WO2006053789A1 - Protection de la peau contre la deterioration associee a un dysfonctionnement induit par le stress des processus apoptotiques et de defense immunitaire - Google Patents

Protection de la peau contre la deterioration associee a un dysfonctionnement induit par le stress des processus apoptotiques et de defense immunitaire Download PDF

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WO2006053789A1
WO2006053789A1 PCT/EP2005/013531 EP2005013531W WO2006053789A1 WO 2006053789 A1 WO2006053789 A1 WO 2006053789A1 EP 2005013531 W EP2005013531 W EP 2005013531W WO 2006053789 A1 WO2006053789 A1 WO 2006053789A1
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stress
compound
use according
composition
agent
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PCT/EP2005/013531
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English (en)
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Audrey Gueniche
Lionel Breton
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L'oreal
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Priority claimed from FR0452721A external-priority patent/FR2878155A1/fr
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Publication of WO2006053789A1 publication Critical patent/WO2006053789A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A61K8/442—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof substituted by amido group(s)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/69—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing fluorine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • the field of the invention relates to the protection of skin and/or of its superficial body growths from deteriorations of the skin and in particular of the epidermis, linked to apoptotic processes amplified under stress conditions and/or to a stress-induced decrease in immune defences.
  • the invention relates to the use of at least one compound of the N-acylaminoamide family in or for the preparation of a composition intended to prevent and/or reduce the apoptotic processes amplified by stress and/or to prevent and/or combat a stress-induced, in particular a UV stress, decrease in the immune defenses of the skin.
  • the invention relates in particular to the prevention and/or treatment of the deteriorations of the skin and/or its superficial body growths linked to a dysfunction of the physiological mechanisms of apoptosis, in particular amplified, which can lead to an excessive destruction of the cells of the skin and/or of the scalp (involved in particular in the formation of sunburn cells, hair loss or androgenic alopecia, and atopic dermatitis) .
  • These deteriorations affect mainly the keratinocytes in the epidermis.
  • physiological mechanism of apoptosis is understood to mean a mechanism which is normally induced in order to re-establish a situation of equilibrium or homeostasis: for example in order to balance the mitotic processes and adjust the size of animal tissues, or to remove cells damaged during inflammatory phenomena, cancerization, autoimmune diseases.
  • skin is understood to mean, according to the invention, the skin extended to the scalp and to the mucous membranes.
  • the present invention relates in particular to the use of at least one compound of the
  • N-acylaminoamide family in a composition as agent intended to protect the skin and/or its superficial body growths against deteriorations linked to apoptotic processes amplified under stress conditions and/or a stress-induced decrease in immune defences.
  • the said compound is intended to prevent and/or reduce and/or repair stress-induced DNA damage and/or to regulate stress-induced dysfunctions of the physiological mechanisms of apoptosis, in particular to reduce the apoptotic processes amplified by stress.
  • the use of these compounds is intended to prevent and/or reduce skin disorders linked to apoptotic processes amplified by UV stress (e.g.: formation of sunburn cells, hair loss) or the risks of photoinduced skin cancers.
  • the preferred compounds used according to the invention are (2- (acetyl- (3-trifluoromethylphenyl) - amino) -3-methylbutyrylamino) acetic acid or ethyl (2- (acetyl (3-trifluoromethylphenyl)amino) -3-methyl- butyrylamino) acetate.
  • the human skin consists of two compartments, the epidermis and the dermis.
  • the epidermis is mainly composed of three types of cell which are the keratinocytes (predominant) , the melanocytes and the Langerhans' cells. Each of these cell types contributes, through its specific functions, to the main role played in the body by the skin, in particular the role of protecting the body against the abovementioned external attacks .
  • the dermis provides the epidermis with a solid support. It is also its feeder component. It mainly consists of fibroblasts and an extracellular matrix which is itself mainly composed of collagen, elastin and glycoproteins which constitute the ground substance. Leukocytes, mastocytes and tissue macrophages are also found therein. Finally, the dermis is crossed by blood vessels and nerve fibres.
  • the human skin is intended in particular to protect the body from dehydration and from external attacks following stress as defined above.
  • UVB and UVA radiation induces in the cells of the skin: - DNA lesions, in the form of breaks in a DNA strand or chemical modifications of nucleotide bases (e.g.: formation of dimers of pyrimidine or dimers of the 4-6 type for example) ;
  • UV-B radiation (290-320 nm; 5% of the total UV radiation) , with the most energetic wavelengths, affects mainly the epidermal cells (keratinocytes) by acting on the DNA;
  • UV-A radiation (320-400 nm; 95% of the total UV radiation) , which is more penetrating, reaches the dermal cells such as the fibroblasts and acts indirectly via the generation of free radicals; - furthermore, prolonged exposure to ultraviolet radiation, particularly to A and/or B type ultraviolet radiation, has the effect of stimulating the expression of collagenases.
  • UVA and UVB radiation have a direct effect on the Langerhans' cells, which are responsible for skin immune responses; this radiation induces changes in the morphology and a reduction in the number of Langerhans' cells and in their antigen- presenting function. These UV attacks result in the suppressive effect on the immune defences, causing a decrease in resistance to pathogenic agents, and in particular an increase in the incidence of certain cancers.
  • basocellular cancers keratinocytic tumours
  • spinocellular cancers malignant melanomas.
  • malignant melanomas The first two are keratinocytic tumours, and the third is a melanocytic tumour.
  • oxidative stress on the constituents of the skin is the result of an imbalance between, on the the one hand, the production of reactive oxygen species, including the superoxide anion, hydrogen peroxide and the hydroxy1 radical, and, on the other hand, the antioxidant mechanisms of cellular defence.
  • Stress-induced DNA damage or genotoxic damage is in principle repaired by the cellular machinery within a time interval which may range from a few minutes for DNA break type lesions, to a few hours for lesions which impair the chemical structure of the DNA.
  • This cellular machinery involves in particular: - a protein p53 which ensures the integrity of the cellular genome and which, when a mutation appears in the DNA of a cell, prevents the affected cell from dividing so long as the lesion has not been repaired; - specialized enzymatic systems (e.g.: nucleotide excision repair NER or global excision repair GER) in cells which normally make it possible to repair these lesions (e.g.: endonuclease T4N5 and photolyase) .
  • nucleotide excision repair NER or global excision repair GER e.g.: nucleotide excision repair NER or global excision repair GER
  • endonuclease T4N5 and photolyase e.g.: endonuclease T4N5 and photolyase
  • the physiological mechanism of apoptosis is a form of highly selective cell destruction which is characterized by distinct, easily observable morphological and biochemical phenomena of the nucleus and the cytoplasm: condensation of chromatin, associated or otherwise with an endonuclease activity, the formation of apoptotic bodies and fragmentation of deoxyribonucleic acid (DNA) because of the activation of endonucleases, into DNA fragments of 180-200 base pairs giving a profile that is easily recognizable by agarose gel electrophoresis, are observed. Apoptotic bodies (cytoplasmic and nuclear elements) are then phagocytosed by the neighbouring cells, without any inflammatory reaction (Kerr JF et al. , Br J Cancer 1972: 26: 239-257) . This mechanism is different from necrosis which corresponds to a cytotoxic process of anarchic destruction.
  • This physiological mechanism of apoptosis may be divided into three perfectly orchestrated steps: - during the stimulation phase, the cell receives a proapoptotic signal (Bad, Bax, Noxa, NAIP) which triggers a signalling pathway specific to each stimulus;
  • a proapoptotic signal Bad, Bax, Noxa, NAIP
  • the cell integrates the signal received and converts it or otherwise to an effector response; and - when the decision to take the cell death route is taken, the cell enters the degradation phase and activates catabolic enzymes.
  • Two main actors orchestrate the morphological and biochemical modifications which accompany the apoptotic process: on the one hand, cysteine proteases,
  • the members of the Bcl-2, Bax and Bad family participate in the final fate of the cell by controlling the permeability of the mitochondrial membranes .
  • Caspases have the role of modifying the activity of proteases of the polymerase, topoisomerase I or DNA-dependent protein kinase type, or various other proteases, resulting in the activation of enzymes promoting apoptosis, and in particular of endonucleases which act on exposed sites between the nucleosomes.
  • caspases 8-9 and 10 The activation of caspases is hierarchical, and an order of cleavage is observed: thus, the initiator caspases (procaspases 8, 9 and 10) cleave the effector or executing caspases (procaspases 3, 6 and 7) , leading to the advanced condensation of chromatin and the oligonucleosomal fragmentation of DNA.
  • DNA repair and/or the physiological mechanism of apoptosis are defective or unbalanced, for example in the following cases:
  • a mutation in the DNA can activate an oncogene (that is to say a gene which promotes cell multiplication) or can inactivate a gene which normally blocks this multiplication (tumour suppressor gene) , and in both cases can lead to dysfunction of the mechanism of apoptosis (repressed) , leading to abnormalities in cell division, in the transcription of genes or in the synthesis of molecules which are essential for the good functioning of the cell;
  • an oncogene that is to say a gene which promotes cell multiplication
  • tumor suppressor gene a gene which normally blocks this multiplication
  • a mutation in the DNA can inactivate the p53 gene, no longer allowing it to induce an apoptosis process when the lesion is too extensive.
  • the physiological mechanism of apoptosis is unbalanced (repressed) ; the cells affected therefore escape this system of control and multiply- without restriction, which can lead to tumour cells.
  • basocellular cancers keratinocytic tumours
  • spinocellular cancers malignant melanomas.
  • malignant melanomas The first two are keratinocytic tumours, and the third is a melanocytic tumour.
  • the physiological mechanism of apoptosis may also be unbalanced but, by contrast, amplified, and be involved in the formation of sunburn cells, in hair loss or androgenic alopecia or in atopic dermatitis.
  • the apoptotic keratinocytes are also the first events causing the loss of intercellular cohesion (acantholysis) during conditions such as atopic dermatitis, which explains in particular the formation of vesicles which are externalized organelles.
  • acantholysis intercellular cohesion
  • vesicles which are externalized organelles.
  • the physiological mechanism of apoptosis which is normally induced in order to • restore a situation of equilibrium or homeostasis .
  • keratinocytes may also'-..in- some cases be unbalanced (stress-induced dysfunction) , that is to say either repressed, which may lead to uncontrolled proliferation of the affected cells and to the formation of skin cancers, or conversely amplified, which may lead to an accelerated or amplified disappearance of the keratinocytes, which is involved in hair loss or in the formation of sunburn cells in the skin, or in atopic dermatitis.
  • agent for homeostatic regulation of apoptosis is understood to mean an agent capable of controlling the dysfunctions of the physiological mechanisms of apoptosis, by restoring apoptosis (activation of mechanisms involving p53) when it is abnormally repressed, or by reducing it (inhibition of caspase) when it is abnormally amplified.
  • agent for protecting and/or repairing DNA damage is understood to mean an agent capable of preventing and/or reducing DNA damage and/or promoting its repair (e.g.: p53 gene activation, repair gene activation and the like) .
  • ⁇ 2- [acetyl- (3-trifluoromethylphenyl)amino] -3-methylbutylamino ⁇ - acetic acid had an anti-TNFcc effect, which is a proinflammatory cytokine playing an important role in immunity and inflammation, and in the control of cell proliferation, differentiation and apoptosis (Baud et al., Trends Cell Biol. 2001 Sep; 11 (9) :372-7) ; it is moreover known that apoptosis of the keratinocytes of the hair bulb in vivo (Ruckert et al. , Br J Dermatol., 2000 Nov; 143(5) : 1036-9) is involved in hair loss.
  • an anti-hair loss/hair regrowth compound (WO 03/000209) , with an agent increasing the synthesis of elastin (FR 2847816) , with a metalloproteinase inhibitor (EP 1 275 372) , or with a muscle relaxant (EP 1 269 990) , to combat the effects of the degradation of the elastic fibres on the skin or the scalp, such as skin ageing or hair loss (downstream action) .
  • the present invention therefore relates to the use of at least one compound of the N- acylaminoamide family in a composition, as agent intended to protect the skin and/or its superficial body growths against the deteriorations linked to apoptotic processes amplified under stress conditions and/or to a stress-induced decrease in immune defences.
  • the invention also relates to the use of at least one compound of the N-acylaminoamide family for the preparation of a composition intended to treat skin conditions linked to apoptoti processes amplified under stress conditions and/or to a stress-induced decrease in immune defences.
  • the said compound or the said composition is thus intended to: - prevent and/or reduce stress-induced, in particular UV-induced, DNA damage and/or promote its repair; and/or
  • the composition used according to the invention will not contain an anti-hair loss/hair regrowth agent; - prevent and/or reduce the apoptotic processes amplified in the keratinocytes; in particular, regulate the activity of caspases involved in the physiological mechanisms of apoptosis which may be unbalanced by stress, and in particular at the level of the caspase 3 activity; and/or regulate the stress-induced expression of inflammatory cytokines involved in the mechanisms of apoptosis, such as TNFoc,- - prevent and/or combat a stress-induced decrease in the immune defences of the skin and/or maintain the immunocompetence of the Langerhans' cells (also referred to as immunosurveillance of the skin) ; - prevent and/or reduce the apoptotic processes of the keratinocytes involved in hair loss; preferably, in this case, the composition used according to the invention will not contain an anti-hair loss/hair regrowth agent; - prevent and/or reduce the apoptotic
  • the stress may be of exogenous origin, such as stress of chemical origin (e.g.: xenobiotics, irritant chemical products and the like) , of environmental origin (e...g-. : temperature, climate, UV radiation, atmospheric pollution, in particular: heavy metals, gaseous pollutants such as sulphur dioxide, ozone and nitrogen oxides, oxidative stress, cigarette smoke and the like), of mechanical origin (e.g.: rubbing during contact with a razor, and the like) , of infectious origin (e.g.: allergen, antigen and the like) , and/or of endogenous origin, such as disorders involving an inflammatory and/or hormonal mechanism.
  • This stress can also induce DNA damage (genotoxic stress) .
  • the stress is linked to UVB radiation.
  • this will involve intense irradiation with UV.
  • the expression "intense irradiation” is understood to mean, according to the invention, an acute (strong irradiation) or intense solar exposure, in particular exposure to zenithal sun or to solar radiation varying by an angle of 30° around this zenithal position and/or when the skin is subjected to UV radiation capable of inducing a solar erythema characterized by redness commonly called “sunburn” and defined by a minimal erythemal dose (MED) .
  • MED minimal erythemal dose
  • the invention aims in particular to prevent or reduce the formation of sunburn cells induced by -short exposures to erythemal doses of solar radiation.
  • the expression "intense solar exposure” according to the invention is understood to mean in particular solar exposure covering the real variations in solar radiation in terms of dose and UVA/UVB ratio, in particular the zenithal condition, it being possible for the said variations to correspond to a so-called erythemal solar exposure.
  • solar radiation according to the invention is understood to mean in particular any radiation equivalent to the natural solar spectrum, in particular to the zenithal spectrum, and comprising at least UVA and UVB radiation in a UVA/UVB ratio of between 10 and 17, preferably greater than or equal to 11 , and less than or equal to 16 .
  • the solar radiation according to the invention may comprise 92% of UVA and 8% of UVB , reproducing the conditions of the zenithal solar spectrum in the UVB domain .
  • the proportion of UVB in the solar radiation defined according to the invention will be between 6 and 9% .
  • radical Rl represents: - (i) a hydrogen atom
  • - (iii) a radical chosen from the radicals -OR; -NH 2 ; -NHR; -NRR'; -NH-COR; -COOR; -COR; with R and R' representing, independently of each other, a saturated or unsaturated, linear, branched or cyclic hydrocarbon radical having 1 to 6 carbon atoms, optionally halogenated, or even perhalogenated, it being possible for the said radicals R and R' to form together with N a 5- or 6-membered carbon ring which may additionally comprise at least one heteroatom chosen from 0, N and/or S in the ring, and/or which may be substituted with 1 to 5 groups, which are identical or different, chosen from -OH 7 - -OR"; -O-COR" ; -SH; -SR"; -S-COR”; -NH 2 ; -NHR"; -NH-COR”; -Hal (halogen) ; -CN; -CO
  • the radical R2 represents a saturated or unsaturated, linear, branched or cyclic hydrocarbon radical having 1 to 18 carbon atoms, optionally substituted with 1 to 5 groups", .which are identical or different, chosen from -OH; -OR,- -O-COR; -SH; -SR; -S-COR; -NH 2 ; -NHR; -NRR'; -NH-COR; -Hal (halogen) ; -CN; -COOR; -COR; with R and R' representing, independently of each other, a saturated or unsaturated, linear, branched or cyclic hydrocarbon radical having 1 to 6 carbon atoms, optionally halogenated, or even perhalogenated, it being possible for the said radicals R and R' to form together with N a 5- or 6-membered carbon ring which may additionally comprise at least one heteroatom chosen from 0, N and/or S in the ring, and/or which may be substituted with 1 to 5 groups, which
  • R representing a saturated or unsaturated, linear, branched or cyclic hydrocarbon radical having 1 to 6 carbon atoms, optionally halogenated, or even perhalogenated;
  • radical R3 represents a radical chosen from those of formula (II) or (III) :
  • - y is an integer between 0 and 5 inclusive, and Y' is an integer between 1 and 5 inclusive;
  • - A is a saturated or unsaturated, linear or branched divalent hydrocarbon radical having 1 to 18 carbon atoms, optionally substituted with 1 to 5 groups, which are identical or different, chosen from -OH; -OR; -O-COR; -SH; -SR; -S-COR; -NH 2 ; -NHR; -NRR' ; -NH-COR; -Hal
  • R and R' representing, independently of each other, a saturated or unsaturated, linear, branched or cyclic hydrocarbon radical having 1 to 6 carbon atoms, optionally halogenated, or even perhalogenated, it being possible for the said radicals R and R' to form together with N a 5- or 6-membered carbon ring which may additionally comprise at least one heteroatom chosen from 0, N and/or S in the ring, and/or which may be substituted with 1 to 5 groups, which are identical or different, chosen from -OH; -OR"; -0-COR”; -SH; -SR"; -S-COR”; -NH 2 ; -NHR"; -NH-COR”; -Hal (halogen); -CN; -COOR”; -COR”; with R" representing a saturated or unsaturated, linear, branched or cyclic hydrocarbon radical having 1 to 6 carbon atoms, optionally halogenated, or even perhalogenated, it being possible for
  • - B represents at least one group, which is . identical or different, chosen from -OH; -OR; -O-COR; -SH; -SR; -S-COR; -NH 2 ; -NHR; -NRR'; -NH-COR; -Halogen; -CN; -COOR; -COR; -NO 2 ; -SO 2 -OR, or represents a saturated or unsaturated, linear or branched hydrocarbon radical;'-having 1 to 18 carbon atoms, optionally substituted with.1 to 5 groups, which are identical or different, chosen from -OH; -OR; -O-COR; -SH; -SR; -S-COR; -NH 2 ; -NHR; -NRR'; -NH-COR; -Hal (halogen, or even perhalogen) ; -CN; -COOR; -COR; -NO 2 ; -SO 2 -OR
  • linear, cyclic or branched hydrocarbon radical is understood to mean in particular the radicals of the alkyl, aryl, aralkyl, alkylaryl, alkenyl and alkynyl type.
  • the C 6 H 5 group present in the radical R3 should be understood as an aromatic cyclic group.
  • the radical Y represents oxygen.
  • the radical Rl represents hydrogen or a saturated or unsaturated, linear or branched, optionally substituted hydrocarbon radical having 1 to 12, and in particular 1, 2, 3, 4, 5 or 6, carbon atoms.
  • the substituents may be chosen from -OH, -OR and/or -P(O)-(OR) 2 with R representing a saturated or unsaturated, linear, branched or cyclic hydrocarbon radical having 1 to 6 carbon atoms, optionally halogenated, or even perhalogenated.
  • the radical Rl represents a methyl, ethyl, propyl or isopropyl radical, optionally substituted with a group -OH or -P(O)-(OR) 2 with R representing methyl, ethyl, propyl or isopropyl.
  • the radical R2 represents a saturated or unsaturated, linear, branched or cyclic, optionally substituted hydrocarbon radical having 1 to 12, in particular 1, 2, 3, 4, 5 or 6, carbon atoms.
  • the substituents may be chosen from -OH and -OR with R representing a saturated or unsaturated, linear, branched or cyclic hydrocarbon radical having 1 to 6 carbon atoms, optionally halogenated, or even perhalogenated.
  • the radical R2 represents a methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or isobutyl radical.
  • A is a saturated or unsaturated, linear or branched, optionally substituted divalent hydrocarbon radical having 1 to 12 carbon atoms.
  • the substituents of A are preferably chosen from -Hal (halogen, or even perhalogen) ; -CN; -COOR; -NO 2 ; -SO 2 -OR; with R representing a saturated or unsaturated, linear, branched or cyclic hydrocarbon radical having 1 to 6 carbon atoms, optionally halogenated, or even perhalogenated.
  • B represents at least one group -OR; -NHR; -CN; -COOR; -COR or represents a hydrocarbon radical chosen from a saturated or unsaturated, linear or branched, optionally substituted hydrocarbon radical having 1 to 12 carbon atoms.
  • the substituents of B are preferably chosen from -Hal (halogen, or even perhalogen) ; -CN; -COOR; -NO 2 ; -SO 2 -OR; with R representing a saturated or unsaturated, linear, branched or cyclic hydrocarbon radical having 1 to 6 carbon atoms, optionally halogenated, or even perhalogenated.
  • R3 represents a group chosen from one of the following formulae:
  • the divalent radical A may be a methylene, an ethylene or a propylene.
  • the radical B represents at least one group -OR; -NHR; -CN; -COOR; -COR for which R denotes a methyl, ethyl, propyl or isopropyl radical, or represents a hydrocarbon radical chosen from a methyl, ethyl, propyl or isopropyl radical, substituted with one or more halogens, in particular chlorine, bromine, iodine or fluorine, and preferably completely halogenated (perhalogenated) , such as perfluorinated. Mention may be made in particular of the perfluoromethyl (-CF3) radical as most particularly preferred.
  • the radical X represents a radical chosen from -OH or -OR 4 , with R 4 representing a saturated or unsaturated, linear, cyclic or branched, optionally substituted hydrocarbon radical having 1 to
  • the substituents may be chosen from -OH and
  • R representing a saturated or unsaturated, linear, branched or cyclic hydrocarbon radical having 1 to 6 carbon atoms, optionally halogenated, or even perhalogenated.
  • the radical X represents a radical chosen from -OH, -OCH 3 , -OC 2 H 5 , -0-C 3 H 7 or -OC 4 H 9 .
  • a radical chosen from -OH, -OCH 3 , -OC 2 H 5 , -0-C 3 H 7 or -OC 4 H 9 there may be mentioned:
  • compositions according to the invention can be easily determined by persons skilled in the art according to the nature of the compound used, the person to be treated and/or the desired effect.
  • this quantity may be between 0.00001 and 20% by weight relative to the total weight of the composition, in particular between 0.001 and 10% by weight, and preferably between 0.05 and 5% by weight, better still between 0.1 and 2% by weight, and preferably between 0.5 and 1% by weight.
  • the compounds of formula (I) may be used in particular, alone or as a mixture, in a composition which comprises a physiologically acceptable medium, in particular in a cosmetic or pharmaceutical composition which therefore further comprises a cosmetically or pharmaceutically acceptable medium.
  • a physiologically acceptable medium in which the compounds according to the invention may be used, and its constituents, their quantity, the galenic form of the composition and its mode of preparation may be chosen by persons skilled in the art on the basis of their general knowledge according to the type of composition desired. ' - '
  • the composition may be in particular in the form of an aqueous or oily solution; of a lotion- or serum-type dispersion; of emulsions of liquid or semiliquid consistency of the milk type which are obtained by dispersing a fatty phase in an aqueous phase (O/W) or conversely (W/O) ; of suspensions or emulsions of soft, semi-solid or solid consistency of the cream or gel type, or of multiple emulsions (W/O/W or 0/W/O) , of microcapsules or microparticles; of vesicular dispersions of the ionic and/or nonionic type.
  • the composition may be in the form of aqueous, alcoholic or aqueous- alcoholic solutions; in the form of creams, gels, emulsions or foams; in the form of aerosol compositions also comprising a propellant under pressure.
  • aqueous form in particular in the form of a dispersion, an emulsion or an aqueous solution, it may comprise an aqueous phase, which may comprise water, a floral water and/or a mineral water.
  • the said aqueous phase may additionally comprise alcohols such as C x -C 6 monoalcohols and/or polyols such as glycerol, butylene glycol, isoprene glycol, propylene glycol and polyethylene glycol.
  • alcohols such as C x -C 6 monoalcohols
  • polyols such as glycerol, butylene glycol, isoprene glycol, propylene glycol and polyethylene glycol.
  • a surfactant preferably in a quantity of 0.01 to 30% by weight relative to the total weight of the composition.
  • composition according to the invention may also comprise at least one coemulsifier which may be chosen from oxyethylenated sorbitan monostearate, fatty alcohols such as stearyl alcohol or cetyl alcohol, or fatty acid esters of polyols such as glyceryl stearate.
  • the composition used according to the invention may also comprise a fatty phase, in particular consisting of fatty substances which are liquid at 25 0 C, such as oils of animal, plant, mineral or synthetic origin, which are volatile or otherwise; fatty substances which are solid at 25°C, such as waxes of animal, plant, mineral or synthetic origin; pasty fatty substances; gums; and mixtures thereof.
  • the composition used according to the invention may additionally comprise the adjuvants customarily used in the field considered, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, active agents, in particular hydrophilic or lipophilic cosmetic or pharmaceutical active agents, preservatives, antioxidants, solvents, perfumes, fillers, pigments, pearlescent agents, odour absorbers and colorants.
  • adjuvants customarily used in the field considered, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, active agents, in particular hydrophilic or lipophilic cosmetic or pharmaceutical active agents, preservatives, antioxidants, solvents, perfumes, fillers, pigments, pearlescent agents, odour absorbers and colorants.
  • These adjuvants depending on their nature, may be introduced into the fatty phase, into the aqueous phase- and/or into the lipid spherules.
  • the said compound of formula (I) will be combined, in the composition, with at least one other agent chosen from a UV-screening agent, an antipollution or anti-free radical agent, an immunomodulating agent, another agent for protecting against and/or repairing genotoxic damage induced by an external attack, and mixtures thereof.
  • at least one other agent chosen from a UV-screening agent, an antipollution or anti-free radical agent, an immunomodulating agent, another agent for protecting against and/or repairing genotoxic damage induced by an external attack, and mixtures thereof.
  • Sunscreening agents are molecules which absorb UV radiation and thus make it possible to avoid the latter reaching the cells of the skin. They can absorb either mainly UVB radiation or mainly UVA radiation, according to their nature. There are two main categories of sunscreening agents, either organic or inorganic (zinc or titanium oxides) . By using them in cosmetic compositions in combination and in a sufficient quantity, .they make it possible to stop a large portion of the UV radiation..
  • UVB + UVA it is necessary to combine several molecules which absorb in additional domains of wavelengths.
  • compositions in accordance with the invention may additionally contain at least one organic photoprotective agent and/or at least one inorganic photoprotective agent which is active in UVA and/or UVB (absorbers) , which are water-soluble or fat-soluble or insoluble in commonly used cosmetic solvents.
  • organic photoprotective agent and/or at least one inorganic photoprotective agent which is active in UVA and/or UVB (absorbers) , which are water-soluble or fat-soluble or insoluble in commonly used cosmetic solvents.
  • compositions in accordance with the invention may additionally contain other additional organic or inorganic UV-screening agents which are active in UVA and/or UVB, which are water-soluble or fat-soluble or insoluble in commonly used cosmetic solvents .
  • the organic photoprotective agents are chosen in particular from anthranilates; cinnamic derivatives; dibenzoylmethane derivatives; salicyclic derivatives; camphor derivatives; triazine derivatives such as those described in patent applications US 4367390, EP863145, EP517104, EP570838, EP796851, EP775698, EP878469, EP933376, EP507691, EP507692, EP790243, EP944624; benzophenone derivatives; ⁇ , ⁇ -diphenylacrylate derivatives; benzotriazole derivatives; benzalmalonate derivatives; benzimidazole derivatives; imidazolines; bisbenzoazolyl derivatives as described in--patents EP669323 and US 2,463,264; p-aminobenzoic acid (PABA) derivatives; methylenebis (hydroxyphenyl benzotriazole) derivatives as described in applications US5,237,071, US5,166,355,
  • photoprotective agents which are active in UV-A and/or UV-B
  • para-aminobenzoic acid derivatives including the following: PABA, Ethyl PABA, Ethyl Dihydroxypropyl PABA, Ethylhexyl Dimethyl PABA sold in particular under the name "ESCALOL 507" by ISP, Glyceryl PABA, PEG-25 PABA sold under the name "UVINUL P25" by BASF,
  • salicylic derivatives including the following: Homosalate sold in particular under the name “NEO HELIOPAN OS” by HAARMANN and REIMER, Dipropyleneglycol Salicylate sold in particular under the name “DIPSAL” by SCHER, TEA Salicylate sold in particular under the name "NEO HELI0PAN ; - TS” by' : HAARMANN- and REIMER,
  • dibenzoylmethane derivatives including the following: Butyl Methoxydibenzoylmethane sold in particular under the trade name "PARSOL 1789" by HOFFMANN LAROCHE, Isopropyl Dibenzoylmethane,
  • cinnamic derivatives including the following: Ethylhexyl Methoxycinnamate sold in particular under the trade name "PARSOL MCX” by HOFFMANN LAROCHE, Isopropyl Methoxy cinnamate, Isoamyl Methoxy cinnamate sold in particular under the trade name "NEO HELIOPAN E 1000" by HAARMANN and REIMER, Cinoxate, DEA Methoxycinnamate, Diisopropyl Methylcinnamate, Glyceryl Ethylhexanoate Dimethoxycinnamate,
  • benzophenone derivatives including the following : Benzophenone- 1 sold in particular under the trade name "UVINUL 400" by BASF , Benzophenone -2 sold in particular under the trade name “UVINUL D50” by BASF , Benzophenone -3 or Oxybenzone sold in particular under the trade name "UVINUL M40" by BASF, Benzophenone -4 sold in particular under the trade name "UVINUL MS40" by BASF, Benzophenone- 5 , Benzophenone- 6 sold in particular under the trade name "HELISORB 11" by NORQUAY, Benzophenone- 8 sold in particular under the trade name "SPECTRASORB UV-24” by AMERICAN CYANAMID, Benzophenone- 9 sold in particular under the trade name "UVINUL DS-49” by BASF , Benzophenone- 12 , and n-hexyl 2 - (4-diethylamino-2 -hydroxybenzoyl) benzo
  • benzyl idenecamphor derivatives including the following: 3 -Benzylidene camphor,
  • benzimidazole derivatives including the following : Phenylbenz imidazole Sulphonic Acid sold in particular under the trade name "EUSOLEX 232" by MERCK, Disodium Phenyl Dibenzimidazole Tetra- sulphonate sold in particular under the trade name "NEO HELIOPAN AP” by HAARMANN and REIMER, • triazine derivatives, including the following:
  • benzotriazole derivatives including the following: Drometrizole Trisiloxane sold under the name "SILATRIZOLE” by RHODIA CHIMIE, Methylene bis- Benzotriazolyl Tetramethylbutylphenol, sold in particular in solid form under the trade name U MIXXIM BB/100" by FAIRMOUNT CHEMICAL or in micronized form as an aqueous dispersion under the trade name "TINOSORB M” by CIBA SPECIALTY CHEMICALS,
  • imidazoline derivatives including Ethylhexyl Dimethoxybenzylidene Dioxoimidazoline Propionate.
  • organic photoprotective agents more particularly preferred are chosen from the following compounds: Ethylhexyl Salicylate, Ethylhexyl Methoxycinnamate, Octocrylene, Phenylbenzimidazole Sulphonic Acid, Benzophenone-3, Benzophenone-4, Benzophenone-5, 4-Methylbenzylidene camphor,
  • the inorganic photoprotective agents are chosen from pigments or even nanopigments (mean size of the primary particles: generally between 5 nm and 100 nm, preferably between 10 nm and 50 nm) of metal oxides which are coated or uncoated such as for example nanopigments of titanium oxide (amorphous or crystallized in rutile and/or anatase form) , iron oxide, zinc oxide, zirconium oxide or cerium oxide which are all UV photoprotective agents well known per se.
  • Conventional coating agents are moreover alumina and/or aluminium stearate.
  • Such nanopigments of metal oxides, coated or uncoated, are described in particular in patent applications EP518772 and EP518773.
  • the screening agents are generally present in the compositions according to the invention in proportions ranging from 0.1 to 20% by weight relative to the total weight of the composition, and preferably ranging from 0.2 to 15% by weight relative to the total weight of the composition.
  • Antipollution or anti-free radical agent is understood to mean any compound capable of trapping ozone, mono- or polycyclic aromatic compounds such as benzopyrene and/or heavy metals such as cobalt, mercury, cadmium and/or nickel.
  • anti- free radical agent is understood to mean any compound capable of trapping free radicals.
  • vitamin C and its derivatives including ascorbyl glucoside; phenols and polyphenols, in particular tannins, ellagic acid and tannic acid; epigallocatechin and natural extracts containing it; olive leaf extracts; tea, in particular green tea, extracts; anthocyanins; rosemary extracts; phenolic acids, in particular chlorogenic acid; stilbenes, in particular resveratrol; derivatives of sulphur amino acids, in particular S-carboxymethylcysteine; ergothioneine; N-acetylcysteine; chelators such as N,N'-bis- (3,4,5-trimethoxybenzyl) ethylenediamine or one of its salts, metal complexes or esters; carotenoids such as crocetin; and various raw materials such as the mixture of arginine, histidine ribonucleate, mannito
  • Induchem and the mixture of ginseng, apple, peach, wheat and barley extracts sold by the company PROVITAL under the trade name Pronalen Bioprotect ® .
  • tannins such as ellagic acid
  • indole derivatives in particular indole-3-carbinol
  • tea in particular green tea, extracts, water hyacinth or Eichornia crassipes extracts
  • water-soluble fraction of maize marketed by the company SOLABIA under the trade name Phytovityl ® .
  • agents for trapping heavy metals which can be used in the composition according to the invention, there may be mentioned in particular chelating agents such as EDTA, the pentasodium salt of ethylenediamine tetramethylenephosphonic acid, N,N'- bis (3,4,5-trimethoxybenzyl) ethylenediamine or one of its salts, metal complexes or esters,- phytic acid; chitosan derivatives; tea, in particular green tea, extracts; tannins such as ellagic acid; sulphur amino acids such as cysteine; water hyacinth (Eichornia crassipes) extracts; and the water-soluble fraction of maize, marketed by the company SOLABIA under the trade name Phytovityl ® .
  • EDTA the pentasodium salt of ethylenediamine tetramethylenephosphonic acid, N,N'- bis (3,4,5-trimethoxybenzyl) ethylenediamine or one of its salt
  • the anti-free radical agents which may be used in the composition according to the invention comprise, in addition to certain antipollution agents mentioned above, lycopene, vitamin E and its derivatives such as tocopheryl acetate; bioflavonoids; co-enzyme QlO or ubiquinone; certain enzymes such as catalase, superoxide dismutase and wheatgerm extracts containing it, lactoperoxidase, glutathione peroxidase and quinone reductases; glutathione; benzylidenecamphor; benzyleye1anones; substituted naphthalenones; pidolates; phytantriol; gamma-oryzanol,• guanosine; lignans; and melatonin.
  • lycopene vitamin E and its derivatives such as tocopheryl acetate
  • bioflavonoids co-enzyme QlO or ubiquinone
  • certain enzymes such as cata
  • Immunomodulating agent is understood to mean an agent capable of re-establishing the immune functions and more particularly those of the epidermis, which contributes towards restoring the natural defences of the skin and thus towards preventing pathogenic conditions and the appearance of cancers.
  • anti-free radical active agents such as for example provitamin A carotenoids such as beta-carotene, non-provitamin A carotenoids such as lycopene, vitamin E and its derivatives, vitamin C and its derivatives, the extracts of Iridaceae (e.g. Iris pallida) described in application EP 1 1-74 120, polysaccharides (oligofucoses). described in application EP 0 818 201, extracts of non-fruiting non-photosynthetic filamentous bacteria (e.g. Vitreoscilla filiformis) described in application EP0604631.
  • agents for protecting against and/or repairing genotoxic damage there may be mentioned in particular enzymes promoting DNA repair, such as photolyase and/or endonuclease T4, or activators of the production of the p53 protein, such as flavonoids.
  • the invention also relates to a composition
  • a composition comprising, in a physiologically acceptable medium, at least one compound of the N-acylaminoamide family combined with at least one other agent chosen from an anti-free radical or antipollution agent, an immunomodulating agent, an agent for protecting against and/or repairing stress-induced genotoxic damage, as defined above, and mixtures thereof.
  • physiologically acceptable medium is understood to mean a medium compatible with the skin and/or the scalp and/or the mucous membranes and/or the superficial body growths.
  • composition will additionally comprise at least one UV-screening agent as defined above.
  • This composition may be a cosmetic composition or a dermatological composition.
  • the quantity of compound to use in the compositions according to the invention can be easily determined by persons skilled in the art according to the nature of the compound used, the person to be treated and/or the desired effect. In general, this quantity may be between 0.00001 and 20% by weight relative to the total weight of the composition, in particular between 0.001 and 10% by weight, and preferably between 0.05 and 5% by weight, better still between 0.1 and 2% by weight, and preferably between 0.5 and 1% by weight.
  • the invention also relates to a cosmetic method for treating aesthetic disorders of the skin and/or the scalp and/or the mucous membranes linked to a dysfunction of the physiological mechanisms of apoptosis, characterized in that a cosmetic composition as defined above is applied to the skin and/or the scalp and/or the mucous membranes.
  • This cosmetic method will be intended in particular to beautify and/or enhance the general appearance of the skin and/or the scalp and/or the mucous membranes exposed to stress.
  • the said method when applied to the skin, is intended to prevent the formation of sunburn cells induced under UV conditions (apoptosis of the keratinocytes) .
  • Applied to the scalp it is intended to prevent and/or reduce hair loss or androgenic alopecia.
  • the composition may be applied daily or several times per day, and for a specific period according to the subject to be treated.
  • This method is particularly advantageous for subjects with a light phototype (I, II, and potentially III) , who are more sensitive to UV radiation and, consequently, to the formation of sunburn cells and to the formation of photoinduced skin cancers.
  • a light phototype I, II, and potentially III
  • EXAMPLE 1 Inhibitory effect of ⁇ 2 - [acetyl - (3 - tri- f luoromethylphenyl) amino] -3 -methylbutyrylamino ⁇ acetic acid on the caspase 3 activity
  • the anti-caspase 3 activity of the test compound ⁇ 2- [acetyl- (3-trifluoromethylphenyl)amino] - 3-methylbutyrylamino ⁇ acetic acid, was determined in vitro with respect to a recombinant (E. coli) human caspase 3.
  • the principle of the evaluation is carried out by quantifying the formation of 7-amino-4- (trifluoromethyl) coumarin (AFC) released by cleavage of Benzyloxycarbonyl-Aspartate-Glutamine-Valine-Aspartate- AFC.
  • Caspase 3 has the property of cleaving the peptide Asp-Glu-Val-Val.
  • the test is carried out in the following manner: The reference standard inhibitory product,
  • Ac-DEVD-CHO (or caspase-3 inhibitor I, Calbiochem ® ) , on the one hand, and the test product, on the other hand, are incubated at 37 0 C for 10 tnin with 20 U/tnl of recombinant caspase 3 in a buffer containing 45 mM Hepes-Tris, 0.9 mM EDTA-Tris, 9 mM DTT and 0.09% CHAPS (pH 7.4), in two separate experiments.
  • reaction is initiated by adding 5 ⁇ M of substrate (Benzyloxycarbonyl-Aspartate- Glutamine-Valine-Aspartate-AFC) and the mixture is incubated for 30 min at 37 0 C.
  • substrate Benzyloxycarbonyl-Aspartate- Glutamine-Valine-Aspartate-AFC
  • the intensity of fluorescence emitted by the product of the reaction AFC at 390 nm and at 535 nra is then determined by fluorimetry using a microplate reader (Gemini XS, Molecular Devices) .
  • EXAMPLE 2 Ef fect of ⁇ 2 - [acetyl- (3 -trif luoromethyl- phenyl)amino] -3-methylbutyrylamino ⁇ acetic acid on cellular protection
  • test is carried out on submerged keratinocyte and fibroblast cultures subjected or not subjected to stress, of the UVB type delivered by
  • TL 012 tubes at doses of between 50 and 100 mJ/cm 2 , and exposed or not exposed to the test product, ⁇ 2- [acetyl- (3-trifluoromethylphenyl)amino] -3-methylbutyrylamino ⁇ - acetic acid.
  • Keratinocytes and fibroblasts are neonatal cells obtained from Clonetics (Portland, OR) , cultured as reported by Boyce ST and Ham RG (J Invest Dermatol., 1983, vol. 81, pp. 33S-40S) .
  • the fibroblasts are cultured in DMEM medium (Life Technology, USA) supplemented with L-glutamine (2 mM, Life Technology) , penicillin (50 IU/ml) , streptomycin (50 mg/ml) and foetal calf serum (1%, Life Technology) .
  • the keratinocytes are cultured in SFM medium without bovine pituitary extract and without EGF.
  • test compound is applied at concentrations of 0.1 mM, 0.2 mM and 1 mM under the following conditions:
  • the p53 protein is stabilized by a post-translational process independently of its transcription level; this causes the activation of p53 which will be involved in the regulation of the cell cycle, DNA repair and replication.
  • the activation of p53 causes the induction of certain associated repair genes p21, Gadd45, XPC, p48, PCNA, Bax. It is thus possible to quantify the effect of the test product on the activation of the p53 protein and the induction of certain genes. Their quantification may be carried out at the level of their mRNA, for example by a RT-PCR technique, and/or of their protein, for example by an immunocytochemistry technique with specific antibodies (Meunier JR et al. , Photochem. Photobiol . 2002, 75(5), pp. 437-447) .
  • Stoppage of the cell cycle The most important consequence of the stabilization of p53 is a stoppage at the level of the cell cycle via the induction of p21, in order to increase the time assigned to repair before replication.
  • the stoppage of the cell cycle occurs predominantly at the Gl/S phase.
  • the measurement of the cells stopped in Gl phase may be considered as a qualitative analysis of the induction of damage to the DNA and the kinetics of appearance of normal cell cycle is the translation of a DNA repair. These analyses may be performed by monitoring the number of cells in each of the phases of the cycles (cell cycle fluorimetric kit and then flow cytometry analysis)
  • the detection of the nature of the damage, its location and the amount of damage to the DNA may be evaluated using anti-pyrimidine dimer antibodies, by evaluating double-strand breaks (anti-CPD antibodies) and/or by evaluating DNA repair enzymes such as endonuclease III and Fpg (Formamido-pyrimidine glycosylase repair enzyme) by specific immunocyto- chemistry (according to Sauvaigo S et al. , Anal. Biochem. 1998, vol. 259, pp. 1-7 and Collins AR et al. , Environ. Health Perspect. 1996, vol. 104(S3), pp. 465- 469) . It is also possible to use a Comet test
  • a 0.5% agarose microgel enveloping the cells is placed in a lysis buffer (2.5 M NaCl, EDTA, 1%
  • this gel is washed and equilibrated with an alkaline buffer (0.3 NaOH, 1 tnM EDTA, 30..min) in order to denature the DNA. Electrophoresis is then performed for 20 min at 25V and 300 mA in the same buffer in the presence of 1% dimethyl sulphoxide. After neutralizing with a Tris buffer (pH 7.5), the DNA is labelled with ethidium bromide (2 ⁇ g/ml) and the comets are examined and photographed with a fluorescence microscope. For the quantification, analysis of
  • a reconstructed epidermis of the EPISKIN ® type will be used, to which the same conditions as those described above will be applied.
  • the evaluations of the DNA damage to this reconstructed epidermis and of the protective and/or repair effect of ⁇ 2- [acetyl- (3-trifluoromethylphenyl) - amino] -3-methylbutyrylamino ⁇ acetic acid on this damage will be carried out according to the protocols described above.
  • the protective and/or repair effect of ⁇ 2- [acetyl- (3-trifluoromethylphenyl) amino] -3-methyl- butyrylamino ⁇ acetic acid may manifest itself by an activation of the mechanisms leading to a production of p53, and/or an induction of the repair genes and enzymes (p21, Gadd45, XPC, p48, PCNA, Bax) , and/or a re-establishment of the normal cell cycle, and/or a decrease in the formation of pyrimidine dinners and of double-strand breaks (decrease in the number of nuclei in the comet state) , compared with a control (in the absence of product) .
  • EXAMPLE 3 Effect of ⁇ 2- [acetyl- (3-trifluoromethyl ⁇ phenyl)amino] -3-methylbutyrylamino ⁇ acetic acid on stress-induced production of TNF- ⁇
  • Normal human epidermal keratinocytes are cultured at 37 0 C in SFM culture medium (serum free medium) supplemented with EGF 5 ⁇ g/ml (epidermal growth factor) and bovine pituitary extract (50 ng/ml) .
  • the culture medium is replaced with SFM medium containing DMSO (0.03% DMSO by volume), for the control condition, or ⁇ 2- [acetyl- (3-trifluoromethyl ⁇ phenyl)amino] -3-methylbutyrylamino ⁇ acetic acid (1.0 or 0.1 mM) .
  • the cells are incubated at 37 0 C for 24 h and then stimulated with variable doses of IFN-gamma or PMA/TPA: the IFN-gamma and the PMA/TPA are added to the culture medium in order to obtain final IFN-gamma concentrations of 300 and 1000 units/ml of IFN-gamma corresponding to 15 and 50 ng/ml respectively; and a final PMA/TPA concentration of 5.0 nM corresponding to 3.0 ng/ml of PMA/TPA.
  • the cells are stimulated for 24 hours, and then the culture medium is removed, centrifuged at 16 000 g for 5 min at 4 0 C and the supernatants are stored at -2O 0 C up to the analysis.
  • cytokines induced by IFN- gamma or PMA/TPA is measured using a ProteoplexTM kit according to the recommendations of the manufacturer (Novagen) .
  • the results obtained are presented in the following table: a % increase in the production of TNF- alpha in pg/ml expressed relative to the total proteins, after stimulation with IFN-gamma or PMA, is measured.
  • EXAMPLE 4 Demonstration of a protective effect of ⁇ 2- [acetyl- (3-trifluoromethylphenyl)amino] -3-methyl- butyrylamino ⁇ acetic acid on photoim ⁇ nunosuppression
  • the functionality of the Langerhans' cells was analysed according to their capacity to induce the proliferation of. allogenic T cells in a mixed lympho- epidermal culture (MLEC) .
  • MLEC mixed lympho- epidermal culture
  • the inhibition of the function of the Langerhans' cells is linked both to a direct effect of UV radiation on the cells and to an indirect effect mediated by cytokines.
  • a 10% ⁇ 2- [acetyl- (3-trifluoromethylphenyl) - amino] -3-methylbutyrylamino ⁇ acetic acid based cream is applied to the forearm of the subjects to be tested.
  • the other forearm serves as a control
  • the application is made 24 hours after UV irradiation corresponding to 3 MED (dose judged necessary to induce an immunosuppressive reaction) and the functionality of the Langerhans' cells is analysed using suction bubbles.
  • the suction bubble method is an easy method for reproducibly obtaining a epidermis in vivo.
  • the principle consists in applying a negative pressure of 300-400 mmHg to 1 cm 2 of skin for 90 to 120 minutes.
  • the suction bubble is then pierced and the roof of the suction bubble is cut in order to collect the dermo- epidermal fragment.
  • the epidermal cells (keratinocytes, Langerhans' cells) are isolated from two suction bubble roofs 10 mm in diameter.
  • the epidermis is delicately introduced with the aid of fine tweezers in a Hank's saline solution supplemented with 10% foetal calf serum.
  • epidermal cells containing 1 to 2% of Langerhans' cells are obtained.
  • the cells are then placed in an RPMI-1640 medium supplemented with 10% human AB serum and antibiotics.
  • the mononuclear cells are isolated from peripheral blood of non-related healthy donors, by centrifugation on Lymphoprep (Pharmingen) .
  • the cellular suspensions are deposited in a Petri dish and an incubation of 1 h 30 min at 37 0 C allows the adhesion of the monocytes.
  • the T lymphocytes contained in the population of non-adherent cells are purified. 10 5 T lymphocytes and 5 X 10 4 epidermal cells obtained from various suction bubble roofs are distributed in the microplate wells, in RPMI-1640 medium supplemented with 10% human AB serum and antibiotics. The trials are carried out in triplicate. Controls are performed with the epidermal cells and the T lymphocytes alone.
  • the lymphocyte proliferation is measured from the 5th to the 6th day of culture by the addition of tritiated thymidine (1 ⁇ ci/well, 5 Ci/mmol) .
  • Composition for protecting the skin from the sun is Composition for protecting the skin from the sun
  • Vitreoscilla filiform ⁇ s extract 0.1%
  • Beta-carotene 0.1% Propylene glycol 23%
  • T4 endonuclease (DNA protector) 0.1% Vitamin E (anti-free radical) 1% Hydroxypropylcellulose (Klucel H sold by the company Hercules) 1.0%

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Abstract

La présente invention concerne l'utilisation d'au moins un composé de la famille N-acylaminoamide, dans une composition contenant un milieu acceptable d'un point de vue physiologique, comme agent destiné à protéger la peau et/ou ses excroissances superficielles contre les détériorations de l'épiderme associées à des processus apoptotiques amplifiés dans des conditions de stress et/ou à une réduction induite par le stress des défenses immunitaires. Ledit composé est destiné, en particulier, à prévenir et/ou à réduire la formation de cellules brûlées par le soleil dans l'épiderme et la formation de tumeurs cutanées photo-induites. Le composé est choisi, en particulier, parmi l'acide acétique {2-[acétyl-(3-trifluorométhylphényl)amino]-3-méthyl-butyrylamino} et l'acétate d'éthyle {2-[acétyl-(3-trifluorométhylphényl)amino]-3-méthylbutyrylamino}.
PCT/EP2005/013531 2004-11-22 2005-11-16 Protection de la peau contre la deterioration associee a un dysfonctionnement induit par le stress des processus apoptotiques et de defense immunitaire WO2006053789A1 (fr)

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FR0452721A FR2878155A1 (fr) 2004-11-22 2004-11-22 Protection de la peau contre les alterations liees a un dysfonctionnement des mecanismes physiologiques d'apoptose
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