Title of Invention

"N - HETEROCYCLYL - METHYLBENZAMIDE DERIVATIVE COMPOUNDS"

Abstract The invention relates to a compound having general formula (I), wherein: R represents a hydrogen atom or a vinyl group; n represents 0,1 or 2; X represents a groups having formula CH or a nitrogen atom; R1 represents a phenyl or naphthyl group, or a cyclohexyl group, or a heteroaryl group; R2 represents a hydrogen atom, or one or more substituents selected from among the halogen atoms and the trifluoromethyl, alkyl, alkoxy, thienyl, phenyloxy, hydroxy, mercapto, thioalkyl, cyano groups or a group having general formula -NR4R5, SO2NR4R5, -SO2-alkyl, -SO2-phenyl, -CONR4R5, -COOR7, -CO-alkyl, -CO-phenyl, -NHCOR8, -NHSO2-alkyl, -NHSO2-phenyl and -NHSO2NR4R5 or a divalent group having formula -OCF2O-; and R4 and R5 each represent a hydrogen atom or an alkyl group or R4 and R5, together with the nitrogen atom bearing same, form a pyrrolidine, piperidine or morpholine ring. Compounds having formula (I) have a unique activity as specific inhibitors of glyt1 and/or glyt2 transporters.
Full Text N-HETEROCYCLYL-METHYLBENZAMIDE DERIVATIVE COMPOUNDS
The subject of the present invention is N-heterocyclyl-
methylbenzamide derivatives, their preparation and
their therapeutic application.
The compounds of the invention correspond to general
formula (I)

in which
R represents a hydrogen atom or a vinyl group;
n represents 0 or 1 or 2 when R represents a hydrogen
atom and n represents 1 when R represents a vinyl
group;
X represents a group of formula CH or a nitrogen atom
when R represents a hydrogen atom and X represents a
group of formula CH when R represents a vinyl group;
R1 represents either a phenyl or naphthyl group
optionally substituted with one or more substituents
chosen from halogen atoms, linear or branched (C1-
C6)alkyl, hydroxyl and (C1-C6) alkoxy groups, the
trifluoromethyl group, or a cyclohexyl group, or a
heteroaryl group chosen from the thienyl, pyridinyl,
oxazolyl, furanyl, thiazolyl, quinolinyl, and
isoquinolinyl groups;
R2 represents either a hydrogen atom, or one or more
substituents chosen from halogen atoms and the
trifluoromethyl, (C1-C6) alkyl, (C1-C6) alkoxy, thienyl,
phenyloxy, hydroxyl, mercapto, thio(C1-C6)alkyl and
cyano groups or a group of general formula -NR4R5,
SO2NR4R5, -SO2-(C1-C6) alkyl, -SO2-phenyl, -CONR4R5, -COOR7,
-CO- (C1-C6) alkyl, -CO-phenyl, -NHCOR8, -NHSO2- (C1-C6) -
alkyl, -NHSO2-phenyl and -NHSO2NR4R5 or a group of
formula -OCF2O attached at the 2- and 3-positions of the
phenyl group;
the groups (C1-C6) alkyl, (C1-C6) alkoxy, -SO2- (C1-C6) alkyl,
-CO- (C1-C6) alkyl and -NHSO2- (C1-C6) alkyl being optionally
substituted with one or more groups R3;
the groups phenyl, -SO2-phenyl, -CO-phenyl and -NHSO2-
phenyl being optionally substituted with a group R6;
R3 represents a halogen atom, or a phenyl, (C1-C6)alkoxy
or -NR4R5 group,
R4 and R5 represent, independently of each other, a
hydrogen atom or a (C1-C6) alkyl group or R4 and R5 form
with the nitrogen atom bearing them a pyrrolidine ring,
a piperidine ring or a morpholine ring;
R6 represents a hydrogen atom, a halogen atom, a
trifluoromethyl group, a cyano group, a hydroxyl group,
a mercapto group, a (C1-C6) alkyl or (C1-C6) alkoxy group;
R7 represents a hydrogen atom or a (C1-C6) alkyl group
optionally substituted with one or more groups R3,or a
phenyl group optionally substituted with a group R6;
R3 represents a (C1-C6)alkyl group optionally
substituted with one or more groups R3, or a (C1-
C6) alkoxy group, or a phenyl group optionally
substituted with a group R6.
Among the compounds of general formula (I), a number of
subgroups of preferred compounds can be distinguished:
group 1: compounds of threo configuration and of
general formula (I) in which n represents 0 or 1;
group 2: compounds of group 1 in whose formula X
represents a group of formula CH;
group 3: compounds of group 2 in whose formula R
represents a hydrogen atom;
group 4: compounds of group 3 in whose formula n
represents 1;
group 5: compounds according to group 4 in whose
formula R1 represents an optionally substituted phenyl
group.
The compounds of formula (I) may contain several
asymmetric centers. They can therefore exist in the
form of enantiomers or diastereoisomers. These
enantiomers, diastereoisomers and mixtures thereof,
including the racemic mixtures, form part of the
invention.
More particularly, the compounds of formula (II, for
which R = H, can exist in the form of threo ((1S,2S)
and (1R,2R)) or erythro ((1S,2R) and (1R,2S))
diastereoisomers or of pure enantiomers or as a mixture
of such isomers.
The compounds of formula (I) can exist in the form of
bases or of addition salts with acids. Such addition
salts form part of the invention.
These salts are advantageously prepared with
pharmaceutically acceptable acids, but the salts of
other acids useful, for example, for the purification
or isolation of the compounds of formula (I) also form
part of the invention. The compounds of formula (I) can
also exist in the form of hydrates or solvates, namely
in the form of associations or combinations with one or
more molecules of water or with a solvent. Such
hydrates and solvates also form part of the invention.
The compounds of the invention exhibit a particular
activity as specific inhibitors of the glycine
transporters glytl and/or glyt2.
The compounds of general formula (I) may be prepared by
a method illustrated by scheme 1 which follows.

According to scheme 1, a diamine of general formula
(II) , in which n, X, R and R1 are as defined above, is
coupled with an activated acid or an acid chloride of
general formula (III) in which Y represents a leaving
group, such as a halogen atom, and R2 is as defined
above, using methods known to persons skilled in the
art.
The diamines of general formula (II) , in which R = H
and n, X and R1 are as defined above, may be prepared by
a method illustrated by scheme 2 which follows.

The ketone of general formula (IV), in which n, X and R1
are as defined above, is reacted with benzyloxy-
hydroxylamine hydrochloride, at the reflux temperature
of pyridine, in order to obtain the oxime of general
formula (V) . The two. forms Z and E of the oxime may be
separated according to methods known to persons skilled
in the art such as chromatography on a silica gel
column.
The oxime (V) , preferably in the Z hydrochloride form,
is then reduced at the reflux temperature of
tetrahydrofuran with lithium aluminum hydride to give
the predominantly threo-diamine of general formula
(II) -
By reducing the E form of the oxime of general formula
(V) , a diamine (II) mixture is obtained in the form of
the two diastereoisomers (threo/erythro).
The erythro- and threo-diastereoisomers may be
separated according to methods known to persons skilled
in the art such as chromatography on a silica gel
column.
Another variant preparation of the diamines of general
formula (II), in which R and R2 are as defined above, n
is equal to 1 and X is a CH, is illustrated by the
scheme 3 which follows.

The alcohols of general formula (VI) are converted to
amines by a Mitsunobu reaction according to the method
described in Bull. Soc. Chim. Belg. (106), 1997, 77-84
and in Tetrahedron: Asymmetry, (6), 1995, 1699-1702.
Moreover, the chiral compounds of general formula (I) ,
corresponding to the enantiomers (1R,2R) or (1S,2S) of
the threo-diastereoisomer and to the enantiomers
(1S,2R) or {1R,2S) of the erythro-diastereoisomer, may
also be obtained either by separating the racemic
compounds by high performance liquid chromatography
(HPLC) on a chiral column, or from the chiral amine
obtained either by resolving the racemic amine of
general formula (II), by the use of a chiral acid, such
as tartaric acid, camphorsulfonic acid, dibenzoyl-
tartaric acid, N-acetylleucine, by fractional and
preferential recrystallization of a diastereoisomeric
salt from a solvent of the alcohol type, or by
enantioselective synthesis from an erythro- or threo-
chiral alcohol using a method similar to that described
in scheme 3. The chiral alcohols may be obtained by a
method similar to that described in Tetrahedron, (55) ,
1999, 27 95-2810. In the case where R represents a vinyl
group and R1 represents a quinolinyl group, the diamine
of general formula (II) may be prepared according to
scheme 3 using the corresponding commercially available
chiral alcohols.
The racemic ketone of general formula (IV) may be
prepared either by deprotonation of an activated
complex of the bridged cyclic amines and reaction with
an electrophile, such as an ester or a Weinreb amide,
according to a method similar to that described in
Chem. Commun., 1999, 1927-1928, or by reaction of an
organometallic compound on the ethyl ester of
2-quinuclidinic acid, according to a method similar to
that described in J. Med. Chem., 1980, 180-184, or by
oxidation of the corresponding alcohol obtained by
various methods similar to those described in J. Org.
Chem., 50, 1985, 29-31 and Chem. Comm., 1999, 1927-1929
with oxidizing agents known to persons skilled in the
art such as manganese dioxide or the oxalyl chloride-
dimethyl sulfoxide system.
The alcohols of general formula (VI) may also be
obtained by reducing the corresponding ketones of
general formula (IV) under conditions known to persons
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 persons skilled in the art.
For example, 4-amino-3-chloro-5-trifluoromethylbenzoic
acid may be prepared by chlorination of 4-amino-5-
trifluoromethylbenzoic acid with sulfuryl chloride in a
chlorinated solvent such as chloroform, according to a
method similar to that described in Arzneim. Forsch.,
34, lia, (1984), 1668-1679.
2,6-Dichloro-3-trifluoromethylbenzoic acid may be
prepared by methods similar to those described in
US 3,823,134.
The benzoic acids derived from sulfonamides may be
prepared according to methods similar to those
described in patents DE-2436263, BE-620741, DE-1158957,
US-3112337, GB-915259, US-3203987, DE-642758, EP-68700,
FR-2396757, DE-2734270, and in J. Pharm. Pharmacol.
(1962), 14, 679-685. The meta-chlorosulfonylated acids
may be obtained according to a method similar to those
described in J. Chem. Soc. (C) , (1968), 13, and in
patents US-2273444, DE-19929076, EP-0556674.
Chlorosulfonylation at the ortho or para position may
be carried out starting with a diazonium salt according
to a method similar to that described in patent
US-3663615 with 4-amino-3-chlorobenzoic acid.
The sulfonamides are obtained by the reaction of the
chlorosulfonylated derivatives in the presence of an
excess of amine in a solvent such as tetrahydrofuran,
at room temperature or under reflux.
The secondary sulfonamides may be methylated according
to a method similar to that described in patent
BE-620741. The primary sulfonamides may be reacted with
an isocyanate, in a solvent such as tetrahydrofuran, in
the presence of a base such as potassium carbonate.
Some sulfoxide derivatives of benzoic acids are
described in patents DE-2056912, DE-2901170 and
US-3953476 or may be obtained by methods similar to
those described in patent BE-872585 and in J". Org.
Chem. (1991), 56(1), 4976-4977.
The benzoic acid derivatives of general formula (III),
in which R2 represents a branched alkyl group, may be
prepared according to methods similar to that described
in patent US-4879426 and in Syn. Lett. (1996), 473-474
and J". Med. Chem. (2001), 44, 1085-1098.
The benzoic acid derivatives of the biphenyl type may
be prepared according to methods known to persons
skilled in the art. Finally, the carbonylated benzoic
acids may be synthesized according to methods similar
to those described in patents US-3725417 and GB-913100
and in Chem. Pharm. Bull., (1988), 36(9), 3462-3467 and
J. Labelled Compd. Radiopharm., (1997), 39(6), 501-508.
The esters or amides may be introduced by direct
carbonylation with a strong base at the para position
of the acid, under the conditions described in
Tetrahedron Lett., (2000), 41, 3157-3160.
Finally, the cyano derivatives of benzoic acids are
obtained by heating a halogenated benzoic acid or ester
in the presence of potassium cyanide, a catalyst of the
tetrakistriphenylphosphinepalladium type, in a solvent
of the tetrahydrofuran type, according to a method
similar to that described in J. Org. Chem. (1967) 62,
25, 8634-8639.
Other acids and acid chlorides of general formula (III)
may be obtained according to methods similar to those
described in patents EP-0556672, US-3801636 and in J.
Chem. Soc, (1927), 25, Chem. Pharm. Bull., 11992),
1789-1792, Aust. J. Chem., (1984), 1938-1950 and
J.O.C. , 1980) , 527.
The examples which follow illustrate the preparation of
a few compounds of the invention. The elemental
microanalyses, and the IR and NMR spectra, and the HPLC
on a chiral column confirm the structures and the
enantiomeric purities of the compounds obtained.
The numbers indicated in brackets in the headings of
the examples correspond to those of the 1st column of
the table given later.
In the names of the compounds, the dash "-" forms part
of the word, and the dash "_" only serves for splitting
at the end of a line; it is deleted in the absence of
splitting, and should not be replaced either by a
normal dash or by a gap.
Example 1 (compound No. 3)
threo-2-Chloro-N- [(1-azabicyclo [2 .2.2] oct-2-yl) phenyl-
methyl]-3-trifluoromethylbenzamide hydrochloride 1:1
1.1. (Z)-1-Azabicyclo[2.2.2]oct-2-yl(phenyl)methanone
O-benzyloxime hydrochloride
2.2 g (9.35 mmol) of 1-azabicyclo[2.2.2]oct-2-
yl(phenyl)methanone (Chem. Commun., 1999, 1927-1928)
and 3 g (18.69 mmol) of benzyloxyhydroxylamine
hydrochloride in 5 0 ml of pyridine are introduced into
a 10 0 ml rounC1-bottomed flask equipped with magnetic
stirring, and the mixture is heated under reflux for
20 h.
After evaporation of the solvents under reduced
pressure, the residue is diluted with water and
chloroform, the aqueous phase is separated, and it is
extracted with chloroform. After washing the combined
organic phases, drying over sodium sulfate and
evaporation of the solvent under reduced pressure, the
residue is purified by chromatography on a silica gel
column, eluting with a mixture of chloroform and
methanol.
There are obtained 0.5 g of a fraction corresponding to
(E)-1-azabicyclo[2.2.2.]oct-2-yl(phenyl)methanone
O-benzyloxime and 2.25 g of another fraction
corresponding to (Z)-1-azabicyclo [2.2.2.]oct-2-
yl(phenyl)methanone O-benzyloxime hydrochloride
m.p. 195-197°C.
1.2. threo-[1-Azabicyclo[2.2.2.]oct-2-yl(phenyl)-
methyl]amine
1.3 g (34.32 mmol) of lithium aluminum hydride in
suspension in 10 ml of tetrahydrofuran are placed in a
250 ml three-necked flask equipped with' magnetic
stirring under a nitrogen atmosphere, 2.2 g (6.16 mmol)
of (Z)-1-azabicyclo[2.2.2.]oct-2-yl(phenyl)methanone
O-benzyloxime hydrochloride are added in portions and
the mixture is heated under reflux for 2 h.
After cooling, the solution is hydrolyzed at 0°C with
successively 1.3 ml of water and then 1.3 ml of aqueous
sodium hydroxide at 15% and 3.9 ml of water. The
heterogeneous mixture is filtered on Celite®, the
filtrate is concentrated under reduced pressure and
then the residue is diluted with IN hydrochloric acid
and chloroform. The organic phase is separated and the
aqueous phase is basified with aqueous ammonia. It is
extracted twice with chloroform. After washing the
combined organic phases, drying over sodium sulfate and
evaporating the solvent under reduced pressure, 1.25 g
of threo-[1-azabicyclo[2.2.2.]oct-2-yl(phenyl)methyl]-
amine are obtained in the form of an oil which
crystallizes and which is used as it is in the next
step.
Melting point: 120-140°C.
1.3. threo-2-Chloro-.W- [ (1-azabicyclo [2 . 2 .. 2] oct-2-yl) -
phenylmethyl]-3 -1ri fluoromethylbenzamide
hydrochloride 1:1
0.51 g (2.12 mmol) of 2-chloro-3-trifluoromethylbenzoic
acid chloride in solution in 5 ml of chloroform is
placed in a 100 ml rounC1-bottomed flask equipped with
magnetic stirring, in the presence of 0.29 g
(2.12 mmol) of potassium carbonate at 0°C, and a
solution of 0.42 g (1.93 mmol) of threo-[1-azabicyclo-
[2.2.2.]oct-2-yl(phenyl)methyl]amine in solution in
5 ml of chloroform is poured in and the mixture is
stirred at room temperature for 6 h.
After hydrolyzing with water and diluting with
chloroform, the aqueous phase is separated and it is
extracted with chloroform. After washing the combined
organic phases, drying over sodium sulfate and
evaporating the solvent under reduced pressure, the
residue is purified by chromatography on a silica gel
column, eluting with a mixture of chloroform and
methanol. 0.18 g of an oily product is obtained.
The latter is dissolved in a few ml of propan-2-ol,
6 ml of a 0. IN hydrochloric acid solution in propan-2-
ol are added and the mixture is concentrated under
reduced pressure in order to reduce the volume of the
solvent. After trituration, 0.15 g of hydrochloride is
finally isolated in the form of a solid.
Melting point: 257-262°C.
Example 2 (compound No. 4)
threo-2, 6-Dichloro-iV- [ (1-azabicyclo [2.2.2] oct-2-
yl)phenylmethyl]-3 -trifluoromethylbenzamide
hydrochloride 1:1
0.36 g (1.38 mmol) of 2,6-dichlo'ro-3-trif luoromethyl-
benzoic acid, 0.187 g (1.38 mmol) of hydroxybenzo-
triazole, 0.264 g (1.38 mmol) of 1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide hydrochloride in solution
in 7 ml of chloroform are introduced into a 100 ml
rounC1-bottomed flask equipped with magnetic stirring,
and the mixture is stirred at room temperature for
3 0 min.
0.3 g (1.38 mmol) of threo-[1-azabicyclo[2.2.2.]oct-2-
yl(phenyl)methyl]amine in solution in 5 ml of
chloroform is added and the mixture is stirred at room
temperature overnight.
After hydrolyzing with water and diluting with
chloroform, the aqueous phase is separated and it is
extracted with chloroform. After washing the combined
organic phases, drying over sodium sulfate and
evaporating the solvent under reduced pressure, the
residue is purified by chromatography on a silica gel
column, eluting with a mixture of chloroform and
methanol. 0.3 7 g of an oily product is obtained.
The latter is dissolved in a few ml of propan-2-ol,
20 ml of a 0.IN hydrochloric acid solution in propan-2-
ol are added and the mixture is concentrated under
reduced pressure in order to reduce the volume of the
solvent. After trituration, 0.35 g of hydrochloride is
finally isolated in the form of a solid.
Melting point: 270-273°C.
Example 3 (compound No. 1,4)
2-Chloro-N-(8a,9S)cinchonan-9-yl)-3-trifluoromethyl-
benzamide hydrochloride 2:1
3.1. 8a:-9S-Cinchonan-9-amine
0.74 g (2.5 mmol) of 8a, 9R-cinchonan-9-ol
(cinchonidine) and 0.79 g (3 mmol) of triphenyl-
phosphine in suspension in 15 ml of tetrahydrofuran are
introduced into a 100 ml three-necked flask equipped
with magnetic stirring, under a nitrogen atmosphere,
and 3.5 ml of a 0.9 M solution of hydrazoic acid in
benzene (3 mmol) are added. A solution of 0.55 ml
(2.75 mmol) of diisopropylcarbodiimide in 1.5 ml of
tetrahydrofuran is added to this solution dropwise and
the mixture is heated at 40°C for 16 h.
0.65 g (2.5 mmol) of triphenylphosphine is added and
the mixture is stirred for 30 min, 0.5 ml of water is
added and the stirring is resumed for 6 h.
The mixture is hydrolyzed with IN hydrochloric acid and
diluted with chloroform. The aqueous phase is basified
with aqueous ammonia and it is extracted several times
with chloroform. After washing the combined organic
phases, drying over sodium sulfate and evaporating the
solvent under reduced pressure, 0.97 g of an orange-
colored oil is obtained containing 8a,9S-cinchonan-9-
amine which is used crude in the next step.
3.2. 2-Chloro-N- (8a, 9S-cinchonan-9-yl) -3-trifluorometh-
ylbenzamide hydrochloride 2:1
According to the method described in Example 1.3,
starting with 0.97 g (3.3 mmol) of 8a,9S-cinchonan-9-
amine, 0.84 g (3.4 mmol) of 2-chloro-3-trifluoromethyl-
benzoic acid chloride and 0.5 g (3.63 mmol) of
potassium carbonate, 0.3 60 g of oil is obtained which
is dissolved in 3 0 ml of IN hydrochloric acid. The
aqueous phase is extracted with chloroform and then the
solvent is evaporated under reduced pressure. 0.26 g of
hydrochloride is thus obtained in the form of a white
solid.
Melting point: 185-205°C; [a] D25 = -5.4 (c=0.986, MeOH) .
Example 4 (compound No. 17)
2,6-Dichloro-N-[(IS)-[(2S)(1-azabicyclo[2.2.2]oct-2-
yDphenylmethyl]-3-(trifluoromethyl)benzamide hydro-
chloride 1:1
4.1 (IS) - [ (2S) -l-Azabicyclo[2.2.2.]oct-2-yl (phenyl) -
methyl]amine D-tartrate
9.4 g (43.45 mmol) of threo-[1-azabicyclo[2.2.2.]oct-2-
yl(phenyl)methyl]amine are dissolved in 150 ml of
ethanol. A solution of 6.52 g (43.45 mmol) of
D-tartaric acid in solution in 200 ml of ethanol is
poured in. After evaporating the solvent under reduced
pressure, the residue is placed in 500 ml of a solution
of ethanol and of water (9/1) and then heated until
dissolution is obtained. After 3 successive
recrystallizations, 5.39 g of (IS) - [ (2S)-1-azabicyclo-
[2.2.2.]oct-2-yl(phenyl)methyl]amine D-tartrate are
obtained.
Melting point: 125-135°C.
[a]D25 = -46.1 (c = 0.616; MeOH).
4.2. 2,6-Dichloro-N- [(IS)-[(2S) (1-azabicyclo[2.2.2]oct-
2-yl)phenylmethyl]-3-(trifluoromethyl)benzamide
hydrochloride 1:1
3.33 g (12.02 mmol) of 2,6-dichloro-3-(trifluoro-
methyl) benzoic acid chloride in solution in 3 0 ml of
chloroform are placed in a 100 ml rounC1-bottomed flask
equipped with magnetic stirring in the presence of
1.82 g (13.22 mmol) of potassium carbonate at 0°C, and
a solution of 2.6 g (12.02 mmol) of (IS) - [ (2S) -1-
azabicyclo [2.2.2.] oct-2-yl (phenyl) methyl ] amine
(obtained by basification of the salt described in 4.1,
followed by extraction) in solution in 40 ml of
chloroform is poured in and the mixture is stirred at
room temperature for 6 h.
After hydrolyzing with water and diluting with
chloroform, the aqueous phase is separated and it is
extracted with chloroform. After washing the combined
organic phases, drying over sodium sulfate and
evaporating the solvent under reduced pressure, the
residue is purified by chromatography on a silica gel
column, eluting with a mixture of chloroform and
methanol.
5.4 g of an oily product are obtained.
The latter is dissolved in a few ml of chloroform,
600 ml of a solution of ether saturated with
hydrochloric acid are added, and the mixture is
concentrated under reduced pressure. The residue is
recrystallized from ethyl acetate. 4.7 g of 2,6-
dichloro-AT- [ (IS) - [ (2S) (1-azabicyclo [2 .2.2]oct-2-
yl)phenylmethyl]-3-(trifluoromethyl)benzamide
hydrochloride are thus obtained.
Melting point: 264-268°C.
[a]D25 = +61.1° (c=0.32; MeOH)
Example 5 (compound No. 26)
threo-N- [1-Azabicyclo[2.2.2]oct-2-yl(4-fiuorophenyl)-
methyl]-2,6-dichloro-3-(trifluoromethyl)benzamide
hydrochloride 1:1
5.1 1-Azabicyclo[2.2.2]oct-2-yl(4-fIuorophenyl)-
methanol
1.11 g (10 mmol) of quinuclidine in 4 0 ml of dry
tetrahydrofuran at 0°C are placed in a 100 ml three-
necked flask under argon. 1.33 ml (10.5 mmol) of ether-
boron trifluoride complex are added dropwise and the
mixture is stirred for 30 min at 0°C (solution A) . In
parallel, 2.47 g (22 mmol) of dry potassium tert-
butoxide in 60 ml of dry tetrahydrofuran are placed in
a 2 50 ml three-necked flask under argon. The mixture is
cooled to -70°C and 22 ml of a 1M solution of sec-
butyl lithium in the cyclohexane/hexane mixture
(22 mmol) are poured in dropwise while izhe temperature
is kept below -60°C (solution B) . At the end of the
addition, the solution A is delivered by a cannula-like
tube into the solution B while the temperature ;_s kept
at around -70°C. The mixture is kept stirring for 2 h.
2.36 mol (22 mmol) of distilled 4-fluorobenzaldehyde in
solution in 20 ml of tetrahydrofuran at -70°C are
placed in a 50 ml three-necked flask under argon. The
solution B is delivered by a cannula-like tube while
the temperature is kept at around -70°C. The resulting
solution is left for 30 min at -70°C and allowed to
rise to -20°C. The mixture is then hydrolyzed with a
10% hydrochloric acid solution. The mixture is
extracted with ether and then the aqueous phase is
taken up and basified with aqueous ammonia. The mixture
is extracted with chloroform and then the solvent is
evaporated under reduced pressure. The residue is
purified by flash chromatography on a silica gel
column, eluting with a mixture of chloroform and
methanol. 0.53 g of 1-azabicyclo[2.2.2]oct-2-yl(4-
fluorophenyl)methanol is thus obtained in the form of a
yellowish solid.
Melting point: 69-70°C.
5.2 1-Azabicyclo[2.2.2]oct-2-yl(4-fluorophenyl)meth-
anone
1.3 ml of dimethyl sulfoxide in 40 ml of
tetrahydrofuran at -70°C are placed in a 250 ml three-
necked flask under nitrogen, and 0.9 ml of oxalyl
chloride (11 mmol) is added dropwise and the mixture is
kept stirring for 30 min at this temperature. A
solution of 1 g (4.6 mmol) of 1-azabicyclo[2.2.2]oct-2-
yl(4-fluorophenyl)methanol in 40 ml of tetrahydrofuran
is added dropwise. After 30 min, 4 ml (27.6 mmol) of
triethylamine are added at -70°C. The reaction mixture
is then stirred for 30 min at -70°C, for 30 min at 0°C
and then for 1 h at room temperature.
The mixture is poured into an aqueous ammonia solution
and then extracted several times with chloroform. The
organic phases are dried over sodium sulfate and
evaporated under reduced pressure. The residue is
purified by chromatography on a silica gel column,
eluting with a mixture of chloroform and methanol. 1 g
of 1-azabicyclo[2.2.2]oct-2-yl(4-fluorophenyl)methanone
is thus obtained.
Melting point: 68-69°C.
5.3 (Z)-1-Azabicyclo[2.2.2]octyl(4-fluorophenyl)meth-
anone O-benzyloxime hydrochloride
According to the procedure described in Example 1.1,
starting with 1.17 g (5 mmol) of ketone, 1.4 g of (Z) -
1-azabicyclo[2.2.2]octyl(4-fluorophenyl)methanone O-
benzyloxime hydrochloride are obtained after
trituration, in ether, of the residue obtained after
the treatment of the reaction.
Melting point: 202-203°C.
5.4 threo-1-Azabicyclo[2.2.2]octyl(4-fluorophenyl)-
methanamine
According to the procedure described in 1.2, starting
with 1.47 g (4.54 mmol) of (Z)-1-azabicyclo[2.2.2]oct-
yl (4-fluorophenyl)methanone O-benzyloxime hydro-
chloride, 1 g of threo-1-azabicyclo[2.2.2]octyl(4-
fluorophenyl)methanamine (diastereoisomeric excess,
de=90%) .
5.5 N- [ (S) - (2S) -l-Azabicyclo[2.2.2]oct-2-yl (4-fluoro-
phenyl) methyl] -2,6-dichloro-3-
(trifluoromethyl)benzamide hydrochloride 1:1
According to the procedure described in 1.3, starting
with 0.39 g (1.66 mmol) of threo-1-azabicyclo-
[2.2.2]octyl(4-fluorophenyl)methanamine, 0.5 g
(1.83 mmol) of 2,6-dichloro-3-trifluoromethylbenzoic
acid chloride, 0.25 g (1.83 mmol) of potassium
carbonate, 0.79 g of threo-N-[1-azabicyclo [2 . 2 . 2] oct-2-
yl(4-fluorophenyl)methyl]-2,6-dichloro-3-(trifluoro-
methyl)benzamide is obtained, after purification by
chromatography, in the form of an oil which is salified
with a solution of gaseous hydrochloric acid in ethyl
ether.
Melting point: 290-291°C.
The other compounds are obtained according to the
methods described in Examples 1, 2 and 5 from other
functionalized aldehydes.
The following Table 1 illustrates the chemical
structures of a few compounds of the invention.
In the "R" column, -CH=CH2 denotes a vinyl group, in the
"Ri" column, C6H5 denotes a phenyl group and 4-C9H6N
denotes a quinolin-4-yl group. In the "Salt" column, -
denotes a compound in the base state, "HCl" denotes a
hydrochloride and "tfa" denotes a trifluoroacetate.
The compounds 14, 19 to 23, 24 of the table exist in
the hydrochloride or dihydrochloride form (see table)
solvated with one or more water molecules.
The compounds 15 and 16 of the table form a pair of
enantiomers which are separated by preparative HPLC
using a 2 0 µm CHIRACEL® AD column and, as solvent, a
95/5 isohexane/propan-2-cl mixture, likewise for the
compounds 17 and 18.
Table 2 gives the physical properties, the melting
points and optical rotations of the compounds of the
table. "(d)" indicates a melting point with
decomposition.
The compounds of the invention were subjected to a
series of pharmacological trials which demonstrated
their importance as substances with therapeutic
activity.
Study of the transport of glycine in SK-N-MC cells
expressing the native human transporter glytl.
The capture of [14C] glycine is studied in SK-N-MC cells
(human neuroepithelial cells) expressing the native
human transporter glytl by measuring the radioactivity
incorporated in the presence or in the absence of the
test compound. The cells are cultured in a monolayer
for 48 h in plates pretreated with fibronectin at
0.02%. On the day of the experiment, the culture medium
is removed and the cells are washed with a Krebs-HEPES
([4-(2-hydroxyethyl)piperiazine]1-ethanesulfonic acid)
buffer at pH 7.4. After a preincubation of 10 min at
37°C in the presence either of buffer (control batch),
or of test compound at various concentrations, or of 10
mM glycine (determination of the nonspecific capture),
10 µM [14C] glycine (specific activity 112 mCi/mmol) are
then added. The incubation is continued for 10 min at
37°C, and the reaction is stopped by 2 washes with a
Krebs-HEPES buffer at pH 7.4. The radioactivity
incorporated by the cells is then estimated after
adding 100 µl of liquid scintillant and stirring for
1 h. The counting is performed on a Microbeta Tri-lux™
counter. The efficacy oZ the compound is determined by
the IC50, the concentration of the compound which
reduces by 50% the specific capture of glycine, defined
by the difference in radioactivity incorporated by the
control batch and the batch which received the glycine
at 10 mM.
The most active compounds of the invention, in this
test, have an IC50 of the order of 0.001 to 10 µM.
The individual results for some compounds are as
follows (IC50 in µM) :
Compound No. 3 0.017
Compound No. 4 0.0 04
Compound No. 14 0.07
Compound No. 17 0.001
Compound No. 2 6 0.07
Study ex vivo of the inhibitory activity of a compound
on the capture of [14C] glycine in mouse cortical
homogenate
Increasing doses of the compound to be studied are
administered by the oral route (preparation by
trituration of the test molecule in a mortar in a
solution of Tween/Methocel™ at 0.5% in distilled water)
or by the intraperitoneal route (dissolution of the
test molecule in physiological saline or preparation by
trituration in a mortar in a solution of
Tween/Methocel™ at 0.5% in water, according to the
solubility of the molecule) to 20 to 25 g Iffa Credo
OF1 male mice on the day of the experiment. The control
group is treated with the vehicle. The doses in mg/kg,
the route of administration and the treatment time are
determined according to the molecule to be studied.
After the animals have been humanely killed by
decapitation at a given time after the administration,
the cortex of each animal is rapidly removed on ice,
weighed and stored at 4°C or frozen at -80°C (in both
cases, the samples are stored for a maximum of 1 day) .
Each sample is homogenized in a Krebs-HEPES buffer at
pH 7.4 at a rate of 10 ml/g of tissue. 20 µ1 of each
homogenate are incubated for 10 min at room temperature
in the presence of 10 mM L-alanine and buffer. The
nonspecific capture is determined by adding 10 mM
glycine to the control group. The reaction is stopped
by filtration under vacuum and the retained
radioactivity is estimated by solid scintillation by
counting on a Microbeta Tri-lux™ counter.
An inhibitor of the capture of [14C] glycine will reduce
the quantity of radioligand incorporated into each
homogenate. The activity of the compound is evaluated
by its EDSO, the dose which inhibits by 50% the capture
of [14C] glycine compared with the control group.
The most potent compounds of the invention, in this
test, have an ED50 of 0.1 to 5 mg/kg by the
intraperitoneal route or by the oral route.
Study of the transport of glycine in mouse spinal cord
homogenate
The capture of [14C] glycine by the transporter glyt2 is
studied in mouse spinal cord homogenate by measuring
the radioactivity incorporated in the presence or in
the absence of the compound to be studied.
After the animals have been humanely killed (Iffa Credo
OF1 male mice weighing 2 0 to 2 5 g on the day of the
experiment) , the spinal cord of each animal is rapidly
removed, weighed and stored on ice. The samples are
homogenized in a Krebs-HEPES ([4-(2-
hydroxyethyl)piperazine]1-ethanesulfonic acid) buffer,
pH 7.4, at a rate of 25 ml/g of tissue.
50 µl of homogenate are preincubated for 10 min at 25°C
in the presence of Krebs-HEPES buffer, pH 7.4 and of
compound to be studied at various concentrations, or of
10 mM glycine in order to determine the nonspecific
capture. The [14C] glycine (specific activity = 112
mCi/mmol) is then added for 10 min at 25°C at the final
concentration of 10 µM. The reaction is stopped by
filtration under vacuum and the radioactivity is
estimated by solid scintillation by counting on a
Microbeta Tri-lux™ counter.
The efficacy of the compound is determined by the
concentration IC50 capable of reducing by 50% the
specific capture of glycine, defined by the difference
in radioactivity incorporated by the control batch and
the batch which received the 10 mM glycine.
The most active compounds of the invention in this test
have an IC50 of the order of 0.02 to 10 µM.
The IC50 of the compound No. 17 is 0.69 µM.
The results of the trials carried out on the compounds
of the invention of general formula (I) show that they
are inhibitors of the glycine transporters glytl which
are predominantly present in the brain, and of the
glycine transporters glyt2, which are predominantly
present in the spinal cord.
The compounds according to the invention can therefore
be used for the preparation of medicaments, in
particular of medicaments inhibiting the glycine
transporters glytl and/or glyt2.
Thus, according to another of its aspects, the subject
of the invention is medicaments which comprise a
compound of formula (I) , or an additional salt thereof
with a pharmaceutically acceptable acid, or a hydrate
or a solvate of the compound of the formula (I).
The compounds of the invention may be used in
particular for the treatment of behavioral disorders
associated with dementia, psychoses, in particular
schizophrenia (deficient form and productive form) and
acute or chronic extrapyramidal symptoms induced by
neuroleptics, for the treatment of various forms of
anxiety, panic attacks, phobias, obsessive-compulsive
disorders, for the treatment of various forms of
depression, including psychotic depression, for the
treatment of disorders due to alcohol abuse or to
withdrawal from alcohol, sexual behavior disorders,
food intake disorders, and for the treatment of
migraine.
Moreover, the compounds of the invention may be used
for the treatment of painful muscular contractures in
rheumatology and in acute spinal pathology, for the
treatment of spastic contractures of medullary or
cerebral origin, for the symptomatic treatment of acute
and subacute pain of mild to moderate intensity, for
the treatment of intense and/or chronic pain, of
neurogenic pain and rebellious algia, for the treatment
of Parkinson's disease and of Parkinsonian symptoms of
neurodegenerative origin or induced by neuroleptics,
for the treatment of primary and secondary generalized
epilepsy, partial epilepsy with a simple or complex
symptomatology, mixed forms and other epileptic
syndromes as a supplement to another antiepileptic
treatment, or in monotherapy, for the treatment of
sleep apnea, and for neuroprotection.
The subject of the present invention is also
pharmaceutical compositions containing an effective
dose of at least one compound according to the
invention, in the form of a pharmaceutically acceptable
base or salt or solvate, and in the form of a mixture,
where appropriate, with one or more suitable
excipients.
Said excipients are chosen according to the
pharmaceutical dosage form and the desired mode of
administration.
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 forms for administration may be, for example,
tablets, gelatin capsules, granules, powders, oral or
injectable solutions or suspensions, patches or
suppositories. For topical administration, it is
possible to envisage ointments, lotions and collyria.
By way of example, a unit form for administration of a
compound according to the invention in tablet form may
comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Croscarmellose sodium 6.0 mg
Corn starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
Said unit forms contain doses in order to allow a daily
administration of 0.01 to 20 mg of active ingredient
per kg of body weight, according to the galenic form.
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 for each patient is
determined by the doctor according to the mode of
administration, the weight and the response of said
patient.
The present invention, according to its other 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 one of its pharmaceutically
acceptable salts or the hydrates or solvates.
WE CLAIM:
1. N-heterocycIyl-methylbenzamide derivative compounds corresponding to general
formula (1)
in which
R represents a hydrogen atom or a vinyl group;
n represents 1 ;
X represents a group of formula CH or a nitrogen atom when R represents a hydrogen
atom and X represents a group of formula CH when R represents a vinyl group;
Rj represents either a phenyl or naphthyl group optionally substituted with one or more
substituents chosen from halogen atoms, linear or branched (C1-C6)alkyl, hydroxyl and
(C1-C6)alkoxy groups, or a cyclohexyl group, or a heteroaryl group chosen from the
thienyl,quinolinyl, and isoquinolinyl groups;
R2 represents either a hydrogen atom, or one or more substituents chosen from halogen
atoms and the trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy, phenyloxy, hydroxyl, or a
group of general formula -NR4R5, SO2NR4R5, or a group of formula -OCF20- attached at
the 2- and 3-positions of the phenyl group;
R1 and R5 represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl
group;
in the form of a free base or of an addition salt with an acid, of a hydrate or of a solvate.
2. Compound as claimed in Claim 1, wherein said compound is of the threo
configuration.
3. Compound as claimed in Claim 2, wherein X represents a group of formula CH.
4. Compound as claimed in Claim 3, wherein R represents a hydrogen atom.
5. Compound as claimed in Claim 4, wherein R1 represents an optionally substituted
phenyl group.
6. Compound as claimed in Claim 1, wherein it is selected from the following
compounds:
threo-2-chloro-N-[(1-azabicyclo[2.2.2]oct-2-yl)phenyImethyl]-3-
trifluoromethylbenzam ide;
threo-2-chloro-N-[(l-azabicyclo[2.2.2]oct-2-yl)phenylmethyl]-3-
trifluoromethylbenzamide hydrochloride;
threo-2,6-dichloro-N-[(l-azabicyclo[2.2.2]oct-2-yl)phenylmethyl]-3-
trifluoromethylbenzamide;
threo-2,6-dichloro-N-[(l-azabicyclo[2.2.2]oct-2-yl)phenylmethyl]-3-
trifluoromethylbenzamide hydrochloride;
2-chloro-N-(8a,9S-cinchonan-9-yl)-3-trifluoromethylbenzamide;
2-chloro-N-(8a,95'-cinchonan-9-yl)-3-trifluoromethylbenzamide hydrochloride;
2,6-dichloro-N-[(1S)-[(25)(l-azabicyclo[2.2.2]oct-2-yl)phenylmethyl]-3-
(trifluoromethyl)benzamide;
2,6-dichloro-N-[(15)-[(25)(l-azabicyclo[2.2.2]oct-2-yl)phenylmethyl]-3-
(trifluoromethyl)benzamide hydrochloride;
threo-iV-[l-azabicyclo[2.2.2]oct-2-yl(4-fluorophenyl)methyl]-2,6-dichloro-3-
(trifluoromethyl)benzamide;
threo-iV-[l-azabicyclo[2.2.2]oct-2-yl(4-fluorophenyl)methyl]-2,6-dichloro-3-
(tri fluorom ethy l)benzam ide hydroch 1 oride.
7. Medicament, comprising a compound as claimed in any one of Claims 1 to 6.
8. Pharmaceutical composition, comprising a compound as claimed in any one of
Claims 1 to 6, and at least one pharmaceutically acceptable excipient.
9. A compound of formula (I) as claimed in any one of Claims 1 to 6 for the
preparation of a medicament capable of being used for the treatment of behavioural
disorders associated with dementia, of psychoses, of various forms of anxiety, panic
attacks, phobias, obsessive-compulsive disorders, of various forms of depression, of
disorders due to alcohol abuse or to withdrawal from alcohol, sexual behaviour disorders,
food intake disorders, and of migraine.
10. A compound of formula (I) as claimed in any one of Claims 1 to 6, for the
preparation of a medicament capable of being used for the treatment of contractures, of
pain, of Parkinson's disease and of Parkinsonian symptoms, of epilepsy, of mixed forms
and other epileptic syndromes as a supplement to another antiepileptic treatment, or in
monotherapy, of sleep apnea, and for neuroprotection.

The invention relates to a compound having
general formula (I), wherein: R represents a hydrogen
atom or a vinyl group; n represents 0,1 or 2; X represents a
groups having formula CH or a nitrogen atom; R1 represents
a phenyl or naphthyl group, or a cyclohexyl group, or a
heteroaryl group; R2 represents a hydrogen atom, or one
or more substituents selected from among the halogen
atoms and the trifluoromethyl, alkyl, alkoxy, thienyl,
phenyloxy, hydroxy, mercapto, thioalkyl, cyano groups
or a group having general formula -NR4R5, SO2NR4R5,
-SO2-alkyl, -SO2-phenyl, -CONR4R5, -COOR7, -CO-alkyl,
-CO-phenyl, -NHCOR8, -NHSO2-alkyl, -NHSO2-phenyl
and -NHSO2NR4R5 or a divalent group having formula
-OCF2O-; and R4 and R5 each represent a hydrogen atom or
an alkyl group or R4 and R5, together with the nitrogen atom
bearing same, form a pyrrolidine, piperidine or morpholine
ring. Compounds having formula (I) have a unique activity as specific inhibitors of glyt1 and/or glyt2 transporters.

Documents:

00925-kolnp-2006 abstract.pdf

00925-kolnp-2006 assignment.pdf

00925-kolnp-2006 claims.pdf

00925-kolnp-2006 correspondence others.pdf

00925-kolnp-2006 form-1.pdf

00925-kolnp-2006 form-3.pdf

00925-kolnp-2006 form-5.pdf

00925-kolnp-2006 international publication.pdf

00925-kolnp-2006 international search authority report.pdf

00925-kolnp-2006-description complete.pdf

925-kolnp-2006-abstract.pdf

925-kolnp-2006-claims.pdf

925-kolnp-2006-description (complete).pdf

925-kolnp-2006-form 1.pdf

925-kolnp-2006-form 13.pdf

925-kolnp-2006-form 3.pdf

925-KOLNP-2006-FORM-27.pdf

925-kolnp-2006-granted-abstract.pdf

925-kolnp-2006-granted-assignment.pdf

925-kolnp-2006-granted-claims.pdf

925-kolnp-2006-granted-correspondence.pdf

925-kolnp-2006-granted-description (complete).pdf

925-kolnp-2006-granted-examination report.pdf

925-kolnp-2006-granted-form 1.pdf

925-kolnp-2006-granted-form 13.pdf

925-kolnp-2006-granted-form 18.pdf

925-kolnp-2006-granted-form 3.pdf

925-kolnp-2006-granted-form 5.pdf

925-kolnp-2006-granted-gpa.pdf

925-kolnp-2006-granted-petition under rule 137.pdf

925-kolnp-2006-granted-reply to examination report.pdf

925-kolnp-2006-granted-specification.pdf

925-kolnp-2006-petition under rule 137.pdf

925-kolnp-2006-reply to examination report.pdf

925-kolnp-2006-specification.pdf

abstract-00925-kolnp-2006.jpg


Patent Number 240989
Indian Patent Application Number 925/KOLNP/2006
PG Journal Number 25/2010
Publication Date 18-Jun-2010
Grant Date 14-Jun-2010
Date of Filing 13-Apr-2006
Name of Patentee SANOFI-AVENTIS
Applicant Address 174, AVENUE DE FRANCE F-75013 PARIS
Inventors:
# Inventor's Name Inventor's Address
1 DARGAZANLI GIHAD 47, BOULEVARD DE LA VANNE, F-94230 CACHAN
2 MAGAT PASCALE 34, AVENUE MAZARIN, F-91380 CHILLY MAZARIN
3 MARABOUT BENOIT 45, BIS, RUE DE VERSAILLES, F-91300 MASSY
4 ROGER PIERRE 6, RUE PAUL VALERY, F-78180, MONTIGNY LE BRETONNEUX
5 ESTENNE-BOUHTOU GENEVIEVE 18, RUE DES JARDINS, F-94550 CHEVILLY-LARUE
PCT International Classification Number C07C229/22; C07C229/26
PCT International Application Number PCT/FR2004/002643
PCT International Filing date 2004-10-15
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0312165 2003-10-17 France