WO1998006695A1 - Melatonin derivatives and their use in cosmetic or dermopharmaceutical compositions - Google Patents

Melatonin derivatives and their use in cosmetic or dermopharmaceutical compositions Download PDF

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Publication number
WO1998006695A1
WO1998006695A1 PCT/FR1996/001276 FR9601276W WO9806695A1 WO 1998006695 A1 WO1998006695 A1 WO 1998006695A1 FR 9601276 W FR9601276 W FR 9601276W WO 9806695 A1 WO9806695 A1 WO 9806695A1
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Prior art keywords
cosmetic
melatonin
homologous
dermopharmaceutical
derivatives
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PCT/FR1996/001276
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French (fr)
Inventor
Daniel Greff
Original Assignee
Sederma S.A.
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Publication date
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Priority to PCT/FR1996/001276 priority Critical patent/WO1998006695A1/en
Priority to AU68243/96A priority patent/AU6824396A/en
Publication of WO1998006695A1 publication Critical patent/WO1998006695A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/11—Encapsulated compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0204—Specific forms not provided for by any of groups A61K8/0208 - A61K8/14
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • 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
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • A61K8/492—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid having condensed rings, e.g. indol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/02—Preparations for cleaning the hair
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/413—Nanosized, i.e. having sizes below 100 nm

Definitions

  • the skin is the largest organ of the body, but also the most exposed to various aggressions: irritations due to the environment (pollution, allergies),
  • melatonin N-acetyl-5-methoxy-tryptamine
  • Patents JP 61221104 (Shiseido) and EP 438856 (Shiseido) claim the use of melatonin to protect the skin against UV irradiation and the actinic aging which results from it, patent JP61212512 (Shiseido)
  • melatonin as a hair growth stimulator.
  • this substance poses the problem of skin absorption: melatonin is not very soluble in the usual cosmetic or dermopharmaceutical excipients.
  • the patents WO95 / 02404 and WO87 / 00432 describe administration systems
  • R a linear or branched C11 to 019 alkyl chain, saturated or unsaturated, hydroxylated or not.
  • the C, H, N, IR and NMR analyzes confirm the structure of the product obtained.
  • the N-lauroyl, N-myristoyl, N-stearoyl, N-arachidoyl, N-behenoyl, N-palmitoleoyl, N-oleoyl, N-linoleoyl, N-linolenoyl and N-arachidonyl derivatives are prepared.
  • alencytoyl (9,10,16-trihydroxypalmitoyl) of 5-methoxytryptamine.
  • the penetration balance is studied: the upper layers of the epidermis are removed by "stripping" using a self-adhesive, the epidermis is separated from the dermis by treatment with trypsin and / or sodium hydroxide, and the survival liquid is collected from the receptor part of the diffusion cells. The quantity of radioactive molecules in each of the fractions is evaluated by scintigraphic counting after mineralization of the samples. The results show that the lipophilic derivative N-palmitoyl-5-methoxytryptamine is concentrated in the epidermis (radioactivity 155 times stronger than for the epidermis treated with melatonin) and in the deeper strippings.
  • the skin is better hydrated (+ 35%) on the treated sites, and firmer (31% increase in tone compared to -2% for the placebo) compared to the initial values.
  • the homologous melatonin derivatives which are the subject of this patent can be used in any galenic form usually used in cosmetic or dermopharmaceutical formulation: O / W and W / O emulsion, milks, lotions, gels, ointments, balms, mousses, body lotions, lotions capillaries, shampoos, soaps, sticks and pencils, sprays, without this list being exhaustive.
  • the concentration of use of these derivatives in the finished cosmetic product can vary between 0.0001 and 10% (w / w), preferably between 0.001 and 1%, particularly preferably between 0.01 and 0.1% by weight of the total composition.
  • the homologous melatonin derivatives which are the subject of this patent can be combined in cosmetic compositions with any other ingredient usually used in cosmetics: extraction and / or synthetic lipids, gelling and viscosifying polymers, surfactants and emulsifiers, hydro- or fat-soluble, extracts of other plants, tissue extracts, marine extracts.
  • the homologous derivatives of melatonin in all their galenical forms can be used in the cosmetic and dermopharmaceutical fields for their anti-wrinkle, anti-aging, seborrhea regulating, hydrating, firming, protective effects. of UV irradiation. They are advantageously used in products for sensitive skin, sun and after-sun creams, products for face and body care, scalp massage lotions, products for preventing aging.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Birds (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cosmetics (AREA)

Abstract

The invention discloses the synthesis and use of novel lipophilic melatonin homologues of general formula (a) in which R = a C11 to C19 alkyl chain, linear or branched, saturated or unsaturate, hydroxylated or not. These derivatives are preferably obtained by 5-methoxy-tryptemin acylation. They are designed for use in cosmetic or dermopharmaceutical compositions for hydrating, regenerating, anti-seborrheic, anti-wrinkle, bleaching skin treatment and for the prevention of actinic damage caused by the sun and by the atmosphere.

Description

DERIVES DE LA MELATONINE ET LEUR UΗLISAΗON DANS LES COMPOSITIONS COSMETIQUES OU DERMOPHARMACEUTIQUES compositions cosmétiques ou dermopharmaceutiquesMELATONIN DERIVATIVES AND THEIR UΗLISAΗON IN COSMETIC OR DERMOPHARMACEUTICAL COMPOSITIONS cosmetic or dermopharmaceutical compositions
La peau est I ' organe le plus grand du corps, mais aussi le plus exposé aux agressions diverses : irritations dues à I ' environnement (pollution, allergies),The skin is the largest organ of the body, but also the most exposed to various aggressions: irritations due to the environment (pollution, allergies),
5 aux intempéries (vent, pluie, froid, rayonnement solaire, dessèchement), aux traitements physiques (rasage, épilation, frottements, chocs). La peau répond à ces agressions par ces moyens de défense que sont I ' épaississement de l'épiderme, les systèmes enzymatiques de défense (SOD, catalase, peroxydases), la réponse inflammatoire et/ou immunitaire,5 to bad weather (wind, rain, cold, solar radiation, drying out), to physical treatments (shaving, hair removal, rubbing, shock). The skin responds to these attacks by these defenses, which are the thickening of the epidermis, the enzyme defense systems (SOD, catalase, peroxidases), the inflammatory and / or immune response,
10 la sécrétion séborrhéique.10 seborrheic secretion.
Aider la peau dans cette tâche est le but de la cosmétologie et dermopharmacologie modernes. Ces disciplines y parviennent en apportant des molécules ou substances stimulantes, protectrices, nourrissantes, réparatrices.Helping the skin in this task is the goal of modern cosmetology and dermopharmacology. These disciplines achieve this by providing stimulating, protective, nourishing, restorative molecules or substances.
15 La molécule appelée mélatonine (N-acétyl-5-méthoxy-tryptamine) est naturellement produite dans la glande pinéale, elle possède un grand nombre de propriétés biologiques. Essentiellement elle intervient dans les processus de la régulation du rythme circadien, mais de nombreuses activités systémiques ont été décrites.15 The molecule called melatonin (N-acetyl-5-methoxy-tryptamine) is naturally produced in the pineal gland, it has a large number of biological properties. Essentially it intervenes in the processes of regulating the circadian rhythm, but many systemic activities have been described.
20 Son emploi dermatologique ou cosmétique a été proposé dans un certain nombre de brevets :20 Its dermatological or cosmetic use has been proposed in a number of patents:
Les brevets JP 61221104 (Shiseido) et EP 438856 (Shiseido) revendiquent l' utilisation de la mélatonine pour protéger la peau contre l' irradiation UV et le vieillissement actinique qui en résulte, le brevet JP61212512 (Shiseido)Patents JP 61221104 (Shiseido) and EP 438856 (Shiseido) claim the use of melatonin to protect the skin against UV irradiation and the actinic aging which results from it, patent JP61212512 (Shiseido)
25 décrit la mélatonine en tant que stimulateur de la croissance des cheveux. Techniquement, cette substance pose le problème de l' absorption cutanée: la mélatonine n ' est pas très soluble dans les excipients cosmétiques ou dermopharmaceutiques habituels. Les brevets WO95/02404 et WO87/00432 décrivent des systèmes d ' administration25 describes melatonin as a hair growth stimulator. Technically, this substance poses the problem of skin absorption: melatonin is not very soluble in the usual cosmetic or dermopharmaceutical excipients. The patents WO95 / 02404 and WO87 / 00432 describe administration systems
30 transdermique qui tentent de remédier, par une technologie de délivrance contrôlée, au problème de solubilité et de diffusion. La découverte objet du présent brevet est le fait que des substances homologues de la mélatonine, portant un groupe N-acyl à longue chaîne grasse à la place du groupe N-acétyl, possèdent une affinité accrue pour la peau et permettent de pénétrer plus facilement dans les couches epidermiques et dermiques. Oes substances peuvent ensuite être désacylées enzymatiquement dans la peau pour libérer la 5- méthoxytryptamine (5-MT), le précurseur de la mélatonine, mais également une molécule active en elle-même. Les dérivés objets du présent brevet correspondent à la formule générale30 transdermal which try to remedy, by a controlled delivery technology, the problem of solubility and diffusion. The discovery which is the subject of this patent is the fact that substances homologous to melatonin, carrying a long fatty chain N-acyl group in place of the N-acetyl group, have an increased affinity for the skin and allow it to penetrate more easily. epidermal and dermal layers. These substances can then be deacylated enzymatically in the skin to release 5-methoxytryptamine (5-MT), the precursor of melatonin, but also an active molecule in itself. The derivatives which are the subject of this patent correspond to the general formula
Figure imgf000004_0001
Figure imgf000004_0001
où R = une chaîne alkyle C11 à 019, linéaire ou ramifiée, saturée ou insaturée, hydroxylée ou non.where R = a linear or branched C11 to 019 alkyl chain, saturated or unsaturated, hydroxylated or not.
La synthèse de ces molécules est effectuée à partir de la 5- méthoxytryptamine, l'attachement de la chaîne acyle se fait par les méthodes connues des anhydrures mixtes, des esters activés, des chlorures d'acide et autres activateurs de couplage amide.The synthesis of these molecules is carried out from 5-methoxytryptamine, the attachment of the acyl chain is done by the known methods of mixed anhydrides, activated esters, acid chlorides and other amide coupling activators.
A titre d' exemple nous décrivons la synthèse de la N-palmitoyl-5- methoxytryptamine :As an example we describe the synthesis of N-palmitoyl-5-methoxytryptamine:
Dans un réacteur de 250 ml équipé d' un réfrigérant, d' une sonde thermométrique, d ' une agitation, d ' une ampoule de coulée et d ' une arrivée d' argon, on introduit la 5-méthoxytryptamine (9.5 g) et 200 ml de tétrahydrofurane (THF). On coule à une température comprise entre -5°C et +5°C en 10 minutes le chlorure de palmitoyle (14.4g), puis en 5 minutes entre -5°C et +5°C la triéthylamine (5.3g). Après la fin de la réaction (suivie par CCM) on laisse revenir à température ambiante, on filtre la suspension ; le filtrat est concentré, recristallisé dans 140 ml de toluène. Après lavage et séchage, on obtient 16.9 g de poudre blanche : N-Palmltoyl-5-méthoxytryptamine (rendement 79%), point de fusion : 99-100°C. Rf (plaque Merck 1.05554 ; acétate d'éthyle) : 0.70, monotache à U V 254 nm.In a 250 ml reactor equipped with a condenser, a temperature probe, a stirring, a dropping funnel and an inlet of argon was charged 5-methoxytryptamine (9.5 g) and 200 ml of tetrahydrofuran (THF). Poured at a temperature between -5 ° C and + 5 ° C in 10 minutes palmitoyl chloride (14.4g), then in 5 minutes between -5 ° C and + 5 ° C triethylamine (5.3g). After the end of the reaction (followed by TLC), the mixture is allowed to return to ambient temperature, the suspension is filtered; the filtrate is concentrated, recrystallized from 140 ml of toluene. After washing and drying, 16.9 g of white powder are obtained: N-Palmltoyl-5-methoxytryptamine (yield 79%), melting point: 99-100 ° C. Rf (Merck plate 1.05554; ethyl acetate): 0.70, single spot at UV 254 nm.
Les analyses C,H,N, IR et RMN confirment la structure du produit obtenu. De la même façon on prépare les dérivés N-lauroyl, N-myristoyl, N-stéaroyl, N-arachidoyl, N-béhénoyl, N-palmitoleoyl, N-oléoyl, N-linoléoyl, N-linolénoyl et N-arachidonyl, N-aleurétoyl (9,10,16- trihydroxypalmitoyl) de la 5-méthoxytryptamine.The C, H, N, IR and NMR analyzes confirm the structure of the product obtained. In the same way, the N-lauroyl, N-myristoyl, N-stearoyl, N-arachidoyl, N-behenoyl, N-palmitoleoyl, N-oleoyl, N-linoleoyl, N-linolenoyl and N-arachidonyl derivatives are prepared. aleurétoyl (9,10,16-trihydroxypalmitoyl) of 5-methoxytryptamine.
Ces molécules sont plus facilement incorporées dans des produits cosmétiques ; elles peuvent être émulsifiées, dissoutes dans les excipients solubilisants (giycols, polyols, solvants polyéthoxylés), incluses dans des liposomes. En plus, ces dérivés lipophiles possèdent une plus forte affinité pour l' épiderme et donc une activité cosmétique accrue. L'essai suivant montre l'avantage de la structure lipophile des dérivés mélatoniques : Exemple n° 1 : [125l]-2-iodomélatonine et [125l]-2-iodo-5-méthoxy-N-palmitoyltryptamine sont appliqués en solution diluée sur un explant de peau, monté dans une cellule de diffusion du type Frantz. Après 30 minutes, 1 heures, 2 heures et 4 heures on étudie le bilan de pénétration : on enlève les couches supérieures de l' épiderme par " stripping " à l'aide d' un auto-adhésif, on sépare I ' épiderme du derme par un traitement à la trypsine et/ou à la soude, et on récolte le liquide de survie de la partie réceptrice des cellules de diffusion. On évalue la quantité de molécules radioactives dans chacune des fractions par comptage scintigraphique après minéralisation des échantillons. Les résultats montrent que le dérivé lipophile N-palmitoyl-5- méthoxytryptamine se concentre dans I ' épiderme (radioactivité 155 fois plus forte que pour l' épiderme traité à la mélatonine) et dans les strippings plus profonds. Peu de radioactivité est trouvée dans le derme et dans le liquide de survie. L' essentiel de la mélatonine non modifiée se trouve dans les toutes premières couches de stripping, donc à un niveau de pénétration où l'activité biologique du produit n' est pas garantie. Les dérivés homologues de la mélatonine objets du présent brevet sont donc particulièrement bien adaptés à une utilisation cosmétique ou dermopharmaceutique par voie topique. En outre, ils ne sont pas irritants, sont bien tolérés, stables et efficaces. A titre d' exemple non limitatif on cite une crème formulée avec le dérivé N-lauroyl-5-MT : Exemple n° 2These molecules are more easily incorporated into cosmetic products; they can be emulsified, dissolved in the solubilizing excipients (giycols, polyols, polyethoxylated solvents), included in liposomes. In addition, these lipophilic derivatives have a stronger affinity for the epidermis and therefore increased cosmetic activity. The following test shows the advantage of the lipophilic structure of the melatonic derivatives: Example No. 1: [ 125 l] -2-iodomelatonin and [ 125 l] -2-iodo-5-methoxy-N-palmitoyltryptamine are applied in solution diluted on a skin explant, mounted in a diffusion cell of the Frantz type. After 30 minutes, 1 hour, 2 hours and 4 hours, the penetration balance is studied: the upper layers of the epidermis are removed by "stripping" using a self-adhesive, the epidermis is separated from the dermis by treatment with trypsin and / or sodium hydroxide, and the survival liquid is collected from the receptor part of the diffusion cells. The quantity of radioactive molecules in each of the fractions is evaluated by scintigraphic counting after mineralization of the samples. The results show that the lipophilic derivative N-palmitoyl-5-methoxytryptamine is concentrated in the epidermis (radioactivity 155 times stronger than for the epidermis treated with melatonin) and in the deeper strippings. Little radioactivity is found in the dermis and in the survival fluid. Most of the unmodified melatonin is found in the very first stripping layers, therefore at a level of penetration where the biological activity of the product is not guaranteed. The homologous melatonin derivatives which are the subject of this patent are therefore particularly well suited for cosmetic or dermopharmaceutical use by the topical route. In addition, they are not irritants, are well tolerated, stable and effective. By way of nonlimiting example, a cream formulated with the N-lauroyl-5-MT derivative is cited: Example No. 2
Solution du dérivé N-lauroyl-5-MT incorporé dans une crème de type soin du visage : BrijR 721 2.4 BrijR 72 2.6Solution of the N-lauroyl-5-MT derivative incorporated into a facial care type cream: Brij R 721 2.4 Brij R 72 2.6
Arlamol" E 8.0Arlamol "E 8.0
Cire d'abeille 0.5Beeswax 0.5
AbilR ZP 2434 3.0Abil R ZP 2434 3.0
Propylène glycol 3.0 CarbopolR 941 0.25Propylene glycol 3.0 Carbopol R 941 0.25
Triéthanolamine 0.250.25 triethanolamine
N-lauroyl-5-MT à 2% dans I ' ethoxydiglycol 7.5N-lauroyl-5-MT at 2% in ethoxydiglycol 7.5
Eau, conservateurs, parfums qsp 100 g.Water, preservatives, perfumes qs 100 g.
L' activité cosmétique de ces dérivés se manifeste par un meilleur aspect de la peau : plus hydratée, moins ridée, plus claire et d' un teint homogène, raffermie et plus tonique comme le montre I ' étude suivante : Exemple n° 3 :The cosmetic activity of these derivatives is manifested by a better appearance of the skin: more hydrated, less wrinkled, clearer and of a homogeneous complexion, firmer and more tonic as shown in the following study: Example No. 3:
25 personnes féminines âgées entre 32 et 59 ans ont appliqué une crème contenant 1.5% de N-palmitoyl-5-MT pendant 4 semaines sur une partie du visage, et une crème placebo sur l'autre, à leur insu. L' évaluation de I ' état de la peau par examen clinique, par auto-évaluation et par diverses méthodes quantitatives (sébométrie, cornéométrie, fermométrie) a montré une très bonne tolérance des crèmes, une amélioration des signes cliniques des peaux sèches, des peaux grasses, des décolorations locales. Selon les mesures de séborrhée, la sécrétion de sébum a diminué de 27% sur le côté traité, elle est restée stable sur le coté placebo. La peau est mieux hydratée (+35%) sur les sites traités, et plus ferme (augmentation du tonus de 31% contre -2% pour le placebo) par rapport aux valeurs initiales. Les dérivés homologues de la mélatonine objets du présent brevet peuvent être utilisés dans toute forme galénique habituellement utilisés en formulation cosmétique ou dermopharmaceutique : émulsion H/E et E/H, laits, lotions, gels, pommades, baumes, mousses, lotions corporelles, lotions capillaires, shampooings, savons, sticks et crayons, sprays, sans que cette liste soit limitative.25 women aged between 32 and 59 years old applied a cream containing 1.5% of N-palmitoyl-5-MT for 4 weeks on one part of the face, and a placebo cream on the other, without their knowledge. The evaluation of the condition of the skin by clinical examination, by self-evaluation and by various quantitative methods (sebometry, corneometry, fermometry) has shown very good tolerance of the creams, an improvement in the clinical signs of dry skin, of the skin. oily, local discoloration. According to seborrhea measurements, the secretion of sebum decreased by 27% on the treated side, it remained stable on the placebo side. The skin is better hydrated (+ 35%) on the treated sites, and firmer (31% increase in tone compared to -2% for the placebo) compared to the initial values. The homologous melatonin derivatives which are the subject of this patent can be used in any galenic form usually used in cosmetic or dermopharmaceutical formulation: O / W and W / O emulsion, milks, lotions, gels, ointments, balms, mousses, body lotions, lotions capillaries, shampoos, soaps, sticks and pencils, sprays, without this list being exhaustive.
La concentration d'utilisation de ces dérivés dans le produit cosmétique fini peut varier entre 0.0001 et 10% (p/p), préférentiellement entre 0.001 et 1 % , particulièrement préférentiellement entre 0.01 et 0.1% au poids de la composition totale. Les dérivés homologues de la mélatonine objets du présent brevet peuvent être combinés dans les compositions cosmétiques avec tout autre ingrédient habituellement utilisé en cosmétique : lipides d'extraction et/ou de synthèse, polymères gélifiants et viscosants, tensioactifs et émulsifiants, principes actifs hydro- ou liposolubles, extraits d'autres plantes, extraits tissulaires, extraits marins.The concentration of use of these derivatives in the finished cosmetic product can vary between 0.0001 and 10% (w / w), preferably between 0.001 and 1%, particularly preferably between 0.01 and 0.1% by weight of the total composition. The homologous melatonin derivatives which are the subject of this patent can be combined in cosmetic compositions with any other ingredient usually used in cosmetics: extraction and / or synthetic lipids, gelling and viscosifying polymers, surfactants and emulsifiers, hydro- or fat-soluble, extracts of other plants, tissue extracts, marine extracts.
Les dérivés homologues de la mélatonine sous toutes leurs formes galéniques (poudre, solution, émulsion) peuvent être utilisés dans les domaines cosmétique et dermopharmaceutique pour leur activité anti-ride, anti-âge, régulatrice de séborrhée, hydratante, raffermissante, protectrice contre les effets de l' irradiation UV. Ils sont avantageusement employés dans les produits pour peaux sensibles, les crèmes solaires et après- solaires, les produits pour soins du visage et du corps, les lotions de massage du cuir chevelu, les produits de prévention du vieillissement. The homologous derivatives of melatonin in all their galenical forms (powder, solution, emulsion) can be used in the cosmetic and dermopharmaceutical fields for their anti-wrinkle, anti-aging, seborrhea regulating, hydrating, firming, protective effects. of UV irradiation. They are advantageously used in products for sensitive skin, sun and after-sun creams, products for face and body care, scalp massage lotions, products for preventing aging.

Claims

REVENDICATIONS
1) Dérivés homologues de la mélatonine synthétique à usage cosmétique ou dermopharmaceutique correspondant à la formule générale1) Homologous derivatives of synthetic melatonin for cosmetic or dermopharmaceutical use corresponding to the general formula
Figure imgf000008_0001
Figure imgf000008_0001
où R = une chaîne alkyle C11 à C19, linéaire ou ramifiée, saturée ou insaturée, hydroxylée ou non.where R = a linear or branched C11 to C19 alkyl chain, saturated or unsaturated, hydroxylated or not.
2 ) Dérivés homologues de la mélatonine synthétique selon la revendication 1 caractérisée en ce qu ' ils sont obtenus par acylation de la fonction aminée du 5-méthoxytryptamine avec les acides gras choisis parmi les suivants : acide laurique, myristique, paimitique, stéarique, arachidique, béhénique, palmitoléique, oléique, linoléique, linolénique, arachidonique, aleurétique.2) Homologous derivatives of synthetic melatonin according to claim 1 characterized in that they are obtained by acylation of the amino function of 5-methoxytryptamine with the fatty acids chosen from the following: lauric, myristic, paimitic, stearic, arachidic acid, behenic, palmitoleic, oleic, linoleic, linolenic, arachidonic, aleuretic.
3) Dérivés homologues de la mélatonine synthétique selon les revendications 1et 2 caractérisées en ce que le dérivé homologue de la mélatonine est préférentiellement la N-Palmitoyl-5- méthoxytryptamine. 4) Compositions cosmétiques ou dermopharmaceutiques caractérisées en ce qu 'elles contiennent au moins un dérivé homologue de la mélatonine selon l' une quelconque des revendications 1 à 3, préalablement solubilisé dans des solvants utilisables dans les domaines cosmétiques et dermopharmaceutiques comme l'eau, l'éthanol, le propanol ou isopropanol, le propylène glycol, le butylène glycol, la glycérine, le polyéthylène glycol, les éthers méthyliques ou éthyiiques des diglycols, les polyols cycliques, les diglycols éthoxylés ou propoxylés ou tout mélange de ces solvants.3) Homologous derivatives of synthetic melatonin according to claims 1 and 2 characterized in that the homologous derivative of melatonin is preferably N-Palmitoyl-5-methoxytryptamine. 4) Cosmetic or dermopharmaceutical compositions characterized in that they contain at least one homologous derivative of melatonin according to any one of claims 1 to 3, previously dissolved in solvents usable in the cosmetic and dermopharmaceutical fields such as water, l ethanol, propanol or isopropanol, propylene glycol, butylene glycol, glycerin, polyethylene glycol, methyl or ethyl ethers of diglycols, cyclic polyols, ethoxylated or propoxylated diglycols or any mixture of these solvents.
5) Compositions cosmétiques ou dermopharmaceutiques caractérisées en ce qu ' elles contiennent au moins un dérivé homologue de la mélatonine selon l' une quelconque des revendications 1 à 4 préalablement incorporé dans des vecteurs cosmétiques comme les liposomes, les chylomicrons, les macro-, micro- et nanoparticules ainsi que les macro-, micro- et nanocapsules, ou absorbé sur des polymères organiques poudreux, les talcs, bentonites et autres supports minéraux.5) Cosmetic or dermopharmaceutical compositions characterized in that they contain at least one homologous derivative of melatonin according to any one of claims 1 to 4 previously incorporated in cosmetic vectors such as liposomes, chylomicrons, macro-, micro- and nanoparticles as well as macro-, micro- and nanocapsules, or absorbed on powdery organic polymers, talcs, bentonites and other mineral supports.
6) Compositions cosmétiques ou dermopharmaceutiques caractérisées en ce qu'elles contiennent le ou les dérivés homologues de la mélatonine selon l'une quelconque des revendications 4 ou 5 à des concentrations qui peuvent varier entre 0.0001% (p/p) et 10%, préférentiellement entre 0.001 et 1% (p/p) et particulièrement entre 0.01 et 0.1% en poids de la composition totale.6) Cosmetic or dermopharmaceutical compositions characterized in that they contain the homologous derivative (s) of melatonin according to any one of claims 4 or 5 at concentrations which can vary between 0.0001% (w / w) and 10%, preferably between 0.001 and 1% (w / w) and particularly between 0.01 and 0.1% by weight of the total composition.
7) Compositions cosmétiques ou dermopharmaceutiques selon l'une quelconque des revendications 4 à 6 caractérisées en ce qu ' elles représentent toute forme galénique employée en cosmétique ou dermopharmacie à savoir les émulsions H/E et E/H, laits, lotions, gels, pommades, baumes, mousses, lotions corporelles, lotions capillaires, shampooings, savons, sticks et crayons, sprays. 8) Compositions cosmétiques ou dermopharmaceutiques selon l'une quelquonque des revendications 4 à 7 caractérisées en ce que les dérivés homologues de la mélatonine selon l' une quelconque des revendications 1 à 3 sont combinés dans les produits finis avec tout autre ingrédient habituellement utilisé en cosmétique ou dermopharmacie : lipides d'extraction et ou de synthèse, polymères gélifiants et viscosants, tensioactifs et émulsifiants, principes actifs hydro- ou liposolubles, extraits de plantes, extraits tissulaires, extraits marins.7) Cosmetic or dermopharmaceutical compositions according to any one of Claims 4 to 6, characterized in that they represent any galenical form used in cosmetics or dermopharmacy, namely O / W and W / O emulsions, milks, lotions, gels, ointments , balms, mousses, body lotions, hair lotions, shampoos, soaps, sticks and pencils, sprays. 8) cosmetic or dermopharmaceutical compositions according to quelquonque of claims 4 to 7 characterized in that the counterparts melatonin derivatives according to any one of claims 1 to 3 are combined in the finished products with any other ingredient usually used in cosmetics or dermopharmacy: extraction and or synthetic lipids, gelling and viscosifying polymers, surfactants and emulsifiers, water- or liposoluble active principles, plant extracts, tissue extracts, marine extracts.
9) Utilisations des dérivés homologues de la mélatonine selon l' une quelconque de revendications 1 à 3 dans les compositions cosmétiques ou dermopharmaceutiques selon I ' une quelconque des revendications 4 à 8 pour les soins de la peau ou du cuir chevelu, particulièrement tous les soins hydratants, raffermissants, anti-rides, anti-séborrhéiques. 9) Use of melatonin homologous derivatives according to one of claims 1 to 3 in cosmetic or dermopharmaceutical compositions I to one of claims 4 to 8 for the care of the skin or the scalp, particularly the care hydrating, firming, anti-wrinkle, anti-seborrheic.
PCT/FR1996/001276 1996-08-09 1996-08-09 Melatonin derivatives and their use in cosmetic or dermopharmaceutical compositions WO1998006695A1 (en)

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WO2005044261A1 (en) * 2003-10-27 2005-05-19 University Of Iowa Research Foundation Melatonin analogue prodrugs
FR2984122A1 (en) * 2011-12-16 2013-06-21 Syntivia COSMETIC COMPOSITION FOR STIMULATING SKIN ANTI-AGING SKIN FUNCTIONS
US9486441B2 (en) 2008-04-21 2016-11-08 Signum Biosciences, Inc. Compounds, compositions and methods for making the same
WO2018046243A1 (en) 2016-09-06 2018-03-15 Unilever N.V. Compounds for reducing cellular melanin content
CN114680114A (en) * 2022-04-27 2022-07-01 华中农业大学 Application of melatonin derivative in preventing and treating plant fungal diseases

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Cited By (12)

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CN1079395C (en) * 1998-03-18 2002-02-20 谭敦宪 Melatonin deriv, its preparation, producing process and use thereof in pharmaceutics
WO2005044261A1 (en) * 2003-10-27 2005-05-19 University Of Iowa Research Foundation Melatonin analogue prodrugs
US9486441B2 (en) 2008-04-21 2016-11-08 Signum Biosciences, Inc. Compounds, compositions and methods for making the same
US20170266161A1 (en) * 2008-04-21 2017-09-21 Signum Biosciences, Inc. Compounds, compositions and methods for making the same
US10583119B2 (en) * 2008-04-21 2020-03-10 Signum Biosciences, Inc. Compounds, compositions and methods for making the same
FR2984122A1 (en) * 2011-12-16 2013-06-21 Syntivia COSMETIC COMPOSITION FOR STIMULATING SKIN ANTI-AGING SKIN FUNCTIONS
WO2013087834A3 (en) * 2011-12-16 2013-10-24 Syntivia Cosmetic composition for stimulating the cellular anti-aging functions of the skin
WO2018046243A1 (en) 2016-09-06 2018-03-15 Unilever N.V. Compounds for reducing cellular melanin content
CN109661224A (en) * 2016-09-06 2019-04-19 荷兰联合利华有限公司 For reducing the compound of cell melanin content
CN109661224B (en) * 2016-09-06 2022-05-24 联合利华知识产权控股有限公司 Compounds for reducing melanin content in cells
CN114680114A (en) * 2022-04-27 2022-07-01 华中农业大学 Application of melatonin derivative in preventing and treating plant fungal diseases
CN114680114B (en) * 2022-04-27 2022-11-15 华中农业大学 Application of melatonin derivative in preventing and treating plant fungal diseases

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