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1-alkyl-5-tetrazolyl/pyrimidinone-1H-indole-3-formonitrile compounds as well as preparation method and application thereof

A pyrimidinone-based and tetrazolyl-based technology, which is applied in the application field of treating and/or preventing hyperuricemia and gout, can solve the problems of undiscovered preparation methods and uses of formic nitrile compounds, and achieves reduction of serum uric acid. level, the effect of good research value

Active Publication Date: 2021-07-27
SHENYANG PHARMA UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] No related reports on 1-alkyl-5-tetrazolyl / pyrimidinonyl-1H-indole-3-carbonitrile compounds and their preparation methods and uses have been found in the prior art

Method used

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  • 1-alkyl-5-tetrazolyl/pyrimidinone-1H-indole-3-formonitrile compounds as well as preparation method and application thereof
  • 1-alkyl-5-tetrazolyl/pyrimidinone-1H-indole-3-formonitrile compounds as well as preparation method and application thereof
  • 1-alkyl-5-tetrazolyl/pyrimidinone-1H-indole-3-formonitrile compounds as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Example 1: Preparation of 5-(1H-tetrazol-5-yl)-1H-indole-3-carbonitrile (Y-5a)

[0069] Preparation of 5-cyano-1H-indole-3-carbaldehyde (Y-3a): 30.0 g (0.211 mol) of 5-cyano indole was added to 200 mL of DMF, and slowly added dropwise under stirring at room temperature Phosphorus 15.0g (0.098mol), after the dropwise addition, mechanically stirred at 75°C for 8h. TLC monitoring, after the reaction is completed, slowly pour 200mL of water into the reaction solution, adjust the pH to 7-8 with 2M sodium hydroxide aqueous solution, continue mechanical stirring at 75°C for 30min, a large amount of yellow solid precipitates, filter with suction, and use 200mL of the filter cake Washed with water three times, air-dried at 50°C for 10 hours to obtain 39.0 g of yellow solid, yield 94.2%, Mp 144.2°C-145.6°C. 1 H NMR (400MHz, DMSO-d 6 )δ11.48(s, 1H), 8.31(d, J=1.7Hz, 1H), 7.81(dd, J=8.5, 1.7Hz, 1H), 7.62(d, J=8.5Hz, 1H), 7.51( t,J=2.8Hz,1H),6.63(s,1H).

[0070] Preparation of 5...

Embodiment 2

[0072]Example 2: Preparation of 1-n-propyl-5-(1H-tetrazol-5-yl)-1H-indole-3-carbonitrile (Y-5b)

[0073] Preparation of 5-cyano-1H-indole-3-carbaldehyde (Y-3a): In a 1000mL three-neck flask, add 30.0g (0.211mol) 5-cyanoindole, 200.0mL DMF, mechanically Stir for 10 min. Slowly drop 15.0 g (0.098 mol) of phosphorus oxychloride into the above reaction solution, and after the drop is completed, mechanically stir at 75° C. for 8 h. After the reaction is complete, slowly pour 200mL of water into the above reaction solution, adjust the pH to 7-8 with 2M aqueous sodium hydroxide solution, continue to stir at 75°C for 45 minutes, a yellow solid precipitates, suction filters, washes with water, and dries to obtain yellow Solid 39.5g, yield: 94.6%, mp: 144.2-145.6°C. MS(ESI) m / z: 169.0[M-H] - ; 1 H NMR (400MHz, DMSO-d 6 )δ11.48(s, 1H), 8.31(d, J=1.7Hz, 1H), 7.81(dd, J=8.5, 1.7Hz, 1H), 7.62(d, J=8.5Hz, 1H), 7.51( t,J=2.8Hz,1H),6.63(s,1H).

[0074] Preparation of 1-n-propyl-5-cyano-1...

Embodiment 3

[0077] Example 3: Preparation of 1-allyl-5-(1H-tetrazol-5-yl)-1H-indole-3-carbonitrile (Y-5c)

[0078] Preparation of 5-cyano-1H-indole-3-carbaldehyde (Y-3a): In a 1000mL three-neck flask, add 30.0g (0.211mol) 5-cyanoindole, 200.0mL DMF, mechanically Stir for 10 min. Slowly drop 15.0 g (0.098 mol) of phosphorus oxychloride into the above reaction solution, and after the drop is completed, mechanically stir at 75° C. for 8 h. After the reaction is completed, slowly pour 200mL of water into the above reaction solution, adjust the pH to 7-8 with 2M sodium hydroxide aqueous solution, continue stirring at 75°C for 30 minutes, a yellow solid precipitates, suction filters, washes with water, and dries to obtain yellow Solid 38.0g, yield: 93.4%, mp: 144.2-145.6°C. MS (ESI) m / z: 169.0 [M-H] - ; 1 H NMR (400MHz, DMSO-d 6 )δ11.48(s, 1H), 8.31(d, J=1.7Hz, 1H), 7.81(dd, J=8.5, 1.7Hz, 1H), 7.62(d, J=8.5Hz, 1H), 7.51( t,J=2.8Hz,1H),6.63(s,1H).

[0079] Preparation of 1-allyl-5-cyano-1H...

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Abstract

The invention relates to 1-alkyl-5-tetrazolyl / pyrimidinone-1H-indole-3-formonitrile compounds as well as a preparation method and application thereof, belonging to the technical field of medicines. The invention provides a series of 1-alkyl-5-(1H-tetrazol-5-yl) / (4-oxo-1,6-dihydropyrimidin-2-yl)-1H-indole-3-formonitrile compounds, and in-vitro xanthine oxidase inhibitory activity tests are carried out on the prepared compounds by adopting an ultraviolet spectrophotometric method; and results show that the prepared compounds have obvious xanthine oxidase inhibitory activity. In acute hyperuricemia rat model tests, the compounds can significantly reduce the uric acid level of serum, and have good in-depth research value as novel xanthine oxidase inhibitors.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a 1-alkyl-5-tetrazolyl / pyrimidinonyl-1H-indole-3-carbonitrile compound and a preparation method thereof and their usefulness in the treatment and / or prevention of high Application in uric acidemia and gout. Background technique [0002] Gout is a metabolic disease caused by disordered purine metabolism or decreased excretion of uric acid, resulting in high serum uric acid concentration, crystallization of urate, deposition in soft tissues or joints, causing inflammation, and then inducing gout. [0003] The main cause of gout is; when the production of uric acid in the body increases or the excretion decreases, it can lead to an increase in the level of uric acid. When it exceeds its solubility limit, uric acid will be deposited in the joints and soft tissues, causing an inflammatory response. Uric acid is the final product of purine metabolism in the human body. Xan...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D209/12A61K31/41A61K31/513A61P19/06
CPCC07D403/04C07D209/12A61P19/06
Inventor 王绍杰杨玉威段雨琳
Owner SHENYANG PHARMA UNIVERSITY
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