Compound, and preparation method and application thereof

A technology of compounds, equivalents, applied in the field of biomedicine

Active Publication Date: 2012-07-11
HAINAN SIMCERE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, 2-pyridone compounds have not been reported for the treatment of tyrosine kinase and / or serine-threonine kinase inhibitors

Method used

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  • Compound, and preparation method and application thereof
  • Compound, and preparation method and application thereof
  • Compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0495] Embodiment 1: preparation compound 67

[0496]

[0497] Weigh 1.27g of about 10mmol of compound S1, 1.71g of about 10mmol of benzyl bromide, and 1.38g of about 10mmol of potassium carbonate in a 250mL reaction flask, add 100mL of DMF, stir at room temperature overnight, concentrate to obtain a yellow solid, and use Petroleum ether-ethyl acetate was eluted according to a gradient of 0-25%, and 1.85 g of yellow oily compound S2 was obtained with a yield of 85%.

[0498] Weigh 1.09g of about 5mmol of compound S2, 0.77g of about 5mmol of compound S3, and 0.61g of about 5mmol of DMAP in a 250mL reaction flask, add 100mL of ethanol, stir at 90°C for 2h, concentrate to obtain a yellow solid, and use Petroleum ether-ethyl acetate was eluted according to a gradient of 0% to 45% R, to obtain 1.41 g of yellow solid compound S4 with a yield of 80%.

[0499] Weigh 1.41g of about 4mmol of compound S4, 0.42g of about 4mmol of Pd-C, stir at room temperature in a hydrogen atmosphere...

Embodiment 2

[0505] Embodiment 2: preparation compound 68

[0506]

[0507] Weigh 1.74g of about 10mmol of compound S7 and 1.19g of about 10mmol of DMF-DMA into a 250mL reaction bottle, add 100mL of DMF, stir at 90°C for 2h, concentrate to obtain a yellow solid, and use petroleum ether-ethyl acetate According to the gradient elution of 0-15%, 2.06 g of compound S8 was obtained as a yellow solid with a yield of 90%.

[0508] Weigh 2.06g of about 9mmol of compound S8, 1.95g of about 9mmol of compound S2, and 1.10g of about 9mmol of DMAP, put them in a 250mL reaction bottle, add 100mL of ethanol, stir and react at 90°C for 2h, and concentrate to obtain a yellow solid. Eluting with petroleum ether-ethyl acetate according to a gradient of 0-45%, 2.82 g of yellow solid compound S9 was obtained with a yield of 85%.

[0509] Weigh 1.84g of about 5mmol of compound S9, 1.42g of about 10mmol of iodomethane, and 0.69g of about 5mmol of potassium carbonate in a 250mL reaction bottle, add 100mL of ace...

Embodiment 3

[0516] Embodiment 3: preparation compound 69

[0517]

[0518] Weigh 1.77 about 5 mmol of compound S4, 0.2 g of about 5 mmol of sodium hydroxide, 50 mL of water, stir at 90°C for 5 h, neutralize with 3 mol / L HCl to pH = 7, filter with suction, and dry to obtain 1.53 g of a yellow solid Compound S13, yield 90%.

[0519] Weigh 1.36 about 4 mmol of compound S13, 0.81 mg of about 4 mmol of EDCI, 0.55 g of about 4 mmol of HOBt, 0.2 g of about 1.64 mmol of DMAP, and 0.5 g of about 4 mmol of p-fluorobenzylamine in a 250 mL reaction bottle 50 mL of DMF and 50 mL of dichloromethane were added, stirred overnight at room temperature, and concentrated to obtain a yellow solid, which was eluted with a gradient of 0% to 5% with methanol-dichloromethane to obtain 1.07 g of yellow solid compound S14 with a yield of 75%.

[0520] Weigh 0.89g of about 2mmol of compound S14, 0.21g of about 2mmol of Pd-C, in a hydrogen atmosphere, stir at room temperature overnight, concentrate to obtain a ye...

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Abstract

The invention provides a compound with the structure shown in a formula I, a preparation method of the compound, and an application of the compound as a tyrosine kinase and/or serine-threonine kinase inhibitor. The compound has a good inhibitory action on the activity of multiple kinases, and has an obvious inhibitory effect on tyrosine kinase and/or serine-threonine kinase in biochemical level and cell level in vitro (P is less than 0.05), and the half inhibitory concentration (IC50) for c-Met kinase is commonly below 10<-6>mol/L; and the compound also has an obvious inhibitory effect on proliferation of multiple tumor cells (P is less than 0.05), and the IC50 is respectively below 10<-5>mol/L. The compound with the structure shown in the formula I can be applied to preparing medicines for treating diseases related to protein kinase in organisms. The formula I is shown in the specification.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a class of compounds and preparation methods, and the application of the compounds in the preparation of tyrosine kinase inhibitors or serine-threonine kinase inhibitors. Background technique [0002] Mammalian cells share similar molecular mechanisms that regulate cell proliferation, differentiation and death throughout the cell cycle. Among them, protein phosphorylation is the main mechanism of transmembrane or intracellular signal transduction, which has the function of regulating cell cycle, and phosphorylation is controlled by protein kinases (PKs) and protein phosphatases. Protein kinases, also known as protein phosphakinases, are a class of enzymes that catalyze protein phosphorylation reactions. They are the largest protein family known so far. All kinases have a very conservative catalytic core and diverse regulation mode. Protein kinases function to transfer the gamma-phosp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D211/90C07D401/14C07D405/14C07D471/04A61K31/444A61K31/4418A61K31/5377A61K31/519A61K31/517A61P35/00A61P9/00A61P3/10A61P37/00
Inventor 丛欣黄伟王鹏刘兆刚明志会施敏锋马玉恒沈超唐锋
Owner HAINAN SIMCERE PHARMA CO LTD
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