CN108283643A - A kind of thiazadione class compound prepare prevent or the drug for the treatment of rheumatoid arthritis in application - Google Patents

Abstract

The present invention relates to the technical field of medicine, in particular to the application of a thiazidedione compound in the preparation of drugs for the prevention or treatment of rheumatoid arthritis. The thiazidedione compound is shown in the following formula. The compound of the present invention significantly inhibits NO generation in RAW264.7 inflammatory cells and fibroblast synoviocytes stimulated by LPS, has obvious inhibitory effect on mouse ear swelling induced by p-xylene, and has significant inhibitory effect on rat toe swelling induced by Freund's adjuvant It has obvious detumescence and anti-inflammation effect, and has obvious inhibitory effect on collagen-induced rheumatoid arthritis, so this type of compound can be used to prevent and treat rheumatoid arthritis.

Description

A thiazidedione compound used in the preparation of prevention or treatment of rheumatoid arthritis application in medicine

technical field

The invention relates to the technical field of medicine, in particular to the application of a thiazidedione compound in the preparation of drugs for preventing or treating rheumatoid arthritis.

Background technique

Rheumatoid arthritis (RA) is one of the most important diseases that endanger human health at present, and is called "the cancer that never dies". RA is a chronic systemic autoimmune inflammatory disease characterized by multi-joint involvement, synovial inflammation, and bone and cartilage destruction. Its pathogenesis has not yet been fully elucidated. Disorders are closely related (Imboden JB. Theimmunopathogenesis of rheumatoid arthritis. Annu RevPathol Mech Dis. 2009, 4:417-434.). In the early stage, the patients have joint redness, swelling, heat pain and dysfunction. In the late stage, the joints may have different degrees of stiffness and deformity, accompanied by bone and skeletal muscle atrophy. From a pathological point of view, rheumatoid arthritis is a widespread inflammatory disease that mainly involves the synovial membrane of the joint, and can later spread to the articular cartilage, bone tissue, joint ligament, and tendon. The prevalence of RA in my country is about 0.3%-0.4%, and there are about 4 million patients. The disability rate is 60% within 5-10 years of the disease course, and 90% of patients in the late stage lose their social labor force and self-care ability, which is the main cause of adult labor force death. One of (DaiSM, Han XH, Zhao DB, Shi YQ, Liu Y, Meng JM. Prevalence of rheumatic symptoms, rheumatoid arthritis, ankylosing spond ylitis, and gout in Shanghai, China: a COPCORD study. J Rheumatol 2003,30:2245- 2251.), thus causing many family problems as well as a huge social burden. The current treatment methods for rheumatoid arthritis mainly include surgical treatment, chemical drug treatment and cytokine biological agent treatment. Surgery is only suitable for advanced deformity cases, and it is expensive and traumatic to the body; long-term application of chemical drugs such as non-steroidal anti-inflammatory drugs, antirheumatic drugs and glucocorticoids can cause gastrointestinal discomfort, bone marrow suppression, Serious adverse reactions such as liver injury and hypertension (Doan T, Massarotti E. Rheumatoid Arthritis: An Overview of New and Emerging Therapies. J Clin Pharmacol. 2005, 45: 751-762.). Therefore, it is still an arduous task and a difficult problem for the world medical community to seek highly effective and low-toxic drugs for the prevention and treatment of RA.

Fructus Xanthii is the dry and mature fruit with involucre of Xanthium fruticosa of Compositae. It is used for wind-cold cold, nasal sinusitis, rheumatic arthralgia, rubella and itching, etc. It is widely used in clinical treatment of rheumatoid arthritis. Our previous research found that thiazidedione compounds are the anti-inflammatory active ingredients of the n-butanol extract of the traditional Chinese medicine Xanthium, and 2-hydroxy-Xanthia thiazidediketone glycosides have anti-inflammatory activity, but no analgesic activity. Caffeoyl xanthiazide diketone glycoside has strong anti-inflammatory and analgesic activity. Studies have reported that it has a significant protective effect on septic mice. Toxin (LPS)-induced sepsis model mice, found that CYXD can significantly reduce the levels of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) in mouse serum, in addition, CYXD can also inhibit LPS-induced sepsis The mRNA expression of TNF-α and IL-6 in mouse macrophages (RAW 264.7) (Wang YH, Li TH, Wu BQ, et al. Protective effects of caffeoyl-xanthiazonoside isolated from fruits of Xanthium strumarium on sepsis mice[J]. Pharm Biol 2015,53(9):1367). The applicant has long been engaged in the research of cocklebur, and has determined that thiazidedione compounds have a good effect on preventing and treating rheumatoid arthritis, and can be used to prepare drugs for preventing and treating rheumatoid arthritis.

Contents of the invention

The object of the present invention is to provide a thiazidedione compound for preventing and treating rheumatoid arthritis, its pharmaceutically acceptable ester, amide or salt and the salt of said ester or amide, pharmaceutical composition and application.

The first aspect of the present invention provides the application of a thiazidedione compound and its pharmaceutically acceptable ester, amide or salt in the preparation of medicine or food for the prevention or treatment of rheumatoid arthritis, said thiazide The oxazinediones are as shown in the general formula I:

Among them: _R1 is selected from H or hydroxyl; _R2 is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, glycoside, wherein the substituents are amino, halogen, carboxyl, hydroxyl, caffeoyl, etc. Organic acid substitution; R ₃ is selected from H, halogen, C1-C8 alkyl or C3-C6 cycloalkyl.

In a preferred embodiment of the present invention, the thiazidedione compound is thiazidedione (hereinafter referred to as compound A): R ₁ =H, R ₂ =H, R ₃ =H.

In a preferred embodiment of the present invention, the thiazidedione compound is thiazidedione glycoside (hereinafter referred to as compound B): R ₁ =H, R ₂ =Glc, R ₃ =H.

In a preferred embodiment of the present invention, the thiazidedione compound is 2-hydroxythiazidedione glycoside (hereinafter referred to as compound C): R ₁ =H, R ₂ =Glc, R ₃ =OH.

In a preferred embodiment of the present invention, the thiazidedione compound is caffeoylthiazidediketoglycoside (hereinafter referred to as compound D): R ₁ =H, R ₂ =Glc-caffeoyl, R ₃ =H .

Preferably, the drug is: using the thiazidedione compound as the only active ingredient, or a pharmaceutical composition containing the thiazidedione compound.

Preferably, in the drug, the amount of thiazidedione compound can account for 0.01% to 50% of the total weight; preferably 0.1% to 10%; more preferably 0.5% to 5%; most preferably 1%-2 %.

Preferably, the pharmaceutical composition can be prepared into a pharmaceutical preparation together with conventional pharmaceutical adjuvants in pharmacy.

Preferably, the pharmaceutical preparations may be tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections and the like. Tablets, granules, capsules, liquids and injections are preferred.

Preferably, the auxiliary agent includes one of pharmaceutically acceptable carriers, diluents, excipients, fillers, disintegrants, binders, emulsifiers, lubricants, flavoring agents, and coloring agents or two or more.

More preferably, the auxiliary agent is dextrin, starch, lactose, sodium carboxymethyl cellulose, sodium lauryl sulfate, croscarmellose sodium, sodium carboxymethyl starch, poloxamer , magnesium stearate, powdered cellulose, talc, etc.

In a preferred embodiment of the present invention, the pharmaceutical preparation is a tablet made of the following raw materials in parts by weight:

In a preferred embodiment of the present invention, the pharmaceutical preparation is a tablet made of the following raw materials in parts by weight:

The second aspect of the present invention provides a drug for preventing or treating rheumatoid arthritis: using the thiazidedione compound as the sole active ingredient, or a drug combination containing the thiazidedione compound things.

The third aspect of the present invention provides a thiazidedione compound and its pharmaceutically acceptable ester, amide or salt as described above in the preparation of drugs for the prevention or treatment of osteoporosis, gum disease, or osteoarthritis The application of described gum disease is selected from gingivitis and periodontitis.

Preferably, the compound is thiazidedione, thiazidediketoglycoside, 2-hydroxythiazidediketoside or caffeoylthiazidediketoside.

The present invention has the advantage that:

The thiazidedione compound of the present invention can significantly inhibit the production of NO in RAW264.7 inflammatory cells and fibroblast synoviocytes stimulated by LPS, and has obvious inhibitory effect on mouse ear swelling induced by xylene. The paw swelling caused by inflammation has obvious detumescence and anti-inflammation effect, and has obvious inhibitory effect on rheumatoid arthritis induced by collagen, so it can be used to prevent and treat rheumatoid arthritis.

Description of drawings

Figure 1: Effects of thiazidedione compounds on the arthritis index of the left hind foot of type II collagen-induced RA model rats;

Figure 2: Inhibitory effect of thiazidedione compounds on type II collagen-induced swelling of the left hind paw of RA model rats;

Figure 3: Effects of thiazidedione compounds on histopathological sections of joints of RA model rats induced by type II collagen.

Detailed ways

The specific implementation modes provided by the present invention will be described in detail below in conjunction with the examples.

Example 1:

1) Effects of compounds on RAW264.7 inflammatory cells stimulated by LPS

The basic pathological change of RA is synovitis. As the central cell that initiates the production of inflammatory mediators in the body, the macrophage system plays a leading role in regulating the inflammatory response process, and can produce a large number of cytokines after being activated. RAW264.7 cells, as a kind of macrophages, participate in the immune process of the body, especially after external interference such as lipopolysaccharide (LPS), they can produce a large number of inflammatory mediators. Nitric oxide synthase (NO-synthase, iNOS) catalyzes the reaction of L-arginine and oxygen molecules to generate nitric oxide (nitric oxide, NO). As an important inflammatory mediator in inflammatory response, NO is involved in mediating cellular immunity and inflammatory response. In acute inflammatory sites, inflammatory substances and inflammatory mediators can induce or increase the synthesis and release of NO, thereby promoting the occurrence of inflammatory reactions. Inhibiting the level of NO is often used as one of the evaluation indicators for drug screening.

2) Pharmacological activity experiment

(1) Toxic effect on RAW 264.7 cells stimulated by LPS

After RAW264.7 cells were digested with 0.25% trypsin containing EDTA, DMEM medium was added to adjust the cell concentration to 1×10 ⁴ cells/mL, and seeded into 96-well plates at an amount of 100 μl per well. After culturing overnight at 5% CO ₂ and 37° C., add 100 μl of medium containing 400 ng/mL LPS and cultivate for 2 hours (200 ng/mL after adding the drug), add various concentrations of medium containing the drug (100 μl/well), The final concentration was 100, 10, 1, 0.1, 0.01 μmol/mL, and cultured in a CO ₂ incubator (37° C.) for 24 hours. Discard the supernatant, add blank medium containing 20 μl MTT (5 mg/mL) to each well (to prevent the drug itself from reacting with MTT), incubate at 37°C for 4 hours, discard the supernatant, add 150 μl DMSO to each well, and place on a shaker. Shake for 10 min, and detect the absorbance value (ODA) of each well at a wavelength of 570 nm with a microplate reader.

(2) Effect on NO production of RAW 264.7 cells stimulated by LPS

Spread RAW264.7 cells at 5× ¹⁰⁵ cells/mL on a 24-well plate, culture them at 5% CO ₂ and 37°C for 24 hours, discard the supernatant and stimulate them with 400ng/mL LPS for 2 hours (200ng /mL), adding various concentrations of drug-containing medium (100 μl/well) so that the final concentration was 10, 1, 0.1 μmol/mL, and cultured in a CO ₂ incubator (37° C.) for 24 h. Take 100 μl of supernatant from each space in a 96-well plate, add 100 μl of Griess reagent prepared in advance, vortex and mix at room temperature, keep it in the dark for 30 min, and measure the absorbance value (OD) at a wavelength of 540 nm.

(3) Effects on LPS-stimulated RAW 264.7 cells IL-1β and TNF-α

Spread RAW264.7 cells at 5× ¹⁰⁵ cells/mL on a 24-well plate, culture them at 5% CO ₂ and 37°C for 24 hours, discard the supernatant and stimulate them with 400ng/mL LPS for 2 hours (200ng /mL), adding various concentrations of drug-containing medium (100 μl/well) so that the final concentration was 10, 1, 0.1 μmol/mL, and cultured in a CO ₂ incubator (37° C.) for 24 h. The experimental method was to detect the content of IL-1β and TNF-α in the cell supernatant according to the instructions of Nanjing Jiancheng IL-1β and TNF-α ELISA kit.

3) Experimental results

When the drug concentration was 100μmol/L and 10μmol/L, A and B showed obvious inhibitory effect on the proliferation of RAW264.7 cells stimulated by LPS. The proliferation of RAW264.7 cells showed obvious inhibitory effect, and all the compounds at 0.1μmol/L and 0.01μmol/L had no obvious inhibitory effect on the proliferation of RAW264.7 cells stimulated by LPS. The results are shown in Table 1. Therefore, in order to avoid the reduction of the level of inflammatory factors caused by the direct cytotoxicity of the compound, drug concentrations of 10, 1, and 0.1 μmol/L were selected for follow-up studies.

The compound of table 1 is to the effect of the RAW 264.7 cell proliferation stimulated by LPS (n=5, )

Note: Compared with LPS group *P<0.05 (inhibition), ^# P<0.05 (proliferation).

After LPS stimulation, the NO concentration of RWA264.7 cells increased significantly, indicating that the modeling was successful. Compounds A, B, C, and D administration groups can significantly reduce the NO level in the supernatant of RWA264.7 cells at concentrations of 10, 1, and 0.1 μmol/L, and there is a dose-effect relationship. The results are shown in Table 2.

The compound of table 2 is to the influence of NO generation in the RAW 264.7 cell stimulated by LPS (n=5, x_±s)

Note: Compared with LPS group *P<0.05.

When the drug concentration was 10 and 1 μmol/L, compounds A, B, C, and D showed obvious inhibitory effects on the levels of IL-1β and TNF-α in LPS-stimulated RAW264.7 cells, and D showed obvious inhibitory effects at 0.1 μmol/L. inhibition.

The influence of the compound of table 3 on the content of IL-1β and TNF-α in the RAW 264.7 cells stimulated by LPS (n=3, x_±s)

Note: Compared with LPS group *P<0.05.

Example 2:

1) Effects of compounds on fibroblast synoviocytes

Rheumatoid arthritis is mainly manifested as the proliferation of synovial tissue, the most representative of which is fibroblast synoviocytes, so this study starts with fibroblast synoviocytes, by comparing the effects of drugs on cell proliferation, and cell proliferation. The measurement of NO in the supernatant reflects the effect of the drug, wherein NO is a highly reactive cytotoxic free radical and immune active mediator synthesized under the induction of iNOS.

2) Pharmacological activity experiment

(1) The effect of active compounds on the proliferation of fibroblast synoviocytes

After the membranous cells were digested with 0.25% EDTA trypsin, DMEM medium was added to adjust the cell concentration to 5×10 ⁴ cells/mL, and seeded into 96-well plates at an amount of 100 μl per well. Cultivate at 5% CO ₂ and 37°C for 24 h, discard the supernatant, add various concentrations of drug-containing medium (100 μl/well), the concentration is 10, 0.5, 0.025 μg/mL, and place in a CO ₂ incubator ( 37°C) for 24 hours. Discard the supernatant, add blank medium containing 20 μl MTT (5 mg/mL) to each well (to prevent the drug itself from reacting with MTT), incubate at 37°C for 4 hours, discard the supernatant, add 150 μL DMSO to each well, and place on a shaker. Shake for 10 min, and detect the absorbance value (ODA) of each well at a wavelength of 570 nm with a microplate reader.

(2) Effects of active compounds on NO production in fibroblast synoviocytes

The synoviocytes were plated on a 24-well plate at 5×10 ⁵ cells/mL, cultured at 5% CO ₂ and 37°C for 24 hours, the supernatant was discarded, and various concentrations of drug-containing media (100 μl/well) were added. 10, 0.5, 0.025 μg/mL, and cultured in a CO ₂ incubator (37°C) for 24 hours. Take 100 μl of supernatant from each space in a 96-well plate, add 100 μl of Griess reagent prepared in advance, vortex and mix at room temperature, keep it in the dark for 30 min, and measure the absorbance value (OD) at a wavelength of 540 nm.

3) Experimental results

Compounds A, B, C, and D showed proliferative effects on FLS cell proliferation at concentrations of 10, 1, and 0.1 μg/mL, but it was not obvious, and it also indicated that the compounds had no toxic side effects on cells.

The compound of table 4 is to the influence of fibroblast synoviocyte proliferation (n=5, )

Note: Compared with LPS group *P<0.05 (inhibition), ^# P<0.05 (proliferation).

The compound of table 5 is to the influence (n=5, x_±s) that NO is produced in the fibroblast synoviocyte

Note: Compared with LPS group *P<0.05.

The results showed that compounds A, B, C, and D could reduce the NO level in the supernatant of FLS cells at concentrations of 10, 1, and 0.01 μg/mL. All the selected compounds can inhibit the release of NO from FLS cells to a certain extent, and the results are shown in Table 5.

Example 3:

1) Effects of compounds on the degree of ear swelling caused by xylene

Xylene can increase the permeability of capillaries. According to the static equilibrium relationship between capillaries and tissues, because the permeability of capillaries increases, the liquid that penetrates into tissues will increase, which is what we see with the naked eye. Inflammatory redness occurs.

2) Experimental method

The male mice were randomly divided into 8 groups according to body weight, 10 in each group, 0.5mL/20g was administered by intragastric administration 60 minutes before inflammation, and 0.05ml of xylene was dropped in the right ear of the mouse, and the left ear was controlled. After 2 hours, the mice were killed by cervical dislocation, and the two ears were cut off along the baseline of the auricles, and round ear pieces were punched in the same part of the left and right ears with a hole punch with a diameter of 7 mm, and weighed.

3) Experimental results

Table 6 Xanthium active substance on the impact of xylene-induced ear swelling in mice (n=10, x_±s)

The results are shown in Table 6. Dexamethasone has a significant inhibitory effect on mouse xylene-induced ear swelling, and the inhibition rate reaches 59.3%. Compared with the model group, compounds A, B, C and D have significant inhibitory effects on ear swelling , with compound D being the most obvious, basically consistent with the effect of the positive drug dexamethasone.

Example 4:

prescription:

preparation

The above-mentioned auxiliary materials are passed through a 60-mesh sieve respectively, after fully mixing caffeoylthiazide diketoposide and sodium lauryl sulfate, sieving and mixing with lactose and sodium carboxymethyl starch, adding magnesium stearate and powdered cellulose to press Tablets, that is, made into 1000 pieces.

Example 5:

prescription:

preparation

The above-mentioned excipients were passed through a 60-mesh sieve respectively, after fully mixing thiazindiketoglycoside and poloxamer 188, sieving and mixing with dextrin and croscarmellose sodium, and preparing granules by wet granulation, passing through Sieve with 80 meshes, dry the granules, add talc powder and press into tablets to obtain 1000 tablets.

Embodiment 6: to the pharmacological activity experiment of the pharmaceutical composition of embodiment 4 and 5

1) The composition of the present invention is on the impact of Freund's adjuvant-inflamed rat toe swelling degree

Research method: Male SD rats, 180-220g, weighed 80 rats, randomly divided into 8 groups according to body weight, 10 rats in each group, free to eat and drink, and to drink water. Divided into model group, positive drug group and high, middle and low dose groups of pharmaceutical composition B and D. Blank group: without any treatment; model group: grind Mycobacterium casei and mix it with liquid paraffin to make 10 mg/mL, and make Freund's complete adjuvant after autoclaving. 0.1 mL was intradermally injected into the left hind toe, and the rat's paw swelled significantly on the 16th day after the adjuvant injection. Intradermal injection (1mg/ml) into the tail root of SD rats, 0.1ml each; positive drug group: dexamethasone, after successful modeling, 0.05mg/kg, intragastric administration, once a day; drug combination Animal group: from the day when the model was successfully established, the rats were given intragastric administration, once a day, high, medium and low, and the doses were 20 mg/kg, 10 mg/kg and 5 mg/kg of drug content, and were administered continuously On the 7th day, the degree of paw swelling on the 1st day and the 7th day of administration was measured, swelling rate=(paw swelling volume on the 7th day after administration-inflamed forefoot volume)/inflamed forefoot volume×100%.

The influence (n=10, x_±s) of table 7 compositions on the degree of swelling of adjuvant toes

Note: *vs model group, p<0.05; **vs model group, p<0.01.

As can be seen from the results shown in Table 7, there is a significant difference between the model group of rat Freund's adjuvant caused toe swelling and the blank group, and the model is built successfully. 1. The low-dose group has a significant inhibitory effect on the toe swelling caused by Freund's adjuvant in rats, especially the high-dose and middle-dose groups basically recover the same as the normal group. It is suggested that the composition has significant anti-inflammation and detumescence effects.

2) Anti-rheumatoid arthritis pharmacodynamics study of caffeoylthiazidediketoglycoside composition

Experimental method: Before the experiment, 90 rats were weighed, and randomly divided into 9 groups according to body weight, 10 rats in each group, free to eat and drink, and to drink water. Divided into blank group, model group, positive drug group and high, middle and low drug composition groups. Blank group: without any treatment; model group: bovine type II collagen acetic acid solution was mixed with an equal volume of Freund's incomplete adjuvant and fully emulsified. On the 0th day, intradermal injection (1mg/ml) was carried out at the base of the tail of SD rats (0.1ml each); 7 days later, the immunization was strengthened, and the root of the tail of the rats was injected with a solution of 0.1ml per mouse as a stimulating injection, and RA animals were induced around the 15th day Model; Positive drug group: dexamethasone, 0.05mg/kg, intragastric administration, once a day; pharmaceutical composition B, D: since the day of successful modeling, rats were administered intragastric administration, daily 1 time, the dose is 10mg/kg, continuous administration for 15 days.

3) Observation indicators

(1) Score the arthritis index for the degree of joint swelling in rats, and score once every 5 days.

(2) Measure the degree of swelling of the rat's toe with a toe volume measuring instrument, and measure once every 5 days.

(3) On the next day after the end of the experiment, blood was taken from the tail vein of the rats, placed in an ice bath for 30 minutes, centrifuged at 2000r/min for 15 minutes, and the supernatant was taken, and TNF-α and IL-1β in the serum of the two groups of rats were determined by ELISA , IL-6, IL-8, IL-17 and Cox-2 levels, according to the kit instructions.

(4) The rat ankle bone tissue was taken for pathological section examination.

4) Experimental results

SPSS14.0 was used to conduct two-sample t-test statistical analysis on the data of the two groups, and the difference was considered statistically significant when P<0.05.

(1) Rat Arthritis Index Score

As shown in Figure 1, on the 15th day of administration, the left hindfoot arthritis index of B and D composition groups were 2.5±0.4 and 2.2±0.2 respectively, and the left hindfoot arthritis index of the model group was 3.7±0.5. The composition can significantly reduce the arthritis index of the left hind foot of RA rats induced by type II collagen, and there is a significant difference compared with the model group, indicating that the composition has a better therapeutic effect on the rat rheumatoid arthritis model.

(2) Rat toe swelling degree

As shown in Figure 2, the left rear toe of the rats in the blank group had no obvious change, and the model group had obvious swelling, which was significantly different from the blank group, suggesting that the modeling was successful; on the 15th day of administration, the B and D composition groups The volume of the left hind paw was 1921±238mm ³ and 1755±187mm ³ , the volume of the left hind paw of the model group was 2403±198mm ³ , and the swelling degree of the left hind toe of rats in the two groups administered with the composition was significantly reduced in the later stage of the experiment, indicating that the composition It has a good therapeutic effect on the rat rheumatoid arthritis model.

(3) Serological indicators

As shown in Table 8, compared with the model group, the composition can significantly reduce the levels of TNF-α, IL-1β, IL-6, IL-8, IL-17 and Cox-2 in serum, indicating that the composition 10mg/ Intragastric administration of kg can significantly reduce the levels of key pro-inflammatory cytokines and bone destruction-related factors in the serum of rheumatoid arthritis animal models, and can effectively alleviate the inflammatory response and bone destruction of RA rats.

Table 8 Effects of Compositions on Type II Collagen-Induced RA Model Rat Serum Cytokine Levels (mean±SD, n=10)

Note: *vs model group, p<0.05; **vs model group, p<0.01.

(4) Pathological slides

As shown in Figure 3, the pathological tissue sections of the rats in the model group showed severe synovial hyperplasia and inflammatory cell infiltration. Both the positive drug dexamethasone and the composition could significantly reduce synovial hyperplasia and inflammatory cell infiltration after administration. Group B and composition D can effectively inhibit inflammatory injury and joint bone destruction in RA model rats.

In view of the evaluation results of the above drug efficacy experiments, the thiazidedione pharmaceutical composition of the present invention has significant anti-rheumatoid arthritis activity, and therefore can be used to prepare anti-rheumatoid arthritis drugs.

The preferred embodiments of the present invention have been specifically described above, but the present invention is not limited to the described embodiments, and those skilled in the art can also make various equivalents without violating the spirit of the present invention. These equivalent modifications or replacements are all included within the scope defined by the claims of the present application.

Claims (9)

1. The application of a thiazidedione compound and its pharmaceutically acceptable ester, amide or salt in the preparation of medicine or food for the prevention or treatment of rheumatoid arthritis, the thiazidedione compound such as Shown in formula I: Among them: _R1 is selected from H or hydroxyl; _R2 is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, glycoside, wherein the substituents are amino, halogen, carboxyl, hydroxyl, caffeoyl, etc. Organic acid substitution; R ₃ is selected from H, halogen, C1-C8 alkyl or C3-C6 cycloalkyl. 2. The application according to claim 1, characterized in that the said thiazidedione compound is thiazidedione, that is, R ₁ =H, R ₂ =H, R ₃ =H. 3. The application according to claim 1, characterized in that the thiazidedione compound is a thiazidedione glycoside, that is, R ₁ =H, R ₂ =Glc, R ₃ =H. 4 . The application according to claim 1 , wherein the thiazinedione compound is 2-hydroxythiazinedione glycoside, that is, R ₁ =H, R ₂ =Glc, R ₃ =OH. 5. The application according to claim 1, characterized in that the thiazidedione compound is caffeoylthiazidediketoglycoside, that is, R ₁ =H, R ₂ =Glc-caffeoyl, R ₃ =H . 6. The application according to claim 1, wherein the drug is: the thiazidedione compound as the only active ingredient, or a drug combination containing the thiazidedione compound things. 7. The application according to claim 6, characterized in that, in the medicament, the content of thiazidedione compounds accounts for 0.01% to 50% of the total weight. 8. The application according to claim 6, characterized in that, in the medicament, the content of thiazidedione compounds accounts for 0.1% to 10% of the total weight. 9. Use of a thiazidedione compound and a pharmaceutically acceptable ester, amide or salt thereof in the preparation of a medicament for the prevention or treatment of osteoporosis, gum disease, or osteoarthritis, wherein the gum disease is selected from Gingivitis and periodontitis; Described thiazide diketone compound is as shown in general formula I: Among them: _R1 is selected from H or hydroxyl; _R2 is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, glycoside, wherein the substituents are amino, halogen, carboxyl, hydroxyl, caffeoyl, etc. Organic acid substitution; R ₃ is selected from H, halogen, C1-C8 alkyl or C3-C6 cycloalkyl.