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Oxadiazole derivative, preparation method therefor and use of oxadiazole derivative in medicines

A technology for compounds and mixtures, applied to oxadiazole derivatives, their preparation and their application in medicine, can solve the problems of not finding good IDO inhibitors and the like

Inactive Publication Date: 2017-06-23
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] IDO inhibitors have good application prospects as drugs in the pharmaceutical industry, but no good IDO inhibitors have yet been found as marketed drugs. In order to achieve better tumor treatment effects and better meet market demand, the inventor hopes Can develop a new generation of selective IDO inhibitors with high efficiency and low toxicity

Method used

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  • Oxadiazole derivative, preparation method therefor and use of oxadiazole derivative in medicines
  • Oxadiazole derivative, preparation method therefor and use of oxadiazole derivative in medicines
  • Oxadiazole derivative, preparation method therefor and use of oxadiazole derivative in medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0162] N-(3-chlorophenyl)-N'-hydroxy-4-(((1R,4R)-4-(sulfamoylamino)cyclohexyl)amino)-1,2,5-oxadiazole-3 - formamidine

[0163]

[0164] first step

[0165] 4-(3-Chlorophenyl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 1b

[0166] 3-(4-Amino-1,2,5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one 1a (2.0g, 7.15mmol, prepared by the method disclosed in the patent application "WO2006122150") was dissolved in 5mL of trifluoroacetic acid, added 5mL of 30% hydrogen peroxide solution, heated to 45°C and stirred for 12 hours. The reaction solution was cooled to 25°C, diluted with 20 mL of ethyl acetate, quenched with 20 mL of saturated sodium thiosulfate solution, separated, the aqueous phase was extracted with ethyl acetate (15 mL×2), the organic phases were combined, anhydrous sodium sulfate After drying and filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtai...

Embodiment 2

[0185] N-(3-bromo-4-fluorophenyl-4-((2,3-dihydro-1H-inden-2-yl)amino)-N'-hydroxyl-1,2,5-oxadiazole- 3-Formamidine

[0186]

[0187] first step

[0188] 4-(3-Bromo-4-fluorophenyl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazole-5(4H )-one 2b

[0189] 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H )-ketone 2a (13.0 g, 41.1 mmol, prepared by the method disclosed in patent application "WO2014066834") was added to 150 mL of trifluoroacetic acid, 90 mL of aqueous hydrogen peroxide (30%), and reacted at 45°C for 48 hours. After the reaction, cool down, add 300mL saturated sodium thiosulfate solution and 150mL ethyl acetate, stir and react for 20 minutes, and detect no peroxide with potassium iodide test paper. The liquid was separated, the aqueous phase was extracted with ethyl acetate (100 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obt...

Embodiment 3

[0198] N-(3-Bromo-4-fluorophenyl-N'-hydroxy-4-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,5-oxadiazole-3 - formamidine

[0199]

[0200] 4-(3-bromo-4-fluorophenyl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5( 4H)-ketone 2b (100mg, 0.27mmol), 1-methyl-1H-pyrazol-4-amine 3a (26.1mg, 0.27mmol) was dissolved in 5mL tetrahydrofuran, and 32.4mL 2.5M sodium hydroxide solution was added, The reaction was stirred for 1.5 hours. After the reaction, pour the reaction solution into ice water, adjust the pH to neutral with 1N hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use thin-layer chromatography to eluent system The resulting residue was purified by A to afford the title product 3 (10 mg, yellow solid) in 10% yield.

[0201] MS m / z(ESI):396.3 / 398.3[M+1]

[0202] 1 H NMR (400MHz, DMSO-d 6 )δ11.52(s,1H),9.02(s,1H),8.61-8.62(m,1H),7.79-7.80(m,1H),7.46-7.48(m,1H),7.17-7.19(m, 1H),6....

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Abstract

The invention relates to an oxadiazole derivative, a preparation method therefor and use of the oxadiazole derivative in medicines. Particularly, the invention relates to an oxadiazole derivative represented by a general formula (I) shown in the description, a preparation method therefor, a pharmaceutical composition containing the derivative and use of the pharmaceutical composition in preparation of drugs for preventing and / or treating diseases with IDO mediated pathological features of a tryptophan metabolism pathway, wherein the diseases comprise cancer, Alzheimer's disease, autoimmune disease, melancholia, anxiety neurosis, cataract, psychological barrier and acquired immunodeficiency syndrome. Each substituent of the general formula (I) is the same as defined in the specification.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to oxadiazole derivatives, their preparation method and their application in medical research. The invention discloses oxadiazole derivatives as IDO inhibitors for treating colorectal disorders mediated by IDO. Diseases characterized by the pathology of amino acid metabolism pathways, including cancer, Alzheimer's disease, autoimmune diseases, depression, anxiety, cataracts, psychological disorders, and AIDS. Background technique [0002] Tumor biotherapy is a new treatment for tumor prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of tumor treatment after surgery, radiotherapy, and chemotherapy (ClinCancer Res, 1997; 3:2623-2629), which obtains the anti-tumor effect by mobilizing the host's natural defense mechanism, such as inhibiting the tumor immune escape mechanism media...

Claims

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Application Information

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IPC IPC(8): C07D271/08C07D413/12A61K31/4245A61K31/454A61P35/00A61P35/02A61P25/28A61P37/06A61P25/22A61P25/24
CPCC07D271/08C07D413/12
Inventor 吕贺军费洪博胡齐悦贺峰陶维康
Owner JIANGSU HENGRUI MEDICINE CO LTD
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