Derivatives of azaspiranyl-alkylcarbamates of 5-member
heterocyclic compounds, preparation thereof and therapeutic
use thereof
The invention relates to azaspiranyl alkylcarbamate
derivatives of 5-membered heterocycles, to their preparation
and to their therapeutic use.
There is still a need to find and develop products that
inhibit the enzyme FAAH (Fatty Acid Amide Hydrolase). The
compounds of the invention satisfy this aim. These compounds
should have metabolic and pharmacokinetic properties and a
safety index that allow their use as medicaments.
The compounds of the invention correspond to the general
formula (I):

in which
R2 represents a hydrogen or fluorine atom or a hydroxyl,
cyano, trifluoromethyl, C1-6-alkyl, C1-6-alkoxy or NR8R9 group;
m, n, o and p represent, independently of each other, an
integer equal to 0, 1, 2 or 3;
A represents a covalent bond or a group C1-8-alkylene;
R1 represents a group R5 optionally substituted with one or
more groups R6 and/or R7;
R5 represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl,
quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, cinnolinyl and naphthyridinyl;
R6 represents a halogen atom or a cyano, -CH2CN, nitro,
hydroxyl, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl,
C1-6-haloalkyl, C1-6-haloalkoxy, C1-6-halothioalkyl, C3-7-
cycloalkyl, C3-7-cycloalkyl-C1-3-alkylene, C3-7-cycloalkyl-
C1-3-alkylene-O-, NR8R9, NR8COR9, NR8CO2R9, NR8SO2R9, MR8SO2NR8R9,
COR8, CO2R8, CONR8R9, SO2R8, SO2NR8R9 or -O-(C1-3-alkylene)-O-
group;
R7 represents a group chosen from furyl, pyrrolyl, thienyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,
pyrazolyl, oxadiazolyl, thiadiazolyl, phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl,
quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, cinnolinyl, naphthyridinyl, imidazo-
pyrimidinyl, thienopyrimidinyl, benzofuryl, benzothienyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
benzisothiazolyl, indolyl, isoindolyl, indazolyl,
pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridyl,
pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl,
thiazolopyridyl, phenyloxy, benzyloxy and pyrimidinoxy; or
the group(s) R7 possibly being substituted with one or more
groups R6 that may be identical to or different from each
other;
R3 represents a hydrogen or fluorine atom, a group C1-6-alkyl
or a trifluoromethyl group;
R4 represents a group chosen from furyl, pyrrolyl, thienyl,
isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl,
thiadiazolyl, imidazolyl, triazolyl and tetrazolyl;
this group being optionally substituted with one or more
substituents chosen from a halogen atom, a group C1-6-alkyl,
C1-6-haloalkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkylene,
C1-6-haloalkoxy, cyano, NR8R9, NR8COR9, NR8CO2R9, NR8SO2R9,
NR8SO2NR8R9, COR8, CO2R8, CONR8R9, CON(R8) (C1-3-alkylene-NR10R11),
SO2R8, SO2NR8R9, -O-(C1-3-alkylene)-O-, phenyl, phenyloxy,
benzyloxy, pyridyl, pyrazinyl, pyridazinyl, triazinyl or
pyrimidinyl; the phenyl, phenyloxy, pyridyl, pyrazinyl,
pyridazinyl, triazinyl and pyrimidinyl groups possibly being
substituted with one or more substituents chosen from a
halogen atom and a cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C1-6-
thioalkyl, C1-6-haloalkyl, C1-6-haloalkoxy, C1-6-halothioalkyl,
C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene group;
R8 and R9 represent, independently of each other, a hydrogen
atom or a group C1-6-alkyl,
or form, with the atom(s) that bear(s) them,
in the case of NR8R9, a ring chosen from azetidine,
pyrrolidine, piperidine, morpholine, thiomorpholine, azepine,
oxazepine and piperazine rings, this ring being optionally
substituted with a group C1-6-alkyl or benzyl;
in the case of NR8COR9, a lactam ring; in the case of NR8CO2R9,
a oxazolidinone, oxazinone or oxazepinone ring; in the case of
NR8SO2R9, a sultam ring; in the case of NR8SO2NR8R9, a
thiazolidine dioxide or thiadiazinane dioxide ring;
R10 and R11 represent, independently of each other, a hydrogen
atom or a group C1-6-alkyl.
Among the compounds of general formula (I), a first subgroup
of compounds is formed from the compounds for which R2
represents a hydrogen atom.
Among the compounds of general formula (I) , a second subgroup
of compounds is formed from the compounds for which the group

R2 being as defined in the general formula (I).
Among the compounds of general formula (I), a third subgroup
of compounds is formed from the compounds for which the group

represents

R2 being as defined in the general formula (I).
Among the compounds of general formula (I), a fourth subgroup
of compounds is formed from the compounds for which A
represents a covalent bond or a group C1-8_alkylene, more
particularly a methylene group.
Among the compounds of general formula (I), a fifth subgroup
of compounds is formed from the compounds for which
R1 represents a group R5 optionally substituted with one or
more groups R6 and/or R7;
R5 represents a pyrimidinyl, pyrazinyl, pyridinyl or
quinolinyl group;
R6 represents a halogen atom, more particularly a bromine,
fluorine or chlorine atom, a group C1-6-haloalkyl, more
particularly trifluoromethyl, or a group C1-6-alkyl, more
particularly an isobutyl;
R7 represents a phenyl, which may be substituted with one or
more groups R6 that are identical to or different from each
other.
Among the compounds of general formula (I), a sixth subgroup
of compounds is formed from the compounds for which
R1 represents a group R5 optionally substituted with one or
more groups R6 and/or R7;
R5 represents a pyridyl or guinolyl group;
R6 represents a halogen atom, more particularly a bromine,
fluorine or chlorine atom, or a group C1-6-haloalkyl, more
particularly trifluoromethyl;
R7 represents a phenyl, which may be substituted with one or
more groups R6 that are identical to or different from each
other.
Among the compounds of general formula (I), a seventh subgroup
of compounds is formed from the compounds for which
R3 represents a hydrogen atom.
Among the compounds of general formula (I) , an eighth subgroup
of compounds is formed from the compounds for which
R4 represents a group chosen from a thiazolyl, an oxazolyl, an
oxadiazolyl and an isoxazolyl;
this group being optionally substituted with one or more
substituents chosen from a group C1-6-alkyl, CONR8R9,
CON(R8) (C1-3-alkylene-NR10R11) or a phenyl; the phenyl group
being optionally substituted with one or more substituents
chosen from a halogen atom;
R8, R9, R10 and R11 represent, independently of each other, a
hydrogen atom or a group C1-6-alkyl, more particularly methyl.
Among the compounds of general formula (I), a ninth subgroup
of compounds is formed from the compounds for which
R4 represents a group chosen from a thiazolyl, an oxazolyl and
an isoxazolyl;
this group being optionally substituted with one or more
groups CONR8R9;
R8 and R9 represent, independently of each other, a hydrogen
atom or a group C1-6-alkyl, more particularly methyl.
Among the compounds of general formula (I), a tenth subgroup
of compounds is formed by the compounds of general formula (I)
in which R1 and/or R2 and/or R3 and/or R4 and/or n and/or m
and/or o and/or p and/or A are all as defined in the above
groups.
Among the compounds of general formula (I) , the following
compounds may be mentioned (IUPAC nomenclature generated by
the AutoNom software):
1. thiazol-4-ylmethyl [7-(6-fluoroquinolin-2-yl)-7-
azaspiro[3.5]non-2-yl]carbamate
2. 3-carbamoyiisoxazol-5-ylmethyl [7-(6-fluoroquinolin-2-
yl)-7-azaspiro[3.5]non-2-yl]carbamate
3. 3-carbamoylisoxazol-5-ylmethyl [7-(5-trifluoromethyl-
pyridin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
4. 3-carbamoylisoxazol-5-ylmethyl [7-(5-bromopyridin-2-yl)-
7-azaspiro[3.5]non-2-yl]carbamate
5. 3-carbamoylisoxazol-5-ylmethyl {7-[5-(4-fluorophenyl)-
pyridin-2-yl]-7-azaspiro[3.5]non-2-yl}carbamate
6. 3-carbamoylisoxazol-5-ylmethyl [7-(6-fluoroquinolin-2-
yl)-7-azaspiro[3.5]non-2-yl]methylcarbamate
7. 3-(methylcarbamoyl)isoxazol-5-ylmethyl [7-(6-fluoro-
quinolin-2-yl)-7-azaspiro[3.5]non-2-yl]methylcarbamate
8. 3-(methylcarbamoyl)isoxazol-5-ylmethyl {7-[5-(4-fluoro-
phenyl )pyridin-2-yl]-7-azaspiro[3.5]non-2-yl}carbamate
9. 3-(methylcarbamoyl)isoxazol-5-ylmethyl [7-(6-fluoro-
quinolin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
10. 3-carbamoylisoxazol-5-ylmethyl {6-[5-(4-fluorophenyl)-
pyridin-2-yl]-6-azaspiro[3.4]oct-2-yl}carbamate
11. 3-(methylcarbamoyl)isoxazol-5-ylmethyl {6-[5-(4-fluoro-
phenyl ) pyridin-2 -yl]-6-azaspiro[3.4]oct-2-yl}carbamate
12. 3-(methylcarbamoyl)isoxazol-5-ylmethyl {6-[5-(4-fluoro-
phenyl )pyridin-2-yl]-6-azaspiro[3.4]oct-2-ylmethyl}carbamate
(isomer I)
13. 3-(methylcarbamoyl)isoxazol-5-ylmethyl {6-[5-(4-fluoro-
phenyl)pyridin-2-yl]-6-azaspiro[3.4]oct-2-ylmethyl}carbamate
(isomer II)
14. 4-carbamoyloxazol-2-ylmethyl [7-(6-fluoroquinolin-2-yl)-
7-azaspiro[3.5]non-2-yl]carbamate
15. 3-(methylcarbamoyl)isoxazol-5-ylmethyl [2-(6-fluoro-
quinolin-2-yl)-2-azaspiro[3.3]hept-6-yl]carbamate
16. 3-(methylcarbamoyl)isoxazol-5-ylmethyl [6-(6-fluoro-
quinolin-2-yl)-6-azaspiro[3.4]oct-2-ylmethyl]carbamate (one
isomer)
17. 3-(methylcarbamoyl)isoxazol-5-ylmethyl {6-[5-(4-fluoro-
phenyl)pyridin-2-yl]-6-azaspiro[3.4]oct-2-yl}carbamate
(isomer I)
18. 3-(methylcarbamoyl)isoxazol-5-ylmethyl {6-[5-(4-fluoro-
phenyl)pyridin-2-yl]-6-azaspiro[3.4]oct-2-yl}carbamate
(isomer II)
19. 3-(methylcarbamoyl)isoxazol-5-ylmethyl [7-(6-chloro-
quinolin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
20. 3-carbamoylisoxazol-5-ylmethyl {2-[5-(4-fluorophenyl)-
pyridin-2-yl]-2-azaspiro[3.3]hept-6-yl}carbamate
21. 3-methylcarbamoylisoxazol-5-ylmethyl [6-(5-bromopyridin-
2-yl)-6-azaspiro[3.4]oct-2-yl]carbamate (one isomer)
22. 3-methylcarbamoylisoxazol-5-ylmethyl [6-(4-trifluoro-
methylpyridin-2-yl)-6-azaspiro[3.4]oct-2-yl]carbamate (one
isomer)
23. 3-methylcarbamoylisoxazol-5-ylmethyl {2-[5-(4-fluoro-
phenyl )pyridin-2-yl] -2-azaspiro[3.3]hept-6-yl}carbamate
24. 3-carbamoylisoxazol-5-ylmethyl [7-(4-trifluoromethyl-
pyrimidin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
25. 3-carbamoylisoxazol-5-ylmethyl {7-[6-(4-fluorophenyl)-
pyrazin-2-yl]-7-azaspiro[3.5]non-2-yl}carbamate
26. 3-(2-dimethylaminoethylcarbamoyl)isoxazol-5-ylmethyl [7-
(4-trifluoromethylpyrimidin-2-yl)-7-azaspiro[3.5]non-2-yl]-
carbamate and the hydrochloride thereof;
27. 3-carbamoylisoxazol-5-ylmethyl {7-[4-(4-fluorophenyl)-
pyridin-2-yl]-7-azaspiro[3.5]non-2-yl}carbamate
28. 3-carbamoylisoxazol-5-ylmethyl [7-(4-chloropyridin-2-
yl)-7-azaspiro[3.5]non-2-yl]carbamate
29. 3-carbamoylisoxazol-5-ylmethyl [7-(4-trifluoromethyl-
pyridin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
30. 3-carbamoylisoxazol-5-ylmethyl {7-[5-(3-fluorophenyl)-
pyridin-2-yl]-7-azaspiro[3.5]non-2-yl}carbamate
31. 3-carbamoylisoxazol-5-ylmethyl [7-(5-isobutylpyridin-2-
yl)-7-azaspiro[3.5]non-2-yl]carbamate
32. 3-carbamoylisoxazol-5-ylmethyl [7-(6-chloroquinolin-2-
yl)-7-azaspiro[3.5]non-2-yl]carbamate
33. 3-methylcarbamoylisoxazol-5-ylmethyl [7-(6-chloro-
quinolin-2-yl)-7-azaspiro[3.5]non-2-ylmethyl]carbamate
34. 3-methylcarbamoylisoxazol-5-ylmethyl [7-(4-trifluoro-
methylpyridin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
35. 3-(4-fluorophenyl)-[l,2,4]oxadiazol-5-ylmethyl [7-(4-
trifluoromethylpyridin-2-yl)-7-azaspiro[3.5]non-2-yl]-
carbamate
36. 4-carbamoyloxazol-2-ylmethyl [7-(4-trifluoromethyl-
pyridin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
37. 5-methyl-3-phenylisoxazol-4-ylmethyl [7-(4-trifluoro-
methylpyridin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
38. 3-ethyl[1,2,4]oxadiazol-5-ylmethyl [7-(4-trifluoro-
methylpyridin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
39. 5-methyl[l,2,4]oxadiazol-3-ylmethyl [7-(4-
trifluoromethylpyridin-2-yl)-7-azaspiro[3.5]non-2-yl]-
carbamate
40. 3-carbamoylisoxazol-5-ylmethyl [6-(4-trifluoromethyl-
pyrimidin-2-yl)-6-azaspiro[2.5]oct-l-yl]carbamate
41. 3-methylcarbamoylisoxazol-5-ylmethyl [6-(4-trifluoro-
methylpyrimidin-2-yl)-6-azaspiro[2.5]oct-l-yl]carbamate.
The compounds of general formula (I) may comprise one or more
asymmetric carbons. They may exist in the form of enantiomers
or diastereoisomers. The compounds of general formula (I) may
also exist in the form of cis or trans stereoisomers. These
stereoisomers, enantiomers and diastereoisomers, and also
mixtures thereof, including racemic mixtures, form part of the
invention.
The compounds of formula (I) may exist in the form of bases or
of acid-addition salts. Such addition salts form part of the
invention.
These salts are advantageously prepared with pharmaceutically
acceptable acids, but the salts of other acids that are
useful, for example, for purifying or isolating the compounds
of formula (I) also form part of the invention.
In the context of the invention, the following definitions
apply:
- Ct-z in which t and z may take values from 1 to 8, a
carbon chain possibly containing from t to z carbon atoms,
for example C1-3 is a carbon chain that may contain from 1 to
3 carbon atoms;
- alkyl, a linear or branched, saturated aliphatic group;
for example, a C1-6-alkyl group represents a linear or
branched carbon chain of 1 to 6 carbon atoms, more
particularly a methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl, pentyl or hexyl;
- alkylene, a linear or branched, saturated divalent alkyl
group, for example a C1-3-alkylene group represents a linear
or branched divalent carbon chain of 1 to 3 carbon atoms,
more particularly a methylene, ethylene, 1-methyl ethyl ene or
propylene;
- cycloalkyl, a cyclic alkyl group, for example a C3-7-
cycloalkyl group represents a cyclic carbon-based group of 3
to 7 carbon atoms, more particularly a cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
- alkoxy, a group -O-alkyl containing a linear or branched,
saturated aliphatic chain;
- thioalkyl, a group -S-alkyl containing a linear or
branched, saturated aliphatic chain;
- haloalkyl, an alkyl group in which one or more hydrogen
atoms have been replaced with a halogen atom;
- haloalkoxy, an alkoxy group in which one or more hydrogen
atoms have been replaced with a halogen atom;
halothioalkyl, a thioalkyl group in which one or more
hydrogen atoms have been replaced with a halogen atom;
- halogen atom, a fluorine, a chlorine, a bromine or an
iodine.
The compounds of the invention may be prepared according to
various methods, illustrated by the schemes that follow.
Thus, a first method (scheme 1) consists in reacting an amine
of general formula (II) , in which A, Rl, R2, m, n, o and p are
as defined in the general formula (I) defined above, with a
carbonate of general formula (III) in which Z represents a
hydrogen atom or a nitro group, and R3 and R4 are as defined in
the general formula (I) defined above, in the presence of a
base such as triethylamine, pyridine, N, N-dimethylamino-
pyridine or diisopropylethylamine in a solvent such as toluene
or dichloroethane, at a temperature between room temperature
and the reflux temperature of the solvent.
One variant for obtaining the compounds of general formula (I)
(scheme 1) consists in reacting an amine of general formula
(II), as defined above, with phenyl or 4-nitrophenyl
chloroformate, in the presence of a base such as triethylamine
or diisopropylethylamine, in a solvent such as dichloromethane
or tetrahydrofuran, at a temperature between 0°C and room
temperature, to give the carbamate derivative of general
formula (IV) , in which A, R1, R2, m, n, o and p are as defined
in the general formula (I) defined above, and Z represents a
hydrogen atom or a nitro group. The carbamate derivative of
general formula (IV) thus obtained is then converted into a
compound of general formula (I), via the action of an alcohol
of general formula HOCHR3R4 (IIIa) , in which R3 and R4 are as
defined in the general formula (I) defined above, in the
presence of a base such as triethylamine, pyridine, N,N-
dimethylaminopyridine or diisopropylethylamine, in a solvent
such as toluene or dichloroethane, at a temperature between
room temperature and the reflux temperature of the solvent.
A second method (Scheme 2 - route A) consists in reacting, in
a first stage, an amine of general formula (IIa), in which A,
R2, m, n, o and p are as defined in the general formula (I)
defined above, and PG represents a protecting group such as a
Boc (terfc-butyloxycarbonyl) , a Cbz (benzyloxycarbonyl) , a
benzyl or a benzhydryl, with a carbonate of general formula
(III) as defined above, under the conditions described above
during the reaction of the amine of general formula (II) with
the carbonate of general formula (III), to obtain a compound
of general formula (Ic) corresponding to the compound of
formula (Ia) in which the spirane nitrogen atom is protected
with a protecting group PG, followed by a deprotection
reaction, for example in the presence of a solution of
hydrochloric acid (5N) in isopropanol or dioxane, to obtain
the intermediate of general formula (Ia), in which A, R2, R3,
R4, m, n, o and p are as defined in the general formula (I).
One variant (Scheme 2 - route A variant) for obtaining the
intermediates of general formula (Ia) consists in reacting an
amine of general formula (IIa), as defined above, with phenyl
or 4-nitrophenyl chloroformate, in the presence of a base such
as triethylamine or diisopropylethylamine, in a solvent such
as dichloromethane or tetrahydrofuran, at a temperature of
between 0°C and room temperature, to give the carbamate
derivative of general formula (IVa), in which A, R2, m, n, o
and p are as defined in the general formula (I) defined above,
PG is as defined above and Z represents a hydrogen atom or a
nitro group. The carbamate derivative of general formula (IVa)
thus obtained is then converted into a compound of general
formula (Ia), via the action of an alcohol of general formula
HOCHR3R4 (IIIa), as defined above, in the presence of a base
such as triethylamine, pyridine, N,N-dimethylaminopyridine or
diisopropylethylamine, in a solvent such as toluene or
dichloroethane, at a temperature of between room temperature
and the reflux temperature of the solvent, followed by a
deprotection reaction, for example in the presence of a
solution of hydrochloric acid (5N) in isopropanol or dioxane.
Next, according to Scheme 2, route A, the compound of general
formula (I) is then obtained by reaction of the compound of
general formula (Ia) with a derivative of general formula R1-U1
(V) , in which R1 is as defined in the general formula (I) and
U1 represents a halogen atom or an O-triflate group, using
aromatic or heteroaromatic nucleophilic substitution reaction
conditions, for example by means of a base such as
triethylamine, diisopropylethylamine, pyridine or N,N-
dimethylaminopyridine in a solvent such as dichloromethane,
dichloroethane, acetonitrile, N,N-dimethylformamide, dioxane
or tetrahydrofuran, at a temperature between 0°C and the
reflux temperature of the solvent. This conversion may also be
performed using the Buchwald N-arylation or N-heteroarylation
conditions, for example by means of a palladium or copper
catalyst.
According to Scheme 2, route B, the compounds of general
formula (I), in which R1 represents a group R5 substituted
especially with a group R6 of the type C1-6-alkyl, C3-7-
cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene, or with a group R7
as defined in the general formula (I) defined above, may also
be prepared according to a coupling reaction, catalysed with a
transition metal, for example palladium(O), performed on the
compound of general formula (Ib), in which A, R2, R3, R4, R5, m,
n, o and p are as defined in the general formula (I) and U2
represents a chlorine, bromine or iodine atom or a triflate
group, U2 being in the position in which it is desired to
introduce the group R6 or R7:
either via a reaction of Suzuki type, for example using an
alkyl, cycloalkyl, aryl or heteroaryl boronic acid,
or according to a reaction of Stille type, for example using
an aryl or heteroaryl trialkyltin derivative,
or via a reaction of Negishi type, for example using an alkyl,
cycloalkyl, aryl or heteroaryl halide zincate.
Next, according to Scheme 2 route B, the intermediate of
general formula (Ib) as defined above is obtained beforehand
by reacting an amine of general formula (Ia) as defined above
with a derivative of general formula U2-R5-U1 (Va) , in which
R5, U1 and U2 are as defined above, using aromatic or
heteroaromatic nucleophilic substitution reactions or Buchwald
N-arylation or N-heteroarylation reactions, for example using
a palladium or copper catalyst.
One variant for obtaining the intermediates of general formula
(Ib) (Scheme 2 - route B variant) consists in reacting, in a
first stage, an amine of general formula (IIb), in which A,
R5, R2, m, n, o and p are as defined in the general formula (I)
defined above, and U2 is as defined above, with a carbonate of
general formula (III) as defined above, under the conditions
described above during the reaction of the amine of general
formula (II) with the carbonate of general formula (III), to
obtain the intermediate of general formula (Ib), in which A,
R5, R2, R3, R4, m, n, o and p are as defined in the general
formula (I), and U2 is as defined above.
Another subject of the present invention relates to a compound
of formula (Ia) as defined above.
Another subject of the present invention relates to a compound
of formula (Ic) as described above.
Another subject of the present invention relates to a compound
of formula (II) as described above.
Another subject of the present invention relates to a compound
of formula (IV) as described above.
The compounds of general formulae (IIa), (IIb), (III), (IIIa) ,
(V) and (Va) and also the other reagents are commercially
available or described in the literature, or may be prepared
according to methods that are described therein or that are
known to those skilled in the art.
In particular, the carbonate of general formula (III) may be
prepared according to any method described in the literature,
for example by reacting an alcohol of general formula HOCHR3R4
(IIIa), in which R3 and R4 are as defined in the general
formula (I) as defined above, with phenyl or 4-nitrophenyl
chloroformate, in the presence of a base such as
triethylamine, N-methylmorpholine or diisopropylethylamine, in
a solvent such as dichloromethane or tetrahydrofuran, at a
temperature between 0°C and room temperature.
The examples that follow illustrate the preparation of a
number of compounds of the invention. These examples are not
limiting, and serve merely to illustrate the invention. The
microanalyses and the IR, NMR and/or LC-MS (liquid
chromatography coupled to mass spectroscopy) spectra confirm
the structures and the purities of the compounds obtained.
LC-MS Method (M+H):
UPLC/TOF - Gradient 3 min - H2O/ACN /TFA TO: 98% A - T1.6 to
T2.1 min: 100% B - T2.5 to T3 min: 98% A route A: H2O + 0.05%
TFA; route B: ACN + 0.035% TFA flow rate: 1.0 mL/min - T° =
40°C - Injection 2 µL Acquity BEH C18 (50x2.1 mm; 1.7 urn)
column; 220 nm.
m.p. (°C) represents the melting point in degrees Celsius.
Rf indicates the retention time obtained by TLC analysis
(thin-layer chromatography).
The numbers given in parentheses in the example titles
correspond to those of the first column of the table
hereinbelow.
The IUPAC (International Union of Pure and Applied Chemistry)
nomenclature was used to name the compounds in the examples
below.
Example 1 (Compound 1)
Thiazol-4-ylmethyl [7-(6-fluoroguinolin-2-yl)-7-azaspiro [3.5]-
non-2-yl]carbamate

1.1. Benzyl (thiazol-4-ylmethoxycarbonylamino)-7-
azaspiro[3.5]nonane-7-carboxylate
A solution containing 0.32 g (1.15 mmol) of benzyl 2-amino-7-
azaspiro[3.5]nonane-7-carboxylate (WO92/22550), 0.36 g
(1.26 mmol) of thiazol-4-ylmethyl 4-nitrophenyl carbonate (WO
2008/013834), 0.45 g (3.44 mmol) of N,N-diisopropylethyl-amine
and 0.014 g (0.11 mmol) of N,N-dimethylaminopyridine in 5 mL
of dichloromethane is heated at 50°C for 2 hours.
Water is added to the reaction medium, the aqueous phase is
separated out and extracted several times with
dichloromethane, and the combined organic phases are washed
with aqueous sodium hydroxide solution (1N) and then with
saturated aqueous ammonium chloride solution. The resulting
phase is dried over sodium sulfate and the filtrate is
concentrated under reduced pressure.
After evaporating off the solvent, the residue obtained is
purified by chromatography on silica gel, eluting with a 95/5
mixture of dichloromethane and methanol.
0.345 g of pure product is thus obtained the form of a white
powder.
LC-MS: M+H = 416
m.p. (°C): 91-93°C
1H NMR (DMSO) d (ppm): 8.80 (s, 1H); 7.50-7.30 (m, 6H); 5.30
(s, 2H); 5.15 (s, 2H); 4.90 (broads, 1H); 4.15 (m, 1H); 3.50
(m, 2H); 3.30 (m, 2H); 2.30 (t, 2H); 1.70-1.40 (m, 6H) .
1.2. Thiazol-4-ylmethyl (7-azaspiro[3.5]non-2-yl)carbamate
1.22 mL (6.98 mmol) of a 5.7N solution of hydrobromic acid in
acetic acid are added slowly to a solution of 0.29 g
(0.70 mmol) of benzyl (thiazol-4-ylmethoxycarbonylamino)-7-
azaspiro [3.5]nonane-7-carboxylate, obtained in step 1.1., in
1 mL of acetic acid, cooled by means of an ice/water bath.
Stirring is continued at room temperature for 1 hour.
After evaporation under reduced pressure, the residue is taken
up in water and basified with aqueous sodium hydroxide
solution (30%). The resulting mixture is extracted several
times with dichloromethane and the combined organic phases are
then dried over sodium sulfate, and the filtrate is
concentrated under reduced pressure. 0.13 8 g of product is
obtained in the form of a colourless oil, which is used
without further purification in the following step.
1H NMR (CDCl3) d (ppm): 8.80 (s, 1H); 7.30 (s, 1H); 5.20 (s,
2H) ; 4.80 (m, 1H); 4.50 (broads, 1H); 4.00 (m, 1H); 2.90-2.70
(m, 3H); 2.40-2.10 (m, 3H); 1.70-1.40 (m, 6H).
1.3. Thiazol-4-ylmethyl [7-(6-fluoroquinolin-2-yl)-7-
azaspiro[3.5]non-2-yl]carbamate
0.135 g (0.48 mmol) of thiazol-4-ylmethyl (7-azaspiro[3.5]non-
2-yl)carbamate, obtained in step 1.2., 0.141 g (0.62 mmol) of
2-bromo-6-fluoroquinoline and 0.186 g (1.44 mmol) of N,N-
diisopropylethylamine are placed in a sealed tube in 1.5 mL of
acetonitrile. The mixture is then heated at 100°C for
12 hours. The reaction medium is allowed to cool to room
temperature and is then taken up in ethyl acetate, the aqueous
phase is separated out and extracted twice with ethyl acetate,
and the combined organic phases are washed with saturated
aqueous ammonium chloride solution and dried over sodium
sulfate. After evaporating off the solvent, the residue
obtained is purified by chromatography on preparative plates,
eluting with a 95/5/0.5 mixture of dichloromethane, methanol
and 2 8% aqueous ammonia.
0.100 g of pure product is thus obtained in the form of a
white powder.
LC-MS: M+H = 427
m.p. (°C): 107-109°C
1H NMR (DMSO) d (ppm) : 8.80 (s, 1H) ; 7.80 (d, 1H) ; 7.60 (m,
1H); 7.35 (s, 1H); 7.30-7.15 (m, 2H); 7.00 (d, 1H) ; 5.30 (s,
2H) ; 4.90 (broad s, 1H); 4.20 (m, 1H); 3.70-3.50 (m, 4H); 2.35
(t, 2H); 1.80-1.60 (m, 6H) .
Example 2 (Compound 5)
3-Carbamoylisoxazol-5-ylmethyl {7- [5-(4-fluorophenyl)pyridin-
2-yl] -7-azaspiro[3.5]non-2-yl}carbamate

2.1. tert-Butyl 2-azido-7-azaspiro[3.5]nonane-7-carboxylate
A solution of 5.90 g (18.47 mmol) of tert-butyl 2-
methanesulfonyloxy-7-azaspiro[3.5]nonane-7-carboxylate (WO
2003/084 948) and 3.60 g (55.41 mmol) of sodium azide in 27 mL
of N,N-dimethylformamide is refluxed for 12 hours under an
inert atmosphere.
The reaction medium is allowed to cool to room temperature and
is then taken up in dichloromethane and water, the aqueous
phase is separated out and extracted twice with
dichloromethane, and the combined organic phases are washed
with saturated aqueous sodium chloride solution and dried over
sodium sulfate. After evaporating off the solvent, 4.78 g of
product are obtained in the form of an orange oil, which is
used without further purification in the following step.
1H NMR (CDCl3) d(ppm): 3.80 (m, 1H) ; 3.20 (m, 4H) ; 2.30-2.10
(m, 2H); 1.90-1.70 (m, 2H); 1.50 (m, 4H); 1.35 (s, 9H).
2.2. tert-Butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate
1.85 g (8.97 mmol) of Lindlar catalyst (PdCaCO3) are added to
a solution of 4.78 g (17.95 mmol) of tert-butyl 2-azido-7-
azaspiro[3.5]nonane-7-carboxylate, obtained in step 2.1., in
70 mL of ethanol. The reaction medium is placed in a Parr
flask under a hydrogen atmosphere (20 psi) at room temperature
for 5 hours. The resulting mixture is filtered through Celite
and the filtrate is then concentrated under reduced pressure.
Water and dichloromethane are added. The aqueous phase is
separated out and then extracted three times with
dichloromethane, and the combined organic phases are washed
with saturated aqueous sodium chloride solution and dried over
sodium sulfate. After evaporating off the solvent, 3.62 g of
product are obtained in the form of an oil, which is used
without further purification in the following step.
1H NMR (DMSO) d (ppm): 3.40 (m, 1H); 3.30-3.10 (m, 4H); 2.25-
2.15 (m, 2H); 1.70 (broads, 2H); 1.50-1.35 (m, 6H) ; 1.30 (m,
9H) .
2.3. tert-Butyl 2-(4-nitrophenoxycarbonylamino)-7-aza-
spiro[3.5]nonane-7-carboxylate
0.922 g (4.58 mmol) of 4-nitrophenyl chloroformate is added
portionwise to a solution of 1.00 g (4.16 mmol) of tart-butyl
2-amino-7-azaspiro[3.5]nonane-7-carboxylate, prepared in step
2.2., 1.34 g (10.40 mmol) of N,N-diisopropylethylamine and
0.05 g (0.42 mmol) of N,N-dimethylaminopyridine in 40 mL of
dichloromethane, cooled to about 0°C. Stirring is continued at
0°C for 3 hours and then at room temperature for 3 hours.
Water is added to the reaction medium, the aqueous phase is
separated out and extracted several times with
dichloromethane, the combined organic phases are washed with
saturated aqueous ammonium chloride solution and then with
saturated aqueous sodium chloride solution and dried over
sodium sulfate, and the filtrate is concentrated under reduced
pressure. 1.8 g of product are thus obtained in the form of an
amorphous beige-coloured solid, which is used without further
purification in the following step.
1H NMR (CDCl3) d(ppm): 8.20 (d.2H); 7.30 (d.2H); 5.30 (broads,
1H); 4.10 (m, 1H); 3.25 (m, 4H); 2.30-2.10 (m, 2H); 1.70 (m,
2H); 1.50 (m, 4H); 1.40 (s, 9H).
2.4. tert-Butyl 2-(3-carbamoylisoxazol-5-ylmethoxycarbonyl-
amino)-7-azaspiro[3.5]nonane-7-carboxylate
A solution of 1.70 g (4.19 mmol) of tert-butyl 2-(4-nitro-
phenoxycarbonylamino)-7-azaspiro[3.5]nonane-7-carboxylate,
prepared in step 2.3., 1.08 g (8.39 mmol) of N,N-
diisopropylethylamine, 0.033 g (0.27 mmol) of N,N-
dimethylaminopyridine and 0.05 g (0.42 mmol) of 3-
carbamoylisoxazol-5-ylmethanol in 20 mL of 1,2-dichloroethane
is heated in a sealed tube at 90°C for 12 hours. The reaction
medium is allowed to cool to room temperature, water is added,
the aqueous phase is separated out and extracted several times
with dichloromethane, and the combined organic phases are
washed with aqueous sodium hydroxide solution (1N) and then
with saturated aqueous ammonium chloride solution and dried
over sodium sulfate, and the filtrate is concentrated under
reduced pressure. The oil obtained is crystallized from ether
and the solid thus obtained is filtered off and then rinsed
thoroughly with ether. After drying under vacuum at about
40°C, 0.910 g of pure product is obtained in the form of a
white powder.
LC-MS: M+H = 409
m.p. (°C): 123-125°C
1H NMR (DMSO) d (ppm) : 8.15 (broads, 1H) ; 7.80 (broad s, 1H) ;
7.70 (d, 1H) ; 6.80 (s, 1H); 5.20 (s, 2H); 4.00 (m, 1H); 3.30-
3.10 (m, 4H); 2.10 (m, 2H); 1.85 (m, 2H); 1.50 (m, 2H) ; 1.40
(s, 9H); 1.30 (m, 2H).
2.5. 3-Carbamoylisoxazol-5-ylmethyl (7-azaspiro[3.5]non-2-yl)-
carbamate hydrochloride
8 mL (32 mmol) of a 4N solution of hydrochloric acid in
dioxane are added slowly to a solution of 0.87 g (2.13 mmol)
of tert-butyl 2-(3-carbamoylisoxazol-5-ylmethoxycarbonyl-
amino)-7-azaspiro[3.5]nonane-7-carboxylate, obtained in step
2.4., in 2 mL of dioxane, cooled by means of an ice/water
bath. Stirring is continued at room temperature for 12 hours.
After evaporation under reduced pressure, 0.77 g of product is
obtained in hydrochloride form, which is used without further
purification in the following step.
1H NMR (D2O) d (ppm): 6.80 (s, 1H); 5.20 (s, 2H); 4.00 (m, 1H);
3.10 (m, 4H); 2.20 (m, 2H); 1.80 (m,6H).
2.6. 3-Carbamoylisoxazol-5-ylmethyl [7-(5-bromopyridin-2-yl)-
7-azaspiro[3.5]non-2-yl]carbamate
0.265 g (1.51 mmol) of 5-bromo-2-fluoropyridine, 0.40 g
(1.16 mmol) of 3-carbamoylisoxazol-5-ylmethyl (7-
azaspiro[3.5]non-2-yl)carbamate hydrochloride, prepared in
step 2.5., and 0.60 g (4.64 mmol) of N, N-diisopropylethylamine
in 3.5 mL of acetonitrile are placed in a sealed tube. 2 mL of
DMF are added and the mixture is then heated at 100°C for
12 hours. The reaction mixture is allowed to cool to room
temperature and is then taken up in dichloromethane and water.
The aqueous phase is separated out and extracted twice with
dichloromethane, and the combined organic phases are washed
with saturated aqueous ammonium chloride solution and then
with saturated aqueous sodium chloride solution and dried over
sodium sulfate, and the filtrate is concentrated under reduced
pressure. The oil obtained is triturated in diisopropyl ether.
The solid thus obtained is filtered off and then rinsed
thoroughly with ether. After drying under vacuum at about
40°C, 0.195 g of pure product is obtained in the form of a
beige-coloured powder.
LC-MS: M+H = 465
m.p. (°C): 165-167°C
1H NMR (DMSO) d (ppm): 8.10 (s, 2H); 7.80 (s, 1H); 7.70 (d,
1H); 7.60 (d, 1H); 6.85 (d, 1H); 6.75 (s, 1H); 5.20 (s, 2H);
4.00 (m, 1H); 3.55 (t, 2H); 3.45 (t, 2H); 2.20 (m, 2H); 1.75
(m; 2H); 1.65-1.45 (m, 4H).
2.7. 3-Carbamoylisoxazol-5-ylmethyl {7-[5-(4-fluorophenyl)-
pyridin-2-yl]-7-azaspiro[3.5]non-2-yl}carbamate
0.160 g (0.34 mmol) of 3-carbamoylisoxazol-5-ylmethyl [7-(5-
bromopyridin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate, obtained
in step 2.6., 0.058 g (0.41 mmol) of 4-fluorophenylboronic
acid, and 0.349 g (1.03 mmol) of caesium carbonate suspended
in 3 mL of a 9/1 mixture of tetrahydrofuran and water are
placed under an inert atmosphere. 0.028 g (0.03 mmol) of
PdCl2dppf .CH2Cl2 is then added. The mixture is then heated at
about 75°C for 12 hours. The resulting mixture is allowed to
cool to room temperature, the salts are separated out by
filtration on Celite, and the filtrate is then taken up in
dichloromethane and water. The aqueous phase is separated out
and extracted twice with dichloromethane, and the combined
organic phases are washed with saturated aqueous sodium
chloride solution and dried over sodium sulfate. After
evaporating off the solvent, the residue obtained is purified
by chromatography on preparative plates, eluting with a
90/10/1 mixture of dichloromethane/methanol and 28% aqueous
ammonia.
0.084 g of pure product is thus obtained in the form of a
white powder.
LC-MS: M+H = 480
m.p. (°C): 216-218°C
1H NMR (DMSO) d (ppm) : 8.40 (s, 1H) ; 8.20 (broad s, 1H) ; 7.90-
7.70 (m, 3H); 7.60 (m, 2H); 7.25 (m, 2H); 6.90 (d, 1H); 6.75
(s, 1H); 5.20 (s, 2H); 4.00 (m, 1H); 3.55 (t, 2H); 3.45 (t,
2H); 2.2 0 (m, 2H); 1.75 (m; 2H); 1.65-1.45 (m, 4H).
Example 3 (Compound 2)
3-Carbamoylisoxazol-5-ylmethyl [7-(6-fluoroquinolin-2-yl)-7-
azaspiro[3.5]non-2-yl]carbamate
The process is performed according to the procedure described
in Example 2 (step 2.6.). Starting with 0.20 g (0.58 mmol) of
3-carbamoylisoxazol-5-ylmethyl (7-azaspiro[3.5]non-2-yl)-
carbamate hydrochloride, described in Example 2 (step 2.5.),
0.170 g (0.75 mmol) of 2-bromo-6-fluoroquinoline and 0.30 g
(2.32 mmol) of N,N-diisopropylethylamine, and after
chromatography on preparative plates, eluting with a 9 0/10/1
mixture of dichloromethane, methanol and 28% aqueous ammonia,
0.05 g of pure product is obtained in the form of a white
powder.
LC-MS: M+H = 455
m.p. (°C): 226-228°C
1H NMR (DMSO) d (ppm): 8.15 (broad s, 1H); 8.00 (d, 1H); 7.85
(broad s, 1H); 7.70 (d, 1H); 7.60 (m, 1H); 7.50 (m, 1H); 7.40
(m, 1H); 7.30 (d, 1H); 6.70 (s, 1H); 5.20 (s, 2H); 4.10 (m,
1H); 3.70-3.50 (m, 4H); 2.35 (t, 2H); 1.80 (t, 2H); 1.70-1.40
(m, 4H) .
Example 4 (Compound 9)
3-(Methylcarbamoyl)isoxazol-5-ylmethyl [7-(6-fluoroquinolin-2-
yl)-7-azaspiro[3.5]non-2-yl]carbamate

4.1. 3-(Methylcarbamoyl)isoxazol-5-ylmethyl 4-nitrophenyl-
carbonate
2.58 g (12.81 mmol) of 4-nitrophenyl chloroformate are added
portionwise to a solution of 2.00 g (12.81 mmol) of 3-
(methylcarbamoyl)isoxazol-5-ylmethanol, 1.52 g (19.21 mmol) of
pyridine and 0.157 g (1.28 mmol) of N,N-dimethylaminopyridine,
in 15 mL of dichloromethane, cooled to about 0°C. Stirring is
continued at 0°C for 1 hour and then at room temperature for
1 hour. The precipitate thus formed is filtered off and then
rinsed thoroughly with diisopropyl ether. After drying under
vacuum at about 60°C, 2.60 g of product are obtained in the
form of a white powder, which is used without further
purification in the following step.
1H NMR (CDCl3) d (ppm) : 8.40(d, 2H) ; 7.50 (d, 2H) ; 7.0 (s, 1H) ;
6.90 (broads, 1H); 5.50 (s, 2H); 3.10 (d, 3H).
4.2. tert-Butyl 2-[3-(methylcarbamoyl)isoxazol-5-ylmethoxy-
carbonylamino]-7-azaspiro[3.5]nonane-7-carboxylate
The process is performed according to the procedure described
in Example 1, step 1.1. Starting with 0.3 g (1.25 mmol) of
tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate,
described in Example 2 (step 2.2.), 0.481 g (1.50 mmol) of 4-
3-(methylcarbamoyl)isoxazol-5-ylmethyl nitrophenyl carbonate,
obtained in step 4.1., 0.403 g (3.12 mmol) of N,N-
diisopropyl ethyl amine and 0.076 g (0.62 mmol) of N, N-
dimethylaminopyridine, and after precipitating with ether and
filtration, 0.3 64 g of product is obtained in the form of an
amorphous beige-coloured solid, which is used without further
purification in the following step.
LC-MS: M+H =423
1H NMR (DMSO) d (ppm): 8.80 (broads, 1H); 7.80 (d, 1H); 6.80
(d, 1H); 5.20 (s, 2H); 4.00 (m, 1H); 3.30-3.10 (m, 4H); 2.80
(s, 3H); 2.10 (m, 2H); 1.70 (m, 2H); 1.50 (m, 2H); 1.40 (s,
9H) ; 1.30 (m, 2H) .
4.3. 3-(Methylcarbamoyl)isoxazol-5-ylmethyl (7-azaspiro-
[3.5]non-2-yl)carbamate hydrochloride
The process is performed according to the procedure described
in Example 2, step 2.5. Starting with 0.364 g (0.86 mmol) of
tert-butyl 2-[3-(methylcarbamoyl)isoxazol-5-ylmethoxycarbonyl-
amino]-7-azaspiro[3.5]nonane-7-carboxylate, obtained in step
4.2., and 3.25 mL (12.92 mmol) of a 4N solution of
hydrochloric acid in dioxane, 0.32 g of product is obtained in
hydrochloride form, which is used without further purification
in the following step.
LC-MS: M+H =359
1H NMR (DMSO) d (ppm): 8.80 (broad s, 2H); 7.80 (d, 1H); 6.80
(S, 1H); 5.20 (s, 2H); 4.0 (m, 1H); 3.00-2.85 (m, 4H); 2.75
(s, 3H); 2.20 (m, 2H); 1.70 (m, 4H); 1.60 (m, 2H).
4.4. 3-(Methylcarbamoyl)isoxazol-5-ylmethyl [7-(6-fluoro-
guinolin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
The process is performed according to the procedure described
in Example 1 (step 1.3.). Starting with 0.163 g (0.45 mmol) of
3- (methylcarbamoyl)isoxazol-5-ylmethyl (7-azaspiro[3.5]non-2-
yl)carbamate hydrochloride, obtained in step 4.3., 0.133 g
(0.59 mmol) of 2-bromo-6-fluoroquinoline and 0.234 g
(1.82 mmol) of N,N-diisopropylethylamine, and after
purification by chromatography on preparative plates, eluting
with a 92.5/7.5/0.75 mixture of dichloromethane, methanol and
28% aqueous ammonia, 0.068 g of pure product is obtained in
the form of a white powder.
LC-MS: M+H =468
m.p. (°C): 193-195°C
1H NMR (DMSO) d (ppm): 8.70 (broads, 1H); 8.00 (d, 1H) ; 7.85
(d, 1H); 7.70 (m, 1H); 7.60 (m, 1H); 7.50 (m, 1H); 7.40 (m,
1H) ; 6.80 (s, 1H); 5.20 (s, 2H); 4.10 (m, 1H); 3.70-3.50 (m,
4H); 2.80(s, 3H) ; 2.20 (t, 2H) ; 1.70 (t, 2H); 1.70-1.50 (m,
4H) .
Example 5 (Compound 6)
3-Carbamoylisoxazol-5-ylmethyl [7-(6-fluoroquinolin-2-yl)-7-
azaspiro[3.5]non-2-yl]methylcarbamate

5.1. tert-Butyl 2-(aminomethyl)-7-azaspiro[3.5]nonane-7-
carboxylate
To a solution of 1.40 g (5.59 mmol) of tert-butyl 2-cyano-7-
azaspiro[3.5]nonane-7-carboxylate (Chem. Pharm. Bull.;
52(6) ,675-687, 2004), in 10 mL of a 1N solution of sodium
hydroxide in ethanol. 0.164 g (2.80 mmol) of Raney nickel is
then added. The reaction medium is placed in a Parr flask
under a hydrogen atmosphere (60 psi) at room temperature for
2 hours. The resulting mixture is filtered through a Buchner
funnel and the filtrate is then concentrated under reduced
pressure. Dichloromethane is added, the aqueous phase is
separated out and extracted three times with dichloromethane,
and the combined organic phases are washed with saturated
aqueous sodium chloride solution and dried over sodium
sulfate. After evaporating off the solvent, 1.212 g of product
are obtained in the form of a colourless oil, which is used
without further purification in the following step.
LC-MS: M+H = 255
1H NMR (DMSO) d (ppm) : 3.30-3.10 (m, 4H) ; 2.50(d, 2H) ; 2.10 (m,
1H); 1.80 (m, 2H); 1.40 (m, 2H) ; 1.30 (m, 13H).
5.2. tert-Butyl 2-[(4-nitrophenoxycarbonylamino)methyl]-7-
azaspiro[3.5]nonane-7-carboxylate
The process is performed according to the procedure described
in Example 2 (step 2.3.). Starting with 1.10 g (4.32 mmol) of
tert-butyl 2-aminomethyl-7-azaspiro[3.5]nonane-7-carboxylate,
prepared in step 5.1., 1.40 g (10.81 mmol) of N,N-
diisopropylethylamine, 0.053 g (0.43 mmol) of N,N-
dimethylaminopyridine and 0.959 g (4.76 mmol) of 4-nitrophenyl
chloroformate, 1.8 g of product are obtained in the form of a
yellow oil, which is used without further purification in the
following step.
5.3. tert-Butyl 2-[(3-carbamoylisoxazol-5-ylmethoxycarbonyl-
amino)methyl]-7-azaspiro[3.5]nonane-7-carboxylate
The process is performed according to the procedure described
in Example 2 (step 2.4.). Starting with 0.50 g (1.19 mmol) of
tert-butyl 2- [(4-nitrophenoxycarbonylamino)methyl] -7-azaspiro-
[3.5]nonane-7-carboxylate, prepared in step 5.2., 0.337 g
(2.38 mmol) of N,N-diisopropylethylamine, 0.073 g (0.60 mmol)
of N,N-dimethylaminopyridine and 0.169 g (1.19 mmol) of 3-
carbamoylisoxazol-5-ylmethanol, 0.50 g of product is obtained
in the form of an oil, which is used without further
purification in the following step.
5.4. 3-Carbamoylisoxazol-5-ylmethyl (7-azaspiro[3.5]non-2-
ylmethyl)carbamate hydrochloride
The process is performed according to the procedure described
in Example 2, step 2.5. Starting with 0.50 g (1.18 mmol) of
tert-butyl 2-[(3-carbamoylisoxazol-5-ylmethoxycarbonylamino)-
methyl]-7-azaspiro[3.5]nonane-7-carboxylate, obtained in step
5.3., and 2.96 mL (11.83 mmol) of a 4N solution of
hydrochloric acid in dioxane, 0.309 g of product is obtained
in hydrochloride form, which is used without further
purification in the following step.
LC-MS: M+H =359
m.p. (°C): 120-122
1H NMR (DMSO) d (ppm) : 8.10 (broad s, 1H) ; 7.80 (broad s, 1H) ;
7.50 (broads, 1H); 6.80 (s, 1H); 5.20 (s, 2H); 3.10 (m, 2H);
2.90 (m, 2H); 2.80 (m, 2H); 2.40 (m, 1H); 1.90 (t, 2H); 1.75
(m, 2H); 1.60 (m, 2H); 1.50 (t, 3H).
5.5. 3-Carbamoylisoxazol-5-ylmethyl [7-(6-fluoroquinolin-2-
yl)-7-azaspiro[3.5]non-2-yl]methylcarbamate
The process is performed according to the procedure described
in Example 1 (step 1.3.). Starting with 0.167 g (0.47 mmol) of
3-carbamoylisoxazol-5-ylmethyl (7-azaspiro[3.5]non-2-
ylmethyl)carbamate hydrochloride, described in step 5.4.,
0.137 g (0.60 mmol) of 2-bromo-6-fluoroquinoline and 0.180 g
(1.40 mmol) of N,N-diisopropylethylamine, and after
purification by chromatography on preparative plates, eluting
with a 90/10/1 mixture of dichloromethane, methanol and 28%
aqueous ammonia, 0.05 g of pure product is obtained in the
form of a white powder.
LC-MS: M+H = 468
m.p. (°C): 190-192°C
1H NMR (DMSO) d (ppm): 8.15 (broad s, 1H); 8.0 (d, 1H); 7.85
(broads, 1H); 7.60-7.35 (m, 4H); 7.25 (d, 1H); 6.75 (s, 1H);
5.20 (s, 2H); 3.70 (t, 2H); 3.60 (t, 2H); 3.10 (t, 2H) ; 2.40
(m, 1H); 1.90 (t, 2H); 1.70 (m, 2H); 1.60 (m, 4H).
Example 6 (Compound 10)
3-Carbamoylisoxazol-5-ylmethyl {6-[5-(4-fluorophenyl) pyridin-
2-yl]-6-azaspiro[3.4]oct-2-yl}carbamate (mixture of isomers)

6.1. tert-Butyl 2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate
0.89 g (23.57 mmol) of sodium borohydride is added portionwise
at 0°C to a solution of 3.54 g (15.71 mmol) of tert-butyl 2-
oxo-6-azaspiro[3.4]octane-6-carboxylate (WO98/06720) diluted
in 40 mL of methanol. The reaction mixture is stirred at room
temperature for 1 hour 30 minutes. After evaporating off the
solvent, water is added to the reaction medium, the aqueous
phase is separated out and extracted several times with
diethyl ether, the combined organic phases are washed with
saturated aqueous sodium chloride solution and dried over
sodium sulfate, and the filtrate is concentrated under reduced
pressure. After evaporating off the solvent, 3.10 g of product
are obtained in the form of a brown oil, which is used, without
further purification in the following step.
1H NMR (DMSO) d (ppm): 4.7 (t, 1H); 4.1 (m, 1H); 3.2 (m, 4H);
2.2 (m, 2H); 1.8 (m, 4H); 1.4 (s, 9H).
6.2.. tert-Butyl 2-methanesulfonyloxy-6-azaspiro[3.4]octane-6-
carboxylate
0.76 mL (5.49 mmol) of triethylamine and then 0.43 mL
(5.49 mmol) of mesyl chloride, are added to a solution of
1.52 g (4.99 mmol) of tert-butyl 2-hydroxy-6-azaspiro[3.4]-
octane-6-carboxylate, obtained in step 6.1., in 45 mL of
dichloromethane. The reaction medium is stirred at room
temperature for 1 hour 3 0 minutes. After evaporating off the
solvent, water is added to the reaction medium, the aqueous
phase is separated out and extracted several times with
dichloromethane, the combined organic phases are washed with
saturated aqueous sodium chloride solution and dried over
sodium sulfate, and the filtrate is concentrated under reduced
pressure. After evaporating off the solvent, 1.90 g of product
are obtained in the form of a brown oil, which is used without
further purification in the following step.
6.3. tert-Butyl 2-azido-6-azaspiro[3.4]octane-6-carboxylate
A solution of 0.46 g (1.51 mmol) of tert-butyl 2-
methanesulfonyloxy-6-azaspiro[3.4]octane-6-carboxylate,
prepared in step 6.2., and 0.19 g (3.01 mmol) of sodium azide
in 5 mL of N, N-dimethylformamide is refluxed for 12 hours
under an inert atmosphere. The reaction medium is allowed to
cool to room temperature and is then taken up in ethyl acetate
and water. The aqueous phase is separated out and extracted
twice with ethyl acetate, and the combined organic phases are
washed with saturated aqueous ammonium chloride solution and
dried over sodium sulfate. After evaporating off the solvent,
0.380 g of product is obtained in the form of an orange-
coloured oil, which is used without further purification in
the following step.
1H NMR (DMSO) d (ppm) : 4.0 (m, 1H); 3.4 (m, 4H); 2.4 (m, 2H);
2.2 (m, 2H); 1.9 (m, 2H); 1.5 (s, 9H) .
6.4. tert-Butyl 2-amino-6-azaspiro[3.4]octane-6-carboxylate
1.50 g (7.27 mmol) of Lindlar catalyst (PdCaCO3) are added to
a solution of 3.67 g (14.54 mmol) of tert-butyl 2-azido-6-
azaspiro[3.4]octane-6-carboxylate, obtained in step 6.3., in
60 mL of ethanol. The reaction medium is placed in a Parr
flask under a hydrogen atmosphere at 20 psi, at room
temperature for 5 hours. The resulting mixture is filtered
through Celite and the filtrate is then concentrated under
reduced pressure. After evaporating off the solvent, the
residue obtained is purified by chromatography on silica gel,
eluting with a 95/5/0.5 mixture of dichloromethane, methanol
and 28% aqueous ammonia.
1.57 g of pure product are thus obtained in the form of a
brown oil.
1H NMR (DMSO) d(ppm): 3.35 (m, 1H); 3.25-3.10 (m, 4H); 2.2 (m,
2H) ; 1.80 (t, 2H); 1.6 (m, 2H); 1.4 (s, 9H) .
6.5. tert-Butyl 2-(3-carbamoylisoxazol-5-ylmethoxycarbonyl-
amino)-6-azaspiro[3.4]octane-6-carboxylate
A solution of 0.3 04 g (1.51 mmol) of 4-nitrophenyl
chloroformate dissolved in 5 mL of 1,2-dichloroethane is added
dropwise to a solution containing 0.284 g (1.66 mmol) of ethyl
5-hydroxymethylisoxazole-3-carboxylate and 0.39 g (3.02 mmol)
of N, iV-diisopropylethylamine in 10 mL of 1,2-dichloroethane,
cooled to about 0°C. Stirring is continued at 0°C for 1 hour
and then at room temperature for 1 hour. 0.39 g (3.02 mmol) of
N,N-diisopropylethylamine and then 0.34 g (1.51 mmol) of tert-
butyl 2-amino-6-azaspiro[3.4]octane-6-carboxylate, prepared in
step 6.4., are added. The reaction medium is stirred at 70°C
for 4 hours. It is allowed to cool to room temperature. Water
is added to the reaction medium, the aqueous phase is
separated out and extracted several times with
dichloromethane, the combined organic phases are washed with
aqueous sodium hydroxide solution (IN) and then with saturated
aqueous ammonium chloride solution and dried over sodium
sulfate, and the filtrate is concentrated under reduced
pressure. 0.44 g of pure product is thus obtained in the form
of an orange oil, which is used without further purification
in the following step.
LC-MS: M+H =424
1H NMR (DMSO) d (ppm): 7.80 (broads, 1H); 6.90 (s, 1H); 5.20
(s, 2H); 4.40 (q, 2H) 4.00 (m, 1H); 3.40 -3.10 (m, 4H); 2.30
(m, 2H); 2.00-1.70 (m, 4H); 1.40 (s, 9H); 1.30 (t, 3H).
6.6. Ethyl 5-(6-azaspiro[3.4]oct-2-ylcarbamoyloxymethyl)-
isoxazole-3-carboxylate trifluoroacetate
0.88 mL (10.39 mmol) of a solution of trifluoroacetic acid is
added slowly to a solution of 0.44 g (1.04 mmol) of tert-butyl
2-(3-carbamoylisoxazol-5-ylmethoxycarbonylamino)-6-azaspiro-
[3.4]octane-6-carboxylate, obtained in step 6.5., in 10 mL of
dichloromethane, cooled by means of an ice/water bath.
Stirring is continued at room temperature for 4 hours.
After evaporation under reduced pressure, 0.45 g of product in
trifluoroacetate form is obtained, which is used without
further purification in step 6.8. below.
6.7. 2-Fluoro-5-(4-fluorophenyl)pyridine
2.51 g (14.29 mmol) of 4-fluorophenylboronic acid, 0.825 g
(0.71 mmol) of Pd(PPh3)4 and 50 mL of 1M sodium carbonate
solution are added to a solution of 2.0 g (14.29 mmol) of 5-
bromo-2-fluoropyridine in 140 mL of a 4/1 mixture of toluene
and ethanol. The mixture is stirred at 90°C for 2 hours.
The resulting mixture is allowed to cool to room temperature.
It is extracted several times with ethyl acetate. The organic
phases are then dried over sodium sulfate and evaporated to
dryness. 2.3 g of pure product are obtained in the form of a
white powder,
m.p. (°C): 98-100
1H NMR (DMSO) d (ppm) : 8.55 (m, 1H) , 8.28 (dd, 1H) , 7.78 (m,
2H), 7.54 (m, 2H) , 7.28 (dd, 1H).
6.8. Ethyl 5-{6-[5-(4-fluorophenyl)pyridin-2-yl]-6-azaspiro-
[3.4]oct-2-ylcarbamoyloxymethyl}-isoxazole-3-carboxylate
The process is performed according to the procedure described
in Example 1 (step 1.3.). Starting with 0.45 g (1.04 mmol) of
ethyl 5-(6-azaspiro[3.4]oct-2-ylcarbamoyloxymethyl) isoxazole-
3-carboxylate trifluoroacetate, described in step 6.6.,
0.198 g (1.04 mmol) of 2-fluoro-5-(4-fluorophenyl)pyridine,
prepared in step 6.7. and 0.40 g (3.12 mmol) of N,N-
diisopropylethylamine, and after purification by
chromatography on preparative plates, eluting with a 96/4
mixture of dichloromethane and methanol, 0.10 g of pure
product is obtained in the form of a wax, which is used
without further purification in the following step.
6.9. 3-Carbamoylisoxazol-5-ylmethyl {6-[5-(4-fluorophenyl)-
pyridin-2-yl]-6-azaspiro[3.4]oct-2-yl}carbamate
In a sealed tube, a solution of 0.045 g (0.09 mmol) of ethyl
5-{6-[5-(4-fluorophenyl)pyridin-2-yl]-6-azaspiro[3.4]oct-2-
ylcarbamoyloxymethyl}isoxazole-3-carboxylate, prepared in step
6.8., in 1.3 mL (9.10 mmol) of a solution (7M) of ammonia in
methanol, is stirred at 70°C for 2 hours.
The mixture is allowed to cool to room temperature and is then
evaporated to dryness. The residue obtained is crystallized
from hot methanol. The precipitate thus formed is filtered off
and then rinsed thoroughly with ether. After drying under
vacuum at about 40°C, 0.01 g of pure product is obtained in
the form of a white powder,
m.p. (°C): 216-218°C
1H NMR (DMSO) d (ppm) : 8.40 (s, 1H) ; 8.20 (broads, 1H) ; 7.80
(broads, 3H); 7.60 (s, 2H); 7.30 (s, 2H); 6.80 (s, 1H); 6.50
(t, 1H); 5.20 (s, 2H); 4.10 (m, 1H); 3.50 -3.30 (m, 4H); 2.30
(m, 2H); 2.00 ( m, 4H).
Example 7 (Compound 11)
3- (Methyl carbamoyl) isoxazol-5-ylmethyl {6- [5- (4-fluorophenyl)-
pyridin-2-yl]-6-azaspiro [3.4 ]oct-2-yl} carbamate (Mixture of
isomers)

The process is performed according to the procedure described
in Example 6 (step 6.9.). Starting with 0.045 g (0.09 mmol) of
ethyl 5-{6-[5-(4-fluorophenyl)pyridin-2-yl]-6-azaspiro [3 . 4] -
oct-2-ylcarbamoyloxymethyl}isoxazole-3-carboxylate, described
in Example 6 (step 6.8.) and 1.14 mL of a solution (8M) of
methylamine in ethanol, and after purification by
chromatography on preparative plates, eluting with ethyl
acetate, 0.009 g of pure product is obtained in the form of a
white powder,
m.p. (°C): 184-186°C
1H NMR (DMSO) d (ppm): 8.70 (s, 1H) ; 8.40 (s, 1H) ; 7.80 (m,
2H); 7.60 (m, 2H); 7.30 (m, 2H); 6.80 (s, 1H); 6.50 (t, 1H) ;
5.20 (s, 2H); 4.10 (m, 1H); 3.50-3.30 (m, 4H); 2.80 (s, 3H) ;
2.30 (m, 2H); 2.00 (m, 4H).
Example 8 (Compound 12)
3-(Methylcarbamoyl)isoxazol-5-ylmethyl 6-[5-(4-fluorophenyl)-
pyridin-2-yl] -6-azaspiro[3.4]oct-2-ylmethylcarbamate (isomer
I)

8.1. tert-Butyl 2-cyano-6-azaspiro[3.4]octane-6-carboxylate:
isomers 1a and 1b
3.05 g (62.21 mmol) of sodium cyanide are added to a solution
of 1.90 g (6.22 mmol) of tert-butyl 2-methanesulfonyloxy-6-
azaspiro[3.4]octane-6-carboxylate, prepared in Example 6 (step
6.2.), in 20 mL of anhydrous dimethyl sulfoxide. The reaction
mixture is then stirred at 13 0°C for 12 hours.
The reaction medium is allowed to warm to room temperature and
is then taken up in ether, the aqueous phase is separated out
and extracted twice with ether, and the combined organic
phases are then dried over sodium sulfate. After evaporating
off the solvent, the residue obtained is purified by
chromatography on silica gel, eluting with a 5/95 mixture of
ethyl acetate and cyclohexane. 0.27 g of isomer la is thus
obtained in the form of white crystals, and 0.20 g of isomer
1b is obtained in the form of a yellow oil.
Isomer 1a
m.p. (°C): 62-64°C
Rf = 0.49 (50/50 ethyl acetate/cyclohexane)
1H NMR (DMSO) d (ppm) : 3.4 (m, 1H) ; 3.1 (m, 4H) ; 2.5 (m, 4H) ;
2.3 (t, 2H); 1.4 (s, 9H).
Isomer 1b
Rf = 0.42 (50/50 ethyl acetate/cyclohexane)
1H NMR (DMSO) d (ppm): 3.4 (m, 1H) ; 3.3 (m, 2H) ; 3.2 (m, 2H) ;
2.5 (s, 4H); 1.9 (m, 2H); 1.4 (s, 9H).
8.2. tert-Butyl 2-aminomethyl-6-azaspiro[3.4]octane-6-
carboxylate: isomer 2a
Raney nickel is added in catalytic amount to a solution of
0.27 g (1.14 mmol) of tert-butyl 2-cyano-6-azaspiro[3.4]-
octane-6-carboxylate (isomer 1a), obtained in step 8.1., in
10 mL of a 1N solution of sodium hydroxide in ethanol. The
reaction medium is placed in a Parr flask under a hydrogen
atmosphere (4 bar), at room temperature for 5 hours.
The resulting mixture is filtered through Celite and the
filtrate is then concentrated under reduced pressure.
Dichloromethane is added, the aqueous phase is separated out
and extracted three times with dichloromethane, and the
combined organic phases are washed with saturated aqueous
sodium chloride solution and dried over sodium sulfate. After
evaporating off the solvent, 0.24 g of product is obtained in
the form of a yellow oil, which is used without further
purification in the following step.
Isomer 2a
LC-MS: M+H =241
1H NMR (DMSO) d (ppm): 3.2 (m, 2H); 3.1 (m, 2H); 2.5 (m, 2H);
2.2 (m, 1H) ; 1.9 (m, 2H) ; 1.7 (m, 2H) ; 1.6 (m, 2H) ; 1.4 (s,
9H) .
8.3. tert-Butyl 2-{[3-(methylcarbamoyl)isoxazol-5-ylmethoxy-
carbonylamino]methyl}-6-azaspiro[3.4]octane-6-carboxylate
The process is performed according to the procedure described
in Example 1, step 1.1. Starting with 0.22 g (0.92 mmol) of
tert-butyl 2-aminomethyl-6-azaspiro[3.4]octane-6-carboxylate
(isomer 2a), described in Example 8 (step 8.2.), 0.294 g
(0.92 mmol) of 3-(methylcarbamoyl)isoxazol-5-ylmethyl 4-nitro-
phenyl carbonate, obtained in step 4.1., 0.236 g (1.83 mmol)
of N,N-diisopropylethylamine and 0.011 g (0.09 mmol) of N,N~
dimethylaminopyridine, and after purification by
chromatography on silica gel, eluting with a 98/2 mixture of
dichloromethane and methanol, 0.310 g of pure product is thus
obtained in the form of an amorphous solid.
LC-MS: M+H = 423
1H NMR (DMSO) d (ppm): 8.80 (broad s, 1H) ; 7.50 (broad s, 1H) ;
6.80 (S, 1H); 5.20 (s, 2H); 3.25 (m, 2H); 3.15 (m, 2H); 3.10
(m, 2H); 2.80 (s, 3H); 2.40 (m, 1H);. 2.00-1.80 (m, 4H); 1.70
(m, 2H); 1.40 (s, 9H) 3.15 (m, 2H).
8.4. 3-(Methylcarbamoyl)isoxazol-5-ylmethyl (6-azaspiro[3.4]-
oct-2-ylmethyl)carbamate trifluoroacetate
The process is performed according to the procedure described
in Example 6, step 6.6. Starting with 0.31 g (0.73 mmol) of
tert-butyl 2-{[3-(methylcarbamoyl) isoxazol-5-ylmethoxy-
carbonylamino]methyl}-6-azaspiro[3.4]octane-6-carboxylate,
obtained in step 8.3. and 0.62 mL (7.34 mmol) of a
trifluoroacetic acid solution, 0.32 g of product in
trifluoroacetate form is obtained, which is used without
further purification in step 8.5. below.
8.5. 3-(Methylcarbamoyl)isoxazol-5-ylmethyl 6-[5-(4-fluoro-
phenyl)pyridin-2-yl]-6-azaspiro[3.4]oct-2-ylmethylcarbamate
(isomer I)
The process is performed according to the procedure described
in Example 1 (step 1.3.). Starting with 0.32 g (0.73 mmol) of
3-(methylcarbamoyl)isoxazol-5-ylmethyl (6-azaspiro[3.4]oct-2-
ylmethyl)carbamate trifluoroacetate, described in step 8.4.,
0.16 g (0.88 mmol) of 2-fluoro-5-(4-fluorophenyl)pyridine,
prepared in step 6.7. and 0.38 g (2.92 mmol) of N,N-
diisopropylethylamine, and after purification by
chromatography on silica gel, eluting with a 98/2/0.2 mixture
of dichloromethane and methanol and aqueous ammonia, 0.07 g of
pure product is thus obtained in the form of a white solid,
m.p. (°C): 171-173°C
LC-MS: M+H = 494
1H NMR (DMSO) d (ppm):8.70 (broads, 1H) ; 8.40 (s, 1H) ; 7.80 (m,
1H); 7.60 (m, 2H); 7.50 (m, 1H); 7.30 (m, 2H); 6.80 (s, 1H);
6.50 (d, 1H); 5.20 (s, 2H); 3.50 (m, 2H); 3.35 (m, 2H); 3.10
(t, 2H) 2.80 (s, 3H) ; 2.40 (m, 1H) ; 2.00 (m, 4H) ; 1.80 (m,
2H).
Example 9 (Compound 13)
3- (Methylcarbamoyl)isoxazol-5-ylmethyl 6- [5-(4-fluorophenyl)-
pyridin-2-yl]-6-azaspiro[3.4]oct-2-ylmethylcarbamate (isomer
II)

9.1. tert-Butyl 2-aminomethyl-6-azaspiro[3.4]octane-6-
carboxylate: isomer 2b
The process is performed according to the procedure described
in Example 8 (step 8.2.). Starting with 0.20 g (0.85 mmol) of
tert-butyl 2-cyano-6-azaspiro[3.4]octane-6-carboxylate,
(isomer lb), described in Example 8 (step 8.1.) and a
catalytic amount of Raney nickel, 0.22 g of product is
obtained in the form of a yellow oil, which is used without
further purification in the following step.
Isomer 2b
LC-MS: M+H = 241
^NMR (DMSO ) 5 (ppm) : 3.2 (m, 2H) ; 3.1 (m, 2H) ; 2.5 (m, 2H) ;
2.2 (m, 1H); 1.9 (m, 4H); 1.7 (m, 2H); 1.4 (s, 9H).
9.2. tert-Butyl 2-[(3-(methylcarbamoyl)isoxazol-5-ylmethoxy-
carbonylamino)methyl]-6-azaspiro[3.4]octane-6-carboxylate
The process is performed according to the procedure described
in Example 1, step 1.1. Starting with 0.24 g (1.00 mmol) of
tert-butyl 2-aminomethyl-6-azaspiro[3.4]octane-6-carboxylate
(isomer 2b), described in Example 9 (step 9.1.), 0.321 g
(1.00 mmol) of 3-(methylcarbamoyl)isoxazol-5-ylmethyl 4-nitro-
phenyl carbonate, obtained in step 4.1., 0.258 g (2.00 mmol)
of N,N-diisopropylethylamine and 0.012 g (0.10 mmol) of N,N-
dimethylaminopyridine, and after purification by
chromatography on silica gel, eluting with a 98/2 mixture of
dichloromethane and methanol, 0.320 g of pure product is thus
obtained in the form of an amorphous solid.
LC-MS: M+H =423
1H NMR (DMSO) d (ppm) : 8.80 (broad s, 1H); 7.50 (broad s, 1H) ;
6.80 (s, 1H); 5.20 (s, 2H); 3.25 (m, 2H); 3.15 (m, 2H); 3.10
(m, 2H); 2.80 (s, 3H); 2.40 (m, 1H); 2.00-1.80 (m, 4H); 1.70
(m, 2H); 1.40 (s, 9H) 3.15 (m, 2H).
9.3. 3-(Methylcarbamoyl)isoxazol-5-ylmethyl (6-azaspiro[3.4]-
oct-2-ylmethyl)carbamate trifluoroacetate
The process is performed according to the procedure described
in Example 6, step 6.6. Starting with 0.32 g (0.76 mmol) of
tert-butyl 2-[(3-(methylcarbamoyl)isoxazol-5-ylmethoxy-
carbonylamino)methyl]-6-azaspiro[3.4]octane-6-carboxylate,
obtained in step 9.2. and 0.64 mL (7.57 mmol) of a
trifluoroacetic acid solution, 0.33 g of product is obtained
in trifluoroacetate form, which is used without further
purification in step 9.4. below.
9.4. 3-(Methylcarbamoyl)isoxazol-5-ylmethyl 6-[5-(4-fluoro-
phenyl)pyridin-2-yl] -6-azaspiro [3 .4] oct-2-ylmethylcarbamate
(isomer II)
The process is performed according to the procedure described
in Example 1 (step 1.3.). Starting with 0.33 g (0.76 mmol) of
3-(methylcarbamoyl)isoxazol-5-ylmethyl (6-azaspiro[3.4]oct-2-
ylmethyl)carbamate trifluoroacetate, described in step 9.3.,
0.174 g (0.91 mmol) of 2-fluoro-5- (4-fluorophenyl)pyridine,
prepared in step 6.7. and 0.393 g (3.04 mmol) of N,N-
diisopropylethylamine, and after purification by
chromatography on silica gel, eluting with a 98/2 mixture of
dichloromethane and methanol, 0.10 g of pure product is thus
obtained in the form of a white solid,
m.p. (°C): 180-182°C
LC-MS: M+H = 494
1H NMR (DMSO) d (ppm): 8.70 (broads, 1H) ; 8.40 (s, 1H) ; 7.80 (m,
1H); 7.60 (m, 2H); 7.50 (m, 1H); 7.30 (m, 2H); 6.80 (s, 1H);
6.50 (d, 1H); 5.20 (s, 2H) ; 3.50 (s, 2H); 3.40 (m, 2H); 3.10
(t, 2H); 2.80 (s, 3H); 2.40 (m, 1H); 2.10 (t, 2H); 1.90 ( t,
2H) 1.80 (t, 2H).
Example 10 (Compound 8)
3-(Methylcarbamoyl)isoxazol-5-ylmethyl 7-[5-(4-fluorophenyl)-
pyridin-2 -yl]-7-azaspiro[3.5]non-2-ylcarbamate

10.1. 7-(5-Bromppyridin-2-yl)-7-azaspiro[3.5]nonan-2-ol
0.24 g (1.35 mmol) of 5-bromo-2-fluoropyridine, 0.20 g
(1.13 mmol) of 7-azaspiro[3.5]nonan-2-ol hydrochloride (JP
2003246780) and 0.51 g (3.94 mmol) of N,N-
diisopropylethylamine in 3 mL of acetonitrile are placed in a
sealed tube. 1 mL of DMF is added and the mixture is then
heated at 95°C for 12 hours. The reaction mixture is allowed
to cool to room temperature and is then taken up in ethyl
acetate and water. The aqueous phase is separated out and the
combined organic phases are then washed with saturated aqueous
ammonium chloride solution and dried over sodium sulfate, and
the filtrate is concentrated under reduced pressure. After
purification by chromatography on silica gel, eluting with a
95/5/0.5 mixture of dichloromethane, methanol and 28% aqueous
ammonia, 0.138 g pure product is thus obtained in the form of
a colourless gum.
LC-MS: M+H = 298
1H NMR (CDCl3) d (ppm) : 8.10 (s, 1H) ; 7.50 (d, 1H) ; 6.50 (d,
1H); 4.3 0 (m, 1H); 3.3 0 (m, 4H); 2.25 (m, 2H); 1.65 (m, 2H);
1.50 (m, 4H).
10.2 . 7- [5- (4-Fluorophenyl)pyridin-2-yl] -7-azaspiro[3 .5]nonan-
2-ol
The process is performed according to the procedure described
in Example 2 (step 2.7.). Starting with 0.138 g (0.46 mmol) of
7- (5-bromopyridin-2-yl) -7-azaspiro[3 .5]nonan-2-ol, obtained in
step 10.1., 0.078 g (0.56 mmol) of 4-fluorophenylboronic acid,
0.454 g (1.39 mmol) of caesium carbonate suspended in 3 mL of
a 9/1 mixture of tetrahydrofuran and water. 0.038 g
(0.05 mmol) of PdCl2dppf.CH22Cl2 is then added. 0.101 g of pure
product is thus obtained in the form of a grey powder,
m.p. (°C): 139-141°C
LC-MS: M+H = 313
1H NMR (CDCl3) d (ppm) : 8.30 (s, 1H) ; 7.60 (d, 1H) ; 7.40 (m,
2H) ; 7.10 (m, 2H); 6.60 (d, 1H); 4.30 (m, 1H) ; 3.30 (m, 4H) ;
2.30 (m, 2H); 1.65 (m, 2H); 1.50 (m, 4H).
10 .3 . 7- [5- (4-Fluorophenyl)pyridin-2-yl] -7-azaspiro [3 .5]non-2-
yl methanesulfonate
The process is performed according to the procedure described
in Example 6 (step 6.2.). 3.25 mL (23.34 mmol) of
triethylamine and then 0.91 mL (11.67 mmol) of mesyl chloride
are added to a solution of 2.43 g (7.78 mmol) of 7-[5-(4-
fluorophenyl)pyridin-2-yl]-7-azaspiro[3.5]nonan-2-ol, obtained
in step 10.2., in 25 mL of dichloromethane. 3.03 g of product
are obtained in the form of a yellow oil, which is used
without further purification in the following step.
10.4. 2-Azido-7-[5-(4-fluorophenyl)pyridin-2-yl]-7-azaspiro-
[3.5]nonane
The process is performed according to the procedure described
in Example 6 (step 6.3.). Starting with 7.66 g (19.62 mmol) of
7-[5-(4-fluorophenyl)pyridin-2-yl]-7-azaspiro[3.5]non-2-yl
methanesulfonate, prepared in step 10.3., and 3.83 g
(58.85 mmol) of sodium azide in 28 mL of N,N-
dimethylformamide. After evaporating off the solvent, 6.60 g
of product are obtained in the form of a brown oil.
10.5. 7-[5-(4-Fluorophenyl)pyridin-2-yl]-7-azaspiro[3.5]non-2-
ylamine
The process is performed according to the procedure described
in Example 6 (step 6.4.). Starting with 6.60 g (19.56 mmol) of
2-azido-7-[5-(4-fluorophenyl)pyridin-2-yl]-7-azaspiro[3.5]-
nonane, obtained in step 10.4., in 28 mL of ethanol, 0.81 g
(3.91 mmol) of Lindlar catalyst (PdCaCO3) is added. 3.89 g of
pure product are thus obtained in the form of a yellow powder,
m.p. (°C): 120-122°C
LC-MS: M+H =312
1H NMR (CDCl3) d (ppm) : 8.45 (s, 1H) ; 7.70 (m, 1H) ; 7.50 (m,
2H); 7.20 (m, 2H); 6.80 (d, 1H); 3.70-3.40 (m, 5H); 2.35 (m,
4H); 1.80-1.50 (m, 6H).
10.6. 3-(Methylcarbamoyl)isoxazol-5-ylmethyl 7-[5-(4-fluoro-
phenyl)pyridin-2-yl]-7-azaspiro[3.5]non-2-ylcarbamate
The process is performed according to the procedure described
in Example 1, step 1.1. Starting with 1.08 g (3.47 mmol) of 7-
[5-(4-fluorophenyl)pyridin-2-yl]-7-azaspiro[3.5]non-2 -ylamine,
described in the preceding step (step 10.5.), 1.34 g
(4.16 mmol) of 3- (methylcarbamoyl) isoxazol-5-ylmethyl 4-
nitrophenyl carbonate, obtained in step 4.1., 1.12 g
(8.67 mmol) of N,N-diisopropylethylamine and 0.212 g
(1.73 mmol) of N,iV-dimethylaminopyridine, and after
purification by chromatography on silica gel, eluting with a
98/2 mixture of dichloromethane and methanol, 0.847 g of pure
product is thus obtained in the form of a white solid,
m.p. (°C): 219-221°C
LC-MS: M+H = 493
1H NMR (DMSO) d (ppm): 8.70 (broads, 1H); 8.40 (s, 1H); 7.90-
7.70 (m, 2H) ; 7.65 (m, 2H) ; 7.25 (m, 2H) ; 6.90 (d, 1H) ;
6.80(s, 1H); 5.20 (s, 2H); 4.00 (m, 1H); 3.55 (t, 2H); 3.45
(t, 2H); 2.80 (s, 3H); 2.20 (m, 2H); 1.75 (m; 2H); 1.65-1.45
(m, 4H) .
Example 11 (Compound 15)
3-(Methylcarbamoyl)isoxazol-5-ylmethyl 2-(6-fluoroquinolin-2-
yl)-2-azaspiro[3.3]hept-6-ylcarbamate
30.83 g (0.471 mmol) of zinc are added. After stirring at room
temperature for 12 hours, the Celite is filtered off and
rinsed with methanol. The filtrate is evaporated to dryness.
The residue obtained is taken up in water and extracted
several times with ethyl acetate. The combined organic phases
are dried over sodium sulfate and the filtrate is concentrated
under reduced pressure. After evaporating off the solvent, the
residue obtained is purified by chromatography on silica gel,
eluting with a 90/10 mixture of cyclohexane and ethyl acetate.
1.78 g of pure product are thus obtained in the form of a
white powder.
m.p. (°C): 117-119°C
LC-MS: M+H = 212
1H NMR (DMSO) d(ppm) : 4.05 (s, 4H) ; 3.30 (s, 4H) ; 1.40 (s, 9H) .
11.3. tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-
carboxylate
The process is performed according to the procedure described
in Example 6, step 6.1. Starting with 1.40 g (6.63 mmol) of
tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate,
obtained in step 11.2., dissolved in 17 mL of methanol and
0.376 g (9.94 mmol) of sodium borohydride. After evaporating
off the solvent and crystallizing from a 70/30 mixture of
petroleum ether and diisopropyl ether, 1.18 g of the expected
product are obtained in the form of a white powder,
m.p. (°C): 131-133°C
LC-MS: M+H =214
1H NMR (DMSO) d(ppm) : 5.00 (s, 1H) ; 3.95 (m, 1H) ; 3.75 (d, 4H) ;
2.40 (m, 2H); 1.90 (m, 2H); 1.40 (s, 9H).
11.4. tert-Butyl 2-azaspiro[3.3]heptane-2-carboxylate 6-
methanesulfonate
The process is performed according to the procedure described
in Example 6, step 6.2. Starting with 0.97 g (4.55 mmol) of
tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate,
obtained in step 11.3. dissolved in 40 mL of dichloromethane,
0.70 mL (5.00 mmol) of triethylamine and 0.39 mL (5.00 mmol)
of mesyl chloride, and after purification on a column of
silica gel, eluting with a 90/10 to 70/30 gradient of a
mixture of cyclohexane and ethyl acetate, 0.790 g of product •
is obtained, which is used without further purification in the
following step.
11.5. tert-Butyl 6-azido-2-azaspiro[3.3]heptane-2-carboxylate
The process is performed according to the procedure described
in Example 2, step 2.1. Starting with 0.780 g (2.68 mmol) of
tert-butyl 2-azaspiro[3.3]heptane-2-carboxylate 6-
methanesulfonate obtained in step 11.4. and 0.350 g
(5.35 mmol) of sodium azide in 8 mL of N,N-dimethylformamide,
0.63 g of product is obtained, which is used without further
purification in the following step.
11.6. tert-Butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate
The process is performed according to the procedure described
in Example 6 (step 6.4.). Starting with 0.638 g (2.68 mmol) of
tert-butyl 6-azido-2-azaspiro[3.3]heptane-2-carboxylate,
obtained in step 11.5., in 11 mL of ethanol, 0.276 g
(1.34 mmol) of Lindlar catalyst (PdCaCO3) is added. After
purification on a column of silica gel, eluting with a
98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous
ammonia, 0.330 g of pure product is obtained in the form of a
white powder.
m.p. (°C): 50-53°C
LC-MS: M+H =213
1H NMR (DMSO+ D2O) d(ppm) : 3.80 (s, 2H) ; 3.70 (s, 2H) ; 3.10 (m,
1H); 2.30 (t, 2H); 1.75 (t, 2H); 1.40 (s, 9H).
11.7. tert-Butyl 6-(3-ethoxycarbonylisoxazol-5-ylmethoxy-
carbonylamino)-2-azaspiro[3.3]heptane-2-carboxylate
0.341 g (2.64 mmol) of -N,N-diisopropylethylamine and 0.2 65 g
(1.32 mmol) of 4-nitrophenyl chloroformate are added to a
solution of 0.226 g (1.32 mmol) of ethyl 5-
hydroxymethylisoxazole-3-carboxylate in 10 mL of
dichloroethane. Stirring is continued at room temperature for
2 hours and 0.280 g (1.32 mmol) of tert-butyl 6-amino-2-
azaspiro[3.3]heptane-2-carboxylate, obtained in step 11.6.,
dissolved in 4 mL of dichloroethane, is then added. Stirring
is continued at room temperature for 4 hours. Water is added
to the reaction medium, the aqueous phase is separated out and
extracted several times with dichloromethane, and the combined
organic phases are washed with aqueous sodium hydroxide
solution (1N) and then with saturated aqueous ammonium
chloride solution. The resulting phase is dried over sodium
sulfate and the filtrate is concentrated under reduced
pressure. After evaporating off the solvent, the residue
obtained is purified by chromatography on silica gel, eluting
with a 98/2 mixture of dichloromethane and methanol.
0.42 g of pure product is thus obtained in the form of an
amorphous solid.
LC-MS: M+H =410
1H NMR (DMSO) d (ppm): 7.70 (d, 1H); 6.90 (s, 1H); 5.20 (s,
2H); 4.40 (m, 3H); 3.85 (m, 2H); 3.75 (s, 2H); 2.40 (t, 2H);
2.10 (t, 2H); 1.40-1.20 (m, 12H).
11.8. Ethyl 5-(2-azaspiro[3.3]hept-6-ylcarbamoyloxymethyl)-
isoxazole-3-carboxylate trifluoroacetate
The process is performed according to the procedure described
in Example 6, step 6.6. Starting with 0.42 g (1.03 mmol) of
tert-butyl 6-(3-ethoxycarbonylisoxazol-5-ylmethoxycarbonyl-
amino)-2-azaspiro[3.3]heptane-2-carboxylate, obtained in step
11.7., and 0.86 mL (10.26 mmol) of a trifluoroacetic acid
solution, 0.43 g of product in trifluoroacetate form is
obtained, which is used without further purification in step
11.9. below.
11.9. Ethyl 5-[2-(6-Fluoroquinolin-2-yl)-2-azaspiro[3.3]hept-
6-ylcarbainoyloxymethyl]isoxazole-3-carboxylate
The process is performed according to the procedure described
in Example 2 (step 2.6.). Starting with 0.43 g (1.03 mmol) of
ethyl 5-(2-azaspiro[3.3]hept-6-ylcarbamoyloxymethyl)isoxazole-
3-carboxylate trifluoroacetate, obtained in step 11.8.,
0.187 g (1.03 mmol) of 2-chloro-6-fluoroquinoline and 0.399 g
(3.09 mmol) of N,N-diisopropylethylamine, and after
chromatography on silica gel, eluting with a 98/2 mixture of
dichloromethane and methanol, 0.15 g of pure product in the
form of a beige-coloured solid is thus obtained.
LC-MS: M+H = 455
m.p. (°C): 107-109°C
1H NMR (DMSO) d (ppm) : 8.05 (d, 1H) ; 7.80 (d, 1H); 7.60 (m,
1H); 7.50 (m, 1H); 7.40 (m, 1H); 6.90 (s, 1H); 6.70 (d, 1H);
5.25 (s, 2H); 4.40 (q, 2H); 4.10 (s, 2H); 4.00 (s, 2H); 3.90
(m, 1H); 2.50 (t, 2H); 2.20 (t, 2H); 1.35 (t, 3H).
11.10. 3-(Methylcarbamoyl)isoxazol-5-ylmethyl 2-(6-fluoro-
quinolin-2-yl)-2-azaspiro[3.3]hept-6-ylcarbamate
In a sealed tube, a solution of 0.13 0 g (0.28 mmol) of ethyl
5-[2-(6-fluoroquinolin-2-yl)-2-azaspiro[3.3]hept-6-ylcarb-
amoyl oxymethyl] isoxazole-3-carboxylate, prepared in step
11.9., in 4.13 mL (28.01 mmol) of a solution (8M) of
methylamine in ethanol, is stirred at room temperature for
5 hours. The mixture is evaporated to dryness. The residue
obtained is crystallized from hot ether. The precipitate thus
formed is filtered off and rinsed thoroughly with ether. After
drying under vacuum at about 60°C, 0.05 g of pure product is
obtained in the form of a white powder,
m.p. (°C): 167-169°C
1H NMR (DMSO) d (ppm): 8.70 (broads, 1H); 8.05 (d, 1H); 7.80
(d, 1H); 7.60 (m, 1H); 7.50 (m, 1H); 7.40 (m, 1H); 6.80 (s,
1H); 6.75 (d, 1H); 5.25 (s, 2H); 4.15 (s, 2H); 4.05 (s, 2H);
3.95 (m, 1H); 2.80 (s, 3H); 2.50 (t, 2H); 2.20 (t, 2H).
Example 12 (Compound 17)
3-(Methylcarbamoyl)isoxazol-5-ylmethyl {6- [5- (4-fluorophenyl) -
pyridin-2-yl]-6-azaspiro[3.4]oct-2-yl}carbamate (isomer I)

12.1 tert-Butyl 2-methanesulfonyloxy-6-azaspiro[3.4]octane-6-
carboxylate (isomers 1 and 1') .
Isomers 1 and 1' of tert-butyl 2-methanesulfonyloxy-6-aza-
spiro[3.4]octane-6-carboxylate, prepared according to the
method described in Example 6 (step 6.2.), are separated by
column-chromatography on silica gel, eluting with a 100/0 to
80/20 eyelohexane/ethyl acetate mixture. 1.69 g of isomer 1 in
the form of a white solid, and 1.62 g of isomer 1_[_ in the form
of a white solid, are thus obtained.
Isomer 1
m.p. (°C): 76-78°C
LC-MS: M+H = 306
Rf = 0.35 (50/50 ethyl acetate/cyclohexane)
1H MR (DMSO) d (ppm) : 5.08 (m, 1H) ; 3.28 (m, 2H) ; 3.20 (m,
2H); 3.15 (s, 3H); 2.42 (m, 2H); 2.22 (m, 2H); 1.85 (m, 2H);
1.40 (s, 9H).
Isomer 1'
m.p. (°C): 79-82°C
LC-MS: M+H =3 06
Rf = 0.29 (50/50 ethyl acetate/cyclohexane)
1H NMR (DMSO) d (ppm): 5.00 (m, 1H); 3.22 (m, 4H), 3.12 (s,
3H), 2.36 (m, 2H); 2.22 (m, 2H), 1.80 (m, 2H); 1.35 (s, 9H).
12.2 tert-Butyl 2-azido-6-azaspiro[3.4]octane-6-carboxylate
(isomer 2')
The process is performed according to the procedure described
in Example 6 (step 6.3.). Starting with 1.62 g (5.30 mmol) of
tert-butyl 2-methanesulfonyloxy-6-azaspiro[3.4] octane-6-
carboxylate (isomer 1'), described in Example 12 (step 12.1.),
and 0.68 g (10.61 mmol) of sodium azide, the product is
obtained in the form of a yellow oil, which is used without
further purification in the following step.
12.3 tert-Butyl 2-amino-6-azaspiro [3.4]octane-6-carboxylate
(isomer 3')
The process is performed according to the procedure described
in Example 6 (step 6.4.). Starting with 1.33 g (5.30 mmol) of
tert-butyl 2-azido-6-azaspiro[3.4]octane-6-carboxylate (isomer
2') and 0.54 g (2.65 mmol) of Lindlar catalyst (PdCaCO3),
0.7 0 g of product is obtained in the form of an oil.
LC-MS: M+H = 227
1H NMR (DMSO +D2O) d (ppm) : 3.24 (m, 1H) ; 3.15 (m, 4H) ; 2.12
(m, 2H); 1.74 (m, 2H); 1.60 (m, 2H); 1.36 (s, 9H).
12.4 tert-Butyl 2-(3-carbamoylisoxazol-5-ylmethoxycarbonyl-
amino)-6-azaspiro[3.4]octane-6-carboxylate (isomer 4')
The process is performed according to the procedure described
in Example 4 (step 4.2). Starting with 0.70 g (3.09 mmol) of
tert-butyl 2-amino-6-azaspiro[3.4]octane-6-carboxylate (isomer
3') and 1.04 g (3.09 mmol) of ethyl 5-(4-nitrophenoxycarbonyl-
oxymethyl) isoxazole-3-carboxylate, 1.10 g of product are
obtained in the form of a gum.
LC-MS: M+H =424
1H NMR (DMSO) d (ppm): 7.80 (bd, 1H); 6.92 (s, 1H); 5.21 (s,
2H) ; 4.35 (q, 2H); 3.98 (m, 1H); 3.21 (m, 2H); 3.15 (m, 2H) ;
2.21 (m, 2H); 1.90 (m, 2H); 1.75 (m, 2H); 1.40 (s, 9H); 1.30
(t, 3H).
12.5 Ethyl 5-(6-azaspiro[3.4]oct-2-ylcarbamoyloxymethyl)-
isoxazole-3-carboxylate trifluoroacetate (isomer 5')
The process is performed according to the procedure described
in Example 6 (step 6.6.). Starting with 1.10 g (2.60 mmol) of
tert-butyl 2-(3-carbamoylisoxazol-5-ylmethoxycarbonylamino)-6-
azaspiro[3.4]octane-6-carboxylate (isomer 4') and 2.19 mL
(25.98 mmol) of trifluoroacetic acid, the product is obtained,
which is used in the following step.
12.6 Ethyl 5-[6-(5-bromopyridin-2-yl)-6-azaspiro[3.4]oct-2-
ylcarbamoyloxymethyl]-isoxazole-3-carboxylate (isomer 6')
The process is performed according to the procedure described
in Example 2 (step 2.6.). Starting with 0.43 g (1.03 mmol) of
ethyl 5-(6-azaspiro [3.4] oct-2-ylcarbamoyloxymethyl) isoxazole-
3-carboxylate trifluoroacetate (isomer 5'), obtained in step
12.5., and 0.45 g (2.60 mmol) of 2-fluoro-5-bromopyridine, and
after chromatography on silica gel, eluting with a 97/3
mixture of dichloromethane and methanol, 0.68 g of pure
product is obtained in the form of an oil.
12.7 Ethyl 5-{6-[5-(4-fluorophenyl)pyridin-2-yl]-6-azaspiro-
[3.4]oct-2-ylcarbamoyloxymethyl}-isoxazole-3-carboxylate
(isomer 7')
The process is performed according to the procedure described
in Example 2 (step 2.7.). Starting with 0.68 g (1.42 mmol) of
ethyl 5-[6-(5-bromopyridin-2-yl)-6-azaspiro[3.4]oct-2-ylcarb-
amoyloxymethyl]isoxazole-3-carboxylate (isomer 6') and 0.23 g
(1.70 mmol) Of 4-fluorophenylboronic acid, 1.38 g (4.26 mmol)
of caesium carbonate and 0.11 g (0.14 mmol) of
PdCl2dppf.CH2Cl2, 0.32 g of a white solid is obtained,
m.p. (°C) = 164-166
LC-MS: M+H = 495
1H NMR (DMSO) d (ppm): 8.40 (s, 1H) ; 7.80 (m, 2H) ; 7.62 (m, 2H) ;
7.22 (t, 2H); 6.89 (s, 1H); 6.50 (d, 1H); 5.21 (s, 2H); 4.35
(q, 2H) ; 4.05 (m, 1H); 3.50 (s, 2H); 3.40 (m, 2H); 2.30 (m,
2H) ; 2.00 (m, 4H) ; 1.30 (t, 3H) .
12.8 3-(Methylcarbamoyl)isoxazol-5-ylmethyl {6-[5-(4-fluoro-
phenyl)pyridin-2-yl]-6-azaspiro[3.4]oct-2-yl}carbamate (isomer
I)
The process is performed according to the procedure described
in Example 6 (step 6.9.). Starting with 0.3 g (0.61 mmol) of
ethyl 5-{6-[5-(4-fluorophenyl)pyridin-2-yl]-6-azaspiro[3.4]-
oct-2-ylcarbamoyloxymethyl}isoxazole-3-carboxylate (isomer 7')
and 15 mL of a solution (1M) of methylamine in tetrahydrofuran
at room temperature, 0.21 g of product is obtained in the form
of a white solid.
LC-MS: M+H =480
m.p. (°C): 203-205
1H NMR (DMSO) d (ppm) : 8.70 (broads, 1H), 8.40 (s, 1H); 7.81
(m, 2H); 7.62 (m, 2H); 7.25 (t, 2H); 6.78 (s, 1H); 6.50 (d,
1H); 5.20 (s, 2H); 4.08 (m, 1H); 3.50 (s, 2H), 3.40 (m, 2H);
2.78 (s, 3H), 2.30 (m, 2H); 1.99 ( m, 4H).
Example 13 (Compound 18)
3-(Methylcarbamoyl)isoxazol-5-ylmethyl {6-[5-(4-fluorophenyl)-
pyridin-2-yl]-6-azaspiro[3.4]oct-2-yl}carbamate (isomer II)

13.1 tert-Butyl 2-azido-6-azaspiro[3.4]octane-6-carboxylate
(isomer 2)
The process is performed according to the procedure described
in Example 6 (step 6.3.). Starting with 2.49 g (8.15 mmol) of
tert-butyl 2-methanesulfonyloxy-6-azaspiro[3.4]octane-6-
carboxylate (isomer 1), described in Example 12 (step 12.1.)
and 1.07 g (16.31 mmol) of sodium azide, the product is
obtained, which is used in the following step.
13.2 tert-Butyl 2-amino-6-azaspiro[3.4]octane-6-carboxylate
(isomer 3)
The process is performed according to the procedure described
in Example 6 (step 6.4.). Starting with 2.05 g (8.15 mmol) of
tert-butyl 2-azido-6-azaspiro[3.4]octane-6-carboxylate (isomer
2) and 0.84 g (4.08 mmol) of Lindlar catalyst (PdCaCO3) ,
1.11 g of product are obtained in the form of a yellow oil.
LC-MS: M+H =227
1H NMR (DMSO +D2O) d (ppm) : 3.25 (m, 1H) ; 3.20 (m, 2H) ; 3.10
(m, 2H); 2.10 (m, 2H); 1.75 (m, 2H); 1.65 (m, 2H); 1.40 (s,
9H) .
13.3 tert-Butyl 2-(3-carbamoylisoxazol-5-ylmethoxycarbonyl-
amino)-6-azaspiro[3 .4]octane-6-carboxylate (isomer 4)
The process is performed according to the procedure described
in Example 4 (step 4.2). Starting with 1.11 g (4.90 mmol) of
tert-butyl 2-amino-6-azaspiro[3.4]octane-6-carboxylate (isomer
3) and 1.64 g (4.90 mmol) of ethyl 5-(4-nitrophenoxycarbonyl-
oxymethyl) isoxazole-3-carboxylate, 1.65 g of product are
obtained in the form of a gum.
LC-MS: M+H =424
1H NMR (DMSO) d (ppm): 7.75 (broad t, 1H) ; 6.90 (s, 1H) ; 5.20
(s, 2H); 4.35 (q, 2H); 3.99 (m, 1H); 3.21 (m, 2H); 3.11 (m,
2H) ; 2.19 (m, 2H); 1.92 (m, 2H); 1.81 (m, 2H) ; 1.41 (s, 9H) ;
1.32 (t, 3H).
13.4 Ethyl 5-(6-azaspiro[3.4]oct-2-ylcarbamoyloxymethyl)-
isoxazole-3-carboxylate trifluoroacetate (isomer 5)
The process is performed according to the procedure described
in Example 6 (step 6.6.). Starting with 1.65 g (3.90 mmol) of
tert-butyl 2-(3-carbamoylisoxazol-5-ylmethoxycarbonylamino)-6-
azaspiro[3.4]octane-6-carboxylate (isomer 4) and 3.28 mL
(38.96 mmol) of trifluoroacetic acid, the product is obtained,
which is used in the following step.
13.5 Ethyl 5-[6-(5-bromopyridin-2-yl)-6-azaspiro[3.4]oct-2-
ylcarbamoyloxymethyl]isoxazole-3-carboxylate (isomer 6)
The process is performed according to the procedure described
in Example 2 (step 2.6.). Starting with 1.7 g (3.90 mmol) of
ethyl 5-(6-azaspiro[3.4]oct-2-ylcarbamoyloxymethyl)isoxazole-
3-carboxylate trifluoroacetate (isomer 5) and 0.68 g
(3.90 mmol) of 2-fluoro-5-bromopyridine, and . after
chromatography on silica gel, eluting with a 98/2 mixture of
dichloromethane and methanol, 1.00 g of pure product is thus
obtained in the form of a gum.
LC-MS: M+H =479
1H NMR (DMSO) d (ppm): 8.11 (s, 1H) ; 7.80 (broad d, 1H) ; 7.60
(d, 1H); 6.90 (s, 1H); 6.40 (d, 1H) , 5.21 (s, 2H); 4.39 (q,
2H) ; 4.01 (m, 1H); 3.39 (m, 2H) ; 3.31 (m, 2H); 2.25 (m, 2H);
2.01 (m, 4H); 1.30 (t, 3H).
13.6 Ethyl 5-{6-[5-(4-Fluorophenyl)pyridin-2-yl]-6-azaspiro-
[3.4]oct-2-ylcarbamoyloxymethyl}isoxazole-3-carboxylate
(isomer T)
The process is performed according to the procedure described
in Example 2 (step 2.7.). Starting with 1.00 g (2.09 mmol) of
ethyl 5-[6-(5-bromopyridin-2-yl)-6-azaspiro[3.4]oct-2-ylcarb-
amoyloxymethyl]isoxazole-3-carboxylate (isomer 6) and 0.29 g
(2.09 mmol) of 4-fluorophenylboronic acid, 2.03 g (6.26 mmol)
of caesium carbonate and 0.17 g (0.21 mmol) of
PdCl2dppf ,CH2Cl2, 0.50 g of a gum is obtained after
chromatography on silica gel, eluting with a 90/10 mixture of
cyclohexane and ethyl acetate.
LC-MS: M+H = 495
1H NMR (DMSO) d (ppm): 8.39 (s, 1H) ; 7.80 (m, 2H) ; 7.60 (m, 2H) ;
7.22 (t, 2H); 6.90 (s, 1H); 6.50 (d, 1H); 5.20 (s, 2H); 4.38
(q, 2H); 4.06 (m, 1H); 3.45 (m, 2H); 3.38 (m, 2H); 2.28 (m,
2H); 2.00 (m, 4H); 1.32 (t, 3H).
13.7 3-(Methylcarbamoyl)isoxazol-5-ylmethyl {6-[5-(4-fluoro-
phenyl)pyridin-2-yl]-6-azaspiro[3.4]oct-2-yl}carbamate (isomer
II)
The process is performed according to the procedure described
in Example 6 (step 6.9.). Starting with 0.50 g (1.01 mmol) of
ethyl 5-{6- [5-(4-fluorophenyl)pyridin-2-yl]-6-azaspiro[3.4]-
oct-2-ylcarbamoyloxymethyl}isoxazole-3-carboxylate (isomer 2)
and 25 mL of a solution (1M) of methylamine in
tetrahydrofuran, at room temperature, 0.32 g of product is
obtained in the form of a white solid,
m.p. (°C): 194-196
LC-MS: M+H = 480
1H NMR (DMSO) d(ppm): 8.70 (broad s, 1H), 8.38 (s, 1H); 7.80
(m, 2H); 7.60 (m, 2H); 7.23 (t, 2H); 6.78 (s, 1H); 6.48 (d,
1H) ; 5.18 (s, 2H); 4.08 (m, 1H); 3.45 (m, 2H) , 3.40 (m, 2H);
2.78 (d, 3H), 2.25 (m, 2H); 2.00 ( m, 4H).
Example 14 (Compound 19)
3-(Methylcarbamoyl)isoxazol-5-ylmethyl [7-(6-chloroquinolin-2-
yl)-7-azaspiro[3.5]non-2-yl]carbamate

14.1 tert-Butyl 2-hydroxyimino-7-azaspiro[3.5]nonane-7-
carboxylate
0.58 g (8.36 mmol) of hydroxylamine hydrochloride and 1.15 g
(8.36 mmol) of potassium carbonate are added to a solution of
1.00 g (4.18 mmol) of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-
7-carboxylate (US 6 498 159) in 60 mL of ethanol, and the
mixture is thenNleft stirring at room temperature for
12 hours. After evaporating off the solvent under reduced
pressure, the residue is taken up in dichloromethane and
water, the aqueous phase is separated out and extracted twice
with dichloromethane, and the combined organic phases are
dried over sodium sulfate. After evaporating off the solvent,
the residue obtained is purified by chromatography on silica
gel, eluting with a 99/1/0.1 mixture of dichloromethane,
methanol and 28% aqueous ammonia. 0.831 g of pure product is
thus obtained in the form of a white powder.
LC-MS: M+H = 255
m.p. (°C): 117-119
1H NMR (CDCl3) d (ppm) : 3.30 (m, 4H) ; 2.60 (d, 4H) ; 1.55 (m,
4H); 1.40 (s, 9H).
14.2 tert-Butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate
To a solution of 0.5.0 g (1.97 mmol) of tert-butyl 2-
hydroxyimino-7-azaspiro[3.5]nonane-7-carboxylate obtained in
the preceding step, in 32 mL of a 7N solution of aqueous
ammonia in methanol. 0.11 g (1.97 mmol) of Raney nickel is
then added. The reaction medium is placed in a Parr flask
under a hydrogen atmosphere (20 psi) at room temperature for
2 hours 30 minutes. The resulting mixture is filtered through
a Buchner funnel and the filtrate is then concentrated under
reduced pressure. The residue is taken up in dichloromethane
and water, the aqueous phase is separated out and extracted
twice with dichloromethane, and the combined organic phases
are washed with saturated aqueous ammonium chloride solution
and are then dried over sodium sulfate. After evaporating off
the solvent, the residue obtained is purified by
chromatography on silica gel, eluting with a 90/10/1 mixture
of dichloromethane, methanol and 28% aqueous ammonia. 0.39 g
of pure product is thus obtained in the form of a colourless
oil.
LC-MS: M+H =241
1H NMR (DMSO) d(ppm): 3.40 (m, 1H) ; 3.30-3.10 (m, 4H); 2.25-
2.15 (m, 2H); 1.70 (broads, 2H); 1.50-1.35 (m, 6H); 1.30 (m,
9H) .
14. 3 tert-Butyl 2-ethoxycarbonylamino-7-azaspiro [3 5]nonane-7-
carboxylate
4.96 g (45.77 mmol) of ethyl chloroformate are added to a
solution containing 10.00 g (41.61 mmol) of tert-butyl 2-
amino-7-azaspiro[3.5]nonane-7-carboxylate obtained in the
preceding step, 13.44 g (104.02 mmol) of N,N-
diisopropyl ethyl amine and 0.51 g (4.16 mmol) of N,N-
dimethylaminopyridine in 300 mL of 1,2-dichloroethane, cooled
to about 0°C. Stirring is continued at 0°C for 1 hour and then
at room temperature for 12 hours. Water is added to the
reaction medium, the aqueous phase is separated out and
extracted several times with dichloromethane, the combined
organic phases are washed with saturated aqueous ammonium
chloride solution and dried over sodium sulfate, and the
filtrate is concentrated under reduced pressure. After
evaporating off the solvent, the residue obtained is purified
by chromatography on silica gel, eluting with a 99/1/0.1
mixture of dichloromethane, methanol and 28% aqueous ammonia.
8.728 g of pure product are thus obtained in the form of a
brown oil.
LC-MS: M+H =313
1H NMR (CDCl3) d (ppm) : 4.80 (broads, 1H) ; 4.10 (m, 3H) ; 3.30
(m, 4H); 2.30 (m, 2H); 1.60 (m, 6H); 1.50 (s, 9H); 1.25 (t,
3H) .
14.4 Ethyl (7-azaspiro[3.5]non-2-yl)carbamate hydrochloride
The process is performed according to the procedure described
in Example 2 (step 2.5.) . Starting with 8.63 g (27.62 mmol) of
tert-butyl 2-ethoxycarbonylamino-7-azaspiro[3.5]nonane-7-
carboxylate obtained in the preceding step and 27.62 mL
(110.50 mmol) of a 4N solution of hydrochloric acid in
dioxane, and after filtration through a sinter funnel and
washing with ether, 5.18 g of product are obtained in
hydrochloride form.
LC-MS: M+H = 249
m.p. (°C): 238-240
1H NMR (DMSO) d (ppm): 8.80 (broads, 1H); 7.40 (d, 1H); 3.90
(m, 3H); 2.80 (m, 4H); 2.10 (m, 2H); 1.60 (m, 6H) ; 1.25 (t,
3H).
14.5 Ethyl [7- (6-chloroquinolin-2-yl)-7-azaspiro[3.5]non-2-
yl]carbamate
0.166 g (0.78 mmol) of ethyl (7-azaspiro[3.5]non-2-yl)-
carbamate, obtained in the preceding step and used in base
form, 0.155 g (0.78 mmol) of 2-chloro-6-chloroquinoline and
0.113 g (0.82 mmol) of potassium carbonate in 2 mL of DMSO are
placed in a sealed tube. The mixture is then heated at 13 0°C
for 12 hours. The reaction mixture is allowed to cool to room
temperature and is then taken up in dichloromethane and water.
The aqueous phase is separated out and extracted twice with
dichloromethane, the combined organic phases are washed with
saturated aqueous ammonium chloride solution and dried over
sodium sulfate, and the filtrate is concentrated under reduced
pressure. After evaporating off the solvent, the residue
obtained is purified by chromatography on silica gel, eluting
with a 98/2/0.2 mixture of dichloromethane, methanol and 28%
aqueous ammonia. 0.151 g of pure product is thus obtained in
the form of a powder.
LC-MS: M+H = 374
m.p. (°C): 137-139
1H NMR (CDCl3) d (ppm) : 7.80 (d, 1H) ; 7.70 (m, 1H) ; 7.60 (m,
1H) ; 7.50 (m, 1H); 7.10 (d, 1H); 4.80 (broads, 1H); 4.20 (m,
3H); 3.70 (m, 4H); 2.50 (m, 2H); 1.90-1.60 (m, 6H); 1.30 (t,
3H) .
14.6 7-(6-Chloroquinolin-2-yl)-7-azaspiro[3.5]non-2-ylamine
0.726 g (12.95 mmol) of potassium hydroxide is added, at room
temperature, to a solution of 0.242 g (0.65 mmol) of ethyl [7-
(6-chloroquinolin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate,
obtained in step 12.5., in 3.25 mL of ethanol/water (1/1). The
mixture is then heated at 110°C for 12 hours. 0.363 g
(6.47 mmol) of potassium hydroxide is added and the mixture is
left stirring for 3 hours. The resulting mixture is allowed to
cool to room temperature and is then concentrated under
reduced pressure. The residue is taken up in dichloromethane
and 1N hydrochloric acid solution. The acidic aqueous phase is
washed with dichloromethane and then basified with aqueous IN
sodium hydroxide solution, which is extracted several times
with dichloromethane. The combined organic phases are then
dried over sodium sulfate and the filtrate is concentrated
under reduced pressure. 0.188 g of expected product is thus
obtained in the form of an oil.
LC-MS: M+H =3 02
1H NMR (DMSO) d (ppm): 8.00 (d, 1H); 7.80 (d, 1H); 7.50 (m,
2H); 7.30 (d, 1H); 3.60 (m, 4H); 3.30 (m, 2H); 2.10 (m, 2H) ;
1.50-1.30 (m, 6H).
14.7 3-(Methylcarbamoyl)isoxazol-5-ylmethyl [7-(6-chloro-
quinolin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
The process is performed according to the procedure described
in Example 1, step 1.1. Starting with 0.181 g (0.60 mmol) of
7-(6-chloroquinolin-2-yl)-7-azaspiro[3.5]non-2-ylamine,
described in the preceding step (step 12.6.), 0.231 g
(0.72 mmol) of 3-methylcarbamoylisoxazol-5-ylmethyl 4-nitro-
phenyl carbonate, obtained in step 4.1., 0.194 g (1.50 mmol)
of N,N-diisopropylethylamine and 0.037 g (0.30 mmol) of N,N-
dimethylaminopyridine in 6 mL of 1-2 dichloroethane, and after
crystallization from ether, the product is filtered off on a
sinter funnel, rinsed with ether and dried under vacuum at
about 70°C. 0.220 g of pure product is thus obtained in the
form of a white powder.
LC-MS: M+H = 484
m.p. (°C): 194-196
1H NMR (DMSO) d (ppm): 8.70 (broad s, 1H); 8.00 (d, 1H); 7.80
(m, 2H); 7.50 (m, 2H) ; 7.30 (d, 1H); 6.80 (s, 1H) ; 5.20 (s,
2H); 4.10 (m, 1H); 3.75-3.55 (m, 4H); 2.80 (s, 3H); 2.20 (m,
2H); 1.70 (m, 2H); 1.70-1.50 (m, 4H).
Example 15 (Compound 31)
3-Carbamoyliso3cazol-5-ylmethyl [7-(5-isobutylpyridin-2-yl)-7-
azaspiro[3.5]non-2-yl]carbamate
15.1. Ethyl [7-(5-bromopyridin-2-yl)-7-azaspiro[3.5]non-2-yl]-
carbamate
0.60 g (2.41 mmol) of ethyl (7-azaspiro [3 .5] non-2-yl) carbamate
hydrochloride, obtained in step 14.4. (Example 14), 0.57 g
(2.41 mmol) 2,5-dibromopyridine and 0.70 g (5.07 mmol) of
potassium carbonate in 2 mL of dimethyl sulfoxide are placed
in a sealed tube. The mixture is then heated at 13 0°C for
15 hours. The reaction medium is allowed to cool to room
temperature and then taken up in saturated sodium chloride
solution and extracted with dichloromethane, and the combined
organic phases are dried over sodium sulfate. After
evaporating off the solvent, the residue obtained is purified
by chromatography on preparative plates, eluting with a
100/0/0 to 99/1/0.1 mixture of dichloromethane, methanol and
28% aqueous ammonia.
0.75 g of pure product is thus obtained in the form of a
powder.
m.p. (°C): 113-115°C
15.2 Ethyl {7-[5-(2-methyl-propenyl)pyridin-2-yl]-7-azaspiro-
[3.5]non-2-yl}carbamate
The process is performed according to the method described in
Example 2 (step 2.7.). Starting with 0.50 g (1.36 mmol) of
ethyl [7-(5-bromopyridin-2-yl)-7-azaspiro[3.5]non-2-yl]-
carbamate, prepared in the preceding step, 0.33 mL (1.63 mmol)
of pinacol 2-methyl-1-propenylboronate (commercial) and 1.33 g
(4.07 mmol) of caesium carbonate, suspended in 9 mL of a 9/1
mixture of tetrahydrofuran and water, and 0.11 g (0.14 mmol)
of PdCl2dppf .CH2Cl2, and after purifying on a column of silica
gel, eluting with a 100/0/0 to 99/1/0.1 mixture of
dichloromethane, methanol and 28% aqueous ammonia, 0.39 g of
expected product is obtained in the form of a wax.
15.3 Ethyl [7-(5-isobutylpyridin-2-yl)-7-azaspiro[3.5] non-2-
yl]carbamate
0.05 g (0.45 mmol) of palladium-on-charcoal is added to a
solution of 0.37 g (1.08 mmol) of ethyl {7-[5-(2-methyl-
propenyl) pyridin-2-yl]-7-azaspiro[3.5]non-2-yl}carbamate
obtained in the preceding step, in 15 mL of methanol. The
reaction medium is placed in a Parr flask under a hydrogen
atmosphere (10 psi) at room temperature for 2 hours. The
resulting mixture is filtered through a Biichner funnel and the
filtrate is then concentrated under reduced pressure. 0.37 g
of expected product is thus obtained in the form of a yellow
wax.
15.4 7-(5-Isobutylpyridin-2-yl)-7-azaspiro[3.5]non-2-ylamine
1.21 g (21.65 mmol) of potassium hydroxide are added, at room
temperature, to a solution of 0.37 g (1.08 mmol) of ethyl [7-
(5-isobutylpyridin-2-yl) -7-azaspiro [3 .5]non-2-yl] carbamate in
5 mL of ethanol/water (1/1) . The mixture is then heated at
110°C for 15 hours. The resulting mixture is allowed to cool
to room temperature and is then concentrated under reduced
pressure. The reaction medium is taken up in saturated sodium
chloride solution and dichloromethane, the aqueous phase is
separated out and extracted with dichloromethane, and the
combined organic phases are dried over sodium sulfate. After
evaporating under reduced pressure and purifying on a column
of silica gel, eluting with a 100/0/0 to 96/4/0.4 mixture of
dichloromethane, methanol and 28% aqueous ammonia, 0.27 g of
expected product is obtained in the form of a wax.
LC-MS: M+H = 274
% NMR (CDCl3) d (ppm) : 8.00 (s, 1H) ; 7.30 (d, 1H) ; 6.60 (d,
1H); 3.50 (m, 3H); 3.40 (m, 2H); 2.30 (m, 4H); 1.80 (m, 1H);
1.70 (m, 4H); 1.50 (m, 4H); 0.90 (d, 6H).
15.5 3-Carbamoylisoxazol-5-ylmethyl 4-nitrophenyl carbonate
2.84 g (14.07 mmol) of 4-nitrophenyl chloroformate are added
portionwise to a solution of 2.00 g (14.07 mmol) of 3-
carbamoylisoxazol-5-ylmethanol, 1.71 mL (21.11 mmol) of
pyridine and 0.17 g (1.41 mmol) of N,N-dimethylaminopyridine
in 15 mL of dichloromethane, cooled to about 0°C. The medium
is stirred at 0°C for 1 hour and then at room temperature for
1 hour. The precipitate formed is filtered off and then rinsed
thoroughly with diisopropyl ether. After drying under vacuum
at about 60°C, 3.12 g of expected product are obtained in the
form of a white solid, which is used without further
purification in the following step.
m.p. (°C): 143-145
1H NMR (DMSO, 400 MHz) d (ppm) : 8.40 (d, 2H) ; 8.25 (broad s,
1H); 7.90 (broads, 1H); 7.65 (d, 2H); 7.0 (s, 1H); 5.50 (s,
2H) .
15.6 3-Carbamoylisoxazol-5-ylmethyl [7-(5-isobutylpyridin-2-
yl)-7-azaspiro[3.5]non-2-yl]carbamate
The process is performed according to the procedure described
in Example 1, step 1.1. Starting with 0.26 g (0.95 mmol) of 7-
(5-isobutylpyridin-2-yl)-7-azaspiro[3.5]non-2-ylamine,
obtained in step 15.4, 0.35 g (1.15 mmol) of 3-carbamoyl-
isoxazol-5-ylmethyl 4-nitrophenyl carbonate, obtained in step
15.5, 0.42 mL (2.39 mmol) of N,iV-diisopropylethylamine and
0.06 g (0.48 mmol) of N,iW-dimethylaminopyridine, in 9 mL of
1,2-dichloroethane, 0.35 g of pure product is obtained in the
form of a white powder,
m.p. (°C): 178-180°C
LC-MS: M+H = 442
1H NMR (DMSO) 5 (ppm): 8.15 (m, 1H) ; 7.90 (m, 1H) ; 7.85 (m,
1H); 7.75 (m, 1H); 7.30 (m, 1H); 6.75 (m, 2H); 5.20 (s, 2H);
4.00 (m, 1H); 3.40 (m, 2H);.3.35 (m, 2H); 2.30 (m, 2H); 2.20
(m, 2H); 1.75 (m, 3H); 1.55 (m, 4H); 0.85 (d, 6H).
Example 16 (Compound 40)
3-Carbamoylisoxazol-5-ylmethyl [6-(4-trifluoromethylpyrimidin-
2-yl)-6-azaspiro[2.5]oct-1-yl]carbamate
16.1 tert-Butyl l-benzyloxycarbonylamino-6-azaspiro[2.5]-
octane-6-carboxylate
5.00 g (19.58 mmol) of 6-tert-butyl 6-azaspiro[2.5]octane-l,6-
dicarboxylate (commercial) are dissolved in 11 mL of toluene,
and 2.99 mL (21.54 mmol) of triethylamine and 4.66 mL
(21.54 mmol) of diphenylphosphonic azide are then added, at
0°C under argon. The mixture is allowed to warm to room
temperature, and is stirred for 1 hour 30 minutes at 110°C.
Benzyl alcohol (2.23 mL; 21.54 mmol) is then added and the
mixture is stirred at 110°C for 15 hours.
After cooling to room temperature, saturated sodium hydrogen
carbonate solution is added, the mixture is extracted with
diethyl ether and the combined organic phases are then washed
successively with saturated sodium hydrogen carbonate solution
and then with saturated sodium chloride solution. The organic
phase is dried over sodium sulfate. After evaporating under
reduced pressure and purifying on a column of silica gel,
eluting with a 100/0/0 to 98/2/0.2 mixture of dichloromethane,
methanol and 28% aqueous ammonia, 5.50 g of expected product
are obtained in the form of an oil.
LC-MS: M+H =361
lR NMR (DMSO) d (ppm) : 7.40 (m, 5H) ; 5.10 (s, 2H); 3.45-3.20
(m, 4H) ; 2.40 (m, 1H); 1.40 (s, 9H); 1.30 (m, 3H), 1.20 (m,
1H) ; 1.75 (m, 1H) ; 1.45 (m, 1H) .
16.2 Benzyl (6-azaspiro[2.5]oct-1-yl)carbamate
The process is performed according to the procedure described
in Example 2 (step 2.5.). Starting with 5.50 g (15.28 mmol) of
tert-butyl 1-benzyloxycarbonylamino-6-azaspiro[2.5]octane-6-
carboxylate obtained in the preceding step and 15.28 mL
(61.10 mmol) of a 4N solution of hydrochloric acid in dioxane,
and after basic extraction, 3.56 g of product are obtained in
the form of a pale yellow powder.
LC-MS: M+H =261
m.p. (°C): 223-225
1H NMR (DMSO) d (ppm) : 7.40 (m, 6H) ; 5.10 (s, 2H); 3.00 (m,
3H); 2.40 (m, 2H); 1.60 (m, 1H); 1.40 (m, 3H); 1.70-1.40 (m,
2H) .
16.3 Benzyl [6-(4-trifluoromethylpyrimidin-2-yl)-6-azaspiro-
[2.5]oct-l-yl]carbamate
0.60 g (2.30 mmol) of benzyl (6-azaspiro[2.5]oct-l-yl)-
carbamate obtained in the preceding step, 0.36 mL (3.00 mmol)
of 2-chloro-4-trifluoromethylpyrimidine and 0.80 mL
(4.61 mmol) of diisopropylethylmaine in 17 mL of acetonitrile
and 3 mL of dimethylformamide are placed in a round-bottomed
flask. The mixture is then heated at 95°C for 15 hours. The
reaction mixture is allowed to cool to room temperature and
then taken up in dichloromethane and water. The aqueous phase
is separated out and extracted twice with dichloromethane, the
combined organic phases are washed with saturated aqueous
ammonium chloride solution and dried over sodium sulfate, and
the filtrate is concentrated under reduced pressure. After
evaporating off the solvent, the residue obtained is purified
by chromatography on silica gel, eluting with a 100/0/0 to
99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous
ammonia. 0.88 g of product is thus obtained in the form of an
oil.
LC-MS: M+H = 407
1H NMR (CDCl3) d (ppm): 8.70 (d, 1H) ; 7.50 (m, 1H) ; 7.40 (m,
4H); 7.20 (m, 1H); 7.00 (d, 1H); 5.10 (s, 2H); 3.95 (m, 2H);
3.70 (m, 2H); 2.50 (m, 1H); 1.50 (m, 2H); 1.30 (m, 2H); 1.75
(m, 1H); 1.50 (m, 1H)
16.4 6-(4-Trifluoromethylpyrimidin-2-yl)-6-azaspiro[2.5]oct-1-
yl amine
The process is performed according to the procedure described
in Example 2 (step 2.5.). Starting with 0.86 g (2.13 mmol) of
benzyl [6-(4-trifluoromethylpyrimidin-2-yl)-6-azaspiro[2.5]-
oct-l-yl]carbamate obtained in the preceding step and 3.74 mL
(21.33 mmol) of a solution of 35% hydrobromic acid in acetic
acid, and after basic extraction and uptake in diethyl ether,
0.32 g of product is obtained in the form of a white powder,
m.p. (°C): 243-245°C
LC-MS: M+H = 273
1H NMR (DMSO) d (ppm): 8.70 (d, 1H); 8.15 (broads, 2H); 7.00
(d, 1H); 4.10 (m, 1H); 4.00 (m, 1H); 3.70 (m, 2H); 2.50 (m,
1H) ; 1.70 (m, 2H) ; 1.50 (m, 1H) ; 1.35 (m, 1H) ; 1.90 (m, 1H) ;
1.80 (m, 1H).
16.5 3-Carbamoylisoxazol-5-ylmethyl [6-(4-trifluoromethyl-
pyrimidin-2-yl)-6-azaspiro[2.5]oct-l-yl]carbamate
The process is performed according to the procedure described
in Example 1, step 1.1. Starting with 0.15 g (0.55 mmol) of 6-
(4-trifluoromethylpyrimidin-2-yl)-6-azaspiro[2.5]oct-l-yl-
amine, obtained in step 16.4, 0.20 g (0.66 mmol) of 3-
carbamoylisoxazol-5-ylmethyl 4-nitrophenyl carbonate, obtained
in step 15.5, 0.24 mL (1.38 mmol) of I^IV-diisopropylethylamine
and 0.03 g (0.28 mmol) of N,2\7-dimethylaminopyridine, in 5 mL
of 1,2-dichloroethane, 0.15 g of pure product is obtained in
the form of a white powder after purification by
chromatography on silica gel, eluting with a 100/0/0 to
98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous
ammonia.
m.p. (°C): 183-185°C
LC-MS: M+H = 441
1H NMR (DMSO) d (ppm): 8.70 (d, 1H); 8.15 (broads, 1H); 7.85
(broads, 1H); 7.70 (broads, 1H); 7.00 (d, 1H); 6.80 (s, 1H);
5.20 (s, 2H); 3.90 (m, 2H); 3.75 (m, 2H); 2.50 (m, 1H); 1.40
(m, 3H); 1.30 (m, 1H); 1.70 (m, 1H); 1.50 (m, 1H)
Table 1 that follows illustrates the chemical structures and
physical properties of a few compounds according to the
invention. In this table:
- all the compounds are in free base form;
- compounds 10 and 11 are mixtures of isomers. Compound 12 is
in the form of isomer I, whereas compound 13 is in the form
of isomer II. Compound 17 is in the form of isomer I,
whereas compound 18 is in the form of isomer II. Compounds
16, 21 and 22 are in the form of an isomer. These isomers
correspond to positional isomers of the chain -A-NH-
relative to the chain -(CH2)nN-.
- the "m.p. (°C)" column gives the melting points of the
products in degrees Celsius (°C).
- Compound 26 is in salt form.
Table 3 that follows gives the results of the LC-MS analyses
for the compounds of Table 1.
LC-MS method (M+H):
UPLC / TOF - Gradient 3 min - H2O / ACN / TFA TO: 98%A - T 1,
6 to T 2.1 min: 100% B - T 2.5 to T 3 min: 98% A Route A: H2O
+ 0.05% TFA; Route B: ACN + 0.035% TFA flow rate: 1.0 mL/min -
T°= 40°C - Injection 2uL - Acquity BEH C18 (50*2.1 mm; 1.7 urn)
column"; 220 nm
The compounds of the invention underwent pharmacological tests
to determine their inhibitory effect on the enzyme FAAH (Fatty
Acid Amide Hydrolase) .
The inhibitory activity was demonstrated in a radioenzymatic
test based on measuring the product of hydrolysis of
anandamide [ethanolamine 1-3H] with FAAH (Life Sciences
(1995), 56, 1999-2005 and Journal of Biochemical and
Biophysical Methods (2004), 60(2), 171-177). Thus, mouse
brains (minus the cerebellum) are removed and stored at -80°C.
The membrane homogenates are prepared extemporaneously by
homogenizing the tissues using a Precellys® machine in
reaction buffer (10 mM Tris-HCl, pH = 8, 150 mM NaCl and 1 mM
ethylenediaminetetraacetic acid (EDTA)). The enzymatic
reaction is performed in 96-well Multiscreen filtration plates
in a final volume of 70 µL. Reaction buffer supplemented with
fatty acid-free bovine serum albumin (BSA, 1 mg/ml) is used
for the enzymatic reaction and the dilution of the compounds
and of the anandamide [ethanolamine 1-3H] . The reaction buffer
containing BSA (43 µL/well) , the diluted test compounds at
different concentrations (7 µL/well containing 1% DMSO) and
the membrane preparation (10 µL/well, i.e. 200 µg of tissue
per test) are successively added to the wells. After
preincubation for 20 minutes of the compounds with the enzyme
at 25°C, the reaction is started by adding anandamide
[ethanolamine 1-3H] . (Specific activity of 15-20 Ci/mmol)
diluted with cold anandamide (10 µL/well, final concentration
of 10 µM, 0.01 µCi per test). After incubation for 20 minutes
at 25°C, the enzymatic reaction is stopped by adding a 5M
solution of active charcoal prepared in 1.5M NaCl buffer and
0.5 M HCl (50 µL/well). The mixture is stirred for 10 minutes
and the aqueous phase containing the ethanolamine [1-3H] is
then recovered by filtration under vacuum and counted by
liquid scintillation.
Under these conditions, the most active compounds of the
invention have IC50 values (concentration that inhibits 50% of
the control enzymatic activity of FAAH) of between 0.001 and
1 µM; for example, compounds 4, 6, 8, 10, 12, 19, 25, 31 and
40 have respective IC50 values of 0.0082, 0.00025, 0.00072,
0.0023, 0.00085, 0.0018, 0.0017, 0.0043 and 0.0005 uM.
It thus appears that the compounds according to the invention
have inhibitory activity on the enzyme FAAH.
The in vivo activity of the compounds of the invention was
evaluated in a test of analgesia.
Thus, the intraperitoneal (i.p.) administration of PBQ
(phenylbenzoquinone, 2 mg/kg in 0.9% sodium chloride solution
containing 5% ethanol) to male OF1 mice weighing 25 to 30 g
causes abdominal stretching, on average 30 torsions or
contractions within a period of 5 to 15 minutes after
injection. The test compounds are administered orally (p.o.)
or intraperitoneally (i.p.) suspended in Tween 80 at 0.5%,
60 minutes or 120 minutes before the administration of PBQ.
Under these conditions, the compounds of the invention that
are the most powerful reduce by 35% to 80% the number of
stretches induced with PBQ, over a dose range of between 1 and
3 0 mg/kg.
For example, compound 5 of Table 1 reduces by 50% the number
of stretches induced with PBQ, at a dose of 30 mg/kg p.o. at
120 minutes.
The enzyme FAAH (Chemistry and Physics of Lipids, (2000), 108,
107-121) catalyses the hydrolysis of the endogenous
derivatives of amides and esters of various fatty acids such
as N-arachidonoylethanolamine (anandamide), N-palmitoyl-
ethanolamine, N-oleoylethanolamine, oleamide or
2-arachidonoylglycerol. These derivatives exert different
pharmacological activities by interacting, inter alia, with
the cannabinoid and vanilloid receptors.
The compounds of the invention block this degradation pathway
and increase the tissue content of these endogenous
substances. In this respect, they may be used in the
prevention and treatment of pathologies in which the
endogenous cannabinoids and/or any other substrate metabolized
by the enzyme FAAH are involved. Mention may be made, for
example, of the following diseases and complaints:
pain, especially acute or chronic pain of neurogenic type:
migraine, neuropathic pain including the forms associated with
the herpes virus and diabetes and chemotherapy, acute or
chronic pain associated with inflammatory diseases: arthritis,
rheumatoid arthritis, osteoarthritis, spondylitis, gout,
vascularitis, Crohn's disease, irritable bowel syndrome, acute
or chronic peripheral pain, vertigo, vomiting, nausea, in
particular post-chemotherapy nausea, eating disorders, in
particular anorexia and cachexia of diverse nature,
neurological and psychiatric pathologies: tremor, dyskinaesia,
dystonia, spasticity, compulsive and obsessive behaviour,
Tourette's syndrome, all forms of depression and anxiety of
any nature or origin, mood disorders, psychoses, acute and
chronic neurodegenerative diseases: Parkinson's disease,
Alzheimer's disease, senile dementia, Huntington's chorea,
lesions associated with cerebral ischaemia and cranial and
medullary trauma, epilepsy, sleeping disorders, including
sleep apnoea, cardiovascular diseases, in particular
hypertension, cardiac arrhythmia, arteriosclerosis, heart
attack, cardiac ischaemia, renal ischaemia, cancers: benign
skin tumours, papillomas and cerebral tumours, prostate
tumours, cerebral tumours (gliobastomas, medullo-epitheliomas,
medullo-blastomas, neuroblastomas, tumours of embryonic
origin, astrocytomas, astroblastomas, ependyomas, oligodendro-
gliomas, plexus tumour, neuroepitheliomas, pineal gland
tumours, ependymoblastomas, malignant meningiomas,
sarcomatoses, malignant melanomas, schwennomas), immune system
disorders, especially autoimmune diseases: psoriasis, lupus
erythematosus, connective tissue diseases, Sjogrer's syndrome,
ankylosing spondylitis, undifferentiated spondylitis, Behcet's
disease, haemolytic autoimmune anaemias, multiple sclerosis,
amyotrophic lateral sclerosis, amylosis, graft rejection,
diseases affecting the plasmocytic line, allergic diseases:
immediate or delayed hypersensitivity, allergic rhinitis or
allergic conjunctivitis, contact dermatitis, parasitic, viral
or bacterial infectious diseases: AIDS, meningitis,
inflammatory diseases, especially articular diseases:
arthritis, rheumatoid arthritis, osteoarthritis, spondylitis,
gout, vascularitis, Crohn's disease, irritable bowel syndrome,
osteoporosis, ocular complaints: ocular hypertension,
glaucoma, pulmonary complaints: respiratory pathway diseases,
bronchospasms, coughing, asthma, chronic bronchitis, chronic
obstruction of the respiratory pathways, emphysema,
gastrointestinal diseases: irritable bowel syndrome,
intestinal inflammatory disorders, ulcers, diarrhoea, urinary
incontinence and inflammation of the bladder.
The use of the compounds according to the invention, in the
form of the base, or a pharmaceutically acceptable acid-
addition salt, hydrate or solvate, for the preparation of a
medicinal product for treating the pathologies mentioned above
forms an integral part of the invention.
A subject of the invention is also medicinal products
comprising a compound of formula (I) , or an acid-addition
salt, or alternatively a pharmaceutically acceptable hydrate
or solvate of the compound of formula (I) . These medicinal
products find their therapeutic use especially in the
treatment of the pathologies mentioned above.
According to another of its aspects, the present invention
relates to pharmaceutical compositions containing, as active
principal, at least one compound according to the invention.
These pharmaceutical compounds contain an effective dose of a
compound according to the invention, or a pharmaceutically
acceptable acid-addition salt, hydrate or solvate of the said
compound, and optionally one or more pharmaceutically
acceptable excipients.
The said excipients are chosen, according to the
pharmaceutical form and the desired administration form, from
the usual excipients known to those skilled in the art.
In the pharmaceutical compositions of the present invention
for oral, sublingual, subcutaneous, intramuscular,
intravenous, topical, local, intrathecal, intranasal,
transdermal, pulmonary, ocular or rectal administration, the
active principal of formula (I) above, or the possible acid-
addition salt, solvate or hydrate thereof, may be administered
in a unit administration form, as a mixture with standard
pharmaceutical excipients, to man and animals for the
prophylaxis or treatment of the above disorders or diseases.
The appropriate unit administration forms comprise oral forms
such as tablets, soft or hard gel capsules, powders, granules,
chewing gums and oral solutions or suspensions, sublingual,
buccal, intratracheal, intraocular and intranasal
administration forms, forms for administration by inhalation,
subcutaneous, intramuscular or intravenous administration
forms and rectal or vaginal administration forms. For topical
administration, the compounds according to the invention may
be used in creams, ointments or lotions.
By way of example, a unit administration form of a compound
according to the invention in the form of a tablet may
comprise the following components:
The said unit forms are dosed to allow a daily administration
of from 0.01 to 20 mg of active principal per kg of body-
weight, depending on the presentation form.
There may be particular cases in which higher or lower doses
are suitable, and such doses also form part of the invention.
According to the usual practice, the dose that is suitable for
each patient is determined by the doctor according to the mode
of administration and the weight and response of the said
patient.
According to another of its aspects, the invention also
relates to a method for treating the pathologies mentioned
above, which comprises the administration of an effective dose
of a compound according to the invention, a pharmaceutically
acceptable acid-addition salt thereof or a solvate or hydrate
of the said compound.
Claims
1. Compound corresponding to formula (I)

in which
R2 represents a hydrogen or fluorine atom or a hydroxyl,
cyano, trifluoromethyl, C1-6-alkyl, C1-6-alkoxy or NR8R9 group;
m, n, o and p represent, independently of each other, an
integer equal to 0, 1, 2 or 3;
A represents a covalent bond or a group C1-8-alkylene;
R1 represents a group R5 optionally substituted with one or
more groups R6 and/or R7;
R5 represents a group chosen from phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl,
quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, cinnolinyl and naphthyridinyl;
R6 represents a halogen atom or a cyano, -CH2CN, nitro,
hydroxyl, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl,
C1-6-haloalkyl, C1-6-haloalkoxy, C1-6-halothioalkyl, C3-7-
cycloalkyl, C3-7-cycloalkyl-C1-3-alkylene, C3-7-cycloalkyl-
C1-3-alkylene-O-, NR8R9, NR8COR9, NR8CO2R9, NR8SO2R9, NR8SO2NR8R9,
COR8, CO2R8, CONR8R9, SO2R8, SO2NR8R9 or -O- (C1-3-alkylene) -O-
group;
R7 represents a group chosen from furyl, pyrrolyl, thienyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,
pyrazolyl, oxadiazolyl, thiadiazolyl, phenyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl,
quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl,
guinoxalinyl, cinnolinyl, naphthyridinyl, imidazo-
pyrimidinyl, thienopyrimidinyl, benzofuryl, benzothienyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
benzisothiazolyl, indolyl, isoindolyl, indazolyl,
pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridyl,
pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl,
thiazolopyridyl, phenyloxy, benzyloxy and pyrimidinoxy; or
the group (s) R7 possibly being substituted with one or more
groups R6 that may be identical to or different from each
other;
R3 represents a hydrogen or fluorine atom, a group C1-6-alkyl
or a trifluoromethyl group;
R4 represents a group chosen from furyl, pyrrolyl, thienyl,
isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl,
thiadiazolyl, imidazolyl, triazolyl and tetrazolyl;
this group being optionally substituted with one or more
substituents chosen from a halogen atom, a group C1-6-alkyl,
C1-6-haloalkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkylene,
C1-6-haloalkoxy, cyano, NR8R9, NR8COR9, NR8CO2R9, NR8SO2R9,
NR8SO2NR8R9, COR8, CO2R8, CONR8R9, CON (R8) (C1-3-alkylene-NR10R11) ,
SO2R8, SO2NR8R9, -O- (C1-3-alkylene) -O-, phenyl, phenyloxy,
benzyloxy, pyridyl, pyrazinyl, pyridazinyl, triazinyl or
pyrimidinyl; the phenyl, phenyloxy, pyridyl, pyrazinyl,
pyridazinyl, triazinyl and pyrimidinyl groups possibly being
substituted with one or more substituents chosen from a
halogen atom and a cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C1-6-
thioalkyl, C1-6-haloalkyl, C1-6-haloalkoxy, C1-6-halothioalkyl,
C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene group;
R8 and R9 represent, independently of each other, a hydrogen
atom or a group C1-6-alkyl,
or form, with the atom(s) that bear(s) them,
in the case of NR8R9, a ring chosen from azetidine,
pyrrolidine, piperidine, morpholine, thiomorpholine, azepine,
oxazepine and piperazine rings, this ring being optionally
substituted with a group C1-6-alkyl or benzyl;
in the case of NR8COR9, a lactam ring; in the case of NR8CO2R9,
a oxazolidinone, oxazinone or oxazepinone ring; in the case of
NR8SO2R9, a sultam ring; in the case of NR8SO2NR8R9, a
thiazolidine dioxide or thiadiazinane dioxide ring;
R10 and R11 represent, independently of each other, a hydrogen
atom or a group C1-6-alkyl;
in the form of base or of acid-addition salt.
2. Compound of formula (I) according to Claim 1, characterized
in that R2 represents a hydrogen atom;
in the form of base or of acid-addition salt.
3. Compound of formula (I) according to Claim 1 or 2,
characterized in that the group

represents

R2 being as defined in the general formula (I) according to
Claim 1;
in the form of base or of acid-addition salt.
4. Compound of formula (I) according to any one of Claims 1 to
3, characterized in that A represents a covalent bond or a
group Ci-s-alkylene; in the form of base or of acid-addition
salt.
5. Compound of formula (I) according to any one of Claims 1 to
4, characterized in that
R1 represents a group R5 optionally substituted with one or
more groups R6 and/or R7;
R5 represents a pyrimidinyl, pyrazinyl, pyridinyl or
quinolinyl group;
R6 represents a halogen atom, a group C1-6-haloalkyl or a
group C1-6-alkyl;
R7 represents a phenyl,, which may be substituted with one or
more groups R6 that are identical to or different from each
other.
in the form of base or of acid-addition salt.
6. Compound of formula (I) according to any one of Claims 1 to
5, characterized in that R3 represents a hydrogen atom; in the
form of base or of acid-addition salt.
7. Compound of formula (I) according to any one of Claims 1 to
6, characterized in that
R4 represents a group chosen from a thiazolyl, an oxazolyl, an
oxadiazolyl and an isoxazolyl;
this group being optionally substituted with one or more
substituents chosen from a group C1-6-alkyl, CONR8R9,
CON(R8) (C1-3-alkylene-NR10R11) or a phenyl; the phenyl group
being optionally substituted with one or more substituents
chosen from a halogen atom;
R8, R9, R10 and R11 represent, independently of each other, a
hydrogen atom or a group C1-6-alkyl;
in the form of base or of acid-addition salt.
8. Compound of formula (I) according to any one of Claims 1 to
7, characterized in that it is chosen from:
thiazol-4-ylmethyl [7-(6-fluoroquinolin-2-yl)-7-
azaspiro[3.5]non-2-yl]carbamate
3-carbamoylisoxazol-5-ylmethyl [7-(6-fluoroguinolin-2-yl)-7-
azaspiro[3.5]non-2-yl]carbamate
3-carbamoylisoxazol-5-ylmethyl [7-(5-trifluoromethylpyridin-
2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
3-carbamoylisoxazol-5-ylmethyl [7-(5-bromopyridin-2-yl)-7-
azaspiro[3.5]non-2-yl]carbamate
3-carbamoylisoxazol-5-ylmethyl {7-[5-(4-fluorophenyl)-
pyridin-2-yl]-7-azaspiro[3.5]non-2-yl}carbamate
3-carbamoylisoxazol-5-ylmethyl [7-(6-fluoroquinolin-2-yl)-7-
azaspiro[3.5]non-2-yl]methylcarbamate
3-(methylcarbamoyl)isoxazol-5-ylmethyl [7-(6-fluoroquinolin-
2-yl)-7-azaspiro[3.5]non-2-yl]methylcarbamate
3-(methylcarbamoyl)isoxazol-5-ylmethyl {7-[5-(4-fluoro-
phenyl)pyridin-2-yl]-7-azaspiro[3.5]non-2-yl}carbamate
3-(methylcarbamoyl)isoxazol-5-ylmethyl [7-(6-fluoroquinolin-
2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
3-carbamoylisoxazol-5-ylmethyl {6-[5-(4-fluorophenyl)-
pyridin-2-yl]-6-azaspiro[3.4]oct-2-yl}carbamate
3-(methylcarbamoyl)isoxazol-5-ylmethyl {6-[5-(4-fluoro-
phenyl)pyridin-2-yl] -6-azaspiro[3.4]oct-2-yl}carbamate
3-(methylcarbamoyl)isoxazol-5-ylmethyl {6-[5-(4-fluoro-
phenyl )pyridin-2-yl] -6-azaspiro[3.4]oct-2-ylmethyl}carbamate
3-(methylcarbamoyl)isoxazol-5-ylmethyl {6-[5-(4-fluoro-
phenyl )pyridin-2-yl] -6-azaspiro[3.4]oct-2-ylmethyl}carbamate
4-carbamoyloxazol-2-ylmethyl [7-(6-fluoroquinolin-2-yl)-7-
azaspiro[3.5]non-2-yl]carbamate
3-(methylcarbamoyl)isoxazol-5-ylmethyl [2-(6-fluoroquinolin-
2-yl)-2-azaspiro[3,3]hept-6-yl]carbamate
3-(methylcarbamoyl)isoxazol-5-ylmethyl [6-(6-fluoroquinolin-
2-yl)-6-azaspiro[3.4]oct-2-ylmethyl]carbamate
3-(methylcarbamoyl)isoxazol-5-ylmethyl {6-[5-(4-fluoro-
phenyl )pyri din- 2 -yl] -6-azaspiro[3.4]oct-2-yl}carbamate
3-(methylcarbamoyl)isoxazol-5-ylmethyl {6-[5-(4-fluoro-
phenyl)pyridin-2-yl]-6-azaspiro[3.4]oct-2-yl}carbamate
3-(methylcarbamoyl)isoxazol-5-ylmethyl [7-(6-chloroquinolin-
2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
3-carbamoylisoxazol-5-ylmethyl {2-[5-(4-fluorophenyl)-
pyridin-2-yl]-2-azaspiro[3.3]hept-6-yl}carbamate
3-methylcarbamoylisoxazol-5-ylmethyl [6-(5-bromopyridin-2-
yl)-6-azaspiro[3.4]oct-2-yl]carbamate
3-methylcarbamoylisoxazol-5-ylmethyl [6-(4-trifluoromethyl-
pyridin-2-yl)-6-azaspiro[3.4]oct-2-yl]carbamate
3-methylcarbamoylisoxazol-5-ylmethyl {2-[5-(4-fluorophenyl)-
pyridin-2-yl]-2-azaspiro[3.3]hept-6-yl}carbamate
3-carbamoylisoxazol-5-ylmethyl [7-(4-trifluoromethyl-
pyrimidin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
3-carbamoylisoxazol-5-ylmethyl {7-[6-(4-fluorophenyl)-
pyrazin-2-yl]-7-azaspiro[3.5]non-2-yl}carbamate
3-(2-dimethylaminoethylcarbamoyl)isoxazol-5-ylmethyl [7-(4-
trifluoromethylpyrimidin-2-yl)-7-azaspiro[3.5]non-2-yl]-
carbamate and the hydrochloride thereof;
3-carbamoylisoxazol-5-ylmethyl {7-[4-(4-fluorophenyl)-
pyridin-2-yl]-7-azaspiro[3.5]non-2-yl}carbamate
3-carbamoylisoxazol-5-ylmethyl [7-(4-chloropyridin-2-yl)-7-
azaspiro[3.5]non-2-yl]carbamate
3-carbamoylisoxazol-5-ylmethyl [7-(4-trifluoromethylpyridin-
2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
3-carbamoylisoxazol-5-ylmethyl {7-[5-(3-fluorophenyl)-
pyridin-2-yl]-7-azaspiro[3.5]non-2-yl}carbamate
3-carbamoylisoxazol-5-ylmethyl [7-(5-isobutylpyridin-2-yl)-
7-azaspiro[3.5]non-2-yl]carbamate
3-carbamoylisoxazol-5-ylmethyl [7-(6-chloroquinolin-2-yl)-7-
azaspiro[3.5]non-2-yl]carbamate
3-methylcarbamoylisoxazol-5-ylmethyl [7-(6-chloroguinolin-2-
yl)-7-azaspiro[3.5]non-2-ylmethyl]carbamate
3-methylcarbamoylisoxazol-5-ylmethyl [7-(4-trifluoromethyl-
pyridin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
3-(4-fluorophenyl)-[1,2,4]oxadiazol-5-ylmethyl [7-(4-
trifluoromethylpyridin-2-yl)-7-azaspiro[3.5]non-2-yl]-
carbamate
4-carbamoyloxazol-2-ylmethyl [7-(4-trifluoromethylpyridin-2-
yl)-7-azaspiro[3.5]non-2-yl]carbamate
5-methyl-3-phenylisoxazol-4-ylmethyl [7-(4-trifluoromethyl-
pyridin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
3-ethyl[1,2,4]oxadiazol-5-ylmethyl [7-(4-trifluoromethyl-
pyridin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
5-methyl[1,2,4]oxadiazol-3-ylmethyl [7-(4-trifluoromethyl-
pyridin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate
3-carbamoylisoxazol-5-ylmethyl [6-(4-trifluoromethyl-
pyrimidin-2-yl)-6-azaspiro[2.5]oct-1-yl]carbamate
3-methylcarbamoylisoxazol-5-ylmethyl [6-(4-trifluoromethyl-
pyrimidin-2-yl)-6-azaspiro[2.5]oct-1-yl]carbamate.
9. Process for preparing a compound of formula (I) according
to any one of Claims 1 to 8, comprising the step that consists
in
reacting an amine of general formula (II) ,

in which A, Ri, R2, m, n, o and p are as defined in the general
formula (I) according to Claim 1,
either with a carbonate of general formula (III)

in which Z represents a hydrogen atom or a nitro group, and R3
and R4 are as defined in the general formula (I) according to
Claim 1,
in the presence of a base, in a solvent at a temperature of
between room temperature and the reflux temperature of the
solvent;
or with phenyl or 4-nitrophenyl chloroformate,
in the presence of a base, in a solvent at a temperature of
between 0°C and room temperature,
to give the carbamate derivative of general formula (IV),

in which A, R1, R2, m, n, o and p are as defined in the general
formula (I) according to Claim 1, and Z represents a hydrogen
atom or a nitro group,
and then in converting the carbamate derivative of general
formula (IV) thus obtained into a compound of general formula
(I), via the action of an alcohol of general formula HOCHR3R4
(IIIa) , in which R3 and R4 are as defined in the general
formula (I) according to Claim 1,
in the presence of a base, in a solvent at a temperature of
between room temperature and the reflux temperature of the
solvent.
10. Process for preparing a compound of formula (I) according
to any one of Claims 1 to 8, comprising the step that consists
in
reacting a compound of general formula (Ia)

in which A, R2, R3, R4, m, n, o and p are as defined in the
general formula (I) according to Claim 1,
with a derivative of general formula R1-U (V) , in which R1 is
as defined in the general formula (I) according to Claim 1 and
U1 represents a halogen atom or an O-triflate group,
using aromatic or heteroaromatic nucleophilic substitution
conditions or using Buchwald N-arylation or N-heteroarylation
conditions.
11. Process for preparing a compound of formula (I) according
to any one of Claims 1 to 8, in which R1 represents a group R5
substituted especially with a group R6 of the type C1-6-alkyl,
C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene, or with a group
R7 as defined in the general formula (I) according to Claim 1,
comprising the step that consists in
performing a coupling reaction, catalysed by means of a
transition metal, oh the compound of general formula (Ib),

in which A, R2, R3, R4, R5, m, n, o and p are as defined in the
general formula (I) according to Claim 1 and U2 represents a
chlorine, bromine or iodine atom or a triflate group, U2 being
in the position in which it is desired to introduce a group R6
or R7:
- either via a reaction of Suzuki type, for example using an
alkyl, cycloalkyl, aryl or heteroaryl boronic acid,
- or according to a reaction of Stille type;
- or via a reaction of Negishi type.
12. Compound of formula (I) according to any one of Claims 1
to 8, in the form of base or of a pharmaceutically acceptable
acid-addition salt, for its use as a medicament.
13. Pharmaceutical composition containing at least one
compound of formula (I) according to any one of Claims 1 to 8,
in the form of base or of a pharmaceutically acceptable acid-
addition salt and optionally one or more pharmaceutically
acceptable excipients.
14. Use of a compound of formula (I) according to any one of
Claims 1 to 8, in the form of base or of a pharmaceutically
acceptable acid-addition salt, for the preparation of a
medicament for preventing or treating a pathology in which the .
endogenous cannabinoids and/or any other substrate metabolized
by the enzyme FAAH are involved.
15. Use of a compound of formula (I) according to any one of
Claims 1 to 8, in the form of base or of a pharmaceutically
acceptable acid-addition salt, for the preparation of a
medicament for preventing or treating acute or chronic pain,
vertigo, vomiting, nausea, eating disorders, neurological and
psychiatric pathologies, acute or chronic neurodegenerative
diseases, epilepsy, sleeping . disorders, cardiovascular
diseases, renal ischaemia, cancers, immune system disorders,
allergic diseases, parasitic, viral or bacterial infectious
diseases, inflammatory diseases, osteoporosis, ocular
complaints, pulmonary complaints,, gastrointestinal diseases or
urinary incontinence.

The invention relates to a compound of the general formula (I) in which R2 is a hydrogen or fluorine atom or a
hydroxyl, cyano, trifluoromethyl, C1-6-alkyl, C1-6-alkoxy, NR8R9 group; m, n, o and p are independently an integer equal to 0, 1, 2
or 3; A is a covalent bond or a C1-8-alkylene group; R1 is an optionally substituted aryl or heteroaryl group; R3 is a hydrogen or
fluorine atom or a C1-6-alkyl group or a trifluoromethyl group; R1 is an optionally substituted 5-member heterocyclic compound;
the compound being in the form of a base or acid addition salt. The invention also relates to the therapeutic use thereof.