CN108047239A - A kind of compound, preparation method and its application in preventing/treating autoimmune disease drug is prepared - Google Patents
A kind of compound, preparation method and its application in preventing/treating autoimmune disease drug is prepared Download PDFInfo
- Publication number
- CN108047239A CN108047239A CN201810034204.5A CN201810034204A CN108047239A CN 108047239 A CN108047239 A CN 108047239A CN 201810034204 A CN201810034204 A CN 201810034204A CN 108047239 A CN108047239 A CN 108047239A
- Authority
- CN
- China
- Prior art keywords
- compound
- autoimmune disease
- formula
- solution
- application
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Abstract
The invention discloses a kind of Formulas(Ⅰ), wherein R is selected from、Or
Description
Technical field
The invention belongs to field of medicaments, are related to a kind of compound, preparation method and its are preparing preventing/treating autoimmunity
Application in property disease medicament.
Background technology
Autoimmune disease is that body occurs immune response to autoantigen and causes caused by damaged self tissue
A kind of disease.At present both at home and abroad to the research of IL-12 families mainly around autoimmune disease, such as multiple sclerosis
(Multiple sclerosis, MS), inflammatory bowel disease(Inflammatory bowel disease, IBD), rheumatoid close
Section is scorching(Rheumatoid Arthritis, RA), psoriasis(psoriasis)Deng.
Rheumatoid arthritis is the autoimmune disease based on synovium of joint chronic inflammation, can cause swollen joint
Bitterly, then cause cartilage destruction, cause joint deformity, different degrees of deformity finally occur.If do not given appropriate treatment, usually
It can cause destruction of joint and deformity, and influence the quality of life of patient.
Psoriasis is commonly called as " psoriasis ", is a kind of common chronic inflammatory skin for being easy to recurrence, characteristic lesions
To be covered with the multilayer silvery white scales of skin that peel off on red papules or patch.Person between twenty and fifty's morbidity is most, and male's morbidity is more than women.The cause of disease and hair
Anttdisease Mechanism is not completely clear and definite, the study found that this sick morbidity hinders with inherent cause, infection streptococcus, immunologic dysfunction, metabolism
Hinder and hormonal change etc. is related.Psoriasis is recurrent, refractory disease, patient is caused on great body and mentally
Injury.
IL-12 is a kind of cellular inflammation factor found in recent years, is mainly produced by T, bone-marrow-derived lymphocyte and monocytes/macrophages
It is raw, there is inflammation effect, promote the generation of T lymphocyte IFN-γ, inhibit the synthesis of IL-10, IL-11 etc., and it is right
It is essential that the TH 1 of TH precursors breaks up, and IL-12 can also directly facilitate bone-marrow-derived lymphocyte hyperplasia, differentiation, and it is anti-to secrete itself
Body, inducing autoimmune disease occur.The p70 heterodimers that IL-12 is made of two subunits of p35 and p40.There is research table
It is bright:Old RA patient PBMC cell supernatants IL-12 is horizontal higher than Normal group, active stage again apparently higher than resting stage, this
IL-12 is prompted to participate in the pathogenic process of rheumatoid arthritis, and is further illustrated with RA mobilities there is certain relation
PBMC is active, synthesis IL-12 increases there are abnormal activation in RA.It is horizontal higher than static from active stage RA IL-12
Phase IL-12 level more fullys illustrate that exception is related in itself with PBMC.
The content of the invention
One of the objects of the present invention is to provide a kind of compound, structure such as formulas(Ⅰ)It is shown,
,
Wherein R is selected from、Or。
* it is expressed as key position.
Another object of the present invention is to provide a kind of Formula(Ⅰ)Synthetic route:
。
Another object of the present invention is to provide a kind of Formula(Ⅰ)Synthetic route synthesis step it is as follows:
1)It is added dropwise cyclohexanol into the solution of sodium hydride at low temperature, after stirring 30 minutes, then by syringe is added dropwise 2,
The THF solution of 4,6- tri- chloro- 3- picolines, be warmed to room temperature stirring 2-5 it is small when, be cooled to 0 DEG C, add saturated ammonium chloride water-soluble
Liquid is reacted with terminating.After heating up, diluting, wash, separation, extraction are dry, again through silica gel column chromatography after filtering, concentration
Purifying, obtain compound 2;
2)Ethyl alcohol, water and 2- oxa- -7- azaspiros [3.5] nonane are packed into three-neck flask, is cooled to about 0 DEG C, chemical combination is added dropwise
The ethyl acetate solution of object 2 keeps temperature to be less than 10 DEG C.After reaction, water on the rocks and stir, precipitation completely after filter out white
Solid by washing, being dried in vacuo, obtains compound 3;
3)Under nitrogen purge, stirred suspension of 3 and one hydrazine hydrate of compound in dioxanes is boiled, flowed back, through later
Continuous processing obtains compound 4;
4)By the acetic acid of compound 4, corresponding aldehyde and catalytic amount in absolute ethyl alcohol-ethyl acetate mixture heating until being formed clear
Clear solution is cooled to 30 DEG C and filters after the completion of reaction.Obtain crude product by subsequent processing, after by it in ethanol solution
It is middle to continue to be heated to reflux cooling crystallization and obtain the final products that purity is more than 99.5%.
Further, the step 1)In low temperature refer to 0-10 DEG C, preferably 0 DEG C, the reaction time for 2-5 it is small when, preferably 4
Hour.
Further, the step 1)Middle cleaning solution saturated sodium bicarbonate aqueous solution and saturated sodium thiosulfate are water-soluble
Liquid can also be washed with water or absolute ethyl alcohol, and preferably saturated sodium bicarbonate aqueous solution and saturated sodium thiosulfate is water-soluble
Liquid.
Further, the step 3)When middle return time is 4-8 small, preferably flow back 6 hours.
Another object of the present invention is to provide a kind of Formula(Ⅰ)Preparing the application in reducing IL-12 drugs.
Another object of the present invention is to provide a kind of Formula(Ⅰ)Preparing prevention and/or treatment autoimmune
Application in disease medicament.
Further, the autoimmune disease is multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis or silver
Consider disease etc. to be worth doing.
The present invention is not to Formula(Ⅰ)Or include Formula(Ⅰ)The method of application of composition especially limited
System, representative method of application include(But it is not limited to):Oral, parenteral(Intravenously, intramuscular or subcutaneous)And part is given
Medicine.Include capsule, tablet, pill, powder and granule for the solid dosage forms of oral medication.In these solid dosage forms,
Formula(Ⅰ)With at least one conventional inert excipients(Or carrier)Mixing, such as sodium citrate or Dicalcium Phosphate or with it is following
Ingredient mixes:(a)Filler or bulking agent, such as starch, lactose, sucrose, glucose, mannitol and silicic acid;(b)Adhesive, example
Such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum;(c)Moisturizer, for example, it is sweet
Oil;(d)Disintegrant, such as agar, calcium carbonate, potato starch or tapioca, alginic acid, some composition silicates, sodium carbonate;
(e)Retarding solvent, such as paraffin;(f)Absorbsion accelerator, such as quaternary ammonium compound;(g)Wetting agent, such as cetanol and single tristearin
Acid glyceride;(h)Adsorbent, such as kaolin;(i)Lubricant, such as the poly- second two of talcum, calcium stearate, magnesium stearate, solid
Alcohol, lauryl sodium sulfate.In capsule, tablet and pill, dosage form can also include buffer.
Wherein, gastrointestinal administration preparation is presently the most common administration form, and convenient experimental operation, therefore, this hair
Formula is carried out using gastric infusion in bright specific embodiment(Ⅰ)The test of pesticide effectiveness, it is not intended that, Formula
(Ⅰ)Administration form be only limitted to gastrointestinal administration, those skilled in the art can be according to Formula(Ⅰ)Physical chemistry
Matter with reference to Modern preparations technology and the actual needs of sufferer, is prepared into injection, scalp absorbable preparation, implantation preparation etc.
Several formulations so as to expand its administration route, and improve target-oriented drug or effectively avoid unnecessary toxic side effect.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture.
Except active ingredient beyond the region of objective existence, liquid dosage form can include the inert diluent routinely used in this field, such as water or other solvents, increase
Solvent and emulsifier, example know ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethylformamide
And oil, the particularly mixture of cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances
Deng.
In addition to these inert diluents, composition can also include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste
Agent, corrigent and fragrance.
Except active ingredient beyond the region of objective existence, suspension can include suspending agent, such as ethoxylation isooctadecane alcohol, polyoxyethylene mountain
Pears alcohol and the mixture of Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these substances etc..
For parenteral injection composition can include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or lotion with for re-dissolving into the aseptic powdery of sterile Injectable solution or dispersion liquid.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
Dosage form for the compounds of this invention of local administration includes ointment, powder, patch, propellant and inhalant.
Active ingredient aseptically with that physiologically acceptable carrier and any preservative, buffer or may need if necessary
Propellant be mixed together.
The compounds of this invention can be administered alone or with other pharmaceutically acceptable other drugs administering drug combinations.
Obviously, the above according to the present invention according to the ordinary technical knowledge and means of this field, is not departing from this hair
Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Specific embodiment
Embodiment 1:Bis- chloro- 6- of 2,4-(Cyclohexyl oxygroup)The synthesis of -3- picolines
At 0 DEG C to sodium hydride NaH(4.51g, 0.188mmol, 60wt%, in mineral oil)THF(200mL)In solution dropwise
Add in cyclohexanol(15.6mL 0.15mol).After being stirred 30 minutes at 0 DEG C, 2,4,6- tri- chloro- 3- first are added dropwise by syringe
Yl pyridines(Compound 1)(26.52g 0.135mol)THF(40mL)Solution.Reaction mixture is heated to room temperature and stirring 4
Hour.The reaction is cooled to 0 DEG C, saturated aqueous ammonium chloride is slowly added to terminate reaction.Reaction mixture is made to be warming up to room
Temperature is diluted with ethyl acetate, and is washed with saturated sodium bicarbonate aqueous solution and saturated aqueous sodium thiosulfate.By organic layer point
It is extracted twice from and by aqueous layer with ethyl acetate.The organic layer of merging is dried, filtered and concentrated with sodium sulphate.Pass through column chromatography
Method(Ethyl acetate/hexane gradient)Purifying, obtains 2,4-, the bis- chloro- 6- of 33.37g(Cyclohexyl oxygroup)- 3- picolines(Chemical combination
Object 2), yield 95%.1H-NMR (400 MHz, CDCl3) δ: 1.08-1.29(m, 5H), 1.58-1.71(m, 3H),
1.90-1.98(m, 2H), 2.40(s, 3H), 4.19(m, 1H), 7.01(s, 1H). 13C-NMR (125 MHz,
CDCl3) δ: 18.26, 24.60, 25.92, 30.44, 76.82, 116.48, 121.22, 146.78, 147.96,
160.53.LC-MS(ESI, pos, ion) m/z: 260[M+H]。
Embodiment 2:7-(The chloro- 6- of 4-(Cyclohexyl oxygroup)- 3- picoline -2- bases)- 2- oxa- -7- azaspiros [3.5]
The synthesis of nonane
Ethyl alcohol is packed into the 2L three-neck flasks equipped with mechanical agitator, thermometer and dropping funel(375mL), water
(375mL)With 2- oxa- -7- azaspiros [3.5] nonane(19.08g 0.15mol), acquired solution is cooled down(Use ice salt bath)Extremely
About 0 DEG C, and by compound 2(33.37g 0.128mol)Ethyl acetate(47.5mL)Solution was added dropwise in about 20 minutes,
Temperature is kept to be less than 10 DEG C.By dropping funel ethyl acetate(20mL)It rinses twice, flushing liquor is transferred to reaction mixture
In.Reaction is checked by TLC to determine when that reaction is completed.After reaction, ice water is added in(375mL), stir 30 minutes, make
Precipitation is complete.White solid is filtered out, is washed with water 6 times(Washing 225mL every time), and be dried in vacuo at 40-50 DEG C, Zhi Daowei
Constant weight is held, obtains product 7-(The chloro- 6- of 4-(Cyclohexyl oxygroup)- 3- picoline -2- bases)- 2- oxa- -7- azaspiros [3.5] nonyl
Alkane(Compound 3), 41.95g, yield 93.4%.1H-NMR (400 MHz, CDCl3) δ: 1.08-1.29(m, 5H),
1.58-1.69(m, 3H), 1.85(t, 4H), 1.90-1.98(m, 2H),2.40(s, 3H), 3.71(t, 4H),
4.18(m, 1H), 4.72(s, 4H), 6.36(s, 1H). 13C-NMR (125 MHz, CDCl3) δ: 12.53,
24.60, 25.92, 28.55, 30.44, 38.75, 45.85, 76.82, 81.26, 102.35, 113.49,
147.28, 158.64,165.91.LC-MS(ESI, pos, ion) m/z: 351[M+H]。
Embodiment 3:7-(6-(Cyclohexyloxy)- 4- diazanyl -3- picoline -2- bases)- 2- oxa- -7- azaspiros [3.5]
The synthesis of nonane
Under nitrogen purge, embodiment 2 is synthesized to obtained compound 3(41.95g 0.120mol)With a hydrazine hydrate(7.51g
0.15mol)In dioxanes(255mL)In suspension boil, and flow back 6 hours.Ice water is added in into reaction mixture
(400mL), and stand overnight.The precipitation of generation is filtered out, is washed with water 3 times(Each 260mL), and vacuum is done at 40-50 DEG C
It is dry until constant weight, obtain 7-(6-(Cyclohexyloxy)- 4- diazanyl -3- picoline -2- bases)- 2- oxa- -7- azaspiros [3.5] nonyl
Alkane(Compound 4), 27.77g, yield 66.8%.1H-NMR (400 MHz, CDCl3) δ: 1.08-1.29(m, 5H),
1.58-1.69(m, 3H), 1.84(t, 4H), 1.88-1.98(m, 4H),2.31(s, 1H), 2.40(s, 3H),
3.71(t, 4H), 4.17(m, 1H), 4.72(s, 4H), 5.21(s, 1H). 13C-NMR (125 MHz, CDCl3)
δ: 11.50, 24.60, 25.92, 28.55, 30.44, 38.75, 45.85, 76.82, 81.26, 85.95,
109.94, 147.44, 161.81,164.78.LC-MS(ESI, pos, ion) m/z: 347[M+H]。
Embodiment 4:(E)-7-(6-(Cyclohexyl oxygroup)-4-(2-(2- ethyl heptamethylenes)Diazanyl)- 3- picolines -2-
Base)The synthesis of -2- oxa- -7- azaspiros [3.5]
The compound 4 that will be synthesized in embodiment 3(27.77g 0.080mol), 2- ethyl enanthaldehyde(12.80g 0.090mol)
With the acetic acid of catalytic amount(0.67g, 11mmol)In absolute ethyl alcohol-ethyl acetate mixture(1:1 volume, each 162mL)Heating is straight
To formation settled solution(55-75℃), TLC shows that the consumption of all initial substances is completed(At least 40 minutes).By reaction mixture
It is cooled to 30 DEG C and filters.With EtOH-EtOAc 1:1 mixture(Each 80mL)Washing reactor and filter, by merging
Filtrate and cleaning solution are condensed into the oily mixture with about 1/3rd initial solvent volumes.In order to promote to precipitate, by oiliness
When mixture stirring at least 2.5 is small(Or at most 12 it is small when).Solid is filtered out, uses absolute ethyl alcohol(Each 115mL)It washes twice simultaneously
It is dry.It obtains(E)-7-(6-(Cyclohexyl oxygroup)-4-(2-(2- ethyl heptamethylenes)Diazanyl)- 3- picoline -2- bases)- 2- oxygen
Miscellaneous -7- azaspiros [3.5](Compound 5)It is canescence or the colorless solid that purity is more than 98%(36.23g yield 96.2%).
In order to obtain higher purity, by compound 5(36.23g 0.077mol)Absolute ethyl alcohol(400mL)Solution is heated to reflux simultaneously
Reflux is until form settled solution.The ethyl alcohol of about 200mL is steamed from solution under reduced pressure, is stirred at room temperature to precipitation and terminates
(About 4 it is small when).Sediment is filtered out, uses ethyl alcohol(100mL)It washes twice, and constant weight is dried under vacuum at 40-50 DEG C, changed
Object 5 is closed, 99.5% colorless solid is more than for purity(32.32g 89.2% yield).1H-NMR (400 MHz, CDCl3)
δ: 0.89(t, 3H), 0.94(t, 3H), 1.08-1.31(m, 11H), 1.44-1.54(m, 2H), 1.58-1.74
(m, 5H), 1.85(t, 4H), 1.90-1.98(m, 2H), 2.40(s, 3H), 2.54(m, 1H),3.71(t, 4H),
4.16(m, 1H), 4.72(s, 4H), 5.21(s, 1H),5.65(d, 1H),7.85(s, 1H). 13C-NMR (125
MHz, CDCl3) δ:11.34, 11.50, 14.00, 23.16, 24.60, 25.92, 26.04, 27.50, 28.55,
30.44, 31.59, 32.81, 38.75, 41.61, 45.85, 76.82, 81.26, 92.47, 109.06,
147.67, 152.74, 160.35, 164.49.LC-MS(ESI, pos, ion) m/z: 471[M+H]。
Test example 1:It is external to inhibit IL-12 experiments
First, THP-1 cell culture
Cell culture:THP-1 is the monocytic series of human peripheral, and THP-1 cell culture is in containing 10%FBS+1%P/S's
In RPMI-1640 culture mediums, culture environment is 37 DEG C, 5%CO2.It can be every 3-4 days plus some fresh culture mediums or direct
Passage.
2nd, cell is handled
THP-1 cells are added in into IFN-γ(100U/mL)Pre-process 22 it is small when, added in the presence of various concentration testing compound
Staphylococcus aureus(0.03%, mass fraction)Stimulated, 18 it is small when after, 1000 × g centrifuge 20 minutes, take supernatant.
3rd, IL-12 is detected
Using human interleukin 12 p70(IL-12)Detection kit(Upper object Science and Technology Ltd. of Haikang nangzan trade name
Abcam)It measures.This kit is with double antibody sandwich ELISA quantitative determination human serum, blood plasma, tissue homogenate, cell cracking
Interleukin 12 p70 in liquid, cell culture supernatant and other biological liquid(IL-12)Content.Specifically used and calculating side
Method refers to specification.
4th, experimental result
The IC of the compounds of this invention50It see the table below:
The formula of different R groups(Ⅰ) | IC50(nM) |
16 | |
4 | |
52 |
Test example 2:HaCat cell proliferation inhibiting rates
Skin epidermis keratinocyte fast breeding is one of notable pathological characters of psoriasis, inhibits horn cell and quickly increases
Psoriasis can effectively be treated by growing.
Immortalized human skin's keratinocyte HaCat is provided by Wuhan University's cell bank cell bank.HaCat cells are connect
It plants in 96 well culture plates, 10000 cells/wells, overnight incubation, condition of culture is:37℃、5% CO2, under the conditions of saturated humidity, training
It supports in the DMEM culture mediums containing 10% hyclone, 100 μ g/mL penicillin and 100 μ g/mL streptomycin sulphates.Next day will contain
The culture solution for having various concentration drug to be measured is added in culture plate, and each concentration sets 3 multiple holes, continues to cultivate 48h.Test group adds
Enter the compounds of this invention, positive controls add in dimethyl fumarate, and control group is not added with drug.4h, which is added in, before culture terminates uses
The diluted MTT solution of PBS(5mg/mL)20μL.After culture, culture solution is discarded, 100 μ L DMSO dissolving cells are added in per hole
The coloring matter of interior precipitation reads absorbance of each hole in 570 nm wavelength with multi-function microplate reader(D)Value, and by following equation
To calculate:The proliferation inhibition rate of cell=(The average D values of the average D values/control wells in 1- drug holes to be measured)× 100%, by cell
Proliferation inhibition rate matched curve made by software acquire IC50Value.
The results show that positive controls IC50It is worth for 72 μm of ol/L, the IC of the compounds of this invention embodiment 450It is worth for 8 μ
Mol/L, much smaller than positive controls.
Test example 3:Internal resisting rheumatoid arthritis effect
Collagen-induced model of rheumatoid arthritis (collagen-induced rheumatoid arthritis, CIA) is mesh
Preceding generally acknowledged arthritis model in the world is mainly used for studying grinding for rheumatoid arthritis pathogenesis and medicine screening
Study carefully.
First, experiment packet, model foundation and dosage regimen
Bull 180~220g SD rats, are grouped at random by weight, every group 8, free diet, water inlet.Group is blank
Group, model group, positive drug group and several medicine groups to be measured, blank group:Not any processing;Model group:By ox II Collagen Type VI eggs
Light-coloured vinegar acid solution is fully emulsified with incomplete Freund's adjuvant of capacity is waited to mix, the 0th day, and SD rats root of the tail carries out intracutaneous injection
(1mg/ml), every 0.1ml;Booster immunization after 7 days causes RA animal models on 15th;Positive drug group:From the 16th day, often
Day 1 dexamethasone(0.05mg/kg)Gastric infusion, successive administration 30d;Medicine group to be measured:From the 16th day, treat one time a day
Survey drug(2mg/kg)Gastric infusion, successive administration 30d.
2nd, item is monitored
1st, the horizontal detection of TNF-α, IL-12
In last dose next day, rat tails venous blood sampling after putting ice bath 30min, centrifuges 15min with 2000r/min, takes
Clearly, TNF-α in rat blood serum, IL-12 levels are measured with ELISA method, rat blood serum TNF-α, the ELISA kit of IL-12 are equal
Purchased from Sigma Co., USA.
2nd, Morphologic observation
In administration process, rat articular swelling degree and toes swelling degree.
3rd, experimental result
The analysis of two sample t test statisticses, P carry out two groups of data using SPSS14.0<Think that difference has statistics when 0.05
Meaning.
TNF-α, IL-12 are horizontal in rat blood serum(Mean ± SD, n=8)
Group | TNF-α(pg/mL) | IL-12(pg/mL) |
Blank group | 53.5±4.6 | 22.4±0.8 |
Model group | 96.3±6.7 | 43.6±1.3 |
Positive drug group | 62.4±5.4* | 29.4±1.2* |
Medicine group embodiment 4 to be measured | 55.4±4.6* | 23.7±1.2* |
Note:* the P compared with model group is represented<0.05.
Upper table can be seen that the medicine group TNF-α to be measured of positive drug group and embodiment 4 and the level of IL-12 compared with model
The equal conspicuousness of group reduces, and the medicine group to be measured of embodiment 4 is less than positive drug group.Morphologic observation finds positive drug group
There is different degrees of reduction to rat articular swelling degree and toes swelling degree with the medicine group to be measured of embodiment 4.
In conclusion the compounds of this invention formula(Ⅰ)It can inhibit the generation of IL-12 in vitro, have to HaCat cell proliferations
Inhibitory action, and show outstanding activity in SD anti-rat collagen induced rheumatoid arthritis models.Illustrate this hair
Bright Formula(Ⅰ)More deep research and development can be carried out as the drug candidate for preparing preventing/treating autoimmune disease.
Claims (5)
1. a kind of compound, structure such as formula(Ⅰ)It is shown,
,
Wherein R is selected from、Or。
2. Formula as described in claim 1(Ⅰ)Synthetic route be:
。
3. Formula as described in claim 1(Ⅰ)Preparing the application in reducing IL-12 drugs.
4. Formula as described in claim 1(Ⅰ)Answering in prevention and/or treatment autoimmune disease drug is prepared
With.
5. application as claimed in claim 4, it is characterized in that, the autoimmune disease is multiple sclerosis, inflammatory bowel
Disease, rheumatoid arthritis or psoriasis.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810034204.5A CN108047239A (en) | 2018-01-15 | 2018-01-15 | A kind of compound, preparation method and its application in preventing/treating autoimmune disease drug is prepared |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810034204.5A CN108047239A (en) | 2018-01-15 | 2018-01-15 | A kind of compound, preparation method and its application in preventing/treating autoimmune disease drug is prepared |
Publications (1)
Publication Number | Publication Date |
---|---|
CN108047239A true CN108047239A (en) | 2018-05-18 |
Family
ID=62126548
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810034204.5A Withdrawn CN108047239A (en) | 2018-01-15 | 2018-01-15 | A kind of compound, preparation method and its application in preventing/treating autoimmune disease drug is prepared |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108047239A (en) |
-
2018
- 2018-01-15 CN CN201810034204.5A patent/CN108047239A/en not_active Withdrawn
Similar Documents
Publication | Publication Date | Title |
---|---|---|
SG174548A1 (en) | New salvianolic acid compound l, preparation method and use thereof | |
JPH02233610A (en) | Vascularization inhibitor | |
EA014070B1 (en) | Use of a herbal composition for the treatment of inflammatory disorders | |
US20080221205A1 (en) | Furan derivatives for preventing and curing osteoporosis and pharmaceutical compositions containing the same | |
US20060004088A1 (en) | Furan derivatives for preventing and curing osteoporosis and pharmaceutical compositions containing the same | |
CN108047239A (en) | A kind of compound, preparation method and its application in preventing/treating autoimmune disease drug is prepared | |
CN107857754B (en) | A kind of compound and its application in preparing preventing/treating medicine for treating rheumatoid arthritis | |
US11896601B2 (en) | Composition for prevention or treatment of allergic disease including inotodiol compound as active ingredient | |
CN107903245B (en) | A kind of compound and its application in preparing treatment medicine for treating rheumatoid arthritis | |
CN108101888A (en) | A kind of compound and its application in preventing/treating autoimmune disease drug is prepared | |
CN108084156A (en) | A kind of compound and its medical usage | |
CN108358890A (en) | A kind of compound and its application in preparing preventing/treating autoimmune disease drug | |
CN108358889A (en) | A kind of compound and its purposes in preparing prevention and/or treatment autoimmune disease drug | |
CN108299385A (en) | A kind of compound, synthetic route and its application in preparing preventing/treating autoimmune disease drug | |
JPH10218769A (en) | Antiulcer agent | |
WO2020038279A1 (en) | Substituted pyrazole compound, and preparation method, pharmaceutical composition, and use thereof | |
CN107880043A (en) | A kind of compound and its purposes in preventing/treating autoimmune disease medicine is prepared | |
CN107903253A (en) | A kind of compound, synthetic route and its application in preventing/treating medicine for treating rheumatoid arthritis is prepared | |
CN114230582A (en) | Novel securinine dimer and preparation method and application thereof | |
CN108904481B (en) | Application of o-hydroxy chalcone analogue in preparation of antioxidant drugs | |
JP6054102B2 (en) | Nitric oxide production promoter or inducer | |
CN107652265B (en) | 1- (piperidin-4-yl) -2- benzimidazole ketone compound and its application | |
WO2020063262A1 (en) | Application of 3'-deoxyinosine in preparation of drug, food or health product for multiple disease | |
EP4001270A1 (en) | Plant extracts enriched with ipolamiide derivatives as immunosuppressants for treating immunological disorders and vitiligo | |
CN113197907B (en) | Application of gardenia acetic acid and derivatives thereof in preparing medicine for treating diabetes |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WW01 | Invention patent application withdrawn after publication | ||
WW01 | Invention patent application withdrawn after publication |
Application publication date: 20180518 |