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Condensed heteroaryl derivatives

一种稠合杂芳基、衍生物的技术，应用在稠合杂芳基衍生物领域，能够解决没有说明、PI3K抑制作用和抗癌作用没有披露等问题

Inactive Publication Date: 2005-06-22
ASTELLAS PHARMA INC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the PI3K inhibitory effect and anticancer effect are neither disclosed nor explained in these existing documents.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

experiment example 1

[0173] Experimental example 1 Inhibition experiment of PI3K (p110α subtype)

[0174] The assay was performed with an enzyme (bovine p110α) produced by a baculovirus expression system. Enzymes were prepared according to "Cell (Cell)" by I Hile et al., 70, 419, 1992. Compounds to be evaluated were prepared as 10 mM (millimolar) DMSO solutions and serially diluted with DMSO.

[0175] Compounds (0.5 μl) and enzymes were evaluated in 25 μl buffer (40 mM Tris-HCl (pH 7.4), 200 mM NaCl, 2 mM dithiothreitol, 5 mM MgCl 2 ) after mixing, add 10 μg PI (Sigma), 2 μCi (microcurie) [γ -32 P] ATP (Amersham Pharmacia), 80 μM (micromolar) non-radioactive ATP (Sigma) in 25 μl of 5 mM Tris-HCl (pH 7.4) buffer to start the reaction. After reacting at 37°C for 15 minutes, add 200 μl of 1M HCl, 400 μl of CHCl 3 / MeOH (1:1), stirring, centrifugation. The organic layer was extracted two more times with 150 microliters of MeOH / 1M HCl (1:1), and its radioactivity was measured by Cerenkov light. ...

experiment example 2

[0179] Experimental Example 2 Intestinal Cancer Cell Proliferation Inhibition Experiment

[0180] Intestinal cancer cell line HCT116 was cultured in McCoy's 5A medium (GIBCO) containing 10% fetal bovine serum. HCT116 (5000 cells / well) was inoculated on a 96-well plate and cultured overnight. Compounds diluted with culture medium were added thereto to a final concentration of 0.1-30 μM (final DMSO concentration, 1%). After culturing for 72 hours, Alamar Blue reagent was added. After 2 hours, the inhibitory activity IC was obtained from the fluorescence intensity ratio of the excitation wavelength of 530 nm and the emission wavelength of 590 nm 50 . of the present invention Co 14 , Co 24 , Co 25 , Co 31 , Co 46 and Co 47 The compound has a good inhibitory effect on cancer cell proliferation.

experiment example 3

[0181] Experimental Example 3 Proliferation Inhibition Experiment of Melanoma Cells

[0182] Melanoma cell line A375 cells were cultured in DMEM medium (GIBCO) containing 10% fetal bovine serum. A375 cells were pre-seeded at 10000 cells / 100 microliters on a 96-well plate containing 1 microliter per well (final concentration 0.001-30 microliters). After 46 hours of incubation, Alamar Blue reagent (10 μl / well) was added. After 2 hours, use the same method as above to determine the IC of the test compound from the fluorescence intensity ratio of the excitation wavelength of 530 nm and the emission wavelength of 590 nm 50 .

[0183] The compounds of the present invention have good growth inhibitory activity. For example, Co 17 , Co 33 , Co 50 , Co 69 , Co 164 , Co 172 , Co 174 , Co 186 , Co 190 and Co 191 It has a good inhibitory effect on the proliferation of melanoma cells. its IC 50 Values ​​were 0.33-4.26 μM. The value of LY294002, which is a well...

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Abstract

The present invention provides a pharmaceutical composition which is useful as a phosphatidylinositol 3 kinase (PI3K) inhibitor and an antitumor agent, and it provides a novel bicyclic or tricyclic fused heteroaryl derivative or a salt thereof which possesses an excellent PI3K inhibiting activity and cancer cell growth inhibiting activity.

Description

[0001] This application is the title of "fused heteroaryl derivatives" with the national application number 01808654.3 after the PCT international application with the international application number PCT / JP 01 / 03650 and the international application date as April 26, 2001 entered the Chinese phase Divisional application of Chinese patent application. technical field [0002] The present invention relates to fused heteroaryl derivatives useful as pharmaceuticals, especially phosphatidylinositol 3-kinase (PI3K) inhibitors and anticancer agents. Background technique [0003] Phosphatidylinositol (hereinafter referred to as "PI") is one of cell membrane phospholipids, which is known to play a role in intracellular information transmission. In particular, it is well understood that PI(4,5) diphosphate (PI(4,5)P2) is broken down by phospholipase C into diacylglycerol and inositol (1,4,5) triphosphate, causing Activation of protein kinase C and intracellular calcium mobilization ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4355A61K31/4365A61K31/437A61K31/444A61K31/519A61K31/5377A61P35/00A61P43/00C07D491/04C07D491/048C07D491/147
CPCA61K31/4355A61K31/4365A61K31/437A61K31/444A61K31/519A61K31/5377C07D491/04A61P1/18A61P13/08A61P13/12A61P17/06A61P19/08A61P27/06A61P29/00A61P3/10A61P35/00A61P43/00A61P9/10
Inventor 早川昌彦贝沢弘行森友博幸川口贤一小泉智信山野真由美松田光阳冈田稔太田光昭
Owner ASTELLAS PHARMA INC
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