MXPA98002761A - Use of a rar-gamma specific agonist ligand to increase the percentage of apopto - Google Patents

Abstract

Use of at least one specific agonist ligand to the RAR-y type receptors in the preparation of a pharmaceutical composition intended to increase the percentage of apoptosis in at least one cell population for which apoptosis can be induced by activation of the receptors of RAR-y type. This composition can be used in particular to treat a disease or a disorder associated with an insufficiency of the percentage of apoptosis in at least one cell population for which apoptosis can be induced by activation of the RAR-y receptors. Use of at least specific agonist ligand to the RAR-y type receptors in a cosmetic composition as an apoptosis inducer. This composition can make it possible to prevent and / or fight against the photo-induced or chronological aging of the pi

Description

USE OF A RAGGAMMA SPECIFIC AGONIST TO INCREASE THE PERCENTAGE OF APOPTOSIS The present invention relates to the use of particular retinoids in the preparation of a pharmaceutical composition with a view to increasing the percentage of apoptosis. These retinoids can also be used in pharmaceutical compositions with a view in particular to preventing and / or combating the photo-induced or chronological aging of the skin. 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 yllie, A.H., Br. J. Cancer, 265, 239 (1972)], but contrary to necrosis, apoptosis does not produce a phenomenon of inflammation. HE REF: 27199 describes that apostosis can occur under different physiological conditions. It is a highly selective form of cell suicide that is 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 In the medical field, a certain number of pathological situations presents a mechanism of modified apoptosis, even mismatched. 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 a cellular hyperproliferation, such as in the case of cancer, autoimmune diseases or allergies, or on the contrary related diseases. with a cellular disappearance, 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, it has been observed in oncology that numerous anticancer drugs, such as dexamethasone, cyclophosphamine and cisplatin, are capable of inducing apoptosis. In the field of cosmetics, the signs of skin aging result essentially from a dysfunction of the main biological mechanisms of the skin, making the mechanism of apoptosis particularly involved. It can therefore be thought that any product that induces the mechanism of apoptosis is a product able to prevent and / or fight against the onset of aging and the signs of aging, such as small wrinkles.

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 treated cells) 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 all-trans retinoic acid and, at the same time, that their differentiation into granulocytes and their 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, today, 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, the 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 (non-specific agonist ligand), while all-trans retinoic acid active, as for him, selectively the RARs (ligand specific agonist 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 substance 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 RARs and RXRs at the same time, contrary to the all-trans retinoic acid that only activates the RARs. Considering what has been said previously, it seems interesting to find new modulators of apoptosis. In this regard, the applicant firm has just discovered that the agonist ligands specific to the RAR-? they are excellent inducers of apoptosis in different cell types, and more particularly in thymocytes. Thus, the present invention has for its object the use of at least one agonist ligand specific to the RAR-α-type receptors. in the preparation of a pharmaceutical composition intended to increase the percentage of apoptosis in at least one cell population for which apoptosis can be induced by the activation of the RAR-? type receptors. Another subject of the invention is the use of at least one agonist ligand specific to the RAR-α-type receptors. in a cosmetic composition as an apotosis inducer of at least one cell population of the skin for which apoptosis can be induced by activation of the RAR-? receptors. Thus, this composition can make it possible to prevent and / or combat the photo-induced or chronological aging of the skin, particularly by eliminating apoptosis of the skin cells that have a deficiency in their reparative function and that accumulate with time. Finally, the subject of the invention is a cosmetic process for preventing and / or combating photoinduced or chronological aging of the skin, characterized in that a cosmetic composition inducing apoptosis is applied to the skin as described above. The pharmaceutical or cosmetic composition according to the invention comprises a physiologically acceptable medium. By agonist ligand specific to the RAR-α type receptors, it is understood according to the invention any agonist ligand having an R ratio of the dissociation constant of this ligand for the RAR-a type receptors with respect to the dissociation constant of this ligand for the RAR-type receptors? greater than or equal to 10 and that 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: 256-267 pages). 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 261-267), Marcel Dekker Inc, 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 specific agonist ligands to the RAR-receptores type receptors, mention may be made in particular of 6-, 3- (1-adamantyl) -4-hydroxyphenyl) -2-naphtanoic acid, (E) -4- (1-) acid hydroxy-1- (5,6,7,8-tetrahydro-5, 5,8,8-tetramethyl-2-naphthyl) -2-prometyl) benzoic acid, 4 - [(E) -2- (3- (1-adamethyl) -4-hydroxyphenyl) -l-prometyl] benzoic acid, 5 ', 5', 8 ', 8' -tetramethyl-5 ', 6', 7 ', 8' -tetrahydro- [2, 2 '] binaphthalenyl-6-carboxylic acid, 2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -benzo [b] thiophene-6-carboxylic acid , 4- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphtho [2,3-b] thiophen-2-yl) benzoic acid, 6- (5, 5) acid , 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalene-2-carbonyl) -naphthalene-2-carboxylic acid, 3,7-dimethyl-7- (1, 2,3,4-tetrahydro) -l, 4a, 9b-trimethyl-1,4-methane-dibenzofuran-8-yl) -2,4,6-heptatrienoic acid, 6- (1, 2, 3, 4-tetrahydro-l, 4a, 9b -trimethyl-1,4-methane-dibenzofuran-8-yl) -naphthalene-2-carboxylic acid, 6- [hyd] Roxylimino- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tatrahydro-naphthalen-2-yl) -methyl] -naphthalene-2-carboxylic acid, 4 - [(6-hydroxy-7 - (1-adamantyl) -2-naphthyl] -benzoic acid, 5- (5, 5,8,8-tetramethyl-5,6,7,8-tetrahydro-anthracen-2-yl) -thiophen-2-acid carboxylic acid, (-) - 6 - [hydroxy- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -methyl] naphthalene-2-carboxylic acid, 6- (3-adamantyl-l-yl-4-prop-2-ynyloxyphenyl) -naphthalene-2-carboxylic acid, 4- [2-oxo-2- (5, 5, 8, 8-tetramethyl-5 , 6, 7, 8-tetrahydro-naphthalen-2-yl) -ethoxy] -benzoic acid, 4 - [- oxo-2- (5, 5, 8, 8-tetramethyl 5,6,7,8-tetrahydro) -naphthalen-2-yl) -acetylamino] -benzoic acid, 4- [2-fluoro-2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) ) acetylaminoj-benzoic acid, 6- [3- (l-adamantyl-4- (2-hydroxypropyl) phenyl-2-naphthoic acid, 5- [3-oxo-3- (5,5,8,8- tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -propenyl] -thiophene-2-carboxylic acid, 6- [3- (l-adamantyl-4- (2,3-dihydroxy) ropil) phenyl] -2-naphthoic, 4- [3-hydroxy- (5,6,7,8-tetrahydro-1,5,5,8,8-tetramethyl-2-naphthyl) -l-propynyl] - benzoic, 4- [3-oxo-3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -prop-1-ynyl] -benzoic acid, 4 - [(3- (1-methylcyclohexyl) -4-hydroxyphenyl) ethynyl-benzoic acid, 4 - [(E) 2- (3- (1-adamantyl) -4-hydroxyphenyl) e-tenyl] - benzoic, 4- [3- (1-adamantyl) -4-hydroxyphenylethynyl] -benzoic acid, 5- [3- (1-adamantyl) -4-hydroxyphenylethynyl] -2-thiophene carboxylic acid, 5- [ 3- (1-adamantyl) -4-methoxyphenylethynyl] -2-thiophene carboxylic acid, 4- [2- (3-tert-butyl-4-methoxyphenyl) -α-pentyl] benzoic acid, 4- acid. { 2- [4-methoxy-3- (1-methyl-cyclohexyl) -phenyl] -propenyl} -benzoic, 6- [3- (l-adamantyl) -4- (3-methoxy-2-hydroxypropyl) phenyl] -2-naphthoic acid, 2-hydroxy-4- [3-hydroxy-3- ( 5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl-9-l-propynyl] -benzoic acid, 6- (5, 5, 8, 8-tetramethyl-5,6, 7, 8-tetrahydro-naphthalen-2-yloxy) -naphthalene-2-carboxylic acid, 6- (5, 5,8,8-tetramethyl-5), 6, 7, 8-tetrahydro-naphthalen-2-ylsulfanyl) -naphthalene-2-carboxylic acid, 4- [2-propoxylimino-2- (5,5,8,8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -acetylaminoj-benzoic acid, 6- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -naphthalen-2 -carboxylic acid, l-methyl-4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-anthracen-2-yl) -lH-pyrrole-2-carboxylic acid, -methoxy-4- (5, 5, 8, 8-tetramethyl-5, 6,7, 8-anthrancen-2-yl) benzoic acid, 4- [2-nonyloxyimino-2- (5,5,8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -acetylaminojbenzoic acid, (-) - 2-hydroxy-4- [3-hydroxy-3- (5,5,8,8) -tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -prop-1-ynyl] -benzoic acid, (+) -2-hydroxy-4- [3-hydroxy-3- (5 , 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -prop-1-ynyl] -benzoic acid, 2-hydroxy-4- [3-hydroxy-3- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-22-yl) -but-1-ynyl] -benzoic acid, 6- (3-bromo-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yloxy) -naphthalene-2-carboxylic acid, 3 - [(5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl) - 2H-1-benzopyran] -7-carboxylic acid, 4- [3- (3, 5-di-tert-butyl-4-hydroxyphenyl) -prop-1-ynyl] -benzoic acid, 4- [3- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -prop-1-ynyl] -benzoic acid, 4- [3- (5,6,7) , 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-natyl) -l-propynyl] -salicylic acid, 4- [. { 3- (l-adamantyl) -4- (2-hydroxyethyl) phenyl} ethinyl] benzoic acid and 4- [. { 3- (1-adamantyl) -4- (3-hydroxypropyl) phenyl} ethinyl] -benzoic acid. Preferably, the agonist ligands specific for RAR-α-type receptors are used in the present invention. having a R ratio greater than or equal to 50. In this regard, it is preferred to use 6, 3- (1-adamantyl) -4-hydroxyphenyl) -2-naphtanoic acid, 6- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carbonyl) -naphthalene-2-carboxylic acid 6- (1, 2, 3, 4-tetrahydro-1,4a, 9b-trimethyl- 1,4-methane-dibenzofuran-8-yl) -naphthalene-2-carboxylic acid, 6- [hydroxyimino- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2) -yl) -methyl] -naphthalene-2-carboxylic acid, 5- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-anthracen-2-yl) -thiophen-2-carboxylic acid , (-) - 6- [Hydroxy- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) methyl] -naphthalene-2-carboxylic acid, the acid 6- [3- (l-adamantyl-4- (2-hydroxypropyl) phenyl] -2-naphtholic, 6- [3- (l-adamantyl-4- (2,3-dihydroxypropylphenyl) -2- Naphthoic, 4- [3- (1-adamantyl) -4-hydroxyphenylethynyl] -benzoic acid, 5- [3- (l-adamantyl) -4-hydroxyphenylethynyl] -2-thiophene carboxylic acid, 5- [ 3- (1-adamantyl) -4-methoxyphenylethynyl] -2-thiophene carboxylic acid, 6- [3- (1-adamantyl) -4- (3-methoxy-2-hydroxypropyl) phenyl] -2-naphtholic acid, acid -methyl-4- (5, 5,8,8-tetramethyl-5,6,7,8-tetrahydroanthra-2-yl) -2-yl) -lH-pyrrole-2-carboxylic acid, (-) - 2-hydroxy-4- [3-hydroxy-3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -prop-1-ynyl] -benzoic acid 2-hydroxy-4- [3-hydroxy-3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -but-1-ynyl] -benzoic acid " 6, 3- (1-Adamantyl) -4-hydroxyphenyl) -2'-naphtanoic acid is particularly preferred. Thus, the pharmaceutical composition comprising the agonist ligand specific to the RAR-α type receptors. it may be used when an increase in the percentage of apoptosis is necessary. Of course, this effect will only be obtained in cell populations for which apoptosis can be induced by the activation of RAR-? and therefore particularly where RAR-α type receptors are present, such as more particularly in the cells from the thymus. An increase in the percentage of apoptosis may be necessary in mainly two cases. The first refers to diseases or disorders related to a failure of the percentage of apoptosis. The second refers to the treatments needed during a transplant to reduce the effects of rejection of the transplanted organ. Indeed, it can be thought that the immunotolerance to the transplanted organ can be increased by decreasing the immune response of the T cells by inducing their percentage of apoptosis. Among the diseases or disorders related to an insufficiency of the percentage of apoptosis, we can mention more particularly the disorders due to precancerous conditions or cancers that may be the consequence of a proliferation of certain cell populations, autoimmune diseases, allergies or inflammatory reactions, in which a too high number of cells causing damage is observed, or also in certain viral infections in which the proteins of the virus have an anti-apoptotic effect. Thus, in autoimmune diseases, insulin-dependent diabetes, chronic active hepatitis, rheumatoid arthritis, pemphigus, plaque sclerosis, myasthenia, systemic lupus erythema, Crohn's disease and psoriasis In pre-cancerous conditions, actinic keratosis may be mentioned. In the case of cancer, one can more particularly cite lympholas, carcinomas, such as cancer of the O.R.L. sphere, and hormone-dependent tumors, such as cancers of the ovaries. Among the viral infections mentioned above, mention may be made of herpes viruses, adenoviruses and smallpox viruses (pox viruses). Among allergies or inflammatory reactions, we can mention contact eczema, atopic eczema, asthma and urticaria. The administration of the composition according to the invention can be carried out enterally, parenterally, topically or ocularly. Preferably, the pharmaceutical composition is conditioned in a form suitable for a 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.

The agonist ligands specific to the RAR-α 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 polymeric 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. The agonist ligands specific to the RAR-α type receptors are used topically or ocularly at a concentration generally between 0.001% and 10% by weight, preferably between 0.1 and 1% by weight, relative to the total weight of the composition. Finally, the subject of the present invention is a method for preventing and / or combating photoinduced or chronological aging of the skin, characterized in that a cosmetic composition inducing apoptosis is applied to the skin as described above, ie comprises in a cosmetically acceptable medium at least one specific ligand to the receptors of the RAR-? type. The compositions as described above may well be further understood to 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, thiamorpholinone, 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 test shows the in vivo efficacy of RAR-β-specific agonist ligand. as an inducer of apoptosis. Male NMRI mice were used for 4 weeks (sold by the LATÍ Society, G? ddllo, Hungary). For the induction of apoptosis in the thymus, these male animals were treated by single injection with either 0.5 mg of dexamethasone, or with 0.5 mg of the 6,3- (l-adamantyl) -4-hydroxyphenyl) -2-naphtanoic, dissolved in a mixture of 0.8 ml of physiological saline 0.2 ml of ethanol. Dexamethasone is a well-known inducer of apoptosis. Thus, an involution of the thymus is observed: thymus weight decrease of approximately 75%, 48 hours after the treatment indicated above. The same is true for 6, 3- (1-adamantyl) -4-hydroxyphenyl) -2-naphthoic acid for which a decrease in thymus weight of approximately 60% is observed 48 hours after treatment. In addition, in parallel to this test, thymus extractions were performed from untreated or treated animals at different times after treatment. After washing and homogenization, the transglutaminase activity was determined by detecting the incorporation of [3H] putrescine in N, N'-dimethylcasein. The activity of the transglutaminase was calculated in nmoles of [3 H] putrescine incorporated into the protein per hour. Tissue transglutaminase is described as one of the effector elements of apoptosis [Piacentini, M. et al. (1994) Apoptosis: the Molecular Basis of Apoptosis in Disease. Curr. Comm. in Cell & Mol. & Biol..8. (Tomei L.D. and Cope, F.O. de.) PP 143-165]. Thus, it is observed that the involution of the thymus described above resulting from the treatment of the mouse with a specific agonist ligand of RAR-? it is a concomitant event and proportional to the activity of tissue transglutaminase. In addition, this involution of the thymus is related to the appearance of DNA fragments after the analysis by electrophoresis on agarose gel of the DNA recovered from this treated thymus (details of the operative mode in Example 2).

EXAMPLE 2 This example demonstrates the in vitro efficacy as an inducer of RAR-? Specific ligand antagonist apoptosis compared to other types of retiniodes. 2 Culture and preparation of cells Suspensions of thymocytes 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 (fragments) and the residue (intact chromatin) was precipitated with an equivalent amount of 10% trichloracetic acid, suspended again in 5% trichloroacetic acid, then quantified using the diphenylamine reagent (Burton, K. (1956) Biochem J. 62, 315-322). - Qualitative analysis of DNA: In parallel, 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 CD666 is the acid (E) -4- (1-hydroxy-l- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -2-propenyl) benzoic acid, CD2325 is 4 - [(E) - 2- (3- (1-adamantyl) -4-hydroxyphenyl) -1-propenyl] benzoic acid, CD2019 is 6- (3- (1-methylcyclohexyl) -4-methoxyphenyl) -2-naphtanoic 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). These results show that the more R increases, the higher the percentage of appearance of DNA fragments increases. Thus, the more specific the RAR-? Ligand, the greater the effect of apoptosis inducer.

Claims (15)

1. Use of at least one specific agonist ligand to the RAR-? in the preparation of a pharmaceutical composition intended to increase the percentage of apoptosis in at least one cell population for which apoptosis can be induced by the activation of type receptors. RAR- ?.

2. Use according to the preceding claim, characterized in that the agonist ligand specific to the RAR-α type receptors. it is chosen from 6, 3- (1-adamantyl) -4-hydroxyphenyl) -2-naphthanoic acid, (E) -4- (1-hydroxy-1- (5,6,7,8-tetrahydro- 5, 5,8, 8-tetramethyl-2-naphthyl) -2-propenyl) benzoic acid, 4 - [(E) -2- (3- (1-adamyl) -4-hydroxyphenyl) -l-propenyl] benzoic, 5 ', 5', 8 ', 8'-tetramethyl-5', 6 ', 7', 8 '-tetrahydro- [2, 2'] binaphthalenyl-6-carboxylic acid, 2- (5 , 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -benzo [b] thiophene-6-carboxylic acid, 4- (5, 5, 8, 8-tetramethyl) -5,6,7,8-tetrahydro-naphtho [2,3-b] thiophen-2-yl) benzoic acid 6- (5,5,8,8-tetramethyl-5,6,7,8- tetrahydro-naphthalene-2-carbonyl) -naphthalene-2-carboxylic acid, 3,7-dimethy1-7- (1, 2, 3, 4-tetrahydro-1,4a, 9b-trimethyl-1,4-methane) dibenzofuran-8-yl) -2,4,6-heptatrienoic acid 6- (1, 2, 3, 4-tetrahydro-l, 4a, 9b-trimeti1-1, 4, -methane-dibenzofuran-8-yl ) -naphthalene-2-carboxylic acid, 6- [hydroxylimino- (5, 5, 8, 8-tetramethyl-5, 6,7, 8-tatrahydro-naphthalen-2-yl) -methyl] -naphthale n-2-carboxylic acid, 4 - [(6-hydroxy-7- (1-adamantyl) -2-naphthyl] -benzoic acid, 5- (5, 5,8,8-tetramethyl-5,6, 7, 8-tetrahydro-anthracen-2-yl) -thiophen-2-carboxylic acid, (-) -6- [hydroxy- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro) -naphthalen-2-yl) -methyl] naphthalene-2-carboxylic acid, 6- (3-adamantyl-l-yl-4-prop-2-ynyloxyphenyl) -naphthalene-2-carboxylic acid, 4- [2 -oxo-2- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -ethoxy] -benzoic acid, 4 - [- oxo-2- (5 , 5, 8, 8-tetramethyl 5,6,7,8-tetrahydro-naphthalen-2-yl) -acetylamino] -benzoic acid, 4- [2-fluoro-2- (5,5,8,8- tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) acetylaminoj-benzoic acid, 6- [3- (l-adamantyl-4- (2-hydroxypropyl) phenyl-2-naphthoic acid, - [3-oxo-3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -propenyl] -thiophen-2-carboxylic acid 6- [ 3- (l-adamantyl-4- (2,3-dihydroxypropyl) phenyl] -2-naphthoic acid, 4- [3-hydroxy- (5,6,7,8-tetrahydro-5,5,8) 8-tetrame til-2-naphthyl) -l-propynyl] -benzoic acid, 4- [3-oxo-3- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-acid) il) -prop-1-ynyl] -benzoic acid, 4 - [(3- (l-methylcyclohexyl) -4-hydroxyphenyl) ethynyl] -benzoic acid, 4 - [(E) 2- (3- (1 -adamantil) -4-hydroxyphenyl) e-tenyl] -benzoic acid, 4- [3- (1-adamantyl) -4-hydroxyphenylethynyl] -benzoic acid, 5- [3- (1-adamantyl) -4- hydroxyphenylethynyl] -2-thiophene carboxylic acid, 5- [3- (1-adamantyl) -4-m-ethoxyphenylethynyl] -2-thiophene carboxylic acid, 4- [2- (3-tert-butyl-4-methoxyphenyl) ) -propenyl] benzoic, acid 4-. { 2- [4-methoxy-3- (1-methyl-cyclohexyl) -phenyl] -propenyl} -benzoic, 6- [3- (l-adamantyl) -4- (3-methoxy-2-hydroxypropyl) phenyl] -2-naphthoic acid, 2-hydroxy-4- [3-hydroxy-3- ( 5, 6, 7, 8-tetrahydro-5,5,8, 8-tetramethyl-2-naphthyl-9-l-propynyl] -benzoic acid, 6- (5, 5, 8, 8-tetramethyl-5,6, 7, 8-tetrahydro-naphthalen-2-yloxy) -naphthalene-2-carboxylic acid, 6- (5, 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl) -naphthalene-2-carboxylic acid, 4- [2-propoxylimino-2- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -acetylaminoj-benzoic acid, 6- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamino) -naphthalene-2-carboxylic acid, l-methyl-4- (5, 5) , 8, 8-tetramethyl-5,6,7,8-tetrahydro-anthracen-2-yl) -lH-pyrrole-2-carboxylic acid, 2-methoxy-4- (5, 5, 8, 8-tetramethyl) -5, 6, 7, 8-anthrancen-2-yl) benzoic acid, 4- [2-nonyloxyimino-2- (5,5,8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalene) -2-yl) -acetylaminobenzoic acid, (-) - 2-hydroxy-4- [3-hydroxy-3- (5, 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -prop-l-inylj-benzoic acid, (+) -2-hydroxy-4- [3-hydroxy] -3- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -prop-l-inylj-benzoic acid, 2-hydroxy-4- [3- hydroxy-3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-22-yl) -but-1-ynyl-benzoic acid, 6- (3-bromo-5) , 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy) -naphthalene-2-carboxylic acid, 3 - [(5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl) -2H-1-benzopyran] -7-carboxylic acid, 4- [3- (3,5-di-tert-butyl-4-hydroxyphenyl) -prop-1 -inyl] -benzoic acid, 4- [3- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -prop-1-ynyl] -benzoic acid, 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-natyl) -1-propynyl-salicylic acid, 4- [. { 3- (1-adamantyl) -4- (2-hydroxyethyl) phenyl} ethinyl] benzoic acid and 4- [. { 3- (1-adamantyl) -4- (3-hydroxypropyl) phenyl} ethinyl] -benzoic acid.

3. Use according to one of the preceding claims, characterized in that the agonist ligand specific to the RAR-α type receptors. presents a R ratio greater than or equal to 50.

4. Use according to any one of the preceding claims, characterized in that the agonist ligand specific to the RAR-α type receptors. is 6, 3- (1-adamantyl) -4-hydroxyphenyl) -2-naphthanoic acid, 6- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2) acid -carbonyl) -naphthalene-2-carboxylic acid, 6- (1, 2, 3, 4-tetrahydro-l, 4a, 9b-trimethyl-1,4-methane-dibenzofuran-8-yl) -naphthalen-2-acid carboxylic acid, 6- [hydroxyimino- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -methyl] -naphthalene-2-carboxylic acid, 5- (5, 5, 8, 8-tetramethyl-5, 6,7, 8-tetrahydro-anthracen-2-yl) -thiophene-2-carboxylic acid, (-) - 6- [hydroxy- (5,5, 8, d-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) methyl] -naphthalene-2-carboxylic acid, 6- [3- (l-adamantyl-4- (2-hydroxypropyl)] phenyl] -2-naphtholic, 6- [3- (l-adamantyl-4- (2,3-dihydroxypropylphenyl) -2-naphthoic acid, 4- [3- (1-adamantyl) -4- hydroxyphenylethynyl] -benzoic acid, 5- [3- (l-adamantyl) -4-hydroxyphenylethynyl] -2-thiophene carboxylic acid, 5- [3- (1-adamantyl) -4-methoxyphenylethynyl] -2-thiophene carboxylic acid , 6- [3- (1-adamantyl) acid -4- (3-methoxy-2-hydroxypropyl) phenyl] -2-naphtholic, l-methyl-4- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydroanthracene-2-acid) il) -2-yl) -lH-pyrrole-2-carboxylic acid, (-) -2-hydroxy-4- [3-hydroxy-3- (5,5,8,8-tetramethyl-5,6, 7, 8-tetrahydro-naphthalen-2-yl) -prop-1-ynyl] -benzoic acid 2-hydroxy-4- [3-hydroxy-3- (5,5,8,8-tetramethyl-5,6) , 7, 8-tetrahydro-naphthalen-2-yl) -but-1-ynyl] -benzoic acid.

5. Use according to the preceding claim, characterized in that the specific agonist ligand to the RAR-? Type receptors is 6, 3- (1-adamantyl) -4-hydroxyphenyl) -2-naphtanoic acid.

6. Use according to any one of the preceding claims, characterized in that the pharmaceutical composition is intended to treat diseases or disorders related to a failure of the percentage of apoptosis.

7. Use according to the preceding claim, characterized in that diseases or disorders related to a failure of the percentage of apoptosis are selected among cancers, precancerous conditions, autoimmune diseases, allergies, inflammatory reactions and certain viral infections.

8. Use according to the preceding claim, characterized in that the autoimmune diseases are insulin-dependent diabetes, rheumatoid arthritis, chronic active hepatitis, pemphigus, platelet sclerosis, myasthenia, systemic lupus erythema, Crohn's disease and psoriasis.

9. Use according to claim 7, characterized in that the cancers are cancer of the sphere O.R.L. and cancers of the ovaries.

10. Use according to claim 7, characterized in that allergies or inflammatory reactions are contact eczema, atopic eczema, asthma and urticaria.

11. Use according to any one of claims 1 to 5, characterized in that the pharmaceutical composition is intended to reduce the effects of rejection of a transplanted organ.

12. Use of at least one specific agonist ligand to the RAR-? in a cosmetic composition as an apoptosis inducer of at least one cell population of the skin for which apoptosis can be induced by the activation of the RAR-? type receptors.

13. Use according to the preceding claim, characterized in that the specific agonist is ligated to the RAR-? Type receptors. it is chosen from the compounds mentioned in claim 2.

14. Cosmetic procedure for preventing and / or combating photoinduced or chronological aging of the skin, characterized in that a cosmetic composition inducing apoptosis comprising, in a cosmetically acceptable medium, at least one agonist ligand specific to the type receptors is applied to the skin. RAR- ?.

15. Process according to the preceding claim, characterized in that the agonist ligand specific to the RAR-α type receptors. is chosen from the compounds recited in claim 2.