Title of Invention

DERIVATIVES OF PIPERIDINYL- AND PIPERAZINYL-ALKYL CARBAMATES, PREPARATION METHODS THEREOF AND APPLICATION OF SAME IN THERAPEUTICS

Abstract The invention relates to a compound having general formula (I), wherein: A = N or CR2; R2 = H, F, OH, CN, CF3, C1-6-alkyl, C1-6-alcoxy; n = 2 or 3 and m = 2 when A = N; n = 1, 2 or 3 and m = 1 or 2 when A = CR2; B = covalent bond or C1-8-alkylene; R1 = optionally-substituted heteroaryl: R3 = CHR4CONHR5; R4 = H or C1-6-alkyl; R5 = H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkylene; the base, the acid addition salt, the hydrate or the solvate thereof. The invention also relates to the application thereof in therapeutics.
Full Text DERIVATIVES OF PIPERIDINYL- AND PIPERAZINYL-ALKYL CARBAMATES,
PREPARATION METHODS THEREOF AND APPLICATION OF SAME IN
THERAPEUTICS
The invention relates to piperidyl- and piperazinyl-
alkylcarbamate derivatives and to the preparation and
therapeutic application thereof.
The compounds of the invention correspond to
the general formula (I):

in which
A represents a nitrogen atom or a group CR2 in which R2
represents a hydrogen or fluorine atom or a hydroxyl,
cyano, trifluoromethyl, C1-6-alkyl or C1-6-alkoxy group;
n represents an integer equal to 2 or 3 and m
represents an integer equal to 2 when A represents a
nitrogen atom;
n represents an integer equal to 1, 2 or 3 and m
represents an integer equal to 1 or 2 when A represents
a group CR2;
B represents a covalent bond or a C1-8-alkylene group;
R1 represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl,
tetrahydroisoquinolyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, cinnolyl,
imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl,
benzothienyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
indazolyl, pyrrolopyridyl, furopyridyl,
dihydrofuropyridyl, thienopyridyl, dihydro-
thienopyridyl, imidazopyridyl, pyrazolopyridyl,
oxazolopyridyl, isoxazolopyridyl and thiazolopyridyl;
the group R1 optionally being substituted with one or
more groups R' and/or R";
R' represents a halogen atom or a cyano, nitro,
hydroxyl, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl, C1-6-
fluoroalkyl, C1-6-fluoroalkoxy, C1-6-fluorothioalkyl,
C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkylene,
azetidinyl, piperidyl, pyrrolidinyl, morpholinyl,
piperazinyl, azepinyl, NH2, NHR5, NR6R7, NR6COR7,
NR6SO2R7, COR6, CO2R6, SO2R6, SO2NR6R7 or -O-(C1-6-
alkylene)-O- group;
R" represents a phenyl, imidazolyl, pyridyl, pyridaz-
inyl, pyrazinyl or pyrimidinyl;
the group(s) R" being optionally substituted with one
or more groups R', which may be identical to or
different from each other;
R3 represents a group of general formula CHR4CONHR5 in
which
R4 represents a hydrogen atom or a C1-6-alkyl group and
R5 represents a hydrogen atom or a C1-6-alkyl, C3-7-
cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene group;
R6 and R7 represent, independently of each other, a C1-6-
alkyl group.
Among the compounds of general formula (I), a
first subgroup of compounds consists of compounds for
which:
A represents a nitrogen atom; and/or
n represents an integer equal to 2 or 3 and m
represents an integer equal to 2; and/or
B represents a C1-8-alkylene group, more particularly an
ethyl or propyl; and/or
R1 represents a group chosen from phenyl, pyridyl,
pyrimidinyl, thiadiazolyl and naphthyl;
the group R1 being optionally substituted with one or
more groups R' and/or R"; and/or
R' represents a halogen atom, more particularly a
chlorine, or a nitro or C1-6-fluoroalkyl group, more
particularly a trifluoromethyl; and/or
R" represents a phenyl optionally substituted with one
or more groups, which may be identical to or different
from each other, chosen from a halogen atom, more
particularly a chlorine, and a cyano, C1-6-alkoxy, more
particularly a methoxy, or C1-6-fluoroalkoxy, more
particularly a trifluoromethoxy, group; and/or
R3 represents a group of general formula CHR4CONHR5 in
which
R4 represents a hydrogen atom and
R5 represents a hydrogen atom or a C1-6-alkyl group,
more particularly a methyl or an ethyl, a C3-7-
cycloalkyl group, more particularly a cyclopropyl, or a
C3-7-cycloalkyl-C1-6-alkylene group, more particularly a
cyclopropyl-methylene.
Among the compounds of general formula (I), a
second subgroup of compounds consists of compounds for
which:
A represents a group CR2 in which R2 represents a
hydrogen or fluorine atom or a hydroxyl group;
and/or
m represents an integer equal to 1 or 2 and n
represents an integer equal to 1 or 2; and/or
B represents a covalent bond or a C1-4-alkylene group,
more particularly a methyl, ethyl or n-propyl; and/or
R1 represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
quinolyl, isoquinolyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, furopyridyl, thieno-
pyrimidinyl, imidazopyrimidinyl, benzothiazolyl,
benzimidazolyl and benzoxazolyl;
the group R1 being optionally substituted with one or
more groups R' and/or R"; and/or
R' represents a halogen atom, more particularly a
fluorine, a chlorine or a bromine, or a cyano group,
C1-6-alkyl, more particularly a methyl, ethyl, n-propyl
or isobutyl, a Cx-6-alkoxy, more particularly a methoxy,
C1-6-fluoroalkyl, more particularly a trifluoromethyl,
C1-6-fluoroalkoxy, more particularly a trifluoromethoxy,
C3-7-cycloalkyl, more particularly a cyclopropyl or
cyclopentyl, pyrrolidinyl, NH2/ NR6R7 or COR6; and/or
R" represents a phenyl, imidazolyl or pyridyl; the
group(s) R" being optionally substituted with one or
more groups R', which may be identical to or different
from each other, more particularly with one or more
chlorine or fluorine atoms; and/or
R3 represents a group of general formula CHR4CONHR5 in
which
R4 represents a hydrogen atom or a C1-6-alkyl group,
more particularly a methyl, and
R5 represents a hydrogen atom or a C1-6-alkyl group,
more particularly a methyl or an ethyl, C3-7-cycloalkyl,
more particularly a cyclopropyl, C3-7-cycloalkyl-C1-C6-
alkylene, more particularly a cyclopropyl-methylene;
and/or
R6 and R7 represent, independently of each other, a C1-6-
alkyl group, more particularly a methyl.
Among the compounds of general formula (I), a
third subgroup of compounds consists of compounds for
which:
A represents a group CR2 in which R2 represents a
hydrogen atom; and/or
m is equal to 2 and n is equal to 2; and/or
B represents an ethyl group; and/or
R1 represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
quinolyl, isoquinolyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, furopyridyl, thieno-
pyrimidinyl, imidazopyrimidinyl, benzothiazolyl,
benzimidazolyl and benzoxazolyl;
the group R1 being optionally substituted with one or
more groups R' and/or R"; and/or
R' represents a halogen atom, more particularly a
fluorine, a chlorine or a bromine, or a cyano group,
C1-6-alkyl, more particularly a methyl, ethyl, n-propyl
or isobutyl, a C1-6-alkoxy, more particularly a methoxy,
C1-6-fluoroalkyl, more particularly a trifluoromethyl,
C1-6-fluoroalkoxy, more particularly a trifluoromethoxy,
C3-7-cycloalkyl, more particularly a cyclopropyl or
cyclopentyl, pyrrolidinyl, NH2, NR6R7 or COR6; and/or
R" represents a phenyl, imidazolyl or pyridyl;
the group(s) R" being optionally substituted with one
or more groups R', which may be identical to or
different from each other, more particularly with one
or more chlorine or fluorine atoms; and/or
R3 represents a group of general formula CHR4CONHR5 in
which
R4 represents a hydrogen atom and
R5 represents a hydrogen atom or a C1-C6-alkyl group,
more particularly a methyl or an ethyl; and/or
R6 and R7 represent, independently of each other, a C1-6-
alkyl group, more particularly a methyl.
A subject of the invention is also, among the
compounds of general formula (I), compounds
corresponding to the general formula (I'):

in which
A represents a nitrogen atom or a group CR2 in which R2
represents a hydrogen or fluorine atom or a hydroxyl,
cyano, trifluoromethyl, C1-5-alkyl or C1-5-alkoxy group;
n represents an integer equal to 2 or 3 and m
represents an integer equal to 2 when A represents a
nitrogen atom;
n represents an integer equal to 1, 2 or 3 and m
represents an integer equal to 1 or 2 when A represents
a group CR2;
B represents a covalent bond or a C1-8-alkylene group;
R1 represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, naphthyl, quinolyl, tetrahydroquinolyl,
isoquinolyl, tetrahydroisoquinolyl, phthalazinyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl,
imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl,
benzothienyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
indazolyl, pyrrolopyridyl, furopyridyl,
dihydrofuropyridyl, thienopyridyl, dihydrothieno-
pyridyl, imidazopyridyl, pyrazolopyridyl,
oxazolopyridyl, isoxazolopyridyl and thiazolopyridyl;
optionally substituted with one or more substituents
chosen from a halogen atom and a cyano, nitro, C1-5-
alkyl, C1-3-alkoxy, C1-5-thioalkyl, C1-5-fluoroalkyl,
C1-3-fluoroalkoxy, C1-3-fluorothioalkyl, C3-5-cycloalkyl,
C3-5-cycloalkyl-C1-3-alkylene, piperidyl, pyrrolidinyl,
morpholinyl, NH2, NHR6, NR6R7, NHCOR6, COR6, CO2R6, SO2R6,
-0-(C1-3-alkylene)-0-, phenyl, pyridyl or pyrimidinyl
group;
the phenyl, pyridyl and pyrimidinyl groups possibly
being substituted with one or more substituents chosen
from a halogen atom and a cyano, nitro, hydroxyl, C1-5-
alkyl, C1-3-alkoxy, C1-5-thioalkyl, C1-5-f luoroalkyl,
C1-3-fluoroalkoxy, C1-3-fluorothioalkyl, C3-5-cycloalkyl,
C3-5-cycloalkyl-C1-3-alkylene, piperidyl, pyrrolidinyl,
morpholinyl, NH2, NHR6, NR6R7, NHCOR6, COR6, CO2R6, SO2R6,
or -0-(Ci-3-alkylene)-0- group;
R3 represents a group of general formula CHR4CONHR5 in
which
R4 represents a hydrogen atom or a C1-3-alkyl group and
R5 represents a hydrogen atom or a C1-3-alkyl, C3-5-
cycloalkyl or C3-5-cycloalkyl-C1-3-alkylene group;
R6 and R7 represent, independently of each other, a C1-3-
alkyl group.
The compounds of general formula (I) may
comprise one or more asymmetric carbons. They may exist
in the form of enantiomers or diastereoisomers. These
enantiomers and diastereoisomers, and also mixtures
thereof, including racemic mixtures, form part of the
invention.
The compounds of general formula (I) may
exist in the form of bases or of acid-addition salts.
Such addition salts form part of the invention.
These salts are advantageously prepared with
pharmaceutically acceptable acids, but the salts of
other acids that are useful, for example, for the
purification or isolation of the compounds of formula
(I) also form part of the invention.
The compounds of general formula (I) may be
in the form of hydrates or solvates, i.e. in the form
of associations or combinations with one or more water
molecules or with a solvent. Such hydrates and solvates
also form part of the invention.
In the context of the invention, the
following definitions apply:
- Ct-z in which t and z may take values from 1 to 8, a
carbon-based chain possibly containing from t to z
carbon atoms, for example a C1-3 carbon-based chain
which may contain from 1 to 3 carbon atoms,
- alkyl, a saturated, linear or branched aliphatic
group, for example a C1-3-alkyl group represents a
linear or branched carbon-based chain of 1 to
3 carbon atoms, more particularly a methyl, ethyl,
propyl or 1-methylethyl,
- alkylene, a saturated, linear or branched divalent
alkyl group, for example a C1-3-alkylene group
represents a linear or branched divalent carbon-based
chain of 1 to 3 carbon atoms, more particularly a
methylene, ethylene, 1-methylethylene or propylene,
- cycloalkyl, a cyclic alkyl group, for example a C3-5-
cycloalkyl group represents a cyclic carbon-based
group of 3 to 5 carbon atoms, more particularly a
cyclopropyl, cyclobutyl or cyclopentyl,
- alkoxy, an -O-alkyl group containing a saturated,
linear or branched aliphatic chain,
- thioalkyl, an -S-alkyl group containing a saturated,
linear or branched aliphatic chain,
- fluoroalkyl, an alkyl group in which one or more
hydrogen atoms have been replaced with a fluorine
atom,
- fluoroalkoxy, an alkoxy group in which one or more
hydrogen atoms have been replaced with a fluorine
atom,
- fluorothioalkyl, a thioalkyl group in which one or
more hydrogen atoms have been replaced with a
fluorine atom,
- halogen atom, a fluorine, a chlorine, a bromine or an
iodine.
The compounds of the invention may be
prepared according to various methods, illustrated by
the schemes that follow.
Thus, a first method (Scheme 1) consists in
reacting an amine of general formula (II), in which A,
B, R1, n and m are as defined above, with a carbonate of
general formula (IIIa) in which Z represents a hydrogen
atom or a nitro group, R4 is as defined above and R
represents a methyl or ethyl group. The carbamate ester
of general formula (la) thus obtained is then converted
into a compound of general formula (I), via aminolysis
using an amine of general formula R5NH2 in which R5 is
as defined above. The aminolysis reaction may be
performed in a solvent such as methanol or a mixture of
solvents such as methanol and tetrahydrofuran or
methanol and dioxane.
One variant for obtaining the compounds of
general formula (I) (Scheme 1) consists in reacting an
amine of general formula (II), as defined above, with a
carbonate of general formula (IIIb), in which Z
represents a hydrogen atom or a nitro group and R4 and
R5 are as defined above, in a solvent such as toluene or
dichloroethane, at a temperature of between 0°C and
80°C.
The carbonates of general formula (IIIa) and
(IIIb) may be prepared according to any method
described in the literature, for example by reacting an
alcohol of general formula HOCHR4COOR, in which R
represents a methyl or ethyl group, or HOCHR4CONHR5 in
which R4 and R5 are as defined above, with phenyl
chloroformate or 4-nitrophenyl chloroformate, in the
presence of a base such as triethylamine or diiso-
propylethylamine.
A second method for obtaining the compounds
of general formula (I) (Scheme 2) consists in reacting
a derivative of general formula (IIa) in which Y
represents a hydroxyl, mesylate or tosylate group or a
chlorine, bromine or iodine atom and A, B, R1, n and m
are as defined above, with an oxazolidinedione of
general formula (IV) in which R4 is as defined above, to
give the oxazolidinedione derivative of general formula
(V). In the case where Y represents a hydroxyl group,
the reaction may be performed according to the
Mitsunobu conditions (Synthesis, 1981, 1-28), for
example via the action of diethyl or diisopropyl
azodicarboxylate in the presence of triphenylphosphine.
In the case where Y represents a chlorine, bromine or
iodine atom or a mesylate or tosylate group, the
reaction may be performed in the presence of a base
such as 1,1,3,3-tetramethylguanidine, sodium hydride or
sodium tert-butoxide in a solvent such as tetrahydro-
furan, acetonitrile or dimethylformamide, at a
temperature of between 0°C and the reflux temperature
of the solvent. The oxazolidinedione derivative of
general formula (V) thus obtained is then converted
into a compound of general formula (I), via aminolysis
using an amine of general formula R5NH2 in which R5 is
as defined above.

The compounds of general formulae (I), (Ia),
(II), (IIa) and (V), in which R1 is substituted with a
group R", may also be prepared by reacting the
corresponding compounds of general formulae (I), (Ia),
(II), (IIa) and (V), for which R1 is substituted with a
chlorine, bromine or iodine atom or with a triflate
group in the position into which the group R" is to be
introduced, with an aryl- or heteroaryl-boronic acid
derivative according to the Suzuki reaction conditions
(Chem. Rev. 1995, 95, 2457-2483) or with an aryl- or
heteroaryl-trialkylstannane derivative according to the
Stille reaction conditions (Angew. Chem. Int. Ed. 1986,
25, 504-524).
The compounds of general formulae (II), (IIa)
and (IV), when their preparation method is not
described, are commercially available or are described
in the literature, or alternatively may be prepared
according to methods that are described therein or
known to those skilled in the art.
The amines of general formula R5NH2 are
commercially available.
According to another of its aspects, a
subject of the invention is also the compounds of
formula (Ia) in which n, m, A, B, R1 and R4 are as
defined above and R represents a methyl or ethyl group.
The compounds of formula (Ia) are useful as synthetic
intermediates for the preparation of the compounds of
formula (I).
According to another of its aspects, a
subject of the invention is also the compounds of
formula (V) in which n, m, A, B, R1 and R4 are as
defined above, the following compounds being excluded:
* 3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-
piperidyl]-2,4-oxazolidinedione
* 3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-
piperidyl]-5-methyl-2,4-oxazolidinedione
* 3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-
piperidyl]-5-ethyl-2,4-oxazolidinedione
* 3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-
piperidyl]-5-propyl-2,4-oxazolidinedione
* 3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-
piperidyl]—5-(1-methylethyl)-2,4-oxazolidinedione.
The compounds of formula (V) are useful as
synthetic intermediates for the preparation of the
compounds of formula (I).
The examples that follow illustrate the
preparation of a number of compounds of the invention.
These examples are not limiting and are given merely to
illustrate the invention. The microanalyses and the IR,
NMR and/or LC/MS (Liquid Chromatography coupled to Mass
Spectroscopy) spectra confirm the structures and
purities of the compounds obtained.
m.p. (°C) represents the melting point in
degrees Celsius.
The numbers indicated in parentheses in the
example titles correspond to those in the first column
of the table hereinbelow.
The IUPAC (International Union of Pure and
Applied Chemistry) nomenclature has been used for the
naming of the compounds in the examples that follow.

1.1. 2-{2-[4-(1-Naphthyl)-1-piperazinyl]ethyl}-lH-
isoindole-1,3(2H) -dione
A suspension of 1.17 g (5.52 mmol) of 1-(1-
naphthyDpiperazine (Tetrahedron Letters, 1998, 39(15),
2219-2222), 0.99 g (7.15 mol) of potassium carbonate
and 1.68 g (6.62 mmol) of 2-(2-bromoethyl)-lH-
isoindole-1,3(2H)-dione in 15 ml of N,N-dimethyl-
formamide is heated at 90°C for 2 hours.
The mixture is allowed to cool to room
temperature and is concentrated under reduced pressure.
The residue is taken up in ethyl acetate and water, the
aqueous phase is separated out and extracted three
times with ethyl acetate, and the combined organic
phases are washed with saturated aqueous sodium

chloride solution and dried over sodium sulfate. After
evaporating off the solvent, the residue obtained is
purified by chromatography on silica gel, eluting with
a 40/60 mixture of ethyl acetate and cyclohexane.
1.14 g of pure product are thus obtained in
the form of an oil.
1.2. 2- [4-(1-Naphthyl)-1-piperazinyl]ethanamine
0.17 ml (3.55 mmol) of hydrazine monohydrate
is added slowly at room temperature to a solution of
1.14 g (2.96 mmol) of 2-{2-[4-(1-naphthyl)-1-piperaz-
inyl] ethyl}-lH-isoindole-l,3 (2H) -dione, prepared in
step 1.1, in 15 ml of ethanol. The reaction mixture is
then refluxed for 1 hour.
The mixture is allowed to cool to room
temperature, the insoluble material is separated out by
filtration and the filtrate is concentrated under
reduced pressure. The residue is taken up in 20 ml of
ether and stirred at room temperature for 20 minutes.
The insoluble material is again separated out and the
filtrate is concentrated under reduced pressure. The
residue obtained is purified by chromatography on
silica gel, eluting with a 90/10/1 mixture of dichloro-
methane, methanol and 28% aqueous ammonia.
0.4 5 g of amine is thus obtained in the form
of a colourless oil.
1.3. Ethyl [(phenyloxycarbonyl)oxy]acetate

32 ml (256 mmol) of phenyl chloroformate are
added slowly at room temperature to a solution of 25 g
(240 mmol) of ethyl glycolate and 55 ml (315 mmol) of
diisopropylethylamine in 500 ml of toluene. Stirring is
continued at room temperature for 2 hours.
The salt formed is separated out and the
filtrate is concentrated under reduced pressure.
53.7 g of oily product are obtained, and are
used without further purification in the following
step.
1.4. Ethyl [({2,4-(l-naphthyl)-l-piperazinyl]ethyl}-
amino)carbonyl]oxyacetate
A solution of 0.45 g (1.76 mmol) of 2-[4-(l-
naphthyl)-1-piperazinyl]ethanamine, prepared in step
1.2, and 0.48 g (2.16 mmol) of ethyl [ (phenyloxy-
carbonyl)oxy]acetate, obtained in step 1.3, in 15 ml of
toluene is heated at 50°C for 6 hours.
The mixture is allowed to cool to room
temperature, the insoluble material is separated out
by filtration and the filtrate is concentrated under
reduced pressure. The residue is taken up in dichloro-
methane and water, the aqueous phase is separated out
and extracted three times with dichloromethane, and the
combined organic phases are washed with saturated
aqueous sodium chloride solution and dried over sodium
sulfate. After evaporating off the solvent, the residue
obtained is purified by chromatography on silica gel,

eluting with a 97/3 and then 93/7 mixture of dichloro-
methane and methanol. 0.4 9 g of pure product is thus
obtained in the form of an oil.
1.5. 2-(Methylamino)-2-oxoethyl 2-[4-(1-naphthyl)-1-
piperazinyl]ethylcarbamate
1.9 ml (3.75 mmol) of a solution (2M) of
methylamine in tetrahydrofuran are added to a solution
of 0.48 g (1.25 mmol) of ethyl [({2,4-(1-naphthyl)-1-
piperazinyl]ethyl}amino)carbonyl]oxyacetate, prepared
in step 1.4, in 5 ml of methanol. Stirring is continued
at room temperature for 1 hour.
After concentrating under reduced pressure,
the residue obtained is purified by chromatography on
silica gel, eluting with a 97/3 mixture of dichloro-
methane and methanol. An oily residue is obtained,
which is taken up with a solution of hydrochloric acid
(5N) in isopropanol. The mixture is concentrated to
dryness and the salt obtained is then recrystallized
from a 1/1 mixture of acetone and diisopropyl ether.
0.23 g of pure monohydrochloride product is
thus obtained in the form of a white solid.
LC-MS: M+H =371
m.p. (°C): 166°C
1H NMR (DMSO) d (ppm): 2.55 (d, 3H); 3.20-3.75
(unresolved peak, 12H); 4.40 (s, 2H); 7.10 (d, 1H) ;
7.35-7.70 (unresolved peak, 4H); 7.80-8.05 (unresolved
peak, 2H); 8.15 (dd, 1H); 10.90 (broad s, 1H).
2.1. 2-[1-(1-Isoquinolyl)-4-piperidyl]ethanol
4.17 g (25.50 mmol) of 1-chloroisoquinoline,
3.62 g (28 mmol) of 2-(4-piperidyl)ethanol, 5.90 g
(61.20 mmol) of sodium tert-butoxide and 0.47 6 g
(0.765 mmol) of BINAP (2,2'-bis(diphenylphosphino)-
1,1'-binaphthyl) suspended in 50 ml of toluene are
introduced under an inert atmosphere. 0.233 g
(0.255 mmol) of tris(dibenzylideneacetone)dipalladium
is then added. The reaction mixture is then refluxed
for 12 hours.
The salts are separated out by filtration
through Celite and the filtrate is then concentrated
under reduced pressure. The residue is taken up in
ethyl acetate and water, the aqueous phase is separated
out and extracted twice with ethyl acetate, and the
combined organic phases are washed with saturated
aqueous sodium chloride solution and dried over sodium
sulfate. After evaporating off the solvent, the residue
obtained is purified by chromatography on silica gel,

eluting with a 97/3 mixture of dichloromethane and
methanol.
3.34 g of product are obtained in the form of
a grey paste.
2.2. 1-[4-(2-Chloroethyl)-1-piperidyl]isoquinoline
2.20 ml (30.10 mmol) of thionyl chloride are
added dropwise to a solution of 3.09 g (12.10 mmol) of
2-[1-(1-isoquinolyl)-4-piperidyl]ethanol, prepared in
step 2.1, in 30 ml of dichloromethane. The reaction
mixture is then refluxed for 5 hours.
The mixture is concentrated to dryness under
reduced pressure. The residue is taken up in 40 ml of
dichloromethane and 30 ml of aqueous sodium hydroxide
solution (1M). The aqueous phase is separated out and
extracted twice with dichloromethane, the combined
organic phases are washed with saturated aqueous sodium
chloride solution and dried over sodium sulfate, and
the filtrate is concentrated under reduced pressure.
2.7 0 g of product are obtained in the form of a brown
paste, which is used without further purification in
the following step.
2.3. 3-[1-(1-Isoquinolyl)-4-piperidyl]propanenitrile
0.63 g (9.57 mmol) of potassium cyanide is
added portionwise to a suspension of 2.63 g (9.57 mmol)
of 1-[4-(2-chloroethyl)-1-piperidyl]isoquinoline,
prepared in step 2.2, and 0.048 g (0.29 mmol) of
potassium iodide in 30 ml of dimethyl sulfoxide. The
reaction mixture is maintained at about 120°C for 16
hours. The mixture is allowed to cool to room
temperature and 90 ml of water and ethyl acetate are
then added. The aqueous phase is separated out and
extracted three times with ethyl acetate, the combined
organic phases are washed with saturated aqueous sodium
chloride solution and dried over sodium sulfate, and
the filtrate is concentrated under reduced pressure.
The residue thus obtained is purified by chromatography
on silica gel, eluting with a 30/70 mixture of ethyl
acetate and cyclohexane.
0.77 g of product is obtained in the form of
a yellow solid,
m.p. (°C): 141-143°C
2.4. 3-[1-(1-Isoquinolyl)-4-piperidyl]propanamine
A solution of 0.77 g (2.90 mmol) of 3-[l-(l-
isoquinolyl)-4-piperidyl]propanenitrile, prepared in
step 2.3, in 16 ml of tetrahydrofuran is added dropwise
to a suspension of 0.22 g (5.80 mmol) of lithium
aluminium hydride in 8 ml of tetrahydrofuran. The
reaction mixture is then refluxed for 5 hours.
The reaction medium is cooled to about 0°C
and 15 ml of aqueous sodium hydroxide solution (1M) are
then added slowly. The mixture is stirred at room
temperature for 30 minutes, followed by portionwise
addition of wet sodium sulfate. The salts are separated
out by filtration through paper and the phases are then
allowed to separate by settling. The aqueous phase is
extracted three times with ethyl acetate, the combined
organic phases are dried over sodium sulfate and the
filtrate is concentrated under reduced pressure. The
residue thus obtained is purified by chromatography on
silica gel, eluting with a 93/7/0.7 mixture of
dichloromethane, methanol and 28% aqueous ammonia.
0.329 g of product is obtained in the form of
a yellow oil that crystallizes at room temperature.
2.5. Ethyl [{3-[1-(1-isoquinolyl)-4-piperidyl]propyl}-
amino)carbonyl]oxyacetate
The process is performed as in Example 1
(step 1.4). Starting with 0.350 g (1.30 mmol) of 3-[l-
(1-isoquinolyl)-4-piperidyl]propanamine, obtained in
step 2.4, and 0.32 g (1.43 mmol) of ethyl [(phenyloxy-
carbonyl)oxy]acetate, prepared in step 1.3 of Example
1, and after chromatography on silica gel, eluting with
a 20/80 and then 30/70 mixture of ethyl acetate and
cyclohexane, 0.383 g of product is obtained in the form
of a yellow paste.
2.6. 2-(Methylamino)-2-oxoethyl 3-[1-(1-isoquinolyl)-4-
piperidyl]propylcarbamate
The process is performed as described in
Example 1 (step 1.5). Starting with 0.380 g (0.95 mmol)
of ethyl [{3-[1-(1-isoquinolyl)-4-piperidyl]propyl}-
amino)carbonyl]oxyacetate, obtained in step 2.5, and
4.8 ml (9.51 mmol) of a solution (2M) of methylamine in
tetrahydrofuran, and after chromatography on silica
gel, eluting with a 98/2 and then 95/5 mixture of
dichloromethane and methanol, 0.211 g of product is
obtained in the form of an oil. This oily residue is
then taken up in a solution of hydrochloric acid (5N)
in isopropanol and the salt formed is filtered off and
then washed with ethyl acetate.
After drying under vacuum at about 4 0°C,
0.204 g of hydrochloride is obtained in the form of an
amorphous white solid.
LC-MS: M+H = 385
1H NMR (DMSO+D2O) d (ppm): 1.30 (m, 2H); 1.40-1.80
(unresolved peak, 5H); 1.90 (broad d, 2H); 2.60 (s,
3H); 3.05 (m, 2H); 3.40 (t, 2H); 4.05 (broad d, 2H);
4.30 (s, 2H); 7.50 (d, 1H); 7.80 (m, 2H); 7.95 (t, 1H);
8.05 (d, 1H); 8.20 (d, 1H).
3.1. 2-{1-[3-(Trifluoromethyl)phenyl]-4-piperidyl}-
ethanol
The process is performed as described in
Example 2 (step 2.1). Starting with 25.6 g
(113.90 mmol) of l-bromo-3-(trifluoromethyl)benzene,
17.66 g (136.60 mmol) of 2-(4-piperidyl)ethanol,
26.24 g (273 mmol) of sodium tert-butoxide, 2.12 g
(3.41 mmol) of BINAP and 1.04 g (1.14 mmol) of tris-
(dibenzylideneacetone)dipalladium, and after
chromatography on silica gel, eluting with a 25/75
mixture of ethyl acetate and cyclohexane, 17.90 g of an
orange-coloured oily residue are obtained. This residue
is then taken up in 100 ml of methanol, a solution of
4.24 g of potassium hydroxide in 15 ml of methanol is
then added and stirring is continued at room
temperature for 1 hour. The mixture is concentrated
under reduced pressure and the residue is then taken up
in chloroform and aqueous hydrochloric acid solution
(1N). The organic phase is separated out and dried over
sodium sulfate, and the filtrate is concentrated under
reduced pressure. 14 g of product are obtained in the
form of a dark yellow oil, which is used without
further purification in the following step.
3.2. 2-{l-[3-(Trifluoromethyl)phenyl]-4-piperidyl}ethyl
methanesulfonate
A solution of 1 g (8.78 mmol) of mesyl
chloride in 5 ml of dichloromethane is added dropwise
under an inert atmosphere to a solution of 2 g
(7.32 mmol) of 2-{1-[3-(trifluoromethyl)phenyl]-4-
piperidyljethanol, obtained in step 3.1, and 1.53 ml
(10.98 mmol) of triethylamine in 40 ml of dichloro-
methane, cooled to about 0°C. Stirring is continued at
0°C for 1 hour and then at room temperature for
2 hours.
Water is added to the reaction medium, the
aqueous phase is separated out and extracted three
times with dichloromethane, the combined organic phases
are washed with saturated aqueous sodium chloride
solution and dried over sodium sulfate, and the
filtrate is concentrated under reduced pressure.
2.5 g of product are thus obtained in the
form of an oil, which is used without further
purification in the following step.
3.3. 3-(2-{1-[3-(Trifluoromethyl)phenyl]-4-piperidyl}-
ethyl)-1,3-oxazolidine-2,4-dione
A solution of 2.3 g (6.545 mmol) of 2-{l-[3-
(trifluoromethyl)phenyl]-4-piperidyl}ethyl methane-
sulfonate, prepared in step 3.2, 0.694 g (6.87 mmol) of
l,3-oxazolidine-2,4-dione (J. Med. Chem., 1991, 34,
1538-1544) and 1.5 g (13.09 mmol) of 1,1,3,3-tetra-
methylguanidine in 30 ml of tetrahydrofuran is refluxed
for 12 hours under an inert atmosphere.
The mixture is concentrated under reduced
pressure. The residue is taken up in dichloromethane
and water, the aqueous phase is separated out and
extracted twice with dichloromethane, and the combined
organic phases are washed with saturated aqueous sodium
chloride solution and dried over sodium sulfate. After
evaporating off the solvent, the residue obtained is
purified by chromatography on silica gel, eluting with
a 20/80 and then 40/60 mixture of ethyl acetate and
cyclohexane.
1.61 g of pure product are obtained in the
form of an oil.
3.4. 2-Amino-2-oxoethyl 2-{1-[3-(trifluoromethyl)-
phenyl]-4-piperidyl}ethylcarbamate
9.3 ml (64.82 mmol) of a solution of aqueous
ammonia (7N) in methanol are added to a solution of
0.77 g (2.16 mmol) of 3-(2-{1-[3-(trifluoromethyl)-
phenyl]-4-piperidyl}ethyl)-1,3-oxazolidine-2,4-dione,
obtained in step 3.3, in 10 ml of a 1/1 mixture of
methanol and tetrahydrofuran. Stirring is continued at
room temperature for 24 hours.
After concentrating under reduced pressure,
the residue obtained is purified by chromatography on
silica gel, eluting with a 97/3 and then 95/5 mixture
of dichloromethane and methanol, followed by
recrystallization from a mixture of ethyl acetate and
diisopropyl ether.
0.370 g of pure product is obtained in the
form of a white solid.
LC-MS: M+H =37 4
m.p. (°C): 140-142°C
1H NMR (CDCI3) d (ppm): 1.30-1.55 (unresolved peak, 5H) ;
1.90 (broad d, 2H); 2.80 (t, 2H); 3.35 (q, 2H); 3.80
(broad d, 2H); 4.60 (s, 2H); 4.90 (broad s, 1H) ; 5.55
(broad s, 1H); 6.05 (broad s, 1H); 7.10 (m, 3H); 7.35
(t, 1H) .

4.1. 2-[1-(6-Methyl-2-pyridyl)-4-piperidyl]ethanol
1 g (7.74 mmol) of 2-(4-piperidyl)ethanol and
0.987 g (7.74 mmol) of 2-chloro-6-methylpyridine are
introduced into an autoclave. The mixture is then
heated at 130°C for 17 hours.
The reaction mixture is allowed to cool to
room temperature and is then taken up in chloroform and
saturated aqueous sodium hydrogen carbonate solution.
The aqueous phase is separated out and extracted twice
with chloroform, the combined organic phases are washed
with saturated aqueous sodium chloride solution and
dried over sodium sulfate, and the filtrate is
concentrated under reduced pressure.
1.21 g of product are thus obtained in the
form of an orange-coloured liquid, which is used
without further purification in the following step.
4.2. 2-[l-(6-Methyl-2-pyridyl)-4-piperidyl]ethyl
methanesulfonate
The process is performed as in Example 3
(step 3.2). Starting with 0.661 g (3 mmol) of 2-[l-(6-
methyl-2-pyridyl)-4-piperidyl]ethanol, obtained in step
4.1, 0.378 g (3.30 mmol) of mesyl chloride and 0.63 ml
(4.50 mmol) of triethylamine, 0.779 g of product is
obtained in the form of an orange-coloured oil, which
is used without further purification in the following
step.
4.3. 3-{2-[1-(6-Methyl-2-pyridyl)-4-piperidyl]ethyl}-
1,3-oxazolidine-2,4-dione
The process is performed according to the
method described in Example 3 (step 3.3). Starting with
0.776 g (2.60 mmol) of 2-[1-(6-methyl-2-pyridyl)-4-
piperidyl]ethyl methanesulfonate, obtained in step 4.2,
0.315 g (3.12 mmol) of 1,3-oxazolidine-2,4-dione and
0.65 ml (5.20 mmol) of 1,1,3,3-tetramethylguanidine,
and after chromatography on silica gel, eluting with a
30/70 mixture of ethyl acetate and cyclohexane, 0.76 g
of pure product is obtained in the form of a yellow
oil.
4.4. 2-(Methylamino)-2-oxoethyl 2-[1-(6-methyl-2-
pyridyl)-4-piperidyl]ethylcarbamate
The process is performed according to the
procedure described in Example 1 (step 1.5). Starting
with 0.841 g (2.77 mmol) of 3-{2-[1-(6-methyl-2-
pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione,
obtained in step 4.3, and 6.9 ml (13.8 6 mmol) of a
solution (2M) of methylamine in tetrahydrofuran,
0.598 g of pure product is obtained in the form of an
oil, after chromatography on silica gel, eluting with a
95/5 mixture of dichloromethane and methanol. This oily
residue is then taken up with a solution of hydro-
chloric acid (5N) in isopropanol and the salt formed is
filtered off and then washed successively with acetone
and then with ether.
After drying under vacuum at about 80°C,
0.492 g of hydrochloride is obtained in the form of a
white powder.
LC-MS: M+H = 335
m.p. (°C): 95-100°C
1H NMR (DMSO+D2O) d (ppm): 0.95-1.45 (unresolved peak,
4H); 1.60 (m, 1H); 1.80 (broad d, 2H); 2.40 (s, 3H) ;
2.60 (s, 3H); 2.90-3.20 (unresolved peak, 4H); 4.10
(broad d, 2H); 4.30 (s, 2H); 6.70 (d, 1H); 7.10 (d,
1H); 7.75 (dd, 1H).
5.1. [1-(1-Isoquinolyl)-4-piperidyl]methanol
The process is performed as described in
Example 2 (step 2.1). Starting with 2.50 g (15.28 mmol)
of 1-chloroisoquinoline, 1.94 g (136.6 mmol) of
4-piperidylmethanol, 3.53 g (36.67 mmol) of sodium
tert-butoxide, 0.285 g (0.46 mmol) of BINAP and 0.140 g
(0.15 mmol) of tris(dibenzylideneacetone)dipalladium,
and after chromatography on silica gel, eluting with a
98/2/0.2 and then 95/5/0.5 mixture of dichloromethane,
methanol and 28% aqueous ammonia, 2.40 g of pure
product are obtained in the form of a viscous orange
oil.
5.2. 3-{[l-(l-Isoquinolyl)-4-piperidyl]methyl}-l,3-
oxazolidine-2,4-dione
A solution of 2.01 g (9.95 mmol) of diiso-
propyl azodicarboxylate (DIAD) in 5 ml of tetrahydro-
furan is added dropwise, under an inert atmosphere, to
a solution of 2.4 g (9.95 mmol) of [1-(1-isoquinolyl)-
4-piperidyl]methanol, prepared in step 5.1, 2.87 g
(10.94 mmol) of triphenylphosphine and 1.21 g
(11.93 mmol) of 1,3-oxazolidine-2,4-dione in 40 ml of
tetrahydrofuran, cooled to about -10°C, the temperature
of the reaction medium being maintained throughout
between -10°C and 0°C. Stirring is then continued at
0°C for 1 hour and then at 25°C for 18 hours.
The mixture is concentrated under reduced
pressure and the residue is taken up in dichloromethane
and 10 ml of aqueous 5% sodium hydroxide solution. The
aqueous phase is separated out and then extracted twice
with dichloromethane. The organic phases are combined
and washed successively with aqueous hydrochloric acid
solution (1N) and then with saturated aqueous sodium
hydrogen carbonate solution and with saturated aqueous
sodium chloride solution. The organic phase is dried
over sodium sulfate and the filtrate is concentrated
under reduced pressure. The residue thus obtained is
purified by chromatography on silica gel, eluting with
a 99/1/0.1 and then 98/2/0.2 mixture of dichloro-
methane, methanol and 28% aqueous ammonia.
3.57 g of oxazolidinedione are thus obtained
in the form of an orange paste.
5.3. 2-(Methylamino)-2-oxoethyl [1-(1-isoquinolyl)-4-
piperidyl]methylcarbamate
The process is performed according to the
procedure described in Example 1 (step 1.5). Starting
with 3.57 g (10.97 mmol) of 3-{[1-(1-isoquinolyl)-4-
piperidyl]methyl}-l,3-oxazolidine-2,4-dione, obtained
in step 5.2, and 27 ml (54.86 mmol) of a solution (2M)
of methylamine in tetrahydrofuran, and after
chromatography on silica gel, eluting with a 95/5/0.5
mixture of dichloromethane, methanol and 28% aqueous
ammonia, 0.90 g of pure product is obtained in the form
of a yellow paste. This residue is then taken up in a
solution of hydrochloric acid (5N) in isopropanol, and
the salt formed is filtered off and then washed with
acetone.
After drying under vacuum at about 80°C,
0.728 g of hydrochloride is obtained in the form of a
pale yellow solid.
LC-MS: M+H = 357
m.p. (°C): 208-212°C (decomposition)
1H NMR (D2O) d (ppm): 1.55 (m, 2H); 1.95 (m, 3H); 2.70
(s, 3H); 3.20 (broad d, 2H); 3.45 (t, 2H); 4.10 (broad
d, 2H); 4.50 (s, 2H); 7.35 (d, 1H); 7.55 (d, 1H); 7.70
(m, 1H); 7.90 (d, 2H); 8.20 (d, 1H).
Example 6 (Compound 158)
2-Am±no-2-oxoethyl 2-[1-(6-fluoro-l-isoquinolyl)-4-
piperidyl]ethylcarbamate
6.1. 2-[1-(6-Fluoro-l-isoquinolyl)-4-piperidyl]ethanol
The process is performed as described in
Example 4 (step 4.1). Starting with 1.52 g (8.39 mmol)
of l-chloro-6-fluoroisoquinoline and 1.20 g (9.23 mmol)
of 2-(4-piperidyl)ethanol, and after chromatography on
silica gel, eluting with a 95/5/0.5 mixture of
dichloromethane, methanol and 28% aqueous ammonia,
0.90 g of pure product is obtained in the form of a
yellow paste.
6.2. 2-[1-(6-Fluoro-l-isoquinolyl)-4-piperidyl]ethyl
methanesulfonate
The process is performed as described in
Example 3 (step 3.2). Starting with 1.47 g (5.36 mmol)
of 2-[1-(6-fluoro-1-isoquinolyl)-4-piperidyl]ethanol,
obtained in step 6.1, 0.675 g (5.89 mmol) of mesyl
chloride and 1.13 ml (8.04 mmol) of triethylamine,
1.80 g of product are obtained in the form of an oil,
which is used without further purification in the
following step.
6.3. 3-{2-[1-(6-Fluoro-l-isoquinolyl)-4-piperidyl]-
ethyl}-l,3-oxazolidine-2, 4-dione
The process is performed according to the
method described in Example 3 (step 3.3). Starting with
1.8 g (5.10 mmol) of 2-[1-(6-fluoro-1-isoquinolyl)-4-
piperidyl]ethyl methanesulfonate, obtained in step 6.2,
0.62 g (6.13 mmol) of 1,3-oxazolidine-2,4-dione and
1.30 ml (10.21 mmol) of 1,1,3,3-tetramethylguanidine,
and after chromatography on silica gel, eluting with a
40/60 mixture of ethyl acetate and cyclohexane, 1.34 g
of pure product are obtained in the form of an
amorphous white solid.
6.4. 2-Amino-2-oxoethyl 2-[1-(6-fluoro-1-isoquinolyl)-
4-piperidyl]ethylcarbamate
The process is performed according to the
procedure described in Example 3 (step 3.4). Starting
with 0.597 g (1.67 mmol) of 3-{2-[1-(6-fluoro-1-iso-
quinolyl)-4-piperidyl]ethyl}-l,3-oxazolidine-2,4-dione,
obtained in Step 6.3, and 14.30 ml (100.20 mmol) of a
solution (7M) of aqueous ammonia in methanol, and after
chromatography on silica gel, eluting with a 95/5
mixture of dichloromethane and methanol, followed by
recrystallization from diisopropyl ether, 0.168 g of
pure product is obtained in the form of a white solid.
LC-MS: M+H =37 5
m.p. (°C): 135-139°C
1H NMR (DMSO) d (ppm): 1.20-1.70 (unresolved peak, 5H) ;
1.80 (broad d, 2H); 2.85 (t, 2H); 3.10 (broad d, 2H);
3.70 (broad d, 2H); 4.30 (s, 2H); 6.95-7.20 (unresolved
peak, 3H); 7.30 (d, 1H); 7.45 (td, 1H); 7.60 (dd, 1H);
8.10 (m, 2H).
Example 7 (Compound 172)
2-(Methylamino)-2-oxoethyl 2-[1-(4-isoquinolyl)-4-
piperidyl] ethylcarbamate hydrochlori.de

7.1. 2-[1-(4-Isoquinolyl)-4-piperidyl]ethanol
The process is performed according to the
protocol described in Example 2 (step 2.1). Starting
with 1 g (4.81 mmol) of 4-bromoisoquinoline, 0.683 g
(5.29 mmol) of 2-(4-piperidyl)ethanol, 1.11 g
(11.50 mmol) of sodium tert-butoxide, 0.090 g
(0.144 mmol) of BINAP and 0.044 g (0.048 mmol) of
tris(dibenzylideneacetone)dipalladium, and after
chromatography on silica gel, eluting with a 97/3 and
then 95/5 mixture of dichloromethane and methanol,
0.810 g of product is obtained in the form of a viscous
green liquid.
7.2. 3-{2-[l-(4-Isoquinolyl)-4-piperidyl]ethyl)-1,3-
oxazolidine-2,4-dione
The procedure described in Example 5 (step
5.2) is used. Starting with 0.801 g (3.12 mmol) of
2-[1-(4-isoquinolyl)-4-piperidyl]ethanol, prepared in
step 7.1, 0.902 g (3.44 mmol) of triphenylphosphine,
0.379 g (3.75 mmol) of 1,3-oxazolidine-2,4-dione and
0.632 g (3.12 mmol) of diisopropyl azodicarboxylate
(DIAD), and after chromatography on silica gel, eluting
with a 98/2 mixture of dichloromethane and methanol,
1 g of product is obtained in the form of a green
paste.
7.3. 2-(Methylamino)-2-oxoethyl 2-[1-(4-isoquinolyl)-4-
piperidyl]ethylcarbamate
The procedure described in Example 1 (step
1.5) is used. Starting with 1 g (2.95 mmol) of 3-{2-[l-
(4-isoquinolyl)-4-piperidyl]ethyl}-!,3-oxazolidine-2,4-
dione, obtained in step 7.2, and 7.40 ml (14.73 mmol)
of a solution (2M) of methylamine in tetrahydrofuran,
and after chromatography on silica gel, eluting with a
95/5 mixture of dichloromethane and methanol, 0.410 g
of pure product is obtained in the form of an amorphous
white solid. This oily residue is then taken up in a
solution of hydrochloric acid (5N) in isopropanol and
the salt formed is filtered off and then washed
successively with acetone and then with diisopropyl
ether.
After drying under vacuum at about 90°C,
0.359 g of hydrochloride is obtained in the form of a
yellow solid.
LC-MS: M+H =371
m.p. (°C): 205-210°C
1H NMR (DMSO) d (ppm): 1.30-1.70 (unresolved peak, 5H);
1.90 (broad d, 2H); 2.60 (d, 3H); 2.90 (t, 2H); 3.15
(m, 2H); 3.50 (broad d, 2H); 4.35 (s, 2H); 7.25 (broad
t, 1H); 7.80 (broad s, 1H); 8.0 (dd, 1H); 8.05-8.30
(unresolved peak, 3H); 8.45 (d, 1H); 9.45 (s, 1H).
Example 8 (Compound 126)
2-(Methylamino)-2-oxoethyl 2-[1-(2-quinolyl)-4-
piperidyl]ethylcarbamate
8.1. 2-[1-(2-Quinolyl)-4-piperidyl]ethanol
The process is performed as in Example 4
(step 4.1). Starting with 2 g (12.20 mmol) of 2-chloro-
quinoline and 1.58 g (12.20 mmol) of 2-(4-piperidyl)-
ethanol, and after chromatography on silica gel,
eluting with a 98/2/0.2 and then 95/5/0.5 mixture of
dichloromethane, methanol and 28% aqueous ammonia,
2.36 g of pure product are obtained in the form of a
pale yellow oil that crystallizes at room temperature.
8.2. 3{2-[1-(2-Quinolyl)-4-piperidyl]ethyl-1,3-
oxazolidine-2,4-dione
The process is performed according to the
procedure described in Example 5 (step 5.2). Starting
with 2.22 g (8.65 mmol) of 2-[1-(2-quinolyl)-4-
piperidyl]ethanol, prepared in step 8.1, 2.50 g
(9.52 mmol) of triphenylphosphine, 1.05 g (10.38 mmoi)
of 1,3-oxazolidine-2,4-dione and 1.75 g (8.65 mmol) of
diisopropyl azodicarboxylate (DIAD), and after
chromatography on silica gel, eluting with a 30/70 and
then 40/60 mixture of ethyl acetate and cyclohexane,
2.63 g of product are obtained in the form of an
amorphous white solid.
8.3. 2-(Methylamino)-2-oxoethyl 2-[1-(2-quinolyl)-4-
piperidyl]ethylcarbamate
The process is performed according to the
procedure described in Example 1 (step 1.5). Starting
with 1.5 g (4.42 mmol) of 3{2-[1-(2-quinolyl)-4-
piperidyl]ethyl-1,3-oxazolidine-2,4-dione, obtained in
step 8.2, and 11 ml (22.10 mmol) of a solution (2M) of
methylamine in tetrahydrofuran, and after
chromatography on silica gel, eluting with a 98/2/0.2
and then 95/5/0.5 mixture of dichloromethane, methanol
and 28% aqueous ammonia, followed by crystallization
from ethyl acetate, 0.405 g of pure product: is obtained
in the form of a white solid.
LC-MS: M+H =371
m.p. (°C): 125-128°C
lH NMR (CDCI3) d (ppm): 1.20-1.60 (unresolved peak, 5H);
1.85 (broad d, 2H); 2.85 (d, 3H); 3.0 (broad t, 2H);
3.30 (broad q, 2H); 4.55 (broad d, 2H); 4.60 (s, 2H);
4.85 (broad s, 1H); 6.10 (broad s, 1H); 7.0 (d, 1H);
7.20 (t, 1H); 7.55 (m, 2H); 7.70 (d, 1H); 7.90 (d, 1H) .
Example 9 (Compound 127)
2-Amino-2-oxoethyl 2-[1-(2-quinolyl)-4-piperidyl]-
ethylcarbamate
The process is performed according to the
procedure described in Example 3 (step 3.4). Starting
with 1.14 g (3.36 mmol) of 3{2-[1-(2-quinolyl)-4-
piperidyl]ethyl}-l,3-oxazolidine-2,4-dione, described
in Example 8 (step 8.2), and 9.60 ml (67.20 mmol) of a
solution (7M) of aqueous ammonia in methanol, and after
chromatography on silica gel, eluting with a 95/5
mixture of dichloromethane and methanol, followed by
recrystallization from ethyl acetate, 0.360 g of pure
product is obtained in the form of a white solid.
LC-MS: M+H = 357
m.p. (°C): 135-137°C
1H NMR (CDCI3) d (ppm): 1.15-1.70 (unresolved peak, 5H);
1.85 (broad d, 2H); 2.95 (t, 2H); 3.35 (q, 2H); 4.55
(broad d, 2H); 4.60 (s, 2H); 4.85 (broad s, 1H); 5.55
(broad s, 1H); 6.05 (broad s, 1H); 7.0 (d, 1H) ; 7.20
(t, 1H) ; 7.55 (t, 1H); 7.60 (d, 1H); 7.70 (d, 1H) ; 7.90
(d, 1H).
Example 10 (Compound 137)
2-Amino-2-oxoethyl 2-[1-(6-chloro-2-quinolyl)-4-
piperidyl]ethylcarbamate
10.1. 2-[1-(6-Chloro-2-quinolyl)-4-piperidyl]ethanol
The process is performed as described in
Example 4 (step 4.1). Starting with 2 g (10.10 mmol) of
2,6-dichloroquinoline and 1.44 g (11.10 mmol) of 2-(4-
piperidyl)ethanol, and after chromatography on silica
gel, eluting with a 98/2 mixture of dichloromethane and
methanol, 2.54 g of pure product are obtained in the
form of a white solid.
10.2. 2-[l-(6-Chloro-2-quinolyl)-4-piperidyl]ethyl
methanesulfonate
The process is performed as described in
Example 3 (step 3.2). Starting with 2.49 g (8.56 mmol)
of 2-[1-(6-chloro-2-quinolyl)-4-piperidyl]ethanol,
obtained in step 10.1, 1.08 g (9.42 mmol) of mesyl
chloride and 1.81 ml (12.84 mmol) of triethylamine,
3.10 g of product are obtained in the form of an oil,
which is used without further purification in the
following step.
10.3. 3-{2-[1-(6-Chloro-2-quinolyl)-4-piperidyl]ethyl}-
1,3-oxazolidine-2/4-dione
The process is performed according to the
method described in Example 3 (step 3.3). Starting with
3 g (8.13 mmol) of 2-[1-(6-chloro-2-quinolyl)-4-
piperidyl]ethyl methanesulfonate, obtained in step
10.2, 1.09 g (10.8 mmol) of 1,3-oxazolidine-2,4-dione
and 2.30 ml (18 mmol) of 1,1,3,3-tetramethylguanidine,
and after chromatography on silica gel, eluting with a
98/2 mixture of dichloromethane and methanol, 2.57 g of
product are obtained.
10.4. 2-Amino-2-oxoethyl 2-[1-(6-chloro-2-quinolyl)-4-
piperidyl]ethylcarbamate
The process is performed according to the
procedure described in Example 3 (step 3.4). Starting
with 1.28 g (3.42 mmol) of 3-{2-[1-(6-chloro-2-

quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2, 4-dione,
obtained in step 10.3, and 22.10 ml (154.08 mmol) of a
solution (7M) of aqueous ammonia in methanol, and after
crystallization from ethanol, 0.64 g of pure product is
obtained in the form of a white solid.
LC-MS: M+H = 391
m.p. (°C): 189-191°C
1H NMR (DMSO) d (ppm): 1.10 (m, 2H); 1.40 (m, 2H); 1.60
(m, 1H); 1.80 (broad d, 2H); 2.90 (broad t, 2H); 3.05
(m, 2H); 4.30 (s, 2H); 4.50 (broad d, 2H); 7.15 (m,
3H); 7.25 (d, 1H); 7.50 (m, 2H); 7.75 (d, 1H); 7.95 (d,
1H) .
Example 11 (Compound 166)
2-(Methylamino)-2-oxoethyl 2-[1-(3-isoquinolyl)-4-
piperidyl]ethylcarbamate
11.1. 2-[1-(3-Isoquinolyl)-4-piperidyl]ethanol
The process is performed as described in
Example 4 (step 4.1). Starting with 1 g (6.11 mmol) of
3-chloroisoquinoline and 0.869 g (6.72 mmol) of 2-(4-
piperidyl)ethanol, and after chromatography on silica
gel, eluting with a 98/2 mixture of dichloromethane and
methanol, 0.34 g of pure product is obtained in the
form of an oil.
11.2. 2-[1-(3-Isoquinolyl)-4-piperidyl]ethyl methane-
sulfonate
The process is performed as described in
Example 3 (step 3.2). Starting with 0.34 g (1.33 mmol)
of 2-[1-(3-isoquinolyl)-4-piperidyl]ethanol, obtained
in step 11.1, 0.18 g (1.59 mmol) of mesyl chloride and
0.30 ml (1.99 mmol) of triethylamine, 0.44 g of product
is obtained in the form of an oil, which is used
without further purification in the following step.
11.3. 3-{2-[l-(3-Isoquinolyl)-4-piperidyl]ethyl}-1,3-
oxazolidine-2,4-dione
The process is performed according to the
method described in Example 3 (step 3.3). Starting with
0.44 g (1.32 mmol) of 2-[1-(3-isoquinolyl)-4-
piperidyl]ethyl methanesulfonate, obtained in step
11.2, 0.16 g (1.58 mmol) of 1,3-oxazolidine-2,4-dione
and 0.30 g (2.63 mmol) of 1,1,3,3-tetramethylguanidine,
»
and after chromatography on silica gel, eluting with a
98/2 mixture of dichloromethane and methanol, 0.25 g of
product is obtained.
11.4. 2-(Methylamino)-2-oxoethyl 2-[1-(3-isoquinolyl)-
4-piperidyl]ethylcarbamate
The process is performed according to the
procedure described in Example 1 (step 1.5). Starting
with 0.24 g (0.71 mmol) of 3-{2-[1-(3-isoquinolyl)-4-
piperidyl]ethyl}-l,3-oxazolidine-2,4-dione, obtained in
step 11.3, and 1.8 ml (3.53 mmol) of a solution (2M) of
methylamine in tetrahydrofuran, and after
chromatography on silica gel, eluting with a 98/2 and
then 96/4 mixture of dichloromethane and methanol,
followed by crystallization from diisopropyl ether,
0.16 g of pure product is obtained in the form of a
white solid.
LC-MS: M+H = 371
m.p. (°C): 156-158°C
1H NMR (CDC13) d (ppm): 1.20-1.70 (unresolved peak, 5H) ;
1.85 (d, 2H); 2.90 (m, 5H); 3.30 (q, 2H); 4.40 (d, 2H) ;
4.60 (s, 2H); 4.85 (broad s, 1H); 6.10 (broad s, 1H);
6.80 (s, 1H); 7.30 (m, 1H); 7.60 (m, 2H); 7.80 (d, 1H);
8. 95 (s, 1H) .
Example 12 (Compound 128)
2-(Methylamino)-2-oxoethyl 2-[4-fluoro-l-(2-quinolyl)-
4-piperidyl]ethylcarbamate
12.1. tert-Butyl 4-hydroxy-4-(2-hydroxyethyl)-1-
piperidinecarboxylate
A solution of 31.20 g (108.50 mmol) of tert-
butyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxy-l-piperidine-
carboxylate (WO 02/16352) in 150 ml of tetrahydrofuran
is added dropwise to a suspension of 4.12 g
(108.50 mmol) of lithium aluminium hydride in 150 ml of
tetrahydrofuran. The mixture is stirred at room
temperature for 2 hours and is then worked up as
described in Example 2 (step 2.4).
26 g of product are obtained in the form of a
yellow oil, which is used without further purification
in the following step.
12.2. tert-Butyl 4-(2-{[tert-butyldiphenylsilyl]oxy}-
ethyl)-4-hydroxy-l-piperidinecarboxylate
A solution of 21.50 ml (82.50 mmol) of tert-
butyldiphenylsilyl chloride in 15 ml of dichloromethane
is added dropwise, under an inert atmosphere, to a
solution of 18.4 g (75 mmol) of tert-butyl 4-hydroxy-4-
(2-hydroxyethyl)-1-piperidinecarboxylate, obtained in
step 12.1, and 11.60 ml (82.50 mmol) of triethylamine
in 100 ml of dichloromethane, cooled to about 0°C. The
mixture is allowed to warm to room temperature and
stirring is then continued for 12 hours. Saturated
aqueous ammonium chloride solution is added to the
reaction medium. The aqueous phase is separated out and
extracted twice with dichloromethane, the combined
organic phases are washed with saturated aqueous sodium
chloride solution and dried over sodium sulfate, and
the filtrate is concentrated under reduced pressure.
The residue thus obtained is purified by chromatography
on silica gel, eluting with a 10/90 and then 20/80
mixture of ethyl acetate and cyclohexane.
33.48 g of product are thus obtained in the
form of a yellow oil.
12.3. tert-Butyl 4-(2-{[tert-butyl(diphenyl)silyl]oxy}-
ethyl)-4-fluoro-1-piperidinecarboxylate
A solution of 1.70 ml (13.40 mmol) of 1,1'-
[ (trifluoro-?4-sulfanyl) imino] diethane (DAST) in 10 ml
of dichloromethane is added dropwise, under an inert
atmosphere, to a solution of 5 g (10.34 mmol) of tert-
butyl 4-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-4-
hydroxy-1-piperidinecarboxylate, obtained in step 12.2,
in 100 ml of dichloromethane, cooled to about 0°C. The
mixture is allowed to warm to room temperature and
stirring is then continued for 12 hours. Saturated
aqueous sodium hydrogen carbonate solution is added to
the reaction medium. The aqueous phase is separated out
and extracted three times with dichloromethane, and the
combined organic phases are washed with saturated
aqueous sodium chloride solution and dried over sodium
sulfate. The filtrate is concentrated under reduced
pressure and the residue thus obtained is then purified
by chromatography on silica gel, eluting with a 10/90
mixture of ethyl acetate and cyclohexane. 4.65 g of
product are thus obtained in the form of an orange-
coloured oil. 0.60 ml of a solution of osmium tetroxide
(2.5%) in tert-butanol is added at room temperature to
a solution of 4.50 g of this oily residue and 1.25 g
(10.7 mmol) of N-methylmorpholine oxide (NMO) in a
mixture of 8 ml of acetone and 6 ml of water. Stirring
is continued for 21 hours. The residue is taken up in
ethyl acetate and water, the aqueous phase is separated
out and extracted twice with ethyl acetate, and the
combined organic phases are washed with saturated
aqueous sodium chloride solution and dried over sodium
sulfate. After evaporating off the solvent, the residue
obtained is purified by chromatography on silica gel,
eluting with a 6/94 mixture of ethyl acetate and
cyclohexane.
3.40 g of product are thus obtained in the
form of a pale yellow oil.
12.4. 4-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-4-
fluoropiperidine
2.80 ml (37.06 mmol) of trifluoroacetic acid
are added slowly to a solution of 3 g (6.17 mmol) of
tert-butyl 4-(2-{[tert-butyldiphenylsilyl]oxy}ethyl)-4-
fluoro-1-piperidinecarboxylate, obtained in step 12.3,
in 20 ml of dichloromethane. Stirring is continued at
room temperature for 5 hours. The reaction mixture is
poured into a mixture of ice-water and 28% aqueous
ammonia. The phases are separated by settling, the
aqueous phase is extracted twice with dichloromethane
and the combined organic phases are washed with
saturated aqueous sodium chloride solution, dried over
sodium sulfate and concentrated under reduced pressure.
2.30 g of product are obtained in the form of
a yellow oil, which is used without further
purification in the following step.
12.5. 2-[4-(2-{[tert-butyldiphenylsilyl]oxy}ethyl)-4-
fluoro-1-piperidyl]quinoline
The process is performed as described in
Example 2 (step 2.1). Starting with 1.18 g (5.68 mmol)
of 2-bromoquinoline (Eur. J. Org. Chem. 2002, 4181-
4184), 2.30 g (5.98 mmol) of 4-(2-{[tert-butyl-
(diphenyl)silyl]oxy}ethyl)-4-fluoropiperidine, obtained
in step 12.4, 0.66 g (6.81 mmol) of sodium tert-
butoxide, 0.149 g (0.239 mmol) of BINAP and 0.074 g
(0.081 mmol) of tris(dibenzylideneacetone)dipalladium,
and after chromatography on silica gel, eluting with a
10/90 mixture of ethyl acetate and cyclohexane, 2.15 g
of pure product are obtained in the form of an orange-
coloured oil.
12.6. 2-[4-Fluoro-l-(2-quinolyl)-4-piperidyl]ethanol
0.40 g (1.26 mmol) of n-tetrabutylammonium
fluoride trihydrate is added to a solution of 2.15 g
(4.19 mmol) of 2-[4-(2-{[tert-butyldiphenylsilyl]-
oxy}ethyl)-4-fluoro-1-piperidyl]quinoline, obtained in
step 12.5, in 20 ml of tetrahydrofuran. Stirring is
continued at room temperature for 4 hours. The mixture
is concentrated to dryness and the residue obtained is
then purified by chromatography on silica gel, eluting
with a 35/65 and then 40/60 mixture of ethyl acetate
and cyclohexane.
0.61 g of product is obtained in the form of
an orange-coloured oil.
12.7. 2-[4-Fluoro-l-(2-quinolyl)-4-piperidyl]ethyl
methanesulfonate
The process is performed as described in
Example 3 (step 3.2). Starting with 0.61 g (2.22 mmol)
of 2-[4-fluoro-l-(2-quinolyl)-4-piperidyl]ethanol,
obtained in step 12.6, 0.280 g (2.45 mmol) of mesyl
chloride and 0.35 ml (2.45 mmol) of triethylamine,
0.80 g of product is obtained in the form of an orange-
coloured oil, which is used without further
purification in the following step.
12.8. 3-{2-[4-Fluoro-l-(2-quinolyl)-4-piperidyl]ethyl}-
1,3-oxazolidine-2,4-dione
The process is performed according to the
method described in Example 3 (step 3.3). Starting with
0.780 g (2.22 mmol) of 2-[4-fluoro-1-(2-quinolyl)-4-
piperidyl]ethyl methanesulfonate, obtained in step
12.7, 0.27 g (2.66 mmol) of 1,3-oxazolidine-2,4-dione
and 0.51 g (4.43 mmol) of 1,1,3,3-tetramethylguanidine,
and after chromatography on silica gel, eluting with a
99/1 mixture of dichloromethane and methanol, 0.520 g
of pure product is obtained in the form of a beige-
coloured solid.
12.9. 2-(Methylamino)-2-oxoethyl 2-[4-fluoro-1-(2-
quinolyl)-4-piperidyl]ethylcarbamate
The process is performed according to the
procedure described in Example 1 (step 1.5). Starting
with 0.52 g (1.46 mmol) of 3-{2-[4-fluoro-1-(2-
quinolyl)-4-piperidyl]ethyl}-l,3-oxazolidine-2,4-dione,
obtained in step 12.8, and 3.6 ml (7.28 mmol) of a
solution (2M) of methylamine in tetrahydrofuran, and
after chromatography on silica gel, eluting with a 99/1
mixture of ethyl acetate and methanol, followed by
crystallization from diethyl ether, 0.390 g of pure
product is obtained in the form of a white solid.
LC-MS: M+H =38 9
m.p. (°C): 147-149°C
1H NMR (CDC13) d (ppm): 1.70-2.10 (unresolved peak, 6H);
2.90 (d, 3H); 3.40 (broad t, 2H); 3.50 (q, 2H); 4.40
(broad d, 2H); 4.60 (s, 2H); 5.15 (broad s, 1H); 6.15
(broad s, 1H); 7.05 (d, 1H); 7.25 (t, 1H); 7.55 (t,
1H); 7.65 (d, 1H); 7.75 (d, 1H); 7.95 (d, 1H).
Example 13 (Compound 49)
2-(Methylamino)-2-oxoethyl 2-[1-(6-isobutyl-2-pyridyl)-
4-piperidyl]ethylcarbamate

13.1. 2-[1-(6-Bromo-2-pyridyl)-4-piperidyl]ethanol
The process is performed as described in
Example 4 (step 4.1). Starting with 30.20 g (127 mmol)
of 2,6-dibromopyridine and 16.45 g (127 mmol) of 2-(4-
piperidyl)ethanol, and after chromatography on silica
gel, eluting with a 30/70 mixture of ethyl acetate and
cyclohexane, 7 g of pure product are obtained in the
form of an oil.
13.2. 2-[1-(6-Bromo-2-pyridyl)-4-piperidyl]ethyl
methanesulfonate
The process is performed as described in
Example 3 (step 3.2). Starting with 7 g (24.50 mmol) of
2-[1-(6-bromo-2-pyridyl)-4-piperidyl]ethanol, obtained
in step 13.1, 2.50 ml (26.90 mmol) of mesyl chloride
and 3.80 ml (26.90 mmol) of triethylamine, 8.68 g of
product are obtained in the form of an oil, which is
used without further purification in the following
step.
13.3. 3-{2-[l-(6-Bromo-2-pyridyl)-4-piperidyl]ethyl}-
1,3-oxazolidine-2,4-dione
The process is performed according to the
method described in Example 3 (step 3.3). Starting with
8.68 g (23.80 mmol) of 2-[1-(6-bromo-2-pyridyl)-4-
piperidyl]ethyl methanesulfonate, obtained in step
13.2, 2.90 g (28.60 mmol) of 1,3-oxazolidine-2,4-dione
and 6 ml (47.60 mmol) of 1, 1,3,3-tetramethylguanidine,
and after chromatography on silica gel, eluting with a
97/3 mixture of dichloromethane and methanol, 4.52 g of
product are obtained in the form of an oil.
13.4. 3-{2-[l-(6-Isobutyl-2-pyridyl)-4-piperidyl]-
ethyl}-l,3-oxazolidine-2,4-dione
2 g (5.43 mmol) of 3-{2-[1-(6-bromo-2-
pyridyl)-4-piperidyl]ethyl}-l,3-oxazolidine-2,4-dione,
prepared in step 13.3, and 0.20 g (0.271 mmol) of
dichlorobis(triphenylphosphine)palladium (Pd(PPh3) 2Cl2)
suspended in 10 ml of tetrahydrofuran are introduced
under an inert atmosphere. 22 ml (10.80 mmol) of a
solution (0.5 M) of bromo(isobutyl)zinc in
tetrahydrofuran are then added. Stirring is continued
at room temperature for 17 hours. The reaction mixture
is poured into water and ethyl acetate. The phases are
separated by settling, the aqueous phase is extracted
twice with ethyl acetate, the combined organic phases
are dried over sodium sulfate and the filtrate is
concentrated under reduced pressure. The residue thus
obtained is purified by chromatography on silica gel,
eluting with a 20/80 mixture of ethyl acetate and
cyclohexane.
1.41 g of product are obtained in the form of
a white solid,
m.p. (°C): 94-96°C
13.5. 2-(Methylamino)-2-oxoethyl 2-[1-(6-isobutyl-2-
pyridyl)-4-piperidyl]ethylcarbamate
The process is performed according to the
procedure described in Example 1 (step 1.5). Starting
with 0.72 g (2.08 mmol) of 3-{2-[1-(6-isobutyl-2-
pyridyl)-4-piperidyl]ethyl}-l,3-oxazolidine-2,4-dione,
obtained in step 13.4, and 5.20 ml (10.40 mmol) of a
solution (2M) of methylamine in tetrahydrofuran, and
after chromatography on silica gel, eluting with a
95/5/0.5 mixture of dichloromethane, methanol and 28%
aqueous ammonia, followed by crystallization from
diisopropyl ether, 0.540 g of pure product is obtained
in the form of a white solid.
LC-MS: M+H =377
m.p. (°C): 97-99°C
1H NMR (DMSO) d (ppm): 0.85 (d, 6H); 1.05 (m, 2H); 1.20-
1.60 (unresolved peak, 3H); 1.70 (broad d, 2H); 2.0 (m,
1H); 2.40 (d, 2H); 2.55 (d, 3H); 2.70 (broad t, 2H) ;
3.05 (broad q, 2H); 4.20 (broad d, 2H); 4.30 (s, 2H);
6.35 (d, 1H); 6.55 (d, 1H); 7.15 (broad t, 1H); 7.40
(dd, 1H); 7.75 (broad s, 1H).
Example 14 (Compound 58)
2-Amino-2-oxoethyl 2-[1-(6-phenyl-2-pyridyl)-4-
piperidyl]methylcarbamate

14.1. 3-{2-[1-(6-Phenyl-2-pyridyl)-4-piperidyl]methyl}-
1,3-oxazolidine-2,4-dione
0.20 g (0.56 mmol) of 3-{2-[1-(6-bromo-2-
pyridyl)-4-piperidyl]methyl}-l,3-oxazolidine-2,4-dione,
prepared according to the procedure described in
Example 13 (steps 13.1, 13.2 and 13.3), 0.089 g
(0.73 mmol) of phenylboronic acid and 0.480 g
(2.25 mmol) of hydrated potassium phosphate suspended
in 3 ml of 1,2-dimethoxyethane are introduced under an
inert atmosphere. 0.040 g (0.0346 mmol) of tetrakis-
(triphenylphosphine)palladium is then added. The
reaction mixture is then maintained at about 85°C for
16 hours. The resulting mixture is concentrated under
reduced pressure. The residue is taken up in ethyl
acetate and water, the aqueous phase is separated out
and extracted twice with ethyl acetate, the combined
organic phases are dried over sodium sulfate and the
filtrate is concentrated under reduced pressure. The
residue thus obtained is purified by chromatography on
silica gel, eluting with a 40/60 mixture of ethyl
acetate and cyclohexane.
0.175 g of product is obtained.
14.2. 2-Amino-2-oxoethyl 2-[1-(6-phenyl-2-pyridyl)-4-
piperidyl]methylcarbamate
The process is performed according to the
procedure described in Example 3 (step 3.4). Starting
with 0.175 g (0.499 mmol) of 3-{2-[1-(6-phenyl-2-
pyridyl)-4-piperidyl]methyl}-1,3-oxazolidine-2,4-dione,
obtained in step 14.1, and 2.5 ml (17.45 mmol) of a
solution (7M) of aqueous ammonia in methanol, 0.070 g
of pure product is obtained in the form of a white
solid, after crystallization from ethyl acetate.
LC-MS: M+H =3 69
m.p. (°C): 131-132°C
1H NMR (CDC13) d (ppm): 1.20-1.90 (unresolved peak, 5H);
2.90 (broad t, 2H); 3.20 (t, 2H); 4.50 (broad d, 2H);
4.60 (s, 2H); 5.0 (broad s, 1H); 5.55 (broad s, 1H) ;
6.15 (broad s, 1H); 6.65 (d, 1H); 7.10 (d, 1H); 7.35-
7.60 (m, 4H); 8.15 (dd, 2H).
Example 15 (Compound 130)
2-(Methylamino)-2-oxoethyl 2-[1-(5-chloro-2-quinolyl)-
4-piperidyl]ethylcarbamate
15.1. 2-[1-(5-Chloro-2-quinolyl)-4-piperidyl]ethanol
The process is performed as described in
Example 4 (step 4.1). Starting with 4.78 g (24.14 mmol)
of 2-chloro-5-chloroquinoline (J. Med. Chem., 2002, 45,
3130-3137) and 3.43 g (26.55 mmol) of 2-(4-piperidyl)-
ethanol, 7 g of product are obtained in the form of an
oil, which is used without further purification in the
following step.
15.2. 2-[1-(5-Chloro-2-quinolyl)-4-piperidyl]ethyl
methanesulfonate
The process is performed as described in
Example 3 (step 3.2). Starting with 7 g (24.07 mmol) of
2-[1-(5-chloro-2-quinolyl)-4-piperidyl]ethanol,
obtained in step 15.1, 3.31 g (28.89 mmol) of mesyl
chloride and 5.10 ml (36.11 mmol) of triethylamine,
8.70 g of product are obtained in the form of an oil,
which is used without further purification in the
following step.
15.3. 3-{2-[l-(5-Chloro-2-quinolyl)-4-piperidyl]ethyl}-
1,3-oxazolidine-2,4-dione
The process is performed according to the
method described in Example 3 (step 3.3). Starting with
8.7 g (23.58 mmol) of 2-[1-(5-chloro-2-quinolyl)-4-
piperidyl]ethyl methanesulfonate, obtained in step
15.2, 2.86 g (28.30 mmol) of 1,3-oxazolidine-2,4-dione
and 5.43 g (47.17 mmol) of 1,1,3,3-tetramethyl-
guanidine, and after chromatography on silica gel,
eluting with a 99.5/0.5 mixture of dichloromethane and
methanol, 6.40 g of product are obtained in the form of
a white solid,
m.p. (°C): 136°C
15.4. 2-(Methylamino)-2-oxoethyl 2-[1-(5-chloro-2-
quinolyl)-4-piperidyl]ethylcarbamate
The process is performed according to the
procedure described in Example 1 (step 1.5). Starting
with 6.40 g (17.12 mmol) of 3-{2-[1-(5-chloro-2-
quinolyl)-4-piperidyl]ethyl}-l,3-oxazolidine-2,4-dione,
obtained in step 15.3, and 60 ml (119.84 mmol) of a
solution (2M) of methylamine in tetrahydrofuran, and
after chromatography on silica gel, eluting with a 98/2
and then 96/4 mixture of dichloromethane and methanol,
followed by crystallization from diisopropyl ether,
5.14 g of product are obtained in the form of a white
solid.
LC-MS: M+H =4 05
m.p. (°C): 158-162°C
1H NMR (CDCl3) d (ppm): 1.10-1.80 (unresolved peak, 5H);
1.9 (broad d, 2H); 2.90 (d, 3H); 3.0 (m, 2H); 3.30 (q,
2H); 4.60 (m, 4H); 4.85 (broad s, 1H); 6.10 (broad s,
1H); 7.05 (d, 1H); 7.25 (d, 1H); 7.40 (dd, 1H); 7.60
(d, 1H); 8.30 (s, 1H).
Table 1 below illustrates the chemical
structures and physical properties of a number of
compounds according to the invention.
In this table:
in the "base or salt" column, "base" represents a
compound in free base form, whereas "HCl" represents
a compound in hydrochloride form;
- OMe represents a methoxy group.
* M+H (LC-MS)
dec. = decomposition of the product
The compounds of the invention underwent
pharmacological trials to determine their inhibitory
effect on the enzyme FAAH (Fatty Acid Amide Hydrolase).
The inhibitory,activity was demonstrated in a
radioenzymatic test based on measuring the product of
hydrolysis (ethanolamine [1-3H]) of anandamide [ethanol-
amine 1-3H] with FAAH {Life Sciences (1995), 56, 1999-
2005 and Journal of Pharmacology and Experimented
Therapeutics (1997), 283, 729-734). Thus, mouse brains
(minus the cerebellum) are removed and stored at -80°C.
Membrane homogenates are prepared extemporaneously by
homogenizing the tissues using a Polytron blender in
10 mM tris-HCl buffer (pH 8.0) containing 150 mM NaCl
and 1 mM EDTA. The enzymatic reaction is then performed
in 70 µl of buffer containing fatty-acid-free bovine
serum albumin (1 mg/ml). To test compounds at different
concentrations, anandamide [ethanolamine 1-3H] (specific
activity of 15-20 Ci/mmol) diluted to 10 uM with cold
anandamide, and the membrane preparation (400 ug of
frozen tissue per test) are successively added. After
15 minutes at 25°C, the enzymatic reaction is quenched
by adding 140 uL of chloroform/methanol (2:1). The
mixture is stirred for 10 minutes and then centrifuged
for 15 minutes at 3500 g. An aliquot (30 uL) of the
aqueous phase containing the ethanolamine [1-3H] is
counted by liquid scintillation. Under these
conditions, the most active compounds of the invention
have IC50 values (concentration that inhibits 50% of the
control enzymatic activity of FAAH) of between 0.001
and 1 µM.
Table 2 below shows the IC50 values of a few
compounds according to the invention.
Table 2

It is thus seen that the compounds according
to the invention have inhibitory activity on the enzyme
FAAH.
The in vivo activity of the compounds of the
invention was evaluated in a test of analgesia.
Thus, the intraperitoneal (i.p.)
administration of PBQ (phenylbenzoquinone, 2 mg/kg in
0.9% sodium chloride solution containing 5% ethanol) to
male OF1 mice weighing 25 to 30 g, causes abdominal
tractions, on average 30 torsions or contractions
during the period of 5 to 15 minutes after injection.
The test compounds are administered orally or intra-
peritoneally as a 0.5% suspension in Tween 80, 60
minutes or 120 minutes before the administration of
PBQ. Under these conditions, the most powerful
compounds of the invention produce a 35% to 70%
reduction in the number of tractions induced with PBQ,
within a dose range of between 1 and 30 mg/kg.
Table 3 below shows the results of the
analgesia test for a few compounds according to the
invention.
The enzyme FAAH (Chemistry and Physics of
Lipids, (2000), 108, 107-121) catalyses the hydrolysis
of the endogenous amide and ester derivatives of
various fatty acids such as N-arachidonoylethanolamine
(anandamide), N-palmitoylethanolamine, N-oleoylethanol-
amine, oleamide or 2-arachidonoylglycerol. These
derivatives exert different pharmacological activities
by interacting, inter alia, with the cannabinoid and
vanilloid receptors.
The compounds of the invention block this
degradation pathway and increase the tissue content of
these endogenous substances. They may be used in this
respect in the prevention and treatment of pathologies
in which the endogenous cannabinoids, and/or any other
substrates metabolized by the enzyme FAAH, are
involved. Examples that may be mentioned include the
following diseases and complaints:
pain, especially acute or chronic pain of neurogenic
type: migraine, neuropathic pain including the forms
associated with the herpes virus and diabetes, acute or
chronic pain associated with inflammatory diseases:
arthritis, rheumatoid arthritis, osteoarthritis,
spondylitis, gout, vascularitis, Crohn's disease,
irritable bowel syndrome,
acute or chronic peripheral pain,
vertigo, vomiting, nausea, in particular post-
chemotherapy nausea,
eating disorders, in particular anorexia and cachexia
of diverse nature,
neurological and psychiatric pathologies: tremor,
dyskinaesia, dystonia, spasticity, compulsive and
obsessive behaviour, Tourette's syndrome, all forms of
depression and anxiety of any nature or origin, mood
disorders, psychoses,
acute and chronic neurodegenerative diseases:
Parkinson's disease, Alzheimer's disease, senile
dementia, Huntington's chorea, lesions associated with
cerebral ischaemia and cranial and medullary trauma,
epilepsy,
sleeping disorders, including sleep apnoea,
cardiovascular diseases, in particular hypertension,
cardiac arrhythmia, arteriosclerosis, heart attack,
cardiac ischaemia,
renal ischaemia,
chronic obstruction of the respiratory pathways,
emphysema,
gastrointestinal diseases: irritable bowel syndrome,
intestinal inflammatory disorders, ulcers, diarrhoea,
urinary incontinence and inflammation of the bladder.
The use of the compounds according to the
invention, in the form of the base, or a
pharmaceutically acceptable acid-addition salt, hydrate
or solvate, for the preparation of a medicinal product
for treating the pathologies mentioned above forms an
integral part of the invention.
A subject of the invention is also medicinal
products comprising a compound of formula (I), or an
acid-addition salt, or alternatively a pharmaceuticaily
acceptable hydrate or solvate of the compound of
formula (I). These medicinal products find their
therapeutic use especially in the treatment of the
pathologies mentioned above.
According to another of its aspects, the
present invention relates to pharmaceutical
compositions containing, as active principal, at least
one compound according to the invention. These
pharmaceutical compounds contain an effective dose of a
compound according to the invention, or a
pharmaceutically acceptable acid-addition salt, hydrate
or solvate of the said compound, and optionally one or
more pharmaceutically acceptable excipients.
The said excipients are chosen, according to
the pharmaceutical form and the desired administration
form, from the usual excipients known to those 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 principal of
formula (I) above, or the possible acid-addition salt,
solvate or hydrate thereof, may be administered in a
unit administration form, as a mixture with standard
pharmaceutical excipients, to man and animals for the
prophylaxis or treatment of the above disorders or
diseases.
The appropriate unit administration forms
comprise oral forms such as tablets, soft or hard gel
capsules, powders, granules, chewing gums and oral
solutions or suspensions, sublingual, buccal, intra-
tracheal, intraocular and intranasal administration
forms, forms for administration by inhalation, sub-
cutaneous, intramuscular or intravenous administration
forms and rectal or vaginal administration forms. For
topical administration, the compounds according to the
invention may be used in creams, ointments or lotions.
By way of example, a unit administration form
of a compound according to the invention in the form of
a tablet may comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Sodium croscarmellose 6.0 mg
Maize starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
The said unit forms are dosed to allow a
daily administration of from 0.01 to 20 mg of active
principal per kg of body weight, depending on the
presentation form.
There may be particular cases in which higher
or lower doses are suitable, and such doses also form
part of the invention. According to the usual practice,
the dose that is suitable for each patient is
determined by the doctor according to the mode of
administration and the weight and response of the said
patient.
According to another of its aspects, the
invention also relates to a method for treating the
pathologies mentioned above, which comprises the
administration of an effective dose of a compound
according to the invention, a pharmaceutically
acceptable acid-addition salt thereof or a solvate or
hydrate of the said compound.
WE CLAIM:
1. Compound corresponding to formula (I)

in which
A represents a nitrogen atom or a group CR2 in which R2
represents a hydrogen or fluorine atom or a hydroxyl,
cyano, trifluoromethyl, C1-6-alkyl or C1-6-alkoxy group;
n represents an integer equal to 2 or 3 and m
represents an integer equal to 2 when A represents a
nitrogen atom;
n represents an integer equal to 1, 2 or 3 and m
represents an integer equal to 1 or 2 when A represents
a group CR2;
B represents a covalent bond or a C1-6-alkylene group;
R1 represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl,
tetrahydroisoquinolyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, cinnolyl,
imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl,
benzothienyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
indazolyl, pyrrolopyridyl, furopyridyl,
dihydrofuropyridyl, thienopyridyl, dihydro-
thienopyridyl, imidazopyridyl, pyrazolopyridyl,
oxazolopyridyl, isoxazolopyridyl and thiazolopyridyl;
the group R1 optionally being substituted with one or
more groups R' and/or R";
R' represents a halogen atom or a cyano, nitro,
hydroxyl, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl, C1-6-
fluoroalkyl, C1-6-fluoroalkoxy, C1-6-fluorothioalkyl,
C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkylene,
azetidinyl, piperidyl, pyrrolidinyl, morpholinyl,
piperazinyl, azepinyl, NH2, NHR6, NR6R7, NR6COR7,
NR6SO2R7, COR6, CO2R6, SO2R6, SO2NR6R7 or -0-(C1-6-
alkylene)-0- group;
R" represents a phenyl, imidazolyl, pyridyl or
pyrimidinyl;
the group(s) R" being optionally substituted with one
or more groups R', which may be identical to or
different from each other;
R3 represents a group of general formula CHR4CONHR5 in
which
R4 represents a hydrogen atom or a C1-6-alkyl group and
R5 represents a hydrogen atom or a C1-6-alkyl, C3-7-
cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene group;
R6 and R7 represent, independently of each other, a C1-6-
alkyl group;
in the form of a base, an acid-addition salt, a hydrate
or a solvate.
2. Compound of formula (I) as claimed in
Claim 1, wherein :
A represents a nitrogen atom;
n represents an integer equal to 2 or 3 and m
represents an integer equal to 2;
B represents a C1-6-alkylene group;
R1 represents a group chosen from phenyl, pyridyl,
pyrimidinyl, thiadiazolyl and naphthyl;
the group R1 being optionally substituted with one or
more groups R' and/or R";
R' represents a halogen atom or a nitro or C1-6-
fluoroalkyl group;
R" represents a phenyl optionally substituted with one
or more groups, which may be identical to or different
from each other, chosen from a halogen atom or a cyano,
C1-6-alkoxy or C1-6-fluoroalkoxy group;
R3 represents a group of general formula CHR4CONHR5 in
which
R4 represents a hydrogen atom and
R5 represents a hydrogen atom or a C1-6-alkyl, C3-7-
cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene group;
in the form of a base, an acid-addition salt, a hydrate
or a solvate.
3. Compound of formula (I) as claimed in
Claim 1, wherein :
A represents a group CR2 in which R2 represents a
hydrogen or fluorine atom or a hydroxyl group;
m represents an integer equal to 1 or 2 and n
represents an integer equal to 1 or 2;
B represents a covalent bond or a C1-4-alkylene group;
R1 represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
quinolyl, isoquinolyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, furopyridyl, thieno-
pyrimidinyl, imidazopyrimidinyl, benzothiazolyl,
benzimidazolyl and benzoxazolyl;
the group R1 being optionally substituted with one or
more groups R' and/or R";
R' represents a halogen atom, a cyano or C1-6-alkyl, a
C1-6-alkoxy, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, C3-7-
cycloalkyl, pyrrolidinyl, NH2, NR6R7 or COR6 group;
R" represents a phenyl, imidazolyl or pyridyl;
the group(s) R" being optionally substituted with one
or more groups R', which may be identical to or
different from each other, more particularly with one
or more chlorine or fluorine atoms;
R3 represents a group of general formula CHR4CONHR5 in
which
R4 represents a hydrogen atom or a C1-6-alkyl group, and
R5 represents a hydrogen atom or a C1-6-aikyl, C3-7-
cycloalxyl or C1-7-cycloalkyl-C1-C6-alkylene group;
R6 and R7 represent, independently of each other, a C1-6-
alkyl group;
in the form of a base, an acid-addition salt, a hydrate
or a solvate.
4. Compound of formula (I) as claimed in
Claim 1 or 3, wherein:
A represents a group CR2 in which R2 represents a
hydrogen atom;
m is equal to 2 and n is equal to 2;
B represents an ethyl group;
R1 represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
quinolyl, isoquinolyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, furopyridyl, thieno-
pyrimidinyl, imidazopyrimidinyl, benzothiazolyl,
benzimidazolyl and benzoxazolyl;
the group R1 being optionally substituted with one or
more groups R' and/or R";
R' represents a halogen atom or a cyano or C1-6-alkyl, a
C1-6-alkoxy, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, C3-7-
cycloalkyl, pyrrolidinyl, NH2, NR6R7 or COR6 group;
R" represents a phenyl, imidazolyl or pyridyl;
the group(s) R" being optionally substituted with one
or more groups R', which may be identical to or
different from each other, more particularly with one
or more chlorine or fluorine atoms;
R3 represents a group of general formula CHR4CONHR5 in
which

R4 represents a hydrogen atom and
R5 represents a hydrogen atom or a C1-C5-alkyl group;
R6 and R7 represent, independently of each other, a C1-6-
alkyl group;
in the form of the base, an acid-addition salt, a
hydrate or a solvate.
5. Process for preparing a compound of
formula (I) as claimed in any one of Claims 1 to 4,
comprising the step consisting of subjecting the
carbamate ester of general formula (la)

in which n, m, A, B, R1 and R4 are as defined in the
general formula (I) as claimed in Claim 1 and R
represents a methyl or ethyl group,
by aminolysis using an amine of general formula R5NH2 in
which R5 is as defined in the general formuia (I)
as claimed in Claim 1.
6. Process for preparing a compound of
general formula (I) as claimed in any one of Claims 1 to
4, comprising the step consisting of subjecting the
oxazolidinedione derivative of general formula (V)
in which n, m, A, B, R1 and R4 are as defined in the
general formula (I) as claimed in Claim 1,
by aminolysis using an amine of general formula R5NH2 in
which R5 is as defined in the general formula (I)
as claimed in claim 1.
7. Compound corresponding to the general
formula (la)

in which
A represents a nitrogen atom or a group CR2 in which R2
represents a hydrogen or fluorine atom or a hydroxyl,
cyano, trifluoromethyl, C1-6-alkyl or C1-6-alkoxy group;
n represents an integer equal to 2 or 3 and m
represents an integer equal to 2 when A represents a
nitrogen atom;
n represents an integer equal to 1, 2 or 3 and m
represents an integer equal to 1 or 2 when A represents
a group CR2;
B represents a covalent bond or a C1-8-alkylene group;
R1 represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl,
tetrahydroisoquinolyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, cinnolyl,
imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl,
benzothienyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
indazolyl, pyrrolopyridyl, furopyridyl,
dihydrofuropyridyl, thienopyridyl, dihydro-
thienopyridyl, imidazopyridyl, pyrazolopyridyl,
oxazolopyridyl, isoxazolopyridyl and thiazolopyridyl;
the group R1 optionally being substituted with one or
more groups R' and/or R";
R' represents a halogen atom or a cyano, nitro,
hydroxyl, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl, C1-6-
fluoroalkyl, C1-6-fluoroalkoxy, C1-6-fluorothioalkyl,
C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkylene,
azetidinyl, piperidyl, pyrrolidinyl, morpholinyl,
piperazinyl, azepinyl, NH2, NHRS, NR6R7, NR6COR7,
NR6SO2R7, COR6, CO2R6, SO2R6, SO2NR6R7 or -0-(C1-6-
alkylene)-O- group;
R" represents a phenyl, imidazolyl, pyridyl, pyrazinyl,
pyridazinyl or pyrimidinyl;
the group(s) R" being optionally substituted with one
or more groups R', which may be identical to or
different from each other;
R4 represents a hydrogen atom or a C1-6-alkyl group;
R6 and R7 represent, independently of each other, a C1-6-
alkyl group;
R represents a methyl or ethyl group.
8. Compound corresponding to the general
formula (V)

in which
A represents a nitrogen atom or a group CR2 in which R2
represents a hydrogen or fluorine atom or a hydroxyl,
cyano, trifluoromethyl, C1-6-alkyl or C1-6-alkoxy group;
n represents an integer equal to 2 or 3 and m
represents an integer equal to 2 when A represents a
nitrogen atom;
n represents an integer equal to 1, 2 or 3 and m
represents an integer equal to 1 or 2 when A represents
a group CR2;
B represents a covalent bond or a C1-3-alkylene group;
R1 represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl,
tetrahydroisoquinolyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, cinnolyl,
imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl,
benzothienyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
indazolyl, pyrrolopyridyl, furopyridyl,
dihydrofuropyridyl, thienopyridyl, dihydro-
thienopyridyl, imidazopyridyl, pyrazolopyridyl,
oxazolopyridyl, isoxazolopyridyl and thiazolopyridyl;
the group R1 optionally being substituted with one or
more groups R' and/or R";
R' represents a halogen atom or a cyano, nitro,
hydroxyl, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl, C1-6-
fluoroalkyl, C1-6-fluoroalkoxy, C1-6-fluorothioalkyl,
C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkylene,
azetidinyl, piperidyl, pyrrolidinyl, morpholinyl,
piperazinyl, azepinyl, NH2, NHR6, NR6R7, NR6COR7,
NR6SO2R7, COR6, CO2R6, SO2R6, SO2NR6R7 or -0-(C1-6-
alkylene)-0- group;
R" represents a phenyl, imidazolyl, pyridyl, pyrazinyl,
pyridazinyl or pyrimidinyl;
the group(s) R" being optionally substituted with one
or more groups R' , which may be identical to or
different from each other;
R4 represents a hydrogen atom or a C1-6-alkyl group;
R6 and R7 represent, independently of each other, a C1-6-
alkyl group;
the following compounds being excluded:
* 3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl) -4-
piperidyl]-2,4-oxazolidinedione
* 3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl) -4-
piperidyl]-5-methyl-2,4-oxazolidinedione
* 3- [ 1- (4-amino-6, 7-dimethoxy-2-quinazolinyl) -4-
piperidyl]-5-ethyl-2,4-oxazolidinedione
* 3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-
piperidyl]-5-propyl-2,4-oxazolidinedione
* 3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-
piperidyl]—5-(1-methylethyl)-2,4-oxazolidinedione.
9. Compound of formula (I) as claimed in any
one of Claims 1 to 4, in the form of the base or of a
pharmaceutically acceptable acid-addition salt, hydrate
or solvate, for its use as a medicament.
10. Pharmaceutical composition containing at
least one compound of formula (I) as claimed in any one
of Claims 1 to 4, in the form of the base or of a
pharmaceutically acceptable acid-addition salt, hydrate
or solvate, and optionally one or more pharmaceutically
acceotable excioients.
11. A compound of formula (I)
as claimed in any one of Claims 1 to 4, in the form of
the base or of a pharmaceutically acceptable acid-
addition salt, hydrate or solvate, for the preparation
of a medicament for preventing or treating a pathology
in which the endogenous cannabinoids and/or any other
substrate metabolized by the enzyme FAAH are involved.
12. A compound of formula (I)
as claimed in any one of Claims 1 to 4, in the form of
the base or of a pharmaceutically acceptable acid-
addition salt, hydrate or solvate, for the preparation
of a medicament for preventing or treating acute or
chronic pain, vertigo, vomiting, nausea, eating
disorders, neurological and psychiatric pathologies,
acute or chronic neurodegenerative diseases, epilepsy,
sleeping disorders, cardiovascular diseases, renal
ischaemia, cancers, immune system disorders, allergic
diseases, parasitic, viral or bacterial infectious
diseases, inflammatory diseases, osteoporosis, ocular
complaints, pulmonary complaints, gastrointestinal
diseases or urinary incontinence.
Abstract: The invention relates to a compound having general formula (I),
wherein: A = N or CR2; R2 = H, F, OH, CN, CF3, C1-6-alkyl, C1-6-alcoxy; n = 2 or
3 and m = 2 when A = N; n = 1, 2 or 3 and m = 1 or 2 when A = CR2; B = covalent
bond or C1-8-alkylene; R1 = optionally-substituted heteroaryl: R3 = CHR4CONHR5;
R4 = H or C1-6-alkyl; R5 = H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkylene;
the base, the acid addition salt, the hydrate or the solvate thereof. The invention also
relates to the application thereof in therapeutics.

Documents:

1981-kolnp-2005-granted-abstract.pdf

1981-kolnp-2005-granted-assignment.pdf

1981-kolnp-2005-granted-claims.pdf

1981-kolnp-2005-granted-correspondence.pdf

1981-kolnp-2005-granted-description (complete).pdf

1981-kolnp-2005-granted-examination report.pdf

1981-kolnp-2005-granted-form 1.pdf

1981-kolnp-2005-granted-form 18.pdf

1981-kolnp-2005-granted-form 3.pdf

1981-kolnp-2005-granted-form 5.pdf

1981-kolnp-2005-granted-gpa.pdf

1981-kolnp-2005-granted-reply to examination report.pdf

1981-kolnp-2005-granted-specification.pdf

1981-kolnp-2005-granted-translated copy of priority document.pdf


Patent Number 234234
Indian Patent Application Number 1981/KOLNP/2005
PG Journal Number 20/2009
Publication Date 15-May-2009
Grant Date 12-May-2009
Date of Filing 06-Oct-2005
Name of Patentee SANOFI-AVENTIS
Applicant Address 174, AVENUE DE FRANCE, F-75013, PARIS
Inventors:
# Inventor's Name Inventor's Address
1 BURNIER PHILIPPE 8, ALLEE DU BEL-AIR, F-78600 MAIAIS
2 ABOUABDELLAH AHMED 2, RUE DES EGLANTIERS, F-94320 THIAIS
3 HOORNAERT CHRISTIAN 49, AVENUE ARISTIDE BRIAND, F-92160 ANTONY
4 JEUNESSE JEAN 6, RUE ANDRE MESSAGER, F-75018 PARIS
5 PUECH FREDERIC 1, ALLEE DE SAVOIR, F-78170 LA CELLE SAINT-CLOUD
6 ABOUABDELLAH AHMED 2, RUE DES EGLANTIERS, F-94320 THIAIS
7 HOORNAERT CHRISTIAN 49, AVENUE ARISTIDE BRIAND, F-92160 ANTONY
8 JEUNESSE JEAN 6, RUE ANDRE MESSAGER, F-75018 PARIS
9 PUECH FREDERIC 1, ALLEE DE SAVOIR, F-78170 LA CELLE SAINT-CLOUD
10 BURNIER PHILIPPE 8, ALLEE DU BEL-AIR, F-78600 MAIAIS
PCT International Classification Number C07D 401/04, 401/14
PCT International Application Number PCT/FR2004/001102
PCT International Filing date 2004-05-06
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 03/05540 2003-05-07 France