Title of Invention

DERIVATIVES OF N-[PHENYL (PYROLIDINE-2-YL) METHYL ] BENZAMIDE AND N-[ ( AZEPAN-2-YL ) PHENYLMETHYL ] BENZAMIDE, PREPARATION METHOD THEREOF AND APPLICATION OF SAME IN THERAPEUTICS

Abstract The invention relates to compounds having genera] formula (I), wherein: n represents the number 1 or 3; R2 represents either H or a cycloalkyl, cycloalkylalky), phenylalkyl, alkenyl, alkynyl group; X represents either H or one or more substituents selected from among halogen atoms and the trifluoromethyl, alkyl and alkoxy groups; and R2 represents H, or one or more substituents selected from among the halogen atoms and the trifluoromethyl, alkyl, alkoxy, cycloalkyl, phenyl, cyano. acetyl, benzoyl, S-alkyl. alkyl-sulfonyl, carboxy and alkoxycar-bonyl groups, or a group having formula NR3R4 SO2NR3R4 or CONR3R4, in which R3 and R4) each represent H or an alkyl or cycloalkyl group or. together with the nitrogen atom, form a pyrrolidine, piperidine or morpholine ring. The invention also relates to the use of said compounds in therapeutics.
Full Text DERIVATIVES OF N-[PHENYL ( PYRR0LIDINE-2-YL) METHYL ]BENZAMIDE AND N-[(AZEPAN-
2-YL)PHENYLMETHYL]BENZAMIDE,PREPARATION METHOD THEREOF AND APPLICATION OF
5 The present invention relates to compounds SAME IN
THERAPEUTICS
corresponding to the general formula (I)
in which
n represents the number 1 or 3,
Ri represents either a hydrogen atom, a linear or
branched (C1-C7)alkyl group optionally substituted with
one or more fluorine atoms, a (C3-C7) cycloalkyl group, a
(C3-C7) eyeloalkyl (C1-C3) alky 1 group, a phenyl (C1-C3) alky 1
group optionally substituted with one or two methoxy
groups, a (C2-C4) alkenyl group, or a (C2-C4) alkynyl
group,
X represents either a hydrogen atom or one or more
substituents chosen from halogen atoms and trifluoro-
methyl and linear or branched (C1-C6)alkyl and
(C1-C6) alkoxy groups,
R2 represents either a hydrogen atom or one or more
substituents chosen from halogen atoms and trifluoro-
methyl, linear or branched (C1-C6)alkyl and (C1-C6)-
alkoxy, (C3-C7)cycloalkyl, phenyl, cyano, acetyl,
benzoyl, S (C1-C6) alkyl, (C1-C6) alkylsulfonyl, carboxyl
and (C1-C6) alkoxycarbonyl groups, or a group of general
formula NR3R4, SO2NR3R4 or CONR3R4, in which R3 and R4
represent, independently of each other, a hydrogen atom
or a linear or branched (C1-C6) alkyl or (C3-C7) cyclo-
alkyl group, or form, with the nitrogen atom that bears
them, a pyrrolidine, piperidine or morpholine ring.
The compounds of general formula (I) may exist in the
form of threo(lJ?,2i?; 1S,2S) or erythro (IS, 2J?; 1R,2S)
racemates or in the form of enantiomers; they may exist
in the form of free bases or of acid-addition salts.
Compounds of structure similar to that of the compounds
of the invention are described in patent US 5 254 569
as analgesics, diuretics, anticonvulsivants,
anesthetics, sedatives and cerebroprotective agents,
via a mechanism of action on the opiate receptors. The
compounds of the invention show particular activity as
specific inhibitors of the glycine transporters glytl
and/or gli£t2. ^
The compounds of general formula (I) in which Ri is
other than a hydrogen atom may be prepared via a
process illustrated by scheme 1 below.
Scheme 1
Coupling of a diamine of general formula (II) of threo
or erythro relative configuration or as a mixture, in
which Ri and X are as defined above (with Ri other than
a hydrogen atom) is performed with an activated acid or
an acid chloride of general formula (III) in which Y
represents an electrophilic group, such as a halogen
atom, and R2 is as defined above, using the methods
known to those skilled in the art.
The pure erythro or threo compounds of general formula
(I) may be obtained according to any method known to
those skilled in the art, for example by separation by
high-performance liquid chromatography.
For n=l with Rx other than a hydrogen atom and X as
defined above, the diamine of general formula (II), of
threo or erythro relative configuration or as a
mixture, may be prepared via the process illustrated by
scheme 2 route A.
The ketone IV in which P represents Boc may be reduced
to the erythro/threo alcohol (X) , the ratio of which
depends on the nature of the hydride used, according to
a method described in J.Chem. Soc. Chem. Cormnun. , 1986,
412-413. The protecting group is then removed according
to a standard method, in a mixture of dichloromethane
and trifluoroacetic acid. The amino alcohol (XI) is
thus obtained, on which an W-alkylation is then
performed using a halogenated derivative of formula RiZ
and a base such as potassium carbonate to give the
functionalized amino alcohol of general formula (XII).
Finally, under standard Mitsunobu conditions, according
to a method described in Bull. Soc. Chim. Belg. (106),
1997, 77-84 in the presence of hydrazoic acid and
triphenylphosphine, the diamine of general formula (II)

For n=l with Ri=CH3 and X as defined above, the diamine
of general formula (II), of threo or erythro relative
configuration or as a mixture, may also be obtained
according to routes B and B' of scheme 2 and according
to scheme 3.
According to route B, the ketone (IV) in which X is as
defined above is reacted with benzylhydroxylamine
hydrochloride in refluxing pyridine to give a mixture
of oxime (V) that is deprotected with trifluoroacetic

acid to obtain the free amine (VI).
Methylation of the pyrrolidine is performed conven-
tionally in refluxing formaldehyde and formic acid to
generate the compound (VII). Finally, hydrogenation of
this compound, catalyzed with palladium-on-charcoal, in
an alcoholic solvent in the presence of aqueous hydro-
chloric acid leads to the diamine of general
formula (II).
According to route B' , the ketone of general formula
(IV) in which P represents C02Et and X is as defined
cibove is reacted with benzylhydroxylamine hydrochloride
in refluxing ethanol to give a mixture of oximes
(VIII), on which is performed a hydrogenation catalyzed
with palladium-on-charcoal in an alcoholic solvent in
the presence of aqueous hydrochloric acid, to give the
carbamate (IX). Reduction of the carbamate of general
formula (IX) with lithiiam aluminum hydride in a
refluxing solvent such as ether gives the diamine of
general formula (II).
According to scheme 3, the amino alcohol (XIII) is
converted into the azide (XIV) under the standard
Mitsunobu conditions, according to a method described
in J.Org. Chem., (64), 1999, 6106-6111. Reduction of
the azide carbamate (XIV) with lithium aluminum hydride
in a refluxing solvent such as tetrahydrofuran gives a
mixture of diamines of general formula (II).
Scheme 3

The diamine of general formula (II) of threo or erythro
relative configuration in which R1 is other than a
hydrogen atom and n = 3 may be prepared via a process
illustrated by scheme 4 below.
Scheme 4
a-Lithiation of the azepane of general formula (XVI) in
which Boo represents a 1,1-dimethylethoxycarbonyl
group, is performed with sec-butyllithium in the
presence of TMEDA (JSr,i\r, W,W-tetramethyl ethyl ene-
diamine) in an ether solvent such as diethyl ether at
-78°C, to react the lithioamine formed in situ with the
benzaldehyde of general formula (XVII) according to a
method described in J.Org. Chem., (58), 5, 1993, 1109-
1117. A mixture of alcohol of general formula (XVIII)
of erythro configuration and of cyclic carbamate of
general formula (XIX) of threo configuration may thus
be obtained.
The carbamate of general formula (XVIII) of erythro
configuration may then be reduced to the erythro
W-methylamino alcohol of general formula (XXII) via the
action of a mixed hydride such as lithium aluminum
hydride, in an ether solvent such as tetrahydrofuran,
between room temperature and the reflux temperature.
The erythro alcohol of general formula (XXII) is then
converted into the erythro intermediate of general
formula (II) in which Ri represents a methyl group, in
two steps: the alcohol function is first converted into
an electrophilic group, for example a methanesulfonate
group, via the action of mesyl chloride, in a
chlorinated solvent such as dichloromethane, and in the
presence of a base such as triethylamine, between 0°C
and room temperature, and the electrophilic group is
then reacted with liquefied ammonia at -50°C, in an
alcohol such as ethanol, in a closed medium such as an
autoclave, between -50°C and room temperature.
The carbamate of general formula (XVIII) of erythro
configuration may also be deprotected using a strong
base such as aqueous potassium hydroxide, in an alcohol
such as methanol, to obtain the corresponding amino
alcohol of general formula (XX). Under the same
hydrolysis conditions, the threo cyclic carbamate of
general formula (XIX) gives the threo amino alcohol of
general formula (XX).
An W-alkylation is then performed using a halogenated
derivative of formula RiZ, in which Ri is as defined
above, but other than a hydrogen atom, and Z represents
a halogen atom, in the presence of a base such as
potassium carbonate, in a polar solvent such as
W, W-dimethylformamide, between room temperature and
100°C, to give the alkylated derivative of general
formula (XXI). This derivative is then treated as
described with respect to the alcohol of general
formula (XXII),
The compounds of general formula (I) in which Ri
represents a hydrogen atom may be prepared from a
compound of general formula (I) in which Ri represents
either an optionally substituted phenylmethyl group,
and in deprotecting the nitrogen of the piperidine
ring, for example with an oxidizing agent or with a
Lewis acid such as boron tribromide or via
hydrogenolysis, or an alkenyl group, preferably allyl,
followed by deprotection with a Pd° complex to give a
compound of general formula (I) in which Ri represents
a hydrogen atom.
Moreover, the chiral compounds of general formula (I)
may also be obtained either by separating the racemic
compounds by high-performance liquid chromatography
(HLPC) on a chiral column, or by starting with the
chiral amine obtained either by resolving the racemic
amine of general formula (II) by using a chiral acid,
such as tartaric acid, camphorsulfonic acid, dibenzoyl-
tartaric acid or 2^-acetyl leucine, by fractional and
preferential recarystallization of a diastereoisomeric
salt in a solvent of alcohol type, or via chiral
synthesis according to route B' or A starting with the
chiral ketone of general formula (IV) of scheme 2, or
alternatively starting with the chiral alcohol of
general formula (XIII) of scheme 3.
The racemic ketone of general formula (IV) may be
prepared according to a method described in Tetrahedron
Lett., (38) (5), 1997, 783-786; Tetrahedron, (59),
2003, 1083-1094. In the chiral series, the ketone of
general formula (IV) or the chiral alcohols of general
formulae (X) and (XIII) may be prepared according to a
method described in international patent application
WO 03/004 468 and in J.Chem.Soc. Perkins Trans I, 1987,
1465-1471. The perhydroazepine of general formula (XVI)
may be prepared according to a method described in
J.Org. Chem., (58), 5, 1993, 1109-1117.
The examples that follow illustrate the preparation of
a number of 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 parentheses in the titles of
the examples correspond to those in the first column of
the table given later.
In the compound names, the hyphen "-" forms part of the
word, and the underscore mark "_" serves merely to
indicate the line break; it should be omitted if a line
break does not occur at that point, and should not be
replaced either with a normal hyphen or with a space.
Example 1 (Compound 1)
Threo-2-chloro-i\r- [ (1-methyl-2-pyrrol idinyl) phenyl-
methyl]-3-trifluoromethylbenzamide hydrochloride 1:1
1.1. tert-Butyl 2-[[(benzyloxy)imino](phenyl)methyl]-
1-pyrrolidinecarboxylate
8.8 g (31.36 mmol) of tejrt-butyl 2-benzoylpyrrolidine-
1-carboxylate and 5.6 g (35.15 mmol) of benzylhydroxyl-
amine hydrochloride dissolved in 100 ml of absolute
ethanol and 35 ml of IM sodium hydroxide are introduced

into a 1000 ml round-bottomed flask equipped with a
magnetic stirrer, and the mixture is refluxed for
16 hours.
After evaporating the reaction medium to dryness under
reduced pressure, the residue is diluted with water and
dichloromethane, and the aqueous phase is separated out
and extracted with dichloromethane. After washing the
combined organic phases, drying over sodium sulfate and
evaporating off the solvent under reduced pressure, the
residue is purified by column chromatography on silica
gel, eluting with a mixture of ethyl acetate and cyclo-
hexane.
8 grams of product are thus obtained in the form of an
oil.
1.2. Phenyl(2-pyrrolidinyl)methanone 0-benzyloxime
8 g (20 mmol) of tert-butyl 2-[[(benzoyloxy)imino]-
(phenyl)methyl]-1-pyrrolidinecarboxylate dissolved in
400 ml of a mixture of 30% trif luoroacetic acid in
dichloromethane are introduced into a 500 ml round-
bottomed flask equipped with a magnetic stirrer, and
the mixture is stirred for 4 hours at room temperature.
After evaporating the reaction medium to dryness under
reduced pressure, the residue is diluted with aqueous
ammonia and dichloromethane, and the aqueous phase is
separated out and extracted with dichloromethane. After
washing the combined organic phases, drying over sodium
sulfate and evaporating the solvent under reduced
pressure, the residue is purified by column chroma-
tography on silica gel, eluting with a mixture of
dichloromethane and methanol.
4 g of product are obtained.
1.3. (1-Methyl-2-pyrrolidinyl)(phenyl)methanone
0-benzyloxime
1.2 g (4.28 mmol) of phenyl(2-pyrrolidinyl)methanone

0-benzyloxime in 4 ml of a mixture (l/l) of formic acid
and aqueous 37% formaldehyde are introduced into a
50 ml round-bottomed flask equipped with a magnetic
stirrer, and the mixture is refluxed for 16 hours.
After evaporating the reaction medium to dryness under
reduced pressure, the residue is diluted with aqueous
ammonia and dichloromethane, and the aqueous phase is
separated out and extracted with dichloromethane. After
washing the combined organic phases, drying over sodium
sulfate and evaporating off the solvent under reduced
pressure, the residue is purified by column chroma-
tography on silica gel, eluting with a mixture of
dichloromethane and methanol.
1.05 g of product are obtained.
1.4. [(1-Methyl-2-pyrrolidinyl)phenyl)methylamine
1.05 g (3.56 mmol) of (1-methyl-2-pyrrolidinyl)-
(phenyl)methanone O-benzyloxime dissolved in a mixture
of 20 ml of ethanol and 10 ml of IN hydrochloric acid
in the presence of a spatula-tip of 10% palladium-on-
charcoal are placed in a Parr flask under a nitrogen
atmosphere. The reagents are placed under a hydrogen
atmosphere and stirred for 8 hours.
After filtering off the catalyst and evaporating the
filtrate under reduced pressure, the residue is diluted
with aqueous ammonia and dichloromethane, and the
aqueous phase is separated out and extracted with
dichloromethane. After washing the combined organic
phases, drying over sodium sulfate and evaporating off
the solvent under reduced pressure, 0.54 g of product
is thus obtained in the form of an oil, which is used
in crude form in the following step.
1.5. Threo-2-chloro-W-[(1-methyl-2-methylpyrrolidinyl)-
phenylmethyl]-3-trifluoromethylbenzamide hydro-
chloride 1:1

0.54 g (2.84 mmol) of [{l-methyl-2-pyrrolidinyl)-
phenyl)methylamine and 0.41 g of potassium carbonate
dissolved in 7 ml of dichloromethane at 0°C are placed
in a 100 ml round-bottomed flask under a nitrogen
atmosphere. A solution of 0.72 g (2.97 mmol) of
2-chloro-3-trifluoromethylbenzoyl chloride dissolved in
3 ml of dichloromethane is added and the mixture is
left for 16 hours at room temperature.
The reaction mixture is diluted with water and
dichloromethane, and the aqueous phase is separated out
and extracted with dichloromethane. After washing the
combined organic phases, drying over sodium sulfate and
evaporating off the solvent under reduced pressure, the
residue is purified by column chromatography on silica
gel, eluting with a mixture of dichloromethane and
methanol.
110 mg of threo-2-chloro-2^-[ (l-methyl-2-pyrrolidinyl)-
phenylmethyl]-3-trifluoromethylbenzamide are thus
isolated.
This product is dissolved in a few ml of 2-propanol,
6 ml of a 0.IN solution of hydrogen chloride in
2-propanol are added and the mixture is concentrated
under reduced pressure in order to reduce the volume of
the solvent. After trituration, 0.10 g of hydrochloride
is finally isolated in the form of a solid.
Melting point: 96-110°C.
Example 2 (Compound 2)
Threo-4-amino-3,5-dichloro-W- [(1-methyl-
2-pyrrolidinyl)phenylmethyl)benzamide hydrochloride 1:1
0.975 g (4.73 mmol) of 4-amino-3,5-dichlorobenzoic
acid, 0.639 g (4.73 mmol) of hydroxybenzotriazole and
0.906 g (4.73 mmol) of 1-[3-(dimethylamino)propyl]-3-
ethylcarbodiimide hydrochloride dissolved in 50 ml of
dichloromethane are introduced into a 100 ml round-

bottomed flask equipped with a magnetic stirrer. The
mixture is left at room temperature for 30 minutes,
0.9 g (4.73 mmol) of [ (l-methyl-2-pyrrolidinyl)phenyl)-
methyl]amine dissolved in 20 ml of dichloromethane is
added and the mixture is left at room temperature
overnight.
After hydrolyzing with water and diluting with
dichloromethane, the aqueous phase is separated out and
is extracted with dichloromethane. After washing the
combined organic phases, drying over sodium sulfate and
evaporating off the solvent under reduced pressure, the
residue is purified by column chromatography on silica
gel, eluting with a mixture of dichloromethane and
methanol.
0.19 g of oily product is obtained.
This product is dissolved in a few ml of 2-propanol,
20 ml of a 0.IN solution of hydrogen chloride in
2-propanol are added, and the mixture is concentrated
under reduced pressure in order to reduce the volume of
the solvent. After trituration, 0.19 g of hydrochloride
is finally isolated in the form of a solid.
Melting point: 155-162°C.
Example 3 (Compound 3)
Threo-W- [(1-allyl-2-pyrrolidinyl)phenylmethyl]-
2-chloro-3-trifluoromethylbenzamide 1:1
3.1. tert-Butyl erythro-2-[hydroxy(phenylmethyl]-
1-pyrrolidinecarboxylate
3 g (10.89 mmol) of tert-butyl 2-benzoyl-1-pyrrolidine-
carboxylat e dissolved in 110 ml of tetrahydrofuran at
-70°C are placed in a 250 ml three-necked flask
equipped with a magnetic stirrer, under a nitrogen
atmosphere. 2 9 ml (43.58 mmol) of a 1. 5M solution of
diisobutylaluminum hydride in toluene are added
dropwise. The mixture is left for 2 hours at -70°C and

the temperature is allowed to rise to -20°C. The
mixture is then hydrolyzed cautiously with 50 ml of
methanol. After evaporating the reaction mixture under
reduced pressure, the residue is diluted with IN hydro-
chloric acid and dichloromethane, and the aqueous phase
is separated out and extracted with dichloromethane.
After washing the combined organic phases, drying over
sodium sulfate and evaporating off the solvent under
reduced pressure, 2.8 g of a mixture mainly containing
the tert-butyl erythro-2-[hydroxy(phenylmethyl]-
1-pyrrolidinecarboxylate diastereoisomer are obtained,
which product is used in crude form in the following
step.
3.2. Erythro-phenyl(2-pyrrolidinyl)methanol trifluoro-
acetate
5 g (21.99 mraol) of tert-butyl erythro-2-[hydroxy-
(phenylmethyl]-1-pyrrolidinecarboxylate dissolved in a
mixture of 75 ml of dichloromethane and 30 ml of
trifluoroacetic acid are placed in a 250 ml round-
bottomed flask equipped with a magnetic stirrer, and
the mixture is stirred. It is left at room temperature
for 2 hours.
The reaction mixture is evaporated under reduced
pressure. 5 g of a mixture containing erythro-
phenyl (2 -pyrrolidinyl) methanol trifluoroacetate are
thus obtained, which product is used in crude form in
the following step.
3.3. Erythro-(l-allyl-2-pyrrolidinyl)phenyDmethanol
5 g (17.16 mmol) of erythro-phenyl(2-pyrrolidinyl)-
methanol trifluoroacetate, 5.9 g (43 mmol) of potassium
carbonate and 1.8 ml (20.6 mmol) of allyl bromide
dissolved in 50 ml of acetonitrile are placed in a
250 ml round-bottomed flask equipped with a magnetic
stirrer, and the mixture is stirred at room temperature
for 16 hours.

After evaporating the reaction medium to dryness under
reduced pressure, the residue is diluted with aqueous
ammonia and dichloromethane, and the aqueous phase is
separated out and extracted with dichloromethane. After
washing the combined organic phases, drying over sodium
sulfate and evaporating off the solvent under reduced
pressure, the residue is purified by column chroma-
tography on silica gel, eluting with a mixture of
dichloromethane and methanol.
1.1 g of a mixture containing erythro-(l-allyl-
2-pyrrolidinyl)phenyl)methanol are thus obtained.
3.4. Erythro-[(1-allyl-2-pyrrolidinyl)phenyl)methyl]-
amine.
1.1 g (5.06 mmol) of erythro-1-(allyl-2-pyrrolidinyl)-
phenyl)methanol and 1.6 g (6.07 mmol) of triphenyl-
phosphine dissolved in 15 ml of tetrahydrofuran are
introduced into a 100 ml three-necked flask equipped
with a magnetic stirrer, under a nitrogen atmosphere.
6 ml of a IM solution of hydrazoic acid in benzene
(6 mmol) are added. A solution of 1.09 ml (0.56 mmol)
of diisopropylcarbodiimide in 10 ml of tetrahydrofuran
is added dropwise to this solution. The mixture is
heated at 40°C for 16 hours, 1.3 g (5.06 mmol) of
triphenylphosphine are then added, the mixture is
stirred for 30 minutes, 0.6 ml of water is then added
and stirring is continued for 6 hours.
The resulting mixture is hydrolyzed with IN hydro-
chloric acid and diluted with chloroform. The aqueous
phase is basified with aqueous ammonia and extracted
several times with chloroform. After washing the
combined organic phases, drying over sodium sulfate and
evaporating off the solvent under reduced pressure, 1 g
of an orange-colored oil containing threo-[(l-allyl-2-
pyrrolidinyl)phenyl)methyl]amine is obtained, which
product is used in crude form in the following step.

3.5. Threo-JvT- [ (1-allyl-2-pyrrolidinyl) phenylmethyl] -
2-chloro-3-trifluoromethylbenzamide
According to the procedure described in Example 1.5,
starting with 1 g (4.62 mmol) of threo-[(1-allyl-
2-pyrrolidinyl)phenyl)methyl]amine, 1.13 g (4.62 mmol)
of 2-chloro-3-trifluoromethylbenzoyl chloride and
0.64 g (4.62 mmol) of potassium carbonate, 20 mg of an
oil that crystallizes are obtained.
Melting point: 117-123°C.
Example 4 (Compound 4)
3- (Aminosulfonyl) -4-chloro-J7- [ (S) - [ (2S) -1-methyl-
2-pyrrolidinyl](phenyl)methyl]benzamide hydrochloride
1:1
4.1. Ethyl 2-[(benzyloxy)imino]phenylmethyl-
1-pyrrolidinecarboxylate
1.36 g (5.5 mmol) of ethyl 2-benzoyl-1-pyrrolidine-
carboxylate dissolved in 3 0 ml of ethanol are
introduced into a 100 ml round-bottomed flask equipped
with a magnetic stirrer, 1.75 g (10.96 mmol) of benzyl-
hydroxylamine hydrochloride are added and the mixture
is refluxed for 12 hours. After evaporating off the
solvent under reduced pressure, the residue is taken up
in ethyl acetate and the organic phase is washed with
saturated sodium chloride solution, dried over sodium
sulfate and evaporated under reduced pressure. 1.95 g
of a yellow oil are obtained, which product is purified
by column chromatography on silica gel, eluting with a
mixture of ethyl acetate and cyclohexane.
1:56 g of product are obtained.
4.2. Ethyl (S)-2-[ (S)-amino(phenyl)methyl]-
1-pyrrolidinecarboxylate and ethyl [phenyl-
(2-pyrrolidinyl)methyl]carbamate
1.56 g (4.43 mmol) of ethyl [(benzoyloxy)imino]-
phenylmethyl-1-pyrrolidinecarboxylate are introduced
into 40 ml of ethanol and 8 ml of IN hydrochloric acid
in a 250 ml Parr flask, 0.15 g of 10% palladium-on-

charcoal is added and the mixture is placed under a
hydrogen atmosphere for 7 hours.
After filtering off the catalyst and evaporating the
filtrate under reduced pressure, the residue is diluted
with aqueous ammonia and dichloromethane, and the
aqueous phase is separated out and extracted with
dichloromethane. After washing the combined organic
phases, drying over sodium sulfate and evaporating the
solvent under reduced pressure, 1 g of a mixture
comprising ethyl (S)-2-[(S)-amino(phenyl)methyl]-
1-pyrrolidinecarboxylate and ethyl [phenyl-
(2-pyrrolidinyl)methyl]carbamate is obtained, which
product is used in crude form in the following step.
4.3. [(S)-[(2S)-(1-Methyl-2-pyrrolidinyl)]phenyl-
methyl]amine
1 g (4 mmol) of the mixture comprising ethyl (S)-2-
[(S)-amino(phenyl)methyl]-1-pyrrolidinecarboxylate and
ethyl [phenyl(2-pyrrolidinyl)methyl]carbamate dissolved
in 2 0 ml of anhydrous ether at 0°C is introduced into a
100 ml round-bottomed flask equipped with a magnetic
stirrer, under a nitrogen atmosphere. 0.8 g (21 mmol)
of lithium aluminum hydride is added portionwise and
the mixture is refluxed for 5 hours.
After cooling, the mixture is successively treated with
0.8 ml of water, 0.8 ml of 15% sodium hydroxide and
2.4 ml of water.
After filtering through Celite®, the filtrate is
concentrated under reduced pressure. The residue
obtained (0.7 g) is purified by column chromatography
on silica gel, eluting with a mixture of dichloro-
methane, methanol and aqueous ammonia. 0.12 g of
product is obtained in the form of a yellow oil.
4.4 . 3- (Aminosulfonyl) -4-chloro-J\r- [ (S) - [ (2S) -1-methyl-
2-pyrrolidinyl](phenyl)methyl]benzamide

hydrochloride 1:1
According to the procedure described in Example 2,
starting with 0.12 g (0.63 mmol) of [(S)-[(2S)-(1-
methyl-2-pyrrolidinyl)]phenylmethyl]amine, 0.12 g
(0.63 mmol) of 1-[3-(dimethylamino)propyl]-3-ethyl-
carbodiimide hydrochloride, 0.085 g (0.63 mmol) of
hydroxybenzotriazole and 0.14 g (0.63 mmol) of
4-chloro-3-sulfonylbenzoic acid, and after work-up and
purification by chromatography on silica gel with a
gradient of dichloromethane and methanol, 0.12 g of
3-(aminosulfonyl)-4-chloro-W-[(S)-[(2S)-l-methyl-2-
pyrrolidinyl](phenyl)methyl]benzamide is obtained.
This product is dissolved in a few ml of 2-propanol,
20 ml of a 0. IN solution of hydrogen chloride in
2-propanol are added and the mixture is concentrated
under reduced pressure in order to reduce the volume of
the solvent. After trituration, 0.09 g of hydrochloride
is finally isolated in the form of a white solid.
Melting point: 165-170°C.
Example 5 (Compound 5)
Erythro-4-amino-3-chloro-W- [1-methyl-2-pyrrolidinyl]-
(phenyl)methyl]-5-(trifluoromethyl)benzamide
hydrochloride 1:1
5.1. Ethyl erythro-[azido(phenyl)methyl]-1-pyrrolidine-
carboxylate
2.9 g (11.6 mmol) of ethyl threo-[hydroxy(phenyl)-
methyl]-1-pyrrolidinecarboxylate dissolved in 150 ml of
tetrahydrofuran at 0°C are placed in a 500 ml round-
bottomed flask equipped with a magnetic stirrer and
under an argon atmosphere. 4.57 g (17.4 mmol) of
triphenylphosphine and 35 mmol of a solution of
hydrazoic acid in toluene are added. 2.74 ml
(17.4 mmol) of ethyl azidodicarboxylate are added
dropwise and the mixture is stirred for 24 hours.
IN sodium hydroxide is added and the mixture is taken

up in ethyl acetate. The organic phase is dried over
sodium sulfate and evaporated under reduced pressure.
10 g of a residue are obtained, and are purified by
chromatography on silica gel with a gradient of
cyclohexane and ethyl acetate. 1.17 g of ethyl erythro-
[azido(phenyl)methyl]-1-pyrrolidinecarboxylate are thus
obtained.
5.2. Erythro-[(1-methyl-2-pyrrolidinyl)phenyl)methyl]-
amine
0.8 g (21.32 mmol) of lithium aluminum hydride is
placed in 25 ml of tetrahydrofuran in a 100 ml three-
necked flask equipped with a magnetic stirrer, under
argon, and a solution of 1.17 g (4.26 mmol) of ethyl
erythro-[azido(phenyl)methyl]-1-pyrrolidinecarboxylate
in 10 ml of tetrahydrofuran is added and the mixture is
heated at 70°C for 2 hours.
After cooling, the mixture is successively treated with
0.8 ml of water, 0.8 ml of 15% sodium hydroxide and
2.4 ml of water.
After filtering through Celite®, the filtrate is
evaporated under reduced pressure and the residue is
purified by chromatography on silica gel with a mixture
of dichloromethane, methanol and aqueous ammonia.
0.16 g of erythro-[(l-methyl-2-pyrrolidinyl)phenyl)-
methyl]amine and 0.15 g of [methylphenyl(2-
pyrrolidinyl) methyl] amine are thus obtained.
5.3. Erythro-4-amino-3-chloro-W-[l-methyl-2-
pyrrolidinyl](phenyl)methyl]-5-(trifluoromethyl)-
benzamide hydrochloride 1:1
According to the procedure described in Example 2,
starting with 0.073 g (0.38 mmol) of erythro-(1-methyl-
2-pyrrolidinyl)]phenyl)methyl] amine, 0.074 g
(0.38 mmol) of 1-[3-(dimethylamino)propyl]-3-ethyl-
carbodiimide hydrochloride, 0.052 g (0.38 mmol) of
hydroxybenzotriazole and 0.092 g (0.63 mmol) of

4-amino-3-chloro-5-trifluoromethylbenzoic acid, and
after work-up and purification by chromatography on
silica gel with a gradient of dichloromethane and
methanol, 0.089 g of erythro-4-amino-3-chloro-W-[1-
methyl-2-pyrrolidinyl](phenyl)methyl]-5-(trifluoro-
methyl)benzamide is obtained.
This product is dissolved in a few ml of 2-propanol,
20 ml of a 0.IN solution of hydrogen chloride in
2-propanol are added and the mixture is concentrated
under reduced pressure in order to reduce the volume of
the solvent. After trituration, 0.07 g of hydrochloride
is finally isolated in the form of a white solid.
Melting point: 130-140°C.
Example 6 (Compound 6)
3- (Aminosulfonyl) -4-chloro-W- [ (i?) - [ (2S) -1-methyl-
2-pyrrolidinyl](phenyl)methyl]benzamide hydrochloride
1:1
Using the synthetic method of Example 5, starting with
the chiral threo amino alcohol ethyl (2S)-2-[2-(S)-
hydroxy(phenyl)methyl]-1-pyrrolidinecarboxylate, 0.12 g
of 3- (aminosulfonyl) -4-chloro-W- [ (J?) - [ (2S) -l-methyl-2-
pyrrolidinyl](phenyl)methyl]benzamide hydrochloride 1:1
is obtained.
Melting point: 190-192°C.
Example 7 (Compound 7)
Erythro-2-chloro-N- [{R)-[{2S)-l-methyl-2-azepanyl]-
(phenyl)methyl]-3-(trifluoromethyl)benzamide
hydrochloride 1:1
7.1. tert-Butyl 2-[hydroxy(phenyl)methyl]-1-azepane-
carboxylate
5 g (25.09 mmol) of tert-butyl 1-azepanecarboxylate and
3.8 ml (25.09 mmol) of tetramethylenediamine dissolved
in 3 0 ml of anhydrous ether at -75°C are placed in a
250 ml three-necked flask equipped with a magnetic

Stirrer, under an argon atmosphere. 21 ml (27.60 mmol)
of 1.3M sec-butyllithium in cyclohexane are added
dropwise. The temperature is allowed to rise to -50°C
over 3 hours (solution A).
3.8 ml (37.63 mmol) of benzaldehyde in 10 ml of
anhydrous ether (solution B) are placed in a 2 50 ml
round-bottomed flask equipped with a magnetic stirrer,
under an argon atmosphere. The two solutions are cooled
to -75°C and solution A is introduced into solution B
while controlling the temperature. At the end of the
addition, the mixture is allowed to warm to room
temperature and is stirred overnight.
After hydrolyzing with saturated ammonium chloride
solution, the aqueous phase is separated out and is
extracted with ethyl acetate. After washing the
combined organic phases, drying over sodium sulfate and
evaporating off the solvent under reduced pressure, the
residue (10 g) is purified by column chromatography on
silica gel, eluting with a mixture of ethyl acetate and
cyclohexane.
2 g of tert-butyl 2-[hydroxy(phenyl)methyl]-1-azepane-
carboxylate are thus obtained.
7.2. (1-Methyl-2-azepanyl)phenyl)methanol
1.2 g (32.74 mmol) of lithium aluminum hydride are
suspended in 10 ml of tetrahydrofuran in a 100 ml two-
necked flask under a nitrogen atmosphere, equipped with
a magnetic stirrer and on which is mounted a condenser.
A solution of 2 g (6.55 mmol) of tert-butyl
2-[hydroxy(phenyl)methyl]-1-azepanecarboxylate in 10 ml
of tetrahydrofuran is added dropwise and the mixture is
refluxed for 5 hours.
After cooling, 5.5 ml of a 0. IM solution of potassium
sodium tartrate are added and the mixture is stirred at
room temperature overnight.
After filtering off the insoluble material under
reduced pressure and rinsing with tetrahydrofuran, the
filtrate is concentrated under reduced pressure. 1.3 6 g
of an oil are obtained, which product is purified by
column chromatography on silica gel, eluting with a
mixture of dichloromethane, methanol and ac[ueous
ammonia.
0.95 g of (1-methyl-2-azepanyl)phenyl)methanol is
obtained.
7.3. [(l-Methyl-2-azepanyl)phenyl)methyl]amine
0.95 g (4.33 mmol) of (1-methyl-2-azepanyl)phenyl)-
methanol and 0.6 ml (4.33 mmol) of triethylamine
dissolved in 20 ml of dichloromethane at 0°C are placed
in a 100 ml round-bottomed flask, under a nitrogen
atmosphere, equipped with a magnetic stirrer. 0.34 ml
of mesyl chloride is added and the mixture is stirred
at room temperature for 3 hours.
After evaporating off the solvents under reduced
pressure, the residue is taken up in 20 ml of ethanol
and is added to a solution of liquefied ammonia in an
autoclave cooled to -50°C. The autoclave is closed and
the mixture is stirred at room temperature for
48 hours.
The reaction mixture is diluted with water and
dichloromethane. The aqueous phase is extracted 3 times
with dichloromethane. After washing the combined
organic phases, drying over sodium sulfate and
evaporating off the solvent under reduced pressure,
1.7 g of [(1-methyl-2-azepanyl)phenyl)methyl]amine are
obtained in the form of an oil, which is used in crude
form in the following step.
7.4. Erythro-2-chloro-W-(l-methyl-2-azepanyl) (phenyl)-
methyl]-3-(trifluoromethyl)benzamide hydrochloride

1:1
According to the procedure described in Example 2,
starting with 1.7 g (7.79 mmol) of [ (l-methYl-2-
azepanyl)phenyl)methyl]amine, 1.49 g (7.79 mmol) of
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydro-
chloride, 1.05 g (7.79 mmol) of hydroxybenzotriazole
and 1.74 g (7.79 mmol) of 2-chloro-3-trifluorobenzoic
acid, and after work-up and purification by
chromatography on silica gel, 0.8 g of erythro-
2-chloro-W- (1-methyl-2-azepanyl) (phenyl)methyl]-3-
(trifluoromethyl)benzamide is obtained.
This product is dissolved in a few ml of 2-propanol,
20 ml of a 0.IN solution of hydrogen chloride in
2-propanol are added and the mixture is concentrated
under reduced pressure in order to reduce the volume of
the solvent. After trituration, 0.48 g of hydrochloride
is finally isolated in the form of a solid.
Melting point: 124-126°C.
Table 1 below illustrates the chemical structures and
the melting points of a number of compounds of the
invention. In the "salt" column, "-" denotes a compound
in base form, "HCl" denotes a hydrochloride and "tfa"
denotes a trifluoroacetate.
Compound 7 exists in the form of a mixture of erythro
(7.5) and threo (2.5).

The compounds of the invention were subjected to a
series of pharmacological tests that demonstrated their
value as therapeutically active substances.
Study of glycine transportation in SK-N-MC cells
expressing the native human transporter glytl
The uptake 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 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
buffer ([4-(2-hydroxyethyl)-1-piperazineethanesulfonic
acid) 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 glycine (determination of the nonspecific
uptake) , 10 µM of [14C] glycine (specific activity
112 mCi/mmol) are then added. Incubation is continued
for 10 minutes at 37°C, and the reaction is quenched by
washing twice with pH 7.4 Krebs-HEPES buffer. The
radioactivity incorporated by the cells is then
estimated after adding 100 /il of liquid scintillant and
stirring for 1 hour. Counting is performed on a
Microbeta Tri-Lux™ counter. The efficacy of the
compound is determined by means of the IC50, which is
the concentration of compound that reduces by 50% the
specific uptake of glycine, defined by the difference
in radioactivity incorporated by the control batch and
the batch that received 10 mM of glycine.
The compounds of the invention have an IC50 in this test
of about from 0.01 to 10 µM.
Study of the glycine transportation in mouse spinal
cord homogenate
The uptake of [14C] glycine by the transporter glyt2 is

studied in mouse spinal cord homogenate by measuring
the radioactivity incorporated in the presence or
absence of test compound.
After euthanizing the animals (male OFl Iffa Credo mice
weighing 2 0 to 25 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 pH
7.4 Krebs-HEPES buffer ([4-(2-hydroxyethyl)-
1-piperazineethanesulfonic acid), in a proportion of
25 ml/g of tissue,
50 µl of homogenate are preincubated for 10 minutes at
25°C in the presence of pH 7.4 Krebs-HEPES buffer and
of test compound at various concentrations, or of 10 mM
of glycine to determine the nonspecific uptake.
[14C] glycine (specific activity = 112 mCi/mmol) is then
added over 10 minutes at 25°C to a final concentration
of 10 µM. The reaction is quenched by vacuum filtration
and the radioactivity is estimated by solid
scintillation by counting on a Microbeta Tri-Lux™
counter. The efficacy of the compound is determined by
means of the IC50, the concentration capable of reducing
by 50% the specific uptake of glycine, defined by the
difference in radioactivity incorporated by the control
batch and the batch that received 10 mM of glycine.
The compounds of the invention have an IC50 in this test
of about from 0.1 to 10 µM.
The results of the tests performed on the compounds of
the invention show that they are inhibitors of the
glycine transporter glytl present in the brain and
glyt2 present in the spinal cord.
These results suggest that the compounds of the
invention may be used for treating behavioral disorders
associated with dementia, psychosis, 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, phobia, compulsive obsessive
disorders, for treating various forms of depression,
including psychotic depression, for treating disorders
caused by alcohol abuse or weaning from alcohol, sexual
behavior disorders, eating disorders and for treating
migraine.
Moreover, the compounds of the invention may be used
for treating painful muscle contracture in rheumatology
and in acute spinal pathology, for treating spastic
contractures of medullary or cerebral origin, for the
symptomatic treatment of acute and subacute pain of
light to moderate intensity, for treating intense
and/or chronic pain, neurogenic pain and intractable
pain, for treating Parkinson's disease and Parkinson-
like symptoms of neurodegenerative origin or induced by
neuroleptics, for treating partial primary and
secondary generalized epilepsy of simple or complex
symptomology, mixed forms and other epileptic syndromes
in addition to another antiepileptic treatment, or in
monotherapy, for the treatment of sleep apnea, and for
neuroprotection.
Accordingly, a 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 base or of pharmaceutically
acceptable salt or solvate, and as a mixture, where
appropriate, with suitable excipients.
Said excipients are chosen according to the
pharmaceutical 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 administration forms may be, for example,
tablets, gel capsules, granules, powders, oral or
injectable solutions or suspensions, transdermal
patches or suppositories. Pomades, lotions and eyedrops
may be envisioned for topical administration.
Said unit forms are dosed to allow a daily
administration of from 0.01 to 20 mg of active
principle per kg of body weight, according to the
galenical form.
To prepare tablets, a pharmaceutical vehicle, which may
be composed of diluents, for instance lactose,
microcrystalline cellulose or starch, and formulating
adjuvants, for instance binders (polyvinylpyrrolidone,
hydroxypropylmethylcellulose, etc.), glidants, for
instance silica, and lubricants, for instance magnesium
stearate, stearic acid, glyceryl tribehenate or sodium
stearylfumarate, are added to the micronized or
nonmicronized active principle. Wetting agents or
surfactants such as sodium lauryl sulfate may also be
added.
The preparation techniques may be direct tableting, dry
granulation, wet granulation or hot melting.
The tablets may be plain, sugar-coated, for example
coated with sucrose, or coated with various polymers or
other suitable materials. They may be designed to allow
rapid, delayed or sustained release of the active
principle by means of polymer matrices or specific
polymers used in the coating.
To prepare gel capsules, the active principle is mixed
with dry pharmaceutical vehicles (simple mixing, dry or
wet granulation, or hot melting), liquid or semisolid

pharmaceutical vehicles.
The gel capsules may be hard or soft, with or without a
film coating, so as to have rapid, sustained or delayed
activity (for example for an enteric form).
A composition in the form of a syrup or elixir or for
administration in the form of drops may contain the
active principle together with a sweetener, preferably
a calorie-free sweetener, methylparaben or propyl-
paraben as antiseptic, a flavoring and a dye.
The water-dispersible powders and granules may contain
the active principle as a mixture with dispersants or
wetting agents, or dispersants such as polyvinyl-
pyrrolidone, and also with sweeteners and flavor
enhancers.
For rectal administration, use is made of suppositories
prepared with binders that melt at the rectal
temperature, for example cocoa butter or polyethylene
glycols.
Aqueous suspensions, isotonic saline solutions or
injectable sterile solutions containing pharma-
cologically compatible dispersants and/or wetting
agents, for example propylene glycol or butylene
glycol, are used for parenteral administration.
The active principle may also be formulated in the form
of microcapsules, optionally with one or more supports
or additives, or alternatively with a polymer matrix or
with a cyclodextrin (transdermal patches, sustained-
released forms) .
The topical compositions according to the invention
comprise a medium that is compatible with the skin.
They may especially be in the form of aqueous,
alcoholic or aqueous-alcoholic solutions, gels, water-

in-oil or oil-in-water emulsions having the appearance
of a cream or a gel, microemulsions or aerosols, or
alternatively in the form of vesicular dispersions
containing ionic and/or nonionic lipids. These
galenical forms are prepared according to the usual
methods of the fields under consideration.
Finally, the pharmaceutical compositions according to
the invention may contain, along with a compound of
general formula (I) , other active principles that may
be useful in the treatment of the disorders and
diseases indicated above.
WE CLAIM ;
1. A compound corresponding to the general formula
(I)
in which
n represents the number 1 or 3,
Ri represents either a hydrogen atom, a linear or
branched (C1-C7) alkyl group substituted or
unsubstituted with one or more fluorine atoms, a (C:j-
C7) cycloalkyl group, a (C3-C7) cycloalkyl (C1-C3) alkyl
group,a phenyl(C1-C3)alkyl group substituted or
unsubstituted with one or two methoxy groups,a C2-C4)
alkenyl group, or a C2-C4) alkynyl group,
X represents either a hydrogen _a^tom or one or more
substituents chosen from halogen atoms and trifluoro-
methyl and linear or branched (C1-C6) alkyl and (C1-C6)
alkoxy groups,
R2 represents either a hydrogen atom or one or more
substituents chosen from halogen atoms and trifluoro-
methyl, linear or branched (C1-C6) alkyl and (C1-C6)-
alkoxy, (C3-C7) cycloalkyl, phenyl, cyano, acetyl,
benzoyl, S (C1-C6) alkyl, (Ci-Cs) alkylsulf onyl, carboxyl
and (C1-C6)alkoxycarbonyl groups, or a group of general
formula NR3R4, SO2NR3R4 or CONR3R4, in which R3 and R4
represent, independently of each other, a hydrogen atom
or a linear or branched (C1-C6)alkyl or (C3-C7) cyclo-
alkyl group, or form, with the nitrogen atom that bears
them, a pyrrolidine, piperidine or morpholine ring,
in the form of base or of acid-addition salt.
2. The compound as claimed in claim 1, wherein it is
of threo relative configuration (1S,2S;1R,2R) .
3. The compound as claimed in claim 1, wherein it is
of (1S,2S) configuration.
4. The compound as claimed in claim 1, wherein it is
of {1R,2R) configuration.
5. The compound as claimed in claim 1, wherein it is
of erythro relative configuration (1S,2R;1R,2S).
6. The compound as claimed in claim 1, wherein it is
of {1R,2S) configuration.
7. The compound as claimed in claim 1, wherein it is
of ilS,2R) configuration.
8. A medicament, wherein it consists of a compound as
claimed in any one of claims 1 to 5.
9. A pharmaceutical composition, wherein it contains
a compound as claimed in any one of claims 1 to 5,
combined with an excipient.

The invention relates to compounds having genera] formula (I), wherein: n represents the number 1 or 3; R2 represents either H or a cycloalkyl, cycloalkylalky), phenylalkyl, alkenyl, alkynyl group; X represents either H or one or more substituents selected from among halogen atoms and the trifluoromethyl, alkyl and alkoxy groups; and R2 represents H, or one or more substituents selected from among the halogen atoms and the trifluoromethyl, alkyl, alkoxy, cycloalkyl, phenyl, cyano. acetyl, benzoyl, S-alkyl. alkyl-sulfonyl, carboxy and alkoxycar-bonyl groups, or a group having formula NR3R4 SO2NR3R4 or CONR3R4, in which
R3 and R4) each represent H or an alkyl or cycloalkyl group or. together with the nitrogen atom, form a pyrrolidine, piperidine or morpholine ring. The invention also relates to the use of said compounds in therapeutics.

Documents:

00927-kolnp-2006 abstract.pdf

00927-kolnp-2006 assignment.pdf

00927-kolnp-2006 claims.pdf

00927-kolnp-2006 correspondence others.pdf

00927-kolnp-2006 description (complete).pdf

00927-kolnp-2006 form-1.pdf

00927-kolnp-2006 form-3.pdf

00927-kolnp-2006 form-5.pdf

00927-kolnp-2006 international publication.pdf

00927-kolnp-2006 international search authority report.pdf

927-KOLNP-2006-ABSTRACT.pdf

927-KOLNP-2006-CANCELLED DOCOMENT.pdf

927-KOLNP-2006-CLAIMS 0.1.pdf

927-KOLNP-2006-CLAIMS 1.1.pdf

927-KOLNP-2006-DESCRIPTION COMPLETE.pdf

927-KOLNP-2006-FORM 1.pdf

927-KOLNP-2006-FORM 3.pdf

927-kolnp-2006-granted-abstract.pdf

927-kolnp-2006-granted-assignment.pdf

927-kolnp-2006-granted-claims.pdf

927-kolnp-2006-granted-correspondence.pdf

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

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

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

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

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

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

927-kolnp-2006-granted-gpa.pdf

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

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927-KOLNP-2006-PITITION UNDER RULE 137.pdf

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abstract-00927-kolnp-2006.jpg


Patent Number 240314
Indian Patent Application Number 927/KOLNP/2006
PG Journal Number 19/2010
Publication Date 07-May-2010
Grant Date 04-May-2010
Date of Filing 13-Apr-2006
Name of Patentee SANOFI-AVENTIS
Applicant Address 174, AVENUE DE FRANCE, F
Inventors:
# Inventor's Name Inventor's Address
1 DARGAZANLI, GIHAD 47 BOULEVARD DE LA VANNE, FR-94230 CACHAN
2 MEDAISKO, FLORENCE 28 AVENUE RONSARD, FR-94100 SAINT-MAUR-DES FOSSES
3 RAKOTOARISOA NATHALIE 7, BOULEVARD DE BRETAGNE, F-91160 LONGJUMEAU
4 ESTENNE-BOUHTOU GENEVIEVE 18 RUE DES JARDINS, FR-94550 CHEVILLYLARUE
PCT International Classification Number C07D 207/09
PCT International Application Number PCT/FR2004/002644
PCT International Filing date 2004-10-15
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 03/12,143 2003-10-17 France