Quinazoline ketone derivant, preparation method and application thereof

A quinazolinone and compound technology, applied in the field of quinazolinone derivatives and their preparation, can solve the problems of photosensitivity, blurred vision, light-colored vision, etc.

Inactive Publication Date: 2009-05-13
TOPHARMAN SHANGHAI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although sildenafil has achieved remarkable clinical curative effect, because it also has different degrees of inhibitory effects on other phosphodiesterase (PDE) isozymes o

Method used

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  • Quinazoline ketone derivant, preparation method and application thereof
  • Quinazoline ketone derivant, preparation method and application thereof
  • Quinazoline ketone derivant, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0179] Example 1 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-Kone

[0180] Step 1: 2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-benzamido]-5,7-dimethoxy-8-bromobenzamide

[0181]

[0182] Dissolve 2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoic acid (0.34g, 1mmol) in 20ml of dichloromethane, add carbonyldiimidazole (CDI, 3mmol) , stirred at room temperature for 0.5h, then added 2-amino-4,6-dimethoxy-3-bromobenzamide (0.28g, 1mmol) to the mixture, continued to stir for 1-6h, and analyzed with TLC Detection of reaction endpoints. After the reaction was completed, the mixed solution was washed with ammonium chloride solution and saturated brine, and the dichloromethane phase was dried with anhydrous magnesium sulfate, then concentrated to dryness under reduced pressure, and the residual solid was recrystallized with ethanol to obtain 0.51 g of a white powder with a yield of 86%. .

[0183] Step 2: Preparation of 2-{2...

Embodiment 2

[0186] Example 2 8-methyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline- 4(3H)-keto

[0187]

[0188] Dissolve 408 mg (3.0 mmol) of anhydrous zinc chloride in 5 mL of dry NMP, add dropwise 2 mL of 2 mol / L methylmagnesium chloride (2.0 mmol) THF solution under ice cooling, and stir at room temperature for 1 hour to obtain methyl zinc reagent.

[0189] 2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4(3H) - Ketone 567mg (10i, 1.0mmol) was mixed in 5mL dry NMP, the methyl zinc reagent prepared above was added, and [(t-Bu)3P]2Pd 25mg (0.05mmol) was added under nitrogen protection, and heated at 40oC for 4 hours, Cool down to room temperature, add 10mL dichloromethane and 20mL water solution, extract the water phase once with 3mL dichloromethane, combine the organic phases, wash once with 2mL water and saturated brine, dry over anhydrous sodium sulfate, and perform silica gel column chromatography (CH2Cl...

Embodiment 3

[0190] Example 3 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-bromo-quinazoline- 4(3H)-keto

[0191]

[0192] Dissolve the compound of Example 1 (0.57g, 1.0mmol) in 20mL of dry dichloromethane, add 2mL of boron tribromide (104uL, 1.1mmol) dichloromethane solution dropwise under cooling and stirring at -10oC, continue stirring for 4 hours, add 1mL diethyl ether, continue to stir for 30 minutes, add 20mL dichloromethane and 50mL 5% NaHCO3 to separate the liquid, extract the aqueous phase once with 10mL dichloromethane, combine the organic phases, wash once with 5mL 5% NaHCO3, saturated brine, anhydrous sulfuric acid Dry over sodium and recrystallize from petroleum ether / dichloromethane to obtain 0.45 g of light yellow solid with a yield of 82%. 1H-NMR (300MHz, CDCl3), δ 11.62(s, 1H), 10.82(brs, 1H), 9.11(d, J=2.3Hz, 1H), 7.90(dd, J=8.8, 2.3Hz, 1H), 7.17(d, J=8.8Hz, 1H), 6.57(s, 1H), 4.41(q, J=7.0Hz, 2H), 4.00(s, 3H), 3.18(m, 4H), 2.56(m, 4H )...

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Abstract

The invention relates to the technical field of medicine, in particular to a quinazolinone derivative, a preparation method and application thereof. The invention discloses quinazolinone compounds as structural general formula (I) or pharmaceutically acceptable salt thereof. Most of the compounds have stronger PDE5 inhibition activity than that of Sildenafil, and have higher selectivity than thatof PDE 6 distributed on a retina. Therefore, the compounds are expected to show better clinical safety and effectiveness, and have wide clinical application prospect.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a quinazolinone derivative and a preparation method and use thereof. Background technique [0002] Phosphodiesterase (PDE) includes 11 enzyme systems (PDE1-PDE11), which reduce the activity of intracellular second messengers by hydrolyzing cAMP or cGMP. Depending on the specificity of the particular PDE substrate being blocked, PDE5 inhibitors can increase intracellular cAMP levels, cGMP levels, or both cAMP and cGMP levels. These inhibitors are competitive inhibitors because they mimic the structure of cAMP and cGMP, which are natural substrates of PDEs. Unlike cAMP and cGMP, inhibitors are not degraded by PDEs. PDEs are known to be involved in a wide range of cellular functions. PDE 5 is a cGMP-specific phosphodiesterase highly expressed in smooth muscle cells of the corpus cavernosum. PDE 5 inhibitors increase dilation of the cavernous sinus by maintaining adequate cGMP l...

Claims

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Application Information

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IPC IPC(8): C07D239/91A61K31/5377A61K31/496A61K31/517A61P15/10
CPCC07D239/91C07C311/48C07D295/215C07C279/18C07C237/44C07D403/12C07D405/12C07C311/21C07C311/29C07C335/32C07D213/42C07D307/22C07D401/12C07C309/73C07C335/22C07C275/42C07D309/14C07D207/09C07D295/192C07C255/57C07D295/26C07D295/13A61P9/12A61P11/08A61P13/08A61P13/10A61P15/00A61P15/10A61P15/14A61P27/06A61P29/00
Inventor 沈敬山郑金赖庆林王震张金凤田广辉
Owner TOPHARMAN SHANGHAI
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