CA2758367A1 - Derivatives of n-[(7-aza-bicyclo[2.2.1]hept-1-yl)-aryl-methyl]-benzamide, preparation thereof, and therapeutic use thereof - Google Patents

Abstract

Compounds of formula (I): in which: R represents a hydrogen atom or a group chosen from (C1d-C6) alkyl, (C3-C7) -cycloalkyl groups, optionally substituted with one or more groups chosen independently; one of the other from fluorine atom, (C3-C7) -cycloalkyl, (C2-C4) alkenyl, phenyl, (C1-C6) alkoxy, hydroxy; the phenyl group is optionally substituted by one or more (C1-C6) alkoxy groups; R 1 represents a phenyl 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 and halo (C 1 -C 6) groups; alkyl, hydroxy, halo- (C1-C6) alkoxy, (C1C6) alkyl-thio, (C1-C6) alkyl-SO2, - R2 represents one or more substituents selected from hydrogen, halogen atoms , halo (C1C6) alkyl, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C7) -cycloalkyl- (C1-C3) alkyl, (C1C6) alkoxy, (C1C6) alkyl-thio (C1C6) alkyl-SO2; in the form of a base or an acid addition salt. Therapeutic use and synthesis method.

Description

WO 2010/11922

2 PCT / FR2010 / 050711 N - [(7-AZA-BICYCLO [2.2.1] HEPT-1-YL) -LAYL-METHYL DERIVATIVES -BENZAMIDE, THEIR PREPARATION AND THEIR APPLICATION
THERAPEUTIC
The present invention relates to derivatives of N - [(7-aza-bicyclo [2.2.1] hept-1-yl) -aryl-methyl-benzamide, their preparation and their application in therapeutic, in the treatment or prevention of diseases involving carriers of the wistaria Glyt1.

The compounds of the invention correspond to the general formula (I) R- N Ri O (I) HN

in which :
- R represents a hydrogen atom or a group selected from groups (C, -C6) alkyl, (C3-C7) -cycloalkyl, optionally substituted with one or more groups independently of one another selected from halogen atoms, groups (C3-C7) -cycloalkyl, (C2-C4) alkenyl, phenyl, (C1-C6) alkoxy, hydroxy; the group phenyl being optionally substituted by one or more groups (C, -C6) alkoxy;
- R, represents a phenyl or naphthyl group, optionally substituted by a or several substituents chosen independently of each other from among the atoms halogen, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halo- (C 1 -C 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, R2 represents one or more substituents chosen from the atom hydrogen, halogen atoms, halo- (C 1 -C 6) alkyl, (C 1 -C 6) alkyl, (C 3 -C
C7) cycloalkyl, (C3-C7) -cycloalkyl- (C1-C3) alkyl, (C1-C6) alkoxy, (C1-C6) alkyl-thio, (C1-C6) alkyl-SO
(C 1 -C 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 as enantiomers. These enantiomers including racemic mixtures are part of the invention.

The compounds of formula (I) may exist in the form of bases or salts of addition to acids. Such addition salts are part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids acceptable but the salts of other useful acids, for example, for the purification or the isolation of the compounds of formula (I) are also 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 may have from t to z carbon atoms, for example Ci-C6 a chain carbon which may have from 1 to 6 carbon atoms;
alkyl, a saturated, linear or branched aliphatic group; for example a group C 1 -C 6 -alkyl 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;
alkylene, a saturated divalent alkyl group, linear or branched, for example a group C, _6-alkylene represents a divalent carbon chain of 1 to 6 atoms linear or branched carbon, for example methylene, ethylene, methylethylene, propylene, - alkoxy, a -O-alkyl group, hydroxy, an -OH group, alkyl-thio, a sulfur atom substituted with an alkyl group;
halogen atom, fluorine, chlorine, bromine or iodine, halo-alkyl, an alkyl group of which one or more hydrogen atoms summer substituted by a halogen. By way of example, mention may be made of groups trifluoromethyl, trifluoroethyl or pentafluoroethyl;
haloalkoxy, an alkoxy group of which one or more hydrogen atoms summer substituted by a halogen.

Among the compounds of general formula (I) which are the subject of the invention, a first group of compounds is constituted by compounds for which:
R represents a hydrogen atom, a (C 1 -C 6) alkyl or benzyl group;
- R, and R2 being as defined above Among the compounds of general formula (I) which are the subject of the invention, a second group of compounds is constituted by compounds for which:

3 - R1 represents a phenyl group;
R and R2 being as defined above.

Among the compounds of general formula (I) which are the subject of the invention, a third group of compounds consists of compounds for which:
R2 represents one or more substituents chosen from the atom hydrogen, halogen atoms, halo (C 1 -C 6) alkyl or (C 1 -C 6) alkyl groups, - R and R1 being as defined above.

Among the compounds of general formula (I) that are the subject of the invention, a fourth group of compounds consists of compounds for which:
R represents a hydrogen atom, a (C 1 -C 6) alkyl or benzyl group;
- R, represents a phenyl group, R2 represents one or more substituents chosen from the atom hydrogen, halogen atoms, halo- (C 1 -C 6) alkyl or (C 1 -C 6) alkyl groups, Among the compounds of general formula (I) which are the subject of the invention, a fifth group of compounds consists of compounds for which:
R represents a hydrogen atom or a methyl, ethyl or benzyl group;
- R, represents a phenyl group, R2 represents one or more substituents chosen from the atom hydrogen, the chlorine atom, the methyl, ethyl or trifluoromethyl groups, in the basic or addition salt to an acid.

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

Among the compounds of general formula (I) which are the subject of the invention, it is possible to include the following compounds:
= N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-methyl-3-yl) 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;

4 = N - [(7-Aza-bicyclo [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;
= (+) - N - [(7-Aza-bicyclo [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-trifluoromethylbenzamide, and its hydrochloride;
= N - [(7-Benzyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-methyl-3-yl) 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) -benzam ide, and its hydrochloride.
The compounds of the invention exhibit a particular activity as inhibitors carriers of glycine Glyt1, including a profile of activity and security improved.

The compounds of general formula (I) can be prepared by a process illustrated by the following diagram 1:

YO

R- Nzz- Ri R2 (III) NH2 - (I) (11) Coupling of a diamine of general formula (11) in which R and R, are as defined above, especially when R represents an atom hydrogen, 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 one halogen atom and R2 is as defined above, using the methods known to those skilled in the art.

Compounds of the general formula (I) in which R represents the atom

Hydrogen can also be prepared from compounds of the formula General (I) wherein R represents:
or a phenylmethyl group by deprotecting the nitrogen by hydrogenolysis, - an alkenyl group, preferably allyl, by deprotecting nitrogen, by example by a complex of palladium zero according to the methods known to man of the job, - a dimethoxybenzyl group by deprotecting by oxidation methods known to those skilled in the art.

Compounds of the general formula (I) in which R is different from the atom of hydrogen, can also be prepared from compounds of formula General (I) wherein R represents a hydrogen atom, or by alkylation of said compound of general formula (I) with an RX type halide or mesylate, in which R is as defined above and X is a mesylate or halogen, in presence of a mineral base, for example potassium carbonate in acetonitrile ; is by an Eschweiler-Clarke type reaction or a reductive amination with a aldehyde or a ketone suitable according to the methods known to man of the job ; with an appropriate epoxide derivative, according to the known methods of the skilled person.

The diamine of general formula (11) can be prepared by the process illustrated speak scheme 2 for the amine of general formula (IIa) and for the amine of formula General (IIb) which follows:

6 H
NOT
NN R1Li N
(VI) C02CH3 CN H2N _ H2N Ri (IV) (V) (Ila) (Ilb) According to Scheme 2, the ester of formula (IV) is converted into nitrile of formula (V), by refluxing the xylene in the presence of the trimethyl 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 aromatic lithiated general formula (VI), wherein R, is as defined above, in a solvent ether, such as tetrahydrofuran or ether, at low temperature, by example -C. An imine is thus obtained which is reduced with a reducing agent such as sodium borohydride in a protic solvent such as methanol, for give the amine of general formula (IIa). The amine (IIa) can be debenzylated by hydrogenation in the presence of palladium catalyst to provide the amine deprotected of general formula (Ilb).

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

7 Moreover, the chiral compounds of general formula (I) corresponding to S or R enantiomers can be obtained by separation of the compounds racemic by high performance liquid chromatography (HPLC) column chiral, or could be obtained by resolution of the racemic amine general formula (11) using a chiral acid, such as dibenzoyltartaric tartaric or by the fractional and preferential recrystallization of a salt diastereoisomeric.
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) can be prepared according to methods known to those skilled in the art.
Acids and acid chlorides of general formula (III) are available in the trade or prepared by analogy with methods known to job.

The examples which follow illustrate the preparation of some compounds of the invention. In these examples:
- Elemental microanalyses, IR and NMR spectra and HPLC on chiral column confirm the structures and enantiomeric purities of 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, etc.
- Numbers indicated in parentheses in the titles of the examples correspond to those in the first column of the table given below, - "decomp." means "decomposition", - The nomenclature used is the nomenclature following the recommendations IUPAC (International Union of Pure and Applied Chemistry).

In the compound names, the hyphen "-" is part of the word, and the hyphen "-"
only serves for the cut at the end of the line; it is to be deleted in the absence of a break, and not must be replaced by a standard hyphen or space.

8 Example 1 (Compound No. 4): N - [(7-Azabicyclo [2.2.1] hept-1-yl) Hydrochloride phenyl-methyl] - (2-chloro-3-trifluoromethyl) benzamide (1: 1) 1.1. (7-Benzyl-7-aza-bicyclo [2.2.1lheptane) -1-carbonitrile In a three-necked 250 ml under nitrogen, the complex of trimethyl and ammonium chloride (about 0.67M), hereinafter referred to as complex A, in placing 1.5 g of dry ammonium chloride (28 mmol) in 30 ml of toluene anhydrous, to which 15 ml of a solution of 2N trimethylaluminium in toluene (30 mmol) and which is left to temperature until the end of the evolution of gas.
In a 250 ml three-necked flask under nitrogen equipped with a condenser, place 1.27 g of (7-methyl benzyl-7-aza-bicyclo [2.2.1] heptan) -1-carboxylate (5.18 mmol) in ml of anhydrous xylene.
20 ml of the complex A (13 mmol) are added dropwise and the night at reflux.
After cooling, the medium is acidified to pH 4-5 with a solution acid 1N hydrochloric acid and is then extracted successively with ethyl acetate (100 ml) then dichloromethane (100 ml).
The organic phases are dried over sodium sulphate, filtered, combined then evaporated under reduced pressure.
The residue is purified by chromatography on a column of silica gel in eluent with a mixture of petroleum ether and ethyl acetate. 210 mg is thus obtained of (7-benzyl-7-aza-bicyclo [2.2.1] heptane) -1-carbonitrile as an oil.

1 H NMR (200 MHz, CDCl 3) δ 7.5 ppm (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 [2.2.1-hept-1-yl] -phenyl-methylamine In a 50 ml three-necked flask under argon, 0.45 g of (7-benzyl-7-aza) bicyclo [2.2.1] heptane) -1-carbonitrile (2.12 mmol) at -70 ° C in 15 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 ° C.
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

9 Sodium borohydride (10.6 mmol) is added in portions. The environment The reaction mixture 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 hydrochloric acid solution 1N
then we extract. The aqueous phase is basified with ammonia and then reextracted 2 times with 50 ml of dichloromethane. The organic phases are combined, dried on sodium sulphate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel eluting with a mixture dichloromethane and ammoniacal methanol. 0.5 g of (7-benzyl) aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methylamine as an oil which crystallizes.
1 H NMR (400 MHz, 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, 1 H), 2.00 (m, 1H), 1.80-1.56 (m, 2H), 1.37 (m, 1H), 1.22-1.06 (m, 2H), 0.97 (m, 1H).
PF = 87-88 ° C
1.3. (7-aza-bicyclo [2.2.llhept-1-yl) -phenyl-methylamine In an autoclave, 0.5 g of (7-benzyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methylamine (1.71 mmol) in solution in 20 ml of ethanol and 3.4 ml of acid hydrochloric acid 1N in the presence of a spatula tip of palladium on charcoal at

10% are placed under a pressure of 7 atmospheres of hydrogen at 50 C during 6 hours. After filtration of the catalyst and concentration of the filtrate under pressure reduced, 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 on sulfate sodium, filtered and evaporated under reduced pressure. 0.28 g is thus obtained of (7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methylamine in the form of an oil which is solidifies in the cold and is used as is in the next step.
1 H NMR (400 MHz, 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).
PF = 62-63 ° C
1.4. N - [(7-aza-bicyclo [2.2.1-hept-1-yl] -phenyl-methyl-2-hydroxychloridate chloro-3-trifluoromethyl) benzam ide (1: 1).
In a 25 ml flask, 0.26 g of (2-chloro-3-trifluoromethyl) benzoic acid (1.19 mmol), 0.16 g of hydroxybenzotriazole (1.19 g) mmol), 0.23 g of 1- [3- (dimethylamino) propyl] -3-ethylcarbohydrochloride.
diimide (1.19 mmol) in solution 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), with 1N sodium hydroxide (3 ml) and with a solution saturated with Sodium chloride (3 ml).
The organic phase is dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is purified by gel column chromatography of silica eluting with a mixture of dichloromethane and ammonia methanol.
260 mg of N - [(7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl are thus obtained.
(2-Chloro-3-trifluoromethyl) benzamide, which is salified in the form of hydrochloride by solubilization of the base in ether, addition of an excess of hydrochloric acid 1 N 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), H), 4.07 (m, 1H), 2.30-0.65 (m, 8H).
Mp = 146.5-147.5 ° C.

EXAMPLE 2 (Compound No. 5): 2-Chloro-N - [(7-ethyl-7-azabate) hydrochloride bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) benzamide (1: 1).
In a 25 ml flask equipped with a condenser, 95 mg of N - [(2-aza) bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide (0.23 mmol) in 2 ml of acetonitrile, 64 mg of potassium carbonate to which add 30 μl of iodoethane (0.36 mmol). The reaction medium is stirred night in 45 C, then 3 hours at 50 C and then is concentrated under reduced pressure. The residue is then diluted with 10 ml of dichloromethane and then washed with water (5 ml).
After extracted, the organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography sure silica gel column eluting with a mixture of dichloromethane and ammonia methanol. 90 mg of 2-chloro-N - [(7-ethyl-7-aza) bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide which is salified as hydrochloride by solubilization of the base in the dichloromethane addition of an excess of 1N hydrochloric acid in the ether and concentration under reduced pressure.
1H NMR (400MHz, DMSO-d6) δ ppm 10.29 (m, 1H), 9.48 (d, J = 9.1Hz, 1H), 8.12 (m, J = 8Hz, 1H), 7.94 (m, J = 7.6Hz, 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), 2.39-1.15 (m, 11H).

11 Mp = 189.5-191.5 ° C.

Example 3 (Compound No. 7): 2-Chloro-N - [(7-methyl-7-azabate) hydrochloride bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide (1: 1) In a 25 ml flask equipped with a condenser, 0.09 g of N - [(2-aza) bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide (0.22 mmol) and 2 ml of formaldehyde in 2 ml of formic acid. The mixture reaction 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 sulphate, filtered and evaporated under reduced pressure. In this way 70 mg of 2-chloro-N - [(7-ethyl-7-aza) bicyclo [2.2. 1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzam ide which is salified as hydrochloride by solubilization of the base in the dichloromethane addition of an excess of 1N hydrochloric acid in the ether and concentration under reduced pressure.

1H NMR (400MHz, DMSO-d6) δ ppm 10.58 (m, 1H), 9.54 (d, J = 9.6Hz, 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 = 244-246C.

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 (Ilb), lithiens of general formula (VI), carboxylic acid derivatives of formula general (III) or suitable alkylating agents.

The following table 1 illustrates the chemical structures of some compounds of the invention.
In the Salts column, - denotes a compound in the basic state, "HCI", means a hydrochloride, the number in parentheses indicates the ratio (acid:
base);
In the columns R, R, and R2:
- CI means chlorine, - CH3 means methyl, Ph denotes phenyl - Bn means benzyl, CF3 means trifluoromethyl,

12 - in column R2, 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 solvated hydrochloride by one or more water molecules.
Compounds Nos. 3 and 6 of Table 1 form a pair of enantiomers which are separated by preparative HPLC, using a 5m Chirobiotic T2 column and in as a solvent a methanol / triethylamine / acetic acid mixture 100 / 0.1 / 0.05. The Absolute stereochemistry was determined by X-ray diffraction.

Table 2 gives the physical properties, melting points and powers rotary compounds of Table 1.

In Table 2:
- column [ad 20-c gives the result of the analysis of the rotatory power of compounds of the table at the wavelength of 589 nM and at the temperature of C. The solvent indicated in parentheses corresponds to the solvent used for realize the measure of the rotary power in degrees and the letter c indicates the solvent concentration in g / 100 ml. NA means that measuring the power rotary is not applicable, The column "m / z" informs the molecular ion (M + H +) or (M +) observed by analysis products by mass spectrometry, either by LC-MS (Liquid Chromatography coupled to Mass Spectroscopy) performed on an Agilent LC-MSD device Trap in ESI positive mode, either by direct introduction by MS (Mass Spectroscopy) on an Autospec M (EBE) device using DCI-NH3 or using the electronic impact technique on a type device Waters GCT.

13 Ri 5 ~ (1) NRR, R2 Stereochemistry salts 1H Ph 2 -CH3,3-CF3 - racemic HCI
2 H Ph 2,6- (Cl) 2,3-CF3 (1: 1) racemic HCI Chiral 3H Ph 2,6- (Cl) 2,3-CF3 (1: 1) levorotatory R
HCI
4 H Ph 2-C1,3-CF3 (1: 1) Racemic HCI
Racemic C2H5 Ph 2-C1,3-CF3 (1: 1) HCI Chiral 6H Ph 2,6- (Cl) 2,3-CF3 (1: 1) dextrogyre S
HCI
7 CH3 Ph 2-C1,3-CF3 (1: 1) Racemic HCI
Racemic 8 Bn Ph 2 -CH3,3-CF3 (1: 1) HCI
Racemic 9 Bn Ph 2-C1,3-CF3 (1: 1) HCI
10 H Ph 2 -Cl, 3-C2H5 (1: 1) racemic

14 LCMS
N PF C [CD] 20 C MH +

3 185-186 -50.73 (MeOH, c = 0.466 g / 100 ml) 443 4 146.5-147.5 NA 409 189.5-191.5 NA 437 6 181.5-182.5 +34.41 (MeOH, c = 0.732g / 100 ml) 443 9 159.5-160.5 NA 499 234.2-235.2 NA 369 The compounds of the invention have been subjected to a series of tests pharmacological who have highlighted their interest as active substances therapeutic.
Study of glycine transport in SK-N-MC cells expressing carrier human glyt1 native.
[14C] glycine uptake is studied in SK-N-MC cells (cells neuro-epithelial cells) expressing the native human transporter glyt1 by the measure of the radioactivity incorporated in the presence or absence of the test compound. The cells are cultured in monolayer for 48 h in plates pre-processed to fibronectin at 0.02%. On the day of the experiment, the culture medium is eliminated and cells are washed with Krebs-HEPES buffer (acid [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 compound at test at different concentrations or 10 mM glycine (determination of the nonspecific uptake), 10 μM [14C] 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 glittering liquid and stirring for 1 h. Counting is carried out on a Microbeta Tri-IUXTM
The effectiveness of the compound is determined by the C150 concentration of the compound who reduces by 50% the specific uptake of glycine, defined by the difference in radioactivity incorporated by the control group and the lot that received glycine 10 mM.
The compounds of the invention, in this test, have a C150 of the order of 0.001 to 10 μM.

Table 3 gives some examples of C150 results for compounds according to the invention.

C150 compound (pM) 1 0.038 2 0.003 0.023 4 0.027 6 0.0016 The results of the tests carried out on the chiral compounds of the invention and their 10 racemates in the general formula (1) show that they are inhibitors of glycine transporter glyt1 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 diseases

Neurodegenerative, to dementia; for the treatment of psychoses, including schizophrenia (deficient form and productive form), symptoms acute or chronic extrapyramidal induced by neuroleptics; for the treatment of various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorder; for the treatment of different forms of depression, including psychotic depression; for the treatment of unrest bipolar, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or withdrawal, behavioral disorders sexual, eating disorders, migraine; pain; of the disorders of the sleep.
The compounds according to the invention can therefore be used for the preparation of drugs, particularly inhibitor drugs the carrier of the wistaria glyt1.

Thus, according to another of its aspects, the subject of the invention is medicaments who

16 comprise a compound of formula (I), or an addition salt thereof to a acid a pharmaceutically acceptable salt or a hydrate or a solvate of the 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 state basic or a pharmaceutically acceptable salt or solvate, and in a mixture, the case with appropriate excipients.

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

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

The unitary forms of administration 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 administration daily from 0.01 to 20 mg of active ingredient per kg of body weight, depending on the form dosage.
To prepare tablets, one adds to the active principle, micronized or not, a pharmaceutical vehicle which may be composed of diluents, for example the lactose, microcrystalline cellulose, starch, and adjuvants of formulation as binders, (polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.), agents like silica, lubricants such as magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate.
of the wetting agents or surfactants such as sodium lauryl sulphate may as well to be added.
The realization techniques can be direct compression, granulation dry, 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 principle active

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

To prepare capsules, the active ingredient is mixed with vehicles pharmaceutical products (simple mixing, dry or wet granulation, or hot), liquid or semi-solid.
Capsules may be hard or soft, film-coated or not, so that have a rapid, prolonged or delayed activity (eg enteric form).

A composition in the form of syrup or elixir or for administration under form drops may contain the active ingredient together with a sweetener, preference acaloric acid, methylparaben or propylparaben as an antiseptic, an agent of palatability and a dye.

Dispersible powders and granules in water may contain the active ingredient in admixture with dispersants or wetting agents, or agents dispersants such as polyvinylpyrrolidone, as well as with sweeteners and of the taste correcting agents.

For rectal administration, suppositories prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing of the dispersants and / or pharmacologically compatible wetting agents, by for example propylene glycol or butylene glycol.

The active ingredient can be formulated also in the form of microcapsules, possibly with one or more supports or additives, or with a matrix polymer or with a cyclodextrin (transdermal patches, release extended).

The topical compositions according to the invention comprise a compatible medium with the skin. They may be in particular in the form of aqueous solutions, alcoholic or hydroalcoholic, gels, water-in-oil or oil-in-oil emulsions in-

18 water having the appearance of a cream or a gel, microemulsions, aerosols, or again in the form of vesicular dispersions containing ionic lipids and / or no Ionic. These galenic forms are prepared according to the usual methods of 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 higher dosages weak are appropriate; such dosages are not outside the scope of the invention. According to convenient usual, the appropriate dosage for each patient is determined by the doctor 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 includes administration to a patient of an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt thereof.

Claims (23)

1. Compound of general formula (I) in which :
R represents a hydrogen atom or a group selected from groups (C1-C6) alkyl, (C3-C7) -cycloalkyl, optionally substituted with one or more groups independently of one another selected from halogen atoms, groups (C3-C7) -cycloalkyl, (C2-C4) alkenyl, phenyl, (C1-C6) alkoxy, hydroxy; the group phenyl is optionally substituted with one or more (C1-C6) alkoxy groups ;
R 1 represents a phenyl or naphthyl group, optionally substituted with a or several substituents chosen independently of each other from among the atoms halogen, (C1-C6) alkyl, (C1-C6) alkoxy, halo- (C1-C6) alkyl, hydroxy, halo- (C1-C6) alkoxy, (C1-C6) alkyl-thio, (C1-C6) alkyl-SO, (C1-C6) alkyl-SO2, R2 represents one or more substituents chosen from the atom hydrogen, halogen atoms, halo (C1-C6) alkyl, (C1-C6) alkyl groups, (C3-C7) cycloalkyl, (C3-C7) -cycloalkyl- (C1-C3) alkyl, (C1-C6) alkoxy, (C1-C6) alkyl-thio, (C1-C6) alkyl-SO
(C1-C6) alkyl-SO2;
in the form of a base or an acid addition salt. 2. Compound of general formula (I) according to claim 1, characterized in that than R represents a hydrogen atom, a (C 1 -C 6) alkyl or benzyl group;
R1 and R2 being as defined in claim 1, in the basic state or salt addition to an acid. 3. Compound of general formula (I) according to claim 1, characterized in that than 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 than R2 represents one or more substituents chosen from the hydrogen atom, the halogen atoms, halo (C1-C6) alkyl or (C1-C6) alkyl groups, R and R1 being as defined in claim 1, in the basic state or salt addition to an acid. 5. Compound of general formula (I) according to claim 1, characterized in that than R represents a hydrogen atom or a (C 1 -C 6) alkyl or benzyl group;
R1 represents a phenyl group, R2 represents one or more substituents chosen from the atom hydrogen, halogen atoms, halo (C1-C6) alkyl or (C1-C6) alkyl groups, in the form of a base or an acid addition salt. R represents a hydrogen atom or a methyl, ethyl or benzyl group;

R 1 represents a phenyl group, R2 represents one or more substituents chosen from the hydrogen atom, atom chlorine, methyl, ethyl or trifluoromethyl, in the basic state or salt addition to an acid 7. Compound according to claim 1 or 2, characterized in that it is chosen among .cndot.N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-methyl-3-trifluoromethyl) -benzamide;
.cndot.N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide, and its hydrochloride;
.cndot. (-) - N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide, and its hydrochloride;
.cndot.N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide, and its hydrochloride;
.cndot.2-Chloro-N - [(7-ethyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) benzamide, and its hydrochloride;
.cndot (+) -. N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide, and its hydrochloride;
.cndot.2-Chloro-N - [(7-methyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] -3 trifluoromethylbenzamide, and its hydrochloride;

.cndot.N - [(7-Benzyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-methyl-3-trifluoromethyl) benzamide, and its hydrochloride;
.cndot.N - [(7-Benzyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) benzamide, and its hydrochloride;
.cndot.N - [(7-Aza-bicyclo [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 the general formula (II) wherein R and R 1 are as defined in claim 1, react with a compound of general formula (III) wherein Y represents a leaving group or a halogen atom and R2 is such as defined in claim 1. 9. Compound of general formula (II) wherein R and R 1 are as defined in claim 1. 10. Medicinal product, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 7, or an addition salt thereof has 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 excipient pharmaceutically acceptable. 12. Use of a compound of formula (I) according to any one of claims 1 to 7, for the preparation of a medicament for treating disorders cognitive and / or behavioral associated with neurodegenerative diseases; at the dementia. 13. Use of a compound of formula (I) according to any one of claims 1-7 for the preparation of a medicament for the treatment of psychoses, of schizophrenia (deficient form and productive form), symptoms acute or chronic extrapyramidal events 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 the treatment of treatment various forms of anxiety, panic attacks, phobias, unrest obsessive compulsive. 15. Use of a compound of formula (I) according to any one of claims 1-7 for the preparation of a medicament for the treatment of different forms of depression, including psychotic depression; for the treatment of the bipolar disorder, manic disorders, mood disorders; for the treatment of alcohol abuse or withdrawal disorders, sexual behavior, eating disorders, migraine. 16. Use of a compound of formula (I) according to any one of claims 1-7 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 treating disorders of sleep. 18. A compound according to any one of claims 1 to 7 for the treatment of Cognitive and / or behavioral disorders associated with diseases neurodegenerative; to madness. 19. A compound according to any one of claims 1 to 7 for the treatment of psychoses, schizophrenia (a form of deficit and a productive form), acute or chronic extrapyramidal symptoms induced by neuroleptics. 20. A compound according to any one of claims 1 to 7 for the treatment of various forms of anxiety, panic attacks, phobias, disorders obsessive compulsive. 21. A compound according to any one of claims 1 to 7, for treatment of different forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood for the treatment of alcohol abuse or withdrawal disorders, disorders of the sexual behavior, 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 of claims 1 to 7 for the treatment of sleeping troubles.