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Gemfibrozil oxime derivative and its use as FXR antagonist

An alcohol solvent and drug technology, applied in the field of FXR antagonist, its preparation, gemfibrozil oxime derivatives, can solve the problem of not being able to improve the plasma lipid density of hypercholesterolemic patients and the like

Active Publication Date: 2017-03-08
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the natural product GS is a highly effective antagonist of FXR, which can reduce the levels of low-density lipoprotein (LDL) and triglyceride (TG) in mice but cannot improve the plasma lipid density of patients with hypercholesterolemia

Method used

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  • Gemfibrozil oxime derivative and its use as FXR antagonist
  • Gemfibrozil oxime derivative and its use as FXR antagonist
  • Gemfibrozil oxime derivative and its use as FXR antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1: the preparation of intermediate α-bromo p-hydroxyacetophenone

[0054] CuBr 2 (4.47g, 20.0mmol) was added to a mixture of ethyl acetate and chloroform (30mL, EA:CHCl 3 The volume ratio is 1:1), stirring at 80°C for 0.5h, then cooling down to 40°C, then adding p-hydroxyacetophenone (1.36g, 10.0mmol) in ethyl acetate solution (15mL) dropwise to the above solution, dropwise After the addition, stir at 80°C for 5 h, add activated carbon for decolorization, and suction filter while hot, spin out the solvent and extract with ethyl acetate (25mL×3), wash the organic phase with water, dry over anhydrous sodium sulfate, and filter the filtrate through silica gel Separation and purification by column chromatography yielded 1.73 g of the intermediate α-bromo-p-hydroxyacetophenone, ESI-MS m / z: 216[M+H] + .

[0055] Preparation of intermediates α-bromo-3,5-dihydroxyacetophenone, α-bromo-3-fluoro-4-hydroxyacetophenone, α-bromo-3-nitro-4-hydroxyacetophenone by the sam...

Embodiment 2

[0056] Example 2: Preparation of intermediate 2-(4-hydroxyphenyl)-2-oxoethyl-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid

[0057] Gemfibrozil (2.50g, 10.0mmol) and K 2 CO 3 (1.37g, 10.0mmol) was added to tetrahydrofuran (30mL) and stirred at room temperature for 0.5h, and a tetrahydrofuran solution (10mL) of α-bromo-p-hydroxyacetophenone (2.15g, 10.0mmol) was added dropwise to the stirred solution, and continued Stir for 12h. The solvent was spun out, acidified with dilute hydrochloric acid, extracted by adding ethyl acetate (25mL×3), the organic phase was washed with water, dried over anhydrous sodium sulfate, and the filtrate was separated and purified by silica gel column chromatography after suction filtration to obtain the intermediate 2-(4- Hydroxyphenyl)-2-oxoethyl-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid 3.21g, ESI-MS m / z: 385[M+ H] + .

[0058] Prepare intermediates 2-(3,5-dihydroxyphenyl)-2-oxoethyl-5-(2,5-dimethylphenoxy)2,2-dimethylpentanoic a...

Embodiment 3

[0059] Example 3: Preparation of intermediate 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanethioic acid

[0060] Dissolve CDI (10.0mmol) and 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid (10.0mmol) in DMF (20mL), stir at room temperature for 1h, and then pass through H 2 S reaction 3h. Add water (100mL) and ethyl acetate (30mL×3) for extraction, and obtain the intermediate 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanethioic acid by column chromatography ,

[0061] 2.41gMS(ESI):m / z=367[M+H] + .

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Abstract

The invention relates to a gemfibrozil oxime derivative and its use as an FXR antagonist. The invention provides a compound shown in the formula (I) or its pharmaceutically acceptable salt and a preparation method thereof. In the formula, R1 represents hydrogen, hydroxyl, methyl, methoxyl, halogen, or a nitro group, R2 represents hydrogen, hydroxyl, methyl, trifluoromethyl or halogen, R3 represents hydrogen, hydroxyl, methyl, methoxyl, halogen or a nitro group, R4 represents hydrogen or methyl, R5 represents hydrogen or methyl, R6 represents hydrogen or methyl, and X represents NH, O or S. In addition, the compound shown in the formula (I) or its pharmaceutically acceptable salt has pharmacological effects of reducing blood fat and is a FXR antagonist.

Description

technical field [0001] The invention belongs to the field of new drug design and synthesis, and in particular relates to a gemfibrozil oxime derivative, its preparation method and its application as an FXR antagonist. Background technique [0002] Cardiovascular and cerebrovascular diseases are currently one of the most serious diseases that endanger human life and health. They are common and frequently-occurring diseases of middle-aged and elderly people, and rank first in morbidity and mortality in many countries. Atherosclerosis is the basis of many cardiovascular and cerebrovascular diseases. A large number of experimental and clinical data prove that atherosclerosis is closely related to abnormal blood lipid metabolism. Therefore, blood lipid regulation has become an important field in the current research of this type of new drug. [0003] Through prospective, random and controlled clinical studies, it has been proved that some statins can reduce the occurrence of ath...

Claims

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Application Information

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IPC IPC(8): C07C251/48C07C249/08C07C327/30A61K31/265A61K31/216A61K31/165A61P3/06
Inventor 年四昀王国平甘侠顾建辉邓轶芳刘全海
Owner SHANGHAI INST OF PHARMA IND
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