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Quinoline derivative, pharmaceutically acceptable salt or solvate thereof, application thereof, medicines and pharmaceutical compositions

A technology of solvates and derivatives, which is applied in the direction of drug combinations, active ingredients of heterocyclic compounds, and medical preparations containing active ingredients, etc., can solve the problems that the anti-tumor effect needs to be improved, so as to prolong the time of drug resistance and improve Curative effect, excellent anti-tumor effect

Active Publication Date: 2019-05-17
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 Cabozantinib (Cabozantinib, code name XL184) and Lenvatinib (Lenvatinib, E7080), both of which are multi-kinase inhibitors targeting VEGF receptors, are a multi-target kinase inhibitor agent, but its antitumor effect needs to be improved

Method used

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  • Quinoline derivative, pharmaceutically acceptable salt or solvate thereof, application thereof, medicines and pharmaceutical compositions
  • Quinoline derivative, pharmaceutically acceptable salt or solvate thereof, application thereof, medicines and pharmaceutical compositions
  • Quinoline derivative, pharmaceutically acceptable salt or solvate thereof, application thereof, medicines and pharmaceutical compositions

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preparation example Construction

[0052] The quinoline derivatives described in the embodiments of the present invention can be prepared by various methods, and the embodiments of the present invention provide a method for preparing the quinoline derivatives with a relatively high yield, comprising 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) obtain described quinoline derivative by reaction of compound (Ie) and compound (If);

[0058]

[0059] R 1 selected from methyl, deuterated methyl, any structure in

[0060] R 2 Any one selected from F, Cl, Br, I, H;

[0061] R 3 selected from F, CHF 2 、CF 3 , any one of Cl.

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

Embodiment 1

[0084] Compound I-1N-(4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1 -The synthetic route of dicarboxamide is as follows:

[0085]

[0086] resolve resolution:

[0087](1) Add p-aminophenol (10.9g, 0.1mol) and triethylamine (30.3g, 0.3mol) into dichloromethane (300ml), stir at room temperature to make it into a uniform suspension state (solution A). Methyl 1-(chlorocarbonyl)cyclopropanecarboxylate (17.82 g, 0.11 mol) was dissolved in 100 ml of dichloromethane to form a solution (Solution B). Add solution B dropwise to solution A, stir the reaction at room temperature after the dropwise addition is completed, track the reaction by TLC (thin layer chromatography analysis), and analyze and confirm that the reaction is completed. After the reaction is completed, the solution after the reaction is filtered to remove insoluble impurities, and the organic phase is washed with dilute hydrochloric acid. Wash once, then wash once with brine, d...

Embodiment 2

[0092] Compound I-2N-(4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl)-N-(4-fluorophenyl)cyclopropane- The synthetic route of 1,1-dicarboxamide is as follows:

[0093]

[0094] Synthetic method can refer to embodiment 1, and in step (1) and step (2), equivalent ratio and reaction condition are all constant, and step (3) compound (I-2e) (8.36g, 0.024mol) and 4-chloro- 6-carbamoyl-7-methoxyquinoline (4.72g, 0.02mol) was added to 70ml of DMF, then sodium hydroxide (1.12g, 0.028mol) was added, under nitrogen protection, the reaction was heated and stirred at 60°C, passed TLC followed the reaction. After the analysis confirmed that the reaction was complete, 80 mL of purified water was added dropwise to the reacted solution. After the solid was precipitated, it was filtered with suction, and the filter cake was washed with ethanol to obtain the crude product. The crude product was purified by column chromatography to obtain compound (I-2). 4.28g, yield 39%.

[0095]...

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Abstract

The invention provides a quinoline derivative, and pharmaceutically acceptable salt or solvate thereof. The invention further provides the application of the quinoline derivative, and the pharmaceutically acceptable salt or solvate thereof as one inhibitor of MET (Mesenchymal to epithelial transition factor), VEGFR (Vascular endothelial growth factor receptor), BRAF (V-raf murine sarcoma viral oncogene homolog B1), PDGFR (Platelet-derived growth factor receptor) and RET (RET proto-oncogene) or the application in the preparation of two or more multi-target inhibitors of MET, VEGFR, BRAF, PDGFRand RET, and the application of the quinoline derivative, and the pharmaceutically acceptable salt or solvate thereof in the preparation of medicines or pharmaceutical compositions used for regulatingand controlling kinase activity or treating kinase related diseases. The invention further provides a medicine or a pharmaceutical composition used for treating angiogenesis abnormal diseases. A structure of the quinoline derivative is shown in a formula (I) (shown in the description), wherein R1 is selected from any one of structure of methyl, deuterated methyl and two chemical elements shown inthe description; R2 is selected from any one of F, Cl, Br, I and H; R3 is selected from any one of F, Cl, Br, I, H, CH3, CHX2, CH2X and CX3; and X is halogen.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and relates to a quinoline derivative, a pharmaceutically acceptable salt or a solvate thereof, an application thereof, a medicine and a medicine composition. Background technique [0002] 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 about 7 million people die. In 2020, there will be 20 million new cancer patients every year. At present, 1.6 million people suffer from cancer in my country every year, and about 1.3 million people die of cancer at the same time. Cancer is becoming the "second killer" of human beings after cardiovascular disease. [0003] With the development of molecular biology, significant progress has be...

Claims

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Application Information

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IPC IPC(8): C07D215/48A61K31/47A61K31/5377A61P35/00A61P27/02A61P27/06A61P29/00A61P3/10A61P35/02A61P35/04
Inventor 陆瑞燕
Owner GUANGZHOU LIUSHUN BIO TEC CO LTD
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