Classifications

• • 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
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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 subject of the invention is a composition for caring for or making up keratin fibers, in particular human fibers, containing an effective amount of a pyrazolic compound and more especially of a pyrazol-carboxamide compound, intended to induce and / or stimulate the growth of keratin fibers and / or curb their fall. It also relates to a cosmetic treatment process intended to stimulate the growth of keratin fibers and / or slow their fall.
• the human keratin fibers to which the invention applies are in particular the hair, the eyebrows, the eyelashes, the beard hair, the mustache hair and the pubic hair. More specifically, the invention applies to human hair and / or eyelashes.
• the invention relates to a composition for caring for or making up hair or eyelashes, containing an effective amount of a pyrazolcarboxamide compound, intended to increase their density and / or improve their appearance.
• Hair growth and renewal is mainly determined by the activity of the hair follicles and their matrix environment. Their activity is cyclical and essentially comprises three phases, namely the anagen phase, the catagen phase and the telogen phase.
• the anagen phase active or growth phase
• a very short and transient catagen phase which lasts a few weeks.
• the hair undergoes an evolution, the follicle atrophies and its dermal implantation appears higher and higher.
• the terminal phase or telogen phase which lasts a few months, corresponds to a resting phase of the follicle and the hair ends up falling out. At the end of this rest period, a new follicle is regenerated on site, and another cycle begins again. The hair is therefore constantly renewed and of the approximately 150,000 hairs in hair, approximately 10% are at rest and will be replaced in a few months.
• Natural hair loss or loss can be estimated, on average, a few hundred hairs per day for a normal physiological state. This permanent physical renewal process undergoes a natural evolution during aging, the hair becomes thinner and their cycles shorter.
• alopecia which is essentially due to a disturbance of the capillary renewal leading initially to the acceleration of the frequency of the cycles to the detriment of the quality of the hair, then of their quantity. Successive growth cycles result in hair that is thinner and shorter and shorter, gradually transforming into an unpigmented down, thus resulting in a gradual depletion of the hair. Areas are preferentially affected, in particular the temporal or frontal gulfs in men and, in women, there is diffuse alopecia of the vertex.
• alopecia also covers a whole family of damage to the hair follicle, the final consequence of which is the permanent, partial or general loss of hair. It is more particularly about androgenic alopecia. In a significant number of cases, early hair loss occurs in genetically predisposed subjects, it is then andro-chrono-genetic alopecia; this form of alopecia especially concerns men.
• compositions which make it possible to suppress or reduce alopecia, and in particular to induce or stimulate hair growth or to reduce hair loss.
• compositions comprising very diverse active agents, such as, for example, 2,4-diamino 6-piperidinopyrimidine 3-oxide or "minoxidil” described in US Pat. Nos. 4,139,619 and US 4,596 812 or its numerous derivatives such as those described for example in patent applications EP 0353123, EP 0356271, EP 0408442, EP 0522964, EP 0420707, EP 0459890, EP 0519819.
• active agents such as, for example, 2,4-diamino 6-piperidinopyrimidine 3-oxide or "minoxidil” described in US Pat. Nos. 4,139,619 and US 4,596 812 or its numerous derivatives such as those described for example in patent applications EP 0353123, EP 0356271, EP 0408442, EP 0522964, EP 0420707, EP 0459890, EP 0519819.
• prostaglandins are molecules with a very short biological half-life time and acting in an autocrine or paracrine manner, this reflecting the local and labile nature of the metabolism of prostaglandins (Narumiya S. et al., 1999, Physiol. Rev., 79 (4), 1193-1226).
• the differentiation programs of the keratinocytes of the epidermis and of the hair follicle are clearly different.
• the keratins of the hair shaft represent a family (Langbein et al., 2001, J. Biol. Chem. 276: 35123-35132) distinct from that expressed in the epidermis, as the differentiation markers such that the keratins rvi and K 10 are not expressed in the hair follicle and in particular in the external sheath (Lenoir et al., 1988, Dev. Biol. 130: 610-620), than trichohyaline (O'Guin et al ., 1992, J. Invest. Dermatol.
• keratin K6irs are expressed in the hair follicle in particular in the internal sheath but not in the epidermis, and that type 1 cyclo-oxygenase, if it is expressed in the epidermis, is not expressed in the keratinocytes of the hair follicle but in the dermal papilla (Michelet. et al ., 1997, J. Invest. Dermatol. 108: 205-209).
• the present invention relates to a composition for caring for or treating keratin fibers and in particular hair fibers, containing at least one particular inhibitor of 15-hydroxy prostaglandin dehydrogenase and a physiologically acceptable medium.
• 15-PGDH is a key enzyme in the deactivation of prostaglandins, in particular PGF2- ⁇ , and PGE2, which are important mediators of hair growth and survival. It meets the EC 1.1.1.141 classification and is NAD + dependent. She was isolated from pork kidney; in particular, its inhibition by a thyroid hormone, tri-iodo thyronine, has been observed at doses much higher than physiological doses.
• US Pat. No. 4,251,658 describes pyrazole compounds with a chemical structure different from that of the pyrazole compounds to which the invention applies.
• the amide group is not found in the compounds described in this patent.
• these compounds are described as inhibitors of 15-PGDH originating from the pig's lung and not from the skin (external organ), in particular human.
• the 15-PGDH present in the pig lung is the same as that present in the human skin, and that a compound presented as an inhibitor of the 15-PGDH of the pig lung is also an inhibitor 15-PGDH present in the human dermis and in particular in the dermal papilla of the hair.
• the present invention therefore relates to a composition for caring for and / or making up keratin fibers, in particular human fibers, containing in a physiologically acceptable medium an effective amount of a pyrazolic compound of formula (I) or of one of its salts:
• R- [and R 2 are chosen independently from:
• R 3 and R 5 are independently chosen from: - hydrogen,
• R 4 is chosen from: - hydrogen
• R 6 , R ' 6 , R " 6 and R'" 6 are chosen from:
• R is chosen from:
• R 7 , R ' 7 , R " 7 and R'” 7 independently represent hydrogen or a saturated or unsaturated, linear or branched CC 20 alkyl;
• A represents a CC 4 alkyl radical, saturated or unsaturated, linear or branched, optionally substituted with at least one substituent T 5 chosen from: R 'and saturated or unsaturated rings of 4 to 7 atoms optionally containing at least one heteroatom from Y, N, S, these cycles possibly being able to be joined, to include a carbonyl or thiocarbonyl function and / or to be substituted by at least one substituent R;
• the invention also relates to the use of at least one pyrazolic compound of formula (I) or of one of its salts, as defined above, as an agent for inducing and / or stimulating the growth of keratin fibers in particular human like the hair and eyelashes of human beings and / or curb their fall and / or increase their density.
• the invention also applies to keratin fibers of mammals of the animal species (dog, horse or cat for example).
• the invention also relates to the cosmetic use of at least one pyrazolic compound of formula (I) or of one of its salts in a cosmetic composition for caring for and / or making up human keratin fibers to induce and / or stimulate their growth, curb their fall and / or increase their density as well as the use of at least one compound of formula (I) or one of its salts for the preparation of a care composition or treatment of human keratin fibers, intended to induce and / or stimulate the growth of fibers and / or slow down their fall and / or increase their density.
• the human keratin fibers to which the invention applies are in particular hair, eyebrows, eyelashes, beard hair, mustache hair and pubic hair. More specifically, the invention applies to human hair and / or eyelashes.
• the invention also relates to the cosmetic use of at least one pyrazolic compound of formula (I) or of one of its salts in a cosmetic composition for human hair care to reduce hair loss and / or increase their density. It also relates to the use of at least one pyrazolic compound of formula (I) or one of its salts for the preparation of a hair composition for humans, intended to induce and / or stimulate the growth of hair and / or curb their fall and / or increase their density.
• the invention relates to the cosmetic use of at least one pyrazolic compound of formula (I) or of one of its salts in a cosmetic composition for human hair care or for the preparation of a human hair composition respectively for treating or intended to treat alopecia of natural origin and in particular androgenic and andro-chrono-genetic.
• this composition makes it possible to maintain the hair in good condition and / or fight against the natural fall of men's hair.
• Another subject of the invention is the cosmetic use of at least one pyrazolic compound of formula (I) or one of its salts, in a cosmetic composition for caring for and / or making up human eyelashes, for induce and / or stimulate the growth of eyelashes and / or increase their density as well as the use of at least one compound of formula (I) or one of its salts, for the preparation of a care composition and / or treatment of human eyelashes, intended to induce and / or stimulate the eyelash growth and / or increase their density.
• This composition thus makes it possible to maintain the eyelashes in good condition and / or to improve their condition and / or their appearance.
• the subject of the invention is also a process for the cosmetic treatment of keratin fibers (hair or eyelashes in particular) and / or of the skin from which said fibers emerge, including the scalp and the eyelids, this process being in particular intended for stimulate the growth of human keratin fibers and / or curb their fall, characterized in that it consists in applying to the keratin fibers and / or the skin from which said fibers emerge, a cosmetic composition comprising an effective amount at least one compound of formula (I) or one of its salts, to leave the latter in contact with the keratin fibers and / or the skin from which said fibers emerge, and optionally to rinse the fibers and / or said skin.
• This treatment process has the characteristics of a cosmetic process insofar as it makes it possible to improve the aesthetics of keratin fibers and in particular of hair and eyelashes by giving them greater vigor and an improved appearance. In addition, it can be used daily for several months, without medical prescription.
• Another subject of the invention is the use of at least one pyrazolic compound of formula (I) or one of its salts as an inhibitor of 15-hydroxy prostaglandin dehydrogenase in human skin. It also relates to the use of at least one pyrazolic compound of formula (I) or of one of its salts for the manufacture of a composition intended for treating disorders linked to 15-hydroxy prostaglandin dehydrogenase in l 'To be human.
• the subject of the present invention is also a process for the cosmetic treatment of the hair and / or scalp, intended to stimulate the growth of human hair and / or to curb its fall, characterized in that it consists in applying to the hair and / or the scalp a cosmetic composition comprising an effective amount of at least one compound of formula (I) or one of its salts, to leave the latter in contact with the hair and / or the scalp, and possibly to rinse the hair and / or the scalp.
• the subject of the present invention is a process for the cosmetic care of human hair and / or scalp, with a view to improving their condition and / or their appearance, characterized in that it consists in applying to the hair and / or leather scalp, a cosmetic composition comprising an effective amount of at least one compound of formula (I) or one of its salts, to leave the latter in contact with the hair and / or the scalp, and optionally to rinse the hair and / or scalp.
• the subject of the invention is also a method of cosmetic care and / or of making up human eyelashes, with a view to improving their condition and / or their appearance, characterized in that it consists in applying to the eyelashes and / or the eyelids a mascara composition comprising at least one compound of formula (I) or one of its salts and leaving the latter in contact with the eyelashes and / or the eyelids.
• This mascara composition can be applied alone or as an undercoat of a conventional pigmented mascara and can be removed as a conventional pigmented mascara.
• the subject of the invention is also a composition for caring for or making up keratin fibers, comprising, in a physiologically acceptable, in particular cosmetic, medium, at least one compound of formula (I) or one of its salts and at least one compound.
• additional active agent promoting the regrowth of human keratin fibers and / or limiting their fall chosen from aminexil, agonists of the FP receptor and vasodilators and more especially chosen from aminexil, minoxidil, latanoprost, butaprost and travoprost.
• Another subject of the invention is the use of at least one compound of formula (I) or one of its salts for the manufacture of a composition intended to preserve the quantity and / or the activity of prostaglandins at the level of the hair follicle.
• the subject of the invention is also the cosmetic use of at least one compound of formula (I) or one of its salts in a cosmetic composition, as an agent for preserving the quantity and / or the activity of prostaglandins at the level of the hair follicle.
• the subject of the invention is also new pyrazole-carboxamide compounds of formula III or one of its salts:
• R 8 represents OH or -S- (CH 2 ) m -R 9 ' , with R g representing H or Hy; T4 represents H or 4-COOH; n represents an integer ranging from 1 to 10 and m represents an integer ranging from 1 to 10; Hy represents a heterocycle of 4 to 7 atoms.
• 15-hydroxy prostaglandin dehydrogenase inhibitor is meant a compound of formula (I) which is capable of inhibiting or decreasing the activity of the enzyme 15-PGDH in particular in humans, and / or capable of inhibit, decrease or slow down the reaction catalyzed by this enzyme.
• the compound of formula (I) is a specific inhibitor of 15-PGDH; by specific inhibitor is meant a compound of formula (I) which has little or no inhibitor of the synthesis of prostaglandins, in particular of the synthesis of PGF2- ⁇ or of PGE2.
• the 15-PGDH inhibitor is little or no inhibitor of prostaglandin synthesis, in particular of the synthesis of PGF2- ⁇ or of PGE2.
• the 15-PGDH inhibitor is little or not at all inhibitor of prostaglandin synthase (PGF synthase).
• PGF synthase is also expressed in the dermal papilla. Maintaining an effective amount of prostaglandins at the site of action therefore results from a complex biological balance between the synthesis and the degradation of these molecules. The exogenous supply of compounds inhibiting catabolism will therefore be less effective if this activity is combined with an inhibition of synthesis.
• the compounds of formula (I) in salified form or not, exhibit an inhibitory activity of 15-PGDH superior to the inhibitory activity of PGF synthase.
• the ratio between the inhibitory activities of PGF synthase and 15-PGDH respectively for a given concentration, determined in particular by the inhibitory concentrations of 50% of the enzymatic activity of PGF synthase (IC 50fS ) and of 15-PGDH (IC 50c ⁇ h ) is at least greater than 1 and in particular at least 3: 1, advantageously greater than or equal to 5: 1.
• the preferred compounds of the invention have an IC 5 o f s IC 5 o d ratio greater than or equal to 10: 1, and in particular greater than or equal to 15.
• At least one means one or more (2, 3 or more).
• the composition may contain one or more compounds of formula (I).
• This or these compounds may be cis or trans or Z or E isomers or a mixture of cis / trans or Z / E isomers. They can also be in tautomeric form.
• This or these compounds can also be enantiomers and / or diastereoisomers or a mixture of these isomers, in particular a racemic mixture.
• the cycles used for R ⁇ R 2 , R 3 , R 4 , R 5 , Re, R'e, R “e, R '" 6, R', " H and T 5 comprise from 4 to 7 atoms and better still from 5 to 6 atoms They can be saturated or unsaturated and possibly contain one or more heteroatoms such as S, N, O or their associations.
• saturated carbon rings which can be used mention may be made of the cyclopentyl or cyclohexyl radical.
• the pyridine, piperidine, morpholine, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrazole, pyrimidine, pyrazine, pyridazine rings can be mentioned.
• the phenyl radical can also be mentioned. be substituted in particular by a substituent such as A or R.
• Ri and R 2 can form a heterocycle with the nitrogen to which they are linked, comprising from 4 to 7 atoms and better still from 5 to 6 atoms and containing from 1 to 3 heteroatoms chosen from O, N, S.
• R 4 it is possible to use as heterocycle, the pyridine, piperidine, morpholine, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine or pyrazine ring.
• these cycles can be alone or joined to another cycle with the same chemical structure or not, and thus form condensed cycles.
• condensed rings mention may be made of the naphthyl, benzofuran, benzothiophene, indole radical.
• alkyl radical is meant in the sense of the invention a hydrocarbon radical which can be linear or branched, saturated or unsaturated.
• the alkyl radical contains from 1 to 10 carbon atoms.
• alkyl radical which can be used in the invention, it is possible to cite the methyl, ethyl, isopropyl, n-butyl, terbutyl, n-hexyl, ethyl-2-hexyl, ethylene, propylene radicals.
• halogen atom it is possible to use chlorine, fluorine or bromine atoms, and better still fluorine and chlorine atoms.
• the compounds of formula (I) are in isolated form, that is to say non-polymeric.
• the pyrazolcarboxamide compound has the following formula (II) or one of its salts:
• R ⁇ [and R 2 , are independently chosen from:
• T ⁇ Ri and R 2 can also form a heterocycle of 4 to 7 atoms with the nitrogen to which they are attached;
• R 3 and R 5 are independently chosen from - hydrogen, - AT,
• R 4 is chosen from: - hydrogen
• R 6 and R ' 6 are chosen from:
• R is chosen from:
• R 7 and R ' 7 independently represent hydrogen or a saturated or unsaturated, linear or branched C 1 -C 4 alkyl;
• A represents a C ⁇ -C 20 alkyl radical, saturated or unsaturated, linear or branched optionally substituted with at least one substituent T 5 chosen from halogens, groups OR 7 , SR 7 , NR R ' 7 , CN, CF 3 , COOR 7 and the saturated or unsaturated rings of 4 to 7 atoms optionally containing at least one heteroatom among O, N, S, these rings possibly being able to be joined and / or to be substituted by at least one substituent R;
• Ti is chosen from OR 6 , SR 6 , NR 6 R ' 6 , CN, CF 3 ,, COOR 6 , halogens, saturated or unsaturated rings from 4 to 7 ⁇ atoms possibly containing at least one heteroatom from O, N , S, these cycles possibly being able to be joined and to be substituted by at least one substituent R.
• At least one of R- and R 2 represents a saturated alkyl radical group, in C r C 2 o and better in CC 10 substituted, by SR 6 or OH.
• R 6 represents an alkyl radical in CrC 20 and better in CC 10 optionally substituted by a heterocycle Hy of 4 to 7 atoms.
• at least one of R ⁇ and R 2 represents a group (CH 2 ) n R 8 with R 8 representing OH or -S- (CH 2 ) m R 9 , with R 9 representing H or Hy, where n and m each represent an integer ranging from 1 to 20 and better still from 1 to 10.
• Ri represents hydrogen and R 2 represents (CH 2 ) n S (CH 2 ) mR9, with n being 2 and m being 1
• Hy represents a heterocycle with 5 atoms comprising for example as heteroatom oxygen, such as furan.
• At least one of R 3 and R 5 represents CF 3 .
• R 3 represents CF 3 and R 5 represents H.
• R 4 represents a hydrocarbon ring comprising 5 to 6 atoms, in particular unsaturated and in particular a phenyl radical optionally substituted by T and for example by 4-COOH.
• the pyrazolcarboxamide compound has the following formula (III) or one of its salts:
• R 8 represents OH or -S- (CH 2 ) m -R 9 , with R 9 representing H or Hy; T4 represents H or 4-COOH; n and m independently represent an integer ranging from 1 to 10 and better still from 1 to 5; Hy representing a heterocycle in particular of 5 to 6 atoms.
• compound salts of formula (I) is meant according to the invention, the organic or inorganic salts of a compound of formula (I).
• inorganic salts which can be used according to the invention, mention may be made of: the sodium or potassium salts as well as the zinc (Zn 2+ ), calcium (Ca 2+ ), copper (Cu 2+ ), iron ( Fe 2+ ), strontium (Sr 2+ ), magnesium (Mg 2+ ), manganese (Mn 2+ ), ammonium; hydroxides, carbonates, halides, chlorides, sulfates, phosphates, nitrates.
• organic salts which can be used according to the invention are, for example, the salts of tri-ethanolamine, mono-ethanolamine, di-ethanolamine, hexadecylamine and N, N, N ', N'-tetrakis- (hydroxy-propyl-2) ethylene diamine, tris-hydroxymethyl.
• the pyrazol-carboxamide compounds of formula (I) or their salts have the property of inducing and / or stimulating the growth of human keratin fibers and in particular hair and eyelashes and / or curbing their loss, or that these compounds can be used topically to increase the density of keratin fibers (in particular hair and eyelashes).
• the effective amount of a compound of formula (I) or one of its salts corresponds to the amount necessary to obtain the desired result (namely to increase the density of keratin fibers such as the hair and eyelashes). Those skilled in the art are therefore able to assess this effective amount which depends on the nature of the compound used, the person to whom it is applied, and the time of this application.
• the compound of formula (I) or one of its salts or mixture of compounds of formula (I) and / or their salt can be used in an amount representing 10 "3 % to 10% of the total weight of the composition and preferably in an amount representing from 10 " 3 to 5% and better still from 10 "2 % to 2% of the total weight of the composition, for example from 0.5 to 2%.
• composition of the invention can be for cosmetic or pharmaceutical use.
• the composition of the invention is for cosmetic use.
• the composition must contain a physiologically acceptable medium which is non-toxic and capable of being applied to the skin, including the scalp and the eyelids, or to the keratin fibers of human beings.
• cosmetic is meant within the meaning of the invention a composition of pleasant appearance, odor and feel.
• the compound of formula (I), salified or not, can be used in a composition which must be ingested, injected or applied to the skin or to keratin fibers (on any skin area or fibers to be treated).
• the compound of formula (I) can be used orally in an amount of 0.1 to 300 mg per day, 5 to 10 mg / day.
• a preferred composition of the invention is a composition for cosmetic use and in particular for topical application to the skin and keratin fibers, and more especially to the scalp, hair and eyelashes.
• composition can be in any known dosage form adapted to the mode of use.
• the composition may take the form of an aqueous, alcoholic or hydroalcoholic solution or suspension or of an oily suspension, of an emulsion of more or less fluid consistency and in particular liquid or semi- liquid, obtained by dispersing a fatty phase in an aqueous phase (O / W) or vice versa (W / O), a solid emulsion (O / W) or (W / O), an aqueous gel, hydroalcoholic or oily more or less fluid or solid, of a free or compacted powder to be used as it is or to be incorporated in a physiologically acceptable medium, or alternatively of microcapsules or microparticles, of vesicular dispersions of ionic and / or nonionic type . It can thus be in the form of a lotion, serum, milk, O / W or W / O cream, ointment, ointment, balm, patch,
• compositions in the form of a foam or else in the form of a spray or aerosol then comprising a propellant under pressure it is also possible to envisage a composition in the form of a foam or else in the form of a spray or aerosol then comprising a propellant under pressure.
• the composition for application to the scalp or the hair may be in the form of a hair care lotion, for example of daily or bi-weekly application, of a shampoo or of a hair conditioner, in particular bi-weekly or weekly application, a liquid or solid soap for cleaning the scalp of daily application, a product for shaping the hairstyle (hairspray, product for styling, styling gel ), a treating mask, a foaming cream or gel for cleaning the hair. It can also be in the form of a hair dye or mascara to be applied by brush or comb.
• composition to which the invention applies can be in the form of a mascara, pigmented or not, to be applied by brush to the eyelashes or else to the beard or mustache hair.
• the composition may be in the form of an aqueous lotion or an oily suspension.
• the composition may be in the form of capsules, granules, drinkable syrups or tablets.
• the composition according to the invention is in the form of a hair cream or lotion, shampoo, hair conditioner, hair mascara or for eyelashes.
• compositions according to the invention are those generally used in the fields considered.
• these compositions are prepared according to the usual methods.
• the proportion of the fatty phase can range from 2% to 80% by weight, and preferably from 5% to 50% by weight relative to the total weight of the composition.
• the aqueous phase is adjusted as a function of the content of fatty phase and of compound (s) (I) as well as that of any additional ingredients, to obtain 100% by weight. In practice, the aqueous phase represents from 5% to 99.9% of the total weight of the composition.
• the fatty phase can contain fatty or oily compounds, liquid at room temperature (25 ° C) and atmospheric pressure (760 mm Hg), generally called oils. These oils may or may not be compatible with each other and form a macroscopically homogeneous liquid fatty phase or a two- or three-phase system.
• the fatty phase can, in addition to oils, contain waxes, gums, lipophilic polymers, "pasty” or viscous products containing solid parts and liquid parts.
• the aqueous phase contains water and optionally an ingredient miscible in any proportion with water such as lower alcohols C 1 to C 8 such as ethanol, isopropanol, polyols such as, propylene glycol, glycerol , sorbitol or acetone or ether.
• lower alcohols C 1 to C 8 such as ethanol, isopropanol, polyols such as, propylene glycol, glycerol , sorbitol or acetone or ether.
• the emulsifiers and co-emulsifiers used to obtain a composition in the form of an emulsion are those generally used in the cosmetic and pharmaceutical fields. Their nature is, moreover, a function of the direction of the emulsion.
• the emulsifier and optionally the co-emulsifier are present in the composition in a proportion ranging from 0.1% to 30% by weight, preferably from 0.5 to 20% by weight and better still from 1 to 8%.
• the emulsion can, in addition, contain lipid vesicles and in particular liposomes.
• the fatty phase can represent more than 90% of the total weight of the composition.
• the composition is an aqueous, alcoholic or hydro-alcoholic solution or suspension and better still a water / ethanol solution or suspension.
• the alcohol fraction can represent from 5% to 99.9% and better still from 8% to 80%.
• the composition is a wax-in-water or wax-in-oil dispersion, a gelled oil, an aqueous gel, pigmented or not.
• composition of the invention may also comprise other ingredients usually used in the fields concerned, chosen from solvents, thickeners or gelling agents of aqueous phase or of oily phase, coloring matters soluble in the medium of the composition , solid particles such as fillers or pigments, antioxidants, preservatives, perfumes, electrolytes, neutralizers, film-forming polymers, blocking agents for UN. such as sunscreens, cosmetic and pharmaceutical active agents with beneficial action for the skin and / or keratin fibers, other than the compounds of formula (I) or (II), their mixtures.
• These additives can be present in the composition according to the quantities generally used in the cosmetic and dermatological field and in particular at a rate of 0.01 to 50% of the total weight of the composition and better still from 0.1 to 20% and for example of 0 , 1 to 10%.
• composition according to the invention in particular namely the specific inhibition of 15-PGDH or 'increase in the density of keratin fibers (capillary or eyelashes), are not or substantially not, altered by the planned addition.
• solvents which can be used in the invention mention may be made of lower C 2 to C 8 alcohols such as ethanol, isopropanol, propylene glycol and certain light cosmetic oils such as C 6 to C 16 alkanes.
• oils which can be used in the invention mention may be made of oils of mineral origin (petrolatum oil, hydrogenated isoparaffin), oils of vegetable origin (fraction shea butter liquid, sunflower oil, apricot oil, alcohol or fatty acid), oils of animal origin (perhydrosqualene), synthetic oils (fatty acid ester, Purcellin oil), silicone oils ( linear or cyclic polydimethylsiloxane, phenyltrimethicone) and fluorinated oils (perfluoropolyethers).
• oils of mineral origin petrolatum oil, hydrogenated isoparaffin
• oils of vegetable origin fraction shea butter liquid, sunflower oil, apricot oil, alcohol or fatty acid
• oils of animal origin perhydrosqualene
• synthetic oils fatty acid ester, Purcellin oil
• silicone oils linear or cyclic polydimethylsiloxane, phenyltrimethicone
• fluorinated oils perfluoropolyethers.
• waxes mention may be made of silicone wax
• emulsifiers which can be used in the invention, mention may, for example, be made of glycerol stearate or laurate, sorbitol stearates or oleates, alkyl dimethiconecopolyol (with alkyl> 8) and their mixtures for a W / O emulsion.
• Polyethylene glycol monostearate or monolaurate, polyoxyethylenated sorbitol stearate or oleate, dimethiconecopolyols and their mixtures can also be used for an O / W emulsion.
• hydrophilic gelling agents which can be used in the invention, mention may be made of carboxyvinyl polymers (carbomers), acrylic copolymers such as acrylate / alkyl acrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, natural gums and clays, and, as lipophilic gelling agents, mention may be made of modified clays such as Bentones, metal salts of fatty acids such as aluminum stearates, hydrophobic treated silica, ethylcellulose, their mixtures.
• the composition can contain a cosmetic or pharmaceutical active other than the compounds of formula (I) which can be hydrophilic and chosen from proteins or protein hydrolysates, amino acids, polyols, urea, allantoin, sugars and sugar derivatives, water-soluble vitamins, plant extracts (those of Iridaceae or soybeans) and hydroxy acids (fruit or salicylic acids); or lipophilic and chosen from retinol (vitamin A) and its derivatives, in particular ester (retinol palmitate), tocopherol (vitamin E) and its derivatives, in particular ester (tocopherol acetate), essential fatty acids, ceramides, essential oils , salicylic acid derivatives such as n-octanoyl-5 salicylic, hydroxy acid esters, phospholipids such as lecithin, mixtures thereof.
• a cosmetic or pharmaceutical active other than the compounds of formula (I) which can be hydrophilic and chosen from proteins or protein hydrolysates, amino acids, polyols,
• additional active compounds are in particular chosen from inhibitors of lipoxygenase as described in EP 0648488, the bradykinin inhibitors described in particular in EP 0845700, prostaglandins and their derivatives in particular those described in WO 98/33497, WO 95/11003, JP 97-100091, JP 96-134242, agonists or prostaglandin receptor antagonists, non-prostanoic prostaglandin analogs as described in EP 1175891 and EP 1175890, WO 01/74307, WO 01/74313, WO 01/74314, WO 01/74315 or WO 01/72268, their mixtures.
• vasodilators As other additional active compounds which promote the growth of keratin fibers (in particular of the hair) which may be present in the composition according to the invention, mention may be made of vasodilators, antiandrogens, cyclosporins and their analogs, antimicrobials and antifungals, anti- inflammatory, retinoids, alone or as a mixture.
• vasodilators which can be used are in particular the potassium channel agonists including minoxidil, as well as the compounds described in US Pat. diaxozide, alone or in combination.
• the antiandrogens which can be used in particular include the steroidal or nonsteroidal inhibitors of 5 ⁇ -reductase, such as finasteride and the compounds described in US 5 516779, cyprosterone acetate, azelaic acid, its salts and its derivatives and the compounds described in US 5,480,913, flutamide, oxendolone, spironolactone, diethylstilbestrol and the compounds described in US patents 5,411,981, 5,565,467 and 4,910,226.
• 5 ⁇ -reductase such as finasteride and the compounds described in US 5 516779, cyprosterone acetate, azelaic acid, its salts and its derivatives and the compounds described in US 5,480,913, flutamide, oxendolone, spironolactone, diethylstilbestrol and the compounds described in US patents 5,411,981, 5,565,467 and 4,910,226.
• the antimicrobial or antifungal compounds can be chosen from selenium derivatives, octopirox, triclocarban, triclosan, pyrithione zinc, itraconazole, asian acid, hinokitiol, mipirocin, tetracyclines, in particular erythromycin and the compounds described in EP 0680745, the clinycin hydrochloride, • benzoyl peroxide or benzyl, minocycline and compounds belonging to the imidazole class, such as econazole, ketoconazole or miconazole or their salts, nicotinic acid esters, including in particular tocopherol nicotinate, benzyl nicotinate and C 1 -C 4 alkyl nicotinates such as methyl or hexyl nicotinates.
• Anti-inflammatory drugs can be chosen from steroidal anti-inflammatory drugs such as glucocorticoids, corticosteroids (for example: hydrocortisone) and nonsteroidal anti-inflammatory drugs such as glycyrrhetinic acid, ⁇ -bisabolol, benzydamine, salicylic acid and. the compounds described in EP 0770399, WO 94/06434 and FR 2268523.
• steroidal anti-inflammatory drugs such as glucocorticoids, corticosteroids (for example: hydrocortisone) and nonsteroidal anti-inflammatory drugs such as glycyrrhetinic acid, ⁇ -bisabolol, benzydamine, salicylic acid and.
• the retinoids can be chosen from isotretinoin, acitretin and tazarotene.
• aminexil 6-0 - [(9Z, 12Z) -octadeca-9,12- dienoyljhexapyranose, benzalkonium chloride, benzethonium chloride, phenol, estradiol, chlorpheniramine maleate, chlorophyllin derivatives, cholesterol, cysteine, methionine, menthol, peppermint oil, calcium panthotenate, panthenol, resorcinol, protein kinase C activators, glycosidase inhibitors, glycosaminoglycanase inhibitors, pyroglutamic acid esters, hexosaccharide acids or acyl- hexosaccharic, substituted aryl ethylenes, N-acylated amino acids, fla
• the composition according to the invention comprises at least one 15-PGDH inhibitor as defined above and at least one prostaglandin or a prostaglandin derivative such as, for example, prostaglandins of series 2, in particular PGF2- ⁇ and PGE2 in the form saline or ester (eg isopropyl esters), their derivatives such as 16.16 dimethyl PGE2, 17 phenyl PGE2, 16.16 dimethyl PGF2- ⁇ , 17 phenyl PGF2- ⁇ prostaglandins of series 1 such as 11 deoxy prostaglandin E1, 1 deoxy prostaglandin E1 in saline or ester form, their analogs in particular latanoprost, travoprost, fluprostenol, cloprostenol, viprostol, butaprost, misoprostol, their salts or their esters.
• prostaglandins of series 2 in particular PGF2- ⁇ and PGE2 in the form saline or ester (eg isopropyl est
• the composition contains at least one non-prostanoic agonist of. EP2 and / or EP4 receptors in particular as described in EP 1175892.
• composition comprising at least the compound of formula (I), salified or not, is in liposomal form, as especially described in document WO 94/22468.
• the compound encapsulated in the liposomes can be delivered selectively to the hair follicle.
• composition according to the invention can be applied in particular to the alopecic areas of the scalp and hair of an individual, and optionally left in contact for several hours and optionally rinsed.
• These applications can be renewed daily for one or more months depending on the individual.
• the areas to be treated of the scalp between 5 and 500 ⁇ l of a solution or composition as defined above, comprising from 0.001% to 5% of inhibitor of 15- PGDH.
• a 1 M hydrazine solution (THF) is added to 25 ml of ethanol.
• THF hydrazine solution
• the suspension is cooled to -15 ° C (CCI 4 / N 2 bath) and the oxobutyrate is added over 30 minutes, dropwise on the hydrazine.
• reaction medium After 2:30 at room temperature, no change being visible by thin layer chromatography, the reaction medium is heated under reflux of ethanol (EtOH) for 16 hours. Once at room temperature, the solvent is then evaporated and the solid obtained is washed twice with 10 ml of pentane and filtered through a frit.
• EtOH ethanol
• the solution is then brought to 10 ° C. and then acidified with 1N HCl. After evaporation under reduced pressure of all of the ethanol and two-thirds of the water, the white precipitate formed is recovered by filtration on a frit, washed with water then dried under high vacuum.
• the fine white powder (2.30 g) obtained is characterized and corresponds to the expected product (Yield: 87%).
• This crude mixture is then chromatographed on silica gel (Flash chromatography, elution hexane / ethyl acetate 3/1, 1% ammonia).
• the fraction corresponding to the expected product (Rf: 0.45 in CH 2 CI 2 /1% NH 3 ) is then isolated and concentrated to dryness.
• the oil obtained is taken up in 2 ml of ethanol and immersed in 100 ml of an ice / water mixture.
• the precipitate obtained is recovered by filtration, filtered on a frit and concentrated to dryness.
• the pyrazole is dissolved in DMF.
• CDI is then quickly added in a single portion and the mixture is kept stirring for about 20 minutes.
• the amine is then added to the syringe with a rapid drip. After 3 hours of stirring, the CCM monitoring of the reaction indicates the disappearance of all of the starting product.
• the reaction medium is then immersed in 80 ml of an ice / water mixture.
• the white precipitate formed after 15 minutes of stirring is then recovered by filtration on a frit and dried by suction.
• the orange solid obtained is then taken up in 50 ml of ether ethyl, washed once with water and dried over sodium sulfate. After filtration on a frit and evaporation under partial vacuum, 0.8 g of a yellow solid are thus obtained.
• the pyrazole is dissolved in DMF.
• CDI is then quickly added in a single portion and the mixture is kept stirring for about 20 minutes.
• the amine is then added to the syringe with a rapid drip. After 3 hours of stirring, the CCM monitoring of the reaction indicates the disappearance of all of the starting product.
• the reaction medium is then immersed in 75 ml of an ice / water mixture.
• the white precipitate formed after 15 minutes of stirring is then recovered by filtration on a frit and dried by suction.
• the orange solid obtained is then taken up in 50 ml of dichloromethane, washed once with water and dried over sodium sulfate. After filtration on a frit and evaporation under partial vacuum, 1.1 g of a yellow solid are thus obtained.
• a second fraction (eluted with Hexane / CH 2 CI 2 1/1) taken up with hexane also makes it possible to isolate a solid.
• the solids are joined and washed 3 times with 10 ml of hexane to obtain 2.21 g of a white solid (Yield 37%).
• H 2 O 2 (30% aq.) H 2 O 2 PM: 34.01 m 8.02 g 70.6 mmol / 6.1 eq.
• reaction medium brought to room temperature is then added to 150 ml of a 2N ice / HCl mixture (2/1).
• the white precipitate formed is filtered on a B ⁇ chner after 30 minutes of stirring and washed 3 times with water. Solubilized in 250 ml of ethyl acetate, dried over MgSO 4 then filtered and evaporated to dryness, 2.25 g of a white solid are thus isolated (Yield: 96%).
• the pyrazole is dissolved in DMF.
• CDI is then quickly added in a single portion and the mixture is kept stirring for about 20 minutes.
• the amine is then added to the syringe with a rapid drop-by-drop pour. After 3 h 30 of stirring, the TLC monitoring of the reaction indicates the disappearance of all of the starting product.
• the reaction medium is then immersed in 80 ml of an ice / water mixture.
• the white precipitate formed after 15 minutes of stirring is then recovered by filtration on a frit and dried by suction.
• the orange solid obtained is then taken up in 50 ml of dichloromethane, washed once with water and dried over sodium sulfate. After filtration on a frit and evaporation under partial vacuum, 0.8 g of a yellow solid are thus obtained.
• the mixture is then brought to room temperature and acidified with a 3N HCl solution.
• the white precipitate obtained is then filtered on a frit, rinsed with water and then dried on a rotary evaporator and then with a dry pump.
• reaction medium is then immersed in 100 ml of an ice / water mixture.
• the white precipitate formed after 15 minutes of stirring is then recovered by filtration on a frit and dried by suction.
• the white solid obtained is then analyzed (TLC, NMR) and two products are thus identified.
• This crude mixture is then chromatographed on silica gel (Flash chromatograph, elution hexane / ethyl acetate 2/1 then 1/1 with 1% formic acid).
• the first fraction (Rf: 0.65 in pure CH 2 CI 2 , 1% HCO 2 H) contains 140 mg of the expected product (Yield 11%).
• the identification was carried out by NMR by analogy with the other synthesized compounds.
• the second fraction contains 500 mg of the product having two amide functions (Yield 30%). Analyzes :
• the enzyme 15-PGDH is obtained as described in application FR 02/05067 filed in the name of L'Oréal, in suspension in a medium suitable for a concentration of 0.3 mg / ml and then blocked at - 80 ° C. For the purposes of the test, this suspension is thawed and stored in ice.
• a 100 mM Tris buffer, pH 7.4, is prepared, containing 0.1 mM of dithiothreitol (D5545, Sigma-AIdrich, L'isie D'Abeau Chesne, BP 701, 38297, Saint Quentin Fallavier), 1, 5 mM of ⁇ -NAD (N6522, Sigma-AIdrich, L'isie D'Abeau Chesne, BP 701, 38297, Saint Quentin Fallavier), 50 ⁇ M of Prostaglandin E 2 (P4172, Sigma- AIdrich, L'isie D'Abeau Chesne, BP 701, 38297, Saint Quentin Fallavier).
• test values (containing the compounds (I)) are compared to the control value (without compound (I)); the results indicated represent the percentage inhibition of 15-PGDH at the concentration of 50 ⁇ M.
• a stock solution titrating 1 mM is prepared in absolute ethanol, brought to 40 ° C; the bottle is placed in an ultrasonic tank to facilitate the solubilization of the product.
• test values (containing the compound (I)) are compared to the control value (without compound (I)); the results indicated represent the percentage of inhibition of PGFS, at a concentration of 50 ⁇ M.
• This lotion is applied to the scalp, once or twice a day, at the rate of 1 ml per application, massaging the scalp lightly to make the active ingredient penetrate. The hair is then dried in the open air. This lotion reduces hair loss and promotes regrowth.
• This lotion is applied to the scalp, once or twice a day, at the rate of 1 ml per application, massaging the scalp lightly to make the active ingredient penetrate. The hair is then dried in the open air.
• This lotion is applied to the scalp, once or twice a day, at the rate of 1 ml per application, gently massaging the scalp to penetrate the active ingredient.
• This mascara is applied to the eyelashes like a classic mascara with a mascara brush.

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  • 2003-11-20 JP JP2004554612A patent/JP2006519755A/ja not_active Withdrawn
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  • 2003-11-20 AU AU2003295041A patent/AU2003295041A1/en not_active Abandoned
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