Pharmaceutical compositions comprising tyrphostins

Abstract

Compounds useful for countering undesired toxic effects to cells, tissues or organs having formula (I) wherein: Ar is a group of formulae (i) or (ii), n is O or, when Ar has formula (i) above, then n may also be 1, R is CN, -GC(S)NH2, -C(O)NHR3 or, when R1 is 4-NO2 and R2 is H or 3-OH, then R may also be a group of formulae (iii), (iv), (v), (vi) where R3 is H, phenyl, phenyl(lower alkyl) or pyridylmethyl; R1 and R2 are each independently H, OH, NO2 or, when R is CN, also CH3, F, or CF3, provided that both R1 and R2 are simultaneously H.

Description

[0001] The present invention concerns compositions which are useful to counter damage caused by harmful agents, particularly anti-neoplastic agents used in cancer treatment, e.g. cytotoxic drugs. Damage in the context of the present invention means adverse effects on either cells, tissue or organs. The present invention also concerns therapeutic methods to counter such damage. Furthermore, the present invention concerns also novel compounds useful in such compositions and methods.[0002] Most of the commonly used antineoplastic treatments, including chemotherapy and radiation, have adverse toxic effects, manifested on dividing cells and in the function of certain organs. Cells which are particularly affected by such treatment are bone marrow cells, skin cells and cells of the gastrointestinal tract epithelium. In addition, such treatments often cause damage to specific organs, such as the kidney and liver. As a result of such toxic effects, the therapeutic index of such treatments is...

AI Technical Summary

Benefits of technology

[0046] It was found in accordance with the invention that when the tyrphostins of formula I are administered together with another therapeutic agent, they do not reduce the therapeutic activity of the other agent, but rather act in reducing its undesired toxic side effects to normal cells or tissue. This means that the therapy with the therapeutic agent will still achieve the same desired therapeutic effect, at the same dosage. For example, in the case of a chemotherapeutic drug, the administration of a tyrphostin will not, or may only minimally affect the effect of the drug in reducing the tumor load or preventing tumor growth or tumor recurrence, at a given administration dosage. In some cases, however, administration of the tyrphostins even intensifies the therapeutic effect of the treatment. The overall effect of the tyrphostins, in such a combination therapy, is thus the increase in the therapeutic index of another therapy, namely, increase in the ratio between the therapeutic effect of the therapy to its undesired toxic side effects. The increase in therapeutic index may at times be used to advantage of increasing the dosage of the therapeutic agent, e.g. the dosage of the cytotoxic agent or radiation, without a concurrent increase in undesired toxic side effects.

Problems solved by technology

Most of the commonly used antineoplastic treatments, including chemotherapy and radiation, have adverse toxic effects, manifested on dividing cells and in the function of certain organs.

In addition, such treatments often cause damage to specific organs, such as the kidney and liver.

As a result of such toxic effects, the therapeutic index of such treatments is limited.

The toxicity of these agents may also be related to the induction of apoptosis in normal cells.

Other agents such as mitimazole, chloropromazin and L-arginine were also administered to animals in various in vivo experiments carried out in connection with toxicity of cisplatin resulting in only preliminary non-conclusive findings.

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