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A class of novel spiroheterocyclic compounds and their use as therapeutic agents

A compound and mixture technology, applied in anti-inflammatory agents, organic chemistry, drug combination, etc., can solve the problems of low selectivity, large toxic and side effects, etc.

Inactive Publication Date: 2011-12-07
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Malignant tumors are currently the most serious type of disease that endangers human life and health. The research on anticancer drugs has always been an important topic in the field of drug research and development. The commonly used drugs for the treatment of clinical tumors are traditional cytotoxic drugs, but these drugs are selective. Low, toxic side effects and other disadvantages

Method used

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  • A class of novel spiroheterocyclic compounds and their use as therapeutic agents
  • A class of novel spiroheterocyclic compounds and their use as therapeutic agents
  • A class of novel spiroheterocyclic compounds and their use as therapeutic agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] Synthetic general method of embodiment 1 compound (I) and partial compound structure analysis

[0134] Dissolve 10 mmol of the corresponding substituted benzaldehyde in 10 mL of absolute ethanol, stir at room temperature for 5 min, then add the corresponding cyclopentanone, acetone or cyclohexanone, and continue stirring for 10 min, the solution remains unchanged. Sodium metal was dissolved in methanol to prepare 18% (w / v) sodium methoxide / methanol solution. Slowly add 1.5mL of the sodium methoxide solution (containing 5mmol of sodium methoxide) into the reaction solution. After stirring for 2-5 hours, a large amount of insoluble yellow matter appears. The reaction solution is detected by TLC, and the raw material 2- Black spots of bromobenzaldehyde, the product spots are clearly yellow. Stop the reaction, filter the reaction solution, wash the product with water first, then wash twice with ice ethanol and ice acetone, and dry in vacuum at 30°C overnight to obtain a ye...

Embodiment 2

[0167] Example 2 Compound (I) Kinase Activity Analysis Test in Vitro

[0168]Caliper-EZ Reader is a detection platform based on the mobility detection technology of microfluidic chip technology, which has the function of real-time kinetic detection. The microfluidic chip is to integrate the steps of sample preparation, biochemical reaction and detection on the chip, which integrates the characteristics of miniaturization, integration and automation; the detection platform applies the basic principle of capillary electrophoresis to the microfluidic environment. Enzyme assays were tested without the addition of stop reagents.

[0169] We will screen the synthesized compounds for FGFR kinase inhibitory activity on the Caliper-EZ Reader platform. The experimental steps are as follows (20μM):

[0170] 1. Prepare 1.25× kinase alkaline buffer and stop buffer.

[0171] a. 1.25× Kinase Alkaline Buffer: 62.5mM HEPES, pH 7.5, 0.001875% Brij-35, 12.5mM MgCl2, 2.5mM DTT

[0172] b. Sto...

Embodiment 3

[0187] Example 3 Some compounds inhibit the proliferation of tumor cells with high FGFR1 expression induced by bFGF

[0188] The compounds with good FGFR1 tyrosine kinase inhibitory activity were selected, and their inhibitory activity on the growth of tumor cells U251 and A549 with high FGFR1 expression induced by bFGF was determined by MTT method. For the activity data, see figure 1 . bFGF was able to stimulate cell proliferation of each tumor cell. The compounds showed good activity of inhibiting bFGF-induced cell proliferation for each tumor cell, and generally showed a good dose-effect relationship, and the inhibitory effect of A549 was quite obvious.

[0189] Each cell includes: blank group, no bFGF and compound; negative group, only bFGF (20ng / mL), no compound; drug-dosed test group, bFGF (20ng / mL), plus DMSO-dissolved compound , the compound is set to three concentrations of 1 μM, 5 μM, and 10 μM. Both the blank group and the negative group were added with the same ...

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Abstract

The present invention relates to general formula (I) spiroheterocyclic compound, its stereoisomer, enantiomer, tautomer or its mixture, or its pharmaceutically acceptable salt, solvate or prodrug, wherein ( II, k, j, P, Q, R1, R2 and R3) are as defined herein, which are useful for the treatment and / or prevention of diseases or conditions mediated by fibroblast growth factors and their receptor signaling pathways, such as cancer . Also disclosed are pharmaceutical compositions comprising the compounds and methods of using the compounds.

Description

technical field [0001] The present invention relates to spiro heterocyclic compounds. In particular, the present invention relates to spiroheterocyclic compounds which are fibroblast growth factor receptor inhibitors and are therefore useful in the treatment of diseases or conditions mediated by fibroblast growth factor and its receptor signaling pathways, such as cancer As well as other diseases and disease states related to the mediation of fibroblast growth factor and its receptor signaling pathway. Background technique [0002] The development of molecularly targeted anti-tumor drugs targeting tyrosine kinases has become a hot and frontier field in life science and pharmaceutical science. Malignant tumors are currently the most serious type of disease that endangers human life and health. The research on anticancer drugs has always been an important topic in the field of drug research and development. The commonly used drugs for the treatment of clinical tumors are trad...

Claims

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Application Information

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IPC IPC(8): C07D487/10C07D487/20C07D491/20C07D491/107C07D495/20C07D495/10C07D209/96A61K31/438A61K31/409A61K31/403A61P35/00A61P13/12A61P29/00A61P25/24A61P25/18A61P9/00A61P11/00
Inventor 李校堃梁广赵承光吴建章蔡跃飘王怡
Owner WENZHOU MEDICAL UNIV
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