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Pyrimidine compound, PI3K inhibitor, pharmaceutical composition comprising PI3K inhibitor and application of inhibitor and pharmaceutical composition

A compound and inhibitor technology, applied in the field of pyrimidine compounds, to achieve good effectiveness and selectivity

Active Publication Date: 2014-04-02
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, there is no PI3K inhibitor on the market so far, and researchers still need to develop more PI3K inhibitor molecules in order to select compounds with better efficacy and selectivity for the treatment of cancer

Method used

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  • Pyrimidine compound, PI3K inhibitor, pharmaceutical composition comprising PI3K inhibitor and application of inhibitor and pharmaceutical composition
  • Pyrimidine compound, PI3K inhibitor, pharmaceutical composition comprising PI3K inhibitor and application of inhibitor and pharmaceutical composition
  • Pyrimidine compound, PI3K inhibitor, pharmaceutical composition comprising PI3K inhibitor and application of inhibitor and pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Example 1: (4-(4-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholine pyrimidin-2-ylamino)phenyl)(4-(methylsulfonyl)piperazine -1-yl)methanone ( ZJQ-33) Synthesis

[0093] step 1 : Synthesis of 5-bromo-4-(trifluoromethyl)pyridin-2-amine

[0094] The structural formula of 5-bromo-4-(trifluoromethyl)pyridin-2-amine:

[0095] Synthetic method: 4-trifluoromethyl-2-aminopyridine (10 g, 61.69 mmol) was dissolved in CH 2 Cl 2 (100 mL), add bromosuccinimide (NBS, 12.08 g, 67.86 mmol) in batches at room temperature, and react overnight at room temperature in the dark. The reaction system uses CH 2 Cl 2 (100 mL) diluted with saturated NaHSO 3 Wash twice, wash once with saturated NaCl aqueous solution, and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography, eluent: petroleum ether / ethyl acetate = 4 / 1, to obtain 13.08 g of the target product as a brown solid, yield...

Embodiment 2

[0125] Example 2: (4-(4-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholine-1,3,5-triazin-2-ylamino)benzene Base) (4-(methylsulfonyl)piperazin-1-yl)methanone (ZJQ-34)

[0126] step 1 : Synthesis of 4-(4,6-dichloro-1,3,5-triazazin-2-yl)morpholine

[0127] The structural formula of 4-(4,6-dichloro-1,3,5-triazazin-2-yl)morpholine:

[0128] Synthetic method: 2,4,6-trichloro-1,3,5-triazazine (5.0 g, 27.33 mmol) was dissolved in CH 2 Cl 2 (100 mL), cooled to -5 ℃, slowly added DIPEA (4.10 mL, 24.64 mmol) and morpholine (2.15 mL, 24.64 mmol) in CH 2 Cl 2 (20 mL) of the mixture, reacted at low temperature for 1 h, raised to 0 °C and reacted overnight. The reaction system uses CH 2 Cl 2 (50 mL), washed twice with 1M HCl (50 mL×2), washed once with saturated NaCl, and dried over anhydrous sodium sulfate. Separation and purification by column chromatography, eluent: PE / EA = 10 / 1-5 / 1, to obtain 4.59 g of the target product as a white solid, yield: 59.74%.

[0129] The NM...

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Abstract

The invention discloses a pyrimidine compound of which the structure is shown in a general formula (I), and also discloses a PI3K inhibitor which is composed of at least one of the following substances: the pyrimidine compound shown in the general formula (I), a steric isomer of the pyrimidine compound, a hydrate of the pyrimidine compound and a pharmaceutically acceptable salt of the pyrimidine compound. The invention also discloses a pharmaceutical composition comprising the PI3K inhibitor, and also discloses application of the PI3K inhibitor in preparation of a drug for treatment and / or prevention and / or auxiliary treatment of a proliferative disease of PI3K action. The pharmaceutical composition is composed of the PI3K inhibitor, at least one pharmaceutically acceptable auxiliary material, an adjuvant or a carrier. The PI3K inhibitor and the pharmaceutical composition comprising the PI3K inhibitor can be applied to inhibition of P13 kinase and the proliferative disease of P13 kinase action, and the inhibitor with better validity and selectivity can be provided for treatment of the proliferative disease of P13 kinase action.

Description

Technical field [0001] The invention involves pyrimidine compounds, PI3K inhibitors, and drug compositions and applications containing PI3K inhibitors. Background technique [0002] Malignant tumors are a type of disease that seriously threatens human life and health. Its incidence and mortality rates are increasing year by year. Human mortality caused by cancer is second only to the second place in cardiovascular and cerebrovascular diseases.At present, the treatment of clinical tumors is divided into traditional cytotoxic drugs and new molecular targeted drugs.The former is mainly used as a coexistence of DNA, RNA, and microtubin, etc., which are commonly related to cell life and death, and non -specific blocking cell division and causing cell death. While killing tumor cells, it also destroys the normal cells of the human body, causing it to cause itLow selectivity and high toxicity; the latter usually has a relatively clear target, mainly acting in the key molecules and signa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04A61K31/5377A61P35/00A61P35/02
CPCC07D401/04
Inventor 鲁桂张吉泉罗永杰罗羽
Owner SUN YAT SEN UNIV
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