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Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors

The technology of a compound, 2-hetcyc2a, is applied in the direction of active ingredients of heterocyclic compounds, anti-inflammatory agents, drug combinations, etc., and can solve problems such as reducing the chance of cure

Inactive Publication Date: 2010-03-24
ARRAY BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patients expressing a mutant form of the receptor have been shown to have a reduced chance of cure

Method used

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  • Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors
  • Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors
  • Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0308] The following examples illustrate the invention. In the examples described below, all temperatures are listed in degrees Celsius unless otherwise indicated. Unless otherwise stated, reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge and used without further purification. Tetrahydrofuran (THF), dichloromethane (DCM, dichloromethane), toluene and dioxane were purchased from Aldrich in Sure sealed vials and used as received.

[0309] The reactions listed below are usually performed under positive pressure of nitrogen or argon or in anhydrous solvents using drying tubes (unless otherwise stated), and reaction flasks are usually equipped with rubber septa for introducing substrates and reagents by syringe. . Glassware is oven-dried and / or heat-dried.

[0310] 1 HNMR spectrum in CDCl 3 、CD 3 OD, D 2 O or d 6 - Obtained in DMSO solution (reported as ppm), using tetramethylsilane (0.00 ppm) or residual solvent...

Embodiment A

[0312] Cellular PDGFR assay

[0313] The ability of the compounds of the present invention to inhibit PDGF-induced phosphorylation of PDGFR was determined by using mouse NIH3T3 cells.

[0314] 25,000 cells in DMEM supplemented with 10% fetal bovine serum will be added to each well of a 96-well cell culture plate. Place the plate at 37 °C / 5% CO 2 Incubate for 6-8 hours in the incubator. Plates were then washed and incubated with serum-free DMEM before returning the cells to 37 °C / 5% CO 2 Incubate for 16-20 hours in the incubator.

[0315] Compound test solutions were added at a final concentration of 0.5% DMSO, and cells were then incubated at 37 °C / 5% CO 2 Incubate for 1 hour in the incubator. PDGF-BB ligand (75ng / mL) was then added and incubated for 15 minutes. Cells were washed with PBS and then fixed in 3.7% formaldehyde in PBS for 10 min. They were subsequently washed in PBS / 0.2% Triton X-100 and permeabilized in 100% MeOH for 10 minutes. Cells were blocked in Ody...

Embodiment B

[0317] Cellular FLT3 assay

[0318]Inhibition of FLT3 ligand (FL)-induced phosphorylated FLT3 in human RS4;11 cells was measured as follows. Cells in RPMI / 10% FCS were plated in 96-well V-bottom plates at a concentration of 1 million cells / well. Diluted compounds were added at a final concentration of 0.5% DMSO over one hour. FL was added at a final concentration of 50 ng / ml. After 15 minutes of incubation, cells were pelleted by centrifugation and then resuspended in lysis buffer. Phospho-FLT3 was detected by a standard ELISA protocol (R&D Systems; DYC368). Briefly, after 20 minutes on ice, the lysates were added to 96-well plates coated with a capture antibody for total FLT3. Phospho-FLT3 was detected by adding antibodies to phosphotyrosine conjugated to HRP. After addition of substrate and cessation of dissolution, the signal was read at A450. Compounds of the invention have an IC of less than 10 μM in this assay 50 .

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Abstract

Compounds of Formula I: in which A, B, R<1>, R<1a>, R<2>, R<3>, R<4>, R<5> R<6>, R<7> and R<8> have the meanings given in the specification, are receptor tyrosine inhibitors useful in the treatment ofdiseases mediated by class 3 and class 5 receptor tyrosine kinases. Particular compounds of this invention have also been found to be inhibitors of Pim-1.

Description

technical field [0001] The present invention relates to novel compounds, pharmaceutical compositions comprising said compounds, processes for preparing said compounds, and the use of said compounds in therapy. More specifically, the present invention relates to certain imidazopyridine compounds useful in the treatment and prevention of diseases mediated by type 3 and type 5 receptor tyrosine kinases. Specific compounds of the invention have also been found to be inhibitors of Pim-1. Background technique [0002] Receptor tyrosine kinases (RTK's) include type 3 receptor tyrosine kinases (PDGF-α, PDGFR-β, MCSF-1R, c-kit and FLT3) and type 5 receptor tyrosine kinases (VEGFR and KDR). Said kinases are known to be frequently aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or gastric cancer, leukemia and ovarian, bronchial or pancreatic cancer (pancreatic cancer), renal cell carcinoma and glioma (glioma). [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/33A61P35/00
CPCC07D471/04A61P1/16A61P11/00A61P13/12A61P17/00A61P17/06A61P19/02A61P21/04A61P25/00A61P29/00A61P35/00A61P35/02A61P35/04A61P37/06A61P43/00A61P7/06A61P3/10A61K31/33
Inventor 谢利·艾伦朱莉·M·格雷斯查克尼古拉斯·C·卡兰弗雷德里克·P·马姆萨特马克·C·芒森詹姆斯·P·里齐约翰·E·鲁宾逊斯蒂芬·T·施拉赫特乔治·T·托帕洛夫赵千约瑟夫·P·莱西卡托斯
Owner ARRAY BIOPHARMA
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