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1,2,5-oxadiazole derivative and purpose thereof

A compound and mixture technology, applied in the field of medicine, can solve problems such as T-cell activation signal transduction blockage, achieve good therapeutic effects, broad application prospects, and significant therapeutic effects

Pending Publication Date: 2019-04-05
SHANGHAI SHENGYUE PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, a large number of studies have shown that IDO is highly expressed in leukemia cells, which inhibits the proliferation of local T cells, inhibits the immune response mediated by T-cells, and blocks the transduction of T-cell activation signals, thereby mediating the escape of tumor cells from the immune system. attack

Method used

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  • 1,2,5-oxadiazole derivative and purpose thereof
  • 1,2,5-oxadiazole derivative and purpose thereof
  • 1,2,5-oxadiazole derivative and purpose thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Synthesis of intermediate 7: 4-(3-bromo-4-fluorophenyl)-3-(4-nitro-1,2,5-oxadiazole-3-)-1,2,4- Oxadiazol-5-one

[0037]

[0038] step 1:

[0039]

[0040]Compound 1 (32g, 485mmol) was dissolved in 500mL of water and heated at 45°C until completely dissolved. Under cooling in an ice-water bath, sodium nitrite (38 g, 533 mmol) and 6N hydrochloric acid (5.5 mL) were added. After reacting in an ice bath for 0.5 hours, the temperature was raised to room temperature and reacted for 1.5 hours. The reaction solution was continued to be cooled in an ice bath, and 50% hydroxylamine hydrochloride aqueous solution (99 g, 1500 mmol) was added dropwise to the reaction solution, stirred for half an hour, and then raised to room temperature for 1 hour of reaction. Heat to reflux for 2 hours. After the reaction, adjust the pH to 7.0 with 80 mL of 6N hydrochloric acid in an ice bath. The precipitate was filtered, washed once with water, and dried to obtain compound 2 ...

Embodiment 2

[0054] Example 2 Synthesis of compound A: (E)-N-(3-bromo-4-fluorophenyl)-N′-hydroxyl-4-(3-sulfonylaminocyclobutylmethylamino)-1,2,5 -Oxadiazole-3-guanidine

[0055]

[0056] step 1:

[0057]

[0058] Dissolve compound 7 (150mg, 0.4mmol) and compound 8 (96mg, 0.6mmol) in 2mL of tetrahydrofuran, add dropwise triethylamine (202mg, 2.0mmol) at room temperature for 5 minutes, add water (10mL), ethyl acetate Extracted twice, dried over anhydrous sodium sulfate, concentrated, petroleum ether to ethyl acetate (8:1) column to give white solid compound 9 (190 mg, 97%).

[0059] Step 2:

[0060]

[0061] Compound 9 (190 mg, 0.40 mmol) was dissolved in 2 mL of dioxane, and dioxane hydrochloride (3 mL) was added to react at room temperature for 1 hour. After the reaction, the reaction solution was spin-dried to obtain white solid compound 10 (163 mg, 98%).

[0062] Step 3:

[0063]

[0064] Dissolve compound 10 (160mg, 0.35mmol) in anhydrous dichloromethane, add triethylam...

Embodiment 3

[0069] Example 3 Synthesis of compound B: (E)-N-(3-bromo-4-fluorophenyl)-N'-hydroxyl-4-(3-sulfonic acid cyclobutylmethylamino)-1,2,5 -Oxadiazole-3-guanidine

[0070]

[0071] step 1:

[0072]

[0073] Dissolve compound 7 (150mg, 0.4mmol) and compound 12 (85mg, 0.6mmol) in 2mL of tetrahydrofuran, add dropwise triethylamine (202mg, 2.0mmol) at room temperature for 5 minutes, add water (10mL), ethyl acetate Extracted twice, dried over anhydrous sodium sulfate, concentrated, petroleum ether to ethyl acetate (8:1) column to give white solid compound 13 (180 mg, 87%).

[0074] Step 2:

[0075]

[0076] Dissolve compound 13 (180mg, 0.35mmol) in anhydrous dichloromethane, add triethylamine (80mg, 0.7mmol), stir in an ice bath for a few minutes, add sulfamoyl chloride (40mg, 0.35mmol) dropwise, continue Stir for half an hour. After the reaction, the reaction solution was spin-dried to obtain white solid compound 14 (120 mg, 72%).

[0077] Step 3:

[0078]

[0079] Com...

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Abstract

The invention discloses a compound having the following general formula (I), wherein K is selected from a cycloalkane group shown in the following formula. The invention also discloses an indoleamine-2,3-dioxygenase inhibitor comprising the compound and an application of the compound in preparation of drugs for treating cancer. The compound of the invention can effectively inhibit cell proliferation, has a good therapeutic effect on various diseases such as cancer, has significant therapeutic effects on breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostatic cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, non-small cell lung cancer, and the like, and has very broad application prospects.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a 1,2,5-oxadiazole derivative as an indoleamine-2,3-dioxygenase inhibitor and its application. Background technique [0002] Indoleamine-2,3-dioxygenase (Indoleamine-2,3-dioxygenase, ID0) was first discovered in cells by the Hayaishi group in 1967. It is a monomeric enzyme containing heme, cDNA encoding protein Composed of 403 amino acids, including IDO1, IDO2, TDO (tryptophan 2,3-dioxygenase). Munn and Mellor first proposed in Science in 1998 that IDO1 plays an immunomodulatory protective role in infants separated from the mother's immune system. Since then, human research on IDO has been rapid and in-depth, and it has been found that it is the rate-limiting enzyme of the catabolism of the tryptophan-kynurenine pathway, and it is widely expressed in various mammalian tissues. In the cells of tumor patients, IDO often plays an important physiological role in inducing immune to...

Claims

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Application Information

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IPC IPC(8): C07D271/08C07D413/12C07D413/04C07D417/12C07D419/12C07F9/653C07F9/6584A61K31/4245A61K31/549A61K31/54A61K31/433A61K31/675A61K31/454A61P35/00A61P35/02A61P25/28A61P25/22A61P25/24A61P25/00A61P31/18A61P27/12A61P37/06A61P19/08
CPCC07D271/08C07D413/04C07D413/12C07D417/12C07D419/12C07F9/65318C07F9/65842
Inventor 孙芳占有妮
Owner SHANGHAI SHENGYUE PHARM TECH CO LTD
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