Antifungal agents of 2,3,4,5-tetrahydro-4H-benzo[b]thiopyrano[4,3,c]pyrazole-2-formamide derivatives

A 3-c, formamide technology, applied in the field of medicine, can solve the problems of poor curative effect, limited clinical application, obvious toxic and side effects of deep fungal infection, etc.

Active Publication Date: 2011-06-08
SHENYANG PHARMA UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Azole antifungal drugs are still the first choice. Although these antifungal drugs have certain curative effects, their clinical application is limited due to their obvious toxic and side effects and poor curative effect on deep fungal infections.

Method used

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  • Antifungal agents of 2,3,4,5-tetrahydro-4H-benzo[b]thiopyrano[4,3,c]pyrazole-2-formamide derivatives
  • Antifungal agents of 2,3,4,5-tetrahydro-4H-benzo[b]thiopyrano[4,3,c]pyrazole-2-formamide derivatives
  • Antifungal agents of 2,3,4,5-tetrahydro-4H-benzo[b]thiopyrano[4,3,c]pyrazole-2-formamide derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1: Preparation of 8-fluoro-3-phenyl-2,3,4,5-tetrahydro-4H-benzo[b]thiopyrano[4,3-c]pyrazole-2-carboxamide

[0068] Step 1: Preparation of 6-fluoro-3-benzylidene-4-thiochromanone

[0069] Add 18.2g (0.1mol) 6-fluoro-4-thiochromanone, 10.6g (0.1mol) benzaldehyde and 200mL 85% phosphoric acid in a 500mL reaction flask, stir and react at 90℃ for 6 hours. After cooling, the reaction solution Slowly poured into 200g of ice water to form a purple precipitate, filtered with suction to obtain crude 6-fluoro-3-benzylidene-4-thiochromanone, which was recrystallized with chloroform-ethanol mixed solvent to obtain 22.2g of refined product. Yield It is 82.2%, mp: 131-133°C.

[0070] Step 2: Preparation of 8-fluoro-3-phenyl-2,3,4,5-tetrahydro-4H-benzo[b]thiopyrano[4,3-c]pyrazole-2-carboxamide

[0071] In a 100mL reaction flask, add 2.7g (0.01mol) 6-fluoro-3-benzylidene-4-thiochromanone, 50mL of absolute ethanol, heat to 50℃ to dissolve it, then add 1.5g (0.02mol) ) 1.6 g (0.02 mol) ...

Embodiment 2

[0074] Example 2: 8-Fluoro-3-phenyl-2,3,4,5-tetrahydro-4H-benzo[b]thiopyrano[4,3-c]pyrazole-2-thioformamide Preparation

[0075] In a 100mL reaction flask, add 2.7g (0.01mol) 6-fluoro-3-benzylidene-4-thiochromanone, 2.3g (0.1mol) thiosemicarbazide, 100ml absolute ethanol, and add 0.1 glacial acetic acid dropwise. ml, heated to reflux for 5 hours, cooled to room temperature, precipitated solid, filtered with suction, rinsed with 10ml of absolute ethanol, and dried to obtain 8-fluoro-3-phenyl-2,3,4,5-tetrahydro-4H- Benzo[b]thiopyrano[4,3-c]pyrazole-2-thioformamide crude product, purified by silica gel column chromatography, the eluent used is petroleum ether: ethyl acetate = 40:1, The refined product was 2.3g, the yield was 67%, mp: 190-193°C. LC-MS(m / z): 343[M+H] + , 1 H-NMR(300MHz, CDCl 3 ): 2.05(s, 2H, NH 2 ), 2.18-2.41(m, 1H, CH), 2.61-2.93(t, 2H), 3.76-3.91(d, J=11.4Hz, 1H, CH), 6.94-7.17(d, J=8.7Hz, 2H , ArH), 7.23-7.38 (m, 1H, ArH), 7.12-7.21 (m, 5H, ArH).

Embodiment 3

[0076] Example 3: N-(3,4-Dichlorophenyl)-8-fluoro-3-(2-furyl)-2,3,4,5-tetrahydro-4H-benzo[b]thiopyran And [4,3-c]pyrazole-2-carboxamide preparation

[0077] Step 1: Preparation of 6-fluoro-3-(2-furylidene)-4-thiochromanone

[0078] In a 100mL reaction flask, add 6g (0.15mol) NaOH, 60mL of water, and then add 30mL of absolute ethanol after dissolving, add 21.8g (0.12mol) 6-fluoro-4-thiochromanone and 13.4g (0.14mol) with stirring ) Furan formaldehyde, stirred at room temperature for 2.5 hours, filtered with suction, the filter cake was rinsed with 20ml of absolute ethanol, and drained to obtain crude 6-fluoro-3-(2-furylidene)-4-thiochromanone. Recrystallize with chloroform-ethanol mixed solvent as solvent to obtain 6-fluoro-3-(2-furylidene)-4-thiochromanone as a yellow solid, yield 23.7g, yield 76%, mp : 150-152°C.

[0079] Step 2: N-(3,4-Dichlorophenyl)-8-fluoro-3-(2-furyl)-2,3,4,5-tetrahydro-4H-benzo[b]thiopyrano [4,3-c]Pyrazole-2-carboxamide preparation

[0080] Add 2.6g (0.01mo...

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Abstract

The invention relates to 2,3,4,5-tetrahydro-4H-benzo[b]thiopyrano[4,3,c]pyrazole-2-formamide derivatives and a preparation method thereof. The structural formula of the compounds is shown in the specifications. The invention also relates to pharmaceutically acceptable salts of the derivatives and medicines taking the derivatives and the salts thereof as active ingredients. The structure of the derivates is obtained according to an association principle in pharmaceutical chemistry; and the inventor has systematically and comprehensively studied the compounds, modified and transformed a plurality of sites in the structure, and tested the in-vitro antifungal activity of the compounds by a double dilution method. Serving as novel antifungal agents, the compounds have higher killing effect on clinically common pathogenic fungi, and can overcome the defects of large toxic and side effect, high possibility of generating tolerance and the like of the clinically widely used azole antifungal medicines at present.

Description

Technical field [0001] The present invention relates to the field of medical technology, in particular to an antifungal derivative and a pharmaceutically acceptable salt thereof. Background technique [0002] Fungal diseases are multiple and difficult to treat. In recent years, due to the large-scale use of antibiotics, hormones, immunosuppressants and other drugs in the clinic, and the widespread development of large-scale operations such as catheters, intubation, and organ transplantation, fungal infections, especially deep fungal infections, have become increasingly serious. Drugs used to treat fungal diseases are scarce. Azole antifungal drugs are still the first choice. Although these antifungal drugs have certain effects, their clinical application is limited due to their obvious side effects and poor efficacy on deep fungal infections. Therefore, it is still a very meaningful work to develop antifungal drugs with high efficiency, low toxicity and new mechanisms of action...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04A61K31/4162A61P31/10A61P17/00
Inventor 郭春苏昕刘扬李翠丽孙历邢昭彬梁隆黄耀宗
Owner SHENYANG PHARMA UNIVERSITY
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