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Indoleamine 2,3-dioxygenase inhibitor and preparation method and applications thereof

A hydroxyl, selected technology, applied in the field of drug development, can solve the problem of increased number and activation

Active Publication Date: 2017-06-23
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Another mechanism leading to immunosuppression is the high expression of indoleamine 2,3-dioxygenase resulting in an increase in kynurenine, which can leave the cell, enter the extracellular matrix, and then enter the nearby lymph Cells regulate CD8+ T cells and regulatory Treg cells by binding AHR transcription factors, the activity of CD8+ cytotoxic T cells is inhibited, and the number of regulatory Treg cells is increased and activated, resulting in immune suppression

Method used

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  • Indoleamine 2,3-dioxygenase inhibitor and preparation method and applications thereof
  • Indoleamine 2,3-dioxygenase inhibitor and preparation method and applications thereof
  • Indoleamine 2,3-dioxygenase inhibitor and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2, 5-oxadiazole-3-carbaoxamidine (1)

[0128]

[0129] Step 1: 4-Amino-N'-hydroxy-1,2,5-oxadiazole-3-carbaoxamidine 1b

[0130] Dissolve malondicyanide (20g, 303mmol) in 350ml of water, heat at 45°C for 5 minutes, then add sodium nitrite (23g, 333.3mmol) under ice-cooling, add 6N HCl (3.4ml) when the temperature rises to 10°C, The temperature rose to 16°C, kept the temperature at 16-18°C and stirred for 1.5 hours, cooled to 13°C, added 50% hydroxylamine aqueous solution (61.7g, 909mmol) at one time, the temperature rose sharply to 27°C, and stirred at this temperature One hour, then reflux for 2 hours, cool to room temperature and stir overnight, add 6N HCl (49ml) dropwise under ice bath, adjust the pH to 7, continue stirring under ice bath, precipitate solid, filter, wash the filter cake with water, and dry to obtain Compound 4-amino-N'-hydroxy-1,2,5-oxadiazole-3-carbaoxamid...

Embodiment 2

[0165] (Z)-N-(3-bromo-4-fluorophenyl)-4-((2-(N,S-dimethylsulfonimidoyl)ethyl)amino)-N'-hydroxyl- 1,2,5-oxadiazole-3-carbaoxamidine (2)

[0166]

[0167] Step 1: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(N,S-dimethylsulfonimidoyl)ethyl)amino)-1, 2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 2a

[0168] Add 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5- Oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (40mg, 0.09mmol), trimethyloxonium tetrafluoroboric acid (20mg, 0.13mmol), dichloromethane (8 mL), stirred at room temperature for 15 minutes, added sodium carbonate (57.3 mg, 0.54 mmol), and reacted overnight at room temperature. Stop the reaction, add water (20mL), extract with ethyl acetate (20mL*2), combine organic phases, wash with saturated sodium chloride (30mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, separate and purify by preparing a silica gel plate (developing solvent: dichloromethane / methanol=10 / 1; eluent: e...

Embodiment 3

[0174] (Z)-N-(3-bromo-4-fluorophenyl)-4-((2-(ethylsulfonimidoyl)ethyl)amino)-N'-hydroxyl-1,2,5- Oxadiazole-3-carbaoxamidine (3)

[0175]

[0176] Step 1: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(ethylthio)ethyl)amino)-1,2,5-oxadiazole-3- base)-1,2,4-oxadiazol-5(4H)-one 3b

[0177] 2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3- yl)-1,2,5-oxadiazol-3-yl)amino)ethyl methanesulfonate 3a (928mg, 2.0mmol) was dissolved in N,N-dimethylformamide (8mL), added ethylsulfide Sodium alkoxide (205mg, 2.2mmol), stirred at room temperature for 20min. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added water (50mL) to quench the reaction, extracted with ethyl acetate (50mL*2), combined organic phases were washed with saturated sodium chloride (50mL), dried over anhydrous sodium sulfate, Filtrate, add silica gel to the filtrate, spin dry column chromatography directly, petroleum ether / ethyl acetate (5 / 1 to 3 / 1), get 4-(3-b...

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Abstract

The invention relates to an indoleamine 2,3-dioxygenase inhibitor with a structure represented by the formula (I) and a preparation method and applications thereof. The indoleamine 2,3-dioxygenase (IDO) inhibitor is the derivative of (Z)-N'-hydroxyl-N-phenyl formamidine, has an extremely high activity on inhibiting IDO, can effectively inhibit the activity of IDO, and can be used to inhibit the immunity inhibition of patients. The inhibitor can be widely used to treat or prevent cancer / tumor, viral infection, depression, neurodegenerative diseases, wounds, age related cataract, organ-graft refection, and autoimmune disease, and can be advantageously to be used as a novel immune-suppressor.

Description

technical field [0001] The invention belongs to the field of drug development, and specifically relates to an indoleamine 2,3-dioxygenase inhibitor and a preparation method and application thereof. Background technique [0002] Indoleamine 2,3-dioxygenase (IDO for short) is a protease related to tryptophan metabolism. Tryptophan is one of the eight essential amino acids. Tryptophan can be used to synthesize proteins in the body. Tryptophan can also be used as a precursor substrate to synthesize 5-hydroxytryptamine and melatonin (N- Acetyl-5-methoxytryptamine). Serotonin and melatonin are neurotransmitters and neuroendocrine hormones involved in the regulation of various neurological and physiological processes in the body. In addition, tryptophan can also produce metabolites such as kynurenine through the kynurenine metabolic pathway. The first step of the kynurenine metabolic pathway is catalyzed by indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase (TDO), tryptop...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/08A61K31/4245A61P35/00A61P35/02A61P37/06A61P31/12A61P25/24A61P25/28A61P27/12
CPCC07D271/08A61K31/4245
Inventor 赵志明吴盛华郭凤英李凯龙黄志强潘忠宗包如迪喻红平徐耀昌
Owner SHANGHAI HANSOH BIOMEDICAL
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