CN107033100B - 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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- CN107033100B CN107033100B CN201710371406.4A CN201710371406A CN107033100B CN 107033100 B CN107033100 B CN 107033100B CN 201710371406 A CN201710371406 A CN 201710371406A CN 107033100 B CN107033100 B CN 107033100B
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- nrf2
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- C—CHEMISTRY; METALLURGY
- 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
Abstract
The present invention relates to field of medicinal chemistry, more particularly 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 the combination of Keap1-Nrf2, to activate Nrf2, with potential anti-inflammatory activity, it can be used for treating numerous diseases relevant to inflammation, such as tumour, Parkinson's disease, senile dementia, Chronic Obstructive Pulmonary Disease, the hardening of artery congee, chronic kidney disease disease, diabetes or rheumatoid arthritis.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of benzothiazole derivant, including the preparation of these derivatives
Method and application in anti-inflammatory field.
Background technique
With aging, the continuous expansion and the continuous variation of living environment of urbanization, much with environment, age-dependent
Disease worldwide has become a serious health problem.These diseases include cancer, inflammation, senile dementia,
Group match property tuberculosis, heart disease, diabetes and Parkinson's disease etc., and how effective prevention and treatment these diseases be the whole world all
In the project of concern.
Oxidative stress (oxidative stress) directly or indirectly macromoleculars such as damaging cells internal protein, lipid
The physiological function of substance, be considered with tumour, inflammation, Parkinson's disease and senile dementia etc..Nrf2 (nuclear factor E2 correlation factor
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 part ARE (Antioxidant responsive element) phase
Interaction adjusts the expression of anti-oxidant albumen and II phase detoxication enzyme, such as NAD (P) H: quinone oxidoreductase (NAD (P) H:
Quinine oxidoreductase1, NQO1), heme oxygenase-1 (hemoxygenase-1, HO-1) etc..Numerous studies table
It is bright, in conjunction with Nrf2 inhibits albumen Keap1 with it under normal operation, it is present in cell.When oxidative stress occurs, Keap1's
Cysteine residues are modified, and Nrf2 protein delivery is caused after conformational change, into nucleus in conjunction with ARE, promote target base
The expression of cause, to play cytoprotection.Under pathological conditions, body can not go up Keap1-Nrf2 dissociation.And Nrf2 albumen
It can degrade through ubiquitination, the expression of core induction antioxidant genes cannot be entered, lead to the generation of disease
(Med.Res.Rev.2012,32,687)。
Multiple labs extensive work in more than 30 years of past, from the native compound or artificial-synthetic compound library
Nrf2 small molecule agonist is screened, the biology that normal body modifies the cysteine residues of Keap1 is simulated by chemical small molecule
Process, release Nrf2 make it enter core, play cytoprotection.Nrf2 activator has been used for treating inflammatory related disorders,
If dimethyl fumarate is ratified by FDA for treating multiple sclerosis, CDDO-Me, which is opening a business, treats 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 No: CN 105566241A) can be activated.But regrettably, make for a long time
Keap1 albumen is modified with covalent bond, sustained activation Nrf2 can cause biggish cytotoxicity, easily lead to canceration.
In recent years, design directly inhibits the small molecule of Keap1-Nrf2 protein interaction to become discovery Keap1-
The new strategy (Curr.Top.Med.Chem.2007,7,972) that Nrf2-ARE access is adjusted.Currently, peptides Keap1-
The Premeabilisation of cells energy power limit of Nrf2 interaction inhibitor its application (Org.Biomol.Chem., 2013,11,3553；
Bioorg.Med.Chem.Lett.2013,23,3029)；Non-peptide micromolecular Keap1-Nrf2 binding inhibitors become the field
Research hotspot.Have multiple drugmakers and colleges and universities at present and all carrying out research in this respect, and reports a series of Keap1-
Nrf2 interaction the direct inhibitor of small molecule (Medchemcomm., 2014,5,93；ChemMedChem.,2014,9,
699；J.Med.Chem.,2014,57,1121；J.Med.Chem., 2016,59,3991), in treatment tumour, inflammation, anti-pa gold
Gloomy disease and anti-senile dementia disease drug research and development aspect show extremely strong application prospect.
Summary of the invention
The present invention discloses a kind of benzothiazole derivant shown in formula I, preparation method and its medical application.It is preliminary living
Property test prove the compounds of this invention have good Keap1-Nrf2 protein protein interaction inhibitory activity, may interfere with
The combination of Keap1-Nrf2 has potential anti-inflammatory activity, can be used for treating numerous diseases relevant to inflammation to activate Nrf2
Disease, such as tumour, Parkinson's disease, senile dementia, Chronic Obstructive Pulmonary Disease, the hardening of artery congee, chronic kidney disease disease, diabetes
Or rheumatoid arthritis.
The compound of the present invention, (E)-allyl-(2- (2- (benzo [d] thiazole -2) -2- nitrile 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 1 compound of formula, the preferred triethylamine of used alkali, diethylamine, sodium carbonate, sodium bicarbonate,
Saleratus, potassium carbonate, cesium carbonate, 11 carbon -7- alkene of dimethyl aminopyridine, pyridine or 1,8- diazabicylo；Solvent is excellent
Select one or more of methanol, ethyl alcohol, 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) 1 compound of formula is into the synthesis step of compound of formula I, the preferred triethylamine of alkali, diethylamine, dimethylamino pyrrole
11 carbon -7- alkene of pyridine, pyridine or 1,8- diazabicylo；The preferred methylene chloride of solvent, acetone, N,N-dimethylformamide, 1,
One or more of 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 test based on fluorescence polarization, performance
Activity out is better than positive control S47 (J.Med.Chem.2014,57,1121).In cell experiment, which can make greatly
Rat cardiomyocyte Nrf2 enters core, and the inflammatory factor for raising Antioxidative Factors HO-1, NQO1 level, while LPS being inhibited to induce
TNF-α, the up-regulation of IL-1 β, IL-6 level.Therefore, which is expected to be further developed as anti-inflammatory agent as lead compound
Object, before there is potential application in preparation prevention and/or the drug for treating tumour, inflammation, Parkinson's disease and senile dementia
Scape.
Detailed description of the invention
Fig. 1 surface plasma resonance experiment measurement compound tries hard to the affine of Keap1 albumen；
Fig. 2 gel electrophoresis figure；
Nrf2 positioning figure in group of cells is observed under Fig. 3 Laser Scanning Confocal Microscope；
It changes the line map in the mRNA level in-site of the promotion of Fig. 4 compound HO-1, NQ01；
It changes the line map on inflammatory factor TNF-a, IL-1 β, the IL-6mRNA of Fig. 5 compound inhibition lipopolysaccharides (LPS) induction are horizontal.
Specific embodiment
The present invention is described in further detail combined with specific embodiments below.
Embodiment 1: the preparation of 1 compound of formula
3.5g benzothiazole -2- acetonitrile and 3.9g 4- (diethylin) salicylide are dissolved in 120mL methanol solution, nitrogen
Gas shielded, subsequent 1mL triethylamine are stirred at room temperature 12 hours.Reaction solution is concentrated later, residue obtains after column chromatographic purifying
5.5g yellow solid compound 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
1 compound of 700mg formula is dissolved in 20mL methylene chloride, 424mg triphosgene and tri- second of 1mL is added to 0 DEG C in ice bath
Amine.It is carried out 1 hour wait react, 166mg allyl alcohol is added, stirred 12 hours.Reaction solution is concentrated under reduced pressure, and residue chromatographs pure through column
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 measures compound to Keap1-Nrf2 protein binding inhibitory activity
Fluorescence polarization method measures Keap1-Nrf2 protein binding inhibitory activity for fluorescence probe (FITC-β Ala-DEETGEF-
OH) it is dissolved in buffer (10mM HEPES, pH 7.4,3.4mM EDTA, 150mM NaCl, 0.005%Tween-20) dilution
It to 10nM, is added in the Keap1 albumen of gradient dilution, room temperature is protected from light incubation 30 minutes, and fluorescence anisotropy value is used
SpectraMax M5e microplate reader reads (ex:485nm, em:535nm).Binding parameters are used according to fluorescence anisotropy value
Mathematica 7 (Wolfram Research Inc.) fitting obtains.Specific formula is as follows:
Experiment carries out single concentration (100 μM) to untested compound, with compound S47 (J.Med.Chem.2014,57,
1121) it is used as control compound, inhibiting rate is
Then compound is dissolved in DMSO buffer (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
Probe (FITC-β Ala-DEETGEF-OH), in the solution of the Keap1 albumen of 400nM, room temperature is protected from light incubation 1 hour.Fluorescence is each
Anisotropy value reads (ex:485nm, em:535nm) with 2 microplate reader of Bioteck Synergy.Binding parameters are according to fluorescence
Anisotropy value is fitted with Mathematica 7 (Wolfram Research Inc.) and is obtained.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 value 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 AFIt respectively combines 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 interaction under 100 μM of concentration
81.25%, protein binding inhibition constant KD2Value is 5.1 μM, is slightly better than positive control S47 (KD2Value is 7.6 μM).
Embodiment 4: surface plasma resonance experiment measures compound to the affinity of Keap1 albumen
It is horizontal to calculate ligand coupling: 1.5 × RL=10440RU；Preenrichment (PH Scouting) selects suitable coupling
PH and ligand concentration: ligand is diluted in the 10mM NaAC of different pH (final ligand concentration is about 25-50 μ g/mL), flows through sky
White chip surface tests the effect of Electrostatic Absorption；It is coupled ligand (Immobilization): first being surveyed with blank chip Electrostatic Absorption
Preenrichment ability is tried, then is handled with EDC, NHS to activate chip surface, then sample introduction ligand, is coupled 600s, final to use
Ethanolamine closes chip surface.
The serial calibration solution that DMSO concentration range is 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 stock solution of analyte, successively decreased step by step with working buffer solution be diluted to series of concentrations (0,250,500,1000,
2000,4000,8000,16000,32000,64000nM.Using Kinetics/Affinity program sample introduction, 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, selects concentration range appropriate and binding curve, deducts reference channel and zero-dose, using steady-state model into
Row Fitting Analysis obtains affinity numerical value and parameter.Experimental result as shown in Figure 1, compound and Keap1 albumen affinity costant
It is 48.1. μM.
Report
Parameters
Embodiment 5: compound promotes Nrf2 to shift into nucleus
It is thin with 4 μM, 8 μM and 16 μM compound processing respectively by rat myocardial cell H9C2 cell seeding in capsule
The control group handled well and experimental group cell are inhaled and abandon culture solution, cleaned once with 1 × PBS by born of the same parents 6h, and addition 1ml pre-cooling 1 ×
PBS scrapes cell with cell scraping, and 4 DEG C, 1000rpm centrifugation 5min is added in the centrifuge tube of pre-cooling in cell with liquid-transfering gun, is inhaled
Supernatant to the greatest extent, it is spare to leave cell precipitation；Extract Nuclear extract and acellular nucleoprotein respectively using kit；10 μ l are taken to extract
Suppressor proteins sample and 5 μ l Nuclear extract samples to eppendorf pipe in, add 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 denaturalized 5min, each 12 μ g of sample loading；60V
Into glue, 120v constant pressure runs glue；With transfer groove 80V/160mA constant current transferring film, 2.5h；The 5% skim milk room temperature envelope that TBST is prepared
Close 1.5h；It discards after milk powder rinsed well with TBST, the dilution proportion one of 1:1000 is pressed with the 5% BSA solution that TBST is prepared
It is anti-, 4 DEG C of pvdf membrane overnight incubations；TBST washes film, and 3 times, each 5min；5% skimmed milk solution prepared with TBST is by two
The anti-dilution proportion by 1:5000, is incubated at room temperature 1h；Film is washed with TBST, 3 times, each 5min；It is used using Chemiluminescence Apparatus
Milipore substrate shows film, with Image J analysis gel electrophoresis figure and quantitatively.8 μM as the result is shown, 16 μM of compounds make nucleus
The horizontal significant up-regulation of interior Nrf2 (shown in Fig. 2).
On the other hand, H9C2 cell 6h are handled with 8 μM of compounds, inhale and abandon culture solution, PBS is cleaned one time, cell through fixation,
After closing, Nrf2 primary antibody four is added and spends night, secondary antibody is incubated for 37 degree and is incubated for 1 hour, and DAPI redyes nucleus, Laser Scanning Confocal Microscope
Nrf2 is located in control group in lower observation group of cells, and Nrf2 is predominantly located in cytoplasm, and 8 μM of compound handles cell
6h, the Nrf2 in nucleus significantly increase (shown in Fig. 3).
Embodiment 6: compound raises HO-1, NQ01mRNA level
Nrf2 enters nuclear energy and enough activates downstream oxydating resistance element, and therefore, we further analyze compound using RT-PCR
Whether downstream oxydating resistance element HO-1 and NQ01 can be activated.By H9C2 cell seeding in capsule, 8 μM of compounds are located respectively
H9C2 cell 2h, 4h and 6h are managed, TRIZOL lytic cell extracts intracellular rna, is reversed to DNA, utilizes real-time quantitative PCR
Instrument analysis, analysis HO-1, NQ01 are horizontal.As a result as shown in figure 4, compound processing cell 2h, 4h and 6h significantly raise HO-
The mRNA level in-site of 1 and NQ01.
Embodiment 7: compound inhibits on the inflammatory factor TNF-a, IL-1 β, IL-6mRNA level of lipopolysaccharides (LPS) induction
It adjusts.
By H9C2 cell seeding in capsule, inflammatory model, 8 μM of changes are established using the LPS stimulation H9C2 cell of 1 μ g/ml
Object and lipopolysaccharides coprocessing H9C2 cell 6h, TRIZOL lytic cell are closed, intracellular rna is extracted, is reversed to DNA, using real-time
Quantitative PCR apparatus analysis.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, the up-regulation of IL-6mRNA level.
Claims (5)
1. a kind of benzothiazole derivant, which is characterized in that it be (E)-allyl-(2- (2- (benzo [d] thiazole -2) -2- nitrile
Vinyl) -5- (diethylamino) phenyl) carbonic ester, such as Formulas I, structural formula are as follows:
。
2. a kind of preparation method of derivative described in claim 1, which comprises the following steps:
；
(1) 1 compound of benzothiazole -2- acetonitrile and 4- (lignocaine) salicylide preparation formula is used；
(2) 1 compound of formula is reacted with triphosgene, allyl alcohol, obtains compound of formula I.
3. a kind of derivative of claim 1 as Keap1-Nrf2 protein protein interaction inhibitor in medicine preparation
Purposes.
4. a kind of pharmaceutical composition, the derivative containing claim 1 and the carrier pharmaceutically received.
5. a kind of pharmaceutical composition, the derivative pharmaceutically acceptable salt containing claim 1 and the carrier pharmaceutically received.
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