CN107033100A - A kind of benzothiazole derivant, preparation method and its medical usage - Google Patents
A kind of benzothiazole derivant, preparation method and its medical usage Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
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Abstract
The present invention relates to medicinal chemistry art, specifically related to a kind of benzothiazole derivant (Formulas I) with anti-inflammatory activity, Preliminary activation test proves that the compounds of this invention has good Keap1 Nrf2 protein protein interaction inhibitory activity, it may interfere with Keap1 Nrf2 combination, so as to activate Nrf2, with potential anti-inflammatory activity, available for treating numerous diseases related to inflammation, such as tumour, Parkinson's, senile dementia, COPD, the hardening of artery congee, chronic kidney disease disease, diabetes or rheumatoid arthritis.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a kind of benzothiazole derivant, including prepared by these derivatives
Method and the application in anti-inflammatory field.
Background technology
It is much related to environment, age with aging, the continuous expansion of urbanization and being continually changing for living environment
Disease is worldwide increasingly becoming a serious health problem.These diseases include cancer, inflammation, senile dementia,
Group match property tuberculosis, heart disease, diabetes and Parkinson's etc., and how effective prevention and treatment these diseases be the whole world all
In the problem of concern.
Oxidative stress (oxidative stress) the directly or indirectly macromolecular such as damaging cells internal protein, lipid
The physiological function of material, be considered as with tumour, inflammation, Parkinson's and senile dementia etc..Nrf2 (nuclear factor E2 correlation factors
2) it is key factor in cellular oxidation stress reaction, by the tune of Keap1 (Keleh sample epoxychloropropane related protein-1) albumen
Control (Free Radic.Biol.Med.2004,36,1208), passes through Antioxidation reaction original paper ARE (Antioxidant responsive element) phase
Interaction, adjusts the expression of anti-oxidant albumen and II phase detoxication enzymes, such as NAD (P) H:Quinone oxidoreductase (NAD (P) H:
Quinine oxidoreductase1, NQO1), heme oxygenase-1 (hemoxygenase-1, HO-1) etc..Numerous studies table
Bright, Nrf2 suppresses albumen Keap1 with it and combined under normal operation, is present in cell.During generation oxidative stress, Keap1's
Cysteine residues are modified, and Nrf2 protein deliveries are caused after conformational change, are combined into nucleus with ARE, promote target base
The expression of cause, so as to play cytoprotection.Under pathological conditions, body can not go up Keap1-Nrf2 dissociation.And Nrf2 albumen
It can be degraded through ubiquitination, it is impossible to enter the expression that core induces antioxidant genes, cause the generation of disease
(Med.Res.Rev.2012,32,687)。
Multiple labs extensive work in past more than 30 years, from the native compound or artificial-synthetic compound storehouse
Nrf2 small molecule agonists are screened, the biology that normal body modifies Keap1 cysteine residues is simulated by chemical small molecule
Process, release Nrf2 makes it enter core, plays cytoprotection.Nrf2 activator has been used for treating inflammatory related disorders,
As dimethyl fumarate is ratified to be used to treat multiple sclerosis by FDA, CDDO-Me is opening a business treatment pulmonary hypertension
Second phase it is clinical.In addition, some natural products and class natural products (curcumin, resveratrol and Cha Er with anti-inflammatory activity
Ketone etc.) also it is verified that Nrf2 (Patent publication Nos can be activated：CN 105566241A).But regrettably, make for a long time
Keap1 albumen is modified with covalent bond, sustained activation Nrf2 can cause larger cytotoxicity, be easily caused canceration.
In recent years, designing the small molecule of directly suppression Keap1-Nrf2 protein interactions becomes discovery Keap1-
One new strategy (Curr.Top.Med.Chem.2007,7,972) of Nrf2-ARE paths regulation.At present, peptides Keap1-
Its application of the Premeabilisation of cells energy power restriction of Nrf2 interaction inhibitors (Org.Biomol.Chem., 2013,11,3553；
Bioorg.Med.Chem.Lett.2013,23,3029)；Non-peptide micromolecular Keap1-Nrf2 binding inhibitors turn into the field
Study hotspot.Existing multiple drugmakers and colleges and universities are all carrying out research in this respect at present, and report a series of Keap1-
The direct inhibitor of small molecule (Medchemcomm., 2014,5,93 of Nrf2 interactions；ChemMedChem.,2014,9,
699；J.Med.Chem.,2014,57,1121；J.Med.Chem., 2016,59,3991), in treatment tumour, inflammation, anti-handkerchief gold
Extremely strong application prospect is shown in terms of gloomy disease and the research and development of anti-senile dementia disease drug.
The content of the invention
The present invention discloses a kind of benzothiazole derivant shown in formula I, its preparation method and its medical application.It is preliminary living
Property test prove the compounds of this invention there is good Keap1-Nrf2 protein protein interaction inhibitory activity, may interfere with
Keap1-Nrf2 combination, so as to activate Nrf2, with potential anti-inflammatory activity, available for treating numerous diseases related to inflammation
Disease, such as tumour, Parkinson's, senile dementia, COPD, the hardening of artery congee, chronic kidney disease disease, diabetes
Or rheumatoid arthritis.
The compound of the present invention, (E)-pi-allyl-(2- (2- (benzo [d] thiazole -2) -2- nitriles vinyl) -5- (diethyl
Amino) phenyl) carbonic ester (Formulas I), structural formula is as follows：
It is as follows the invention also discloses the preparation method of compound of formula I：
1) in the synthesis step of the compound of formula 1, the preferred triethylamine of alkali that is used, diethylamine, sodium carbonate, sodium acid carbonate,
Saleratus, potassium carbonate, cesium carbonate, dimethyl aminopyridine, pyridine or the carbon -7- alkene of 1,8- diazabicylos 11；Solvent is excellent
Select the one or more in methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, 1,4- dioxane and acetonitrile；The reaction
Temperature is 0 DEG C~80 DEG C, and the reaction time is 1~24 hour.
2) compound of formula 1 is into the synthesis step of compound of formula I, the preferred triethylamine of alkali, diethylamine, dimethylamino pyrrole
Pyridine, pyridine or the carbon -7- alkene of 1,8- diazabicylos 11；The preferred dichloromethane of solvent, acetone, N,N-dimethylformamide, 1,
One or more in 4- dioxane, dimethyl sulfoxide and acetonitrile；The reaction temperature be -10 DEG C~80 DEG C, the reaction time be 1~
24 hours.
The present invention is based on Nrf2-Keap1 protein protein interactions, it was found that a kind of benzo with good pharmacological activity
Thiazole.The compound is in the Keap1-Nrf2 protein protein interaction Inhibition tests based on fluorescence polarization, performance
The activity gone out is better than positive control S47 (J.Med.Chem.2014,57,1121).In cell experiment, the compound can make greatly
Rat cardiomyocyte Nrf2 enters core, and raises Antioxidative Factors HO-1, NQO1 level, while suppressing the inflammatory factor of LPS inductions
TNF-α, the up-regulation of IL-1 β, IL-6 levels.Therefore, the compound is expected to, as lead compound, be further developed as anti-inflammatory agent
Thing, before there is potential application in preparing the medicine for preventing and/or treating tumour, inflammation, Parkinson's and senile dementia
Scape.
Brief description of the drawings
Fig. 1 surface plasma resonance experiments determine compound and the affine of Keap1 albumen are tried hard to；
Fig. 2 gel electrophoresis figures；
Nrf2 positioning figure in each group cell is observed under Fig. 3 Laser Scanning Confocal Microscopes；
Fig. 4 compounds promote to change the line map in HO-1, NQ01 mRNA level in-site；
Fig. 5 compounds suppress to change the line map in inflammatory factor TNF-a, IL-1 β, IL-6mRNA level of lipopolysaccharides (LPS) induction.
Embodiment
With reference to specific embodiment, the present invention is described in further detail.
Embodiment 1：The preparation of the compound of formula 1
3.5g benzothiazole -2- acetonitriles and 3.9g 4- (diethylin) salicylide are dissolved in 120mL methanol solutions, nitrogen
Gas shielded, subsequent 1mL triethylamines are stirred at room temperature 12 hours.Reaction solution is concentrated afterwards, residue is obtained after purification through column chromatography
5.5g yellow solid compounds formula 1, yield 79%.1H NMR(600MHz,CDCl3) δ 8.01 (1H, d, J=6Hz), 7.90 (1H,
D, J=6Hz), 7.47 (1H, dd, J=6,6Hz), 7.35 (1H, dd, J=6,6Hz), 7.29 (1H, d, J=6Hz), 6.48
(1H, d, J=6Hz), 6.40 (1H, s), 3.42 (4H, t, J=6Hz), 1.22 (6H, t, J=6Hz)13C NMR(150MHz,
CDCl3)δ156.1,151.6,142.2,137.2,130.9,130.2,126.2,124.8,122.6,122.4,121.7,
121.4,111.0,108.2,97.1,96.9,45.3,12.7.ESI-MS m/z:350.1[M+H]+.
Embodiment 2：The preparation of compound of formula I
The compound of 700mg formulas 1 is dissolved in 20mL dichloromethane, ice bath adds 424mg triphosgenes and the second of 1mL tri- to 0 DEG C
Amine.Question response is carried out 1 hour, adds 166mg allyl alcohols, is stirred 12 hours.Reaction solution is concentrated under reduced pressure, and residue is pure through column chromatography
220mg yellow solid compound Formulas I, yield 25% are obtained after change.1H NMR(400MHz,CDCl3)δ8.82(1H,s),8.02
(1H, d, J=8Hz), 7.92 (1H, d, J=8Hz), 7.51-7.35 (3H, m), 6.63 (1H, d, J=12Hz), 6.14-6.07
(1H, m), 6.48 (1H, s), 5.48 (1H, d, J=8Hz), 5.31 (1H, d, J=8Hz), 4.86 (2H, s Hz), 3.45 (4H,
Q, J=8.0Hz), 1.24 (6H, t, J=7.0Hz)13C NMR(100MHz,CDCl3)δ161.5,159.6,155.8,153.1,
152.4,151.9,139.8,137.0,132.7,130.8,126.1,124.5,122.3,121.6,118.2,114.2,
109.9,108.6,97.0,67.0,45.1,12.7.ESI-MS m/z:434.8[M+H]+.
Embodiment 3：Fluorescence polarization method determines compound to Keap1-Nrf2 protein binding inhibitory activity
Fluorescence polarization method determine Keap1-Nrf2 protein bindings inhibitory activity by fluorescence probe (FITC-β Ala-DEETGEF-
OH) it is dissolved in buffer solution (10mM HEPES, pH 7.4,3.4mM EDTA, 150mM NaCl, 0.005%Tween-20) dilution
To 10nM, it is added in the Keap1 albumen of gradient dilution, room temperature lucifuge is incubated 30 minutes, fluorescence anisotropy value is used
SpectraMax M5e ELIASAs read (ex:485nm,em:535nm).Binding parameters are used according to fluorescence anisotropy value
Mathematica 7 (Wolfram Research Inc.) fittings are obtained.Specific formula is as follows：
Experiment carries out single concentration (100 μM) to testing compound, with compound S47 (J.Med.Chem.2014,57,
1121) as control compound, inhibiting rate is
Then compound is dissolved in DMSO buffer solution (10mM HEPES, pH 7.4,3.4mM EDTA, 150mM
NaCl, 0.005%Tween -20) it is diluted to and needs concentration (1%DMSO), 20 μ L compounds are added to 60 μ L and contain 10nM fluorescence
In probe (FITC-β Ala-DEETGEF-OH), the solution of 400nM Keap1 albumen, room temperature lucifuge is incubated 1 hour.Fluorescence is each
Anisotropy value reads (ex with the ELIASAs of Bioteck Synergy 2:485nm,em:535nm).Binding parameters are according to fluorescence
Anisotropy value is obtained with Mathematica 7 (Wolfram Research Inc.) fittings.Specific formula is as follows：
Wherein a=KD1+KD2+LST+LT-RT；B=(LT-RT)KD1+(LST-RT)KD2+KD1KD2；C=-KD1KD2RT；
In formula, Q values be fluorescence probe with combined under highest protein concentration after fluorescence intensity and free state it is glimmering
The ratio of luminous intensity, FSBFor fluorescence probe bound fraction, ABAnd AFRespectively combine each to different with the probe under free state
Property value, KD1It is the binding parameters of probe, LSTFor concentration and probe concentration, RTFor protein concentration, KD2Press down for the protein binding of compound
Constant processed.
Test result compound of formula I is to the inhibiting rate of Keap1-Nrf2 protein protein interactions under 100 μM of concentration
81.25%, its protein binding inhibition constant KD2It is worth for 5.1 μM, slightly better than positive control S47 (KD2It is worth for 7.6 μM).
Embodiment 4：Surface plasma resonance experiment determines affinity of the compound to Keap1 albumen
Calculate ligand coupling level：1.5 × RL=10440RU；Preenrichment (PH Scouting), the suitable coupling of selection
PH and ligand concentration：Part is diluted in different pH 10mM NaAC (final ligand concentration is about 25-50 μ g/mL), sky is flowed through
White chip surface, tests the effect of Electrostatic Absorption；It is coupled part (Immobilization)：First surveyed with blank chip Electrostatic Absorption
Preenrichment ability is tried, then is handled with EDC, NHS to activate chip surface, then sample introduction part, 600s is coupled, it is final to use
Ethanolamine closes chip surface.
The serial calibration solution that DMSO concentration ranges are 4.5%-5.8% is prepared, respectively before whole analytes, whole
Sample introduction calibration solution, the concentration error for DMSO in calibration analyte after analyte and after every 30 analytes.
By the storing solution of analyte, successively decreased step by step with working buffer solution be diluted to series concentration (0,250,500,1000,
2000、4000、8000、16000、32000、64000nM.Using Kinetics/Affinity program sample introductions, sample is with flow velocity 30
μ L/min, sample introduction 120s, dissociate 120s.
Obtained data are analyzed with using Biacore T200Evaluation Software.Calculate solvent DMSO
Concentration correction curve, the appropriate concentration range of selection and binding curve, are deducted reference channel and zero-dose, are entered using steady-state model
Row Fitting Analysis, obtains affinity numerical value and parameter.Experimental result is as shown in figure 1, compound and the affinity costant of Keap1 albumen
For 48.1. μM.
Report
Parameters
Embodiment 5：Compound promotes Nrf2 to be shifted into nucleus
By rat myocardial cell H9C2 cell seedings in capsule, handle thin with 4 μM, 8 μM and 16 μM compounds respectively
Born of the same parents 6h, the control group handled well and experimental group cell are inhaled and abandon nutrient solution, with 1 × PBS once, and addition 1ml precoolings 1 ×
PBS, cell is scraped with cell sleaker, and cell is added in the centrifuge tube of precooling 4 DEG C, 1000rpm centrifugation 5min with liquid-transfering gun, inhaled
Supernatant, leaves cell precipitation standby to the greatest extent；Extract Nuclear extract and acellular nucleoprotein respectively using kit；10 μ l are taken to extract
Suppressor proteins sample and 5 μ l Nuclear extracts samples in eppendorf pipes, plus ddH2O supplies 10 μ l, is surveyed using BCA
Protein concentration；Separation gel 12% is made, glue 5% is concentrated；100 DEG C of protein samples are denatured 5min, each μ g of sample loading 12；60V
Enter glue, 120v constant pressures run glue；With transfer groove 80V/160mA constant current transferring films, 2.5h；The 5% skim milk room temperature envelope that TBST is prepared
Close 1.5h；Discard after milk powder rinsed well with TBST, the BSA solution of 5% prepared with TBST is by 1:1000 dilution proportion one
It is anti-, 4 DEG C of overnight incubations of pvdf membrane；TBST washes film, 3 times, each 5min；5% skimmed milk solution prepared with TBST is by two
It is anti-to press 1:5000 dilution proportion, is incubated at room temperature 1h；Film, 3 times, each 5min are washed with TBST；Used using Chemiluminescence Apparatus
Milipore substrates show film, and gel electrophoresis figure is analyzed and quantitative with Image J.As a result 8 μM of display, 16 μM of compounds make nucleus
Interior Nrf2 levels are significantly raised (shown in Fig. 2).
On the other hand, H9C2 cell 6h are handled with 8 μM of compounds, nutrient solution is abandoned in suction, PBS one time, cell through fixation,
After closing, add Nrf2 primary antibodies four and spend night, secondary antibody is incubated 37 degree and is incubated 1 hour, and DAPI redyes nucleus, Laser Scanning Confocal Microscope
Nrf2 is positioned in control group in lower observation each group cell, and Nrf2 is predominantly located in cytoplasm, 8 μM of compound processing cell
Nrf2 in 6h, nucleus significantly increases (shown in Fig. 3).
Embodiment 6：Compound raises HO-1, NQ01mRNA level
Nrf2 enters nuclear energy and enough activates downstream oxydating resistance element, therefore, and we further analyze compound using RT-PCR
Whether downstream oxydating resistance element HO-1 and NQ01 can be activated.By H9C2 cell seedings in capsule, 8 μM of compounds are located respectively
H9C2 cells 2h, 4h and 6h are managed, TRIZOL cell lysis extracts intracellular rna, is reversed to DNA, utilizes real-time quantitative PCR
Instrument is analyzed, and analyzes HO-1, NQ01 level.As a result as shown in figure 4, compound processing cell 2h, 4h and 6h significantly raise HO-
1 and NQ01 mRNA level in-site.
Embodiment 7：Compound suppresses in inflammatory factor TNF-a, IL-1 β, IL-6mRNA level of lipopolysaccharides (LPS) induction
Adjust.
By H9C2 cell seedings in capsule, H9C2 cells are stimulated to set up inflammatory model, 8 μM of changes using 1 μ g/ml LPS
Compound and lipopolysaccharides coprocessing H9C2 cells 6h, TRIZOL cell lysis, extract intracellular rna, are reversed to DNA, using real-time
Quantitative PCR apparatus is analyzed.As a result as shown in figure 5,8 μM compound processing cell 6h can significantly inhibit LPS induction inflammatory because
Sub- TNF-a, IL-1 β, IL-6mRNA level up-regulation.
Claims (6)
1. a kind of benzothiazole derivant, it is characterised in that it is (E)-pi-allyl-(2- (2- (benzo [d] thiazole -2) -2- nitriles
Vinyl) -5- (diethylamino) phenyl) carbonic ester (Formulas I), its structural formula is：
2. the preparation method of derivative described in a kind of claim 1, it is characterised in that comprise the following steps：
(1) benzothiazole -2- acetonitriles and the compound of 4- (lignocaine) salicylides formula 1 are used；
(2) compound of formula 1 is reacted with triphosgene, allyl alcohol, obtains compound of formula I.
3. a kind of derivative of claim 1 is as Keap1-Nrf2 protein protein interaction inhibitor in medicine is prepared
Purposes.
4. a kind of pharmaceutical composition, the derivative containing claim 1 or its pharmaceutically acceptable salt and pharmaceutically receive
Carrier.
5. the derivative and its pharmaceutically acceptable salt described in a kind of claim 1 are used to prepare treatment and/or prevention and scorching
Purposes in the medicine of the related disease of disease.
6. the purposes described in a kind of claim 5, it is characterised in that the disease related to inflammation is tumour, Parkinson's, old age
Dementia, COPD, the hardening of artery congee, chronic kidney disease disease, diabetes or rheumatoid arthritis.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108610410A (en) * | 2018-05-14 | 2018-10-02 | 浙江海洋大学 | A kind of rapid screening method of Keap1-Nrf2-ARE accesses inhibiting factor |
| US11427601B1 (en) | 2018-08-20 | 2022-08-30 | Janssen Pharmaceutica Nv | Inhibitors of KEAP1-Nrf2 protein-protein interaction |
| CN116003397A (en) * | 2023-03-24 | 2023-04-25 | 凯思凯旭(上海)医药科技有限公司 | Benzo-polycyclic thiazoline amide compound and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566241A (en) * | 2016-01-18 | 2016-05-11 | 中国药科大学 | 1-sulfonamide-4-aryloxy compound, preparation method and medical application of 1-sulfonamide-4-aryloxy compound |
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- 2017-05-24 CN CN201710371406.4A patent/CN107033100B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566241A (en) * | 2016-01-18 | 2016-05-11 | 中国药科大学 | 1-sulfonamide-4-aryloxy compound, preparation method and medical application of 1-sulfonamide-4-aryloxy compound |
Non-Patent Citations (2)
| Title |
|---|
| CHUNLIN ZHUANG 等: ""Rapid Identification of Keap1−Nrf2 Small-Molecule Inhibitors through Structure-Based Virtual Screening and Hit-Based Substructure Search"", 《J. MED. CHEM.》 * |
| ZHENG-YU JIANG 等: ""Discovery of Potent Keap1-Nrf2 Protein-Protein Interaction Inhibitor Based on Molecular Binding Determinants Analysis"", 《J. MED. CHEM.》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108610410A (en) * | 2018-05-14 | 2018-10-02 | 浙江海洋大学 | A kind of rapid screening method of Keap1-Nrf2-ARE accesses inhibiting factor |
| US11427601B1 (en) | 2018-08-20 | 2022-08-30 | Janssen Pharmaceutica Nv | Inhibitors of KEAP1-Nrf2 protein-protein interaction |
| US11897900B2 (en) | 2018-08-20 | 2024-02-13 | Janssen Pharmaceutica Nv | Inhibitors of KEAP1-Nrf2 protein-protein interaction |
| CN116003397A (en) * | 2023-03-24 | 2023-04-25 | 凯思凯旭(上海)医药科技有限公司 | Benzo-polycyclic thiazoline amide compound and application thereof |
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