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Antitumor compound used as AXL inhibitor and application of antitumor compound

A compound, drug technology, applied in the field of medicinal chemistry

Inactive Publication Date: 2019-10-15
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Axl, Tyro3, ​​and c-Met receptor tyrosine kinases show their respective tissue-specific expression patterns, especially AXL kinase inhibitors have very promising application prospects, but there are still many major challenges in the development of this variety

Method used

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  • Antitumor compound used as AXL inhibitor and application of antitumor compound
  • Antitumor compound used as AXL inhibitor and application of antitumor compound
  • Antitumor compound used as AXL inhibitor and application of antitumor compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1 Compound 5 Synthesis

[0077]

[0078] Synthesis of Compound 1: Take a 1.0L three-necked flask, add 100.0g of acetylacetaldehyde dimethyl acetal, 11.0g of piperidinium acetate and 400ml of toluene, then slowly add 50.0g of malononitrile, react at 35°C for 16.0h, After the reaction finished, add 200ml of water to wash, separate the layers, keep the organic phase, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to dryness to obtain 130.0g compound 1, which is propylene malononitrile and propenylene malononitrile ( 10:1) mixture.

[0079] Synthesis of Compound 2: Take a 250ml three-neck flask, add 70ml of concentrated sulfuric acid, stir at 0°C, slowly add compound 1 dropwise, after the addition is complete, raise the temperature to 50°C for 5.0 hours, after the reaction, drop to 0°C, add dropwise to In 200ml of 0°C water, a solid precipitated out, and it was filtered with suction. The filter cake was rinsed with 50ml of water, drain...

Embodiment 2

[0083] The preparation of embodiment 2 compound I-1

[0084]

[0085] I-1-1 Synthesis: Take a 100ml three-necked flask, add 2.23g 4-chloro-6,7-dimethoxyquinoline, 1.63g p-aminophenol, 1.44g sodium tert-butoxide, 10ml DMAC, and react at 105°C After 12.0 hours, the reaction of the raw materials was basically complete, poured into 100ml of water, and filtered with suction to obtain a brown-black solid, and 2.05g of compound I-1-1 was obtained by column chromatography.

[0086] Synthesis of I-1: Take a 100ml three-neck flask, add 300mg I-1-1, 150mg compound 3, 570mg HBTU, 390mg DIEA and 10ml DMF in sequence, react at 25°C for 3.0h, the raw materials are basically reacted completely, add the reaction solution into 100ml water, and filter with suction , filter cake column chromatography to obtain 15 mg of compound I-1, MS m / z=432.2 (M+1), 1 H NMR (400MHz, d6-DMSO) δ: 10.83(s, 1H), 8.49-8.48(m, 1H), 8.21-8.18(m, 1H), 7.99-7.98(m, 1H), 7.55-7.53(m , 1H), 7.45-7.41 (m, 4H), 7.22-7...

Embodiment 3

[0087] The preparation of embodiment 3 compound 1-2

[0088]

[0089] I-2-1 Synthesis: Take a 100ml three-necked flask, add 2.23g 4-chloro-6,7-dimethoxyquinoline, 1.91g 4-amino-2-fluorophenol, 1.44g sodium tert-butoxide, 10ml DMAC , reacted at 105°C for 12h, the raw materials were basically reacted completely, poured into 100ml of water, and filtered with suction to obtain a brown-black solid, and column chromatography gave 1.50g of compound I-2-1.

[0090] I-2 Synthesis: Take a 100ml three-necked flask, add 315mg of compound I-2-1, 150mg of compound 3, 570mg of HBTU, 390mg of DIEA, and 10ml of DMF in sequence, and react at 25°C for 3.0h. The raw materials are basically reacted completely, and the reaction solution is added to 100ml of water , a large amount of solids precipitated, suction filtration, filter cake column chromatography to obtain 20 mg of compound I-2, MS m / z=450.5 (M+1), 1 HNMR (400MHz, d6-DMSO) δ: 10.82(s, 1H), 8.52-8.50(m, 1H), 8.03-8.02(m, 1H), 7.94-7.92...

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PUM

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Abstract

The invention discloses a compound shown in a general formula (I) or pharmaceutically acceptable salt of the compound and preparation methods of the compound and the salt, and further discloses pharmaceutical composition containing the compound and an application of the compound and the pharmaceutical composition in preparation of an AXL inhibitory drug. The AXL inhibitory drug is used for treating tumor, nephropathy, immune system disease or circulatory system disease.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to an AXL inhibitor and its preparation method and application. Background technique [0002] Molecular targeted therapy for various malignant tumors has received extensive attention and great attention. Molecular targeted drugs are highly selective, broad-spectrum effective, and safer than cytotoxic chemotherapeutic drugs. They are currently a new direction in the development of tumor treatment. [0003] Axl (also known as: UFO, ARK, Tyro7) is a receptor tyrosine kinase cloned from tumor cells. Gas6 (growth arrest-specific protein 6), which was cloned as a gene specifically expressed at the time of cell proliferation arrest, is known to be a ligand of Axl. Axl activated by binding to Gas6 transmits a signal through phosphorylation. Since this signaling activates the Erk1 / 2 pathway or the PI3K / Akt pathway, compounds that inhibit Axl activation are useful in the treat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14C07D405/14C07D471/04A61K31/4709A61K31/496A61P35/00A61P13/12A61P37/06A61P35/04
CPCA61P13/12A61P35/00A61P35/04A61P37/06C07D401/12C07D401/14C07D405/14C07D471/04
Inventor 张孝清宋志春包金远何东伟
Owner NANJING HUAWE MEDICINE TECH DEV
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