMCL-668 improves the learning and memory ability of the 3xTg-AD mouse model of Alzheimer's disease;

[0022] Figure 2 Compound SOMCL-668 reduces cortical and hippocampal cell damage in 3xTg-AD mice;

[0023] Figure 3 Compound SOMCL-668 reduces apoptosis of cortical and hippocampal cells in 3xTg-AD mice;

[0024] Figure 4 Compound SOMCL-668 reduces Aβ deposition and Tau phosphorylation in 3xTg-AD mice;

[0025] Figure 5 Compound SOMCL-668 increases the phosphorylation of the Erk1 / 2 signaling pathway in 3xTg-AD mice;

[0026] Figure 6 Compound SOMCL-668 weakens Aβ-induced cytotoxicity in nerve cells;

[0027] Figure 7 The effects of treatment with different concentrations and times of SOMCL-668 on cell signaling pathways;

[0028] Figure 8 Inhibiting the expression of Erk1 / 2 weakens the protective effect of SOMCL-668 in Aβ 1-42 induced PC12 cell damage. Detailed Embodiments

[0029] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. For those conditions not specified in the embodiments, they are carried out according to conventional conditions or the conditions recommended by the manufacturer. For the reagents or instruments whose manufacturers are not specified, they are all conventional products that can be obtained through commercial purchase.

[0030] The following presents a benzazepine-containing compound proposed in this application Specifically describe the Alzheimer's disease prevention and treatment drugs containing ligands and their applications.

[0031] The present invention provides an Alzheimer's disease prevention and treatment drug containing a benzazepine ligand, and the benzazepine ligand is SOMCL-668, and its structural formula is shown in formula (I):

[0032]

[0033] The benzazepine skeleton in compound SOMCL-668, as a common pharmacophore of Sigma-1 ligand, has a high matching degree with the allosteric site of the receptor. The hydroxyl group (HO-) and N-methyl (N-CH) may be stably bound to the secondary site of the receptor through hydrogen bonds or hydrophobic interactions, inducing conformational changes, thereby enhancing the activity of Sigma-1R. And the allosteric activation mechanism is different from that of traditional orthosteric agonists. By promoting the translocation of Sigma-1R from the endoplasmic reticulum to the cell membrane or mitochondria-related membranes, it regulates the Ca 2 + signal, ER stress response and other neuroprotective pathways, and then improves synaptic dysfunction and neuroinflammation in Alzheimer's disease. In addition, the allosteric properties of this compound may endow it with higher receptor subtype selectivity, reduce cross-interaction with Sigma-2R or other non-target receptors, and reduce potential side effects. It not only achieves the same therapeutic effect as orthosteric matching, but also avoids the adverse reactions of orthosteric ligands, realizing the precise regulation of target proteins.

[0034] Furthermore, Alzheimer's disease is caused by abnormal expression of APP / β-Amyloid, p-Tau (Thr 181), p-Tau (Thr 396), p-ERK1 / 2 and p-CREB proteins. The benzazepine ligand can achieve the effect of preventing or treating Alzheimer's disease by regulating the expression levels of the above specific proteins.

[0035] In some preferred embodiments, the drug is prepared by adding SOMCL-668 as an active ingredient to a pharmaceutically acceptable carrier and / or excipient to form a pharmaceutically acceptable dosage form. The dosage form of the drug includes injection preparations or oral preparations.

[0036] The present invention also provides the application of an Alzheimer's disease prevention and treatment drug containing a benzazepine #imgpt15# ligand in the prevention or treatment of Alzheimer's disease.

[0037] Furthermore, the drug can be used to alleviate the decline in learning and memory ability in Alzheimer's disease, resist oxidative stress damage in Alzheimer's disease, inhibit apoptosis of nerve cells in Alzheimer's disease, improve amyloid plaque deposition or / and reduce neurofibrillary tangles, and alleviate β-Amyloid-induced neurocytotoxicity.

[0038] The features and properties of the present invention will be further described in detail below in conjunction with the embodiments.

[0039] Example 1: Effect of compound SOMCL-668 on improving learning and memory ability in a mouse model of Alzheimer's disease.

[0040] Eleven-month-old 3xTg transgenic mice were used as an AD animal model, all of which were female, and age-matched C57BL / 6 wild-type mice were used as controls. Thirty-two 3xTg-AD transgenic mice were randomly divided into four groups of 8 mice each, including: a vehicle group, a SOMCL-668 2.5 mg / kg group, a SOMCL-668 5 mg / kg group, and a SOMCL-668 10 mg / kg group. Mice were intraperitoneally injected with the vehicle and different concentrations of the compound SOMCL-668 daily. After 1 month of administration, the Morris water maze test was performed, and then the samples were taken for subsequent experiments.

[0041] The Morris water maze consists of a movable platform. The pool is divided into four quadrants, and there are four equally spaced marked points along the wall as the entry points for the mice. During the experiment, the water temperature was maintained at 22-26 °C. One hour before the start of the experiment, the mice were placed in the laboratory where the water maze was located in advance to adapt to the environment. The first 5 days before each water maze experiment were the place navigation test, and the 6th day was the spatial probe test. During the place navigation test, the platform was fixed in the middle of one of the quadrants, about 1 cm above the water surface. The experiment was carried out at a fixed time in the morning every day, and the time for the mice to find the platform was recorded, which was the latency of the mice. Each mouse was placed into the water from one of the four quadrants facing the pool wall, and each mouse was tested 4 times for 60 s. If the mouse could find the platform within 60 s, the mouse could rest on the platform for 10 s; if the mouse could not find the platform within 60 s, the experimenter would guide the mouse to the platform and the mouse would also rest for 10 s. At this time, the latency of the mouse was 60 s. The time for the mouse to find the platform and the movement route were recorded by the camera system and the software acquisition system. The above operations were repeated on the 2nd, 3rd, 4th, and 5th days. The average latency of the mice in the 5-day place navigation test was statistically analyzed as an index to evaluate the learning ability of the mice. Twenty-four hours after the end of the place navigation test, the platform hidden underwater was removed for the spatial probe test.

[0042] Select a point farther from the platform as the entry point and place the mice in the water. Record the movement trajectories of the mice within 60 s, the number of times they cross the platform, and the residence time of the mice in the quadrant where the platform is located. Calculate the percentage of time of each group of mice in the platform quadrant to measure the spatial orientation ability and memory ability of the mice. The acquisition and processing of all data were completed by the Morris water maze image automatic monitoring and processing system.

[0043] Result analysis, as Figure 1 The data in the figure show that as the training time of each group of mice increased, the average escape latency of the mice gradually decreased, indicating that the mice had developed a memory of the location of the underwater platform after training; the escape latency of 3xTg-AD mice was longer than that of WT mice, while the escape latency of the mice treated with SOMCL-668 was shorter than that of 3xTg-AD mice. The spatial exploration experiment showed that the percentage of time of 3xTg-AD mice in the target quadrant after treatment with SOMCL-668 was significantly longer than that of the untreated 3xTg-AD mice. It shows that SOMCL-668 has the effect of improving the learning and memory ability of Alzheimer's disease model mice.

[0044] Example 2: Effect of compound SOMCL-668 on the damage of cortical and hippocampal neurons in 3xTg-AD mice.

[0045] Thirty-two transgenic Alzheimer's disease mice were divided into 4 groups, with 8 mice in each group. Eight C57BL / 6 wild-type mice of the same age were used as controls. Weigh the mice before administration and calculate the dosage according to the body weight. Administer the drug every day for one month. Anesthetize the mice by intraperitoneal injection of 4% chloral hydrate, quickly cut open the chest to expose the heart, insert a syringe filled with normal saline into the aorta through the left ventricle, wash the blood, and then replace it with 4% paraformaldehyde for perfusion. After the mice became stiff all over, take out the mouse brain, place it in 4% paraformaldehyde for fixation for 24 h, then transfer it to 30% sucrose for dehydration in turn. After the brain completely sank to the bottom of the bottle, take it out and make continuous coronal sections with a cryostat, with each section being 20 μm thick.

[0046] Perform Nissl staining on the brain sections: Fix the brain sections with 4% paraformaldehyde for 10 min, wash them with distilled water for 2 min / 2 times, then immerse them in Nissl staining solution for 5 - 10 min, wash them with distilled water for a few seconds 2 times, and rinse them with 95% ethanol for a few seconds. Dehydrate, clear, and mount with neutral gum. Observe the staining results under a microscope.

[0047] The results are as Figure 2 shown. Use Nissl staining to examine the cell viability of cortical and hippocampal neurons. SOMCL-668 significantly increased the number of Nissl bodies in 3xTg-AD mice and alleviated nerve cell damage.

[0048] Example 3: Effect of compound SOMCL-668 on apoptosis of cortical and hippocampal cells in 3xTg-AD mice.

[0049] Thirty-two transgenic Alzheimer's disease mice were divided into 4 groups, with 8 mice in each group. Eight C57BL / 6 wild-type mice of the same age were used as controls. Before administration, the body weights were measured respectively, and the dosage was calculated according to the body weight. The mice were administered daily for one month. The mice were anesthetized by intraperitoneal injection of 4% chloral hydrate. The chest was quickly cut open to expose the heart. A syringe filled with normal saline was inserted into the aorta through the left ventricle. After washing the blood, 4% paraformaldehyde was used for perfusion. After the mice became stiff all over, the mouse brains were taken out, placed in 4% paraformaldehyde for fixation for 24 h, and then transferred to 30% sucrose in turn for dehydration. After the brains completely sank to the bottom of the bottle, they were taken out and continuously coronal sectioned with a cryostat, with each section being 20 μm thick.

[0050] Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was performed on brain sections: fixed with 4% paraformaldehyde for 60 min, washed with PBS for 10 min × 2 times, incubated with PBS containing 0.5% Triton X-100 at room temperature for 5 min. 50 μl of TUNEL detection solution was added to the samples and incubated at 37 °C in the dark for 60 min. Washed with PBS, 10 min × 3 times, incubated with DAPI at 37 °C for 30 min, washed with PBS for 10 min × 3 times, sealed with a fluorescence blocking solution, and the slides were observed under a microscope for the degree of color development.

[0051] The results are as Figure 3 shown. Apoptosis in the cortex and hippocampus of mice was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Finally, SOMCL-668 reduced apoptosis in the cerebral cortex and hippocampus of 3xTg-AD mice.

[0052] Example 4: Effect of compound SOMCL-668 on amyloid plaque deposition and Tau phosphorylation in the brains of 3xTg-AD mice.

[0053] Thirty-two transgenic Alzheimer's disease mice were divided into 4 groups, with 8 mice in each group. Eight C57BL / 6 wild-type mice of the same age were used as controls. Before administration, the body weights were measured respectively, and the dosage was calculated according to the body weight. The mice were administered daily for one month. The mice were anesthetized by intraperitoneal injection of 4% chloral hydrate. The chest was quickly cut open to expose the heart. A syringe filled with normal saline was inserted into the aorta through the left ventricle. After washing the blood, 4% paraformaldehyde was used for perfusion. After the mice became stiff all over, the mouse brains were taken out, placed in 4% paraformaldehyde for fixation for 24 h, and then transferred to 30% sucrose in turn for dehydration. After the brains completely sank to the bottom of the bottle, they were taken out and continuously coronal sectioned with a cryostat, with each section being 20 μm thick.

[0054] Perform Thioflavine S staining on brain sections: Place the brain sections in 0.1% staining solution and soak for 30 min, wash with distilled water 2 min × 3 times, incubate in 80% ethanol for 6 min. Thioflavine S itself carries blue-green fluorescence. Place the glass slides under a microscope for observation.

[0055] Perform Western blotting experiment on brain sections: Add 100 μL of PMSF (concentration 100 mM) to every 10 mL of RIPA protein lysate; and add phosphatase inhibitor and protease inhibitor, mix well, and place on ice for 20 min for standby. Chop the mouse brain tissue thoroughly on ice, put it into the lysate, and perform thorough tissue homogenization with a grinding rod on ice. Centrifuge at 12000 rpm, 4 °C for 15 min. The obtained supernatant is the protein extract, and perform Western blotting experiment to detect the expression of APP, p-Tau (Thr181), and p-Tau (Ser396) proteins.

[0056] The results of Thioflavine S staining are as Figure 4 shown. The deposition of Aβ in the brains of 3xTg-AD mice increased significantly, while SOMCL-668 significantly reduced the expression of Aβ marker protein in the brains of 3xTg-AD mice; the results of Western blotting experiment are as Figure 4 shown. The phosphorylation of Tau protein in the brains of 3xTg-AD mice increased significantly, while SOMCL-668 significantly reduced the expression of this marker protein in the brains of 3xTg-AD mice.

[0057] Example 5: Effect of compound SOMCL-668 on the Erk1 / 2 signaling pathway in the brains of 3xTg-AD mice.

[0058] Thirty-two Alzheimer's disease transgenic mice were divided into 4 groups, with 8 mice in each group. Eight C57BL / 6 wild-type mice of the same age were used as controls. The body weights were measured before administration, and the dosage was calculated based on the body weight. The mice were administered drugs daily for one month. The mice were anesthetized by intraperitoneal injection of 4% chloral hydrate. The chest was quickly cut open to expose the heart. A syringe filled with normal saline was inserted into the aorta through the left ventricle. After washing the blood, 4% paraformaldehyde was used for perfusion. After the mice became stiff all over, the brain tissues were dissected and separated, and the olfactory bulbs were removed. The intact brains were taken out. 100 μL of PMSF with a concentration of 100 mM was added to every 10 mL of RIPA protein lysate; and phosphatase inhibitors and protease inhibitors were added and mixed well, and then placed on ice for 20 min for standby. The brain tissues of the mice were minced thoroughly on ice and put into the lysate, and then tissue homogenization was carried out thoroughly with a grinding rod on ice. Centrifugation was carried out at 12,000 rpm and 4 °C for 15 min. The obtained supernatant was the protein extract, and western blotting was performed to detect the expression of p-ERK1 / 2, T-ERK1 / 2, p-CREB and T-CREB proteins.

[0059] The results were as Figure 5 shown that SOMCL-668 treatment could increase the phosphorylation of p-ERK1 / 2 and p-CREB proteins in the brains of Alzheimer's disease transgenic mice, further indicating that SOMCL-668 could enhance the activity of the ERK1 / 2 pathway in the brains of Alzheimer's disease transgenic mice.

[0060] Example 6: Effect of compound SOMCL-668 on Aβ-induced neurocytotoxicity.

[0061] PC12, SH-SY5Y cells and primary neurons were seeded in 96-well plates at a density of 0.5×10 4 per well. After culturing for 24 h, the culture medium was replaced with a medium containing different concentrations of SOMCL-668 and Aβ 25-35 or Aβ 1-42 to continue culturing the cells to study whether SOMCL-668 could reverse the cytotoxicity caused by Aβ 25-35 or Aβ 1-42 to the cells. The MTT cytotoxicity assay was performed after 24 h.

[0062] Isolation and culture of primary neurons: To further test the protective effect of SOMCL-668 on Aβ toxicity in primary neurons, primary cortical neurons were isolated from the brains of 17-day-old fetal mice and cultured on poly-D-lysine-coated coverslips for 7 d for subsequent experiments.

[0063] MTT assay: The cultured neuron cells were incubated with Aβ oligomers. At the same time, without using different concentrations of SOMCL-668, after co-culturing for 24 hours, MTT was added and incubated at 37°C for 3 hours. Then, the MTT was removed, and 100 μl of DMSO was added to each well for dissolution. The OD value was detected by an enzyme-linked immunosorbent assay (ELISA) reader.

[0064] The results are as Figure 6 shown. The MTT assay was used to detect the survival rates of three types of nerve cells, PC12, SH-SY5Y cells, and primary mouse neurons, in groups with or without SOMCL-668 treatment and with or without Aβ induction. It shows that SOMCL-668 protects PC12 cells in a concentration-dependent manner and reduces the cytotoxicity induced by Aβ in SH-SY5Y human neuroblastoma cells and primary mouse neurons.

[0065] Example 7: Effect of compound SOMCL-668 on the signaling pathway in PC12 cells.

[0066] PC12 cells were cultured in DMEM (Dulbecco's Modified Eagle's) medium supplemented with 10% fetal bovine serum (FBS) and 100 μg / ml streptomycin and placed in an incubator at 37°C and 5% CO2. Then, PC12 cells were treated with SOMCL-668 at different concentrations and time points.

[0067] Cells treated with SOMCL-668 at different concentrations and time points or untreated were collected, washed with cold phosphate-buffered saline (PBS), and lysed on ice in 1× sample lysis buffer containing freshly added protease and phosphatase inhibitors. The lysed cells were centrifuged at 13,000 rpm for 15 minutes for protein quantification. Proteins were separated by polyacrylamide gel electrophoresis and transferred to a PVDF membrane. The membrane was blocked in 5% non-fat milk in PBST for 1 hour. Subsequently, the primary antibody was added and incubated overnight at 4°C. The next day, the membrane was washed three times with 1× TBST and then incubated with a horseradish peroxidase-conjugated secondary antibody at room temperature for 1 hour, and exposed using an ECL detection kit. Thus, the expression of proteins related to the signaling pathway was further examined in vitro.

[0068] The results are as Figure 7 shown. PC12 cells were treated with SOMCL-668 at different concentrations and time points, and protein samples of each group of cells were collected for Western Blot analysis. The phosphorylation of ERK1 / 2 and CREB in PC12 cells increased in a concentration- and time-dependent manner with SOMCL-668.

[0069] Example 8: Compound SOMCL-668 acts on Aβ through the ERK1 / 2 pathway 1-42Exerts a protective effect on induced PC12 cell injury.

[0070] PC12 cells were cultured in DMEM medium supplemented with 10% fetal bovine serum (FBS) and 100 μg / ml streptomycin and maintained in a humidified environment at 37 °C and 5% CO2.

[0071] After pretreatment of PC12 cells with PD98059 for 30 min, compound SOMCL-668 was added and incubated for 1 h, followed by addition of Aβ 1-42 and incubation for 24 h. After treatment, changes in MTT, LDH release, intracellular ROS level, and cell membrane potential were detected.

[0072] After knocking out ERK1, ERK2, and ERK1 / 2 with Crisper cas9 in PC12 cells, MTT assays were performed to detect the survival rates of cells in each group with or without SOMCL-668 treatment and with or without Aβ 1-42 induction.

[0073] The results, as Figure 8 shown, indicated that the ERK1 / 2 inhibitor PD98059 could reduce the protective effect of SOMCL-668 against Aβ 1-42 toxicity and restore the reduction of ROS accumulation and mitochondrial transmembrane potential in Aβ 1-42 induced PC12 cells; after knocking out ERK1, ERK2, and ERK1 / 2, the protective effect of SOMCL-668 against Aβ 1-42 neurotoxicity was significantly inhibited.

[0074] In summary, SOMCL-668 exhibits multifaceted neuroprotective effects in the prevention and treatment of Alzheimer's disease and has important potential application value. First, it can significantly reduce neuronal cell damage in 3xTg-AD mice by increasing the number of Nissl bodies and decreasing apoptosis in the cerebral cortex and hippocampus, thereby protecting the structural and functional integrity of neurons. Second, SOMCL-668 can effectively target two key pathological features of AD: on the one hand, it significantly reduces the deposition of Aβ in the brain and the expression of its marker proteins, and on the other hand, it inhibits the hyperphosphorylation of Tau protein, thus alleviating the pathological accumulation of amyloid plaques and neurofibrillary tangles. In addition, SOMCL-668 plays a core role by activating the ERK1 / 2 signaling pathway, enhancing downstream CREB phosphorylation in a concentration- and time-dependent manner, and thereby resisting Aβ-induced neurotoxicity. The results of the above examples demonstrate that this compound can not only reduce oxidative stress (such as ROS accumulation) and mitochondrial dysfunction, but also reverse the damage of Aβ to cell viability depending on the ERK1 / 2 pathway - gene knockout or inhibitor treatment of ERK1 / 2 will significantly weaken its protective effect. These mechanisms together indicate that SOMCL-668 provides a new strategy for the drug treatment of Alzheimer's disease by multi-target intervention in the pathological process of AD, including improving neuronal survival, reducing the aggregation of toxic proteins, and enhancing the endogenous anti-damage signals in cells.

[0075] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention can have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A drug for preventing and treating Alzheimer's disease containing a benzazepine ligand, characterized in that The benzazepine ligand is SOMCL-668, and its structural formula is shown in Formula (I):

2. A drug for preventing and treating Alzheimer's disease containing a benzazepine ligand according to claim 1, characterized in that, The Alzheimer's disease is caused by abnormal expression of APP / β-Amyloid, p-Tau (Thr 181), p-Tau (Thr 396), p-ERK1 / 2 and p-CREB proteins. ​ 3. A drug for preventing and treating Alzheimer's disease containing a benzazepine ligand according to claim 1, characterized in that, The drug is prepared by using SOMCL-668 as an active ingredient and adding pharmaceutically acceptable carriers and / or excipients to form a pharmaceutically acceptable dosage form.

4. A drug for preventing and treating Alzheimer's disease containing a benzazepine ligand, characterized in that The dosage form of the drug includes an injection preparation or an oral preparation.

5. Use of a drug for preventing and treating Alzheimer's disease containing a benzazepine ligand according to any one of claims 1-4 in the prevention and / or treatment of Alzheimer's disease. ​ 6. The application according to claim 5, wherein Application of the drug in relieving the decline of learning and memory ability in Alzheimer's disease.

7. The application according to claim 5, characterized in that, Application of the drug in resisting oxidative stress injury in Alzheimer's disease.

8. The application according to claim 5, wherein Application of the drug in inhibiting apoptosis of nerve cells in Alzheimer's disease.

9. The application according to claim 5, wherein Application of the drug in improving amyloid plaque deposition or / and reducing neurofibrillary tangles.

10. The application according to claim 5, characterized in that Application of the drug in reducing β-Amyloid-induced neurocytotoxicity.

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