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Substitute quinazolines derivative with Aurora kinase inhibitory activity and application thereof

A compound and hydrate technology, applied in organic active ingredients, medical preparations containing active ingredients, organic chemistry, etc., can solve problems such as arrhythmia and time difference

Active Publication Date: 2016-04-20
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have found that the drug can cause the risk of QTc prolongation in patients (QTc is the time difference between the corrected T wave and Q wave on the electrocardiogram, and QTc prolongation can easily lead to arrhythmia). In November 2007, Merck terminated the phase II of VX-680 Clinical trials (ExpertOpin.InvestingDrugs.2009,18,379)

Method used

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  • Substitute quinazolines derivative with Aurora kinase inhibitory activity and application thereof
  • Substitute quinazolines derivative with Aurora kinase inhibitory activity and application thereof
  • Substitute quinazolines derivative with Aurora kinase inhibitory activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0136] N-(5-methyl-1H-pyrazol-3-yl)-7-(4-methylpiperazin-1-yl)-4-amino-2-phenethylquinazoline

[0137]

[0138] Step 1: 4-Chloro-2-(3-phenylpropanamido)benzoic acid

[0139]

[0140] 2-Amino-4-chlorobenzoic acid (10.3g, 60mmol), potassium carbonate (24.9g, 180mmol) was added to 200mL of acetonitrile, and the freshly prepared phenylpropionyl chloride (72mmol) was slowly added dropwise, and the reaction was completed after the dropwise addition The temperature of the system was raised to 80°C, heated to reflux for 5 hours, a large amount of precipitates were formed in the reaction system, 1N hydrochloric acid solution was added to adjust the pH value to 2, about 100mL of dichloromethane was added, after vigorous stirring, the amide intermediate (12.4g, 68 %). 1 HNMR (400MHz, DMSO-d 6 )δ:13.89(s,1H),11.24(s,1H),8.59(s,1H),7.96(d,J=8.5Hz,1H),7.31-7.13(m,6H),2.93(t,J =7.4Hz, 2H), 2.73(t, J=7.4Hz, 2H). 13 CNMR (100MHz, DMSO-d 6 )δ: 170.9, 168.7, 141.8, 140.5, 138.4, 132.8...

Embodiment 2

[0151] 2-(1-amino-2-phenethyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(4-methylpiperazin-1-yl)quinazoline- 4-amine

[0152]

[0153] Step 1: 2-Amino-4-(4-methylpiperazin-1-yl)benzamide

[0154]

[0155] Dissolve 4-chloro-2nitrobenzonitrile (5.5g, 30mmol) and methylpiperazine (7.4mL, 66mmol) in 50mL of dioxane, reflux at 110°C for 16 hours, and remove the dioxane under reduced pressure. Add dichloromethane after the hexacyclic ring to extract, the organic phase is dried with anhydrous sodium sulfate, the intermediate obtained by concentration is dissolved in 100mL ethanol, wet Pd / C (300mg) and hydrazine hydrate (5.8mL, 120mmol) are added, and the reaction system is React overnight at 80 degrees, remove the organic solvent under reduced pressure, add MeOH:CH 2 Cl 2 (1:10) about 150mL solvent dissolved product, through diatomaceous earth column, MeOH:CH 2 Cl 2 (1:10) solvent washing, the solid obtained after the organic phase was concentrated was washed with a small amount of ...

Embodiment 3

[0163] N-(5-Methyl-1H-pyrazol-3-yl)-2-phenethylquinazolin-4-amine

[0164]

[0165] Step 1: 2-Phenylethylquinazolin-4(3H)-one

[0166]

[0167] Suspend 2-aminobenzamide (8.2g, 60mmol) and potassium carbonate (2equiv.) in dry acetonitrile, and gradually add phenylpropionyl chloride (9.8mL, 66mmol). Reflux for 5 hours, add 100mL of water, and obtain the intermediate by suction filtration. Dissolve the intermediate in 100mL of ethanol, add 10M NaOH (4 equiv.) solution dropwise at 0°C, stir at room temperature for 30 minutes, then use concentrated hydrochloric acid at 0°C After neutralization, a large amount of solids were precipitated. After removing an appropriate amount of ethanol under reduced pressure, 100 mL of water was added, and the target product (13.2 g, 88%) was obtained by suction filtration.

[0168] Step 2: N-(5-Methyl-1H-pyrazol-3-yl)-2-phenethylquinazolin-4-amine

[0169]

[0170] Dissolve 2-phenethylquinazolin-4(3H)-one (125 mg, 0.5 mmol), PyBrop (303 ...

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Abstract

The invention discloses a substitute quinazolines derivative with Aurora kinase inhibitory activity and application thereof. The substitute quinazolines derivative is a compound as shown in a formula (I) and a formula (II),or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic substance,tautomer or prodrug. A medicine composition includes one or more of the compound as shown in the formula (I) and the formula (II),or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic substance,tautomer or prodrug. The application of the substitute quinazolines derivative with the Aurora kinase inhibitory activity comprises application of the compound as shown in the formula (I) and the formula (II),or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic substance,tautomer or prodrug to preparation of medicine for inhibiting Aurora kinase; or application of the compound as shown in the formula (I) and the formula (II), or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic substance,tautomer or prodrug to preparation of medicine for treating and / or preventing and / or relieving and / or conducting auxiliary treating and / or treating proliferative diseases; or application of the compound as shown in the formula (I) and the formula (II),or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic substance,tautomer or prodrug to preparation of medicine for resisting to tumor. The series compound has good inhibitory activity on Aurora kinase.

Description

technical field [0001] The invention relates to substituted quinazoline derivatives with Aurora kinase inhibitory activity and applications thereof. Background technique [0002] Cancer, as well as other hyperproliferative diseases, is characterized by uncontrolled cell proliferation. Loss of normal regulation of cell proliferation often occurs due to damage to genes that regulate cellular pathways that progress through the cell cycle. Studies have shown that in eukaryotic cells, an ordered cascade of protein phosphorylation controls the cell cycle. Several families of proteases with important roles in this cascade have been identified. The activity of many of the aforementioned kinases is markedly increased in human tumors compared with normal tissues. This may be due to increased protein expression levels or changes in the expression of coactivator or repressor proteins. Aurora kinase encodes a serine-threonine protein kinase that regulates the cell cycle (see Trends i...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D403/14C07D401/14A61K31/517A61P35/00
CPCC07D401/14C07D403/12C07D403/14
Inventor 鲁桂彭伟涂正超龙亮罗羽刘强
Owner SUN YAT SEN UNIV
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