EP1470157A2 - Novel peptide derivatives, preparation and therapeutic and cosmetic application thereof - Google Patents

Novel peptide derivatives, preparation and therapeutic and cosmetic application thereof

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Publication number
EP1470157A2
EP1470157A2 EP20030717360 EP03717360A EP1470157A2 EP 1470157 A2 EP1470157 A2 EP 1470157A2 EP 20030717360 EP20030717360 EP 20030717360 EP 03717360 A EP03717360 A EP 03717360A EP 1470157 A2 EP1470157 A2 EP 1470157A2
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EP
European Patent Office
Prior art keywords
ala
trp
group
nle
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP20030717360
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German (de)
French (fr)
Inventor
Anne-Marie Résidence Le Galoubet PINEL
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Institut Europeen de Biologie Cellulaire
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Institut Europeen de Biologie Cellulaire
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Application filed by Institut Europeen de Biologie Cellulaire filed Critical Institut Europeen de Biologie Cellulaire
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • 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
    • A61K8/04—Dispersions; Emulsions
    • 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
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/06—Preparations for styling the hair, e.g. by temporary shaping or colouring
    • A61Q5/065—Preparations for temporary colouring the hair, e.g. direct dyes
    • 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
    • A61Q5/10—Preparations for permanently dyeing the hair
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to pseudopeptide derivatives reproducing the peripheral effects of alpha-MSH (“Melanocyte Stimulating Hormone”), their preparation and their therapeutic and cosmetic application.
  • alpha-MSH Melanocyte Stimulating Hormone
  • Alpha-MSH is a substance naturally produced by the human organism known to have numerous physiological activities: antipyretics, anti-inflammatories and pigments. As a mediator, alpha-MSH has specific receptors, five of which have been described and each has 7 transmembrane domains. In the skin, the above-mentioned activities involve the “melanocortin-1” receptor (MC-lr). At this level, the binding of alpha-MSH induces the activation of a G protein (having an ⁇ subunit of G ⁇ s type) which will itself stimulate adenylyl cyclase and thus produce adenosine mono phosphate cyclical (or cAMP).
  • G protein having an ⁇ subunit of G ⁇ s type
  • cAMP cAMP response elements
  • CREB cAMP response elements
  • melanins the coloring of the skin and hair is due to a common category of pigments: melanins.
  • the production of these melanins in the skin is ensured by the melanocytes, cells located at the level of the basement membrane of the epidermis and in the hair follicles.
  • the synthesis of melanins is controlled by the activity of an enzyme: tyrosinase. It is the production of this enzyme (as well as that of the associated enzymes: TRP-1 & TRP-2) which is stimulated by the binding of alpha-MSH to its MC-1 receptor.
  • melanin The production of melanin by tyrosinase takes place within cytoplasmic organelles: the premelanosomes. Once filled with melanins, these organelles are called melanosomes and are transferred, via the dendrites of the melanocyte, to neighboring cells: keratinocytes. The melanin is thus distributed in the epidermis, ensuring its browning and its protection.
  • Melanin a natural pigment known for its anti-free radical properties and absorbing solar radiation, is the physiological protective agent of the skin. There is no compound available in dermocosmetology that can stimulate the production of this pigment in humans.
  • alpha-MSH by binding to the MC-1 receptor, inhibits the induction of NOSi (or NOS2), NFKB and induces the expression of mRNA followed by the production of the anti-inflammatory cytokine IL-10.
  • NOSi NOS2
  • NFKB NFKB
  • This cytokine is opposed to the release of cytokines from inflammation like IL -1, IL6, IL-8, TNF- ⁇ , or INF ⁇ .
  • the keratinocytes which constitute 95% of the cell population of the epidermis are considered to be reservoirs for IL-1 and have MC-1 receptors on their cell surface.
  • IL-1 IL-1 receptors
  • the binding of alpha-MSH to these receptors allows modulation of local inflammatory phenomena.
  • the present invention thus aims to provide small linear pseudopeptide compounds having melanotropic and / or anti-inflammatory, anti-allergic activities. More specifically, the subject of the invention is new peptides corresponding to formula (I)
  • R represents a hydrogen atom or a protective group which can be chosen from an acetyl group, a benzoyl group, a tosyl group, a benzene sulfonyl group, a benzyloxycarbonyl group or a pyridinepropionyl group.
  • V represents a natural or unnatural amino acid, of configuration L, chosen from norleucine, norvaline and 2-N-Me-norleucine.
  • X represents a natural or unnatural amino acid, of L or D configuration, of aromatic character chosen from phenylalanine, 1-naphthylalanine, 2-naphthylalanine, phenylglycine, benzothienylalanine, 4,4'-biphenylalanine, 3, 3-diphenylalanine, Phomophenylalanine, Pindanylglycine, 4-methylphenylalanine, thienylalanine, p-nitro-phenylalanine, halogenophenylalanine where the halogen can be a chlorine, bromine, iodine or fluorine atom in meta, ortho or para of the phenyl group.
  • Y represents a natural amino acid of configuration L, of basic character chosen from arginine, lysine or ornithine.
  • amino acids Ala, His and Trp respectively at positions 2, 3 and 6 in the peptide of formula (I) are of configuration L.
  • the peptides of formula (I) may contain one or more asymmetric carbon atoms. They can exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures are part of the invention.
  • these new peptides have an activity for stimulating pigmentation and / or limiting local inflammatory phenomena in the skin or mucous membranes.
  • the peptides according to the invention are useful in the prevention and / or treatment of pathologies such as atopic dermatitis, psoriasis, vitiligo, erythema, inflammatory alopecia, eczema or asthma, which are initiated at the cellular level and can be attenuated by the direct intervention of compounds which mimic natural mediators.
  • the peptides which are the subject of the present invention therefore constitute a spectacular innovation in skin care.
  • the present invention thus also relates to the use of one or more peptides of formula (I) for the manufacture of a medicament having an anti-inflammatory and / or anti-allergic effect as well as the use of one or more peptides of formula (I) for the manufacture of a cosmetic product having a melanotropic activity.
  • R represents a protective group which can be chosen from an acetyl group, a benzene sulfonyl group, a tosyl group or a pyridinepropionyl group
  • V represents a natural amino acid or not chosen from norleucine and 2-
  • N-Me-norleucine of configuration L.
  • X represents a natural or non-aromatic amino acid chosen from phenylalanine, 2-naphthylalanine, homophenylalanine, thienylalanine or p-nitro-phenylalanine, of configuration D or L.
  • Y represents a natural amino acid of configuration L , of a basic character chosen from arginine or lysine.
  • the compounds of general formula (I) can be prepared according to various methods known to a person skilled in the art, in particular by chemical synthesis processes in solution or on solid support. Synthesis on a support with resin is particularly suitable.
  • the resins which can be used mention may be made of the resin of the Rink amide type (or 4- (2 ′, 4′-dimethoxyphenyl-fmoc-aminomethyl) - ⁇ henoxy resin) (H. Rink, Tetrahedron Let., 1987 , 28, 3787) and the MBHA resin (or 4-methyl-benzhydrylamine resin) (GR Matsueda et al. Peptides, 1981, 2, 45).
  • the starting materials are protected amino acids.
  • the protective groups can be an acetyl group (Ac) or a 9-fluorenylmethoxycarbonyl group (Fmoc) on the main amine function, a tert-butyloxycarbonyl group (Boc), a Trityl group (Trt), a group 2,2, 5,7,8- pentamethylchroman-6-sulfonyl (Pmc) on the functions of the side chains. Washing, coupling and deprotection techniques are well known to those skilled in the art.
  • Example 1 Compound No. 1 in the Table
  • This peptide is synthesized by synthesis on a solid support with a resin of the Rink amide type, the functionalization of which is between 0.3 and 0.6 mmol / g of resin.
  • the Rink amide resin is firstly prepared, by washing with DMF (2 washes), then deprotection is carried out as described below. For each amino acid to be coupled, the steps of coupling the amino acid, washing the resin, deprotecting the amino function of the main chain of the amino acid, and again washing the resin are repeated. Coupling: 2 equivalents of BOP (or HBTU), 2 equivalents of DIEA (or NMM) and 2 equivalents of Fmoc-AA-OH for 2 hours in DMF.
  • the peptide is cleaved from the resin using a TFA / dichloromethane 50/50 mixture with 2% ethanediol for 1 h 30 min.
  • the dichloromethane and the TFA are evaporated under nitrogen flow, then precipitated with diethyl ether and purified on preparative liquid chromatography, with a C1 reverse phase column.
  • BOP Benzotriazole-l-yl-oxy-tris (dimemylamino) phosphonium hexafluorophosphate
  • This peptide is synthesized by synthesis on a solid support with a resin of the Rink amide type, the functionalization of which is between 0.3 and 0.6 mmol / g of resin.
  • HPLC High Performance Liquid Chromatography
  • the purities are expressed as a relative percentage relative to the surface of the peaks of the crude product before purification and the retention times (TR) are expressed in minutes.
  • TR retention times
  • - PyrProp represents a pyridinepropionyl group
  • DHomoPhe homophenylalanine of configuration D
  • Nap represents the 2-naphthylalanine of configuration L
  • - DPhe represents the phenylalanine of configuration D
  • - NMe-Nle represents 2-N-Me-Norleucine of configuration L.
  • a synthesis on a support can be carried out with a resin of the Rink amide type as described in Example 1.
  • amino acids are introduced in protected form onto the side chains if necessary, the main function being protected by an Fmoc group.
  • the molecules used for these syntheses are according to the position:
  • Trp 6 Fmoc-Trp (Boc) -OH
  • Y 5 Fmoc-Arg (Pmc) -OH, Fmoc-Lys (Boc) -OH
  • Ala 2 Fmoc-Ala-OH
  • Ala 1 Ac-Nle-OH, Fmoc-Nle-OH in the case of terminal protection other than acetyl protection.
  • the terminal protections (R) will be introduced, after a deprotection step, by coupling, using the following reagents: benzene sulfonyl chloride, pyridine propionyl chloride and tosyl chloride.
  • the peptides of the invention have been the subject of pharmacological tests making it possible to determine their effects after their safety has been confirmed by the appropriate toxicity and tolerance tests.
  • peptide No. 1 and alpha-MSH The action of peptide No. 1 and alpha-MSH on the production of tyrosinase has been demonstrated in vitro on maintained human melanocytes.
  • the production of tyrosinase was monitored on the M4Be line by western-blotting using an anti-human tyrosinase antibody. After 24 hours of culture, the cells are added with alpha-MSH or peptide No. 1 at a concentration of 10 " M final.
  • the cells are peeled off and lysed in NaH 2 PO 4 50mM buffer pH 6.8 + 1% Triton XI 00 + ImM PMSF
  • the protein level of the various samples is determined by assay with bicinconinic acid and 100 ⁇ g of sample is deposited per well of 15% electrophoresis gel d 'acrylamide / bisacrylamide.
  • the samples are migrated for 3 hours at 70 mA. Transfer to a nitrocellulose membrane (Schleicher & Schuell, ref Protari) is carried out overnight at 10 V.
  • the membrane is blocked with buffer at pH 7, 6 (200mM Tris; 1.37 M NaCl; 1M HC1) + 0.1% Tween + 5% BSA, for 1 hour at 37 ° C.
  • the revelation is carried out firstly by a goat anti-tyrosinase antibody human (Santa Cruz, ref SC-7833) diluted to 1 / 1000th at 4 ° C overnight, then incubated with an anticor ps goat anti-immunoglobulin coupled with peroxidase (Sigma, ref A8919) diluted to 1/10000 at room temperature for 1 hour.
  • the presence of tyrosinase is visualized by chemiluminescence using an ECL detection kit (Amersham Pharmacia Biotech, ref. RPN2109) which prints a photographic film (Amersham Pharmacia Biotech, ref. RPN2103K) reported in Figure 1/1.
  • the ultra structural analysis of melanocytes and melanosomes was carried out by electron microscopy.
  • the fine sections were subjected to a double contrast technique and then observed at magnifications of up to x 12,000 (Jeol 1200EX).
  • peptide No. 1 in the table induces a statistically significant increase in skin browning (tanning) by 54% (p ⁇ 0.05, Student's t test). Clinical observation of the treated areas did not show any sign of intolerance. Compared to placebo, peptide No. 1 in the table induces a statistically significant increase (+ 68%, p ⁇ 0.01) in the quantity of melanin in the epidermis of the volunteers. The analysis of variance according to the Fisher test reveals a very significant product effect with a risk of less than 1%.
  • the ultra-structural analysis of the melanocytes reveals an important influence of the treatment with large cells, a developed nucleus with little heterochromatin, very abundant cellular organelles and dendrites loaded with eumelanosomes. All these signs testify to an intense activity of biosynthesis of melanin, perfectly physiological.
  • melanosomes in keratinocytes show that they naturally accumulate at the apical level of the cell nucleus constituting a typical "nuclear parasol".
  • Peptide No. 1 in the table applied topically has been shown to be able to significantly stimulate skin melanogenesis in humans. It is also perfectly tolerated locally.
  • Anti-inflammatory activity has been demonstrated as follows: In the skin, irritants such as surfactants are responsible for inflammatory reactions characterized by the extracellular expression of cytokines such as interleukin-1 alpha (IL- la). The keratinocyte model in SDS-stimulated culture was used to assess the anti-inflammatory potential of peptide # 1 in the table.
  • irritants such as surfactants are responsible for inflammatory reactions characterized by the extracellular expression of cytokines such as interleukin-1 alpha ( IL- la).
  • IL- la interleukin-1 alpha
  • NCTC 2544 human keratinocytes are cultured with peptide No. 1 in the table at a concentration of 10 ⁇ 6 M for 72 hours. After rinsing, the SDS is introduced at a concentration of 85 mg / 1 and left in contact for 24 hours.
  • the extracellular IL-1 ⁇ levels in the supernatant are determined by the ELIS A method (Immunotech, ref 0755) chosen for the absence of interference with the SDS.
  • Peptide No. 1 reduces by approximately 42% the expression of IL-1 ⁇ by keratinocytes in culture stressed by SDS.
  • the treatment consists of a topical application on the internal face of the forearm 2 times / day for 2 weeks at a rate of 2 ⁇ l / cm 2 over 75 cm 2 .
  • the arm is protected from any sun exposure.
  • the solar radiation is given by a 150 W xenon arc lamp with a UVA & B spectrum ranging from 290 to 390 nm.
  • Six doses of light intensity in geometric progression of 25% are applied to the treated areas through liquid light guides.
  • the colorimetric measurements are made with the Chromameter TM CR 300.
  • the chromaticity coordinates (L; a & b *) are determined relative to a nearby non-irradiated area.
  • a differential ⁇ a *> 2.5 allows the DEM to be precisely defined 24 hours after the last treatment, the treated and control areas are irradiated with increasing doses of UV calculated to frame the DEM of each individual. After 24 h and 72 h, the irradiated area is evaluated by colorimetric measurements.
  • the evaluation criterion is the D.E.M. : the lowest dose of UV A&B that causes erythema.
  • peptide No. 1 in the gel table topically makes it possible to increase the resistance of the skin to the appearance of an erythema caused by excessive solar irradiation.
  • peptides of the invention have anti-inflammatory, anti-allergic and melanotropic activity.
  • the peptides of the invention can therefore be used for the preparation of medicaments intended for treating allergies, in particular cutaneous, inflammatory reactions and disorders of melanogenesis.
  • These drugs thus find their use in therapy in particular in the prevention and / or treatment of atopic dermatitis, psoriasis, vitiligo, erythema and in particular photo-induced erythema, inflammatory alopecia, eczema and asthma.
  • the present invention relates to pharmaceutical compositions containing, as active principle, a peptide according to the invention.
  • These pharmaceutical compositions can in particular be adapted to a local application on the skin and the mucous membranes.
  • compositions contain an effective dose of a peptide according to the invention, and one or more suitable pharmaceutical excipients.
  • Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.
  • the active principle of formula (I) above its optional salt or hydrate can be administered in unit administration form, in mixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.
  • Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intranasal administration forms, subcutaneous, intramuscular or intravenous administration and forms of rectal administration.
  • the compounds according to the invention can be used in creams, ointments, liquid or spray aerosols (sprays), gels, lotions and patches.
  • the dose of active ingredient administered per day can reach 0.5 mg / kg, in one or more doses.
  • the appropriate dosage for each patient is determined by the doctor according to the method of administration, the weight and the response of said patient.
  • a pharmaceutical excipient such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • the tablets can be coated with sucrose, a cellulose derivative, or other materials.
  • the tablets can be produced by different techniques, direct compression, dry granulation, wet granulation or hot melting.
  • a preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.
  • aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol, may be used.
  • the present invention according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration of a peptide according to the invention or one of its pharmaceutically acceptable salts.
  • a cosmetic composition comprising a compound of formula (I) which can be administered by mucous or topical route also forms part of the invention as well as the use of a compound of formula (I) for the preparation of a cosmetic product having a melanotropic effect.
  • the subject of the invention is dermocosmetic compositions comprising a peptide of formula (I) according to the invention for topical application which can take the form of solutions, lotions, emulsions, liquid or spray aerosols (sprays), gels or creams that can be used in particular as a skin preparation agent for sun exposure, a tanning accelerator recolouring white hair, skin soothing, anti-erythematosus.
  • a peptide of formula (I) for topical application
  • the pharmaceutical compositions, cosmetic products or dermocosmetic compositions which are the subject of the invention as described above containing mixtures of peptides according to the invention also form part of the invention.

Abstract

The invention relates to peptides of formula (1) R-V l-Ala2-His3-X4-Y5-Trp 5-NH2 wherein R represents a hydrogen atom or a protective group which can be chosen from among a benzoyl group, a tosyl group, a benzene sulfonyl group, a benzyloxycarbonyl group or a pyridinepropionyl group; V represents a natural amino acid or not chosen from among norleucine, norvaline and 2-N-Me-norleucine, X represents a natural amino acid or not having an aromatic character chosen from among phenylalanine, 1-naphtylalanine, 2-naphtylalanine, phenylglycine, benzothienylalanine, 4,4'-biphenylalanine, 3,3-diphenylalanine, homophenylalanine, indanylglycine, 4-methylphenylalanine, thienylalanine, p-nitrophenylalanine, halogenophenylalanine of configuration L or D; Y represents a natural amino acid of configuration L, having a basic character chosen from among arginine, lysine or ornithine, the enantiometers or diastereoisomers, and the mixtures thereof, including racemic mixtures. The invention also relates to a method for the preparation and application thereof in the field of therapeutics or cosmetics.

Description

NOUVEAUX DERIVES PEPTIDIQUES, LEUR PREPARATION ET LEUR APPLICATION THÉRAPEUTIQUE ET COSMETIQUENEW PEPTIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC AND COSMETIC APPLICATION
La présente invention a pour objet des dérivés pseudopeptidiques reproduisant les effets périphériques de l'alpha-MSH (« Mélanocyte Stimulating Hormone »), leur préparation et leur application thérapeutique et cosmétique.The present invention relates to pseudopeptide derivatives reproducing the peripheral effects of alpha-MSH (“Melanocyte Stimulating Hormone”), their preparation and their therapeutic and cosmetic application.
L'alpha-MSH est une substance naturellement produite par l'organisme humain connue pour avoir de très nombreuses activités physiologiques : antipyrétiques, antiinflammatoires et pigmentantes. En tant que médiateur, l'alpha-MSH possède des récepteurs spécifiques dont cinq ont été décrits et possèdent chacun 7 domaines transmembranaires. Au niveau de la peau, les activités précédemment citées font intervenir le récepteur « melanocortin-1 » (MC-lr). A ce niveau, la fixation de l'alpha-MSH induit l'activation d'une protéine G (présentant une sous unité α de type Gγs) qui va elle-même stimuler l'adénylyl cyclase et ainsi produire de l'adénosine mono phosphate cyclique (ou AMPc).Alpha-MSH is a substance naturally produced by the human organism known to have numerous physiological activities: antipyretics, anti-inflammatories and pigments. As a mediator, alpha-MSH has specific receptors, five of which have been described and each has 7 transmembrane domains. In the skin, the above-mentioned activities involve the “melanocortin-1” receptor (MC-lr). At this level, the binding of alpha-MSH induces the activation of a G protein (having an α subunit of Gγs type) which will itself stimulate adenylyl cyclase and thus produce adenosine mono phosphate cyclical (or cAMP).
La production d'AMPc induit l'activation de protéines kinases de type A qui vont activer par phosphorylation les protéines capables de se lier aux éléments de réponse à l'AMPc (ou CREB) au niveau de l'ADN des gènes de la cellule. Ceci conduit à l'expression de médiateurs qui exercent alors leurs effets sur les cellules cibles. Chez les mammifères la coloration de la peau et des poils est due à une catégorie commune de pigments : les mélanines. La production de ces mélanines dans la peau est assurée par les mélanocytes, cellules localisées au niveau de la membrane basale de l'épiderme et dans les follicules pileux. La synthèse des mélanines est contrôlée par l'activité d'une enzyme : la tyrosinase. C'est la production de cette enzyme (ainsi que celle des enzymes associées : TRP-1 & TRP-2) qui est stimulée par la fixation de l'alpha-MSH sur son récepteur MC-1.The production of cAMP induces the activation of type A protein kinases which will activate by phosphorylation the proteins capable of binding to cAMP response elements (or CREB) at the level of the DNA of the cell genes. This leads to the expression of mediators which then exert their effects on the target cells. In mammals the coloring of the skin and hair is due to a common category of pigments: melanins. The production of these melanins in the skin is ensured by the melanocytes, cells located at the level of the basement membrane of the epidermis and in the hair follicles. The synthesis of melanins is controlled by the activity of an enzyme: tyrosinase. It is the production of this enzyme (as well as that of the associated enzymes: TRP-1 & TRP-2) which is stimulated by the binding of alpha-MSH to its MC-1 receptor.
La production de mélanine par la tyrosinase a lieu au sein d'organelles cytoplasmiques : les prémélanosomes. Une fois remplies de mélanines ces organelles sont appelées mélanosomes et sont transférées, par l'intermédiaire des dendrites du mélanocyte, aux cellules voisines : les kératinocytes. La mélanine est répartie ainsi dans l'épiderme, assurant son brunissement et sa protection. La mélanine, pigment naturel reconnu pour ses propriétés antiradicalaires et absorbantes des rayonnements solaires, est l'agent protecteur physiologique de la peau. Il n'existe pas de composé disponible en dermocosmétologie qui puisse stimuler la production de ce pigment chez l'homme. De plus, le mécanisme des effets anti-inflammatoires de l'alpha-MSH n'est pas totalement élucidé mais de nombreux faits expérimentaux convergent et donnent à penser que l'alpha-MSH, en se fixant sur le récepteur MC-1, inhibe l'induction de la NOSi (ou NOS2), de NFKB et induit l'expression du mRNA suivie de la production de la cytokine anti-inflammatoire IL- 10. Cette cytokine s'oppose à la libération des cytokines de l'inflammation comme IL-1 , IL6, IL-8, TNF-α, ou INFγ.The production of melanin by tyrosinase takes place within cytoplasmic organelles: the premelanosomes. Once filled with melanins, these organelles are called melanosomes and are transferred, via the dendrites of the melanocyte, to neighboring cells: keratinocytes. The melanin is thus distributed in the epidermis, ensuring its browning and its protection. Melanin, a natural pigment known for its anti-free radical properties and absorbing solar radiation, is the physiological protective agent of the skin. There is no compound available in dermocosmetology that can stimulate the production of this pigment in humans. In addition, the mechanism of anti-inflammatory effects of alpha-MSH is not fully understood but many experimental facts converge and suggest that alpha-MSH, by binding to the MC-1 receptor, inhibits the induction of NOSi (or NOS2), NFKB and induces the expression of mRNA followed by the production of the anti-inflammatory cytokine IL-10. This cytokine is opposed to the release of cytokines from inflammation like IL -1, IL6, IL-8, TNF-α, or INFγ.
Les kératinocytes qui constituent 95% de la population cellulaire de l'épiderme sont considérés comme des réservoirs à IL-1 et présentent à leur surface cellulaire des récepteurs MC-1. Ainsi, la fixation de l'alpha-MSH sur ces récepteurs permet une modulation des phénomènes inflammatoires locaux. L'alpha-MSH est un tridecapeptide de formule Acétyl-SerXTyr2-Ser3-Met4-Glu5- His6-Phe7-Arg8-T 9-Gly10-Lysu-Pro12-Val13-NH2 (ou Ser =sérine, Tyr ≈ tyrosine, Met = méthionine, Glu = acide glutamique, His = histidine, Phe = phenylalanine, Arg = arginine, Trp = tryptophane, Gly - glycine, Lys = lysine, Pro = proline et Val = valine) De très nombreux travaux scientifiques ont établi les séquences actives de l'alpha-MSH qui sont classiquement décrites comme étant l'heptapeptide 4-10 pour les effets mélanotropes (Haskell-Luevano et al. J. Med. Chem. 1997, 40, 2133-2139) et le tripeptide 11-13 pour les effets anti-inflammatoires (Hiltz M.E. et Lipton J.M. Peptides 1990, 11 , 979-982.). De plus, les travaux récents ont conduit divers auteurs à déposer des brevets décrivant des structures cyclisées (Hruby et al. US 5,674,839 & US 6,054,556).The keratinocytes which constitute 95% of the cell population of the epidermis are considered to be reservoirs for IL-1 and have MC-1 receptors on their cell surface. Thus, the binding of alpha-MSH to these receptors allows modulation of local inflammatory phenomena. Alpha-MSH is a tridecapeptide with the formula Acetyl-SerXTyr 2 -Ser 3 -Met 4 -Glu 5 - His 6 -Phe 7 -Arg 8 -T 9 -Gly 10 -Lys u -Pro 12 -Val 13 -NH 2 (or Ser = serine, Tyr ≈ tyrosine, Met = methionine, Glu = glutamic acid, His = histidine, Phe = phenylalanine, Arg = arginine, Trp = tryptophan, Glyglycine, Lys = lysine, Pro = proline and Val = valine ) Numerous scientific studies have established the active sequences of alpha-MSH which are classically described as being heptapeptide 4-10 for melanotropic effects (Haskell-Luevano et al. J. Med. Chem. 1997, 40, 2133-2139) and tripeptide 11-13 for anti-inflammatory effects (Hiltz ME and Lipton JM Peptides 1990, 11, 979-982.). In addition, recent work has led various authors to file patents describing cyclized structures (Hruby et al. US 5,674,839 & US 6,054,556).
La présente invention a ainsi pour but de fournir des composés pseudopeptidiques linéaires de petite taille présentant des activités mélanotropes et/ou anti-inflammatoires, anti-allergiques. Plus précisément, l'invention a pour objet de nouveaux peptides répondant à la formule (I)The present invention thus aims to provide small linear pseudopeptide compounds having melanotropic and / or anti-inflammatory, anti-allergic activities. More specifically, the subject of the invention is new peptides corresponding to formula (I)
R-V1-Ala2-His3-X4-Y5-Trp6-NH2 (I)RV 1 -Ala 2 -His 3 -X 4 -Y 5 -Trp 6 -NH 2 (I)
dans laquellein which
R représente un atome d'hydrogène ou un groupe protecteur pouvant être choisi parmi un groupe acétyle, un groupe benzoyle, un groupe tosyle, un groupe benzène sulfonyle, un groupe benzyloxycarbonyle ou un groupe pyridinepropionyle.R represents a hydrogen atom or a protective group which can be chosen from an acetyl group, a benzoyl group, a tosyl group, a benzene sulfonyl group, a benzyloxycarbonyl group or a pyridinepropionyl group.
V représente un acide aminé naturel ou non, de configuration L, choisi parmi la norleucine, la norvaline et la 2-N-Me-norleucine.V represents a natural or unnatural amino acid, of configuration L, chosen from norleucine, norvaline and 2-N-Me-norleucine.
X représente un acide aminé naturel ou non, de configuration L ou D, à caractère aromatique choisi parmi la phenylalanine, la 1 -naphtylalanine, la 2- naphtylalanine, la phenylglycine, la benzothienylalanine, la 4,4'-biphénylalanine, la 3,3-diphénylalanine, Phomophénylalanine, Pindanylglycine, la 4- méthylphénylalanine, la thienylalanine, la p-nitro-phénylalanine, l 'halogenophenylalanine où l'halogène peut être un atome de chlore, de brome, d'iode ou de fluor en meta, ortho ou para du groupe phényle.X represents a natural or unnatural amino acid, of L or D configuration, of aromatic character chosen from phenylalanine, 1-naphthylalanine, 2-naphthylalanine, phenylglycine, benzothienylalanine, 4,4'-biphenylalanine, 3, 3-diphenylalanine, Phomophenylalanine, Pindanylglycine, 4-methylphenylalanine, thienylalanine, p-nitro-phenylalanine, halogenophenylalanine where the halogen can be a chlorine, bromine, iodine or fluorine atom in meta, ortho or para of the phenyl group.
Y représente un acide aminé naturel de configuration L, à caractère basique choisi parmi l'arginine, la lysine ou l'ornithine.Y represents a natural amino acid of configuration L, of basic character chosen from arginine, lysine or ornithine.
Les acides aminés Ala, His et Trp respectivement aux positions 2, 3 et 6 dans le peptide de formule (I) sont de configuration L.The amino acids Ala, His and Trp respectively at positions 2, 3 and 6 in the peptide of formula (I) are of configuration L.
Les peptides de formule (I) peuvent comporter un ou plusieurs atomes de carbone asymétriques. Ils peuvent exister sous forme d'énantiomères ou de diastéréoisomères. Ces énantiomères, diastéréoisomères, ainsi que leurs mélanges, y compris les mélanges racémiques font partie de l'invention.The peptides of formula (I) may contain one or more asymmetric carbon atoms. They can exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures are part of the invention.
Ces nouveaux peptides possèdent une activité de stimulation de la pigmentation et/ou de limitation des phénomènes inflammatoires locaux au niveau de la peau ou des muqueuses. En particulier les peptides selon l'invention sont utiles dans la prévention et/ou le traitement de pathologies telles que la dermatite atopique, le psoriasis, le vitiligo, l'érythème, les alopécies inflammatoires, l'eczéma ou l'asthme, qui sont initiées au niveau cellulaire et peuvent être atténuées par l'intervention directe de composés qui miment les médiateurs naturels.These new peptides have an activity for stimulating pigmentation and / or limiting local inflammatory phenomena in the skin or mucous membranes. In particular, the peptides according to the invention are useful in the prevention and / or treatment of pathologies such as atopic dermatitis, psoriasis, vitiligo, erythema, inflammatory alopecia, eczema or asthma, which are initiated at the cellular level and can be attenuated by the direct intervention of compounds which mimic natural mediators.
Les peptides objets de la présente invention constituent donc une innovation spectaculaire en matière de soin cutané.The peptides which are the subject of the present invention therefore constitute a spectacular innovation in skin care.
La présente invention concerne ainsi en outre l'utilisation d'un ou plusieurs peptides de formule (I) pour la fabrication d'un médicament ayant un effet antiinflammatoire et/ou anti-allergique ainsi que l'utilisation d'un ou plusieurs peptides de formule (I) pour la fabrication d'un produit cosmétique ayant une activité mélanotrope.The present invention thus also relates to the use of one or more peptides of formula (I) for the manufacture of a medicament having an anti-inflammatory and / or anti-allergic effect as well as the use of one or more peptides of formula (I) for the manufacture of a cosmetic product having a melanotropic activity.
Parmi les composés de formule (I) objets de la présente invention on peut citer les composés préférés qui se définissent comme suit :Among the compounds of formula (I) which are subjects of the present invention, mention may be made of the preferred compounds which are defined as follows:
R représente un groupe protecteur pouvant être choisi parmi un groupe acétyle, un groupe benzène sulfonyle, un groupe tosyle ou un groupe pyridinepropionyle, V représente un acide aminé naturel ou non choisi parmi la norleucine et la 2-R represents a protective group which can be chosen from an acetyl group, a benzene sulfonyl group, a tosyl group or a pyridinepropionyl group, V represents a natural amino acid or not chosen from norleucine and 2-
N-Me-norleucine, de configuration L.N-Me-norleucine, of configuration L.
X représente un acide aminé naturel ou non à caractère aromatique choisi parmi la phenylalanine, la 2-naphtylalanine, l'homophénylalanine, la thienylalanine ou la p-nitro-phénylalanine, de configuration D ou L. Y représente un acide aminé naturel de configuration L, à caractère basique choisi parmi l' arginine ou la lysine.X represents a natural or non-aromatic amino acid chosen from phenylalanine, 2-naphthylalanine, homophenylalanine, thienylalanine or p-nitro-phenylalanine, of configuration D or L. Y represents a natural amino acid of configuration L , of a basic character chosen from arginine or lysine.
L'alanine, l'histidine et le tryptophane, respectivement aux positions 2, 3 et 6 dans le peptide de formule (I) sont de configuration L.Alanine, histidine and tryptophan, respectively in positions 2, 3 and 6 in the peptide of formula (I) are of configuration L.
Conformément à l'invention on peut préparer les composés de formule générale (I) selon des divers procédés connus de l'homme du métier, notamment par des procédés de synthèse chimique en solution ou sur support solide. La synthèse sur support avec résine est particulièrement adaptée. Parmi les résines que l'on peut utiliser, on peut citer la résine de type Rink amide (ou résine 4-(2',4'- diméthoxyphényl-fmoc-aminométhyl)-ρhénoxy) (H. Rink, Tetrahedron Let., 1987, 28, 3787) et la résine MBHA (ou résine 4-méthyl-benzhydrylamine) (G. R. Matsueda et al. Peptides, 1981, 2, 45).In accordance with the invention, the compounds of general formula (I) can be prepared according to various methods known to a person skilled in the art, in particular by chemical synthesis processes in solution or on solid support. Synthesis on a support with resin is particularly suitable. Among the resins which can be used, mention may be made of the resin of the Rink amide type (or 4- (2 ′, 4′-dimethoxyphenyl-fmoc-aminomethyl) -ρhenoxy resin) (H. Rink, Tetrahedron Let., 1987 , 28, 3787) and the MBHA resin (or 4-methyl-benzhydrylamine resin) (GR Matsueda et al. Peptides, 1981, 2, 45).
Les produits de départ sont des acides aminés protégés. Les groupes protecteurs peuvent être un groupe acétyle (Ac) ou un groupe 9-fluorényl- méthoxycarbonyle (Fmoc) sur la fonction aminé principale, un groupe tert- butyloxycarbonyle (Boc), un groupe Trityle (Trt), un groupe 2,2,5,7,8- pentaméthylchroman-6-sulfonyle (Pmc) sur les fonctions des chaînes latérales. Les techniques de lavage, de couplage et de déprotection sont bien connues de l'homme de l'art. Elles sont par exemple décrites dans Fmoc solid Phase Peptide synthesis : a practical approach : W.C. Chan and P.D. White (oxford University Press) ou Chemical approaches to the synthesis of peptides and proteins - Paul Lloyd- Williams, Fernando Albericio, Ernest Giralt (CRC Press Boca Raton, N.Y.).The starting materials are protected amino acids. The protective groups can be an acetyl group (Ac) or a 9-fluorenylmethoxycarbonyl group (Fmoc) on the main amine function, a tert-butyloxycarbonyl group (Boc), a Trityl group (Trt), a group 2,2, 5,7,8- pentamethylchroman-6-sulfonyl (Pmc) on the functions of the side chains. Washing, coupling and deprotection techniques are well known to those skilled in the art. They are for example described in Fmoc solid Phase Peptide synthesis: a practical approach: WC Chan and PD White (oxford University Press) or Chemical approaches to the synthesis of peptides and proteins - Paul Lloyd- Williams, Fernando Albericio, Ernest Giralt (CRC Press Boca Raton, NY).
Les exemples suivants illustrent la présente invention.The following examples illustrate the present invention.
Exemple 1 : composé n°l du tableauExample 1: Compound No. 1 in the Table
(R = Ac, V = Nie, X = DPhe, Y = Arg, Ala2, His3 et Trp6 de configuration L)(R = Ac, V = Nie, X = DPhe, Y = Arg, Ala 2 , His 3 and Trp 6 of configuration L)
On procède à la synthèse de ce peptide par une synthèse sur support solide avec une résine de type Rink amide dont la fonctionnalisation est comprise entre 0,3 et 0,6 mmole/g de résine.This peptide is synthesized by synthesis on a solid support with a resin of the Rink amide type, the functionalization of which is between 0.3 and 0.6 mmol / g of resin.
On prépare dans un premier temps la résine Rink amide, par lavage avec du DMF (2 lavages) puis on réalise la déprotection comme décrit plus bas. Pour chaque aminoacide à coupler, on répète les étapes de couplage de l'aminoacide, de lavage de la résine, de déprotection de la fonction aminé de la chaîne principale de l'aminoacide, et à nouveau de lavage de la résine. Couplage : 2 équivalents de BOP (ou HBTU), 2 équivalents de DIEA (ou NMM) et 2 équivalents de Fmoc-AA-OH pendant 2 heures dans du DMF.The Rink amide resin is firstly prepared, by washing with DMF (2 washes), then deprotection is carried out as described below. For each amino acid to be coupled, the steps of coupling the amino acid, washing the resin, deprotecting the amino function of the main chain of the amino acid, and again washing the resin are repeated. Coupling: 2 equivalents of BOP (or HBTU), 2 equivalents of DIEA (or NMM) and 2 equivalents of Fmoc-AA-OH for 2 hours in DMF.
Lavage : 2 lavages avec du DMF, 1 lavage avec du méthanol, 2 lavages avec du dichlorométhane et 1 lavage avec du DMF. Déprotection : mélange DMF/pipéridine 80/20 avec 2% d'éthanediol (piégeur de radicaux), une fois 3 minutes puis 7 minutes.Washing: 2 washes with DMF, 1 wash with methanol, 2 washes with dichloromethane and 1 wash with DMF. Deprotection: DMF / piperidine 80/20 mixture with 2% ethanediol (radical scavenger), once 3 minutes then 7 minutes.
Lavage : (idem précédemment).Washing: (same as above).
Après les différents couplages d'aminoacides, on clive le peptide de la résine en utilisant un mélange TFA/dichlorométhane 50/50 avec 2% d'éthanediol pendant lh30.After the various amino acid couplings, the peptide is cleaved from the resin using a TFA / dichloromethane 50/50 mixture with 2% ethanediol for 1 h 30 min.
On évapore le dichlorométhane et le TFA sous flux d'azote, puis on précipite avec du diéthyléther et on purifie sur Chromatographie Liquide préparative, avec une colonne phase inverse Cl 8.The dichloromethane and the TFA are evaporated under nitrogen flow, then precipitated with diethyl ether and purified on preparative liquid chromatography, with a C1 reverse phase column.
La synthèse de Ac-Nle-Ala-His-DPhe-Arg-Trp-NH2 se fait avec les aminoacides protégés (Fmoc— AA-OH) suivants :The synthesis of Ac-Nle-Ala-His-DPhe-Arg-Trp-NH2 is carried out with the following protected amino acids (Fmoc— AA-OH):
Fmoc-Trp(Boc)-OH Fmoc-Arg(Pmc)-OH Fmoc-DPhe-OH Fmoc-His(Trt)-OH Fmoc-Ala-OHFmoc-Trp (Boc) -OH Fmoc-Arg (Pmc) -OH Fmoc-DPhe-OH Fmoc-His (Trt) -OH Fmoc-Ala-OH
Ac-Nle-OHAc-Nle-OH
Abréviations :Abbreviations:
Fmoc : 9-fluorénylméthoxycarbonylFmoc: 9-fluorenylmethoxycarbonyl
TFA : Acide trifluoracétiqueTFA: Trifluoroacetic acid
DMF : DiméthylformamideDMF: Dimethylformamide
BOP : Hexafluorophosphate de benzotriazole-l-yl-oxy-tris(dimémylamino) phosphoniumBOP: Benzotriazole-l-yl-oxy-tris (dimemylamino) phosphonium hexafluorophosphate
HBTU : Hexafluorophosphate de 2-(lH- benzotriazole-l-yl)l,l,3,3- tétraméthyluroniumHBTU: 2- (1H- benzotriazole-1-yl) hexafluorophosphate l, l, 3,3- tetramethyluronium
DIEA : Diisopropyl éthyl aminéDIEA: Diisopropyl ethyl amino
NMM : N Méthyl morpholineNMM: N Methyl morpholine
On obtient le peptide souhaité dont les résultats d'analyse sont présentés dans le tableau qui suit. Exemple 2 composé n°2 du tableauThe desired peptide is obtained, the analysis results of which are presented in the table below. Example 2 compound n ° 2 of the table
(R = Ac , V = Nie, X = DPhe , Y = Lys, Ala2, His3 et Trp6 de configuration L)(R = Ac, V = Nie, X = DPhe, Y = Lys, Ala 2 , His 3 and Trp 6 of configuration L)
On procède à la synthèse de ce peptide par une synthèse sur support solide avec une résine de type Rink amide dont la fonctionnalisation est comprise entre 0,3 et 0,6 mmole/g de résine.This peptide is synthesized by synthesis on a solid support with a resin of the Rink amide type, the functionalization of which is between 0.3 and 0.6 mmol / g of resin.
La synthèse se fait suivant le même mode opératoire que celui décrit dans l'exemple 1. Les aminoacides utilisés pour la synthèse sont les suivants : Fmoc-Trp(Boc)-OHThe synthesis is carried out according to the same procedure as that described in Example 1. The amino acids used for the synthesis are the following: Fmoc-Trp (Boc) -OH
Fmoc-Lys(Boc)-OHFmoc-Lys (Boc) -OH
Fmoc-DPhe-OHFmoc-DPhe-OH
Fmoc-His(Trt)-OHFmoc-His (Trt) -OH
Fmoc-Ala-OH Ac-Nle-OHFmoc-Ala-OH Ac-Nle-OH
Les caractéristiques analytiques de ce peptide sont rapportées dans le tableau qui suit.The analytical characteristics of this peptide are reported in the table below.
Le tableau qui suit illustre les structures chimiques et reprend les résultats analytiques de quelques composés de l'invention ainsi que leurs Masses Moléculaires (MM) exprimées en g/mole.The following table illustrates the chemical structures and shows the analytical results of some compounds of the invention as well as their Molecular Masses (MM) expressed in g / mole.
Il a été effectué pour chacun des composés de l'invention, une analyse parAn analysis was carried out for each of the compounds of the invention.
Chromatographie Liquide Haute Performance (HPLC) et une analyse parHigh Performance Liquid Chromatography (HPLC) and analysis by
Spectrométrie de Masse (SM). HPLC :Mass spectrometry (SM). HPLC:
Phase stationnaire : Colonne de type Cl 8 Phase inverse dont les dimensions sont :Stationary phase: Cl 8 type column Reverse phase whose dimensions are:
4,6x50 mm, 3,5μm4.6x50 mm, 3.5μm
Phase mobile : mélange binaire composé d'eau (avec 0,1% de TFA) et d'acétonitrileMobile phase: binary mixture composed of water (with 0.1% TFA) and acetonitrile
(avec 0,1% de TFA). Méthode : gradient en 12 minutes de 0% à 80% en acétonitrile (0, 1 % de TFA).(with 0.1% TFA). Method: gradient in 12 minutes from 0% to 80% in acetonitrile (0.1% TFA).
Longueur d'onde de détection : 214 nmDetection wavelength: 214 nm
Dans le tableau, les puretés sont exprimées en pourcentage relatif par rapport à la surface des pics du produit brut avant purification et les temps de rétention (T.R.) sont exprimées en minutes. S M :In the table, the purities are expressed as a relative percentage relative to the surface of the peaks of the crude product before purification and the retention times (TR) are expressed in minutes. SM:
Electrospray Positif, avec une tension de cône de 9V, une température de la source àPositive electrospray, with a cone voltage of 9V, a source temperature at
120°C et un temps de balayage de 6 secondes.120 ° C and a scanning time of 6 seconds.
Dans le tableau sont rapportés la valeur de l'ion moléculaire [M+H]+ et dans certains cas l'ion dichargé [M+2H]2XIn the table are reported the value of the molecular ion [M + H] + and in some cases the dicharged ion [M + 2H] 2 X
TableauBoard
Dans ce tableau : - Ac représente un groupe acétyle,In this table: - Ac represents an acetyl group,
- BzlSO2 représente un groupe benzène sulfonyle,- BzlSO 2 represents a benzene sulfonyl group,
- PyrProp représente un groupe pyridinepropionyle,- PyrProp represents a pyridinepropionyl group,
- Tos représente un groupe tosyle, - DHomoPhe représente l'homophénylalanine de configuration D,- Tos represents a tosyle group, DHomoPhe represents homophenylalanine of configuration D,
- DThi représente la thienylalanine de configuration D,- DThi represents thienylalanine of configuration D,
- DpNO2Phe représente la p-nitrophénylalanine de configuration D,DpNO 2 Phe represents p-nitrophenylalanine of configuration D,
- L2,Nap représente la 2-naphtylalanine de configuration L, - DPhe représente la phenylalanine de configuration D,- L2, Nap represents the 2-naphthylalanine of configuration L, - DPhe represents the phenylalanine of configuration D,
- Nie représente la norleucine de configuration L,- Nie represents norleucine of configuration L,
- NMe-Nle représente la 2-N-Me-Norleucine de configuration L.- NMe-Nle represents 2-N-Me-Norleucine of configuration L.
On peut procéder pour ces composés à une synthèse sur support avec une résine de type Rink amide comme décrit dans l'exemple 1.For these compounds, a synthesis on a support can be carried out with a resin of the Rink amide type as described in Example 1.
On introduit les aminoacides sous forme protégée sur les chaînes latérales si nécessaire, la fonction a iné principale étant protégée par un groupement Fmoc. Les molécules utilisées pour ces synthèses sont selon la position :The amino acids are introduced in protected form onto the side chains if necessary, the main function being protected by an Fmoc group. The molecules used for these syntheses are according to the position:
Trp6 : Fmoc-Trp(Boc)-OH Y5 : Fmoc-Arg(Pmc)-OH, Fmoc-Lys(Boc)-OHTrp 6 : Fmoc-Trp (Boc) -OH Y 5 : Fmoc-Arg (Pmc) -OH, Fmoc-Lys (Boc) -OH
X4 : Fmoc-DPhe-OH, Fmoc-D-pNO2Phe-OH, Fmoc-DThi-OH, Fmoc-X 4 : Fmoc-DPhe-OH, Fmoc-D-pNO 2 Phe-OH, Fmoc-DThi-OH, Fmoc-
L2,Nap-OH, Fmoc-DHomoPhe-OHL2, Nap-OH, Fmoc-DHomoPhe-OH
His3 : Fmoc-His(Trt)-OHHis 3 : Fmoc-His (Trt) -OH
Ala2: Fmoc-Ala-OH Ala1 : Ac-Nle-OH, Fmoc-Nle-OH dans le cas d'une protection terminale autre que la protection acétyle.Ala 2 : Fmoc-Ala-OH Ala 1 : Ac-Nle-OH, Fmoc-Nle-OH in the case of terminal protection other than acetyl protection.
Dans ce cas, les protections terminales (R) seront introduites, après une étape de déprotection, par couplage, en utilisant les réactifs suivants : chlorure de benzène sulfonyle, chlorure de pyridine propionyle et chlorure de tosyle.In this case, the terminal protections (R) will be introduced, after a deprotection step, by coupling, using the following reagents: benzene sulfonyl chloride, pyridine propionyl chloride and tosyl chloride.
Les peptides de l'invention ont fait l'objet d'essais pharmacologiques permettant de déterminer leurs effets après que leur innocuité ait été confirmée par les tests de toxicité et de tolérance adéquats.The peptides of the invention have been the subject of pharmacological tests making it possible to determine their effects after their safety has been confirmed by the appropriate toxicity and tolerance tests.
1. L'affinité des peptides du tableau pour le récepteur MCl-r a été démontrée in vitro sur une lignée mélanocytaire par la production d'AMPc. La détermination de l'effet des peptides selon l'invention en comparaison avec l'alpha-MSH sur l'activation de l'adénylyl cyclase par des mélanocytes maintenus in vitro a été réalisée en utilisant une méthodologie notamment décrite dans Beavo J.A. et al. Mol. Pharmacol., 6(6), 597-603, 1970 et dans Montague W. Cook J. R., Biochem J, 122(1), 1971. On utilise des mélanocytes murins (lignée S91 Cloudman) capables de synthétiser des mélanines.1. The affinity of the peptides in the table for the MCl-r receptor has been demonstrated in vitro on a melanocyte line by the production of cAMP. The determination of the effect of the peptides according to the invention in comparison with alpha-MSH on the activation of adenylyl cyclase by melanocytes maintained in vitro was carried out using a methodology notably described in Beavo JA et al. Mol. Pharmacol., 6 (6), 597-603, 1970 and in Montague W. Cook JR, Biochem J, 122 (1), 1971. Murine melanocytes (S91 Cloudman line) are used which are capable of synthesizing melanins.
La production d'AMPc a été suivie par méthode EIA (Amersham Pharmacia Biotech, kit Biotrack réf RPN225) en suivant les recommandations du fournisseur. Nous avons déterminé le pourcentage de réponse induit par les diverses molécules criblées comparativement à l'alpha-MSH (100%). Toutes les conditions expérimentales ont été réalisées en double.The production of cAMP was monitored by the EIA method (Amersham Pharmacia Biotech, Biotrack kit ref RPN225) following the supplier's recommendations. We determined the percentage of response induced by the various screened molecules compared to alpha-MSH (100%). All the experimental conditions were carried out in duplicate.
L'action du peptide n°l et de l'alpha-MSH sur la production de tyrosinase a été démontrée in vitro sur des mélanocytes humains maintenus. La production de tyrosinase a été suivie sur la lignée M4Be par western-blotting à l'aide d'un anticorps anti tyrosinase humaine. Après 24 heures de culture les cellules sont additionnées d'alpha-MSH ou du peptide n°l à la concentration de 10" M finale. 24 heures plus tard, les cellules sont décollées par grattage et lysées dans du tampon NaH2PO4 50mM pH 6,8 + 1% Triton XI 00 + ImM PMSF. Le taux de protéines des divers échantillons est déterminé par dosage à l'acide bicinconinique. Il est déposé 100 μg d'échantillon par puits de gel d'électrophorèse à 15% d'acrylamide/bisacrylamide. Les échantillons sont mis à migrer 3 heures à 70 mA. Le transfert sur membrane de nitrocellulose (Schleicher & Schuell, réf Protari) est effectué une nuit à 10 V. La membrane est bloquée avec du tampon à pH 7,6 (200mM Tris; 1,37 M NaCl; 1M HC1) + 0,1% Tween + 5% de BSA, pendant 1 heure à 37°C. La révélation est effectuée dans un premier temps par un anticorps de chèvre anti-tyrosinase humaine (Santa Cruz, réf SC-7833) dilué au l/1000ème à 4°C pendant une nuit. On incube ensuite avec un anticorps anti- immunoglobuline de chèvre couplé à la péroxydase (Sigma, réf A8919) dilué au l/10000ème à température ambiante pendant 1 heure. La présence de tyrosinase est visualisée par chimioluminescence grâce à un kit de détection ECL (Amersham Pharmacia Biotech, réf. RPN2109) qui impressionne un film photographique (Amersham Pharmacia Biotech, réf. RPN2103K) rapporté à la figure 1/1.The action of peptide No. 1 and alpha-MSH on the production of tyrosinase has been demonstrated in vitro on maintained human melanocytes. The production of tyrosinase was monitored on the M4Be line by western-blotting using an anti-human tyrosinase antibody. After 24 hours of culture, the cells are added with alpha-MSH or peptide No. 1 at a concentration of 10 " M final. 24 hours later, the cells are peeled off and lysed in NaH 2 PO 4 50mM buffer pH 6.8 + 1% Triton XI 00 + ImM PMSF The protein level of the various samples is determined by assay with bicinconinic acid and 100 μg of sample is deposited per well of 15% electrophoresis gel d 'acrylamide / bisacrylamide. The samples are migrated for 3 hours at 70 mA. Transfer to a nitrocellulose membrane (Schleicher & Schuell, ref Protari) is carried out overnight at 10 V. The membrane is blocked with buffer at pH 7, 6 (200mM Tris; 1.37 M NaCl; 1M HC1) + 0.1% Tween + 5% BSA, for 1 hour at 37 ° C. The revelation is carried out firstly by a goat anti-tyrosinase antibody human (Santa Cruz, ref SC-7833) diluted to 1 / 1000th at 4 ° C overnight, then incubated with an anticor ps goat anti-immunoglobulin coupled with peroxidase (Sigma, ref A8919) diluted to 1/10000 at room temperature for 1 hour. The presence of tyrosinase is visualized by chemiluminescence using an ECL detection kit (Amersham Pharmacia Biotech, ref. RPN2109) which prints a photographic film (Amersham Pharmacia Biotech, ref. RPN2103K) reported in Figure 1/1.
2. Une étude en double aveugle des effets mélanostimulants par voie topique du peptide n° 1 du tableau a été menée chez l'homme.2. A double-blind study of the topical melanostimulatory effects of peptide No. 1 in the table was carried out in humans.
Douze volontaires sains ayant donné leur consentement éclairé se sont appliqués, 2 fois par jour pendant 3 semaines, sur la face interne des avant-bras un gel du peptide n°l à 10 ppm et son placebo. Les bras n'étant pas exposés au soleil, ils ont reçu une exposition solaire artificielle exactement calibrée de 0,6 D.E.M. (Dose Érythémateuse Minimale) une fois par j our du 16eme au 20eme j our.Twelve healthy volunteers having given their informed consent applied, twice a day for 3 weeks, on the inner face of the forearms a gel of peptide No. 1 at 10 ppm and its placebo. The arms are not exposed to sunlight, they received an artificial sun exposure exactly calibrated 0.6 DEM (Low Dose erythematous) once j our 16 th to 20 th j our.
24h après le dernier traitement, une évaluation clinique des zones traitées a été faite en aveugle et l'intensité de coloration a été cotée selon une échelle d'indices à cinq niveaux. Un prélèvement biopsique a ensuite été réalisé afin de quantifier la mélanine produite et d'évaluer les conséquences ultra structurales du traitement. La quantification de la mélanine épidermique a été réalisée sur des coupes histologiques par analyse d'image après marquage au AgNO3. Seules les couches actives de l'épiderme ont été analysées (du stratum ger inativum au stratum spinosum) par le Quantimet Leica après numérisation (caméra CCD Sony).24 hours after the last treatment, a clinical evaluation of the treated areas was made blind and the staining intensity was rated according to a five-level index scale. A biopsy sample was then taken in order to quantify the melanin produced and to assess the ultra-structural consequences of the treatment. The quantification of epidermal melanin was carried out on histological sections by image analysis after labeling with AgNO 3 . Only the layers active epidermis were analyzed (from stratum ger inativum to stratum spinosum) by Quantimet Leica after scanning (Sony CCD camera).
L'analyse ultra structurale des mélanocytes et mélanosomes a été réalisée en microscopie électronique. Les coupes fines ont été l'objet d'une technique de double contraste puis observée à des grossissements allant jusqu'à x 12000 (Jeol 1200EX).The ultra structural analysis of melanocytes and melanosomes was carried out by electron microscopy. The fine sections were subjected to a double contrast technique and then observed at magnifications of up to x 12,000 (Jeol 1200EX).
Par rapport au placebo, le peptide n°l du tableau induit une augmentation statistiquement significative du brunissement de la peau (bronzage) de 54% (p< 0.05, test t de Student). L'observation clinique des zones traitées n'a fait apparaître aucun signe d'intolérance. Par rapport au placebo, le peptide n°l du tableau induit une augmentation statistiquement significative (+ 68%, p<0.01) de la quantité de mélanine dans l'épiderme des volontaires. L'analyse de variance selon le test de Fisher fait ressortir un effet produit très significatif avec un risque inférieur à 1%.Compared to placebo, peptide No. 1 in the table induces a statistically significant increase in skin browning (tanning) by 54% (p <0.05, Student's t test). Clinical observation of the treated areas did not show any sign of intolerance. Compared to placebo, peptide No. 1 in the table induces a statistically significant increase (+ 68%, p <0.01) in the quantity of melanin in the epidermis of the volunteers. The analysis of variance according to the Fisher test reveals a very significant product effect with a risk of less than 1%.
La comparaison des résultats individuels fait par ailleurs ressortir une excellente corrélation entre les deux méthodes.The comparison of the individual results also reveals an excellent correlation between the two methods.
L'analyse ultra structurale des mélanocytes fait ressortir une influence importante du traitement avec des cellules de grande taille, un noyau développé présentant peu d'hétérochromatine, des organites cellulaires très abondants et des dendrites chargés d'eumélanosomes. Tous ces signes témoignent d'une activité intense de biosynthèse de mélanine, parfaitement physiologique.The ultra-structural analysis of the melanocytes reveals an important influence of the treatment with large cells, a developed nucleus with little heterochromatin, very abundant cellular organelles and dendrites loaded with eumelanosomes. All these signs testify to an intense activity of biosynthesis of melanin, perfectly physiological.
L'étude des mélanosomes dans les kératinocytes montre qu'ils s'accumulent naturellement au niveau apical du noyau cellulaire constituant un "parasol nucléaire" typique.The study of melanosomes in keratinocytes shows that they naturally accumulate at the apical level of the cell nucleus constituting a typical "nuclear parasol".
Le peptide n° 1 du tableau appliqué par voie topique se montre capable de stimuler significativement la mélanogénèse cutanée chez l'homme. Il est par ailleurs parfaitement toléré au niveau local.Peptide No. 1 in the table applied topically has been shown to be able to significantly stimulate skin melanogenesis in humans. It is also perfectly tolerated locally.
3. L'activité anti-inflammatoire a été mise en évidence comme suit : Au niveau de la peau, des agents irritants tels que les surfactants sont responsables de réactions inflammatoires caractérisées par l'expression extracellulaire de cytokines comme l'interleukine-1 alpha (IL- la). Le modèle du kératinocyte en culture stimulé au SDS a été utilisé pour apprécier le potentiel anti-inflammatoire du peptide n° 1 du tableau.3. Anti-inflammatory activity has been demonstrated as follows: In the skin, irritants such as surfactants are responsible for inflammatory reactions characterized by the extracellular expression of cytokines such as interleukin-1 alpha ( IL- la). The keratinocyte model in SDS-stimulated culture was used to assess the anti-inflammatory potential of peptide # 1 in the table.
On met en culture des kératinocytes humains NCTC 2544 avec le peptide n° 1 du tableau à la concentration de 10"6 M pendant 72h. Après rinçage, le SDS est introduit à la concentration de 85 mg/1 et laissé en contact 24h.NCTC 2544 human keratinocytes are cultured with peptide No. 1 in the table at a concentration of 10 −6 M for 72 hours. After rinsing, the SDS is introduced at a concentration of 85 mg / 1 and left in contact for 24 hours.
On détermine les taux d'IL-lα extracellulaires dans le surnageant par méthode ELIS A (Immunotech, réf 0755) choisie pour l'absence d'interférence avec le SDS.The extracellular IL-1α levels in the supernatant are determined by the ELIS A method (Immunotech, ref 0755) chosen for the absence of interference with the SDS.
Effet du peptide n° 1 du tableau sur la libération de IL- la par les kératinocytes NCTC2544 stimulés au SDS :Effect of peptide n ° 1 of the table on the release of IL-la by the keratinocytes NCTC2544 stimulated with SDS:
Le peptide n°l réduit d'environ 42% l'expression d'IL-lα par les kératinocytes en culture stressés par du SDS.Peptide No. 1 reduces by approximately 42% the expression of IL-1α by keratinocytes in culture stressed by SDS.
4. On détermine l'effet du peptide n°l du tableau sur l'érythème photo-induit in vivo chez l'homme.4. The effect of peptide No. 1 in the table on the photo-induced erythema in vivo in humans is determined.
Quatorze volontaires sains adultes des deux sexes, de phototypes de classes III & IV (clairs & intermédiaires) et d'Angle Typologique Individuel (ITA°) de 50 à 28° ont donné leur consentement éclairé à leur participation à l'étude.Fourteen healthy adult volunteers of both sexes, of phototypes of classes III & IV (clear & intermediate) and of Individual Typological Angle (ITA °) from 50 to 28 ° gave their informed consent to their participation in the study.
Le traitement consiste en une application topique sur la face interne de l'avant bras 2 fois /jour pendant 2 semaines à raison de 2μl/cm2 sur 75 cm2. Pendant l'étude, le bras est protégé de toute exposition solaire.The treatment consists of a topical application on the internal face of the forearm 2 times / day for 2 weeks at a rate of 2 μl / cm 2 over 75 cm 2 . During the study, the arm is protected from any sun exposure.
Le rayonnement solaire est donné par une lampe à arc xénon de 150 W et de spectre UVA & B allant de 290 à 390 nm. Six doses d'intensité lumineuse en progression géométrique de 25% sont appliquées sur les zones traitées au travers de guides de lumière liquides.The solar radiation is given by a 150 W xenon arc lamp with a UVA & B spectrum ranging from 290 to 390 nm. Six doses of light intensity in geometric progression of 25% are applied to the treated areas through liquid light guides.
Les mesures colorimétriques sont faites au Chromamètre™ CR 300. La détermination des coordonnées de chromaticité (L ; a & b*) se fait par rapport à une zone proche non irradiée. Un différentiel Δa* >2,5 permet de définir avec précision la D.E.M. 24h après le dernier traitement, les zones traitées et témoins sont irradiées par des doses croissantes d'UV calculées pour encadrer la D.E.M. de chaque individu. Après 24 h et 72 h, on procède à l'évaluation de la zone irradiée par mesures colorimétriques.The colorimetric measurements are made with the Chromameter ™ CR 300. The chromaticity coordinates (L; a & b *) are determined relative to a nearby non-irradiated area. A differential Δa *> 2.5 allows the DEM to be precisely defined 24 hours after the last treatment, the treated and control areas are irradiated with increasing doses of UV calculated to frame the DEM of each individual. After 24 h and 72 h, the irradiated area is evaluated by colorimetric measurements.
Le critère d'évaluation est la D.E.M. : la plus faible dose d'UV A&B qui provoque un érytheme.The evaluation criterion is the D.E.M. : the lowest dose of UV A&B that causes erythema.
On observe une élévation statistiquement significative de la D.E.M. avec le traitement au peptide n° 1 du tableau.There is a statistically significant increase in D.E.M. with the treatment with peptide n ° 1 of the table.
Evaluation de la D.E.M. après exposition aux UVA&B en J/cm2 Evaluation of DEM after exposure to UVA & B in J / cm 2
*Valeur statistiquement significative (L.S.D. et test "t" en séries appariées, p<0.05)* Statistically significant value (L.S.D. and "t" test in paired series, p <0.05)
L'application du peptide n°l du tableau en gel par voie topique permet d'augmenter la résistance de la peau à l'apparition d'un érytheme provoqué par une irradiation solaire excessive.The application of peptide No. 1 in the gel table topically makes it possible to increase the resistance of the skin to the appearance of an erythema caused by excessive solar irradiation.
Il apparaît donc que les peptides de l'invention ont une activité antiinflammatoire, anti-allergique et mélanotrope.It therefore appears that the peptides of the invention have anti-inflammatory, anti-allergic and melanotropic activity.
Les peptides de l'invention peuvent donc être utilisés pour la préparation de médicaments destinés à traiter les allergies notamment cutanées, les réactions inflammatoires et les troubles de la mélanogénèse. Ces médicaments trouvent ainsi leur emploi en thérapeutique notamment dans la prévention et/ou le traitement de la dermatite atopique, le psoriasis, le vitiligo, l'érythème et en particulier l'érythème photo induit, les alopécies inflammatoires, l'eczéma et l'asthme.The peptides of the invention can therefore be used for the preparation of medicaments intended for treating allergies, in particular cutaneous, inflammatory reactions and disorders of melanogenesis. These drugs thus find their use in therapy in particular in the prevention and / or treatment of atopic dermatitis, psoriasis, vitiligo, erythema and in particular photo-induced erythema, inflammatory alopecia, eczema and asthma.
Selon un autre de ses aspects, la présente invention concerne des compositions pharmaceutiques renfermant en tant que principe actif, un peptide selon l'invention. Ces compositions pharmaceutiques peuvent notamment être adaptées à une application locale sur la peau et les muqueuses.According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a peptide according to the invention. These pharmaceutical compositions can in particular be adapted to a local application on the skin and the mucous membranes.
Ainsi, ces compositions pharmaceutiques contiennent une dose efficace d'un peptide selon l'invention, et un ou plusieurs excipients pharmaceutiques convenables.Thus, these pharmaceutical compositions contain an effective dose of a peptide according to the invention, and one or more suitable pharmaceutical excipients.
Les dits excipients sont choisis selon la forme pharmaceutique et le mode d'administration souhaité.Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.
Dans les compositions pharmaceutiques de la présente invention pour l'administration orale, sublinguale, sous-cutanée, intramusculaire, intra-veineuse, topique, intratrachéale, intranasale, transdermique (patch) ou rectale, le principe actif de formule (I) ci-dessus son sel ou hydrate éventuel, peut être administré sous forme unitaire d'administration, en mélange avec des excipients pharmaceutiques classiques, aux animaux et aux êtres humains pour la prophylaxie ou le traitement des troubles ou des maladies ci-dessus. Les formes unitaires d'administration appropriées comprennent les formes par voie orale telles que les comprimés, les gélules, les poudres, les granules et les solutions ou suspensions orales, les formes d'administration sublinguale, buccale, intratrachéale, intranasale, les formes d'administration sous-cutanée, intramusculaire ou intraveineuse et les formes d'administration rectale. Pour l'application topique, on peut utiliser les composés selon l'invention dans des crèmes, pommades, aérosols liquides ou pulvérisés (sprays), gels, lotions et patchs.In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal (patch) or rectal administration, the active principle of formula (I) above its optional salt or hydrate can be administered in unit administration form, in mixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intranasal administration forms, subcutaneous, intramuscular or intravenous administration and forms of rectal administration. For topical application, the compounds according to the invention can be used in creams, ointments, liquid or spray aerosols (sprays), gels, lotions and patches.
Quelle que soit la voie, la dose de principe actif administrée par jour peut atteindre 0,5 mg/kg, en une ou plusieurs prises.Whatever the route, the dose of active ingredient administered per day can reach 0.5 mg / kg, in one or more doses.
Il peut y avoir des cas particuliers où des dosages plus élevés ou plus faibles sont appropriés, de tels dosages appartiennent également à l'invention. Selon la pratique habituelle, le dosage approprié à chaque patient est déterminé par le médecin selon le mode d'administration, le poids et la réponse dudit patient. Lorsqu'on prépare une composition solide sous forme de comprimés, on mélange l'ingrédient actif principal avec un excipient pharmaceutique, tel que la gélatine, l'amidon, le lactose, le stéarate de magnésium, le talc, la gomme arabique ou analogues. On peut enrober les comprimés de saccharose, d'un dérivé cellulosique, ou d'autres matières. Les comprimés peuvent être réalisés par différentes techniques, compression directe, granulation sèche, granulation humide ou fusion à chaud.There may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention. According to usual practice, the appropriate dosage for each patient is determined by the doctor according to the method of administration, the weight and the response of said patient. When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical excipient, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative, or other materials. The tablets can be produced by different techniques, direct compression, dry granulation, wet granulation or hot melting.
On obtient une préparation en gélules en mélangeant l'ingrédient actif avec un diluant et en versant le mélange obtenu dans des gélules molles ou dures.A preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.
Pour une administration parentérale, on peut utiliser des suspensions aqueuses, des solutions salines isotoniques ou des solutions stériles et injectables qui contiennent des agents de dispersion et/ou des mouillants pharmacologiquement compatibles, par exemple le propylèneglycol ou le butylèneglycol.For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol, may be used.
La présente invention selon un autre de ses aspects, concerne également une méthode de traitement des pathologies ci-dessus indiquées qui comprend l'administration d'un peptide selon l'invention ou un de ses sels pharmaceutiquement acceptables.The present invention according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration of a peptide according to the invention or one of its pharmaceutically acceptable salts.
Une composition cosmétique comprenant un composé de formule (I) pouvant être administré par voie muqueuse ou topique fait également partie de l'invention ainsi que l'utilisation d'un composé de formule (I) pour la préparation d'un produit cosmétique ayant un effet mélanotrope.A cosmetic composition comprising a compound of formula (I) which can be administered by mucous or topical route also forms part of the invention as well as the use of a compound of formula (I) for the preparation of a cosmetic product having a melanotropic effect.
Selon un dernier aspect, l'invention a pour objet des compositions dermo- cosmétiques comprenant un peptide de formule (I) selon l'invention pour application topique pouvant prendre la forme de solutions, lotions, émulsions, aérosols liquides ou pulvérisés (sprays), gels ou de crèmes utilisables en particulier comme préparateur de la peau aux expositions solaires, accélérateur de bronzage recolorant des cheveux blancs, apaisant cutané, anti-érythémateux. Il doit être entendu que les compositions pharmaceutiques, produits cosmétiques ou compositions dermocosmétiques objets de l'invention tels que décrits ci-dessus contenant des mélanges de peptides selon l'invention font également partie de l'invention.According to a last aspect, the subject of the invention is dermocosmetic compositions comprising a peptide of formula (I) according to the invention for topical application which can take the form of solutions, lotions, emulsions, liquid or spray aerosols (sprays), gels or creams that can be used in particular as a skin preparation agent for sun exposure, a tanning accelerator recolouring white hair, skin soothing, anti-erythematosus. It should be understood that the pharmaceutical compositions, cosmetic products or dermocosmetic compositions which are the subject of the invention as described above containing mixtures of peptides according to the invention also form part of the invention.
5. Effet de la stimulation de cellules SAEC1 de sujets normaux, ou de cellules polynucléaires neutrophiles et monocytes de patients atteints d'asthme sévère, cortico dépendants, par le peptide n° 1 comparé à la dexaméthasone : a) Cellules épithéliales : . SAEC (cellules épithéliales humaines primaires en culture) origine : petites bronches de sujets normaux,5. Effect of stimulation of SAEC 1 cells of normal subjects, or of neutrophilic polynuclear cells and monocytes of patients with severe, cortico-dependent asthma, by peptide No. 1 compared to dexamethasone: a) Epithelial cells:. SAEC (primary human epithelial cells in culture) origin: small bronchi of normal subjects,
. Expansion sur flasque, trypsinisation et mise en puits (plaque de 48 puits),. Expansion on flange, trypsinization and well setting (48-well plate),
. A confluence, incubation 24 h. en puits,. At confluence, 24 h incubation. well,
. Non stimulé, + TNFalpha (25ng/ml) + peptide N° 1 du tableau de 10"5M à 10"8M + Dexaméthasone 10"7M. Unstimulated, + TNFalpha (25ng / ml) + peptide N ° 1 from the table from 10 "5 M to 10 " 8 M + Dexamethasone 10 "7 M
. Récupération des surnageants, stock -20°C,. Recovery of supernatants, stock -20 ° C,
. Dosage de l'IL-8 par KIT ELISA.. Assay of IL-8 by KIT ELISA.
L'effet de la stimulation de cellules SAEC par le peptide n° 1 est représenté à la figure 2 (NS = non stimulé, DEX = Dexaméthasone).The effect of stimulation of SAEC cells by peptide No. 1 is shown in FIG. 2 (NS = unstimulated, DEX = Dexamethasone).
b) 8 patients atteints d'asthme sévère, cortico dépendants : . Sang héparine : 30 ml,b) 8 patients with severe asthma, corticosteroid dependent:. Heparin blood: 30 ml,
. Séparation sur gradient de Percoll (62-72%),. Separation on Percoll gradient (62-72%),
. Monocytes et neutrophiles >95% viabilité >99%, . Cellules reprises et lavées dans RPMI,. Monocytes and neutrophils> 95% viability> 99%,. Cells taken up and washed in RPMI,
. 107 cellules/ml, incubation 24 h en puits,. 107 cells / ml, 24 h incubation in a well,
. Non stimulé, + peptide N° 1 du tableau de 10"6M à 10"8M + Dexaméthasone. Unstimulated, + peptide N ° 1 from the table from 10 "6 M to 10 " 8 M + Dexamethasone
10"7M,10 "7 M,
. Récupération des surnageants, stock -20°C, . Dosage de l'IL-8 par KIT ELISA. L'effet de la stimulation de monocytes cortico dépendants (CD) par le peptide n° 1 est représenté à la figure 3 (NS = non stimulé, DEX = Dexaméthasone).. Recovery of supernatants, stock -20 ° C,. Assay of IL-8 by KIT ELISA. The effect of the stimulation of cortico-dependent monocytes (CD) by peptide No. 1 is represented in FIG. 3 (NS = unstimulated, DEX = Dexamethasone).
L'effet de la stimulation de polynucléaires neutrophiles cortico dépendants (CD) par le peptide n° 1 est représenté à la figure 4 (NS = non stimulé, DEX = Dexaméthasone).The effect of the stimulation of corticosteroid-dependent neutrophils (CD) by peptide No. 1 is represented in FIG. 4 (NS = unstimulated, DEX = Dexamethasone).
Ces résultats nous montrent que l'activité du peptide n° 1 du tableau est 10 fois supérieure à celle de la Dexaméthasone.These results show that the activity of peptide No. 1 in the table is 10 times greater than that of Dexamethasone.
1 SAEC: Small Airway Epithelial Cells 1 SAEC: Small Airway Epithelial Cells

Claims

Revendications claims
1. Peptide répondant à la formule (I)1. Peptide corresponding to formula (I)
R-V1-Ala2-His3-X4-Y5-Tφ6-NH2 (I)RV 1 -Ala 2 -His 3 -X 4 -Y 5 -Tφ 6 -NH 2 (I)
dans laquellein which
R représente un atome d'hydrogène ou un groupe protecteur pouvant être choisi parmi un groupe acétyle, un groupe benzoyle, un groupe tosyle, un groupe benzène sulfonyle un groupe benzyloxycarbonyle ou un groupe pyridinepropionyle, V représente un acide aminé naturel ou non, de configuration L, choisi parmi la norleucine, la norvaline et la 2-N-Me-norleucine.R represents a hydrogen atom or a protective group which can be chosen from an acetyl group, a benzoyl group, a tosyl group, a benzene sulfonyl group, a benzyloxycarbonyl group or a pyridinepropionyl group, V represents a natural or unnatural amino acid, of configuration L, chosen from norleucine, norvaline and 2-N-Me-norleucine.
X représente un acide aminé naturel ou non, de configuration L ou D, à caractère aromatique choisi parmi phenylalanine, 1 -naphtylalanine, 2-naphtylalanine, phenylglycine, benzothienylalanine, 4,4'-biphénylalanine, 3,3-diphénylalanine, homophénylalanine, indanylglycine, 4-méthylphénylalanine, thienylalanine, p-nitro- phénylalanine, halogenophenylalanine où l'halogène peut être un atome de chlore, de brome, d'iode ou de fluor en meta, ortho ou para du groupe phényle.X represents a natural or unnatural amino acid, of L or D configuration, with aromatic character chosen from phenylalanine, 1 -naphthylalanine, 2-naphthylalanine, phenylglycine, benzothienylalanine, 4,4'-biphenylalanine, 3,3-diphenylalanine, homophenylalanine, indanylglycine , 4-methylphenylalanine, thienylalanine, p-nitro-phenylalanine, halogenophenylalanine where the halogen can be a chlorine, bromine, iodine or fluorine atom in meta, ortho or para of the phenyl group.
Y représente un acide aminé naturel de configuration L, à caractère basique choisi parmi l'arginine, la lysine ou l'ornithine, leurs énantiomères ou diastéréoisomères, ainsi que leurs mélanges, y compris les mélanges racémiques, les acides aminés Ala, His et Trp respectivement aux positions 2, 3 et 6 étant de configuration L.Y represents a natural amino acid of configuration L, of basic character chosen from arginine, lysine or ornithine, their enantiomers or diastereoisomers, as well as their mixtures, including racemic mixtures, the amino acids Ala, His and Trp respectively in positions 2, 3 and 6 being of configuration L.
2. Composé de formule (I) selon la revendication 1, caractérisé en ce que R représente un groupe protecteur pouvant être choisi parmi un groupe acétyle, un groupe benzène sulfonyle ou un groupe pyridinepropionyle,2. Compound of formula (I) according to claim 1, characterized in that R represents a protective group which can be chosen from an acetyl group, a benzene sulfonyl group or a pyridinepropionyl group,
V représente un acide aminé naturel ou non de configuration L, choisi parmi la norleucine et la 2-N-Me-norleucine.V represents a natural amino acid or not of configuration L, chosen from norleucine and 2-N-Me-norleucine.
X représente un acide aminé naturel ou non, de configuration D ou L, à caractère aromatique choisi parmi phenylalanine, 2-naphtylalanine, homophénylalanine, thienylalanine ou p-nitro-phénylalanine. Y représente un acide aminé naturel de configuration L, à caractère basique choisi parmi arginine ou lysine, leurs énantiomères ou diastéréoisomères, ainsi que leurs mélanges, y compris les mélanges racémiques.X represents a natural or unnatural amino acid, of configuration D or L, of aromatic character chosen from phenylalanine, 2-naphthylalanine, homophenylalanine, thienylalanine or p-nitro-phenylalanine. Y represents a natural amino acid of configuration L, of basic character chosen from arginine or lysine, their enantiomers or diastereoisomers, as well as their mixtures, including racemic mixtures.
Les acides aminés Ala, His et Trp respectivement aux positions 2, 3 et 6 étant de configuration L.The amino acids Ala, His and Trp respectively at positions 2, 3 and 6 are of configuration L.
3. Composé selon la revendication 1 ou 2 , caractérisé en ce qu'il est choisi parmi3. Compound according to claim 1 or 2, characterized in that it is chosen from
- Ac-Nle-Ala-His-DPhe-Arg-Trp-NH2, - Ac-Nle-Ala-His-DPhe-Lys-Trp-NH2, - Ac-Nle-Ala-His-DThi-Arg-Trρ-NH2,- Ac-Nle-Ala-His-DPhe-Arg-Trp-NH 2 , - Ac-Nle-Ala-His-DPhe-Lys-Trp-NH 2 , - Ac-Nle-Ala-His-DThi-Arg-Trρ -NH 2 ,
- BzlSO2-Nle-Ala-His-DPhe-Arg-Trp-NH2,- BzlSO 2 -Nle-Ala-His-DPhe-Arg-Trp-NH 2 ,
- Tos-Nle-Ala-His-DPhe-Arg-Trp-NH2,- Tos-Nle-Ala-His-DPhe-Arg-Trp-NH 2 ,
- BzlSO2-Nle-Ala-His-DPhe-Lys-Trp-NH2,- BzlSO 2 -Nle-Ala-His-DPhe-Lys-Trp-NH 2 ,
- BzlSO2-Nle-Ala-His-DpNO2Phe-Lys-Trp-NH2, - BzlSO2-Nle-Ala-His-DThi-Lys-Trp-NH2,- BzlSO 2 -Nle-Ala-His-DpNO 2 Phe-Lys-Trp-NH 2 , - BzlSO 2 -Nle-Ala-His-DThi-Lys-Trp-NH 2 ,
- Ac-Nle-Ala-His-DThi-Lys-Trp-NH2, - PyrProp-Nle-Ala-His-DpNO2Phe-Lys-Trp-NH2, - PyrProp-Nle-Ala-His-DpNO2Phe-Arg-Trp-NH2, - Ac-Nle-Ala-His-L2,Nap-Lys-Trp-NH2, - Ac-MeNle-Ala-His-DhomoPhe-Arg-Trp-NH2, - Ac-Nle-Ala-His-DhomoPhe-Arg-Trp-NH2, leurs énantiomères ou diastéréoisomères, ainsi que leurs mélanges, y compris les mélanges racémiques.- Ac-Nle-Ala-His-DThi-Lys-Trp-NH 2 , - PyrProp-Nle-Ala-His-DpNO 2 Phe-Lys-Trp-NH 2 , - PyrProp-Nle-Ala-His-DpNO 2 Phe -Arg-Trp-NH 2 , - Ac-Nle-Ala-His-L2, Nap-Lys-Trp-NH 2 , - Ac-MeNle-Ala-His-DhomoPhe-Arg-Trp-NH 2 , - Ac-Nle -Ala-His-DhomoPhe-Arg-Trp-NH 2 , their enantiomers or diastereoisomers, as well as their mixtures, including racemic mixtures.
4. Procédé de préparation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 3, caractérisé en ce que l'on procède par synthèse sur support avec résine.4. Method for preparing a compound of formula (I) according to any one of claims 1 to 3, characterized in that one proceeds by synthesis on a support with resin.
5. Médicament caractérisé en ce qu'il consiste en un composé de formule (I) selon l'une quelconque des revendications 1 à 3. 5. Medicament, characterized in that it consists of a compound of formula (I) according to any one of claims 1 to 3.
6. Composition pharmaceutique, caractérisée en ce qu'elle comprend un composé de formule (I) selon l'une quelconque des revendications 1 à 3, en association avec tout excipient approprié.6. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3, in combination with any suitable excipient.
7. Produit cosmétique pour administration muqueuse ou topique, caractérisé en ce qu'il comprend un composé de formule (I) selon l'une quelconque des revendications l à 3.7. Cosmetic product for mucosal or topical administration, characterized in that it comprises a compound of formula (I) according to any one of claims l to 3.
8. Produit cosmétique à activité mélanotrope, caractérisé en ce qu'il comprend un composé de formule (I) selon l'une quelconque des revendications 1 à 3.8. Cosmetic product with melanotropic activity, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3.
9. Produit cosmétique préparateur aux expositions solaires et accélérateur de bronzage de la peau, recolorant des cheveux blancs, apaisant cutané ou anti- érythémateux, caractérisé en ce qu'il comprend un composé de formule (I) selon l'une quelconque des revendications 1 à 3.9. Cosmetic product preparing for sun exposure and accelerating tanning of the skin, recolouring white hair, soothing the skin or anti-erythematosus, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3.
10. Composition dermocosmétique pour application topique pouvant prendre la forme d'une solution, d'une lotion, d'une émulsion, d'un aérosol liquide ou pulvérisé, d'un gel, ou d'une crème, caractérisé en ce qu'elle comprend un composé de formule (I) selon l'une quelconque des revendications 1 à 3.10. Dermocosmetic composition for topical application which may take the form of a solution, a lotion, an emulsion, a liquid or spray aerosol, a gel, or a cream, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3.
11. Utilisation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 3 pour la préparation d'un médicament destiné à prévenir et/ou traiter les allergies notamment cutanées, les réactions inflammatoires et les troubles de la mélanogénèse.11. Use of a compound of formula (I) according to any one of claims 1 to 3 for the preparation of a medicament intended for preventing and / or treating allergies in particular cutaneous, inflammatory reactions and disorders of melanogenesis .
12. Utilisation d'un composé de formule (I) selon la revendication 11, caractérisée en ce que le médicament est destiné à traiter la dermatite atopique, l'eczéma, le psoriasis, le vitiligo, l'érythème et en particulier l'érythème photo induit, les alopécies inflammatoires, ou l'asthme. 12. Use of a compound of formula (I) according to claim 11, characterized in that the medicament is intended for treating atopic dermatitis, eczema, psoriasis, vitiligo, erythema and in particular erythema photo induced, inflammatory alopecia, or asthma.
13. Utilisation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 3 pour la préparation d'un produit cosmétique ayant un effet. mélanotrope et anti-érythémateux. 13. Use of a compound of formula (I) according to any one of claims 1 to 3 for the preparation of a cosmetic product having an effect. melanotropic and anti-erythematous.
EP20030717360 2002-02-01 2003-01-31 Novel peptide derivatives, preparation and therapeutic and cosmetic application thereof Withdrawn EP1470157A2 (en)

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Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9453219B2 (en) * 2003-05-15 2016-09-27 Mello Biotech Taiwan Co., Ltd. Cosmetic designs and products using intronic RNA
FR2870242B1 (en) * 2004-05-11 2010-08-20 Inst Europeen Biologie Cellulaire PEPTIDES OR PEPTIDE CONJUGATES DERIVED FROM MSH AND THEIR USE IN THE COSMETIC TREATMENT OF CANITIA.
FR2870243B1 (en) * 2004-05-11 2010-11-19 Centre Nat Rech Scient AGONIST TRIPEPTIDE CONJUGATES OF MSH
FR2870244B1 (en) * 2004-05-11 2011-01-07 Centre Nat Rech Scient ALPHA-MSH ANTAGONIST DIPEPTIDE CONJUGATES
TWI415628B (en) 2006-02-28 2013-11-21 Avon Prod Inc Compositions containing peptides with non-natural amino acids and methods of use
US8481006B2 (en) * 2008-04-25 2013-07-09 New Sunshine, Llc Melt formula
US20090269375A1 (en) * 2008-04-25 2009-10-29 Diahne Patnode Tanning compositions containing juice concentrate
WO2009151383A1 (en) * 2008-06-09 2009-12-17 Palatin Technologies, Inc. Melanocortin receptor-specific peptides for the treatment of obesity and other diseases associated with melanocortin receptor function
BRPI0909947A2 (en) 2008-06-09 2017-06-27 Palatin Technologies Inc '' cyclic peptide, pharmaceutical composition, method of treating a disease, indication, condition or syndrome mediated by melanocortin receptor in humans or non-human mammals, and, condition treatment method that reacts to changes in melanocortin receptor function in humans or nonhuman mammals ''
JP2011195451A (en) * 2008-06-20 2011-10-06 Fukuoka Univ Peptide
KR101726893B1 (en) 2009-06-08 2017-04-13 팔라틴 테크놀로지스 인코포레이티드 Melanocortin receptor-specific peptides
EP2440572B1 (en) 2009-06-08 2017-04-05 Palatin Technologies, Inc. Lactam-bridged melanocortin receptor-specific peptides
UY32690A (en) * 2009-06-08 2011-01-31 Astrazeneca Ab SPECIFIC PEPTIDES FOR MELANOCORTIN RECEPTORS
CN102712674A (en) 2009-11-23 2012-10-03 帕拉丁科技公司 Melanocortin-1 receptor-specific linear peptides
EP2504352B1 (en) 2009-11-23 2018-11-14 Palatin Technologies, Inc. Melanocortin-1 receptor-specific cyclic peptides
WO2012158960A2 (en) 2011-05-17 2012-11-22 H. Lee Moffitt Cancer Center & Research Institute, Inc. Melanocortin 1 receptor ligands and methods of use
US9290539B2 (en) 2011-05-17 2016-03-22 The Arizona Board Of Regents On Behalf Of The University Of Arizona Melanotropin ligands for skin care
FR3004927B1 (en) * 2013-04-29 2016-08-05 Oreal COMPOSITION COMPRISING AT LEAST THREE ACTIVE INGREDIENTS FOR COLORING AND / OR PIGMENTING KERATINIC MATERIALS.
KR101713127B1 (en) * 2014-05-13 2017-03-10 (주)케어젠 Peptides Having Activity for Increasing Melanin Synthesis and Inhibiting Fat Synthesis and Uses Thereof
US9821023B2 (en) 2014-06-10 2017-11-21 The Arizona Board Of Regents On Behalf Of The University Of Arizona Methods for the treatment of central nervous system (CNS) disorders and mood disorders
US9814755B2 (en) 2014-06-10 2017-11-14 The Arizona Board Of Regents On Behalf Of The University Of Arizona Methods for the treatment of depression and anxiety
US20170022252A1 (en) 2014-06-10 2017-01-26 The Arizona Board Of Regents On Behalf Of The University Of Arizona Novel modulators of melanocortin receptors
EP3088417A1 (en) * 2015-04-28 2016-11-02 Vallaurix Pte. Ltd. Pharmaceutical compound
US10550157B2 (en) 2015-10-16 2020-02-04 Arizona Board Of Regent On Behalf Of The University Of Arizona Compositions and methods for treating central nervous system (CNS) disorders and mood disorders
JP6541118B1 (en) * 2018-04-27 2019-07-10 株式会社成和化成 Cosmetic base and hair cosmetic containing the cosmetic base, skin lightening agent
TWI742389B (en) * 2019-06-21 2021-10-11 和和實業股份有限公司 Peptide for promote melanin production and the method thereof
FR3112478B1 (en) 2020-07-15 2022-12-02 France Cosmephyl Lab New compositions combining hemp derivatives and at least one peptide and their use
CN113876622A (en) * 2021-11-08 2022-01-04 广东重生药业科技有限公司 Aurora essence lotion and preparation method thereof
FR3134519A1 (en) 2022-04-14 2023-10-20 France Cosmephyl-Lab NEW COMPOSITIONS COMBINING AT LEAST ONE INORGANIC SOLAR FILTER AND THEIR USE
EP4292581A1 (en) 2022-06-16 2023-12-20 Bella Aurora Labs, S.A. Hair repigmenting composition

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002064734A2 (en) * 2000-12-19 2002-08-22 Palatin Technologies, Inc. Identification of target-specific folding sites in peptides and proteins
WO2003006620A2 (en) * 2001-07-11 2003-01-23 Palatin Technologies, Inc. Linear and cyclic melanocortin receptor-specific peptides

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5674839A (en) 1987-05-22 1997-10-07 Competitive Technologies, Inc. Cyclic analogs of alpha-MSH fragments
US5683981A (en) 1987-05-22 1997-11-04 Competitive Technologies, Inc. Cyclic bridged analogs of α-MSH and methods thereof
FR2710340B1 (en) 1993-09-22 1995-12-15 D Hinterland Lucien Dussourd Alpha-MSH peptide derivatives and their application.
US6054556A (en) 1995-04-10 2000-04-25 The Arizona Board Of Regents On Behalf Of The University Of Arizona Melanocortin receptor antagonists and agonists
FR2753707B1 (en) 1996-09-23 1998-12-11 NUCLEOPEPTIDE COMPLEXES, COSMETOLOGICAL AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND USES
DE19653736C2 (en) * 1996-12-12 2002-11-21 Lancaster Group Gmbh Cosmetic preparation with added peptide
GB9808229D0 (en) * 1998-04-17 1998-06-17 Quadrant Holdings Cambridge Melanocortin receptor ligands
FR2781157B1 (en) * 1998-07-15 2000-08-25 Oreal ANTI-INFLAMMATORY COMPOSITION
GB0012370D0 (en) * 2000-05-22 2000-07-12 Quadrant Holdings Cambridge Peptoids

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002064734A2 (en) * 2000-12-19 2002-08-22 Palatin Technologies, Inc. Identification of target-specific folding sites in peptides and proteins
WO2003006620A2 (en) * 2001-07-11 2003-01-23 Palatin Technologies, Inc. Linear and cyclic melanocortin receptor-specific peptides

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