Pharmaceutical compositions comprising tyrphostins

Details Pharmaceutical compositions comprising tyrphostins Pharmaceutical compositions comprising tyrphostins

1999-04-07

2002-07-30

Gerstl, Robert (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S525000

Reexamination Certificate

active

06426366

ABSTRACT:

FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
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 limited.
It is a long felt want in medical research to try and develop treatment modalities and means which will reduce the unwanted toxic side effects, without affecting the therapeutic activity of the drugs, thus increasing their therapeutic index.
Apoptosis or programmed cell death is a fundamental physiological mechanism of cell death regulated during embryonal development and normal homeostasis mechanisms within the body. Recent data indicated that the anti tumor effect of a variety of chemotherapeutic agents is related to their ability to induce apoptosis. The toxicity of these agents may also be related to the induction of apoptosis in normal cells.
Preliminary reports have described use of various pharmacological agents for the prevention of nephrotoxicity resulting from the use of anti-cancer drugs (Skinner, R.,
Current Opinion in Oncology,
7:310-315, 1995). Attempts were made to counteract the severe chronic proximal tubular toxicity resulting from use of the cytotoxic drug Cisplatin. In in vivo experiments in rats, para-aminobenzoic acid (PABA) co-administered together with cisplatin resulted in reduced nephrotoxicity of the cisplatin without reducing its anti-tumor activity. 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.
The drug amifostine which is dephosphorylated to yield a thiol moiety was also used for reducing anti-toxic effects of anti-neoplastic drugs (
Cancer Res.,
55:4069, 1995).
GENERAL DESCRIPTION OF THE INVENTION
The present invention provides, by a first of its aspects, a pharmaceutical composition for countering, i.e. reducing or preventing, damage to cells or tissue comprising, as an active agent, an effective amount of a compound of the general formula I:
wherein:
Ar is a group of the formulae
n is 0 or, when Ar has the formula (i) above, then n may also be 1,
R is CN, —C(S)NH
2
, —C(O)NHR
3
or, when R
1
is 4-NO
2
and R
2
is H or 3-OH, then R may also be a group of the formula
 where R
3
is H, phenyl, phenyl(lower alkyl) or pyridylmethyl;
R
1
and R
2
are each independently H. OH, NO
2
or, when R is CN, also CH
3
, F, or CF
3
, provided that both R
1
and R, are not simultaneously H, together with a pharmaceutically acceptable carrier.
Said active agent and said pharmaceutical composition may be administered to or contacted with cells or tissue in a variety of conditions to reduce or prevent undesired damage to cells, tissues or organs. Examples of such conditions are such which may lead to apoptosis. Preventing of undesired apoptosis is a specific embodiment of the invention. Such conditions may also be exposure of said cells, tissue or organ to harmful factors, which may be exogenous or endogenous factors, as well as other physiological conditions, which may lead to damage, e.g. change in temperature, impairment of blood flow, exposure an ionizing irradiation, etc. The damage to be prevented may also be a result of natural physiological deterioration processes, e.g. such occurring( in cells, tissue or organs, maintained, grown or cultured ex vivo.
The present invention also provides a method of treatment of an individual, for countering damage to cells, tissue or organ, comprising administering to the individual an effective amount of a compound having the general formula I.
The term “effective amount” should be understood as meaning an amount of the active compound, which is effective in countering damage manifested in either destruction of normal (non-diseased) cells or damage to a tissue or organ.
The harmful factor may be an exogenous agent e.g., a therapeutic drug having a cytotoxic effect (e.g. anti-neoplastic drugs), irradiation, noxious chemicals, etc. In addition, the harmful factor may be endogenous, such as free radicals the level of which rises in the course of various metabolic or other disorders, auto-antibodies, cytokines, etc.
The pharmaceutical compositions of the invention may be used in the framework of treatment of various diseases, disorders or conditions such as AIDS, conditions which may give rise to hepatotoxicity, radiation injuries, reducing or inhibiting damage to grafted cells or tissue as a result of graft rejection, for the treatment of intoxications, e.g. paracetamol intoxication, for countering adverse effects of noxious solvents and carriers of therapeutic drugs, countering alcohol-caused damages, etc. Furthermore, the compositions may also be used for countering non-desired immune mediated reactions or an inflammatory response, e.g. septic shock, to reduce damage caused by autoimmune reactions and others. Finally, the pharmaceutical compositions of the invention also may be used- in ex vivo preservation of cells, tissues or organs used for transplantation to reduce or prevent cell or tissue deterioration or death which may otherwise occur during the time they are kept ex vivo prior to transplantation, etc.
The pharmaceutical compositions of the invention are especially useful to counter toxic effects of cytotoxic or anti-metabolic drugs, particularly such as used in cancer therapy. Occasionally, the pharmaceutical composition of the invention will be administered in conjunction with the cytotoxic drug. A pharmaceutical composition according to this embodiment may comprise such a drug in combination with a compound of above formula I.
The compounds of formula I belong to a family of compounds known as Tyrphostin compounds (Levitzki, A. and Gazit, A.
Science,
267:1782, 1995). In the following text, a compound of Formula I will be referred to as “Tyrphostin” and compositions comprising such compounds will at times be referred to as “Tyrphostin compositions”.
Out of the tyrphostins of formula I, some are known, albeit for uses other than those provided by the invention, and others are novel. The novel tyrphostins, which constitute another, independent aspect of the invention, are those of formula I, wherein Ar, R
1
R
2
and R
3
are as defined above, with the provisos that
a) R cannot be
b) when R is CN and n is 0, then
(ba) if one of R
1
and R
2
is H or OH, then the other cannot represent NO
2
;
(bb) if one of R
1
and R
2
is H or F, then the other cannot represent H or F; and
c) when R
1
is 4-NO
2
, R
2
is H and n is 0, then R cannot represent—C(O)NH
2
or —C(S)NH
2
.
Preferred compounds of formula I for use in the compositions are those wherein R is CN, —C(S)NH
2
, —C(O)NHCH
2
C
6
H
5
or a group of the formula
and n is 0, R
1
is 4-NO
2
and R
2
is H.
Examples of tyrphostins are shown in compound Table I. Some of the tyrphostins shown in Compound Table I are novel, and these novel tyrphostins are shown also in Compound Table II.
Compound Table I

No.
R
R1
R2
m.p. ° C.
Ref.
1
AG1714
CN
4-NO
2
H
153
1

AG1791
4-NO
2
H
238
2

AG1744
4-NO
2
H
277
3

AG1820
4-NO
2
H
103
4

AG1822
4-NO
2
H
220
—

AG1801
4-NO
2
H
181
—

AG1824
4-NO
2
H
238
—

AG1823
4-NO
2
H
187
—

AG1798
4-NO
2
H

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