CN103145739A - Pyrimido thiazole type compounds with anti-inflammatory effect and application thereof in preparation of anti-inflammatory medicaments - Google Patents
Pyrimido thiazole type compounds with anti-inflammatory effect and application thereof in preparation of anti-inflammatory medicaments Download PDFInfo
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Abstract
The invention provides pyrimido thiazole type compounds as well as a medicament composition and an anti-inflammatory application thereof.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, particularly, the present invention relates to have the Kui Linpyrimido quinoline thiazole compound of anti-inflammatory action.In addition, the invention still further relates to the pharmaceutical composition of these compounds and antiphlogistic use etc.
Background technology
Inflammation is very common in human body as a kind of important pathologic process, and itself is as a kind of autoimmune response of body for the stimulation of external or allosome.And reply imbalance or when too replying the damage certainly that causes body, just developed into inflammation when this.So most disease all is accompanied by mediation and the generation of inflammation, and the mediation of inflammation and make disease increase the weight of for the damage of body, as rheumatic arthritis, diabetic complications, cancer, atherosclerosis, inflammatory bowel etc.In these processes, proinflammatory factor such as TNF-α, IL-6, IL-1 β etc. play an important role.
Also do not have at present theory can this compounds of correct Prediction can anti-inflammatory structure activity relationship.Yet, the inventor has obtained also [3,2-a] pyrimidines of a series of thiazoles through long-term and arduous research experiment, find that they have anti-inflammatory activity, especially can be used for the treatment of by TNF-α and/or IL-6 and exceed that normal amount is expressed and discharge and the disease that causes.
Summary of the invention
The technical problem to be solved in the present invention is to provide new anti-inflammatory compound and medicine thereof.
Particularly, the invention provides the compound shown in formula (I) or its pharmacy acceptable salt:
Wherein:
R
1Be low alkyl group, lower alkoxy ,-O (CH
2) nN (R
3) (R
4) ,-(CH
2) nN (R
3) (R
4) or-N (R
5) (CH
2) nN (R
3) (R
4);
R
2Being selected from can be by optional aryl, heterocyclic radical or the heteroaryl that replaces of 1 to 3 identical or different substituting group, described substituting group be selected from alkyl, halogen, alkoxyl group ,-R
6-N (R
7) R
8With-R
6-O-R
7-N (R
9) R
8
Wherein, R
3-R
5Expression low alkyl group or cycloalkyl, and n represents 1-5;
R
6Be the alkylidene chain of chemical bond or straight chain independently;
R
7Be the alkylidene chain of straight chain independently;
R
8Or R
9Be independently selected from hydrogen and alkyl, perhaps R
8And R
9Thereby become independently ring to make-N (R
9) R
8Form heterocyclic radical or heteroaryl.
In the present invention, the model that at first we stimulate the RAW264.7 scavenger cell to discharge inflammatory factor (TNF-α and IL-6) inhibition with compound to LPS has carried out the primary dcreening operation (details are seen embodiment 2) of compound extracorporeal anti-inflammatory activity, thiazole of the present invention also [3,2-a] pyrimidine analogue all has anti-inflammatory activity preferably, and is particularly evident with compound H 19, two compounds of H23.Therefore, we select these two compounds further to carry out suppressing dose-effect relationship (details the are seen embodiment 3) research that the LPS stimulating expression of macrophage discharges inflammatory factor, the inhibition of finding 19 couples of TNF-α of compound H and IL-6 has good dose-effect relationship, wherein the inhibiting rate IC50 of IL-6 and TNF-α reached respectively 0.83 μ M and 4.17 μ M, but compound H 23 is without obvious dose-dependence.Therefore we have chosen compound H 19 and have characterized its anti-inflammatory activity as probe compound in the animal body, studied compound and LPS has been caused the impact of the survival rate of dead mouse, find that LPS group mouse is all dead within 5 days, dosing group mouse lethality rate obviously reduces (details are seen embodiment 5).
When in the specification sheets that is used in this patent and appended claim, unless opposite appointment is arranged, following term has indicated meaning:
" alkyl " refers to the hydrocarbon chain group of straight or branched, only formed by carbon and hydrogen atom, do not contain nonsaturation, has one to 12 carbon atom, be preferably one to eight carbon atom, more preferably one to six carbon atom, and it is connected to all the other parts of molecule by singly-bound, for example methyl, ethyl, n-propyl, 1-methylethyl (sec.-propyl), normal-butyl, n-pentyl, 1,1-dimethyl ethyl (tertiary butyl), 3-methyl hexyl, 2-methyl hexyl etc.Wherein, " low alkyl group " refers to have an alkyl to six carbon atom.
" alkylidene chain " refers to the bivalent hydrocarbon chain of straight or branched, links all the other part and groups of molecule, only is comprised of carbon and hydrogen, do not contain nonsaturation, and has one to 12 carbon atom.Alkylidene chain to molecule all the other partly reach can be by a carbon or any two carbon in chain to the tie point of this group.
" alkoxyl group " refers to formula-ORa.Group, wherein Ra is the alkyl that defines as mentioned, contains one to 12 carbon atom.
" aryl " refers to aromatic monocyclic or polynuclear hydrocarbon loop systems, only is comprised of hydrogen and carbon, and contains 6 to 19 carbon atoms, and it is saturated that wherein said loop systems can be part.Aromatic yl group includes but not limited to the group as fluorenyl, phenyl and naphthyl.
" halogen " refers to bromine, chlorine, fluorine or iodine.
" heterocyclic radical " refers to the first non-aromatic ring group of stable 3-to 18-, and it comprises two to 17 carbon atoms and one to ten heteroatoms that is selected from nitrogen, oxygen and sulphur.Unless clearly address in addition in this specification sheets, heterocyclic radical can be the loop systems at monocycle, dicyclo, three rings or Fourth Ring, and it can comprise loop systems that condense or bridge joint; And the nitrogen in heterocyclic radical, carbon or sulphur atom are optionally oxidized; Nitrogen-atoms is optionally by quaternary ammoniated; And heterocyclic radical can be part or fully saturated.
" heteroaryl " refers to the first aromatic ring group of 5-to 18-, and it comprises three to 17 carbon atoms and one to ten heteroatoms that is selected from nitrogen, oxygen and sulphur.For purpose of the present invention, heteroaryl can be the loop systems at monocycle, dicyclo, three rings or Fourth Ring, and it can comprise loop systems that condense or bridge joint; And the nitrogen in heteroaryl, carbon or sulphur atom are optionally oxidized; Nitrogen-atoms is optionally quaternized.
" independently " refer to the substituting group of its restriction (as, R
4, R
5, R
6Or R
7) or substituent combination, if occur more than twice or twice at the compound shown in formula (I), they can be identical, can be also different.
According to other embodiment of the present invention, the present invention relates to a kind of anti-inflammatory drug and with the medicine of inflammation related disease, the cause of disease of described disease is to be caused by inflammation at least in part, and described disease includes but not limited to following disease: alleviate rheumatoid arthritis, osteoarthritis, SpA, urarthritis, rheumatic arthritis, the acute attack stage of various chronic arthritiss or the arthralgia symptom of persistence; Treat non-arthrogenous various soft tissue rheumatism pain, as damaging pain after shoulder pain, tenosynovitis, bursitis, myalgia and motion; Acute light, moderate pain, as, after operation, after wound, after strain, primary dysmenorrhoea, toothache, headache; Ischemic damage and reperfusion, as, cerebral ischemia re-pouring, myocardial ischemia-reperfusion; Atherosclerosis; Hepatitis; Lymphadenitis; Pneumonia; Dysentery; Ecphyaditis.
According to other embodiment of the present invention, the present invention relates to a kind of pharmaceutical composition that is used for the treatment of inflammatory diseases, it contains any or multiple or its pharmacologically acceptable salt and the pharmaceutical excipient thereof as above-described formula (I) compound of activeconstituents for the treatment of significant quantity; " pharmaceutical composition " refers to that any or multiple or its pharmacologically acceptable salt in formula of the present invention (I) compound unites use with the anti-inflammatory drug that now gone on the market, the composition of the control inflammatory disease class medicine for preparing, the anti-inflammatory drug that has gone on the market comprises various steroidal anti-inflammatory drugs things and non-steroidal anti-inflammatory drug; Pharmacy acceptable salt is more such salt, they keep the desirable biological activity of parent compound, and do not give undesirable toxicological action, the example of such salt comprises the salt that forms with mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid etc.; With the salt of organic acid formation, as acetic acid, oxalic acid, tartrate, toxilic acid, citric acid, xitix etc.; And the salt that is formed by the element negatively charged ion, as chlorine, bromine and iodine; " pharmaceutical excipient " refers to the pharmaceutical carrier of pharmaceutical field routine, includes but not limited to any adjuvant, carrier, vehicle, glidant, sweeting agent, thinner, sanitas, dyestuff/tinting material, odorant, tensio-active agent, wetting agent, dispersion agent, suspension agent, stablizer, isotonic agent, solvent or the emulsifying agent that can accept for people or domestic animal that be approved as by united States food and drug administration.。
Preparation of the present invention comprises that those (for example are suitable for oral, rectum, part, oral cavity, hypogloeeis, parenteral, subcutaneous, muscle, intravenously) and the preparation of percutaneous dosing, although in the situation that any given, optimum route will depend on character and the seriousness of the illness for the treatment of and the character that depends on the particular active compounds of using.
For the ease of understanding, the present invention has quoted open source literature, and these documents are in order more clearly to describe the present invention, its in full content all include this paper in and carry out reference.Below will describe in detail the present invention by specific embodiment and accompanying drawing.It needs to be noted, these descriptions are only exemplary descriptions, do not consist of limitation of the scope of the invention.According to the discussion of this specification sheets, many variations of the present invention, change have been all obviously concerning one of ordinary skill in the art.
Description of drawings:
Here cited compound is just in order to illustrate better compounds category of the present invention and structure formation, and unrestricted the present invention.
Fig. 1 illustrates synthetic thiazole also path and the part of compounds structure of [3,2-a] pyrimidines;
Fig. 2 illustrates the also activity of [3,2-a] pyrimidines to the inhibition of LPS stimulation RAW264.7 scavenger cell release IL-6 and TNF-α of thiazole;
Fig. 3 illustrates that active compound H19, H23 suppress LPS and stimulate the RAW264.7 scavenger cell to discharge the dose-effect relationship of IL-6 and TNF-α;
Fig. 4 illustrates compound H 19 from prevention and treats two aspects and improve the mouse survival rate lethal to LPS;
Embodiment
In non-limiting example below, the present invention will be described in more detail.
Synthesizing of embodiment 1 compound
Intermediate 12-sulfydryl-4-methyl-6-phenyl-1, the preparation of 6-dihydro-pyrimidine-5-carboxylic acid's ethyl ester: in the 250ml round-bottomed flask that stirs with electromagnetism, add phenyl aldehyde 5.3g (0.05mol), methyl aceto acetate 7.8g (0.06mol), thiocarbamide 5.7g (00.75mol), thionamic acid 3.75g (0.04mol), dehydrated alcohol 50ml, reflux 2h, cooling, filter, washing, drying gets 11.7g intermediate 1, yield 85%.
the preparation of compound: in the 100ml round-bottomed flask with backflow prolong and drying tube, add 2-sulfydryl-4-methyl-6-phenyl-1,6-dihydro-pyrimidine-5-carboxylic acid's ethyl ester 0.552g (0.002mol), ethyl chloroacetate 0.244g (0.002mol), pyridine 0.18g (0.002mol), dehydrated alcohol 10ml, backflow 4h, then add aromatic aldehyde or heterocyclic aldehydes 0.002mol, piperidines or morpholine 0.17g (0.002mol), continue backflow 4h, reaction solution is cooling, filter, fully washing, glacial acetic acid recrystallization or silicagel column purifying get compound H 1-H33.
Compound H 162-(2-bromophenyl) methylene radical-7-methyl-3-oxygen-5-phenyl-2,3-dihydro-5H-thiazole is [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester also: yellow powder, m.p:174.7-177.6 ℃.
1H NMR (600MHz, DMSO-d6) δ (ppm): 7.856 (s, 1H), 7.799 (d, J=7.8Hz, 1H), 7.575-7.606 (m, 2H), (7.409-7.435 m, 1H), 7.347-7.380 (m, 2H), (7.312-7.367 m, 3H), 6.049 (s, 1H), (4.030-4.057 m, 2H), 2.390 (m, 3H), 1.099-1.122 (m, 3H) .ESI-MS m/z:423.4 (M+H)
+, 445.2 (M+Na)
+.
Compound 182-(2,3-3,5-dimethylphenyl) methylene radical-7-methyl-3-oxygen-5-phenyl-2,3-dihydro-5H-thiazole is [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester also: yellow powder, m.p:165.9-169.8 ℃.
1H NMR (600MHz, DMSO-d6) δ (ppm): 7.843 (s, 1H), 7.345-7.367 (m, 3H), 7.302-7.314 (m, 3H), 7.168 (m, 2H), 6.040 (s, 1H), 4.015-4.061 (m, 2H), 2.384 (s, 3H), (2.327 s, 3H), 2.307 (s, 3H), 1.101-1.125 (m, 3H) .ESI-MS m/z:433.2 (M+H)
+, 455.1 (M+Na)
+.
Compound H 192-(4-morpholinyl phenyl) methylene radical-7-methyl-3-oxygen-5-phenyl-2,3-dihydro-5H-thiazole is [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester also: yellow powder, m.p; 179.8-181.0 ℃.
1H NMR (600MHz, DMSO-d6) δ (ppm): 7.679 (s, 1H), (7.460 d, J=9.0Hz, 2H), (7.332-7.360 m, 3H), 7.273-7.302 (m, 2H), 7.211 (d, J=7.2Hz, 1H), 7.053 (d, J=7.8Hz, 1H), 6.043 (s, 1H), (3.992-4.072 m, 2H), 3.713-3.730 (m, 4H), 3.286-3.309 (m, 4H), 2.385 (m, 3H), 1.089-1.389 (m, 3H) .ESI-MS m/z:490.1 (M+H)
+, 512.1 (M+Na)
+.
Compound H 202-(2-hydroxy 3-methoxybenzene base) methylene radical-7-methyl-3-oxygen-5-phenyl-2,3-dihydro-5H-thiazole is [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester also: yellow powder, m.p:232.1-234.4 ℃.
1H NMR (600MHz, DMSO-d6) δ (ppm): 9.816 (br.s, 1H), 7.984 (s, 1H), 7.306-7.350 (m, 2H), 7.291-7.295 (m, 3H), 7.083 (d, J=9.0Hz, 1H), (6.909-6.983 m, 2H), 6.038 (s, 1H), (4.029-4.053 m, 2H), 3.828 (s, 3H), (2.380 s, 3H), 1.109-1.133 (m, 3H) .ESI-MS m/z:451.2 (M+H)
+, 438.1 (M+Na)
+.
Compound H 212-naphthyl methylene radical-7-methyl-3-oxygen-5-phenyl-2,3-dihydro-5H-thiazole is [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester also: yellow powder, m.p:202.3-204.6 ℃.
1H NMR (600MHz, DMSO-d6) δ (ppm): 8.202 (s, 1H), (8.032-8.060 m, 2H), 7.965 (d, J=7.8Hz, 1H), 7.930-7.933 (m, 1H), 7.698 (d, J=7.8Hz, 1H), 7.589-7.631 (m, 2H), (7.293-7.378 m, 5H), 6.067 (s, 1H), 4.043-4.066 (m, 2H), 3.828 (s, 3H), 2.403 (s, 3H), (1.118-1.142 m, 3H) .ESI-MS m/z:455.1 (M+H)
+.
Compound H 222-(2-thiotolene base) methylene radical-7-methyl-3-oxygen-5-phenyl-2,3-dihydro-5H-thiazole is [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester also: yellow powder, m.p:180.1-182.2 ℃.
1H NMR (600MHz, DMSO-d6) δ (ppm): 7.966 (s, 1H), 7.498 (d, J=3.6Hz, 1H), 7.333-7.358 (m, 2H), (7.277-7.300 m, 3H), 7.010 (d, J=3.6Hz, 1H), 6.029 (s, 1H), 4.011-4.070 (m, 2H), 2.558 (s, 3H), 2.383 (s, 3H), 1.101-1.132 (m, 3H) .ESI-MS m/z:425.1 (M+H)
+, 447.1 (M+Na)
+.
Compound H 232-(1-methylpyrrole base) methylene radical-7-methyl-3-oxygen-5-phenyl-2,3-dihydro-5H-thiazole is [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester also: yellow powder, m.p:221.2-224.5 ℃.
1HNMR (600MHz, DMSO-d6) δ (ppm): 7.625 (s, 1H), 7.343-7.355 (m, 2H), (7.281-7.299 m, 3H), 7.218 (m, 1H), (6.579 d, J=2.4Hz, 1H), 6.321 (d, J=2.4Hz, 1H), 6.035 (s, 1H), (4.030-4.056 m, 2H), 3.730 (s, 3H), (2.380 s, 3H), 1.111-1.135 (m, 3H) .ESI-MS m/z:408.4 (M+H)
+, 430.3 (M+Na)
+.
Embodiment 2 compounds discharge the inhibition of inflammatory factor to the LPS stimulating expression of macrophage
The external preliminary anti-inflammatory activity that the method that adopts compound to stimulate the RAW264.7 scavenger cell to discharge inflammatory factor (TNF-α and IL-6) inhibition to LPS has been tested compound, concrete grammar is as follows: 1.2 * 10
6Individual RAW264.7 scavenger cell is incubated at 37 ℃ with the DMEM nutrient solution, upgrade nutrient solution after 24 hours, and add tested compounds (final concentration is 10 μ M) pre-treatment 2 hours, LPS with 0.5 μ g/mL continues to process 22 hours again, collects nutrient solution and detects TNF-α and IL-6 content with the ELISA method; Collecting cell detects total protein concentration, and the ELISA result is divided by more accurate with corresponding total protein concentration, calibrates as 100 take TNF-α and the IL-6 content of LPS control group; Each compound repeated test 3 times, calculating mean value and error amount.Do contrast with positive drug curcumine (Cur) during test.Compound is seen Fig. 2 to the inhibition activity of TNF-α and IL-6 release.Active compound of the present invention all has the activity that suppresses preferably IL-6 and TNF-a release; And the control compounds activity is not good, does not have prospect in medicine.The TNF-a that most of active compound stimulates LPS discharges the minimizing effect is arranged, particularly, and the active compound that obviously is much better than curcumine: H8, H19, H23; And the inhibition of IL-6 obviously is more preferably: H11, H19, H20, H21, H22, H23, H24, H26, H28, particular significant effect be: H19 and H23.
Further test active compound and suppressed the dose-effect relationship that LPS stimulates RAW264.7 scavenger cell release TNF-α and IL-6, method: with embodiment 2.Experimental data is seen Fig. 3.Compound all has dose-effect relationship preferably to the inhibition activity of TNF-α and IL-6, wherein compound H 19 demonstrates dose relationship preferably, its inhibiting rate IC50 to IL-6 and TNF-α has reached respectively 0.83 μ M and 4.17 μ M, but compound H 23 is without significant dose-dependence.
Embodiment 4 active compound H19 cause the impact of the survival rate of dead mouse on LPS
Male C57BL/6 mouse is from Wenzhou Medical College's experimentation on animals center acquisition.Mouse is raised at constant temperature round the clock in the Animal House of the 12-12h rhythm and pace of moving things with standard rodent food and water.Animal spends week age to carry out the environmental compatibility growth before the experiment beginning at least.Relate to the approval (approval documents: 2009/APWC/0031) that agreement that animal uses all obtains Wenzhou Medical College's animal policy and the welfare council.Compound H 19 used in experiment is water-soluble formulation of making.The pH value of solution is 7.36 and through 0.22 filtering with microporous membrane.Body weight be the mouse of 18-22g each 15min is through tail vein injection compound H 19 (200 μ L, 15mg/kg) before or after the tail vein injection LPS (20mg/kg), control group mice is given the blank solution of same volume.Body weight and the mortality ratio of record mouse in one week.Experimental data is seen Fig. 4.Found that H19 prior to lps injection, can not alleviate the mortality ratio of mouse, can not reach good preventive effect; But but can well alleviate the mortality ratio of mouse in lps injection after H19, that is to say that 19 pairs of inflammation of compound H have played good result for the treatment of.
Claims (10)
1. Kui Linpyrimido quinoline thiazole derivative and pharmacologically acceptable salt thereof with following general formula I:
In formula,
R
1Be low alkyl group, lower alkoxy ,-O (CH
2) nN (R
3) (R
4) ,-(CH
2) nN (R
3) (R
4) or-N (R
5) (CH
2) nN (R
3) (R
4);
R
2Being selected from can be by optional aryl, heterocyclic radical or the heteroaryl that replaces of 1 to 3 identical or different substituting group, described substituting group be selected from alkyl, halogen, alkoxyl group ,-R
6-N (R
7) R
8With-R
6-O-R
7-N (R
9) R
8
Wherein, R
3-R
5Expression low alkyl group or cycloalkyl, and n represents 1-5;
R
6Be the alkylidene chain of chemical bond or straight chain independently;
R
7Be the alkylidene chain of straight chain independently;
R
8Or R
9Be independently selected from hydrogen and alkyl, perhaps R
8And R
9Thereby become independently ring to make-N (R
9) R
8Form heterocyclic radical or heteroaryl.
2. compound claimed in claim 1, it is selected from following compounds:
Compound H 16:2-(2-bromophenyl) methylene radical-7-methyl-3-oxygen-5-phenyl-2,3-dihydro-5H-thiazole is [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester also;
Compound H 18:2-(2,3-3,5-dimethylphenyl) methylene radical-7-methyl-3-oxygen-5-phenyl-2,3-dihydro-5H-thiazole is [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester also;
Compound H 19:2-(4-morpholinyl phenyl) methylene radical-7-methyl-3-oxygen-5-phenyl-2,3-dihydro-5H-thiazole is [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester also;
Compound H 20:2-(2-hydroxy 3-methoxybenzene base) methylene radical-7-methyl-3-oxygen-5-phenyl-2,3-dihydro-5H-thiazole is [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester also;
Compound H 21:2-naphthyl methylene radical-7-methyl-3-oxygen-5-phenyl-2,3-dihydro-5H-thiazole is [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester also;
Compound H 22:2-(2-thiotolene base) methylene radical-7-methyl-3-oxygen-5-phenyl-2,3-dihydro-5H-thiazole is [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester also;
Compound H 23:2-(1-methylpyrrole base) methylene radical-7-methyl-3-oxygen-5-phenyl-2,3-dihydro-5H-thiazole is [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester also.
4. the arbitrary described compound of claim 1-3, its be used for the treatment of inflammation (as, acute inflammation or chronic inflammatory diseases) or the disease relevant to inflammation.
5. be used for the treatment of inflammation (as, acute inflammation or chronic inflammatory diseases) or the pharmaceutical composition of the disease relevant to inflammation, it comprises arbitrary described compound and the pharmaceutically acceptable carrier of claim 1-3.
6. pharmaceutical composition claimed in claim 5, it is made into tablet, capsule, oral liquid, injection, pulvis, paste or external medicinal liquid.
The arbitrary described compound of claim 1-3 for the preparation of the treatment inflammation (as, acute inflammation or chronic inflammatory diseases) or the medicine of the disease relevant to inflammation in application.
The treatment inflammation (as, acute inflammation or chronic inflammatory diseases) or the method for the disease relevant to inflammation, it comprises arbitrary described compound from the claim 1-3 of significant quantity to the patient that use.
9. compound claimed in claim 4, pharmaceutical composition claimed in claim 5, application claimed in claim 7 or method claimed in claim 8, wherein inflammation or the disease relevant to inflammation be by inflammatory cytokine (as, TNF-α and/or IL-6) exceed that normal amount is expressed and discharge and the disease that causes.
10. compound claimed in claim 4, pharmaceutical composition claimed in claim 5, application claimed in claim 7 or method claimed in claim 8, wherein inflammation or the disease relevant to inflammation are selected from pyemia, rheumatoid arthritis, systemic lupus erythematous and related syndromes, osteoarthritis, alimentary canal inflammation, polymyositis, dermatomyositis, vasculitic syndrome, urarthritis, neural inflammation, rheumatic arthritis, chemical pain, inflammatory pain, granuloma, granulomatous angiitis, arteritis, skin inflammation, autoimmune disorder, pimelitis, retroperitoneal fibrosis, hepatitis, pneumonia, pancreatitis, allergic inflammation, systemic inflammatory response syndrome, septicemia, septic shock, the metabolic disease relevant to inflammation and complication thereof.
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CN104017002A (en) * | 2013-03-01 | 2014-09-03 | 中国科学院上海药物研究所 | Dihydropyrimidinone compound and application thereof |
CN106749337A (en) * | 2016-11-25 | 2017-05-31 | 温州医科大学 | A kind of simultaneously [3,2 a] pyridine derivatives and its application in anti-inflammatory drug is prepared of thiazole |
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