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Ido inhibitor and preparation method and application thereof

A technology of phenyl and compound, applied in the field of IDO inhibitor and its preparation, can solve the problem of unsatisfactory inhibition effect of IDO inhibitor

Active Publication Date: 2020-09-15
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Before 2010, there were very few IDO inhibitor compounds with IC50 at the nanomolar level, and there is currently no IDO inhibitor drug on the market at home and abroad
[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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  • Ido inhibitor and preparation method and application thereof
  • Ido inhibitor and preparation method and application thereof
  • Ido inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Embodiment 1: the preparation of compound I-1

[0109]

[0110] Synthesis of compound 7:

[0111]Take a 100ml three-necked flask, add 1.23g of 5-bromo-2,4-dichloropyrimidine, add 5ml of ethanol to dissolve it, put it in a refrigerator under nitrogen protection, add 0.54g of triethylamine at 0°C, and take 1.5g of 2 , 4,5,6-tetrahydro-2-(methylsulfonyl)pyrrolo[3,4-C]pyrazole, after adding 20ml of ethanol to dissolve it, add it dropwise to the above reaction solution at 0°C, the reaction solution Solids were precipitated in the solution, and the low-temperature reaction was continued for 2 h after the addition was completed. TLC detected that the reaction of the raw materials was complete, and the reaction was stopped, and 1.74 g of off-white solids were obtained by suction filtration, with a yield of 85%.

[0112] Synthesis of compound I-1:

[0113] Add 0.20g compound 1, 0.13g 4-fluoro, 3-trifluoromethylbenzeneboronic acid, 0.06gPd(dppf)Cl to a 100ml single-necked bo...

Embodiment 2

[0115] The synthesis of embodiment 2 compound I-48

[0116]

[0117] Preparation of intermediate 8 compound:

[0118] Weigh 0.60g of compound 1 in a 100mL reaction bottle, then weigh 0.26g of 3-thiophene boronic acid, 0.14g of Pd(dppf)Cl 2 And 0.66g of potassium carbonate, finally added 10mL of DMA and 1mL of water, replaced with nitrogen three times and placed in an oil bath, raised to 80 ° C for 1 h. TLC detected that the reaction was complete, quenched by adding 100mL of water, extracted with 50ml*2EA, combined the organic layers and dried with anhydrous sodium sulfate, spin-dried under reduced pressure, column chromatography (petroleum ether: ethyl acetate), and obtained 300mg of the final product as intermediate Body 2, with a purity of 99%.

[0119] Synthesis of Compound I-48:

[0120] Weigh 0.29g of intermediate 8 in a 100mL reaction flask, then weigh 0.28g of 4-fluoro-3-trifluoromethylbenzeneboronic acid, 0.10g of Pd(dppf)Cl 2 And 0.36g potassium carbonate, fina...

Embodiment 3

[0121] The synthesis of embodiment 3 compound I-52

[0122]

[0123] Synthesis of Compound 9: Take a 100ml single-necked bottle, add 5.0g Fmoc proline, 0.5g methylamine, 3.2g EDCI and 3.0g triethylamine, 50ml dichloromethane to dissolve and react at room temperature for 3 hours, TLC detects that the reaction of the raw materials is complete, stop To react, add 50ml of DCM to dilute, wash with 25ml*2 dilute HCl, 50ml*2 saturated sodium chloride, dry over anhydrous sodium sulfate, spin dry under reduced pressure to obtain a crude product, and column chromatography to obtain 4.5g white solid.

[0124] Synthesis of Compound 10: Take a 100ml single-necked bottle, add 4.5g of Compound 3, 2ml of pyridine and 10ml of DMF in sequence, and react at room temperature for 2 hours, TLC detects that the raw materials are completely reacted, stop the reaction, add 50ml of DCM to dilute, wash with 50ml*2 saturated sodium chloride, Dry over anhydrous sodium sulfate, spin dry under reduced pr...

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PUM

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Abstract

The present invention provides pharmaceutically acceptable salts, isomers, racemates, diastereomers, and pharmaceutical compositions of Formula I, Formula II, Formula III, or Formula IV and application thereof in treatment of indoleamine-(2,3)-dioxygenase-related diseases, specifically in the treatment of tumors, Alzheimer's disease, depression, cataracts and other various serious diseases; wherein R, R2, W and other groups are as shown in the specification. Preliminary drug activity studies show that the compounds have significant IDO inhibitory activity. Simultaneously, SD rats are used as test animals, concentrations of the compounds in the plasma at different time points after intragastric administration of the compounds in the rats are detected by LC / MS / MS method, pharmacokinetic behaviors of the compounds in the bodies of the rats are studied, results showed that the compounds have a significant pharmacokinetic absorption effect and have a good clinical application prospect.

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, so IDO plays an important role in inhibiting T cell immu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D403/14C07D401/14C07D403/04A61K31/506A61P35/00A61P25/28A61P25/24A61P27/12
CPCC07D401/14C07D403/04C07D403/14C07D487/04
Inventor 张孝清宋志春包金远
Owner NANJING HUAWE MEDICINE TECH DEV
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