A hydrazine-containing indoleamine 2,3-bisoxidase inhibitor

A technology of group and alkyl group, applied in the field of IDO inhibitor containing hydrazine group and its preparation, can solve the problem of inability to directly regulate the immune response system of immune cells and the like

Active Publication Date: 2021-09-17
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Traditional tumor therapies are all macromolecule or cell therapy, which target cell surface receptors and cannot directly regulate the large and complex immune response system in immune cells

Method used

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  • A hydrazine-containing indoleamine 2,3-bisoxidase inhibitor
  • A hydrazine-containing indoleamine 2,3-bisoxidase inhibitor
  • A hydrazine-containing indoleamine 2,3-bisoxidase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Example 1 Synthesis of compound I-1

[0080]

[0081] The first step. 5.0g of compound 2 was dissolved in 25.0ml of ethyl acetate (EA), 4.7g of p-chloroaniline was added in batches, TLC detected the reaction until the reaction was complete, 0.5ml of triethylamine was added dropwise to quench the reaction, and ethyl acetate was added. Ester and water, separated, the organic phase was washed with saturated NaCl solution and anhydrous NaSO 4 Dry, filter with suction, concentrate the filtrate under reduced pressure, and purify by column chromatography to obtain 6.2 g of off-white solid compound 15;

[0082] The second step. 5.0g of compound 15 was dissolved in 100ml of tetrahydrofuran (THF), 3.2g of N,N-carbonyldiimidazole was added, the temperature was raised to 70°C and the reaction was performed until TLC detected that the reaction of the raw materials was complete, the reaction was stopped, the temperature was cooled to room temperature, and the pressure was reduced...

Embodiment 2

[0087] Example 2 Synthesis of compound I-38

[0088]

[0089] The first step. Take 5.0g malononitrile, add 10ml water-soluble clear, then cool down to below 0°C, add 6.0g sodium nitrite, stir for 1.0h, turn off the refrigeration, add 1.35ml 4N hydrochloric acid, move to room temperature and stir for 2.0h , then cooled to below 0°C, slowly added dropwise 15.5g of 50% hydroxylamine aqueous solution, heated to reflux after the dropwise addition, refluxed for 3 hours, cooled to 6°C, stirred overnight, and below 0°C, slowly added dropwise dilute hydrochloric acid to adjust pH =5 or so, a large amount of solid was precipitated, and 10.0 g of compound 1 was obtained by suction filtration;

[0090] Step 2. Dissolve 10.0g of compound 1 in 50ml of acetic acid, then add 100ml of water, 38ml of 6N HCl and 13.0g of sodium chloride, after dissolving, drop to below 0°C, slowly add 5.3g of sodium nitrite / 15ml dropwise Aqueous solution, and control the temperature below 0 °C, continue to...

Embodiment 3

[0096] Example 3 Synthesis of compound I-34:

[0097]

[0098] The first step. Dissolve 280mg of compound 11 in 5ml of tetrahydrofuran, add 120mg of triethylamine and then cool down to below 0°C, slowly add 290mg of p-trifluoromethoxybenzenesulfonyl chloride, TLC detects that the reaction of the raw materials is complete, add 25ml of water to quench , extracted with ethyl acetate, retained the organic phase, washed the organic phase with saturated NaCl solution and dried with anhydrous NaSO , suction filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound 12, which was directly put into the next step;

[0099] The second step. The above-mentioned compound 12 is dissolved in 1ml of tetrahydrofuran, and 1ml of 85% hydrazine hydrate is added. TLC detects that the reaction of the raw materials is complete, and most of the THF is removed under reduced pressure. Chromatography yielded 50 mg of compound 1-34 as an off-white solid.

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Abstract

The present invention provides a kind of IDO inhibitor shown in formula I and formula II and its preparation method, wherein R 1 , R 2 , The definition of the X group is as shown in the description. The present invention also provides a pharmaceutical composition containing the compound of formula I or formula II and its use. Use of the compound and a pharmaceutically acceptable salt thereof in the preparation of a disease drug related to indoleamine 2,3-dioxygenase (IDO), specifically in the treatment of cancer, Alzheimer's disease, depression, cataract and many other major diseases. The compound of the invention has high efficiency and low toxicity, has potential medical value and broad market prospect.

Description

technical field [0001] The art belongs to the field of antitumor drugs, and in particular relates to an IDO inhibitor containing a hydrazine group and a preparation method and application thereof. Background technique [0002] Traditional tumor therapies are macromolecular or cell therapies, which target cell surface receptors and cannot directly regulate the huge and complex immune response system in immune cells. There are many immunosuppressive molecules in the tumor microenvironment. The immunotherapy strategy to improve the tumor immune microenvironment by regulating the function of these inhibitory molecules is called immunotherapy. This regulatory system involving hundreds of proteins has some nodes that may be related to PD. -1 has similar functions or synergistic effects with PD-1 antibodies, and these targets are most suitable for modulation by small molecule drugs. Therefore, immunotherapy is also known as a breakthrough in the history of tumor treatment. [000...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D271/08C07D413/12C07D487/04C07D413/14C07D417/12A61K31/4245A61K31/506A61K31/427A61K31/496A61K31/5377A61K31/454A61P35/00A61P25/28A61P25/24A61P27/12
CPCC07D271/08C07D413/12C07D413/14C07D417/12C07D487/04A61K31/4245A61K31/427A61K31/454A61K31/496A61K31/506A61K31/5377A61P25/24A61P25/28A61P27/12A61P35/00
Inventor 张孝清宋志春包金远
Owner NANJING HUAWE MEDICINE TECH DEV
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