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2-amino-1,3,4-thiadiazine and 2-amino-1,3,4-oxadiazine based antifungal agents

A technology of antifungal agents and diazines, which can be applied in the direction of antifungal agents, medical preparations containing active ingredients, active ingredients of heterocyclic compounds, etc., and can solve the problems of flucytosine’s limited therapeutic use

Inactive Publication Date: 2018-08-03
F2G LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, widespread resistance to flucytosine limits its therapeutic use

Method used

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  • 2-amino-1,3,4-thiadiazine and 2-amino-1,3,4-oxadiazine based antifungal agents
  • 2-amino-1,3,4-thiadiazine and 2-amino-1,3,4-oxadiazine based antifungal agents
  • 2-amino-1,3,4-thiadiazine and 2-amino-1,3,4-oxadiazine based antifungal agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0220] Example 1: 5-(2-Methoxy-ethyl)-6H-[1,3,4]thiadiazin-2-ylamine

[0221]

[0222] A) Preparation of 1-chloro-4-methoxy-butan-2-one.

[0223] At 0°C, to anhydrous AlCl 3 (4.87g, 36.6mmol) dissolved in 50mL of anhydrous CH 2 Cl 2 To the resulting solution was added dropwise 3-chloro-2-ethoxymethoxy-propene (5.0 g, 36.6 mmol) in CH 2 Cl 2 solution, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with 200 mL of ice water, and then the mixture was subjected to standard ether treatment to gradually reach the desired product yield of 4 g (80%). The product was a brown liquid, which was obtained as crude The product is used in the next step.

[0224] B) Preparation of 5-(2-methoxy-ethyl)-6H-[1,3,4]thiadiazin-2-ylamine.

[0225] To a solution of 1-chloro-4-methoxybutan-2-one (4.0 g, 29.3 mmol) dissolved in 40 mL of acetonitrile was added thiosemicar...

Embodiment 2

[0226] Example 2: 5-m-tolyl-6H-[1,3,4]thiadiazin-2-ylamine hydrobromide

[0227]

[0228] To a solution of 3-methylphenacyl bromide (1.0 g, 4.3 mmol) in ethanol (20 mL) was added thiosemicarbazide (400 mg, 4.3 mmol) at 0°C, and after the addition was complete, the mixture was allowed to warm to room temperature and stir overnight. The resulting slurry was cooled to -20°C and the precipitate was collected by filtration, washed with cold ethanol and dried in vacuo. The pale yellow solid was suspended in 20 mL of ethanol containing 1 mL of 48% aqueous hydrobromic acid. The mixture was heated to reflux for 30 minutes, then cooled to room temperature overnight. The precipitate was filtered and purified by silica gel column chromatography using hexane:EtOAc (49:1) to afford 950 mg (70%) of 5-m-tolyl-6H-[1,3,4]thiadiazine-2- amine hydrobromide.

Embodiment 3

[0229] Example 3: 5-(3-Chloro-phenyl)-6H-[1,3,4]thiadiazin-2-ylamine hydrobromide

[0230]

[0231] A) Preparation of 2-bromo-1-(3-chloro-phenyl)-ethanone.

[0232] To a stirred solution of 1-(3-chloro-phenyl)-ethanone (5.0 g, 32.3 mmol) in chloroform (75 mL) was added bromine (1.66 mL, 32.2 mmol) at 5-10 °C. After the addition was complete, the temperature of the reaction mixture was slowly raised to room temperature and stirred at room temperature for 1 hour. The reaction was monitored by TLC, after the reaction was completed, the reaction was washed with 10% Na 2 S 2 o 3 solution (100 mL), the reaction mixture was diluted with CH 2 Cl 2 (50 mL) for extraction. The organic layer was washed with water (400 mL), dried and concentrated to afford 7.2 g (96%) of crude 2-bromo-1-(3-chloro-phenyl)-ethanone, which was used without purification in the following one step.

[0233] B) Preparation of 5-(3-chloro-phenyl)-6H-[1,3,4]thiadiazin-2-ylamine hydrobromide

[0234] To...

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PUM

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Abstract

The invention provides a compound which is a diazine of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for use as an antifungal agent. The formula (I) is shown in the specification, wherein X, N', C', A and E are as defined herein. The invention also provides the compound of Formula (I) as defined herein.

Description

technical field [0001] The present invention relates to diazine compounds of formula (I). The compounds can be used to treat animals or humans. For example, the compounds can be used to treat or prevent fungal infections. Background technique [0002] Invasive fungal infections are recognized as diseases of immunocompromised hosts. Over the past two decades, the number of recorded cases of fungal infection has increased significantly (Groll et al., 1996. J Infect 33, 23-32). This is due in part to increased awareness and improved diagnosis of fungal infections. However, the increase in incidence is largely due to a substantial increase in the number of susceptible individuals. This is due to a number of factors, including new and aggressive immunosuppressive therapies, increased survival of patients in intensive care, an increase in the number of transplant procedures, and greater use of antibiotics worldwide. [0003] Fungal infections occur with high frequency in cert...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/06C07D417/12C07D285/16A61K31/54A61P31/10
CPCA61K31/549A61P31/10C07D285/16C07D417/06C07D417/12A61K45/06
Inventor 格雷厄姆·爱德华·莫里斯·西布利拉尔斯·乔纳斯·马尔姆斯特伦约翰娜·玛丽亚·拉森
Owner F2G LTD
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