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Indoleamine-2,3-dioxygenase inhibitor, preparation method and uses thereof

A C3-C7, solvate technology, applied in the field of medicinal chemistry, can solve the problems of drug metabolism, stability, toxicity, etc.

Pending Publication Date: 2019-08-16
HINOVA PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, INCB-24360, a series of oral small molecule inhibitors of IDO being developed by Incyte, is also undergoing phase III clinical trials, mainly for the treatment of various cancers including myelodysplastic syndromes, but in clinical trials Toxicity issues of certain drug metabolism stability

Method used

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  • Indoleamine-2,3-dioxygenase inhibitor, preparation method and uses thereof
  • Indoleamine-2,3-dioxygenase inhibitor, preparation method and uses thereof
  • Indoleamine-2,3-dioxygenase inhibitor, preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Example 1: N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-sulfamoylethyl)amino)-1,2,5-oxadiazole-3- Methylamine (1)

[0109]

[0110] The first step: synthesis of intermediate 1-1:

[0111] Compound SM1-1 was prepared by literature method (WO 2017106062). The raw material SM1-1 (0.1mmol, 37mg) and 2-aminoethanesulfonamide hydrochloride (0.2mmol, 32mg, Shanghai Bi De Pharmaceutical Co., Ltd.) were dissolved in 2mL of THF, and 0.5mL of saturated sodium bicarbonate solution was added to react at room temperature overnight. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with 0.5N hydrochloric acid and then with saturated brine. After the organic phase was separated, the organic layer was concentrated under reduced pressure. The obtained crude product was purified by thin-layer chromatography to obtain 22 mg of a white solid (Intermediate 1-1), with a yield of 48%.

[0112] The second step: synthesis of compound 1:

[0113] Int...

Embodiment 2

[0116] Example 2: N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(N-methylsulfamoyl)ethyl)amino)-1,2,5- Oxadiazole-3-methimidine (2)

[0117]

[0118] The first step: synthesis of intermediate 2-1:

[0119] Intermediate 1-1 (113mg, 0.25mmol) and potassium carbonate (70mg, 0.5mmol) were sequentially added to DMF (5mL), then methyl iodide (36mg, 0.25mmol) was added slowly, stirred overnight at room temperature, TLC monitored the reaction materials disappear. Add 10 mL of water, extract with 20 mL of ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, purify by prep-TLC, develop with ethyl acetate / n-hexane=1 / 1, and obtain 20 mg of intermediate 2-1, yield: 17%.

[0120] Intermediate 2-1 (20 mg, 0.04 mmol) was added to 5 mL of tetrahydrofuran, 1.5 mL of sodium hydroxide (2N) solution was added, and the reaction was stirred at room temperature for 30 minutes, and the reaction raw materials basically disappeared as monitored by TLC. Add 10 mL of water, ex...

Embodiment 3

[0122] Example 3: N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(N-ethylsulfamoyl)ethyl)amino)-1,2,5- Oxadiazole-3-methimidine (3)

[0123] Compound 3 was prepared by a synthesis method similar to Example 1 using SM1-1 and SM2-3 as raw materials.

[0124]

[0125] Step 1: Synthesis of SM2-3:

[0126] Ethylamine hydrochloride (81.5mg, 1.0mmol) was dissolved in 5mL DCM, triethylamine (303mg, 3.0mmol) was added, and 2-benzenedi(form)imidoethanesulfonyl chloride (273mg , 1.0 mmol), reacted for 15 min, and monitored the reaction by TLC until the disappearance of the starting material. Added 10 mL of water, extracted with 10 mL of DCM, washed the organic layer with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by thin layer chromatography (DCM / MeOH=10:1) to obtain 65 mg of a white solid product. Rate: 23%.

[0127] Dissolve the white solid product (65mg, 0.23mmol) in 5mL of ethanol, add hydrazine hydrate (17.7...

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PUM

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Abstract

The present invention provides a compound represented by a formula (I), and relates to a pharmaceutical composition containing the compound represented by the formula (I), and uses of the compound inpreparation of indoleamine-2,3-dioxygenase (IDO) inhibitor drugs. According to the present invention, the prepared compound has obvious inhibitory effect on IDO protease, and is metabolically stable in vivo; and the compound or the pharmaceutical composition thereof can be used for the preparation of IDO inhibitor drugs, and can further be used for the preparation of drugs for preventing and / or treating diseases having pathological characteristics of IDO-mediated tryptophan metabolism pathway.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to an indoleamine-2,3-dioxygenase inhibitor and its preparation method and application. Background technique [0002] Malignant tumors are currently one of the major diseases that threaten human health and life. According to statistics from the National Health and Family Planning Commission, the incidence of tumors in mainland my country is about 235 / 100,000, and the mortality rate is about 144.3 / 100,000. [0003] Due to the unrestricted growth of malignant tumors in invasion and metastasis, the three conventional treatment methods (surgery, radiotherapy and chemotherapy) currently used in clinical practice cannot completely remove or completely kill tumor cells, so tumor metastasis or recurrence often occurs. Tumor biotherapy is a new treatment for tumor prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/08C07D413/12A61K31/4245A61K31/4523A61K31/496A61K31/5377A61P35/00A61P25/28A61P25/24A61P25/22A61P25/00A61P27/12A61P31/18A61P37/00
CPCC07D271/08C07D413/12A61P35/00A61P25/28A61P25/24A61P25/22A61P25/00A61P27/12A61P31/18A61P37/00A61P37/02
Inventor 杜武任闻吕海斌李海波温坤何锦云秦德坤李兴海陈元伟
Owner HINOVA PHARM INC
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