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Inhibitor of mitogen protein kinase p38 and preparation method of inhibitor

A technology for protein kinases and inhibitors, applied in the field of inhibitors of mitogen protein kinase p38 and its preparation, can solve the problems of inconvenient use and high production costs, and achieve good practicability, low production costs and good economy The effect of benefits and social effects

Inactive Publication Date: 2014-03-26
WUXI ALLNATURE BIOLOGICAL SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these biologics have achieved great success, as macromolecular drugs, they have inherent huge defects, that is, they are expensive to produce and inconvenient to use (cannot be taken orally)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1 5-amino-6-phenylnicotinamide

[0021] In a 500 mL round bottom flask was added 6-hydroxynicotinic acid (13.90 g, 100 mmol), followed by glacial acetic acid (100 mL). Under stirring, fuming nitric acid (5 mL) was added dropwise into the reaction flask through a constant pressure dropping funnel. The reaction was heated to 60°C and maintained until the raw materials were consumed. The reaction liquid was cooled and poured into ice water, and the solid was collected by filtration. The crude product was purified by column chromatography to obtain the product 5-nitro-6-hydroxynicotinic acid (7.92g). MS: m / z=185 (M+H).

[0022] Add 5-nitro-6-hydroxynicotinic acid (7.90g) into a sealed tube containing phosphorus oxybromide (50mL), heat the system to 120°C and maintain it overnight, pour the reaction solution into ice water after cooling, and collect by filtration Solid, the crude product was purified by column chromatography to obtain the product 5-nitro-6-bromonic...

Embodiment 2

[0027] Example 2 5-amino-N-(4'-chlorophenyl)-6-phenylnicotinamide

[0028] In a 15 mL round bottom flask were added 5-nitro-6-phenylnicotinoyl chloride (0.13 g), dichloromethane (5 mL). 4-Chloroaniline (0.13 g) and Hunig's base were added to the reaction system. The reaction was stirred for 0.5h, the reaction solution was poured into ice water, extracted with ethyl acetate, the extract was washed with 0.1M dilute hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the product 5-nitro-N-(4 '-Chlorophenyl)-6-phenylnicotinamide (0.18g). MS: m / z = 355 (M+H).

[0029] 5-Nitro-N-(4'-chlorophenyl)-6-phenylnicotinamide (0.18g) was dissolved in ethyl acetate (20mL) and 10% Pd-C (25mg) was added, and the reaction was placed in hydrogenation In the device, hydrogenate at 60 psi pressure for 5h, remove the catalyst by filtration, and after the filtrate is concentrated, the crude product is purified by column chromatog...

Embodiment 3

[0030] Example 3 5-amino-N-phenyl-6-phenylnicotinamide

[0031]In a 15 mL round bottom flask were added 5-nitro-6-phenylnicotinoyl chloride (0.13 g), dichloromethane (5 mL). To the reaction was added aniline (0.10 g) and Hunig's base. The reaction was stirred for 0.5h, the reaction solution was poured into ice water, extracted with ethyl acetate, the extract was washed with 0.1M dilute hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the product 5-nitro-N-phenyl -6-Phenylnicotinamide (0.13g). MS: m / z = 320 (M+H).

[0032] 5-Nitro-N-phenyl-6-phenylnicotinamide (0.13g) was dissolved in ethyl acetate (20mL) and 10% Pd-C (25mg) was added, and the reaction was placed in a hydrogenation device at 60 psi pressure Hydrogenation at high temperature for 5h, removal of catalyst by filtration, concentration of the filtrate and purification of the crude product by column chromatography to obtain the product 5-amino-...

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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 [0001] The invention relates to the technical field of biomedicine, in particular to an inhibitor of mitogen protein kinase p38 and a preparation method thereof. Background technique [0002] TNF-α (Tumor Necrosis Factor α) is the main cytokine that causes inflammatory response, and it plays a vital role in the pathogenesis of rheumatoid arthritis, asthma and other diseases. In the past ten years, the research on TNF has made a breakthrough. Inhibition of the action of TNF using biological agents such as capacitative TNF receptors or TNF monoclonal antibodies has led to epoch-making treatments for diseases in the inflammatory field such as rheumatoid arthritis. Such drugs as Enbrel, Remicade, and Humira have an annual sales volume of more than 3 billion US dollars. [0003] The formation of TNF-α in vivo is regulated by a series of kinases. Mitogen activated protein kinase (mitogen activated protein kinase) p38 plays a very important role in the informatio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/82C07D213/81A61K31/455A61K31/4418A61P19/02A61P29/00
Inventor 龙霞吴俊军
Owner WUXI ALLNATURE BIOLOGICAL SCI & TECH CO LTD
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