WO2010106269A2 - Derivatives of n-[(2-aza-bicyclo[2.1.1]hex-1-yl)-aryl-methyl]-heterobenzamide, preparation thereof and application of same in therapeutics - Google Patents

Derivatives of n-[(2-aza-bicyclo[2.1.1]hex-1-yl)-aryl-methyl]-heterobenzamide, preparation thereof and application of same in therapeutics Download PDF

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WO2010106269A2
WO2010106269A2 PCT/FR2010/050447 FR2010050447W WO2010106269A2 WO 2010106269 A2 WO2010106269 A2 WO 2010106269A2 FR 2010050447 W FR2010050447 W FR 2010050447W WO 2010106269 A2 WO2010106269 A2 WO 2010106269A2
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hex
alkyl
phenyl
compound
methyl
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PCT/FR2010/050447
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French (fr)
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WO2010106269A3 (en
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Geneviève ESTENNE-BOUHTOU
Abdel-Kader Mafroud
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Sanofi-Aventis
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Priority claimed from FR0901219A external-priority patent/FR2943056A1/en
Priority claimed from FR0901810A external-priority patent/FR2944283B1/en
Priority to BRPI1009496A priority Critical patent/BRPI1009496A2/en
Priority to CN2010800121453A priority patent/CN102356074A/en
Priority to MX2011009677A priority patent/MX2011009677A/en
Priority to JP2012500292A priority patent/JP2012520345A/en
Application filed by Sanofi-Aventis filed Critical Sanofi-Aventis
Priority to CA2755526A priority patent/CA2755526A1/en
Priority to RU2011141778/04A priority patent/RU2011141778A/en
Priority to EP10715932A priority patent/EP2408763A2/en
Priority to AU2010224720A priority patent/AU2010224720A1/en
Priority to SG2011066867A priority patent/SG174434A1/en
Publication of WO2010106269A2 publication Critical patent/WO2010106269A2/en
Publication of WO2010106269A3 publication Critical patent/WO2010106269A3/en
Priority to IL215104A priority patent/IL215104A0/en

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • 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
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Definitions

  • the present invention relates to ⁇ / - [(2-aza-bicyclo [2.2.1] hex-1-yl) -aryl-methyl] -heterobenzamide derivatives, to their preparation and their therapeutic application in the treatment of or the prevention of diseases involving glycine carriers Glyti.
  • R represents a hydrogen atom or a group chosen from (d-C 6 ) alkyl, (C 3 -C 7 ) -cycloalkyl, benzyl or allyl groups, optionally substituted by one or more groups chosen independently one of the other from halogen atoms, (C 3 -C 7 ) -cycloalkyl, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, hydroxy;
  • R 1 represents a phenyl or naphthyl group, optionally substituted with one or more substituents chosen independently of one another from halogen atoms, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, (CrC 6) alkyl, hydroxy, halo (C 1 -C 6) alkoxy, (C r C 6) alkyl-thio, (C r C 6) alkyl-SO, (C r C 6) alkyl-SO 2;
  • Het represents a heteroaryl group
  • R 2 represents one or more substituents selected from hydrogen, halogen atoms, halo groups (CrC 6) alkyl, (Ci-C 6) alkyl, (C 3 -C 7) cycloalkyl,
  • the compounds of formula (I) have an asymmetric carbon atom. They can therefore exist in the form of enantiomers. These enantiomers including racemic mixtures are part of the invention.
  • the compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
  • salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example for the purification or the isolation of the compounds of formula (I), also form part of the invention.
  • heteroaryl group a 5 or 10 membered mono or bicyclic heteroaromatic group comprising from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulfur.
  • a heteroaryl group mention may be made of pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine and triazine groups.
  • a first group of compounds consists of the compounds for which:
  • R represents a hydrogen atom, a benzyl group or an allyl group; R1, Het and R2 being as defined above, in the form of a base or an acid addition salt.
  • a second group of compounds consists of compounds for which:
  • R 1 represents a phenyl or naphthyl group, optionally substituted with one or more groups chosen independently of one another from halogen atoms, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) groups; BlCOXy, halo- (C 1 -C 6 ) alkyl;
  • R, Het and R2 being as defined above, in the form of a base or an addition salt with an acid.
  • a third group of compounds consists of the compounds for which: Het represents an indole, thiophene or pyridine group; R 1, R 1 and R 2 being as defined above, in the form of a base or an addition salt with an acid.
  • a fourth group of compounds consists of the compounds for which:
  • R 2 represents one or more substituents selected from hydrogen, halogen atoms, halo groups (Ci-C 6) alkyl, benzyl, (Ci-C 6) alkyl- thio;
  • R, R 1 and Het being as defined above, in the form of a base or an addition salt with an acid.
  • a fifth group of compounds is constituted by the compounds for which:
  • R represents a hydrogen atom, a benzyl group or an allyl group
  • R 1 represents a phenyl or naphthyl group, optionally substituted with one or more substituents chosen independently of one another from halogen atoms, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen (Ci -C 6 ) alkyl,
  • Het represents an indole, thiophene or pyridine group
  • R 2 represents one or more substituents chosen from a hydrogen atom, halogen atoms, halo- (C 1 -C 6 ) alkyl, benzyl, (C 1 -C 6 ) alkyl-thio groups; in the form of a base or an acid addition salt.
  • a sixth group of compounds is constituted by compounds for which: R represents a hydrogen atom, a benzyl group or an allyl group;
  • R 1 represents a phenyl or naphthyl group, optionally substituted by one or more substituents chosen independently of one another from the fluorine atom, the methyl, methoxy or trifluoromethyl groups;
  • Het represents an indole, thiophene or pyridine group; - R 2 represents one or more substituents chosen from a hydrogen atom, bromine or chlorine atoms, trifluoromethyl, methylethio or benzyl groups, in the form of a base or addition salt with an acid.
  • the compounds of the invention exhibit particular activity as inhibitors of Glyti glycine transporters, including an improved activity and safety profile.
  • the compounds of general formula (I) in which R is different from the hydrogen atom may also be prepared from compounds of general formula (I) in which R represents a hydrogen atom, or by alkylation of said compound of general formula (I) with an RX-type halide or mesylate, wherein R is as defined above and X is mesylate or halogen, in the presence of a mineral base, for example potassium carbonate in acetonitrile; either by an Eschweiler-Clarke type reaction or a reductive amination with an appropriate aldehyde or ketone according to the methods known to those skilled in the art; or with an appropriate epoxy derivative, according to the methods known to those skilled in the art.
  • a mineral base for example potassium carbonate in acetonitrile
  • the compounds of general formula (I) in which the group R 1 is a phenyl group substituted by a hydroxyl may be obtained from the corresponding compound of general formula (I) substituted by a methoxy, using the methods known to man of the job.
  • the diamine of general formula (II) can be prepared by processes illustrated by Schemes 2 for the amine (IIa) and 3 for the amine (Nb) and (IIc) which follow:
  • the ester (IV) is converted to the amide (V) by heating the trimethylaluminum complex and the appropriate amine, such as morpholine, under the reflux of a solvent such as toluene.
  • the amine (V) may be deprotected using a phenyllithium-type lithian in a solvent such as tetrahydrofuran at low temperature, for example at -70 ° C.
  • the ⁇ -allylation is then carried out by means of bromide. allyl in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile at room temperature, to obtain the compound (VII).
  • the morpholinic amide of formula (VII) is reacted with the lithiated aromatic compound of general formula (VIII), in which R 1 is as defined above, in an ethereal solvent such as ether or tetrahydrofuran, at low temperature. temperature.
  • a ketone of general formula (IX) is thus obtained which is reacted with the hydrochloride of O benzylhydroxylamine, at reflux of pyridine, to obtain a mixture of oxime Z / E of general formula (X).
  • the oxime (X) is then reduced at reflux of the ether by the lithium aluminum hydride double, to provide the diamine of general formula (IIa).
  • the chiral compounds of general formula (I) corresponding to the S or R enantiomers can be obtained by separation of the racemic compounds by high performance liquid chromatography (HPLC) on a chiral column, or could be obtained by resolution of the racemic amine of general formula (II) using a chiral acid, such as dibenzoyl-tartaric acid or by fractional and preferential recrystallization of a diastereoisomeric salt.
  • HPLC high performance liquid chromatography
  • the ester of formula (IV) is prepared according to a method described in J. Org. Chem.
  • nitrile of formula (XI) is prepared according to a method described in Tetrahedron:
  • the lithiated derivatives of general formula (VIII) can be prepared according to methods known to those skilled in the art. Acids and acid chlorides of general formula (III) are commercially available or prepared by analogy with methods known to those skilled in the art.
  • the hyphen "-" is part of the word, and the hyphen “_” is only used for the cut at the end of the line; it must be deleted in the absence of a cut, and must not be replaced by a normal dash or a space.
  • Example 1 (Compound No. 1): ⁇ - [(2-Allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene 2-carboxamide.
  • EXAMPLE 2 (Compound No. 2): ⁇ -R (2-Aza-bicyclo [2.2.1] hex-1-yl] -phenyl-methyl-4- (4,5-dibromo) -thiophene-2-carboxamide.
  • Example 4 (Compound No. 4): (+) - ⁇ / - [(2-Azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) hydrochloride thiophene-2-carboxamide (1: 1).
  • This compound is obtained according to the method described in Example 2, starting from the compound No. 17 described in Example 3, after salification in hydrochloride form by solubilization of the base in ether, addition of an excess of 1 N hydrochloric acid in ether and then concentration under reduced pressure.
  • Example 5 (Compound No. 18): (-) - ⁇ / - [(2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenylmethyl] - (4,5-dibromo) ) -thiophene-2-carboxamide.
  • the compound is obtained by preparative HPLC separation of ⁇ / - [(2-allyl-2-azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene -2-carboxamide (compound No. 1) by using a Chiralpak ® AD 20 .mu.m and as solvent acetonitrile / propan-2-ol 80:20.
  • 1 H NMR 400 MHz, DMSO-d 6) ⁇ ppm 8.65 (m, 1H), 8.15 (s, 1H), 7.4-7.2 (m, 5H),
  • Example 6 (Compound No. 5): (-) - ⁇ / - [(2-Azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) hydrochloride thiophene-2-carboxamide (1: 1).
  • This compound is obtained according to the method described in Example 2, starting from the compound No. 18 described according to Example 5, after salification in hydrochloride form by solubilization of the base in ether, addition of an excess of 1 N hydrochloric acid in ether and then concentration under reduced pressure.
  • Example 7 N- (2-Aza-bicyclohexyl) -1-hex-1-yl) -phenyl-methyl- (2-methylsulfanyl) -nicotinamide.
  • the medium is acidified with a 1N hydrochloric acid solution, and then the ether phase is extracted.
  • aqueous phase is basified with ammonia and then reextracted twice with 100 ml of dichloromethane.
  • the organic phases are combined, then dried over sodium sulphate, filtered and evaporated under reduced pressure. There is thus obtained 4.15 g of (2-benzyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methylamine (Nb) in the form of an oil which crystallizes in the cold.
  • An analytical sample is obtained in hydrochloride form by solubilization of the base in ether, addition of an excess of 1N hydrochloric acid in ether and concentration under reduced pressure.
  • An analytical sample is obtained in hydrochloride form by solubilization of the base in ether, addition of an excess of 1N hydrochloric acid in ether, and concentration under reduced pressure.
  • the reaction medium is then diluted with 10 ml of dichloromethane and then washed successively with water (5 ml), with 1N sodium hydroxide solution (5 ml) and with saturated sodium chloride solution (5 ml).
  • the organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure.
  • the residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and ammoniacal methanol. 63 mg of ⁇ - [(2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (2-methylsulfanyl) -nicotinamide are thus obtained in the form of a powder.
  • Table 2 gives the physical properties, melting points and rotational potency of the compounds of Table 1;
  • the column [ ⁇ D ] 2 o ° c gives the result of analysis of the rotatory power of the compounds of the table at the wavelength of 589 nM and at the temperature of
  • the compounds of the invention have been subjected to a series of pharmacological tests which have demonstrated their interest as substances with therapeutic activities. Study of glycine transport in SK-N-MC cells expressing the native human qlyti transporter.
  • [ 14 C] glycine uptake is studied in SK-N-MC (human neuroepithelial cells) cells expressing the native human glyti transporter by measuring the radioactivity incorporated in the presence or absence of the test compound.
  • the cells are cultured in monolayer for 48 h in 0.02% fibronectin pretreated plates. On the day of the experiment, the culture medium is removed and the cells are washed with Krebs-HEPES buffer ([4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid) at pH 7.4. After 10 minutes of preincubation at 37 ° C.
  • Krebs-HEPES buffer [4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid
  • the compounds of the invention in this test, have a Cl 5 o of the order of 0.01 to 10 ⁇ M.
  • Table 3 shows some examples of Cl 50 results for compounds according to the invention.
  • the compounds of the invention can be used for the treatment of cognitive and / or behavioral disorders associated with neurodegenerative diseases, dementia; for the treatment of psychoses, in particular schizophrenia (deficient form and productive form), acute or chronic extrapyramidal symptoms induced by neuroleptics; for the treatment of various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders; for the treatment of various forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or withdrawal, sexual behavior disorders, eating disorders, migraine; pain ; sleep disorders.
  • the compounds according to the invention can therefore be used for the preparation of medicaments, in particular inhibitory drugs of the glycine glycine transporter.
  • the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid.
  • the present invention also relates to pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the form of a base or of a pharmaceutically acceptable salt, and in a mixture, where appropriate, with suitable excipients.
  • Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.
  • compositions according to the invention can thus be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal, intraocular administration.
  • the unit dosage forms may be, for example, tablets, capsules, granules, powders, oral solutions or suspensions or injectables, transdermal patches, suppositories.
  • topical administration it is possible to envisage ointments, lotions and eye drops.
  • Said unit forms are dosed to allow a daily administration of 0.01 to 20 mg of active ingredient per kg of body weight, according to the dosage form.
  • a pharmaceutical carrier which may be composed of diluents, for example lactose, microcrystalline cellulose, starch, and formulation adjuvants such as binders (polyvinylpyrrolidone), is added to the active ingredient, whether micronized or not; , hydroxypropyl methylcellulose, etc.), flow agents such as silica, lubricants such as magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate. Wetting agents or surfactants such as sodium lauryl sulphate may also be added.
  • the production techniques can be direct compression, dry granulation, wet granulation or hot melt.
  • the tablets may be bare, sugar-coated, for example with sucrose, or coated with various polymers or other suitable materials. They can be designed to allow rapid, delayed or prolonged release of the active ingredient through polymer matrices or specific polymers used in the coating.
  • the active ingredient is mixed with dry pharmaceutical vehicles (simple mixing, dry or wet granulation, or hot melting), liquid or semi-solid.
  • dry pharmaceutical vehicles simple mixing, dry or wet granulation, or hot melting
  • liquid or semi-solid may be hard or soft, film-coated or not, so as to have a rapid, prolonged or delayed activity (for example for an enteric form).
  • a composition in the form of syrup or elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably acaloric, methylparaben or propylparaben as antiseptic, a flavoring agent and a dye.
  • a sweetener preferably acaloric, methylparaben or propylparaben as antiseptic, a flavoring agent and a dye.
  • Water-dispersible powders and granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or dispersing agents such as polyvinylpyrrolidone, as well as with sweeteners and taste-correcting agents.
  • dispersing agents or wetting agents or dispersing agents such as polyvinylpyrrolidone
  • sweeteners and taste-correcting agents for rectal administration, suppositories prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols, are used.
  • aqueous suspensions For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol, are used.
  • pharmacologically compatible dispersing agents and / or wetting agents for example propylene glycol or butylene glycol
  • the active ingredient may also be formulated in the form of microcapsules, optionally with one or more supports or additives, or with a polymer matrix or with a cyclodextrin (transdermal patches, sustained-release forms).
  • the topical compositions according to the invention comprise a medium compatible with the skin. They may be in particular in the form of aqueous solutions, alcoholic or aqueous-alcoholic, gels, water-in-oil or oil-in-water emulsions having the appearance of a cream or a gel, microemulsions, aerosols, or in the form of vesicular dispersions containing ionic and / or nonionic lipids. These galenic forms are prepared according to the usual methods of the fields considered.
  • a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
  • the dose of active ingredient administered per day can reach 0.1 to 20 mg / kg, in one or more doses.
  • the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
  • the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of pharmaceutically acceptable salts thereof.

Abstract

The invention relates to compounds of general formula (I) wherein R is a hydrogen atom or a group selected from the groups (C1-C6) aIkyI, (C3-C7) cycloalkyl, benzyl or allyl optionally substituted by at least one group selected independently from each other from the halogen atoms, the groups (C3-C7) cycloalkyl, (C1-C6) alkyl, (C1-C6) BlCOXy, hydroxy; R1 is a phenyl or naphtyl group, optionally substituted by at least one substitutent selected independently from each other from the halogen atoms, the groups (CrC6) alkyl, (C1-C6) BlCOXy, halo-(C1-C6) alkyl, hydroxy, halo-(C1C6) alcoxy, (C1-C6) alkyl-thio, (C1-C6)alkyl-SO, (C1C6) alkyl-SO2; Het is a heteroaryl group; and R2 is at least one substituent selected from the hydrogen atom, the halogen atoms, the groups halo-(d-C6) alkyl, (C1C6) alkyl, (C3-C7) cycloalkyl, (C3-C7)-cycloalkyl-(C1-C3) alkyl, (C1- C6) alcoxy, benzyl, (C1C6) alkyl-thio, (C1C6) alkyl-SO, (C1C6) alkyl-SO2; in the base state or as addition salts for acids. The invention also relates to the use of said compounds in therapeutics and synthesis methods.

Description

DERIVES DE Λ/-[(2-AZA-BICYCLO[2.1. "I]HEX-I -YL)-ARYL-METHYL]- Λ / - [(2-AZA-BICYCLO [2.1. "I] HEX-I-YL) -ARYL-METHYL DERIVATIVES -
HETEROBENZAMIDE, LEUR PREPARATION ET LEUR APPLICATION ENHETEROBENZAMIDE, THEIR PREPARATION AND THEIR APPLICATION
THERAPEUTIQUE.THERAPEUTIC.
La présente invention se rapporte à des dérivés de Λ/-[(2-aza-bicyclo[2.2.1]hex-1-yl)- aryl-méthyl]-hétérobenzamide, à leur préparation et leur application en thérapeutique, dans le traitement ou la prévention de maladies impliquant les transporteurs de la glycine Glyti .The present invention relates to Λ / - [(2-aza-bicyclo [2.2.1] hex-1-yl) -aryl-methyl] -heterobenzamide derivatives, to their preparation and their therapeutic application in the treatment of or the prevention of diseases involving glycine carriers Glyti.
Les composés de l'invention répondent à la formule générale (I)The compounds of the invention correspond to the general formula (I)
Figure imgf000003_0001
Figure imgf000003_0001
dans laquelle : - R représente un atome d'hydrogène ou un groupe choisi parmi les groupes (d- C6)alkyle, (C3-C7)-cycloalkyle, benzyle ou allyle, éventuellement substitué par un ou plusieurs groupes choisis indépendamment l'un de l'autre parmi les atomes d'halogène, les groupes (C3-C7)-cycloalkyle, (Ci-C6)alkyle, (Ci-C6)alcoxy, hydroxy ;in which: R represents a hydrogen atom or a group chosen from (d-C 6 ) alkyl, (C 3 -C 7 ) -cycloalkyl, benzyl or allyl groups, optionally substituted by one or more groups chosen independently one of the other from halogen atoms, (C 3 -C 7 ) -cycloalkyl, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, hydroxy;
- Ri représente un groupe phényle ou naphtyle, éventuellement substitué par un ou plusieurs substituants choisis indépendamment l'un de l'autre parmi les atomes d'halogène, les groupes (CrC6)alkyle, (Ci-C6)alcoxy, halo-(CrC6)alkyle, hydroxy, halo-(C1-C6)alcoxy, (CrC6)alkyle-thio, (CrC6)alkyle-SO, (CrC6)alkyle-SO2 ;R 1 represents a phenyl or naphthyl group, optionally substituted with one or more substituents chosen independently of one another from halogen atoms, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, (CrC 6) alkyl, hydroxy, halo (C 1 -C 6) alkoxy, (C r C 6) alkyl-thio, (C r C 6) alkyl-SO, (C r C 6) alkyl-SO 2;
- Het représente un groupe hétéroaryle ;Het represents a heteroaryl group;
- R2 représente un ou plusieurs substituants choisis parmi l'atome d'hydrogène, les atomes d'halogène, les groupes halo-(CrC6)alkyle, (Ci-C6)alkyle, (C3-C7)cycloalkyle,- R 2 represents one or more substituents selected from hydrogen, halogen atoms, halo groups (CrC 6) alkyl, (Ci-C 6) alkyl, (C 3 -C 7) cycloalkyl,
(C3-C7)-cycloalkyl-(Ci-C3)alkyle, (CrC6)alcoxy, benzyle, (CrC6)alkyle-thio, (Cr (C 3 -C 7 ) -cycloalkyl- (C 1 -C 3 ) alkyl, (C 1 -C 6 ) alkoxy, benzyl, (C 1 -C 6 ) alkyl-thio, (C r
C6)alkyle-SO, (CrC6)alkyle-SO2; à l'état de base ou de sel d'addition à un acide.C 6) alkyl-SO, (C r C 6) alkyl-SO 2; in the form of a base or an acid addition salt.
Les composés de formule (I) comportent un atome de carbone asymétrique. Ils peuvent donc exister sous forme d'énantiomères. Ces énantiomères y compris les mélanges racémiques, font partie de l'invention.The compounds of formula (I) have an asymmetric carbon atom. They can therefore exist in the form of enantiomers. These enantiomers including racemic mixtures are part of the invention.
Les composés de formule (I) peuvent exister à l'état de bases ou de sels d'addition à des acides. De tels sels d'addition font partie de l'invention.The compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
Ces sels sont avantageusement préparés avec des acides pharmaceutiquement acceptables, mais les sels d'autres acides utiles, par exemple pour la purification ou l'isolement des composés de formule (I), font également partie de l'invention.These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example for the purification or the isolation of the compounds of formula (I), also form part of the invention.
Dans le cadre de l'invention, on entend par :In the context of the invention, the following terms mean:
Ct-Cz où t et z peuvent prendre les valeurs de 1 à 6, une chaîne carbonée pouvant avoir de t à z atomes de carbone, par exemple Ci-C6 une chaîne carbonée qui peut avoir de 1 à 6 atomes de carbone ; alkyle, un groupe aliphatique saturé, linéaire ou ramifié ; par exemple un groupe Ci-C6-alkyle représente une chaîne carbonée de 1 à 6 atomes de carbone, linéaire ou ramifiée, par exemple un méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, te/f-butyle, pentyle, hexyle; alcoxy, un groupe -O-alkyle ; hydroxy, un groupe -OH, - un allyle, un groupe -(CH2)-CH=CH2 alkyle-thio, un atome de soufre substitué par un groupe alkyle ; atome d'halogène, un fluor, un chlore, un brome ou un iode ; halo-alkyle, un groupe alkyle dont un ou plusieurs atomes d'hydrogène ont été substitués par un halogène. A titre d'exemple, on peut citer les groupes trifluorométhyle, trifluoroéthyle, pentafluoroéthyle ; Ct-Cz, where t and z can take the values from 1 to 6, a carbon chain which can have from t to z carbon atoms, for example Ci--C 6 carbon chain which can have from 1 to 6 carbon atoms; alkyl, a saturated, linear or branched aliphatic group; for example a Ci-C 6 -alkyl group represents a carbon chain of 1 to 6 carbon atoms, linear or branched, for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl ; alkoxy, a -O-alkyl group; hydroxy, a -OH group, an allyl, a - (CH 2 ) -CH = CH 2 alkyl-thio group, an alkyl substituted sulfur atom; halogen atom, fluorine, chlorine, bromine or iodine; halo-alkyl, an alkyl group of which one or more hydrogen atoms have been substituted by a halogen. By way of example, mention may be made of trifluoromethyl, trifluoroethyl and pentafluoroethyl groups;
- groupe hétéroaryle, un groupe hétéroaromatique mono ou bicyclique à 5 ou 10 chaînons comprenant de 1 à 3 hétéroatomes choisis parmi l'azote, l'oxygène et le soufre. A titre d'exemple de groupe hétéroaryle, on peut citer les groupes pyrrole, furane, thiophène, pyrazole, imidazole, triazole, tétrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine, indole, isoindole, benzimidazole, indazole, indolizine, benzofuran, isobenzofuran, benzothiophène, benzo[c]thiophène, pyrrolopyridine, imidazopyridine, pyrazolopyridine, triazolopyridine, tétrazolopyridine, pyrrolopyrimidine, imidazopyrimidine, pyrazolopyrimidine, triazolopyrimidine, tétrazolopyrimidine, pyrrolopyrazine, imidazopyrazine, pyrazolopyrazine, triazolopyrazine, tétrazolopyrazine, pyrrolopyridazine, imidazopyridazine, pyrazolopyridazine, triazolopyridazine, tétrazolopyridazine, pyrrolotriazine, imidazotriazine, pyrazolotriazine, triazolotriazine, tétrazolotriazine, furopyridine, furopyrimidine, furopyrazine, furopyridazine, furotriazine, oxazolopyridine, oxazolopyrimidine, oxazolopyrazine, oxazolopyridazine, oxazolotriazine, isoxazolopyridine, isoxazolopyrimidine, isoxazolopyrazine, isoxazolopyridazine, isoxazolotriazine, oxadiazolopyridine, oxadiazolopyrimidine, oxadiazolopyrazine, oxadiazolopyridazine, oxadiazolotriazine, benzoxazole, benzisoxazole, benzoxadiazole, thiénopyridine, thiénopyrimidine, thiénopyrazine, thiénopyridazine, thiénotriazine, thiazolopyridine, thiazolopyrimidine, thiazolopyrazine, thiazolopyridazine, thiazolotriazine, isothiazolopyridine, isothiazolopyrimidine, isothiazolopyrazine, isothiazolopyridazine, isothiazolotriazine, thiadiazolopyridine, thiadiazolopyrimidine, thiadiazolopyrazine, thiadiazolopyridazine, thiadiazolotriazine, benzothiazole, benzoisothiazole, benzothiadiazole, quinoline, isoquinoline, cinnoline, phthalazine, quinoxaline, quinazoline, naphthyridine, benzotriazine, pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyridotriazine, pyrimidopyrimidine, pyrimidopyrazine, pyrimidopyridazine, pyrimidotriazine, pyrazinopyrazine, pyrazinopyridazine, pyrazinotriazine, pyridazinopyridazine, pyridazinotriazine.heteroaryl group, a 5 or 10 membered mono or bicyclic heteroaromatic group comprising from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulfur. By way of example of a heteroaryl group, mention may be made of pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine and triazine groups. indole, isoindole, benzimidazole, indazole, indolizine, benzofuran, isobenzofuran, benzothiophene, benzo [c] thiophene, pyrrolopyridine, imidazopyridine, pyrazolopyridine, triazolopyridine, tétrazolopyridine, pyrrolopyrimidine, imidazopyrimidine, pyrazolopyrimidine, triazolopyrimidine, tétrazolopyrimidine, pyrrolopyrazine, imidazopyrazine, pyrazolopyrazine, triazolopyrazine, tetrazolopyrazine, pyrrolopyridazine, imidazopyridazine, pyrazolopyridazine, triazolopyridazine, tétrazolopyridazine, pyrrolotriazine, imidazotriazine, pyrazolotriazine, triazolotriazine, tétrazolotriazine, furopyridine, furopyrimidine, furopyrazine, furopyridazine, furotriazine, oxazolopyridine, oxazolopyrimidine, oxazolopyrazine, oxazolopyridazine, oxazolotriazine, isoxazolopyridine, isoxazolopyrimidine, isoxazolopyrazine, isoxazolopyridazine, isoxazolotriazine, oxadiazolopyridine, oxadiazolopyrimidine, oxadiazolopyrazine, oxadiazolopyridazine, oxadiazolotriazine, benzoxazole, benzisoxazole, benzoxadiazole, thienopyridine, thienopyrimidine, thiénopyrazine, thiénopyridazine, thiénotriazine, thiazolopyridine, thiazolopyrimidine, thiazolopyrazine, thiazolopyridazine, thiazolotriazine, isothiazolopyridine, isothiazolopyrimidine, isothiazolopyrazine, isothiazolopyridazine, isothiazolotriazine, thiadiazolopyridine, thiadiazolopyrimidine, thiadiazolopyrazine, thiadiazolopyridazine, thiadiazolotriazine, benzothiazole, benzoisothiazole, benz othiadiazole, quinoline, isoquinoline, cinnoline, phthalazine, quinoxaline, quinazoline, naphthyridine, benzotriazine, pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyridotriazine, pyrimidopyrimidine, pyrimidopyrazine, pyrimidopyridazine, pyrimidotriazine, pyrazinopyrazine, pyrazinopyridazine, pyrazinotriazine, pyridazinopyridazine, pyridazinotriazine.
Parmi les composés de formule générale (I) objets de l'invention, un premier groupe de composés est constitué par les composés pour lesquels :Among the compounds of general formula (I) that are the subject of the invention, a first group of compounds consists of the compounds for which:
R représente un atome d'hydrogène, un groupe benzyle ou un groupe allyle ; R1 , Het et R2 étant tels que définis ci-dessus, à l'état de base ou de sel d'addition à un acide.R represents a hydrogen atom, a benzyl group or an allyl group; R1, Het and R2 being as defined above, in the form of a base or an acid addition salt.
Parmi les composés de formule générale (I) objets de l'invention, un second groupe de composés est constitué par les composés pour lesquels :Among the compounds of general formula (I) that are the subject of the invention, a second group of compounds consists of compounds for which:
R1 représente un groupe phényle ou naphtyle, éventuellement substitué par un ou plusieurs groupes choisis indépendamment l'un de l'autre parmi les atomes d'halogène, les groupes (C1-C6)alkyle, (C1-C6)BlCOXy, halo-(C1-C6)alkyle ;R 1 represents a phenyl or naphthyl group, optionally substituted with one or more groups chosen independently of one another from halogen atoms, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) groups; BlCOXy, halo- (C 1 -C 6 ) alkyl;
R, Het et R2 étant tels que définis ci-dessus, à l'état de base ou de sel d'addition à un acide.R, Het and R2 being as defined above, in the form of a base or an addition salt with an acid.
Parmi les composés de formule générale (I) objets de l'invention, un troisième groupe de composés est constitué par les composés pour lesquels : Het représente un groupe indole, thiophène ou pyridine ; R, R1 et R2 étant tels que définis ci-dessus, à l'état de base ou de sel d'addition à un acide.Among the compounds of general formula (I) that are the subject of the invention, a third group of compounds consists of the compounds for which: Het represents an indole, thiophene or pyridine group; R 1, R 1 and R 2 being as defined above, in the form of a base or an addition salt with an acid.
Parmi les composés de formule générale (I) objets de l'invention, un quatrième groupe de composés est constitué par les composés pour lesquels :Among the compounds of general formula (I) that are the subject of the invention, a fourth group of compounds consists of the compounds for which:
R2 représente un ou plusieurs substituants choisis parmi l'atome d'hydrogène, les atomes d'halogène, les groupes halo-(Ci-C6)alkyle, benzyle, (Ci-C6)alkyle- thio ;R 2 represents one or more substituents selected from hydrogen, halogen atoms, halo groups (Ci-C 6) alkyl, benzyl, (Ci-C 6) alkyl- thio;
R, R1 et Het étant tels que définis ci-dessus, à l'état de base ou de sel d'addition à un acide.R, R 1 and Het being as defined above, in the form of a base or an addition salt with an acid.
Parmi les composés de formule générale (I) objets de l'invention, un cinquième groupe de composés est constitué par les composés pour lesquels :Among the compounds of general formula (I) that are the subject of the invention, a fifth group of compounds is constituted by the compounds for which:
- R représente un atome d'hydrogène, un groupe benzyle ou un groupe allyle ; - Ri représente un groupe phényle ou naphtyle, éventuellement substitué par un ou plusieurs substituants choisis indépendamment l'un de l'autre parmi les atomes d'halogène, les groupes (CrC6)alkyle, (CrC6)alcoxy, halo-(Ci-C6)alkyle,R represents a hydrogen atom, a benzyl group or an allyl group; R 1 represents a phenyl or naphthyl group, optionally substituted with one or more substituents chosen independently of one another from halogen atoms, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen (Ci -C 6 ) alkyl,
- Het représente un groupe indole, thiophène ou pyridine ;Het represents an indole, thiophene or pyridine group;
- R2 représente un ou plusieurs substituants choisis parmi l'atome d'hydrogène, les atomes d'halogène, les groupes halo-(CrC6)alkyle, benzyle, (Ci-C6)alkyle-thio ; à l'état de base ou de sel d'addition à un acide.R 2 represents one or more substituents chosen from a hydrogen atom, halogen atoms, halo- (C 1 -C 6 ) alkyl, benzyl, (C 1 -C 6 ) alkyl-thio groups; in the form of a base or an acid addition salt.
Parmi les composés de formule générale (I) objets de l'invention, un sixième groupe de composés est constitué par les composés pour lesquels : - R représente un atome d'hydrogène, un groupe benzyle ou un groupe allyle ;Among the compounds of general formula (I) which are subjects of the invention, a sixth group of compounds is constituted by compounds for which: R represents a hydrogen atom, a benzyl group or an allyl group;
- R1 représente un groupe phényle ou naphtyle, éventuellement substitué par un ou plusieurs substituants choisis indépendamment l'un de l'autre parmi l'atome de fluor, les groupes méthyle, methoxy ou trifluorométhyleR 1 represents a phenyl or naphthyl group, optionally substituted by one or more substituents chosen independently of one another from the fluorine atom, the methyl, methoxy or trifluoromethyl groups;
- Het représente un groupe indole, thiophène ou pyridine ; - R2 représente un ou plusieurs substituants choisis parmi l'atome d'hydrogène, les atomes de brome ou de chlore, les groupes trifluorométhyle, methylethio ou benzyle, à l'état de base ou de sel d'addition à un acide.Het represents an indole, thiophene or pyridine group; - R 2 represents one or more substituents chosen from a hydrogen atom, bromine or chlorine atoms, trifluoromethyl, methylethio or benzyl groups, in the form of a base or addition salt with an acid.
Les combinaisons des groupes un à six ci-dessus font également partie de l'invention. Parmi les composés de formule générale (I) objets de l'invention, on peut notamment citer les composés suivants :The combinations of groups one to six above are also part of the invention. Among the compounds of general formula (I) which are subjects of the invention, mention may be made especially of the following compounds:
Λ/-[(2-Allyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(4,5-dibromo)-thiophène-2- carboxamide ;N - [(2-Allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide;
Λ/-[(2-Aza-bicyclo[2.1.1 ]hex-1 -yl)-phényl-méthyl]-(4,5-dibromo)-thiophène-2- carboxamide ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(2,5-dichloro)-thiophène-3- carboxamide ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (2,5-dichloro) -thiophene-3-carboxamide;
(+)-Λ/-[(2-Aza-bicyclo[2.1.1 ]hex-1 -yl)-phényl-méthyl]-(4,5-dibromo)-thiophène-2- carboxamide, et son chlorhydrate ;(+) - Λ / - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide, and its hydrochloride;
(-)-Λ/-[(2-Aza-bicyclo[2.1.1 ]hex-1 -yl)-phényl-méthyl]-(4,5-dibromo)-thiophène-2- carboxamide, et son chlorhydrate ;(-) - Λ / - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide, and its hydrochloride;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-(4-fluoro-phényl)-méthyl]-(3-chloro-4- trifluorométhyl)-pyridine-2-carboxamide ;N - [(2-Azabicyclo [2.1.1] hex-1-yl) - (4-fluoro-phenyl) -methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide;
N-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-2-méthylsulfanyl-nicotinamide ;N - [(2-Azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] -2-methylsulfanyl-nicotinamide;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(3-chloro-4-trifluorométhyl)- pyridine-2-carboxamide ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(1-benzyl)-1 H-indole-4- carboxamide ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (1-benzyl) -1H-indole-4-carboxamide;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-naphthalèn-2-yl-méthyl]-(3-chloro-4- trifluorométhyl)-pyridine-2-carboxamide, et son chlorhydrate ;N - [(2-Azabicyclo [2.1.1] hex-1-yl) -naphthalen-2-ylmethyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide, and its hydrochloride ;
Λ/-[(2-Aza-bicyclo[2.1.1 ]hex-1 -yl)-naphthalèn-2-yl-méthyl]-2-méthylsulfanyl- nicotinamide, et son chlorhydrate ;Λ / - [(2-Azabicyclo [2.1.1] hex-1-yl) -naphthalen-2-ylmethyl] -2-methylsulfanyl-nicotinamide, and its hydrochloride;
Λ/-[(2-aza-bicyclo[2.1.1 ]hex-1 -yl)-(3-méthoxy-phényl)-méthyl]-(3-chloro-4- trifluorométhyl)-pyridine-2-carboxamide, et son chlorhydrate ;N - [(2-aza-bicyclo [2.1.1] hex-1-yl) - (3-methoxy-phenyl) -methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide, and its hydrochloride;
Λ/-[(2-Aza-bicyclo[2.1.1 ]hex-1 -yl)-(3-méthoxy-phényl)-méthyl]-2-méthylsulfanyl- nicotinamide, et son chlorhydrate ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) - (3-methoxy-phenyl) -methyl] -2-methylsulfanyl-nicotinamide, and its hydrochloride;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-m-tolyl-méthyl]-2-méthylsulfanyl-nicotinamide, et son chlorhydrate ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -m-tolyl-methyl] -2-methylsulfanyl-nicotinamide, and its hydrochloride;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-(3-trifluorométhyl-phényl)-méthyl]-(3-chloro-4- trifluorométhyl)-pyridine-2-carboxamide, et son chlorhydrate ; Λ/-[(2-Aza-bicyclo[2.1.1 ]hex-1 -yl)-m-tolyl-méthyl]-(3-chloro-4-trifluorométhyl)- pyridine-2-carboxamide, et son chlorhydrate ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) - (3-trifluoromethyl-phenyl) -methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide, and its hydrochloride; N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -m-tolyl-methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide, and its hydrochloride;
(+)-Λ/-[(2-Allyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(4,5-dibromo)-thiophène- 2-carboxamide ;(+) - Λ- [[2-Allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide;
(-)-Λ/-[(2-Allyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(4,5-dibromo)-thiophène-(-) - Λ / - [(2-Allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene
2-carboxamide ;2-carboxamide;
Λ/-[(2-benzyl-2-aza-bicyclo[2.1.1]hex-1-yl)-(3-trifluorométhyl-phényl)-méthyl]-(3- chloro-4-trifluorométhyl)-pyridine-2-carboxamide et son chlorhydrate ; Λ/-[(2-benzyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(2,5-dichloro)-thiophène-3- carboxamide et son chlorhydrate ; Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(3,6-dichloro)-pyridine-2- carboxamide et son chlorhydrate ;N - [(2-benzyl-2-azabicyclo [2.1.1] hex-1-yl) - (3-trifluoromethyl-phenyl) -methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2 carboxamide and its hydrochloride; N - [(2-benzyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (2,5-dichloro) -thiophene-3-carboxamide and its hydrochloride; N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (3,6-dichloro) -pyridine-2-carboxamide and its hydrochloride;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(3-chloro-5-trifluorométhyl)-pyridine- 2-carboxamide ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (3-chloro-5-trifluoromethyl) -pyridine-2-carboxamide;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(6-chloro-3-trifluorométhyl)-pyridine- 2-carboxamide ;N - [(2-Azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (6-chloro-3-trifluoromethyl) -pyridine-2-carboxamide;
Les composés de l'invention présentent une activité particulière comme inhibiteurs des transporteurs de la glycine Glyti , notamment un profil d'activité et de sécurité améliorés.The compounds of the invention exhibit particular activity as inhibitors of Glyti glycine transporters, including an improved activity and safety profile.
Les composés de formule générale (I), peuvent être préparés par un procédé illustré par le schéma 1 qui suit :The compounds of general formula (I) can be prepared by a process illustrated by Scheme 1 which follows:
SCHEMA 1SCHEME 1
Figure imgf000008_0001
(N)
Figure imgf000008_0001
(NOT)
On effectue un couplage d'une diamine de formule générale (II), dans laquelle R et R1 sont tels que définis ci-dessus, notamment quand R représente un atome d'hydrogène ou un groupe allyle, avec un acide activé, par exemple via un anhydride mixte ou un chlorure d'acide de formule générale (III) dans laquelle Y représente un groupe partant dérivé par exemple de benzotriazole, d'acylurée ou un atome d'halogène et R2 est tel que défini ci-dessus, en utilisant les méthodes connues de l'Homme du métier. Les composés de formule générale (I) dans laquelle R représente l'atome d'hydrogène peuvent être aussi préparés à partir de composés de formule générale (I) dans laquelle R représente :Coupling of a diamine of general formula (II) in which R and R 1 are as defined above, especially when R represents a hydrogen atom or an allyl group, with an activated acid, for example via an anhydride mixture or an acid chloride of general formula (III) in which Y represents a leaving group derived for example from benzotriazole, acylurea or a halogen atom and R 2 is as defined above, using the methods known to those skilled in the art. The compounds of general formula (I) in which R represents the hydrogen atom may also be prepared from compounds of general formula (I) in which R represents:
- soit un groupe protecteur que l'on peut déprotéger par hydrogénolyse,- a protecting group that can be deprotected by hydrogenolysis,
- soit un groupe allyle, en déprotégeant l'azote, par exemple par un complexe du palladium « zéro », selon les méthodes connues de l'Homme du métier.or an allyl group, by deprotecting the nitrogen, for example by a palladium "zero" complex, according to the methods known to those skilled in the art.
Les composés de formule générale (I) dans laquelle R est différent de l'atome d'hydrogène peuvent être aussi préparés à partir de composés de formule générale (I) dans laquelle R représente un atome d'hydrogène, soit par alkylation dudit composé de formule générale (I) avec un halogénure ou mésylate du type RX, dans lequel R est tel que défini ci-dessus et X est mésylate ou halogène, en présence d'une base minérale, par exemple le carbonate de potassium dans l'acétonitrile ; soit par une réaction de type Eschweiler-Clarke ou une amination réductrice avec un aldéhyde ou une cétone appropriés selon les méthodes connues de l'Homme du métier ; soit avec un dérivé époxyde approprié, selon les méthodes connues de l'Homme du métier.The compounds of general formula (I) in which R is different from the hydrogen atom may also be prepared from compounds of general formula (I) in which R represents a hydrogen atom, or by alkylation of said compound of general formula (I) with an RX-type halide or mesylate, wherein R is as defined above and X is mesylate or halogen, in the presence of a mineral base, for example potassium carbonate in acetonitrile; either by an Eschweiler-Clarke type reaction or a reductive amination with an appropriate aldehyde or ketone according to the methods known to those skilled in the art; or with an appropriate epoxy derivative, according to the methods known to those skilled in the art.
Les composés de formule générale (I) dans laquelle le groupe Ri est un groupe phényle substitué par un hydroxy peuvent être obtenus à partir du composé correspondant de formule générale (I) substitué par un méthoxy, en utilisant les méthodes connues de l'Homme du métier.The compounds of general formula (I) in which the group R 1 is a phenyl group substituted by a hydroxyl may be obtained from the corresponding compound of general formula (I) substituted by a methoxy, using the methods known to man of the job.
La diamine de formule générale (II) peut être préparée par des procédés illustrés par les schémas 2 pour l'aminé (lia) et 3 pour l'aminé (Nb) et (Ile) qui suivent : The diamine of general formula (II) can be prepared by processes illustrated by Schemes 2 for the amine (IIa) and 3 for the amine (Nb) and (IIc) which follow:
Figure imgf000010_0001
Figure imgf000010_0001
(lia)(IIa)
L'ester (IV) est transformé en amide (V) en chauffant le complexe triméthylaluminium et l'aminé appropriée, telle que la morpholine, au reflux d'un solvant tel que le toluène. L'aminé (V) peut-être déprotégée en utilisant un lithien de type phényllithium dans un solvant tel que le tétrahydrofurane à basse température, par exemple à - 700C. On procède ensuite à une Λ/-allylation au moyen du bromure d'allyle en présence d'une base telle que le carbonate de potassium, dans un solvant tel que l'acétonitrile à température ambiante, pour obtenir le composé (VII). On fait réagir l'amide morpholinique de formule (VII) avec l'aromatique lithié de formule générale (VIII), dans laquelle Ri est tel que défini ci-dessus, dans un solvant éthéré tel que l'éther ou le tétrahydrofurane, à basse température. On obtient ainsi une cétone de formule générale (IX) que l'on fait réagir avec le chlorhydrate de la O- benzylhydroxylamine, au reflux de la pyridine, pour obtenir un mélange d'oxime Z/E de formule générale (X).The ester (IV) is converted to the amide (V) by heating the trimethylaluminum complex and the appropriate amine, such as morpholine, under the reflux of a solvent such as toluene. The amine (V) may be deprotected using a phenyllithium-type lithian in a solvent such as tetrahydrofuran at low temperature, for example at -70 ° C. The β-allylation is then carried out by means of bromide. allyl in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile at room temperature, to obtain the compound (VII). The morpholinic amide of formula (VII) is reacted with the lithiated aromatic compound of general formula (VIII), in which R 1 is as defined above, in an ethereal solvent such as ether or tetrahydrofuran, at low temperature. temperature. A ketone of general formula (IX) is thus obtained which is reacted with the hydrochloride of O benzylhydroxylamine, at reflux of pyridine, to obtain a mixture of oxime Z / E of general formula (X).
L'oxime (X) est ensuite réduite au reflux de l'éther par l'hydrure double d'aluminium et de lithium, pour fournir la diamine de formule générale (lia).The oxime (X) is then reduced at reflux of the ether by the lithium aluminum hydride double, to provide the diamine of general formula (IIa).
SCHEMA 3SCHEME 3
Figure imgf000011_0001
Figure imgf000011_0001
Selon le schéma 3, on fait réagir un nitrile de formule (Xl), avec l'aromatique lithié de formule générale (VIII), dans laquelle Ri est tel que défini ci-dessus, dans un solvant éthéré tel que le tétrahydrofurane ou l'éther, à basse température, par exemple -According to Scheme 3, a nitrile of formula (XI) is reacted with the lithiated aromatic compound of general formula (VIII), in which R 1 is as defined above, in an ethereal solvent such as tetrahydrofuran or ether, at low temperature, for example -
700C. On obtient ainsi une imine qui est réduite avec un réducteur tel que le borohydrure de sodium dans un solvant protique tel que le méthanol, pour donner l'aminé de formule générale (Nb). L'aminé (Nb) peut être débenzylée par hydrogénation en présence de catalyseur au palladium pour fournir l'aminé déprotégée (Ile).70 0 C. This gives an imine which is reduced with a reducing agent such as sodium borohydride in a protic solvent such as methanol, to give the amine of general formula (Nb). The amine (Nb) can be debenzylated by hydrogenation in the presence of palladium catalyst to provide the deprotected amine (Ile).
Par ailleurs les composés chiraux de formule générale (I) correspondants aux énantiomères S ou R peuvent être obtenus par séparation des composés racémiques par chromatographie liquide à haute performance (CLHP) sur colonne chirale, ou pourraient être obtenus par dédoublement de l'aminé racémique de formule générale (II) par utilisation d'un acide chiral, tel que l'acide dibenzoyl- tartrique ou par la recristallisation fractionnée et préférentielle d'un sel diastéréoisomérique. L'ester de formule (IV) est préparé selon une méthode décrite dans J. Org. Chem.,Moreover, the chiral compounds of general formula (I) corresponding to the S or R enantiomers can be obtained by separation of the racemic compounds by high performance liquid chromatography (HPLC) on a chiral column, or could be obtained by resolution of the racemic amine of general formula (II) using a chiral acid, such as dibenzoyl-tartaric acid or by fractional and preferential recrystallization of a diastereoisomeric salt. The ester of formula (IV) is prepared according to a method described in J. Org. Chem.
2003, 9348-9355.2003, 9348-9355.
Le nitrile de formule (Xl) est préparé selon une méthode décrite dans Tetrahedron :The nitrile of formula (XI) is prepared according to a method described in Tetrahedron:
Asymmetry, 2006 (17), 252-258.Asymmetry, 2006 (17), 252-258.
Les dérivés lithiés de formule générale (VIII) peuvent être préparés selon des méthodes connues de l'Homme du métier. Les acides et chlorures d'acide de formule générale (III) sont disponibles dans le commerce ou préparés par analogie à des méthodes connues de l'Homme du métier.The lithiated derivatives of general formula (VIII) can be prepared according to methods known to those skilled in the art. Acids and acid chlorides of general formula (III) are commercially available or prepared by analogy with methods known to those skilled in the art.
Les exemples qui vont suivre illustrent la préparation de quelques composés de l'invention. Dans ces exemples :The examples which follow illustrate the preparation of some compounds of the invention. In these examples:
- Les microanalyses élémentaires, les spectres I. R. et R. M. N. et la CLHP sur colonne chirale confirment les structures et les puretés énantiomériques des composés obtenus, - Pour les descriptions RMN, "m" signifie multiplet, "s" singulet, "t" triplet, "d" doublet, "q" quadruplet, dxd signifie double doublet, txt signifie triple triplet, dxt double triplet, etc.Elemental microanalyses, IR and NMR spectra and chiral column HPLC confirm the structures and enantiomeric purities of the compounds obtained. For the NMR descriptions, "m" means multiplet, "s" singlet, "t" triplet, " d "doublet", "q" quadruplet, dxd means double doublet, txt means triple triplet, dxt double triplet, etc.
- Les numéros indiqués entre parenthèses dans les titres des exemples correspondent à ceux de la 1ere colonne du tableau 1 , - "décomp." signifie "décomposition",- The numbers indicated in parentheses in the titles of the examples correspond to those of the 1 st column of Table 1 - "decomp." means "decomposition",
- Pour les composés sous forme de sel, les chiffres entre parenthèses indiquent le rapport (acide :base) ;- For compounds in salt form, the figures in parentheses indicate the ratio (acid: base);
- "ee" signifie excès énantiomérique ;- "ee" means enantiomeric excess;
- La nomenclature employée est la nomenclature suivant les recommandations IUPAC (International Union of Pure and Applied Chemistry).- The nomenclature used is the nomenclature following IUPAC (International Union of Pure and Applied Chemistry) recommendations.
Dans les noms des composés, le tiret "-" fait partie du mot, et le tiret "_" ne sert que pour la coupure en fin de ligne ; il est à supprimer en l'absence de coupure, et ne doit être remplacé ni par un tiret normal ni par un espace.In the names of the compounds, the hyphen "-" is part of the word, and the hyphen "_" is only used for the cut at the end of the line; it must be deleted in the absence of a cut, and must not be replaced by a normal dash or a space.
Exemple 1 (composé n°1) : Λ/-[(2-Allyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl- méthyl]- (4,5-dibromo)-thiophène-2-carboxamide.Example 1 (Compound No. 1): Λ- [(2-Allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene 2-carboxamide.
1.1 (2-Benzoyl-2-aza-bicvclor2.1.1lhex-1-yl)-morpholin-4-yl-méthanone Dans un tricol de 500 ml sous argon, on additionne goutte à goutte 10 ml de morpholine (115 mmoles) à une solution de 29 ml de triméthylaluminium 2N (58 mmoles) dans 200 ml de toluène anhydre et on chauffe à 600C pendant 15 minutes.1.1 (2-Benzoyl-2-aza-bicyclo [2.1.1] hex-1-yl) -morpholin-4-yl-methanone In a three-necked 500 ml under argon, 10 ml of morpholine (115 mmol) are added dropwise to a solution of 29 ml of 2N trimethylaluminium (58 mmol) in 200 ml of anhydrous toluene and heated at 60 ° C. for 15 minutes.
Une solution de 20 g d'ester éthylique de l'acide 2-benzoyl-2-aza- bicyclo[2.1.1]hexane-1-carboxylique (77,1 mmoles) dans 190 ml de toluène anhydre est canulée dans le milieu réactionnel, qui est ensuite chauffé une nuit au reflux.A solution of 20 g of 2-benzoyl-2-azabicyclo [2.1.1] hexane-1-carboxylic acid ethyl ester (77.1 mmol) in 190 ml of anhydrous toluene is canulated in the reaction medium. which is then heated overnight to reflux.
Après refroidissement, on hydrolyse précautionneusement avec 60 ml d'eau en agitant. Le précipité formé est filtré sur Célite® puis rincé au dichlorométhane. Le filtrat est évaporé sous pression réduite.After cooling, it is hydrolysed carefully with 60 ml of water stirring. The precipitate formed is filtered through Celite ® and then rinsed with dichloromethane. The filtrate is evaporated under reduced pressure.
Le résidu obtenu est trituré dans l'éther. On obtient ainsi 18,35 g de 2-benzoyl-2- aza-bicyclo[2.1.1]hex-1-yl)-morpholin-4-yl-méthanone sous forme d'un solide beige foncé.The residue obtained is triturated in ether. 18.35 g of 2-benzoyl-2-aza-bicyclo [2.1.1] hex-1-yl) -morpholin-4-yl-methanone are thus obtained in the form of a dark beige solid.
RMN 1H (400 MHz, DMSO-d6) δ ppm 7,69 (d, J = 8 Hz, 2H), 7,56-7,45 (m, 3H), 3,76 (d, J = 7,7 Hz, 1 H), 3,64-3,26 (m, 9H), 2,73 (t, J = 2,7 Hz, 1 H), 2,10 (m, 2H), 1 ,97 (m, 1 H), 1 ,52 (m, 1 H). PF : 176-177°C 1 H NMR (400 MHz, DMSO-d 6) δ ppm 7.69 (d, J = 8 Hz, 2H), 7.56-7.45 (m, 3H), 3.76 (d, J = 7, 7 Hz, 1H), 3.64-3.26 (m, 9H), 2.73 (t, J = 2.7 Hz, 1H), 2.10 (m, 2H), 1.97 ( m, 1H), 1.52 (m, 1H). Mp 176-177 ° C
1.2. (2-Aza-bicvclor2.1.1lhex-1-yl)-morpholin-4-yl-méthanone.1.2. (2-Aza-bicvclor2.1.1lhex-1-yl) -morpholin-4-yl-methanone.
Dans un tricol de 1 L sous argon, on place 10 g de 2-benzoyl-2-aza- bicyclo[2.1.1]hex-1-yl)-morpholin-4-yl-méthanone (composé obtenu selon l'étape 1.1 ) (33,3 mmoles) dans 400 ml de tétrahydrofurane anhydre à -700C. On additionne goutte à goutte 50 ml de phényl lithium 0,8 M (cyclohexane/éther) (40 mmoles) et on laisse agiter la solution obtenue pendant 1 h à -700C.In a 1 L three-neck under argon, 10 g of 2-benzoyl-2-azabicyclo [2.1.1] hex-1-yl) -morpholin-4-yl-methanone (compound obtained according to step 1.1) are placed. ) (33.3 mmol) in 400 ml of anhydrous tetrahydrofuran at -70 ° C. 50 ml of 0.8 M phenyl lithium (cyclohexane / ether) (40 mmol) are added dropwise and the solution obtained is stirred for 1 h at -70 ° C.
On hydrolyse avec 100 ml d'eau et on laisse remonter à température ambiante. Après extraction, la phase organique est concentrée puis le résidu est repris dans l'éther. Cette phase éthérée est versée dans la phase aqueuse préalablement acidifiée. Après extraction, la phase aqueuse est basifiée avec de l'ammoniaque puis extraite au dichlorométhane (3x200 ml). Les phases organiques sont séchées sur sulfate de sodium, filtrées et évaporées sous pression réduite. On obtient ainsi 5,2 g de (2-aza-bicyclo[2.1.1]hex-1-yl)-morpholin-4-yl-méthanone sous forme d'un solide beige foncé. RMN 1H (400 MHz, DMSO-d6) δ ppm 3,71 (m, 2H), 3,55 (m, 4H), 3,44 (m, 2H), 2,87 (s, 2H), 2,69 (s élargi, 1 H), 2,60 (t, J = 2,9 Hz, 1 H), 1 ,84 (m, 2H), 1 ,43 (m, 2H). PF : 97,5-98 °CIt is hydrolyzed with 100 ml of water and allowed to rise to room temperature. After extraction, the organic phase is concentrated and the residue is taken up in ether. This ethereal phase is poured into the previously acidified aqueous phase. After extraction, the aqueous phase is basified with ammonia and then extracted with dichloromethane (3 × 200 ml). The organic phases are dried over sodium sulphate, filtered and evaporated under reduced pressure. 5.2 g of (2-aza-bicyclo [2.1.1] hex-1-yl) -morpholin-4-yl-methanone are thus obtained in the form of a dark beige solid. 1 H NMR (400 MHz, DMSO-d 6) δ ppm 3.71 (m, 2H), 3.55 (m, 4H), 3.44 (m, 2H), 2.87 (s, 2H), 2 , 69 (widened, 1H), 2.60 (t, J = 2.9 Hz, 1H), 1.84 (m, 2H), 1.43 (m, 2H). Mp 97.5-98 ° C
1.3. (2-Allyl-2-aza-bicvclor2.1.1lhex-1-yl)-morpholin-4-yl-méthanone. Dans un ballon de 500 ml, on place 7,4 g de (2-aza-bicyclo[2.1.1]hex-1-yl)- morpholin-4-yl-méthanone (composé obtenu selon l'étape 1.2) (37,7 mmoles) dans 100 ml d'acétonitrile et 10,4 g de carbonate de potassium (75,4 mmoles). A cette suspension est ajoutée goutte à goutte une solution de 3,9 ml de bromure d'allyle (45,2 mmoles). Le milieu réactionnel est agité pendant la nuit à température ambiante, puis concentré sous pression réduite. Le résidu est solubilisé dans 100 ml de dichlorométhane. La phase organique est lavée à l'eau, séchée sur sulfate de sodium, filtrée puis évaporée sous pression réduite. On obtient ainsi 8,9 g de (2-allyl-2-aza-bicyclo[2.1.1]hex-1-yl)-morpholin-4-yl- méthanone sous forme d'huile.1.3. (2-Allyl-2-aza-bicvclor2.1.1lhex-1-yl) -morpholin-4-yl-methanone. In a 500 ml flask was placed 7.4 g of (2-aza-bicyclo [2.1.1] hex-1-yl) -morpholin-4-yl-methanone (compound obtained according to step 1.2) (37). 7 mmol) in 100 ml of acetonitrile and 10.4 g of potassium carbonate (75.4 mmol). To this suspension is added dropwise a solution of 3.9 ml of allyl bromide (45.2 mmol). The reaction medium is stirred overnight at ambient temperature and then concentrated under reduced pressure. The residue is solubilized in 100 ml of dichloromethane. The organic phase is washed with water, dried over sodium sulphate, filtered and then evaporated under reduced pressure. 8.9 g of (2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -morpholin-4-yl-methanone are thus obtained in the form of an oil.
RMN 1H (400 MHz, DMSO-d6) δ ppm 5,85 (m, 1 H), 5,24 (m, 1 H), 5,09 (m, 1 H), 3,78 (t élargi, J = 4,7 Hz, 2H), 3,54 (m, 4H), 3,44 (m, 2H), 3,05 (d élargi, J = 5,7 Hz, 2H), 2,69 (s élargi, 2H), 2,56 (t élargi, J = 3 Hz, 1 H), 1 ,83 (m, 2H), 1 ,68 (m, 2H). 1 H NMR (400 MHz, DMSO-d 6) δ ppm 5.85 (m, 1H), 5.24 (m, 1H), 5.09 (m, 1H), 3.78 (t extended, J = 4.7 Hz, 2H), 3.54 (m, 4H), 3.44 (m, 2H), 3.05 (broadened d, J = 5.7 Hz, 2H), 2.69 (s). expanded, 2H), 2.56 (t extended, J = 3 Hz, 1H), 1.83 (m, 2H), 1.68 (m, 2H).
1.4 (2-Allyl-2-aza-bicvclor2.1.1lhex-1-yl)-phényl-méthanone.1.4 (2-Allyl-2-aza-bicyclo [2.2.1] hex-1-yl) -phenyl-methanone.
Dans un tricol de 250 ml sous argon, on place 3,2 g de (2-allyl-2-aza- bicyclo[2.1.1]hex-1-yl)-morpholin-4-yl-méthanone (composé obtenu selon I'étape1.3) (13,5 mmoles) dans 70 ml de tétrahydrofurane à -700C. On coule goutte à goutte 16,2 ml de phényllithium 1 M (cyclohexane/éther) et on laisse pendant 1 heure à - 700C. Après hydrolyse avec 20 ml d'eau, on laisse remonter à température ambiante. Après évaporation du solvant sous pression réduite, le résidu est repris dans l'acétate d'éthyle. Après extraction, la phase organique est séchée sur sulfate de sodium, filtrée et évaporée sous pression réduite. On purifie le résidu par chromatographie sur colonne de gel de silice en éluant avec un mélange d'éther de pétrole et d'acétate d'éthyle. On obtient ainsi 2 g de (2-allyl-2-aza-bicyclo[2.1.1]hex- 1-yl)-phényl-méthanone sous forme d'huile.In a three-necked 250 ml under argon, 3.2 g of (2-allyl-2-azabicyclo [2.1.1] hex-1-yl) -morpholin-4-yl-methanone (compound obtained according to I 'étape1.3) (13.5 mmoles) in 70 ml of tetrahydrofuran at -70 0 C. is poured dropwise 16.2 ml of phenyl lithium (1 M cyclohexane / ether) and left for 1 hour at - 70 0 C. After hydrolysis with 20 ml of water, allowed to warm to room temperature. After evaporation of the solvent under reduced pressure, the residue is taken up in ethyl acetate. After extraction, the organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel, eluting with a mixture of petroleum ether and ethyl acetate. 2 g of (2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenylmethanone are thus obtained in the form of an oil.
RMN 1H (400 MHz, DMSO-d6) δ ppm 8,28 (m, 2H), 7,64 (txt, J = 7,3 et 1 ,4 Hz, 1 H), 7,52 (m, 2H), 5,73 (m, 1 H), 5,20 (m, J = 17 et 2 Hz, 1 H), 5 (m, J = 10 et 2 Hz, 1 H), 2,99 (dxt, J = 5,6 et 1 ,5 Hz, 2H), 2,86 (s, 2H), 2,70 (t, J = 2,9 Hz, 1 H), 1 ,99-1 ,85 (m, 4H). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (m, 2H), 7.64 (txt, J = 7.3 and 1.4 Hz, 1H), 7.52 (m, 2H) ), 5.73 (m, 1H), 5.20 (m, J = 17 and 2 Hz, 1H), 5 (m, J = 10 and 2 Hz, 1H), 2.99 (dxt, J = 5.6 and 1.5 Hz, 2H), 2.86 (s, 2H), 2.70 (t, J = 2.9 Hz, 1H), 1.99-1.85 (m, 4H).
1.5. (2-Allyl-2-aza-bicvclor2.1.1lhex-1-yl)-phényl-méthanone O-benzyl-oxime.1.5. (2-Allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methanone O-benzyl-oxime.
Dans un ballon de 50 ml on place 0,8 g de 2-allyl-2-aza-bicyclo[2.1.1]hex-1-yl)- phényl-méthanone (composé selon l'étape 1.4) (3,7 mmoles) dans 12 ml de pyridine puis on ajoute 0,91 g de chlorhydrate de O-benzylhydroxylamine (7,4 mmoles). Le milieu réactionnel est chauffé une nuit au reflux, puis concentré sous pression réduite.In a 50 ml flask, 0.8 g of 2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) phenylmethanone (compound according to step 1.4) (3.7 mmol) are placed in a 50 ml flask. ) in 12 ml of pyridine and then 0.91 g of O-benzylhydroxylamine hydrochloride (7.4 mmol) are added. The reaction medium is heated overnight under reflux and then concentrated under reduced pressure.
Le résidu est repris à l'eau basifiée avec de l'ammoniaque puis extrait 3 fois au dichlorométhane. Les phases organiques sont réunies, lavées dans une solution saturée de chlorure de sodium, puis sont séchées sur sulfate de sodium, filtrées et évaporées sous pression réduite. Le produit brut est purifié par chromatographie sur colonne de gel de silice en éluant avec un mélange de dichlorométhane et de méthanol ammoniacal. On obtient ainsi 1 ,2 g de (2-allyl-2-aza-bicyclo[2.1.1]hex-1- yl)-phényl-méthanone O-benzyl-oxime sous forme d'huile.The residue is taken up in basified water with ammonia and then extracted 3 times with dichloromethane. The organic phases are combined, washed with saturated sodium chloride solution, then dried over sodium sulfate, filtered and filtered. evaporated under reduced pressure. The crude product is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and ammoniacal methanol. There is thus obtained 1.2 g of (2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methanone O-benzyl-oxime in the form of an oil.
RMN 1H (400 MHz, DMSO-d6) δ ppm 7,49-7,45 (m, 2H), 7,42-7,26 (m, 8H), 5,76 (m, 1 H), 5,17 (m, J = 17 Hz et 1 ,7 Hz, 1 H), 5,09 (s, 1 H), 5,03 (m, 1 H), 3,06 (dxt, J = 5,9 Hz et 1 ,4 Hz, 2H), 2,66 (s élargi, 2H), 2,62 (t élargi, J = 3 Hz, 2H), 1 ,79 (m, 2H), 1 ,63 (m, 2H). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.49 to 7.45 (m, 2H), 7.42 to 7.26 (m, 8H), 5.76 (m, 1H), 5 , 17 (m, J = 17 Hz and 1.7 Hz, 1H), 5.09 (s, 1H), 5.03 (m, 1H), 3.06 (dxt, J = 5.9 Hz and 1.4 Hz, 2H), 2.66 (s extended, 2H), 2.62 (t extended, J = 3 Hz, 2H), 1.79 (m, 2H), 1.63 (m, 2H).
1.6 (2-Allyl-2-aza-bicvclor2.1.1lhex-1-yl)-phényl-méthylamine .1.6 (2-Allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methylamine.
Dans un tricol de 50 ml sous azote, on place 0,32 g d'hydrure double de lithium et d'aluminium (8,4 mmoles) dans 15 ml d'éther. On additionne ensuite une solution de 0,7 g de (2-allyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthanone O-benzyl-oxime (composé selon l'étape 1.5) (2,1 mmoles) dans 3 ml d'éther, puis on chauffe à 400C pendant 3 heures. Après refroidissement, le milieu réactionnel est hydrolyse à 00C avec 1 ,4 ml d'une solution aqueuse 0,1 M de tartrate double de sodium et de potassium pendant une nuit. Après filtration du milieu réactionnel, le filtrat est concentré sous pression réduite. Le résidu est purifié par chromatographie sur colonne de gel de silice en éluant avec un mélange de dichlorométhane et de méthanol ammoniacal. On obtient ainsi 0,3 g de (2-allyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthylamine sous forme d'huile.In a three-necked 50 ml under nitrogen, place 0.32 g of lithium aluminum hydride (8.4 mmol) in 15 ml of ether. A solution of 0.7 g of (2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenylmethanone O-benzyl-oxime (compound according to step 1.5) is then added ( 2.1 mmol) in 3 ml of ether and then heated at 40 0 C for 3 hours. After cooling, the reaction medium is hydrolyzed at 0 ° C. with 1.4 ml of a 0.1 M aqueous solution of sodium and potassium double tartrate overnight. After filtration of the reaction medium, the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and ammoniacal methanol. 0.3 g of (2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methylamine are thus obtained in the form of an oil.
RMN 1H (400 MHz, DMSO-d6) δ ppm 7,36-7,15 (m, 5H), 5,87 (m, 1 H), 5,23 (m, 1 H), 5,06 (m, 1 H), 4,14 (s, 1 H), 3,36 (m, J = 13,5 et 5,5 Hz, 1 H), 3,06 (m, J = 13,5 et 6,4 Hz, 1 H), 2,76 (d élargi, J = 8 Hz, 1 H), 2,43 (m, 2H), 1 ,78 (s élargi, 2H), 1 ,39-1 ,21 (m, 3H), 1 ,08 (m, 1 H). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.36 to 7.15 (m, 5H), 5.87 (m, 1H), 5.23 (m, 1H), 5.06 ( m, 1H), 4.14 (s, 1H), 3.36 (m, J = 13.5 and 5.5 Hz, 1H), 3.06 (m, J = 13.5 and 6). , 4Hz, 1H), 2.76 (d widened, J = 8Hz, 1H), 2.43 (m, 2H), 1.78 (s extended, 2H), 1, 39-1, 21 (m, 3H), 1.08 (m, 1H).
1.7 Λ/-r(2-Allyl-2-aza-bicvclor2.1.1lhex-1-yl)-phényl-méthyll- (4,5-dibromo)-thiophène- 2-carboxamide1.7? -? - (2-Allyl-2-aza-bicyl) -2.1.1-hex-1-yl) -phenyl-methyl-(4,5-dibromo) -thiophene-2-carboxamide
Dans un ballon de 250 ml, on place 1 ,75 g de (2-allyl-2-aza-bicyclo[2.1.1]hex-1-yl)- phényl-méthylamine (composé selon l'étape 1.6) (7,66 mmoles) dans 30 ml de dichlorométhane à 00C en présence de 2,1 g de carbonate de potassium (15,3 mmoles). On ajoute une solution de 2,8 g de chlorure d'acide (4,5-dibromo)- thiophène-2-carboxylique (9,2 mmoles) dans 20 ml de dichlorométhane et on laisse agiter une nuit à température ambiante. Le milieu réactionnel est ensuite dilué avec 100 ml de dichlorométhane puis lavé successivement à l'eau (50 ml), la soude 1 NIn a 250 ml flask, 1.75 g of (2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methylamine (compound according to step 1.6) (7, 66 mmol) in 30 ml of dichloromethane at 0 ° C. in the presence of 2.1 g of potassium carbonate (15.3 mmol). A solution of 2.8 g of (4,5-dibromo) -thiophene-2-carboxylic acid chloride (9.2 mmol) in 20 ml of dichloromethane is added and the mixture is stirred overnight at room temperature. The reaction medium is then diluted with 100 ml of dichloromethane and then washed successively with water (50 ml), 1N sodium hydroxide
(50 ml) et dans une solution saturée de chlorure de sodium (50 ml). La phase organique est séchée sur sulfate de sodium, filtrée et évaporée sous pression réduite. Le résidu est purifié par chromatographie sur colonne de gel de silice en éluant avec un mélange de dichlorométhane et de méthanol ammoniacal. On obtient ainsi 3,2 g de Λ/-[(2-allyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]- (4,5- dibromo)-thiophène-2-carboxamide.(50 mL) and in saturated sodium chloride solution (50 mL). The organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and ammoniacal methanol. 3.2 g of Λ- [(2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2 are thus obtained. carboxamide.
RMN 1H (400 MHz, CDCI3) δ ppm 7,40-7,08 (m, 7H), 5,79 (m, 1 H), 5,18 (m, 1 H), 5,06 (m, 1 H), 4,98 (m, 1 H), 3,36 (m, 1 H), 3,07 (m, 1 H), 2,87 (m, 1 H), 2,54 (m, 1 H), 2,46 (m, 1 H), 1 ,55-1 ,22 (m, 4H). PF = 59-60 0C 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.40-7.08 (m, 7H), 5.79 (m, 1H), 5.18 (m, 1H), 5.06 (m , 1H), 4.98 (m, 1H), 3.36 (m, 1H), 3.07 (m, 1H), 2.87 (m, 1H), 2.54 (m. , 1H), 2.46 (m, 1H), 1, 55-1, 22 (m, 4H). Mp = 59-60 0 C
Exemple 2 (composé n°2) : Λ/-r(2-Aza-bicyclor2.1.πhex-1 -vl)-phényl-méthvπ-(4,5- dibromo)-thiophène-2-carboxamide.EXAMPLE 2 (Compound No. 2): Λ -R (2-Aza-bicyclo [2.2.1] hex-1-yl] -phenyl-methyl-4- (4,5-dibromo) -thiophene-2-carboxamide.
Dans un ballon de 10 ml sous argon muni d'un réfrigérant on place 4,7 mg de palladium tétrakis(triphénylphospine) (0,004 mmole) et 0,19 g d'acide N, N- diméthylbarbiturique (1 ,2 mmole) en solution dans 2 ml de dichlorométhane. Le milieu réactionnel est chauffé à 400C, puis on ajoute 0,2 g de Λ/-[(2-allyl-2-aza- bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(4,5-dibromo)-thiophène-2-carboxamideIn a 10 ml flask under argon provided with a condenser, 4.7 mg of palladium tetrakis (triphenylphospine) (0.004 mmol) and 0.19 g of N, N-dimethylbarbituric acid (1.2 mmol) in solution are placed in solution. in 2 ml of dichloromethane. The reaction medium is heated to 40 ° C., then 0.2 g of Λ- [(2-allyl-2-azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - ( 4,5-dibromo) -thiophene-2-carboxamide
(composé 1 ) (0,4 mmole) dans 2 ml de dichlorométhane, puis on chauffe encore 2 heures à 400C. Après refroidissement, on dilue avec 10 ml de dichlorométhane et on hydrolyse ensuite avec 5 ml d'une solution de carbonate de sodium. La phase organique est séparée et lavée deux fois avec 5 ml d'acide chlorhydrique 1 N. Les phases aqueuses sont réunies puis basifiées avec de l'ammoniaque à pH 9 et ensuite extraites 2 fois avec 25 ml de dichlorométhane. Les phases organiques sont séchées sur sulfate de sodium, filtrées et évaporées sous pression réduite. Le résidu est purifié par chromatographie sur colonne de gel de silice en éluant avec un mélange de dichlorométhane et de méthanol ammoniacal. On obtient ainsi 70 mg de Λ/-[(2-aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(4,5-dibromo)-thiophène-2- carboxamide sous forme de poudre.(Compound 1) (0.4 mmol) in 2 ml of dichloromethane, and the mixture is then heated for a further 2 hours at 40 ° C. After cooling, it is diluted with 10 ml of dichloromethane and then hydrolyzed with 5 ml of a carbonate solution sodium. The organic phase is separated and washed twice with 5 ml of 1N hydrochloric acid. The aqueous phases are combined and then basified with aqueous ammonia at pH 9 and then extracted twice with 25 ml of dichloromethane. The organic phases are dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and ammoniacal methanol. There is thus obtained 70 mg of Λ / - [(2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide in powder form .
RMN 1H (400 MHz, DMSO-d6) δ ppm 8,69 (d, J = 8,8 Hz, 1 H), 8,15 (s, 1 H), 7,39 (m, 2H), 7,33 (m, 2H), 7,26 (m, 1 H), 5,29 (d, J = 7,8 Hz, 1 H), 2,79 (s, 2H), 2,63 (m, J = 2,8 Hz,1 H), 1 ,62 (m, 2H), 1 ,15 (m, 2H). PF = 189-190°C Exemple 3 (composé n°17) : (+)-Λ/-[(2-allyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl- méthyl]- (4,5-dibromo)-thiophène-2-carboxamide. 1 H NMR (400 MHz, DMSO-d 6) δ ppm 8.69 (d, J = 8.8 Hz, 1H), 8.15 (s, 1H), 7.39 (m, 2H), 7 , 33 (m, 2H), 7.26 (m, 1H), 5.29 (d, J = 7.8 Hz, 1H), 2.79 (s, 2H), 2.63 (m, J = 2.8 Hz, 1H), 1.62 (m, 2H), 1.15 (m, 2H). Mp = 189-190 ° C Example 3 (Compound No. 17): (+) - Λ / - [(2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenylmethyl] - (4,5-dibromo) ) -thiophene-2-carboxamide.
Ce composé est obtenu par séparation par HPLC préparative du Λ/-[(2-allyl-2-aza- bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(4,5-dibromo)-thiophène-2-carboxamideThis compound is obtained by preparative HPLC separation of Λ / - [(2-allyl-2-azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene -2-carboxamide
(composé n°1 ) en utilisant une colonne CHIRALpak® AD 20μm et en tant que solvant un mélange acétonitrile/propan-2-ol 80/20.(Compound No. 1) by using a Chiralpak ® AD 20 .mu.m and as solvent a mixture of acetonitrile / propan-2-ol 80:20.
RMN 1H (400 MHz, DMSO-d6) δ ppm 8,65 (m, 1 H), 8,15 (s, 1 H), 7,4-7,2 (m, 5H), 5,75 (m, 1 H), 5,40 (m, 1 H), 5,30 (m, 1 H), 5,02 (m, 1 H), 3,20 (m, 2H), 2,70 (m, 1 H), 2,60-2,50 (m, 2H), 1 ,58 (m, 1 H), 1 ,4 (m, 3H). ee= 99,7% [αD] 20°c MeOH = +39,2° c= 0,475 g/100 ml 1 H NMR (400 MHz, DMSO-d 6) δ ppm 8.65 (m, 1H), 8.15 (s, 1H), 7.4-7.2 (m, 5H), 5.75 ( m, 1H), 5.40 (m, 1H), 5.30 (m, 1H), 5.02 (m, 1H), 3.20 (m, 2H), 2.70 (m , 1H), 2.60-2.50 (m, 2H), 1. 58 (m, 1H), 1, 4 (m, 3H). ee = 99.7% [α D ] 20 ° C MeOH = + 39.2 ° c = 0.475 g / 100 ml
Exemple 4 (composé n°4) : Chlorhydrate du (+)-Λ/-[(2-aza-bicyclo[2.1.1]hex-1 - yl)-phényl-méthyl]-(4,5-dibromo)-thiophène-2-carboxamide (1 :1).Example 4 (Compound No. 4): (+) - Λ / - [(2-Azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) hydrochloride thiophene-2-carboxamide (1: 1).
Ce composé est obtenu selon la méthode décrite dans l'exemple 2, en partant du composé n°17 décrit dans l'exemple 3, après salification sous forme de chlorhydrate par solubilisation de la base dans l'éther, ajout d'un excès d'acide chlorhydrique 1 N dans l'éther puis concentration sous pression réduite.This compound is obtained according to the method described in Example 2, starting from the compound No. 17 described in Example 3, after salification in hydrochloride form by solubilization of the base in ether, addition of an excess of 1 N hydrochloric acid in ether and then concentration under reduced pressure.
RMN 1H (400 MHz, DMSO-d6) δ ppm 9,77 (m, 1 H), 9,55 (d, J = 8,9 Hz, 1 H), 8,93 (m, 1 H), 8,46 (s, 1 H), 7,56-7,38 (m, 5H), 5,70 (d, J = 9,2 Hz, 1 H), 3,30 (m, 2H), 2,84 (m, 1 H), 2,10 (m, 1 H), 1 ,87 (m, 1 H), 1 ,66 (m, 2H). PF = 211-213°C ee= 99,7% 1 H NMR (400 MHz, DMSO-d 6) δ ppm 9.77 (m, 1H), 9.55 (d, J = 8.9 Hz, 1H), 8.93 (m, 1H), 8.46 (s, 1H), 7.56-7.38 (m, 5H), 5.70 (d, J = 9.2 Hz, 1H), 3.30 (m, 2H), 2 84 (m, 1H), 2.10 (m, 1H), 1.87 (m, 1H), 1.66 (m, 2H). Mp = 211-213 ° C ee = 99.7%
[αD] 20°c MeOH = +35,5° C= 1 ,02 g/100 ml[α D ] 20 ° C MeOH = + 35.5 ° C = 1.02 g / 100 ml
Exemple 5 (composé n°18) : (-)-Λ/-[(2-allyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl- méthyl]-(4,5-dibromo)-thiophène-2-carboxamide.Example 5 (Compound No. 18): (-) - Λ / - [(2-allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenylmethyl] - (4,5-dibromo) ) -thiophene-2-carboxamide.
Le composé est obtenu par séparation par HPLC préparative du Λ/-[(2-allyl-2-aza- bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(4,5-dibromo)-thiophène-2-carboxamide (composé n°1 ) en utilisant une colonne CHIRALpak® AD 20μm et en tant que solvant un mélange acétonitrile/propan-2-ol 80/20. RMN 1H (400 MHz, DMSO-d6) δ ppm 8,65 (m, 1 H), 8,15 (s, 1 H), 7,4-7,2 (m, 5H),The compound is obtained by preparative HPLC separation of Λ / - [(2-allyl-2-azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene -2-carboxamide (compound No. 1) by using a Chiralpak ® AD 20 .mu.m and as solvent acetonitrile / propan-2-ol 80:20. 1 H NMR (400 MHz, DMSO-d 6) δ ppm 8.65 (m, 1H), 8.15 (s, 1H), 7.4-7.2 (m, 5H),
5,75 (m, 1 H), 5,40 (m, 1 H), 5,30 (m, 1 H), 5,02 (m, 1 H), 3,20 (m, 2H), 2,70 (m, 1 H), 2,60-2,50 (m, 2H), 1 ,58 (m, 1 H), 1 ,4 (m, 3H). ee= 100% [αD] 20°c MeOH = -36,4° c= 0,45 g/100 ml5.75 (m, 1H), 5.40 (m, 1H), 5.30 (m, 1H), 5.02 (m, 1H), 3.20 (m, 2H), 2 , 70 (m, 1H), 2.60-2.50 (m, 2H), 1. 58 (m, 1H), 1, 4 (m, 3H). ee = 100% [α D ] 20 ° c MeOH = -36.4 ° c = 0.45 g / 100 ml
Exemple 6 (composé n°5) : Chlorhydrate du (-)-Λ/-[(2-aza-bicyclo[2.1.1]hex-1- yl)-phényl-méthyl]- (4,5-dibromo)-thiophène-2-carboxamide (1 :1).Example 6 (Compound No. 5): (-) - Λ / - [(2-Azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) hydrochloride thiophene-2-carboxamide (1: 1).
Ce composé est obtenu selon la méthode décrite dans l'exemple 2, en partant du composé n°18 décrit selon l'exemple 5, après salification sous forme de chlorhydrate par solubilisation de la base dans l'éther, ajout d'un excès d'acide chlorhydrique 1 N dans l'éther puis concentration sous pression réduite.This compound is obtained according to the method described in Example 2, starting from the compound No. 18 described according to Example 5, after salification in hydrochloride form by solubilization of the base in ether, addition of an excess of 1 N hydrochloric acid in ether and then concentration under reduced pressure.
RMN 1H (400 MHz, DMSO-d6) δ ppm 9,52 (d, J = 9,2 Hz, 1 H), 8,42 (s, 1 H), 7,50- 7,34 (m, 5H), 5,66 (d, J = 8,9 Hz, 1 H), 3,25 (m, 2H), 2,80 (m, 1 H), 2,07 (m, 1 H), 1 ,83 1 H NMR (400 MHz, DMSO-d 6) δ ppm 9.52 (d, J = 9.2 Hz, 1H), 8.42 (s, 1H), 7.50-7.34 (m, 5H), 5.66 (d, J = 8.9 Hz, 1H), 3.25 (m, 2H), 2.80 (m, 1H), 2.07 (m, 1H), 1H NMR (CDCl3)? 83
(m, 1 H), 1 ,62 (m, 2H).(m, 1H), 1.62 (m, 2H).
PF = 227-228°C ee= 100%Mp = 227-228 ° C ee = 100%
[αD] 20°c MeOH = -36,2° c= 1 ,02 g/100 ml[α D ] 20 ° C MeOH = -36.2 ° c = 1.02 g / 100 ml
Exemple 7 (composé n° 7) : Λ/-r(2-Aza-bicvclor2.1.nhex-1-vl)-phényl-méthvn-(2- méthylsulfanyl)-nicotinamide.Example 7 (Compound No. 7): N- (2-Aza-bicyclohexyl) -1-hex-1-yl) -phenyl-methyl- (2-methylsulfanyl) -nicotinamide.
7.1 (2-Benzyl-2-aza-bicvclor2.1.1lhex-1-yl)-phényl-méthylamine. Dans un tricol de 500 ml sous argon, on place 3 g de 2-benzyl-2-aza- bicyclo[2.1.1]hexane-1-carbonitrile (Xl) (15,1 mmoles) à -700C dans 100 ml de tétrahydrofurane anhydre. On additionne goutte à goutte 37,8 ml d'une solution 0,87.1 (2-Benzyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methylamine. In a three-necked 500 ml under argon, 3 g of 2-benzyl-2-azabicyclo [2.1.1] hexane-1-carbonitrile (Xl) (15.1 mmol) are placed at -70 ° C. in 100 ml. anhydrous tetrahydrofuran. 37.8 ml of a 0.8 solution are added dropwise
M (cyclohexane/éther) de phényl-lithium (30,2 mmoles).M (cyclohexane / ether) phenyl lithium (30.2 mmol).
On laisse agiter pendant 2 heures et demie à -700C, puis on hydrolyse à -20°C avec 30 ml d'eau.Stirring is allowed for 2.5 hours at -70 ° C. and then hydrolyzed at -20 ° C. with 30 ml of water.
Après extraction, la phase organique est concentrée puis le résidu est repris dans 40 ml de méthanol. 2,8 g de borohydrure de sodium (75 mmoles) y sont ajoutés par portions. Le milieu réactionnel est laissé sous agitation la nuit à température ambiante. Après évaporation sous pression réduite, le résidu est repris par 100 ml d'éther etAfter extraction, the organic phase is concentrated and the residue is taken up in 40 ml of methanol. 2.8 g of sodium borohydride (75 mmol) are added in portions. The reaction medium is left stirring overnight at room temperature. After evaporation under reduced pressure, the residue is taken up in 100 ml of ether and
100 ml d'eau. On acidifie le milieu avec une solution d'acide chlorhydrique 1 N, puis on extrait la phase étherée.100 ml of water. The medium is acidified with a 1N hydrochloric acid solution, and then the ether phase is extracted.
La phase aqueuse est basifiée avec de l'ammoniaque puis réextraite 2 fois avec 100 ml de dichlorométhane. Les phases organiques sont réunies, puis séchées sur sulfate de sodium, filtrées et évaporées sous pression réduite. On obtient ainsi 4,15 g de (2-benzyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthylamine (Nb) sous forme d'une huile qui cristallise au froid.The aqueous phase is basified with ammonia and then reextracted twice with 100 ml of dichloromethane. The organic phases are combined, then dried over sodium sulphate, filtered and evaporated under reduced pressure. There is thus obtained 4.15 g of (2-benzyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methylamine (Nb) in the form of an oil which crystallizes in the cold.
RMN 1H (200 MHz1CDCI3) δ ppm 7,6-7,3 (m, 5H), 4,4 (s, 1 H), 4,2 (d, J = 16 Hz, 1 H), 3,6 (d,J = 16 Hz, 1 H), 3,0 (d, J = 9 Hz, 1 H), 2,6 (m, 1 H), 2,4 (d,J = 9 Hz, 1 H),1 ,8 (s élargi, 2H), 1 ,6-1 ,2 (m, 4H). PF = 63,5-64°C. 1 H NMR (200 MHz 1 CDCl 3 ) δ ppm 7.6-7.3 (m, 5H), 4.4 (s, 1H), 4.2 (d, J = 16 Hz, 1H), 3.6 (d, J = 16Hz, 1H), 3.0 (d, J = 9Hz, 1H), 2.6 (m, 1H), 2.4 (d, J = 9Hz) , 1H), 1, 8 (broad, 2H), 1, 6-1, 2 (m, 4H). Mp 63.5-64 ° C.
Un échantillon analytique est obtenu sous forme de chlorhydrate par solubilisation de la base dans l'éther, ajout d'un excès d'acide chlorhydrique 1 N dans l'éther puis concentration sous pression réduite.An analytical sample is obtained in hydrochloride form by solubilization of the base in ether, addition of an excess of 1N hydrochloric acid in ether and concentration under reduced pressure.
PF = 140-1420CMp = 140-142 ° C
7.2 (2-Aza-bicyclo[2.1.11hex-1-yl)-phényl-méthylamine7.2 (2-Aza-bicyclo [2.1.11hex-1-yl] -phenyl-methylamine
Dans une fiole de Parr, on place sous 4 atmosphères d'hydrogène à 400C pendant 3 heures 0,43 g de (2-benzyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthylamine (1 ,54 mmole) dans 20 ml d'éthanol et 5 ml d'acide chlorhydrique 1 N en présence d'une pointe de spatule de palladium sur charbon à 10%.In a Parr flask, 0.43 g of (2-benzyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl) are placed under 4 atmospheres of hydrogen at 40 ° C. for 3 hours. methylamine (1. 54 mmol) in 20 ml of ethanol and 5 ml of 1N hydrochloric acid in the presence of a tip of palladium spatula on charcoal 10%.
Après filtration du catalyseur et concentration du filtrat sous pression réduite, le résidu est repris dans 30 ml de dichlorométhane et 30 ml d'eau basifiée avec de l'ammoniaque. Après extraction, la phase organique est séchée sur sulfate de sodium, filtrée et évaporée sous pression réduite. On obtient ainsi 0,24 g de (2-aza- bicyclo[2.1.1]hex-1-yl)-phényl-méthylamine sous forme d'une huile jaune qui se solidifie au froid et que l'on utilise telle quelle dans l'étape suivante.After filtration of the catalyst and concentration of the filtrate under reduced pressure, the residue is taken up in 30 ml of dichloromethane and 30 ml of water basified with ammonia. After extraction, the organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. 0.24 g of (2-azabicyclo [2.1.1] hex-1-yl) -phenyl-methylamine are thus obtained in the form of a yellow oil which solidifies in the cold and which is used as it is in the next step.
PF = 46.5-47°CM.p. = 46.5-47 ° C
Un échantillon analytique est obtenu sous forme de chlorhydrate par solubilisation de la base dans l'éther, ajout d'un excès d'acide chlorhydrique 1 N dans l'éther, puis concentration sous pression réduite.An analytical sample is obtained in hydrochloride form by solubilization of the base in ether, addition of an excess of 1N hydrochloric acid in ether, and concentration under reduced pressure.
RMN 1H (400 MHz, DMSO-d6) δ ppm 10,12-8,71 (m, 4H), 7,46-7,35 (m, 6H), 4,83 (m, 1 H), 3,15 (m, 2H), 2,72 (m, 1 H), 2,10 (m, 1 H), 1 ,89 (m, 1 H), 1 ,57 (t élargi, J = 9,3 1 H NMR (400 MHz, DMSO-d 6) δ ppm 10.12-8.71 (m, 4H), 7.46-7.35 (m, 6H), 4.83 (m, 1H), 3 , (M, 2H), 2.72 (m, 1H), 2.10 (m, 1H), 1.89 (m, 1H), 1. 57 (t expanded, J = 9.3
Hz, 1 H), 1 ,36 (t élargi, J = 9,3 Hz, 1 H). PF = 220-2230C décomp.Hz, 1H), 1, 36 (t extended, J = 9.3 Hz, 1 H). PF = 220-223 ° C decomp.
7.3 Λ/-r(2-Aza-bicvclor2.1.1lhex-1-yl)-phényl-méthyll-(2-méthylsulfanyl)-nicotinamide Dans un ballon de 25 ml, on place 0,22 g d'acide (2-méthylsulfanyl)-nicotinique (1 ,27 mmole), 0,17g d'hydroxybenzotriazole (1 ,27 mmole), 0,25 g de chlorhydrate de 1-[3-(diméthylamino)propyl]-3-éthylcarbo-diimide (1 ,27 mmole) en solution dans 2 ml de dichlorométhane et on agite le mélange à température ambiante pendant 15 minutes. On ajoute 0,2 g (1 ,0 mmoles) de (2-aza-bicyclo[2.1.1]hex-1-yl)-phényl- méthylamine en solution dans 2 ml de dichlorométhane et on agite à température ambiante pendant une nuit.7.3 Λ / -r (2-Aza-bicyclo-1,2,1-hex-1-yl) -phenyl-methyl-2- (2-methylsulfanyl) -nicotinamide In a 25 ml flask was placed 0.22 g of acid (2- methylsulfanyl) -nicotinic acid (1.27 mmol), 0.17 g of hydroxybenzotriazole (1.27 mmol), 0.25 g of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1, 27 mmol) in solution in 2 ml of dichloromethane and the mixture is stirred at room temperature for 15 minutes. 0.2 g (1.0 mmol) of (2-aza-bicyclo [2.1.1] hex-1-yl) -phenylmethylamine dissolved in 2 ml of dichloromethane are added and the mixture is stirred at room temperature overnight. .
Le milieu réactionnel est ensuite dilué avec 10 ml de dichlorométhane puis lavé successivement à l'eau (5 ml), à la soude 1 N (5 ml) et avec une solution saturée de chlorure de sodium (5 ml). La phase organique est séchée sur sulfate de sodium, filtrée et évaporée sous pression réduite. Le résidu est purifié par chromatographie sur colonne de gel de silice en éluant avec un mélange de dichlorométhane et de méthanol ammoniacal. On obtient ainsi 63 mg de Λ/-[(2-aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(2- méthylsulfanyl)-nicotinamide sous forme de poudre. PF = 141-143°C RMN 1H (400 MHz, DMSO-d6) δ ppm 8,79 (d, J = 8,5 Hz, 1 H), 8,55 (dxd, J = 5 Hz et 1 ,7 Hz, 1 H), 7,76 (dxd, J = 7,5 Hz et 1 ,8 Hz, 1 H), 7,43-7,18 (m, 6H), 5,30 (d, J = 8,6 Hz, 1 H), 2,77 (m, 2H), 2,63 (m, 1 H), 2,45 (s, 3H), 1 ,70 (m, 1 H), 1 ,64 (m, 1 H), 1 ,14 (m, 2H).The reaction medium is then diluted with 10 ml of dichloromethane and then washed successively with water (5 ml), with 1N sodium hydroxide solution (5 ml) and with saturated sodium chloride solution (5 ml). The organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and ammoniacal methanol. 63 mg of Λ- [(2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (2-methylsulfanyl) -nicotinamide are thus obtained in the form of a powder. Mp = 141-143 ° C 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (d, J = 8.5 Hz, 1H), 8.55 (dxd, J = 5 Hz and 1, 7 Hz, 1H), 7.76 (dxd, J = 7.5 Hz and 1.8 Hz, 1H), 7.43-7.18 (m, 6H), 5.30 (d, J = 8.6 Hz, 1H), 2.77 (m, 2H), 2.63 (m, 1H), 2.45 (s, 3H), 1.70 (m, 1H), 1.64. (m, 1H), 1, 14 (m, 2H).
Les autres composés décrits dans le tableau 1 sont obtenus suivant les méthodes décrites dans les exemples 1 à 7 à partir des aminés de formule (lia), (Nb), (Ile), de lithiens de formule (VIII) ou de dérivés d'acides carboxyliques de formule (III) appropriés.The other compounds described in Table 1 are obtained according to the methods described in Examples 1 to 7 from the amines of formula (IIa), (Nb), (IIc), lithiens of formula (VIII) or derivatives of carboxylic acids of formula (III) suitable.
Le tableau 1 qui suit illustre les structures chimiques de quelques composés de l'invention.Table 1 which follows illustrates the chemical structures of some compounds of the invention.
Dans la colonne :In the column :
- "Sels" : « - » désigne un composé à l'état de base, "HCI" désigne un chlorhydrate, le chiffre entre parenthèses indique le rapport (acide : base), - Les composés du tableau se présentent sous la forme de chlorhydrate solvaté par une ou plusieurs molécules d'eau, Dans les colonnes R, Ri et R2 :- "Salts": "-" means a compound in the basic form, "HCI" means a hydrochloride, the number in parentheses indicates the ratio (acid: base), - The compounds in the table are in the form of hydrochloride solvated by one or more molecules of water, In the columns R, Ri and R 2 :
- « Cl » signifie chlore, « Br » signifie brome,- "Cl" means chlorine, "Br" means bromine,
- « CH3 » signifie méthyle,- "CH 3 " means methyl,
- « OCH3 » signifie méthoxy, - « Ph » signifie phényle,- "OCH 3 " means methoxy, - "Ph" means phenyl,
- « CF3 » signifie trifluorométhyle,- "CF 3 " means trifluoromethyl,
- « Bn » signifie benzyle ;- "Bn" means benzyl;
- dans la colonne « R2 », le chiffre devant les substituants indique la position dans la formule générale (I),- in the column "R 2 ", the number in front of the substituents indicates the position in the general formula (I),
Le tableau 2 donne les propriétés physiques, points de fusion et pouvoirs rotatoires des composés du tableau 1 ; Dans le tableau 2 : la colonne [αD] 2o°c renseigne le résultat d'analyse du pouvoir rotatoire des composés du tableau à la longueur d'onde de 589 nM et à la température deTable 2 gives the physical properties, melting points and rotational potency of the compounds of Table 1; In Table 2: the column [α D ] 2 o ° c gives the result of analysis of the rotatory power of the compounds of the table at the wavelength of 589 nM and at the temperature of
200C. Le solvant indiqué entre parenthèses correspond au solvant employé pour réaliser la mesure du pouvoir rotatoire en degrés et la lettre « c » indique la concentration du solvant en g/100 ml. « N.A. » signifie que la mesure du pouvoir rotatoire n'est pas applicable, - la colonne "m/z" renseigne l'ion moléculaire (M+H+) ou (M+) observé par analyse des produits par spectrométrie de masse, soit par LC-MS (Liquid Chromatography coupled to Mass Spectroscopy) réalisée sur un appareil de type Agilent LC-MSD Trap en mode ESI positif, soit par introduction directe par MS (Mass Spectroscopy) sur un appareil Autospec M (EBE) en utilisant la technique DCI- NH3 ou en utilisant la technique d'impact électronique sur un appareil de type20 0 C. The solvent in parentheses corresponds to the solvent used to perform the measurement of the optical rotation in degrees and the letter 'c' indicates the concentration of the solvent in g / 100 ml. "NA" means that the measurement of the rotatory power is not applicable, - the "m / z" column informs the molecular ion (M + H + ) or (M + ) observed by analysis of the products by mass spectrometry, either by LC-MS (Liquid Chromatography coupled to Mass Spectroscopy) carried out on an Agilent LC-MSD Trap apparatus in ESI positive mode, or by direct introduction by MS (Mass Spectroscopy) on an Autospec M device (EBE) using the DCI-NH 3 technique or by using the electronic impact technique on a device of the type
Waters GCT. Waters GCT.
TABLEAU 1
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000023_0001
TABLE 1
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000023_0001
TABLEAU 2TABLE 2
Figure imgf000023_0002
Figure imgf000023_0002
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. Etude du transport de la glycine dans les cellules SK-N-MC exprimant le transporteur humain qlyti natif.The compounds of the invention have been subjected to a series of pharmacological tests which have demonstrated their interest as substances with therapeutic activities. Study of glycine transport in SK-N-MC cells expressing the native human qlyti transporter.
La capture de [14C]glycine est étudiée dans les cellules SK-N-MC (cellules neuro- épithéliales humaines) exprimant le transporteur humain glyti 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-éthanesulfonique) 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 1 12 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 Cl50, 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.[ 14 C] glycine uptake is studied in SK-N-MC (human neuroepithelial cells) cells expressing the native human glyti transporter by measuring the radioactivity incorporated in the presence or absence of the test compound. The cells are cultured in monolayer for 48 h in 0.02% fibronectin pretreated plates. On the day of the experiment, the culture medium is removed and the cells are washed with Krebs-HEPES buffer ([4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid) at pH 7.4. After 10 minutes of preincubation at 37 ° C. in the presence of either buffer (control group) or test compound at different concentrations or 10 mM glycine (non-specific capture determination), 10 μM [ 14 C] glycine (specific activity 112 mCi / mmol) are then added. Incubation is continued for 10 min at 37 ° C, and the reaction is stopped by 2 washes with Krebs-HEPES buffer pH 7.4. The radioactivity incorporated by the cells is then estimated after adding 100 μl of liquid scintillant and stirring for 1 h. Counting is performed on a Microbeta Tri-lux ™ counter. The effectiveness of the compound is determined by the Cl 50 concentration of the compound which decreases by 50% the specific uptake of glycine, defined by the difference in radioactivity incorporated by the control group and the lot which received glycine at 10 mM.
Les composés de l'invention, dans ce test, présentent une Cl5o de l'ordre de 0,01 à 10 μM.The compounds of the invention, in this test, have a Cl 5 o of the order of 0.01 to 10 μM.
Le tableau 3 indique quelques exemples de résultats de Cl50 pour des composés selon l'invention.Table 3 shows some examples of Cl 50 results for compounds according to the invention.
TABLEAU 3TABLE 3
Figure imgf000024_0001
Figure imgf000024_0001
Les résultats des essais in vitro effectués sur les composés chiraux de l'invention et leurs racémates selon la formule générale (I) montrent qu'ils sont inhibiteurs du transporteur de la glycine glyti présents dans le cerveau.The results of the in vitro tests carried out on the chiral compounds of the invention and their racemates according to the general formula (I) show that they are inhibitors of the glycine glycine transporter present in the brain.
Ces résultats suggèrent que les composés de l'invention peuvent être utilisés pour le traitement des troubles cognitifs et/ou comportementaux associés à des maladies neurodégénératives, à la démence ; pour le traitement des psychoses, notamment de la schizophrénie (forme déficitaire et forme productive), 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 bipolaires, des troubles maniaques, des troubles de l'humeur ; 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, de la migraine ; de la douleur ; des troubles du sommeil.These results suggest that the compounds of the invention can be used for the treatment of cognitive and / or behavioral disorders associated with neurodegenerative diseases, dementia; for the treatment of psychoses, in particular schizophrenia (deficient form and productive form), acute or chronic extrapyramidal symptoms induced by neuroleptics; for the treatment of various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders; for the treatment of various forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or withdrawal, sexual behavior disorders, eating disorders, migraine; pain ; sleep disorders.
Les composés selon l'invention peuvent donc être utilisés pour la préparation de médicaments, en particulier de médicaments inhibiteurs du transporteur de la glycine giyti .The compounds according to the invention can therefore be used for the preparation of medicaments, in particular inhibitory drugs of the glycine glycine transporter.
Ainsi, selon un autre de ses aspects, l'invention a pour objet des médicaments qui comprennent un composé de formule (I), ou un sel d'addition de ce dernier à un acide pharmaceutiquement acceptable.Thus, according to another of its aspects, the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid.
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 pharmaceutiquement acceptable, et en mélange, le cas échéant, avec des excipients convenables.The present invention also relates to pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the form of a base or of a pharmaceutically acceptable salt, and in a mixture, where appropriate, with suitable excipients.
Lesdits excipients sont choisis selon la forme pharmaceutique et le mode d'administration souhaité.Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.
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.The pharmaceutical compositions according to the invention can thus be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal, intraocular 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 dosage forms may be, for example, tablets, capsules, granules, powders, oral solutions or suspensions or injectables, transdermal patches, suppositories. For topical administration, it is possible to envisage ointments, lotions and eye drops. Said unit forms are dosed to allow a daily administration of 0.01 to 20 mg of active ingredient per kg of body weight, according to the dosage form.
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, hydroxy-propylméthylcellulose, etc), des agents d'écoulement comme la silice, des lubrifiants comme le stéarate de magnésium, l'acide stéarique, le tribéhénate de glycérol, le stéaryl-fumarate 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.To prepare tablets, a pharmaceutical carrier which may be composed of diluents, for example lactose, microcrystalline cellulose, starch, and formulation adjuvants such as binders (polyvinylpyrrolidone), is added to the active ingredient, whether micronized or not; , hydroxypropyl methylcellulose, etc.), flow agents such as silica, lubricants such as magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate. Wetting agents or surfactants such as sodium lauryl sulphate may also be added. The production techniques can be direct compression, dry granulation, wet granulation or hot melt.
Les comprimés peuvent être nus, dragéifiés, par exemple par du saccharose, ou enrobés avec divers polymères ou autres matières appropriées. Ils 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.The tablets may be bare, sugar-coated, for example with sucrose, or coated with various polymers or other suitable materials. They can be designed to allow rapid, delayed or prolonged release of the active ingredient through polymer matrices or specific polymers 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. 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).To prepare capsules, the active ingredient is mixed with dry pharmaceutical vehicles (simple mixing, dry or wet granulation, or hot melting), liquid or semi-solid. The capsules may be hard or soft, film-coated or not, so as to have a rapid, prolonged or delayed activity (for example for an enteric form).
Une composition sous forme de sirop ou d'élixir ou pour l'administration sous forme de gouttes peut contenir le principe actif conjointement à un édulcorant, de préférence acalorique, du méthylparaben ou du propylparaben comme antiseptique, un agent de sapidité et un colorant.A composition in the form of syrup or elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably acaloric, methylparaben or propylparaben as antiseptic, a flavoring agent and a dye.
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 édulcorants 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.Water-dispersible powders and granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or dispersing agents such as polyvinylpyrrolidone, as well as with sweeteners and taste-correcting agents. For rectal administration, suppositories prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols, are used.
Pour une administration parentérale, on utilise des suspensions aqueuses, des solutions salines isotoniques ou des solutions stériles injectables 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 ingredient may also be formulated in the form of microcapsules, optionally with one or more supports or additives, or with a polymer matrix or with a cyclodextrin (transdermal patches, sustained-release forms).
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 solutions, alcoholic or aqueous-alcoholic, gels, water-in-oil or oil-in-water emulsions having the appearance of a cream or a gel, microemulsions, aerosols, or in the form of vesicular dispersions containing ionic and / or nonionic lipids. These galenic forms are prepared according to the usual methods of the fields considered.
A titre d'exemple, une forme unitaire d'administration d'un composé selon l'invention sous forme de comprimé peut comprendre les composants suivants :By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
Composé selon l'invention 50,0 mgCompound according to the invention 50.0 mg
Mannitol 223,75 mgMannitol 223.75 mg
Croscaramellose sodique 6,0 mg Amidon de maïs 15,0 mgCroscaramellose sodium 6.0 mg Corn starch 15.0 mg
Hydroxypropyl-méthylcellulose 2,25 mgHydroxypropyl methylcellulose 2.25 mg
Stéarate de magnésium 3,0 mgMagnesium stearate 3.0 mg
Par voie orale, la dose de principe actif administrée par jour peut atteindre 0,1 à 20 mg/kg, en une ou plusieurs prises.Orally, the dose of active ingredient administered per day can reach 0.1 to 20 mg / kg, in one or more doses.
Il peut y avoir des cas particuliers où des dosages plus élevés ou plus faibles sont appropriés ; de tels dosages ne sortent pas du cadre de l'invention. Selon la pratique habituelle, le dosage approprié à chaque patient est déterminé par le médecin selon le mode d'administration, le poids et la réponse dudit patient.There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
La présente invention, selon un autre de ses aspects, concerne également une méthode de traitement des pathologies ci-dessus indiquées qui comprend l'administration, à un patient, d'une dose efficace d'un composé selon l'invention, ou un de ses sels pharmaceutiquement acceptables. The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of pharmaceutically acceptable salts thereof.

Claims

REVENDICATIONS
1. Composé de formule générale (I)1. Compound of general formula (I)
Figure imgf000029_0001
Figure imgf000029_0001
dans laquelle :in which :
- R représente un atome d'hydrogène ou un groupe choisi parmi les groupes (C1- C6)alkyle, (C3-C7)-cycloalkyle benzyle ou allyle, éventuellement substitué par un ou plusieurs groupes choisis indépendamment l'un de l'autre parmi les atomes d'halogène, les groupes (C3-C7)-cycloalkyle, (C1-C6)alkyle, (C1-C6)BlCOXy, hydroxy, ;R represents a hydrogen atom or a group chosen from (C 1 -C 6 ) alkyl, (C 3 -C 7 ) -cycloalkyl benzyl or allyl groups, optionally substituted with one or more groups independently selected from one of the other one of the halogen atoms, the (C 3 -C 7 ) -cycloalkyl, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) -ClCOXy, hydroxy groups;
- R1 représente un groupe phényle ou naphtyle, éventuellement substitué par un ou plusieurs substituants choisis indépendamment l'un de l'autre parmi les atomes d'halogène, les groupes (CrC6)alkyle, (CrC6)alcoxy, halo-(CrC6)alkyle, hydroxy, halo-(C1-C6)alcoxy, (CrC6)alkyle-thio, (CrC6)alkyle-SO, (CrC6)alkyle-Sθ2 ;- R 1 represents a phenyl or naphthyl group, optionally substituted with one or more substituents chosen independently of one another from halogen atoms, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halo ( CrC 6 ) alkyl, hydroxy, halo- (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) alkyl-thio, (C 1 -C 6 ) alkyl-SO, (C 1 -C 6 ) alkyl-SO 2;
- Het représente un groupe hétéroaryle ;Het represents a heteroaryl group;
- R2 représente un ou plusieurs substituants choisis parmi l'atome d'hydrogène, les atomes d'halogène, les groupes halo-(CrC6)alkyle, (C1-C6)alkyle, (C3-C7)cycloalkyle, (C3-C7)-cycloalkyl-(C1-C3)alkyle, (C1-C6)BlCOXy, benzyl, (CrC6)alkyle-thio, (C1- C6)alkyle-SO, (CrC6)alkyle-SO2 ; à l'état de base ou de sel d'addition à un acide.- R 2 represents one or more substituents selected from hydrogen, halogen atoms, halo groups (CrC 6) alkyl, (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl (C 3 -C 7 ) -cycloalkyl- (C 1 -C 3 ) alkyl, (C 1 -C 6 ) B-C0C04, benzyl, (C 1 -C 6 ) alkyl-thio, (C 1 -C 6 ) alkyl- SO (C r C 6) alkyl-SO 2; in the form of a base or an acid addition salt.
2. Composé de formule générale (I) selon la revendication 1 , caractérisé en ce que R représente un atome d'hydrogène, un groupe benzyle ou un groupe allyle ; R1 , Het et R2 étant tels que définis dans la revendication 1 , à l'état de base ou de sel d'addition à un acide.2. Compound of general formula (I) according to claim 1, characterized in that R represents a hydrogen atom, a benzyl group or an allyl group; Wherein R 1, Het and R 2 are as defined in claim 1, in the form of a base or an acid addition salt.
3. Composé de formule générale (I) selon la revendication 1 , caractérisé en ce que R1 représente un groupe phényle ou naphtyle, éventuellement substitué par un ou plusieurs groupes choisis indépendamment l'un de l'autre parmi les atomes d'halogène, les groupes (CrC6)alkyle, (CrC6)alcoxy, halo-(C1-C6)alkyle ; R, Het et R2 étant tels que définis dans la revendication 1 , à l'état de base ou de sel d'addition à un acide.3. Compound of general formula (I) according to claim 1, characterized in that R 1 represents a phenyl or naphthyl group, optionally substituted by one or more groups chosen independently of one another from halogen atoms, groups (CrC 6) alkyl, (Ci-C 6) alkoxy, halo- (C 1 -C 6) alkyl; R, Het and R2 being as defined in claim 1, in the form of a base or an acid addition salt.
4. Composé de formule générale (I) selon la revendication 1 , caractérisé en ce que Het représente un groupe indole, thiophène ou pyridine ;4. Compound of general formula (I) according to claim 1, characterized in that Het represents an indole, thiophene or pyridine group;
R, R1 et R2 étant tels que définis dans la revendication 1 , à l'état de base ou de sel d'addition à un acide.Wherein R 1, R 1 and R 2 are as defined in claim 1, in the form of a base or an acid addition salt.
5. Composé de formule générale (I) selon la revendication 1 , caractérisé en ce que R2 représente un ou plusieurs substituants choisis parmi l'atome d'hydrogène, les atomes d'halogène, les groupes halo-(C1-C6)alkyle, benzyle, (C1-C6)alkyle-thio ;5. Compound of general formula (I) according to claim 1, characterized in that R 2 represents one or more substituents chosen from the hydrogen atom, the halogen atoms and the halogen (C 1 -C 6) groups. ) alkyl, benzyl, (C 1 -C 6 ) alkylthio;
R, R1 et Het étant tels que définis dans la revendication 1 , à l'état de base ou de sel d'addition à un acide.R, R 1 and Het being as defined in claim 1, in the form of a base or an acid addition salt.
6. Composé de formule générale (I) selon la revendication 1 , caractérisé en ce que6. Compound of general formula (I) according to claim 1, characterized in that
- R représente un atome d'hydrogène, un groupe benzyle ou un groupe allyle ;R represents a hydrogen atom, a benzyl group or an allyl group;
- Ri représente un groupe phényle ou naphtyle, éventuellement substitué par un ou plusieurs substituants choisis indépendamment l'un de l'autre parmi les atomes d'halogène, les groupes (CrC6)alkyle, (CrC6)alcoxy, halo-(Ci-C6)alkyle, - Het représente un groupe indole, thiophène ou pyridine ;R 1 represents a phenyl or naphthyl group, optionally substituted with one or more substituents chosen independently of one another from halogen atoms, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen (Ci -C 6 ) alkyl, - Het represents an indole, thiophene or pyridine group;
- R2 représente un ou plusieurs substituants choisis parmi l'atome d'hydrogène, les atomes d'halogène, les groupes halo-(CrC6)alkyle, benzyle, (Ci-C6)alkyle-thio ; à l'état de base ou de sel d'addition à un acide.R 2 represents one or more substituents chosen from a hydrogen atom, halogen atoms, halo- (C 1 -C 6 ) alkyl, benzyl, (C 1 -C 6 ) alkyl-thio groups; in the form of a base or an acid addition salt.
7. Composé de formule générale (I) selon la revendication 1 ou 6, caractérisé en ce que7. Compound of general formula (I) according to claim 1 or 6, characterized in that
- R représente un atome d'hydrogène, un groupe benzyle ou un groupe allyle ;R represents a hydrogen atom, a benzyl group or an allyl group;
- Ri représente un groupe phényle ou naphtyle, éventuellement substitué par un ou plusieurs substituants choisis indépendamment l'un de l'autre parmi l'atome de fluor, les groupes méthyle, methoxy ou trifluorométhyleR 1 represents a phenyl or naphthyl group, optionally substituted by one or more substituents chosen independently of one another from the fluorine atom, the methyl, methoxy or trifluoromethyl groups;
- Het représente un groupe indole, thiophène ou pyridine ;Het represents an indole, thiophene or pyridine group;
- R2 représente un ou plusieurs substituants choisis parmi l'atome d'hydrogène, les atomes de brome ou de chlore, les groupes trifluorométhyle, methylthio ou benzyle, à l'état de base ou de sel d'addition à un acide. - R 2 represents one or more substituents chosen from a hydrogen atom, bromine or chlorine atoms, trifluoromethyl, methylthio or benzyl groups, in the form of a base or of an addition salt with an acid.
8. Composé selon l'une des revendications 1 à 7, caractérisé en ce qu'il est choisi parmi :8. Compound according to one of claims 1 to 7, characterized in that it is chosen from:
Λ/-[(2-Allyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(4,5-dibromo)-thiophène-2- carboxamide ;N - [(2-Allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide;
Λ/-[(2-Aza-bicyclo[2.1.1 ]hex-1 -yl)-phényl-méthyl]-(4,5-dibromo)-thiophène-2- carboxamide ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(2,5-dichloro)-thiophène-3- carboxamide ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (2,5-dichloro) -thiophene-3-carboxamide;
(+)-Λ/-[(2-Aza-bicyclo[2.1.1 ]hex-1 -yl)-phényl-méthyl]-(4,5-dibromo)-thiophène-2- carboxamide, et son chlorhydrate ;(+) - Λ / - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide, and its hydrochloride;
(-)-Λ/-[(2-Aza-bicyclo[2.1.1 ]hex-1 -yl)-phényl-méthyl]-(4,5-dibromo)-thiophène-2- carboxamide, et son chlorhydrate ;(-) - Λ / - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide, and its hydrochloride;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-(4-fluoro-phényl)-méthyl]-(3-chloro-4- trifluorométhyl)-pyridine-2-carboxamide ;N - [(2-Azabicyclo [2.1.1] hex-1-yl) - (4-fluoro-phenyl) -methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide;
N-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-2-méthylsulfanyl-nicotinamide ;N - [(2-Azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] -2-methylsulfanyl-nicotinamide;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(3-chloro-4-trifluorométhyl)- pyridine-2-carboxamide ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(1-benzyl)-1 H-indole-4- carboxamide ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (1-benzyl) -1H-indole-4-carboxamide;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-naphthalèn-2-yl-méthyl]-(3-chloro-4- trifluorométhyl)-pyridine-2-carboxamide, et son chlorhydrate ;N - [(2-Azabicyclo [2.1.1] hex-1-yl) -naphthalen-2-ylmethyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide, and its hydrochloride ;
Λ/-[(2-Aza-bicyclo[2.1.1 ]hex-1 -yl)-naphthalèn-2-yl-méthyl]-2-méthylsulfanyl- nicotinamide, et son chlorhydrate ;Λ / - [(2-Azabicyclo [2.1.1] hex-1-yl) -naphthalen-2-ylmethyl] -2-methylsulfanyl-nicotinamide, and its hydrochloride;
Λ/-[(2-aza-bicyclo[2.1.1]hex-1-yl)-(3-méthoxy-phényl)-méthyl]-(3-chloro-4- trifluorométhyl)-pyridine-2-carboxamide, et son chlorhydrate ;N - [(2-azabicyclo [2.1.1] hex-1-yl) - (3-methoxy-phenyl) -methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide, and its hydrochloride;
Λ/-[(2-Aza-bicyclo[2.1.1 ]hex-1 -yl)-(3-méthoxy-phényl)-méthyl]-2-méthylsulfanyl- nicotinamide, et son chlorhydrate ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) - (3-methoxy-phenyl) -methyl] -2-methylsulfanyl-nicotinamide, and its hydrochloride;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-m-tolyl-méthyl]-2-méthylsulfanyl-nicotinamide, et son chlorhydrate ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -m-tolyl-methyl] -2-methylsulfanyl-nicotinamide, and its hydrochloride;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-(3-trifluorométhyl-phényl)-méthyl]-(3-chloro-4- trifluorométhyl)-pyridine-2-carboxamide, et son chlorhydrate ; Λ/-[(2-Aza-bicyclo[2.1.1 ]hex-1 -yl)-m-tolyl-méthyl]-(3-chloro-4-trifluorométhyl)- pyridine-2-carboxamide, et son chlorhydrate ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) - (3-trifluoromethyl-phenyl) -methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide, and its hydrochloride; N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -m-tolyl-methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2-carboxamide, and its hydrochloride;
(+)-Λ/-[(2-Allyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(4,5-dibromo)-thiophène- 2-carboxamide ;(+) - Λ- [[2-Allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene-2-carboxamide;
(-)-Λ/-[(2-Allyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(4,5-dibromo)-thiophène-(-) - Λ / - [(2-Allyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (4,5-dibromo) -thiophene
2-carboxamide ;2-carboxamide;
Λ/-[(2-benzyl-2-aza-bicyclo[2.1.1]hex-1-yl)-(3-trifluorométhyl-phényl)-méthyl]-(3- chloro-4-trifluorométhyl)-pyridine-2-carboxamide et son chlorhydrate ; Λ/-[(2-benzyl-2-aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(2,5-dichloro)-thiophène-3- carboxamide et son chlorhydrate ; Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(3,6-dichloro)-pyridine-2- carboxamide et son chlorhydrate ;N - [(2-benzyl-2-azabicyclo [2.1.1] hex-1-yl) - (3-trifluoromethyl-phenyl) -methyl] - (3-chloro-4-trifluoromethyl) -pyridine-2 carboxamide and its hydrochloride; N - [(2-benzyl-2-aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (2,5-dichloro) -thiophene-3-carboxamide and its hydrochloride; N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (3,6-dichloro) -pyridine-2-carboxamide and its hydrochloride;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(3-chloro-5-trifluorométhyl)-pyridine- 2-carboxamide ;N - [(2-Aza-bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (3-chloro-5-trifluoromethyl) -pyridine-2-carboxamide;
Λ/-[(2-Aza-bicyclo[2.1.1]hex-1-yl)-phényl-méthyl]-(6-chloro-3-trifluorométhyl)-pyridine- 2-carboxamide ;N - [(2-Azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (6-chloro-3-trifluoromethyl) -pyridine-2-carboxamide;
9. Procédé de préparation d'un composé de formule générale (I) selon la revendication 1 , caractérisé en ce qu'un composé de formule générale (II)9. Process for the preparation of a compound of general formula (I) according to claim 1, characterized in that a compound of general formula (II)
(N)(NOT)
R NH2 dans laquelle R et R1 sont tels que définis selon la revendication 1 , réagit avec un composé de formule générale (III)R NH 2 in which R and R 1 are as defined in claim 1, reacts with a compound of general formula (III)
Figure imgf000032_0001
dans laquelle Y représente un groupe partant ou un atome de chlore et Het et R2 sont définis selon la revendication 1.
Figure imgf000032_0001
wherein Y is a leaving group or a chlorine atom and Het and R 2 are as defined in claim 1.
10. Composé de formule (II)10. Compound of formula (II)
Figure imgf000033_0001
dans laquelle R et R1 sont définis selon la revendication 1.
Figure imgf000033_0001
wherein R and R 1 are as defined in claim 1.
11. Médicament, caractérisé en ce qu'il comprend un composé de formule (I) selon l'une quelconque des revendications 1 à 8, ou un sel d'addition de ce composé à un acide pharmaceutiquement acceptable.11. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 8, or a salt of addition of this compound to a pharmaceutically acceptable acid.
12. Composition pharmaceutique, caractérisée en ce qu'elle comprend un composé de formule (I) selon l'une quelconque des revendications 1 à 8, ou un sel pharmaceutiquement acceptable de ce composé, ainsi qu'au moins un excipient pharmaceutiquement acceptable.12. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
13. Utilisation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 8 pour la préparation d'un médicament destiné au traitement des troubles cognitifs et/ou comportementaux associés à des maladies neurodégénératives ; à la démence.13. Use of a compound of formula (I) according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of cognitive and / or behavioral disorders associated with neurodegenerative diseases; to madness.
14. Utilisation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 8 pour la préparation d'un médicament destiné au traitement des psychoses, de la schizophrénie (forme déficitaire et forme productive), des symptômes extrapyramidaux aigus ou chroniques induits par les neuroleptiques.14. Use of a compound of formula (I) according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of psychoses, schizophrenia (deficient form and productive form), acute extrapyramidal symptoms or chronic induced by neuroleptics.
15. Utilisation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 8 pour la préparation d'un médicament destiné au traitement des diverses formes d'anxiété, des attaques de panique, des phobies, des troubles obsessionnels compulsifs.15. Use of a compound of formula (I) according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of various forms of anxiety, panic attacks, phobias, obsessive disorders compulsive.
16. Utilisation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 8 pour la préparation d'un médicament destiné au traitement des différentes formes de dépression, y compris la dépression psychotique ; pour le traitement des troubles bipolaires, des troubles maniaques, des troubles de l'humeur ; 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, de la migraine. 16. Use of a compound of formula (I) according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of various forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or withdrawal, sexual behavior disorders, eating disorders, migraine.
17. Utilisation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 8 pour la préparation d'un médicament destiné au traitement de la douleur.17. Use of a compound of formula (I) according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of pain.
18. Utilisation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 8 pour la préparation d'un médicament destiné au traitement des troubles du sommeil.18. Use of a compound of formula (I) according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of sleep disorders.
19. Composé selon l'une quelconque des revendications 1 à 8, pour le traitement des troubles cognitifs et/ou comportementaux associés à des maladies neurodégénératives ; à la démence.19. A compound according to any one of claims 1 to 8 for the treatment of cognitive and / or behavioral disorders associated with neurodegenerative diseases; to madness.
20. Composé selon l'une quelconque des revendications 1 à 8, pour le traitement des psychoses, de la schizophrénie (forme déficitaire et forme productive), des symptômes extrapyramidaux aigus ou chroniques induits par les neuroleptiques.20. Compound according to any one of claims 1 to 8, for the treatment of psychoses, schizophrenia (deficient form and productive form), acute or chronic extrapyramidal symptoms induced by neuroleptics.
21. Composé selon l'une quelconque des revendications 1 à 8, pour le traitement des diverses formes d'anxiété, des attaques de panique, des phobies, des troubles obsessionnels compulsifs.21. A compound according to any one of claims 1 to 8 for the treatment of various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders.
22. Composé selon l'une quelconque des revendications 1 à 8, pour le traitement des différentes formes de dépression, y compris la dépression psychotique ; pour le traitement des troubles bipolaires, des troubles maniaques, des troubles de l'humeur ; 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, de la migraine.22. A compound according to any one of claims 1 to 8 for the treatment of various forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or withdrawal, sexual behavior disorders, eating disorders, migraine.
23. Composé selon l'une quelconque des revendications 1 à 8, pour le traitement de la douleur.23. A compound according to any one of claims 1 to 8 for the treatment of pain.
24. Composé selon l'une quelconque des revendications 1 à 8, pour le traitement des troubles du sommeil. 24. A compound according to any one of claims 1 to 8 for the treatment of sleep disorders.
PCT/FR2010/050447 2009-03-16 2010-03-15 Derivatives of n-[(2-aza-bicyclo[2.1.1]hex-1-yl)-aryl-methyl]-heterobenzamide, preparation thereof and application of same in therapeutics WO2010106269A2 (en)

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SG2011066867A SG174434A1 (en) 2009-03-16 2010-03-15 Derivatives of n-[(2-aza-bicyclo[2.1.1]hex-1-yl)-aryl-methyl]-heterobenzamide, preparation thereof and application of same in therapeutics
AU2010224720A AU2010224720A1 (en) 2009-03-16 2010-03-15 Derivatives of N-[(2-aza-bicyclo [2.1.1]hex-1-yl)-aryl-methyl]-heterobenzamide, preparation thereof and application of same in therapeutics
CN2010800121453A CN102356074A (en) 2009-03-16 2010-03-15 Derivatives of n-[(2-aza-bicyclo[2.1.1]hex-1-yl)-aryl-methyl]-heterobenzamide, preparation thereof and application of same in therapeutics
MX2011009677A MX2011009677A (en) 2009-03-16 2010-03-15 Derivatives of n-[(2-aza-bicyclo[2.1.1]hex-1-yl)-aryl-methyl]-het erobenzamide, preparation thereof and application of same in therapeutics.
JP2012500292A JP2012520345A (en) 2009-03-16 2010-03-15 Derivatives of N-[(2-aza-bicyclo [2.1.1] hex-1-yl) -aryl-) methyl] -heterobenzamide, their preparation and their use in therapy
BRPI1009496A BRPI1009496A2 (en) 2009-03-16 2010-03-15 n - [(2-aza-bicyclo [2.1.1] hex-1-yl) arylmethyl] heterobenzamide derivatives, their preparation and their therapeutic application
CA2755526A CA2755526A1 (en) 2009-03-16 2010-03-15 Derivatives of n-[(2-aza-bicyclo[2.1.1]hex-1-yl)-aryl-methyl]-heterobenzamide, preparation thereof and application of same in therapeutics
RU2011141778/04A RU2011141778A (en) 2009-03-16 2010-03-15 Derivatives of N - [(2-azabicyclo [2.1.1] HEX-1-IL) arylmethyl] heterobenzamide, their production and their use in therapy
EP10715932A EP2408763A2 (en) 2009-03-16 2010-03-15 Derivatives of n-ý(2-aza-bicycloý2.1.1¨hex-1-yl)-aryl-methyl¨-heterobenzamide, preparation thereof and application of same in therapeutics
IL215104A IL215104A0 (en) 2009-03-16 2011-09-12 Derivatives of n-[(2-aza-bicyclo[2.1.1]hex-1-yl)-aryl-methyl]-heterobenzamide, preparation thereof and application of same in therapeutics

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FR09/01219 2009-03-16
FR0901219A FR2943056A1 (en) 2009-03-16 2009-03-16 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
FR09/01810 2009-04-14
FR0901810A FR2944283B1 (en) 2009-04-14 2009-04-14 N- (2-AZA-BICYCLO) -2.1.1-HEX-1-YL) -ARYL-METHYL-HETEROBENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE

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AU2010224720A1 (en) 2011-10-06
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AR075837A1 (en) 2011-04-27
SG174434A1 (en) 2011-10-28
CA2755526A1 (en) 2010-09-23
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EP2408763A2 (en) 2012-01-25
IL215104A0 (en) 2011-12-29

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