Phosphoinositide 3-kinase (P13K) inhibitor, pharmaceutical composition containing P13K inhibitor, and application of phosphoinositide kinase inhibitor and pharmaceutical composition

A kind of kinase inhibitor, hydrate technology, applied in the field of medicine

Active Publication Date: 2014-01-01
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 kinase inhibitor molecules in order to select compounds with better efficacy and selectivity for the treatment of cancer

Method used

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  • Phosphoinositide 3-kinase (P13K) inhibitor, pharmaceutical composition containing P13K inhibitor, and application of phosphoinositide kinase inhibitor and pharmaceutical composition
  • Phosphoinositide 3-kinase (P13K) inhibitor, pharmaceutical composition containing P13K inhibitor, and application of phosphoinositide kinase inhibitor and pharmaceutical composition
  • Phosphoinositide 3-kinase (P13K) inhibitor, pharmaceutical composition containing P13K inhibitor, and application of phosphoinositide kinase inhibitor and pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0130] Example 1: Synthesis of pyrimidine compound ZJQ-04.

[0131] Step 1: Synthesis of 5-bromo-4-(trifluoromethyl)pyridin-2-amine.

[0132] The structural formula of 5-bromo-4-(trifluoromethyl)pyridin-2-amine:

[0133] Synthetic method: Dissolve 4-trifluoromethyl-2-aminopyridine (10 g, 61.69 mmol) in CH 2 Cl 2 (100 mL), bromosuccinimide (NBS, 12.08 g, 67.86 mmol) was added in portions at room temperature, and reacted overnight at room temperature in the dark. The reaction system uses CH 2 Cl 2 (100mL) 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: 87.96%.

[0134] The NMR data of the product are 1 H NMR (400MHz, CDCl 3 )δ: 8.28(s, 1H), 6.78(s, 1H), 4.82(s, 2H...

Embodiment 2

[0170] Example 2: Synthesis of pyrimidine compound ZJQ-05.

[0171] Step 1: (2R,4R)-1-tert-butyl-2-methyl-4-((tert-butyldimethylsilyl)oxy)tetrahydropyrrole-1,2-dicarboxylate synthesis.

[0172] The structural formula of (2R,4R)-1-tert-butyl-2-methyl-4-((tert-butyldimethylsilyl)oxy)tetrahydropyrrole-1,2-dicarboxylate:

[0173] Synthetic method: Dissolve (2R,4R)-1-tert-butyl-2-methyl 4-hydroxytetrahydropyrrole-1,2-dicarbonate (5g, 20.40mmol) in dichloromethane (40mL), DIPEA (7.46mL, 44.87mmol) was cooled to -40°C, tert-butyldimethylsilyl triflate (5.63mL, 24.48mmol) was added dropwise and stirring was continued for 3h. A large amount of water was added to quench the reaction, and dichloromethane was added for extraction, dried over anhydrous sodium sulfate, concentrated, and purified by column, eluent: PE / EA=3 / 1, and 6.63 g of the target product was obtained with a yield of 90.45%.

[0174] The mass spectrum data of the product is LC-MS: 360.2 (M+H). Same as in WO 20091371...

Embodiment 3

[0200] Example 3: Synthesis of pyrimidine compound ZJQ-22.

[0201] (-)-5-(6-morpholine-2-((4RS, 7RS)-tetrahydro)-2H-[1,4]dioxin)[2,3-c]pyrrol-6(3H)-yl )pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine, the structural formula of compound ZJQ-22:

[0202]

[0203] Synthesis method: ZJQ-04 prepared in Example 1 is resolved, separation conditions: reversed-phase chiral preparative column (lu 5u cellose-2 of Pheromones), mobile phase: methanol / water=95 / 5; purity: 99.90%; retention time: 13.94min, the resolution product ZJQ-22 was obtained.

[0204] The high-resolution mass spectrometry data of the resolved product is HRMS (ESI): m / z[M+H] + calcd.for[C 20 h 24 f 3 N 6 o 3 ] + : 453.1856, found: 453.1845. Optical rotation data is From the above data, it can be seen that the product prepared by the above method is the target product (-)-5-(6-morpholine-2-((4RS, 7RS)-tetrahydro)-2H-[1,4]dioxin) [2,3-c]pyrrol-6(3H)-yl)pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine,...

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Abstract

The invention discloses a phosphoinositide 3-kinase (P13K) inhibitor, a pharmaceutical composition containing the P13K inhibitor, and application of the P13K inhibitor and the pharmaceutical composition. The P13K inhibitor comprises a pyrimidine compound and a stereoisomer/hydrate/pharmaceutically-acceptable salt thereof. The pyrimidine compound has a general formula I of which the structure is shown in the specification. The P13K inhibitor and the pharmaceutical composition containing the same can be used for inhibiting PI3 Ks and treating proliferative diseases on which the PI3 Ks act. According to the invention, high-effectiveness and high-selectivity inhibitors for treating proliferative diseases on which PI3Ks act can be provided.

Description

technical field [0001] The present invention relates to the technical field of medicine, and more specifically refers to a PI3K kinase inhibitor, a pharmaceutical composition containing it and applications thereof. Background technique [0002] Malignant tumors are a type of disease that seriously threatens human life and health. Its morbidity and mortality are increasing year by year. Human mortality due to cancer ranks second only to cardiovascular and cerebrovascular diseases. At present, the clinical drugs for tumor treatment are divided into traditional cytotoxic drugs and new molecular targeted drugs. The former mainly acts on DNA, RNA, tubulin and other common components that are critical to cell life and death, non-specifically blocking cell division and causing cell death. While killing tumor cells, it also destroys normal cells in the human body, resulting in Low selectivity and high toxicity; while the latter usually has a relatively clear target, mainly acting o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/056C07D491/08C07D401/04C07D413/14A61K31/5377A61P35/00A61P35/02
CPCC07D401/04C07D413/14C07D491/056C07D491/08
Inventor 鲁桂张吉泉陈晖旋罗羽罗永杰
Owner SUN YAT SEN UNIV
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