6, 7, 8, 9-tetrahydro-[1, 4]oxazepine[3, 2-g] quinazoline derivative, preparation method and application thereof

A technology of oxazepine and quinazoline, applied to 6,7,8,9-tetrahydro-[1,4]oxazepine[3,2-g]quinazoline derivatives and their derivatives In the field of preparation and use, it can solve the problems of primary and acquired drug resistance, etc.

Inactive Publication Date: 2014-08-06
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although tyrosine kinase inhibitors have played an important role in cancer treatment, their primary and acquired drug resistance has become a bottleneck that limits the further improvement of their

Method used

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  • 6, 7, 8, 9-tetrahydro-[1, 4]oxazepine[3, 2-g] quinazoline derivative, preparation method and application thereof
  • 6, 7, 8, 9-tetrahydro-[1, 4]oxazepine[3, 2-g] quinazoline derivative, preparation method and application thereof
  • 6, 7, 8, 9-tetrahydro-[1, 4]oxazepine[3, 2-g] quinazoline derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] 4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-bromo-1-oxo-2-buten-1-yl]amino}-6,7,8,9-tetra Hydrogen-[1,4]Oxynitrogen Zazo[3,2-g]quinazoline

[0098]

[0099] step 1

[0100] 1,3-Propanediol (59g) was added to dry tetrahydrofuran (500ml) at room temperature, and NaH (21g) was added to the reaction liquid in batches under the protection of nitrogen in an ice bath, and the reaction was completed at room temperature for 1 hour. At room temperature, 7-fluoro-6-nitroquinazolinone (50 g) was added to the reaction mixture in one portion, and kept at 75° C. overnight. Spot plate showed complete reaction. Under ice bath, add acetic acid to adjust PH=7, add water (500ml), concentrate to 500ml, solid precipitates, filter, wash with water (400ml), dry under reduced pressure at 40°C overnight to obtain 59g yellow solid (compound 1b), The yield is 99%.

[0101] step 2

[0102] Compound 1b (20 g) was suspended in SOCl 2 (100ml), adding POCl in sequence 3 (20ml) and DMF (0.5ml)...

Embodiment 2

[0116] 4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-6, 7,8,9-four Hydrogen-[1,4]oxazepine[3,2-g]quinazoline

[0117]

[0118] Compound 1i (200 mg) was dissolved in DMF (3 ml), and morpholine (110 mg) was added. Reacted at room temperature for 1 hour, the plate reaction was complete, added water (10ml), filtered, dried, and the crude product was purified by column chromatography (dichloromethane / methanol=50:1) to obtain 61 mg of white solid (compound 1), yield 30 %. ESI-MSm / z: 497[M+H] + ; 1 H-NMR (DMSO-d 6 ,500MHz)δ(ppm): 9.74(s,1H,Ar-H),8.64(s,1H,Ar-H),8.49(s,1H,NH),8.19(dd,J=2.6,6.8Hz, 1H, Ar-H), 7.82-7.85 (m, 1H, Ar-H), 7.43-7.47 (m, 2H, Ar-H), 6.66 (td, J=5.4, 15.3Hz, 1H, CH=CH) ,5.90(d,J=15.5Hz,1H,CH=CH),4.76-4.79(m,1H,CHHO),4.50-4.52(m,1H,CHHO),3.96(t,J=9.6Hz,1H, CHHN),3.19-3.26(s,4H,2×CH 2 O), 3.05(t, J=10.1Hz, 1H, CHHN), 2.92(d, J=5.2Hz, 2H, CH 2 N),2.18(s,4H,2×CH 2 N),1.90-2.12(m,2H,CH 2 ).

Embodiment 3

[0120] 4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-methyl-piperazin-1-yl)-1-oxo-2-buten-1-yl] ammonia Base}-6,7,8,9-tetrahydro-[1,4]oxazepine[3,2-g]quinazoline

[0121]

[0122] The specific experimental operation was the same as that in Example 2. 100 mg of compound (1i) and 60 mg of N-methylpiperazine were added to obtain 31 mg of white solid (compound 2), with a yield of 33%. ESI-MSm / z: 510[M+H] + ; 1 H-NMR (DMSO-d 6 ,500MHz)δ(ppm): 9.76(s,1H,Ar-H),8.64(s,1H,Ar-H),8.50(s,1H,NH),8.18(dd,J=2.6,6.8Hz, 1H, Ar-H), 7.83-7.86(m, 1H, Ar-H), 7.46(t, J=9.1Hz, 1H, Ar-H), 7.43(s, 1H, Ar-H), 6.65(td ,J=5.2,15.3Hz,1H,CH=CH),5.89(d,J=15.3Hz,1H,CH=CH),4.76-4.79(m,1H,CHHO),4.50-4.52(m,1H, CHHO), 3.96(t, J=9.5Hz, 1H, CHHN), 3.05(t, J=10.4Hz, 1H, CHHN), 2.90(d, J=4.4Hz, 2H, CHHN) 2 N),2.19(s,4H,2×CH 2 N),2.07-2.09(m,2H,CH 2 ),1.92-1.95(m,4H,2×CH 2 N),1.89(s,3H,CH 3 ).

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Abstract

The invention relates to a 6, 7, 8, 9-tetrahydro-[1, 4]oxazepine[3, 2-g] quinazoline derivative with a structure shown as formula I, tautomers, stereisomers and pharmaceutically acceptable salts thereof, especially pharmaceutically acceptable salts formed by the derivative and inorganic or organic acids or alkalis, and also relates to a preparation method, and application of the receptor tyrosine kinase inhibition property of the compounds in preparation of drugs treating proliferative diseases like cancer. (formula I).

Description

technical field [0001] The invention relates to a 6,7,8,9-tetrahydro-[1,4]oxazepine[3,2-g]quinazoline derivative, a preparation method thereof and a pharmaceutical composition containing the derivative compounds and their use as therapeutic agents, especially as protein kinase inhibitors, and the invention also relates to intermediates of such compounds. Background technique [0002] Protein kinases (Protein Kinases) are the largest protein family known so far. All kinases have very conserved catalytic cores and diverse regulatory modes, and the primary structures of these catalytic cores have high homology, but each Classes have their specificities. Protein kinases function to transfer the gamma-phosphate group of ATP to specific amino acid residues on their substrates. According to the specificity of these amino acid residues, protein kinases can be divided into four categories, of which the main two are protein tyrosine kinase (Protein Tyrosine Kinase, PTK) and protein ...

Claims

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Application Information

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IPC IPC(8): C07D498/04A61K31/553A61P35/00
CPCC07D498/04
Inventor 陈庆财赵俊赵小伟蔡继兰陈祥峰孙敏孙焕亮王飞栋孔陵生丁阳
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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