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Phenyl-(pyrazolo[1,5-alpha]pyridin-3-yl)methanone derivatives

An alkyl and hydroxyl technology, applied in the field of medicinal chemistry, can solve problems such as liver toxicity and side effects

Active Publication Date: 2018-03-06
JIANGSU ATOM BIOSCI & PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although benzbromarone has serious liver toxic side effects, it is still the most curative gout drug in the world

Method used

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  • Phenyl-(pyrazolo[1,5-alpha]pyridin-3-yl)methanone derivatives
  • Phenyl-(pyrazolo[1,5-alpha]pyridin-3-yl)methanone derivatives
  • Phenyl-(pyrazolo[1,5-alpha]pyridin-3-yl)methanone derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Example 1: (2-Ethylpyrazolo[1,5-a]pyridin-3-yl)(4-hydroxyphenyl)methanone (5) and (3,5-dibromo-4-hydroxybenzene Synthesis of (2-ethylpyrazolo[1,5-a]pyridin-3-yl)methanone (6)

[0085]

[0086] Step A: A mixture of 1-aminopyridinium iodide (15.54 g, 70.0 mmol), ethyl 2-pentynoate (9.72 g, 77.1 mmol), potassium carbonate (21.26 g, 154 mmol) and DMF (150 mL) was stirred at room temperature Stirring was continued for 4.5 hours. Add water (450 mL), filter, and wash the filter cake with water (100 mL) to obtain ethyl 2-ethylpyrazolo[1,5-a]pyridine-3-carboxylate (1). This compound was directly used in the next reaction without purification.

[0087]Step B: A mixture of the whole crude compound 1, ethanol (30 mL), THF (30 mL) and 2M aqueous sodium hydroxide solution (70 mL) was stirred at 60 °C overnight. About half of the solvent was distilled off under reduced pressure, water (150 mL) was added, and the pH value was adjusted to 5-6 with 2M hydrochloric acid. Filtration...

Embodiment 2

[0092] Example 2: Synthesis of (2-ethylpyrazolo[1,5-a]pyridin-3-yl)(4-hydroxyl-3,5-diiodophenyl)methanone (7)

[0093]

[0094] To a solution of compound 5 (233 mg, 0.875 mmol) in methanol (10 mL) were added anhydrous sodium acetate (158 mg, 1.93 mmol) and iodine (489 mg, 1.93 mmol), and the resulting mixture was stirred under reflux for 1 hour. A solution of sodium hydroxide (63 mg, 1.58 mmol) in water (15 mL) was then added and reflux was continued for 1 hour. After cooling to room temperature, saturated aqueous sodium bisulfite was added dropwise to the reaction mixture until the color faded. Water (30 mL) was added, extracted with ethyl acetate (40 mL×2), 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=1:20-1:1 elution) to obtain (2-ethylpyrazolo[...

Embodiment 3

[0095] Example 3: Synthesis of 5-(2-ethylpyrazolo[1,5-a]pyridine-3-carbonyl)-2-hydroxyl-3-iodobenzonitrile (8)

[0096]

[0097] A mixture of compound 7 (280 mg, 0.540 mmol), cuprous cyanide (58 mg, 0.648 mmol) and DMF (6 mL) was stirred at 100 °C overnight. After cooling to room temperature, water (30 mL) was added and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with water (20 mL×2) and saturated brine (10 mL) successively, 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=1:10-20:1 elution) to obtain 5-(2-ethylpyrazolo[1 ,5-a]pyridine-3-carbonyl)-2-hydroxy-3-iodobenzonitrile (8). 1 H NMR (DMSO-d6, 300MHz) δ8.71 (d, J=6.9Hz, 1H), 8.05 (d, J=2.1Hz, 1H), 7.52 (d, J=2.1Hz, 1H), 7.45-7.33 (m, 2H), 6.99-6.95 (m, 1H), 2.83 (q, J=7.5Hz, 2H), 1.22 (t, J=7.5Hz, 3H). MS (EI, m / z): 416.0 [M-H] -...

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Abstract

The invention discloses phenyl-(pyrazolo[1,5-alpha]pyridin-3-yl)methanone derivatives, which are compounds shown as a general formula (I) or pharmaceutically acceptable salts thereof. The compounds orthe pharmaceutically acceptable salts thereof can be applied to uric acid excretion promotion for treating or preventing hyperuricemia and gout, or can be used for treating diabetes.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of phenyl-(pyrazolo[1,5-a]pyridin-3-yl)methanone compounds, compositions thereof and applications in medicine. Background technique [0002] Gout is a chronic metabolic disease caused by long-term hyperuricemia in the human body. Uric acid is the end product of human purine metabolism, dissolved in the blood, and most of the uric acid is excreted through the kidneys. When purine metabolism in the human body is disordered, resulting in increased production of uric acid, or excessive intake of high-purine foods, and poor excretion of uric acid (accounting for 80-85% of patients), it will accumulate a large amount in the blood to reach saturation, and urate crystals will appear , deposited in joints and soft tissues, thereby inducing gout (Richette P, Bardin T. Gout. Lancet. 2010, 375(9711): 318-328). Therefore, the serum uric acid level is a clinical discrim...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61P3/10A61P13/12A61P19/06A61P9/12A61P29/00A61P25/00A61P9/04A61P9/00A61P19/02
CPCC07D471/04
Inventor 史东方傅长金承曦朱江华顾杰杨艳
Owner JIANGSU ATOM BIOSCI & PHARMA CO LTD
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