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Derivative adopting pyridino-[2,3-d]pyridine as mother nucleus as well as preparation method and application thereof

A 3-d, derivative technology, applied in the direction of medical preparations, drug combinations, and pharmaceutical formulations containing active ingredients, which can solve the problem of reducing drug inhibitory activity, producing drug resistance, and drug molecules unable to form covalent bonds with them, etc. problems, to achieve significant therapeutic and effective results

Active Publication Date: 2018-09-21
LIAONING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Unfortunately, clinical data show that after long-term use of Osimertinib (AZD-9291), the patient's EGFR exon 20 site will produce a new C797S mutation, which will greatly reduce the therapeutic effect of the drug
In vitro studies have shown that the mutation of the C797S site of EGFR kinase will prevent the drug molecule from forming a covalent bond with it, reducing the binding ability of the drug molecule to EGFR kinase, thereby reducing the inhibitory activity of the drug and resulting in drug resistance.

Method used

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  • Derivative adopting pyridino-[2,3-d]pyridine as mother nucleus as well as preparation method and application thereof
  • Derivative adopting pyridino-[2,3-d]pyridine as mother nucleus as well as preparation method and application thereof
  • Derivative adopting pyridino-[2,3-d]pyridine as mother nucleus as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The preparation of embodiment 1 compound 1

[0031]

[0032] step 1

[0033]

[0034] Dissolve raw material 1 (10g, 1eq) in acetonitrile (30ml), add boc anhydride (14g, 1.2eq) dropwise at 25°C, heat up to 60°C after dropwise addition, react for 10h, spin off part of the solvent, and cool to crystallize , filtered to obtain a filter cake, washed with acetonitrile solvent to obtain intermediate 2. The filtrate and washing liquid were combined, and 8 g of boc anhydride was added to continue the reaction. After 10 h, the second cooling crystallization was performed, and the operation was repeated 5 times to obtain 14 g of intermediate 2 as a light yellow solid, with a recovery rate of 91%.

[0035] LC-MS(ESI):m / z 287.10(M+H) +

[0036] step 2

[0037]

[0038] Add intermediate 2 (3g, 1eq), N,N,N-trimethylethylenediamine (1.6g, 1.5eq), potassium carbonate (4.99g, 2eq) into a 100ml eggplant-shaped bottle in sequence, and heat up to 60°C , TLC detected that the r...

Embodiment 2

[0061] The synthesis of embodiment 2 compound 2

[0062]

[0063] step 1

[0064]

[0065] Dissolve raw material 1 (10g, 1eq) in acetonitrile (30ml), then add boc anhydride (14g, 1.2eq) dropwise at 25°C, then rise to 60°C, react for 10h, spin off part of the solvent, cool to crystallize, and filter The filter cake was washed with acetonitrile solvent to obtain intermediate 2. The filtrate and washing liquid were combined, and 8 g of boc anhydride was added to continue the reaction. After 10 h, the second cooling crystallization was performed, and the operation was repeated 5 times to obtain 14 g of intermediate 2 as a light yellow solid, with a recovery rate of 91%.

[0066] LC-MS(ESI):m / z 287.10(M+H) +

[0067] step 2

[0068]

[0069] Intermediate 2 (1.5g, 1eq), morpholine (0.54g, 1.2eq), and potassium carbonate (1.45g, 2eq) were added to a 100ml eggplant-shaped bottle, the temperature was raised to 80°C, and the reaction time was 4h. TLC detected that the react...

Embodiment 3

[0092] The preparation of embodiment 3 compound 3

[0093]

[0094] step 1

[0095]

[0096] Dissolve raw material 1 (10g, 1eq) in acetonitrile (30ml), then add boc anhydride (14g, 1.2eq) dropwise at 25°C, then rise to 60°C, react for 10h, spin off part of the solvent, cool to crystallize, and filter to obtain The filter cake was washed with acetonitrile solvent to obtain intermediate 2. The filtrate and washing liquid were combined, and 8 g of boc anhydride was added to continue the reaction. After 10 h, the second cooling crystallization was performed, and the operation was repeated 5 times to obtain 14 g of intermediate 2 as a light yellow solid, with a recovery rate of 91%.

[0097] LC-MS(ESI):m / z 287.10(M+H) +

[0098] step 2

[0099]

[0100] Add intermediate 2 (1.5g, 1eq), piperazine methanesulfonate (1.03g, 1.2eq), potassium carbonate (1.45g, 2eq) into a 100ml eggplant-shaped bottle, dissolve in DMF, heat up to 80°C, and react After 14 hours, TLC detected t...

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PUM

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Abstract

The invention discloses a derivative adopting pyridine-[2,3-d] pyridine as a mother nucleus as well as a preparation method and application thereof. The derivative of the invention is a compound having an inhibition effect for tumor cells mutated for EGFR tyrosine kinase and can be used for treating, jointly treating or preventing various cancers. Particularly, the effect of the compound for treating the mutation type of del19, L858R and T790M of EGFR is significant.

Description

technical field [0001] The invention discloses a derivative with a pyrido[2,3-d]pyrimidine structure as the core, its pharmaceutically acceptable salt, prodrug, solvate, its preparation method and its medical application. Background technique [0002] As the largest public health problem in the world, malignant tumors have become common and frequently-occurring diseases that seriously threaten human health. Studies have shown that EGFR is over-expressed in many different tumors, and it plays a very important role in cell proliferation, so it is one of the potential anti-tumor drug targets. In recent years, the development of targeted drugs targeting EGFR has achieved encouraging results. The first-generation EGFR inhibitors Gefitinib, Erlotinib, and Icotinib targeting EGFR and the second-generation EGFR inhibitor Afatinib have been approved for clinical treatment of non-small cell lung cancer. [0003] EGFR (also referred to as ErbB1 or HER1) is a part of the ErbB family o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/519A61K31/5377A61P35/00
CPCA61P35/00C07D471/04
Inventor 陈烨丁实纪经超刘举刘雨彤周子筠
Owner LIAONING UNIVERSITY
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