4-substituted p-methyl sulfonamide anilino-quinazoline derivatives and preparation method and application thereof

A technology of methanesulfonamide and quinazoline, applied in the application of antitumor drugs, the field of preparing the 4-substituted p-methanesulfonamide anilino-quinazoline derivatives, can solve the problem of increasing the difficulty of curing and recurrence the probability of

Inactive Publication Date: 2012-07-11
天津天诚新药评价有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

If the receptors of cancer cells are overexpressed or overactivated, the cancer cells will ...

Method used

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  • 4-substituted p-methyl sulfonamide anilino-quinazoline derivatives and preparation method and application thereof
  • 4-substituted p-methyl sulfonamide anilino-quinazoline derivatives and preparation method and application thereof
  • 4-substituted p-methyl sulfonamide anilino-quinazoline derivatives and preparation method and application thereof

Examples

Experimental program
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Embodiment 1

[0023] The preparation of embodiment 12-benzyloxy-4-nitroaniline

[0024] 4 g (25.97 mmol) of 2-amino-5-nitrophenol, 4.9 g (28.65 mmol) of benzyl bromide, 7.18 g (52.02 mmol) of potassium carbonate were placed in a 100 ml round-bottomed flask, 30 ml of acetone was added, and the reaction was carried out at 60°C for 1.5 h, recrystallized from ethyl acetate to obtain 2-benzyloxy-4-nitroaniline as a yellow solid (3.8 g g, 58.8%), m.p. 98-99°C; 1 H NMR (400MHz, DMSO): δ 5.23 (s, 2H, CH 2 O), 6.412 (s, 2H, NH 2 ), 6.6756.697 (d, 1H, ArH), 7.324-7.675 (m, 7H, ArH), ESI-MS: m / z 245 [M+H] + .

Embodiment 2

[0025] Example 21-(N-methanesulfonyl)-2-benzyloxy-4-nitroaniline preparation

[0026] 1 g (4.10 mmol) of 2-benzyloxy-4-nitroaniline was placed in a 100 ml round-bottomed flask, 16 ml of DMF was added, and the mixture was stirred uniformly. The system was placed in an ice bath, and 0.4 g of sodium hydrogen (16.67 mmol) was added in portions. Stir at room temperature for 30 min under nitrogen protection. 1.42 g (12.40 mmol) of methylsulfonyl chloride was weighed and slowly added to the system. Stir overnight at room temperature. 30 ml of water was added to the system, and a large amount of precipitation occurred. Filter and wash with water to obtain pale yellow solid powder. It was dissolved in DMF, and the pH was adjusted to 9-10 with 3N aqueous sodium hydroxide solution. The reaction was carried out at 90° C. for 6 h, and then cooled to room temperature naturally. Adjust pH=1-2 with 5N hydrochloric acid, a lot of precipitation appeared in the system, filter and wash with ...

Embodiment 3

[0027] Example 3 Preparation of N-(4-amino-2-(benzyloxy)phenyl)methanesulfonamide

[0028] 1-(N-methanesulfonyl)-2-benzyloxy-4-nitroaniline 0.2g (0.62mmol), FeCl 3 6H 2 O 0.67g (2.48mmol) was placed in a 50ml round bottom flask, then 7ml DMF and H were added 2 O(6:1), stirred at room temperature for 30 min. 0.4 g of Zn powder (6.13 mmol) was weighed, slowly added to the system, and stirred at room temperature for 3 h to stop the reaction. The reaction solution was filtered, the filtrate was taken, diluted with 1-2 times the amount of water, extracted with ethyl acetate, HCl / ethyl acetate was added, a large amount of precipitation appeared, and the solution was filtered. It was dissolved in water, adjusted to basic pH, extracted with ethyl acetate, evaporated to dryness under reduced pressure to obtain N-(4-amino-2-(benzyloxy)phenyl)methanesulfonamide (0.16 g, 92.3%) ), m.p.103-104℃; 1 H NMR (400MHZ DMSO): δ 2.734 (s, 3H, CH 3 ), 5.024(s, 2H, NH 2 ), 5.154(s, 2H, CH 2 O...

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and relates to 4-substituted p-methyl sulfonamide anilino-quinazoline derivatives with a general formula (I), wherein R1 and R2 respectively have meanings limited in the specifications. The invention also relates to a preparation method of the derivatives, physiologically acceptable salt composed of the derivatives and inorganic or organic acid or alkali, and a pharmaceutical composition containing the same. The compound has valuable pharmacological properties, has an inhibitory effect on signal transduction caused by PTK (Protein Tyrosine Kinase), and especially has higher inhibitory activity on a mutant EGFR (Epidermal Growth Factor Receptor) (L858R/T790M) and an HER2 (Human Epidermal Growth Factor Receptor 2). The invention also relates to a method for treating diseases, especially diseases characterized by abnormal erbB family PTK activity, by using the derivatives.

Description

technical field [0001] The present invention relates to 4-substituted p-methanesulfonamidoanilino-quinazoline derivatives or pharmaceutically acceptable salts thereof, these compounds have antitumor activity. The present invention also relates to a method for preparing the 4-substituted p-methanesulfonamidoanilino-quinazoline derivatives, pharmaceutical compositions containing these derivatives and their application in antitumor drugs. Background technique [0002] Tyrosine Kinase Inhibitor mainly acts on Epidermal Growth Factor Receptor (EGFR). EGFR has an important influence and control correlation on the growth of cancer cells. If the receptors of cancer cells are overexpressed or overactivated, the cancer cells will grow in large numbers, thereby increasing the difficulty of cure and the chance of recurrence. EGFR receptors can be divided into four types of human epidermal growth factor receptors (Human Epidermal Receptors). The first type is usually called EGFR, the ...

Claims

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Application Information

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IPC IPC(8): C07D405/04C07D405/14A61K31/517A61K31/5377A61P35/00
Inventor 李祎亮蔡志强刘巍石玉邹美香张士俊商倩孟凡翠徐为人李洪明刘经国纪潇朗商骐鸣
Owner 天津天诚新药评价有限公司
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