AU2938899A

AU2938899A - Use of retinoic acid activity inhibitors to slow down hair loss

Info

Publication number: AU2938899A
Application number: AU29388/99A
Authority: AU
Inventors: Jean-Daniel Doutremepuich; Carole Marconnet
Original assignee: Galderma Research and Development SNC
Current assignee: Galderma Research and Development SNC
Priority date: 1998-03-31
Filing date: 1999-03-24
Publication date: 1999-10-18
Also published as: BR9908411A; KR20010042104A; JP2002509870A; CN1298290A; AR015551A1; PL343004A1; HUP0102411A3; NO20004880L; CA2324899A1; FR2776511A1; WO1999049838A1; EP1066017A1; HUP0102411A2; RU2193877C2; IL137859A0; ZA200004483B; FR2776511B1; NO20004880D0

Description

WO 99/49838 PCT/FR99/00687 USE OF INHIBITORS OF THE ACTIVITY OF RETINOIC ACID TO SLOW DOWN HAIR LOSS The present invention relates, in its most 5 general aspect, to the use, in a cosmetic composition or for the preparation of a pharmaceutical composition to slow down or prevent the growth of hairs and/or the hair, of at least one inhibitor of the activity of retinoic acid. The compositions according to the 10 present invention are also intended to slow down the loss of hairs and/or the hair. The invention also relates to a non-therapeutic treatment process for modifying hair growth. In human beings, hair growth and its renewal 15 are mainly determined by the activity of the hair follicles. Their activity is cyclic and essentially comprises three phases, namely the anagenic phase, the catagenic phase and telogenic phase. The active anagenic phase or growth phase, 20 which lasts several years and in the course of which the hair gets longer, is followed by a very short and transient catagenic phase which lasts a few weeks, and then by a rest phase, known as the telogenic phase, which lasts a few months. 25 At the end of the rest period, the hairs fall out and a new cycle starts. The hair is thus in constant renewal and, out of the approximately 2 150,000 hairs which make up a head of hair, at any moment, about 10% of them are at rest and will thus be replaced within a few months. In a large number of cases, early loss of 5 hair occurs in individuals who are genetically predisposed, and this especially affects men. This more particularly involves androgenetic or androgenic alopecia or alternatively androgeno-genetic alopecia. This alopecia is essentially due to a 10 disruption in hair renewal, which results, in a first stage, in acceleration of the frequency of the cycles at the expense of the quality and then the quantity of the hairs. A gradual thinning of the head of hair takes place by regression of the so-called "terminal" hairs 15 at the downy stage. Certain regions are preferentially affected, in particular the temporal or frontal areas in men, and a diffuse alopecia of the vertex is observed in women. Substances for suppressing or reducing the 20 effect of alopecia, and in particular for reducing hair loss or for inducing or stimulating hair growth, have been sought for many years in the cosmetics and pharmaceutical industries. In this respect, a large number of very 25 diverse active substances or compounds has, admittedly, already been proposed. As a reminder, mention will be made, inter alia, of vitamins such as vitamin E, amino acids such as, for example, serine or methionine, 3 vasodilators such as acetylcholine and derivatives thereof, female hormones such as, for example, oestradiol, keratolytic agents such as salicylic acid or chemical compounds such as, for example, 5 2,4-diamino-6-piperidinopyrimidine 3-oxide or "Minoxidil" described in US 4 596 812, or alternatively the many derivatives thereof such as those described, for example, in patent applications EP 353 123, EP 356 271, EP 408 442, EP 522 964, EP 420 707, 10 EP 459 890 and EP 519 819. Mention may also be made of 6-amino 1,2-dihydro-l-hydroxy-2-imino-4-piperidinopyrimidine and derivatives thereof, which are described more particularly in patent US-A-4 139 619. 15 It remains that it would generally be advantageous and useful to have available active substances other than those already known. Although Minoxidil remains the reference compound in the field, it has appreciable side effects 20 which complicate its use. The discovery of substances with an effect on hair growth and/or hair loss without having any inconvenient side effects remains a major object of research. 25 Moreover, it is advantageous to find compounds capable of slowing down the growth of hairs and/or the hair.

4 It is known in general that all-trans retinoic acid acts on cell differentiation and/or proliferation by interacting with nuclear receptors or RARs (retinoic acid receptors) contained in the cell 5 nucleus. Many synthetic structural analogues of all trans retinoic-acid or of 9-cis-retinoic acid, commonly referred to as "retinoids", have been described to date in the literature. Three identified sub-types of PAR receptor, referred to respectively as RAR-a, RAR-P and 10 RAR-y, exist at the present time. After binding the ligand (i.e. all-trans retinoic acid), these receptors interact with the promoter region of genes regulated by retinoic acid at the level of specific response elements (RAREs). 15 Certain analogues can bind to and activate a specific RAR receptor sub-type (a, P or y) . Finally, other analogues show no specific selective activity with respect to these various receptors. In this regard, and by way of example, all-trans retinoic acid 20 activates RARs (RAR-specific agonist ligand), irrespective of the sub-type. Retinoic acid and retinoids in general, on binding with the RAR receptors allowing the activity of the RAR receptors to be regulated, have been described 25 as being able to treat many skin disorders or complaints, and more particularly alopecia. On the contrary, retinoic acid antagonists inhibit the activity of retinoic acid or metabolites 5 thereof at the cellular level. This more particularly concerns RAR antagonists which bind to the RAR receptors, but do not induce the activity observed for retinoic acid or retinoids. 5 Thus, it has been shown that RARa receptor antagonists inhibit the cell differentiation induced by retinoids on cells of the HL60 cell line or, on the contrary, reverse the inhibition of proliferation of mouse B-cells which is induced by retinoids (C. Apfel 10 et al., Proc. Natl. Acad. Sci. USA, 89, 1992, 7129 7133). Various retinoic acid antagonists are described in patent application EP 0 740 937. They are recommended for treating disorders and/or complaints 15 associated with an over-regulation of the RAR receptors and/or with hypervitaminosis A, usually being reflected by an inflammatory, allergic and/or immunological component, such as psoriasis. They are also described as treating alopecia. 20 After considerable research, the Applicant has now found that by inhibiting the activity of retinoic acid in the skin cells in the region of the hair follicles, it is possible, entirely surprisingly and unexpectedly, to substantially slow down the hair 25 cycle and more particularly the anagenic phase or the telogenic phase. Even more specifically, it has been found that by inhibiting the activity of retinoic acid, it is 6 possible to slow down and/or prevent the growth of hairs and/or the hair and/or slow down the loss of hairs and/or the hair. This discovery forms the basis of the present 5 invention. Thus, according to a first aspect of the present invention, the use is now proposed, in or for the preparation of a cosmetic or pharmaceutical composition, preferably a dermatological composition, 10 which is intended to slow down and/or prevent the growth of hairs and/or the hair, of at least one inhibitor of the activity of retinoic acid. In a second aspect of the invention, the use is now proposed, in or for the preparation of a 15 cosmetic or pharmaceutical composition, preferably a dermatological composition, which is intended to slow down the loss of hairs and/or the hair, of at least one inhibitor of the activity of retinoic acid. The inhibitors of the activity of retinoic 20 acid may act according to two routes, the first by accelerating the cellular metabolism of retinoic acid so as to reduce its cellular concentration, and the second by antagonizing its action at the cellular level. 25 According to the invention, the inhibitors of the activity of retinoic acid can thus be accelerators of the metabolism of retinoic acid or of antagonists, inverse agonists or partial agonists of retinoic acid.

7 According to the invention, the expression "retinoic acid antagonists" preferably means compounds which inhibit the action of retinoic acid and/or of its metabolites and/or of retinoids. These'are, more 5 particularly, RAR antagonists which bind to the RAR receptors without, however, activating them. This refers more particularly to compounds which inhibit the "in vivo" activity of retinoic acid, which are selected according to the test described in 10 patent application EP 96 401 170 filed on 31 May 1996 in the name of CIRD GALDERMA. This concerns a process for identifying RAR-antagonist molecules, characterized in that it comprises the following steps: (i) a sufficient amount of an RAR-agonist molecule is applied 15 topically to a region of a mammal's skin, (ii) a molecule liable to have RAR-antagonist activity is administered systemically or topically to this same mammal or to this same region of the mammal's skin, before, during or after step (i), and (iii) the 20 response on the region of the mammal's skin thus treated is evaluated. Thus, when the molecule administered is an RAR antagonist, the increase in the thickness of the region of the mammal's skin treated with an RAR-agonist molecule is not observed or is 25 reduced. An inhibition of the response is thus observed. In practice, the mammal is a rodent such as a mouse, a rat, a guinea pig, a hamster or a rabbit. The region of the mammal's skin used can be any region of 8 the mammal's body. The response on the region of skin thus treated of the mammal to be evaluated corresponds to a clinical change in this region of skin. In general, this response to be evaluated corresponds to a 5 change in the thickness of the region of skin thus treated. The thickness of the region of skin thus treated can be measured by any method known per se. When the region of skin used is smooth, its thickness can be measured by folding it. In more practical terms, 10 the skin of the ear is used. In this case, the thickness of the ear can be measured with an "oditest" micrometer. Needless to say, the evaluation of step (iii) corresponds to a measurement of the response of the region of skin thus treated and to a comparison 15 of this measurement with that of the response of the same region of treated skin, under the same conditions, with the RAR-agonist molecule alone. The RAR-agonist molecules are preferably chosen from compounds capable of inducing the differentiation of mouse embryonic 20 teratocarcinoma (F9) cells. The secretion of the plasminogen activator which accompanies this differentiation is an indicator of the biological response of the F9 cells to these compounds. It is also known that the ability of these compounds to induce the 25 plasminogen activator is directly correlated with their affinity to and activity on the RAR receptors endogenous to the F9 cells (Skin Pharmacol., 1990, 3, pp. 256-267). Among the RAR-agonist molecules which 9 induce F9 cell differentiation, mention may be made more particularly of: - all-trans retinoic acid, - 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl 5 2-naphthyl)-6-benzo[b]thiophenecarboxylic acid,

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4 -[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl 2-naphthyl)carboxamido]benzoic acid, - 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl 2-naphthyl)carbamoyl]benzoic acid. 10 The sufficient amount of an RAR-agonist molecule to be applied corresponds to that at which a response is observed in the treated region of the mammal's skin after step (i). Thus, preferably and depending on the nature of the RAR-agonist molecule 15 used, this amount ranges between 0.0001% and 2% by weight per volume of solution applied. In the text hereinbelow and hereinabove, the expression "topical route" means any technique for administering a product by applying it directly to a 20 superficial (or external) region of the body, and the expression "systemic route" means any technique for administering a product via a route other than the topical route, for example enterally and/or parenterally. In the case of the systemic route, the 25 oral route is preferably used. The retinoic acid antagonists are, in particular, compounds described in the patent applications EP 661 259, EP 740 937, EP 658 553, 10 EP 568 898, WO 95/33745, WO 97/09297 and WO 94/14777, and in several scientific publications, in particular Eyrolles et al. (J. Med. Chem., 37, 1994, 1508-1517; Med. Chem. Res., 2, 1992, 361-367) and Kaneko et al. 5 (Med. Chem. Res., 1, 1991, 220-225), which are incorporated herein by reference and which inhibit the action of retinoic acid and/or retinoids. The RAR antagonists which are useful according to the invention are selected in particular 10 from the following compounds: - 4- [7- (1-adamantyl) -6-methoxyethoxymethoxy 2-naphthyl]benzoic acid - 4- [7- (1-adamantyl) -6-methoxyethoxymethoxy 2-naphthyl]salicylic acid, 15 - 6- [7- (1-adamantyl) -6-methoxyethoxymethoxy 2-naphthyl]nicotinic acid, - 4-{[5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl) 2-naphthyl]ethynyl}benzoic acid, - (E)-4-[2-(4,4-dimethyl-7-heptyloxy-1,1-dioxo 20 3,4-dihydro-2H-1-benzothiopyran-6-yl)propenyl]benzoic acid, - 4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl 1-(3-pyridylmethyl)anthra[1,2-b]pyrrol-3-yl]benzoic acid, 25 - 4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl 1-(3-pyridylmethyl)thioanthra[1,2-b]pyrrol-3-yl]benzoic acid, 11 - 4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl 1-(3-pyridylmethyl)anthra[1,2-d]pyrazol-3-yl]benzoic acid, - 4-[3-(diadamantyl)-4-methoxybenzamido]benzoic acid, 5 - 4-[3-(diadamantyl)-4-methoxybenzoyloxy]benzoic acid, - 4-(N-phenyl-5,6,7,8-tetrahydro-5,5,8,8 tetramethylnaphtho[2,3-d]imidazol-2-yl)benzoic acid, - 4-(N-benzyl-5,6,7,8-tetrahydro-5,5,8,8 tetramethylnaphtho[2,3-dimidazol-2-yl)benzoic acid, 10 - 4-(5H-7,8,9,10-tetrahydro-5,7,7,10,10 pentamethylbenzo[c]naphtho[2,3-b][1,4]diazepin 3-yl)benzoic acid, - 4-[1-(1-methoxy-2,2,2-trifluoroethyl)-5,6,7,8 tetrahydro-5,5,8,8-tetramethyl-3-anthracenyl]benzoic 15 acid, - 4-(5,5-dimethyl-8-phenyl-5,6-dihydronaphth 2-ylethynyl)benzoic acid, - 4-(5,5-dimethyl-8-p-tolyl-5,6-dihydronaphth 2-ylethynyl)benzoic acid, 20 - 4-[4-(biphenyl-2-yl)but-3-en-1-ynyl)benzoic acid, - (E)-4-[[3-oxo-3-[3-(1-adamantyl)-4-methoxyethoxy methoxyphenyl]-1-propenyll]benzoic acid. The RAR antagonists which are useful according to the invention are preferably selected from 25 the following compounds: - 4-(5,5-dimethyl-8-p-tolyl-5,6-dihydronaphth 2-ylethynyl)benzoic acid, 12 - 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy 2-naphthyl]benzoic acid, - 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy 2-naphthyl]salicylic acid, 5 - 6-[7-(1-adamantyl)-6-methoxyethoxymethoxy 2-naphthyl]nicotinic acid. Even more preferentially, the RAR antagonists which are useful according to the invention are selected from the following compounds: 10 - 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy 2-naphthyllsalicylic acid, - 6-[7-(1-adamantyl)-6-methoxyethoxymethoxy 2-naphthyl]nicotinic acid. Other characteristics, aspects, objects and 15 advantages of the invention will emerge even more clearly on reading the description which follows, as well as the various concrete, but in no way limiting, examples intended to illustrate it. It may be noted in general that, in the 20 context of the present invention, it is obviously entirely possible to use mixtures of inhibitors, providing, of course, that these mixtures remain compatible with the desired effect. The amount of inhibitor which can be used 25 according to the invention obviously depends on the desired effect. It also depends on the inhibitor. It can thus vary within a wide range.

13 To give an order of magnitude, if an inhibitor of the activity of retinoic acid is used in a cosmetic composition, this composition can contain the inhibitor in an amount representing from 0.0001% to 5% 5 relative to the total weight of the composition and preferably in an amount representing from 0.01% to 2% relative to the total weight of the composition. To give an order of magnitude, if an inhibitor of the activity of retinoic acid is used to 10 prepare a dermatological composition, this composition can contain the inhibitor in an amount representing from 0.001% to 15% relative to the total weight of the composition and preferably in an amount representing from 0.1% to 10% relative to the total weight of the 15 composition. In general, it will be noted that all the above products can be conventionally packaged in a form suitable for the mode of administration or application selected for these products (lotions, shampoos, 20 tablets, syrups, nutritional supplements and the like). The compositions can be conventionally packaged in a form which is suitable for the various modes of administration or application envisaged (lotions, shampoos, tablets, syrups and the like). 25 Thus, the compositions are preferably packaged in a form which is suitable for topical application. The compositions according to the invention can also incorporate various conventional and common 14 additives, in particular cosmetic additives in the case of topical applications (in particular hair products), which are chosen, for example, from UV screening agents, thickeners, penetrating agents such as urea, 5 organic solvents such as ethanol, isopropanol or alkylene glycol-s, surfactants chosen from nonionic surfactants such as alkylpolyglycosides, cationic surfactants, anionic surfactants and amphoteric surfactants, dyes, antidandruff agents, fragrances and 10 preserving agents. Needless to say, the compounds added to the compositions are chosen by a person skilled in the art such that they do not contravene the desired effect of the present invention. 15 It is also possible to incorporate into the compositions products already known as having activity in the field of slowing down and/or inhibiting the growth of hairs and/or the hair. In this regard, mention may be made, for 20 example, of cyclooxygenase inhibitors and/or lipoxygenase activators, such as those mentioned in patent applications EP-A-94/402 055, WO-A-94/27586 or WO-A-94/27563. Similarly, it is possible to incorporate into 25 the compositions products already known as having an activity in the field of the loss of hairs and/or the hair and/or products which have activity in the treatment of alopecia.

15 Irrespective of the composition envisaged, it is possible to combine the inhibitor of the activity of retinoic acid and the other component(s) that are active on the growth of hairs and/or the hair in a 5 single composition. However, specific embodiments may be envisaged, and in particular the inhibitor of the activity of retinoic acid and the other active component(s) may be administered simultaneously, separately or sequentially. 10 Thus, one subject of the invention is a product comprising at least one inhibitor of the activity of retinoic acid and at least one other active component, as a combination product for simultaneous, separate or sequential use to slow down and/or inhibit 15 the growth of hairs and/or the hair. A subject of the invention is also a product comprising at least one inhibitor of the activity of retinoic acid and at least one other active component, as a combination product for simultaneous, separate or 20 sequential use to slow down the loss of hairs and/or the hair. In one specific embodiment, the inhibitor of the activity of retinoic acid and the other active component(s) may be packaged separately in the form of 25 a kit whose components will be mixed together at the time of use. One subject of the invention is thus a kit comprising at least one inhibitor of the activity of 16 retinoic acid and at least one other active component, for simultaneous, separate or sequential use to slow down and/or inhibit the growth of hairs and/or the hair. 5 The invention also relates to a kit comprising at least one inhibitor of the activity of retinoic acid and at least one other active component, for simultaneous, separate or sequential use to slow down the loss of hairs and/or the hair. 10 According to the invention, the inhibitor of the activity of retinoic acid can be used in an amount ranging from 0.0001% to 15% by weight and preferably ranging from 0.01% to 10%. Similarly, the cyclooxygenase inhibitor or 15 the lipoxygenase activator can be used in an amount ranging from 0.001% to 5% by weight and preferably ranging from 0.01% to 0.1%. According to yet another aspect of the present invention, a non-therapeutic treatment process 20 for slowing down or preventing the growth of hairs and/or the hair is also proposed, this process comprising the topical and/or systemic administration to the body of at least one inhibitor of the activity of retinoic acid, at doses as defined previously, the 25 body preferably being a human being. According to yet another aspect of the present invention, a non-therapeutic treatment process for slowing down the loss of hairs and/or the hair is 17 also proposed, this process comprising the topical and/or systemic administration to the body of at least one inhibitor of the activity of retinoic acid, at doses as defined previously, the body preferably being 5 a human being. The inhibitor of the activity of retinoic acid is preferably administered topically. According to one particularly preferred embodiment of the process according to the invention, 10 compositions as defined previously are applied to the skin and/or the scalp. In order to obtain appreciable effects, the frequency of administration or application of the compositions according to the invention is about one to 15 two times a day. In this regard, it will be noted that the sufficient amounts of inhibitory agents to be used in the context of the invention may generally remain very small. The present invention finds particularly 20 useful applications in the field of treating various pathologies affecting the pilosebaceous units of the skin and/or the scalp, in particular hirsutism. Concrete examples illustrating the invention will now be given. In the text hereinabove and 25 hereinbelow, the percentages are given on a weight basis, except where otherwise mentioned.

18 Example 1: 42-day-old male C57BL6 mice are selected for their hair cycle in the rest phase (telogenic phase). They are then shaved (DO). Since melanin synthesis 5 takes place only on hairs in the active phase, the skin of the shaved mice is pink. The animals are divided into two groups, one receiving a composition comprising an inhibitor of the activity of retinoic acid, and the other being treated 10 with the vehicle for this composition. 50 pl of these compositions are applied daily from Dl to a 'shaved area of skin (3 cm 2 ) at concentrations ranging from 0.1% to 0.3% of the inhibitor of the activity of retinoic acid. 15 The animals are observed daily and the criteria corresponding to the area thus treated are noted daily. The criteria are as follows: Criterion 0: uniformly pink skin 20 Criterion 1: appearance of a grey coloration as marks on the shaved area Criterion 2: appearance of the first hair stalks on the shaved area Criterion 3: grey colour over the entire shaved area 25 Criterion 4: presence of hairs over the entire shaved area Criterion 5: regrown hair not distinct from the hair remaining in place 19 The results are given in the tables which follow. These results correspond to the area under the curve corresponding to the change of each criterion as a function of time (maximum duration of observation: 5 90 days). Criteria CD2665 CD2848 CD2848 Vehicle (0.1%) (0.1%) (0.3%) 1 7655 7745 7605 7935 2 7425 7455 7270 7660 3 6735 6935 6650 7185 4 6445 6605 6325 6865 5 3025 2690 1935 3225 Table 1 Criteria CD2665 CD3106 Vehicle (0.1%) (0.1%) 1 7972 8031 8422 2 7683 7731 8150 3 6900 7131 7606 4 6639 6869 7189 5 4850 2450 5506 Table 2 20 Criteria CD2665 CD2665 CD2822 Vehicle (0.1%) (0.3%) (0.1%) 1 9235 9535 9635 9650 2 9050 9235 9405 9385 3 8005 8500 9105 9065 4 -7555 8260 8880 8720 5 4335 5200 6465 5485 Table 3 CD2665 represents 4-[7-(1-adamantyl) 6-methoxyethoxymethoxy-2-naphthyl]benzoic acid, CD2822 represents 6-[7-(1-adamantyl) 5 6-methoxyethoxymethoxy-2-naphthyl]nicotinic acid, CD3106 represents 4-(5,5-dimethyl-8-p-tolyl 5,6-dihydronaphth-2-ylethynyl)benzoic acid, CD2848 represents 4- [7- (1-adamantyl) 6-methoxyethoxymethoxy-2-naphthyl] salicylic acid. 10 The restart of the growth and lengthening of the individual hairs are significantly delayed in the animals which were treated with an inhibitor of the activity of retinoic acid, in comparison with animals treated with the vehicle. 15 Example 2: Examples of formulations illustrating the invention. These compositions are obtained by simply mixing together the various components.

21 Composition 1: Leave-in lotion 4- [7- (1-Adamantyl) -6 -methoxyethoxymethoxy 2-napthyl]benzoic acid 1.0 g Propylene glycol 22.8 g 5 950 Ethanol 55.1 g Purified water- qs 100 g Composition 2: Rinse-out lotion 4- [7- (1-Adamantyl) -6-methoxyethoxymethoxy 10 2-napthyl]salicylic acid 5.0 g Propylene glycol 22.8 g Absolute ethanol qs 100 g Composition 3: Leavq-in lotion 15 4-(5,5-Dimethyl-8-p tolyl-5,6 dihydronaphth-2-ylet hynyl) benzoic acid 8.0 g 950 Ethanol 55.1 g Purified water qs 100 g

Claims

1. Use, in or for the preparation of a cosmetic or pharmaceutical composition, preferably a dermatological composition, which is intended to slow 5 down and/or prevent the growth of hairs and/or the hair, of at least one inhibitor of the activity of retinoic acid.

2. Use, in or for the preparation of a cosmetic or pharmaceutical composition, preferably a 10 dermatological composition, which is intended to slow down the loss of hairs and/or the hair, of at least one inhibitor of the activity of retinoic acid.

3. Use according to either of the preceding claims, characterized in that the inhibitor of the 15 activity of retinoic acid is administered topically or systemically.

4. Use according to the preceding claim, characterized in that the inhibitor of the activity of retinoic acid is administered topically. 20

5. Use according to any one of the preceding claims, characterized in that the inhibitor of the activity of retinoic acid is chosen from: 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy 2-naphthyl]benzoic acid, 25 - 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy 2-naphthyl]salicylic acid, 23 - 6-[7-(1-adamantyl)-6-methoxyethoxymethoxy 2-naphthyl]nicotinic acid, - 4-{[5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl) 2-naphthyl]ethynyl}benzoic acid, 5 - (E)-4-[2-(4,4-dimethyl-7-heptyloxy-1,1-dioxo 3,4-dihydro-2H=l-benzothiopyran-6-yl)propenyl]benzoic acid, - 4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl 1-(3-pyridylmethyl)anthra[1,2-b]pyrrol-3-yllbenzoic 10 acid, - 4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl 1-(3-pyridylmethyl)thioanthra[1,2-b]pyrrol-3-yllbenzoic acid, - 4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl 15 1-(3-pyridylmethyl)anthra[1,2-d]pyrazol-3-yl]benzoic acid, - 4-[3-(diadamantyl)-4-methoxybenzamido]benzoic acid, - 4-[3-(diadamantyl)-4-methoxybenzoyloxylbenzoic acid, - 4-(N-phenyl-5,6,7,8-tetrahydro-5,5,8,8 20 tetramethylnaphtho[2,3-d]imidazol-2-yl)benzoic acid, - 4-(N-benzyl-5,6,7,8-tetrahydro-5,5,8,8 tetramethylnaphtho[2,3-d]imidazol-2-yl)benzoic acid, - 4-(5H-7,8,9,10-tetrahydro-5,7,7,10,10 pentamethylbenzo[cnaphtho[2,3-b] [1,4]diazepin 25 3-yl)benzoic acid, - 4-[1-(1-methoxy-2,2,2-trifluoroethyl)-5,6,7,8 tetrahydro-5,5,8,8-tetramethyl-3-anthracenyl]benzoic acid, 24 - 4-(5,5-dimethyl-8-phenyl-5,6-dihydronaphth 2-ylethynyl)benzoic acid, - 4-(5,5-dimethyl-8-p-tolyl-5,6-dihydronaphth 2-ylethynyl)benzoic acid, 5 - 4-[4-(biphenyl-2-yl)but-3-en-1-ynyl)benzoic acid, - (E)-4-[[3-oxo-3-[3-(l-adamantyl)-4-methoxyethoxy methoxyphenyl]-1-propenyl]]benzoic acid.

6. Use in a cosmetic composition according to any one of the preceding claims, characterized in 10 that the inhibitor of the activity of retinoic acid is at a concentration ranging from 0.0001% to 5% and preferably from 0.01% to 2% by weight relative to the total weight of the composition.

7. Use for the preparation of a 15 dermatological composition according to any one of Claims 1 to 5, characterized in that the inhibitor of the activity of retinoic acid is at a concentration ranging from 0.001% to 15% and preferably from 0.1% to 10% by weight relative to the total weight of the 20 composition.

8. Non-therapeutic treatment process for slowing down or preventing the growth of hairs, which comprises the topical and/or systemic administration to the body of at least one inhibitor of the activity of 25 retinoic acid as defined in Claims 1 and 3 to 6.

9. Non-therapeutic treatment process for slowing down the loss of hairs and/or the hair, which comprises the topical and/or systemic administration to 25 the body of at least one inhibitor of the activity of retinoic acid as defined in Claims 2 to 6.

10. Product, characterized in that it comprises at least one inhibitor of the activity of 5 retinoic acid and at least one other active component, for simultaneous, separate or sequential use to slow down and/or inhibit the growth of hairs and/or the hair.

11. Product, characterized in that it 10 comprises at least one inhibitor of the activity of retinoic acid and at least one other active component, for simultaneous, separate or sequential use to slow down the loss of hairs and/or the hair.

12. Product according to either of Claims 10 15 and 11, characterized in that it is in the form of a kit.