A medicament for treating rheumatoid arthritis and use thereof

Abstract

The present application provides a medicine for treating rheumatoid arthritis and its use. The compound of the present application is a resveratrol analogue with the structure of formula I, which has excellent swelling and anti-inflammatory effects in the prevention and treatment of rheumatoid arthritis, and thus can well prevent and treat rheumatoid arthritis.

Description

Technical Field

[0001] This invention relates to the field of medicine, and more specifically, to a drug for treating rheumatoid arthritis and its uses. Background Technology

[0002] Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease that primarily affects the joints, impacting approximately 0.5% to 1% of the world's population. Most patients experience bone erosion within two years prior to onset and RA is associated with various comorbidities, including cardiovascular disease, osteoporosis, interstitial lung disease, infections, malignancies, and psychosocial disorders. Currently, the main treatments for rheumatoid arthritis include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and disease-modifying antirheumatic drugs (DMARDs). However, some patients do not respond well to treatment or experience side effects such as gastrointestinal, hepatic, renal, hematologic, and neurotoxicity, as well as serious infections.

[0003] Traditional Chinese medicine (TCM) has advantages in treating diseases through multiple targets and pathways. Monomer compounds of TCM are the main active ingredients extracted and isolated from it. Several TCM monomers have been shown to have therapeutic effects on rheumatoid arthritis, mainly including: flavonoids, such as tangeretin (Lin N, et al. Biochem. Pharmacol, 2003, 65(12): 2065-2071), puerarin (Cheng Xiao, et al. European Journal of Pharmacology, 2011, 666(1-3): 242-250), epigallocatechin ester (Lin RW, et al. Biochemical and Biophysics Research Communication, 2009, 379(4): 1033-1037), genistein (Gao Bo et al. Journal of Integrated Traditional and Western Medicine, 2009, 7(7): 636-641), quercetin (Wang Youqing et al. Journal of Immunology, ...). 2019, 35(6): 485-491.), punicein (GE G, et al. SciChina Life Sci, 2022, 65(3): 588-603); alkaloids, such as sinomenine (Gao Peifang et al. Journal of Shandong University of Traditional Chinese Medicine, 2011, 35(1): 31-33.), tetramethylpyrazine (Wang Jianjie et al. International Journal of Immunology, 2010, 33(1): 692-721), matrine (NIU Y, et al. Cell Biol Int, 2017, 41(6):611-621); phenylpropanoids, such as ferulic acid (Chen Weihai et al. Journal of Beijing University of Traditional Chinese Medicine, 2006, 29(10): 690-693); phenols, such as resveratrol (Tian Jing et al. Chinese Journal of Traditional Chinese Medicine, 2010, 35(4): 1878-1882; Tang Lingli et al. Journal of Central South University (Medical Edition), 2006, 31(4): 528-533; Byun HS, et al. Rheumatol, 2008, 47(3): 301-308), curcumin (Zhu Liyan et al. Qingdao Medical and Health, 2010, 42(3): 161-163; Xing Guosheng et al. Chinese Journal of Hospital Pharmacy, 2009, 29(11): 827-875); terpenoids, such as triptolide (Guo Jiandong. Chinese Journal of Clinical Rehabilitation, 2004, 8(21): 4218-4218), triptolide (Jeong-Hyung Lee, et al. Biochem Pharmacol, 2006, 72(10): 1311-1321), artesunate (Zhang Changcheng et al.).(Guangdong Medical Journal, 2009, 30(7): 1048-1049, etc.)

[0004] However, the monomeric compounds in traditional Chinese medicine often have insufficient activity. Therefore, it is necessary to develop more drugs for the treatment of rheumatoid arthritis. Summary of the Invention

[0005] In view of the problems existing in the prior art, the present invention provides a drug for treating rheumatoid arthritis, which has excellent anti-swelling and anti-inflammatory effects and can effectively prevent and treat rheumatoid arthritis.

[0006] The drug for treating rheumatoid arthritis according to the present invention has the structure shown in Formula I: R1-R4 and R6 are independently selected from hydrogen, deuterium, hydroxyl, mercapto, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, haloC1-C6 alkyl, haloC1-C6 alkoxy, haloC1-C6 alkylthio, cyano, nitro, and C1-C6 alkylamino. R5 is selected from hydrogen, deuterium, C1-C6 alkyl, and halogenated C1-C6 alkyl; R7 and R8 are selected from hydrogen, deuterium, and C1-C6 alkyl groups; n is selected from 0, 1, 2, 3 or 4.

[0007] The present invention also relates to pharmaceutically acceptable salts, prodrugs, or metabolites of the compounds of Formula I.

[0008] The present invention also relates to a pharmaceutical composition comprising at least one compound of Formula I or a pharmaceutically acceptable salt, prodrug, or metabolite thereof.

[0009] The present invention also relates to the use of the compound of formula I in the preparation of pharmaceuticals.

[0010] The invention also involves methods for preventing or treating rheumatoid arthritis.

[0011] The present invention also relates to a method for preparing the compound of formula I. Detailed Implementation

[0012] It should be understood that the terms or words used in the specification and claims should not be construed as having the meaning defined in a dictionary, but rather as having a meaning consistent with their meaning in the context of the invention, based on the principle that the concept of a term may be appropriately defined by the inventor for the best explanation of the invention.

[0013] The term "halogen" refers to fluorine, chlorine, bromine, and iodine. The halogen is preferably fluorine, chlorine, or bromine, more preferably chlorine or bromine.

[0014] The term "alkyl" whether used alone or as part of a substituent includes saturated straight-chain or branched hydrocarbon groups, preferably containing 1-10 carbon atoms, more preferably 1-6 carbon atoms, and most preferably 1-4 carbon atoms. Examples of alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl, but are not limited thereto.

[0015] This invention provides a medicament for treating rheumatoid arthritis, having the structure shown in Formula I: R1-R4 and R6 are independently selected from hydrogen, deuterium, hydroxyl, mercapto, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, haloC1-C6 alkyl, haloC1-C6 alkoxy, haloC1-C6 alkylthio, cyano, nitro, and C1-C6 alkylamino. R5 is selected from hydrogen, deuterium, C1-C6 alkyl, and halogenated C1-C6 alkyl; R7 and R8 are selected from hydrogen, deuterium, and C1-C6 alkyl groups; n is selected from 0, 1, 2, 3 or 4.

[0016] The compounds of Formula I described in this invention include pharmaceutically acceptable salts, prodrugs, or metabolites thereof.

[0017] In one embodiment, R1-R4 are independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

[0018] Preferably, R1 and R4 are selected from hydrogen and C1-C6 alkyl groups.

[0019] Preferably, R2 and R3 are selected from hydrogen, hydroxyl, and C1-C6 alkoxy groups.

[0020] More preferably, R2 and R3 are selected from hydrogen and hydroxyl groups.

[0021] Optionally, both R2 and R3 are selected from hydrogen.

[0022] Optionally, one of R2 and R3 is selected from hydroxyl, and the other is selected from hydrogen and hydroxyl.

[0023] Optionally, R2 is selected from hydroxyl groups, and R3 is selected from hydrogen and hydroxyl groups.

[0024] In one implementation, R5 is selected from hydrogen.

[0025] In one implementation, R6 is selected from hydrogen.

[0026] In one implementation, R7 and R8 are selected from hydrogen and methyl.

[0027] Preferably, R7 and R8 are selected from hydrogen.

[0028] In a preferred embodiment, the compound is selected from: .

[0029] The pharmaceutically acceptable salt of the compound of formula I provided by this invention refers to the base addition salt formed by the compound and a pharmaceutically acceptable base, wherein the base addition salt is a sodium salt, potassium salt, ammonium salt, calcium salt, aluminum salt, magnesium salt, ethylenediamine salt or ethanolamine salt.

[0030] The prodrug of Formula I provided by this invention refers to a compound that can be metabolized into the compound of this invention in vivo, and includes, without limitation, esters, etc.

[0031] The metabolites of the compounds of Formula I provided by this invention refer to the pharmaceutically acceptable and effective metabolites of the compounds of this invention.

[0032] The present invention provides a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt, prodrug, or metabolite thereof.

[0033] In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient.

[0034] In one embodiment, the pharmaceutically acceptable excipient includes one or more of the following: diluent, filler, binder, disintegrant, emulsifier, lubricant, flow aid, flavoring agent, odorant, and coloring agent.

[0035] Preferably, the diluent may be selected from: starch, disaccharide, sucrose, lactose, polysaccharide, sugar alcohol, mannitol, sorbitol, maltitol, xylitol, cellulose, cellulose ether, hydroxypropyl cellulose, microcrystalline cellulose, calcium carbonate, and calcium hydrogen phosphate.

[0036] Preferably, the filler may be selected from: starch, compressible starch, dextrin, sucrose, lactose, fructose, glucose, xylitol, mannitol, microcrystalline cellulose, calcium carbonate, magnesium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, magnesium oxide, aluminum hydroxide, calcium carboxymethyl cellulose, and sodium carboxymethyl cellulose.

[0037] Preferably, the adhesive may be selected from: hydroxypropyl methylcellulose, polyvinylpyrrolidone, starch paste, dextrin, glucose and its syrup, sucrose and its syrup, lactose and its syrup, fructose and its syrup, sorbitol, gelatin paste, gum arabic paste, tragacanth paste, microcrystalline cellulose, methylcellulose, sodium carboxymethyl cellulose, ethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, calcium carboxymethyl cellulose, polymethyl methacrylate, alginate, sodium alginate, polyethylene glycol, and colloidal magnesium aluminum silicate.

[0038] Preferably, the disintegrant can be selected from: sodium carboxymethyl starch, hydroxypropyl starch, croscarmellose sodium, croscarmellose polyvinylpyrrolidone, and low-substituted hydroxypropyl methylcellulose.

[0039] Preferably, the emulsifier may be selected from: poloxamer, sodium lauryl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, fatty acid sorbitan, polysorbates, polyoxyethylene castor oil, PEG-glycerol caprylate, PEG-glycerol laurate, and PEG-glycerol stearate.

[0040] Preferably, the lubricant may be selected from: stearic acid, calcium stearate, magnesium stearate, zinc stearate, talc, glyceryl monostearate, glyceryl palmitate, magnesium dodecyl sulfate, polyethylene glycol, and sodium stearyl fumarate.

[0041] The dosage form of the pharmaceutical composition of the present invention can be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, droplets, suppositories, films, patches, aerosols, sprays, etc.; semi-solid dosage forms can be ointments, gels, pastes, etc.

[0042] The pharmaceutical compositions of the present invention can be present as unit dosage forms or prepared by any method known in the pharmaceutical field. All methods include the step of binding the active compound to a carrier constituting one or more components.

[0043] In the pharmaceutical composition of the present invention, the amount of the compound may be from 0.01% to 50% of the total weight of the composition, preferably from 0.1% to 10%, more preferably from 0.5% to 5%, and most preferably from 1% to 2%.

[0044] The effective dosage of the compounds in the pharmaceutical compositions of the present invention can be determined based on age, weight, sex, method of administration, health condition, and severity of illness. For example, the dosage for an adult weighing 70 kg is 0.1-1000 mg / day, preferably 1-500 mg / day. Such administration can be done once or multiple times a day, as determined by a physician or pharmacist.

[0045] The compounds of the present invention can be used in combination with other pharmaceutical agents, which can be used to treat, prevent, inhibit, or improve diseases or conditions for which the compounds of the present invention are useful. Therefore, the present invention provides a pharmaceutical combination comprising the compounds of the present invention and other pharmaceutical agents that can be used to treat, prevent, inhibit, or improve diseases or conditions for which the compounds of the present invention are useful.

[0046] The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt, prodrug or metabolite thereof in the preparation of a medicament for the prevention or treatment of rheumatoid arthritis.

[0047] The present invention also provides a method for preventing or treating rheumatoid arthritis, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt, prodrug, or metabolite thereof to a patient in need.

[0048] In a preferred embodiment, the method further includes administering other agents that can be used to treat, prevent, inhibit, or improve diseases or conditions for which the compounds of the present invention are useful before, during, or after administering the compound of Formula I or a pharmaceutically acceptable salt, prodrug, or metabolite thereof.

[0049] The present invention also provides a method for preparing a compound of formula I, the method comprising the following steps: Step I: Compound a reacts with 1,2,4-triazole in the presence of I2 to generate an intermediate of formula b. Step II: The intermediate of formula b reacts with the compound of formula c to generate the compound of formula I'; In compounds of formula I', R7' and R8' are independently selected from C1-C6 alkyl groups; as well as, Optional Step III To convert compound I' into compound I whose R7 and R8 are selected from hydrogen.

[0050] In one embodiment, step I is carried out in the presence of an alkali selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide.

[0051] In one embodiment, step II is carried out in the presence of a base selected from triethylamine and pyridine.

[0052] In one embodiment, step III is performed in the presence of boron tribromide.

[0053] Beneficial effects This invention provides a drug for treating rheumatoid arthritis and its uses. The compound of this invention is a resveratrol analogue, which has excellent anti-swelling and anti-inflammatory effects in the prevention and treatment of rheumatoid arthritis, and therefore can effectively prevent and treat rheumatoid arthritis.

[0054] The invention is described in more detail below to aid in understanding it.

[0055] It should be understood that the terms or words used in the specification and claims should not be construed as having the meaning defined in a dictionary, but rather as having a meaning consistent with their meaning in the context of this invention, based on the principle that the concept of a term may be appropriately defined by the inventor for the best description of the invention. Preferred methods and materials are described below, but similar or equivalent methods and materials may also be used in the practice or testing of this invention. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0056] Example 1: Preparation of Compound 1 Under nitrogen protection, 1.46 g (10 mmol) of compound 1-a, 1.38 g (20 mmol) of 1,2,4-triazole, 3.87 g (15 mmol) of iodine, and 6.91 g (50 mmol) of anhydrous potassium carbonate were added to 100 mL of DMF, and the mixture was stirred at 80 °C for 15 h. After the reaction was completed, the mixture was cooled to room temperature, 200 mL of water was added, and the mixture was extracted with ethyl acetate (300 mL × 3). The extracts were combined and washed once with saturated sodium carbonate aqueous solution and once with distilled water. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was recrystallized from ethanol to obtain intermediate 1-b. After drying, intermediate 1-b was dissolved in 100 mL of chloroform, and then 2.56 g (10 mmol) of compound 1-c and 0.5 mL of triethylamine were added. The mixture was stirred under reflux for 10 h. After the reaction was complete, the mixture was cooled to room temperature, washed once with saturated sodium carbonate aqueous solution and once with distilled water, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (eluent: cyclohexane:methanol = 5:1) to give intermediate 1-d, 2.88 g, yield 72%. MS m / z: 401.2 [M+H]+ Under nitrogen protection, 2.00 g (5 mmol) of intermediate 1-d and 1.5 g (6 mmol) of boron tribromide were added to 80 mL of dichloromethane and stirred at room temperature for 8 h. The reaction solution was poured into 500 mL of water to settle, and the precipitate was filtered out. The precipitate was recrystallized from methanol to give compound 1, 1.74 g, with a yield of 93%.

[0057] MS m / z: 373.1 [M+H] + Elemental analysis: C 23 H 16 Theoretical values ​​for O5: C, 74.19; H, 4.33; O, 21.48; Actual values: C, 74.22; H, 4.34; O, 21.43.

[0058] 1 H NMR (400 MHz, DMSO- d 6) δ 8.53 (s, 2H), 8.07 (d, J = 8.5 Hz, 1H), 7.67– 7.58 (t, J = 8.5 Hz, 1H), 7.56 - 7.46 (m, 3H), 7.33 (d, J = 8.5 Hz, 1H), 7.16(d, J = 8.4 Hz, 2H), 6.93 (d, J = 16.3 Hz, 1H), 6.84 (d, J = 16.2 Hz, 1H), 6.42 (s, 2H), 6.15 (s, 1H), 5.37 (s, 1H).

[0059] Example 2: Preparation of Compound 2 Under nitrogen protection, 1.62 g (10 mmol) of compound 2-a, 1.38 g (20 mmol) of 1,2,4-triazole, 3.87 g (15 mmol) of iodine, and 6.91 g (50 mmol) of anhydrous potassium carbonate were added to 100 mL of DMF, and the mixture was stirred at 80 °C for 12 h. After the reaction was completed, the mixture was cooled to room temperature, 200 mL of water was added, and the mixture was extracted with ethyl acetate (300 mL × 3). The extracts were combined, washed once with saturated sodium carbonate aqueous solution and once with distilled water, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was recrystallized from ethanol to obtain intermediate 2-b. After drying, the crude product was dissolved in 100 mL of chloroform, and then 2.56 g (10 mmol) of compound 1-c and 0.5 mL of triethylamine were added. The mixture was stirred under reflux for 8 h. After the reaction was complete, the mixture was cooled to room temperature, washed once with saturated sodium carbonate aqueous solution and once with distilled water, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 8:1) to give intermediate 2-d, 3.17 g, yield 76%. MS m / z: 417.2 [M+H] + Under nitrogen protection, 2.08 g (5 mmol) of intermediate 2-d and 1.5 g (6 mmol) of boron tribromide were added to 80 mL of dichloromethane and stirred at room temperature for 10 h. The reaction solution was poured into 500 mL of water to settle, and the precipitate was filtered out and recrystallized from the solution by acetonitrile to give compound 2, 1.75 g, with a yield of 90%.

[0060] MS m / z: 389.1 [M+H] + Elemental analysis: C 23 H 16 Theoretical values ​​for O6: C, 71.13; H, 4.15; O, 24.72; Actual values: C, 71.11; H, 4.14; O, 24.76.

[0061] 1 H NMR (400 MHz, DMSO- d 6) δ 10.73 (s, 1H), 8.53 (s, 2H), 7.99 (d, J =8.5 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.5Hz, 1H), 6.93 (d, J= 16.2 Hz, 1H), 6.84 (d, J = 16.2 Hz, 1H), 6.78 (s, 1H), 6.42(s, 2H), 6.15 (s, 1H), 5.39 (s, 1H). Example 3: Preparation of Compound 3 Under nitrogen protection, 1.78 g (10 mmol) of compound 3-a, 1.38 g (20 mmol) of 1,2,4-triazole, 3.87 g (15 mmol) of iodine, and 6.91 g (50 mmol) of anhydrous potassium carbonate were added to 100 mL of DMF, and the mixture was stirred at 80 °C for 10 h. After the reaction was completed, the mixture was cooled to room temperature, 200 mL of water was added, and the mixture was extracted with ethyl acetate (300 mL × 3). The extracts were combined and washed once with saturated sodium carbonate aqueous solution and once with distilled water. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was recrystallized from ethanol to obtain intermediate 2-b. After drying, the crude product was dissolved in 100 mL of chloroform, and then 2.56 g (10 mmol) of compound 1-c and 0.5 mL of triethylamine were added. The mixture was stirred under reflux for 8 h. After the reaction was complete, the mixture was cooled to room temperature, washed once with saturated sodium carbonate aqueous solution and once with distilled water, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 8:1) to give intermediate 3-d, 3.03 g, yield 70%. MS m / z: 433.2 [M+H] + Under nitrogen protection, 2.16 g (5 mmol) of intermediate 3-d and 1.5 g (6 mmol) of boron tribromide were added to 80 mL of dichloromethane and stirred at room temperature for 14 h. The reaction solution was poured into 500 mL of water to settle, and the precipitate was filtered out. The precipitate was recrystallized from methanol-cyclohexane (volume ratio 9:1) to give compound 3, 1.84 g, with a yield of 91%.

[0062] MS m / z: 405.2 [M+H] + Elemental analysis: C 23 H 16 Theoretical values ​​for O7: C, 68.32; H, 3.99; O, 27.70; Actual values: C, 68.34; H, 4.00; O, 27.66.

[0063] 1 H NMR (400 MHz, DMSO- d6) δ 10.82 (s, 1H), 8.98 (s, 1H), 8.53 (s, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.33 (s, 1H), 7.16 (d, J = 8.3 Hz, 2H), 6.93 (d, J = 16.2Hz, 1H), 6.84 (d, J = 16.3 Hz, 1H), 6.78 (s, 1H), 6.42 (s, 2H), 6.15 (s, 1H), 5.52 (s, 1H).

[0064] Pharmacodynamic studies - Efficacy of the compounds of this invention in treating rheumatoid arthritis 1. Medicine Compounds 1-3, resveratrol, were dissolved in physiological saline containing 2% propylene glycol before the experiment.

[0065] 2. Reagents Acid-soluble type II collagen (CII) and Freund's incomplete adjuvant were purchased from Sigma-Aldrich; the TNF-α kit and IL-1β kit were purchased from Wuhan Saipei Biotechnology.

[0066] 3. Animals The experimental male 8-week-old Wistar rats were purchased from the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences.

[0067] 2 Methods Dissolve CII in 0.1 mol·L⁻¹ -1 Acetic acid (content 2 mg·L) -1 Before the experiment, the CII solution was added dropwise to cold Freund's incomplete adjuvant (1 mg / L). -1 Inflammation was induced by injecting 0.25 mL into the plantar skin of the left hind paw of each rat.

[0068] Forty-eight male Wistar rats (170±20 g) were randomly divided into six groups: a blank control group, a model group, compound 1-3 groups, and a positive control group. CII was administered on the day of inflammation induction. Compound 1-3 groups received intraperitoneal injections of 5 mg / kg of each compound daily. -1 The drug was administered for a total of 28 days. The positive control group received intraperitoneal injections of 5 mg / kg of resveratrol daily. -1The model group was given an equal volume of physiological saline after inflammation was induced, while the blank control group used physiological saline as the inflammatory substance. The right hind paw was the observation subject. Starting from day 10 after inflammation was induced, the incidence rate of the right hind paw in each group was recorded daily. On days 14, 16, 18, 20, 24, and 28, the swelling rate of the right hind paw (volume of toe after administration / volume before administration × 100%) was recorded. On day 28, blood was collected from the femoral artery of rats, serum was extracted, and refrigerated for testing.

[0069] Cytokine assays: TNF-α and IL-1β were performed using an ELISA kit, and the assays were performed according to the kit instructions.

[0070] All statistical indicators are expressed as mean ± standard deviation (x±s), and comparisons between groups were analyzed using SPSS 26.0 statistical software. The results are shown in Table 1 and Table 2.

[0071] Table 1: Effects of compounds on CII-induced paw edema rate in rats Note: Compared with the blank control group # P<0.05, ## P<0.01; compared with the model group, P<0.05, P<0.01; compared with the positive control group, & P<0.05, && P<0.01.

[0072] As shown in Table 1, rats in the model group began to develop right hind paw swelling 14 days after inflammation induction, with the swelling reaching its peak around 20 days post-inflammatory induction. Compared with the model group, the compound of this invention significantly inhibited rat paw swelling, not only delaying the onset of swelling but also inhibiting its rate and intensity. The higher the paw swelling rate in the model group, the stronger the inhibitory effect. The drug showed the greatest reduction in rat paw swelling rate around 20 days post-inflammatory induction. Furthermore, compared with the resveratrol group, the compound of this invention exhibited significantly better inhibitory effects on rat paw swelling (P<0.05 or P<0.01).

[0073] Table 2 Note: Compared with the blank control group ## P<0.01; compared with the model group, P<0.01; compared with the positive control group, & P<0.05, && P<0.01.

[0074] As shown in Table 2, compared with the blank group, the serum TNF-α and IL-1β levels in the model group were significantly increased on day 28 after inflammation. Compared with the model group, compounds 1-3 could significantly reduce the serum TNF-α and IL-1β levels in rats, and the reduction was significantly greater than that in the resveratrol group (P<0.05).

[0075] The above experiments demonstrate that the compound of the present invention has excellent preventive and therapeutic effects on rheumatoid arthritis.

[0076] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in, R1, R4, and R6 are selected from hydrogen; R2 and R3 are selected from hydrogen and hydroxyl groups; R5 is selected from hydrogen; R7 and R8 are selected from hydrogen; n is selected from 0, 1, 2, 3 or 4.

2. The compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from: 。 3. A pharmaceutical composition comprising at least one compound of formula I according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to claim 3, characterized in that, The pharmaceutical composition also includes pharmaceutically acceptable excipients.

5. The use of a compound of formula I according to any one of claims 1-2 or its pharmaceutically acceptable use in the preparation of a medicament for the prevention or treatment of rheumatoid arthritis.

6. A method for preparing the compound of formula I according to claim 1, the method comprising the following steps: Step I: Compound a reacts with 1,2,4-triazole in the presence of I2 to generate an intermediate of formula b. Step II: The intermediate of formula b reacts with the compound of formula c to generate the compound of formula I'; In compounds of formula I', R7' and R8' are independently selected from C1-C6 alkyl groups; as well as, Step III To convert compound I' into compound I whose R7 and R8 are selected from hydrogen.

7. The method according to claim 6, characterized in that, Step I is carried out in the presence of an alkali selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide; Step II is carried out in the presence of an alkali selected from triethylamine and pyridine; Step III is carried out in the presence of boron tribromide.

Images