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Substituted thienobenzoquinone compounds and their preparation methods and applications

A compound and synthesis method technology, applied in the field of medicine, can solve the problems of lack of antifungal drugs, low bioavailability, limited clinical application, etc., and achieve the effect of broad-spectrum antifungal activity

Active Publication Date: 2016-09-28
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 thienobenzoquinone compounds and their preparation methods and applications
  • Substituted thienobenzoquinone compounds and their preparation methods and applications
  • Substituted thienobenzoquinone compounds and their preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: Preparation of 5-azido-2-nitrobenzo[b]thiophene-4,7-dione (1)

[0051] Take 5-bromo-2-nitrobenzo[b]thiophene-4,7-dione (1.43g, 5mmol) and dissolve it in 15mL of methanol, dichloromethane and water mixture (volume ratio is 9:2: 2) Then add solid sodium azide (812mg, 2.5eq) and continue to stir at room temperature for 2 hours. Dichloromethane was added to the reaction solution for extraction, the aqueous phase was adjusted to pH=11 with 10% sodium hydroxide solution, and then NaClO solution was added to quench the excess sodium azide. After the organic phase was dried, it was spin-dried to obtain a brown solid powder (1.13g, yield: 90.2%). 1 HNMR(400MHz, CDCl 3 )δppm: 8.25 (s, 1H), 6.46 (s, 1H).

Embodiment 2

[0052] Example 2: Preparation of 5-methoxy-2-nitrobenzo[b]thiophen-4,7-dione (2)

[0053] Add the raw material 5-bromo-2-nitrobenzo[b]thiophen-4,7-dione (27.4mg, 0.1mmol) to the mixed solvent of toluene (5mL) and methanol (0.5mL), and then add cesium carbonate solid (47mg, 0.14mmol, 1.50eq), stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, dried, and the solvent was removed. The residue was separated on a silica gel column (developing solvent: 70% petroleum ether 30% ethyl acetate) to obtain 17.8 mg of a yellow solid with a yield of 77.3%. 1 H NMR(400MHz, CDCl 3 )δppm: 3.95 (s, 3H) 6.18 (s, 1H) 8.28 (s, 1H).

[0054] Compound 3 can be obtained by repeating the steps in Example 2.

Embodiment 3

[0055] Example 3: Preparation of 5-azido-benzo[b]thiophene-4,7-dione (Ⅲ)

[0056] Take 5-bromo-benzo[b]thiophene-4,7-dione (1.21g, 5mmol) and dissolve it in a mixture of 20mL methanol, dichloromethane and water (volume ratio 9:2:2), then Add solid sodium azide (812 mg, 2.5 eq) and continue stirring at room temperature for 2 hours. Dichloromethane was added to the reaction solution for extraction, the aqueous phase was adjusted to pH=11 with 10% sodium hydroxide solution, and then NaClO solution was added to quench the excess sodium azide. After the organic phase is dried, it is spin-dried to obtain a brown solid powder (0.91g, yield: 88.8%). 1 H NMR(400MHz, CDCl 3 )δppm: 7.67(d,J=4.8Hz,1H), 7.58(d,J=4.8Hz,1H), 6.34(s,1H).

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Abstract

The invention relates to the technical field of medicine, and provides substituted thieno-quinone compounds and pharmaceutically acceptable salts thereof. The structural general formula of the substituted thieno-quinone 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 present invention relates to the technical field of medicine, in particular to a new substituted thienoquinone compound, a preparation method, and application as an antifungal medicine. Background technique [0002] In recent years, the abuse of antibiotics, tumor radiotherapy and chemotherapy, organ transplantation and other factors have caused immunosuppression. In addition to the rapid increase in AIDS patients, deep infections of Candida albicans, Aspergillus fumigatus, Pneumocystis carinii and Cryptococcus neoformans have increased significantly, and deep fungi Infection has now become the main cause of death from major diseases such as AIDS and tumors. However, clinically ideal antifungal drugs are scarce. Polyene antibiotics (such as amphotericin B) that act on fungal cell membrane lipids are the first choice for treatment, but they have serious side effects and severely limited clinical application. Azole drugs (such as fluconazole, itraconazo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/62C07D409/04C07D409/12A61K31/381A61K31/4192A61K31/4025A61K31/5377A61P31/10
Inventor 张万年盛春泉江志赶董国强缪震元姚建忠
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY