MXPA98002760A - Linking rar-gamma antagonist or rar-alpha agonist as inhibitor of the apopto - Google Patents

Abstract

The present invention relates to the use of at least one ligand selected from a specific agonist ligand at the RAR-alpha type receptors and a specific antagonist ligand at the RAR-y type receptors in the preparation of a pharmaceutical composition intended to decrease the percentage of apoptosis in at least one cell population. These compositions may particularly serve to treat a disease or disorder related to an excess of the percentage of apoptosis in at least one cellulose population.

Description

LINKING RAR-GAMMA ANTAGONIST OR RAR-ALPHA AGONIST AS AN APOPTOSIS INHIBITOR The present invention relates to the use of particular retinoids in the preparation of a pharmaceutical composition with a view to decreasing the percentage of apoptosis. There are two types of mechanisms involved in the death of cells. The first of a classical type is called necrosis. Morphologically, the necrosis is characterized by a swelling of the mitochondria and the cytoplasm and by a nuclear alteration, followed by the destruction of the cells and their autolosis, being accompanied by a phenomenon of inflammation. The necrosis occurs passively and incidentally. Tissue necrosis is usually due to a physical trauma of the cells or to a chemical poison, for example. The other form of cell death is called apoptosis [Kerr, J.F.R. and Wyllie, A.H., Br. J. Cancer, 265, 239 (1972)], but contrary to necrosis, apoptosis does not produce a phenomenon of inflammation. It is described that apostosis can occur under different physiological conditions. It is a highly selective form of cell suicide that REF: 27200 characterized by easily observable morphological and biochemical phenomena. Thus, a condensation of chromatin associated or not with endonuclease activity, the formation of apoptotic bodies and a fragmentation of deoxyribonucleic acid (DNA) by the activation of endonucleases in DNA fragments of 180-200 base pairs (these fragments can be observed by electrophoresis on agarose gel). Apoptosis can be considered as a programmed death of the cells involved in the development, differentiation and renewal of tissues. It is also considered that the differentiation, growth and maturation of the cells are closely related to apoptosis and that the substances capable of playing a role on the differentiation, growth and maturation of the cells are also related to the phenomenon of apoptosis Thus, in a human being with good health, there is a balance between all these phenomena. In the medical field, a certain number of pathological situations presents a mechanism of modified apoptosis, even mismatched, or a mechanism of apoptosis that does not provide a mismatch of another biological phenomenon to reach equilibrium. Thus, it is described that a voluntary modulation of apoptosis by inducing or repressing it can make it possible to treat numerous diseases related to an insufficiency of the percentage of apoptosis, such as in the case of cancer, autoimmune diseases or allergies, or on the contrary diseases related to an excess of the percentage of apoptosis, such as in the cases of human immunodeficiency virus (HIV) immunodeficiency syndrome, neurodegenerative diseases (Alzheimer's disease) or excessive damage induced in myocardial infarction. Specifically, numerous inhibitors of apoptosis have already been described, such as cycloheximide, cyclosporine and certain interleukins. In the field of retiniodes, it is known that all-trans retinoic acid is a potent modulator (ie an inhibitor or, on the contrary, a stimulator, depending on the nature of the cells treated) of the differentiation and proliferation of numerous normal or transformed cell types. For example, they inhibit the differentiation of epithelial cells, such as the keratinocytes of the epidermis. It also inhibits the proliferation of numerous transformed cells such as melanoma cells. These effects on proliferation and differentiation can simultaneously affect the same cell type, as is the case, for example, for human promyelocytic cells, referenced HL-60; Thus, it is known that the proliferation of these cells is inhibited by the all-trans and retinoic acid., at the same time, that its differentiation into granulocytes and its apoptosis is induced. It is generally known that all-trans retinoic acid (all-trans retinoic acid) acts on the differentiation and proliferation of cells interacting with nuclear receptors called RARs (Retinoic Acid Receptors) contained in the cell nucleus. There are, nowadays, three identified sub-types of RAR receptors called respectively RAR-a, RAR-ß and RAR- ?. These receptors, after ligand binding (ie all-trans retinoic acid), interact with the promoter region of genes regulated by retinoic acid at the level of specific response elements (RARE). To be fixed on the response elements, the RARs are heterodimerized with another type of receptors known under the name of RXRs. The natural ligand of the RXRs is 9-cis-retinoic acid. The RXRs are considered as "master regulatory proteins" because they interact with other members of the steroid / thyroid receptor superfamily to form heterodimers, such as the RARs, such as the vitamin D3 receptor (VDR), the triiodothyroxine receptor ( TR) and the PPARs (Peroxisome Proliferator Activated Receptors). In addition, RXRs can interact with specific response elements (RXRE) in the form of homodimers. These complex interactions and the existence of multiple receptors RARs and RXRs expressed differently depending on the tissue and the cell type explain the pleiyotropic effects of retinoids in practically all cells. Numerous synthetic structural analogs of the all-trans or 9-cis-retinoic acid retinoic acid, commonly referred to as "retinoids", have been described so far in the literature. Some of these molecules are capable of fixing and activating specifically the RARs or, on the contrary, the RXRs. In addition, some analogs can be set and activate a particular sub-type of RAR receiver (a, ß, or?). Other analogues, finally, do not exhibit any particular selective activity with respect to these different receptors. In this regard, and for example, 9-cis-retinoic acid activates both RARs and RXRs, without notable selectivity for one or other of these receptors (nonspecific agonist ligand), while all-trans retinoic acid active, as for him, selectively the RARs (ligand agonists specific RARs), any sub-type confused. In a general and qualitatively way, a given substance (or ligand) is called specific to a given family of receptors (respectively with respect to a particular recipient of this family) when the indicated subtance has an affinity for the set of recipients of this family (respectively for the particular recipient of this family) stronger than the one that presents on the other hand for all the receivers of any other family (respectively for all other receivers, of this same family or not). It is described that 9-cis retinoic acid and all-trans retinoic acid are modulators of apoptosis (activator or inhibitor of apoptosis particularly depending on cell type) and that 9-cis retinoic acid is the most active of these two modulators, this can be explained by the fact that it activates both the RARs and the RXRs, contrary to the all-trans retinoic acid that only activates the RARs. Considering what has been said previously, it would seem interesting to find new modulators of apoptosis. In this regard, the applicant firm has just discovered that agonist ligands specific to RAR-a type receptors or ligand-specific antagonists to RAR-type receptors. they are excellent inhibitors of apoptosis in different cell types, and more particularly in thymocytes, this apoptosis having been induced by means of the RAR-? or receptors of T cells (T-cell receptors). Thus, the present invention has for its object the use of at least one ligand selected from a specific agonist ligand to the RAR-a type receptors and a specific antagonist ligand to the RAR-α type receptors. in the preparation of a pharmaceutical composition intended to decrease the percentage of apoptosis in at least one cell population. More particularly, the cell population corresponds to cells in which apoptosis can be regulated by induction and / or inhibition by means of the RAR-? and / or RAR-a or in which apoptosis can be regulated by induction by the T cell receptors. The pharmaceutical composition according to the invention comprises a physiologically acceptable medium. By agonist ligand specific to the RAR-a type receptors, it is understood according to the invention any agonist ligand having a dissociation constant for the RAR-a type receptors at least 10 times lower than its dissociation constant for the type receptors. RAR-? and that induces the differentiation of F9 cells. By "ligand-specific antagonist" to the RAR-α type receptors, it is understood according to the invention any ligand that has a dissociation constant for the RAR-α type receptors. at least 10 times lower than its dissociation constant for the RAR-a type receptors and which do not induce the differentiation of F9 cells. It is known in fact that all-trans retinoic acid and some of its analogs are capable of inducing the differentiation of mouse embryonic teratocarcinoma (F9) cells, they are then considered as agonists to RAR receptors. The secretion of the plasminogen activator that accompanies this deference is an index of the biological response of F9 cells to retinoids (Skin pharmacol, 1990; 3: pages 256-267). The dissociation constants are determined by means of classical tests by the person skilled in the art. These assays are particularly described in the following references: (1) "Selective Synthetic Ligands for Nuclear Retinoic Acid Receptor Subtypes" in RETINIODS, Progress in Research and Clinical Applications, Chapter 19 (pages 2.61-267), Marcel Dekker Ine, edited by Maria A. Livrea and Lester Packer; (2) "Synthetic Retinoids: Receptor Selectivity and Biological Activity" in Pharmacol Skin, Basel, Karger, 1993, Volume 5, pages 117-127; (3) "Selective Synthetic Ligands for Human Nuclear Retinoic Acid Receptors" in Skin Pharmacology, 1992, Vol. 5 pages 57-65; (4) "Identification of Synthetic Retinoids with Selectivity for Human Nuclear Retinoic Acid Receptor-?" in Biochemical and Biophysical Research Communications, Vol. 186, No. 2, July 1992, pages 977-983; (5) "Selective High Affinity RAR-a or RAR-ß Retinoic Acid Receptor Ligands" in Mol. Pharmacol., Vol 40. pages 556-562. Other characteristics, aspects, objects and advantages of the invention will appear even more clearly with the reading of the description that follows, as well as of the various concrete examples, but in a limiting manner, intended to illustrate it. Among the agonist ligands specific for the RAR-a type receptors, there can be particularly mentioned 4- ((5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalenyl) carboxamido) benzoic, 4- ((5, 6,7,8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalenyl) carbamoyl) benzoic acid and 2-hydroxy-4- (5,5,8) acid , 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalene-2-carboxamide) -benzoic acid. Preferably, among the agonist ligands specific for receptors of the RAR-a type, at least one agonist ligand having a dissociation constant for the RAR-a type receptors at least 20 times lower than its equivalent is used in the present invention. dissociation constant for the RAR-? type receptors such as 4- ((5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-n-phthalenyl) carboxamido) benzoic acid and the acid 2-hydroxy-4- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxamido) -benzoic acid. Among the antagonist ligands specific to RAR-receptores type receptors, mention may be made in particular of 2-hydroxy-4- [7- (l-4- [7- (1-adamantyl) -6-benzyloxy-2-naphthyl] ] benzoic acid, 2-hydroxy-4- [7-adamantyl) -6-hexyloxy-2-naphthyl] benzoic acid, 4- [7- (l-adamantyl) -6-methoxyethoxymethoxy-2-naphthylbenzoic acid, the acid 5- [7- (1-adamantyl) -6-benzyloxy-2-naphthyl] -2-thiophenecarboxylic acid, 4- [7- (1-adamantyl) -6-benzyloxy-2-naphthyl] benzoic acid; - [7- (1-adamantyl) -6-benzyloxycarbonyl-2-naphthyl] benzoic acid, 2-hydroxy-4- [7- (1-adamantyl) -6- (4-fluorobenzyl) oxy-2-naphthylbenzoic acid, 4- [7- (1-adamantyl) -6-heptyloxy-2-naphthyl] benzoic acid, 6- [7- (1-adamantyl) -6-methoxyethoxymethoxy-2-naphthyl] nicotinic acid, 2- hydroxy-4- [7- (1-adamantyl) -6-methoxyethoxymethoxy-2-naphthyl] benzoic acid, 2-chloro-4- [7- (1-adamantyl) -6-methoxyethoxymethoxy-2-naphthyl] benzoic acid, 4- [7- (l-adamantyl) -6-methoxybutyloxy-2-naphthyl] benzoic acid, 4- [7- (1-adamantyl) -6-methoxymethoxypropyl-2-naphthylbenzoic acid, 4- [7- (1-adamantyl) -6-methoxyethoxypropyl-2-naphthylbenzoic acid and 4- [7- (1-adamantyl)] -6-acetyloxybutoxy-2-naphthylbenzoic acid. Preferably, the agonist ligands specific for RAR-? Type receptors are used in the present invention, at least one antagonist ligand having a dissociation constant for the RAR-type receptors? at least 20 times lower than its dissociation constant for RAR-a type receptors, such as 4- [7- (1-adamantyl) -6-methoxyethoxymethoxy-2-naphthylbenzoic acid.

Thus, the pharmaceutical composition according to the invention can be used when a decrease in the percentage of apoptosis is necessary for at least one cell population. More particularly, the cell population corresponds to cells in which apoptosis can be regulated by induction and / or inhibition by means of RAR-γ-type receptors. and / or RAR-a or in which apoptosis can be regulated by induction by means of T cell receptors, and therefore particularly in cell populations where RAR-? and / or RAR-a or T cell receptors are present, such as for example in cells from the thymus where these three types of receptors are present. A decrease in the percentage of apoptosis may be necessary when there is an excess percentage of apoptosis, resulting in this excess of genetic or acquired conditions presented by the person to whom it is desired to administer the pharmaceutical composition. These genetic or acquired conditions favor the accumulation of signals that induce apoptosis or lower the threshold at which these signals induce apoptosis. Among the diseases or disorders related to an excess percentage of apoptosis, mention may be made more particularly of the immunodeficiency syndrome of the human immunodeficiency virus (HIV), neurodegenerative diseases, myelodysplastic syndromes (such as aplastic anemia), ischemic syndromes (such as myocardial infarction), liver diseases induced by toxins (such as alcohol), alopecia, skin damage due to UV rays, lichen planus, skin atrophy , the cataract or also the rejection of transplants. Thus, in neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other diseases related to brain degeneration, such as Creutzfeld Jakob disease, may be more particularly cited. The administration of the composition according to the invention can be carried out enterally, parenterally, topically or ocularly. Preferably, the pharmaceutical composition is packaged in a form that is suitable for systemic application (for injection or perfusion). By enteral route, the composition, more particularly the pharmaceutical composition, can be presented in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid or polymeric vesicles that allow a controlled release. Parenterally, the composition can be in the form of solutions or suspensions for perfusion or injection. Ligands selected from agonist ligands specific for RAR-a type receptors and antagonist ligands specific for RAR-a type receptors. used according to the invention are generally administered at a daily dose of about 0.01 mg / kg to 100 mg / kg of body weight in 1 to 3 doses. Topically, the pharmaceutical or cosmetic composition according to the invention is more particularly intended for the treatment of the skin and mucous membranes and can be presented in the form of ointments, creams, milks, ointments, powders, tampons, soaked , of solutions, of gels, of sprays, of lotions or of suspensions. It can also be in the form of microspheres or nanospheres or lipid or polymeric vesicles or polymer patches and hydrogels that allow a controlled release. This topical composition can be presented either in anhydrous form, or in an aqueous form. By ocular route, they are mainly eye drops. 1 Ligands selected from agonist ligands specific for RAR-a type receptors and antagonist ligands specific for RAR-a type receptors. they are used topically or ocularly at a concentration generally comprised between 0.001% and 10% by weight, preferably between 0.1 and 1% by weight, relative to the total weight of the composition. The compositions, as described above, can of course also contain inert or even pharmacodynamically active additives or combinations of these additives, and particularly: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or cojic acid, emollients; moisturizing agents such as glycerol, PEG 400, thiamorfolia, and their derivatives or else urea; anti-seborrheic or anti-acne agents, such as S-carboxymethyl-cysteine, S-benzyl-cysteamine, its salts or derivatives thereof, or benzoyl peroxide; antifungal agents such as ketoconazole or the 4,5-polymethylene-3-isothiazolidones; antibacterials, carotenoids and, particularly, ß-carotene; anti-psoriatic agents such as anthralin and its derivatives; and finally the acids 5, 8, 11, 14, -teicinoic eicosa and trichoic 5, 8, 11-eicosa, their esters and amides. These compositions may also contain flavor enhancers, preservatives such as parahydroxybenzoic acid esters, stabilizing agents, moisture regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifying agents, UV-A and UV filters. -B, antioxidants, such as α-tocopherol, butylated hydroxyanisole or butylated hydroxytoluene. Of course, the person skilled in the art will take care to choose the one or more compounds to be added to these compositions in such a way that the advantageous properties intrinsically related to the present invention are not substantially altered by the considered addition. A number of examples intended to illustrate the present invention will be given below, by way of limitation, in no way limiting.

EXAMPLE 1 This example demonstrates the in vitro efficacy as an inhibitor of apoptosis of ligand antagonists specific for RAR- ?, the apoptosis having been induced by other retiniodes.

Culture and preparation of cells Thymocyte suspensions were prepared from the thymus glands of 4 week old NMRI male mice (sold by the LATÍ Society, Gódóllo, Hungary) untreated. The medium used is Sigma RPMI 1640 medium supplemented in fetal calf serum from Gibco, 2mN glutamine, 100UI penicillin and 100 μg streptomycin / ml. The thymocytes were then washed and diluted to obtain a final concentration of 107 cells / ml, before incubation at 37 ° C in a humidified incubator under an atmosphere of 5% C02 and 95% air. The death of the cells was measured by taking trypan blue.

Qualitative and quantitative DNA analysis The thymocytes were incubated in 24 wells with various compounds to be tested. After 6 hours of incubation, 0.8 ml of cell suspensions were subjected to lysis by the addition of 0.7 ml of lysis buffer containing 0.5% (v / v) of Triton X-100, 10 mM Tris. , 20mM EDTA, pH 8.0, before centrifugation for 15 minutes at 13000g.

- Quantitative DNA analysis: The DNA content in the supernatant (the fragments) and the residue (intact chromatin) was precipitated with an equivalent amount of 10% trichroacetic acid, suspended again in 5% trichloroacetic acid, then quantified using the diphenylamine reagent (Burton, K. (1956) Biochem J. 62, 315-322). - Qualitative DNA analysis: At the same time, the supernatant was precipitated overnight in ethanol containing 0.15 mM NaCl. The residues were redissolved in a buffer containing 10 mM Tris, 1 mM EDTA, pH 8.0, treated with RNase, sequentially extracted with the same volume of phenol, chloroform / isoamyl alcohol (24/1) and precipitated in ethanol before of electrophoresis for 3 hours at 60V in 1.8% agarose gel. The DNA fragments were then visualized by UV after the gel was colored with ethidium bromide. The gels obtained present the image of a scale of multiple DNA fragments of 180 to 200 base pairs typical of an induction of apoptosis. The degree of fragmentation is related to the number of positive dead cells according to the trypan blue test throughout the trials. The results of the quantitative analysis are indicated in Table 1 below.

Table ATRA is the retinoic acid all-trans 9-cisRA is the acid 9-cis retinoic acid CD437 is the acid 6, 3- (1-adamantyl) -4-hydroxyphenyl) -2- naphtanic acid CD2665 is the acid 4- [7- ( 1-adamanti1) -6- methoxyethoxymethoxy-2-naphthylbenzoic acid. The percentage of DNA fragment in this table corresponds to the difference in percentage of DNA fragment obtained in treated thymocytes and the percentage of DNA fragment obtained in untreated thymocytes (basal percentage of apoptosis of these thymocytes). This table clearly shows that the apoptosis induced by ATRA, 9-cisRA and CD437 is inhibited by CD2665, which is a specific antagonist ligand of the RAR-? Receptors.

EXAMPLE 2 This example demonstrates the in vitro efficacy as an inhibitor of RAR-a-specific agonist ligand apoptosis, with apoptosis being induced by another retinoid. The procedure was carried out in the same manner as in the preceding example, modifying the nature of the ligands to be tested and their concentration. Thus, CD437 (6-, 3- (1-adamantyl) -4-hydroxyphenyl) -2-naphthanoic acid) (at a single concentration) was incubated with the thymocytes in the presence of different concentrations of CD336 (4- (5 , 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-22-naphthalenyl) carboxamido) enzoic). Table 2 below groups the results obtained.

Table 2 The percentage of DNA fragment in this table corresponds to the percentage difference of DNA fragment obtained in treated thymocytes and the percentage of DNA fragment obtained in untreated thymocytes (basal percentage of apoptosis of these thymocytes). Thus, this table clearly shows that the apoptosis induced by CD437 which is a specific agonist ligand of the RAR-? tare inhibited in a dose-dependent manner by CD336 which is a specific agonist ligand of the RAR-a type receptors.

EXAMPLE 3 This example demonstrates the in vitro efficacy as an inhibitor of RAR-a specific agonist ligand apoptosis, apoptosis having been induced by the activation of a T cell receptor. The procedure was carried out in the same way as in Example 1, modifying the nature of the compounds to be tested and their concentration. It is known that T cells differentiate into mature T lymphocytes in the thymus. During this differentiation, T cells proliferate and generate receptors on T cells. Cells that express receptors on potentially autoreactive cells and that interreact with cells that present an antigen undergo apoptosis (negative selection) (Smith et al. (1989) Nature 337, 181-184). In vitro, this selection can be mimicked by stimulating the CD3 molecule associated with a receptor to T cells by simultaneously adding phorbol dibutyrate and an ionophore Ca ++ (Iseki et al (1991) J. Immunol 147, 4286-4292). Thus, phorbol dibutyrate (5ng / ml) and Ca ++ ionophore (0.5 μM) were incubated with thymocytes in the absence or in the presence of different concentrations of CD336 (4- ((5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalenyl) carboxamido)) benzoic acid). Table 3 below groups the results obtained.

Table P + C means phorbol dibutyrate (5ng / ml) and an ionophore Ca ++ (0.5 μM) The percentage of DNA fragment in this table corresponds to the percentage difference of fragment of DNA obtained in treated thymocytes and the percentage of DNA fragment obtained in untreated thymocytes (basal percentage of apoptosis of these thymocytes).

Thus, this table clearly shows that apoptosis induced by P + C is inhibited in a dose-dependent manner by CD336 which is a specific agonist ligand of the RAR-a type receptors.

EXAMPLE 4 This assay shows the in vivo efficiency of the RAR-β-specific antagonist ligand. as an inhibitor of apoptosis, apoptosis having been induced by a RAR-? specific agonist ligand. Male NMRI mice were used for 4 weeks (sold by the LATÍ Society, Godóllo, Hungary). For the induction of apoptosis in the thymus, these male animals were treated by single intraperitoneal injection with 0.5 mg of 6-, 3- (1-adamantyl) -4-hydroxyphenyl) -2-naphtanoic acid, dissolved in 40 μl of DMSO and 0.5 ml of 20% ethanol. To see the inhibitory effect of apoptosis induced by a specific agonist ligand of RAR-? in the thymus, the male mice were treated by single intraperitoneal injection with a mixture of 0.5 mg of 6-, 3- (1-adamantyl) -4-hydroxyphenyl) -2-naphtanoic acid (CD437) and of 5 mg of 4 - [7- (1-adamantyl) -6-methoxyethoxymethoxy-2-naphthyl] benzoic acid (CD2665), this mixture having been dissolved in 40 μl of DMSO and 0.5 ml of 20% ethanol. For control, male mice were treated by single intraperitoneal injection of a mixture of 40 μl of DMSO and 0.5 ml of 20% ethanol. CD2665 was likewise tested only under the same conditions as above in 0.5 mg. The thymus weight was determined after 48 hours of treatment, the results are shown in Table 4 below.

Table Thus, an involution of the type is observed after a treatment with CD 437 alone, no significant change was observed with CD 2665, while the association of CD 2665 and CD 437 presents a much less important involution of the thymus than that observed with CD 437 alone.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Having described the invention as above, property is claimed as contained in the following:

Claims (9)

1. Use of at least one ligand selected from a specific agonist ligand to the RAR-a type receptors and a specific antagonist ligand to the RAR-α type receptors. in the preparation of a pharmaceutical composition intended to decrease the percentage of apoptosis in at least one cell population.

2. Use according to the preceding claim, characterized in that the cell population corresponds to cells in which apoptosis can be regulated by induction and / or inhibition by means of receptors of RAR-? Types. and / or RAR-a or in which apoptosis can be regulated by induction by means of T-cell receptors.

3. Use according to one of the preceding claims, characterized in that the specific antagonist ligand to the RAR-α type receptors is chosen from 2-hydroxy-4- [7- (1-adamantyl) -6-benzyloxy-2-naphthylbenzoic acid. , 2-hydroxy-4- [7- (1-adamantyl) -6-hexyloxy-2-naphthylbenzoic acid, 2 4- [7- (1-adamantyl) -6-methoxyethoxymethoxy-2-naphthylbenzoic acid; 5- [7- (1-adamantyl) -6-benzyloxy-2-naphthyl] -2-thiophenecarboxylic acid; - [7- (l-adamantyl) -6-benzyloxy-2-naphthylbenzoic acid, 4- [7- (1-adamantyl) -6-benzyloxycarbonyl-2-naphthylbenzoic acid, 2-hydroxy-4- [7- (1-adamantyl) -6- (4-fluorobenzyl) oxy-2-naphthylbenzoic acid, 4- [7- (1-adamantyl) -6-heptyloxy-2-naphthylbenzoic acid, 6- [7- (1- adamantyl) -6-methoxyethoxymethoxy-2-naphthyl] nicotinic acid, 2-hydroxy-4- [7- (1-adamantyl) -6-methoxyethoxymethoxy-2-naphthylbenzoic acid, 2-chloro-4- [7- ( 1-adamantyl) -6-methoxyethoxymethoxy-2-naphthyl] benzoic acid, 4- [7- (l-adamantyl) -6-methoxybutyloxy-2-naphthyl] benzoic acid, 4- [7- (1-adamantyl)] -6-methoxymethoxyproxy-yl-2-naphthylbenzoic acid, 4- [7- (1-adamantyl) -6-methoxyethoxypropyl-2-naphthylbenzoic acid and 4- [7- (1-adamantyl) -6-acetyloxybutoxy-2] -naftiljbenzoico.

4. Use according to one of the preceding claims, characterized in that the antagonist ligand specific to the RAR-α-type receptors. presents a dissociation constant of this ligand for the RAR-? at least 20 times lower than the dissociation constant of this ligand for the RAR-a type receptors, such as 4- [7- (1-adamantyl) -6-methoxyethoxymethoxy-2-naphthylbenzoic acid.

5. Use according to claim 1, characterized in that the agonist ligand specific to the RAR-a type receptors has a dissociation constant for the RAR-a type receptors at least 20 times lower than its dissociation constant for the type receptors. RAR- ?.

6. Use according to one of claims 1, 2 and 5, characterized in that the ligand agonist specific to the type receptors RAR-a is chosen from 4- ((5, 6, 7, 8-tetrahydro-5,5,8, 8-tetramethyl-2-naphthalenyl) carboxamido) benzoic acid and 2-hydroxy-4- (5-hydroxy) acid. , 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxamido) -benzoic acid.

7. Use according to any one of the preceding claims, characterized in that the pharmaceutical composition is intended to treat diseases related to an excess of the percentage of apoptosis.

8. Use according to the preceding claim, characterized in that the diseases related to an excess of the percentage of apoptosis are selected from the immunodeficiency syndrome of the human immunodeficiency virus (HIV), the neurodegenerative diseases, the myelodysplastic syndromes, the ischemia syndromes, the diseases of the liver induced by toxins, alopecia, skin damage due to UV rays, lichen planus, skin atrophy, cataracts or also the rejection of transplants.

9. Use according to the preceding claim, characterized in that the neurodegenerative diseases are selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other diseases related to brain degeneration, such as Creutzfeld Jakob disease.