CN102633715B - Inhibitor of mitogen protein kinase p38 and preparation method of inhibitor - Google Patents
Inhibitor of mitogen protein kinase p38 and preparation method of inhibitor Download PDFInfo
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- CN102633715B CN102633715B CN201210080000.8A CN201210080000A CN102633715B CN 102633715 B CN102633715 B CN 102633715B CN 201210080000 A CN201210080000 A CN 201210080000A CN 102633715 B CN102633715 B CN 102633715B
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Abstract
The invention discloses an inhibitor of mitogen protein kinase p38 as well as a preparation method and application of the inhibitor. The inhibitor is an amino nicotinamide compound or an amino pyrazinamide compound. The preparation method mainly comprises the following steps: nitrifying 6-hydroxyl nicotinic acid to generate 5-nitro-6-hydroxyl nicotinic acid; treating 5-nitro-6-hydroxyl nicotinic acid with phosphorus oxybromide so as to convert 5-nitro-6-hydroxyl nicotinic acid into 5-nitro-6-bromonicotinic acid; carrying out Suzuki coupling reaction on 5-nitro-6-bromonicotinic acid to generate 5-nitro-6-aryl nicotinic acid; reacting 5-nitro-6-aryl nicotinic acid with oxalyl chloride to obtain 5-nitro-6-aryl nicotinamide; and carrying out hydrogenation reduction on a nitro group to obtain 5-amino-6-aryl nicotinamide. According to the invention, the inhibitor of the mitogen protein kinase p38 is a small molecular inhibitor which can effectively inhibit the synthesis of in vivo TNF (tumor necrosis factor)-alpha, has the curative effect of a large molecular inhibitor on diseases, is low in production cost, can be orally taken so that a patient can conveniently use the inhibitor, has good practicability, and can generate good economic and social effects.
Description
Technical field
The present invention relates to biological medicine technology field, be specifically related to inhibitor of a kind of mitogen protein kinase p38 and preparation method thereof.
Background technology
TNF-α (tumor necrosis factor alpha) is the major cytokine of reaction of causing inflammation, and it is in rheumatoid arthritis, and effect is breathed heavily etc. in the pathogenesis of disease and played vital effect.Past ten over several years, has been obtained breakthrough progress to the research of TNF.Applying biological preparation has caused field of inflammation disease as the epoch-making methods for the treatment of of rheumatoid arthritis as the effect that the TNF acceptor of capacitive or TNF monoclonal antibody suppress TNF.Such medicine is as Enbrel, Remicade, and Humira annual turnover is all more than 3,000,000,000 dollars.
Tumor necrosis factor alpha formation is in vivo subject to a series of kinase whose regulation and control.Mitogen protein kinase (mitogen activated protein kinase) p38 plays a very important role in the synthetic TNF-α of cell and other help the information exchanging process of inflammatory cytokines.Suppress p38 and can stop cell generation TNF-α to help inflammatory cytokines with other, thereby rheumatoid arthritis is played to therapeutic action.The regulatory mechanism of p38 is: when cell is upset, thus the tyrosine phosphorylation that p38 is activated to downstream, thus cause that the chain reaction in downstream drives synthetic a series of cytokine to comprise TNF.
Experiment confirms the inhibition of p38 can block in the body of TNF synthetic, has at present the micromolecular inhibitor of some p38 respectively in the clinical trial of different steps.These tests have proved that p38 inhibitor can treat some inflammatory diseases effectively as rheumatoid arthritis etc.
Rheumatoid arthritis is a kind of general systemic autoimmune diseases, and it affects the population in the whole world 1%, and sickness rate is at the speed increase with annual 0.04%.Proved cytokine (cytokines) as the excessive formation of TNF-α be the major cause that causes rheumatoid arthritis, TNF-α stimulates other help the synthetic of inflammatory cytokines (proinflammatory cytokines) and lure the release of matrix metalloproteinase (MMP) and attack osteoarthrosis.Macromole medicine can suppress TNF-α as Enbrel, Humira, Remicade, thereby has obtained the therapeutic action to rheumatoid arthritis.Although these biotechnological formulations have been obtained huge success, yet they are as macromole medicine, have inherent great drawback, are that production cost is expensive, use not easily (cannot be oral).Therefore we will develop micromolecular tnf inhibitor as anti-inflammatory new drug, this class medicine is expected to the curative effect that keeps macromole tnf inhibitor to have disease, thereby it greatly reduces patient and social burden by production cost is significantly reduced, our the small molecules medicine of exploitation will have oral curative effect simultaneously, thereby make patient easy to use.This low cost and convenience will dominate the market rapidly our new drug.
Mitogen protein kinase (mitogen activated protein kinase) p38 plays a very important role in the synthetic TNF-α of cell and other help the information exchanging process of inflammatory cytokines, suppresses p38 and can stop cell to produce TNF-α and other helps inflammatory cytokines.Testing confirmation can block in the body of TNF-α synthetic to the inhibition of p38.Our target is a kind of novel p38 inhibitor of invention to stop the synthetic of TNF-α in body, thus find a kind of can be as macromolecular drug if Enbrel, Humira, Remicade etc. be to the medicative small molecules new drug of rheumatoid arthritis.
Summary of the invention
Goal of the invention: for the deficiencies in the prior art, the object of this invention is to provide a kind of inhibitor of mitogen protein kinase p38, to realize stoping the synthetic of TNF-α in body to stop.Another object of the present invention is to provide the preparation method of the inhibitor of above-mentioned mitogen protein kinase p38.
Technical scheme: in order to realize foregoing invention object, the technical solution used in the present invention is:
An inhibitor for mitogen protein kinase p38, is aminonicotinamide class, amino Isonicotinamide compounds, and general structure comprises general formula I (aminonicotinamide class) and the amino Isonicotinamide class of general formula I I();
The structure of general formula I, II is:
In formula, R
1, R
2represent H, halogen, C
nh
2n+1, CF
3, carboxyl, hydroxyl, C
nh
2nnH, OC
nh
2n+1; R
3represent C
nh
2n+1nH, amino, hydroxyl, NHR (R represents aryl), aryl, the integer of n=1 ~ 10.
The preparation method of aminonicotinamide class is: 6-hydroxy niacin is through nitrated generation 5-nitro-6-hydroxy niacin, 5-nitro-6-hydroxy niacin is processed and is converted into 5-nitro-6-bromo-nicotinic acid again through Suzuki linked reaction generation 5-nitro-6-aryl nicotinic acid through tribromo oxygen phosphorus, 5-nitro-6-aryl nicotinic acid reacts with oxalyl chloride and generates 5-nitro-6-aryl nicotinoyl chlorine, 5-nitro-6-aryl nicotinoyl chlorine reacts and obtains 5-nitro-6-aryl niacinamide with corresponding amine, then obtains 5-amino-6-aryl niacinamide through hydro-reduction nitro.
The preparation method of amino Isonicotinamide class: 2-hydroxy-isonicotinic acid is through nitrated generation 5-nitro-2-hydroxy-isonicotinic acid, 5-nitro-2-hydroxy-isonicotinic acid is processed and is converted into 5-nitro-2-bromine isonicotinic acid again through Suzuki linked reaction generation 5-nitro-2-aryl γ-picolinic acid through tribromo oxygen phosphorus, 5-nitro-2-aryl γ-picolinic acid reacts with oxalyl chloride and generates the different nicotinoyl chlorine of 5-nitro-2-aryl, the different nicotinoyl chlorine of 5-nitro-2-aryl reacts and obtains 5-nitro-2-aryl Isonicotinamide with corresponding amine, then obtains 5-amino-2-aryl Isonicotinamide through hydro-reduction nitro.
Application in the synthetic medicine of the inhibitor of mitogen protein kinase p38 TNF-α in for the preparation of prevention body.
The inhibitor of mitogen protein kinase p38 is in the application for the preparation of in treatment medicine for treating rheumatoid arthritis.
The inhibitor of mitogen protein kinase p38 is in the application for the preparation of in treatment anti-inflammatory drug.
Beneficial effect: the inhibitor of mitogen protein kinase p38 of the present invention, it is a kind of micromolecular inhibitor, can effectively stop synthesizing of the interior TNF-α of body, there is the curative effect that macromole tnf inhibitor has disease, production cost is low, can realize orally, thereby allow, patient is easy to use has a good practicality, can produce good economic benefit and social effect.
Embodiment
Below in conjunction with specific embodiment, the present invention will be further explained.
Embodiment 1 5-amino-6-phenyl niacinamide
In 500mL round-bottomed flask, add 6-hydroxy niacin (13.90g, 100mmol), then add Glacial acetic acid (100mL).Under agitation, nitrosonitric acid (5mL) is added drop-wise in reaction flask by constant pressure funnel.Reaction is heated to 60 ℃ and to be maintained to raw material consumption complete, after reaction solution is cooling, pour in frozen water, solid collected by filtration, thick product after purifying by column chromatography product 5-nitro-6-hydroxy niacin (7.92g), MS:m/z=185(M+H).
5-nitro-6-hydroxy niacin (7.90g) is joined in the tube sealing that contains tribromo oxygen phosphorus (50mL), system is heated to 120 ℃ and maintain and spend the night, after reaction solution is cooling, pour in frozen water, solid collected by filtration, thick product obtains product 5-nitro-6-bromo-nicotinic acid (8.82 g) after purifying by column chromatography, MS:m/z=248(M+H).
In 100mL round-bottomed flask, add 5-nitro-6-bromo-nicotinic acid (2.48g), phenylo boric acid (1.25g), Isosorbide-5-Nitrae-dioxane (30mL), aqueous sodium carbonate (2M, 15mL).Mixed system passes through, after deaeration in condenser, nitrogen protection, to add tetrakis triphenylphosphine palladium (80mg).Reaction is heated to 90 ℃ and to be maintained to raw material consumption complete, after reaction solution is concentrated in cooling falling back, solid collected by filtration, thick product after purifying by column chromatography product 5-nitro-6-benzene nicotinic acid (2.05g), MS:m/z=245(M+H).
In 50mL round-bottomed flask, add 5-nitro-6-benzene nicotinic acid (2.05g), oxalyl chloride (20mL), DMF(1 drips), 3h is stirred in reaction, after reaction solution is cooling after concentrating, pours in frozen water, and solid collected by filtration obtains product 5-nitro-6-benzene nicotinoyl chlorine (2.25g).
In the 15mL round-bottomed flask that fills ammoniacal liquor (5mL), add 5-nitro-6-benzene nicotinoyl chlorine (0.26g), 0.5h is stirred in reaction, reaction solution is poured in frozen water, with 1M sodium hydroxide solution, regulates pH to 12, and solid collected by filtration obtains product 5-nitro-6-benzene niacinamide (0.15g).MS：m/z=244（M+H）。
5-nitro-6-benzene niacinamide (0.15g) is dissolved in ethyl acetate (20mL) and adds 10%Pd-C (25mg), reaction is placed in hydrogenation apparatus hydrogenation 5h under 60 psi pressure, filter and remove catalyzer, after filtrate is concentrated, thick product obtains product 5-amino-6-benzene niacinamide (95mg) after purifying by column chromatography, MS:m/z=214(M+H).
Embodiment 2 5-amino-N-(4 '-chloro-phenyl-)-6-phenyl niacinamide
In 15mL round-bottomed flask, add 5-nitro-6-benzene nicotinoyl chlorine (0.13g), methylene dichloride (5mL).In reaction system, add 4-chloroaniline (0.13g) and Hunig ' s alkali.0.5h is stirred in reaction, reaction solution is poured in frozen water, ethyl acetate extraction, extraction liquid after 0.1M dilute hydrochloric acid is washed, saturated common salt washing, anhydrous sodium sulfate drying, filtering and concentrating obtain product 5-nitro-N-(4 '-chloro-phenyl-)-6-phenyl niacinamide (0.18g).MS：m/z=355（M+H）。
5-nitro-N-(4 '-chloro-phenyl-)-6-phenyl niacinamide (0.18g) is dissolved in ethyl acetate (20mL) and adds 10%Pd-C (25mg), reaction is placed in hydrogenation apparatus hydrogenation 5h under 60 psi pressure, filter and remove catalyzer, after filtrate is concentrated, thick product obtains product 5-amino-N-(4 '-chloro-phenyl-)-6-phenyl niacinamide (135mg) after purifying by column chromatography, MS:m/z=325(M+H).
Embodiment 3 5-amino-N-phenyl-6-phenyl niacinamide
In 15mL round-bottomed flask, add 5-nitro-6-benzene nicotinoyl chlorine (0.13 g), methylene dichloride (5mL).In reaction system, add aniline (0.10g) and Hunig ' s alkali.0.5h is stirred in reaction, and reaction solution is poured in frozen water, ethyl acetate extraction, extraction liquid after 0.1M dilute hydrochloric acid is washed, saturated common salt washing, anhydrous sodium sulfate drying, filtering and concentrating obtain product 5-nitro-N-phenyl-6-phenyl niacinamide (0.13g).MS：m/z=320（M+H）。
5-nitro-N-phenyl-6-phenyl niacinamide (0.13g) is dissolved in ethyl acetate (20mL) and adds 10%Pd-C (25mg), reaction is placed in hydrogenation apparatus hydrogenation 5h under 60 psi pressure, filter and remove catalyzer, after filtrate is concentrated, thick product obtains product 5-amino-N-phenyl-6-phenyl niacinamide (105mg) after purifying by column chromatography, MS:m/z=290(M+H).
Embodiment 4 3-amino-2-phenyl Isonicotinamides
In 500mL round-bottomed flask, add 2-hydroxy-isonicotinic acid (13.90g, 100mmol), then add Glacial acetic acid (100mL).Under agitation, nitrosonitric acid (5mL) is added drop-wise in reaction flask by constant pressure funnel.Reaction is heated to 60 ℃ and to be maintained to raw material consumption complete, after reaction solution is cooling, pour in frozen water, solid collected by filtration, thick product after purifying by column chromatography product 3-nitro-2-hydroxy-isonicotinic acid (2.02g), MS:m/z=185(M+H).
3-nitro-2-hydroxy-isonicotinic acid (2.02g) joins in the tube sealing that contains tribromo oxygen phosphorus (50mL), system is heated to 120 ℃ and maintain and spend the night, after reaction solution is cooling, pour in frozen water, solid collected by filtration, thick product obtains product 3-nitro-2-bromine isonicotinic acid (2.32g) after purifying by column chromatography, MS:m/z=248(M+H).
In 100mL round-bottomed flask, add 3-nitro-2-bromine isonicotinic acid (1.32g), phenylo boric acid, Isosorbide-5-Nitrae-dioxane, aqueous sodium carbonate.Mixed system passes through, after deaeration in condenser, nitrogen protection, to add tetrakis triphenylphosphine palladium (40mg).Reaction is heated to 90 ℃ and to be maintained to raw material consumption complete, after reaction solution is concentrated in cooling falling back, solid collected by filtration, thick product after purifying by column chromatography product 3-nitro-2-benzene γ-picolinic acid (1.01g), MS:m/z=245(M+H).
In 50mL round-bottomed flask, add 3-nitro-2-benzene γ-picolinic acid (1.01g), oxalyl chloride (20mL), DMF(1 to drip), 3h is stirred in reaction, after cooling after reaction solution is concentrated, pour in frozen water, solid collected by filtration obtains the different nicotinoyl chlorine of product 3-nitro-2-benzene (1.05g).
In the 15mL round-bottomed flask that fills ammoniacal liquor (5mL), add the different nicotinoyl chlorine of 3-nitro-2-benzene (0.16g), 0.5h is stirred in reaction, reaction solution is poured in frozen water, with 1M sodium hydroxide solution, regulates pH to 12, and solid collected by filtration obtains product 3-nitro-2-benzene Isonicotinamide (0.11g).MS：m/z=244（M+H）。
3-nitro-2-benzene Isonicotinamide (0.11g) is dissolved in ethyl acetate (20mL) and adds 10%Pd-C (25mg), reaction is placed in hydrogenation apparatus hydrogenation 5h under 60 psi pressure, filter and remove catalyzer, after filtrate is concentrated, thick product obtains product 3-amino-2-benzene Isonicotinamide (76mg) after purifying by column chromatography, MS:m/z=214(M+H).
Embodiment 5
As the biological activity test of embodiment 1 ~ 4 gained compound by below, to detect the inhibition that their generate p38 kinases and TNF active, and experimental result shows, the compound shown in general formula I, II to kinase whose the inhibitions activity of p38 at IC
50between=1 nM ~ 20uM, the inhibition activity that TNF is generated is at IC
50between=10 nM ~ 40uM.
The test of p38 kinase inhibiting activity
Test is carried out in the 96-orifice plate at the bottom of V-shape, and enzyme, substrate (myelin basic protein and Triphosaden), test compound are dissolved in respectively (50 mM Tris pH 7.5,10 mM MgCl in buffered soln
2, 50 mM NaCl and 1 mM DTT).P38 kinases is first incubated in advance 10min with test compound before adding substrate, and reaction is carried out 45min in 25 ℃ of environment, then by adding 5mL 0.5M EDTA cancellation.Reaction mixture sucks the filtration unit of prewetting with Skatron Micro96 Cell Harvester (Skatron), and rinses with PBS damping fluid.Filter cake is by microwave drying 1min and MeltilLex A scintillation wax(Wallac) process, then use Microbeta scintillation counter Model 1450(Wallac) metering.
To the synthetic inhibition test of lipopolysaccharides (LPS) induction TNF
Human body monocyte THP-1 cell, preserving containing in RPMI 1640 substratum of 10% foetal calf serum, adds such cell sample (the every 80mL of 40,000 cell), and then adds test compound (10mL) in flat 96-orifice plate.Finally add LPS(10mL/well) and allow it reach the concentration of 1ug/mL.System is at 37 ℃ and 5%CO
2under environment, hatching is spent the night.Take out supernatant liquor and measure through ELISA.
Claims (4)
1. an inhibitor for mitogen protein kinase p38, is characterized in that: be 5-amino-6-phenyl niacinamide, 5-amino-N-(4 '-chloro-phenyl-)-6-phenyl niacinamide and 5-amino-N-phenyl-6-phenyl niacinamide.
2. the application in the synthetic medicine of the inhibitor of mitogen protein kinase p38 claimed in claim 1 TNF-α in for the preparation of prevention body.
3. the inhibitor of mitogen protein kinase p38 claimed in claim 1 is in the application for the preparation of in treatment medicine for treating rheumatoid arthritis.
4. the inhibitor of mitogen protein kinase p38 claimed in claim 1 is in the application for the preparation of in treatment anti-inflammatory drug.
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| CN112441970A (en) * | 2019-09-04 | 2021-03-05 | 天津医科大学 | 2, 5-disubstituted-3-aminopyridine compound and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4920119A (en) * | 1986-12-12 | 1990-04-24 | Hoffmann-La Roche Inc. | Triazine derivatives |
| CN1633416A (en) * | 2002-02-12 | 2005-06-29 | 史密丝克莱恩比彻姆公司 | Nicotinamide derivates useful as p38 inhibitors |
| CN101500567A (en) * | 2006-06-16 | 2009-08-05 | 史密丝克莱恩比彻姆公司 | Use of a P38 kinase inhibitor for treating psychiatric disorders |
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2012
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4920119A (en) * | 1986-12-12 | 1990-04-24 | Hoffmann-La Roche Inc. | Triazine derivatives |
| CN1633416A (en) * | 2002-02-12 | 2005-06-29 | 史密丝克莱恩比彻姆公司 | Nicotinamide derivates useful as p38 inhibitors |
| CN101500567A (en) * | 2006-06-16 | 2009-08-05 | 史密丝克莱恩比彻姆公司 | Use of a P38 kinase inhibitor for treating psychiatric disorders |
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