Title of Invention

NOVEL COMPOUNDS FOR INHIBITING FAAH ENZYME, PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME

Abstract Compound corresponding to the general formula (I): The compounds of the invention correspond to the general formula (I): in which m, n = 1 to 3 and m + n = 2 to 5; p = 1 to 7; A = single bond or X, Y and/or Z; X = optionally substituted methylene; Y = C2-alkenylene, which is optionally substituted, or C2-alkynylene; Z = C3-7- cycloalkyl; R1 represents a group of aryl or heteroaryl type; R2 represents a hydrogen or fluorine atom or a hydroxyl, C1-6-alkoxy or NR8R9 group; R3 represents a hydrogen atom or a C1-6-alkyl group; R4 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl or C3-7- cycloalkyl-C1-3-alkyl group; in the base form or in the form of an addition salt with an acid, of a hydrate or of a solvate. Application in therapeutics.
Full Text

A subject-matter of the invention is aryl-
and heteroarylpiperidinecarboxylate derivatives, their
preparation and their application in therapeutics.
Phenylalkylcarbamate and dioxanyl-2-alkyl-
carbamate derivatives and derivatives of aryloxyalkyl-
carbamate type, disclosed respectively in the documents
FR 2 850 377 A, WO 2004/020430 A2 and PCT/FR2005/00028,
which are inhibitors of the enzyme FAAH (Fatty Acid
Amido Hydrolase) are already known.
There still exists a need to find and to
develop products which are inhibitors of the enzyme
FAAH. The compounds of the invention meet this aim.
The compounds of the invention correspond to
the general formula (I):

in which
m and n represent integers ranging from 1 to 3 such
that m + n is an integer ranging from 2 to 5;

p represents an integer ranging from 1 to 7;
A represents a single bond or is chosen from one or
more groups X, Y and/or Z;
X represents a methylene group optionally substituted
by one or two C1-6-alkyl, C3-7-cycloalkyl or C3-7-
cycloalkyl-C1-3-alkylene groups;
Y represents either a C2-alkenylene group optionally
substituted by one or two C1-6-alkyl, C3-7-cycloalkyl or
C3-7-cycloalkyl-C1-3-alkylene groups; or a C2-alkynylene
group;
Z represents a group of formula:

o represents an integer ranging from 1 to 5;
r and s represent integers and are defined such that
r+s is a number ranging from 1 to 5;
R1 represents an R5 group optionally substituted by one
or more R6 and/or R7 groups;
R2 represents a hydrogen or fluorine atom or a hydroxyl,
C1-6-alkoxy or NR8R9 group;
R3 represents a hydrogen atom or a C1-6-alkyl group;
R4 represents a hydrogen atom or a C1-6-alkyl, C3-7-
cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl group;
R5 represents a group chosen from a phenyl, pyridyl,
pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,

pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl,
thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,
naphthyl, quinolinyl, tetrahydroquinolinyl,
isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl,
quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl,
benzofuranyl, dihydrobenzofuranyl, benzothienyl,
dihydrobenzothienyl, indolyl, indolinyl, indazolyl,
isoindolyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl,
pyrrolopyridyl, furopyridyl, thienopyridyl,
imidazopyridyl, oxazolopyridyl, thiazolopyridyl,
pyrazolopyridyl, isoxazolopyridyl or
isothiazolopyridyl;
R6 represents a halogen atom or a cyano, nitro,
C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, hydroxyl,
C1-6-thioalkyl, C1-6-f luoroalkyl, C1-6-f luoroalkoxy,
C1-6-fluorothioalkyl, NR8R9, NR8COR9, NR8CO2R9, NR8SO2R9,
COR8, CO2R8, CONR8R9, SO2R8, SO2NR8R9 or -O- (C1-3-alkylene) -
O- group or a ring chosen from the azetidine,
pyrrolidine, piperidine, morpholine, thiomorpholine,
azepine or piperazine rings, this ring optionally being
substituted by a C1-6-alkyl or benzyl group;
R7 represents a phenyl, phenyloxy, benzyloxy, naphthyl,
pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group;

it being possible for the R7 group or groups to be
substituted by one or more R6 groups which are identical
to or different from one another;
R8 and R9 represent, independently of one another, a
hydrogen atom or a C1-6-alkyl group.
In the context of the invention, the
compounds of general formula (I) can thus comprise
several groups A which are identical to or different
from one another.
Among the compounds of general formula (I), a
first subgroup of compounds is composed of the
compounds for which:
m and n represent integers equal to 1 or 2 such that
m + n is an integer ranging from 2 to 4;
p represents an integer ranging from 1 to 3;
A represents a single bond or a methylene or C2-
alkynylene group;
R1 represents an R5 group optionally substituted by one
or more R6 and/or R7 groups;
R2 represents a hydrogen atom or a hydroxyl group;
R3 represents a hydrogen atom or a C1-6-alkyl group;
R4 represents a hydrogen atom or a C1-6-alkyl, C3-7-
cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl group;
R5 represents a group chosen from a phenyl, pyridyl,
pyrimidinyl, imidazolyl, thiazolyl, pyrazolyl,
isoxazolyl, oxadiazolyl, naphthyl,

tetrahydroquinolinyl, isoquinolinyl, tetrahydroiso-
quinolinyl, indolyl, indolinyl, benzimidazolyl,
benzoxazolyl, benzothiazolyl, benzotriazolyl or
pyrrolopyridyl;
R6 represents a halogen atom, more particularly a
bromine, a chlorine or a fluorine, or a cyano, C1-6-
alkyl, more particularly a methyl, a butyl or an
isobutyl, C3-7-cycloalkyl, more particularly a
cyclopentyl, C1-6-alkoxy, more particularly a methoxy or
an ethoxy, or C1-6-f luoroalkyl, more particularly a
trifluoromethyl, group or a pyrrolidine or piperidine
ring, this ring optionally being substituted by a C1-6-
alkyl group, more particularly an isopropyl;
R7 represents a phenyl group which can be substituted by
one or more R6 groups which are identical to or
different from one another.
Among the compounds of general formula (I), a
second subgroup of compounds is composed of the
compounds for which:
m and n represent integers equal to 1 or 2 such that
m + n is an integer ranging from 2 to 4;
p represents an integer ranging from 1 to 3;
A represents a single bond or a methylene or C2-
alkynylene group;
R1 represents an R5 group optionally substituted by one
or more R6 and/or R7 groups;

R2 represents a hydrogen atom or a hydroxyl group;
R3 represents a hydrogen atom or a C1-6-alkyl group;
R4 represents a hydrogen atom or a C1-6-alkyl, C3-7-
cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl group;
R5 represents a group chosen from a phenyl, pyridyl,
pyrimidinyl, thiazolyl, isoxazolyl, naphthyl or
isoquinolinyl;
R6 represents a halogen atom, more particularly a
bromine, a chlorine or a fluorine, or a cyano, C1-6-
alkyl, more particularly a methyl, a butyl or an
isobutyl, C3-7-cycloalkyl, more particularly a
cyclopentyl, C1-6-alkoxy, more particularly a methoxy or
an ethoxy, or C1-6-fluoroalkyl, more particularly a
trifluoromethyl, group or a pyrrolidine or piperidine
ring, this ring optionally being substituted by a C1-6-
alkyl group, more particularly an isopropyl;
R7 represents a phenyl group which can be substituted by
one or more R6 groups which are identical to or
different from one another.
Among the compounds of general formula (I), a
third subgroup of compounds is composed of the
compounds for which:
m, n, p, A and R1 are as defined in the first subgroup
defined above;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom or a C1-6-alkyl group, more

particularly a methyl.
Mention may be made, among the compounds of
the subgroups defined above, of the following
compounds:
- 2-(methylamino)-2-oxoethyl 4-{5-[4-(trifluoro-methyl)
phenyl]pyrid-2-yl}piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(4'-chlorobiphenyl-4-
yl)-4-hydroxypiperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(4'-ethoxybiphenyl-4-
yl)-4-hydroxypiperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(3',4'-dichlorobiphenyl-
4-yl)-4-hydroxypiperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(3'-chloro-
4'-fluorobiphenyl-4-yl)-4-hydroxypiperidine-1-
carboxylate
- 2-(methylamino)-2-oxoethyl 4-[(6-cyclopentylpyrid-2-
yl)methyl]piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[2-(3-chloro-phenyl)
ethyl]piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[2-(4-chloro-phenyl)
ethyl]piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-{2-[3-(trifluoro-methyl)
phenyl]ethyl}piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-{2-[4-(trifluoro-methyl)
phenyl]ethyl}piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(2-(biphenyl-3-yl)

ethyl)-piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[2-(1-naphthyl)-ethyl]
piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[2-(2-naphthyl)-ethyl]
piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[2-(6-cyclopentylpyrid-
2-yl)ethyl]piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[2-(6-(pyrrolidin-1-yl)
pyrid-2-yl)ethyl]piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(2-(isoquinolin-1-yl)
ethyl)piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(3-chloro-phenyl)
propyl]piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(4-chloro-phenyl)
propyl]piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-{3-[3-(trifluoro-methyl)
phenyl]propyl}piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-{3-[4-(trifluoro-methyl)
phenyl]propyl}piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(3-cyano-phenyl)
propyl]piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(3-(biphenyl-2-yl)
propyl)piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(3-(biphenyl-3-yl)
propyl)piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(1-naphthyl)-propyl]

piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(2-naphthyl)-propyl]
piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(1,3-thiazol-2-yl)
propyl]piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[(3-chloro-phenyl)
ethynyl]piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[(4-chloro-phenyl)
ethynyl]piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(biphenyl-3-ylethynyl)
piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(1-naphthylethynyl)-
piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(2-naphthylethynyl)-
piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(3-(biphenyl-2-yl)prop-
2-yn-1-yl)piperidine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[(6-(pyrrolidin-1-yl)
pyrid-2-yl)methyl]piperidine-1-carboxylate
Among the compounds of general formula (I),
one subfamily of compounds is composed of the compounds
corresponding to the general formula (I'):


in which
m and n represent integers ranging from 1 to 3 such
that m + n is an integer ranging from 2 to 5;
p represents an integer ranging from 1 to 7;
A represents a single bond or is chosen from one or
more groups X, Y and/or Z;
X represents a methylene group optionally substituted
by one or two C1-6-alkyl, C3-7-cycloalkyl or C3-7-
cycloalkyl-C1-3-alkylene groups;
Y represents either a C2-alkenylene group optionally
substituted by one or two C1-6-alkyl, C3-7-cycloalkyl or
C3-7-cycloalkyl-C1-3-alkylene groups; or a C2-alkynylene
group;
Z represents a group of formula:

o represents an integer ranging from 1 to 5;
r and s represent integers and are defined such that
r+s is a number ranging from 1 to 5;
R1 represents an R5 group optionally substituted by one
or more R6 and/or R7 groups;

R2 represents a hydrogen or fluorine atom or a hydroxyl,
C1-6-alkoxy or NR8R9 group;
R3 represents a hydrogen atom or a C1-6-alkyl group;
R4 represents a hydrogen atom or a C1-6-alkyl, C3-7-
cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl group;
R5 represents a group chosen from a phenyl, pyridyl,
pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,
pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl,
thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,
naphthyl, quinolinyl, tetrahydroquinolinyl,
isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl,
quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl,
benzofuranyl, dihydrobenzofuranyl, benzothienyl,
dihydrobenzothienyl, indolyl, indolinyl, indazolyl,
isoindolyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl,
pyrrolopyridyl, furopyridyl, thienopyridyl,
imidazopyridyl, oxazolopyridyl, thiazolopyridyl,
pyrazolopyridyl, isoxazolopyridyl or
isothiazolopyridyl;
R6 represents a halogen atom or a cyano, nitro, C1-6-
alkyl, C1-6-alkoxy, hydroxyl, C1-6-thioalkyl, C1-6-
fluoroalkyl, C1-6-fluoroalkoxy, C1-6-fluorothioalkyl,
NR8R9, NR8COR9, NR8CO2R9, NR8SO2R9, COR8, CO2R8, CONR8R9,

SO2R8, SO2NR8R9 or -O- (C1-3-alkylene) -O- group;
R7 represents a phenyl, phenyloxy, benzyloxy, naphthyl,
pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group;
it being possible for the R7 group or groups to be
substituted by one or more R6 groups which are identical
to or different from one another;
R8 and R9 represent, independently of one another, a
hydrogen atom or a C1-6-alkyl group or form, with the
atom or atoms which carry them, a ring chosen from an
azetidine, pyrrolidine, piperidine, morpholine,
thiomorpholine, azepine or piperazine ring optionally
substituted by a C1-6-alkyl or benzyl group.
Among the compounds of general formula (I'),
a first subgroup of compounds is composed of the
compounds for which:
m and n represent integers equal to 1 or 2 such that
m + n is an integer ranging from 2 to 4;
p represents an integer equal to 1 or 2;
A represents a single bond or a methylene group;
R1 represents an R5 group optionally substituted by one
or more R6 and/or R7 groups ;
R2 represents a hydrogen or fluorine atom or a hydroxyl,
C1-6-alkoxy or NR8R9 group;
R3 represents a hydrogen atom or a C1-6-alkyl group;
R4 represents a hydrogen atom or a C1-6-alkyl, C3-7-
cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl group;

R5 represents a group chosen from a phenyl, imidazolyl,
naphthyl, tetrahydroquinolinyl, tetrahydroiso-
quinolinyl, indolyl, indolinyl, benzimidazolyl,
benzotriazolyl or pyrrolopyridyl;
R6 represents a halogen atom, more particularly a
bromine, a chlorine or a fluorine, or a C1-6-alkyl, more
particularly a methyl or a butyl, C1-6-alkoxy, more
particularly a methoxy or an ethoxy, or C1-6-
fluoroalkyl, more particularly a trifluoromethyl,
group;
R7 represents a phenyl group which can be substituted by
one or more R6 groups which are identical to or
different from one another.
Among the compounds of general formula (I'),
a second subgroup of compounds is composed of the
compounds for which:
m, n, p, A and Rx are as defined in the first subgroup
defined above;
R3 represents a hydrogen atom;
R4 represents a hydrogen atom or a C1-6-alkyl group, more
particularly a methyl.
Mention may be made, among the compounds of
general formula (I'), of the following compounds:
- 2-amino-2-oxoethyl 4-phenylpiperidine-1-carboxylate;
- 2-(methylamino)-2-oxoethyl 4-phenylpiperidine-1-
carboxylate;

- 2-amino-2-oxoethyl 4-[3-(trifluoromethyl)-phenyl]
piperidine-1-carboxylate;
- 2-(methylamino)-2-oxoethyl 4-[3-(trifluoro-methyl)
phenyl]piperidine-1-carboxylate;
- 2-(methylamino)-2-oxoethyl 4-(4-phenyl-lH-imidazol-1-
yl)piperidine-1-carboxylate;
- 2-(methylamino)-2-oxoethyl 4-(1H-1,2,3-benzotriazol-
1-yl)piperidine-1-carboxylate;
- 2-(methylamino)-2-oxoethyl 4-(4-bromophenyl)-4-
hydroxypiperidine-1-carboxylate;
- 2-(methylamino)-2-oxoethyl 4-(4'-fluorobiphenyl-4-
yl)-4-hydroxypiperidine-1-carboxylate;
- 2-(methylamino)-2-oxoethyl 4-(4'-chlorobiphenyl-4-
yl)-4-hydroxypiperidine-1-carboxylate;
- 2-(methylamino)-2-oxoethyl 4-hydroxy-4-
(4'-methylbiphenyl-4-yl)piperidine-1-carboxylate;
- 2-(methylamino)-2-oxoethyl 4-(4'-butylbiphenyl-4-yl)-
4-hydroxypiperidine-1-carboxylate;
- 2-(methylamino)-2-oxoethyl 4-hydroxy-4-[4'-
(trifluoromethyl)biphenyl-4-yl]piperidine-1-
carboxylate;
- 2-(methylamino)-2-oxoethyl 4-hydroxy-4-[4'-
(methyloxy)biphenyl-4-yl]piperidine-1-carboxylate;
- 2-(methylamino)-2-oxoethyl 4-[4'-(ethyloxy)biphenyl-
4-yl]-4-hydroxypiperidine-1-carboxylate;
- 2-(methylamino)-2-oxoethyl 4-(3',4'-dichlorobiphenyl-

4-yl)-4-hydroxypiperidine-1-carboxylate;
- 2-(methylamino)-2-oxoethyl 4-[3'-fluoro-4'-
(methyloxy)biphenyl-4-yl]-4-hydroxypiperidine-1-
carboxylate;
- 2-(methylamino)-2-oxoethyl 4-(3'-chloro-4'-fluoro-
biphenyl-4-yl)-4-hydroxypiperidine-1-carboxylate;
- 2-(methylamino)-2-oxoethyl 4-(naphth-2-ylmethyl)-
piperidine-1-carboxylate;
- 2-(methylamino)-2-oxoethyl 4-(biphenyl-4-ylmethyl)
piperidine-1-carboxylate;
- 2-amino-2-oxoethyl 4-(1H-indol-1-ylmethyl)piperidine-
1-carboxylate;
- 2-amino-2-oxoethyl 4-(2,3-dihydro-1H-indol-1-
ylmethyl)piperidine-1-carboxylate;
- 2-amino-2-oxoethyl 4-(3,4-dihydroquinolin-1(2H)-
ylmethyl)piperidine-1-carboxylate;
- 2-amino-2-oxoethyl 4-(3,4-dihydroisoquinolin-2(1H)-
ylmethyl)piperidine-1-carboxylate;
- 2-amino-2-oxoethyle 4-(1H-pyrrolo[2,3-b]pyrid-1-
ylmethyl)piperidine-1-carboxylate;
- 2-amino-2-oxoethyl 4-(1H-benzimidazol-1-ylmethyl)
piperidine-1-carboxylate;
- 2-amino-2-oxoethyl 4-[(4-phenyl-1H-imidazol-1-yl)
methyl]piperidine-1-carboxylate;
- 2-amino-2-oxoethyl 3-(2-phenylethyl)pyrrolidine-1-
carboxylate;

- 2-amino-2-oxoethyl 4-[2-(3,4-dihydroquinolin-1(2H)-
yl)ethyl]piperidine-1-carboxylate;
- 2-amino-2-oxoethyl 4-[2-(3,4-dihydroisoquinolin-2
(1H)-yl)ethyl]piperidine-1-carboxylate;
- 2-amino-2-oxoethyl 4-[2-(1H-indol-1-yl)ethyl]-
piperidine-1-carboxylate;
- 2-amino-2-oxoethyl 4-[2-(2,3-dihydro-1H-indol-1-yl)
ethyl]piperidine-1-carboxylate;
- 2-amino-2-oxoethyl 4-[2-(1H-pyrrolo[2,3-b]pyrid-1-yl)
ethyl]piperidine-1-carboxylate;
- 2-amino-2-oxoethyl 4-[2-(IH-benzimidazol-1-yl)ethyl]
piperidine-1-carboxylate;
- 2-amino-2-oxoethyl 4-[2-(4-phenyl-1H-imidazol-1-yl)
ethyl]piperidine-1-carboxylate.
The compounds of general formula (I) can
comprise one or more asymmetric carbons. They can exist
in the form of enantiomers or of diastereoisomers.
These enantiomers and diastereoisomers, and their
mixtures, including the racemic mixtures, form part of
the invention.
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, of use, for example, in the purification

or the isolation of the compounds of formula (I), also
form part of the invention. The compounds of general
formula (I) can exist in the form of hydrates or of
solvates, namely in the form of combinations or of
associations with one or more molecules of water or
with a solvent. Such hydrates and solvates also form
part of the invention.
In the context of the invention:
Ct-z, where t and z can take the values from 1
to 7, is understood to mean a carbon chain which
can have from t to z carbon atoms, for example C1-3
a carbon chain which can have from 1 to 3 carbon
atoms;
alkyl is understood to mean a saturated,
linear or branched, aliphatic group; for example a
C1-6-alkyl group represents a linear or branched
carbon chain of 1 to 6 carbon atoms, more
particularly a methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tert-butyl, pentyl or hexyl;
- alkylene is understood to mean a saturated,
linear or branched, divalent alkyl group, for
example a C1-3-alkylene group represents a linear
or branched divalent carbon chain of 1 to 3 carbon
atoms, more particularly a methylene, ethylene,
1-methylethylene or propylene;
cycloalkyl is understood to mean a cyclic

alkyl group, for example a C3-7-cycloalkyl group
represents a cyclic carbon group of 3 to 7 carbon
atoms, more particularly a cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl;
alkenylene is understood to mean an
unsaturated divalent aliphatic group comprising 2
carbons, more particularly an ethylene;
C2-alkynylene is understood to mean a -C≡C-
group;
alkoxy is understood to mean an -O-alkyl
group comprising a saturated, linear or branched,
aliphatic chain;
thioalkyl is understood to mean an -S-alkyl
group comprising a saturated, linear or branched,
aliphatic chain;
fluoroalkyl is understood to mean an alkyl
group, one or more hydrogen atoms of which have
been substituted by a fluorine atom;
fluoroalkoxy is understood to mean an alkoxy
group, one or more hydrogen atoms of which have
been substituted by a fluorine atom;
fluorothioalkyl is understood to mean a
thioalkyl group, one or more hydrogen atoms of
which have been substituted by a fluorine atom;
halogen atom is understood to mean a

fluorine, a chlorine, a bromine or an iodine.
The compounds of the invention can be
prepared according to the method illustrated by the
following scheme.


The compounds of the invention can be
prepared by reacting an amine of general formula (II),
in which R1, A, R2, p, m and n are as defined in the
general formula (II), with a carbonate of general
formula (III), in which Z represents a hydrogen atom or
a nitro group, R3 is as defined in the general formula
(I) and R represents a methyl or ethyl group, in a
solvent, such as toluene, dichloroethane, acetonitrile

or a mixture of these solvents, at a temperature of
between 0°C and 80°C. The carbamate-esters of general
formula (IV) thus obtained are subsequently converted
to compounds of general formula (I) by aminolysis using
an amine of general formula R4NH2, where R4 is as
defined in the general formula (I). The aminolysis
reaction can be carried out in a solvent, such as
methanol or ethanol, or a mixture of solvents, such as
methanol and tetrahydrofuran.
The compounds of general formula (I) or (IV)
in which R1 represents a group of aryl-aryl, aryl-
heteroaryl, heteroaryl-aryl or heteroaryl-heteroaryl
type can also be prepared by reaction of the
corresponding compounds of general formula (I) or (IV)
for which R5 is substituted by a chlorine, bromine or
iodine atom or by a triflate group in the position
where the R7 group has to be introduced with an aryl- or
heteroarylboronic acid derivative according to the
Suziki reaction conditions (Chem. Rev., 1995, 95, 2457-
2483) or with an aryl- or heteroaryltrialkylstannane
derivative according to the Stille reaction conditions
(Angew. Chem. Int. Ed., 1986, 25, 504-524).
The carbonates of general formula (III) can
be prepared according to any method described in the
literature, for example by reaction of an alcohol of
general formula HOCHR3COOR, where R represents a methyl

or ethyl group, with phenyl or 4-nitrophenyl chloro-
formate in the presence of a base, such as
triethylamine or diisopropylethylamine.
The compounds of general formula (II) and the
amines of general formula R4NH2, when their method of
preparation is not described, are commercially
available or are described in the literature or can be
prepared according to various methods described in the
literature or known to a person skilled in the art.
The compounds of general formula (IV) in
which R1, A, R2, R3, p, m and n are as defined in the
general formula (I) and R represents a methyl or ethyl
group are novel and also form part of the invention.
They are of use as synthetic intermediates in the
preparation of the compounds of general formula (I).
The examples which will follow illustrate the
preparation of a few compounds of the invention. These
examples are not limiting and only illustrate the
invention. The microanalyses, the IR and NMR spectra
and/or the LC-MS (Liquid Chromatography coupled to Mass
Spectroscopy) confirm the structures and the purities
of the compounds obtained.
M.p. (°C) represents the melting point in degrees
Celsius.
The numbers shown in brackets in the titles of the
examples correspond to those in the 1st column in the

table below.
The IUPAC nomenclature was used to name the
compounds in the following examples. For example, for
the biphenyl group, the following notation was
observed:

Example 1 (compound No. 14)
2-(Methylamino)-2-oxoethyl 4-(4-phenyl-1H-imidazol-1-
yl)piperidine-1-carboxylate

1.1. 1,1-Dimethylethyl 4-[(methylsulphonyl)oxy]-
piperidine-1-carboxylate
1.4 ml (17.9 mmol) of methanesulphonyl
chloride are added dropwise with stirring to a
solution, cooled with an ice bath, of 3.0 g (14.9 mmol)
of 1,1-dimethylethyl 4-hydroxypiperidine-1-carboxylate
and of 2.2 ml (17.9 mmol) of triethylamine in 6 0 ml of
dichloromethane. Stirring is continued at 0°C for one
hour and then at ambient temperature for 4 hours. The
reaction mixture is diluted with 100 ml of
dichloromethane and is washed successively with 100 ml

of an aqueous sodium hydrogencarbonate solution, with a
saturated aqueous ammonium chloride solution and then
with a saturated aqueous sodium chloride solution. The
organic phase is dried over sodium sulphate and
evaporated to dryness. The residue is subsequently
triturated from a 50/50 mixture of cyclohexane and of
diethyl ether to produce 3.7 g of product in the form
of a white solid.
1.2. 1,1-Dimethylethyl 4-(4-phenyl-1H-imidazol-1-yl)-
piperidine-1-carboxylate
A solution of 4.0 g (27.9 mmol) of 4-phenyl-
imidazole in 40 ml of N,N-dimethylformamide is added
dropwise to a suspension, cooled with an ice bath, of
1.1 g (27.9 mmol) of sodium hydride (60% suspension in
oil) in 30 ml of N,N-dimethylformamide. The mixture is
subsequently stirred at ambient temperature for one
hour, is then cooled to 0°C and 2.6 g (9.3 mmol) of
1,1-dimethylethyl 4-[(methylsulphonyl)oxy]piperidine-1-
carboxylate, obtained in stage 1.1., in solution in
20 ml of N,N-dimethylformamide, are added dropwise. The
reaction mixture is subsequently heated at 80°C for
2 hours. It is cooled to ambient temperature and
diluted with 150 ml of water and 150 ml of ethyl
acetate. Separation by settling is carried out and the
aqueous phase is extracted twice with 100 ml of ethyl

acetate. The organic phases are washed with two times
100 ml of water and then with 100 ml of a saturated
aqueous sodium chloride solution. They are dried over
sodium sulphate and evaporated to dryness. The residue
is purified by chromatography on silica gel, elution
being carried out with a 98/2 mixture of
dichloromethane and of methanol, to produce 1.0 g of
product in the form of a yellow oil.
1.3. 4-(4-Phenyl-1H-imidazol-1-yl)piperidine
5.6 ml (76.3 mmol) of trifluoroacetic acid
are added dropwise to a solution, cooled with an ice
bath, of 1.0 g (3.05 mmol) of 1,1-dimethylethyl
4 -(4-phenyl-Iff-imidazol-1-yl)piperidine-1-carboxylate,
obtained in stage 1.2., in 60 ml of dichloromethane.
The mixture is subsequently stirred at ambient
temperature for one hour and is evaporated to dryness.
The residue is taken up in 25 ml of water, and 2 ml of
a 30% aqueous sodium hydroxide solution are added. The
mixture is stirred for 3 0 minutes and is then extracted
four times with 80 ml of dichloromethane. The organic
phases are subsequently washed with a saturated aqueous
sodium chloride solution, dried over sodium sulphate
and evaporated to dryness to produce 0.7 g of product
in the form of a yellow oil used as is in the following
stage.

1.4. 2-(Ethyloxy)-2-oxoethyl 4-(4-phenyl-1H-imidazol-1-
yl)piperidine-1-carboxylate
A solution of 1.0 g (4.4 mmol) of 4-(4-
phenyl-1H-imidazol-1-yl)piperidine, prepared according
to stage 1.3., and of 1.18 g (5.2 mmol) of ethyl
[(phenyloxycarbonyl)oxy]acetate (J. Med. Chem., 1999,
42, 277-290) in 50 ml of toluene is heated at 60°C
overnight. The mixture is subsequently evaporated to
lOdryness and the residue is taken up in 80 ml of ethyl
acetate and 80 ml of water. Separation by settling is
carried out and the aqueous phase is extracted with
three times 80 ml of ethyl acetate. The organic phases
are subsequently washed with 80 ml of a saturated
aqueous sodium chloride solution. They are dried over
sodium sulphate and evaporated to dryness. The residue
is purified by chromatography on silica gel, elution
being carried out with a 98/2 mixture of
dichloromethane and of methanol, to produce 0.3 5 g of
product.
1.5. 2-(Methylamino)-2-oxoethyl 4-(4-phenyl-1H-
imidazol-1-yl)piperidine-1-carboxylate
0.35 g (0.98 mmol) of 2-(ethyloxy)-2-oxoethyl
4-(4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate,
obtained in stage 1.4., is dissolved in 7 ml of

methanol. 1.5 ml (3 mmol) of a 2M solution of
methylamine in tetrahydrofuran are added. After 16
hours at ambient temperature, a further 1 ml (2 mmol)
of a 2M solution of methylamine in tetrahydrofuran is
added and reaction is allowed to take place for an
additional 6 hours. The mixture is evaporated to
dryness and the residue is purified by chromatography
on silica gel, elution being carried out with a 98/2
then 97/3, 96/4 and 95/5 mixture of dichloromethane and
of methanol. Trituration is subsequently carried out
from diethyl ether to produce 0.2 0 g of product in the
form of a white solid.
Melting point (°C): 192-194
LC-MS : M+H = 343
1H NMR (CDCl3) δ (ppm) : 7.75 (d, 2H) , 7.60 (s, 1H) ,
7.40 (m, 2H), 7.25 (m, 2H), 6.05 (broad s, 1H), 4.65
(s, 2H), 4.35 (m, 2H), 4.15 (m, 1H), 3.05 (m, 2H), 2.90
(d, 3H), 2.20 (m, 2H), 2.05-1.85 (m, 2H).
Example 2 (compound No. 32)
2-(Methylamino)-2-oxoethyl 4-(4-bromophenyl)-4-hydroxy-
piperidine-1-carboxylate


2.1. 2-(Ethyloxy)-2-oxyethyl 4-(4-bromophenyl)-4-
hydroxypiperidine-1-carboxylate
A mixture of 2.24 g (10 mmol) of ethyl
[(phenyloxycarbonyl)oxy]acetate and 2.56 g (10 mmol) of
4-(4-bromophenyl)-4-piperidinol in solution in 40 ml of
toluene is heated at 50°C for 20 hours. The solution is
evaporated to dryness on a water bath under reduced
pressure. An oil is obtained and is used directly in
the following stage.
2.2. 2-(Methylamino)-2-oxoethyl 4-(4-bromophenyl)-4-
hydroxypiperidine-1-carboxylate
The 2-(ethyloxy)-2-oxyethyl 4-(4-
bromophenyl)-4-hydroxypiperidine-1-carboxylate obtained
in stage 2.1. is stirred for 3 hours in a 33% solution
of methylamine in methanol. The solution is
concentrated on a water bath under reduced pressure.
The residue is purified by chromatography on silica
gel, elution being carried out with ethyl acetate.
2.6 g of product are obtained in the form of an oil
which gradually solidifies.
Melting point (°C): 57-60
LC-MS : M+H = 371
1H NMR (d6-DMSO) δ (ppm) : 7.55 (broad s, 1H) , 7.50 (d,
2H), 7.40 (d, 2H), 5.20 (s, 1H), 4.40 (s, 2H), 3.80 (m,
2H) , 3.20 (m, 2H) , 2.60 (d, 3H) , 1.90-1.50 (m, 4H) .

Example 3 (compound No. 40)
2-(Methylamino)-2-oxoethyl 4-(3',4'-dichlorobiphenyl-4-
yl)-4 -hydroxypiperidine-1-carboxylate

0.1 g (0.27 mmol) of 2-(methylamino)-2-
oxoethyl 4-(4-bromophenyl)-4-hydroxypiperidine-1-
carboxylate, obtained according to Example 2, 0.077 g
(0.4 mmol) of 3,4-dichlorophenylboronic acid, 10 mg of
tetrakis(triphenylphosphine)palladium(0), 2 ml of 2M
aqueous sodium carbonate solution, 0.5 ml of ethanol
and 4 ml of toluene degassed beforehand with nitrogen
are mixed. The mixture is heated at 80°C with stirring
for 20 hours. It is filtered under hot conditions
through a hydrophobic cartridge, rinsing is carried out
with tetrahydrofuran (THF) and evaporation to dryness
is carried out. The residue is purified by LC-MS
chromatography on a silica phase, elution being carried
out with a cyclohexane/ethyl acetate/methanol gradient,
to produce 0.069 g of crystalline product.
Melting point (°C) : 156-158
LC-MS : M+H = 438

1H NMR (d6-DMSO) δ (ppm) : 7.95 (s, 1H) , 7.80 (m, 1H) ,
7.70 (m, 4H), 7.60 (m, 2H) , 5.20 (s, 1H), 4.45 (s, 2H),
4.00 (m, 2H), 3.25 (m, 2H), 2.60 (d, 3H), 1.95 (m, 2H),
1.65 (m, 2H).
Example 4 (compound No. 43)
2-(Methylamino)-2-oxoethyl 4-(naphth-2-ylmethyl)-
piperidine-1-carboxylate

4.1. 1,1-Dimethylethyl 4-(naphth-2-ylmethyl)piperidine-
1-carboxylate
8.0 ml of a 0.5N solution (4 mmol) of 9-bora-
bicyclo[3.3.1]nonane in tetrahydrofuran are added under
15an argon atmosphere to a solution of 0.789 g (4 mmol)
of 1,1-dimethylethyl 4-methylidenepiperidine-1-
carboxylate (Tetrahedron Letters, 1996, 37(30), 5233-
5234) in solution in 5 ml of tetrahydrofuran. The
mixture is heated at reflux for 3 hours. It is cooled
to ambient temperature and 0.787 g (3,8 mmol) of 2-
bromonaphthalene in solution in 9 ml of
N,N-dimethylformamide, 0.82 9 g (6.0 mmol) of potassium
carbonate in solution in 1 ml of water and 0.16 g
(0.20 mmol) of the [1,1'-bis(diphenylphosphino)

ferrocene]dichloropalladium(II)-dichloromethane complex
are added. The mixture is heated at reflux overnight.
The reaction mixture is diluted with 150 ml of ethyl
acetate and 50 ml of water. The organic phase is
separated by settling and is washed with 25 ml of water
and then with 25 ml of a saturated aqueous sodium
chloride solution. It is dried over magnesium sulphate
and evaporated under vacuum. The residue is purified by
chromatography on silica gel, elution being carried out
with a 99/1 then 95/5 and 90/10 mixture of cyclohexane
and of ethyl acetate, to produce 0.79 g of product in
the form of a colourless viscous liquid.
4.2. 4 -(Naphth-2-ylmethyl)piperidine
0.79 g (2.43 mmol) of 1,1-dimethylethyl
4-(naphth-2-ylmethyl)piperidine-1-carboxylate, obtained
in stage 4.1., is dissolved in 10 ml of
dichloromethane, and 2 ml (25 mmol) of trifluoroacetic
acid are added. The mixture is stirred at ambient
temperature for 3 hours. It is evaporated under reduced
pressure, then 4 ml of 1,2-dichloroethane are added and
the mixture is again evaporated. The residue is taken
up in a mixture of 50 ml of dichloromethane and of
15 ml of a 10% aqueous sodium hydroxide solution. The
organic phase is separated by settling and the aqueous
phase is extracted twice with 25 ml of dichloromethane.

The organic phases are washed with 15 ml of a saturated
aqueous sodium chloride solution, then dried over
sodium sulphate and evaporated under vacuum to provide
0.52 g of product in the form of an orange oil used as
is in the following stage.
4.3. 2-(Ethoxy)-2-oxoethyl 4-(naphth-2-ylmethyl)-
piperidine-1-carboxylate
A mixture of 0.52 g (2.3 mmol) of 4-(naphth-
2-ylmethyl)piperidine, obtained in stage 4.2., and of
0.6 9 g (3.11 mmol) of ethyl [(phenyloxycarbonyl)oxy]
acetate in 10 ml of toluene and 5 ml of acetonitrile is
heated at 60°C overnight. The mixture is evaporated
under vacuum. The residue is purified by chromatography
15on silica gel, elution being carried out with a 90/10
then 85/15 and 80/20 mixture of cyclohexane and of
ethyl acetate, to produce 0.56 g of product in the form
of a colourless viscous liquid.
4.4. 2-(Methylamino)-2-oxoethyl 4-(naphth-2-ylmethyl)-
piperidine-1-carboxylate
0.54 g (1.52 mmol) of 2-(ethoxy)-2-oxoethyl
4-(naphth-2-ylmethyl)piperidine-1-carboxylate, obtained
in stage 4.3., is dissolved in 3 ml of methanol, and
3 ml (6.0 mmol) of a 2M solution of methylamine in
tetrahydrofuran are added. Reaction is allowed to take

place overnight at ambient temperature, then 1.5 g of
silica are added and the mixture is evaporated. The
residue is purified by chromatography on silica gel,
elution being carried out with a 98.5/1.5 and then 97/3
mixture of dichloromethane and of methanol. The product
is subsequently recrystallized from a mixture of ethyl
acetate and of diisopropyl ether to produce 0.43 g of
product in the form of a white solid.
Melting point (°C): 150-152
LC-MS : M+H 341
1H NMR (CDCl3) δ (ppm) : 7.80 (m, 3H) , 7.60 (s, 1H) ,
7.45 (m, 2H), 7.30 (d, 1H), 6.10 (m, 1H), 4.60 (s, 2H),
4.15 (m, 2H), 2.85 (d, 3H), 2.85-2.75 (m+d, 4H), 1.90-
1.70 (m, 3H) , 1.35-1.15 (m, 2H) .
Example 5 (compound No. 107)
2-(Methylamino)-2-oxoethyl 4-[3-(4-chlorophenyl)prop-2-
yn-1-yl]piperidine-1-carboxylate

5.1. tert-Butyl 4-(2-oxoethyl)piperidine-1-carboxylate
70.9 g (167 mmol) of 1,1,1-tris(acetyloxy)-
1,1-dihydro-1,2-benziodoxol-3-(1H) -one (Dess-Martin

reagent) are added portionwise to a solution, cooled to
0°C, of 30.4 g (132 mmol) of tert-butyl 4-(2-
hydroxyethyl)piperidine-1-carboxylate in 150 ml of
dichloromethane. The mixture is stirred at ambient
temperature for 2 hours, then 150 ml of a 10% aqueous
sodium thiosulphate (Na2S2O3) solution are added and
stirring is continued for an additional 30 minutes. The
organic phase is separated by settling, washed with a
saturated aqueous sodium carbonate solution, dried over
sodium sulphate and evaporated to dryness to produce
30.1 g (132 mmol) of product in the form of a
colourless oil used as is in the following stage.
5.2. tert-Butyl 4-(3,3-dibromoprop-2-en-1-yl)
piperidine-1-carboxylate
4 7.6 ml (531 mmol) of tribromomethane and
then 59.6 g (531 mmol) of potassium tert-butoxide are
added to a solution, cooled to -20°C, of 139.4 g
(531 mmol) of triphenylphosphine in 440 ml of toluene.
Stirring is continued at -20°C for 15 minutes and then
a solution of 30.1 g (131 mmol) of tert-butyl 4-(2-
oxoethyl)piperidine-1-carboxylate, prepared in stage
5.1., in 240 ml of toluene is added. Stirring is
continued at ambient temperature for 3 hours. 300 ml of
25diethyl ether are added, the solid formed is filtered
off and the filtrate is evaporated. The residue is

purified by chromatography on silica gel, elution being
carried out with dichloromethane, to produce 32.6 g
(85 mmol) of product in the form of a yellow oil.
5.3. tert-Butyl 4-(prop-2-yn-1-yl)piperidine-
1-carboxylate
32.6 g (85 mmol) of tert-butyl 4-(3,3-
dibromoprop-2-en-1-yl)piperidine-1-carboxylate,
prepared in stage 5.2., are dissolved in 420 ml of
anhydrous tetrahydrofuran. The solution is cooled to
-78°C and 106 ml of a 1.6M solution of n-butyllithium
(170 mmol) in hexane, dissolved in 10 0 ml of anhydrous
tetrahydrofuran, are added dropwise while stirring
well. Stirring is continued at -78°C for 3 hours and
then at -20°C for 1 hour. The mixture is cooled to -78°
C and 13 0 ml of a 1.25M solution of hydrochloric acid
in ethanol are added. The mixture is subsequently
reheated to ambient temperature over 1 hour. Water and
ethyl acetate are added. The organic phase is separated
by settling, washed with a saturated aqueous sodium
chloride solution, dried over sodium sulphate and
evaporated to dryness. The residue is purified by
chromatography on silica gel, elution being carried out
with dichloromethane and then with a 98/2 mixture of
dichloromethane and of methanol, to produce 32.4 g
(85.2 mmol) of product in the form of a colourless oil.

5.4. tert-Butyl 4-[3 -(4-chlorophenyl)prop-2-yn-1-yl]-
piperidine-1-carboxylate
2.29 g (9.6 mmol) of l-chloro-4-iodobenzene
and 1.7 ml (12 mmol) of triethylamine are dissolved in
5 ml of tetrahydrofuran. 0.076 g (0.40 mmol) of cuprous
iodide and 0.16 8 g (0.24 mmol) of the bis
(triphenylphosphine)palladium dichloride complex are
added under argon, followed, dropwise, by a solution of
1.78 g (8 mmol) of tert-butyl 4-(prop-2-yn-1-yl)
piperidine-1-carboxylate, prepared in stage 5.3., in 3
ml of tetrahydrofuran. Stirring is continued overnight.
25 ml of water and 100 ml of ethyl acetate are added.
The organic phase is separated by settling, washed
successively with 25 ml of 10% aqueous ammonia, 25 ml
of water and 2 5 ml of a saturated aqueous sodium
chloride solution, dried over magnesium sulphate and
evaporated to dryness. The residue is purified by
chromatography on silica gel, elution being carried out
with a 95/5 and then 90/10 mixture of cyclohexane and
of ethyl acetate, to produce 2.15 g (6.44 mmol) of
product in the form of a yellow oil.
5.5. 4-[3-(4-Chlorophenyl)prop-2-yn-1-yl]piperidine
2.13 g (6,38 mmol) of tert-butyl 4-[3-(4-
chlorophenyl)prop-2-yn-1-yl]piperidine-1-carboxylate,

obtained in stage 5.4., are dissolved in 15 ml of
dichloromethane. A solution of 4.9 ml (63.8 mmol) of
trifluoroacetic acid in 5 ml of dichloromethane is
added dropwise. Reaction is allowed to take place at
ambient temperature overnight and then the mixture is
evaporated to dryness. 25 ml of dichloromethane are
added and the mixture is again evaporated to dryness.
The residue is subsequently taken up in a mixture of
70 ml of ethyl acetate, 10 ml of a 1N aqueous sodium
hydroxide solution and 10 ml of 3 0% aqueous ammonia.
The organic phase is separated by settling, washed with
2 times 10 ml of water and then with 10 ml of a
saturated aqueous sodium chloride solution, dried over
sodium sulphate and evaporated to dryness to produce
1.3 9 g (5.94 mmol) of product in the form of a brown
oil used as is in the following stage.
5.6. 2-Ethoxy-2-oxoethyl 4-[3-(4-chlorophenyl)prop-2-
yn-1-yl]piperidine-1-carboxylate
A solution of 1.39 g (5.94 mmol) of 4-[3-(4-
chlorophenyl)prop-2-yn-1-yl]piperidine, prepared in
stage 5.5, and of 1.86 g (8.33 mmol) of ethyl
[(phenyloxycarbonyl)oxy]acetate in 12 ml of toluene is
heated at 70°C for 5 hours. The mixture is evaporated
to dryness and the residue is purified by
chromatography on silica gel, elution being carried out

with a 90/10 and then 80/20 mixture of cyclohexane and
of ethyl acetate, to produce 1.89 g (5.19 mmol) of
product in the form of a viscous oil.
5.7. 2-(Methylamino)-2-oxoethyl 4-[3-(4-chlorophenyl)
prop-2-yn-1-yl]piperidine-1-carboxylate
0.91 g (2.51 mmol) of 2-ethoxy-2-oxoethyl 4-
[3-(4-chlorophenyl)prop-2-yn-1-yl]piperidine-1-
carboxylate, prepared in stage 5.6., is dissolved in
4 ml of methanol. 2.5 ml (25 mmol) of a 33% solution of
methylamine in ethanol are added and the mixture is
left overnight at ambient temperature. It is evaporated
to dryness and the residue is purified by
chromatography on silica gel, elution being carried out
with a 99.5/0.5 and then 98/2 and 96/4 mixture of
dichloromethane and of methanol. The product is
crystallized from hexane and is then dried under vacuum
to produce 0.50 g (1.43 mmol) of product in the form of
a white powder.
Melting point (°C): 101-103
LC-MS : M+H = 349
1H NMR (CDCl3) δ (ppm) : 7.20 (m, 4H) , 6.30 (m, 1H) , 4.50
(broad s, 2H), 4.10 (broad d, 2H), 2.75 (m+d, 5H), 2.30
(d, 2H) , 1.85-1.60 (m, 3H) , 1.35-1.15 (m, 2H) .


Example 6 (compound No. 83)
2-(Methylamino)-2-oxoethyl 4-[3-(4-chlorophenyl)
propyl]piperidine-1-carboxylate

0.156 g (0.448 mmol) of 2-(methylamino)-2-
oxoethyl 4-[3-(4-chlorophenyl)prop-2-yn-1-yl]
piperidine-1-carboxylate, prepared according to Example
5, is dissolved in 2 ml of ethanol. 16 mg of platinum
dioxide are added. The mixture is stirred under a
hydrogen atmosphere at ambient pressure and ambient
temperature for 2 hours and then at 40°C for an
additional 2 hours. The mixture is filtered through
celite and the filtrate is evaporated. The residue is
purified by HPLC chromatography on Nucleosil gel,
elution being carried out with a 70/30/0 to 0/80/20
gradient of hexane, of ethyl acetate and of methanol,
to produce 0.108 mg (0.306 mmol) of product in the form
of a white solid.
Melting point (°C): 118-120
LC-MS : M+H =3 53
1H NMR (CDCl3) δ (ppm) : 7.25 (d, 2H) , 7.10 (d, 2H) , 6.05
(m, 1H), 4.60 (s, 2H), 4.10 (broad d, 2H), 2.90 (d,
3H), 2.80 (broad t, 2H), 2.60 (t, 2H), 1.75-1.55 (m,
4H), 1.45 (m, 1H), 1.35-1.05 (m, 4H).

Example 7 (compound No. 74)
2-(Methylamino)-2-oxoethyl 4-(2-(isoquinolin-1-yl)
ethyl)-1-piperidinecarboxylate

7.1. tert-Butyl 4-(iodomethyl)-1-piperidinecarboxylate
14.15 g (55.74 mmol) of iodine (I2) are added
in small portions to a solution, cooled to
approximately 0°C, of 10 g (46.45 mmol) of tert-butyl
4-(hydroxymethyl)-1-piperidinecarboxylate, of 15.84 g
(60.38 mmol) of triphenylphosphine and of 4.74 g
(69.67 mmol) of imidazole in 200 ml of dichloromethane
while keeping the temperature of the reaction medium
between 0°C and 5°C. Stirring is continued at 0°C for 1
hour and then at ambient temperature for 4 hours.
100 ml of water and 300 ml of ethyl acetate
are added. The organic phase is separated by settling,
washed successively with a saturated aqueous sodium
thiosulphate solution and a saturated aqueous sodium
chloride solution, dried over sodium sulphate and
concentrated under reduced pressure. The residue
obtained is purified by chromatography on silica gel,

elution being carried out with a 90/10 mixture of
cyclohexane and of ethyl acetate. 13.70 g (42.13 mmol)
of product are obtained in the form of a colourless
oil.
7.2. tert-Butyl 4-(2-(isoquinolin-1-yl)ethyl)-1-
piperidinecarboxylate
10 ml (20 mmol) of a solution (2M) of lithium
diisopropylamide (LDA) in a mixture of tetrahydrofuran
and of n-hexane are added dropwise to a solution,
cooled to approximately -70°C, of 2.202 g (15.38 mmol)
of 1-methylisoquinoline in 150 ml of tetrahydrofuran.
Stirring is continued at -70°C for 10 minutes and then
a solution of 5 g (15.38 mmol) of tert-butyl 4-
(iodomethyl)-1-piperidinecarboxylate, obtained in stage
7.1., in 30 ml of tetrahydrofuran is added slowly.
After stirring at -70°C for 30 minutes, 100 ml of a
saturated aqueous ammonium chloride solution are added.
The mixture is allowed to return to ambient
temperature and the aqueous phase is separated and then
extracted 3 times with ethyl acetate. The combined
organic phases are washed with a saturated aqueous
sodium chloride solution, dried over sodium sulphate
and concentrated under reduced pressure. The residue
obtained is purified by chromatography on silica gel,
elution being carried out with a 99/1 and then 98/2

mixture of dichloromethane and of methanol. 1.80 g
(5.29 mmol) of product are obtained in the form of a
yellow oil.
7.3. 1-(2-(Piperidin-4-yl)ethyl)isoquinoline
3.90 ml (23.50 mmol) of a solution of
hydrochloric acid (6N) in isopropanol are added at
ambient temperature to a solution of 1.60 g (4.70 mmol)
of tert-butyl 4-(2-(isoquinolin-1-yl)ethyl)-1-
piperidinecarboxylate, obtained in stage 7.2., in 15 ml
of 1,4-dioxane. The reaction mixture is subsequently
brought to approximately 60°C for 12 hours.
The mixture is concentrated to dryness under
reduced pressure. The hydrochloride obtained is taken
up in 5 ml of water and then a 20% aqueous sodium
hydroxide solution is slowly added with stirring to
pH 9. The aqueous phase is extracted twice with
chloroform and the combined organic phases are washed
with a saturated aqueous sodium chloride solution,
dried over sodium sulphate and concentrated under
reduced pressure. 0.400 g (1.66 mmol) of product is
obtained in the form of a brown oil.
7.4. 2-Ethoxy-2-oxoethyl 4-(2-(isoquinolin-1-yl)ethyl)-
1-piperidinecarboxylate
A solution of 0.320 g (1.33 mmol) of 1-(2-

(piperidin-4-yl)ethyl)isoquinoline, obtained in stage
7.3., and of 0.3 88 g (1.73 mmol) of ethyl
[(phenyloxycarbonyl)oxy]acetate in 10 ml of toluene is
heated at 70°C for 18 hours.
The mixture is allowed to return to ambient
temperature and concentrated under reduced pressure and
then the residue thus obtained is purified by
chromatography on silica gel, elution being carried out
with a 40/60 mixture of ethyl acetate and of
cyclohexane. 0.390 g (1.05 mmol) of product is thus
obtained in the form of a viscous oil.
7.5. 2-(Methylamino)-2-oxoethyl 4-(2-(isoquinolin-1-yl)
ethyl)-1-piperidinecarboxylate
2.60 ml (5.13 mmol) of a solution of
methylamine (2M) in tetrahydrofuran are added to a
solution of 0.380 g (1.03 mmol) of 2-ethoxy-2-oxoethyl
4-(2-(isoquinolin-1-yl)ethyl)-1-piperidinecarboxylate,
prepared in stage 7.4., in 10 ml of methanol. Stirring
is continued at ambient temperature for 12 hours.
After concentrating under reduced pressure,
the residue obtained is purified by chromatography on
silica gel, elution being carried out with a 95/5
mixture of dichloromethane and of methanol. A solid is
obtained and is recrystallized from a mixture of ethyl
acetate and of diisopropyl ether. 0.315 g (0.88 mmol)

of product is thus obtained in the form of a white
solid.
LC-MS : M+H = 356
Melting point (°C): 126-128
1H NMR (CDCl3) δ (ppm) : 8.50 (d, 1H) , 8.15 (d, 1H) , 7.90
(d, 1H), 7.70 (m, 2H), 7.55 (d, 1H), 6.10 (broad s,
1H), 4.60 (broad s, 2H), 4.20 (m, 2H), 3.35 (dd, 2H),
2.90 (m+d, 5H), 1.90 (m, 4H), 1.65 (m, 1H), 1.30 (m,
2H) .
The chemical structures and the physical
properties of a few compounds according to the
invention are illustrated in the following table. In
this table:
- all the compounds are in the free base form,
- n-butyl represents a linear butyl group.









The compounds of the invention have formed
the subject of pharmacological trials which make it
possible to determine their inhibitory effect on the
enzyme FAAH (Fatty Acid Amido Hydrolase).
The inhibitory activity was demonstrated in a
radioenzymatic test based on the measurement of the
product of hydrolysis ( (1-3H)ethanolamine) of ((1-3H)
ethanolamine)-anandamide by FAAH (Life Sciences (1995),
56, 1999-2005 and Journal of Pharmacology and

Experimental Therapeutics (1997), 283, 729-734). Thus,
mouse brains (minus the cerebellum) are removed and
stored at -80°C. The membrane homogenates are prepared
at the time of use by homogenization of the tissues
with a Polytron in a 10 mM Tris-HCl buffer (pH 8.0)
comprising 150 mM NaCl and 1 mM EDTA. The enzymatic
reaction is subsequently carried out in 70 µl of buffer
comprising bovine serum albumin free from fatty acids
(1 mg/ml). The test compounds, at various
concentrations, the ( (1-3H)ethanolamine)-anandamide
(specific activity of 15-20 Ci/mmol), diluted to 10 µM
with non-radiolabelled anandamide, and the membrane
preparation (400 µg of frozen tissue per assay) are
successively added. After 15 minutes at 25°C, the
enzymatic reaction is halted by addition of 140 µl of
chloroform/methanol (2:1). The mixture is stirred for
minutes and is then centrifuged at 3500 g for 15
minutes. An aliquot (30 µl) of the aqueous phase
comprising the (1-3H) ethanolamine is counted by liquid
scintillation.
Under these conditions, the most active
compounds of the invention exhibit IC50 values
(concentration which inhibits the control enzymatic
activity of FAAH by 50%) of between 0.001 and 1 µM.
For example, compounds Nos. 39 and 40 in the
table exhibit IC50 values of 0.095 and 0.098 µM

respectively.
It is therefore apparent that the compounds
according to the invention have an inhibitory activity
on the enzyme FAAH.
The in vivo activity of the compounds of the
invention was evaluated in a test for analgesia.
Thus, the intraperitoneal (i.p.)
administration of PBQ (phenylbenzoquinone, 2 mg/kg in a
0.9% sodium chloride solution comprising 5% of ethanol)
to male OF1 mice weighing 25 to 30 g causes abdominal
tractions, on average 30 twisting or contracting
motions during the period from 5 to 15 minutes after
injection. The test compounds are administered, orally
(p.o.) or intraperitoneally (i.p.) in suspension in
0.5% Tween 80, 60 minutes or 120 minutes before the
administration of PBQ. Under these conditions, the most
powerful compounds of the invention reduce by 3 5 to 70%
the number of tractions induced by the PBQ, within a
range of doses of between 1 and 3 0 mg/kg.
For example, compound No. 57 in the table
reduces by 37% and by 74% the number of tractions
induced by the PBQ, at a dose of 3 mg/kg p.o., at 60
minutes and at 120 minutes respectively.
The enzyme FAAH (Chemistry and Physics of
Lipids, (2000), 108, 107-121) catalyses the hydrolysis
of endogenous derivatives of amides and esters of

various fatty acids, such as N-arachidonoylethanolamine
(anandamide), N-palmitoylethanolamine,
N-oleoylethanolamine, oleamide or
2-arachidonoylglycerol. These derivatives have various
pharmacological activities by interacting, inter alia,
with the cannabinoid and vanilloid receptors.
The compounds of the invention block this
decomposition pathway and increase the tissue level of
these endogenous substances. They can therefore be used
in the prevention and treatment of pathologies in which
endogenous cannabinoids and/or any other substrate
metabolized by the enzyme FAA.H are involved.
Mention may be made, for example, of the
following diseases and conditions:
Pain, in particular acute or chronic pain of neurogenic
type: migraine, neuropathic pain, including forms
associated with the herpes virus and with diabetes;
acute or chronic pain associated with inflammatory
diseases: arthritis, rheumatoid arthritis,
osteoarthritis, spondylitis, gout, vasculitis, Crohn's
disease, irritable bowel syndrome;
acute or chronic peripheral pain;
dizziness, vomiting, nausea, in particular resulting
from chemotherapy;
eating disorders, in particular anorexia and cachexia
of various natures;

neurological and psychiatric pathologies: tremors,
dyskinesias, dystonias, spasticity, obsessive-
compulsive behaviour, Tourette's syndrome, all forms of
depression and of anxiety of any nature and origin,
mood disorders, psychoses;
acute and chronic neurodegenerative diseases:
Parkinson's disease, Alzheimer's disease, senile
dementia, Huntington's chorea, lesions related to
cerebral ischaemia and to cranial and medullary trauma;
epilepsy;
sleep disorders, including sleep apnoea;
cardiovascular diseases, in particular hypertension,
cardiac arrhythmias, arteriosclerosis, heart attack,
cardiac ischaemia;
renal ischaemia;
cancers: benign skin tumours, brain tumours and
papillomas, prostate tumours, cerebral tumours
(glioblastomas, medulloepitheliomas, medulloblastomas,
neuroblastomas, tumours of embryonic origin,
astrocytomas, astroblastomas, ependymomas,
oligodendrogliomas, plexus tumour, neuroepitheliomas,
epiphyseal tumour, ependymoblastomas, malignant
meningiomas, sarcomatosis, malignant melanomas,
schwannomas);
disorders of the immune system, in particular
autoimmune diseases: psoriasis, lupus erythematosus,

diseases of the connective tissue or collagen diseases,
Sjogren's syndrome, ankylosing spondylitis,
undifferentiated spondylitis, Behcet's disease,
autoimmune haemolytic anaemia, multiple sclerosis,
amyotrophic lateral sclerosis, amyloidosis, graft
rejection, diseases affecting the plasmocytic line;
allergic diseases: immediate or delayed
hypersensitivity, allergic rhinitis or conjunctivitis,
contact dermatitis;
parasitic, viral or bacterial infectious diseases:
AIDS, meningitis;
inflammatory diseases, in particular joint diseases:
arthritis, rheumatoid arthritis, osteoarthritis,
spondylitis, gout, vasculitis, Crohn's disease,
irritable bowel syndrome; osteoporosis;
eye conditions: ocular hypertension, glaucoma;
pulmonary conditions: diseases of the respiratory
tract, bronchospasm, coughing, asthma, chronic
bronchitis, chronic obstruction of the respiratory
tract, emphysema;
gastrointestinal diseases: irritable bowel syndrome,
inflammatory intestinal disorders, ulcers, diarrhoea;
urinary incontinence and bladder inflammation.
The use of a compound of formula (I), in the
base or pharmaceutically acceptable salt, hydrate or
solvate form, in the preparation of a medicament

intended to treat the abovementioned pathologies forms
an integral part of the invention.
Another subject-matter of the invention is
medicaments which comprise a compound of formula (I) or
a pharmaceutically acceptable salt, hydrate or solvate
of the compound of formula (I). These medicaments are
used in therapeutics, in particular in the treatment of
the abovementioned pathologies.
According to another of its aspects, the
present invention relates to pharmaceutical
compositions including, as active principle, at least
one compound according to the invention. These
pharmaceutical compositions comprise an effective dose
of a compound according to the invention or a
pharmaceutically acceptable salt, hydrate or solvate of
the said compound and optionally one or more
pharmaceutically acceptable excipients.
The said excipients are chosen, depending on
the pharmaceutical form and the method of
administration desired, from the usual excipients which
are known to a person skilled in the art.
In the pharmaceutical compositions of the
present invention for oral, sublingual, subcutaneous,
intramuscular, intravenous, topical, local,
intrathecal, intranasal, transdermal, pulmonary, ocular
or rectal administration, the active principle of

formula (I) above or its optional salt, solvate or
hydrate can be administered in a single-dose
administration form, as a mixture with conventional
pharmaceutical excipients, to animals and to man for
the prophylaxis or the treatment of the above disorders
or diseases.
Appropriate single-dose administration forms
comprise oral forms, such as tablets, soft or hard
gelatin capsules, powders, granules, chewing gums and
oral solutions or suspensions, forms for sublingual,
buccal, intratracheal, intraocular or intranasal
administration or for administration by inhalation,
forms for subcutaneous, intramuscular or intravenous
administration and forms for rectal or vaginal
administration. For topical application, the compounds
according to the invention can be used in creams,
ointments or lotions.
By way of example, a single-dose
administration form of a compound according to the
invention in the form of a tablet can comprise the
following components:


Magnesium stearate 3.0 mg
The said single-dose forms comprise a dose
which makes possible a daily administration of 0.01 to
2 0 mg of active principle per kg of body weight,
depending upon the pharmaceutical dosage form.
There may be specific cases where higher or
lower dosages are appropriate; such dosages also come
within the invention. According to the usual practice,
the dosage appropriate to each patient is determined by
the doctor according to the method of administration,
the weight and the response of the said patient.
According to another of its aspects, the
invention also relates to a method for the treatment of
the pathologies indicated above which comprises the
administration of an effective dose of a compound
according to the invention, of one of its
pharmaceutically acceptable salts or of a solvate or of
a hydrate of the said compound.

WE CLAIM:
1. Compound corresponding to the general formula (I)

chosen from the compounds of the following table:







in the base form or in the form of an addition salt
with an acid, of a hydrate or of a solvate.
2. Process for the preparation of a compound of
formula (I) as claimed in Claim 1, comprising the stage
consisting in converting the carbamate-ester of general
formula (IV)

in which R1, A, R2, R3, p, m and n are as defined in the
formula (I) as claimed in Claim 1 and R represents a
methyl or ethyl group,

by aminolysis using an amine of general formula R4NH2,
in which R4 is as defined in the formula (I) according
to Claim 1.
3. Compound corresponding to the general formula (IV)

in which R1, A, R2, R3, p, m and n are as defined in the
formula (I) as claimed in Claim 1 and R represents a
methyl or ethyl group.
4. Medicament comprising a compound of formula (I) as
claimed in Claim 1, or a pharmaceutically acceptable
salt or hydrate or solvate of the compound of formula
(I).
5. Pharmaceutical composition comprising at least one
compound of formula (I) as claimed in Claim 1, in the
base or pharmaceutically acceptable salt, hydrate or
solvate form, and optionally one or more
pharmaceutically acceptable excipients.
6. Compound of formula (I) as claimed in Claim 1, in
the base or pharmaceutically acceptable salt, hydrate
or solvate form, for its use as medicament.

7. Pharmaceutical composition as claimed in claim 5,
which is capable of being used for preparation of a
medicament intended to prevent or treat acute or
chronic pain, dizziness, vomiting, nausea, eating
disorders, neurological and psychiatric pathologies,
acute or chronic neurodegenerative diseases, epilepsy,
sleep disorders, cardiovascular diseases or renal
ischaemia.


Compound corresponding to the
general formula (I):
The compounds of the invention
correspond to the general formula (I):

in which m, n = 1 to 3 and m + n = 2 to 5; p = 1 to 7;
A = single bond or X, Y and/or Z; X = optionally
substituted methylene; Y = C2-alkenylene, which is
optionally substituted, or C2-alkynylene; Z = C3-7-
cycloalkyl; R1 represents a group of aryl or heteroaryl
type; R2 represents a hydrogen or fluorine atom or a
hydroxyl, C1-6-alkoxy or NR8R9 group; R3 represents a
hydrogen atom or a C1-6-alkyl group; R4 represents a
hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl or C3-7-
cycloalkyl-C1-3-alkyl group; in the base form or in the
form of an addition salt with an acid, of a hydrate or
of a solvate. Application in therapeutics.

Documents:

02247-kolnp-06 abstract.pdf

02247-kolnp-06 assignment.pdf

02247-kolnp-06 claims.pdf

02247-kolnp-06 correspondence others.pdf

02247-kolnp-06 description(complete).pdf

02247-kolnp-06 form-1.pdf

02247-kolnp-06 form-3.pdf

02247-kolnp-06 form-5.pdf

02247-kolnp-06 international publication.pdf

02247-kolnp-06 international search authority report.pdf

2247-KOLNP-2006-ABSTRACT 1.1.pdf

2247-KOLNP-2006-AMANDED CLAIMS.pdf

2247-KOLNP-2006-ASSIGNMENT 1.1.pdf

2247-KOLNP-2006-ASSIGNMENT 1.2.pdf

2247-KOLNP-2006-CERTIFIED COPIES(OTHER COUNTRIES).pdf

2247-KOLNP-2006-CORRESPONDENCE 1.1.pdf

2247-KOLNP-2006-CORRESPONDENCE 1.2.pdf

2247-KOLNP-2006-CORRESPONDENCE.pdf

2247-KOLNP-2006-DESCRIPTION (COMPLETE) 1.1.pdf

2247-KOLNP-2006-EXAMINATION REPORT REPLY RECIEVED.pdf

2247-KOLNP-2006-EXAMINATION REPORT.pdf

2247-KOLNP-2006-FORM 1-1.1.pdf

2247-KOLNP-2006-FORM 18 1.1.pdf

2247-kolnp-2006-form 18.pdf

2247-KOLNP-2006-FORM 2.pdf

2247-KOLNP-2006-FORM 3 1.2.pdf

2247-KOLNP-2006-FORM 3-1.1.pdf

2247-KOLNP-2006-FORM 5 1.2.pdf

2247-KOLNP-2006-FORM 5-1.1.pdf

2247-KOLNP-2006-GPA.pdf

2247-KOLNP-2006-GRANTED-ABSTRACT.pdf

2247-KOLNP-2006-GRANTED-CLAIMS.pdf

2247-KOLNP-2006-GRANTED-DESCRIPTION (COMPLETE).pdf

2247-KOLNP-2006-GRANTED-FORM 1.pdf

2247-KOLNP-2006-GRANTED-FORM 2.pdf

2247-KOLNP-2006-GRANTED-SPECIFICATION.pdf

2247-KOLNP-2006-OTHERS 1.1.pdf

2247-KOLNP-2006-OTHERS.pdf

2247-KOLNP-2006-PETITION UNDER RULE 137-1.1.pdf

2247-KOLNP-2006-PETITION UNDER RULE 137.pdf

2247-KOLNP-2006-REPLY TO EXAMINATION REPORT 1.1.pdf

abstract-02247-kolnp-2006.jpg


Patent Number 252397
Indian Patent Application Number 2247/KOLNP/2006
PG Journal Number 20/2012
Publication Date 18-May-2012
Grant Date 14-May-2012
Date of Filing 08-Aug-2006
Name of Patentee SANOFI AVENTIS
Applicant Address 174, AVENUE DE FRANCE F-75013, PARIS
Inventors:
# Inventor's Name Inventor's Address
1 ABOUABDELLAH, AHMED 2 RUE DES EGLANTIERS, FR-94320, THIAIS
2 HOORNAERT, CHRISTIAN 49 AVENUE ARISTIDE BRIAND, FR-92160, ANTONY
3 LARDENOIS, PATRICK 18 RUE VARENGUE, FR-92340, BOURG-LA-REINE
4 MARGUET FRANK 21 RUE D'AMBLAINVILLIERS, FR-91370, VERRIERES LE BUISSON
5 ALMARIO, GARCIA, ANTONIO 26 AVENUE ROGER SALENGRO, FR-92290, CHATENAY MALABRY
PCT International Classification Number C07D 471/04
PCT International Application Number PCT/FR2005/000453
PCT International Filing date 2005-02-25
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0401950 2004-02-26 France