New pyrimidine-2,4,6-trione derivatives, processes for their production and pharmaceutical agents cnotaining these compounds

A compound, pyrimidine technology, applied in the field of pyrimidine-2, can solve the problem of low oral effectiveness

Inactive Publication Date: 2002-10-16
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Some of these compounds show high activity as inhibitors of matrix metalloproteinases, but their oral availability is very low

Method used

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  • New pyrimidine-2,4,6-trione derivatives, processes for their production and pharmaceutical agents cnotaining these compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] 5-(4-(4-Chloro-phenoxy)-phenyl)-5-(4-pyrimidin-2-yl-piperazine)-pyrimidine-2,4,6-trione

[0040] A) 1-(4-(4-chloro-phenoxy)-phenyl-ethanone

[0041] 4-Fluoro-acetophenone (24.4 g) was dissolved in dimethylformamide (180 ml), and 4-chlorophenol (22.8 g) and potassium carbonate (29.5 g) were added. The mixture was heated at reflux for 7 hours with stirring. After cooling, the mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with water, dried and evaporated to give 38 g of a crystalline solid. M.p.66-68°C.

[0042] B) 2-(4-(4-chloro-phenoxy)-phenyl)-morpholin-4-yl-ethanthione

[0043] 12.4 g of the product obtained by the above procedure were mixed with sulfur (4 g) and morpholine (8.8 ml). The mixture was heated to 150°C for 2 hours, cooled in an ice bath and treated with ethanol (20ml) for 30 minutes. The precipitated crystals were collected and recrystallized from ethanol to obtain 13 g of the title compound. m.p.104...

Embodiment 2

[0057] 5-[4-(4-Chloro-phenoxy)-phenyl]-5-(2,3,5,6-tetrahydro-[1,2']bispyrazinyl-4-yl)-pyrimidine -2,4,6-trione

[0058] Similar to Example 1, step H, the title compound was prepared using 330 mg of 1-(pyrazin-2-yl)-piperazine instead of N-(pyrimidin-2-yl)-piperazine to obtain 460 mg of title compound. Determined by mass spectrometry: m / e: 492.

Embodiment 3

[0060] No.

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PUM

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Abstract

A compound of formula (I) having metalloprotease inhibitor activity: R represents a substituted or unsubstituted phenoxy, phenylsulfanyl, phenylsulfinyl, phenylsulfonyl, phenylamino or phenylmethyl residue radical, and R2 represents an optionally substituted aryl or heteroaryl residue.

Description

field of invention [0001] The present invention relates to novel derivatives of 5,5-disubstituted pyrimidine-2,4,6-triones. These compounds show significant antitumor and antimetastatic activity. Background of the invention [0002] In normal tissues, there is a balance between synthesis and breakdown. The extracellular matrix is ​​degraded by proteases belonging to at least three families of matrix metalloproteases. These are collagenase, gelatinase and stromelysin. Usually, specific inhibitors exist for inhibiting these catabolic enzymes, such as α2 macroglobulin and TIMP (= tissue inhibitor of metalloproteases (MMP)), so that excessive degradation of the extracellular matrix does not occur. Adamalysins are a related family of proteases. A well-known member of snake venom proteases is TACE (TNF-alpha-converting enzyme). [0003] At least 17 distinct yet highly homologous MMP species have been characterized, including interstitial fibroblast collagenase (MMP-1, HFC), n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/60A61K31/515A61P35/00A61P35/04A61P43/00C07D239/00C07D239/54C07D239/545C07D239/62C07D241/02C07D295/00C07D403/04C07D403/12C07D405/12
CPCA61K31/515C07D239/545C07D405/12A61P35/00A61P35/04A61P43/00A61K31/00
Inventor 弗兰克·格拉姆斯汉斯-威利·克雷尔赫伯特·莱纳特埃内斯托·门塔格尔德·齐默尔曼
Owner F HOFFMANN LA ROCHE & CO AG
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