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Tyrosine kinase irreversible inhibitor and preparation method and applications thereof

A tyrosine kinase and inhibitor technology, applied in the field of tyrosine kinase irreversible inhibitors or their pharmaceutically acceptable salts and their preparation, can solve problems such as loss of activity

Active Publication Date: 2013-01-16
GUANGZHOU HENOVCOM BIOSCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The EGFR T790M mutation is an important cause of drug resistance. The change of the amino acid residue skeleton caused by the mutation makes reversible EGFR inhibitors such as gefitinib and erlotinib hydrochloride break away from the ATP binding region of ErbB receptor tyrosine kinase , thereby inactivating the

Method used

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  • Tyrosine kinase irreversible inhibitor and preparation method and applications thereof
  • Tyrosine kinase irreversible inhibitor and preparation method and applications thereof
  • Tyrosine kinase irreversible inhibitor and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Compound 1, N-(3-(4-(1-(3-fluorophenyl)-1H-indazol-5-amino)-quinazolin-6-yl)-prop-2-yne)-acrylamide preparation.

[0075] Line one:

[0076]

[0077] According to above-mentioned route, step 1) prepares compound I-2, i.e. 2-amino-5-iodobenzoic acid methyl ester, method is as follows:

[0078] In a 250mL two-necked flask equipped with a dropping funnel, add 50.19g (332.42mmol) methyl anthranilate, 100mL tert-butyl alcohol and 50mL water, add 44.32g (174.52mmol) elemental iodine in batches under stirring, then slowly Add 40mL of 30% hydrogen peroxide dropwise, and heat to 50°C in an oil bath for 2h. The reaction was monitored by TLC. After the reaction, cool the reaction system to room temperature, add 50 mL of saturated aqueous sodium bisulfite solution, stir well, then extract three times with 150 mL of ethyl acetate, combine the organic phases, wash with 50 mL of saturated brine, dry over anhydrous sodium sulfate, and spin evaporate About 100 mL of ethyl acetate...

Embodiment 2

[0103] Compound 2, (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazol-5-amino)-quinazolin-6-yl)-prop-2- Preparation of alkyne)-but-2-enamide.

[0104] Step 1)-4) is the same as embodiment 1, and step 5) is as follows:

[0105] Select 2-butenoic acid to perform condensation reaction with 1-6a, and the operation method is as in Example 1 to obtain the target product.

[0106] The characterization data of this compound are: 1H NMR (400MHz, DMSO-d6) δppm 10.01(s, 1H), 8.50(s, 1H), 8.25(s, 1H), 8.16(s, 1H), 7.84(s, 1H ), 7.72(s, 1H), 7.54-7.64(m, 3H), 7.33-7.39(m, 1H), 7.04-7.12(m, 4H), 6.67-6.72(m, 1H), 5.95(d, J =14.8Hz, 1H), 5.70(s, 2H), 4.27(d, J=5.2Hz, 2H), 1.81(d, J=6.0Hz, 3H).ESI-MS m / z: 491.2(M+H ), 489.2 (M-H).

[0107] The compound structural formula is:

[0108]

Embodiment 3

[0110] Compound 3, (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazol-5-amino)-quinazolin-6-yl)-prop-2- Preparation of alkyne)-4-morpholinobutyl-2-enamide.

[0111] Step 1)-4) is the same as embodiment 1, and step 5) is as follows:

[0112] 4-Morpholine 2-butenoic acid was selected for condensation reaction with 1-6a, and the operation method was as in Example 1 to obtain the target product.

[0113] The characterization data of this compound are: 1H NMR (400MHz, DMSO-d6) δppm 10.01(s, 1H), 8.50(s, 1H), 8.25(s, 1H), 8.16(s, 1H), 7.84(s, 1H ), 7.72(s, 1H), 7.54-7.64(m, 3H), 7.33-7.39(m, 1H), 7.04-7.12(m, 4H), 6.67-6.72(m, 1H), 6.05-6.15(m , 1H), 5.70(s, 2H), 4.27(d, J=4.0Hz, 2H), 3.53(t, J=4.8Hz, 4H), 3.04(d, J=6.4Hz, 2H), 2.32(s , 4H). ESI-MS m / z: 576.2 (M+H), 574.2 (M-H).

[0114] The compound structural formula is:

[0115]

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Abstract

The invention provides a tyrosine kinase irreversible inhibitor shown in a formula I or pharmaceutically acceptable salt thereof, a preparation method for the tyrosine kinase irreversible inhibitor and applications of the tyrosine kinase irreversible inhibitor. The invention belongs to the field of pharmaceutical chemistry. The tyrosine kinase irreversible inhibitor or the pharmaceutically acceptable salt thereof is very high in activity of inhibiting growth of cancer cells, and is especially remarkable in effect of inhibiting the growth of cancer cells with high expression of an epidermal growth factor receptor (EGFR) and type-2 human epidermal growth factor receptor (HER2).

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to an irreversible inhibitor of tyrosine kinase or a pharmaceutically acceptable salt thereof, a preparation method and application thereof. Background technique [0002] Normally, cells need to obtain growth signals from a quiescent state to a proliferative state. These growth signals are transferred to cells through specific signaling molecules binding to receptors on the cell membrane. EGF is one of the most important growth signaling molecules. The EGF receptor is a multifunctional transmembrane glycoprotein widely distributed on various tissue cells of the human body. It belongs to one of the members of the ErbB family. There are four members in this family, namely EGFR (HER1 / erbB-1), HER2 (erbB-2 / neu), HER3 (erbB-3), HER4 (erbB-4). They are all single polypeptide chains, with a relative molecular mass of about 1.7×105 to 1.85×105, and are encoded by genes loc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/517A61K31/5377A61K31/519C07D403/12C07D239/94C07D495/04A61P35/00
CPCC07D495/04C07D239/94A61K31/519A61K31/517A61K31/5377A61P35/00
Inventor 张健存
Owner GUANGZHOU HENOVCOM BIOSCI CO LTD
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