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Nitrogen-substituted phenyl pyrazole xanthine oxidoreductase inhibitor and preparation and application thereof

A technology of phenylpyrazoles and reductase inhibitors, which is applied in the field of nitrogen-substituted phenylpyrazole xanthine oxidoreductase inhibitors and their preparation and application, and can solve urate crystal deposition, kidney damage, etc. problem, to achieve the effect of excellent inhibitory effect and excellent inhibitory effect

Active Publication Date: 2017-05-10
广州奈米微晶生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although low-dose benzbromarone has a stronger effect on lowering blood uric acid than allopurinol, the urate crystals produced by the excretion of such drugs are easy to deposit in the urinary tract, leading to varying degrees of kidney damage

Method used

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  • Nitrogen-substituted phenyl pyrazole xanthine oxidoreductase inhibitor and preparation and application thereof
  • Nitrogen-substituted phenyl pyrazole xanthine oxidoreductase inhibitor and preparation and application thereof
  • Nitrogen-substituted phenyl pyrazole xanthine oxidoreductase inhibitor and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] 1-(3'-cyano-4'-piperidine-phenyl)-3-methyl-pyrazole-4-carboxylic acid (I 1 )Synthesis

[0058] (1) 5-bromo-2-fluoro-1-cyanobenzene (II 1 , 2.64g, 13mmol) was dissolved in DMSO (20mL), adding K 2 CO 3 (5.4g, 39mmol), piperidine (3.3g, 39mmol), reacted at 100°C for 6h, followed by TLC to complete the reaction. The reaction solution was cooled to room temperature, diluted with 100 mL of water, extracted with ethyl acetate (100 mL×3), washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated to remove the solvent under reduced pressure to obtain a yellow liquid 5-bromo-2-piperidine- Benzonitrile (III 1 )3.3g, the yield is 95.7%.

[0059] (2)N 2 Under protection, 3-methyl-1H-pyrazole-4-carboxylic acid methyl ester (0.14g, 1.0mmol), CuI (19.1mg, 0.1mmol), K 2 CO 3 (0.29g, 2.1mmol), III 1 (0.318g, 1.2mmol), (E)-N,N'-dimethyl-1,2-cyclohexyldiamine (28.5mg, 0.2mmol) and DMF (3mL) were added in a 25mL two-necked flask, 110 React at ℃ for 24 h, ...

Embodiment 2

[0063] 1-(3'-cyano-4'-piperidine-phenyl)-pyrazole-4-carboxylic acid (I 2 )Synthesis

[0064] (1) With embodiment 1.

[0065] (2)N 2 Under protection, ethyl 1H-pyrazole-4-carboxylate (0.22g, 1.6mmol), CuI (30mg, 0.16mmol), K 2 CO 3 (0.45g, 3.3mmol), III 1 (0.5g, 1.9mmol), (E)-N,N'-dimethyl-1,2-cyclohexyldiamine (45mg, 0.3mmol) and DMF (3mL) were added to a 25mL two-neck flask, 110°C React for 24 hours, cool to room temperature, add 10 mL of water to dilute, extract with ethyl acetate (15 mL×3), wash with saturated brine (10 mL), dry over anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, and purify on a silica gel column (V 乙酸乙酯 :V 石油醚 =4:1), white solid 1-(3'-cyano-4'-piperidine-phenyl)-pyrazole-4-carboxylic acid ethyl ester (IV 2 )0.28g, yield 55.0%.

[0066] (3)IV 2 (0.28g, 0.86mmol) was dissolved in a mixed solution of THF (24mL) and ethanol (24mL), added 4mL of 1M NaOH aqueous solution, refluxed for 1h, cooled to room temperature, added 1M ...

Embodiment 3

[0069] 1-(3'-nitro-4'-piperidine-phenyl)-3-methyl-pyrazole-4-carboxylic acid (I 3 )Synthesis

[0070] (1) 5-bromo-2-fluoro-1-nitrobenzene (II 2 , 3.3g, 15mmol) was dissolved in DMSO (20mL), adding K 2 CO 3 (6.2g, 45mmol), piperidine (3.8g, 45mmol), reacted at 100°C for 4h, followed by TLC to complete the reaction. The reaction solution was cooled to room temperature, diluted with 100 mL of water, extracted with ethyl acetate (100 mL×3), washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated to remove the solvent under reduced pressure to obtain 5-bromo-2-piperidine as an orange liquid -1-nitrobenzene (III 3 )4.2g, the yield is 98.2%.

[0071] (2)N 2 Under protection, 3-methyl-1H-pyrazole-4-carboxylic acid methyl ester (0.14g, 1.0mmol), CuI (19.1mg, 0.1mmol), K 2 CO 3 (0.29g, 2.1mmol), III 3 (0.34g, 1.2mmol), (E)-N,N'-dimethyl-1,2-cyclohexyldiamine (28.5mg, 0.2mmol) and DMF (3mL) were added in a 25mL two-necked flask, 110 React at ℃ for 24...

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Abstract

The invention belongs to the technical field of pharmaceutical and chemical industry and discloses nitrogen-substituted phenyl pyrazole xanthine oxidoreductase inhibitor and preparation and application thereof. The nitrogen-substituted phenyl pyrazole xanthine oxidoreductase inhibitor has a structural formula shown as in formula (I), wherein each of R1 and R2 independently represents hydrogen or C1-C6 alkyl, or R1, R2 and nitrogen atoms connecting R1 and R2 together form monocyclic nitrogen-bearing heterocyclic group having 3-6 carbon atoms, R3 is nitryl or cyano, and R4 is hydrogen, methyl or trifluoromethyl. The compound of formula (I) prepared herein has a chemical structure different from that of known xanthine oxidoreductase inhibitors, and a new route to prepare anti-hyperuricemia or gout drugs is provided.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and specifically relates to a nitrogen substituent phenylpyrazole xanthine oxidoreductase inhibitor and its preparation and application. Background technique [0002] Uric acid is the end product of purine metabolism in the body, which is produced by hypoxanthine and xanthine under the action of xanthine oxidase (XO). Due to the lack of urate oxidase in the purine metabolic pathway of humans and primates, uric acid cannot be degraded into allantoin, which is very soluble in water, and most of the uric acid can only be excreted through the kidneys, which makes humans prone to hyperuricemia disease. [0003] Hyperuricemia can lead to gout and renal insufficiency, and is further thought to be a contributing factor to coronary heart disease. In addition, hyperuricemia is also considered to be closely related to the formation of adult diseases such as hypertension. Therefore,...

Claims

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Application Information

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IPC IPC(8): C07D401/10C07D413/10C07D403/10C07D231/14A61P19/06
CPCC07D231/14C07D401/10C07D403/10C07D413/10
Inventor 张雷吴芳萍李晶邹亚珂
Owner 广州奈米微晶生物科技有限公司
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