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Substituted tricyclo-quinone compounds, and preparation method and application thereof

A technology for tricyclic quinones and compounds, which is used in the application of substituted tricyclic quinones and their preparation, as an antifungal drug, and can solve the problems of low bioavailability, large toxic and side effects, and high price

Active Publication Date: 2013-08-28
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, clinically ideal antifungal drugs are lacking
Polyene antibiotics (such as amphotericin B) that act on fungal cell membrane lipids are the first choice for treatment, but their clinical application is severely limited due to their severe side effects
Azole drugs (such as fluconazole, itraconazole, and voriconazole) that act on lanosterol 14α-demethylase (CYP51) are currently the most widely used antifungal drugs, but these drugs are due to cytochrome Inhibition of P450 enzymes can cause significant drug-drug interactions and is ineffective against drug-resistant strains
Lipopeptide drugs (such as caspofungin and micafungin) that act on fungal cell wall β-1,3 glucan synthase are expensive and have low bioavailability

Method used

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  • Substituted tricyclo-quinone compounds, and preparation method and application thereof
  • Substituted tricyclo-quinone compounds, and preparation method and application thereof
  • Substituted tricyclo-quinone compounds, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0114] Example 1: Preparation of 5,5-dibromo-6,7-dihydrobenzo[b]thiophene-4(5H)-one (II)

[0115] Add CuBr to a 500 mL round bottom flask 2 (28.2g, 126mmol, 4eq) and 80mL ethyl acetate. Heat this suspension to 80°C for a few minutes. Then 80 mL of a chloroform solution in which 6,7-dihydrobenzo[b]thiophene-4(5H)-one VIII (4.78 g, 31.45 mmol) was dissolved was added. After the addition was complete, the mixture was stirred overnight at this temperature. After the reaction of starting materials was complete the mixture was concentrated to dryness in vacuo. The residue was diluted with ethyl acetate and filtered through alumina. Filtrate with saturated NaHCO 3 After washing, the organic phase was dried over sodium sulfate and concentrated after filtration to obtain 9.5 g of white crystal product with a yield of 97%. 1 H NMR (400MHz, CDCl 3 )δppm: 7.51(d,J=5.2Hz,1H),7.20(d,J=5.2Hz,1H),3.18(s,4H).

Embodiment 2

[0116] Example 2: Preparation of 5-bromobenzo[b]thiophen-4-ol (Ⅲ)

[0117] The compound 5,5-dibromo-6,7-dihydrobenzo[b]thiophen-4(5H)-one (9.6 g, 31 mmol) and DMF (100 mL) were added into a 250 mL round bottom flask. To this solution was added lithium carbonate (14 g, 186. mmol, 6 eq). The reaction mixture was heated to 100°C under nitrogen for 6 hours. The reaction solution was then cooled to room temperature and filtered. The filtrate was diluted with water, acidified to pH = 1 with HCl, and extracted with ethyl acetate. The organic phase was washed with water and brine, concentrated and purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1:50) to obtain 6.82 g of white solid with a yield of 95.8%. 1 H NMR (400MHz, CDCl 3 )δppm:7.52(d,J=5.2Hz,1H),7.41(d,J=5.2Hz,1H),7.40(d,J=8.4,1H),7.35(d,J=8.4,1H),5.89 (br s,4H).

Embodiment 3

[0118] Example 3: Preparation of 5-bromobenzo[b]thiophene-4,7-dione (IV)

[0119] Into a 500 mL round bottom flask was added phenol 5-bromobenzo[b]thiophen-4-ol (4.6 g, 20 mmol), 80 mL acetic acid, 120 mL trifluoroacetic acid and a few drops of water. The reaction mixture was cooled to zero with an ice-water bath, and then iodobenzene diacetate (19.3 g, 60 mmol, 3 eq) was added in portions. After the addition was complete, the mixture was stirred for an additional 10 minutes and at room temperature for 20 minutes. Then 100 mL of methanol was added, and after stirring for 10 minutes, water and dichloromethane were added. The organic phase was separated and concentrated. The concentrated residue was purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether=1:50) to obtain 3.91 g of a yellow solid with a yield of 80.5%. 1 H NMR (400MHz, CDCl 3 )δppm: 7.73(d, J=5.2Hz, 1H), 7.66(d, J=5.2Hz, 1H), 7.42(s, 1H); 13 C NMR (100MHz, CDCl 3 )δppm: 177,174,14...

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Abstract

The invention relates to the technical field of medicine, and provides substituted tricyclo-quinone compounds and pharmaceutically acceptable salts thereof. The structural general formula of the substituted aromatic tetracyclic compounds is disclosed in the specification. The invention also provides a preparation method of the compounds and application of the compounds in preparation of antifungal drugs.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a novel substituted tricyclic benzoquinone compound, a preparation method thereof, and an application as an antifungal drug. Background technique [0002] In recent years, factors such as the abuse of antibiotics, tumor radiotherapy and chemotherapy, and organ transplantation have caused immunosuppression. In addition, the number of AIDS patients has increased rapidly. Infection has become the main cause of death from major diseases such as AIDS and cancer. However, clinically ideal antifungal drugs are lacking. Polyene antibiotics (such as amphotericin B) that act on fungal cell membrane lipids are the first choice for treatment, but their clinical application is severely limited due to their severe side effects. Azole drugs (such as fluconazole, itraconazole, and voriconazole) that act on lanosterol 14α-demethylase (CYP51) are currently the most widely used antifungal drugs,...

Claims

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Application Information

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IPC IPC(8): C07D495/04C07D498/04C07D333/74A61K31/4743A61K31/5377A61K31/424A61K31/4439A61K31/381A61P31/10
CPCC07D498/04
Inventor 盛春泉张万年江志赶张向化董国强缪震元姚建忠
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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