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Triazine compounds as pi3 kinase and mtor inhibitors

a technology of mtor inhibitors and triazine compounds, which is applied in the direction of phosphorous compound active ingredients, drug compositions, immunological disorders, etc., can solve problems such as process blockag

Inactive Publication Date: 2009-12-10
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes a new group of compounds that can inhibit two proteins, mTOR and PI3 kinases, which are involved in cancer development. These compounds can be used to treat various forms of cancer. The patent also provides methods for making and using these compounds.

Problems solved by technology

However, in the presence of mTOR inhibitors, this process is blocked.

Method used

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  • Triazine compounds as pi3 kinase and mtor inhibitors
  • Triazine compounds as pi3 kinase and mtor inhibitors
  • Triazine compounds as pi3 kinase and mtor inhibitors

Examples

Experimental program
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Effect test

example 1

Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-4-ylurea

Step 1: Preparation of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine

[0720]To a stirred solution of cyanuric chloride (18.4 g, 10 mmol) in acetone (100 ml) and crushed ice (500 g), a mixture of triethylamine (30.0 g, excess) and morpholine (17.4 g, 20 mmol) was added at −10° C. After the addition, reaction mixture was stirred at room temperature and for 1 hour and diluted with 50 ml water. Separated white solid was filtered and washed with water. The white solid was dried and filtered. The crude product was found to be pure and taken to next step without purification. Yield: 25 g, 87%; (M+H) 286.7.

Step 2: Preparation of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline

[0721]A mixture of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (1.4 g, 4.9 mmoles), a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmoles), sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic ...

example 2

Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-pyridin-3-ylurea

[0725]Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.08 g 0.23 mmoles) and 3-pyridyl isocyanate (30 mg, 0.25 mmoles) the title compound was isolated as a white solid. The product was purified by Silica gel column chromatography by eluting it with 10% MeOH: ethyl acetate. Yield; 60 mg (56%); (M+H)=463.5.

example 3

Preparation of 1-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-3-phenylurea

[0726]Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (140 mg, 0.40 mmoles) and phenyl isocyanate (72 mg, 0.61 mmoles), the title compound was isolated as a white solid. The product was purified by Silica gel column chromatography by eluting it with ethyl acetate. Yield: 0.128 g (68%) (M+H)=462.3.

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Abstract

Compounds of formula Iwherein:R1 isand R2, R4, and R6-9 are defined herein, and pharmaceutically acceptable salts and esters thereof. These compounds inhibit PI3 kinase and mTOR, and may be used to treat diseases mediated by PI3 kinase and mTOR, such as a variety of cancers. Methods for making and using the compounds of this invention are disclosed. Various compositions containing the compounds of this invention are also disclosed.

Description

FIELD OF THE INVENTION[0001]This invention relates to 2,4,6-substituted [1,3,5]triazine compounds in which one substituent is an optionally substituted morpholino, tetrahydropyranyl or dihydropyranyl group, which inhibit PI3 kinase and mTOR, to processes for preparing them, to methods of treatment using them and to pharmaceutical compositions containing them.BACKGROUND OF THE INVENTION[0002]Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of the phospholipids in cell membranes. In recent years it has become clear that PI plays an important role also in intracellular signal transduction. It is well recognized in the art that PI (4,5) bisphosphate (PI(4,5)P2 or PIP2) is degraded into diacylglycerol and inositol (1,4,5) triphosphate by phospholipase C to induce activation of protein kinase C and intracellular calcium mobilization, respectively [M. J. Berridge et al., Nature, 312, 315 (1984); Y. Nishizuka, Science, 225, 1365 (1984)].[0003]Phosphatidylinositol-3 kinase (“PI3...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5375C07D413/04C07D413/14C07D405/14C07D417/14C07D491/08C07D498/08A61K31/5377A61K31/541A61K31/7068A61K31/675A61K33/24A61K39/395A61P19/00A61P35/00
CPCC07D251/18C07D451/06C07D403/12C07D403/14C07D405/12C07D405/14C07D413/04C07D413/14C07D453/02C07D491/113C07D498/08A61K31/5377A61K45/06C07D409/12C07D407/14C07D401/14C07D401/04C07D401/12A61P1/18A61P13/08A61P13/12A61P17/06A61P19/00A61P19/02A61P19/08A61P27/02A61P29/00A61P35/00A61P35/02A61P37/00A61P37/02A61P43/00A61P9/00A61P9/10A61P9/14
Inventor VENKATESAN, ARANAPAKAM MUDUMBAICHEN, ZECHENGDEHNHARDT, CHRISTOPH MARTINDOS SANTOS, OSVALDODELOS SANTOS, EFREN GUILLERMOZASK, ARIEVERHEIJEN, JEROEN CUNERAKAPLAN, JOSHUA AARONRICHARD, DAVID JAMESAYRAL-KALOUSTIAN, SEMIRAMISMANSOUR, TAREK SUHAYLGOPALSAMY, ARIAMALACURRAN, KEVIN JOSEPHSHI, MENGXIAO
Owner WYETH LLC
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