EP1680402A1 - Derivatives of n-[[phenyl(piperidine-2-yl)methyl]benzamide, preparation method thereof and applications of same in therapeutics - Google Patents

Derivatives of n-[[phenyl(piperidine-2-yl)methyl]benzamide, preparation method thereof and applications of same in therapeutics

Info

Publication number
EP1680402A1
EP1680402A1 EP04791551A EP04791551A EP1680402A1 EP 1680402 A1 EP1680402 A1 EP 1680402A1 EP 04791551 A EP04791551 A EP 04791551A EP 04791551 A EP04791551 A EP 04791551A EP 1680402 A1 EP1680402 A1 EP 1680402A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
group
general formula
disorders
hydrogen atom
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04791551A
Other languages
German (de)
French (fr)
Inventor
Gihad Dargazanli
Geneviève ESTENNE-BOUHTOU
Pascale Magat
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Original Assignee
Sanofi Aventis France
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
Publication of EP1680402A1 publication Critical patent/EP1680402A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Ri represents either a hydrogen atom, or a linear or branched (C ⁇ -C) alkyl group optionally substituted by one or more fluorine atoms, or a (CC 7 ) cycloalkyl group, or a (C3-C7) cycloalkyl- group (C 1 -C3) alkyl, either a phenyl group (C ⁇ ⁇ C 3 ) alkyl optionally substituted by one or two methoxy groups, or a (C 2 -C 4 ) alkenyl group, or a (C 2 -C) alkynyl group ,
  • X represents a hydrogen atom or one or more substituents chosen from halogen atoms and trifluoromethyl groups, (C 1 -C 4 ) alkyl and (C 1 -C 4 ) linear or branched alkoxy
  • R 2 represents a group selected from the groups naphthalenyl, pyridinyl, pyri idinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyidolol, pyolazolyl, pyrazolyl thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzothi
  • the compounds of general formula (I) can exist in the form of the threo racemate ⁇ 1R, 2R; 1.5.2S) or in the form of (1R, 2R) or (1S, 2S) enantiomers; they can exist in the form of free bases or of addition salts with acids.
  • the preferred compounds of the invention lack activity on opiate receptors or 5-HT3 and exhibit particular activity as specific inhibitors of the glycine transporters glytl and / or glyt2.
  • a diamine of general formula is coupled (II), in which Ri and X are as defined above (with Ri different from a hydrogen atom) with an activated acid or an acid chloride of general formula (III) in which Y represents a group OH activated or a
  • chlorine atom and R 2 is as defined above, using the methods known to those skilled in the art.
  • the diamine of general formula (II) can be prepared by a process illustrated by scheme 2 which follows.
  • the Weinreb amide of formula (IV) is reacted with the phenyllithium derivative of general formula (V), in which X is as defined above, in an ethereal solvent such as diethyl ether, between -30 ° C and room temperature; a ketone of general formula (VI) is obtained which is reduced to alcohol of threo configuration of general formula (VII) by a reducing agent such as K-Selectride® or L-Selectride® (tri-sec-butyl- potassium or lithium borohydride), in an ethereal solvent such as tetrahydrofuran, between -78 ° C and room temperature.
  • the carbamate of general formula (VII) can then be reduced to N-methylaminoalcohol threo of general formula (VIII) by the action of a mixed hydride such as lithium aluminum hydride, in a
  • n ⁇ éthanesulfonate by the action of methylsulfonyl chloride, in a chlorinated solvent such as dichloromethane, and in the presence of a base such as triethylamine, between 0 ° C and room temperature, then reacting the nucleofuge group with ammonia liquefied at -50 ° C, in an alcohol such as ethanol, in a closed environment such as an autoclave, between -50 ° C and room temperature.
  • the diamine of general formula (II) is obtained in which R 1 represents a methyl group and X represents a hydrogen atom in the form of a mixture of the two threo / erythro 9/1 diastereoisomers. It can be salified, for example with oxalic acid, then purified by recrystallization of the oxalate formed in a mixture of alcohol and an ethereal solvent such as methanol and diethyl ether, to obtain the diastereoisomer threo (1R, 2R; 1S, 2S) pure.
  • the compounds of general formula (II) in which R 1 represents a hydrogen atom can be prepared according to scheme 2, with the use of a compound of general formula (I) in which R 1 represents an optionally substituted phenylmethyl group, then deprotection of the nitrogen of the piperidine ring, for example by an oxidizing agent or by a Lewis acid, such as boron tribromide, or by hydrogenolysis, either an alkenyl group, preferably allyl, and deprotecting the nitrogen by a complex of the Pd °, to obtain a compound of general formula (I) in which Ri represents a hydrogen atom.
  • the chiral compounds of general formula (I) corresponding to the (1R, 2R) or (1S, 2S) enantiomers of the threo diastereoisomer can also be obtained by separation of the racemic compounds by high performance liquid chromatography (HPLC) on a chiral column, or by splitting the racemic amine of general formula (II) by using a chiral acid such as tartaric acid, camphorsulfonic acid, dibenzoyltartaric acid or N-acetylleucine, by fractional and preferential recrystallization d 'a diastereoisomeric salt, in an alcohol type solvent, or by enantioselective synthesis according to scheme 2 with the use of a chiral einreb amide of formula (IV).
  • HPLC high performance liquid chromatography
  • the Weinreb amide of formula (IV) racemic or chiral, as well as the ketone of general formula (VI), can be prepared according to a method analogous to that described in Eur. J. Med. Chem. , 35, (2000), 979-988 and J. Med. Chem. , 41, (1998), 591-601.
  • the phenyllithium compound of general formula (V) where X represents a hydrogen atom is commercially available. Its substituted derivatives can be prepared according to a method analogous to that described in Tetrahedron Lett. , 57, 33, (1996), 5905-5908.
  • the pyridineoxime of general formula (XI) can be prepared according to a method analogous to that described in patent application EP-0366006.
  • the amine of general formula (IX) in which X represents a hydrogen atom can be prepared in chiral series according to a method described in patent US-2928835.
  • the amine of general formula (XIII) can be prepared according to a method analogous to that described in Chem. Pharm. Bull. , 32, 12, (1984), 4893-4906 and Synthesis, (1976), 593-595.
  • the acids and acid chlorides of general formula (III) are commercially available, except for 4- [2-chloro-3- (trifluoromethyl) phenyl] -1H-imidazole-2-carboxylic acid, which can be prepared under conditions comparable to those described in patent application EP-0365030 and in patent US-3336300.
  • the precipitate formed is collected by filtration and dried under reduced pressure.
  • Threo (1-methylpiperidin-2-yl) - phenylmethanamine ethanedioate 2 1.
  • 14.8 g (31.89 mmol) of 2- (benzyloxyiminophenylmethyl) -1-methylpyridinium trifluoromethanesulfonate and 0.74 g of platinum oxide are placed in 50 ml of ethanol and 50 ml hydrochloric acid IN and hydrogenation is carried out for 5 h.
  • the ethanol is evaporated off under reduced pressure, the residue is extracted with dichloromethane, the aqueous phase is separated, an ammonia solution is added thereto and it is extracted with dichloromethane.
  • Threo-2,5-dichloro-W- [(1-methyl-2-piperidinyl) (phenyl) methyl] thiophene-3-carboxamide hydrochloride 1 1. 0.768 g (4 mmol) of 2, 5-dichlorothiophene-3-carboxylic acid dissolved in 15 ml of dichloromethane are introduced into a 100 ml flask, then 0.651 ml (4.7 mmol) of triethylamine and 0.447 are successively added ml (4.7 mmol) of ethyl chloroformate, and the reaction mixture is stirred at room temperature for 2 h.
  • threo- (1-methyl-piperidin-2-yl) phenylmethanamine prepared according to example 1.2
  • the mixture is treated with water, it is extracted several times with dichloromethane, the organic phases are washed with water and then with an IN aqueous solution of sodium hydroxide, then with a saturated aqueous solution of sodium chloride, they are dried over sodium and the solvent is evaporated off under reduced pressure, the residue is purified by chromatography on a column of silica gel eluted nt with a mixture of dichloromethane and methanol.
  • N - denotes a compound in the basic state and
  • HC1 denotes a hydrochloride.
  • the compounds of the invention have been subjected to a series of pharmacological tests which have demonstrated their advantage as substances with therapeutic activities.
  • glycine transport in SK-N-MC cells expressing the native glytl human transporter The uptake of [ 14 C] glycine is studied in SK-N-MC cells (human neuroepithelial cells) expressing the native glytl human transporter by measuring the radioactivity incorporated in the presence or absence of the test compound.
  • the cells are cultured in a monolayer for 48 h in plates pretreated with 0.02% fibronectin. On the day of the experiment, the culture medium is eliminated and the cells are washed with a Krebs-HEPES buffer ([4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid) at pH 7.4.
  • Krebs-HEPES buffer [4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid
  • the efficacy of the compound is determined by the IC 5 o, the concentration of compound which reduces by 50% the specific capture of glycine, defined by the difference in radioactivity incorporated by the control batch and the batch which received the glycine at 10 mM.
  • the compounds of the invention, in this test, have an IC 50 of the order of 0.01 to 10 ⁇ M. Study of glycine transport in the mouse spinal cord homogenate.
  • the uptake of [ 14 C] glycine by the glyt2 transporter is studied in the mouse spinal cord homogenate by measuring the radioactivity incorporated in the presence or absence of the compound to be studied.
  • the reaction is stopped by vacuum filtration and the radioactivity is estimated by solid scintillation by counting on a Microbeta Tri-lux TM counter.
  • the effectiveness of the compound is determined by the IC 50 concentration capable of decreasing the specific glycine uptake by 50%, defined by the difference in radioactivity incorporated by the control batch and the batch which received the 10 mM glycine.
  • the compounds of the invention, in this test have an IC 50 of the order of 0.01 to 10 ⁇ M.
  • the compounds of the invention can be used for the treatment of behavioral disorders associated with dementia, psychoses, in particular schizophrenia (deficit form and productive form) and acute or chronic extrapyramidal symptoms induced by neuroleptics.
  • schizophrenia deficit form and productive form
  • extrapyramidal symptoms induced by neuroleptics for the treatment of various forms of anxiety, panic attacks, phobias, obsessive compulsive disorder
  • for the treatment of various forms of depression, including psychotic depression for the treatment of disorders due to abuse or withdrawal alcohol, sexual behavior disorders, eating disorders, and for the treatment of migraine.
  • the compounds of the invention can be used for the treatment of painful muscular contractures in rheumatology and in acute spinal pathology, for the treatment of spastic contractures of medullary or cerebral origin, for the symptomatic treatment of acute and subacute pain.
  • mild to moderate intensity for the treatment of intense and / or chronic pain, neurogenic pain and rebellious pain, for the treatment of Parkinson's disease and parkinsonian symptoms of neurodegenerative origin or induced by neuroleptics
  • the present invention also relates to pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the base state or of a pharmaceutically acceptable salt or solvate, and as a mixture, as the case may be. if necessary, with suitable excipients. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.
  • the pharmaceutical compositions according to the invention can thus be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal, intraoccular administration.
  • the unit administration forms can be, for example, tablets, capsules, granules, powders, oral or injectable solutions or suspensions, transdermal patches ("patch"), suppositories.
  • patch transdermal patches
  • ointments ointments, lotions and eye drops can be considered.
  • Said unit forms are dosed to allow daily administration of 0.01 to 20 mg of active principle per kg of body weight, depending on the dosage form.
  • a pharmaceutical carrier is added to the active principle, micronized or not, which can be composed of diluents, such as, for example, lactose, microcrystalline cellulose, starch, and formulation adjuvants such as binders, (polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.), flow agents such as silica, lubricants such as magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate. Wetting agents or surfactants such as sodium lauryl sulfate can also be added.
  • the production techniques can be direct compression, dry granulation, wet granulation or hot melting.
  • the tablets can be plain, coated, for example with sucrose, or coated with various polymers or other suitable materials. They can be designed to allow rapid, delayed or prolonged release of the active ingredient using polymer matrices or polymers specific used in the coating.
  • the active ingredient is mixed with dry pharmaceutical vehicles (simple mixing, dry or wet granulation, or hot fusion), liquids or semi-solids.
  • the capsules can be hard or soft, film-coated or not, so as to have rapid, prolonged or delayed activity (for example for an enteric form).
  • a composition in the form of a syrup or elixir or for administration in the form of drops may contain the active principle together with a sweetener, preferably calorie-free, methylparaben or propylparaben as an antiseptic, a flavoring agent and a coloring agent.
  • a sweetener preferably calorie-free, methylparaben or propylparaben as an antiseptic, a flavoring agent and a coloring agent.
  • the powders and granules dispersible in water can contain the active principle in mixture with dispersing agents or wetting agents, or dispersing agents such as polyvinylpyrrolidone, as well as with sweeteners and flavor correcting agents.
  • aqueous suspensions For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol, are used.
  • pharmacologically compatible dispersing agents and / or wetting agents for example propylene glycol or butylene glycol
  • the active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives, or with a polymer matrix or with a cyclodextrin (transdermal patches, extended release forms).
  • compositions according to the invention comprise a medium compatible with the skin. They may be in particular in the form of aqueous, alcoholic or hydroalcoholic solutions, gels, water-in-oil or oil-in-water emulsions having the appearance of a cream or gel, microemulsions, d aerosols, or in the form of vesicular dispersions containing ionic and / or nonionic lipids. These dosage forms are prepared according to the usual methods of the fields considered.
  • compositions according to the invention may contain, alongside a compound of general formula (I), other active ingredients which may be useful in the treatment of the disorders and diseases indicated above.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Addiction (AREA)
  • Epidemiology (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Nutrition Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The invention relates to a compound having general formula (I), wherein: R1 represents either a hydrogen atom or an alkyl, cycloalkylalkyl, phenylalkyl, alkenyl, alkynyl group; X represents a hydrogen atom or one or more substituents selected from among halogen atoms and the trifluoromethyl, alkyl and alkoxy groups; and R2 represents a group selected from among the naphthalenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzothiazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzotriazolyl, benzisothiazolyl, dihydroindolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl, pyrazolopyridinyl, isoxazolopyridinyl, isothiazolopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl groups. The invention also relates to the use of said compound in therapeutics.

Description

DERIVES DE N- λ * PHENY ( PIPΞRIDIN -2-YL. ) METHYL 1 BENZAMIDE , LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUEN- λ * PHENY (PIPΞRIDIN -2-YL.) METHYL 1 BENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
Les composés de l'invention répondent à la formule générale (I)The compounds of the invention correspond to the general formula (I)
dans laquelle in which
Ri représente soit un atome d'hydrogène, soit un groupe (Cι-C ) alkyle linéaire ou ramifié éventuellement substitué par un ou plusieurs atomes de fluor, soit un groupe (C-C7) cycloalkyle, soit un groupe (C3-C7) cycloalkyl- (C1-C3) alkyle, soit un groupe phényl (Cι~C3) alkyle éventuellement substitué par un ou deux groupes méthoxy, soit un groupe (C2-C4) alcényle, soit un groupe (C2-C ) alcynyle,Ri represents either a hydrogen atom, or a linear or branched (Cι-C) alkyl group optionally substituted by one or more fluorine atoms, or a (CC 7 ) cycloalkyl group, or a (C3-C7) cycloalkyl- group (C 1 -C3) alkyl, either a phenyl group (Cι ~ C 3 ) alkyl optionally substituted by one or two methoxy groups, or a (C 2 -C 4 ) alkenyl group, or a (C 2 -C) alkynyl group ,
X représente un atome d' hydrogène ou un ou plusieurs substituants choisis parmi les atomes d'halogènes et les groupes trifluorométhyle, (C1-C4) alkyle et (C1-C4) alcoxy linéaires ou ramifiés, R2 représente un groupe choisi parmi les les groupes naphtalényle, pyridinyle, pyri idinyle, pyrazinyle, pyridazinyle, triazinyle, indanyle, indényle, quinoléinyle, isoquinoléinyle, quinazolinyle, quinoxalinyle, phtalazinyle, thiényle, furyle, pyrrolyle, imidazolyle, pyrazolyle, oxazolyle, thiazolyle, isoxazolyle, isothiazolyle, thiadiazolyle, oxadiazolyle, triazolyle, benzothiényle, benzofuryle, benzimidazolyle, benzothiazolyle, indolyle, isoindolyle, indazolyle, benzoxazolyle, benzisoxazolyle, benzotriazolyle, benzisothiazolyle, dihydroindolyle, pyrrolopyridinyle, furopyridinyle, thiénopyridinyle, imidazopyridinyle, oxazolopyridinyle, thiazolopyridinyle, pyrazolopyridinyle, isoxazolopyridinyle, isothiazolopyridinyle, tétrahydroquinoléinyle, tétrahydrolsoquinoléinyle, et éventuellement sunstitué par un ou plusieurs substituants choisis parmi les atomes d'halogènes et les groupes (C1-C4) alkyles, (C1-C4) alcoxy, thio (C1-C4) alkyles ou phényles éventuellement substitués par un ou plusieurs substituents choisis parmi les atomes d'halogènes et les groupes trifluorométhyle, (C1-C4) alkyles et (C1-C4) alcoxy.X represents a hydrogen atom or one or more substituents chosen from halogen atoms and trifluoromethyl groups, (C 1 -C 4 ) alkyl and (C 1 -C 4 ) linear or branched alkoxy, R 2 represents a group selected from the groups naphthalenyl, pyridinyl, pyri idinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyidolol, pyolazolyl, pyrazolyl thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzothiazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzotriazolyl, benzisothiazolyl, dihydroindolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl, pyrazolopyridinyle, isoxazolopyridinyle, isothiazolopyridinyle, tetrahydroquinolinyl, tétrahydrolsoquinoléinyle and optionally sunstitué by one or more substituents selected from halogen atoms and the groups (C1-C 4) alkyl, (C 1 -C 4) alkoxy, thio (C 1 -C 4) alkyls or phenyls optionally substituted by one or more substituents chosen from halogen atoms and trifluoromethyl groups, (C 1 -C4) alkyls and (C1-C4) alkoxy.
Les composés de formule générale (I) peuvent exister sous forme du racémate thréo { 1R, 2R ; 1.5,2S) ou sous forme d' énantiomères ( 1R, 2R) ou (1S, 2S) ; ils peuvent exister à l'état de bases libres ou de sels d'addition à des acides.The compounds of general formula (I) can exist in the form of the threo racemate {1R, 2R; 1.5.2S) or in the form of (1R, 2R) or (1S, 2S) enantiomers; they can exist in the form of free bases or of addition salts with acids.
Des composés de structure analogue à celle des composés de l'invention sont décrits dans le brevet US-5254569 comme analgésiques, diurétiques, anticon~vulsivants, anesthé- siques, sédatifs, cérébroprotecteurs, par un, mécanisme d'action sur les récepteurs opiacés. D'autres composés de structure analogue sont décrits dans la demande de brevet EP-0499995 comme antagonistes 5-HT3 utiles dans le traitement des désordres psychotiques, des maladies neurologiques, des symptômes gastriques, des nausées et des vomissements .Compounds of structure analogous to that of the compounds of the invention are described in patent US Pat. No. 5,254,569 as analgesics, diuretics, anticonvulsants, anesthetics, sedatives, cerebroprotectors, by a mechanism of action on opiate receptors. Other compounds of similar structure are described in patent application EP-0499995 as 5-HT 3 antagonists useful in the treatment of psychotic disorders, neurological diseases, gastric symptoms, nausea and vomiting.
Les composés préférés de l' inventi on sont dépourvus d' activité sur les récepteurs opia cés ou 5-HT3 et présentent une activité particuliè re comme inhibiteurs spécifiques des transporteurs de l a glycine glytl et/ou glyt2 .The preferred compounds of the invention lack activity on opiate receptors or 5-HT3 and exhibit particular activity as specific inhibitors of the glycine transporters glytl and / or glyt2.
Les composés de formule générale (I) dans laquelle Ri est différent d'un atome d'hydrogène peuvent être préparés par un procédé illustré par le schéma 1 qui suit.The compounds of general formula (I) in which R 1 is different from a hydrogen atom can be prepared by a process illustrated by scheme 1 which follows.
On effectue un couplage d' une diamine de formule générale ( II ) , dans laquelle Ri et X sont tels que définis ci-dessus (avec Ri différent d' un atome d' hydrogène ) avec un acide activé ou un chlorure d' acide de formule générale ( III ) dans laquelle Y représente un groupe OH activé ou unA diamine of general formula is coupled (II), in which Ri and X are as defined above (with Ri different from a hydrogen atom) with an activated acid or an acid chloride of general formula (III) in which Y represents a group OH activated or a
Schéma 1Diagram 1
A^< ( III ) "2A ^ <(III) "2
atome de chlore et R2 est tel que défini ci-dessus, en utilisant les méthodes connues de l'homme du métier.chlorine atom and R 2 is as defined above, using the methods known to those skilled in the art.
La diamine de formule générale (II) peut être préparée par un procédé illustré par le schéma 2 qui suit.The diamine of general formula (II) can be prepared by a process illustrated by scheme 2 which follows.
On fait réagir l'amide de Weinreb de formule (IV) avec le dérivé de phényllithium de formule générale (V) , dans laquelle X est tel que défini ci-dessus, dans un solvant éthéré tel que l'éther diéthylique, entre -30°C et la température ambiante ; on obtient une cétone de formule générale (VI) que l'on réduit en alcool de configuration thréo de formule générale (VII) par un agent réducteur tel que le K-Selectride® ou le L-Selectride® (tri-sec-butyl- borohydrure de potassium ou de lithium) , dans un solvant éthéré tel que le tétrahydrofurane, entre -78°C et la température ambiante. Le carbamate de formule générale (VII) peut ensuite être réduit en N-méthylaminoalcool thréo de formule générale (VIII) par action d'un hydrure mixte tel que l'hydrure double d'aluminium et de lithium, dans unThe Weinreb amide of formula (IV) is reacted with the phenyllithium derivative of general formula (V), in which X is as defined above, in an ethereal solvent such as diethyl ether, between -30 ° C and room temperature; a ketone of general formula (VI) is obtained which is reduced to alcohol of threo configuration of general formula (VII) by a reducing agent such as K-Selectride® or L-Selectride® (tri-sec-butyl- potassium or lithium borohydride), in an ethereal solvent such as tetrahydrofuran, between -78 ° C and room temperature. The carbamate of general formula (VII) can then be reduced to N-methylaminoalcohol threo of general formula (VIII) by the action of a mixed hydride such as lithium aluminum hydride, in a
Schéma 2Diagram 2
solvant éthéré tel que le tétrahydrofurane, entre la température ambiante et la température de reflux. On transforme ensuite l'alcool thréo de formule générale (VIII) en intermédiaire thréo de formule générale (II) où Ri représente un groupe méthyle en deux: étapes : on transforme d' abord" la fonction alcool en groupe nucléofuge, par exemple un groupe nαéthanesulfonate, par action du chlorure de méthylsulfonyle, dans un solvant chloré tel que le dichlorométhane, et en présence d'une base telle que la triéthylamine, entre 0°C et la température ambiante, puis on fait réagir le groupe nucléofuge avec de l'ammoniac liquéfié à -50°C, dans un alcool tel que l'éthanol, dans un milieu clos tel qu'un autoclave, entre -50°C et la température ambiante. On peut également déprotéger le carbamate de formule générale (VII) au moyen d'une base forte telle que la potasse aqueuse, dans un alcool tel que le méthanol pour obtenir l' aminoalcool thréo de formule générale (IX), procéder ensuite à une -alkylation au moyen d'un dérivé halogène de formule RXZ, dans laquelle Rx est tel que défini ci-dessus, mais différent d'un atome d'hydrogène, et Z représente un atome d'halogène, en présence d'une base telle que le carbonate de potassium, dans un solvant polaire tel que le N, N-diméthylformamide, entre la température ambiante et 100°C. On traite ensuite l'alcool de formule générale (X) ainsi obtenu comme décrit à propos de l'alcool de formule générale (VIII). ethereal solvent such as tetrahydrofuran, between room temperature and reflux temperature. Is then converted to the threo alcohol of general formula (VIII) threo intermediate of general formula (II) wherein R represents a methyl group into two steps: converting first "the alcohol function into an electrophilic group, e.g. a group nαéthanesulfonate, by the action of methylsulfonyl chloride, in a chlorinated solvent such as dichloromethane, and in the presence of a base such as triethylamine, between 0 ° C and room temperature, then reacting the nucleofuge group with ammonia liquefied at -50 ° C, in an alcohol such as ethanol, in a closed environment such as an autoclave, between -50 ° C and room temperature. It is also possible to deprotect the carbamate of general formula (VII) by means of a strong base such as aqueous potassium hydroxide, in an alcohol such as methanol to obtain the amino alcohol threo of general formula (IX), then proceed to a - alkylation by means of a halogen derivative of formula R X Z, in which R x is as defined above, but different from a hydrogen atom, and Z represents a halogen atom, in the presence of a base such as potassium carbonate, in a polar solvent such as N, N-dimethylformamide, between room temperature and 100 ° C. The alcohol of general formula (X) thus obtained is then treated as described with respect to the alcohol of general formula (VIII).
Une autre variante de procédé, illustrée par le schéma 3 qui suit, peut être utilisée dans le cas où Rx représente un groupe méthyle et X représente un atome d'hydrogène. On quaternarise la pyridineoxime de formule (XI), par exemple par action du trifluorométrianesulfonate de méthyle, dans un solvant éthéré tel que l'éther diéthylique à température ambiante. On soumet ensuite le sel de pyridinium ainsi obtenu, de formule (XII) à une hydrogénation sous atmosphère d'hydrogène, en présence d'un catalyseur tel que l'oxyde de platine, dans un mélange d'alcool et d'acide aqueux tel que l'éthanol et l'acide chlorhydrique IN. On obtient la diamine de formule générale (II) où Ri représente un groupe méthyle et X représente un atome d'hydrogène sous forme d'un mélange des deux diastéréoisomères thréo/érythro 9/1. On peut la salifier, par exemple avec de l'acide oxalique, puis la purifier par recristallisation de l'oxalate formé dans un mélange d' alcool et d' un solvant éthéré tel que le méthanol et l'éther diéthylique, pour obtenir le diastéréoisomère thréo (1R, 2R ; 1S,2S) pur. Schéma 3Another variant of the process, illustrated by diagram 3 which follows, can be used in the case where R x represents a methyl group and X represents a hydrogen atom. The pyridineoxime of formula (XI) is quaternized, for example by the action of methyl trifluorometrianesulfonate, in an ethereal solvent such as diethyl ether at room temperature. The pyridinium salt thus obtained, of formula (XII) is then subjected to hydrogenation under a hydrogen atmosphere, in the presence of a catalyst such as platinum oxide, in a mixture of alcohol and aqueous acid such than ethanol and IN hydrochloric acid. The diamine of general formula (II) is obtained in which R 1 represents a methyl group and X represents a hydrogen atom in the form of a mixture of the two threo / erythro 9/1 diastereoisomers. It can be salified, for example with oxalic acid, then purified by recrystallization of the oxalate formed in a mixture of alcohol and an ethereal solvent such as methanol and diethyl ether, to obtain the diastereoisomer threo (1R, 2R; 1S, 2S) pure. Diagram 3
Les composés de formule générale (II) dans laquelle Ri représente un atome d'hydrogène peuvent être préparés suivant le schéma 2, avec utilisation d'un composé de formule générale (I) dans laquelle Ri représente un groupe phénylméthyle éventuellement substitué, puis déprotection de l'azote du cycle pipéridine, par exemple par un agent oxydant ou par un acide de Lewis, tel que le tribromure de bore, ou par hydrogénolyse, soit un groupe alcényle, de préférence allyle, et à déprotéger l'azote par un complexe du Pd°, pour obtenir un composé de formule générale (I) dans laquelle Ri représente un atome d'hydrogène.The compounds of general formula (II) in which R 1 represents a hydrogen atom can be prepared according to scheme 2, with the use of a compound of general formula (I) in which R 1 represents an optionally substituted phenylmethyl group, then deprotection of the nitrogen of the piperidine ring, for example by an oxidizing agent or by a Lewis acid, such as boron tribromide, or by hydrogenolysis, either an alkenyl group, preferably allyl, and deprotecting the nitrogen by a complex of the Pd °, to obtain a compound of general formula (I) in which Ri represents a hydrogen atom.
Par ailleurs les composés chiraux de formule générale (I) correspondant aux énantiomères ( 1R, 2R) ou (1S,2S) du diastéréoisomère thréo peuvent être également obtenus par séparation des composés racémiques par chromatographie liquide à haute performance (CLHP) sur colonne chirale, ou par dédoublement de l'aminé racémique de formule générale (II) par utilisation d'un acide chiral tel que l'acide tartrique, l'acide camphorsulfonique, l'acide dibenzoyltartrique ou la N-acétylleucine, par la recristallisation fractionnée et préférentielle d'un sel diastéréoisomérique, dans un solvant de type alcool, ou encore par synthèse enantiosélective selon le schéma 2 avec utilisation d'un amide de einreb chiral de formule (IV).Furthermore, the chiral compounds of general formula (I) corresponding to the (1R, 2R) or (1S, 2S) enantiomers of the threo diastereoisomer can also be obtained by separation of the racemic compounds by high performance liquid chromatography (HPLC) on a chiral column, or by splitting the racemic amine of general formula (II) by using a chiral acid such as tartaric acid, camphorsulfonic acid, dibenzoyltartaric acid or N-acetylleucine, by fractional and preferential recrystallization d 'a diastereoisomeric salt, in an alcohol type solvent, or by enantioselective synthesis according to scheme 2 with the use of a chiral einreb amide of formula (IV).
L' amide de Weinreb de formule ( IV) racémi que ou chiral , ainsi que la cétone de formule générale (VI) , peuvent être préparés selon une méthode analogue à celle décrite dans Eur. J. Med. Chem . , 35, (2000), 979-988 et J. Med. Chem . , 41, (1998), 591-601. Le composé phényllithié de formule générale (V) où X représente un atome d'hydrogène est disponible dans le commerce. Ses dérivés substitués peuvent être préparés selon une méthode analogue à celle décrite dans Tetrahedron Lett . , 57, 33, (1996), 5905-5908. La pyridineoxime de formule générale (XI) peut être préparée selon une méthode analogue à celle décrite dans la demande de brevet EP-0366006. L'aminé de formule générale (IX) dans laquelle X représente un atome d'hydrogène peut être préparée en série chirale selon une méthode décrite dans le brevet US-2928835. Enfin, l'aminé de formule générale (XIII) peut être préparée selon une méthode analogue à celle décrite dans Chem . Pharm . Bull . , 32 , 12, (1984), 4893-4906 et Synthesis, (1976), 593-595.The Weinreb amide of formula (IV) racemic or chiral, as well as the ketone of general formula (VI), can be prepared according to a method analogous to that described in Eur. J. Med. Chem. , 35, (2000), 979-988 and J. Med. Chem. , 41, (1998), 591-601. The phenyllithium compound of general formula (V) where X represents a hydrogen atom is commercially available. Its substituted derivatives can be prepared according to a method analogous to that described in Tetrahedron Lett. , 57, 33, (1996), 5905-5908. The pyridineoxime of general formula (XI) can be prepared according to a method analogous to that described in patent application EP-0366006. The amine of general formula (IX) in which X represents a hydrogen atom can be prepared in chiral series according to a method described in patent US-2928835. Finally, the amine of general formula (XIII) can be prepared according to a method analogous to that described in Chem. Pharm. Bull. , 32, 12, (1984), 4893-4906 and Synthesis, (1976), 593-595.
Les acides et chlorures d'acides de formule générale (III) sont disponibles dans le commerce, sauf l'acide 4- [2-chloro-3- (trifluorométhyl)phényl] -lH-imidazole-2- carboxylique, qui peut être préparé dans des conditions comparables à celles décrites dans la demande de brevet EP-0365030 et dans le brevet US-3336300.The acids and acid chlorides of general formula (III) are commercially available, except for 4- [2-chloro-3- (trifluoromethyl) phenyl] -1H-imidazole-2-carboxylic acid, which can be prepared under conditions comparable to those described in patent application EP-0365030 and in patent US-3336300.
Les exemples qui vont suivre illustrent la préparation de quelques composés de l'invention. Les microanalyses élémentaires, les spectres I.R. et R. .N. et la CLHP sur colonne chirale confirment les structures et les puretés énantiomériques des composés obtenus. Les numéros indiqués entre parenthèses dans les titres des exemples correspondent à ceux de la 1ère colonne du tableau donné plus loin. Exemple 1 (Composé N°4) .The examples which follow illustrate the preparation of some compounds of the invention. Elementary microanalyses, IR and R .N spectra. and HPLC on a chiral column confirm the enantiomeric structures and purities of the compounds obtained. The numbers indicated in parentheses in the titles of the examples correspond to those in the 1st column of the table given below. Example 1 (Compound No. 4).
Chlorhydrate de thréo-2, 5-dichloro-N- [ (l-méthyl-2- pipéridinyl) (phényl) éthyl] -3-thiophènecarboxamide 1:1.Threo-2,5-dichloro-N- [(1-methyl-2-piperidinyl) (phenyl) ethyl] -3-thiophenecarboxamide hydrochloride 1: 1.
1.1. Trifluorométhanesulfonate de 2- (benzyloxyimino- phénylméthyl) -1-méthylpyridinium.1.1. 2- (Benzyloxyimino-phenylmethyl) -1-methylpyridinium trifluoromethanesulfonate.
A une suspension de 35 g (120 mmoles) de phényl (pyridin-To a suspension of 35 g (120 mmol) of phenyl (pyridin-
2-yl)méthanone O-benzyloxime dans 200 ml d' éther diéthylique on ajoute, goutte à goutte et à 0°C, 17,4 ml (120 mmoles) de trifluorométhanesulfonate de méthyle et on agite le mélange à température ambiante pendant 3 h.2-yl) methanone O-benzyloxime in 200 ml of diethyl ether is added dropwise and at 0 ° C, 17.4 ml (120 mmol) of methyl trifluoromethanesulfonate and the mixture is stirred at room temperature for 3 h .
On recueille le précipité formé par filtration et on le sèche sous pression réduite.The precipitate formed is collected by filtration and dried under reduced pressure.
On obtient 49 g de produit qu'on utilise tel quel dans l'étape suivante.49 g of product are obtained, which product is used as it is in the next step.
1.2. Ethanedioate de thréo- (l-méthylpipéridin-2-yl) - phénylméthanamine 2:1. Dans une fiole de Parr on place 14,8 g (31,89 mmoles) de trifluorométhanesulfonate de 2- (benzyloxyiminophényl- méthyl) -1-méthylpyridinium et 0,74 g d'oxyde de platine dans 50 ml d' éthanol et 50 ml d'acide chlorhydrique IN et on effectue une hydrogénation pendant 5 h. On évapore l' éthanol sous pression réduite, on extrait le résidu avec du dichloromethane, on sépare la phase aqueuse, on y ajoute une solution d'ammoniaque et on l'extrait avec du dichloromethane. Après lavage des phases organiques réunies, séchage sur sulfate de sodium, filtration et évaporation du solvant sous pression réduite, on obtient 6,7 g de produit huileux comprenant 10% de diastereoisomere érythro. On prépare l' ethanedioate en dissolvant ces 6,7 g de base dans le méthanol, par action de deux équivalents d'acide éthanedioïque dissous dans le minimum de méthanol. On purifie le sel obtenu par recristallisation dans un mélange de méthanol et d' éther diéthylique. On isole finalement 4,7 g d' ethanedioate du diastereoisomere thréo pur. Point de fusion : 156-159°C.1.2. Threo (1-methylpiperidin-2-yl) - phenylmethanamine ethanedioate 2: 1. In a Parr flask, 14.8 g (31.89 mmol) of 2- (benzyloxyiminophenylmethyl) -1-methylpyridinium trifluoromethanesulfonate and 0.74 g of platinum oxide are placed in 50 ml of ethanol and 50 ml hydrochloric acid IN and hydrogenation is carried out for 5 h. The ethanol is evaporated off under reduced pressure, the residue is extracted with dichloromethane, the aqueous phase is separated, an ammonia solution is added thereto and it is extracted with dichloromethane. After washing the combined organic phases, drying over sodium sulphate, filtration and evaporation of the solvent under reduced pressure, 6.7 g of oily product are obtained comprising 10% of erythro diastereoisomer. The ethanedioate is prepared by dissolving these 6.7 g of base in methanol, by the action of two equivalents of ethanedioic acid dissolved in the minimum amount of methanol. The salt obtained is purified by recrystallization from a mixture of methanol and diethyl ether. Finally, 4.7 g of ethanedioate are isolated from the pure threo diastereoisomer. Melting point: 156-159 ° C.
1.3. Chlorhydrate de thréo-2, 5-dichloro-W- [ (l-méthyl-2- pipéridinyl) (phényl) méthyl] thiophène-3-carboxamide 1:1. Dans un ballon de 100 ml on introduit 0,768 g (4 mmoles) d'acide 2, 5-dichlorothiophène-3-carboxylique en solution dans 15 ml de dichloromethane, puis on ajoute successivement 0,651 ml (4,7 mmoles) de triéthylamine et 0,447 ml (4,7 mmoles) de chloroformiate d'éthyle, et on agite le mélange réactionnel à température ambiante pendant 2 h. On ajoute 0,80 g (3,9 mmoles) de thréo (1-méthylpipéridin- 2-yl)phénylméthanamine en solution dans 15 ml de dichloromethane et on poursuit l'agitation à température ambiante pendant 12 h. On traite le mélange avec de l'eau et on l'extrait plusieurs fois avec du dichloromethane. Après lavage des phases organiques avec de l'eau puis avec une solution aqueuse de soude IN, séchage sur sulfate de sod±um, filtration et evaporation du solvant sous pression réduite on purifie le résidu par chromatographie sur colonne de gel de silice en éluant avec un mélange 97/3 à 95/5 de dichloromethane et de méthanol. On obtient 0,6 g de produit huileux dont on prépare le chlorhydrate par addition d'une solution 0,1N d'acide chlorhydrique dans le propan-2-ol. Après evaporation des solvants sous pression réduite on recristallise le solide blanc obtenu dans un mélange d' éther isopropylique et de propan-2-ol. On isole finalement 0,474 g de chlorhydrate sous forme de solide blanc. Point de fusion : 216-217°C. Exemple 2 (Composé N°5) .1.3. Threo-2,5-dichloro-W- [(1-methyl-2-piperidinyl) (phenyl) methyl] thiophene-3-carboxamide hydrochloride 1: 1. 0.768 g (4 mmol) of 2, 5-dichlorothiophene-3-carboxylic acid dissolved in 15 ml of dichloromethane are introduced into a 100 ml flask, then 0.651 ml (4.7 mmol) of triethylamine and 0.447 are successively added ml (4.7 mmol) of ethyl chloroformate, and the reaction mixture is stirred at room temperature for 2 h. 0.80 g (3.9 mmol) of threo (1-methylpiperidin-2-yl) phenylmethanamine dissolved in 15 ml of dichloromethane is added and stirring is continued at room temperature for 12 h. The mixture is treated with water and extracted several times with dichloromethane. After washing the organic phases with water and then with an aqueous solution of IN sodium hydroxide, drying over sodium sulfate ± um, filtration and evaporation of the solvent under reduced pressure, the residue is purified by chromatography on a column of silica gel, eluting with a 97/3 to 95/5 mixture of dichloromethane and methanol. 0.6 g of oily product is obtained, the hydrochloride of which is prepared by adding a 0.1N solution of hydrochloric acid in propan-2-ol. After evaporation of the solvents under reduced pressure, the white solid obtained is recrystallized from a mixture of isopropyl ether and propan-2-ol. 0.474 g of hydrochloride is finally isolated in the form of a white solid. Melting point: 216-217 ° C. Example 2 (Compound No. 5).
Chlorhydrate de 2, 5-dichloro-iV- [ (S) - [ (2S) -l-méthyl-2- pipéridinyl] (phényl)méthyl] thiophène-3-carboxamide 1:1.2,5-dichloro-iV- [(S) - [(2S) -1-methyl-2-piperidinyl] (phenyl) methyl] thiophene-3-carboxamide hydrochloride 1: 1.
2.1 (25) -2-benzoylpipéridine-l-carboxylate de 1 , 1-diméthyléthyle . Dans un ballon de 500 ml, sous atmosphère d'azote, on introduit 11,8 g (43,3 mmoles) de (2S) -2- (IV-méthoxy- N-méthylcarbamoyl ) pipéridine-1-carboxylate de 1, 1-diméthyléthyle dans 100 ml d' éther diéthylique anhydre, on refroidit le milieu à -23°C, on ajoute, goutte à goutte, 21,6 ml (43,2 mmoles) d'une solution 1,8M de phényllithium dans un mélange 70/30 de cyclohexane et dr éther diéthylique et on agite le mélange à température ambiante pendant 3 h. Après hydrolyse avec une solution aqueuse saturée de chlorure de sodium on sépare la phase aqueuse et on l'extrait avec de l'acétate d'éthyle. On sèche la phase organique sur sulfate de sodium, on la filtre, on la concentre sous pression réduite et on purifie le résidu par chromatographie sur colonne de gel de silice en éluant avec un mélange d'acétate d'éthyle et de cyclohexane. On obtient 4,55 g de produit solide. Point de fusion : 123-125°C. [α]25 D=-25,4° (c=2,22 ; CH2C12) ee=97,2%.2.1 (25) -2-Benzoylpiperidine-1-1-dimethylethylcarboxylate. 11.8 g (43.3 mmol) of (2S) -2- (IV-methoxy- N-methylcarbamoyl) piperidine-1-carboxylate of 1.1 are introduced into a 500 ml flask under a nitrogen atmosphere -dimethylethyl in 100 ml of anhydrous diethyl ether, the medium is cooled to -23 ° C, 21.6 ml (43.2 mmol) of a 1.8M solution of phenyllithium in a mixture are added dropwise 70/30 cyclohexane and r diethyl ether and stirred at room temperature for 3 h. After hydrolysis with a saturated aqueous solution of sodium chloride, the aqueous phase is separated and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered, concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of ethyl acetate and cyclohexane. 4.55 g of solid product are obtained. Melting point: 123-125 ° C. [α] 25 D = -25.4 ° (c = 2.22; CH 2 C1 2 ) ee = 97.2%.
2.2. (1S) -2- [ (2S) -hydroxy (phényl)méthyl] pipéridine- 1-carboxylate de 1, 1-diméthyléthyle . Dans un ballon de 500 ml, sous atmosphère d'azote, on introduit 4,68 g (16,2 mmoles) de (2S) -2-benzoylpipéridine- 1-carboxylate de 1, 1-diméthyléthyle dans 170 ml de tétrahydrofurane anhydre, on refroidit la solution à -78 °C, on ajoute, goutte à goutte , 48,5 ml (48,5 mmoles) d'une solution 1M de L-Selectride® (tri-sec-butylborohydrure de lithium) dans le tétrahydrofurane, et on agite le mélange à température ambiante pendant 5 h. On l'hydrolyse à froid lentement avec 34 ml d'eau et 34 ml d'une solution aqueuse à 35% de peroxyde d'hydrogène, et on laisse le mélange revenir à température ambiante en l'agitant pendant 2 h.2.2. (1S) -2- [(2S) -hydroxy (phenyl) methyl] piperidine-1-1-dimethylethylcarboxylate. 4.68 g (16.2 mmol) of (2S) -2-benzoylpiperidine-1-1, 1-dimethylethylcarboxylate in 170 ml of anhydrous tetrahydrofuran are introduced into a 500 ml flask under a nitrogen atmosphere. the solution is cooled to -78 ° C., 48.5 ml (48.5 mmol) of a 1M solution of L-Selectride® (tri-sec-lithium butylborohydride) in tetrahydrofuran is added dropwise and the mixture is stirred at room temperature for 5 h. Cold hydrolysis slowly with 34 ml of water and 34 ml of a 35% aqueous solution of hydrogen peroxide, and the mixture is allowed to return to ambient temperature while stirring for 2 h.
On le dilue avec de l'eau et de l'acétate d'éthyle,- , on sépare la phase aqueuse, on l'extrait avec de l'acétate d'éthyle. Après lavage des phases organiques réunies, séchage, séchage sur sulfate de sodium, filtration et evaporation on purifie le résidu par chromatographie sur colonne de gel de silice en éluant avec un mélange d'acétate d'éthyle et de cyclohexane.It is diluted with water and ethyl acetate, -, the aqueous phase is separated, it is extracted with ethyl acetate. After washing the combined organic phases, drying, drying over sodium sulfate, filtration and evaporation, the residue is purified by chromatography on a column of silica gel, eluting with a mixture of ethyl acetate and cyclohexane.
On obtient 4,49 g d'une huile jaune pâle. [ ]25 D=+63,75° (c=0,8 ; CH2C12) ee=97,8%.4.49 g of a pale yellow oil are obtained. [] 25 D = + 63.75 ° (c = 0.8; CH 2 C1 2 ) ee = 97.8%.
2.3. (1S) - [ (2S) - (l-méthylpipéridin-2-yl) ] phenylmethanol. Dans un bicol de 200 ml, sous atmosphère d'azote, on introduit 2,96 g (78,1 mmoles) d'hydrure double d'aluminium et de lithium dans 50 ml de tétrahydrofurane anhydre, on chauffe le mélange au reflux, on ajoute 4,49 g (15 4 mmoles) d'une solution de (1S) -2- [ (2S) -hydroxy (phényl) - méthyl]pipéridine-l-carboxylate de 1, 1-diméthyléthyle dans 35 ml de tétrahydrofurane et on maintient le mélange au reflux pendant 3,5 h. On le refroidit, on l'hydrolyse lentement avec une solution 0,1M de tartrate double de potassium et de sodium et on laisse le mélange sous agitation pendant une nuit. On le filtre et on rince le précipité avec du tétrahydrofurane, puis on concentre le filtrat sous pression réduite. On obtient 2,95 g d'un produit huileux incolore.2.3. (1S) - [(2S) - (1-methylpiperidin-2-yl)] phenylmethanol. 2.96 g (78.1 mmol) of double aluminum and lithium hydride in 50 ml of anhydrous tetrahydrofuran are introduced into a 200 ml two-necked flask under nitrogen, the mixture is heated to reflux, add 4.49 g (15 4 mmol) of a solution of (1S) -2- [(2S) -hydroxy (phenyl) - methyl] piperidine-1, 1-dimethylethylcarboxylate in 35 ml of tetrahydrofuran and the mixture is maintained at reflux for 3.5 h. It is cooled, hydrolyzed slowly with a 0.1M solution of potassium and sodium double tartrate and the mixture is left to stir overnight. It is filtered and the precipitate is rinsed with tetrahydrofuran, then the filtrate is concentrated under reduced pressure. 2.95 g of a colorless oily product are obtained.
2.4. (lS)-[ (2S)-(l-méthylpipéridin-2-yl) ]phényl- méthanamine . Dans un ballon de 250 ml , sous atmosphère d' azote , on introduit 2 , 95 g ( 14 , 4 mmoles ) de ( 1S) - [ ( 2S) - ( 1-méthyl- pipéridin-2-yl ) ] phenylmethanol et 2 ml ( 14 , 4 mmoles ) de triéthyla ine dans 70 ml de dichloromethane anhydre , on refroidit le milieu à 0°C, on ajoute 1,1 ml (14,4 mmoles) de chlorure de méthanesulfonyle, on laisse le mélange revenir lentement à température ambiante pendant 2 h et on le concentre sous pression réduite. Dans un autoclave muni d'une agitation magnétique et refroidi à -50°C on introduit de l'ammoniac liquéfié, on ajoute une solution du méthanesulfonate précédemment préparé dans 30 ml d' éthanol absolu, on ferme l'autoclave et on maintient l'agitation pendant 48 h. On transvase le mélange dans un ballon, on évapore les solvants sous pression réduite et on isole l'aminé sous forme de produit huileux qu'on utilise tel quel dans l'étape suivante.2.4. (1S) - [(2S) - (1-methylpiperidin-2-yl)] phenylmethanamine. 2.95 g (14.4 mmol) of (1S) - [(2S) - (1-methyl-piperidin-2-yl)] phenylmethanol and 2 are introduced into a 250 ml flask under a nitrogen atmosphere. ml (14.4 mmol) of triethylamine in 70 ml of anhydrous dichloromethane, the medium is cooled to 0 ° C., 1.1 ml (14.4 mmol) of methanesulfonyl chloride are added, the mixture is allowed to slowly return to room temperature for 2 h and concentrated under reduced pressure. Liquefied ammonia is introduced into an autoclave fitted with a magnetic stirrer and cooled to -50 ° C., a solution of the previously prepared methanesulfonate in 30 ml of absolute ethanol is added, the autoclave is closed and the stirring for 48 h. The mixture is transferred to a flask, the solvents are evaporated off under reduced pressure and the amine is isolated in the form of an oily product which is used as it is in the following step.
2.5. Chlorhydrate de 2, 5-dichloro-N- [ (1S)-[(2S) -1- méthyl-2-pipéridinyl] (phényl)méthyl] thiophène-3- carboxamide 1:1. Dans un ballon de 250 ml on introduit 0,37 g (1,88 mmole) d'acide 2, 5-dichlorothiophène-3-carboxylique dans 15 ml de dichloromethane, on ajoute successivement 0,31 ml (2,25 mmoles) de triéthylamine et 0,21 ml (2,25 mmoles) de chloroformiate d'éthyle et on agite le mélange à température ambiante pendant 1 h. On ajoute 0,38 g (1,88 mmole) de (1S) - [ (2S) - (1-méthylpipé- ridin-2-yl) ] phénylméthanamine en solution dans 10 ml de dichloromethane et on poursuit l'agitation à température ambiante pendant 12 h. On traite le mélange avec de l'eau, on l'extrait plusieurs fois avec du dichloromethane, on réunit les phases organiques, on les lave avec une solution aqueuse IN de soude, on les sèche sur sulfate de sodium, on filtre et on concentre le filtrat sous pression réduite. On purifie le résidu brut par chromatographie sur colonne de gel de silice en éluant avec un mélange 98/2 de dichloromethane et de méthanol contenant 0,1% d'ammoniaque On obtient 0,368 g de produit huileux dont on prépare le chlorhydrate par addition d'une solution 0,1N d'acide chlorhydrique dans le propan-2-ol.2.5. 2,5-dichloro-N- [(1S) - [(2S) -1-methyl-2-piperidinyl] (phenyl) methyl] thiophene-3-carboxamide hydrochloride 1: 1. 0.37 g (1.88 mmol) of 2, 5-dichlorothiophene-3-carboxylic acid is introduced into a 250 ml flask in 15 ml of dichloromethane, and 0.31 ml (2.25 mmol) is successively added. triethylamine and 0.21 ml (2.25 mmol) of ethyl chloroformate and the mixture was stirred at room temperature for 1 h. 0.38 g (1.88 mmol) of (1S) - [(2S) - (1-methylpiperidin-2-yl)] phenylmethanamine added in solution in 10 ml of dichloromethane is added and stirring is continued at temperature ambient for 12 h. The mixture is treated with water, it is extracted several times with dichloromethane, the organic phases are combined, they are washed with an aqueous IN sodium hydroxide solution, they are dried over sodium sulphate, filtered and concentrated the filtrate under reduced pressure. The crude residue is purified by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloromethane and methanol containing 0.1% of ammonia. 0.368 g of oily product is obtained, the preparation of which is prepared. hydrochloride by addition of a 0.1N solution of hydrochloric acid in propan-2-ol.
Après evaporation du solvant sous pression réduite on recristallise le solide dans un mélange de propan-2-ol et d' éther isopropylique.After evaporation of the solvent under reduced pressure, the solid is recrystallized from a mixture of propan-2-ol and isopropyl ether.
On isole finalement 0,36 g de chlorhydrate sous forme de solide jaune pâle.0.36 g of hydrochloride is finally isolated in the form of a pale yellow solid.
Point de fusion : 134-136A [α]25 D=+45,6 (c=0,99) ;CH3OH.Melting point: 134-136A [α] 25 D = + 45.6 (c = 0.99); CH 3 OH.
Exemple 3 (Composé N°18) .Example 3 (Compound No. 18).
Chlorhydrate de thréo-4- [2-chloro-3- (trifluorométhyl) - phényl] -N- [ (l-méthyl-2-pipéridinyl) (phényl)méthyl] -1H- imidazole-2-carboxamide 1:1. Dans un ballon de 50 ml on introduit 0,1 g (0,344 mmole) d' acide 4- (2-chloro-3- (trifluorométhyl) phényl] -1H- imidazole-2-carboxylique, 0,066 g (0,344 mmole) de chlorhydrate de 1- [3- (diméthylamino) propyl] -3- éthylcarbodiimide, 0,047 g (0,344 mmole) de 1-hydroxybenzotriazole en solution dans 10 ml de dichloromethane, et on agite le mélange à température ambiante pendant 5 min. On ajoute 0,072 g (0,344 mmole) de thréo- (1-méthyl- pipéridin-2-yl) phénylméthanamine (préparée selon l'exemple 1,2) dans quelques ml de dichloromethane et on poursuit l'agitation pendant 6 h. On traite le mélange avec de l'eau, on l'extrait plusieurs fois avec du dichloromethane, on lave les phases organiques avec de l'eau puis avec une solution aqueuse IN de soude, puis avec une solution aqueuse saturée de chlorure de sodium, on les sèche sur sulfate de sodium et on évapore le solvant sous pression réduite. On purifie le résidu par chromatographie sur colonne de gel de silice en éluant avec un mélange de dichloromethane et de méthanol. On obtient 91 mg de produit dont on prépare le chlorhydrate par addition d'une solution 0,1N d'acide chlorhydrique dans le propan-2-ol. On évapore partiellement le solvant sous pression réduite pour obtenir, après cristallisation, 104 mg de composé solide blanc. Point de fusion : 188-195°C. Le tableau de la page suivante illustre les structures chimiques et les propriétés physiques de quelques composés de l'invention.Threo-4- [2-chloro-3- (trifluoromethyl) - phenyl] -N- [(1-methyl-2-piperidinyl) (phenyl) methyl] -1H-imidazole-2-carboxamide hydrochloride 0.1 g (0.344 mmol) of 4- (2-chloro-3- (trifluoromethyl) phenyl] -1H-imidazole-2-carboxylic acid, 0.066 g (0.344 mmol) of hydrochloride are introduced into a 50 ml flask of 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide, 0.047 g (0.344 mmol) of 1-hydroxybenzotriazole dissolved in 10 ml of dichloromethane, and the mixture is stirred at room temperature for 5 min. 0.072 g is added (0.344 mmol) of threo- (1-methyl-piperidin-2-yl) phenylmethanamine (prepared according to example 1.2) in a few ml of dichloromethane and stirring is continued for 6 h. The mixture is treated with water, it is extracted several times with dichloromethane, the organic phases are washed with water and then with an IN aqueous solution of sodium hydroxide, then with a saturated aqueous solution of sodium chloride, they are dried over sodium and the solvent is evaporated off under reduced pressure, the residue is purified by chromatography on a column of silica gel eluted nt with a mixture of dichloromethane and methanol. 91 mg of product are obtained, the hydrochloride of which is prepared by the addition of a 0.1N solution of hydrochloric acid in propan-2-ol. The solvent is partially evaporated under reduced pressure to obtain, after crystallization, 104 mg of white solid compound. Melting point: 188-195 ° C. The table on the following page illustrates the chemical structures and the physical properties of some compounds of the invention.
Dans la colonne "Sel", N-" désigne un composé à l'état de base et "HC1" désigne un chlorhydrate. Le pouvoir rotatoire du composé N°5 est [ ] 25 D=+45, 6° (c≈0,99) ;CH3OH. In the "Salt" column, N - "denotes a compound in the basic state and" HC1 "denotes a hydrochloride. The rotational power of compound N ° 5 is [] 25 D = + 45.6 ° (c≈0 , 99); CH 3 OH.
TableauBoard
Les composés de l'invention ont été soumis à une série d'essais pharmacologiques qui ont mis en évidence leur intérêt comme substances à activités thérapeutiques. The compounds of the invention have been subjected to a series of pharmacological tests which have demonstrated their advantage as substances with therapeutic activities.
Etude du transport de la glycine dans les cellules SK-N-MC exprimant le transporteur humain glytl natif. La capture de [14C] glycine est étudiée dans les cellules SK-N-MC (cellules neuro-épithéliales humaines) exprimant le transporteur humain glytl natif par la mesure de la radioactivité incorporée en présence ou en absence du composé à tester. Les cellules sont cultivées en monocouche pendant 48 h dans des plaques prétraitées à la fibronectine à 0,02%. Le jour de l'expérience, le milieu de culture est éliminé et les cellules sont lavées par un tampon Krebs- HEPES (acide [4- (2-hydroxyéthyl) pipérazine-1-éthanesul- fonique) à pH 7,4. Après 10 min de préincubation à 37°C en présence soit de tampon (lot témoin) , soit de composé à tester à différentes concentrations ou de 10 mM de glycine (détermination de la capture non spécifique) , 10 μM de [14C] glycine (activité spécifique 112 mCi/mmole) sont ensuite ajoutés. L'incubation se poursuit pendant 10 min à 37°C, et la réaction est arrêtée par 2 lavages avec un tampon Krebs-HEPES à pH 7,4. La radioactivité incorporée par les cellules est alors estimée après ajout de 100 μl de scintillant liquide et agitation pendant 1 h. Le comptage est réalisé sur compteur Microbeta Tri-lux™. L'efficacité du composé est déterminée par la CI5o, concentration du composé qui diminue de 50% la capture spécifique de glycine, définie par la différence de radioactivité incorporée par le lot témoin et le lot qui a reçu la glycine à 10 mM. Les composés de l'invention, dans ce test, ont une CI50 de l'ordre de 0,01 à 10 μM. Etude du transport de la glycine dans 1 * homogénat de moelle épinière de souris.Study of glycine transport in SK-N-MC cells expressing the native glytl human transporter. The uptake of [ 14 C] glycine is studied in SK-N-MC cells (human neuroepithelial cells) expressing the native glytl human transporter by measuring the radioactivity incorporated in the presence or absence of the test compound. The cells are cultured in a monolayer for 48 h in plates pretreated with 0.02% fibronectin. On the day of the experiment, the culture medium is eliminated and the cells are washed with a Krebs-HEPES buffer ([4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid) at pH 7.4. After 10 min of preincubation at 37 ° C in the presence of either buffer (control batch), or of test compound at different concentrations or 10 mM glycine (determination of non-specific capture), 10 μM of [ 14 C] glycine (specific activity 112 mCi / mmol) are then added. Incubation continues for 10 min at 37 ° C, and the reaction is stopped by 2 washes with Krebs-HEPES buffer at pH 7.4. The radioactivity incorporated by the cells is then estimated after adding 100 μl of liquid scintillant and stirring for 1 h. The counting is carried out on a Microbeta Tri-lux ™ counter. The efficacy of the compound is determined by the IC 5 o, the concentration of compound which reduces by 50% the specific capture of glycine, defined by the difference in radioactivity incorporated by the control batch and the batch which received the glycine at 10 mM. The compounds of the invention, in this test, have an IC 50 of the order of 0.01 to 10 μM. Study of glycine transport in the mouse spinal cord homogenate.
La capture de [14C] glycine par le transporteur glyt2 est étudiée dans l'homogénat de moelle épinière de souris par la mesure de radioactivité incorporée en présence ou en absence de composé à étudier.The uptake of [ 14 C] glycine by the glyt2 transporter is studied in the mouse spinal cord homogenate by measuring the radioactivity incorporated in the presence or absence of the compound to be studied.
Après euthanasie des animaux (souris mâles OF1 Iffa Credo pesant 20 à 25 g le jour de l'expérience) , la moelle épinière de chaque animal est rapidement prélevée, pesée et conservée sur glace. Les échantillons sont homogénéisés dans un tampon Krebs-HEPES (acide [4- (2—hydroxyéthyl) pipé- razine-1-éthanesulfonique) , pH 7,4, à raison de 25 ml/g de tissu. 50 μl d' omogénat sont pré-incubés pendant 10 min à 25°C en présence de tampon Krebs-HEPES , pH 7,4 et de composé à étudier à différentes concentrations, ou de 10 mM de glycine pour déterminer la capture non spécifique. La [1C] glycine (activité spécifique = 112mCi/mmole) est ensuite ajoutée pendant 10 min à 25°C à la concentration finale de 10 μM. La réaction est arrêtée par filtration sous vide et la radioactivité est estimée par scintillation solide par comptage sur un compteur Microbeta Tri-lux™. L'efficacité du composé est déterminée par la concentration CI50 capable de diminuer de 50% la capture spécifique de glycine, définie par la différence de radioactivité incorporée par le lot témoin et le lot qui a reçu la glycine 10 mM. Les composés de l'invention, dans ce test, ont une CI50 de l'ordre de 0,01 à 10 μM.After euthanasia of the animals (OF1 Iffa Credo male mice weighing 20 to 25 g on the day of the experiment), the spinal cord of each animal is quickly removed, weighed and stored on ice. The samples are homogenized in a Krebs-HEPES ([4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid) buffer, pH 7.4, at a rate of 25 ml / g of tissue. 50 μl of omogenate are pre-incubated for 10 min at 25 ° C in the presence of Krebs-HEPES buffer, pH 7.4 and of compound to be studied at different concentrations, or of 10 mM glycine to determine the non-specific uptake. The [ 1 C] glycine (specific activity = 112mCi / mmol) is then added for 10 min at 25 ° C to the final concentration of 10 μM. The reaction is stopped by vacuum filtration and the radioactivity is estimated by solid scintillation by counting on a Microbeta Tri-lux ™ counter. The effectiveness of the compound is determined by the IC 50 concentration capable of decreasing the specific glycine uptake by 50%, defined by the difference in radioactivity incorporated by the control batch and the batch which received the 10 mM glycine. The compounds of the invention, in this test, have an IC 50 of the order of 0.01 to 10 μM.
Ces résultats suggèrent que les composés de l'invention peuvent être utilisés pour le traitement des troubles comportementaux associés à la démence, des psychoses, en particulier de la schizophrénie (forme déficitaire et forme productive) et des symptômes extrapyramidaux aigus ou chroniques induits par les neuroleptiques, pour le traitement des diverses formes d'anxiété, des attaques de panique, des phobies, des troubles obsessionnels compulsifs, pour le traitement des différentes formes de dépression, y compris la dépression psychotique, pour le traitement des troubles dus à l'abus ou au sevrage d'alcool, des troubles du comportement sexuel, des troubles de la prise de nourriture, et pour le traitement de la migraine.These results suggest that the compounds of the invention can be used for the treatment of behavioral disorders associated with dementia, psychoses, in particular schizophrenia (deficit form and productive form) and acute or chronic extrapyramidal symptoms induced by neuroleptics. , for the treatment of various forms of anxiety, panic attacks, phobias, obsessive compulsive disorder, for the treatment of various forms of depression, including psychotic depression, for the treatment of disorders due to abuse or withdrawal alcohol, sexual behavior disorders, eating disorders, and for the treatment of migraine.
De plus, les composés de l'invention peuvent être utilisés pour le traitement des contractures musculaires douloureuses en rhumatologie et en pathologie rachidienne aiguë, pour le traitement des contractures spastiques d'origine médullaire ou cérébrale, pour le traitement symptomatique des douleurs aiguës et subaiguës d'intensité légère à modérée, pour le traitement des douleurs intenses et/ou chroniques, des douleurs neurogènes et algies rebelles, pour le traitement de la maladie de Parkinson et des symptômes parkinsoniens d'origine neurodégénérative ou induits par des neuroleptiques, pour le traitement des épilepsies généralisées primaires et secondaires, partielles à symptomatologie simple ou complexe, des formes mixtes et autres syndromes épileptiques en complément d'un autre traitement antiépileptique, ou en monothérapie, pour le traitement des apnées du sommeil, et pour la neuroprotection .In addition, the compounds of the invention can be used for the treatment of painful muscular contractures in rheumatology and in acute spinal pathology, for the treatment of spastic contractures of medullary or cerebral origin, for the symptomatic treatment of acute and subacute pain. mild to moderate intensity, for the treatment of intense and / or chronic pain, neurogenic pain and rebellious pain, for the treatment of Parkinson's disease and parkinsonian symptoms of neurodegenerative origin or induced by neuroleptics, for the treatment of generalized primary and secondary epilepsies, partial with simple or complex symptomatology, mixed forms and other epileptic syndromes in addition to another antiepileptic treatment, or as monotherapy, for the treatment of sleep apnea, and for neuroprotection.
C'est pourquoi la présente invention a également pour objet des compositions pharmaceutiques contenant une dose efficace d'au moins un composé selon l'invention, à l'état de base ou de sel ou de solvat pharmaceutiquement acceptable, et en mélange, le cas échéant, avec des excipients convenables. Lesdits excipients sont choisis selon la forme pharmaceutique et le mode d'administration souhaité. Les compositions pharmaceutiques selon l'invention peuvent ainsi être destinées à l'administration orale, sublinguale, sous-cutanée, intramusculaire, intraveineuse, topique, intratrachéale, intranasale, transdermique, rectale, intraocculaire .This is why the present invention also relates to pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the base state or of a pharmaceutically acceptable salt or solvate, and as a mixture, as the case may be. if necessary, with suitable excipients. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration. The pharmaceutical compositions according to the invention can thus be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal, intraoccular administration.
Les formes unitaires d'administration peuvent être, par exemple, des comprimés, des gélules, des granules, des poudres, des solutions ou suspensions orales ou injectables, des timbres transdermiques ("patch"), des suppositoires. Pour l'administration topique on peut envisager des pommades, lotions et collyres. Lesdites formes unitaires sont dosées pour permettre une administration journalière de 0,01 à 20 mg de principe actif par kg de poids corporel, selon la forme galénique.The unit administration forms can be, for example, tablets, capsules, granules, powders, oral or injectable solutions or suspensions, transdermal patches ("patch"), suppositories. For topical administration, ointments, lotions and eye drops can be considered. Said unit forms are dosed to allow daily administration of 0.01 to 20 mg of active principle per kg of body weight, depending on the dosage form.
Pour préparer des comprimés on ajoute au principe actif, micronisé ou non, un véhicule pharmaceutique qui peut être composé de diluants, comme par exemple le lactose, la cellulose microcristalline, l'amidon, et des adjuvants de formulation comme des liants, (polyvinylpyrrolidone, hydroxypropylméthylcellulose, etc) , des agents d'écoulement comme la silice, des lubrifiants comme le stéarate de magnésium, l'acide stéaricque, le tribehenate de glycerol, le stéarylfumarate de sodium. Des agents mouillants ou tensioactifs tels que le laurylsulfate de sodium peuvent aussi être ajoutés. Les techniques de réalisation peuvent être la compression directe, la granulation sèche, la granulation humide ou la fusion à chaud. Les comprimés peuvent être nus, dragéifiés, par exemple par du saccharose, ou enrobés avec divers polymères ou autres matières appropriées. Il peuvent être conçus pour permettre une libération rapide, retardée ou prolongée du principe actif grâce à des matrices polymères ou à des polymères spécifiques utilisés dans l'enrobage.To prepare tablets, a pharmaceutical carrier is added to the active principle, micronized or not, which can be composed of diluents, such as, for example, lactose, microcrystalline cellulose, starch, and formulation adjuvants such as binders, (polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.), flow agents such as silica, lubricants such as magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate. Wetting agents or surfactants such as sodium lauryl sulfate can also be added. The production techniques can be direct compression, dry granulation, wet granulation or hot melting. The tablets can be plain, coated, for example with sucrose, or coated with various polymers or other suitable materials. They can be designed to allow rapid, delayed or prolonged release of the active ingredient using polymer matrices or polymers specific used in the coating.
Pour préparer des gélules on mélange le principe actif avec des véhicules pharmaceutiques secs (simple mélange, granulation sèche ou humide, ou fusion à chaud) , liquides ou semi-solides.To prepare capsules, the active ingredient is mixed with dry pharmaceutical vehicles (simple mixing, dry or wet granulation, or hot fusion), liquids or semi-solids.
Les gélules peuvent être dures ou molles, pelliculées ou non, de manière à avoir une activité rapide, prolongée ou retardée (par exemple pour une forme entérique) .The capsules can be hard or soft, film-coated or not, so as to have rapid, prolonged or delayed activity (for example for an enteric form).
Une composition sous forme de sirop ou d ' élixir ou pour l ' administration sous forme de gouttes peut contenir le principe actif conj ointement à un edulcorant, de préférence acalorique, du méthylparaben ou du propylparaben comme antiseptique, un agent de sapidité et un colorant .A composition in the form of a syrup or elixir or for administration in the form of drops may contain the active principle together with a sweetener, preferably calorie-free, methylparaben or propylparaben as an antiseptic, a flavoring agent and a coloring agent.
Les poudres et granules dispersibles dans de l ' eau peuvent contenir le principe actif en mélange avec des agents de dispersion ou des agents mouillants , ou des agents dispersants comme la polyvinylpyrrolidone, de même qu ' avec des edulcorant s et des agents correcteurs de goût . Pour l ' administration rectale, on recourt à des suppositoires préparés avec des liants fondant à la température rectale, par exemple du beurre de cacao ou des polyéthylèneglycols .The powders and granules dispersible in water can contain the active principle in mixture with dispersing agents or wetting agents, or dispersing agents such as polyvinylpyrrolidone, as well as with sweeteners and flavor correcting agents. Suppositories prepared with binders that melt at the rectal temperature, for example cocoa butter or polyethylene glycols, are used for rectal administration.
Pour une administration parentérale, on utilise des suspensions aqueuses , des solutions salines isotoniques ou des solutions stériles inj ectables contenant des agents de dispersion et/ou des mouillants pharmacologiquement compatibles, par exemple le propylèneglycol ou le butylène- glycol .For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol, are used.
Le principe actif peut être formulé également sous forme de microcapsules , éventuellement avec un ou plusieurs supports ou additifs, ou bien avec une matrice polymère ou avec une cyclodextrine (timbres transdermiques, formes à libération prolongée) .The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives, or with a polymer matrix or with a cyclodextrin (transdermal patches, extended release forms).
Les compositions topiques selon l'invention comprennent un milieu compatible avec la peau. Elles peuvent se présenter notamment sous forme de solutions aqueuses, alcooliques ou hydroalcooliques, de gels, d'émulsions eau-dans-huile ou huile-dans-eau ayant l'aspect d'une crème ou d'un gel, de microémulsions, d'aérosols, ou encore sous forme de dispersions vésiculaires contenant des lipides ioniques et/ou non ioniques. Ces formes galéniques sont préparées selon les méthodes usuelles des domaines considérés.The topical compositions according to the invention comprise a medium compatible with the skin. They may be in particular in the form of aqueous, alcoholic or hydroalcoholic solutions, gels, water-in-oil or oil-in-water emulsions having the appearance of a cream or gel, microemulsions, d aerosols, or in the form of vesicular dispersions containing ionic and / or nonionic lipids. These dosage forms are prepared according to the usual methods of the fields considered.
Enfin, les compositions pharmaceutiques selon l'invention peuvent contenir, à côté d'un composé de formule générale (I), d'autres principes actifs qui peuvent être utiles dans le traitement des troubles et maladies indiqués ci-dessus. Finally, the pharmaceutical compositions according to the invention may contain, alongside a compound of general formula (I), other active ingredients which may be useful in the treatment of the disorders and diseases indicated above.

Claims

Revendications . Composé répondant à la formule générale ( I )Claims. Compound corresponding to the general formula (I)
dans laquelle in which
Ri représente soit un atome d'hydrogène, soit un groupe (Cχ-C7) alkyle linéaire ou ramifié éventuellement substitué par un ou plusieurs atomes de fluor, soit un groupe (C3-C7) cycloalkyle, soit un groupe (C3-C7) cycloalkyl- (Cχ-C3) alkyle, soit un groupe phényl (Cι~C3) alkyle éventuellement substitué par un ou deux groupes méthoxy, soit un groupe (C2-C) alcényle, soit un groupe (C2-C4) alcynyle,Ri represents either a hydrogen atom, or a linear or branched (Cχ-C 7 ) alkyl group optionally substituted by one or more fluorine atoms, or a (C 3 -C 7 ) cycloalkyl group, or a (C 3) group -C 7 ) cycloalkyl- (Cχ-C 3 ) alkyl, either a phenyl group (Cι ~ C 3 ) alkyl optionally substituted by one or two methoxy groups, or a (C 2 -C) alkenyl group, or a group (C 2 -C 4 ) alkynyl,
X représente un- atome d' hydrogène ou un ou plusieurs substituants choisis parmi les atomes d' halogènes et les groupes trif luorométhyle, (C1-C4) alkyle et (C1-C4) alcoxy linéaires ou ramifiés ,X represents a hydrogen atom or one or more substituents chosen from halogen atoms and trifluoromethyl groups, (C 1 -C 4 ) alkyl and (C1-C4) linear or branched alkoxy,
R2 représente un groupe choisi parmi les les groupes naphtalényle, pyridinyle, pyrimidinyle, pyrazinyle, pyridazinyle, triazinyle, indanyle , indényle , quinoléinyle, is oquinoléinyle, quinazolinyle, quinoxalinyle, phtalazinyle, thiényle, furyle, pyrrolyle, imidazolyle, pyrazolyle , oxazolyle, thiazolyle, isoxazolyle, is othiazolyle , thiadiazolyle, oxadiazolyle, triazolyle, benzothiényle, benzofuryle , benzimidazolyle, benzothiazolyle, indolyle, isoindolyle, indazolyle, benzoxazolyle, benzisoxazolyle, benzotriazolyle, benzisothiazolyle , dihydroindolyle, pyrrolopyridinyle, fu ropyridinyle , thiénopyridinyle, imidazopyridinyle, oxazolopyridinyle , thiazolopyridinyle, pyrazolopyridinyle, is oxazolopyridinyle , isothiazolopyridinyle, tétrahydroquinoléinyle, tétrahydroisoquinoléinyle, et éventuellement sunstitué par un ou plusieurs substituants choisis parmi les atomes d'halogènes et les groupes (Cι-C4) alkyles, (C1-C4) alcoxy, thio (C1-C4) alkyles ou phényles éventuellement substitués par un ou plusieurs substituants choisis parmi les atomes d'halogènes et les groupes trifluorométhyle, (C1-C4) alkyles et (Cι-C ) alcoxy, à l'état de base libre ou de sel d'addition à un acide.R 2 represents a group chosen from the naphthalenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, quinolinyl, is oquinolineinyl, quinazolinyl, quinoxalinyl, phthalazinyl, thienyl, furyl, pyrrolyl, imolazylazyl groups , isoxazolyl, is othiazolyle, thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzothiazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzotriazolyl, benzisothiazolyl, dihydroindolyl, pyrrolopyridinyl, fu ropyridinyle, thienopyridinyl, imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl, pyrazolopyridinyle , is oxazolopyridinyle, isothiazolopyridinyle, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and optionally substituted with one or more substituents chosen from halogen atoms and (Cι-C 4 ) alkyl, (C 1 -C 4 ) alkoxy, thio (C1-C4) alkyl or optionally substituted phenyl groups by one or more substituents chosen from halogen atoms and trifluoromethyl groups, (C 1 -C 4 ) alkyls and (Cι-C) alkoxy, in the form of free base or of addition salt with an acid.
2. Médicament caractérisé ence qu'il consiste en un composé selon la revendications 1.2. Medicinal product characterized in that it consists of a compound according to claims 1.
3. Composition pharmaceutique, caractérisée en ce qu'elle comprend un composé selon la revendications 1, associé à un excipient.3. Pharmaceutical composition, characterized in that it comprises a compound according to claims 1, associated with an excipient.
4. Utilisation d'un composé selon la revendication 1 pour la préparation d' un médicament destiné au traitement des troubles comportementaux associés à la démence, des psychoses, des diverses formes d'anxiété, des attaques de panique, des phobies, des troubles obsessionnels compulsifs, des différentes formes de dépression, des troubles dus à l'abus ou au sevrage d'alcool, des troubles du comportement sexuel, des troubles de la prise de nourriture et de la migraine.4. Use of a compound according to claim 1 for the preparation of a medicament intended for the treatment of behavioral disorders associated with dementia, psychoses, various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders compulsive, various forms of depression, disorders due to the abuse or withdrawal of alcohol, disorders of sexual behavior, disorders of food intake and migraine.
5. Utilisation d'un composé selon la revendication 1 pour la préparation d'un médicament destiné au traitement des contractures, de la douleur, de la maladie de Parkinson et des symptômes parkinsoniens, des épilepsies, des formes mixtes et autres syndromes épileptiques en complément d'un autre traitement antiépileptique, ou en monothérapie, des apnées du sommeil, et pour la neuroprotection. 5. Use of a compound according to claim 1 for the preparation of a medicament intended for the treatment of contractures, pain, Parkinson's disease and parkinsonian symptoms, epilepsies, mixed forms and other epileptic syndromes in addition another antiepileptic treatment, or as monotherapy, sleep apnea, and for neuroprotection.
EP04791551A 2003-10-17 2004-10-15 Derivatives of n-[[phenyl(piperidine-2-yl)methyl]benzamide, preparation method thereof and applications of same in therapeutics Withdrawn EP1680402A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0312140A FR2861074B1 (en) 2003-10-17 2003-10-17 N- [PHENYL (PIPERIDIN-2-YL) METHYL] BENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
PCT/FR2004/002640 WO2005037792A1 (en) 2003-10-17 2004-10-15 Derivatives of n-``phenyl(piperidine-2-yl) methyl benzamide, preparation method thereof and applications of same in therapeutics

Publications (1)

Publication Number Publication Date
EP1680402A1 true EP1680402A1 (en) 2006-07-19

Family

ID=34385233

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04791551A Withdrawn EP1680402A1 (en) 2003-10-17 2004-10-15 Derivatives of n-[[phenyl(piperidine-2-yl)methyl]benzamide, preparation method thereof and applications of same in therapeutics

Country Status (18)

Country Link
US (2) US7750025B2 (en)
EP (1) EP1680402A1 (en)
JP (1) JP2007508358A (en)
KR (1) KR20060094079A (en)
CN (1) CN1882540A (en)
AU (1) AU2004281214B2 (en)
BR (1) BRPI0415504A (en)
CA (1) CA2542373A1 (en)
FR (1) FR2861074B1 (en)
IL (1) IL174942A (en)
MA (1) MA28101A1 (en)
ME (1) MEP12508A (en)
NO (1) NO20062105L (en)
NZ (1) NZ547164A (en)
RS (1) RS20060318A (en)
RU (1) RU2351588C2 (en)
WO (1) WO2005037792A1 (en)
ZA (1) ZA200603937B (en)

Families Citing this family (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2842804B1 (en) 2002-07-29 2004-09-03 Sanofi Synthelabo N- [PHENYL (PIPERIDIN-2-YL) METHYL] BENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
GB0600427D0 (en) * 2006-01-10 2006-02-15 Glaxo Group Ltd Compounds
KR20090117950A (en) 2007-03-08 2009-11-16 더 보드 오브 트러스티스 오브 더 리랜드 스탠포드 쥬니어 유니버시티 Mitochondrial aldehyde dehydrogenase-2 modulators and methods of use thereof
FR2917735B1 (en) * 2007-06-21 2009-09-04 Sanofi Aventis Sa NEW SUBSTITUTED INDAZOLES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
WO2009013535A1 (en) * 2007-07-23 2009-01-29 Astrazeneca Ab 2-azabicyclo(2.2.2)octane derivatives as modulators of the glycine transporter i receptor
US8420670B2 (en) 2007-08-22 2013-04-16 Abbott Laboratories 4-benzylaminoquinolines, pharmaceutical compositions containing them, and their use in therapy
CN103224487A (en) 2008-04-01 2013-07-31 雅培股份有限两合公司 Tetrahydroisoquinolines, pharmaceutical compositions containing them, and their use in therapy
WO2010028175A1 (en) 2008-09-08 2010-03-11 The Board Of Trustees Of The Leland Stanford Junior University Modulators of aldehyde dehydrogenase activity and methods of use thereof
KR20110082180A (en) * 2008-10-28 2011-07-18 더 보드 오브 트러스티스 오브 더 리랜드 스탠포드 쥬니어 유니버시티 Modulators of aldehyde dehydrogenase and methods of use thereof
WO2010086251A1 (en) * 2009-01-27 2010-08-05 F. Hoffmann-La Roche Ag Aroylamino - and heteroaroylamino-substituted piperidines as glyt-1 inhibitors
WO2010087761A1 (en) * 2009-01-28 2010-08-05 Astrazeneca Ab 2-aza-bicyclo[2.2.2]octane compounds and uses thereof
AR075442A1 (en) 2009-02-16 2011-03-30 Abbott Gmbh & Co Kg AMINOTETRALINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND THEIR USES IN THERAPY
TW201038569A (en) 2009-02-16 2010-11-01 Abbott Gmbh & Co Kg Heterocyclic compounds, pharmaceutical compositions containing them, and their use in therapy
TW201036980A (en) * 2009-03-16 2010-10-16 Sanofi Aventis N-[(2-azabicyclo[2.1.1]hex-1-yl)(aryl)methyl]heteroben zamide derivatives, their preparation and their therapeutic application
FR2944283B1 (en) * 2009-04-14 2011-05-06 Sanofi Aventis N- (2-AZA-BICYCLO) -2.1.1-HEX-1-YL) -ARYL-METHYL-HETEROBENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR2943056A1 (en) * 2009-03-16 2010-09-17 Sanofi Aventis New N-(2-aza-bicyclo(2.2.1)-hex-1-yl)-aryl-methyl-heterobenzamide derivatives are glycine transporter 1 inhibitors useful to treat e.g. dementia, psychosis, schizophrenia, anxiety, panic attacks, and obsessive compulsive disorder
JP5618047B2 (en) * 2010-01-29 2014-11-05 国立大学法人千葉大学 Positron tomography and positron emitting compounds
US9045459B2 (en) * 2010-08-13 2015-06-02 AbbVie Deutschland GmbH & Co. KG Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US8883839B2 (en) 2010-08-13 2014-11-11 Abbott Laboratories Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy
US8877794B2 (en) 2010-08-13 2014-11-04 Abbott Laboratories Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9051280B2 (en) 2010-08-13 2015-06-09 AbbVie Deutschland GmbH & Co. KG Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy
US8846743B2 (en) 2010-08-13 2014-09-30 Abbott Laboratories Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
US10457659B2 (en) 2011-04-29 2019-10-29 The Board Of Trustees Of The Leland Stanford Junior University Compositions and methods for increasing proliferation of adult salivary stem cells
US9309200B2 (en) 2011-05-12 2016-04-12 AbbVie Deutschland GmbH & Co. KG Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy
CA2844275A1 (en) 2011-08-05 2013-02-14 AbbVie Deutschland GmbH & Co. KG Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy
WO2013072520A1 (en) 2011-11-18 2013-05-23 AbbVie Deutschland GmbH & Co. KG N-substituted aminobenzocycloheptene, aminotetraline, aminoindane and phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
FR2983197B1 (en) * 2011-11-29 2014-07-25 Assist Publ Hopitaux De Paris USE OF PHACETOPERANE TO TREAT A DISORDER DEFICIT OF ATTENTION HYPERACTIVITY
US9365512B2 (en) 2012-02-13 2016-06-14 AbbVie Deutschland GmbH & Co. KG Isoindoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US9670162B2 (en) 2013-03-14 2017-06-06 The Board Of Trustees Of The Leland Stanford Junio Mitochondrial aldehyde dehyrogenase-2 modulators and methods of use thereof
US9650334B2 (en) 2013-03-15 2017-05-16 Abbvie Inc. Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9656955B2 (en) 2013-03-15 2017-05-23 Abbvie Inc. Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy
AU2014336154A1 (en) 2013-10-17 2016-04-28 AbbVie Deutschland GmbH & Co. KG Aminotetraline and aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
CN105992764A (en) 2013-10-17 2016-10-05 艾伯维德国有限责任两合公司 Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US9550754B2 (en) 2014-09-11 2017-01-24 AbbVie Deutschland GmbH & Co. KG 4,5-dihydropyrazole derivatives, pharmaceutical compositions containing them, and their use in therapy
RU2680526C1 (en) * 2016-07-05 2019-02-22 Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" (Томский НИМЦ) Neuroprotective means, having the properties of antioxidant and nitric oxide donator
WO2018232264A1 (en) * 2017-06-15 2018-12-20 The Board Of Regents Of The University Of Oklahoma Benzamide derivatives for inhibiting endoplasmic reticulum (er) stress

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2928835A (en) 1959-02-19 1960-03-15 Rhone Poulenc Sa New esters
US3336300A (en) 1965-04-13 1967-08-15 American Home Prod 1, 2, 3, 4-tetrahydro-5h-benzodiazepin-5-ones
JPH02262562A (en) 1988-10-20 1990-10-25 Ishihara Sangyo Kaisha Ltd Imidazole compound
JP2765876B2 (en) 1988-10-24 1998-06-18 科研製薬株式会社 Pyridyl ketoxime ether derivatives
US5254569A (en) * 1991-01-14 1993-10-19 The Du Pont Merck Pharmaceutical Company (Amidomethyl)nitrogen heterocyclic analgesics
JP3026845B2 (en) * 1991-02-20 2000-03-27 日清製粉株式会社 Piperidine derivative
FR2838739B1 (en) * 2002-04-19 2004-05-28 Sanofi Synthelabo N- [PHENYL (PIPERIDIN-2-YL) METHYL) BENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
FR2842804B1 (en) * 2002-07-29 2004-09-03 Sanofi Synthelabo N- [PHENYL (PIPERIDIN-2-YL) METHYL] BENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
FR2861076B1 (en) 2003-10-17 2006-01-06 Sanofi Synthelabo N-HETEROCYCLYMETHYLBENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR2861071B1 (en) 2003-10-17 2006-01-06 Sanofi Synthelabo N- [PHENYL (ALKYLPIPERIDIN-2-YL) METHYL] BENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR2861073B1 (en) * 2003-10-17 2006-01-06 Sanofi Synthelabo N- [HETEROARYL (PIPERIDIN-2-YL) METHYL] BENZAMIDE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF
FR2861070B1 (en) 2003-10-17 2006-01-06 Sanofi Synthelabo DERIVATIVES OF N- [PHENYL (PYRROLIDIN-2-YL) METHYL] BENZAMIDE AND N - [(AZEPAN-2-YL) PHENYLMETHYL] BENZAMIDE, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR2906251B1 (en) * 2006-09-22 2008-11-07 Sanofi Aventis Sa PYRROLIZINE, INDOLIZINE AND QUINOLIZINE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005037792A1 *

Also Published As

Publication number Publication date
MEP12508A (en) 2010-06-10
BRPI0415504A (en) 2006-12-12
JP2007508358A (en) 2007-04-05
AU2004281214A1 (en) 2005-04-28
RU2006116885A (en) 2007-11-27
IL174942A0 (en) 2006-08-20
FR2861074B1 (en) 2006-04-07
KR20060094079A (en) 2006-08-28
MA28101A1 (en) 2006-08-01
WO2005037792A1 (en) 2005-04-28
IL174942A (en) 2011-03-31
US20060223885A1 (en) 2006-10-05
FR2861074A1 (en) 2005-04-22
NZ547164A (en) 2009-11-27
NO20062105L (en) 2006-05-10
US7750025B2 (en) 2010-07-06
ZA200603937B (en) 2009-01-28
RU2351588C2 (en) 2009-04-10
CA2542373A1 (en) 2005-04-28
RS20060318A (en) 2008-11-28
AU2004281214B2 (en) 2010-07-08
CN1882540A (en) 2006-12-20
US20100234424A1 (en) 2010-09-16

Similar Documents

Publication Publication Date Title
EP1680402A1 (en) Derivatives of n-[[phenyl(piperidine-2-yl)methyl]benzamide, preparation method thereof and applications of same in therapeutics
EP1499589B1 (en) Derivatives of n-phenyl(piperidin-2-yl)methyl benzamide, the preparation method thereof and application of same in therapeutics
EP1527048B1 (en) N-[phenyl(piperidin-2-yl)methyl]benzamide derivatives, preparation thereof, and use thereof in therapy
EP1680418B1 (en) Derivatives of n-[heteroaryl(piperidine-2-yl)methyl]benzamide, preparation method thereof and application of same in therapeutics
EP1680400B1 (en) Derivatives of n-[ phenyl(pyrrolidine-2-yl)methyl]benzamide and n-[ (azepan-2-yl)phenylmethyl]benzamide, preparation method thereof and application of same in therapeutics
EP1682503B1 (en) Derivatives of n-[phenyl(alkylpiperidine-2-yl)methyl]benzamide, preparation method thereof and application of same in therapeutics
WO2004013100A2 (en) N-[phenyl(piperidin-2-yl)methyl]benzamide derivatives, preparation thereof, and use thereof in therapy
WO2008037881A2 (en) Derivatives of pyrrolizine, indolizine and quinolizine, preparation thereof and therapeutic use thereof
EP0520882B1 (en) 2-Aminopyrimidin-4-carboxamide derivatives, their preparation and their application in therapy
EP0522914A1 (en) 2-Piperidinylpyrimidin-4-carboxamide derivatives, their preparation and their application in therapy
CA2758367A1 (en) Derivatives of n-[(7-aza-bicyclo[2.2.1]hept-1-yl)-aryl-methyl]-benzamide, preparation thereof, and therapeutic use thereof
MXPA06004268A (en) Derivatives of n-``phenyl(piperidine-2-yl) methyl benzamide, preparation method thereof and applications of same in therapeutics
EP2396334A1 (en) N-[(2-azabicyclo[2.1.1]hex-1-yl]-aryl-methyl]-benzamide derivatives, preparation thereof, and therapeutic use thereof
EP2396335A1 (en) N-[(6-azabicyclo[3.2.1]oct-1-yl)-aryl-methyl]-benzamide derivatives, preparation thereof, and therapeutic use thereof

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20060517

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL HR LT LV MK

17Q First examination report despatched

Effective date: 20090126

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: SANOFI

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: SANOFI

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: SANOFI

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20120411