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Amino-quinazoline derivative with antineoplastic activity and its salts

A technology of aminoquinazoline and methoxyquinazoline, applied in the field of chemistry, can solve the problems of low efficiency of non-small cell lung cancer, unsatisfactory clinical effect and the like

Inactive Publication Date: 2009-02-18
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the clinical effect of IRESSA is still not ideal, and the effective rate for non-small cell lung cancer is less than 25%.

Method used

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  • Amino-quinazoline derivative with antineoplastic activity and its salts
  • Amino-quinazoline derivative with antineoplastic activity and its salts
  • Amino-quinazoline derivative with antineoplastic activity and its salts

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 4-(3'-chloro-4'-fluoroanilino)-6-(3'-N-(4'-hydroxypiperidinyl))propoxy)-7-methoxyquinazole Preparation of morphine (compound 7)

[0027]

[0028] Compound 7

[0029] Preparation of the first step 6,7-dimethoxy-4(3H)-quinolinone (compound 1)

[0030]

[0031] Compound 1

[0032] The starting material 4,5-dimethoxy-2-aminobenzoic acid (79.0 g, 400 mmol) and 95 ml of formamide were heated to reflux at 180° C. and stirred for 5 h. Stop heating, add 200ml of cold water to the hot solution, stir at room temperature for 10min, let stand for 50min, filter, wash the filter cake with 3×100ml of water, and dry in vacuo to obtain 11.9g of off-white solid powder with a yield of 14.2%. 1 HNMR (DMSO-d 6 , 400Hz), δ 12.14(s, 1H), 7.89(s, 1H), 7.47(s, 1H), 7.13(s, 1H), 3.83(s, 6H); MS(EI) m / z 207(M +1) + .

[0033] Preparation of the second step 7-hydroxy-7-methoxy-4(3H)-quinolinone (compound 2)

[0034]

[0035] Compound 2

[0036] Compound 1 (26.5g, 128.6mm...

Embodiment 2

[0058] 4-(3'-chloro-4'-fluoroanilino)-6-(3'-N-(3'-hydroxypiperidinyl))propoxy)-7-methoxyquinazoline (compound 8) Preparation

[0059]

[0060] Compound 8

[0061] Compound 6 (100mg, 0.313mmol), N-(3'-chloropropyl)-3-hydroxypiperidine (78mg, 0.438mmol), in a flask, add 250mg K 2 CO 3 , 47mgNaI, 5ml DMF, placed in an oil bath at 110°C for 4 hours, stopped heating, cooled naturally to room temperature, then added 30ml water and 30ml ethyl acetate to the reaction solution, separated the liquid, extracted the aqueous phase with 30ml ethyl acetate, The organic phases were combined, washed twice with 50 ml of water, then washed with saturated saline solution, dried over anhydrous magnesium sulfate, and rotary evaporated to obtain 78.0 mg of brown solid powder with a yield of 70.5%. 1 HNMR (CDCl 3 )δ 8.614(s,1H), 8.543(s,1H), 8.008-7.960(m,1H), 7.676-7.668(m,1H), 7.438(s,1H), 7.213(s,1H), 7.115( t, J=8.8Hz, 1H), 4.338-4.317(m, 1H), 4.215-4.197(m, 1H), 3.971(s, 4H), 3.481(s, 2H...

Embodiment 3

[0063] 4-(3'-chloro-4'-fluoroanilino)-6-(3'-N-(3'-hydroxypyrrolidinyl))propoxy)-7-methoxyquinazoline (compound 9 )

[0064]

[0065] Compound 9

[0066] Compound 6 (100mg, 0.313mmol), N-(3'-chloropropyl)-3-hydroxypyrrolidine (72mg, 0.438mmol), in a flask, add 250mg K 2 CO 3 , 47mgNaI, 5ml DMF, placed in an oil bath at 110°C for 4 hours, stopped heating, cooled naturally to room temperature, then added 30ml water and 30ml ethyl acetate to the reaction solution, separated the liquid, extracted the aqueous phase with 30ml ethyl acetate, The organic phases were combined, washed twice with 50 ml of water, then washed with saturated saline solution, dried over anhydrous magnesium sulfate, and rotary evaporated to obtain a brown solid powder, which was passed through a silica gel column, and the eluent was PE:EA=2:1 to obtain 76 mg solid, yield 66.5%. 1 HNMR (CDCl 3 )δ 8.617(s, 1H), 8.415(s, 1H), 7.966-7.944(dd, J=6.4Hz, 2.4Hz, 1H), 7.639-7.601(m, 1H), 7.478(s, 1H), 7.203 (s...

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Abstract

The present invention provides an amido quinazoline derivative which has recipient singal conductance for inhibition of epidermal growth factors with anti-tumor activity. The novel compounds with a structure identical to quinazoline has quite high activity for inhibition of tumor cells, in particular to the remarkable inhibition effects on the growth of tumor cells of EGFR high expression. And the effective inhibition concentration is 5 times higher than the medicine IRESSA on the market.

Description

technical field [0001] The invention relates to the field of chemical technology, in particular to an aminoquinazoline derivative with antitumor activity and its salts and a preparation method thereof. technical background [0002] The Epidermal Growth Factor Receptor (EGFR) family belongs to the receptor tyrosine kinase family and is an important regulator of cell growth, differentiation and survival. Its members include: erbB-1 (EGFR, HER1), erbB -2 (HER2), erbB-3 (HER3), and erbB-4 (HER4). They are similar in structure, and are composed of an extracellular ligand-binding region, a single-chain transmembrane region and a highly conserved protein tyrosine kinase region. This structure has the function of a receptor, and has the ability to directly convert extracellular signals into intracellular effects, and is a novel transmembrane transmission method. Once the receptor binds to a specific ligand, the receptor can be activated through the autophosphorylation of the corre...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D403/12C07D487/08C07D495/08A61K31/506A61P35/00
CPCC07D487/08C07D401/12C07D403/12C07D491/08C07D495/08A61P35/00
Inventor 张健存郑建龙黄小光
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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