N-[(2-AZABICYCLO[2.1.1]HEX-1-YL)-ARYL-METHYL]-BENZAMIDE DERIVATIVES,
PREPARATION THEREOF AND THERAPEUTIC USE THEREOF
The present invention relates to N-[(2-azabicyclo[2.2.1]hex-1-yl)(aryl)methyl]-
benzamide derivatives, to their preparation and to their therapeutic application in the
treatment or prevention of diseases involving glycine transporters GlyT1.
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)cyclo-
alkyl groups, these groups optionally being substituted by one or more groups
chosen, independently of one another, from the fluorine atom or (C3-C7)cycloalkyl,
(C2-C4)alkenyl, phenyl, (C1-C6)alkoxy or hydroxyl groups; the phenyl group is
optionally substituted by one or more (C1-C6)alkoxy groups;
- R1 represents a phenyl or naphthyl group which is optionally substituted by one or
more substituents chosen, independently of one another, from halogen atoms or
(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, NR4R5, NR3C(O)OR4, NR3SO2R4,
NR3C(O)R6, hydroxyl, halo(C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkyl-SO2, phenyl or
heteroaryl groups, the phenyl group being optionally substituted by one or more
substituents independently chosen from halogen atoms or (C1-C6)alkyl, (C1-C6)alkoxy,
halo(C1-C6)alkyl, NR4R5, NR3C(O)OR4, NR3SO2R4, NR3C(O)R6, hydroxyl, halo(C1-
C6)alkoxy, (C1-C6)alkylthio or (C1-C6)alkyl-SO2 groups and the heteroaryl group being
optionally substituted by one or more substituents independently chosen from halogen
atoms or (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or NR4R5 groups;
- R2 represents one or more substituents chosen from the hydrogen atom, halogen
atoms or (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkyl, halo(C1-C6)alkyl,
(C1-C6)alkoxy, NR4R5, phenyl, heteroaryl, cyano, acetyl, (C1-C6)alkylthio, (C1-
C6)alkylsulphonyl, carboxyl or (C1-C6)alkoxycarbonyl groups; the phenyl group being
optionally substituted by one or more substituents independently chosen from halogen
atoms or (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, NR4R5, NR3C(O)OR4,
NR3SO2R4, NR3C(O)R6, hydroxyl, halo(C1-C6)alkoxy, (C1-C6)alkylthio or (C1-C6)alkyl-
SO2 groups and the heteroaryl group being optionally substituted by one or more
substituents independently chosen from halogen atoms or (C1-C6)alkyl, (C1-C6)alkoxy,
halo(C1-C6)alkyl or NR4R5 groups;
- R3, R4 and R5 represent, independently of one another, a hydrogen atom or a
(C1-C6)alkyl group;
- R6 represents a (C1-C6)alkyl group;
- R4 and R5 can together form, with the nitrogen atom which carries them, a ring
chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine
or azepine rings optionally substituted by a (C1-C6)alkyl group;
- R3 and R4 can together form, with the atoms which carry them, a 5- or 6-membered
ring;
- R3 and R6can together form, with the atoms which carry them, a 5- or 6-membered
ring;
in the form of the base or of an addition salt with an acid.
The compounds of formula (I) comprise an asymmetric carbon atom. They can thus
exist in the form of enantiomers. These enantiomers, including racemic mixtures,
come within the scope of the invention.
The compounds of formula (I) can exist in the form of bases or of addition salts with
acids. Such addition salts come within the scope of the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids but
the salts of other acids, for example for use in the purification or isolation of the
compounds of formula (I), also come within the invention.
In the context of the invention:
- Ct-Cz, where t and z can take the values from 1 to 6, is understood to mean a
carbon chain which can have from t to z carbon atoms; for example, C1-C6 is
understood to mean a carbon chain which can have from 1 to 6 carbon atoms;
- alkyl is understood to mean a saturated, linear or branched, aliphatic group; for
example, a (C1-C6)alkyl group represents a linear or branched carbon chain of 1 to
6 carbon atoms, for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-
butyl, pentyl or hexyl;
- alkenyl is understood to mean a mono- or polyunsaturated and linear or branched
aliphatic group comprising, for example, 1 or 2 ethylenic unsaturations,
- alkylene is understood to mean a saturated, linear or branched, divalent alkyl
group; for example, a C1-6-alkylene group represents a linear or branched divalent
carbon chain of 1 to 6 carbon atoms, for example a methylene, ethylene, 1 -methyl-
ethylene or propylene,
- amino is understood to mean an NH2 group;
- alkoxy is understood to mean an -O-alkyl group,
acetyl is understood to mean a -C(O)- group,
- cyano is understood to mean a -CN group,
- hydroxyl is understood to mean an -OH group,
halogen atom is understood to mean a fluorine, a chlorine, a bromine or an iodine,
- haloalkyl is understood to mean an alkyl group, one or more hydrogen atoms of
which have been replaced by a halogen. Mention may be made, by way of
examples, of the trifluoromethyl, trifluoroethyl or pentafluoroethyl groups,
- heteroaryl is understood to mean a 5- or 6-membered aromatic monocyclic group
comprising from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulphur.
Mention may be made, as examples of heteroaryl group, of the pyrrole, furan,
thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole,
thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine or
triazine groups.
Among the compounds of general formula (I) which are subject-matters of the
invention, a first group of compounds is composed of the compounds for which R
represents a hydrogen atom or a (C1-C6)alkyl group optionally substituted by one or
more groups chosen, independently of one another, from the fluorine atom or
(C2-C4)alkenyl, hydroxyl, (C3-C7)cycloalkyl or phenyl groups;
R1, R2, R3, R4, R5 and R6 being as defined above.
Among the compounds of general formula (I) which are subject-matters of the
invention, a second group of compounds is composed of the compounds for which R
represents a hydrogen atom or a methyl, ethyl, propyl, isobutyl or allyl group, the
methyl, ethyl or isobutyl group or groups being optionally substituted by one or more
groups chosen, independently of one another, from the fluorine atom, the hydroxyl
group, a cyclopropyl group or a phenyl group;
R1, R2, R3, R4, R5 and R6 being as defined above.
Among the compounds of general formula (I) which are subject-matters of the
invention, a third group of compounds is composed of the compounds in which R1
represents a phenyl or naphthyl group optionally substituted by one or more halogen
atoms or (C1-C6)-alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, NR4R5 or hydroxyl groups;
R, R2, R3, R4 and R5 being as defined above.
Among the compounds of general formula (I) which are subject-matters of the
invention, a fourth group of compounds is composed of the compounds in which R1
represents a phenyl or naphthyl group optionally substituted by one or more halogen
atoms or methyl, methoxy, trifluoromethyl, NH2 or hydroxyl groups;
R, R2, R4 and R5 being as defined above.
Among the compounds of general formula (I) which are subject-matters of the
invention, a fifth group of compounds is composed of the compounds for which R2
represents one or more substituents chosen from the hydrogen atom, halogen atoms
or NR4R5, (C1-C6)alkoxy, halo(C1-C6)alkyl, (C1-C6)alkylthio or (C1-C6)alkyl-SO2 groups;
R, R1, R3, R4, R5 and R6 being as defined above.
Among the compounds of general formula (I) which are subject-matters of the
invention, a sixth group of compounds is composed of the compounds for which R2
represents one or more substituents chosen from the hydrogen atom, halogen atoms
or methyl, ethyl, NH2, methoxy, trifluoromethyl, methanesulphanyl or ethanesulphonyl
groups;
R, R1, R3, R4, R5 and R6 being as defined above.
Among the compounds of general formula (I) which are subject-matters of the
invention, a seventh group of compounds is composed of the compounds for which:
- R represents a hydrogen atom or a methyl, ethyl, propyl, isobutyl or allyl group, the
methyl, ethyl or isobutyl group or groups being optionally substituted by one or more
groups chosen, independently of one another, from the fluorine atom or hydroxyl,
cyclopropyl or phenyl groups;
- R1 represents a phenyl or naphthyl group optionally substituted by one or more
halogen atoms or methyl, methoxy, trifluoromethyl, NH2 or hydroxyl groups;
- R2 represents one or more substituents chosen from the hydrogen atom, halogen
atoms or methyl, ethyl, NH2, methoxy, trifluoromethyl, methanesulphanyl or
ethanesulphonyl groups;
and their addition salts with an acid.
The combinations of the groups one to seven below as defined above also come
within the scope of the invention.
Mention may in particular be made, among the compounds of general formula (I)
which are subject-matters of the invention, of the following compounds:
N-[(4-Aminophenyl)(2-azabicyclo[2.1.1]hex-1-yl)methyl]-2-chloro-3-(trifluoromethyl)-
benzamide and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(m-tolyl)methyl]-2-chloro-3-(trifluoromethyl)benzamide
and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(3-methoxyphenyl)methyl]-2-chloro-3-(trifluoro-
methyl)benzamide and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)[3-(trifluoromethyl)phenyl]methyl]-2-chloro-3-
(trifluoromethyl)benzamide and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-chloro-3-(trifluoromethyl)benzamide;
2-Amino-N-[(2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-5-bromo-4-chlorobenzamide;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-methyl-3-(trifluoromethyl)-
benzamide;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2,6-dichloro-3-(trifluoromethyl)-
benzamide;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-chloro-5-(trifluoromethyl)benzamide
and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-chloro-6-fluoro-3-methylbenzamide;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-chloro-5-(methylsulphanyl)-
benzamide;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-chloro-3-methylbenzamide and its
hydrochloride;
(-)-N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-chloro-3-(trifluoromethyl)-
benzamide and its hydrochloride;
(+)-N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-chloro-3-(trifluoromethyl)-
benzamide and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-4-chloro-5-(ethanesulphonyl)-2-
methoxybenzamide and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)(4-fluorophenyl)methyl]-2-chloro-3-(trifluoromethyl)-
benzamide;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)(naphth-2-yl)methyl]-2-chloro-3-(trifluoromethyl)-
benzamide and its hydrochloride;
2-Chloro-N-{(phenyl)[2-methyl-2-azabicyclo[2.1.1]hex-1 -yl]methyl}-3-(trifluoromethyl)-
benzamide and its hydrochloride;
2-Chloro-N-[(2-ethyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-3-(trifluoromethyl)-
benzamide and its hydrochloride;
N-[(2-Allyl-2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-amino-5-bromo-4-chloro-
benzamide;
2-Amino-5-bromo-4-chloro-N-[(phenyl)(2-propyl-2-azabicyclo[2.1.1]hex-1 -yl)methyl]-
benzamide and its hydrochloride;
2,6-Dichloro-N-{[2-(2-hydroxy-2-methylpropyl)-2-azabicyclo[2.1.1]hex-1 -yl]
(phenyl)methyl}-3-(trifluoromethyl)benzamide and its hydrochloride;
2,6-Dichloro-N-{(phenyl)[2-(2,2,2-trifluoroethyl)-2-azabicyclo[2.1.1]hex-1 -yl]methyl}-3-
(trifluoromethyl)benzamide;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(3-hydroxyphenyl)methyl]-2-chloro-3-(trifluoromethyl)-
benzamide and its hydrochloride;
2-Chloro-N-[(2-cyclopropylmethyl-2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-3-
(trifluoromethyl)benzamide and its hydrochloride;
(+)-2-Chloro-N-[(2-ethyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-3-
(trifluoromethyl)benzamide and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2,6-dimethylbenzamide and its
hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-ethylbenzamide and its
hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)(m-tolyl)methyl]-2,6-dichloro-3-(trifluoromethyl)-
benzamide and its hydrochloride;
N-[(2-Ethyl-2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2,6-dimethylbenzamide and its
hydrochloride;
2-Ethyl-N-[(2-ethyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]benzamide and its
hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-6-chloro-2-methyl-3-(trifluoromethyl)-
benzamide and its hydrochloride;
N-[(2-Benzyl-2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-chloro-3-(trifluoromethyl)-
benzamide and its hydrochloride.
The compounds of the invention exhibit a specific activity as inhibitors of glycine
transporters GlyT1, in particular an improved activity profile and an improved safety
profile.
The compounds of general formula (I) can be prepared by a process illustrated by the
following Scheme 1.

A diamine of general formula (II), in which R and R1 are as defined above, in
particular when R represents a hydrogen atom or an allyl or phenylmethyl group, is
coupled with an activated acid, for example an acid activated via a mixed anhydride
or an acid chloride, of general formula (III), in which Y represents a leaving group
derived, for example, from benzotriazole or acylurea or a halogen atom and R2 is as
defined above, using methods known to a person skilled in the art.
The compounds of general formula (I) in which R represents a hydrogen atom can
also be prepared from compounds of general formula (I) in which R represents:
- either a phenylmethyl group, by deprotecting the nitrogen by hydrogenolysis,
- or an alkenyl group, preferably an allyl group, by deprotecting the nitrogen, for
example with a palladium(O) complex, according to methods known to a person skilled
in the art.
The compounds of general formula (I) in which R is other than the hydrogen atom can
also be prepared from compounds of general formula (I) in which R represents a
hydrogen atom either by alkylation of the said compound of general formula (I) with a
halide or mesylate of the RX type, in which R is as defined above and X is mesylate or
halogen, in the presence of an inorganic base, for example potassium carbonate in
acetonitrile; or by a reaction of Eschweiler-Clarke type or a reductive amination with
an appropriate aldehyde or an appropriate ketone, according to methods known to a
person skilled in the art; or with an appropriate epoxide derivative, according to
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 by a hydroxyl can be obtained from the corresponding compound of
general formula (I) substituted by a methoxy, using methods known to a person skilled
in the art.
The diamine of general formula (II) can be prepared by processes illustrated by the
following Scheme 2, for the amine (lla), and the following Scheme 3, for the amines
(llb) and (llc):
The ester (IV) is converted to the amide (V) by heating the trimethylaluminium
complex and the appropriate amine, such as morpholine, at reflux of the solvent, such
as toluene. The amine (V) can be deprotected, in order to obtain the compound (VI),
by using a lithium compound of phenyllithium type in a solvent, such as
tetrahydrofuran, at low temperature, for example at -70°C. An N-allylation is
subsequently carried out using allyl bromide in the presence of a base, such as
potassium carbonate, in a solvent, such as acetonitrile, at ambient temperature, in
order to obtain the compound (VII). The morpholine amide of formula (VII) can be
reacted with the lithiated aromatic compound of general formula (VIII), in which R1 is
as defined above, in an ethereal solvent, such as ether or tetrahydrofuran, at low
temperature. A ketone of general formula (IX) is thus obtained and is reacted with
O-benzylhydroxylamine hydrochloride, at reflux of pyridine, in order to obtain a Z/E
mixture of oxime of general formula (X).
The oxime (X) is subsequently reduced at reflux of the ether by lithium aluminium
hydride, in order to provide the diamine of formula (lla).

According to Scheme 3, a nitrile of formula (XI) is reacted with the lithiated aromatic
compound of general formula (VIII), in which R1 is as defined above, in an ethereal
solvent, such as tetrahydrofuran or ether, at low temperature, for example -70°C. An
imine is thus obtained and is reduced with a reducing agent, such as sodium
borohydride, in a protic solvent, such as methanol, to give the amine of general
formula (llb). The amine (llb) can be debenzylated by hydrogenation in the presence
of palladium catalyst to provide the deprotected amine (llc).
Furthermore, the chiral compounds of general formula (I) corresponding to the S or R
enantiomers can be obtained by separation of the racemic compounds by high
performance liquid chromatography (HPLC) on a chiral column or might be obtained
by resolution of the racemic amine of general formula (II) by use of a chiral acid, such
as dibenzoyltartaric acid, or by the fractional and preferential recrystallization of a
diastereoisomeric salt.
The ester of formula (IV) is prepared according to a method described in J. Org.
Chem., 2003, 9348-9355.
The nitrile of formula (XI) is prepared according to a method described in
Tetrahedron: Asymmetry, 2006(17), 252-258.
The lithiated derivatives of general formula (VIII) can be prepared according to
methods known to a person skilled in the art.
The acids and acid chlorides of general formula (III) are available commercially or are
prepared by analogy to methods known to a person skilled in the art.
The examples which will follow illustrate the preparation of some compounds of the
invention. In these examples:
- the elemental microanalyses, the IR and NMR spectra and chiral column HPLC
confirm the structures and the enantiomeric purities of the compounds obtained,
- for the NMR descriptions, "m" means multiplet, "s" singlet, "t" triplet, "d" doublet, "q"
quartet, "dxd" double doublet, "txt" triple triplet, "dxt" double triplet, and the like.
- The numbers shown between brackets in the titles of the examples correspond to
those in the 1st column in Tables 1 and 2,
- "decomp." means "decomposition",
- the roman numerals in brackets correspond to the corresponding general formulae
shown in the synthetic schemes,
- the nomenclature employed is the nomenclature according to the IUPAC
(International Union of Pure and Applied Chemistry) recommendations.
In the names of the compounds, the hyphen "-" forms part of the word and the
"underline" symbol"_" is used only for the break at the line end; it is to be omitted in
the absence of a break and should be replaced neither by an ordinary hyphen nor by
a space.
Example 1 (compound No. 9): N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-
chloro-5-(trifluoromethyl)benzamide hydrochloride (1:1)
1.1 (2-Benzoyl-2-azabicvclo[2.1.1]hex-1-yl)(morpholin-4-yl)methanone (compound of
formula V)
10 ml of morpholine (115mmol) are added dropwise to a solution of 29 ml of 2N
trimethylaluminium (58 mmol) in 200 ml of anhydrous toluene in a 500 ml three-
necked flask under argon and the mixture is heated at 60°C for 15 minutes. A solution
of 20 g of ethyl 2-benzoyl-2-azabicyclo[2.1.1]hexane-1-carboxylate (77.1 mmol) in
190 ml of anhydrous toluene is transferred via a tube into the reaction medium, which
is subsequently heated at reflux overnight. After cooling, the mixture is carefully
hydrolysed with 60 ml of water while stirring. The precipitate formed is filtered off on
Celite® and then rinsed with dichloromethane. The filtrate is evaporated under
reduced pressure.
The residue obtained is triturated from ether. 18.35 g of (2-benzoyl-2-
azabicyclo[2.1.1]hex-1-yl)(morpholin-4-yl)methanone of general formula (V) are thus
obtained in the form of a dark beige solid.
1H NMR (400 MHz, d6-DMSO) d ppm 7.69 (d, J = 8 Hz, 2H), 7.56-7.45 (m, 3H), 3.76
(d, J = 7.7 Hz, 1H), 3.64-3.26 (m, 9H), 2.73 (t, J = 2.7 Hz, 1H), 2.10 (m, 2H), 1.97 (m,
1H), 1.52 (m, 1H).
M.p.: 176-177°C
1.2. (2-Azabicyclo[2.1.1]hex-1-yl)(morpholin-4-yl)methanone (compound of formula
Vl)
10 g of (2-benzoyl-2-azabicyclo[2.1.1]hex-1-yl)(morpholin-4-yl)methanone (V)
(33.3 mmol) are placed in 400 ml of anhydrous tetrahydrofuran at -70°C in a 1 I three-
necked flask under argon. 50 ml of 0.8M phenyllithium (cyclohexane/ether) (40 mmol)
are added dropwise and the solution obtained is left at -70°C for 1 h.
Hydrolysis is carried out with 100 ml of water and the mixture is allowed to return to
ambient temperature. After extracting, the organic phase is concentrated and then the
residue is taken up in ether. This ethereal phase is poured into the preacidified
aqueous phase. After extracting, the aqueous phase is basified with aqueous
ammonia and then extracted with dichloromethane (3 x 200 ml). The organic phases
are dried over sodium sulphate, filtered and evaporated under reduced pressure.
5.2 g of (2-azabicyclo[2.1.1]hex-1-yl)(morpholin-4-yl)methanone (VI) are thus obtained
in the form of a dark beige solid.
1H NMR (400 MHz, d6-DMSO) d ppm 3.71 (m, 2H), 3.55 (m, 4H), 3.44 (m, 2H), 2.87
(s, 2H), 2.69 (broad s, 1H), 2.60 (t, J = 2.9 Hz, 1H), 1.84 (m, 2H), 1.43 (m, 2H).
M.p.: 97.5-98°C
1.3. (2-Allyl-2-azabicyclo[2.1.1]hex-1-yl)(morpholin-4-yl)methanone (compound of
fomula VII)
7.4 g of (2-azabicyclo[2.1.1]hex-1-yl)(morpholin-4-yl)methanone (VI) (37.7 mmol) are
placed in 100 ml of acetonitrile and 10.4 g of potassium carbonate (75.4 mmol) in a
500 ml round-bottomed flask. A solution of 3.9 ml of allyl bromide (45.2 mmol) is
added dropwise to this suspension. The reaction medium is stirred overnight at
ambient temperature and then concentrated under reduced pressure.
The residue is dissolved in 100 ml of dichloromethane. The organic phase is washed
with water, dried over sodium sulphate, filtered and then evaporated under reduced
pressure. 8.9 g of (2-allyl-2-azabicyclo[2.1.1]hex-1-yl)(morpholin-4-yl)methanone of
general formula (VII) are thus obtained in the form of an oil.
1H NMR (400 MHz, d6-DMSO) d ppm 5.85 (m, 1H), 5.24 (m, 1H), 5.09 (m, 1H), 3.78
(broad t, J = 4.7 Hz, 2H), 3.54 (m, 4H), 3.44 (m, 2H), 3.05 (broad d, J = 5.7 Hz, 2H),
2.69 (broad s, 2H), 2.56 (broad t, J = 3 Hz, 1H), 1.83 (m, 2H), 1.68 (m, 2H).
1.4. (2-Allyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methanone (compound of general
formula IX)
3.2 g of (2-allyl-2-azabicyclo[2.1.1]hex-1-yl)(morpholin-4-yl)methanone (VII)
(13.5 mmol) are placed in 70 ml of tetrahydrofuran at -70°C in a 250 ml three-necked
flask under argon. 16.2 ml of 1M phenyllithium (cyclohexane/ether) are run in
dropwise and the mixture is left at -70°C for one hour. After hydrolysis with 20 ml of
water, the mixture is allowed to return to ambient temperature. After evaporating the
solvent under reduced pressure, the residue is taken up in ethyl acetate. After
extracting, 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, elution being carried out with a mixture of petroleum ether and ethyl acetate.
2 g of (2-allyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methanone are thus obtained in the
form of an oil (compound of general formula IX).
1H NMR (400 MHz, d6-DMSO) d ppm 8.28 (m, 2H), 7.64 (txt, J = 7.3 and 1.4 Hz, 1H),
7.52 (m, 2H), 5.73 (m, 1H), 5.20 (m, J = 17 and 2 Hz, 1H), 5 (m, J = 10 and 2 Hz, 1H),
2.99 (dxt, J = 5.6 and 1.5 Hz, 2H), 2.86 (s, 2H), 2.70 (t, J = 2.9 Hz, 1H), 1.99-1.85 (m,
4H).
1.5. (2-Allyl-2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methanone O-benzvloxime
(compound of general formula X)
0.8 g of (2-allyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methanone (IX) (3.7 mmol) is
placed in 12 ml of pyridine in a 50 ml round-bottomed flask and then 0.91 g of O-
benzylhydroxylamine hydrochloride (7.4 mmol) is added. The reaction medium is
heated at reflux overnight and then concentrated under reduced pressure.
The residue is taken up in water basified with aqueous ammonia and then extracted
three times with dichloromethane. The organic phases are combined, washed with a
saturated sodium chloride solution, dried over sodium sulphate, filtered and
evaporated under reduced pressure. The crude product is purified by chromatography
on a column of silica gel, elution being carried out with a mixture of dichloromethane
and ammoniacal methanol. 1.2 g of (2-allyl-2-azabicyclo[2.1.1]hex-1-yl)
(phenyl)methanone O-benzyloxime of general formula (X) are thus obtained in the
form of an oil.
1H NMR (400 MHz, d6-DMSO) d ppm 7.49-7.45 (m, 2H), 7.42-7.26 (m, 8H), 5.76 (m,
1H), 5.17 (m, J = 17 Hz and 1.7 Hz, 1H), 5.09 (s, 1H), 5.03 (m, 1H), 3.06 (dxt, J = 5.9
Hz and 1.4 Hz, 2H), 2.66 (broad s, 2H), 2.62 (broad t, J = 3 Hz, 2H), 1.79 (m, 2H),
1.63 (m,2H).
1.6. [(2-Allyl-2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]amine (Ila)
0.32 g of lithium aluminium hydride (8.4 mmol) is placed in 15 ml of ether in a 50 ml
three-necked flask under nitrogen. A solution of 0.7 g of (2-allyl-2-
azabicyclo[2.1.1]hex-1-yl)(phenyl)methanone O-benzyloxime (X) (2.1 mmol) in 3 ml of
ether is subsequently added and then the mixture is heated at 40°C for 3 hours. After
cooling, the reaction medium is hydrolysed at 0°C with 1.4 ml of a 0.1 M aqueous
double tartrate solution overnight.
After filtering the reaction medium, the filtrate is concentrated under reduced
pressure. The residue is purified by chromatography on a column of silica gel, elution
being carried out with a mixture of dichloromethane and ammoniacal methanol. 0.3 g
of [(2-allyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]amine (lla) is thus obtained in
the form of an oil.
1H NMR (400 MHz, d6-DMSO) d ppm 7.36-7.15 (m, 5H), 5.87 (m, 1H), 5.23 (m, 1H),
5.06 (m, 1H), 4.14 (s, 1H), 3.36 (m, J = 13.5 and 5.5 Hz, 1H), 3.06 (m, J = 13.5 and
6.4 Hz, 1H), 2.76 (broad d, J = 8 Hz, 1H), 2.43 (m, 2H), 1.78 (broad s, 2H), 1.39-1.21
(m, 3H), 1.08 (m, 1H).
1.7._______N-[(2-Allyl-2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-chloro-5-(trifluoro-
methyl)benzamide (la)
0.15 g of [(2-allyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]amine (lla) (0.66 mmol)
is placed in 3 ml of dichloromethane at 0°C in the presence of 0.18 g of potassium
carbonate (1.31 mmol) in a 25 ml round-bottomed flask. A solution of 0.19 g of 2-
chloro-5-(trifluoromethyl)benzoyl chloride (0.79 mmol) in 2 ml of dichloromethane is
added and the mixture is left stirring at ambient temperature overnight. The reaction
medium is subsequently diluted with 10 ml of dichloromethane and then washed
successively with water (5 ml), a 1N sodium hydroxide solution (5 ml) and a saturated
sodium chloride solution (5 ml).
The organic phase is dried over sodium sulfate, filtered and evaporated under
reduced pressure. The residue is purified by chromatography on a column of silica
gel, elution being carried out with a mixture of dichloromethane and ammoniacal
methanol. 0.24 g of N-[(2-allyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-chloro-5-
(trifluoromethyl)benzamide (la) is thus obtained in the form of an oil.
1H NMR (400 MHz, d6-DMSO) d ppm 9.10 (d, J = 8.8 Hz, 1H), 7.85 (dxd, J = 8.5 and
2.3 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.64 (dxd, J = 2.2 Hz, 1H), 7.43-7.25 (m, 5H),
5.86 (m, 1H), 5.36 (d, J = 8.7 Hz, 1H), 5.27 (m, 1H), 5.10 (m, 1H), 3.40-3.27 (m, 3H),
3.19 (m, 1H), 2.79 (m, J = 8.4 Hz, 1H), 1.53 (m, 1H), 1.45-1.29 (m, 3H).
1.8. N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-chloro-5-(trifluoromethyl)benz-
amide hydrochloride (1:1).
3.5 mg of palladiumtetrakis(triphenylphosphine) (0.003 mmol) and 0.14 g of N,N-
dimethylbarbituric acid (0.9 mmol) in solution in 1 ml of dichloromethane are placed in
a 10 ml round-bottomed flask under argon provided with a reflux condenser. The
reaction medium is heated at 40°C before adding 0.13 g of N-[(2-allyl-2-
azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-chloro-5-(trifluoromethyl)benzamide (la)
(0.3 mmol) in 2 ml of dichloromethane and then the mixture is heated at 40°C for a
further 2 hours. After cooling, the mixture is diluted with 10 ml of dichloromethane and
subsequently hydrolyzed with 5 ml of a sodium carbonate solution.
The organic phase is separated and washed twice with 5 ml of 1N hydrochloric acid.
The aqueous phases are combined, then basified with aqueous ammonia to pH 9 and
subsequently extracted twice with 25 ml of dichloromethane. The organic phases are
dried over sodium sulphate, filtered and evaporated under reduced pressure. 0.1 g of
N-[(2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-chloro-5-(trifluoromethyl)benzamide
is thus obtained, which product is salified in the hydrochloride form by dissolution of
the base in ether, followed by addition of an excess of 1N hydrochloric acid in ether.
The solid obtained is filtered off and then dried under vacuum.
1H NMR (400 MHz, d6-DMSO) d ppm 9.48 (d, J = 8.8 Hz, 1H), 9.13 (m, 1H), 8 (d, J =
2.1 Hz, 1H), 7.88 (dxd, J = 8.6 and 2.3 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.50-7.35 (m,
5H), 5.69 (d, J = 8.8 Hz, 1H), 3.41-3.19 (m, 2H), 2.79 (t, J = 3 Hz, 1H), 2.03 (m, 1H),
1.79 (m, 1H), 1.55 (m,2H).
M.p. = 162.5-163.5°C
Example 2 (compound No. 5): N-[(2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-
chloro-3-(trifluoromethyl)benzamide hydrochloride (1:1).
2.1 [(2-Benzyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]amine of general formula
(IIb),
3 g of 2-benzyl-2-azabicyclo[2.1.1]hexane-1-carbonitrile (XI) (15.1 mmol) are placed
at -70°C in 100 ml of anhydrous tetrahydrofuran in a 500 ml three-necked flask under
argon. 37.8 ml of a 0.8M solution (cyclohexane/ether) of phenyllithium (30.2 mmol)
are added dropwise.
The reaction mixture is left at -70°C for two and a half hours and is then hydrolysed at
-20°C with 30 ml of water.
After extracting, the organic phase is concentrated and then the residue is taken up in
40 ml of methanol. 2.8 g of sodium borohydride (75 mmol) are added thereto
portionwise. The reaction medium is left stirring at ambient temperature overnight.
After evaporating under reduced pressure, the residue is taken up in 100 ml of ether
and 100 ml of water.
The medium is acidified with a 1N hydrochloric acid solution and then the ethereal
phase is extracted.
The aqueous phase is basified with aqueous ammonia and then reextracted twice
with 100 ml of dichloromethane. The organic phases are combined and then dried
over sodium sulphate, filtered and evaporated under reduced pressure. 4.15 g of [(2-
benzyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]amine (llb) are thus obtained in the
form of an oil which crystallizes in the cold.
1H NMR (200 MHz, CDCl3) d ppm 7.6-7.3 (m, 5H), 4.4 (s, 1H), 4.2 (d, J = 16 Hz, 1H),
3.6 (d, J = 16 Hz, 1H), 3.0 (d, J = 9 Hz, 1H), 2.6 (m,1H), 2.4 (d, J = 9 Hz, 1H), 1.8
(broad s, 2H), 1.6-1.2 (m, 4H).
M.p. = 63.5-64°C.
An analytical sample is obtained in the form of the hydrochloride by dissolution of the
base in ether, addition of an excess of 1N hydrochloric acid in ether and then
concentration under reduced pressure.
M.p. = 140-142°C
2.2 [(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]amine (llc)
0.43 g of [(2-benzyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]amine (llb)
(1.54 mmol) is placed in 20 ml of ethanol and 5 ml of 1N hydrochloric acid, in the
presence of a spatula tip of 10% palladium-on-charcoal, in a Parr bottle under 4
atmospheres of hydrogen at 40°C for 3 hours.
After filtering of the catalyst and then concentrating under reduced pressure, the
residue is taken up in 30 ml of dichloromethane and 30 ml of water basified with
aqueous ammonia. After extracting, the organic phase is dried over sodium sulphate,
filtered and evaporated under reduced pressure. 0.24 g of [(2-azabicyclo[2.1.1]hex-1-
yl)(phenyl)methyl]amine (llc) is thus obtained in the form of a yellow oil which solidifies
in the cold and which is used as is in the following stage.
M.p. = 46.5-47°C
An analytical sample is obtained in the form of the hydrochloride by dissolution of the
base in ether, addition of an excess of 1N hydrochloric acid in ether and then
concentration under reduced pressure.
1H NMR (400 MHz, d6-DMSO) d ppm 10.12-8.71 (m, 4H), 7.46-7.35 (m, 6H), 4.83 (m,
1H), 3.15 (m, 2H), 2.72 (m, 1H), 2.10 (m, 1H), 1.89 (m, 1H), 1.57 (broad t, J = 9.3 Hz,
1H), 1.36 (broad t, J = 9.3 Hz, 1H).
M.p. = 220-223°C (decomp.)
2.3 N-[(2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-chloro-3-(trifluoromethyl)benz-
amide hydrochloride (1:1).
2.4 g of 2-chloro-3-(trifluoromethyl)benzoic acid (10.8 mmol), 1.45 g of
hydroxybenzotriazole (10.8 mmol) and 2.1 g of 1-[3-(dimethylamino)propyl]-3-
ethylcarbodiimide hydrochloride (10.8 mmol) are placed in solution in 20 ml of
dichloromethane in a 250 ml round-bottomed flask and the mixture is stirred at
ambient temperature for 15 minutes. 1.7 g (9.0 mmol) of [(2-azabicyclo[2.1.1]hex-1-
yl)(phenyl)methyl]amine (llc) in solution in 20 ml of dichloromethane are added and
the mixture is stirred at ambient temperature overnight.
The reaction medium is subsequently diluted with 10 ml of dichloromethane and then
successively washed with water (5 ml), 1N sodium hydroxide solution (5 ml) and a
saturated sodium chloride solution (5 ml).
The organic phase is dried over sodium sulphate, filtered and evaporated under
reduced pressure.
1.8 g of N-[(2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-chloro-3-(trifluoro-
methyl)benzamide are thus obtained. An analytical sample is obtained in the form of
the hydrochloride by dissolution of the base in dichloromethane, addition of an excess
of 1N hydrochloric acid in ether and then concentration under reduced pressure.
1H NMR (400 MHz, d6-DMSO) d ppm 9.09 (d, J = 9 Hz, 1H), 7.94 (dxd, J = 7.8 Hz
and 1.8 Hz, 1H), 7.68 (m, 1H), 7.63 (m, 1H), 7.41-7.31 (m, 4H), 7.27 (m, 1H), 5.33 (d,
J = 8.8 Hz, 1H), 2.78 (m, 2H), 2.64 (t, J = 2.9 Hz, 1H), 2.20 (m, 1H), 1.68 (m, 2H),
1.14 (m,2H).
M.p. =148-150°C
Example 3 (compound No. 19): 2-Chloro-N-[(2-ethyl-2-azabicyclo[2.1.1]hex-1 -yl)
(phenyl)methyl]-3-(trifluoromethyl)benzamide hydrochloride (1:1)
0.15 g of N-[(2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-chloro-3-(trifluoro-
methyl)benzamide (0.38 mmol) and 0.10 g of potassium carbonate (0.76 mmol) are
placed in 2 ml of acetonitrile in a 25 ml round-bottomed flask and 40 ul of iodoethane
(0.46 mmol) are added thereto.
The reaction medium is stirred at ambient temperature overnight and then
concentrated under reduced pressure. The residue is subsequently diluted with 10 ml
of dichloromethane and then washed with water (5 ml).
The organic phase is dried over sodium sulphate, filtered and evaporated under
reduced pressure. 82 mg of 2-chloro-N-[(2-ethyl-2-azabicyclo[2.1.1]hex-1-yl)
(phenyl)methyl]-3-(trifluoromethyl)benzamide are thus obtained, which product is
salified in the form of the hydrochloride by dissolution of the base in dichloromethane,
addition of an excess of 1N hydrochloric acid in ether and then concentration under
reduced pressure.
1H NMR (400 MHz, d6-DMSO) d ppm 9.06 (d, J = 8.6 Hz, 1H), 7.94 (dxd, J = 7.3 Hz
and 2.1 Hz, 1H), 7.67-7.59 (m, 2H), 7.37 (m, 4H), 7.28 (m, 1H), 5.33 (d, J = 8.8 Hz,
1H), 2.76-2.52 (m, 5H), 1.50 (m, 1H), 1.37 (m, 3H), 1.04 (t, J = 7.2 Hz, 3H).
M.p. = 152-155°C
Example 4 (compound No. 22): 2,6-Dichloro-N-{[2-(2-hydroxy-2-methylpropyl)-2-
azabicyclo[2.1.1]hex-1 -yl](phenyl)methyl}-3-(trifluoromethyl)benzamide hydrochloride
(1:1).
196 mg of N-[(2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2,6-dichloro-3-
(trifluoromethyl)benzamide (0.46 mmol) are placed in 2 ml of absolute ethanol in the
presence of 0.81 ml of 2,2-dimethyloxirane (9.13 mmol) in a sealed tube under argon.
The reaction medium is heated at 100°C for 40 minutes using microwave radiation.
After evaporating the solvent under reduced pressure, the residue is taken up in a
mixture of water and dichloromethane. After extracting, 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, elution being carried out with a
mixture of dichloromethane and methanol. 58 mg of 2,6-dichloro-N-{[2-(2-hydroxy-2-
methylpropyl)-2-azabicyclo[2.1.1]hex-1 -yl](phenyl)methyl}-3-(trifluoromethyl)-
benzamide are thus obtained in the form of an oil, which product is salified by
dissolution in ether, addition of an excess of 1N hydrochloric acid in ether and then
concentration under reduced pressure.
1H NMR (400 MHz, d6-DMSO) d ppm 9.91 - 9.46 (m, 2H), 7.97 (m, 1H), 7.79 (m,
1H), 7.60-7.29 (m, 5H), 5.87-5.54 (m, 1H), 5.31 (m, 1H), 3.93 - 3.21 (m, 4H), 2.75 (m,
1H), 2.25-1.43 (m, 4H), 1.31 (m, 6H).
M.p.: 178.5-179.0°C
Example 5 (compound No. 23'): 2,6-Dichloro-N-{(phenyl)[2-(2,2,2-trifluoroethyl)-2-
azabicyclo[2.1.1]hex-1-yl]methyl}-3-(trifluoromethyl)benzamide
117 mg of N-[(2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2,6-dichloro-3-
(trifluoromethyl)benzamide (0.27 mmol) are placed in 1.5 ml of absolute ethanol in the
presence of 46 mg of sodium hydrogencarbonate (0.55 mmol) and 64 mg of 2,2,2-
trifluoroethyl trifluoromethanesulphonate (0.27 mmol) in a sealed tube under argon.
The reaction medium is heated at 100°C for 4 h. After evaporating the solvent under
reduced pressure, the residue is taken up in water and dichloromethane. After
extracting, 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, elution being carried out with a mixture of dichloromethane and methanol.
58 mg of 2,6-dichloro-N-{(phenyl)[2-(2,2,2-trifluoroethyl)-2-azabicyclo[2.1.1]hex-1-
yl]methyl}-3-(trifluoromethyl)benzamide are thus obtained.
1H NMR (400 MHz, d6-DMSO) d ppm 7.59 (d, J = 8.5 Hz, 1H), 7.40-7.17 (m, 5H),
6.62 (m, 1H), 5.08 (d, J = 5 Hz, 1H), 3.26 (m, 1H), 3.07 (d, J = 8.8 Hz, 1H), 2.92 (m,
1H), 2.72 (d, J = 8.8 Hz, 2H), 2.57 (m, 1H), 1.55-1.12 (m, 4H).
M.p.: 82-83°C
Example 6 (compound No. 18): 2-Chloro-N-[(2-methyl-2-azabicyclo[2.1.1]hex-1 -yl)
(phenyl)methyl]-3-(trifluoromethyl)benzamide hydrochloride (1:1).
0.15 g of N-[(2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-chloro-(3-trifluoromethyl)-
benzamide (0.39 mmol) and 2 ml of formaldehyde are placed in 2 ml of formic acid in
a 25 ml round-bottomed flask. The reaction mixture is heated at 100°C overnight.
After cooling, the medium is hydrolysed, basified to pH = 9 with aqueous ammonia
and then extracted with ethyl acetate. The organic phase is dried over sodium
sulphate, filtered and evaporated under reduced pressure. 2,6-Dichloro-N-[(2-methyl-
2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-3-(trifluoromethyl)benzamide is obtained
in the form of an oil, which product is salified by dissolution of the base in ether,
addition of an excess of 1N hydrochloric acid in ether and then concentration under
reduced pressure. 80 mg of 2,6-dichloro-N-[(2-methyl-2-azabicyclo[2.1.1]hex-1-yl)
(phenyl)methyl]-3-(trifluoromethyl)benzamide hydrochloride are obtained.
1H NMR (400 MHz, d6-DMSO) d ppm 10.80 - 10.42 (m, 1H), 9.51 (m, 1H), 8.31-7.29
(m, 8H), 5.78 (m, 1H), 4.01-1.03 (m, 10H).
M.p.: 168.5-169.56C
The other compounds described in Table 1 are obtained according to the methods
described in Examples 1 to 7 starting from the appropriate amines of formula (Ila),
(llb) or (llc), from appropriate lithium compounds of formula (VIII), from appropriate
carboxylic acid derivatives of formula (III) or from appropriate alkylating agents.
The chemical structures of some compounds of the invention are illustrated in the
following Table 1.
In the table:
- In the "Salts" column, - denotes a compound in the form of the base, "HCI" denotes a
hydrochloride and the figure in brackets indicates the (base:acid) ratio,
- in the R, R1 and R2 columns:
- "CI" means chlorine,
- "Br" means bromine,
- "CH3" means methyl,
- "C2H5" means ethyl,
- "NH2" means amino,
- "OCH3" means methoxy,
- "Ph" means phenyl,
- "SO2C2H5" means ethanesulphonyl,
- "CF3" means trifluoromethyl,
- in the "R2" column, the figure in front of the substituents indicates their position in the
general formula (I),
- the compounds in the table are provided in the form of the hydrochloride solvated by
one or more water molecules,
- compounds Nos. 13 and 14 in the table form a pair of enantiomers which are
separated by preparative HPLC using a CHIRALpak® AD 20 urn column and, as
solvent, a 95/5 isohexane/propan-2-ol mixture.
The physical properties, melting points and optical rotations of the compounds of
Table 1 are given in Table 2.
In Table 2
- the [aD]20°C column gives the analytical result for the optical rotation of the
compounds in the table at the wavelength of 589 nM and at the temperature of 20°C.
The solvent shown in brackets corresponds to the solvent employed in carrying out
the measurement of the optical rotation in degrees and the letter "c" shows the
concentration of the solvent in g/100 ml; "N.A." means that the measurement of the
optical rotation is not applicable,
- the "LCMS MH+" column gives the molecular ion (M+H+) or (M+) observed by
analysis of the products by mass spectrometry, either by LC-MS (Liquid
Chromatography coupled to Mass Spectroscopy), carried out on a device of Agilent
LC-MSD Trap type in positive ESI mode, or by direct introduction by MS (Mass
Spectroscopy) on an Autospec M (EBE) device using the DCI-NH3 technique or using
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 10 mM of glycine
(determination of the non-specific uptake), 10 µM 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 µl 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 10 mM glycine.
The compounds of the invention have, in this test, an IC50 of the order of 0.001 to
10 µM.
Some examples of IC50 results for compounds according to the invention are shown in
Table 3.

The results of the trials carried out on the chiral compounds of the invention and their
racemates in the general formula (I) in which R2 represents in particular one or more
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 behavioural disorders associated with
neurodegenerative diseases or dementia; for the treatment of psychoses, in particular
schizophrenia (deficit form and productive form); or acute or chronic extrapyramidal
symptoms induced by neuroleptics; for the treatment of various forms of anxiety,
panic attacks, phobias or obsessive-compulsive disorders; for the treatment of various
forms of depression, including pyschotic depression; for the treatment of bipolar
disorders, manic disorders or mood disorders; or for the treatment of disorders due to
alcohol abuse or withdrawal, disorders of sexual behaviour, eating disorders,
migraine, pain or sleep disorders.
The compounds according to the invention can thus be used in the preparation of
medicaments, in particular of medicaments which are inhibitors of the glycine
transporter GlyT1.
Thus, according to another of its aspects, the subject-matter of the invention is
medicaments which comprise a compound of formula (I) or an addition salt of the
latter with a pharmaceutically acceptable acid or also a hydrate or a solvate of the
compound of formula (I).
Another subject-matter 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, as a mixture, if
appropriate, with suitable excipients.
The said excipients are chosen according to 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.
The said unit forms are dosed to allow a daily administration of 0.01 to 20 mg of active
principle per kg of body weight, according to 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, hydroxypropylmethylcellulose, and
the like), 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 or surface-active agents, 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 parental 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 vehicles 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 the tablet form can comprise the following components:

Orally, the dose of active principle administered daily can reach from 0.1 to 20 mg/kg,
taken once or on several occasions.
There may be specific cases where higher or lower dosages are appropriate; such
dosages do not depart from the scope of the invention. According to the usual
practice, the dosage appropriate to each patient is determined by the physician
according to the method of administration and the weight and the response of the said
patient.
The present invention, according to another of its aspects, also relates to a method for
the treatment of the pathologies indicated above which comprises the administration,
to a patient, of an effective dose of a compound according to the invention or one of
its pharmaceutically acceptable salts.
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)cyclo-
alkyl groups, these groups optionally being substituted by one or more groups chosen,
independently of one another, from the fluorine atom or (C3-C7)cycloalkyl,
(C2-C4)alkenyl, phenyl, (C1-C6)alkoxy or hydroxyl groups; the phenyl group is
optionally substituted by one or more (C1-C6)alkoxy groups;
- R1 represents a phenyl or naphthyl group which is optionally substituted by one or
more substituents chosen, independently of one another, from halogen atoms or
(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, NR4R5, NR3C(O)OR4, NR3SO2R4,
NR3C(O)R6, hydroxyl, halo(C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkyl-SO2, phenyl or
heteroaryl groups, the phenyl group being optionally substituted by one or more
substituents independently chosen from halogen atoms or (C1-C6)alkyl, (C1-C6)alkoxy,
halo(C1-C6)alkyl, NR4R5, NR3C(O)OR4, NR3SO2R4, NR3C(O)R6, hydroxyl, halo(C1-
C6)alkoxy, (C1-C6)alkylthio or (C1-C6)alkyl-SO2 groups and the heteroaryl group being
optionally substituted by one or more substituents independently chosen from halogen
atoms or (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl or NR4R5 groups;
- R2 represents one or more substituents chosen from the hydrogen atom, halogen
atoms or (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkyl, halo(C1-C6)alkyl,
(C1-C6)alkoxy, NR4R5, phenyl, heteroaryl, cyano, acetyl, (C1-C6)alkylthio, (C1-
C6)alkylsulphonyl, carboxyl or (C1-C6)alkoxycarbonyl groups; the phenyl group being
optionally substituted by one or more substituents independently chosen from halogen
atoms or (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, NR4R5, NR3C(O)OR4,
NR3SO2R4, NR3C(O)R6, hydroxyl, halo(C1-C6)alkoxy, (C1-C6)alkylthio or (C1-C6)alkyl-
SO2 groups and the heteroaryl group being optionally substituted by one or more
substituents independently chosen from halogen atoms or (C1-C6)alkyl, (C1-C6)alkoxy,
halo(C1-C6)alkyl or NR4R5 groups;
- R3, R4 and R5 represent, independently of one another, a hydrogen atom or a
(C1-C6)alkyl group;
- R6 represents a (C1-C6)alkyl group;
- R4 and R5 can together form, with the nitrogen atom which carries them, a ring
chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine
or azepine rings optionally substituted by a (C1-C6)alkyl group;
- R3 and R4 can together form, with the atoms which carry them, a 5- or 6-membered
ring;
- R3 and R6 can together form, with the atoms which carry them, a 5- or 6-membered
ring;
in the form of the base or of an addition salt with an acid.
2. Compound of general formula (I) according to Claim 1, characterized in that R
represents a hydrogen atom or a (C1-C6)alkyl group optionally substituted by one or
more groups chosen, independently of one another, from the fluorine atom or (C2-
C4)alkenyl, hydroxyl, (C3-C7)cycloalkyl or phenyl groups.
3. Compound of general formula (I) according to Claim 1 or 2, characterized in that R1
represents a phenyl or naphthyl group optionally substituted by one or more halogen
atoms or (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, NR4R5 or hydroxyl groups.
4. Compound of general formula (I) according to any one of Claims 1 to 3,
characterized in that R2 represents one or more substituents chosen from the
hydrogen atom, halogen atoms or NR4R5, (C1-C6)alkoxy, halo(C1-C6)alkyl, (C1-
C6)alkylthio or (C1-C6)alkyl-SO2 groups.
5. Compound of general formula (I) according to any one of Claims 1 to 4,
characterized in that:
- R represents a hydrogen atom or a methyl, ethyl, propyl, isobutyl or allyl group, the
methyl, ethyl or isobutyl group or groups being optionally substituted by one or more
groups chosen, independently of one another, from the fluorine atom or hydroxyl,
cyclopropyl or phenyl groups;
- R1 represents a phenyl or naphthyl group optionally substituted by one or more
halogen atoms or methyl, methoxy, trifluoromethyl, NH2 or hydroxyl groups;
- R2 represents one or more substituents chosen from the hydrogen atom, halogen
atoms or methyl, ethyl, NH2, methoxy, trifluoromethyl, methanesulphanyl or
ethanesulphonyl groups;
and their addition salts with an acid.
6. Compound according to any one of Claims 1 to 5, characterized in that it is chosen
from:
N-[(4-Aminophenyl)(2-azabicyclo[2.1.1]hex-1-yl)methyl]-2-chloro-3-(trifluoromethyl)-
benzamide and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(m-tolyl)methyl]-2-chloro-3-(trifluoromethyl)benzamide
and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(3-methoxyphenyl)methyl]-2-chloro-3-(trifluoro-
methyl)benzamide and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)[3-(trifluoromethyl)phenyl]methyl]-2-chloro-3-
(trifluoromethyl)benzamide and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-chloro-3-(trifluoromethyl)benzamide;
2-Amino-N-[(2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-5-bromo-4-chlorobenzamide;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-methyl-3-(trifluoromethyl)-
benzamide;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2,6-dichloro-3-(trifluoromethyl)-
benzamide;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-chloro-5-(trifluoromethyl)benzamide
and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-chloro-6-fluoro-3-methylbenzamide;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-chloro-5-(methylsulphanyl)-
benzamide;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-chloro-3-methylbenzamide and its
hydrochloride;
(-)-N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-chloro-3-(trifluoromethyl)-
benzamide and its hydrochloride;
(+)-N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-chloro-3-(trifluoromethyl)-
benzamide and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-4-chloro-5-(ethanesulphonyl)-2-
methoxybenzamide and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(4-fluorophenyl)methyl]-2-chloro-3-(trifluoromethyl)-
benzamide;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(naphth-2-yl)methyl]-2-chloro-3-(trifluoromethyl)-
benzamide and its hydrochloride;
2-Chloro-N-{(phenyl)[2-methyl-2-azabicyclo[2.1.1]hex-1 -yl]methyl}-3-(trifluoromethyl)-
benzamide and its hydrochloride;
2-Chloro-N-[(2-ethyl-2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-3-(trifluoromethyl)-
benzamide and its hydrochloride;
N-[(2-Allyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-amino-5-bromo-4-chloro-
benzamide;
2-Amino-5-bromo-4-chloro-N-[(phenyl)(2-propyl-2-azabicyclo[2.1.1]hex-1 -yl)methyl]-
benzamide and its hydrochloride;
2,6-Dichloro-N-{[2-(2-hydroxy-2-methylpropyl)-2-azabicyclo[2.1.1]hex-1 -yl]
(phenyl)methyl}-3-(trifluoromethyl)benzamide and its hydrochloride;
2,6-Dichloro-N-(phenyl)[2-(2,2,2-trifluoroethyl)-2-azabicyclo[2.1.1]hex-1 -yl]methyl}-3-
(trifluoromethyl)benzamide;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(3-hydroxyphenyl)methyl]-2-chloro-3-(trifluoromethyl)-
benzamide and its hydrochloride;
2-Chloro-N-[(2-cyclopropylmethyl-2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-3-
(trifluoromethyl)benzamide and its hydrochloride;
(+)-2-Chloro-N-[(2-ethyl-2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-3-
(trifluoromethyl)benzamide and its hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2,6-dimethylbenzamide and its
hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2-ethylbenzamide and its
hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(m-tolyl)methyl]-2,6-dichloro-3-(trifluoromethyl)-
benzamide and its hydrochloride;
N-[(2-Ethyl-2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-2,6-dimethylbenzamide and its
hydrochloride;
2-Ethyl-N-[(2-ethyl-2-azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]benzamide and its
hydrochloride;
N-[(2-Azabicyclo[2.1.1]hex-1 -yl)(phenyl)methyl]-6-chloro-2-methyl-3-(trifluoromethyl)-
benzamide and its hydrochloride;
N-[(2-Benzyl-2-azabicyclo[2.1.1]hex-1-yl)(phenyl)methyl]-2-chloro-3-(trifluoromethyl)-
benzamide and its hydrochloride.
7. Process for preparation of a compound of general formula (I) according to Claim 1,
characterized in that a compound of general formula (II):

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

in which Y represents an activated OH group or a chlorine atom and R2 is as defined
according to Claim 1.
8. Medicament, characterized in that it comprises a compound of formula (I) according
to any one of Claims 1 to 6 or an addition salt of this compound with a
pharmaceutically acceptable acid.
9. Pharmaceutical composition, characterized in that it comprises a compound of
formula (I) 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 (I) according to any one of Claims 1 to 6 in the
preparation of a medicament intended for the treatment of cognitive and/or
behavioural disorders associated with neurodegenerative diseases or dementia.
11. Use of a compound of formula (I) according to any one of Claims 1 to 6 in the
preparation of a medicament intended for the treatment of psychoses, schizophrenia
(deficit form and productive form) or acute or chronic extrapyramidal symptoms
induced by neuroleptics.
12. Use of a compound of formula (I) according to any one of Claims 1 to 6 in the
preparation of a medicament intended for the treatment of various forms of anxiety,
panic attacks, phobias or obsessive-compulsive disorders.
13. Use of a compound of formula (I) according to any one of Claims 1 to 6 in the
preparation of a medicament intended for the treatment of various forms of
depression, including psychotic depression; in the treatment of bipolar disorders,
manic disorders or mood disorders; or in the treatment of disorders due to alcohol
abuse or withdrawal, disorders of sexual behaviour, eating disorders or migraine.
14. Use of a compound of formula (I) according to any one of Claims 1 to 6 in the
preparation of a medicament intended for the treatment of pain.
15. Use of a compound of formula (I) according to any one of Claims 1 to 6 in the
preparation of a medicament intended for the treatment of sleep disorders.
16. Compound according to any one of Claims 1 to 6, for the treatment of cognitive
and/or behavioural disorders associated with neurodegenerative diseases or
dementia.
17. Compound according to any one of Claims 1 to 6, for the treatment of psychoses,
schizophrenia (deficit form and productive form) or acute or chronic extrapyramidal
symptoms induced by neuroleptics.
18. Compound according to any one of Claims 1 to 6, for the treatment of various
forms of anxiety, panic attacks, phobias or obsessive-compulsive disorders.
19. Compound according to any one of Claims 1 to 6, for the treatment of various
forms of depression, including psychotic depression; for the treatment of bipolar
disorders, manic disorders or mood disorders; or for the treatment of disorders due to
alcohol abuse or withdrawal, disorders of sexual behaviour, eating disorders or
migraine.
20. Compound according to any one of Claims 1 to 6, for the treatment of pain.
21. Compound according to any one of Claims 1 to 6, for the treatment of sleep
disorders.

The invention relates to N-[(2-aza-bicyclo[2.2.1]hex-1-yl)-aryl-methyl]-benzamide derivatives of the general
formula (I) where: R is a hydrogen atom or a (C1-C6)alkyl group, (C3-C7)-cycloalkyl, optionally substituted by one or more
fluorine, (C3-C7)-cycloalkyl, (C2-C4)alkenyl, phenyl, (C1-C6)alkoxy, hydroxy; R1 is phenyl or naphtyl optionally substituted by one
or more halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo-(C1-C6)alkyl, NR4R5, (C1-C6)alkylthio, (C1-C6)alkyl-SO2, phenyl or heteroaryl,;
R2 is one or more hydrogen or halogen atoms, halo-(C1-C6)alkyl, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)-cycloalkyl-(C1-C3)alkyl;
R3, R4 and R5 are independently a hydrogen atom or a (C1-C6)alkyl group; R6 is a (C1-C6)alkyl group; R3 and R4 as well as R3 and
R6 may form, together with the atoms having them, a 5- or 6-member ring; R4 and R5 may form together a ring selected from
azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, azepine, optionally substituted by a (C1-C6)alkyl group.
The invention also relates to the therapeutic use thereof and to a method for synthesizing same.