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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/08—Bridged systems
• • A—HUMAN NECESSITIES
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  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/32—Alcohol-abuse
• • 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]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/14—Nitrogen atoms not forming part of a nitro radical

Definitions

• the present invention relates to ⁇ / - [(7-aza-bicyclo [2.2.1] hept-1-yl) -aryl-methyl] -benzamide derivatives, to their preparation and their therapeutic application in the treatment of or the prevention of diseases involving glycine carriers Glyti.
• R represents a hydrogen atom or a group chosen from (C 1 -C 6 ) alkyl, (C 3 -C 7 ) -cycloalkyl groups, optionally substituted with one or more groups chosen independently of one another from halogen atoms, (C 3 -C 7 ) -cycloalkyl, (C 2 -C 4 ) alkenyl, phenyl, (C 1 -C 6 ) alkoxy, hydroxy; the phenyl group being optionally substituted by one or more (C 1 -C 6 ) alkoxy groups;
• R 1 represents a phenyl or naphthyl group, optionally substituted by one or more substituents chosen independently of one another from halogen atoms, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy groups, halo (CrC 6) alkyl, hydroxy, halo (C r C 6) alkoxy, (C r C 6) alkyl-thio, (C r C 6) alkyl-SO, (Ci-C 6) alkyl-SO 2 - R 2 represents one or more substituents selected from hydrogen, halogen atoms, halo groups (CrC 6) alkyl, (Ci-C 6) alkyl, (C 3 -C 7) cycloalkyl (C 3 -C 7 ) -cycloalkyl- (C 1 -C 3 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) alkyl
• the compounds of formula (I) have an asymmetric carbon atom. They can therefore exist in the form of enantiomers. These enantiomers, including racemic mixtures, form part of the invention.
• the compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
• salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I), also form part of the invention.
• Ct-Cz where t and z can take the values from 1 to 6, a carbon chain which can have from t to z carbon atoms, for example Ci--C 6 carbon chain which can have from 1 to 6 carbon atoms; alkyl, a saturated, linear or branched aliphatic group; for example, a C 1 -C 6 -alkyl group represents a linear or branched carbon chain of 1 to 6 carbon atoms, for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl group; ; - alkylene, saturated divalent alkyl group, linear or branched, for example a Ci -6 alkylene group represents a divalent carbon chain of 1 to 6 carbon atoms, linear or branched, for example methylene, ethylene, 1- methylethylene, propylene, alkoxy, -O-alkyl, -hydroxy
• halo-alkoxy an alkoxy group of which one or more hydrogen atoms have been substituted by a halogen.
• a first group of compounds consists of the compounds for which:
• R represents a hydrogen atom, a (C 1 -C 6 ) alkyl or benzyl group
• R 1 and R 2 being as defined above
• a second group of compounds consists of compounds for which: - R1 represents a phenyl group;
• R and R2 being as defined above.
• a third group of compounds consists of compounds for which:
• R 2 represents one or more substituents chosen from a hydrogen atom, halogen atoms, halo (Ci-C 6 ) alkyl or (Ci-C 6 ) alkyl groups, R and R 1 being as defined herein; -above.
• a fourth group of compounds consists of the compounds for which:
• R represents a hydrogen atom, a (C 1 -C 6 ) alkyl or benzyl group
• Ri represents a phenyl group
• R 2 represents one or more substituents chosen from a hydrogen atom, halogen atoms, halo- (C 1 -C 6 ) alkyl or (C 1 -C 6 ) alkyl groups,
• a fifth group of compounds is constituted by the compounds for which:
• R represents a hydrogen atom or a methyl, ethyl or benzyl group
• Ri represents a phenyl group
• R 2 represents one or more substituents chosen from a hydrogen atom, a chlorine atom, methyl, ethyl or trifluoromethyl groups, in the form of a base or an addition salt with an acid.
• the compounds of the invention exhibit particular activity as inhibitors of Glyti glycine transporters, including an improved activity and safety profile.
• the compounds of general formula (I) in which R is different from the hydrogen atom can also be prepared from compounds of general formula (I) in which R represents a hydrogen atom, or by alkylation of said compound of general formula (I) with a halide or mesylate of the RX type, in which R is as defined above and X is a mesylate or halogen, in the presence of a mineral base, for example potassium carbonate in the acetonitrile; either by an Eschweiler-Clarke type reaction or a reductive amination with an appropriate aldehyde or ketone according to the methods known to those skilled in the art; or with an appropriate epoxy derivative, according to the methods known to those skilled in the art.
• a mineral base for example potassium carbonate in the acetonitrile
• the diamine of general formula (II) can be prepared by the process illustrated by scheme 2 for the amine of general formula (IIa) and for the amine of general formula (Nb) which follows:
• the ester of formula (IV) is converted into nitrile of formula (V), by heating at reflux of xylene in the presence of the trimethylaluminium complex and ammonium chloride previously formed, according to a method described in Synthetic Commun., 1982, 12 (13), 989-993 and in Tetrahedron Lett., 1979, (51), 4907-4910.
• the nitrile of formula (V) is then reacted with the lithiated aromatic compound of general formula (VI), in which R 1 is as defined above, in an ethereal solvent such as tetrahydrofuran or ether, at low temperature. for example - 70 ° C.
• amine of general formula (IIa) An imine is thus obtained which is reduced with a reducing agent such as sodium borohydride in a protic solvent such as methanol to give the amine of general formula (IIa).
• a reducing agent such as sodium borohydride in a protic solvent such as methanol
• a protic solvent such as methanol
• the amine (IIa) can be debenzylated by hydrogenation in the presence of palladium catalyst to provide deprotected amine of general formula (Nb).
• the benzyl group could in particular be replaced by another protecting group, for example by an allyl group or a dimethoxybenzyl group, either by debenzylating then by reprotecting, for example by means of a reaction.
• alkylation with the appropriate electrophile for example an allyl bromide or a dimethoxybenzyl bromide, according to the methods known to those skilled in the art; either according to the method described in Tetrahedron: Asymmetry, 2006 (17), 252-258, replacing benzylamine with allylamine or dimethoxybenzylamine, especially 2,4-dimethoxybenzylamine.
• the chiral compounds of general formula (I) corresponding to the S or R enantiomers can be obtained by separation of the racemic compounds by high performance liquid chromatography (HPLC) on a chiral column, or could be obtained by resolution of the racemic amine of general formula (II) using a chiral acid, such as dibenzoyl-tartaric acid or by fractional and preferential recrystallization of a diastereoisomeric salt.
• HPLC high performance liquid chromatography
• ester of formula (IV) is prepared according to a method described in Tetrahedron,
• nitrile of formula (V) could also be prepared according to a method described in Tetrahedron: Asymmetry, 2006 (17), 252-258.
• lithiated derivatives of general formula (VI) may be prepared according to methods known to those skilled in the art.
• Acids and acid chlorides of general formula (III) are commercially available or prepared by analogy with methods known to those skilled in the art.
• m means multiplet, "s” singlet, “t” triplet, “d” doublet, "q” quadruplet, dxd means double doublet, txt means triple triplet, dxt double triplet, and so on.
• Example 1 (Compound No. 4): ⁇ - [(7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) benzamide hydrochloride (1 : 1)
• complex A the trimethylaluminium / ammonium chloride complex (approximately 0.67M) is prepared, hereinafter referred to as complex A, by placing 1.5 g of dry ammonium chloride (28 mmol) in 30 ml of anhydrous toluene, to which 15 ml of a solution of 2N trimethylaluminum in toluene (30 mmol) are added after cooling and that it is left at room temperature until the end of the gas evolution.
• the medium is acidified to pH 4-5 with 1N hydrochloric acid solution and then extracted successively with ethyl acetate (100 ml) and then dichloromethane (100 ml).
• the organic phases are dried over sodium sulphate, filtered, combined and then evaporated under reduced pressure.
• Example 2 (Compound No. 5): 2-Chloro- ⁇ [- [(7-ethyl-7-azabicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) hydrochloride ) benzamide (1: 1). 25 mg of ⁇ / - [(2-azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (2-chloro-3-ol) were placed in a 25 ml flask equipped with a condenser.
• Example 3 (Compound No. 7): 2-Chloro-N - [(7-methyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) hydrochloride ) -benzamide (1: 1) In a 25 ml flask equipped with a condenser, 0.09 g of ⁇ / - [(2-azabicyclo [2.1.1] hex-1-yl) -phenyl is placed -methyl] - (2-chloro-3-trifluoromethyl) -benzamide (0.22 mmol) and 2 ml of formaldehyde in 2 ml of formic acid. The reaction mixture is heated at 100 ° C.
• the compounds of the table are in the form of hydrochloride solvated with one or more water molecules.
• the compounds 3 and 6 in Table 1 form a pair of enantiomers which are separated by preparative HPLC, using a column Chirobiotic ® T2 5 .mu.m and as a solvent methanol / triethylamine / acetic acid 100 / 0.1 / 0.05. Absolute stereochemistry was determined by X-ray diffraction.
• Table 2 gives the physical properties, melting points and rotational potency of the compounds of Table 1.
• the compounds of the invention have been subjected to a series of pharmacological tests which have demonstrated their interest as substances with therapeutic activities.
• [ 14 C] glycine uptake is studied in SK-N-MC (human neuroepithelial cells) cells expressing the native human glyti transporter by measuring the radioactivity incorporated in the presence or absence of the test compound.
• the cells are cultured in monolayer for 48 h in 0.02% fibronectin pretreated plates. On the day of the experiment, the culture medium is removed and the cells are washed with Krebs-HEPES buffer ([4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid) at pH 7.4. After 10 minutes of preincubation at 37 ° C.
• Krebs-HEPES buffer [4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid
• the effectiveness of the compound is determined by the IC50 concentration of the compound which decreases by 50% the specific uptake of glycine, defined by the difference in radioactivity incorporated by the control group and the batch which received glycine at 10 mM.
• the compounds of the invention, in this test, have a Cl 5 o of the order of 0.001 to 10 ⁇ M.
• Table 3 shows some examples of Cl 5 results for compounds according to the invention.
• the compounds of the invention can be used for the treatment of cognitive and / or behavioral disorders associated with neurodegenerative diseases, dementia; for the treatment of psychoses, in particular schizophrenia (deficient form and productive form), acute or chronic extrapyramidal symptoms induced by neuroleptics; for the treatment of various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders; for the treatment of various forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or withdrawal, sexual behavior disorders, eating disorders, migraine; pain ; sleep disorders.
• the compounds according to the invention can therefore be used for the preparation of medicaments, in particular inhibitory drugs of the glycine glycine transporter.
• the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid or a hydrate or a solvate of the compound of formula (I).
• the present invention also relates to pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the form of a base or a pharmaceutically acceptable salt or solvate, and in a mixture, where appropriate, with suitable excipients.
• Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.
• compositions according to the invention can thus be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal, intraocular administration.
• the unit dosage forms may be, for example, tablets, capsules, granules, powders, oral or injectable solutions or suspensions, transdermal patches, suppositories.
• topical administration it is possible to envisage ointments, lotions and eye drops.
• Said unit forms are dosed to allow a daily administration of 0.01 to 20 mg of active ingredient per kg of body weight, according to the dosage form.
• a pharmaceutical carrier which may be composed of diluents, for example lactose, microcrystalline cellulose, starch, and formulation adjuvants such as binders (polyvinylpyrrolidone), is added to the active ingredient, whether micronized or not; , hydroxypropyl methylcellulose, etc.), flow agents such as silica, lubricants such as magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate. Wetting agents or surfactants such as sodium lauryl sulphate may also be added.
• diluents for example lactose, microcrystalline cellulose, starch, and formulation adjuvants such as binders (polyvinylpyrrolidone)
• flow agents such as silica
• lubricants such as magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate.
• Wetting agents or surfactants such as sodium la
• the production techniques can be direct compression, dry granulation, wet granulation or hot melt.
• the tablets may be bare, sugar-coated, for example with sucrose, or coated with various polymers or other suitable materials. They can be designed to allow rapid, delayed or prolonged release of the active ingredient thanks to polymer matrices or specific polymers used in the coating.
• the active ingredient is mixed with dry pharmaceutical vehicles (simple mixing, dry or wet granulation, or hot melting), liquid or semi-solid.
• the capsules may be hard or soft, film-coated or not, so as to have a rapid, prolonged or delayed activity (for example for an enteric form).
• a composition in the form of syrup or elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably acaloric, methylparaben or propylparaben as antiseptic, a flavoring agent and a dye.
• a sweetener preferably acaloric, methylparaben or propylparaben as antiseptic, a flavoring agent and a dye.
• Water-dispersible powders and granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or dispersing agents such as polyvinylpyrrolidone, as well as with sweeteners and taste-correcting agents.
• suppositories prepared with binders melting at the rectal temperature for example cocoa butter or polyethylene glycols, are used.
• aqueous suspensions For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol, are used.
• pharmacologically compatible dispersing agents and / or wetting agents for example propylene glycol or butylene glycol
• the active ingredient may also be formulated in the form of microcapsules, optionally with one or more supports or additives, or with a polymer matrix or with a cyclodextrin (transdermal patches, sustained-release forms).
• compositions according to the invention comprise a medium compatible with the skin. They may be in the form of aqueous, alcoholic or aqueous-alcoholic solutions, gels, water-in-oil or oil-in-oil emulsions. water having the appearance of a cream or a gel, microemulsions, aerosols, or in the form of vesicular dispersions containing ionic and / or nonionic lipids. These galenic forms are prepared according to the usual methods of the fields considered.
• a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
• the dose of active ingredient administered per day can reach 0.1 to 20 mg / kg, in one or more doses.
• the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
• the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of pharmaceutically acceptable salts thereof.

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