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5-lipoxygenase inhibitor and preparation method, medical composite and application thereof

A solvate, compound technology, applied in 5-lipoxygenase inhibitor, application in medicine, compound of general formula and the field of preparation thereof, can solve the problems of low bioavailability, methemoglobin and the like

Inactive Publication Date: 2010-03-31
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although many inhibitors about inhibiting 5-LOX have been reported so far, including compounds with hydroxyurea structural fragments, hydroxamate compounds, and compounds with aryl alcohol and aryl carboxylic acid fragments, etc., these compounds, Including zileuton, usually have serious side effects, such as hepatotoxicity, easy formation of methemoglobin, and low bioavailability
In recent years, people have a strong demand for effective and safe 5-LOX inhibitors, and a lot of efforts have been made in the development of 5-LOX inhibitors, but there are still no other safe and reliable 5-LOX inhibitors on the market

Method used

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  • 5-lipoxygenase inhibitor and preparation method, medical composite and application thereof
  • 5-lipoxygenase inhibitor and preparation method, medical composite and application thereof
  • 5-lipoxygenase inhibitor and preparation method, medical composite and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0089] The preparation of embodiment 12,6-dichloro-N-(4-methoxyphenyl) pyrimidin-4-amine

[0090] Dissolve 1g (5.5mmol) of 2,4,6-trichloropyrimidine in 25mL of absolute ethanol, add 0.64g (6.0mmol) of anhydrous sodium carbonate and 0.62g (6.6mmol) of p-methoxyaniline, stir and heat Reflux for 1.5 hours. After cooling to room temperature, 25 mL of water was added to precipitate a precipitate, which was washed with a large amount of water and dried in vacuum overnight to obtain a gray powder product. Pure product was obtained by recrystallization from absolute ethanol. Yield 90%. Mp 160-161°C; 1 H NMR (CDCl 3 ): δ3.84 (s, 3H), 6.36 (s, 1H), 6.96 (d, 2H), 7.2 (d, 2H), 7.37 (br, 1H); LRMS (EI) m / z 269 (M + ).

Embodiment 2

[0091] Example 2 6-Chloro-N 2 , N 4 - Preparation of two (4-methoxyphenyl) pyrimidine-2,4-diamine

[0092] Dissolve 0.27g (1mmol) of 2,6-dichloro-N-(4-methoxyphenyl)pyrimidin-4-amine in 25mL of dioxane solution, add 0.22g (2mmol) of anhydrous sodium carbonate and 3.3 mmol of p-methoxyaniline was heated to reflux for 48 hours, and the reaction was detected by TLC. Cool to room temperature, add water, extract with ethyl acetate (20mL×3), combine organic layers, MgSO 4 Dry, filter, and evaporate to dryness to obtain a residue, which is separated on a silica gel column to obtain the product.

Embodiment 3

[0093] Example 3 N 2 , N 4 - Preparation of bis(4-methoxyphenyl)-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine (1a)

[0094] Add 0.2g 6-chloro-N to a 50mL eggplant-shaped bottle 2 , N 4 - Bis(4-methoxyphenyl)pyrimidine-2,4-diamine and 10 mL of N-methylpiperazine, heated to reflux overnight. Cool to room temperature, add water, extract with ethyl acetate (20mL×3), combine the organic layers, and wash with water (20mL×1), saturated NaCl aqueous solution (20mL×1), MgSO 4 Dry, filter, and evaporate to dryness to obtain a residue. Esco flash preparative separation chromatography (PE / EA=4 / 1) purifies, obtains final product N 2 , N 4 - bis(4-methoxyphenyl)-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine. Yield: 83%. Mp 156-157°C; 1 H NMR (300Hz, DMSO-d 6 ): δ2.20(s, 3H), 3.36(m, 4H), 3.44(m, 4H), 3.71(s, 3H), 3.73(s, 3H), 5.39(s, 1H), 6.82(d, 2H), 6.85(d, 2H), 7.48(d, 2H), 7.58(d, 2H); LRMS(EI) m / z 420(M + ); HRMS(EI) m / z calculated value C 23 h 28 N 6 o 2 (M + )...

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Abstract

The invention provides a 5-lipoxygenase inhibitor and a preparation method, a medical composite and an application thereof. More specifically, the invention provides a compound shown in general formula (I) or acceptable salt, solvate or hydrate thereof in pharmacy. The invention also relates to a preparation method, medical composite and application of the compound. The biological activity experiment shows that the compound of the invention is effective 5-LOX small molecule inhibitor with novel structure. Therefore the compound is expected to be developed to be new powerful chemical entity forcuring diseases related to leukotriene.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a 5-lipoxygenase inhibitor used for treating diseases related to leukotrienes. More specifically, the present invention relates to a novel compound of general formula (I) with a pyrimidine structure capable of inhibiting 5-lipoxygenase and a preparation method thereof; the present invention also relates to pharmaceutical compositions comprising such compounds, and Application of the compound and its pharmaceutical composition in preparing medicines for preventing and treating diseases related to 5-lipoxygenase metabolic pathway. Background technique [0002] 5-Lipoxygenase (5-LOX) is a key enzyme in the process of arachidonic acid (AA) metabolism to produce biologically active leukotrienes (LTs). Leukotrienes can cause lung contraction, pulmonary mucus secretion, and increase vascular permeability. They are not only a powerful constrictor of coronary arteries, but also have th...

Claims

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Application Information

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IPC IPC(8): C07D239/50A61K31/5377A61P29/00A61P9/00
Inventor 柳红蒋华良周宇郑明月叶德举罗小民朱维良陈凯先
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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