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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
  • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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  • C07D213/02—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
  • 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
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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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
  • C07D333/06—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
  • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
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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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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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  • C07D487/08—Bridged systems

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.

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