Title of Invention

DERIVATIVES OF ALKYLPIPERAZINE- AND ALKYLHOMOPIPERAZINE- CARBOXYLATES, PREPARATION METHOD THEREOF AND USE OF SAME AS FAAH ENZYME INHIBITORS

Abstract The invention relates to a compound having general formula (I), wherein: n = 1 or 2; p represents an integer varying between 1 and 7; A is selected from one or more X, Y and/or Z groups; X = optionally-substituted methylene; Y = C2-alkenylene, optionally substituted, or C2-alkynylene; Z = C3-7-cycloalkyl; G= single bond, O, S, SO, SO2, C=O or CH(OH); R1 represents an aryl- or heteroaryl-type group; and R2 represents a hydrogen atom or a C1-6- alkyl group; R3 represents a hydrogen atom or a C1-6- alkyl, C3-7--cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl group, said compound taking the form of a base, an acid addition salt, a hydrate or a solvate. The invention also relates to the use thereof as FAAH enzyme inhibitors for the treatment of pain, inflammation, neurodegenerative diseases, etc.
Full Text DERIVATIVES OF ALKYLPIPERAZINE- AND ALKYLHOMOPIPERAZINE-
CARBOXYLATES, PREPARATION METHOD THEREOF AND USE OF SAME AS
FAAH ENZYME INHIBITORS
The invention relates to alkylpiperazine- and
alkylhomopiperazine-carboxylate derivatives, to their
preparation and to their application in therapy.
Already known are phenylalkylcarbamate, dioxane-2-
alkylcarbamate and 1-piperazine- and 1-homopiperazine-
carboxylate derivatives, described respectively in the
documents WO 2004/067498 A, WO 2004/020430 A and
PCT/FR2004/00328, which are inhibitors of the enzyme FAAH
(fatty acid amide hydrolase).
There is still a need to find and develop products
which inhibit the enzyme FAAH. The compounds of the
invention meet this goal.
The compounds of the invention are of the general
formula (I)

in which
n represents an integer 1 or 2;
p represents an integer ranging from 1 to 7;
A is selected 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;
G represents a single bond, an oxygen or sulphur atom or an
SO, SO2, C=O or CH(OH) group;
R1 represents a group R4 optionally substituted by one or
more groups R5 and/or R6;
R4 represents a group selected from a phenyl, pyridinyl,
pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl,
furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,
thiadiazolyl, triazolyl, tetrazolyl, naphthalenyl,
diphenylmethyl, quinolinyl, tetrahydroquinolinyl,
isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl,
quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl,
benzofuranyl, dihydrobenzofuranyl, benzothienyl,
dihydrobenzothienyl, indolyl, indolinyl, indanyl, indazolyl,


isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,
benzothiazolyl, benzisothiazolyl, benzotriazolyl,
benzoxadiazolyl, benzothiadiazolyl, pyrrolopyridinyl,
furopyridinyl, thienopyridinyl, imidazopyridinyl,
oxazolopyridinyl, thiazolopyridinyl, pyrazolopyridinyl,
isoxazolopyridinyl and isothiazolopyridinyl;
R5 represents a halogen atom or a cyano, nitro, C1-6-alkyl,
C1-6-alkoxy, hydroxyl, C1-6-thioalkyl, C1-6-f luoroalkyl,
C1-6-fluoroalkoxy or C1-6-fluorothioalkyl group, a group
NR7R8, NR7COR8, NR7CO2R8, NR7SO2R8, COR7, CO2R7, CONR7R8, SO2R7 or
SO2NR7R8, or an -O- (C1-3-alkylene) -O group;
R6 represents a phenyl, phenyloxy, benzyloxy, naphthalenyl,
pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl group, the
group or groups R6 being optionally substituted by one or
more groups R5 identical to or different from one another;
R7 and R8 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 selected from azetidine,
pyrrolidine, piperidine, morpholine, thiomorpholine, azepine
and piperazine, this ring being optionally substituted by a
C1-6-alkyl or benzyl group;
R2 represents a hydrogen atom or a C1-6-alkyl group;
R3 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl
or C3-7-cycloalkyl-C1-3-alkyl group.
In the context of the invention the compounds of
general formula (I) may therefore comprise two or more
groups A identical to or different from another.


Among the compounds of general formula (I) a first
subgroup of compounds is composed of the compounds for
which:
n represents an integer 1 or 2;
p represents an integer ranging from 1 to 7;
A is selected from one or more groups X and/or Y;
X represents a methylene group optionally substituted by one
or two C1-6-alkyl, more particularly methyl, groups;
Y represents either a C2-alkenylene group or a C2-alkynylene
group;
G represents a single bond, an oxygen atom or a C=0 group;
R1 represents a group R4 optionally substituted by one or
more groups R5 and/or R6;
R4 represents a group selected from a phenyl, naphthalenyl,
diphenylmethyl, quinolinyl, indolyl, pyrazolyl, isoxazolyl,
pyrimidinyl and thiazolyl;
R5 represents a halogen atom, more particularly a chlorine,
a fluorine, a bromine or an iodine, or a cyano group, a
C1-6-alkyl group, more particularly a methyl, an isopropyl or
a tert-butyl, a C1-6-alkoxy group, more particularly a
methoxy, a C1-6-fluoroalkyl group, more particularly a
trifluoromethyl, a C1-C6-fluoroalkoxy group, more
particularly a trif luoromethoxy, or an -O- (C1-3-alkylene) -O
group, more particularly an -OCH2O-;
R6 represents a phenyl, naphthalenyl or benzyloxy group;
R2 represents a hydrogen atom or a C1-6-alkyl group;
R3 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl


or C3-7-cycloalkyl-C1-3-alkyl group.
Among the compounds of general formula (I) a
second subgroup of compounds is composed of the compounds
for which:
n represents an integer 1;
p represents an integer ranging from 1 to 4;
A is selected from one or more groups X and/or Y;
X represents a methylene group optionally substituted by one
or two C1-6-alkyl, more particularly methyl, groups;
Y represents a C2-alkynylene group;
G represents a single bond or an oxygen atom;
R1 represents a group R4 optionally substituted by one or
more groups R5 and/or R6;
R4 represents a group selected from a phenyl, naphthalenyl
or isoxazolyl;
R5 represents a halogen atom, more particularly a chlorine
or a fluorine, or a cyano group, a C1-6-alkoxy group, more
particularly a methoxy, a C1-6-fluoroalkyl group, more
particularly a trifluoromethyl;
R6 represents a phenyl group;
R2 represents a hydrogen atom or C1-6-alkyl group;
R3 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl
or C3-7-cycloalkyl-C1-3-alkyl group.
Among the compounds of general formula (I) a third
subgroup of compounds is composed of the compounds for
which:
n, p, A, X, Y, Z, o, r, s, G, Rl, R4, R5, R6, R7 and R8 are as


defined in the general formula (I) or in the subgroups as
defined above;
R2 represents a hydrogen atom;
R3 represents a hydrogen atom or a C1-6-alkyl group, more
particularly a methyl, a C3-7-cycloalkyl group, more
particularly a cyclopropyl or a C3-7-cycloalkyl-C1-3-alkyl
group, more particularly a -CH2-cyclopropyl.
Among the compounds of general formula (I) mention
may be made of the following compounds:
- 2-(methylamino)-2-oxoethyl 4-(2-biphenyl-3-ylethyl)-
piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(2-biphenyl-4-ylethyl)-
piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4- [2-(1-naphthyl)ethyl]-
piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-{2-[3-(4-chlorophenyl)-
isoxazol-5-yl]ethyl}piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-{2-[5-(4-chlorophenyl)-
isoxazol-3-yl]ethyl}piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(3-biphenyl-3-ylpropyl)-
piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(3-biphenyl-4-ylpropyl)-
piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-(3-biphenyl-3-yl-1,1-
dimethylpropyl)piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(3'-chlorobiphenyl-3-yl)
propyl]piperazine-1-carboxylate


- 2-(methylamino)-2-oxoethyl 4-[3-(4'-chlorobiphenyl-3-yl)
propyl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(3'-methoxybiphenyl-3-yl)
propyl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(4'-methoxybiphenyl-3-yl)
propyl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(3'-chlorobiphenyl-4-yl)
propyl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(4'-chlorobiphenyl-4-yl)
propyl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(2-naphthyl)propyl]-
piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-{3-[5-(4-chlorophenyl)-
isoxazol-3-yl]propyl}piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-{3-[3-(4-chlorophenyl)-
isoxazol-5-yl]propyl}piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[4-(3-chlorophenyl)butyl]
piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[4-(4-chlorophenyl)butyl]-
piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-{4-[3-(trifluoromethyl)-
phenyl]butyl}piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-{4-[4-(trifluoromethyl)-
phenyl]butyl}piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-{4-[4-(trifluoromethylphenyl]
but-3-yn-1-yl}piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[5-(3-chlorophenyl)pent-4-yn-


1-yl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[5-(2,4-dichlorophenyl)pent-
4-yn-1-yl] piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[5-(2,5-dichlorophenyl)pent-
4-yn-1-yl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[5-(3,4-dichlorophenyl)pent-
4-yn-1-yl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[5-(3-chloro-4-fluorophenyl)
pent-4-yn-1-yl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(2-chlorophenoxy)propyl]
piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(3-chlorophenoxy)propyl]
piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(4-chlorophenoxy)propyl]
piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(2,3-dichlorophenoxy)
propyl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(2,4-dichlorophenoxy)
propyl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(2,5-dichlorophenoxy)
propyl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(2,6-dichlorophenoxy)
propyl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(3,5-dichlorophenoxy)-
propyl]piperazine-1-carboxylate.
The compounds of general formula (I) may include
one or more asymmetric carbons. They may exist in the form


of enantiomers or diastereoisomers. The compounds of general
formula (I) may also exist in the form of cis (Z) or trans
(E) stereoisomers. These stereoisomers , enantiomers and
diastereoisomers, and also their mixtures, including the
racemic mixtures, form part of the invention.
The compounds of formula (I) may exist in the form
of bases or of addition salts with acids. Addition salts of
this kind form part of the invention.
These salts are advantageously prepared with
pharmaceutically acceptable acids, although the salts of
other acids useful, for example, for purifying or isolating
compounds of formula (I) likewise form part of the
invention.
The compounds of general formula (I) may be in the
form of hydrates or solvates, namely in the form of
associations or combinations with one or more molecules of
water or with a solvent. Hydrates and solvates of this kind
likewise form part of the invention.
In the context of the invention the terms have the
following meanings:
Ct-z, where t and z may take the values from 1 to 7, is
a carbon chain which may have from t to z carbon atoms; for
example, C1-3 is a carbon chain which may have 1 to 3 carbon
atoms;
alkyl is a linear or branched saturated aliphatic
group; for example, a C1-6-alkyl group represents a carbon
chain of 1 to 6 carbon atoms which is linear or branched,


more particularly a methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl, pentyl or hexyl;
alkylene is a linear or branched, saturated divalent
alkyl group; for example, a C1-3-alkylene group represents a
divalent carbon chain of 1 to 3 carbon atoms which is linear
or branched, more particularly methylene, ethylene,
1-methylethylene or propylene;
cycloalkyl is a cyclic alkyl group; for example,
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 a divalent unsaturated aliphatic group
having 2 carbons, more particularly an ethylene,
C2-alkynylene is a -C≡C- group;
alkoxy is an -O-alkyl group having a linear or
branched, saturated aliphatic chain;
thioalkyl is an -S-alkyl group having a linear or
branched, saturated aliphatic chain;
fluoroalkyl is an alkyl group of which one or more
hydrogen atoms have been substituted by a fluorine atom;
fluoroalkoxy is an alkoxy group of which one or more
hydrogen atoms have been substituted by a fluorine atom;
fluorothioalkyl is a thioalkyl group of which one or
more hydrogen atoms have been substituted by a fluorine
atom; and
a halogen atom is a fluorine, a chlorine, a bromine or
an iodine.

The compounds of the invention may be prepared
according to various methods, which are illustrated by the
schemes which follow.
Thus according to a first method (scheme 1) the
compounds of general formula (I) may be prepared by reacting
an amine of general formula (IV), in which R1, G, A, p and n
are as defined in the general formula (I), with a carbonate
of general formula (IIIa), in which V represents a hydrogen
atom or nitro group, R2 is as defined in the general formula
(I) and R represents a methyl or ethyl group. The carbamate-
ester of general formula (II) thus obtained is subsequently
converted into a compound of general formula (I) by
aminolysis using an amine of general formula R3NH2, in which
R3 is as defined in the general formula (I). The aminolysis
reaction may be carried out in a solvent such as methanol or
ethanol or in a mixture of solvents such as methanol and
tetrahydrofuran.

Another method (scheme 2) of obtaining compounds
of general formula (I) involves reacting a piperazine or

homopiperazine derivative of general formula (VII), in which
PG represents a protective group such as a tert-
butyloxycarbonyl (Boc), with a carbonate of general formula
(IIIb), in which V represents a hydrogen atom or a nitro
group and R2 and R3 are as defined in the general formula
(I), then deprotecting the resultant compound, in the
presence for example of a solution of hydrochloric acid in a
solvent such as isopropanol. The carbamate-amide of general
formula (V) thus obtained is subsequently converted into a
compound of general formula (I) by reaction with a
derivative of general formula (VI), in which Rl, G, p and A
are as defined in the general formula (I) and W represents a
chlorine, bromine or iodine atom or a mesylate or tosylate
group. The N-alkylation reaction may be carried out in a
solvent such as acetonitrile or toluene in the presence of a
base such as potassium carbonate or diisopropylethylamine.

The compounds of general formula (I), (II) and
(IV), in which R1 represents a group of aryl-aryl, aryl-
heteroaryl, heteroaryl-aryl or heteroaryl-heteroaryl type
may also be prepared by reacting corresponding compounds of
general formula (I), (II) or (IV) for which R4 is


substituted by a chlorine, bromine or iodine atom or by a
triflate group, in the position where the group R6 is to be
introduced, with an aryl- or heteroaryl-boronic acid
derivative in accordance with the Suzuki reaction conditions
(Chem. Rev. 1995, 95, 2457-2483) or with an aryl- or
heteroaryl-trialkylstannane derivative in accordance with
the Stille reaction conditions (Angew. Chem. Int. Ed. 1986,
25, 504-524) .
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
respective general formula HOCHR2COOR where R represents a
methyl or ethyl group, or HOCHR2CONHR3 where R3 is as defined
in the general formula (I), with phenyl chloroformate or 4-
nitrophenyl chloroformate, in the presence of a base such as
triethylamine or diisopropylethylamine.
The compounds of general formula (IV), (VI) and
(VII), and also the amines of general formula R3NH2, when
their preparation method is not described, are available
commercially or are described in the literature, or may be
prepared according to various methods described in the
literature or known to the skilled person.
The invention, according to another of its
aspects, likewise provides the compounds of formula (II) and
(V) . These compounds are useful as intermediates in the
synthesis of the compounds of formula (I).
The examples which follow illustrate the

preparation of some compounds of the invention. These
examples are not limitative and merely illustrate the
invention. The microanalyses, 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 indicated between parentheses in the
titles of the examples correspond to those in the 1st column
of the table thereafter.
Example 1 (compound 85)
2-(methylamino)-2-oxoethyl trans-4-(3-phenylprop-2-en-1-yl)
piperazine-1-carboxylate

1.1. 2-(ethoxy)-2-oxoethyl trans-4-(3-phenylprop-
2-en-1-yl)piperazine-1-carboxylate
A solution of 1.40 g (6.93 mmol) of trans-
1-cinnamylpiperazine and 1.74 g (7.76 mmol) of ethyl
{[(phenoxy)carbonyl]oxy}acetate (J. Med. Chem., 1999, 42,
277-290) in 15 ml of toluene is heated at 80°C overnight. It
is evaporated to dryness and the residue is taken up in
50 ml of ethyl acetate. It is washed with 2 times 20 ml of
water and 1 times 10 ml of saturated aqueous sodium chloride


solution. It is dried over sodium sulphate and evaporated to
dryness. The residue is purified by chromatography on silica
gel, eluting with a 50/50 mixture of cyclohexane and ethyl
acetate, then with ethyl acetate, to give 0.814 g of product
in the form of a pale yellow oil.
1.2. 2-(methylamino)-2-oxoethyl trans-4-(3-
phenylprop-2-en-1-yl)piperazine-1-carboxylate
0.8 g (2.4 mmol) of 2-(ethoxy)-2-oxoethyl trans-4-
(3-phenylprop-2-en-1-yl)piperazine-1-carboxylate, obtained
in step 1.1., is dissolved in 10 ml of a 2M solution of
methylamine (20 mmol) in methanol. The solution is left to
react for an hour and a half at ambient temperature and is
then evaporated to dryness. The residue is purified by
chromatography on silica gel, eluting first with ethyl
acetate and then with a mixture 90/10 mixture of ethyl
acetate and methanol. This gives 0.548 g of a white powder.
Melting point (°C): 109-111
LC-MS : M+H = 318
1H NMR (DMSO-d6) : δ (ppm) : 7.80 (broad s, 1H) ; 7.50-7.15 (m,
5H); 6.55 (d, 1H); 6.25 (td, 1H); 4.40 (s, 2H); 3.40 (m,
4H); 3.10 (d, 2H); 2.60 (d, 3H); 2.40 (m, 4H).
Example 2 (compound 99)
2-amino-2-oxoethyl 4-{3-[3-(trifluoromethyl)phenyl]prop-2-
yn-1-yl}-l,4-diazepane-1-carboxylate


2.1. 4-{3-[3-(trifluoromethyl)phenyl]prop-2-yn-1-
yl}-l,4-diazepane-1-carbaldehyde
A mixture of 1.28 g (10 mmol) of 1,4-diazepane-1-
carbaldehyde and 0.33 g (11 mmol) of paraformaldehyde in
13 ml of dioxane is heated at 80°C until a homogeneous
solution is obtained. 1.70 g (10 mmol) of 3-
trifluoromethylphenylacetylene in solution in 7 ml of
dioxane and 1.81 g (10 mmol) of copper diacetate are added.
The mixture is heated at 80°C for 4 hours. It is cooled to
ambient temperature and diluted with 75 ml of ethyl acetate.
The organic phase is washed with 25 ml of 3 0% ammonia
solution and with saturated aqueous sodium chloride
solution. It is dried over sodium sulphate and evaporated to
dryness. The residue is purified by chromatography on silica
gel, eluting with a 98/2/0.2 then 96/4/0.4 and 94/6/0.6
mixture of dichloromethane, methanol and 3 0% ammonia, to
give 2.67 g of product in the form of a yellow oil.
2.2. 4-{3-[3-(trifluoromethyl)phenyl]prop-2-yn-1-
yl}-1,4-diazepane
2.63 g (8.48 mmol) of 4-{3-[3-(trifluoromethyl)
phenyl]prop-2-yn-1-yl}-1,4-diazepane-1-carbaldehyde,
obtained in step 2.1., are dissolved in 7.5 ml of methanol.


3.5 ml of a 35% aqueous sodium hydroxide (30 mmol) solution
are added and the mixture is heated at reflux for 3 hours.
It is cooled to ambient temperature. It is diluted with
20 ml of water and 75 ml of dichloromethane. The phases are
separated and then the aqueous phase is extracted with 2
times 25 ml of dichloromethane. The organic phases are
washed with 25 ml of water and then with 25 ml of saturated
aqueous sodium chloride solution. They are dried over sodium
sulphate and evaporated to dryness, to give 2.25 g of
product in the form of a red oil, which is used as it is in
the following step.
2.3. 2-(ethyloxy)-2-oxoethyl 4-{3-[3-
(trifluoromethyl)phenyl]prop-2-yn-1-yl}-1,4-diazepane-1-
carboxylate
A solution of 2.25 g (7.95 mmol) of 4-{3-[3-
(trifluoromethyl)phenyl]prop-2-yn-1-yl}-l,4-diazepane,
obtained in step 2.2., and 2.68 g (11.9 mmol) of ethyl
{[(phenyloxy)carbonyl]oxy}acetate in 10 ml of toluene is
heated at 60°C overnight. 5 g of silica are added and the
mixture is evaporated to dryness. The residue is purified by
chromatography on silica gel, eluting with a 60/40 then
40/60 mixture of cyclohexane and ethyl acetate and then with
ethyl acetate, to give 2.42 g of product in the form of an
orange-coloured oil.
2.4. 2-amino-2-oxoethyl 4-{3-[3-(trifluoromethyl)
phenyl]prop-2-yn-1-yl}-1,4-diazepane-1-carboxylate
0.77 g (1.87 mmol) of 2-(ethyloxy)-2-oxoethyl 4-

{3-[3-(trifluoromethyl)phenyl]prop-2-yn-1-yl}-1,4-diazepane-
1-carboxylate, obtained in step 2.3., is dissolved in 14 ml
of a 7M solution of ammonia (98 mmol) in methanol. The
solution is left to react at ambient temperature overnight
and then 2 g of silica are added and it is evaporated to
dryness. The residue is purified by chromatography on silica
gel, eluting with a 97/3/0.3 then 95/5/0.5 and 93/7/0.7
mixture of dichloromethane, methanol and 3 0% ammonia. The
eluate is subsequently recrystallized from a mixture of
ethyl acetate and diisopropyl ether, to give 0.57 g of white
crystals.
Melting point (°C): 102-104
LC-MS : M+H =3 84
1H NMR (CDCl3) δ(ppm): 7.70 (s, 1H) ; 7.55 (m, 2H) ; 7.45 (d,
1H); 6.15 (broad m, 1H); 5.50 (broad m, 1H); 4.65 (s, 2H);
3.65 (m+s, 6H); 2.85 (m, 4H); 1.95 (m, 2H).
Example 3 (compound 13 0)
2-(methylamino)-2-oxoethyl 4-{2-[(4-chlorophenyl)oxy]ethyl}
piperazine-1-carboxylate

3.1. 4-nitrophenyl 2-(methylamino)-2-oxoethyl
carbonate
A suspension of 2.62 g (29.4 mmol) of 2-hydroxy-N-


methylacetamide and 16.5 g (58.7 mmol) of supported
diisopropylethylamine (Ps-DIEA from Argonaut, loading =
3.56 mmol/g) in 250 ml of dichloromethane is admixed in
small portions and at ambient temperature with 5.93 g
(29.4 mmol) of 4-nitrophenyl chloroformate. Orbital stirring
is continued at ambient temperature for 16 hours. The resin
is filtered off and rinsed with 150 ml of dichloromethane
and the filtrate is concentrated under reduced pressure.
This gives 6 g of product in the form or a light yellow
solid, which is used as it is in the following step.
3.2. 1,1-dimethylethyl 2-(methylamino)-2-oxoethyl
piperazine-1,4-dicarboxylate
A solution, cooled to 0°C, of 1.1 g (3 mmol) of 4-
nitrophenyl 2-(methylamino)-2-oxoethyl carbonate, prepared
in step 3.1., in 10 ml of 1,2-dichloroethane is admixed
dropwise at about 0°C with a solution of 0.53 g (2.85 mmol)
of 1,1-dimethylethyl piperazine-1-carboxylate in 5 ml of
1,2-dichloroethane. Stirring is continued at 0°C for 1 hour,
then at ambient temperature for 3 hours.
The mixture is concentrated under reduced
pressure. The residue is purified by chromatography on
silica gel, eluting with a 20/80 mixture of ethyl acetate
and cyclohexane and then gradually increasing the gradient
to end with elution with ethyl acetate. The eluate is
triturated in diisopropyl ether, to give 0.61 g of product
in the form of a white solid, which is used as it is in the
following step.


3.3. 2-(methylamino)-2-oxoethyl piperazine-
1-carboxylate hydrochloride
A solution of 2.68 g (8.9 mmol) of 1,1-
dimethylethyl 2-(methylamino)-2-oxoethyl piperazine-1,4-
dicarboxylate, obtained according to step 3.2., in 25 ml of
dichloromethane is admixed with 25 ml of a 6N solution of
hydrochloric acid in isopropanol. Stirring is continued at
ambient temperature for 1 hour. The organic phase is
separated by filtration through a hydrophobic cartridge and
is concentrated under reduced pressure. Trituration in
isopropanol gives 2.05 g of product.
Melting point (°C): 167-169°C
3.4. 2-(methylamino)-2-oxoethyl 4-{2-[(4-
chlorophenyl)oxy]ethyl}piperazine-1-carboxylate
A solution of 0.073 g (0.3 mmol) of 2-
(methylamino)-2-oxoethyl piperazine-1-carboxylate
hydrochloride, prepared in step 3.3., 0.13 g (0.9 mmol) of
potassium carbonate and 0.069 g (0.29 mmol) of 1-(2-
bromoethoxy)-4-chlorobenzene in 3 ml of acetonitrile is
heated at 85°C for 16 hours. After cooling to ambient
temperature, the inorganic components are filtered off
through a cartridge fitted with a frit and containing
celite. The cartridge is rinsed with acetone and the
filtrate is concentrated under reduced pressure.
Chromatography on silica gel, eluting with a 95/5 mixture of
dichloromethane and methanol, followed by crystallization
from diisopropyl ether give 0.089 g of product in the form

of a white solid.
LC-MS: M+H = 356
Melting point: 159-161°C
1H NMR (CDCl3) δ (ppm) : 7.25 (dd, 2H) ; 6.85 (dd, 2H) ; 6.05
(broad S, 1H); 4.60 (s, 2H); 4.10 (t, 2H) ; 3.55 (m, 4H);
2.90 (d, 3H); 2.85 (t, 2H); 2.60 (m, 4H).
Example 4 (compound 25)
2-(methylamino)-2-oxoethyl 4-(2-naphthalen-2-ylethyl)-
piperazine-1-carboxylate

A solution, cooled to 0°C, of 0.13 g (0.75 mmol)
of 2-naphthalen-2-ylethanol and 0.19 ml (1.13 mmol) of
diisopropylethylamine in 7.5 ml of dichloromethane is
admixed with 0.07 ml (0.9 mmol) of methanesulphonyl
chloride. Stirring is continued in the cold for 0.5 hour,
then at ambient temperature for 2 hours. The solution is
concentrated under reduced pressure.
The residue is taken up in 5 ml of acetonitrile,
and 0.12 g (0.5 mmol) of 2-(methylamino)-2-oxoethyl
piperazine-1-carboxylate hydrochloride, prepared in
accordance with Example 3.3., and 0.2 0 g (1.5 mmol) of
potassium carbonate are added. The mixture is heated at 70°C
for 16 hours. After cooling to ambient temperature, it is

concentrated under reduced pressure. The residue is
suspended in dichloromethane and washed with saturated
sodium bicarbonate solution and then with water. The organic
phase is recovered by filtration on a hydrophobic membrane
and is concentrated under reduced pressure. Chromatography
on silica gel, eluting with a 95/5 mixture of
dichloromethane and methanol, followed by crystallization
from diisopropyl ether, give 0.069 g of product in the form
of a white solid.
LC-MS: M+H = 356
Melting point: 133-135°C
1H NMR (CDCl3) δ(ppm): 7.85 (m, 3H) ; 7.65 (s, 1H) ; 7.55-7.30
(m, 3H); 6.05 (broad S, 1H); 4.60 (s, 2H) ; 3.55 (m, 4H) ;
3.05-2.65 (m, 7H); 2.55 (m, 4H).
Example 5 (compound 50)
2-(methylamino)-2-oxoethyl 4-(3-biphenyl-3-yl-1,1-
dimethylpropyl)piperazine-1-carboxylate hydrochloride

5.1. 1-(2,2-dimethylpropanoyl)-4-(1,1-
dimethylprop-2-yn-1-yl)piperazine
0.756 g (6 mmol) of 1,1-dimethylprop-2-yn-1-yl
acetate (J. Org. Chem. 1994, 59, 2282-4) and 2.235 g


(12 mmol) of 1,1-dimethylethyl piperazine-1-carboxylate are
dissolved in 9 ml of tetrahydrofuran and then 0.059 g
(0.6 mmol) of cuprous chloride is added. The mixture is
heated at reflux for 3 hours. After cooling to ambient
temperature, 100 ml of ethyl acetate, 10 ml of 1N aqueous
sodium hydroxide and 2 ml of 30% ammonia are added. The
organic phase is separated off and washed with 2 times 10 ml
of water and then with 10 ml of saturated aqueous sodium
chloride solution. It is dried over sodium sulphate and
evaporated. The product is purified by chromatography on
silica gel, eluting with an 85/15 then 75/25 and 65/35
mixture of cyclohexane and ethyl acetate, to give 1.19 g
(4.71 mmol) of product in the form of a pale yellow solid.
Melting point: 106-109°C
5.2. 1-(3-biphenyl-3-yl-1,1-dimethylprop-2-yn-1-
yl)-4-(2,2-dimethylpropanoyl)piperazine
1.05 g (4.5 mmol) of 3-bromobiphenyl and 0.9 g
(3.6 mmol) of 1-(2,2-dimethylpropanoyl)-4-(1,1-dimethylprop-
2-yn-1-yl)piperazine, prepared in step 5.1., 0.75 ml
(5.38 mmol) of triethylamine and 0.028 g (0.11 mmol) of
triphenylphosphine are dissolved in 8 ml of tetrahydrofuran.
Under an argon atmosphere, 0.126 g (0.18 mmol) of the
dichloride complex of bis(triphenylphosphine) palladium is
added. The mixture is stirred for 15 minutes and then
0.014 g (0.07 mmol) of cuprous iodide is added. The mixture
is stirred at ambient temperature for 4 hours and then at
60°C overnight. After cooling to temperature it is diluted


with 25 ml of ethyl acetate and filtered on paper. The solid
is rinsed with 4 times 10 ml of ethyl acetate. 4 g of silica
are added to the filtrate, which is evaporated to dryness.
The residue is purified by chromatography on silica gel,
eluting with a 90/10 then 80/20 and 70/30 mixture of
cyclohexane and ethyl acetate, to give 0.90 g (2.22 mmol) of
product in the form of a orange-coloured oil.
5.3. 1,1-dimethylethyl 4-(3-biphenyl-3-yl-1,1-
dimethylpropyl)piperazine-1-carboxylate
0.87 g (2.15 mmol) of 1-(3-biphenyl-3-yl-1,1-
dimethylprop-2-yn-1-yl)-4-(2,2-dimethylpropanoyl)piperazine,
prepared in step 5.2., is dissolved in a mixture of 5 ml of
methanol and 15 ml of ethyl acetate. 0.2 g of platinum oxide
is added and the mixture is stirred under a hydrogen
atmosphere at 40 psi for 6 hours. It is filtered on paper
and the filter product is rinsed with 3 times 10 ml of ethyl
acetate. 2 g of silica are added to the filtrate, which is
evaporated to dryness. The residue is purified by
chromatography on silica gel, eluting with a 90/10 then
85/15 and 80/20 mixture of cyclohexane and ethyl acetate, to
give 0.36 g (0.88 mmol) of product in the form of a
colourless oil.
5.4. 1-(3-biphenyl-3-yl-1,1-dimethylpropyl)-
piperazine
0.65 ml (8.4 mmol) of trifluoroacetic acid is
added to a solution of 0.3 5 g (0.86 mmol) of
1,1-dimethylethyl 4-(3-biphenyl-3-yl-1,1-dimethylpropyl)-


piperazine-1-carboxylate, prepared in step 5.3., in 5 ml of
dichloromethane. The mixture is stirred for 2 hours and then
0.65 ml of trifluoroacetic acid is added. It is stirred for
2 more hours and then diluted with 10 ml of 1,2-
dichloroethane and evaporated to dryness. The residue is
taken up in a mixture of 50 ml of dichloromethane and 20 ml
of 15% aqueous sodium hydroxide solution. The phases are
separated and the aqueous phase is extracted with 2 times
20 ml of dichloromethane. The organic phases are washed with
10 ml of water and then with 20 ml of saturated aqueous
sodium chloride solution, dried over sodium sulphate and
evaporated, to give 0.25 g (0.81 mmol) of product in the
form of a yellow oil.
5.5. 2-(methylamino)-2-oxoethyl 4-(3-biphenyl-3-
yl-1,1-dimethylpropyl)piperazine-1-carboxylate hydrocloride
A solution of 0.25 g (0.81 mmol) of 1-(3-biphenyl-
3-yl-1,1-dimethylpropyl)piperazine, prepared in step 5.4.,
and 1.5 g (1.22 mmol) of ethyl {[(phenyloxy)carbonyl]oxy}
acetate is heated at 60°C overnight and then evaporated to
dryness. The residue is dissolved in a mixture of 4 ml of a
2M methylamine (8 mmol) solution in tetrahydrofuran and 2 ml
of methanol. The solution is left to react overnight and
then 1 g of silica is added and the mixture is evaporated.
The product is purified by chromatography on silica gel,
eluting with a 98/2 then 96/4 and 94/6 mixture of
dichloromethane and methanol, to give 0.23 g (0.54 mmol) of
product in the form of a colourless gum.

The product is dissolved in 5 ml of ethyl acetate,
and 1 ml of a 5N solution of hydrochloric acid in
isopropanol is added. The mixture is evaporated to dryness.
The residue is taken up in 15 ml of hot ethyl acetate. The
solid is filtered off, rinsed with 2 times 3 ml of ethyl
acetate and dried, to give 0.215 g (0.46 mmol) of product in
the form of white powder.
LC-MS: M+H = 424
Melting point: 212-216°C (dec.)
1H NMR (CDCl3) δ(ppm): 12.50 (broad s, 1H) ; 7.55 (d, 2H) ;
7.40 (m, 6H); 7.20 (d, 1H); 6.05 (broad s, 1H); 4.60 (s,
2H) ; 4.30-4.10 (m, 4H) ; 3.55 (broad d, 2H) ; 3.05-2.75 (m+d,
5H); 2.15 (m, 2H); 1.70 (s, 8H).
Example 6 (compound 29)
2-(methylamino)-2-oxoethyl 4-{2-[3-(4-chlorophenyl)isoxazol-
5-yl]ethyl}piperazine-1-carboxylate

6.1. 2- [3-(4-chlorophenyl)isoxazol-5-yl]ethanol
1.63 ml (11.58 mmol) of triethylamine are added
dropwise to a solution of 1.18 ml (15.57 mmol) of but-4-yn-
l-ol and 2.0 g (10.52 mmol) of 4-chloro-N-
hydroxybenzenecarboximidoyl chloride (J. Med. Chem. 1998,
41, 4556-66) in 30 ml of dichloromethane, cooled with an ice


bath. The mixture is left to react at ambient temperature
overnight. 50 ml of dichloromethane are added and the
mixture is washed with 2 times 50 ml of water and then with
50 ml of saturated aqueous sodium chloride solution. After
drying over sodium sulphate, the system is evaporated. The
residue is purified by chromatography on silica gel, eluting
with an 80/20 then 70/30 mixture of cyclohexane and ethyl
acetate, to give 1.1 g (4.91 mmol) of product in the form of
a white solid.
Melting point: 65-67°C
6.2. 2-(methylamino)-2-oxoethyl 4-{2-[3-(4-
chlorophenyl)isoxazol-5-yl]ethyl}piperazine-1-carboxylate
A solution of 0.100 g (0.447 mmol) of 2-[3-(4-
chlorophenyl)isoxazol-5-yl]ethanol, prepared in step 6.1.,
and 0.082 ml (0.47 mmol) of" diisopropylethylamine in 5 ml of
dichloromethane, is admixed with 0.036 ml (0.469 mmol) of
methanesulphonyl chloride. The mixture is stirred at ambient
temperature for 4 hours and then washed with saturated
aqueous ammonium chloride solution and saturated aqueous
sodium chloride solution. It is concentrated under reduced
pressure. The residue is taken up in 5 ml of acetonitrile,
and 0.107 g (0.45 mmol) of 2-(methylamino)-2-oxoethyl
piperazine-1-carboxylate hydrochloride, prepared in
accordance with Example 3.3., and 0.186 g (1.35 mmol) of
potassium carbonate are added. The mixture is heated at 75°C
for 16 hours. After cooling to ambient temperature, it is
concentrated under reduced pressure. The residue is taken up

in ethyl acetate and washed with water and then with
saturated aqueous sodium chloride solution. The mixture is
evaporated and the residue is purified by chromatography on
silica gel, eluting with dichloromethane and then with a
90/10 mixture of dichloromethane and methanol. This gives
0.054 g (0.132 mmol) of product in the form of a white
solid.
LC-MS: M+H = 407
Melting point: 130-132°C
1H NMR (DMSO-d6) δ (ppm) : 7.85 (d, 2H) ; 7.75 (unresolved
complex, 1H); 7.55 (d, 2H); 6.85 (s, 1H); 4.40 (s, 2H); 3.40
(m, 4H); 2.95 (t, 2H); 2.70 (t, 2H); 2.55 (d, 3H); 2.40 (m,
4H) .
Example 7 (compound 52)
2-(methylamino)-2-oxoethyl 4-[3-(3'-chlorobiphenyl-3-yl)
propyl]piperazine-1-carboxylate

7.1. 3-(3-bromophenyl)propan-1-ol
A suspension of 1.84 g (8 mmol) of 3-(3-
bromophenyl)propionic acid and 0.91 g (24 mmol) of sodium
borohydride in 20 ml of THF, cooled to 0°C, is admixed in
small portions with 3.2 ml (25 mmol) of trifluoroborane-
diethyl ether complex. Stirring is continued in the cold for


1 hour, and then at ambient temperature for 16 hours. The
reaction mixture is cooled to 0°C and neutralized to a pH of
7-8 by adding a 1N solution of aqueous sodium hydroxide. It
is concentrated under reduced pressure and then the residue
is taken up in water. It is extracted with dichloromethane
and dried over sodium sulphate. Following filtration, the
organic phase is concentrated under reduced pressure. This
gives 1.62 g (7.53 mmol) of product in the form of an oil,
which is used as it is in the following step.
7.2. 2-(methylamino)-2-oxoethyl 4-[3-(3-bromo-
phenyl)propyl]piperazine-1-carboxylate
A solution of 1.57 g (6.7 mmol) of 3-(3-
bromophenyl)propan-1-ol, prepared in step 7.1., and 1.73 ml
(10.1 mmol) of diisopropylethylamine in 3 8 ml of
dichloromethane, cooled to 0°C, is admixed with 0.63 ml
(8.14 mmol) of methanesulphonyl chloride. Stirring is
continued in the cold for 0.5 hour and then at ambient
temperature for 2 hours. The mixture is concentrated under
reduced pressure and then the residue is suspended in 35 ml
of acetonitrile. 1.34 g (5.35 mmol) of 2-(methylamino)-2-
oxoethyl piperazine-1-carboxylate hydrochloride, prepared in
accordance with Example 3.3., and 2.2 g (16 mmol) of
potassium carbonate are added. The mixture is heated at 75°C
for 16 hours. After cooling to ambient temperature it is
concentrated under reduced pressure and then the residue is
taken up in water. It is extracted with ethyl acetate and
dried over sodium sulphate. Following filtration, the


organic phase is concentrated under reduced pressure. It is
purified by chromatography on silica gel, eluting with a
98/2 mixture of dichloromethane and methanol.
Crystallization from diisopropyl ether gives 0.84 g
(2.10 mmol) of white crystals.
7.3. 2-(methylamino)-2-oxoethyl 4-[3-
(3'-chlorobiphenyl-3-yl)propyl]piperazine-1-carboxylate
A suspension of 0.14 g (0.35 mmol) of 2-(methylamino)-2-
oxoethyl 4-[3-(3-bromophenyl)propyl]piperazine-
1-carboxylate, prepared in step 7.2., in a mixture of 4 ml
of toluene and 0.6 ml of ethanol is admixed with 0.08 g
(0.07 mol) of the tetrakis(triphenylphosphine)palladium
complex, 1.05 ml (2.1 mmol) of a 2M aqueous solution of
sodium carbonate and 0.22 g (1.4 mmol) of 3-
chlorobenzeneboronic acid. The mixture is heated to 150°C
under microwave irradiation for 5 minutes and the organic
phase is recovered by filtration on a cartridge equipped
with a frit and containing celite and sodium sulphate. The
cartridge is rinsed with toluene and the filtrate is
concentrated under reduced pressure. The product is purified
by chromatography on silica gel, eluting with a 90/10
mixture of ethyl acetate and methanol. The eluate is
subsequently taken up in n-heptane, to give 0.086 g
(0.18 mmol) of product in the form of white crystals.
LC-MS: M+H = 430
Melting point: 82-85°C
1H NMR δ (ppm): 7.35 (m, 8H) ; 6.05 (broad s, 1H) ; 4.6 (s,

2H); 3.55 (m, 4H); 2.85 (d, 3H); 2.75 (t, 2H); 2.45 (m, 6H) ;
1.9 (m, 2H).
Table 1 below illustrates the chemical structures and the
physical properties of some compounds according to the
invention. In the "base or salt" column, "base" represents a
compound in the form of the free base, whereas "HCl"
represents a compound in hydrochloride form.


















ethanolamine] by FAAH (Life Sciences (1995), 56, 1999-2005
and Journal of Pharmacology and Experimental Therapeutics
(1997), 283, 729-34). Accordingly, mouse brains (minus the
cerebellum) are removed and stored at -80°C. Membrane
homogenates are prepared at the time of use by homogenizing
the tissues in a Polytron in a 10 mM Tris-HCl buffer (pH 8)
containing 150 mM NaCl and 1 mM EDTA. The enzyme reaction is
subsequently conducted in 70 ul of buffer containing bovine
serum albumin without fatty acids (1 mg/ml). In succession,
the test compounds, at various concentrations, anandamide
[1-3H ethanolamine] (specific activity: 15-20 Ci/mmol)
diluted to 10 uM with cold anandamide, and the membrane
preparation (400 ug of frozen tissue per assay) are added.
After 15 minutes at 25°C the enzyme reaction is terminated
by adding 14 0 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 µl) of the aqueous phase
containing the 1-3H ethanolamine is counted by liquid
scintillation.
Under these conditions, the most active compounds
of the invention exhibit IC50 values (concentration
inhibiting by 50% the control enzyme activity of FAAH) of
between 0.001 and 1 uM.
Table 2 below shows the IC50 of some compounds
according to the invention
Table 2


It is therefore apparent that the compounds
according to the invention have an inhibitory effect on the
FAAH enzyme.
The in vivo activity of the compounds of the
invention was evaluated in an analgesia test.
Accordingly, intraperitoneal (i.p.) administration
of PBQ (phenylbenzoquinone, 2 mg/kg in a 0.9% sodium
chloride solution containing 5% of ethanol) to male OF1 mice
weighing 25 to 3 0 g causes abdominal stretches, on average
3 0 twists or contractions 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
Tween 80 at 0.5%, 60 minutes or 120 minutes before the
administration of PBQ. Under these conditions the most
potent compounds of the invention reduce by 35 to 70% the
number of stretches induced by PBQ, within a dose range of
between 1 and 3 0 mg/kg. For example, compounds 4 9 and 69 of
the table reduce by 43% and 47% respectively, the number of
stretches induced by PBQ, at a dose of 10 mg/kg at 12 0
minutes.
The FAAH enzyme (Chemistry and Physics of Lipids,
(2000), 108, 107-21) catalyses the hydrolysis of endogenous
derivatives of amides and of esters of various fatty acids


such as W-arachidonylethanolamine (anandamide),
N-palmitoylethanolamine, N-oleoylethanolamine, oleamide or
2-arachidonoylglycerol. These derivatives exert various
pharmacological activities by interacting, inter alia, with
cannabinoid and vanilloid receptors.
The compounds of the invention block this
degradation pathway and increase the tissue level of these
endogenous substances. They can be used in this respect in
the prevention and treatment of pathologies in which
endogenous cannabinoids and/or any other substrates
metabolized by the FAAH enzyme are involved. Mention may be
made, for example, of the following diseases and conditions:
pain, especially acute or chronic pain of the 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,
especially that subsequent to chemotherapy; eating
disorders, especially anorexia and cachexia of various
kinds; neurological and psychiatric pathologies: shaking,
dyskinesia, dystonia, spasticity, obsessive-compulsive
behaviours, Tourette's syndrome, all forms of depression and
anxiety of any kind and cause, mood disorders, psychoses;
acute and chronic neurodegenerative diseases: Parkinson's
disease, Alzheimer's disease, senile dementia, Huntington's


chorea, lesions associated with cerebral ischemia and with
cranial and medullary trauma; epilepsy; sleep disorders,
including sleep apnoea; cardiovascular diseases, especially
hypertension, cardiac arrhythmias, arteriosclerosis, heart
attack, cardiac ischemias; renal ischemia; cancers: benign
skin tumours, papillomas and brain tumours, prostate
tumours, brain tumours (glioblastomas, medulloepitheliomas,
medulloblastomas, neuroblastomas, tumours of embryonic
origin, astrocytomas, astroblastomas, ependyomas,
oligodendrogliomas, plexus tumour, neuroepitheliomas,
epiphyseal tumour, ependymoblastomas, malignant meningiomas,
sarcomatoses, malignant melanomas, schwannomas); disorders
of the immune system, especially autoimmune diseases:
psoriasis, lupus erythematosis, diseases of the connective
tissue or collagen diseases, Sjogrer's syndrome, ankylosing
spondylarthritis, undifferentiated spondylarthritis,
Behcet's disease, haemolytic autoimmune anaemias, multiple
sclerosis, amyotrophic lateral sclerosis, amyloses,
transplant 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,
especially diseases of the joints: arthritis, rheumatoid
arthritis, osteoarthritis, spondylitis, gout, vasculitis,
Crohn's disease, irritable bowel syndrome; osteoporosis;
ocular conditions: ocular hypertension, glaucoma; pulmonary


conditions: diseases of the respiratory tracts,
bronchospasms, coughing, asthma, chronic bronchitis, chronic
obstruction of the respiratory tracts, emphysema;
gastrointestinal diseases: irritable bowel syndrome,
intestinal inflammatory disorders, ulcers, diarrhoea;
urinary incontinence and bladder inflammation.
The use of compounds according to the invention in
base, salt, hydrate or pharmaceutically acceptable solvate
form for preparing a medicinal product intended for treating
the abovementioned pathologies forms an integral part of the
invention.
The invention likewise provides medicinal products
which comprise a compound of formula (I), or an acid
addition salt or else a hydrate or a pharmaceutically
acceptable solvate of the compound of formula (I). These
medicinal products are employed in therapy, particularly in
the treatment of the abovementioned pathologies.
In accordance with another of its aspects the
present invention provides pharmaceutical compositions
comprising as active principle at least one compound
according to the invention. These pharmaceutical
compositions include an effective dose of a compound
according to the invention, or an acid addition salt or a
hydrate or pharmaceutically acceptable solvate of the said
compound, and optionally one or more pharmaceutically
acceptable excipients.
The said excipients are selected, according to the


pharmaceutical form and the desired mode of administration,
from the customary excipients, which are known to the
skilled person.
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 acid addition
salt, solvate or hydrate where appropriate, may be
administered in single-dose administration form, in a
mixture with conventional pharmaceutical excipients, to
animals and to humans for the prophylaxis or treatment of
the above disorders or diseases.
The unit-dose administration forms which are
appropriate include 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 and intranasal administration and
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 may be used in
creams, ointments or lotions.
By way of example a single-dose administration
form of a compound according to the invention in tablet form
may comprise the following components:

Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Croscaramellose sodium 6.0 mg
Maize starch 15.0 mg
Hydroxypropyl-methylcellulose 2.25 mg
Magnesium stearate 3.0 mg
The said single-dose forms contain a dose
permitting daily administration of from 0.01 to 20 mg of
active principle per kg of bodyweight, depending on the
pharmaceutical form.
There may be particular cases in which higher or
lower dosages are appropriate; such dosages also belong to
the invention. In accordance with common 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 provides a method of treating the pathologies indicated
above, which comprises administering an effective dose of a
compound according to the invention, one of its addition
salts with a pharmaceutically acceptable acid, or a solvate
or a hydrate of the said compound.

WE CLAIM :
1. Compound of the formula (I)

(I)
in which
n represents an integer 1 or 2;
p represents an integer ranging from 1 to 7;
A is selected 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;

G represents a single bond, an oxygen or sulphur atom or an
SO, SO2, C=O or CH(OH) group;
R1 represents a group R4 optionally substituted by one or
more groups R5 and/or R6;
R4 represents a group selected from a phenyl, pyridinyl,
pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl,
furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,
thiadiazolyl, triazolyl, tetrazolyl, naphthalenyl,
diphenylmethyl, quinolinyl, tetrahydroquinolinyl,
isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl,
quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl,
benzofuranyl, dihydrobenzofuranyl, benzothienyl,
dihydrobenzothienyl, indolyl, indolinyl, indanyl,
indazolyl, isoindolyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl,
pyrrolopyridinyl, furopyridinyl, thienopyridinyl,
imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl,
pyrazolopyridinyl, isoxazolopyridinyl and
isothiazolopyridinyl;
R5 represents a halogen atom or a cyano, nitro, C1-6-alkyl,
C1-6-alkoxy, hydroxyl, C1-6-thioalkyl, C1-6-f luoroalkyl,
C1-6-fluoroalkoxy or C1-C6-f luorothioalkyl group, a group
NR7R8, NR7COR8, NR7CO2R8, NR7SO2R8, COR7, CO2R7, CONR7R8, SO2R7 or
SO2NR7R8, or an -O- (C1-3-alkylene) -O group;
R6 represents a phenyl, phenyloxy, benzyloxy, naphthalenyl,
pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl group, the
group or groups R6 being optionally substituted by one or


more groups R5 identical to or different from one another;
R7 and R8 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 selected from azetidine,
pyrrolidine, piperidine, morpholine, thiomorpholine,
azepine and piperazine, this ring being optionally
substituted by a C1-6-alkyl or benzyl group;
R2 represents a hydrogen atom or a C1-6-alkyl group;
R3 represents a hydrogen atom or a C1-6-alkyl,
C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl group;
in the form of a base, addition salt with an acid, hydrate
or solvate.
2. Compound of formula (I) as claimed in Claim
1, characterized in that
n represents an integer 1 or 2;
p represents an integer ranging from 1 to 7;
A is selected from one or more groups X and/or Y;
X represents a methylene group optionally substituted by
one or two C1-6-alkyl groups;
Y represents either a C2-alkenylene group or a C2-alkynylene
group;
G represents a single bond, an oxygen atom or a C=O group;
R1 represents a group R4 optionally substituted by one or
more groups R5 and/or R6;
R4 represents a group selected from a phenyl, naphthalenyl,
diphenylmethyl, quinolinyl, indolyl, pyrazolyl, isoxazolyl,
pyrimidinyl and thiazolyl;
R5 represents a halogen atom or a cyano group, a C1-6-alkyl
group, a C1-6-alkoxy group, a C1-6-fluoroalkyl group, a C1-C6-


fluoroalkoxy group, or an -O-(C1-3-alkylene)-O group;
R6 represents a phenyl, naphthalenyl or benzyloxy group;
R2 represents a hydrogen atom or a C1-6-alkyl group;
R3 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl
or C3-7-cycloalkyl-C1-3-alkyl group;
in the form of a base, addition salt with an acid, hydrate
or solvate.
3. Compound of formula (I) as claimed in Claim
1 or 2, characterized in that
n represents the integer 1;
p represents an integer ranging from 1 to 4;
A is selected from one or more groups X and/or Y;
X represents a methylene group optionally substituted by
one or two C1-6-alkyl groups;
Y represents a C2-alkynylene group;
G represents a single bond or an oxygen atom;
R1 represents a group R4 optionally substituted by one or
more groups R5 and/or R6;
R4 represents a group selected from a phenyl, naphthalenyl
or isoxazolyl;
R5 represents a halogen atom or a cyano group, a C1-6-alkoxy
group, a C1-6-fluoroalkyl group;
R6 represents a phenyl group;
R2 represents a hydrogen atom or C1-6-alkyl group;
R3 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl
or C3-7-cycloalkyl-C1-3-alkyl group;
in the form of a base, addition salt with an acid, hydrate
or solvate.
4. Compound of formula (I) as claimed in any


one of Claims 1 to 3, characterized in that
R2 represents a hydrogen atom;
R3 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl
or C3-7-cycloalkyl-C1-3-alkyl group.
5. Compound of formula (I) as claimed in Claim
1, selected from:
2-(methylamino)-2-oxoethyl 4-(2-biphenyl-3-ylethyl)-
piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-(2-biphenyl-4-ylethyl)-
piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[2-(1-naphthyl)ethyl]-
piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-{2-[3-(4-chlorophenyl)-
isoxazol-5-yl]ethyl}piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-{2-[5-(4-chlorophenyl)-
isoxazol-3-yl]ethyl}piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-(3-biphenyl-3-ylpropyl)-
piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-(3-biphenyl-4-ylpropyl)-
piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-(3-biphenyl-3-yl-1,1-
dimethylpropyl)piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[3-(3'-chlorobiphenyl-
3-yl)propyl]piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[3-(4'-chlorobiphenyl-3-
yl)propyl]piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[3-(3'-methoxybiphenyl-3-
yl)propyl]piperazine-1-carboxylate

2-(methylamino)-2-oxoethyl 4-[3-(4'-methoxybiphenyl-3-
yl)propyl]piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[3-(3'-chlorobiphenyl-
4-yl)propyl]piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[3-(4'-chlorobiphenyl-
4-yl)propyl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(2-naphthyl)propyl]-
piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-{3-[5-(4-chlorophenyl)-
isoxazol-3-yl]propyl}piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-{3-[3-(4-chlorophenyl)-
isoxazol-5-yl]propyl}piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[4-(3-chlorophenyl)-
butyl]piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[4-(4-chlorophenyl)butyl]-
piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-{4-[3-(trifluoromethyl)-
phenyl]butyl}piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-{4-[4-(trifluoromethyl)-
phenyl]butyl}piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-{4-[4-(trifluoromethyl-
phenyl]but-3-yn-1-yl}piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[5-(3-chlorophenyl)pent-4-
yn-1-yl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[5-(2,4-dichlorophenyl)pent-
4-yn-1-yl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[5-(2,5-dichlorophenyl)pent-
4-yn-1-yl]piperazine-1-carboxylate


- 2-(methylamino)-2-oxoethyl 4-[5-(3,4-dichlorophenyl)pent-
4-yn-1-yl]piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[5-(3-chloro-4-
fluorophenyl)pent-4-yn-1-yl]piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[3-(2-
chlorophenoxy)propyl]piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[3-(3-chlorophenoxy)-
propyl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(4-chlorophenoxy)-
propyl]piperazine-1-carboxylate
- 2-(methylamino)-2-oxoethyl 4-[3-(2,3-dichloro-
phenoxy)propyl]piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[3-(2,4-dichloro-
phenoxy)propyl]piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[3-(2,5-dichloro-
phenoxy)propyl]piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[3-(2, 6-dichloro-
phenoxy)propyl]piperazine-1-carboxylate
2-(methylamino)-2-oxoethyl 4-[3-(3,5-dichlorophenoxy)-
propyl]piperazine-1-carboxylate.
6. Process for preparing a compound of formula
(I) as claimed in any one of Claims 1 to 5, comprising the
step consisting in converting the carbamate ester of
general formula (II)


in which R1, R2, G, A, p and n 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 R3NH2 in
which R3 is as defined in the general formula (I).
7. Process for preparing a compound of formula
(I) as claimed in any one of Claims 1 to 5, comprising the
step consisting in converting the carbamate-amide of
general formula (V)

in which R2, R3 and n are as defined in the general formula
(I) as claimed in Claim 1,
by reaction with a derivative of general formula R1-G-[A]P-W
(VI) , in which R1, G, p and A are as defined in the general
formula (I) and W represents a chlorine, bromine or iodine
atom, or a mesylate or tosylate group.
8. Compound of the general formula (II),


in which R1, R2, G, A, p and n are as defined in the general
formula (I) as claimed in Claim 1 and R represents a methyl
or ethyl group.
9. Compound of the general formula (V),

in which R2, R3 and n are as defined in the general formula
(I) as claimed in Claim 1.
10. Compound of formula (I) as claimed in any
one of Claims 1 to 5, in the form of a base, addition salt
with an acid, hydrate or pharmaceutically acceptable
solvate, for its use as a medicinal product.
11. Pharmaceutical composition comprising at
least one compound of formula (I) as claimed in any one of
Claims 1 to 5, in the form of a base, addition salt with an
acid, hydrate or pharmaceutically acceptable solvate, and
optionally one or more pharmaceutically acceptable
excipients.


The invention relates to a compound
having general formula (I), wherein: n = 1 or 2; p
represents an integer varying between 1 and 7; A is
selected from one or more X, Y and/or Z groups; X
= optionally-substituted methylene; Y = C2-alkenylene,
optionally substituted, or C2-alkynylene; Z =
C3-7-cycloalkyl; G= single bond, O, S, SO, SO2, C=O
or CH(OH); R1 represents an aryl- or heteroaryl-type
group; and R2 represents a hydrogen atom or a C1-6-
alkyl group; R3 represents a hydrogen atom or a C1-6-
alkyl, C3-7--cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl group, said compound taking the form of a base, an acid addition salt, a hydrate or
a solvate. The invention also relates to the use thereof as FAAH enzyme inhibitors for the treatment of pain, inflammation, neurodegenerative
diseases, etc.

Documents:

02282-kolnp-2006 abstract.pdf

02282-kolnp-2006 claims.pdf

02282-kolnp-2006 correspondence others.pdf

02282-kolnp-2006 description(complete).pdf

02282-kolnp-2006 form-1.pdf

02282-kolnp-2006 form-3.pdf

02282-kolnp-2006 form-5.pdf

02282-kolnp-2006 gpa.pdf

02282-kolnp-2006 international publication.pdf

02282-kolnp-2006 international search authority report.pdf

02282-kolnp-2006-assignment.pdf

02282-kolnp-2006-correspondence-1.1.pdf

2282-KOLNP-2006-ABSTRACT 1.1.pdf

2282-kolnp-2006-amanded claims 1.1.pdf

2282-KOLNP-2006-AMANDED CLAIMS.pdf

2282-kolnp-2006-assignment.pdf

2282-kolnp-2006-correspondence 1.2.pdf

2282-kolnp-2006-correspondence.pdf

2282-kolnp-2006-description (complete) 1.2.pdf

2282-kolnp-2006-english translation.pdf

2282-KOLNP-2006-EXAMINATION REPORT REPLY RECIEVED.pdf

2282-kolnp-2006-examination report.pdf

2282-KOLNP-2006-FORM 1 1.1.pdf

2282-kolnp-2006-form 13.1.pdf

2282-KOLNP-2006-FORM 13.pdf

2282-kolnp-2006-form 18.1.pdf

2282-kolnp-2006-form 18.pdf

2282-KOLNP-2006-FORM 2.pdf

2282-KOLNP-2006-FORM 3 1.1.pdf

2282-kolnp-2006-form 3.pdf

2282-kolnp-2006-form 5.pdf

2282-kolnp-2006-gpa.pdf

2282-kolnp-2006-granted-abstract.pdf

2282-kolnp-2006-granted-claims.pdf

2282-kolnp-2006-granted-description (complete).pdf

2282-kolnp-2006-granted-form 1.pdf

2282-kolnp-2006-granted-form 2.pdf

2282-kolnp-2006-granted-specification.pdf

2282-KOLNP-2006-OTHERS 1.1.pdf

2282-kolnp-2006-others.pdf

2282-kolnp-2006-petition under rule 137-1.1.pdf

2282-KOLNP-2006-PETITION UNDER RULE 137.pdf

2282-kolnp-2006-reply to examination report.pdf

2282-kolnp-2006-translated copy of priority document.pdf

abstract-02282-kolnp-2006.jpg


Patent Number 248998
Indian Patent Application Number 2282/KOLNP/2006
PG Journal Number 38/2011
Publication Date 23-Sep-2011
Grant Date 20-Sep-2011
Date of Filing 10-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 F94320 THIAIS
2 HOORNAERT CHRISTIAN 49 AVENUE ARTISTIDE BRIAND F-92160 ANTONY
3 LI ADRIEN TAK 14 RUE PIERRE BONNARD F-92260 FONTENAY AUX ROSES
4 ALMARIO GARCIA ANTONIO 26 AVENUE ROGER SALENGRO F-92290 CHATENAY MALABRY
PCT International Classification Number A61K 31/551
PCT International Application Number PCT/FR2005/000450
PCT International Filing date 2005-02-25
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0401953 2004-02-26 France