Indole derivative as well as preparation method and application thereof

A technology of indole derivatives and derivatives, applied in the field of medicine, can solve problems such as cardiovascular toxicity, liver and kidney damage, and achieve the effect of reducing toxicity

Active Publication Date: 2021-06-22
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, Resinade has cardiovascular toxicity and can cause liver and kidney damage
So far, no xanthine oxidase and URAT1 dual-target inhibitors have been marketed, so the development of highly efficient and low-toxic xanthine oxidase, URAT1 inhibitors and their dual-target inhibitors has good application prospects

Method used

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  • Indole derivative as well as preparation method and application thereof
  • Indole derivative as well as preparation method and application thereof
  • Indole derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] The preparation process of 2-(1H-indole-3-carboxamido)benzoic acid (compound 1) comprises:

[0065] Add 3-indolecarboxylic acid (50.00 g, 0.31 mol), 300 mL of dichloromethane, 70 mL of thionyl chloride, and 3 mL of DMF to the reaction flask in sequence, raise the temperature to reflux, and stir for 1 h. The reaction solution was evaporated to dryness under reduced pressure, and 100 mL of dichloromethane was added to evaporate to dryness again to remove residual thionyl chloride. Add 300mL of dichloromethane to make acid chloride suspension for later use. Take another 2000mL three-necked flask, add methyl anthranilate (42.63g, 0.28mol), triethylamine (32g, 0.31mol), and 500mL of dichloromethane in an ice-water bath and stir. The acid chloride suspension was added dropwise to the reaction solution, stirred for 30 min after dropping, and then turned to room temperature to react overnight. TLC monitoring, the reaction was completed, the solvent was evaporated under reduce...

Embodiment 2

[0071] The preparation process of 2-(1-isoamyl-1H-indole-3-carboxamido)benzoic acid (compound 2) comprises:

[0072] Using 3-indolecarboxylic acid as the starting material, the intermediate compound 1C was prepared in the manner of Example 1;

[0073] Add intermediate compound 1C (2g, 6.8mmol), anhydrous potassium carbonate (1.23g, 13.6mmol), potassium iodide (0.11g, 0.68mmol) and DMF25mL to a 100ml single-necked bottle, stir at room temperature for 0.5h, and add bromine dropwise thereto Substituting isopentane (0.94g, 8.2mmol), the temperature was raised to 60°C for reaction. After the reaction was complete as monitored by TLC, the reaction solution was cooled to room temperature, the filtrate was poured into 50mL water, and ethyl acetate was added for extraction (20mL×2). The organic phases were combined, and the organic phase was washed successively with saturated sodium bicarbonate (10 mL×3) and saturated sodium chloride (10 mL×2). Add anhydrous sodium sulfate to the orga...

Embodiment 3

[0079] 2-[1-(pyridin-2-yl)-1H-indole-3-carboxamido]benzoic acid (compound 23):

[0080] Using 3-indolecarboxylic acid as the starting material, the intermediate compound 1C was prepared in the manner of Example 1;

[0081]Add intermediate compound 1C (2g, 6.8mmol), anhydrous potassium carbonate (1.97g, 14.3mmol), 2-bromopyridine (1.40g, 8.8mmol), trans-1,2-ring Hexamethylenediamine (0.15g, 1.4mmol), cuprous iodide (0.06g, 0.3mmol) and 2mL of 1,4-dioxane were heated to 110°C for 10h under nitrogen protection. After the completion of the reaction was monitored by TLC, the reaction solution was cooled to room temperature, saturated sodium chloride was added, and extracted with ethyl acetate (20 mL×2). The organic phases were combined, and the organic phase was washed successively with saturated sodium bicarbonate (10 mL×3) and saturated sodium chloride (10 mL×2). The organic phase was dried overnight by adding anhydrous sodium sulfate, filtered with suction, and evaporated to r...

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Abstract

The invention discloses an indole derivative as well as a preparation method and application thereof, belongs to the technical field of medicines, and particularly relates to an indole derivative as shown in a general formula I, the invention also relates to a preparation method of the compound, a pharmaceutical composition taking the compound as an active component, and application of the compound in preparation of anti-gout drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to an indole derivative with the activity of inhibiting xanthine oxidase and organic anion transporter 1 (URAT1) and its preparation method and application. Background technique [0002] Uric acid is the final product of purine metabolism in the human body, and it is mainly excreted through the kidneys in its original form. When xanthine oxidase catalyzes hypoxanthine and xanthine to generate too much uric acid or the excretion of uric acid decreases due to body reasons, the serum uric acid level will increase, and the overall level exceeds 0.42mmol / L, which is called hyperuricemia. Long-term hyperuricemia is an important factor in inducing gout, cardiovascular disease, chronic kidney disease and type II diabetes. Xanthine oxidase is the rate-limiting enzyme that catalyzes the oxidation of hypoxanthine to xanthine and further oxidation to uric acid. Its inhibition can ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/42C07D403/04C07D401/06C07D403/06C07D409/06C07D417/06C07D417/14C07D401/14A61K31/404A61K31/5377A61K31/506A61K31/4439A61K31/497A61K31/427A61P19/06
CPCC07D209/42C07D403/04C07D401/06C07D403/06C07D409/06C07D417/06C07D417/14C07D401/14A61P19/06
Inventor 王绍杰高骏孟维宇毛青
Owner SHENYANG PHARMA UNIVERSITY
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