CN104478828B - 2-amino-7-replaces benzothiazole compound and preparation method thereof and purposes - Google Patents
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- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
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Abstract
The invention belongs to medicinal chemistry art, replace benzothiazole compound and preparation method thereof and purposes more particularly to 2-amino-7-.2-amino-7-of the present invention replaces benzothiazole compound can significantly inhibit the synthesis of cultured rat hepatic stellate cells collagen type I and the extracellular matrix activated, and regulate and control the expression of relevant synthetic gene and enzyme, the outer pericentral siphon of hepatic fibrosis in mice model cell is generated and also has obvious inhibitory action, it is possible to as the medicine of anti-hepatitis or anti-hepatic fibrosis；The preparation method that 2-amino-7-replaces benzothiazole compound, it is prepared, and raw material sources are extensive, reactions steps is shorter, post processing is easy, and productivity is higher.
Description
Technical field
The invention belongs to medicinal chemistry art, replace benzothiazole compound and preparation method thereof and purposes more particularly to 2-amino-7-.
Background technology
Hepatopathy is one of disease of serious threat human health.According to the cause of disease, it is broadly divided into infectious hepatopathy and non-infectious hepatopathy.Infectious hepatopathy includes: the hepatopathy etc. that hepatitis B (HBV), hepatitis C (HCV) and hepatitis D (HDV), schistosomicide cause；Non-infectious hepatopathy includes: hepatopathy that hepatopathy that inborn errors of metabolism (hepatolenticular degeneration, hemachromatosis, α1-antitrypsin deficiency etc.) causes, chemical metabolization defect (chronic alcoholic liver disease, chronic drug hepatopathy) cause, autoimmune hepatitis, Primary Hepatic juice liver cirrhosis, primary sclerosing cholangitis etc..
According to statistics, hepatitis is one of disease that the ill area in the current whole world is huge and number of patients is numerous, and China is also one of district occurred frequently of hepatitis, and the Chinese about more than 10% are by hepatites virus infections mistake.
To the preventing and treating of hepatitis mainly to vaccinate in prior art, and Hepatitis B virus vaccine is achieved with good preventive effect.But, but without the vaccine developed for other types hepatitis such as hepatitis C, this also leads to can't prevent infectious hepatitis comprehensively.The factors such as the bad habits such as excessive drinking, smoking, living environment, inherited genetic factors, can make hepatitis and then develop into the more serious diseases such as hepatic fibrosis, liver cirrhosis even hepatocarcinoma.Hepatitis and hepatocarcinoma patient are tormented by the serious illness throughout the year, medical expense is very high, the interferon for the treatment of hepatitis and hepatocarcinoma at present, interleukin and antiviral drugs etc. are all taken high, and effect is barely satisfactory, it causes the economic loss number of a people and society in 10,000,000,000,000, therefore, researches and develops the new treatment Fibrotic medicine of hepatitis regulating liver-QI and is significant.
Summary of the invention
For this, the technical problem to be solved is in that to provide a kind of 2-amino-7-to replace benzothiazole compound, and further discloses its preparation method and for preparing the purposes for the treatment of hepatitis and hepatic fibrosis medicines.
For solving above-mentioned technical problem, the present invention is achieved through the following technical solutions:
The present invention such as 2-amino-7-shown in formula I replaces benzothiazole compound:
Wherein, R1Selected from methyl, ethyl, OCH3、CF3、SCF3, OH, acetyl group.
Preferably, above-claimed cpd of the present invention, R1For CF3、SCF3, acetyl group.
The officinal salt of above-claimed cpd of the present invention, hydrate, solvate, unformed body, monocrystalline and eutectic.
The preparation method of above-claimed cpd of the present invention, comprises the following steps: be dissolved in 10-20mL acetic acid by 0.01-0.05mmol3-substituted aniline, adds 30-50mmol potassium thiocyanate and stirs 15 minutes.5-15mmol bromine is dissolved in 0.3-1.0mL acetic acid, is slowly added in aforementioned reactants, water-bath temperature 20-40 DEG C, and stirring overnight, is filtered, and taking precipitate 10-30mL ethyl acetate is washed 2-5 time.Merging filtrate and cleaning mixture, after alkalizing with ammonia spirit, then rinse 1-4 time with 50-150mL strong brine, being concentrated into 20-40mL, upper flash chromatography, with normal hexane: acetone 6:1-3:1 (v/v) eluting, collect eluent, volatilize solvent, obtain 2-amino-7-and replace benzothiazole compound.
Preferably, the above-mentioned preparation method of the present invention, the mol ratio of described 3-substituted aniline and described potassium thiocyanate, described bromine is 3:45:10.
Preferably, the above-mentioned preparation method of the present invention, described in be dissolved in acetic acid the concentration of 3-substituted aniline be 0.6-3.0mol/L.
The above-claimed cpd of the present invention purposes in preparation treatment hepatitis or hepatic fibrosis medicines.
A kind of medicine treating hepatitis or hepatic fibrosis of the present invention, with above-claimed cpd for effective ingredient.
With above-claimed cpd of the present invention for effective ingredient, conventionally technique, selectively add the clinically-acceptable preparation that customary adjuvant is made.
2-amino-7-shown in formula I of the present invention replaces benzothiazole compound can significantly inhibit the synthesis of cultured rat hepatic stellate cells collagen Types I and the extracellular matrix activated, and regulate and control the expression of relevant synthetic gene and enzyme, the outer pericentral siphon of hepatic fibrosis in mice model cell is generated there is obvious inhibitory action, it is possible to as the medicine of anti-hepatitis and/or anti-hepatic fibrosis；It addition, the preparation method that the 2-amino-7-shown in formula I of the present invention replaces benzothiazole compound, it is prepared, and raw material sources are extensive, reactions steps is shorter, post processing is easy, and productivity is higher.
Experimental example
The treatment Fibrotic research of hepatitis regulating liver-QI of experimental example 12-amino-7-trifluoromethyl mercaptobenzothiazoler
1, experimental technique
The separation of 1.1 cell cultivation-rat hepatocytes and cultivation
Containing DMEM or the RPMI-1640 culture fluid of 10-15%FBS, 100U/mLpenicillin and 100ug/mLstreptomycin, 37 DEG C, 5%CO2Cultivating cell, culture fluid is changed once for every 4 days.
It is utilized respectively propagation and the existence/mortality rate of mtt assay and In situ cell apoptosis (TUNEL) kit detection cell.
The separation of rat hepatocytes and cultivation will according to Riccalton-Banks in 2003, the method that Yata etc. describes for 1999, and the liver of results fresh rat separates and purification of rat hepatocyte (HSC), sets up complete hepatic cell line.The i.e. liver by perfusion in situ technology separation Adult male rats (500-600g) with pronase and collagenase.Original cell suspension is obtained by the centrifugal step by step of noncontinuity, and its degree of purification reaches the homogeneity of more than 95%.Cell is by unencapsulated plastic tissue container suspension culture in the DMEM culture fluid containing 10%FCS, and cell density is 1.5 × 105cells/cm2.Two days later, wash cell debris and the cell not adhered to off, within every 2-3 days, change a culture fluid.Evaluate the purity cultivating cell and can use the autofluorescence of microscopic examination vitamin A, it is also possible to detect by the method for immunocytochemistry, as monoclonal antibody α-SMA and desmin. cytoactive platform expect that blue method detects.
HSC is generally circular in shape, and is resting state when being incubated at culture dish.But, after the cultivation of about 10 days, it is active and very flat that they become, in star.They express alpha-SMA and desmin biomarker, hyper-proliferative, anti-differentiation becomes the cell myofibroblast of high enrichment.
In experiment, initial 24 hours add the 2-amino-7-trifluoromethyl mercaptobenzothiazoler of embodiment 1 preparation of 5-10 μM in active HSC, change DMEM+10%FCS afterwards into.In preliminary study, it is known that be exposed to the 2-amino-7-trifluoromethyl mercaptobenzothiazoler HSC that enough impact was active in 24 hours.Use microarray harvesting, be analyzed by the method for immunofluorescence and RT-PCR in 24-48 hour after process.
The generation of 1.2 hepatic fibrosis in mice models and administration process
Experiment adopts the male Balb/c mice of 6-8 week old, adopts the condition of 12 h light, 12 h dark, gives standard test animal feed and the water of abundance.
Animal liver fibrosis model group, adopts 2 lumbar injection CCl weekly4(0.56mL/kg the weight of animals is dissolved in 0.1mL olive oil), continuously injection 4 weeks.CCl4Matched group, adopts CCl4Injection 4 weeks continuously, then give oral corresponding water or the water containing Triton-X100.No. 22 animal feeding pins with gauge ball head of oral employing carry out gavage, and at CCl4In two weeks after treatment, every day gives gavage.Negative control group, mice adopts oral administration gavage water or the water containing 2%Triton-X100, but does not give CCl4Process.In experimental group, animal is at 4 weeks CCl of injection continuously42-amino-7-trifluoromethyl the mercaptobenzothiazoler two weeks (1 day 1 time) of embodiment 1 preparation of rear continuation oral 5mg/kg, 5mg/kg and 50mg/kg.2-amino-7-trifluoromethyl mercaptobenzothiazoler mother solution (10mg/mL) is the fresh solution that 2-amino-7-trifluoromethyl mercaptobenzothiazoler embodiment 1 prepared is dissolved in the deionized water of 2%TritonX-100, prepares every time.
After experiment terminates, put to death after mice is processed with excessive anesthetis, then dissect tissues such as obtaining liver, kidney and stomach, be fixed on after being cut into small pieces in the formalin buffer of 10%, and carry out experimental record.Liver tissue sample first by paraffin embedding, is then cut into the thin slice of 4um on microtome, and after past Lasaxing Oilfield, total collagen protein Hematoxylin-eosin dyes.The amplification quantitatively adopting 20X of dyeing, randomly selects 5 sites in the sample of each section, then pass through MetaMorph image analysis software and come the region of quantifying positive dyeing.
1.3 SABC and immunofluorescence
Antibody TIMP is purchased from SantaCruzBiotechnology, is purchased from Pharmingen, BDLab and SantaCruzLab including antibody collagen protein-I, collagen protein-II and collagen protein-III, 1:100 dilution etc..Antibody and detectable are from SantaCruzLab, SigmaLab, InvitrogenLab, PharmingenLab, BDLab and ZymedLab etc..
The tissue sample of cutting fixes 24 hours with the paraformaldehyde of 4% immediately, soaks with paraffin afterwards；Tissue is cut into the section of 5um thickness；Dimethylbenzene dewaxes, and after graded ethanol rehydration, cuts into slices and boils 10min in the sodium citrate buffer solution being placed in microwave oven 10mM, pH6.8；Cut into slices and process with the hydrogen peroxide methanol solution of 3%, close the activity of endogenous peroxydase, then close 10min with confining liquid (5% dry milk PBS dilutes), at room temperature hatch 1 to 2 hours by primary antibodie.
With PBS three times, each 5min；Afterwards, two anti-and avidin connection horseradish peroxidases hatch 10min；Section peroxidase or alkali phosphatase display substrate, then redye with haematoxylin and use PBS；Immunofluorescence operates as previously mentioned, and cell kind is on the coverslip processed with poly-D-lysine, and the paraformaldehyde with 4% fixes cell.Except two anti-be fluorescent dye except, other all will by OlympusFV-1000 Laser Scanning Confocal Microscope record and analysis with the similar process of SABC, staining power and location.
1.4SDS-PAGE gel electrophoresis and Westernblot analysis of protein
SDS-PAGE completes on the gel of 10%, is moved on to by protein transduction on nitrocellulose filter or the Hybond nitrocellulose filter of 0.2 μm, with 120Vh transfer all night.
Immunoblot experiment, with cell lysate (50mMNaCl, 20mMTris, pH7.6,1% Nonidet NonidetP-40, the 1xproteaseinhibitormixture) cell lysis 1 hour of 200ul.4 DEG C afterwards, 16,000xg, centrifugal 10min removes product of cell lysis.The concentration of native protein is measured with protein detection reagent kit.Take the protein lysate of total protein concentration 25 μ g and color molecule amount marker as label, detect by the monoclonal antibody (SantaCruzLab) of collagen protein-I, collagen protein-II and collagen protein-III and TIMP, also hatch trace with rabbit b-actin monoclonal antibody (1:1000 dilution) or β-tubulin (1:1000 dilution).Then, resist with the two of horseradish peroxidase (HRP) labelling of anti-mouse or anti-rabbit and detect, observe testing result by the method for the chemiluminescence (ECL) of enhancing and ECL film.
1.5 Semiquatitative RT-PCR assay and real-time quantitative RT-PCR detection
Total serum IgE is extracted with TRIzol reagent or Qiagen test kit.CDNA the first chain is synthesized by SuperscriptFirstStrandSynthesisSystem, the operation of real-time quantitative RT-PCR points out (SuperScriptIIIPlatinumTwo-StepqRT-PCRKitwithSYBRGreen, Invitrogen) according to manufacturer.With the cDNA sample of 1 μ L, 1xPCR buffer, 1.5mMMgCl2, 0.2mMdNTP, the primer of 1 μM is mixed into performing PCR reaction.
2, experimental result
2.12-amino-7-trifluoromethyl mercaptobenzothiazoler suppresses the synthesis of activated hepatic stellate cells collagen
Experimental result is as it is shown in figure 1, the 2-amino-7-trifluoromethyl mercaptobenzothiazoler of embodiment 1 preparation can efficiently suppress the synthesis of the I-type collagen of the rat sternzellen activated.
2.22-amino-7-trifluoromethyl mercaptobenzothiazoler suppresses extracellular matrix synthesize and regulate and control the expression of synthetic gene and enzyme of being correlated with
Adopt the real-time PCR of sxemiquantitative to detect I type, type III, IV collagen type, MMP-1, MMP-2, MMP-3, MMP-9 and TIMP-1 expression.
Experimental result is as in figure 2 it is shown, the expression of I type, type III collagen protein is significantly inhibited effect by the 2-amino-7-trifluoromethyl mercaptobenzothiazoler of embodiment 1 preparation, and IV collagen type is then more weak.Sxemiquantitative Real time PCR results also shows, along with the increase of 2-amino-7-trifluoromethyl mercaptobenzothiazoler concentration, the drug dose of 2-amino-7-trifluoromethyl mercaptobenzothiazoler becomes positive correlation with the vigor of MMP-1, MMP-3.
Exactly because MMP-3 is a catalyst promoting MMP-1 degraded NTx albumen, 2-amino-7-trifluoromethyl mercaptobenzothiazoler suppresses the gene expression of NTx albumen with dose dependent fashion, increases the expression of MMP-1 and MMP-3 simultaneously.On the other hand, Reversine concentration and MMP-2 and MMP-2 are negative correlation.MMP-2 and MMP-9 is considered as the degraded participating in the collagen protein 3 of degeneration and collagen protein 4, therefore, and I, type III collagen protein direct relation.Additionally, have studied the expression of Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1).Result of study shows, becomes negative correlation between MMP2/9 and TIMP-1.
Visible, 2-amino-7-trifluoromethyl mercaptobenzothiazoler suppresses MMP2/9 as the inhibitor similar with TIMP-1, and then jointly plays accumulative effect with TIMP-1.The discovery of new MMP inhibitor depends on further research.The data of real-time PCR, not only confirm previous result of study, and show 2-amino-7-trifluoromethyl mercaptobenzothiazoler than Reversine in suppressing the expression of human liver microsome proteins NTx more effective.
The inhibitory action that the outer pericentral siphon of hepatic fibrosis in mice model cell is generated by 2.32-amino-7-trifluoromethyl mercaptobenzothiazoler
Set up hepatic fibrosis in mice model group, adopt 2 lumbar injection CCl weekly4(dosage: 0.56mL/kg the weight of animals, be dissolved in 0.1mL olive oil), continuously injection 4 weeks.Animal is at 4 weeks CCl of injection continuously42-amino-7-trifluoromethyl the mercaptobenzothiazoler two weeks (1 day 1 time) of embodiment 1 preparation of rear continuation oral 5mg/kg, 5mg/kg and 50mg/kg.Owing to 2-amino-7-trifluoromethyl mercaptobenzothiazoler is hydrophobic, and bioavailability is poor, oral after comparatively fast removed by body, adopt 2-amino-7-trifluoromethyl mercaptobenzothiazoler and TritonX-100 complex to maximize its aqueous phase dissolved degree (10mg/mL).TritonX-100 is a kind of common surfactant, and for the enhancing of the compound of lipophilic medicine and medicine overall therapeutic effect, and non-processor matched group contrasts.
As it is shown on figure 3, and CCl4Independent injection group is compared, and only occurs in that slight collagen deposition granule increases and fatty hepatitis once in a while.Semi-quantitative PCR assay demonstrates this result further.Low dose group (5mg/kg) 2-amino-7-trifluoromethyl mercaptobenzothiazoler can reduce CCl4The extrtacellular matrix deposition of liver after process；CCl is significantly more decreased compared with the matched group of injection TritonX-1004The extrtacellular matrix deposition of liver after process.Result shows, compares with matched group, 5mg/kg, 25mg/kg, and 50mg/kg2-amino-7-trifluoromethyl mercaptobenzothiazoler can reduce the accumulation of extracellular matrix significantly.After 50mg/kg2-amino-7-trifluoromethyl mercaptobenzothiazoler processes, lobules of liver shows and without CCl4The result that process group is similar, only occurs in that minimal amount of collagen deposition thing.Although, it is likely to the overall collagen level after needing longer drug treating time that 2-amino-7-trifluoromethyl mercaptobenzothiazoler just can be made to process return to and untreated fish group level, but the above results is it has been shown that 2-amino-7-trifluoromethyl mercaptobenzothiazoler can as the medicine for the treatment of hepatic fibrosis.
Accompanying drawing explanation
It is clearly understood to make present disclosure be easier to, below according to specific embodiments of the invention and in conjunction with accompanying drawing, the present invention is described in more detail, wherein:
Fig. 1 is the experimental result of the synthesis that 2-amino-7-trifluoromethyl mercaptobenzothiazoler suppresses activated hepatic stellate cells collagen Types I in experimental example 1, wherein, figure A is the experimental result of matched group, figure B is the experimental result after 31.3 μMs of 2-amino-7-trifluoromethyl mercaptobenzothiazolers process, what C represented is NTx albumen, and what N represented is nucleus；
Fig. 2 is the quantitative real-time PCR method research 2-amino-7-trifluoromethyl mercaptobenzothiazoler experimental result to the effect of liver fibrosis related genes in experimental example 1；
Fig. 3 is the 2-amino-7-trifluoromethyl mercaptobenzothiazoler experimental result that after processing, total collagen protein Hematoxylin-eosin dyes in experimental example 1, and wherein, NT_C is without CCl4Process group, NT_MC is without CCl4Process group+group of solvents, CC_C is CCl4Process group, CC_MC is CCl4Process+group of solvents, CC_A1 (CCl4Process group+5mg/kg embodiment 1 compound), CC_A5 (CCl4Process group+25mg/kg embodiment 1 compound), CC_A10 (CCl4Process group+50mg/kg embodiment 1 compound).
Detailed description of the invention
The synthesis of embodiment 12-amino-7 trifluoromethyl mercaptobenzothiazoler
0.01mmol3-trifluoromethyl mercaptoaniline is dissolved in 10mL acetic acid, adds 30mmol potassium thiocyanate and stir 25 minutes.13mmol bromine is dissolved in 0.7mL acetic acid, is slowly added in aforementioned reactants, water-bath temperature 20 DEG C, and stirring overnight, is filtered, and taking precipitate 25mL ethyl acetate is washed 3 times.Merging filtrate and cleaning mixture, after alkalizing with ammonia spirit, rinse 2 times with 120mL strong brine again, being concentrated into 20mL, upper flash chromatography, with normal hexane: acetone 5:1-4:1 (v/v) eluting, collect eluent, volatilizing solvent, obtain 2-amino-7-trifluoromethyl mercaptobenzothiazoler 1.38g, productivity is 55%.1H-NMR(CDCl3, 500MHz), 4.14 (brs, 2H), 6.79 (dd, J=8.5Hz, J=2.5Hz, 1H), 7.06 (d, J=2.5Hz, 1H), 7.54 (d, J=8.0Hz, 1H)；ESI-MS (m/z, %): 249.26 (M-H)-。
Obviously, above-described embodiment is only for clearly demonstrating example, and is not the restriction to embodiment.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.Here without also cannot all of embodiment be given exhaustive.And the apparent change thus extended out or variation are still among the protection domain of the invention.
Claims (8)
1. the 2-amino-7-as shown in formula I replaces benzothiazole compound:
Wherein, R1For SCF3。
2. a preparation method for compound described in claim 1, comprises the following steps: be dissolved in acetic acid by 3-trifluoromethyl mercaptoaniline, adds potassium thiocyanate mixing, is then slowly added into bromine acetic acid solution, reacts at 25 DEG C；By reactant filtration, taking precipitate ethyl acetate rinse, merging filtrate and cleaning mixture, it is purified by conventional method, to obtain final product.
3. preparation method according to claim 2, it is characterised in that the mol ratio of described 3-trifluoromethyl mercaptoaniline and described potassium thiocyanate, described bromine is 1-5:30-50:5-15.
4. preparation method according to claim 3, it is characterised in that the mol ratio of described 3-trifluoromethyl mercaptoaniline and described potassium thiocyanate, described bromine is 3:45:10.
5. the preparation method according to claim 3 or 4, it is characterised in that described in be dissolved in acetic acid the concentration of 3-trifluoromethyl mercaptoaniline be 0.6-3.0mol/L.
6. the purposes in preparation treatment hepatitis or hepatic fibrosis medicines of the compound described in claim 1.
7. treat a medicine for hepatitis or hepatic fibrosis, with compound described in claim 1 for effective ingredient.
8. a clinically-acceptable preparation, with compound described in claim 1 for effective ingredient, conventionally technique, selectively add customary adjuvant and make.
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