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Kynurenine Pathway Inhibitors

A technology for selecting compounds, applied in the field of application in the preparation of drugs for treating tumors, and can solve the problems of large dosage, many times of administration, and short half-life.

Active Publication Date: 2021-09-03
CSTONE PHARM (SUZHOU) CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing clinical kynurenine pathway inhibitors have problems such as CYP inhibition (NLG 0919), large dosage, short half-life, frequent administration (INCB-24360), poor solubility (BMS-986205), etc.
Therefore, inhibitors of the kynurenine pathway without the above-mentioned disadvantages remain an unmet medical need

Method used

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  • Kynurenine Pathway Inhibitors
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  • Kynurenine Pathway Inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0119]

[0120]

[0121] Synthesis of compound 1-b:

[0122] At 0°C, iodomethane (185.33g) was added to compound 1-a (98.5g) in acetone (1500mL), reacted at 25°C for 1 hour, filtered, and the filter cake was spin-dried to obtain compound 1-b.

[0123] Synthesis of compound 1-d:

[0124] At 0°C, slowly drop thionyl chloride (96.92g, 814.69mmol) into absolute ethanol solution (1000mL), then add compound 1-c (95g, hydrochloride) and react at 80°C After 12 hours, it was concentrated under reduced pressure to obtain compound 1-d.

[0125] Synthesis of compound 1-e:

[0126] At 90°C, to a solution of compound 1-d (98g, hydrochloride) and N,N-diisopropylethylamine (141.01g, 1.09mol) in dioxane (1400mL) and water (350mL) Add compound 1-b (208.74g, 818.28mmol) in batches, react at 900°C for 12 hours, concentrate under reduced pressure to remove the solvent dioxane, add 1000 ml of ethyl acetate, and wash the solution with saturated sodium chloride solution for 3 times, 1000 ml...

Embodiment 2

[0141]

[0142] Synthesis of compound 2

[0143] Compound 1-l (50 mg) was dissolved in DMF (5 mL), and DIEA (98.39 mg) and HATU (86.84 mg) were added to the solution at 25° C. The resulting mixture was stirred at 25° C. for 30 minutes. Then, 2-a (23.59 mg) was added to the reaction solution, and the resulting mixture was stirred at 25°C for 12 hours. Water (10 mL) was added to the reaction solution to quench the reaction and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure to obtain the crude product. The crude product is purified by preparative chromatography to obtain compound 2.

[0144] 1 H NMR (400MHz, CCl 3 D) δppm 1.69-1.91 (m, 3H) 2.00-2.10 (m, 3H) 2.33-2.56 (m, 6H) 3.00 (br d, J = 11.74Hz, 2H) 3.18 (br t, J = 11.80Hz, 1H )6.77-6.88 (m, 2H) 7.31 (d, J = 4.65Hz, 1H) 7.39-7.48 (m, 1H) 7.61 (dd, J = 10.33, 2.63Hz, 1H) 8.03-8.15 (m, 1H) 8.28 (td, J=9.23, 5.99Hz, 1H) 8.8...

Embodiment 3

[0146]

[0147] Synthesis of Compound 3

[0148] Compound 1-l (50 mg) was dissolved in DMF (3 mL), and DIEA (98.39 mg) and HATU (86.84 mg) were added to the solution at 25° C. The resulting mixture was stirred at 25° C. for 30 minutes. Then, to 3-a (23.31 mg) was added to the reaction solution, and the resulting mixture was stirred at 25°C for 12 hours. Water (10 mL) was added to the reaction solution to quench the reaction and extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure to obtain the crude product. The crude product is purified by preparative chromatography to obtain compound 3.

[0149] 1 H NMR (400MHz, CCl 3 D) δppm 1.68-1.92 (m, 3H) 1.96-2.10 (m, 3H) 2.25-2.58 (m, 6H) 3.02 (br d, J = 11.25Hz, 2H) 3.18 (br t, J = 12.10Hz, 1H ) 7.01 (dd, J = 8.01, 1.04Hz, 1H) 7.17 (s, 1H) 7.21 (s, 1H) 7.37-7.48 (m, 2H) 7.60 (dd, J = 10.33, 2.63Hz, 1H) 7.66 (s , 1H) 8.07-8.14 (m, 1H) ...

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Abstract

The present invention discloses a new compound as a kynurenine pathway inhibitor, and specifically discloses a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.

Description

[0001] This application claims the following priority: [0002] CN201810143151.0, the filing date is February 11, 2018. technical field [0003] The present invention relates to a new compound as a kynurenine pathway inhibitor, and specifically discloses a compound represented by formula (I) and a pharmaceutically acceptable salt thereof. The present invention also relates to the application of the compound represented by formula (I) and the pharmaceutically acceptable salt thereof in the preparation of drugs for treating tumors. Background technique [0004] Malignant tumors are one of the major diseases that endanger human life today. In the past hundred years, in order to fight against malignant tumors, human beings have developed a variety of diagnosis and treatment methods including the most commonly used chemotherapy, surgery, radiotherapy and targeted therapy. These therapies delay the development of tumors to a certain extent and prolong the lives of patients. How...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/02A61K31/496A61P35/00
CPCA61K31/496A61P35/00C07D217/02
Inventor 周明陆剑宇胡国平胡利红丁照中黎健陈曙辉
Owner CSTONE PHARM (SUZHOU) CO LTD
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