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Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same

一种化合物、药学的技术，应用在有效作为黄嘌呤氧化酶抑制剂的新化合物、该化合物的制备和含有该化合物的药物组合物领域，能够解决致命、不可预测、差顺应性等问题

Active Publication Date: 2012-07-11
LG CHEM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, allopurinol is known to cause gastrointestinal side effects and rashes, exhibiting poor compliance with chronic administration
In particular, in patients administered allopurinol, the side effect of Stevens-Johnson syndrome was reported, albeit at a low rate, which was unpredictable and fatal (Felix Arellano et al., Ann. Pharm., 1993, 27, 337-43)
Side effects of this severity are known to be accompanied by cellular necrosis of the skin and oral mucosa, which, in the absence of appropriate treatment, can result in death in approximately 25% of patients

Method used

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  • Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same
  • Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same
  • Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0212] Preparation Example 1: Synthesis of ethyl 1-(1H-indol-5-yl)pyrazole-4-carboxylate

[0213]

[0214] 1H-Pyrazole-4-carboxylic acid ethyl ester (1.00 g, 7.14 mmol) and 1H-indol-5-ylboronic acid (1.15 g, 7.14 mmol) were dissolved in N,N-dimethylformamide (70 mL) middle. Copper(II) acetate (0.972 g, 5.35 mmol) and pyridine (1.2 mL, 14.8 mmol) were added, and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (1.40 g, 5.47 mmol, 77% yield).

[0215] NMR: 1 H-NMR (CDCl 3)δ8.39(1H, s), 8.30(1H, br), 8.11(1H, s), 7.92(1H, d), 7.54(1H, dd), 7.47(1H, d), 7.31(1H, t ), 6.64-6.62 (1H, m), 4.35 (2H, q), 1.39 (1H, t)

[0216] Mass spectrum (EI) 256 (M + +1)

preparation example 2

[0217] Preparation 2: Synthesis of ethyl 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylate The title compound was obtained by the following steps (1), (2) and (3) .

[0218] (1) Synthesis of ethyl 1-(3-formyl-1H-indol-5-yl)pyrazole-4-carboxylate

[0219]

[0220] Oxalyl chloride (0.56mL, 6.6mmol) was added into anhydrous dichloromethane (50mL), N,N-dimethylformamide (0.51mL, 6.6mmol) was added thereto at 0°C, and the mixture was heated at 0°C Stir for 30 minutes. To the reaction solution was added a mixture of ethyl 1-(1H-indol-5-yl)pyrazole-4-carboxylate (1.40 g, 5.47 mmol) obtained in Preparation Example 1 and dichloromethane (50 mL). The mixture was stirred at room temperature under reflux for 1 hour, and the solvent was removed. Tetrahydrofuran (100 mL) and 20% aqueous ammonium acetate (100 mL) were added, then it was heated for 30 minutes while stirring at reflux. After the reaction, the reaction solution was cooled. Ethyl acetate was added, and the mixture was wash...

preparation example 3

[0231] Preparation Example 3: Synthesis of ethyl 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylate

[0232]

[0233] Ethyl 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylate (13.84 g, 49.38 mmol) obtained in Preparation 2 was dissolved in acetonitrile (200 mL). Cesium carbonate (32.17 g, 98.74 mmol) and 2-iodopropane (19.7 mL, 198 mmol) were added, then heated for 5 hours while stirring at reflux. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained solid was purified by column chromatography to obtain the title compound (13.87 g, 43.03 mmol, 87% yield).

[0234] NMR: 1 H-NMR (CDCl 3 )δ8.48(1H, s), 8.16(1H, s), 8.06(1H, d), 7.82(1H, s), 7.78(1H, dd), 7.57(1H, d), 4.80-4.73(1H , m), 4.38 (2H, q), 1.64 (6H, d), 1.42 (3H, t)

[0235] Mass spectrum (EI) 323 (M + +1)

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Abstract

The present invention relates to novel compounds which are effective as an inhibitor for xanthine oxidase, a process for preparing the same, and a pharmaceutical composition comprising a therapeutically effective amount of the same.

Description

technical field [0001] The present invention relates to novel compounds of formula (1) effective as xanthine oxidase inhibitors, processes for preparing the compounds and pharmaceutical compositions containing the compounds in a therapeutically effective amount: [0002] [0003] in [0004] A, D, E, G, Y and Q are as defined below. Background technique [0005] Xanthine oxidase is known as an enzyme that converts hypoxanthine into xanthine, and further converts the xanthine thus formed into uric acid. Although most mammals have uricase, humans and chimpanzees do not, so uric acid is known to be the end product of purine metabolism (S.P. Bruce, Ann. Pharm., 2006, 40, 2187-2194). A persistently elevated concentration of uric acid in the blood can lead to a variety of diseases, typically including gout. [0006] As mentioned above, gout is caused by elevated uric acid levels in the body and refers to a disease in which uric acid crystals accumulated in cartilage, ligamen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/02C07D209/04A61K31/40A61P3/10
CPCC07D403/04C07D409/04C07D405/14C07D401/04A61P1/00A61P1/04A61P13/12A61P19/02A61P19/06A61P27/02A61P29/00A61P3/00A61P3/04A61P3/06A61P9/00A61P9/04A61P9/10A61P9/12A61P3/10A61K31/4155
Inventor 宋正旭金根泰崔盛弼郑哲圭朴德星崔恩宝金泰勳朴贤静朴完洙朴喜戌丘冀哲V·阿特莫弗
Owner LG CHEM LTD
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