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Deuterated bisarylurea compound and preparation method thereof, and application of compound in preparation of antitumor drug

A bisaryl urea and ether compound technology, which is applied in the fields of chemistry and medicine, can solve the problems of increased difficulty in continued use, complete remission and partial remission of advanced renal cancer, etc.

Active Publication Date: 2016-02-24
MARINE BIOMEDICAL RES INST OF QINGDAO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Clinical data show that the standard treatment regimen of sorafenib alone has a low rate of complete remission (CR) and partial remission (PR) for advanced renal cancer
In addition, hepatocellular carcinoma is very prone to drug resistance to sorafenib, which may be the main obstacle to limit the further use of the drug
In addition, with the wide application of Sorafenib, its toxic and side effects are gradually emerging.
In the treatment of hepatocellular carcinoma, sorafenib can cause dose-dependent skin toxicity, such as rash, desquamation, hand-foot syndrome, mucositis, hair loss, itching, dryness and other toxic side effects, which increases the risk of continued use of the drug. extremely difficult

Method used

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  • Deuterated bisarylurea compound and preparation method thereof, and application of compound in preparation of antitumor drug
  • Deuterated bisarylurea compound and preparation method thereof, and application of compound in preparation of antitumor drug
  • Deuterated bisarylurea compound and preparation method thereof, and application of compound in preparation of antitumor drug

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: The synthetic route of compound D1 is as follows:

[0049]

[0050] (1) Dissolve 3 g of 4-chloropyridine-2-carboxylic acid methyl ester in 8 ml of 40% methylamine aqueous solution by mass ratio, react at room temperature for 3 hours, after the reaction is complete, add dichloromethane for extraction, dry, filter, concentrate and evaporate to dryness The oil was obtained with a yield of 87%, which was directly used in the next reaction.

[0051] (2) Dissolve the oil in step (1) in tetrahydrofuran for later use; take 700 mg of 1,5-dideuterium-4-p-aminophenol and add it to 10 ml of N,N-dimethylformamide for dissolution, then add 815 mg of t- Potassium butoxide, then add the above-mentioned tetrahydrofuran solution in which the oil is dissolved, dropwise; heat to 100°C for reaction, after the reaction is complete, pour the reaction solution into water, extract with dichloromethane, dry, filter, concentrate and evaporate to dryness, and the column layer Analy...

Embodiment 2

[0054] Embodiment 2: The synthetic route of compound D2 is as follows:

[0055]

[0056] (1) Dissolve 206mg of methyl 4-chloropyridine-2-carboxylate in tetrahydrofuran for later use; then take 100mg of deuterated methylamine hydrochloride and add water to dissolve it, then add 242mg of triethylamine. The solution was reacted at room temperature for 3 hours. After the reaction was complete, water and dichloromethane were added for extraction. The organic layer was separated, dried, concentrated and evaporated to dryness to obtain an oil with a yield of 78%, which was directly used in the next reaction.

[0057] (2) Dissolve the oil in step (1) in tetrahydrofuran for later use, take 700mg of 1,5-dideuterium-4 aminophenol and add it to 10ml of N,N-dimethylformamide to dissolve, then add 815mg of tert-butanol Potassium, then add the above-mentioned tetrahydrofuran solution of dissolved oil dropwise, and the drop is completed; heat to 100°C for reaction, after the reaction is co...

Embodiment 3

[0060] Embodiment 3: The synthetic route of compound D3 is as follows:

[0061]

[0062] (1) Dissolve 206mg of methyl 4-chloropyridine-2-carboxylate in tetrahydrofuran for later use; add 100mg of deuterated methylamine hydrochloride into water to dissolve, then add 242mg of triethylamine, after the addition is complete, drop it into the above-mentioned tetrahydrofuran solution, React at room temperature. After the reaction is complete, add water and dichloromethane to extract, separate the organic layer, dry, concentrate and evaporate to dryness to obtain an oily substance with a yield of 78%, which is directly used in the next reaction.

[0063] (2) Dissolve the oil in step (1) in tetrahydrofuran for later use, take 1.81g of p-aminophenol and add 25ml of N,N-dimethylformamide to dissolve, then add 2.5g of potassium tert-butoxide, and then dropwise add The above tetrahydrofuran solution in which the oil was dissolved was dripped and heated to 100°C for reaction. After the r...

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Abstract

The invention provides a deuterated bisarylurea compound and a preparation method thereof, and application of the compound in preparation of an antitumor drug. The compound has a structure as shown in a general formula (I). The preparation method comprises the following steps: with methyl 4-chloropyridine-2-formate as a raw material, sucjecting methyl 4-chloropyridine-2-formate and methylamine or deuterated methylamine to a substitution reaction; then subjecting a product obtained in the previous step to condensation with p-aminophenol or deuterated p-aminophenol; and reacting a product obtained in the previous step with 4-chloro-3-(trifluoromethyl)phenyl isocyanate or deuterated 4-chloro-3-(trifluoromethyl)phenyl isocyanate so as to prepare the deuterated bisarylurea compound. Experiment results show that the deuterated bisarylurea compound provided by the invention has tumor treatment effect. The invention also provides application of the compound to research and development of the antitumor drug.

Description

technical field [0001] The invention belongs to the technical field of chemistry and medicine, and relates to a pharmaceutical compound and its preparation method and application, in particular to a deuterated bisaryl urea compound, its preparation method and its application in the preparation of antitumor drugs. Background technique [0002] Sorafenib (Sorafenib, 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)ureide]phenoxy}pyridine-2-carboxamide) is produced by Bayer AG of Germany and the U.S. The first oral multikinase inhibitor co-developed by Onyx and the only drug approved for the treatment of advanced liver cancer. It has also recently been approved for the treatment of thyroid cancer in humans. [0003] Clinical data show that the standard treatment regimen of sorafenib alone has a low complete remission (CR) and partial remission (PR) rate for advanced renal cancer. In addition, hepatocellular carcinoma is very prone to drug resistance to sorafenib, which may be a majo...

Claims

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Application Information

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IPC IPC(8): C07D213/81A61K31/44A61P35/00
CPCC07B2200/05C07D213/81
Inventor 李文保李峰张良赵建春程贺娟管华诗
Owner MARINE BIOMEDICAL RES INST OF QINGDAO CO LTD
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