Title of Invention

DERIVATIVES OF N-''PHENYL (PIPERIDINE-2YL) METHYL BENZAMIDE, IN THERAPEUTICS

Abstract The invention relates to a compound having general formula (I), wherein: R1 represents either a hydrogen atom or an alkyl, cycloalkylalkyl, phenylalkyl, alkenyl, alkynyl group; X represents a hydrogen atom or one or more substituents selected from among halogen atoms and the trifluoromethyl, alkyl and alkoxy groups; and R2 represents a group selected from among the naphthalenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzothiazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzotriazolyl, benzisothiazolyl, dihydroindolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopy- ridinyl, oxazolopyridinyl, thiazalopyridinyl, pyrazolopyridinyl, isoxazolopyridinyl, isothiazolopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl groups. The invention also relates to the use of said compound in therapeutics.
Full Text The compounds of the invention correspond to the
general formula (I)

in which
R1 represents either a hydrogen atom or a linear or
branched (C1-C7)alkyl group optionally substituted with
one or more fluorine atoms, or a (C3-C7) cycloalkyl
group, or a (C3-C7) cycloalkyl (C1-C3) alkyl group, or a
phenyl (C1-C3) alkyl group optionally substituted with one
or two methoxy groups, or a (C2-C4) alkenyl or
(C2 - C4)alkynyl group,
X represents a hydrogen atom or one or more
substituents chosen from halogen atoms and trifluoro-
methyl and linear or branched (C1-C4) alkyl and
(C1-C4) alkoxy groups,
R2 represents a group chosen from naphthyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridyl, triazinyl, indanyl,
indenyl, guinolyl, isoquinolyl, quinazolyl, quinoxalyl,
phthalazinyl, thienyl, furyl, pyrrolyl, imidazolyl,
pyrazolyl, oxazolyl, thiazolyl, isoxazolyl,
isothiazolyl, thiadiazolyl, oxadiazolyl, triazolyl,
benzothienyl, benzofuryl, benzimidazolyl,
benzothiazolyl, indolyl, isoindolyl, indazolyl,
benzoxazolyl, benzisoxazolyl, benzotriazolyl,
benzisothiazolyl, dihydroindolyl, pyrrolopyridyl, furo-
pyridyl, thienopyridyl, imidazopyridyl, oxazolopyridyl,
thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl,
isothiazolopyridyl, tetrahydroquinolyl and tetra-
hydroisoquinolyl groups, and optionally substituted

with one or more substituents chosen from halogen atoms
and (C1-C4)alkyl, (C1-C4) alkoxy, thio (C1-C4) alkyl or
phenyl groups optionally substituted with one or more
substituents chosen from halogen atoms and
trifluoromethyl, (C1-C4) alkyl and (C1-C4) alkoxy groups.
The compounds of general formula (I) may exist in the
form of the threo racemate (112,2R; IS, 2S) or in the form
of enantiomers (1R,2R) or (1S,2S); 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.
Other compounds of similar structure are described in
patent application EP-0 499 995 as 5-HT3 antagonists
that are useful in the treatment of psychotic
disorders, neurological diseases, gastric symptoms,
nausea and vomiting.
The preferred compounds of the invention lack activity
on the opiate or 5-HT3 receptors and show particular
activity as specific inhibitors of the glycine
transporters glytl and/or glyt2.
The compounds of general formula (I) in which R-i is
other than a hydrogen atom may be prepared via a
process illustrated by Scheme 1 below.
Coupling of a diamine of general formula (II), in which
R1 and X are as defined above (with R1 other than a
hydrogen atom) with an activated acid or an acid
chloride of general formula (III) in which Y represents
an activated OH group or a chlorine atom and R2 is as
defined above, is performed using the methods known to
those skilled in the art.


The Weinreb amide of formula (IV) is reacted with the
phenyllithium derivative of general formula (V) , in
which X is as defined above, in an ether solvent such
as diethyl ether, between -30°C and room temperature; a
ketone of general formula (VI) is obtained, which is
reduced to the alcohol of threo configuration of
general formula (VII) with a reducing agent such as

K-Selectride® or L-Selectride® (potassium or lithium
tri-sec-butylborohydride), in an ether solvent such as
tetrahydrofuran, between -78°C and room temperature.
The carbamate of general formula (VII) may then be
reduced to threo I\T-methylamino alcohol of general
formula (VIII) 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 threo alcohol of general formula (VIII) is then
converted into the threo intermediate of general
formula (II) in which Rx 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 methanesulfonyl 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 (VII) may also be
deprotected using a strong base such as aqueous
potassium hydroxide, in an alcohol such as methanol, to
give the threo amino alcohol of general formula (IX) ,
followed by an W-alkylation using a halogenated
derivative of formula RiZ, in which Rx 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
N,N- dimethylformamide, between room temperature and
100°C. The alcohol of general formula (X) thus obtained
is then treated as described with respect to the
alcohol of general formula (VIII).
Another process variant, illustrated by Scheme 3 below,
may be used when Ri represents a methyl group and X

represents a hydrogen atom. The pyridine oxime of
formula (XI) is guaternized, for example via the action
of methyl trifluoromethanesulfonate, in an ether
solvent such as diethyl ether, at room temperature. The
pyridinium salt thus obtained, of formula (XII), is
then subjected to a hydrogenation under a hydrogen
atmosphere, in the presence of a catalyst such as
platinum oxide, in a mixture of alcohol and of aqueous
acid such as ethanol and IN hydrochloric acid. The
diamine of general formula (II) in which Rx represents a
methyl group and X represents a hydrogen atom is
obtained in the form of a 9/1 threo/erythro mixture of
the two diastereoisomers. It can be salified, for
example with oxalic acid, and then purified by
recrystallization of the oxalate formed from a mixture
of alcohol and of an ether solvent such as methanol and
diethyl ether, to give the pure threo diastereoisomer
(1R,2JR;1S,2S) .

The compounds of general formula (II) in which Ri
represents a hydrogen atom may be prepared according to
Scheme 2, with use of a compound of general formula (I)
in which Rx represents an optionally substituted
phenylmethyl group, followed by deprotection of the
nitrogen of the piperidine ring, for example with an
oxidizing agent or with a Lewis acid, such as boron
tribromide, or via hydrogenolysis, i.e. an alkenyl
group, preferably an allyl group, and in deprotecting
the nitrogen with a Pd° complex, to obtain a compound of

general formula (I) in which Rx represents a hydrogen
atom.
Moreover, the chiral compounds of general formula (I)
corresponding to the (1R,2R) or (1S,2S) enantiomers of
the threo diastereoisomer may also be obtained by
separation of the racemic compounds by high-performance
liquid chromatography (HPLC) on a chiral column, or by
resolution of the racemic amine of general formula (II)
by using a chiral acid such as tartaric acid,
camphorsulfonic acid, dibenzoyltartaric acid or N-
acetyl leucine, by fractional and preferential
recrystallization of a diastereoisomeric salt, in a
solvent of alcohol type, or alternatively via
enantioselective synthesis according to Scheme 2 with
use of a chiral Weinreb amide of formula (IV).
The racemic or chiral Weinreb amide of formula (IV) ,
and also the ketone of general formula (VI) , may be
prepared according to a method similar to that
described in Eur. J. Med. Chem., 35, (2000), 979-988
and J. Med. Chem., 41, (1998), 591-601. The
phenyllithium compound of general formula (V), in which
X represents a hydrogen atom, is commercially
available. Its substituted derivatives may be prepared
according to a method similar to that described in
Tetrahedron Lett., 57, 33, (1996), 5905-5908. The
pyridine oxime of general formula (XI) may be prepared
according to a method similar to that described in
patent application EP-0 366 006. The amine of general
formula (IX) in which X represents a hydrogen atom may
be prepared in the chiral series according to a method
described in patent US-2 928 835. Finally, the amine of
general formula (XIII) may be prepared according to a
method similar to that described in Chem. Pharm. Bull.,
32, 12, (1984), 4893-4906 and Synthesis, (1976),
593-595.

The acids and acid chlorides of general formula (III)
are commercially available, except for 4- [2-chloro-3-
(tri fluoromethyl)phenyl]-1H-imidazole-2 -carboxyli c
acid, which may be prepared under conditions comparable
to those described in patent application EP-0 365 030
and in patent US-3 336 300.
The examples that follow illustrate the preparation of
a number of compounds of the invention. The elemental
microanalyses, 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 given in parentheses in the titles of the
examples correspond to those in the first column of the
table given later.
Example 1 (Compound 4)
Threo-2,5-dichloro-N- [(1-methyl-2-piperidyl) (phenyl)-
methyl]-3-thiophenecarboxamide hydrochloride 1:1
1.1. 2 -(Benzyloxyiminophenylmethyl)-1-methylpyridinium
trifluoromethanesulfonate
To a suspension of 35 g (120 mmol) of phenyl(2-
pyridyl)methanone O-benzyl oxirae in 2 00 ml of diethyl
ether are added dropwise, at 0°C, 17.4 ml (120 mmol) of
methyl trifluoromethanesulfonate and the mixture is
stirred at room temperature for 3 hours. The
precipitate formed is collected by filtration and dried
under reduced pressure.
49 g of product are obtained, which product is used
without further purification in the following step.
1.2. Threo-(l-methylpiperidin-2-yl)phenylmethanamine
ethanedioate 1:2

14.8 g (31.89 mmol) of 2-(benzyloxyiminophenyl-
methyl)-1-methylpyridinium trifluoromethanesulfonate
and 0.74 g of platinum oxide are placed in 50 ml of
ethanol and 50 ml of IN hydrochloric acid in a Parr
flask, and hydrogenation is performed for 5 hours.
The ethanol is evaporated off under reduced pressure,
the residue is extracted with dichloromethane, the
aqueous phase is separated out, aqueous ammonia
solution is added thereto and the mixture is extracted
with dichloromethane. After washing the combined
organic phases, drying over sodium sulfate, filtering
and evaporating off the solvent under reduced pressure,
6.7 g of oily product comprising 10% of erythro
diastereoisomer are obtained.
The ethanedioate is prepared by dissolving these 6.7 g
of base in methanol, via the action of two equivalents
of ethanedioic acid dissolved in a minimum amount of
methanol.
The salt obtained is purified by recrystallization from
a mixture of methanol and diethyl ether.
4.7 g of ethanedioate of the pure threo diastereoisomer
are finally isolated.
Melting point: 156-159°C.
1.3. Threo-2,5-dichloro-2tf-(1-methyl-2-piperidyl)
(phenyl)methyl]thiophene-3-carboxamide
hydrochloride 1:1
0.768 g (4 mmol) of 2,5-dichlorothiophene-3-carboxylic
acid dissolved in 15 ml of dichloromethane is
introduced into a 100 ml round-bottomed flask, 0.651 ml
(4.7 mmol) of triethylamine and 0.447 ml (4.7 mmol) of
ethyl chloroformate are then added and the reaction
mixture is stirred at room temperature for 2 hours.

0.80 g (3.9 mmol) of threo-(1-methyl-2-
piperidyDphenylmethanamine dissolved in 15 ml of
dichloromethane is added and stirring is continued at
room temperature for 12 hours.
The mixture is treated with water and extracted several
times with dichloromethane. After washing the organic
phases with water and then with aqueous IN sodium
hydroxide solution, .drying over sodium sulfate,
filtering and evaporating off the solvent under reduced
pressure, the residue is purified by column
chromatography on silica gel, eluting with a 97/3 to
95/5 mixture of dichloromethane and methanol.
0.6 g of oily product is obtained, the hydrochloride of
which is prepared by adding a 0.IN solution of hydrogen
chloride in 2-propanol.
After evaporating off the solvents under reduced
pressure, the white solid obtained is recrystallized
from a mixture of isopropyl ether and 2-propanol.
0.474 g of hydrochloride is finally isolated in the
form of a white solid.
Melting point: 216-217°C.
Example 2 (Compound 5)
2,5-Dichloro-itf-[(S)-[(2S)-1-methyl-2-piperidyl]-
(phenyl)methyl]thiophene-3-carboxamide hydrochloride
1:1
2.1. 1,1-dimethylethy1 (2S)-2-benzoylpiperidine-l-
carboxylate
11.8 g (43.3 mmol) of 1,1-dimethylethyl (2S)-2-(N-
methoxy-N-methylcarbamoyl)piperidine-1-carboxylate are
introduced into 100 ml of anhydrous diethyl ether in a
500 ml round-bottomed flask, under a nitrogen
atmosphere, the medium is cooled to -23°C, 21.6 ml

(43.2 mmol) of a 1. 8M solution of phenyllithium in a
70/30 mixture of cyclohexane and diethyl ether are
added dropwise and the mixture is stirred at room
temperature for 3 hours. After hydrolysis with
saturated aqueous sodium chloride solution, the aqueous
phase is separated out and extracted with ethyl
acetate. The organic phase is dried over sodium
sulfate, filtered and concentrated under reduced
pressure, and the residue is purified by column
chromatography on silica gel, eluting with a mixture of
ethyl acetate and cyclohexane.
i
1
4.68 g (16.2 mmol) of 1,1-dimethylethyl (2S) -2-benzoyl-
piperidine-1-carboxylate are introduced into 170 ml of
anhydrous tetrahydrofuran in a 500 ml round-bottomed
flask, under a nitrogen atmosphere, the solution is
cooled to -78°C, 48.5 ml (48.5 mmol) of a 1M solution
of L-Selectride® (lithium tri-sec-butylborohydride) in
tetrahydrofuran are added dropwise and the mixture is
stirred at room temperature for 5 hours.
The resulting mixture is hydrolyzed slowly under cold
conditions with 34 ml of water and 34 ml of aqueous 35%
hydrogen peroxide solution, and the mixture is allowed
to warm to room temperature while stirring over 2
hours.
The resulting mixture is diluted with water and ethyl
acetate, and the aqueous phase is separated out and
extracted with ethyl acetate. After washing the
combined organic phases, drying over sodium sulfate,
filtering and evaporating, the residue is purified by

column chromatography on silica gel, eluting with a
mixture of ethyl acetate and cyclohexane.

2.96 g (78.1 mmol) of lithium aluminum hydride are
introduced into 50 ml of anhydrous tetrahydrofuran in a
200 ml two-necked flask, under a nitrogen atmosphere,
the mixture is refluxed, 4.4 9 g (15.4 mmol) of a
solution of 1,1-dimethylethyl (IS)-2-[(2S)-hydroxy
(phenyl)methyl]piperidine-1-carboxylate in 35 ml of
tetrahydrofuran are added and the mixture is maintained
at reflux for 3.5 hours.
The mixture is cooled, hydrolyzed slowly with 0. 1M
potassium sodium tartrate solution and stirred
overnight. The resulting mixture is filtered, the
precipitate is rinsed with tetrahydrofuran and the
filtrate is then concentrated under reduced pressure.

2.95 g (14.4 mmol) of (IS) - [ (2S) - (1-methyl-2-
piperidyl)]phenylmethanol and 2 ml (14.4 mmol) of
triethylamine are introduced into 70 ml of anhydrous
dichloromethane in a 250 ml round-bottomed flask, under
a nitrogen atmosphere, the medium is cooled to 0°C,
1.1 ml (14.4 mmol) of methanesulfonyl chloride are
added and the mixture is allowed to return slowly to
room temperature over 2 hours and is concentrated under
reduced pressure.

Liquefied ammonia is introduced into an autoclave
equipped with a magnetic stirrer and cooled to -50°C, a
solution of the methanesulfonate prepared above in
3 0 ml of absolute ethanol is added, and the autoclave
is closed and stirred for 48 hours.
The mixture is transferred into a round-bottomed flask,
the solvents are evaporated off under reduced pressure
and the amine is isolated in the form of an oily-
product, which is used without further purification in
the following step.

0.37 g (1.88 mmol) of 2,5-dichlorothiophene-3-
carboxylic acid is introduced into 15 ml of
dichloromethane in a 250 ml round-bottomed flask,
0.31 ml (2.25 mmol) of triethylamine and 0.21 ml
(2.25 mmol) of ethyl chloroformate are successively
added and the mixture is stirred at room temperature
for 1 hour.
0.38 g (1.88 mmol) of (IS) - [ (2S) - (1-methyl-2-
piperidyl)]phenylmethanamine dissolved in 10 ml of
dichloromethane is added and stirring is continued at
room temperature for 12 hours.
The mixture is treated with water and extracted several
times with dichloromethane, the organic phases are
combined, washed with aqueous IN sodium hydroxide
solution, dried over sodium sulfate and filtered, and
the filtrate is concentrated under reduced pressure.
The crude residue is purified by column chromatography
on silica gel, eluting with a 98/2 mixture of
dichloromethane and methanol containing 0.1% aqueous
ammonia. 0.368 g of oily product is obtained, the

hydrochloride of which is prepared by addition of a
0.1N solution of hydrogen chloride in 2-propanol.
After evaporating off the solvent under reduced
pressure, the solid is recrystallized from a mixture of
2-propanol and isopropyl ether.
(
(
I
Example 3 (Compound 18)
Threo-4-[2-chloro-3-(trifluoromethyl)phenyl]-N- [(1-
methyl-2-piperidyl)(phenyl)methyl]-lH-imidazole-2-
carboxamide hydrochloride 1:1
0.1 g (0.344 mmol) of 4-(2-chloro-3-(trifluoro-
methyl) phenyl]-lH-imidazole-2-carboxylic acid, 0.066 g
(0.344 mmol) of 1-[3-(dimethylamino)propyl]-3-ethyl-
carbodiimide, and 0.047 g (0.344 mmol) of 1-hydroxy-
benzotriazole dissolved in 10 ml of dichloromethane are
introduced into a 50 ml round-bottomed flask and the
mixture is stirred at room temperature for 5 minutes.
0.072 g (0.344 mmol) of threo-(l-methyl-2-
piperidyDphenylmethanamine (prepared according to
Example 1.2) is added to a few ml of dichloromethane
and stirring is continued for 6 hours.
The mixture is treated with water and extracted several
times with dichloromethane, the organic phases are
washed with water and then with aqueous IN sodium
hydroxide solution, then with saturated aqueous sodium
chloride solution and dried over sodium sulfate, and
the solvent is evaporated off under reduced pressure.
The residue is purified by column chromatography on
silica gel, eluting with a mixture of dichloromethane
and methanol.

91 mg of product is obtained, the hydrochloride of
which is prepared by adding a 0.IN solution of hydrogen
chloride in 2-propanol. The solvent is partially
evaporated off under reduced pressure to obtain, after
crystallization, 104 mg of solid white compound.
Melting point: 188-195°C.
The table on the following page illustrates the
chemical structures and the physical properties of a
number of compounds according to the invention.
In the "Salt" column, "-" denotes a compound in base
form and "HC1" denotes a hydrochloride.
The optical rotation of compound 5 is [a] 25D = +45.6°
(c = 0.99); CH3OH.











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-piperazine]ethanesulfonic
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 of glycine (determination of the nonspecific
uptake), 10 /xM 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 fil 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 /zM.
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 0F1 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-piperazine]ethanesulfonic 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.
These results suggest that the compounds of the
invention may be used for treating 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, 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
stearyl fumarate, 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.
i 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), or liquid or
5 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 pharmacologically
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
R1 represents either a hydrogen atom or a linear or
branched (C1-C7)alkyl group substituted or not
substituted with one or more fluorine atoms, or a
(C3-C7) cycloalkyl group, or a (C3-C7) cycloalkyl (C1-
C3) alkyl group, or a phenyl (C1-C3) alkyl group
optionally substituted with one or two methoxy
groups, or a (C2-C4) alkenyl group, or a (C2-C4)
alkynyl group,
X represents a hydrogen atom or one or more
substituents chosen from halogen atoms and
trifluoromethyl and linear or branched (C1-C4)alkyl
and (C1-C4) alkoxy groups,
R2 represents a group chosen from naphthyl,
pyridinyl, pyrimidinyl, pyrazinyl, pyridyl,
triazinyl, indanyl, indenyl, quinolyl,
isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl,
thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl,
oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,
thiadiazolyl, oxadiazolyl, triazolyl,
benzothienyl, benzofuryl, benzimidazolyl,
benzothiazolyl, indolyl, isoindolyl, indazolyl,
benzoxazolyl, benzisoxazolyl, benzotriazolyl,
benzisothiazolyl, dihydroindolyl, pyrrolopyridyl,
furopyridyl, thienopyridyl, imidazopyridyl,
oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl,

isoxazolopyridyl, isothiazolopyridyl, tetrahydro-
quinolyl and tetrahydroisoquinolyl groups, and
optionally substituted with one or more
substituents chosen from halogen atoms and (C1-C4)
alkyl, (C1-C4) alkoxy, thio (C1-C4) alkyl or phenyl
groups optionally substituted with one or more
substituents chosen from halogen atoms and
trifluoromethyl, (C1-C4) alkyl and (C1-C4) alkoxy
groups,
in the form of free base or of acid-addition salt.
2. Compound as claimed in claim 1, wherein it is
chosen amongst:
- Threo-2,5-dichloro-N-[ (l-methyl-2-piperidyl)(phenyl)-
methyl] -3-thiophenecarboxamide hydrochloride 1:1;
2, 5-Dichloro-N-[ (S)-[ (2S)-l-methyl-2-piperidyl] -
(phenyl)methyl] thiophene-3-carboxamide hydrochloride
1:1;
Threo-4-[ 2-chloro-3-(trifluoromethyl) phenyl] -N-[ (1-
methyl-2-piperidyl) (phenyl)methyl] -lH-imidazole-2-
carboxamide hydrochloride 1:1;
3. A medicament, wherein it consists of a compound
as claimed in claim 1 or 2.
4. A pharmaceutical composition, wherein it comprises
a compound as claimed in claim 1 or 2, combined
with an excipient.
5. A compound as claimed in claim 1 or 2 for
the preparation of a medicament for treating
behavioral disorders in relation with dementia,
psychoses, various forms of anxiety, panic
attacks, phobias, compulsive obsessive disorders,
various forms of depression, disorders caused by

alcohol abuse or weaning from alcohol, sexual
behavior disorders, eating disorders and migraine.
A compound as claimed in claim 1 or 2 for the
preparation of a medicament for treating
contracture, pain, Parkinson' s disease and
Parkinson-like symptoms, epilepsy, mixed forms and
other epileptic syndromes in addition to another
antiepileptic treatment, or in monotherapy, and
sleep apnea, and for neuroprotection.

The invention relates to a compound having general formula
(I), wherein: R1 represents either a hydrogen atom or an alkyl, cycloalkylalkyl,
phenylalkyl, alkenyl, alkynyl group; X represents a hydrogen atom or one or
more substituents selected from among halogen atoms and the trifluoromethyl,
alkyl and alkoxy groups; and R2 represents a group selected from among the
naphthalenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl,
indenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl,
isothiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuryl,
benzimidazolyl, benzothiazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl,
benzisoxazolyl, benzotriazolyl, benzisothiazolyl, dihydroindolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopy-
ridinyl, oxazolopyridinyl, thiazalopyridinyl, pyrazolopyridinyl, isoxazolopyridinyl, isothiazolopyridinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl groups. The invention also relates to the use of said compound in therapeutics.

Documents:

00934-kolnp-2006 -abstract.pdf

00934-kolnp-2006 -description (complete).pdf

00934-kolnp-2006 assignment.pdf

00934-kolnp-2006 claims.pdf

00934-kolnp-2006 correspondence others.pdf

00934-kolnp-2006 form-1.pdf

00934-kolnp-2006 form-3.pdf

00934-kolnp-2006 form-5.pdf

00934-kolnp-2006 international publication.pdf

00934-kolnp-2006 international search authority report.pdf

934-KOLNP-2006-ABSTRACT.pdf

934-KOLNP-2006-CANCELLED DOCOMENT.pdf

934-KOLNP-2006-CLAIMS.pdf

934-KOLNP-2006-DESCRIPTION COMPLETE.pdf

934-KOLNP-2006-FORM 1.pdf

934-KOLNP-2006-FORM 13.pdf

934-KOLNP-2006-FORM 3.pdf

934-kolnp-2006-granted-abstract.pdf

934-kolnp-2006-granted-assignment.pdf

934-kolnp-2006-granted-claims.pdf

934-kolnp-2006-granted-correspondence.pdf

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

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

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

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

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

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

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

934-kolnp-2006-granted-gpa.pdf

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

934-kolnp-2006-granted-specification.pdf

934-kolnp-2006-granted-translated copy of priority document.pdf

934-KOLNP-2006-INTERNATIONAL SEARCH REPORT.pdf

934-KOLNP-2006-PETITION UNDER RULE 137.pdf

934-KOLNP-2006-PETITION UNDER SECTION 137-1.1.pdf

934-KOLNP-2006-REPLY TO EXAMINATION REPORT-1.1.pdf

934-KOLNP-2006-REPLY TO EXAMINATION REPORT-1.2.pdf

934-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf

934-KOLNP-2006-TRANSLATED COPY OF PRIORITY DOCUMENT-1.1.pdf

934-KOLNP-2006-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf

abstract-00934-kolnp-2006.jpg


Patent Number 235646
Indian Patent Application Number 934/KOLNP/2006
PG Journal Number 37/2009
Publication Date 11-Sep-2009
Grant Date 11-Sep-2009
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 ESTENNE-BOUHTOU GENEVIEVE 18, RUE DES JARDINS, F-94550, CHEVILLY-LARUE
2 DARGAZANLI GIHAD 47, BOULEVARD DE LA VANNE, F-94230, CACHAN
3 MAGAT PASCALE 34, AVENUE MAZARIN, F-91380, CHILLY MAZARIN
PCT International Classification Number A61K 31/445
PCT International Application Number PCT/FR2004/002640
PCT International Filing date 2004-10-15
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0312140 2003-10-17 France