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Mesylate of dibenzo[b,d]thiophene STAT3 (Signal Transducer and Activator of Transcription-3) inhibitor and preparation method and application of mesylate

A technology of methanesulfonate and methanesulfonic acid, applied in drug combination, active ingredient of heterocyclic compounds, organic chemistry, etc., can solve problems such as water solubility and difference in bioavailability

Inactive Publication Date: 2019-02-15
NANJING ADVANCED BIOLOGICAL MATERIALS & PROCESS EQUIP INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the process of compound (I) druggability research, the inventors of the present invention found that different compound (I) medicinal salts have large differences in water solubility, bioavailability, etc.

Method used

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  • Mesylate of dibenzo[b,d]thiophene STAT3 (Signal Transducer and Activator of Transcription-3) inhibitor and preparation method and application of mesylate
  • Mesylate of dibenzo[b,d]thiophene STAT3 (Signal Transducer and Activator of Transcription-3) inhibitor and preparation method and application of mesylate
  • Mesylate of dibenzo[b,d]thiophene STAT3 (Signal Transducer and Activator of Transcription-3) inhibitor and preparation method and application of mesylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Preparation of 2-aminomethyl-4H-chromen-4-one hydrochloride

[0029] The preparation of step 1 2-acetoxyacetophenone

[0030]

[0031] Add 2-hydroxyacetophenone (100mmol), acetyl chloride (250mmol) and potassium carbonate (500mmol) into the reaction flask, add 300ml of acetone, reflux reaction for 12h, after the reaction, evaporate the solvent under reduced pressure, add water, ethyl acetate Esters were extracted, dried over anhydrous sodium sulfate, and concentrated to obtain an oil, which was directly used for the next step.

[0032] Step 2 Preparation of 2-methyl-4H-chromen-4-one

[0033]

[0034] Weigh 2-acetoxyacetophenone (50mmol) into a reaction flask, add 100ml DMSO to dissolve, add sodium hydrogen (150mmol) in batches at 0-5°C, after the addition is complete, raise it to room temperature and stir for 3h. After the reaction, Add water to the reaction solution, dilute hydrochloric acid to adjust the pH value to weak acidity, extract with ethyl a...

Embodiment 2

[0044] Example 2 Preparation of 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine

[0045] Preparation of step 1 methyl 4-nitrobenzoate

[0046]

[0047] Weigh 4-nitrobenzoic acid (250mmol) in a reaction flask, add 300mL of methanol to dissolve, add thionyl chloride (375mmol) dropwise, and reflux for 12 hours after the dropwise reaction. After the reaction, spin dry under reduced pressure and add saturated bicarbonate The sodium solution adjusted the pH to 7-8, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound, which was directly used for the next step.

[0048] Step 2 Preparation of 6-(4-nitrophenyl)-1,3,5-triazine-2,4-(1H,3H)-dione

[0049]

[0050] Weigh biuret (100mmol) into the reaction flask, add 150mL ethylene glycol dimethyl ether to dissolve, add sodium hydride (83.4mmol) in batches at 0-5°C, after the addition is complete, stir the reaction at 50°C for 1h, then add 4-Nitrobenzoic acid methyl ester (83...

Embodiment 3

[0056] Example 3 4-chloro-6-(4-nitrophenyl)-N-(2-methyl-4H-chromene-4-one base)-1,3,5-triazin-2-amine preparation

[0057]

[0058] Weigh 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine (50mmol) obtained in Example 2 into a reaction flask, add 100mL tetrahydrofuran to dissolve, add Example 1 The resulting 2-aminomethyl-4H-chromen-4-one hydrochloride 2-(trifluoromethyl)-pyridin-4-amine (55mmol), sodium carbonate (100mmol), reflux for 72h, filter, column Chromatographic purification afforded the title compound.

[0059] ES: M / Z 416[M+H] + .

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and relates to mesylate of a dibenzo[b,d]thiophene STAT3 (Signal Transducer and Activator of Transcription-3) inhibitor and a preparation method and application of the mesylate, particularly, the invention relates to the mesylate of 4-(dibenzo[b,d]thiophene-4-yl)-6-(4-allyl acylamino phenyl)-N-(2-methyl-4H-chromene-4-keto)-1,3,5-triazine-2-amine and the preparation method and the application of the mesylate, the structure of the mesylate of 4-(dibenzo[b,d]thiophene-4-yl)-6-(4-allyl acylamino phenyl)-N-(2-methyl-4H-chromene-4-keto)-1,3,5-triazine-2-amine is shown in the description, and the mesylate is good in water solubility, high in bioavailability and good in stability.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to the methanesulfonate of dibenzo[b,d]thiophene STAT3 inhibitors and its preparation method and application. Specifically, the invention relates to 4-(dibenzo[b,d] Thiophen-4-yl)-6-(4-acrylaminophenyl)-N-(2-methyl-4H-chromen-4-one)-1,3,5-triazine-2- Amine mesylate and its preparation method and use. Background technique [0002] Cancer is a general term for a large class of malignant tumors, which is characterized by unlimited and endless proliferation. Cancer cells consume a large amount of nutrients in the patient's body, and at the same time release a variety of toxins, causing a series of symptoms in the human body, resulting in weight loss, weakness, anemia, loss of appetite, fever, and serious organ function damage, causing necrosis and bleeding Co-infection, the patient eventually died due to organ failure. [0003] Signal Transducer and Activator of Transcription-3 (STAT...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/14A61K31/53A61P35/00
CPCA61P35/00C07D409/14
Inventor 郭程杰
Owner NANJING ADVANCED BIOLOGICAL MATERIALS & PROCESS EQUIP INST CO LTD
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