EP2419431A1

EP2419431A1 - Derivatives of n-[(7-aza-bicyclo[2.2.1]hept-1-yl)-aryl-methyl]-benzamide, preparation thereof, and therapeutic use thereof

Info

Publication number: EP2419431A1
Application number: EP10723665A
Authority: EP
Inventors: Gihad Dargazanli; Geneviève ESTENNE-BOUHTOU
Original assignee: Sanofi SA
Current assignee: Sanofi SA
Priority date: 2009-04-14
Filing date: 2010-04-13
Publication date: 2012-02-22
Also published as: KR20120013378A; AR076276A1; BRPI1015484A2; FR2944284A1; IL215673A0; JP2012523448A; MX2011010929A; SG175222A1; CA2758367A1; WO2010119222A1; TW201041581A; AU2010238409A1; UY32561A

Abstract

The inventions relates to the compounds of formula (I) where: R is a hydrogen atom or a group selected from the (C₁d- C₆)alkyl and (C₃-C₇)-cycloalkyl groups, optionally substituted by one or more groups independently selected from a fluorine atom, the (C₃-C₇)-cycloalkyl, (C₂-C₄)alkenyl, phenyl, (C₁-C₆)alkoxy, and hydroxy groups; the phenyl group being optionally substituted by one or more (C₁-C₆)alkoxy groups; R₁ is a phenyl group optionally substituted by one or more substituants independently selected from halogen atoms, the (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo-(C₁C₆)alkyl, hydroxy, halo-(C₁-C₆)alkoxy, (C₁-C₆)alkyl-thio, and (C₁-C₆)alkyl-SO₂ groups; R₂ is one or more substituants selected from hydrogen atoms, halogen atoms, the halo-(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₃)alkyl, (C₁C₆)alkoxy, (C₁C₆)alkyl-thio, and (C₁-C₆)alkyl-SO₂ groups; in the form of a base or an addition salt to an acid. The invention further relates to the use thereof in therapy and to a method for synthesizing same.

Description

Λ / - [(7-AZA-BICYCLO [2.2.1] HEPT-1-YL) -LAYL-METHYL DERIVATIVES -

BENZAMIDE, THEIR PREPARATION AND THEIR APPLICATION

THERAPEUTIC

The present invention relates to Λ / - [(7-aza-bicyclo [2.2.1] hept-1-yl) -aryl-methyl] -benzamide derivatives, to their preparation and their therapeutic application in the treatment of or the prevention of diseases involving glycine carriers Glyti.

The compounds of the invention correspond to the general formula (I)

in which :

R represents a hydrogen atom or a group chosen from (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) -cycloalkyl groups, optionally substituted with one or more groups chosen independently of one another from halogen atoms, (C ₃ -C ₇ ) -cycloalkyl, (C ₂ -C ₄ ) alkenyl, phenyl, (C ₁ -C ₆ ) alkoxy, hydroxy; the phenyl group being optionally substituted by one or more (C ₁ -C ₆ ) alkoxy groups;

R 1 represents a phenyl or naphthyl group, optionally substituted by one or more substituents chosen independently of one another from halogen atoms, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy groups, halo (CrC ₆₎ alkyl, hydroxy, halo (C _r C ₆₎ alkoxy, (C _r C ₆₎ alkyl-thio, (C _r C ₆₎ alkyl-SO, (Ci-C ₆₎ alkyl-SO ₂ - 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 (C ₃ -C ₇ ) -cycloalkyl- (C ₁ -C ₃ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkyl -SO (dC ₆ ) alkyl-SO ₂ ; in the form of a base or an acid addition salt.

The compounds of formula (I) have an asymmetric carbon atom. They can therefore exist in the form of enantiomers. These enantiomers, including racemic mixtures, form 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.

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.

In the context of the invention, the following terms mean:

_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 C ₁ -C ₆ -alkyl group represents a linear or branched carbon chain of 1 to 6 carbon atoms, for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl group; ; - alkylene, saturated divalent alkyl group, linear or branched, for example a Ci _-6 alkylene group represents a divalent carbon chain of 1 to 6 carbon atoms, linear or branched, for example methylene, ethylene, 1- methylethylene, propylene, alkoxy, -O-alkyl, -hydroxy, -OH, alkyl-thio, sulfur atom substituted by alkyl; halogen atom, fluorine, chlorine, bromine or iodine, haloalkyl, alkyl group of which one or more hydrogen atoms have been substituted by halogen. By way of example, mention may be made of trifluoromethyl, trifluoroethyl or pentafluoroethyl groups; halo-alkoxy, an alkoxy group of which one or more hydrogen atoms have been substituted by a halogen.

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 represents a hydrogen atom, a (C ₁ -C ₆ ) alkyl or benzyl group;

R ₁ and R 2 being as defined above

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 represents a phenyl group;

R and R2 being as defined above.

Among the compounds of general formula (I) that are the subject of the invention, a third group of compounds consists of compounds for which:

R ₂ represents one or more substituents chosen from a hydrogen atom, halogen atoms, halo (Ci-C ₆ ) alkyl or (Ci-C ₆ ) alkyl groups, R and R 1 being as defined herein; -above.

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:

R represents a hydrogen atom, a (C ₁ -C ₆ ) alkyl or benzyl group;

Ri represents a phenyl group,

R ₂ represents one or more substituents chosen from a hydrogen atom, halogen atoms, halo- (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkyl groups,

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 represents a hydrogen atom or a methyl, ethyl or benzyl group; Ri represents a phenyl group,

R ₂ represents one or more substituents chosen from a hydrogen atom, a chlorine atom, methyl, ethyl or trifluoromethyl groups, in the form of a base or an addition salt with an acid.

The combinations of groups one to five as defined above are also part of the invention.

Among the compounds of general formula (I) which are subjects of the invention, mention may especially be made of the following compounds: • Λ / - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-methyl-3-trifluoromethyl) benzamide;

• N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) benzamide, and its hydrochloride;

(-) - N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) benzamide, and its hydrochloride; • Λ - [(7-Azabicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide, and its hydrochloride;

2-Chloro-N - [(7-ethyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide, and its hydrochloride; (+) - Λ / - [(7-Azabicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) benzamide, and its hydrochloride;

2-Chloro-N - [(7-methyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] -3-trifluoromethyl-benzamide, and its hydrochloride;

• Λ - [(7-Benzyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-methyl-3-trifluoromethyl) -benzamide, and its hydrochloride;

N - [(7-Benzyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide, and its hydrochloride;

N - [(7-Azabicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-ethyl) -benzamide, and its hydrochloride.

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) can be prepared by a process illustrated by Scheme 1 which follows:

SCHEME 1

( 'I)

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, a phenylmethyl group, with an activated acid, for example via a mixed anhydride or an acid chloride of the 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:

or a phenylmethyl group by deprotecting the nitrogen by hydrogenolysis,

or an alkenyl group, preferably 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,

- A dimethoxybenzyl group by deprotecting by oxidation methods known to those skilled in the art.

The compounds of general formula (I) in which R is different from the hydrogen atom, can 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 a halide or mesylate of the RX type, in which R is as defined above and X is a mesylate or halogen, in the presence of a mineral base, for example potassium carbonate in the 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.

The diamine of general formula (II) can be prepared by the process illustrated by scheme 2 for the amine of general formula (IIa) and for the amine of general formula (Nb) which follows:

SCHEME 2

(IV) (V) (IIa) (Hb)

According to Scheme 2, the ester of formula (IV) is converted into nitrile of formula (V), by heating at reflux of xylene in the presence of the trimethylaluminium complex and ammonium chloride previously formed, according to a method described in Synthetic Commun., 1982, 12 (13), 989-993 and in Tetrahedron Lett., 1979, (51), 4907-4910. The nitrile of formula (V) is then reacted with the lithiated aromatic compound of general formula (VI), in which R 1 is as defined above, in an ethereal solvent such as tetrahydrofuran or ether, at low temperature. for example - 70 ^° C. An imine is thus obtained 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 (IIa). The amine (IIa) can be debenzylated by hydrogenation in the presence of palladium catalyst to provide deprotected amine of general formula (Nb).

For the compounds of formula (IV) and (V), the benzyl group could in particular be replaced by another protecting group, for example by an allyl group or a dimethoxybenzyl group, either by debenzylating then by reprotecting, for example by means of a reaction. alkylation with the appropriate electrophile, for example an allyl bromide or a dimethoxybenzyl bromide, according to the methods known to those skilled in the art; either according to the method described in Tetrahedron: Asymmetry, 2006 (17), 252-258, replacing benzylamine with allylamine or dimethoxybenzylamine, especially 2,4-dimethoxybenzylamine. 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 Tetrahedron,

2002 (58), 10167-10171. The nitrile of formula (V) could also be prepared according to a method described in Tetrahedron: Asymmetry, 2006 (17), 252-258.

The lithiated derivatives of general formula (VI) may 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 examples which follow illustrate the preparation of some compounds of the invention. In these examples: Elemental microanalyses, I.R. and R.MN spectra and chiral column HPLC confirm the structures and enantiomeric purities of the compounds obtained,

For NMR descriptions, "m" means multiplet, "s" singlet, "t" triplet, "d" doublet, "q" quadruplet, dxd means double doublet, txt means triple triplet, dxt double triplet, and so on.

The numbers indicated in parentheses in the titles of the examples correspond to those in the 1st column of the table given below,

"Decomp." means "decomposition",

The nomenclature used is the nomenclature following the International Union of Pure and Applied Chemistry (IUPAC) recommendations.

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. Example 1 (Compound No. 4): Λ- [(7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) benzamide hydrochloride (1 : 1)

1.1. (7-Benzyl-7-aza-bicylo [2.2.11 heptane] -1-carbonitrile In a 250 ml three-necked layer under nitrogen, the trimethylaluminium / ammonium chloride complex (approximately 0.67M) is prepared, hereinafter referred to as complex A, by placing 1.5 g of dry ammonium chloride (28 mmol) in 30 ml of anhydrous toluene, to which 15 ml of a solution of 2N trimethylaluminum in toluene (30 mmol) are added after cooling and that it is left at room temperature until the end of the gas evolution.

In a 250 ml three-necked flask under nitrogen equipped with a condenser, 1.27 g of methyl (7-benzyl-7-aza-bicyclo [2.2.1] heptan) -1-carboxylate (5.18 mmol) are placed. in 100 ml of anhydrous xylene. 20 ml of complex A (13 mmol) are added dropwise and the mixture is heated at reflux overnight.

After cooling, the medium is acidified to pH 4-5 with 1N hydrochloric acid solution and then extracted successively with ethyl acetate (100 ml) and then dichloromethane (100 ml). The organic phases are dried over sodium sulphate, filtered, combined and then evaporated under reduced pressure.

The residue is purified by column chromatography on silica gel eluting with a mixture of petroleum ether and ethyl acetate. 210 mg of (7-benzyl-7-aza-bicyclo [2.2.1] heptane) -1-carbonitrile are thus obtained in the form of an oil.

¹ H NMR (200 MHz ₁ CDCl ₃ ) δ ppm 7.5 (m, 5H), 3.75 (s, 2H), 3.40 (m, 1H), 2.25 (m, 2H), 2 , 0 (m, 4H), 1, 4 (m, 2H).

1.2. (7-Benzyl-7-aza-bicyclo [2.2.11hept-1-yl) -phenyl-methylamine

In a three-necked 50 ml under argon, 0.45 g of (7-benzyl-7-aza-bicyclo [2.2.1] heptane) -1-carbonitrile (2.12 mmol) is placed at -70 ^° C. in ml of anhydrous tetrahydrofuran. 5.65 ml of a solution are added dropwise

0.75M (cyclohexane / ether) phenyl lithium (4.24 mmol).

It is left for 2 hours and a half at -70 ^° C. and then hydrolyzed at -20 ° C. with 10 ml of water. After extraction with ethyl acetate, the organic phase is concentrated under reduced pressure and the residue is taken up in 20 ml of methanol. 0.40 g of Sodium borohydride (10.6 mmol) is added in portions. The reaction medium is left stirring overnight at room temperature. After evaporation under reduced pressure, the residue is taken up in 25 ml of ether and 25 ml of water. The medium is acidified with a 1N hydrochloric acid solution and then extracted. The aqueous phase is basified with ammonia and then reextracted twice with 50 ml of dichloromethane. The organic phases are combined, 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 dichloromethane and ammoniacal methanol mixture. 0.5 g of (7-benzyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methylamine are thus obtained in the form of an oil which crystallizes.

¹ H NMR (400 MHz ₁ CDCl ₃ ) δ ppm 7.56 -7.22 (m, 10H), 4.31 (s, 1H), 3.86 (d, J = 13.3 Hz, 1H) ), 3.37 (d, J = 13.3 Hz, 1H), 3.19 (t, J = 4.5 Hz, 1H), 2.23 (m, 1H), m, 1H), 1.80-1.56 (m, 2H), 1.37 (m, 1H), 1.22-1.06 (m, 2H), 0.97 (m, 1H); ). Mp = 87-88 ° C

1.3. (7-aza-bicyclo [2.2.11hept-1-yl) -phenyl-methylamine

In an autoclave, 0.5 g of (7-benzyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenylmethylamine (1.71 mmol) dissolved in 20 ml of ethanol and 3 ml. 4 ml of 1 N hydrochloric acid in the presence of a spatula tip of 10% palladium on carbon are placed under a pressure of 7 atmospheres of hydrogen at 50 ^° C. for 6 hours. After filtration of the catalyst and concentration of the filtrate under reduced pressure, the residue is taken up in 25 ml of dichloromethane and 25 ml of water basified with ammonia. After extraction, the organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. 0.28 g of (7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methylamine are thus obtained in the form of an oil which solidifies in the cold and which is used as it is in the 'next step. ¹ H NMR (400 MHz ₁ CDCl ₃ ) δ ppm 7.36 -7.13 (m, 5H), 4.24 (s, 1H), 3.49 (t, J = 4.8 Hz, 1H ), 1, 74-1, 15 (m, 8H). Mp = 62-63 ° C 1.4. Λ N- (7-aza-bicyclo-2,2,2-hept-1-yl) -phenyl-methyl-2- (2-chloro-3-trifluoromethyl) -benzamide hydrochloride (1: 1).

0.26 g of (2-chloro-3-trifluoromethyl) benzoic acid (1.19 mmol), 0.16 g of hydroxybenzotriazole (1.19 mmol), 0.23 g are placed in a 25 ml flask. g of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.19 mmol) dissolved in 5 ml of dichloromethane and the mixture is stirred at room temperature for 15 minutes. 0.2 g (1.0 mmol) of (7-aza) bicyclo [2.2.1] hept-1-yl) -phenyl-methylamine dissolved in 2 ml of dichloromethane and stirred at room temperature overnight. The reaction medium is then diluted with 2 ml of dichloromethane and then washed successively with water (3 ml), 1N sodium hydroxide (3 ml) and with a saturated solution of sodium chloride (3 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. 260 mg of Λ- [(7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) benzamide are thus obtained, which is salified in the form of hydrochloride by solubilization of the base in ether, adding an excess of 1N hydrochloric acid in ether and concentration under reduced pressure.

¹ H NMR (300 MHz, DMSO-d 6) δ ppm 9.52 (d, J = 9 Hz, 1H), 9.32 (m, 1H), 8.92 (m, 1H), 7, 96 (m, 2H), 7.65 (m, 1H), 7.55-7.30 (m, 5H), 5.69 (d, J = 9.1 Hz, 1H), 4.07 (m, 1H), 2.30-0.65 (m, 8H). Mp = 146.5-147.5 ° C.

Example 2 (Compound No. 5): 2-Chloro-Λ [- [(7-ethyl-7-azabicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) hydrochloride ) benzamide (1: 1). 25 mg of Λ / - [(2-azabicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (2-chloro-3-ol) were placed in a 25 ml flask equipped with a condenser. -trifluoromethyl) -benzamide (0.23 mmol) in 2 ml of acetonitrile, 64 mg of potassium carbonate to which 30 μl of iodoethane (0.36 mmol) are added. The reaction mixture is stirred overnight at 45 ° C, then 3 hours at 50 ⁰ C and then is concentrated under reduced pressure. The residue is then diluted with 10 ml of dichloromethane and washed with water (5 ml). After extraction, the organic phase is dried over sodium sulfate, filtered and 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. 90 mg of 2-chloro-Λ [[(7-ethyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide are thus obtained. salified in hydrochloride form by solubilization of the base in dichloromethane, addition of an excess of 1 N hydrochloric acid in ether and concentration under reduced pressure. ¹ H NMR (400 MHz, DMSO-d 6) δ ppm 10.29 (m, 1H), 9.48 (d, J = 9.1 Hz, 1H), 8.12 (m, J = 8 Hz) , 1H), 7.94 (m, J = 7.6 Hz, 1H), 7.71-7.31 (m, 6H), 5.68 (d, J = 9.3 Hz, 1H). 4.21 (m, 1H), 3.41-3.03 (m, 2H), 2.39-1, (m, 11H). PF = I Sg ₁ OI gI ₁ O ⁰ C.

Example 3 (Compound No. 7): 2-Chloro-N - [(7-methyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) hydrochloride ) -benzamide (1: 1) In a 25 ml flask equipped with a condenser, 0.09 g of Λ / - [(2-azabicyclo [2.1.1] hex-1-yl) -phenyl is placed -methyl] - (2-chloro-3-trifluoromethyl) -benzamide (0.22 mmol) and 2 ml of formaldehyde in 2 ml of formic acid. The reaction mixture is heated at 100 ^° C. for 72 hours. After cooling, the medium is hydrolyzed, basified to pH 9 with ammonia and then extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. There is thus obtained 70 mg of 2-chloro-N - [(7-ethyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide which is salified in hydrochloride form by solubilization of the base in dichloromethane, addition of an excess of 1 N hydrochloric acid in ether and concentration under reduced pressure.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.58 (m, 1H), 9.54 (d, J = 9.6 Hz, 1H), 8.26 (m, J = 7, 4 Hz, 1H), 7.97 (m, J = 7.6 Hz, 1H), 7.75-7.33 (m, 7H), 5.71 (d, J = 9.4 Hz, 1H), 4.05 (m, 1H), 2.87 (m, 3H), 2.44-1, 18 (m, 8H). Mp = 244-246 ° C.

The other compounds listed in the table are obtained according to the methods described in Examples 1 to 3 from amines of general formula (IIa) or (Nb), of lithiens of general formula (VI), of carboxylic acid derivatives of general formula (III) or suitable alkylating agents.

Table 1 which follows illustrates the chemical structures of some compounds of the invention.

In the "Salts" column, "-" denotes a compound in the base state, "HCI" means a hydrochloride, the number in parentheses indicates the ratio (acid: base); In the columns R, Ri and R ₂ :

- "Cl" means chlorine,

- "CH ₃ " means methyl,

- "Ph" means phenyl, - "Bn" means benzyl,

- "CF ₃ " means trifluoromethyl, - in the column "R ₂ ", the number in front of the substituents indicates the position in the general formula (I),

The compounds of the table are in the form of hydrochloride solvated with one or more water molecules. The compounds 3 and 6 in Table 1 form a pair of enantiomers which are separated by preparative HPLC, using a column Chirobiotic ^® T2 5 .mu.m and as a solvent methanol / triethylamine / acetic acid 100 / 0.1 / 0.05. Absolute stereochemistry was determined by X-ray diffraction.

Table 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

20 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.

TABLE 1 TABLE 2

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 transporter glvti.

[ 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 IC50 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 batch which received glycine at 10 mM. The compounds of the invention, in this test, have a Cl ₅ o of the order of 0.001 to 10 μM.

Table 3 shows some examples of Cl ₅ results for compounds according to the invention.

TABLE 3

The results of the tests carried out on the chiral compounds of the invention and their racemates in the general formula (I) show that they are inhibitors of the glycine glycine transporter present in the brain.

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.

The compounds according to the invention can therefore be used for the preparation of medicaments, in particular inhibitory drugs of the glycine glycine transporter.

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 or a hydrate or a solvate of the compound of formula (I).

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 a pharmaceutically acceptable salt or solvate, and in a mixture, where appropriate, with suitable excipients.

Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.

The pharmaceutical compositions according to the invention can thus be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal, intraocular administration.

The unit dosage forms may be, for example, tablets, capsules, granules, powders, oral or injectable solutions or suspensions, 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.

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.

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 thanks to polymer matrices or specific polymers used in the coating.

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).

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.

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.

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.

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 the form of aqueous, alcoholic or aqueous-alcoholic solutions, gels, water-in-oil or oil-in-oil emulsions. water 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.

By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg

Croscaramellose sodium 6.0 mg

Corn starch 15.0 mg

Hydroxypropyl methylcellulose 2.25 mg

Magnesium stearate 3.0 mg

Orally, the dose of active ingredient administered per day can reach 0.1 to 20 mg / kg, in one or more doses.

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.

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

1. Compound of general formula (I)

in which :

R represents a hydrogen atom or a group chosen from (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) -cycloalkyl groups, optionally substituted with one or more groups chosen independently of one another from halogen atoms, (C ₃ -C ₇ ) -cycloalkyl, (C ₂ -C ₄ ) alkenyl, phenyl, (C ₁ -C ₆ ) alkoxy, hydroxy; the phenyl group is optionally substituted with one or more (C ₁ -C ₆ ) alkoxy groups;

R 1 represents a phenyl or naphthyl group, optionally substituted by one or more substituents chosen independently of one another from halogen atoms, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy groups, halo (CrC ₆₎ alkyl, hydroxy, halo (C _r C ₆₎ alkoxy, (C _r C ₆₎ alkyl-thio, (C _r C ₆₎ alkyl-SO, (Ci-C ₆₎ alkyl-SO ₂ ,

- 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, (C ₃ -C ₇ ) -cycloalkyl- (C ₁ -C ₃ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkyl-SO (dC ₆ ) alkyl -SO ₂ ; in the form of a base or an acid addition salt.

2. Compound of general formula (I) according to claim 1, characterized in that R represents a hydrogen atom, a (C ₁ -C ₆ ) alkyl or benzyl group; Wherein R 1 and R 2 are as defined in claim 1, in the form of a base or an acid addition salt.

3. Compound of general formula (I) according to claim 1, characterized in that R1 represents a phenyl group; R and R2 being as defined in claim 1, in the basic state or salt addition to an acid.

4. Compound of general formula (I) according to claim 1, characterized in that R ₂ represents one or more substituents chosen from a hydrogen atom, halogen atoms, halo (Ci-C ₆ ) groups. alkyl or (C ₁ -C ₆ ) alkyl,

R and R 1 being as defined in claim 1, in the form of a base or an acid addition salt.

5. Compound of general formula (I) according to claim 1, characterized in that - R represents a hydrogen atom or a group (C ₁ -C ₆ ) alkyl, benzyl;

Ri represents a phenyl group,

R ₂ represents one or more substituents chosen from the hydrogen atom, the halogen atoms, the halo- (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkyl groups, in the basic state or addition salt to an acid.

R represents a hydrogen atom or a methyl, ethyl or benzyl group; R 1 represents a phenyl group,

R ₂ represents one or more substituents chosen from a hydrogen atom, a chlorine atom, methyl, ethyl or trifluoromethyl groups, in the form of a base or of an addition salt with an acid

7. Compound according to claim 1 or 2, characterized in that it is chosen from: • Λ / - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2) 3-methyl-3-trifluoromethyl) benzamide; • N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) benzamide, and its hydrochloride;

(-) - N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) benzamide, and its hydrochloride;

• Λ - [(7-Azabicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide, and its hydrochloride;

2-Chloro-N - [(7-ethyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide, and its hydrochloride;

(+) - Λ / - [(7-Azabicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) benzamide, and its hydrochloride; 2-Chloro-N - [(7-methyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] -3-trifluoromethyl-benzamide, and its hydrochloride; • Λ - [(7-Benzyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-methyl-3-trifluoromethyl) -benzamide, and its hydrochloride; N - [(7-Benzyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide, and its hydrochloride; N - [(7-Azabicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-ethyl) -benzamide, and its hydrochloride.

8. Process for the preparation of a compound of general formula (I) according to claim 1, characterized in that a compound of general formula (II)

in which R and R ₁ are as defined in claim 1, reacts with a compound of general formula (III)

wherein Y is a leaving group or a halogen atom and R ₂ is as defined in claim 1.

9. Compound of general formula (II)

wherein R and R 1 are as defined in claim 1.

10. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 7, or an addition salt of this compound to a pharmaceutically acceptable acid.

11. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 7, or a salt pharmaceutically acceptable, of this compound, and at least one pharmaceutically acceptable excipient.

12. Use of a compound of formula (I) according to any one of claims 1 to 7 for the preparation of a medicament for the treatment of cognitive and / or behavioral disorders associated with neurodegenerative diseases; to madness.

13. Use of a compound of formula (I) according to any one of claims 1 to 7, for the preparation of a medicament for the treatment of psychoses, schizophrenia (deficient form and productive form), extrapyramidal symptoms acute or chronic induced by neuroleptics.

14. Use of a compound of formula (I) according to any one of claims 1 to 7 for the preparation of a medicament for treatment for the treatment of various forms of anxiety, panic attacks, phobias , obsessive compulsive disorders.

15. Use of a compound of formula (I) according to any one of claims 1 to 7, 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.

16. Use of a compound of formula (I) according to any one of claims 1 to 7 for the preparation of a medicament for the treatment of pain.

17. Use of a compound of formula (I) according to any one of claims 1 to 7, for the preparation of a medicament for the treatment of sleep disorders.

18. A compound according to any one of claims 1 to 7 for the treatment of cognitive and / or behavioral disorders associated with neurodegenerative diseases; to madness.

19. Compound according to any one of claims 1 to 7, for the treatment of psychoses, schizophrenia (deficient form and productive form), acute or chronic extrapyramidal symptoms induced by neuroleptics.

20. Compound according to any one of claims 1 to 7, for the treatment of various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders.

21. A compound according to any one of claims 1 to 7 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.

22. A compound according to any one of claims 1 to 7 for the treatment of pain.

23. A compound according to any one of claims 1 to 7 for the treatment of sleep disorders.