5-Membered heterocyclic compound
cyclopenta[c]pyrrolylalkylcarbamate derivatives, preparation
thereof, and therapeutic use thereof
The invention relates to cyclopenta[c]pyrrolylalkylcarbamate
derivatives of 5-membered heterocycles, to their preparation
and to their therapeutic use.
There is still a need to find and develop products that
inhibit the enzyme FAAH (Fatty Acid Amide Hydrolase). The
compounds of the invention satisfy this aim.
The compounds of the invention correspond to the general
formula (I):
in which
R2 represents a hydrogen or fluorine atom or a hydroxyl,
cyano, trif luoromethyl, Ci-e-alkyl, Ci_6-alkoxy or NRaR9
group;
m and p have the value 1;
n and o have the same value and have the value 0 or 1 ;
A represents a covalent bond or a group CVs-alkylene;
Ri represents a group R5 optionally substituted with one or
more groups R6 and/or R7;
R5 represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
naphthalenyl, quinolinyl, isoquinolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, cinnolinyl and naphthyridinyl;
Rs represents a halogen atom or a cyano, -CH2CN, nitro,
hydroxyl, CV6-alkyl, Ci_5-alkoxy, Ci^-thioalkyl,
Ci-6-haloalkyl, Cx-6-haloalkoxy, Cx.g-halothioalkyl, C3.7-
cycloalkyl, C3-7-cycloalkyl-Ci-3-alkylene, C3.7-cycloalkyl-
Ci-3-alkylene-0-, NR8R9, NR8COR9/ NR8C02R9, NR8S02R9,
NR8S02NR8R9, COR8, C02R8, CONR8R9, S02R8, S02NR8R9 or -0-(Ci_3-
alkylene)-0- group;
R7 represents a group chosen from furyl, pyrrolyl,
thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
imidazolyl, pyrazolyl, phenyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl and triazinyl; the group (s) R7
possibly being substituted with one or more groups Rs that

may be identical to or different from each other;
R3 represents a hydrogen or fluorine atom, a group Ci-6-alkyl
or a trifluoromethyl group;
R4 represents a 5-membered heterocycle chosen from furyl,
pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl,
isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, imidazole,
triazolyl and tetrazolyl;
this heterocycle being optionally substituted with one or
more substituents chosen from a halogen atom, a d-6-alkyl,
Ci-s-haloalkyl, C3.-7-cycloalkyl, C3.7-cycloalkyl-d-3-alkylene,
Cx-s-haloalkoxy, cyano, NR8Rg, NR8COR9, NR8C02R9, NR8S02R9,
NR8S02NR8R9, COR8, C02R8, CONR8R9/ CON(R8) (d-3-alkylene-
NR10R11) , S02R8, S02NR8R9 or -0-(d-3-alkylene)-0- group;
R8 and R9 represent, independently of each other, a hydrogen
atom or a C^g-alkyl group,
or form, with the atom(s) that bear(s) them,
in the case of NR8R9, a ring chosen from azetidine,
pyrrolidine, piperidine, morpholine, thiomorpholine,
azepine, oxazepine and piperazine rings, this ring being
optionally substituted with a d-6_a-lkyl or benzyl group;
in the case of NR8COR9, a lactam ring; in the case of
NR8C02R9, an oxazolidinone, oxazinone or oxazepinone ring; in
the case of NR8S02R9, a sultam ring,- in the case of
NR8S02NR8R9, a thiazolidine dioxide or thiadiazinane dioxide
ring;
Rio and Rn represent, independently of each other, a
hydrogen atom or a Ci-6-alkyl group.
Among the compounds of general formula (I), a first subgroup
of compounds is formed from the compounds for which R2
represents a hydrogen atom or a fluorine atom. Among the
compounds of general formula (I) , a second subgroup of
compounds is formed from the compounds for which R2
represents a hydrogen atom. Among the compounds of general
formula (I) , a third subgroup of compounds is formed from
the compounds for which R2 represents a fluorine atom.
Among the compounds of general formula (I), a fourth
subgroup of co'mpounds is formed from the compounds for which
m, n, o and p have the value 1. Among the compounds of
general formula (I) , a fifth subgroup is formed from the
compounds for which m and p have the value 1, and, n and o
have the value 0.

Among the compounds of general formula (I), a sixth subgroup
of compounds is formed from the compounds for which A
represents a covalent bond, a methylene or an ethylene.
Among the compounds of general formula (I) , a seventh
subgroup of compounds is formed from the compounds for which
A represents a covalent bond.
Among the compounds of general formula (I), an eighth
subgroup of compounds is formed from the compounds for which
A represents a methylene. Among the compounds of general
formula (I) , a ninth subgroup of compounds is formed from
the compounds for which A represents an ethylene.
Among the compounds of general formula (I), a tenth subgroup
of compounds is formed from the compounds for which Rx
represents a group R5 which is unsubstituted or is
substituted with one or more groups R6 and/or R7;
R5 represents a pyridyl or quinolinyl group;
R6 represents a halogen atom, more particularly a fluorine
or bromine atom, or a Ci-6-haloalkyl group, more
particularly a trifluoromethyl group or a Ci_6-alkyl group,
more particularly a methyl group;
R7 represents a group chosen from pyrazolyl, pyridyl and
phenyl, the latter groups possibly being substituted with
one or more groups Rs that may be identical to or
different from each other.
Among the compounds of general formula (I) , an eleventh
subgroup of compounds is formed from the compounds for
which Ri represents a group R5 substituted with one or more
groups R6 and/or R7;
R5 represents a pyridyl group, more particularly a
pyrid-2-yl group;
R6 represents a halogen atom, more particularly a fluorine
or bromine atom, or a Cx-g-haloalkyl group, more
particularly a trifluoromethyl group or a Ci_6-alkyl group,
more particularly a methyl group;
R7 represents a group chosen from pyrazolyl, pyridyl and
phenyl, the latter groups possibly being substituted with
one or more groups R6 that may be identical to or
different from each other.
Among the compounds of general formula (I) , a twelfth
subgroup of compounds is formed from the compounds for

which Ri represents a group R5 substituted with one or more
groups R6;
R5 represents a quinolinyl group, more particularly a
quinolin-2-yl group;
R6 represents a halogen atom, more particularly a fluorine
atom.
Among the compounds of general formula (I) , a thirteenth
subgroup of compounds is formed from the compounds for which
R3 represents a hydrogen atom.
Among the compounds of general formula (I) , a fourteenth
subgroup of compounds is formed from the compounds for which
R4 represents a group chosen from a thiazolyl, a triazolyl,
or an isoxazolyl;
this group being unsubstituted or substituted with one or
more Ci-6-alkyl, C02R8 or CONR8R9 groups;
R8 and R9 represent, independently of each other, a hydrogen
atom or a Ci-6-alkyl group. More particularly, the Ci_s-alkyl
group is a methyl or ethyl.
Among the compounds of general formula (I) , a fifteenth
subgroup of compounds is formed from the compounds for which
R4 represents a thiazol-4-yl group, this group being
unsubstituted.
Among the compounds of general formula (I) , a sixteenth
subgroup of compounds is formed from the compounds for which
R4 represents an isoxazol-5-yl group;
this group being substituted with one or more C02R8 or
CONR8Rg groups;
R8 and Rg represent, independently of each other, a hydrogen
atom or a Ci-g-alkyl group. More particularly, the (Ve-alkyl
group is a methyl or ethyl.
Among the compounds of general formula (I) , a seventeenth
subgroup of compounds is formed from the compounds for which
R4 represents a 1H-1,2,4-triazol-5-yl group; this group
being substituted with one or more Cn-6-alkyl groups.
Among the compounds of general formula (I) , an eighteenth
subgroup of compounds is formed by the compounds of general
formula (I) in which Rx and/or R2 and/or R3 and/or R4 and/or
n and/or m and/or o and/or p and/or A are all as defined in
the above groups.

Among the compounds of general formula (I), the following
compounds may be mentioned (IUPAC nomenclature generated by
the AutoNom software):
1. thiazol-4-ylmethyl ({ (3a.R, 5s, 6aS) -2- [6- (trif luoro-
methyl)pyrid-2-yl]octahydrocyclopenta[c]pyrrol-S-
ylJmethyl) carbamate (exo)
2. thiazol-4-ylmethyl { [ (3ai?, 5s, 6aS) -2- (5-bromopyrid-2-
yl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}carbamate
(exo)
3. thiazol-4-ylmethyl ({(3a£,5s,6aS)-2-[5-(4-fluoro-
phenyl)pyrid-2-yl]octahydrocyclopenta[c] pyrrol-5-yl}-
methyl)carbamate (exo)
4. thiazol-4-ylmethyl ({ (3ai?, 5s, 6aS) -2- [5- (1-methyl- 1W-
pyrazol-4-yl)pyrid-2-yl]octahydrocyclopenta[c]pyrrol-5-
yl}methyl)carbamate (exo)
5. thiazol-4-ylmethyl {(3a£,5s,6aS)-2-[6-(trifluoro-
methyl)pyrid-2-yl]octahydrocyclopenta[c]pyrrol-5-yl}-
carbamate (exo)
6. thiazol-4-ylmethyl [ (3ai?, 5s, 6&S) -2- (6-f luoroquinolin-2-
yl)octahydrocyclopenta[c]pyrrol-5-yl]carbamate (exo)

7. (1 -methyl- 1H-1,2, 4 -triazol- 5 -yl) methyl ({ (3ai?, 5s, 6aS) -
2- [5- (4-fluorophenyl)pyrid-2-yl]octahydrocyclopenta [c] -
pyrrol-5-yl}methyl)carbamate (exo)
8. (l-methyl-li/-l,2,4-triazol-5-yl)methyl { [ (3ai?, 5s, 6a5) -
2- (5'-fluoro-2,3'-bipyrid-6-yl)octahydrocyclopenta[c]-
pyrrol-5-yl]methyl}carbamate (exo)
9. (3-carbamoylisoxazol-5-yl)methyl ({ (3ai?, 5s, 6a.S) -2- [5-
(4-fluorophenyl)pyrid-2-yl]octahydrocyclopenta[c]pyrrol-5-
yl}methyl)carbamate (exo)
10. [3-(methylcarbamoyl)isoxazol-5-yl]methyl {2-
[ {3aR,5r, 6a5)-2-(5-bromopyrid-2-yl)octahydrocyclopenta[c]-
pyrrol-5-yl]ethyl}carbamate (endo)
11. (3-carbamoylisoxazol-5-yl)methyl {2- [ (3ai?, 5r, 6aS) -2- (5-
bromopyrid-2-yl)octahydrocyclopenta[c]pyrrol-5-yl]ethyl} -
carbamate (endo)
12. (3-carbamoylisoxazol-5-yl)methyl { [ (3ai?, 5r, 6aS)-5-
fluoro-2-(6-fluoroquinolin-2-yl)octahydrocyclopenta [c] -

pyrrol-5-yl]methyl}carbamate (exo)
13. [3-(methylcarbamoyl)isoxazol-5-yl]methyl
{ [ (3aJ?, 5s, 6aS) -2- (6-f luoroquinolin-2-yl) octahydrocyclo-
penta[c]pyrrol-5-yl]methyl}carbamate (exo)
14. [3-(methylcarbamoyl)isoxazol-5-yl]methyl [3-(6-fluoro-
quinolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate
15. ethyl 5-{[({3- [5-(4-fluorophenyl)pyrid-2-yl]-3-aza-
bicyclo [3.1.0] hex-6-yl}carbamoyl)oxy] methylJisoxazole-3-
carboxylate

16. (3 -carbamoylisoxazol-5-yl)methyl [3-(6-fluoroquinolin-
2-yl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate
17. (3-carbamoylisoxazol-5-yl)methyl {3-[5-(4-fluoro-
phenyl) pyrid- 2 -yl] -3-azabicyclo[3.1.0]hex-6-yl}carbamate
18. [3-(methylcarbamoyl)isoxazol-5-yl]methyl {3-[5-(4-
fluorophenyl)pyrid-2-yl]-3-azabicyclo[3.1.0]hex-6-yl} -
carbamate
19. [3-(dimethylcarbamoyl)isoxazol-5-yl]methyl {3- [5-(4-
fluorophenyl)pyrid-2-yl]-3-azabicyclo[3.1.0]hex-6-yl}-
carbamate
The compounds of general formula (I) may comprise 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 or trans
stereoisomers. These stereoisomers, enantiomers and
diastereoisomers, and also mixtures thereof, including
racemic mixtures, form part of the invention.
The compounds of 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 pharmaceutical^
acceptable acids, but the salts of other acids that are
useful, for example, for purifying or isolating the compounds
of formula (I) 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 C1-3 is a carbon-based chain that may-
contain from 1 to 3 carbon atoms;
- alkyl, a linear or branched, saturated aliphatic group;
for example, a Ci-6-alkyl group represents a linear or
branched carbon-based chain of 1 to 6 carbon atoms, more
particularly a methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl, pentyl or hexyl;
- alkylene, a linear or branched, saturated 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_7-
cycloalkyl group represents a cyclic carbon-based group of
3 to 7 carbon atoms, more particularly a cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
- alkoxy, an -0-alkyl group containing a linear or branched,
saturated aliphatic chain;
- thioalkyl, an -S-alkyl group containing a linear or
branched, saturated aliphatic chain;
- haloalkyl, an alkyl group in which one or more hydrogen
atoms have been replaced with a halogen atom;
- haloalkoxy, an alkoxy group•in which one or more hydrogen
atoms have been replaced with a halogen atom;
- halothioalkyl, a thioalkyl group in which one or more
hydrogen atoms have been replaced with a halogen atom;
- halogen atom, a fluorine, a chlorine, a bromine or an
iodine.
- The term 'era' corresponds to the group -R2 in the trans
position relative to the ring junction hydrogens. The term
'endo' corresponds to the group -R2 in the cis position
relative to the ring junction hydrogens.
- r and s indicate the stereochemistry of the pseudo-
asymmetric carbon atoms, according to IUPAC rules.
The compounds of the invention may be prepared according to
various methods, illustrated by the schemes that follow.
These methods, and also the intermediate compounds used, are
a subject of the present invention.


Thus, a first method (scheme 1) consists in reacting an
amine of general formula (II) , in which A, R1; R2, m, n, o
and p are as defined in the general formula (I) defined
above, with a carbonate of general formula (III) in which Z
represents a hydrogen atom or a nitro group, and R3 and R4
are as defined in the general formula (I) defined above, in
the presence of a base such as triethylamine, pyridine, N,N-
dimethylaminopyridine or diisopropylethylamine in a solvent
such as toluene or dichloroethane, at a temperature between
room temperature and the reflux temperature of the solvent.
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 phenyl or 4-nitrophenyl
chloroformate, in the presence of a base such as
triethylamine or diisopropylethylamine, in a solvent such as
dichloromethane or tetrahydrofuran, at a temperature between
0°C and room temperature, to give the carbamate derivative
of general formula (IV) , in which A, Ri, R2, m, n, o and p
are as defined in the general formula (I) defined above, and
Z represents a hydrogen atom or a nitro group. The carbamate
derivative of general formula (IV) thus obtained is then
converted into a compound of general formula (I) , via the
action of an alcohol of general formula HOCHR3R4 (Ilia), as
defined above, in the presence of a base such as

triethylamine, pyridine, N,.W-dimethylaminopyridine or
diisopropylethylamine, in a solvent such as toluene or
dichloroethane, at a temperature between room temperature
and the reflux temperature of the solvent.

A second method (Scheme 2) consists in reacting, in a first
stage, an amine of general formula (Ila), in which A, R2, m,
n, o and p are as defined in the general formula (I) defined
above, and PG represents a protecting group such as a Boc
(tert-butyloxycarbonyl) , a Cbz (benzyloxycarbonyl), a benzyl
or a benzhydryl, with a carbonate of general formula (III)
as defined above, under the conditions described above
during the reaction of the amine of general formula (II)
with the carbonate of general formula (III), followed by a
deprotection reaction, for example in the presence of a
solution of hydrochloric acid (5N) in isopropanol or
dioxane, to obtain the intermediate of general formula (la),
in which A, R2, R3, R4, m, n, o and p are as defined in the
general formula (I) .
One variant for obtaining the intermediates of general
formula (la) (Scheme 2 - variant 2a) consists in reacting an
amine of general formula (Ila), as defined above, with
phenyl or 4-nitrophenyl chloroformate, in the presence of a
base such as triethylamine or diisopropylethylamine, in a
solvent such as dichloromethane or tetrahydrofuran, at a

temperature of between 0°C and room temperature, to give the
carbamate derivative of general formula (IVa), in which A,
R2, m, n, o and p are as defined in the general formula (I)
defined above, PG is as defined above and Z represents a
hydrogen atom or a nitro group. The carbamate derivative of
general formula (IVa) thus obtained is then converted into a
compound of general formula (la), via the action of an
alcohol of general formula HOCHR3R4 (Ilia), as defined
above, in the presence of a base such as triethylamine,
pyridine, N, W-dimethylaminopyridine or diisopropyl-
ethylamine, in a solvent such as toluene or dichloroethane,
at a temperature of between room temperature and the reflux
temperature of the solvent, followed by a deprotection
reaction, for example in the presence of a solution of
hydrochloric acid (5N) in isopropanol or dioxane.
The compound of general formula (I) is then obtained by
reaction of the compound of general formula (la) with a
derivative of general formula (V) , in which Rx is as defined
in the general formula (I) and Ui represents a halogen atom
or a triflate group, using aromatic or heteroaromatic
nucleophilic substitution reaction conditions, for example
by means of a base such as triethylamine, diisopropyl-
ethylamine, pyridine or N, N-dimethylaminopyridine in a
solvent such as dichloromethane, dichloroethane,
acetonitrile, N,N-dimethylformamide, dioxane or tetrahydro-
furan, at a temperature between 0°C and the reflux
temperature of the solvent. This conversion may also be
performed using the Buchwald N-arylation or N-
heteroarylation conditions, for example by means of a
palladium or copper catalyst.
According to Scheme 2, the compounds of general formula (I),
in which Rt represents a group R5 substituted especially
with a group Rs of the Ci_6-alkyl, C3-7-cycloalkyl or C3.7-
cycloalkyl-Ci_3-alkylene type, or with a group R7 as defined
in the general formula (I) defined above, may also be
prepared according to a coupling reaction, catalysed by
means of a transition metal, for example palladium (0) ,
performed on the compound of general formula (lb), in which
A, R2, R3, R4/ R5, m, n, o and p are as defined in the
general formula (I) and U2 represents a chlorine, bromine or
iodine atom or a triflate group, U2 being in the position in
which it is desired to introduce the group R5 or R7 (Scheme

pyrrol- 5-ylcarbamate;
(1-methyl-1H-1, 2 , 4-triazol-5-yl) methyl [ (3aJ?, 5s, 6aS) -
octahydrocyclopenta[c]pyrrol-5-ylmethyl]carbamate;
(3-carbamoylisoxazol-5-yl)methyl [ (3a.R, 5s, 6a.S) -octahydro-
cyclopenta [c]pyrrol-5-ylmethyl] carbamate;
ethyl 5-{ [ ({2-[(3afl,5r,6aS)-octahydrocyclopenta[c] pyrrol-5-
yl]ethyl}carbamoyl)oxy]methyl}isoxazole-3-carboxylate;
ethyl 5-{ [ ({ [ (3ai?, 5r, 6aS) -5-f luorooctahydrocyclopenta [c] -
pyrrol-5-yl]methyl}carbamoyl)oxy]methyl}isoxazole-3-
carboxylate; and
ethyl 5-{[(3-azabicyclo[3.1.0]hex-6-ylcarbamoyl)oxy]methyl} -
isoxazole-3-carboxylate.
Another subject of the present invention relates to the
compounds of general formula (II) :

in which A, Rlt R2, m, n, o and p are as defined in the
general formula (I).
Another subject of the present invention relates to the
compounds of general formula (IV):

in which A, Rl7 R2, m, n, o and p are as defined in the
general formula (I) , and Z represents a hydrogen atom or a
nitro group.
The other compounds of general formulae (II), (Ila), (lib),
(III), (Ilia), (V) and (Va) and also the other reactants are
commercially available or described in the literature, or
else may be prepared according to methods that are described
therein or that are known to those skilled in the art.
The examples that follow illustrate the preparation of a
number of compounds of the invention. These examples are not
limiting, and serve 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 the purities of the compounds obtained.
MP (°C) represents the melting point in degrees Celsius.
Rf indicates the retention time obtained by TLC (thin-layer
chromatography) analysis.
The numbers given in parentheses in the titles of the
examples correspond to those of the first column of the
tables hereinbelow.
The IUPAC (International Union of Pure and Applied
Chemistry) nomenclature was used to name the compounds in
the examples below.
Example 1 (Compound No. 2)
Thiazol-4-ylmethyl { [ (3aJ?, 5s, 6aS) -2- (5-bromopyrid-2-yl) -
octahydrocyclopenta[c]pyrrol-5-yl]methyl} carbamate (exo)
1.1. tert-Butyl (3a.R, 5s, 6aS) -5-cyanohexahydrocyclopenta [c] -
pyrrole-2(1H) -carboxylate
2.3 g (7.53 mmol) of tert-butyl (3a£,5r,6aS)-5-[(methyl-
sulfonyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
(WO 2006/108059) are put into solution in 25 ml of
dimethylsulphoxide then 3.69 g (75.31 mmol) of sodium
cyanide are added. The mixture is stirred at 8 0°C for 1
hour.
It is allowed to return to room temperature and diluted by
adding water and ethyl acetate. The aqueous phase is
extracted with ethyl acetate, then the combined organic
phases are dried over sodium sulphate, filtered and the
filtrate is evaporated to dryness. The residue thus obtained
is purified by chromatography on silica gel, eluting with a
95/5 to 85/15 mixture of cyclohexane and ethyl acetate.
0.81 g of product is obtained in the form of a white solid.
Melting point (°C): 62-64°C
XH NMR (DMSO) 5 (ppm) : 3.48 (m, 2H) , 3.19 (m, 1H) , 3.00 (m,
2H) , 2.78 (m, 2H) , 1.99 (m, 2H) , 1.88 (m, 2H) , 1.39 (s, 9H) .
1.2. tert-Butyl (3ai?, 5s, 6aS) -5- (aminomethyl) hexahydrocyclo-
penta [c]pyrrole-2(1H) -carboxylate
0.54 g (2.29 mmol) of tert-butyl (3ai?, 5s, 6aS) -5-
cyanohexahydrocyclopenta[c]pyrrole-2(ltf)-carboxylate,

obtained in step 1.1., is put into solution in 20 ml of a 1M
solution of sodium hydroxide in ethanol in the presence of a
catalytic amount of Raney nickel (50% in water). The
solution is stirred at room temperature under a hydrogen
pressure of 4 bar using a Parr apparatus for 6 hours. After
evaporating the ethanol, the solution is taken up in water
and dichloromethane. The aqueous phase is extracted several
times with dichloromethane. The combined organic phases are
then washed with a saturated aqueous solution of sodium
chloride then dried over sodium sulphate. After filtration
and evaporation to dryness, 0.550 g of a colourless oil is
obtained.
LC-MS: M+H = 241
XH NMR (DMSO) 5 (ppm) : 3.45 (m, 2H) , 2.98 (m, 2H) , 2.64 (m,
2H), 2.45 (d, 2H), 2.03 (m, 1H), 1.54 (m, 2H), 1.44 (m, 2H),
1.40 (s, 9H).
1.3. tert-Butyl (3aR,5s,6aS)-5-({ [(1,3-thiazol-4-ylmethoxy) -
carbonyl]amino}methyl)hexahydrocyclopenta[c]pyrrole-2 (Iff) -
carboxylate
0.550 g (2.29 mmol) of tert-butyl (3ai?, 5s, 6aS) -5- (amino-
methyl) hexahydrocyclopenta [c] pyrrole-2 (Iff) -carboxylate,
obtained in step 1.2., 0.02 8 g (0.23 mmol) of N, N- dimethyl -
4-aminopyridine, 1.20 ml (6.87 mmol) of N,N-
diisopropylethylamine and 0.705 g (2.52 mmol) of thiazol-4-
ylmethyl 4-nitrophenylcarbonate (WO 2008/013834) are put
into solution in 20 ml of 1,2-dichloroethane. The mixture is
stirred at 70°C for 1 hour and 30 minutes.
After returning to room temperature, water is added to the
reaction medium. After extracting the aqueous phase with
dichloromethane, the organic phases are successively washed
three times with a 1M aqueous solution of sodium hydroxide,
then twice with a saturated aqueous solution of ammonium
chloride. After having dried the organic phases over sodium
sulphate, they are filtered and the filtrate is evaporated
to dryness. Thus, 1 g of crude product is obtained, which is
used as is in the following step.
1.4. Thiazol-4-ylmethyl [ (3aJ?, 5s, 6a.S) -octahydrocyclopenta-
[c]pyrrol-5-ylmethyl]carbamate.
0.905g (2.29 mmol) of tert-butyl (3a£,5s,6aS)-5-({[(thiazol-

4-ylmethoxy)carbonyl]amino}methyl)hexahydrocyclopenta [c] -
pyrrole-2(1H) -carboxylate, obtained in step 1.3., is put
into solution in 20 ml of dichloromethane then 1.93 ml
(22.90 mmol) of trifluoroacetic acid are added. The mixture
is stirred at room temperature for 3 hours.
A treatment with 1M sodium hydroxide, after extraction with
dichloromethane then drying over sodium sulphate and
evaporating to dryness, resulted in 0.66 g of an orange oil.
LC-MS: M+H = 282
1H NMR (DMSO) 5 (ppm) : 8.95 (s, 1H) , 7.48 (s, 1H) , 7.10
(broad S, 1H) , 4.92 (s, 2H) , 2.80 (m, 4H) , 2.33 (m, 2H) ,
2.20 (m, 2H), 1.98 (m, 1H), 1.23 (m, 4H).
1.5. Thiazol-4-ylmethyl { [ {3aR,5s,6aS)-2-(5-bromopyrid-2-
yl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}carbamate
0.40 g (1.42 mmol) of thiazol-4-ylmethyl [ (3aR, 5s, 6aS) -octa-
hydrocyclopenta [c]pyrrol-5-ylmethyl]carbamate, obtained in
step 1.4., is put into solution in 4 ml of acetonitrile in a
sealed tube. 0.27 g (1.56 mmol) of 5-bromo-2-fluoropyridine
and 0.5 ml of N, N-diisopropylethylamine are added. The
mixture is stirred at 100°C for 6 hours.
After returning to room temperature, water and ethyl acetate
are added. The aqueous phase is extracted several times with
ethyl acetate. The combined organic phases are washed with a
saturated aqueous solution of ammonium chloride then dried
over sodium sulphate. Purification on a silica gel column
while eluting with a 99/1 then 96/4 mixture of
dichloromethane and methanol made it possible to obtain
0.3 0 g of product in the form of a beige solid.
Melting point (°C): 114-116°C
LC-MS: M+H = 437
XH NMR (DMSO) 5 (ppm): 9.10 (s, 1H) , 8.12 (s, 1H) , 7.65 (m,
2H) , 7.30 (broad s, 1H) , 6.48 (d, 1H) , 5.12 (s, 2H) , 3.53 (m,
2H) , 3.15 (m, 2H) , 2.96 (m, 2H) , 2.82 (m, 2H) , 2.21 (m, 1H),
1.58 (m, 4H).
Example 2 (Compound No. 3)
Thiazol-4-ylmethyl ({ (3aJ?, 5s, 6aS) -2- [5- (4-f luorophenyl) -
pyrid-2-yl]octahydrocyclopenta[c]pyrrol-5-yl}methyl)-
carbamate (exo)
Under an inert atmosphere, the following are introduced:

0.125 g (0.29 mmol) of thiazol-4-ylmethyl { [ (3ai?, 5s, 6aS)-2-
(5-bromopyrid-2-yl)octahydrocyclopenta[c]pyrrol-5-yl]-
methyl}carbamate, prepared in Example 1, step 1.5, 0.04 8 g
(0.34 mmol) of 4-fluorophenylboronic acid, 0.279 g
(0.86 mmol) of caesium carbonate in suspension in 2.5 ml of
a 9/1 mixture of tetrahydrofuran and water. Added next is
0.023 g (0.03 mmol) of PdCl2dppf. CH2C12. The mixture is then
heated at around 75°C for 2 hours and 30 minutes.
It is allowed to return to room temperature, then the
filtrate is taken up with ethyl acetate and water, the
aqueous phase is separated and extracted twice with ethyl
acetate, the combined organic phases are washed with a
saturated aqueous solution of sodium chloride and dried over
sodium sulphate. After evaporating the solvent, the residue
obtained is purified by preparative thin layer
chromatography, eluting with ethyl acetate. 0.07g of a beige
solid is obtained.
Melting point (°C): 129-131°C
LC-MS: M+H = 453
XH NMR (DMSO) 5 (ppm) : 9.10 (s, 1H) , 8.38 (s, 1H) , 7.80 (d,
1H), 7.61 (m, 3H), 7.32 (broad s, 1H), 7.21 (m, 2H), 6.58 (d,
1H), 5.11 (s, 2H) , 3.60 (m, 2H), 3.12 (m, 2H), 2.99 (m, 2H),
2.81 (m, 2H), 2.21 (m, 1H), 1.56 (m, 4H).
Example 3 (Compound No. 5)
Thiazol-4-ylmethyl{ (3a,R,5s, 6a.S) -2- [6- (trif luoromethyl) pyrid-
2-yl]octahydrocyclopenta[c]pyrrol-5-yl}carbamate (exo)
3.1. terfc-Butyl (3ai?, 5s, 6a£) -5-aminohexahydrocyclopenta [c] -
pyrrole-2(1H) -carboxylate
1.0 g (3.27 mmol) of tert-butyl (3a#,5r,6aS)-5-[(methyl-
sulfonyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
(WO 2006/108059) is put into solution in 25 ml of N, N-
dimethylformamide then 0.29 g (4.46 mmol) of sodium azide is
added. The mixture is then stirred at 90°C for 2 hours and
3 0 minutes.
It is allowed to return to room temperature and diluted by
adding water and ethyl acetate. The aqueous phase is
extracted with ethyl acetate, then the combined organic
phases are dried over sodium sulphate, filtered and the
filtrate is evaporated to dryness. The residue obtained is

used as is in the following step.
The compound tert-butyl (3aJ?, 5s, 6aS) -5-azidohexahydrocyclo-
penta[c]pyrrole-2(1H)-carboxylate, obtained previously, is
put into solution in 15 ml of ethanol with 0.34 g
(1.63 mmol) of Lindlar catalyst in a Parr apparatus under a
pressure of 20 psi hydrogen at room temperature for 3 hours.
After filtrating over celite and evaporating to dryness,
tert-butyl (3ai?, 5s, 6aS) -5-
aminohexahydrocyclopenta[c]pyrrole-2(1H) -carboxylate is
obtained in the form of oil that is used as is in the
following step.
LC-MS: M+H = 227
XH NMR (DMSO) 5 (ppm): 3.41 (m, 3H), 2.99 (m, 2H), 2.68 (m,
2H), 1.54 (m, 2H), 1.50 (m, 2H), 1.45 (s, 9H).
3.2. Thiazol-4-ylmethyl (3ai?, 5s, 6aS)-octahydrocyclopenta [c] -
pyrrol-5-ylcarbamate
The procedure described in Example 1, step 1.3 is followed.
Starting from 0.74 g (3.27 mmol) of tert-butyl (3aR, 5s,6aS)-
5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate,
obtained in step 3.1., 1.71 ml (9.81 mmol) of N, N-diiso-
propylethylamine, 0.04 g (0.33 mmol) of N,N-dimethy1amino-
pyridine and 0.91 g (3.27 mmol) of thiazol-4-ylmethyl 4-
nitrophenylcarbonate (WO 2008/013834), 1.5 g of crude
product are obtained, which are used as is in the following
step.
The product tert-butyl (3a£,5s,6a£)-5-{[(thiazol-4-yl-
methoxy)carbonyl]amino}hexahydrocyclopenta[c]pyrrole-2(1H) -
carboxylate, obtained previously, is put into solution in
30 ml of dichloromethane then 2.76 ml of trifluoroacetic
acid are added. The mixture is stirred at room temperature
for 15 hours.
After a basic treatment with a 1M aqueous solution of sodium
hydroxide and extraction with dichloromethane, 0.690 g of
thiazol-4-ylmethyl (3ai?, 5s, 6aS) -octahydrocyclopenta-
[c] pyrrol-5-ylcarbamate is obtained in the form of a white
solid.
Melting point (°C): 135-137°C
LC-MS: M+H = 268
XH NMR (DMSO) 5 (ppm): 9.14 (s, 1H) , 7.70 (s, 1H) , 7.25
(broad s, 1H) , 5.14 (s, 2H) , 3.95 (m, 1H) , 2.95 (m, 2H) ,
2.55 (m, 2H), 2.48 (m, 2H), 1.60 (m, 4H).

3.3. Thiazol-4-ylmethyl { (3ai?, 5s, 6aS) -2- [6- (trif luoro-
methyl)pyrid-2-yl]octahydrocyclopenta[c]pyrrol-5-yl}-
carbamate
The procedure described in Example 1, step 1.5. is followed.
Starting from 0.1 g (0.37 mmol) of thiazol-4-ylmethyl
(3ai?,5s, 6a.S) -octahydrocyclopenta [c] pyrrol-5-ylcarbamate,
0.2 ml (1.12 mmol) of N, N-diisopropylethylamine and 0.07 g
(0.45 mmol) of 2-fluoro-6-trifluoromethylpyridine, and after
silica gel preparative thin layer chromatography, eluting
with ethyl acetate, 0.08 g of pure product is obtained in
the form of a solid.
Melting point (°C): 148-150°C
LC-MS: M+H = 413
XH NMR (DMSO) 5 (ppm): 9.11 (s, 1H), 7.70 (m, 2H), 7.40 (m,
1H) , 7.01 (d, 1H) , 6.78 (d, 1H) , 5.12 (s, 2H) , 4.00 (m, 1H) ,
3.58 (m, 2H), 3.28 (m, 2H), 2.90 (m, 2H), 1.78 (m, 4H).
Example 4 (Compound No. 8)
(1 -Methyl- 1H-1,2, 4-triazol-5-yl)methyl { [ (3ai?, 5s, 6aS) -2- (51-
fluoro-2,3'-bipyrid-6-yl)octahydrocyclopenta[c]pyrrol-5-yl]-
methyl}carbamate (exo)
4.1 tert-Butyl (3a.R, 5s, 6aS) -5- ({ [ (4-nitrophenoxy) carbonyl] -
amino}methyl)hexahydrocyclopenta[c] pyrrole-2(1H)-carboxylate
Added to a solution of 1.24 g (5.16 mmol) of tert-butyl
(3ai?, 5s,6aS) -5- (aminomethyl) hexahydrocyclopenta [c] pyrrole-
2 {1H) -carboxylate, obtained in Example 1, step 1.2., and of
1.80 ml (10.32 mmol) of N, N-diisopropylethylamine in 30 ml
of 1,2-dichloroethane, is a solution of 1.14 g (5.68 mmol)
of para-nitrophenyl chloroformate in 20 ml of 1,2-dichloro-
ethane at around 0°C. The mixture is then stirred at room
temperature for 15 hours.
A saturated aqueous solution of ammonium chloride is added
to the reaction medium. The aqueous phase is extracted
several times with dichloromethane. The organic phases are
then washed with a saturated aqueous solution of ammonium
chloride then dried over sodium sulphate. Purification on a
silica gel column while eluting with a 99/1 then 90/10
mixture of cyclohexane and ethyl acetate made it possible to
obtain 1.3 0 g of product in the form of a solid.

Melting point (°C): 132-134°C
XH NMR (DMSO) 5 (ppm) : 8.26 (d, 2H) , 8.06 (m, 1H), 7.40 (d,
2H), 3.44 (m, 2H), 3.01 (m, 4H), 2.67 (m, 2H), 2.25 (m, 1H),
1.58 (m, 4H), 1.38 (s, 9H).
4.2. 6-Bromo-5'-fluoro-[2,3']bipyridyl
Added to a solution of 2.00 g (8.44 mmol) of 2,6-dibromo-
pyridine in 8 0 ml of a 4/1 mixture of toluene and ethanol,
are 1.18 g (8.44 mmol) of 5-fluoropyridine-3-boronic acid,
0.48 g (0.42 mmol) of Pd(PPh3)4 and 25 ml of a 1M aqueous
solution of sodium carbonate. The mixture is stirred at 90°C
for 2 hours.
it is allowed to return to room temperature, the aqueous
phase is extracted several times with ethyl acetate. The
combined organic phases are dried over sodium sulphate,
filtered and evaporated to dryness. The residue thus
obtained is purified on a silica gel column, eluting with a
99/1 to 97/3 mixture of dichloromethane and methanol. 0.80 g
of product is thus obtained in the form of a white solid.
Melting point (°C): 122-124°C
LC-MS: M+H = 253
XH NMR (DMSO) 5 (ppm): 9.10 (s, 1H) , 8.72 (s, 1H) , 8.30 (d,
1H) , 8.20 (d, 1H) , 7.92 (t, 1H) , 7.75 (s, 1H) .
4.3. (l-methyl-lH-l,2,4-triazol-5-yl)methyl { [ (3aR, 5s, 6aS) -
2-(5'-fluoro-2,3'-bipyrid-6-yl)octahydrocyclopenta[c]pyrrol-
5-yl]methyl}carbamate
Added to a solution of 0.084 g (0.74 mmol) of (2-methyl-2H-
[1,2,4]triazol-3-yl)methanol in 5 ml of 1,2-dichloroethane
are 0.26 ml (1.48 mmol) of N,JV-diisopropylethylamine, 0.01
g (0.07 mmol) of N,N-dimethylaminopyridine and 0.30 g
(0.74 mmol) of tert-butyl (3aR, 5s, 6aS)-5-({ [ (4-
nitrophenoxy)-
carbonyl]amino}methyl)hexahydrocyclopenta[c]pyrrole-2 (1H) -
carboxylate, obtained in step 4.1.. The mixture is stirred
at room temperature for 5 hours.
After adding water, the aqueous phase is extracted three
times with dichloromethane. The combined organic phases are
successively washed with a 1M aqueous solution of sodium
hydroxide then with a saturated aqueous solution of ammonium
chloride. The organic phase is dried over sodium sulphate,
filtered and evaporated to dryness. Thus, 0.31 g of crude

product is obtained, which is used as is in the following
step.
0.28 g (0.74 mmol) of tert-butyl (3a#,5s,6aS)-5- [ ({ [ (1-
methyl-lH-1,2,4-triazol-5-yl)methoxy]carbonyl}amino)methyl]-
hexahydrocyclopentafc]pyrrole-2(1H) -carboxylate, obtained
previously, is put into solution in 5 ml of dichloromethane
then 0.62 ml (7.40 mmol) of trifluoroacetic acid are added.
The mixture is stirred at room temperature for 15 hours.
A treatment with 1M sodium hydroxide, after extraction with
dichloromethane then drying over sodium sulphate and
evaporating to dryness, resulted in 0.18 g of an orange oil,
used as is in the following step according to the procedure
described in Example 1, step 1.5..
Starting from 0.06 g (0.21 mmol) of (1-methyl-1H-1,2,4-
triazol-5-yl)methyl [ (3a.R, 5s, 6aS) -octahydrocyclopenta [c] -
pyrrol-5-ylmethyl]carbamate, obtained previously, 0.07 ml
(0.43 mmol) of N, W-diisopropylethylamine and 0.05 g (0.21
mmol) of 6-bromo-5'-fluoro-[2,3']bipyridyl, obtained in step
4.2., 0.022 g of product is obtained in the form of a white
solid.
Melting point (°C): 136-138°C
LC-MS: M+H = 452
XH NMR (DMSO) 5 (ppm): 9.15 (s, 1H), 8.60 (s, 1H), 8.30 (m,
1H), 7.90 (s, 1H), 7.62 (m, 1H), 7.45 (broad s, 1H), 7.31 (m,
1H) , 6.57 (d, 1H) , 5.15 (s, 2H) , 3.88 (s, 3H) , 3.68 (m, 2H) ,
3.28 (m, 2H) , 2.99 (m, 2H) , 2.85 (m, 2H) , 2.25 (m, 1H) , 1.60
(m, 4H).
Example 5 (Compound No. 9)
(3-Carbamoylisoxazol-5-yl)methyl ({(3a£,5s,6aS)-2- [5- (4-
fluorophenyl)pyrid-2-yl]octahydrocyclopenta[c]pyrrol-5-yl}-
methyl)carbamate (exo)
5.1. terfc-Butyl (3ai?, 5s, 6aS) -5- [ ({ [ (3-carbamoylisoxazol-5-
yl)methoxy]carbonyl}amino)methyl]hexahydrocyclopenta[c]-
pyrrole-2(1H) -carboxylate
The procedure described in Example 4, step 4.3 is followed.
Starting from 0.48 g (1.18 mmol) of tert-butyl (3ai?, 5s, 6aS) -
5-({[(4-nitrophenoxy)carbonyl]amino}methyl)hexahydro-
cyclopenta [c] pyrrole- 2 (1H) -carboxylate, obtained in Example
4, step 4.1., 0.17 g (1.18 mmol) of 5-(hydroxymethyl)-3-
isoxazolecarboxamide, 0.41 ml (2.37 mmol) of N, N-

diisopropylethylamine and 0.01 g (0.12 mmol) of N,N-4-
dimethylaminopyridine, and after recrystallization in
diethyl ether, 0.24 g of product is obtained in the form of
a white solid.
Melting point (°C): 186-188°C
LC-MS: M+H = 409
XH NMR (DMSO) 5 (ppm) : 8.11 (broad s, 1H) , 7.82 (broad s,
1H) , 7.48 (broad s, 1H) , 6.75 (s, 1H) , 5.20 (s, 2H), 3.42 (m,
2H), 2.98 (m, 4H), 2.64 (m, 2H), 2.18 (m, 1H), 1.48 (m, 4H),
1.38 (s, 9H).
5.2. 2-Fluoro-5-(4-fluoro-phenyl)pyridine
The procedure described in Example 4, step 4.2 is followed.
Starting from 2.0 g (14.29 mmol) of 4-fluorobenzeneboronic
acid, 5.21 g (14.29 mmol) of 5-bromo-2-fluoropyridine, 0.82
g (0.71 mmol) of Pd(PPh3)4 and 50 ml of a 1M aqueous
solution of sodium carbonate, 2.30 g of product is obtained
in the form of a white solid.
Melting point (°C): 98-100°C
LC-MS: M+H = 192
XH NMR (DMSO) 5 (ppm): 8.55 (m, 1H), 8.28 (dd, 1H), 7.78 (m,
2H) , 7.54 (m, 2H) , 7.28 (dd, 1H) .
5.3. (3-carbamoylisoxazol-5-yl)methyl ({ (3aJ?, 5s, 6aS) -2- [5-
(4-fluorophenyl)pyrid-2-yl]octahydrocyclopenta[c]pyrrol-5-
yl}methyl)carbamate
The procedure described in Example 4, step 4.3 is followed.
Starting from 0.20 g (1.18 mmol) of tert-butyl (3ai?, 5s, 6aS) -
5-[({[(3-carbamoylisoxazol-5-yl)methoxy]carbonyl}amino)-
methyl]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate,
obtained in step 5.1., and 0.41 ml (4.90 mmol) of
trifluoroacetic acid, 0.27 g of (3-carbamoylisoxazol-5-yl)-
methyl [ (3a.R, 5s, 6a.S) -octahydrocyclopenta [c] pyrrol-5-yl-
methyl]carbamate is obtained in trifluoroacetate form used
as is in the following step according to the procedure
described in Example 1, step 1.5..
Starting from 0.10 g (0.24 mmol) of (3-carbamoylisoxazol-5-
yl) methyl [ (3ai?, 5s, 6aS) -octahydrocyclopenta [c] pyrrol-5-yl-
methyl]carbamate, obtained previously, 0.16 ml (0.95 mmol)
of N, N-diisopropylethylamine and 0.04 g (0.24 mmol) of 2-
fluoro-5-(4-fluorophenyl)pyridine, obtained in step 5.2.,

and after silica gel preparative thin layer chromatography,
eluting with a 90/10/1 mixture of
dichloromethane/methanol/aqueous ammonia, 0.018 g of product
is obtained in the form of a white solid.
Melting point ("C): 208-210°C
LC-MS: M+H = 480
XH NMR (DMSO) 5 (ppm) : 8.40 (s, 1H) , 7.95 (broad s, 1H) ,
7.78 (d, 1H) , 7.68 (broad s, 1H) , 7.60 (m, 2H) , 7.35 (broad
s, 1H) , 7.22 (m, 2H) , 6.75 (s, 1H) , 6.52 (d, 1H) , 5.19 (s,
2H) , 3.61 (m, 2H) , 3.22 (m, 2H) , 3.01 (m, 2H) , 2.82 (m, 2H) ,
2.25 (m, 1H), 1.60 (m, 4H).
Example 6 (Compound No. 10)
[3- (Methylcarbamoyl) isoxazol-5-yl] methyl {2- [ (3aR, 5r, 6aS) -2-
(5-bromopyrid-2-yl)octahydrocyclopenta[c]pyrrol-5-yl]ethyl}
carbamate (endo)
6.1. tert-Butyl (3a.R, 5r, 6aS) -5- (2-aminoethyl) hexahydrocyclo-
penta[c]pyrrole- 2(1H) -carboxylate
0.95 g (5.37 mmol) of diethyl cyanomethylphosphonate is put
into solution in 6 ml of tetrahydrofuran then 0.21 g
(5.37 mmol) of sodium hydride is added at room temperature.
After stirring for 10 min, 1.1 g (4.88 mmol) of tert-butyl
(3ai^,6a5) -5-oxohexahydrocyclopenta [c] pyrrole-2 (1H) -
carboxylate (Tetrahedron, 1993, 49(23), 5047-54) in 9 ml of
tetrahydrofuran are added. The mixture is stirred at room
temperature for 2 hours.
After adding water, the product is extracted several times
with ethyl acetate, then the combined organic phases are
dried over sodium sulphate. After filtration and evaporation
to dryness, tert-butyl (3ai?, 5Z, 6aS) -5- (cyanomethylidene) -
hexahydrocyclopenta[c]pyrrole-2(1H) -carboxylate is obtained,
which is used as is in the following step.
1.24 g (4.88 mmol) of tert-butyl (3ai?, SZ, 6aS) -5- (cyano-
methylidene) hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate,
obtained previously, are put into solution in 50 ml of a 1M
solution of sodium hydroxide in ethanol in the presence of a
catalytic amount of Raney nickel, at 50% in water. It is
then stirred at room temperature for 4 hours, under a
hydrogen pressure of 4 bar using a Parr apparatus.
After filtering over celite and evaporating the ethanol, the
residue obtained is taken up in water and dichloromethane.

The product is extracted several times with dichloromethane.
The combined organic phases are then washed using a
saturated aqueous solution of sodium chloride, then dried
over sodium sulphate. After filtration and evaporation to
dryness, 1.0 g of tert-butyl (3aR, 5r, 6aS) -5- (2-aminoethyl) -
hexahydrocyclopenta[c]pyrrole-2(1H) -carboxylate is obtained
in the form of an orange oil, which is used as is in the
following step.
MS: M+ = 254
XH NMR (DMSO) 5 (ppm) : 3.35 (m, 2H) , 3.10 (m, 2H) , 2.52 (m,
4H) , 2.02 (m, 2H) , 1.93 (m, 1H) , 1.40 (m, 2H) , 1.38 (s, 9H) ,
0.92 (m, 2H).
6.2. tert-Butyl (3aK, 5r, 6a.S) -5- {2- [ ({ [3- (ethoxycarbonyl) -
isoxazol-5-yl]methoxy}carbonyl)amino]ethyl}hexahydrocyclo-
penta [c]pyrrole-2(1H)-carboxylate
Added slowly to a solution of 0.3 3 g (1.97 mmol) of ethyl 5-
hydroxymethylisoxazole-3-carboxylate and 0.34 ml (1.97 mmol)
of N,W-diisopropylethylamine in 10 ml of 1,2-dichloroethane,
cooled to 0°C, is 0.43 g (2.16 mmol) of p-nitrophenyl
chloroformate in solution in 5 ml of dichloroethane. The
mixture is then stirred at room temperature for 2 hours then
a solution of 0.5 g (1.97 mmol) of tert-butyl (3aR,5r,6aS)-
5-(2-aminoethyl)hexahydrocyclopenta[c]pyrrole-2(1H) -
carboxylate, obtained in step 6.1., and 0.34 ml (1.97 mmol)
of N,N-diisopropylethylamine are added. The mixture is then
heated at 70°C for 3 hours.
After returning to room temperature, water is added then the
aqueous phase is extracted several times with
dichloromethane. The combined organic phases are then
successively washed with a 1M aqueous solution of sodium
hydroxide (three times) then with a saturated aqueous
solution of ammonium chloride (twice). The organic phase is
dried over sodium sulphate, filtered and evaporated to
dryness. After purification on a silica gel column eluting
with a 99/1 then 97/3 mixture of dichloromethane and
methanol, 0.44 g of pure product is obtained in the form of
an orange oil.
LC-MS: M+H = 452
*H NMR (DMSO) 5 (ppm) : 7.40 (broad s, 1H) , 6.36 (s, 1H) , 5.19
(s, 2H) , 4.37 (q, 2H) , 3.32 (m, 2H) , 3.08 (m, 2H) , 2.98 (m,

2H) , 2.52 (m, 2H) , 2.00 (m, 2H) , 1.83 (m, 1H) , 1.46 (m, 2H),
1.38 (s, 9H), 1.32 (t, 3H) , 0.90 (m, 2H).
6.3. Ethyl 5-{ [ ({2- [ (3ai?, 5r, 6aS) -2- (5-bromopyrid-2-yl)octa-
hydrocyclopenta[c]pyrrol-5-yl]ethyl}carbamoyl)oxy]methyl}-
isoxazole-3-carboxylate
The procedure described in Example 1, step 1.4 is followed.
Starting from 0.44 g (0.97 mmol) of fcert-butyl (3ai?, 5r, 6a£) -
5-{2-[({ [3-(ethoxycarbonyl)isoxazol-5-yl] methoxy}carbonyl)-
amino]ethyl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate,
obtained in step 6.2. and 0.82 ml (9.74 mmol) of trifluoro-
acetic acid, ethyl 5- { [ ({2- [ (3a£, 5r, 6aS) -octahydrocyclo-
penta[c]pyrrol-5-yl]ethyl}carbamoyl)oxy]methyl}isoxazole-3-
carboxylate is obtained in trifluoroacetate form, used as is
in the following step according to the procedure described
in Example 1, step 1.5..
Starting from 0.45 g (0.97 mmol) of ethyl 5-{[({2-
[ (3ai?, 5r, 6aS) -octahydrocyclopenta [c] pyrrol-5-yl] ethyl} -
carbamoyl)oxy]methyl}isoxazole-3-carboxylate, obtained
previously, 0.51 ml (2.91 mmol) of N,N-
diisopropylethylamine, and 0.17 g (0.97 mmol) of 5-bromo-2-
fluoropyridine, and after chromatography on silica gel
eluting with a 99/1 to 98/2 mixture of dichloromethane and
methanol, 0.19 g of pure product is obtained in the form of
a white solid.
Melting point (°C): 105-107°C
LC-MS: M+H = 507
2H NMR (DMSO) 5 (ppm) : 8.10 (d , 1H) , 7.61 (d, 1H) , 7.45
(broad t, 1H) , 6.86 (s, 1H) , 6.45 (d, 1H) , 5.19 (s, 2H) ,
4.37 (q, 2H), 3.42 (m, 2H), 3.28 (m, 2H), 3.00 (m, 2H), 2.68
(m, 2H) , 2.11 (m, 2H) , 1.89 (m, 1H) , 1.54 (m, 2H) , 1.31 (t,
3H), 0.97 (m, 2H).
6.4. [3-(methylcarbamoyl)isoxazol-5-yl]methyl {2-
[ (3aJ?, 5r, 6aS) -2- (5-bromopyrid-2-yl) octahydrocyclopenta [c] -
pyrrol-5-yl]ethyl} carbamate
0.070 g (0.14 mmol) of ethyl 5-{ [({2-[(3a£,5r,6aS)-2-(5-
bromopyrid-2-yl)octahydrocyclopenta[c]pyrrol-5-yl]ethyl}-
carbamoyl)oxy]methyl}isoxazole-3-carboxylate, obtained in
step 6.3., is put into solution in 1.7 ml of a 8M solution
of methylamine in ethanol. The mixture is stirred at room

temperature for 2 hours then evaporated to dryness. After
high-temperature recrystallization in ether, 0.031 g of
product is obtained in the form of a white solid.
Melting point (°C): 157-159°C
LC-MS: M+H = 492
XH NMR (DMSO) 5 (ppm) : 8.67 (m, 1H) , 8.10 (d, 1H) , 7.60 (dd,
1H) , 7.39 (broad t, 1H) , 6.74 (s, 1H) , 6.45 (d, 1H) , 5.16 (s,
2H) , 3.40 (m, 2H) , 3.22 (m, 2H) , 3.00 (m, 2H) , 2.97 (d, 3H) ,
2.75 (m, 2H), 2.10 (m, 2H), 1.89 (m, 1H), 1.46 (m, 2H), 0.98
(m, 2H) .
Example 7 (Compound No. 12)
(3-Carbamoylisoxazol-5-yl)methyl { [ (3al?, 5r, 6aS) -5-fluoro-2-
(6-fluoroquinolin-2-yl)octahydrocyclopenta[c]pyrrol-5-yl]-
methyl}carbamate (exo)
7.1. tert-Butyl {3aR,5r, 6aS)- 5-cyano- 5-hydroxyhexahydro-
cyclopenta[c]pyrrole-2(1H) -carboxylate
1.0 g (4.44 mmol) of terfc-butyl (3ai?, 6aS) -5-oxohexahydro-
cyclopenta[c]pyrrole-2(1H)-carboxylate (Tetrahedron, 1993,
49{23), 5047-54) are put into solution in 5 ml of a
water/methanol (l/l) mixture. The reaction medium is cooled
to 0°C then 0.21 g (4.44 mmol) of sodium cyanide and 0.47 g
(8.44 mmol) of ammonium chloride are added. The mixture is
stirred at room temperature for 20 hours.
It is evaporated to dryness then the residue is taken up
with dichloromethane and water. The aqueous phase is
extracted several times with dichloromethane. The combined
organic phases are dried over sodium sulphate, filtered and
evaporated to dryness. Thus, 0.59 g of product is obtained
in the form of a white solid, used as is in the following
step.
Melting point (°C): 168-170°C
2H NMR (DMSO) 5 (ppm): 6.34 (broad s, 1H) , 3.40 (m, 2H) ,
3.20 (m, 2H), 2.82 (m, 2H), 2.28 (m, 2H), 1.82 (m, 2H), 1.40
(s, 9H).
7.2. tert-Butyl (3a£,5r, 6aS)-5-cyano-5-fluorohexahydrocyclo-
penta[c]pyrrole-2(1H) -carboxylate
A solution of 0.50 g (1.98 mmol) of tert-butyl (3a.R, 5r, 6a.S) -
5-cyano-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H) -

carboxylate, obtained in step 7.1., 0.32 g (1.98 mmol) of
diethylaminosulphur trifluoride (DAST) in 6 ml of dichloro-
methane is stirred at room temperature for 30 minutes.
A saturated aqueous solution of sodium hydrogen carbonate is
added, then the aqueous phase is extracted several times
with dichloromethane. The combined organic phases are dried
over sodium sulphate, filtered and evaporated to dryness.
Thus, 0.4 7 g of product is obtained in the form of an orange
oil, used as is in the following step.
MS: M+H = 255
19F NMR (DMSO) 6 (ppm): -142.58
7.3. tert-Butyl (3ai?, 5r, 6aS) -5- (aminomethyl) -5-f luorohexa-
hydrocyclopenta [c] pyrrole-2 (lJf) -carboxylate
Added slowly to a solution of 0.47 g (1.85 mmol) of tert-
butyl (3aJ?, 5r, 6aS) -5-cyano-5-f luorohexahydrocyclopenta [c] -
pyrrole-2(1H) -carboxylate, obtained in step 7.2., in 4 ml of
tetrahydrofuran, cooled to 0°C, are 7.39 ml (7.39 mmol) of a
1M solution of borane in tetrahydrofuran. The mixture is
stirred at 0°C for 1 hour then ethanol is slowly added. The
stirring is continued for around 3 minutes.
It is allowed to return to room temperature then evaporated
to dryness. The residue obtained is taken up with a
saturated aqueous solution of ammonium chloride and
dichloromethane. The aqueous phase is extracted several
times with dichloromethane. The combined organic phases are
dried over sodium sulphate, filtered and evaporated to
dryness.
Thus, 0.42 g of product is obtained, used as is in the
following step.
LC-MS: M+H = 259
19F NMR (DMSO) 5 (ppm): -143.43
7.4. tert-Butyl (3ai?,5r,6aS)-5-{ [({ [3-(ethoxycarbonyl)-
i soxazol-5-yl]methoxy}carbonyl)amino]methyl}- 5 -fluoro-
hexahydrocyclopenta[c]pyrrole-2{1H)-carboxylate
The procedure described in Example 3, step 3.4. is followed.
Starting from 0.40 g (1.55 mmol) of terfc-butyl (3ai?, 5r, 6aS)-
5-(aminomethyl)-5-fluorohexahydrocyclopenta[c]pyrrole-2(1H) -
carboxylate, obtained in step 7.3., 0.26 g (1.55 mmol) of
ethyl 5-hydroxymethylisoxazole-3-carboxylate, 0.54 ml

(3.10 mmol) of N, N-diisopropylethylamine and 0.31 g
(1.55 mmol) of para-nitrophenyl chloroformate, 0.18 g of
product is obtained in the form of a colourless oil.
LC-MS: M+H = 455
1H NMR (DMSO) 5 (ppm) : 7.76 (broad t, 1H) , 6.90 (s, 1H) ,
5.25 (s, 2H), 4.38 (q, 2H), 3.38 (m, 2H), 3.30 (m, 2H), 3.18
(m, 2H), 2.70 (m, 2H), 2.05 (m, 2H), 1.74 (m, 2H), 1.40 (s,
9H) , 1.33 (t, 3H) .
7.5. Ethyl 5-{ [ ({ [ (3aJ?, 5r, 6aS) -5-fluoro-2- (6-fluoroquinolin-
2-yl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}carbamoyl) -
oxy]methyl}isoxazole-3 -carboxylate
The procedure described in Example 1, step 1.4. is followed.
Starting from 0.17 g (0.37 mmol) of tert-butyl (3a£, 5r,6aS)-
5-{ [({ [3-(ethoxycarbonyl)isoxazol-5-yl]methoxy}carbonyl) -
amino]methyl}-5-fluorohexahydrocyclopentafc]pyrrole-2 (1H) -
carboxylate, obtained in step 7.4., and 0.31 ml (0.425 mmol)
of trifluoroacetic acid, the amine ethyl 5-
{ [ ({ [ (3a.R, 5r, 6aS) -5-f luorooctahydrocyclopenta [c] pyrrol-5-
yl]methyl}carbamoyl)oxy]methyl}isoxazole-3-carboxylate is
obtained in trif luoroacetate form, used as is in the
following step according to the procedure described in
Example 1, step 1.5..
Starting from 0.17 g (0.37 mmol) of ethyl 5-
{ [ ({ [ (3aJ?, 5r, 6a.S) -5-f luorooctahydrocyclopenta [c] pyrrol-5-
yl]methyl}carbamoyl)oxy]methyl}isoxazole-3-carboxylate,
obtained previously, 0.19 ml (1.11 mmol) of N, W-diisopropyl-
ethylamine and 0.08 g (0.37 mmol) of 2-bromo-6-
fluoroquinoline, and by eluting with a 99/1 to 97/3 mixture
of dichloromethane and methanol, 0.08 g of product is
obtained in the form of a white solid.
Melting point (°C): 130-132°C
LC-MS: M+H = 501
XH NMR (DMSO) 5 (ppm): 8.00 (d, 1H) , 7.80 (broad t, 1H) ,
7.59 (m, 1H) , 7.50 (dd, 1H) , 7.39 (m, 1H) , 7.00 (d, 1H) ,
6.90 (s, 1H), 5.25 (s, 2H), 4.38 (q, 2H), 3.80 (m, 2H), 3.50
(m, 2H) , 3.37 (m, 2H) , 2.90 (m, 2H) , 2.15 (m, 2H) , 1.85 (m,
2H), 1.30 (t, 3H).
7.6. (3-Carbamoylisoxazol-5-yl) methyl { [ (3ai?, 5r, 6aS)-5-
fluoro-2-(6-fluoroquinolin-2-yl)octahydrocyclopenta[c]-
pyrrol- 5-yl]methyl}carbamate

The procedure described in Example 6, step 6.4. is followed.
Starting from 0.07 g (0.15 mmol) of ethyl 5-
{ [ ({ [ (3ai?, 5r, 6aS) -5-fluoro-2- (6-f luoroquinolin-2-yl) octa-
hydrocyclopenta[c]pyrrol-5-yl]methyl}carbamoyl)oxy]methyl}-
isoxazole-3-carboxylate, obtained in step 7.5., and 2.14 ml
of a 7M solution of ammonia in methanol, and after high-
temperature crystallization in diethyl ether, 0.04 g of
product is obtained in the form of a white solid.
Melting point (°C): 228-230
LC-MS: M+H = 472
XH NMR (DMSO) 5 (ppm) : 8.13 (broad s, 1H) , 8.00 (d, 1H) ,
7.83 (broad s, 1H) , 7.77 (broad t, 1H) , 7.58 (m, 1H) , 7.50
(m, 1H) , 7.39 (m, 1H) , 6.96 (d, 1H) , 6.77 (s, 1H) , 5.23 (s,
2H) , 3.80 (m, 2H) , 3.50 (m, 2H) , 3.38 (m, 2H) , 2.90 (m, 2H) ,
2.15 (m, 2H), 1.85 (m, 2H).
Example 8 (Compound No. 14)
[3-(Methylcarbamoyl)isoxazol- 5-yl]methyl [3-(6-fluoro-
quinolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate
8.1 tert-Butyl 6-[({ [3-(ethoxycarbonyl)isoxazol-5-yl] -
methoxy}carbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-
carboxylate
The procedure described in Example 3, step 3.4. is followed.
Starting from 3.00 g (15.13 mmol) of tert-butyl 6-amino-3-
azabicyclo[3.1.0]hexane-3-carboxylate, 2.58 g (15.13 mmol)
of ethyl 5-hydroxymethyl-isoxazole-3-carboxylate, 5.27 ml
(30.26 mmol) of N, AT-diisopropylethylamine and 3.05 g
(15.13 mmol) of para-nitrophenyl chloroformate, 4.5 0 g of
product are obtained in the form of a colourless oil (75%).
LC-MS: M-H = 394
XH NMR (DMSO) 5 (ppm): 7.72 (s broad, 1H) , 6.90 (s, 1H) ,
5.22 (s, 2H), 4.40 (q, 2H), 3.45 (m, 2H), 3.32 (m, 2H), 2.19
(m, 1H), 1.68 (m, 2H), 1.40 (s, 9H), 1.32 (t, 3H)
8.2 Ethyl 5-[({ [3-(6-fluoroquinolin-2-yl)-3-azabicyclo-
[3.1.0] hex-6-yl]carbamoyl}oxy)methyl]isoxazole-3-carboxylate
The procedure described in Example 1, step 1.4. is followed.
Starting from 4.50 g (11.38 mmol) of tert-butyl 6-[({[3-
(ethoxycarbonyl)isoxazol-5-yl]methoxy}carbonyl)amino]-3-aza-

bicyclo[3.1.0]hexane-3-carboxylate and 9.59 ml (113.81 mol)
of trifluoroacetic acid, the amine ethyl 5-{[(3-azabicycle-
[3.1.0]hex-6-ylcarbamoyl)oxy]methyl}isoxazole-3-carboxylate
is obtained in trifluoroacetate form, used as is in the
following step according to the procedure described in
Example 1, step 1.5..
Starting from 1.55 g (3.79 mmol) of ethyl 5-{[(3-
azabicyclo [3.1.0]hex-6-ylcarbamoyl)oxy]methyl}isoxazole-3-
carboxylate in trifluoroacetate form, 1.98 ml (11.37 mmol)
of N,iV-diisopropylethylamine, and 0.68 g (3.79 mmol) of 2-
chloro-6-fluoro-quinoline, and eluting with a 99/1 to 98/2
mixture of dichloromethane and methanol, 0.61 g (36%) of
product is obtained in the form of an orange oil.
LC-MS: M+H = 441
2H NMR (DMSO) 5 (ppm) : 8.01 (d, 1H) , 7.80 (s broad, 1H) ,
7.64 (m, 1H), 7.50 (m, 1H), 7.40 (m, 1H), 6.95 (m, 2H), 5.25
(s, 2H) , 4.38 (q, 2H), 3.85 (m, 2H), 3.55 (m, 2H) , 2.35 (m,
1H), 1.90 (m, 2H), 1.30 (m, 3H)
8.3 [3-(Methylcarbamoyl)isoxazol- 5-yl]methyl [3-(6-fluoro-
quinolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate
The procedure described in Example 6, step 6.4. is followed.
Starting from 0.30 g (0.68 mmol) of ethyl 5-[({[3-(6-fluoro-
quinolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl] carbamoyl}oxy)-
methyl]isoxazole-3-carboxylate and 8.50 ml of an 8M solution
of methylamine in ethanol, and after high-temperature
crystallization in diethyl ether, 0.17 g (60%) of product is
obtained in the form of a white solid.
Melting point (°C): 220-222°C
LC-MS: M+H = 426
XH NMR (DMSO) 5 (ppm): 8.73 (broad s, 1H) , 8.04 (d, 1H) ,
7.80 (broads, 1H), 7.62 (m, 1H), 7.54 (m, 1H), 7.42 (m, 1H),
6.97 (d, 1H), 6.81 (s, 1H), 5.22 (m, 2H), 3.86 (m, 2H) , 3.57
(m, 2H), 2.80 (d, 3H), 2.35 (m, 1H), 1.90 (m, 2H)
Table 1 that follows illustrates the chemical structures and
physical properties of a few compounds according to the
invention.
In this table all the compounds are in free base form.

The compounds of the invention underwent pharmacological
tests to determine their inhibitory effect on the enzyme
FAAH (Fatty Acid Amide Hydrolase).
Protocole 1
The inhibitory activity was demonstrated in a radioenzymatic
test based on measuring the product of hydrolysis of
anandamide [ethanolamine 1-3H] with FAAH {Life Sciences
(1995), 56, 1999-2005 and Journal of Biochemical and
Biophysical Methods (2004), 60(2), 171-177). Thus, mouse
brains (minus the cerebellum) are removed and stored
at -80°C. The membrane homogenates are prepared
extemporaneously by homogenizing the tissues using a
Precellys" machine in reaction buffer (lOmM Tris-HCl, pH =
8, 150mM NaCl and ImM ethylenediaminetetraacetic acid
(EDTA)). The enzymatic reaction is performed in 96-well
Multiscreen filtration plates in a final volume of 70 ul.
Reaction buffer supplemented with fatty acid-free bovine

serum albumin (BSA, 1 mg/ml) is used for the enzymatic
reaction and the dilution of the compounds and of the
anandamide [ethanolamine 1-3H] . The reaction buffer
containing BSA (43 ul/well), the diluted test compounds at
various concentrations (7 ul/well containing 1% DMSO) and
the membrane preparation (10 ul/well, i.e. 200 ug of tissue
per test) are successively added to the wells. After
preincubation for 2 0 minutes of the compounds with the
enzyme at 25°C, the reaction is started by adding anandamide
[ethanolamine 1-3H] (specific activity of 15-20 Ci/mmol)
diluted with cold anandamide (10 ul/well, final
concentration of IOJLIM, 0.01 /zCi per test). After incubation
for 20 minutes at 25°C, the enzymatic reaction is stopped by
adding a 5M solution of activated carbon prepared in 1.5M
NaCl buffer and 0. 5M HC1 (50 jul/well) . The mixture is
stirred for 10 minutes then the aqueous phase containing the
ethanolamine [1-3H] is recovered by filtration under vacuum
and counted by liquid scintillation.
Protocole 2
The inhibitory activity was demonstrated via a fluorescent
technique in an enzymatic test based on measuring the
fluorescent product of hydrolysis of arachidonoyl 7-amino-4-
methylcoumarin amide (AAMC) with FAAH (Analytical
Biochemistry (2005), 343:143-151, J. of Biomolecular
Screening (2006), 11 (5) :519-527 and J. of Neurosciences
Methods (2007), 161:47-54). Thus, mouse brains (minus the
cerebellum) are withdrawn and stored at -80°C. The brain
homogenates are prepared extemporaneously by homogenizing
the tissues using a Precellys machine in reaction buffer
(lOmM Tris-HCl, pH = 8, 15 0mM NaCl and lmM ethylenediamine-
tetraacetic acid (EDTA)). The enzymatic reaction is
performed in black polystyrene 384-well plates in a final
volume of 50 /zL. Reaction buffer supplemented with fatty
acid-free bovine serum albumin (BSA, 1 mg/ml) is used for
the enzymatic reaction, the dilution of the compounds and
the dilution of the AAMC. Reaction buffer containing the BSA
(25 pl/well), the diluted test compounds at various
concentrations (5 ul/well containing 1% DMSO) and the
membrane preparation (10 uL/well, i.e. 200 ug of tissue per
test) are successively added to the wells. After
preincubation for 20 minutes of the compounds with the
enzyme at 25°C, the reaction is started by adding 10 fih of

substrate per well (AAMC, final concentration of 10 µM) .
After incubation for 40 minutes at 37°C, the aminomethyl
coumarin (AMC) produced is measured by fluorescent counting
(Envision plate reader).
Under the conditions of protocole 1, the most active
compounds of the invention have IC50 values (concentration
that inhibits 50% of the control enzymatic activity of FAAH)
of between 0.001µM and 1µM. For example, compounds Nos. 1,
3, 4, 7, 8, 10 and 12 have respective IC50 values of 200nM,
0.98nM, 8.5nM, 170nM, 1.lnM and 2.4nM.
Under the conditions of protocole 2, the most active
compounds of the invention have IC50 values (concentration
that inhibits 50% of the control enzymatic activity of FAAH)
of between 0.001µM and 1µM. For example, compound No. 14 has
a respective IC50 value of 12nM.
It thus appears that the compounds according to the
invention have an inhibitory activity on the enzyme FAAH.
The in vivo activity of the compounds of the invention can
be evaluated in a test of analgesia.
Thus, the intraperitoneal (i.p.) administration of PBQ
(phenylbenzoquinone, 2 mg/kg in a 0.9% sodium chloride
solution containing 5% ethanol) to male 0F1 mice weighing 25
to 30 g causes abdominal stretching, on average 30 torsions
or contractions within a period of 5 to 15 minutes after
injection. The test compounds are administered orally (p.o.)
or intraperitoneally (i.p.) suspended in Tween 80 at 0.5%,
60 minutes or 120 minutes before the administration of PBQ.
Under these conditions, the most powerful compounds reduce
by 35% to 80% the number of stretches induced with PBQ, over
a dose range of between 1 and 3 0 mg/kg.
The enzyme FAAH (Chemistry and Physics of Lipids, (2000) ,
108, 107-121) catalyses the hydrolysis of the endogenous
derivatives of amides and esters of various fatty acids such
as N-arachidonoylethanolamine (anandamide), iV-palmitoyl-
ethanolamine, iV-oleoylethanolamine, 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. In this respect, they may be used in the
prevention and treatment of pathologies in which the
endogenous cannabinoids and/or any other substrate
metabolized by the enzyme FAAH are involved. Mention may be
made, for example, of 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 and chemotherapy, 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, sleep disorders, including sleep apnoea,
cardiovascular diseases, in particular hypertension, cardiac
arrhythmia, arteriosclerosis, heart attack, cardiac
ischaemia, renal ischaemia, cancers: benign skin tumours,
papillomas and cerebral tumours, prostate tumours, cerebral
tumours (gliobastomas, medullo-epitheliomas, medullo-
blastomas, neuroblastomas, tumours of embryonic origin,
astrocytomas, astroblastomas, ependyomas, oligodendro-
gliomas, plexus tumour, neuroepitheliomas, pineal gland
tumours, ependymoblastomas, malignant meningiomas,
sarcomatoses, malignant melanomas, schwennomas), immune
system disorders, especially autoimmune diseases: psoriasis,
lupus erythematosus, connective tissue diseases, Sjogrer's
syndrome, ankylosing spondylitis, undifferentiated
spondylitis, Behcet's disease, haemolytic autoimmune
anaemias, multiple sclerosis, amyotrophic lateral sclerosis,
amylosis, graft rejection, diseases affecting the
plasmocytic line, allergic diseases: immediate or delayed
hypersensitivity, allergic rhinitis or allergic
conjunctivitis, contact dermatitis, parasitic, viral or

bacterial infectious diseases: AIDS, meningitis,
inflammatory diseases, especially articular diseases:
arthritis, rheumatoid arthritis, osteoarthritis,
spondylitis, gout, vascularitis, Crohn's disease, irritable
bowel syndrome, osteoporosis, ocular complaints: ocular
hypertension, glaucoma, pulmonary complaints: respiratory
pathway diseases, bronchospasms, coughing, asthma, chronic
bronchitis, 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 base, or of a pharmaceutically acceptable acid-
addition salt, hydrate or solvate, for the preparation of a
medicament for treating the pathologies mentioned above
forms an integral part of the invention.
Another subject of the invention is medicaments comprising
a compound of formula (I), or an acid-addition salt, or
else a pharmaceutically acceptable hydrate or solvate of
the compound of formula (I) . The therapeutic use of these
medicaments is 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 said compound, and optionally one or more
pharmaceutically acceptable excipients.
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-

ABSTRACT

The invention relates to compounds of the general formula (I) where: R2 is a hydrogen or fluorine atom or a
hydroxyl, cyano, trifluoromethyl, C1-6-alkyl C1-6-alkoxy, or NR8R9 group; m and p have a value of 1; n and o have the same value
which is 0 or 1; A is a covalent bond or a C1-6-alkylene group; R1 is an optionally substituted aryl or heteroaryl group; R3 is a
hydrogen or fluorine atom or a C1-6-alkyl group or a trifluoromethyl group; R4 is an optionally substituted 5-membered
heterocyclic compound; wherein the compounds can be in the state of a base or an acid addition salt. The present invention can be
used in therapeutics.