WO1995021615A1 - Utilisation d'arylcyclobutylalkylamines dans le traitement de crises et de troubles neurologiques - Google Patents

Utilisation d'arylcyclobutylalkylamines dans le traitement de crises et de troubles neurologiques Download PDF

Info

Publication number
WO1995021615A1
WO1995021615A1 PCT/EP1995/000440 EP9500440W WO9521615A1 WO 1995021615 A1 WO1995021615 A1 WO 1995021615A1 EP 9500440 W EP9500440 W EP 9500440W WO 9521615 A1 WO9521615 A1 WO 9521615A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyclobutyl
formula
treatment
dimethyl
compound
Prior art date
Application number
PCT/EP1995/000440
Other languages
English (en)
Inventor
William Roger Buckett
Original Assignee
Knoll Ag
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 Knoll Ag filed Critical Knoll Ag
Priority to AU15782/95A priority Critical patent/AU1578295A/en
Publication of WO1995021615A1 publication Critical patent/WO1995021615A1/fr

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
    • A61K31/435—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline

Definitions

  • arylcyclobutylalkylamines for the treatment of seizures and neurologi ⁇ cal disorders.
  • This invention relates to administration to an animal in need thereof of derivatives of arylcyclobutylalkylamines, and pharmaceutical 5 compositions containing them, in a method of treatment of seizures, neurological disorders such as epilepsy and/or as conditions in which there is neurological damage such as brain trauma, cerebral ischaemia, haemorrhage, head injuries and stroke.
  • the present invention provides a method of treatment (including therapy and prophylaxis) in animals of one or more clinical conditions selected from seizures, neurological disorders and conditions in which there is neurological damage, which comprises 5 administering to an animal in need thereof a therapeutically or prophylactically effective amount of a compound of formula I
  • R 1 represents C- j __g alkyl, pyridyl or (when Y is other than a bond) H;
  • R and R J independently represent K, C1--4 alkyl or formyl;
  • R 4 and R 5 independently represent H, halo, phenyl, trifluoromethyl, C- j __3 alkyl or C- ⁇ . ⁇ alkoxy; or if R 4 and R 5 are on adjacent carbon atoms, R 4 and R ⁇ together with the carbon atoms to which they are attached represent a second benzene ring, which is optionally fused to a third benzene ring; and
  • Y represents a bond or methylene (optionally substituted with one or two C- j __3 alkyl) .
  • Preferred compounds of formula I for administering in the method of treatment of present invention are those in which:
  • R 1 represents methyl, propyl, butyl, pentyl, pyrid-2-yl or (when Y is other than a bond) H;
  • R 2 represents H, methyl or formyl
  • R 3 represents H or methyl
  • R 4 and R 5 independently represent H, bromo, chloro, fluoro, phenyl, trifluoromethyl or methoxy; or R 4 and R 5 together with the benzene ring to which they are attached form phenanthryl; and Y represents a bond, methylene or dimethylmethylene.
  • a most preferred compound for administering in the method of treatment of the present invention is N,N- dimethyl -1 - [ 1- (4 -chloropheny1 ) cyclobutyl] -3 - methylbutylamine, particularly in the form of its hydrochloride, even more particularly in the form of its hydrochloride monohydrate.
  • Seizures result from the discharge of a large collection of neurones in abnormal synchrony and may be accompanied by loss of consciousness. They are often a symptom of some underlying clinical condition for example one or more of the following: neurological disorders such as epilepsy and conditions in which there is neurological damage such as brain trauma, cerebral ischaemia, haemorrhage, head injuries and stroke. Seizures may also occur (particularly in children) due to one or more of the following: birth injuries, rickets, pyretus, irritation (for example bowel irritation) , diseases of the brain (for example meningitis, encephalitis and/or tumours) and/or asphyxia. Seizures may be disabling particularly if chronic, and may have serious consequences.
  • neurological disorders such as epilepsy and conditions in which there is neurological damage such as brain trauma, cerebral ischaemia, haemorrhage, head injuries and stroke. Seizures may also occur (particularly in children) due to one or more of the following: birth injuries, rickets,
  • Occurrence of seizures may be reduced or eliminated by chronic, prophylactic drug treatment, although this may not cure the underlying clinical condition.
  • the most common cause of seizures in adults is epilepsy which occurs in about one percent of the general population.
  • Many epileptics find currently available anti-convulsants are not effective in controlling their seizures.
  • Currently available anti-convulsants also have undesirable side effects, particularly if used chronically. Such side effects include drowsiness, dose dependent side effects and/or rare allergic and/or idiosyncratic reactions.
  • a preferred compound of formula I is N,N-dimethyl-l- [1- (4- chlorophenyl) -cyclobutyl] -3-methylbutylamine (also known by the non- proprietary name of sibutramine) .
  • the particularly preferred form of this compound is N,N- dimethyl-1- [1- (4-chloro heny1 ) cyclobutyl] -3 - methylbutylamine hydrochloride monohydrate (sibutramine hydrochloride) which is described in European Patent Application 0230742 A. The remaining compounds described herein have been disclosed in GB 2128991.
  • a substituent group which comprises three or more atoms signifies a group which may comprise a straight chain or a group which is branched, for example, an alkyl group may comprise propyl which includes n-propyl and isopropyl, butyl which includes ri-butyl, sec-butyl, isobutyl and tert-butyl.
  • the total number of certain atoms is specified herein for certain substituents, for example C- j __g alkyl signifies an alkyl group having from 1 to 6 carbon atoms.
  • the term 'halo' as used herein signifies fluoro, chloro, bromo and iodo. If ring substituents (for example R and R 5 ) are other than H, the substituents may replace any H attached to an atom in the ring and may be located at any available position on the ring.
  • Certain compounds of formula I may form salts of formula I with organic and/or inorganic acids (for example acid addition salts) .
  • Particularly suitable salts of formula I which are pharmaceutically acceptable and which may be formed with acids comprise salts of acidic amino acids and/or suitable derivatives thereof (for example salts of glutamic acids and/or N-carbamoyl- phenylalanine) , salts of suitable inorganic acids (for example salts of hydrobromic, hydrochloric, hydriodic, nitric, phosphoric, sulphonic and/or sulphuric acids) and/or salts of suitable organic acids (for example salts of acetic, alkylsulphonic, alkylsulphuric, arylsulphonic, arylsulphuric, ascorbic, benzoic, cinnamic, citric, dibenozyltartaric, dodecanoic, fumaric, gluconic, glycollic, isothionic, lact
  • Salts of formula I include all pharmaceutically acceptable salts that may be formed from multivalent acids (for example acid metal salts [such as bicarbonate and/or hydrogen orthophosphate salts] ) and all enantiomeric salts formed with pharmaceutically acceptable chiral acids and/or any mixtures of enantiomers of such salts (for example (+) tartrates and/or (-) tartrates) .
  • Salts of formula I may be prepared by reacting corresponding compounds of formula I which are not salts with suitable acids in a conventional manner.
  • the method of treatment of the present invention includes administering of all pharmaceutically acceptable salts of formula I and/or any mixtures thereof.
  • Particularly preferred salts of formula I are the monohydrochloride, dihydrochloride and maleate salts.
  • Certain compounds of formula I may have a structure such that they are not superimposable on their mirror image (for example compounds of formula I with one or more chiral centres) and thus exist as different enantiomeric forms which may or may not be optically active.
  • compounds of formula I may contain a chiral centre at the asymmetrically substituted carbon atom to which R 1 is attached.
  • Compounds of formula I that contain a single chiral centre exist as two enantiomeric forms.
  • the method of treatment of the present invention includes administering all pharmaceutically acceptable, enantiomerically pure enantiomers of compounds of formula I and/or any mixtures of such enantiomers (for example racemic mixtures) .
  • Enantiomers may be obtained by methods known to those skilled in the art. Such methods typically include one or more of any of the following: resolution via formulation of diastereoisomeric salts and/or complexes which may be separated, for example, by crystallisation; formation of diasterseoisomeric derivatives and/or complexes which may be separated (for example, by crystallisation, gas-liquid chromatography and/or liquid chromatography) , followed by the liberation of the desired enantiomer from the separated derivative; selective reaction of one enantiomer using an enantiomer-specific reagent followed by separation of the modified and/or unmodified enantiomers; biochemical methods (for example fermentation with living organisms such as moulds, yeasts and/or bacteria [optionally such organisms being genetically modified] and/or enzymatic modification [such as esterification, oxidation and/or reduction] ) ; gas-liquid chromatography and/or liquid chromatography in a chiral environment (for example on a
  • Certain compounds of formula I may contain two or more chiral centres and thus may exist as one or more diastereoisomeric pairs. Diastereoisomers may be separated by methods known to those skilled in the art, for example by chromatography and/or crystallisation and individual enantiomers within the diastereoisomers may be separated as described above.
  • the method of treatment of present invention includes administering all pharmaceutically acceptable diastereoisomers of compounds of formula I and/or any mixtures thereof.
  • Compounds of formula I may exist as solvates (for example if the solvent is water the hydrates may be hemihydrates, monohydrates and/or dihydrates) or as an unsolvated form (for example an anhydrous form) .
  • the degree of solvation may also be non-stoichiometric.
  • the method of treatment of present invention includes administering of all pharmaceutically acceptable solvates of compounds of formula I and/or any mixtures thereof.
  • a particularly preferred solvate of compounds of formula I is the monohydrate.
  • the term 'Active Compound' denotes one or more compound or compounds of formula I (comprising any of the different forms described herein) and/or any mixtures thereof.
  • the Active Compound comprises the preferred and/or particularly preferred compounds of formula I described herein.
  • Specific compounds which may comprise the Active Compound are the compounds specifically mentioned herein which have been shown to be active in the pharmacological tests described herein.
  • composition denotes one or more pharmaceutical compositions and/or any mixtures thereof comprising a therapeutically and/or prophylactically effective amount of one or more compounds of formula I
  • Pharmaceutical Composition comprises the preferred and/or particularly preferred compounds of formula I described herein. Specific compounds which may be incorporated into the Pharmaceutical Composition are those compounds of formula I which have been shown to be active in the pharmacological tests described herein.
  • composition suitable for use in the methods of treatment of the present invention may take the form of any pharmaceutical compositions suitable for such methods of administration (for example one or more of the Pharmaceutical Compositions described herein and/or any mixtures thereof) .
  • Pharmaceutical Compositions will be accompanied by written and/or printed directions for their use and/or administration in the method of treatment of the present invention.
  • compositions may be prepared by any method known to those skilled in the art, for example by bringing the Active Compound into association with suitable inert diluents, carriers and/or any other optional ingredients (for example those described herein) .
  • the ingredients of the Pharmaceutical Composition may be uniformly and/or intimately admixed and the resultant Pharmaceutical Composition may be shaped (for example by compressing and/or moulding) .
  • the Pharmaceutical Composition may also be formulated in a manner known to those skilled in the art, to give a modified release (for example rapid, delayed, sustained and/or controlled release) of the Active Compound.
  • Pharmaceutically acceptable diluents and/or carriers suitable for use in Pharmaceutical Compositions are well known in the art of pharmacy.
  • the excipients used in the preparation of Pharmaceutical Compositions are the excipients known in the pharmacist's art.
  • Pharmaceutical Compositions may be administered orally in known pharmaceutical forms for such administration which may be solid or fluid. Dosage forms suitable for oral administration may comprise cachets, caplets, capsules, dragees, elixirs, extrudates, granules, lozenges, pastilles, pills, pellets, powders, solutions, suspensions, syrups, tablets and/or troches.
  • Solid oral dosage forms may be prepared by mixing the Active Compound with one or more of the following ingredients which are pharmaceutically acceptable: inert diluents, disintegrating agents, lubricants, binders and or any mixtures thereof. It will be appreciated by those skilled in the art that a particular ingredient may perform more than one function (for example maize starch may act as a diluent, binder and/or disintegrating agent) .
  • Inert diluents may comprise sugars (for example lactose, fructose, sucrose, powdered sugar and/or mixtures thereof) , sugar alcohols (for example mannitol) , celluloses (for example microcrystalline cellulose) , starches (for example maize starch, other pharmaceutical grade starch and/or mixtures thereof) , dextrin, clays (for example kaolin), inorganic material (for example calcium phosphate, calcium sulphate and/or sodium chloride) and/or mixtures thereof.
  • sugars for example lactose, fructose, sucrose, powdered sugar and/or mixtures thereof
  • sugar alcohols for example mannitol
  • celluloses for example microcrystalline cellulose
  • starches for example maize starch, other pharmaceutical grade starch and/or mixtures thereof
  • dextrin for example kaolin
  • inorganic material for example calcium phosphate, calcium sulphate and/or sodium chloride
  • Disintegrating agents may comprise starches (for example maize starch, sodium starch glycolate and/or mixtures thereof), agar, bentonite, celluloses (for example methyl cellulose, carboxymethylcellulose, microcrystalline cellulose, hydroxypropyl cellulose and/or mixtures thereof), alginic acid, alginate salts, guar gum, croscarmellose sodium, sodium lauryl sulphate, colloidal silicon dioxide and/or mixtures thereof.
  • starches for example maize starch, sodium starch glycolate and/or mixtures thereof
  • agar bentonite
  • celluloses for example methyl cellulose, carboxymethylcellulose, microcrystalline cellulose, hydroxypropyl cellulose and/or mixtures thereof
  • alginic acid for example methyl cellulose, carboxymethylcellulose, microcrystalline cellulose, hydroxypropyl cellulose and/or mixtures thereof
  • alginic acid for example methyl cellulose, carboxymethylcellulose, microcrystalline cellulose, hydroxypropyl cellulose and/or mixture
  • Lubricating agents may comprise stearic acid, stearates (for example magnesium stearate, calcium stearate and/or glyceryl palmtostearate) , talc, polyethylene glycol, glyceryl behenate and/or mixtures thereof.
  • stearic acid for example magnesium stearate, calcium stearate and/or glyceryl palmtostearate
  • talc polyethylene glycol
  • polyethylene glycol glyceryl behenate and/or mixtures thereof.
  • Binders may comprise starches (for example maize starch) , gelatin, sugars (for example sucrose, molasses, lactose and/or mixtures thereof) and/or natural and/or synthetic gums (for example acacia, sodium alginate, extract of Irish moss, celluloses [such as carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, micro-crystalline cellulose and/or mixtures thereof] , polyethylene glycol, waxes, polyvinylpyrrolidone and/or mixtures thereof) .
  • starches for example maize starch
  • gelatin for example sucrose, molasses, lactose and/or mixtures thereof
  • natural and/or synthetic gums for example acacia, sodium alginate, extract of Irish moss, celluloses [such as carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, micro-crystalline cellulose and/or mixtures thereof] , polyethylene glyco
  • Solid oral dosage forms of the present invention may further comprise one or more of the following ingredients and/or mixtures thereof: colouring agents (for example conventional pharmaceutically acceptable and/or food desirable dyes and/or colorants) ; sweetening agents (for example intense sweeteners [such as aspartame and/or saccharin] ) ; flavouring agents (for example pharmaceutically acceptable and/or food desirable flavours) ; anti-microbial agents (for example methyl p- hydroxybenzoate, propyl p-hydroxybenzoate-sodium benzoate, sodium propionate and/or sorbic acid) ; anti-oxidants (for example ascorbic acid, sodium ascorbate, sodium metabisulphate and/or propyl gallate) ; wetting agents (for example sodium lauryl sulphate) ; and/or one or more pharmaceutically acceptable couples (for example those comprising an acid and a carbonate and/or bicarbonate salt) , which effervesce to aid dissolution if the solid dosage form is added to water
  • Solid dosage forms of the present invention may also optionally comprise one or more other pharmaceutically acceptable ingredients and/or mixtures thereof, which are known in the art to permit production of oral dosage forms by known methods (for example blending, filling and/or tabletting) .
  • Such ingredients may comprise: agents to aid the flow of ingredients (for example talc and/or colloidal silicon dioxide) ; compression agents to increase the strength of the solid dosage form (for example sorbitol and/or lactose) ; and/or ionic and/or non-ionic surface active agents (for example sodium lauryl sulphate) to disperse the Active Compound within the solid dosage form and prevent grit forming at the surface of the solid dosage form.
  • solid oral dosage forms are shaped to be more convenient for general use.
  • Solid oral dosage forms may be formulated in a manner known to those skilled in the art so as to give a sustained release of the Active Compound.
  • Enteric coated, solid oral dosage forms comprising Pharmaceutical Compositions may be advantageous, depending on the nature of the Active Compound.
  • Various materials for example shellac and/or sugar, may be present as coatings, or to otherwise modify the physical form of the oral dosage form.
  • tablets and/or pills may, if desired, be provided with enteric coatings (such as membranes) by known methods, for example by the use of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and/or anionic polymers of methacrylic acid and/or its esters.
  • the enteric coating may comprise a plasticiser (for example diethyl phthalate, tributyl citrate and/or triacetin) .
  • a plasticiser for example diethyl phthalate, tributyl citrate and/or triacetin
  • Capsules and/or caplets (for example hard or soft gelatin capsules) comprising the Active Compound (with or without added excipients [such as a fatty oil] ) , may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner. The contents of capsules and/or caplets may be formulated using known methods to give sustained release of the Active Compound.
  • the Active Compound may be formulated into granules and/or powders with or without additional excipients.
  • the granules and/or powders may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example water) before ingestion.
  • the granules and/or powders may contain disintegrants (for example pharmaceutically acceptable effervescent couples formed from acids and carbonate and/or bicarbonate salts) to facilitate dispersion in liquid media.
  • Fluid oral dosage forms comprising the Pharmaceutical Compositions are preferably liquid oral dosage forms and may be elixirs, solutions, syrups and/or suspensions which contain the Active Compound in pharmaceutically acceptable media.
  • Pharmaceutically acceptable solvents comprise water, glycol, oils and/or alcohols.
  • Media suitable for preparing syrups and/or suspensions may comprise aqueous media, oily media and/or emulsions in the presence of one or more pharmaceutically acceptable suspending agents (for example starches, gums [such as xanthan gum], celluloses [such as methylcellulose, hydroxyethyl-cellulose and/or sodium carboxymethylcellulose] , gelatin, glycerin, hydrogenated fats and/or sorbitol).
  • a pharmaceutically acceptable suspending agents for example starches, gums [such as xanthan gum], celluloses [such as methylcellulose, hydroxyethyl-cellulose and/or sodium carboxymethylcellulose] , gelatin, glycerin, hydrogenated fats and/or
  • Suitable oily media may comprise vegetable oils (for example arachis oil and/or sunflower oil) , other edible oils (for example almond oil and/or fractionated coconut oil) and/or oily esters (for example esters of glycerin, propylene glycol and/or ethanol) .
  • Fluid oral dosage forms may further comprise one or more of the following which are pharmaceutically acceptable: agents which vary osmotic pressure (for example salts) , colouring agents, emulsifiers (for example lecithin, sorbitan monooleate and/or acacia), flavouring agents, pH adjusting agents (for example buffers), preservatives, sweetening agents and/or mixtures thereof.
  • Fluid oral dosage forms may also be prepared from dry products (for example granules and/or powders) which are presented for reconstitution with a suitable vehicle (for example those media described above) .
  • compositions may be administered rectally in the known pharmaceutical forms for such administration (for example suppositories with a base comprising sugars, starches, stearates, hard fats, se i- synthetic glycerides, cocoa butter, polyethylene glycols and/or any mixtures thereof) .
  • a base comprising sugars, starches, stearates, hard fats, se i- synthetic glycerides, cocoa butter, polyethylene glycols and/or any mixtures thereof.
  • compositions may also be administered parenterally (for example subcutaneously, intramuscularly, intradermally and/or intravenously [such as by injection and/or infusion] ) in the known pharmaceutical dosage forms for parenteral administration (for example sterile suspensions in aqueous and/or oily media and/or sterile solutions in suitable solvents, preferably isotonic with the blood of the intended patient).
  • parenteral dosage forms may be sterilised (for example by micro-filtration and/or using suitable sterilising agents [such as ethylene oxide] ) .
  • parenteral dosage forms may be stored in suitable sterile sealed containers (for example ampoules and/or vials) until use. To enhance stability during storage the parenteral dosage form may be frozen after filling the container and fluid (for example water) may be removed under reduced pressure.
  • suitable sterile sealed containers for example ampoules and/or vials
  • compositions may be administered nasally in known pharmaceutical forms for such administration (for example sprays, aerosols, nebulised solutions and/or powders) .
  • Metered dose systems known to those skilled in the art (for example aerosols and/or inhalers) may be used.
  • compositions may be administered to the buccal cavity (for example sub-lingually) in known pharmaceutical forms for such administration (for example slow dissolving tablets, chewing gums, troches, lozenges, pastilles, gels, pastes, mouthwashes, rinses and/or powders) .
  • Topical Compositions Pharmaceutical compositions may be administered topically in forms suitable for topical administration (hereinafter known as Topical Compositions) .
  • the amount of Active Compound in a Topical Composition should be such that a therapeutically and/or prophylactically effective amount of the Active Compound would be delivered during the period of time which the Topical Composition is intended to be on the skin.
  • Topical vehicles suitable for use in the Topical Compositions may comprise pharmaceutically acceptable foam, paste, salve, lotion, cream, ointment, oil, emulsion and/or gel bases; and/or compositions suitable for application as a spray and/or aerosol. Topical vehicles may also comprise topical delivery devices such as cataplasms, poultices, patches and/or impregnated bandages.
  • Topical Compositions may comprise a matrix in which the Active Compound is administered transdermally by being held in contact with the skin.
  • the Active Compound may also be delivered transdermally from a suitable Topical Composition by electrotransport and/or iontophoresis.
  • Topical Compositions suitable for transdermal administration may further comprise the Active Compound optionally held in an aqueous solution which may be dissolved and/or dispersed in an adhesive and/or polymer base (for example on a patch) .
  • Suitable transdermal Topical Compositions may also be prepared by mixing and/or dispersing the Active Compound in topical vehicles together with potential transdermal accelerants (such as dimethyl sulphoxide and/or propylene glycol) .
  • Suitable creams may be prepared by incorporating the active compound in petroleum and/or light liquid paraffins which are then dispersed in aqueous media using surfactants.
  • Ointments may be prepared by mixing the active compound with mineral oils, petrolatum and/or waxes (for example paraffin wax and/or beeswax) .
  • Gels may be prepared by mixing the active compound with gelling agents (for example those described below) in the presence of water and/or optionally a base. Clear gels may comprise clarifying agents (for example denaturated alcohols [such as denaturated ethanol] ) .
  • Topical Compositions that comprise emulsions may comprise either oil-in-water or water-in-oil emulsions.
  • the oil phase of such emulsions may comprise one or more of the following ingredients: hydrocarbon oils, waxes, natural oils, silicone oils, fatty acid esters, fatty alcohols and/or any mixtures thereof.
  • Pharmaceutical Compositions that are emulsions may be prepared using emulsifiers suitable for use in water-in-oil and/or oil- in-water emulsions and preferably acceptable for use in Topical Compositions.
  • Such emulsifiers may comprise any suitable emulsifiers well known to those skilled in the art.
  • Topical Compositions may also comprise ionic or non-ionic surface active agents to promote greater therapeutic and/or prophylactic activity in the Topical Compositions if applied topically.
  • the surface active agents may also comprise emulsifying ingredients and/or surfactants even if the Topical Compositions are other than emulsions.
  • Topical Compositions may additionally comprise further components well known to those skilled in the art and/or any mixtures thereof, for example: emulsion stabilisers, sequestrants, emollients, humectants, moisturisers, thickening agents, gelling agents, film formers, perfumes, anti-oxidants, preservatives, colouring agents and/or mixtures thereof.
  • emulsion stabilisers for example: sequestrants, emollients, humectants, moisturisers, thickening agents, gelling agents, film formers, perfumes, anti-oxidants, preservatives, colouring agents and/or mixtures thereof.
  • Topical Compositions may further comprise pH adjusting agents.
  • the pH adjusting agents are present in an amount which is sufficient to activate the thickening and/or gelling agents, if present, and which will keep the pH of the Topical Composition within pharmaceutically and cosmetically acceptable limits that will not damage the skin. More preferably the pH of the Topical Composition is from about 5.0 to about 9.0.
  • the pH adjusting agents may comprise sodium citrate, sodium hydroxide, potassium hydroxide, and/or N,N,N'N'-tetrakis (2-hydroxypropyl)- ethylenediamine (available commercially under the trade name Quadrol) .
  • Active Compounds may also be administered by continuous infusion either from an external source (for example by intravenous infusion) and/or from a source of the Active Compound placed within the body.
  • Internal sources include implants and/or implanted reservoirs containing the Active Compound to be infused from which the Active Compound is continuously released (for example by osmosis) .
  • Liquid implants may comprise suspensions and/or solutions in a pharmaceutically acceptable solvent of the Active Compound to be infused
  • Solid implants may be in the form of an implanted support (for example synthetic resins and/or waxy materials) for the Active Compound to be infused.
  • the support may be a single body containing all the Active Compound or a series of several bodies each containing part of the Active Compound to be delivered.
  • the amount of Active Compound present in an internal source should be such that a therapeutically and/or prophylactically effective amount of the Active Compound is delivered over a long period of time.
  • Active Compounds that have a high lipid solubility may be suitable for use in so-called depot formulations which provide a source of the Active Compound located within the body 'for example by intra-muscular injection).
  • Depot f- .emulations may comprise the Active Compound in a pharmaceutically acceptable oil.
  • composition in the form of particles of very small size, for example as obtained by fluid energy milling.
  • the Active Compound may be bound (for example by sorption, incorporation and/or chemically) to nanoparticles which are colloidal polymeric particles of a size typically less than 1 micron.
  • the distribution of such nanoparticles in the body and hence the sites of delivery of the Active Compound can be effected by coating the surface of the nanoparticles appropriately
  • the Active Compound may, if desired, be associated with other compatible, pharmacologically active ingredients.
  • the Active Compound and/or the Pharmaceutical Composition is indicated for therapeutic and/or prophylactic use as a medicament for the treatment in animals of one or more clinical conditions selected from: seizures, neurological disorders and conditions in which there is neurological damage.
  • Specific clinical conditions for which the Active Compound and/or the Pharmaceutical Composition are indicated comprise brain trauma, cerebral ischaemia, epilepsy, haemorrhage, head injuries and stroke.
  • the therapeutic and/or prophylactic activity of compounds falling within the disclosure of formula I has been demonstrated by means of various pharmacological tests such as in vitro tests and in vivo tests in standard laboratory animals. Such tests include the test of pharmacological activity described herein. Therefore the present invention provides a method of treatment in animals of one or more clinical conditions selected from: seizures, neurological disorders and conditions in which there is neurological damage, which comprises administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of the Active Compound and/or the Pharmaceutical Composition.
  • the term 'treatment' as used herein includes both therapeutic and/or prophylactic use of the Active Compound and/or the Pharmaceutical Composition.
  • the Active Compound and/or the Pharmaceutical Composition may be used to provide a systemic therapeutic and/or prophylactic effect.
  • prophylactic use of the Active Compound and/or the Pharmaceutical Composition comprises administering ' to an animal in need thereof the Active Compound and/or the Pharmaceutical Composition to prevent of the onset of one or more clinical conditions selected from: seizures neurological disorders and conditions in which there is neurological damage; and/or use of the Active Compound and/or the Pharmaceutical Composition as a neuroprotective agent to protect an animal against one or more clinical conditions selected from: seizures, neurological disorders and conditions in which there is neurological damage.
  • Animals that may be treated according to the present invention comprise human beings as well as non- human animals.
  • the term comprises both humans and non-human animals.
  • &-..--human animals that may be so treated comprise any animal (including non-mammals) that has any of the clinical conditions described herein.
  • the animals treated according to the invention are mammals (for example the animal species tested as described herein) , more preferably human beings.
  • the pharmacological effects of the Active Compound and/or the Pharmaceutical Composition in the clinical conditions described herein may arise from activity blocking one or more voltage-dependent sodium ion (Na + ) channels in neurones, potentiating the transmission of the neurotransmitter gamma-amino butyric acid (GABA) , attenuating the transmission of the excitatory amino acids (for example glutamic and/or aspartic) and activating one or more potassium ion (K + ) and/or calcium ion (Ca 2+ ) channels in neurones (for example voltage dependant K A channels and/or calcium ion [Ca ] activated SK a channels) .
  • GABA neurotransmitter gamma-amino butyric acid
  • K + potassium ion
  • Ca 2+ calcium ion
  • another aspect of the present invention is a method of treatment as described herein in which the Active Compound and/or the Pharmaceutical Composition administered has activity blocking one or more voltage-dependent sodium ion (Na + ) channels in neurones, potentiating the transmission of the neurotransmitter gamma-amino butyric acid (GABA) , inhibiting excitatory amino acid neurotransmission, activating one or more potassium ion (K + ) channels in neurones and activating one or more calcium (Ca ) channels in neurones.
  • GABA neurotransmitter gamma-amino butyric acid
  • K + potassium ion
  • Ca calcium
  • the precise amount of the Active Compound administered to a particular animal, preferably a mammal, more preferably a human being, in the method of treatment of the present invention will depend on a number of factors (for example: the specific compound administered, its mode of administration and/or the use for which it is intended; the particular clinical condition being treated and/or its severity; and/or the age, body mass and/or past clinical history of the patient to be treated) and always lies within the sound discretion of the person administering and/or supervising the treatment (for example a medical practitioner [such as nurse and/or physician] and/or veterinarian) .
  • a suitable daily dose of the Active Compound for administration to an animal is generally from about O.Olmg/day per kg of the animal's body mass to about lOmg/kg/day given in a single dose and/or in divided doses at one or more times during the day.
  • the total dose of the Active Compound administered per day may be generally from about O.lmg to about 500mg.
  • the Pharma c eutical Composition may contain from about 0.1% to about 99% by weight of the Active Compound and is generally prepared in unit dose form, a unit dose of Active Compound generally being from about O.lmg to about 500mg. If the Active Compound is a salt the masses indicated above refer to the mass of the corresponding Active Compound that is other than a salt .
  • a further aspect of the present invention provides the use of the Active Compound and/or the Pharmaceutical
  • a yet further aspect of the present invention provides use of the Active Compound and/or the Pharmaceutical Composition for treating in animals in need thereof, one or more clinical conditions selected from: seizures, neurological disorders and conditions in which there is neurological damage.
  • a still further aspect of the present invention provides a pharmaceutical composition for treating in animals one or more clinical conditions selected from: seizures, neurological disorders and conditions in which there is neurological damage; comprising a therapeutically and/or prophylactically effective amount of the Active Compound in conjunction with a pharmaceutically acceptable diluent or carrier.
  • the pharmacological activity of compounds of formula I in the methods of the present invention was demonstrated by activity of certain compounds of formula I (those compounds so tested referred to hereinafter as 'Test Compounds') in the following pharmacological test: the inhibition of seizures induced by maximal electroshock (referred to hereinafter as the MESM Test) .
  • mice In the MESM experiments, groups of male mice in the weight range 25 to 30 grammes had free access to food and water until the start of the experiment. The mice were divided into two groups, a control group and a test group to which Test Compounds would be administered.
  • the control group received an oral dose of 10 ml/kg of a vehicle of 1% aqueous methylcellulose solution.
  • the test group received orally, suspended in the same dose of the methylceullose vehicle, a Test Compound at a dose of either 100 mg/kg for initial testing or, if enough Test Compound was available, at a range of doses to determine an ED ⁇ Q (see below) .
  • an electroshock of duration 1.0 second was administered to all mice in both groups through ear clip electrodes moistened with saline.
  • the electroshock had an intensity of 99mA, frequency of 50 Hz and pulse width of 0.4 s. Such a shock would generally be expected to induce a seizure in the mice.
  • mice in each group were observed, the number of mice in each group exhibiting tonic hind limb extension was recorded and thus the percentage of mice in which seizures had been inhibited was determined. The greater the anticonvulsant activity of the Test Compound, the higher was the percentage recorded in the MESM test. Test Compounds with a percentage inhibition of greater than or equal to 50% were deemed to be active in the MESM Test.
  • Examples 1, 2, 3, 4, 5, 7, 11 and 16 herein have been exemplified in the applicant's British patent GB 2098602 (corresponding to examples 4d, 9c, 10c, 11, 4h, lOh, lOy and lOr respectively) and can be prepared as described therein.
  • Examples 6, 8, 9, 10, 12, 13, 14, 15, 17, 18, 19, 21, 22 and 23 are disclosed generally in GB 2098602A and processes for their preparation are disclosed generally therein.
  • Example 20 is disclosed generally in GB 212899A and processes for its preparation are described generally therein.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur un procédé de traitement (comprenant la thérapie et la prophylaxie) d'animaux souffrant d'un ou plusieurs troubles cliniques tels que: crises, les troubles neurologiques tels que l'épilepsie et des troubles résultat d'une lésion neurologique telle que le traumatisme cérébral, l'ischémie cérébrale, l'hémorragie, les traumatismes crâniens et les attaques. Ce procédé consiste à administrer à un animal nécessitant ce traitement une dose thérapeutiquement et/ou prophylactiquement efficace d'un ou plusieurs composés de la formule (I), y compris tous les sels pharmaceutiquement acceptables de ceux-ci dans lesquels: R1 représente alkyle C¿1-6?, pyridyle ou (lorsqu'Y n'est pas une liaison) H; R?2 et R3¿ représentent, indépendamment, H, alkyle C¿1-4? ou formyle; R?4 et R5¿ représentent, indépendamment, H, halo, phényle, trifluorométhyle, alkyle C¿1-3? ou alcoxy C1-3; ou bien si R?4 et R5¿ sont sur des atomes de carbone adjacents, R4 et R5, ainsi que les atomes de carbone auxquels ils sont liés, représentent un deuxième cycle benzène qui est éventuellement soudé à un troisième cycle benzène; et Y représente une liaison ou méthylène (éventuellement substitué par un ou deux alkyles C¿1-3?). Un composé particulièrement préféré de la formule (I) et destiné à être administré dans le cadre du procédé de traitement décrit ci-dessus est N,N-diméthyl-1-[1-(4-chlorophényl)cyclobutyl]-3-méthylbutylamine (sibutramine), se présentant notamment sous la forme de ses sels d'hydrochlorure et/ou de monohydrate d'hydrochlorure.
PCT/EP1995/000440 1994-02-11 1995-02-09 Utilisation d'arylcyclobutylalkylamines dans le traitement de crises et de troubles neurologiques WO1995021615A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU15782/95A AU1578295A (en) 1994-02-11 1995-02-09 Use of arylcyclobutylalkylamines for the treatment of seizures and neurological disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9402641A GB9402641D0 (en) 1994-02-11 1994-02-11 Therapeutic agents
GB9402641.6 1994-02-11

Publications (1)

Publication Number Publication Date
WO1995021615A1 true WO1995021615A1 (fr) 1995-08-17

Family

ID=10750231

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/000440 WO1995021615A1 (fr) 1994-02-11 1995-02-09 Utilisation d'arylcyclobutylalkylamines dans le traitement de crises et de troubles neurologiques

Country Status (5)

Country Link
AU (1) AU1578295A (fr)
GB (1) GB9402641D0 (fr)
IL (1) IL112602A0 (fr)
WO (1) WO1995021615A1 (fr)
ZA (1) ZA951088B (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000010551A2 (fr) * 1998-08-24 2000-03-02 Sepracor Inc. Procedes d'utilisation d'inhibiteurs de recaptage de la dopamine et compositions contenant ces derniers
WO2000032178A2 (fr) * 1998-12-02 2000-06-08 Peter Sterling Mueller Traitement de troubles decoulant de deficiences organiques
US6288125B1 (en) * 2000-03-17 2001-09-11 Knoll Pharmaceuticals Company Treatment of hiatial hernia
US6316490B1 (en) 1995-11-17 2001-11-13 Merck & Co., Inc. Substituted aryl compounds useful as modulators of acetylcholine receptors
US6339106B1 (en) 1999-08-11 2002-01-15 Sepracor, Inc. Methods and compositions for the treatment and prevention of sexual dysfunction
US6399826B1 (en) 1999-08-11 2002-06-04 Sepracor Inc. Salts of sibutramine metabolites, methods of making sibutramine metabolites and intermediates useful in the same, and methods of treating pain
US6476078B2 (en) 1999-08-11 2002-11-05 Sepracor, Inc. Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction
US6610887B2 (en) 2001-04-13 2003-08-26 Sepracor Inc. Methods of preparing didesmethylsibutramine and other sibutramine derivatives
US6696495B2 (en) 1998-12-02 2004-02-24 Snowden Pharmaceuticals, Llc Treatment of disorders secondary to organic impairments
US6974838B2 (en) 1998-08-24 2005-12-13 Sepracor Inc. Methods of treating or preventing pain using sibutramine metabolites
WO2006073292A1 (fr) * 2005-01-06 2006-07-13 Cj Corporation Sels d'acide inorganique de sibutramine
WO2006073290A1 (fr) * 2005-01-06 2006-07-13 Cj Corporation Sel d'acide dicarboxylique de sibutramine
WO2006073291A1 (fr) * 2005-01-06 2006-07-13 Cj Corporation Sel d'acide sulfonique de sibutramine
AU2007200334B2 (en) * 1998-08-24 2010-07-01 Sepracor, Inc. Methods of using and compositions comprising dopamine reuptake inhibitors
CN102786444A (zh) * 2012-07-24 2012-11-21 上海瑞博化学有限公司 一种西布曲明类似物的磺酸盐的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3526656A (en) * 1967-05-25 1970-09-01 Parke Davis & Co (1-arylcyclobutyl)carbonyl carbamic acid derivatives
EP0339280A2 (fr) * 1988-03-31 1989-11-02 The Boots Company PLC Emploi de la N,N-diméthyl-1-(1-(4-chlorophényl)cyclobutyl)-3-méthylbuthylamine pour le traitement des désordres cérébraux
WO1994000114A1 (fr) * 1992-06-23 1994-01-06 Sepracor Inc. Procedes et compositions utilises pour traiter la depression et d'autres affections avec de la sibutramine (-) optiquement pure

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3526656A (en) * 1967-05-25 1970-09-01 Parke Davis & Co (1-arylcyclobutyl)carbonyl carbamic acid derivatives
EP0339280A2 (fr) * 1988-03-31 1989-11-02 The Boots Company PLC Emploi de la N,N-diméthyl-1-(1-(4-chlorophényl)cyclobutyl)-3-méthylbuthylamine pour le traitement des désordres cérébraux
WO1994000114A1 (fr) * 1992-06-23 1994-01-06 Sepracor Inc. Procedes et compositions utilises pour traiter la depression et d'autres affections avec de la sibutramine (-) optiquement pure

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"A comparison of various antidepressant drugs demonstrates a rapid desensitisation of alpha-2 adrenoceptors exclusively by sibutramine hydrochloride", PSYCHOPHARMACOLOGY, vol. 107, no. 4, pages 497 - 502 *

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6316490B1 (en) 1995-11-17 2001-11-13 Merck & Co., Inc. Substituted aryl compounds useful as modulators of acetylcholine receptors
EP1475086A3 (fr) * 1998-08-24 2006-12-13 Sepracor Inc. metabolites de la sibutramine
WO2000010551A2 (fr) * 1998-08-24 2000-03-02 Sepracor Inc. Procedes d'utilisation d'inhibiteurs de recaptage de la dopamine et compositions contenant ces derniers
AU2007200334B2 (en) * 1998-08-24 2010-07-01 Sepracor, Inc. Methods of using and compositions comprising dopamine reuptake inhibitors
AU2007200334B8 (en) * 1998-08-24 2010-10-21 Sepracor, Inc. Methods of using and compositions comprising dopamine reuptake inhibitors
US6974838B2 (en) 1998-08-24 2005-12-13 Sepracor Inc. Methods of treating or preventing pain using sibutramine metabolites
US7071234B2 (en) 1998-08-24 2006-07-04 Sepracor Inc. Methods of treating or preventing erectile dysfunction
EP1475086A2 (fr) * 1998-08-24 2004-11-10 Sepracor Inc. metabolites de la sibutramine
CN100415222C (zh) * 1998-08-24 2008-09-03 塞普拉科有限公司 使用多巴胺重摄取抑制剂的方法和包含它们的组合物
WO2000010551A3 (fr) * 1998-08-24 2000-09-21 Sepracor Inc Procedes d'utilisation d'inhibiteurs de recaptage de la dopamine et compositions contenant ces derniers
JP2002523366A (ja) * 1998-08-24 2002-07-30 セプラコア インコーポレーテッド ドーパミン再取込みインヒビターを含有する組成物及びその使用方法
US6331571B1 (en) 1998-08-24 2001-12-18 Sepracor, Inc. Methods of treating and preventing attention deficit disorders
US6538034B2 (en) 1998-08-24 2003-03-25 Thomas P. Jerussi Methods of treating or preventing weight gain, obesity, and related disorders
US6323242B1 (en) 1998-12-02 2001-11-27 Peter Sterling Mueller Treatment of disorders secondary to organic impairments
US6696495B2 (en) 1998-12-02 2004-02-24 Snowden Pharmaceuticals, Llc Treatment of disorders secondary to organic impairments
WO2000032178A2 (fr) * 1998-12-02 2000-06-08 Peter Sterling Mueller Traitement de troubles decoulant de deficiences organiques
WO2000032178A3 (fr) * 1998-12-02 2000-10-05 Peter Sterling Mueller Traitement de troubles decoulant de deficiences organiques
US6399826B1 (en) 1999-08-11 2002-06-04 Sepracor Inc. Salts of sibutramine metabolites, methods of making sibutramine metabolites and intermediates useful in the same, and methods of treating pain
US6339106B1 (en) 1999-08-11 2002-01-15 Sepracor, Inc. Methods and compositions for the treatment and prevention of sexual dysfunction
US6974837B2 (en) 1999-08-11 2005-12-13 Sepracor Inc. Compositions comprising sibutramine metabolites in combination with phosphodiesterase inhibitors
US6710087B2 (en) 1999-08-11 2004-03-23 Sepracor, Inc. Methods of treating or preventing neuropathic pain using sibutramine metabolites
US6476078B2 (en) 1999-08-11 2002-11-05 Sepracor, Inc. Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction
US6288125B1 (en) * 2000-03-17 2001-09-11 Knoll Pharmaceuticals Company Treatment of hiatial hernia
US6894189B2 (en) 2001-04-13 2005-05-17 Sepracor Inc. Methods of preparing didesmethylsibutramine and other sibutramine derivatives
US6610887B2 (en) 2001-04-13 2003-08-26 Sepracor Inc. Methods of preparing didesmethylsibutramine and other sibutramine derivatives
WO2006073290A1 (fr) * 2005-01-06 2006-07-13 Cj Corporation Sel d'acide dicarboxylique de sibutramine
WO2006073291A1 (fr) * 2005-01-06 2006-07-13 Cj Corporation Sel d'acide sulfonique de sibutramine
WO2006073292A1 (fr) * 2005-01-06 2006-07-13 Cj Corporation Sels d'acide inorganique de sibutramine
US7393977B2 (en) 2005-01-06 2008-07-01 Cj Cheiljedang Corporation Dicarboxylic acid salt of sibutramine
JP2008526836A (ja) * 2005-01-06 2008-07-24 シージェー チェイルジェダン コーポレーション シブトラミンの無機酸塩
US7429679B2 (en) 2005-01-06 2008-09-30 Cj Corporation Sulphonic acid salt of sibutramine
US7432398B2 (en) 2005-01-06 2008-10-07 Cj Corporation Inorganic acid salts of sibutramine
CN102786444A (zh) * 2012-07-24 2012-11-21 上海瑞博化学有限公司 一种西布曲明类似物的磺酸盐的制备方法

Also Published As

Publication number Publication date
GB9402641D0 (en) 1994-04-06
IL112602A0 (en) 1995-12-08
ZA951088B (en) 1996-01-23
AU1578295A (en) 1995-08-29

Similar Documents

Publication Publication Date Title
US5459164A (en) Medical treatment
WO1995021615A1 (fr) Utilisation d'arylcyclobutylalkylamines dans le traitement de crises et de troubles neurologiques
KR100432825B1 (ko) 식이 장애 치료용 약제학적 조성물
JPH10513455A (ja) 緑内障治療用のデプレニル化合物
CN105367485A (zh) 用于预防和/或治疗中枢神经系统退行性失调的新颖组合物
ES2199374T3 (es) Derivados de 1-(1-(4-clorofenil)ciclobutil)-3-metilbutilamina para reducir el nivel de acido urico en seres humanos.
CN103200941A (zh) 用于降低眼内压的[3-(1-(1h-咪唑-4-基)乙基)-2-甲基苯基]甲醇的酯前药
BG104568A (bg) Фармацевтичен състав, съдържащ сибутрамин и орлистат
EP0869956B1 (fr) Compositions pharmaceutiques
US20070219201A1 (en) Combination of atomoxetine and a 5ht1a receptor agonist for treating adhd and other disorders
US6376552B1 (en) Treatment of gallstones
WO2000056318A1 (fr) Traitement de la douleur neuropathique ou de la cellulomyalgie
US6355685B1 (en) Method of treating anxiety disorders
SK18242001A3 (sk) Terapeutické prípravky na báze sibutramínu vrátane jeho enantiomérov a farmaceuticky prijateľných solí a orlistatu a ich použitie
US6441046B1 (en) Control of metabolism
JP2563158B2 (ja) ノナテトラエン酸誘導体
ES2358888T3 (es) Medicamento que contiene un derivado de pirimidina.
US20040198837A1 (en) Treatment of neuropathic pain or fibromyalgia
US20030008897A1 (en) Method of controlling weight gain associated with therapeutic drugs
ZA200107679B (en) Treatment of hiatial hernia.
MXPA98003443A (en) Method for the treatment of protozoi infections
WO2000056316A1 (fr) Traitement des calculs biliaires

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW MX NL NO NZ PL PT RO RU SD SE SI SK TJ TT UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA