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Antifungal agent 2-[(2,3-dihydro-4H-benzo-[b]thiapyran-4-ylidene) hydrazono]-4-oxotetrahydro thiazole (oxazole)-5-acetic acid derivative

The technology of oxotetrahydrothiazole and oxotetrahydrooxazole is applied in the field of medicine and can solve the problems of poor curative effect of deep fungal infection, limited clinical application, obvious toxic and side effects and the like

Active Publication Date: 2012-05-16
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 agent 2-[(2,3-dihydro-4H-benzo-[b]thiapyran-4-ylidene) hydrazono]-4-oxotetrahydro thiazole (oxazole)-5-acetic acid derivative
  • Antifungal agent 2-[(2,3-dihydro-4H-benzo-[b]thiapyran-4-ylidene) hydrazono]-4-oxotetrahydro thiazole (oxazole)-5-acetic acid derivative
  • Antifungal agent 2-[(2,3-dihydro-4H-benzo-[b]thiapyran-4-ylidene) hydrazono]-4-oxotetrahydro thiazole (oxazole)-5-acetic acid derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1: 2-[(3-Benzyl-6-fluoro-2,3-dihydro-4H-benzo[b]thiopyran-4-ylidene)hydrazono]-4-oxotetrahydro Preparation of thiazole-5-acetic acid

[0071] Step 1: Preparation of 1-(3-benzyl-6-fluoro-4-thiochromanone) thiosemicarbazone

[0072] Put 2.7g (10mmol) 3-benzyl-6-fluoro-4-thiochromanone, 1g (10mmol) thiosemicarbazide and 70ml absolute ethanol into a 250ml reaction bottle, add 0.5ml of concentrated hydrochloric acid dropwise, and heat to The reaction was refluxed for 12 hours, TLC monitored the reaction end point, a yellow solid was precipitated, the reaction solution was cooled to room temperature, filtered with suction, and the filter cake was rinsed twice with 15-25ml ethanol to obtain 3.0 g of a light yellow solid with a yield of 88.0%, LC-MS (m / z): 346[M+H] + , Mp160-161°C.

[0073] Step 2: 2-[(3-Benzyl-6-fluoro-2,3-dihydro-4H-benzo[b]thiopyran-4-ylidene)hydrazono]-4-oxotetrahydrothiazole - Preparation of 5-acetic acid

[0074] Drop into 3.4g (10mmol) 1-(3-be...

Embodiment 2

[0075] Example 2: 2-[(3-Benzyl-6-fluoro-2,3-dihydro-4H-benzo[b]thiopyran-4-ylidene)hydrazono]-4-oxotetrahydro Preparation of oxazole-5-acetic acid

[0076] Step 1: Preparation of 1-(3-benzyl-6-fluoro-4-thiochromanone) semicarbazone

[0077] Put 2.7g (10mmol) 3-benzyl-6-fluoro-4-thiochromanone, 0.75g (10mmol) semicarbazide and 50ml absolute ethanol in a 250ml reaction bottle, add 0.5ml concentrated hydrochloric acid dropwise, and heat to reflux Reacted for 10 hours, TLC monitored the reaction end point, the reaction solution was cooled to room temperature, solids were precipitated, filtered with suction, and the filter cake was rinsed twice with 15-25ml ethanol to obtain 2.8g of a light yellow solid with a yield of 84%, LC-MS (m / z): 330[M+H] + , Mp188-190°C.

[0078] Step 2: 2-[(3-Benzyl-6-fluoro-2,3-dihydro-4H-benzo[b]thiopyran-4-ylidene)hydrazono]-4-oxotetrahydrooxa Preparation of azole-5-acetic acid

[0079] Put 3.3g (10mmol) 1-(3-benzyl-6-fluoro-4-thiochromanone) semi...

Embodiment 3

[0080] Example 3: 2-[(3-Benzyl-6-chloro-2,3-dihydro-4H-benzo[b]thiopyran-4-ylidene)hydrazono]-4-oxotetrahydro Preparation of thiazole-5-acetic acid

[0081] Step 1: Preparation of 1-(3-benzyl-6-chloro-4-thiochromanone) thiosemicarbazone

[0082] Put 2.9g (10mmol) 3-benzyl-6-chloro-4-thiochromanone, 1g (10mmol) thiosemicarbazide and 70ml absolute ethanol in a 250ml reaction bottle, add 0.5ml of concentrated hydrochloric acid dropwise, and heat to The reaction was refluxed for 12 hours, TLC monitored the end of the reaction, a yellow solid was precipitated, the reaction solution was cooled to room temperature, filtered with suction, and the filter cake was rinsed twice with 15-25ml ethanol to obtain 3.0 g of a light yellow solid with a yield of 83%, LC-MS (m / z): 362[M+H] + , Mp171-173°C.

[0083] Step 2: 2-[(3-Benzyl-6-chloro-2,3-dihydro-4H-benzo[b]thiopyran-4-ylidene)hydrazono]-4-oxotetrahydrothiazole - Preparation of 5-acetic acid

[0084] Drop into 3.6g (10mmol) 1-(3-ben...

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Abstract

The invention relates to the technical field of medicines, in particular relates to a 2-[(2,3-dihydro-4H-benzo-[b]thiapyran-4-ylidene) hydrazono]-4-oxotetrahydro thiazole (oxazole)-5-acetic acid derivative or a salt thereof and a preparation method thereof, and also relates to a medicine taking the derivative or salt thereof as an active ingredient. Results of a test used for testing in vitro anti-fungal activity of the compound provided by the invention by adopting a two-fold concentration dilution method show that the compound has strong killing effect on clinically common pathogenic fungi and can overcome the defects that azoles antifungal drugs which are widely used clinically at present have high toxic and side effects, easily generate drug resistance and the like.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a series of antifungal compounds or pharmaceutically acceptable salts 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; 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. ...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D417/12A61K31/422A61K31/427A61P31/10A61P17/00
Inventor 郭春苏昕刘扬骆伟邢昭彬孙历李翠丽梁隆黄耀宗
Owner SHENYANG PHARMA UNIVERSITY
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