Alkyl-heterocycle carbamate derivatives, their preparation and
their therapeutic application
A subject-matter of the invention is alkyl-heterocycle
carbamate derivatives, their preparation and their therapeutic
application .
There still exists a need to find and develop products which
are inhibitors of the enzyme FAAH (Fatty Acid Amide
Hydrolase) . The compounds of the invention meet this
ob ective .
Furthermore, these compounds have to exhibit metabolic and
pharmacokinetic properties and a safety index which allow them
to be used as medicaments.
The compounds of the invention correspond to the general
formula (I):
(I)
in which:
- R2 represents a hydrogen or fluorine atom or a hydroxyl,
cyano, trif luoromethyl , Ci-6-alkyl, Ci-6-alkoxy or -NR R group;
- n and m represent, independently of one another, an integer
equal to 1 , 2 or 3 , it being understood that the sum m+n is at
most equal to 5 ;
- A represents a covalent bond, an oxygen atom, a Ci-6-alkylene
group or an -O-Ci-6-alkylene group in which the end represented
by an oxygen atom is bonded to the R group;
- R i represents an R5 group optionally substituted by one or
more R and/or R groups;
R5 representing a group chosen from a phenyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl,
quinolinyl, isoquinolinyl , phthalazinyl , quinazolinyl ,
quinoxalinyl , cinnolinyl, naphthyridinyl , benzothiazolyl ,
benzisothiazolyl , benzoxazolyl , benzisoxazolyl ,
benzimidazolyl , isobenzof uranyl , benzof uranyl ,
benzothiophenyl , benzothiadiazolyl , benzoxadiazolyl ,
indazolyl, indolizinyl, indolyl, isoindolyl, imidazopyridinyl ,
imidazopyrimidinyl , imidazopyrazinyl , imidazopyridazinyl ,
triazolopyridinyl , pyrrolopyridinyl , pyrrolopyrimidinyl ,
pyrrolopyrazinyl , pyrrolopyridazinyl , pyrrolotriazinyl ,
pyrazolopyridinyl , pyrazolopyrimidinyl , pyrazolopyrazinyl ,
pyrazolopyridazinyl , furopyridinyl , furopyrimidinyl ,
furopyrazinyl , furopyridazinyl , furotriazinyl ,
oxazolopyridinyl , oxazolopyrimidinyl , oxazolopyrazinyl ,
oxazolopyridazinyl , isoxazolopyridinyl , isoxazolopyrimidinyl ,
isoxazolopyrazinyl , isoxazolopyridazinyl , oxadiazolopyridinyl ,
thienopyridinyl , thienopyrimidinyl , thienopyrazinyl ,
thienopyridazinyl , thienotriazinyl , thiazolopyridinyl ,
thiazolopyrimidinyl , thiazolopyrazinyl , thiazolopyridazinyl ,
isothiazolopyridinyl , isothiazolopyrimidinyl ,
isothiazolopyrazinyl , isothiazolopyridazinyl or
thiadiazolopyridinyl ;
R representing a halogen atom or a cyano, -CH2CN, nitro,
hydroxyl, Ci-8-alkyl, Ci-6-alkoxy, Ci-6-thioalkyl, Ci-6-haloalkyl,
Ci-6-haloalkoxy, Ci-6-halothioalkyl , C 3- -cycloalkyl ,
C 3- -cycloalkyl-Ci-3-alkylene, C 3- -cycloalkyl-Ci-3-alkylene-0- ,
(CH2)p-NR R , -NR COR , -NR C02R , -NR S02R , -NR S02NR R , -COR , -
C02R , - (CH2)p-CONR R , -S02R , -S02NR R or -0- (Ci_3-alkylene) -0-
group;
R representing a group chosen from a phenyl, phenyl-Ci-4-
alkylene-, phenyl- (CH2)p-0-, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl,
imidazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl,
tetrazolyl, thiazolyl, isothiazolyl , oxadiazolyl,
thiadiazolyl , imidazopyrimidinyl , thienopyrimidinyl ,
benzof uranyl , benzothienyl , benzimidazolyl , benzoxazolyl ,
benzisoxazolyl , benzothiazolyl , benzisothiazolyl , indolyl,
isoindolyl, indazolyl, pyrrolopyridinyl , furopyridinyl ,
thienopyridinyl , imidazopyridinyl , pyrazolopyridinyl ,
oxazolopyridinyl , isoxazolopyridinyl or thiazolopyridinyl ; it
being possible for the R group or groups to be substituted by
one or more R groups which are identical to or different from
one another;
p representing a number which can have the value 0 , 1 , 2 or
3 ;
- R 3 represents a hydrogen or fluorine atom, a Ci-6 _ alkyl group
or a trif luoromethyl group;
- R represents a 5-membered heterocycle chosen from a furanyl,
pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl,
isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, imidazolyl,
triazolyl or tetrazolyl;
this heterocycle optionally being substituted by one or more
substituents chosen from a halogen atom or a Ci-6-alkyl, Ci-6 _
haloalkyl, C 3- -cycloalkyl , C 3- -cycloalkyl-Ci-3-alkylene, C 1-6-
haloalkoxy, cyano, -NR R , -NR C(0)R , -NR C02R ,
-NR S02R9, -NR S02NR R , -C(0)R , -C0 2R , -C(0)NR R ,
-C (O)N (R ) (Ci-3-alkylene-NRioRii) , -S0 2R , -S0 2NR R or -0- (C1-3-
alkylene) -0- group;
R and R representing, independently of one another, a
hydrogen atom or a Ci-6 _ alkyl group,
or forming, with the nitrogen atom or atoms which carry them,
in the case of NR R , a ring chosen from the azetidine,
pyrrolidine, piperidine, morpholine, thiomorpholine, azepine,
oxazepine or piperazine rings, this ring optionally being
substituted by a Ci-6-alkyl or benzyl group;
in the case of NR COR , a lactam ring;
in the case of NR C02R , an oxazolidinone, oxazinone or
oxazepinone ring;
in the case of NR SO2R , a sultam ring;
in the case of R SO2 R R , a thiazolidine dioxide or
thiadiazinane dioxide ring;
R o and R representing, independently of one another, a
hydrogen atom or a Ci-6 _ alkyl group;
with the exclusion of the following compound:
5-methylisoxazol-3-ylmethyl 4-hydroxy-4- (4-chlorophenyl) -
piperidine-l-carboxylate .
Among the compounds of general formula (I), a first subgroup
of compounds is composed of the compounds for which R2
represents a hydrogen atom.
Among the compounds of general formula (I), a second subgroup
of compounds is composed of the compounds for which m and n
represent, independently of one another, the value 1 or 2 .
Among the compounds of general formula (I), a third subgroup
of compounds is composed of the compounds for which m and n
each represent the value 2 .
Among the compounds of general formula (I), a fourth subgroup
of compounds is composed of the compounds for which A
represents an -O-Ci-6-alkylene group in which the end
represented b y an oxygen atom is bonded to the R group, in
particular an -0- (CH2 ) 2~ group, also known as an ethyleneoxy
group .
Among the compounds of general formula (I), a fifth subgroup
of compounds is composed of the compounds for which A
represents an -O-Ci-6-alkylene group in which the end
represented b y an oxygen atom is bonded to the R group, in
particular an -0-C¾- group, also known as a methyleneoxy
grou .
Among the compounds of general formula (I), a sixth subgroup
of compounds is composed of the compounds for which R
represents an R5 group optionally substituted b y one or more R
and/or R groups;
R5 representing a group chosen from a phenyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl,
quinolinyl, isoquinolinyl , phthalazinyl , quinoxalinyl ,
quinazolinyl , cinnolinyl, naphthyridinyl , benzothiazolyl ,
benzisothiazolyl , benzoxazolyl , benzisoxazolyl ,
benzimidazolyl , isobenzof uranyl , benzof uranyl ,
benzothiophenyl , indazolyl, indolizinyl, indolyl, isoindolyl,
pyrrolopyridinyl , furopyridinyl or thienopyridinyl ;
R representing a halogen atom or a cyano, -CH 2CN, nitro,
hydroxyl, Ci-8-alkyl, Ci-6-alkoxy, Ci-6-thioalkyl, Ci-6-haloalkyl,
Ci-6-haloalkoxy, Ci-6-halothioalkyl , C 3- -cycloalkyl ,
C 3- -cycloalkyl-Ci-3-alkylene, C 3- -cycloalkyl-Ci-3-alkylene-0- ,
(CH2)p-NR R , -NR COR , -NR C02R , -NR S02R , -NR S02NR R , -COR , -
C02R , - (CH2)p-CONR R , -S0 2R , -S0 2NR R or -0- (Ci_3-alkylene) -0-
group;
R representing a group chosen from a phenyl, phenyl-Ci-4-
alkylene-, phenyl- (CH2)p-0-, pyridinyl, pyridazinyl,
isoxazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, tetrazolyl,
pyrimidinyl, thiazolyl, pyrazinyl, triazinyl or benzoxazolyl;
it being possible for the R7 group or groups to be substituted
b y one or more R groups, which are identical to or different
from one another, as defined above;
p representing a number which can have the value 0 , 1 , 2 or
3 ;
R and R representing, independently of one another, a
hydrogen atom or a Ci-6 _ alkyl group;
or forming, with the nitrogen atom(s) which carry them,
in the case of NR R , a ring chosen from the azetidine,
pyrrolidine, piperidine, morpholine, thiomorpholine, azepine,
oxazepine or piperazine rings, this ring optionally being
substituted by a Ci-6-alkyl or benzyl group;
in the case of NR COR , a lactam ring;
in the case of R CO2 9 , an oxazolidinone, oxazinone or
oxazepinone ring;
in the case of R SO2R9, a sultam ring;
in the case of R SO2 R R , a thiazolidine dioxide or
thiadiazinane dioxide ring.
Among the compounds of general formula (I), a seventh subgroup
of compounds is composed of the compounds for which R
represents an R5 group optionally substituted by one or more R
and/or R groups;
R 5 representing a group chosen from a phenyl,
benzothiazolyl , pyridinyl, pyridazinyl, pyrimidinyl,
pyrazinyl, triazinyl, naphthyl, quinolinyl, isoquinolinyl ,
phthalazinyl , quinoxalinyl , cinnolinyl, naphthyridinyl or
indolyl ;
R representing a halogen atom or a cyano, -CH2CN, nitro,
hydroxyl, Ci-s-alkyl, Ci-6-alkoxy, Ci-6-thioalkyl, Ci-6-haloalkyl,
Ci-6-haloalkoxy, Ci-6-halothioalkyl , C 3- -cycloalkyl ,
C 3- -cycloalkyl-Ci-3-alkylene, C 3- -cycloalkyl-Ci-3-alkylene-0- ,
(CH2)p-NR R , -NR COR , -NR C02R , -NR S02R , -NR S02NR R , -COR , -
C02R , - (CH2)p-CONR R , -S02R , -S02NR R or -0- (Ci-3-alkylene) -0-
group;
R representing a group chosen from a phenyl, phenyl-Ci-4-
alkylene-, phenyl- (CH2)p-0-, pyridinyl, pyridazinyl,
isoxazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, tetrazolyl,
pyrimidinyl, thiazolyl, pyrazinyl, triazinyl or benzoxazolyl ;
it being possible for the R7 group or groups to be substituted
by one or more R groups which are identical to or different
from one another;
p representing a number which can have the value 0 , 1 , 2 or
3 ;
R and R representing, independently of one another, a
hydrogen atom or a Ci-6 _ alkyl group,
or forming, with the nitrogen atom which carries them,
in the case of R R , a ring chosen from azetidine,
pyrrolidine, piperidine, morpholine, thiomorpholine, azepine,
oxazepine or piperazine rings, this ring optionally being
substituted by a Ci-6-alkyl or benzyl group;
in the case of R COR , a lactam ring;
in the case of R CO2R9 , an oxazolidinone, oxazinone or
oxazepinone ring;
in the case of R SO2R9 , a sultam ring;
in the case of R SO2 R R , a thiazolidine dioxide or
thiadiazinane dioxide ring.
Among the compounds of general formula (I), an eighth subgroup
of compounds is composed of the compounds for which R
represents a group chosen from a phenyl, benzothiazolyl ,
naphthyl, quinolinyl, isoquinolinyl or indolyl, optionally
substituted by one or more R and/or R groups;
R representing a halogen atom or a cyano, Ci-s-alkyl, C 1-6-
alkoxy, Ci-6-haloalkyl, Ci-6-haloalkoxy, C 3- -cycloalkyl ,
- (CH2)p-NR R , -NRgCOR , -C0 2R , - (CH2)p-CONR R , -S0 2R or
-S0 2N R R group;
R 7 representing a group chosen from a phenyl, phenyl-Ci-4-
alkylene-, phenyl- (CH2)p-0-, isoxazolyl, benzothiazolyl,
pyrrolyl, pyrazolyl, tetrazolyl, thiazolyl or benzoxazolyl ; it
being possible for the R 7 group or groups to be substituted by
one or more R groups, which are identical to or different from
one another, as defined above;
p representing a number which can have the value 0 or 1 ;
R and R 9 representing, independently of one another, a
hydrogen atom or a Ci-6 _ alkyl group; or else
R and R9 forming, with the nitrogen atom which carries
them,
in the case of - R R , a morpholine ring;
in the case of - R COR , a lactam ring.
Among the compounds of general formula (I), a ninth subgroup
of compounds is composed of the compounds for which R 3
represents a hydrogen atom.
Among the compounds of general formula (I), a tenth subgroup
of compounds is composed of the compounds for which R
represents a 5-membered heterocycle chosen from a pyrazolyl,
imidazolyl, thiazolyl, isothiazolyl , oxazolyl or isoxazolyl;
this heterocycle optionally being substituted by one or
more -C(0)NRsR substituents in which R g and R 9 each represent a
hydrogen atom.
Among the compounds of general formula (I), an eleventh
subgroup of compounds is composed of the compounds for which R
represents a 5-membered heterocycle chosen from a thiazolyl or
isoxazolyl;
this heterocycle optionally being substituted by one or
more -C(0)NRsR substituents in which R g and R 9 each represent a
hydrogen atom.
Among the compounds of general formula (I), mention may be
made of a twelfth subgroup represented by the compounds of
formula (Ii) :
in which Ri, A , R4, n and m are as defined above.
Other subgroups composed of the compounds of formula (Ii) also
come within the present invention.
Thus, among the compounds of abovementioned general formula
(Ii), a subgroup of compounds is composed of the compounds for
which A represents an -0-(CH2)2 ~ group.
Among the compounds of abovementioned general formula (Ii), a
subgroup of compounds is composed of the compounds for which A
represents an -0-C¾- group.
Among the compounds of general formula (I), mention may be
made of a thirteenth subgroup represented by the compounds of
formula (Iii) :
in which R , A , n and m are as defined above.
Other subgroups composed of the compounds of formula (Iii)
also come within the present invention.
Thus, among the compounds of abovementioned general formula
(Iii), a subgroup of compounds is composed of the compounds
for which A represents an -0-(0¾)2 - group.
Thus, among the compounds of abovementioned general formula
(Iii), a subgroup of compounds is composed of the compounds
for which A represents an -0-C¾- group.
Among the compounds of general formula (I), a fourteenth
subgroup is composed of the compounds of general formula (I)
in which:
- R 2 represents a hydrogen atom;
- m and n represent, independently of one another, the value 1
or 2 ;
A represents an -O-Ci-6-alkylene group in which the end
represented by an oxygen atom is bonded to the R group, in
particular an ethyleneoxy ou methyleneoxy group;
- R represents a group chosen from a phenyl, benzothiazolyl ,
naphthyl, quinolinyl, isoquinolinyl or indolyl, optionally
substituted by one or more R and/or R groups;
R representing:
- a halogen atom, in particular a chlorine, fluorine or
bromine ;
- a cyano group;
- a Ci-8-alkyl group, in particular a methyl, isopropyl,
1,1,3,3-tetramethylbutyl or tert-butyl;
- a Ci-6 _ alkoxy group, in particular a methoxy, hexyloxy,
butoxy, ethoxy;
- a Ci-6-haloalkyl group, in particular a trif luoromethyl ,
pentaf luoroethyl ;
- a Ci-6-haloalkoxy group, in particular a trif luoromethoxy
or dif luoromethoxy ;
- a C 3- -cycloalkyl group, in particular a cyclopentyl;
- a - (C¾) p- R R group, in which p has the value 0 or 1 ; R g
and R9 each represent a hydrogen atom or R g and R9 each
represent a methyl, or else R and R9 form, with the
nitrogen atom which carries them, a morpholine ring;
- an - R COR group, in which R g represents a hydrogen atom
and R9 represents a methyl, or else R and R9 form, with the
nitrogen atom which carries them, a lactam ring, in
particular a -lactam ring;
- a -CO 2R group, in which R g represents a methyl;
- a - (C¾) p-CO R R group, in which p has the value 0 or 1
and R and R each represent a hydrogen atom;
- an - SO2 group, in which R g represents a methyl;
- an - SO2 R R group, in which R g and R 9 each represent a
hydrogen atom;
R7 representing a group chosen from a phenyl group; a
phenyl -C -4-alkylene- group, in particular a 1,1-dimethyl-lphenylmethylene
or a benzyl; a phenyl- (C¾) P
_ 0- group in which
p has a value of 0 or 1 ; or an isoxazolyl, benzothiazolyl ,
pyrrolyl, pyrazolyl, tetrazolyl, thiazolyl or benzoxazolyl
group; it being possible for the R7 group or groups to be
substituted by one or more R groups, which are identical to or
different from one another, as defined above, such as a
halogen atom or a cyano group;
- R3 represents a hydrogen atom;
- R represents a 5-membered heterocycle chosen from a
thiazolyl or isoxazolyl; this heterocycle optionally being
substituted by one or more -C(0 ) NR R substituents in which R g
and R 9 each represent a hydrogen atom.
Among the compounds of general formula (I), a fifteenth
subgroup of compounds is composed of the compounds of general
formula (I) in which, simultaneously, R and/or R2 and/or R3
and/or R and/or n and/or m and/or A are as defined in the
above subgroups .
Among the compounds of general formula (I), the following
compounds may be cited (IUPAC nomenclature generated by the
AutoNom software) :
1 . Thiazol-2-ylmethyl 4- [2- (4-chloronaphth-l-yloxy) ethyl] -
piperidine-l-carboxylate
2 . Thiazol-2-ylmethyl 4- [2- (4-fluorophenoxy) ethyl] piperidinel-
carboxylate
3 . Thiazol-4-ylmethyl 4- [2- (4-fluorophenoxy) ethyl] piperidine-
1-carboxylate
4 . Thiazol-4-ylmethyl 4- [2- (4- {trifluoromethyl jphenoxy) -
ethyl ]piperidine-l-carboxylate
5 . Thiazol-4-ylmethyl 4- [2- (4-chlorophenoxy) ethyl] piperidinel-
carboxylate
6 . Thiazol-5-ylmethyl 4- [2- (4-fluorophenoxy) ethyl] piperidinel-
carboxylate
7 . Thiazol-5-ylmethyl 4- [2- (4-chlorophenoxy) ethyl] piperidine-
1-carboxylate
8 . Thiazol-5-ylmethyl 4- [2- (4- {trifluoromethyl jphenoxy) -
ethyl ]piperidine-l-carboxylate
9 . Thiazol-4-ylmethyl 4- [2- (7-methoxynaphth-2-yloxy) ethyl] -
piperidine-l-carboxylate
10. Thiazol-4-ylmethyl 4- [2- (4-cyanophenoxy) ethyl] -
piperidine-l-carboxylate
11. Thiazol-4-ylmethyl (+/-) -3- (6-methoxynaphth-2-yloxymethyl
)pyrrolidine -1-carboxylate
12. Thiazol-4-ylmethyl (+/-) -3- (7-methoxynaphth-2-yloxymethyl)
pyrrolidine -1-carboxylate
13. Thiazol-4-ylmethyl (+/-) -3- (3, 4-dichlorophenoxymethyl
)pyrrolidine -1-carboxylate
14. Thiazol-4-ylmethyl 4- [2- (6-methoxynaphth-2-yloxy) -
ethyl ]piperidine-l-carboxylate
15. Thiazol-4-ylmethyl 4- [2- (naphth-2-yloxy) ethyl] -
piperidine-l-carboxylate
16. Thiazol-4-ylmethyl (+/-) -3- (4-chloronaphth-l-yloxymethyl
)pyrrolidine -1-carboxylate
17. Thiazol-4-ylmethyl (+/-) -3- (naphth-2-yloxymethyl) -
pyrrolidine-l-carboxylate
18. Thiazol-4-ylmethyl 4- [2- (4 '-fluorobiphenyl-4-yloxy) -
ethyl ]piperidine-l-carboxylate
19. Thiazol-4-ylmethyl 4- [2- (quinolin- 6-yloxy) ethyl] -
piperidine-l-carboxylate and its hydrochloride
20. Thiazol-4-ylmethyl 4- [2- (isoquinolin- 6-yloxy) ethyl] -
piperidine-l-carboxylate and its hydrochloride
21. Thiazol-4-ylmethyl (+/-) -3- (3 '-cyanobiphenyl-3-
yloxymethyl )pyrrolidine-l-carboxylate
22. Thiazol-4-ylmethyl (+/-) -3- ( '-fluorobiphenyl-4-
yloxymethyl) pyrrolidine-l-carboxylate
23. Thiazol-4-ylmethyl (+/-) -3- (5-chloronaphth-2-yloxymethyl
)pyrrolidine-l-carboxylate
24. Thiazol-4-ylmethyl (+/-) -3- (3- {trifluoromethoxy }-
phenoxymethyl )pyrrolidine-l-carboxylate
25. Thiazol-4-ylmethyl (+/-) -3- [4- (1-methyl-l-phenylethyl)
phenoxymethyl] pyrrolidine-l-carboxylate
26. Thiazol-4-ylmethyl (+/-) -3- (quinolin-3-yloxymethyl) -
pyrrolidine-l-carboxylate
27. Thiazol-4-ylmethyl (+/-) -3- (isoquinolin- 6-yloxymethyl)
pyrrolidine-l-carboxylate
28. Thiazol-4-ylmethyl (+/-) -3- (quinolin-7-yloxymethyl) -
pyrrolidine-l-carboxylate
29. Thiazol-4-ylmethyl (+/-) -3- (isoquinolin-7-yloxymethyl
)pyrrolidine-l-carboxylate
30. Thiazol-4-ylmethyl (+/-) -3- (4-chloro-3- {trifluoromethyl
jphenoxymethyl) pyrrolidine-l-carboxylate
31. Thiazol-4-ylmethyl (+/-) -3- (5-fluoronaphth-2-yloxymethyl
)pyrrolidine-l-carboxylate
32. Thiazol-2-ylmethyl 4- [2- (2, 4-dimethylphenoxy) ethyl] -
piperidine-l-carboxylate
33. Thiazol-2-ylmethyl 4- [2- (2, 3-dichlorophenoxy) ethyl] -
piperidine-l-carboxylate
34. Thiazol-2-ylmethyl 4- [2- (2, 4-dichlorophenoxy) ethyl] -
piperidine-l-carboxylate
35. Thiazol-2-ylmethyl 4- [2- (2, 5-dichlorophenoxy) ethyl] -
piperidine-l-carboxylate
36. Thiazol-2-ylmethyl 4- [2- (3, 4-dichlorophenoxy) ethyl] -
piperidine-l-carboxylate
37. Thiazol-2-ylmethyl 4- [2- (3, 5-dichlorophenoxy) ethyl] -
piperidine-l-carboxylate
38. Thiazol-2-ylmethyl 4- [2- (4-cyclopentylphenoxy) -
ethyl ]piperidine-l-carboxylate
39. Thiazol-2-ylmethyl 4- [2- (2- {benzoxazol-2-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate
40. Thiazol-2-ylmethyl 4- [2- (4- {benzyloxy jphenoxy) ethyl] -
piperidine-l-carboxylate
41. Thiazol-2-ylmethyl 4- [2- (4- {carbamoylmethyl jphenoxy) -
ethyl ]piperidine-l-carboxylate
42. Thiazol-2-ylmethyl 4- [2- (quinolin-7-yloxy) ethyl] -
piperidine-l-carboxylate and its trif luoroacetate
43. Thiazol-2-ylmethyl 4- [2- (quinolin- 6-yloxy) ethyl] -
piperidine-l-carboxylate and its trif luoroacetate
44. Thiazol-2-ylmethyl 4- [2- (4-cyano-3-f luorophenoxy) -
ethyl ]piperidine-l-carboxylate
45. Thiazol-2-ylmethyl 4- [2- (biphenyl-2-yloxy) ethyl] -
piperidine-l-carboxylate
46. Thiazol-2-ylmethyl 4- [2- (2-isopropyl-5-methylphenoxy)
ethyl ]piperidine-l-carboxylate
47. Thiazol-2-ylmethyl 4- [2- (3- {trif luoromethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate
48. Thiazol-2-ylmethyl 4- {2- [ - (1,1,3 ,3-tetramethylbutyl)
phenoxy] ethyl }piperidine-l-carboxylate
49. Thiazol-2-ylmethyl 4- [2- (4-benzylphenoxy) ethyl] -
piperidine-l-carboxylate
50. Thiazol-2-ylmethyl 4- [2- (4- {pyrrol-l-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
51. Thiazol-2-ylmethyl 4- [2- (4-carbamoylphenoxy) ethyl] -
piperidine-l-carboxylate
52. Thiazol-2-ylmethyl 4- [2- (3-cyanophenoxy) ethyl] -
piperidine-l-carboxylate
53. Thiazol-2-ylmethyl 4- [2- (3, 5-di {tert-butyl jphenoxy) -
ethyl ]piperidine-l-carboxylate
54. Thiazol-2-ylmethyl 4- [2- (2-benzylphenoxy) ethyl] -
piperidine-l-carboxylate
55. Thiazol-2-ylmethyl 4- [2- (8- {acetylamino }naphth-2-
yloxy) ethyl ]piperidine-l-carboxylate
56. Thiazol-2-ylmethyl 4- [2- (3- {methoxycarbonyl }naphth-2-
yloxy) ethyl ]piperidine-l-carboxylate
57. Thiazol-2-ylmethyl 4- [2- (3-phenoxyphenoxy) ethyl] -
piperidine-l-carboxylate
58. Thiazol-2-ylmethyl 4- [2- (isoquinolin-7-yloxy) ethyl] -
piperidine-l-carboxylate and its trif luoroacetate
59. Thiazol-2-ylmethyl 4- [2- (4-hexyloxyphenoxy) ethyl] -
piperidine-l-carboxylate
60. Thiazol-2-ylmethyl 4- [2- (3-butoxyphenoxy) ethyl] -
piperidine-l-carboxylate
61. Thiazol-2-ylmethyl 4- [2- (quinolin-5-yloxy) ethyl] -
piperidine-l-carboxylate and its trif luoroacetate
62. Thiazol-2-ylmethyl 4- [2- (3- {pentaf luoroethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate
63. Thiazol-2-ylmethyl 4- [2- (5- {acetylamino }naphth-2-
yloxy) ethyl ]piperidine-l-carboxylate
64. Thiazol-2-ylmethyl 4- [2- (5-bromo-2-chlorophenoxy) -
ethyl ]piperidine-l-carboxylate
65. Thiazol-2-ylmethyl 4- [2- (2-methylquinolin-6-yloxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
66. Thiazol-2-ylmethyl 4- [2- (4 '-cyanobiphenyl-3-yloxy) -
ethyl ]piperidine-l-carboxylate
67. Thiazol-2-ylmethyl 4- [2- (6-cyanonaphth-2-yloxy) -
ethyl] piperidine-l-carboxylate
68. Thiazol-2-ylmethyl 4- [2- (4- {thiazol-2-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate
69. Thiazol-2-ylmethyl 4- [2- (biphenyl-3-yloxy) ethyl] -
piperidine-l-carboxylate
70. Thiazol-2-ylmethyl 4- [2- (biphenyl-4-yloxy) ethyl] -
piperidine-l-carboxylate
71. Thiazol-2-ylmethyl 4- [2- (2-cyanoquinolin-8-yloxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
72. Thiazol-2-ylmethyl 4- [2- (4-chloro-2-cyanophenoxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
73. Thiazol-2-ylmethyl 4- [2- (2-methylbenzothiazol-5-
yloxy) ethyl ]piperidine-l-carboxylate
74. Thiazol-2-ylmethyl 4- [2- (4 '-cyanobiphenyl-4-yloxy) -
ethyl ]piperidine-l-carboxylate
75. Thiazol-2-ylmethyl 4- [2- (2- {morpholin-4-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate
76. Thiazol-2-ylmethyl 4- [2- (4-chloro-2- {isoxazol-5-yl }-
phenoxy) ethyl ]piperidine-l-carboxylate
77. Thiazol-4-ylmethyl 4- [2- (2, 4-dimethylphenoxy) ethyl] -
piperidine-l-carboxylate
78. Thiazol-4-ylmethyl 4- [2- (2, 3-dichlorophenoxy) ethyl] -
piperidine-l-carboxylate
79. Thiazol-4-ylmethyl 4- [2- (naphth-l-yloxy) ethyl] -
piperidine-l-carboxylate
80. Thiazol-4-ylmethyl 4- [2- (3- {dimethylamino jphenoxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
81. Thiazol-4-ylmethyl 4- [2- (3- {trif luoromethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate
82. Thiazol-4-ylmethyl 4- [2- (4-benzylphenoxy) ethyl] -
piperidine-l-carboxylate
83. Thiazol-4-ylmethyl 4- [2- (2-ethoxyphenoxy) ethyl] -
piperidine-l-carboxylate
84. Thiazol-4-ylmethyl 4- {2- [4- (1-methyl-l-phenylethyl )-
phenoxy] ethyl }piperidine-l-carboxylate
85. Thiazol-4-ylmethyl 4- [2- (4-phenoxyphenoxy) ethyl] -
piperidine-l-carboxylate
86. Thiazol-4-ylmethyl 4- [2- (2-bromo-4-f luorophenoxy) -
ethyl ]piperidine-l-carboxylate
87. Thiazol-4-ylmethyl 4- [2- (2-benzylphenoxy) ethyl] -
piperidine-l-carboxylate
88. Thiazol-4-ylmethyl 4- [2- (3-phenoxyphenoxy) ethyl] -
piperidine-l-carboxylate
89. Thiazol-4-ylmethyl 4- [2- (4- {hexyloxy jphenoxy) ethyl] -
piperidine-l-carboxylate
90. Thiazol-4-ylmethyl 4- [2- (3-butoxyphenoxy) ethyl] -
piperidine-l-carboxylate
91. Thiazol-4-ylmethyl 4- [2- (4-chloro-5-isopropyl-2-
methylphenoxy) ethyl ]piperidine-l-carboxylate
92. Thiazol-4-ylmethyl 4- [2- (3- {pentafluoroethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (5- {acetylamino }naphth-2
yloxy) ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (5-bromo-2-chlorophenoxy)
ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (4 '-cyanobiphenyl-3-yloxy)
ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (6-cyanonaphth-2-yloxy)
ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (4- {thiazol-2-yl jphenoxy)
ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (biphenyl-3-yloxy) ethyl]
piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (biphenyl-4-yloxy) ethyl]
piperidine-l-carboxylate
. Thiazol-4-ylmethyl 4- [2- (4-chloro-2-cyanophenoxy)
ethyl ]piperidine-l-carboxylate
. Thiazol-4-ylmethyl 4- [2- (2-methylbenzothiazol-5
yloxy) ethyl ]piperidine-l-carboxylate
. Thiazol-4-ylmethyl 4- [2- (4 '-cyanobiphenyl-4-yloxy)
ethyl ]piperidine-l-carboxylate
. Thiazol-4-ylmethyl 4- [2- (2- {morpholin-4-yl jphenoxy)
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
. Thiazol-4-ylmethyl 4- [2- (4-chloro-2- {isoxazol-5-yl }
phenoxy) ethyl ]piperidine-l-carboxylate
. Thiazol-2-ylmethyl 4- [2- (4- {dimethylaminomethyl }
phenoxy) ethyl ]piperidine-l-carboxylate and its trifluoro
acetate
. Thiazol-2-ylmethyl 4- [2- (naphth-2-yloxy) ethyl]
piperidine-l-carboxylate
107. Thiazol-2-ylmethyl 4- [2- (naphth-l-yloxy) ethyl] -
piperidine-l-carboxylate
108. Thiazol-2-ylmethyl 4- [2- (7-methoxynaphth-2-yloxy) -
ethyl ]piperidine-l-carboxylate
109. Thiazol-4-ylmethyl 4- [2- (2-cyclopentylphenoxy) -
ethyl ]piperidine-l-carboxylate
110. Thiazol-4-ylmethyl 4- [2- (2-benzyloxyphenoxy) ethyl] -
piperidine-l-carboxylate
111. Thiazol-4-ylmethyl 4- [2- (isoquinolin-7-yloxy) ethyl] -
piperidine-l-carboxylate and its trif luoroacetate
112. Thiazol-4-ylmethyl 4- [2- (quinolin-5-yloxy) ethyl] -
piperidine-l-carboxylate and its trif luoroacetate
113. Thiazol-4-ylmethyl 4- [2- (2-methylquinolin-6-yloxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
114. Thiazol-4-ylmethyl 4- [2- (2-cyanoquinolin-8-yloxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
115. Thiazol-4-ylmethyl 4- [2- (2, 4-dichlorophenoxy) ethyl] -
piperidine-l-carboxylate
116. Thiazol-4-ylmethyl 4- [2- (4-cyclopentylphenoxy) -
ethyl] piperidine-l-carboxylate
117. Thiazol-4-ylmethyl 4- [2- (2- {benzoxazol-2-yl }-
phenoxy) ethyl ]piperidine-l-carboxylate
118. Thiazol-4-ylmethyl 4- [2- (4-cyano-3-f luorophenoxy) -
ethyl ]piperidine-l-carboxylate
119. Thiazol-4-ylmethyl 4- {2- [ - (1,1,3 ,3-tetramethylbutyl)
phenoxy] ethyl }piperidine-l-carboxylate
120. Thiazol-4-ylmethyl 4- [2- (4- {pyrrol-l-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
121. Thiazol-4-ylmethyl 4- [2- (3, 5-di {tert-butyl jphenoxy) -
ethyl ]piperidine-l-carboxylate
. Thiazol-4-ylmethyl 4- [2- (4- {dimethylaminomethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate and its
trifluoroacetate
. Thiazol-4-ylmethyl 4- [2- (2-methylquinolin-8-yloxy) -
ethyl ]piperidine-l-carboxylate and its trifluoroacetate
. Thiazol-4-ylmethyl 4- [2- (3-cyanophenoxy) ethyl] -
piperidine-l-carboxylate
. Thiazol-5-ylmethyl 4- (2-phenoxyethyl) piperidine-1-
carboxylate
. Thiazol-5-ylmethyl 4- [2- (biphenyl-4-yloxy) ethyl] -
piperidine-l-carboxylate
. Thiazol-5-ylmethyl 4- [2- (4-carbamoylphenoxy) ethyl]
piperidine-l-carboxylate
. Thiazol-5-ylmethyl 4- [2- (4-fluorophenoxy) ethyl] -
piperidine-l-carboxylate
. Thiazol-5-ylmethyl 4- [2- (2, 4-dimethylphenoxy) ethyl]
piperidine-l-carboxylate
. Thiazol-5-ylmethyl 4- [2- (4- {dimethylaminomethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate and its
trifluoroacetate
. Thiazol-5-ylmethyl 4- [2- (2, 3-dichlorophenoxy) ethyl] -
piperidine-l-carboxylate
. Thiazol-5-ylmethyl 4- [2- (2, 4-dichlorophenoxy) ethyl]
piperidine-l-carboxylate
. Thiazol-5-ylmethyl 4- [2- (2, 5-dichlorophenoxy) ethyl] -
piperidine-l-carboxylate
. Thiazol-5-ylmethyl 4- [2- (3, 5-dichlorophenoxy) ethyl]
piperidine-l-carboxylate
. Thiazol-5-ylmethyl 4- [2- (4-cyclopentylphenoxy) -
ethyl ]piperidine-l-carboxylate
136. Thiazol-5-ylmethyl 4- [2- (naphth-2-yloxy) ethyl] -
piperidine-l-carboxylate
137. Thiazol-5-ylmethyl 4- [2- (naphth-l-yloxy) ethyl] -
piperidine-l-carboxylate
138. Thiazol-5-ylmethyl 4- [2- (2-methylquinolin-8-yloxy) -
ethyl ]piperidine-l-carboxylate
139. Thiazol-5-ylmethyl 4- [2- (2- {benzoxazol-2-yl }-
phenoxy) ethyl ]piperidine-l-carboxylate
140. Thiazol-5-ylmethyl 4- [2- (4- {benzyloxy jphenoxy) ethyl] -
piperidine-l-carboxylate
141. Thiazol-5-ylmethyl 4- [2- (4-sulphamoylphenoxy) ethyl] -
piperidine-l-carboxylate
142. Thiazol-5-ylmethyl 4- [2- (isoquinolin-5-yloxy) ethyl] -
piperidine-l-carboxylate
143. Thiazol-5-ylmethyl 4- [2- (4- {carbamoylmethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate
144. Thiazol-5-ylmethyl 4- [2- (quinolin-7-yloxy) ethyl] -
piperidine-l-carboxylate
145. Thiazol-5-ylmethyl 4- [2- (quinolin- 6-yloxy) ethyl] -
piperidine-l-carboxylate
146. Thiazol-5-ylmethyl 4- [2- (quinolin-8-yloxy) ethyl] -
piperidine-l-carboxylate
147. Thiazol-5-ylmethyl 4- [2- (3- {dimethylamino jphenoxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
148. Thiazol-5-ylmethyl 4- [2- (4-cyano-3-f luorophenoxy) -
ethyl ]piperidine-l-carboxylate
149. Thiazol-5-ylmethyl 4- [2- (biphenyl-2-yloxy) ethyl] -
piperidine-l-carboxylate
150. Thiazol-5-ylmethyl 4- [2- (biphenyl-3-yloxy) ethyl] -
piperidine-l-carboxylate
151. Thiazol-5-ylmethyl 4- [2- (3- {trif luoromethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate
152. Thiazol-5-ylmethyl 4- [2- (4-benzylphenoxy) ethyl] -
piperidine-l-carboxylate
153. Thiazol-5-ylmethyl 4- [2- (2-ethoxyphenoxy) ethyl] -
piperidine-l-carboxylate
154. Thiazol-5-ylmethyl 4- [2- (2-cyclopentylphenoxy) ethyl] -
piperidine-l-carboxylate
155. Thiazol-5-ylmethyl 4- {2- [4- (1-methyl-l-phenylethyl )-
phenoxy] ethyl }piperidine-l-carboxylate
156. Thiazol-5-ylmethyl 4- [2- (4-phenoxyphenoxy) ethyl] -
piperidine-l-carboxylate
157. Thiazol-5-ylmethyl 4- [2- (2-bromo-4-f luorophenoxy) -
ethyl ]piperidine-l-carboxylate
158. Thiazol-5-ylmethyl 4- [2- (4- {pyrrol-l-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate
159. Thiazol-5-ylmethyl 4- [2- (3-cyanophenoxy) ethyl] -
piperidine-l-carboxylate
160. Thiazol-5-ylmethyl 4- [2- (3, 5-di {tert-butyl jphenoxy) -
ethyl] piperidine-l-carboxylate
161. Thiazol-5-ylmethyl 4- [2- (2-benzylphenoxy) ethyl] -
piperidine-l-carboxylate
162. Thiazol-5-ylmethyl 4- [2- (2- {benzyloxy jphenoxy) ethyl] -
piperidine-l-carboxylate
163. Thiazol-5-ylmethyl 4- [2- (2-cyanoquinolin-8-yloxy) -
ethyl ]piperidine-l-carboxylate
164. Thiazol-5-ylmethyl 4- [2- (3- {methoxycarbonyl }naphth-2-
yloxy) ethyl ]piperidine-l-carboxylate
165. Thiazol-5-ylmethyl 4- [2- (3-phenoxyphenoxy) ethyl] -
piperidine-l-carboxylate
166. Thiazol-5-ylmethyl 4- [2- (4-chloro-2-cyanophenoxy) -
ethyl ]piperidine-l-carboxylate
167. Thiazol-5-ylmethyl 4- [2- (isoquinolin-7-yloxy) ethyl] -
piperidine-l-carboxylate
168. Thiazol-5-ylmethyl 4- [2- (4- {hexyloxy jphenoxy) ethyl] -
piperidine-l-carboxylate
169. Thiazol-5-ylmethyl 4- [2- (3-butoxyphenoxy) ethyl] -
piperidine-l-carboxylate
170. Thiazol-5-ylmethyl 4- [2- (4-chloro-5-isopropyl-2-
methylphenoxy) ethyl] piperidine-l-carboxylate
171. Thiazol-5-ylmethyl 4- [2- (2-methylbenzothiazol-5-
yloxy) ethyl ]piperidine-l-carboxylate
172. Thiazol-5-ylmethyl 4- [2- (quinolin-5-yloxy) ethyl] -
piperidine-l-carboxylate
173. Thiazol-5-ylmethyl 4- [2- (3- {pentafluoroethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate
174. Thiazol-5-ylmethyl 4- [2- (5-bromo-2-chlorophenoxy) -
ethyl ]piperidine-l-carboxylate
175. Thiazol-5-ylmethyl 4- [2- (4- {difluoromethoxy jphenoxy) -
ethyl] piperidine-l-carboxylate
176. Thiazol-5-ylmethyl 4- [2- (4 '-cyanobiphenyl-3-yloxy) -
ethyl ]piperidine-l-carboxylate
177. Thiazol-5-ylmethyl 4- [2- (6-cyanonaphth-2-yloxy) -
ethyl ]piperidine-l-carboxylate
178. Thiazol-5-ylmethyl 4- [2- (4- {thiazol-2-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate
179. Thiazol-5-ylmethyl 4- [2- (7-methoxynaphth-2-yloxy) -
ethyl ]piperidine-l-carboxylate
180. Thiazol-5-ylmethyl 4- [2- (4-chloro-2- {isoxazol-5-yl }-
phenoxy) ethyl ]piperidine-l-carboxylate
181. Thiazol-5-ylmethyl 4- [2- (2-carbamoyl-4-chlorophenoxy)
ethyl ]piperidine-l-carboxylate
182. Thiazol-5-ylmethyl 4- [2- (5- {acetylamino }naphth-2-
yloxy) ethyl ]piperidine-l-carboxylate
183. Thiazol-5-ylmethyl 4- [2- (4 '-cyanobiphenyl-4-yloxy) -
ethyl ]piperidine-l-carboxylate
184. Thiazol-5-ylmethyl 4- [2- (4- {methanesulphonyl }-
phenoxy) ethyl ]piperidine-l-carboxylate
185. Thiazol-5-ylmethyl 4- [2- (5-acetylamino-2-propylphenoxy)
ethyl] piperidine-l-carboxylate
186. Thiazol-5-ylmethyl 4- [2- (-indol- 6-yloxy) ethyl] -
piperidine-l-carboxylate
187. Thiazol-5-ylmethyl 4- {2- [4-fluoro-2- (lH-pyrazol-3-
yl) phenoxy] ethyl }piperidine-l-carboxylate
188. Thiazol-5-ylmethyl 4- [2- (4-cyano-2-f luorophenoxy) -
ethyl ]piperidine-l-carboxylate
189. Thiazol-5-ylmethyl 4- [2- (2-isopropyl-5-methylphenoxy)
ethyl ]piperidine-l-carboxylate
190. Thiazol-5-ylmethyl 4- [2- (2- {morpholin-4-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
191. Thiazol-5-ylmethyl 4- [2- (2-methylquinolin-6-yloxy) -
ethyl ]piperidine-l-carboxylate
192. Thiazol-5-ylmethyl 4- {2- [4- (2-oxopyrrolidin-l-yl )-
phenoxy] ethyl }piperidine-l-carboxylate
193. Thiazol-5-ylmethyl 4- [2- (3- {tetrazol-l-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate
194. Thiazol-2-ylmethyl (R) -3- (naphth-2-yloxymethyl) -
pyrrolidine-l-carboxylate (enantiomer I )
195. Thiazol-2-ylmethyl (S) -3- (naphth-2-yloxymethyl) -
pyrrolidine-l-carboxylate (enantiomer II)
196. Thiazol-2-ylmethyl (+/-) -3- (5-chloronaphth-2-yloxymethyl
)pyrrolidine-l-carboxylate
197. Thiazol-2-ylmethyl (+/-) -3- ( '-fluorobiphenyl-4-
yloxymethyl )pyrrolidine-l-carboxylate
198. 3-Carbamoylisoxazol-5-ylmethyl 4- [2- (4-f luorophenoxy)
ethyl ]piperidine-l-carboxylate
199. 3-Carbamoylisoxazol-5-ylmethyl 4- [2- (4- {trif luoromethoxy
jphenoxy) ethyl ]piperidine-l-carboxylate
200. 3-Carbamoylisoxazol-5-ylmethyl (-) - (R) -3- (naphth-2-
yloxymethyl) pyrrolidine-l-carboxylate (enantiomer I )
201. 3-Carbamoylisoxazol-5-ylmethyl (+/-) -3- (6-methoxynaphth-
2 -yloxymethyl )pyrrolidine-l-carboxylate
202. 3-Carbamoylisoxazol-5-ylmethyl (+) - (S) -3- (naphth-2-
yloxymethyl) pyrrolidine-l-carboxylate (enantiomer II).
The compounds of general formulae (I), (Ii) and (Iii) can
comprise one or more asymmetric carbon atoms. They can exist
in the form of enantiomers or diastereoisomers . These
enantiomers and diastereoisomers and their mixtures, including
the racemic mixtures, come within the invention.
The compounds of formulae (I), (Ii) and (Iii) can exist in the
form of bases or of addition salts with acids. Such addition
salts come within the invention.
These salts are advantageously prepared with pharmaceutically
acceptable acids but the salts of other acids, for example of
use in the purification or the isolation of the compounds of
formulae (I), (Ii) and (Iii), also come within the invention.
The compounds of formulae (I), (Ii) and (Iii) and/or salts
thereof may form solvates or hydrates and the invention
includes all such solvates and hydrates.
The term « hydrates » and « solvates » mean that the compounds
of formulae (I), (Ii) and (Iii) according to the invention can
be combined or associated with one or more water or solvent
molecules. This is only a chemical characteristic of such
compounds, which can be applied for all organic compounds of
this type.
In the context of the invention:
- Ct-z where t and z can take the values from 1 to 8 , is
understood to mean a carbon-comprising chain which can have
from t to z carbon atoms, for example C 1-3 is understood to
mean a carbon-comprising chain which can have from 1 to 3
carbon atoms;
- alkyl is understood to mean a saturated and linear or
branched aliphatic group; for example, a Ci-6 -alkyl group
represents a linear or branched carbon-comprising chain of 1
to 6 carbon atoms, more particularly a methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl;
- alkylene is understood to mean a saturated and linear or
branched divalent alkyl group; for example, a Ci-3 -alkylene
group represents a linear or branched divalent carboncomprising
chain of 1 to 3 carbon atoms, more particularly a
methylene, ethylene, 1-methylethylene or propylene;
- cycloalkyl is understood to mean a cyclic alkyl group; for
example, a C3-7 -cycloalkyl group represents a cyclic carboncomprising
group of 3 to 7 carbon atoms, more particularly a
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl;
- alkoxy is understood to mean an -O-alkyl group comprising a
saturated and linear or branched aliphatic chain;
- thioalkyl is understood to mean an -S-alkyl group comprising
a saturated and linear or branched aliphatic chain;
- haloalkyl is understood to mean an alkyl group, one or more
hydrogen atoms of which have been replaced by a halogen atom;
- haloalkoxy is understood to mean an alkoxy group, one or more
hydrogen atoms of which have been replaced by a halogen atom;
- halothioalkyl is understood to mean a thioalkyl group, one or
more hydrogen atoms of which have been replaced by a halogen
atom;
- halogen atom is understood to mean a fluorine, a chlorine, a
bromine or an iodine;
- TFA is understood to mean trifluoroacetic acid;
- ACN is understood to mean acetonitrile .
Within the meaning of the present invention, it should be
noted that the terms "ranging from ... to ..." and "between ... and
..." mean that the limits are also considered.
The term « preventing » , as used herein, means reducing the
risk of onset or slowing the occurrence of a given phenomenom,
namely in the present invention, a pathology in which
endogenous cannabinoids and/or other substrates metabolized by
the enzyme FAAH are involved such as the pathologies as
defined below.
Another subject-matter of the invention is targeted at a
process for the preparation of the compounds of formula (I)
according to the invention, comprising the stage consisting in
reacting an amine derivative, a compound of following general
formula (II):
(II)
in which R , ¾ , A , n and m are as defined in the formula (I)
defined above,
with a carbonate of following general formula (III) :
(Ill)
in which Z represents a hydrogen atom or a nitro group and R 3
and R are as defined in the general formula (I) defined above,
in the presence of a base, such as triethylamine,
pyridine, N ,W-dimethylaminopyridine or N ,W-diisopropylethylamine,
in an organic solvent, such as toluene,
acetonitrile or dichloroethane, at a temperature between
ambient temperature and the reflux temperature of the solvent.
In addition, the compounds of the invention can be prepared
according to different methods illustrated by the following
schemes. These methods and the intermediate compounds used are
also a subject-matter of the present invention.
If appropriate, a compound of formula (II) can be protected,
in particular at its amine functional group, according to
methods well known to a person skilled in the art.
Mention may be made, as examples of protective groups and also
of protecting and deprotecting methods, of the work
"Protective Groups in Organic Synthesis" , Green et al ., 2nd
Edition (John Wiley & Sons, Inc., New York) .
A preparation process employing a protected compound of
formula (II) is, for example, described in the following
Scheme 1 .
As regards more particularly the compounds of general formula
(I) in which A more particularly represents an oxygen atom or
an -O-Ci-6-alkylene group, they can also be prepared according
to the procedure described in the following Scheme 1 .
This preparation method (Scheme 1 ) consists in reacting, in a
first step, an alcohol of general formula (Ila), in which ¾ , m
and n are as defined in the general formula (I) as defined
above, G represents a portion of the group A as defined in the
general formula (I), namely either a covalent bond or the C -
alkylene portion of the -O-Ci-6-alkylene group, and PG
represents a protective group, such as a Boc (tertbutyloxycarbonyl
), a Cbz (benzyloxycarbonyl) , a benzyl or a
benzhydryl ;
- either with an alcohol derivative of general formula
(IV), in which R is as defined above, using the Mitsunobu
reaction conditions (Synthesis, 1981, 1-28),
or with a halogenated derivative of general formula
(IVa), in which R is as defined above and X represents a
fluorine, chlorine, bromine or iodine atom, using aromatic
or heteroaromatic nucleophilic substitution reactions or
Buchwald O-arylation or O-heteroarylation reactions, for
example using a palladium or copper catalyst;
followed b y a deprotection reaction, for example in the
presence of trif luoroacetic acid or of a solution of
hydrochloric acid in isopropanol or dioxane, to result in the
amine of general formula (lib) in which G , R2, and n are as
defined in the amine of formula (Ila) above and R is as
defined in the general formula (I) as defined above. An
alternative to the Mitsunobu reaction consists in reacting an
alcohol derivative of general formula (IV) with a compound
said to be of general formula (He) and deriving from the
activation by a tosylate group of the alcohol functional group
of a compound of general formula (Ha) . The derivative of
general formula (lib) thus obtained is subsequently converted
to the 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.
An alternative form of producing the compounds of general
formula (I) (Scheme 1 ) in which A more particularly represents
an oxygen atom or an -O-Ci-6-alkylene group consists in
deprotecting an alcohol of general formula (Ha) as defined
above, according to a deprotection reaction as defined above,
in order to obtain an aminoalcohol of general formula (He),
and in then reacting this aminoalcohol of general formula
(He) in which R2, m and n are as defined in the general
formula (I) defined above and G represents a portion of the
group A as defined in the general formula (I), namely either a
covalent bond or the Ci-6-alkylene portion of the -O-Ci-6 -
alkylene group, with a carbonate of general formula (HI) as
defined above under the conditions described above, to result
in the carbamate derivative of general formula (la) in which
R2, R3, R4, m and n are as defined in the general formula (I)
defined above and G represents a portion of the group A as
defined in the general formula (I), namely either a covalent
bond or the Ci-6-alkylene portion of the -O-Ci-6-alkylene group.
The carbamate derivative (la) thus obtained is subsequently
converted to the compound of general formula (I) by the action
of an alcohol of general formula RiOH (IV) as defined above by
using the Mitsunobu reaction conditions or by the action of a
halogenated derivative of general formula R (IVa) as defined
above by using aromatic or heteroaromatic nucleophilic
substitution reactions or Buchwald O-arylation or 0-
heteroarylation reactions, for example using a palladium or
copper catalyst.
As regards more particularly the compounds of general formula
(I) in which R represents an R5 group substituted in
particular by an R group of Ci-6-alkyl, C 3- -cycloalkyl or C3-7-
cycloalkyl-Ci-3-alkylene type or by an R group as defined in
the general formula (I) defined above, they can also be
prepared according to the procedure described in the following
Scheme 2 .
Suzuki
or Stille
or Negishi
(I)
Thus, the first stage consists in reacting an amine of general
formula (lid), in which A , R2, R5, m and n are as defined in
the general formula (I) defined above and U i 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, to result in the carbamate
derivative of general formula (lb) in which A , ¾ , R3, R , R5,
and n are as defined in the general formula (I) defined above
and U i is as defined above. The coupling reaction catalysed by
means of a transition metal, such as palladium (0), is
subsequently carried out on the key intermediate of general
formula (lb) as defined above, U i being in the position where
it is desired to introduce the R or R group (Scheme 2 ) :
- either by a reaction of Suzuki type, for example using an
alkyl-, cycloalkyl-, aryl- or heteroarylboronic acid,
- or according to a reaction of Stille type, for example using
a trialkylaryltin or trialkylheteroaryltin derivative,
or by a reaction of Negishi type, for example using an
alkyl-, cycloalkyl-, aryl- or heteroarylzinc halide
derivative .
Alternatively, the other compounds of general formulae (II),
(Ila), (lib), (He), (lid), (III), (IV) and (IVa) and the
other reactants are commercially available or are described in
the literature or else can be prepared according to methods
which are described therein or which are known to a person
skilled in the art.
Another subject-matter of the present invention
compounds of general formula (la) :
in which R2, R3, R , m and n are as defined in the general
formula (I) and G represents a portion of the group A as
defined in the general formula (I), namely either a covalent
bond or the Ci-6 -alkylene portion of the -O-Ci-6 -alkylene group.
Mention may be made, among these compounds, of:
• thiazol-2-ylmethyl 4- (2-hydroxyethyl) piperidine-1-
carboxylate
• thiazol-4-ylmethyl 3- (hydroxymethyl) pyrrolidine-1-
carboxylate .
Another subject-matter of the present invention is the
compounds of general formula (II) :
(ID
in which A , R , ¾ , m and n are as defined in the general
formula (I).
Mention may be made, among these compounds, of:
• 4- [2- (4-chloronaphth-l-yloxy) ethyl] piperidine
• 3- (6-methoxynaphth-2-yloxymethyl) pyrrolidine
• 3 '- (pyrrolidin-3-ylmethoxy) biphenyl-3-carbonitrile
• 3- (5-chloronaphth-2-yloxymethyl) pyrrolidine
• 3- (3- {trifluoromethoxy jphenoxymethyl) pyrrolidine
• 3- [4- (1-methyl-l-phenylethyl) phenoxymethyl] pyrrolidine
• 7- (pyrrolidin-3-ylmethoxy) quinoline
• 3- (pyrrolidin-3-ylmethoxy) quinoline
• 3- (4-chloro-3- {trifluoromethyl jphenoxymethyl) pyrrolidine
• 7- (pyrrolidin-3-ylmethoxy) isoquinoline
• 3- (5-fluoronaphth-2-yloxymethyl) pyrrolidine
• 3- (4 '-fluorobiphenyl-4-yloxymethyl) pyrrolidine
The following examples illustrate the preparation of some
compounds of the invention. These examples are not limiting
and serve only to illustrate the invention. The NMR spectra
and/or the LC-MS (Liquid Chromatography-Mass Spectroscopy)
confirm the structures and the purities 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 shown in brackets in the titles of the examples
correspond to those in the 1st column of the tables below.
The IUPAC (International Union of Pure and Applied Chemistry)
nomenclature was used in the naming of the compounds in the
examples below.
Example 1 (Compound No. 17)
Thiazol-4-ylmethyl 3- (naphth-2-yloxymethyl) pyrrolidine- 1-
carboxylate
1.1 Thiazol-4-ylmethyl 3- (hydroxymethyl) pyrrolidine-1-
carboxylate
A solution of 3.00 g (10.70 mmol) of thiazol-4-ylmethyl 4-
nitrophenyl carbonate in 2 0 ml of dichloromethane is added at
ambient temperature, via a dropping funnel, to a solution of
1.13 g (11.24 mmol) of pyrrolidin-3-ylmethanol (commercial) in
2 0 ml of methanol. The solution is stirred for 15 hours. Water
is subsequently added to the reaction medium. After extraction
of the aqueous phase with dichloromethane, the organic phases
are successively washed with a 1M aqueous sodium hydroxide
solution and then with a saturated aqueous sodium chloride
solution. After having dried the organic phases over sodium
sulphate, the mixture is filtered and the filtrate is
evaporated to dryness. 0.56 g of the desired product is thus
obtained in the form of an oil after purification on a column
of silica gel, elution being carried out with a
dichloromethane/methanol (97/3 to 95/5) mixture.
1.2 Thiazol-4-ylmethyl 3- (naphth-2-yloxymethyl) pyrrolidine-1-
carboxylate
0.25 g (1.03 mmol) of thiazol-4-ylmethyl 3-
(hydroxymethyl) pyrrolidine-l-carboxylate is dissolved in 8 m l
of toluene. 0.35 g (1.34 mmol) of triphenylphosphine and
0.16 g (1.13 mmol) of naphth-2-ol are added and then the
medium is cooled to 0°C for slow addition of a solution of
0.27 g (1.34 mmol) of diisopropyl azodicarboxylate in 2 m l of
toluene. The medium is stirred at ambient temperature for
14 hours. The residue obtained is taken up in water and
extracted twice with dichloromethane . The combined organic
phases are washed with a saturated aqueous sodium chloride
solution, dried over sodium sulphate, filtered and
concentrated under vacuum. The residue is purified by
chromatography on silica gel, elution being carried out with a
99/1 to 98/2 mixture of dichloromethane and methanol. 0.15 g
of the expected product is obtained in the form of a powder.
M.p. (°C) : 90-92
LC-MS: M+H = 369
H NMR (d 6-DMSO) (ppm) : 9.10 (s, 1H) ; 7.85 (m, 3H) ; 7.70 (m,
1H) ; 7.50 (m, 1H) ; 7.35 (m, 2H) ; 7.20 (m, 1H) ; 5.20 (s, 2H) ;
4.10 (m, 2H) ; 3.60 (m, 1H) ; 3.50 (m, 1H) ; 3.40 (m, 1H) ; 3.30
(m, 1H) ; 2.70 (m, 1H) ; 2.10 (m, 1H) ; 1.80 (m, 1H)
Example 2 (Compound No. 22)
Thiazol-4-ylmethyl 3- ( '-fluorobiphenyl -4-yloxyme thyl) -
pyrrolidine- 1-carboxylate
2.1 tert-Butyl 3- (4 '-fluorobiphenyl-4-yloxymethyl) pyrrolidine-
1-carboxylate
The procedure is the same as for Example 1 (Stage 1.2)
starting from 1.50 g (7.45 mmol) of tert-butyl 3-
(hydroxymethyl) pyrrolidine-l-carboxylate (commercial), 2.15 g
(11.18 mmol) of 4 '-fluorobiphenyl-4-ol, 2 .93 g (11.18 mmol) of
triphenylphosphine and 2.26 g (11.18 mmol) of diisopropyl
azodicarboxylate . After purification by chromatography on a
column of silica gel, elution being carried out with
dichloromethane, 1.55 g of the expected product are obtained
in the form of an oil.
2.2 3- (4 '-Fluorobiphenyl-4-yloxymethyl) pyrrolidine
1.55 g (4.17 mmol) of tert-butyl 3- (4 '-fluorobiphenyl-4-
yloxymethyl) pyrrolidine-l-carboxylate are dissolved in 40 m l
of dichloromethane and then, at 0°C, 6.00 ml (80.77 mmol) of
trif luoroacetic acid are subsequently added. After stirring at
ambient temperature for two hours, the mixture is concentrated
to dryness and then the residue is taken up in water and
dichloromethane. A saturated sodium hydrogencarbonate solution
is added and then the aqueous phase is extracted with
dichloromethane. The combined organic phases are washed with a
saturated aqueous sodium chloride solution, dried over sodium
sulphate, filtered and concentrated under vacuum. 0.98 g of
product is obtained in the form of an oil, used as is in the
following stage.
2.3 Thiazol-4-ylmethyl 3- (4 '-fluorobiphenyl-4-yloxymethyl) -
pyrrolidine-l-carboxylate
0.30 g (1.07 mmol) of thiazol-4-ylmethyl 4-nitrophenyl
carbonate, 0.34 g (1.28 mmol) of 3- (4 '-fluorobiphenyl-4-
yloxymethyl) pyrrolidine, 0.20 g (1.61 mmol) of N,Ndiisopropylethylamine
and 0.01 g (0.11 mmol) of
dimethylaminopyridine are dissolved in 10 m l of 1,2-
dichloroethane . The mixture is stirred at 70°C for 4 hours.
After returning to ambient temperature, water is added to the
reaction medium. After extraction of the aqueous phase with
dichloromethane, the organic phases are successively washed
three times with a 1M aqueous sodium hydroxide solution and
then twice with a saturated aqueous ammonium chloride
solution. After having dried the organic phases over sodium
sulphate, they are filtered and the filtrate is evaporated to
dryness. After purification by chromatography on a column of
silica gel, elution being carried out with dichloromethane and
methanol (98/2), 0.16 g of the expected product is obtained in
the form of a powder.
M.p. (°C) : 115-117
LC-MS: M+H = 413
H NMR (d 6-DMSO) (ppm) : 9.10 (s, 1H) ; 7.70 (m, 3H) ; 7.60 (d,
2H) ; 7.30 (m, 2H) ; 7.05 (m, 2H) ; 5.20 (s, 2H) ; 4.05 (m, 2H) ;
3.60 (m, 1H) ; 3.50 (m, 1H) ; 3.35 (m, 1H) ; 3.20 (m, 1H) ; 2.70
(m, 1H) ; 2.10 (m, 1H) ; 1.80 (m, 1H)
Example 3 (Compound No. 200)
3-Carbamoylisoxazol-5-ylmethyl (-) - (R) -3- (naphth-2-yloxymethyl)
pyrrolidine-l-carboxylate
3.1 tert-Butyl (R) -3- (naphth-2-yloxymethyl) pyrrolidine-lcarboxylate
The procedure is the same as for Example 1 (Stage 1.2)
starting from 2.00 g (9.94 mmol) of tert-butyl (R) -3-
(hydroxymethyl) pyrrolidine-l-carboxylate (commercial), 2.00 g
(13.91 mmol) of naphth-2-ol, 3.90 g (14.91 mmol) of
triphenylphosphine and 3.01 g (14.91 mmol) of diisopropyl
azodicarboxylate . 1.75 g of product are obtained in the form
of an oil after purification on a column of silica gel,
elution being carried out with dichloromethane .
3 .2 (R) -3- (naphth-2-yloxymethyl) pyrrolidine
The procedure is the same as for Example 2 (Stage 2.2)
starting from 1.75 g (5.34 mmol) of tert-butyl (R) -3- (naphth-
2-yloxymethyl) pyrrolidine-l-carboxylate and 5.00 m l
(67.31 mmol) of trif luoroacetic acid. 1.20 g of product are
obtained in the form of an oil.
3.3 3-Carbamoylisoxazol-5-ylmethyl 4-nitrophenyl carbonate
2.84 g (14.07 mmol) of 4-nitrophenyl chlorof ormate are added
in small portions to a solution, cooled to approximately 0°C,
of 2.00 g (14.07 mmol) of 3-carbamoylisoxazol-5-ylmethanol ,
1.71 m l (21.11 mmol) of pyridine and 0.17 g (1.41 mmol) of
N N -dimethylaminopyridine in 15 m l of dichloromethane. The
medium is kept stirred at 0°C for 1 hour and then at ambient
temperature for 1 hour. The precipitate formed is filtered off
and then copiously rinsed with diisopropyl ether. After drying
under vacuum at approximately 60°C, 3.12 g (72%) of the
expected product are obtained in the form of a white solid
used as is in the following stage.
M.p. (°C) : 143-145
H NMR (d 6-DMSO, 400 MHz) (ppm) : 8.40 (d, 2H) ; 8.25 (broad s ,
1H) ; 7.90 (broad s , 1H) ; 7.65 (d, 2H) ; 7.0 (s, 1H) ; 5.50 (s,
2H) .
3.4 3-Carbamoylisoxazol-5-ylmethyl (-) - (R) -3- (naphth-2-yloxymethyl
)pyrrolidine-l-carboxylate
0.21 g (0.92 mmol) of (R) -3- (naphth-2-yloxymethyl) pyrrolidine
is dissolved in 3.80 m l of dichloromethane and then 0.31 g
(1.01 mmol) of 3-carbamoylisoxazol-5-ylmethyl 4-nitrophenyl
carbonate and 0.15 m l (1.38 mmol) of N-methylmorpholine are
added. The mixture is stirred at ambient temperature for
2 0 hours and then water is added to the reaction medium. After
extraction of the aqueous phase with dichloromethane, the
organic phases are successively washed three times with a 1M
aqueous sodium hydroxide solution and then twice with a
saturated aqueous ammonium chloride solution. After having
dried the organic phases over sodium sulphate, they are
filtered and the filtrate is evaporated to dryness. 0.14 g of
the desired product is thus obtained in the form of a white
solid after purification on a column of silica gel, elution
being carried out with a dichloromethane/methanol mixture, and
then taken up in isopropyl ether.
M.p. (°C) : 138-140
LC-MS: M+H = 396
H NMR (d 6-DMSO) (ppm) : 8.15 (broad s , 1H) ; 7.80 (m, 4H) ;
7.50 (m, 1H) ; 7.35 (m, 2H) ; 7.20 (m, 1H) ; 6.80 (s, 1H) ; 5.30
(s, 2H) ; 4.10 (m, 2H) ; 3.65 (m, 1H) ; 3.50 (m, 1H) ; 3.40 (m,
1H) ; 3.30 (m, 1H) ; 2.80 (m, 1H) ; 2.10 (m, 1H) ; 1.85 (m, 1H)
] 20°c _7 9 1 7 ° c = 0.312; DMSO, 589 nm)
Example 4 (Compound No. 202)
3-Carbamoylisoxazol-5-ylmethyl (+) - (S) -3- (naphth-2-yloxymethyl
)pyrrolidine- 1-carboxylate
4.1 tert-Butyl (S) -3- (naphth-2-yloxymethyl) pyrrolidine-1-
carboxylate
The procedure is the same as for Example 1 (Stage 1.2)
starting from 2.00 g (9.94 mmol) of tert-butyl (S)-3-
(hydroxymethyl) pyrrolidine-l-carboxylate (commercial), 2.00 g
(13.91 mmol) of naphth-2-ol, 3.90 g (14.91 mmol) of
triphenylphosphine and 3.01 g (14.91 mmol) of dnsopropyl
azodicarboxylate . 2.80 g of product are obtained in the form
of an oil after purification on a column of silica gel,
elution being carried out with dichloromethane .
4.2 (S) -3- (Naphth-2-yloxymethyl) pyrrolidine
The procedure is the same as for Example 2 (Stage 2.2)
starting from 1.75 g (5.34 mmol) of tert-butyl (S) -3- (naphth-
2-yloxymethyl) pyrrolidine-l-carboxylate and 5.00 m l
(67.31 mmol) of trif luoroacetic acid. The product is obtained
in the form of an oil after purification on a column of silica
gel, elution being carried out with a
dichloromethane/methanol/aqueous ammonia (90/9/1) mixture.
4.3 3-Carbamoylisoxazol-5-ylmethyl (+) - (S) -3- (naphth-2-yloxymethyl
)pyrrolidine-l-carboxylate
The procedure is the same as for Example 3 (Stage 3.4)
starting from 0.21 g (0.95 mmol) of (S) -3- (naphth-2-
yloxymethyl) pyrrolidine, 0.32 g (1.04 mmol) of 3-
carbamoylisoxazol-5-ylmethyl 4-nitrophenyl carbonate (Stage
4.3) and 0.16 m l (1.42 mmol) of N-methylmorpholine . 0.21 g of
a powder is obtained after purification on a column of silica
gel, elution being carried out with a dichloromethane/methanol
mixture, and trituration from isopropyl ether.
M.p. (°C) : 139-141
LC-MS: M+H = 396
H NMR (d 6-DMSO) (ppm) : 8.15 (broad s , 1H) ; 7.80 (m, 4H) ;
7.50 (m, 1H) ; 7.35 (m, 2H) ; 7.20 (m, 1H) ; 6.80 (s, 1H) ; 5.30
(s, 2H) ; 4.10 (m, 2H) ; 3.65 (m, 1H) ; 3.50 (m, 1H) ; 3.40 (m,
1H) ; 3.30 (m, 1H) ; 2.80 (m, 1H) ; 2.10 (m, 1H) ; 1.85 (m, 1H)
2o°c +9.944° c = 0.036; DMSO, 589 nm)
The chemical structures and the physical properties of some
compounds according to the invention are illustrated in the
following Table 1 . In this table, the compounds are in the
free base or salt form.
* A represents an -O-Ci-6-alkylene group in which the end
represented by an oxygen atom is bonded to the R group.
Table 1
(I)

Base or
R m n A* R2 R R4 salt
N base
2 2 -OCH2CH2- H H
N base XX 2 2 -OCH2CH2- H H
base
N
2 2 -OCH2CH2- H H
Me e Me
base
N
2 2 -OCH2CH2- H H
base
N
2 2 -OCH2CH2- H H
CN base
N
2 2 -OCH2CH2- H H
base
N
2 2 -OCH2CH2- H H
N base
2 2 -OCH2CH2- H H
CN N base
2 2 -OCH2CH2- H H
N base
2 2 -OCH2CH2- H H

The results of the H NMR analyses and the melting points
(M.p.) for the compounds in Table 1 are given in the following
Table 2 .
Table 2
M.p.
N ° NMR 400 MHz d6-DMSO/CDCl3
(°C)
8.25 (m, 2H); 7.80 (d, IH); 7.60 (m, 2H); 7.50 (d, IH); 7.40 (d, IH); 6.70
1 (d, IH); 5.45 (s, 2H); 4.20 (m, 4H); 2.90 (m, 2H); 1.80 (m; 5H); 1.30 (m, oil
2H)
7.80 (d, IH); 7.70 (d, IH); 7.10 (m, 2H); 6.90 (m, 2H); 5.35 (s, 2H); 4.00 oil
(m, 2H); 2.85 (m, 2H); 1.70 (m, 5H); 1.10 (m, 2H)
8.80 (s, IH); 7.40 (s, IH); 7.00 (m, 2H); 6.85 (m, 2H); 5.30 (s, 2H); 4.20
76-78
(m, 2H); 4.00 (m, 2H); 2.80 (m, 2H); 1.70 (m, 5H); 1.25 (m, 2H)
9.10 (s, IH), 7.65 (s, IH); 7.60 (d, 2H); 7.10 (d, 2H); 5.20 (s, 2H); 4.10 (m,
oil
2H); 4.00 (m, 2H); 2.80 (m, 2H); 1.70 (m, 5H); 1.15 (m, 2H)
9.10 (s, IH); 7.65 (s, IH); 7.30 (d, 2H); 6.90 (d, 2H); 5.10 (s, 2H); 3.90 (m,
53-55
4H); 2.80 (m, 2H); 1.70 (m, 4H); 1. 10 (m, 2H)
8.80 (s, IH); 7.90 (s, IH); 7.00 (m, 2H); 6.80 (m, 2H); 5.30 (s, 2H); 4.20
96-98
(m, 2H); 4.00 (m, 2H); 2.80 (m, 2H); 1.75 (m, 6H); 1.20 (m, 2H)
9.10 (s, IH); 7.90 (s, IH); 7.30 (d, 2H); 6.95 (d, 2H); 5.30 (s, 2H); 3.90 (m,
93-97
4H); 2.80 (m, 2H); 1.60 (m, 6H); 1. 10 (m, 2H)
9.10 (s, IH); 7.95 (s, IH); 7.60 (d, 2H); 7.10 (d, 2H); 5.30 (s, 2H); 4.10 (m,
47-49
2H); 3.95 (m, 2H); 2.80 (m, 2H); 1.65 (m, 6H); 1.10 (m, 2H)
9.10 (s, IH); 7.75 (s, IH); 7.70 (m, 2H); 7.20 (m, 2H); 6.95 (m, 2H); 5.15
(s, 2H); 4.10 (m, 2H); 4.00 (m, 2H); 3.80 (s, 3H); 2.80 (m, 2H); 1.70 (m, 95-97
5H); 1.15 (m, 2H)
8.80 (s, IH); 7.60 (d, 2H); 7.40 (s, IH); 6.95 (d, 2H); 5.30 (s, 2H); 4.20 (m,
108-1 10
2H); 4.05 (m, 2H); 2.80 (m, 2H); 1.75 (m, 5H); 1.20 (m, 2H)
8.80 (s, IH); 7.65 (m, 2H); 7.40 (s, IH); 7.10 (m, 4H), 5.30 (s, 2H); 4.05 (m,
2H); 3.90 (s, 3H); 3.80-3.35 (m, 4H); 2.80 (m, IH); 2.20 (m, IH); 1.90 (m, 128-130
IH)
8.80 (s, IH); 7.70 (m, 2H); 7.40 (s, IH); 7.05 (m, 4H), 5.35 (s, 2H); 4.10 (m,
2H); 3.90 (s, 3H); 3.80 (m, IH); 3.65 (m, IH); 3.55 (m, IH); 3.40 (m, IH); 112-1 14
2.80 (m, IH); 2.20 (m, IH); 1.90 (m, IH)
8.80 (s, IH); 7.40 (s, IH); 7.35 (d, IH); 7.00 (s, IH); 6.75 (d, IH); 5.30 (s,
2H); 3.90 (m, 2H); 3.70 (m, IH); 3.60 (m, IH); 3.50 (m, IH); 3.30 (m, IH); 78-80
2.70 (m, IH); 2.10 (m, IH); 1.80 (m, IH)
8.80 (s, IH); 7.65 (m, 2H); 7.40 (s, IH); 7.10 (m, 4H); 5.30 (s, 2H); 4.20
(m, 2H); 4.10 (m, 2H); 3.90 (s, 3H); 2.80 (m, 2H); 1.80 (m, 5H); 1.25 (m, 100-102
2H)
8.80 (s, IH); 7.80 (m, 3H); 7.45 (m, IH); 7.40 (m, 2H); 7.15 (m, 2H); 5.30
(s, 2H); 4.25 (m, 2H); 4.20 (m, 2H); 2.90 (m, 2H); 1.85 (m, 5H); 1.25 (m, 88-90
2H)
9.10 (m, IH); 8.50 (m, 2H); 7.95 (m, IH); 7.85 (m, IH); 7.75 (d, IH); 7.70
(m, IH); 7.00 (d, IH); 5.60 (s, 2H); 4.40 (m, 2H); 4.10 (m, IH); 4.00 (m, 84-86
IH); 3.85 (m, IH); 3.70 (m, IH); 3.20 (m, IH); 2.50 (m, IH); 2.30 (m, IH)
9.10 (s, IH); 7.85 (m, 3H); 7.70 (m, IH); 7.50 (m, IH); 7.35 (m, 2H); 7.20
(m, IH); 5.20 (s, 2H); 4.10 (m, 2H); 3.60 (m, IH); 3.50 (m, IH); 3.40 (m, 90-92
IH); 3.30 (m, IH); 2.70 (m, IH); 2.10 (m, IH); 1.80 (m, IH)
8.80 (s, IH); 7.50 (m, 4H); 7.40 (s, IH); 7.10 (m, 2H); 6.95 (d, 2H); 5.30 (s,
62-64
2H); 4.20 (m, 2H); 4.10 (m, 2H); 2.85 (m, 2H); 1.80 (m, 5H); 1.25 (m, 2H)
9.10 (s, IH); 9.05 (m, IH); 8.80 (d, IH); 8.20 (d, IH); 7.90 (m, IH); 7.70
(m, 3H); 5.20 (s, 2H); 4.25 (m, 2H); 4.00 (m, 2H); 2.85 (m, 2H); 1.80 (m, 140-150
5H); 1.15 (m, 2H)
9.70 (s, IH); 9.10 (s, IH); 8.60 (d, IH); 8.45 (d, IH); 8.30 (d, IH); 7.80 (s,
IH); 7.70 (m, 2H); 5.20 (s, 2H); 4.35 (m, 2H); 4.00 (m, 2H); 2.85 (m, 2H); 150-160
1.80 (m, 5H); 1.20 (m, 2H)
9.10 (s, IH); 8.20 (s, IH); 8.10 (d, IH); 7.85 (d, IH); 7.70 (m, 2H); 7.40 (m,
IH); 7.30 (m, 2H); 7.00 (m, IH); 5.20 (s, 2H); 4.10 (m, 2H); 3.60 (m, IH);
oil
3.50 (m, IH); 3.40 (m, IH); 3.20 (m, IH); 2.70 (m, IH); 2.10 (m, IH); 1.80
(m, IH)
9.10 (s, IH); 7.70 (m, 3H); 7.60 (d, 2H); 7.30 (m, 2H); 7.05 (m, 2H); 5.20
(s, 2H); 4.05 (m, 2H); 3.60 (m, IH); 3.50 (m, IH); 3.35 (m, IH); 3.20 (m, 115-1 17
IH); 2.70 (m, IH); 2.10 (m, IH); 1.80 (m, IH)
9.10 (s, IH); 8.10 (d, IH); 7.80 (d, IH); 7.70 (m, IH); 7.50 (m, 3H); 7.30 (d,
IH); 5.20 (s, 2H); 4.15 (m, 2H); 3.60 (m, IH); 3.50 (m, IH); 3.40 (m, IH); 89-91
3.25 (m, IH); 2.80 (m, IH); 2.10 (m, IH); 1.80 (m, IH)
9.10 (s, IH); 7.70 (s, IH); 7.40 (m, IH); 7.05 (m, IH); 6.95 (m, 2H); 5.20
(s, 2H); 4.05 (m, 2H); 3.60 (m, IH); 3.50 (m, IH); 3.35 (m, IH); 3.20 (m, 54-56
IH); 2.70 (m, IH); 2.10 (m, IH); 1.80 (m, IH)
9.10 (s, IH); 7.70 (s, IH); 7.30-7. 10 (m, 7H); 6.90 (m, 2H); 5.20 (s, 2H);
4.00 (m, 2H); 3.60 (m, IH); 3.50 (m, IH); 3.35 (m, IH); 3.20 (m, IH); 2.70 76-78
(m, IH); 2.05 (m, IH); 1.75 (m, IH); 1.60 (s, 6H)
9.10 (s, IH); 8.70 (s, IH); 8.00 (d, IH); 7.90 (m, IH); 7.80 (m, IH); 7.70
(m, IH); 7.60 (m, 2H); 5.20 (s, 2H); 4.20 (m, 2H); 3.65 (m, IH); 3.55 (m, 83-85
IH); 3.40 (m, IH); 3.30 (m, IH); 2.80 (m, IH); 2.10 (m, IH); 1.85 (m, IH)
9.20 (s, IH); 9.10 (m, IH); 8.40 (d, IH); 8.05 (d, IH); 7.70 (m, 2H); 7.40
(m, IH); 7.30 (d, IH); 5.20 (s, 2H); 4.20 (m, 2H); 3.60 (m, IH); 3.50 (m, 122-124
IH); 3.40 (m, IH); 3.30 (m, IH); 2.75 (m, IH); 2.10 (m, IH); 1.80 (m, IH)
9.10 (s, IH); 8.80 (s, IH); 8.30 (d, IH); 7.90 (d, IH); 7.70 (m, IH); 7.40 (m,
28 2H); 7.30 (d, IH); 5.20 (s, 2H); 4.20 (m, 2H); 3.60 (m, IH); 3.50 (m, IH); 94-96
3.40 (m, IH); 3.30 (m, IH); 2.80 (m, IH); 2.10 (m, IH); 1.80 (m, IH)
9.20 (s, IH); 9.10 (s, IH); 8.40 (d, IH); 7.90 (d, IH); 7.80 (d, IH); 7.70 (m,
IH); 7.55 (s, IH); 7.45 (d, IH); 5.20 (s, 2H); 4.20 (m, 2H); 3.60 (m, IH);
29 121-123
3.50 (m, IH); 3.40 (m, IH); 3.30 (m, IH); 2.80 (m, IH); 2.10 (m, IH); 1.80
(m, IH)
9.10 (s, IH); 7.65 (m, 2H); 7.40 (s, IH); 7.30 (d, IH); 5.20 (s, 2H); 4.10 (m,
30 2H); 3.60 (m, IH); 3.50 (m, IH); 3.40 (m, IH); 3.20 (m, IH); 2.70 (m, IH); 60-62
2.10 (m, IH); 1.80 (m, IH)
9.10 (s, IH); 8.00 (d, IH); 7.70 (m, 2H); 7.50 (m, 2H); 7.30 (d, IH); 7.15
31 (m, IH); 5.20 (s, 2H); 4.15 (m, 2H); 3.60 (m, IH); 3.50 (m, IH); 3.40 (m, 76-78
IH); 3.30 (m, IH); 2.80 (m, IH); 2.10 (m, IH); 1.85 (m, IH)
7.90 (m, 4H); 7.75 (d, IH); 7.50 (m, IH); 7.35 (m, 2H); 7.20 (d, IH); 5.35
194 (s, 2H); 4.15 (m, 2H); 3.65 (m, IH); 3.55 (m, IH); 3.45 (m, IH); 3.30 (m, 100-1 12
IH); 2.80 (m, IH); 2.15 (m, IH); 1.85 (m, IH)
7.90 (m, 4H); 7.75 (d, IH); 7.50 (m, IH); 7.35 (m, 2H); 7.20 (d, IH); 5.35
195 (s, 2H); 4.15 (m, 2H); 3.65 (m, IH); 3.55 (m, IH); 3.45 (m, IH); 3.30 (m, 112-1 14
IH); 2.80 (m, IH); 2.15 (m, IH); 1.85 (m, IH)
8.10 (d, IH); 7.85 (m, 2H); 7.75 (d, IH); 7.50 (m, 3H); 7.40 (d, IH); 5.35 (s,
196 2H); 4.20 (m, 2H); 3.65 (m, IH); 3.55 (m, IH); 3.45 (m, IH); 3.30 (m, IH); 100-102
2.80 (m, IH); 2.15 (m, IH); 1.85 (m, IH)
7.85 (m, IH); 7.75 (m, IH); 7.65 (m, 2H); 7.60 (d, 2H); 7.30 (m, 2H); 7.05
197 (d, 2H); 5.40 (s, 2H); 4.10 (m, 2H); 3.60 (m, IH); 3.50 (m, IH); 3.40 (m, 81-83
IH); 3.30 (m, IH); 2.70 (m, IH); 2.10 (m, IH); 1.80 (m, IH)
8.15 (bs, IH); 7.85 (bs, IH); 7.15 (m, 2H); 7.00 (m, 2H); 6.80 (s, IH); 5.25
198 106-108
(s, 2H); 4.00 (m, 4H); 2.90 (m, 2H); 1.70 (m, 5H); 1.10 (m, 2H)
8.15 (bs, IH); 7.85 (bs, IH); 7.30 (d, 2H); 7.05 (d, 2H); 6.80 (s, IH); 5.25
199 112-1 15
(s, 2H); 4.05 (m, 4H); 2.85 (m, 2H); 1.70 (m, 5H); 1.10 (m, 2H)
8.15 (bs, IH); 7.80 (m, 4H); 7.50 (m, IH); 7.35 (m, 2H); 7.20 (m, IH); 6.80
200 (s, IH); 5.30 (s, 2H); 4.10 (m, 2H); 3.65 (m, IH); 3.50 (m, IH); 3.40 (m, 138-140
IH); 3.30 (m, IH); 2.80 (m, IH); 2.10 (m, IH); 1.85 (m, IH)
8.15 (bs, IH); 8.85 (bs, IH); 8.75 (m, 2H); 7.30 (m, 2H); 7.20 (m, 2H); 6.80
201 (s, IH); 5.30 (s, 2H); 4.10 (m, 2H); 3.90 (s, 3H); 3.60 (m, IH); 3.50 (m, 193-195
IH); 3.40 (m, IH); 3.30 (m, IH); 2.80 (m, IH); 2.10 (m, IH); 1.85 (m, IH)
8.15 (bs, IH); 7.80 (m, 4H); 7.50 (m, IH); 7.35 (m, 2H); 7.20 (m, IH); 6.80
202 (s, IH); 5.30 (s, 2H); 4.10 (m, 2H); 3.65 (m, IH); 3.50 (m, IH); 3.40 (m, 139-141
IH); 3.30 (m, IH); 2.80 (m, IH); 2.10 (m, IH); 1.85 (m, IH)
The results for the masses M+H measured by LC-MS and the
retention times for the compounds in Table 1 are given in the
following Table 3 .
LC-MS conditions:
Method A:
HPLC/ZQ - Gradient 10 min
Mobile phases: Phase A : CH3COONH 4 + 3% ACN
Phase B : ACN
Stationary phase/column: Kromasil C18 column
Dimensions: 50*2.1 mm; 3.5 m
Flow rate: D = 0.8 ml/min
Temperature of the column: T = 40 °C
Injection volume: V = 5 ΐ
Gradient: T = 0 min: 100% of A , from T = 5.5 min to T = 7 min:
100% of B , from T = 7.1 min to T = 10 min: 100% of A .
Method B:
UPLC/TOF - Gradient 3 min
Mobile phases: Phase A : H20 + 0.05% of TFA
Phase B : ACN + 0.035% of TFA
Stationary phase/column: Acquity BEH C18 column
Dimensions: 50*2.1 mm; 1.7 m
Flow rate: D = 1.0 ml/min
Temperature of the column: T = 40 °C
Injection volume: V = 2 ΐ
Gradient: T = 0 min: 98% of A and 2% of B , from T = 1.6 min to
T = 2.1 min: 100% of B , from T = 2.5 min to T = 3 min: 98% of
A and 2% of B .
Method C:
LC/TRAP - Gradient 2 0 min
Mobile phases: H20/CH3COONH 4/ACN
Stationary phase/column: Kromasil C18 column
Method D :
LC/ZQ - Gradient 2 0 min
Mobile phases: TFA/ACN
Stationary phase/column: Kromasil C18 column
Method E :
LC/TOF - Gradient 2 0 min
Mobile phases H2O/CH 3COONH 4/ACN
Stationary phase/column: Kromasil C18 column
Method F :
Stationary phase/column: Jsphere
Dimensions: 33*2 mm; 4 m
Gradient: H20 + 0.05% F :ACN + 0.05% TFA; 2:98 (1 min) to 95:5
(5.0 min) to 95:5 (6.25 min).
Method G :
Stationary phase/column: Waters XBridge C18
Dimensions: 4.6*50 mm; 2.5 m
Gradient: H20 + 0.05% TFA: ACN + 0.05% TFA; 95:5 (0 min) to 95:5
(0.3 min) to 5:95 (3.5 min) to 5:95 (4 min).
Method H :
YMC
Stationary phase/column: Jsphere
Dimensions: 33*2 mm; 4 m
Gradient: H20 + 0.1% TFA :ACN + 0.08% TFA; 95:5 (0 min) to 5:95
(2.5 min) to 5:95 (3 min) .
Table 3
N ° Method M+H Retention time
1. D 431 10.40
2 . A 365 9.70
3 . D 365 8.80
4 . D 415 10.00
5 . D 381 9.80
6 . D 365 9.00
7 . D 381 9.70
8 . C 415 10.50
9 . D 427 10.00
10. D 372 8.30
11. E 399 8.50
12. D 387 10.50
13. D 387.01 10.00
14. D 427 11.10
15. D 397 11.50
16. D 403 10.00
17. D 369 8.90
18. D 441 10.70
19. D 398 5.70
20. D 398 5.80
21. D 420 9.40
22. D 413 10.00
23. D 403 10.40
24. D 403 9.60
25. D 437 11.00
26. D 370 6.00
27. D 370 5.30
28. D 370 5.20
29. D 370 5.30
30. D 421 10.10
31. D 387 9.90
32. F 375.12 4.20
33. F 414.98 4.10
34. F 414.98 4.19
35. F 414.97 4.1 1
36. F 414.99 4.17
37. F 415.03 4.30
38. F 415.16 4.60
39. F 464.05 3.95
40. F 453.10 4.17
41. F 404.09 2.81
42. F 398.09 2.52
43. F 398.07 2.50
44. F 390.04 3.55
45. F 423.09 4.14
46. F 403.15 4.44
47. F 415.06 4.07
48. F 459.19 4.90
49. F 437.16 4.29
50. F 412.09 3.93
51. F 390.10 2.86
52. F 372.07 3.72
53. F 459.21 5.15
54. F 437.15 4.27
55. H 454.41 2.01
56. F 455.09 3.89
57. F 439.09 4.19
58. F 398.08 2.51
59. F 447.16 4.73
60. F 419.15 4.29
61. F 398.07 2.55
62. F 465.04 4.27
63. F 454.08 3.17
64. F 460.92 4.14
65. F 412.08 2.51
66. F 448.07 4.04
67. F 422.06 3.78
68. F 430.01 3.65
69. F 423.12 4.24
70. F 423.1 1 4.22
71. F 423.05 3.39
72. F 406.01 3.66
73. F 418.03 3.56
74. F 448.07 3.94
75. F 432.10 2.82
76. F 448.00 3.92
77. F 375.12 4.04
78. F 415.00 3.91
79. F 397.1 1 4.08
80. F 390.13 2.59
81. F 415.06 3.97
82. F 437.1 1 4.19
83. F 391.12 3.55
84. F 465.20 4.44
85. F 439.09 4.17
86. F 442.97 3.80
87. G 437.1 1 3.87
88. G 439.10 3.77
89. G 447.1 1 4.16
90. G 419.12 3.85
91. G 437.03 4.26
92. G 465.01 3.79
93. G 454.1 1 2.85
94. G 460.94 3.76
95. F 448.1 1 3.56
96. G 422.09 4.31
97. G 430.04 3.23
98. G 423.10 3.79
99. G 423.10 3.78
100. G 406.03 3.33
101. G 418.05 3.15
102. G 448.09 3.51
103. G 432.12 2.57
104. G 448.03 3.53
105. F 404.13 2.55
106. F 397.07 3.99
107. F 397.08 4.13
108. F 427.08 4.03
109. G 415.1 1 4.08
110. G 453.13 3.63
111. G 398.1 1 2.39
112. G 398.1 1 2.37
113. G 412.14 2.38
114. G 423.08 3.08
115. H 415.27 2.49
116. H 415.27 2.49
117. H 464.38 2.34
118. H 390.33 2.12
119. H 459.45 3.04
120. H 412.36 2.37
121. H 459.45 2.92
122. H 404.39 1.35
123. H 412.36 1.36
124. H 372.32 2.10
125. F 347.16 3.55
126. F 423.20 4.12
127. F 390.2 2.71
128. F 365.15 3.60
129. F 375.20 4.06
130. F 404.24 2.49
131. G 415.04 3.95
132. F 415.10 4.01
133. F 415.09 3.99
134. F 415.12 4.15
135. H 415.1 1 4.38
136. F 397.20 3.94
137. F 397.19 3.97
138. F 412.20 2.43
139. F 464.19 3.85
140. F 453.21 4.09
141. F 426.16 2.82
142. F 398.18 2.48
143. F 404.20 2.81
144. F 398.19 2.47
145. F 398.19 2.50
146. F 398.17 2.40
147. F 390.22 2.57
148. F 390.16 3.46
149. F 423.18 4.06
150. F 423.20 4.09
151. F 415.12 3.88
152. F 437.22 4.13
153. F 391.20 3.53
154. F 415.27 4.41
155. F 465.29 4.42
156. F 439.20 4.08
157. F 443.06 3.87
158. F 412.21 3.85
159. F 372.17 3.43
160. F 459.33 4.84
161. F 437.23 4.15
162. F 453.21 3.89
163. F 423.18 3.37
164. F 455.2 3.70
165. F 439.20 4.05
166. F 406.13 3.55
167. F 398.18 2.49
168. F 447.29 4.55
169. F 419.27 4.25
170. F 437.23 4.56
171. F 418.15 3.37
172. F 398.18 2.52
173. F 465.15 4.07
174. F 461.03 4.08
175. F 413.15 3.69
176. F 448.20 3.86
177. F 422.07 3.76
178. F 430.14 3.53
179. F 427.21 3.88
180. F 448.15 3.81
181. F 424.15 3.04
182. F 454.23 3.1 1
183. F 448.20 3.99
184. F 425.16 3.00
185. F 446.13 3.44
186. F 386.2 3.36
187. F 431.19 3.19
188. F 390.15 3.36
189. F 403.28 4.34
190. F 432.22 2.72
191. F 412.20 2.49
192. F 430.21 3.05
193. F 415.20 3.17
194. D 369 4.70
195. D 369 4.73
196. A 403 5.08
197. A 4 13 5.00
198. B 392 1.14
199. B 458 1.28
200. B 396 1.15
201 . A 426 1.13
202. B 396 1.15
The compounds of the invention form the subject of
pharmacological trials which make it possible to determine
their inhibitory effect on the enzyme FAAH (Fatty Acid Amide
Hydrolase) .
1/ Radioenzymatic test
The inhibitory activity was demonstrated in a radioenzymatic
test based on the measurement of the product of hydrolysis of
anandamide [ethanolamine 1- H ] by 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 at the time of use by homogenization
of the tissues using a Precellys® device in the reaction
buffer (Tris-HCl 10 mM pH=8, NaCl 150 mM and
ethylenediaminetetraacetic acid (EDTA) 1 mM) . The enzymatic
reaction is carried out in 96-well Multiscreen filtration
plates in a final volume of 70 ΐ . Reaction buffer
supplemented with bovine serum albumin free from fatty acids
(BSA, 1 mg/ml) is used for the enzymatic reaction, the
dilution of the compounds and the dilution of the anandamide
[ethanolamine 1- H ] . Reaction buffer comprising the BSA
(43 ΐ /well) , the diluted test compounds at different
concentrations (7 ΐ /well comprising 1% of DMSO) and the
membrane preparation (10 ΐ /well, i.e. 200 g of tissue per
trial) are successively added to the wells. After
preincubating the compounds with the enzyme at 25°C for
2 0 minutes, the reaction is initiated by the addition of
anandamide [ethanolamine 1- H ] (specific activity of 15-
2 0 Ci/mmol) diluted with cold anandamide (10 ΐ /well, final
concentration of 10 , 0.01 , per trial) . After incubating
at 25°C for 2 0 minutes, the enzymatic reaction is halted by
addition of a 5M active charcoal solution prepared in a 1 .5M
NaCl and 0 .5M HC1 buffer (50 ΐ /well) . The mixture is stirred
for 10 minutes and then the aqueous phase comprising the [1-
H ]ethanolamine is recovered by filtration under vacuum and
counted by liquid scintillation.
Under these conditions, the most active compounds of the
invention exhibit C I50 values (concentration which inhibits the
control enzymatic activity of FAAH by 50%) of between 0.1 and
1000 nM, preferably between 0.1 and 500 nM, preferably between
0.2 and 100 nM, indeed even between 0.2 and 50 nM. For
example, compounds No. 26, No. 38, No. 39, No. 49, No. 60,
No. 90, No. 196, No. 199, No. 200 and No. 202 have respective
C I50 values of 86 nM, 14 nM, 13 nM, 19 nM, 95 nM, 92 nM,
252 nM, 350 nM, 122 nM and 8 nM.
It is thus apparent that the compounds according to the
invention have an inhibitory activity on the enzyme FAAH.
The in vivo activity of the compounds of the invention can be
evaluated in a test for analgesia.
2/ Test for analgesia
The intraperitoneal (i.p.) administration of PBQ
(phenylbenzoquinone , 2 mg/kg in a 0.9% sodium chloride
solution comprising 5% of ethanol) to male OF1 mice weighing
25 to 30 g causes abdominal tractions, on average 30 twisting
or contracting motions during the period from 5 to 15 minutes
after injection. The test compounds are administered, orally
(p.o.) or intraperitoneally (i.p.) in suspension in 0.5% Tween
80, 60 minutes or 120 minutes before the administration of
PBQ. Under these conditions, the most powerful compounds
reduce by 30 to 80% the number of tractions induced by the
PBQ, within a range of doses of between 1 and 30 mg/kg.
The enzyme FAAH (Chemistry and Physics of Lipids, (2000), 108,
107-121) catalyses the hydrolysis of endogenous derivatives of
amides and esters of various fatty acids, such as
W-arachidonoylethanolamine (anandamide) , N-palmitoylethanolamine,
W-oleoylethanolamine, oleamide or
2-arachidonoylglycerol . These derivatives exert various
pharmacological activities by interacting, inter alia, with
the cannabinoid and vanilloid receptors.
The compounds of the invention block this decomposition
pathway and increase the tissue level of these endogenous
substances. They can therefore be used in the prevention and
treatment of pathologies in which endogenous cannabinoids
and/or any other substrate metabolized by the enzyme FAAH are
involved. Mention may be made, for example, of the following
diseases and conditions:
pain, in particular acute or chronic pain of neurogenic type:
migraine, neuropathic pain, including forms associated with
the herpes virus and with diabetes and with chemotherapy;
acute or chronic pain associated with inflammatory diseases:
arthritis, rheumatoid arthritis, osteoarthritis, spondylitis,
gout, vasculitis, Crohn's disease, irritable bowel syndrome;
acute or chronic peripheral pain; dizziness, vomiting, nausea,
in particular resulting from chemotherapy; eating disorders,
in particular anorexia and cachexia of various natures;
neurological and psychiatric pathologies: tremors,
dyskinesias, dystonias, spasticity, obsessive-compulsive
behaviour, Tourette's syndrome, all forms of depression and of
anxiety of any nature and origin, mood disorders, psychoses;
acute or chronic neurodegenerative diseases: Parkinson's
disease, Alzheimer's disease, senile dementia, Huntington's
chorea, lesions related to cerebral ischaemia and to cranial
and medullary trauma; epilepsy; sleep disorders, including
sleep apnoea; cardiovascular diseases, in particular
hypertension, cardiac arrhythmias, arteriosclerosis, heart
attack, cardiac ischaemia; renal ischaemia; cancers: benign
skin tumours, brain tumours and papillomas, prostate tumours,
cerebral tumours (glioblastomas, medulloepitheliomas,
medulloblastomas , neuroblastomas, tumours of embryonic origin,
astrocytomas, astroblastomas , ependymomas, oligodendrogliomas,
plexus tumour, neuroepitheliomas, epiphyseal tumour,
ependymoblastomas , malignant meningiomas, sarcomatosis ,
malignant melanomas, schwannomas) ; disorders of the immune
system, in particular autoimmune diseases: psoriasis, lupus
erythematosus, diseases of the connective tissue or collagen
diseases, Sjogren's syndrome, ankylosing spondylitis,
undifferentiated spondylitis, Behcet's disease, autoimmune
haemolytic anaemia, multiple sclerosis, amyotrophic lateral
sclerosis, amyloidosis, graft rejection, diseases affecting
the plasmocytic line; allergic diseases: immediate or delayed
hypersensitivity, allergic rhinitis or conjunctivitis, contact
dermatitis; parasitic, viral or bacterial infectious diseases:
AIDS, meningitis; inflammatory diseases, in particular joint
diseases: arthritis, rheumatoid arthritis, osteoarthritis,
spondylitis, gout, vasculitis, Crohn's disease, irritable
bowel syndrome; osteoporosis; eye conditions: ocular
hypertension, glaucoma; pulmonary conditions: diseases of the
respiratory tract, bronchospasm, coughing, asthma, chronic
bronchitis, chronic obstruction of the respiratory tract,
emphysema; gastrointestinal diseases: irritable bowel
syndrome, inflammatory intestinal disorders, ulcers,
diarrhoea; urinary incontinence and bladder inflammation.
The use of the compounds according to the invention, in the
form of the base, of an addition salt with an acid, of a
hydrate or of a solvate which is pharmaceutically acceptable,
in the preparation of a medicament intended to treat the
abovementioned pathologies forms an integral part of the
invention.
Compounds according to the invention, in the form of the base,
of an addition salt with an acid, of a hydrate or of a solvate
which is pharmaceutically acceptable, for their use in the
preparation of a medicament intended to treat the
abovementioned pathologies forms an integral part of the
invention .
Another subject-matter of the invention is medicaments which
comprise a compound of formula (I), (Ii) or (Iii), or an
addition salt with an acid, or a hydrate or a solvate which is
pharmaceutically acceptable of the compound of formula (I),
(Ii) or (Iii) . These medicaments are used therapeutically, in
particular in the treatment of the abovementioned pathologies.
According to another of its aspects, the present invention
relates to pharmaceutical compositions including, as active
principle, at least one compound according to the invention.
These pharmaceutical compositions comprise an effective dose
of a compound according to the invention, or an addition salt
with an acid, or a hydrate, or a solvate which is
pharmaceutically acceptable of the said compound, and
optionally one or more pharmaceutically acceptable excipients.
The said excipients are chosen, depending on the
pharmaceutical form and the method of administration desired,
from the usual excipients which are known to a person skilled
in the art.
In the pharmaceutical compositions of the present invention
for oral, sublingual, subcutaneous, intramuscular,
intravenous, topical, local, intrathecal, intranasal,
transdermal, pulmonary, ocular or rectal administration, the
active principle of formula (I), (Ii) or (Iii) above or its
optional addition salt with an acid, solvate or hydrate can be
administered in a unit administration form, as a mixture with
conventional pharmaceutical excipients, to animals and to man
for the prophylaxis or the treatment of the above disorders or
diseases .
Appropriate unit administration forms comprise oral forms,
such as tablets, soft or hard gelatin capsules, powders,
granules, chewing gums and oral solutions or suspensions,
forms for sublingual, buccal, intratracheal, intraocular or
intranasal administration or for administration by inhalation,
forms for subcutaneous, intramuscular or intravenous
administration and forms for rectal or vaginal administration.
For topical application, the compounds according to the
invention can be used in creams, ointments or lotions.
By way of example, a unit administration form of a compound
according to the invention in the form of a tablet can
comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Croscarmellose sodium 6.0 mg
Maize starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
The said unit forms comprise a dose which makes possible a
daily administration of 0.01 to 20 mg of active principle per
kg of body weight, depending upon the pharmaceutical dosage
form.
There may be specific cases where higher or lower dosages are
appropriate; such dosages also come within the invention.
According to the usual practice, the dosage appropriate to
each patient is determined by the doctor according to the
method of administration and the weight and the response of
the said patient.
According to another of its aspects, the invention also
relates to a method for the treatment of the pathologies
indicated above which comprises the administration of an
effective dose of a compound according to the invention, of
one of its addition salts with a pharmaceutically acceptable
acid or of a solvate or of a hydrate of the said compound.
Claims
1 . Com ound corresponding 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 -NR R group;
- n and m represent, independently of one another, an integer
equal to 1 , 2 or 3 , it being understood that the sum m+n is at
most equal to 5 ;
- A represents a covalent bond, an oxygen atom, a Ci-6-alkylene
group or an -O-Ci-6-alkylene group in which the end represented
by an oxygen atom is bonded to the R group;
- R i represents an R5 group optionally substituted by one or
more R and/or R groups;
R5 representing a group chosen from a phenyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl,
quinolinyl, isoquinolinyl , phthalazinyl , quinazolinyl ,
quinoxalinyl , cinnolinyl, naphthyridinyl , benzothiazolyl ,
benzisothiazolyl , benzoxazolyl , benzisoxazolyl ,
benzimidazolyl , isobenzof uranyl , benzof uranyl ,
benzothiophenyl , benzothiadiazolyl , benzoxadiazolyl ,
indazolyl, indolizinyl, indolyl, isoindolyl, imidazopyridinyl ,
imidazopyrimidinyl , imidazopyrazinyl , imidazopyridazinyl ,
triazolopyridinyl , pyrrolopyridinyl , pyrrolopyrimidinyl ,
pyrrolopyrazinyl , pyrrolopyridazinyl , pyrrolotriazinyl ,
pyrazolopyridinyl , pyrazolopyrimidinyl , pyrazolopyrazinyl ,
pyrazolopyridazinyl , furopyridinyl , furopyrimidinyl ,
furopyrazinyl , furopyridazinyl , furotriazinyl ,
oxazolopyridinyl , oxazolopyrimidinyl , oxazolopyrazinyl ,
oxazolopyridazinyl , isoxazolopyridinyl , isoxazolopyrimidinyl ,
isoxazolopyrazinyl , isoxazolopyridazinyl , oxadiazolopyridinyl ,
thienopyridinyl , thienopyrimidinyl , thienopyrazinyl ,
thienopyridazinyl , thienotriazinyl , thiazolopyridinyl ,
thiazolopyrimidinyl , thiazolopyrazinyl , thiazolopyridazinyl ,
isothiazolopyridinyl , isothiazolopyrimidinyl ,
isothiazolopyrazinyl , isothiazolopyridazinyl or
thiadiazolopyridinyl ;
R representing a halogen atom or a cyano, -CH 2CN, nitro,
hydroxyl, Ci-8-alkyl, Ci-6-alkoxy, Ci-6-thioalkyl, Ci-6-haloalkyl,
Ci-6-haloalkoxy, Ci-6-halothioalkyl , C 3- -cycloalkyl ,
C 3- -cycloalkyl-Ci-3-alkylene, C 3- -cycloalkyl-Ci-3-alkylene-0- ,
(CH2)p-NR R , -NR COR , -NR C02R , -NR S02R , -NR S02NR R , -COR , -
C02R , - (CH2)p-CONR R , -S0 2R , -S0 2NR R or -0- (Ci_3-alkylene) -0-
group;
R representing a group chosen from a phenyl, phenyl-Ci-4-
alkylene-, phenyl- (CH2)p-0-, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl,
imidazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl,
tetrazolyl, thiazolyl, isothiazolyl , oxadiazolyl,
thiadiazolyl , imidazopyrimidinyl , thienopyrimidinyl,
benzof uranyl , benzothienyl , benzimidazolyl , benzoxazolyl ,
benzisoxazolyl , benzothiazolyl , benzisothiazolyl , indolyl,
isoindolyl, indazolyl, pyrrolopyridinyl , furopyridinyl ,
thienopyridinyl, imidazopyridinyl , pyrazolopyridinyl ,
oxazolopyridinyl , isoxazolopyridinyl or thiazolopyridinyl; it
being possible for the R7 group or groups to be substituted by
one or more R groups which are identical to or different from
one another;
p representing a number which can have the value 0 , 1 , 2 or
3 ;
- R 3 represents a hydrogen or fluorine atom, a Ci-6 _ alkyl group
or a trif luoromethyl group;
- R represents a 5-membered heterocycle chosen from a furanyl,
pyrrolyl, thienyl, thiazolyl, isothiazolyl , oxazolyl,
isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl , imidazolyl,
triazolyl or tetrazolyl;
this heterocycle optionally being substituted by one or more
substituents chosen from a halogen atom or a C - 6-alkyl, Ci - _
haloalkyl, C 3- -cycloalkyl , C 3- -cycloalkyl - C -3-alkylene, Ci - 6-
haloalkoxy, cyano, -NR R , -NR C(0 )R , -NR C02R ,
-NR S02R9, -NR S02NR R , - C(0 )R , -C02R , - C(0 )NR R ,
- C(0 )N(R8) (Ci -3-alkylene -NRi oRi i ) , -S02R , -S02NR R9 or -0- (Ci-3-
alkylene) -0- group;
R and R representing, independently of one another, a
hydrogen atom or a Ci - 6_ alkyl group,
or forming, with the nitrogen atom or atoms which carry them,
in the case of NR R , a ring chosen from the azetidine,
pyrrolidine, piperidine, morpholine, thiomorpholine, azepine,
oxazepine or piperazine rings, this ring optionally being
substituted by a Ci - 6-alkyl or benzyl group;
in the case of NR COR , a lactam ring;
in the case of NR C02R , an oxazolidinone, oxazinone or
oxazepinone ring;
in the case of NR S02R , a sultam ring;
in the case of NR S02NR R , a thiazolidine dioxide or
thiadiazinane dioxide ring;
R o and R representing, independently of one another, a
hydrogen atom or a Ci - 6_ alkyl group;
with the exclusion of the following compound:
5-methylisoxazol-3-ylmethyl 4-hydroxy-4- (4-chlorophenyl) -
piperidine- 1-carboxylate,
in the form of the base or of an addition salt with an acid.
2 . Compound of formula (I) according to Claim 1 , characterized
in that R2 represents a hydrogen atom;
in the form of the base or of an addition salt with an acid.
3 . Compound of formula (I) according to Claim 1 or 2 ,
characterized in that m and n represent, independently of one
another, the value 1 or 2;
in the form of the base or of an addition salt with an acid.
4 . Compound of formula (I) according to any one of the
preceding claims, characterized in that A represents an -O-Ci-
6-alkylene group in which the end represented by an oxygen atom
is bonded to the R group;
in the form of the base or of an addition salt with an acid.
5 . Compound of formula (I) according to any one of the
preceding claims, characterized in that R represents an R5
group optionally substituted by one or more R and/or R
groups ;
R5 representing a group chosen from a phenyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl,
quinolinyl, isoquinolinyl , phthalazinyl , quinoxalinyl ,
quinazolinyl , cinnolinyl, naphthyridinyl , benzothiazolyl ,
benzisothiazolyl, benzoxazolyl , benzisoxazolyl ,
benzimidazolyl , isobenzof uranyl , benzof uranyl ,
benzothiophenyl , indazolyl, indolizinyl, indolyl, isoindolyl,
pyrrolopyridinyl , furopyridinyl or thienopyridinyl ;
R representing a halogen atom or a cyano, -CH2CN, nitro,
hydroxyl, Ci-8-alkyl, Ci-6-alkoxy, Ci-6-thioalkyl, Ci-6-haloalkyl,
Ci-6-haloalkoxy, Ci-6-halothioalkyl , C3- -cycloalkyl ,
C3- -cycloalkyl-Ci-3-alkylene, C3- -cycloalkyl-Ci-3-alkylene-0- ,
(CH2)p-NR R , -NR COR , -NR C02R , -NR S02R , -NR S02NR R , -COR , -
C02R , - (CH2)p-CONR R , -S02R , -S02NR R or -0- (Ci_3-alkylene) -0-
group;
R representing a group chosen from a phenyl, phenyl-Ci-4-
alkylene-, phenyl- (CH2)p-0-, pyridinyl, pyridazinyl,
isoxazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, tetrazolyl,
pyrimidinyl, thiazolyl, pyrazinyl, triazinyl or benzoxazolyl ;
it being possible for the R group or groups to be substituted
by one or more R groups, which are identical to or different
from one another, as defined above;
p representing a number which can have the value 0 , 1 , 2 or
3 ;
R and R 9 representing, independently of one another, a
hydrogen atom or a Ci-6 _ alkyl group;
or forming, with the nitrogen atom or atoms which carry
them,
in the case of R R , a ring chosen from the azetidine,
pyrrolidine, piperidine, morpholine, thiomorpholine, azepine,
oxazepine or piperazine rings, this ring optionally being
substituted by a Ci-6-alkyl or benzyl group;
in the case of R COR , a lactam ring;
in the case of R CO2R9, an oxazolidinone, oxazinone or
oxazepinone ring;
in the case of R SO2R9, a sultam ring;
in the case of R SO2 R R , a thiazolidine dioxide or
thiadiazinane dioxide ring;
in the form of the base or of an addition salt with an acid.
6 . Compound of formula (I) according to any one of the
preceding claims, characterized in that R 3 represents a
hydrogen atom;
in the form of the base or of an addition salt with an acid.
7 . Compound of formula (I) according to any one of the
preceding claims, characterized in that R represents a 5-
membered heterocycle chosen from a thiazolyl or isoxazolyl;
this heterocycle optionally being substituted by one or more -
C (0 ) R R substituents in which g and R9 each represent a
hydrogen atom;
in the form of the base or of an addition salt with an acid.
8 . Compound of formula (I) according to claim 1 which is
chosen among the following compounds :
Thiazol-2-ylmethyl 4- [2- (4-chloronaphth-l-yloxy) ethyl] -
piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- (4-fluorophenoxy) ethyl] piperidine-lcarboxylate
Thiazol-4-ylmethyl 4- [2- (4-fluorophenoxy) ethyl] piperidine-lcarboxylate
Thiazol-4-ylmethyl 4- [2- (4- {trifluoromethyl jphenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (4-chlorophenoxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (4-fluorophenoxy) ethyl] piperidine-1-
carboxylate
Thiazol-5-ylmethyl 4- [2- (4-chlorophenoxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (4- {trifluoromethyl jphenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (7-methoxynaphth-2-yloxy) ethyl] -
piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (4-cyanophenoxy) ethyl] piperidine-lcarboxylate
Thiazol-4-ylmethyl (+/-) -3- (6-methoxynaphth-2-yloxymethyl)
pyrrolidine-l-carboxylate
Thiazol-4-ylmethyl (+/-) -3- (7-methoxynaphth-2-yloxymethyl
)pyrrolidine-l-carboxylate
Thiazol-4-ylmethyl (+/-) -3- (3, 4-dichlorophenoxymethyl
)pyrrolidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (6-methoxynaphth-2-yloxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (naphth-2-yloxy) ethyl] piperidine-lcarboxylate
Thiazol-4-ylmethyl (+/-) -3- (4-chloronaphth-l-yloxymethyl
)pyrrolidine-l-carboxylate
Thiazol-4-ylmethyl (+/-) -3- (naphth-2-yloxymethyl) pyrrolidine-1-
carboxylate
Thiazol-4-ylmethyl 4- [2- (4 '-fluorobiphenyl-4-yloxy) -
ethyl] piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (quinolin-6-yloxy) ethyl] piperidine-lcarboxylate
and its hydrochloride
Thiazol-4-ylmethyl 4- [2- (isoquinolin-6-yloxy) ethyl] piperidine-lcarboxylate
and its hydrochloride
Thiazol-4-ylmethyl (+/-) -3- (3 '-cyanobiphenyl-3-
yloxymethyl )pyrrolidine-l-carboxylate
Thiazol-4-ylmethyl (+/-) -3- (4 '-fluorobiphenyl-4-
yloxymethyl )pyrrolidine-l-carboxylate
Thiazol-4-ylmethyl (+/-) -3- (5-chloronaphth-2-yloxymethyl)
pyrrolidine-l-carboxylate
Thiazol-4-ylmethyl (+/-) -3- (3- {trifluoromethoxy }-
phenoxymethyl )pyrrolidine-l-carboxylate
Thiazol-4-ylmethyl (+/-) -3- [4- (1-methyl-l-phenylethyl)
phenoxymethyl] pyrrolidine-l-carboxylate
Thiazol-4-ylmethyl (+/-) -3- (quinolin-3-yloxymethyl )pyrrolidinel-
carboxylate
Thiazol-4-ylmethyl (+/-) -3- (isoquinolin- 6-yloxymethyl
)pyrrolidine-l-carboxylate
Thiazol-4-ylmethyl (+/-) -3- (quinolin-7-yloxymethyl) pyrrolidine-
1-carboxylate
Thiazol-4-ylmethyl (+/-) -3- (isoquinolin-7-yloxymethyl
)pyrrolidine-l-carboxylate
Thiazol-4-ylmethyl (+/-) -3- (4-chloro-3- {trif luoromethyl
jphenoxymethyl) pyrrolidine-l-carboxylate
Thiazol-4-ylmethyl (+/-) -3- (5-fluoronaphth-2-yloxymethyl
)pyrrolidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- (2, 4-dimethylphenoxy) ethyl] piperidine- 1-
carboxylate
Thiazol-2-ylmethyl 4- [2- (2, 3-dichlorophenoxy) ethyl] piperidine- 1-
carboxylate
Thiazol-2-ylmethyl 4- [2- (2, 4-dichlorophenoxy) ethyl] piperidine- 1-
carboxylate
Thiazol-2-ylmethyl 4- [2- (2, 5-dichlorophenoxy) ethyl] piperidine- 1-
carboxylate
Thiazol-2-ylmethyl 4- [2- (3, 4-dichlorophenoxy) ethyl] piperidine- 1-
carboxylate
Thiazol-2-ylmethyl 4- [2- (3, 5-dichlorophenoxy) ethyl] piperidine- 1-
carboxylate
Thiazol-2-ylmethyl 4- [2- (4-cyclopentylphenoxy) ethyl] piperidine-
1-carboxylate
Thiazol-2-ylmethyl 4- [2- (2- {benzoxazol-2-yl jphenoxy) -
ethyl ]piperidine- 1-carboxylate
Thiazol-2-ylmethyl 4- [2- (4- {benzyloxy jphenoxy) ethyl] piperidine-
1-carboxylate
Thiazol-2-ylmethyl 4- [2- (4- {carbamoylmethyl jphenoxy) -
ethyl ]piperidine- 1-carboxylate
Thiazol-2-ylmethyl 4- [2- (quinolin-7-yloxy) ethyl] piperidine- 1-
carboxylate and its trif luoroacetate
Thiazol-2-ylmethyl 4- [2- (quinolin-6-yloxy) ethyl] piperidine- 1-
carboxylate and its trif luoroacetate
Thiazol-2-ylmethyl 4- [2- (4-cyano-3-f luorophenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- (biphenyl-2-yloxy) ethyl] piperidine-lcarboxylate
Thiazol-2-ylmethyl 4- [2- (2-isopropyl-5-methylphenoxy)
ethyl ]piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- (3- {trif luoromethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate
Thiazol-2-ylmethyl 4-{2- [4- (1, 1 , 3 ,3-tetramethylbutyl)
phenoxy] ethyl }piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- (4-benzylphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-2-ylmethyl 4- [2- (4- {pyrrol-l-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
Thiazol-2-ylmethyl 4- [2- (4-carbamoylphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-2-ylmethyl 4- [2- (3-cyanophenoxy) ethyl] piperidine-lcarboxylate
Thiazol-2-ylmethyl 4- [2- (3, 5-di{ tert-butyl }phenoxy) -
ethyl] piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- (2-benzylphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-2-ylmethyl 4- [2- (8- {acetylamino }naphth-2-
yloxy) ethyl ]piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- (3- {methoxycarbonyl }naphth-2-
yloxy) ethyl ]piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- (3-phenoxyphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-2-ylmethyl 4- [2- (isoquinolin-7-yloxy) ethyl] piperidine-1-
carboxylate and its trif luoroacetate
Thiazol-2-ylmethyl 4- [2- (4-hexyloxyphenoxy) ethyl] piperidine-1-
carboxylate
Thiazol-2-ylmethyl 4- [2- (3-butoxyphenoxy) ethyl] piperidine-1-
carboxylate
Thiazol-2-ylmethyl 4- [2- (quinolin-5-yloxy) ethyl] piperidine-1-
carboxylate and its trif luoroacetate
Thiazol-2-ylmethyl 4- [2- (3- {pentafluoroethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- (5- {acetylamino }naphth-2-
yloxy) ethyl] piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- (5-bromo-2-chlorophenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- (2-methylquinolin-6-yloxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
Thiazol-2-ylmethyl 4- [2- (4 '-cyanobiphenyl-3-yloxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- (6-cyanonaphth-2 -yloxy) ethyl ]piperidinel-
carboxylate
Thiazol-2-ylmethyl 4- [2- (4- {thiazol-2-yl jphenoxy) -
ethyl] piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- (biphenyl-3-yloxy) ethyl] piperidine-lcarboxylate
Thiazol-2-ylmethyl 4- [2- (biphenyl-4-yloxy) ethyl] piperidine-lcarboxylate
Thiazol-2-ylmethyl 4- [2- (2-cyanoquinolin-8-yloxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
Thiazol-2-ylmethyl 4- [2- (4-chloro-2-cyanophenoxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
Thiazol-2-ylmethyl 4- [2- (2-methylbenzothiazol-5-
yloxy) ethyl ]piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- ( '-cyanobiphenyl-4-yloxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- (2- {morpholin-4-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2 - (4-chloro-2-{isoxazol-5-yl}-
phenoxy) ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (2, 4-dimethylphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-4-ylmethyl 4- [2- (2, 3-dichlorophenoxy) ethyl] piperidine-1-
carboxylate
Thiazol-4-ylmethyl 4- [2- (naphth-l-yloxy) ethyl] piperidine-lcarboxylate
Thiazol-4-ylmethyl 4- [2- (3- {dimethylamino jphenoxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
Thiazol-4-ylmethyl 4- [2- (3- {trif luoromethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (4-benzylphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-4-ylmethyl 4- [2- (2-ethoxyphenoxy) ethyl] piperidine-1-
carboxylate
Thiazol-4-ylmethyl 4-{2- [4- (1-methyl-l-phenylethyl) -
phenoxy] ethyl }piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (4-phenoxyphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-4-ylmethyl 4- [2- (2-bromo-4-f luorophenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (2-benzylphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-4-ylmethyl 4- [2- (3-phenoxyphenoxy) ethyl] piperidine-1-
carboxylate
Thiazol-4-ylmethyl 4- [2- (4- {hexyloxy jphenoxy) ethyl] piperidine-1-
carboxylate
Thiazol-4-ylmethyl 4- [2- (3-butoxyphenoxy) ethyl] piperidine-1-
carboxylate
Thiazol-4-ylmethyl 4- [2- (4-chloro-5-isopropyl-2-
methylphenoxy) ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (3- {pentafluoroethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (5- {acetylamino }naphth-2-
yloxy) ethyl] piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (5-bromo-2-chlorophenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (4 '-cyanobiphenyl-3-yloxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (6-cyanonaphth-2 -yloxy) ethyl ]piperidinel-
carboxylate
Thiazol-4-ylmethyl 4- [2- (4- {thiazol-2-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (biphenyl-3-yloxy) ethyl] piperidine-1-
carboxylate
Thiazol-4-ylmethyl 4- [2- (biphenyl-4-yloxy) ethyl] piperidine-lcarboxylate
Thiazol-4-ylmethyl 4- [2- (4-chloro-2-cyanophenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (2-methylbenzothiazol-5-
yloxy) ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (4 '-cyanobiphenyl-4-yloxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (2- {morpholin-4-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
Thiazol-4-ylmethyl 4- [2- (4-chloro-2- {isoxazol-5-yl }-
phenoxy) ethyl ]piperidine-l-carboxylate
Thiazol-2-ylmethyl 4- [2- (4- {dimethylaminomethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate and its trif luoroacetate
Thiazol-2-ylmethyl 4- [2- (naphth-2-yloxy) ethyl] piperidine-lcarboxylate
Thiazol-2-ylmethyl 4- [2- (naphth-l-yloxy) ethyl] piperidine-lcarboxylate
Thiazol-2-ylmethyl 4- [2- (7-methoxynaphth-2-yloxy) -
ethyl] piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (2-cyclopentylphenoxy) ethyl] piperidinel-
carboxylate
Thiazol-4-ylmethyl 4- [2- (2-benzyloxyphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-4-ylmethyl 4- [2- (isoquinolin-7-yloxy) ethyl] piperidine-lcarboxylate
and its trif luoroacetate
Thiazol-4-ylmethyl 4- [2- (quinolin-5-yloxy) ethyl] piperidine-lcarboxylate
and its trif luoroacetate
Thiazol-4-ylmethyl 4- [2- (2-methylquinolin-6-yloxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
Thiazol-4-ylmethyl 4- [2- (2-cyanoquinolin-8-yloxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
Thiazol-4-ylmethyl 4- [2- (2, 4-dichlorophenoxy) ethyl] piperidine-lcarboxylate
Thiazol-4-ylmethyl 4- [2- (4-cyclopentylphenoxy) ethyl] piperidinel-
carboxylate
Thiazol-4-ylmethyl 4- [2- (2- {benzoxazol-2-yl }-
phenoxy) ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (4-cyano-3-f luorophenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4-{2- [4- (1, 1 , 3 ,3-tetramethylbutyl)
phenoxy] ethyl }piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (4- {pyrrol-l-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
Thiazol-4-ylmethyl 4- [2- (3, 5-di {tert-butyl jphenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-4-ylmethyl 4- [2- (4- {dimethyl aminome thy1}-
phenoxy) ethyl ]piperidine-l-carboxylate and its trif luoroacetate
Thiazol-4-ylmethyl 4- [2- (2-methylquinolin-8-yloxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
Thiazol-4-ylmethyl 4- [2- (3-cyanophenoxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- (2-phenoxyethyl) piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (biphenyl-4-yloxy) ethyl] piperidine-1-
carboxylate
Thiazol-5-ylmethyl 4- [2- (4-carbamoylphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (4-fluorophenoxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (2, 4-dimethylphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (4- {dimethylaminomethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate and its trif luoroacetate
Thiazol-5-ylmethyl 4- [2- (2, 3-dichlorophenoxy) ethyl] piperidine-1-
carboxylate
Thiazol-5-ylmethyl 4- [2- (2, 4-dichlorophenoxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (2, 5-dichlorophenoxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (3, 5-dichlorophenoxy) ethyl] piperidine-1-
carboxylate
Thiazol-5-ylmethyl 4- [2- (4-cyclopentylphenoxy) ethyl] piperidine-
1-carboxylate
Thiazol-5-ylmethyl 4- [2- (naphth-2-yloxy) ethyl] piperidine-1-
carboxylate
Thiazol-5-ylmethyl 4- [2- (naphth-l-yloxy) ethyl] piperidine-1-
carboxylate
Thiazol-5-ylmethyl 4- [2- (2-methylquinolin-8-yloxy) -
ethyl] piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (2- {benzoxazol-2-yl }-
phenoxy) ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (4- {benzyloxy} phenoxy) ethyl] piperidinel-
carboxylate
Thiazol-5-ylmethyl 4- [2- (4-sulphamoylphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (isoquinolin-5-yloxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (4- {carbamoylmethyl }-
phenoxy) ethyl] piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (quinolin-7-yloxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (quinolin-6-yloxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (quinolin-8-yloxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (3- {dimethylamino jphenoxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
Thiazol-5-ylmethyl 4- [2- (4-cyano-3-f luorophenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (biphenyl-2-yloxy) ethyl] piperidine-1-
carboxylate
Thiazol-5-ylmethyl 4- [2- (biphenyl-3-yloxy) ethyl] piperidine-1-
carboxylate
Thiazol-5-ylmethyl 4- [2- (3- {trif luoromethyl }-
phenoxy) ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (4-benzylphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (2-ethoxyphenoxy) ethyl] piperidine-1-
carboxylate
Thiazol-5-ylmethyl 4- [2- (2-cyclopentylphenoxy) ethyl] piperidinel-
carboxylate
Thiazol-5-ylmethyl 4-{2- [4- (1-methyl-l-phenylethyl) -
phenoxy] ethyl }piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (4-phenoxyphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (2-bromo-4-f luorophenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (4- {pyrrol-l-yl jphenoxy) -
ethyl] piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (3-cyanophenoxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (3, 5-di{ tert-butyl }phenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (2-benzylphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (2- {benzyloxy} phenoxy) ethyl] piperidinel-
carboxylate
Thiazol-5-ylmethyl 4- [2- (2-cyanoquinolin-8-yloxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (3- {methoxycarbonyl }naphth-2-
yloxy) ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2 - (3-phenoxyphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (4-chloro-2-cyanophenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (isoquinolin-7-yloxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (4- {hexyloxy jphenoxy) ethyl] piperidine-1-
carboxylate
Thiazol-5-ylmethyl 4- [2- (3-butoxyphenoxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (4-chloro-5-isopropyl-2-
methylphenoxy) ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (2-methylbenzothiazol-5-
yloxy) ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (quinolin-5-yloxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4- [2- (3- {pentafluoroethyl }-
phenoxy) ethyl] piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (5-bromo-2-chlorophenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (4- {difluoromethoxy jphenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (4 '-cyanobiphenyl-3-yloxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (6-cyanonaphth-2-yloxy) ethyl ]piperidinel-
carboxylate
Thiazol-5-ylmethyl 4- [2- (4- {thiazol-2-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (7-methoxynaphth-2-yloxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (4-chloro-2- {isoxazol-5-yl }-
phenoxy) ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (2-carbamoyl-4-chlorophenoxy)
ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (5- {acetylamino }naphth-2-
yloxy) ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (4 '-cyanobiphenyl-4-yloxy) -
ethyl] piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (4- {methanesulphonyl }-
phenoxy) ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (5-acetylamino-2-propylphenoxy)
ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (lH-indol- 6-yloxy) ethyl] piperidine-lcarboxylate
Thiazol-5-ylmethyl 4-{2- [4-fluoro-2- (lH-pyrazol-3-
yl) phenoxy] ethyl }piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (4-cyano-2-f luorophenoxy) -
ethyl] piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (2-isopropyl-5-methylphenoxy)
ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (2- {morpholin-4-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate and its trif luoroacetate
Thiazol-5-ylmethyl 4- [2- (2-methylquinolin-6-yloxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-5-ylmethyl 4-{2- [4- (2-oxopyrrolidin-l-yl) -
phenoxy] ethyl }piperidine-l-carboxylate
Thiazol-5-ylmethyl 4- [2- (3- {tetrazol-l-yl jphenoxy) -
ethyl ]piperidine-l-carboxylate
Thiazol-2-ylmethyl (R) -3- (naphth-2-yloxymethyl) pyrrolidine-1-
carboxylate (enantiomer I )
Thiazol-2-ylmethyl (S) -3- (naphth-2-yloxymethyl) pyrrolidine-1-
carboxylate (enantiomer II)
Thiazol-2-ylmethyl (+/-) -3- (5-chloronaphth-2-yloxymethyl
)pyrrolidine-l-carboxylate
Thiazol-2-ylmethyl (+/-) -3- ( '-fluorobiphenyl-4-
yloxymethyl )pyrrolidine-l-carboxylate
3-Carbamoylisoxazol-5-ylmethyl 4- [2- (4-f luorophenoxy)
ethyl] piperidine-l-carboxylate
3-Carbamoylisoxazol-5-ylmethyl 4- [2- (4- {trif luoromethoxy
jphenoxy) ethyl ]piperidine-l-carboxylate
3-Carbamoylisoxazol-5-ylmethyl (-) - (R) -3- (naphth-2-
yloxymethyl) pyrrolidine-l-carboxylate (enantiomer I )
3-Carbamoylisoxazol-5-ylmethyl (+/-) -3- (6-methoxynaphth-2-
yloxymethyl )pyrrolidine-l-carboxylate
3-Carbamoylisoxazol-5-ylmethyl (+) - (S) -3- (naphth-2-
yloxymethyl) pyrrolidine-l-carboxylate (enantiomer II) .
9 . Compound according to any one of the preceding claims,
characterized in that the com ound is of formula (Ii) :
in which Ri, A , R4, n and m are as defined in one of
preceding claims;
in the form of the base or of an addition salt with an acid.
10. Compound according to any one of the preceding claims,
characterized in that the compound is of formula (Iii) :
in which R , A , n and are as defined in one of Claims 1 to 9 ;
in the form of the base or of an addition salt with an acid.
11. Process for the preparation of a compound according to any
one of Claims 1 to 10, comprising the stage consisting in
reacting an amine derivative, a compound of following general
formula (II):
(II)
in which R , R2, A , n and m are as defined in one of the
preceding claims,
with a carbonate of following general formula (III) :
(Hi)
in which Z represents a hydrogen atom or a nitro group and R 3
and R are as defined in one of the preceding claims,
in the presence of a base, such as triethylamine,
pyridine, N ,W-dimethylaminopyridine or N ,W-diisopropylethylamine,
in an organic solvent, such as toluene,
acetonitrile or dichloroethane, at a temperature between
ambient temperature and the reflux temperature of the solvent.
12. Compound according to any one of Claims 1 to 10, in the
form of a base or of an addition salt with a pharmaceutically
acceptable acid, for the use thereof as medicament.
13. Pharmaceutical composition comprising at least one
compound according to any one of Claims 1 to 10, in the form
of the base or of an addition salt with a pharmaceutically
acceptable acid, and optionally one or more pharmaceutically
acceptable excipients.
14. Compound according to any one of Claims 1 to 10 in the
form of the base or of an addition salt with a
pharmaceutically acceptable acid, for its use in the
preparation of a medicament intended to prevent or to treat a
pathology in which endogenous cannabinoids and/or any other
substrate metabolized by the enzyme FAAH are involved.
15. Compound according to any one of Claims 1 to 10, in the
form of the base or of an addition salt with a
pharmaceutically acceptable acid, for its use in the
preparation of a medicament intended to prevent or treat acute
or chronic pain of neurogenic type, acute or chronic pain
associated with inflammatory diseases, acute or chronic
peripheral pain, dizziness, vomiting, nausea, eating
disorders, neurological and psychiatric pathologies, acute or
chronic neurodegenerative diseases, epilepsy, sleep disorders,
cardiovascular diseases, renal ischaemia, cancers, disorders
of the immune system, allergic diseases, parasitic, viral or
bacterial infectious diseases, inflammatory diseases,
osteoporosis, eye conditions, pulmonary conditions,
gastrointestinal diseases, urinary incontinence or bladder
inflammation .