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Novel IDO inhibitor, preparation method, pharmaceutical composition and use thereof

A compound and pharmaceutical technology applied in the field of IDO inhibitors

Active Publication Date: 2020-06-30
北京华氏开元医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Therefore, IDO inhibitors are important targets for tumor immunotherapy. At present, several IDO inhibitors are in the clinical research stage at home and abroad, and no products have been approved for marketing. Therefore, it is of great significance to research and develop new IDO inhibitors.

Method used

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  • Novel IDO inhibitor, preparation method, pharmaceutical composition and use thereof
  • Novel IDO inhibitor, preparation method, pharmaceutical composition and use thereof
  • Novel IDO inhibitor, preparation method, pharmaceutical composition and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] (1) The substance represented by the structure of formula (1) in the present invention: 2-(6-fluoro-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole The preparation method of -4-yl)-N-(4-fluorophenyl) propanamide

[0092]

[0093] step 1:

[0094] Put p-fluorophenylhydrazine 1a (75.68g, 600mmol), 1-benzylpiperidine-3,5-dione 1b (121.94g, 600mmol), acetic acid (600ml), trifluoroacetic acid (300ml) in a 2L reaction flask In the process, heat up to system reflux, stir and react for 8 hours, TLC monitors the reaction, after the reaction is completed, cool to room temperature, add 500ml of ethyl acetate and 200ml of water, stir and stand for layering, and extract the water layer twice with 100ml of ethyl acetate, The organic layers were combined, heated and concentrated, and separated by column chromatography to obtain 148.00 g of an off-white solid (Intermediate 1c), with a yield of 83.8%.

[0095] Step 2:

[0096] The compound 1c (117.73g, 400mmol) and potassium ca...

Embodiment 2

[0110] Preparation of compound 2: 3N-(4-chlorophenyl)-2-(6-fluoro-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]ind Indol-4-yl)propionamide

[0111] The preparation method of intermediate 1i is the same as that of Example 1, except that compound 1i (3.76g, 10mmol), p-chloroaniline (1.56g, 11mmol) and diisopropylethylamine (1.94 g, 15mmol) was dissolved in DMF (50ml), HATU (5.70g, 12mmol) was added at 25°C, the reaction was incubated, and the reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, extracted with ethyl acetate (100ml), and the organic layer was dried , concentrated, and separated by column chromatography to obtain 3.18 g of off-white solid with a yield of 65.4%.

[0112] The intermediate obtained above (3.00g, 6.2mmol) was dissolved in dichloromethane (20ml), and trifluoroacetic acid (10ml) was added at 25°C, stirred at room temperature for 4 hours, the reaction was stopped, and the solvent and trifluoroacetic acid...

Embodiment 3

[0114] Preparation of compound 3: 2-(6-fluoro-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-4-yl)-N-( 4-methoxyphenyl)propionamide

[0115] The preparation method of intermediate 1i is the same as in Example 1, except that compound 1i (3.76g, 10mmol), p-methoxyaniline (1.35g, 11mmol) and diisopropylethylamine obtained in Example 1 were (1.94g, 15mmol) was dissolved in DMF (50ml), and HATU (5.70g, 12mmol) was added at 25°C, the reaction was incubated, and the reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, extracted with ethyl acetate (100ml), organic The layer was dried, concentrated, and separated by column chromatography to obtain 2.95 g of off-white solid with a yield of 61.3%.

[0116] The intermediate obtained above (2.50g, 5.19mmol) was dissolved in dichloromethane (20ml), and trifluoroacetic acid (10ml) was added at 25°C, stirred at room temperature for 4 hours, the reaction was stopped, and the solvent and t...

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Abstract

The invention discloses a novel IDO inhibitor, and a preparation method, a pharmaceutical composition, and applications thereof. The novel IDO inhibitor is a compound with a structure represented by formula A, or a pharmaceutically acceptable salt, a hydrate, a solvate, or an isotopic compound of the compound. The structure characteristic is that, the mother nucleus is 2-(2, 3, 4, 9-tetrahydro-1H-pyridine [3, 4-b]indole-4-yl)acetamide. The compound, and the stereoisomer, the nontoxic pharmaceutical acceptable salt, the hydrate, the solvate, and the isotopic compound of the compound can be usedfor treating tumors, virus infection, organ transplantation rejection, or autoimmune diseases.

Description

technical field [0001] The present invention relates to the technical field of IDO inhibitors, in particular to 2-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-4-yl)acetamide derivatives, Stereoisomers and non-toxic pharmaceutically acceptable salts thereof, or their hydrates or solvates as active ingredients in pharmaceutical compositions, and pharmaceutical compositions comprising them as active ingredients that can modulate or inhibit indoleamine 2 , 3-dioxygenase (IDO) activity and preparation method thereof. Background technique [0002] Indole 2,3-dioxygenase (IDO) is a heme-containing monomeric protein in cells, which was first discovered in 1967. In vivo and in vitro, under the action of superoxide anion as a cofactor, IDO metabolizes indoleamine derivatives, such as tryptophan, tryptamine, 5-methyltryptamine, 5-hydroxytryptamine, etc., through the mediation of the pyrrole ring. It is the only rate-limiting enzyme outside the liver that can catalyze the catabolism of L...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/437A61P35/00A61P37/00A61P31/12A61P35/02
CPCA61P31/12A61P35/00A61P35/02A61P37/00C07D471/04
Inventor 王永广葛志敏程可建潘海群苏小庭戴信敏
Owner 北京华氏开元医药科技有限公司
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