N-[(6-AZABICYCLO[3.1.1lOCT-5-YL)ARYLMETHYL]HETEROBENZAMIDE
DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE OF SAME
The present invention relates to derivatives of N-[(6-azabicyclo[3.1.1]oct-5-
yl)arylmethyl]heterobenzamide, to the preparaiion thereof and to the therapeuiic use
thereof, in the treatment or prevention of diseases involving GlyT1 glycine
transporters.
The compounds of the invention correspond to the general formula (I):

in which:
- R represents a hydrogen atom or a group chosen from (C1-C6)alkyl or (C3-C7)-
cycloalkyl groups, which is optionally substituted with one or more groups chosen
independently from one another from a halogen atom, and (C3-C7)cycloalkyl, (C1-
C6)alkyl, (C1-C6)alkoxy or hydroxy groups;
- R1 represents a phenyl group, optionally substituted with one or more substituenss
chosen, independenlly from one another, from halogen atoms, and (C1-C6)alkyl, (C1
C6)alkoxy, halo(C1-C6)alky,, hydroxy, halo(C1-C6)alkoxy, (C1-C6)alkylthio, (C1
C6)alkyl-SO or (C1-C6)alkyl-SO2 groups;
- Het represents a heteroaryl group;
- R2 represents one or more substituents chosen from a hydrogen atom, halogen
atoms and halo(C1-C6)alkyl, (C1-C6)alkyl, (C3-C7)cycloakkyl, (C3-C7)cycloalkyl(C1-
C3)alky,, phenyl, benzyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkyl-SO and (C1-
C6)alkyl-SO2 groups;
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 (I) are also part of the invention.
Within the context of the invention, the following definitions apply:
- Ct-CZ where t and z may take the values of 1 to 6: a carbon-based chain which
may have from t to z carbon atoms, for example C1-C6 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-C6-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 NH2 group;
- alkoxy: an -O-alkyl group;
- hydroxy: an-OH group;
- alkylthio: 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 pentafluoroethyl groups; and
- heteroaryl group: a 5- or 10-membered heteroaromatic monocyclic or tricyclic
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, pyrazole, imidazole, triazole, tetrazole, oxazole,
isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine,
pyrazine, pyridazine, triazine, indole, isoindole, benzimidazole, indazole,
indolizine, benzofuran, isobenzofuran, benzothiophene, benzo[c)thiophen,

pyrrolopyridine, imidazopyridine, pyrazolopyridine, triazolopyridine,
tetrazolopyridine, pyrrolopyrimidine, imidazopyrimidine, pyrazolopyrimidine,
triazolopyrimidine, tetrazolopyrimidine, pyrrolopyraznne, imidazopyrazine,
pyrazolopyrazine, triazolopyrazine, tetrazolopyrazine, pyrrolopyiidazine,
imidazopyiidazine, pyrazolopyiidazine, triazolopyridazine, tetrazolopyridazine,
pyrrolotriazine, imidazotriazine, pyrazolotriazine, triazolotriaznne, tetrazolotriazine,
furopyridine, furopyrimidin, furopyrazin,, furopyiidazine, furotriazine,
oxazolopyridine, oxazolopyrimidine, oxazolopyrazine, oxazolopyridazine,
oxazolotriazne,, isoxazolopyridine, isoxazolopyrimidine, isoxazolopyrazine,
isoxazolopyridazine, isoxazolotriaznne, oxadiazolopyridine, oxadiazolopyrimidine,
oxadiazolopyrazine, oxadiazolopyridazine, oxadiazolotriazine, benzoxazole,
benzisoxazole, benzoxadiazoe,, thienopyridine, thienopyrimidine, thienopyrazine,
thienopyiidazine, thienotriazine, thiazolopyridine, thiazolopyrimidine,
thiazolopyrazine, thiazolopyiidazine, thiazolotriaznne, isothiazolopyridine,
isothiazolopyrimidine, isothiazolopyrazine, isothiazolopyridazine,
isothiazolothazine, thiadiazolopyridine, thiadiazolopyiimidine, thiadiazolopyrazine,
thiadiazolopyridazine, thiadiazolotriazine, benzothiazole, benzoisothiazole,
benzothiadiazol,, quinoiine, isoquinoiine, cinnoiine, phthalazine, quinoxaiine,
quinazoiine, naphthyridine, benzotriazine, pyridopyrimidine, pyridopyrazine,
pyridopyridaznne, pyridotriazine, pyrimidopyrimidine, pyrimidopyrazine,
pyrimidopyiidazine, pyrimidotriazine, pyrazinopyrazine, pyrazinopyridazine,
pyrazinotiiazin,, pyridazinopyridazine and pyridazinotriazine groups.
Among the compounds of general formula (I) that are subjects of the invention, a first
group of compounds is constituted by the compounds for which:
- R1 represents a phenyl group optionally substituted with one or more substituenss
chosen, independently from one anothe,, from halogen atoms, (C1-C6)alkyl or
halo(C1-C6)alkyl groups;
- R, Het and R2 being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, a
second group of compounds is constituted by the compounds for which:
- Het represents an imidazole, isoxazole, indole, thiophene or pyridine group;
- R, R1, and R2 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:
- R2 represents one or more substituenss chosen from a hydrogen atom, halogen
atoms, halo(C1-C6)alkyl, (C1-C6)alkyl, phenyl, benzyl, (C1-C6)alkoxy or (C1-
C6)alkylthio groups;
- R1, Het and R1 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:
- R1 represents a phenyl group optionally substituted with one or more substituenss
chosen, independenlly from one another, from halogen atoms, (C1-C6)alkyl or
halo(C1-C6)alkyl groups;
- Het represents an imidazole, isoxazole, indole, thiophene or pyridine group;
- R2 represents one or more substituenss chosen from a hydrogen atom, halogen
atoms, halo(C1-C6)alkyl, (C1-C6)alkyl, phenyl, benzyl, (C1-C6)alkoxy or (C1-
C6)alkylthio groups.
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:
- R1 represents a phenyl group optionally substituted with one or more substituenss
chosen, independently from one another, from fluorine atoms, methyl or
trifluoromethyl groups;
- Het represents an imidazole, isoxazole, indole, thiophene or pyridine group;
- R2 represents one or more substituenss chosen from a hydrogen atom, chlorine
atoms, methyl, methoxy, trifluoromethyl, methylthio, phenyl or benzyl groups.
The combinations of groups one to five as defined above are also part of the
invention.
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[3.2.1]oct-5-y))phenylmethyl](2,5-dichloro)thiophene-3-
carboxamide;

N-[(6-Azabicyclo[3.2.1]oct-5-yl)phenylmethyl]-2-methylsulfanylnicotinamide;
N-[(6-Azabicyclo[3.2.1]oct-5-yl)phenylmethyl](3-chloro-4-trifluoromethyl)pyridine-2-
carboxamide and its hydrochloiide;
N-[(6-Azabicyclo[3.2.1]oct-5-yl)phenylmethyl](5-methyl-3-phenyl)isoxazole-4-
carboxamide;
N-[(6-Azabicyclo[3.1.1]oct-5-yl)phenylmethyl](1-benzyl-2-ethyl-5-methoxy)-1H-
indole-3-carboaamide;
[(6-Azabicyclo[3.2.1]oct-5-yl)phenylmethyl](1-benzyl)-1H-indole-4-carboxamide;
N-[(6-Azabicyclo[3.1.1]oct-5-yl)phenylmethyl](1-methyl)-1H-imidazole-4-
carboxamide;
N-[(6-Azabicyclo[3.2.1]oct-5-yl)(4-fluorophenyl)methyl]-2-methylsulfanyl-
nicotinamide and its hydrochloride;
N-[(6-Azabicyclo[3.2.1]oct-5-yl)(4-fluorophenyl)methyl](3-chloro-4-trifluoromethyl)-
pyhdine-2-carboxamide and its hydrochloride;
N-[(-6-Azabicyclo[3.1.1 ]oct-5-yl)-m-tolylmethyl]-2-methylsulfanylnicotinamide and its
hydrochloride;
N-[(6-Azabicyclo[3.2.1]oct-5-yl)(3-trifluoromethylphenyl)methyl](3-chloro-4-
trifluoromethyl)pyhdine-2-carboxamide and its hydrochlorid..
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 (I) may be prepared by a process illustrated by
scheme 1 below:
SCHEME 1


A diamine of general formula (II), in which Rand R1 are as defined above, especially
when R represents a hydrogen atom, is coupled with an activated acid, for example
via a mixed anhydride or an acid chloride of general formula (III) in which 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 a person
skilled in the art.
The compounds of general formula (I) in which R represents a hydrogen atom may
also be prepared from compounds of general formula (I) in which R represents a
protective group which can be deprotected via hydrogenolysis.
The compounds of general formula (I) in which R is other than a hydrogen atom may
also be prepared starting from compounds of general formula (I) 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 a mesylate or a halogen atom, 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, or with a
suitable epoxide derivative according to the methods known to a person skilled in the
art, or with a suitable epoxide derivative 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.


According to scheme 2, the nitrile of formula (IVa) is reacted with the Iithiated
aromatic compound of general formula (V), in which R1 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 (1a) may
be debenzylated by hydrogenation in the presence of a palladium catalyst in order to
provide the deprotected amine (llb) (Scheme 2).
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 (lla) 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.
The Iithiated 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 (III) 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".
- "ee" stands for enantiomeric excess;
- 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.2): N-(6-azabicyclo[3.2.1]oct-5-yl)phenylmethyl](2-
methylsulphanyl)nicotinamide.
1.1 Phenyl-[6-((R)-1-phenylethyn-6-azabicyclo[3.2.1loct-5-yHmethylamine.
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-carbonitrile (IVa) (4.16 mmol) at -70°C in 35 ml of
anhydrous tetrahydrofuran. 7.4 ml of a 1.13M solution (cyclohexane/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 -20X with
15 ml of water.
After extraction, the organic phase is concentrated under reduced pressure, then the
residue is taken up in 20 ml of methanol. 0.79 g of sodium borohydride (20.8 mmol)
is 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, filtered and evaporated under reduced

pressure. Thus 1.5 9 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 9 of phenyl-[6-((/R)-1-phenylethyl)-6-azabicyclo[3.2.1]oct-5-yl]methylamine are
obtained, a mixture of 2 chiral diastereoisomers, in oil form.
1H NMR (400 MHz, DMSO-d6) 8 ppm 7.6-7.10 (m, 10H), 4.20 (2.5H), 3.60 (0.5 H),
3.3-3.0 (m, 1.5H), 2.60 (m, 0.5H) 2.4-2.0 (m, 3H),1.8-0.8 (m, 10H).
1.2(6-Azabicyclo[3.2.1]oct-5-vnphenylmethylamine.
Placed in a Parr flask are 4 9 of a compound of formula (Ma) (12,5 mmol) in 80 ml 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, 19 of (6-azabicyclo[3.2.1]oct-5-
yl)phenylmethylamine 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
1H NMR (400 MHz, DMSO-d6) 8 ppm 9.14 (m, 4H), 7.76 (m, 2H), 7.56 -7.43 (m, 4H),
5.09 (broad s, 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).
1.3N-[(6-azabicyclo[3.2.1]oct-5-vnphenylmethvn(2-methylsulphanvnnicotinamide.
Placed in a 25 ml round-bottomed flask are 155 mg of (2-methylsulphanyl)nicotinic
acid (0.92 mmol), 124 mg of hydroxybenzotriazole (0.92 mmol) and 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 ambient temperature
for 15 minutes. 200 mg (0.92 mmol) of (6-azabicyclo[3.2.1]oct-5-
yl)phenylmethylamine 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 ml of dichloromethane, then washed

successiveyy with water (5 ml), with 1N sodium hydroxide (5 ml) and with a saturated
solution of sodium chloride (5 ml).
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 methano.. Thus, 108mg of A/-[(6-
azabicyclo[3.2.1]oct-5-yl)phenylmethyl](2-methylsulphanyl)nicotinamide are
obtained, in the form of a powder.
1H NMR (400 MHz,CDCI3) 8 ppm 8.51 (dxd, J = 4.8 Hz and 1.8 Hz, 1H), 7.89 (dxd, J
= 7.5 Hz and 1.8 Hz, 1H), 7.50 -7.40 (m, 3H), 7.34 -7.24 (m, 3H), 7.06 (m, 1H), 4.98
(d, J = 6.8 Hz, 1H), 3.07-2.97 (m, 2H), 2.64 (s, 3H), 2.28 (m, 1H), 1.79-1.27 (m, 8H).
MP=138-140°C
The other compounds listed in Table 1 are obtained according to the method
described in Example 1, from the amine of formula (Mb).
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 hydrochloiide, the
number between parentheses indicates the (acidbase) ratio;
- The compounds of the table are in the hydrochloride form solvated by one or more
molecules of water.
In the columns R, R1 and R2:
-"CI" stands for chlorine;
- "CH3" stands for methyl; "C2Hs" stands for ethyl;
-"OCH3" stands for methoxy;
-"Ph" stands for pheny;;
- "CF3" stands for trifluoromethyl; and
- in the column "R2", the number in front of the substituents indicates the position in
the general formula (I).
Table 2 gives the physical properties and melting points of the compounds from
Table 1.
In Table 2:
- 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 Spectroscop)) performed on a machine of Agilent LC-MSD Trap
type in positive ESI mode, or by direct introduciion by MS (Mass Spectroscopy) on
an Autospec M (EBE) machine using the DCI-NH3 technique or by using the electron
impact technique on a machine of Waters GCT type.



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 GlyT1.
The uptake of [14C]glycine 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 [14C]glycine (specific activity
112 mCi/mmol) are subsequently added. Incubation is continued for 10 min at 37°C

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 IC50, 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 IC50 of the order of 0.1 to
10uM.
Table 3 indicates some examples of IC50 results for compounds according to the
invention.

The results of the in vitro tests carried out on the compounds of the invention
according to the general formula (I) 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 sleep disorders.

The compounds according to the invention may therefore be used for preparing
medicaments, in particular medicaments that are inhibitors of the GlyT1glycine
transporter.
Thus, according to another of its aspects, one subject of the invention is
medicaments which comprise a compound of formula (I), or an addition salt of the
latter with a pharmaceutical^ acceptable acid.
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 salt, 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 principle. Wetting agents or surfactants, such as sodium lauryl
sulphate, can also be added.
The preparation techniques can be direct tableting, dry granulation, wet granulation
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 example 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 mg
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 (I):

in which:
- R represents a hydrogen atom or a group chosen from (C1-C6)alkyl or (C3-C7)-cycooalkyl
groups, which is optionally substituted with one or more groups chosen independently from
one another from a halogen atom, and (C3-C7)cycloalkyl, (C1-C6)alkyl, (C1-C6)alkoxy or
hydroxy groups;
- R1 represents a phenyl group, optionally substituted with one or more substituenss chosen,
independenlly from one another, from halogen atoms, and (C1-C6)alkyl, (C1-C6)alkoxy,
halo(C1-C6)alkyl, hydroxy, halo(C1-C6)alkoxy,(C1-C6)alkylthio, (C1-C6)alky--SO or (C1-
C6)alkyl-SO2 groups;
- Het represents a heteroaryl group;
- R2 represents one or more substituents chosen from a hydrogen atom, halogen atoms and
halo(C1-C6)alkyl, (C1-C6)alky,, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)al,yl, pheny,, benzyl,
(C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6))alkyl-SO and (C1-C6)alkyl-SO2 groups;
in the form of a base or addition salt with an acid.
2. Compound of general formula (I) according to Claim 1, characteiized in that:
- R1 represents a phenyl group optionally substituted with one or more substituents
chosen, independenlly from one another, from halogen atoms,(C1-C6)alkyl or halo(C1-
C6)alkyl groups;
- R, Het and R2 being as defined in Claim 1, in the form of a base or addition salt with an
acid.
3. Compound of general formula (I) according to Claim 1, characteiized in that:
- Het represents an imidazole, isoxazole, indole, thiophene or pyridine group;
- R, R1 and R2 being as defined in Claim 1, in the form of a base or addition salt with an acid.

4. Compound of general formula (I) according to Claim 1, characteiized in that:
- R2 represents one or more substituents chosen from a hydrogen atom, halogen atoms,
halo(C1-C6)alkyl, (C1-C6)alkyl, phenyl, benzyl, (C1-C6)alkoxy or (C1-C6)alkylthio groups;
- R1, Het and R1 being as defined in Claim 1, in the form of a base or addition salt with an
acid.
5. Compound of general formula (I) according to Claim 1, characteiized in that: .
- R1 represents a phenyl group optionally substituted by one or more substituents chosen,
independently from one another, from halogen atoms, (C1-C6)alkyl or halo(C1-C6)alkyl
groups;
- Het represents an imidazole, isoxazole, indole, thiophene or pyridine group;
- R2 represents one or more substituents chosen from a hydrogen atom, halogen atoms,
halo(C1-C6)alkyl, (C1-C6)alky,, phenyl, benzyl, (C1-C6)alkoxy or (C1-C6)alkylthio,
in the form of a base or addition salt with an acid.
6. Compound of general formula (I) according to Claim 1 or 5, characteiized in that:
R1 represents a phenyl group optionally substituted with one or more substituenss chosen,
independently from one another, from fluorine atoms, methyl or trifluoromethyl groups;
Het represents an imidazole, isoxazole, indole, thiophene or pyridine group;
R2 represents one or more substituents chosen from a hydrogen atom, chlorine atoms,
methy,, methoxy, trifluoromethyl, methylthio, phenyl or benzyl groups, in the form of a base
or addition salt with an acid.
7. Compound according to one of Claims 1 to 6, characteiized in that it is chosen from:
N-[(6-Azabicyclo[3.2.1]oct-5-yl)phenylmethyl](2,5-dichloro)thiophene-3-
carboxamid;;
N-[(6-Azabicyclo[3.2.1]oct-5-yl)phenylmethyl]-2-methylsulfanylnicotinamide;
N-[(6-Azabicyclo[3.2.1]oct-5-yl)phenylmethyl](3-chloro-4-trifluoromethy))pyridine-2-
carboxamide and its hydrochloride;
N-[(6-Azabicyclo[3.2.1]oct-5-yl)phenylmethyl](5-methyl-3-phenyl)isoxazole-4-
carboxamide;
N-[(6-Azabccyclo[3.1.1]oct-5-y))phenylmethyl](1-benzyl-2-ethyl-5-methoxy)-1H-
indole-3-carboxamide;
[(6-Azabicyclo[3.1.1]oct-5-yl)phenylmethyl](1-benzyl)-1H-indole-4-carboxamide;

N-[(6-Azabicyclo[3.2.1]oct-5-yl)phenylmethyl](1-methyl)-1H-imidazole-4-
carboxamide;
N-[(6-Azabicyclo[3.2.1joct-5-yl)(4-fluorophenyl)methyl]-2-methylsulfanyl-
nicotinamide and its hydrochloride;
N-[(6-Azabicyclo[3.2.1joct-5-yl)(4-fluorophenyl)methyl](3-chloro-4-trifluoromethyl)-
pyridine-2-carboxamide and its hydrochloride;
N-[(-6-Azabicycoo[3.1.1joct-5-y))-m-tolylmethyl]-2-methylsulfanylnicotinamide and its
hydrochloride;
N-[(6-Azabicyclo[3.2.1]oct-5-yl)(3-trifluoromethylphenyl)methyl](3-chloro-4-
trifluoromethyl)pyridine-2-carboxamide and its hydrochloride.
8. Process for preparing a compound of general formula (I) according to Claim 1,
characteiized in that a compound of general formula (II):

in which Rand R1 are as defined according to Claim 1, reacts with a compound of general
formula (III):

in which Y represents a leaving group or a chlorine atom and Het and R2 are defined
according to Claim 1.
9. Compounds of formula (II)

in which Rand R1 are defined according to Claim 1.
10. Medicamen,, characteiized in that it comprises a compound of formula (I) according to
any one of Claims 1 to 7, or an addition salt of this compound with a pharmaceutically
acceptable acid.

11. Pharmaceutical composition, characterized in that it comprises a compound of formula (I)
according to any nee of Claims 1 to 7, or a pharmaceutically acceptable salt of this
compound, and also at least one pharmaceutically acceptable excipient.
12. Use of a compound of formula (I) according to any nee of Claims 1 to 7 for the
preparation of a medicament intended for treating cognitive andlor behavioural disorders
associated with neurodegenerative diseases or with dementia.
13. Use of a compound of formula (I) according to anyone of Claims 1 to 7, for the
preparation of a medicament intended for treating psychoses, schizophrenia (deficit form and
productive form) and acute or chronic neuroleptic-induced extrapyramidal symptoms.
14. Use of a compound of formula (I) according to any one of Claims 1 to 7 for the
preparation of a medicament intended for treating various forms of anxiety, panic attacks,
phobias and obsessive-compulsive disorders.
15. Use of a compound of formula (I) according to any nee of Claims 1 to 7 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.
16. Use of a compound of formula (I) according to anyone of Claims 1 to 7, for the
preparation of a medicament intended for treating pain.
17. Use of a compound of formula (I) according to anyone of Claims 1 to 7, for the
preparation of a medicament intended for treating sleep disorders.
18. Compound according to any one of Claims 1 to 7, for treating cognitive andlor
behavioural disorders associated with neurodegenerative diseases and with dementia.
19. Compound according to anyone of Claims 1 to 7, for treating psychoses, schizophrenia
(deficit form and productive form) and acute or chronic neuroleptic-induced extrapyramidal
symptoms.
20. Compound according to anyone of Claims 1 to 7, for treating various forms of anxiety,

panic attacks, phobias and obsessive-compulsive disorders.
21. Compound according to any one of Claims 1 to 7, 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 withdrawa,, disorders of
sexual behaviou,, eating disorders and migraine disorders.
22. Compound according to anyone of Claims 1 to 7, for treating pain.
23. Compound according to anyone of Claims 1 to 7, for treating sleep disorders.

Abstract:

The invention relates to a compound of the general formula (I), where: R is a hydrogen atom or a group selected
from the (C1-C6)alkyl or (C3-C7)-cycloalkyl groups, optionally substituted by one or more groups independently selected from a
halogen atum and the (C3-C7)-cycloalkyl, (C1-C6)alkyl, (C1-C6)alkoxy, and hydroxy groups; R1 is a phenyl group optionally
substituted by one or more substituents independently selected from halogen atoms and the (C1-C6)alkyl, (C1-C6)alkoxy, halo-
(C1-C6)alkyl, hydroxy, halo-(C1-C6)alkoxy, (C1-C6)alkyl-thio, (C1-C6)alkyl-SO, and (C1-C6)alkyl-SO2 groups; R2 is one or more
substituents selected from a hydrogen atom, halogen atoms, and the halo-(C1-C6)alkyl, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)-
cycloalkyl-(C1C3)aliyl, phenyl, benzyl, (C1-C6)alkoxy, (C1-C6)alkyl-thio, (C1-C6))alkyl-SO, and (C1-C6)alkyl-SO2 groups; and Het
is a heteroaryl group; wherein said compound is in the form of a base or an acid addition salt. The invention also relates to the
taapeutic use thereof and to a method for synthesising same.