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Fused imidazole derivative having IDO/TDO inhibition activity and having structure represented by formula (I), preparation method and applications thereof

A compound and unsubstituted technology, applied in the field of fused imidazole derivatives and their preparation, can solve the problem of no IDO/TDO inhibitor on the market, etc.

Active Publication Date: 2017-11-03
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] IDO activation is closely related to the pathogenesis of various diseases, and it is an important target in the fields of tumors, Alzheimer's disease, Parkinson's disease, depression and other related diseases. Inhibitors against IDO / TDO can liberate the body's defense system and help T cells to better attack tumors, so it has the potential to treat a wide range of tumor types. IDO / TDO inhibitors have broad application prospects, but so far no IDO / TDO inhibitors have been marketed. Therefore, it is necessary to find and develop new and highly effective The IDO inhibitor has important theoretical significance and application value

Method used

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  • Fused imidazole derivative having IDO/TDO inhibition activity and having structure represented by formula (I), preparation method and applications thereof
  • Fused imidazole derivative having IDO/TDO inhibition activity and having structure represented by formula (I), preparation method and applications thereof
  • Fused imidazole derivative having IDO/TDO inhibition activity and having structure represented by formula (I), preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] 1-((5H-imidazo[5,1-a]isoindol-5-yl)methyl)-3-(4-cyanophenyl)urea

[0102]

[0103] The first step: the preparation of 1-(2-bromobenzyl)-1H-imidazole

[0104]

[0105] Dissolve o-bromotoluene (20g, 117mmol), bromosuccinimide (22.0g, 123mmol), and azobisisobutyronitrile (1g) in dry carbon tetrachloride (200mL), and heat to reflux under nitrogen protection 16 hours. After the reaction was cooled to room temperature, it was filtered, imidazole (15.9 g, 234 mmol) and potassium carbonate (33 g, 234 mmol) were added to the filtrate, and heated to reflux for 5 hours under nitrogen protection. LC-MS showed that the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and the residue was dissolved in dichloromethane (100 mL) and washed with water (2×50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by flash silica gel column to obtain 1-(2-bromobenzyl)...

Embodiment 2

[0129] 1-(4-cyanophenyl)-3-((6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)methyl)urea

[0130]

[0131] The first step: the preparation of 1-(2-fluoro-6-bromobenzyl)-1H-imidazole

[0132]

[0133] Dissolve 1-bromo-3-fluoro-2-toluene (8.0g, 42.3mmol), bromosuccinimide (9.0g, 50.8mmol), azobisisobutyronitrile (300mg) in dry tetrachloride carbon (100 mL), heated to reflux for 16 hours under nitrogen protection. After the reaction was cooled to room temperature, it was filtered, imidazole (8.7g, 126.9mmol) and potassium carbonate (17.5g, 126.9mmol) were added to the filtrate, and heated to reflux for 5 hours under nitrogen protection. LC-MS showed that the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by flash silica gel column chromatography to obtain 1-(2-bromo-6-fluorobenzyl)-1H-imidazole (6.0 g).

[0134] The second step: the preparation of 6-fluoro-5H-imidazo[5,1-a]isoindole

[0135]

[0136...

Embodiment 3

[0151] 1-(4-bromophenyl)-3-((6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)methyl)urea

[0152]

[0153] 2-(6-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)acetic acid (200mg, 0.86mmol), diphenylphosphoryl azide (DPPA) (475mg, 1.72mmol), Triethylamine (180mg, 1.72mmol), p-bromoaniline (300mg, 1.72mmol) were dissolved in anhydrous toluene (20mL), and heated to reflux for 4 hours under nitrogen protection. LC-MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was dissolved in dichloromethane (20 mL), washed with water (2×10 mL) and saturated brine (10 mL) successively. The organic phase was dried filtered and concentrated. The residue was purified by flash silica gel column and reverse flash column to give 1-(4-bromophenyl)-3-((6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl ) methyl) urea (6.0 mg).

[0154] LC-MS: 401.0,t R =2.118min;

[0155] 1 H NMR (400MHz,MeOD)δ7.96(s,1H),7.56-7.43(m,2H),7.42-7.31(m,2H),7.27-7.18(m,3H),7.15-7.03(m,1H ),5...

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Abstract

The present invention relates to a fused imidazole derivative having IDO / TDO inhibition activity and having a structure represented by a formula (I), a preparation method and applications thereof. According to the present invention, the series of the fused imidazole derivatives have high IDO / TDO inhibition activity, can be widely used for treating or preventing cancers or tumors, viral infections, depression, neurodegenerative disorders, trauma, age-related cataract, organ transplant rejections or autoimmune diseases, can further be used to inhibit the immune suppression of patients, and are expected to be developed into the new generation of the immunosuppressive agent. The formula (I) is defined in the specification.

Description

technical field [0001] The invention belongs to the technical field of drug development, and specifically relates to a fused imidazole derivative with IDO / TDO inhibitory activity and a preparation method and application thereof. Background technique [0002] Tryptophan (Trp) is an essential amino acid for the human body, and it is an essential nutrient for the human body to synthesize protein, niacin and the neurotransmitter 5-hydroxytryptamine (serotonin). Tryptophan has two metabolic pathways in the body: the serotonin pathway and the kynurenine pathway. A small part of tryptophan generates 5-hydroxytryptophan through tryptophan hydroxylase, about 95% of tryptophan is produced in indoleamine 2,3-dioxygenase (indoleamine 2,3-dioxygenase, IDO) or tryptophan Kynurenine is generated under the action of 2,3-dioxygenase (tryptophan 2,3-dioxygenase, TDO). Kynurenine also has two metabolic pathways, most of which generate 3-hydroxykynurenine (3-hydroxykynurenine) under the actio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4188A61K31/5377A61K31/496A61P35/00A61P31/12A61P25/24A61P25/28A61P17/02A61P27/12A61P37/02A61P37/06
CPCC07D487/04A61K31/4188A61K31/496A61K31/5377
Inventor 仝朝龙包如迪李元念
Owner SHANGHAI HANSOH BIOMEDICAL
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