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Hetero ring derivative

A kind of technology of heterocycle and heterocycle group, applied in the field of heterocycle derivatives and/or their salts, can solve the problem of no PI3K inhibitory effect and the like

Inactive Publication Date: 2012-01-11
ASTELLAS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But there is no record of PI3K inhibition

Method used

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Examples

Experimental program
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Effect test

manufacture example 1

[0240] Potassium carbonate (5.3 g) and 2-( Difluoromethyl)-1H-benzimidazole (3.9 g), and the mixture was stirred at room temperature for 5 hours. Water (300 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (300 mL). The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10~40:60) to obtain 1-[6-chloro-2-(methyl Sulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-1H-benzimidazole (5.49 g).

manufacture example 2

[0242] N, N-dimethyl Potassium carbonate (1.4 g) and morpholine (0.88 mL) were added to the formamide (11 mL) solution, and the mixture was stirred at room temperature for 1 hour. Water (150 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (150 mL). The organic layer was washed with saturated brine (150 mL), and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 to 50:50) to obtain 2-(difluoromethyl)-1-[ 2-(Methylsulfanyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (2.1 g).

manufacture example 3

[0244] In 2-(difluoromethyl)-1-[2-(methylsulfanyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (3g) in dichloromethane (60 mL) m-chloroperbenzoic acid (75%, containing water) (1.9 g) was added under ice-cooling, and the mixture was stirred at 0° C. for 15 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane (200 mL). The organic layer was washed with water (200 mL) and saturated brine (200 mL), and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 98:2) to obtain 2-(difluoromethyl)-1-[ 2-(Methylsulfinyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (2.8 g). The Rf value of this compound in silica gel TLC (chloroform:methanol=10:1) was 0.56.

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PUM

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Abstract

Disclosed is a novel excellent prophylactic or therapeutic method for rejections in various types of organ transplantation, allergic diseases, autoimmune diseases, hematologic tumors and others, which relies on a selective inhibitory activity on PI3Kd and / or an inhibitory activity on the production of IL-2 and / or an inhibitory activity on the proliferation of B cells (including an inhibitory activity on the activation of B cells). It is found that a tri-substituted triazine derivative or a tri-substituted pyrimidine derivative has a selective inhibitory activity on PI3Kd and / or an inhibitory activity on the production of IL-2 and / or an inhibitory activity on the proliferation of B cells (including an inhibitory activity on the activation of B cells) and can be used as a prophylactic or therapeutic agent for rejections in various types of organ transplantation, allergic diseases (e.g., asthma, atopic dermatitis), autoimmune diseases (e.g., rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn diseases, systemic lupus erythematosus), hematologic tumors (e.g., leukemia) and others.

Description

technical field [0001] The present invention relates to a heterocyclic derivative with pharmacological activity and / or its salt. The present invention also relates to a medicament or a pharmaceutical composition comprising the above-mentioned heterocyclic derivative and / or a salt thereof as an active ingredient. Background technique [0002] Phosphatidylinositol-3-kinase (PI3K) is a lipid signaling kinase ubiquitously present in various species ranging from plants and yeast to mammals represented by humans. PI3K is an enzyme that phosphorylates the 3-hydroxyl group of phosphatidylinositol, phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-diphosphate, which are cell membrane phospholipids, and generates phosphatidylinositol from each substrate. Alcohol-3-phosphate, phosphatidylinositol-3,4-diphosphate and phosphatidylinositol-3,4,5-triphosphate (PIP3). These resulting phosphorylated phosphatidylinositols function as intracellular second messengers. In particu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61K31/5377A61K31/541A61K31/55A61P1/04A61P11/06A61P17/00A61P17/06A61P19/02A61P29/00A61P35/02A61P37/02A61P37/06A61P37/08A61P43/00C07D401/14C07D403/14C07D405/14C07D413/14C07D417/14
CPCA61K31/541C07D403/04C07D417/14A61K31/55C07D405/14C07D401/14C07D409/14C07D403/14A61K31/5377C07D413/14A61P1/04A61P11/06A61P17/00A61P17/06A61P19/02A61P29/00A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00
Inventor 高桥史江今田直盐饱雅彦加藤浩二深堀英彦
Owner ASTELLAS PHARMA INC
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