EP0752994A1 - IMIDAZO[1,2-a]PYRAZIN-4-ONE DERIVATIVES, THEIR PREPARATION AND DRUGS CONTAINING THEM - Google Patents

IMIDAZO[1,2-a]PYRAZIN-4-ONE DERIVATIVES, THEIR PREPARATION AND DRUGS CONTAINING THEM

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Publication number
EP0752994A1
EP0752994A1 EP95914407A EP95914407A EP0752994A1 EP 0752994 A1 EP0752994 A1 EP 0752994A1 EP 95914407 A EP95914407 A EP 95914407A EP 95914407 A EP95914407 A EP 95914407A EP 0752994 A1 EP0752994 A1 EP 0752994A1
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EP
European Patent Office
Prior art keywords
formula
compounds
receptor
imidazole
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP95914407A
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German (de)
French (fr)
Inventor
Jean-Claude Aloup
François Audiau
Michel Barreau
Dominique Damour
Arielle Genevois-Borella
Patrick Jimonet
Serge Mignani
Yves Ribeill
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Aventis Pharma SA
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Rhone Poulenc Rorer SA
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Publication of EP0752994A1 publication Critical patent/EP0752994A1/en
Ceased legal-status Critical Current

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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
    • 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
    • A61P25/24—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
    • A61P25/26—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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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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Abstract

Compounds of formula (I), wherein ring A is selected from rings 1, 2 and 3, wherein R is a CH2 radical or a sulphur, oxygen or nitrogen atom substituted by an alkyl radical, salts thereof, preparation thereof and drugs containing same. The compounds of formula (I) have valuable pharmacological properties and are alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, said receptor also being known as the quisqualate receptor. Furthermore, the compounds of formula (I) are non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, and particularly NMDA receptor glycine modulation site ligands.

Description

DERIVES D'IMIDAZ0.1.2-a1PYRAZINE-4-ONE. LEUR PREPARATION ET LES MEDICAMENTS LES CONTENANT IMIDAZ0.1.2-a1PYRAZINE-4-ONE DERIVATIVES. THEIR PREPARATION AND THE MEDICINES CONTAINING THEM
La présente invention concerne des composés de formule :The present invention relates to compounds of formula:
leurs sels, leur préparation et les médicaments les contenant.their salts, their preparation and the drugs containing them.
Dans la formule (I) le cycle A est choisi parmi les cycles suivantsIn formula (I) cycle A is chosen from the following cycles
11
dans lesquels R représente un radical CH? ou un atome de soufre, d'oxygène ou d'azote substitué par un radical alkyle en chaîne droite ou ramifiée et contenant, de préférence, 1 à 6 atomes de carbone.in which 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.
Les composés de formule (I) peuvent être préparés par cyclisation en présence d'acétate d'ammonium d'un dérivé de formule :The compounds of formula (I) can be prepared by cyclization in the presence of ammonium acetate of a derivative of formula:
dans laquelle le cycle A a les mêmes significations que dans la formule (I) et R-j représente un radical alkyle inférieur (de préférence 1 à 4 C). Cette cyclisation s'effectue, de préférence, au sein d'un solvant inerte tel que l'acide acétique, à la température d'ébullition du milieu réactionnel.in which 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.
Les dérivés de formule (II) peuvent être obtenus par action d'un dérivé halogène de formule :The derivatives of formula (II) can be obtained by the action of a halogen derivative of formula:
dans laquelle la cycle A a les mêmes significations que dans la formule (I) et Hal représente un atome d'halogène, sur un imidazole-2-carboxylate d'alkyle.in which ring A has the same meanings as in formula (I) and Hal represents a halogen atom, on an alkyl imidazole-2-carboxylate.
Cette réaction s'effectue soit par fusion à une température comprise entre 120 et 180°C, soit au sein d'un solvant inerte tel que le diméthylformamide, en présence d'une base telle qu'un hydrure de métal alcalin (hydrure de sodium par exemple), à une température voisine de 20°C ou l'éthanol à la température d'ébullition du milieu réactionnel.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.
Les dérivés de formule (III) peuvent être obtenus par halogénation des cétones correspondantes au moyen d'un agent d'halogénation tel que le brome, le chlore, au sein d'un solvant inerte tel qu'un solvant chloré (chlorure de méthylène, chloroforme par exemple), à une température de -15°C ou au sein de l'acide acétique, à une température voisine de 20°C, ou un halogènure de cuivre, au sein du dioxanne, à une température voisine de 100°C ou par application ou adaptation des méthodes décrites par E.J. COREY, J. Am. Chem. Soc, 75, 2301 (1953), N.A. CREETH et N.F. THORPE, J.C.S. 93, 1508 (1908), J.N. SRIVASTAVA, J. Indian Chem. Soc, 67(3), 210 (1990) et R. LESSER et coll., Chem. Ber., 56, 1642 (1923).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).
Les cétones peuvent être obtenues par application ou adaptation des méthodes décrites par I.G. HINTON et F.G. MANN, J. Chem. Soc, part I, 599 (1959), C. NORMANT-CHEFNAY, Bull. Soc. Chim. Fr., 1351 (1971).The 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).
L'imidazole-2-carboxylate d'éthyle peut être obtenu selon la méthode décrite dans le brevet US 3600399. Les composés de formule (I) peuvent également être préparés par cyclisation d'un dérivé de formule :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:
dans laquelle le cycle A a les mêmes significations que dans la formule (I). in which cycle A has the same meanings as in formula (I).
La cyclisation s'effectue généralement au moyen d'un acide tel que l'acide chlorhydrique, l'acide acétique, au sein d'un solvant inerte tel qu'un alcool (méthanol ou éthanol par exemple) à la température d'ébullition du milieu réactionnel.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.
Les dérivés de formule (IV) peuvent être obtenus par action d'ammoniac sur un dérivé de formule (II).The derivatives of formula (IV) can be obtained by the action of ammonia on a derivative of formula (II).
Cette réaction s'effectue, de préférence, au sein d'un solvant inerte tel qu'un alcool (méthanol ou éthanol par exemple), à une température voisine de 20°C.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.
Les composés de formule (I) peuvent être purifiés par les méthodes connues habituelles, par exemple par cristallisation, chromatographie ou extraction.The compounds of formula (I) can be purified by the usual known methods, for example by crystallization, chromatography or extraction.
Les composés de formule (I) peuvent être éventuellement transformés en sels d'addition avec un acide minéral ou organique par action d'un tel acide au sein d'un solvant organique tel qu'un alcool, une cétone, un éther ou un solvant chloré.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.
Ces sels font également partie de l'invention.These salts are also part of the invention.
Comme exemples de sels pharmaceutiquement acceptables, peuvent être cités les acétate, propionate, succinate, benzoate, fumarate, maléate, oxalate, méthanesulfonate, iséthionate, théophyllinacétate, salicylate, méthylène-bis-β-oxynaphtoate, chlorhydrate, sulfate, nitrate et phosphate. Les composés de formule (I) présentent des propriétés pharmacologiques intéressantes. Ces composés sont des antagonistes du récepteur de l'acide α-amino-3-hydroxy-5-méthyl-4-isoxazolepropionique (AMPA), connu aussi sous le nom de récepteur du quisqualate.As examples of pharmaceutically acceptable salts, there may be mentioned the acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophyllinacetate, salicylate, methylene-bis-β-oxynaphtoate, hydrochloride, sulfate, nitrate and phosphate. The compounds of formula (I) have interesting pharmacological properties. These compounds are antagonists of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, also known as the quisqualate receptor.
Par ailleurs, les composés de formule (I) sont des antagonistes non compétitifs du récepteur N-méthyl-D-aspartate (NMDA) et, plus particulièrement, ce sont des ligands pour les sites modulateurs de la glycine du récepteur NMDA.Furthermore, 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.
Ces composés sont donc utiles pour traiter ou prévenir toutes les ischémies (telles l'ischémie focale ou globale) consécutives à des accidents vasculaires cérébraux, un arrêt cardiaque, une hypotension artérielle, une intervention chirurgicale cardiaque ou pulmonaire ou une hypoglycémie sévère. Ils sont également utiles dans le traitement des effets dus à une anoxie, qu'elle soit périnatale ou consécutive à une noyade ou à des lésions cérébro-spinales. Ces composés peuvent également être utilisés pour traiter ou prévenir l'évo¬ lution de maladies neurodégénératives, de la chorée d'HUNTINGTON, de la maladie d'ALZHEIMER, de la sclérose latérale amyotrophique, de l'atrophie olivo-pontocérébelleuse et de la maladie de PARKINSON. Ces composés peuvent aussi être utilisés vis-à-vis des manifestations épileptogènes et/ou convulsives, pour le traitement des traumatismes cérébraux ou spinaux, des traumatismes liés à la dégénérescence de l'oreille interne (R. PUJOL et coll., Neuroreport, 3, 299-302 (1992) ou de la rétine (J.L MONSINGER et coll., Exp. Neurol., 113, 10-17 (1991), de l'anxiété (KEHNE et coll., Eur. J. Pharmacol., 193, 283 (1991)), de la dépression (TRULLAS et coll.,Eur. J. Pharmacol., 185, 1 (1990)), de la schizophrénie (REYNOLDS, TIPS, 13, 116 (1992)), du syndrome de TOURETTE, des encéphalopathies hépatiques, en tant qu'analgésiques (DICKENSON et coll., Neurosc. Letters, 121 , 263 (1991)), antiinflammatoires (SLUTA et coll., Neurosci. Letters, 149, 99-102 (1993)) antianorexiques (SORRELS et coll., Brain Res., 572, 265 (1992)), antimigraineux, antiémétiques et pour traiter les empoisonnements par des neurotoxines ou d'autres substances agonistes du récepteur NMDA, ainsi que les troubles neurologiques associés aux maladies virales telles que le sida (LIPTON et coll., Neuron, 7, 111 (1991)), la rage, la rougeole et le tétanos (BAGETTA et coll., Br. J. Pharmacol., 101 , 776 (1990)). Ces composés sont aussi utiles pour la prévention des symptômes d'abstinence aux drogues et à l'alcool et de l'inhibition de l'accoutumance et de la dépendance aux opiacés. Ils peuvent également être utilisés dans le traitement des déficits liés à des anomalies mitochondriales telles que la myopathie mitochondriale, le syndrome de LEBER, l'encéphalopathie de WERNICKE, le syndrome de RETT, l'homocystéinémie, l'hyperprolinémie, l'hydroxybutirique-aminoacidurie, l'encéphalopathie saturnine (intoxication chronique au plomb) et la déficience en sulfite oxydase.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. Pharmacol., 185, 1 (1990)), schizophrenia (REYNOLDS, TIPS, 13, 116 (1992)), syndrome TOURETTE, hepatic encephalopathies, as analgesics (DICKENSON et al., Neurosc. Letters, 121, 263 (1991)), antiinflammatories (SLUTA et al., Neurosci. Letters, 149, 99-102 (1993)) (SORRELS et al., Brain Res., 572, 265 (1992)), antimigraine, antiemetics and to treat poisoning with neurotoxins or other NMDA receptor agonist substances, as well as tr neurological cells associated with viral diseases such as AIDS (LIPTON et al., Neuron, 7, 111 (1991)), rabies, measles and tetanus (BAGETTA et al., Br. J. Pharmacol., 101, 776 (1990)). These Compounds are also useful for the prevention of symptoms of abstinence from drugs and alcohol and the inhibition of addiction and dependence on opiates. They can also be used in the treatment of deficits linked to 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.
L'affinité des composés de formule (I) vis-à-vis du récepteur AMPA a été déterminée en étudiant l'antagonisme de la fixation spécifique du [3H]-AMPA sur des membranes de cortex cérébral de rat (HONORE et coll., Neuroscience letters, 54, 27 (1985)). Le [3H]-AMPA est mis à incuber en présence de 0,2 mg de protéines à 4°C pendant 30 minutes dans du tampon KH2PO4 10mM, KSCN 100mM, pH7,5. La fixation non spécifique est déterminée en présence de L-glutamate 1 mM. La radioactivité liée est séparée par filtration sur filtres PHARMACIA (Printed Filtermate A). L'activité inhibitrice de ces produits est inférieure ou égale à 100 μM.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 μM.
L'affinité des composés de formule (I) pour le site glycine lié au récepteur NMDA a été déterminée en étudiant l'antagonisme de la fixation spécifique du [3H]-DCKA sur des membranes de cortex cérébral de rat selon la méthode décrite par T. CANTON et coll., J. Pharm. Pharmacol., 44, 812 (1992). Le [3H]-DCKA (20nM) est mis à incuber en présence de 0,1 mg de protéines à 4°C pendant 30 minutes dans du tampon HEPES 50 mM, pH7,5. La fixation non spécifique est déterminée en présence de glycine 1mM. La radioactivité liée est séparée par filtration sur filtres Whatman GF/B. L'activité inhibitrice de ces produits est inférieure ou égale à 100 μM.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 μM.
Les composés de formule (I) présentent une toxicité faible. Leur DL50 est supérieure à 50 mg/kg par voie IP chez la souris.The compounds of formula (I) have a low toxicity. Their LD50 is greater than 50 mg / kg by the IP route in mice.
Les exemples suivants illustrent l'invention. EXEMPLE 1The following examples illustrate the invention. EXAMPLE 1
1 ,35 g de 1-[2-oxocyclopentyl)]imidazole-2-carboxylate d'éthyle sont dissous dans 120 ml d'une solution 2,5 N de méthanol ammoniacal et la solution est conservée pendant 20 heures à une température voisine de 20°C puis concentrée à sec sous pression réduite (15 mm Hg; 2 kPa) à 35°C. Le produit est mis en suspension dans 20 ml d'oxyde d'isopropyle, filtré, lavé 2 fois par 20 ml au total d'oxyde d'isopropyle puis séché à l'air. Le produit (1 ,1 g) est mis en suspension dans 10 ml d'acétate d'éthyle, filtré, lavé avec 5 ml d'acétate d'éthyle puis séché sous pression réduite (15 mm Hg; 2 kPa) à 40°C. 0,5 g de produit ainsi obtenu (sur 1 g au total) est dissous dans 7,5 ml de méthanol et la solution, additionnée de 0,8 ml d'acide chlorhydrique concentré, est conservée pendant 1 heure à une température voisine de 20°C puis concentrée sous pression réduite (15 mm Hg; 2 kPa) à 40°C. Le produit (0,5 g), additionné de 0,3 g préparé dans les mêmes conditions, est dissous dans 102 ml d'isopropanol bouillant et la solution, additionnée de noir décolorant, est filtrée à chaud, refroidie, additionnée de 102 ml d'oxyde d'isopropyle et conservée pendant 1 heure à une température voisine de 5°C. Les cristaux apparus sont séparés par filtration, lavés avec 5 ml d'oxyde d'isopropyle et séchés sous pression réduite (1 mm Hg; 0,13 kPa) à 80°C. On obtient ainsi 0,3 g de chlorhydrate de 5H,6H-7,8-dihydro-cyclopent[e]imidazo[1 ,2-a]pyrazine-4-one (2 moles d'acide pour 3 moles de base) (Spectre de R.M.N.: [200 MHz; (CD3)2SO d6; δ en ppm) : 2,20 (mt, 2H : -CH2- central); 2,76 et 2,92 (t, J=7 Hz, 2H chacun : =C-CH2-); 7,79 et 7,98 (2d, J=1 Hz, 1 H chacun : -H de l'imidazole); 11 ,90 (mf, 1 H : -CONH-)).1.35 g of ethyl 1- [2-oxocyclopentyl)] imidazole-2-carboxylate are dissolved in 120 ml of a 2.5 N solution of ammoniacal methanol and the solution is kept for 20 hours at a temperature close to 20 ° C then concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 35 ° C. The product is suspended in 20 ml of isopropyl ether, filtered, washed twice with 20 ml of total isopropyl ether and then air dried. 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. 0.3 g of 5H, 6H-7,8-dihydro-cyclopent [e] imidazo [1, 2-a] pyrazine-4-one hydrochloride is thus obtained (2 moles of acid for 3 moles of base) ( NMR spectrum: [200 MHz; (CD3) 2SO d6; δ in ppm): 2.20 (mt, 2H: -CH2- central); 2.76 and 2.92 (t, J = 7 Hz, 2H each: = C-CH2-); 7.79 and 7.98 (2d, J = 1 Hz, 1 H each: -H of imidazole); 11.90 (mf, 1H: -CONH-)).
Le 1-[2-oxocyclopentyl)]imidazole-2-carboxylate d'éthyle peut être préparé de la façon suivante : une solution de 2,8 g d'imidazole-2-carboxylate d'éthyle dans 30 ml de dimêthylformamide anhydre est ajoutée goutte à goutte en 15 minutes à une suspension de 0,6 g d'hydrure de sodium à 80% dans 10 ml de dimêthylformamide anhydre maintenue sous atmosphère d'azote à une température voisine de 25°C. Après 15 minutes d'agitation, une solution de 5,6 g de 2-bromocyclopentanone à 78% dans 10 ml de dimêthylformamide anhydre est ajoutée goutte à goutte en 10 minutes. Le mélange est agité pendant une heure à la même température, additionné lentement de 20 ml d'eau distillée, versé sur 500 ml d'eau distillée et extrait 4 fois avec 400 ml au total de dichlorométhane. Les extraits organiques sont réunis, lavés avec 100 ml d'eau distillée, séchés sur du sulfate de sodium anhydre et concentrés à sec sous pression réduite (15 mm Hg; 2 kPa) à 50°C. Le produit obtenu (4,9 g) est chromatographie sur 245 g de gel de silice neutre (0,020-0,045 mm) contenus dans une colonne de 5,5 cm de diamètre en éluant sous pression par un mélange de dichlorométhane et d'acétate d'éthyle (70-30 en volumes) et en recueillant des fractions de 70 ml. Les fractions 47 à 105 sont concentrées à sec sous pression réduite (15 mm Hg; 2 kPa) à 50°C. On obtient ainsi 1 ,34 g de 1-[2-oxocyclopentyl)]imidazole-2-carboxylate d'éthyle sous la forme d'une huile jaune.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.
La 2-bromocyclopentanone peut être préparée comme décrit par E.J. COREY, J. Am. Chem. Soc, 75, 2301 (1953).2-bromocyclopentanone can be prepared as described by E.J. COREY, J. Am. Chem. Soc, 75, 2301 (1953).
L'imidazole-2-carboxylate d'éthyle peut être préparé comme décrit dans le brevet US 3600399.Ethyl imidazole-2-carboxylate can be prepared as described in US Pat. No. 3,600,399.
EXEMPLE 2EXAMPLE 2
A une solution saturée d'ammoniac dans le méthanol (100 ml), on ajoute lentement sous agitation une solution de 1 ,3 g de 1-[1-(2- oxoindanyl)]imidazole-2-carboxylate d'éthyle dans 50 ml de méthanol. On maintient l'agitation pendant une nuit à une température voisine de 20°C et concentre le mélange réactionnel à l'évaporateur rotatif. Le produit obtenu (1 ,34 g) est dissous dans 40 ml de méthanol bouillant puis on ajoute lentement 15 ml d'acide chlorhydrique concentré et maintient à l'ébullition pendant 5 minutes. Le mélange réactionnel est ensuite refroidi dans un bain glacé et laissé ainsi sous agitation pendant 90 minutes pour cristallisation. Les cristaux formés sont filtrés, lavés avec 2 fois 10 ml de méthanol et séchés sous pression réduite (1 mm Hg; 0,13 kPa) à une température voisine de 20°C. On obtient 39 mg de 5H,6H-imidazo[1 ,2-a]indéno[2,1- e]pyrazine-4-one sous forme de solide gris clair fondant au-dessus de 260°C (Spectre de R.M.N.: 300MHz; DMSO d6; δ en ppm : 3,91 (s, 2H : -CH2- en 6); 7,32 et 7,45 (2t, J=7,5 Hz, 1 H chacun : -H en 8 et -H en 9); 7,60 et 8,03 (2d, J=7,5 Hz, 1 H chacun : -H en 7 et -H en 10); 8,09 et 8,73 (2s larges, 1 H chacun : -H de l'imidazole); 12,90 (mf, 1 H: -CONH-)).To a saturated solution of ammonia in methanol (100 ml), a solution of 1.3 g of ethyl 1- [1- (2- oxoindanyl)] imidazole-2-carboxylate in 50 ml is added slowly with stirring. methanol. Stirring is continued overnight at a temperature in the region of 20 ° C. and the reaction mixture is concentrated on a rotary evaporator. The product obtained (1.34 g) is dissolved in 40 ml of boiling methanol, then 15 ml of concentrated hydrochloric acid are slowly added and the mixture is kept boiling for 5 minutes. The reaction mixture is then cooled in an ice bath and left to stir for 90 minutes for crystallization. The crystals formed are filtered, washed with 2 times 10 ml of methanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) at a temperature in the region of 20 ° C. 39 mg of 5H, 6H-imidazo [1, 2-a] indeno [2,1-e] pyrazine-4-one are obtained in the form of a light gray solid melting above 260 ° C. (NMR spectrum: 300 MHz ; DMSO d6; δ in ppm: 3.91 (s, 2H: -CH2- in 6); 7.32 and 7.45 (2t, J = 7.5 Hz, 1 H each: -H in 8 and - H in 9); 7.60 and 8.03 (2d, J = 7.5 Hz, 1 H each: -H in 7 and -H in 10); 8.09 and 8.73 (2s wide, 1H each: -H of imidazole); 12.90 (mf, 1 H: -CONH-)).
Le 1-[1-(2-oxoindanyl)]imidazole-2-carboxylate d'éthyle peut être préparé de la manière suivante : on chauffe à reflux pendant 4 heures 2,8 g d'imidazole- 2-carboxylate d'éthyle, 60 ml d'éthanol et 2,1 g de 1-bromo-2-indanone. Le mélange réactionnel est ensuite concentré à l'évaporateur rotatif et purifié par chromatographie sur colonne de silice (400 g) avec un mélange de dichlorométhane et d'acétate d'éthyle (70-30 en volumes). On obtient ainsi 1 ,3 g de 1-[1-(2-oxoindanyl)]imidazole-2-carboxylate d'éthyle sous forme de meringue brune utilisée telle quelle à l'étape suivante (Spectre de RMN : 300 MHz, CDCI3; δ en ppm : 1 ,40 (t, J=7,5 Hz, 3H: -CH3); 3,77 (s, 2H: -CH2-); 4,35 (q, J=7,5 Hz, 2H : -COOCH?-); 6,91 (s large, 1 H : CH-); 7,10 et de 7,20 à 7,50 (respectivement d (J=7,5 Hz) et mt, respectivement 1 H et 3H : -H aromatiques); 7,25 et 7,42 (2s larges, 1 H chacun : -H de l'imidazole)).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). 1.3 g of ethyl 1- [1- (2-oxoindanyl)] imidazole-2-carboxylate are thus obtained in the form of a brown meringue used as such in the following step (NMR spectrum: 300 MHz, CDCl3; δ in ppm: 1.40 (t, J = 7.5 Hz, 3H: -CH3); 3.77 (s, 2H: -CH2-); 4.35 (q, J = 7.5 Hz, 2H : -COOCH? -); 6.91 (broad s, 1 H: CH-); 7.10 and 7.20 to 7.50 (respectively d (J = 7.5 Hz) and mt, respectively 1 H and 3H: -H aromatic); 7.25 and 7.42 (2s wide, 1H each: -H of imidazole)).
La 1-bromo-2-indanone peut être préparée comme décrit par N.A. CREETH et N.F. THORPE, J.Chem.Soc 93, 1508 (1908).1-bromo-2-indanone can be prepared as described by N.A. CREETH and N.F. THORPE, J.Chem.Soc 93, 1508 (1908).
EXEMPLE 3EXAMPLE 3
0,3 g de 1-[2-(1-oxo-1 ,2,3,4-tétrahydronaphtyl)]imidazole-2-carboxamide est dissous dans 45 ml de méthanol bouillant et la solution, additionnée de noir décolorant, est filtrée. Le filtre est lavé avec 10 ml de méthanol bouillant puis le filtrat et le lavage sont réunis, additionnés de 6 ml de solution aqueuse d'acide chlorhydrique 12N, maintenus à l'ébullition pendant 1 heure et conservés pendant 15 heures à 5°C. Les cristaux apparus sont séparés par filtration, lavés avec 1 ml de méthanol glacé et séchés sous pression réduite (1 mm Hg; 0,13 kPa) à 80°C. On obtient ainsi 0,16 g de 5H-10,11-dihydro- benzo[f]imidazo[1 ,2-a]quinoxaline-4-one se décomposant sans fondre au- dessus de 260°C (Spectre de R.M.N.: (300 MHz; DMSO d6; δ en ppm) : 3,03 (m, 4H : -CH2-CH2-); de 7,25 à 7,40 et 7,88 (respectivement m et dd (J=7,5 et 2 Hz), 3H et 1 H : IH aromatiques); 7,62 et 8,05 (2d, J=1 ,5 Hz, 1 H chacun : -H de l'imidazole); 11 ,56 (s large, 1 H : -NH-)).0.3 g of 1- [2- (1-oxo-1, 2,3,4-tetrahydronaphthyl)] imidazole-2-carboxamide is dissolved in 45 ml of boiling methanol and the solution, mixed with bleaching black, is filtered . The filter is washed with 10 ml of boiling methanol, then the filtrate and the washing are combined, added with 6 ml of 12N aqueous hydrochloric acid solution, kept at the boil for 1 hour and stored for 15 hours at 5 ° C. The crystals which appear are separated by filtration, washed with 1 ml of ice-cold methanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 80 ° C. 0.16 g of 5H-10.11-dihydro-benzo [f] imidazo [1, 2-a] quinoxaline-4-one is thus obtained decomposing without melting above 260 ° C. (NMR spectrum: ( 300 MHz; DMSO d6; δ in ppm): 3.03 (m, 4H: -CH2-CH2-); from 7.25 to 7.40 and 7.88 (respectively m and dd (J = 7.5 and 2 Hz), 3H and 1 H: aromatic IH); 7.62 and 8.05 (2d, J = 1.5 Hz, 1 H each: -H of imidazole); 11, 56 (s broad, 1 H: -NH-)).
La 1-[2-(1 -oxo-1, 2,3,4-tétrahydronaphtyl)]imidazole-2-carboxamide peut être préparée de la façon suivante : 0,6 g de 1-[2-(1-oxo-1 ,2,3,4- tétrahydronaphtyl)]imidazole-2-carboxylate d'éthyle est dissous dans 40 ml d'une solution 3 N de méthanol ammoniacal et la solution est conservée pendant 20 heures à une température voisine de 20°C puis concentrée à sec sous pression réduite (15 mm Hg; 2 kPa) à 35°C. Le produit obtenu est mis en suspension dans 10 ml d'oxyde d'isopropyle, filtré, lavé 2 fois par 4 ml au total d'oxyde d'isopropyle puis séché sous pression réduite (15 mm Hg; 2 kPa) à une température voisine de 20°C. On obtient ainsi 0,42 g de 1-[2-(1 -oxo-1 ,2,3,4-tétrahydronaphtyl)]imidazole-2-carboxamide sous forme d'un solide fondant à 250°C.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. The product obtained is suspended in 10 ml of isopropyl ether, filtered, washed twice with 4 ml in total of isopropyl ether and then dried under reduced pressure (15 mm Hg; 2 kPa) at a similar temperature. 20 ° C. 0.42 g of 1- [2- (1-oxo-1, 2,3,4-tetrahydronaphthyl)] imidazole-2-carboxamide is thus obtained in the form of a solid melting at 250 ° C.
Le 1-[2-(1 -oxo-1 , 2,3,4-tétrahydronaphtyl)]imidazole-2-carboxylate d'éthyle peut être préparé de la façon suivante : une solution de 2,8 g d'imidazole-2- carboxylate d'éthyle dans 30 ml de dimêthylformamide anhydre est additionnée goutte à goutte en 10 minutes à une température voisine de 20°C à une suspension de 0,6 g d'hydrure de sodium à 80% dans 10 ml de dimêthylformamide anhydre maintenue sous atmosphère d'azote. Après 10 minutes d'agitation, une solution de 5,4 g de 2-bromo-3,4-dihydro-2H- naphtalène-1-one dans 18 ml de dimêthylformamide anhydre est ajoutée goutte à goutte en 15 minutes à la même température. Le mélange est agité pendant 1 heure 30 minutes puis, après addition lente de 20 ml d'eau, versé sur 600 ml d'eau distillée et extrait 4 fois par 800 ml au total de chloroforme. Les extraits organiques sont réunis, lavés avec 200 ml d'eau distillée, séchés sur du sulfate de sodium anhydre et concentrés à sec sous pression réduite (15 mm Hg; 2 kPa) à 40°C. Le produit obtenu (3,26 g) est chromatographie sur 200 g de gel de silice neutre (0,020-0,045 mm) contenus dans une colonne de 4,6 cm de diamètre en éluant sous pression avec un mélange dichlorométhane-acétate d'éthyle (70-30 en volumes) et en recueillant des fractions de 70 ml. Les fractions 15 à 35 sont réunies et concentrées à sec sous pression réduite ( 15 mm Hg; 2 kPa) à 40°C. On obtient ainsi 0,6 g de 1-[2-(1-oxo-1 ,2,3,4-tétrahydronaphtyl)]imidazole-2- carboxylate d'éthyle fondant à 98°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. After 10 minutes of stirring, a solution of 5.4 g of 2-bromo-3,4-dihydro-2H-naphthalene-1-one in 18 ml of anhydrous dimethylformamide is added dropwise over 15 minutes at the same temperature . The mixture is stirred for 1 hour 30 minutes then, after the slow addition of 20 ml of water, poured into 600 ml of distilled water and extracted 4 times with 800 ml in total of chloroform. The organic extracts are combined, washed with 200 ml of distilled water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 40 ° C. 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.
La 2-bromo-3,4-dihydro-2H-naphtalène-1-one peut être préparée comme décrit par J.N. SRIVASTAVA, J. Indian Chem. Soc, 67(3), 210 (1990). 102-bromo-3,4-dihydro-2H-naphthalene-1-one can be prepared as described by JN SRIVASTAVA, J. Indian Chem. Soc, 67 (3), 210 (1990). 10
EXEMPLE 4EXAMPLE 4
Un mélange de 5,9 g d'imidazole-2-carboxylate d'éthyle et de 6 g de 3-bromo-isothiochromanne-4-one est chauffé pendant 10 minutes à 130°C, refroidi à 20°C et dissous dans 80 ml de dichlorométhane. La solution est lavée avec 40 ml d'eau distillée et, après décantation, la phase aqueuse est extraite 3 fois avec 120 ml au total de dichlorométhane. Les phases organiques sont réunies, lavées avec 40 ml d'une solution saturée d'hydrogénocarbonate de sodium, 2 fois avec 80 ml au total d'eau distillée, séchées sur du sulfate de magnésium anhydre et concentrées à sec sous pression réduite (15 mm Hg; 2 kPa) à 35°C. Le produit obtenu (6,5 g) est chromatographie sur 400 g de gel de silice neutre (0,020-0,045 mm) contenus dans une colonne de 5,6 cm de diamètre en éluant sous pression avec un mélange dichlorométhane-acétate d'éthyle (80-20 en volumes) et en recueillant des fractions de 60 ml. Les fractions 33 à 70 sont réunies et concentrées à sec sous pression réduite (15 mm Hg; 2 kPa) à 40°C. 0,94 g de produit ainsi obtenu (sur le 1 ,02 g obtenu au total) est dissous dans 30 ml d'acide acétique et la solution, additionnée de 27 g d'acétate d'ammonium, est chauffée à l'ébullition pendant 20 minutes. Le mélange est refroidi à une température voisine de 20°C et, après addition de 20 ml d'eau distillée, le solide apparu est séparé par filtration, lavé 2 fois avec 20 ml au total d'eau distillée et séché à l'air. Le produit (0,7 g) est dissous dans 35 ml de dimêthylformamide bouillante et la solution, additionnée de noir décolorant, est filtrée à chaud, refroidie et conservée pendant 16 heures à une température voisine de 5°C. Les cristaux apparus sont séparés par filtration, lavés avec de la dimêthylformamide glacée et séchés sous pression réduite (1 mm Hg; 0,13 kPa) à 100°C. On obtient ainsi 0,26 g de 5H.10H- [2]benzothiopyranno[4,3-e]imidazo[1 ,2-a]pyrazine-4-one se décomposant sans fondre au-dessus de 260°C (Spectre de R.M.N.: (300 MHz; DMSO d6; δ en ppm) : 4,23 (s, 2H : -CH2-S-); de 7,38 à 7,45 et 7,77 (2m, respectivement 3H et 1 H : aromatiques); 7,59 et 7,88 (2d, J=1 ,5 Hz, 1 H chacun : -H de l'imidazole); 11 ,85 (s large, 1 H : -NH-)).A mixture of 5.9 g of ethyl imidazole-2-carboxylate and 6 g of 3-bromo-isothiochroman-4-one is heated for 10 minutes at 130 ° C, cooled to 20 ° C and dissolved in 80 ml of dichloromethane. The solution is washed with 40 ml of distilled water and, after decantation, the aqueous phase is extracted 3 times with 120 ml in total of dichloromethane. The organic phases are combined, washed with 40 ml of a saturated sodium hydrogencarbonate solution, twice with 80 ml in total of distilled water, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 35 ° C. The product obtained (6.5 g) is chromatographed on 400 g of neutral silica gel (0.020-0.045 mm) contained in a column 5.6 cm in diameter, eluting under pressure with a dichloromethane-ethyl acetate mixture ( 80-20 by volume) and collecting 60 ml fractions. Fractions 33 to 70 are combined and concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 40 ° C. 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. The crystals which appear are separated by filtration, washed with ice-cold dimethylformamide and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 100 ° C. 0.26 g of 5H.10H- [2] benzothiopyranno [4,3-e] imidazo [1, 2-a] pyrazine-4-one is thus obtained which decomposes without melting above 260 ° C. (Spectrum of NMR: (300 MHz; DMSO d6; δ in ppm): 4.23 (s, 2H: -CH2-S-); from 7.38 to 7.45 and 7.77 (2m, 3H and 1H respectively: aromatic); 7.59 and 7.88 (2d, J = 1.5 Hz, 1 H each: -H of imidazole); 11.85 (broad s, 1 H: -NH-)).
La 3-bromo-isothiochromanne-4-one peut être préparée selon la méthode décrite par R. LESSER et coll., Chem. Ber., 56, 1642 (1923). Les médicaments selon l'invention sont constitués par un composé de formule (I) ou un sel d'un tel composé, à l'état pur ou sous forme d'une composition dans laquelle il est associé à tout autre produit pharmaceutiquement compatible, pouvant être inerte ou physiologiquement actif. Les médicaments selon l'invention peuvent être employés par voie orale, parentérale, rectale ou topique.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.
Comme compositions solides pour administration orale, peuvent être utilisés des comprimés, des pilules, des poudres (capsules de gélatine, cachets) ou des granulés. Dans ces compositions, le principe actif selon l'invention est mélangé à un ou plusieurs diluants inertes, tels que amidon, cellulose, saccharose, lactose ou silice, sous courant d'argon. Ces compositions peuvent également comprendre des substances autres que les diluants, par exemple un ou plusieurs lubrifiants tels que le stéarate de magnésium ou le talc, un colorant, un enrobage (dragées) ou un vernis.As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, 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. 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.
Comme compositions liquides pour administration orale, on peut utiliser des solutions, des suspensions, des émulsions, des sirops et des élixirs pharmaceutiquement acceptables contenant des diluants inertes tels que l'eau, l'éthanol, le glycérol, les huiles végétales ou l'huile de paraffine. Ces compositions peuvent comprendre des substances autres que les diluants, par exemple des produits mouillants, édulcorants, épaississants, aromatisants ou stabilisants.As liquid 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. These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
Les compositions stériles pour administration parentérale peuvent être de préférence des solutions aqueuses ou non aqueuses, des suspensions ou des émulsions. Comme solvant ou véhicule, on peut employer l'eau, le propylèneglycol, un polyéthylèneglycol, des huiles végétales, en particulier l'huile d'olive, des esters organiques injectables, par exemple l'oléate d'éthyle ou d'autres solvants organiques convenables. Ces compositions peuvent également contenir des adjuvants, en particulier des agents mouillants, isotonisants, émulsifiants, dispersants et stabilisants. La stérilisation peut se faire de plusieurs façons, par exemple par filtration aseptisante, en incorporant à la composition des agents stérilisants, par irradiation ou par chauffage. Elles peuvent également être préparées sous forme de compositions solides stériles qui peuvent être dissoutes au moment de l'emploi dans de l'eau stérile ou tout autre milieu stérile injectable.The sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As 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.
Les compositions pour administration rectale sont les suppositoires ou les capsules rectales qui contiennent, outre le produit actif, des excipients tels que le beurre de cacao, des glycérides semi-synthétiques ou des polyéthylèneglycols.The 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.
Les compositions pour administration topique peuvent être par exemple des crèmes, lotions, collyres, collutoires, gouttes nasales ou aérosols.The compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.
En thérapeutique humaine, les composés selon l'invention sont particulière- ment utiles pour le traitement et/ou la prévention des conditions qui requiè¬ rent l'administration d'un antagoniste du récepteur AMPA ou d'un antagoniste du récepteur NMDA. Ces composés sont notamment utiles pour traiter ou prévenir toutes les ischémies et en particulier l'ischémie cérébrale, les effets dus à une anoxie, l'évolution de maladies neurodégénératives, de la chorée d'HUNTINGTON, de la maladie d'ALZHEIMER, de la sclérose latérale amyo- trophique, de l'atrophie olivo-pontocérébelleuse et de la maladie de PAR- KINSON, vis-à-vis des manifestations épileptogènes et/ou convulsives, pour le traitement des traumatismes cérébraux et spinaux, des traumatismes liés à le dégénérescence de l'oreille interne ou de la rétine, de l'anxiété, de la dé- pression, de la schizophrénie, du syndrome de TOURETTE, de l'encéphalopathie hépatique, en tant qu'analgésiques, antiinflammatoires, antianorexiques, antimigraineux, antiémétiques et pour traiter les empoisonnements par des neurotoxines ou d'autres substances agonistes du récepteur NMDA, ainsi que les troubles neurologiques associés aux maladies virales telles que le sida, la rage, la rougeole et le tétanos. Ces composés sont aussi utiles pour la prévention des symptômes d'abstinence aux drogues et à l'alcool et de l'inhibition de l'accoutumance et de la dépendance aux opiacés ainsi que pour le traitement des déficits liés à des anomalies mitochondriales telles que la myopathie mitochondriale, le syndrome de LEBER, l'encéphalopathie de WERNICKE, le syndrome de RETT, l'homocystéinémie, l'hyperprolinémie, l'hydroxybutirique-aminoacidurie, l'encéphalopathie saturnine (intoxication chronique au plomb) et la déficience en sulfite oxydase. Les doses dépendent de l'effet recherché, de la durée du traitement et de la voie d'administration utilisée; elles sont généralement comprises entre 10 mg et 100 mg par jour par voie orale pour un adulte avec des doses unitaires allant de 5 mg à 50 mg de substance active.In human therapy, 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, measles and tetanus. 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.
D'une façon générale, le médecin déterminera la posologie appropriée en fonction de l'âge, du poids et de tous les autres facteurs propres au sujet à traiter.In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.
Les exemples suivants illustrent des compositions selon l'invention :The following examples illustrate compositions according to the invention:
EXEMPLE AEXAMPLE A
On prépare, selon la technique habituelle, des gélules dosées à 50 mg de produit actif ayant la composition suivante :Using the usual technique, capsules containing 50 mg of active product having the following composition are prepared:
- Composé de formule (I) 50 mg- Compound of formula (I) 50 mg
- Cellulose 18 mg- Cellulose 18 mg
- Lactose 55 mg - Silice colloïdale 1 mg- Lactose 55 mg - Colloidal silica 1 mg
- Carboxyméthylamidon sodique 10 mg- Carboxymethyl starch sodium 10 mg
- Talc 10 mg- Talc 10 mg
- Stéarate de magnésium 1 mg- Magnesium stearate 1 mg
EXEMPLE BEXAMPLE B
On prépare selon la technique habituelle des comprimés dosés à 50 mg de produit actif ayant la composition suivante :Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique:
- Composé de formule (I) 50 mg- Compound of formula (I) 50 mg
- Lactose 104 mg- Lactose 104 mg
- Cellulose 40 mg - Polyvidone 10 mg- Cellulose 40 mg - Polyvidone 10 mg
- Carboxyméthylamidon sodique 22 mg- Carboxymethyl starch sodium 22 mg
- Talc 10 mg- Talc 10 mg
- Stéarate de magnésium 2 mg- Magnesium stearate 2 mg
- Silice colloïdale 2 mg - Mélange d'hydroxyméthylcellulose, glycérine, oxyde de titane (72-3,5-24,5) q.s.p. 1 comprimé pellicule terminé à 245 mg EXEMPLE C- Colloidal silica 2 mg - Mixture of hydroxymethylcellulose, glycerin, titanium oxide (72-3,5-24,5) qs 1 film-coated tablet finished at 245 mg EXAMPLE C
On prépare une solution injectable contenant 10 mg de produit actif ayant la composition suivante :A solution for injection containing 10 mg of active product having the following composition is prepared:
- Composé de formule (I) 10 mg - Acide benzoïque 80 mg- Compound of formula (I) 10 mg - Benzoic acid 80 mg
- Alcool benzylique 0,06 ml- Benzyl alcohol 0.06 ml
- Benzoate de sodium 80 mg- Sodium benzoate 80 mg
- Ethanol à 95 % 0,4 ml- 95% ethanol 0.4 ml
- Hydroxyde de sodium 24 mg - Propylène glycol 1,6 ml- Sodium hydroxide 24 mg - Propylene glycol 1.6 ml
- Eau q.s.p. 4 ml - Water q.s.p. 4 ml

Claims

REVENDICATIONS
1 - Composés de formule1 - Compounds of formula
dans laquelle le cycle A est choisi parmi les cycles suivantsin which cycle A is chosen from the following cycles
dans lesquels R représente un radical CH? ou un atome de soufre, d'oxygène ou d'azote substitué par un radical alkyle en chaîne droite ou ramifiée ou les sels de ces composés et contenant 1 à 6 atomes de carbone.in which R represents a CH radical? or a sulfur, oxygen or nitrogen atom substituted by a straight or branched chain alkyl radical or the salts of these compounds and containing 1 to 6 carbon atoms.
2 - Procédé de préparation des composés de formule (I) selon la revendication 1 caractérisé en ce que l'on cyclise en présence d'acétate d'ammonium un ester de formule :2 - Process for preparing the compounds of formula (I) according to claim 1 characterized in that an ester of formula is cyclized in the presence of ammonium acetate:
dans laquelle le cycle A à les mêmes significations que dans la revendication 1 et R-| représente un radical alkyle inférieur, isole le produit et le transforme éventuellement en sel. 3 - Procédé de préparation des composés de formule (I) selon la revendication 1 caractérisé en ce que l'on cyclise un dérivé de formule :in which ring A has the same meanings as in claim 1 and R- | represents a lower alkyl radical, isolates the product and optionally transforms it into a salt. 3 - Process for preparing the compounds of formula (I) according to claim 1 characterized in that a derivative of formula is cyclized:
(ιv) (ιv)
dans laquelle le cycle A a les mêmes significations que dans la revendication 1 , isole le produit et le transforme éventuellement en sel.in which ring A has the same meanings as in claim 1, isolates the product and optionally transforms it into salt.
4 - Médicaments caractérisés en ce qu'ils contiennent en tant que principe actif au moins un composé de formule (I) selon la revendication 1ou un sel d'un tel composé. 4 - Medicines characterized in that they contain as active ingredient at least one compound of formula (I) according to claim 1 or a salt of such a compound.
EP95914407A 1994-03-28 1995-03-23 IMIDAZO[1,2-a]PYRAZIN-4-ONE DERIVATIVES, THEIR PREPARATION AND DRUGS CONTAINING THEM Ceased EP0752994A1 (en)

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FR9403585A FR2717811B1 (en) 1994-03-28 1994-03-28 Imidazo [1,2-a] pyrazine-4-one derivatives, their preparation and drugs containing them.
FR9403585 1994-03-28
PCT/FR1995/000361 WO1995026352A1 (en) 1994-03-28 1995-03-23 IMIDAZO[1,2-a]PYRAZINE-4-ONE DERIVATIVES, PREPARATION THEREOF AND DRUGS CONTAINING SAME

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EP0752994A1 true EP0752994A1 (en) 1997-01-15

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US7732162B2 (en) 2003-05-05 2010-06-08 Probiodrug Ag Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases
EP2089383B1 (en) 2006-11-09 2015-09-16 Probiodrug AG 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
US9126987B2 (en) 2006-11-30 2015-09-08 Probiodrug Ag Inhibitors of glutaminyl cyclase
AU2008220785B2 (en) 2007-03-01 2013-02-21 Vivoryon Therapeutics N.V. New use of glutaminyl cyclase inhibitors
US9656991B2 (en) 2007-04-18 2017-05-23 Probiodrug Ag Inhibitors of glutaminyl cyclase
PL2475428T3 (en) 2009-09-11 2015-12-31 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
US9181233B2 (en) 2010-03-03 2015-11-10 Probiodrug Ag Inhibitors of glutaminyl cyclase
DK2545047T3 (en) 2010-03-10 2014-07-28 Probiodrug Ag Heterocyclic Inhibitors of Glutaminyl Cyclase (QC, EC 2.3.2.5)
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
EP2686313B1 (en) 2011-03-16 2016-02-03 Probiodrug AG Benzimidazole derivatives as inhibitors of glutaminyl cyclase
RU2743998C2 (en) * 2015-11-13 2021-03-01 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Pyranodipyridine compound
PL3461819T3 (en) 2017-09-29 2020-11-30 Probiodrug Ag Inhibitors of glutaminyl cyclase

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US5153196A (en) * 1991-06-05 1992-10-06 Eli Lilly And Company Excitatory amino acid receptor antagonists and methods for the use thereof
ATE404201T1 (en) * 1992-06-22 2008-08-15 Univ California GLYCINE RECEPTOR ANTAGONISTS AND THEIR USE
FR2696466B1 (en) * 1992-10-02 1994-11-25 Rhone Poulenc Rorer Sa 5H, 10H-imidazo [1,2-a] indeno [1,2-e] pyrazine-4-one derivatives, their preparation and the medicaments containing them.

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FR2717811A1 (en) 1995-09-29
ZA952486B (en) 1996-01-15
FR2717811B1 (en) 1996-04-26
AU2141695A (en) 1995-10-17
WO1995026352A1 (en) 1995-10-05
JPH09510730A (en) 1997-10-28
IL113151A0 (en) 1995-06-29

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