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Novel indoleamine-2,3-dioxygenase inhibitor as well as preparation method and application thereof

A technology of polymorphism and triethylamine, which is applied in the direction of pharmaceutical formulations, medical preparations containing active ingredients, organic active ingredients, etc., to achieve the effects of easy industrial production, high yield, and simple operation

Active Publication Date: 2012-07-04
SHENYANG XINMA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the synthesis of functionalized tryptanthrins is a challenge for organic synthesis

Method used

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  • Novel indoleamine-2,3-dioxygenase inhibitor as well as preparation method and application thereof
  • Novel indoleamine-2,3-dioxygenase inhibitor as well as preparation method and application thereof
  • Novel indoleamine-2,3-dioxygenase inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Example 1: 8-(4-phenyl-1H-1,2,3-triazol-1-ylmethyl)tryptanthrin

[0102] (1) Preparation of 1-azidomethyl-4-nitrobenzene

[0103]

[0104] Add p-nitrobenzyl chloride (162mg, 1mmol), sodium azide (120μL, 1.2mmol), and dimethyl sulfoxide (121mg, 1.2mmol) into the reaction flask in sequence, and keep the aluminum foil away from light, and react at room temperature for 0.5-1h. TLC detection showed that after the reaction was completed, water was added to the reaction system, extracted with ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate, and ethyl acetate was removed by vacuum rotary evaporation to obtain a light yellow-brown liquid, which was directly used in the next step reaction;

[0105] (2) Preparation of 1-(4-nitrobenzyl)-4-phenyl-1H-1,2,3-triazole

[0106]

[0107] 1-azidomethyl-4-nitrobenzene (178mg, 1mmol), sodium ascorbate (79mg, 0.4mmol), cuprous iodide (38mg, 0.2mmol), acetonitrile (3mL), water (0.3mL) and Ph...

Embodiment 2

[0124] Example 2: 2-fluoro-8-(4-phenyl-1H-1,2,3-triazol-1-ylmethyl)tryptanthrin

[0125]

[0126] The isatin derivative (304 mg, 1 mmol) containing 1,2,3-triazole structure prepared in step (5) of Example 1 and 5-fluoroisatic anhydride (purchased from Yancheng Medico Chemical Manufacturing Co., Ltd. ) (181mg, 1mmol) was added to the reaction flask, then triethylamine and toluene were added, the temperature was raised to 110°C, and the reaction was stirred under reflux for 4h. After recrystallization, 275 mg of a dark yellow-green solid was finally obtained, with a yield of 65%.

[0127] The characterization data are as follows: 1 H-NMR (400MHz, CDCl 3 ): δ=8.65(d, 1H), 8.07(m, 2H), 7.82(m, 5H), 7.57(m, 1H), 7.43(t, 2H), 7.35(t, 1H), 5.69(s, 2H).

Embodiment 3

[0128] Example 3: Preparation of 8-fluoro-2-(4-phenyl-1H-1,2,3-triazolylmethyl)tryptanthrin

[0129] (1) Synthesis of isatoic anhydride containing triazole structure

[0130]

[0131] Add 0.42mL of glacial acetic acid and 0.42mL of acetic anhydride to a 25mL reaction flask, then add (152mg, 0.5mmol) indole quinone (see Example 1) containing a triazole structure in batches, and heat the reaction solution to 80- 90°C, then add chromium trioxide in batches, and continue to react for 3 hours. After TLC detection shows that the raw materials have reacted completely, cool the reaction solution to room temperature, add 1.5mL of water, filter with suction, wash the solid with a large amount of water, and drain it with an oil pump to get a green color. The solid needn't be separated and left for the next reaction.

[0132] (2) Synthesis of tryptanthrin IDO inhibitors containing 1,2,3-triazole structure at the 2-position

[0133]

[0134] Add 5-fluoroindolequinone (purchased fro...

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Abstract

The invention relates to a novel indoleamine-2,3-dioxygenase (IDO) inhibitor, as well as a preparation method and an application thereof. The inhibitor is compounds of a formula I or pharmaceutically-acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, wherein R1 or R2 is independently selected from H, C1-C5 alkyl, halogen and a substituent of a formula II and either of R1 and R2 is the substituent of the formula II; R3 is an aryl group; and n is equal to 0, 1, 2 or 3. Compared with the know IDO inhibitors, the novel IDO inhibitor has significant inhibitory effect on IDO and can be used for treatment of diseases having IDO-mediated tryptophan metabolic pathway pathological features, such as tumors, cancers, Alzheimer's disease, autoimmune diseases, cataract, psychological disorders, depression and / or anxiety. The preparation method of the novel IDO inhibitor has the advantages of being convenient in operation, having mild reaction conditions and reducing solvent consumption and pollution, thereby facilitating industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a tryptanthrin-like indoleamine-2,3-dioxygenase inhibitor containing a 1,2,3-triazole structure and a preparation method and application thereof. Background technique [0002] Indoleamine-2,3-dioxygenase (abbreviated as IDO; MW 48,000; EC 1.13.11.42) is a heme-containing enzyme that is the first enzyme in the mammalian tryptophan metabolic pathway and is a limiting enzyme. fast enzyme. IDO catalyzes the oxidation reaction of the essential amino acid tryptophan into N-formylkynurenine through dioxygen, and is responsible for cleaning up tryptophan in the human body. By degrading tryptophan, IDO creates a microenvironment of tryptophan deficiency in the body, which in turn leads to the occurrence of various diseases closely related to tryptophan deficiency, such as cancer, cataracts, and nervous disorders. Therefore, finding highly effective inhibitors based on IDO ...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P25/00A61P25/22A61P25/24A61P25/28A61P27/12A61P35/00A61P37/02
CPCC07D487/04A61K31/519A61P25/00A61P25/22A61P25/24A61P25/28A61P27/12A61P35/00A61P35/02A61P37/00A61P37/02A61P43/00
Inventor 匡春香王勇王淑君陈斌关玉晶刘莹田宁
Owner SHENYANG XINMA PHARMA
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