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Oxygen-substituted phenylimidazole XOR/URAT1 dual inhibitor, preparation and applications thereof

A dual inhibitor, phenylimidazole technology, applied in the field of oxygen-substituted phenylimidazole XOR/URAT1 dual inhibitors and its preparation and application, to achieve excellent inhibitory effects

Active Publication Date: 2019-09-06
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004]Currently, the overall research on XOR / URAT1 dual inhibitors is still in the early stage of development, requiring a lot of preliminary exploration and accumulation

Method used

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  • Oxygen-substituted phenylimidazole XOR/URAT1 dual inhibitor, preparation and applications thereof
  • Oxygen-substituted phenylimidazole XOR/URAT1 dual inhibitor, preparation and applications thereof
  • Oxygen-substituted phenylimidazole XOR/URAT1 dual inhibitor, preparation and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] 4-(3-cyano-4-ethoxy-phenyl)-1H-imidazole-2-carboxylic acid (A 1 )Synthesis:

[0046] (1) After dissolving p-hydroxyacetophenone (1, 2.0g, 14.7mmol) in aqueous ammonia, add KI (12g, 73.5mmol) and I 2 (3.7g, 14.7mmol) into an aqueous solution. Stir the reaction at room temperature overnight, after TLC traced the complete reaction, filter, and the filtrate was acidified with concentrated hydrochloric acid, filtered to obtain a yellow precipitate, and the crude product was recrystallized with methanol-water=7:3 to obtain 3-iodo-4-hydroxy-acetophenone (2 )3.13g, yield 80.7%.

[0047] (2) 3-iodo-4 hydroxy-acetophenone (2, 4.0g, 15.3mmol), K 2 CO 3 (6.3g, 45.8mmol) was added to the flask, then DMF was added, stirred at room temperature for 0.5h, then ethyl iodide (7.1g, 45.8mmol) was added, reacted at 80°C, and the reaction was complete after 3h. After adding water to dilute, add ethyl acetate to extract 3 times, wash 2 times with water, then wash 2 times with saturated b...

Embodiment 2

[0057] 4-(3-cyano-4-isopropoxy-phenyl)-1H-imidazole-2-carboxylic acid (A 2 )Synthesis:

[0058] (1) After dissolving p-hydroxyacetophenone (1, 2.0g, 14.7mmol) in ammonia water, add the configured KI (12g, 73.5mmol) and I 2 (3.7g, 14.7mmol) in aqueous solution. Stir the reaction at room temperature overnight, after TLC traced the complete reaction, filter, and the filtrate was acidified with concentrated hydrochloric acid, filtered to obtain a yellow precipitate, and the crude product was recrystallized with methanol-water=7:3 to obtain 3-iodo-4-hydroxy-acetophenone (2 )3.13g, yield 80.7%.

[0059] (2) 3-iodo-4 hydroxy-acetophenone (2, 4.0 g, 15.3 mmol), K 2 CO 3 (6.3g, 45.8mmol) and 20mL of DMF were added to the flask, stirred at room temperature for 0.5h, added iodoisopropane (7.8g, 45.8mmol), reacted at 80°C, and the reaction was complete after 3h. Add 150 mL of water to dilute, extract with ethyl acetate (100 mL×3), wash twice with water, then wash twice with saturated...

Embodiment 3

[0069] 4-(3-cyano-4-isobutoxy-phenyl)-1H-imidazole-2-carboxylic acid ethyl ester (A 3 )Synthesis:

[0070] (1) Dissolve p-hydroxyacetophenone (1, 2.0g, 14.7mmol) in aqueous ammonia, add to the mixture containing KI (12g, 73.5mmol) and I 2 (3.7g, 14.7mmol) into an aqueous solution. Stir the reaction at room temperature overnight, after TLC traced the complete reaction, filter, and the filtrate was acidified with concentrated hydrochloric acid, filtered to obtain a yellow precipitate, and the crude product was recrystallized with methanol-water=7:3 to obtain 3-iodo-4-hydroxy-acetophenone (2 )3.13g, yield 80.7%.

[0071] (2) 3-iodo-4 hydroxy-acetophenone (2, 4.0g, 15.3mmol), K 2 CO 3 (6.3g, 45.8mmol) and 20mL DMF were added to the flask, stirred at room temperature for 0.5h, and bromoisobutane (6.3g, 45.8mmol) was added, and reacted at 85°C, and the reaction was complete after 3h. Add 150 mL of water to dilute, extract with ethyl acetate (100 mL×3), wash twice with water, th...

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Abstract

The invention belongs to the technical field of medicinal chemical industry, and discloses an oxygen-substituted phenylimidazole XOR / URAT1 dual inhibitor, preparation and applications thereof, whereinthe oxygen-substituted phenylimidazole XOR / URAT1 dual inhibitor has a structure represented by a formula (A), R1 represents C1-C7 alkyl, R2 is -COOH or -COOC2H5, and R3 is -H or -CH3. According to the present invention, the oxygen-substituted phenylimidazole XOR / URAT1 dual inhibitor has the chemical structure different from the known XOR / URAT1 dual inhibitor, has excellent effects on both key targets of XOR and URAT1 related to gout, and can be used for preparing anti-hyperuricemia or anti-gout drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and specifically relates to an oxygen-substituted phenylimidazole XOR / URAT1 dual inhibitor and its preparation and application. Background technique [0002] Epidemiological studies from different countries have shown that the prevalence and incidence of gout are increasing, causing a huge economic burden on people. Hyperuricemia is an important risk factor for gout, and it is related to renal insufficiency, cardiovascular disease, hypertension, hyperlipidemia, cancer, diabetes, etc. loss, or a combination of both. In patients with hyperuricemia, 90% is due to inefficient renal excretion. In humans, 90% of uric acid is reabsorbed back into the blood by the renal proximal tubule in large quantities. This reabsorption process mainly depends on human urate Transporter 1 (hURAT1, SLC22A12), whose function is to regulate blood uric acid levels, has certain similarities with ur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/90A61K31/4164A61P19/06A61P19/02A61P9/04A61P9/00A61P9/12A61P13/12A61P29/00
CPCC07D233/90A61P19/06A61P19/02A61P9/04A61P9/00A61P9/12A61P13/12A61P29/00
Inventor 李晶周海燕朱欣颖张雷关溯
Owner SOUTH CHINA UNIV OF TECH
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