EP2164486A2 - Verwendung von 4-phenyl-imidazol-2-thionen als tyrosinase-hemmer zur herstellung pharmazeutischer oder kosmetischer zusammensetzungen zur behandlung oder vorbeugung von pigmenterkrankungen - Google Patents

Verwendung von 4-phenyl-imidazol-2-thionen als tyrosinase-hemmer zur herstellung pharmazeutischer oder kosmetischer zusammensetzungen zur behandlung oder vorbeugung von pigmenterkrankungen

Info

Publication number
EP2164486A2
EP2164486A2 EP08805933A EP08805933A EP2164486A2 EP 2164486 A2 EP2164486 A2 EP 2164486A2 EP 08805933 A EP08805933 A EP 08805933A EP 08805933 A EP08805933 A EP 08805933A EP 2164486 A2 EP2164486 A2 EP 2164486A2
Authority
EP
European Patent Office
Prior art keywords
thione
dihydroimidazole
compound
imidazole
radical
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.)
Withdrawn
Application number
EP08805933A
Other languages
English (en)
French (fr)
Inventor
Jean-Guy Boiteau
Isabelle Pelisson
Itaru Suzuki
Branislav Musicki
Marielle Berthier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Galderma Research and Development SNC
Original Assignee
Galderma Research and Development SNC
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Galderma Research and Development SNC filed Critical Galderma Research and Development SNC
Publication of EP2164486A2 publication Critical patent/EP2164486A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/42—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
    • A61K2800/782—Enzyme inhibitors; Enzyme antagonists

Definitions

  • the invention relates to the use of 4-phenylimidazole-2-thiones compounds as tyrosinase inhibitors for the preparation of pharmaceutical or cosmetic compositions 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.
  • 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. (Toyofuku K, Wada I, Spritz RA, Hearing VJ, The Molecular Basis of Oculocutaneous Albinism Type 1 (OCA1): Biochem J 2001; 355: 259-269).
  • imidazole-2-thiones derivatives already known, 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). Others have been reported in US4798843 to be dopamine-beta-hydroxylase inhibitors. The compounds described in this patent are effective in preventing gastric ulcers.
  • EP131973 also teaches the use of certain compounds derived from imidazole-2-thiones as inhibitors of gastric acid secretion useful in the treatment against ulcers
  • Patent JP05132422 discloses the use of certain imidazole-2-thiones as a tyrosinase inhibitor. However, no aryl-substituted imidazole-2-thiones derivative is described in this document. No tyrosinase inhibitory activity is shown for compounds of 4-aryl-imidazole-2-thione structure. However, the Applicant has unexpectedly and surprisingly found that certain compounds of 4-phenyl-imidazole-2-thione structure, object of the present invention have a tyrosinase inhibitory activity much greater than that of the compounds of Patent JP05132422.
  • the present invention relates to the use of the compounds of general formula (I) below for the preparation of a pharmaceutical composition for the treatment or prevention of pigment disorders:
  • R1 and R2 identical or different, represent:
  • R1 and R2 which are identical or different, represent a C1-C5 alkyl radical, or form a a hydrocarbon ring with 5 or 6 atoms, it being understood that 1 or 2 carbon atom (s) of said hydrocarbon ring may optionally be replaced by 1 or 2 oxygen atom (s),
  • 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.
  • 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.
  • 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 an alkyl radical comprising from 1 to 4 carbon atoms.
  • the C1-C4 alkoxycarbonyl radical is chosen from the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl radicals.
  • C 1 -C 6 alkoxy denotes an oxygen atom substituted with 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.
  • halogen is a fluorine, chlorine or bromine atom.
  • the preferred compounds of general formula (I) are those for which R1 and R2, which may be identical or different, represent a hydrogen or 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: R2 represents a hydrogen and - R1 represents a hydrogen or a C1-C7 alkyl radical or a C3-C7 cycloalkyl radical.
  • the compounds of the present invention have an IC 50 value (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 their 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, and preferably hyperpigmentary disorders.
  • the compounds used according to the invention are particularly suitable for the treatment and / or prevention of pigment disorders, and preferably hyperpigmentary disorders such as melasma, chloasma, lentigines, senile lentigo, irregular hyperpigmentations related photo aging, freckles, post-inflammatory hyperpigmentations due to abrasion and / or burning and / or scarring and / or dermatitis and / or contact allergy; nevi, hyperpigmentations with genetic determinism, hyperpigmentations of metabolic or medicinal origin, melanomas or any other hyperpigmentary lesion.
  • hyperpigmentary disorders such as melasma, chloasma, lentigines, senile lentigo, irregular hyperpigmentations related photo aging, freckles, post-inflammatory hyperpigmentations due to abrasion and / or burning and / or scarring and / or dermatitis and / or contact allergy; nevi, hyperpigmentations
  • the subject of the present invention is also a pharmaceutical composition intended in particular for the treatment of the abovementioned affections, and which comprises, in a pharmaceutically acceptable carrier and compatible with the mode of administration chosen for the latter, a compound of general formula (I) under a 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 under 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.
  • 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.
  • composition comprising, in a cosmetically acceptable support, at least one of the compounds 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 10% by weight, relative to the total weight of the composition.
  • 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 are UV-A and UV-B filters
  • antioxidants such as ⁇ -tocopherol, butyl-hydroxy-anisole or butyl-hydroxy-toluene, 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 derivatives, or benzoyl peroxide;
  • 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, treated with Trypsin, washed in PBS, and counted.
  • 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 resulting supernatant constitutes the cell lysate used as a source of tyrosinase in the enzyme test.
  • the tests are carried out in duplicate in 384-well plates under a total volume of 50 ⁇ l. Each well contains: - 40 ⁇ l of solution containing 1.25 mM L-tyrosine, 6.25 ⁇ M L-DOPA (cofactor) and 3.75 mM MBTH in buffer B (sodium phosphate 62.25 mM pH 6.8 - 2.5% dimethylformamide)
  • 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
  • control 50% of activity the 5 .mu.l of inhibitor are replaced by 5 .mu.l of phenylthiourea at 300 .mu.M in DMSO

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dermatology (AREA)
  • Birds (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)
EP08805933A 2007-06-05 2008-06-04 Verwendung von 4-phenyl-imidazol-2-thionen als tyrosinase-hemmer zur herstellung pharmazeutischer oder kosmetischer zusammensetzungen zur behandlung oder vorbeugung von pigmenterkrankungen Withdrawn EP2164486A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0755468A FR2916976B1 (fr) 2007-06-05 2007-06-05 Utilisation de 4-phenyl-imidazole-2-thiones comme inhibiteurs de la tyrosinase, pour la preparation de composition pharmaceutiques ou cosmetiques destinees au traitement ou a la prevention des desordres pigmentaires.
PCT/FR2008/050993 WO2008152330A2 (fr) 2007-06-05 2008-06-04 Utilisation de 4-phenyl-imidazole-2-thiones comme inhibiteurs de la tyrosinase, pour la préparation de compositions pharmaceutiques ou cosmétiques destinées au traitement ou à la prévention des désordres pigmentaires

Publications (1)

Publication Number Publication Date
EP2164486A2 true EP2164486A2 (de) 2010-03-24

Family

ID=38866280

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08805933A Withdrawn EP2164486A2 (de) 2007-06-05 2008-06-04 Verwendung von 4-phenyl-imidazol-2-thionen als tyrosinase-hemmer zur herstellung pharmazeutischer oder kosmetischer zusammensetzungen zur behandlung oder vorbeugung von pigmenterkrankungen

Country Status (11)

Country Link
US (1) US20100160401A1 (de)
EP (1) EP2164486A2 (de)
JP (1) JP2010529095A (de)
KR (1) KR20100017632A (de)
CN (1) CN101678000A (de)
AU (1) AU2008263665A1 (de)
CA (1) CA2688234A1 (de)
FR (1) FR2916976B1 (de)
MX (1) MX2009012711A (de)
RU (1) RU2009148786A (de)
WO (1) WO2008152330A2 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013083645A2 (en) * 2011-12-07 2013-06-13 Unilever Plc Skin lightening composition

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4798843A (en) * 1987-07-09 1989-01-17 Smithkline Beckman Corporation 2-mercaproimidazole dopamine-β-hydroxylase inhibitors
JPH05124923A (ja) * 1991-04-09 1993-05-21 Sansho Seiyaku Co Ltd メラニン生成抑制外用剤
JPH05132422A (ja) * 1991-04-09 1993-05-28 Sansho Seiyaku Co Ltd メラニン生成抑制外用剤
FR2917087B1 (fr) * 2007-06-05 2012-09-21 Galderma Res & Dev Nouveaux 4-phenyl-imidazole-2-thiones comme inhibiteurs de la tyrosinase, leur procede de preparation et leur utilisation en medecine humaine ainsi qu'en cosmetique.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008152330A2 *

Also Published As

Publication number Publication date
CA2688234A1 (fr) 2008-12-18
AU2008263665A1 (en) 2008-12-18
MX2009012711A (es) 2009-12-08
FR2916976B1 (fr) 2009-09-04
CN101678000A (zh) 2010-03-24
JP2010529095A (ja) 2010-08-26
WO2008152330A2 (fr) 2008-12-18
RU2009148786A (ru) 2011-07-20
US20100160401A1 (en) 2010-06-24
KR20100017632A (ko) 2010-02-16
WO2008152330A3 (fr) 2009-02-26
FR2916976A1 (fr) 2008-12-12

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