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Quinazoline, pyridopyrimidine or pyrimidopyrimidine derivative epidermal growth factor inhibitor and preparing method and application thereof

A technology of epidermal growth factor and pyridopyrimidine, which is applied in the field of medicine, can solve the problems of drug loss of effect and drug resistance of patients, and achieve strong killing activity, good selectivity, and reduce toxic and side effects

Inactive Publication Date: 2017-03-15
NANJING LEIKEXING BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

One of the mutations occurs at the gatekeeper residue 790 of the EGFR tyrosine kinase, and the original L-threonine (T) at this site is replaced by L-methionine (M), which is called T790M Mutation, after the mutation, EGF tyrosine kinase R no longer combines with gefitinib and erlotinib, so that the drug loses its effect and the patient develops drug resistance

Method used

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  • Quinazoline, pyridopyrimidine or pyrimidopyrimidine derivative epidermal growth factor inhibitor and preparing method and application thereof
  • Quinazoline, pyridopyrimidine or pyrimidopyrimidine derivative epidermal growth factor inhibitor and preparing method and application thereof
  • Quinazoline, pyridopyrimidine or pyrimidopyrimidine derivative epidermal growth factor inhibitor and preparing method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: 2-{4'-fluoro-5'-[N,N-dimethylaminomethyl-(E)-acrylamido]-2'-methoxy}anilino-4-(1” -Methyl-1H-3 "-indole) quinazoline (compound 201) preparation

[0037]

[0038] The preparation of 2,4-dichloroquinazoline:

[0039]

[0040] 2,4-Dihydroxyquinazoline (3.0g, 18.5mmol) was dissolved in phosphorus oxychloride (22ml), heated to 108°C and refluxed for about 3 hours. The reaction solution gradually turned into a brownish-yellow clear liquid. LCMS detected that the reaction was complete. The reaction solution was slowly added dropwise into crushed ice and stirred to precipitate a large amount of off-white solid. The filtrate was concentrated and dried under reduced pressure to obtain off-white solid, 3.1 g, purity: 98%, yield: 83%. LC-MS(ESI):m / z 200(M+H) + .

[0041] Preparation of 2-chloro-4-(1-methyl-1H-3-indole)quinazoline:

[0042]

[0043] Dissolve 2,4-dichloroquinazoline (1.0g, 5.02mmol) in ethylene glycol dimethyl ether (18ml), stir in an ice bat...

Embodiment 2

[0053] Example 2: 2-{4'-dimethylamino-5'-[N,N-dimethylaminomethyl-(E)-acrylamido]-2'-methoxy}anilino-4- Preparation of (1”-methyl-1H-3”-indole)quinazoline (compound 202)

[0054]

[0055] Preparation of 2-{4'-dimethylamino-5'-nitro-2'-methoxy}anilino-4-(1"-methyl-1H-3"-indole)quinazoline:

[0056]

[0057] 2-{4'-fluoro-5'-nitro-2'-methoxy}anilino-4-(1"-methyl-1H-3"-indole)quinazoline (445mg, 1.0mmol ) was dissolved in N,N-dimethylformamide (5ml), added dimethylamine (50mg, 1.113mmol) and N,N-diisopropylethylamine (500mg, 4.048mmol), stirred at 86°C React for 3 hours. LCMS detected that the reaction was complete. Cool to room temperature, add the reaction solution dropwise to stirring water, a large amount of solids are precipitated, filter with suction, wash the filter cake with a small amount of water, dissolve the filter cake in dichloromethane, add dropwise to stirring petroleum ether for beating treatment, the obtained solid is pumped Filter dry. Obtained 455 mg...

Embodiment 3

[0064] Example 3: 2-{4-(1-methyl-N,N-dimethylaminoethyl)amino-5'-(3'-N,N-dimethylaminomethyl-propene Preparation of acyl)-amino-2'-methoxy}anilino-4-(1"-methyl-1H-3"-indole)quinazoline (compound 203)

[0065]

[0066] 2-{4-(1-methyl-N,N-dimethylaminoethyl)amino-5'-nitro-2'-methoxy}anilino-4-(1”-methyl Preparation of -1H-3"-indole) quinazoline

[0067]

[0068] 2-{4'-fluoro-5'-nitro-2'-methoxy}anilino-4-(1"-methyl-1H-3"-indole)quinazoline (400mg, 0.9mmol ) was dissolved in dimethylsulfoxide (7ml), stirred at room temperature, N,N,N-trimethylethylenediamine (105mg, 1.0mmol) and N,N,-diisopropylethylamine ( 0.4ml), then heated to 86°C and stirred for three hours. LCMS detected that the reaction was complete. Stop the reaction, cool to room temperature, slowly add the reaction solution into the stirring ice water, precipitate a large amount of solid, filter with suction, and dry the filter cake. The obtained crude product is beaten with dichloromethane and petroleum ethe...

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Abstract

The invention discloses a selectivity inhibitor of a clinical mutant of EGFR protein tyrosine kinase. The selectivity inhibitor of the clinical mutant of EGFR protein tyrosine kinase has a structure which is shown in the formula (1) (The formula (1) is defined in the description), and is a double aromatic nucleus template compound containing quinazoline, pyridopyrimidine or pyrimidopyrimidine. The invention further discloses a preparing method of the compound and an application of the compound as the selectivity inhibitor of the clinical mutant of EGFR protein tyrosine kinase, especially an inhibiting effect of the compound in a T790M-variation EGFR and an application in treating diseases such as renal carcinoma, lung cancer, prostate gland cancer, pancreatic cancer, breast cancer and spongiocytoma, wherein the diseases are related to overexpression of the epidermal growth factor receptor EGFR.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a quinazoline, pyridopyrimidine or bispyrimidine derivative epidermal growth factor inhibitor and a preparation method and application thereof. Background technique [0002] Epidermal Growth Factor Receptor EGFR (Epidermal Growth Factor Receptor) is a kind of ErbB receptor family, is a kind of glycoprotein, belongs to tyrosine kinase type receptor, cell membrane runs through, molecular weight 170KDa. EGFR is located on the surface of the cell membrane and binds to ligands to activate EGF and TGF (transforming growth factor). After activation, EGFR is converted from a monomer to a dimer and activates its intracellular kinase pathway to guide downstream phosphorylation, including MPAK, Akt and JNK pathways, and induce cell proliferation. Studies have shown that there are high or abnormal expressions of EGFR in many solid tumors, and EGFR is related to the proliferation, angiogenesis, tumor...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D471/04C07D487/04A61K31/517A61K31/519A61P35/00
CPCC07D403/04C07D471/04C07D487/04
Inventor 李红玲杰克吴
Owner NANJING LEIKEXING BIOTECH CO LTD
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