SG173607A1

SG173607A1 - N-[(6-azabicyclo[3.2.1]oct-1-yl)-aryl-methyl]-benzamide derivatives, preparation thereof, and therapeutic use thereof

Info

Publication number: SG173607A1
Application number: SG2011057213A
Authority: SG
Inventors: Gihad Dargazanli; Genevieve Estenne-Bouhtou; Florence Medaisko
Original assignee: Sanofi Sa
Priority date: 2009-02-10
Filing date: 2010-02-09
Publication date: 2011-09-29
Also published as: KR20110118813A; WO2010092287A1; FR2941954B1; EP2396335A1; JP2012517412A; MX2011008459A; CN102388050A; CA2751866A1; BRPI1008544A2; FR2941954A1; AR075380A1; UY32429A; AU2010212703A1; IL214487A0; TW201034667A

Description

N-[(6-AZABICYCLO[3.2.1]0CT-1-YL)ARYLMETHYL]BENZAMIDE DERIVATIVES,

PREPARATION THEREOF AND THERAPEUTIC USE THEREOF

The present invention relates to derivatives of N-{(6-azabicyclo[3.2.1]oct-1- yharylmethyllbenzamide, to the preparation thereof and to the therapeutic use thereof, in the treatment or prevention of diseases involving GlyT1 glycine transporters.

The compounds of the invention correspond to the general formula (1): lm

HN-_©

Se (1) in which: - R represents a hydrogen atom or a group chosen from (C+-Colalkyl or (C4-C)- cycloalkyl groups, these groups being optionally substituted with one or more groups chosen independently from one another from a fluorine atom, and (C;-C)cycloalkyl, {Cy-Ci)alkenyl, phenyl, (C,-Cg)alkoxy or hydroxy groups; the phenyl group being optionally substituted with one or more alkoxy groups; - Ry represents a phenyl or naphthyl group, optionally substituted with one or more substituents chosen, independently from one another, from halogen atoms, and (C;-

Gelalkyl, (C4-Cslalkoxy, halo(Ci-Celalkyl, NR4Rs, NR;C(Q)OR4, NR;SO.R,,

NR3C(O)Rs, hydroxy, halo(C4-Cg)alkoxy, (C4-Ce)alkylthio, (C-Celalkyl-SO,, phenyl or heteroaryl groups, the phenyl group being optionally substituted with one or more substituents chosen independently from halogen atoms, and (C:-Cgalkyl, (C,-

Cejalkoxy, halo(Cs~Cglalkyl, NR4R;, NR:;C(O)OR:, NR3SO,R,, NR;C(O)Rs, hydroxy, halo(C.-Cg)alkoxy, {C4-Cg)alkylthio and (C+-Ce)alkyl-SO, groups, the heteroaryl group being optionally substituted with one or more substituents chosen independently from halogen atoms and (C:-Cgalkyl, (Cr-Celalkoxy, halo(Cs-Celalkyl or NR4Rs groups; - R; represents one or more substituents chosen from a hydrogen atom, halogen atoms and (Ci-Ce)alkyl, (C;-C)cycloalkyl, (Cs-Crieycloalkyl(Cy-Ca)alkyl, halo(C;-

Cealkyl, (Ci-Cgalkoxy, NR4Rs, phenyl, heteroaryl, cyano, acetyl, (Cy-Ce)thicalkyl, (C4-Celalkylsulphonyl, carboxy or (C1-Co)alkoxycarbonyl groups; the phenyl group being optionally substituted with one or more substituents chosen independently from halogen atoms, and (Cs-Celalkyl, (C4-Cgalkoxy, halo(Cs-Cg)alkyl, NR4Rs,

NRG(O)OR4, NR3SOzRs, NR;C(O)Rs, hydroxy, halo{C;-Cs)alkoxy, {C1-Cg)alkyithio and (C+-Cglalkyl-SO; groups, the heteroaryl group being optionally substituted with one or more substituents chosen independently from halogen atoms and {C4-Cslalkyl, (C+-Cg)alkoxy, halo(C4-Cg)alkyl or NR,Rs groups; - Rs, Rs and Rj represent, independently of one another, a hydrogen atom or a (Cy-Celalkyl group; - Re represents a (C,-Cglalkyl group; - Ry and Rs may together form, with the nitrogen atom which bears them, a ring chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine or azepine rings, optionally substituted by a (C4-Cg)alkyl group; - Rs and Ry may together form, with the atoms which bear them, a 5- or 6-membered ring; - Rs and Rg may together form, with the atoms that bear them, a 5- or 6-membered ring; in the form of a base or addition salt with an acid.

The compounds of formula (I) comprise three asymmetric carbon atoms. They may 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 addition salts with acids. Such addition salts are part of the invention.

These salts are advantageously prepared with pharmaceutically acceptable acids, but salts of other acids that are useful, for example, for the purification or isolation of the compounds of formula (1) are also part of the invention.

Within the context of the invention, the following definitions apply: - GC; where t and z may take the values of 1 to 8: a carbon-based chain which may have from t to z carbon atoms, for example C..Cs is a carbon-based chain which may have from 1 to 6 carbon atoms: - alkyl: a linear or branched saturated aliphatic group; for example a C1.Ce-alkyl group represents a linear or branched carbon-based chain having from 1 to 6 carbon atoms, for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, pentyl or hexyl; - alkenyl: a linear or branched monounsaturated or polyunsaturated aliphatic group comprising, for example, one or two ethylenically unsaturated groups; = amino: an NH; group; - alkoxy: an ~O-alkyl group; - acetyl a -C(O)- group; - Cyano: a ~CN group; 16 - hydroxy: an ~OH group; - thioalkyl: a sulphur atom substituted with an alkyl group; - halogen atom: a fluorine, a chlorine, a bromine or an iodine; - haloalkyl: an alkyl group of which one or more hydrogen atoms have been substituted with a halogen. By way of example, mention may be made of trifluoromethyl, trifluoroethyl or pentaflucroethyl groups; and - heteroaryl: a 5- or 6-membered aromatic monocyclic group comprising from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulphur. By way of example of a heteroaryl group, mention may be made of pyrrole, furan, thiophene, pyrazoie, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine or triazine groups.

Among the compounds of general formula (1) that are subjects of the invention, a first group of compounds is constituted by the compounds for which R represents a hydrogen atom or a (C-Cg)alky! group;

Ry, Ry Rs, Ry and Rg being as defined above,

Among the compounds of general formula (f} that are subjects of the invention, a second group of compounds is constituted by the compounds for which R represents a hydrogen atom or a methyl or ethyl group; 300 Ry, Ry Ry, Ry, Rs and Rg being as defined above.

Among the compounds of general formula (I) that are subjects of the invention, a third group of compounds is constituted by the compounds for which Rs represents a phenyl group, optionally substituted with one Or more substituents chosen, independently from one another, from halogen atoms, (C1-Cq)alkyt, halo(C-Cs)alkyl, (C4-Ce)alkoxy or hydroxy groups;

R, Ra, Rs, Rs and R; being as defined above.

Among the compounds of general formula (I) that are subjects of the invention, a fourth group of compounds is constituted by the compounds for which R, represents a phenyl group, optionally substituted with one or more substituents chosen, independently from one another, from halogen atoms, methyl, ethyl, trifluoromethyl, methoxy or hydroxy groups;

R1, Ra, Rs, Re, Rs and Rg being as defined above.

Among the compounds of general formula (I) that are subjects of the invention, a fifth group of compounds is constituted by the compounds for which R; represents one or more substituents chosen from a hydrogen atom, halogen atoms, halo(C,-Cg)alkyi, (C+-Ce)alkyl, (C4-Cg)alkoxy or (C4-Ce)alkyl-SO, groups;

R, R1, Rs, Rs and Rs being as defined above.

I5

Among the compounds of general formula (I) that are subjects of the invention, a sixth group of compounds is constituted by the compounds for which R, represents one or more substituents chosen from a hydrogen atom, halogen atoms, trifluoromethyl, methyl, methoxy or ethanesulphonyl groups;

R, Ry, Ry, Rg and Ry being as defined above.

Among the compounds of general formula (I) that are subjects of the invention, a seventh group of compounds is constituted by the compounds for which: - R represents a hydrogen atom or a methyl or ethyl group: - Ry represents a phenyl group, optionally substituted by one or more substituents chosen, independently from one another, from halogen atoms or methyl, ethyi, trifluoromethyl, methoxy or hydroxy groups: and - R; represents one or more substituents chosen from a hydrogen atom, halogen atoms or trifluoromethyl, methyl, methoxy or ethanesulphonyt groups, inthe form of a base or addition salt with an acid.

The combinations of groups one to seven as defined above are also part of the fnvention.

Among the compounds of general formula (I) that are subjects of the invention, mention may especially be made of the following compounds:

N-[(6-Azabicyclo[3.2. tloct-5-yl)phenyimethyl}(2-methyl-3-trifluoromethy!)benzamide:

N-[{(6-Azabicyclo[3.2.1 Joct-5-yl)phenyimethyl)(3-methoxy-2-methyl)benzamide:

N-[(6-Azabicyclo[3.2.1 Joct-5-yl)yphenylmethyl](2,6-dichloro-3- trifluoromethyl)benzamide and its hydrochloride:

N-[B-Azabicyclo[3.2.1 Joct-5-yl)phenylmethyi](2-chloro-3-trifluoromethyl Yoenzamide and its hydrochloride; (+)-N-[(6-Azabicyclo[3.2.1}oct-5-yl Jphenylmsthyl)(2-chloro-3- trifluoromethyl)benzamide and its hydrochloride; (-}-N-{(6-Azabicycio]3.2.1 Joct-5-yl)phenylmethyt](2,6-dichtoro-3- trifluoromethyl}benzamide and its hydrochloride: (-)-N-[(6-Azabicyclo[3.2.1]oct-5-yl)phenyimethyl}(2-chioro-3- trifluoromethyl)benzamide and its hydrochloride: {+)-N-[(6-Azabicyclo[3.2. 1]oct-5-yl)phenylmethyl}(2,6-dichloro-3- trifluoromethyl)benzamide and its hydrochloride:

N-[(6-Azabicyclo[3.2.1 loct-5-yl)phenylmethyl](4-chioro-5-ethanesulphonyl-2- methoxy)benzamide and its hydrochloride;

N-[{6-Azabicyclo[3.2.1 Joct-5-yl)phenylmethyl)(2-chloro-5-trifluoromethyl)benzamide and its hydrochloride:

N-[(6-Azabicyclo[3.2.1]oct-5-yl)phenylmethyl)(2,6-dichioro)benzamide:

N-[(6-Azabicyclo[3.2.1 Joct-5-yl)phenyimethyl}(3-chloro-2-methyl)oenzamide:

N-[(6-Azabicyclo[3.2.1]oct-5-yl)-(4-fluorophenyl)methyt](2-chloro-3- trifluoromethylbenzamide:;

N-[(-6-Azabicyclo[3.2.1 loct-5-yl)-(4-fluorophenyhimethyl](2,6-dichloro-3- trifluoromethyl}benzamide:;

N-[{-6-Azabicyclo[3.2. TJoct-5-y1)-(3-methoxyphenyl)methyi](2,6-dichloro-3- ftrifluoromethyl)benzamide;

N-[(6-Azabicyclo[3.2.1 Joct-5-yl-(3-methoxyphenyl)methyl}(2-chioro-3- trifluoromethyl)benzamide:

N-{6-Azabicyclo[3.2.1]oct-5-yl-(3-hydroxyphenylymethyi](2-chloro-3- trifluoromethyl)benzamide;

N-[(6-Azabicyclo[3.2. 1joct-5-yi)-(3-hydroxyphenyl)methyl](2,6-dichloro-3- trifluoromethyl)benzamide;

N-[(6-Azabicyclo[3.2.1]oct-5-yI)-m-tolyimethyl}(2-chloro-3-trifluoromethylbenzamide and its hydrochloride; 2-Chloro-N-[(6-ethyl-6-azabicyclo[3.2. 1]oct-5-yl)phenylmethyi](3- trifluoromethyhbenzamide:

N-[(6-Azabicyclo[3.2. 1loct-5-yl-m-tolylmethyl}(2,6-dichloro-3-

trifluoromethyh)benzamide; 2-Chloro-N-[(6-methyl-6-azabicyclo[3.2.1]oct-5-yl)phenylmethyl](3- trifluoromethyl)benzamide and its hydrochloride:

N-[(6-Azabicyclo[3.2.1]oct-5-y1)-(3-bromophenyl)methyl](2-chloro-3- trifluoromethyl)benzamide and its hydrochloride:

N-[(6-Azabicyclo[3.2. 1]oct-5-y1)-(3-bromophenylimethyi](2,6-dichtoro-3- trifluoromethyl)penzamide and its hydrochloride:

N-[6-Azabicyclo[3.2. 1]oct-5-yl-(3-trifluoromethylphenyl)methyl](2-chloro-3- trifiuoromethyl)benzamide and its hydrochloride: (+)-2,6-Dichioro-N-[(6-ethyl-6-azabicycio[3.2. 1]oct-5-yl)phenyimethyT](3- trifluoromethyl)benzamide and its hydrochloride; 2-Chioro-N-{(6-ethyl-6-azabicyclo[3.2. Tjoct-5-yl)-(3-trifluoromethylphenylimethyl](3- trifluoromethyl)benzamide and its hydrochloride.

The compounds of the invention have a particular activity as inhibitors of GlyT1 glycine transporters, especially improved activity and safety profiles.

The compounds of general formula (1) may be prepared by a process illustrated by scheme 1 below.

SCHEME 1

Y Oo (1H)

LL R, R \

R NH, I (1) (i)

A diamine of general formula (11), in which R and R, are as defined above, especially when R represents a hydrogen atom, or an allyl or phenylmethyl group, is coupled with an activated acid, for example via a mixed anhydride or an acid chloride of general formula (Ilt} in which Y represents a leaving group derived, for example, from benzotriazole, acylurea or a halogen atom and R, is as defined above, using the methods known to a person skilied in the art.

The compounds of general formula (1) in which R represents a hydrogen atom may also be prepared from compounds of general formula (1) in which R represents:

- either a phenylmethy! group, by deprotecting the nitrogen via hydrogenolysis; - or an alkenyl, preferably ally! group, by deprotecting the nitrogen, for example via a palladium "zero" complex according to the methods known to a person skilled in the art.

The compounds of general formula (1) in which R is other than a hydrogen atom may also be prepared starting from compounds of general formula (1) in which R represents a hydrogen atom, either by alkylation with a halide or mesylate of RX type, in which R is as defined above and X is mesylate or halogen, in the presence of a mineral base, for example potassium carbonate in acetonitrile, or via an

Eschweiler-Clarke reaction or via a reductive amination with a suitable aldehyde or ketone according to the methods known to a person skilled in the art.

The compounds of general formula (I} in which the R1 group is a phenyl group substituted with a hydroxy may be obtained from the corresponding compound of general formula (I) substituted with a methoxy, by using the methods known to a person skilled in the art.

The diamine of general formula (Il) may be prepared by the processes illustrated by scheme 2 for the amine (fla) and (Ilb} and scheme 3 for the amine (lic) below.

SCHEME 2

R,Li

ENG

{CN ! H R,

Oe { en NH, HN (Iva) (lia) (IIb)

SCHEME 3

R,Li

N Ww 3

N N oe OR

H.C H,C HN {IVc) (fle)

According to scheme 2, the nitrile of formula (IVa) is reacted with the lithiated aromatic compound of general formula (V), in which Ry is as defined 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, in particular, diastereoselectively reduced with a reducing agent such as sodium borohydride in a protic solvent such as methanol in order to give the amine of general formula (lla). The amine (lla) may be debenzylated by hydrogenation in the presence of a palladium catalyst in order to provide the deprotected amine (lb) (Scheme 2).

According to scheme 3, it is also possible to react the nitrile of formula (IVe) with the lithiated aromatic compound of general formula (V), in which R is as defined 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 stich as sodium borohydride in a protic solvent such as methanol in order to give the amine of general formula (lic) (Scheme 3).

Furthermore, the chiral compounds of general formula (I) may be obtained by separation of the racemic compounds via high performance liquid chromatography (HPLC) on a chiral column, or by separation, via silica gel chromatography, of the chiral diastereoisomers of the amine of general formula (lia) 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 (Vc) is synthesized in accordance with this same reference, using allytamine.

The lithiated aryl compounds of general formula {V} may be prepared according to methods known to a person skilled in the art.

The acids and acid chlorides of general formula (111) are commercially available or are prepared by analogy with methods known to a person skilled in the art.

The following examples illustrate the preparation of some compounds of the invention. In these examples: - The elemental microanalyses, the IR and NMR spectra and the chiral column

HPLC confirm the structures and the enantiomeric purities of the compounds obtained. - For the NMR descriptions, "m" stands for multiplet, "s" singlet, “t" triplet, "d" doublet, "q" quadruplet, dxd stands for double doublet, txt stands for triple triplet, dxt double triplet, etc. - The numbers indicated between parentheses in the titles of the examples correspond to those from the first column of the table given below, - The term "decomp." stands for “decomposition”. - The roman numerals between parentheses correspond to the corresponding general formulae which are indicated in the synthesis schemes. - The nomenclature used is the nomenclature according to the IUPAC (International

Union of Pure and Applied Chemistry) recommendations.

In the names of the compounds, the dash "-" is part of the word and the dash “ "is only used for the break at the end of the line; it should be deleted in the absence of a break and should not be replaced by a normal dash nor by a space.

Example 1 (compound No. 3): N-[(6-azabicyclo[3.2.1]oct-5-yl)phenylmethyl](2,6- dichtoro-3-trifluoromethyl)benzamide hydrochloride (1:1). 1.1 Phenyl-{6-((R}-1-phenylethyl)-6-azabicyclo 3.2. toet-5-ylimethylamine (lla).

Placed in a 100 ml three-necked flask, under argon, is 1 g of 6-((R)-1-phenylethyl)-6- azabicyclo[3.2.1]octane-5-carbonitrite (IVa) (4.16 mmol} at -70°C in 35ml of anhydrous tetrahydrofuran. 7.4 ml of a 1.13M solution (cyciohexane/ether) of phenyllithium (8.32 mmol} are added dropwise.

The mixture is left for two and a half hours at -70°C, then hydrolysed at -20°C with 15 mi of water.

After extraction, the organic phase is concentrated under reduced pressure, then the residue is taken up in 20 ml of methanol. 0.78 g of sodium borohydride (20.8 mmol) are added thereto in portions. The reaction medium is left stirring overnight at ambient temperature.

After evaporation under reduced pressure, the residue is taken up with 50 ml of ether and 50 ml of water. The medium is acidified with a 1N hydrochloric acid solution, then extracted. The aqueous phase is basified with aqueous ammonia then re- extracted two times with 50 ml of dichloromethane. The organic phases are combined, dried over sodium sulphate, filitered and evaporated under reduced pressure. Thus 1.5 g of an oil is obtained, which is purified by chromatography over a silica gel column by eluting with a mixture of dichloromethane and methanol. Thus, 1.15 g of phenyl-[6-((R)-1-phenylethyl)-6-azabicyclo[3.2. 1Joct-5-yiImethylamine (la) are obtained, a mixture of 2 chiral diastereoisomers, in oil form. 1.2 (6-Azabicyclo[3.2.1 loct-5-vliphenvimethylamine (|Ib).

Placed in a Parr flask are 4 g of a compound of formula (lla) (12.5 mmol) in 80 mi of methanol in the presence of a spatula tipful of 20% palladium hydroxide under 4 atmospheres of hydrogen at ambient temperature for 6 hours.

After filtration of the catalyst and evaporation of the filtrate under reduced pressure, the residue is taken up with 10 ml of dichloromethane and 20 ml of aqueous ammonia. After extraction, the organic phase is washed in a saturated solution of sodium chloride, dried over sodium sulphate, filtered, then the solvent is evaporated under reduced pressure. Thus, ig of (6-azabicyclo[3.2.1]oct-5- yl)phenylmethylamine of formula (lib) is obtained in oil form, which may be used crude in the subsequent step.

An analytical sample is obtained by salification of the base with a 2N hydrochloric ether solution then trituration in ether.

MP = 215-225°C 'H NMR (400 MHz, DMSO-d6) & ppm 9.14 (m, 4H), 7.76 (m, 2H), 7.56 -7.43 (m, 4H), 5.09 (broad s, TH), 3.49 (m, 1H), 3.11 (m, 1H), 2.72 (m, 1H), 2.19 (m, 1H), 1.87 (m,

TH), 1.83 =1.37 (m, 8H). 1.3 N-[{6-azabicyclol3.2.1 loct-5-yhphenyimethyl}(2,6-dichloro-3-trifluoromethyl) benzamide hydrochloride (1:1).

Placed in a 25ml round-bottomed flask are 240 mg of (2,6-dichloro-3- trifluoromethyl)benzoic acid (0.92 mmol), 124mg of hydroxybenzotriazole (0.92mmol) and 180mg of 1-[3-(dimethylamino)propyi]-3-ethylcarbodiimide hydrochloride (0.92 mmol) in solution in 5 ml of dichloromethane and the mixture is stirred at ambient temperature for 15 minutes. 200 mg (0.92 mmol) of (6- azabicyclo[3.2.1]oct-5-yl)phenylmethylamine of formula (lib) in solution in 5 ml of dichloromethane are added and the mixture is stirred at ambient temperature overnight.

The reaction medium is then diluted with 10 mi of dichloromethane, then washed successively with water (5 ml), with 1N sodium hydroxide (5 ml) and with a saturated solution of sodium chloride (5 mi).

The organic phase is dried over sodium sulphate, filtered and evaporated under reduced pressure.

The residue is purified by chromatography over a silica gel column by eluting with a mixture of dichloromethane and methanol. Thus, 180mg of NJ(6- azabicyclo[3.2.1]Joct-6-yl)phenylimethyl}(2,6-dichloro-3-trifluoromethyl)benzamide are obtained, which is saiified to the hydrochloride form by dissolving the base in dichloromethane, adding an excess of IN hydrochloric acid in ether, then concentrating under reduced pressure.

MP = 249.5-250.5°C 'H NMR (400 MHz, DMSO-d6) & ppm 9.79 (m, 1H), 8.66 (d, J = 9 Hz, 1H), 8.86 (m,

TH), 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)phenyimethyi]- (2,6-dichloro-3-triffuoromethyl)benzamide hydrochloride (1:1). 2.1. First diastereoisomer of phenyl- 6-({R)-1-phenylethyl)-6-azabicyclo[3.2.1]oct-5- ylimethvlamine (lla)

The two diastereoisomers (lla) may be separated by separation over silica gel with, as an eluent, a mixture of dichloromethane and methanol. The least polar compound is phenyl-[6-((R)-1-phenylethyl)-6-azabicyclo[3.2. 1Joct-5-yljmethylamine (lat). "H NMR (400 MHz, DMSO-d) § 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-Azabicyclo[3.2.1 loct-5-yl)phenvimethylamine (IIb1) enantiomer

This compound is obtained according to Example 1.2 by starting from the compound of formula (Ha1).

Compound of formula (l1b1) in base form.

MP = 84-85°C ee=100% [0a] 200c CHCI3= +55.2 ¢ = 0.80 g/100 mi "MH NMR (400 MHz, CDCls) 8 ppm 7.29 7.13 (m, 5H), 3.72 (s, 1H), 3.01 (m, J = 5.4 Hz and 10 Hz, 1H), 2.87 (m, J = 10 Hz and 1 Hz, TH), 2.25 (m, 1H), 1.83 (m, 1H), 1.70 (m, 3H), 1.58 (m, 1H), 1.52-1.39 (m, 2H}, 1.31- 1.08 (m, 4H). 2.3 _(+)-N-[(6-azabicyclo]3.2.1 loct-5-yl)phenyimethyl (2,6-dichloro-3-trifluoromethyl) benzamide hydrochloride (1:1),

This compound is obtained according fo Example 1.3 by starting from the compound of formula (Hib1). An analytical sample is obtained in hydrochloride form by dissolving the base in dichloromethane, adding an excess of 1N hydrochloric acid in ether, then concentrating under reduced pressure.

MP: 241-242°C ee:95%

[00] 20:c MeOH = +30.7 ¢ = 0.75 g/100 ml 'H NMR (400 MHz, DMSO-d6) & ppm 9.62 (d, J = 8.9 Hz, 1H), 9.42 (m, 1H), 8,84 (m,

AH), 7.97 (m, 1H), 7.80 (m, tH), 7.59 (m, 2H), 7.46 (m, 2H), 7.39 (m, 1H), 5.70 (broad d, J = 9 Hz, 1H), 3.49 (m, 1H), 3.13 (m, 1H), 2.65 (m, 1H), 2.11-1.20 (m, 9H)

Example 3 (compound No. 6): (-)-N-[(6-azabicyclo[3.2.1]oct-5-yl)phenyimethyl]- (2,8-dichioro-3-trifluoromethyl)benzamide hydrochloride (1:1). 3.1 Second diastereoisomer of phenyl- 6-((R}-1-phenylethy| )-6-azabicyclo{3.2.1]oct-

S-ylimethylamine (l1a2)

The 2 diasterecisomers (lla) may be separated by a separation over silica gel with, as an eluent, a mixture of dichloromethane and methanol. The most polar compound is phenyl-C-[6-((R)-1-phenylethyl)-6-azabicyclo]3.2. 1joct-5-yljmethylamine (Ifa2).

'H NMR {400 MHz, DMSO-d6) & ppm 7.46 (m, 2H), 7.34 (m, 2H), 7.29-7.14 {m, 6H), 4.23 (0, 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-vliphenylmethylamine (I[b2) enantiomer

This compound is obtained according to Example 1.2 by starting from the compound of formula (I1a2).

A compound of formula (11b2) in base form.

MP=82.5-83.5°C ee=93% [0p] 20c CHCl = -18.3° ¢ = 0.58 g/100 mi 'H NMR (400 MHz, CDCls} & ppm 7.29-7.13 (m, 5H), 3.72 (s, 1H), 3.02 (m, J =

I5 5.4 Hzand 10 Hz, 1H), 2.88 (m, J = 10 Hz and 1 Hz, TH), 2.25 (m, 1H), 1.83 (m, 1H), 1.70 (m, 3H), 1.59 (m, 1H), 1.52-1.39 (m, 2H), 1.33-1.08 (m, 4H). 3.3 (-)-N-[(6-azabicyclo 3.2. Tloct-5-ylphenylmethyll(2,6-dichloro-3-trifiuoromethyl) benzamide hydrochloride (1:1).

This compound is obtained according to Example 1.3 by starting from the compound of formula (i1b2).

MP: 192-183°C ee=92% [oplocc MeOH = -40.5° ¢ = 0.194 g/100 mi "H NMR (400 MHz, DMSO-d) 8 ppm 9.61 (d, J = 8.6 Hz, 1H), 9.54 (m, 1H), 8.83 (m,

TH), 7.97 (m, J = 8.8 Hz, 1H), 7.79 (m, 1H), 7.60 (m, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.38 (m, 1H), 5.71 (d, J = 8.5 Hz, 1H), 3.49 (m, TH), 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-azabicyclo[3.2.1]oct-5- yl)phenyimethyl](3-triffuoromethyl)benzamide.

Placed in a 25 ml round-bottomed flask are 0.17 g of N-[(6-azabicyclo[3.2.1]oct-5- yl)phenylmethyl}(2-chloro-3-trifiucromethyhbenzamide (0.40 mmol) and 0.084 g of potassium carbonate (0.60 mmol) in 4 mi of acetonitrile, to which 50 pl of iodoethane (0.60 mmol) are added.

The reaction medium is stirred overnight at ambient temperature, then for 3 hours at 50°C, and then concentrated under reduced pressure. The residue is then diluted with 10 mi of dichloromethane, then washed with water {5 ml).

After extraction, the organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure. Thus, 158 mg of an oil is obtained which is purified by chromatography over a silica gel column by eluting with a mixture of dichloromethane and methanol. Thus, 84 mg of 2-chioro-N-[(6-ethyl-6- azabicyclo[3.2. 1]oct-5-yl)phenylmethyl](3-trifluoromethyl)benzamide are obtained in powder form.

MP: 160-162°C 'H NMR (400 MHz, DMSO-d6) 6 ppm 8.60 (d, J = 7.7 MHz, 1H), 7.92 (m, 1H), 7.63 (m, 2H), 7.43-7.21 (m, 5H), 4.93 (d, J = 7.7 Hz, TH), 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-azabicyclo]3.2.1}oct-5- yliphenylmethyl}(3-trifluoromethyl)benzamide hydrochloride (1:1),

Placed in a 25 ml round-bottomed flask are 0.127 g of N-[(6-azabicyclo[3.2.1]oct-5- yhphenylmethyl](2-chloro-3-trifluoromethyl)benzamide (0.30 mmol) and 1mi of formaldehyde in 2 ml of formic acid. The reaction mixture is heated at 100°C overnight. After cooling, the medium is hydrolysed, basified to pH 9 with aqueous ammonia, then extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and evaporated under reduced pressure.

The residue is purified by chromatography over a silica gel column by eluting with a mixture of dichloromethane and ammoniacal methanol, Thus, 113 mg are obtained of an oil which is salified to hydrochloride form by dissolving the base in dichloromethane, adding an excess of IN hydrochloric acid in ether, then concentrating under reduced pressure.

MP: 186-188°C "H NMR (400 MHz, DMSO-d6) & 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, TH), 2.73 - 2.50 (m, 4H), 2.40 (m, TH),

2.10 - 1.38 (m, 7H).

Example 6 (compound No. 23): N-[(6-azabicyclo[3.2.1]oct-5-y1)-(3-bromo_ phenyl)methyl}(2-chioro-3-trifluoromethyl)benzamide hydrochloride (1:1). 6.1. 6-Allyl-6-azabicyclo[3.2.1]octane-5-carbonitrile (Ve).

Placed in a 5 ml sealed tube under argon are 0.5 g of 3-chloromethylcyclohexanone (3.4 mmol), 3 ml of anhydrous methanol, 0.93 ml of acetone cyanhydrin (10.2 mmol) and 0.26 ml of allylamine (3.4 mmol). The reaction mixture is heated for 3 days at 100°C. After cooling, the reaction medium is poured over 10 ml of a 1N solution of aqueous sodium hydroxide. After two extractions 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 over a silica gel column by eluting with a mixture of petroleum ether and ethyl acetate. Thus, 426 mg of 6-allyl-6- azabicyclo[3.2.1]octane-5-carbonitrile (IVc) are obtained in oil form. 'H NMR (400 MHz, DMSO-d6) § ppm 8.60 (d, J = 7.7 Hz, 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, SH). 6.2. (6-Allyl-6-azabicycio[3.2.1 loct-5-y1)-(3-bromophenyl)methylamine (tic).

The compound is obtained according to the method described in Example 1.1, by starting from 1g of 6-allyl-6-azabicyclo[3.2.1]octane-5-carbonitrile (IVe), 2.5 equivalents of 3-bromophenyllithium and 5 equivalents of sodium borohydride. After purification by chromatography over a silica gel column by eluting with a mixture of dichloromethane and ammoniacal methanol, 260mg of an oil are obtained containing 140mg of (6-allyl-6-azabicyclo[3.2.1]oct-5-yl)-(3-bromophenyljmethyl amine (lic) (0.42 mmol) used as is in the subsequent step. 6.3 N-[(6-Aliyl-6-azabicyclo[3.2. 1joct-5-v] -(3-bromophenylymethyl](2-chioro-3- trifluoromethylbenzamide.

Placed in a 25 mi round-bottomed flask are 260 mg of (6-allyl-6-azabicyclo[3.2. 1Joct-

5-yl)-(3-bromophenyl)methylamine (lic) (0.42 mmol) in 8 ml of dichloromethane at 0°C in the presence of 118 mg of potassium carbonate {0.78 mmol).

Then 188 mg of the acid chloride of (2-chloro-3-trifluoro)benzoic acid (0.78 mmol) are added. The reaction medium is stirred overnight at ambient temperature. After hydrolysis and extraction, the organic phase is washed with 1N sodium hydroxide, dried over sodium sulphate, filtered, then concentrated under reduced pressure,

After purification by chromatography over a silica gel column by eluting with a mixture of dichloromethane and ammoniacal methanol, 146 mg of N-[(6-allyl-6-aza_ bicyclo[3.2.1]oct-5-y1)-(3-bromophenyl)methyll(2-chioro-3-trifluoromethyl)benzamide are obtained in the form of an oil. "MH NMR (400 MHz, DMSO-d6) 6 ppm 8.68 (d, J = 7.7 Hz, 1H), 7,91 (d, J = 7.7 Hz,

TH), 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, TH), 1.77 (m, 1H), 1.54-0.77 (m, 7H). 8.4 N-[{6-Azabicyclof3.2.1 loct-5-y1)-(3-bromophenvlimethyl}(2-chioro-3-triflucro methyl}benzamide hydrochloride.

Placed in a sealed tube under argon are 19mg of palladium tetrakis(triphenylphosphine) (0.02 mmol) and 0.078 g of N,N-dimethylbarbituric acid (0.5 mmol) in solution in 3 ml of dichloromethane. The reaction medium is heated at 40°C before adding 0.09g of N-[(6-allyl-6-azabicyclo[3.2.1]oct-5-yl)-(3-bromo_ phenylimethyl](2-chloro-3-triflucromethyl)benzamide (0.17 mmol) in 3m of dichloromethane. The reaction medium is heated for 2 hours at 40°C. After cooling, it is diluted with 10 ml of dichloromethane and then hydrolysed with 5 mi of a sodium carbonate solution.

The organic phase is separated and washed twice with 5 mi of 1N hydrochloric acid.

The aqueous phases are combined then basified with aqueous ammonia to pH 9, then extracted twice with 25 mi of dichloromethane. The organic phases are dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is purified by chromatography over a silica gel column by eluting with a mixture of dichloromethane and ammoniacal methanol. Thus, 62mg of N-[(6- azabicyclo[3.2.1]oct-5-yl)-(3-bromophenyl)methy(](2-chloro-3-triflucromethyl)- benzamide are obtained, which is salified to hydrochloride form by dissolving the base in dichloromethane, adding an excess of 1N hydrochloric acid in ether,

concentrating under reduced pressure, triturating in ether then filtering.

MP: 250.5-251.5°C "H NMR (400 MHz, DMSO-d6} 6 ppm 9.62 (m, 1H), 9.45 (d, J= 9.2 Hz, 1H), 8.94 (m, 1H), 7.97 (dxd, J= 8 and 1.5 Hz, 1H), 7.91 (Mm, TH) 7.77 (dxd, J= 7.8 and 1.4 Hz, TH), 7.87 (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, TH), 2.08 (m, 1H) 1.94 (m, 1H), 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 amines of formula (lla), (lib), (He), lithiated compounds of formula (V), carboxylic acid derivatives of formula (IH) or suitable alkylating agents.

Table 1 below illustrates the chemical structures of some compounds of the invention.

In the column: - "Salts", "-" denotes a compound in base form, "HCI" denotes a hydrochloride, the number between parentheses indicates the (acid:base) ratio; - The compounds of the table are in the hydrochloride form solvated by one or more molecules of water, in the columns R, R; and Ry: - "CI" stands for chlorine: - "CH," stands for methyl; - "NH," stands for amino; - "OCH," stands for methoxy; - "Ph" stands for phenyl; - "80,C,Hs" stands for ethanesulphony!; - "CF" stands for trifluoromethyl; and - in the column "Ry", the number in front of the substituents indicates their position in the general formula (1).

Table 2 gives the physical properties, melting points and optical rotations of the compounds from Table 1.

In Tabie 2: - the column "[aplagec” indicates the result of analysis of the optical rotation of the compounds of the table at a wavelength of 589 nM and at a temperature of 20°C.

The solvent indicated between parentheses corresponds to the solvent used for measuring the optical rotation, in degrees, and the letter "go indicates the concentration of the solvent in g/100 ml. "N.A." means that the optical rotation measurement is not applicable:

- the column "m/z" indicates the molecular ion (M+H") or (M") observed by analysis of the products by mass spectrometry, either by LC-MS (Liquid Chromatography coupled to Mass Spectroscopy) performed on a machine of Agilent LC-MSD Trap type in positive ES! mode, or by direct introduction by MS (Mass Spectroscopy) on an Autospec M (EBE) machine using the DCI-NH; technique or by using the electron impact technigue on a machine of Waters GCT type.

TABLE 1

Es

N

\ O

R HN

R2

Nol RT Re R, Salts Stereochemistry

Diasterecisomer 1, 1 H Ph 2-CH3,3-CF4 racemic

Diastereoisomer 1, 2 H Ph 2-CH3,3-OCHj5 racemic

HCI Diastereoisomer 1, 3 H Ph 2,6(Cl),,3-CF; (1:1) racemic

HCI Diastereocisomer 1, 4 H Ph 2-Cl,.3-CF, } (1:1) racemic

HCI

H Ph 2-C1,3-CF; (1:1) Dextrorotatory chiral

HCI cle] om 2,6-(Cl),,3- CF (1:1) Levorotatory chiral

HCI

7 H Ph 2-Cl,3-CF, (1:1) Levorotatory chiral 8 | H 2,6-(Cl),,3~ CF HCI (1) | Dextrorotatory chiral

HCl Diastereocisomer 1, 9 H Ph 2-0OCH;,4-Cl1,5-S0,C,H; (1:1) racemic

N HCI Diasterecisomer 1,

H Ph 2-Cl, 5-CF, (1.1) racemic

CT Diastereoisomer 1. 11 H Ph 2,6-(CI), - } racemic

Diastereoisomer 1, 12 H Ph 2-CHs,3-Cl racemic

Diastereoisomer 1, 13 H 4-F-Ph 2-Cl1,3-CF; racemic

Diastereoisomer 1, 141 H 4-F-Ph 2,6-(Cl)2,3-CF, racemic

Diastereoisomer 1,

H [3-OCH;-Ph 2,6~(Cl);,3-CF4 racemic

Diastereoisomer 1, 16 H | 3-OCH;-Ph 2-Cl1,3-CF, racemic

Diastereoisomer 1, 17 H 3-0OH-Ph 2-Cl.3-CF3 racemic

Diastereocisomer 1, 18 H 3-OH-Ph 2,6-(Cl),;,3-CF; racemic

HCI Diastereoisomer 1, 19 H 3-CHs-Ph 2-Cl,3-CF, i (1:1) racemic

Diastereoisomer 1, | CyH;5 Ph 2-Cl,3-CF; . racemic

Diastereocisomer 1, 21 H 3-CHa-Ph 2,6-(Cl),,3-CF; racemic

HC Diastereoisomer 1, 22 | CH, Ph 2-Cl,3-CF, . (1:1) racemic

HCI Diastereocisomer 1, 23 H 3-Br-Ph 2-Cl,3-CF, (1:1) racemic

HCI Diastereoisomer 1, 24 H 3-Br-Ph 2,6-(Cl);,3-CF4 (1:1) racemic

HCI Diasterecisomer 1,

H 3-CFs-Ph 2-Cl1,3-CF4 (1:1) racemic

HCI } 26 | CoM; Ph 2,6-(Cl},,3-CF3 (1:1) Dextrorotatory chiral

HCI Diastereoisomer 1, 27 | C,Hs | 3-CF,-Ph 2-Cl,3-CF, (1:1) racemic

TABLE 2

MH"

Tp wsms TWA am

P| mem TA

S[mesEs | TA a lm TNA

LN a

I a Re LN wee Tee a [oO] ee TA a

Tm TRA

ET TA

S| mee TTA

ET WA an

Ce] ee TR we mE wa

Ce] Ee TTA a 186-188 N.A. 437 250-251 NLA. wo +55.37 (CHCl, c=0.736 g/ 270.5-272.5 100 mi) 147-148 NA.

The compounds of the invention have been subjected to a series of pharmacological trials which have demonstrated their advantage as substances possessing therapeutic activities.

Study of glycine transportation in SK-N-MC cells expressing the native human transporter GIlyT1,

The uptake of [*Clglycine is studied in SK-N-MC cells (human neuroepithelial cells) expressing the native human transporter GlyT1 by measuring the radioactivity incorporated in the presence or absence of the test compound. The cells are cultured as a monolayer for 48 hours in plates pretreated with 0.02% fibronectin. On the day of the experiment, the culture medium is removed and the cells are washed with Krebs-HEPES (4-(2-hydroxyethyl}piperazine-1-ethanesulphonic acid) buffer at pH 7.4. After preincubation for 10 minutes at 37°C in the presence either of buffer (control batch) or of test compound at various concentrations or of 10mM of glycine (determination of the non-specific uptake), 10 uM of [“Clglycine (specific activity 112 mCi/mmol) are subsequently added. Incubation is continued for 10 min at 37°C

I5 and the reaction is halted by washing twice with pH 7.4 Krebs-HEPES buffer. The radioactivity incorporated by the cells is then estimated after adding 100 ul of liquid scintillant and stirring for 1 h. Counting is carried out on a Microbeta Tri-Lux™ counter. The effectiveness of the compound is determined by the ICs, the concentration of the compound which reduces by 50% the specific uptake of glycine, defined by the difference in radioactivity incorporated by the control batch and the batch which received the 10mM glycine.

The compounds of the invention have, in this test, an ICs, of the order of 0.001 to 10uM.

Table 3 indicates some examples of ICs, results for compounds according to the invention,

TABLE 3

I = 2 Tr

Fem sew

TTT

Wem

YT oe

EE A

The results of the tests carried out on the chiral compounds of the invention and their racemates in the general formula (1) in which Ra represents, in particular, one or more halogen atoms or triftuoromethyl groups show that they are inhibitors of the

GlyT1 glycine transporter present in the brain.

These results suggest that the compounds of the invention may be used for treating cognitive and/or behavioural disorders associated with neurodegenerative diseases and with dementia; for treating psychoses, especially schizophrenia (deficit form and productive form) and acute or chronic neuroleptic-induced extrapyramidal symptoms; for treating various forms of anxiety, panic attacks, phobias and obsessive- compulsive disorders; for treating various forms of depression, including psychotic depression; for treating bipolar disorders, manic disorders and mood disorders; for treating disorders due to alcohol abuse or withdrawal, disorders of sexual behaviour, eating disorders and migraine disorders; pain; and sieep disorders.

The compounds according to the invention may therefore be used for preparing medicaments, in particular medicaments that are inhibitors of the GlyT1 glycine transporter.

Thus, according to another of its aspects, one subject of the invention is medicaments which comprise a compound of formula (1), or an addition salt of the latter with a pharmaceutically acceptable acid or else a hydrate or a solvate of the compound of formula (1).

Another subject of the present invention is pharmaceutical compositions comprising an effective dose of at least one compound according to the invention, in the form of the base or a pharmaceutically acceptable salt or solvate, and as a mixture, if appropriate, with suitable excipients.

Said excipients are chosen depending on the pharmaceutical form and the method of administration desired.

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

The unit administration forms can be, for example, tablets, gelatin capsules, granules, powders, solutions or suspensions to be taken orally or to be injected, patches or suppositories. Ointments, lotions and collyria can be envisaged for topical administration.

Said unit forms are dosed to allow a daily administration of 0.01 to 20 mg of active principle per kg of body weight, depending on the pharmaceutical dosage form.

To prepare tablets, a pharmaceutical vehicle, which can be composed of diluents, such as, for example, lactose, microcrystalline cellulose or starch, and formulation adjuvants, such as binders (polyvinylpyrrolidone, hydroxypropyl methyl cellulose, etc), flow agents, such as silica, or lubricants, such as magnesium stearate, stearic acid, glyceryl tribehenate or sodium stearylfumarate, is added to the micronized or unmicronized active principie. Wetting agents or surfactants, such as sodium laury sulphate, can also be added.

The preparation techniques can be direct tableting, dry granulation, wet granutation or hot melt.

The tablets can be bare, coated with sugar, for example with sucrose, or coated with various polymers or other appropriate materials. They can be designed to make possible rapid, delayed or sustained release of the active principle by virtue of polymer matrices or of specific polymers used in the coating.

To prepare gelatin capsules, the active principle is mixed with dry pharmaceutical vehicles (simple mixing, dry or wet granulation, or hot melt) or liquid or semisolid pharmaceutical vehicles.

The gelatin capsules can be hard or soft and coated or uncoated with a thin film, so as to have a rapid, sustained or delayed activity (for example, for an enteric form).

A composition in the form of a syrup or an elixir or for administration in the form of drops can comprise the active principle in conjunction with a sweetener, preferably a calorie-free sweetener, methylparaben or propylparaben, as antiseptic, a flavour enhancer and a colorant.

The water-dispersible powders and granules can comprise the active principle as a mixture with dispersing agents or wetting agents, or dispersing agents, such as polyvinylpyrrolidone, as well as with sweeteners and flavour-correcting agents.

Recourse is had, for rectal administration, to suppositories prepared with binders which melt at the rectal temperature, for exampie cocoa butter or polyethylene glycols.

Use is made, for parenteral administration, of aqueous suspensions, isotonic saline solutions or injectable sterile solutions comprising pharmacologically compatible dispersing agents and/or wetting agents, for example propylene glycol or butylene glycol.

The active principle can also be formulated in the form of microcapsules, optionally with one or more supports or additives or else with a polymer matrix or with a cyclodextrin (patches or sustained release forms).

The topical compositions according to the invention comprise a medium compatible with the skin. They can be provided in particular in the form of aqueous, alcoholic or aqueous/alcoholic solutions, of gels, of water-in-oil or oil-in-water emulsions having the appearance of a cream or of a gel, of microemulsions or of aerosols or in the form of vesicular dispersions comprising ionic and/or nonionic lipids. These pharmaceutical dosage forms are prepared according to methods conventional in the fields under consideration.

By way of example, a unit administration form 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

Maize starch 15.0 mg

Hydroxypropyl methyl cellulose | 2.25 my

Magnesium stearate 3.0 mg

Via the oral route, the dose of active principle administered per day may range from 0.1 to 20 mg/kg, in one or more dosage intakes.

There may be particular cases in which higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to standard practice, the dosage that is appropriate for each patient is determined by the physician depending on the mode of administration and the weight and response of said patient.

The present invention, according to another of its aspects, also relates to a method for treating the pathologies indicated above, which comprises the administration to a patient of an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt thereof.

Claims

1. Compound of general formula (1): Es LER ae (1) - R represents a hydrogen atom or a group chosen from (Ci-Cs)alkyl or (Cs Cr)eycloalkyl groups, these groups being optionally substituted with one or more groups chosen independently from one another from a fluorine atom, and (Cs- Cy)eycloalkyl, (C,-Cylalkenyl, phenyl, (C+-Celalkoxy or hydroxy groups: the phenyl group being optionally substituted with one or more alkoxy groups: - R¢ represents a phenyl or naphthyl group, optionally substituted with one or more substituents chosen, independently from one another, from halogen atoms, and (Cq- Celalkyl, (Ci-Celalkoxy, halo(Cs-Celalkyl, NRyRs, NR;C(O)ORs, NR3SO,R,, NR3;C(O)Re, hydroxy, halo(C-Cg)alkoxy, (C4-Cs)alkylthio, (C1-Cg)alkyl-SO,, phenyl or heteroaryl groups, the phenyl group being optionally substituted with one or more substituents chosen independently from halogen atoms, and (Ci-Colalkyl, (Ci Celalkoxy, halo(C:-Cglalkyl, NR,R;, NR:C{O)OR,, NR3;SOLR,, NR;C(O)Re, hydroxy, halo(C+-Cg)alkoxy, (C4-Cglalkylthio and (C+-Ce)alkyl-SO, groups, the heteroaryl group being optionally substituted with one or more substituents chosen independently from halogen atoms and (Cy-Cg)alkyl, (C4-Celalkoxy, halo(C+-Cg)alkyl or NR,Rs groups; - Ry represents one or more substituents chosen from a hydrogen atom, halogen atoms and (Cs-Cgalkyl, (Cs-Crleycloalkyl, {Cs-Cr)eycloalkyl(C.-Cy)alkyl, halo(C;- Csalkyl, (Cs-Cs)alkoxy, NR4Rs, phenyl, heteroaryi, cyano, acetyl, (Cq-Ce)thioalkyl, {C+-Ce)alkyisulphonyl, carboxy or (C4-Co)alkoxycarbonyl groups; the phenyl group being optionally substituted with one or more substituents chosen independently from halogen atoms, and (C:-Cg)alkyl, (Cr-Co)alkoxy, haio(C+-Cg)alkyl, NR4Rs, NR3C(O)ORy, NR3SO;Rs, NR3C(O)Rs, hydroxy, halo(C4-Ce)alkoxy, (C4-Cslalkylthio and (C4-Cg)alkyl-SO; groups, the heteroaryl group being optionally substituted with one or more substituents chosen independently from halogen atoms and {C4-Colalkyl, (C4-Ce)alkoxy, halo(C+-Ce)alkyl or NR4Rs groups; - Ra, Ry and Rs represent, independently of one another, a hydrogen atom or a {C4-Cg)alkyl group; - Re represents a (C4-Ce)alkyl group; - Ry and Rs may together form, with the nitrogen atom which bears them, a ring chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine or azepine rings, optionally substituted by a (C4-Cs)alkyl group; - Ry and R4 may together form, with the atoms which bear them, a 5- or 6-membered ring; - Rs and Rg may together form, with the atoms that bear them, a 5- or 6-membered ring; in the form of a base or addition salt with an acid.

2. Compound of general formula (1) according to Claim 1, characterized in that R represents a hydrogen atom or a (C4-Cg)alkyl group.

3. Compound of general formula (1) according to Claim 1 or 2, characterized in that Rs represents a phenyl group, optionally substituted with one or more substituents chosen, independently from one another, from halogen atoms, and {C4-Celalkyl, halo(C+-Ce)alkyl, (C-Ce)alkoxy or hydroxy groups.

4. Compound of general formula (1) according to any one of Claims 1 to 3, characterized in that R, represents one or more substituents chosen from a hydrogen atom, halogen atoms and halo(Cs-Cg)atkyl, (C1-Cgalkyl, {C1-Cslalkoxy or (C-Cs)alkyl-SO, groups.

5. Compound of general formuta (I) according to any one of Claims 1 to 4, characterized in that; - R represents a hydrogen atom or a methyl or ethyl group: - Ri represents a phenyl group, optionally substituted with one or more substituents chosen, independently from one another, from halogen atoms and methyl, ethyl, trifluoromethyt, methoxy or hydroxy groups; and - Ro represents one or more substituents chosen from a hydrogen atom, halogen atoms, and trifluoromethyl, methyl, methoxy or ethanesulphonyi groups; in the form of a base or addition salt with an acid.

6. Compound according to any cne of Claims 1 to 5, characterized in that it is chosen from: N-[(B-Azabicyclo[3.2.1]oct-5-yl)phenyimethyl](2-methyl-3-trifuoromethyi)benzamide: N-[(6-Azabicyclo[3.2.1 Joct-5-yl}phenyimethyl](3-methoxy-2-methyl)benzamide; N-[(6-Azabicyclo[3.2.1]oct-5-yl)phenyimethyl}(2,6-dichioro-3- trifluoromethyl}benzamide and its hydrochloride:

N-[6-Azabicyclo[3.2.1 loct-5-yl)phenyimethyl}(2-chloro-3-trifluoromethyl)benzamide and its hydrochloride;

(+)-N-[{(6-Azabicyclo[3.2.1 loct-5-yl)phenylmethyl](2-chloro-3- trifluoromethyl)benzamide and its hydrochloride:

(-)-N-[{6-Azabicyclo[3.2. 1]oct-5-yl)phenylmethyl](2,6-dichioro-3- trifluoromethyl)benzamide and its hydrochloride:

(-)-N-[{6-Azabicyclo[3.2.1 Joct-5-yl)phenylmethyl](2-chioro-3- trifluoromethyl)benzamide and its hydrochloride: (+)-N-{(6-Azabicyclo[3.2.1]oct-5-yl)phenylmethyl](2,6-dichloro-3- trifluoromethyl}benzamide and its hydrochloride;

N-[(6-Azabicyclo[3.2.1 Joct-5-yl)phenylmethyl}(4-chioro-5-ethanesulphonyl-2- methoxy)benzamide and its hydrochloride: N-[(6-Azabicyclo[3.2.1]oct-5-yh)phenylmethyl](2-chloro-5-trifluoromethylbenzamide and its hydrochloride;

N-[(6-Azabicyclo[3.2. Tloct-5-yl)phenylmethyi}(2,6-dichloro)benzamide: N-[(6-Azabicyclo[3.2.1 Joct-5-yl)phenylmethyl](3-chloro-2-methylibenzamide: N-[(6-Azabicyclo[3.2.1Joct-5-yl)~(4-fluorophenyl)methyi](2-chloro-3- trifluoromethyl}benzamide;

N-[(-6-Azabicyclo[3.2.1 Joct-5-yi}-{4-fluorophenyl)methyl])(2,6-dichloro-3- trifluoromethyl)benzamide:;

N-[(-6-Azabicyclof3.2. 1]oct-5-y1)-(3-methoxyphenyl)methyl)(2,6-dichloro-3- trifluoromethyl)benzamide;

N-[{6-Azabicyclo[3.2.1 loct-5-yl-(3-methoxyphenylymethyt](2-chioro-3- trifluoromethyilbenzamide; N-[8-Azabicyclo[3.2.1]oct-5-yl-(3-hydroxyphenylymethyl(2-chloro-3- trifluoromethyl)benzamide; N-{(6-Azabicycio[3.2.1]oct-5-yl)-(3-hydroxyphenyl)methyl}(2,6-dichloro-3- triftuoromethyl)benzamide;

N-[(6-Azabicyclo[3.2.1 Joct-5-yt)-m-tolylmethyl}(2-chioro-3-trifiluoromethyl)benzamide and its hydrochloride:

2-Chloro-N-[(6-ethyl-6-azabicyclo[3.2. 1Joct-5-yl)phenylmethyl](3-

trifluoromethyl)benzamide; N-[(6-Azabicyclo[3.2. tjoct-5-yl-m-tolyimethyl}(2,6-dichloro-3- trifluoromethyl)benzamide: 2-Chloro-N-[(6-methy}-6-azabicyclo[3.2. 1]oct-5-yl)phenylmethyl](3- trifluoromethyl)benzamide and its hydrochloride: N-[(6-Azabicyclo[3.2.1]oct-5-yI)-(3-bromophenylymethyl}(2-chloro-3- trifluoromethyl)benzamide and its hydrochloride; N-[(6-Azabicyclo[3.2.1]oct-5-y1)-(3-bromophenyl)methyl](2,6-dichioro-3- trifluoromethyl)benzamide and its hydrochloride; N-[6-Azabicyclo[3.2.1]oct-5-yl-(3-trifluoromethylphenylmethyl](2-chloro-3- trifluoromethyf)benzamide and its hydrochloride: (+)-2,6-Dichloro-N-[(6-sthyl-6-azabicyclof3.2.1]oct-5-yl)phenylmethyl](3- trifluoromethyl)benzamide and its hydrochloride: 2-Chloro-N-{(6-ethyl-6-azabicyclo[3.2. 1]oct-5-yi)-(3-triflucromethylphenylymethyl](3- trifluoromethyl}benzamide and its hydrochloride.

7. Process for preparing a compound of generai formula (1) according to Claim 1, characterized in that a compound of general formula (10): £ R1 N (1 \ R NH, in which R and Ry are as defined according to Claim 1, reacts with a compound of general formula (IH): Y 0 (11) R, in which Y represents an activated OH group or a chiorine atom and R;, is as defined according to Ciaim 1.

8. Medicament, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 8, or an addition salt of this compound with a pharmaceutically acceptable acid.

9. Pharmaceutical composition, characterized in that it comprises a compound of formula (1) according to any one of Claims 1 to 6, or a pharmaceutically acceptable salt of this compound, and also at least one pharmaceutically acceptable excipient.

10. Use of a compound of formula (1) according to any one of Claims 1 to 6 for the preparation of a medicament intended for treating cognitive and/or behavioural disorders associated with neurodegenerative diseases and with dementia.

11. Use of a compound of formula (1) according to any one of Claims 1 to 8, for the preparation of a medicament intended for treating psychoses, schizophrenia (deficit form and productive form) and acute or chronic neuroleptic-induced extrapyramidal symptoms.

12. Use of a compound of formula (1) according to any one of Claims 1 to 6 for the preparation of a medicament intended for treating various forms of anxiety, panic attacks, phobias and obsessive-compulsive disorders.

13. Use of a compound of formula (1) according to any one of Claims 1 to 8 for the preparation of a medicament intended for treating various forms of depression, including psychotic depression; for treating bipolar disorders, manic disorders and mood disorders; for treating disorders due to alcohol abuse or withdrawal, disorders of sexual behaviour, eating disorders and migraine disorders.

14. Use of a compound of formula (1) according tc any one of Claims 1 to 6, for the preparation of a medicament intended for treating pain.

15. Use of a compound of formula (1) according to any one of Claims 1 fo 6, for the preparation of a medicament intended for treating sleep disorders.

16. Compound according to any one of Claims 1 to 6, for treating cognitive and/or behavioural disorders associated with neurodegenerative diseases and with dementia.

17. Compound according to any one of Claims 1 to 6, for treating psychoses, schizophrenia (deficit form and productive form) and acute or chronic neuroleptic- induced extrapyramidal symptoms.

18. Compound according to any one of Claims 1 to ©, for treating various forms of anxiety, panic attacks, phobias and obsessive-compulsive disorders.

19. Compound according to any one of Claims 1 to 8, for treating various forms of depression, including psychotic depression: for treating bipolar disorders, manic disorders and mood disorders; for treating disorders due to alcohol abuse or withdrawal, disorders of sexual behaviour, eating disorders and migraine disorders.

20. Compound according to any one of Claims 1 to 6, for treating pain.

21. Compound according to any one of Claims 1 to 8, for treating sleep disorders.