Spiro compound as indoleamine 2, 3-dioxygenase inhibitor

A compound, solvate technology, applied in the treatment of proliferative diseases, immune-related diseases and/or inflammatory diseases, infectious diseases, and can solve the problem of ineffective immune tolerance

Pending Publication Date: 2022-07-01
QILU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The results suggest that although the IDO pathway plays an important role in the body's immune tolerance to foreign antigens, it does not seem to play a role in maintaining the body's immune tolerance to self-antigens

Method used

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  • Spiro compound as indoleamine 2, 3-dioxygenase inhibitor
  • Spiro compound as indoleamine 2, 3-dioxygenase inhibitor
  • Spiro compound as indoleamine 2, 3-dioxygenase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] Embodiment 1 (synthesis method 1)

[0124] (S or R)-6-(1-((4-Chlorophenyl)amino)-1-oxopropan-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate isopropyl Ester 1a; (R or S)-6-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-2-azaspiro[3.3]heptane-2-carboxy Isopropyl acid 1b

[0125]

[0126] step 1

[0127]

[0128] To a stirred solution of ethyl 2-(diethoxyphosphoryl)propionate (6.8 g, 28.4 mmol, 1.2 equiv) in dry tetrahydrofuran (68 Sodium hydride (1.9 g, 47.3 mmol, 2.0 equiv, 60% mixture in mineral oil) was added. The mixture was warmed to room temperature and stirred at the same temperature for 15 minutes; then to it was added tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (5 g, 23.7 mmol, 1.0 equiv) in dry tetrahydrofuran (50 mL). The reaction was stirred under nitrogen protection at room temperature for 3 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, the reaction solution was co...

Embodiment 2

[0149] Example 2 (Synthetic Method II)

[0150] (S or R)-N-(4-chlorophenyl)-2-(2-(5-fluorobenzo[d]isoxazol-3-yl)-2-azaspiro[3.3]heptane- 6-yl)propionamide 2a; (R or S)-N-(4-chlorophenyl)-2-(2-(5-fluorobenzo[d]isoxazol-3-yl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)propionamide 2b

[0151]

[0152] step 1

[0153]

[0154] To compound 1-5 (193.59 mg, 0.69 mmol, 1.50 equiv) and 3-chloro-5-fluoro-benzo[d]isoxazole (100 mg, 0.46 mmol, 1 equiv) in N,N-dimethylacetamide (5 mL) was added cesium carbonate (301.67 mg, 0.93 mmol, 2.0 equiv). The resulting mixture was stirred at 80 degrees Celsius for 16 hours. The progress of the reaction was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction mixture was directly purified by reverse phase chromatography (C18 column): eluted with 50%→70% acetonitrile / water within 10 minutes; detector: UV 254 nm; compound 2-1 (white solid) was obtained. , 50 mg, 21% yield). MS(ESI,m / z):414.1 / 416.1[M+H] + ....

Embodiment 3

[0160] Embodiment 3 (synthesis method III)

[0161] (R or S)-N-(4-chlorophenyl)-2-(2-(5-fluoro-2-(trifluoromethyl)benzoyl)-2-azaspiro[3.3]heptane- 6-yl)propionamide 3a; (S or R)-N-(4-chlorophenyl)-2-(2-(5-fluoro-2-(trifluoromethyl)benzoyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)propionamide 3b

[0162]

[0163] step 1

[0164]

[0165] At room temperature, 5-fluoro-2-(trifluoromethyl)benzoic acid (89.6 mg, 0.43 mmol, 1.2 equiv) and 2-(7-azobenzotriazole)-N,N,N ',N'-Tetramethylurea hexafluorophosphate (191.0 mg, 0.50 mmol, 1.4 equiv) was dissolved in N,N-dimethylformamide (1 mL). The resulting mixture was stirred at room temperature for 15 minutes and then compound 1-5 (100 mg, 0.36 mmol, 1.0 equiv.) and diisopropylethylamine (129.8 mg, 1.0 mmol, 2.8 equiv.) were added sequentially, followed by continuing at room temperature. The reaction was carried out for 3 hours. The reaction process was monitored by liquid mass and thin-layer chromatography. After the reaction, ...

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Abstract

The invention provides a compound which has a spiro structure and can be used as an indoleamine 2, 3-dioxygenase (IDO) inhibitor, a pharmaceutical composition containing the compound, and application of the compound in preparation of drugs for treating proliferative diseases, infectious diseases, immune-related diseases and / or inflammatory diseases.

Description

technical field [0001] The present invention relates to spiro compounds that modulate or inhibit the activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing the compounds, and the use of the compounds of the present invention for the treatment of proliferative diseases (such as cancer), Methods of infectious disease, immune-related disease and / or inflammatory disease. Background technique [0002] Tryptophan is an essential amino acid in the human body. Part of the tryptophan obtained from the diet is used to synthesize protein and the neurotransmitter serotonin, and the rest is mainly metabolized through the kynurenine pathway, which is formed through a series of steps. Nicotinamide adenine dinucleotide (NAD+). Indoleamine 2,3-dioxygenase (IDO) is a monomeric oxidoreductase containing heme that catalyzes the degradation of tryptophan to N-formyl-kynurenine, the kynurenine of tryptophan. The first step of the amino acid metabolism pathway is a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/12C07D413/04C07D221/20C07C251/50C07C271/24C07C237/22A61K31/192A61K31/337A61K31/423A61K31/422A61K31/167A61K31/438A61P37/06A61P29/00A61P35/00A61P31/12A61P31/18A61P25/28A61P25/24A61P25/00A61P35/02A61P31/04A61P33/02A61P33/06A61P19/02A61P11/06A61P13/12A61P17/06A61P1/18A61P1/00A61P7/06A61P7/00A61P9/10A61P19/10A61P25/16A61P17/00A61P37/08
CPCC07D205/12C07D413/04C07D221/20C07C251/50C07C271/24C07C237/22A61P37/06A61P29/00A61P35/00A61P31/12A61P31/18A61P25/28A61P25/24A61P25/00A61P35/02A61P31/04A61P33/02A61P33/06A61P19/02A61P11/06A61P13/12A61P17/06A61P1/18A61P1/00A61P7/06A61P7/00A61P9/10A61P19/10A61P25/16A61P17/00A61P37/08C07C2602/50C07C2601/08
Inventor 吴晓冉邓伟林栋毛海斌陈冬妹赵谈封付健民张宁张冬梅徐艳玲赵树雍
Owner QILU PHARMA CO LTD
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