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Indoleamine 2,3-bisoxidase inhibitor and its preparation method and use

A compound and oxygen atom technology, applied in the field of medicinal chemistry, can solve problems that have not yet been applied to clinical treatment

Active Publication Date: 2020-06-19
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] At present, there are still high technical barriers in the research and development of IDO inhibitors, and the existing me-too IDO inhibitor molecules have not yet been applied to clinical treatment

Method used

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  • Indoleamine 2,3-bisoxidase inhibitor and its preparation method and use
  • Indoleamine 2,3-bisoxidase inhibitor and its preparation method and use
  • Indoleamine 2,3-bisoxidase inhibitor and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098]

[0099] Step 1: Dissolve 632mg of compound I-24-1 in 20ml of tetrahydrofuran, add 486mg of carbonyldiimidazole (CDI), and react at 50°C for 0.5h. After the reaction, remove the solvent under reduced pressure, add 30ml of water, wash with dilute hydrochloric acid Adjust the pH to 4-5, add ethyl acetate to extract twice, combine the organic phases, wash twice with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, and spin dry under reduced pressure to obtain compound I-24-2 (650mg, class white solid); Step 2: 650mg of compound I-24-2 was added to a mixed solvent of 20ml of trifluoroacetic acid and 12ml of hydrogen peroxide, and placed at 70°C for overnight reaction. Compound I-24-3 (315 mg, pale yellow solid) was obtained by filtration and drying;

[0100] Step 3: Dissolve 315mg of compound I-24-3 in 20ml of tetrahydrofuran, add dropwise 224mg / 10ml of compound 1 in tetrahydrofuran, and react at room temperature for 12.0h. After the reaction, remove...

Embodiment 2

[0107]

[0108] Step 1: Dissolve 320mg of compound I-24-3 in 20ml of tetrahydrofuran, add dropwise 262mg / 10ml of compound 2 in tetrahydrofuran, and react at room temperature for 6.0h. After the reaction, remove the solvent under reduced pressure, add ethyl acetate and water, and separate the layers , the organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and spin-dried under reduced pressure to obtain compound I-20-1 (364 mg, off-white solid);

[0109] Step 2: Dissolve 364mg of compound I-20-1 in 20ml of dichloromethane, add 4ml of trifluoroacetic acid, and react at room temperature for 2.0h. After the reaction, remove the solvent under reduced pressure, add 20ml of water, and adjust the pH with saturated sodium bicarbonate to about 8, add ethyl acetate to extract twice, combine the organic phases, wash twice with saturated sodium chloride solution, dry over anhydrous sodium sulfate, spin dry under reduced pressure to...

Embodiment 3

[0115]

[0116] Step 1: Dissolve 200mg of compound I-24-3 in 20ml of tetrahydrofuran, add 97mg / 10ml of compound 3 tetrahydrofuran solution dropwise, and react at room temperature for 6.0h. After the reaction, remove the solvent under reduced pressure, add ethyl acetate and water, and separate the layers , the organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and spin-dried under reduced pressure to obtain compound I-1-1 (180 mg, off-white solid);

[0117] Step 2: Dissolve 180mg of compound I-1-1 in 20ml of tetrahydrofuran, add 1ml of 2.5M sodium hydroxide solution, and react at room temperature for 2.0h. After the reaction is completed, add saturated ammonium chloride solution and ethyl acetate, separate liquid, and organic phase Washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, spin-dried under reduced pressure, and obtained compound I-1 (15 mg, off-white solid, purity: 96.4%...

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Abstract

The present invention provides a novel indoleamine 2,3-dioxygenase inhibitor and its preparation method and pharmaceutical composition, wherein n, Y, Z, R 1 , R 2 , R 3 , R 4 The definition is as shown in the manual. Also provided is the use of the compound and its pharmaceutically acceptable salts and isomers in the preparation of drugs for diseases related to indoleamine 2,3-dioxygenase (IDO), specifically in the Applications in the treatment of cancer, Alzheimer's disease, depression, cataracts and many other major diseases. The compound of the invention has good activity, has potential medical value and broad market prospects.

Description

technical field [0001] This field belongs to the field of medicinal chemistry, and specifically relates to a high-efficiency IDO inhibitor and its preparation method and application. Background technique [0002] Indoleamine 2,3-dioxygenase (IDO) is the only rate-limiting enzyme that catalyzes the catabolism of tryptophan along the kynurenine pathway outside the liver, and is widely distributed in human and animal tissues. in many tissues and cells. IDO can inhibit the proliferation of pathogenic microorganisms by reducing the concentration of tryptophan in the microenvironment; IDO is also closely related to nervous system diseases. Accumulation of neurotoxic metabolites; some evidence suggests that IDO is involved in the induction of immune tolerance. Studies on mammalian pregnancy, tumor drug resistance, chronic infection and autoimmune diseases have shown that cells expressing IDO can inhibit T cell responses and promote tolerance. Both tolerance and graft immune tole...

Claims

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Application Information

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IPC IPC(8): C07D271/08C07D413/12C07D417/12A61K31/454A61K31/4245A61K31/5355A61K31/427A61K31/5377A61P35/00A61P25/28A61P25/24A61P27/12
CPCC07D271/08C07D413/12C07D417/12C07D413/04A61P25/24A61P25/28A61P27/12A61P35/00C07D413/08
Inventor 张孝清宋志春包金远
Owner NANJING HUAWE MEDICINE TECH DEV
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