EP2164845A1 - Novel 4-heteroaryl-imidazole-2-thiones used as tyrosinase inhibitors, method for preparing same and use thereof in human medicine and cosmetology - Google Patents

Novel 4-heteroaryl-imidazole-2-thiones used as tyrosinase inhibitors, method for preparing same and use thereof in human medicine and cosmetology

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Publication number
EP2164845A1
EP2164845A1 EP08805935A EP08805935A EP2164845A1 EP 2164845 A1 EP2164845 A1 EP 2164845A1 EP 08805935 A EP08805935 A EP 08805935A EP 08805935 A EP08805935 A EP 08805935A EP 2164845 A1 EP2164845 A1 EP 2164845A1
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Prior art keywords
thione
dihydroimidazole
general formula
compound
composition
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Application number
EP08805935A
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German (de)
French (fr)
Inventor
Jean-Guy Boiteau
Corinne Millois Barbuis
Karine Bouquet
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Galderma Research and Development SNC
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Galderma Research and Development SNC
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Publication of EP2164845A1 publication Critical patent/EP2164845A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to novel 4-heteroarylimidazole-2-thiones compounds as industrial and useful products. It also relates to their process of preparation and their use, as inhibitors of tyrosinase, in pharmaceutical or cosmetic compositions intended for the treatment or prevention of pigment disorders.
  • the pigmentation of the skin results from the synthesis of melanin by dendritic cells, melanocytes.
  • Melanocytes contain organelles called melanosomes that transfer melanin into the upper layers of keratinocytes that are then transported to the surface of the skin by differentiation of the epidermis.
  • tyrosinase is a key enzyme that catalyzes the first two steps of melanin synthesis. Homozygous tyrosinase mutations cause type I oculocutaneous albinism characterized by a complete absence of melanin synthesis.
  • heteroaryl-imidazole-2-thiones derivatives some have been described as having anti-inflammatory properties (S. maeda, M. suzuki, T. Iwasaki, K. Matsumoto, Y. Iwazawa, Chem Pharm.Bull 1984, 32, 7, 2536-2543).
  • Patent JP05132422 discloses the use of certain imidazole-2-thiones as a tyrosinase inhibitor. However, no derivative of imidazole-2-thiones substituted at 4 with a heteroaryl is described in this document. No tyrosinase inhibitory activity is shown for 4-heteroaryl-imidazole-2-thione compounds.
  • X is an oxygen atom or a sulfur atom
  • a C 1 -C 7 alkyl radical a C 3 -C 7 cycloalkyl radical, one of the ring carbon atoms possibly being replaced by an oxygen atom or sulfur atom;
  • R1 and R2 which are identical or different, are chosen from:
  • a C 1 -C 7 alkyl radical a C 3 -C 7 cycloalkyl radical, one of the ring carbon atoms possibly being replaced by an oxygen or sulfur atom;
  • R 1 and R 2 may form a hydrocarbon ring of 5 or 6 carbon atoms, as well as their salts and tautomeric forms.
  • the present invention also relates to the use of the compounds of formula (I), their salts or their tautomeric forms for the preparation of a pharmaceutical composition intended for the treatment or prevention of hyperpigmentary disorders.
  • salts of the compounds of general formula (I) with a pharmaceutically acceptable acid there may be mentioned preferably the salts with an organic acid or with an inorganic acid.
  • Suitable inorganic acids are, for example, hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid.
  • suitable organic acids are picric acid, methanesulfonic acid, ethanesulfonic acid and trifluoromethanesulfonic acid.
  • the compounds of general formula (I) may also exist in the form of hydrates or solvates with water or with a solvent.
  • Suitable solvents for forming solvates or hydrates are, for example, alcohols such as ethanol or isopropanol or water.
  • heterocyclic radical of the compounds according to the invention of general formula (II):
  • C3-C7 cycloalkyl denotes a saturated, cyclic hydrocarbon-based chain comprising from 3 to 7 carbon atoms.
  • the C 3 -C 7 cycloalkyl radical is chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radicals.
  • C1-C7 alkyl denotes a saturated hydrocarbon chain, linear or branched, comprising from 1 to 7 carbon atoms.
  • the C 1 -C 7 alkyl radical is chosen from methyl, ethyl, propyl, i-propyl, butyl, t-butyl, pentyl, hexyl and heptyl radicals.
  • C1-C4 alkyl denotes a saturated hydrocarbon chain, linear or branched, comprising from 1 to 4 carbon atoms.
  • the C 1 -C 4 alkyl radical is chosen from methyl, ethyl, propyl, i-propyl, butyl and t-butyl radicals.
  • C 4 -C 9 cycloalkylalkyl denotes a saturated hydrocarbon chain, linear or branched, substituted by a cycloalkyl radical and comprising from 4 to 9 carbon atoms.
  • the C 4 -C 9 cycloalkylalkyl radical is chosen from cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl and cyclohexylethyl radicals.
  • C1-C4 alkoxycarbonyl denotes a carboxy radical substituted by a linear or branched saturated hydrocarbon-based chain containing from 1 to 4 carbon atoms.
  • the C1-C4 alkoxycarbonyl radical is chosen from the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl radicals.
  • C1-C6 alkoxycarbonyl denotes a carboxy radical substituted by a linear or branched saturated hydrocarbon-based chain comprising from 1 to 6 carbon atoms.
  • the C1-C6 alkoxy radical is chosen from methoxy, ethoxy, propoxy, butoxy, pentoxy and hexyloxy radicals.
  • the compounds of general formula (I) that are particularly preferred are those for which:
  • R1 represents a hydrogen
  • R2 represents a C1-C7 alkyl radical or a C3-C7 cycloalkyl radical.
  • the compounds of general formula (I) that are particularly preferred are those for which the heterocyclic radical of general formula (II) represents a thiophene of general formula (IIa).
  • Step a the commercial heterocycles (1) are acetylated according to the conventional synthesis conditions, for example in the presence of acetic anhydride and phosphoric acid, to yield the methyl ketones (2) (Kotha, S. Kashinath, D. Lahiri Sunoj, RB, Eur J Org Chem 2004, (19), 4003-4013).
  • Step b The alpha bromo ketones of the general formula (3)
  • methyl ketones (2) are commercially available or can be prepared from methyl ketones (2) according to conventional methods of synthesis, for example by the action of dibroma in a solvent such as dichloromethane (Laufer, S .; Striegel, H. -G .; Neher, K. Zechmeister, P., Donat, C., Stolingwa, K .; Baur, S., Tries, S. Kammermeier, T., Dannhardt, G. Kiefer, W, Arch Pharm 1997, 330 (9), 307; -312)
  • a solvent such as dichloromethane
  • Step c the alpha bromo ketones (3) are reacted with sodium diformamide for example in acetonitrile (Yinglin, H. Hongwen, H. Synthesis, 1990, 615) to give after hydrolysis of the reaction crude with acid hydrochloric acid for example (Ying-Lin, H., Hong-Wen, HH, Tetrahedron Lett, 1989, 30, 5285) hydrochlorides of acyl amines of general formula (4).
  • Step d a cyclization reaction of the compounds of general formula (4) with potassium thiocyanate makes it possible to obtain the imidazole-2-thiones of general formula (I) (Mor, M .; Bordi, F .; Silva, C, Rivara, S., Crivori, P., Plazzi, PV, Ballabeni, V., Caretta, A., Barocelli, E., Impicciatore, Carrupt, P., A., Testa, BJ Med. Chem 1997; 40 (16); 2571-2578.)
  • the compounds of the present invention have a value of IC 50 (dose inhibiting 50% of the enzymatic activity) with respect to tyrosinase less than or equal to 10 ⁇ M and more particularly less than or equal to 1 ⁇ M .
  • the invention therefore relates to the use of at least one compound of general formula (I) as defined above for the preparation of a pharmaceutical or cosmetic composition in which said compound has a tyrosinase inhibitory activity.
  • the invention also relates to a product chosen from compounds of formula (I) for its use in the treatment and / or prevention of pigment disorders.
  • the invention also relates to a method of therapeutic or cosmetic treatment, comprising the administration of a pharmaceutical or cosmetic composition comprising said compound, as a tyrosinase inhibitor.
  • the invention also relates to the use of a compound of general formula (I) as defined above for the preparation of a medicament for the treatment of pigment disorders, especially hyperpigmentary disorders.
  • the compounds used according to the invention are particularly suitable for the treatment and the prevention of pigmentary disorders such as melasma, chloasma, lentigines, senile lentigo, irregular hyperpigmentations related to photo aging, freckles, post inflammatory hyperpigmentations due to abrasion or burn or scarring or dermatitis or contact allergy, Nevis, hyperpigmentations with genetic determinism, hyperpigmentations of metabolic or medicinal origin, melanomas or any other hyperpigmentary lesion.
  • pigmentary disorders such as melasma, chloasma, lentigines, senile lentigo, irregular hyperpigmentations related to photo aging, freckles, post inflammatory hyperpigmentations due to abrasion or burn or scarring or dermatitis or contact allergy, Nevis, hyperpigmentations with genetic determinism, hyperpigmentations of metabolic or medicinal origin, melanomas or any other hyperpigmentary lesion.
  • the subject of the present invention is also a pharmaceutical composition intended in particular for the treatment of the abovementioned conditions, which comprises, in a pharmaceutically acceptable carrier and compatible with the mode of administration chosen for the latter, at least one compound of general formula (I) under one of its tautomeric forms, or a salt thereof with a pharmaceutically acceptable acid.
  • pharmaceutically acceptable carrier is meant a medium compatible with the skin, mucous membranes and integuments.
  • composition according to the invention can be carried out topically.
  • the pharmaceutical composition is packaged in a form suitable for topical application. Topically, it is meant to be administered on the skin or mucous membranes.
  • the pharmaceutical composition according to the invention is more particularly intended for the treatment of the skin and mucous membranes and may be in liquid, pasty or solid form, and more particularly in the form of ointments, creams, milks , ointments, powders, soaked swabs, syndets, solutions, gels, sprays, mousses, suspensions, sticks, shampoos, or washing bases. It may also be in the form of suspensions of microspheres or nanospheres or lipid or polymeric vesicles or polymeric or gelled patches allowing controlled release.
  • the compositions used for a topical application have a concentration of compound according to the invention generally between 0.001% and 10% by weight, preferably between 0.01% and 5% by weight, relative to the total weight of the composition. .
  • the compounds of general formula (I) according to the invention also find application in the cosmetics field, in particular in the protection against the harmful aspects of the sun, for preventing and / or for combating photo-induced or chronological aging of the skin. skin and integuments.
  • the invention therefore also relates to a cosmetic composition
  • a cosmetic composition comprising, in a cosmetically acceptable support, at least one compound of general formula (I).
  • cosmetically acceptable carrier is meant a medium compatible with the skin, mucous membranes and integuments.
  • the subject of the invention is also the cosmetic use of a compound of formula (I) or of a composition comprising at least one compound of general formula (I) for preventing and / or treating the signs of skin aging.
  • the subject of the invention is also the cosmetic use of a compound of formula (I) or of a composition comprising at least one compound of general formula (I) for body or hair hygiene.
  • the cosmetic composition according to the invention containing, in a cosmetically acceptable support, a compound of general formula (I), or one of its tautomeric forms or a salt thereof with a pharmaceutically acceptable acid, can in particular be in the form of a cream, a milk, a gel, suspensions of microspheres or nanospheres or lipid or polymeric vesicles, soaked swabs, solutions, sprays, foams, sticks, soaps, washing bases or shampoos.
  • the concentration of compound of general formula (I) in the cosmetic composition is preferably between 0.001% and 3% by weight, relative to the total weight of the composition.
  • the pharmaceutical and cosmetic compositions as described above may also contain inert additives, or even pharmacodynamically active additives for pharmaceutical compositions, or combinations of these additives, and in particular:
  • UV-A and UV-B filters antioxidants, such as ⁇ -tocopherol, butylhydroxyanisole or butylhydroxytoluene, superoxide dismutase, ubiquinol;
  • moisturizing agents such as glycerol, PEG 400, thiamorpholinone, and its derivatives or urea; antiseborrhoeic or antiacne agents, such as S-carboxymethylcysteine, S-benzylcysteamine, their salts or their derivatives, or benzoyl peroxide.
  • the residue is filtered on a silica eluting patch: 20% ethyl acetate and 80% heptane. 8 g of a brown oil are obtained.
  • the preceding oil is dissolved in 24 mL of tetrahydrofuran and cooled to 0 ° C. 0.84 mL of diethyl phosphite and 0.92 mL of thethylamine are added to the reaction mixture. The mixture is stirred for 1 hour at 0 ° C. and then for 4 hours at room temperature.
  • the reaction medium is poured into 200 ml of ice-water and then extracted with 200 ml of ethyl acetate.
  • Example 3 4- (5-methylthiophen-2-yl) -1,3-dihydroimidazole-2-thione 1 H NMR (DMSO 400 MHz.): 2.41 (s, 3H, CH 3); 6.72 (s, 1H, CH); 6.91 (s, 1H, CH);
  • Inhibitor activity is measured from a B16F1 cell lysate (murine melanoma line).
  • the tyrosinase present in these cells catalyzes the hydroxylation of L-tyrosine to L-DOPA and then the oxidation of L-DOPA to dopaquinone.
  • MBTH 3-methyl-2-benzothiazolinone hydrazone
  • dopaquinone is trapped to form a pink complex which absorbs at 520 nm.
  • the B16F1 cells are cultured in DMEM medium + 10% fetal calf serum + 10 -9 M ⁇ MSH for 4 days at 37 ° C. under 7% CO 2 .
  • the plate is incubated at 37 ° C. and a spectrophotometric reading is carried out at 520 nm after 6 hours of incubation. To overcome any absorption of the products, one works in corrected absorbance (absorbance at time 6h - absorbance at time zero).
  • Inhibitors are tested in dose response to calculate an IC50 (inhibiting dose

Abstract

The invention relates to novel 4-heteroaryl-imidazole-2-thiones compounds of the following general formula (I), to compositions containing the same, to a method for preparing the same and to the use thereof in pharmaceutical or cosmetic compositions for treating or preventing pigment disorders.

Description

Nouveaux 4-héteroaryl-imidazole-2-thiones comme inhibiteurs de la tyrosinase, leur procédé de préparation et leur utilisation en médecine humaine ainsi qu'en cosmétique Novel 4-heteroarylimidazole-2-thiones as tyrosinase inhibitors, process for their preparation and their use in human medicine and cosmetics
L'invention se rapporte à de nouveaux composés 4-hetéroaryl-imidazole-2-thiones à titre de produits industriels et utiles. Elle se rapporte également à leur procédé de préparation et à leur utilisation, en tant qu'inhibiteurs de la tyrosinase, dans des compositions pharmaceutiques ou cosmétiques destinées au traitement ou à la prévention des désordres pigmentaires.The invention relates to novel 4-heteroarylimidazole-2-thiones compounds as industrial and useful products. It also relates to their process of preparation and their use, as inhibitors of tyrosinase, in pharmaceutical or cosmetic compositions intended for the treatment or prevention of pigment disorders.
La pigmentation de la peau, notamment humaine, résulte de la synthèse de mélanine par les cellules dendritiques, les mélanocytes. Les mélanocytes contiennent des organelles appelés mélanosomes qui transfèrent la mélanine dans les couches supérieures de kératinocytes qui sont alors transportés à la surface de la peau par la différentiation de l'épiderme.The pigmentation of the skin, especially human skin, results from the synthesis of melanin by dendritic cells, melanocytes. Melanocytes contain organelles called melanosomes that transfer melanin into the upper layers of keratinocytes that are then transported to the surface of the skin by differentiation of the epidermis.
Parmi les enzymes de la mélanogenèse, la tyrosinase est une enzyme clé qui catalyse les deux premières étapes de la synthèse de mélanine. Des mutations homozygotes de la tyrosinase provoquent un albinisme oculocutané de type I caractérisé par une totale absence de synthèse de mélanine.Among the enzymes of melanogenesis, tyrosinase is a key enzyme that catalyzes the first two steps of melanin synthesis. Homozygous tyrosinase mutations cause type I oculocutaneous albinism characterized by a complete absence of melanin synthesis.
Pour traiter les désordres de la pigmentation résultant d'un accroissement de la production de mélanine pour lesquels il n'existe pas de traitement répondant à toutes les attentes des patients et des dermatologues il s'avère important de développer de nouvelles approches thérapeutiquesTo treat pigmentation disorders resulting from an increase in melanin production for which there is no treatment that meets all the expectations of patients and dermatologists, it is important to develop new therapeutic approaches.
La plupart des composés éclaircissants de la peau déjà connus sont des phénols/catéchols. Ces composés inhibent la tyrosinase mais la majorité d'entre eux sont cytotoxiques pour les mélanocytes par suite de phénomène d'oxydation conduisant à la formation de quinones responsables de cette toxicité. Cet effet toxique risque de provoquer une dépigmentation permanente de la peau.Most skin lightening compounds already known are phenols / catechols. These compounds inhibit tyrosinase but the majority of them are cytotoxic for melanocytes as a result of oxidation phenomenon leading to the formation of quinones responsible for this toxicity. This toxic effect may cause permanent depigmentation of the skin.
Or, la Demanderesse a maintenant découvert de manière inattendue et surprenante que de nouveaux composés de structure 4-heteroaryl-imidazole-2-thione présentent une très bonne activité inhibitrice de l'enzyme tyrosinase et une très faible cytotoxicité.However, the Applicant has now unexpectedly and surprisingly discovered that new compounds of 4-heteroaryl-imidazole-2-thione structure have very good inhibitory activity of tyrosinase enzyme and very low cytotoxicity.
Ces composés trouvent des applications en médecine humaine, notamment en dermatologie, et dans le domaine de la cosmétique.These compounds find applications in human medicine, especially in dermatology, and in the field of cosmetics.
Parmi les dérivés heteroaryl-imidazole-2-thiones déjà connus, certains ont été décrits comme ayant des propriétés anti-inflammatoires (S. maeda, M. suzuki, T. Iwasaki, K. Matsumoto, Y. Iwazawa, Chem. Pharm. Bull. 1984, 32, 7, 2536-2543).Of the previously known heteroaryl-imidazole-2-thiones derivatives, some have been described as having anti-inflammatory properties (S. maeda, M. suzuki, T. Iwasaki, K. Matsumoto, Y. Iwazawa, Chem Pharm.Bull 1984, 32, 7, 2536-2543).
Le brevet JP05132422 divulgue l'utilisation de certains imidazole-2-thiones comme inhibiteur de la tyrosinase. Toutefois, aucun dérivé d'imidazole-2-thiones substitué en 4 par un heteroaryle n'est décrit dans ce document. Aucune activité inhibitrice de la tyrosinase n'est montrée pour des composés de structure 4-heteroaryle-imidazole-2- thione.Patent JP05132422 discloses the use of certain imidazole-2-thiones as a tyrosinase inhibitor. However, no derivative of imidazole-2-thiones substituted at 4 with a heteroaryl is described in this document. No tyrosinase inhibitory activity is shown for 4-heteroaryl-imidazole-2-thione compounds.
Or, la demanderesse a trouvé de façon inattendue et surprenante que certains composés de structure 4-heteroaryl-imidazole-2-thione, objet de la présente invention, présentent une activité inhibitrice de la tyrosinase largement supérieure à celle des composés du brevet JP05132422.However, the Applicant has unexpectedly and surprisingly found that certain compounds of structure 4-heteroaryl-imidazole-2-thione, object of the present invention, have a tyrosinase inhibitory activity much greater than that of the compounds of Patent JP05132422.
Ainsi, la présente invention concerne des composés de formule générale (I) suivante :Thus, the present invention relates to compounds of general formula (I) below:
dans laquelle :in which :
X est un atome d'oxygène ou un atome de soufre,X is an oxygen atom or a sulfur atom,
Y est un atome de carbone ou un atome d'azote, lorsque R2=H, alors R1 représente :Y is a carbon atom or a nitrogen atom, when R2 = H, then R1 represents:
- un radical alkyle en C1 -C7, - un radical cycloalkyle en C3-C7, un des atomes de carbone du cycle pouvant éventuellement être remplacé par un atome d'oxygène, ou de soufre,a C 1 -C 7 alkyl radical; a C 3 -C 7 cycloalkyl radical, one of the ring carbon atoms possibly being replaced by an oxygen atom or sulfur atom;
- un radical cycloalkylalkyle en C4-C9,a C 4 -C 9 cycloalkylalkyl radical,
- un carboxy,a carboxy,
- un alkoxy C1 -C6 carbonyle, ou - un radical akyle en C1 -C4 substitué par un alkoxy C1 -C4 carbonyle,a C1 -C6 alkoxycarbonyl, or a C1 -C4 alkyl radical substituted with a C1 -C4 alkoxycarbonyl,
et lorsque R2 est différent d'un atome d'hydrogène, alors R1 et R2, identiques ou différents, sont choisis parmi :and when R2 is different from a hydrogen atom, then R1 and R2, which are identical or different, are chosen from:
- un radical alkyle en C1 -C7, - un radical cycloalkyle en C3-C7, un des atomes de carbone du cycle pouvant éventuellement être remplacé par un atome d'oxygène ou de soufre,a C 1 -C 7 alkyl radical; a C 3 -C 7 cycloalkyl radical, one of the ring carbon atoms possibly being replaced by an oxygen or sulfur atom;
- un radical cycloalkylalkyle en C4-C9,a C 4 -C 9 cycloalkylalkyl radical,
- un carboxy,a carboxy,
- un alkoxy C1 -C6 carbonyle, ou - un radical akyle en C1 -C4 substitué par un alkoxy C1 -C4 carbonyle,a C1 -C6 alkoxycarbonyl, or a C1 -C4 alkyl radical substituted with a C1 -C4 alkoxycarbonyl,
et lorsque R2 est en position ortho par rapport à R1 , alors R1 et R2 peuvent former un cycle hydrocarboné à 5 ou 6 atomes de carbone, ainsi que leurs sels et formes tautomères.and when R 2 is ortho to R 1, then R 1 and R 2 may form a hydrocarbon ring of 5 or 6 carbon atoms, as well as their salts and tautomeric forms.
La présente invention concerne également l'utilisation des composés de formule (I), de leurs sels ou de leurs formes tautomères pour la préparation d'une composition pharmaceutique destinée au traitement ou à la prévention des désordres hyperpigmentaires.The present invention also relates to the use of the compounds of formula (I), their salts or their tautomeric forms for the preparation of a pharmaceutical composition intended for the treatment or prevention of hyperpigmentary disorders.
Les formes tautomères peuvent être représentées de la manière suivante : The tautomeric forms can be represented as follows:
(I) (la) (Ib)(I) (la) (Ib)
Parmi les sels d'addition des composés de formule générale (I) avec un acide pharmaceutiquement acceptable, on peut citer de préférence les sels avec un acide organique ou avec un acide inorganique.Among the addition salts of the compounds of general formula (I) with a pharmaceutically acceptable acid, there may be mentioned preferably the salts with an organic acid or with an inorganic acid.
Les acides inorganiques appropriés sont par exemple les acides halohydriques comme l'acide chlorhydrique ou l'acide bromhydrique, l'acide sulfurique, l'acide nitrique. Les acides organiques appropriés sont par exemple l'acide picrique, l'acide méthane sulfonique, l'acide éthane sulfonique, l'acide trifluorométhane-sulfonique.Suitable inorganic acids are, for example, hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid. Examples of suitable organic acids are picric acid, methanesulfonic acid, ethanesulfonic acid and trifluoromethanesulfonic acid.
Les composés de formule générale (I) peuvent également exister sous formes d'hydrates ou de solvates avec de l'eau ou avec un solvant. Les solvants appropriés pour former des solvates ou des hydrates sont par exemple les alcools comme l'éthanol ou l'isopropanol ou l'eau.The compounds of general formula (I) may also exist in the form of hydrates or solvates with water or with a solvent. Suitable solvents for forming solvates or hydrates are, for example, alcohols such as ethanol or isopropanol or water.
Selon la présente invention, le radical hétérocyclique des composés selon l'invention, de formule générale (II) :According to the present invention, the heterocyclic radical of the compounds according to the invention, of general formula (II):
est choisi parmi les hétérocycles suivants : is selected from the following heterocycles:
Selon la présente invention, on désigne par cycloalkyle en C3-C7 une chaîne hydrocarbonée saturée, cyclique, comprenant de 3 à 7 atomes de carbone. De préférence, le radical cycloalkyle en C3-C7 est choisi parmi les radicaux cyclopropyle, cyclobutyle, cyclopentyle, cyclohexyle et cycloheptyle.According to the present invention, the term C3-C7 cycloalkyl denotes a saturated, cyclic hydrocarbon-based chain comprising from 3 to 7 carbon atoms. Preferably, the C 3 -C 7 cycloalkyl radical is chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radicals.
Selon la présente invention, on désigne par alkyle en C1 -C7 une chaîne hydrocarbonée saturée, linéaire ou ramifiée, comprenant de 1 à 7 atomes de carbone. De préférence, le radical alkyle en C1 -C7 est choisi parmi les radicaux méthyle, éthyle, propyle, i-propyle, butyle, t-butyle, pentyle, hexyle et heptyle.According to the present invention, C1-C7 alkyl denotes a saturated hydrocarbon chain, linear or branched, comprising from 1 to 7 carbon atoms. Preferably, the C 1 -C 7 alkyl radical is chosen from methyl, ethyl, propyl, i-propyl, butyl, t-butyl, pentyl, hexyl and heptyl radicals.
Selon la présente invention, on désigne par alkyle en C1 -C4 une chaîne hydrocarbonée saturée, linéaire ou ramifiée, comprenant de 1 à 4 atomes de carbone. De préférence, le radical alkyle en C1 -C4 est choisi parmi les radicaux méthyle, éthyle, propyle, i-propyle, butyle et t-butyle.According to the present invention, the term C1-C4 alkyl denotes a saturated hydrocarbon chain, linear or branched, comprising from 1 to 4 carbon atoms. Preferably, the C 1 -C 4 alkyl radical is chosen from methyl, ethyl, propyl, i-propyl, butyl and t-butyl radicals.
Selon la présente invention, on désigne par cycloalkylalkyle en C4-C9 une chaîne hydrocarbonée saturée, linéaire ou ramifiée, substituée par un radical cycloalkyle et comprenant de 4 à 9 atomes de carbone. De préférence, le radical cycloalkylalkyle en C4-C9 est choisi parmi les radicaux cyclopropylméthyle, cyclopropylethyle, cyclobutylmethyle, cyclobutylethyle, cyclopentylmethyle, cyclopentylethyle, cyclohexylmethyle, et cyclohexylethyle.According to the present invention, the term C 4 -C 9 cycloalkylalkyl denotes a saturated hydrocarbon chain, linear or branched, substituted by a cycloalkyl radical and comprising from 4 to 9 carbon atoms. Preferably, the C 4 -C 9 cycloalkylalkyl radical is chosen from cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl and cyclohexylethyl radicals.
Selon la présente invention, on désigne par alkoxy C1 -C4 carbonyle un radical carboxy substitué par une chaîne hydrocarbonée saturée, linéaire ou ramifiée, comprenant de 1 à 4 atomes de carbone. De préférence, le radical alkoxy C1 -C4 carbonyle est choisi parmi les radicaux méthoxycarbonyle, éthoxycarbonyle, propoxycarbonyle et butoxycarbonyle. Selon la présente invention, on désigne par alkoxy C1 -C6 carbonyle un radical carboxy substitué par une chaîne hydrocarbonée saturée, linéaire ou ramifiée, comprenant de 1 à 6 atomes de carbone. De préférence, le radical alkoxy C1 -C6 est choisi parmi les radicaux méthoxy, éthoxy, propoxy, butoxy, pentoxy et hexyloxy.According to the present invention, C1-C4 alkoxycarbonyl denotes a carboxy radical substituted by a linear or branched saturated hydrocarbon-based chain containing from 1 to 4 carbon atoms. Preferably, the C1-C4 alkoxycarbonyl radical is chosen from the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl radicals. According to the present invention, C1-C6 alkoxycarbonyl denotes a carboxy radical substituted by a linear or branched saturated hydrocarbon-based chain comprising from 1 to 6 carbon atoms. Preferably, the C1-C6 alkoxy radical is chosen from methoxy, ethoxy, propoxy, butoxy, pentoxy and hexyloxy radicals.
Selon la présente invention, les composés de formule générale (I) particulièrement préférés sont ceux pour lesquels:According to the present invention, the compounds of general formula (I) that are particularly preferred are those for which:
- R1 représente un hydrogène etR1 represents a hydrogen and
- R2 représente un radical alkyle en C1 -C7 ou un radical cycloalkyle en C3-C7.- R2 represents a C1-C7 alkyl radical or a C3-C7 cycloalkyl radical.
Selon la présente invention, les composés de formule générale (I) particulièrement préférés sont ceux pour lesquels le radical hétérocyclique de formule générale (II) représente un thiophène de formule générale (lia).According to the present invention, the compounds of general formula (I) that are particularly preferred are those for which the heterocyclic radical of general formula (II) represents a thiophene of general formula (IIa).
Parmi les composés de formule générale (I) entrant dans le cadre de la présente invention, on peut notamment citer les suivants :Among the compounds of general formula (I) within the scope of the present invention, there may be mentioned in particular:
1. 4-(5-ethyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione1. 4- (5-ethyl-thiophen-2-yl) -1,3-dihydroimidazole-2-thione
2. 4-(5-propyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione 3. 4-(5-methyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione2. 4- (5-propylthiophen-2-yl) -1,3-dihydroimidazole-2-thione 3. 4- (5-methylthiophen-2-yl) -1,3-dihydroimidazole -2-thione
4. 4-(4-methyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione4. 4- (4-methylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
5. 4-(2,5-dimethyl-thiophen-3-yl)-1 ,3-dihydro-imidazole-2-thione5. 4- (2,5-Dimethylthiophen-3-yl) -1,3-dihydroimidazole-2-thione
6. 4-(3-propyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione6. 4- (3-propylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
7. 4-(4-propyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione 8. 4-(4-ethyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione7. 4- (4-propylthiophen-2-yl) -1,3-dihydroimidazole-2-thione 8. 4- (4-ethylthiophen-2-yl) -1,3-dihydroimidazole -2-thione
9. 4-(2,5-dimethyl-furan-3-yl)-1 ,3-dihydro-imidazole-2-thione9. 4- (2,5-Dimethyl-furan-3-yl) -1,3-dihydroimidazole-2-thione
10. 4-(5-methyl-furan-2-yl)-1 ,3-dihydro-imidazole-2-thione10. 4- (5-methyl-furan-2-yl) -1,3-dihydroimidazole-2-thione
1 1. 4-(2,4-dimethyl-thiazol-5-yl)-1 ,3-dihydro-imidazole-2-thione1,1- (2,4-Dimethyl-thiazol-5-yl) -1,3-dihydroimidazole-2-thione
12. 4-(5-cyclopentyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione 13. 4-(5-cyclohexyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione12. 4- (5-Cyclopentyl-thiophen-2-yl) -1,3-dihydro-imidazol-2-thione; 4- (5-cyclohexyl-thiophen-2-yl) -1,3-dihydro-imidazole; -2-thione
14. 4-(4-cyclopentyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione14. 4- (4-Cyclopentylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
15. 4-(4-cyclohexyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione15. 4- (4-Cyclohexylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
16. 4-(5-cyclopropyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione16. 4- (5-cyclopropylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
17. 4-(4-cyclopropyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione 18. 4-(5-cyclopropyl-methyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione17. 4- (4-cyclopropylthiophen-2-yl) -1,3-dihydroimidazole-2-thione 18. 4- (5-Cyclopropyl-methyl-thiophen-2-yl) -1,3-dihydro-imidazole-2-thione
19. 4-(5-isobutyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione19. 4- (5-isobutylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
20. 4-(5-butyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione20. 4- (5-butylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
21. 5-(2-thioxo-2,3-dihydro-1 H-imidazol-4-yl)-thiophene-3-carboxylate de methyle 22. l'acide 5-(2-thioxo-2,3-dihydro-1 H-imidazol-4-yl)-thiophene-3- carboxylique21. Methyl 5- (2-thioxo-2,3-dihydro-1H-imidazol-4-yl) -thiophene-3-carboxylate 22. 5- (2-thioxo-2,3-dihydro) acid 1H-imidazol-4-yl) -thiophene-3-carboxylic
Les composés de formule générale (I) sont préparés suivants les schémas réactionnels généraux présentés à la figure 1.The compounds of general formula (I) are prepared according to the general reaction schemes presented in FIG.
En utilisant le schéma réactionnel de la figure 1 :Using the reaction scheme of Figure 1:
Etape a : les hétérocycles commerciaux (1 ) sont acétylés suivant les conditions classiques de synthèse comme par exemple en présence d'anhydride acétique et d'acide phosphorique pour conduire aux méthylcétones (2) (Kotha, S.; Kashinath, D.; Lahiri, K.; Sunoj, R. B.; Eur J Org Chem 2004, (19), 4003-4013).Step a: the commercial heterocycles (1) are acetylated according to the conventional synthesis conditions, for example in the presence of acetic anhydride and phosphoric acid, to yield the methyl ketones (2) (Kotha, S. Kashinath, D. Lahiri Sunoj, RB, Eur J Org Chem 2004, (19), 4003-4013).
Etape b : Les alpha bromo cétones de formule générale (3)Step b: The alpha bromo ketones of the general formula (3)
sont commerciales ou peuvent être préparées à partir des méthylcétones (2) suivant des méthodes classiques de synthèse comme par exemple par action du dibrome dans un solvant comme le dichlorométhane (Laufer, S.; Striegel, H. -G.; Neher, K.; Zechmeister, P.; Donat, C; Stolingwa, K.; Baur, S.; Tries, S.; Kammermeier, T.; Dannhardt, G.; Kiefer, W.; Arch Pharm 1997, 330 (9), 307-312) are commercially available or can be prepared from methyl ketones (2) according to conventional methods of synthesis, for example by the action of dibroma in a solvent such as dichloromethane (Laufer, S .; Striegel, H. -G .; Neher, K. Zechmeister, P., Donat, C., Stolingwa, K .; Baur, S., Tries, S. Kammermeier, T., Dannhardt, G. Kiefer, W, Arch Pharm 1997, 330 (9), 307; -312)
Etape c : les alpha bromo cétones (3) sont mises en réaction avec du diformamide de sodium par exemple dans de l'acétonitrile (Yinglin, H.; Hongwen, H.; Synthesis, 1990, 615) pour donner après hydrolyse du brut réactionnel avec de l'acide chlorhydrique par exemple (Ying-Lin, H.; Hong-Wen, H. H.; Tetrahedron Lett ,1989, 30, 5285) les chlorhydrates des acyl-amines de formule générale (4).Step c: the alpha bromo ketones (3) are reacted with sodium diformamide for example in acetonitrile (Yinglin, H. Hongwen, H. Synthesis, 1990, 615) to give after hydrolysis of the reaction crude with acid hydrochloric acid for example (Ying-Lin, H., Hong-Wen, HH, Tetrahedron Lett, 1989, 30, 5285) hydrochlorides of acyl amines of general formula (4).
R1 HClR1 HCl
(4) O NH2 (4) O NH 2
Etape d : une réaction de cyclisation des composés de formule générale (4) à l'aide de thiocyanate de potassium permet d'obtenir les imidazole-2-thiones de formule générale (I) (Mor, M.; Bordi, F.; Silva, C; Rivara, S.; Crivori, P.; Plazzi, P. V.; Ballabeni, V.; Caretta, A.; Barocelli, E.; Impicciatore, M.; Carrupt, P. -A.; Testa, B. J. Med. Chem. 1997; 40 (16); 2571 -2578.)Step d: a cyclization reaction of the compounds of general formula (4) with potassium thiocyanate makes it possible to obtain the imidazole-2-thiones of general formula (I) (Mor, M .; Bordi, F .; Silva, C, Rivara, S., Crivori, P., Plazzi, PV, Ballabeni, V., Caretta, A., Barocelli, E., Impicciatore, Carrupt, P., A., Testa, BJ Med. Chem 1997; 40 (16); 2571-2578.)
De façon avantageuse, les composés de la présente invention présentent une valeur d'IC50 (dose inhibant 50% de l'activité enzymatique) vis-à-vis de la tyrosinase inférieure ou égale à 10μM et plus particulièrement inférieure ou égale à 1 μM.Advantageously, the compounds of the present invention have a value of IC 50 (dose inhibiting 50% of the enzymatic activity) with respect to tyrosinase less than or equal to 10 μM and more particularly less than or equal to 1 μM .
L'invention vise donc l'utilisation d'au moins un composé de formule générale (I) tel que défini ci-dessus pour la préparation d'une composition pharmaceutique ou cosmétique dans laquelle ledit composé a une activité inhibitrice de la tyrosinase. L'invention concerne également un produit choisi parmi les composés de formule (I) pour son utilisation dans le traitement et/ou la prévention des désordres pigmentaires.The invention therefore relates to the use of at least one compound of general formula (I) as defined above for the preparation of a pharmaceutical or cosmetic composition in which said compound has a tyrosinase inhibitory activity. The invention also relates to a product chosen from compounds of formula (I) for its use in the treatment and / or prevention of pigment disorders.
L'invention concerne également une méthode de traitement thérapeutique ou cosmétique, comprenant l'administration d'une composition pharmaceutique ou cosmétique comprenant ledit composé, en tant qu'inhibiteur de la tyrosinase.The invention also relates to a method of therapeutic or cosmetic treatment, comprising the administration of a pharmaceutical or cosmetic composition comprising said compound, as a tyrosinase inhibitor.
L'invention concerne également l'utilisation d'un composé de formule générale (I) tel que défini ci-dessus pour la préparation d'un médicament destiné au traitement des désordres pigmentaires, notamment des désordres hyperpigmentaires.The invention also relates to the use of a compound of general formula (I) as defined above for the preparation of a medicament for the treatment of pigment disorders, especially hyperpigmentary disorders.
En effet, les composés utilisés selon l'invention sont particulièrement appropriés au traitement et à la prévention des désordres pigmentaires tels que le mélasma, le chloasma, les lentigines, le lentigo sénile, les hyperpigmentations irrégulières liées au photo vieillissement, les taches de rousseur, les hyperpigmentations post inflammatoire dues à une abrasion ou à une brûlure ou à une cicatrice ou à une dermatose ou à une allergie de contact, les nevis, les hyperpigmentations à déterminisme génétique, les hyperpigmentations d'origine métabolique ou médicamenteuse, les mélanomes ou tout autre lésion hyperpigmentaire.Indeed, the compounds used according to the invention are particularly suitable for the treatment and the prevention of pigmentary disorders such as melasma, chloasma, lentigines, senile lentigo, irregular hyperpigmentations related to photo aging, freckles, post inflammatory hyperpigmentations due to abrasion or burn or scarring or dermatitis or contact allergy, Nevis, hyperpigmentations with genetic determinism, hyperpigmentations of metabolic or medicinal origin, melanomas or any other hyperpigmentary lesion.
La présente invention a aussi pour objet une composition pharmaceutique destinée notamment au traitement des affections susmentionnées, qui comprend, dans un support pharmaceutiquement acceptable et compatible avec le mode d'administration retenu pour cette dernière, au moins un composé de formule générale (I) sous une de ses formes tautomériques, ou un de ses sels avec un acide pharmaceutiquement acceptable.The subject of the present invention is also a pharmaceutical composition intended in particular for the treatment of the abovementioned conditions, which comprises, in a pharmaceutically acceptable carrier and compatible with the mode of administration chosen for the latter, at least one compound of general formula (I) under one of its tautomeric forms, or a salt thereof with a pharmaceutically acceptable acid.
Par support pharmaceutiquement acceptable, on entend un milieu compatible avec la peau, les muqueuses et les phanères.By pharmaceutically acceptable carrier is meant a medium compatible with the skin, mucous membranes and integuments.
L'administration de la composition selon l'invention peut être effectuée par voie topique. De préférence, la composition pharmaceutique est conditionnée sous une forme convenant à une application par voie topique. Par voie topique, on entend une administration sur la peau ou les muqueuses.The administration of the composition according to the invention can be carried out topically. Preferably, the pharmaceutical composition is packaged in a form suitable for topical application. Topically, it is meant to be administered on the skin or mucous membranes.
Par voie topique, la composition pharmaceutique selon l'invention est plus particulièrement destinée au traitement de la peau et des muqueuses et peut se présenter sous forme liquide, pâteuse, ou solide, et plus particulièrement sous forme d'onguents, de crèmes, de laits, de pommades, de poudres, de tampons imbibés, de syndets, de solutions, de gels, de sprays, de mousses, de suspensions, de sticks, de shampoings, ou de bases lavantes. Elle peut également se présenter sous forme de suspensions de microsphères ou nanosphères ou de vésicules lipidiques ou polymériques ou de patches polymériques ou gélifiés permettant une libération contrôlée. Les compositions utilisées pour une application par voie topique ont une concentration en composé selon l'invention généralement comprise entre 0,001 % et 10% en poids, de préférence entre 0,01 % et 5% en poids, par rapport au poids total de la composition.Topically, the pharmaceutical composition according to the invention is more particularly intended for the treatment of the skin and mucous membranes and may be in liquid, pasty or solid form, and more particularly in the form of ointments, creams, milks , ointments, powders, soaked swabs, syndets, solutions, gels, sprays, mousses, suspensions, sticks, shampoos, or washing bases. It may also be in the form of suspensions of microspheres or nanospheres or lipid or polymeric vesicles or polymeric or gelled patches allowing controlled release. The compositions used for a topical application have a concentration of compound according to the invention generally between 0.001% and 10% by weight, preferably between 0.01% and 5% by weight, relative to the total weight of the composition. .
Les composés de formule générale (I) selon l'invention trouvent également une application dans le domaine cosmétique, en particulier dans la protection contre les aspects néfastes du soleil, pour prévenir et/ou pour lutter contre le vieillissement photo-induit ou chronologique de la peau et des phanères.The compounds of general formula (I) according to the invention also find application in the cosmetics field, in particular in the protection against the harmful aspects of the sun, for preventing and / or for combating photo-induced or chronological aging of the skin. skin and integuments.
L'invention a donc également pour objet une composition cosmétique comprenant, dans un support cosmétiquement acceptable, au moins un composé de formule générale (I). Par support cosmétiquement acceptable, on entend un milieu compatible avec la peau, les muqueuses et les phanères.The invention therefore also relates to a cosmetic composition comprising, in a cosmetically acceptable support, at least one compound of general formula (I). By cosmetically acceptable carrier is meant a medium compatible with the skin, mucous membranes and integuments.
L'invention a également pour objet l'utilisation cosmétique d'un composé de formule (I) ou d'une composition comprenant au moins un composé de formule générale (I) pour prévenir et/ou traiter les signes du vieillissement cutané.The subject of the invention is also the cosmetic use of a compound of formula (I) or of a composition comprising at least one compound of general formula (I) for preventing and / or treating the signs of skin aging.
L'invention a aussi pour objet l'utilisation cosmétique d'un composé de formule (I) ou d'une composition comprenant au moins un composé de formule générale (I) pour l'hygiène corporelle ou capillaire.The subject of the invention is also the cosmetic use of a compound of formula (I) or of a composition comprising at least one compound of general formula (I) for body or hair hygiene.
La composition cosmétique selon l'invention contenant, dans un support cosmétiquement acceptable, un composé de formule générale (I), ou une de ses formes tautomères ou un de ses sels avec un acide pharmaceutiquement acceptable, peut se présenter notamment sous forme d'une crème, d'un lait, d'un gel, de suspensions de microsphères ou nanosphères ou vésicules lipidiques ou polymériques, de tampons imbibés, de solutions, de sprays, de mousses, de sticks, de savons, de bases lavantes ou de shampooings.The cosmetic composition according to the invention containing, in a cosmetically acceptable support, a compound of general formula (I), or one of its tautomeric forms or a salt thereof with a pharmaceutically acceptable acid, can in particular be in the form of a cream, a milk, a gel, suspensions of microspheres or nanospheres or lipid or polymeric vesicles, soaked swabs, solutions, sprays, foams, sticks, soaps, washing bases or shampoos.
La concentration en composé de formule générale (I) dans la composition cosmétique est de préférence comprise entre 0,001 % et 3% en poids, par rapport au poids total de la composition. Les compositions pharmaceutiques et cosmétiques telles que décrites précédemment peuvent en outre contenir des additifs inertes, ou même pharmacodynamiquement actifs pour ce qui concerne les compositions pharmaceutiques, ou des combinaisons de ces additifs, et notamment :The concentration of compound of general formula (I) in the cosmetic composition is preferably between 0.001% and 3% by weight, relative to the total weight of the composition. The pharmaceutical and cosmetic compositions as described above may also contain inert additives, or even pharmacodynamically active additives for pharmaceutical compositions, or combinations of these additives, and in particular:
- des agents mouillants ;- wetting agents;
- des agents d'amélioration de la saveur ;- flavor enhancers;
- des agents conservateurs tels que les esters de l'acide parahydroxybenzoïque ;preserving agents such as esters of parahydroxybenzoic acid;
- des agents stabilisants ; - des agents régulateurs d'humidité ;stabilizing agents; humidity regulating agents;
- des agents régulateurs de pH ;pH regulating agents;
- des agents modificateurs de pression osmotique ;osmotic pressure modifying agents;
- des agents émulsionnants ;emulsifying agents;
- des filtres UV-A et UV-B ; - des antioxydants, tels que l'α-tocophérol, le butylhydroxyanisole ou le butylhydroxytoluène, la Super Oxyde Dismutase, l'Ubiquinol ;UV-A and UV-B filters; antioxidants, such as α-tocopherol, butylhydroxyanisole or butylhydroxytoluene, superoxide dismutase, ubiquinol;
- des émollients ;- emollients;
- des agents hydratants comme le glycérol, le PEG 400, la thiamorpholinone, et ses dérivés ou l'urée ; - des agents antiséborrhéiques ou antiacnéiques, tels que la S- carboxyméthylcystéine, la S-benzyl-cystéamine, leurs sels ou leurs dérivés, ou le peroxyde de benzoyle.moisturizing agents such as glycerol, PEG 400, thiamorpholinone, and its derivatives or urea; antiseborrhoeic or antiacne agents, such as S-carboxymethylcysteine, S-benzylcysteamine, their salts or their derivatives, or benzoyl peroxide.
Bien entendu, l'homme du métier veillera à choisir le ou les éventuels composés à ajouter à ces compositions de telle manière que les propriétés avantageuses attachées intrinsèquement à la présente invention ne soient pas ou substantiellement pas altérées par l'addition envisagée.Of course, those skilled in the art will take care to choose the optional compound (s) to be added to these compositions in such a way that the advantageous properties intrinsically attached to the present invention are not or not substantially impaired by the envisaged addition.
Il va maintenant être donné, à titre d'illustration et sans aucun caractère limitatif, plusieurs exemples d'obtention de composés de formule générale (I) selon l'invention, des résultats d'activité biologique de ces composés ainsi que diverses formulations à base de tels composés.Several examples of obtaining compounds of general formula (I) according to the invention, results of biological activity of these compounds as well as various formulations based on these compounds will now be given by way of illustration and without any limiting character. such compounds.
Exemple 1 : 4-(5-Ethvl-thiophen-2-vl)-1 ,3-dihvdro-imidazole-2-thione 1 -(5-ethyl-thiophen-2-yl)-ethanoneExample 1 4- (5-Ethyl-thiophen-2-yl) -1,3-dihydroimidazole-2-thione 1 - (5-ethyl-thiophen-2-yl) -ethanone
Dans un tricol de 50 ml on met en solution 5 g (44.6 mmol, 1 eq) de 2-ethylthiophène dans 28 ml_ d'anhydride acétique, 0.5 ml d' acide ortho phosphorique sont ajoutés puis le mélange réactionnel est chauffé 1 heure à 80°C. Les acides sont évaporés sous pression réduite, puis l'huile obtenue est filtrée sur un patch de sillice (éluant :In a 50 ml three-necked flask, 5 g (44.6 mmol, 1 eq) of 2-ethylthiophene are dissolved in 28 ml of acetic anhydride, 0.5 ml of ortho phosphoric acid are added and the reaction mixture is then heated for 1 hour at 80 ° C. ° C. The acids are evaporated under reduced pressure, and the oil obtained is filtered on a patch of silica (eluent:
20% acétate d'éthyle, 80% heptane) après évaporation des solvants : 5.2 g de 1 -(5- ethyl-thiophen-2-yl)-ethanone sont obtenus sous forme d'une huile marron. Rendement : 76 %20% ethyl acetate, 80% heptane) after evaporation of the solvents: 5.2 g of 1- (5-ethyl-thiophen-2-yl) -ethanone are obtained in the form of a brown oil. Yield: 76%
2-bromo-1 -(5-ethyl-thiophen-2-yl)-ethanone2-bromo-1- (5-ethyl-thiophen-2-yl) -ethanone
Dans un tricol de 100 mL à température ambiante et sous azote, 5.2 g (33.7 mmol, 1 eq) de 1 -(5-ethyl-thiophène-2-yl)-ethanone sont mis en solution dans 50 mL de dichlorométhane, 2 mL (38.8 mmol, 1.15 eq) de dibrome sont ajoutés goutte à goutte. Le mélange réactionnel est agité 16 heures à température ambiante puis 3 heures à 45 °C. Le milieu réactionnel est transféré sur 100 mL d'une solution de thiosulfate de sodium puis extrait avec 100 ml de dichlorométhane, la phase organique est séchée sur sulfate de magnésium, puis les solvants sont évaporés. Le résidu est filtré sur un patch de silice éluant : 20% Acétate d'éthyle et 80% heptane. 8 g d'une huile marron sont obtenus. L'huile précédente est mise en solution dans 24 mL de tétrahydrofuranne et refroidie à 0°C. 0.84 mL de diethylphosphite et 0.92 mL de thethylamine sont ajoutés au mélange réactionnel. Le mélange est agité 1 heure à 0°C puis 4 heures à température ambiante. Le milieu réactionnel est versé sur 200 mL d'eau glacée puis extrait avec 200 mL d'Acétate d'éthyle. Les phases organiques sont séchées sur sulfate de magnésium puis le résidu est chromatographié sur gel de silice (5% Acétate d'éthyle / 95% Heptane). 5 g de 2- bromo-1 -(5-ethyl-thiophen-2-yl)-ethanone sont obtenus sous forme d'une huile jaune orangée. Rendement = 63 %In a three-necked 100 mL at room temperature and under nitrogen, 5.2 g (33.7 mmol, 1 eq) of 1- (5-ethyl-thiophen-2-yl) -ethanone are dissolved in 50 mL of dichloromethane, 2 mL. (38.8 mmol, 1.15 eq) of bromine are added dropwise. The reaction mixture is stirred for 16 hours at room temperature and then for 3 hours at 45 ° C. The reaction medium is transferred to 100 ml of a solution of sodium thiosulfate and then extracted with 100 ml of dichloromethane, the organic phase is dried over magnesium sulfate, and the solvents are evaporated. The residue is filtered on a silica eluting patch: 20% ethyl acetate and 80% heptane. 8 g of a brown oil are obtained. The preceding oil is dissolved in 24 mL of tetrahydrofuran and cooled to 0 ° C. 0.84 mL of diethyl phosphite and 0.92 mL of thethylamine are added to the reaction mixture. The mixture is stirred for 1 hour at 0 ° C. and then for 4 hours at room temperature. The reaction medium is poured into 200 ml of ice-water and then extracted with 200 ml of ethyl acetate. The organic phases are dried over magnesium sulphate and the residue is then chromatographed on silica gel (5% ethyl acetate / 95% heptane). 5 g of 2-bromo-1- (5-ethylthiophen-2-yl) -ethanone are obtained in the form of an orange-yellow oil. Yield = 63%
2-(5-ethyl-thiophen-2-yl)-2-oxo-ethyl-ammonium Dans un tricol de 100 mL à température ambiante et sous azote, 2.7 g (1 1.6 mmol) de 2-bromo-1 -(5-ethyl-thiophen-2-yl)-ethanone sont dissous dans dans 50 mL d'acétontrile, 1.21 g (12.75 mmol) de sodium diformamide sont ajoutés puis le mélange est agité pendant 48 heures à température ambiante. Le milieu réactionnel est filtré puis le résidu est repris dans 40 ml d'une solution d'acide chlorhydrique 1 M dans l'éthanol et chauffé à 50°C pendant 4 heures. Les solvants sont évaporés puis 30 mL d'éther diéthylique sont ajoutés. Le solide est filtré pour donner 2.2 g de 2-(5- ethyl-thiophen-2-yl)-2-oxo-ethyl-ammonium sous forme d'un solide beige. Rendement : 91 %2- (5-ethyl-thiophen-2-yl) -2-oxo-ethyl-ammonium In a three-necked 100 mL at room temperature and under nitrogen, 2.7 g (1 1.6 mmol) of 2-bromo-1- (5-ethyl-thiophen-2-yl) -ethanone are dissolved in 50 mL of acetontrile, 1.21 g (12.75 mmol) of sodium diformamide are added and the mixture is stirred for 48 hours at room temperature. The reaction medium is filtered and the residue is taken up in 40 ml of a 1M hydrochloric acid solution in ethanol and heated at 50 ° C. for 4 hours. The solvents are evaporated and then 30 ml of diethyl ether are added. The solid is filtered to give 2.2 g of 2- (5-ethyl-thiophen-2-yl) -2-oxo-ethyl-ammonium as a beige solid. Yield: 91%
4-(5-ethyl-thiophen-2-yl)-1 ,3-dihvdro-imidazole-2-thione4- (5-ethyl-thiophen-2-yl) -1,3-dihydroimidazole-2-thione
Dans un tricol de 50 mL à température ambiante et sous azote, 4.51 g (93 mmol) de thiocyanate de potassium sont mis en solution dans 22 mL d'eau en présence de 3.2 ml d'acide chlorhydrique 1 M puis 2.17 g (10.3 mmol) de 2-(5-ethyl-thiophen-2-yl)-2- oxo-ethyl-ammonium sont ajoutés. Le milieu réactionnel est agité à reflux jusqu'à disparition du produit de départ. Le précipité est filtré, puis lavé avec de l'eau et de l'acétate d'éthyle : 0.9 g d'un solide jaune ocre sont obtenus. Après recristallisation dans de l'acétate d'éthyle 0.42 g de 4-(5-ethyl-thiophen-2-yl)-1 ,3-dihydro-imidazole- 2-thione sous forme de solide jaune clair sont obtenus. Rendement : 20 %In a three-necked 50 ml room temperature and under nitrogen, 4.51 g (93 mmol) of potassium thiocyanate are dissolved in 22 ml of water in the presence of 3.2 ml of 1 M hydrochloric acid and then 2.17 g (10.3 mmol). ) 2- (5-ethyl-thiophen-2-yl) -2-oxo-ethyl-ammonium are added. The reaction medium is stirred at reflux until the starting material disappears. The precipitate is filtered and then washed with water and ethyl acetate: 0.9 g of an ocher yellow solid are obtained. After recrystallization from ethyl acetate, 0.42 g of 4- (5-ethylthiophen-2-yl) -1,3-dihydroimidazole-2-thione as a light yellow solid are obtained. Yield: 20%
RMN 1 H (DMSO, 400 MHz) : 1.21 (t, 3H, J = 7 Hz, CH3) ; 2.75 (q, 2H, J = 7 Hz, CH2) ; 6.75 (m, 1 H, CH) ; 7.05 (s, 1 H, CH) ; 7.17 (m, 1 H, CH) ; 12.0 (s, 1 H, NH) ; 12.5 (s, 1 H, NH). RMN 13C (DMSO, 100 MHz) : 16.2, 23.1 , 1 1 1.4, 124.0, 124.6, 124.7, 128.1 , 146.1 , 161.9. 1 H NMR (DMSO, 400 MHz): 1.21 (t, 3H, J = 7 Hz, CH 3 ); 2.75 (q, 2H, J = 7 Hz, CH 2 ); 6.75 (m, 1H, CH); 7.05 (s, 1H, CH); 7.17 (m, 1H, CH); 12.0 (s, 1H, NH); 12.5 (s, 1H, NH). 13 C NMR (DMSO, 100 MHz): 16.2, 23.1, 1.4, 124.0, 124.6, 124.7, 128.1, 146.1, 161.9.
De manière analogue à l'exemple précédent on obtient :In a similar way to the previous example, we obtain:
Exemple 2: 4-(5-propyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thioneExample 2 4- (5-propylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
RMN 1 H (DMSO, 400 MHz) : 1.04 (t, 3H, J = 7 Hz, CH3) ; 1.73 (m, 2H, CH2) ; 2.84 (t, 2H, J = 7 Hz, CH2) ; 6.87 (m, 1 H, CH) ; 7.19 (s, 1 H, CH) ; 7.30 (m, 1 H, CH) ; 12.1 (s, 1 H, NH) ; 12.7 (s, 1 H, NH). 1 H NMR (DMSO, 400 MHz): 1.04 (t, 3H, J = 7 Hz, CH 3 ); 1.73 (m, 2H, CH 2 ); 2.84 (t, 2H, J = 7 Hz, CH 2 ); 6.87 (m, 1H, CH); 7.19 (s, 1H, CH); 7.30 (m, 1H, CH); 12.1 (s, 1H, NH); 12.7 (s, 1H, NH).
RMN 13C (DMSO. 100 MHz) : 13.9, 24.8, 31.7, 1 11.4, 124.0, 124.6, 125.5, 128.3, 144.2, 161.9. 13 C NMR (100 MHz DMSO): 13.9, 24.8, 31.7, 11.4, 124.0, 124.6, 125.5, 128.3, 144.2, 161.9.
Exemple 3: 4-(5-methyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione RMN 1 H (DMSO. 400 MHz) : 2.41 (s, 3H, CH3) ; 6.72 (s, 1 H, CH) ; 6.91 (s, 1 H, CH) ;Example 3 4- (5-methylthiophen-2-yl) -1,3-dihydroimidazole-2-thione 1 H NMR (DMSO 400 MHz.): 2.41 (s, 3H, CH 3); 6.72 (s, 1H, CH); 6.91 (s, 1H, CH);
7.15 (s, 1 H, CH) ; 12.0 (s, 1 H, NH) ; 12.5 (s, 1 H, NH).7.15 (s, 1H, CH); 12.0 (s, 1H, NH); 12.5 (s, 1H, NH).
RMN 13C (DMSO. 100 MHz) : 15.3, 1 1 1 .4, 124.2, 124.4, 126.4, 128.5, 138.6, 161 .8. 13 C NMR (100 MHz DMSO): 15.3, 11.1.4, 124.2, 124.4, 126.4, 128.5, 138.6, 161.8.
Exemple 4: 4-(4-methyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thioneExample 4 4- (4-methylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
RMN 1 H (DMSO. 400 MHz) : 2.17 (s, 3H, CH3) ; 7.02 (s, 1 H, CH) ; 7.12 (s, 1 H, CH) ; 7.19 (s, 1 H, CH) ; 12.1 (s, 1 H, NH) ; 12.6 (s, 1 H, NH). 1 H NMR (DMSO 400 MHz.): 2.17 (s, 3H, CH 3); 7.02 (s, 1H, CH); 7.12 (s, 1H, CH); 7.19 (s, 1H, CH); 12.1 (s, 1H, NH); 12.6 (s, 1H, NH).
RMN 13C (DMSO. 100 MHz) : 15.8, 1 1 1 .9, 120.2, 124.4, 126.4, 130.5, 138.0, 162.0. 13 C NMR (100 MHz DMSO): 15.8, 11.1.9, 120.2, 124.4, 126.4, 130.5, 138.0, 162.0.
Exemple 5: 4-(2,5-dimethyl-thiophen-3-yl)-1 ,3-dihydro-imidazole-2-thioneExample 5 4- (2,5-Dimethyl-thiophen-3-yl) -1,3-dihydroimidazole-2-thione
RMN 1H (DMSO. 400 MHz) : 2.37 (2s, 6H, CH3) ; 6.93 (s, 1 H, CH) ; 6.98 (s, 1 H, CH) 1 H NMR (DMSO 400 MHz.): 2.37 (2s, 6H, CH 3); 6.93 (s, 1H, CH); 6.98 (s, 1H, CH)
; 12.1 (s, 1 H, NH) ; 12.3 (s, 1 H, NH).; 12.1 (s, 1H, NH); 12.3 (s, 1H, NH).
RMN 13C (DMSO. 100 MHz) : 14.2, 14.7, 1 12.3, 124.8, 125.0, 125.3, 131 .6, 135.0, 13 C NMR (100 MHz DMSO): 14.2, 14.7, 12.3, 124.8, 125.0, 125.3, 131.6, 135.0,
160.5.160.5.
Exemple 6: 4-(3-propyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thioneExample 6 4- (3-propylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
RMN 1H (DMSO. 400 MHz) : 0.86 (t, 3H, J = 7 Hz, CH3) ; 1.55 (hex, 2H, J = 7 Hz, CH2) ; 2.56 (t, 2H, J = 7 Hz, CH2) ; 6.96 (s, 1 H, CH) ; 7.02 (d, 1 H, J = 5Hz, CH) ; 7.51 (d, 1 H, J = 5Hz, CH) ; 12.2 (si, 2H, NH). 1 H NMR (DMSO: 400 MHz): 0.86 (t, 3H, J = 7 Hz, CH 3 ); 1.55 (hex, 2H, J = 7 Hz, CH 2 ); 2.56 (t, 2H, J = 7 Hz, CH 2 ); 6.96 (s, 1H, CH); 7.02 (d, 1H, J = 5Hz, CH); 7.51 (d, 1H, J = 5Hz, CH); 12.2 (si, 2H, NH).
RMN 13C (DMSO. 100 MHz) : 13.9, 22.9, 30.4, 1 13.9, 122.0, 123.6, 125.3, 129.3, 140.7, 161 .1 . 13 C NMR (100 MHz DMSO): 13.9, 22.9, 30.4, 13.9, 122.0, 123.6, 125.3, 129.3, 140.7, 161.1.
Exemple 7: Test d'inhibition de l'activité tyrosinaseEXAMPLE 7 Inhibition Test for Tyrosinase Activity
L'activité des inhibiteurs est mesurée à partir d'un lysat de cellules B16F1 (lignée de mélanome murin). En présence du substrat L-tyrosine, la tyrosinase présente dans ces cellules catalyse l'hydroxylation de la L-tyrosine en L-DOPA puis l'oxydation de la L-DOPA en dopaquinone. En présence de MBTH (3-methyl-2-benzo-thiazolinone hydrazone), la dopaquinone est piégée pour former un complexe rosé qui absorbe à 520 nm.Inhibitor activity is measured from a B16F1 cell lysate (murine melanoma line). In the presence of the L-tyrosine substrate, the tyrosinase present in these cells catalyzes the hydroxylation of L-tyrosine to L-DOPA and then the oxidation of L-DOPA to dopaquinone. In the presence of MBTH (3-methyl-2-benzothiazolinone hydrazone), dopaquinone is trapped to form a pink complex which absorbs at 520 nm.
Les cellules B16F1 sont cultivées en milieu DMEM + 10% de sérum de veau fœtal + 10"9 M d'αMSH pendant 4 jours à 37°C sous 7% de CO2. Elles sont traitées à laThe B16F1 cells are cultured in DMEM medium + 10% fetal calf serum + 10 -9 M αMSH for 4 days at 37 ° C. under 7% CO 2 .
Trypsine, lavées en PBS, numérées et culottées. Le culot est repris à 107 cellules/ml en tampon de lyse (phosphate de sodium 10 mM pH 6.8 - Igepal 1 %) et la suspension est traitée aux ultra-sons pendant 10 secondes. Après centrifugation 30 minutes à 4000 rpm, le surnageant obtenu constitue le lysat cellulaire utilisé comme source de tyrosinase dans le test enzymatique.Trypsin, washed in PBS, scanned and chewed. The pellet is taken up at 10 7 cells / ml in lysis buffer (10 mM sodium phosphate pH 6.8 - Igepal 1%) and the suspension is treated with ultrasound for 10 seconds. After centrifugation for 30 minutes at 4000 rpm, the supernatant obtained constitutes the cell lysate used as a source of tyrosinase in the enzyme test.
Les essais sont réalisés en duplicates en plaques 384 puits sous un volume total de 50 μl. Chaque puits contient :The tests are carried out in duplicate in 384-well plates under a total volume of 50 μl. Each well contains:
- 40 μl de solution contenant 1.25 mM L-tyrosine, 6.25 μM L-DOPA (cofacteur) et 3.75 mM MBTH en tampon B (phosphate de sodium 62.25 mM pH 6.8 - 2.5% dimethylformamide) - 5 μl d'inhibiteur dilué en DMSO- 40 μl of solution containing 1.25 mM L-tyrosine, 6.25 μM L-DOPA (cofactor) and 3.75 mM MBTH in buffer B (62.25 mM sodium phosphate pH 6.8 - 2.5% dimethylformamide) - 5 μl of inhibitor diluted in DMSO
- 5μl de lysat cellulaire dilué au ΛA en tampon Tris HCI 50 mM pH 7.55 μl of cell lysate diluted with Λ A in 50 mM Tris HCl buffer pH 7.5
La plaque est incubée à 37°C et une lecture spectrophotométrique est réalisée à 520 nm après 6 heures d'incubation. Pour s'affranchir d'une absorption éventuelle des produits, on travaille en absorbance corrigée (absorbance au temps 6h - absorbance au temps zéro).The plate is incubated at 37 ° C. and a spectrophotometric reading is carried out at 520 nm after 6 hours of incubation. To overcome any absorption of the products, one works in corrected absorbance (absorbance at time 6h - absorbance at time zero).
Les inhibiteurs sont testés en dose réponse pour calculer une IC50 (dose inhibantInhibitors are tested in dose response to calculate an IC50 (inhibiting dose
50% de l'activité enzymatique).50% of the enzymatic activity).
Plusieurs contrôles internes sont ajoutés dans chaque expérience :Several internal controls are added in each experiment:
- contrôle 100% d'activité : les 5 μl d'inhibiteur sont remplacés par 5μl de DMSO - contrôle 50% d'activité : les 5 μl d'inhibiteur sont remplacés par 5μl de phénylthiourée à 300 μM en DMSO100% activity control: the 5 .mu.l of inhibitor are replaced by 5 .mu.l of DMSO-control 50% activity: the 5 .mu.l of inhibitor are replaced by 5 .mu.l of phenylthiourea at 300 .mu.M in DMSO
- contrôle 0% d'activité : le substrat L-tyrosine est remplacé par du tampon B.0% activity control: the L-tyrosine substrate is replaced by buffer B.
Les résultats obtenus pour les composés de l'invention sont présentés dans le tableau A :The results obtained for the compounds of the invention are shown in Table A:
Tableau ATable A
Exemple 8: FormulationsExample 8: Formulations
Dans cet exemple, on a illustré diverses formulations concrètes à base des composés selon l'invention.In this example, various concrete formulations based on the compounds according to the invention have been illustrated.
VOIE TOPIQUETOPICAL WAY
(a) Onguent(a) Ointment
- Composé 1 0,020 g- Compound 1 0.020 g
- Myristate d'isopropyle 81 ,700 g- Isopropyl myristate 81, 700 g
- Huile de vaseline fluide 9,100 g- Fluid Vaseline Oil 9.100 g
- Silice ("Aérosil 200") 9,180 g- Silica ("Aerosil 200") 9.180 g
(b) Onguent(b) Ointment
- Composé 6 0,300 g- Compound 6 0.300 g
- Vaseline blanche codex qsp 100 g- white Vaseline codex qs 100 g
(c) Crème Eau-dans-Huile non ionique(c) Non-ionic Water-in-Oil Cream
- Composé 1 0,100 g- Compound 1 0.100 g
- Mélange d'alcools de lanoline émulsifs, de cires et d'huiles ("Eucerine anhydre") 39,900 g- Mixture of emulsified lanolin alcohols, waxes and oils ("Anhydrous Eucerine") 39,900 g
- Parahydroxybenzoate de méthyle 0,075 g - Parahydroxybenzoate de propyle 0,075 g- Methyl parahydroxybenzoate 0.075 g - Propyl parahydroxybenzoate 0.075 g
- Eau déminéralisée stérile qsp 100 g- Sterile demineralized water qs 100 g
(d) Lotion(d) Lotion
- Composé 6 0,100 g - Polyéthylène glycol (PEG 400) 69,900 g- Compound 6 0.100 g - Polyethylene glycol (PEG 400) 69.900 g
- Ethanol à 95% 30,000 g (e) Onguent hydrophobe- 95% ethanol 30,000 g (e) Hydrophobic ointment
- Composé 2 0,300 g- Compound 2 0.300 g
- Miristate d'isopropyle 36,400 g - Huile de silicone ("Rhodorsil 47 V 300" 36,400 g- Isopropyl Miristate 36,400 g - Silicone Oil ("Rhodorsil 47 V 300" 36,400 g
- Cire d'abeille 13,600 g- beeswax 13,600 g
- Huile de silicone ("AbN 300.000 est" qsp 100 g- Silicone oil ("AbN 300.000 is" qs 100 g
(f) Crème Huile-dans-Eau non ionique - Composé 4 1 ,000 g(f) Nonionic Oil-in-Water Cream - Compound 4 1, 000 g
- Alcool cétylique 4,000 g- Cetyl alcohol 4,000 g
- Monostéarate de glycérole 2,500 g- Glycerol monostearate 2,500 g
- Stéarate de PEG 50 2,500 g- PEG Stearate 50 2,500 g
- Beurre de karité 9,200 g - Propylène glycol 2,000 g- Shea butter 9,200 g - Propylene glycol 2,000 g
- Parahydroxybenzoate de méthyle 0,075 g- Methyl parahydroxybenzoate 0.075 g
- Parahydroxybenzoate de propyle 0,075 g- propyl parahydroxybenzoate 0.075 g
- Eau déminéralisée stérile qsp 100 g - Sterile demineralized water qs 100 g

Claims

Revendications claims
1. Composé de formule générale (I)1. Compound of general formula (I)
dans laquelle : X est un atome d'oxygène ou un atome de soufre, Y est un atome de carbone ou un atome d'azote,in which: X is an oxygen atom or a sulfur atom, Y is a carbon atom or a nitrogen atom,
lorsque R2=H, alors R1 représente :when R2 = H, then R1 represents:
- un radical alkyle en C1 -C7a C 1 -C 7 alkyl radical
- un radical cycloalkyle en C3-C7, un des atomes de carbone du cycle pouvant éventuellement être remplacé par un atome d'oxygène, ou de soufre,a C 3 -C 7 cycloalkyl radical, one of the carbon atoms of the ring possibly being replaced by an oxygen atom, or sulfur,
- un radical cycloalkylalkyle en C4-C9a C 4 -C 9 cycloalkylalkyl radical
- un carboxy, - un alkoxy C1 -C6 carbonyle, oua carboxy, a C1-C6 alkoxycarbonyl, or
- un radical akyle en C1 -C4 substitué par un alkoxy C1 -C4 carbonyle,a C1-C4 alkyl radical substituted with a C1-C4 alkoxycarbonyl,
lorsque R2 est différent d'un atome d'hydrogène, alors R1 et R2, identiques ou différents, sont choisis parmi : - un radical alkyle en C1 -C7,when R2 is different from a hydrogen atom, then R1 and R2, which are identical or different, are chosen from: a C1-C7 alkyl radical,
- un radical cycloalkyle en C3-C7, un des atomes de carbone du cycle pouvant éventuellement être remplacé par un atome d'oxygène, ou de soufre,a C 3 -C 7 cycloalkyl radical, one of the carbon atoms of the ring possibly being replaced by an oxygen atom, or sulfur,
- un radical cycloalkylalkyle en C4-C9, - un carboxy,a C 4 -C 9 cycloalkylalkyl radical, a carboxy,
- un alkoxy C1 -C6 carbonyle, eta C1-C6 alkoxycarbonyl, and
- un radical akyle en C1 -C4 substitué par un alkoxy C1 -C4 carbonyle.a C1-C4 alkyl radical substituted with a C1-C4 alkoxycarbonyl.
et lorsque R2 est en position ortho par rapport à R1 , alors R1 et R2 peuvent former un cycle hydrocarboné à 5 ou 6 atomes de carbone, ainsi que leurs sels et leurs formes tautomèresand when R 2 is ortho to R 1, then R 1 and R 2 can form a hydrocarbon ring with 5 or 6 carbon atoms, as well as their salts and tautomeric forms
2. Composé selon la revendication 1 , caractérisé en ce qu'il se présente sous forme d'un sel formé avec un acide choisi parmi les acides inorganiques et les acides organiques.2. Compound according to claim 1, characterized in that it is in the form of a salt formed with an acid selected from inorganic acids and organic acids.
3. Composé selon la revendication 1 ou 2, caractérisé en ce qu'il se présente sous la forme d'un hydrate ou d'un solvate3. Compound according to claim 1 or 2, characterized in that it is in the form of a hydrate or a solvate
4. Composé selon l'une des revendications 1 à 3 caractérisé en ce que le radical hétérocyclique de formule générale (II)4. Compound according to one of claims 1 to 3 characterized in that the heterocyclic radical of general formula (II)
représente un thiophène de formule générale (lia) represents a thiophene of general formula (IIa)
5. Composé selon l'une des revendications 1 à 4 caractérisé en ce que R1 représente un hydrogène et R2 représente un radical alkyle en C1 -C7 ou un radical cycloalkyle en C3-C7.5. Compound according to one of claims 1 to 4 characterized in that R1 represents a hydrogen and R2 represents a C1-C7 alkyl radical or a C3-C7 cycloalkyl radical.
6. Composé selon l'une des revendications 1 à 5, caractérisé en ce que le composé de formule générale (I) est choisi dans le groupe constitué par : 6. Compound according to one of claims 1 to 5, characterized in that the compound of general formula (I) is chosen from the group consisting of:
1. 4-(5-ethyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione1. 4- (5-ethyl-thiophen-2-yl) -1,3-dihydroimidazole-2-thione
2. 4-(5-propyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione2. 4- (5-propylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
3. 4-(5-methyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione 4. 4-(4-methyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione3. 4- (5-Methylthiophen-2-yl) -1,3-dihydroimidazole-2-thione 4. 4- (4-methylthiophen-2-yl) -1,3-dihydroimidazole -2-thione
5. 4-(2,5-dimethyl-thiophen-3-yl)-1 ,3-dihydro-imidazole-2-thione5. 4- (2,5-Dimethylthiophen-3-yl) -1,3-dihydroimidazole-2-thione
6. 4-(3-propyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione6. 4- (3-propylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
7. 4-(4-propyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione7. 4- (4-propylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
8. 4-(4-ethyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione8. 4- (4-ethyl-thiophen-2-yl) -1,3-dihydroimidazole-2-thione
9. 4-(2,5-dimethyl-furan-3-yl)-1 ,3-dihydro-imidazole-2-thione9. 4- (2,5-Dimethyl-furan-3-yl) -1,3-dihydroimidazole-2-thione
10. 4-(5-methyl-furan-2-yl)-1 ,3-dihydro-imidazole-2-thione10. 4- (5-methyl-furan-2-yl) -1,3-dihydroimidazole-2-thione
1 1. 4-(2,4-dimethyl-thiazol-5-yl)-1 ,3-dihydro-imidazole-2-thione1,1- (2,4-Dimethyl-thiazol-5-yl) -1,3-dihydroimidazole-2-thione
12. 4-(5-cyclopentyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione12. 4- (5-Cyclopentylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
13. 4-(5-cyclohexyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione13. 4- (5-Cyclohexylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
14. 4-(4-cyclopentyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione14. 4- (4-Cyclopentylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
15. 4-(4-cyclohexyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione15. 4- (4-Cyclohexylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
16. 4-(5-cyclopropyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione16. 4- (5-cyclopropylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
17. 4-(4-cyclopropyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione17. 4- (4-cyclopropylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
18. 4-(5-cyclopropyl-methyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione18. 4- (5-Cyclopropyl-methyl-thiophen-2-yl) -1,3-dihydro-imidazole-2-thione
19. 4-(5-isobutyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione19. 4- (5-isobutylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
20. 4-(5-butyl-thiophen-2-yl)-1 ,3-dihydro-imidazole-2-thione20. 4- (5-butylthiophen-2-yl) -1,3-dihydroimidazole-2-thione
21 5-(2-thioxo-2,3-dihydro-1 H-imidazol-4-yl)-thiophene-3-carboxylate de methyleMethyl 5- (2-thioxo-2,3-dihydro-1H-imidazol-4-yl) -thiophene-3-carboxylate
22 l'acide 5-(2-thioxo-2,3-dihydrc-1 H-imidazol-4-yl)-thiophene-3- carboxylique5- (2-Thioxo-2,3-dihydrophen-1H-imidazol-4-yl) -thiophene-3-carboxylic acid
7. Composé selon l'une quelconque des revendications 1 à 6 utilisé à titre de médicament.7. A compound according to any of claims 1 to 6 as a medicament.
8. Utilisation d'un composé selon l'une quelconque des revendications 1 à 6 pour la fabrication d'une composition pharmaceutique destinée au traitement ou à la prévention des désordres hyperpigmentaires.8. Use of a compound according to any one of claims 1 to 6 for the manufacture of a pharmaceutical composition for the treatment or prevention of hyperpigmentary disorders.
9. Utilisation selon la revendication 8, caractérisée en ce que les désordres hyperpigmentaires sont choisis parmi le melasma, le chloasma, les lentigines, le lentigo sénile, les hyperpigmentaîions irrégulières liées au photo vieillissement, les taches de rousseur, les hyperpigmentations post-inflammatoires dues à une abrasion ou à une brûlure ou à une cicatrice ou à une dermatose ou à une allergie de contact, les nevis, les hyperpigmentations à déterminisme génétique, les hyperpigmentations d'origine métabolique ou médicamenteuse, et les mélanomes.9. Use according to claim 8, characterized in that the hyperpigmentary disorders are selected from melasma, chloasma, lentigines, senile lentigo, irregular hyperpigmenta- tions related to photo aging, freckles, post-inflammatory hyperpigmentations due to abrasion or burning or scar or dermatitis or contact allergy, nevis, hyperpigmentations with genetic determinism, hyperpigmentations of metabolic or medicinal origin, and melanomas.
10. Composition pharmaceutique, caractérisée en ce qu'elle comprend, dans un support pharmaceutiquement acceptable, au moins un composé de formule générale (I) tel que défini à l'une quelconque des revendications 1 à 6.10. Pharmaceutical composition, characterized in that it comprises, in a pharmaceutically acceptable carrier, at least one compound of general formula (I) as defined in any one of claims 1 to 6.
11. Composition selon la revendication 10 caractérisée en ce que la concentration en composé de formule générale (I) est comprise entre 0,001 % et 10% en poids par rapport au poids total de la composition.11. Composition according to claim 10 characterized in that the concentration of compound of general formula (I) is between 0.001% and 10% by weight relative to the total weight of the composition.
12. Composition selon les revendications 10 ou 1 1 caractérisée en ce que la concentration en composé de formule générale (I) est comprise entre 0,01 % et 5% en poids par rapport au poids total de la composition.12. Composition according to claims 10 or 1 1 characterized in that the concentration of compound of general formula (I) is between 0.01% and 5% by weight relative to the total weight of the composition.
13. Composition cosmétique, caractérisée en ce qu'elle comprend, dans un support cosmétiquement acceptable, au moins un composé de formule générale (I) tel que défini à l'une quelconque des revendications 1 à 613. Cosmetic composition, characterized in that it comprises, in a cosmetically acceptable support, at least one compound of general formula (I) as defined in any one of Claims 1 to 6.
14. Composition selon la revendication 13, caractérisée en ce que la concentration en composé de formule générale (I) est comprise entre 0,001 % et 3% en poids par rapport au poids total de la composition.14. Composition according to Claim 13, characterized in that the concentration of compound of general formula (I) is between 0.001% and 3% by weight relative to the total weight of the composition.
15. Utilisation cosmétique d'un composé selon l'une des revendications 1 à 6 ou d'une composition telle que définie à l'une des revendications 13 ou 14 pour prévenir et/ou traiter les signes du vieillissement cutané.15. Cosmetic use of a compound according to one of claims 1 to 6 or a composition as defined in one of claims 13 or 14 for preventing and / or treating the signs of skin aging.
16. Utilisation cosmétique d'un composé selon l'une des revendications 1 à 6 ou d'une composition telle que définie à l'une des revendications 13 ou 14 pour l'hygiène corporelle ou capillaire. 16. Cosmetic use of a compound according to one of claims 1 to 6 or a composition as defined in one of claims 13 or 14 for personal hygiene or capillary.
EP08805935A 2007-06-05 2008-06-04 Novel 4-heteroaryl-imidazole-2-thiones used as tyrosinase inhibitors, method for preparing same and use thereof in human medicine and cosmetology Withdrawn EP2164845A1 (en)

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FR0755473A FR2917089B1 (en) 2007-06-05 2007-06-05 NOVEL 4-HETEROARYL-IMIDAZOLE-2-THIONES AS INHIBITORS OF TYROSINASE, PROCESS FOR THEIR PREPARATION AND THEIR USE IN HUMAN MEDICINE AND COSMETICS
PCT/FR2008/050995 WO2008152332A1 (en) 2007-06-05 2008-06-04 Novel 4-heteroaryl-imidazole-2-thiones used as tyrosinase inhibitors, method for preparing same and use thereof in human medicine and cosmetology

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TWI508950B (en) * 2014-08-29 2015-11-21 Univ Hungkuang 3-methyl-2-sulfanyl-2,3-dihydro-1H-imidazole-1-carboxylic acid Tertiary butyl ester and its preparation method and use
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US4159338A (en) * 1977-02-09 1979-06-26 E. I. Du Pont De Nemours And Company Antiinflammatory-4,5-dicyclic-2-(substituted thio)-imidazoles and their corresponding sulfoxides and sulfones
JPH05124923A (en) * 1991-04-09 1993-05-21 Sansho Seiyaku Co Ltd External preparation with melanin production-inhibitory activity
JPH05132422A (en) * 1991-04-09 1993-05-28 Sansho Seiyaku Co Ltd Melanogenesis-inhibitory drug for external use
US7115748B2 (en) * 2004-12-07 2006-10-03 Allergan, Inc. Method of making imidazole-2-thiones
FR2917087B1 (en) * 2007-06-05 2012-09-21 Galderma Res & Dev NOVEL 4-PHENYL-IMIDAZOLE-2-THIONES AS INHIBITORS OF TYROSINASE, PROCESS FOR THEIR PREPARATION AND THEIR USE IN HUMAN MEDICINE AND COSMETICS

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CN101679388A (en) 2010-03-24
KR20100028090A (en) 2010-03-11
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JP2010529097A (en) 2010-08-26
US7989483B2 (en) 2011-08-02
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WO2008152332A1 (en) 2008-12-18
FR2917089B1 (en) 2009-07-17

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