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Novel IDO (indoleamine 2,3-dioxygenase) inhibitor

A compound and pharmaceutical technology, applied in the field of IDO inhibitors and their preparation, can solve the problems of unsatisfactory inhibitory efficacy of IDO inhibitors and the like

Inactive Publication Date: 2018-06-29
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, there are still high technical barriers in the research and development of IDO inhibitors, and the inhibitory efficacy of existing IDO inhibitors is not satisfactory. As drugs with new drug targets and new mechanisms, IDO inhibitors can be applied to the treatment of tumors, Alzheimer’s disease, depression, cataract and other major diseases, which have a very good market value. In order to meet the current clinical needs for IDO-regulated metabolites, a series of IDO inhibitors with drug activity are to be studied, which is of great significance to the medical field. the meaning of

Method used

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  • Novel IDO (indoleamine 2,3-dioxygenase) inhibitor

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] The preparation of embodiment 1 compound I-1

[0062]

[0063] Step 1: Synthesis of Compound 1

[0064] Add 5.05g of 5-bromo-2,4-dichloropyrimidine to a 100ml one-mouth bottle successively, add 25ml of ethanol to dissolve it, place it at 0°C, add 2.25g of triethylamine, weigh 3.50g of Boc hydrazine, and use 50ml After the ethanol is dissolved, drop it into the above reaction solution at low temperature. After the dropwise addition, transfer it to room temperature and stir for 2 hours. TLC detects that the raw material has reacted completely. Spin off the ethanol, pour it into water, add EA for extraction, and wash once with citric acid aqueous solution. , washed twice with saturated sodium chloride, extracted once with water, combined the organic phases, dried and spin-dried to obtain compound 1 as a pale yellow solid.

[0065] The second step: the synthesis of compound 2

[0066] Add 0.5g compound 1, 0.74g phenylboronic acid, 0.28g Pd(dppf)Cl to the 100ml one-mout...

Embodiment 2

[0074] The preparation of embodiment 2 compound 1-2

[0075]

[0076] The first step: the synthesis of compound 6

[0077] Add 0.20g of compound 5 to a 100ml one-mouth bottle in turn, add 10ml of methanol to dissolve it, then add 5ml of concentrated hydrochloric acid, react at 50°C for half an hour, TLC detects that the raw materials have reacted completely, spin off the methanol, pour into water and add ammonia water to adjust to a weak base nature, added EA to extract, the organic phase was washed twice with saturated sodium chloride, the organic phase was dried and spin-dried to obtain a brownish black oily liquid, and compound 6 was obtained by column chromatography.

[0078] The second step: the synthesis of compound I-2

[0079] Add 0.21g of compound 6 to a 100ml single-necked bottle in turn, add 10ml of DMF to dissolve it, then add 0.20g of p-toluenesulfonyl chloride dissolved in 2ml of DMF dropwise at low temperature, after the addition is completed, stir at low te...

Embodiment 3

[0082] The preparation of embodiment 3 compound 1-3

[0083]

[0084] The first step: the synthesis of compound 5

[0085] Add 1.01g compound 1, 1.05g m-methylphenylboronic acid, 0.18g Pd(dppf)Cl to 100ml one-port bottle 2 , 1.28g of potassium carbonate, 30ml of 1,4-dioxane and 5ml of water, reacted at 100°C for 12 hours under the protection of nitrogen, TLC detected that the raw materials were completely reacted, poured into water, extracted with EA, and the organic phase was saturated with chlorinated Washed twice with sodium, extracted once with water, combined the organic phases, dried and spin-dried, and separated by column chromatography to obtain 0.14 g of compound 5 as an off-white solid.

[0086] The second step: the synthesis of compound 8

[0087] Add 0.20g of compound 5 to a 100ml one-mouth bottle in turn, add 10ml THF to dissolve it, then add 3ml concentrated hydrochloric acid, react at room temperature for 2 hours, TLC detects that the raw materials have rea...

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Abstract

The invention provides an IDO (indoleamine 2,3-dioxygenase) inhibitor as shown in a formula I as well as a preparation method thereof, wherein the definitions of W, M and Ar groups are shown in the description. Meanwhile, the invention provides a pharmaceutical composition containing a compound of the formula I as well as application thereof. The invention relates to application of the compound ofthe formula I and pharmaceutically acceptable salt to preparation of IDO related disease medicines, in particular to application to treatment on various serious diseases such as tumor, alzheimer's disease, depression and cataract. The primary medicine activity research result indicates that the IDO inhibitor has high IDO inhibition activity and has potential medicinal value.

Description

technical field [0001] This field belongs to the field of antitumor drugs, and specifically relates to an 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 tolerance play an impor...

Claims

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Application Information

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IPC IPC(8): C07D239/42C07D239/47C07D403/04C07D401/04C07D401/14C07D405/14C07D405/04C07D409/14A61K31/505A61K31/506A61P35/00A61P25/28A61P25/24A61P27/12
CPCC07D239/42C07D239/47C07D401/04C07D401/14C07D403/04C07D405/04C07D405/14C07D409/14
Inventor 宋志春包金远苏梅何东伟张孝清
Owner NANJING HUAWE MEDICINE TECH DEV
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