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Thienopyrimidine and furopyrimidine derivative, its preparation method and application in medicines

A technology for pyrimidine derivatives, which is applied in the field of pyrimidine derivatives and their preparation, can solve the problems of low drug resistance and achieve the effects of low drug resistance, novel structure, and obvious EGFR inhibitory activity

Active Publication Date: 2013-05-08
JIANGSU DESANO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, with the clinical application of these drugs, it has been found that not all patients with high expression of EGFR can respond to these drugs, and some tumors that initially responded to Gefitinib (Gefitinib) reappeared after several months of treatment. progress
These results suggest that currently used EGFR inhibitor antineoplastic drugs have natural or secondary drug resistance, therefore, the development of new drugs with low drug resistance or can alleviate early inhibitor resistance has become an important factor for tyrosine kinase inhibition. The new development direction of the agent

Method used

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  • Thienopyrimidine and furopyrimidine derivative, its preparation method and application in medicines
  • Thienopyrimidine and furopyrimidine derivative, its preparation method and application in medicines
  • Thienopyrimidine and furopyrimidine derivative, its preparation method and application in medicines

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1: Preparation of compound I-1 and compound II-1

[0054]

[0055] first step:

[0056] Dissolve p-carboxyphenylboronic acid pinacol ester (1g, 4.03mmol) in dichloromethane (10ml, 0.16mol) and N,N-dimethylformamide (1ml, 13.0mmol) at room temperature, add N-ethyl Piperazine (0.6ml, 4.8mmol), and sequentially added 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.93g, 4.8mmol), N-hydroxybenzo Triazole (0.66g, 4.8mmol), triethylamine (0.84ml, 6.04mmol), stirring reaction at room temperature until TLC monitoring raw material reaction is complete, in reaction solution, add 10ml water, stir 30 minutes, dichloromethane (50ml *3) extraction, and then washed with saturated sodium chloride solution (50ml*2), the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain: (4-ethyl-piperazin-1-yl)- [4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (1.4 g, pale yellow solid), d...

Embodiment 2

[0070] Embodiment 2: preparation compound I-2 and compound II-2

[0071]

[0072] first step:

[0073] P-carboxyphenylboronic acid pinacol ester (3g, 12.10mmol) was dissolved in dichloromethane (27ml, 0.422mol) and N,N-dimethylformamide (9ml, 0.116mol) at room temperature, and N-formaldehyde was added Piperazine (1.45g, 14.5mmol), and successively add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.79g, 14.4mmol), N-hydroxybenzo Triazole (1.98g, 12.9mmol), triethylamine (2.5ml, 17.99mmol), stirring reaction at room temperature until TLC monitoring raw material reaction is complete, in reaction solution, add 30ml water, stir 30 minutes, dichloromethane (100ml *3) extraction, and then washed with saturated sodium chloride solution (100ml*2), the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain: (4-methyl-piperazin-1-yl)- [4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (1.5...

Embodiment 3

[0082] Embodiment 3: preparation compound I-3 and compound II-3

[0083]

[0084] first step:

[0085] P-carboxyphenylboronic acid pinacol ester (3g, 12.10mmol) was dissolved in dichloromethane (27ml, 0.422mol) and N,N-dimethylformamide (9ml, 0.116mol) at room temperature, and 1-cyclo Propylmethylpiperazine (2.3g, 14.9mmol), and successively added 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.79g, 14.4mmol), N- Hydroxybenzotriazole (1.98g, 12.9mmol), triethylamine (2.5ml, 17.99mmol), the reaction was stirred at room temperature until the reaction of the raw materials monitored by TLC was complete, 30ml of water was added to the reaction solution, stirred for 30 minutes, and dichloro Extracted with methane (100ml*3), washed with saturated sodium chloride solution (100ml*2), dried the organic phase with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain: (4-cyclopropylcarbonyl-piperazine- 1-yl)-[4-(4,4,5,5-tetramethyl-[1...

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Abstract

The invention discloses a thienopyrimidine and furopyrimidine derivative, its preparation method and its application in medicines. The derivative is a compound shown as general formula I, general formula II, general formula III or general formula IV. The thienopyrimidine and furopyrimidine pyrimidine derivative provided in the invention has an obvious EGFR (epidermal growth factor receptor) inhibitory activity, and some of the compounds also have an obvious inhibitory activity on VEGFR (vascular endothelial growth factor receptor), so that the thienopyrimidine and furopyrimidine pyrimidine derivative can be expected to be developed into tyrosine kinase EGFR or / and VEGFR inhibitors, which can be used for preparation of drugs preventing or treating diseases related to EGFR and / or VEGFR. Therefore, the derivative provided in the invention provides a new development direction and approach for developing novel tyrosine kinase inhibitor drugs that have low resistance or can alleviate early inhibitor resistance, and has wide application prospect and medicinal value.

Description

technical field [0001] The present invention relates to thienopyrimidine derivatives and their preparation methods and applications, in particular to a thienopyrimidine and furopyrimidine derivatives having epidermal growth factor receptor EGFR and / or vascular growth factor receptor VEGFR inhibitory activity The compound, its preparation method and its application in medicine belong to the technical field of medicinal chemistry. Background technique [0002] Tumor is one of the most serious diseases threatening human health, and its treatment mainly includes radiotherapy, chemotherapy and surgery. In recent years, with the development of cell biology and tumor pharmacology, the chemotherapeutic drug treatment of tumors has undergone tremendous changes. Traditional chemotherapeutic drugs are gradually abandoned because they non-specifically block cell division, thereby killing tumor cells and causing normal cell death. At the same time, they target key node proteins in abnor...

Claims

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Application Information

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IPC IPC(8): C07D495/04C07D491/048A61K31/519A61K31/5377A61P35/00A61P35/04
CPCC07D495/04A61K31/519C07D491/048A61K31/5377A61P35/00A61P35/04
Inventor 安晓霞别平彦刘俊杨午立
Owner JIANGSU DESANO PHARMA
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