CN103254151A - Benzisoxa thiazoles 5-LOX and mPGES-1 inhibitor and application - Google Patents
Benzisoxa thiazoles 5-LOX and mPGES-1 inhibitor and application Download PDFInfo
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Abstract
The invention discloses a benzisoxa thiazole compound which is used as a double-function inhibitor of 5-lipoxygenase (5-LOX) and prostaglandin E synthetase (mPGES-1), and the compound has the structure shown in the formula IV, wherein, R1, R2 and R3 represent hydrogen, alkyl, alkyloxy or halogen respectively, or R2 and R1 or R3 form a ring, thereby representing 1, 3-butadiene subunit. The external and whole blood enzyme activity test of the compound for 5-LOX and mPGES-1 confirms that the compound has the double-function inhibition activity for 5-lipoxygenase and prostaglandin E synthetase, and can be used for preparing medicaments for treating and preventing various inflammations.
Description
Technical field
The present invention relates to treat and prevent the medicine of various inflammation, be particularly related to the benzo isothiazole compound as 5-lipoxygenase (5-LOX) and the difunctional inhibitor of PGE synthetic enzyme (mPGES-1), and preparation method thereof, and this compound is in preparation treatment with prevent application in the various inflammation medicines.
Background technology
Inflammation is to have the defensive raction that the biological tissue of vascular system takes place damage factor, and when this defensive raction excessive activation or when out of hand, inflammatory factor will be attacked damage human body self tissue, and is diseases induced, possible threat to life when serious.The generation of inflammation is the complex process that polymolecular participates in regulation and control, considers the effect of selected drug targets in the disease overall network in the early stage of medicament research and development, researches and develops many target agents and is expected to reduce toxic side effect, for the treatment of inflammation significance is arranged.
Arachidonic acid (AA) metabolism network is the network that produces inflammatory factor, in AA metabolism network, phosphatide is discharged arachidonic acid by Phospholipase A2 (PLA2) hydrolysis, subsequently by two metabolic pathway: (one) generates various prostaglandin(PG)s (PGs) by the effect of cyclooxygenase (COX), and the key enzyme that this path produces inflammation has COX-2, PGE synthetic enzyme (mPGES-1); (2) effect by 5-lipoxygenase (5-LOX) generates leukotriene (LTs), lipid peroxide, and the key enzyme that produces inflammation has 5-LOX, leukotriene A lytic enzyme (LTA4H).Studies show that, exist between these two paths and influence each other that path of single inhibition will cause inflammatory factor to pass through another path expressing.The multi-functional inhibitor that designs in two paths that act on simultaneously in this network can have following advantage:
One, suppresses inflammatory factor leukotriene and the prostaglandin(PG) that two pathways metabolisms produce simultaneously, increase antiphlogistic effects, avoided causing because of the inhibition of a pathways metabolism situation of the activation of another pathways metabolism.
Two, multi-functional inhibitor is little to the more single depressant of functions of the inhibition of single enzyme, and caused side effect is less (difunctional inhibitor Da Bufeilong for example, inhibition has been proved to be not have stomach toxicity with the marketed drug indomethacin is suitable) also.
5-lipoxygenase (EC 1.13.11.34) is key enzyme (Radmark, the O. that the metabolism arachidonic acid produces inflammatory mediator leukotrienes compound; Samuelsson, B., Regulation of 5-lipoxygenase enzyme activity.Biochem.Bioph.Res.Co.2005,338 (1), 102-110.).The adjusting of 5-LOX has important effect to generation and the development of inflammation related disease, and this enzyme is considered to one of important target of anti-inflammatory drug design.Zileuton (zileuton) is at present only 5-LOX inhibitor (Lehnigk, the B. that enters clinical study and use as prescription drugs; Rabe, K.F.; Dent, G.; Herst, R.S.; Carpentier, P.J.; Magnussen, H., Effects of a5-lipoxygenase inhibitor, ABT-761, on exercise-induced bronchoconstriction and urinaryLTE4in asthmatic patients.Eur.Respir.J.1998,11 (3), 617-623.), be used for the treatment of the relevant disease of asthma.
PGE synthetic enzyme (EC 5.3.99.3) is key enzyme (Friesen, the R.W. that the metabolism arachidonic acid produces the inflammatory mediator prostanoid; Mancini, J.A., Microsomal prostaglandin E-2synthase-1 (mPGES-1): A novel anti-inflammatory therapeutic target.J.Med.Chem.2008,51, (14), 4059-4067.).MPGES-1 was found in 1999, it is positioned at the least significant end that the prostanoid inflammatory mediator produces path, up-regulated expression amount just under inflammation-induced only, mPGES-1 is considered to avoid the inflammation drug targets of toxic side effect, does not also have the mPGES-1 inhibitor to enter clinical trial at present.
Summary of the invention
The purpose of this invention is to provide a kind of benzo isothiazole compound, as the difunctional inhibitor that suppresses 5-lipoxygenase and PGE synthetic enzyme simultaneously.
Another object of the present invention is to provide the preparation method of above-mentioned benzo isothiazole compound.
The present invention also aims to provide above-mentioned benzo isothiazole compound for the preparation for the treatment of with prevent application in the various inflammation medicines.
The present invention has set up the comparison mould established model of 5-lipoxygenase (5-LOX), after optimizing this model with the molecular docking of molecular dynamics simulation and known inhibitor, in the Specs compound library, carry out the virtual screening of 5-LOX inhibitor, the molecular docking result of binding compounds and PGE synthetic enzyme (mPGES-1) structural models then, the compound skeleton is carried out composition optimizes, designed and synthesized a class benzo isothiazole compound, and this benzo isothiazole compound is carried out the enzyme test alive of the external and whole blood of 5-LOX and mPGES-1, confirm the difunctional inhibitor activity of its 5-lipoxygenase and PGE synthetic enzyme.
Benzo isothiazole compound provided by the present invention has following general structure:
Wherein, R
1, R
2, R
3Identical or different, independently represent hydrogen, alkyl, alkoxyl group, halogen, perhaps R separately
2With R
1Or R
3Cheng Huan, Joint Representative's 1,3-butadiene subunit.
Abovementioned alkyl is preferably the straight or branched alkyl of C1～C6, more preferably the straight or branched alkyl of C1～C3, for example methyl, ethyl, propyl group and sec.-propyl.
Above-mentioned alkoxyl group is preferably the straight or branched alkoxyl group of C1～C6, more preferably the straight or branched alkoxyl group of C1～C3, for example methoxyl group, oxyethyl group and propoxy-.
The object lesson of above-mentioned general formula compound has:
1) 3-(3-aminomethyl phenyl) amido-6-nitro-1,1-titanium dioxide benzo isothiazole (PKUMDL_AAL_101): R
1=R
3=H, R
2=CH
3
2) 3-anilino-6-nitro-1,1-titanium dioxide benzo isothiazole (PKUMDL_AAL_102): R
1=R
2=R
3=H;
3) 3-(4-p-methoxy-phenyl) amido-6-nitro-1,1-titanium dioxide benzo isothiazole (PKUMDL_AAL_103): R
1=R
2=H, R
3=OCH
3
4) 3-(3,4-Dimethoxyphenyl) amido-6-nitro-1,1-titanium dioxide benzo isothiazole (PKUMDL_AAL_104): R
1=H, R
2=R
3=OCH
3
5) 3-(1-naphthyl) amido-6-nitro-1,1-titanium dioxide benzo isothiazole (PKUMDL_AAL_105): R
3=H, R
2With R
3Cheng Huanwei 1,3-butadiene subunit;
6) 3-(3-chloro-phenyl-) amido-6-nitro-1,1-titanium dioxide benzo isothiazole (PKUMDL_AAL_106): R
1=R
3=H, R
2=Cl;
7) 3-(3-bromophenyl) amido-6-nitro-1,1-titanium dioxide benzo isothiazole (PKUMDL_AAL_107): R
1=R
3=H, R
2=Br.
Benzo isothiazole compound of the present invention can prepare by the following method:
6-nitro-1,1,3-trioxy--2,3-dihydro-benzisothiazole is through the intermediate 3-chloro-6-nitro-1 shown in the chlorination reaction production II, 1-dioxo-benzisothiazole, the various substituted aniline reactions shown in this intermediate and the formula III obtain target product (formula IV).R wherein
1, R
2, R
3Identical or different, independently represent hydrogen, alkyl, alkoxyl group, halogen, perhaps R separately
2With R
1Or R
3Cheng Huan, Joint Representative's 1,3-butadiene subunit.
Benzo isothiazole compound of the present invention shows the test alive of the enzyme of 5-LOX and mPGES-1 and whole blood test result, this compounds is inhibited to 5-lipoxygenase and PGE synthetic enzyme, is the difunctional inhibitor of 5-lipoxygenase and PGE synthetic enzyme.
Benzo isothiazole compound of the present invention or its pharmaceutical salts as effective constituent, are added the conventional medicine carrier, can or prevent the medicine of various inflammation for the preparation for the treatment of.
Description of drawings
Fig. 1 is the molecular docking figure of Compound P KUMDL_AAL_101 and 5-LOX structural models.
Fig. 2 is the molecular docking figure of Compound P KUMDL_AAL_101 and mPGES-1 structural models.
Embodiment:
Following examples are used for explanation the present invention, and method of the present invention is put into practice in expression, and it does not have any restriction to scope of the present invention.Those skilled in the art may find apparent realization additive method of the present invention for them, all should think that those methods are included in the scope of the present invention.
The virtual screening of embodiment 1,5-LOX inhibitor and the design of difunctional inhibitor
One, makes up the comparison mould established model of 5-LOX
Be not directly used at present the crystalline structure of 5-LOX inhibitor screening.The flexibility of the structure-activity pocket of known rabbit source 15-LOX is bigger, has " open " and " close " two kinds of conformations, and its active pocket has only under the state of " close " conformation and enough spaces just arranged in conjunction with micromolecular inhibitor.We have set up the comparison mould established model of 5-LOX on the basis of rabbit source 15-LOX (PDB entry:2P0M) " close " conformation, and optimize this model with the molecular docking of molecular dynamics simulation and known inhibitor.
Two, the virtual screening of 5-LOX inhibitor
Based on the comparison mould established model through optimizing, utilize the method for molecular docking and pharmacophore coupling combination, the Specs database that comprises about 200,000 compounds is carried out virtual screening.Database is divided into four groups on a rough averagely, and service routine DOCK 6.0 is docked to the substrate binding pocket of 5-LOX model with all compound rigidity, selects 9,999 the highest molecules of butt joint marking from every group.Service routine PSCORE generates pharmacophore from protein structure, and butt joint conformation and the pharmacophore of 39,996 compounds selecting mated, and selects 4,347 the highest molecules of coupling marking.Service routine AutoDock 4.0 carries out flexible docking (Lamarckian genetic algorithm with these compounds, energy assessment number of times 25,000,000, move 20 times), select prediction in conjunction with 1,000 compound of free energy maximum, in conjunction with conformation, last hand picking goes out 105 compounds according to their prediction.
Three, 5-LOX inhibitor design
Compound 3-(3-aminomethyl phenyl) amido-6-nitro-1 that virtual screening is obtained, 1-titanium dioxide benzo isothiazole (PKUMDL_AAL_101) carries out the molecular docking (see figure 1) with the structural models of 5-LOX, the result shows that inhibitor and 5-LOX have following interaction: two aromatic rings occupy two hydrophobic cavities of substrate binding pocket respectively, and are connected by flexible chain; Aromatic ring 1 is five-membered ring fused benzene, and the place cavity has positive electricity, and electronegativity group and the pocket of flexible chain connection interatomic potential have Coulomb attraction on the aromatic ring, and produces hydrogen bonds with Histidine 600, forms the specificity combination; Aromatic ring 2 is phenyl ring derivative or naphthalene nucleus.
Four, mPGES-1 inhibitor design
Compound P KUMDL_AAL_101 is docked (see figure 2) with the structural models of mPGES-1, the result shows because the pocket of mPGES-1 is broad, hydrophobic surface is long-pending big, can with the aromatic ring generation hydrophobic interaction of inhibitor, electronegativity group on the aromatic ring 1 and the arginine in the pocket 126 generate hydrogen bond simultaneously, form the specificity combination.
By above-mentioned molecular docking result, design the difunctional inhibitor general formula of following 5-LOX and mPGES-1:
Wherein, R
1, R
2, R
3Identical or different, independently represent hydrogen, alkyl, alkoxyl group, halogen, perhaps R separately
2With R
1Or R
3Cheng Huan, Joint Representative's 1,3-butadiene subunit.
Synthesizing of embodiment 2, difunctional inhibitor
With compound 3-(3-aminomethyl phenyl) amido-6-nitro-1,1-titanium dioxide benzo isothiazole (PKUMDL_AAL_101) is described the synthetic method of this type of difunctional inhibitor for example below.
Reagent and condition: (a) SOCl
2, DMF (cat.), Dioxane, 110 ℃, 1.5h; (b) NEt3, THF, rt, 4～6h.
Under the argon shield, in the round-bottomed flask of drying, add 0.23g (1mmol) 6-nitro-1,1; 3-trioxy--2,3-dihydro-benzisothiazole and 10mL 1,4-dioxane (Dioxane); after stirring is dissolved solid fully, add 0.36g (3mmol) sulfur oxychloride (SOCl
2) 0.5mL dimethyl formamide (DMF) solution, 110 ℃ of reflux 1.5h reaction is finished, decompression steams solvent and excess chlorination sulfoxide, namely gets intermediate 3-chloro-6-nitro-1,1-dioxo-benzisothiazole need not purifying and directly carries out next step reaction.In the round-bottomed flask that contains intermediate, add the 15mL tetrahydrofuran (THF) successively, 0.3g (3mmol) triethylamine and 0.11g (1mmol) meta-aminotoluene, stirring at room, TLC detects, and the 6h reaction is finished.Decompression steams tetrahydrofuran (THF), and residual solid gets light yellow crystal 0.22g, productive rate 70% with ethyl acetate/normal hexane recrystallization.
Adopt other benzo isothiazole compounds of method for preparing, other compound titles of being synthesized are as follows:
PKUMDL_AAL_102:3-anilino-6-nitro-1,1-titanium dioxide benzo isothiazole
PKUMDL_AAL_103:3-(4-p-methoxy-phenyl) amido-6-nitro-1,1-titanium dioxide benzo isothiazole
PKUMDL_AAL_104:3-(3,4-Dimethoxyphenyl) amido-6-nitro-1,1-titanium dioxide benzo isothiazole
PKUMDL_AAL_105:3-(1-naphthyl) amido-6-nitro-1,1-titanium dioxide benzo isothiazole
PKUMDL_AAL_106:3-(3-chloro-phenyl-) amido-6-nitro-1,1-titanium dioxide benzo isothiazole
PKUMDL_AAL_107:3-(3-bromophenyl) amido-6-nitro-1,1-titanium dioxide benzo isothiazole
Physical constant and the spectroscopic data of above-claimed cpd are listed table 1 in, wherein obtain on nuclear magnetic resonance spectrometer VarianMercury 400M (DMSO solvent, TMS reference)
1H NMR spectroscopic data obtains mass-spectrometric data at VG-ZAB-HS.Fusing point shows micro melting point apparatus mensuration with Tyke, Beijing X-4 of Instr Ltd. numeral, and the fusing point of this series compound all is higher than 300 ℃.
Table 1. target compound physical constant and spectroscopic data
---expression does not measure.
The external activity of embodiment 3, fluorescence spectrophotometry 5-LOX
The survey of spectrophotofluorimetry live principle be based on the reaction intermediate 5-HPETE of 5-LOX can be with fluorescent color-developing agent H
2The DCFDA oxidation generates the molecule DCF of high fluorescence activity, and its excitation wavelength is 500nm, and emission wavelength is 520nm.Survey when living, and the damping fluid of earlier 5-LOX enzyme adding survey being lived (50mM Tris-HCl, pH 7.5,0.2mM ATP, 0.1mM dithiothreitol (dithiothreitol (DTT), DTT), 0.1mM EDTA, 0.5mM CaCl
2) in, 25 ℃ of incubation 10min balances in 96 orifice plates.Add developer H
2DCFDA (final concentration is 10 μ M) and arachidonic acid AA substrate (final concentration is 25 μ M) initial action, and with the growing amount of fluorescence microplate reader monitoring fluorescence-causing substance DCF (excitation wavelength is 500nm, and emission wavelength is 520nm) over time.The initial rate method is adopted in experiment, and the fluorescence intensity velocity of variation when reacting to be less than 10% fluorescent color-developing agent is as the initial rate of reaction.All experiments are all finished under 25 ℃, and surveying live body is 220 μ l.
When measuring micromolecular compound to the restraining effect of enzyme, small molecules need dissolve with DMSO, and wants earlier and enzyme one adds the substrate initial action after arising from 25 ℃ of preincubate 10min again.When containing DMSO in the system, the final concentration of DMSO (v/v) is generally 5%, can not surpass 10%, otherwise can cause enzyme deactivation.The concentration of substrate A A is 25 μ M when measuring micromolecular inhibiting rate.
The external activity of embodiment 4, enzyme-linked immunosorbent assay mPGES-1
The enzymic activity of mPGES-1 is to transform the PGE2 that produces by quantitative assay mPGES-1 catalytic substrate PGH2 to characterize.The PGE2 amount that catalysis produces uses PGE2 enzyme-linked immunosorbent assay kit (Cayman) to measure.Measuring method is referring to the test kit specification sheets.Survey when living, earlier substrate PGH2 is joined in 96 orifice plates of 4 ℃ of constant temperature.Add 100 μ l enzyme initiation reactions.Behind 4 ℃ of reaction 1min, add 150 μ l stop buffers (50mM FeCl2 and 100mM citric acid) termination reaction.Solution uses the PGE2 enzyme-linked immunosorbent assay kit to measure the content of product P GE2 after diluting.It should be noted that unstable decomposition easily under the substrate PGH2 high temperature, will place 4 ℃ of isoperibols during use always.
When measuring micromolecular compound to the restraining effect of enzyme, small molecules need dissolve with DMSO, and wants earlier and enzyme one joins initial action in the substrate after arising from 4 ℃ of preincubate 15min again.When containing DMSO in the system, the final concentration of DMSO (v/v) is generally 2%, can not surpass 10%, otherwise can cause enzyme deactivation.The concentration of substrate PGH2 is 17 μ M when measuring micromolecular inhibiting rate.
The whole blood active testing of embodiment 5, compound
We measured compound people's whole blood (Human Whole Blood, HWB) in to the inhibition activity of two paths, the effect of agent in true system is inhibited.In people's whole blood active testing, by in human blood fresh, anti-freezing, adding the active or expression of relevant enzyme in the exogenous agents stimulation inflammation path, measure the amount of arachidonic acid metabolite, thereby characterize the activity of inhibitor.
One, compound is to the whole blood active testing of 5-LOX inhibition
The principle of 5-LOX whole blood active testing adopts calcium ion carrier A 23187 to prepare the whole blood inflammatory model in fresh, as to add antithrombotics human blood.The A23187 carrier is a kind of movability ionophore, and its function is divalent cations such as transportation calcium ion, magnesium ion.When the transportation positively charged ion enters cell, two hydrogen ions are brought to the extracellular, can stimulate the activity of 5-LOX path, connect immunosorbent by enzyme and measure (Enzyme-Linked Immunosorbnent Assay, ELISA) method is measured the content of the downstream metabolites leukotriene B4 (LTB4) of 5-LOX path, the LTB that adopts Cayman Chemical company to provide
4The ELISA test kit finish.
Survey when living, the blood flow volume according to need are handled adds an amount of heparin (heparin) in the EP pipe of sterilization in advance, smears evenly, and its final concentration in blood is 10～20U.I./ml.Collect the healthy volunteer's who does not take NSAIDs in two weeks vein whole blood, with the heparin anti-freezing, divide fast to install in the EP pipe of 1.5ml, every pipe 500 μ l have added the DMSO solution of 2 μ l inhibitor or 2 μ l DMSO in advance as V in the EP pipe
0, in 37 ℃, 150 rotational oscillations swing hatches 20min, adds 2 μ l A23187 (perhaps DMSO is as blank) again, hatch 30min in 37 ℃ of appropriateness concussions, be put into stopped reaction on ice, in 4 ℃, the centrifugal 5min of 3000g collects upper plasma, and every Guan Yueneng obtains blood plasma 200-250 μ l, carries out next step LTB
4The ELISA method of content is measured.If do not use blood plasma at once, Ying Yu-80 ℃ preservation.
Two, compound is to the whole blood active testing of mPGES-1 inhibition
The principle of mPGES-1 whole blood active testing adopts lipopolysaccharides to prepare the whole blood inflammatory model in fresh, as to add antithrombotics human blood.Lipopolysaccharides is a kind of macromole that is found in the intestinal bacteria adventitia, is a kind of intracellular toxin, can bring out strong immune response.Connect immunosorbent by enzyme and measure (Enzyme-LinkedImmunosorbnent Assay, ELISA) method is measured the content of the enzyme reaction product prostaglandin E2 (PGE2) of mPGES-1, and the ELISA test kit of the PGE2 that employing Cayman Chemical company provides is finished.
Survey when living, the blood flow volume according to need are handled adds an amount of heparin in the EP pipe of sterilization in advance, smears evenly, and its final concentration in blood is 10～20U.I./ml.Collect the healthy volunteer's who does not take NSAIDs in two weeks vein whole blood, with the heparin anti-freezing, divide fast with the volley of rifle fire to install in 96 orifice plates, every hole 100 μ l have added the DMSO solution of 1 μ l inhibitor or 1 μ l DMSO in advance as V in the EP pipe
0, in 37 ℃, 400 rotational oscillations swing hatches 15min, adds 2 μ l lipopolysaccharides (perhaps 40mM PBS+100mM NaCl damping fluid is as blank) again, hatches 24h in 37 ℃ of appropriateness concussions.Be put into stopped reaction on ice, in 4 ℃, the centrifugal 5min of 3000g collects upper plasma, and every Guan Yueneng obtains blood plasma 10-20 μ l, carries out the ELISA method of next step PGE2 content and measures.If do not use blood plasma at once, Ying Yu-80 ℃ preservation.
At synthetic 7 the 5-lipoxygenases of embodiment 2 and the difunctional inhibitor of benzo isothiazole of PGE synthetic enzyme, the enzyme that adopts embodiment 3,4,5 method to carry out 5-lipoxygenase and PGE synthetic enzyme live test and whole blood test, each compound carries out parallel testing three times, the results are shown in Table 2.
The active testing of table 2. compound
In the table 2, positive is the inhibitor of 5-lipoxygenase with reference to zileuton, and positive is the inhibitor of PGE synthetic enzyme with reference to MF63.
In this series, majority of compounds all keeps difunctional activity.The hydrophobic grouping that introduce the position between phenyl ring is all influential to two enzymes, and the effect of halogen and methyl is suitable, but the introducing of methoxyl group makes activity significantly reduce.When phenyl ring becomes naphthalene nucleus, two enzyme inhibition activities all are significantly increased, the vital role of hydrophobic grouping has been described.External two enzymes are all had the PKUMDL_AAL_105 of inhibition, do not measure whole blood and suppress active, may follow in whole blood influenced with other protein binding or dynamic behavior due to.
Live test and whole blood test result of above enzyme shows that compound of the present invention can suppress 5-lipoxygenase and PGE synthetic enzyme simultaneously, is the novel 5-lipoxygenase that do not appear in the newspapers and the difunctional inhibitor of PGE synthetic enzyme.Benzo isothiazole compound of the present invention or its pharmaceutical salts as effective constituent, are added the conventional medicine carrier, can or prevent the medicine of various inflammation for the preparation for the treatment of.
The pharmaceutical salts of benzo isothiazole compound of the present invention refers to pharmacy acceptable salt, the salt that forms with mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid for example, or the salt that forms with organic acids such as citric acid, succsinic acid, Citric Acid, acetic acid, tartrate, methylsulfonic acids.
The conventional medicine carrier refers to nontoxic solid-state, semi-solid state or liquid weighting agent, thinner, adjuvant, lapping or other pharmaceutical adjuncts.According to the known technology of this area, can pharmaceutical composition be made various formulations according to the needs of therapeutic purpose, route of administration.
Claims (11)
1. benzo isothiazole compound, general structure is as follows:
Wherein, R
1, R
2, R
3Identical or different, represent hydrogen, alkyl, alkoxy or halogen separately, perhaps R
2With R
1Or R
3Cheng Huan, Joint Representative's 1,3-butadiene subunit.
2. benzo isothiazole compound as claimed in claim 1 is characterized in that, described alkyl is the straight or branched alkyl of C1～C6; Described alkoxyl group is the straight or branched alkoxyl group of C1～C6.
3. benzo isothiazole compound as claimed in claim 2 is characterized in that, described alkyl is the straight or branched alkyl of C1～C3; Described alkoxyl group is the straight or branched alkoxyl group of C1～C3.
4. benzo isothiazole compound as claimed in claim 1, it is characterized in that, described benzo isothiazole compound is one of following compounds: 3-(3-aminomethyl phenyl) amido-6-nitro-1,1-titanium dioxide benzo isothiazole, 3-anilino-6-nitro-1,1-titanium dioxide benzo isothiazole, 3-(4-p-methoxy-phenyl) amido-6-nitro-1,1-titanium dioxide benzo isothiazole, 3-(3, the 4-Dimethoxyphenyl) amido-6-nitro-1,1-titanium dioxide benzo isothiazole, 3-(1-naphthyl) amido-6-nitro-1,1-titanium dioxide benzo isothiazole, 3-(3-chloro-phenyl-) amido-6-nitro-1,1-titanium dioxide benzo isothiazole and 3-(3-bromophenyl) amido-6-nitro-1,1-titanium dioxide benzo isothiazole.
5. the preparation method of the arbitrary described benzo isothiazole compound of claim 1～4, shown in the following reaction formula:
The nitro-1,1 of 6-shown in the formula I, 3-trioxy--2,3-dihydro-benzisothiazole is through the intermediate 3-chloro-6-nitro-1 shown in the chlorination reaction production II, 1-dioxo-benzisothiazole, the substituted aniline shown in this intermediate and the formula III reacts, and obtains the benzo isothiazole compound of formula IV; Wherein, R
1, R
2, R
3Identical or different, represent hydrogen, alkyl, alkoxy or halogen separately, perhaps R
2With R
1Or R
3Cheng Huan, Joint Representative's 1,3-butadiene subunit.
6. the arbitrary described benzo isothiazole compound of claim 1～4 is as the purposes of 5-LOX and mPGES-1 inhibitor.
7. the application of the arbitrary described benzo isothiazole compound of claim 1～4 in the medicine of preparation treatment or preventing inflammation.
8. a pharmaceutical composition contains the arbitrary described benzo isothiazole compound of claim 1～4 or its pharmaceutical salts, and contains pharmaceutical carrier.
9. pharmaceutical composition as claimed in claim 8 is characterized in that, described pharmaceutical salts is the salt that described benzo isothiazole compound and mineral acid form, and described mineral acid comprises hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid.
10. pharmaceutical composition as claimed in claim 8 is characterized in that, described pharmaceutical salts is the salt that described benzo isothiazole compound and organic acid form, and described organic acid comprises citric acid, succsinic acid, Citric Acid, acetic acid, tartrate, methylsulfonic acid.
11., it is characterized in that described pharmaceutical carrier comprises nontoxic solid-state, semi-solid state or liquid weighting agent, thinner, adjuvant, lapping as the arbitrary described pharmaceutical composition of claim 8～10.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085401A (en) * | 2015-08-17 | 2015-11-25 | 北京大学 | Hexahydroindazole 15-lipoxidase (15-LOX) activator and application thereof |
| CN108586294A (en) * | 2018-05-29 | 2018-09-28 | 王若锴 | A kind of carbamide derivative and its application in preventing inflammation |
| CN112480062A (en) * | 2020-12-14 | 2021-03-12 | 陕西中医药大学 | 5-lipoxygenase activating protein activity inhibitor and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085401A (en) * | 2015-08-17 | 2015-11-25 | 北京大学 | Hexahydroindazole 15-lipoxidase (15-LOX) activator and application thereof |
| CN108586294A (en) * | 2018-05-29 | 2018-09-28 | 王若锴 | A kind of carbamide derivative and its application in preventing inflammation |
| CN112480062A (en) * | 2020-12-14 | 2021-03-12 | 陕西中医药大学 | 5-lipoxygenase activating protein activity inhibitor and preparation method thereof |
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| Publication number | Publication date |
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| CN103254151B (en) | 2015-10-28 |
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