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Inhibition of phosphoinositide 3-kinase beta

A technology of kinase and β inhibitors, applied in medical preparations containing active ingredients, blood diseases, extracellular fluid diseases, etc., can solve problems such as unidentified

Inactive Publication Date: 2005-10-26
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, prior to the present invention, a signaling role important for shear stress-induced platelet activation other than hemostasis had not been identified.

Method used

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  • Inhibition of phosphoinositide 3-kinase beta
  • Inhibition of phosphoinositide 3-kinase beta
  • Inhibition of phosphoinositide 3-kinase beta

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0208] Example 1. Synthesis of (±)-7-methyl-2-morpholin-4-yl-9-(1-phenylaminoethyl)-pyrido[1,2-a]pyrimidin-4-one ( TGX-221: R 1 =CH 3 , R 2 =CH 3 , R 3 =H)

[0209]

[0210] Compound 2: To a solution of 2-amino-3-bromo-5-methylpyridine (1) (45 g, 0.45 mol) in dichloromethane (500 mL) was added malonyl dichloride (25 mL , 0.25mol). The mixture was stirred at room temperature for 48 hours. The precipitated pale yellow solid was collected by filtration, washed with dichloromethane (3 x 100 mL), and dried under vacuum to give product 2 (52.5 g). The filtrate was concentrated under reduced pressure. The resulting residue was suspended in water and stirred for 1 hour. The solution was filtered, and the filtrate was washed with solid NaNCO 3 Neutralization gave unreacted 2-amino-3-bromo-5-methylpyridine (6 g). The crude compound was used in the next synthetic step without further purification.

[0211] 1 H NMR (300MHz, DMSO-d 6 )δ 8.72(s, 1H),

[0212] 8.28(s, 1H), ...

Embodiment 2

[0218] Example 2. Preparation of pyridine-substituted benzopyrone derivatives

[0219] 8-(Substituted)-2-(4-pyridyl)-4H-1-benzopyran-4-ones were prepared following the general procedure adapted from Cushman and Nagarathnam, 1990, Tetrahedron Letters 31:6497. Briefly, various precursors 2-hydroxyacetophenones (1) were treated with methyl isonicotinate and derivatives followed by ring closure and dehydration to yield pyridine-substituted products (3). Then through various coupling reactions in R 1 import specific substituents.

[0220]

[0221] Substituents on acetophenone (R) may include, but are not limited to, bromo, hydroxy, acetamido, methoxymethyl, methyl, ethyl, methoxy, trifluoromethanesulfonyloxy, and acetyl substitution base. Substituents on isonicotinate (R') include, but are not limited to, chloro, methyl and amino substituents. Reagents for the condensation reaction include lithium bis(trimethylsilyl)amide, sodium hydride, 1,8-diazabicyclo[2.2 .2] Undecane...

Embodiment 2a

[0225] Example 2a : 6-methyl-8-acetyl-2-(4-pyridyl)-4H-1-benzopyran-4-one

[0226]

[0227] 3′-Acetyl-2′-hydroxy-5′-methylacetophenone

[0228] A mixture of 2-hydroxy-5-methylacetophenone (15 g, 0.1 mol) in dichloromethane (100 ml) was treated with triethylamine (13.9 ml), dimethylaminopyridine (1.22 g) and acetic anhydride ( 9.5 ml) and stirred overnight at room temperature. The mixture was then poured into water (300ml) and extracted with dichloromethane (3 x 60ml). The combined mixture was washed with saturated NaHCO 3 Washed with aqueous solution, dried (Na 2 SO 4 ) and removal of the solvent gave a colorless oil (19.5 g).

[0229] The product was dissolved in dichloromethane (200ml) at 0°C and treated with aluminum chloride (19.5g), then stirred at room temperature for 5 days. The solution was treated with ice (50 g) and 2N hydrochloric acid (50 ml), then stirred at room temperature for 1 hour. The dichloromethane layer was separated and the aqueous layer wa...

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Abstract

The present invention relates to a selective depressant of phosphoinositide (PI) 3-kinase Beta, which is applied to the anti-thrombosis therapy, and a method of screening a compound used by a novel anti-thrombosis therapy by detecting the selective inhibitory activity of the PI 3-kinase Beta of the compound.

Description

Background of the invention [0001] I. Field of Invention [0002] The present invention broadly relates to a new antithrombotic therapy and compounds useful in the new therapy. More particularly, the present invention relates to selective inhibitors of phosphoinositide (PI) 3-kinase beta, the use of such selective inhibitors in antithrombotic therapy, and the selection of PI 3-kinase beta by detection of compounds A method for screening compounds that can be used in this new antithrombotic therapy based on their sexual inhibitory activity. [0003] II. Description of related fields [0004] Platelets are specialized adhesive cells that play an important role in the hemostasis process. Under normal conditions, platelets neither adhere nor are activated by the vascular endothelium. However, damage to the endothelium or rupture of the plaque exposes the flowing blood to various thrombogenic factors including collagen, fibronectin and von Willebrand factor (vWF). Circulating ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04
Inventor S·P·杰克逊A·D·罗伯逊V·肯切P·汤普逊H·普拉巴哈兰K·安德逊B·阿博特I·贡卡尔夫斯W·内斯比特S·舍恩维尔德D·赛利克
Owner ASTRAZENECA AB
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