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Hydrazino-containing indoleamine 2,3-dioxygenase inhibitors

A technology of groups and alkyl groups, applied in the field of IDO inhibitors containing hydrazine groups and its preparation, can solve problems such as the inability to directly regulate the immune response system of immune cells

Active Publication Date: 2018-10-23
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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  • Hydrazino-containing indoleamine 2,3-dioxygenase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Example 1 Synthesis of Compound I-1

[0080]

[0081] The first step. Dissolve 5.0g of compound 2 with 25.0ml of ethyl acetate (EA), add 4.7g of p-chloroaniline in batches, TLC detects that the reaction is complete, drop 0.5ml of triethylamine to quench the reaction, add ethyl acetate ester and water, separated, and the organic phase was washed with saturated NaCl solution and washed with 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] Step 2. Dissolve 5.0g of compound 15 in 100ml of tetrahydrofuran (THF), add 3.2g of N,N-carbonyldiimidazole, heat up to 70°C and react until TLC detects that the reaction of the raw materials is complete, stop the reaction, cool to room temperature, and depressurize Concentrate, add ethyl acetate and dilute hydrochloric acid, and separate the layers. The organic phase was washed with saturated NaCl...

Embodiment 2

[0087] Embodiment 2 compound I-38 is synthesized

[0088]

[0089] Step 1. Take 5.0g of malononitrile, add 10ml of water solution, then cool down to below 0°C, add 6.0g of sodium nitrite, stir for 1.0h, turn off the refrigeration, add 1.35ml of 4N hydrochloric acid, move to room temperature and stir for 2.0h , then lower the temperature to below 0°C, slowly add 15.5g of 50% hydroxylamine aqueous solution dropwise, after the dropwise addition, heat up to reflux, cool to 6°C after reflux for 3 hours, stir overnight, as for below 0°C, slowly add dilute hydrochloric acid dropwise to adjust the pH = around 5, a large amount of solids were precipitated, and 10.0 g of compound 1 was obtained by suction filtration;

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

Embodiment 3

[0096] Embodiment 3 compound I-34 is synthesized:

[0097]

[0098] Step 1. Dissolve 280mg of compound 11 in 5ml of tetrahydrofuran, add 120mg of triethylamine and 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 , filtered with suction, and concentrated the filtrate under reduced pressure to obtain the crude compound 12, which was directly injected into the next step;

[0099] The second step. Dissolve the above-mentioned compound 12 with 1ml tetrahydrofuran, add 1ml 85% hydrazine hydrate, TLC detects that the raw materials have reacted completely, spin off most of the THF under reduced pressure, a large amount of solids are precipitated, suction filter and rinse the filter cake with water, and the col...

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Abstract

The present invention provides IDO inhibitors represented by a formula I and a formula II, and a preparation method thereof, wherein R1, R2 and a group X are defined in the specification. The invention further provides a pharmaceutical composition containing the compound represented by the formula I or the compound represented by the formula II, and uses thereof, and uses of the compounds and pharmaceutically acceptable salts thereof in preparation of drugs for diseases associated with indoleamine 2,3-dioxygenase (IDO), particularly in treatment of cancers, Alzheimer's disease, depression, cataract and a variety of major diseases. According to the present invention, the compounds have characteristics of high effect, low toxicity, potential medicinal value and broad market prospect. The formulas I and II are defined in the specification.

Description

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

Claims

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Application Information

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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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