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1H-indazole-4-ether compound and application of 1H-indazole-4-ether compound serving as IDO inhibitor

A compound and solvate technology, applied in the preparation of carbon-based compounds, amino compounds, and organic compounds, etc., can solve the problems of inhibiting killing effect, stagnation of synthesis, and reducing the concentration of tryptophan.

Active Publication Date: 2018-01-23
XIHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Under normal circumstances, IDO is expressed at a low level in the body, but most tumor cells will form a high expression of IDO, which converts L-tryptophan into N-formylkynurenine, reducing the color of the cell microenvironment. The concentration of tryptophan makes the synthesis of tryptophan-dependent T cells stagnate in the G1 phase, and the proliferation of T cells is inhibited, thereby inhibiting the killing effect of the body's immune system on tumor tissue

Method used

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  • 1H-indazole-4-ether compound and application of 1H-indazole-4-ether compound serving as IDO inhibitor
  • 1H-indazole-4-ether compound and application of 1H-indazole-4-ether compound serving as IDO inhibitor
  • 1H-indazole-4-ether compound and application of 1H-indazole-4-ether compound serving as IDO inhibitor

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Experimental program
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Effect test

Embodiment 1

[0075] The preparation of embodiment 1 compound of the present invention

[0076] 1. Synthesis of key intermediates

[0077] 1, the synthesis of methyl m-iodomethylbenzoate (5)

[0078]

[0079] Compound 1 (1.00g, 6.67mmol) was dissolved in 15mL of methanol, and SOCl was added under stirring at 0°C 2 (1.45mL, 20.00mmol), warmed up to room temperature and stirred for 12h, then the reaction was complete by TCL detection. The reaction solution was concentrated, water was added to the residue, and saturated NaHCO 3 The aqueous solution was adjusted to pH=7-8. Extracted 3 times with ethyl acetate. The organic layer was washed with water, dried, and concentrated to obtain compound 3 (0.83 g, yield 76%) as a pale yellow oil. It was directly used in the next step of synthesis without purification by column chromatography.

[0080] Compound 3 (1.00g, 6.09mmol) and I 2 (0.93g, 3.67mmol) dissolved in 10mL CH 2 Cl 2 , cooled to -5°C and stirred. Dissolve 1,1,3,3-tetramethyldi...

Embodiment 2

[0122] Embodiment 2 The inhibitory activity of the compound of the present invention to IDO protein

[0123] Recombinant human IDO protein is expressed in Escherichia coli and purified by nickel affinity chromatography. The compound's IDO inhibitory activity test uses L-tryptophan as a substrate. The compounds to be tested were dissolved in 10% DMSO solution to prepare dilutions. Take 5uL of the diluted solution and add it to the 100μL reaction system. The 100 μL reaction system contained 0.5% DMSO, 40 nmol / L IDO, 900 μmol / LL-tryptophan, and other reaction coexistents (potassium phosphate buffer, ascorbic acid, catalase, methylene blue). The reaction mixture was incubated at 37°C for 180 minutes, and then trichloroacetic acid was added to terminate the reaction. The concentration of N-formylkynurenine produced was measured at 321 nm using a Tecan Infinite M1000 microplate reader to evaluate the inhibitory activity of the compound on IDO. The negative control was 5 μL of bu...

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Abstract

The invention discloses a 1H-indazole-4-ether compound, a preparation method thereof, and application of the 1H-indazole-4-ether compound serving as an IDO inhibitor. The 1H-indazole-4-ether compoundcan be used for preventing and / or treating various diseases such as Alzheimer's disease, cataract, infection related to cell immune activation, autoimmune disease, AIDS, cancer, depression or tryptophan metabolic disorder.

Description

technical field [0001] The present invention relates to 1H-indazole-4-ether compound, and also relates to its preparation method and application as IDO inhibitor. Background technique [0002] Indoleamine 2,3-dioxygenase (Indoleamine 2,3-dioxygenase, IDO) catalyzes the epoxidation and cleavage of indole in indoleamine molecules such as tryptophan, making it catabolized by the kynuric acid pathway. fast enzyme. [0003] IDO plays an important role in tumor immune immunity and tumorigenesis. Under normal circumstances, IDO is expressed at a low level in the body, but most tumor cells will form a high expression of IDO, which converts L-tryptophan into N-formylkynurenine, reducing the color of the cell microenvironment. The concentration of tryptophan makes the synthesis of tryptophan-dependent T cells stagnate in the G1 phase, and the proliferation of T cells is inhibited, thereby inhibiting the killing effect of the body's immune system on tumor tissues. At the same time, ...

Claims

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Application Information

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IPC IPC(8): C07D231/56C07C67/307C07C67/08C07C69/78C07C41/22C07C43/225C07C45/64C07C47/575C07C209/74C07C211/52C07C221/00C07C223/06A61K31/416A61P25/28A61P27/12A61P31/00A61P37/02A61P31/18A61P35/00A61P25/24
Inventor 王周玉钱珊杨羚羚赖朋李国菠刘思言李会周王伟何彦颖张曼
Owner XIHUA UNIV
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