Quinazoline compound used as EGFR (epidermal growth factor receptor) inhibitor

A compound, CH2CH2F technology, applied in the field of formula compounds or their pharmaceutically acceptable salts, can solve problems such as the inability of drugs to meet market demands, the inability of drugs to reach effective therapeutic concentrations and the like

Active Publication Date: 2018-10-12
MEDSHINE DISCOVERY INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the existence of the blood-brain barrier (BBB), many drugs cannot reach effective therapeutic concentrations, so these drugs cannot meet market demand

Method used

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  • Quinazoline compound used as EGFR (epidermal growth factor receptor) inhibitor
  • Quinazoline compound used as EGFR (epidermal growth factor receptor) inhibitor
  • Quinazoline compound used as EGFR (epidermal growth factor receptor) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0266] Compound 1A

[0267]

[0268] 2-Amino-4-methoxybenzoic acid (5.00 g, 29.91 mmol) was dissolved in acetic acid (10 ml) and acetonitrile (100 ml), and liquid bromine (4.78 g , 29.91 mmol) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at 20° C. for 1 hour. TLC showed the reaction was complete. After the reaction solution was concentrated, it was slurryed with water (100 ml) and petroleum ether (100 ml) successively. Drying in vacuo afforded Compound 1A. 1 H NMR (400MHz, DMSO-d 6 )=7.76(s, 1H), 6.41(s, 1H), 3.79(s, 3H).

[0269] Compound 1B

[0270]

[0271] Compound 1A (5.9 g, 18.94 mmol) and formamidine acetate (3.55 g, 34.10 mmol) were dissolved in ethylene glycol monomethyl ether (10 ml), and the reaction solution was stirred at 120° C. for 3 hours under a nitrogen atmosphere . TLC showed the reaction was complete. The reaction solution was cooled to room temperature, a solid precipitated, filtered, and the filte...

Embodiment 2

[0300] Compound 2A

[0301]

[0302] At -78°C under a nitrogen atmosphere, lithium hexamethyldisilazide (1M, 60.23 ml) was added to tetrahydrofuran (60 ml), and ethyl acetate (5.84 g, 66.25 mmol ), tert-butyl 4-oxopiperidine-1-carboxylate (10.00 g, 50.19 mmol) dissolved in tetrahydrofuran (40 ml) was added dropwise to the reaction solution, and the temperature was slowly raised to 0° C., and stirred for 10 hours. TLC showed the reaction was complete. Concentrate the reaction solution to about 60 ml, add saturated ammonium chloride solution (80 ml) to the reaction solution, extract with ethyl acetate (50 ml×3), and wash the combined organic phase with saturated ammonium chloride solution (60 ml) Afterwards, it was dried with anhydrous sodium sulfate (5 g) and concentrated to obtain compound 2A. 1 HNMR (400MHz, deuterated chloroform)d=4.22-4.13(m,2H),3.81(br.s.,1H),3.71(t,J=6.1Hz,2H),3.19(br.s.,2H) , 2.45 (s, 2H), 1.70-1.61 (m, 2H), 1.51 (br.s., 2H), 1.44 (s, 9H), 1.27 (t,...

Embodiment 3

[0322] Compound 3A

[0323]

[0324] Prepared according to the method of compound 1I, replacing 1H with tert-butyl 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate to obtain compound 3A. 1 H NMR (400MHz, DMSO-d6) = 8.72 (br.s., 1H), 8.44 (br.s., 1H), 7.58 (br.s., 1H), 7.47 (br.s., 2H), 7.31 (s, 2H), 3.98 (s, 3H), 3.82 (s, 2H), 3.63-3.50 (m, 4H), 1.87-1.69 (m, 4H), 1.41 (s, 9H). LCMS (ESI): m / z: 558.2 [M+1].

[0325] Compound 3B

[0326]

[0327] Prepared according to the method of compound 1J, replacing 1I with 3-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-oxo- tert-butyl 1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate to give compound 3B. The crude product was used directly in the next step. 1 H NMR (400MHz, deuterated methanol)=8.77(s,1H),8.71(s,1H),7.58-7.50(m,2H),7.46(s,1H),7.30(dt,J=1.2,8.1Hz ,1H), 4.15(s,3H), 4.01(s,2H), 3.43-3.36(m,4H), 2.29-2.15(m,4H). LCMS (ESI): m / z: 458.3 [M+1].

[0328] Compound 3

[0329]

[0330] Prepared ac...

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Abstract

The invention discloses a novel quinazoline compound, and particularly discloses a compound shown in a formula (XV) and a pharmaceutically acceptable salt thereof. (The formula (XV) is shown in the description.)..

Description

technical field [0001] The invention relates to a quinazoline compound used as an EGFR inhibitor for the treatment of brain metastasis cancer. Specifically, the present invention relates to a compound of formula (XV) or a pharmaceutically acceptable salt thereof as an inhibitor of EGFR mutation for the treatment of brain metastases. Background technique [0002] Lung cancer is one of the most common malignant tumors in the world, and has become the number one cause of death from malignant tumors in urban population in my country. Non-small cell lung cancer accounts for about 80% of all lung cancers, and about 75% of the patients are in the advanced stage when they are discovered, and the 5-year survival rate is very low. Genetic aberrations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) have been identified as one of the key drivers of NSCLC progression. [0003] EGFR (epidermal growth factor receptor, referred to as EGFR, ErbB-1 or HER1) is a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/10C07C51/41C07C57/145A61P35/00A61P35/04
CPCA61P35/00A61P35/04C07D498/10C07D471/10C07D498/04C07D413/04A61K45/06C07D403/14C07D413/10
Inventor 刘希乐丁照中陈曙辉吴凌云胡利红万海文张路
Owner MEDSHINE DISCOVERY INC
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