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Indoleamine 2,3-dioxygenase inhibitor and application thereof

一种选自、烷基的技术，应用在医药领域，能够解决抑制效力低下等问题

Pending Publication Date: 2018-11-02
TRANSTHERA SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the existing indoleamine 2,3-dioxygenase (IDO) inhibitors generally have low inhibitory efficacy, and there is currently no indoleamine 2,3-dioxygenase (IDO) inhibitor drug available

Method used

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  • Indoleamine 2,3-dioxygenase inhibitor and application thereof
  • Indoleamine 2,3-dioxygenase inhibitor and application thereof
  • Indoleamine 2,3-dioxygenase inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0142] EA: ethyl acetate

[0143] PE: petroleum ether

[0144] DMA: N,N-Dimethylacetamide

[0145] THF: Tetrahydrofuran

[0146] DCM: dichloromethane

[0147] TEA: Triethanolamine

[0148] TFA: Trifluoroacetic acid

preparation example 1

[0149] Preparation Example 1 Synthesis of 4-amino-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine

[0150]

[0151] Step 1: Synthesis of 4-amino-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine

[0152]

[0153] Add the raw material malononitrile (50.0g, 0.76mol, 1.0eq) into a four-neck flask, heat to dissolve (about 50°C), add water (0.5L), and put in an ice-water bath at about 10°C, add sodium nitrite (57.72 g, 0.83mol, 1.1eq), after the addition was completed, hydrochloric acid (6N, 8.5mL) was added dropwise below 10°C, after the drop was completed, the mixture was stirred in an ice-water bath for 0.5h until the temperature remained constant, and the above reaction solution was designated as A. H 2 NOH·HCl (158.4g, 2.28mol, 3.0eq) was dissolved in water (255mL), and a solution of potassium hydroxide (127.9g, 2.28mol, 3.0eq) in water (255mL) was added thereto. ℃) stirred for 10 min, and the above reaction solution was denoted as B. Cool the reactio...

preparation example 2

[0163] Preparation 2 4-(3-bromo-4-fluorophenyl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazole- Synthesis of 5(4H)-ketone

[0164]

[0165] Step 1: 3-(4-Amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo4-fluorophenyl)-1,2,4-oxadiazol-5( Synthesis of 4H)-ketone

[0166]

[0167] 4-Amino-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine (5.0g, 15.8mmol, 1.0eq) was dissolved in Add carbonyldiimidazole (3.85g, 23.7mmol, 1.5eq) to ethyl acetate (65mL), heat the reaction at 60°C for 0.5h, monitor the completion of the reaction by TLC, cool the reaction solution to room temperature, wash with 1mol / L hydrochloric acid (65mL× 2), combine the organic phases, separate the organic phases, concentrate to dryness, the crude product is subjected to beating and suction filtration with methyl tert-butyl ether to obtain 3-(4-amino-1,2,5-oxadiazol-3-yl) -4-(3-Bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (3.53 g, yield: 65%).

[0168] Step 2: 4-(3-Bromo-4-fluorophenyl)-3...

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PUM

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Abstract

The invention belongs to the technical field of medicines and particularly relates to a compound represented by a formula I (shown in the description) as well as pharmaceutically acceptable salt and stereisomer of the compound. X, Y, Z, R1, R2, R3, R1a, R2a, m and N in the formula I are defined in the description. The invention further relates to pharmaceutical preparations, pharmaceutical compositions of the compounds and use of the pharmaceutical preparations and the pharmaceutical compositions in preparation of drugs for treating related diseases abnormally medicated by indoleamine 2,3-dioxygenase (IDO).

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to indoleamine 2,3-dioxygenase (IDO) inhibitor compounds, pharmaceutically acceptable salts and stereoisomers thereof, and pharmaceutical preparations and pharmaceutical compositions of these compounds , and its use in the preparation of medicines for treating related diseases mediated by indoleamine 2,3-dioxygenase (IDO) abnormalities. Background technique [0002] Tryptophan (Trp) is an essential amino acid used in the body to biosynthesize proteins, niacin and the neurotransmitter serotonin (serotonin). Indoleamine 2,3-dioxygenase (IDO) is an intracellular heme-containing monomeric enzyme that is widely distributed in many tissues and cells of humans and animals. IDO can catalyze the first step of indole epoxidative cleavage of L-tryptophan to generate kynurenine, which is also a key rate-limiting reaction. IDO is expressed at a low level in the normal state of the body, and its...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D271/08A61K31/4245A61K31/454A61K31/5377A61P31/00A61P25/00A61P35/00A61P35/02A61P31/16A61P31/14A61P31/22A61P31/18A61P25/28A61P25/24A61P37/02
CPCA61P25/00A61P25/24A61P25/28A61P31/00A61P31/14A61P31/16A61P31/18A61P31/22A61P35/00A61P35/02A61P37/02C07D271/08C07D413/12C07B2200/07A61P31/12A61P37/06C07D493/08
Inventor 吴永谦李琳
Owner TRANSTHERA SCIENCES (NANJING) INC
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