Application of pyrimidine compound in preparation of medicine for preventing and / or treating osteoarthritis

Abstract

The invention discloses an application of a pyrimidine compound in preparation of a medicine for preventing and / or treating osteoarthritis. The invention provides the application of the pyrimidine compound in the medicine for preventing and / or treating osteoarthritis for the first time. Experiments show that the compound can relieve pain in the joint area of a mouse, meanwhile, cartilage injury of the mouse with osteoarthritis can be obviously relieved, and the joint fibrosis process is inhibited; in addition, the pyrimidine compound can obviously inhibit the formation of osteophyte in a joint area; in addition, the compound significantly inhibits expression of inflammation-related markers in osteoarthritis model mouse joint regions and serum. The experiment shows that the pyrimidine compound can achieve the purpose of improving osteoarthritis, and has very important significance on drug development and prevention and treatment of the diseases in the future.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the use of a pyrimidine compound in the preparation of a medicament for the prevention and / or treatment of osteoarthritis. Background Technology

[0002] Osteoarthritis is a chronic, progressive degenerative disease affecting all joints, primarily involving articular cartilage, synovium, and subchondral bone. Its core pathology is the progressive degeneration and destruction of articular cartilage.

[0003] Osteoarthritis is characterized by a long course and slow progression. It can occur in early adulthood and is not uncommon even in people under 50. It has a long-term impact on patients' mobility and daily activities, and can lead to a decline in quality of life for decades. Therefore, early prevention or effective delay of disease progression has important clinical and social significance.

[0004] Currently, first-line treatments for osteoarthritis mainly include drug intervention, physical therapy, and surgery. Among drug treatments, nonsteroidal anti-inflammatory drugs (NSAIDs) can provide short-term pain relief, but long-term use can easily cause gastrointestinal damage and liver and kidney toxicity; chondroprotective agents have a slow onset of action and limited efficacy for patients in the middle and late stages. Physical therapies such as heat application, massage, and acupuncture can only temporarily relieve symptoms and are unlikely to reverse the pathological process. Surgical treatments such as joint replacement surgery can significantly improve joint function, but they are highly invasive, expensive, and carry risks such as infection and thrombosis, and require a certain level of overall health from the patient, making them not universally applicable.

[0005] In summary, our understanding of the pathogenesis of osteoarthritis remains insufficient, and existing treatments all have limitations to varying degrees. There is an urgent clinical need to develop safer, more effective, and more convenient new treatment strategies to improve the current challenges in prevention and treatment. Summary of the Invention

[0006] The main objective of this invention is to provide the use of pyrimidine compounds in the preparation of medicaments for the prevention and / or treatment of osteoarthritis, thereby overcoming the shortcomings of the prior art.

[0007] To achieve the aforementioned objectives, the technical solution adopted by this invention includes: This invention provides the use of pyrimidine compounds (denoted as: compound SQ-030) or pharmaceutically acceptable derivatives thereof in the preparation of medicaments for the prevention and / or treatment of osteoarthritis, said pyrimidine compounds having a structure as shown in formula (I): ; Formula (I).

[0008] This invention also provides a pharmaceutical composition for the prevention and / or treatment of osteoarthritis, comprising: a pyrimidine compound or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient; said pyrimidine compound having a structure as shown in formula (I): ; Formula (I); The pharmaceutically acceptable derivatives include any one or more combinations of pharmaceutically acceptable salts, polymorphs, eutectics, and radiolabeled forms.

[0009] The present invention also provides the use of the aforementioned pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of osteoarthritis.

[0010] Compared with existing technologies, the beneficial effects of this invention are as follows: This invention is the first to propose the application of compound SQ-030 or its pharmaceutically acceptable derivatives in the prevention and / or treatment of osteoarthritis. Experiments show that administration of compound SQ-030 can significantly alleviate joint pain in mice; simultaneously, compound SQ-030 significantly increases the number of chondrocytes and counteracts osteoarthritis tissue fibrosis; furthermore, compound SQ-030 can significantly inhibit osteophyte formation in the joint area; additionally, compound SQ-030 significantly inhibits the expression of inflammation-related markers in the serum of osteoarthritis model mice. These experiments demonstrate that compound SQ-030 can improve osteoarthritis, which is of great significance for future drug development and prevention and treatment of this type of disease. Attached Figure Description

[0011] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0012] Figure 1 This is a statistical graph showing the joint pain threshold of mice in an osteoarthritis model under control and those given the SQ-030 compound in a typical embodiment of the present invention. Figure 2 This is a comparison image of H&E staining in a control group and mice treated with SQ-030 compound in a typical embodiment of the present invention. Figures 3a-3b This is a comparison chart of bone safflower and fast green staining of mice with osteoarthritis model under control and mice treated with SQ-030 compound in a typical embodiment of the present invention, and a statistical chart of OARSI score based on safflower and fast green staining. Figures 4-5This is a Micro-CT comparison image and data analysis of the bones of mice in an osteoarthritis model under control and treated with SQ-030 compound, as shown in a typical embodiment of the present invention. Figures 6-7 The diagram shows the expression levels of mRNA related to cartilage synthesis and metabolism, as well as the expression levels of mRNA related to inflammation, in a control group and mice with osteoarthritis model after mRNA was extracted from bone tissue of mice given SQ-030 compound, in a typical embodiment of the present invention. Figure 8 This is a graph showing the analysis of serum inflammatory markers in mice with osteoarthritis model under control and those given SQ-030 compound in a typical embodiment of the present invention. Detailed Implementation

[0013] In view of the deficiencies of the prior art, the inventors of this case, through long-term research and extensive practice, have proposed the technical solution of this invention. The technical solution of this invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0014] Specifically, as one aspect of the technical solution of this invention, it relates to the use of a pyrimidine compound (denoted as: compound SQ-030) or a pharmaceutically acceptable derivative thereof in the preparation of a medicament for the prevention and / or treatment of osteoarthritis, said pyrimidine compound having a structure as shown in formula (I): ; Formula (I).

[0015] In this invention, compound SQ-030 synergistically treats osteoarthritis through the following multiple pathways: (1) Relieves joint pain and reduces cartilage wear in mice; (2) Protect cartilage: Maintain collagen fiber arrangement, reduce proteoglycan loss and cartilage damage, and reduce osteophyte formation in joint area; (3) Inhibit inflammation: Reduce the level of inflammatory factors in the joint area and serum.

[0016] In some embodiments, the osteoarthritis is mechanically heterogeneous induced bone and joint damage.

[0017] Furthermore, the drug can relieve joint pain following bone and joint injury induced by uneven mechanical force.

[0018] Furthermore, the drug can reduce the level of serum inflammatory factors in bone and joint injuries induced by uneven mechanical forces.

[0019] In some preferred embodiments, when the drug is applied to a mouse model of osteoarthritis, the drug can relieve pain in the joint area of ​​the mouse.

[0020] In some preferred embodiments, when the drug is applied to a mouse model of osteoarthritis, the drug promotes the stabilization of cartilage structure in the mouse.

[0021] In some preferred embodiments, when the drug is applied to a mouse model of osteoarthritis, the drug is able to inhibit cartilage fibrosis in the mice.

[0022] In some preferred embodiments, when the drug is applied to a mouse model of osteoarthritis, the drug is able to reduce osteophyte formation in the joint area of ​​the mouse.

[0023] In some preferred embodiments, when the drug is applied to a mouse model of osteoarthritis, the drug is able to reduce the levels of serum inflammatory factors in the mice.

[0024] In some preferred embodiments, when the drug is applied to a mouse model of osteoarthritis, the drug is able to reduce the expression of osteoarthritis-related inflammatory markers in the mice.

[0025] Furthermore, the drug can reduce the expression of osteoarthritis-related inflammatory markers in mice by more than 30%.

[0026] Furthermore, the osteoarthritis-related inflammatory markers include, but are not limited to, matrix metalloproteinase 3 (MMP3), matrix metalloproteinase 13 (MMP13), interleukin-1β (IL-1β), or tumor necrosis factor-α (TNF-α).

[0027] The drug of this invention improves osteoarthritis through at least one of the following mechanisms: (a) relieving joint pain; (b) protecting the integrity of cartilage structure and inhibiting fibrosis; (c) slowing down osteophyte formation in mice; and (d) reducing the levels of inflammatory factors in the joint area and serum, thereby combating the progression of osteoarthritis.

[0028] The drug in this invention can significantly improve joint pathological indicators in a model of bone and joint injury induced by uneven mechanical force.

[0029] Another aspect of the present invention provides a pharmaceutical composition for the prevention and / or treatment of osteoarthritis, comprising: a pyrimidine compound or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient; said pyrimidine compound having a structure as shown in formula (I): ; Formula (I); The pharmaceutically acceptable derivatives include any one or more combinations of pharmaceutically acceptable salts, polymorphs, eutectics, and radiolabeled forms.

[0030] In some preferred embodiments, when the pharmaceutical composition is applied to a mouse model of osteoarthritis, the pharmaceutical composition can relieve pain in the joint area of ​​the mouse.

[0031] In some preferred embodiments, when the pharmaceutical composition is applied to a mouse model of osteoarthritis, the pharmaceutical composition is at least able to promote the stabilization of cartilage structure in the mice.

[0032] In some preferred embodiments, when the pharmaceutical composition is applied to a mouse model of osteoarthritis, the pharmaceutical composition is able to inhibit cartilage fibrosis in the mice.

[0033] In some preferred embodiments, when the pharmaceutical composition is applied to a mouse model of osteoarthritis, the pharmaceutical composition is able to inhibit osteophyte formation in the joint area of ​​the mouse.

[0034] In some preferred embodiments, when the pharmaceutical composition is applied to a mouse model of osteoarthritis, the pharmaceutical composition can reduce the levels of serum inflammatory factors in the mice.

[0035] In some preferred embodiments, when the pharmaceutical composition is applied to a mouse model of osteoarthritis, the pharmaceutical composition is able to reduce the expression of osteoarthritis-related inflammatory markers in the mice.

[0036] Furthermore, the pharmaceutical composition can reduce the expression of osteoarthritis-related inflammatory markers in mice by more than 30%.

[0037] Furthermore, the osteoarthritis-related inflammatory markers include, but are not limited to, matrix metalloproteinase 3 (MMP3), matrix metalloproteinase 13 (MMP13), interleukin-1β (IL-1β), or tumor necrosis factor-α (TNF-α).

[0038] Another aspect of the present invention provides the use of the aforementioned pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of osteoarthritis.

[0039] The technical solution of the present invention will be further described in detail below with reference to several preferred embodiments and accompanying drawings. This embodiment is implemented on the premise of the technical solution of the invention, and provides detailed implementation methods and specific operation processes. However, the protection scope of the present invention is not limited to the following embodiments.

[0040] Unless otherwise specified, the experimental materials used in the examples below can be purchased from conventional biochemical reagent companies.

[0041] I. Experimental Procedures Experimental Animals: The male C57BL / 6 mice used in this example were purchased from Jiangsu Jicui Yakang Biotechnology Co., Ltd., with the license number SCXK(Beijing)2007 - 0001. The mice were placed under standard conditions with a humidity of 50 ± 10% and a temperature of 23 ± 2°C, and allowed to adapt to survival for 12 hours each in the day and night. The mice had free access to water and food. All animal management and treatment protocols were approved by the Animal Ethics Committee of Xuzhou Medical University. All experiments were conducted in accordance with the recommendations of the "Ethical Guidelines for the Care and Use of Animals".

[0042] Example 1 Construction of Osteoarthritis Model 1. Animals: C57BL / 6 mice (male, 8 - week - old) were used and randomly divided into a control group (n = 6) and an SQ - 030 administration group (n = 6).

[0043] 2. Surgical Induction of OA: A mechanical force imbalance model was established by transecting the anterior cruciate ligament, and the OA phenotype was confirmed 8 weeks after the surgery.

[0044] Example 2 Pain Measurement Experiment in Mice The Von Frey filament method was classically used to measure pain in mice: A set of nylon monofilaments with calibrated intensities was used, manually applied vertically to the animal's skin, and the 50% mechanical withdrawal threshold (50% MWT) was determined by the "up - down method".

[0045] (1) Animal Adaptation: Three days before the experiment, the mice were placed in the experimental room to adapt to the environment. On the test day, the mice were individually placed in a test device (such as a transparent plexiglass box with a metal mesh bottom) and allowed to adapt for 15 - 60 minutes in a quiet and dark environment until they stopped exploring and remained relatively stationary.

[0046] (2) Equipment and Environment: Check whether the Von Frey filaments are intact. Strictly control the experimental environment: The temperature is maintained at 22 - 25°C, the humidity is 40 - 60%, and the environment is quiet (noise less than 40 decibels) to avoid interference of these factors on the pain threshold.

[0047] (3) The stimulation site is the central area of the plantar surface of the hind paw, avoiding the thick part of the footpad.

[0048] (4) Stimulation Application: Use forceps to hold the selected - intensity monofilament, gently press it perpendicular to the skin surface, keep the monofilament bent for 1 - 2 seconds and then withdraw it.

[0049] (5) Reaction Observation: Immediately observe whether the animal shows clear pain responses such as paw withdrawal, paw flicking, and paw licking.

[0050] (6) “Up-down” sequence: Start with a monofilament of medium intensity. If the animal does not respond, use a monofilament of higher intensity for the next stimulation; if it responds, use a monofilament of lower intensity for the next stimulation. The stimulation interval should be at least 30 seconds.

[0051] (7) Termination and Recording: Repeat the above steps until there are two consecutive "responses" or "no responses", or the preset number of measurements is completed (e.g., 6 effective stimuli). Record the intensity of each stimulus and the animal's response (positive √ or negative ×) in detail.

[0052] (8) Threshold calculation: Using the classic Dixon formula or dedicated software, the 50% mechanical withdrawal response threshold (50% MWT) is calculated based on the last few stimulus sequences recorded by the "up and down method".

[0053] Example 3 H&E staining Specific experimental methods include: 1. Preparation of paraffin sections (1) Bone tissue fixation: Take bone tissue from each group of mice in Example 1, remove soft tissue, fix in 4% paraformaldehyde at room temperature for 24 hours, wrap with gauze, mark, rinse with running water overnight; (2) Dehydration and transparency: The dehydration box is placed in the dehydrator and dehydrated by sequentially applying alcohol in the following order: 75% alcohol for 4 hours, 85% alcohol for 2 hours, 90% alcohol for 2 hours, 95% alcohol for 1 hour, anhydrous ethanol I for 30 minutes, anhydrous ethanol II for 30 minutes, benzene for 5-10 minutes, xylene I for 5-10 minutes, and xylene II for 5-10 minutes. (3) Paraffin impregnation and embedding: 65°C melted paraffin I for 1 hour, 65°C melted paraffin II for 1 hour, 65°C melted paraffin III for 1 hour. The paraffin-impregnated tissues were embedded in the embedding machine. First, the molten paraffin was placed into the embedding frame. Before the paraffin solidified, the tissues were removed from the dehydration box and placed into the embedding frame according to the embedding surface requirements, and the corresponding labels were affixed. The tissues were cooled on a -20°C freezing stage. After the paraffin solidified, the paraffin blocks were removed from the embedding frame and the paraffin blocks were trimmed. (4) Sectioning and spreading: Section the slides to a thickness of 5μm using a microtome, spread them in a 50℃ water bath, pick up the slides and mount them on clean glass slides, and bake them in a 60℃ oven overnight. After sectioning, mark the slides and store them for later use.

[0054] 2. Perform H&E staining (1) Dewaxing and rehydration: The sections were dewaxed twice with xylene (15 minutes each time), and then dehydrated for 5 minutes each in 100%, 95%, 90%, 80%, 70%, and 50% alcohol, respectively. Finally, they were rehydrated in distilled water for 3 minutes. (2) Hematoxylin staining: The sections were stained in hematoxylin staining solution for 15 minutes, rinsed with tap water for 3 minutes, and separated by hydrochloric acid alcohol (99 ml of 70% alcohol + 1 ml of concentrated hydrochloric acid) for 10 seconds. (3) Blueing and dehydration: Rinse with tap water for 10 minutes to turn it blue. Place the slices in 50%, 70%, 80%, and 90% alcohol for 5 minutes each to dehydrate; (4) Eosin counterstaining: stain with 1% eosin solution for 2 minutes, then dehydrate in 95% alcohol and 100% alcohol for 3 minutes each until the color boundary is clear; (5) Clearing and mounting: After clearing with xylene for 3 minutes, mount with neutral resin; (6) After sealing, place the slide in a 50°C oven to dry and observe the changes in each tissue structure under a light microscope.

[0055] Example 4: Observation of bone tissue by safranin-fast green staining 1. Preparation of paraffin sections Same as the method in Example 3.1 above.

[0056] 2. Safranin-Fixed Green Staining (1) Dewaxing and rehydration: The sections were dewaxed twice with xylene (15 minutes each time), and then dehydrated for 5 minutes each in 100%, 95%, 90%, 80%, 70%, and 50% alcohol, respectively. Finally, they were rehydrated in distilled water for 3 minutes. (2) Safranin staining: Add safranin staining solution, incubate at room temperature for 2 hours, and rinse briefly with running water; (3) Fast green staining: Fast green staining for about 1 minute; (4) Dehydration, clearing, and mounting: Place the sections in 50%, 70%, 80%, 90%, 95%, and 100% alcohol for 5 minutes each, clear with xylene for 3 minutes, and then mount with neutral resin. (5) After sealing, place the slide in a 50°C oven to dry and observe the changes in each tissue structure under a light microscope.

[0057] Example 5: Micro-CT scan analysis of bone structure changes in mice (1) Scanning: The sample is taken out of the fixative, the excess liquid is wiped off with gauze, the sample is placed on the instrument scanning bed and scanning is started. The original image is obtained after scanning.

[0058] (2) Reconstruction: The original image was reconstructed using the 3D reconstruction software Recon.

[0059] (3) Analysis: The target region ROI was analyzed using the data analysis software Avatar. All samples were analyzed in the same region to obtain the required parameter values ​​and export the data.

[0060] Example 6 qRT-PCR (1) Place 0.02g of tissue and 500 μL of Trizol lysis buffer into a grinding tube, add nuclease-free grinding beads, homogenize with a homogenizer until the tissue is completely broken, and let stand at room temperature for 10 minutes to allow it to fully lyse.

[0061] (2) After adding 100 μL of chloroform, shake rapidly up and down for 15 seconds, let stand at room temperature for 10 minutes, and then put the sample into a centrifuge and centrifuge at 12000 rpm for 15 minutes.

[0062] (3) Carefully transfer the upper aqueous phase to a new EP tube, add 300 μL of isopropanol and let stand at room temperature for 10 minutes. Then put the sample into a centrifuge and centrifuge at 12000 rpm for 10 minutes.

[0063] (4) After centrifugation, discard the supernatant, add 500 μL of pre-cooled 75% ethanol to the precipitate, wash it with a pipette, put the sample into a centrifuge, centrifuge at 12000 rpm for 10 minutes, and repeat once.

[0064] (5) After centrifugation, discard the supernatant, open the EP tube and place it at room temperature for 10 minutes. Add 80 μL of nuclease-free water to the tube and measure the RNA concentration.

[0065] (6) Prepare reverse transcription working solution according to Table 1.

[0066] Table 1: RNA reverse transcription reaction system

[0067] Reverse transcription conditions: 37℃, 15 min → 85℃, 5 s → 4℃ (hold); (7) Prepare the amplification system according to Table 2. The total volume of the reaction system is 10.00 μL.

[0068] Table 2: qRT-PCR reaction system

[0069] Example 7: Detection of serum inflammation-related markers using a mouse ELISA kit. (1) Take out the required strips from the aluminum foil bag after equilibration at room temperature for 20 minutes, and seal the remaining strips in a self-sealing bag and put them back at 4℃.

[0070] (2) Set up standard wells and sample wells, and add 50 μL of standard at different concentrations to each standard well; (3) Add 10 μL of the sample to be tested to the sample well first, and then add 40 μL of sample diluent; do not add to the blank well.

[0071] (4) Except for the blank wells, add 100 μL of horseradish peroxidase (HRP) labeled detection antibody to each of the standard wells and sample wells, seal the reaction wells with sealing film, and incubate at 37°C in a water bath or incubator for 60 min.

[0072] (5) Discard the liquid, pat dry on absorbent paper, fill each well with washing liquid, let stand for 1 minute, shake off the washing liquid, pat dry on absorbent paper, and repeat the washing process 5 times.

[0073] (6) Add 50 μL of substrate A and B to each well and incubate at 37°C in the dark for 15 min.

[0074] (7) Add 50 μL of stop solution to each well. Within 15 min, measure the OD value of each well at a wavelength of 450 nm and calculate the relevant indicators according to the instructions.

[0075] II. Experimental Results (1) Compound SQ-030 can significantly relieve joint pain in mice. Age-appropriate mice were selected, and anterior cruciate ligament transection surgery was performed to establish an osteoarthritis model. After surgery, the mice were randomly divided into two groups: one group received saline, and the other group received compound SQ-030. The dosage was 1 mg / kg based on the mouse's body weight, administered every two days. After 8 weeks of treatment, samples were collected and analyzed. Three days before sample collection, a pain test was performed on the mice. The results showed that the saline group mice had a decreased mechanical withdrawal threshold, exhibiting typical symptoms of exacerbated arthritis pain. Conversely, the SQ-030 treatment group mice had a significantly increased mechanical withdrawal threshold, such as... Figure 1 As shown, this suggests that compound SQ-030 can relieve pain symptoms associated with arthritis.

[0076] (2) Compound SQ-030 significantly reduced bone tissue wear in osteoarthritis model mice. Subsequently, the fixed bone tissue was further sectioned with paraffin and stained with H&E. The staining revealed severe cartilage wear in the saline group, exhibiting typical arthritis symptoms, such as… Figure 2 As shown. Conversely, administration of compound SQ-030 reduced articular cartilage wear in mice, as... Figure 2 As shown in the figure. These results confirm that the SQ-030 compound has a significant protective effect against bone damage caused by osteoarthritis.

[0077] (3) Compound SQ-030 significantly reduced the degree of fibrosis in osteoarthritis model mice. Healthy articular cartilage has a highly ordered extracellular matrix structure, which is maintained at homeostasis by stable chondrocytes. After cartilage damage, chondrocytes may undergo stress responses, including abnormal proliferation, phenotypic transformation, and alterations in matrix synthesis patterns. Some chondrocytes may undergo "dedifferentiation," transforming into a fibroblast-like phenotype and synthesizing an abnormal matrix dominated by type I collagen, replacing the normal matrix originally dominated by type II collagen and proteoglycans. This reparative fibrocartilage-like tissue is inferior to normal hyaline cartilage in both structure and mechanical properties. Its formation is accompanied by enhanced cartilage catabolism, further disrupting the joint microenvironment and accelerating the pathological process of osteoarthritis. Subsequently, safranin-fast green staining revealed that the degree of fibrosis in arthritic mice treated with SQ-030 was significantly reduced compared to the saline control group. Figures 3a-3b The OARSI score based on safranin-fast green staining showed that the degree of damage to the articular cartilage in the SQ-030 group mice was significantly reduced compared to the control group. A lower score indicates less pathological changes in the cartilage tissue and more intact structural preservation. Figures 3a-3b This suggests that the SQ-030 compound may counteract the progression of fibrosis during arthritis.

[0078] The morphological analysis results were validated by qRT-PCR analysis of the joint tissue. After administration of SQ-030 compound, the levels of type II collagen gene (Col2a1), SRY-associated HMG box gene 9 (Sox9), and agglutinin gene (Acan), markers promoting collagen formation, were significantly increased. Conversely, the levels of type I collagen α1 chain gene (Col1a1), matrix metalloproteinase 13 (Mmp13), and matrix metalloproteinase 3 (Mmp3), markers promoting collagen degradation, were significantly decreased. This resulted in the promotion of cartilage collagen synthesis while inhibiting collagen degradation, thus slowing down the fibrosis process of joint cartilage. Figure 6 .

[0079] (4) Compound SQ-030 can reduce osteophyte formation in the joint area of ​​arthritic mice. The typical pathological features of osteoarthritis include not only degeneration of articular cartilage but also significant osteophyte formation at the joint margins. For example... Figure 4 As shown in the 3D reconstructed images based on Micro-CT scans, compared with the model group, the SQ-030-treated mice showed reduced osteophyte volume and more regular morphology in the joint region, more intact articular bone structure, and significantly reduced bone microstructural damage. The SQ-030-treated group showed significant improvements in bone volume fraction (BV / TV), bone mineral density (BMD), trabecular separation (Tb.Sp), and structural model index (SMI) compared to the control group. Figure 5These results suggest that the SQ-030 compound has the effect of inhibiting abnormal osteophyte formation and maintaining joint bone structure stability in arthritis models, and may have a positive ameliorative effect on joint remodeling after osteoarthritis surgery.

[0080] (5) Compound SQ-030 can inhibit the inflammatory process in arthritic mice. Osteoarthritis is often accompanied by the release of inflammatory factors. These pro-inflammatory factors promote the production of proteolytic enzymes, which degrade the extracellular matrix, further causing joint tissue damage. qRT-PCR analysis of joint tissue showed that administration of the SQ-030 compound significantly reduced the relative mRNA expression levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TnF-α), markers of inflammation in the joint region of mice. Figure 7 Further validation using ELISA revealed that administration of the SQ-030 compound significantly reduced the levels of matrix metalloproteinase 13 (MMP13), matrix metalloproteinase 3 (MMP3), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α)—markers of inflammation—in mouse serum, consistent with their expression patterns in tissues. Figure 8 As shown, this suggests that compound SQ-030 has an inhibitory effect on the inflammatory process of osteoarthritis.

[0081] In addition, the inventors of this case also conducted experiments with other raw materials, process operations, and process conditions described in this specification, referring to the aforementioned embodiments, and obtained relatively ideal results in all cases.

[0082] It should be understood that the technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made to the technical solutions of the present invention without departing from the spirit and scope of the claims are within the scope of protection of the present invention.

Claims

1. Use of a pyrimidine compound or a pharmaceutically acceptable derivative thereof in the preparation of a medicament for the prevention and / or treatment of osteoarthritis, said pyrimidine compound having a structure as shown in formula (I): ； Formula (I).

2. The use according to claim 1, characterized in that: When the drug is applied to a mouse model of osteoarthritis, it can relieve pain in the joint area of ​​the mouse.

3. The use according to claim 1, characterized in that: When the drug is applied to a mouse model of osteoarthritis, it promotes the stabilization of cartilage structure in the mice. And / or, when the drug is applied to a mouse model of osteoarthritis, the drug is able to inhibit cartilage fibrosis in the mice.

4. The use according to claim 1, characterized in that: When the drug is applied to a mouse model of osteoarthritis, it can reduce osteophyte formation in the joint area of ​​the mice.

5. The use according to claim 1, characterized in that: When the drug is applied to a mouse model of osteoarthritis, it can reduce the levels of serum inflammatory factors in the mice. And / or, when the drug is applied to a mouse model of osteoarthritis, the drug can reduce the expression of osteoarthritis-related inflammatory markers in the mice; preferably, the drug can reduce the expression of osteoarthritis-related inflammatory markers in the mice by more than 30%; preferably, the osteoarthritis-related inflammatory markers include matrix metalloproteinase 3, matrix metalloproteinase 13, interleukin-1β, or tumor necrosis factor-α.

6. A pharmaceutical composition for the prevention and / or treatment of osteoarthritis, characterized in that, include: A pyrimidine compound or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier and / or excipient; said pyrimidine compound having a structure as shown in formula (I): ； Formula (I); The pharmaceutically acceptable derivatives include any one or more combinations of pharmaceutically acceptable salts, polymorphs, eutectics, and radiolabeled forms.

7. The pharmaceutical composition according to claim 6, characterized in that: When the pharmaceutical composition is applied to a mouse model of osteoarthritis, it can relieve pain in the joint area of ​​the mouse.

8. The pharmaceutical composition according to claim 6, characterized in that: When the pharmaceutical composition is applied to a mouse model of osteoarthritis, the pharmaceutical composition is able to at least promote the stabilization of cartilage structure in the mice; And / or, when the pharmaceutical composition is applied to a mouse model of osteoarthritis, the pharmaceutical composition is able to inhibit cartilage fibrosis in the mice; And / or, when the pharmaceutical composition is applied to a mouse model of osteoarthritis, the pharmaceutical composition is able to inhibit osteophyte formation in the joint area of ​​the mouse.

9. The pharmaceutical composition according to claim 6, characterized in that: When the pharmaceutical composition is applied to a mouse model of osteoarthritis, the pharmaceutical composition can reduce the levels of serum inflammatory factors in the mice; And / or, when the pharmaceutical composition is applied to a mouse model of osteoarthritis, the pharmaceutical composition can reduce the expression of osteoarthritis-related inflammatory markers in mice; preferably, the pharmaceutical composition can reduce the expression of osteoarthritis-related inflammatory markers in mice by more than 30%; preferably, the osteoarthritis-related inflammatory markers include matrix metalloproteinase 3, matrix metalloproteinase 13, interleukin-1β, or tumor necrosis factor-α.

10. Use of the pharmaceutical composition of any one of claims 6-9 in the preparation of a medicament for the prevention and / or treatment of osteoarthritis.

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