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Carboxylic acid derivative and application of carboxylic acid derivative serving as FXR (farnesoid X receptor) antagonist

A solvent and drug technology, applied in the field of new drug design and synthesis, can solve the problem of not being able to improve the plasma lipid density of patients with high cholesterol

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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  • Carboxylic acid derivative and application of carboxylic acid derivative serving as FXR (farnesoid X receptor) antagonist
  • Carboxylic acid derivative and application of carboxylic acid derivative serving as FXR (farnesoid X receptor) antagonist
  • Carboxylic acid derivative and application of carboxylic acid derivative serving as FXR (farnesoid X receptor) antagonist

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1: Preparation of compound 2-methyl-2-(4-(4-chlorobenzoyl)-phenoxy)-propionyl chloride shown in formula (III)

[0041]

[0042] Dissolve 31.8 g of 2-methyl-2-(4-(4-chlorobenzoyl)-phenoxy)-propionic acid in 200 mL of dichloromethane, add 1 mL of N,N-dimethylformamide and stir, Add 19.0 g of oxalyl chloride dropwise at 0°C, react at room temperature for 3 hours, spin out dichloromethane to obtain 2-methyl-2-(4-(4-chlorobenzoyl)-phenoxy)-propionyl chloride 30.8g, yield 91.4%.

Embodiment 2

[0043] Embodiment 2: the preparation of compound 1

[0044]

[0045] Dissolve 3.37g of 2-methyl-2-(4-(4-chlorobenzoyl)-phenoxy)-propionyl chloride in 25mL of 1,4-dioxane for later use, and 1.38g of p-hydroxybenzoic acid Add to 1,4-dioxane:water / 1:1 20mL mixed solvent, add 10mL 2N sodium hydroxide at 0°C, stir for 30 minutes, then add the reserved solution dropwise at 0°C, Stirring was continued for 10 hours, acidified, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and column chromatographed to obtain 3.51 g of the target compound with a yield of 80.1%. mp:183.1-185.2℃,ESI-MS m / z:437[M-H] + ,439[M+H] + . 1 H NMR (400MHz, DMSO) δ13.08(s, 1H), 8.01(d, J=8.4Hz, 2H), 7.80(d, J=8.4Hz, 2H), 7.74(d, J=8.4Hz, 2H ), 7.63(d, J=8.4Hz, 2H), 7.29(d, J=8.4Hz, 2H), 7.09(d, J=8.4Hz, 2H), 1.82(d, 6H).

Embodiment 3

[0046] Embodiment 3: the preparation of compound 2

[0047]

[0048] Dissolve 3.37g of 2-methyl-2-(4-(4-chlorobenzoyl)-phenoxy)-propionyl chloride in 25mL of 1,4-dioxane for later use, and 1.37g of p-aminobenzoic acid Add to 1,4-dioxane:water / 1:1 20mL mixed solvent, add 10mL 2N sodium hydroxide at 0°C, stir for 30 minutes, then add the reserved solution dropwise at 0°C, Stirring was continued for 10 hours, acidified, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to column chromatography to obtain 3.78 g of the target compound with a yield of 86.3%. ESI-MSm / z:436[M-H] + . 1 H NMR (400MHz, DMSO) δ10.33 (s, 1H), 7.87 (d, J = 8.4Hz, 2H), 7.79 (d, J = 8.4Hz, 2H), 7.74–7.68 (m, 4H), 7.59 (d,J=8.4Hz,2H),7.03(d,J=8.4Hz,2H),1.65(s,6H).

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Abstract

The invention relates to preparation of carboxylic acid derivatives and application of the carboxylic acid derivatives serving as an FXR (farnesoid X receptor) antagonist and particularly provides a compound shown as a formula (I), or a pharmaceutically acceptable salt of the compound and a preparation method of the compound. In the formula (I) as shown in the specification, R1 is selected from hydrogen, methyl, methoxyl, halogen, nitryl and carboxyl; X is selected from NH or O; n1 is 0 or 1; n2 is 0 or 1; R1 and a radical as shown in the specification are positioned at any substitution positions of a benzene ring. The compound shown as the formula (I) or the pharmaceutically acceptable salt thereof has a pharmacological effect of blood fat reduction and can be used as the FXR antagonist.

Description

technical field [0001] The invention belongs to the field of new drug design and synthesis, and specifically relates to a novel carboxylic acid 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 ...

Claims

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Application Information

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IPC IPC(8): C07C235/16C07C231/02C07C69/712C07C67/08A61K31/196A61K31/216A61P3/06
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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