Uses of novel organoselenium compounds with pro-oxidant...

Details Uses of novel organoselenium compounds with pro-oxidant... Uses of novel organoselenium compounds with pro-oxidant...

2000-08-28

2002-06-18

Kifle, Bruce (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S183000, C514S359000, C540S108000, C540S117000, C540S132000, C544S001000, C548S121000

Reexamination Certificate

active

06407083

ABSTRACT:

The present invention relates to the use of novel organoselenium compounds as pro-oxidizing agents, their methods of preparation and pharmaceutical compositions and application thereof.
PRIOR ART
The reactive oxygen entities (ROEs), such as, for example, the superoxide anion (O
2
−
) and hydrogen peroxide (H
2
O
2
), coming from metabolism of oxygen, generated within the cell are under the control of the antioxidizing protection system. This system is composed in particular of macromolecules with enzymatic activity such as superoxide dismutases (SOD), catalase and glutathione peroxidases, as well as small molecules with high reducing potential such as, for example, glutathione, vitamin E, vitamin C and lipoic acid. This antioxidizing system plays a central role in the prevention of <<oxidative stress>> and its deleterious consequences (1).
In normal physiological situations, an equilibrium between the production and the decomposition of these reactive oxygen entities (ROEs) already exists in the cell. If this fragile equilibrium becomes durably disrupted under the influence of a physical stimulus (UV, ionizing radiation, . . . ), or an internal chemical stimulus (cytokines), or an external chemical stimulus (xenobiotics, cigarettes, . . . ) the production of these ROEs surpassing the antioxidizing protection system, the cellular structures (membranes, mitochondria, DNA, . . . ) are destroyed. This phenomenon being able to lead irreversibly to cellular death if this imbalance attains a critical threshold. This general physiopathological mechanism has been proposed in a large number of diseases such as inflammatory diseases (see Ann. Rev. Physiol.; 1986, 48, 681-692 and Ann. Rev. Resp. Dis. 1989, 139, 1553-1564), cardiovascular diseases (see Free Radic. Biol. Med.; 1994, 16, 35-41), the genesis of certain cancers (see Science; 1983, 221, 1256-1264 and Ann. Rev. Pharmacol. Toxicol.; 1985, 25, 509-528 as well as Free Radic. Biol. Med.; 1994, 16, 99-109) as well as for the phenomenon of ageing.
The controlled generation of these ROEs has proved to be formidable weapon for the destruction of certain target cells such as tumor cells. The pharmacological concept consisting in the use of cytotoxic drugs which generate reactive oxygen entities was implicitly bound to the mode of action of anti-cancer drugs such as, for example, bleomycin (see <<Bleomycin: chemical, biochemical and biological aspects>>; Hecht S. M. ed.; (1979); Springer Verlag, N.Y.; 24) whose target is DNA, anthracyclines (daunorubicin, daunomycin, . . . ) (see P. N. A. S.; 1986, 83, 4514 and Biochem.; 1987, 26, 3776), mitomycin C and its analogues (Int. J. Radiat. Oncol. Biol. Phys.; 1979, 5, 851), nitroimidazoles (misonidazole, pimonidazole, . . . ) (see Int. J. Radiat. Oncol. Biol. Phys.; 1992, 22, 643 and 649) amongst others.
Furthermore, it has been demonstrated that the toxicity of organoselenium compounds of the selenol and/or diselenide type is in a large part due to the catalytic reduction of oxygen giving superoxide and hydrogen peroxide (see Arch. Biochem. Biophys.; 1992, 296, 328-336).
On the other hand, various benzisoselenazolines and benzisoselenazines were described by the Applicant in the prior U.S. Pat. No. 2,718,441 which possess a therapeutic activity as antioxidizing and anti-inflammatory agents. The substituents on the benzene ring can occupy any of the positions and no compound described possesses an aromatic substituent in a position ortho to the selenium, with the exception of one sole compound which possesses a nitro substitution in ortho combined with a dimethyl substitution in benzylic position.
One of the aims of the present invention is to conceive organoselenium compounds possessing a catalytic pro-oxidizing activity, i.e. an activity generating reactive oxygen entities which can destroy a target cell, in particular a pathogenic cell, such as a tumor cell.
These compounds must be able to penetrate the interior of the target tissues or cells, they must be water-soluble at active concentrations and must efficiently reduce oxygen to give toxic by-products.
These aims are attained by this invention which consists in the design of novel organoselenium derivatives whose pro-oxidizing and cytotoxic activities as well as their methods of preparation are described.
It is completely surprising, in the framework of the present invention, that the organoselenium derivatives possess a pro-oxidizing activity, given that the organoselenium compounds described in the prior application of the applicant, FR-A-94 04107, which had been shown to possess an anti-oxidizing activity and had been tested as such. From this fact, although it had been described that the radicals R
1
and R
2
could stand for —NO
2
, in general, their position on the benzene ring was not specified and only one example described the synthesis of a derivative bearing a nitro group in the position ortho to the selenium on the benzene ring. This compound was claimed as a novel compound, but was inactive as an anti-oxidizing agent.
DESCRIPTION OF THE INVENTION
The aim of the present invention is:
1) to solve the novel technical problem consisting in providing novel organoselenium derivatives possessing excellent pro-oxidizing and cytotoxic activities, which can thus constitute a valuable active ingredient in the framework of pharmaceutical compositions;
2) to solve the novel technical problem, set forth above, with a solution which also provides a method for the preparation of these compounds which is relatively easy to carry out;
These aspects of the technical problem- described above are simultaneously solved by the present invention by a simple solution, with a preparation method which is relatively easy to carry out and which gives good yields.
In a first aspect, the present invention provides novel organoselenium compounds of the following general formula(I):
General Formula I
wherein:
R
1
is selected from a group consisting of: hydrogen; C
1
-C
6
alkyl; ar(C
1
-C
6
)alkyl; ar(C
1
-C
6
)alkyl substituted on aryl by one or more identical or different groups selected from C
1
-C
6
alkyl, trifluoromethyl, C
1
-C
6
alkoxy, hydroxyl, nitro, amino, C
1
-C
6
alkylamino, di(C
1
-C
6
-alkyl)amino, sulfonyl, sulfonamide, sulfo(C
1
-C
6
-alkyl), —CO
2
H, and —CO
2
—(C
1
-C
6
)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C
1
-C
6
alkyl, trifluoromethyl, C
1
-C
6
alkoxy, hydroxyl, nitro, amino, C
1
-C
6
alkylamino, di(C
1
-C
6
-alkyl)amino, sulfonyl, sulfonamide, sulfo(C
1
-C
6
-alkyl), —CO
2
H, and —CO
2
—(C
1
-C
6
)alkyl; —COR
8
; —COOR
8
; —CONH
2
; —CONR
8
R
9
; —(CH
2
)
p
R
10
; and —(CH
2
)
p
Vect;
R
2
is selected from the group consisting of: hydrogen; C
1
-C
6
alkyl; ar(C
1
-C
6
)alkyl; ar(C
1
-C
6
)alkyl substituted on aryl by one or more identical or different groups selected from C
1
-C
6
alkyl, trifluoromethyl, C
1
-C
6
alkoxy, hydroxyl, nitro, amino, C
1
-C
6
alkylamino, di(C
1
-C
6
-alkyl)amino, sulfonyl, sulfonamide, sulfo(C
1
-C
6
-alkyl), —CO
2
H, and —CO
2
—(C
1
-C
6
)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C
1
-C
6
alkyl, trifluoromethyl, C
1
-C
6
alkoxy, hydroxyl, nitro, amino, C
1
-C
6
alkylamino, di(C
1
-C
6
-alkyl)amino, sulfonyl, sulfonamide, sulfo(C
1
-C
6
-alkyl), —CO
2
H, and —CO
2
—(C
1
-C
6
)alkyl; —COR
8
; —COOR
8
; —CONH
2
; —CONR
8
R
9
; —(CH
2
)
p
R
10
; and —(CH
2
)
p
Vect;
R
3
is selected from the group consisting of: hydrogen; C
1
-C
6
alkyl; ar(C
1
-C
6
)alkyl; ar(C
1
-C
6
)alkyl substituted on aryl by one or more identical or different groups selected from C
1
-C
6
alkyl, trifluoromethyl, C
1
-C
6
alkoxy, hydroxyl, nitro, amino, C
1
-C
6
alkylamino, di(C
1
-C
6
-alkyl)amino, sulfonyl, sulfonamide, sulfo(C
1
-C
6
-alkyl), —CO
2
H, and —CO
2
—(C
1
-C
6
)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C
1
-C
6
alkyl, trifluoromethyl, C
1
-C
6
alkoxy, hydroxyl, nitro, amino, C
1
-C
6
alkylamino, di(C
1
-C
6
-alkyl)amino, sulfonyl,

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