Cyclopenta[c]pyrrole-2-carboxylate derivatives, preparation
thereof and therapeutic use thereof
The invention relates to cyclopenta[c]pyrrole-2-carboxylate
derivatives, 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_6-alkyl, Ci-6-alkoxy or NR8Rg
group;
m, n; o and p represent, independently of each other, a
number ranging from 0 to 3 and are such that each of m+o
and n+p is less than or equal to 4;
A represents a covalent bond, an oxygen atom, a group
Ci-6-alkylene or a group -O-Ci-6-alkylene in which the end
represented by an oxygen atom is bonded to the group Ri and
the end represented by an alkylene group is bonded to the
carbon of the bicycle;
Ri represents a group R5 that is unsubstituted or
substituted with one or more groups R6 and/or R7;
Rs represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl,
quinolyl, isoquinolyl, phthalazinyl, quinazolinyl,
quinoxalinyl, cinnolinyl, naphthyridinyl, benzothiazolyl,
benzoxazolyl, benzimidazolyl, benzisothiazolyl,
bensisoxazolyl, indazolyl and benzotriazolyl;
R6 represents a halogen atom or a cyano, -CH2CN, nitro,
hydroxyl, Ci-6-alkyl, C^6-alkoxy, Ci-6-thioalkyl,

Ci-e-haloalkyl, Ci-e-haloalkoxy, Ci-6-halothioalkyl, C3-7-
cycloalkyl, C3-7-cycloalkyl-Ci-3-alkylene, C3-7-cycloalkyl-
Ci-3-alkylene-O-, NR8R9, NR8COR9, NR8C02R9/ NR8S02R9,
NR8S02NR8R9, COR8, C02R8, CONR8R9, S02R8, S02NR8R9 or -0-(C1-3-
alkylene)-0- group;
R7 represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; the
group(s) R7 possibly being substituted with one or more
groups R6, which may be identical or different;
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, pyrrazolyl, oxadiazolyl, thiadiazolyl,
imidazole, triazolyl and tetrazolyl;
this heterocycle being unsubstituted or substituted with one
or more substituents chosen from a halogen atom and a group
Ci-s-alkyl, Ci-6-haloalkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-
Ci-3-alkylene, Ci-6-haloalkoxy, cyano, NRBR9, NR8COR9# NR8C02R9,
NR8S02R9, NR8S02NR8R9, C0RB, C02R8, CONR8R9/
C0N(R8) (Ci-3-alkylene-NRioRn) , S02R8, S02NR8R9 or -0-(C1-3-
alkylene)-0-;
R8, R9j Rio and Rn represent, independently of each other, a
hydrogen atom or a group Ci-6-alkyl,
or form, with the atom(s) that bear them,
in the case of NR8R9, a ring chosen from azetidine,
pyrrolidine, piperidine, rnorpholine, thiomorpholine,
azepine, oxazepine and piperazine rings, this ring being
optionally substituted with a group Ci-6-alkyl or benzyl;
in the case of NR8C0Rg, 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.
Among the compounds of general formula (I), a first subgroup
of compounds is formed by the compounds for which R2
represents a hydrogen atom or a hydroxyl group. Among the
compounds of general formula (I) , a second subgroup of
compounds is formed by the compounds for which R2 represents
a hydrogen atom.
Among the compounds of general formula (I), a third subgroup
of compounds is formed by the compounds for which m, n and o

30. thiazol-4-ylmethyl (3aJ?, 4.R, 6aS) -4- [ (4' -ethoxybiphenyl-
3-yl)oxy]hexahydrocyclopenta[c]pyrrole-2(Iff) -carboxylate
(endo)
31. (3-carbamoylisoxazol-5-yl)methyl (3ai?, 5s, 6aS) -5- [ (4 ' -
fluorobiphenyl-4-yl)oxy]hexahydrocyclopenta[c]pyrrole-
2(Iff) -carboxylate (exo)
32. [3- (methylcarbamoyl) isoxazol-5-yl]methyl (3aJ?, 5s, GaS) -5-
(4-chloro-2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-
2(Iff) -carboxylate (exo)
33. (3-carbamoylisoxazol-5-yl)methyl (3aR,5s,6aS)-5- (4-
chloro-2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-
2[1H) -carboxylate (exo)
34. (3-carbamoylisoxazol-5-yl)methyl (3ai?, 5s, 6a.S) -5- (4-
chloro-3-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-
2 (Iff) -carboxylate (exo)
35. [3- (methylcarbamoyl) isoxazol-5-yl]methyl (3ai?, 5s, 6aS) -5-
(4-chloro-3-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-
2 (Iff) - carboxylate (exo)
36. (3-carbamoylisoxazol-5-yl)methyl (3ai?, 5s, 6&S) -5- (2, 4-
dichlorophenoxy)hexahydrocyclopenta[c]pyrrole-2 (Iff) -
carboxylate (exo)
37. [3-(methylcarbamoyl)isoxazol-5-yl]methyl (3&R,5s,6a5) -5-
(2, 4-dichlorophenoxy)hexahydrocyclopenta[c]pyrrole-2 (Iff) -
carboxylate (exo)
38. (3-carbamoylisoxazol-5-yl)methyl (3&R,5s,6aS) -5-
(isoquinolin-7-yloxy) hexahydrocyclopenta [ c]pyrrole-2 (Iff) -
carboxylate (exo)
39. (3-carbamoylisoxazol-5-yl)methyl (3af?, 5s, 6aS) -5-
(isoquinolin-6-yloxy)hexahydrocyclopenta[c]pyrrole-2 (Iff) -
carboxylate (exo)
40. (3-carbamoylisoxazol-5-yl)methyl (3af?, 5r, 6aS) -5- (4-
fluoro-l,3-benzothiazol-2-yl)-5-hydroxyhexahydrocyclo-
penta[c]pyrrole-2 (Iff)-carboxylate (exo)

41. (4-carbamoyloxazol-2-yl)methyl {3aR,5s,6aS)-5- [ (7-
ethoxy-2-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2 (Iff) -
carboxylate (exo)
42 . (3-{[2-(dimethylamino)ethyl]carbamoyl}isoxazol-5-yl)-
methyl (3a.R, 5s, 6aS) -5- (4-f luorophenoxy)hexahydrocyclo-
penta [c] pyrrole- 2 (Iff) -carboxylate (exo), and its
hydrochloride
43. [4-(methylcarbamoyl)oxazol-2-yl]methyl (3af?,5s,SaS) -5-
[(7-ethoxy-2-naphthyl)oxy]hexahydrocyclopenta[c]pyrrol e-
2 (Iff) -carboxylate (exo)
44. (3-dimethylcarbamoylisoxazol-5-yl)methyl (3af?, 5s, 6aS) -5-
(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2 (Iff) -
carboxylate (exo)
45. (3-methylcarbamoylisoxazol-5-yl)methyl (3af?, 5s, SaS) -5-
[(4'-fluorobiphenyl-4-yl)oxy]hexahydrocyclopenta[c]-
pyrrole-2 (Iff) -carboxylate (exo)
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 a carbon-based chain possibly
containing from 1 to 3 carbon atoms;
- alkyl, a linear or branched saturated aliphatic group; for
example a group Ci-6-alkyl 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 group Ci-3-alkylene 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 group C3-7-
cycloalkyl represents a cyclic carbon-based group of 3 to
7 carbon atoms, more particularly a cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
- alkoxy, a group -0-alkyl containing a linear or branched
saturated aliphatic chain;
- thioalkyl, a group -S-alkyl 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 ' exo' corresponds to the group -A-Rl in the cis
position relative to the ring junction hydrogens. The
term *endo' corresponds to the group -A-Rl in the trans
position relative to the ring junction hydrogens;
- r and s indicate the stereochemistry of the pseudo-
asymmetric carbon atoms, according to the 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
subjects of the present invention.
Scheme 1


Thus, a first preparation method (Scheme 1) consists in
reacting an amine of general formula (II), in which A, Ri,
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, 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 N,iV-diisopropylethylamine, in a
solvent such as toluene, acetonitrile or dichloroethane, at
a temperature between room temperature and the reflux
temperature of the solvent.

A second method (Scheme 2) for obtaining the compounds of
general formula (I) in which A more particularly represents
an oxygen atom or a group -0-Ci_6-alkylene- consists in
reacting, in a first stage, an alcohol of general formula
(Ila) , in which R2, m, n, o and p are as defined in the
general formula (I) defined above, G represents a part of
the group A as defined in the general formula (I) , namely
either a covalent bond or the Ci-6-alkylene- part of the
group -0-Ci-6-alkylene-, and PG represents a protecting group
such as a Boc (tert-butyloxycarbonyl) , a Cbz
(benzyloxycarbonyl), a benzyl or a benzhydryl;
- either with an alcohol derivative of general formula

RiOH (IV) , in which Ri is as defined above, using the
Mitsunobu reaction conditions (Synthesis, 1981, 1-28),
- or with a halo derivative of general formula RiX
(iVa), in which Ri is as defined above and X represents
a fluorine, chlorine, bromine or iodine atom, using the
aromatic or heteroaromatic nucleophilic substitution or
Buchwald O-arylation or O-heteroarylation reactions,
for example using a palladium or copper catalyst,-
followed by a deprotection reaction, for example in the
presence of trifluoroacetic acid or of a solution of
hydrogen chloride in isopropanol or dioxane, to give the
amine of general formula (lib) in which G, R2, m, n, o and p
are as defined in the general formula (Ila) defined above
and Ri is as defined above. The derivative of general
formula (lib) thus obtained is then converted into a
compound of general formula (I) according to a condensation
reaction with a carbonate of general formula (III) as
defined above, under the conditions described above (Scheme
1) .
One variant for obtaining the compounds of general formula
(I) (Scheme 2), in which A more particularly represents an
oxygen atom or a group -O-Ci-6-alkylene-, consists in
deprotecting an alcohol of general formula (Ila) as defined
above), according to a deprotection reaction as defined
above, so as to obtain an amino alcohol of general formula
(lie), and then in reacting this amino alcohol of general
formula (lie) in which G, R2, m, n, o and p are as defined
in the general formula (Ila) defined above, with a carbonate
of general formula (III) as defined above, under the
conditions described above (Scheme 1), to give the carbamate
derivative of general formula (la), in which G, R2, R3, R4,
m, n, o and p are as defined in the general formula (Ila)
defined above. The carbamate derivative (la) thus obtained
is then converted into a compound of general formula (I) via
the action of an alcohol of general formula RiOH (IV) as
defined above, using the Mitsunobu reaction conditions or
via the action of a halo derivative of general formula RXX
(IVa) as defined above using aromatic or heteroaromatic
nucleophilic substitution or Buchwald O-arylation or 0-
heteroarylation reactions, for example using a palladium or
copper catalyst.


A third method (Scheme 3) was developed for the synthesis of
the compounds of general formula (I), in which Ri represents
a group R5 substituted especially with a group R6 of the
type Ci-6-alkyl, C3-7-cycloalkyl or C3-.7-cycloalkyl-Ci-3-
alkylene, or with a group R7 as defined in the general
formula (I) defined above. Thus, the first step consists in
reacting an amine of general formula (lid), in which A, R2,
R5, m, n, o and p are as defined in the general formula (I)
defined above and Ui represents a chlorine, bromine or
iodine atom or a triflate group, with a carbonate of general
formula (III) as defined above, under the conditions
described above (Scheme 1), to give the carbamate derivative
of general formula (lb), in which A, R2, R3, R4, R5, m, n, o
and p are as defined in the general formula (I) defined
above and Ui is as defined above. The coupling reaction
catalysed with a transition metal such as palladium(O) is
then performed on the key intermediate of general formula
(lb) as defined above, Ui being in the position in which it
is desired to introduce the group R6 or R7 (Scheme 3) :
- either via a reaction of Suzuki type, for example using an
alkyl, cycloalkyl, aryl or heteroaryl boronic acid,
- or according to a reaction of Stille type, for example
using an aryl or heteroaryl tri-alkylstannous derivative,
- or via a reaction of Negishi type, for example using an
alkyl, cycloalkyl, aryl or heteroaryl halide zincate
derivative.
Another subject of the present invention relates to the
compounds of general formula (la)


in which R2, R3, R4, m, n, o and p are as defined in the
general formula (I), and G represents part of the group A as
defined in the general formula (I), namely either a covalent
bond or the Ci-6-alkylene part of the group -O-Ci-6-alkylene.
Among these compounds, mention may be made of:
[3-(ethoxycarbony1)isoxazol-5-yl]methyl (3aR,5r,6aS)-5-
hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate;
thiazol-2-ylmethyl (3ai?, 5r, 6a.S) -5-hydroxyhexahydrocyclo-
penta [ c]pyrrole-2 (Iff) -carboxylate.
Another subject of the present invention relates to the
compounds of general formula (II):

in which Ri, R2, m, n, o and p are as defined in the general
formula (I), A represents an oxygen atom or a covalent bond,
given that when A represents a covalent bond, then Ri
represents a benzothiazolyl group.
Among these compounds, mention may be made of:
(3aR,5s,6aS)-5-[3-(trifluoromethyl)phenoxy]octahydrocyclo-
penta [c] pyrrole;
(3aR,5s,6aS)-5-(4-fluorophenoxy)octahydrocyclopenta[c]-
pyrrole (1H NMR 400 MHz DMSO, 5 (ppm) : 7.10 (t, 2H) ; 6.95
(m, 2H); 4.85 (m, 1H); 2.90 (m, 2H) ; 2.75 (m, 4H); 2.00 (m,
2H) ; 1.70 (m, 2H) ) ;
(3aR,5r,6aS)-5-(4-fluoro-1,3-benzothiazol-2-yl)octahydro-
cyclopenta [c]pyrrol-5-ole;
(3aR,5s,6aS)-5-(4-Chloro-3-fluorophenoxy)octahydrocyclo-
penta [c]pyrrole;
(3aR,5s,6aS)-5-(4-chlorophenoxy)octahydrocyclopenta[c]-
pyrrole;
(3aR,5s,6aS)-5-[(7-ethoxy-2-naphthyl)oxy]octahydrocyclo-
penta [c]pyrrole;
(3ai?, 5r, 6aS) -5- [ (4 ' -ethoxybiphenyl-3-yl) oxy] octahydrocyclo-

penta[c]pyrrole,•
(3BLR,5S, 6aS)-5- [ (4' -ethoxybiphenyl-3-yl) oxy] octahydrocyclo-
penta[c]pyrrole ;
(3a.R, AS, 6aS)-A-[(4-chloro-l-naphthyl)oxy]octahydrocyclo-
penta[c]pyrrole;
(3ai?, AR, 6aS)-A- [ (4' -ethoxybiphenyl-3-yl) oxy]octahydrocyclo-
penta[c]pyrrole.
Another subject of the present invention relates to the
compounds of general formula (lie):
in which Ri, R2, m, n, o and p are as defined in the general
formula (I), A represents an oxygen atom or a covalent bond,
given that when A represents a covalent bond, then Rl
represents a benzothiazolyl group.
Among these compounds, mention may be made of:
tert-butyl (3ai?, 5r, 6aS) -5- [ (4 ' -ethoxybiphenyl-3-yl) oxy] hexa-
hydrocyclopenta[c]pyrrole-2(1H) -carboxylate;
{3aR,5s,6aS)-5-(3-bromophenoxy)
tert-butyl hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate;
tert-butyl (3a.R, 5s, 6aS) -5- [ (4 ' -ethoxybiphenyl-3-yl) oxy]hexa-
hydrocyclopenta[c]pyrrole-2(1H)-carboxylate;
tert-butyl (3ai?, AS, 6aS) -4- [ (4-chloro-l-naphthyl) oxy]hexa-
hydrocyclopenta[c]pyrrole-2(1H)-carboxylate;
tert-butyl (3aR,AR,6aS)-A-(3-bromophenoxy)hexahydrocyclo-
penta[c]pyrrole-2(1H) -carboxylate;
tert-butyl (3ai?, AR, 6aS) -A- [ (4' -ethoxybiphenyl-3-yl) oxy]hexa-
hydrocyclopenta[c]pyrrole-2(1H) -carboxylate;
tert-butyl (3aR, 5r, 6a5") -5- (4-f luoro-1, 3-benzothiazol-2-yl) -
5-hydroxyhexahydrocyclopenta[c]pyrrole-2 (lif) -carboxylate.
The other compounds of general formulae (II), (Ila), (lib),
(He), (lid), (III), (IV) and (IVa) and also the other
reagents are commercially available or described in the
literature, or alternatively 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 few
compounds of the invention. These examples are not limiting,
and serve merely to illustrate the invention. The
microanalyses, IR and NMR spectra and/or the LC-MS (liquid
chromatography coupled to mass spectroscopy) spectra confirm
the structures and impurities of the compounds obtained.
m.p. (°C) represents the melting point in degrees Celsius.
Rf indicates the retention time obtained by TLC (thin-layer
chromatography) analysis.
The numbers indicated in parentheses in the example titles
correspond to those in the first column of the tables
hereinbelow.
The IUPAC (International Union of Pure and Applied Chemists)
nomenclature has been used for the naming of the compounds
in the examples below.
Example 1 (Compound 6)
thiazol-2-ylmethyl (3ai?,5r, 6aS)-5-[ (4'-ethoxybiphenyl-3-yl) -
oxy]hexahydrocyclopenta[c]pyrrole-2(1H) -carboxylate (endo)
1.1. tert-butyl {3aR,5s,6a£)-5-(3-bromophenoxy)hexahydro-
cyclopenta[c]pyrrole-2(1H)-carboxylate
0.2 0 g (0.88 mmol) of tert-butyl (3a£,5r,6a5)-5-hydroxyhexa-
hydrocyclopenta[c]pyrrole-2(Iff) -carboxylate (obtained
according to a process described in WO 2006/108 059) is
dissolved in 4.4 mL of dimethylformamide, and 0.19 g (1.10
mmol) of l-bromo-3-iodobenzene and 0.03 g (1.32 mmol) of
sodium hydride are then added. The mixture is stirred at
90°C for 15 hours. The resulting mixture is diluted by
adding water and ethyl acetate. This mixture is extracted
with ethyl acetate and the combined organic phases are then
dried over sodium sulfate and evaporated to dryness after
filtration. The residue is purified by chromatography on
silica gel, eluting with a mixture of cyclohexane and ethyl
acetate. 0.175 g (52%) of expected product is obtained in
the form of a colourless oil.
1.2. tert-butyl (3ai?, 5r, 6aS) -5- [ (4 ' -ethoxybiphenyl-3-
yl) oxy]hexahydrocyclopenta[c]pyrrole-2 (1H) -carboxylate
Under an inert atmosphere, 0.17 0 g (0.44 mmol) of tert-butyl

(3a.R, 5s, 6aS) -5- (3-bromophenoxy)hexahydrocyclopenta[c] -
pyrrole-2(Iff) -carboxylate, obtained in step 1.1., 0.088 g
(0.53 mmol) of 4-ethoxyphenylboronic acid and 0.434 g
(1.33 mmol) of caesium carbonate are introduced into 5 ml of
a 9/1 mixture of tetrahydrofuran and water. 0.036 g
(0.04 mmol) of PdCl2dppf .CH2C12 is added and the medium is
heated at 75°C for 15 hours. The medium is allowed to cool
to room temperature and then diluted with ethyl acetate and
water. The organic phase is separated out and extracted
twice with ethyl acetate, and the combined organic phases
are washed with saturated aqueous sodium chloride solution
and dried over sodium sulfate. After evaporating off the
solvent, the residue is purified by chromatography on silica
gel, eluting with a mixture of cyclohexane and ethyl acetate.
0.145 g (77%) of expected product is obtained in the form of
an oil.
LC-MS: M+H = 424
1.3 . (3ai?, 5r, 6aS) -5- [ (4' -ethoxybiphenyl-3-yl)oxy] octahydro-
cyclopenta[c]pyrrole
0.14 g (0.34 mmol) of tert-butyl (3ai?, 5r, 6aS) -5- [ (4' -
ethoxybiphenyl-3-yl)oxy]hexahydrocyclopenta[c]pyrrole-2 (1H) -
carboxylate, obtained in step 1.2., is dissolved in
dichloromethane, and 1.71 mL (6.85 mmol) of a 4N solution of
hydrogen chloride in dioxane are then added. The mixture is
stirred at room temperature for 2 hours.
Work-up with 1M sodium hydroxide after extraction with
dichloromethane and then drying over sodium sulfate and
evaporation to dryness gives 0.084 g of a colourless oil.
1.4. thiazol-2-ylmethyl (3ai?, 5r, 6aS)-5-[ (4'-ethoxybiphenyl-
3-yl)oxy]hexahydrocyclopenta[c]pyrrole-2[1H)-carboxylate
0.07 g (0.28 mmol) of (3aR, 5r, 6aS) -5- [ (4 ' -ethoxybiphenyl-3-
yl)oxy]octahydrocyclopenta[c]pyrrole, obtained in step 1.3.,
is dissolved in 2.5 mL of dichloromethane and 0.06 mL
(0.34 mmol) of W,iV-diisopropylethylamine and 0.09 g
(0.31 mmol) of thiazol-4-ylmethyl (4-nitrophenyl)carbonate
(WO 2008/013 834) is then added. The mixture is stirred at
room temperature for 15 hours and then diluted with ethyl
acetate. The organic phase is washed successively with
aqueous 1M sodium hydroxide solution and then twice with
saturated aqueous sodium chloride solution, dried over

sodium sulfate, filtered and evaporated to dryness. The
residue obtained is purified by chromatography on silica
gel, eluting with a mixture of cyclohexane and ethyl acetate.
0.088 g (67%) of expected product is obtained in the form of
a yellow oil.
LC-MS: M+H = 465
XH NMR (DMSO) 5 (ppm): 7.80 (d, 1H); 7.70 (d, 1H); 7.60 (d,
2H) ; 7.30 (t, 1H); 7.15 (d, 1H); 7.05 (s, 1H) ; 7.00 (d, 2H) ;
6.80 (d, 1H); 5.35 (S, 2H) ; 5.00 (m, 1H) ; 4.10 (q, 2H) ; 3.55
(m, 2H); 3.35 (m, 2H); 2.75 (m, 2H); 2.30 (m, 2H); 1.70 (m,
2H) ; 1.35 (t, 3H) .
Example 2 (Compound 7)
l,2,3-thiadiazol-4-ylmethyl (3a£,5s,6aS)-5-(4-chlorophen-
oxy)hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate (exo)
2.1. (3ai?, 5s, 6aS) -5- (4-chlorophenoxy)octahydrocyclopenta-
[c]pyrrole
2.00 g (8.80 mmol) of fcert-butyl (3aR,5r,6aS)-5-hydroxyhexa-
hydrocyclopenta[c]pyrrole-2(1H)-carboxylate (see synthesis:
WO 2006/108 059) are dissolved in 88 mL of toluene. 2.77 g
(10.56 mmol) of triphenylphosphine and 1.47 g (11.44 mmol)
of 4-chlorophenol are added, and then the medium is cooled
to 0°C, followed by slow addition of a solution of 1.69 g
(9.68 mmol) of diethyl azodicarboxylate in 10 mL of toluene.
The medium is stirred for 14 hours at room temperature.
The resulting mixture is concentrated under reduced
pressure. The residue obtained is taken up in aqueous IN
sodium hydroxide solution and extracted twice with
dichloromethane. The combined organic phases are washed once
with saturated aqueous sodium chloride solution, dried over
sodium sulfate, filtered and concentrated under vacuum. The
residue obtained is taken up in 50 mL of dichloromethane,
followed by deprotection by slow addition of 50 mL of a 4N
solution of hydrogen chloride in dioxane. After stirring for
1 hour at room temperature, the medium is concentrated under
vacuum and the residue is taken up in aqueous IN
hydrochloric acid solution. The aqueous phase is extracted
twice with ethyl acetate and then slowly basified to pH 10
by addition of p'otassium carbonate. The aqueous phase is
extracted three times with dichloromethane. These three
organic extracts are combined, washed once with saturated

aqueous sodium chloride solution, dried over sodium sulfate,
filtered and concentrated under vacuum. The residue is
purified by chromatography on silica gel, eluting with a
98/2/0.2 to 95/5/0.5 mixture of dichloromethane, methanol
and 3 0% aqueous ammonia. 1.22 g (61%) of expected product
are obtained in the form of a wax.
LC-MS: M+H = 238
XH NMR (DMSO) 5 (ppm): 7.35 (d, 2H); 7.00 (d, 2H) ; 4.95 (m,
1H) ; 3.55 (broad s, 1H) ; 2.80 (m, 2H) ; 2.75-2.60 (m, 4H) ;
2.00 (m, 2H); 1.70 (m, 2H).
2.2. l,2,3-thiadiazol-4-ylmethyl (3ai?, 5s, 6aS)-5-(4-chloro-
phenoxy) hexahydrocyclopenta [ c]pyrrole-2 (Iff) -carboxylate
0.070 g (0.61 mmol) of 1,2,3-thiadiazole-4-methanol
(DD232495) and 0.18 mL (1.06 mmol) of N,N-
diisopropylethylamine are dissolved in 1 mL of 1,2-
dichloroethane and then cooled to 0°C. 0.11 g (0.56 mmol) of
p-nitrophenyl chloroformate dissolved in 2 mL of 1,2-
dichloroethane is added. The mixture is stirred at room
temperature for 15 minutes and a solution of 0.12 g
(0.50 mmol) of (3aR,5s,6aS)-5-(4-chlorophenoxy)octahydro-
cyclopenta[c]pyrrole, obtained in step 2.1., is then added.
The mixture is heated at 60°C for 15 hours.
After cooling to room temperature, aqueous IN sodium
hydroxide solution is added, and the product is extracted
with dichloromethane. The combined organic phases are then
washed successively with saturated aqueous ammonium chloride
solution, and then with saturated aqueous sodium chloride
solution. After drying the organic phases over sodium
sulfate, they are filtered and evaporated to dryness. After
purifying on a column of silica gel, eluting with a 99/1/0.1
mixture of dichloromethane, methanol and 30% aqueous
ammonia, 0.068 g (58%) of expected product is obtained in
the form of a white powder.
Melting point (°C): 122-124°C
LC-MS: M+H =380
XH NMR (DMSO) 5 (ppm): 9.20 (s, 1H) ; 7.30 (d, 2H); 6.90 (d,
2H); 5.55 (s, 2H); 4.95 (m, 1H); 3.55 (m, 2H); 3.20 (m, 2H) ,-
2.80 (m, 2H); 2.05-1.90 (m, 2H) ; 1.90-1.80 (m, 2H) .
Example 3 (Compound 8)
(5-tert-butyl-l, 3 , 4-thiadiazol-2-yl)methyl (3ai?, 5s, 6aS) -5-

(4-chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H) -
carboxylate (exo)
3.1 (5-tert-butyl-[1,3,4]thiadiazol-2-yl)methanol
1 g (4.67 mmol) of ethyl 5-tert-butyl-1,3,4-thiadiazole-2-
carboxylate is dissolved in 45 mL of methanol and 0.3 53 g
(9.33 mmol) of sodium borohydride is added portionwise, with
stirring, at room temperature. The medium is stirred for
1 hour at room temperature and then concentrated under
vacuum. The residue obtained is taken up in aqueous solution
saturated with sodium chloride. The aqueous solution is
brought to ph 7 by slowly adding, with stirring, aqueous IN
hydrochloric acid solution. After stirring for 1 hour at
room temperature, the aqueous phase is extracted three times
with dichloromethane and the combined organic phases are
then washed once with saturated aqueous sodium chloride
solution, dried over sodium sulfate, filtered and
concentrated to dryness. 0.802 g (100%) of the expected
product is obtained in the form of an oil.
LC-MS: M+H = 173
XH NMR (CDC13) 5 (ppm): 5.10 (d, 2H); 4.60 (t, 1H); 1.65 (s,
9H) .
3.2. (5-tert-butyl-1,3,4-thiadiazol-2-yl)methyl
(3ai?, 5s, 6a.S) -5- (4-chlorophenoxy)hexahydrocyclopenta[c] -
pyrrole-2(Iff) -carboxylate
The process is performed according to the procedure
described in Example 2, step 2.2. Starting with 0.10 g (0.42
mmol) of {3&R,5s,6a£) -5-(4-chlorophenoxy)octahydro-
cyclopenta[c]pyrrole, obtained in step 2.1., 0.07 g
(0.46 mmol) of (5-tert-butyl-[1,3,4]thiadiazol-2-yl)methanol,
obtained in step 3.1., 0.08 g (0.42 mmol) of para-nitro-
phenyl chloroformate and 0.15 mL (0.88 mmol) of N, N-
diisopropylethylamine, and after chromatography on
preparative silica gel plates, eluting with a 98/2/0.2
mixture of dichloromethane, methanol and 3 0% aqueous
ammonia, 0.08 g (54%) of expected product is obtained in the
form of a wax.
LC-MS: M+H =43 6
2H NMR (DMSO) 5 (ppm): 7.30 (d, 2H) ; 6.90 (d, 2H) ; 5.4 (s,
2H) ; 4.95 (m, lH) ,- 3.55 (m, 2H) ,- 3.25 (m, 2H) ; 2.85 (m, 2H) ;
2.00 (m, 2H); 1.90 (m, 2H); 1.45 (s, 9H).

Example 4 (Compound 16)
(3-carbamoylisoxazol-5-yl)methyl (3aR,5s,6a£)-5-[3-
(tri fluoromethyl)phenoxy]hexahydrocyclopenta[c]pyrrole-
2 (Iff) -carboxylate (exo)
4.1. (3aJ?, 5s, 6aS) -5- [3- (trif luoromethyl)phenoxy] octahydro-
cyclopenta[c]pyrrole
The process is performed according to the procedure
described in Example 2, step 2.1. Starting with 1.4 g
(6.16 mmol) of tert-butyl (3ai?, 5r, 6a5)-5-hydroxyhexahydro-
cyclopenta [c]pyrrole-2 (1H)-carboxylate (see synthesis: WO
2006/108 059), 1.39 g (8.62 mmol) of 3-trifluoromethyl-
phenol, 1.39 g (8.01 mmol) of diethyl azodicarboxylate,
2.26 g (8.62 mmol) of triphenylphosphine and 30 mL of a 4N
solution of hydrogen chloride in dioxane, 0.48 g (29%) of
expected product is obtained in the form of a wax.
LC-MS: M+H = 272
XH NMR (CDC13) 5 (ppm) : 7.45 (t, lH) ; 7.30-7.05 (m, 3H) ;
4.95 (tq, 1H); 3.05-2.70 (m, 6H); 2.25 (m, 2H); 1.65 (m, 2H).
4.2. 3-carbamoylisoxazol-5-ylmethyl 4-nitrophenyl carbonate
To a solution of 2.0 g (14.07 mmol) of 3-carbamoylisoxazol-
5-ylmethanol, 1.71 ml (21.11 mmol) of pyridine and 0.17 g
(1.41 mmol) of N, N- dime thy laminopyri dine in 15 mL of
dichloromethane, cooled to about 0°C, are added portionwise
2.84 g (14.07 mmol) of 4-nitrophenyl chloroformate. The
medium is kept stirring at 0°C for 1 hour and then at room
temperature for 1 hour.
The precipitate formed is filtered off and then rinsed
thoroughly with diisopropyl ether. After drying under vacuum
at about 60°C, 3.12 g (72%) of expected product are obtained
in the form of a white solid, which is used without further
purification in the following step,
m.p. (°C): 143-145°C
XH NMR (DMSO) 5 (ppm): 8.40 (d, 2H) ; 8.25 (broad s, 1H) ;
7.90 (broads, 1H); 7.65 (d, 2H); 7.0 (s, 1H); 5.50 (s, 2H).
4.3. (3-carbamoylisoxazol-5-yl)methyl (3af?, 5s, 6a5) -5- [3-
(trifluoromethyl)phenoxy]hexahydrocyclopenta[c]pyrrole-
2 (Iff) -carboxylate
The process is performed according to the procedure

described in Example 1, step 1.3. Starting with 0.15 g of
(3aJ?, 5s, 6&S) -5- [3- (trifluoromethyl)phenoxy]octahydrocyclo-
penta[c]pyrrole, obtained in step 4.1., 0.18 g (0.61 mmol)
of 3-carbamoylisoxazol-5-ylmethyl 4-nitrophenyl carbonate,
obtained in step 4.2., 0.03 g (0.28 mmol) of N, N-
dimethylaminopyridine and 0.21 mL (1.22 mmol) of N,N-
diisopropylethylamine, and after chromatography on silica
gel, eluting with a mixture from 99/1/0.1 to 97/3/0.3 of
dichloromethane, methanol and 30% aqueous ammonia, 0.21 g
(87%) of expected product is obtained in the form of a white
powder.
Melting point (°C): 130-132°C
LC-MS: M+H = 440
XH EMR (DMSO) 5 (ppm): 8.15 (s, 1H); 7.85 (s, 1H); 7.55 (t,
1H) ; 7.25 (d, 1H) ; 7.20 (d, 1H) ; 7.15 (S, 1H) ; 6.80 (s, 1H) ;
5.25 (s, 2H); 5.10 (m, 1H); 3.55 (m, 2H); 3.20 (m, 2H); 2.85
(m, 2H); 2.05-1.95 (m, 2H) ; 1.95-1.80 (m, 2H) .
Example 5 (Compound 22)
(4-carbamoylthiazol-2-yl) methyl (3af?, 5s, 6&S) -5- [ (7-ethoxy-2-
naphthyl) oxy]hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate
(exo)
5.1. (3af?, 5s, 6aS) -5- [ (7-ethoxy-2-naphthyl) oxy] octahydro-
cyclopenta[c]pyrrole
The process is performed according to the procedure
described in Example 2, step 2.1. Starting with 1.4 g
(6.16 mmol) of tert-butyl (3ai?, 5r, 6&S) -5-hydroxyhexa-
hydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate (see synthesis:
WO 2006/108 059), 1.51 g (8.00 mmol) of 7-ethoxy-2-naphthol,
1.28 g (7.39 mmol) of diethyl azodicarboxylate and 1.93 g
(7.39 mmol) of triphenylphosphine, and 30 mL of a 4N
solution of hydrogen chloride in dioxane, 1.36 g (74%) of
expected product are obtained in the form of an oil.
LC-MS: M+H = 298
XH NMR (DMSO) 5 (ppm): 7.70 (d, 2H) ; 7.20 (m, 2H) , 7.00 (m,
2H) , 5.05 (m, 1H) ; 4.15 (dq, 2H) ; 2.95 (m, 2H) ; 2.85-2.50
(m, 4H); 2.10 (m, 2H); 1.85 (m, 2H); 1.40 (t, 3H).
5.2. methyl 2-hydroxymethylthiazole-4-carboxylate
5-2.1. ethyl 2-[(acetyloxy)methyl]thiazole-4-

carboxylate
2.7 g (10.80 mmol) of ethyl 2-(bromomethyl)thiazole-4-
carboxylate are dissolved in 108 mL of acetonitrile. 2.225 g
(22.67 mmol) of potassium acetate are added and the medium
is stirred at room temperature for 14 hours.
The resulting mixture is concentrated under reduced pressure.
The residue obtained is taken up in aqueous sodium chloride
solution and extracted twice with dichloromethane. The
combined organic phases are dried over sodium sulfate,
filtered and concentrated to dryness. 2.347 g (95%) of
expected product are obtained in the form of a wax.
XH NMR (CDC13) 6 (ppm) : 8.15 (s, 1H) ; 5.35 (s, 2H) ; 4.35 (dq,
2 H) ; 2.10 (s, 3H); 1.35 (t, 3H) .
5.2.2. methyl 2-hydroxymethylthiazole-4-carboxylate
2.347 g (10.24 mmol) of ethyl 2-acetoxymethylthiazole-4-
carboxylate, obtained in step 5.2.1., are dissolved in
100 mL of a 5/1 mixture of dichloromethane and methanol.
2.5 8 mL (11.2 6 mmol) of a 4.37N solution of sodium methoxide
in methanol are added and the medium is stirred at room
temperature for two hours and then concentrated under
reduced pressure. The residue obtained is taken up in
saturated aqueous sodium chloride solution and extracted
three times with dichloromethane. The combined organic
phases are washed once with saturated aqueous sodium
chloride solution, dried over sodium sulfate, filtered and
concentrated to dryness. The residue obtained is purified by
chromatography on silica gel, eluting with a 9 8/2/0.2
mixture of dichloromethane, methanol and 3 0% aqueous ammonia.
0.92 g of expected product is obtained in the form of a
white powder.
Melting point (°C): 158-160°C
XH NMR (CDCI3) 5 (ppm): 8.10 (s, 1H) ; 4.95 (s, 2H) ; 3.90 (s,
3H) ; 2.50 (broad s, 1H).
5.3. [4-(methoxycarbonyl)thiazol-2-yl]methyl (3aR,5s, 6&S) -5-
[(7-ethoxy-2-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-
2(1H) -carboxylate
The process is performed according to the procedure
described in Example 2, step 2.2. Starting with 0.25 g (0.84
mmol) of (3ai?,5s,6aS) -5-[ (7-ethoxy-2-naphthyl)oxy]-

octahydrocyclopenta[c]pyrrole, obtained in step 5.1., 0.18 g
(1.09 mmol) of methyl 2-hydroxymethylthiazole-4-carboxylate,
obtained in step 5.2., 0.20 g (1.01 mmol) of para-nitro-
phenyl chlorof ormate and 0.37 mL (2.10 mmol) of N, N-
diisopropylethylamine, and after chromatography on silica
gel, eluting with a 99/1/0.1 mixture of dichloromethane,
methanol and aqueous ammonia, 0.25 g of expected product is
obtained in the form of a wax.
5.4. (4-carbamoylthiazol-2-yl)methyl (3af?,5s,6aS)-5-[(7-
ethoxy-2-naphthyl) oxy]hexahydrocyclopenta[c]pyrrole-2 (Iff) -
carboxylate
In a sealed tube, 0.125 g (0.25 mmol) of [4-
(methoxycarbonyl) thiazol-2-yl]methyl (3af?, 5s, 6aS) -5- [ (7-
ethoxy-2-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2 (Iff) -
carboxylate, obtained in step 5.3., is dissolved in 5 mL of
methanol. 10 mL (70 mmol) of a 7N solution of ammonia in
methanol are added and the medium, in a sealed tube, is
heated at 60°C for 14 hours with stirring.
The medium cooled to room temperature is concentrated under
vacuum and the residue obtained is chromatographed on
preparative plates of silica gel, eluting with a 95/5/0.5
mixture of dichloromethane, methanol and 30% aqueous
ammonia. 0.072 g (59%) of the expected product is thus
obtained in the form of a white powder.
Melting point (°C): 143-145°C
LC-MS: M+H = 482
*H NMR (DMSO) 5 (ppm) : 8.30 (s, 1H) ; 7.75 (d, 2H) ; 7.75 (s,
1H) ; 7.60 (s, 1H) ; 7.20 (m, 2H) ; 6.95 (m, 2H); 5.40 (s, 2H) ;
5.10 (m, 1H) ; 4.15 (dq, 2H) ; 3.60 (m, 2H) ; 3.25 (m, 2H) ;
2.90 (m, 2H); 2.15-2.05 (m, 2H); 2.05-1.90 (m, 2H); 1.40 (t,
3H) .
Example 6 (Compound 25)
[3- (methylcarbamoyl) isoxazol-5-yl]methyl (3aJ?, 5s, 6aS) -5- [ (7-
ethoxy-2-naphthyl) oxy]hexahydrocyclopenta[c]pyrrole-2 (Iff) -
carboxylate (exo)
6.1. 3-methylcarbamoylisoxazol-5-ylmethyl 4-nitrophenyl
carbonate
The process is performed according to the procedure

described in Example 4 (step 4.2.). Starting with 2.00 g
(12.81 mmol) of 3-methylcarbamoylisoxazol-5-ylmethanol,
2.58 g (12.81 mmol) of 4-nitrophenyl chloroformate, 1.52 g
(19.21 mmol) of pyridine and 0.157 g (1.28 mmol) of N,N-
dimethylaminopyridine, 2.6 g (63%) of pure product are
obtained in the form of a white powder,
m.p. (°C): 166-168°C
XH NMR (CDC13) 5 (ppm) : 8.40 (d, 2H) ,- 7.50 (d, 2H) ; 7.0 (s,
1H); 6.90 (broads, 1H); 5.50 (s, 2H); 3.10 (d, 3H).
6.2. [3-(methylcarbamoyl)isoxazol-5-yl]methyl (3aR,5s,6aS)-
5-[(7-ethoxy-2-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-
2 (Iff) -carboxylate
The process is performed according to the procedure
described in Example 1, step 1.3. Starting with 0.15 g
(0.50 mmol) of (3af?, 5s, 6aS) -5- [ (7-ethoxy-2-naphthyl) oxy] -
octahydrocyclopenta[c]pyrrole, obtained in step 5.1., 0.17 g
(0.55 mmol) of 3-methylcarbamoylisoxazol-5-ylmethyl 4-nitro-
phenyl carbonate, obtained in step 6.1., 0.03 g (0.28 mmol)
of N,ff-dimethylaminopyridine and 0.19 mL (1.11 mmol) of N,N-
diisopropylethylamine, and after chromatography on silica
gel, eluting with a 98/2/0.2 mixture of dichloromethane,
methanol and aqueous ammonia, 0.13 g (54%) of expected
product is obtained in the form of a white powder.
Melting point (°C): 108-110°C
LC-MS: M+H = 480
XH NMR (DMSO) 5 (ppm): 8.69 (s, lH); 7.69 (d, 2H); 7.18 (s,
1H) ; 7.16 (s, 1H) ; 6.95 (m, 2H) ; 6.81 (s, 1H) , 5.25 (s, 2H) ;
5.06 (m, 1H) ; 4.12 (dq, 2H) ; 3.56 (m, 2H) ; 3.23 (m, 2H) ;
2.85 (m, 2H); 2.77 (d, 3H); 2.06 (m, 2H); 1.94 (m, 2H); 1.38
(t, 3H).
Example 7 (Compound 26)
[4- (methylcarbamoyl) oxazol-2-yl]methyl (3af?, 5s, 6a5) -5- (4-
chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2 (iff) -
carboxylate (exo)
7.1 methyl 2-hydroxymethyloxazole-4-carboxylate
7.1.1. ethyl 2-[(acetyloxy)methyl]oxazole-4-carboxylate

9.5 g (10.80 mmol) of ethyl 2-(bromomethyl)oxazole-4-
carboxylate are dissolved in 135 mL of acetonitrile. 9.96 g
(101.47 mmol) of potassium acetate are added and the medium
is stirred at room temperature for 14 hours.
The resulting mixture is concentrated under vacuum. The
residue obtained is taken up in aqueous sodium chloride
solution and extracted twice with dichloromethane. The
combined organic phases are dried over sodium sulfate,
filtered and concentrated under reduced pressure. 8.50 g of
an oily residue are obtained, which product is used without
further purification in the following step.
7.1.2. methyl 2-(hydroxymethyl)oxazole-4-carboxylate
8.50 g (11.16 mmol) of ethyl 2-acetoxymethyloxazole-4-
carboxylate, obtained in step 7.1.1., are dissolved in
280 mL of a 5/1 mixture of dichloromethane and methanol.
2.55 mL (11.16 mmol) of a 4.37N solution of sodium methoxide
in methanol are added and the medium is stirred at room
temperature for three hours.
The resulting mixture is cooled to 0°C, followed by addition
of 10 mL of saturated aqueous ammonium chloride solution,
and then concentrated under reduced pressure. The residue
obtained is taken up in saturated aqueous sodium chloride
solution and extracted three times with dichloromethane. The
combined organic phases are washed once with saturated
aqueous sodium chloride solution, dried over sodium sulfate,
filtered and concentrated to dryness. The residue obtained
is purified by chromatography on silica gel, eluting with a
mixture from 99/1/0.1 to 97/3/0.3 of dichloromethane,
methanol and 3 0% aqueous ammonia. 1.3 g of expected product
are obtained in the form of a brown oil.
Melting point (°C): 81-82°C
^ NMR (CDC13) 5 (ppm): 8.25 (s, 1H); 4.85 (s, 2H); 4.00 (s,
3H); 3.50 (S, 1H).
7.2. [4-(methoxycarbonyl)oxazol-2-yl]methyl (3aB,5s,6aS)-5-
(4-chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H) -
carboxylate
The process is performed according to the procedure
described in Example 2, step 2.2. Starting with 0.15 g
(0.63 mmol) of {3&R, 5s, 6aS) -5- (4-chlorophenoxy) octahydro-
cyclopenta[c]pyrrole, obtained in step 2.1., 0.12 g

(0.82 mmol) of methyl 2-hydroxymethyloxazole-4-carboxylate,
obtained in step 7.1.2., 0.15 g (0.76 mmol) of para-nitro-
phenyl chloroformate and' 0.27 mL (1.58 mmol) of N,N-
diisopropylethylamine, and after chromatography on silica
gel, eluting with a 99/1/0.1 mixture of dichloromethane,
methanol and aqueous ammonia, 0.24 g (90%) of expected
product is obtained in the form of an oil.
7.3. [4-(methylcarbamoyl)oxazol-2-yl]methyl {3aR,5s,6&S) -5-
(4-chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(Iff) -
carboxylate
The process is performed according to the procedure
described in Example 5, step 5.4. Starting with 0.24 g
(0.58 mmol) of [4-(methoxycarbonyl)oxazol-2-yl]methyl
(3aRr5s,6aS)-5-(4-chlorophenoxy)hexahydrocyclopenta[c]-
pyrrole-2(Iff) -carboxylate, obtained in step 7.2., and
8.00 mL (64 mmol) of an 8N solution of methylamine in
ethanol, and after chromatography on preparative silica gel
plates, eluting with a 95/5/0.5 mixture of dichloromethane,
methanol and aqueous ammonia, 0.11 g (45%) of expected
product is obtained in the form of a white powder.
Melting point (°C): 104-106°C
LC-MS: M+H =420
*H NMR (DMSO) 5 (ppm) : 8.60 (s, 1H) ; 8.25 (s, 1H) ; 7.30 (d,
2H); 6.95 (d, 2H); 5.20 (s, 2H); 4.95 (m, 1H); 3.55 (m, 2H);
3.20 (m, 2H); 2.85 (m, 2H); 2.80 (d, 3H); 2.05-1.95 (m, 2H) ;
1.95-1.80 (m, 2H).
Example 8 (Compound 31)
(3-carbamoylisoxazol-5-yl)methyl {3&R,5s,6&S)-5-[(4'-fluoro-
biphenyl-4-yl)oxy]hexahydrocyclopenta[c]pyrrole-2(Iff) -
carboxylate (exo)
8.1. (3aff, 5r, 6aS) -octahydrocyclopenta[c]pyrrol-5-ol
hydrochloride (1:1)
3.00 g (13.20 mmol) of tert-butyl (3ai?, 5r, 6aS) -5-hydroxy-
hexahydrocyclopenta[c]pyrrole-2(Iff) -carboxylate (see
synthesis: WO 2006/108 059) are dissolved in 150 mL of a 2/1
mixture of dioxane and 1,2-dichloroethane. 30 mL (120 mmol)
of a 4N solution of hydrogen chloride in dioxane are poured
into the medium with stirring. After stirring for 3 hours at

room temperature, the medium is concentrated to dryness and
the product obtained in hydrochloride form is taken up in
diethyl ether for organization of the salt. After filtering
off and drying under reduced pressure, 1.745 g (81%) of the
expected product are obtained in the form of a hygroscopic
solid.
lK NMR (DMSO) 5 (ppm) : 9.40 (S, 1H) ; 8.75 (s, lH) ; 5.10 (s,
1H) ; 4.15 (tq, 1H) ; 3.25 (m, 2H) ; 3.10 (m, 2H) ; 2.80 (m,
2H); 1.85 (m, 2H); 1.55 (m, 2H).
8.2. [3- (ethoxycarbonyl) isoxazol-5-yl]methyl (3ai?, 5r, 6aS) -5-
hydroxyhexahydrocyclopenta[c]pyrrole-2(Iff) -carboxylate
0.627 g (3.67 mmol) of ethyl 5-(hydroxymethyl)isoxazole-3-
carboxylate is dissolved in 10 mL of dichloromethane,
1.17 mL (6.72 mmol) of W,i\7-diisopropylethylamine are added
and the medium is cooled to 0°C, followed by addition of a
solution of 0.647 g (3.21 mmol) of 4-nitrophenyl
chloroformate in 5 mL of dichloromethane. The medium is
stirred for one hour at room temperature and then added
slowly to a solution, cooled beforehand to -10°C, of 0.50 g
(3.06 mmol) of (3ai?, 5r, 6aS) -octahydrocyclopenta[c]pyrrol-5-
ol hydrochloride, obtained in step 8.1., and 0.59 mL
(3.36 mmol) of 2V, N-diisopropylethylamine in 15 mL of a 2/1
mixture of dichloromethane and methanol. After stirring for
3 hours at room temperature, aqueous IN sodium hydroxide
solution is added and the medium is extracted three times
with dichloromethane. The combined organic phases are washed
once with saturated aqueous sodium chloride solution, dried
over sodium sulfate, filtered and concentrated under reduced
pressure. The residue obtained is purified by chromatography
on silica gel, eluting with a 99/1 and then 98/2 mixture of
dichloromethane and methanol. 0.78 g (79%) of the expected
product is obtained in the form of an oil.
LC-MS: M+H = 325
XH NMR (DMSO) 5 (ppm): 6.90 (s, 1H) ; 5.25 (s, 2H) ; 4.60 (d,
1H) ; 4.40 (dq, 2H) ; 4.10 (tq, 1H) ; 3.50 (m, 2H) ; 3.30 (m,
2H); 2.55 (m, 2H); 2.00 (m, 2H); 1.35 (m, 5H).
8.3. [3-(ethoxycarbonyl)isoxazol-5-yl]methyl (3aR,5s, 6&S)-5-
(4-bromophenoxy)hexahydrocyclopenta[c]pyrrole-2 (Iff) -
carboxylate

0.76 g (2.34 mmol) of [3-(ethoxycarbonyl)isoxazol-5-yl]-
methyl (3a£,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-
2 (1H)-carboxylate, obtained in step 8.2., is dissolved in
24 mL of toluene. 0.737 g (2.81 mmol) of triphenylphosphine
and 0.527 g (3.05 mmol) of 4-bromophenol are added, and the
medium is then cooled to 0°C, followed by slow addition of a
solution of 0.49 g (2.81 mmol) of diethyl azodicarboxylate
in 3 mL of toluene. The medium is stirred for 14 hours at
room temperature and then concentrated under vacuum. The
residue obtained is taken up in aqueous IN sodium hydroxide
solution and extracted twice with dichloromethane. The
combined organic phases are washed once with saturated
aqueous sodium chloride solution, dried over sodium sulfate,
filtered and concentrated under vacuum. The residue obtained
is purified by chromatography on silica gel, eluting with
dichloromethane and then with a 99/1 mixture of
dichloromethane and methanol. 0.87 g (61%) of expected
product is obtained in the form of a wax.
LC-MS: M+H =479
2H NMR (DMSO) 5 (ppm) : 7.45 (d, 2H) ; 6.95 (s, 1H) ; 6.90 (d,
2H) ; 5.25 (s, 2H) ; 4.95 (tq, lH) ; 4.35 (dq, 2H) ; 3.55 (m,
2H); 3.25 (m, 2H) ; 2.85 (m, 2H); 1.95 (m, 2H) ; 1.85 (m, 2H) ;
1.35 (t, 3H).
8.4. (3-carbamoylisoxazol-5-yl)methyl (3a.R, 5s, 6a.S) -5- (4-
bromophenoxy)hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate
The process is performed according to the procedure
described in Example 5, step 5.4. Starting with 0.350 g
(0.73 mmol) of [3- (ethoxycarbonyl)isoxazol-5-yl]methyl
(3a.R, 5s, 6aS) -5- (4-bromophenoxy)hexahydrocyclopenta[c] -
pyrrole-2(IF) -carboxylate, obtained in step 8.3., in 5 mL of
methanol and 5 mL (35 mmol) of a 7N solution of ammonia in
methanol, and after chromatography on silica gel, eluting
with a mixture from 99/1/0.1 to 98/2/0.2 of dichloromethane,
methanol and aqueous ammonia, 0.072 g (59%) of the expected
product is obtained in the form of a white powder.
Melting point (°C): 132-134°C
LC-MS: M+H = 450
!H NMR (DMSO) 6 (ppm): 8.15 (s, 1H) ; 7.85 (s, 1H) ; 7.45 (d,
2H) ; 6.90 (d, 2H) ; 6.80 (s, 1H) ; 5.25 (s, 2H) ; 4.95 (tq,
1H); 3.55 (m, 2H) ; 3.20 (m, 2H); 2.85 (m, 2H); 2.22 (m, 2H) ;
1.85 (m, 2H).

8.5. (3-carbamoylisoxazol-5-yl)methyl (3aR,5s,6aS)-5-[(4'-
fluorobiphenyl-4-yl)oxy]hexahydrocyclopenta[c]pyrrole-2(Iff) -
carboxylate
Under an inert atmosphere, 0.20 g (0.44 irimol) of (3-
carbamoylisoxazol-5-yl)methyl (3afJ, 5s, 6a5) -5- (4-bromophen-
oxy) hexahydrocyclopenta [c]pyrrole-2 (Iff) -carboxylate,
obtained in step 8.4., 0.074 g (0.53 mmol) of 4-fluoro-
phenylboronic acid and 0.434 g (1.33 mmol) of caesium
carbonate are placed in 11 mL of a 10/1 mixture of
tetrahydrofuran and water. 0.03 6 g (0.04 mmol) of
PdCl2dppf .CH2C12 is added and the medium is then heated at
about 75°C for 15 hours.
After cooling to room temperature, the medium is taken up in
dichloromethane and saturated aqueous sodium carbonate
solution. The aqueous phase is extracted twice with
dichloromethane and the combined organic phases are then
washed with saturated aqueous sodium chloride solution,
dried over sodium sulfate, filtered and concentrated under
reduced pressure. The residue obtained is purified by
chromatography on silica gel, eluting with dichloromethane
and then with a 98/2/0.2 mixture of dichloromethane,
methanol and 3 0% aqueous ammonia. 0.14 g (72%) of the
expected product is obtained in the form of a white powder.
Melting point(°C): 200-201°C
LC-MS: MH- = 464
XH NMR (DMSO) 5 (ppm) : 5 (ppm) : 8.15 (s, 1H) ; 7.85 (s, lH) ;
7.65 (t, 2H); 7.55 (d, 2H); 7.25 (t, 2H); 7.00 (d, 2H); 6.80
(s, 1H); 5.25 (s, 2H); 5.00 (m, 1H); 3.55 (m, 2H) ; 3.25 (m,
2H) ; 2.85 (m, 2H); 2.05 (m, 2H); 1.90 (m, 2H) .
Example 9 (Compound 27)
(3-carbamoylisoxazol-5-yl)methyl (3aJ?, 5s, 6aS) -5- [ (4-chloro-
1-naphthyl) oxy] hexahydrocyclopenta [c]pyrrole-2 (Iff) -
carboxylate (exo)
9.1. [3-(ethoxycarbonyl) isoxazol-5-yl]methyl (3aJ?, 5s, 6aS) -5-
[ (4-chloro-l-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-
2 (Iff) -carboxylate
The process is performed according to the procedure
described in Example 8, step 8.3. Starting with 0.60 g (1.85
mmol) of [3-(ethoxycarbonyl)isoxazol-5-yl]methyl
(3af?, 5r, 6aS) -5-hydroxyhexahydrocyclopenta[c]pyrrole-2 (Iff) -

carboxylate, obtained in step 8.2., 0.39 g (2.22 mmol) of 4-
chloro-1-naphthol, 0.35 g (2.03 mmol) of diethyl
azodicarboxylate and 0.58 g (2.22 mmol) of
triphenylphosphine, and after chromatography on silica gel,
eluting with dichloromethane and then with a 99/1 mixture of
dichloromethane and methanol, 0.94 g (54%) of expected
product is obtained in the form of an oil.
LC-MS: M+(NH4+) = 502
XH NMR (DMSO) 5 (ppm): 8.25 (d, 1H) ; 8.10 (d, 1H) ; 7.70 (t,
1H) ; 7.65 (t, 1H); 7.60 (d, 1H); 6.95 (d, 1H); 6.95 (s, 1H);
5.30 (s, 2H) ; 5.20 (tq, lH) ; 4.40 (dq, 2H) ; 3.55 (m, 2H) ;
3.25 (m, 2H); 2.90 (m, 2H); 2.15 (m, 2H); 1.95 (m, 2H); 1.35
(t, 3H).
9.2. (3-carbamoylisoxazol-5-yl)methyl (3aJ?,5s, 6aS)-5-[ (4-
chloro-1-naphthyl)oxylhexahydrocyclopenta[c]pyrrole-2 (Iff) -
carboxylate
The process is performed according to the procedure
described in Example 8, step 8.4. Starting with 0.40 g
(0.82 mmol) of [3-(ethoxycarbonyl)isoxazol-5-yl]methyl
(3aJ?, 5s, 6aS) -5- [ (4-chloro-l-naphthyl) oxylhexahydrocyclo-
penta [c]pyrrole-2(Iff)-carboxylate, obtained in step 9.1.,
and 10 mL (70 mmol) of a 7M solution of ammonia in methanol,
and after chromatography on silica gel, eluting with a
mixture from 99/1/0.1 to 98/2/0.2 of dichloromethane,
methanol and aqueous ammonia, 0.23 g (61%) of the expected
product is obtained the form of a solid,
m.p. (°C): 185-187
LC-MS: M+H = 456
:H NMR (DMSO) 5 (ppm): 8.25 (d, 1H) ; 8.15 (d, 1H); 8.15 (s,
1H) ; 7.85 (S, 1H) ; 7.70 (t, 1H) ; 7.65 (t, 1H) ; 7.60 (d, 1H) ;
6.95 (d, 1H); 6.80 (s, 1H), 5.25 (s, 2H); 5.20 (m, 1H); 3.60
(m, 2H); 3.25 (m, 2H); 2.95 (m, 2H); 2.15 (m, 2H); 1.95 (m,
2H) .
Example 10 (Compound 28)
[3- (methylcarbamoyl) isoxazol-5-yl]methyl (3ai?, 5s, 6aS) -5- [ (4-
chloro-1-naphthyl) oxylhexahydrocyclopenta [c]pyrrole-2 (Iff) -
carboxylate (exo)
The process is performed according to the procedure
described in Example 8, step 8.4. Starting with 0.40 g (0.82

mmol) of [3-(ethoxycarbonyl)isoxazol-5-yl]methyl
(3aR, 5s,6aS)-5-[(4-chloro-l-naphthyl)oxyjhexahydrocyclo-
penta[c]pyrrole-2(1H)-carboxylate, obtained in step 9.1.,
and 10 mL (80 mmol) of an 8M solution of methylamine in
ethanol, and after chromatography on silica gel, eluting
with a 99/1/0.1 mixture of dichloromethane methanol and 30%
aqueous ammonia, 0.16 g (55%) of the expected product is
obtained in the form of a white powder,
m.p. (°C): 131-133°C
LC-MS: M+H = 470
1H NMR (DMSO) 5 (ppm): 8.70 (s, 1H); 8.25 (d, 1H); 8.15 (d,
1H) ; 7.75 (t, 1H) ; 7.65 (t, lH) ; 7.60 (d, 1H); 6.95 (d, lH) ;
6.82 (s, 1H) , 5.25 (s, 2H) ,- 5.20 (m, 1H) ; 3.55 (m, 2H) ; 3.25
(m, 2H); 2.95 (m, 2H); 2.80 (d, 3H); 2.15 (m, 2H); 1.95 (m,
2H) .
Example 11 (Compound 18)
thiazol-2-ylmethyl (3aR, 5s,6aS)-5-[(4'-ethoxybiphenyl-3-
yl) oxy]hexahydrocyclopenta[c]pyrrole-2 (Iff)-carboxylate (exo)
11.1. tert-butyl (3a.R, 5s, 6aS) -5- (3-bromophenoxy)hexahydro-
cyclopenta[c]pyrrole-2 (Iff) -carboxylate
0.20 g (0.88 mmol) of tert-butyl (3ai?, 5r, 6aS) -5-hydroxyhexa-
hydrocyclopenta[c]pyrrole-2(Iff) -carboxylate (WO 2006/108
059), 0.19 g (1.10 mmol) of 3-bromophenol, 0.21 g
(1.06 mmol) of diisopropyl azodicarboxylate and 0.34 g
(1.09 mmol) of resin-supported triphenylphosphine
(triphenylphosphine, polymer-supported, 3.2 mmol/g on
polystyrene), are dissolved in 3.5 mL of toluene. The
mixture is stirred at room temperature for 15 hours. After
filtering off the resin, ethyl acetate is added and the
organic phases are then washed with aqueous IN sodium
hydroxide solution. The organic phases are dried over sodium
sulfate, filtered and concentrated under reduced pressure.
The residue obtained is purified by chromatography on silica
gel, eluting with a 95/5 and then 90/10 mixture of
cyclohexane and ethyl acetate. 0.14 g (42%) of expected
product is thus obtained in the form of an oil.
11.2. tert-butyl (3ai?, 5s, 6aS) -5- [ (4 ' -ethoxybiphenyl-3-yl) -
oxy]hexahydrocyclopenta[c]pyrrole-2(Iff) -carboxylate

Under an inert atmosphere, 0.14 g (0.37 mmol) of tert-butyl
(3aJ?, 5s, 6aS) -5- (3-broraophenoxy)hexahydrocyclopenta [c] -
pyrrole-2(Iff) -carboxylate, obtained in step 11.1., 0.08 g
(0.51 mmol) of 4-ethoxyphenylboronic acid and 0.04 g
(1.04 mmol) of lithium chloride are placed in 3.6 mL of a
1/1/0.4 mixture of ethanol, toluene and water. 0.46 mL
(0.92 mmol) of aqueous 2M sodium carbonate solution and
0.02 g (0.02 mmol) of Pd(PPh3)4 are added to the medium.
After heating for 15 hours at 75°C, the medium is allowed to
cool to room temperature, and then taken up in ethyl acetate
and water. The aqueous phase is extracted twice with ethyl
acetate and then the combined organic phases are washed with
saturated aqueous sodium chloride solution, dried over
sodium sulfate, filtered and concentrated under reduced
pressure. The residue obtained is purified by chromatography
on silica gel, eluting with a 95/5 and then 90/10 mixture of
cyclohexane and ethyl acetate. 0.088 g (57%) of expected
product is thus obtained in the form of a wax.
11.3. (3aR, 5s,6aS) -5-[(4'-ethoxybiphenyl-3-yl)oxy]octahydro-
cyclopenta[c]pyrrole
The process is performed according to the procedure
described in Example 1, step 1.2. Starting with 0.08 g (0.21
mmol) of terfc-butyl (3aR,5s,6aS)-5-[(4'-ethoxybiphenyl-3-
yl)oxy]hexahydrocyclopenta[c]pyrrole-2(Iff) -carboxylate,
obtained in step 11.2., and 1.04 mL of a 4N solution of
hydrogen chloride in dioxane, 0.06 g (96%) of expected
product is obtained in the form of an oil.
11.4. thiazol-2-ylmethyl (3ai?, 5s, 6aS)-5-[ (4 '-ethoxybiphenyl-
3-yl) oxy]hexahydrocyclopenta[c] pyrrole-2 (Iff) -carboxylate
The process is performed according to the procedure
described in Example 1, step 1.3. Starting with 0.06 g (0.20
mmol) of (3ai?, 5s, 6aS) -5- [ (4' -ethoxybiphenyl-3-yl) oxy]-
octahydrocyclopentafc]pyrrole, obtained in step 11.3.,
0.04 mL (0.22 mmol) of -A^iV-diisopropylethylamine and 0.05 g
(0.18 mmol) of thiazol-4-ylmethyl 4-nitrophenyl carbonate
(WO 2008/013 834), and after chromatography on silica gel,
eluting with a 95/5 and then 90/10 mixture of cyclohexane
and ethyl acetate, 0.05 g (69%) of expected product is
obtained in the form of an oil.
LC-MS: M+H = 465

XH NMR (DMSO) 5 (ppm): 7.80 (d.lH); 7.75 (d, 1H); 7.60 (d,
2H); 7.35 (t, 1H); 7.15 (d, 1H); 7.05 (s, 1H) ; 7.00 (d, 2H) ;
6.85 (d, 1H); 5.35 (s, 2H); 5.10 (m, 1H); 4.10 (q, 2H); 3.55
(m, 2H); 3.30 (m, 2H) ; 2.90 (m, 2H); 2.10 (m, 2H); 1.90 (m,
2H) ; 1.40 (t, 3H)
Example 12 (Compound 1)
thiazol-2-ylmethyl (3af?, 5s, 6aS) -5- (4-chlorophenoxy)hexa-
hydrocyclopenta[c]pyrrole-2(Iff) -carboxylate (exo)
12 .1. thiazol-2-ylmethyl [3aR, 5r, 6aS) -5-hydroxyhexahydro-
cyclopenta[c]pyrrole-2(Iff) -carboxylate
The process is performed according to the procedure
described in Example 1, step 1.3. Starting with 1.02 g (6.23
iranol) of (3af?,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-ol
hydrochloride, obtained according to step 8.1. of Example 8,
2.09 g (7.85 iranol) of thiazol-4-ylmethyl 4-nitrophenyl
carbonate (WO 2008/013 834) and 3.25 mL (18.66 mmol) of N,N-
diisopropylethylamine, and after chromatography on silica
gel, eluting with a 98/2/0.2 and then 97/3/0.3 mixture of
dichloromethane, methanol and 30% aqueous ammonia, 0.34 g
(20%) of expected product is obtained in the form of a wax.
12.2. thiazol-2-ylmethyl (3af?, 5s, 6aS) -5- (4-chlorophenoxy) -
hexahydrocyclopenta[c]pyrrole-2 (If?) -carboxylate
The process is performed according to the procedure
described in Example 11, step 11.1. Starting with 0.04 g
(0.16 mmol) of 1,3-thiazol-2-ylmethyl {3aR, 5r, 6aS) -5-
hydroxyhexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate,
obtained in step 12.1., 0.02 g (0.19 mmol) of 4-chloro-
phenol, 0.04 g (0.20 mmol) of diisopropyl azodicarboxylate
and 0.08 g (0.25 mmol) of resin-supported triphenylphosphine
(triphenylphosphine, polymer-supported, 3.2 mmol/g on
polystyrene), and after chromatography on silica gel,
eluting with a 95/5 and then 90/10 mixture of cyclohexane
and ethyl acetate, 0.025 g (41%) of expected product is
obtained the form of a solid,
m.p. (°C): 75-77°C
LC-MS: M+H = 379
XH NMR (DMSO) 5 (ppm): 7.8 (d, 1H) ; 7.75 (d, 1H) ; 7.35 (d,
2H); 6.90 (d, 2H); 5.35 (s, 2H); 4.95 (m, lH); 3.55 (m, 2H);
3.25 (broad m, 2H); 2.85 (broad m, 2H); 2.0 (m, 2H); 1.85 (m,

2H) .
Example 13 (Compound 29)
thiazol-4-ylmethyl {3aR,4S,6aS)-4-[(4-chloro-l-naphthyl)-
oxy]hexahydrocyclopenta[c]pyrrole-2(Iff)-carboxylate (exo)
13.1. tert-butyl (3af?, 4.R, 6a.S) -4-hydroxyhexahydrocyclopenta-
[c]pyrrole-2(Iff) -carboxylate
Under an inert atmosphere, 1.00 g (4.44 mmol) of tert-butyl
(3ai?, 6aS) -4-oxohexahydrocyclopenta[c]pyrrole-2 (Iff) -
carboxylate is dissolved in 15 mL of anhydrous
tetrahydrofuran; the medium is cooled to -78°C and 6.66 mL
(6.66 mmol) of a solution of lithium tri-sec-borohydride (L-
Selectride) at IN in tetrahydrofuran are then added
dropwise. The medium is allowed to warm to room temperature
over three hours with stirring, and then cooled to 0°C,
followed by dropwise addition of 35% aqueous hydrogen
peroxide solution until the evolution of gas has ceased. The
medium is diluted with water and extracted three times with
ethyl acetate. The combined organic phases are washed once
with saturated aqueous sodium chloride solution, dried over
sodium sulfate, filtered and concentrated under reduced
pressure. 0.826 g (82%) of the expected product is obtained
in the form of a colourless oil.
13.2. tert-butyl (3ai?, 45, 6&S) -4- [ (4-chloro-l-naphthyl) oxy] -
hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate
The process is performed according to the procedure
described in Example 11, step 11.1. Starting with 0.15 g
(0.66 mmol) of tert-butyl (3af?, 4R, 6aS) -4-hydroxyhexahydro-
cyclopenta[c]pyrrole-2 (Iff)-carboxylate, obtained in step
13.1., 0.130 g (0.73 mmol) of 4-chloro-l-naphthol, 0.160 g
(0.79 mmol) of diisopropyl azodicarboxylate and 0.206 g
(0.659 mmol) of resin-supported triphenylphosphine
(triphenylphosphine, polymer-supported, 3.2 mmol/g on
polystyrene), and after chromatography on silica gel,
eluting with a 95/5 and then a 90/10 mixture of cyclohexane
and ethyl acetate, 0.077 g (30%) of expected product is
obtained.
13.3 . (3af?, 45, 6aS) -4- [ (4-chloro-l-naphthyl) oxy] octahydro-

cyclopenta[c]pyrrole
The process is performed according to the procedure
described in Example 1, step 1.2. Starting with 0.103 g
(0.27 mmol) of tert-butyl (3aR,AS,6aS)-4-[(4-chloro-l-
naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2[1H) -
carboxylate, obtained in step 13.2., and 1.33 mL of a 4N
solution of hydrogen chloride in dioxane, and after
chromatography on silica gel, eluting with a 97/3/0.3 and
then 96/4/0.4 mixture of dichloromethane, methanol and 30%
aqueous ammonia, 0.068 g (89%) of expected product is
obtained in the form of a red oil.
13.4. thiazol-4-ylmethyl (3aR, AS, 6aS)-4-[(4-chloro-l-
naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(IF) -carboxylate
The process is performed according to the procedure
described in Example 1, step 1.3. Starting with 0.059 g
(0.21 mmol) of (3ai?, AS, GaS) -4- [ (4-chloro-l-naphthyl) oxy] -
octahydrocyclopenta[c]pyrrole, obtained in step 13.3.,
0.04 mL (0.25 mmol) of N,i\T-diisopropyl ethyl amine and 0.066 g
(0.23 mmol) of thiazol-4-ylmethyl 4-nitrophenyl carbonate
(WO 2008/013 834), and after chromatography on silica gel,
eluting with a 95/5 and then 90/10 mixture of cyclohexane
and ethyl acetate, 0.017 g (19%) of expected product is
obtained in the form of an oil.
LC-MS: M+H = 429
XH NMR (DMSO) 5 (ppm): 9.10 (s, 1H); 8.25 (d, 1H); 8.15 (d,
1H) ; 7.75-7.60 (m, 4H); 7.00 (d, 1H); 5.20 (s, 2H) ; 4.90 (s,
1H); 3.70 (m, 1H); 3.60 (m, 1H); 3.30 (m, 2H); 2.90 (m, 2H) ;
2.20 (m, 2H); 1.90 (m, 1H); 1.55 (m, 1H).
Example 14 (Compound 30)
thiazol-4-ylmethyl {3aR,AR,6aS) -4-[(4'-ethoxybiphenyl-3-
yl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H) -carboxylate
(endo)
14.1. tert-butyl (3aJ?, AR, 6aS) -4- (3-bromophenoxy)hexahydro-
cyclopenta [c]pyrrole-2(1H) -carboxylate
The process is performed according to the procedure
described in Example 1, step 1.1. Starting with 0.150 g

(0.66 mmol) of tert-butyl (3aR, 4 J?, 6aS) -4-hydroxyhexahydro-
cyclopenta[c]pyrrole-2(1H) -carboxylate, obtained in step
13.1., 0.144 g (0.82 mmol) of l-bromo-3-fluorobenzene,
0.024 g (0.99 mmol) of sodium hydride and 3 mL of N,N-
dimethylformamide, and after chromatography on silica gel,
0.083 g (33%) of the expected product is obtained in the
form of a colourless oil.
14.2. tert-butyl {3aR,4R,6aS)-4-[(4'-ethoxybiphenyl-3-yl)-
oxy]hexahydrocyclopenta[c]pyrrole-2(1H) -carboxylate
The process is performed according to the procedure
described in Example 11, step 11.2. Starting with 0.123 g
(0.324 mmol) of tert-butyl (3aR,4R,6aS)-4-(3-bromophenoxy)-
hexahydrocyclopenta[c]pyrrole-2(1H) -carboxylate, obtained in
step 14.1., 0.075 g (0.45 mmol) of 4-ethoxyphenylboronic
acid, 0.039 g (0.91 mmol) of lithium chloride, 0.40 mL
(0.80 mmol) of aqueous 2N sodium carbonate solution and
0.02 g (0.02 mmol) of Pd(PPh3)4, and after chromatography on
silica gel, 0.105 g (77%) of the expected product is
obtained in the form of a colourless oil.
14.3. (3aJ?, 4R, 6aS) -4- [ (4 ' -ethoxybiphenyl-3-yl) oxy] octahydro-
cyclopenta[c]pyrrole
The process is performed according to the procedure
described in Example 1, step 1.2. Starting with 0.105 g
(0.25 mmol) of tert-butyl (3aR,AR,6aS)-4-[(4'-ethoxy-
biphenyl-3-yl)oxy]hexahydrocyclopenta[c]pyrrole-2(Iff) -
carboxylate, obtained in step 14.2., and 1.24 mL of a 4N
solution of hydrogen chloride in dioxane, and after
chromatography on silica gel, 0.068 g (84%) of expected
product is obtained in the form of an oil.
14.4. thiazol-4-ylmethyl (3aR, 4i?, 6aS) -4- [ (4 ' -ethoxybiphenyl-
3-yl) oxy ]hexahydroeyelopenta[c] pyrrole-2 (Iff) -carboxylate
The process is performed according to the procedure
described in Example 1, step 1.3. Starting with 0.053 g
(0.19 mmol) of (3aJ?, 4R, 6aS) -4- [ (4 ' -ethoxybiphenyl-3-
yl)oxy]octahydrocyclopenta[c]pyrrole, obtained in step
14.3., 0.04 mL (0.23 mmol) of W,AT-diisopropylethylamine and
0.068 g (0.21 mmol) of thiazol-4-ylmethyl 4-nitrophenyl
carbonate (WO 2008/013 834) , and after chromatography on

silica gel, eluting with a 95/5 and then a 90/10 mixture of
cyclohexane and ethyl acetate, 0.055 g (63%) of expected
product is obtained in the form of an oil.
LC-MS: M+H = 465
XH NMR (DMSO) 5 (ppm) : 9.10 (s, 1H) ; 7.70 (s, 1H); 7.60 (d,
2H) ; 7.35 (t, 1H); 7.20 (d, 1H); 7.10 (s, 1H); 7.00 (d, 2H) ;
6.90 (d, 1H); 5.20 (s, 2H); 4.90 (q, 1H); 4.10 (q, 2H); 3.60
(m, 2H); 3.30 (m, 2H); 3.05 (m, 1H) ; 2.80 (m, 1H) ; 2.10 (m,
1H); 1.85 (m, 2H); 1.55 (m, 1H); 1.35 (t, 3H) .
Example 15 (Compound 40)
(3-carbamoylisoxazol-5-yl)methyl (3aJ?; 5r, 6aS) -5- (4-fluoro-
l,3-benzothiazol-2-yl)-5-hydroxyhexahydrocyclopenta[c]-
pyrrole-2(IF) -carboxylate (exo)
15.1 4-fluoro-2-benzothiazole
2.00 g (10.14 mmol) of 4-fluoro-2-benzothiazolecarboxylic
acid are dissolved in 50 mL of an equal-volume mixture of
toluene and ethanol. 2.508 g (13.19 mmol) of para-
toluenesulfonic acid monohydrate are added. After refluxing
for 14 hours, the medium is concentrated to dryness and the
residue is taken up in saturated aqueous sodium carbonate
solution. The aqueous phase is extracted twice and the
combined organic phases are then washed once with saturated
aqueous sodium chloride solution, dried over sodium sulfate
and concentrated under reduced pressure. 1.5 g (97%) of
expected product are obtained in the form of an oil.
15.2 tert-butyl (3aR,5r,6aS)-5-(4-fluoro-l,3-benzothiazol-2-
yl) -5-hydroxyhexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate
Under an inert atmosphere, 1 g (6.53 mmol) of 4-fluoro-2-
benzothiazole (obtained in step 15.1) is dissolved in 3 0 mL
of tetrahydrofuran. The medium is cooled to -78°C and
4.49 mL (7.18 mmol) of a 1.6 M solution of n-butyllithium
are added dropwise. The medium is allowed to warm to 0°C and
then cooled again to -7 8°C, followed by addition of a
solution of 1.618 g (7.18 mmol) of tert-butyl (3a£, 6aS)-5-
oxohexahydrocyclopenta[c]pyrrole-2(Iff) -carboxylate in 5 mL
of tetrahydrofuran. The medium is allowed to cool to room
temperature with stirring for one hour and then hydrolysed
with saturated aqueous ammonium chloride solution. The
medium is extracted three times with dichloromethane and the

combined organic phases are then washed once with saturated
aqueous sodium chloride solution, dried over sodium sulfate
and then concentrated under vacuum. After chromatography on
silica gel, eluting with dichloromethane and then with a
99/1/0.1 mixture of dichloromethane, methanol and 30%
aqueous ammonia, and reorganization of the solid obtained in
diethyl ether, 1 g (41%) of the expected product is obtained
in the form of a white powder.
LC-MS: M+H = 379
'H KMR (DMSO) 5 (ppm): 7.95 (d, 1H); 7.45 (m, 1H); 7.35 (t,
1H) ; 6.45 (s, 1H); 3.55 (t, 2H); 3.35 (m, 2H) ; 3.00 (m, 2H);
2.45 (m, 2H); 2.00 (d, 2H); 1.45 (s, 9H).
15.3 (3ai?, 5r, 6aS)-5- (4-fluoro-l, 3-benzothiazol-2-yl) octa-
hydrocyclopenta[c]pyrrol-5-ole hydrochloride
0.50 g (1.32 mmol) of tert-butyl (3aJ?, 5r, 6aS) -5- (4-f luoro-
1,3-benzothiazol-2-yl)-5-hydroxyhexahydrocyclopenta[c]-
pyrrole-2 (Iff) -carboxylate is dissolved in 3 0 mL of
dichloromethane. 5.00 mL (20.00 mmol) of a 4N solution of
hydrogen chloride in dioxane are added slowly to the medium
cooled to -5°C with stirring, and the medium is then allowed
to cool to room temperature with stirring for 14 hours. The
medium is concentrated to dryness under reduced pressure.
After reorganization of the residue obtained in diethyl
ether and filtration, 0.388 g (93%) of the expected product
is obtained in the form of a brown powder.
LC-MS: M+H = 279
XH NMR (DMSO) 5 (ppm): 7.95 (d 1H) ; 7.45 (m, 1H) ; 7.35 (t,
1H) ; 3.45 (t, 2H); 3.25 (m, 2H); 3.15 (m, 2H); 2.45 (m, 2H) ;
2.15 (d, 2H).
15.4 (3-carbamoylisoxazol-5-yl)methyl (3ai?, 5r, 6aS) -5- (4-
fluoro-1,3-benzothiazol-2-yl)-5-hydroxyhexahydrocyclopenta-
[c]pyrrole-2(1H) -carboxylate
In a sealed tube, 0.380 g (1.21 mmol) of (3aR,5r,6aS)-5-(4-
fluoro-1,3-benzothiazol-2-yl)octahydrocyclopenta[c]pyrrol-S-
ole hydrochloride is suspended in 6 mL of 1,2-dichloroethane.
0.408 g (1.33 mmol) of 3-carbamoylisoxazol-5-ylmethyl 4-
nitrophenyl carbonate, obtained in step 4.2., 0.074 g
(0.60 mmol) of N,iV-dimethylaminopyridine and 0.63 mL
(3.62 mmol) of N,JV-diisopropylethylamine are added and the
medium is stirred for 10 minutes at room temperature,

followed by heating at 70°C for 4 hours with stirring. The
medium is allowed to cool to room temperature, and is
diluted with dichloromethane and aqueous IN sodium hydroxide
solution. The aqueous phase is extracted twice with
dichloromethane and the combined organic phases are then
washed once with saturated aqueous ammonium chloride
solution and once with saturated aqueous sodium chloride
solution, dried over sodium sulfate, filtered and
concentrated under vacuum. After chromatography on the
residue on silica gel, eluting with a 99/1/0.1 and then a
98/2/0.2 mixture of dichloromethane, methanol and 30%
aqueous ammonia, 0.392 g (72%) of the expected product is
obtained in the form of a white powder,
m.p. (°C): 173-174°C
LC-MS: M+H = 447
XH NMR (DMSO) 5 (ppm) : 8.15 (s, 1H) ; 7.90 (d, 1H) ; 7.85 (s,
1H) ; 7.40 (t, 1H) ; 7.35 (t, 1H); 6.80 (S, 1H) ; 6.45 (s, 1H) ;
5.25 (s, 2H); 3.65 (m, 2H); 3.45 (d, 2H); 3.00 (m, 2H); 2.50
(m, 2H); 2.00 (d, 2H) .
Example 16 (Compound 42)
(3-{[2-(dimethylamino)ethyl]carbamoyl}isoxazol-5-yl)methyl
(3ai?, 5s, 6aS) -5- (4-f luorophenoxy) hexa-
hydrocyclopentafc]pyrrole -2 (1H)-carboxylate (exo)
16.1. [3-(ethoxycarbonyl) isoxazol-5-yl]methyl (3ai?, 5s, 6aS) -
5- (4-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2 (Iff) -
carboxylate
The process is performed according to the procedure
described in Example 8, step 8.3. Starting with 0.70 g (2.16
mmol) of [3-(ethoxycarbonyl)isoxazol-5-yl]methyl
(3a.R, 5r, 6aS) -5-hydroxyhexahydrocyclopenta[c]pyrrole-2 {±H) -
carboxylate obtained in step 8.2., 0.679 g (2.59 mmol) of
triphenylphosphine, 0.290 g (2.59 mmol) of 4-fluorophenol
and 0.451 g (2.59 mmol) of diethyl azodicarboxylate, and
after chromatography on silica gel, eluting with
dichloromethane and then with a 99/1 mixture of
dichloromethane and methanol, 0.80 g (88.6%) of expected
product is obtained in the form of a brown wax.
LC-MS: M+H = 419
XH NMR (CDC13) 5 (ppm): 6.90 (t, 2H) ; 6.70 (m, 3H); 5.15 (s,
2H) ; 4.75 (tq, 1H) ; 4.35 (dq, 2H) ; 3.55 (m, 2H) ; 3.25 (m,

2H); 2.85 {m, 2H); 2.10 (m, 2H); 1.70 (m, 2H) ; 1.35 (t, 3H) .
16.2. (3-{[2-(dimethylamino)ethyl]carbamoyl}isoxazol-5-yl)-
methyl (2a.R, 5s, 6aS) -5- (4-fluorophenoxy)hexahydrocyclopenta-
[c]pyrrole-2 (ltf)-carboxylate (hydrochloride 1/1))
0.40 g (0.96 mmol) of [3-(ethoxycarbonyl)isoxazol-5-yl]-
methyl (3ai?, 5s, 6aS) -5- (4-fluorophenoxy)hexahydrocyclopenta-
[c]pyrrole-2(1H)-carboxylate and 0.084 g (0.96 mmol) of N,N-
dimethylethylenediamine are dissolved in 5 mL of methanol.
The medium is heated for 4 hours at 60°C and then allowed to
cool to room temperature and concentrated to dryness. The
residue is purified by chromatography on silica gel, eluting
with a 97/3/0.3 and then 95/5/0.5 mixture of
dichloromethane, methanol and 30% aqueous ammonia. 0.267 g
(60.7%) of the expected product is obtained in the form of
an oil, which is dissolved in 10 mL of dichloromethane. 1 mL
of a 4N solution of hydrogen chloride in dioxane is added
and the medium is stirred for one hour and then concentrated
under reduced pressure. After reorganization of the residue
in diethyl ether, filtering and drying under vacuum, 0.262 g
(90.9%) of the corresponding expected hydrochloride is
obtained in the form of a white powder.
Melting point (°C): 146-148°C
LC-MS: M+H =461
XH NMR (DMSO) 5 (ppm): 10.10 (broad s, 1H) ; 9.05 (t, 1H) ;
7.10 (t, 2H); 6.95 (m, 3H); 5.25 (s, 2H); 4.90 (m, 1H); 3.65
(m, 2H); 3.55 (m, 2H); 3.25 (m, 2H); 3.20 (m, 2H); 2.85 (s,
8H) ; 2.00 (m, 2H) ; 1.85 (m, 2H) .
Example 17 (Compound 34)
(3-carbamoylisoxazol-5-yl)methyl (3al?, 5s, 6aS) -5- (4-chloro-3-
fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H) -
carboxylate (exo)
17.1. (3aR,5s,6aS)-5-(4-chloro-3-fluorophenoxy)octahydro-
cyclopenta[c]pyrrole
The process is performed according to the procedure
described in Example 2, step 2.1. Starting with 5.0 g
(22.00 mmol) of tert-butyl (3&R, 5r, 6aS) -5-hydroxyhexahydro-
cyclopentafc]pyrrole-2(1H) -carboxylate (see synthesis: WO
2006/108 059), 3.87 g (26.40 mmol) of 4-chloro-3-fluoro-
phenol, 4.41 g (25.30 mmol) of diethyl azodicarboxylate,
6.64 g (25.30 mmol) of triphenylphosphine and 20 mL of a 4N

solution of hydrogen chloride in dioxane, 4.86 g (86.5%) of
expected product are obtained in the form of a wax.
LC-MS: M+H = 256
^ NMR (CDC13) 5 (ppm): 7.25 (t, 1H); 6.65 (m, 2H) ; 4.85 (tq,
1H) ; 3.05-2.70 (m, 6H) ,- 2.20 (m, 2H) ; 1.60 (m, 2H) .
17.2. (3-carbamoylisoxazol-5-yl)methyl (3ai?, 5s, 6aS) -5- (4-
chloro-3-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H) -
carboxylate
The process is performed according to the procedure
described in Example 1, step 1.3. Starting with 1.20 g (4.69
mmol) of (3aR,5s,6aS)-5-(4-chloro-3-fluorophenoxy)-
octahydrocyclopenta[c]pyrrole, obtained in step 17.1.,
1.73 g (5.63 mmol) of 3-carbamoylisoxazol-5-ylmethyl 4-
nitrophenyl carbonate, obtained in step 4.2., 0.287 g
(2.35 mmol) of JV,iV-dimethylaminopyridine and 2.04 mL
(11.73 mmol) of N,iV-diisopropylethylamine, and after
chromatography on silica gel, eluting with a 9 8/2/0.2
mixture of dichloromethane, methanol and 30% aqueous
ammonia, 1.45 g (73%) of expected product are obtained in
the form of a white powder.
Melting point (°C): 100-102°C
LC-MS: M+H = 424
XH NMR (DMSO) 5 (ppm): 8.15 (s, 1H); 7.85 (s, 1H); 7.45 (t,
1H) ; 7.05 (m, 1H) ; 6.80 (d, 2H) ; 5.25 (s, 2H) ; 5.00 (m, 1H) ;
3.55 (m, 2H); 3.20 (d, 2H); 2.85 (m, 2H); 2.00 (m, 2H); 1.90
(m, 2H).
Table 1 below 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 with the
exception of the compound of Example 42, which is in the
form of the hydrochloride in a base/salt proportion of
1/1;

Protocol 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 (10 mM Tris-HCl, pH =
8, 150 mM NaCl and 1 mM ethylenediaminetetraacetic acid
(EDTA)). The enzymatic reaction is performed in 96-well
Multiscreen filtration plates in a final volume of 7 0 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
different 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 20 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 pL/well, final
concentration of 10 uM, 0.01 uCi per test). After incubation
for 20 minutes at 25°C, the enzymatic reaction is stopped by
adding a 5M solution of active charcoal prepared in 1.5M
NaCl buffer and 0.5 M HC1 (50 uL/well) . The mixture is
stirred for 10 minutes and the aqueous phase containing the
ethanolamine [1-3H] is then recovered by filtration under
vacuum and counted by liquid scintillation.
Protocol 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 (10 mM Tris-HCl, pH = 8, 150 mM NaCl and 1
mM ethylenediaminetetraacetic acid (EDTA)). The enzymatic
reaction is performed in black polystyrene 3 84-well plates
in a final volume of 50 uL. 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 uL/well) , the diluted test compounds
at different concentrations (5 uL/well containing 1% DMSO)
and the membrane preparation (10 uL/well, i.e. 2 00 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 uL of
substrate per well (AAMC, final concentration of 10 uM) .
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 protocol 1, the compounds of the
invention that are the most active have IC50 values
(concentration that inhibits 50% of the control enzymatic
activity of FAAH) of between 0.001 and 1 uM. For example,
compounds 3, 7, 12, 23, 28 .and 34 have respective IC50 values
of 3.5 nM, 89 nM, 19 nM, 34 nM, 12 nM and 3.2 nM.
Under the conditions of protocol 2, the compounds of the
invention that are the most active have IC50 values
(concentration that inhibits 50% of the control enzymatic
activity of FAAH) of between 0.001 and 1 uM. For example,
compounds 44 and 45 have respective IC50 values of 7.4 nM and
0.47 nM.
It thus appears that the compounds according to the
invention have inhibitory activity on the enzyme FAAH.
The in vivo activity of the compounds of the invention was
evaluated in a test of analgesia.

Thus, the intraperitoneal (i.p.) administration of PBQ
(phenylbenzoguinone, 2 mg/kg in 0.9% sodium chloride
solution containing 5% ethanol) to male OFl mice weighing 25
to 30 g causes abdominal stretching, on average 3 0 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 compounds of the invention that
are the most powerful reduce by 35% to 80% the number of
stretches induced with PBQ, over a dose range of between 1
and 3 0 mg/kg.
For example, compounds 24 and 35 of Table 1 reduce by 50%
the number of stretches induced with PBQ, at a dose of 30
mg/kg p.o. at 120 minutes.
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 JV-arachidonoyl ethanol amine (anandamide) , JV-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, sleeping 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 the base, or a pharmaceutically acceptable acid-
addition salt, hydrate or solvate, for the preparation of a
medicinal product for treating the pathologies mentioned
above forms an integral part of the invention.
A subject of the invention is also medicinal products
comprising a compound of formula (I) , or an acid-addition
salt, or alternatively a pharmaceutically acceptable hydrate
or solvate of the compound of formula (I) . These medicinal
products find their therapeutic use especially in the
treatment of the pathologies mentioned above.
According to another of its aspects, the present invention
relates to pharmaceutical compositions containing, as active
principal, at least one compound according to the invention.
These pharmaceutical compounds contain an effective dose of
a compound according to the invention, or a pharmaceutically
acceptable acid-addition salt, hydrate or solvate of the
said compound, and optionally one or more pharmaceutically
acceptable excipients.
The said excipients are chosen, according to the
pharmaceutical form and the desired administration form,
from the usual excipients known to those skilled in the art.
In the pharmaceutical compositions of the present invention
for oral, sublingual, subcutaneous, intramuscular,
intravenous, topical, local, intrathecal, intranasal,
transdermal, pulmonary, ocular or rectal administration, the
active principal of formula (I) above, or the possible acid-
addition salt, solvate or hydrate thereof, may be
administered in a unit administration form, as a mixture

with standard pharmaceutical excipients, to man and animals
for the prophylaxis or treatment of the above disorders or
diseases.
The appropriate unit administration forms comprise oral
forms such as tablets, soft or hard gel capsules, powders,
granules, chewing gums and oral solutions or suspensions,
sublingual, buccal, intratracheal, intraocular and
intranasal administration forms, forms for administration by-
inhalation, subcutaneous, intramuscular or intravenous
administration forms and rectal or vaginal administration
forms. For topical administration, the compounds according
to the invention may be used in creams, ointments or
lotions.
By way of example, a unit administration form of a compound
according to the invention in the form of a tablet may
comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Sodium croscarmellose 6.0 mg
Corn starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3 . 0 mg
The said unit forms are dosed to allow a daily
administration of from 0.01 to 20 mg of active principal per
kg of body weight, depending on the presentation form.
There may be particular cases in which higher or lower doses
are suitable, and such doses also form part of the
invention. According to the usual practice, the dose that is
suitable for each patient is determined by the doctor
according to the mode of administration and the weight and
response of the said patient.
According to another of its aspects, the invention also
relates to a method for treating the pathologies mentioned
above, which comprises the administration of an effective

dose of a compound according to the invention, a
pharmaceutically acceptable acid-addition salt thereof or. a
solvate or hydrate of the said compound.

Claims
1. Compound corresponding to formula (I)

in which
R2 represents a hydrogen or fluorine atom or a hydroxyl,
cyano, trifluoromethyl, Ci-s-alkyl, Ci-6-alkoxy or NR8R9 group;
m, n, o and p represent, independently, of each other, a number
ranging from 0 to 3 and are such that each of m+o and n+p is
less than or equal to 4;
A represents a covalent bond, an oxygen atom, a group
Ci-6-alkylene or a group -O-Ci-6-alkylene in which the end
represented by an oxygen atom is bonded to the group Ri and the
end represented by an alkylene group is bonded to the carbon
of the bicycle;
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, naphthyl, quinolyl,
isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl,
cinnolinyl, naphthyridinyl, benzothiazolyl, benzoxazolyl,
benzimidazolyl, benzisothiazolyl, bensisoxazolyl, indazolyl
and benzotriazolyl;
R6 represents a halogen atom or a cyano, -CH2CN, nitro,
hydroxyl, Ci-6-alkyl, Ci-6-alkoxy, Ci-6-thioalkyl, Ci-6-haloalkyl,
Ci-6-haloalkoxy, Ci-6-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 phenyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl and triazinyl; the group(s) R7 possibly
being substituted with one or more groups R6, which may be
identical or different; the group(s) R7 possibly being
substituted with one or more groups R6, which may be identical
or different;

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, pyrrazolyl, oxadiazolyl, thiadiazolyl, imidazole,
triazolyl and tetrazolyl;
this heterocycle being unsubstituted or substituted with one
or more substituents chosen from a halogen atom and a group Ci-
6-alkyl, Ci-6-haloalkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-
Ci-3-alkylene, Ci-6-haloalkoxy, cyano, NR8R9, NR8COR9, NR8C02R9,
NR8S02R9, NR8S02NR8R9, COR8, C02R8, CONR8R9, C0N(R8) (Ci-3-alkylene-
NR10R11) , S02R8, S02NR8R9 or -0-(Ci-3-alkylene)-0-;
Rs, R9, Rio and Rii represent, independently of each other, a
hydrogen atom or a group Ci-6-alkyl,
or form, with the atom(s) that bear 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 group Ci-6-alkyl or benzyl;
in the case of NR8COR9, a lactam ring; in the case of NR8C02R9,
an oxazolidinone, oxazinone or oxazepinone ring; in the case
of NR8S02Rg, a sultam ring; in the case of NR8S02NR8R9, a
thiazolidine dioxide or thiadiazinane dioxide ring;
in the form of the base or of an acid-addition salt.
2. Compound of formula (I) according to Claim 1, characterized
in that R2 represents a hydrogen atom or a hydroxyl group;
in the form of the base or of an acid-addition salt.
3. Compound of formula (I) according to Claim 1 or 2,
characterized in that m, n, o and p have the value 1, or
alternatively m and o have the value 1, n has the value 0 and
p has the value 2 ;
in the form of the base or of an acid-addition salt.
4. Compound of formula (I) according to any one of Claims 1 to
3, characterized in that A represents a covalent bond or an
oxygen atom; in the form of the base or of an acid-addition
salt.
5. Compound of formula (I) according to any one of Claims 1 to
4, characterized in that Ri represents a group R5 that is
unsubstituted or substituted with one or more groups R6 and/or

R7;
R5 represents a phenyl, naphthyl, benzothiazolyl or
isoguinolyl group;
R6 represents a halogen atom or a group Ci-6-haloalkyl or a
group Ci-g-alkoxy;
R7 represents a phenyl that may be substituted with one or
more groups Re, which may be identical or different; in the
form of the base or of an acid-addition salt.
6. Compound of formula (I) according to any one of Claims 1 to
5, characterized in that R3 represents a hydrogen atom; in the
form of the base or of an acid-addition salt.
7. Compound of formula (I) according to any one of Claims 1 to
6, characterized in that R4 represents a group chosen from a
thiazolyl, a thiadiazolyl, a triazolyl, an oxazolyl and an
isoxazolyl;
this group being unsubstituted or substituted with one or more
groups Ci-6-alkyl, CONR8R9 or CON(R8) (Ci-3-alkylene-NR10Rii) ;
R8, R9/ Rio and Ru represent, independently of each other, a
hydrogen atom or a group Ci-5-alkyl;
in the form of the base or of an acid-addition salt.
8. Compound of formula (I) chosen from:
thiazol-2-ylmethyl (3af?, 5s, 6aS) -5- (4-chlorophenoxy)hexahydro-
cyclopenta[c]pyrrole-2 (Iff) -carboxylate (exo)
thiazol-2-ylmethyl (3aJ?, 5s,6aS)-5-[4-(trifluoromethyl)phen-
oxy]hexahydrocyclopenta[c]pyrrole-2 (Iff)-carboxylate (exo)
thiazol-2-ylmethyl (3af?,5s,6aS)-5-[(7-ethoxy-2-naphthyl)-
oxy]hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate (exo)
thiazol-2-ylmethyl (3af?, 5r, 6aS) -5- [3- (trif luoromethyl)phen-
oxy]hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate (endo)
thiazol-2-ylmethyl (3ai?, 5s, 6aS) -5- [3- (trif luoromethyl) phen-
oxy]hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate (exo)
thiazol-2-ylmethyl (3af?, 5r, 6aS) -5- [ (4 ' -ethoxybiphenyl-3-yl) -
oxy]hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate (endo)
1, 2, 3-thiadiazol-4-ylmethyl (3ai?, 5s, 6aS) -5- (4-chlorophenoxy) -

hexahydrocyclopenta[c]pyrrole-2(Iff) -carboxylate (exo)
(5-tert-butyl-l,3,4-thiadiazol-2-yl)methyl (3aR, 5s,6aS)-5-(4-
chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(Iff) -carboxylate
(exo)
l,2,3-thiadiazol-4-ylmethyl (3aJ?, 5s, 6aS) -5-(4-f luorophenoxy) -
hexahydrocyclopenta[c]pyrrole-2(Iff)-carboxylate (exo)
(3-carbamoylisoxazol-5-yl)methyl (3af?, 5s, 6aS) -5- (4-fluorophen-
oxy)hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate (exo)
[3-(methylcarbamoyl)isoxazol-5-yl]methyl (3aR,5s,6aS)-5- (4-
chlorophenoxy)hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate
(exo)
(3-carbamoylisoxazol-5-yl)methyl (3aJ?, 5s, 6aS) -5- (4-chlorophen-
oxy)hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate (exo)
(1 -methyl-Iff-1, 2 , 4-triazol-5-yl)methyl (3aR, 5s, 6aS) -5-(4-
chlorophenoxy) hexahydrocyclopenta [ c] pyrrole-2 (Iff) -carboxylate
(exo)
(4-carbamoylthiazol-2-yl)methyl (3af?, 5s, 6aS) -5- (4-chlorophen-
oxy)hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate (exo)
[4- (methylcarbamoyl) thiazol-2-yl]methyl (3af?, 5s, 6aS) -5- (4-
chlorophenoxy) hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate
(exo)
(3-carbamoylisoxazol-5-yl)methyl (3af?, 5s, 6aS) -5- [3-
(trifluoromethyl)phenoxy]hexahydrocyclopenta[c]pyrrole-2(Iff) -
carboxylate (exo)
[3- (methylcarbamoyl) isoxazol-5-yl]methyl (3aJ?, 5s, 6aS) -5- [3-
(trifluoromethyl)phenoxy]hexahydrocyclopenta[c]pyrrole-2(Iff) -
carboxylate (exo)
thiazol-2-ylmethyl (3&R,5s,6aS)-5-[(4'-ethoxybiphenyl-3-yl)-
oxy]hexahydrocyclopenta [c]pyrrole-2 (Iff) -carboxylate (exo)
(4-carbamoyloxazol-2-yl)methyl (3aJR, 5s, 6aS) -5- (4-chlorophen-
oxy) hexahydrocyclopenta [c]pyrrole-2 (Iff) -carboxylate (exo)

thiazol-4-ylmethyl (3aJ?, 45, 6aS) -4- [ (6-methoxy-2-naphthyl) -
oxy]hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate (exo)
thiazol-4-ylmethyl (3&R,4R,6aS)-4-[3-(trifluoromethyl)phen-
oxy]hexahydrocyclopenta[c]pyrrole-2(Iff)-carboxylate (endo)
(4-carbamoylthiazol-2-yl)methyl {3aR, 5s, 6aS)-5-[(7-ethoxy-2-
naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(Iff)-carboxylate
(exo)
[4- (methylcarbamoyl) thiazol-2-yl]methyl (3aJ?, 5s, 6aS) -5- [ (7-
ethoxy-2-naphthyl) oxy]hexahydrocyclopenta [c]pyrrole-2 (Iff) -
carboxylate (exo)
(3-carbamoylisoxazol-5-yl)methyl (3af?, 5s, 6aS) -5- [ (7-ethoxy-2-
naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(Iff) -carboxylate
(exo)
[3- (methylcarbamoyl) isoxazol-5-yl]methyl (3a.R, 5s, 6aS) -5- [ (7-
ethoxy-2-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(Iff) -
carboxylate (exo)
[4- (methylcarbamoyl) oxazol-2-yl]methyl (3ai?, 5s, 6aS) -5- (4-
chlorophenoxy) hexahydrocyclopenta [c]pyrrole-2 (Iff) -carboxylate
(exo)
(3-carbamoylisoxazol-5-yl)methyl (3af?, 5s, 6aS) -5- [ (4-chloro-l-
naphthyl) oxy] hexahydrocyclopenta [ c] pyrrole-2 (Iff) -carboxylate
(exo)
[3- (methylcarbamoyl) isoxazol-5-yl]methyl (3af?, 5s, 6aS) -5- [ (4-
chloro-1-naphthyl) oxy]hexahydrocyclopenta [c]pyrrole-2 (Iff) -
carboxylate (exo)
thiazol-4-ylmethyl (3af?,4S,6aS)-4-[(4-chloro-l-naphthyl)-
oxy]hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate (exo)
thiazol-4-ylmethyl (3aR, 4R, 6aS) -4- [ (4'-ethoxybiphenyl-3-yl)-
oxy]hexahydrocyclopenta[c]pyrrole-2 (Iff) -carboxylate (endo)
(3-carbamoylisoxazol-5-yl)methyl (3af?, 5s, 6aS) -5- [ (4 ' -f luoro-
biphenyl-4-yl) oxy]hexahydrocyclopenta [c]pyrrole-2 (Iff) -

carboxylate (exo)
[3-(methylcarbamoyl)isoxazol-5-yl]methyl (3a£, 5s, 6aS)-5-(4-
chloro-2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(Iff) -
carboxylate (exo)
(3-carbamoylisoxazol-5-yl)methyl [3&R, 5s,6aS)-5-(4-chloro-2-
fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2{Iff)-carboxylate
(exo)
(3-carbamoylisoxazol-5-yl)methyl (3ai?, 5s, 6aS) -5- (4-chloro-3-
fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(Iff)-carboxylate
(exo)
[3- (methylcarbamoyl) isoxazol-5-yl]methyl (3aJ?, 5s, 6a5") -5- (4-
chloro-3-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H) -
carboxylate (exo)
(3-carbamoylisoxazol-5-yl)methyl (3a.R, 5s, 6aS) -5- (2 , 4-dichloro-
phenoxy)hexahydrocyclopenta[c]pyrrole-2(1H) -carboxylate (exo)
[3- (methylcarbamoyl) isoxazol-5-yl]methyl (3ai?, 5s, 6a5) -5- (2, 4-
dichlorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
(exo)
(3-carbamoylisoxazol-5-yl)methyl (3aJ?, 5s, 6aS) -5- (isoquinolin-7-
yloxy) hexahydrocyclopenta [c]pyrrole-2 (1H) -carboxylate (exo)
(3-carbamoylisoxazol-5-yl)methyl (3a.R, 5s, 6aS) -5- (isoquinolin-6-
yloxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (exo)
(3-carbamoylisoxazol-5-yl)methyl (3ai?, 5r, 6aS) -5- (4-f luoro-1, 3-
benzothiazol-2-yl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-
2[1H) -carboxylate (exo)
(4-carbamoyloxazol-2-yl)methyl (3ai?, 5s, 6aS) -5- [ (7-ethoxy-2-
naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H) -carboxylate
(exo)
(3-{[2-(dimethylamino)ethyl]carbamoyl}isoxazol-5-yl)methyl
(3aR,5s,6aS) -5-(4-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-
2(1H) -carboxylate (exo), and its hydrochloride

[4- (methylcarbamoyl)oxazol-2-yl]methyl (3af?, 5s, 6aS) -5- [ (7-
ethoxy-2-naphthyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H) -
carboxylate (exo)
(3-dimethylcarbamoylisoxazol-5-yl)methyl (3aJ?, 5s, 6aS) -5- (4-
fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2{1H)-carboxylate
(exo)
(3-methylcarbamoylisoxazol-5-yl)methyl (3ai?, 5s, 6&S) -5- [ (4' -
fluorobiphenyl-4-yl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H) -
carboxylate (exo).
9. Process for preparing a compound of formula (I) according
to any one of Claims 1 to 8, comprising the step consisting in
reacting either an amine of general formula (II) ,

in which A, Rl7 R2, m, n, o and p are as defined in the general
formula (I) according to Claim 1,
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) according to
Claim 1,
in the presence of a base, in a solvent at a temperature of
between room temperature and the reflux temperature of the
solvent.
10. Process for preparing a compound of formula (I) according
to any one of Claims 1 to 8, comprising the step consisting in
reacting a compound of general formula (la)
in which R2, R3, R4, m, n, o and p are as defined in the
general formula (I) according to Claim 1, and G represents

part of the group A as defined in the general formula (I),
namely either a covalent bond or the Ci-e-alkylene part of the
group -O-Ci-6-alkylene;
with either an alcohol derivative of general formula RiOH (IV),
in which Ri is as defined in the general formula (I) according
to Claim 1, using the Mitsunobu reaction conditions;
or with a halo derivative of general formula RiX (IVa) , in
which Ri is as defined in the general formula (I) according to
Claim 1, and X represents a fluorine, chlorine, bromine or
iodine atom, using aromatic or heteroaromatic nucleophilic
substitution, or Buchwald O-arylation or O-heteroarylation
reactions.
11. Process for preparing a compound of formula (I) according
to any one of Claims 1 to 8, in which Ri represents a group R5
substituted especially with a group R6 of the type Ci-6-alkyl,
C3-7-cycloalkyl or C3-7-cycloalkyl-Ci-3-alkylene, or with a group
R7 as defined in the general formula (I) according to Claim 1,
comprising the step consisting in performing a coupling
reaction, catalysed with a transition metal, 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) according to Claim 1 and Ui represents a
chlorine, bromine or iodine atom or a triflate group, Ui being
in the position in which it is desired to introduce the group
R6 or R7:
- either via a reaction of Suzuki type, p for example using an
alkyl, cycloalkyl, aryl or heteroaryl boronic acid,
- or according to a reaction of Stille type, for example using
an aryl or heteroaryl tri-alkylstannous derivative;
- or via a reaction of Negishi type, for example using an
alkyl, cycloalkyl, aryl or heteroaryl halide zincate
derivative.
12. Compound of general formula (la)


in which R2, R3, R4, m, n, o and p are as defined in Claim 1,
and G represents part of the group A as defined in the general
formula (I), namely either a covalent bond or the Ci_6-alkylene
part of the group -0-Ci_6-alkylene.
13. Compound of general formula (II),

in which Ri, R2, m, n, o and p are as defined in Claim 1, A
represents an oxygen atom or a covalent bond, given that when
A represents a covalent bond, then Ri represents a
benzothiazolyl group.
14. Compounds of general formula (lie):

in which Ri, R2, m, n, o and p are as defined in Claim 1, A
represents an oxygen atom or a covalent bond, given that when
A represents a covalent bond, then Ri represents a
benzothiazolyl group.
15. Compound of formula (I) according to any one of Claims 1
to 8, in the form of the base or of a pharmaceutical ly
acceptable acid-addition salt, for its use as a medicament.
16. Pharmaceutical composition containing at least one
compound of formula (I) according to any one of Claims 1 to 8,
in the form of the base or of a pharmaceutically acceptable
acid-addition salt and optionally one or more pharmaceutically
acceptable excipients.
17. Use of a compound of formula (I) according to any one of

Claims 1 to 8; in the form of the base or of a
pharmaceutically acceptable acid-addition salt, for the
preparation of a medicament for preventing or treating a
pathology in which the endogenous cannabinoids and/or any
5 substrate metabolized by the enzyme FAAH are involved.
18. Use. of a compound of formula (I) according to any one of
Claims 1 to 8, in the form of the base or of a
pharmaceutically acceptable acid-addition salt, for the
10 preparation of a medicament for preventing or treating acute
or chronic pain of neurogenic type, acute or chronic pain
associated with inflammatory diseases, acute or chronic
peripheral pain, vertigo, vomiting, nausea, eating behaviour
disorders, neurological and psychiatric pathologies, acute or
15 chronic neurodegenerative diseases, epilepsy, sleeping
disorders, cardiovascular diseases, renal ischaemia, cancer,
immune system disorders, allergic diseases, parasitic, viral
or bacterial infectious diseases, inflammatory diseases,
osteoporosis, ocular complaints, pulmonary complaints,
2 0 gastrointestinal diseases, urinary incontinence or bladder
inflammation. f~^]

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, n, o and p independently are a number from 0 to 3; A
is a covalent bond, an oxygen atom, a C1-6-alkylene group or a -O-C1-6-alkylene group in which the end that is an oxygen atom is
bonded to the R1 group while the end that is an alkylene group is bonded to the carbon of the bicyclic compound; R1 is an
optionally substituted aryl or heteroaryl group; R3 is a hydrogen or fluorine atom or a C1-6-alkyl or trifiuoromethyl group; R4 is an
optionally substituted 5-membered heterocyclic compound; wherein the compounds can be in the slate of n base or an acid
addition salt. The invention can be used in therapeutics.