Oxadiazole derivative, preparing method of oxadiazole derivative and application of oxadiazole derivative to medicines

A technology of compounds and mixtures, applied in the field of oxadiazole derivatives, their preparation and their application in medicine, can solve the problems of not finding a good IDO inhibitor

Active Publication Date: 2017-04-19
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, preparing method of oxadiazole derivative and application of oxadiazole derivative to medicines
  • Oxadiazole derivative, preparing method of oxadiazole derivative and application of oxadiazole derivative to medicines
  • Oxadiazole derivative, preparing method of oxadiazole derivative and application of oxadiazole derivative to medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0171] (S)-N-(3-bromo-4-fluorophenyl)-4-((2,3-dihydroxypropyl)thio)-N'-hydroxy-1,2,5-oxadiazole- 3-Formamidine

[0172]

[0173]

[0174] first step

[0175] 4-(3-Bromo-4-fluorophenyl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazole-5(4H )-ketone

[0176] 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H )-ketone 1a (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 hydrogen peroxide solution (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. Separate the liquids, extract the aqueous phase with ethyl acetate (100 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the resulting r...

Embodiment 2

[0190] (R)-N-(3-bromo-4-fluorophenyl)-4-((2,3-dihydroxypropyl)thio)-N'-hydroxy-1,2,5-oxadiazole- 3-Formamidine

[0191]

[0192] first step

[0193] (R)-4-(3-bromo-4-fluorophenyl)-3-(4-(((2,2-dimethyl-1,3-dioxolan-4-yl)methyl) Thio)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

[0194] 4-(3-bromo-4-fluorophenyl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5( 4H)-Kone 1b (300 mg, 0.81 mmol) was dissolved in 15 mL of tetrahydrofuran, and (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol 2a (143 mg , 0.96mmol, prepared by the known method "European Journal of Organic Chemistry, 2006, (21), 4805-4812"), potassium carbonate (223mg, 1.62mmol) was added, and reacted at 25°C for 48 hours. After the reaction, the title product (R)-4-(3-bromo-4-fluorophenyl)-3-(4-(((2,2-dimethyl-1,3-dioxolane- 4-yl)methyl)thio)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 2b, without purification Proceed directly to the next reaction.

[0195] second step

[0196] (R)-N-(3-bromo-4-fluor...

Embodiment 3

[0204] N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(1-(sulfamoylamino)cyclopropyl)ethyl)thio)-1,2,5 -Oxadiazole-3-carboxamidine

[0205]

[0206] first step

[0207] S-(2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)ethyl)acetylsulfate

[0208] Dissolve 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)ethylmethylsulfonate 3a (1.2g, 4.3mmol, prepared by the method disclosed in the patent application "WO2013020993") in 15mL Add thioacetic acid (327 mg, 4.3 mmol) and cesium carbonate (1.39 g, 4.3 mmol) to tetrahydrofuran, and react at 65° C. for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, 50 mL of water was added, extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product S- (2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)ethyl)acetylsulfate 3b (200 mg, yellow oil), the product was dir...

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Abstract

The invention relates to an oxadiazole derivative, a preparing method of the oxadiazole derivative and application of the oxadiazole derivative to medicines, in particular to an oxadiazole derivative shown in the general formula (1), a preparing method of the oxadiazole derivative, a medicine composition comprising the derivative and application of the oxadiazole derivative to treatment of diseases with the tryptophan metabolic pathway pathological feature mediated by IDO. The diseases include the cancer, the alzheimer disease, the autoimmune disease, the depression, the anxiety disorder, the cataract, the psychological disorder and the AIDS. Definition of substituent groups in the general formula (1) is the same with the definition of the substituent groups 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): C07D413/12C07D271/08A61K31/4245C07D413/14A61P31/18A61P31/04A61P25/28A61P25/14A61P25/16A61P37/02A61P25/22A61P25/24A61P25/18A61P35/00A61P35/02A61P27/12A61P27/02
CPCC07D271/08C07D413/12C07D413/14
Inventor 屠汪洋刘志伟费洪博吕贺军贺峰陶维康孙飘扬
Owner JIANGSU HENGRUI MEDICINE CO LTD
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