N-(3-(pyrimidine-2-yl)phenyl)benzenesulfonamide derivative, and pharmaceutical composition, preparation method and application thereof

A technology for medicines and compounds is applied in the field of preparation of N-phenyl)benzenesulfonamide derivatives and pharmaceutical compositions to achieve the effect of good antitumor pharmacological activity

Active Publication Date: 2020-10-02
北京鑫开元医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs have obvious deficiencies, therefore, research and discovery of new c-Met inhibitors are of great significance

Method used

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  • N-(3-(pyrimidine-2-yl)phenyl)benzenesulfonamide derivative, and pharmaceutical composition, preparation method and application thereof
  • N-(3-(pyrimidine-2-yl)phenyl)benzenesulfonamide derivative, and pharmaceutical composition, preparation method and application thereof
  • N-(3-(pyrimidine-2-yl)phenyl)benzenesulfonamide derivative, and pharmaceutical composition, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] 1-(4-(N-(3-(5-((1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)phenyl)aminosulfonyl)phenyl)piperidine- 4-Formamide

[0057]

[0058] first step:

[0059] Compound 1a (57.4g, 200.0mmol), compound 1b (38.2g, 200.0mmol), K 2 CO 3 (30.4g, 220.0mmol) was dissolved in DMF (500ml), and reacted at 60°C for 8 hours, and the reaction was detected by thin layer chromatography (TLC). After the reaction was completed, part of the solvent was removed under reduced pressure, and water (500ml) was added. , was extracted twice with ethyl acetate (500ml), the organic layer was dried, concentrated and separated by chromatography to obtain 55.3g of compound 1c, with a yield of 69.4%. Compound 1c was an off-white solid.

[0060] Step two:

[0061] Compound 1c (39.8g, 100.0mmol) was dissolved in hydrogen chloride-ethyl acetate solution (500ml), stirred and reacted at 25°C for 8 hours, and detected by TLC. After the reaction was completed, the reaction was quenched with saturated sodium...

Embodiment 2

[0067] 4-(4-(N-(3-(5-((1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)phenyl)aminosulfonyl)phenyl)piperazine- Methyl 1-formate

[0068]

[0069] Compound 1f was synthesized according to the method of the first step, the second step and the third step in Example 1.

[0070] Compound 1f (5.2g, 10.0mmol), compound 2a (1.4g, 10.0mmol), CsCO 3 (4.9g, 15.0mmol), PPh 3 (262.0mg, 1.0mmol), Pd(OAc) 2 (112 mg, 0.5 mmol) was dissolved in DMF (50 ml), heated to 100 ° C for 6 hours, after the reaction was completed, water (50 ml) was added to quench the reaction, ethyl acetate (100 ml) was extracted twice, the organic layer was dried, filtered, and column Chromatographic separation afforded 3.3 g of off-white solid, yield 56.8%, ESI(+) m / z=581.2.

Embodiment 3

[0072] 4-(4-cyanopiperidin-1-yl)-N-(3-(5-((1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)phenyl)amino Sulfonyl)phenyl)benzenesulfonamide

[0073]

[0074] Compound 1f was synthesized according to the method of the first step, the second step and the third step in Example 1.

[0075] Compound 1f (5.2g, 10.0mmol), compound 3a (1.1g, 10.0mmol), CsCO 3 (4.9g, 15.0mmol), PPh 3 (262.0mg, 1.0mmol), Pd(OAc) 2 (112 mg, 0.5 mmol) was dissolved in DMF (50 ml), heated to 100 ° C for 6 hours, after the reaction was completed, water (50 ml) was added to quench the reaction, ethyl acetate (100 ml) was extracted twice, the organic layer was dried, filtered, and column Chromatographic separation afforded 2.8 g of off-white solid, yield 51.3%, ESI(+) m / z=547.2.

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Abstract

The invention belongs to the technical field of biological medicine, and provides an N-(3-(pyrimidine-2-yl)phenyl)benzenesulfonamide derivative, and a pharmaceutical composition, a preparation methodand application thereof. The N-(3-(pyrimidine-2-yl)phenyl)benzenesulfonamide derivative is a compound with a structure of formula I, or a stereoisomer or pharmaceutically acceptable salt and isotope compound thereof. The structure of the formula I is shown in the specification; and in the formula I, R1 and R2 can form a substituted or unsubstituted piperidine or piperazine ring, and R3 representsa (1-methylpiperidine-4-yl)methyl group, a (2-oxopiperidine-4-yl)methyl group or a (4-oxocyclohexyl)methyl group. The N-(3-(pyrimidine-2-yl) phenyl) benzenesulfonamide derivative can be used as an effective c-Met inhibitor, and meanwhile, the pharmaceutical composition of the N-(3-(pyrimidine-2-yl)phenyl)benzenesulfonamide derivative has good multiple anti-tumor pharmacological activities.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to an N-(3-(pyrimidin-2-yl)phenyl)benzenesulfonamide derivative, a pharmaceutical composition, a preparation method and an application. Background technique [0002] Cancer is one of the major diseases that threaten human health. At present, the main treatment methods for cancer include drug therapy, surgical treatment, radiotherapy, etc., among which drug therapy is one of the most commonly used treatment methods. Traditional cytotoxic drugs cannot distinguish between tumor cells and normal cells, often causing serious side effects, while targeted drugs use tumor cells as specific targets, can accurately act on tumors, and can effectively improve the treatment level of cancer. Reduce the rate of adverse reactions. [0003] Receptor tyrosine kinases (receptor tyrosine kinases, abbreviated as RTKs) are key enzymes that catalyze the autophosphorylation of tyrosine resi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D401/12C07D239/34A61K31/635A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D239/34C07D401/12C07D401/14
Inventor 王永广李雪莲万晓梦苏小庭戴信敏
Owner 北京鑫开元医药科技有限公司
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