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EGFR (epidermal growth factor receptor) inhibitor for targeted therapy of cancers, and preparation method and application thereof

A cancer, condensation reaction technology, applied in the field of EGFR inhibitors, to achieve the effect of small side effects

Active Publication Date: 2016-05-18
TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the second-generation inhibitors have solved the problem of drug resistance to a certain extent, due to their high inhibition of wild-type EGFR, side effects such as diarrhea and rash

Method used

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  • EGFR (epidermal growth factor receptor) inhibitor for targeted therapy of cancers, and preparation method and application thereof
  • EGFR (epidermal growth factor receptor) inhibitor for targeted therapy of cancers, and preparation method and application thereof
  • EGFR (epidermal growth factor receptor) inhibitor for targeted therapy of cancers, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1, the preparation of compound 1

[0034]

[0035] Add 16 μL of acetyl chloride (the molar ratio of AZD9291 to acetyl chloride is 1:1.1) and 69 μL of N,N-diiso Propylethylamine. Stir at 20 °C for 30 min. After the reaction was detected by TLC, the reaction solution was washed with saturated sodium bicarbonate solution (25 mL), extracted three times with dichloromethane (25 mL×3), and the obtained organic solvent layers were combined together, and the organic solvent was removed on a rotary evaporator. Purification by silica gel column (methanol / dichloromethane 1:30) gave compound 1.

[0036] 1 H-NMR (400MHz, DMSO-d6) δ (ppm) 10.01 (s, 1H), 8.52 (d, J = 5.2Hz, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 7.84 (d ,J=8.0Hz,1H),7.53(d,J=5.2Hz,1H),7.47(d,J=8.0Hz,1H),7.19(t,J=8.0Hz,1H),7.11(s,1H ), 7.00(t, J=8.0Hz, 1H), 6.39-6.36(m, 1H), 6.18(d, J=16.8Hz, 1H), 5.72(d, J=11.6Hz, 1H), 3.85(s ,3H),3.71(s,3H),2.92(s,2H),2.76(s,3H),2.40(s,4H),2.21(s,6H);LRMS(ESI)calcdforC ...

Embodiment 2

[0037] Embodiment 2, the preparation of compound 2

[0038]

[0039]Add 19 μL of propionyl chloride (the molar ratio of AZD9291 to propionyl chloride is 1:1.1) and 69 μL of N,N-diiso Propylethylamine. Stir at 25 °C for 30 min. After the reaction was detected by TLC, the reaction solution was washed with saturated sodium bicarbonate solution (25 mL), extracted three times with dichloromethane (25 mL×3), and the obtained organic solvent layers were combined together, and the organic solvent was removed on a rotary evaporator. Purification on a silica gel column (methanol / dichloromethane=1:30) gave compound 2.

[0040] 1 H-NMR (400MHz, DMSO-d6) δ (ppm) 9.94 (s, 1H), 8.50 (d, J = 5.12Hz, 1H), 8.36 (s, 1H), 8.10 (s, 1H), 7.84 (d ,J=7.68Hz,1H),7.53-7.45(m,2H),7.20-7.16(m,1H),7.07(s,1H),7.00-6.97(m,1H),6.48(br,1H), 6.20-6.15(m,1H),5.72-5.70(m,1H),3.84(s,3H),3.71(s,3H),3.00(br,2H),2.75-2.73(m,5H),2.28( br,6H),1.08(t,J=7.88Hz,3H);LRMS(ESI)calcdforC 16 h 18 Cl 2 N 2 O[M+H] ...

Embodiment 3

[0041] Embodiment 3, the preparation of compound 3

[0042]

[0043] Add 18 μL acryloyl chloride (the molar ratio of AZD9291 to acryloyl chloride is 1:1.1) and 69 μL N,N-diisopropyl Ethylamine. Stir at room temperature for 30 min. After the reaction was detected by TLC, the reaction solution was washed with saturated sodium bicarbonate solution (25 mL), extracted three times with dichloromethane (25 mL×3), and the obtained organic solvent layers were combined together, and the organic solvent was removed on a rotary evaporator. Purification by silica gel column (methanol / dichloromethane 1:30) gave compound 3.

[0044] 1 H-NMR (400MHz, DMSO-d6) δ (ppm) 10.03 (s, 1H), 8.49 (d, J = 5.48Hz, 1H), 8.37 (s, 1H), 8.17 (s, 1H), 7.54 (d ,J=5.48Hz,1H),7.47(d,J=8.24Hz,1H),7.19(t,J=7.60Hz,1H),7.09(s,1H),6.97(t,J=7.60Hz,1H ),6.79-6.73(m,1H),6.44-6.36(m,,1H),7.06(s,1H),6.29(dd,J=16.8Hz,J=1.6Hz,1H),6.17(dd,J =16.8Hz, J=1.6Hz,1H),5.75-5.70(m,2H),3.85(s,3H),3.38(s,3H),2,76(br,2H),2.76(...

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Abstract

The invention discloses an EGFR (epidermal growth factor receptor) inhibitor for targeted therapy of cancers, and a preparation method and application thereof. The structural formula of the EGFR inhibitor is disclosed as Formula I, wherein R is H, OH, NR', C1-C3 alkyl, C1-C3 alkenyl, aryl or heterocycle, and R' is C1-C3 alkyl. The EGFR inhibitor can be used for preventing and / or treating cancers, such as human skin squamous carcinoma or lung cancer. Compared with the existing inhibitors (such as AZD9291, afatinib and the like), the EGFR inhibitor disclosed by the invention has novel chemical structure. The EGFR inhibitor can selectively inhibit cell lines of EGFR double mutants (EGFRT790M / L858R), and has lower inhibition activities for EGFR wild type cells. Therefore, the EGFR inhibitor disclosed by the invention can be used for treating the patient with lung cancer with EGFRT790M / L858R mutants, and has lower side effect (caused by the inhibition of the wild type EGFR, such as afatinib).

Description

technical field [0001] The invention relates to an EGFR inhibitor for targeted treatment of cancer, a preparation method and application thereof. Background technique [0002] Malignant tumor is a common and frequently-occurring disease that seriously threatens human health. It is caused by abnormal proliferation of cells in the human body. Lung cancer, gastrointestinal cancer and liver cancer are the most common tumors in men, accounting for more than 70% of all cases (lung cancer 23%, gastric cancer 15.2%, liver cancer 13.57%, esophageal cancer 10.46%, colorectal cancer 9.39%), while breast cancer, Lung cancer, gastrointestinal cancer and liver cancer are the most common tumors in women, accounting for more than 60% of all cases (breast cancer 16.97%, lung cancer 14.85%, colorectal cancer 9.68%, gastric cancer 8.53%, liver cancer 6.17%). With the aging population in China, the prevalence of cancer is bound to increase. In addition, environmental pollution has also increa...

Claims

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Application Information

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IPC IPC(8): C07D403/04A61K31/506A61P35/00
CPCA61K31/506C07D403/04
Inventor 饶燏杨兴林王廷亮
Owner TSINGHUA UNIV
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