Aniline substituted quinazoline derivative

A technology of substituents and amine groups, which is used in the field of preparing drugs for the treatment of tumors, can solve the problems of uncontrolled cell reproduction, abnormal mutation or overexpression, etc.

Active Publication Date: 2012-03-21
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, under certain conditions, these receptors are either mutated or overexpressed and become abnormal, causin

Method used

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  • Aniline substituted quinazoline derivative
  • Aniline substituted quinazoline derivative
  • Aniline substituted quinazoline derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0197] Example 1N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-6-oxocyclohex-1-enamide (compound 1) preparation

[0198]

[0199] (1) Preparation of N-(4-(3-chloro-4-fluoroaniline)-7-methoxyquinazolin-6-yl)-2-oxocyclohexylamide

[0200]

[0201] 2-oxocyclohexanoic acid (670mg, 4.72mmol), HATU (2.69g, 7.08mmol) and DIEA (1.22g, 9.46mmol) were dissolved in 20mL DMF, stirred at room temperature for 20min, then added N 4 -(3-Chloro-4-fluoroaniline)-7-methoxyquinazoline-4,6-diamine (1.0g, 3.14mmol), reacted at 50°C for 24h. Add water, extract with dichloromethane, dry, concentrate and separate by column chromatography (dichloromethane:methanol=30:1) to obtain N-(4-(3-chloro-4-fluoroaniline)-7-methoxyquin Azolin-6-yl)-2-oxocyclohexylamide 570 mg, yield 41%.

[0202] (2) Preparation of N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-6-oxocyclohex-1-enamide

[0203]

[0204] Under an ice-water bath, dissolve pyridine (102mg, 1.29mmol) and phenylsel...

Embodiment 2

[0207] Example 2 (E)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-(3-morpholinone-4-yl )-2-butenamide (C Compound 2) Preparation

[0208]

[0209] (1) Preparation of (E)-4-(3-morpholinone-4-yl)butenoic acid methyl ester

[0210]

[0211] 3-Morpholinone (10.1g, 0.1mol), methyl 4-bromocrotonate (25g, 0.12mol), cesium carbonate (97g, 0.3mol) and PdCl 2 (dppf)(2g, 2.7mmol) was dissolved in 200mL of dioxane, heated to 100°C for 12h. Add water and extract with ethyl acetate, dry, concentrate and separate by silica gel column to obtain 5.2 g of oily substance with a yield of 41%.

[0212] (2) Preparation of (E)-4-(3-morpholinone-4-yl)butenoic acid

[0213]

[0214] Dissolve (E)-4-(3-morpholinone-4-yl)butenoic acid methyl ester (500mg, 2.5mmol) in 30mL methanol, add barium hydroxide (476mg, 1.5mmol) at -10°C Aqueous solution, stirred and reacted for 16h. After the reaction, the pH was adjusted to 2, extracted with ethyl acetate, dried, concentrated and...

Embodiment 3

[0220] Example 3 (E)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl 1-4-(4-methyl-2-piperazine Keto-1-yl)-2-butene Preparation of Amide (Compound 3)

[0221]

[0222] (1) Preparation of 4-methyl-2-piperazinone

[0223]

[0224]Dissolve 2-piperazinone (2.0g, 20mmol) and 5mL aqueous formaldehyde solution in 20mL THF, add sodium borohydride (2.28g, 60mmol) under ice water, rise to room temperature and react for 2h, then quench with pasty sodium sulfate , filtered, and the solvent was evaporated to dryness to obtain 4-methyl-2-piperazinone. The product was directly used in the next reaction without further treatment.

[0225] (2) Preparation of (E)-4-(4-methyl-2-piperazinone-1-yl)butenoic acid methyl ester

[0226]

[0227] 4-Methyl-2-piperazinone (1.5 g, 13 mmol) was added to a THF solution of NaH (60%, 720 mg, 18.0 mmol) under an ice-water bath, and reacted for 20 min. Methyl 4-bromocrotonate (2.31 g, 13 mmol) was added dropwise and the reaction was co...

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Abstract

The invention belongs to the technical field of medicine and specifically relates to an aniline substituted quinazoline derivative with a general formula (I), pharmaceutically acceptable salt thereof or stereo isomer thereof. R1, R2, R3, R4, R5, R6, L and n are defined in the instruction. The invention also relates to a preparation method of the compounds, medicinal preparations containing the compounds and purpose of the compounds in preparation of medicaments for treating tumour.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to aniline-substituted quinazoline derivatives, pharmaceutically acceptable salts or stereoisomers thereof, preparation methods of these compounds, pharmaceutical preparations containing these compounds, and preparation of these compounds Use in medicines for treating tumors. Background technique [0002] Protein tyrosine kinases, a class of enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine residues located on protein substrates, play a role in normal cell growth. Many growth factor receptor proteins act through tyrosine kinases and affect signaling through this process to regulate cell growth. Under certain conditions, however, these receptors either mutate or become overexpressed and become abnormal, causing cells to multiply uncontrollably, leading to tumor growth and ultimately the well-known disease known as cancer. Growth factor receptor protein ty...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D413/12C07D403/12C07D413/14C07D493/08C07D401/14C07D471/10A61K31/517A61K31/5377A61P35/00A61P17/00A61P13/08
Inventor 黄振华
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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