EP1998779A2 - Use of (3s)-n-hydroxy-4-({4-ý(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide or (s)-n-hydroxy-4-(4-but-2-ynyloxy-benzenesulfonyl) -2,2-dimethyl-thiomorpholine -3-carboxamide for treating inflammatory skin pathologies - Google Patents

Use of (3s)-n-hydroxy-4-({4-ý(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide or (s)-n-hydroxy-4-(4-but-2-ynyloxy-benzenesulfonyl) -2,2-dimethyl-thiomorpholine -3-carboxamide for treating inflammatory skin pathologies

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Publication number
EP1998779A2
EP1998779A2 EP07731755A EP07731755A EP1998779A2 EP 1998779 A2 EP1998779 A2 EP 1998779A2 EP 07731755 A EP07731755 A EP 07731755A EP 07731755 A EP07731755 A EP 07731755A EP 1998779 A2 EP1998779 A2 EP 1998779A2
Authority
EP
European Patent Office
Prior art keywords
hydroxy
pharmaceutically acceptable
carboxamide
dimethyl
thiomorpholine
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Withdrawn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
EP07731755A
Other languages
German (de)
French (fr)
Inventor
Thibaud Biadatti
Marlène SCHUPPLI
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 EP1998779A2 publication Critical patent/EP1998779A2/en
Withdrawn legal-status Critical Current

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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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a new use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable solvates or hydrates, for the preparation of a medicament for preventing and / or treating inflammatory pathologies cutaneous and preferentially eczema or psoriasis.
  • Patent application WO 00/44709 discloses a family of hydroxamic acid derivatives arylsulfonamide, inhibitors of TNF-alpha converting enzyme, which are useful for the treatment or prevention of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, aprodontal disease, transplant rejection, insulin resistance, bone disease and AIDS.
  • the present invention thus relates to the use of at least one compound chosen from the following compounds of formula (I):
  • R corresponds to a -CH3 radical or a CH 2 OH radical
  • their pharmaceutically acceptable salts their pharmaceutically acceptable solvates or their hydrates
  • a medicament for preventing and / or treating inflammatory skin diseases.
  • pathologies include all forms of psoriasis, whether cutaneous, mucous or ungual, psoriatic arthritis, or atopy skin, such as eczema or respiratory atopy or gingival hypertrophy.
  • the invention relates more specifically to the use of (3S) -N-hydroxy-4 - ( ⁇ 4 - [(4-hydroxy-2-butynyl) oxy] phenyl ⁇ sulfonyl) -2,2-dimethyl-3-thiomorpholine carboxamide (or Apratastat) or (S) -N-Hydroxy-4- (4-but-2-ynyloxy-benzenesulfonyl) -2,2-dimethyl-thiomorpholine-3-carboxamide, a pharmaceutically acceptable salt thereof, pharmaceutically acceptable solvates or hydrates for the preparation of a medicament for preventing and / or treating inflammatory skin diseases.
  • the salts of the compounds of formula (I) according to the invention include salts with organic or inorganic bases, for example the alkali metal salts, such as the lithium, sodium and potassium salts.
  • hydrate of a compound of formula (I) is meant the combination of this compound with one or more molecules of water.
  • solvate of a compound of formula (I) is meant the association resulting from the attachment of a solvent to the crystals of compound of formula (I) formed in the presence of this solvent.
  • the compounds of formula (I), their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates or their hydrates must be formulated into a pharmaceutical composition, preferably a dermatological composition.
  • compositions especially dermatological compositions, comprising at least one compound chosen from compounds of formula (I) in which R corresponds to a -CH3 radical or a CH 2 OH radical, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and their hydrates, for the treatment and / or prevention of inflammatory skin diseases, and in particular all forms of psoriasis, whether it is cutaneous, mucous or ungual, and even psoriatic arthritis, or cutaneous atopy, such as eczema or respiratory atopy or gingival hypertrophy.
  • R corresponds to a -CH3 radical or a CH 2 OH radical
  • their pharmaceutically acceptable salts their pharmaceutically acceptable solvates and their hydrates
  • the present invention more particularly relates to pharmaceutical compositions, especially dermatological compositions, comprising at least one compound chosen from the compounds of formula (I), their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates or their hydrates, preferentially for the treatment and / or the prevention of eczema or psoriasis.
  • compositions may be intended and therefore suitable for oral, topical, enteral, parenteral, ocular, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration.
  • the compound of formula (I) optionally in the form of a pharmaceutically acceptable salt, solvate and / or hydrate, alone or in combination with another active ingredient, may be administered in unit dosage form, in admixture with conventional pharmaceutical carriers or excipients to animals and humans.
  • the pharmaceutical composition is packaged in a form suitable for oral or topical administration.
  • compositions according to the invention comprise at least one compound of formula (I), or one of its pharmaceutically acceptable salts, pharmaceutically acceptable solvates or hydrates, in an amount sufficient to obtain the desired prophylactic or therapeutic effect.
  • the dosage varies with the age, sex and weight of the patient.
  • the compound of formula (I), or one of its salts, solvates or hydrates will preferably be administered at a rate of from 0.01 to 100 mg / kg and per day, advantageously from 0.01 to 50 mg / kg, and day. It is also possible to administer such doses in 2 to 4 daily administrations. Although these assays are examples of average situations, there may be special cases where higher or lower dosages are appropriate, such assays also belong to the invention.
  • compositions according to the invention comprise a physiologically acceptable carrier or at least one pharmaceutically acceptable excipient, chosen according to the pharmaceutical form, in particular the dermatological form, desired and the mode of administration chosen.
  • physiologically acceptable carrier and pharmaceutically acceptable excipient are meant respectively a carrier and excipient compatible with the skin, mucous membranes and integuments.
  • the pharmaceutical or dermatological composition may be in the form of tablets, capsules, dragees, pills, syrups, suspensions, solutions, powders, granules, emulsions, capsules, microspheres or nanospheres or lipid or polymeric vesicles for controlled release.
  • the composition may be in the form of solutions or suspensions for infusion or injection.
  • the active ingredient may be mixed with at least one inert diluent, such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • other additives such as a lubricant such as magnesium stearate, may be added.
  • a buffer may be added in the case of capsules, tablets or pills in particular.
  • an inert diluent such as water may be used.
  • the pharmaceutical composition according to the invention is more particularly intended for the treatment of the skin and mucous membranes and may be present in the form of ointments, creams, milks, ointments, powders, soaked swabs, syndets, solutions, gels, sprays, mousses, suspensions, lotions, 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 patches and hydrogels allowing controlled release.
  • This topical composition may be in anhydrous form, in aqueous form or in the form of an emulsion.
  • the compound of formula (I), or one of its salts, solvates or hydrates, when administered topically is used at a concentration generally of between 0.001 and 10% by weight, preferably between 0.01 and 5%. by weight, relative to the total weight of the composition.
  • compositions as described above may therefore contain inert or even pharmacodynamically active additives, or combinations of these additives, and in particular:
  • pH regulating agents osmotic pressure modifying agents; emulsifying agents;
  • UV-A and UV-B filters are UV-A and UV-B filters
  • antioxidants such as ⁇ -tocopherol, butylhydroxyanisole or butylhydroxytoluene, superoxide dismutase, ubiquinol or certain metal chelators;
  • depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid;
  • 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;
  • antibiotics such as erythromycin and its esters, neomycin, clindamycin and its esters, tetracyclines;
  • antifungal agents such as ketoconazole or polymethylene-4,5-isothiazolidones-3;
  • Minoxidil (2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine); 1,1-dioxide) and phenytoin (5,4-diphenylimidazolidine 2,4-dione);
  • anti-psoriatic agents such as anthralin and its derivatives; - eicosa-5,8,11,14-tetraynoic and eicosa-5,8,11-triynoic acids, their esters and amides;
  • retinoids that is to say ligands of the RAR or RXR receptors, natural or synthetic;
  • VDR receptors ligands of VDR receptors
  • - corticosteroids or estrogens ligands of VDR receptors
  • ⁇ -hydroxy acids and ⁇ -keto acids or their derivatives such as lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acids, as well as their salts, amides or esters, or ⁇ -hydroxy acids or their derivatives, such as salicylic acid and its salts, amides or esters; ion channel blockers such as potassium channels; or, more particularly for the pharmaceutical compositions, in combination with medicaments known to interfere with the immune system (for example cyclosporin, FK 506, glucocorticoids, monoclonal antibodies, soluble receptors, cytokines or of growth ).
  • medicaments known to interfere with the immune system for example cyclosporin, FK 506, glucocorticoids, monoclonal antibodies, soluble receptors, cytokines or of growth .
  • the compounds of formula (I) are especially synthesized as described in application WO00 / 44709.
  • the edema is induced by a single application of 20 ⁇ l of TPA dissolved in acetone at 0.01%.
  • the test compound is diluted in the TPA solution and applied at a concentration of 0.1%, 0.3% and 1%.
  • VdB ⁇ -methasone valerate
  • Apratastat has a dose-dependent anti-inflammatory effect, and reduces TPA-induced ear edema by 25% (NS) (at 0.1%), 47% (**) (at 0.3%) and 49% (**) (at 1%).

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to the use of a compound of formula (I) wherein R corresponds to a -CH3 radical or a CH<SUB>2</SUB>OH radical, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate thereof, for preparing a medicament for preventing and/or treating inflammatory skin pathologies. The invention more precisely relates to the use of (3S)-N-hydroxy-4-({4-[(4- hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide (or apratastat) or (S)-N-hydroxy-4-(4-but-2-ynyloxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxamide, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvent or hydrate thereof, for preparating a medicament for preventing and/or treating inflammatory skin pathologies.

Description

Utilisation du (3S)-N-hydroxy-4-({4-[(4-hydroxy-2-butynyl)oxy]phényl}sulfonyl)-Use of (3S) -N-hydroxy-4 - ({4 - [(4-hydroxy-2-butynyl) oxy] phenyl} sulfonyl) -
2,2-diméthyl-3-thiomorpholine carboxamide ou du (S)-N-Hydroxy-4-(4-but-2- ynyloxy-benzenesulfonyl) -2,2-dimethyl-thiomorpholine -3-carboxamide dans le traitement de pathologies inflammatoires cutanées.2,2-dimethyl-3-thiomorpholine carboxamide or (S) -N-Hydroxy-4- (4-but-2-ynyloxy-benzenesulfonyl) -2,2-dimethyl-thiomorpholine-3-carboxamide in the treatment of pathologies inflammatory skin.
La présente invention concerne une nouvelle utilisation d'un composé de formule (I) ou d'un de ses sels pharmaceutiquement acceptables, solvats pharmaceutiquement acceptables ou hydrates, pour la préparation d'un médicament destiné à prévenir et/ou à traiter des pathologies inflammatoires cutanées et préférentiellement l'eczéma ou le psoriasis.The present invention relates to a new use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable solvates or hydrates, for the preparation of a medicament for preventing and / or treating inflammatory pathologies cutaneous and preferentially eczema or psoriasis.
La demande de brevet WO 00/44709 décrit une famille de dérivés d'acide hydroxamique arylsulfonamide, inhibiteurs de l'enzyme de conversion du TNF- alpha, qui sont utiles pour le traitement ou la prévention de l'arthrite, de métastases tumorales, de l'ulcération des tissus, une cicatrisation anormale des plaies, de maladies aprodontales, du rejet de greffe, de la résistance à l'insuline, de maladies des os et du SIDA.Patent application WO 00/44709 discloses a family of hydroxamic acid derivatives arylsulfonamide, inhibitors of TNF-alpha converting enzyme, which are useful for the treatment or prevention of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, aprodontal disease, transplant rejection, insulin resistance, bone disease and AIDS.
Il a maintenant été trouvé, de façon inattendue, que certains des composés de cette demande étaient actifs pour prévenir et/ou traiter des pathologies inflammatoires cutanées, et préférentiellement l'eczéma ou le psoriasis.It has now been found, unexpectedly, that some of the compounds of this application were active in preventing and / or treating inflammatory skin diseases, and preferentially eczema or psoriasis.
La présente invention se rapporte donc à l'utilisation d'au moins un composé choisi parmi les composés de formule (I) suivante:The present invention thus relates to the use of at least one compound chosen from the following compounds of formula (I):
dans laquelle R correspond à un radical -CH3 ou un radical CH2OH, leurs sels pharmaceutiquement acceptables, leurs solvats pharmaceutiquement acceptables ou leurs hydrates, pour la préparation d'un médicament destiné à prévenir et/ou à traiter les pathologies inflammatoires cutanées. Ces pathologies sont notamment toutes les formes de psoriasis, qu'il soit cutané, muqueux ou unguéal, le rhumatisme psoriasique, ou encore l'atopie cutanée, telle que l'eczéma ou l'atopie respiratoire ou encore l'hypertrophie gingivale.in which R corresponds to a -CH3 radical or a CH 2 OH radical, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates or their hydrates, for the preparation of a medicament for preventing and / or treating inflammatory skin diseases. These pathologies include all forms of psoriasis, whether cutaneous, mucous or ungual, psoriatic arthritis, or atopy skin, such as eczema or respiratory atopy or gingival hypertrophy.
L'invention concerne plus précisément l'utilisation du (3S)-N-hydroxy-4-({4-[(4- hydroxy-2-butynyl)oxy]phényl}sulfonyl)-2,2-diméthyl-3-thiomorpholine carboxamide (ou Apratastat) ou du (S)-N-Hydroxy-4-(4-but-2-ynyloxy-benzenesulfonyl) -2,2- dimethyl-thiomorpholine-3-carboxamide, d'un de ses sels pharmaceutiquement acceptables, solvats pharmaceutiquement acceptables ou hydrates, pour la préparation d'un médicament destiné à prévenir et/ou à traiter les pathologies inflammatoires cutanées.The invention relates more specifically to the use of (3S) -N-hydroxy-4 - ({4 - [(4-hydroxy-2-butynyl) oxy] phenyl} sulfonyl) -2,2-dimethyl-3-thiomorpholine carboxamide (or Apratastat) or (S) -N-Hydroxy-4- (4-but-2-ynyloxy-benzenesulfonyl) -2,2-dimethyl-thiomorpholine-3-carboxamide, a pharmaceutically acceptable salt thereof, pharmaceutically acceptable solvates or hydrates for the preparation of a medicament for preventing and / or treating inflammatory skin diseases.
Les sels des composés de formule (I) selon l'invention comprennent des sels avec des bases organiques ou minérales, par exemple les sels des métaux alcalins, comme les sels de lithium, de sodium, de potassium.The salts of the compounds of formula (I) according to the invention include salts with organic or inorganic bases, for example the alkali metal salts, such as the lithium, sodium and potassium salts.
Par hydrate d'un composé de formule (I), on entend la combinaison de ce composé avec une ou plusieurs molécules d'eau.By hydrate of a compound of formula (I) is meant the combination of this compound with one or more molecules of water.
Par solvat d'un composé de formule (I), on entend l'association résultant de la fixation d'un solvant sur les cristaux de composé de formule (I) formés en présence de ce solvant.By solvate of a compound of formula (I) is meant the association resulting from the attachment of a solvent to the crystals of compound of formula (I) formed in the presence of this solvent.
Pour leur utilisation en tant que médicament, les composés de formule (I), leurs sels pharmaceutiquement acceptablesjeurs solvats pharmaceutiquement acceptables ou leurs hydrates, doivent être formulés en composition pharmaceutique, de préférence dermatologique.For their use as a medicament, the compounds of formula (I), their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates or their hydrates, must be formulated into a pharmaceutical composition, preferably a dermatological composition.
La présente invention a donc également pour objet des compositions pharmaceutiques, notamment dermatologiques, comprenant au moins un composé choisi parmi les composés de formule (I) dans laquelle R correspond à un radical -CH3 ou un radical CH2OH, leurs sels pharmaceutiquement acceptables, leurs solvats pharmaceutiquement acceptables et leurs hydrates, pour le traitement et/ou la prévention des pathologies inflammatoires cutanées, et notamment toutes les formes de psoriasis, qu'il soit cutané, muqueux ou unguéal, et même le rhumatisme psoriasique, ou encore l'atopie cutanée, telle que l'eczéma ou l'atopie respiratoire ou encore l'hypertrophie gingivale.The subject of the present invention is therefore also pharmaceutical compositions, especially dermatological compositions, comprising at least one compound chosen from compounds of formula (I) in which R corresponds to a -CH3 radical or a CH 2 OH radical, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and their hydrates, for the treatment and / or prevention of inflammatory skin diseases, and in particular all forms of psoriasis, whether it is cutaneous, mucous or ungual, and even psoriatic arthritis, or cutaneous atopy, such as eczema or respiratory atopy or gingival hypertrophy.
La présente invention a plus particulièrement pour objet des compositions pharmaceutiques, notamment dermatologiques, comprenant au moins un composé choisi parmi les composés de formule (I), leurs sels pharmaceutiquement acceptables, leurs solvats pharmaceutiquement acceptables ou leurs hydrates, préférentiellement pour le traitement et/ou la prévention de l'eczéma ou du psoriasis.The present invention more particularly relates to pharmaceutical compositions, especially dermatological compositions, comprising at least one compound chosen from the compounds of formula (I), their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates or their hydrates, preferentially for the treatment and / or the prevention of eczema or psoriasis.
De telles compositions peuvent être destinées, et donc adaptées, à une administration par voie orale, topique, entérale, parentérale, oculaire, sublinguale, inhalée, sous-cutanée, intramusculaire, intraveineuse, transdermique, locale ou rectale. Le composé de formule (I), éventuellement sous la forme d'un sel, solvat et/ou hydrate, pharmaceutiquement acceptable, seul ou en association avec un autre principe actif, peut être administré sous une forme unitaire d'administration, en mélange avec des supports ou excipients pharmaceutiques classiques, aux animaux et aux êtres humains. De préférence, la composition pharmaceutique est conditionnée sous une forme convenant à une administration par voie orale ou topique.Such compositions may be intended and therefore suitable for oral, topical, enteral, parenteral, ocular, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration. The compound of formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate and / or hydrate, alone or in combination with another active ingredient, may be administered in unit dosage form, in admixture with conventional pharmaceutical carriers or excipients to animals and humans. Preferably, the pharmaceutical composition is packaged in a form suitable for oral or topical administration.
Les compositions selon l'invention comprennent au moins un composé de formule (I), ou un de ses sels pharmaceutiquement acceptables, solvats pharmaceutiquement acceptables ou hydrates, en quantité suffisante pour obtenir l'effet prophylactique ou thérapeutique souhaité. La posologie utile varie selon l'âge, le sexe et le poids du patient.The compositions according to the invention comprise at least one compound of formula (I), or one of its pharmaceutically acceptable salts, pharmaceutically acceptable solvates or hydrates, in an amount sufficient to obtain the desired prophylactic or therapeutic effect. The dosage varies with the age, sex and weight of the patient.
Le composé de formule (I), ou un de ses sels, solvats ou hydrates sera, de préférence, administré à raison de 0,01 à 100 mg/kg et par jour, avantageusement de 0,01 à 50 mg/kg et par jour. Il est également possible d'administrer de telles doses, en 2 à 4 administrations quotidiennes. Bien que ces dosages soient des exemples de situations moyennes, il peut y avoir des cas particuliers où des dosages plus élevés ou plus faibles sont appropriés, de tels dosages appartiennent également à l'invention.The compound of formula (I), or one of its salts, solvates or hydrates, will preferably be administered at a rate of from 0.01 to 100 mg / kg and per day, advantageously from 0.01 to 50 mg / kg, and day. It is also possible to administer such doses in 2 to 4 daily administrations. Although these assays are examples of average situations, there may be special cases where higher or lower dosages are appropriate, such assays also belong to the invention.
Les compositions selon l'invention comprennent un support physiologiquement acceptable ou au moins un excipient pharmaceutiquement acceptable, choisi selon la forme pharmaceutique, notamment dermatologique, souhaitée et le mode d'administration choisi.The compositions according to the invention comprise a physiologically acceptable carrier or at least one pharmaceutically acceptable excipient, chosen according to the pharmaceutical form, in particular the dermatological form, desired and the mode of administration chosen.
Par support physiologiquement acceptable et excipient pharmaceutiquement acceptable, on entend respectivement un support et un excipient compatibles avec la peau, les muqueuses et les phanères.By physiologically acceptable carrier and pharmaceutically acceptable excipient is meant respectively a carrier and excipient compatible with the skin, mucous membranes and integuments.
Pour une administration par voie orale, la composition pharmaceutique ou dermatologique, peut se présenter sous la forme de comprimés, de gélules, de dragées, de pilules, de sirops, de suspensions, de solutions, de poudres, de granulés, d'émulsions, de capsules, de microsphères ou nanosphères ou vésicules lipidiques ou polymériques permettant une libération contrôlée. Par voie parentérale, la composition peut se présenter sous forme de solutions ou suspensions pour perfusion ou pour injection.For an oral administration, the pharmaceutical or dermatological composition may be in the form of tablets, capsules, dragees, pills, syrups, suspensions, solutions, powders, granules, emulsions, capsules, microspheres or nanospheres or lipid or polymeric vesicles for controlled release. Parenterally, the composition may be in the form of solutions or suspensions for infusion or injection.
Pour obtenir une composition solide pour administration orale, le principe actif pourra être mélangé avec au moins un diluant inerte, tel que le sucrose, le lactose ou l'amidon. En général, d'autres additifs, tel qu'un lubrifiant comme le stéarate de magnésium, pourront être ajoutés. Dans le cas de capsules, comprimés ou pilules notamment, un tampon pourra être ajouté. Dans le cas des compositions liquides orales, un diluant inerte tel que de l'eau pourra être utilisé.To obtain a solid composition for oral administration, the active ingredient may be mixed with at least one inert diluent, such as sucrose, lactose or starch. In general, other additives, such as a lubricant such as magnesium stearate, may be added. In the case of capsules, tablets or pills in particular, a buffer may be added. In the case of oral liquid compositions, an inert diluent such as water may be used.
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 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 lotions, de sticks, de shampoings, ou de bases lavantes. Elle peut également se présenter sous forme de suspensions de microsphères ou nanosphères ou vésicules lipidiques ou polymériques ou de patches polymériques et d'hydrogels permettant une libération contrôlée. Cette composition par voie topique peut se présenter sous forme anhydre, sous forme aqueuse ou sous la forme d'une émulsion.Topically, the pharmaceutical composition according to the invention is more particularly intended for the treatment of the skin and mucous membranes and may be present in the form of ointments, creams, milks, ointments, powders, soaked swabs, syndets, solutions, gels, sprays, mousses, suspensions, lotions, 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 patches and hydrogels allowing controlled release. This topical composition may be in anhydrous form, in aqueous form or in the form of an emulsion.
Le composé de formule (I), ou un de ses sels, solvats ou hydrates, lorsqu'il est administré par voie orale est administré à raison de 0,01 à 100 mg/kg et par jour, avantageusement de 0,01 à 50 mg/kg.The compound of formula (I), or one of its salts, solvates or hydrates, when administered orally is administered at a rate of 0.01 to 100 mg / kg and per day, advantageously from 0.01 to 50 mg / kg.
Le composé de formule (I), ou un de ses sels, solvats ou hydrates, lorsqu'il est administré par voie topique est utilisé à une concentration 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.The compound of formula (I), or one of its salts, solvates or hydrates, when administered topically is used at a concentration generally of between 0.001 and 10% by weight, preferably between 0.01 and 5%. by weight, relative to the total weight of the composition.
On peut également utiliser, pour le traitement d'une pathologie inflammatoire cutanée, et plus particulièrement de l'eczéma ou du psoriasis, au moins un composé de formule (I), ou un de ses sels pharmaceutiquement acceptables ou un de ses solvats pharmaceutiquement acceptables ou hydrates, en association avec un autre principe actif.It is also possible to use, for the treatment of an inflammatory skin pathology, and more particularly eczema or psoriasis, at least one compound of formula (I), or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof or hydrates, in combination with another active ingredient.
Les compositions pharmaceutiques et dermatologiques telles que décrites précédemment peuvent donc contenir des additifs inertes, ou même pharmacodynamiquement actifs, ou des combinaisons de ces additifs, et notamment :The pharmaceutical and dermatological compositions as described above may therefore contain inert or even pharmacodynamically active additives, or combinations of these additives, and in particular:
- des agents mouillants ; - des agents d'amélioration de la saveur ;- wetting agents; - flavor enhancers;
- des agents conservateurs tels que les esters de l'acide parahydroxybenzoïque ;preserving agents such as esters of parahydroxybenzoic acid;
- des agents stabilisants ;stabilizing agents;
- des agents régulateurs d'humidité ;humidity regulating agents;
- des agents régulateurs de pH ; - des agents modificateurs de pression osmotique ; - des agents émulsionnants ;pH regulating agents; osmotic pressure modifying agents; emulsifying agents;
- des filtres UV-A et UV-B ;UV-A and UV-B filters;
- des antioxydants, tels que l'α-tocophérol, le butylhydroxyanisole ou le butylhydroxytoluène, la super oxyde dismutase, l'ubiquinol ou certains chélatants de métaux ;antioxidants, such as α-tocopherol, butylhydroxyanisole or butylhydroxytoluene, superoxide dismutase, ubiquinol or certain metal chelators;
- des agents dépigmentants tels que l'hydroquinone, l'acide azélaïque, l'acide caféïque ou l'acide kojique ;depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid;
- des émollients ;- emollients;
- des agents hydratants comme le glycérol, le PEG 400, la thiamorpholinone, et ses dérivés ou l'urée ;moisturizing agents such as glycerol, PEG 400, thiamorpholinone, and its derivatives or urea;
- des agents antiséborrhéiques ou antiacnéiques, tels que la S- carboxyméthylcystéine, la S-benzyl-cystéamine, leurs sels ou leurs dérivés, ou le peroxyde de benzoyle ;antiseborrhoeic or antiacne agents, such as S-carboxymethylcysteine, S-benzylcysteamine, their salts or their derivatives, or benzoyl peroxide;
- des antibiotiques comme l'érythromycine et ses esters, la néomycine, la clindamycine et ses esters, les tétracyclines ;antibiotics such as erythromycin and its esters, neomycin, clindamycin and its esters, tetracyclines;
- des agents antifongiques tels que le kétoconazole ou les polyméthylène-4,5 isothiazolidones-3 ;antifungal agents such as ketoconazole or polymethylene-4,5-isothiazolidones-3;
- des agents favorisant la repousse des cheveux, comme le Minoxidil (2,4-diamino- 6-pipéridino-pyrimidine-3-oxyde) et ses dérivés, le Diazoxide (7-chloro 3-méthyl 1,2,4- benzothiadiazine-1 ,1-dioxyde) et le Phénytoïne (5,4-diphényl-imidazolidine 2,4-dione) ;agents promoting the regrowth of the hair, such as Minoxidil (2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine); 1,1-dioxide) and phenytoin (5,4-diphenylimidazolidine 2,4-dione);
- des agents anti-inflammatoires non stéroïdiens ;nonsteroidal anti-inflammatory agents;
- des caroténoïdes et, notamment, le β-carotène ;carotenoids and, in particular, β-carotene;
- des agents anti-psoriatiques tels que l'anthraline et ses dérivés; - des acides eicosa-5,8,11,14-tétraynoïque et eicosa-5,8,11-triynoïque, leurs esters et amides ;anti-psoriatic agents such as anthralin and its derivatives; - eicosa-5,8,11,14-tetraynoic and eicosa-5,8,11-triynoic acids, their esters and amides;
- des rétinoïdes, c'est à dire des ligands des récepteurs RAR ou RXR, naturels ou synthétiques ;retinoids, that is to say ligands of the RAR or RXR receptors, natural or synthetic;
- des ligands des récepteurs VDR ; - des corticostéroïdes ou des œstrogènes ;ligands of VDR receptors; - corticosteroids or estrogens;
- des α-hydroxy acides et des α-céto acides ou leurs dérivés, tels que les acides lactique, malique, citrique, glycolique, mandélique, tartrique, glycérique, ascorbique, ainsi que leurs sels, amides ou esters, ou des β-hydroxy acides ou leurs dérivés, tels que l'acide salicylique ainsi que ses sels, amides ou esters ; - des bloqueurs de canaux ioniques tels que les canaux potassiques ; - ou encore, plus particulièrement pour les compositions pharmaceutiques, en association avec des médicaments connus pour interférer avec le système immunitaire (par exemple, la cyclosporine, le FK 506, les glucocorticoïdes, les anticorps monoclonaux, les récepteurs solubles, les cytokines ou les facteurs de croissance...).α-hydroxy acids and α-keto acids or their derivatives, such as lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acids, as well as their salts, amides or esters, or β-hydroxy acids or their derivatives, such as salicylic acid and its salts, amides or esters; ion channel blockers such as potassium channels; or, more particularly for the pharmaceutical compositions, in combination with medicaments known to interfere with the immune system (for example cyclosporin, FK 506, glucocorticoids, monoclonal antibodies, soluble receptors, cytokines or of growth ...).
Bien entendu, l'homme du métier veillera à choisir le ou les éventuels composés à ajouter à ces compositions de telle manière que l'effet sur le psoriasis ou l'eczéma désiré ne soit pas, ou substantiellement pas altéré 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 effect on psoriasis or the desired eczema is not, or not substantially, impaired by the envisaged addition.
Les composés de formule (I) sont notamment synthétisés comme cela est décrit dans la demande WO00/44709.The compounds of formula (I) are especially synthesized as described in application WO00 / 44709.
L'étude des propriétés du composé de formule (I) a montré que le composé de formule (I), ainsi que ses sels, solvats ou hydrates pharmaceutiquement acceptables ne sont pas toxiques, et sont doués d'une activité antiinflammatoire dans le traitement de l'eczéma et/ou du psoriasis, qui se manifeste aussi bien par voie topique que orale.The study of the properties of the compound of formula (I) has shown that the compound of formula (I), as well as its pharmaceutically acceptable salts, solvates or hydrates are not toxic, and are endowed with an anti-inflammatory activity in the treatment of eczema and / or psoriasis, which is manifested both topically and orally.
EXEMPLE 1 : COMPOSITIONSEXAMPLE 1: COMPOSITIONS
A- VOIE ORALEA- ORAL WAY
Comprimé de 0.2 g0.2 g tablet
- Composé de formule (I) 0,001 g- Compound of formula (I) 0.001 g
- Amidon 0,114 g- 0.114 g starch
- Phosphate bicalcique 0,020 g- Dicalcium phosphate 0.020 g
- Silice 0,020 g- Silica 0.020 g
- Lactose 0,030 g - Talc 0,010 g- Lactose 0.030 g - Talc 0.010 g
- Stéarate de magnésium 0,005 g- magnesium stearate 0.005 g
B- VOIE TOPIQUEB- TOPICAL ROUTE
(a) Onguent(a) Ointment
-Composé de formule (I) 0,30 g-Compound of formula (I) 0.30 g
- Vaseline blanche codex qsp 100 g- white Vaseline codex qs 100 g
(b) Lotion(b) Lotion
- Composé de formule (I) 0,10 g- Compound of formula (I) 0.10 g
- Polyéthylène glycol (PEG 400) 69,90 g - Ethanol à 95% 30,00 g- Polyethylene glycol (PEG 400) 69.90 g - 95% Ethanol 30.00 g
EXEMPLE 2 : Evaluation de l'activité anti-inflammatoire de l'Apratastat après une application topique unique dans le test de l'œdème de l'oreille de souris induit par le TPA sur les souris Balb/cEXAMPLE 2 Evaluation of the anti-inflammatory activity of Apratastat after a single topical application in the TPA-induced mouse ear edema test on Balb / c mice
Traitement :Treatment :
L'oedème est induit par application unique de 20μl de TPA dissous dans l'acétone à 0.01%. Le composé à tester est dilué dans la solution de TPA et appliqué à une concentration de 0.1%, 0.3% et 1%.The edema is induced by a single application of 20 μl of TPA dissolved in acetone at 0.01%. The test compound is diluted in the TPA solution and applied at a concentration of 0.1%, 0.3% and 1%.
Un contrôle positif, le valérate de β-méthasone (VdB) est également testé. L'épaisseur de l'oreille de souris est mesurée à T+6h.A positive control, β-methasone valerate (VdB) is also tested. The thickness of the mouse ear is measured at T + 6h.
Résultats : Les résultats sont présentés en figure 1.Results: The results are presented in Figure 1.
Après une application unique topique du contrôle positif valérate de bétaméthasone (0.01%) dilué dans la solution de TPA, une réduction de l'œdème de l'oreille de 93 %(***) est observée.After a single topical application of betamethasone valerate positive control (0.01%) diluted in the TPA solution, a 93% reduction in ear edema (***) is observed.
L'Apratastat a un effet anti-inflammatoire dose-dépendant, et réduit l'œdème de l'oreille induit par le TPA de 25% (NS) (à 0.1%), 47 %(**) (à 0.3%) et 49% (**) (à 1%). Apratastat has a dose-dependent anti-inflammatory effect, and reduces TPA-induced ear edema by 25% (NS) (at 0.1%), 47% (**) (at 0.3%) and 49% (**) (at 1%).

Claims

REVENDICATIONS
1. Utilisation d'au moins un composé choisi parmi les composés de formule (I) :1. Use of at least one compound chosen from the compounds of formula (I):
dans laquelle R correspond à un radical -CH3 ou un radical CH2OH, leurs sels pharmaceutiquement acceptables, leurs solvats pharmaceutiquement acceptables et leurs hydrates, pour la préparation d'un médicament destiné à prévenir et/ou à traiter les pathologies inflammatoires cutanées. in which R corresponds to a -CH3 radical or a CH 2 OH radical, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and their hydrates, for the preparation of a medicament for preventing and / or treating inflammatory skin diseases.
2. Utilisation selon la revendication 1, caractérisée en ce que le composé de formule (I) est le (3S)-N-hydroxy-4-({4-[(4-hydroxy-2-butynyl)oxy]phényl}sulfonyl)-2,2- diméthyl-3-thiomorpholine carboxamide.2. Use according to claim 1, characterized in that the compound of formula (I) is (3S) -N-hydroxy-4 - ({4 - [(4-hydroxy-2-butynyl) oxy] phenyl} sulfonyl -2,2-dimethyl-3-thiomorpholine carboxamide.
3. Utilisation selon la revendication 1, caractérisée en ce que le composé de formule (I) est le (S)-N-Hydroxy-4-(4-but-2-ynyloxy-benzenesulfonyl) -2,2-dimethyl- thiomorpholine-3-carboxamide.3. Use according to claim 1, characterized in that the compound of formula (I) is (S) -N-Hydroxy-4- (4-but-2-ynyloxy-benzenesulfonyl) -2,2-dimethylthiomorpholine -3-carboxamide.
4. Utilisation selon l'une des revendications précédentes, caractérisée en ce que les pathologies inflammatoires cutanées sont choisies parmi l'eczéma et le psoriasis.4. Use according to one of the preceding claims, characterized in that the inflammatory skin diseases are selected from eczema and psoriasis.
5. Utilisation selon l'une des revendications 1 à 4, caractérisée en ce que le médicament est adapté à une administration orale.5. Use according to one of claims 1 to 4, characterized in that the drug is suitable for oral administration.
6. Utilisation selon l'une des revendications 1 à 4, caractérisée en ce que le médicament est adapté à une administration topique.6. Use according to one of claims 1 to 4, characterized in that the drug is suitable for topical administration.
7. Utilisation d'une composition pharmaceutique comprenant au moins un composé choisi parmi les composés de formule (I) : dans laquelle R correspond à un radical -CH3 ou un radical CH2OH, leurs sels pharmaceutiquement acceptables, leurs solvats pharmaceutiquement acceptables et leurs hydrates, pour préparer un médicament destiné à prévenir et/ou traiter les pathologies inflammatoires cutanées choisies parmi l'eczéma et le psoriasis. 7. Use of a pharmaceutical composition comprising at least one compound chosen from the compounds of formula (I): in which R corresponds to a -CH3 radical or a CH 2 OH radical, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and their hydrates, for preparing a medicament for preventing and / or treating the cutaneous inflammatory pathologies chosen from eczema and psoriasis.
EP07731755A 2006-03-20 2007-03-16 Use of (3s)-n-hydroxy-4-({4-ý(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide or (s)-n-hydroxy-4-(4-but-2-ynyloxy-benzenesulfonyl) -2,2-dimethyl-thiomorpholine -3-carboxamide for treating inflammatory skin pathologies Withdrawn EP1998779A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0602429A FR2898497B1 (en) 2006-03-20 2006-03-20 USE OF APRATASTAT OR (S) -N-HYDROXY-4- (4-BUT-2-YNYLOXY-BENZENESULFONYL) -2,2-DIMETHYL-THIOMORPHOLIN-3-CARBO XAMIDE IN THE TREATMENT OF SKIN INFLAMMATORY DISEASES
PCT/FR2007/050939 WO2007107663A2 (en) 2006-03-20 2007-03-16 Use of (3s)-n-hydroxy-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide or (s)-n-hydroxy-4-(4-but-2-ynyloxy-benzenesulfonyl) -2,2-dimethyl-thiomorpholine -3-carboxamide for treating inflammatory skin pathologies

Publications (1)

Publication Number Publication Date
EP1998779A2 true EP1998779A2 (en) 2008-12-10

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EP07731755A Withdrawn EP1998779A2 (en) 2006-03-20 2007-03-16 Use of (3s)-n-hydroxy-4-({4-ý(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide or (s)-n-hydroxy-4-(4-but-2-ynyloxy-benzenesulfonyl) -2,2-dimethyl-thiomorpholine -3-carboxamide for treating inflammatory skin pathologies

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US (1) US20090137569A1 (en)
EP (1) EP1998779A2 (en)
CA (1) CA2645327A1 (en)
FR (1) FR2898497B1 (en)
WO (1) WO2007107663A2 (en)

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HUE030114T2 (en) 2010-07-08 2017-04-28 Kaken Pharma Co Ltd N-hydroxyformamide derivative and pharmaceutical containing same
GB2483499A (en) 2010-09-10 2012-03-14 S3 Res & Dev Ltd Diagnostics and Analysis of a Set Top Box
FR3046933B1 (en) * 2016-01-25 2018-03-02 Galderma Research & Development NLRP3 INHIBITORS FOR THE TREATMENT OF INFLAMMATORY SKIN CONDITIONS

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US5594106A (en) * 1993-08-23 1997-01-14 Immunex Corporation Inhibitors of TNF-α secretion
AR035313A1 (en) * 1999-01-27 2004-05-12 Wyeth Corp ACETILENIC TACE INHIBITORS OF HYDROXAMIC ACID OF SULFONAMIDE BASED ON ALFA-AMINO ACIDS, PHARMACEUTICAL COMPOSITIONS AND THE USE OF THE SAME FOR THE MANUFACTURE OF MEDICINES.
US6225311B1 (en) * 1999-01-27 2001-05-01 American Cyanamid Company Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors
WO2004032846A2 (en) * 2002-10-07 2004-04-22 Bristol-Myers Squibb Company Triazolone and triazolethione derivatives
GT200500139A (en) * 2004-06-08 2005-07-25 METHOD FOR THE PREPARATION OF HYDROXAMIC ACIDS

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See references of WO2007107663A2 *

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FR2898497A1 (en) 2007-09-21
WO2007107663A2 (en) 2007-09-27
WO2007107663A3 (en) 2007-11-22
FR2898497B1 (en) 2008-05-16
US20090137569A1 (en) 2009-05-28

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