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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems
• • 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
• • 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
  • A61P25/08—Antiepileptics; Anticonvulsants
• • 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
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  • 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
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• • A—HUMAN NECESSITIES
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
• • 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
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/02—Antidotes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • 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
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D495/14—Ortho-condensed systems

Definitions

• the present invention relates to compounds of formula:
• cycle A is chosen from the following cycles
• R represents a CH radical? or a sulfur, oxygen or nitrogen atom substituted by a straight or branched chain alkyl radical and preferably containing 1 to 6 carbon atoms.
• the compounds of formula (I) can be prepared by cyclization in the presence of ammonium acetate of a derivative of formula:
• ring A has the same meanings as in formula (I) and Rj represents a lower alkyl radical (preferably 1 to 4 C).
• This cyclization is preferably carried out in an inert solvent such as acetic acid, at the boiling temperature of the reaction medium.
• ring A has the same meanings as in formula (I) and Hal represents a halogen atom, on an alkyl imidazole-2-carboxylate.
• This reaction is carried out either by fusion at a temperature between 120 and 180 ° C, or in an inert solvent such as dimethylformamide, in the presence of a base such as an alkali metal hydride (sodium hydride for example), at a temperature close to 20 ° C. or ethanol at the boiling temperature of the reaction medium.
• a base such as an alkali metal hydride (sodium hydride for example), at a temperature close to 20 ° C. or ethanol at the boiling temperature of the reaction medium.
• the derivatives of formula (III) can be obtained by halogenation of the corresponding ketones by means of a halogenating agent such as bromine, chlorine, in an inert solvent such as a chlorinated solvent (methylene chloride, chloroform for example), at a temperature of -15 ° C or within acetic acid, at a temperature close to 20 ° C, or a copper halide, within dioxane, at a temperature close to 100 ° C or by application or adaptation of the methods described by EJ COREY, J. Am. Chem. Soc, 75, 2301 (1953), N.A. CREETH and N.F. THORPE, J.C.S. 93, 1508 (1908), J.N. SRIVASTAVA, J. Indian Chem. Soc, 67 (3), 210 (1990) and R. LESSER et al., Chem. Ber., 56, 1642 (1923).
• a halogenating agent such as bromine, chlorine
• ketones can be obtained by application or adaptation of the methods described by I.G. HINTON and F.G. MANN, J. Chem. Soc, part I, 599 (1959), C. NORMANT-CHEFNAY, Bull. Soc. Chim. Fr., 1351 (1971).
• Ethyl imidazole-2-carboxylate can be obtained according to the method described in US Pat. No. 3,600,399.
• the compounds of formula (I) can also be prepared by cyclization of a derivative of formula:
• cycle A has the same meanings as in formula (I).
• the cyclization is generally carried out by means of an acid such as hydrochloric acid, acetic acid, in an inert solvent such as an alcohol (methanol or ethanol for example) at the boiling temperature of the reaction medium.
• an acid such as hydrochloric acid, acetic acid
• an inert solvent such as an alcohol (methanol or ethanol for example) at the boiling temperature of the reaction medium.
• the derivatives of formula (IV) can be obtained by the action of ammonia on a derivative of formula (II).
• This reaction is preferably carried out in an inert solvent such as an alcohol (methanol or ethanol for example), at a temperature in the region of 20 ° C.
• an inert solvent such as an alcohol (methanol or ethanol for example)
• the compounds of formula (I) can be purified by the usual known methods, for example by crystallization, chromatography or extraction.
• the compounds of formula (I) can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid within an organic solvent such as an alcohol, a ketone, an ether or a solvent chlorine.
• organic solvent such as an alcohol, a ketone, an ether or a solvent chlorine.
• salts there may be mentioned the acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophyllinacetate, salicylate, methylene-bis- ⁇ -oxynaphtoate, hydrochloride, sulfate, nitrate and phosphate.
• the compounds of formula (I) have interesting pharmacological properties. These compounds are antagonists of the ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, also known as the quisqualate receptor.
• AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
• the compounds of formula (I) are non-competitive antagonists of the N-methyl-D-aspartate receptor (NMDA) and, more particularly, they are ligands for the glycine modulating sites of the NMDA receptor.
• NMDA N-methyl-D-aspartate receptor
• These compounds are therefore useful for treating or preventing all ischemias (such as focal or global ischemia) consecutive to cerebrovascular accidents, cardiac arrest, hypotension, cardiac or pulmonary surgery or severe hypoglycemia. They are also useful in the treatment of effects due to anoxia, whether perinatal or consecutive to drowning or cerebro-spinal lesions. These compounds can also be used to treat or prevent the development of neurodegenerative diseases, HUNTINGTON's chorea, ALZHEIMER's disease, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and the disease by PARKINSON.
• These compounds can also be used with respect to epileptogenic and / or convulsive manifestations, for the treatment of cerebral or spinal traumas, traumas linked to the degeneration of the inner ear (R. PUJOL et al., Neuroreport, 3 , 299-302 (1992) or retina (JL MONSINGER et al., Exp. Neurol., 113, 10-17 (1991), anxiety (KEHNE et al., Eur. J. Pharmacol., 193 , 283 (1991)), depression (TRULLAS et al., Eur. J.
• mitochondrial anomalies such as mitochondrial myopathy, LEBER syndrome, WERNICKE encephalopathy, RETT syndrome, homocysteinemia, hyperprolinemia, hydroxybutiric-aminoaciduria , saturnine encephalopathy (chronic lead poisoning) and sulfite oxidase deficiency.
• the affinity of the compounds of formula (I) vis-à-vis the AMPA receptor was determined by studying the antagonism of the specific binding of [3H] -AMPA on membranes of rat cerebral cortex (HONORE et al., Neuroscience letters, 54, 27 (1985)).
• the [3H] -AMPA is incubated in the presence of 0.2 mg of protein at 4 ° C for 30 minutes in 10mM KH2PO4 buffer, 100mM KSCN, pH7.5.
• Non-specific binding is determined in the presence of 1 mM L-glutamate.
• the bound radioactivity is separated by filtration on PHARMACIA filters (Printed Filtermate A).
• the inhibitory activity of these products is less than or equal to 100 ⁇ M.
• the affinity of the compounds of formula (I) for the glycine site linked to the NMDA receptor was determined by studying the antagonism of the specific binding of [3H] -DCKA on membranes of rat cerebral cortex according to the method described by T CANTON et al., J. Pharm. Pharmacol., 44, 812 (1992).
• the [ 3 H] -DCKA (20 nM) is incubated in the presence of 0.1 mg of proteins at 4 ° C. for 30 minutes in 50 mM HEPES buffer, pH 7.5.
• the non-specific binding is determined in the presence of 1mM glycine.
• the bound radioactivity is separated by filtration on Whatman GF / B filters.
• the inhibitory activity of these products is less than or equal to 100 ⁇ M.
• the compounds of formula (I) have a low toxicity. Their LD50 is greater than 50 mg / kg by the IP route in mice.
• the product (1.1 g) is suspended in 10 ml of ethyl acetate, filtered, washed with 5 ml of ethyl acetate and then dried under reduced pressure (15 mm Hg; 2 kPa) at 40 ° vs.
• 0.5 g of product thus obtained (out of 1 g in total) is dissolved in 7.5 ml of methanol and the solution, supplemented with 0.8 ml of concentrated hydrochloric acid, is kept for 1 hour at a temperature close to 20 ° C then concentrated under reduced pressure (15 mm Hg; 2 kPa) at 40 ° C.
• the product (0.5 g), added with 0.3 g prepared under the same conditions, is dissolved in 102 ml of boiling isopropanol and the solution, added with bleaching black, is filtered hot, cooled, added with 102 ml of isopropyl ether and stored for 1 hour at a temperature in the region of 5 ° C.
• the crystals which appear are separated by filtration, washed with 5 ml of isopropyl ether and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 80 ° C.
• Ethyl 1- [2-oxocyclopentyl)] imidazole-2-carboxylate can be prepared as follows: a solution of 2.8 g of ethyl imidazole-2-carboxylate in 30 ml of anhydrous dimethylformamide is added drop by drop in 15 minutes in a suspension of 0.6 g of 80% sodium hydride in 10 ml of anhydrous dimethylformamide maintained under a nitrogen atmosphere at a temperature in the region of 25 ° C. After 15 minutes of stirring, a solution of 5.6 g of 78% 2-bromocyclopentanone in 10 ml of anhydrous dimethylformamide is added dropwise over 10 minutes.
• the mixture is stirred for one hour at the same temperature, added slowly 20 ml of distilled water, poured over 500 ml of distilled water and extracted 4 times with 400 ml in total of dichloromethane.
• the organic extracts are combined, washed with 100 ml of distilled water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 50 ° C.
• the product obtained (4.9 g) is chromatographed on 245 g of neutral silica gel (0.020-0.045 mm) contained in a column 5.5 cm in diameter, eluting under pressure with a mixture of dichloromethane and acetate d ethyl (70-30 by volume) and collecting 70 ml fractions.
• Fractions 47 to 105 are concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 50 ° C.
• 1.34 g of ethyl 1- [2-oxocyclopentyl)] imidazole-2-carboxylate are thus obtained in the form of a yellow oil.
• 2-bromocyclopentanone can be prepared as described by E.J. COREY, J. Am. Chem. Soc, 75, 2301 (1953).
• Ethyl imidazole-2-carboxylate can be prepared as described in US Pat. No. 3,600,399.
• Ethyl 1- [1- (2-oxoindanyl)] imidazole-2-carboxylate can be prepared in the following manner: 2.8 g of ethyl imidazole-2-carboxylate are refluxed for 4 hours, 60 ml of ethanol and 2.1 g of 1-bromo-2-indanone. The reaction mixture is then concentrated on a rotary evaporator and purified by chromatography on a silica column (400 g) with a mixture of dichloromethane and ethyl acetate (70-30 by volume).
• 1-bromo-2-indanone can be prepared as described by N.A. CREETH and N.F. THORPE, J.Chem.Soc 93, 1508 (1908).
• 1- [2- (1 -oxo-1, 2,3,4-tetrahydronaphthyl)] imidazole-2-carboxamide can be prepared as follows: 0.6 g of 1- [2- (1-oxo- 1, 2,3,4- ethyl tetrahydronaphthyl)] imidazole-2-carboxylate is dissolved in 40 ml of a 3 N solution of ammoniacal methanol and the solution is stored for 20 hours at a temperature in the region of 20 ° C and then concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 35 ° C.
• Ethyl 1- [2- (1 -oxo-1,2,3,4-tetrahydronaphthyl)] imidazole-2-carboxylate can be prepared as follows: a solution of 2.8 g of imidazole-2 - ethyl carboxylate in 30 ml of anhydrous dimethylformamide is added dropwise over 10 minutes at a temperature in the region of 20 ° C to a suspension of 0.6 g of 80% sodium hydride in 10 ml of anhydrous dimethylformamide maintained under a nitrogen atmosphere.
• the product obtained (3.26 g) is chromatographed on 200 g of neutral silica gel (0.020-0.045 mm) contained in a column 4.6 cm in diameter, eluting under pressure with a dichloromethane-ethyl acetate mixture ( 70-30 by volume) and collecting 70 ml fractions. Fractions 15 to 35 are combined and concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 40 ° C. 0.6 g of ethyl 1- [2- (1-oxo-1, 2,3,4-tetrahydronaphthyl)] imidazole-2-carboxylate, melting at 98 ° C., is thus obtained.
• 0.94 g of product thus obtained (out of the 1.02 g obtained in total) is dissolved in 30 ml of acetic acid and the solution, supplemented with 27 g of ammonium acetate, is heated to boiling for 20 minutes. The mixture is cooled to a temperature in the region of 20 ° C. and, after the addition of 20 ml of distilled water, the solid which appears is separated by filtration, washed twice with 20 ml in total of distilled water and air dried . The product (0.7 g) is dissolved in 35 ml of boiling dimethylformamide and the solution, supplemented with bleaching black, is filtered hot, cooled and stored for 16 hours at a temperature in the region of 5 ° C.
• 3-Bromo-isothiochroman-4-one can be prepared according to the method described by R. LESSER et al., Chem. Ber., 56, 1642 (1923).
• the medicaments according to the invention consist of a compound of formula (I) or a salt of such a compound, in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product, which can be inert or physiologically active.
• the medicaments according to the invention can be used orally, parenterally, rectally or topically.
• compositions for oral administration tablets, pills, powders (gelatin capsules, cachets) or granules can be used.
• the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon.
• inert diluents such as starch, cellulose, sucrose, lactose or silica
• These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.
• compositions for oral administration there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
• inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
• These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
• the sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions.
• solvent or vehicle water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable.
• These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared as sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
• compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
• compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.
• the compounds according to the invention are particularly useful for the treatment and / or prevention of conditions which require the administration of an AMPA receptor antagonist or an NMDA receptor antagonist.
• These compounds are in particular useful for treating or preventing all ischemia and in particular cerebral ischemia, the effects due to anoxia, the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and PAR-KINSON disease, vis-à-vis epileptogenic and / or convulsive manifestations, for the treatment of cerebral and spinal traumas, traumas linked to degeneration inner ear or retina, anxiety, depression, schizophrenia, TOURETTE syndrome, hepatic encephalopathy, as analgesics, antiinflammatories, antianorexics, antimigraine, antiemetics and to treat poisoning with neurotoxins or other NMDA receptor agonists, as well as neurological disorders associated with viral diseases such as AIDS, rabies, mea
• These compounds are also useful for the prevention of symptoms of drug and alcohol abstinence and the inhibition of addiction and dependence on opiates as well as for the treatment of deficits associated with mitochondrial abnormalities such as mitochondrial myopathy, LEBER syndrome, WERNICKE encephalopathy, RETT syndrome, homocysteinemia, hyperprolinemia, hydroxybutiric aminoaciduria, saturnine encephalopathy (chronic lead poisoning) and sulfite oxidase deficiency.
• the doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 10 mg and 100 mg per day orally for an adult with unit doses ranging from 5 mg to 50 mg of active substance.
• the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.
• capsules containing 50 mg of active product having the following composition are prepared:
• Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique:
• a solution for injection containing 10 mg of active product having the following composition is prepared:

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