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New xanthine oxidase inhibitor compound and pharmaceutical composition thereof

A compound and pharmaceutical technology, applied in the field of a new class of xanthine oxidase inhibitor compounds and their pharmaceutical compositions, can solve the problems of high incidence, abnormal liver function and the like

Active Publication Date: 2014-08-13
南京厚生药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still common adverse reactions such as abnormal liver function, rash, diarrhea, headache, nausea, vomiting, abdominal pain, dizziness and arthralgia, and most of the adverse reactions are mild to moderate
Moreover, the incidence of cardiovascular adverse events (including myocardial infarction, stroke, and cardiovascular death) was higher with febuxostat than with allopurinol, although there was no statistical significance
[0012] In the past 20 years, the incidence of gout in the world has shown an upward trend (N.L.Edwards, Arthritis & Rheumatism, 2008, 58, 2587~2590), while gout has There has been no satisfactory drug for the treatment of gout, and further research and development of new effective anti-gout drugs are urgently needed

Method used

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  • New xanthine oxidase inhibitor compound and pharmaceutical composition thereof
  • New xanthine oxidase inhibitor compound and pharmaceutical composition thereof
  • New xanthine oxidase inhibitor compound and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] 2-(7-cyano-2,2-dimethyl-2,3-dihydro-benzofuran-5-yl)-4-methyl-thiazole-5-carboxylic acid ( 8 )Synthesis

[0090]

[0091] Step A: Thioacetamide (17.0 g, 226.7 mmol) and p-hydroxybenzonitrile (18.0 g, 151.1 mmol) were added to concentrated hydrochloric acid (470 mL), and the resulting mixture was stirred at 50 °C for 3 hours, and TLC analysis indicated a reaction Finish. The reaction solution was cooled to 0°C, filtered, the filter cake was washed with a small amount of water, and dried in vacuum to obtain a yellow powder p-hydroxythiobenzamide ( 1 ) (26.0g). The product was directly used in the next reaction without purification. MS (EI, m / z): 154.1 [M+H] + .

[0092] Step B: Compound 1 (25.0 g, 163.2 mmol) and ethyl 2-chloroacetoacetate (26.5 g, 161.0 mmol) were added to absolute ethanol (75 mL), and the resulting mixture was stirred under reflux for 3 hours, and TLC analysis indicated that the reaction was complete. The reaction solution was cooled to 0°C, a...

Embodiment 2

[0104] 2-(7-iodo-2,2-dimethyl-2,3-dihydro-benzofuran-5-yl)-4-methyl-thiazole-5-carboxylic acid ( 9 )Synthesis

[0105]

[0106] compound 6 According to the example 1 The method in experimental step H is hydrolyzed and acidified to give 2-(7-iodo-2,2-dimethyl-2,3-dihydro-benzofuran-5-yl)-4-methyl-thiazole- 5-Formic acid ( 9 ).

[0107] 1 H NMR (DMSO- d 6 , 400MHz) δ 8.07 (d, J = 1.6 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 3.21 (s, 2H), 2.64 (s, 3H), 1.47 (s, 6H). MS (EI, m / z): 413.9 [M-H] - .

Embodiment 3

[0109] 2-(7-cyano-2,2-dimethyl-2,3-dihydro-benzofuran-5-yl)-4-trifluoromethyl-thiazole-5-carboxylic acid ( 19 )Synthesis

[0110]

[0111] Step A: Dissolve methylparaben (2.0 g, 13.1 mmol) in DMF (14 mL), then add anhydrous potassium carbonate (2.18 g, 15.8 mmol), potassium iodide (0.2 g, 1.20 mmol) and 3 - Chloro-2-methyl-1-propene (1.78 g, 19.7 mmol), and the resulting mixture was stirred at 80°C overnight. Cool to room temperature, add water (60 mL), extract with ethyl acetate (30 mL×3), wash the combined organic phase with water (30 mL), and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by silica gel column (200~300 mesh silica gel, ethyl acetate:petroleum ether=1:10 elution) to obtain 4-(2-methyl-allyloxy)-benzoic acid methyl ester( 10 ) (2.7 g). The yield was 99.5%.

[0112] Step B: Compound 10 (2.7 g, 13.1 mmol) was dissolved in NMP (18 mL), the reaction solution was stirred overnight at 200 °...

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PUM

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Abstract

Disclosed are a compound of formula (I) or pharmaceutically acceptable salt thereof, wherein R1 is selected from H, halogen, C1-2 alkyl, substituted C1-2 alkyl, and C1-2 alkoxy, and R1 is CH3 when ring A is pentabasic monocyclic heteroaryl; R2 is CN, I, C1, Br, -CF3, or -OCH3; R3 is H or D; ring A is thiazole, selenazole, oxazole, or pyridine; ring E is formula (A), (B), or (C); G1 is selected from O or NRa; G2, G3, and G4 are independently selected from -CRa or -CRbRc; Ra is selected from H, deuterium, halogen, C1-6 alkyl, or substituted C1-6 alkyl, and Ra does not comprise deuterium or halogen when Ra is connected to N; Rb and Rc are each independently selected from H, deuterium, halogen, C1-4 alkyl, or substituted C1-4 alkyl; and optionally Rb and Rc may cyclize to form C3-7 membered cycloalkyl or substituted C3-7 membered cycloalkyl. The compound or pharmaceutically acceptable salt thereof is used to prepare drugs for preventing or treating hyperuricemia, gout, diabetic nephropathy, inflammatory diseases, and neurological diseases.

Description

[0001] technical field [0002] The present invention relates to novel compounds of formula (I) effective as xanthine oxidase inhibitors, processes for their preparation and pharmaceutical compositions containing them in therapeutically effective amounts and their medical use, especially as xanthine oxidase inhibitors. Use of purine oxidase inhibitor for treating and preventing gout, hyperuricemia and related diseases. [0003] [0004] Among them A, E, R 1 , R 2 , R 3 and R 4 as defined below. Background technique [0005] Gout is a group of heterogeneous diseases caused by long-term purine metabolism disorder and elevated blood uric acid causing tissue damage. The clinical features are: hyperuricemia (hyperuricemia), recurrent acute gouty arthritis, tophi deposition, characteristic chronic arthritis and joint deformities, often involving the kidneys to cause chronic interstitial nephritis and renal uric acid stone formation. The above manifestations can exist alon...

Claims

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Application Information

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IPC IPC(8): C07D417/04C07D421/04C07D413/04A61K31/427A61K31/41A61K31/422A61P19/06A61P3/10A61P13/12A61P29/00A61P25/00
CPCC07D311/76C07D311/20A61K31/427C07D413/04C07D417/04C07D421/04A61P3/10A61P13/12A61P19/06A61P25/00A61P29/00C07D405/04
Inventor 史东方傅长金张昌朋刘俊
Owner 南京厚生药业有限公司
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