FR2991579A1 - Use of new or known pyrimidine compounds as agent for preventing and/or treating aesthetic disorder of scalp, preferably dandruff of the scalp associated with dryness of scalp, hyperseborrhea of the scalp, unbalanced ecoflora and pruritus - Google Patents

Abstract

Cosmetic use of an effective amount of at least one pyrimidine compounds (Q) or its salt as an agent for preventing and/or treating aesthetic disorder of scalp, is claimed. Cosmetic use of an effective amount of at least one pyrimidine compounds (Q) of formulae (I) and (II) and their salts as an agent for preventing and/or treating aesthetic disorder of scalp, is claimed. R1 : H or -C(O)R8; R8 : linear or branched, optionally saturated 1-4C-alkyl or phenyl; R2 : H, linear or branched, optionally saturated 1-12C-alkyl group or monovalent group of formula (Ia) or (IIb); R3-R7 : H, -NO 2, -OH, -OR8, -CN, Br, Cl, I, F, -CF 3, linear or branched, optionally saturated 1-4C-alkyl, phenyl, -OC(O)-R8 or -O-Ph-X; X : H, -OH, -NO 2, F, linear or branched, optionally saturated 1-4C-alkyl or alkoxy; and R, R1a : H or linear or branched 1-4C-alkyl. An independent claim is included for the pyrimidine compound (I) or its salt. [Image] [Image] ACTIVITY : Dermatological; Antipruritic. MECHANISM OF ACTION : None given.

Description

The present invention aims to provide novel compounds for preventing and / or treating a disorder, particularly aesthetic, of the scalp. In particular, the present invention relates to dandruff disorders of the scalp. The scalp is an epidermis with continual renewal, like the rest of the cutaneous tissue, and rich in sebaceous glands. Normally, the scalp is renewed by removing the superficial cells of the skin, insensitively and not visible. However, an excessive renewal of the stratum corneum cells of the scalp, for various reasons, can lead to the formation of large, thick, visible to the naked eye cells known as "dandruff".

The dandruff states are chronic, frequent, recurrent, and socially disabling conditions because of their manifest unsightly nature, and affecting a large part of the world population. Different factors can promote the appearance of dandruff. For example, one can mention the stress, the winter period, a defect of hydration, or the colonization of the skin or the hair follicles by the yeast Malassezia sp .. These factors have, in particular, for common character to provoke and / or promote an inflammatory skin condition. Such inflammation enhances the appearance or even increases the presence of dandruff. Moreover, the dandruff condition of the scalp results in an alteration of the barrier function of the epidermis or can generate sensations of itching or pruritus, leading to scraping behaviors amplifying the phenomenon of dandruff. While active molecules, such as antifungals, effectively treat dandruff, they do, however, only treat the consequences of a disorder and not its cause or origin, thus leading to a constraint of continued use of the dandruff. these assets. In addition, the effectiveness of these treatments is only suspensive and involves rigorous monitoring by the user (frequency of use and sufficient application time). As a result, many failures occur in the implementation of these treatments and are usually attributable to: poor protocol monitoring; non-compliance with the frequency of use; non-cosmetic appearance of the product; irritation of the washing base; poor compliance with the duration of application; weariness. It is therefore of great importance to discover new targets, new active compounds acting on the origin of skin disorders and treating the epidermis. Furthermore, it has been described in the applications filed under the numbers FR 10 601 83 and FR 10 601 79, that the interaction between SASPase and FLG2 leads to an increase in the proteolytic activity of SASPase. This proteolytic activity is involved in the degradation of corneodesmosin, and therefore participates in the regulation of epidermal homeostasis, in particular through the regulation of the phenomena of desquamation, proliferation or differentiation of cells. On the other hand, this function of SASPase has been confirmed by the observation of its ability to hydrolyze certain forms of Filaggrin, a protein essential for the organization, function, and hydration of the epidermal barrier (Matsui et al. ., EMBO Mol Med, 2011, 3: 320). The fact of having active compounds capable of modulating this interaction is therefore a major asset in the realization of a cosmetic or therapeutic arsenal with regard to aesthetic disorders or pathological disorders of the scalp. There remains a need to have new assets likely to have a beneficial cosmetic or therapeutic action on the states of the scalp. There is also a need for new assets capable of preventive and / or protective action against dandruff conditions which is sustainable in time. There is also a need for new assets to prevent and / or treat an inflammatory condition of the scalp. There is also a need for new assets to prevent and / or treat a pruritic condition and seborrheic dermatitis of the scalp. There is also a need for new compositions effective to prevent and / or treat a condition of the scalp, fat or dry, and which are pleasant and comfortable to implement, thus promoting compliance with the treatment. There is also a need for new assets to enhance the scalp barrier properties of the scalp. The object of the present invention is to satisfy these needs. Thus, according to a first object, the invention relates to the cosmetic use, as an agent for preventing and / or treating a disorder of the scalp, of an effective amount of at least one compound represented by one of the general formulas (Ta) or (Ib): wherein R 1 represents H or a group -C (O) R 8, with R 8 being a linear or branched, saturated or unsaturated C 1 -C 4 or even C 2 -C 3 alkyl; or being a phenyl; R2 represents H; a C 1 -C 12, in particular C 1 -C 6 or even C 2 -C 4, linear or branched, saturated or unsaturated alkyl group; or a group selected from: wherein R3, R4, R5, R6, R7 are, independently of one another, H; -NO2; -OH ; -0R8; -CN; Br; Cl; I; F; -CF3; a linear or branched, saturated or unsaturated C 1 -C 4 or even C 2 -C 3 alkyl; phenyl; -OC (O) -R8; -O-Ph-X, with X representing H, -OH, -NO2, a fluorine, a linear or branched, saturated or unsaturated C 1 -C 4 alkyl, or even C 2 -C 3 alkoxy; R8 being as defined above, - R and R ', which may be identical or different, represent H or a linear or branched C 1 -C 4 or even C 2 -C 3 alkyl, or a physiologically acceptable salt thereof. Unexpectedly, the inventors have observed that such compounds make it possible to induce and stimulate the accelerated formation of a thickened Stratum Corneum, are endowed with strong anti-proliferative properties, modify the balance proliferation / differentiation of the cells of the skin towards a decrease of the living layers and an increase of the cornified layers, and / or favor the maturation of the Stratum Corneum (SC) and / or the increase of layers of the SC. All of these properties thus make the compounds of the invention particularly effective against disorders of the scalp, including dandruff conditions of the scalp. The use of a compound of the invention makes it possible to restore a normal scalp, in perfect homeostasis. According to another advantage, a use according to the invention can reduce and / or treat pruritus of the scalp consecutive to aggressive external or intrinsic factors such as stress, the winter period, lack of hydration or colonization of the skin or hair follicles by the yeast Malassezia sp.

According to another advantage, a use according to the invention can promote the hydration and maintenance of the integrity of the scalp. According to another of its aspects, the present invention relates to a compound of the invention, in an effective amount in a pharmaceutical or dermatological composition, for preventing and / or treating a pathological disorder of the scalp.

In particular, such a composition is effective in preventing and / or treating a state of aggravated dryness or xerosis of the scalp, pruritus of the scalp or seborrheic dermatitis of the scalp. According to another of its aspects, the present invention relates to a cosmetic method for treating and / or preventing an aesthetic disorder of the scalp in an individual in need, comprising at least one step of administration to said individual, of at least a quantity effective of at least one compound of the invention. In particular, a method of the invention is advantageously used in individuals having a dandruff condition of the scalp. According to another of its aspects, the present invention relates to a compound represented by the general formula (IIa): in which: - Ri represents H, and - R2 represents a saturated linear or branched C1-C3 alkyl; benzyl; or MeO OHe OH - R and R 'represent a methyl, or a physiologically acceptable salt thereof. According to another of its aspects, the present invention relates to a cosmetic or dermatological composition comprising, in a physiologically acceptable medium, an effective amount of at least one compound of general formula (IIa) as defined above, and in particular below .

For the purposes of the present invention, the term prevent means reducing a risk of manifestation or reducing a probability of occurrence of the phenomenon concerned. For the purposes of the present invention, the term "effective amount" of a compound of the invention, a sufficient and necessary amount of this compound to exert a preventive effect and / or treatment with regard to disorders of the leather scalp. Such an amount can be determined by any method known to those skilled in the art, for example by means of in vitro, ex vivo or in vivo tests, such as clinical trials. For the purposes of the present invention, the term "physiologically or cosmeceutically or pharmaceutically acceptable medium" means a medium compatible with administration to an individual, especially on the scalp of this individual. Scalp Disorders A scalp with excessive dryness or excessive secretion of sebum may manifest a skin disorder that may manifest itself through a dandruff condition. Depending on the case, such disorder of the scalp will be characterized by the presence of dry or oily dandruff, or even pruritus and / or inflammation of the epidermis. According to the degree of intensity of the manifestation of the disorder of the scalp, this one can raise an aesthetic disorder of the scalp or a pathological disorder of the scalp. Such classification is within the skill of those skilled in the art.

According to one embodiment, a disorder of the scalp may be a dandruff condition of the scalp. The dandruff conditions of the scalp may be of the fatty type or of the dry type. The dry dandruff conditions of the scalp are more frequently manifested, and / or are amplified, during disorders of the hydration of the skin, and in particular during severe dryness of the epidermis of the scalp. They can translate xerosis of the scalp, if necessary associated with an excessively fast renewal of its stratum corneum. Dry dandruff is usually small in size, white or gray, and spreads over the scalp and clothing that creates an unsightly visual effect. Itching associated with dryness of the scalp can lead to erythema, pruritus, or even an inflammatory condition. In addition, the scalp is rich in sebaceous glands. It has been observed that hypersecretion of sebum, or seborrhea, can cause discomfort, sensations of discomfort, aesthetic disorders, or even skin pathology. Thus, an excessive secretion of sebum favors the appearance of a fatty dandruff condition of the scalp or fatty dandruff. On the other hand, these tend to be more easily itchy. Fatty skin states can lead to or be associated with seborrheic dermatitis of the scalp. Affected individuals have an erythematous scalp covered by large, oily and yellow scales that accumulate to form bundles. They have a pruriginous scalp, and often have burning sensations on affected areas. In the dandruff states of the scalp, the skin barrier is unbalanced, its integrity and hydration are altered and its ecoflora disturbed. The skin of the scalp is irritated and itchy, fragile, less hydrated and susceptible to infections. The uses, processes and compositions according to the invention thus prove to be particularly effective: to prevent and / or treat a dandruff condition of the scalp, whether dry or greasy, to prevent and / or treat a condition dermal scalp associated with dry scalp, hyperseborrhea of the scalp, unbalanced ecoflora, pruritus, inflammation of the scalp, or an unbalanced scalp barrier function, - to improve comfort of the scalp. - to preserve and / or enhance the integrity of the barrier functions of the skin of the scalp. - to prevent and / or treat seborrheic pruritus and / or dermatitis of the scalp, - to prevent and / or treat the disorders, particularly aesthetic, of the scalp associated with excessive dryness, or even xerosis, - to prevent and / or to treat the disorders, particularly aesthetic, of the scalp related to an excess of excretion and / or sebum secretion, - to improve the hygiene and / or the care of the scalp, - to confer a feeling of well-being to the scalp, - to preserve and / or enhance the integrity of the barrier functions of the scalp, - to maintain and / or restore the biomechanical properties of the scalp, - to restore a balanced ecoflora of the scalp, or - to prevent and / or treat inflammatory conditions of the scalp. Preferably, a compound of the invention is particularly suitable for preventing and / or treating a dandruff condition of the scalp is associated with dryness of the scalp, hyperseborrhea of the scalp, unbalanced ecoflora, itching, inflammation of the leather hairy, or a barrier function of the scalp unbalanced; or to improve the comfort of the scalp; or to preserve and / or enhance the integrity of the barrier functions of the scalp skin; or prevent and / or treat pruritus and / or seborrheic dermatitis of the scalp. In particular, a compound of the invention may be more particularly dedicated to preventing and / or treating a dandruff condition of the scalp, to improving the comfort of the scalp, to preserving and / or enhancing the integrity of the barrier functions of the scalp. scalp skin, or to prevent and / or treat pruritus and / or seborrheic dermatitis of the scalp.

Compounds According to one embodiment, a compound more particularly considered according to the invention may be represented by the general formulas (Ta) or (Ib) as defined above.

According to a preferred embodiment, a compound of the invention may be represented by the general formula (Ta) in which: R1 represents H, - R2 represents H; a C 1 -C 12, in particular C 1 -C 6, or even C 2 -C 4, linear or branched, saturated or unsaturated alkyl group; or a group selected from: wherein R3, R4, R5, R6, R7 are, independently of one another, H; -NO2; -OH; -0R8; -CN; F; -CF3; a linear or branched, saturated or unsaturated C 1 -C 4 or even C 2 -C 3 alkyl; phenyl; -OC (O) -R8; -O-Ph-X with X representing H, -OH, -NO2, a fluorine, a linear or branched, saturated or unsaturated C 1 -C 4 alkyl or alkoxy; with R 8 being a linear or branched, saturated or unsaturated C 1 -C 4 alkyl or even C 2 -C 3 alkyl, or being a phenyl, R 1 and R ', which may be identical or different, represent H or a C 1 -C 4 alkyl, or C2-C3, linear or branched, or a physiologically acceptable salt thereof.

According to another preferred embodiment, a compound of the invention may be represented by the general formula (Ta) in which: R1 represents H, - R2 represents H; a C 1 -C 12, in particular C 1 -C 6, or even C 2 -C 4, linear or branched, saturated or unsaturated alkyl group; or a group selected from: wherein R3, R4, R5, R6, R7 are, independently of one another, H; -OH; -0R8; CN; a linear or branched, saturated or unsaturated C 1 -C 4 or even C 2 -C 3 alkyl; phenyl; -OC (O) -R8; -O-Ph-X with X representing H, -OH, a linear or branched, saturated or unsaturated C 1 -C 4 or even C 2 -C 3 alkyl or alkoxy; with R8 being a linear or branched, saturated or unsaturated C 1 -C 4 alkyl, or being a phenyl, - R and R ', which may be identical or different, represent H or a methyl, or a physiologically acceptable salt thereof.

According to yet another preferred embodiment, a compound of the invention may be represented by the general formula (Ta) in which: R1 represents H, - R2 represents H, a C1-C6 alkyl group, or even C2- C4, linear or branched, saturated; or a group selected from: R7 R6 R5 or wherein R3, R4, R5, R6, R7 are, independently of one another, H; -OH ; -0R8; -CN; a linear or branched, saturated or unsaturated C 1 -C 4 or even C 2 -C 3 alkyl; with R8 being a linear or branched, saturated or unsaturated C 1 -C 4 or even C 2 -C 3 alkyl, or being a phenyl, - R and R 'represent a methyl, or a physiologically acceptable salt thereof.

According to yet another preferred embodiment, a compound of the invention may be represented by the general formula (Ta) in which: - R 1 represents H, - R 2 represents a C 1 -C 4 or even C 2 -C 3 alkyl group, linear or branched, saturated or unsaturated; or a group selected from: or wherein R3, R4, R5, R6, R7 are, independently of one another, H; -OH; -0R8; CN; a linear or branched, saturated or unsaturated C 1 -C 3 alkyl; phenyl; with R 8 being a linear or branched, saturated or unsaturated C 1 -C 3 alkyl, - R and R ', which may be identical or different, represent H or a linear or branched, saturated or unsaturated C 1 -C 3 alkyl, or a physiologically active salt; acceptable of it.

According to yet another preferred embodiment, a compound of the invention may be represented by the general formula (Ta) in which: - R 1 represents H, - R 2 represents a C 1 -C 4 or even C 2 -C 3 alkyl group, linear or branched, saturated, and preferably represents a methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tert-butyl, and preferably an iso-propyl butyl; a group R 3 R 4 R 5 R 7 R 6 R 3 R 4 R 5 in which R 3, R 4, R 5, R 6 and R 7 represent, independently of one another, H; -OH ; -0R8; -CN, with R8 being linear or branched, saturated or unsaturated C1-C2 alkyl, and preferably methyl; or a group R 7 R 6 R 3 R 4 R 5 in which R 3, R 4, R 5, R 6, R 7 represent H, - R and R ', which may be identical or different, represent H or a linear or branched, saturated or unsaturated C 1 -C 2 alkyl, and preferably methyl, or a physiologically acceptable salt thereof. More preferably, R2 can represent a group chosen from: R7 R6 R3 R4 R5 15 or in which R3 and R7 represent H, and R4, R5 and R6 represent, independently of one another, a group as defined previously, and preferably H; -OH; -0R8; -CN, with R8 representing a C1-C2 alkyl, linear or branched, saturated or unsaturated, and preferably a methyl. According to yet another preferred embodiment, a compound of the invention may be chosen from: OH (4); (3); (5), (1) (7); (10); (9); OR (11); or a physiologically acceptable salt. The invention also relates, as such, to a compound represented by the general formula (IIa): IIa in which: - Ri represents H, and - R2 represents a saturated linear or branched C1-C3 alkyl; benzyl; or MeO OHe OH - R and R 'represent a methyl, or a physiologically acceptable salt thereof. Still more preferably, the subject of the invention is, as such, a compound chosen from: (9) or (10); or a physiologically acceptable salt thereof. According to one embodiment, the compounds (1) to (3), (5) and (6), and preferably (3), (5) and (6), and more may be considered more particularly for the invention. more preferably, the compounds (3) and (6), or a physiologically acceptable salt thereof. According to another embodiment, compounds (6) and (8) to (10), or a physiologically acceptable salt thereof, may also be preferred. A physiologically acceptable salt of a compound of general formula (Ia), (Ib), or (IIa) according to the invention may be a salt of a compound of general formula (Ia), (Ib), or (IIa) and an alkali metal, an alkaline earth metal or ammonium, comprising the salts obtained with organic ammonium bases, or salts of a compound of the general formula (Ia), (Ib), or (IIa) and organic or inorganic acid. Salts more particularly suitable for the invention may be sodium, potassium, calcium, magnesium salts, quaternary ammonium salts such as tetramethylammonium or tetraethylammonium, and addition salts with ammonia and physiologically acceptable organic amines, such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, ethanolamine or tris- (2-hydroxyethyl) -amine. (6); (8); HINN Salts of a compound of general formula (Ta), (Ib), or (IIa) and of inorganic acid suitable for the invention can be obtained with hydrochloric acid, hydrobromic acid, sulfuric acid , nitric acid or phosphoric acid. Salts of a compound of general formula (Ta), (Ib), or (IIa) and of organic acid suitable for the invention can be obtained with or carboxylic acids and sulfonic acids such as formic acid, acetic acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, malonic acid, benzoic acid, maleic acid, fumaric acid and , tartaric acid, methanesulfonic acid, benzenesulphonic acid or p-toluenesulphonic acid.

A compound of the invention may be used in a proportion of 0.01 to 10% by weight, preferably 0.1 to 5% by weight relative to the total weight of the composition containing it. Compounds of the invention may be obtained by any method known to those skilled in the art.

In particular the pyrido-pyrimidine-triones derivatives of the invention can be obtained by means of the Hantzsch reaction allowing a single-step synthesis. The Hantzsch reaction is known in the literature (in particular Bioorg, Chem Chem 2005, 13, 66786684), and is schematized hereafter: ## STR1 ## be obtained using a Radley system, under an inert atmosphere, with refrigeration equipment and a hot plate, provided with magnetic stirring. Different methods of treatment and purification can be applied. The Hantzsch reaction can sometimes lead to oxidized compounds: de-arylated product and / or dehydrogenated product (pyridine skeleton). In some cases, an additional reduction step, for example using a reducing agent such as NaBat, can be carried out.

Compositions A compound of the invention is advantageously formulated in a composition which may be in any galenical form normally available for the indication and the method of administration chosen.

A composition according to the invention comprises a physiologically or pharmaceutically acceptable medium. A composition according to the invention can be administered orally, topically, or intradermally or subcutaneously, and preferably topically. According to one embodiment, a composition topically according to the invention may advantageously be formulated in any dosage form suitable for the care of the scalp, and may be in the form of ointments, creams, solutions, gels, emulsions, foams or aerosol compositions containing a propellant, milks, ointments, powders, soaked swabs, lotions, or suspensions. They may also be in the form of microspheres or nanospheres or lipid or polymeric vesicles or polymeric patches and hydrogels allowing controlled release. These compositions may be in anhydrous or aqueous form according to the dermocosmetic indication retained. A composition intended for topical administration may be an aqueous, hydroalcoholic or oily solution, a solution or a dispersion of the lotion or serum type, a liquid or semi-liquid consistency emulsion of the milk type, obtained by dispersion of a phase in a water phase (O / W) or vice versa (W / O), a suspension or an emulsion, of soft, semi-solid or solid consistency, of the cream type or of the aqueous or anhydrous gel type, a multiple emulsion (E / H / E or H / E / H), a microemulsion, a nanoemulsion, a microcapsule preparation, a microparticle preparation, or an ionic and / or nonionic type vesicular dispersion, or a wax / aqueous phase dispersion . According to one embodiment, a composition of the invention may also be in the form of a transdermal system allowing active or passive release of the active (s) by transdermia, for example patch or gel patch (hydrogel ). These compositions are prepared according to the usual methods.

In the case of a composition according to the invention for oral administration, it favors the use of an ingestible support, the nature of which is adapted according to the type of composition considered. Examples of suitable foodstuffs are tablets, capsules or lozenges, suspensions, oral supplements in dry form and oral supplements in liquid form, milk, yogurt, cheese, fermented milks, fermented products. milk-based products, ices, cereal-based products or fermented cereal-based products, milk-based powders, formulas for children and infants, confectionery-type foods, chocolate, cereals, or especially pet food. By composition for the oral route is meant, for example, nutritional, nutraceutical, cosmeceutical or pharmaceutical compositions comprising at least one compound according to the invention. The formulation of oral compositions according to the invention can be carried out by any usual method known to those skilled in the art to produce oral solutions, dragees, capsules, gels, emulsions, swallowing tablets or chewable, capsules, especially soft or hard capsules, granules for dissolving, syrups, solid or liquid foods and hydrogels for controlled release, food bars, powders, compacted or not, suspensions or liquid solutions confectionery, fermented milk, fermented cheeses, chewing gums, toothpastes or spray solutions. The oral compositions may be in anhydrous form or in aqueous form according to the dermocosmetic indication. A compound of the invention may also be formulated with the excipients and components customary for such oral compositions or food supplements, namely in particular fatty and / or aqueous components, humectants, thickeners, preservatives, texture, flavor and / or coating agents, and / or antioxidants. The formulating agents and excipients for oral composition, and especially for food supplements, are known in the art and are not the subject of a detailed description here. According to another embodiment, a compound that is suitable for the invention can be used subcutaneously or intradermally.

In such an implementation, an active agent that is suitable for the invention may be packaged in the form of a sterile aqueous or non-aqueous isotonic solution, in the form of a dispersion, suspension or emulsion prepared, if appropriate, just before administration, from a sterile powder, for example freeze-dried, which is then reconstituted in the form of a sterile injectable solution or a dispersion at the time of its use. By "sterile" is meant to qualify a formulation capable of ensuring the required safety for intraepidermal and / or intradermal and / or subcutaneous administration.

A composition suitable for the invention may comprise any excipient usually used in the field of sterile injectable solutions. Administration of a composition of the invention may be carried out by any technique and / or injection device suitable for intraepidermal and / or intradermal and / or subcutaneous injection. Thus, such administration can be done by mesotherapy. For the intradermal route, systemic patching may be preferred. A composition according to the invention may further comprise any formulation agent or any additional cosmetically or dermatologically acceptable active agent. The amounts of these various agents or active agents are those conventionally used in the field under consideration, and are in particular determined so as not to affect the desired properties for a compound of the invention or for a composition of the invention. A cosmetic or dermatological active agent that is suitable for the invention may be chosen from moisturizers, prodesquamants, vitamins, essential fatty acids, hydroxy acids, sulphated polysucts, sphingolipids, UV filters, antioxidant compounds, anti-inflammatory agents, acne, anti-inflammatory agents, tanning agents (in the absence of UV radiation), depigmenting agents, mattifying agents, proteins or hydrolysates of proteins, probiotics, amino acids, polyols, urea and its derivatives, jasmonic acid and its derivatives, allantoin, sugars and sugar derivatives, water-soluble vitamins, plant extracts and hydroxy acids, retinol and its derivatives, tocopherol and its derivatives, essential fatty acids, ceramides, essential oils, salicylic acid and its derivatives, vitamin D3 and its derivatives, retinoids and their derivatives, PPAR-gamma agonists, anti-hair loss or hair regrowth agents such as potassic channel openers, anti-perspirants, anti-seborrhoeic drugs, anti-dandruff, anti-androgens, and mixtures of these active agents. A composition of the invention may comprise any formulating agent commonly used in the art. By way of examples of formulation agents that are suitable for the invention, mention may be made of hydrophilic gelling agents, lipophilic gelling agents, surfactants, fillers, odor absorbers, dyestuffs, film-forming polymers, fatty oils such as volatile or nonvolatile oils, pasty or solid fatty substances, such as waxes or gums, solvents, such as ethanol or propylene glycol or a thermal and / or mineral water.

Packaging article A packaging article of the invention will naturally be chosen by those skilled in the art depending on the dosage form of the composition to be packaged. Thus, for liquid compositions, containers may be used consisting of a rigid envelope comprising means for dispensing the composition. These dispensing means may be a single orifice whose closure is provided by a removable cap, or a push button associated with a pump for expelling a portion of the composition contained in the container. Also, the compositions of the invention in liquid form can be packaged in containers of the aerosol flask type. A composition of the invention in semi-liquid or pasty form may advantageously be packaged in a pot, a cream tube, or in a container with flexible or deformable walls and provided with an orifice which can be closed by a removable cap, the composition being expelled through the orifice by pressure on the walls, or a bottle with a push button and a pump as indicated above. According to a particular embodiment, a packaging article capable of accommodating a composition according to the invention may be made of glass, metal, alloy, coated papers such as wax-coated papers such as, for example, papers coated with beeswax. which in particular have properties as a natural preservative.

Alternatively, a composition according to the invention can be stored under vacuum, in an airtight compartment, hermetically sealed, for example in the image of a vacuum brick, commonly used in the food industry. The packaging article can be made at least in part of plastics or other suitable polymeric materials.

According to a particular embodiment, the packaging article may also be produced using materials making it possible to isolate the composition from all light sources. The packaging article may also be at least partly made of thermal insulation materials. Examples of such materials are fabrics, silicone-coated fiberglass fabrics, ceramic fiber-based textiles, cellulose fibers, polystyrene, styrofoam, and silicone films. 'packaging. It is also possible to use a cold gel or liquid as thermal insulation material. According to a particular embodiment, the packaging article is disposable and opened just before its use by the consumer. According to one embodiment, a composition of the invention formulated in the solid state can be, for example, packaged in a pot, a stick tube, for example a tube for lipstick.

Cosmetic treatment process As indicated above, the invention relates to a cosmetic process dedicated to individuals having, or likely to present, an aesthetic disorder of the scalp, in particular as defined above. A method according to the invention may further comprise a step of observing a reduction or even a disappearance of the aesthetic disorder considered. Preferably, a method according to the invention may be implemented topically, orally, intradermally, intraepidermally, or subcutaneously. Even more preferably, a process according to the invention is carried out topically or orally.

A method of the invention may be carried out, topically, in particular by application to the scalp of at least one layer of a cosmetic or dermatological composition comprising, as active ingredient, at least one compound of the invention , and more particularly of a cosmetic composition as defined above. A cosmetic process of the invention may be carried out orally, in particular by administering at least one cosmetic cosmetic food composition comprising, as active ingredient, at least one compound of the invention, and in particular a composition food to cosmetic referred to as defined above. A cosmetic process of the invention may be carried out daily for example, for example for example a single administration per day or administration twice a day, for example once in the morning and once in the evening . A cosmetic process of the invention may be carried out over a period of time varying from one week to several weeks, or even several months, this period being able to be repeated after periods of non-treatment, for several months or even years. .

By way of example, a compound of the invention may be administered, for example, 2 to 3 times daily, or more, and generally over an extended period of at least 4 weeks, or even 4 to 15 weeks, with the if necessary one or more periods of interruption. A method of the invention may advantageously comprise the administration of a composition of the invention in combination, simultaneously, sequentially or separately in time, with the administration of an additional cosmetic or dermatological composition, distinct from the composition of the invention, and intended for the care of the scalp. Any additional cosmetic or dermatological composition may be suitable for the invention, provided of course that its association with a composition of the invention does not affect the properties sought for the latter. The person skilled in the art knows how to appreciate on the basis of his knowledge the additional cosmetic or dermatological compositions that may be suitable. In the following description and examples, unless otherwise indicated, percentages are percentages by weight and ranges of values in the form "between ... and ..." include the specified lower and upper bounds. The ingredients are mixed, before they are shaped, in the order and under conditions easily determined by those skilled in the art. The content and the nature of the ingredients used in the compositions of the invention are adjusted by those skilled in the art so as not to substantially affect the properties required for the compositions of the invention. The following examples are presented by way of illustration and not limitation of the field of the invention.

Fi2ure 1: illustrates an HIES observation of an EpiskinTM model at D13 after systemic treatment over 5 days with a compound of the invention. Fi2ure 2: illustrates immunolabeling of Ki67 performed from EpiskinTM samples processed in the absence and presence of a compound of the invention. Fi2ure 3: illustrates a Western Blot of Cornéosdesmosine made from samples of EpiskinTM treated in the absence and in the presence of a compound of the invention.

EXAMPLES Example 1 Synthesis of compounds (1) to (6) and (8) The compounds of the invention (1) to (6) and (8) can be obtained using a Radley system, under an inert atmosphere, with equipment refrigerant and a hot plate, provided with magnetic stirring. Two methods of treatment and purification can be applied. The protocol detailed below relates to the compound (2).

Reagents Reagents Supplier purity MW n eq. mmol m (gr) Volume 1,3-indanedione Aldrich 97% 146.15 1 34.21 1 562606-368 3-hydroxybenzaldehyde Acros 98.5% 122.12 1 34.21 0.84 A0275828 6-amino-1, 3- Dimethyluracil Aldrich 98% 155.16 1 34.21 1.06 569176-209 Aldrich Acetic Acid 15V 15 61180 Procedure: Equipment: Radley tube equipped with magnetic stirring, placed under a nitrogen atmosphere. Indanedione (1g), 3-hydroxybenzaldehyde (0.84g) and 6-amino-1,3-dimethyluracil (1.06g) are suspended in acetic acid (15ml). The suspension is refluxed. Total solubilization of the reaction medium is observed then the progressive formation of a yellow precipitate. The progress of the reaction is monitored by thin layer chromatography (DCM / MeOH 90/10). After a night at reflux, we observe the total disappearance of indanedione. Treatment and purification: Method A: The heterogeneous reaction medium is filtered on sintered, rinsed abundantly with an ethanol / water mixture (1/1) and then with ethanol. The orange solid is then dried under vacuum in the presence of P2O5. The solid is triturated with acetone (30V) for twenty minutes, sintered and dried under vacuum. 2.5g of an orange solid are thus obtained. Yield 94%. Method B: For certain reaction media, the desired product does not precipitate, even cold. The mixture is then concentrated to dryness by co-evaporation with toluene, and the residue is then purified by chromatography on silica gel (dichloromethane / methanol gradient), before being triturated in isopropyl ether. A final trituration in boiling water makes it possible to obtain the desired compounds after sintering and drying on P205 in vacuo.

Analytical Description of Products: Compound (1) Reagents involved: 1,3-indanedione, 3-methoxybenzaldehyde, 6-amino-1,3-dimethyluracil. Purification according to method B.

Average yield: 44%; solid red-orange. NMR 111 (300MHz, DMSO-d6): LC / MX coherent: x-terra MS C18 column 4.6 * 150mm, 5jam, HCOOH / MeCN, tr = 10.69min,> 98% at 256.3 nm; ESI + mass: [M + H] = 402.0, [M + Nar = 423.9; EST-: [M-H] = 400.9 Compound (2) Engaged reagents: 1,3-indanedione, 3-hydroxybenzaldehyde, 6-amino-1,3-dimethyluracil. Purification according to Method A. Average yield: 94%; solid orange.

NMRIII (300MHz, DMSO-d6): LC / MS consistent: x-terra MS C18 column 4.6 * 150mm, 5jam, HCOOH / MeCN, tr = 8.96min,> 98% at 256.3nm; Mass ESI +: [M + Hr = 388.1, [M + Na] = 410.1, [MM + Na] = 797.4; EST-: [M-EIT = 386.1 Compound (3) Reagents involved: 1,3-indanedione, 4-hydroxy-3-methoxybenzaldehyde, 6-amino-1,3-dimethyluracil. Purification according to Method A. Average yield: 41%; solid orange. NMRIII (300MHz, DMSO-d6): LC / MS coherent: x-terra MS C18 column 4.6 * 150mm, 5p, m, HCOOH / MeCN, tr = 9.05min,> 96% at 256.3nm; ESI + mass: [M + Na] + = 440.0; EST-: [M-HT = 416.0 Compound (4) Reagents involved: 1,3-indanedione, 4-methoxybenzaldehyde, 6-amino-1,3-dimethyluracil. Purification according to Method A. Average yield: 82%; solid orange. NMRIII (300MHz, DMSO-d6): consistent.

LC / MS: x-terra M5 C18 column 4.6 * 150mm, 5p, m, HCOOH / MeCN, tr = 10.59min,> 99% at 256.3nm; ESI + mass: [M + Na] = 424.3; EST-: [M-EIT = 400.3 Compound (5) Reagents involved: 1,3-indanedione, 4-hydroxybenzaldehyde, 6-amino-1,3-dimethyluracil. Purification according to Method A. Average yield: 56%; solid orange. NMRIII (300MHz, DMSO-d6): LC / MS consistent: x-terra MS C18 column 4.6 * 150mm, 5p, m, HCOOH / MeCN, tr = 8.9min,> 98% at 256.3nm; Mass ESI +: [M + Nar = 410.2; EST-: [M-EIT = 386.2 Compound (6) Reagents involved: 1,3-indanedione, 3,5-dimethoxy-4-hydroxybenzaldehyde, 6-amino-1,3-dimethyluracil. Purification according to method B.

Average yield: 45%; solid orange. NMRIII (300MHz, DMSO-d6): LC / MS consistent: x-terra MS MS C18 4.6 * 150mm, 5p, m, HCOOH / MeCN, tr = 8.89min,> 96% at 257.5nm; ESI + mass: [M + Nar = 470.2; EST-: [M-HT = 446.2 Compound (8) Reagents involved: 1,3-indanedione, acetaldehyde, 6-amino-1,3-dimethyluracil. Purification according to Method A. Average yield: 52%; solid orange. NMRIII (300 MHz, DMSO-d6): LC / MS coherent: no technique consistent with the NMR spectrum (partial oxidation of the product) ESI + mass: [M + Nar = 310.1; EST-: [M-EIT = 308.1 EXAMPLE 2 Synthesis of the Compounds (6), (9) and (10) These Compounds were Obtained Using the Protocol Described previously (Example 1) Completed by an Additional Reduction Step . The reducing agent NaBH4 makes it possible to recover the desired reduced product.

The experimental procedure is detailed for the compound (10). Reagents Reagents MW Supplier eq. mmol m (gr) Volume (ml) Aromatic compound from the reaction of 349.3 1 6.30 2.2 Sodium borohydride Acros 37.83 1.5 + 1 15.75 0.36 + 0.24 A0201210001 Tetrahydrofuran Aldrich 30V 65m! Procedure: Equipment: Tricol 100m! equipped with a magnetic stirrer, a refrigerant, and placed under a nitrogen atmosphere. The so-called aromatic compound (2.2g) is suspended in tetrahydrofuran (65m1). Sodium borohydride (360 mg) is added portionwise at room temperature and then the mixture is gradually heated to 45 ° C. Thin layer chromatography (TLC) progress control, after 3 hours of reaction, shows the presence of raw material. Sodium borohydride (240 mg) is again added to the reaction medium in portions. After stirring for 3 h at 45 ° C., traces of raw material are visible by TLC (DCM / MeOH 90/10).

Treatment and purification: The reaction medium is poured on an ice / water mixture. The precipitate observed is filtered and rinsed with water. After drying under vacuum, the residue is triturated in isopropyl ether, sintered and then triturated again in boiling water. After drying under vacuum in the presence of P2O5, a white solid is obtained: 1.9 g (yield: 86%). Analytical Description of Products: Compound (6) Average Yield: 63%; white solid. NMRIII (300MHz, DMSO-d6): LC / MS coherent: x-terra MS C18 column 4.6 * 15 mm, 5 μm, H C 00 H / MeCN, tr = 11.79min,> 96% at 210.0 nm; ESI + mass: [M + Hr = 372.2; EST-: [M-HT = 370.1 Compound (7) Average yield: 38%; white solid. NMRIII (300MHz, DMSO-d6): LC / MS coherent: x-terra MS MS C18 4.6 * 150mnr 5jam, HCOOH / MeCN, tr = 12.48min,> 94% at 210.0nm; ESI + mass: [M + H] + = 386.1; EST-: [M-H] - = 384.0. Compound (8) Average yield: 86%; white solid. NMRIII (300 MHz, DMSO-d6): LC / MS coherent: x-terra MS C18 column 4.6 * 150 mm, 5 μm, HCOOH / MeCN, tr = 12.62min,> 96% at 210.0 nm; Mass E5I +: [M + Hr = 352.2; EST-: [M-HT = 350.2 EXAMPLE 3 Characterization of the compounds of the invention on an in vitro skin model The study was carried out in 3 steps: the molecules first modeled and synthesized were used to treat EpiskinTM reconstructed epidermis kits. - Then a protein study on histological sections and cell extracts was performed. - In a second time, a selection of molecules was evaluated on a Real SkinTM model.

Material & Methods EpiskinTM reconstructed epidermis The reconstructed epidermis, received from the EPISKIN company at six days of reconstruction, was re-cultured as soon as it was received in 3.5m1 of differentiation medium (EPISKINTM medium) under insert (in emersion) for 48h. to the incubator (37 ° C, 5% CO2). The epidermides were then brought into contact with the compounds to be tested systemically. The differentiation culture medium EPISKINTM is changed to a differentiation medium containing the compounds to be tested with 0.1% final DMSO vehicle. The epidermis were re-cultured in the incubator for 48 hours. A new systemic treatment is made for an additional 72 hours of culture in the incubator. For the treatment with EpiskinTM, each test compound was prepared extemporaneously by weighing and dissolved in 10 mM in DMSO, then was used to treat 3 samples of reconstructed epidermis. In addition, each compound to be tested was used in a proportion of 1 and 10 μM final in the culture medium (0.1% final DMSO). The positive controls used were Vitamin D3, Retinol, and Calcipotriol (an analogue of Vitamin D3). The epidermis was removed (3 epidermis per treatment) for histological analyzes and protein extracts (the same reconstructed epidermis is used for the histological study and the protein extract). Histological preparations The morphological control of the treated reconstructed epidermis was carried out using a HIES (Hematoxylin-Eosin-Safran) staining according to a standard protocol on histological sections of the samples included in paraffin (toluene bath: three times 15 minutes; alcohols at 100 ° C: two times a minute, alcohols at 95 ° C for one minute, rinsing in water baths, hematoxylin bath: once for 2 minutes, rinsing in water baths, short soaking in a bath of hydrochloric acid, rinsing with water, eosin bath: once a minute, rinsing with water, short dipping in a bath of alcohol at 100 °, bath of saffron (5 minutes); soaking in an alcohol bath at 100 °, toluene bath: three times 2 minutes).

Fluorescent labeling Epidermal samples were included in OCT for freezing in liquid nitrogen and then stored at -80 ° C. The blocks obtained were cut with a cryostat at 7 μm thickness, the slides were dried and stored at -20 ° C pending immunostaining. For the chosen markers, the antibodies used and their dilutions are listed in the following table: Mouse anti-Novocastra MM1 anti-mouse antibody Dilution 1/20 Western Blots The remainder of the epidermis of each sample was milled at the vibratory mill (Retsch M1V1400) 2x30Htz, 3 minutes; with a stainless steel ball of 3mm diameter (Retsch No. 22.455.0002) in 3001.11 of native buffer +: Tris Buffer (thermo No. 28376); Final 1M NaCl (Sigma No. 57653); Triton X100 1% final (Calbiochem No. 648466); protease inhibitors (complete Roche No. 11873580), pepstatin ljaM final (Roche No. 1359053). The extract was then centrifuged at 14000 rpm for 5 min and the supernatant was filtered on Ultrafree 0.4511M (Millipore UFC3OHVNB). The extracts were determined by the BCA method (Pierce No. 23225) according to the supplier's protocol and equilibrated to 0.3 mg / ml. Abnova Mouse Antibody 1041-A01 1/3000 Anti-CornEodesmosin Dilution Results Morphological Observations Figure 1 illustrates a HIES observation of an Episkin model at D13 after systemic treatment over 5 days with compound (3).

The effect observed on the general structure of the epidermis, illustrated in FIG. 1, reveals that the compounds of the invention induce and stimulate a more or less marked disappearance of the living layers pushed towards the accelerated formation of a Stratum Corneum plus or less thickened.

Results of the immunolabelings The markers chosen for the immunolabelings is Ki67, making it possible to inform on a possible modification of the cell proliferation in the basal layer. The results, illustrated in FIG. 2 with the compound (5) of the invention, show that the compounds of the invention induce a clear and sometimes complete reduction in Ki67 labeling, and therefore have strong anti-proliferative properties. . Proteomic results The chosen marker in proteomics is Cornéodesmosine, which provides information on the possible activation of the proteolytic maturation of the Stratum Corneum. Generally in reconstructed skin models this maturation is severely limited. The results, illustrated in FIG. 3 with the compound (1) of the invention, show that the compounds of the invention induce an increase in the soluble fragments of corneodesmosin, reflecting an acceleration of the Stratum Corneum maturation phenomenon and / or increase in the number of SC layers. Summary Table of Results The results detailed above are summarized in the table below. For each of the monitored parameters, the score for the most active compound among the tested compounds (effect larger or smaller than the reference) is indicated by an asterisk. The effect is usually noted for the highest concentration used (10 aM). Some compounds showed effects at the lowest tested concentrations (1 μM). The relative ranking in this table takes this into account. Compound HES CDSN Ki67 Vitamin D3 0 0 0 / - Retinol (1001aM) 0 0 / + 0 Calcipotriol ++ ± - (1) + ++ (*) - (2) + ++ 0 (3) ++ + - - (5) + + - (6) I ++ (*) 1+ II Table Abbreviations: HES = Hematoxylin - Eosin - Saffron (HES) CDSN = CornEodesmosin The above results reveal that the compounds of the invention are endowed with vitamin D3-type properties, particularly advantageous, for preventing and / or treating a disorder of the scalp, in particular a dandruff condition.

Example 4 Shampoo Example The following shampoo was prepared according to the following table. The amounts are indicated as percent by weight of active ingredient (M.A.) based on the total weight of the composition. Shampoo% by weight of MA Monoisopropanolamide of coconut acids (Empilan CIS sold by the company Hunsmann) 0.24 Cocamidopropyl betaine at 38% by weight in aqueous solution (Tego betain F50 sold by the company Evonikgolschmidt) 2,4 Lauryl ether sulfate sodium hydroxide with 2.2 moles of ethylene oxide at 26% by weight in aqueous solution (Texapon AOS 225 UP sold by the company Cognis) 15.5 Sodium chloride 1.1 Compound 6 1 Sodium benzoate 0.5 Salicylic acid 0.2 Polydimethylsiloxane 500,000 cSt (molecular weight 250,000) (Silbione 70047V500000 sold 2 by the company Blutestar) Mixture 1- (hexadecyloxy) -2-octadecanol / cetyl alcohol (Mexanyl GY sold by the company Chimex) 2,5 Carboxyvinyl polymer (Carbopol 980 sold by LUBRIZOL) 0.3 Propylene glycol 0.1 Glycerol 2 pH agent Qs pH 5.3 Fragrance 0.5 Water qs 100

Claims (10)

REVENDICATIONS1. Cosmetic use, as an agent for preventing and / or treating an aesthetic disorder of the scalp, of an effective amount of at least one compound represented by one of the general formulas (Ia) or (Ib): Fp F2 NN R2 0 lb in which: R1 represents H or a group -C (O) R8, with R8 being linear or branched, saturated or unsaturated C 1 -C 4 alkyl, or phenyl; R2 represents H; a linear or branched, saturated or unsaturated C 1 -C 12 alkyl group; or a group selected from: wherein R 1, R 4, R 8, R 6 represent, independently of one another, H; R 3 R 7 R 4 R 6 R 4 R 5 R 3 R 7 R 6 R 5; -NO2; -OH ; -0R8; -CN; Br; Cl; I; F; -CF3; a linear or branched, saturated or unsaturated C 1 -C 4 alkyl; phenyl; -OC (O) -R8; -O-Ph-X, with X representing H, -OH, -NO2, a fluorine, a linear or branched, saturated or unsaturated C 1 -C 4 alkyl or alkoxy; R8 being as defined above, - R and R ', identical or different, represent H or a linear or branched C1-C4 alkyl, or a physiologically acceptable salt thereof. 2. Use according to claim 1, wherein said compound is of general formula (Ia) wherein: - RI is 1-1, - R2 is H; a linear or branched, saturated or unsaturated C 1 -C 12 alkyl group; or a group selected from: wherein R3, R4, R5, R6, R7 are, independently of one another, H; - NO2; -OH ; -0R8; -CN; F; -CF3; a linear or branched, saturated or unsaturated C1-C4 alkyl; phenyl; -OC (O) -R8; -O-Ph-X with X representing H, -OH, -NO2, a fluorine, a linear or branched, saturated or unsaturated C 1 -C 4 alkyl or alkoxy; with R 8 being linear or branched, saturated or unsaturated C 1 -C 4 alkyl, or being phenyl, R 1 and R ', which may be identical or different, represent H or linear or branched C 1 -C 4 alkyl, or physiologically acceptable salt thereof. 3. Use according to claim 1 or 2, wherein said compound is of general formula (Ia) wherein: R1 is H, - R2 is H; a linear or branched, saturated or unsaturated C1-C12 alkyl group; or a group selected from: wherein R3, R4, R5, R6, R7 are independently of each other H; R3 R7 R4 R6 R7 R6 R3 R4 R5 R5 OR - OH ; -0R8; CN; a linear or branched, saturated or unsaturated C 1 -C 4 alkyl; phenyl; -OC (O) -R8; -O-Ph-X with X representing H, -OH, a linear or branched, saturated or unsaturated C 1 -C 4 alkyl or alkoxy; with R 8 being a linear or branched, saturated or unsaturated C 1 -C 4 alkyl, or being a phenyl, R 1 and R ', which may be identical or different, represent H or a methyl, and their physiologically acceptable salts. 4. Use according to one of the preceding claims, wherein said compound is of general formula (1a) wherein: - RI represents H, - R2 represents H, a linear or branched, C1-C6 alkyl, saturated; or a group selected from: wherein R3, R4, R5, R6, R7 are, independently of each other, H; - OH ; -0R8; -CN; a linear or branched, saturated or unsaturated C 1 -C 4 alkyl; with R8 being linear or branched, saturated or unsaturated C1-C4 alkyl, or being phenyl, - R and R 'are methyl, or a physiologically acceptable salt thereof. 5. Use according to one of the preceding claims, wherein said compound is selected from: 33. MODIFIED CLAIMS H 1 N N 0 o OH (2); OH 1 (3); FR 55269 (4); OH (5); 6. Use according to one of the preceding claims, wherein said compound is used in a proportion of 0.01 to 10% by weight, preferably 0.1 to 5% by weight relative to the total weight of the composition. container. or (11); or a physiologically acceptable salt. (7); (6); (10); FR 12 5269 34. MODIFIED CLAIMS 7. Use according to one of the preceding claims, wherein the disorder of the scalp a dandruff condition of the scalp. 8. Use according to the preceding claim, wherein the dandruff condition of the scalp is associated with dry scalp, hyperseborrhea of the scalp, unbalanced ecoflora, pruritus, inflammation of the scalp, or barrier function of the scalp. unbalanced scalp. 9. Use according to one of the preceding claims, wherein said compound is intended to improve the comfort of the scalp. 10. Use according to one of the preceding claims, wherein said compound IO is intended to preserve and / or enhance the integrity of the barrier functions of the skin of the scalp. 1 1. Compound as defined according to one of claims 1 to 6, in an effective amount in a pharmaceutical or dermatological composition, for preventing and / or treating a pathological disorder of the scalp. 12. Compound according to the preceding claim, said compound being intended to prevent and / or treat seborrheic pruritus and / or dermatitis of the scalp. 13. Cosmetic process for treating and / or preventing an aesthetic disorder of the scalp in an individual in need, comprising at least one step of administering to said individual, at least an effective amount of at least one compound as defined according to one of claims 1 to 5. 14. Compound represented by the general formula (IIa): wherein R 1 is H, and R 2 is a linear C 1 -C 3 alkyl or branched, saturated; benzyl; or MeO-OHe R and R 'are methyl, or a physiologically acceptable salt thereof. 15. Cosmetic or dermatological composition comprising, in a physiologically acceptable medium, an effective amount of at least one compound of general formula (IIa) as defined in claim 14.5