Novel pyrazole 5-lipoxygenase small molecule inhibitors, preparation method, pharmaceutical composition and application thereof

A technology of compounds and mixtures, applied in the fields of 5-lipoxygenase inhibitors, drugs, compounds with pyrazole structure and their preparation, can solve the problems of low bioavailability and easy formation of methemoglobin

Inactive Publication Date: 2009-09-30
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, including compounds with hydroxyurea structural fragments, hydroxamate compounds, and compounds with aryl alcohol and aryl carboxylic acid fragments, etc., but these compounds , including zileuton, usually have serious side effects, such as hepatotoxicity, methemoglobin formation, 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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  • Novel pyrazole 5-lipoxygenase small molecule inhibitors, preparation method, pharmaceutical composition and application thereof
  • Novel pyrazole 5-lipoxygenase small molecule inhibitors, preparation method, pharmaceutical composition and application thereof
  • Novel pyrazole 5-lipoxygenase small molecule inhibitors, preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Preparation of N-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(4-sulfamoylphenyl)-5-phenyl-1H-pyrazole-3-amide (DC301)

[0117] 1.1 Preparation of 3,5-di-tert-butyl-4-hydroxyaniline

[0118] Dissolve 2,6-di-tert-butylphenol in 40 ml of n-hexane, and heat to 50°C, slowly add 17 ml of 30% nitric acid aqueous solution (about half an hour), dropwise, and the temperature of the reaction solution is maintained at 50-50°C. React overnight between 55 degrees. A yellow precipitate precipitated, was suction filtered, washed three times with n-hexane (10 ml×3), washed once with water (10 ml), and dried in vacuum to obtain the intermediate product 2,6-di-tert-butyl-4-nitrophenol. Yield: 95%; Melting point: 152-155°C. 1 HNMR (CDCl 3 ): δ 8.14(s, 2H), 5.94(s, 1H), 1.49(s, 18H); EI-MS m / z 251(M + ).

[0119] The intermediate product 2,6-di-tert-butyl-4-nitrophenol was dissolved in 20 ml of absolute ethanol, 2.0 mol of Sn and 4 ml of concentrated hydrochloric acid were added, and the rea...

Embodiment 2

[0132] The preparation of N-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(4-sulfamoylphenyl)-5-(p-tolyl)-1H-pyrazole-3-amide ( DC315)

[0133] Acetophenone is replaced by 4-methylacetophenone, and all the other required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product N-(3,5-di-tert-butyl-4-hydroxyphenyl)-1 -(4-sulfamoylphenyl)-5-(p-tolyl)-1H-pyrazole-3-amide. Melting point: 184-187°C; 1 HNMR (CDCl 3 ): δ 1.46(s, 18H), 2.38(s, 3H), 4.94(br, 2H), 5.12(s, 1H), 7.09(s, 1H), 7.13(dd, 2H), 7.18(dd, 2H ), 7.52 (dd, 2H), 7.54 (d, 2H), 7.98 (dd, 2H), 8.58 (s, 1H); LRMS (EI) m / z 560 (M + ); HRMS(EI) m / z calculated value C 31 h 36 N 4 o 4 S(M + )560.2457, the measured value is 560.2441.

Embodiment 3

[0135] N-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(4-sulfamoylphenyl)-5-(p-methoxyphenyl)-1H-pyrazole-3-amide Preparation of (DC316)

[0136] Acetophenone is replaced with 4-methoxyacetophenone, and all the other required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product N-(3,5-di-tert-butyl-4-hydroxyphenyl)- 1-(4-sulfamoylphenyl)-5-(p-methoxyphenyl)-1H-pyrazole-3-amide. Melting point: 219-221°C; 1 H NMR (DMSO): δ 1.40 (s, 18H), 3.77 (s, 3H), 7.00 (dd, 2H), 7.07 (s, 1H), 7.27 (dd 2H), 7.63 (m, 4H), 7.90 ( dd, 2H), 9.90 (s, 1H); LRMS (EI) m / z 576 (M + ); HRMS(EI) m / z calcd C 31 h 36 N 4 o 5 S(M + )576.2406, found 576.2410.

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Abstract

The invention relates to novel pyrazole 5-lipoxygenase small molecule inhibitors shown in a general formula (I), enantiomers, diastereoisomers, racemic modifications, mixtures, and pharmaceutically acceptable salts thereof. The invention also relates to a method for preparing the pyrazole compounds. In addition, the pyrazole compounds have better prevention and treatment effect on diseases related to leukotriene produced by an experimental 5-lipoxygenase (5-LOX) metabolic pathway. The biological experimental activity shows that the compounds are effective 5-LOX small molecule inhibitors with novel structures. Therefore, the compounds expect to be developed into novel powerful chemical entities for treating diseases such as inflammation, cancer, asthma and atherosclerosis related to 5-LOX and the 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 (I) with a pyrazole structure capable of inhibiting 5-lipoxygenase and a preparation method thereof; the present invention also relates to pharmaceutical compositions comprising such compounds, and the compounds Application of the invention 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 the func...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/12C07D231/14A61K31/415A61K31/4155A61P11/14A61P9/10A61P35/00A61P29/00A61P19/10
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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