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Substituted urea compound, its pharmaceutically acceptable salt or its solvate, its application, medicine and pharmaceutical composition

A compound, the technology of replacing urea, applied in the direction of drug combination, organic chemistry, medical preparations containing active ingredients, etc., can solve the problem that the tumor suppressing effect needs to be improved, and achieve prolonging the time of drug resistance, broad application prospects, and improving curative effect. Effect

Active Publication Date: 2022-01-25
GUANGZHOU LIUSHUN BIO TEC CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The marketed drugs Sorafenib (Nexavar) and Lenvatinib (Lenvatinib, E7080), both of which are multi-kinase inhibitors targeting VEGF receptors, are multi-target kinase inhibitors, However, its antitumor effect needs to be improved

Method used

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  • Substituted urea compound, its pharmaceutically acceptable salt or its solvate, its application, medicine and pharmaceutical composition
  • Substituted urea compound, its pharmaceutically acceptable salt or its solvate, its application, medicine and pharmaceutical composition
  • Substituted urea compound, its pharmaceutically acceptable salt or its solvate, its application, medicine and pharmaceutical composition

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preparation example Construction

[0052] The substituted urea compound described in the embodiment of the present invention can be prepared by various methods, and the embodiment of the present invention provides a method for preparing the substituted urea compound with a higher yield, which includes the following steps:

[0053] (1) compound (Ic) is obtained by reacting compounds (Ia) and (Ib);

[0054]

[0055] (2) obtain compound (Ie) by reaction of compound (Ic) and (Id);

[0056]

[0057] (3) obtaining the substituted urea compound by reacting compound (Ie) and compound (If);

[0058]

[0059] Among them, R 1 selected from methoxy or deuterated methoxy;

[0060] R 2 selected from methyl, deuterated methyl, any structure in

[0061] R 3 Any one selected from F, Cl, Br, I.

[0062] Compound (Ia) and Compound (Ib) are pharmaceutical intermediates and can be purchased. In step (1), compound (Ia) and compound (Ib) are amidated under basic catalytic conditions to obtain compound (Ic). Used ba...

Embodiment 1

[0083] The synthetic route of compound I-1 1-(2-chloro-4-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-cyclopropylurea is as follows:

[0084]

[0085] resolve resolution:

[0086] (1) Add 4-amino-2-chloro-phenol (12.7g, 0.1mol) and sodium bicarbonate (16.8g, 0.2mol) to tetrahydrofuran (100ml) and water (100ml), stir at room temperature to make it Uniform suspension state (solution A). Phenyl chloroformate (18.8 g, 0.12 mol) was dissolved in tetrahydrofuran (50 mL) to form a solution (Solution B). Add solution B dropwise to solution A, stir the reaction at room temperature after the dropwise addition, track the reaction by TLC, analyze and confirm the completion of the reaction, and perform post-treatment. The post-processing steps include: standing the reaction solution for liquid separation, extracting the aqueous phase with 100 mL of ethyl acetate, washing the organic phase with saturated brine three times, adding anhydrous sodium sulfate to dry, suction filtering, and ...

Embodiment 2

[0091] The synthetic route of compound I-2 1-(2-fluoro-4-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-cyclopropylurea is as follows:

[0092]

[0093] The synthetic method can refer to Example 1, the equivalent ratio and reaction conditions in step (1) and step (2) are all constant, the reactant equivalent in step (3) is constant, and the reaction condition is 40 ℃ heating and stirring reaction. The post-treatment steps include: adding 100 mL of water to the reaction solution, crystallizing at room temperature under stirring, suction filtration, and washing the filter cake twice with purified water. The resulting solid was slurried in ethanol (200 mL), suction filtered, and vacuum-dried to obtain 6.05 g of compound (I-2), with a yield of 76%.

[0094] The NMR data of the obtained compound (I-2) are: 1H NMR (400MHz, DMSO) δ (ppm): 8.62 (s, 1H), 8.26 (d, 1H), 8.03 (s, 1H), 7.62 (s, 1H),7.55(d,1H),7.43(s,1H),7.32(d,1H),7.20(d,1H),4.12-3.96(m,6H),2.70-2.60(m,1H),0.73 (q, 2H),...

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Abstract

The present invention provides a substituted urea compound, its pharmaceutically acceptable salt or its solvate. The present invention also provides the application of the substituted urea compound, its pharmaceutically acceptable salt or its solvate as an inhibitor of MET, VEGFR, PDGFR and RET or in the preparation of MET, VEGFR, PDGFR and RET The application of two or more multi-target inhibitors, and the use of the substituted urea compound, its pharmaceutically acceptable salt or its solvate in the preparation of regulating kinase activity or treating kinase-related diseases The application of the medicine or pharmaceutical composition. The present invention also provides a medicine or a medicine composition for treating abnormal angiogenesis diseases. The structure of the substituted urea compound is shown in formula (I), R 1 selected from methoxy or deuterated methoxy; R 2 Any structure selected from methyl, deuterated methyl, and R; 3 Any one selected from F, Cl, Br, I.

Description

[0001] related application [0002] This application requires a Chinese patent filed on September 25, 2018, with application number 2018111165044, entitled "Substituted Urea Compounds, Pharmaceutically Acceptable Salts or Solvates, Pharmaceutical Compositions, Preparation Methods and Applications thereof" priority of the application, which is hereby incorporated by reference in its entirety. technical field [0003] The invention belongs to the technical field of biomedicine, and relates to a substituted urea compound, its pharmaceutically acceptable salt or its solvate, its application, medicine and pharmaceutical composition. Background technique [0004] Cancer is a series of diseases characterized by the uncontrolled proliferation and spread of abnormal cells. It is one of the major diseases that seriously endanger human health. According to the report of the World Health Organization, the number of cancer patients in the world increases by 10 million every year, and abo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/88A61P35/00A61P29/00A61P3/10A61P27/02A61P35/02A61P35/04A61P19/02A61P17/00A61P37/08A61K31/517
CPCA61P3/10A61P17/00A61P19/02A61P27/02A61P29/00A61P35/00A61P35/02A61P35/04A61P37/08A61K31/517C07D239/88
Inventor 陆瑞燕
Owner GUANGZHOU LIUSHUN BIO TEC CO LTD
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