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Multi-target tyrosine kinase inhibitor as well as preparation method and application thereof

A technology of tyrosine kinase and application, which is applied in organic chemistry, drug combination, antineoplastic drugs, etc., and can solve the problems of low efficacy and adverse reactions of lenvatinib

Pending Publication Date: 2021-11-02
SICHUAN GUOKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, lenvatinib still has the problems of low drug efficacy and serious adverse reactions, so there is still an urgent need to develop a new RTKs inhibitor that can improve efficacy

Method used

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  • Multi-target tyrosine kinase inhibitor as well as preparation method and application thereof
  • Multi-target tyrosine kinase inhibitor as well as preparation method and application thereof
  • Multi-target tyrosine kinase inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1, the preparation of compound 1

[0043] The synthetic route is:

[0044]

[0045] The specific preparation methods include:

[0046] Add 12.6g (50.0mmol) of compound A (50.0mmol), ammonia-methanol solution (150.0mmol) and 50mL methanol to the reaction flask, react at 20-30°C for 16h, add 250mL water and 250mL ethyl acetate to the system, separate and collect the organic layer, organic The phase was washed successively with 100 mL of water, 50 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compound B. Purified by silica gel column (PE:EA=2:1) ​​to obtain 7.9g, yield 67.0%, LC / MS m / z=237.2[M+H] + .

[0047] Dissolve 5.72g (45.0mmol) of compound C in 45mL DMF, slowly add 1.80g (45.0mmol) of hydrogen extraction agent NaH, stir at room temperature for 30min, then add 7.1g (30.0mmol) of compound B, react at 60°C for 4h, cool down to Add 250mL of water and 250mL of ethyl acetate at room temperat...

Embodiment 2

[0050] Embodiment 2, the preparation of compound 2

[0051] The synthetic route is:

[0052]

[0053] Synthesize F with the method of Example 1, take 0.70g (1.5mmol) of compound F, 0.48g (3.0mmol) of compound G-2, 0.45g (4.5mmol) of triethylamine and 5mL of DMF, and react the reaction system at 80°C After 4 hours, the temperature was lowered to room temperature, 25 mL of water and 50 mL of EA were added, and the organic phase was collected. The organic phase was washed with 10 mL of water and then concentrated to dryness under reduced pressure to obtain the crude compound 2, which was then purified by a silica gel column to obtain 0.27 g of the pure compound 2, with a yield of 38.0%. . LC / MS m / z=479.1[M+H] + , 1 HNMR(DMSO-d6):3.99(s,3H),4.26-4.28(m,2H),5.72-5.74(m,1H),6.12-6.14(m,1H),6.49(d,J=5.5Hz, 1H),7.21-7.24(m,2H),7.50-7.5(m,2H),7.85(s,1H),7.98(s,1H),8.25-8.26(m,1H),8.62-8.65(m, 2H).

Embodiment 3

[0054] Embodiment 3, the preparation of compound 3

[0055] The synthetic route is:

[0056]

[0057] Synthesize F with the method of Example 1, take 0.70g (1.5mmol) of compound F, 0.40g (3.0mmol) of compound G-3, 0.45g (4.5mmol) of triethylamine and 5mL of DMF, and react the reaction system at 80°C After 4 hours, the temperature was lowered to room temperature, 25 mL of water and 50 mL of EA were added, and the organic phase was collected. The organic phase was washed with 10 mL of water and concentrated to dryness under reduced pressure to obtain a crude compound 3, which was then purified by a silica gel column to obtain 0.28 g of a pure compound 3 with a yield of 41.0%. . LC / MS m / z=451.1[M+H] + , 1 HNMR(DMSO-d6):0.45-0.47(m,4H),1.30-1.32(m,1H),3.99(s,3H),4.26-4.28(m,2H),5.71-5.72(m,1H), 5.90-5.91(m,1H),6.48-6.49(m,1H),7.20-7.25(m,2H),7.49-7.52(m,1H),7.85(s,1H),7.99(s,1H), 8.25-8.27(m,1H),8.62-8.65(m,2H).

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Abstract

The invention provides a compound as shown in a formula I or pharmaceutically acceptable salt thereof, which can inhibit various tyrosine kinases, has an inhibiting effect on VEGFR1, VEGFR2, VEGFR3, FGFR1, FGFR 2, FGFR 3, FGFR 4, PDGFR alpha, KIT, RET and the like, is used as a multi-target tyrosine kinase inhibitor, and has a potential application prospect in prevention and / or treatment of tumors related to tyrosine kinase overexpression.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a multi-target tyrosine kinase inhibitor and its preparation method and application. Background technique [0002] Malignant tumor (cancer) has become one of the most serious public health problems in China and even in the world in the 21st century, seriously threatening human health. The use of anticancer drugs for chemotherapy is one of the main means of treating cancer at present. However, commonly used chemotherapy drugs often have the ability to inhibit and kill tumors through toxicity to tumor cells, and have toxic and side effects on normal cells. There are disadvantages such as easy to produce drug resistance and poor curative effect. Therefore, the current research is more focused on new anti-tumor drugs with molecular targeting. [0003] Since tyrosine kinases (RTKs) exist in most tumor-causing genes, drugs targeting tyrosine kinases such as VEGFR, EGFR, ...

Claims

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Application Information

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IPC IPC(8): C07D215/48A61P35/00A61P35/02
CPCC07D215/48A61P35/00A61P35/02
Inventor 温万东石万棋史焱代明星吴瑕
Owner SICHUAN GUOKANG PHARMA
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