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4-substituted p-methylsulfonamidoanilino-quinazoline derivatives and their preparation methods and uses

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: 2015-09-23
天津天诚新药评价有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If the receptors of cancer cells are overexpressed or overactivated, the cancer cells will grow in large numbers, thus increasing the difficulty of curing and the probability of recurrence

Method used

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  • 4-substituted p-methylsulfonamidoanilino-quinazoline derivatives and their preparation methods and uses
  • 4-substituted p-methylsulfonamidoanilino-quinazoline derivatives and their preparation methods and uses
  • 4-substituted p-methylsulfonamidoanilino-quinazoline derivatives and their preparation methods and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0024] Put 4g (25.97mmol) of 2-amino-5-nitrophenol, 4.9g (28.65mmol) of benzyl bromide, and 7.18g (52.02mmol) of potassium carbonate in a 100ml round bottom flask, add 30ml of acetone, and reflux at 60°C for 1.5 h, recrystallized from ethyl acetate to give 2-benzyloxy-4-nitroaniline (3.8g g, 58.8%) as a yellow solid, m.p.98-99°C; 1 H NMR (400MHz, DMSO): δ5.23(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] Preparation of Example 21-(N-methylsulfonyl)-2-benzyloxy-4-nitroaniline

[0026] Put 1 g (4.10 mmol) of 2-benzyloxy-4-nitroaniline in a 100 ml round bottom flask, add 16 ml of DMF, and stir well. The system was placed in an ice bath, and 0.4 g of sodium hydrogen (16.67 mmol) was added in batches. Stir at room temperature for 30 min under nitrogen protection. Measure 1.42 g (12.40 mmol) of methanesulfonyl chloride, and slowly add it into the system. Stir overnight at room temperature. 30ml of water was added to the system, and a large amount of precipitation occurred. Filter and wash with water to obtain light 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 naturally cooled to room temperature. Adjust the pH to 1-2 with 5N hydrochloric acid, a large amount of precipitation appeared in the system, filtered and washed with water to obtain a...

Embodiment 3

[0027] The preparation of embodiment 3N-(4-amino-2-(benzyloxy) phenyl) methanesulfonamide

[0028] 0.2 g (0.62 mmol) of 1-(N-methylsulfonyl)-2-benzyloxy-4-nitroaniline, FeCl 3 6H 2 O 0.67g (2.48mmol) was placed in a 50ml round bottom flask, and then 7ml of DMF and H 2 O (6:1), stirred at room temperature for 30 min. Weigh 0.4g Zn powder (6.13mmol), slowly add to the system, stir at room temperature for 3h, stop the reaction. Filter the reaction solution, take the filtrate, dilute it with 1-2 times the amount of water, then extract it with ethyl acetate, add HCl / ethyl acetate, a large amount of precipitation occurs, and filter it. Dissolve it in water, adjust the pH to alkaline, extract with ethyl acetate, and evaporate to dryness under reduced pressure to obtain N-(4-amino-2-(benzyloxy)phenyl)methanesulfonamide (0.16g, 92.3% ), m.p.103-104°C; 1 H NMR (400MHZ DMSO): δ2.734(s, 3H, CH 3 ), 5.024 (s, 2H, NH 2 ), 5.154 (s, 2H, CH 2 O), 6.094-7.524 (m, 8H, ArH), 8.46 (s, 1H,...

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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-methylsulfonamidoanilino-quinazoline derivatives or pharmaceutically acceptable salts thereof, and these compounds have antitumor activity. The present invention also relates to a method for preparing said 4-substituted p-methylsulfonamidoanilino-quinazoline derivatives, a pharmaceutical composition containing these derivatives and their application in antineoplastic 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 curing and the probability of recurrence. EGFR receptors can be divided into four types of human epidermal growth factor receptors (Human Epidermal Receptor). The first type is usually ca...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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