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Compound for preventing, treating or alleviating hyperuricemia or gout and application thereof

A uric acid and composition technology, applied in the field of medicinal chemistry, can solve the problems of not being able to use for a long time, and the sales of Resinard is not high, and achieve the effect of long half-life, good stability, and strong URAT1 inhibitory effect

Active Publication Date: 2021-03-02
CHENGDU SINTANOVO BIOTECHNOLOGV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these two drugs have side effects such as liver and kidney toxicity, and cannot be used in clinical practice for a long time. This is also the biggest reason for the low sales of Resinard

Method used

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  • Compound for preventing, treating or alleviating hyperuricemia or gout and application thereof
  • Compound for preventing, treating or alleviating hyperuricemia or gout and application thereof
  • Compound for preventing, treating or alleviating hyperuricemia or gout and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] The preparation of embodiment 1 compound 1

[0048] The reaction scheme is as follows:

[0049]

[0050] Specific steps are as follows:

[0051] Step 1: Synthesis of Intermediate 1-1

[0052] Dissolve tetrachloronitrobenzene S1 (13.05g, 50mmol) in dimethylsulfoxide (100mL), add sodium hydrosulfide (2.80g, 50mmol), and react at room temperature for 24h. The reaction solution was quenched with dilute hydrochloric acid (2M, 50 mL), added water (500 mL), extracted with ethyl acetate (3×500 mL), and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica gel, eluent was dichloromethane / methanol, 20 / 1 to 3 / 1 gradient elution) to obtain 6.98 g of yellow powder 1-1, yield 54%.

[0053] 1 H NMR (300MHz, CDCl 3 )δ5.12(s,1H),8.57(s,1H).

[0054] ESI-MS(m / z):257.2(M+H + )

[0055] Step 2: Synthesis of Intermediate 1-2

[0056] 1-1 (5.17g, 20mmol) was dissolved in ethanol (80...

Embodiment 2

[0077] The reaction scheme is as follows:

[0078]

[0079] Specific steps are as follows:

[0080] Step 1: Synthesis of Intermediate 2-1

[0081] 2,6-dichloro-4-aminophenol S3 (5.34g, 30mmol), deuterated hydrochloric acid solution (20%w / w in D 2 (2) (1.5 mL) was added into heavy water (30 mL), and refluxed for 72 h under the protection of argon. After cooling to room temperature, excess potassium carbonate was added to neutralize the reaction mixture. Extracted with ethyl acetate (3×100 mL), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and purified by column chromatography (silica gel, eluent was dichloromethane / methanol, gradient 20 / 1 to 1 / 1 washing) to obtain 4.91 g of brown oil 2-1. Yield 91%, deuterated rate 96%.

[0082] 1 H NMR (300MHz, CDCl 3 )δ6.55 (undeuterated part, s, 0.08H), 6.16(s, 2H), 9.80(s, 1H).

[0083] ESI-MS(m / z):180.3(M+H + )

[0084] Step 2: Synthesis of Intermediate 2-2

[0085] Slowly add 2-1 (4...

Embodiment 3

[0097] The reaction scheme is as follows:

[0098]

[0099] Specific steps are as follows:

[0100] Step 1: Synthesis of Intermediate 4-1

[0101] Dilute paraformaldehyde-d2 (1.5 g, 50.0 mmol) with water (10 mL), add diisopropyl ether (10 mL) and S5 (626 mg, 5.0 mmol), and react overnight at room temperature. The organic layer was separated and the aqueous layer was extracted with diisopropyl ether (3 x 20 mL). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 560 mg of brown oil 4-1 with a purity of 90% by LCMS and a yield of 80%, which was directly used in the next reaction without purification.

[0102] ESI-MS (m / z): 140.1 (M+H + )

[0103] Step 2: Synthesis of Intermediate 4-2

[0104] 3,5-Dichloro-4-hydroxybenzoic acid S2 (414mg, 2.00mmol) was dissolved in N,N-dimethylformamide (10mL), and N,N,N',N'-tetramethyl- O-(7-azabenzotriazol-1-yl)urea hexa...

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PUM

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Abstract

The invention provides a URAT1 inhibitor, which has a structure as shown in a formula I, or pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. Compared with a drug Dotinurad on themarket, the series of novel deuterated compounds provided by the invention show a stronger inhibition effect on URAT1 transport protein.

Description

technical field [0001] The present invention relates to the technical field of medicinal chemistry, in particular to a compound for preventing, treating or alleviating hyperuricemia or gout and its application, specifically, to a URAT1 inhibitor, its pharmaceutical composition and its application. Background technique [0002] Hyperuricemia is caused by excess production or insufficient excretion of uric acid and is considered a predisposing factor for several diseases that seriously affect quality of life. For example, hyperuricemia is considered a predisposing factor for gout, the most common form of inflammatory arthritis, which is characterized by severe joint pain and tenderness caused by the accumulation of urate crystals. [0003] According to WHO's Global Burden of Disease report, there were 34 million gout cases worldwide in 2016. Gout affects 1% to 2% of adults in Western countries, including 3.7% in the United States and 1.4% in Europe. In China, hyperuricemia i...

Claims

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Application Information

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IPC IPC(8): C07D277/62A61P19/06A61P13/04A61P3/04A61P3/06A61P3/10A61P3/00A61P13/12A61P9/00A61K31/428
CPCC07D277/62A61P19/06A61P13/04A61P3/04A61P3/06A61P3/10A61P3/00A61P13/12A61P9/00C07B2200/05
Inventor 付晓平高剑钟国庆李四军黄波袁瑜李元波
Owner CHENGDU SINTANOVO BIOTECHNOLOGV CO LTD
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