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: 2013-06-12
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) of 6-fluoro-4-thiochromanone, 10.6g (0.1mol) of benzaldehyde and 200mL of 85% phosphoric acid in sequence in a 500mL reaction flask, stir and react at 90°C for 6 hours, cool the reaction solution Slowly poured into 200g of ice water to form a purple precipitate, which was filtered by suction to obtain the crude product of 6-fluoro-3-benzylidene-4-thiochromanone, which was recrystallized with chloroform-ethanol mixed solvent to obtain 22.2g of the fine product, the yield 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] Add 2.7g (0.01mol) 6-fluoro-3-benzylidene-4-thiochromanone and 50mL absolute ethanol to a 100mL reaction flask, heat to 50°C to dissolve, then...

Embodiment 2

[0072] Example 2: 8-fluoro-3-phenyl-2,3,4,5-tetrahydro-4H-benzo[b]thiopyrano[4,3-c]pyrazole-2-thiocarboxamide preparation of

[0073] Add 2.7g (0.01mol) of 6-fluoro-3-benzylidene-4-thiochromanone, 2.3g (0.1mol) of thiosemicarbazide, 100ml of absolute ethanol into a 100mL reaction flask, and dropwise add glacial acetic acid 0.1 ml, heated to reflux for 5 hours, cooled to room temperature, precipitated solid, suction filtered, rinsed with 10ml of absolute ethanol, dried to obtain 8-fluoro-3-phenyl-2,3,4,5-tetrahydro-4H- The crude product of benzo[b]thiapyrano[4,3-c]pyrazole-2-thiocarboxamide was purified by silica gel column chromatography, wherein the eluent used was petroleum ether:ethyl acetate=40:1, 2.3 g of fine product was obtained, 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...

Embodiment 3

[0074] Example 3: N-(3,4-dichlorophenyl)-8-fluoro-3-(2-furyl)-2,3,4,5-tetrahydro-4H-benzo[b]thiopyran Preparation of [4,3-c]pyrazole-2-carboxamide

[0075] Step 1: Preparation of 6-fluoro-3-(2-furylidene)-4-thiochromanone

[0076] Add 6g (0.15mol) NaOH and 60mL water successively into a 100mL reaction flask, add 30mL absolute ethanol after dissolving, add 21.8g (0.12mol) 6-fluoro-4-thiochromanone and 13.4g (0.14mol) under stirring ) furfural, stirred at room temperature for 2.5 hours, suction filtered, and the filter cake was rinsed with 20ml of absolute ethanol, and after being drained, the crude product of 6-fluoro-3-(2-furyl methylene)-4-thiochromanone was obtained. Using chloroform-ethanol mixed solvent as solvent to carry out recrystallization to obtain 6-fluoro-3-(2-furyl methylene)-4-thiochromanone fine product as a yellow solid, yield 23.7g, yield 76%, mp : 150-152°C.

[0077] Step 2: N-(3,4-Dichlorophenyl)-8-fluoro-3-(2-furyl)-2,3,4,5-tetrahydro-4H-benzo[b]thiopyra...

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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 invention relates to the technical field of medicine, in particular to an antifungal derivative and a pharmaceutically acceptable salt thereof. Background technique [0002] Mycosis is a multiple, refractory disease. In recent years, due to the extensive use of drugs such as antibiotics, hormones, and immunosuppressants, and the widespread use of large-scale operations such as catheters, intubations, and organ transplants, fungal infections, especially deep fungal infections, have become increasingly serious. Drugs for the treatment of fungal diseases are scarce. 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. Therefore, it is still a very meaningful work to develop antifungal drugs with high efficiency, low toxicity and new mechanism of action. Co...

Claims

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Application Information

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Patent Type & Authority Patents(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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