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Use of pyridino[3,4-b]indol derivative as IDO inhibitor

A technology of inhibitors and uses, applied in the field of pyrido[3,4-b]indole derivatives as IDO inhibitors, can solve the problems of reducing tryptophan concentration, inhibiting killing effect, and stagnant synthesis.

Active Publication Date: 2016-06-01
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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  • Use of pyridino[3,4-b]indol derivative as IDO inhibitor
  • Use of pyridino[3,4-b]indol derivative as IDO inhibitor
  • Use of pyridino[3,4-b]indol derivative as IDO inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 Preparation of the key intermediate of the compound of the present invention

[0041] 1. Synthesis of 2-(9H-pyrido[3,4-b]indol-9-yl) ethyl acetate (2)

[0042]

[0043] Put the raw material compound 1 (0.50g, 2.98mmol) and 60% NaH (0.24g, 5.96mmol) purchased from Bailingwei with CAS No. 244-63-3; Product No. 230515 in a round-bottomed flask, and then use 10mL DMF to After dissolving and stirring at room temperature for 2 hours, ethyl bromoacetate (0.49 mL, 4.46 mmol) was added dropwise to the above reaction solution and reacted at room temperature for 5 hours. TLC detected that the raw material had basically reacted completely.

[0044] Add water and extract 3 times with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The crude product was subjected to silica gel column chromatography (CH 2 Cl 2 :CH 3 OH=60:1) to obtain a light yellow solid compound 2 (0.40 g, yield 54%).

[0045] Compound 2: 1 HNMR(400MHz, CDCl 3 ): δ8.85(s,1H), 8....

Embodiment 2

[0063] Example 2 Synthesis of N-benzyl-2-(9H-pyrido[3,4-b]indol-9-yl)acetamide (5a)

[0064]

[0065] Use 2mLCH first 2 Cl 2 Dissolve compound 4 (0.05g, 0.22mmol), gradually add benzylamine (0.05mL, 0.44mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt under stirring at 0°C Acid salt (EDCI, 0.05g, 0.27mmol), 1-hydroxybenzotriazole (HOBT, 0.04g, 0.27mmol) and N, N-diisopropylethylamine (DIEA, 0.09mL, 0.44mmol), After the addition, the temperature was raised to room temperature and the reaction was stirred for 12 hours. TLC detection showed that the reaction was complete.

[0066] Add water and extract three times with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated. The crude product was subjected to silica gel column chromatography (CH 2 Cl 2 :CH 3 OH=60:1) was purified to obtain a white solid compound 5a (0.04g, yield 58%).

[0067] Compound 5a: The purity is 98% by HPLC test; 1 HNMR(400MHz, CDCl 3 ): δ (ppm) 8.91 (s, 1H), 8.55 (d, J = 5...

Embodiment 3

[0068] Example 3 Synthesis of N-(pyridine-3-methylene)-2-(9H-pyrido[3,4-b]indol-9-yl)acetamide (5b)

[0069]

[0070] Use 2mLCH first 2 Cl 2 Dissolve compound 4 (0.03g, 0.13mmol), gradually add pyridine-3-methylamine (0.03g, 0.26mmol), EDCI (0.03g, 0.16mmol), HOBT (0.02g, 0.16mmol) under stirring at 0°C And DIEA (0.06mL, 0.26mmol), after the addition was completed, the reaction was stirred for 12h after warming to room temperature, and the reaction was complete as detected by TLC.

[0071] Add water, use CH 2 Cl 2 Extracted three times, the organic layer was dried over magnesium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (CH 2 Cl 2 :CH 3 OH=10:1) was purified to obtain a white solid compound 5b (0.03g, yield 71%).

[0072] Compound 5b: The purity is 98% by HPLC test; 1 HNMR(400MHz, CDCl 3 ): δ (ppm) 8.80 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 8.39 (d, J = 4.7 Hz, 1H), 8.28 (d, J = 1.7 Hz, 1H), 8.14 (d,J=7.8Hz,1H),7.92(d,J=5.2Hz,1H), 7....

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Abstract

The invention discloses uses of pyridino[3,4-b]indol derivatives in preparation of IDO inhibitor medicines. A compound in the invention can be used for preventing and / or treating various diseases such as Alzheimer disease, cataracts, cellular immunity activation-related infections, autoimmune diseases, aids, cancers, depressions, tryptophan metabolic disorders or the like.

Description

Technical field [0001] The present invention relates to the use of pyrido[3,4-b]indole derivatives as IDO inhibitors. Background technique [0002] Indoleamine2,3-dioxygenase (IDO) catalyzes the cleavage of indole epoxidation in indoleamine molecules such as tryptophan, making it the rate-limiting rate of catabolism according to the kynuric acid pathway Enzyme. [0003] IDO plays an important role in tumor immunity and tumorigenesis. Under normal circumstances, IDO is expressed at a low level in the body, while most tumor cells will form a high expression of IDO, which converts L-tryptophan to N-formylkynurenine, reducing the color in the cell microenvironment. The concentration of amino acid makes tryptophan-dependent T cell synthesis stagnate in the G1 phase, and T cell proliferation is inhibited, thereby inhibiting the body's immune system from killing tumor tissues. At the same time, the metabolites of tryptophan under the action of IDO are cytotoxic, which can directly diss...

Claims

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Application Information

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IPC IPC(8): A61K31/437A61P25/28A61P27/12A61P37/02A61P31/00A61P31/18A61P35/00A61P25/24
CPCA61K31/437
Inventor 钱珊王周玉杨羚羚李国菠张曼王伟何彦颖陈泉龙
Owner XIHUA UNIV
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