Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
  • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
  • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
  • C07D251/40—Nitrogen atoms
  • C07D251/48—Two nitrogen atoms
  • C07D251/52—Two nitrogen atoms with an oxygen or sulfur atom attached to the third ring carbon atom
• • 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
  • A61K8/4966—Triazines or their condensed derivatives
• • 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
• • 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 invention relates to new derivatives of 2,4-diamino-triazine-1, 3, 5, to their preparation and to cosmetic or pharmaceutical compositions intended in particular for use in topical application in the treatment and prevention of hair loss. hair and stimulating its regrowth.
• the subject of the invention is therefore new derivatives of 2,4-diamino-triazine-1, 3, 5 substituted in position 6.
• the invention also relates to cosmetic and / or pharmaceutical compositions comprising using these compounds.
• R denotes a linear C 1 -C 12 alkyl radical which can carry one or more halogen atoms
• branched C 3 -C 12 alkyl radical which can carry at least one halogen atom
• R 'de notes a hydrogen atom, an alkoxycarbonyl group of formula:
• R 1 denotes a C 1 -C 6 alkyl radical
• X denotes an oxygen atom or an -OSO 3 ⁇ group
• the aromatic ring more particularly denotes a phenyl group; halogen designates in particular fluorine, chlorine or bromine; the alkoxy group preferably has 1 to 6 carbon atoms.
• the 2,4-diamino-6 alkoxy-triazine-1,3,5 derivatives of formula (I) can be prepared according to the following reaction scheme:
• the compounds according to the invention of formula (I) are prepared by oxidation of the triazines of formula (II), for example by means of a perbenzoic acid of formula:
• Z represents a halogen atom, a C 1 -C 4 alkyl or alkoxy group or a nitro group
• a suitable solvent such as C 1 -C 4 alkanols, ethers derived from ethylene glycol, acetone or a mixture of these solvents.
• Other peracids can also be used to effect this oxidation.
• the triazines of formula (II) can also be oxidized by means of magnesium monoperoxyphthalate (MMPP) in an appropriate solvent, such as C 1 -C 4 alcohols or a hydroalcoholic mixture.
• MMPP magnesium monoperoxyphthalate
• R 'denotes an alkoxycarbonyl group are obtained from the 2,4-diamino-6 alkoxy-6 triazine-1, 3, 5 oxide-3 derivatives described above
• Obtaining these derivatives is generally carried out by the action of an excess of chloroformic ester on the corresponding 2,4-diamino derivative by operating in a polar aprotic solvent, such as dichloromethane, in the presence of a tertiary amine. , such as triethylamine or pyridine, at a temperature between 0 and 50 ° C.
• a polar aprotic solvent such as dichloromethane
• a tertiary amine such as triethylamine or pyridine
• one of the tautomeric forms can be predominant over the other.
• the compounds of formula (I), in accordance with the invention, can be converted into their cosmetically or pharmaceutically acceptable acid addition salts, such as the salts of sulfuric, hydrochloric, hydrobromic, phosphoric, acetic, benzoic, salicylic acids. , glycolic, succinic, nicotinic, tartaric, maleic, pamoic, methane sulfonic, picric, lactic, etc.
• Particularly preferred compounds are diamino-2,4 (n-butyloxy) -6 triazine-1, 3, 5 oxide-3, diamino-2,4 (methyl-6-triazine-1, 3, 5 oxide-3, diamino-2,4 (n-octyloxy) -6 triazine-1, 3, 5 oxide-3, diamino-2,4 (n-hexênyl-5 oxy) -6 triazine-1, 3, 5 oxide-3, 2,4-diamino (2-phenylethyloxy) -6 triazine-1, 3,5 oxide-3, 2,4-diamino isopropyloxy-6 triazine-1, 3,5 oxide-3, diamino hydroxide -2.4 n-butyloxy-6 sulfooxy-3 triazinium, di (ethyloxycarbamoyl) -2, 4 n-butyloxy-6 triazine-1, 3, 5 oxide-3.
• the sulfur trioxide-pyridine, sulfur trioxide-triethylamine or sulfur trioxide-ethyl diisopropylamine complexes are used as the sulfation reagent.
• the solvents used are preferably dimethylformamide, acetonitrile, chloroform or their binary mixtures.
• the temperature is of the order of 0 to 25oC and the reaction time varies between 1 hour and 24 hours.
• compositions in accordance with the invention contain, in a physiologically acceptable medium, at least one compound corresponding to formula (I) or one of its addition salts with physiologically acceptable acids, with a view to being applied in the cosmetic field or pharmaceutical, especially in topical application.
• compositions are intended for the treatment and prevention of hair loss and in particular of alopecia, alopecia as well as desquamating dermatitis.
• compositions may comprise, as physiologically acceptable medium, any medium suitable for topical application, either in cosmetics or in pharmacy, and which is compatible with the active substance.
• the compounds according to the invention can be found in this medium, either in the dissolved state or in the dispersed state, in particular in micronized form.
• compositions intended for use in pharmacy are in the form of an ointment, a tincture, a cream, an ointment, a powder, a patch, a soaked tampon, a solution, an emulsion or a vesicular emulsion, a lotion, gel, spray or suspension. They can be either anhydrous or aqueous, depending on the clinical indication.
• the compounds according to the invention are present in these pharmaceutical compositions at concentrations of between 0.1 and 10% by weight, and in particular of between 0.2 and 5% by weight.
• the cosmetic compositions are in particular intended to be used in the form of a lotion, gel, soap, shampoo, aerosol or foam and contain, in a cosmetically acceptable carrier, at least one compound of formula (I) or the one of its acid addition salts.
• the concentration of the compounds of formula (I) in these compositions is preferably between 0.01 and 5% by weight and in particular between 0.05 and 3% by weight.
• compositions in accordance with the invention may contain various additives usually used in cosmetics or in pharmacy and in particular active substances, such as hydrating agents such as thiamorpholine and its derivatives or urea; antiseborrhoeic agents such as S-carboxymethylcysteine, S-benzylcysteamine and their derivatives; thioxolone.
• active substances such as hydrating agents such as thiamorpholine and its derivatives or urea
• antiseborrhoeic agents such as S-carboxymethylcysteine, S-benzylcysteamine and their derivatives
• thioxolone such as thioxolone.
• the compounds according to the invention can be combined with compounds which further improve their activity on regrowth and / or on the braking of hair loss, such as more particularly the following compounds:
• Nicotinic acid esters including more particularly C 1 -C 6 alkyl nicotinates and in particular methyl nicotinate;
• t-trans retinoic acid also called tretinoin, isotretinoin, retinol or vitamin A and its derivatives, such as acetate, palmitate or propionate, motretinide, etretinate, t-trans zinc retinoate;
• - antibacterial agents chosen more particularly from macrolides, pyranosides and tetracyclines and in particular erythromycin;
• estriol such as estriol or analogues or thyroxine and its salts
• - antiandrogenic agents such as oxendolone, spironolactone, diethylstilbestrol;
• the compounds in accordance with the invention can also be combined with surfactants, more particularly those chosen from nonionic and amphoteric surfactants.
• nonionic surfactants mention will be made in particular of the polyhydroxypropyl ethers described in French patents No. 1,477,048; 2,091,516; 2,169,787; 2,328,763; 2,574,786; oxyethylenated (C 8 -C 9 ) alkyl phenols containing from 1 to 100 moles of ethylene oxide and preferably 5 to 35 moles of ethylene oxide; the alkylpolyglycosides of formula:
• amphoteric surfactants are more particularly the amphocarboxyglycinates and amphocarboxypropionates defined in the CTFA dictionary, 3rd edition, 1982, and sold in particular under the name Miranol ® by the company Miranol.
• the compounds according to the invention can be introduced into carriers which further improve the activity at the regrowth level, while having both advantageous properties from a cosmetic point of view, such as volatile ternary mixtures of alkyl ether.
• alkylene especially alkyl in C 1 -C 4 alkylene, C 1 -C 4 glycol or of dialkylene glycol, preferably dialkylene C 1 -C 4 glycol, ethyl alcohol and water , the glycolic solvent designating more particularly the monoethyl ethers of ethylene glycol, the monomethyl ether of propylene glycol, the monoethyl ether of diethylene glycol.
• the compounds in accordance with the invention can also be introduced into gelled or thickened supports, such as essentially aqueous supports gelled with heterobiopolysaccharides, such as xanthan gum or cellulose derivatives, hydroalcoholic supports gelled with polyhydroxy ethylacrylate or methacrylate or essentially aqueous supports thickened, in particular by polyacrylic acids crosslinked with a polyfunctional agent, such as Carbopol sold by the company GOODRICH.
• a polyfunctional agent such as Carbopol sold by the company GOODRICH.
• compositions may also contain preserving agents, stabilizing agents, pH regulating agents, agents modifying osmotic pressure, emulsifying agents, UVA and UVB filters, antioxidant agents such as ⁇ -tocopherol, butylhydroxyanisole, butylhydroxytoluene.
• the physiologically acceptable medium can consist of water or a mixture of water and a solvent or a mixture of solvents, the solvents being chosen from organic solvents acceptable from the cosmetic or pharmaceutical point of view and chosen more particularly from lower C 1 -C 4 alcohols, such as ethyl alcohol, isopropyl alcohol, tert-butyl alcohol, alkylene glycols, alkylene glycol and dialkylene glycol alkyl ethers, such as ethylene glycol monoethyl ether, propylene glycol monomethyl ether, diethylene glycol monoethyl ether.
• the solvents, when they are present, are present in proportions of between 1 and 80% by weight relative to the total weight of the composition.
• Physiologically acceptable media can be thickened using thickening agents usually used in cosmetics or pharmacy, and there may be mentioned more particularly heterobiopolysaccharides such as xanthan gum, scleroglucans, cellulose derivatives such as cellulose ethers, acrylic polymers, crosslinked or not.
• thickening agents usually used in cosmetics or pharmacy, and there may be mentioned more particularly heterobiopolysaccharides such as xanthan gum, scleroglucans, cellulose derivatives such as cellulose ethers, acrylic polymers, crosslinked or not.
• the thickeners are preferably present in proportions of between 0.1 and 5% by weight and in particular between 0.4 and 3% by weight relative to the total weight of the composition.
• the subject of the invention is also a method of cosmetic treatment of the hair or the scalp, consisting in applying to them at least one composition as defined above, with a view to improving the aesthetics of the hair.
• composition containing the compounds of formula (I) defined above for the preparation of a medicament having the effect of inducing or stimulating hair growth and to stop their fall.
• the treatment consists mainly in applying to the alopecic areas of the scalp of an individual, the composition as defined above.
• the preferred mode of application consists in applying 1 to 2 g of the composition to the alopecic zone, at a frequency of one to two applications per day, for 1 to 7 days per week and this for a period of 1 to 6 months.
• compositions can in particular be used in the treatment of alopecia areata, hair loss, flaking dermatitis.
• the mixture is heated for 24 hours at 45 ° C., then the mixture is brought to dryness.
• Precipitation is carried out by adding water, the precipitate obtained is filtered and washed with water.
• the precipitate obtained is filtered.
• the mother liquors are basified with soda.
• the precipitate obtained is filtered.
• Diamino-2,4 isopropyloxy-6 triazine-1,3,5 oxide-3 According to the procedure described in Example 1.
• Diamino-2,4 (n-hexenyl-5-oxy) -6 triazine-1,3,5 oxide-3 According to the procedure described in Example 1.
• Diamino-2,4 (n-octyloxy) -6 triazine-1,3,5 oxide-3 According to the procedure described in Example 1.
• Diamino-2,4 (phenyl 2-ethyloxy) -6 triazine-1,3,5 oxide-3 According to the procedure described in Example 1.
• the yield is 39.4%.
• the mixture is stirred for 1 hour at room temperature.
• the organic phase is dried over sodium sulfate, then evaporated to dryness.
• the precipitate obtained is recrystallized from a 1/1 hexane / acetone mixture.
• This composition is in the form of a lotion.
• 1 to 2 g of this composition are applied to the alopecic areas of the scalp, possibly accompanied by a massage to promote its penetration, at the rate of one to two applications per day, for three months of treatment.
• a lotion of the following composition is prepared
• a lotion of the following composition is prepared

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• Health & Medical Sciences (AREA)
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• Engineering & Computer Science (AREA)
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• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Cosmetics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1990
  • 1990-06-19 FR FR9007664A patent/FR2663327B1/fr not_active Expired - Lifetime
• 1991
  • 1991-06-17 JP JP3511106A patent/JPH05500819A/ja active Pending
  • 1991-06-17 WO PCT/FR1991/000481 patent/WO1991019701A1/fr not_active Ceased
  • 1991-06-17 EP EP91912033A patent/EP0487698A1/de not_active Withdrawn
  • 1991-06-17 CA CA002064910A patent/CA2064910A1/fr not_active Abandoned

Non-Patent Citations (1)

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