URAT1 inhibitor for promoting uric acid excretion

A compound and pharmaceutical technology, applied in the field of URAT1 inhibitor compounds, can solve the problems of high incidence of serious adverse events, bleak future, and lack of significant curative effect

Active Publication Date: 2018-09-04
JIANGSU ATOM BIOSCI & PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Zurampic also has a variety of toxic and side effects: (1) The drug may cause fatal cardiovascular disease, non-fatal myocardial infarction, or cerebral infarction in patients with moderately severe cardiovascular adverse reactions
(2) Adverse reactions related to renal function will occur after the initial treatment of Zurampic. When taking 400mg alone, the incidence of serious adverse events is the highest. Therefore, high-dose single use is clinically prohibited, and renal function needs to be tested regularly before and after treatment.
Although the FDA has approved the marketing of Zurampic, the lack of significant efficacy and high toxicity make the future of this product bleak

Method used

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  • URAT1 inhibitor for promoting uric acid excretion
  • URAT1 inhibitor for promoting uric acid excretion
  • URAT1 inhibitor for promoting uric acid excretion

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1: (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methanol Synthesis of Ketone (5)

[0072]

[0073] Step A: Dissolve 2-aminopyridine (2.0g, 21.3mmol) and triethylamine (2.58g, 25.5mmol) in dichloromethane (20mL), then add propionyl chloride (2.07g, 22.4mmol) dropwise in an ice-water bath ). After the addition was complete, the resulting mixture was stirred overnight at room temperature. Water (40 mL) was added, extracted with dichloromethane (40 mL×3), the combined organic phases were washed with saturated brine (30 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=1:15-1:10 elution) to obtain N-(pyridin-2-yl)propionamide ( 1) (2.74g). The yield was 85.6%.

[0074] Step B: A mixture containing compound 1 (300 mg, 2.0 mmol), 2-bromo-1-(4-methoxyphenyl)ethanone (460...

Embodiment 2

[0078] Example 2: (3,5-dibromo-4-hydroxyphenyl)(5,6,6,7,8-pentadeutero-2-ethyl-5,6,7,8-tetrahydroimidazo[ Synthesis of 1,2-a]pyridin-3-yl)methanone (10)

[0079]

[0080] Step A: Add 60% sodium hydride (1.68 g, 42 mmol) in portions to a solution of p-methoxyacetophenone (3.0 g, 20.0 mmol) in DMF (15 mL) at -10-0°C. After the addition was complete, stirring was continued at this temperature for 40 minutes, then ethyl propionate (2.04 g, 20 mmol) was added dropwise. After the addition was complete, the resulting mixture was stirred overnight at room temperature. Water (60 mL) was added, extracted with ethyl acetate (30 mL×3), the combined organic phases were washed with saturated brine (20 mL×2), 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=1:30 elution) to obtain 1-(4-methoxyphenyl)pentane-1.3- Diketone (6) (3.16 g). ...

Embodiment 3

[0084] Example 3: Synthesis of 5-(2-ethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile (16)

[0085]

[0086] Step A: Add 4-methoxyacetophenone (44.0 g, 293 mmol) to 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane alkane di(tetrafluoroborate) salt (104g, 294mmol), iodine (38.6g, 152mmol) and acetonitrile (440mL). After the addition was complete, the resulting mixture was stirred overnight at room temperature. Water (1350 mL) was added to the reaction mixture, and a large amount of solid precipitated out. Filtration and drying gave 3-iodo-4-methoxyacetophenone (11) (70.0 g). The yield was 86.5%.

[0087] Step B: A mixture containing compound 11 (70.0 g, 254 mmol), cuprous cyanide (34.0 g, 380 mmol) and DMF (400 mL) was stirred at 130 °C overnight. Cool to room temperature, filter through diatomaceous earth, add water (1600mL), extract with ethyl acetate (800mL×3), the combined organic phases are washed with water (400mL×2) and saturate...

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PUM

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Abstract

The invention belongs to the field of medicinal chemistry, and in particular relates to a URT1 inhibitor for promoting uric acid excretion, which is a compound represented by the structure of the formula (I) or a pharmaceutically acceptable salt thereof. Experiments show that the compound provided by the invention has excellent inhibitory effect to hURAT1 transport uric acid in HEK293 transfectedcells and has a good application prospect in treatment of hyperuricemia or gout. The formula (I) is shown in the description.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of URAT1 inhibitor compounds with uric acid excretion function and applications of the compounds. Background technique [0002] Gout is the most common form of arthritis caused by hyperuricemia. At present, there are nearly 100 million gout patients in the world, and its market size is huge. According to statistics, the incidence of gout in Europe is about 1-2%, mostly middle-aged and elderly men (Michael Doherty, Tim L Jansen, George Nuki, et al. Gout: why is this curable disease soseldom cured? Annals of the Rheumatic Diseases. 2012,71(11):1765-1770); the number of gout patients in the United States has reached 8.3 million (Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheumatol 2011,63(10):3136-3141); the number of hyperuricemia pati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D231/56C07D491/052C07D487/04A61K31/416A61K31/437A61K31/519A61K31/4162A61P19/06A61P13/12C07B59/00
CPCA61P13/12A61P19/06C07B59/002C07D231/56C07D471/04C07D487/04C07D491/052C07B2200/05A61K31/437A61K31/343A61K31/416A61K31/4162A61K31/519C07D307/80C07B59/00
Inventor 史东方朱江华顾杰承曦杨艳周禾李鹏飞吴帆
Owner JIANGSU ATOM BIOSCI & PHARMA CO LTD
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