Fused imidazole compounds with indoleamine 2,3-dioxygenase inhibition activity

A compound, imidazolo technology, applied in the field of condensed imidazole compounds, can solve the problems of large toxic side effects and high dosage

Active Publication Date: 2018-06-26
SHENZHEN CHIPSCREEN BIOSCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no suitable IDO inhibitor has been listed so far. The existing IDO inhibitors in the clinical research stage have the disadvantages of high dosage and high toxicity.

Method used

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  • Fused imidazole compounds with indoleamine 2,3-dioxygenase inhibition activity
  • Fused imidazole compounds with indoleamine 2,3-dioxygenase inhibition activity
  • Fused imidazole compounds with indoleamine 2,3-dioxygenase inhibition activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] Preparation of 4-iodo-1-trityl-1H-imidazole

[0144]

[0145] 4-Iodo-1H-imidazole (20 g, 103 mmoles) was dissolved in DMF (100 mL), then triethylamine (15.1 mL, 108 mmoles) and tritylmethyl chloride (27.8 g, 100 mmoles) were added. The reaction solution was stirred at room temperature for 48h, then poured into ice water (500mL), a large amount of solid was precipitated, filtered, and dried to obtain a white solid 4-iodo-1-trityl-1H-imidazole (40g, 91.7mmol, 88.9%).

[0146] LC-MS (m / z): 437 (M+1).

Embodiment 2

[0148] Preparation of 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde

[0149]

[0150] 4-iodo-1-trityl-1H-imidazole (38.7g, 88.8mmol), (2-formylphenyl) boronic acid (20.0g, 133mmol) and K 3 PO 4 (56.4g, 266mmol) was dissolved in 1,4-dioxane (300mL) and water (60mL), nitrogen was bubbled into the reaction solution for 5min, and then Pd(PPh 3 ) 4 (5.12g, 4.44mmol), and continue to bubble nitrogen into the reaction solution for 5min. The reaction was carried out at 90° C. for 16 h under the protection of nitrogen. Cool down after the reaction, filter with diatomaceous earth, dilute the filtrate with water (100mL) and EA (300mL), let stand and separate the layers, extract the aqueous phase with EA (300mL×2; combine the organic phases, add water (100mL) and saturated saline (100mL×3) washing. The organic phase was concentrated under reduced pressure to obtain a residue, which was purified by column purification with PE / EA=3 / 1 to obtain light brown viscous oil 2-(1-trityl-1H-imida...

Embodiment 3

[0152] Preparation of (E)-4-(3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)acryloyl)piperidine-1-carboxylic acid tert-butyl ester

[0153]

[0154] 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde (4.0g, 9.66mmol) was dissolved in a mixed solution of anhydrous THF (20mL) and anhydrous EtOH (20mL), cooled to 0 °C, then EtONa (986 mg, 14.5 mmol), tert-butyl 4-acetylpiperidine-1-carboxylate (2.29 g, 10.1 mmol) were added. Then the reaction solution was stirred at room temperature overnight. After LCMS detected that the reaction was complete, it was diluted with ice water (30 mL), THF was distilled off under reduced pressure, filtered with suction, and the filter cake was drained as much as possible to obtain a white solid crude product (E)-4-(3 -(2-(1-Trityl-1H-imidazol-4-yl)phenyl)acryloyl)piperidine-1-carboxylic acid tert-butyl ester (6.0 g), used directly in the next step.

[0155] LC-MS (m / z): 624 (M+1).

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Abstract

The invention relates to fused imidazole compounds, and a preparation method and application thereof. The structure of the compounds is shown in a general formula I, wherein the definitions of each group are as described in the specification. The compounds are capable of selectively inhibiting indoleamine 2,3-dioxygenase (IDO). The compounds provided by the invention can be used as IDO inhibitorsfor the treatment and/or prevention of diseases with the pathological characteristics of IDO mediated tryptophan metabolism pathways, such as cancer, eye diseases, autoimmune diseases, psychological disorders, depression, anxiety and other diseases.

Description

technical field [0001] The present invention relates to a fused imidazole compound having indoleamine 2,3-dioxygenase (Indoleamine 2,3-dioxygenase, IDO) inhibitory activity, its preparation method and its therapeutic effect on indoleamine-2,3-dioxygenase Clinical application in diseases associated with abnormal oxygenase activity. Background technique [0002] Tryptophan (Trp) is an essential amino acid for the human body. Part of the tryptophan obtained from the diet is used to synthesize protein, niacin and the neurotransmitter 5-HT, and the rest is mainly metabolized through the kynurenine pathway (Leklem J.E., Am J Clin Nutr, 1971 , 24(6):659-672). Indoleamine 2,3-dioxygenase (IDO) is the key enzyme involved in this metabolic pathway. [0003] Indoleamine 2,3-dioxygenase, an intracellular heme-containing enzyme, was first discovered in the intestine of rabbits in 1967 (Yamaoto S. et al., J Biol Chem, 1967, 242 (22):5260-5266), which is the only rate-limiting enzyme o...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D519/00A61K31/454A61K31/501A61K31/4709A61K31/519A61P35/00A61P27/02A61P37/02A61P25/22A61P25/24A61P25/00G01N21/64
CPCG01N21/6402C07D487/04C07D519/00A61P25/00A61P25/22A61P25/24A61P27/02A61P35/00A61P37/02C07D307/91
Inventor 余金迪鲁先平李志斌辛利军朱江飞付超
Owner SHENZHEN CHIPSCREEN BIOSCIENCES CO LTD
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