CA2751866A1 - N-[(6-azabicyclo[3.2.1]oct-1-yl)-aryl-methyl]-benzamide derivatives, preparation thereof, and therapeutic use thereof - Google Patents

Abstract

The present invention relates to N - [(6-aza-bicyclo [3.2.1] oct-1-yl) -aryl-methyl] -benzamide derivatives of formula (I). R represents a hydrogen atom or a (C1-C6) alkyl, (C3-C7) -cycloalkyl group, optionally substituted by one or more fluorine, (C3-C7) -cycloalkyl, (C2-C4) alkenyl, phenyl, (C1-C6) alkoxy, hydroxy; R 1 represents a phenyl or naphthyl, optionally substituted by one or more halogen, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halo- (C 1 -C 6) alkyl, NR 4 R 5, (C 1 -C 6) alkyl-thio, ( C1-C6) alkyl-SO2, phenyl or heteroaryl; R2 represents one or more hydrogen, halogen, halo- (C1-C6) alkyl, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C7) -cycloalkyl- (C1-C3) atoms; alkyl; R3, R4 and R5 represent independently of each other a hydrogen atom or a (C1-C6) alkyl group; R6 represents a (C1-C6) alkyl group; R4 and R5 may together form a ring selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, azepine rings, optionally substituted by a (C1-C6) alkyl group. Therapeutic use and synthesis method.

Description

N - [(6-AZA-BICYCLO [3.2.1] OCT-1-YL) -LARYL-METHYL] -BENZAMI DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION

The present invention relates to derivatives of N - [(6-aza-bicyclo [3.2.1] oct-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) NM ~ R HN O

(I) in which :
- R represents a hydrogen atom or a group selected from groups (C, -C6) alkyl, (C3-C7) -cycloalkyl, these groups being optionally substituted by a or more groups chosen independently of each other from the atom of fluorine, (C 3 -C 7) -cycloalkyl, (C 2 -C 4) alkenyl, phenyl, (C 1 -C 6) alkoxy groups, hydroxy; the phenyl group being optionally substituted by one or more groups 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, NR4R5, NR3C (O) OR4, NR3SO2R4, NR3C (O) R6, hydroxy, halo- (C1-C6) alkoxy, (C1-C6) alkyl-thio, (C 1 -C 6) alkyl-SO 2, phenyl or heteroaryl, the phenyl group being optionally substituted with one or more substituents selected independently among the halogen atoms, the (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halogen, (VS,-C6) alkyl, NR4R5, NR3C (O) OR4, NR3SO2R4, NR3C (O) R6, hydroxy, halo (C, -C6) alkoxy, (C 1 -C 6) alkyl-thio, (C 1 -C 6) alkyl-SO 2, the heteroaryl group being eventually substituted with one or more substituents independently selected from carbon halogen, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halo- (C 1 -C 6) alkyl, NR4R5;
R2 represents one or more substituents chosen from the atom hydrogen, halogen atoms, (C, -C6) alkyl, (C3-C7) cycloalkyl, (C3-C7) -cycloalkyl-

2 (C 1 -C 3) alkyl, halo (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, NR 4 R 5, phenyl, heteroaryl, cyano, acetyl, (C 1 -C 6) thioalkyl, (C 1 -C 6) alkylsulfonyl, carboxy or (C 1 -C 6) C6) alkoxycarbonyl;
the phenyl group being optionally substituted by one or more substituents independently selected from halogen atoms, (C 1 -C 6) alkyl groups, (C 1 -C 6) alkoxy, halo (C 1 -C 6) alkyl, NR 4 R 5, NR 3 C (O) OR 4 NR 3 SO 2 R 4, NR 3 C (O) R 6, hydroxy, halo- (C 1 -C 6) alkoxy, (C 1 -C 6) alkyl-thio, (C 1 -C 6) alkyl-SO 2, the group heteroaryl being optionally substituted with one or more substituents choose independently of the halogen atoms, the (C 1 -C 6) alkyl groups, (C 1 -C6) alkoxy, halo- (C1-C6) alkyl, NR4R5;
- R3, R4 and R5 represent independently of one another an atom hydrogen or a (C 1 -C 6) alkyl group;
R6 represents a (C1-C6) alkyl group;
- R4 and R5 can form together, with the nitrogen atom which carry them, a cycle selected from the azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, azepine, optionally substituted with a (C 1 -C 6) alkyl group;
- R3 and R4 can form together, with the atoms that carry them, a cycle at 5 or 6 links;
- R3 and R6 can form together, with the atoms that carry them, a cycle at 5 or 6 links;
in the form of a base or an acid addition salt.

The compounds of formula (I) have 3 asymmetric carbon atoms. They can therefore exist in the form of diastereoisomers and 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 Cl-C6 a chain carbon which may have from 1 to 6 carbon atoms;

3 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;
alkenyl, a linear or branched mono- or poly-unsaturated aliphatic group, comprising for example one or two ethylenic unsaturations, - amino, an NH 2 group alkoxy, a -O-alkyl group;
acetyl, a -C (O) - group, - cyano, a group -CN, hydroxy, an -OH group, thioalkyl, a sulfur atom substituted with an alkyl group;
halogen atom, fluorine, chlorine, bromine or iodine, haloalkyl, an alkyl group of which one or more hydrogen atoms have been substituted by a halogen. By way of example, mention may be made of groups trifluoromethyl, trifluoroethyl, pentafluoroethyl, heteroaryl, a 5- or 6-membered aromatic monocyclic group comprising from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. As examples of heteroaryl groups that may be mentioned are the pyrrole and furan groups, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine triazine.

Among the compounds of general formula (I) which are the subject of the invention, a first group of compounds is constituted by the compounds for which R represents an atom hydrogen or a (C 1 -C 6) alkyl group;
R 1, R 2, R 3, R 4 and R 5 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 the compounds for which R represents a hydrogen atom or a methyl, ethyl group;
R 1, R 2, R 3, R 4, R 5 and R 6 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 the compounds for which R represents a phenyl group, optionally substituted with one or more substituents choose

4 independently of each other among the halogen atoms, the groups (C, -C6) alkyl, halo- (C1-C6) alkyl, (C1-C6) alkoxy, hydroxy;
R, R2, R3, R4 and R5 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 the compounds for which R represents a phenyl group, optionally substituted with one or more substituents choose independently of each other among the halogen atoms, the groups methyl, ethyl, trifluoromethyl, methoxy, hydroxy;
R 1, R 2, R 3, R 4, R 5 and R 6 being as defined above.

Among the compounds of general formula (I) which are the subject of the invention, a fifth group of compounds consists of the compounds for which R2 represents a or more substituents selected from the hydrogen atom, the atoms halogen, halo- (C 1 -C 6) alkyl, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, (C 1 -C 6) alkyl-SO2;
R, R 1, R 3, R 4 and R 5 being as defined above.

Among the compounds of general formula (I) which are the subject of the invention, a sixth group of compounds is constituted by the compounds for which R2 represents one or several substituents chosen from the hydrogen atom, the atoms halogen, the trifluoromethyl, methyl, methoxy, ethanesulfonyl groups R, R 1, R 3, R 4 and R 5 being as defined above.

Among the compounds of general formula (I) which are the subject of the invention, a seventh group of compounds consists of compounds for which:
R represents a hydrogen atom or a methyl or ethyl group;
R, represents a phenyl group, optionally substituted with one or many substituents chosen independently of each other from among the atoms halogen, methyl, ethyl, trifluoromethyl, methoxy, hydroxy;
R2 represents one or more substituents chosen from the atom hydrogen, halogen atoms, trifluoromethyl, methyl, methoxy, ethanesulfonyl, in the form of a base or an acid addition salt.

The combinations of groups one to seven 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 - [(6-Azabicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2-methyl-3-trifluoromethyl) -benzamide;

N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-methoxy-2-methyl) -benzamide;
N - [(6-Azabicyclo [3.2.1] oct-5-yl) -phenylmethyl] - (2,6-dichloro-3-) trifluoromethyl) -benzamide and its hydrochloride;
N- [6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide and its hydrochloride;
(+) - N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2-chloro-3-) trifluoromethyl) -benzamide and its hydrochloride;
(-) - N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2,6-dichloro-3-) trifluoromethyl) -benzamide and its hydrochloride;
(-) - N - [(6-Azabicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2-chloro-3-) trifluoromethyl) -benzamide and its hydrochloride;
(+) - N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2,6-dichloro-3-) trifluoromethyl) -benzamide and its hydrochloride;
N - [(6-Azabicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (4-chloro-5-ethanesulfonyl) -2-methoxy) -benzamide and its hydrochloride;
N - [(6-Azabicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2-chloro-5-trifluoromethyl) -benzamide and its hydrochloride;
N - [(6-Azabicyclo [3.2.1] oct-5-yl) phenylmethyl] - (2,6-dichloro) benzamide;
N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-chloro-2-methyl) -benzamide ;
N - [(6-Azabicyclo [3.2.1] oct-5-yl) - (4-fluoro-phenyl) -methyl] - (2-chloro-3-) trifluoromethyl) benzamide;
N - [(- 6-Aza-bicyclo [3.2.1] oct-5-yl) - (4-fluoro-phenyl) -methyl] - (2,6-dichloro) -3-trifluoromethyl) benzamide;
N - [(- 6-Aza-bicyclo [3.2.1] oct-5-yl) - (3-methoxy-phenyl) -methyl] - (2,6-dichloro) -3-trifluoromethyl) benzamide;
N - [(6-Azabicyclo [3.2.1] oct-5-yl- (3-methoxy-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) benzamide;
N- [6-Aza-bicyclo [3.2.1] oct-5-yl- (3-hydroxy-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) benzamide;
N - [(6-Azabicyclo [3.2.1] oct-5-yl) - (3-hydroxy-phenyl) -methyl] - (2,6-dichloro) -3-trifluoromethyl) benzamide;

6 N - [(6-Azabicyclo [3.2.1] oct-5-yl) -m-tolyl-methyl] - (2-chloro-3-) trifluoromethyl) -benzamide and its hydrochloride;
2-Chloro-N - [(6-ethyl-6-aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide;
N - [(6-Aza-bicyclo [3.2.1] oct-5-yl-m-tolyl-methyl] - (2,6-dichloro-3-) trifluoromethyl) -benzamide;
2-Chloro-N - [(6-methyl-6-aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide and its hydrochloride;
N - [(6-Azabicyclo [3.2.1] oct-5-yl) - (3-bromo-phenyl) -methyl] - (2-chloro-3-) trifluoromethyl) benzamide and its hydrochloride;
N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) - (3-bromo-phenyl) -methyl] - (2,6-dichloro) -3-trifluoromethyl) benzamide and its hydrochloride;
N- [6-Aza-bicyclo [3.2.1] oct-5-yl- (3-trifluoromethyl-phenyl) -methyl] - (2-chloro) trifluoromethyl) benzam ide and its hydrochloride;
(+) - 2,6-Dichloro-N - [(6-ethyl-6-aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-trifluoromethyl) benzamide and its hydrochloride;
2-Chloro-N - [(6-ethyl-6-aza-bicyclo [3.2.1] oct-5-yl) - (3-trifluoromethyl-phenyl) -methyl] -(3-trifluoromethyl) benzamide 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
(III) Ri R2 NOT
R NH2 - (I) (II) Coupling of a diamine of general formula (11) in which R and R, are as defined above, especially when R represents an atom WO 2010/09228

7 PCT / FR2010 / 050204 of hydrogen, an allyl or phenylmethyl group, with an activated acid, by for example via a mixed anhydride or an acid chloride of general formula (III) in Y represents a leaving group derived for example from benzotriazole, acylurea or a halogen atom and R2 is as defined above, using the methods known to those skilled in the art.
Compounds of general formula (I) in which R represents an atom of hydrogen can also be prepared from compounds of 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.

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 with a 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 the potassium carbonate in acetonitrile, either by a reaction of Eschweiler Clarke or by reductive amination with an aldehyde or a ketone appropriate according to the methods known to those skilled in the art, according to the known methods of the skilled person.

Compounds of the general formula (I) in which the R group is a group hydroxy-substituted phenyl can be obtained from the compound corresponding compound of general formula (I) substituted with methoxy, using the methods known to those skilled in the art.

The diamine of general formula (II) can be prepared by the processes illustrated by Schemes 2 for amine (IIa) and (IIb) and 3 for amine (IIc) which follow.

8 RiLi (V) 'N
N CN HRH Ri Kl "-CH 3 C 3 NH 2 H2N
(IVa) (Ila) (Ilb) RiLi (V) NN
dl --- l CN R1 (IVc) (IIc) According to Scheme 2, the nitrile of formula (IVa) is reacted with the lithiated aromatic of general formula (V), wherein R, is as defined above, in a an ethereal solvent such as tetrahydrofuran or ether, at low temperature, by example at -70 C. An imine is thus obtained which is especially reduced diastereoselectively with a reducing agent such as sodium borohydride, in one protic solvent such as methanol to give the amine of general formula (He has).
The amine (IIa) can be debenzylated by hydrogenation in the presence of a catalyst at palladium to provide deprotected amine (1 lb) (Scheme 2).
According to Scheme 3, the nitrile of formula (IVc) can also be reacted, with the lithiated aromatic of general formula (V), in which R, is such that defined above above, in an ethereal solvent such as tetrahydrofuran or ether, at low temperature for example at -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 (IIc) (Scheme 3).

Moreover, the chiral compounds of general formula (I) can be obtained by separation of racemic compounds by high-performance liquid chromatography performance (HPLC) on a chiral column, or by separation by chromatography sure

9 silica gel of the chiral diastereoisomers of the amine of the general formula (Ila) then debenzylation as described in Scheme 2.

The nitrile of formula (IVa) is prepared according to a method described in Tetrahedron:
Asymmetry, 2006 (17), 252-258 and the nitrile of formula (IVc) is synthesized according to this same reference, using allylamine.
The lithiated aryls of general formula (V) 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 those skilled in the art 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 roman numerals in parentheses correspond to the general formulas which are indicated in the synthesis schemes, - 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.

Example 1 (Compound No. 3): N - [(6-Azabicyclo [3.2.1] oct-5-yl) Hydrochloride phenyl-methyl] - (2,6-di-chloro-3-trifluoromethyl) -benzamide (1: 1).

1.1 Phenyl- [6 - ((R) -1-phenyl-ethyl) -6-aza-bicyclo [3.2.1 loct-5-VII-methylamine (He has).

In a 100 ml three-necked flask under argon, 1 g of 6 - ((R) -1-phenyl-ethyl) -6-aza bicyclo [3.2.1] octane-5-carbonitrile (IVa) (4.16 mmol) at -70 ° C in 35 ml of anhydrous tetrahydrofuran. 7.4 ml of a solution are added dropwise 1,13M
(cyclohexane / ether) phenyl lithium (8.32 mmol).
It is left for 2 hours and a half at -70 ° C. and then hydrolyzed at -20 ° C. with 15 ml of water.
After extraction, the organic phase is concentrated under reduced pressure and the The residue is taken up in 20 ml of methanol. 0.79 g of sodium borohydride (20.8 mmoles) are added in portions. The reaction medium is left under stirring the

10 night at room temperature.
After evaporation under reduced pressure, the residue is taken up in 50 ml of ether and 50 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. We obtain thus 1.5 g an oil that is purified by silica gel column chromatography in eluent with a mixture of dichloromethane and methanol. We obtain 1.15 g of phenyl- [6 - ((R) -1-phenyl-ethyl) -6-aza-bicyclo [3.2.1] oct-5-yl] -methylamine (He has), mixture of 2 chiral diastereoisomers, in the form of an oil.

1.2 (6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methylamine (IIb).

In a Parr flask, 4 g of compound of formula (IIa) (12.5 mmol) are placed.
in 80 ml of methanol in the presence of a tip of spatula of hydroxide 20% palladium under 4 atmospheres of hydrogen at room temperature 6 hours.
After filtration of the catalyst and evaporation of the filtrate under pressure reduced, the residue is taken up in 10 ml of dichloromethane and 20 ml of ammonia. After extraction, the organic phase is washed in a saturated solution of sodium chloride, dried over sodium sulphate, filtered and the solvent is evaporated under pressure scaled down. We thus obtaining 1 g of (6-aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methylamine from formula (Ilb) as an oil that can be used raw in the next step.
An analytical sample is obtained by salification of the base with a solution 2N hydrochloric ether and trituration in ether.
Mp = 215-225 ° C

11 1 H NMR (400 MHz, DMSO-d 6) δ ppm 9.14 (m, 4H), 7.76 (m, 2H), 7.56 -7.43 (m, 4H), 5.09 (brs, 1H), 3.49 (m, 1H), 3.11 (m, 1H), 2.72 (m, 1H), 2.19;
(m, 1H), 1.87 (m, 1H), 1.83 - 1.37 (m, 8H).

1.3 N - [(6-aza-bicyclo [3.2.1-oct-5-yl] -phenyl-methyl) -2,6-hydrochloride dichloro-3-trifluoromethyl) benzamide (1: 1).
In a 25 ml flask, 240 mg of acid (2,6-dichloro-3-trifluoromethyl) -benzoic acid (0.92 mmol), 124 mg of hydroxybenzotriazole (0.92 mmol), 180 mg of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.92 mmol) in solution in 5 ml of dichloromethane and the mixture is stirred at room temperature room temperature for 15 minutes. 200 mg (0.92 mmol) of (6-aza) bicyclo [3.2.1] oct-5-yl) -phenyl-methylamine of formula (IIb) in solution in 5 ml of dichloromethane and stirred at room temperature overnight.
The reaction medium is then diluted with 10 ml of dichloromethane and wash successively with water (5 ml), with 1 N sodium hydroxide (5 ml) and with a solution saturated with sodium chloride (5 ml).
The organic phase is dried over sodium sulphate, filtered and evaporated under reduced pressure.
The residue is purified by chromatography on a column of silica gel in eluent with a mixture of dichloromethane and methanol. In this way 180 mg of N - [(6-aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) -benzam ide which is salified as hydrochloride by solubilization of the base in the dichloromethane, addition of an excess of 1 N hydrochloric acid in the ether and concentration under reduced pressure.

Mp = 249.5-250.5 ° C .;
1H NMR (400MHz, DMSO-d6) δ ppm 9.79 (m, 1H), 9.66 (d, J = 9Hz, 1H), 8.86 (M, 1H), 8.01 (m, 1H), 7.84 (m, 1H), 7.69 (m, 2H), 7.50 (m, 2H), 7.42 (m, 1H). ) 5.79 (d, J
= 9.1 Hz, 1H), 3.57 (m, 1H), 3.16 (m, 1H), 2.69 (m, 1H), 2.16-1.84 (m, 3H), 1.77 -1.38 (m, 5H).

Example 2 (Compound No. 8): (+) - N - [(6-Azabicyclo [3.2.1] oct-5-yl) Hydrochloride phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide (1: 1).

2.1. First diastereoisomer of phenyl - [6 - ((R) -1-phenyl-ethyl) -6-aza-bicyclo [3.2.1-oct-5-yll-methylamine (IIa1)

12 The two diastereoisomers (IIa) can be separated by gel separation silica with as eluent a mixture of dichloromethane and methanol. The compound less polar is phenyl- [6 - ((R) -1-phenyl-ethyl) -6-aza-bicyclo [3.2.1] oct-5-yl] -methylamine (Ila1).

1H NMR (400MHz, DMSO-d6) δ ppm 7.47 (m, 4H), 7.39 -7.17 (m, 6H), 4.26 (s, 1H), 4.23 (m, 1H), 3.17 (m, 1H), 3.56 (d, J = 8.7 Hz, 1H), 2.28 (m, 1H), 2.07;
(m, 1H), 2.00 (m, 2H), 1.65 (m, 1H), 1.54 (d, J = 6.8 Hz, 3H), 1.28-0.86 (m, 6H) 2.2. (+) (6-aza-bicyclo [3.2.1-oct-5-yl] -phenyl-methylamine (IIb1) enantiomer This compound is obtained according to Example 1.2 starting from the compound of formula (Ila1).
Compound of formula (Ilb1) in base form.
PF = 84-85 ° C
ee = 100%
[DI 20-C CHCl 3 = + 55.2 c = 0.80 g / 100 ml 1 H NMR (400 MHz, CDCl 3) δ ppm 7.29 7.13 (m, 5H), 3.72 (s, 1H), 3.01 (m, J =
5.4 Hz and 10 Hz, 1 H), 2.87 (m, J = 10 Hz and 1 Hz, 1 H), 2.25 (m, 1 H), 1.83 (m, 1 H), 1.70 (m, 3H), 1.58 (m, 1H), 1.52-1.39 (m, 2H), 1.31-1.08 (m, 4H).

2.3 (+) - N - [(6-aza-bicyclo [3.2.1-oct-5-yl] -phenyl-methyl) -2,6-hydrochloride dichloro-3-trifluoromethyl) benzamide (1: 1).
This compound is obtained according to Example 1.3 starting from the compound of formula (Ilb1). An analytical sample is obtained in the form of hydrochloride by solubilization of the base in dichloromethane, addition of an excess of acid 1N hydrochloric acid in ether and then concentration under reduced pressure.

PF: 241-242 ° C
ee: 95%
[D] 20-C MeOH = + 30.7 c = 0.75 g / 100 ml 1 H NMR (400 MHz, DMSO-d 6) δ ppm 9.62 (d, J = 8.9 Hz, 1H), 9.42 (m, 1H), 8.84 (m, 1H), 7.97 (m, 1H), 7.80 (m, 1H), 7.59 (m, 2H), 7.46 (m, 2H), 7.39 (m, 1H). ) 5.70 (d widened, J = 9 Hz, 1H), 3.49 (m, 1H), 3.13 (m, 1H), 2.65 (m, 1H), 2.11-1.20 (M, 9H)

13 Example 3 (Compound No. 6): (-) - N - [(6-aza-bicyclo [3.2.1] oct-5- hydrochloride yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide (1: 1).

3.1 Second diastereoisomer of phenol- [6 - ((R) -1-phenol-ethyl) -6-aza-bicyclo [3.2.1-oct-5-yl-methylamine (Ila2) The two diastereoisomers (IIa) can be separated by gel separation silica with as eluent a mixture of dichloromethane and methanol. The compound the most polar is phenyl-C- [6 - ((R) -1-phenyl-ethyl) -6-aza-bicyclo [3.2.1] oct-5-yl] -methylamine (Ila2).

1 H NMR (400 MHz, DMSO-d 6) δ ppm 7.46 (m, 2H), 7.34 (m, 2H), 7.29-7.14 (m, 6H), 4.23 (q, J = 6.8 Hz, 1H), 3.56 (m, 1H), 3.21 (m, 1H), 3.06 (m, 1H), 2.26 (m, 1H), 2.19 (m, 2H), 1.75 -1.16 (m, 10H), 0.89 (m, 2H).
3.2 (-) - (6-Azabicyclo [3.2.1-oct-5-yl] -phenyl-methylamine (IIb2) enantiomer This compound is obtained according to Example 1.2 starting from the compound of formula (Ila2).
Compound of formula (IIb2) in base form Mp = 82.5-83.5 ° C
ee = 93%
[DI 20-C CHCl 3 = -18.3 c = 0.58 g / 100 ml 1 H NMR (400 MHz, CDCl 3) δ ppm 7.29 -7.13 (m, 5H), 3.72 (s, 1H), 3.02 (m, J =
5.4 Hz and 10 Hz, 1 H), 2.88 (m, J = 10 Hz and 1 Hz, 1 H), 2.25 (m, 1 H), 1.83 (m, 1 H), 1.70 (m, 3H), 1.59 (m, 1H), 1.52-1.39 (m, 2H), 1.33-1.08 (m, 4H).

3.3 (-) - N - [(6-aza-bicyclo [3.2.1-oct-5-yl] -phenol-methyl) hydrochloride (2,6-dichloro-3-trifluoromethyl) benzamide (1: 1).
This compound is obtained according to Example 1.3 starting from the compound of formula (IIb2) PF: 192-193 ° C
ee = 92%
[DI 20-C MeOH = -40.5 c = 0.194g / 100 ml 1 H NMR (400 MHz, DMSO-d 6) δ ppm 9.61 (d, J = 8.6 Hz, 1H), 9.54 (m, 1H), 8.83 (m, 1 H), 7.97 (m, J = 8.8 Hz, 1H), 7.79 (m, 1H), 7.60 (m, 2H), 7.46 (t, J = 7, 7 Hz, 2H),

14 7.38 (m, 1H), 5.71 (d, J = 8.5 Hz, 1H), 3.49 (m, 1H), 3.13 (m, 1H), 2.65 (m, 1H), 2.11-1.78 (m, 3H), 1.71-1.22 (m, 6H).

Example 4 (Compound No. 20): 2-Chloro-N - [(6-ethyl-6-aza-bicyclo [3.2.1] oct-5-yl) phenyl-methyl] - (3-trifluoromethyl) -benzamide.

In a 25 ml flask, 0.17 g of N - [(6-aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide (0.40 mmol) and 0.084 g of carbonate of potassium (0.60 mmol) in 4 ml of acetonitrile, to which 50 ml of of iodoethane (0.60 mmol).
The reaction medium is stirred overnight at room temperature, then 3 hours at 50 C and then concentrated under reduced pressure. The residue is then diluted with 10 ml of dichloromethane and then washed with water (5 ml).
After extraction, the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. This gives 158 mg of an oil which is purified by column chromatography on silica gel eluting with a mixed dichloromethane and methanol. This gives 84 mg of 2-chloro-N - [(6-ethyl 6-aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide under powder form.
PF 160-162 ° C
1H NMR (400MHz, DMSO-d6) δ ppm 8.60 (d, J = 7.7Hz, 1H), 7.92 (m, 1H), 7.63.
(m, 2H), 7.43-7.21 (m, 5H), 4.93 (d, J = 7.7 Hz, 1H), 3.41 (m, 1H), 2.82 (m, 1H), 2.62 -2.39 (m, 2H), 2.20 (m, 2H), 1.72 (m, 1H), 1.53-0.84 (m, 9H).
Example 5 (Compound No. 22): 2-Chloro-N - [(6-methyl-6-azabate) hydrochloride bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide (1: 1).

In a 25 ml flask was placed 0.127 g of N - [(6-aza-bicyclo [3.2.1] oct-5-yl) -phenylmethyl] - (2-chloro-3-trifluoromethyl) -benzamide (0.30 mmol) and 1 ml of formaldehyde in 2 ml of formic acid. The reaction mixture is heated to 100 C overnight. After cooling, the medium is hydrolysed, basified to pH
9 with ammonia and extracted with ethyl acetate. The sentence organic is dried over sodium sulfate, filtered and evaporated under reduced pressure.

The residue is purified by chromatography on a column of silica gel in eluent with a mixture of dichloromethane and ammoniacal methanol. We thus obtain 113 mg of an oil which is salified in the form of hydrochloride by solubilization of the base in dichloromethane, addition of an excess of 1N hydrochloric acid ether and concentration under reduced pressure.

FP: 186-188 ° C
1 H NMR (400 MHz, DMSO-d 6) δ ppm 10.20 (m, 1H), 9.34 (d, J = 9.8 Hz, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.68 (m, 3H), 7.53 -7.38 (m, 3H), 5.74 (d, J = 9.8 Hz, 1H), 4.16 (m, 1H), 3.10 (m, 1H), 2.73 - 2.50 (m, 4H), 2.40 (m, 1H), 2.10 -1.38 (m, 7H).
Example 6 (Compound No. 23): N - [(6-aza-bicyclo [3.2.1] oct-5-yl) hydrochloride (3-bromo-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) -benzamide (1: 1).

6.1. 6-Allyl-6-aza-bicyclo [3.2.1] octane-5-carbonitrile (IVc).
In a sealed 5 ml tube under argon, 0.5 g of 3-chloromethylcyclohexanone (3.4 mmol), 3 ml of anhydrous methanol, 0.93 ml acetone cyanohydrin (10.2 mmol) and 0.26 ml of allylamine (3.4 mmol). The The reaction mixture is heated for 3 days at 100 C. After cooling, the middle The reaction mixture is poured into 10 ml of a 1N aqueous sodium hydroxide solution. After two extracted with dichloromethane, the combined organic phases are washed with a saturated solution of sodium chloride, dried over sodium sulphate, filtered then the solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica gel column eluting with a mixture of ether of oil and ethyl acetate. In this way 426 mg of 6-allyl-6-aza-bicyclo [3.2. 1] octane-5-carbonitrile (IVc) as an oil.

1H NMR (400MHz, DMSO-d6) δ ppm 8.60 (d, J = 7.7Hz, 1H), 7.92 (m, 1H), 7.63.
(m, 2H), 7.43-7.21 (m, 5H), 4.93 (d, J = 7.7 Hz, 1H), 3.41 (m, 1H), 2.82 (m, 1H), 2.62-2.39 (m, 2H), 2.20 (m, 2H), 1.72 (m, 1H), 1.53 -0.84 (m, 9H).

6.2. (6-Allyl-6-azabicyclo [3.2.lloct-5-yl) - (3-bromo-phenyl) -methylamine (IIc).

The compound is obtained according to the method described in Example 1.1, in starting from 1 g of 6-allyl-6-aza-bicyclo [3.2.1] octane-5-carbonitrile (IVc), 2.5 equivalents of 3-bromophenyl lithium and 5 equivalents of sodium borohydride. After purification by column chromatography on silica gel eluting with a mixture of dichloromethane and ammoniacal methanol, 260 mg of oil containing 140 mg of (6-allyl-6-aza-bicyclo [3.2.1] oct-5-yl) - (3-bromine phenyl) -methylamine (IIc) (0.42 mmol) used as in the next step.
6.3 N - [(6-Allyl-6-aza-bicyclo [3.2.1-tert-5-yl] - (3-bromo-phenyl) -methyl] -2-chloro-3-trifluoromethyl) benzamide.

In a 25 ml flask, 260 mg of (6-allyl-6-aza-bicyclo [3.2.1] oct-5-yl) - (3-bromo-phenyl) -methylamine (IIc) (0.42 mmol) in 8 ml of dichloromethane at 0 VS
in the presence of 118 mg of potassium carbonate (0.78 mmol).
189 mg of (2-chloro-3-trifluoro) acid chloride are then added.
benzoic acid (0.78 mmol). The reaction medium is stirred overnight at room temperature room. After hydrolysis and extraction, the organic phase is washed with the 1N sodium hydroxide, dried over sodium sulphate, filtered and then concentrated under pressure scaled down. After purification by chromatography on a column of silica gel in eluting with a mixture of dichloromethane and ammoniacal methanol, gets 146 mg of N - [(6-allyl-6-aza-bicyclo [3.2.1] oct-5-yl) - (3-bromo-phenyl) methyl] -(2-chloro-3-trifluoromethyl) benzamide as an oil.
1 H NMR (400 MHz, DMSO-d 6) δ ppm 8.68 (d, J = 7.7 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.63 (m, 2H), 7.58 (m, 1H), 7.44 (m, 1H), 7.40 (m, 1H), 7.28 (d, J); =
7.8 Hz, 1H), 5.81 (m, 1H), 5.22 (m, 1H), 5.00 (m, 1H), 4.97 (d, J = 7.7 Hz, 1H), 3.53.
(m, 1H), 3.34 (m, 1H), 3.07 (m, 1H), 2.37 (m, 1H), 2.18 (m, 1H), 1.77 (m, 1H), 1.54 (m, 1H), -0.77 (m, 7H).
6.4 N - [(6-aza-bicyclo [3.2.1-oct-5-yl] - (3-bromo-phenyl) -methyl] -hydrochloride (2-chloro-3-trifluoromethyl) -benzam ide.

In a sealed tube under argon, 19 mg of palladium tetrakis (triphenylphosphine) (0.02 mmol) and 0.078 g of N, N-dimethyl barbiturate (0.5 mmol) in solution in 3 ml of dichloromethane. The the reaction medium is heated to 40 ° C. before adding 0.09 g of N - [(6-allyl-6) aza bicyclo [3.2.1] oct-5-yl) - (3-bromo-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) -benzamide (0.17 mmol) in 3 ml of dichloromethane. We heat 2 hours C. After cooling, dilute with 10 ml of dichloromethane and then hydrolyzed with 5 ml of a solution of sodium carbonate.

The organic phase is separated and washed twice with 5 ml of the acid hydrochloric 1 N. The aqueous phases are combined and then basified with ammonia at pH

then extracted twice with 25 ml of dichloromethane. Organic phases are dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with a mixture of dichloromethane and ammoniacal methanol. This gives 62 mg of N - [(6-Azabicyclo [3.2.1] oct-5-yl) - (3-bromo-phenyl) -methyl] - (2-chloro-3-) trifluoromethyl) -benzamide which is salified as hydrochloride by solubilization of the base in dichloromethane, addition of an excess of acid 1N hydrochloric acid in ether, concentration under reduced pressure, trituration in ether and filtration.

PF: 250.5-251.5 ° C
1H NMR (400MHz, DMSO-d6) δ ppm 9.62 (m, 1H), 9.45 (d, J = 9.2Hz, 1H), 8.94 (M, 1H), 7.97 (dxd, J = 8 and 1.5 Hz, 1H), 7.91 (m, 1H) 7.77 (dxd, J = 7.8 and 1.4) Hz, 1H), 7.67 (t, J = 7.6 Hz, 2H), 7.59 (m, J = 8 Hz, 1H), 7.43 (t, J = 7.9 Hz, 2H), 5.74 (d, J = 9.1 Hz, 1H), 3.50 (m, 1H), 3.15 (m, 1H), 2.64 (m, 1H), 2.08 (m, 1H) 1.94 (m , 1 H), 1.80 (m, 1H), 1.72-1.40 (m, 5H).

The other compounds listed in Table 1 are obtained according to the methods described in Examples 1 to 6, from the amines of formula (IIa), (IIb), (Ilc), lithiens of formula (V), carboxylic acid derivatives of formula (III) or agents appropriate alkylating agents.
The following table 1 illustrates the chemical structures of some compounds of the invention.
In the column - "Salts", - means a compound in the basic form, "HCI", means a hydrochloride, the number in parenthesis indicates the ratio (acid: base), - The compounds of the table are in the form of solvated hydrochloride by one or more water molecules, In the columns R, R, and R2:
- - CI means chlorine, - CH3 means methyl, NH2 is amino, - OCH3 means methoxy, Ph denotes phenyl - SO2C2H5 means ethanesulfonyl, CF3 means trifluoromethyl, - in column R2, the number in front of the substituents indicates their position in the general formula (I).
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 Waters GCT.

R HN

NRR, R2 Stereochemistry salts Diastereoisomer 1, 1H Ph 2 -CH3,3-CF3 -racemic Diastereoisomer 1, 2H Ph 2 -CH3,3-OCH3 -racemic HCI Diastereoisomer 1, 3 H Ph 2,6 (CI) 2,3-CF3 (1: 1) racemic HCI Diastereoisomer 1, 4 H Ph 2-C1,3-CF3 (1: 1) racemic HCI
H Ph 2-C1,3-CF3 (1: 1) Chiral dextrorotatory HCI
6H Ph 2,6- (Cl) 2,3-CF3 (1: 1) Chiral levorotatory HCI
7 H Ph 2-C1,3-CF3 (1: 1) Chiral levorotatory HCI
8H Ph 2,6- (Cl) 2,3-CF3 (1) Chiral dextrorotatory 9H Ph 2 -OCH 3, 4-Cl 5 SO 2 Cl 2 HCl Diastereoisomer 1, (1: 1) racemic HCI Diastereoisomer 1, H Ph 2-C1, 5-CF3 (1: 1) racemic Diastereoisomer 1, 11 h Ph 2,6- (Cl) 2 -racemic Diastereoisomer 1, 12 H Ph 2 -CH3,3-CI -racemic 13 H 4 -F-Ph 2 -Cl 3 -CF 3 - Diastereoisomer 1, racemic Diastereoisomer 1, 14 H 4 -F-Ph 2,6- (Cl) 2,3-CF 3 -racemic 3-OCH3-Diastereoisomer 1, 15 H 2,6- (Cl) 2,3-CF3 -Racemic Ph 3-OCH3-Diastereoisomer 1,

16 H 2-C1,3-CF3 -Racemic Ph Diastereoisomer 1,

17H 3-OH-Ph 2 -Cl, CF 3 -racemic Diastereoisomer 1,

18H 3-OH-Ph 2,6- (Cl) 2,3-CF3 -racemic HCI Diastereoisomer 1,

19 H 3 -CH3-Ph 2-C1,3-CF3 (1: 1) racemic Diastereoisomer 1,

C2H5 Ph 2 -C1.3-CF3 -racemic Diastereoisomer 1,

21 H 3 -CH3-Ph 2,6- (Cl) 2,3-CF3 -racemic HC Diastereoisomer 1,

22 CH3 Ph 2-C1,3-CF3 (1: 1) racemic HCI Diastereoisomer 1,

23 H 3 -Br-Ph 2-C1,3-CF3 (1: 1) racemic HCI Diastereoisomer 1,

24 H 3 -Br-Ph 2,6- (Cl) 2,3-CF3 (1: 1) racemic HCI Diastereoisomer 1, H3-CF3-Ph2-C1,3-CF3 (1: 1) racemic HCI
C2H5 Ph 2,6- (Cl) 2,3-CF3 (1: 1) Chiral dextrorotatory HCI Diastereoisomer 1, 27 C2H5 3-CF3-Ph 2-C1,3-CF3 (1: 1) racemic LCMS
NFC [a0] 20 C MH +
1 58.5-59.5 NA 403 3 249.5-250.5 NA 457 265.5-266.5 32.0 (MeOH, c = 0.66 g / 100 ml) 423 6 192-193 -40.5 (MeOH, c = 0.196 g / 100 ml) 457 266.5-267.5 -26.4 (MeOH, c = 0.73 g / 100 ml) 423 8 241-242 30.7 (MeOH, c = 0.75g / 100ml) 457 24 278.5-279 NA 535 +55.37 (CHCl3, c = 0.736g / 100 26 270.5-272.5 C 485 MID) The compounds of the invention have been subjected to a series of tests pharmacological have highlighted their interest as substances with therapeutic activities.

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 cell are cultured in monolayer for 48 h in plates pretreated with the fibronectin at 0.02%. On the day of the experiment, the culture medium is eliminated and cells are washed with Krebs-HEPES buffer (4- (2-hydroxyethyl) piperazine 1-ethanesulfonic acid) at pH 7.4. After 10 min preincubation at 37 C in the presence is buffer (control group), or test compound at different concentrations or mM glycine (non-specific capture determination), 10 μM of [14C] glycine (specific activity 112 mCi / mmol) are then added. Incubation is continues 10 min at 37 ° C., and the reaction is stopped by 2 washes with one buffer Krebs-HEPES at pH 7.4. The radioactivity incorporated by the cells is then estimated after addition of 100 μl of liquid scintillant and stirring for 1 h. The counting is performed on Microbeta Tri-IuxTM counter. The effectiveness of the compound is determined by the C150, concentration of the compound which decreases by 50% the specific capture of glycine, defined by the difference in radioactivity incorporated by the control group and the lot that has received glycine at 10 mM.
The compounds of the invention, in this test, have a C150 of the order of 0.001 to 10 μM.

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

C150 compound (pM) 0.020 0.04 0.29 11 0.90 16 0.163 0.045 0.006 23 0.036 0.547 The results of the tests carried out on the chiral compounds of the invention and their racemates in the general formula (1) in which R2 represents in particular one or

Several halogen atoms or trifluoromethyl groups show that they are inhibitors of the 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 diseases, dementia; for the treatment of psychoses, especially of schizophrenia (deficient form and productive form), symptoms acute or chronic extrapyramidal induced by neuroleptics; for the treatment various forms of anxiety, panic attacks, phobias, unrest obsessive compulsive; for the treatment of different forms of depression, including including psychotic depression; for the treatment of disorders bipolar, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or withdrawal, sexual behavior disorders, disorders of the food intake, migraine; pain ; sleep disorders.

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 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 can be considered ointments, lotions and eye drops.
Said unit forms are dosed to allow administration daily 0.01 to 20 mg of active ingredient per kg of body weight, depending on the form dosage.

To prepare tablets are added to the active ingredient, 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, acid stearic acid, glycerol tribehenate, sodium stearyl fumarate. of the agents wetting agents or surfactants such as sodium lauryl sulphate can also 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. It can be designed to allow rapid, delayed or prolonged release of the active ingredient 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 made of 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 mixture with dispersing agents 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 agents dispersion and / or pharmacologically compatible wetting agents, by example the 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-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

26 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 mode of administration, weight and 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 of its pharmaceutically acceptable salts.

Claims (21)

1. Compound of general formula (I) R represents a hydrogen atom or a group selected from groups (C1-C6) alkyl, (C3-C7) -cycloalkyl, these groups being optionally substituted with one or many groups selected independently from one another from the fluorine atom, groups (C3-C7) -cycloalkyl, (C 2 -C 4) alkenyl, phenyl, (C 1 -C 6) alkoxy, hydroxy; the group phenyl being optionally substituted with one or more alkoxy groups;
R 1 represents a phenyl or naphthyl group, optionally substituted with a or many substituents chosen independently of each other from among the atoms halogen, the (C1-C6) alkyl, (C1-C6) alkoxy, halo- (C1-C6) alkyl, NR4R5, NR3C (O) OR4 groups, NR3SO2R4, NR3C (O) R6, hydroxy, halo- (C1-C6) alkoxy, (C1-C6) alkyl-thio, (C1-C6) alkyl-SO2, phenyl or heteroaryl, the phenyl group being optionally substituted with one or many substituents independently selected from halogen atoms, the groups (C1 C6) alkyl, (C1-C6) alkoxy, halo- (C1-C6) alkyl, NR4R5, NR3C (O) OR4, NR3SO2R4, NR3C (O) R6, hydroxy, halo- (C1-C6) alkoxy, (C1-C6) alkyl-thio, (C1-C6) alkyl-SO2, the group heteroaryl optionally substituted with one or more substituents selected independently among halogen atoms, (C1-C6) alkyl, (C1-C6) alkoxy, halo- (C1-C6) alkyl, NR4R5;
R2 represents one or more substituents chosen from the atom of hydrogen, atoms halogen, (C1-C6) alkyl, (C3-C1) cycloalkyl, (C3-C1) -cycloalkyl-(C1-C3) alkyl, halo- (C1-C6) alkyl, (C1-C6) alkoxy, NR4R5, phenyl, heteroaryl, cyano, acetyl, (C1-C6) thioalkyl, (C1-C6) alkylsulfonyl, carboxy or (C1-C6) alkoxycarbonyl; the phenyl group optionally substituted with one or more substituents selected independently among the halogen atoms, the (C1-C6) alkyl, (C1-C6) alkoxy, halogen, (C1-C6) alkyl, NR4R5, NR3C (O) OR4 NR3SO2R4, NR3C (O) R6, hydroxy, halo- (C1-C6) alkoxy, (C1-C6) alkyl-thio, (C1-C6) alkyl-SO2, the heteroaryl group being optionally substituted with or many substituents independently selected from halogen atoms, the groups (C1 C6) alkyl, (C1-C6) alkoxy, halo- (C1-C6) alkyl, NR4R5;
- R3, R4 and R5 represent independently of one another an atom hydrogen or (C1-C6) alkyl group;

- R6 represents a (C1-C6) alkyl group;
- R4 and R5 can form together, with the nitrogen atom which carry them, a chosen cycle among the azetidine, pyrrolidine, piperidine, morpholine rings, thiomorpholine, piperazine, azepine, optionally substituted with a (C1-C6) alkyl group;
- R3 and R4 can form together, with the atoms that carry them, a cycle at 5 or 6 links;
- R3 and R6 can form together, with the atoms that carry them, a cycle at 5 or 6 links;
in the form of a base or an acid addition salt. 2. Compound of general formula (I) according to claim 1, characterized in that that R
represents a hydrogen atom, or a (C 1 -C 6) -alkyl group. 3. Compound of general formula (I) according to claim 1 or 2, characterized in that R1 represents a phenyl group, optionally substituted by one or more substituents independently of one another selected from halogen atoms, groups (C1-C6) alkyl, halo- (C1-C6) alkyl, (C1-C6) alkoxy, hydroxy. 4. Compound of general formula (I) according to any one of claims 1 at 3, characterized in that R2 represents one or more substituents selected from atom hydrogen, halogen atoms, halo (C1-C6) alkyl groups, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkyl-SO2. 5. Compound of general formula (I) according to any one of claims 1 to 4, characterized in what:
R represents a hydrogen atom or a methyl or ethyl group;
R 1 represents a phenyl group, optionally substituted with one or many substituents chosen independently of each other from among the atoms halogen, the methyl, ethyl, trifluoromethyl, methoxy, hydroxy groups;
R2 represents one or more substituents chosen from the atom of hydrogen, atoms halogen, trifluoromethyl, methyl, methoxy, ethanesulfonyl;
in the form of a base or an acid addition salt. 6. Compound according to any one of claims 1 to 5, characterized in that is chosen among:
N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2-methyl-3-trifluoromethyl) -benzamide;
N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-methoxy-2-methyl) -benzamide;

N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) benzamide and its hydrochloride;
N- [6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide and its hydrochloride;
(+) - N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) benzamide and its hydrochloride (-) - N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) benzamide and its hydrochloride;
(-) - N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) benzamide and its hydrochloride;
(+) - N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide and its hydrochloride;
N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (4-chloro-5-ethanesulfonyl-2-methoxy) -benzamide and its hydrochloride;
N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (2-chloro-5-trifluoromethyl) -benzamide and its hydrochloride;
N - [(6-Azabicyclo [3.2.1] oct-5-yl) phenylmethyl] - (2,6-dichloro) benzamide;
N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-chloro-2-methyl) -benzamide ;
N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) - (4-fluoro-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) -benzamide;
N - [(- 6-Aza-bicyclo [3.2.1] oct-5-yl) - (4-fluoro-phenyl) -methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide;
N - [(- 6-Aza-bicyclo [3.2.1] oct-5-yl) - (3-methoxy-phenyl) -methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide;
N - [(6-Aza-bicyclo [3.2.1] oct-5-yl- (3-methoxy-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) -benzamide;
N- [6-Aza-bicyclo [3.2.1] oct-5-yl- (3-hydroxy-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) -benzamide;
N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) - (3-hydroxy-phenyl) -methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide;
N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) -m-tolyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide and its hydrochloride 2-Chloro-N - [(6-ethyl-6-aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide;
N - [(6-Aza-bicyclo [3.2.1] oct-5-yl-m-tolyl-methyl] - (2,6-dichloro-3-trifluoromethyl) benzamide;
2-Chloro-N - [(6-methyl-6-aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide and its hydrochloride;

N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) - (3-bromo-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) -benzamide and its hydrochloride;
N - [(6-Aza-bicyclo [3.2.1] oct-5-yl) - (3-bromo-phenyl) -methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide and its hydrochloride;
N- [6-Aza-bicyclo [3.2.1] oct-5-yl- (3-trifluoromethyl-phenyl) -methyl] - (2-chloro-3-trifluoromethyl) -benzamide and its hydrochloride;
(+) - 2,6-Dichloro-N - [(6-ethyl-6-aza-bicyclo [3.2.1] oct-5-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide and its hydrochloride;
2-Chloro-N - [(6-ethyl-6-aza-bicyclo [3.2.1] oct-5-yl) - (3-trifluoromethyl-phenyl) -methyl] - (3-trifluoromethyl) benzamide and its hydrochloride; 7. Process for preparing 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 an activated OH group or a chlorine atom and R2 is as defined according to claim 1. 8. Medicinal product, characterized in that it comprises a compound of formula (I) according to one any of claims 1 to 6, or an addition salt of this compound to a acid pharmaceutically acceptable. 9. Pharmaceutical composition, characterized in that it comprises a compound Formula (I) according to any one of claims 1 to 6, or a salt pharmaceutically acceptable, of this compound, as well as at least one pharmaceutically acceptable excipient. 10. Use of a compound of formula (I) according to any one of Claims 1 to 6 for the preparation of a medicament for treating disorders cognitive and / or behavioral conditions associated with neurodegenerative diseases; to madness. 11. Use of a compound of formula (I) according to any one of Claims 1 to 6 for the preparation of a medicament for the treatment of psychoses, schizophrenia (deficient form and productive form), acute extrapyramidal symptoms or chronic induced by neuroleptics. 12. Use of a compound of formula (I) according to any one of Claims 1 to 6 for the preparation of a medicament for treatment for treatment various forms of anxiety, panic attacks, phobias, disorders obsessive compulsive. 13. Use of a compound of formula (I) according to any one of Claims 1 to 6 for the preparation of a medicament for the treatment of different forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood disorders; for the treatment of disorders due to abuse alcohol withdrawal, sexual behavior problems, taking food, migraine. 14. Use of a compound of formula (I) according to any one of Claims 1 to 6 for the preparation of a medicament for the treatment of pain. 15. Use of a compound of formula (I) according to any one of Claims 1 to 6 for the preparation of a medicament for the treatment of sleep. 16. A compound according to any one of claims 1 to 6 for the treatment of disorders cognitive and / or behavioral associated with neurodegenerative diseases; at Madness. 17. A compound according to any of claims 1 to 6 for the treatment of psychoses, schizophrenia (a form of deficit and a productive form), symptoms acute or chronic extrapyramidal events induced by neuroleptics. 18. A compound according to any one of claims 1 to 6 for the treatment of various forms of anxiety, panic attacks, phobias, disorders obsessive compulsive. 19. A compound according to any one of claims 1 to 6 for the treatment of different forms of depression, including psychotic depression; for the treatment of bipolar disorder, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or withdrawal, behavioral disorders sexual eating disorders, migraine. 20. A compound according to any one of claims 1 to 6 for the pain treatment. 21. A compound according to any one of claims 1 to 6 for the treatment of disorders some sleep.