WO2001053301A1

WO2001053301A1 - Chimeric molecules consisting of psoralen and retinoid, preparation method, uses thereof for treating cell hyperproliferation pathologies and in particular psoriasis

Info

Publication number: WO2001053301A1
Application number: PCT/FR2001/000153
Authority: WO
Inventors: Michel Giraud; Zo Andriamialisoa; René SANTUS; Térésa SA E MELO
Original assignee: Centre National De La Recherche Scientifique (Cnrs); Instituto Superior Tecnico
Priority date: 2000-01-19
Filing date: 2001-01-18
Publication date: 2001-07-26
Also published as: FR2803849B1; FR2803849A1

Abstract

The invention concerns novel chimeric molecules having a cytotoxic and/or phytocytotoxic activity consisting of at least a retinoid molecule covalently bound via a linking arm to a psoralen molecule or one of its derivatives. The invention also concerns the method for preparing said molecules and their use for treating cell hyperproliferation pathologies, and in particular in PUVA treatment of psoriasis.

Description

"CHIMERIC MOLECULES FORMED FROM PSORALENE AND RETINOID, THEIR PREPARATION PROCESS, AND THEIR

APPLICATIONS IN THE TREATMENT OF CELL HYPERPROLIFERATION PATHOLOGIES AND IN PARTICULAR OF

The present invention relates to new molecules as medicaments intended for the treatment of pathologies of cellular hyperproliferation and more particularly intended for the treatment of psoriasis. Psoriasis is a chronic inflammatory dermatosis easily recognizable by specific clinical symptoms characterized by red spots covered with abundant scales, whitish, dry and crumbly, located mainly on the elbows and forearms, knees and legs, and scalp . Sometimes these lesions can spread to the rest of the body, producing psoriasis universalis or even erythrodermic psoriasis by its pustular particular form or by its association with rheumatism; this type of psoriasis is a very serious and debilitating infection that can jeopardize the patient's vital prognosis. Psoriasis, which is a mild condition in the vast majority of cases, is psychologically difficult for patients who suffer from it because of the characteristic formation of lesions and rashes.

About 2% of the total population of Western countries are affected by this disease. The usual age of onset for psoriasis ranges from fifteen to thirty, although it can be present at any age.

At present, the cause and mechanism of psoriasis has not yet been fully elucidated. Skin lesions and rashes are caused by an abnormal hyperproliferation of keratinocytes, a disorder of the differentiation of these keratinocytes and an infiltration of inflammatory cells into the dermis and epidermis. Different classifications of psoriasis have been proposed but it is generally classified into psoriasis vulgaris, pustular psoriasis, psoriatic arthritis and guttate psoriasis and their analogues. Of these, psoriasis vulgaris is the most common type and accounts for 80-90% of all psoriasis.

It is recognized that psoriasis has a large genetic part. Different loci of susceptibility to psoriasis have been located: PSORS 1 on chromosome 6 (6 p21.3), PSORS 2 on chromosome 17q, PSORS 3 on chromosome 4q and PSORS 4 on chromosome 1CEN- q21.3. In addition to genetic factors, there are environmental factors that affect the onset, form or severity of the disease; among these, mention should be made of infections, in particular bacterial infections caused by streptococci, drugs, food, climate and stress. At present, the therapeutic methods of treatment envisaged by doctors are based on controlling the hyperfunctional proliferation of epidermal cells, controlling the inflammatory response, promoting immuno-modulation, and decreasing the risk of bacterial infection. Examples of therapeutic treatments conventionally used are given below.

A first type of treatment concerns the topical use of corticosteroids. This type of treatment has the immediate effect of reducing the skin lesions of psoriasis. However, the prolonged administration of topical corticosteroids causes tachyphylaxis and local side effects justifying other therapeutic approaches for this chronic pathology.

A second type of psoriasis treatment concerns the use of psoralen derivatives which are natural molecules found in plants. This method consists in the administration of these psoralens in the form of external or internal preparation in association with the exposure of the skin of patients thus treated with long wavelength type A ultraviolet rays (UN. A.); this is called PUVA therapy (Parrish et al, 1974; Jiang et al, 1998). The principle of this treatment is based, on the one hand, on the ability of 5-methoxy-psoralen and 8-methoxy-psoralen to bind to the double helix of the DNA molecule and by absorption of UVA radiation by these psoralens, to form photoadducts with the pyrimidine bases of DNA. Such training blocks any transmission of the message along the double helix, thus stopping any protein synthesis and any cellular multiplication. In normal cells, such blockage of the DNA helix is speeded up by the cellular DNA repair system. Conversely, in cells in the hyper-proliferation phase, that is to say cells with an accelerated division cycle, such as cells affected by psoriasis or cancer cells, such repair systems do not have time to do their work and the links of psoralen to DNA stop the enzymatic machinery of these cells. This explains why 5-methoxy-psoralen and 8-methoxy-psoralen do not affect the multiplication of normal cells and selectively block diseased cells which have accelerated proliferation. On the other hand, the psoralens used in PUVAtherapy are incorporated into cell membranes and, by the formation of photoadducts with polyunsaturated fatty acids, alter the intracellular signaling pathways, in particular those involving growth factors such as EGF (Dall'Acqua and Martinelli, 1991). This type of treatment is not fully satisfactory since certain types of psoriasis cannot be treated by this method. Furthermore, this method of treatment has another disadvantage which is that, when PUVA therapy is applied for a long time, a phenomenon similar to aging of the skin occurs with sometimes even, the particular formation of a lentigo. In addition, because of the photogenotoxic properties of psoralens, the frequency of skin cancers increases significantly in the areas treated with PUVAtherapy. Phototherapy (and UN radiation) is a third type of treatment for psoriasis. As in the case of heliotherapy, this involves performing irradiation with ultraviolet rays for a long time. This type of treatment not only causes aging of the skin, but also induces carcinogenesis.

Another means of treating psoriasis is the external use of coal tar. Coal tar inhibits the growth of epidermal cells so that the size of the lesions decreases relatively quickly and long periods of remission can be achieved. However, such treatment may cause dermatosis or folliculitis (acne).

Another method of treatment used to treat psoriasis is the administration of methotrexate. Methotrexate is a folic acid antagonist; the use of methotrexate is effective for the treatment of pustular psoriasis. However, administration of methotrexate for a long time causes side effects such as disruption of liver function and suppression of myeloproliferation.

Another treatment for psoriasis currently in use is retinoid administration. The term "retinoid" is the general term used to designate retinoic acid, which is an active metabolite of vitamin A, and also compounds "retinoic acid-like" with similar biological activities (for review, The retinoids vol. 1-2, MB Sporn et al. Eds. Académie Press, New York, 1984). Retinoids have important physiological functions; they are involved in the cellular differentiation of immature cells into specialized cells during the development process and in the activation of cell proliferation. Retinoids are also considered to have an immunomodulatory effect. Retinoids are used for the preventive and therapeutic treatment of diseases of vitamin A deficiency, hyperkeratosis, diseases of the epithelial tissue, rheumatism, leukemia and certain types of cancer. Internal administration of retinoids such as etretinate is particularly effective in treating pustular psoriasis and erythrodermic psoriasis. However, retinoids have harmful effects on the mucous membranes. In addition, abnormal serum lipoprotein levels are occasionally observed following administration of retinoids. On the other hand, retinoids are teratogenic and are likely to accumulate and stay inside the body for a long time. Thus, the application of retinoids in a woman likely to have children should be avoided.

Currently, treatment combinations using psoralen and retinoid molecules are used in clinical dermatology using photochemotherapy (Re-PUVA-therapy) to treat a number of tumor and non-tumor skin diseases such as psoriasis. , T-cell cutaneous leukemia (mycosis fungoides), actinic keratosis and parapsoriasis (For review see "Light-activated drugs" August 1988 Sci. Am. No. 68 and Mϋchenberger et al. (1997)).

Current treatments for pathologies of cellular hyperproliferation, and of psoriasis in particular, are not satisfactory because they are more or less effective, associated with side effects linked to the use of molecules and / or UN radiation. . in too large doses. For example, the treatment of psoriasis by administration of psoralens by the oral route uses doses of between 1 mg and 1.2 mg per kilo of body weight per PUVA therapy session (French patent Ν ° 2,406,444).

Because of the drawbacks mentioned above, it would be interesting to have a more effective treatment, which is less toxic to the patient. Based on the observation that the retinoid / PUNA-therapy combination

(Re-PUVA therapy) presents in a good proportion of patients a higher efficacy than PUVA therapy alone in the treatment by extracorporeal chemotherapy of a skin condition such as psoriasis or mycosis fungoides, the inventors envisaged creating chimeric molecules which associate two partners psoralen and retinoid by a covalent bond. The inventors have thought that the simultaneous presence of these two types of molecules at the same biological targets of PUVA-therapy could considerably increase the effectiveness of such treatment.

Quite surprisingly and unexpectedly, the chimeric molecule according to the invention exhibits an antiproliferative effect with respect to keratinocytes, incomparably greater than those of the two constituents taken separately. This unexpected synergistic effect makes it possible to obtain molecules 250 times more effective than those used in Re-PUVA therapy.

The present invention therefore relates to a chimeric molecule characterized in that it comprises at least one retinoid molecule covalently linked via a linker to the carbon atom in position 5 ′ or 8 ′ of a psoralen molecule or one of its derivatives and characterized in that said retinoid and psoralen molecules exhibit antiproliferative cellular activity and in that said linker comprises at least one hydrocarbon chain composed of at least three carbon atoms and at least one hetero. More particularly, the molecule according to the invention corresponds to the following formula:

in which R 1 independently represents a hydrogen atom, a halogen atom chosen from fluorine, chlorine, bromine, iodine, a hydroxyl group (-OH), an amino group, a thiol group (-SH) , a -CN group, a -CO2H group, a -Cθ2-C1-Cs alkyl group, a -O-CO-C1-Cs alkyl group, a linear or branched C1-Cs alkyl, alkenyl or al ynyl group, a C3-C6 cycloalkyl group, an alkyloxy, alkylamino, dialkylamino, C1-C6 alkylthio group, a substituted or unsubstituted aryl group, an aryloxy, arylamino, diarylamino, substituted or unsubstituted arylthio group; L represents said link arm such that L is chosen from a group -O-alkyl- (pyridinium) _m -, -S-alkyl- (pyridinium) _m -, -O- CO-alkyl- (pyridinium) m-, in wherein the alkyl group is linear or branched C3-C8 and m = 0 or 1; R4 and R. independently represent a hydrogen atom, a linear or branched C1-C5 alkyl group; n represents an integer from 1 to 10; the double bond

is of configuration Z or E; R is chosen from a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C4-C6 cycloalkenyl group, a substituted or unsubstituted phenyl group, the substituent being chosen from fluoro, chloro, iodo groups , bromo, hydroxyl, amine, thiol, -CN, -CO2H, -Cθ2-C1-Cs alkyl, linear or branched C1-Cs alkyl, C1-Cs alkoxy group.

By C1-C5 alkyl, we generally mean radicals the alkyl residue of which comprises between 1 and 8 carbon atoms chosen from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl groups, t-butyl, pentyl, hexyl, heptyle and octyl. They can be linear or branched alkyl residues. The term “C3-C6 cycloalkyl” is intended to denote generally, radicals the alkyl residue of which comprises 3 to 6 carbon atoms chosen from the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

By C 1 -C 6 alkoxy is intended to denote preferably the methoxy, ethoxy and propoxy, butoxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy groups. Preferably, it is the methoxy group.

The term “aryl” denotes generally aromatic and heteroaromatic groups, in particular aryls chosen from phenyl, thienyl, furanyl, pyridyl or naphthyl groups. Aryl radicals can also be substituted by one or more substituents chosen in particular from C1-C5 alkyl radicals, C1-Cs alkyloxy radicals or halo radicals; the substituted aryl radical is preferably a benzyl radical. The halo radicals are preferably chosen from fluorine, chlorine, bromine or iodine atoms.

When the molecules according to the invention comprise at least 1 asymmetric carbon, the present invention relates to the corresponding racemates, as well as its pure enantiomers or their mixtures in all proportions. The invention also relates to the therapeutically acceptable salts of the derivatives of the invention; these salts are the usual salts of the technique, organic or inorganic, in particular hydrochlorides, tosylates, mesylates, citrates as well as solvated molecules such as hydrates or hemihydrates of the compounds of the general formula above.

According to a preferred embodiment, the link arm L of the molecule of the invention represents a group

the -O- being covalently bonded to said carbon atom in position

5 'or 8' of said psoralen molecule.

According to another preferred embodiment, in the molecule of the invention, Ri represents hydrogen and the 8 ′ carbon atom of the psoralen molecule is covalently linked to L; according to yet another preferred embodiment, Ri represents hydrogen and the 5 'carbon atom of the psoralen molecule is covalently linked to

L.

The present invention also relates to the molecule of the invention for which n = 4 and such that

represented - Ci4R4 = Ci3R5-Cι ₂ R4 = CιιR5-CιoR4 = C9R5-C8R4 = C7R5-, in which formula, R4 represents hydrogen, R5 at Cπ and C ₇ represents hydrogen, R5 at Ci3 and Cg represents methyl, and in which the double bonds are of configuration E. The invention also relates to the molecule for which n = 4 and such that - [CR4 = CR5] n- represents

in which formula, R4 represents hydrogen, R5 at Cn and C7 represents hydrogen, R5 at C1 and Cg represents methyl, and in which the double bonds are in configuration E with the exception of the double bond which is of configuration Z.

The invention also relates to the molecule for which n = 3 and such that - [CR ₄ = CR ₅ ] _ι- represents -Cι ₂ R4 = CiiR5-CioR4 = C R5-C8R4 = C ₇ R5- in which formula, R4 represents hydrogen, R5 at Cπ and C ₇ represent hydrogen, R5 at Cg represents methyl and in which the double bonds are of configuration E.

The invention also relates to the molecule of the invention for which n = 1 and such that

represented

in which formula R4 and R5 represent hydrogen and in which the double bond is of configuration E.

According to another preferred embodiment of the invention, the molecule is characterized in that R is chosen from the group consisting of 2,6,6-trimethyl-1-cyclohexene-1-yl, 2,6,6- trimethyl-2-cyclohexene-1-yl and a phenyl unsubstituted or substituted by a methoxy group.

More particularly, the invention provides chimeric psoralen-retinoid molecules in which the 8 ′ carbon of the psoralen molecule is involved in a covalent bond with the binding arm L. The present invention therefore relates more particularly to the above molecule defined and in which Ri is hydrogen, L represents a group

the -O- being covalently linked to the said carbon atom in position 8 'of the said psoralen molecule, n = 4 and

represents -Ci4R4 = Ci3R5-Ci2R4 = C ₁₁ R5-Cio 4 = C9R5-C8R4 = C7R5- in which formula R4 represents hydrogen, R5 at Cπ and C7 represents hydrogen, R5 at C13 and Cg represents a methyl, and in which the double bonds are of configuration E.

According to another preferred embodiment, the molecule according to the invention is characterized in that Ri is hydrogen, L represents a group

the -O- being covalently linked to the said carbon atom in position 8 'of said psoralen molecule, n = 4 and - [CR4 = CR5] n- represents -Ci4R4 = Ci3R5-Ci2R4 = CiiR5-CioR4 = C R5 -C8R4 = C7R5- in which R4 is hydrogen, R5 in Cπ and C7 represents hydrogen, R5 in Ci3 and Cg represents methyl, and in which the double bonds are of configuration E with the exception of the double bond

which is of configuration Z.

the -O- being covalently linked to the said carbon atom in position 8 'of said psoralen molecule, n = 3 and - [CR4 = CR5] _n - represents -Ci2R4 = CiiR5-Cιo 4 = C9R5-C8R4 = C7R5 - in which formula R4 is hydrogen, R5 at Cπ and C7 represent hydrogen, R5 at Cg represents methyl and in which the double bonds are of configuration E.

-0- (CH ₂ ) ₃ → T \ le -O- being covalently linked to said carbon atom in position 8 'of said psoralen molecule, n = 3 and - [CR4 = CR5] n- represents -Ci2R4 = CnR5-CιoR4 = C9R5-C8R4 = C7R5- in which formula R4 is hydrogen, R5 at Cπ and C7 represent hydrogen, R5 at Cg represents methyl and in which the double bonds are of configuration E, at exception of double bond

which is of configuration Z.

the -O- being covalently linked to the said carbon atom in position 8 'of the said psoralen molecule, n = 1 and - [CR4 = CR5] _n - represents

in which formula R ₄ and R5 represent hydrogen and in which the double bond is of configuration E. It is also within the scope of the invention to provide psoralen-retinoid chimeric molecules according to the invention in which the 5 ′ carbon of the psoralen molecule is involved in a covalent bond with the binding arm L. In fact, 5-methoxy-psoralen and 8-methoxy-psoralen having a different cellular phototoxicity, it is interesting to develop chimeric molecules of these two compounds. Consequently, the present invention relates to a molecule according to the invention which is characterized in that Ri is hydrogen, L represents a group

-0- (CH ₂ ) ₃

the -O- being covalently linked to the said carbon atom in position 5 'of the said psoralen molecule, n = 4 and

represents: Ci4R4 = Ci3R5-Ci2R4 = CιιR5-CιoR4 = CgR5-C8R4 = C7R5- in which R4 is hydrogen, R5 at Cπ and C7 represents hydrogen, R5 at C13 and Cg represents a methyl, and in which the double connections are of configuration E.

-O- (CH ₂ ; -o

the -O- being covalently linked to the said carbon atom in position 5 'of said psoralen molecule, n = 4 and ~ [CR4 = CR5] n- represents -Ci4 4 = Ci3R5-Ci2R4 = CnR5-CιoR4 = C R5-C8R4 = C7R5- in which R4 is hydrogen, R5 in Cu and C7 represents hydrogen, R5 in C13 and Cg represents methyl, and in which the double bonds are of configuration E with the exception of the double bond

which is of configuration Z.

According to another preferred embodiment, the compound according to the invention is characterized in that Ri is hydrogen, L represents a group

the -O- being covalently linked to the said carbon atom in position 5 ′ of said psoralen molecule, n = 3 and - [CR4 = CR5] n- represents -Ci2R4 ⁼ CiiR5-CιoR4 = C R5-CsR4 = C7R5 - in which R4 is hydrogen, R5 in Cu and C7 represent hydrogen, R5 in Cg represents methyl and in which the double bonds are of configuration E.

the -O- being covalently linked to the said carbon atom in position 5 'of the said psoralen molecule, n = 3 and - [CR4 = CR5] __- represents -Ci2R4 = CπR5-Cιo 4 = CgR5-CsR4 ⁼ C7R5 - in which R4 is hydrogen, R5 in Cu and C7 represent hydrogen, R5 in C9 represents methyl and in which the double bonds are of configuration E, with the exception of the double bond

which is of configuration Z. According to another preferred embodiment, the molecule according to the invention is characterized in that Ri is hydrogen, L represents a group

-0- (CH ₂ ), -

the -O- being covalently linked to the said carbon atom in position 5 ′ of the said psoralen molecule, n = 1 and

represents -CsR4 = C7R5- in which formula R4 and R5 represent hydrogen and in which the double bond is of configuration E. According to an even more preferred embodiment, the invention relates to the preceding compounds for which R is chosen from 2,6,6-trimethyl-1-cyclohexene-1-yl, 2,6,6-trimethyl-2-cyclohexene-1-yl, and a phenyl unsubstituted or substituted by a methoxy group.

Thus, the invention relates more particularly to the molecule called chimera 13 of formula:

Also preferably, the invention relates to the molecule called chimera of formula:

Also preferably, the invention relates to the molecule called chimera 3 of formula:

Also preferably, the invention relates to the molecule called MOP / CIN of formula:

Also preferably, the invention relates to the molecule called MOP / 4MO of formula:

The invention also relates to a process for the preparation of a molecule as previously described, characterized in that it comprises the following steps: (i) Synthesis of the amide

NH-CO - [CR ₄ = CR ₅ l> R from the corresponding acid HOOC- [CR4 = CR5] _n -R in the presence of 4 amino-pyridine and DCC, in which R4 and R5 independently represent a hydrogen atom, a linear Ci-Cs alkyl group or branched, substituted or not, n represents an integer from 1 to 10, the double bond

is of configuration Z or E and R is chosen from a substituted or unsubstituted C3-G3 cyclo-alkyl group, a substituted or unsubstituted C4-C6 cyclo-alkenyl group, a substituted or unsubstituted phenyl group, the substituent being chosen from fluoro, chloro, iodo, bromo, hydroxyl, amino, thiol, -CN, -CO2H, -Cθ2-C1-C6 alkyl, C1-C8 alkyl; (fi) Reaction of said amide with a haloalkyloxy-psoralen or one of its substituted derivatives.

According to a more particular embodiment of the invention, the method is characterized in that said halo-alkyloxy-psoralen is chosen from the group composed of 5-bromo-propyloxy-psoralen and 8-bromo-propyloxy-psoralen. According to a preferred embodiment, the process for preparing the molecule according to the invention is characterized in that said corresponding acid is all-trans retinoic acid (13E) whose name according to the official nomenclature is acid E, E, E, E 3,7 dimethyl-9 (2,6,6-trimethyl-1-cyclohexene-lyle) 2,4,6,8, nonatetraenoic and that said haloalkyloxy-psoralen is 8-bromo -propyloxy- psoralen. According to another preferred embodiment, the process for preparing the molecule according to the invention is characterized in that said corresponding acid is retinoic acid 13 CIS (13Z) whose name according to the official nomenclature is acid Z, E, E, E, 3,7 dimethyl-9 (2,6,6 trimethyl-1-cyclohexene-1-yl) 2,4,6,8 nonatetraenoic and that said halo-alkyloxy-psoralen is 8-bromo- propyloxy-psoralen. According to another preferred embodiment, the process for preparing the molecule according to the invention is characterized in that said corresponding acid is the retinoid 11 E whose name according to the official nomenclature is acid E, E, E 5- methyl-7 (2,6,6 trimethyl-1-cyclohexene-1-yl) 2,4,6 heptatrienoic and that said halo-alkyloxy-psoralen is 8-bromo-propyloxy-psoralen. According to another preferred embodiment, the process for preparing the molecule according to the invention is characterized in that said corresponding acid is a cinnamic acid of configuration E, preferably chosen from (E) 3 (phenyl) acid - 2-propenoic acid and (E) 3- (4methoxy ~ phenyl) -2-propenoic acid and that said halo-alkyloxy-psoralen is 8-bromo-propyloxypsoralen.

The invention also relates to a chimeric molecule as previously described as a medicament; and more particularly, the invention relates to a chimeric molecule as previously described as a medicament intended for the treatment of a pathology involving cellular hyperproliferation. By cellular hyper-proliferation is meant the ability temporarily or definitively acquired by certain cells of the body to divide and thus proliferate at a speed and / or frequency greater than that of a similar normal cell. from a healthy organism and taken as control. Among the pathologies involving cellular hyperproliferation, it is worth mentioning psoriasis, parapsoriasis, cutaneous lymphomas, actinic hyperkeratosis, basal cell carcinomas, spinocellular carcinomas, cutaneous melanoma. More particularly, the invention relates to a chimeric molecule as previously described as a medicament intended for the treatment of psoriasis.

The invention also relates to a pharmaceutical composition characterized in that it comprises an effective amount of a molecule according to the invention and a pharmaceutically acceptable vehicle.

The pharmaceutical composition according to the invention can be formulated in the form of different preparations suitable for topical administration, for oral or rectal administration, for parenteral administration. Examples of pharmaceutical compositions suitable for topical administration include creams, ointments, lotions, oils, patches, sprays or all other products for external application. Examples of pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, powders, granules, liquids, syrups, among others. Examples of pharmaceutical compositions for parenteral administration include, for example, intravenous, intradermal, intramuscular, or subcutaneous injections.

The optimal modes of administration, the dosages and the galenical forms of the molecules according to the invention or of the pharmaceutical compositions according to the invention can be determined according to the criteria generally taken into account in the establishment of a treatment adapted to a patient as for example the patient's age or body weight, the seriousness of his general condition, the tolerance to treatment and the side effects observed. Among the pharmaceutically acceptable vehicles, mention should be made, in a non-exhaustive manner, of excipients, binders, lubricants, coating agents, diluents, dissolving agents, isotonic agents, pH-modifying agents, stabilizers. For the topical administration of the molecules of the invention, different pharmaceutically acceptable vehicles can be used such as for example oils derived from petroleum of different viscosity, oils derived from salicylated petroleum, mineral oils, vegetable oils, lanolin, emulsions, alcoholic solutions.

Due to the skin barrier and also to that developed by certain cells vis-à-vis their environment, such as cancer cells for example, and in particular because of the phenomenon of thickening of the cell membrane, the penetration of the chimeric molecule according to the invention can be slow and difficult. It may therefore be advantageous to introduce into the pharmaceutical and / or cosmetic composition according to the invention penetration agents such as isopropyl myristate or dimethylsulfoxide (DMSO). The invention also relates to the use of a chimeric molecule according to the invention for the preparation of a medicament or of a pharmaceutical composition according to the invention for the treatment and / or prevention of a pathology involving hyperproliferation cellular and more particularly psoriasis. The cells in the hyperproliferation phase treated with the chimeric molecule or the composition according to the invention are simultaneously or in a time-shifted manner irradiated with ultraviolet rays. When the ultraviolet rays used are UV A, it is then a PUVA therapy. The invention also aims to provide a pharmaceutical composition, in particular a dermatological composition, intended for topical and / or oral, and / or parenteral administration for the treatment of psoriasis. This composition is characterized in that it contains a therapeutically effective amount of a chimeric molecule according to the invention and a pharmaceutically acceptable vehicle. When this composition is intended for external topical application in the context of a PUVA therapy, it may also comprise one or more filters for ultraviolet B rays. As mentioned above, the treatment of diseases involving cell hyperproliferation, and more particularly skin diseases such as psoriasis, with the compounds or the composition of the invention comprises exposure to near UVA radiation which is in the range 320 to 380 nm. By way of example, this treatment consists in applying the chimeric molecules or the composition according to the invention to the affected parts of the skin, approximately 30 min to one hour, before the irradiation of these parts by UVA The dose dTJ. VA is adapted to the different skin phototypes and to the number and nature of the session. As an indication, the dose for each treatment ranges from 5 J / cm ² to 10 J / cm ² . However, doses of up to 20 J / cm ² can be used for a short time. In general, a PUVA therapy treatment continues at the rate of 3 sessions per week for 4 to 6 weeks. It should be emphasized that these parameters are given for information only and cannot be limiting.

In the case of tumors accessible by natural routes, such as melanoma or a cancerous tumor of the mucous membranes, the use of the chimeric molecule according to the invention as a medicament or the use of the pharmaceutical composition according to the invention is applicable. In the context of PUVA therapy, the nature, doses and wavelengths of the radiation must be adapted to reach the tissue to be treated. The chimeric molecules according to the invention can also be used in cosmetology. The invention therefore also relates to a cosmetic composition characterized in that it contains an effective amount of at least one chimeric molecule according to the invention and a cosmetically acceptable vehicle intended for external application. The vehicles for such compositions are well known to those skilled in the art, so it is not necessary to present them in detail. The cosmetic compositions according to the invention can be creams, ointments, lotions, oils, patches, sprays or in any other product for external application. The cosmetic composition according to the invention may also contain at least one filter or at least one sunscreen. Among the sun filters for ultraviolet rays B (UN. B), it is worth mentioning ethyl paramethoxycinnamate-hexyl, 1,7,7-trimethyl-3 (methyl-4-benzylidene) bicyclo (2,2, 1 ) - 2-heptanone. Finally, the molecule according to the invention or the composition described above can be used in the field of cosmetics to stimulate the pigmentation of the skin and / or promote the tanning of the skin and / or prevent, erase and treat wrinkles, fine lines of the skin and / or fight against aging by fighting sagging skin and / or subcutaneous and / or improve the texture of the skin and revive the radiance of the skin. The amount of active ingredients used in the cosmetic composition is not critical and may vary according to the desired use; in general, the chimeric molecules according to the invention represent 0.01% to 0.5% by weight of the composition.

Other characteristics and advantages of the present invention will be better demonstrated on reading the following examples. In these examples we will refer to the following figures:

Figure 1: Viability of NCTC 2544 keratinocytes in in vitro culture as a function of the concentration of the chimera in the culture medium.

The cells are incubated overnight (18 h) with increasing concentrations of the 3 chimeric molecules. Viability is determined by the neutral red test.

Figure 2: Viability of NCTC 2544 keratinocytes in in vitro culture as a function of the concentration of the amide derivative of retinoic acid 13E.

The cells are incubated for 3 or 18 h at increasing concentrations of 13E retinoic acid amide. Viability is determined by the neutral red test.

Figure 3: Viability of NCTC 2544 keratinocytes in in vitro culture treated overnight with a non-cytotoxic dose of 8-MOP or of chimeric molecule 13 or 3 as a function of the irradiation dose U.V.A.

The treated cells are treated overnight with 50 μM of 8-MOP or with 1 μM of chimera 13 or chimera 3 and then irradiated with U.V.A. at different doses. Viability is determined by the neutral red test.

Figure 4: Viability of NCTC 2544 keratinocytes in in vitro culture treated overnight with a non-cytotoxic dose of amide of retinoic acid 13E (amide) and the ethyl ester of retinoic acid (ester) depending on the dose of UVA irradiation

The cells are treated overnight with 50 μM of the amide or with 50 μM of the ester and then irradiated with U.V.A. at different doses. Viability is determined in neutral red.

Figure 5: Viability of NCTC 2544 keratinocytes in in vitro culture treated overnight with 8-MOP and MOP / CIN as a function of the dose of UVA irradiation. The cells are treated overnight with 50 μM of 8-MOP or 10 μM of MOP / CIN and then irradiated with 1TJVA at different doses. Phototoxicity is measured 24 hours after irradiation. Each condition is the average of three measurements. Viability is determined in neutral red.

Figure 6: Effect of the concentration of chimeric molecules on the 24-hour survival of NCTC 2544 keratinocytes. The compounds MOP / 4MO and MOP / CIN appear to be more toxic than 8-MOP.

EXAMPLES

The examples described are the procedures relating to the chimeric molecules 13 and 15 derived respectively from the retinoic acids 13E and 13Z and from 8-methoxy-psoralen (8-MOP).

EXAMPLE 1: SYNTHESIS OF CHIMERIC MOLECULES 13 AND 15

1.1 Synthesis of amides

To a solution of retinoic acid 13E or 13Z (1 mmol) in CH2Cl2 (100 ml) is added DCC (1 mmol). After 5 hours of stirring the solvent is evaporated and the residue taken up in a mixture of CH3CO2CH5 / CHOH 99/1. The amides are obtained with a yield of 75% after filtration and evaporation of the solvents.

1.1.1. 13E retinoic acid amide:

IR (pellet KBr, cm- ¹ ): 2950, 1685.

8.50 (d, 2H, J = 6, C17H and C20H); 7.55 (d, 2H, J = 6, CisH and C ₁₉ H); 7.47 (s, 1H, NH); 7.08 (dd, 1H, J = 16 and 15, C11H); 6.30 (m, 2H, C ₇ H and C ₈ H); 6.13 (m, 2H, C10H and C12H); 5.81 (s, 1H, Cι _4H); 2.39 (s, 3H, C13CH3); 2.05 (m, 2H, C ₃ H); 2.03 (s, 3H, C9CH3); 1.74 (s, 3H, C2CH3); 1.64 (m, 2H, C ₄ H); 1.50 (m, 2H, C ₅ H); 1.05 (s, 6H, C ₆ CH ₃ ).

165.7 (CO); 152.6; 150, 1; 139.9 and 135.3 (Ci, C ₂ , Cg and C13); 135.4 (C ₇ ); 131, 1 and 120.6 (Ca-, C ₃ -, C ₄ -, C ₅ - and C ₆ >); 131.8 (Cu); 130.7 (C10); 129.4 (C12); 113.9 (Cι ₄ ); 40.0 (C ₅ ); 34.3 (Ce); 33.5 (C ₃ ); 29.4 and 22.1 (C2CH3 and C ₆ CH ₃ ); 19.6 (C ₄ ); 14.2 (C9CH3).

1.1.2. 13 Z retinoic acid amide

IR (film): 3300, 2950, 1690.

RMNΗ (CDC13)

8.50 (d, 2H, J = 6, C ₃ Η and C ₅ -H); 7.55 (d, 2H, J = 6, Ca-H and Cβ-H); 7.37 (s, 1H, NH); 7.05 (dd, 1H, J = 17 and 15, C11H); 6.32 (m, 2H, C ₇ H and C ₈ H); 6.17 (m, 2H, C10H and C12H); 5.67 (s, 1H, Cι _4H); 2.10 (s, 3H, C13CH3); 1.72 (s, 3H, C2CH3); 1.62 (m, 2H, C ₄ H); 1.47 (m, 2H, C ₅ H); 1.03 (s, 6H, CeCHs) 1.2. Synthesis of chimeric molecules

A solution of 8-bromo-propyloxy-psoralen (1 mmol) and of amide (1 mmol) is heated for 6 h at reflux of CH3NO2. After evaporation of the solvent and chromatography on Siθ2 the chimeric molecules are obtained with a yield of 50%:

1.2.1. Chimeric molecule 13:

IR (film) 3000, 1695

8.80 (m, 4H, C17H, C_ ₈ H, Cι ₉ H and C20H); 7.83 (d, 1H, J = 9, C ₃ Η); 7.76 (d, 1H, J = 2, C ₇ Η); 7.45 (2s, 2H, C ₅ <H and NH); 7.09 (m, 1H, CnH); 6.85

(d, 1H, J ≈ 2, Cβ-H); 6.32 (m, 2H, C ₇ H and C ₈ H); 6.19 (m, 3H, C ₁ 0H, Cι ₂ H and C14H); 4.98 (t, 2H, J = 6, Cg-H); 4.42 (t, 2H, J = 6, Ci H); 2.39 (s,

3H, C13CH3); 2.05 (s, 3H, C ₉ CH ₃ ); 2.03 (s, 3H, C2CH3); 1.64 (m, 2H,

C ₄ H); 1.50 (m, 2H, C ₅ H); 1.05 (s, 6H, C ₆ CH ₃ ).

1.2.2. Chimera 15 molecule:

IR (film) 3000, 1695.

8.74 (m, 4H, C ₁₇ H, C ₁₈ H, C ₁ H and C20H); 7.83 (d, 1H, J = 10, C ₃ -H); 7.50 (2s, 2H, C ₅ -H and NH); 6.89 (d, 1H, J = 6, Cg-H); 6.30 (m, 2H, C ₇ H and CsH); 6, 15 (m, 3H, C10H, C12H and Cι _4H); 4.87 (t, 2H, J = 6, Cg-H); 4.40 (t, 2H, J = 6, C9Η); 2.10 (s, 3H, C13CH3); 2.03 (m, 2H, C ₃ H); 2.00 (s, 3H, C9CH3); 1.72 (s, 3H, C2CH3); 1.62 (m, 2H, C ₄ H); 1.47 (m, 2H, C ₅ H); 1.03 (s, 6H, CeCHs). ¹³ C NMR (CDC13)

165.2 (CO); 150.7; 149.7; 140, 1 and 137.5 (Ci, C, Cg and C ₁₃ ); 137.2 (Ce 129.0; 130, 1 and 118, 1 (C ₂ -, C ₃ -, C ₄ ', C ₅ > and Ce-); 132.6 (Cπ); 130.2 (C ₁₀ 128.6 (Cia); 113.5 (Cι ₄ ; 39.5 (Cs); 34, 1 (Ce); 33.0 (C ₃ ); 28.8 (C ₆ CH) 21.6 (C ₂ CH); 19, 1 (C ₄ ); 14.0 (CisCH); 12.8 (C ₉ CH ₃ ).

EXAMPLE 2: STUDY OF BIOLOGICAL AND PHOTOBIOLOGICAL PROPERTIES OF CHIMERIC MOLECULES 13 AND 15 ON NCTC 2544 KERATINOCYTES.

2.1 Culture protocol for NCTC 2544

2.1. l. Cells

NCTC 2544, human skin epithelial cells - keratinocytes. Cells probably contaminated with HeLa (Chromosomes type A G6PD and HeLa) (JNCI (1957) 18,709)

2.1.2 Culture medium used

1) EMEM (Minimum Essential Medium with Earle's salts) lx (Gibco - Cat. N ° 51200-038) 500 mL without phenol red, without glutamine.

(storage at + 4 ° C).

2) lOOx non-essential amino acids (Gibco - Cat n ° 11140-035) (storage at + 4 ° C).

3) Fetal calf serum (SVF) 4) L-Glutamine 100 x (Gibco - Cat n ° 25030-024) (storage at + 4 ° C). 5) Penicillin / Streptomycin 10,000 IU / mL (Gibco - Cat n ° 15140-114) (storage at + 4 ° C). The culture medium used is composed of EMEM, 1% of nonessential amino acids, 10% FCS, 2% of L-Glutamine, 1% of Penicillin / Streptomycin, i.e. for 100 mL: 86 mL EMEM + 1 mL non-essential amino acids + 10 mL SVF + 2 mL Gin + 1 mL Penicillin / Streptomycin.

2.1.3 Culture

They are carried out in 75 cm ² boxes, with 15 ml of medium per box. At confluence, the dish contains between 12 and 16 million cells. At high confluence, the concentration can reach 20 million cells / box. At confluence the cells are divided and seeded in new boxes at lower concentrations; to do this, the medium is aspirated, the cells are rinsed twice with Puck's - EDTA or PBS without Ca ²⁺ / Mg ²⁺ then trypsinize 5 to 10 minutes with 2 mL of trypsin at 37 ° C; the trypsinization reaction is stopped by adding 8 mL of medium + FCS (the α-macroglobulin contained in the serum stops the action of trypsin). The cells are counted and then seeded in new boxes. To make one pass per week, inoculate the new boxes at 000 600,000 cells / box.

2.2 Cell viability test at Neutral Red (RN) (Lasarow et al, 1992)

2.2.1 Stock Solutions

Solution 1 (storage at room temperature)

1 ml of formaldehyde (formaldehyde) 40% + 10 g CaCl ₂ 2H ₂ O + H ₂ O qs 100 ml ot i

+ 7.55 g CaCl ₂ anhydrous + H ₂ O qs 100 rn

Solution 2 (storage at room temperature) 19 ml of glacial acetic acid + 50 ml ethanol + 31 ml H2O The aqueous mother solution of neutral red reagent at 13.85 mM is stored protected from light at + 4 ° C (0.4%).

2.2.2. Preparation the day before The stock solution is diluted before each incubation to 1/80 in the culture medium used WITHOUT phenol red.

This solution is placed for 24 h in the CO2 oven and then centrifuged for 20 min. at 3000 g. Dose with the supernatant.

Three empty dishes (without cells) are also incubated with culture medium. These boxes will be treated at RN in the same way as the others to determine the background noise.

2.2.3. dosage

The cellular medium is aspirated; then the cells are washed twice with PBS; 0.5 ml of neutral red reagent (RN) are deposited for a 35 mm diameter petri dish.

The cells are incubated for 3 h in the CO2 oven. The medium is then aspirated and the cells rinsed 1 time with PBS and then fixed with 0.5 ml of solution 1 for 1 minute (NOTE: This time is critical, if necessary, it is necessary to operate in series of 10 dishes ). Solution 1 is then aspirated; the dye is extracted by incubating the cells for 5 to 10 min. with 0.5 or 1 ml of solution 2. The absorption is read at 550 nm (V = 330 μl in microplates) by providing 3 wells for a blank (330 μl of solution 2).

2.3 Study of intrinsic cytotoxicity

The cytotoxicity of compounds 13, 15 and 3 was tested against a line of keratinocytes NCTC 2544 derived from a human skin strain of the "Caucasian" type and immortalized. The confluence cells were incubated in a 35 mm petri dish at 37 ° C. in a drying oven. CO2 with the various chimeras or 8-methoxypsoralen in culture medium (Minimum Essential Medium with Earle's knows) containing 10% fetal calf serum, whatever the incubation time.

Figure 1 shows the viability of these keratinocytes incubated overnight with increasing concentrations of the 3 chimeric molecules. The viability was determined by the so-called "Neutral Red" test which measures, 24 hours after the end of the treatment with chimeras, the incorporation of the Neutral Red by the cells. Neutral Red is a lysosomotropic substance that can only be retained by living cells. After only 3 hours of incubation with 5 μM of the chimeric molecule 3 taken as an example, we still observe 75% survival while no trace of toxicity is observed after 1 h of incubation with this concentration of the chimeric compound 3 Similar results are obtained with the chimeric molecules 13 and 15. FIG. 2 shows, on the other hand, the relatively low cytotoxicity of the amide derivative of retinoic acid 13 E prepared according to the synthesis described above and left in contact for 3 h or 18 h with NCTC 2544.

2.4 Study of photocytotoxicity

By way of example, the photocytotoxicity of the chimeric molecules 13 and 3 shown in FIG. 3 was determined as a function of the dose of UVA irradiation with respect to the same cells by irradiating the petri dishes containing the cells treated for 1 night with a non-cytotoxic dose of 1 μM of each of the chimeric molecules. Incubation with 1 μM of chimeric molecule 15 then irradiation with UVA of the treated NCTC 2544 gives completely comparable results. To compare, the photocytotoxicity recorded with the same cells treated overnight with 50 μM of 8- is given. methoxypsoralen (FIG. 3) or with 50 μM of the amide of retinoic acid 13 E, the synthesis of which is described above, or with the same concentration of the ethyl ester of retinoic acid (FIG. 4).

The phototoxicity of the MOP / CIN chimeric molecule shown in FIG. 5 was determined as a function of the U.V.A. irradiation dose. vis-à-vis the same NCTC2544 cells by irradiating the petri dishes containing the cells treated overnight with a non-cytotoxic dose of 50 μM of MOP / CIN. We give to compare the photocytotoxicity recorded with the same cells treated overnight with 50 μM of 8-MOP. FIG. 6 also shows that the chimeric molecules MOP / 4MO and MOP / CIN are more cytotoxic at 24 hours than 8-MOP.

The chimeric molecules 13, 15, MOP / 4MO and MOP / CIN demonstrate, in our model system of human keratinocytes in culture, antiproliferative biological and photobiological activities undoubtedly superior to the psoralens (in particular 8-MOP and 5-MOP) currently used in PUVA therapy. We can predict a significant potential for this type of molecules in the context of treatment with conventional or extra-PUVA therapy for malignant skin conditions (fungal mycosis) or psoriasis resistant to PUVA conventional therapy. In addition, these chimeric molecules make it possible to use lower doses of drugs (of the order of 2 orders of magnitude) as well as lower doses of irradiation than those necessary in current PUVA therapy. Their cost should be very competitive compared to the overall cost of the current Re-PUVA treatment. REFERENCES

DaU'Acqua and Martelli (1991) Photosensitizing action of furocoumarins on membrane components and consequent intracellular events, J. Photochem. Photobiol. B. Biol., 8: 235-254;

Jiang et al. (1999) Extracorporeal photochemotheraphy for cutaneous T-cell lymphoma: a 9.7-year experience. Photodermatol. Photoimmunol. Photomed. 15: 161-165;

JNCI (1957) 18, 709;

Lasarow et al. (1992) Quantitative in vitro assessment of photoxicity by a fibroplast neutral red assay, JID 98: 725-729

Muchenberger and α. (1997) British Journal of Dermatology 137: 587-589;

Parrish et al. (1974) New England Journal of Medicine 291: 1207-1211;

Sporn et al. (1984) The retinoids, Académie Press vol.1-2;

Zarebska (1994) Cell membrane, a target for PUVAtherapy. J. Photochem. Photobiol. B. Biol. 23: 101-109

Claims

1. Chimeric molecule, characterized in that it comprises at least one retinoid molecule covalently linked via a linker to the carbon atom in position 5 'or 8' of a psoralen molecule or one derivatives thereof and characterized in that: (i) said retinoid and psoralen molecules exhibit antiproliferative cellular activity; (ii) said linking arm comprises at least one hydrocarbon chain composed of at least three carbon atoms and at least one heteroatom.

2. Molecule according to claim 1 of general formula

in which :

R 1 independently represents a hydrogen atom, a halogen atom chosen from F, Cl, Br, I, a hydroxyl group (-OH), an amino group, a thiol group (-SH), a -CN group, a group -

CO ₂ H, a -Cθ2-C1-C6 alkyl group, a -O-CO-C1-Cs alkyl group, a linear or branched C1-Cs alkyl, alkenyl or alkynyl group, a C-cycloalkyl group ₃ -C6, an alkyloxy, alkylamino, dialkylamino, C1-C6 alkythio group, a substituted or unsubstituted aryl group, an aryloxy, arylamino, diarylamino, substituted or unsubstituted arylthio group;

• L represents said link arm as L is chosen from: a group -O-alkyl- (pyridinium) m-, -S-alkyl- (pyridinium) _m -, -O- CO-alkyl- (pyridinium) _m -, in which the alkyl group is linear C ₃ -Cs or branched and m = 0 or 1;

• R4 and R5 independently represent a hydrogen atom, a linear or branched C1-C5 alkyl group;

• n represents an integer from 1 to 10;

• The double bond

is of configuration Z or E;

• R is chosen from a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C4-C6 cyclo-alkenyl group, a substituted or unsubstituted phenyl group, the substituent being chosen from fluoro, chloro, iodo groups , bromo, hydroxyl, amine, thiol, -CN, - CO2H, -Cθ2-C1-C5 alkyl, C1-Cs alkyl, C1-Cs alkoxy.

3. Molecule according to claim 2, characterized in that Ri is hydrogen and the carbon atom in position 8 'of said psoralen molecule is covalently linked to L.

4. Molecule according to claim 2, characterized in that Ri is hydrogen and the carbon atom in position 5 ′ of said psoralen molecule is linked covalently to L.

5. Molecule according to any one of claims 2 to 4, in which L represents a group

the -O- being covalently linked to said carbon atom in position 5 'or 8' of said psoralen molecule.

6. Molecule according to claims 2 to 5, characterized in that n = 4 and in that

represented : -Ci4R4 = Ci3R5-Ci2R4 = CιιR5-CιoR4 = C9R5-CsR4 = C7R5-, in which R ₄ represents hydrogen, R5 in Cπ and C7 represents hydrogen, R5 in C13 and Cg represents a methyl, and in which the double bonds are of configuration E.

7. Molecule according to claims 2 to 5, characterized in that n = 4 and in that

represented :

-Ci4R4 = Ci3R5-Ci2R4 = CιιR5-CιoR4 = C R5-CsR4 = C7R5-, in which, R ₄ represents hydrogen, R5 in Cu and C7 represents hydrogen, R5 in C13 and Cg represents a methyl, and in which double bonds are of configuration E with the exception of the double bond

which is of configuration Z.

8. Molecule according to claims 2 to 5, characterized in that n = 3 and in that

represented :

-Ci2R4 = CιιR5-CιoR4 = CgR5-C8R4 = C7R5- in which, R4 represents hydrogen, R5 in Cu and C7 represent hydrogen, R5 in Cg represents methyl and in which the double bonds are of configuration E.

9. Molecule according to claims 2 to 5, characterized in that n = 1 and in that

represents: -G3R4 = C7R5- in which R4 and R5 represent hydrogen and in which the double bond is of configuration E.

10. Molecule according to claims 2 to 9, characterized in that R is chosen from the group consisting of 2,6,6-trimethyl-1-cyclohexene-1-yl, 2,6,6-trimethyl-2-cyclohexene -l-yl, of a substituted or unsubstituted phenyl.

11. Molecule according to claim 2, in which: • Ri is hydrogen, • L represents a group

the -O- being covalently linked to the said carbon atom in position 8 ′ of the said psoralen molecule,

• n = 4 and - [CR4 = CR5] ι_- represents:

-Ci4R4 = Ci3R5-Ci2R4 = CιιR5-CιoR4 = C9R5-CsR4 = C7R5- in which R ₄ is hydrogen, R5 in Cπ and C7 represents hydrogen, R5 in C13 and C9 represents a methyl, and in which the double connections are of configuration E.

12. Molecule according to claim 2, in which:

• Ri is hydrogen,

• L represents a group

• n = 4 and

represented :

-Ci4R4 = Ci3R5-Ci2R4 = CιιR5-CιoR4 = C9R5-C ₈ R4 = C7R5- in which R ₄ is hydrogen, R5 at Cπ and C7 represents hydrogen, R5 at Cι ₃ and C9 represents a methyl, and in which double bonds are of configuration E with the exception of the double bond

which is of configuration Z.

13. Molecule according to claim 2, in which • Ri is hydrogen;

• L represents a group

• n = 3 and

represents: -Ci2R4 = CπR5-CιoR4 = C9R5-CsR4 = C7R5- in which R4 is hydrogen, R5 at Cπ and C7 represent hydrogen, R5 at Cg represents methyl and in which the double bonds are of configuration E.

14. Molecule according to claim 2, in which • Ri is hydrogen;

• L represents a group

• n = 3 and - [CR4 = CR5] _n - represents:

-Ci R4 = CπR5-CιoR4 = C9R5-C8R4 = C7R5- in which R4 is hydrogen, R5 in Cπ and C7 represent hydrogen, R5 in Cg represents methyl and in which the double bonds are of configuration E to l exception of the double bond

which is of configuration Z.

15. The molecule of claim 2, wherein

• Ri is hydrogen;

• L represents a group

• n = 1 and - [CR4 = CR5] n- represents:

in which R4 and R5 represent hydrogen and in which the double bond is of configuration E.

16. Molecule according to claim 2, in which:

• Ri is hydrogen, • L represents a group

the -O- being covalently linked to the said carbon atom in position 5 ′ of the said psoralen molecule,

• not

represents: -Ci4R4 = Cι ₃ R5-Ci2R4 = CιιR5-CιoR4 = C9R5-C ₈ R4 = C7R5- in which R ₄ is hydrogen, R5 in Cu and C7 represents hydrogen, R ₅ in C13 and Cg represents a methyl, and in which the double bonds are of configuration E.

17. Molecule according to claim 2, in which:

• Ri is hydrogen,

• L represents a group

• n = 4 and - [CR4 = CR5] n- represents: -Ci4R4 = Ci3R5-Ci2R4 = CιιR5-CιoR4 = C R5-CsR4 = C7R5- in which R ₄ is hydrogen, R5 in Cπ and C7 represents l ' hydrogen, Rs at C13 and C9 represents a methyl, and in which the double bonds are of configuration E with the exception of the double bond

which is of configuration Z.

18. The molecule of claim 2, wherein

• Ri is hydrogen;

• L represents a group

the -O- being covalently linked to the said carbon atom in position 5 'of the said psoralen molecule, • n = 3 and

represented :

-Ci R4 = CnR5-Cιo 4 = C9R5-C8R4 = C7R5- in which R ₄ is hydrogen, R5 in Cπ and C7 represent hydrogen, Rs in Cg represents methyl and in which the double bonds are of configuration E .

19. A molecule according to claim 2, in which • Ri is hydrogen;

• L represents a group

the -O- being covalently linked to the said carbon atom in position 5 ′ of the said psoralen molecule, • n = 3 and - [CR4 = CR5] n- represents:

-Ci2R4 = CιιR5-CιoR4 = C9R5-C8R4 = C7R5- in which R4 is hydrogen, Rs in Cπ and C7 represent hydrogen, R5 in C9 represents methyl and in which the double bonds are of configuration E to l exception of double bond

which is of configuration Z.

20. The molecule of claim 2, wherein

• Ri is hydrogen;

• L represents a group

the -O- being covalently linked to the said carbon atom in position 5 ′ of the said psoralen molecule, • n = 1 and

represented :

in which R and R5 represent hydrogen and in which the double bond is of configuration E.

21. Molecule according to any one of claims 11 to 20, characterized in that R is 2,6,6-trimethyl-1-cyclohexene-1-yl.

22. Molecule according to any one of claims 11 to 20, characterized in that R is 2,6,6-trimethyl-2-cyclohexene-1-yl.

23. Molecule according to any one of claims 11 to 20, characterized in that R is selected from phenyl and substituted phenyl.

24. Molecule according to claim 23, characterized in that said substituted phenyl is methoxyphenyl.

25. A molecule according to claim 21 of formula

26. Molecule according to claim 21 of formula

27. Molecule according to claim 21 of formula

28. Molecule according to claim 23 of formula

29. Molecule according to claim 24 of formula

30. Process for the preparation of a molecule according to claims 11 to 29, characterized in that it comprises the following steps: • Synthesis of the amide

€> NH-CO - [CR ₄ = CR ₅ ] n. R

from the corresponding acid HOOC- [CR4 = CRs] nR in the presence of 4 amino-pyridine and DCC, in which R4 and Rs independently represent a hydrogen atom, a linear or branched C1-Cs alkyl group, substituted or unsubstituted, n represents an integer from 1 to 10, the double bond -CR4 = CRs- is of configuration Z or E and R is chosen from a cyclo-C3-C6 alkyl group substituted or not, a cyclo group substituted or unsubstituted C4-C6 alkenyl, a substituted or unsubstituted phenyl group, the substituent being chosen from fluoro, chloro, iodo, bromo, hydroxyl, amino, thiol, -CN, -CO2H, -Cθ2-C1-alkyl Cs, C1-Cs alkyl, C_-Cs alkoxy. • Reaction of said amide with a halo-alkyloxy-psoralen or one of its substituted derivatives.

31. The method of claim 30, characterized in that said halo-alkyloxy-psoralen is selected from the group consisting of 5-bromo-propyloxy-psoralen and 8-bromo-propyloxy-psoralen.

32. Process according to claim 31 for the preparation of a molecule according to claim 25, characterized in that the said corresponding acid is all-trans retinoic acid 13 E (acid E, E, E, E 3,7-dimethyl- 9 (2,6,6-trimethyl-1-cyclohexene-1-yl) 2,4,6,8 nonatetraenoic) and that said halo-alkyloxy-psoralen is 8-bromo-propyloxy-psoralen.

33. Process according to claim 31 for the preparation of a molecule according to claim 26, characterized in that said corresponding acid is retinoic acid 13 Z (acid Z, E, E, E, 3, 7 dimethyl-9 (2 , 6,6 trimethyl-1-cyclohexene-1-yl) 2,4,6,8 nonatetraenoic) and that said halo-alkyloxy-psoralen is 8-bromo-propyloxy-psoralen.

34. Process according to claim 31 for the preparation of a molecule according to claim 27, characterized in that said corresponding acid is the retinoid 11 E (acid E, E, E 5-methyl-7 (2,6,6 trimethyl- 1-cyclohexene-1-yl) 2,4,6 heptatrienoic) and that said halo-alkyloxy-psoralen is 8-bromo-propyloxy-psoralen.

35. A method according to claim 31 for the preparation of a molecule according to claim 28, characterized in that said acid corresponding to (E) 3 (phenyl) -2-propenoic acid and that said haloalkyloxy-psoralen is 8-bromo-propyloxy-psoralen.

36. Process according to claim 31 for the preparation of a molecule according to claim 28, characterized in that said acid corresponding to (E) 3 (4-methoxy-phenyl) -2-propenoic acid and that said halo-alkyloxy -psoralen is 8-bromo-propyloxy-psoralen.

37. Molecule according to one of claims 1 to 29 as a medicament.

38. Molecule according to one of claims 1 to 29 as a medicament intended for the treatment of a pathology involving cellular hyperproliferation.

39. Molecule according to claim 38, characterized in that said pathology is chosen from the group composed of psoriasis, parapsoriasis, cutaneous lymphomas, actinic hyperperatosis, cutaneous melanoma, cutaneous carcinomas.

40. Molecule according to claim 39, characterized in that said pathology is psoriasis.

41. Pharmaceutical composition, characterized in that it comprises an effective amount of a molecule according to one of claims 1 to 29 and a pharmaceutically acceptable vehicle.

42. Use of a molecule according to any one of claims 1 to 29 for the preparation of a medicament or of a pharmaceutical composition according to claim 41 for the treatment and / or prevention of a pathology involving cell hyperproliferation .

43. Use according to claim 42, characterized in that said pathology is chosen from the group consisting of psoriasis, parapsoriasis, cutaneous lymphomas, actinic hyperkeratosis, cutaneous melanoma, cutaneous carcinomas.

44. Use according to claim 43, characterized in that said pathology is psoriasis.

45. Use according to claims 42 to 44, characterized in that the cells in the hyperproliferation phase are simultaneously or in a time-shifted manner irradiated with ultraviolet rays.

46. Use according to claim 45, characterized in that the ultraviolet rays are U.V.A.

47. Pharmaceutical composition, in particular dermatological composition, intended for topical administration for the preventive and / or curative treatment of psoriasis characterized in that it contains a therapeutically effective amount of a molecule according to claims 1 to 29 and a pharmaceutically acceptable vehicle .

48. Composition according to claim 47, characterized in that it further comprises one or more filters of ultraviolet rays B.

49. Use of a composition according to claims 47 or 48 in combination with irradiation with ultraviolet A (U.V.A.) rays of cells affected by psoriasis, simultaneously or over time.

50. Cosmetic composition characterized in that it contains an effective amount of a molecule according to claims 1 to 29 and a cosmetically acceptable vehicle.

51. Cosmetic composition according to claim 50, characterized in that it also contains at least one sun filter or at least one sun screen.

52. Use of a molecule according to any one of claims 1 to 29 or of a composition according to claims 50 or 51 in the field of cosmetics for:

(i) Stimulate skin pigmentation; and or

(ii) promote the tanning of the skin; and / or (iii) Prevent, erase and treat wrinkles and fine lines on the skin; and or

(iv) Fight against aging by fighting against sagging skin and / or subcutaneous; and or

(v) Improve the texture of the skin and revive the radiance of the skin.