4-phenoxyquinoline and alpha-acyloxyamide compound and preparation method and application thereof

A technology of acyloxyamide and phenoxyquinoline, which is applied in the field of cancer related to c-Met, can solve the problems that have not been reported, and achieve the effect of high purity, strong inhibitory activity and novel structure

Active Publication Date: 2019-09-27
威海惠安康生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The present invention relates to 4-phenoxyquinoline a-acyloxyamide compounds as tyrosine kinase inhibitors, especially c-Met inhibitors, which have not been reported

Method used

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  • 4-phenoxyquinoline and alpha-acyloxyamide compound and preparation method and application thereof
  • 4-phenoxyquinoline and alpha-acyloxyamide compound and preparation method and application thereof
  • 4-phenoxyquinoline and alpha-acyloxyamide compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1: the synthesis of target compound Ia

[0035]

[0036] Step 1. The synthesis of 4-(2-fluoro-4-nitrophenyloxy)-6,7-dimethoxyquinoline, the reaction formula is as follows:

[0037]

[0038] Take 4-chloro-6,7-dimethoxyquinoline (6.71g, 30.0mmol) and 2-fluoro4-nitrophenol (5.65g, 36.0mmol) in 60mL of chlorobenzene, and slowly heat to 140°C , Continue to react at this temperature for 20h. Heating was then stopped, cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved with dichloromethane, washed with saturated potassium carbonate solution and water successively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA=3:1), 6.30 g of a light yellow solid was obtained, and the yield was 61%. Mp: 161–163°C.1 H NMR (400MHz, DMSO-d 6 )δ8.56(d, J=5.2Hz, 1H), 8.43(dd, J=2.4, 10.4Hz, 1H), 8.18(d, J=8.8Hz, 1H), 7.60(t, J=8.4Hz, 1H), ...

Embodiment 2

[0051] Embodiment 2: the synthesis of target compound Ib

[0052]

[0053] The experimental procedure was the same as in Example Ia, only benzoic acid was used instead of thiophene-2-carboxylic acid. White solid, yield: 72.4%. Mp:91-93℃. 1 H NMR (400MHz, DMSO-d 6 )δ10.70(s,1H),8.46(d,J=5.6Hz,1H),8.02(d,J=7.2Hz,2H),7.87(dd,J=2.0,12.8Hz,1H),7.68( t,J=7.2Hz,1H),7.56(d,J=7.6Hz,2H),7.53(s,1H),7.50(dd,J=1.6,9.2Hz,1H),7.44(d,J=8.8 Hz, 1H), 7.40(s, 1H), 6.46(d, J=4.8Hz, 1H), 5.31(q, J=6.8Hz, 1H), 3.94(s, 6H), 1.61(d, J=6.8 Hz,3H). 13 C NMR (100MHz, DMSO-d 6 )δ169.2, 165.3, 159.5, 153.5 (d, J = 244.2Hz), 152.8, 149.6, 148.6, 146.1, 137.7 (d, J = 9.9Hz), 135.8 (d, J = 12.3Hz), 133.6, 129.4 (2C ), 129.3, 128.8(2C), 124.2, 116.2(d, J=2.5Hz), 114.5, 108.2(d, J=23.0Hz), 107.6, 102.1, 99.0, 70.8, 55.8(2C), 17.4.ESI- MS: m / z 491.1[M+H] + .

Embodiment 3

[0054] Embodiment 3: the synthesis of target compound Ic

[0055]

[0056] The experimental procedure is the same as in Example Ia, except that n-butyraldehyde is used instead of acetaldehyde, and benzoic acid is used instead of thiophene-2-carboxylic acid. White solid, yield: 68.3%. Mp:99-101℃. 1 H NMR (400MHz, DMSO-d 6)δ10.62(s,1H),8.45(d,J=4.8Hz,1H),8.03(d,J=7.6Hz,2H),7.86(d,J=13.2Hz,1H),7.69(t, J=7.6Hz, 1H), 7.58-7.54(m, 2H), 7.52(s, 1H), 7.48-7.41(m, 2H), 7.39(s, 1H), 6.45(d, J=5.2Hz, 1H ),5.19(t,J=7.2Hz,1H),3.93(s,6H),1.98-1.91(m,2H),1.56-1.49(m,2H),0.97(t,J=7.2Hz,3H) . 13 CNMR (100MHz, DMSO-d 6 )δ168.7, 165.5, 159.4, 153.5 (d, J = 244.3Hz), 152.7, 149.5, 148.9, 146.4, 137.6 (d, J = 9.7Hz), 135.8 (d, J = 12.3Hz), 133.8, 129.5 (2C ),129.2,128.9(2C),124.3,116.2(d,J=1.5Hz),114.6,108.2(d,J=22.6Hz),107.9,102.1,99.0,74.2,55.8(2C),33.4,18.3, 13.7. ESI-MS: m / z 519.2 [M+H] + .

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Abstract

The invention relates to a 4-phenoxyquinoline and alpha-acyloxyamide compound I. The 4-phenoxyquinoline and alpha-acyloxyamide compound I is taken as a protein tyrosine kinase (PTK) inhibitor, particularly a c-Met inhibitor. The invention also relates to a preparation method of the compound; the invention further relates to application of the 4-phenoxyquinoline and alpha-acyloxyamide compound I as a drug to the treatment of PTK c-Met related diseases, particularly c-Met related cancer.

Description

technical field [0001] The present invention relates to a kind of 4-phenoxyquinolino α-acyloxy amides compound, its intermediate, preparation method and its use as medicine to treat diseases related to tyrosine kinase c-Met, especially c - Use in Met-associated cancer. [0002] Background of the invention [0003] Malignant tumors have always been a serious threat to human life and health, and their effective treatment is still a worldwide problem. In recent years, the advancement of science and technology has gradually clarified the nature of tumors, and people have realized that the essence of cancer is the unlimited proliferation of cells caused by the imbalance of cell signal transduction pathways. As a basic regulatory mechanism of cells, signal transduction transmits various extracellular signals to the inside of cells, so that cells can respond and realize processes such as proliferation, differentiation, and apoptosis. Protein kinases (PKs) are involved in this proce...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/12C07D215/22C07D405/12A61K31/47A61K31/4709A61P35/00
CPCC07D409/12C07D215/22C07D405/12A61P35/00
Inventor 吴彦超南祥李惠静
Owner 威海惠安康生物科技有限公司
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