Styryl compounds which inhibit EGF receptor protein tyrosine kinase

a technology of egf receptor and tyrosine kinase, which is applied in the field of egf receptor protein tyrosine kinase inhibition, can solve the problems of high toxicity of compounds, unsatisfactory, and tumor cells are more readily attacked, and achieve the effect of inhibiting egf receptor kinase and effectively inhibiting egf-dependent autophosphorylation of receptors

Inactive Publication Date: 2005-07-19
YISSUM RES DEV CO OF THE HEBREWUNIVERSITY OF JERUSALEM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0052]Compounds within the scope of the present invention have a specific affinity toward the substrate site of the tyrosine kinase domain of EGF receptors, inhibit EGF receptor kinase more than they inhibit PDGF receptor kinase and also effectively inhibit EGF-dependent autophosphorylation of the receptor.

Problems solved by technology

This is not particularly desirable because insulin is needed by the body to perform other biological functions which are not related to cell proliferation.
These compounds are highly toxic since their inhibitory activity is not limited to cancer cells, with the distinction, however, that tumor cells are more readily attacked by the aforesaid inhibitors because these cells divide more rapidly and their DNA metabolism is consequently more active.
These cases, however, are the exception and the chemotherapeutic treatment for the majority of the various types of cancer is non-specific.

Method used

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  • Styryl compounds which inhibit EGF receptor protein tyrosine kinase
  • Styryl compounds which inhibit EGF receptor protein tyrosine kinase
  • Styryl compounds which inhibit EGF receptor protein tyrosine kinase

Examples

Experimental program
Comparison scheme
Effect test

example 1

3,4-Dihydroxybenzylidene malononitrile

[0146]To 11 g (80 mmol) of 3,4-dihydroxybenzaldehyde and 5.5 g (83 mmol) of malononitrile in 40 ml of ethanol, 7 drops of piperidine were added and the mixture was heated at 70° C. for 0.5-1 hour and then poured into water. The resulting solid precipitate was separated by filtration to give 12.7 g (86% yield) of a yellow solid, m.p. 225° C.

examples 2-4

[0147]Following the same procedure as set forth for Example 1 above, the following were prepared: Example 2, 3-methoxy-4,5-dihydroxybenzylidene malononitrile, m.p. 235° C.; Example 3, 3,5-di-tert butyl-4-hydroxybenzylidene malononitrile, m.p. 135° C.; and Example 4, 3,5-di-tert butylbenzylidene malononitrile, m.p. 95°-98° C.

example 5

α-Hydroxy-3,4,5-trihydroxybenzylidene malononitrile

[0148]To 2 g (30 mmol) of malononitrile and 4 ml (40 mmol) of triethylamine in 100 ml of CH2Cl2, triacetyl galloyl chloride (prepared from 7 g (24 mmol) of triacetyl gallic acid and thionyl chloride) in 50 ml CH2Cl2 was added. The resulting mixture was then stirred for two hours at room temperature, poured into 50 ml water and hydrolyzed by heating for 2 minutes at 80° C. with a solution of 2.5 g NaOH in 30 ml ethanol. The mixture was extracted with ethyl acetate and the organic extract was further worked up by washing with water, drying, filtering and evaporation. Chromatography on silica gel gave 1.5 g (29% yield) of the product as an oily solid.

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Abstract

A method of inhibiting cell proliferation in a patient suffering from such disorder comprising administering to said patient an effective amount of a composition comprising, in admixture with a pharmaceutically acceptable carrier, a compound, or a pharmaceutically acceptable salt thereof, which is a substituted styrene compound which can also be a naphthalene, an indane or a benzoxazine; including nitrile and molononitrile compounds, and pharmaceutical compositions comprising, in admixture with a pharmaceutically acceptable carrier, a pharmaceutically-effective amount of such compound.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This is a continuation of application(s) Ser. No. 07 / 515,602 filed on Apr. 27, 1990, now abandoned which is a continuation-in-part of U.S. application Ser. No. 07 / 287,908, filed Dec. 21, 1988 now abandoned.FIELD OF THE INVENTION[0002]This invention relates to the inhibition of cell proliferation. More specifically, this invention relates to the use of low molecular weight styryl compounds in inhibiting cell proliferation, including compounds which are useful protein tyrosine kinase (PTK) inhibitors.[0003]Normal cellular reproduction is believed to be triggered by the exposure of the cellular substrate to one or more growth factors, examples of which are insulin, epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). Such growth factors are typically specific for corresponding growth factor receptors which are imbedded in and which penetrate through the cellular membrane. The initiation of cellular reproduction is believed...

Claims

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Application Information

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IPC IPC(8): A61K31/19A61K31/165A61K31/275A61K31/185A61K31/36A61K31/357C07D317/62C07D317/00A61K31/16A61K31/38A61K31/44A61K31/535
CPCA61K31/165A61K31/19A61K31/275A61K31/36C07C255/00C07D317/62
Inventor LEVITZKI, ALEXANDERGILON, CHAIMCHOREV, MICHAELGAZIT, AVIV
Owner YISSUM RES DEV CO OF THE HEBREWUNIVERSITY OF JERUSALEM LTD
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