EP3411010A1 - Nouveaux composes propynyl bi-aromatiques, compositions pharmaceutiques et cosmetiques les contenant et utilisations - Google Patents

Nouveaux composes propynyl bi-aromatiques, compositions pharmaceutiques et cosmetiques les contenant et utilisations

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Publication number
EP3411010A1
EP3411010A1 EP17714002.7A EP17714002A EP3411010A1 EP 3411010 A1 EP3411010 A1 EP 3411010A1 EP 17714002 A EP17714002 A EP 17714002A EP 3411010 A1 EP3411010 A1 EP 3411010A1
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Prior art keywords
radical
compounds according
group
radicals
chosen
Prior art date
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EP17714002.7A
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German (de)
English (en)
French (fr)
Inventor
Thibaud Portal
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Galderma Research and Development SNC
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Galderma Research and Development SNC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/19—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups having unsaturation outside the aromatic ring
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • 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
    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/66—Polycyclic acids with unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the invention relates, as new and useful industrial products, to bi-aromatic compounds. It also relates to the use of these novel compounds in pharmaceutical compositions intended for use in human or veterinary medicine, or even in cosmetic compositions.
  • the compounds according to the invention have a marked activity in the fields of cell differentiation and proliferation, and find applications more particularly in the topical and systemic treatment of dermatological disorders linked to a disorder of keratinization, dermatological conditions (or others) with an inflammatory and / or immunoallergic component, and dermal or epidermal proliferations, whether benign or malignant.
  • These compounds can also be used in the treatment of connective tissue degenerative diseases, to fight against aging of the skin, whether photoinduced or chronological, and to treat cicatrization disorders. They also find an application in the ophthalmological field, particularly in the treatment of corneopathies.
  • the compounds according to the invention can also be used in cosmetic compositions for body and hair hygiene.
  • the compounds according to the invention may be represented by the following general formula (I):
  • Ar represents a radical chosen from the radicals of formulas (a) or (b) below:
  • Ri represents: (i) a hydrogen atom
  • R2 and R3 represent a hydrogen atom, a linear or branched alkyl radical having 1 to 20 carbon atoms, a radical -ORg or a radical -SRg, Rg having the meaning given below, it being understood that R2 and R3, taken together, can form with the adjacent aromatic ring a 5- or 6-membered ring optionally substituted with methyl groups and / or optionally interrupted by an oxygen or sulfur atom,
  • R4 represents a hydrogen atom, a halogen atom, a lower alkyl radical or a radical -ORg, Rg having the meaning given below, it being understood that in all of the above:
  • Rg represents a hydrogen atom, a lower alkyl radical, a linear or branched alkyl radical having from 1 to 20 carbon atoms, a radical -O-CH3-R9 or a radical -CO-Rg, Rg having the meaning given herein; -after,
  • R7 represents:
  • - Re represents a hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, an alkenyl radical, a mono or polyhydroxyalkyl radical, an optionally substituted aryl or aralkyl radical or a sugar residue or an amino acid residue; or peptide,
  • Rg represents a lower alkyl radical or methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl,
  • R 'and R represent a hydrogen atom, a lower alkyl radical, a mono or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid or peptide or sugar residue or, taken together, form a heterocycle; ,
  • - 1 is an integer equal to 0,1 or 2
  • the invention also relates to the salts of the compounds of formula (I) above in the case where R 1 represents a carboxylic acid function, as well as the optical and geometric isomers of said compounds.
  • the compounds according to the invention are in the form of salts, they are preferably salts of an alkali metal or alkaline earth metal, or else zinc or an organic amine.
  • lower alkyl radical means a radical having from 1 to 6 carbon atoms, preferably methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.
  • linear or branched alkyl radical having 1 to 20 carbon atoms is meant in particular the methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.
  • monohydroxyalkyl radical is meant a radical preferably having 2 or 3 carbon atoms, especially a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.
  • polyhydroxyalkyl radical is meant a radical preferably containing from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5 radicals. tetrahydroxypentyl or the remainder of pentaerythritol.
  • aryl radical is preferably meant a phenyl radical optionally substituted with at least one halogen atom, a hydroxyl or a nitro function.
  • aralkyl radical is preferably meant benzyl or phenethyl optionally substituted by at least one halogen atom, a hydroxyl or a nitro function.
  • alkenyl radical is meant a radical preferably containing from 1 to 5 carbon atoms and having one or more ethylenic unsaturations, such as more particularly the allyl radical.
  • sugar residue is meant a radical derived in particular glucose, galactose or mannose, or else glucuronic acid.
  • Amino acid residue is understood to mean in particular a residue derived from lysine, glycine or aspartic acid, and by peptide residue is more particularly meant a dipeptide or tripeptide residue resulting from the combination of amino acids. .
  • heterocycle is preferably a piperidino, morpholino, pyrrolidino or piperazino radical, optionally substituted in the 4-position by a C 1 -C 8 alkyl or mono or polyhydroxyalkyl radical as defined above.
  • R 4 and R 5 represent a halogen atom, this is preferably a fluorine, chlorine and bromine atom.
  • the compounds of formula (I) that are more particularly preferred are those for which R5 represents -OH, R7 represents an ORs radical, and Ri 1 represents a radical -ORg, RQ and R-
  • the compounds according to the invention are particularly suitable in the following treatment areas:
  • a keratinization disorder with an inflammatory and / or immunoallergic component and in particular all forms of psoriasis be it cutaneous, mucous or ungueal, and even psoriatic arthritis, or atopic skin, such as eczema or respiratory atopy or gingival hypertrophy; the compounds can also be used in certain inflammatory conditions that do not have a keratinization disorder,
  • the compounds according to the invention can be advantageously used in combination with other compounds with retinoid-like activity, with vitamin D or their derivatives, with corticosteroids, with anti-free radicals ⁇ -hydroxy or ⁇ -keto acids or their derivatives, or again with ion channel blockers.
  • vitamin D or their derivatives is meant, for example, the derivatives of vitamin D2 or D3 and in particular 1,25-dihydroxyvitamin D3.
  • anti-free radicals is meant for example ⁇ -tocopherol, Superoxide Dismutate, Ubiquinol or certain metal chelants.
  • ⁇ -hydroxy or ⁇ -keto acids or their derivatives means lactic, malic, citric, glycolic, mandelic, tartic, glycenic or ascorbic acids or their salts, amides or esters.
  • ion channel blockers for example, means Minoxidil (2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives.
  • the subject of the present invention is also medicinal compositions containing at least one compound of formula (I) as defined above, one of its optical or geometric isomers or one of its salts.
  • the subject of the present invention is thus a novel medicinal composition intended in particular for the treatment of the abovementioned affections, and which is characterized in that it comprises, in a pharmaceutically acceptable carrier and compatible with the mode of administration chosen for the latter, at least one compound of formula (I), one of its optical or geometric isomers or one of its salts.
  • the administration of the compounds according to the invention may be carried out enterally, parenterally, topically or ocularly.
  • the drugs may be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid or polymeric vesicles allowing controlled release.
  • the compositions may be in the form of solutions or suspensions for infusion or for injection.
  • the compounds according to the invention are generally administered at a daily dose of about 0.01 mg / kg to 100 mg / kg of body weight, and this at a rate of 1 to 3 doses.
  • compositions based on compounds according to the invention are more particularly intended for the treatment of skin and mucous membranes and may then be in the form of ointments, creams, milks, ointments, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They may also be in the form of microspheres or nanospheres or lipid or polymeric vesicles or polymeric patches and hydrogels allowing controlled release. These compositions topically can also be in either anhydrous form or in aqueous form, depending on the clinical indication.
  • Eyes are mainly eye drops.
  • compositions for topical or ocular use contain at least one compound of formula (I) as defined above, or one of its optical or geometric isomers or one of its salts, at a concentration preferably between 0.001% and 5% by weight relative to the total weight of the composition.
  • the compounds of formula (I) according to the invention also find application in the cosmetic field, in particular in the personal and capillary hygiene and in particular for the treatment of acne-prone skin, for the regrowth of hair, fall, to fight against the greasiness of the skin or the hair, in the protection against the harmful aspects of the sun or in the treatment of the physiologically dry skins, to prevent and / or to fight against the photo-induced or chronological aging.
  • the compounds according to the invention may also be advantageously used in combination with other compounds with retinoid-type activity, with vitamin D or their derivatives, with corticosteroids, with free radical scavengers, ⁇ -hydroxy or ⁇ -keto acids or their derivatives, or even with ion channel blockers, all these different products being as defined above.
  • the present invention therefore also relates to a cosmetic composition which is characterized in that it comprises, in a cosmetically acceptable carrier and suitable for topical application, at least one compound of formula (I) as defined above or the one of its optical or geometric isomers or one of its salts, this cosmetic composition possibly being in the form of a cream, a milk, a lotion, a gel, microspheres or nanospheres or lipid or polymeric vesicles, soap or shampoo.
  • the concentration of compound of formula (I) in the cosmetic compositions according to the invention is advantageously between 0.001% and 3% by weight relative to the entire composition.
  • the medicinal and cosmetic compositions according to the invention may further contain inert or even pharmacodynamically or cosmetically active additives or combinations of these additives, and especially: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; moisturizing agents such as glycerol, PEG 400, thiamorpholinone, and its derivatives or even urea; antiseborrhoeic or antiacne agents, such as S-carboxymethylcysteine, S-benzylcysteamine, their salts or their derivatives, or benzoyl peroxide; antibiotics such as erythromycin and its esters, neomycin, clindamycin and its esters, tetracyclines; antifungal agents such as ketoconazole or polymethylene-4,5-isothiazolidone-3; hair regrowth agents, such as Minoxidil (2,4-diamino-6-pipe
  • compositions according to the invention may also contain flavor enhancers, preservatives such as parahydroxybenzoic acid esters, stabilizing agents, moisture regulating agents, pH regulating agents, preservatives and the like.
  • preservatives such as parahydroxybenzoic acid esters
  • stabilizing agents moisture regulating agents, pH regulating agents, preservatives and the like.
  • osmotic pressure modifiers such as parahydroxybenzoic acid esters
  • emulsifiers such as parahydroxybenzoic acid esters
  • stabilizing agents moisture regulating agents, pH regulating agents, preservatives and the like.
  • osmotic pressure modifiers such as osmotic pressure modifiers, emulsifiers, UV-A and UV-B filters, antioxidants, such as ⁇ -tocopherol, butylhydroxyanisole or butylhydroxytoluene.
  • Activation of the receptors by an agonist (activator) in HeLa cells leads to the expression of a reporter gene, luciferase, which in the presence of a substrate generates light.
  • Receptor activation can therefore be measured by quantifying the luminescence produced after incubation of the cells in the presence of a reference antagonist.
  • the activating products move the antagonist of its site thus allowing the activation of the receptor.
  • the measurement of the activity is done by the quantification of the increase of the light produced. This measurement makes it possible to determine the activating activity of the compound useful in the invention.
  • KdApp apparent Kd
  • the test product is used at 10 concentrations and the reference antagonist at 7 concentrations.
  • the cells are in contact with a concentration of the test product and a concentration of the reference antagonist.
  • Measurements are also made for total agonist controls otherwise called 100% control (4- [2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) propenyl] - benzoic acid) and inverse agonist control, otherwise known 0% (acid 4 - ⁇ (E) -3- [4- (4-tert-butyl-phenyl) -5,5-tetramethyl-1 8.8 5.6 7,8-tetrahydro-naphthalen-2-yl] -3-oxo-propenyl ⁇ -benzoic acid).
  • the AC50 is calculated by plotting the product curve at the concentration of the reference ligand giving 80% activation. The activation percentage corresponding to the maximum level of activity obtained is also measured.
  • the HeLa cell lines used are stable transfectants containing the ERE-pGlob-Luc-SV-Neo plasmids (reporter gene) and RAR ( ⁇ , ⁇ , ⁇ ) ER-DBD-puro. These cells are inoculated into 96-well plates at the rate of 10,000 cells per well in 00 ⁇ of DMEM medium without phenol red and supplemented with 10% of delipidated calf serum. The plates are then incubated at 37 ° C, 7% CO 2 for 4 hours.
  • the culture medium is removed by inversion and 00 ⁇ l of a 1: 1 PBS (phosphate buffer solution) Luciferin is added to each well. After 5 minutes, the plates are read by the luminescence reader.
  • PBS phosphate buffer solution

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Emergency Medicine (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Urology & Nephrology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pain & Pain Management (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
EP17714002.7A 2016-02-03 2017-02-03 Nouveaux composes propynyl bi-aromatiques, compositions pharmaceutiques et cosmetiques les contenant et utilisations Withdrawn EP3411010A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662290707P 2016-02-03 2016-02-03
PCT/IB2017/000075 WO2017134513A1 (fr) 2016-02-03 2017-02-03 Nouveaux composes propynyl bi-aromatiques, compositions pharmaceutiques et cosmetiques les contenant et utilisations

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EP3411010A1 true EP3411010A1 (fr) 2018-12-12

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FR2767526B1 (fr) 1997-08-21 2002-10-04 Galderma Rech Dermatologique Composes bi-aromatiques relies par un radical heteroethynylene et compositions pharmaceutiques et cosmetiques les contenant
US5256694A (en) * 1984-09-22 1993-10-26 Basf Aktiengesellschaft Diarylacetylenes, their preparation and their use
DE3434946A1 (de) 1984-09-22 1986-04-03 Basf Ag, 6700 Ludwigshafen Diarylacetylene, ihre herstellung und verwendung
KR950014443B1 (ko) * 1986-07-16 1995-11-28 엠. 클리그만 알버트 일광손상된 인체피부를 치료하기 위한 레티노이드를 함유하는 조성물
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AU636595B2 (en) * 1989-01-19 1993-05-06 Ortho Pharmaceutical Corporation Method for the treatment or prevention of intrinsically aged skin with retinoids
CA1335651C (en) 1989-01-20 1995-05-23 Albert M. Kligman Method for the treatment or prevention of intrinsically aged skin with retinoids
FR2713635B1 (fr) 1993-12-15 1996-01-05 Cird Galderma Nouveaux composés propynyl bi-aromatiques, compositions pharmaceutiques et cosmétiques les contenant et utilisations.
US5498795A (en) * 1994-12-29 1996-03-12 Allergan, Inc. Acetylenes disubstituted with hydroxyaryl and aryl or heteroaryl groups having retinoid-like biological activity
US5776699A (en) * 1995-09-01 1998-07-07 Allergan, Inc. Method of identifying negative hormone and/or antagonist activities
FR2746098B1 (fr) * 1996-03-14 1998-04-30 Composes propynyl biaromatiques
TW544448B (en) * 1997-07-11 2003-08-01 Novartis Ag Pyridine derivatives
FR2767525B1 (fr) 1997-08-21 1999-11-12 Cird Galderma Derives biphenyliques substitues par un radical aromatique ou heteroaromatique et compositions pharmaceutiques et cosmetiques les contenant
NZ535616A (en) 2000-11-07 2006-03-31 Novartis Ag Indolymaleimide derivatives as protein kinase c inhibitors
US7226951B2 (en) * 2003-12-17 2007-06-05 Allergan, Inc. Compounds having selective cytochrome P450RAI-1 or selective cytochrome P450RAI-2 inhibitory activity and methods of obtaining the same
FR2894960B1 (fr) 2005-12-15 2008-02-29 Galderma Res & Dev Derives biphenyliques agonistes selectifs du recepteurs rar-gamma
EP2130908A3 (en) * 2006-08-29 2010-01-06 Reinnervate Limited Retinoid compounds and their use
US10995052B2 (en) * 2016-02-03 2021-05-04 Galderma Research & Development Biaromatic propynyl compounds, pharmaceutical and cosmetic compositions containing same, and uses thereof

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BR112018015888B1 (pt) 2021-11-09
KR20180126467A (ko) 2018-11-27
RU2753863C2 (ru) 2021-08-24
RU2018131460A (ru) 2020-03-04
CN109414384A (zh) 2019-03-01
US10995052B2 (en) 2021-05-04
AU2017214615A1 (en) 2018-09-20
US10377694B2 (en) 2019-08-13
US20180079707A1 (en) 2018-03-22
CA3013411A1 (en) 2017-08-10
US20210355067A1 (en) 2021-11-18
JP2019509262A (ja) 2019-04-04
AU2021240298A1 (en) 2021-10-28
AU2021206817A1 (en) 2021-08-12
US20190337881A1 (en) 2019-11-07
WO2017134513A1 (fr) 2017-08-10
EA201891761A1 (ru) 2019-01-31
BR112018015888A2 (pt) 2019-03-06
SG11201806628UA (en) 2018-09-27
MX2018009351A (es) 2019-01-10
RU2018131460A3 (es) 2020-03-24

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