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

A kind of thiazadione class compound prepare prevent or the drug for the treatment of rheumatoid arthritis in application Download PDF

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CN108283643A
CN108283643A CN201711420139.1A CN201711420139A CN108283643A CN 108283643 A CN108283643 A CN 108283643A CN 201711420139 A CN201711420139 A CN 201711420139A CN 108283643 A CN108283643 A CN 108283643A
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thiazadione
class compound
drug
compound
rheumatoid arthritis
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蒋益萍
韩婷
薛黎明
辛海量
郑承剑
张巧艳
余璐瑶
沈慧
叶冰竹
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Second Military Medical University SMMU
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Second Military Medical University SMMU
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Abstract

The present invention relates to pharmaceutical technology field, application of specifically a kind of thiazadione class compound in preparing prevention or treatment medicine for treating rheumatoid arthritis, the thiazadione class compound is shown below.Compound of the present invention stimulates RAW264.7 inflammatory cells and significantly inhibits NO at fiber synovial cell and generates for LPS, paraxylene causes mice ear to have obvious inhibiting effect, cause scorching rat toes swelling that there is apparent functions of detumescence, relieving inflammation effect in Freund's adjuvant, collagen-induced rheumatoid arthritis is significantly inhibited, therefore such compound can be used for preventing rheumatoid arthritis.

Description

A kind of thiazadione class compound is prevented or treatment rheumatoid arthritis preparing Application in drug
Technical field
The present invention relates to pharmaceutical technology fields, specifically, being that a kind of thiazadione class compound is prevented or controlled preparing Treat the application in medicine for treating rheumatoid arthritis.
Background technology
Rheumatoid arthritis (RA) is currently to endanger one of the most important diseases of human health, is referred to as " not dead cancer Disease ".RA is a kind of itself to be exempted from for the chronic generalized of main feature with multi-joint involvement, synovial membrane inflammation, bone and cartilage destruction etc. Epidemic disease inflammatory disease, pathogenesis not yet illustrate completely so far, generally believe disorderly with factors such as heredity, infection and immunological regulations Closely related (Imboden JB.Theimmunopathogenesis of rheumatoid arthritis.Annu Rev Pathol Mech Dis.2009,4:417-434.).Patient has joint red and swollen heat pain and dysfunction performance early stage, to late period When, joint may occur in which different degrees of stiff deformity, and with the atrophy of bone and skeletal muscle.Pathology angle sees that rheumatoid closes Section inflammation is a kind of main popularity involved synovium of joint, can feed through to articular cartilage, bone tissue, articular ligament and tendon later Diseases associated with inflammation.The illness rate of China RA about 0.3%-0.4%, there are about 4,000,000 patients, course of disease 5-10 disability rates are 60%, 90% patient of late period loses social labor power and self care ability, is one of the main reason for adult labour dies (Dai SM,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.), therefore many family problems and huge are caused Burden on society.The method of Current treatments rheumatoid arthritis mainly has operative treatment, chemotherapy and cell factor The treatment of class biological agent.Surgical operation is only applicable to late deformity case, and somewhat expensive, larger to body wound；Chemistry The prolonged application of drug such as non-steroidal anti-inflammatory drugs, antirheumatic drug and glucocorticoid etc. can cause gastrointestinal discomfort, bone marrow suppression, The serious adverse reaction such as hepatic injury, hypertension (Doan T, Massarotti E.Rheumatoid Arthritis:An Overview of New and Emerging Therapies.J Clin Pharmacol.2005,45:751-762.).Cause This, the drug for seeking the prevention RA of high-efficiency low-toxicity is still the challenge and problem that world medical circle faces.
The achene of Siberian cocklebur is fruit of the drying and ripening with involucre of feverfew Siberian cocklebur, is used for anemofrigid cold, nasosinusitis, rheumatism numbness Bitterly, the cards such as rubella itch, in wide clinical application in treatment rheumatoid arthritis.We have found thiazadione class at early-stage study The anti-inflammatory active ingredient that object is Chinese medicine achene of Siberian cocklebur n-butanol extract is closed, 2- hydroxyls-achene of Siberian cocklebur thiazine diketone glycosides has anti-inflammatory work Property, but without analgesic activities.Caffeoyl achene of Siberian cocklebur thiazine diketone glycosides has very strong anti-inflammatory and antalgic activity, and research report is to pyemia Mouse has notable protective effect, caffeoyl achene of Siberian cocklebur thiazine diketone glycosides (CYXD) intraperitoneal injection to be lost in what endotoxin (LPS) induced Blood stasis model mouse finds that CYXD can significantly reduce tumor necrosis factor α in mice serum (TNF-α) and interleukin-6 (IL-6) horizontal, in addition, CYXD may also suppress the mRNA of mouse macrophage (RAW 264.7) TNF-α and IL-6 of LPS inductions Express (Wang YH, Li TH, Wu BQ, et al.Protective effects of caffeoyl-xanthiazonoside isolated from fruits of Xanthium strumarium on sepsis mice[J].Pharm Biol2015, 53(9):1367).The applicant long campaigns achene of Siberian cocklebur is studied, and determines that thiazadione class compound has good prevention rheumatoid Arthritic effect can be used for preparing prevention rheumatoid arthritis drug.
Invention content
The purpose of the present invention is to provide a kind of thiazadione class compounds of prevention rheumatoid arthritis, and its pharmaceutically Acceptable ester, amide or salt and the salt of the ester or amide, pharmaceutical composition and application.
The first aspect of the present invention, provide a kind of thiazadione class compound and its pharmaceutically acceptable ester, amide or Salt is preparing the application in preventing or treating the drug or food of rheumatoid arthritis, and the thiazadione class compound is such as Shown in general formula I：
Wherein：R1Selected from H or hydroxyl；R2Selected from H, halogen, the alkyl of substituted or unsubstituted C1-C6, glycosyl, wherein Substituent group is the various organic acid substitutions such as amino, halogen, carboxyl, hydroxyl, coffee acyl；R3Selected from H, halogen, C1-C8 alkyl or C3-C6 naphthenic base.
In a preferred embodiment of the present invention, the thiazadione class compound be thiazadione (hereinafter referred to as Compound A)：R1=H, R2=H, R3=H.
In a preferred embodiment of the present invention, the thiazadione class compound is that thiazadione glycosides is (following Claim compound B)：R1=H, R2=Glc, R3=H.
In a preferred embodiment of the present invention, the thiazadione class compound is 2- hydroxyl thiazadione glycosides (hereinafter referred to as compound C)：R1=H, R2=Glc, R3=OH.
In a preferred embodiment of the present invention, the thiazadione class compound is caffeoyl thiazadione glycosides (hereinafter referred to as compound D)：R1=H, R2=Glc-caffeoyl, R3=H.
Preferably, the drug is：Using the thiazadione class compound as sole active composition, or include institute The pharmaceutical composition for the thiazadione class compound stated.
Preferably, in the drug, the amount of thiazadione class compound can account for 0.01% to the 50% of total weight； It is preferred that 0.1% to 10%；More preferable 0.5% to 5%；Most preferably 1%-2%.
Preferably, pharmaceutical preparation can be made with the conventional acceptable assistant in pharmacy in the pharmaceutical composition.
Preferably, the pharmaceutical preparation can be tablet, pill, pulvis, liquid, suspension, lotion, granule, glue Capsule, suppository and injection etc..Preferred tablet, granule, capsule, liquid and injection.
Preferably, the adjuvant includes pharmaceutically acceptable carrier, diluent, excipient, filler, disintegration One of agent, adhesive, emulsifier, lubricant, corrigent, colorant kind or two or more.
It is furthermore preferred that the adjuvant be dextrin, starch, lactose, sodium carboxymethylcellulose, lauryl sodium sulfate, Croscarmellose sodium, sodium carboxymethyl starch, pool fall husky nurse, magnesium stearate, powdered cellulose, talcum powder etc..
In a preferred embodiment of the present invention, the pharmaceutical preparation is tablet, by the raw material of following parts by weight It is made：
In a preferred embodiment of the present invention, the pharmaceutical preparation is tablet, by the raw material of following parts by weight It is made：
The second aspect of the present invention provides a kind of drug prevented or treat rheumatoid arthritis：With the thiazine Cyclohexadione compounds are as sole active composition, or include the pharmaceutical composition of the thiazadione class compound.
The third aspect of the present invention provides a kind of thiazadione class compound as described above and its pharmaceutically acceptable Ester, amide or salt are preparing the application in preventing or treating osteoporosis, gingivitis or osteoarthritis drugs, the gum Disease is selected from gingivitis and periodontitis.
Preferably, the compound is thiazadione, thiazadione glycosides, 2- hydroxyl thiazadione glycosides or caffeoyl thiazine Two ketosides.
The invention has the advantages that：
Thiazadione class compound of the present invention is for stimulating RAW264.7 inflammatory cells for LPS and being slided at fiber Theca cell significantly inhibits NO generations, and paraxylene causes mice ear to have obvious inhibiting effect, and Freund's complete adjuvant is caused Scorching rat paw edema has apparent functions of detumescence, relieving inflammation effect, has apparent inhibit for collagen-induced rheumatoid arthritis Effect, therefore can be used for preventing rheumatoid arthritis.
Description of the drawings
Fig. 1：Thiazadione class compound induces II Collagen Type VIs the influence of the left back podarthritis index of RA rat models；
Fig. 2：Thiazadione class compound induces II Collagen Type VIs the inhibiting effect of the left back whole swelling of RA rat models；
Fig. 3：Thiazadione class compound induces II Collagen Type VIs the influence of RA rat model joint tissue pathological sections.
Specific implementation mode
It elaborates to specific implementation mode provided by the invention with reference to embodiment.
Embodiment 1：
1) compound influences the RAW264.7 inflammatory cells that LPS is stimulated
Pathological change basic RA is synovitis.As the internal centrocyte for starting inflammatory mediator and generating, macrophage System plays a leading role during regulating and controlling inflammatory reaction, and large amount of cell factor can be generated after being activated.RAW264.7 cells are made For a kind of macrophage, immunity of organism process is participated in, it is outer in particular by lipopolysaccharides (lipopolysaccharide, LPS) etc. A large amount of inflammatory mediators can be generated after boundary's interference.Nitricoxide synthase (NO-synthase, iNOS) is catalyzed L-arginine and oxygen molecule Reaction generates nitric oxide (nitricoxide, NO).As an important inflammatory mediator in inflammatory reaction, NO participates in mediating Cellular immunity and inflammatory reaction.At acute inflammation position, inflammation-causing substance and inflammatory mediator can induce or increase the synthesis of NO and release It puts, to promote the reaction of inflammation to occur, NO levels is inhibited to be often used as one of evaluation index of drug screening.
2) pharmacological activity is tested
(1) to the toxic effect of 264.7 cells of RAW of LPS stimulations
After 0.25% pancreatin digestion of the RAW264.7 cells containing EDTA, DMEM culture mediums are added and adjust cell concentration to 1 ×104Cell/mL, the amount with 100 μ l per hole are seeded in 96 orifice plates.In 5%CO2With 37 DEG C under the conditions of after overnight incubation, add The medium culture 2h (being 200ng/mL after dosing) of 100 μ l LPS containing 400ng/mL, is added the pastille culture medium of each concentration (100 holes μ l/), make its final concentration of 100,10,1,0.1,0.01 μm of ol/mL, in CO2It is cultivated for 24 hours in incubator (37 DEG C).It will Supernatant discards, and the blank cultures (preventing drug itself from reacting with MTT) containing 20 μ l MTT (5mg/mL) are added in each hole, 37 DEG C of incubation 4h, abandon supernatant, and 150 μ l DMSO are added per hole, 10min are shaken on oscillator, with microplate reader Detection wavelength 570nm Under each hole absorbance value (ODA).
(2) influence that the 264.7 cell NO of R AW of LPS stimulations are generated
By RAW264.7 cells with 5 × 105A/mL is laid on 24 orifice plates, in 5%CO2With 37 DEG C under the conditions of cultivate for 24 hours after, abandon Pastille culture medium (the 100 μ l/ of each concentration are added with the LPS stimulations 2h (for 200ng/mL after dosing) of 400ng/mL in supernatant Hole), make its final concentration of 10,1,0.1 μm of ol/mL, in CO2It is cultivated for 24 hours in incubator (37 DEG C).Each sky takes 100 μ l supernatants In 96 orifice plates, it is added and is protected from light standing after whirlpool under room temperature shakes mixing with the 100 μ l of Griess reagents got ready in advance 30min surveys absorbance value (OD) at 540nm wavelength.
(3) to the influence of R AW 264.7 the cell IL-1 β and TNF-α of LPS stimulations
By RAW264.7 cells with 5 × 105A/mL is laid on 24 orifice plates, in 5%CO2With 37 DEG C under the conditions of cultivate for 24 hours after, abandon Pastille culture medium (the 100 μ l/ of each concentration are added with the LPS stimulations 2h (for 200ng/mL after dosing) of 400ng/mL in supernatant Hole), make its final concentration of 10,1,0.1 μm of ol/mL, in CO2It is cultivated for 24 hours in incubator (37 DEG C).Experimental method is built according to Nanjing Illustrate to detect IL-1 β, TNF-α content in cell supernatant at IL-1 β, TNF-α ELISA kit.
3) experimental result
When drug concentration is 100 μm of ol/L and 10 μm of ol/L, A, B show the RAW264.7 cell Proliferations that LPS is stimulated Apparent inhibiting effect, when drug concentration is 1 μm of ol/L, RAW264.7 cell Proliferation tables that compound A, B, C, D stimulate LPS Reveal apparent inhibiting effect, compounds all 0.1 μm of ol/L and 0.01 μm of ol/L increases the RAW264.7 cells that LPS is stimulated Grow no obvious inhibiting effect.The results are shown in Table 1.Therefore, it is since compound is direct to avoid the reduction of inflammatory factor level Cytotoxicity caused by, follow-up study choose drug concentration be 10,1,0.1 μm of ol/L.
1 compound of table to LPS 264.7 cell Proliferations of RAW stimulated influence (n=5,)
Note：With LPS group ratio * P<0.05 (inhibition),#P<0.05 (proliferation).
After LPS stimulations, RWA264.7 cell NO concentration is significantly raised, shows modeling success.Compound A, B, C, D administration group It is horizontal to can obviously reduce NO in RWA264.7 cell supernatants in a concentration of 10,1,0.1 μm of ol/L, and is closed at dosage effect System.It the results are shown in Table 2.
The influence (n=5, x_ ± s) that NO is generated in 264.7 cells of RAW that 2 compound of table stimulates LPS
Note：With LPS group ratio * P<0.05.
When drug concentration is 10 and 1 μm of ol/L, in the RAW264.7 cells that compound A, B, C, D stimulate LPS IL-1 β and TNF-α level shows apparent inhibiting effect, and D shows apparent inhibiting effect when 0.1 μm of ol/L.
The influence (n=3, x_ ± s) of IL-1 β and TNF-α content in 264.7 cells of RAW that 3 compound of table stimulates LPS
Note：With LPS group ratio * P<0.05.
Embodiment 2：
1) compound is to the influence at fiber synovial cell
Rheumatoid arthritis is mainly shown as the hyperplasia of synovial tissue, wherein most representative, to be into fiber synovial membrane thin Born of the same parents, therefore this research is started with from fiber synovial cell, in influence and the cell supernatant by comparing drug cell proliferation The measurement of NO, to react the function and effect of drug, wherein NO be a kind of high response cell toxicant for being synthesized under iNOS inductions from By base and immunocompetence medium.
2) pharmacological activity is tested
(1) reactive compound is at the value-added effect of fiber synovial cell
After theca cell is using the 0.25% pancreatin digestion of EDTA, DMEM culture mediums are added and adjust cell concentration to 5 × 104Carefully Born of the same parents/mL, the amount with 100 μ l per hole are seeded in 96 orifice plates.In 5%CO2With 37 DEG C under the conditions of cultivate for 24 hours, after discarding supernatant, add Enter the pastille culture medium (100 holes μ l/) of each concentration, a concentration of 10,0.5,0.025 μ g/mL, in CO2In incubator (37 DEG C) Culture is for 24 hours.Supernatant is discarded, the blank cultures containing 20 μ l MTT (5mg/mL), which are added, in each hole (prevents drug itself and MTT React), 37 DEG C of incubation 4h abandon supernatant, 150 μ L DMSO are added per hole, shakes 10min on oscillator, is detected with microplate reader The absorbance value (ODA) in each hole under wavelength 570nm.
(2) influence of the reactive compound to being generated at fiber synovial cell NO
Synovial cell is with 5 × 105A/mL is laid on 24 orifice plates, in 5%CO2With 37 DEG C under the conditions of cultivate for 24 hours after, abandon supernatant, The pastille culture medium (100 holes μ l/) of each concentration, a concentration of 10,0.5,0.025 μ g/mL, in CO is added2Incubator (37 DEG C) Middle culture is for 24 hours.Each sky takes 100 μ l supernatants in 96 orifice plates, is added in advance with the 100 μ l of Griess reagents got ready, in room temperature item Under part after whirlpool concussion mixing, it is protected from light and stands 30min, absorbance value (OD) is surveyed at 540nm wavelength.
3) experimental result
Compound A, B, C, D it is a concentration of in 10,1,0.1 μ g/mL when, proliferation function is shown to FLS cell Proliferations, but It is not obvious, while showing that toxic side effect is not present in compound on intracellular
4 compound of table at fiber synovial cell proliferation influence (n=5,)
Note：With LPS group ratio * P<0.05 (inhibition),#P<0.05 (proliferation).
Influence (n=5, x_ ± s) of 5 compound of table to being generated at NO in fiber synovial cell
Note：With LPS group ratio * P<0.05.
The results show that compound A, B, C, D can be reduced when concentration is in 10,1,0.01 μ g/mL in FLS cell supernatants NO is horizontal.Selected compounds can inhibit the release of FLS cells NO to a certain extent, and the results are shown in Table 5.
Embodiment 3：
1) compound paraxylene causes the influence of ear thickness
Dimethylbenzene can increase the permeability of capillary, according to existing static balancing relationship between capillary and tissue come Analysis, because capillary permeability increases, then the liquid for penetrating into tissue just increases, that is, our visually see show As there is inflammatory redness.
2) experimental method
Male mice is randomly divided into 8 groups by weight, every group 10, causes 60min gastric infusion 0.5mL/20g before inflammation, it will Dimethylbenzene 0.05ml drops are in mouse auris dextra, left ear control.Mouse cervical vertebra taken off after 2h lethal, two ears are cut along auricle baseline, with straight Diameter is that the card punch of 7mm lays round auricle at the same position of left and right ear respectively, is weighed.
3) experimental result
6 achene of Siberian cocklebur active material paraxylene of table causes the influence (n=10, x_ ± s) of mice ear degree
The results are shown in Table 6, and dexamethasone there is significant inhibiting effect, inhibiting rate to reach mouse caused by dimethylbenzene xylene ear swelling To 59.3%, compound A, B, C and D have the function of significantly inhibiting ear swelling compared with model group, the brightest with compound D It is aobvious, it is almost the same with positive drug dexamethasone effect.
Embodiment 4：
Prescription：
It prepares
Above-mentioned auxiliary material crosses 60 mesh sieve respectively, after caffeoyl thiazadione glycosides and lauryl sodium sulfate are sufficiently mixed, with Lactose, sodium carboxymethyl starch sieving mixing, are added magnesium stearate and powdered cellulose tabletting to get being made 1000.
Embodiment 5：
Prescription：
It prepares
Above-mentioned auxiliary material crosses 60 mesh sieve respectively, thiazadione glycosides and pool is fallen after husky nurse 188 is sufficiently mixed, with dextrin, crosslinking Sodium carboxymethylcellulose sieving mixing, is prepared as particle in a manner of wet granulation, crosses 80 mesh sieve, dries particle, talcum powder is added Tabletting is to get being made 1000.
Embodiment 6：Pharmacological activity experiment to the pharmaceutical composition of embodiment 4 and 5
1) present composition causes Freund's adjuvant the influence of scorching rat toes swelling degree
Research method：Male SD rat, 180~220g, 80 rat weights are randomly divided into 8 groups, every group 10 by weight Only, free diet, water inlet.It is divided into model group, the high, medium and low dosage group of positive drug group and pharmaceutical composition B and D.Blank group： Not any processing；Model group：It will be mixed with atoleine after the grinding of cheese mycobacterium, and be made into 10mg/mL, after high pressure sterilization Freund's complete adjuvant is made.In the left back toes of 0.1mL intracutaneous injections, from after adjuvant injection the 16th day, rat paw edema is apparent.SD Rat root of the tail carries out intracutaneous injection (1mg/ml), every 0.1ml；Positive drug group：Dexamethasone, from after modeling success, 0.05mg/ Kg, gastric infusion, one time a day；Pharmaceutical composition group：From modeling success, rat oral gavage administration is given, one time a day, High, medium and low, dosage is that content of dispersion is 20mg/kg, 10mg/kg and 5mg/kg successive administration 7 days, surveys administration the 1st day and the 7th day Paw swelling, scorching front foot volume × 100% of swelling rate=(the 7th day foot swelling volume-cause inflammation front foot volume after administration)/cause.
Influence (n=10, x_ ± s) of 7 composition of table to adjuvant toes swelling degree
Note：* vs model groups, p<0.05；* vs model groups, p<0.01.
Result is found out shown in table 7, and toes swelling model group caused by rat Freund's adjuvant has significance difference with blank group Different, model building success, thiazadione class compound, B, D composition are in high, medium and low dosage group to caused by rat Freund's adjuvant There is significant inhibiting effect, especially high, middle dose group to restore consistent with normal group substantially for toes swelling.Prompt this composition With significant resist inflammation on repercussive function.
2) caffeoyl thiazadione glycoside composition resisting rheumatoid disease arthritis pharmacodynamic study
Experimental method：By 90 rat weights before experiment, 9 groups are randomly divided by weight, every group 10, free diet, Water inlet.It is divided into blank group, model group, positive drug group and high, medium and low group of pharmaceutical composition.Blank group：Not any processing；Mould Type group：Ox II collagen types acetum is mixed with the incomplete Freund's adjuvant of equal capacity, it is fully emulsified.0th day, SD was big Rat-tail root carries out intracutaneous injection (1mg/ml), every 0.1ml；After 7 days, booster immunization, rat root of the tail is noted with 0.1ml/ solution It penetrates as booster injection, causes RA animal models within the 15th day or so；Positive drug group：Dexamethasone, 0.05mg/kg, gastric infusion, One time a day；Pharmaceutical composition B, D：From modeling success, rat oral gavage administration is given, one time a day, is containing pharmaceutical quantities 10mg/kg, successive administration 15d.
3) observation index
(1) arthritis index scoring is carried out to rat articular swelling degree, scoring in every 5 days is primary.
(2) it uses toes capacity measurer to measure rat toes swelling degree, measures within every 5 days primary.
(3) terminate next day in experiment, rat tails venous blood sampling is centrifuged after setting ice bath 30min with 2000r/min 15min takes supernatant, and TNF-α, IL-1 β, IL-6, IL-8, IL-17 and Cox-2 water in two groups of rat blood serums are measured with ELISA method It is flat, it is operated by kit specification.
(4) rat ankle joint bone tissue is taken to carry out check pathological section.
4) experimental result
The analysis of two sample t test statistics, P are carried out using SPSS14.0 pairs of two groups of data<Think that difference has system when 0.05 Meter learns meaning.
(1) rat arthritis index score
As shown in Figure 1, administration the 15th day, the left back podarthritis index of B, D composition group is respectively 2.5 ± 0.4 and 2.2 ± 0.2, the left back podarthritis index of model group is 3.7 ± 0.5, and two compositions can significantly reduce the RA rats of II Collagen Type VIs induction Left back podarthritis index, there are significant differences compared with model group, show composition to rat rheumatoid arthritis mould Type has preferable therapeutic effect.
(2) rat toes swelling
As shown in Fig. 2, the left back toes of blank group rat are without substantially changeing, model group has apparent swelling, is deposited with blank group In significant difference, modeling success is prompted；It is administered the 15th day, the left back sufficient volume of B, D composition group is 1921 ± 238mm3With 1755±187mm3, the left back sufficient volume of model group is 2403 ± 198mm3, two compositions administration group rat phase left back foot after the test Toe swelling degree significantly mitigates, and shows that composition has preferable therapeutic effect to rat model of rheumatoid arthritis.
(3) serological index
As shown in table 8, compared with model group, composition can significantly reduce TNF-α in serum, IL-1 β, IL-6, IL-8, The level of IL-17 and Cox-2 illustrates that composition 10mg/kg gastric infusions can significantly reduce rheumatoid arthritis animal model The level of key pro-inflammatory cytokines and destruction of bone correlation factor in serum, can be effectively relieved RA rats inflammatory reaction and Destruction of bone.
8 composition of table induces II Collagen Type VIs influence (mean ± SD, the n of RA rat models Cytokine of Serum level =10)
Note：* vs model groups, p<0.05；* vs model groups, p<0.01.
(4) pathological section
As shown in figure 3, model group rats histopathologic slide shows that synovial hyperplasia and inflammatory cell infiltration are serious, positive drug Synovial hyperplasia and inflammatory cell infiltration can be substantially reduced after dexamethasone and composition administration, composition B can with composition D groups Effectively inhibit inflammation damnification and the joint destruction of bone of RA rat models.
In view of above-mentioned effect experiment evaluation result, thiazadione class pharmaceutical composition of the invention has notable resisting rheumatoid disease Property arthritis activity, therefore can be used for preparing resisting rheumatoid arthritis drug.
The preferred embodiment of the invention is illustrated above, but the invention be not limited to it is described Embodiment, those skilled in the art can also make various equivalent under the premise of without prejudice to the invention spirit Modification or replacement, these equivalent modifications or replacement are all contained in the application claim limited range.

Claims (9)

1. a kind of thiazadione class compound and its pharmaceutically acceptable ester, amide or salt are preparing prevention or treatment rheumatoid Application in the arthritic drug of property or food, the thiazadione class compound are shown in formula I：
Wherein：R1Selected from H or hydroxyl；R2Selected from H, halogen, the alkyl of substituted or unsubstituted C1-C6, glycosyl, wherein replacing Base is the various organic acid substitutions such as amino, halogen, carboxyl, hydroxyl, coffee acyl；R3Selected from H, halogen, C1-C8 alkyl or C3- C6 naphthenic base.
2. application according to claim 1, which is characterized in that the thiazadione class compound is thiazadione, i.e. R1 =H, R2=H, R3=H.
3. application according to claim 1, which is characterized in that the thiazadione class compound is thiazadione glycosides, That is R1=H, R2=Glc, R3=H.
4. application according to claim 1, which is characterized in that the thiazadione class compound is 2- hydroxyls thiazine two Ketoside, i.e. R1=H, R2=Glc, R3=OH.
5. application according to claim 1, which is characterized in that the thiazadione class compound is caffeoyl thiazine two Ketoside, i.e. R1=H, R2=Glc-caffeoyl, R3=H.
6. application according to claim 1, which is characterized in that the drug is：With the thiazadione class chemical combination Object is as sole active composition, or includes the pharmaceutical composition of the thiazadione class compound.
7. application according to claim 6, which is characterized in that in the drug, the content of thiazadione class compound Account for 0.01% to the 50% of total weight.
8. application according to claim 6, which is characterized in that in the drug, the content of thiazadione class compound Account for 0.1% to the 10% of total weight.
9. a kind of thiazadione class compound and its pharmaceutically acceptable ester, amide or salt prevent in preparation or treatment sclerotin is dredged Application in pine, gingivitis or osteoarthritis drugs, the gingivitis are selected from gingivitis and periodontitis；The thiazine two Ketone compounds are as shown in general formula I：
Wherein：R1Selected from H or hydroxyl；R2Selected from H, halogen, the alkyl of substituted or unsubstituted C1-C6, glycosyl, wherein replacing Base is the various organic acid substitutions such as amino, halogen, carboxyl, hydroxyl, coffee acyl；R3Selected from H, halogen, C1-C8 alkyl or C3- C6 naphthenic base.
CN201711420139.1A 2017-12-25 2017-12-25 A kind of thiazadione class compound prepare prevent or the drug for the treatment of rheumatoid arthritis in application Pending CN108283643A (en)

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CN108514568A (en) * 2018-05-14 2018-09-11 黑龙江中医药大学 The preparation method and its medical usage of thiazides compounds in the achene of Siberian cocklebur
CN109498625A (en) * 2018-12-29 2019-03-22 温州医科大学附属第医院 A kind of pharmaceutical composition and preparation method thereof for treating Chronic Obstructive Pulmonary Disease
CN110038023A (en) * 2019-04-19 2019-07-23 温州医科大学 A kind of pharmaceutical composition for the antiallergic activity substituting the achene of Siberian cocklebur
CN114767701A (en) * 2022-05-09 2022-07-22 黑龙江中医药大学 Medicine for treating acne and application thereof

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CHENG ZHI,ET AL.: "A NEW THIAZINEDIONE GLYCOSIDE FROM THE FRUIT OF Xanthium sibiricum，Chemistry of Natural Compounds", 《CHEMISTRY OF NATURAL COMPOUNDS》 *
YAN-HONG WANG,ET AL: "Protective effects of caffeoylxanthiazonoside isolated from fruits of Xanthium strumarium on sepsis mice", 《PHARM BIOL》 *
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108514568A (en) * 2018-05-14 2018-09-11 黑龙江中医药大学 The preparation method and its medical usage of thiazides compounds in the achene of Siberian cocklebur
CN109498625A (en) * 2018-12-29 2019-03-22 温州医科大学附属第医院 A kind of pharmaceutical composition and preparation method thereof for treating Chronic Obstructive Pulmonary Disease
CN109498625B (en) * 2018-12-29 2021-04-16 温州医科大学附属第一医院 Pharmaceutical composition for treating chronic obstructive pulmonary disease and preparation method thereof
CN110038023A (en) * 2019-04-19 2019-07-23 温州医科大学 A kind of pharmaceutical composition for the antiallergic activity substituting the achene of Siberian cocklebur
CN110038023B (en) * 2019-04-19 2021-05-07 温州医科大学 Anti-allergic pharmaceutical composition for replacing cocklebur fruit
CN114767701A (en) * 2022-05-09 2022-07-22 黑龙江中医药大学 Medicine for treating acne and application thereof
CN114767701B (en) * 2022-05-09 2023-10-20 黑龙江中医药大学 Medicine for treating acne and application thereof

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Application publication date: 20180717