HURAT1 (human urate anion transporter 1) inhibitors and application thereof

A compound and pharmaceutical technology, applied in the field of URAT1 inhibitor compounds, can solve the problems of lack of anti-gout drugs, high incidence of serious adverse events, adverse reactions, etc.

Active Publication Date: 2018-11-02
JIANGSU ATOM BIOSCI & PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clinical trials have shown that Lesinurad has a variety of toxic and side effects: (1) The drug may cause fatal cardiovascular disease, non-fatal myocardial infarction or brain exhaustion in patients with moderately severe cardiovascular adverse reactions
(2) Adverse reactions related to renal function will occur after the initial treatment of Lesinurad. When 400 mg is taken alone, the incidence of serious adverse events is the highest. Therefore, high-dose monotherapy is prohibited clinically, and renal function needs to be tested regularly before and after treatment.
However, due to the lack of good anti-gout drugs in the market, they are still widely used in more than 20 countries including China, Germany, Japan, Brazil, and New Zealand

Method used

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  • HURAT1 (human urate anion transporter 1) inhibitors and application thereof
  • HURAT1 (human urate anion transporter 1) inhibitors and application thereof
  • HURAT1 (human urate anion transporter 1) inhibitors and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Embodiment 1: Synthesis of (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-2H-indazol-3-yl)methanone (6)

[0063]

[0064] Step A: A mixture containing indazole (5.00 g, 42.3 mmol), ethyl iodide (13.2 g, 90.3 mmol), potassium hydroxide (5.50 g, 98.0 mmol) and ethanol (60 mL) was stirred at 65 °C for 5 hours . Cool to room temperature and filter to remove insoluble matter. The solvent was evaporated under reduced pressure, then water (30 mL) was added, extracted with dichloromethane (20 mL×3), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether=1:20-1:5 elution) to obtain 2-ethyl-2H-indazole (1) (1.56g) and 1-ethyl-1H-indazole (2) (3.06g). The yields were 25.2% and 49.5%, respectively. Compound 1: 1 H NMR (DMSO-d 6 , 400MHz) δ8.37(s, 1H), 7.69 (d, J=8.4Hz, 1H), 7.60(d, J=8.4Hz, 1H), 7.24-7.20(m, 1H), 7.05-7.01(m , 1H), 4.46...

Embodiment 2

[0069] Example 2: Synthesis of 2,6-dibromo-4-[(2-ethyl-2H-indazol-3-yl)hydroxymethyl]phenol (7)

[0070]

[0071] Sodium borohydride (90 mg, 2.38 mmol) was added to compound 6 (100 mg, 0.236 mmol) in methanol (10 mL). After the addition was complete, the resulting mixture was stirred at reflux for 30 minutes, and then sodium borohydride (90 mg, 2.38 mmol) was added. ), stirring was continued for 1 hour under reflux. Water (20 mL) was added, the pH value was adjusted to 6-7 with 2M aqueous citric acid solution, extracted with ethyl acetate (20 mL×3), the combined organic phases were washed with water (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether=1:20-1:3 elution) to obtain 2,6-dibromo-4-[(2 -Ethyl-2H-indazol-3-yl)hydroxymethyl]phenol (7). 1 H NMR (DMSO-d 6 , 400 MHz) δ9.99(s, 1H), 7.55(d, J=8.8Hz, 1H), 7.51(s, 2...

Embodiment 3

[0072] Example 3: Synthesis of (3,5-dibromo-4-hydroxyphenyl)(1-ethyl-1H-indazol-3-yl)methanone (10)

[0073]

[0074] Step A: A mixture containing compound 2 (2.59g, 17.7mmol), p-methoxybenzoyl chloride (3.02g, 17.7mmol) and anhydrous aluminum chloride (3.54g, 26.6mmol) was stirred overnight at 105°C . Cool to room temperature, add water (30 mL) and ethyl acetate (30 mL), and stir for about 5 minutes. The layers were separated, the aqueous layer was extracted with ethyl acetate (10 mL×3), the combined organic phases were washed with water (15 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether = 1:25-1:15 elution) to obtain (1-ethyl-1H-indazole-3 -yl)(4-methoxyphenyl)methanone (8) (990 mg). The yield was 21.1%. 1 H NMR (DMSO-d 6 , 400MHz) δ8.34-8.29 (m, 3H), 7.88 (d, J=8.4Hz, 1H), 7.56-7.52 (m, 1H), 7.41-7.37 (m, 1H)...

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Abstract

The invention belongs to the field of medicinal chemistry and particularly relates to hURAT1 (human urate anion transporter 1) inhibitors and an application thereof. Specifically, the hURAT1 inhibitors are compounds with structure shown as formula (I) or (II) in the description or pharmaceutically acceptable salts of the compounds. Experiments prove that the compounds have good inhibition effect on uric acid transport of the hURAT1 in an HEK293 transfection cell, which shows that the compounds have good application prospect in treatment of hyperuricemia or gout.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of URAT1 inhibitor compounds and applications of the compounds. Background technique [0002] Gout is a metabolic disease caused by hyperuricemia. When the purine metabolism in the human body is disordered or excessive intake of high-purine foods leads to increased production of uric acid, and the kidneys cannot excrete uric acid smoothly, resulting in blood uric acid concentration exceeding the normal level and reaching saturation, a large amount of urate accumulates and crystallizes. Deposited in joints, tendons, kidneys and other parts, eventually leading to recurrent arthritic pain (Richette P, Bardin T. Gout. Lancet. 2010, 375(9711): 318-328). Hyperuricemia is clinically defined when the blood uric acid concentration in men is >7 mg / dL or in women is greater than 6 mg / dL. The cause of about 80-85% of patients with hyperuricemia is poor excretion of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/56C07D471/04A61K31/416A61K31/437A61P19/06
CPCC07D231/56C07D471/04
Inventor 史东方周禾朱江华李鹏飞承曦杨艳顾杰吴帆
Owner JIANGSU ATOM BIOSCI & PHARMA CO LTD
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