Title of Invention

PYRAZOLYL DERIVATIVES IN THE FORM OF DRUGS FOR TREATING ACUTE OR CHRONIC NEURONAL REGRESSIONS

Abstract The invention relates to novel derivatives of general formula (I), wherein A, if present, is an alkyl radical (C1-C6), an alkenyl radical (C3-C6), an alkynyl radical (C3-C6), a cycloalkyl radical (C3-C7), a cycloalkenyl radical (C5-C7), R1 is a NR6R7, azacycloalkyl (C4-C7), azacycloalkenyl (C5-C7) azabicycloalkyl (C5-C9) and azabicycloalkenyl (C5-C9) group; A-R1 is such that nitrogen of R1 et nitrogen 1 of pyrazole are indispensably separated by at lest two carbon atoms, R3 is an H, halogen, OH, SH, NH2, ORc, SRc, SORa, SO2Ra, NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra and NHSO2Ra radical; R4 is an aryl or heteroaryl radical; R5 is a H, halogen, CF3, CHF2, CH2F, linear or branched alkyl (C1-C6) and cycloalkyl (C3-C7) radical, the racemics, enantiomers and diastereoisomers thereof and the mixtures thereof, tautomers thereof and the pharmaceutically acceptable salts thereof.
Full Text

PYRAZOLYL DERIVATIVES IN THE FORM OF DRUGS FOR TREATING
ACUTE OR CHRONIC NEURONAL REGRESSIONS

The present invention relates to novel ligands for
acetylcholine receptors of the nicotinic type. These
compounds are more particularly ligands for α7
nicotinic receptors. These properties suggest that the
compounds of the invention may be useful, in animals
including humans, as a curative and/or symptomatic
treatment for the prevention, diagnosis and/or
monitoring of the evolution of disorders or diseases
which involve a disturbance of nicotinic receptor
function or which respond favorably to a modulation of
said receptors. More particularly, the compounds of the
invention could be useful in psychiatric disorders or
diseases or neurological disorders or diseases of the
central nervous system involving the impairment of
cognitive functions, of attention, of the ability to
concentrate, to learn and to memorize, or of the
processing of sensory information. They may also be
useful in the treatment, prevention, diagnosis and/or
monitoring of the evolution of diseases involving
neurodegenerative processes which are spontaneous or
which are subsequent to lesions, and of diseases
involving inflammatory phenomena. The present invention
also refers to the methods of treatment involving
nicotinic receptors consisting of the administration,
to animals including humans, of therapeutically
effective doses of one or more compounds of the
invention. The present invention also relates to the
use, for diagnostic purposes, of analogs of these
derivatives in which one or more atoms have been
replaced with an isotope with an atomic mass or a mass
number which is different to the atomic mass or to the
mass number of the atoms usually encountered naturally.

of the invention may be useful for establishing a
decrease in the consumption of addictive substances,
for helping to maintain an abstinence with respect to
said substances or for reducing the symptoms of
withdrawal therefrom. In the context of the present
invention, the term "addictive substance" applies to
licit or illicit substances, the consumption of which
may give rise to abuse and/or dependency, such as, for
example, nicotine and tobacco products, alcohol,
cannabis derivatives, opiates, cocaine, barbiturates,
benzodiazepines and pyschostimulants.
The compounds of the invention could also have an
advantage in the treatment of acute or chronic pain,
such as post-surgical pain, pain subsequent to
amputation (phantom limb pain), pain associated with
cancerous lesions, with migraines, with neuropathies
and muscle pains such as fibromyalgia. In addition, the
compounds of the invention could also be used in the
context of the treatment of disorders or diseases
involving inflammatory processes, such as, for example,
in the gastrointestinal tract, ulcerative colitis,
Crohn's disease, irritable bowel syndrome or diarrhea
and, elsewhere in the body, arthritis (including
rheumatoid arthritis) and skin inflammations such as
acne. Finally, the compounds of the invention could be
useful in endocrine disorders such as pheochromocytoma
and smooth muscle contraction-related disorders.
The present invention also covers the use of the
compounds of the invention for diagnostic purposes or
for the purposes of medical imaging. It comprises the
diagnostic and imaging methods consisting of the
analysis, by noninvasive methods, of the distribution
of a tracer compound within the intact body of an
animal, including humans, using physical means such as
positon emission tomography, single-photon tomography,
magnetic resonance spectroscopy and nuclear magnetic

A subject of the present invention is therefore the use
of pyrazole derivatives of formula (I)

and their pharmaceutically acceptable salts, for
preparing medicinal products and pharmaceutical
compositions, as ligands for Many disorders or diseases are associated with a
nicotinic receptor dysfunction and may thus benefit
from a modulation of said receptors using the compounds
of the invention to correct the symptoms thereof and/or
to slow down, stop or reverse the evolution thereof. In
this regard, the compounds of the invention are more
particularly advantageous in the case of psychiatric
disorders or diseases or neurological disorders or
diseases of the central nervous system, such as, for
example, an impairment of the ability to learn, to
concentrate or to memorize, slight cognitive
impairments, senile dementia, vascular dementia, Levy
body dementia, Alzheimer's disease, Parkinson's
disease, Huntington's chorea, Tourette's syndrome,
neuronal degeneration subsequent to a trauma, to
strokes, to ischemia or to brain hypoxia, multisystem
atrophy, progressive supranuclear paralysis,
amyotrophic lateral sclerosis, peripheral neuropathies,
motor disorders such as dyskinesia, tardive dyskinesia,
hyperkinesia, dystonia and epilepsy, attention deficit
hyperactivity disorders, schizophrenia, depression,
manic depressive psychosis, anxiety, phobias,
obsessive-compulsive disorders, post-traumatic stress
syndrome, panic attacks, eating disorders such as
anorexia, bulimia and obesity, or sleep disorders
including those associated with jetlag. The compounds

resonance imaging, computed X-ray tomodensitometry
(scanner) or a combination of these techniques. In the
Context of the present invention, the term "tracer
compound" denotes the compounds of the invention, their
enantiomers or their prodrugs which may or may not be
used in a labeled form allowing them to be detected by
physical means as described above. The labeling
consists in replacing one or more atoms in the
compounds of the invention with an isotope with an
atomic mass or a mass number which is different to the
atomic mass or to the mass number of these atoms such
as they are usually encountered naturally. It may also
consist in adding to the compounds of the invention
chemical groups carrying such isotopes, by means, for
example, of methylating reagents. The isotopes used
may, for example, be radionuclide isotopes of hydrogen,
of carbon, of nitrogen, of oxygen, of fluorine, of
phosphorus, of sulfur, of chlorine, of iodine or of
technetium, such as, respectively, 2H, 3H, 1:LC, 13C, 14C,
13N, 15O, 17O, 18F, 35S, 36C1, 123I, 125I and 131I. The
labeled compounds can be synthesized according to the
methods described in the procedures of the present
invention by substituting one or more reagents in the
synthetic process with identical reagents containing
the label isotope(s).
The present invention relates to derivatives of formula
(I) in which:
A is, if it is present, a (C1-C6) alkyl radical, a
(C3-C6) alkenyl radical, a (C3-C6) alkynyl radical, a
(C3-C7) cycloalkyl radical or a (C5-C7) cycloalkenyl
radical; these radicals are optionally substituted with
one or more substituents chosen from (C1-C5) alkyl,
(C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,
(C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl and halogen,

R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7)
azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9)
zabicycloalkenyl group; these groups are optionally
substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C5) cycloalkyl and halogen,
A-R1 is such that the nitrogen of Rl and the nitrogen
in the 1-position of the pyrazole are necessarily
separated by at least two carbon atoms,
R3 is an H, halogen, OH, SH, NH2, ORc, SRc, SORa, SO2Ra,
NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra or NHSO2Ra radical,
R4 is an aryl or heteroaryl radical being optionally
substituted with one or more substituents chosen from
halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2,
C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb,
C(S) NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, O-C(O)Ra,
-O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHC0NH2,
NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)
heterocycloalkyl, polyfluoroalkyl, trifluoromethyl-
sulfanyl, trifluoromethoxy, linear or branched (C1-C6)
alkyl, (C2-C6) alkenyl and (C2-C6) alkynyl, these
substituents being optionally substituted with one or
more alkyl, halogen, OH, methoxy,
R5 is an H, halogen, CF3, CHF2, CH2F, linear or branched
(C1-C6) alkyl or (C3-C7) cycloalkyl radical,
Ra is linear or branched (C1-C6) alkyl, alkenyl,
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, (C4-C7)heterocycloalkyl,
arylalkyl, heteroarylalkyl, aryl, heteroaryl or
polyfluoroalkyl,
Rb is, independently of Ra, a hydrogen, linear or
branched (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7)
cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) hetero-

cycloalkyl, (C4-C7) heterocycloalkyl, arylalkyl,
heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,
Ra and Rb may form a saturated or unsaturated ring
containing 5, 6 or 7 ring members, which may or may not
have a hetero atom such as 0, S or N, this ring being
optionally substituted with one or more alkyl and/or
halogen radicals,
Rc is a linear or branched (C1-C6) alkyl, (C3-C6)
alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7)
cycloalkenyl, (C4-C7) heterocycloalkyl (C4-C7)hetero-
cycloalkyl, (hetero)arylalkyl, (hetero)aryl, (poly) -
fluoroalkyl, C(O)R8, C(S)R8 or SO2R8 radical,
R6 and R7 are, independently of one another, a
hydrogen, (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6)
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, an arylalkyl or
heteroarylalkyl,
R6 and R7 may form a saturated or unsaturated ring with
5, 6 or 7 ring members, which may or may not have a
hetero atom such as 0, S or N and which is optionally
substituted with one or more alkyls and/or halogens,
R8 is an Ra or NRaRb radical,
their racemates, enantiomers and diastereoisomers and
their mixtures, their tautomers and their
pharmaceutically acceptable salts.
Preferably, the present invention relates to
derivatives of formula (I) in which:
A is, if it is present, a (C1-C6) alkyl radical, a
(C3-C6) alkenyl radical, a (C3-C6) alkynyl radical, a
(C3-C7) cycloalkyl radical or a (C5-C7) cycloalkenyl

radical; these radicals are optionally substituted with
one or more substituents chosen from (C1-C5) alkyl,
(C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,
(C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl and halogen,
R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7)
azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9)
azabicycloalkenyl group; these groups are optionally
substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C5) cycloalkyl and halogen,
A-R1 is such that the nitrogen of R1 and the nitrogen
in the 1-position of the pyrazole are necessarily
separated by at least two carbon atoms,
R3 is an OH, NH2, OMe or H radical,
R4 is an aryl or heteroaryl radical being optionally
substituted with one or more substituents chosen from
halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2,
C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb,
C(S)NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, 0-C(O)Ra,
-O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHC0NH2,
NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)
heterocycloalkyl, polyfluoroalkyl, trifluoromethyl-
sulfanyl, trifluoromethoxy, linear or branched (C1-C6)
alkyl, (C2-C6) alkenyl and (C2-C6) alkynyl, these
substituents being optionally substituted with one or
more alkyl, halogen, OH, methoxy,
R5 is a hydrogen or Me radical,
Ra is linear or branched (C1-C6) alkyl, alkenyl,
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, arylalkyl, heteroarylalkyl,
aryl, heteroaryl or polyfluoroalkyl,

Rb is, independently of Ra, a hydrogen, linear or
branched (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7)
cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) hetero-
cycloalkyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl or polyfluoroalkyl,
Ra and Rb may form a saturated or unsaturated ring
containing 5, 6 or 7 ring members, which may or may not
have a hetero atom such as 0, S or N, this ring being
optionally substituted with one or more alkyl and/or
halogen radicals,
Rc is a linear or branched (C1-C6) alkyl, (C3-C6)
alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7)
cycloalkenyl, (C4-C7) heterocycloalkyl, (hetero)-
arylalkyl, (hetero)aryl, (poly)fluoroalkyl, C(O)R8,
C(S)R8 or SO2R8 radical,
R6 and R7 are, independently of one another, a
hydrogen, (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6)
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, an arylalkyl or
heteroarylalkyl,
R6 and R7 may form a saturated or unsaturated ring with
5, 6 or 7 ring members, which may or may not have a
hetero atom such as 0, S or N and which is optionally
substituted with one or more alkyls and/or halogens,
R8 is an Ra or NRaRb radical,
their racemates, enantiomers and diastereoisomers and
their mixtures, their tautomers and their
pharmaceutically acceptable salts.
More particularly, the present invention relates to
derivatives of formula (I) in which:

A is, if it is present, a (C1-C6) alkyl radical, a
(C3-C6) alkenyl radical, a (C3-C6) alkynyl radical, a
(C3-C7) cycloalkyl radical or a (C5-C7) cycloalkenyl
radical; these radicals are optionally substituted with
one or more substituents chosen from (C1-C5) alkyl,
(C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,
(C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl and halogen,
Rl is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7)
azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9)
azabicycloalkenyl group; these groups are optionally
substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C5) cycloalkyl and halogen,
A-R1 is such that the nitrogen of Rl and the nitrogen
in the 1-position of the pyrazole are necessarily
separated by at least two carbon atoms,
R3 is an OH, NH2, OMe or H radical,
R4 is an aryl or heteroaryl radical being optionally
substituted with one or more substituents chosen from
halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2,
C(S)NH2, SO2H, SO2NH2/ NHCHO, C(O)Ra, C(O)0Ra, C(O)NRaRb,
C(S)NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, 0-C(O)Ra,
-O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2,
NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)
heterocycloalkyl, polyfluoroalkyl, trifluoromethyl-
sulfanyl, trifluoromethoxy, linear or branched (C1-C6)
alkyl, (C2-C6) alkenyl and (C2-C6) alkynyl, these
substituents being optionally substituted with one or
more alkyl, halogen, OH, methoxy,
R5 is a hydrogen,
Ra is linear or branched (C1-C6) alkyl, alkenyl,
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,

(C4-C7) heterocycloalkyl, arylalkyl, heteroarylalkyl,
aryl, heteroaryl or polyfluoroalkyl,
Rb is, independently of Ra, a hydrogen, linear or
branched (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7)
cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) hetero-
cycloalkyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl or polyfluoroalkyl,
Ra and Rb may form a saturated or unsaturated ring
containing 5, 6 or 7 ring members, which may or may not
have a hetero atom such as 0, S or N, this ring being
optionally substituted with one or more alkyl and/or
halogen radicals,
Rc is a linear or branched (C1-C6) alkyl, (C3-C6)
alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7)
cycloalkenyl, (C4-C7) heterocycloalkyl,
(hetero)arylalkyl, (hetero)aryl, (poly)fluoroalkyl,
C(O)R8, C(S)R8 or SO2R8 radical,
R6 and R7 are, independently of one another, a
hydrogen, (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6)
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, an arylalkyl or
heteroarylalkyl,
R6 and R7 may form a saturated or unsaturated ring with
5, 6 or 7 ring members, which may or may not have a
hetero atom such as 0, S or N and which is optionally
substituted with one or more alkyls and/or halogens,
R8 is an Ra or NRaRb radical,
their racemates, enantiomers and diastereoisomers and
their mixtures, their tautomers and their
pharmaceutically acceptable salts.

In the definitions above and those which follow, the
(C1-C6) alkyl radicals contain 1 to 6 carbon atoms in a
straight or branched chain; the (C3-C7) cycloalkyl
radicals contain 3 to 7 carbon atoms; the alkenyl
radicals contain 2 to 6 carbon atoms and one to 2
conjugated or unconjugated double bonds in a straight
or branched chain, the double bond not being in the
alpha-position with respect to a hetero atom; the
alkynyl radicals contain 2 to 6 carbon atoms and one to
2 conjugated or unconjugated triple bonds in a straight
or branched chain, the triple bond not being in the
alpha-position with respect to a hetero atom; the aryl
radicals are chosen from phenyl, naphthyl or indenyl;
the heteroaryl radicals contain 3 to 10 ring members,
optionally containing one or more hetero atoms chosen
from oxygen, sulfur and nitrogen, in particular
thiazolyl, thienyl, pyrrolyl, pyrazolyl, pyridinyl,
furyl, imidazolyl, oxazolyl, pyrazinyl, pyrimidyl,
tetrazolyl, oxadiazolyl, thiadiazolyl, isoxadiazolyl,
isothiadiazolyl, isothiazolyl, isoxazolyl, triazolyl,
indolyl, benzofuranyl, benzothienyl, azaindolyl,
pyrazolyl, indolyl; the halogen radical is either
chlorine, iodine, fluorine or bromine; the (C4-C7)
azacycloalkyl radicals contain a nitrogen and 4 to 7
carbon atoms and in particular azetidinyl,
pyrrolidinyl, piperidinyl; the azacycloalkenyl radicals
contain a nitrogen and 5 to 7 carbon atoms; the (C5-C9)
azabicycloalkyl radicals contain 5 to 9 carbon atoms
and are illustrated in a nonlimiting manner in list
(A) ; the (C5-C9) azabicycloalkenyl radicals contain 5
to 9 carbon atoms and are illustrated in a nonlimiting
manner in list (B) ; the (C4-C7) heterocycloalkyl
radicals contain 5 to 7 carbon atoms and one or more
hetero atoms chosen from oxygen, sulfur and nitrogen;
the polyfluoroalkyl radicals contain 1 to 6 carbon
atoms in a straight or branched chain, which are
substituted with one or more fluorine atoms and in
particular trifluoromethyl, difluoromethyl;

By way of illustration, below are structures of list
A) ; these structures may be linked to the main ring
via any of their positions:


By way of illustration, below are structures of list
(B) ; these structures may be linked to the main ring
via any of their positions:


The compounds of formula (I) exhibit one or more
asymmetric carbons and can therefore be in the form of
isomers, of racemates, of enantiomers and of
diastereoisomers; these are also part of the invention
as are mixtures thereof.
The present invention also relates to the
pharmaceutical compositions containing as active
principle a derivative of formula (I) in which:
A is, if it is present, a (C1-C6) alkyl radical, a
(C3-C6) alkenyl radical, a (C3-C6) alkynyl radical, a
(C3-C7) cycloalkyl radical or a (C5-C7) cycloalkenyl
radical; these radicals are optionally substituted with
one or more substituents chosen from (C1-C5) alkyl,

(C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,
(C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl and halogen,
Rl is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7)
azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9)
azabicycloalkenyl group; these groups are optionally
substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C5) cycloalkyl and halogen,
A-R1 is such that the nitrogen of Rl and the nitrogen
in the 1-position of the pyrazole are necessarily
separated by at least two carbon atoms,
R3 is an H, halogen, OH, SH, NH2, ORc, SRc, SORa, SO2Ra,
NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra or NHSO2Ra radical,
R4 is an aryl or heteroaryl radical being optionally
substituted with one or more substituents chosen from
halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2,
C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb,
C(S) NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, 0-C(O)Ra,
-O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2,
NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)
heterocycloalkyl, polyfluoroalkyl, trifluoromethyl-
sulfanyl, trifluoromethoxy, linear or branched (C1-C6)
alkyl, (C2-C6) alkenyl and (C2-C6) alkynyl, these
substituents being optionally substituted with one or
more alkyl, halogen, OH, methoxy,
R5 is an H, halogen, CF3, CHF2, CH2F, linear or branched
(C1-C6) alkyl or (C3-C7) cycloalkyl radical,
Ra is linear or branched (C1-C6) alkyl, alkenyl,
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, arylalkyl, heteroarylalkyl,
aryl, heteroaryl or polyfluoroalkyl,

Rb is, independently of Ra, a hydrogen, linear or
branched (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7)
eycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) hetero-
cycloalkyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl or polyfluoroalkyl,
Ra and Rb may form a saturated or unsaturated ring
containing 5, 6 or 7 ring members, which may or may not
have a hetero atom such as 0, S or N, this ring being
optionally substituted with one or more alkyl and/or
halogen radicals,
Rc is a linear or branched (C1-C6) alkyl, (C3-C6)
alkenyl, (C3-C6) alkynyl, (C3-C7) eycloalkyl, (C5-C7)
cycloalkenyl, (C4-C7) heterocycloalkyl, (hetero)-
arylalkyl, (hetero)aryl, (poly)fluoroalkyl, C(O)R8,
C(S)R8 or SO2R8 radical,
R6 and R7 are, independently of one another, a
hydrogen, (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6)
alkynyl, (C3-C7) eycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, an arylalkyl or
heteroarylalkyl,
R6 and R7 may form a saturated or unsaturated ring with
5, 6 or 7 ring members, which may or may not have a
hetero atom such as 0, S or N and which is optionally
substituted with one or more alkyls and/or halogens,
R8 is an Ra or NRaRb radical,
their racemates, enantiomers and diastereoisomers, and
their mixtures, their tautomers and their
pharmaceutically acceptable salts.
Preferably, the present invention also relates to
pharmaceutical compositions containing as active
principle a derivative of formula (I) in which:

A is, if it is present, a (C1-C6) alkyl radical, a
(C3-C6) alkenyl radical, a (C3-C6) alkynyl radical, a
(C3-C7) cycloalkyl radical or a (C5-C7) cycloalkenyl
radical; these radicals are optionally substituted with
one or more substituents chosen from (C1-C5) alkyl,
(C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,
(C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl and halogen,
R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7)
azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9)
azabicycloalkenyl group; these groups are optionally
substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C5) cycloalkyl and halogen,
A-R1 is such that the nitrogen of Rl and the nitrogen
in the 1-position of the pyrazole are necessarily
separated by at least two carbon atoms,
R3 is an OH, NH2, OMe or H radical,
R4 is an aryl or heteroaryl radical being optionally
substituted with one or more substituents chosen from
halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2,
C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb,
C(S)NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, 0-C(O)Ra,
-O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2/
NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)
heterocycloalkyl, polyfluoroalkyl, trifluoromethyl-
sulfanyl, trifluoromethoxy, linear or branched (C1-C6)
alkyl, (C2-C6) alkenyl and (C2-C6) alkynyl, these
substituents being optionally substituted with one or
more alkyl, halogen, OH, methoxy,
R5 is a hydrogen or Me radical,

Ra is linear or branched (C1-C6) alkyl, alkenyl,
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, arylalkyl, heteroarylalkyl,
aryl, heteroaryl or polyfluoroalkyl,
Rb is, independently of Ra, a hydrogen, linear or
branched (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7)
cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) hetero-
cycloalkyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl or polyfluoroalkyl,
Ra and Rb may form a saturated or unsaturated ring
containing 5, 6 or 7 ring members, which may or may not
have a hetero atom such as 0, S or N, this ring being
optionally substituted with one or more alkyl and/or
halogen radicals,
Re is a linear or branched (C1-C6) alkyl, (C3-C6)
alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7)
cycloalkenyl, (C4-C7) heterocycloalkyl, (hetero)-
arylalkyl, (hetero)aryl, (poly)fluoroalkyl, C(O)R8,
C(S)R8 or SO2R8 radical,
R6 and R7 are, independently of one another, a
hydrogen, (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6)
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, an arylalkyl or
heteroarylalkyl,
R6 and R7 may form a saturated or unsaturated ring with
5, 6 or 7 ring members, which may or may not have a
hetero atom such as 0, S or N and which is optionally
substituted with one or more alkyls and/or halogens,
R8 is an Ra or NRaRb radical,

their racemates, enantiomers and diastereoisomers and
their mixtures, their tautomers and their
pharmaceutically acceptable salts.
More particularly, the present invention also relates
to the pharmaceutical compositions containing as active
principle a derivative of formula (I) in which:
A is, if it is present, a (C1-C6) alkyl radical, a
(C3-C6) alkenyl radical, a (C3-C6) alkynyl radical, a
(C3-C7) cycloalkyl radical or a (C5-C7) cycloalkenyl
radical; these radicals are optionally substituted with
one or more substituents chosen from (C1-C5) alkyl,
(C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,
(C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl and halogen,
Rl is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7)
azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9)
azabicycloalkenyl group; these groups are optionally
substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C5) cycloalkyl and halogen,
A-R1 is such that the nitrogen of Rl and the nitrogen
in the 1-position of the pyrazole are necessarily
separated by at least two carbon atoms,
R3 is an OH, NH2, OMe or H radical,
R4 is an aryl or heteroaryl radical being optionally
substituted with one or more substituents chosen from
halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2,
C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb,
C(S)NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, 0-C(O)Ra,
-O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2,
NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)
heterocycloalkyl, polyfluoroalkyl, trifluoromethyl-
sulfanyl, trifluoromethoxy, linear or branched (C1-C6)

alkyl, (C2-C6) alkenyl and (C2-C6) alkynyl, these
substituents being optionally substituted with one or
more alkyl, halogen, OH, methoxy,
R5 is a hydrogen,
Ra is linear or branched (C1-C6) alkyl, alkenyl,
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, arylalkyl, heteroarylalkyl,
aryl, heteroaryl or polyfluoroalkyl,
Rb is, independently of Ra, a hydrogen, linear or
branched (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7)
cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) hetero-
cycloalkyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl or polyfluoroalkyl,
Ra and Rb may form a saturated or unsaturated ring
containing 5, 6 or 7 ring members, which may or may not
have a hetero atom such as 0, S or N, this ring being
optionally substituted with one or more alkyl and/or
halogen radicals,
Re is a linear or branched (C1-C6) alkyl, (C3-C6)
alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7)
cycloalkenyl, (C4-C7) heterocycloalkyl, (hetero)aryl-
alkyl, (hetero)aryl, (poly)fluoroalkyl, C(O)R8, C(S)R8
or SO2R8 radical,
R6 and R7 are, independently of one another, a
hydrogen, (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6)
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, an arylalkyl or
heteroarylalkyl,
R6 and R7 may form a saturated or unsaturated ring with
5, 6 or 7 ring members, which may or may not have a
hetero atom such as 0, S or N and which is optionally
substituted with one or more alkyls and/or halogens,

R8 is an Ra or NRaRb radical,
their racemates, enantiomers and diastereoisomers and
their mixtures, their tautomers and their
pharmaceutically acceptable salts.
The present invention also relates to the use as a
medicinal product of the pyrazole derivatives of
formula (I) in which:
A is, if it is present, a (C1-C6) alkyl radical, a
(C3-C6) alkenyl radical, a (C3-C6) alkynyl radical, a
(C3-C7) cycloalkyl radical or a (C5-C7) cycloalkenyl
radical; these radicals are optionally substituted with
one or more substituents chosen from (C1-C5) alkyl,
(C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,
(C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl and halogen,
R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7)
azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9)
azabicycloalkenyl group; these groups are optionally
substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C5) cycloalkyl and halogen,
A-R1 is such that the nitrogen of Rl and the nitrogen
in the 1-position of the pyrazole are necessarily
separated by at least two carbon atoms,
R3 is an H, halogen, OH, SH, NH2, ORc, SRc, SORa, SO2Ra,
NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra or NHSO2Ra radical,
R4 is an aryl or heteroaryl radical being optionally
substituted with one or more substituents chosen from
halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2,
C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb,
C(S) NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, 0-C(O)Ra,
-O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHC0NH2,

NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)
heterocycloalkyl, polyfluoroalkyl, trifluoromethyl-
sulfanyl, trifluoromethoxy, linear or branched (C1-C6)
alkyl, (C2-C6) alkenyl and (C2-C6) alkynyl, these
substituents being optionally substituted with one or
more alkyl, halogen, OH, methoxy,
R5 is an H, halogen, CF3, CHF2, CH2F, linear or branched
(C1-C6) alkyl or (C3-C7) cycloalkyl radical,
Ra is linear or branched (C1-C6) alkyl, alkenyl,
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, arylalkyl, heteroarylalkyl,
aryl, heteroaryl or polyfluoroalkyl,
Rb is, independently of Ra, a hydrogen, linear or
branched (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7)
cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) hetero-
cycloalkyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl or polyfluoroalkyl,
Ra and Rb may form a saturated or unsaturated ring
containing 5, 6 or 7 ring members, which may or may not
have a hetero atom such as 0, S or N, this ring being
optionally substituted with one or more alkyl and/or
halogen radicals,
Re is a linear or branched (C1-C6) alkyl, (C3-C6)
alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7)
cycloalkenyl, (C4-C7) heterocycloalkyl, (hetero)-
arylalkyl, (hetero)aryl, (poly)fluoroalkyl, C(O)R8,
C(S)R8 or SO2R8 radical,
R6 and R7 are, independently of one another, a
hydrogen, (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6)
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, an arylalkyl or
heteroarylalkyl,

R6 and R7 may form a saturated or unsaturated ring with
5, 6 or 7 ring members, which may or may not have a
hetero atom such as 0, S or N and which is optionally
substituted with one or more alkyls and/or halogens,
R8 is an Ra or NRaRb radical,
their racemates, enantiomers and diastereoisomers, and
their mixtures, their tautomers and their
pharmaceutically acceptable salts.
Preferably, the present invention relates to the use as
medicinal product of the pyrazole derivatives of
formula (I) in which:
A is, if it is present, a (C1-C6) alkyl radical, a
(C3-C6) alkenyl radical, a (C3-C6) alkynyl radical, a
(C3-C7) cycloalkyl radical or a (C5-C7) cycloalkenyl
radical; these radicals are optionally substituted with
one or more substituents chosen from (C1-C5) alkyl,
(C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,
(C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl and halogen,
Rl is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7)
azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9)
azabicycloalkenyl group; these groups are optionally
substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C5) cycloalkyl and halogen,
A-R1 is such that the nitrogen of Rl and the nitrogen
in the 1-position of the pyrazole are necessarily
separated by at least two carbon atoms,
R3 is an OH, NH2, OMe or H radical,

R4 is an aryl or heteroaryl radical being optionally-
substituted with one or more substituents chosen from
halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2,
C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb,
C(S)NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, 0-C(O)Ra,
-O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHC0NH2,
NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)
heterocycloalkyl, polyfluoroalkyl, trifluoromethyl-
sulfanyl, trifluoromethoxy, linear or branched (C1-C6)
alkyl, (C2-C6) alkenyl and (C2-C6) alkynyl, these
substituents being optionally substituted with one or
more alkyl, halogen, OH, methoxy,
R5 is a hydrogen or Me radical,
Ra is linear or branched (C1-C6) alkyl, alkenyl,
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, arylalkyl, heteroarylalkyl,
aryl, heteroaryl or polyfluoroalkyl,
Rb is, independently of Ra, a hydrogen, linear or
branched (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7)
cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) hetero-
cycloalkyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl or polyfluoroalkyl,
Ra and Rb may form a saturated or unsaturated ring
containing 5, 6 or 7 ring members, which may or may not
have a hetero atom such as 0, S or N, this ring being
optionally substituted with one or more alkyl and/or
halogen radicals,
Re is a linear or branched (C1-C6) alkyl, (C3-C6)
alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7)
cycloalkenyl, (C4-C7) heterocycloalkyl, (hetero)-
arylalkyl, (hetero)aryl, (poly)fluoroalkyl, C(O)R8,
C(S)R8 or SO2R8 radical,

R6 and R7 are, independently of one another, a
hydrogen, (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6)
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, an arylalkyl or
heteroarylalkyl,
R6 and R7 may form a saturated or unsaturated ring with
5, 6 or 7 ring members, which may or may not have a
hetero atom such as 0, S or N and which is optionally
substituted with one or more alkyls and/or halogens,
R8 is an Ra or NRaRb radical,
their racemates, enantiomers and diastereoisomers and
their mixtures, their tautomers and their
pharmaceutically acceptable salts.
More particularly, the present invention relates to the
use as a medicinal product of pyrazole derivatives of
formula (I) in which:
A is, if it is present, a (C1-C6) alkyl radical, a
(C3-C6) alkenyl radical, a (C3-C6) alkynyl radical, a
(C3-C7) cycloalkyl radical or a (C5-C7) cycloalkenyl
radical; these radicals are optionally substituted with
one or more substituents chosen from (C1-C5) alkyl,
(C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,
(C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl and halogen,
R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7)
azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9)
azabicycloalkenyl group; these groups are optionally
substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C5) cycloalkyl and halogen,

A-R1 is such that the nitrogen of R1 and the nitrogen
in the 1-position of the pyrazole are necessarily-
separated by at least two carbon atoms,
R3 is an OH, NH2, OMe or H radical,
R4 is an aryl or heteroaryl radical being optionally
substituted with one or more substituents chosen from
halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2,
C(S)NH2, SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)0Ra, C(O)NRaRb,
C(S)NRaRb, S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, 0-C(O)Ra,
-O-C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHC0NH2,
NHCONRaRb, NHSO2Ra, aryl, heteroaryl, (C4-C7)
heterocycloalkyl, polyfluoroalkyl, trifluoromethyl-
sulfanyl, trifluoromethoxy, linear or branched (C1-C6)
alkyl, (C2-C6) alkenyl and (C2-C6) alkynyl, these
substituents being optionally substituted with one or
more alkyl, halogen, OH, methoxy,
R5 is a hydrogen,
Ra is linear or branched (C1-C6) alkyl, alkenyl,
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, arylalkyl, heteroarylalkyl,
aryl, heteroaryl or polyfluoroalkyl,
Rb is, independently of Ra, a hydrogen, linear or
branched (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7)
cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) hetero-
cycloalkyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl or polyfluoroalkyl,
Ra and Rb may form a saturated or unsaturated ring
containing 5, 6 or 7 ring members, which may or may not
have a hetero atom such as O, S or N, this ring being
optionally substituted with one or more alkyl and/or
halogen radicals,

Rc is a linear or branched (C1-C6) alkyl, (C3-C6)
alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7)
cycloalkenyl, (C4-C7) heterocycloalkyl, (hetero)aryl-
alkyl, (hetero)aryl, (poly)fluoroalkyl, C(O)R8, C(S)R8
or SO2R8 radical,
R6 and R7 are, independently of one another, a
hydrogen, (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6)
alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, an arylalkyl or
heteroarylalkyl,
R6 and R7 may form a saturated or unsaturated ring with
5, 6 or 7 ring members, which may or may not have a
hetero atom such as 0, S or N and which is optionally
substituted with one or more alkyls and/or halogens,
R8 is an Ra or NRaRb radical,
their racemates, enantiomers and diastereoisomers and
their mixtures, their tautomers and their
pharmaceutically acceptable salts.
Among the compounds of formula (I) which are useful
according to the invention, mention may be made of the
following compounds:
1-[2-(3-Methoxy-4-phenylpyrazol-1-yl)ethyl]piperidine
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-
pyrazol-1-ol
3-(3-Benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-
azabicyclo[2.2.2]octane
3-(3-Methoxy-4-phenylpyrazol-1-ylmethyl)-1-
azabicyclo[2.2.2]octane

1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-lH-pyrazol-3-
ol
1-(2-Perhydroazepin-1-ylethyl)-4-phenyl-lH-pyrazol-3-ol
1-[2-(2-Methylpiperidin-1-yl)ethyl]-4-phenyl-lH-
pyrazol-3-ol
1-[2-(4-Fluoropiperidin-1-yl)ethyl]-4-phenyl-lH-
pyrazol-3-ol
1-[2-(3-Methylpiperidin-1-yl)ethyl]-4-phenyl-lH-
pyrazol-3-ol
1-[2-(3,6-Dihydro-2H-pyridin-1-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol
1-[2-(7-Azabicyclo[2.2.1]hept-7-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol
1-[2-(2-Azabicyclo[2.2.2]oct-2-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol
1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol
1-[2-Dimethylaminoethyl]-4-phenyl-lH-pyrazol-3-ol
1-[3-Dimethylaminopropyl]-4-phenyl-lH-pyrazol-3-ol
1-[2-((2S,6R)-2,6-Dimethylpiperidin-1-yl)ethyl]-4-
phenyl-lH-pyrazol-3-ol
1-[2-Diethylaminoethyl]-4-phenyl-lH-pyrazol-3-ol
1-(2-Diisopropylaminoethyl)-4-phenyl-lH-pyrazol-3-ol
4-Phenyl-1-(2-pyrrolidin-1-ylethyl)-lH-pyrazol-3-ol

3-(3-Methoxy-4-phenylpyrazol-1-yl)-1-azabicyclo-
[2. 2. 2] octane
1-[2-(3-Difluoromethoxy-4-phenylpyrazol-1-yl)ethyl]-
piperidine
4-Phenyl-1-(2-piperidin-1-ylethyl)-lH-pyrazol-3-ylamine
4-Phenyl-1-(2-piperidin-1-ylethyl)-lH-pyrazol-3-ylamine
N-[4-Phenyl-1-(2-piperidin-1-ylethyl)-lH-pyrazol-
3-yl]acetamide
N-[4-Phenyl-1-(2-piperidin-1-ylethyl)-lH-pyrazol-
3-yl]methanesulfonamide
1-(2-Dimethylaminopropyl)-4-phenyl-lH-pyrazol-3-ol
1-(l-Methylpiperidin-3-ylmethyl)-4-phenyl-lH-pyrazol-
3-ol
5-Methyl-4-phenyl-1-(2-piperidin-1-ylethyl)-lH-pyrazol-
3-ol
4-(3-Aminophenyl)-1-(2-dimethylaminoethyl)-lH-pyrazol-
3-ol
N-{3- [3-Hydroxy-1- (2-dimethylaminoethyl) -lH-pyrazol-
4-yl]phenyl}acetamide
4-(4-Aminophenyl)-1-(2-dimethylaminoethyl)-lH-pyrazol-
3-ol
1- (2-Dimethylaminoethyl) -4- (4 ' -f luorobiphenyl-3-yl) -1H-
pyrazol-3-ol

4-Biphenyl-3-yl-1-(2-dimethylaminoethyl)-lH-pyrazol-
3-ol
1-(2-Dimethylaminoethyl)-4-(4'-fluorobiphenyl-4-yl)-1H-
pyrazol-3-ol
1-(2-Piperidin-1-ylethyl)-4-pyridin-2-yl-lH-pyrazol-
3-ol
1-(2-Piperidin-1-ylethyl)-4-pyridin-4-yl-lH-pyrazol-
3-ol
4-(4-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(4-Trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-
lH-pyrazol-3-ol
4-Phenyl-1-(2-piperidin-1-ylpropyl)-lH-pyrazol-3-ol
3-(4-Phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]-
octane
4-(5-Chlorothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(3-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(2-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(3-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(4-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol

4-(4-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(3-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
1-(2-Piperidin-1-ylethyl)-4-(3-trifluoromethylphenyl)-
lH-pyrazol-3-ol
1-(2-Piperidin-1-ylethyl)-4-pyridin-3-yl-lH-pyrazol-
3-ol
4-(4-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(3-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(2-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(2-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
1-(l-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-
pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(3-chlorophenyl)-1H-
pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(3-fluorophenyl)-1H-
pyrazol-3-ol
1-(l-Methylpyrrolidin-3-yl)-4-phenyl-lH-pyrazol-3-ol
1-[2-(l-Methylpyrrolidin-2-yl)ethyl]-4-phenyl-lH-
pyrazol-3-ol

1-(Pyrrolidin-3-yl)-4-phenyl-lH-pyrazol-3-ol
V[(l-Methylpyrrolidin-2-(S)-yl)methyl]-4-phenyl-1H-
pyrazol-3-ol
4-Phenyl-1-(2-piperidin-1-ylethyl)-lH-pyrazol-3-ol
1-[2-(4-Phenylpyrazol-1-yl)ethyl]piperidine
1-[2-(4-Methylpiperidin-1-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol
3-(3-Difluoromethoxy-4-phenylpyrazol-1-ylmethyl)-1-
azabicyclo[2.2.2]octane
3-(4-Phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]octane
4-Benzo[b]thiophen-2-yl-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-Phenyl-1-piperidin-3-yl-lH-pyrazol-3-ol
1-(2-Piperidin-1-ylethyl)-4-thiophen-3-yl-lH-pyrazol-
3-ol
1-(2-Piperidin-1-ylethyl)-4-p-tolyl-lH-pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-2-ylmethyl)-4-phenyl-lH-
pyrazol-3-ol
(S)-1-(l-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-lH-
pyrazol-3-ol
(R)-1-(l-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-lH-
pyrazol-3-ol
4 -Phenyl-1-pyrrolidin-3-ylmethyl-lH-pyrazol-3 -ol

1-(2-Piperidin-1-ylethyl)-4-thiophen-2-yl-1H-pyrazol-
3-ol
4-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
4-yl]benzamide
3-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
4-yl]benzamide
1-[(S)-1-(l-Azabicyclo[2.2.2]oct-3-yl)methyl]-4-phenyl-
lH-pyrazol-3-ol
1-[(R)-1-(1-Azabicyclo[2.2.2]oct-3-yl)methyl]-4-phenyl-
lH-pyrazol-3-ol
1-[(1S,4R)-2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-
phenyl-1H-pyrazol-3-ol
1-[(1R,4S)-2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-
phenyl-1H-pyrazol-3-ol
1-((R)-1-Methylpyrrolidin-2-ylmethyl)-4-phenyl-1H-
pyrazol-3-ol
1-((S)-1-Methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazol-
3-ol
1-((R)-1-Methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazol-
3-ol
1-[1-(7-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-phenyl-
lH-pyrazol-3-ol
1-(1-Azabicyclo[2.2.1]hept-3-yl)-4-phenyl-1H-pyrazol-
3-ol
4-Phenyl-1-piperidin-2-ylmethyl-1H-pyrazol-3-ol

1-(l-Methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazol-
3-ol
1-(l-Ethylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazol-
3-ol
1-(1-Methyl-2-piperidin-1-ylethyl)-4-phenyl-IH-pyrazol-
3-ol
1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)-1-methylethyl]-4-
phenyl-1H-pyrazol-3-ol
1-(2-Dimethylaminocyclopentyl)-4-phenyl-1H-pyrazol-3-ol
1-(R)-1-Azabicyclo[2.2.2]oct-3-yl-4-(4-chlorophenyl)-
lH-pyrazol-3-ol
1-(S)-1-Azabicyclo[2.2.2]oct-3-yl-4-(4-chlorophenyl)-
lH-pyrazol-3-ol
1-(R)-1-Azabicyclo[2.2.2]oct-3-yl-4-(3-chlorophenyl)-
lH-pyrazol-3-ol
1-(S)-1-Azabicyclo[2.2.2]oct-3-yl-4-(3-chlorophenyl)-
lH-pyrazol-3-ol
1-(R)-1-Azabicyclo[2.2.2]oct-3-yl-4-(3-fluorophenyl)-
lH-pyrazol-3-ol
1-(S)-1-Azabicyclo[2.2.2]oct-3-yl-4-(3-fluorophenyl)-
lH-pyrazol-3-ol
4-(5-Bromothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(5-Phenylthiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol

1-(2-Piperidin-1-ylethyl)-4-(5-pyridin-2-ylthiophen-
2-yl)-1H-pyrazol-3-ol
4-(4-Chlorothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(4-Bromophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-ol
1-(2-Piperidin-1-ylethyl)-4-(3-trifluoromethoxyphenyl)-
lH-pyrazol-3-ol
4-(3,4-Dichlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(3,5-Dichlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(6-Chloropyridin-2-yl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(lH-Indol-6-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-ol
4-(lH-Indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-ol
4-(lH-Indol-3-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-ol
4-(1-Methyl-1H-indol-3-yl)-1-(2-piperidin-1-ylethyl)-
lH-pyrazol-3-ol
N-{4-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
4-yl]phenyl}methanesulfonamide
N-{3-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
4-yl]phenyl}methanesulfonamide

4-[3-(1H-Imidazol-2-yl)phenyl]-1-(2-piperidin-1-yl-
ethyl)-1H-pyrazol-3-ol
4-[4-(lH-Imidazol-2-yl)phenyl]-1-(2-piperidin-1-yl-
ethyl)-1H-pyrazol-3-ol
4-(3-Chloro-4-hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-
lH-pyrazol-3-ol
4-(4-Hydroxy-3-methylphenyl)-1-(2-piperidin-1-ylethyl)-
lH-pyrazol-3-ol
4-(4-Amino-3-chlorophenyl)-1-(2-piperidin-1-ylethyl)-
lH-pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(5-chlorothiophen-2-
yl)-1H-pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(5-chloro-
thiophen-2-yl)-1H-pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-chloro-
phenyl)-1H-pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(3-chloro-
phenyl)-1H-pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(3-fluoro-
phenyl)-1H-pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(3-
hydroxyphenyl)-1H-pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-hydroxy-
phenyl)-1H-pyrazol-3-ol

1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-(5-chloro-
thiophen-2-yl)-1H-pyrazol-3-ol
>
1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-(4-chloro-
phenyl)-1H-pyrazol-3-ol
1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-(3-chloro-
phenyl)-1H-pyrazol-3-ol
1- [2- (2-Azabicyclo[2.2.1]hept-2-yl)ethyl] -4- (3-fluoro-
phenyl)-1H-pyrazol-3-ol
1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-(3-hydroxy-
phenyl)-1H-pyrazol-3-ol
1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-(4-hydroxy-
phenyl) -1H-pyrazol-3-ol
1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-(3-chloro-
4-hydroxyphenyl)-1H-pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(3-chloro-
4-hydroxyphenyl)-1H-pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(3 -hydroxypheny1)-1H-
pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-hydroxypheny1)-1H-
pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(3-chloro-4-hydroxy-
phenyl) -1H-pyrazol-3-ol
2-[1-(2-Piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide
N-Methyl-2-[1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]-
benzamide

2-[1-(2-Piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzene-
sulfonamide
>
N-Methyl-2-[1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-
yl]benzenesulfonamide
{2-[1-(2-Piperidin-1-ylethyl)-1H-pyrazol-4-yl]phenyl}-
methanol
4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazole-3-thiol
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-
ylamine
N-[1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-IH-pyrazol-
3-yl]methanesulfonamide
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazole-
3-thiol
4-[1-(l-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-
2-chlorophenol
4-[1-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-
phenol
3-[4-(4-Chlorophenyl)pyrazol-1-ylmethyl]-1-azabicyclo-
[2.2.2]octane
4-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-IH-pyrazol-
4-yl]phenol
4-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-1H-pyrazol-
4-yl]-2-chlorophenol
3-(3-Cyclopropylmethoxy-4-phenylpyrazol-1-ylmethyl)-
1-azabicyclo[2.2.2]octane

3- [4- (4-Chlorophenyl)-3-cyclopropylmethoxypyrazol-
1-ylmethyl]-1-azabicyclo[2.2.2]octane
>-
4-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-3-cyclopropyl-
methoxy-1H-pyrazol-4-yl]phenol
4-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-3 -cyclopropyl-
methoxy-1H-pyrazol-4-yl]-2-chlorophenol
3-[4-Phenyl-3-(2,2,2 -trifluoroethoxy)pyrazol-1-yl-
methyl] -1-azabicyclo[2.2.2]octane
3-[4-(4-Chlorophenyl)-3-(2,2,2-trifluoroethoxy)pyrazol-
1-ylmethyl]-1-azabicyclo[2.2.2]octane
4-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-3-(2,2,2-
trifluoroethoxy)-1H-pyrazol-4-yl]phenol
4-[1-(l-Azabicyclo[2.2.2]oct-3-ylmethyl)-3-(2,2,2-
trifluoroethoxy)-1H-pyrazol-4-yl]-2-chlorophenol
N-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-
pyrazol-3-yl]methanesulfonamide
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-
pyrazole-3-thiol
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-
pyrazol-3-ylamine
2- [2-(4-Phenylpyrazol-1-yl)ethyl]-2-azabicyclo-
[2.2.1]heptane
2-{2-[4-(4-Chlorophenyl)pyrazol-1-yl]ethyl}-2-aza-
bicyclo[2.2.1]heptane
4-{l-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-1H-
pyrazol-4-yl}phenol

4-{l-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-1H-
pyrazol-4-yl}-2-chlorophenol
1-[2-(2-Ethyl-4-methylpyrrolidin-1-yl)ethyl]-4-phenyl-
lH-pyrazole-3-thiol
N-{l-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-phenyl-
lH-pyrazol-3-yl}methanesulfonamide
1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ylamine
4-(4-Chlorophenyl)-1-[2-(2-ethyl-4-methylpyrrolidin-
1-yl)ethyl]-1H-pyrazole-3-thiol
N- [1- [2- (2-Azabicyclo[2.2.1]hept-2-yl)ethyl] -4- (4-
chlorophenyl)-1H-pyrazol-3-yl]methanesulfonamide
1- [2- (2-Azabicyclo[2.2.1]hept-2-yl)ethyl] -4- (4-chloro-
phenyl)-1H-pyrazol-3-ylamine
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-
pyrazole-3-thiol
N-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-chloro-
phenyl )-1H-pyrazol-3-yl]methanesulfonamide
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-chloro-
phenyl) -1H-pyrazol-3-ylamine
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-chloro-
phenyl) -1H-pyrazole-3-thiol
1-(l-Methylperhydroazepin-3-yl)-4-phenyl-1H-pyrazol-
3-ol
1-(2-Methylaminocyclopentyl)-4-phenyl-1H-pyrazol-3-ol

1-(3-Dimethylaminocyclopentyl)-4-phenyl-1H-pyrazol-3-ol
1-(3-Methylaminocyclopentyl)-4-phenyl-1H-pyrazol-3-ol
1-(2-Dimethylaminocyclohexyl)-4-phenyl-1H-pyrazol-3-ol
1-(2-Methylaminocyclohexyl)-4-phenyl-1H-pyrazol-3-ol
1-(3-Dimethylaminocyclohexyl)-4-phenyl-1H-pyrazol-3-ol
1-(3-Methylaminocyclohexyl)-4-phenyl-1H-pyrazol-3-ol
1-(Octahydroindolizin-3-ylmethyl)-4-phenyl-1H-pyrazol-
3-ol
1-((S)-1-Ethylpyrrolidin-2-ylmethyl)-4-phenyl-1H-
pyrazol-3-ol
4 -Phenyl-1-pyrrolidin-3-ylmethyl-1H-pyrazol-3-ol
1-( (2R) 1-Methylpyrrolidin-2-ylmethyl)-4-phenyl-1H-
pyrazol-3-ol
4-Phenyl-1-(piperidin-3-yl)-1H-pyrazol-3-ol
1-(l-Methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-
ol
1-(l-Methylazepan-3-yl)-4-phenyl-1H-pyrazol-3-ol
4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol
4-(Thiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-ol
4-(3,4-Dichlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol

4-(4-Bromophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3 ol
4-(lH-Indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-ol
4-(5-Bromothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
2-[1-(2-Piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide
4-(2-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazole
4-(lH-Indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole
4-(4-Methylphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(lH-indol-5-yl)-1H-
pyrazole
(+)-1-(Azabicyclo[2.2.2]oct-3-yl)-4-(lH-indol-5-yl)-1H-
pyrazole
(-)-1-(Azabicyclo[2.2.2]oct-3-yl)-4-(lH-indol-5-yl)-1H-
pyrazole
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(5-chlorothiophen-2-
yl)-1H-pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(5-chlorothiophen-2-
yl)-1H-pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-2-ylmethyl)-4-phenyl-1H-
pyrazol-3-ol

3-[4-(3,5-Difluorophenyl)pyrazol-1-yl]-1-
azabicyclo[2.2.2]octane
4-Benzo[b]thiophen-2-yl-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
1-(2-Piperidin-1-ylethyl)-4-thiophen-3-yl-1H-pyrazol-3-
ol
4-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-
yl]benzamide
3-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-
yl]benzamide
(-)-1-(l-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-
pyrazol-3-ol
(+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-
pyrazol-3-ol
(-)-1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-
pyrazol-1-ol
(+)-1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-
pyrazol-1-ol
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-
chlorophenyl)-1H-pyrazol-3-ol
(-)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-
lH-pyrazol-3-ol
(+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-
lH-pyrazol-3-ol
(-)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-fluorophenyl)-
lH-pyrazol-3-ol

( + ) -1- (l-Azabicyclo[2.2.2]oct-3-yl) -4- (4-fluorophenyl) -
1H-pyrazol-3-ol
3-[4-(4-Chlorophenyl)pyrazol-1-yl]-1-azabicyclo-
[2.2.2]octane
3-[4-(4-Chlorophenyl)pyrazol-1-ylmethyl]-1-
azabicyclo[2.2.2]octane
3-[4-(3-Chloro-4-methoxyphenyl)pyrazol-1-ylmethyl]-1-
azabicyclo[2.2.2]octane
4-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-1H-pyrazol-4-
yl]-2-chlorophenol
4-[1-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl] -2-
chlorophenol
(-)-4-[1-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-
yl]-2-chlorophenol
(+)-4-[1-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-
yl]-2-chlorophenol
(+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-
pyrazol-3-ol
(-)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-
pyrazol-3-ol
(+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-
pyrazol-3-ylamine
(-)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-
pyrazol-3-ylamine

(+)-1-(l-Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-4-yl)-
1H-pyrazole
(-)-1-(l-Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-4-yl)-
lH-pyrazole,
their racemates, enantiomers and diastereoisomers and
their mixtures, their tautomers and their
pharmaceutically acceptable salt.
The methods of obtaining the derivatives of the present
invention are illustrated below and, in order for it to
be easier to read the processes, the compounds of
formula (I) are divided up into eight subfamilies (Ia)
for R3 = OH, (Ib) for R3 = ORc, (Ic) for R3 = H, (Id)
for R3 = NH2, (Ie) for R3 = NHCHO, NRaRb, NHC(O)Ra,
NHC(S)Ra, NHSO2Ra, (If) for R3 = SH, (Ig) for R3 = SRc,
and (Ih) for R3 = S(O)Ra, SO2Ra. The definitions of
various substituents are the same as those of formula
(I), unless otherwise indicated.
For easy reading, groups GP, GP', GP", GP'", GPiv and GPV
are groups which protect functions sensitive to the
reaction conditions and are introduced as defined in
T.W. Greene et al. , Protective Groups in Organic
Synthesis, Wiley-Interscience, third edition (1999),
capable of being unaffected by the subsequent steps of
the synthesis and of being deprotected under conditions
which do not affect the rest of the molecule.
The derivatives of formula (I) for which R3 is a
hydroxyl (Ia) can be obtained from derivatives of
formula (II) (I with R3 = OGP) for which GP is a
hydroxyl function-protecting group.


The term "GP" is intended to mean a hydroxyl function-
protecting group, as defined in T.W. Greene et al. ,
Protective Groups in Organic Synthesis, Wiley-
Interscience, third edition (1999), capable of being
unaffected by the subsequent steps of the synthesis and
of being deprotected under conditions which do not
affect the rest of the molecule. For example, the GP
group may be a silyl-containing group such as tert-
butyldimethylsilyl, triisopropylsilyl or diphenyl-
methylsilyl, or an alkyl, aralkyl, alkylidene,
cycloalkylidene, heteroalkyl or heterocycloalkyl
residue such as methyl, allyl, cyclohex-2-enyl, benzyl
or tetrahydropyran-2-yl. The GP group is preferably a
benzyl or a cyclohex-2-enyl. The deprotection of the GP
group is carried out according to the methods described
in T.W. Greene et al. , Protective Groups in Organic
Synthesis, Wiley-Interscience, third edition (1999).
For example, when the GP group is a benzyl, the
deprotection is carried out by hydrolysis in the
presence of concentrated hydrochloric acid in an
alcohol such as ethanol, methanol or isopropanol at a
temperature of between 20°C and the boiling temperature
of the reaction medium, preferably in ethanol, at the
boiling temperature of the reaction medium.
Alternatively, the debenzylation can be carried out by
the following successive operations:
a) Formation of the hydrochloride of the compound to be
deprotected in the presence of hydrochloric acid in
aqueous solution or in solution in an organic solvent

such as ethanol, methanol, dioxane or diethyl ether, at
a temperature in the region of 2 0°C;
b) Hydrogenation in the presence of a catalyst such as
palladium-on-charcoal, in an alcohol such as ethanol,
methanol or isopropanol, at a hydrogen pressure of
between 1 bar and 2 0 bar and at a temperature of
between 20 °C and the boiling temperature of the
reaction medium.
The hydrogenolysis of the benzyl group can also be
carried out in the presence of a catalyst such as
palladium-on-charcoal, in the presence of concentrated
hydrochloric acid, in an alcohol such as ethanol,
methanol or isopropanol, at a hydrogen pressure of
between 1 bar and 3 0 bar and at a temperature of
between 20°C and the boiling temperature of the
reaction medium. The reaction can also be carried out
with ammonium formate, in the presence of a catalyst
such as palladium-on-charcoal, in an alcohol such as
ethanol, methanol or isopropanol, at a temperature
between 20°C and the boiling temperature of the
reaction medium, preferably in methanol at the boiling
temperature of the reaction medium.
When the GP group is a cyclohexenyl, the deprotection
is carried out by hydrolysis in acid medium, for
example in the presence of a solution of hydrochloric
acid in an ether or an alcohol, in a solvent such as
methanol or ethanol at a temperature of between 2 0°C
and the boiling temperature of the reaction medium.
The derivatives of formula I for which R3 is ORc (Re
being different to C(O)R8, C(S)R8, SO2R8) , H, NH2 or OGP
(lb) , (Ic) , (Id) or (II) can be obtained according to
three different synthetic pathways.

The first synthetic pathway consists in using compounds
of formula (III) :

The compounds of formula (lb) , (Ic) , (Id) or (II) can
be obtained from a pyrazole of formula (III) and a
compound of formula (IV) Rl-A-X for which X = a
function such as CI, Br, I, OTs, OMs or OTf. The
alkylation is carried out under an inert atmosphere,
for example under argon or under nitrogen, in basic
medium in an aprotic solvent, for example in the
presence of sodium hydride, in an aprotic solvent such
as dimethylformamide, at a temperature of between 2 0°C
and the boiling temperature of the reaction medium, or
in the presence of potassium tert-butoxide, in a
solvent such as dimethylformamide, at a temperature of
between 2 0°C and the boiling temperature of the
reaction medium. The reaction can also be carried out
in the presence of potassium carbonate and, optionally,
of potassium iodide, in a solvent such as acetone,
methyl ethyl ketone, acetonitrile or dimethylformamide,
preferably in methyl ethyl ketone, at the boiling
temperature of the reaction medium.
The compounds (IV) are commercial or can be obtained
from the corresponding alcohols of formula R1-A-0H by
methods known to those skilled in the art such as those
described in J. March, Advanced Organic Chemistry,
Wiley-Interscience, fourth edition (1992) or
R.C. Larock, Comprehensive Organic Transformations, VCH
Publishers (1989). The alcohols of formula R1-A-0H are
commercial or can be obtained by adapting methods
described in the literature using the basic general
knowledge of those skilled in the art.

The second synthetic pathway can be used for the
compounds of formula (I) for which R3 is ORc (Rc being
different to C(O)R8, C(S)R8, SO2R8) , H or OGP, and Rl-A
is a group in which the radical A is connected to Rl by
a nitrogen atom.

The compounds of formula (Ib) , (Ic) or (II) can be
obtained in three or four steps from the pyrazoles of
formula (III) according to the following protocol:
a) Alkylation of the pyrazole (III) with a compound of
formula (V) GP'O-A-X in which GP' is a hydroxyl
function-protecting group, as defined in T.W. Greene
and al., Protective Groups in Organic Synthesis, Wiley-
Interscience, third edition (1999) , capable of being
unaltered during the alkylation step and of being
deprotected under conditions which do not affect the
rest of the molecule (for example, the GP' group may be
a silyl-containing group such as tert-butyldimethyl-
silyl, triisopropylsilyl or diphenylmethylsilyl, or an
aralkyl, alkylidene, cycloalkylidene, heteroalkyl, or

heterocycloalkyl residue such as allyl, cyclohex-2-
enyl, benzyl or tetrahydropyran-2-yl); the GP' group is
preferably a tetrahydropyran-2-yl or tert-butyldi-
methylsilyl group; the radical X is a function such as
CI, Br, I, OTs, OMs or OTf. The alkylation is carried
out under an inert atmosphere, for example under argon
or under nitrogen, in basic medium in an aprotic
solvent, for example in the presence of sodium hydride,
in an aprotic solvent such as dimethylformamide, at a
temperature of between 20°C and the boiling temperature
of the reaction medium, or in the presence of potassium
tert-butoxide, in a solvent such as dimethylformamide,
at a temperature of between 2 0°C and the boiling
temperature of the reaction medium. The reaction may
also be carried out in the presence of potassium
carbonate and, optionally, of potassium iodide, in a
solvent such as acetone, methyl ethyl ketone,
acetonitrile or dimethylformamide, preferably in methyl
ethyl ketone, at the boiling temperature of the
reaction medium.
b) Production of the intermediates of formula (VI)
after cleavage of the GP' protective group according to
the methods described in T.W. Greene and al.,
Protective Groups in Organic Synthesis, Wiley-
Interscience, third edition (1999), and not affecting
the other functions carried by the molecule. For
example, when the GP' group is a tetrahydropyran-2-yl,
the deprotection of the alcohol may be carried out in
acid medium, for example in the presence of aqueous
hydrochloric acid, in a solvent such as ethanol or
methanol, at a temperature of between 2 0°C and the
boiling temperature of the reaction medium, preferably
in the presence of aqueous hydrochloric acid, in
ethanol, at a temperature in the region of 2 0°C.
a') Alternatively, when A is an ethyl or (C5-C7)
cycloalkyl radical, these radicals being optionally

substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C7) cycloalkyl, arylalkyl,
heteroarylalkyl, aryl and heteroaryl, the intermediates
of formula (VI) can be obtained by reaction between a
compound of formula (III) and a suitable epoxide in the
presence of a base such as potassium tert-butoxide, in
an aprotic solvent such as dimethylformamide, at a
temperature between 20 °C and the boiling temperature of
the reaction medium, according to J.M. Villalgordo,
Synthesis 1999, 1613.
c) Activation of the alcohol residue of the compounds
of formula (VI), for example by formation of a tosylate
or of a mesylate designated "Act" in the synthesis
scheme. The reaction is then carried out with tosyl
chloride or mesyl chloride in basic medium, for example
in the presence of pyridine, in a solvent such as
dichloromethane, at a temperature of between -2 0°C and
the boiling temperature of the reaction medium,
preferably at a temperature of between -10°C and a
temperature in the region of 2 0°C.
d) Substitution of the activated alcohol residue with a
primary or secondary amine of formula R1H. The reaction
is carried out in basic medium, for example in the
presence of potassium carbonate, in a polar solvent,
such as dimethylformamide or acetonitrile, at a
temperature of between 20°C and the boiling temperature
of the reaction medium, preferably in
dimethylformamide, at a temperature in the region of
80°C.
The compounds (V) are commercial or can be obtained
from the corresponding alcohols of formula GP'0-A-OH by
methods known to those skilled in the art as described
in J. March, Advanced Organic Chemistry, Wiley-
Interscience, fourth edition (1992) or R.C. Larock,
Comprehensive Organic Transformations, VCH Publishers

(1989) . The alcohols of formula GP'0-A-OH are
commercial or can be obtained, for example, by
monoprotection of a dialcohol of formula HO-A-OH
according to methods known to those skilled in the art
as described in J. March, Advanced Organic Chemistry,
Wiley-Interscience, fourth edition (1992) or
R.C. Larock, Comprehensive Organic Transformations, VCH
Publishers (198 9). The compounds of formula HO-A-OH are
commercial or available to those skilled in the art
using or adapting methods described in the literature.
A third synthetic pathway consists, when R3 is ORc (Re
being different to C(O)R8, C(S)R8, SO2R8), H or OGP, in
carrying out the synthesis from a derivative of formula
(VII) according to the synthesis scheme described
below.

The compounds of formula (lb) , (Ic) , and (II) can be
obtained in two steps from the compounds of formula
(VII) for which Y = Br, I or CI (preferably Br or I) :
a) Alkylation of the 4-halopyrazole of formula (VII)
with a compound of formula (IV) as defined above. The
reaction is carried out under an inert atmosphere, for
example under argon or under nitrogen, in basic medium
in an aprotic solvent, for example in the presence of
sodium hydride, in an aprotic solvent such as
dimethylformamide, at a temperature of between 20°C and
the boiling temperature of the reaction medium, or in
the presence of potassium tert-butoxide, in a solvent

such as dimethylformamide, at a temperature of between
20 °C and the boiling temperature of the reaction
naedium. The reaction can also be carried out in the
presence of potassium carbonate and, optionally, of
potassium iodide, in a solvent such as acetone, methyl
ethyl ketone, acetonitrile or dimethylformamide,
preferably in methyl ethyl ketone, at the boiling
temperature of the reaction medium.
b) Suzuki coupling of the intermediate obtained and of
a boronic acid, of an alkyl or cycloalkyl boronate or
of a (hetero)aryldialkyl boron of formula (VIII) for
which Rx is an alkyl or cycloalkyl radical. The
reaction is carried out under an inert atmosphere in
the presence of an inorganic base such as K3P04, Na2C03
or Ba(0H)2/ and of a palladium salt (catalyst) such as
dichlorobis(triphenylphosphine)palladium (PdCl2 (PPh3) 2),
tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) or
(diphenylphosphino)ferrocenyl palladium (PdCl2dppf), in
a solvent such as dimethylformamide, dimethoxyethane,
tetrahydrofuran, dioxane, toluene, xylene or ethanol,
optionally in the presence of water, at a temperature
of between 2 0°C and the boiling temperature of the
reaction medium (Kotha S. et al. , Tetrahedron 2002,
58_, 9633) .
The boronic acids, alkyl or cycloalkyl boronates or
(hetero)aryldialkyl boron of formula (VIII) are
commercial or are obtained using or adapting methods
described in the literature, for example in
G.W. Kabalka et al. , Tetrahedron Letters 1986, 27_,
3843, J.F. Nicoud et al. , Tetrahedron Letters 1993,
34, 8237, J.M. Tour et al. , J. Amer. Chem. Soc. 1994,
116, 11723, or T.J.J. Mueller et al. , Synthesis 2002,
S, 1163.
The intermediates of formula (III), when there is a
radical ORc (Re being different to C(O)R8, C(S)R8,

SO2R8) and OGP in the 3-position of the pyrazole, are
obtained according to the reaction scheme represented
below:

The pyrazoles of formula (III) can be obtained in four
steps from the compounds of formula (IX) according to
the following protocol:
a) Condensation of an (aryl)alkyl (hetero)aryl acetate
for which Rx = alkyl or aralkyl, of formula (IX), with
an aminomethylenation agent or a carbonylation agent of
formula (X) for which Ry is a CI, O-alkyl, O-aralkyl
or O-CO-alkyl radical, preferably for which Ry is an
O-alkyl radical. The aminomethylenation reaction can be
carried out in the presence of a reagent such as
N,N,N',N',N",N"-hexamethylmethanetriamine, C-methoxy-
N,N,N',N'-tetramethylmethanediamine or C-tert-butoxy-
N,N,N',N'-tetramethylmethanediamine, in the absence of
solvent or in a solvent such as tetrahydrofuran or
dioxane at a temperature of between 2 0°C and the
boiling temperature of the reaction medium, preferably
in the presence of C-tert-butoxy-N,N,N',N'-tetramethyl-
methanediamine in tetrahydrofuran at a temperature of

between 20°C and the boiling temperature of the
reaction medium. The carbonylation reaction between an
Caryl)alkyl (hetero)aryl acetate and a carbonylation
agent of formula (X) is carried out under an inert
atmosphere, for example under argon or under nitrogen,
in basic medium, for example in the presence of sodium
hydride, in an aprotic solvent such as
dimethylformamide, at a temperature of between -20 °C
and the boiling temperature of the solvent, preferably
at a temperature in the region of 2 0°C.
b) Formation of the lH-pyrazol-3-ol ring by reaction of
the intermediate obtained in the preceding step with
hydrazine, generally in monohydrate form, in an alcohol
such as ethanol, propanol or isopropanol, at a
temperature of between 20°C and the boiling temperature
of the reaction medium, preferably in ethanol, at the
boiling temperature of the reaction medium.
c) Protection of the nitrogen in the 1-position of the
lH-pyrazol-3-ol with a protective group such as an
acetyl, alkyloxycarbonyl or tosyl, preferably with an
acetyl group. The reaction is carried out with an
acetylating, alkyloxycarbonylating or tosylating agent,
preferably with acetic anhydride without solvent or in
the presence of a solvent such as pyridine, at a
temperature of between 2 0°C and the boiling temperature
of the reaction medium, preferably at a temperature in
the region of 100°C.
d) Protection of the hydroxyl group of the pyrazole or
introduction of the -Rc residue onto the hydroxyl of
the pyrazole, followed by deprotection of the nitrogen
in the 1-position of the pyrazole. The protection of
the hydroxyl group of the pyrazole and the introduction
of the -Rc residue onto the hydroxyl of the pyrazole
can be carried out, for example, by alkylation of the
hydroxyl group of the pyrazole with the compounds of

formula GP-X or Rc-X for which X is a function such as
Cl, Br, I, OTs, OMs or OTf. When Rc = Me or Et,
dimethyl sulfate or diethyl sulfate can also be used as
alkylating agent and will preferably be chosen. The
reaction is carried out in basic medium, for example in
the presence of a base such as potassium carbonate, in
a solvent such as acetone, methyl ethyl ketone,
acetonitrile or dimethylformamide, at a temperature of
between 20°C and the boiling temperature of the
reaction medium, preferably in methyl ethyl ketone, at
the boiling temperature of the reaction medium. When
Rc = -CHF2, the alkylation can be carried out with
methyl chlorodifluoroacetate, in basic medium, for
example in the presence of a base such as potassium
carbonate, in a solvent such as dimethylformamide, at a
temperature of between 2 0°C and the boiling temperature
of the reaction medium, preferably at a temperature in
the region of 65°C. The deprotection of the nitrogen in
the 1-position of the pyrazole is carried out according
to the methods described in T.W. Greene et al. ,
Protective Groups in Organic Synthesis, Wiley-
Interscience, third edition (1999). For example, when
the protective group is an acetyl, the deprotection can
be carried out in the presence of a base such as sodium
hydroxide or potassium carbonate, in an alcohol such as
ethanol or methanol, to which a solvent such as
tetrahydrofuran or dioxane is optionally added, at a
temperature of between 20°C and the boiling temperature
of the reaction medium, preferably in the presence of
sodium hydroxide in a mixture of ethanol and
tetrahydrofuran, at a temperature in the region of
20°C.
The compounds of formula (IX) are commercial or can be
obtained using or adapting methods described in the
literature.

The compounds of formula (X) are commercial or can be
obtained using or adapting methods described in the
literature.
The compounds of formula GP-X are commercial. The
compounds of formula Rc-X are commercial or can be
obtained from the corresponding alcohols of formula
Rc-OH by the methods known to those skilled in the art
as described in J. March, Advanced Organic Chemistry,
Wiley-Interscience, fourth edition (1992) or
R.C. Larock, Comprehensive Organic Transformations, VCH
Publishers (1989). The alcohols of formula Rc-OH are
commercial or can be obtained using or adapting methods
described in the literature.
The intermediates of formula (III), when there is a
hydrogen in the 3-position of the pyrazole, are
obtained according to the reaction scheme represented
below:

The compounds of formula (III) can be obtained from the
compounds of formula (XI) or (XII) and hydrazine,
generally in monohydrate form. The reaction is carried
out, for example, in an alcohol such as ethanol,
propanol or isopropanol, at a temperature in the region
of 2 0°C and the boiling temperature of the reaction
medium, preferably in ethanol, at the boiling
temperature of the reaction medium.
The compounds of formula (XI) or (XII) are commercial
or can be obtained using or adapting methods described
in the literature.

The intermediates of formula (III), when there is a
radical ORc (Rc being different to C(O)R8, C(S)R8,
SO2R8) or OGP or H in the 3-position of the pyrazole,
can also be obtained according to the reaction scheme
represented below:
1
The compounds of formula (III) can be prepared in three
or four steps from compounds of formula (VII):
a) Protection of the compounds of formula (VII), for
example with a tosyl, mesyl or acetyl group, preferably
with a tosyl group. This reaction is carried out
according to the processes known to those skilled in
the art and described in T.W. Greene et al., Protective
Groups in Organic Synthesis, Wiley-Interscience, third
edition (1999) . For example, when the protective group
is a tosyl, the reaction is carried out with tosyl
chloride in basic medium, for example in the presence
of sodium hydride or of potassium tert-butoxide in an
aprotic solvent such as dimethylformamide at a
temperature between -10°C and the boiling temperature
of the reaction medium.
b) Introduction of the R4 group by Suzuki coupling or
by two consecutive Stille reactions. The introduction
of the R4 group by Suzuki coupling is carried out using
the protected 4-halopyrazole obtained in the preceding
step and a boronic acid, an alkyl or cycloalkyl
boronate or a (hetero)aryldialkyl boron of formula
(VIII) for which Rx is an alkyl or cycloalkyl radical,
under an inert atmosphere, in the presence of an

inorganic base such as K3PO4 , Na2CO3 or Ba(OH)2, of a
palladium salt (catalyst) such as dichlorobis-
(triphenylphosphine)palladium (PdCl2 (PPh3) 2), tetrakis-
(triphenylphosphine)palladium (Pd(PPh3)4) or (diphenyl-
phosphino) ferrocenyl palladium (PdCl2dppf) , in a solvent
such as dimethylformamide, dimethoxyethane, tetra-
hydrofuran, dioxane, toluene, xylene or ethanol,
optionally in the presence of water, at a temperature
of between 20 °C and the boiling temperature of the
reaction medium. Alternatively, the introduction of the
R4 group can be carried out with two consecutive Stille
reactions. The first Stille reaction is carried out
under an inert atmosphere using the protected
4-halopyrazole obtained in the preceding step and
bis(tributyltin) in the presence of cuprous iodide, of
a palladium salt (catalyst) such as palladium diacetate
(Pd(OAc)2) and of triphenylphosphine, in a solvent such
as tetrahydrofuran at a temperature of between 2 0°C and
the boiling temperature of the reaction medium,
according to A.I. Scott et al., Tetrahedron Lett. 1996,
37, 3247. The second Stille reaction is carried out
using the organotin above and a halogenated aromatic
derivative of formula R4-Z for which Z is a Br, I or CI
radical (preferably Br or I) , with a palladium salt
(catalyst) such as tris(dibenzylidene)dipalladium
(Pd2dba3) and tristrifurylphosphine, in a solvent such
as dioxane at a temperature of between 2 0°C and the
boiling temperature of the reaction medium, according
to U. Hacksell et al. , Bioorg. & Med. Chem. Lett.,
1994, 2837.
c) Cleavage of the protective group introduced in the
first step. This reaction is carried out according to
the processes known to those skilled in the art and
described in T.W. Greene et al. , Protective Groups in
Organic Synthesis, Wiley-Interscience, third edition
(1999) . For example, when the protective group is a
tosyl, the reaction can be carried out with

tetrabutylammonium fluoride in a solvent such as
tetrahydrofuran or dioxane at a temperature between
20°C and the boiling temperature of the reaction medium
according to T. Sakamoto et al. , Tetrahedron Lett.
1998, 39_, 595.
The intermediates (III), when there is an NH2 radical in
the 3-position of the pyrazole, can be obtained
according to the following scheme:

The compounds of formula (III) can be obtained by
condensation of hydrazine, generally in monohydrate
form, with a 2-(hetero)aryl-3-oxopropionitrile of
formula (XIII) in acid medium, for example in the
presence of acetic acid, in an alcohol such as ethanol,
propanol or isopropanol, at a temperature of between
20°C and the boiling temperature of the reaction
medium, preferably in ethanol, at the boiling
temperature of the reaction medium.
The compounds of formula (XIII) can be obtained using
or adapting methods described in the literature.
The intermediates (VII) for which there is an H, OGP or
ORc (Re being different to C(O)R8, C(S)R8, SO2R8) in the
3-position of the pyrazole are obtained from the
derivative of formula (XIV)


The intermediates (VII) for which Y = Br, I or CI
(preferably Br or I) are commercial or can be obtained
from intermediates of formula (XIV). The reaction is
carried out with a halogenating agent such as bromine
or iodine chloride in a solvent such as dichloromethane
or chloroform, in the presence of a base such as
potassium carbonate, at a temperature of between -10°C
and the boiling temperature of the reaction medium,
preferably with bromine, in dichloromethane, at a
temperature in the region of 2 0°C.
The intermediates (XIV) for which there is a hydrogen
in the 3-position of the pyrazole are commercial or are
obtained using or adapting the methods described in the
literature.
The intermediates (XIV) for which there is an OGP
radical or an ORc radical (Re being different to
C(O)R8, C(S)R8, SO2R8) in the 3-position of the pyrazole
can be obtained in two steps from compounds of formula
(XV) according to the following protocol:

a) Protection of the nitrogen in the 1-position of the
lH-pyrazol-3-ol with a protective group such as an
acetyl, alkyloxycarbonyl or tosyl, preferably with an
acetyl group. The reaction is carried out with an
acetylating, alkyloxycarbonylating or tosylating agent,
preferably with acetic anhydride without solvent or in
the presence of a solvent such as pyridine, at a
temperature of between 2 0°C and the boiling temperature
of the reaction medium, preferably at a temperature in
the region of 100°C.

b) Protection of the hydroxyl group of the pyrazole or
introduction of the -Re residue onto the hydroxyl of
the pyrazole, followed by deprotection of the nitrogen
in the 1-position of the pyrazole. The protection of
the hydroxyl group of the pyrazole and the introduction
of the -Re residue onto the hydroxyl of the pyrazole
can be carried out by alkylation of the hydroxyl group
of the pyrazole with the compounds of formula GP-X or
Rc-X for which X is a function such as Cl, Br, I, OTs,
OMs or OTf. When Re is a methyl or ethyl group,
dimethyl sulfate or diethyl sulfate can also be used as
alkylating agent and will preferably be chosen. The
reaction is carried out in basic medium, for example in
the presence of a base such as potassium carbonate, in
a solvent such as acetone, methyl ethyl ketone,
acetonitrile or dimethylformamide, at a temperature of
between 20°C and the boiling temperature of the
reaction medium, preferably in methyl ethyl ketone, at
the boiling temperature of the reaction medium. When Re
is a CHF2 group, the alkylation can be carried out with
methyl chlorodifluoroacetate, in basic medium, for
example in the presence of a base such as potassium
carbonate, in a solvent such as dimethylformamide, at a
temperature of between 2 0°C and the boiling temperature
of the reaction medium, preferably at a temperature in
the region of 65°C. The deprotection of the nitrogen of
the pyrazole is carried out according to the methods
described in T.W. Greene et al. , in Protective Groups
in Organic Synthesis, Wiley-Interscience, third edition
(1999) . For example, when the protective group is an
acetyl, the deprotection can be carried out in the
presence of a base such as sodium hydroxide or
potassium carbonate, in an alcohol such as ethanol or
methanol, with a solvent such as tetrahydrof uran or
dioxane being optionally added, at a temperature of
between 20°C and the boiling temperature of the
reaction medium, preferably in the presence of sodium

hydroxide in a mixture of ethanol and tetrahydrofuran,
at a temperature in the region of 2 0°C.
The compounds of formula (XV) are obtained using or
adapting the methods described in the literature.
The compounds of formula (Id) can also be obtained in
seven or eight steps from the compounds of formula
(XVI) for which Y = Br, I or Cl (preferably Br or I) ,
according to the following protocol:

a) Protection of the 4-halo-3-nitropyrazoles of formula
(XVI), for example with a 2-trimethylsilanylethoxy-
methyl group. This reaction is carried out according to
the processes known to those skilled in the art and
described in T.W. Greene et al. , Protective Groups in
Organic Synthesis, Wiley-Interscience, third edition
(1999) . For example, the reaction is carried out with
2-trimethylsilanylethoxymethyl chloride in basic
medium, for example in the presence of sodium hydride

in an aprotic solvent such as dimethylformamide at a
temperature of between -10°C and the boiling
temnperature of the reaction medium.
b) Introduction of the R4 group by means of Suzuki
coupling or by means of two consecutive Stille
reactions. The introduction of the R4 group by means of
Suzuki coupling is carried out using the protected
4-halo-3-nitropyrazole obtained in the preceding step
and a boronic acid, an alkyl or cycloalkyl boronate or
a (hetero)aryldialkyl boron of formula (VIII) for which
Rx is an alkyl or cycloalkyl radical, under an inert
atmosphere, in the presence of an inorganic base such
as K3PO4, Na2CO3 or Ba(OH)2, and of a palladium salt
(catalyst) such as dichlorobis(triphenylphosphine)-
palladium (PdCl2 (PPh3) 2), tetrakistriphenylphosphine
palladium (Pd(PPh3)4) or diphenylphosphinoferroceynyl
palladium (PdCl2dppf) , in a solvent such as
dimethylformamide, dimethoxyethane, tetrahydrofuran,
dioxane, toluene, xylene or ethanol, optionally in the
presence of water at a temperature of between 2 0°C and
the boiling temperature of the reaction medium.
Alternatively, the introduction of the R4 group can be
carried out by means of two consecutive Stille
reactions. The first Stille reaction is carried out
under an inert atmosphere using the protected 4-halo-3-
nitropyrazole obtained in the preceding step and
bis(tributyltin) in the presence of cuprous iodide, of
a palladium salt (catalyst) such as palladium diacetate
(Pd(OAc)2) and of triphenylphosphine, in a solvent such
as tetrahydrofuran, at a temperature of between 2 0 °C
and the boiling temperature of the reaction medium,
according to AI. Scott et al. , Tetrahedron Lett. 1996,
37, 3247. The second Stille reaction is carried out
using the preceding organotin and a halogenated
aromatic derivative of formula R4-Z for which Z is a
Br, I or CI radical (preferably Br or I) , with a
palladium salt (catalyst) such as tris(dibenzylidene)-

dipalladium (Pd2dba3) and tristrifurylphosphine, in a
solvent such as dioxane at a temperature of between
20°C and the boiling temperature of the reaction
medium, according to U. Hacksell et al., Bioorg. & Med.
Chem. Lett., 1994, 2837.
e) Reduction of the nitro function according to a
protocol as described in J. March, Advanced Organic
Chemistry, Wiley-Interscience, fourth edition (1992) or
R.C. Larock, Comprehensive Organic Transformations, VCH
Publishers (1989). For example, this reaction can be
carried out using iron in the presence of ammonium
chloride in a mixture of an alcohol such as ethanol and
of water at a temperature of between 2 0°C and the
boiling temperature of the reaction medium.
f) Double protection of the amino residue obtained in
the preceding step with a protective group GPV. The
group GPV is an amine-protecting group as defined in
T.W. Greene et al., Protective Groups in Organic
Synthesis, Wiley-Interscience, third edition (1999) and
resistant to the conditions for deprotecting the group
GPiV. For example, the group GPV may be an allyl, a
benzyl or a para-methoxybenzyl. The group GPV is
introduced according to the processes known to those
skilled in the art and described in T.W. Greene et al.,
Protective Groups in Organic Synthesis, Wiley-
Interscience, third edition (1999) . For example, when
the protective group GPV is an allyl, the reaction is
carried out with allyl bromide in the presence of a
base such as cesium carbonate, in an aprotic solvent
such as acetonitrile or dimethylformamide, at a
temperature of between 2 0°C and the boiling temperature
of the reaction medium.
g) Cleavage of the protective group GPiV introduced in
the first step, according to the processes known to
those skilled in the art and described in T.W. Greene

et al. , Protective Groups in Organic Synthesis, Wiley-
Interscience, third edition (1999) . For example, when
the protective group GPiV is a 2-trimethylsilanylethoxy-
methyl, the reaction can be carried out with
tetrabutylammonium fluoride in a solvent such as
tetrahydrofuran or dioxane, at a temperature of between
20°C and the boiling temperature of the reaction
medium.
h) Alkylation of the compound obtained in the preceding
step with a compound of formula (IV) R1-A-X, as defined
above. The reaction is carried out under an inert
atmosphere, for example under argon or under nitrogen,
in basic medium in an aprotic solvent, for example in
the presence of sodium hydride, in an aprotic solvent
such as dimethylformamide, at a temperature of between
2 0°C and the boiling temperature of the reaction
medium, or in the presence of potassium tert-butoxide,
in a solvent such as dimethyl formamide, at a
temperature of between 20°C and the boiling temperature
of the reaction medium. The reaction can also be
carried out in the presence of potassium carbonate and,
optionally, of potassium iodide, in a solvent such as
acetone, methyl ethyl ketone, acetonitrile or
dimethylformamide, preferably in methyl ethyl ketone,
at the boiling temperature of the reaction medium.
i) Cleavage of the protective group GPV introduced in
step f) , according to the processes known to those
skilled in the art and described in T.W. Greene et al.,
Protective Groups in Organic Synthesis, Wiley-
Interscience, third edition (1999). For example, when
the protective group GPV is an allyl, the reaction can
be carried out with a palladium salt such as
tetrakistriphenylphosphine palladium (Pd(PPh3)4) in the
presence of an acid such as N,N-dimethylbarbituric
acid, in an aprotic solvent such as dichloromethane, at

a temperature of between 2 0°C and the boiling
temperature of the reaction medium.
The compounds of formula (XVI) are commercially
available or are obtained by analogy with methods
described in the literature.
The compounds (Ib) for which Rc is a C(O)R8, C(S)R8 or
SO2R8 radical can be obtained from the compounds (Ia)
according to the protocols known to those skilled in
the art and described, for example, in J. March,
Advanced Organic Chemistry, Wiley-Interscience, fourth
edition (1992), R.C. Larock, Comprehensive Organic
Transformations, VCH Publishers (198 9) or Bradford P.
Mundy and Michael G. Ellerd, Name Reactions and
Reagents in Organic Synthesis, A. Wiley-Interscience
Publication (1988).
The compounds (Ie) can be obtained from the compounds
(Id) according to the protocols known to those skilled
in the art and described, for example, in J. March,
Advanced Organic Chemistry, Wiley-Interscience, fourth
edition (1992), R.C. Larock, Comprehensive Organic
Transformations, VCH Publishers (1989) or Bradford
P. Mundy and Michael G. Ellerd, Name Reactions and
Reagents in Organic Synthesis, A. Wiley-Interscience
Publication (1988) .
The compounds (If) can be obtained from the compounds
(Ia) by reaction with a thionating agent, such as, for
example, Lawesson's reagent, and according to the
protocols described, for example, in J. March, Advanced
Organic Chemistry, Wiley-Interscience, fourth edition
(1992) .
The compounds (Ig) can be obtained from the compounds
(If) according to the protocols known to those skilled
in the art and described, for example, in J. March,
Advanced Organic Chemistry, Wiley-Interscience, fourth

edition (1992), R.C. Larock, Comprehensive Organic
Transformations, VCH Publishers (1989) or Bradford P.
Mimdy and Michael G. Ellerd, Name Reactions and
Reagents in Organic Synthesis, A. Wiley-Interscience
Publication (1988).
The compounds (Ih) can be obtained by oxidation of the
compounds (Ig) for which Rc = Ra using reagents such
as, for example, hydrogen peroxide, potassium
permanganate or oxone, and according to the protocols
described, for example, in J. March, Advanced Organic
Chemistry, Wiley-Interscience, fourth edition (1992) .
The compounds of formula (I) for which the R4 group is
substituted with one or more OH radicals can be
obtained by demethylation of the corresponding
methoxylated compounds according to a protocol which
does not affect the rest of the molecule, as described
in Protective Groups in Organic Synthesis, T.W. Greene,
Ed. by Wiley, third edition (1999). This reaction can,
for example, be carried out with boron tribromide in a
solvent such as dichloromethane at a temperature of
between -5°C and the boiling temperature of the
reaction medium.
The compounds of formula (I) for which the R4 group is
substituted with one or more NH2 radicals can be
obtained by reduction of the corresponding nitro
compounds according to a protocol as described in
J. March, Advanced Organic Chemistry, Wiley-
Interscience, fourth edition (1992) or R.C. Larock,
Comprehensive Organic Transformations, VCH Publishers
(1989) . For example, this reaction can be carried out
by hydrogenation in the presence of a catalyst such as
palladium-on-charcoal and, optionally, of an acid such
as hydrochloric acid, in an alcohol such as ethanol,
methanol or isopropanol, at a hydrogen pressure of
between 1 bar and 2 0 bar and at a temperature of

between 2 0°C and the boiling temperature of the
reaction medium.
The compounds of formula (Ib) , (Ic) or (II) for which
the R4 group is substituted with one or more NRaRb,
NHC(O)Ra, C(O)NRaRb, NHSO2Ra or NHC(S)Ra radicals can be
obtained by reduction of the corresponding nitro
compounds, followed by appropriate functionalization of
the amino derivatives obtained. The reduction of the
nitro compounds is carried out according to a protocol
which does not affect the rest of the molecule, as
described in J. March, Advanced Organic Chemistry,
Wiley-Interscience, fourth edition (1992) or
R.C. Larock, Comprehensive Organic Transformations, VCH
Publishers (1989). For example, this reaction can be
carried out with a reducing agent such as iron powder,
in the presence of ammonium chloride in a mixture of
water and of an alcohol such as methanol or ethanol, at
a temperature between 20°C and the boiling temperature
of the reaction medium, preferably in ethanol at the
boiling temperature of the reaction medium. The
functionalization of the resulting amino derivatives is
carried out according to methods which do not affect
the rest of the molecule, known to those skilled in the
art and described, for example, in J. March, Advanced
Organic Chemistry, Wiley-Interscience, fourth edition
(1992), R.C. Larock, Comprehensive Organic
Transformations, VCH Publishers (1989), Bradford P.
Mundy and Michael G. Ellerd, Name Reactions and
Reagents in Organic Synthesis, A. Wiley-Interscience
Publication (1988) or Hartwig J.F., Angew. Chem. Int.
Ed. Engl. 1998, 2047.
The compounds of formula (lb) , (Ic) or (II) for which
the R4 group is substituted with one or more aryl or
heteroaryl radicals can be obtained from the
corresponding halogenated compounds (preferably
brominated or iodinated) and from suitable boronic

acids, alkyl or cycloalkyl boronates or
(het ero)aryldialkyl borons by Suzuki coupling. This
reaction is carried out under an inert atmosphere in
the presence of an inorganic base such as K3PO4, Na2CO3
or Ba(OH)2, of a palladium salt (catalyst) such as
dichlorobis(triphenylphosphine)palladium (PdCl2 (PPh3)2),
tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) or
(diphenylphosphino)ferrocenyl palladium (PdCl2dppf) , in
a solvent such as dimethylformamide, dimethoxyethane,
tetrahydrofuran, dioxane, toluene, xylene or ethanol,
optionally in the presence of water, at a temperature
of between 2 0°C and the boiling temperature of the
reaction medium.
The compounds of formula (I) are isolated and can be
purified by conventional known methods, for example by
crystallization, chromatography or extraction.
The compounds of formula (I) can be optionally
transformed into addition salts with an inorganic or
organic acid by reaction of such an acid in an organic
solvent such as an alcohol, a ketone or an ether or a
chlorinated solvent. These salts are also part of the
invention.
As examples of pharmaceutically acceptable salts,
mention may be made of the following salts:
benzenesulfonate, hydrobromide, hydrochloride, citrate,
ethanesulfonate, fumarate, gluconate, iodate, maleate,
isethionate, methanesulfonate, nitrate, oxalate,
palmoate, phosphate, salicylate, succinate, sulfate,
tartrate, theophylline acetate and p-toluenesulfonate.
The compounds of the invention have been tested
with regard to their ability to bind nicotinic
receptors containing the α7 subunit by means of a
binding assay on rat brain membrane preparations
according to the methods described below:

Membrane preparations:
Frozen samples of Sprague-Dawley female rat brain
hippocampus were conserved at -20°C until use. The
hippocampi from 10 rats were grouped together and
homogenized using a Polytron grinder in 10 volumes of a
buffer, cooled in ice, having the following
composition: KCl (11 mM) ; KH2PO4 (6 mM) ; NaCl (13 7 mM) ;
Na2HPO4 (8 mM) ; HEPES (2 0 mM) ; iodoacetamide (5 mM) ;
EDTA (1.5 mM) ; PMSF (0.1 mM) . The pH was adjusted to
7.4 using NaOH. The mixture obtained was centrifuged at
24 000 g for 20 minutes at 4°C and the pellet was
resuspended in 2 0 volumes of ice-cold water. After
incubation for 60 minutes at 4°C, a further pellet was
obtained by centrifugation at 24 000 g for 20 minutes
at 4°C. The latter was resuspended in buffer having the
above composition and frozen at -20°C. On the day of
the assay, the membranes were thawed, centrifuged at
24 000 g for 2 0 minutes, and then resuspended at a
final concentration of 2-5 mg of proteins/ml in
Dulbecco phosphate buffer at pH 7.4 containing 0.05% of
bovine serum albumin.
Measurement of the affinity for receptors containing
the al subunit:
The binding of the compounds of the invention to
receptors containing the a7 subunit was measured by
competition with respect to [3H]-methyllycaconitine
( [3H]-MLA), a radiolabeled tracer which recognizes a7
receptors (Davies et al., Neuropharmacology 1999, 38,
679-690), according to conventional methods adapted to
the 96-well-plate format. The ability of the compounds
of the invention to displace the binding of [3H]-MLA to
rat hippocampal membranes was determined in duplicate
after incubation for 2 hours at ambient temperature.
Each well contained a sample of approximately 150 µg of

membrane proteins, 5 nM of [3H]-MLA and one of the
compounds of the invention diluted to a given
concentration in Dulbecco phosphate buffer at pH 7.4
containing 0.05% of bovine serum albumin, for a final
volume of 150 µL. The nonspecific binding was
determined in specific wells containing 10 µM of non-
radiolabeled MLA. The incubation was stopped by-
filtering the content of each well through glass fiber
filters (Whatman GF/B) presoaked in a solution of
polyethylenimine at 0.33% in Dulbecco phosphate buffer
so as to decrease the nonspecific binding. The filters
were then washed 3 times with Dulbecco phosphate
buffer, and then dried at 50°C for approximately
2 hours. The radioactivity retained on the filters was
measured by applying scintillant (MeltiLex A, Perkin
Elmer) followed by counting by luminometry (Trilux 1450
microbeta, Perkin-Elmer).
Data analysis
For each compound tested, the residual radioactivity on
the filters was expressed in counts per minutes. The
determinations in duplicate were averaged and the
concentration of compound which inhibits by half the
specific binding of the radioactive tracer (IC50) was
calculated by curvilinear regression using specific
software (GraphPad Prism). The apparent affinity
constants Ki for the compounds of the invention were
calculated using the Cheng and Prusoff equation (Cheng
and Prusoff, Biochem. Pharmacol. 1973, 22_, 3099-3108) .
The compounds of the invention which were studied in
this assay exhibit a Ki value of less than 10 µM.
The following examples illustrate the invention in a
nonlimiting manner.
Example 1

1-[2-(3-Methoxy-4-phenylpyrazol-1-yl)ethyl]piperidine
dihydrochloride
0.303 g of sodium hydride (at 75% by mass in liquid
petroleum jelly) is added gradually, under an argon
atmosphere and at ambient temperature, to a solution of
0.25 g of 3-methoxy-4-phenylpyrazole in 20 cm3 of
anhydrous dimethylformamide. After stirring for three
quarters of an hour at a temperature in the region of
50°C, 0.793 g of 1-(2-chloroethyl)piperidine is added
in small portions, and the mixture is then heated for
8 hours at a temperature in the region of 50°C. The
mixture is cooled to ambient temperature, 10 cm3 of
water are then added, and the mixture is concentrated
to dryness under reduced pressure (3 kPa) . The
evaporation residue is taken up in 25 cm3 of water and
extracted with 2 50 cm3 of ethyl acetate. The organic
phase is washed with 3 times 25 cm3 of water, and is
then dried over anhydrous magnesium sulfate, filtered
and concentrated to dryness under reduced pressure (3
kPa) , so as to give an oily residue which is purified
by chromatography on silica gel (particle size 15-35
µm) , eluting with a mixture of ethyl acetate and
cyclohexane (67 /33 by volume). After concentration of
the fractions under reduced pressure, 0.3 g of a
colorless oil is obtained, which is dissolved in 15 cm3
of acetone and 3 0 cm3 of an approximately 3M solution of
hydrochloric ether are added. The white precipitate
formed is filtered and then dried under vacuum (70 Pa)
at a temperature of 60°C. 0.325 g of 1-[2-(3-methoxy-
4-phenylpyrazol-1-yl)ethyl]piperidine dihydrochloride
is thus obtained in the form of a white solid which
melts at 208°C (with decomposition).
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 1.40
(mt: 1H) ; from 1.60 to 1.90 (mt: 5H) ; 2.94 (mt: 2H) ;
from 3.40 to 3.60 (mt: 4H) ; 3.95 (s: 3H); 4.47 (t, J =
6.5 Hz: 2H) ; 7.2 9 (broad t, J = 7.5 Hz: 1H) ; 7.3 6

(broad t, J = 7.5 Hz: 2H) ; 7.62 (broad d, J = 7.5 Hz:
2H); 8.14 (s: 1H); 10.03 (unresolved peak: 1H).
IR spectrum (KBr): 3031; 2945; 2632; 2540; 1606; 1579;
1518; 1456; 1411; 1047; 1030; 764 and 697 cm-1.
The 3-methoxy-4-phenylpyrazole can be prepared in the
following way:
A suspension of 2 g of 1-(3-hydroxy-4-phenylpyrazol-
1-yl)ethanone, 1.37 g of potassium carbonate and
1.13 cm3 (1.5 g) of dimethyl sulfate in 70 cm3 of
2-butanone is stirred at a temperature of 70 °C for 4
hours. 24 cm3 of a 1.66N sodium hydroxide solution are
added to the mixture, which is stirred for 4 hours at
ambient temperature and then partially concentrated
under reduced pressure (3 kPa) in order to drive off
the 2-butanone. The residue is taken up with 10 cm3 of
water and extracted with 250 cm3 of ethyl acetate. The
organic phase is washed with 3 times 25 cm3 of water,
and is then dried over anhydrous magnesium sulfate,
filtered and concentrated to dryness under reduced
pressure (3 kPa) , so as to give a light brown solid
residue, which is purified by chromatography on silica
gel (particle size 15-35 µm) , eluting with a mixture of
dichloromethane and methanol (98.5/1.5 by volume).
After concentration of the fractions under reduced
pressure, 0.3 g of 3-methoxy-4-phenylpyrazole is
obtained in the form of a pale yellow powder which
melts at 150°C.
The 1-(3-hydroxy-4-phenylpyrazol-1-yl)ethanone can be
prepared in the following way:
3.4 cm3 of acetic anhydride are added, over 10 minutes,
to a solution of 6.4 g of 4-phenyl-1H-pyrazol-3 -ol in
64 cm3 of pyridine preheated to 100°C. After a further
30 minutes at 100°C, the mixture is cooled and poured
into 60 0 cm3 of a water-ice mixture. The precipitate

which appears is filtered, washed with 4 times 100 cm3
of ice-water then with 4 times 100 cm3 of heptane, and
then dried under vacuum (70 Pa) at a temperature of
60°C. 5.09 g of 1-(3-hydroxy-4-phenylpyrazol-1-yl)-
ethanone are thus obtained in the form of a beige
powder which melts at 215°C.
The 4-phenyl-1H-pyrazol-3-ol can be obtained according
to the method described by D.L. Selwood et al., J. Med.
Chem. 2001, 44, 78-93.
Example 2
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-
pyrazol-1-ol dihydrochloride
A suspension of 0.67 g of 3-(3-benzyloxy-4-phenyl-
pyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octane and
0.08 g of palladium-on-charcoal (10%) in 20 cm3 of
ethanol is stirred in an autoclave under a hydrogen
pressure of 500 kPa, at a temperature of 20°C, for 20
hours. The reaction medium is then filtered over
Celite® and concentrated to dryness under reduced
pressure (3 kPa) , so as to give a pasty residue, which
is covered with 50 cm3 of acetone and triturated
overnight. After filtration of the solid which has
appeared and drying under vacuum (70 Pa) at a
temperature of 60°C, 0.265 g of 1-(1-
azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-1-
ol dihydrochloride is obtained in the form of
hygroscopic beige crystals which melt at around 24 0°C
(with decomposition).
1H NMR spectrum (300 MHz, (CD3)2SO d6,δ in ppm) : from
1.65 to 1.95 (mt: 4H); from 1.95 to 2.15 (mt: 1H); from
2.4 0 to 2.60 (mt: 1H); 2.96 (broad dd, J = 12.5 and 7.5
Hz: 1H); from 3.10 to 3.4 0 (mt: 5H); 4.03 (dd, J = 13.5
and 7.5 Hz: 1H) ; 4.10 (dd, J = 13.5 and 7.5 Hz: 1H) ;
7.15 (broad t, J = 7.5 Hz: 1H) ; 7.34 (broad t, J =

7.5 Hz: 2H) ; 7.66 (broad d, J = 7.5 Hz: 2H) ; 8.00 (s:
1H) ; 10.51 (unresolved peak: 1H) .
IR spectrum (KBr): 3417; 2940; 2546; 1601; 1474; 1388;
1189; 768; 702 and 611 cm"1.
Example 3
3-(3-Benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-aza-
bicyclo[2.2.2]octane dihydrochloride
A solution of 5 g of 3-benzyloxy-4-phenylpyrazole in
3 0 cm3 of anhydrous dimethylformamide are added
gradually, under an argon atmosphere and at ambient
temperature, to a suspension of 3.84 g of sodium
hydride (75% by mass in liquid petroleum jelly) in 20
cm3 of anhydrous dimethylformamide. After stirring for
three quarters of an hour at a temperature in the
region of 50°C, 11.78 g of 3-chloromethyl-1-
azabicyclo[2.2.2]octane hydrochloride are added in
small portions, and the mixture is then heated for 18
hours at a temperature in the region of 50 °C. The
mixture is cooled to ambient temperature and 2 5 cm3 of
water are then added slowly, and the mixture is then
run into 300 cm3 of water and extracted with two times
300 cm3 of ethyl acetate. The pooled organic phases are
washed with 3 times 100 cm3 of water, and then dried
over anhydrous magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (3 kPa) .
The oily residue obtained is purified by chromatography
on alumina, eluting with a mixture of ethyl acetate and
methanol (90/10 by volume). After concentration of the
fractions under reduced pressure, 2.81 g of a brown oil
are obtained, which oil is dissolved in 200 cm3 of
ethanol and 6.2 5 cm3 of an approximately 6M aqueous
hydrochloric acid solution are added. The solution is
concentrated to dryness under reduced pressure (3 kPa) .
The residue is taken up with 2 00 cm3 of ethanol and
redried, twice. 3.01 g of 3-(3-benzyloxy-4-

phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octane
dihydrochloride are thus obtained in the form of a
beige foam.
1H NMR spectrum (400 MHz, (CD3)2SO d6,8 in ppm) : from
1.65 to 1.90 (mt: 4H); 2.06 (mt: 1H); from 2.50 to 2.65
(mt: 1H); 2.94 (dd, J = 10 and 5 Hz: 1H); from 3.10 to
3.40 (mt: 5H) ; 4.11 (dd, J = 10.5 and 6 Hz: 1H) ; 4.16
(dd J = 10.5 and 6 Hz: 1H) ; 5.33 (s: 2H) ; 7.07 (broad
t, J = 7.5 Hz: 1H) ; 7.3 6 (broad t, J = 7.5 Hz: 3H) ;
7.43 (broad t, J = 7.5 Hz: 2H) ; 7.50 (broad d, J =
7.5 Hz: 2H) ; 7.65 (broad d, J = 7.5 Hz: 2H) ; 8.14 (s:
1H) ; 10.51 (unresolved peak: 1H) .
IR spectrum (KBr): 3031; 2936; 2803; 2564; 1606; 1578;
1569; 1510; 1454; 1435; 1360; 1046; 1024; 764; 697; 615
and 511 cm"1.
The 3-benzyloxy-4-phenylpyrazole can be prepared in the
following way:
A suspension of 5.7 g of 1-(3-hydroxy-4-phenylpyrazol-
1-yl) ethanone, 3.9 g of potassium carbonate and 3.7 cm3
(5.3 g) of benzyl bromide in 250 cm3 of 2-butanone is
stirred at the boiling temperature of the reaction
medium for two and a quarter hours. The insoluble
inorganic material is removed by filtration and the
filtrate is concentrated to dryness under reduced
pressure (3 kPa). The residue is dissolved in 50 cm3 of
tetrahydrofuran, 50 cm3 of methanol and 1 cm3 of a ION
sodium hydroxide solution are added and the mixture is
stirred for a quarter of an hour at ambient temperature
and then concentrated to dryness under reduced pressure
(3 kPa) . The residue is taken up with 5 cm3 of water and
extracted with 2 50 cm3 of ethyl acetate. The organic
phase is dried over anhydrous magnesium sulfate,
filtered and concentrated to dryness under reduced
pressure (3 kPa), so as to give a white solid residue,
which is triturated in a mixture of isopropyl ether and
petroleum ether. After filtration and air-drying, 4.43

g of 3-benzyloxy-4-phenylpyrazole are obtained in the
form of a white solid which melts at 163°C.
Example 4
3-(3-Methoxy-4-phenylpyrazol-1-ylmethyl)-1-aza-
bicyclo[2.2.2]octane hydrochloride monohydrate
0.99 g of sodium hydride (75% by mass in liquid
petroleum jelly) is added gradually, under an argon
atmosphere and at ambient temperature, to a solution of
0.9 g of 3-methoxy-4-phenylpyrazole in 15 cm3 of
anhydrous dimethylformamide. After stirring for three
quarters of an hour at a temperature in the region of
50°C, 3.04 g of 3-chloromethyl-1-azabicyclo [2.2.2] -
octane hydrochloride are added in small portions, and
the mixture is then heated for 16 hours at a
temperature in the region of 50°C. The mixture is
cooled to ambient temperature, 10 cm3 of water are then
added slowly, and the mixture is concentrated under
reduced pressure (3 kPa) . The residue is taken up with
25 cm3 of water and extracted with 3 times 100 cm3 of
ethyl acetate. The pooled organic phases are washed
with 3 times 25 cm3 of water, and then dried, filtered
and concentrated to dryness under reduced pressure (3
kPa) . The oily residue obtained is purified by
chromatography on alumina, eluting with a mixture of
ethyl acetate and methanol (90/10 by volume). After
concentration of the fractions under reduced pressure,
0.3 g of a brown oil is obtained, which is dissolved in
4 0 cm3 of acetone, and 35 cm3 of approximately 3M
hydrochloric ether are added. The solution is
concentrated to dryness under reduced pressure (3 kPa)
and the pasty residue is washed with two times 50 cm3 of
ethyl ether and then triturated in 5 0 cm3 of ethyl ether
overnight. After filtration of the solid obtained and
drying under vacuum (70 Pa) at a temperature of 60°C,
0.25 g of 3-(3-methoxy-4-phenylpyrazol-1-ylmethyl)-1-

azabicyclo [2.2.2] octane hydrochloride monohydrate is
obtained in the form of a white powder which melts at
around 125°C (with decomposition). 1H NMR spectrum (300
MHz, (CD3)2SO d6, δ in ppm): from 1.60 to 1.90 (mt: 4H);
2.05 (unresolved peak: 1H); from 2.45 to 2.60 (mt: 1H);
2.94 (broad dd, J = 13 and 7 Hz: 1H); from 3.05 to 3.4 0
(mt: 5H); 3.93 (s: 3H); 4.12 (mt: 2H); 7.17 (broad t, J
= 7.5 Hz: 1H) ; 7.3 5 (broad t, J = 7.5 Hz: 2H) ; 7.62
(broad d, J = 7.5 Hz: 2H) ; 8.10 (s: 1H) ; from 9.40 to
9.90 (very broad unresolved peak: 1H).
IR spectrum (KBr): 2942; 2562; 1609; 1579; 1517; 1458;
1406; 1048; 1030; 759; 698; 601 and 508 cm"1.
Example 5
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-
3-ol dihydrochloride
A suspension of 0.163 g of 3- (3-benzyloxy-4-phenyl-
pyrazol-1-yl)-1-azabicyclo[2.2.2]octane, 0.3 8 cm3 of 6M
hydrochloric acid and 0.024 g of palladium-on-charcoal
(at 10%) in 20 cm3 of ethanol is stirred in an autoclave
under a hydrogen pressure of 1 000 kPa, at a
temperature of 20°C for 8 hours. The reaction medium is
then filtered over Celite ® and concentrated to dryness
under reduced pressure (3 kPa), so as to give a
hygroscopic oily residue, which is dissolved in 10 cm3
of water and lyophilized. 0.083 g of 1-(1-azabicyclo-
[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-1-ol dihydro-
chloride is thus obtained in the form of an amorphous
brown solid.
1H NMR spectrum (3 00 MHz, (CD3)2SO d6, δ in ppm) : from
1.65 to 2.05 (mt: 4H) ; 2.41 (mt: 1H) ; 3.26 (mt: 3H) ;
3.40 (mt: 1H) ; 3.77 (mt: 2H) ; 4.68 (mt: 1H) ; 7.15
(broad t, J = 7.5 Hz: 1H) ; 7.34 (broad t, J = 7.5 Hz:
2H); 7.69 (broad d, J = 7.5 Hz: 2H); 8.22 (s: 1H); from
10.15 to 10.75 (broad unresolved peak: 1H); 11.07
(unresolved peak: 1H).

IR spectrum (KBr): 3417; 2956; 2806; 2666; 1607; 1580;
1522; 1450; 1168; 995; 762; 697; 671 and 513 cm"1.
The 3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo-
[2.2.2]octane can be prepared in the following way:
0.96 g of sodium hydride (at 75% by mass in liquid
petroleum jelly) is added gradually, under an argon
atmosphere and at ambient temperature, to a solution of
0.5 g of 3-benzyloxy-4-phenylpyrazole in 3 0 cm3 of
anhydrous dimethylformamide. After stirring for three
quarters of an hour at a temperature in the region of
50°C, a solution of 0.725 g of 3-[ (methanesulfonyl)-
oxy]-1-azabicyclo[2.2.2]octane in 5 cm3 of anhydrous
dimethylformamide is added dropwise, and the mixture is
then heated for 2 0 hours at a temperature in the region
of 110°C. The mixture is cooled to ambient temperature,
5 cm3 of water are then added slowly, and the mixture is
concentrated under reduced pressure (3 kPa) . The
residue is taken up with 10 cm3 of water and extracted
with 50 cm3 of ethyl acetate. The organic phase is
washed with 3 times 10 cm3 of water, and is then dried,
filtered and concentrated to dryness under reduced
pressure (3 kPa). The oily residue obtained is purified
by preparative HPLC on 10^ C8 Kromasil, eluting with a
mixture of acetonitrile and water (50/50 by volume) and
then of acetonitrile and ammoniacal methanol (7M) (98/2
by volume). After concentration of the fractions under
reduced pressure, 0.163 g of 3-(3-benzyloxy-
4-phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]octane is
obtained in the form of a yellow oil, which is used as
it is in the following step.
The 3-[(methanesulfonyl)oxy]-1-azabicyclo[2.2.2]octane
can be obtained according to the method described by
S.M. Jenkins et al. , J. Med. Chem. 1992, 35_, 2392-2406.
Example 6

1-(2-Perhydroazepin-1-ylethyl)-4-phenyl-1H-pyrazol-3-ol
dihydrochloride
A suspension of 0.65 g of 1- [2-(3-benzyloxy-4-
phenylpyrazol-1-yl)ethyl]perhydroazepine, 1.44 cm3 of 6M
hydrochloric acid and 0.092 g of palladium-on-charcoal
(at 10%) in 20 cm3 of ethanol is stirred in an autoclave
under a hydrogen pressure of 1 00 0 kPa, at a
temperature of 2 0°C for 8 hours. The reaction medium is
then filtered over Celite® and concentrated to dryness
under reduced pressure (3 kPa) . The residue is
triturated in 40 cm3 of acetone and isolated by
filtration. 0.541 g of 1-(2-perhydroazepin-1-ylethyl)-
4-phenyl-1H-pyrazol-3-ol dihydrochloride is thus
obtained in the form of a beige powder which melts at
228°C (with decomposition).
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 1.64
(mt: 4H) ; 1.84 (mt: 4H) ; 3.17 (mt: 2H) ; from 3.25 to
3.55 (mt: 4H); 4.41 (t, J = 6.5 Hz: 2H); 7.15 (broad t,
J = 7.5 Hz: 1H); 7.34 (broad t, J = 7.5 Hz: 2H); 7.65
(broad d, J = 7.5 Hz: 2H); 8.05 (s: 1H); 10.35
(unresolved peak: 1H); 10.49 (unresolved peak: 1H).
IR spectrum (KBr): 3431; 2934; 2638; 2422; 1608; 1582;
1572; 1528; 1452; 1210; 1179; 1013; 760; 692; 673 and
511 cm"1.
The 1- [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]per-
hydroazepine can be prepared in the following way:
A suspension of 1 g of 1-[(toluene-4-sulfonyl)oxy]-2-
(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl, 0.29 cm3 of
perhydroazepine and 0.88 g of potassium carbonate in
25 cm3 of acetonitrile is stirred for 3 hours at a
temperature in the region of 80°C, and then 0.15 cm3 of
perhydroazepine is added and the heating is continued
for 2 hours. The mixture is concentrated to dryness
under reduced pressure (3 kPa). The residue is taken up

sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl
are obtained in the form of a colorless viscous oil,
which is used as it is in the following step. Mass
spectrum (EI) : m/z 448 (M+-) , m/z 91 (base peak) .
The 2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethanol can be
prepared in the following way:
750 cm3 of 37% hydrochloric acid are added, at ambient
temperature, to a solution of 17 g of 3-benzyloxy-
4-phenyl-1-[2-(tetrahydropyran-2-yloxy)ethyl] -1H-
pyrazole in 750 cm3 of ethanol. After stirring for 2
hours at ambient temperature, the mixture is
concentrated to dryness under reduced pressure (3 kPa) .
The residue is taken up with 1 dm3 of ethanol and
concentrated to dryness, 3 times, so as to give 13.8 g
of 2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethanol in the
form of a solid which melts at 115°C, which is used as
it is in the following step.
The 3-benzyloxy-4-phenyl-1-[2-(tetrahydropyran-2-yl-
oxy)ethyl]-1H-pyrazole can be prepared in the following
way:
3.07 g of sodium hydride (at 75% by mass in liquid
petroleum jelly) are added gradually, under an argon
atmosphere and at ambient temperature, to a solution of
16 g of 3~benzyloxy-4-phenylpyrazole in 110 cm3 of
anhydrous dimethylformamide. After stirring for three
quarters of an hour at a temperature in the region of
50°C, a solution of 11.06 cm3 (15.31 g) of 2-(2-bromo-
ethoxy)tetrahydropyran in 4 0 cm3 of anhydrous
dimethylformamide is added dropwise, and the mixture is
then heated for three quarters of an hour at a
temperature in the region of 5 0°C. 25 cm3 of water are
then added slowly to the mixture, which is then run
into 90 cm3 of water and extracted with 3 times 3 00 cm3
of ethyl acetate. The pooled organic phases are washed

with 3 times 100 cm3 of water, and then dried, filtered
and concentrated to dryness under reduced pressure
(3 kPa). The oily residue obtained is purified by
chromatography on silica gel (particle size 20-45 /zm) ,
eluting with a mixture of dichloromethane and ethyl
acetate (90/10 by volume). After concentration of the
fractions under reduced pressure, 17.35 g of
3-benzyloxy-4-phenyl-1-[2-(tetrahydropyran-2-
yloxy)ethyl]-1H-pyrazole are obtained in the form of a
colorless pasty solid, which is used as it is in the
following step.
1H NMR spectrum (300 MHz, (CD3) 2SO d6, δ in ppm) : from
1.25 to 1.75 (mt: 6H) ; from 3.25 to 3.45 (mt: 1H); 3.60
(ddd, J = 11.5-8.5 and 3 Hz: 1H) ; 3.72 (mt: 1H) ; 3.94
(ddd, J = 10.5-6 and 4.5 Hz: 1H); 4.16 (mt: 2H); 4.55
(mt: 1H) ; 5.32 (s: 2H) ; 7.14 (tt, J = 7.5 and 1.5 Hz:
1H) ; from 7.25 to 7.45 (mt: 3H) ; 7.33 (broad t, J =
7.5 Hz: 2H) ; 7.50 (broad d, J = 7.5 Hz: 2H) ; 7.63
(broad d, J = 7.5 Hz: 2H); 8.05 (s: 1H).
Example 7
1-[2-(2-Methylpiperidin-1-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol dihydrochloride
A suspension of 0.58 g of 1- [2-(3-benzyloxy-4-phenyl-
pyrazol-1-yl)ethyl]-2-methylpiperidine, 1.29 cm3 of 6M
hydrochloric acid and 0.082 g of palladium-on-charcoal
(at 10%) in 20 cm3 of ethanol is stirred in an autoclave
under a hydrogen pressure of 1 000 kPa, at a
temperature of 20°C for 8 hours. The reaction medium is
then filtered over Celite® and concentrated to dryness
under reduced pressure (3 kPa) . The residue is
triturated in 4 0 cm3 of acetone and isolated by
filtration. 0.54 g of 1-[2-(2-methylpiperidin-1-yl)-
ethyl]-4-phenyl-1H-pyrazol-3-ol dihydrochloride is thus
obtained in the form of a beige powder which melts at
118°C (with decomposition).

1H NMR spectrum (300 MHz, (CD3)2SO d6 with addition of a
few drops of CD3COOD d4, δ in ppm): 1.2 9 (d, J = 6.5 Hz:
3H) ; from 1.3 5 to 1.95 (mt: 6H) ; 3.04 (ddd, J = 12-9
and 3.5 Hz: 1H); from 3.30 to 3.50 (mt: 3H); from 3.50
to 3.65 (mt: 1H); 4.3 7 (t, J = 6.5 Hz: 2H); 7.14 (broad
t, J = 7.5 Hz: 1H) ; 7.33 (broad t, J = 7.5 Hz: 2H) ;
7.64 (broad d, J= 7.5 Hz: 2H); 8.02 (s: 1H).
IR spectrum (KBr): 3051; 2949; 2653; 2565; 1606; 1581;
1522; 1441; 1228; 1171; 995; 768; 700; 671 and 587 cm"1.
The 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-
2-methylpiperidine can be prepared in the following
way:
A suspension of 1 g of 1-[(toluene-4-sulfonyl)oxy]-
2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl, 0.46 cm3 of
2-methylpiperidine and 0.8 8 g of potassium carbonate in
25 cm3 of acetonitrile is stirred for 6 hours at a
temperature in the region of 80 °C. The mixture is
concentrated to dryness under reduced pressure (3 kPa).
The residue is taken up with 50 cm3 of water and
extracted with 2 00 cm3 of ethyl acetate. The organic
phase is washed with 3 times 25 cm3 of water, and is
then dried, filtered and concentrated to dryness under
reduced pressure (3 kPa) . The oily residue obtained is
purified by chromatography on silica gel (particle size
15-35 jj,m) , eluting with a mixture of dichloromethane
and methanol (97/3 by volume). After concentration of
the fractions under reduced pressure, 0.65 g of 1-[2-
(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-methyl-
piperidine is obtained in the form of a colorless
viscous oil, which is used as it is in the following
step.
Mass spectrum (EI) : m/z 375 (M+) , m/z 112 (base peak) .
Example 8

1-[2-(4-Fluoropiperidin-1-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol dihydrochloride
A suspension of 0.5 g of 1-[2-(3-benzyloxy-4-
phenylpyrazol-1-yl)ethyl]-4-fluoropiperidine, 1.1 cm3 of
6M hydrochloric acid and 0.071 g of palladium-on-
charcoal (at 10%) in 20 cm3 of ethanol is stirred in an
autoclave under a hydrogen pressure of 1 000 kPa, at a
temperature of 20°C for 8 hours. The reaction medium is
then filtered through Celite® and concentrated to
dryness under reduced pressure (3 kPa) . The residue is
triturated in 4 0 cm3 of acetone and isolated by
filtration. 0.54 g of 1-[2-(4-fluoropiperidin-1-yl)-
ethyl]-4-phenyl-1H-pyrazol-3-ol dihydrochloride is thus
obtained in the form of a beige powder which melts at
228°C (with decomposition).
1H NMR spectrum (400 MHz, (CD3)2SO d6 with addition of a
few drops of CD3COOD d4, δ in ppm) : from 2.00 to 2.25
(mt: 4H) ; 3.29 (unresolved peak: 4H) ; 3.52 (t, J =
6 Hz: 2H) ; 4.40 (t, J = 6 Hz: 2H) ; 4.94 (broad d, J =
48 Hz: 1H); 7.14 (broad t, J = 7.5 Hz: 1H); 7.33 (broad
t, J = 7.5 Hz: 2H) ; 7.65 (broad d, J = 7.5 Hz: 2H) ;
7.99 (s: 1H).
IR spectrum (KBr): 3054; 2963; 2633; 2531; 1608; 1582;
1528; 1452; 1177; 1031; 1015; 764; 698 and 509 cm"1.
The 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-
4-fluoropiperidine can be prepared in the following
way:
A suspension of 1 g de 1-[(toluene-4-sulfonyl)oxy]-
2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl, 0.702 g of
4-fluoropiperidine hydrobromide and 1.18 g of potassium
carbonate in 2 5 cm3 of acetonitrile is stirred for
6 hours at a temperature in the region of 80°C. The
mixture is concentrated to dryness under reduced
pressure (3 kPa). The residue is taken up with 50 cm3 of
water and extracted with 2 00 cm3 of ethyl acetate. The

organic phase is washed with 3 times 25 cm3 of water,
and is then dried, filtered and concentrated to dryness
usder reduced pressure (3 kPa). The oily residue
obtained is purified by chromatography on silica gel
(particle size 15-35 µm) , eluting with a mixture of
dichloromethane and methanol (98.5/1.5 by volume).
After concentration of the fractions under reduced
pressure, 0.61 g of 1- [2-(3-benzyloxy-4-phenylpyrazol-
1-yl)ethyl]-4-fluoropiperidine is obtained in the form
of a colorless viscous oil, which is used as it is in
the following step.
Mass spectrum (EI) : m/z 379 (M+) , m/z 250 and m/z 116
(base peak).
Example 9
1-[2-(3-Methylpiperidin-1-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol dihydrochloride
A suspension of 0.57 g of 1- [2- (3-benzyloxy-4-phenyl-
pyrazol-1-yl)ethyl]-3-methylpiperidine, 1.2 7 cm3 of 6M
hydrochloric acid and 0.081 g of palladium-on-charcoal
(at 10%) in 20 cm3 of ethanol is stirred in an autoclave
under a hydrogen pressure of 1 00 0 kPa, at a
temperature of 20°C for 8 hours. The reaction medium is
then filtered over Celite® and concentrated to dryness
under reduced pressure (3 kPa) . The residue is
triturated in 75 cm3 of acetone and isolated by
filtration. 0.198 g of 1-[2-(3-methylpiperidin-1-yl)-
ethyl]-4-phenyl-1H-pyrazol-3-ol dihydrochloride is thus
obtained in the form of a pale yellow powder which
melts at 220°C (with decomposition).
1H NMR spectrum (300 MHz, (CD3)2SO d6 with addition of a
few drops of CD3COOD, δ in ppm) : 0.89 (d, J = 7 Hz: 3H) ;
1.05 (mt: 1H) ; from 1.60 to 2.00 (mt: 4H) ; 2.58 (mt:
1H) ; 2.83 (very broad t, J = 12 Hz: 1H) ; from 3.30 to
3.55 (mt: 4H) ; 4.3 9 (t, J = 6.5 Hz: 2H) ; 7.13 (broad

t, J = 7.5 Hz: 1H) ; 7.32 (broad t, J = 7.5 Hz: 2H) ;
7.63 (broad d, J = 7.5 Hz: 2H); 7.99 (s: 1H).
IR spectrum (KBr): 3057; 2960; 2651; 2550; 1607; 1581;
1523; 454; 1179; 761; 697; 614 and 513 cm"1.
The 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-3-
methylpiperidine can be prepared in the following way:
A suspension of 1 g of 1-[(toluene-4-sulfonyl)oxy]-
2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl, 0.46 cm3 of
3-methylpiperidine and 0.8 8 g of potassium carbonate in
25 cm3 of acetonitrile is stirred for 6 hours at a
temperature in the region of 8 0°C. The mixture is
concentrated to dryness under reduced pressure (3 kPa) .
The residue is taken up with 50 cm3 of water and
extracted with 2 00 cm3 of ethyl acetate. The organic
phase is washed with 3 times 25 cm3 of water, and is
then dried, filtered and concentrated to dryness under
reduced pressure (3 kPa) . The oily residue obtained is
purified by chromatography on silica gel (particle size
15-35 µm) , eluting with a mixture of dichloromethane
and methanol (97/3 by volume). After concentration of
the fractions under reduced pressure, 0.58 g of 1-[2-
(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-3-methyl-
piperidine is obtained in the form of a colorless
viscous oil, which is used as it is in the following
step.
Mass spectrum (EI): m/z 375 (M+-), m/z 112 (base peak).
Example 10
1-[2-(3,6-Dihydro-2H-pyridin-1-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol dihydrochloride
A solution of 0.6 g of 1-[2-(3-benzyloxy-4-phenyl-
pyrrol-1-yl)ethyl]-1,2,3,6-tetrahydropyridine in a
mixture of 5 cm3 of 37% hydrochloric acid and of 5 cm3
of ethanol is heated at 8 0°C for 6 hours and then

concentrated to dryness under reduced pressure (3 kPa).
The residue is taken up with 100 cm3 of ethanol and
concentrated to dryness, 4 times. The residue is
triturated in 4 0 cm3 of acetone and isolated by
filtration. 0.403 g of 1-[2-(3,6-dihydro-2H-pyridin-
1-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol dihydrochloride is
thus obtained in the form of a brown powder which melts
at 192°C.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 2.29
(very broad d, J = 18 Hz: 1H) ; from 2.40 to 2.60 (mt:
1H); 3.07 (mt: 1H); 3.47 (mt: 1H); 3.55 (mt: 2H); 3.62
(very broad d, J = 16.5 Hz: 1H) ; 3.84 (broad d, J =
16.5 Hz: 1H) ; 4.47 (t, J = 6.5 Hz: 2H) ; 5.72 (broad d,
J = 10.5 Hz: 1H); 5.93 (very broad d, J = 10.5 Hz: 1H);
7.15 (broad t, J = 7.5 Hz: 1H) ; 7.34 (broad t, J =
7.5 Hz: 2H) ; 7.66 (broad d, J = 7.5 Hz: 2H) ; 8.06 (s:
1H) ; from 10.20 to 10.80 (broad unresolved peak: 1H) ;
10.88 (unresolved peak: 1H).
IR spectrum (KBr): 3422; 2948; 2688; 2579; 1607; 1526;
1452; 1184; 1023; 768; 699; 667; 670 and 511 cm"1.
The 1-[2-(3-benzyloxy-4-phenylpyrrol-1-yl)ethyl]-
1,2,3,6-tetrahydropyridine can be prepared in the
following way:
A suspension of 1 g of 1-[(toluene-4-sulfonyl)oxy]-2-
(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl, 0.3 6 cm3 of
1,2,3,6-tetrahydropyridine and 0.88 g of potassium
carbonate in 25 cm3 of acetonitrile is stirred for 6
hours at a temperature in the region of 80 °C. The
mixture is concentrated to dryness under reduced
pressure (3 kPa). The residue is taken up with 50 cm3 of
water and extracted with 2 00 cm3 of ethyl acetate. The
organic phase is washed with 3 times 25 cm3 of water,
and is then dried, filtered and concentrated to dryness
under reduced pressure (3 kPa). The oily residue
obtained is purified by chromatography on silica gel
(particle size 15-35 µm) , eluting with a mixture of

dichloromethane and methanol (97/3 by volume). After
concentration of the fractions under reduced pressure,
0.6 g of 1- [2- (3-benzyloxy-4-phenylpyrrol-1-yl) ethyl] -
1,2,3,6-tetrahydropyridine is obtained in the form of a
colorless viscous oil, which is used as it is in the
following step.
Mass spectrometry (CI): m/z 360 ( [M+H]+) (base peak).
Example 11
1-[2-(7-Azabicyclo[2.2.1]hept-7-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol dihydrochloride
3 cm3 of 1M hydrochloric acid are added to a solution of
0.6 g of 7-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-
7-azabicyclo[2.2.1]heptane in 40 cm3 of ethanol and the
mixture is stirred for a quarter of an hour at ambient
temperature and then concentrated to dryness under
reduced pressure (3 kPa) . The residue obtained and
0.078 g of palladium-on-charcoal (at 10%) are suspended
in 2 0 cm3 of ethanol and stirred in an autoclave under a
hydrogen pressure of 1 0 00 kPa, at a temperature of
20°C for 8 hours. The reaction medium is then filtered
over Celite® and concentrated to dryness under reduced
pressure (3 kPa). The residue is triturated in 25 cm3 of
acetone and isolated by filtration. 0.466 g of 1-[2-(7-
azabicyclo[2.2.1]hept-7-yl)ethyl]-4-phenyl-1H-pyrazol-
3-ol dihydrochloride is thus obtained in the form of a
white powder which melts at 22 8°C (with decomposition).
1H NMR spectrum (300 MHz, (CD3)2SO d6,δ in ppm) : 1.66
(unresolved peak: 4H); 2.00 (unresolved peak: 4H); 3.43
(mt: 2H) ; 3.93 (broad s: 2H) ; 4.43 (broad t, J =
6.5 Hz: 2H) ; 7.15 (broad t, J = 7.5 Hz: 1H) ; 7.35
(broad t, J = 7.5 Hz: 2H) ; 7.65 (broad d, J = 7.5 Hz:
2H) ; 8.08 (s: 1H) ; from 10.35 to 10.55 (broad
unresolved peak: 1H); 10.47 (unresolved peak: 1H).

IR spectrum (KBr): 2988; 2789; 2661; 2537; 1608; 1533;
1449; 1279; 1179; 875; 761; 698; 674 and 510 cm"1.
The 7-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-7-
azabicyclo [2.2.1]heptane can be prepared in the
following way:
A suspension of 1 g of 1- [ (toluene-4-sulfonyl)oxy]-2-
(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl, 0.616 g of
7-azabicyclo[2.2.1]heptane hydrochloride and 0.88 g of
potassium carbonate in 25 cm3 of acetonitrile is stirred
for 5 hours at a temperature in the region of 8 0°C. The
mixture is concentrated to dryness under reduced
pressure (3 kPa). The residue is taken up with 30 cm3 of
water and extracted with 2 50 cm3 of ethyl acetate. The
organic phase is washed with 3 times 3 0 cm3 of water,
and is then dried, filtered and concentrated to dryness
under reduced pressure (3 kPa). The oily residue
obtained is purified by chromatography on silica gel
(particle size 15-35 µm) , eluting with a mixture of
dichloromethane and methanol (98/2 by volume). After
concentration of the fractions under reduced pressure,
0.6 g of 7-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-
7-azabicyclo [2.2.1]heptane is obtained in the form of a
colorless viscous oil, which is used as it is in the
following step.
Mass spectrum (CI): m/z 374 ( [M+H]+) (base peak).
Example 12
1- [2-(2-Azabicyclo[2.2.2]oct-2-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol dihydrochloride
2 cm3 of 6M hydrochloric acid is added to a solution of
0.9 g of 2-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-
2-azabicyclo[2.2.2]octane in 50 cm3 of ethanol, and the
mixture is stirred for a quarter of an hour at ambient
temperature and then concentrated to dryness under

reduced pressure (3 kPa) . The residue obtained and
0.124 g of palladium-on-charcoal (at 10%) are suspended
in 2 0 cm3 of ethanol and stirred in an autoclave under a
hydrogen pressure of 1 000 kPa, at a temperature of
20°C for 8 hours. The reaction medium is then filtered
over Celite® and concentrated to dryness under reduced
pressure (3 kPa). The residue is triturated in 25 cm3 of
acetone and isolated by filtration. 0.56 g of l-[2-(2-
azabicyclo[2.2.2]oct-2-yl)ethyl]-4-phenyl-1H-pyrazol-
3-ol dihydrochloride is thus obtained in the form of a
beige powder which melts at 171°C (with decomposition).
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.50 to 1.75 (mt: 6H) ; 1.90 (very broad s: 1H) ; from
2.00 to 2.15 (mt: 1H); 2.28 (mt: 1H); 2.86 (very broad
dd, J = 12 and 4.5 Hz: 1H); from 3.35 to 3.55 (mt: 1H) ;
3.3 8 (very broad s: 1H) ; 3.55 (broad t, J = 6.5 Hz:
2H); 4.46 (broad t, J = 6.5 Hz: 2H); 7.14 (broad t, J =
7.5 Hz: 1H) ; 7.34 (broad t, J = 7.5 Hz: 2H) ; 7.65
(broad d, J = 7.5 Hz: 2H); 8.04 (s: 1H); 10.84
(unresolved peak: 1H).
IR spectrum (KBr): 2949; 2870; 2629; 2184; 1608; 1579;
1510; 1455; 1198; 870; 761; 692; 670 and 510 cm"1.
The 2-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-
azabicyclo[2.2.2]octane can be prepared in the
following way:
A suspension of 1 g of 1-[(toluene-4-sulfonyl)oxy]-2-
(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl, 0.563 g of
2-azabicyclo[2.2.2]octane hydrochloride and 0.8 8 g of
potassium carbonate in 25 cm3 of acetonitrile is stirred
for 8 hours at a temperature in the region of 8 0°C. The
mixture is concentrated to dryness under reduced
pressure (3 kPa). The residue is taken up with 3 0 cm3 of
water and extracted with 2 00 cm3 of ethyl acetate. The
organic phase is washed with twice 3 0 cm3 of water, and
is then dried, filtered and concentrated to dryness
under reduced pressure (3 kPa). The oily residue
obtained is purified by chromatography on silica gel

(particle size 15-35 µm) , eluting with a mixture of
dichloromethane and methanol (95/5 by volume). After
concentration of the fractions under reduced pressure,
0.92 g of 2-[2-(3-benzyloxy-4-phenylpyrazol-1-
yl)ethyl]-2-azabicyclo[2.2.2]octane is obtained in the
form of a colorless viscous oil, which is used as it is
in the following step.
Mass spectrum (CI): m/z 388 ( [M+H]+) (base peak).
The 2-azabicyclo[2.2.2]octane hydrochloride can be
obtained according to the method described by M. Yokota
et al., Eur. J. Med. Chem. Chim. Ther., 1997, 32 (5),
377-384.
Example 13
1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol dihydrochloride
1.6 cm3 of 6M hydrochloric acid are added to a solution
of 0.7 g of 2-[2-(3-benzyloxy-4-phenylpyrazol-1-
yl)ethyl]-2-azabicyclo[2.2.1]heptane in 50 cm3 of
ethanol, and the mixture is stirred for a quarter of an
hour at ambient temperature and then concentrated to
dryness under reduced pressure (3 kPa) . The residue
obtained and 0.10 g of palladium-on-charcoal (at 10%)
are suspended in 2 0 cm3 of ethanol and stirred in an
autoclave under a hydrogen pressure of 1 000 kPa, at a
temperature of 2 0°C for 8 hours. The reaction medium is
then filtered over Celite® and concentrated to dryness
under reduced pressure (3 kPa) . The residue is
triturated in 4 0 cm3 of acetone and isolated by
filtration. 0.565 g of 1-[2-(2-azabicyclo[2.2.1]hept-
2-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol dihydrochloride is
thus obtained in the form of a beige powder which melts
at 173°C (with decomposition).

1H NMR spectrum (400 MHz, (CD3)2SO d6 with addition of a
few drops of CD3COOD d4, at a temperature of 3 63 K, δ in ppm) : from 1.45 to 1.55 (mt: 1H) ; from 1.65 to 1.80
(mt: 3H) ; from 1.95 to 2.05 (mt: 2H) ; 2.65 (mt: 1H) ;
from 3.10 to 3.25 (broad unresolved peak: 2H) ; 3.4 8
(mt: 1H) ; 3.59 (mt: 1H) ; 4.04 (mt: 1H) ; 4.34 (broad t,
J = 6.5 HZ: 2H) ; 7.15 (broad t, J = 7.5 Hz: 1H) ; 7.32
(broad t, J = 7.5 Hz: 2H) ; 7.62 (broad d, J = 7.5 Hz:
2H); 7.90 (s: 1H).
IR spectrum (KBr): 2955; 2827; 2601; 2554; 1607; 1528;
1454; 1177; 1010; 767; 699; 672 and 515 cm"1.
The 2-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-
azabicyclo[2.2.1]heptane can be prepared in the
following way:
A suspension of 1 g of 1- [ (toluene-4-sulfonyl)oxy]-2-
(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl, 0.51 g of
2-azabicyclo[2.2.1]heptane hydrochloride and 0.88 g of
potassium carbonate in 25 cm3 of acetonitrile is stirred
for 8 hours at a temperature in the region of 8 0°C. The
mixture is concentrated to dryness under reduced
pressure (3 kPa). The residue is taken up with 3 0 cm3 of
water and extracted with 200 cm3 of ethyl acetate. The
organic phase is washed with two times 3 0 cm3 of water,
and is then dried, filtered and concentrated to dryness
under reduced pressure (3 kPa). The oily residue
obtained is purified by chromatography on silica gel
(particle size 15-35 µm) , eluting with a mixture of
dichloromethane and methanol (95/5 by volume). After
concentration of the fractions under reduced pressure,
0.75 g of 2-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)-
ethyl]-2-azabicyclo[2.2.1]heptane is obtained in the
form of a colorless viscous oil, which is used as it is
in the following step.
Mass spectrum (EI) : m/z 373 (M+) , m/z 110 (base peak) .

The 2-azabicyclo[2.2.1]heptane hydrochloride can be
obtained according to the method described by
•J.R. Malpass et al. , J.C.S., Perkin Trans. 1 1977, S,
874-884.
Example 14
1-[2-Dimethylaminoethyl]-4-phenyl-1H-pyrazol-3-ol
dihydrochloride
The process is carried out as in example 2, but with
0.10 g of [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-
dimethylamine dihydrochloride and 0.012 g of palladium-
on-charcoal (at 10%). 0.049 g of 1- [2-dimethylamino-
ethyl]-4-phenyl-1H-pyrazol-3-ol dihydrochloride is thus
obtained in the form of a beige powder which melts at
around 135°C (with decomposition).
1H NMR spectrum (300 MHz, (CD3)2SO d6,δ in ppm) : 2.81
(d, J = 5 Hz: 6H); 3.51 (mt: 2H); 4.38 (t, J = 6.5 Hz:
2H); 7.16 (broad t, J = 7.5 Hz: 1H); 7.35 (broad t, J
= 7.5 Hz: 2H); 7.65 (broad d, J = 7.5 Hz: 2H); 8.05 (s:
1H) ; 10.27 (unresolved peak: 1H) ; from 10.30 to 10.70
(very broad unresolved peak: 1H).
IR spectrum (KBr): 3311; 2985; 2558; 2463; 1629; 1582;
1508; 1467; 1409; 1190; 985; 760; 687 and 673 cm"1.
The [2-(3 -benzyloxy-4-phenylpyrazol-1-yl)ethyl]di-
methylamine dihydrochloride can be prepared in the
following way:
0.154 g of sodium hydride (at 75% by mass in liquid
petroleum jelly) is added gradually, under an argon
atmosphere and at ambient temperature, to a solution of
0.25 g of 3-benzyloxy-4-phenylpyrazole in 3 cm3 of
anhydrous dimethylformamide, followed, after
disappearance of the foams, by 0.5 g of (2-bromoethyl)-
dimethylamine hydrobromide. After stirring for 2 hours
at ambient temperature, water is slowly added and the
mixture is extracted with ethyl acetate. The organic

phase is dried over magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (3 kPa) .
The oily residue obtained is purified by chromatography
on silica gel, eluting with a mixture of
dichloromethane, methanol and aqueous ammonia at 2 8%
(90/8/2 by volume). After concentration of the
fractions under reduced pressure, 0.21 g of an oil is
obtained, which is dissolved in ethyl ether, has 1 cm3
of an approximately 3M hydrochloric ether solution
added to it, and is returned to dryness. The residue is
triturated in acetone and then isolated by filtration.
0.1 g of [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-
dimethylamine dihydrochloride is thus obtained in the
form of white crystals which melt at 105°C.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 2.82
(d, J = 5 Hz: 6H) ; 3.57 (mt: 2H); 4.34 (t, J = 6.5 Hz:
2H) ; 5.36 (s: 2H) ; 7.18 (broad t, J = 7.5 Hz: 1H) ; from
7.3 0 to 7.50 (mt: 5H) ; 7.52 (broad d, J = 7.5 Hz: 2H) ;
7.65 (broad d, J = 7.5 Hz: 2H) ; 8.17 (s: 1H) ; 9.68
(unresolved peak: 1H).
The (2-bromoethyl)dimethylamine hydrobromide can be
obtained according to the method described by
L.H. Amundsen et al. , J. Am. Chem. Soc. 1941, 63_, 305-
307.
Example 15
1-[3-Dimethylaminopropyl]-4-phenyl-1H-pyrazol-3-ol
dihydrochloride
The process is carried out as in example 2, but with
0.274 g of [3-(3-benzyloxy-4-phenylpyrazol-1-yl)-
propyl]dimethylamine dihydrochloride and 0.04 g of
palladium-on-charcoal (at 10%). 0.209 g of 1-[3-
dimethylaminopropyl]-4-phenyl-1H-pyrazol-3-ol dihydro-
chloride is thus obtained in the form of a beige powder
which melts at around 208°C (with decomposition).

1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 2.20
(mt: 2H) ; 3.5 (d, J = 5 Hz: 6H) ; 3.07 (mt: 2H) ; 4.04
(C, J = 6.5 Hz: 2H) ; 7.13 (broad t, J = 7.5 Hz: 1H) ;
7.33 (broad t, J = 7.5 Hz: 2H) ; 7.66 (broad d, J =
7.5 Hz: 2H) ; 7.99 (s: 1H) ; 10.82 (unresolved peak: 1H) .
IR spectrum (KBr): 3078; 2954; 2591; 2470; 1603; 1476;
1369; 1268; 1188; 881; 763; 700; 570 and 494 cm"1.
The [3-(3-benzyloxy-4-phenylpyrazol-1-yl)propyl]di-
methylamine dihydrochloride can be prepared in the
following way:
3.6 cm3 of 1N sodium hydroxide solution are added to a
suspension of 0.38 g of [3- (3-benzyloxy-4-
phenylpyrazol-1-yl)propyl]dimethylamine oxalate in
10 cm3 of water and the mixture is stirred for a quarter
of an hour and then extracted with 3 times 25 cm3 of
ethyl acetate. The pooled organic phases are dried over
magnesium sulfate, and then concentrated to dryness
under reduced pressure (3 kPa). The residue obtained is
dissolved in 2 5 cm3 of ethanol, an excess of an
approximately 3M hydrochloric ether solution is added,
and the mixture is returned to dryness. 0.2 74 g of
[3-(3-benzyloxy-4-phenylpyrazol-1-
yl)propyl]dimethylamine dihydrochloride is thus
obtained in the form of a pasty white solid used as it
is in the following step.
The [3-(3-benzyloxy-4-phenylpyrazol-1-yl)propyl]di-
methylamine oxalate can be prepared in the following
way:
0.106 g of sodium hydride (at 75% by mass in liquid
petroleum jelly) is added gradually, under an argon
atmosphere and at ambient temperature, to a solution of
0.25 g of 3-benzyloxy-4-phenylpyrazole in 15 cm3 of
anhydrous dimethylformamide. After stirring for three
quarters of an hour at a temperature in the region of
50°C, 0.316 g of (3-chloropropyl) dimethylamine

hydrochloride is added in small portions and the
mixture is then stirred for 16 hours at ambient
temperature. The mixture is run into 150 cm3 of water
and extracted with 3 times 150 cm3 of ethyl acetate. The
pooled organic phases are washed with 50 cm3 of water,
and are then dried over anhydrous magnesium sulfate,
filtered and concentrated to dryness under reduced
pressure (3 kPa). The oily residue obtained (0.8 g) is
dissolved in 10 cm3 of ethyl ether and a solution of
0.09 g of oxalic acid in 5 cm3 of ethyl ether is added.
The white precipitate formed is filtered and then dried
under vacuum (70 Pa) at ambient temperature. 0.395 g of
[3 -(3-benzyloxy-4-phenylpyrazol-1-yl)propyl]dimethyl-
amine oxalate is thus obtained in the form of a white
solid used as it is in the following step.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 2.15
(mt: 2H) ; 3 0 (s: 6H) ; 2.98 (mt: 2H) ; 4.08 (t, J =
6.5 Hz: 2H) ; 5.33 (s: 2H) ; 7.16 (broad t, J = 7.5 Hz:
1H); from 7.30 to 7.45 (mt: 3H); 7.43 (broad t, J = 7.5
Hz: 2H); 7.51 (broad d, J = 7.5 Hz: 2H); 7.65 (broad d,
J = 7.5 Hz: 2H); 8.09 (s: 1H).
Example 16
1-[2-((2S,6R)-2,6-Dimethylpiperidin-1-yl)ethyl]-4-
phenyl-1H-pyrazol-3-ol dihydrochloride
The process is carried out as in example 2, but with
0.123 g of (2S,6R)-1-[2-(3-benzyloxy-4-phenylpyrazol-
1-yl)ethyl]-2,6-dimethylpiperidine dihydrochloride and
0.014 g of palladium-on-charcoal (at 10%). 0.075 g of
1-[2-((2S,6R)-2,6-dimethylpiperidin-1-yl)ethyl]-4-
phenyl-1H-pyrazol-3-ol dihydrochloride is thus obtained
in the form of a beige powder which melts at around
206°C (with decomposition).
1H NMR spectrum (400 MHz, (CD3)2SO d6, at a temperature
of 403K, δ in ppm): 1.36 (d, J = 6.5 Hz: 6H) ; 1.57 (mt:
1H); from 1.65 to 1.90 (mt: 5H); 3.28 (unresolved peak:

2H) ; 3.49 (unresolved peak: 2H) ; 4.36 (broad t, J =
6.5 Hz: 2H) ; 7.15 (tt, J = 7.5 and 1.5 Hz: 1H) ; 7.33
(iSroad t, J = 7.5 Hz: 2H) ; 7.66 (broad d, J = 7.5 Hz:
2H); 8.00 (s: 1H).
IR spectrum (KBr): 3428; 3058; 2978; 2942; 2657; 2571;
1606; 1580; 1521; 1452; 1388; 1173; 997; 914; 766; 699;
671 and 511 cm"1.
The (2S,6R)-1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)-
ethyl]-2,6-dimethylpiperidine dihydrochloride can be
prepared in the following way:
0.5 cm3 of an approximately 3M hydrochloric ether
solution is added to a solution of 0.117 g of (2S,6R)-
1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2,6-
dimethylpiperidine in 25 cm3 of ethanol, which is then
brought back to dryness. 0.123 g of (2S,6R)-1-[2 - (3-
benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2,6-dimethyl-
piperidine dihydrochloride is thus obtained in the form
of a colorless paste used as it is in the following
step.
The (2S,6R)-1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)-
ethyl]-2,6-dimethylpiperidine can be prepared in the
following way:
0.211 g of sodium hydride (at 75% by mass in liquid
petroleum jelly) is added gradually, under an argon
atmosphere and at ambient temperature, to a solution of
0.25 g of 3-benzyloxy-4-phenylpyrazole in 20 cm3 of
anhydrous dimethylformamide. After stirring for three
quarters of an hour at a temperature in the region of
50°C, 0.636 g of (2S,6R)-1-(2-chloroethyl)-2, 6-
dimethylpiperidine hydrochloride is added in small
portions, and the mixture is then stirred for 16 hours
at ambient temperature. The mixture is run into 150 cm3
of water and extracted with twice 150 cm3 of ethyl
acetate. The pooled organic phases are washed with

50 cm3 of water, and are then dried over anhydrous
magnesium sulfate, filtered and concentrated to dryness
under reduced pressure (3 kPa). The oily residue
obtained is dissolved in 25 cm3 of ethyl ether and a
solution of 0.09 g of oxalic acid in 25 cm3 of ethyl
ether is added. The pasty product formed is washed with
3 times 25 cm3 of ethyl ether, and is then taken up with
25 cm3 of water, 4 cm3 of 1N sodium hydroxide solution
are added, and the mixture is stirred for a quarter of
an hour and then extracted with two times 2 5 cm3 of
ethyl acetate. The pooled organic phases are dried over
magnesium sulfate, and then concentrated to dryness
under reduced pressure (3 kPa). The oily residue
obtained is purified by chromatography on silica gel,
eluting with a mixture of ethyl acetate and methanol
(80/20 by volume). After concentration of the fractions
under reduced pressure, 0.117 g of (2S, 6R)-1-[2-(3-
benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2,6-dimethyl-
piperidine is obtained in the form of a colorless oil
used as it is in the following step. 1H NMR spectrum
(300 MHz, (CD3)2SO d6, δ in ppm) : 1.08 (d, J = 6.5 Hz:
6H) ; 1.17 (broad double t, J = 12 and 3 Hz: 2H) ; 1.28
(mt: 1H); 1.53 (broad d, J = 12 Hz: 2H); 1.62 (mt: 1H) ;
2.48 (mt: 2H) ; 2.95 (t, J = 6.5 Hz: 2H) ; 3.98 (t, J =
6.5 Hz: 2H) ; 5.32 (s: 2H) ; 7.15 (tt, J = 7.5 and
1.5 Hz: 1H); from 7.30 to 7.45 (mt: 1H); 7.34 (broad t,
J = 7.5 Hz: 2H) ; 7.42 (broad t, J = 7.5 Hz: 2H) ; 7.52
(broad d, J = 7.5 Hz: 2H) ; 7.66 (broad d, J = 7.5 Hz:
2H); 8.10 (s: 1H).
The (2S,6R)-1-(2-chloroethyl)-2,6-dimethylpiperidine-
amine hydrochloride can be obtained according to the
method described by R. Dahlbom et al. , Acta
Pharmaceutica Suecica 1969, 6_ (3), 413-418.
Example 17
1- [2-Diethylaminoethyl]-4-phenyl-1H-pyrazol-3-ol
dihydrochloride

The process is carried out as in example 2, but with
0.31 g of [2-(3-benzyloxy-4-phenylpyrazol-1-
yl)ethyl]diethylamine dihydrochloride and 0.04 g of
palladium-on-charcoal (at 10%). 0.139 g of 1-[2-
diethylaminoethyl]-4-phenyl-1H-pyrazol-3-ol
dihydrochloride is thus obtained in the form of a white
powder which melts at around 174°C (with
decomposition) .
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 1.23
(t, J = 7 Hz: 6H) ; 3.12 (very broad q, J = 7 Hz: 4H) ;
3.46 (very broad t, J = 6.5 Hz: 2H); 4.40 (broad t, J =
6.5 Hz: 2H) ; 7.14 (broad t, J = 7.5 Hz: 1H) ; 7.33
(broad t, J = 7.5 Hz: 2H) ; 7.65 (broad d, J = 7.5 Hz:
2H) ; 8.07 (s: 1H) ; 10.46 (unresolved peak: 1H) ; from
10.60 to 10.85 (broad unresolved peak: 1H).
IR spectrum (KBr): 3065; 2974; 2589; 2484; 1609; 1530;
1454; 1179; 1012; 765; 693; 677 and 508 cm"1.
The [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diethyl-
amine dihydrochloride can be obtained in the following
way:
The process is carried out as in example 15, but with
0.31 g of [2-(3-benzyloxy-4-phenylpyrazol-1-yl)-
ethyl]diethylamine oxalate. 0.31 g of [2-(3-benzyloxy-
4-phenylpyrazol-1-yl)ethyl]diethylamine dihydrochloride
is thus obtained in the form of a colorless gum used as
it is in the following step.
The [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diethyl-
amine oxalate can be obtained in the following way:
The process is carried out as in example 15, but with
0.211 g of sodium hydride (at 75% by mass in liquid
petroleum jelly) and 0.516 g of (2-chloroethyl)diethyl-
amine hydrochloride. 0.376 g of [2- (3-benzyloxy-4-
phenylpyrazol-1-yl)ethyl]diethylamine oxalate is thus

obtained in the form of a white powder which melts at
133°C.
41 NMR spectrum (300 MHz, (CD3)2SO d6, 6 in ppm) : 1.12
(t, J = 7 Hz: 6H); 2.98 (broad q, J = 7 Hz: 4H); 3.3 5
(very broad t, J = 6.5 Hz: 2H) ; 4.31 (broad t, J =
6.5 Hz: 2H) ; 5.35 (s: 2H) ; 7.17 (broad t, J = 7.5 Hz:
1H) ; 7.36 (mt: 3H) ; 7.43 (broad t, J = 7.5 Hz: 2H) ;
7.51 (broad d, J = 7.5 Hz: 2H); 7.65 (broad d, J = 7.5
Hz: 2H); 8.14 (s: 1H).
Example 18
1-(2-Diisopropylaminoethyl)-4-phenyl-1H-pyrazol-3-ol
dihydrochloride
The process is carried out as in example 2, but with
0.21 g of [2-(3-benzyloxy~4-phenylpyrazol-1-yl)ethyl]-
diisopropylamine dihydrochloride and 0.025 g of
palladium-on-charcoal (at 10%). 0.122 g of l-[2-diiso-
propylaminoethyl]-4-phenyl-1H-pyrazol-3-ol
dihydrochloride is thus obtained in the form of a beige
powder which melts at around 220°C (with
decomposition).
1H NMR spectrum (300 MHz, (CD3)2SO d6, 6 in ppm): 1.32
(broad d, J = 7 Hz: 6H) ; 1.34 (broad d, J = 7 Hz: 6H) ;
3.47 (unresolved peak: 2H); 3.71 (mt: 2H); 4.40 (broad
t, J = 6.5 Hz: 2H) ; 7.14 (broad t, J = 7.5 Hz: 1H) ;
7.33 (broad t, J = 7.5 Hz: 2H) ; 7.65 (broad d, J =
7.5 Hz: 2H) ; 8.12 (s: 1H) ; 9.96 (unresolved peak: 1H) ;
10.49 (broad s: 1H) .
IR spectrum (KBr): 2984; 2654; 2507; 2469; 1607; 1580;
1531; 1453; 1193; 759; 693; 673 and 511 cm"1.
The [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diiso-
propylamine dihydrochloride can be obtained in the
following way:

The process is carried out as in example 15, but with
0.31 g of [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-
diisopropylamine oxalate. 0.21 g of [2-(3-benzyloxy-
4-phenylpyrazol-1-yl)ethyl]diisopropylamine dihydro-
chloride is thus obtained in the form of a beige semi-
solid used as it is in the following step.
The [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diiso-
propylamine oxalate can be obtained in the following
way:
The process is carried out as in example 15, but with
0.211 g of sodium hydride (at 75% by mass in liquid
petroleum jelly) and 0.6 g of (2-
chloroethyl)diisopropylamine hydrochloride. 0.312 g of
[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diethylamine
oxalate is thus obtained in the form of a white powder
which melts at 134°C.
1H NMR spectrum (300 MHz, (CD3)2SO d6 with addition of a
few drops of CD3COOD d4, δ in ppm) : 1.21 (d, J = 6 Hz:
12H) ; 3.39 (broad t, J = 6.5 Hz: 2H) ; 3.57 (mt: 2H) ;
4.30 (t, J = 6.5 Hz: 2H); 5.35 (s: 2H); 7.17 (broad t,
J = 7.5 Hz: 1H) ; 7.35 (mt: 3H) ; 7.41 (broad t, J =
7.5 Hz: 2H) ; 7.49 (broad d, J = 7.5 Hz: 2H) ; 7.65
(broad d, J = 7.5 Hz: 2H); 8.10 (s: 1H).
Example 19
4-Phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-3-ol
dihydrochloride
The process is carried out as in example 2, but with
0.285 g of 3-benzyloxy-4-phenyl-1-(2-pyrrolidin-1-
ylethyl) -1H-pyrazole dihydrochloride and 0.037 g of
palladium-on-charcoal (at 10%). 0.101 g of 4-phenyl-1-
(2-pyrrolidin-1-ylethyl)-1H-pyrazol-3-ol dihydro-
chloride is thus obtained in the form of a beige powder
which melts at around 173°C (with decomposition).

1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.80 to 2.10 (mt: 4H) ; from 2.90 to 3.10 (unresolved
peak: 2H) ; from 3.45 to 3.65 (unresolved peak: 4H) ;
4.34 (broad t, J = 6.5 Hz: 2H) ; 7.14 (broad t, J =
7.5 Hz: 1H) ; 7.33 (broad t, J = 7.5 Hz: 2H) ; 7.65
(broad d, J = 7.5 Hz: 2H) ; 8.02 (s: 1H) ; from lo'.30 to
10.60 (broad unresolved peak: 1H) ; 10.43 (unresolved
peak: 1H).
IR spectrum (KBr): 3416; 3054; 2973; 2670; 2585; 2476;
2405; 1608; 1581; 1527; 1453; 1247; 1175; 1011; 768;
702; 673 and 514 cm"1.
The 3-benzyloxy-4-phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-
pyrazole dihydrochloride can be obtained in the
following way:
The process is carried out as in example 15, but with
0.34 g of 3-benzyloxy-4-phenyl-1-(2-pyrrolidin-
l-ylethyl) -1H-pyrazole oxalate. 0.285 g of 3-benzyloxy-
4-phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-pyrazole
dihydrochloride is thus obtained in the form of a beige
gum used as it is in the following step.
The 3-benzyloxy-4-phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-
pyrazole oxalate can be obtained in the following way:
The process is carried out as in example 15, but with
0.211 g of sodium hydride (at 75% by mass in liquid
petroleum jelly) and 0.51 g of 1-(2-chloroethyl)-
pyrrolidine hydrochloride. 0.3 54 g of 3-benzyloxy-
4-phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-pyrazole oxalate
is thus obtained in the form of a white powder which
melts at 144°C.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): 1.87
(mt: 4H) ; 3.10 (mt: 4H) ; 3.46 (mt: 2H) ; 4.33 (t, J =
6.5 Hz: 2H) ; 5.35 (s: 2H) ; 7.18 (broad t, J = 7.5 Hz:
1H) ; 7.36 (mt: 3H) ; 7.43 (broad t, J = 7.5 Hz: 2H) ;

7.52 (broad d, J = 7.5 Hz: 2H) ; 7.66 (broad d, J =
7.5 Hz: 2H); 8.13 (s: 1H).
Example 2 0
3-(3-Methoxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]-
octane hydrochloride
1.94 g of potassium tert-butoxide are added gradually,
under an argon atmosphere and at ambient temperature,
to a solution of 1.2 g of 3-methoxy-4-phenylpyrazole in
20 cm3 of anhydrous dimethylformamide. After stirring
for 1.5 hours at ambient temperature, a solution of
2.8 g of 3-[(methanesulfonyl)oxy]-1-azabicyclo[2.2.2]-
octane in 2 0 cm3 of anhydrous dimethylformamide is added
dropwise, and the mixture is then heated for 16 hours
at a temperature in the region of 100°C. The mixture is
cooled to ambient temperature and is then concentrated
under reduced pressure (3 kPa). The residue is taken up
with 3 0 cm3 of water and extracted with 250 cm3 of ethyl
acetate. The organic phase is washed with 3 times 3 0 cm3
of water, and dried, filtered and concentrated to
dryness under reduced pressure (3 kPa). The oily
residue obtained is purified by chromatography on
silica gel, eluting with a mixture of ethyl acetate and
methanol (90/10, then 75/25 by volume). After
concentration of the fractions under reduced pressure,
0.3 6 g of an oil is obtained, which is dissolved in
15 cm3 of acetone, and 5 cm3 of an approximately 1M
hydrochloric ether solution are added. The precipitate
which has appeared is triturated overnight and then
isolated by filtration. 0.308 g of 3-(3-methoxy-4-
phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]octane
hydrochloride is thus obtained in the form of a
hygroscopic beige powder which melts at around 2 07°C
(with decomposition).
1H NMR spectrum (3 00 MHz, (CD3)2SO d6, δ in ppm) : from
1.65 to 2.05 (mt: 4H) ; 2.42 (mt: 1H) ; 3.28 (mt: 3H) ;

from 3.3 5 to 3.55 (mt: 1H) ; 3.8 0 (mt: 2H) ; 3.97 (s:
3H) ; 4.75 (mt: 1H) ; 7.18 (broad t, J = 7.5 Hz: 1H) ;
7:36 (broad t, J = 7.5 Hz: 2H) ; 7.65 (broad d, J =
7.5 Hz: 2H); 8.30 (s: 1H) ; 10.76 (unresolved peak: 1H) .
IR spectrum (KBr): 3430; 2939; 2907; 2666; 2584; 1607;
1580; 1570; 1518; 1454; 1409; 1049; 1028; 764; 698; 623
and 513 cm-1.
Example 21
1-[2-(3-Difluoromethoxy-4-phenylpyrazol-1-yl)ethyl] -
piperidine hydrochloride
The process is carried out as in example 1, but with
0.25 g of 3-difluoromethoxy-4-phenyl-1H-pyrazole,
0.3 03 g of sodium hydride (at 75% by mass in liquid
petroleum jelly) and 0.6 g of 1- (2-chloroethyl)-
piperidine hydrochloride, and then eluting with a
mixture of dichloromethane and methanol (95/5 by
volume). 0.175 g of 1-[2-(3-difluoromethoxy-4-phenyl-
pyrazol-1-yl)ethyl]piperidine hydrochloride is thus
obtained in the form of a white solid which melts at
around 174°C (with decomposition).
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 1.40
(unresolved peak: 1H); from 1.60 to 1.90 (mt: 5H); 2.94
(unresolved peak: 2H) ; 3.47 (very broad d, J = 12 Hz:
2H) ; 3.54 (unresolved peak: 2H) ; 4.55 (broad t, J =
6.5 Hz: 2H) ; 7.2 9 (tt, J = 7.5 and 2.5 Hz: 1H) ; 7.41
(t, J = 72 Hz: 1H) ; 7.44 (broad t, J = 7.5 Hz: 2H) ;
7.59 (broad d, J = 7.5 Hz: 2H) ; 8.30 (s: 1H) ; from
10.00 to 10.20 (unresolved peak: 1H).
IR spectrum (KBr): 3100; 2931; 2644; 2543; 1609; 1581;
1507; 1482; 1456; 1364; 1181; 1125; 1100; 1076; 761;
694 and 513 cm"1.
The 3-difluoromethoxy-4-phenyl-1H-pyrazole can be
prepared in the following way:

A suspension of 2.55 g of 1-(3-hydroxy-4-phenylpyrazol-
1-yl)ethanone, 1.75 g of potassium carbonate and 1.82 g
of methyl 2-chloro-2,2-difluoroacetate in 40 cm3 of
dimethylformamide is stirred, under an argon
atmosphere, at ambient temperature for 16 hours and
then at a temperature of 65 °C for 8 hours. After
cooling, 10 cm3 of a ION sodium hydroxide solution are
added and the mixture is stirred for 1 hour at ambient
temperature, and then concentrated under reduced
pressure (3 kPa). The residue is extracted with 2 00 cm3
of ethyl acetate. The organic phase is washed with 3
times 25 cm3 of water, dried and concentrated under
reduced pressure (3 kPa) . The oily residue obtained is
purified by chromatography on silica gel, eluting with
a mixture of dichloromethane and methanol (99/1 by
volume). After concentration of the fractions under
reduced pressure, 0.8 g of 3-difluoromethoxy-4-phenyl-
1H-pyrazole is obtained in the form of a yellow solid
which melts at 125°C. Mass spectrum (EI): m/z 210 (M+')
(base peak), m/z 160 [M - CF2]+-.
Example 22
4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine
dihydrochloride
10 cm3 of 1N hydrochloric ether solution is added, in
excess, to a solution of 0.2 g of 4-phenyl-1- (2-
piperidin-1-ylethyl)-1H-pyrazol-3-ylamine in 10 cm3 of
methanol, and the mixture is concentrated to dryness
under reduced pressure (3 kPa) . The residue provides,
after trituration in ethyl ether, 0.244 g of 4-phenyl-
1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine
dihydrochloride in the form of white crystals which
melt at around 12 0°C.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.25 to 1.55 (mt: 1H); from 1.60 to 1.90 (mt: 5H); 2.95
(unresolved peak: 2H); 3.44 (unresolved peak: 2H); 3.51

(mt: 2H) ; 4.53 (t, J = 6.5 Hz: 2H) ; 7.2 7 (broad t,
J = 7.5 Hz: 1H) ; 7.42 (broad t, J = 7.5 Hz: 2H) ; 7.56
(Broad d, J = 7.5 Hz: 2H); 8.07 (s: 1H); 10.46
(unresolved peak: 1H).
IR spectrum (KBr): 3277; 2945; 2630; 2545; 1612; 1540;
1451; 1099; 1005; 768; 707; 572 and 559 cm-1.
The 4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-yl-
amine can be prepared in the following way:
A suspension of 1.59 g of 4-phenyl-1H-pyrazol-3-
ylamine, 2.2 g of 1-(2-chloroethyl)piperidine
hydrochloride, 4 g of potassium carbonate and 1.66 g of
potassium iodide in 50 cm3 of 2-butanone is stirred at
the boiling temperature of the reaction medium for
22 hours. After cooling, the mixture is brought to
dryness under reduced pressure (3 kPa) . The residue is
taken up with 40 cm3 of 0. 5N sodium hydroxide solution
and extracted with 50 cm3 of ethyl acetate. The organic
phase is dried over magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (3 kPa).
The yellow oily residue is purified by chromatography
on basic alumina, eluting successively with a mixture
of ethyl acetate and dichloromethane (50/50 by volume)
and then with pure ethyl acetate. 0.2 g of 4-phenyl-1-
(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine is thus
obtained in the form of a white solid which melts at
96°C and has an Rf of 0.4 (ethyl acetate, aluminum
oxide plate reference 105731, Merck).
1H NMR spectrum (300 MHz, (CD3)2SO d6, 6 in ppm) : 1.40
(mt: 2H) ; 1.4 9 (mt: 4H) ; 2.3 9 (broad t, J = 5 Hz: 4H) ;
2.64 (t, J = 6.5 Hz: 2H) ; 3.98 (t, J = 6.5 Hz: 2H) ;
4.63 (s: 2H) ; 7.15 (tt, J = 7.5 and 1.5 Hz: 1H) ; 7.34
(broad t, J = 7.5 Hz: 2H); 7.49 (broad d, J = 7.5 Hz:
2H); 7.74 (s: 1H).

The 4-phenyl-1H-pyrazol-3-ylamine can be prepared
according to the method described by S.A. Lang, Jr. et
al., J. Heterocyclic Chem. 1977, 14, 65-69.
Example 23
4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine
dihydrochloride
2 cm3 of a 1M lithium aluminum hydride solution are
added gradually, at ambient temperature and under an
argon atmosphere, to a solution of 0.25 g of N-[4-
phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-yl]-
formamide in 10 cm3 of anhydrous tetrahydrofuran. After
stirring for 66 hours at ambient temperature, 1 cm3 of
1N sodium hydroxide solution is added gradually and the
mixture is extracted with 2 0 cm3 of ethyl acetate. After
removal of the gel by filtration, the organic phase is
concentrated to dryness under reduced pressure (3 kPa).
The oily residue obtained is purified by chromatography
on basic alumina, eluting with a mixture of
dichloromethane and ethyl acetate (80/20 by volume).
After concentration of the fractions under reduced
pressure, a colorless oil is obtained, which is
dissolved in 10 cm3 of ethyl ether, and 1 cm3 of an
approximately 6N solution of hydrochloric dioxane is
added, and the mixture is then concentrated to dryness
under reduced pressure (3 kPa) . The residue is
triturated in acetone and isolated by filtration.
0.045 g of 4-phenyl-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ylamine dihydrochloride is thus obtained in
the form of a white solid which melts at around 165°C
(with decomposition).
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.25 to 1.50 (unresolved peak: 1H) ; from 1.60 to 1.90
(mt: 5H); 1.6 (s: 3H); 2.94 (unresolved peak: 2H); from
3.40 to 3.65 (mt: 4H) ; 4.42 (t, J = 6.5 Hz: 2H) ; 7.20
(broad t, J = 7.5 Hz: 1H) ; 7.3 7 (broad t, J = 7.5 Hz:

2H); 7.47 (broad d, J = 7.5 Hz: 2H); 7.89 (s: 1H); 9.93
(unresolved peak: 1H).
IR spectrum (KBr): 3289; 2943; 2600; 2534; 2481; 1627;
1530; 1446; 1342; 1189; 850; 770; 706 and 499 cm"1.
The N-[4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-
yl]formamide can be prepared in the following way:
A solution of 0.24 g of 4-phenyl-1-(2-piperidin-1-
ylethyl) -1H-pyrazol-3-ylamine in 10 cm3 of ethyl formate
is stirred at the boiling temperature of the reaction
medium for 23 hours. After cooling, the mixture is
concentrated to dryness under reduced pressure (3 kPa).
0.31 g of N-[4-phenyl-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-yl] formamide is thus obtained in the form of
a colorless lacquer, which is used as it is in the
following step.
1H NMR spectrum (4 00 MHz, (CD3)2SO d6, at a temperature
of 373 K, δ in ppm): 1.42 (mt: 2H); 1.52 (mt: 4H); 2.45
(t, J = 5 Hz: 4H); 3.6 (t, J = 6.5 Hz: 2H); 4.17 (t, J
= 6.5 Hz: 2H) ; 7.24 (broad t, J = 7.5 Hz: 1H) ; 7.38
(broad t, J = 7.5 Hz: 2H) ; 7.49 (broad d, J = 7.5 Hz:
2H) ; 7.96 (s: 1H) ; 8.30 (broad d, J = 5 Hz: 1H) ; 9.49
(unresolved peak: 1H).
IR spectrum (KBr): 34434; 3218; 2955; 2799; 1683; 1631;
1607; 1325; 1289; 765; 698 and 592 cm"1.
Example 24
N-[4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-yl]-
acetamide oxalate
0.1 cm3 of acetic anhydride is added to a solution of
0.27 g of 4-phenyl-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ylamine in 5 cm3 of chloroform, and the
mixture is then stirred at ambient temperature for
100 hours. After the mixture has been concentrated to
dryness under reduced pressure (3 kPa), 15 cm3 of a

saturated sodium hydrogen carbonate solution are added
to the residue, which is extracted with 2 0 cm3 of ethyl
arcetate. The organic phase is dried over magnesium
sulfate, filtered and concentrated to dryness under
reduced pressure (3 kPa) . The oily residue obtained is
dissolved in 10 cm3 of acetone and 0.1 g of oxalic acid
is added. The solution obtained is concentrated to
dryness under reduced pressure (3 kPa) and the residue
is triturated in ethyl ether and isolated by
filtration. 0.05 g of N-[4-phenyl-1-(2-piperidin-1-
ylethyl)-1H-pyrazol-3-yl]acetamide oxalate is thus
obtained in the form of a hygroscopic white solid.
1H NMR spectrum (3 0 0 MHz, (CD3)2SO d6, δ in ppm) : 1.52
(mt: 2H) ; 1.70 (mt: 4H) ; 2.01 (broad s: 3H) ; 3.01
(unresolved peak: 4H) ; 3.3 6 (broad t, J = 6.5 Hz: 2H) :
4.44 (broad t, J = 6.5 Hz: 2H); 7.25 (broad t,
J = 7.5 Hz: 1H) ; 7.38 (broad t, J = 7.5 Hz: 2H) ; 7.47
(broad d, J = 7.5 Hz: 2H) ; 8.11 (broad s: 1H) ; 9.66
(unresolved peak: 1H).
IR spectrum (KBr): 3258; 3026; 2952; 2683; 2540; 1725;
1640; 1525; 1447; 1373; 1202; 1008; 765 and 700 cm"1.
Example 25
N-[4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-yl]-
methanesulfonamide
0.06 cm3 of methanesulfonyl chloride is added to a
solution of 0.18 g of 4-phenyl-1-(2-piperidin-1-
ylethyl) -1H-pyrazol- 3 -ylamine in 5 cm3 of chloroform,
and the mixture is then stirred at ambient temperature
for 22 hours. 0.04 cm3 of methanesulfonyl chloride is
added to the mixture and the stirring is continued at
ambient temperature for 3 hours. 15 cm3 of a saturated
sodium hydrogen carbonate solution are added to the
mixture, which is extracted with 25 cm3 of ethyl
acetate. The organic phase is dried over magnesium
sulfate, filtered and concentrated to dryness under

reduced pressure (3 kPa) . The oily residue obtained is
purified by chromatography on basic alumina, eluting
successively with pure ethyl acetate and then with a
mixture of ethyl acetate and methanol (3 0/1 by volume).
After concentration of the fractions under reduced
pressure, a colorless residue is obtained, which is
crystallized by trituration from ethyl ether and
isolated by filtration. 0.05 g of N- [4-phenyl-1-(2-
piperidin-1-ylethyl)-1H-pyrazol-3-yl]-methanesulfonamide
is thus obtained in the form of a white solid which
melts at 121°C.
1H NMR spectrum (300 MHz, (CD3)2SO d6,δ in ppm) : from
1.40 to 1.55 (mt: 6H) ; 2.41 (broad t, J = 5 Hz: 4H) ;
3.1 (t, J = 6.5 Hz: 2H) ; 3.11 (s: 3H) ; 4.18 (t, J =
6.5 Hz: 2H) ; 7.23 (broad t, J = 7.5 Hz: 1H) ; 7.38
(broad t, J = 7.5 Hz: 2H) ; 7.69 (broad d, J = 7.5 Hz:
2H) ; 8.06 (s: 1H) ; from 9.00 to 9.70 (very broad
unresolved peak: 1H).
IR spectrum (KBr): 3105; 2928; 1610; 1440; 1321; 1149;
976; 765; 699; 524 and 518 cm"1.
Example 2 6
1-(2-Dimethylaminopropyl)-4-phenyl-1H-pyrazol-3-ol
dihydrochloride
1 cm3 of a 4N hydrochloric solution in dioxane is added
gradually, at a temperature in the region of 20°C, to a
solution of 0.42 g of {2-[3-(cyclohex-2-enyloxy)-
4-phenylpyrazol-1-yl]-1-methylethyl}dimethylamine in
5 cm3 of methanol, with stirring. After stirring for 15
hours at a temperature in the region of 2 0°C, the
reaction mixture is concentrated to dryness under
reduced pressure (2.7 kPa) and dried at 40°C under
reduced pressure (2.7 kPa) so as to give 0.37 g of
1-(2-dimethylaminopropyl)-4-phenyl-1H-pyrazol-3-ol
dihydrochloride in the form of a white solid which

melts at 189°C. Mass spectrum (CI): m/z 246 (MH+) base
peak.
The {2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-
l-methylethyl}dimethylamine can be prepared in the
following way:
A solution of 1 g of 3-(cyclohex-2-enyloxy)-4-phenyl-
1H-pyrazole in 5 cm3 of dimethylformamide is added to a
suspension, which is stirred under an argon atmosphere,
of 1.3 g of sodium hydride (at 75% in liquid petroleum
jelly) in 5 cm3 of dimethylformamide. After stirring for
15 minutes at a temperature in the region of 20°C, and
then for 30 minutes at 50°C, the reaction medium is
cooled to a temperature in the region of 20°C, and
1.3 g of (2-chloro-1-methylethyl)dimethylamine
hydrochloride are added with stirring, and the mixture
is then brought to 50°C for 15 hours. After the
addition of a further 0.14 g of sodium hydride at 75%
in liquid petroleum jelly and a further 0.7 g of
(2-chloro-1-methylethyl)dimethylamine hydrochloride,
the reaction is continued for 15 hours at 50°C, and the
reaction medium is then cooled to a temperature in the
region of 2 0°C and concentrated to dryness under
reduced pressure (2.7 kPa) . The residue obtained is
taken up in 100 cm3 of water; the resulting aqueous
phase is extracted with 3 times 3 0 cm3 of
dichloromethane, and the organic phase is dried over
magnesium sulfate and concentrated to dryness under
reduced pressure (2.7 kPa) . 1.2 g of a brown oil is
obtained, which is purified by flash chromatography on
silica under an argon pressure (50 kPa) [eluent:
dichloromethane/methanol (95/5 by volume)]. After
concentration of the fractions to dryness under reduced
pressure (2.7 kPa) , 0.42 g of {2-[3-(cyclohex-2-
enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl}dimethyl-
amine is obtained in the form of an oil [TLC: eluent:

dichloromethane/methanol (95/5 by volume), Rf = 0.13].
Mass spectrum (EI): m/z 325 (M+-) , m/z 72 (C4H10N+-).
The 3-(cyclohex-2-enyloxy)-4-phenyl-1H-pyrazole can be
prepared in the following way:
2.02 g of 1-(3-hydroxy-4-phenylpyrazol-1-yl)ethanone,
1.2 7 cm3 of 3-bromocyclohexene and 1.52 g of potassium
carbonate are added to 2 0 cm3 of methyl ethyl ketone
with stirring at a temperature in the region of 2 0°C.
After heating for 3 hours at the reflux of the solvent,
the reaction medium is cooled to a temperature in the
region of 2 0°C and concentrated to dryness under
reduced pressure (2.7 kPa). The residue obtained is
taken up in a mixture of 2 0 cm3 of tetrahydrofuran and
2 0 cm3 of methanol, and 2 cm3 of 5N sodium hydroxide are
then added thereto with stirring. After stirring for
3 0 minutes at a temperature in the region of 2 0°C, the
reaction medium is concentrated to dryness under
reduced pressure (2.7 kPa) , which results in a residue
which is solubilized in 100 cm3 of ethyl acetate. The
organic solution is washed with two times 2 0 cm3 of
water and with 2 0 cm3 of water saturated with sodium
chloride, dried over magnesium sulfate, filtered, and
evaporated to dryness under reduced pressure (2.7 kPa).
The solid obtained is taken up with 5 cm3 of ethyl
acetate under hot conditions with stirring; 40 cm3 of
diisopropyl ether are added to the solution, which is
brought to the reflux of the solvent for 15 minutes and
then cooled to a temperature in the region of 2 0°C. A
first crystallization crop is filtered off, washed with
10 cm3 of diisopropyl ether and 10 cm3 of pentane, and
dried under reduced pressure (2.7 kPa) to give 1.07 g
of 3-(cyclohex-2-enyloxy)-4-phenyl-1H-pyrazole in the
form of a white powder. The crystallization filtrate is
evaporated to dryness under reduced pressure (2.7 kPa)
and taken up with 2 0 cm3 of diisopropyl ether, and
20 cm3 of pentane are added; a second crystallization
crop is filtered off and dried under reduced pressure

(2.7 kPa), to give 0.33 g of a batch which is identical
to the preceding one [TLC: eluent: cyclohexane/ethyl
acetate (70/30 by volume), Rf = 0.23]. Mass spectrum
(EI): m/z 240 (M+"), m/z 160 [ (M-CSH8)+-] .
Example 27
1-(l-Methylpiperidin-3-ylmethyl)-4-phenyl-1H-pyrazol-
3-ol
0.86 g of 3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-
1-methylpiperidine, 0.1 g of palladium-on-charcoal at
10%, 10 cm3 of cyclohexene and 2 0 cm3 of ethanol are
added to 2 0 cm3 of ethanol at a temperature in the
region of 20°C. After 15 hours at 50°C, 0.1 g of
palladium-on-charcoal at 10% and 10 cm3 of cyclohexene
are added to the reaction medium; the mixture is
brought to the reflux of the solvent for 1 hour, and a
further 15 cm3 of cyclohexene are then added and the
reaction is continued at the reflux of the solvent for
5 hours. The catalyst is filtered off over supercel,
and the solution is evaporated to dryness under reduced
pressure (2.7 kPa) to give 0.48 g of a solid which is
triturated in 10 cm3 of a mixture of diisopropyl ether
and pentane. After filtration, 0.3 g of a solid is
obtained, which is used again in reaction with 10 cm3 of
ethanol, 10 cm3 of cyclohexene and 0.1 g of palladium-
on-charcoal at 10% with stirring and at the reflux of
the solvent for 15 hours. The catalyst is filtered off
over supercel, and the filtrate is evaporated to
dryness under reduced pressure (2.7 kPa) to give 0.3 g
of a solid which is purified by flash chromatography on
silica under an argon pressure (50 kPa) [eluent:
dichloromethane/methanol/3 8% aqueous ammonia solution
(88/10/2 by volume)]. After concentration of the
fractions under reduced pressure (2.7 kPa), 0.15 g of a
yellowish solid is obtained, which is taken up in 70 cm3
of methanol at a temperature in the region of 2 0 °C.

1 cm3 of 4N hydrochloric acid in dioxane is added to the
solution, which is stirred for 15 minutes at a
temperature in the region of 2 0°C and is then
evaporated to dryness under reduced pressure (2.7 kPa)
to give 0.19 g of a foam which is triturated in
diisopropyl ether and filtered. The deliquescent solid
is taken up with 1 cm3 of 1N sodium hydroxide, and the
aqueous phase is washed with dichloromethane, partially
evaporated under reduced pressure (2.7 kPa), adjusted
to pH 8 by adding 0. 1N hydrochloric acid, and
extracting with dichloromethane. The organic phase is
dried over magnesium sulfate, filtered and evaporated
under reduced pressure (2.7 kPa) to give 0.15 g of
1-(l-methylpiperidin-3-ylmethyl)-4-phenyl-1H-pyrazol-3-
ol in the form of a cream foam which melts at 132°C.
Mass spectrum (ES) : m/z 272 (MH+) .
The 3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-
methylpiperidine can be prepared in the following way:
0.4 g of sodium hydride at 75% in liquid petroleum
jelly is added gradually, at a temperature in the
region of 20°C, to a solution of 1 g of 3-benzyloxy-
4-phenyl-1H-pyrazole in 10 cm3 of dimethylformamide
under an argon atmosphere and with stirring, and the
mixture is then brought to 50°C for 10 minutes. After
the addition of 1.5 g of 3-chloromethyl-1-
methylpiperidine hydrochloride, the reaction medium is
heated at 80°C for 15 hours, and is then cooled to a
temperature in the region of 2 0°C and poured into
10 0 cm3 of water. The mixture is extracted with
dichloromethane; the organic phase is dried over
magnesium sulfate, filtered and evaporated to dryness
under reduced pressure (2.7 kPa) to give 1.6 g of a
brown oil which is purified by flash chromatography on
silica under an argon pressure (50 kPa) [eluent:
dichloromethane/methanol (95/5 by volume)]. After
concentration of the fractions to dryness under reduced

pressure (2.7 kPa), 0.86 g of 3-(3-benzyloxy-4-phenyl-
pyrazol-1-ylmethyl)-1-methylpiperidine is obtained in
the form of a yellow oil [TLC: eluent:
dichloromethane/methanol/3 8% aqueous ammonia solution
(88/10/2 by volume), Rf = 0.41]. Mass spectrum (EI):
m/z 361 (M+-), m/z 270 [ (M-C7H7)+] .
Example 2 8
5-Methyl-4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-ol dihydrochloride
1.5 cm3 of a 4N hydrochloric solution in dioxane are
added gradually, with stirring, at a temperature in the
region of 20°C, to a solution of 0.3 g of l-{2-[3-
(cyclohex-2-enyloxy)-5-methyl-4-phenylpyrazol-1-yl]-
ethyl}piperidine in 10 cm3 of methanol. After stirring
for 15 hours at a temperature in the region of 20°C,
the reaction mixture is concentrated to dryness under
reduced pressure (2.7 kPa) . The residue is triturated
in diisopropyl ether, filtered, and dried under reduced
pressure (2.7 kPa) at 40°C for 2 hours to give 0.19 g
of 5-methyl-4-phenyl-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol dihydrochloride in the form of a cream
solid which melts at 222°C. Mass spectrum (CI): m/z 286
(MH+) .
The l-{2-[3-(cyclohex-2-enyloxy)-5-methyl-4-phenyl-
pyrazol-1-yl]ethyl}piperidine can be prepared in the
following way:
0.2 g of sodium hydride at 75% in liquid petroleum
jelly is added gradually, at a temperature in the
region of 20°C, to a solution of 0.46 g of 3-(cyclohex-
2-enyloxy)-5-methyl-4-phenyl-1H-pyrazole in 15 cm3 of
dimethylformamide with stirring and under an argon
atmosphere. After heating for 5 minutes at 50°C, 0.67 g
of 1-(2-chloroethyl)piperidine hydrochloride is added

to the reaction medium, and the solution is then heated
at 80°C for 15 hours. The reaction medium is poured
into 100 cm3 of water; the aqueous phase is extracted
with dichloromethane, which is dried over magnesium
sulfate and concentrated to dryness under reduced
pressure (2.7 kPa). The resulting brown oil (0.8 g) is
purified by flash chromatography on silica under an
argon pressure (50 kPa) [eluent: dichloro-
methane/methanol (95/5 by volume)]. After concentration
of the fractions to dryness under reduced pressure
(2.7 kPa) , 0.3 g of 3-(cyclohex-2-en-1-yloxy)-5-methyl-
4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazole is
obtained in the form of a yellow oil [TLC: eluent:
dichloromethane/methanol (90/10 by volume), Rf = 0.27].
Mass spectrum (CI) : m/z 3 66 (MH+) .
The 3-(cyclohex-2-enyloxy)-5-methyl-4-phenyl-1H-pyrazole
can be prepared in the following way:
0.54 cm3 of 5N sodium hydroxide is added gradually, at a
temperature in the region of 20°C, to a solution, with
stirring, of 0.8 g of 1-[3-(cyclohex-2-enyloxy)-5-
methyl-4-phenylpyrazol-1-yl]ethanone in a mixture of
20 cm3 of methanol and 2 0 cm3 of tetrahydrofuran. After
stirring for 6 hours at a temperature in the region of
20°C, the reaction mixture is concentrated to dryness
under reduced pressure (2.7 kPa), and the residue is
taken up with 100 cm3 of dichloromethane and 10 cm3 of
water; the organic phase is separated by settling out,
dried over magnesium sulfate, filtered and concentrated
to dryness under reduced pressure (2.7 kPa) to give
0.46 g of 3-(cyclohex-2-enyloxy)-5-methyl-4-phenyl-1H-
pyrazole in the form of a yellow gum [TLC: eluent:
cyclohexane/ethyl acetate (70/30 by volume),
Rf = 0.19]. Mass spectrum (EI) : m/z (254 M+-), m/z 174
t(M-C6H8)+] .

The 1-[3-(cyclohex-2-enyloxy)-5-methyl-4-phenylpyrazol-
1-yl]ethanone can be prepared in the following way:
2 g of 1-(3-hydroxy-5-methyl-4-phenylpyrazol-1-
yl) ethanone, 1.3 g of potassium carbonate and 1.06 cm3
of 3-bromocyclohexene are added to 100 cm3 of methyl
ethyl ketone at 2 0°C with stirring. After heating at
the reflux of the solvent for 5 hours, the reaction
medium is cooled to a temperature in the region of 2 0°C
and then concentrated to dryness under reduced pressure
(2.7 kPa). The residue is taken up with 100 cm3 of water
and 100 cm3 of dichloromethane; the organic phase is
separated by settling out, dried over magnesium
sulfate, filtered and concentrated to dryness under
reduced pressure (2.7 kPa) . The resulting brown oil
(2.7 g) is purified by flash chromatography on silica
[eluent: cyclohexane/ethyl acetate (70/30 by volume)].
After concentration of the fractions to dryness under
reduced pressure (2.7 kPa), 0.8 g of 1- [3-(cyclohex-2-
enyloxy)-5-methyl-4-phenylpyrazol-1-yl]ethanone is
obtained in the form of a yellow oil [TLC: eluent:
cyclohexane/ethyl acetate (70/30 by volume),
Rf = 0.74]. Mass spectrum (EI): m/z 296 (M+'), m/z 174
[(216-C2H20)+-] .
The 1-(3-hydroxy-5-methyl-4-phenylpyrazol-1-yl)ethanone
can be prepared in the following way:
0.85 cm3 of acetic anhydride is added to a solution of
1.74 g of 5-methyl-4-phenyl-1H-pyrazol-3-ol (CAS No.:
64754-67-2) in 17 cm3 of pyridine with stirring and
which has been brought to 100°C. After heating at this
temperature for 3 0 minutes, the reaction medium is
cooled to a temperature in the region of 20°C and is
then poured into 100 cm3 of a mixture of ice and water.
The solution is extracted with 2 times 50 cm3 of ethyl
acetate; the organic phases are pooled, washed with
twice 100 cm3 of water, dried over magnesium sulfate,

filtered and evaporated to dryness under reduced
pressure (2.7 kPa) ; 2 g of 1-(3-hydroxy-5-methyl-4-
phenylpyrazol-1-yl)ethanone are obtained in the form of
an orangey-ye How oil. Mass spectrum (EI) : m/z 216
(M+-) , m/z 174 [(M-C2H20)+'] .
Example 2 9
4-(3-Aminophenyl)-1-(2-dimethylaminoethyl)-1H-pyrazol-
3-ol trihydrochloride
A solution of 500 mg of {2- [3-benzyloxy-4-(3-
nitrophenyl)pyrazol-1-yl]ethyl}dimethylamine in 15 cm3
of methanol is added to a mixture of 860 mg of ammonium
formate and of 5 0 mg of palladium hydroxide at 10% in
15 cm3 of methanol, and this mixture is heated for 3
hours at the reflux of the solvent with stirring. The
reaction medium is then filtered over supercel, and the
filtrate is evaporated under reduced pressure
(2.7 kPa) . The reaction crude is taken up with
dichloromethane and the resulting mixture is washed
successively with a saturated aqueous hydrogen
carbonate solution, water and a saturated aqueous
sodium chloride solution. The aqueous phases are pooled
and evaporated under reduced pressure (2.7 kPa). The
residue obtained is taken up with methanol and the
suspension is filtered. After evaporation of the
filtrate under reduced pressure (2.7 kPa), the residual
solid is triturated in 3N hydrochloric ethanol. The
precipitate formed is filtered off and dried under
vacuum (2.7 kPa) to give 110 mg of 4-(3-aminophenyl)-1-
(2-dimethylaminoethyl)-1H-pyrazol-3-ol trihydrochloride
in the form of a beige solid.
IR spectrum (KBr): 3432; 2839; 2689; 2586; 1627; 1603;
1523; 1462; 1178; 786 and 696 cm-1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 2.80
(s: 6H); 3.45 (t, J = 6.5 Hz: 2H); 4.41 (t, J = 6.5 Hz:
2H) ; 7.10 (broad d, J = 8 Hz: 1H) ; 7.42 (t, J = 8 Hz:

1H); 7.58 (broad d, J = 8 Hz: 1H); 7.67 (broad s: 1H);
8.10 (s: 1H); from 9.50 to 10.40 (very broad unresolved
peak: 1H); 10.50 (unresolved peak: 1H); 10.73
(unresolved peak: 1H).
The {2-[3-benzyloxy-4-(3-nitrophenyl)pyrazol-1-yl]-
ethyl}dimethylamine can be prepared in the following
way:
A solution of 3.45 g of 3-benzyloxy-4-(3-nitrophenyl)-
1H-pyrazole in 50 cm3 of dimethylformamide is added to a
suspension of 1.13 g of sodium hydride (at 75% in
liquid petroleum jelly) in 50 cm3 of dimethylformamide
under an argon atmosphere and with stirring. After
heating at 50°C for 30 minutes, the mixture is stirred
for 1 h at a temperature in the region of 2 0°C and is
then cooled in an ice bath and a solution of 4.5 g of
(2-bromoethyl)dimethylamine hydrobromide in 50 cm3 of
dimethylformamide is added. The reaction mixture is
stirred for 15 h at a temperature in the region of
2 0°C, and 1.5 h at 50°C, and is then cooled to a
temperature in the region of 2 0°C and poured into
400 cm3 of water. The aqueous phase is extracted twice
with ethyl acetate. The organic phases are pooled,
washed successively with water and a saturated aqueous
sodium chloride solution, dried over magnesium sulfate,
filtered and evaporated under reduced pressure
(2.7 kPa) to give an orange-colored oil which is
purified by flash chromatography on silica under an
argon pressure (50 kPa) [eluent: ethyl acetate, then
ethyl acetate/methanol (90/10 by volume) ] . After
concentration of the fractions under reduced pressure,
1.7 g of {2-[3-benzyloxy-4-(3-nitrophenyl)pyrazol-1-
yl] ethyl} dimethyl amine are obtained in the form of an
orange-colored oil. Mass spectrum (EI) : m/z 366 (M+),
m/z 91 (C7H7+) , m/z 71 (C4H9N+), m/z 58 (C3H8N+) .

The 3-benzyloxy-4-(3-nitrophenyl)-1H-pyrazole can be
prepared in the following way:
2.75 g of potassium carbonate and 2.2 cm3 of benzyl
bromide are added to a suspension of 4.1 g of l-[3-
hydroxy-4-(3-nitrophenyl)pyrazol-1-yl]ethanone in
50 cm3 of methyl ethyl ketone with stirring. The
mixture is heated at the reflux of the solvent for
2.5 h, cooled to a temperature in the region of 20°C,
and filtered. The filtrate is evaporated under reduced
pressure (2.7 kPa) and the residue is taken up with
25 cm3 of tetrahydrofuran and 25 cm3 of methanol and
1 cm3 of ION sodium hydroxide is added thereto. After
stirring for 3 0 min at a temperature in the region of
2 0°C, the reaction medium is evaporated under reduced
pressure (2.7 kPa) . The reaction crude is taken up in
dichloromethane. The organic phase is washed
successively with water and a saturated aqueous sodium
chloride solution, dried over magnesium sulfate,
filtered and evaporated under reduced pressure
(2.7 kPa) to give an oil which is triturated in
diisopropyl ether. The precipitate formed is filtered
and dried under vacuum (2.7 kPa) to give 3.47 g of
3-benzyloxy-4-(3-nitrophenyl)-1H-pyrazole in the form
of a yellow solid.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 5.40
(s: 2H); 7.36 (broad t, J = 7.5 Hz: 1H); 7.44 (broad t,
J = 7.5 Hz: 2H); 7.55 (broad d, J = 7.5 Hz: 2H) ; 7.64
(t, J = 8 Hz: 1H); 8.00 (dd, J = 8 and 2 Hz: 1H); 8.13
(broad d, J = 8 Hz: 1H) ; 8.33 (s: 1H) ; 8.62 (t, J =
2 Hz: 1H) ; from 12.00 to 12.80 (very broad unresolved
peak: 1H).
The 1-[3-hydroxy-4-(3-nitrophenyl)pyrazol-1-yl]ethanone
can be prepared in the following way:
A solution of 3.8 g of dimethylammonium 4-(3-
nitrophenyl)-1H-pyrazol-3-olate in 40 cm3 of pyridine,

under an argon atmosphere and with stirring, is heated
to 90°C and 1.5 cm3 of acetic anhydride are then added
dropwise. After heating for 1 h at 90°C, the reaction
medium is cooled to a temperature in the region of 20°C
and is poured into 100 cm3 of ice-cold water. The
precipitate formed is filtered, washed 3 times with
water and dried under vacuum (2.7 kPa) to give 4.33 g
of a solid which is used again in reaction with 40 cm3
of pyridine and 0.39 cm3 of acetic anhydride according
to the protocol stated above. 4.1 g of 1-[3-hydroxy-4-
(3-nitrophenyl)pyrazol-1-yl]ethanone are obtained in
the form of a pale yellow solid. IR spectrum (KBr) :
3118; 3082; 2669; 1730; 1604; 1520; 1390; 1349; 1256;
1223; 1101; 748 and 719 cm"1.
The dimethylammonium 4-(3-nitrophenyl)-1H-pyrazol-
3-olate can be prepared in the following way:
A solution, with stirring, of 9.3 g of benzyl ester of
3-dimethylamino-2-(3-nitrophenyl)acrylic acid and
1.4 cm3 of hydrazine monohydrate in 100 cm3 of ethanol
is heated for 3 h at the reflux of the solvent, and
then cooled in an ice bath. The solid formed is
filtered off, washed with water, and dried under vacuum
(2.7 kPa) to give 4.44 g of dimethyl ammonium 4-(3-
nitrophenyl)-1H-pyrazol-3-olate in the form of an
orange-colored solid.
IR spectrum (KBr): 3346; 3199; 3071; 2855; 2685; 2386;
1583; 1538; 1469; 1350; 934; 766; 747 and 681 cm"1.
The benzyl ester of 3-dimethylamino-2-(3-nitrophenyl)-
acrylic acid can be prepared in the following way:
11.5 cm3 of C-tert-butoxy-N,N,N',N'-tetramethylmethane-
diamine is added to a solution of 10 g of benzyl ester
of 2- (3-nitrophenyl) acrylic acid in 100 cm3 of
tetrahydrofuran and the mixture is heated for 15 h at
the reflux of the solvent. After cooling to a

temperature in the region of 20°C, the reaction mixture
is evaporated to dryness under reduced pressure
(2.7 kPa) . The residue is taken up with ethyl acetate
and the organic solution is washed 3 times with water
and then with a saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered and
evaporated under reduced pressure (2.7 kPa) . The brown
oil obtained is purified by flash chromatography on
silica under an argon pressure (50 kPa) [eluent:
cyclohexane/ethyl acetate (70/30 by volume)]. After
concentration of the fractions under reduced pressure,
9.3 g of benzyl ester of 3-dimethylamino-2-(3-
nitrophenyl)acrylic acid are obtained in the form of an
orange-colored oil. Mass spectrum (EI): m/z 326 (M+'),
m/z 235 [ (M - C7H7)+] , m/z 91 (C7H7+) .
Example 3 0
N-{3-[3-Hydroxy-1-(2-dimethylaminoethyl)-1H-pyrazol-4-
yl]phenyl}acetamide dihydrochloride
1.8 cm3 of 3N hydrochloric diethyl ether are added to a
solution of 400 mg of N- {3- [3-benzyloxy-1-(2-
dimethylaminoethyl)-1H-pyrazol-4-yl]phenyl}acetamide in
20 cm3 of ethanol. After stirring for 15 min at a
temperature in the region of 20°C, the solution is
evaporated to dryness under reduced pressure (2.7 kPa) .
The residue is taken up in 20 cm3 of ethanol. The
solution obtained is introduced into an autoclave, and
50 mg of palladium-on-charcoal at 10% are added, and it
is then placed under hydrogen (5 bar) . After stirring
for 2 h at a temperature in the region of 2 0°C, the
reaction medium is filtered over supercel and the
filtrate is evaporated. The yellow oil obtained
(44 0 mg) is dissolved in 2 0 cm3 of ethanol and used
again in reaction with 50 mg of palladium-on-charcoal
at 10%, under hydrogen (5 bar), at 40°C and with
stirring for 4 h. The reaction medium is then filtered

over supercel, the filtrate is evaporated, and the
residue is triturated in diisopropyl ether. The
precipitate formed is filtered, and dried under vacuum
(2.7 kPa) to give 289 mg of N-{3-[3-hydroxy-1- (2-
dimethylaminoethyl)-1H-pyrazol-4-yl]phenyl}acetamide
dihydrochloride in the form of a pale yellow solid.
IR spectrum (KBr): 3242; 3130; 2967; 2573; 2464; 1678;
1614; 1588; 1525; 1462; 1258; 1187; 787 and 690 cm"1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 2.05
(s: 3H); 2.80 (broad s: 6H); 3.48 (broad t, J = 6.5 Hz:
2H) ; 4.35 (broad t, J = 6.5 Hz: 2H) ; 7.23 (t, J =
7.5 Hz: 1H) ; 7.31 (broad d, J = 7.5 Hz: 1H) ; 7.38
(broad d, J = 7.5 Hz: 1H); 7.89 (broad S: 1H); 7.95 (s:
1H) ; from 9.60 to 9.85 (broad unresolved peak: 1H) ;
9.91 (broad s: 1H); 10.45 (broad s: 1H).
The N-{3-[3-benzyloxy-1-(2-dimethylaminoethyl)-1H-
pyrazol-4-yl]phenyl}acetamide can be prepared in the
following way:
0.116 cm3 of acetyl chloride is added to a solution of
500 mg of 3-[3-benzyloxy-1-(2-dimethylaminoethyl)-1H-
pyrazol-4-yl]phenylamine and 0.418 cm3 of triethylamine
in 2 0 cm3 of dichloromethane under an argon atmosphere
and with stirring, while maintaining the temperature of
the medium at 5°C. After stirring for 15 h at a
temperature in the region of 20°C, a further 0.1 cm3 of
triethylamine and 0.1 cm3 of acetyl chloride are added
to the reaction mixture and the reaction is continued
for 2 -h. The reaction medium is then washed
successively twice with water and a saturated aqueous
sodium chloride solution, dried over magnesium sulfate,
filtered and evaporated under reduced pressure
(2.7 kPa) to give 540 mg of N-{3-[3-benzyloxy-1-(2-
dimethylaminoethyl)-1H-pyrazol-4-yl]phenyl}acetamide in
the form of a yellow oil.

IR spectrum (CC14) : 3444; 3305; 2945; 2822; 2773; 1670;
1614; 1588; 1549; 1502; 1452; 1423; 1357; 1177; 1018;
695 and 537 cm"1.
The 3-[3-benzyloxy-1-(2-dimethylaminoethyl)-1H-pyrazol-
4-yl]phenylamine can be prepared in the following way:
A solution of 1.1 g of {2-[3-benzyloxy-4-(3-
nitrophenyl)pyrazol-1-yl]ethyl}dimethylamine in 15 cm3
of ethanol is added to a mixture, with stirring, of
84 0 mg of iron powder, 2 00 mg of ammonium chloride in
15 cm3 of ethanol and 15 cm3 of water, heated at the
reflux of the solvent. The stirring is continued for
3 h at the reflux of the solvent and then for 15 h at a
temperature in the region of 2 0°C. The reaction mixture
is filtered and the filtrate is evaporated. The residue
is taken up with a mixture of ethyl acetate, water and
IN sodium hydroxide. The organic phase is separated by
settling out, washed successively with water and a
saturated aqueous sodium chloride solution, dried over
magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa) to give 1 g of 3-[3-
benzyloxy-1-(2-dimethylaminoethyl)-1H-pyrazol-4-
yl] phenyl amine in the form of an orange-colored oil.
Mass spectrum (EI): m/z 336 (M+-) , m/z 265 [ (M - C7H7)+] ,
m/z 91(C7H7+), m/z 71(C4H9N+-), m/z 58 (C3H8N+) .
Example 31
4-(4-Aminophenyl)-1-(2-dimethylaminoethyl)-1H-pyrazol-
3-ol dihydrochloride
1.2 cm3 of 3N hydrochloric diethyl ether are added to a
solution of 250 mg of {2-[3-benzyloxy-4-(4-nitro-
phenyl)pyrazol-1-yl]ethyl}dimethylamine in 2 0 cm3 of
ethanol. After stirring for 2 0 minutes at a temperature
in the region of 20°C, the solution is evaporated to
dryness under reduced pressure (2.7 kPa) . The residue

is taken up with 20 cm3 of ethanol. The solution
obtained is introduced into an autoclave and 3 6 mg of
palladium-on-charcoal at 10% are added, and it is then
placed under hydrogen (7 bar) . After stirring for 5 h
at 40°C, the reaction medium is filtered over supercel,
the filtrate is evaporated and the residue is
triturated in diisopropyl ether. The precipitate formed
is filtered, and dried under vacuum (2.7 kPa) to give
169 mg of 4-(4-aminophenyl)-1-(2-dimethylaminoethyl)-
lH-pyrazol-3-ol dihydrochloride in the form of a yellow
solid.
IR spectrum (KBr): 3372; 3296; 3205; 3025; 1627; 1592,
1522; 1514; 1451; 1280; 1177; 828; 612 and 525 cm"1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 2.75
(s: 6H) ; 3.42 (mt: 2H) ; 4.27 (t, J = 6 Hz: 2H) ; from
4.70 to 5.30 (broad unresolved peak: 2H); 6.55 (d, J =
8.5 Hz: 2H) ; 7.31 (d, J = 8.5 Hz: 2H) ; 7.75 (s: 1H) ;
10.08 (unresolved peak: 1H).
The {2-[3-benzyloxy-4-(4-nitrophenyl)pyrazol-1-yl]-
ethyl}dimethylamine can be prepared in the following
way:
A solution of 3 g of 3-benzyloxy-4-(4-nitrophenyl)-1H-
pyrazole in 50 cm3 of dimethylformamide is added to a
suspension of 980 mg of sodium hydride (at 75% in
liquid petroleum jelly) in 50 cm3 of dimethylformamide
under an argon atmosphere and with stirring. After
heating for 3 0 min at 50°C, the mixture is stirred for
1 h at a temperature in the region of 2 0°C and is then
cooled in an ice bath and a solution of 4.7 g of
(2-bromoethyl)dimethylamine hydrobromide in 50 cm3 of
dimethylformamide is added. The reaction medium is
stirred for 15 h at a temperature in the region of 20°C
and is then poured into 4 00 cm3 of water. The aqueous
phase is extracted twice with ethyl acetate. The
organic phases are pooled, washed successively with
water twice and a saturated aqueous sodium chloride

solution, dried over magnesium sulfate, filtered and
evaporated under reduced pressure (2.7 kPa) to give an
ofange-colored oil which is purified by flash
chromatography on silica under an argon pressure
(50 kPa) [eluent: ethyl acetate, then ethyl
acetate/methanol (90/10 by volume)]. After
concentration of the fractions under reduced pressure,
1.2 g {2-[3-benzyloxy-4-(4-nitrophenyl)pyrazol-1-yl]-
ethyl}dimethylamine are obtained in the form of a brown
oil. Mass spectrum (EI): m/z 366 (M+-), m/z 91 (C7H7+) ,
m/z 71 (C4H9N+-), m/z 58 (C3H8N+) .
The 3-benzyloxy-4-(4-nitrophenyl)-1H-pyrazole can be
prepared in the following way:
3 g of potassium carbonate and 2.2 cm3 of benzyl
bromide are added to a suspension of 4.5 g of l-[3-
hydroxy-4-(4-nitrophenyl)pyrazol-1-yl]ethanone in
50 cm3 of methyl ethyl ketone with stirring. The
mixture is heated at the reflux of the solvent for
2.5 h, cooled to a temperature in the region of 20°C,
and filtered. The filtrate is evaporated under reduced
pressure (2.7 kPa) and the residue is taken up with
25 cm3 of tetrahydrofuran and 25 cm3 of methanol, and
2 cm3 of ION sodium hydroxide are then added. After
stirring for 3 0 min at a temperature in the region of
20°C, the reaction medium is evaporated under reduced
pressure (2.7 kPa) . The reaction crude is taken up in
dichloromethane. The organic phase is washed
successively with water and a saturated aqueous sodium
chloride solution, dried over magnesium sulfate,
filtered and evaporated under reduced pressure
(2.7 kPa) to give an oil which is triturated in
diisopropyl ether. The precipitate formed is filtered
and dried under vacuum (2.7 kPa) to give 3 g of
3-benzyloxy-4-(4-nitrophenyl)-1H-pyrazole in the form
of an ochre solid.

1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 5.41
(s: 2H); from 7.3 0 to 7.60 (mt: 5H); 7.97 (d, J = 9 Hz:
2H) ; 8.23 (d, J = 9 Hz: 2H) ; 8.36 (s: 1H) ; 12.49
(unresolved peak: 1H).
The 1-[3-hydroxy-4-(4-nitrophenyl)pyrazol-1-yl]-
ethanone can be prepared in the following way:
A solution of 4.85 g of dimethylammonium 4-(4-
nitrophenyl)-1H-pyrazol-3-olate in 40 cm3 of pyridine,
under an argon atmosphere and with stirring, is heated
to 90°C and 2 cm3 of acetic anhydride are then added
dropwise. After heating for 1 h at 90°C, the reaction
medium is cooled to a temperature in the region of 2 0°C
and is poured into 100 cm3 of ice-cold water. The
precipitate formed is filtered, washed three times with
water, and dried under vacuum (2.7 kPa) to give 4.5 g
of 1-[3-hydroxy-4-(4-nitrophenyl)pyrazol-1-yl]ethanone
in the form of a yellow solid.
IR spectrum (KBr): 3370; 3128; 2980; 2587; 1721; 1615;
1600; 1509; 1341; 1224; 1111; 855; 757 and 643 cm"1.
The dimethylammonium 4-(4-nitrophenyl)-1H-pyrazol-
3-olate can be prepared in the following way:
A solution, with stirring, of 10.7 g of methyl ester of
3-dimethylamino-2-(4-nitrophenyl)acrylic acid and of
2.1 cm3 of hydrazine monohydrate in 120 cm3 of ethanol
is heated for 3 h at the reflux of the solvent, and
cooled in an ice bath. The solid formed is filtered,
rinsed with diisopropyl ether, and dried under vacuum
(2.7 kPa) to give 5 g of dimethylammonium 4- (4-nitro-
phenyl) -1H-pyrazol- 3 -olate in the form of an orange-
colored solid.
IR spectrum (KBr): 3188; 3089; 2909; 2728; 2423; 1603;
1589; 1567; 1538; 1501; 1345; 1330; 1212; 1112; 923;
880; 761 and 581 cm"1.

The methyl ester of 3-dimethylamino-2-(4-nitrophenyl)-
acrylic acid can be prepared in the following way:
16.6 cm3 of C-tert-butoxy-N,N,N',N'-tetramethylmethane-
diamine are added to a solution of 10.5 g of methyl
ester of 2-(4-nitrophenyl) acrylic acid in 100 cm3 of
tetrahydrofuran, and the mixture is heated for 2.5 h at
the reflux of the solvent. After stirring for 15 h at a
temperature in the region of 2 0°C, the reaction mixture
is evaporated to dryness under reduced pressure
(2.7 kPa) . The residue is taken up with ethyl acetate
and the organic solution is washed with three times
water, and then dried over magnesium sulfate, filtered
and evaporated under reduced pressure (2.7 kPa) to give
10.7 g of methyl ester of 3-dimethylamino-2-(4-
nitrophenyl)acrylic acid in the form of a brown oil.
IR spectrum (CC14) : 2949; 1693; 1603; 1519; 1433; 1344;
1219; 1095; 1048 and 855 cm"1.
Example 32
1-(2-Dimethylaminoethyl)-4-(4'-fluorobiphenyl-3-yl)-1H-
pyrazol-3-ol dihydrochloride
1.2 cm3 of 3N hydrochloric diethyl ether are added to a
solution of 300 mg of {2-[3-benzyloxy-4-(4'-fluoro-
biphenyl-3-yl)pyrazol-1-yl]ethyl}dimethylamine in 2 0 cm3
of ethanol. After stirring for 3 0 min at a temperature
in the region of 20°C, the solution is evaporated to
dryness under reduced pressure (2.7 kPa). The residue
is taken up with 20 cm3 of ethanol. The solution
obtained is introduced into an autoclave and 14 mg of
palladium-on-charcoal at 10% are added, and it is then
placed under hydrogen (7 bar) . After stirring for 5 h
at 30°C, the reaction medium is filtered over supercel,
and the filtrate is evaporated. Diisopropyl ether is
added to the residue, resulting in a suspension, which

is heated at the reflux of the solvent and filtered
under hot conditions. The resulting solid is dried
under vacuum (2.7 kPa) to give 84 mg of l-(2-
dimethylaminoethyl)-4-(4'-fluorobiphenyl-3-yl)-1H-
pyrazol-3-ol dihydrochloride in the form of a white
powder.
IR spectrum (KBr): 3049; 2962; 2682; 2355; 1608; 1514;
1460; 1221; 1184; 1162; 843; 804; 703 and 560 cm"1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 2.76
(broad s: 6H); 3,45 (mt: 2H); 4.32 (broad t, J = 6 Hz:
2H) ; 7.32 (t, J = 8.5 Hz: 2H) ; from 7.35 to 7.50 (mt:
2H); 7.66 (mt: 1H); 7.70 (dd, J = 9 and 6 Hz: 2H); 7.90
(broad s: 1H) ; 8.14 (s: 1H) ; 9.76 (unresolved peak:
1H) ; 10.50 (broad s: 1H) .
The {2-[3-benzyloxy-4-(4'-fluorobiphenyl-3-yl)pyrazol-
1-yl]ethyl}dimethylamine can be prepared in the
following way:
860 mg of 4-f luorophenylboronic acid, 1.3 g of
potassium phosphate and 330 mg of bis (triphenyl-
phosphine)palladium chloride are added to a stirred
solution of 620 mg of {2-[3-benzyloxy-4-(3 -
bromophenyl)pyrazol-1-yl]ethyl}dimethylamine in 25 cm3
of toluene under an argon atmosphere. After heating at
the reflux of the solvent for 15 h, the reaction medium
is cooled to a temperature in the region of 20°C, ethyl
acetate and water are added, and the mixture is
filtered over supercel. The filtrate is separated by
settling out and the organic phase is then washed
successively with 0.5N sodium hydroxide, water and a
saturated aqueous sodium chloride solution; it is dried
over magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa) . The brown oil obtained
(1.3 g) is purified by flash chromatography on alumina
CRB1 under an argon pressure (50 kPa) [eluent:
cyclohexane/ethyl acetate (80/20 by volume)]. After
concentration of the fractions under reduced pressure,

300 mg of {2-[3-benzyloxy-4-(4'-fluorobiphenyl-3-yl)-
pyrazol-1-yl]ethyl}dimethylamine are obtained in the
form of a yellow oil.
IR spectrum (CC14): 2823; 2773; 1610; 1571; 1515; 1462;
1358; 1235; 1158; 1014; 837; 696 and 559 cm"1.
The {2-[3-benzyloxy-4-(3-bromophenyl)pyrazol-1-yl]-
ethyl}dimethylamine can be prepared in the following
way:
A solution of 7.67 g of 3-benzyloxy-4-(3-bromophenyl)-
lH-pyrazole in 7 0 cm3 of dimethylformamide is added to a
suspension of 2.25 g of sodium hydride (at 75% in
liquid petroleum jelly) in 70 cm3 of dimethylformamide
under an argon atmosphere and with stirring. After
heating for 3 0 min at 50°C, the mixture is stirred for
1 h at a temperature in the region of 20°C and is then
cooled in an ice bath and a solution of 10.85 g of
(2-bromoethyl)dimethylamine hydrobromide in 100 cm3 of
dimethylformamide is added. The reaction medium is
stirred for 15 h at a temperature in the region of
20°C, and for 3 h at 50°C, and is then cooled to a
temperature in the region of 20°C and poured into 500
cm3 of water. The aqueous phase is extracted twice with
ethyl acetate. The organic phases are pooled, washed
successively with water twice and a saturated aqueous
sodium chloride solution, dried over magnesium sulfate,
filtered and evaporated under reduced pressure (2.7
kPa) to give an orange-colored oil which is purified by
flash chromatography on silica under an argon pressure
(50 kPa) [eluent: ethyl acetate, ethyl acetate/methanol
(90/10 by volume)]. After concentration of the
fractions under reduced pressure, 2.4 g of {2-[3-
benzyloxy-4-(3-bromophenyl)pyrazol-1-yl]ethyl}dimethyl-
amine are obtained in the form of an orange-colored
oil.
Mass spectrum (CI): m/z 400 (MH+) , m/z 322 [(M -
Br + 2H)+] .

The 3-benzyloxy-4-(3-bromophenyl)-1H-pyrazole can be
prepared in the following way:
2.6 g of potassium carbonate and 2.05 cm3 of benzyl
bromide are added to a suspension of 4.4 g of l-[3-
benzyloxy-4-(3-bromophenyl)pyrazol-1-yl]ethanone in
50 cm3 of methyl ethyl ketone with stirring. The mixture
is heated at the reflux of the solvent for 2.5 h,
cooled to a temperature in the region of 20°C, and
filtered. The filtrate is evaporated under reduced
pressure (2.7 kPa) , and the residue is taken up with
25 cm3 of tetrahydrofuran and 25 cm3 of methanol, and
1 cm3 of 10N sodium hydroxide is then added. After
stirring for 3 0 min at a temperature in the region of
2 0°C, the reaction medium is evaporated under reduced
pressure (2.7 kPa) . The reaction crude is taken up in
dichloromethane. The organic phase is washed
successively with water twice and a saturated aqueous
sodium chloride solution, dried over magnesium sulfate,
filtered and evaporated under reduced pressure
(2.7 kPa) to give an oil which is purified by flash
chromatography on silica under an argon pressure
(50 kPa) [eluent: cyclohexane/ethyl acetate (80/20 by
volume)]. After concentration of the fractions under
reduced pressure, 3.3 g of 3-benzyloxy-4-(3 -
bromophenyl)-1H-pyrazole are obtained in the form of a
cream solid.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 5.35
(s: 2H); from 7.25 to 7.40 (mt: 3H); 7.42 (broad t, J =
7.5 Hz: 2H); 7.51 (broad d, J = 7.5 Hz: 2H); 7.71 (dt,
J = 7.5 and 2 Hz: 1H) ; 7.93 (broad s: 1H) ; 8.18 (s:
1H); 12.25 (unresolved peak: 1H).
The 1-[4-(3-bromophenyl)-3-hydroxypyrazol-1-yl]ethanone
can be prepared in the following way:

A solution of 4.3 g of 4-(3-bromophenyl)-1H-pyrazol-
3-ol in 4 0 cm3 of pyridine, under an argon atmosphere
and with sti rring, is heated to 90°C and 1.6 cm3 of
acetic anhydride are then added dropwise. After heating
for 1 h at 90°C, the reaction medium is cooled to a
temperature in the region of 2 0°C and is poured into
100 cm3 of ice-cold water. The precipitate formed is
filtered, washed three times with water and dried under
vacuum (2.7 kPa) to give 4.42 g of l-[4-(3-
bromophenyl)-3-hydroxypyrazol-1-yl]ethanone in the form
of a cream solid.
IR spectrum (KBr): 3125; 2687; 2577; 1729; 1616; 1529;
1391; 1318; 1256; 1219; 945; 791; 715 and 629 cm"1.
The 4-(3-bromophenyl)-1H-pyrazol-3-ol can be prepared
in the following way:
A solution, with stirring, of 12.22 g of methyl ester
of 2-(3-bromophenyl)-3-dimethylaminoacrylic acid and of
2.1 cm3 of hydrazine monohydrate in 100 cm3 of ethanol
is heated at the reflux of the solvent for 3 h. The
reaction mixture is evaporated to dryness under reduced
pressure (2.7 kPa) and the residue is triturated in
diisopropyl ether. The solid formed is filtered and is
dried under vacuum (2.7 kPa) to give 5.1 g of
dimethylammonium 4-(3-bromophenyl)-1H-pyrazol-3-olate
in the form of a cream solid. The filtrate is
evaporated under reduced pressure (2.7 kPa), the
residue is triturated in diisopropyl ether, and the
solid formed is filtered and dried under vacuum
(2.7 kPa) , resulting in 4.3 g of 4-(3-bromophenyl)-1H-
pyrazol-3-ol in the form of a cream solid.
IR spectrum (KBr): 3099; 2768; 2668; 1620; 1590; 1410;
1241; 1081; 787; 712 and 689 cm"1.
The methyl ester of 2-(3-bromophenyl)-3-dimethylamino-
acrylic acid can be prepared in the following way:

14.4 cm3 of C-tert-butoxy-N,N,N',N'-tetramethylmethane-
diamine are added to a solution of 10.5 g of methyl
ester of 2- (3-bromophenyl) acrylic acid in 100 cm3 of
tetrahydrofuran and the mixture is heated at the reflux
of the solvent for 2.5 h. After stirring for 15 h at a
temperature in the region of 20°C, the reaction mixture
is evaporated to dryness under reduced pressure
(2.7 kPa) . The residue is taken up with ethyl acetate,
and the organic solution is washed with 3 times water,
and then dried over magnesium sulfate, filtered and
evaporated under reduced pressure (2.7 kPa) to give
12.22 g of methyl ester of 2-(3-bromophenyl)-3-
dimethylaminoacrylic acid in the form of a yellow oil.
IR spectrum (CCl4) : 2947; 2813; 1691; 1603; 1432; 1285;
1221; 1098 and 694 cm-1.
Example 33
4-Biphenyl-3-yl-1-(2-dimethylaminoethyl)-1H-pyrazol-
3-ol dihydrochloride
1 cm3 of 3N hydrochloric diethyl ether is added to a
solution of 121 mg of {2- [3-benzyloxy^-biphenyl-
3-ylpyrazol-1-yl] ethyl }dimethylamine in 2 0 cm3 of
ethanol. After stirring for 3 0 min at a temperature in
the region of 20°C, the solution is evaporated to
dryness under reduced pressure (2.7 kPa). The residue
is taken up with 2 0 cm3 of ethanol. The solution
obtained is introduced into an autoclave, 11 mg of
palladium-on-charcoal at 10% are added, and it is then
placed under hydrogen (7 bar) . After stirring for 5 h
at 30°C, the reaction medium is filtered over supercel,
and the filtrate is evaporated. Diisopropyl ether is
added to the residue, resulting in a suspension which
is heated at the reflux of the solvent and filtered
under hot conditions. The resulting solid is dried
under vacuum (2.7 kPa) to give 69 mg of 4-biphenyl-

3-yl-1-(2-dimethylaminoethyl)-1H-pyrazol-3-ol
dihydrochloride in the form of a white powder.
IR spectrum (KBr) : 3054; 2959; 2685; 2299; 1606; 1522;
1457; 1298; 1182; 760; 698 and 671 cm"1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 2.79
(unresolved peak: 6H) ; 3.43 (unresolved peak: 2H) ;
4.31 (unresolved peak: 2H) ; from 7.25 to 7.55 (mt: 5H) ;
7.68 (mt: 3H) ; 7.94 (broad s: 1H) ; 8.15 (s: 1H) ; from
9.45 to 9.65 (broad unresolved peak: 1H) ; 10.49 (broad
s: 1H).
The {2-[3-benzyloxy-4-biphenyl-3-ylpyrazol-1-yl]ethyl}-
dimethylamine can be prepared in the following way:
503 mg of phenylboronic acid, 8 91 mg of potassium
phosphate and 217 mg of bis(triphenylphosphine)-
palladium chloride are added to a stirred solution of
550 mg of {2-[3-benzyloxy-4-(3-bromophenyl)pyrazol-1-
yl]ethyl}dimethylamine in 2 5 cm3 of toluene under an
argon atmosphere. After heating at the reflux of the
solvent for 15 h, 168 mg of phenylboronic acid, 297 mg
of potassium phosphate and 148 mg of bis(triphenyl-
phosphine) palladium chloride are added to the reaction
medium and the reaction is continued at the same
temperature for 15 h. The mixture is then cooled to a
temperature in the region of 2 0°C, ethyl acetate and
water are added, and it is filtered over supercel. The
filtrate is separated by settling out, and the organic
phase is then washed successively with 0. 5N sodium
hydroxide, water and a saturated aqueous sodium
chloride solution; it is dried over magnesium sulfate,
filtered and evaporated under reduced pressure
(2.7 kPa) . The brown oil obtained (1.2 g) is purified
by flash chromatography on alumina CTB1 under an argon
pressure (50 kPa) [eluent: cyclohexane/ethyl acetate
(8 0/2 0 by volume)]. After concentration of the
fractions under reduced pressure, 3 00 mg of an orange-
colored oil are obtained, which is again used in a

with 50 cm3 of water and extracted with 2 00 cm3 of ethyl
acetate. The organic phase is washed with 3 times 25 cm3
of water, and is then dried, filtered and concentrated
to dryness under reduced pressure (3 kPa) . The oily
residue obtained is purified by chromatography on
silica gel (particle size 15-35 µm) , eluting with a
mixture of dichloromethane and methanol (96/4 by
volume). After concentration of the fractions under
reduced pressure, 0.72 g of 1- [2-(3-benzyloxy-4-
phenylpyrazol-1-yl)ethyl]perhydroazepine is obtained in
the form of a colorless viscous oil, which is used as
it is in the following step. Mass spectrum (EI) : m/z
375 (M+) , m/z 112 (base peak) .
The 1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-
phenylpyrazol-1-yl)ethyl can be prepared in the
following way:
59 cm3 of triethylamine are added dropwise, at ambient
temperature, to a suspension of 13.7 g of
2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethanol hydro-
chloride in 400 cm3 of dichloromethane. The reaction
mixture is cooled to around 5°C and a solution of
22.5 g of toluene-4-sulfonyl chloride in 200 cm3 of
dichloromethane is added, over 0.5 hours. After
stirring for 16 hours at ambient temperature, the
mixture is concentrated to dryness under reduced
pressure (3 kPa) . The residue is taken up with 100 cm3
of water and extracted with (500 + 250) cm3 of ethyl
acetate. The pooled organic phases are washed with 3
times 100 cm3 of water, and then dried over anhydrous
magnesium sulfate, filtered and concentrated to dryness
under reduced pressure (3 kPa). The oily residue
obtained is purified by chromatography on silica gel
(particle size 15-35 µm) , eluting with dichloromethane
and then a mixture of dichloromethane and methanol
(95/5 by volume). After concentration of the fractions
under reduced pressure, 19 g of 1-[(toluene-4-

reaction for 15 h with 25 cm3 of toluene, 503 mg of
phenylboronic acid, 891 mg of potassium phosphate and
217 mg of bis(triphenylphosphine)palladium chloride
according to the protocol described above. A brown oil
is obtained (800 mg), which is purified by flash
chromatography on alumina CTB1 under an argon pressure
(50 kPa) [eluent: cyclohexane/ethyl acetate (80/20 by
volume)]. After concentration of the fractions under
reduced pressure (2.7 kPa), 120 mg of {2-[3-benzyloxy-
4-biphenyl-3-yl-pyrazol-1-yl]ethyl}dimethylamine are
obtained in the form of a yellow oil.
IR spectrum (CC14) : 3065; 3033; 2823; 2774; 1609; 1579;
1505; 1450; 1240 and 699 cm"1.
Example 34
1-(2-Dimethylaminoethyl)-4-(4'-fluorobiphenyl-4-yl)-1H-
pyrazol-3-ol dihydrochloride
0.06 cm3 of 12N hydrochloric acid is added to a solution
of 200 mg of {2-[3-benzyloxy-4-(4'-fluorobiphenyl-
4-yl)pyrazol-1-yl]ethyl}dimethylamine in 2 0 cm3 of
ethanol. The mixture is introduced into an autoclave,
28 mg of palladium-on-charcoal at 10% are added, and it
is then placed under hydrogen (5 bar) . After stirring
for 4 h at 40°C, the reaction medium is filtered over
supercel and the filtrate is evaporated. The residue is
triturated in diisopropyl ether. The solid obtained,
dissolved in 20 cm3 of ethanol, is used again in a
reaction in an autoclave with 10 mg of palladium-on-
charcoal at 10% and under hydrogen (7 bar). After
stirring for 5 h at 35°C, the reaction mixture is
filtered over supercel and the filtrate is evaporated.
The residue is triturated in diisopropyl ether,
filtered and dried under vacuum (2.7 kPa) to give 77 mg
of 1-(2-dimethylaminoethyl)-4-(4'-fluorobiphenyl-4-yl)-
lH-pyrazol-3-ol dihydrochloride in the form of a beige
solid.

IR spectrum (KBr): 2964; 2676; 2468; 1611; 1585; 1528;
1514; 1493; 1460; 1234; 1161; 826; 810 and 511 cm'1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 2.79
(broad s: 6H); 3.48 (unresolved peak: 2H); 4.36 (broad
t, J = 6,5 Hz: 2H) ; 7.3 0 (broad t, J = 9 Hz: 2H) ; 7 . 65
(broad d, J = 8 Hz: 2H) ; from 7.70 to 7.80 (mt: 4H) ;
8.09 (s: 1H); 9.92 (unresolved peak: 1H); 10.52 (broad
S: 1H).
The {2-[3-benzyloxy-4-(4'-fluorobiphenyl-4-yl)pyrazol-
l-yl] ethyl}dimethylamine can be prepared in the
following way:
770 mg of 4-fluorophenylboronic acid, 1.19 g of
potassium phosphate and 2 90 mg of
bis(triphenylphosphine)palladium chloride are added to
a stirred solution of 500 mg of {2-[3-benzyloxy-4-(4-
bromophenyl)pyrazol-1-yl]ethyl}dimethylamine in 25 cm3
of toluene under an argon atmosphere. After heating at
the reflux of the solvent for 15 h, the reaction
mixture is cooled to a temperature in the region of
20°C, ethyl acetate and water are added, and it is
filtered over supercel. The filtrate is separated by
settling out, and the organic phase is then washed
successively with 0.5N sodium hydroxide, water and a
saturated aqueous sodium chloride solution; it is dried
over magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa) . The brown oil obtained
(800 mg) is purified by flash chromatography on alumina
CTB1 under an argon pressure (50 kPa) [eluent:
cyclohexane/ethyl acetate (80/20 by volume)]. After
concentration of the fractions under reduced pressure
(2.7 kPa), 220 mg of {2-[3-benzyloxy-4-(4'-fluoro-
biphenyl-4-yl)pyrazol-1-yl]ethyl}dimethylamine are
obtained in the form of a yellow oil.
Mass spectrum (EI) : m/z 415 (M+'), m/z 344 [ (M
C4H9N)+], m/z 91 (C7H7+) , m/z 58 (C3H8N+) .

The {2-[3-benzyloxy-4-(4-bromophenyl)pyrazol-1-yl]-
ethyl}dimethylamine can be prepared in the following
way:
A solution of 5.2 g of 3-benzyloxy-4-(4-bromophenyl)-
lH-pyrazole in 50 cm3 of dimethylformamide is added to a
suspension of 1.36 g of sodium hydride (at 75% in
liquid petroleum jelly) in 50 cm3 of dimethyl formamide
under an argon atmosphere and with stirring. After
heating at 50°C for 30 min, the mixture is stirred for
1 h at a temperature in the region of 20°C, and is then
cooled in an ice bath and a solution of 5.5 g of
(2-bromoethyl)dimethylamine in 50 cm3 of
dimethylformamide is added. The reaction medium is
stirred for 15 h at a temperature in the region of
20°C, and is then cooled to a temperature in the region
of 2 0°C and poured into 4 00 cm3 of water. The aqueous
phase is extracted twice with ethyl acetate. The
organic phases are pooled, washed successively with
water twice and a saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered and
evaporated under reduced pressure (2.7 kPa) to give a
brown oil which is purified by flash chromatography on
silica under an argon pressure (50 kPa) [eluent: ethyl
acetate, ethyl acetate/methanol (90/10 by volume)].
After concentration of the fractions under reduced
pressure, 2.3 g of {2-[3-benzyloxy-4-(4-
bromophenyl)pyrazol-1-yl]ethyl}dimethylamine are
obtained in the form of a yellow oil.
Mass spectrum (EI): m/z 399 (M+'), m/z 328 [ (M -
C4H9N)+], m/z 91 (C7H7+"), m/z 58 (C3H8N+) .
The 3-benzyloxy-4-(4-bromophenyl)-1H-pyrazole can be
prepared in the following way:
3.88 g of potassium carbonate and 3.1 cm3 of benzyl
bromide are added to a suspension of 6.58 g de l-[3-
benzyloxy-4-(4-bromophenyl)pyrazol-1-yl]ethanone in

70 cm3 of methyl ethyl ketone with stirring. The mixture
is heated at the reflux of the solvent for 2.5 h,
caoled to a temperature in the region of 2 0°C, and
filtered. The filtrate is evaporated under reduced
pressure (2.7 kPa) , and the residue is taken up with
50 cm3 of tetrahydrofuran and 50 cm3 of methanol and
1.5 cm3 of ION sodium hydroxide are then added. After
stirring for 3 0 min at a temperature in the region of
20°C, the reaction medium is evaporated under reduced
pressure (2.7 kPa) . The reaction crude is taken up in
dichloromethane. The organic phase is washed
successively with two times water and a saturated
aqueous sodium chloride solution, dried over magnesium
sulfate, filtered and evaporated under reduced pressure
(2.7 kPa) . The solid obtained is triturated in
diisopropyl ether, filtered and dried under vacuum
(2.7 kPa) to give 2.9 g of 3-benzyloxy-4-(4-bromo-
phenyl)-1H-pyrazole in the form of a beige solid. The
filtrate is evaporated under reduced pressure (2.7 kPa)
and the residue is taken up with dichloromethane. The
organic solution is washed with water and a saturated
aqueous sodium chloride solution, dried over magnesium
sulfate, filtered and evaporated under reduced pressure
(2.7 kPa) . The resulting solid is triturated in
diisopropyl ether, filtered and dried under vacuum
(2.7 kPa) to give a further 2.3 g of 3-benzyloxy-4- (4-
bromophenyl)-1H-pyrazole in the form of a beige solid.
1H NMR spectrum (400 MHz, (CD3)2SO d6, δ in ppm) : 5.35
(s: 2H) ; 7.35 (broad t, J = 7.5 Hz: 1H) ; 7.42 (broad
t, J = 7.5 Hz: 2H) ; 7.50 (broad d, J = 7.5 Hz: 2H) ;
7.51 (broad d, J = 8.5 Hz: 2H) ; 7.65 (broad d, J =
8.5 Hz: 2H); 8.09 (s: 1H).
The 1- [4-(4-bromophenyl)-3-hydroxypyrazol-1-yl]ethanone
can be prepared in the following way:
A solution of 6 g of 4-(4-bromophenyl)-1H-pyrazol-3-ol
in 50 cm3 of pyridine, under an argon atmosphere and

with stirring, is heated to 90°C, and 2.25 cm3 of acetic
anhydride are then added dropwise. After heating at
90°C for 1 h, the reaction medium is cooled to a
temperature in the region of 2 0°C and poured into
150 cm3 of ice-cold water. The precipitate formed is
filtered, washed three times with water and dried under
vacuum (2.7 kPa) to give 6.6 g of 1-[4-(4-bromophenyl)-
3-hydroxypyrazol-1-yl] ethanone in the form of a white
solid.
IR spectrum (KBr): 3132; 2968; 2696; 2653; 1714; 1621;
1533; 1417; 1392; 1328; 1279; 1231; 1008; 949; 822; 645
and 508 cm"1.
The 4-(4-bromophenyl)-1H-pyrazol-3-ol can be prepared
in the following way:
A solution, with stirring, of 11.5 g of ethyl ester of
2-(4-bromophenyl)-3-dimethylaminoacrylic acid and of
1.9 cm3 of hydrazine monohydrate in 100 cm3 of ethanol is
heated at the reflux of the solvent for 3 h. The
reaction mixture is evaporated to dryness under reduced
pressure (2.7 kPa) and the residue is triturated in
diisopropyl ether. The solid formed is filtered and is
dried under vacuum (2.7 kPa) to give 6 g of 4-(4-
bromophenyl)-1H-pyrazol-3-ol in the form of a white
solid.
IR spectrum (KBr): 3299; 3123; 2958; 2674; 1606; 1579;
1517; 1488; 1399; 1163; 1080; 1008; 824 and 509 cm"1.
The ethyl ester of 2-(4-bromophenyl)-3-dimethylamino-
acrylic acid can be prepared in the following way:
13.5 cm3 of C-tert-butoxy-N,N,N',N'-tetramethylmethane-
diamine are added to a solution of 10 g of ethyl ester
of 2-(4-bromophenyl) acrylic acid in 100 cm3 of
tetrahydrofuran and the mixture is heated at the reflux
of the solvent for 3 h. After stirring for 15 h at a
temperature in the region of 20°C, the reaction mixture

is evaporated to dryness under reduced pressure
(2.7 kPa) . The residue is taken up with ethyl acetate,
and the organic solution is washed 3 times with water
and then dried over magnesium sulfate, filtered and
evaporated under reduced pressure (2.7 kPa) to give
11.3 g of ethyl ester of 2-(4-bromophenyl)-3-
dimethylaminoacrylic acid in the form of a yellow oil.
Mass spectrum (CI) : m/z 298 (MH+) .
Example 3 5
1-(2-Piperidin-1-ylethyl)-4-pyridin-2-yl-1H-pyrazol-
3-ol dihydrochloride
10 cm3 of 4N hydrochloric dioxane are added to a
solution of 1.6 g of 2-[3-(cyclohex-2-enyloxy)-1-(2-
piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridine in 20 cm3
of dioxane. After stirring for 15 h at a temperature in
the region of 2 0°C, the suspension is filtered, and the
solid is rinsed once with dioxane and then three times
with diisopropyl ether, and is dried under vacuum
(2.7 kPa) to give 55 mg of 1-(2-piperidin-1-ylethyl)-4-
pyridin-2-yl-1H-pyrazol-3-ol dihydrochloride in the
form of a white powder.
IR spectrum (KBr): 3037; 2943; 2644; 2541; 1633; 1606;
1577; 1454; 1179; 782 and 685 cm-1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 1.40
(mt: 1H) ; from 1.60 to 1.90 (mt: 5H) ; 2.95 (mt: 2H) ;
from 3.35 to 3.55 (mt : 4H) ; 4.57 (t, J = 6.5 Hz: 2H) ;
7.58 (mt: 1H) ; 8.15 (broad d, J = 7 Hz: 1H) ; 8.31
(broad t, J = 7 Hz: 1H); 8.61 (broad d, J = 5 Hz: 1H);
8.69 (broad s: 1H); 10.64 (unresolved peak: 1H).
The 2-[3-(cyclohex-2-enyloxy)-1-(2-piperidin-1-yl-
ethyl) -1H-pyrazol -4 -yl] pyridine can be prepared in the
following way:

A suspension of 1.5 g of 2-[3-(cyclohex-2-enyloxy)-1H-
pyrazol-4-yl]pyridine in 20 cm3 of dimethylformamide is
afided to a suspension of 500 mg of sodium hydride (at
75% in liquid petroleum jelly) in 15 cm3 of
dimethylformamide under an argon atmosphere and with
stirring. After heating at 50°C for 30 min, the mixture
is stirred for 30 min at a temperature in the region of
20°C, and a solution of 1.6 g of 1-(2-chloroethyl)-
piperidine hydrochloride is then added. The reaction
medium is stirred for 15 h at a temperature in the
region of 2 0°C and is then poured into water. The
aqueous phase is extracted twice with ethyl acetate.
The organic phases are pooled, washed successively with
water and a saturated aqueous sodium chloride solution,
dried over magnesium sulfate, filtered and evaporated
under reduced pressure (2.7 kPa) to give a yellow oil
which is purified by flash chromatography on alumina
CTB1 under an argon pressure (50 kPa) [eluent:
cyclohexane/ethyl acetate (90/10 by volume)]. After
concentration of the fractions under reduced pressure,
1.6 g of 2-[3-(cyclohex-2-enyloxy)-1-(2-piperidin-
1-ylethyl)-1H-pyrazol-4-yl]pyridine are obtained in the
form of a pale yellow oil.
Mass spectrum (EI): m/z 352 (M+), m/z 271 [ (M - C6H9)+],
m/z 111 (C7H13N+), m/z 98 (C6H12N+) .
The 2-[3-(cyclohex-2-enyloxy)-1H-pyrazol-4-yl]pyridine
can be prepared in the following way:
5.4 g of potassium carbonate and 4.6 cm3 of
3-bromocyclohexene are added to a suspension of 7.1 g
of 1-(3-hydroxy-4-pyridin-2-ylpyrazol-1-yl)ethanone in
70 cm3 of methyl ethyl ketone with stirring. The
mixture is heated at the reflux of the solvent for 4 h,
cooled to a temperature in the region of 2 0°C, and
evaporated under reduced pressure (2.7 kPa). The
residue is taken up with 50 cm3 of tetrahydrofuran and
50 cm3 of methanol, and 7 cm3 of 5N sodium hydroxide are

then added along with water until complete
solubilization of the medium. After stirring for 15 h
at a temperature in the region of 20°C, the reaction
medium is evaporated under reduced pressure (2.7 kPa).
The reaction crude is taken up with ethyl acetate and
water. The insoluble solid is filtered off and dried
under reduced pressure (2.7 kPa) to give 5.3 g of 2-[3-
(cyclohex-2-enyloxy)-1H-pyrazol-4-yl]pyridine in the
form of a white powder.
IR spectrum (KBr): 3180; 2928; 2723; 1602; 1533; 1497;
1463; 1288; 1065; 786 and 700 cm"1.
The 1-(3-hydroxy-4-pyridin-2-ylpyrazol-1-yl)ethanone
can be prepared in the following way:
A solution, stirred and under an argon atmosphere, of
7.3 g of 4-pyridin-2-yl-1H-pyrazol-3-ol hydrochloride
in 70 cm3 of pyridine is heated to 100°C, and 3.75 cm3 of
acetic anhydride are then added dropwise. After heating
at 100°C for 1.5 h, the reaction medium is cooled to a
temperature in the region of 2 0°C and is poured into
150 cm3 of ice-cold water. The precipitate formed is
filtered, washed three times with water and dried under
vacuum (2.7 kPa) to give 7.1 g of 1-(3-hydroxy-4-
pyridin-2-ylpyrazol-1-yl)ethanone in the form of a pale
yellow solid.
IR spectrum (KBr): 3157; 2396; 1719; 1608; 1391; 1274;
1223; 1000; 929; 790 and 618 cm"1.
The 4-pyridin-2-yl-1H-pyrazol-3-ol hydrochloride can be
prepared in the following way:
A solution, with stirring, of 18 g of ethyl ester of
3-dimethylamino-2-pyridin-2-ylacrylic acid and of
3.95 cm3 of hydrazine monohydrate in 120 cm3 of ethanol
is heated at the reflux of the solvent for 3 h. The
reaction mixture is concentrated under reduced pressure
(2.7 kPa), 3N hydrochloric ethanol is added, and the

mixture is cooled in an ice bath. The solid formed is
filtered, and is dried under vacuum (2.7 kPa) to give
11. 3 g of 4-pyridin-2-yl-1H-pyrazol-3-ol hydrochloride
in the form of a yellow solid.
IR spectrum (KBr): 3166; 1644; 1620; 1587; 1551; 1430;
1209; 1159; 907; 774 and 518 cm"1.
The ethyl ester of 3-dimethylamino-2-pyridin-2-yl-
acrylic acid can be prepared in the following way:
20 cm3 of C-tert-butoxy-N,N,N',N'-tetramethyl-
methanediamine are added to a solution of 13 g of ethyl
ester of 2-pyridin-2-ylacrylic acid in 100 cm3 of
tetrahydrofuran, heating is carried out at the reflux
of the solvent for 15 h, and the reaction mixture is
then cooled to a temperature in the region of 2 0°C and
evaporated to dryness under reduced pressure (2.7 kPa).
The resulting brown oil is purified by flash
chromatography on silica under an argon pressure
(50 kPa) [eluent: cyclohexane/ethyl acetate (90/10 by
volume)]. After concentration of the fractions under
reduced pressure, 18 g of ethyl ester of
3-dimethylamino-2-pyridin-2-ylacrylic acid are obtained
in the form of an orange-colored oil.
IR spectrum (CCl4) : 2980; 2929; 1686; 1619; 1602; 1297;
1271; 1219; 1096 and 1085 cm"1.
Example 3 6
1-(2-Piperidin-1-ylethyl)-4-pyridin-4-yl-1H-pyrazol-3-
ol dihydrochloride monohydrate
7 cm3 of 12N hydrochloric acid are added to a stirred
solution of 720 mg of 4-[3-benzyloxy-1-(2-piperidin-1-
ylethyl)-1H-pyrazol-4-yl]pyridine in 7 cm3 of ethanol.
After 7 h at the reflux of the solvent, and then 15 h
at a temperature in the region of 20°C, the reaction
medium is evaporated under reduced pressure (2.7 kPa) .

The residue is taken up with ethanol, and the mixture
is then evaporated to dryness under reduced pressure
(2.7 kPa) . The operation is repeated twice, ethanol is
then added to the solid and the mixture is heated at
the reflux of the solvent. After cooling of the
solution in an ice bath, the crystals formed are
filtered off and dried under vacuum (2.7 kPa) to give
300 mg of 1-(2-piperidin-1-ylethyl)-4-pyridin-4-yl-1H-
pyrazol-3-ol dihydrochloride monhydrate in the form of
a white solid.
IR spectrum (KBr): 3495; 3414; 3197; 2934; 2652; 2545;
1637; 1599; 1540; 1513; 1206; 813 and 523 cm"1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.3 0 to 1.60 (very broad unresolved peak: 1H) ; from
1.60 to 1.90 (mt: 5H) ; from 2.85 to 3.05 (unresolved
peak: 2H); from 3.30 to 3.45 (mt: 2H); 3.49 (t,
J = 6.5 Hz: 2H); 4.54 (t, J = 6.5 Hz: 2H); 8.12 (broad
d, J = 7 Hz: 2H) ; 8.67 (s: 1H) ; 8.69 (broad d, J =
7 Hz: 2H); 11.75 (unresolved peak: 1H).
The 4-[3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-4-yl]pyridine can be prepared in the following
way:
A solution of 720 mg of 4-(3-benzyloxy-1H-pyrazol-4-
yl)pyridine in 20 cm3 of dimethylformamide is added to a
suspension of 23 0 mg of sodium hydride (at 75% in
liquid petroleum jelly) in 10 cm3 of dimethylformamide
under an argon atmosphere and with stirring. After
heating at 50°C for 30 min, the mixture is stirred for
30 min at a temperature in the region of 20°C, and a
solution of 740 mg of 1-(2-chloroethyl)piperidine
hydrochloride is then added. The reaction medium is
stirred for 15 h at a temperature in the region of 20°C
and is then poured into water. The aqueous phase is
extracted twice with ethyl acetate. The organic phases
are pooled, washed successively with water and a
saturated aqueous sodium chloride solution, dried over

magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa) to give an orange-colored
oi?l which is purifed by flash chromatography on alumina
CTB1 under an argon pressure (50 kPa) [eluent:
cyclohexane/ethyl acetate (90/10, then 80/20 by
volume)]. After concentration of the fractions under
reduced pressure, 720 mg of 4- [3-benzyloxy-1-(2-
piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridine are
obtained in the form of a pale yellow oil.
IR spectrum (CH2C12) : 2940; 1604; 1573; 1513; 1453;
1363; 1172; 992; 815; 676 and 534 cm"1.
The 4-(3-benzyloxy-1H-pyrazol-4-yl)pyridine can be
prepared in the following way:
1.8 g of potassium carbonate and 1.55 cm3 of benzyl
bromide are added to a suspension of 2.4 g of 1-(3-
hydroxy-4-pyridin-4-ylpyrazol-1-yl)ethanone in 25 cm3 of
methyl ethyl ketone with stirring. The mixture is
heated at the reflux of the solvent for 3 h, cooled to
a temperature in the region of 20°C, and filtered. The
filtrate is evaporated under reduced pressure
(2.7 kPa). The resulting brown oil is purified by flash
chromatography on silica under an argon pressure
(50 kPa) [eluent: ethyl acetate/cyclohexane (80/20 by
volume)]. After concentration of the fractions under
reduced pressure, 72 0 mg of 4-(3-benzyloxy-1H-pyrazol-
4-yl) pyridine are obtained in the form of a white
solid.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 5.27
(s: 2H); 7.36 (tt, J = 7.5 and 1.5 Hz: 1H); 7.44 (tt, J
= 7.5 and 1.5 Hz: 2H); 7.52 (broad d, J = 7.5 Hz: 2H) ;
7.66 (dd, J = 5 and 2 Hz: 2H); 8.33 (s: 1H); 8.47 (dd,
J = 5 and 2 Hz: 2H) ; from 12.2 5 to 12.50 (unresolved
peak: 1H).
The 1-(3-hydroxy-4-pyridin-4-ylpyrazol-1-yl)ethanone
can be prepared in the following way:

A suspension of 2.5 g of 4-pyridin-4-yl-1H-pyrazol-3-ol
hydrochloride in 2 5 cm3 of pyridine, with stirring and
under an argon atmosphere, is heated to 10 0°C, and
1.25 cm3 of acetic anhydride are then added dropwise.
After heating at 100°C for 2 h, the reaction medium is
cooled in an ice bath. The solid formed is filtered
off, washed with water and then with heptane, and dried
under vacuum (2.7 kPa) to give 1-(3-hydroxy-4-pyridin-
4-ylpyrazol-1-yl)ethanone, which is used directly in
the following step.
The 4-pyridin-4-yl-1H-pyrazol-3-ol hydrochloride can be
prepared in the following way:
A solution, with stirring, of 12.46 g of ethyl ester of
3-dimethylamino-2-pyridin-4-ylacrylic acid and of
2.75 cm3 of hydrazine monohydrate in 80 cm3 of ethanol is
heated at the reflux of the solvent for 3 h. The
reaction mixture is cooled in an ice bath, and the
solid formed is filtered off and taken up with water.
The suspension is adjusted to pH 6 with 1N hydrochloric
acid and is then filtered. The solid obtained is washed
with water and is dried under vacuum (2.7 kPa) to give
5.1 g of 4-pyridin-4-yl-1H-pyrazol-3-ol hydrochloride
in the form of a yellow solid.
IR spectrum (KBr): 3355; 2464; 2059; 1965; 1637; 1575;
1527; 1207; 1193; 1075; 1022; 914; 838 and 519 cm"1.
The ethyl ester of 3-dimethylamino-2-pyridin-4-yl-
acrylic acid can be prepared in the following way:
24 cm3 of C-tert-butoxy-N,N,N',N'-tetramethylmethane-
diamine are added to a solution of 15 cm3 of ethyl ester
of 2-pyridin-4-ylacrylic acid in 100 cm3 of
tetrahydrofuran and heating is carried out at the
reflux of the solvent for 15 h, and the reaction
mixture is then evaporated to dryness under reduced

pressure (2.7 kPa) . The residue is taken up with ethyl
acetate, and the organic solution is washed twice with
water and a saturated aqueous sodium chloride solution,
dried over magnesium sulfate, filtered and evaporated
under reduced pressure (2.7 kPa) . The brown oil
obtained is purified by flash chromatography on silica
under an argon pressure (50 kPa) [eluent:
cyclohexane/ethyl acetate (90/10 by volume)]. After
concentration of the fractions under reduced pressure,
12.46 g of ethyl ester of 2-pyridin-4-ylacrylic acid
are obtained in the form of an orange-colored oil.
IR spectrum (CC14) : 2981; 1690; 1596; 1280; 1218; 1095
and 1051 cm"1.
Example 37
4-(4-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
0.5 g of 3-benzyloxy-4-(4-fluorophenyl)-1-(2-piperidin-
l-ylethyl) -1H-pyrazole hydrochloride is introduced into
an autoclave with 12.8 mg of palladium-on-charcoal (at
10%) and 25 cm3 of ethanol. The device is placed under a
hydrogen pressure of 500 kPa at a temperature of 2 5°C
for 5 hours. After cooling to a temperature in the
region of 20°C, the reaction medium is filtered over
supercel; the filtrate is washed with 3 times 100 cm3 of
ethanol, and concentrated to dryness under reduced
pressure (2 kPa) . The residue obtained is purified by
chromatography, under a nitrogen pressure of 50 kPa, on
a column of silica gel (particle size 20-45 µ; diameter
1 cm; height 2 5 cm), eluting with a mixture of
dichloromethane and of a 2N solution of ammoniacal
methanol (93/7 by volume). Concentration is performed
under reduced pressure (2 kPa) ; 160 mg of 4-(4-fluoro-
phenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol are
obtained in the form of a white solid.

1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.3 0 to 1.55 (mt: 6H); 2.4 0 (broad t, J = 5.5 Hz: 4H);
2.65 (t, J = 7 Hz: 2H) ; 4.00 (t, J = 7 Hz: 2H) ; 7.15
(t, J = 9 Hz: 2H) ; 7.65 (dd, J = 9 and 5.5 Hz: 2H) ;
7.91 (s: 1H); 10.32 (broad s: 1H). Mass spectrum (EI):
m/z 289 (M+-) , m/z 98 (base peak) .
The 3-benzyloxy-4-(4-fluorophenyl)-1-(2-piperidin-1-
ylethyl)-1H-pyrazole can be prepared in the following
way:
A suspension of 0.80 g of 3-benzyloxy-4-bromo-1-(2-
piperidin-1-ylethyl)-1H-pyrazole, 1.12 g of
4-fluorophenylboronic acid, 0.20 g of dichloro-
bis(triphenylphosphine)palladium and 1.88 g of
potassium phosphate in 3 0 cm3 of 1,2-dimethoxyethane is
stirred, under an argon atmosphere, at the boiling
temperature of the reaction medium, for 14 hours. After
cooling, 3 0 cm3 of a saturated sodium hydrogen carbonate
solution are added to the mixture, which is extracted
with 30 cm3 of ethyl acetate. The organic phase is dried
over magnesium sulfate, filtered and concentrated to
dryness under reduced pressure (3 kPa) . The residue is
purified by chromatography on silica gel, eluting with
a mixture of ethyl acetate and methanol (3 0/1 by
volume). After concentration of the fractions under
reduced pressure, 0.57 g of a yellowish oil is
obtained, which is used as it is in the following step.
0.57 g of 3-benzyloxy-4-(4-fluorophenyl)-1-(2-
piperidin-1-ylethyl)-1H-pyrazole is taken up with 5 cm3
of diethyl ether and 0.5 cm3 of a 4N solution of
hydrochloric acid in diethyl ether. The precipitate
formed is filtered over dried. 0.5 g of 3-benzyloxy-4-
(4-fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole
is obtained. 1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): from 1.25 to 1.50 (mt: 1H) ; from 1.60 to 1.85
(mt: 5H) ; 2.91 (mt: 2H) ; 3.44 (very broad d, J = 12.5
Hz: 2H); 3.52 (mt: 2H); 4.47 (broad t, J = 6.5 Hz: 2H);

5.34 (s: 2H) ; 7.72 (t, J = 9 Hz: 2H); from 7.30 to 7.45
(mt: 3H); 7.51 (broad d, J = 7.5 Hz: 2H); 7.68 (dd, J =
9 * and 6 Hz: 2H) ; 8.16 (s: 1H) ; from 9.70 to 10.00
(unresolved peak: 1H).
The 3-benzyloxy-4-bromo-1-(2-piperidin-1-ylethyl)-1H-
pyrazole can be prepared in the following way:
5.6 g of sodium hydride (at 75% by mass in liquid
petroleum jelly) and 25 cm3 of anhydrous
dimethylformamide are added gradually, at a temperature
in the region of 5°C, to a solution of 8 g of
3-benzyloxy-4-bromo-1H-pyrazole hydrochloride in 100 cm3
of anhydrous dimethylformamide. After stirring for
1 hour at ambient temperature, 6.93 g of 1-(2-chloro-
ethyl)piperidine hydrochloride and 3 0 cm3 of anhydrous
dimethylformamide are added in small portions. After
stirring for 21 hours at ambient temperature, the
excess sodium hydride is destroyed by slowly adding
water, and the reaction medium is then run into 1 dm3 of
water and extracted with 2 times 2 00 cm3 of ethyl
acetate. The pooled organic phases are dried over
magnesium sulfate, filtered and concentrated to dryness
under reduced pressure (3 kPa). The oily residue
obtained is taken up with 2 0 cm3 of acetone and run into
a solution of 3.6 g of oxalic acid in 30 cm3 of acetone.
The solid formed is triturated and then isolated by
filtration and dried at ambient temperature, to give
11.3 g of 3-benzyloxy-4-bromo-1-(2-piperidin-1-
ylethyl) -1H-pyrazole oxalate. 5 0 cm3 of a saturated
sodium hydrogen carbonate solution are added to 5 g of
this oxalate and the mixture is extracted with
2 x 100 cm3 of ethyl acetate. The pooled organic phases
are dried over magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (3 kPa).
3.84 g of 3-benzyloxy-4-bromo-1-(2-piperidin-1-
ylethyl) -1H-pyrazole are thus obtained in the form of a
light oil.

1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.25 to 1.55 (mt: 6H) ; 2.35 (broad t, J = 5 Hz: 4H) ;
2'61 (t, J = 6.5 Hz: 2H) ; 4.04 (t, J = 6.5 Hz: 2H) ;
5.20 (s: 2H); from 7.30 to 7.50 (mt: 5H); 7.81 (s: 1H).
The 3-benzyloxy-4-bromo-1H-pyrazole hydrochloride can
be prepared in the following way:
A solution of 2.6 cm3 of bromine in 50 cm3 of
dichloromethane is added dropwise, over 0.5 hour, to a
suspension of 8.76 g of 3-benzyloxy-1H-pyrazole and
11 g of sodium carbonate in 100 cm3 of dichloromethane,
which has been cooled and kept at around 5°C with
stirring. After stirring for 0.5 hour at this
temperature, 20 cm3 of 0. IN sodium thiosulfate solution
is added to the mixture, which is stirred for a further
1 hour at around 5°C, and then 100 cm3 of
dichloromethane are added and the mixture is separated
by settling out. The organic phase is extracted again
with 50 cm3 of water and the organic phases are pooled
and dried over magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (3 kPa) .
The oily residue obtained is taken up with 10 cm3 of 6N
hydrochloric dioxane and the solid formed is triturated
in ethyl ether and isolated by filtration. 12.5 g of
3-benzyloxy-4-bromo-1H-pyrazole are thus obtained in
the form of a white solid which melts at around 8 0°C
(with decomposition).
Mass spectrum (EI) : m/z 252 (M+') , m/z 91 (base peak) .
XH NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): 5.22
(s: 2H); from 7.30 to 7.50 (mt: 5H); 7.81 (s: 1H); from
11.80 to 12.70 (very broad unresolved peak: 1H).
The 3-benzyloxy-1H-pyrazole can be prepared in the
following way:
50 cm3 of a saturated sodium hydrogen carbonate solution
are added to 10.6 g of 3-benzyloxy-1H-pyrazole

hydrochloride and the mixture is extracted with
2 x 150 cm3 of dichloromethane. The pooled organic
phases are dried over magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (3 kPa)
to give 8.76 g of 3-benzyloxy-1H-pyrazole in the form
of an oil, which is used as it is in the following
step.
The 3-benzyloxy-1H-pyrazole hydrochloride can be
prepared in the following way:
A suspension of 11 g of 1-(3-hydroxypyrazol-1-yl)-
ethanone, 12.5 g of potassium carbonate and 11.3 cm3
(16.25 g) of benzyl bromide in 250 cm3 of 2-butanone is
stirred at the boiling temperature of the mixture for
1.2 5 hours. The insoluble inorganic material is then
removed by filtration and the filtrate is concentrated
to dryness under reduced pressure (3 kPa) . The oily
residue obtained is dissolved in a mixture of 150 cm3 of
tetrahydrofuran and 100 cm3 of methanol, and 4 cm3 of a
10M sodium hydroxide solution are then added thereto.
After stirring for 0.65 hour at ambient temperature,
the mixture is concentrated to dryness under reduced
pressure (3 kPa) . The pasty residue obtained is taken
up with 250 cm3 of ethyl acetate and washed with 2 times
10 cm3 of brine. The organic phase is dried over
magnesium sulfate, filtered and concentrated under
reduced pressure (3 kPa) . 100 cm3 of IN hydrochloric
ether are added to the residue and the solid formed is
triturated and then isolated by filtration. The solid
is solubilized in 250 cm3 of isopropanol at around 60°C,
and the mixture is then partially concentrated until
the first crystals appear, 5 cm3 isopropyl acetate are
added, and the mixture is cooled to around 0°C. After
filtration and drying, 10.6 g of 3-benzyloxy-1H-
pyrazole hydrochloride are obtained in the form of
salmon-pink crystals which melt at 100°C.

1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 5.16
(s: 2H) ; 5.75 (d, J = 3 Hz: 1H); from 7.30 to 7.50 (mt:
5H); 7.57 (d, J = 3 Hz: 1H).
The 1-(3-hydroxypyrazol-1-yl)ethanone can be prepared
in the following way:
A solution of 9.5 cm3 of acetic anhydride in 18 cm3 of
pyridine is added slowly, over 0.33 hours, to a
solution of 8.4 g of lH-pyrazol-3-ol (No. CAS
60456-92-0) in 38 cm3 of pyridine preheated to 95°C, and
this temperature is then maintained for 1 hour. The
mixture is then concentrated under reduced pressure
(3 kPa) . 100 cm3 of ethyl ether are added to the
residual suspension, which is triturated to finish off
the crystallization. After filtration and drying, 11 g
of 1-(3-hydroxypyrazol-1-yl)ethanone are obtained in
the form of whitish crystals which sublimate at around
215°C.
XH NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): 2.50
(s: 3H) ; 6.02 (d, J = 3 Hz: 1H) ; 8.15 (d, J = 3 Hz:
1H); from 10.80 to 11.20 (unresolved peak: 1H).
Example 3 8
4-(4-Trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-
lH-pyrazol-3-ol dihydrochloride
600 mg of 3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1-
(2-piperidin-1-ylethyl)-1H-pyrazole in 4.5 cm3 of
ethanol and 4.5 cm3 of 12N hydrochloric acid are brought
to reflux at a temperature in the region of 10 0°C for
7 hours. After cooling to a temperature in the region
of 20°C, the reaction medium is concentrated to dryness
under reduced pressure (2 kPa); the residue is
precipitated from a mixture of diisopropyl ether and
acetone. 464 mg of 4-(4-trifluoromethoxyphenyl)-1-(2-

piperidin-1-ylethyl)-1H-pyrazol-3-ol dihydrochloride
are obtained in the form of a white powder.
IR spectrum (KBr): 3428; 2951; 2642; 2538; 1615; 1591;
1533; 1456; 1275; 1219; 1159; 1012; 856 and 806 cm"1.
XE NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 1.41
(mt: 1H); from 1.60 to 1.85 (mt: 5H); 2.94 (unresolved
peak: 2H); 3.4 6 (mt: 4H); 4.41 (mt: 2H); 7.34 (broad d,
J = 8 Hz: 2H) ; 7.76 (d, J = 8 Hz: 2H) ; 8.09 (s: 1H) ;
10.04 (broad unresolved peak: 1H); 10.62 (broad s: 1H).
The 3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1-(2-
piperidin-1-ylethyl)-1H-pyrazole can be prepared in the
following way:
560 mg of 3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1H-
pyrazole in 15 cm3 of anhydrous dimethylformamide are
cooled, with stirring, to a temperature in the region
of -5°C and under an inert atmosphere; 14 0 mg of sodium
hydride at 75% in liquid petroleum jelly are added
portionwise to the reaction medium and the temperature
is allowed to return to approximately 20°C. 431 mg of
1-(2-chloroethyl)piperidine hydrochloride are then
added and the stirring is maintained at this
temperature for 15 hours. The reaction medium is taken
up with 3 00 cm3 of ice-cold water and 300 cm3 of ethyl
acetate. The organic phase is separated by settling
out, washed with 2 00 cm3 of water and concentrated to
dryness under reduced pressure (2 kPa) . The residue is
purified on an FC50SI-HP silica cartridge, eluting with
a mixture of dichloromethane and methanol (95/5 by
volume). The product obtained is again purified on an
FC50SI-HP silica cartridge, eluting with a mixture of
dichloromethane and methanol (98/2 by volume). 600 mg
of 3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1-(2-
piperidin-1-ylethyl)-1H-pyrazole are obtained in the
form of a colorless oil. Mass spectrum (CI) : m/z 446
( [M+H] +) (base peak) .

The 3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1H-pyrazole
can be prepared in the following way:
1.07 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4- (4-
trifluoromethoxyphenyl)-1H-pyrazole, 5 cm3 of a IN
solution of n-tetrabutylammonium fluoride in
tetrahydrofuran and 50 cm3 of tetrahydrofuran are
heated, with stirring, at the reflux of the solvent for
15 hours. The reaction medium is cooled to a
temperature in the region of 20°C, and taken up with
3 00 cm3 of ethyl acetate and 100 cm3 of water. The
organic phase is separated by settling out, dried over
anhydrous magnesium sulfate, filtered and concentrated
to dryness under reduced pressure (2 kPa) . The residue
obtained is purified on an FC50SI-HP silica cartridge,
eluting with dichloromethane. 560 mg of 3-benzyloxy-4-
(4-trifluoromethoxyphenyl)-1H-pyrazole are obtained in
the form of a powder. Mass spectrum (EI) : m/z 334 (M+-),
m/z 91 (base peak).
The 3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-trifluoro-
methoxyphenyl) -1H-pyrazole can be prepared in the
following way:
2.04 g of 4-trifluoromethoxyphenylboronic acid, 4.96 cm3
of a 2N aqueous potassium carbonate solution and 496 mg
of tetrakis(triphenylphosphine)palladium are added to a
solution of 1.5 g of 3-benzyloxy-4-iodo-1-(toluene-4-
sulfonyl)-1H-pyrazole in a mixture of 4 0 cm3 of toluene
and ethanol (4/1 by volume) in a three-necked flask.
The three-necked flask containing the reaction medium
is placed in a bath preheated to a temperature in the
region of 120°C; the stirring is continued for 90
minutes at this temperature. The mixture is then cooled
to a temperature in the region of 2 0°C, and filtered
over supercel. The filtrate is taken up with 300 cm3 of
ethyl acetate and 100 cm3 of water. The organic phase is
separated by settling out and concentrated to dryness

under reduced pressure (2 kPa). The residue obtained is
purified on an FC50SI-HP silica cartridge, eluting with
a mixture of cyclohexane and ethyl acetate (90/10 by
volume). 1.07 g of 3-benzyloxy-1-(toluene-4-sulfonyl)-
4-(4-trifluoromethoxyphenyl)-1H-pyrazole are obtained
in the form of a yellow powder. Mass spectrum (CI): m/z
489 ([M+H]+), m/z 335 (base peak).
The 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-
pyrazole can be prepared in the following way:
5 g of 3-benzyloxy-4-(4-iodophenyl)-1H-pyrazole in
110 cm3 of dimethylformamide are cooled while stirring,
under an inert atmosphere, to a temperature in the
region of -5°C. 587 mg of sodium hydride at 75% in
liquid petroleum jelly are added portionwise and the
mixture is allowed to return to a temperature in the
region of 2 0°C. 4.4 g of para-tolunesulfonyl chloride
are then added and the stirring is maintained at this
temperature for 15 hours. The reaction medium is taken
up with 300 cm3 of ice-cold water and 500 cm3 of ethyl
acetate. The organic phase is separated by settling
out, washed with 3 00 cm3 of water and 3 00 cm3 of a
saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, filtered and concentrated
to dryness under reduced pressure (2 kPa) . The residue
is crystallized from diisopropyl ether. 7.24 g of
3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole
are obtained in the form of a powder. Mass spectrum
(EI): m/z 454 (M+), m/z 299, m/z 91 (base peak).
The 3-benzyloxy-4-iodo-1H-pyrazole can be prepared in
the following way:
A suspension of 0.32 g of 3-benzyloxy-1H-pyrazole,
0.3 g of sodium acetate and 0.65 g of iodine in 50 cm3
of chloroform is stirred at ambient temperature for
26 hours. 50 cm3 of a 0.5N sodium thiosulfate solution

are then added to the mixture, which is stirred until
decoloration is observed and separated by settling out.
The aqueous phase is extracted again with 2 5 cm3 of
chloroform. The pooled organic phases are dried over
magnesium sulfate, filtered and concentrated under
reduced pressure (3 kPa) . The residue obtained is
purified by chromatography on silica gel, eluting with
a mixture of cyclohexane and ethyl acetate (80/2 0 by
volume). After concentration of the fractions under
reduced pressure, a colorless oil is obtained which
crystallizes rapidly and provides 0.4 g of 3-benzyloxy-
4-iodo-1H-pyrazole in the form of a white solid having
an Rf of 0.6 [mixture of cyclohexane and ethyl acetate
(50/50 by volume) , plate of silica gel 60 F254
reference 105719, Merck] . Mass spectrum (EI) : m/z 3 00
(M+.) (base peak).
XH NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 5.22
(s: 2H); from 7.30 to 7.50 (mt: 5H); 7.74 (s: 1H); from
12.20 to 12.60 (broad unresolved peak: 1H).
Example 3 9
4-Phenyl-1-(2-piperidin-1-ylpropyl)-1H-pyrazol-3-ol
dihydrochloride
2 cm3 of a 4N solution of hydrochloric acid in dioxane
are added, at a temperature in the region of 2 0°C, to a
mixture of 150 mg of 1-{2-[3 -(cyclohex-2-enyloxy)-4-
phenylpyrazol-1-yl]-1-methylethyl}piperidine in 5 cm3 of
anhydrous methanol. The reaction medium is stirred at
this temperature for 2 0 hours, concentrated to dryness
under reduced pressure (2 kPa), and taken up with 2 0 cm3
of dichloromethane. The solution is concentrated to
dryness under reduced pressure (2 kPa) . The residue is
precipitated with 2 0 cm3 of diisopropyl ether. 110 mg of
4-phenyl-1-(2-piperidin-1-ylpropyl)-1H-pyrazol-3-ol
dihydrochloride are obtained in the form of a yellow
solid.

IR spectrum (KBr): 3431; 2949; 2651; 2521; 1606; 1580;
1527; 1451; 1175; 1121; 1012; 765; 698 and 672 cm"1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): 1.24
(d, J = 6.5 Hz: 3H) ; 1.44 (mt: 1H) ; from 1.65 to 1.95
(mt: 5H) ; 2.95 (mt: 1H) ; 3.10 (mt: 1H) ; from 3.35 to
3.55 (mt: 2H) ; 3.71 (mt: 1H) ; 4.21 (dd, J = 14.5 and
7.5 Hz: 1H) ; 4.43 (dd, J = 14.5 and 5.5 Hz: 1H) ; 7.15
(broad t, J = 7.5 Hz: 1H) ; 7.34 (broad t, J= 7.5 Hz:
2H); 7.66 (broad d, J = 7.5 Hz: 2H); 8.01 (s: 1H); 9.51
(unresolved peak: 1H); 10.51 (s: 1H).
The l-{2- [3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-
l-methylethyl}piperidine can be prepared in the
following way:
A mixture of 0.5 g of methanesulfonic acid 2-[3-
(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-
methylethyl ester, 0.4 cm3 of piperidine and 1.0 g of
potassium carbonate in 2 0 cm3 of dimethylformamide is
heated while stirring at a temperature in the region of
80°C for 6 hours and then for 15 hours at a temperature
in the region of 20°C. The reaction medium is taken up
with 100 cm3 of water and 100 cm3 of ethyl acetate. The
organic phase is separated by settling out, washed with
2 times 100 cm3 of water and 100 cm3 of a saturated
aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, filtered and concentrated to dryness
under reduced pressure (2 kPa). The residue is purified
by chromatography, under a nitrogen pressure of 50 kPa,
on a column of silica gel (particle size 20-45 p.;
diameter 2 cm; height 4 0 cm), eluting with a mixture of
cyclohexane and ethyl acetate (80/20 by volume). After
concentration of the fractions under reduced pressure
(2 kPa), 150 mg of 1-{2-[3 -(cyclohex-2-enyloxy)-4-
phenylpyrazol-1-yl]-1-methylethyl}piperidine are
obtained in the form of a yellow oil. Mass spectrum
(EI): m/z 365 (M+'), m/z 112 (base peak).

The methanesulfonic acid 2-[3-(cyclohex-2-enyloxy)-4-
phenylpyrazol-1-yl]-1-methylethyl ester can be prepared
in the following way:
1 cm3 of methanesulfonyl chloride and 2.59 cm3 of
triethylamine are added to a stirred solution of 55 0 mg
of 1-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-
propan-2-ol in 3 0 cm3 of dichloromethane, at a
temperature in the region of 2 0°C. The reaction medium
is stirred for 7 hours at a temperature in the region
of 20°C, and taken up with 50 cm3 of distilled water and
50 cm3 of ethyl acetate. The organic phase is separated
by settling out, dried over anhydrous magnesium
sulfate, filtered and concentrated to dryness under
reduced pressure (2 kPa) . The residue is purified by
chromatography, under a nitrogen pressure of 50 kPa, on
a column of silica gel (particle size 20-45 (J.; diameter
4 cm; height 60 cm) , eluting with a mixture of
cyclohexane and ethyl acetate (80/20 by volume). After
concentration of the fractions under reduced pressure
(2 kPa), 300 mg of methanesulfonic acid 2-[3-(cyclohex-
2-enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl ester
are obtained in the form of a colorless oil. Mass
spectrum (EI) : m/z 376 (M+") , m/z 296 (base peak) .
The 1-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-
propan-2-ol can be prepared in the following way:
2.4 g of 3-(cyclohex-2-enyloxy)-4-phenyl-1H-pyrazole
are dissolved in 25 cm3 of anhydrous dimethylformamide
under an inert atmosphere and with stirring. 2.24 g of
potassium tert-butoxide, followed by 0.7 cm3 of
methyloxirane are added at a temperature in the region
of 2 0°C. The reaction medium is heated at a temperature
in the region of 60°C for 1 hour. A further 0.7 cm3 of
methyloxirane is then added and the mixture is heated
for 1 hour at a temperature in the region of 60°C. The
mixture is cooled to a temperature in the region of

2 0°C, and taken up with 2 00 cm3 of water and 2 00 cm3 of
ethyl acetate. The organic phase is separated by-
settling out, washed with 3 times 200 cm3 of water and
2 00 cm3 of a saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (2 kPa) .
The residue is purified by chromatography, under a
nitrogen pressure of 50 kPa, on a column of silica gel
(particle size 20-45 µ; diameter 4 cm; height 50 cm) ,
eluting with a mixture of cyclohexane and ethyl acetate
(80/20 by volume). After concentration of the fractions
under reduced pressure (2 kPa) , 450 mg of 1- [3-
(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]propan-2-ol
are obtained in the form of a colorless oil. Mass
spectrum (EI): m/z 298 (M+'), m/z 218, m/z 173 (base
peak)
Example 40
3-(4-Phenylpyrazol-1-ylmethyl)-1-aza-bicyclo[2.2.2]-
octane dihydrochloride
A solution of 0.4 g of 3-(pyrazol-1-ylmethyl)-1-
azabicyclo[2.2.2]octane in 5 cm3 of dimethylformamide is
added to a mixture of 0.4 g of sodium hydride at 75% in
liquid petroleum jelly and of 10 cm3 of dimethyl-
formamide. The reaction medium is heated at a
temperature in the region of 50°C for approximately
1 hour, and the solution is then cooled to a
temperature in the region of 20°C. 1.75 g of 3-chloro-
methylquinuclidine are added slowly, and the reaction
medium is heated at a temperature in the region of 5 0°C
for 16 hours and then cooled to a temperature in the
region of 20°C. The mixture is taken up with 100 cm3 of
water and 100 cm3 of ethyl acetate. The organic phase is
separated by settling out, washed with 2 times 100 cm3
of water and 10 0 cm3 of a saturated aqueous sodium
chloride solution, and then concentrated to dryness

under reduced pressure (2 kPa). The residue is purified
by chromatography, under a nitrogen pressure of 50 kPa,
on a column of alumina CTB1 (diameter 3 cm; height
4 0 cm) , eluting with ethyl acetate and then with a
mixture of ethyl acetate and methanol (98/2, 95/5 then
90/10 by volume), collecting fractions of 60 cm3.
Fractions 14 to 2 0 are concentrated under reduced
pressure. The residue obtained is purified a second
time by chromatography, under a nitrogen pressure (50
kPa) , on a column of alumina CTB1 (diameter 3 cm;
height 4 0 cm), eluting with ethyl acetate and then with
a mixture of ethyl acetate and methanol (98/2, 95/5
then 90/10 by volume), collecting fractions of 60 cm3.
Fractions 14 to 2 0 are concentrated under reduced
pressure. 150 mg of 3-(4-phenylpyrazol-1-ylmethyl)-1-
azabicyclo[2.2.2]octane are obtained. The
dihydrochloride is prepared with 1.2 cm3 of a 4. 7N
solution of hydrochloric acid in isopropyl ether and 5
cm3 of ethanol. 230 mg of 3-(4-phenylpyrazol-1-yl-
methyl) -1-azabicyclo [2 . 2 . 2] octane dihydrochloride are
obtained.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): from
1.65 to 1.95 (mt: 4H); from 2.00 to 2.15 (mt: 1H); 2.62
(mt: 1H) ; 2.97 (broad dd, J = 13 and 7 Hz: 1H) ; from
3.10 to 3.40 (mt: 5H); 4.25 (dd, J = 13 and 8 Hz: 1H) ;
4.32 (dd, J = 13 and 8 Hz: 1H) ; 7.21 (broad t, J =
7.5 Hz: 1H); 7.38 (t, J = 7.5 Hz: 2H); 7.59 (broad d, J
= 7.5 Hz: 2H) ; 7.94 (s: 1H) ; 8.25 (s: 1H) ; 10.44
(unresolved peak: 1H) . Mass spectrum (EI) : m/z 267 (M+')
(base peak), m/z 183, m/z 123.
The 4-phenyl-1H-pyrazole can be prepared in the
following way:
1.044 g of 4-phenyl-1-(toluene-4-sulfonyl)-1H-pyrazole,
7 cm3 of a IN solution of n-tetrabutylammonium fluoride
in tetrahydrofuran and 3 5 cm3 of tetrahydrofuran are
heated at a temperature in the region of 70 °C for

6 hours. A further 3.5 cm3 of a 1N solution of
n-tetrabutylammonium fluoride in tetrahydrofuran are
added and heating is continued for 15 hours at this
temperature. The reaction medium is cooled to a
temperature in the region of 2 0°C, concentrated to
dryness under reduced pressure (2 kPa) and then taken
up with 100 cm3 of ethyl acetate and 100 cm3 of water.
The organic phase is separated by settling out, washed
with 100 cm3 of water and 100 cm3 of a saturated aqueous
sodium chloride solution, dried over anhydrous
magnesium sulfate, filtered and concentrated to dryness
under reduced pressure (2 kPa) The residue obtained is
taken up with 20 cm3 of dichloromethane. The precipitate
is filtered off and dried. 0.4 g of 4-phenyl-1H-
pyrazole is obtained in the form of a white powder.
Mass spectrum (EI) : m/z 144 (M+') (base peak) .
The 4-phenyl-1-(toluene-4-sulfonyl)-1H-pyrazole can be
prepared in the following way:
11.72 g of phenylboronic acid are added to a stirred
solution of 8.7 g of 4-iodo-1-(toluene-4-sulfonyl)-1H-
pyrazole in 2 00 cm3 of 1,2-dimethoxyethane under an
inert atmosphere. The reaction medium is heated to
110°C and then 20.63 g of finely ground tribasic
potassium phosphate and 2.18 g of bis(triphenyl-
phosphine)palladium chloride are added; the mixture is
heated at the reflux of the solvent for 3 hours and
then cooled to a temperature in the region of 2 0°C and
then filtered over supercel. The filtrate is taken up
with 250 cm3 of ethyl acetate and washed with 8 times
100 cm3 of water and 100 cm3 of a saturated aqueous
sodium chloride solution. The organic phase is
separated by settling out, dried over anhydrous
magnesium sulfate, filtered and concentrated to dryness
under reduced pressure (2 kPa). The residue is purified
by chromatography, under a nitrogen pressure of 50 kPa,
on a column of silica gel (particle size 20-45 u;

diameter 6 cm; height 45 cm), eluting with a mixture of
cyclohexane and ethyl acetate (7 0/3 0 by volume),
collecting fractions of 20 cm3. Fractions 6 to 12 are
concentrated under reduced pressure. 4.04 g of 4-
phenyl-1-(toluene-4-sulfonyl)-1H-pyrazole are obtained
in the form of white crystals. Mass spectrum (EI) : m/z
298 (M+') (base peak), m/z 234, m/z 91.
The 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole can be
prepared in the following way:
A stirred solution of 10 g of 4-iodo-1H-pyrazole in
300 cm3 of dimethylformamide, under an inert atmosphere,
is cooled to a temperature in the region of -3°C. 1.8 g
of sodium hydride at 75% in liquid petroleum jelly are
added over 5 minutes and the temperature is allowed to
return to approximately 20°C. 13.9 g of para-
toluenesulfonyl chloride are then added and the
stirring is maintained for 3 hours at this temperature.
The reaction medium is taken up with 100 g of ice and
then 700 cm3 of water and 700 cm3 of ethyl acetate. The
organic phase is separated by settling out, washed with
9 times 300 cm3 of water and 2 times 100 cm3 of an
aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, filtered and then concentrated under
reduced pressure (2 kPa). The residue is recrystallized
from 1 000 cm3 of diisopropyl ether. 10.9 g of 4-iodo-1-
(toluene-4-sulfonyl)-1H-pyrazole are obtained in the
form of white crystals. Mass spectrum (EI): m/z 348
(M+"), m/z 284, m/z 91 (base peak).
Example 41
4-(5-Chlorothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol hydrochloride
The product is prepared according to the procedure
described for the preparation of 4- (4-trifluoro-

methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-
ol, using 400 mg of 3-benzyloxy-4-(5-chlorothiophen-2-
yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole, 3.3 cm3 of
12N hydrochloric acid and 3.3 cm3 of ethanol. The medium
is taken up with diisopropyl ether and filtered over
sintered glass. The filtrate is precipitated from
ethanol. 160 mg of the expected product are obtained in
the form of a powder.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.25 to 1.50 (mt: 1H); from 1.60 to 1.90 (mt: 5H); from
2.80 to 3.00 (unresolved peak: 2H) ; from 3.35 to 3.50
(mt: 4H) ; 4.4 0 (broad t, J = 6.5 Hz: 2H) ; 7.0 0 (d,
J = 5.5 Hz: 1H) ; 7.03 (d, J = 5.5 Hz: 1H) ; 7.97 (s:
1H) ; from 10.00 to 10.30 (unresolved peak: 1H) ; 10.78
(broad s: 1H) . Mass spectrum (CI): m/z 312 ( [M+H]+)
(base peak).
The 3-benzyloxy-4-(5-chlorothiophen-2-yl)-1-(2-
piperidin-1-ylethyl)-1H-pyrazole can be prepared in the
following way:
The product is prepared according to the procedure
described for the preparation of 3-benzyloxy-4- (4-
trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazole, using 345 mg of 3-benzyloxy-4-(5-
chlorothiophen-2-yl)-1H-pyrazole, 100 mg of sodium
hydride at 75% in liquid petroleum jelly, 305 mg of
1-(2-chloroethyl)piperidine and 10 cm3 of anhydrous
dimethylformamide. After purification on an FC50SI-HP
silica cartridge, eluting with a mixture of
dichloromethane and methanol (95/5 by volume), 400 mg
of the expected product are obtained in the form of an
orange-colored oil. Mass spectrum (CI): m/z 402 ([M+H]+)
(base peak).
The 3-benzyloxy-4-(5-chlorothiophen-2-yl)-1H-pyrazole
can be prepared in the following way:

The product is prepared according to the procedure
described for the preparation of 3-benzyloxy-4-(4-
trifluoromethoxyphenyl)-1H-pyrazole, using 74 0 mg of
3-benzyloxy-4-(5-chlorothiophen-2-yl)-1-(toluene-4-
sulfonyl)-1H-pyrazole, 3.8 cm3 of a IN solution of
n-tetrabutylammonium fluoride in tetrahydrofuran and
3 8 cm3 of tetrahydrofuran. After purification on an
FC50SI-HP silica cartridge, eluting with a mixture of
dichloromethane and methanol (95/5 by volume), 345 mg
of the expected product are obtained in the form of an
ecru-colored powder. Mass spectrum (EI): m/z 290 (M+'),
m/z 91 (base peak)
The 3-benzyloxy-4-(5-chlorothiophen-2-yl)-1-(toluene-4-
sulfonyl)-1H-pyrazole can be prepared in the following
way:
589 mg of 2-bromo-5-chlorothiophene, 32.5 mg of
tris(trifuryl)phosphine and 34.7 mg of tris(di-
benzylideneacetone)dipalladium are added, with stirring
and under an inert atmosphere, to a solution of 1.8 g
of 3-benzyloxy-1-(toluene-4-sulfonyl)-4-tributyl-
stannanyl-1H-pyrazole in 2 0 cm3 of dioxane. The reaction
medium is heated at a temperature in the region of
10 0 °C for 15 hours. The mixture is then cooled to a
temperature in the region of 20°C, and filtered over
supercel. The filtrate is concentrated to dryness under
reduced pressure (2 kPa), and taken up with
cyclohexane; the insoluble material is filtered off
over sintered glass, and the filtrate is concentrated
to dryness under reduced pressure (2 kPa); the residue
obtained is purified on an FC50SI-HP silica cartridge,
eluting with a mixture of cyclohexane and ethyl acetate
(90/10 by volume). 200 mg of 3-benzyloxy-4-(5-
chlorothiophen-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrazole
are obtained in the form of a yellow powder. Mass
spectrum (EI) : m/z 444 (M+-) , m/z 289 and m/z 91 (base
peak).

The 3-benzyloxy-1- (toluene-4-sulfonyl) -4-tributyl-
stannanyl-1H-pyrazole can be prepared in the following
way:
32 5 mg of triphenylphosphine, 5.9 cm3 of 1,1,1,2,2,2-
hexabutyldistannane and 141.3 mg of palladium diacetate
are added, with stirring and under an inert atmosphere,
to a solution of 4.4 g of 3-benzyloxy-4-iodo-1-
(toluene-4-sulfonyl)-1H-pyrazole in 45 cm3 of
dimethylformamide. The reaction medium is heated at a
temperature in the region of 8 0°C for 1 hour. The
mixture is then cooled to a temperature in the region
of 20°C, and filtered over supercel. The filtrate is
taken up with 2 00 cm3 of water and 100 cm3 of ethyl
acetate. The organic phase is separated by settling
out, washed with 3 times 100 cm3 of water, dried over
anhydrous magnesium sulfate, filtered and concentrated
to dryness under reduced pressure (2 kPa). The residue
is purified by chromatography, under a nitrogen
pressure of 50 kPa, on a column of silica gel (particle
size 20-45 (i; diameter 2 cm; height 40 cm) , eluting
with a mixture of cyclohexane and ethyl acetate (95/5
by volume). 4.5 g of 3-benzyloxy-1-(toluene-4-
sulfonyl)-4-tributylstannanyl-1H-pyrazole are obtained
in the form of a yellow oil. Mass spectrum (EI) : m/z
618 (M+-), m/z 561 (base peak).
Example 42
4-(3-Methoxyphenyl)-1-(2-piperidin-1-ylethyl) -1H-
pyrazol-3-ol hydrochloride
The product is prepared according to the procedure
described for the preparation of 4-(4-trifluorometh-
oxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol,
using 760 mg of 3-benzyloxy-4-(3-methoxyphenyl)-1-(2-
piperidin-1-ylethyl)-1H-pyrazole, 6.5 cm3 of 12N

hydrochloric acid and 6.5 cm3 of ethanol. The medium is
concentrated to dryness under reduced pressure (2 kPa);
the residue is precipitated from ethanol. 232 mg of the
expected product are obtained in the form of a powder.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.25 to 1.50 (unresolved peak: 1H) ; from 1.60 to 1.90
(mt: 5H); from 2.80 to 3.05 (unresolved peak: 2H); from
3.35 to 3.55 (unresolved peak: 4H) ; 3.78 (s: 3H); 4.38
(mt: 2H) ; 6.72 (ddd, J = 7-6 and 3 Hz: 1H) ; from 7.15
to 7.30 (mt: 3H) ; 8.05 (s: 1H) ; from 9.80 to 10.10
(broad unresolved peak: 1H) ; 10.45 (unresolved peak:
1H) . Mass spectrum (EI): m/z 301 (M+-), m/z 98 (base
peak) .
The 3-benzyloxy-4-(3-methoxyphenyl)-1-(2-piperidin-1-
ylethyl)-1H-pyrazole can be prepared in the following
way:
The product is prepared according to the procedure
described for the preparation of 3-benzyloxy-4-(4-
trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazole, using 590 mg of 3-benzyloxy-4- (3-
methoxyphenyl)-1H-pyrazole, 176 mg of sodium hydride at
75% in liquid petroleum jelly, 542 mg of 1-(2-
chloroethyl)piperidine and 10 cm3 of anhydrous
dimethylformamide. After purification on an FC50SI-HP
silica cartridge, eluting with a mixture of
dichloromethane and methanol (98/2 by volume), 7 60 mg
of the expected product are obtained in the form of a
colorless oil. Mass spectrum (EI) : m/z 391 (M+'), m/z 98
(base peak).
The 3-benzyloxy-4-(3-methoxyphenyl)-1H-pyrazole can be
prepared in the following way:
The product is prepared according to the procedure
described for the preparation of 3-benzyloxy-4-(4-
trifluoromethoxyphenyl)-1H-pyrazole, using 1.32 g of

3-benzyloxy-4-(3-methoxyphenyl)-1-(toluene-4-sulfonyl)-
lH-pyrazole, 6.94 cm3 of a IN solution of
n-tetrabutylammonium fluoride in tetrahydrofuran and
80 cm3 of tetrahydrofuran. After purification by
precipitation from diethyl ether and purification on an
FC50SI-HP silica cartridge, eluting with a mixture of
dichloromethane and methanol (95/5 by volume), 590 mg
of the expected product are obtained. Mass spectrum
(EI): m/z 280 (M+-), m/z 91 (base peak).
The 3-benzyloxy-4-(3-methoxyphenyl)-1-(toluene-4-
sulfonyl)-1H-pyrazole can be prepared in the following
way:
The product is prepared according to the procedure
described for the preparation of 3-benzyloxy-1-
(toluene-4-sulfonyl)-4-(4-trifluoromethoxyphenyl)-1H-
pyrazole, using 1.5 g of 3-benzyloxy-4-iodo-1-(toluene-
4-sulfonyl)-1H-pyrazole, 1.5 g of 3-methoxyphenyl-
boronic acid, 496 mg of tetrakis(triphenylphosphine)-
palladium, and 496 cm3 of a 2N aqueous solution of
potassium carbonate in a mixture of 3 0 cm3 of toluene
and ethanol (4/1 by volume). After purification on an
FC50SI-HP silica cartridge, eluting with a mixture of
cyclohexane and ethyl acetate (90/10 by volume), 1.13 g
of the expected product are obtained in the form of
pale yellow crystals. Mass spectrum (EI): m/z 434 (M+'),
m/z 279 and m/z 91 (base peak).
Example 43
4-(2-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol hydrochloride
The product is prepared according to the procedure
described for the preparation of 4-(4-trifluoromethoxy-
phenyl) -1- (2-piperidin-1-ylethyl)-1H-pyrazol-3-ol,
using 450 mg of 3-benzyloxy-4-(2-methoxyphenyl)-1-(2-

piperidin-1-ylethyl)-1H-pyrazole, 3.8 cm3 of 12N
hydrochloric acid and 3.8 cm of ethanol. The medium is
concentrated to dryness under reduced pressure (2 kPa);
the residue is precipitated from acetonitrile. 380 mg
of the expected product are obtained in the form of a
yellow powder.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.25 to 1.50 (mt: 1H); from 1.60 to 1.90 (mt: 5H); 2.94
(mt: 2H) ; from 3.30 to 3.60 (mt : 4H) ; 3.86 (s: 3H) ;
4.44 (t, J = 6.5 Hz: 2H) ; 6.95 (double doublet of
triplet, J = 7.5 and 1 Hz: 1H) ; 7.05 (broad d, J = 7.5
Hz: 1H) ; 7.17 (double doublet of triplet, J = 7.5 and
1.5 Hz: 1H) ; 7.91 (dd, J = 7.5 and 1.5 Hz: 1H) ; 8.03
(s: 1H) ; from 10.10 to 10.30 (unresolved peak: 1H) ;
from 10.20 to 10.45 (broad unresolved peak: 1H).
Mass spectrum (CI): m/z 302 ([M+H]+) (base peak).
The 3-benzyloxy-4-(2-methoxyphenyl)-1-(2-piperidin-1-
ylethyl)-1H-pyrazole can be prepared in the following
way:
The product is prepared according to the procedure
described for the preparation of 3-benzyloxy-4-(4-
trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazole, using 382 mg of 3-benzyloxy-4-(2-methoxy-
phenyl) -1H-pyrazole, 114 mg of sodium hydride at 75% in
liquid petroleum jelly, 351 mg of 1-(2-chloroethyl)-
piperidine and 11 cm3 of anhydrous dimethylformamide.
After purification on an FC50SI-HP silica cartridge,
eluting with a mixture of dichloromethane and methanol
(95/5 by volume) , 450 mg of the expected product are
obtained in the form of a pale yellow oil. Mass
spectrum (EI) : m/z 391 (M+')7 m/z 98 (base peak) .
The 3-benzyloxy-4-(2-methoxyphenyl)-1H-pyrazole can be
prepared in the following way:

The product is prepared according to the procedure
described for the preparation of 3-benzyloxy-4-(4-
trifluoromethoxyphenyl)-1H-pyrazole, using 720 mg of
3-benzyloxy-4-(2-methoxyphenyl)-1-(toluene-4-sulfonyl)-
lH-pyrazole, 3.5 cm3 of an N solution of n-tetrabutyl-
ammonium fluoride in tetrahydrofuran and 5 0 cm3 of
tetrahydrofuran. After purification on an FC50SI-HP
silica cartridge, eluting with a mixture of
dichloromethane and methanol (95/5 by volume), 382 mg
of the expected product are obtained in the form of a
pinkish beige solid. Mass spectrum (EI): m/z 280 (M+.),
m/z 91 (base peak).
The 3-benzyloxy-4-(2-methoxyphenyl)-1-(tolune-4-
sulfonyl)-1H-pyrazole can be prepared in the following
way:
The product is prepared according to the procedure
described for the preparation of 3-benzyloxy-1-
(toluene-4-sulfonyl)-4-(4-trifluoromethoxyphenyl)-1H-
pyrazole, using 1 g of 3-benzyloxy-4-iodo-1-(toluene-4-
sulfonyl)-1H-pyrazole, 1 g of 2-methoxyphenylboronic
acid, 33 0 mg of tetrakis(triphenylphosphine)palladium,
and 3.3 cm3 of a 2N aqueous solution of potassium
carbonate in a mixture of 15 cm3 of toluene and ethanol
(4/1 by volume). After purification on an FC50SI-HP
silica cartridge, eluting with a mixture of cyclohexane
and ethyl acetate (80/20 by volume) , 720 mg of the
expected product are obtained in the form of a beige
powder. Mass spectrum (CI) : m/z 435 ( [M+H]+) and m/z
281 (base peak).
Example 44
4-(3-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol hydrochloride

A stirred solution of 516 mg of 4- (3-methoxyphenyl)-1-
(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol hydrochloride
in 13 cm3 of dichloromethane, under an inert atmosphere,
is cooled to a temperature in the region of -78 °C.
4.3 8 cm3 of boron tribromide are added and the stirring
is continued for 15 hours at a temperature in the
region of 20°C. The solution is taken up with methanol
and is then concentrated to dryness under reduced
pressure (2 kPa). The residue is taken up with 2 0 cm3 of
water and 2 0 cm3 of dichloromethane. The organic phase
is separated by settling out; the aqueous phase is
washed with a saturated aqueous sodium bicarbonate
solution until a pH of 8-8.4 is obtained (pH meter),
and then taken up with dichloromethane. The organic
phase is separated by settling out, and concentrated to
dryness under reduced pressure (2 kPa) . The white
powder obtained is taken up with 0.4 cm3 of 12N
hydrochloric acid and 5 cm3 of dioxane. The mixture is
stirred for 10 minutes and is then concentrated to
dryness under reduced pressure (2 kPa). 198 mg of 4-(3-
hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-
ol hydrochloride are obtained in the form of an ecru-
colored powder.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.25 to 1.50 (mt: 1H); from 1.60 to 1.90 (mt: 5H); 2.94
(mt: 2H) ; from 3.30 to 3.55 (mt: 4H) ; 4.40 (t, J =
6.5 Hz: 2H) ; 6.55 (ddd, J = 8-3 and 1.5 Hz: 1H) ; from
7.00 to 7.15 (mt: 3H); 8.06 (s: 1H); from 9.10 to 9.40
(broad unresolved peak: 1H) ; from 9.90 to 10.10
(unresolved peak: 1H) ; from 10.30 to 10.45 (unresolved
peak: 1H) . Mass spectrum (EI): m/z 287 (M+.) , m/z 98
(base peak).
Example 45
4-(4-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol hydrochloride

200 mg of 4-(4-methoxyphenyl)-1-(2-piperidin-1-
ylethyl)-1H-pyrazol-3-ol hydrochloride are brought to
pH 7 (Lyphan paper) with a IN aqueous sodium hydroxide
solution. The organic phase is extracted with
dichloromethane and concentrated to dryness under
reduced pressure (2 kPa). The residue is taken up with
5 cm3 of dichloromethane. The stirred solution is cooled
to a temperature in the region of -7 8 °C. 1.7 cm3 of
boron tribromide are added and the stirring is
continued for 15 hours at a temperature in the region
of 20°C. The solution is taken up with 20 cm3 of ice-
cold water and 10 cm3 of dichloromethane. The organic
phase is separated by settling out; the aqueous phase
is washed with dichloromethane and then with a
saturated aqueous sodium bicarbonate solution until a
pH of 8-8.4 (pH meter) is obtained, and then taken up
with dichloromethane. The organic phase is separated by
settling out, and concentrated to dryness under reduced
pressure (2 kPa). The white powder obtained is taken up
with 3 00 µl of 12N hydrochloric acid and 5 cm3 of
dioxane. The mixture is stirred for 10 minutes and then
concentrated to dryness under reduced pressure (2 kPa).
101 mg of 4-(4-hydroxyphenyl)-1-(2-piperidin-1-
ylethyl)-1H-pyrazol-3-ol hydrochloride are obtained in
the form of an ecru-colored powder.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.25 to 1.50 (mt: 1H); from 1.60 to 1.90 (mt: 5H); 2.92
(mt: 2H) ; from 3.30 to 3.50 (mt: 4H) ; 4.38 (t, J =
6.5 Hz: 2H) ; 6.75 (broad d, J = 8.5 Hz: 2H) ; 7.45
(broad d, J = 8.5 Hz: 2H) ; 7.85 (s: 1H) ; from 9.10 to
9.35 (broad unresolved peak: 1H) ; from 10.00 to 10.20
(unresolved peak: 1H) ; from 10.15 to 10.30 (unresolved
peak: 1H).
Mass spectrum (EI): m/z 287 (M+.), m/z 98 (base peak).
Example 46

4-(4-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol dihydrochloride
7 cm3 of IN hydrochloric diethyl ether are added to a
solution of 640 mg of 1-{2- [3-benzyloxy-4-(4-
methoxyphenyl)pyrazol-1-yl]ethyl}piperidine in 20 cm3 of
ethanol. After stirring for 3 0 min at a temperature in
the region of 20°C, the solution is evaporated to
dryness under reduced pressure (2.7 kPa). The residue
is taken up with 2 0 cm3 of ethanol. The solution
obtained is introduced into an autoclave, and 87 mg of
palladium-on-charcoal at 10% are added, and it is then
placed under hydrogen (8 bar) . After stirring for 8 h
at a temperature in the region of 30°C, the reaction
medium is filtered over supercel and the filtrate is
evaporated. Diisopropyl ether is added to the residue,
resulting in a suspension, which is heated at the
reflux of the solvent and filtered under hot
conditions. The resulting solid is dried under vacuum
(2.7 kPa) to give 400 mg of 4-(4-methoxyphenyl)-1-(2-
piperidin-1-ylethyl)-1H-pyrazol-3-ol dihydrochloride in
the form of a white powder.
IR spectrum (KBr): 3052; 2933; 2655; 2559; 1578; 1569;
1518; 1501; 1453; 1248; 1170; 1020; 837; 810; 652 and
52 8 cm-1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.3 0 to 1.50 (mt: 1H); from 1.60 to 1.90 (mt: 5H); from
2.80 to 3.05 (mt: 2H) ; 3.46 (mt: 4H) ; 3.76 (s: 3H) ;
4.37 (broad t, J = 6 Hz: 2H); 6.93 (d, J = 8.5 Hz: 2H);
7.57 (d, J = 8.5 Hz: 2H); 7.92 (broad s: 1H); from 9.75
to 9.95 (broad unresolved peak: 1H) ; 10.32 (broad s:
1H) .
The l-{2-[3-benzyloxy-4-(4-methoxyphenyl)pyrazol-1-
yl]ethyl}piperidine can be prepared in the following
way:

2 g of 4-methoxyphenylboronic acid, 2.85 g of potassium
phosphate and 750 mg of
bis(triphenylphosphine)palladium chloride are added to
a stirred solution of 1.2 g of 1-[2-(3-benzyloxy-4-
bromopyrazol-1-yl)ethyl]piperidine in 60 cm3 of 1,2-
dimethoxyethane under an argon atmosphere. After
heating for 15 h at the reflux of the solvent, the
reaction medium is evaporated under reduced pressure
(2.7 kPa) . Ethyl acetate and water are added to the
residue, which is filtered over supercel. The filtrate
is separated by settling out, and the organic phase is
washed successively with water, a saturated aqueous
hydrogen carbonate solution, and a saturated aqueous
sodium chloride solution; it is dried over magnesium
sulfate, filtered and evaporated under reduced pressure
(2.7 kPa) . The brown oil obtained (3.6 g) is purified
by flash chromatography on alumina CTB1 under an argon
pressure (50 kPa) [eluent: cyclohexane/ethyl acetate
(90/10 by volume)]. After concentration of the
fractions under reduced pressure (2.7 kPa), 700 mg of
l-{2- [3-benzyloxy-4-(4-methoxyphenyl)pyrazol-1-
yl]ethyl}piperidine are obtained in the form of a
yellow oil.
Mass spectrum (EI): m/z 391 (M+-), m/z 280 [ (M -
C7H13N)+], m/z 111 (C7H13N+), m/z 98 (CeH12N+) , m/z
91 (C7H7+) .
Example 47
4-(3-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol dihydrochloride
3.5 cm3 of 12N hydrochloric acid are added to a stirred
solution of 400 mg of 1-{2-[3-benzyloxy-4-(3-
fluorophenyl)pyrazol-1-yl]ethyl}piperidine in 3.5 cm3 of
ethanol. After 7 h at the reflux of the solvent, and
then 15 h at a temperature in the region of 2 0°C, the
reaction medium is evaporated to dryness under reduced

pressure (2.7 kPa) . The residue is dried under vacuum
(2.7 kPa) at 45°C for 1 h, and is triturated in
diisopropyl ether. The precipitate formed is filtered
and dried under vacuum (2.7 kPa) to give 350 mg de
4-(3-fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol dihydrochloride in the form of a white
solid.
IR spectrum (KBr): 2951; 2647; 2540; 1619; 1586; 1530;
1456; 1267; 1178; 882; 785; 687 and 523 cm"1.
1H NMR spectrum (300 MHz, (CD3)2SO d6 with the addition
of a few drops of CD3COOD d4, δ in ppm) : 1.42 (mt: 1H) ;
from 1.60 to 1.90 (mt: 5H); 2.95 (mt: 2H); from 3.4 0 to
3.55 (mt: 2H) ; 3.50 (t, J= 6.5 Hz: 2H) ; 4.39 (t, J =
6.5 Hz: 2H) ; 6.95 (tdd, J = 7.5-3 and 1 Hz: 1H) ; from
7.30 to 7.50 (mt: 3H); 8.09 (s: 1H).
The l-{2-[3-benzyloxy-4-(3-fluorophenyl)pyrazol-1-yl]-
ethyl}piperidine can be prepared in the following way:
1.15 g of 3-fluorophenylboronic acid, 4.1 cm3 of a 2N
aqueous potassium carbonate solution and 475 mg of
tetrakis(triphenylphosphine)palladium are added to a
stirred solution, under an argon atmosphere, of 1 g of
1-[2-(3-benzyloxy-4-bromopyrazol-1-yl)ethyl]piperidine
in a mixture of 2 0 cm3 of toluene and of 5 cm3 of
ethanol. After heating at the reflux of the solvent for
3 h and at a temperature in the region of 2 0°C for
15 h, ethyl acetate and water are added to the reaction
medium, which is filtered over supercel. The filtrate
is separated by settling out, and the organic phase is
then washed successively with 2 times water and a
saturated aqueous sodium chloride solution; it is dried
over magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa) . The brown oil obtained
(2.1 g) is purifed by flash chromatography on silica
under an argon pressure (50 kPa) [eluent: ethyl
acetate]. After concentration of the fractions under
reduced pressure, 400 mg of 1-{2-[3-benzyloxy-4- (3-

fluorophenyl)pyrazol-1-yl]ethyljpiperidine are obtained
in the form of a yellow oil.
IR spectrum (CC14) : 2939; 2854; 2802; 1617; 1586; 1509;
1463; 1432; 1359; 1272; 1187; 1169; 1160; 1043; 883;
695 and 687 cm"1.
Example 48
1-(2-Piperidin-1-ylethyl)-4-(3-trifluoromethylphenyl)-
lH-pyrazol-3-ol dihydrochloride
5 cm3 of 12N hydrochloric acid are added to a stirred
solution of 470 mg of 1-{2-[3-benzyloxy-4-(3-trifluoro-
methylphenyl) pyrazol-1-yl]ethyl}piperidine in 5 cm3 of
ethanol. After 7 h at the reflux of the solvent, and
then 15 h at a temperature in the region of 20°C, the
reaction medium is evaporated to dryness under reduced
pressure (2.7 kPa) . The residue is dried under vacuum
(2.7 kPa) at 45°C for 1 h, and is then triturated in
diisopropyl ether. The precipitate formed is filtered
and dried under vacuum (2.7 kPa) to give 350 mg of
1-(2-piperidin-1-ylethyl)-4-(3-trifluoromethylphenyl)-
lH-pyrazol-3-ol dihydrochloride in the form of a pale
yellow solid.
IR spectrum (KBr): 2955; 2629; 2533; 1619; 1533; 1325;
1188; 1170; 1117; 1076; 800; 696 and 688 cm"1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 1.40
(mt: 1H) ; from 1.60 to 1.90 (mt: 5H) ; 2.94 (mt: 2H) ;
from 3.30 to 3.55 (mt: 4H) ; 4.43 (t, J = 6.5 Hz: 2H) ;
7.50 (broad d, J = 7.5 Hz: 1H) ; 7.59 (t, J = 7.5 Hz:
1H) ; 7.95 (broad d, J = 7.5 Hz: 1H) ; 8.01 (broad s:
1H) ; 8.22 (s: 1H) ; 10.24 (unresolved peak: 1H) ; from
10.60 to 10.90 (broad unresolved peak: 1H).
The l-{2-[3-benzyloxy-4-(3-trifluoromethylphenyl)-
pyrazol-1-yl]ethyl}piperidine can be prepared in the
following way:

1.58 g of 3-trifluoromethylphenylboronic acid, 4.1 cm3
of a 2N aqueous potassium carbonate solution and 475 mg
of tetrakis(triphenylphosphine)palladium are added to a
stirred solution, under an argon atmosphere, of 1 g of
1-[2-(3-benzyloxy-4-bromopyrazol-1-yl)ethyl]piperidine
in a mixture of 2 0 cm3 of toluene and of 5 cm3 of
ethanol. After heating at the reflux of the solvent for
3 h, the reaction medium is evaporated under reduced
pressure (2.7 kPa) . Ethyl acetate and water are added
to the residue, which is filtered over supercel. The
filtrate is separated by settling out, and the organic
phase is then washed successively with 2 times water
and a saturated aqueous sodium chloride solution; it is
dried over magnesium sulfate, filtered and evaporated
under reduced pressure (2.7 kPa) . The brown oil
obtained (3 g) is purified by flash chromatography on
silica under an argon pressure (50 kPa) [eluent: ethyl
acetate/methanol (95/5 by volume)]. After concentration
of the fractions under reduced pressure (2.7 kPa), a
residue is obtained which is taken up with ethyl
acetate. The solution is treated with carbon black,
filtered and evaporated under reduced pressure
(2.7 kPa) to give 470 mg of 1- {2- [3-benzyloxy-4- (3-
trifluoromethylphenyl)pyrazol-1-yl]ethyl}piperidine in
the form of an orange-colored oil.
1H NMR spectrum (3 00 MHz, (CD3)2SO dS, δ in ppm) : from
1.30 to 1.55 (mt: 6H); 2.40 (unresolved peak: 4H); 2.70
(unresolved peak: 2H) ; 4.10 (unresolved peak: 2H) ,- 5.34
(s: 2H) ; from 7.30 to 7.55 (mt: 6H) ; 7.58 (t, J =
7.5 Hz: 1H); 7.92 (broad d, J = 7.5 Hz: 1H); 8.03
(broad s: 1H); 8.25 (s: 1H).
Example 49
1-(2-Piperidin-1-ylethyl)-4-pyridin-3-yl-1H-pyrazol-
3-ol dihydrochloride

7 cm3 of 12N hydrochloric acid are added to a stirred
solution of 720 mg of 3-[3-benzyloxy-1-(2-piperidin-1-
ylethyl)-1H-pyrazol-4-yl]pyridine in 7 cm3 of ethanol.
After 7 h at the reflux of the solvent, and then 15 h
at a temperature in the region of 2 0°C, the reaction
medium is evaporated to dryness under reduced pressure
(2.7 kPa) . The residue is taken up with ethanol, and
the mixture is then evaporated to dryness under vacuum
(2.7 kPa) . The operation is repeated twice, and the
solid is then dried under vacuum (2.7 kPa) at 45°C for
1 h, and is triturated in acetone. The precipitate
formed is filtered off and dried under vacuum (2.7 kPa)
to give 190 mg of 1- (2-piperidin-1-ylethyl)-4-pyridin-
3-yl-1H-pyrazol-3-ol dihydrochloride in the form of a
white solid.
IR spectrum (KBr): 2970; 2434; 2931; 1601; 1551; 1460;
1307; 1178; 825; 691 and 624 cm"1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 1.40
(mt: 1H) ; from 1.60 to 1.90 (mt: 5H) ; 2.94 (mt: 3H) ;
from 3.25 to 3.65 (mt: 3H) ; 4.50 (t, J = 6.5 Hz: 2H) ;
7.88 (broad dd, J = 8 and 5 Hz: 1H); 8.39 (s: 1H); 8.55
(broad d, J = 8 Hz: 1H); 8.60 (broad d, J = 5 Hz: 1H);
9.02 (broad d, J = 1.5 Hz: 1H); 10.60 (unresolved peak:
1H); 11.20 (unresolved peak: 1H).
The 3- [3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-4-yl]pyridine can be prepared in the following
way:
580 mg of 3-diethylboranylpyridine, 690 mg of sodium
carbonate dissolved in 20 cm3 of water, and 390 mg of
tetrakis(triphenylphosphine)palladium are added to a
stirred solution of 950 mg of 1-[2-(3-benzyloxy-4-
bromopyrazol-1-yl)ethyl]piperidine in 100 cm3 of dioxane
and under an argon atmosphere. After heating at the
reflux of the solvent for 3 h, the reaction medium is
cooled to a temperature in the region of 2 0°C, ethyl
acetate and water are added, and the mixture is

filtered over supercel. The filtrate is separated by
settling out, and the organic phase is then washed with
water and a saturated aqueous sodium chloride solution;
it is dried over magnesium sulfate, filtered and
evaporated under reduced pressure (2.7 kPa). The brown
oil obtained (2 g) is purified by flash chromatography
on alumina CTB1 under an argon pressure (50 kPa)
[eluent: cyclohexane/ethyl acetate (97/3 by volume),
then ethyl acetate]. After concentration of the
fractions under reduced pressure (2.7 kPa), a residue
is obtained which is purified by flash chromatography
on silica under an argon pressure (50 kPa) [eluent:
ethyl acetate/methanol (90/10 by volume)]. After
concentration of the fractions under reduced pressure
(2.7 kPa) , 220 mg of 3-[3-benzyloxy-1-(2-piperidin-1-
ylethyl)-1H-pyrazol-4-yl]pyridine are obtained in the
form of a yellow oil.
IR spectrum (CC14) : 2940; 2854; 2801; 1599; 1575; 1505;
1453; 1362; 1167; 1020; 708 and 702 cm"1.
Example 50
4-(4-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol dihydrochloride
3.5 cm3 of 12N hydrochloric acid are added to a stirred
solution of 470 mg of l-{2-[3-benzyloxy-4-(4-
chlorophenyl)pyrazol-1-yl]ethyl}piperidine in 3.5 cm3 of
ethanol. After 7 h at the reflux of the solvent, and
then 15 h at a temperature in the region of 20°C, the
reaction mixture is evaporated to dryness under reduced
pressure (2.7 kPa) . The residue is dried under vacuum
(2.7 kPa) at 45°C for 2 h, and is then triturated in
diisopropyl ether. The precipitate formed is filtered
and dried under vacuum (2.7 kPa) to give 430 mg of
4-(4-chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol dihydrochloride in the form of a white
solid.

IR spectrum (KBr): 2952; 2640; 2534; 1607; 1578; 1552;
1521; 1455; 1191; 1093; 1011; 830; 818 and 516 cm"1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 1.39
(mt: 1H) ; from 1.60 to 1.85 (mt: 5H) ; 2.92 (mt : 2H) ;
from 3.35 to 3.45 (mt: 2H) ; 3.46 (broad t, J = 6.5 Hz:
2H) ; 4.42 (t, J = 6.5 Hz: 2H) ; 7.39 (dmt, J = 8.5 Hz:
2H) ; 7.67 (dmt, J = 8.5 Hz: 2H) ; 8.08 (s: 1H) ; 10.39
(unresolved peak: 1H).
The l-{2-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-
ethyl}piperidine can be prepared in the following way:
A solution of 440 mg of 3-benzyloxy-4-(4-chlorophenyl)-
lH-pyrazole in 2 0 cm3 of dimethylformamide is added to a
suspension of 132 mg of sodium hydride (at 75% in
liquid petroleum jelly) in 15 cm3 of dimethylformamide
under an argon atmosphere and with stirring. After
heating at 50°C for 30 min, the mixture is stirred for
3 0 min at a temperature in the region of 2 0°C, and
400 mg of 1-(2-chloroethyl)piperidine hydrochloride are
then added. The reaction medium is stirred for 15 h at
a temperature in the region of 2 0°C, and is then poured
into water. The aqueous phase is extracted twice with
ethyl acetate. The organic phases are pooled, washed
successively with water and a saturated aqueous sodium
chloride solution, dried over magnesium sulfate,
filtered and evaporated under reduced pressure
(2.7 kPa) to give a pale yellow oil, which is purified
by flash chromatography on alumina CTB1 under an argon
pressure (50 kPa) [eluent: cyclohexane/ethyl acetate
(95/5, then 90/10 by volume)]. After concentration of
the fractions under reduced pressure, 470 mg of l-{2-
[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-
yl] ethyl}piperidine are obtained in the form of a pale
yellow oil.
IR spectrum (CC14) : 2938; 1574; 1509; 1482; 1452; 1358;
1171; 1094; 1037; 1014; 834; 695 and 511 cm"1.

The 3-benzyloxy-4-(4-chlorophenyl)-1H-pyrazole can be
prepared in the following way:
2 cm3 of IN solution of tetrabutylammonium fluoride in
tetrahydrofuran are added to a stirred solution, under
an argon atmosphere, of 800 mg of 3-benzyloxy-4-(4-
chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in
2 0 cm3 of tetrahydrofuran. After heating at the reflux
of the solvent for 2 h, 0.5 cm3 of IN solution of
tetrabutylammonium fluoride in tetrahydrofuran is added
to the reaction medium, which is maintained at 60°C for
15 h. A further 0.5 cm3 of IN solution of
tetrabutylammonium fluoride in tetrahydrofuran is added
to the solution, which is heated at the reflux of the
solvent for a further 2 h. The reaction medium is then
cooled to a temperature in the region of 2 0°C and
evaporated under reduced pressure (2.7 kPa). Ethyl
acetate is added to the residue, and the organic phase
is washed successively with two times water and a
saturated aqueous sodium chloride solution; it is dried
over magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa) . The resulting yellow solid
is purified by flash chromatography on silica under an
argon pressure (50 kPa) [eluent: eyelohexane/ethyl
acetate (8 0/2 0 by volume), then ethyl acetate]. After
concentration of the fractions under reduced pressure
(2.7 kPa), 440 mg of 3-benzyloxy-4-(4-chlorophenyl)-1H-
pyrazole are obtained in the form of a white solid.
Mass spectrum (EI): m/z 284 (M+-), m/z 206 [ (M -
C6H6)+] , m/z 91 (C7H7+) .
The 3-benzyloxy-4-(4-chlorophenyl)-1-(toluene-4-
sulfonyl)-1H-pyrazole can be prepared in the following
way:
1.15 g of 4-chlorophenylboronic acid, 3.6 cm3 of a 2N
aqueous potassium carbonate solution and 3 60 mg of
tetrakis(triphenylphosphine)palladium are added to a

stirred solution, under an argon atmosphere, of 1.1 g
of 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-
pyrazole in 2 0 cm3 of toluene to which 5 cm3 of ethanol
have been added. After heating at the reflux of the
solvent for 15 h, the reaction medium is evaporated
under reduced pressure (2.7 kPa). Ethyl acetate, water
and carbon black are added to the residue, which is
filtered over supercel. The filtrate is separated by
settling out, and the organic phase is then washed
successively with two times water and a saturated
aqueous sodium chloride solution; it is dried over
magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa) . The brown oil obtained
(2.6 g) is purified by flash chromatography on silica
under an argon pressure (50 kPa) [eluent:
cyclohexane/ethyl acetate (90/10 by volume)]. After
concentration of the fractions under reduced pressure
(2.7 kPa), 800 mg of 3-benzyloxy-4-(4-chlorophenyl)-1-
(toluene-4-sulfonyl)-1H-pyrazole are obtained in the
form of an orange-colored solid. Mass spectrum
(CI): m/z 456 (MNH4+) , m/z 439 (MH+) .
Example 51
4-(3-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol dihydrochloride
5 cm3 of 12N hydrochloric acid are added to a stirred
solution of 550 mg of 1-{2-[3-benzyloxy-4-(3-
chlorophenyl)pyrazol-1-yl]ethyl}piperidine in 5 cm3 of
ethanol. After 7 h at the reflux of the solvent, and
then 15 h at a temperature in the region of 20°C, the
reaction medium is evaporated to dryness under reduced
pressure (2.7 kPa) . The residue is dried under vacuum
(2.7 kPa) at 45°C for 2 h, and is then triturated in
diisopropyl ether. The precipitate formed is filtered
and dried under vacuum (2.7 kPa) to give 460 mg of
4-(3-chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-

pyrazol-3-ol dihydrochloride in the form of a white
solid.
IK spectrum (KBr): 2951; 2637; 2436; 1394; 1603; 1565;
1521; 1454; 1180; 778 and 689 cm"1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 1.40
(mt: 1H) ; from 1.60 to 1.90 (mt: 5H) ; 2.95 (mt: 2H) ;
from 3.35 to 3.55 (mt: 4H) ; 4.40 (t, J = 6.5 Hz: 2H) ;
7.20 (dmt, J = 8 Hz: 1H); 7.37 (t, J = 8 Hz: 1H); 7.62
(broad d, J = 8 Hz: 1H) ; 7.73 (t, J = 2 Hz: 1H) ; 8.14
(s: 1H); 9.90 (unresolved peak: 1H); 10.69 (unresolved
peak: 1H).
The l-{2- [3-benzyloxy-4-(3-chlorophenyl)pyrazol-1-yl]-
ethyl}piperidine can be prepared in the following way:
A solution of 500 mg of 3-benzyloxy-4-(3-chlorophenyl)-
lH-pyrazole in 2 0 cm3 of dimethylformamide is added to a
suspension of 142 mg of sodium hydride (at 75% in
liquid petroleum jelly) in 15 cm3 of dimethylformamide
under an argon atmosphere and with stirring. After
heating at 50°C for 30 min, the mixture is stirred for
3 0 min at a temperature in the region of 20°C, and a
solution of 500 mg of 1-(2-chloroethyl)piperidine
hydrochloride is then added. The reaction medium is
stirred at a temperature in the region of 2 0°C for
15 h, and is then poured into water. The aqueous phase
is extracted twice with ethyl acetate. The organic
phases are pooled, washed successively with water and a
saturated aqueous sodium chloride solution, dried over
magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa) to give a yellow oil which
is purified by flash chromatography on alumina CTB1
under an argon pressure (50 kPa) [eluent:
cyclohexane/ethyl acetate (95/5 by volume)]. After
concentration of the fractions under reduced pressure,
550 mg of 1-{2-[3-benzyloxy-4-(3-chlorophenyl)pyrazol-
1-yl]ethyl}piperidine are obtained in the form of a
yellow oil.

IR spectrum (CCl4) : 2938; 2853; 1603; 1574; 1507; 1452;
1357; 1260; 1174; 1046; 997; 695 and 687 cm"1.
The 3-benzyloxy-4-(3-chlorophenyl)-1H-pyrazole can be
prepared in the following way:
4.6 cm3 of a 1N solution of tetrabutylammonium fluoride
in tetrahydrofuran are added to a stirred solution,
under an argon atmosphere, of 810 mg of 3-benzyloxy-4-
(3-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in
2 0 cm3 of tetrahydrofuran. After heating at the reflux
of the solvent for 15 h, the reaction medium is
evaporated under reduced pressure (2.7 kPa) and ethyl
acetate is added to the residue. The organic phase is
washed successively with two times water and a
saturated aqueous sodium chloride solution; it is dried
over magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa) . The resulting oil (0.7 g)
is purified by flash chromatography on silica under an
argon pressure (50 kPa) [eluent: cyclohexane/ethyl
acetate (70/30 by volume)]. After concentration of the
fractions under reduced pressure (2.7 kPa), 500 mg of
3-benzyloxy-4-(3-chlorophenyl)-1H-pyrazole are obtained
in the form of a white solid.
IR spectrum (KBr): 3148; 2957; 1601; 1505; 1446; 1422;
1355; 1237; 1229; 1046; 785; 729; 682 and 597 cm"1.
The 3-benzyloxy-4-(3-chlorophenyl)-1-(toluene-4-
sulfonyl)-1H-pyrazole can be prepared in the following
way:
1.03 g of 3-chlorophenylboronic acid, 3.3 cm3 of a 2N
aqueous potassium carbonate solution and 380 mg of
tetrakis(triphenylphosphine)palladium are added to a
stirred solution, under an argon atmosphere, of 1 g of
3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole
in 2 0 cm3 of toluene to which 5 cm3 of ethanol have been
added. After heating at the reflux of the solvent for

2.5 h, the reaction medium is evaporated under reduced
pressure (2.7 kPa) . Ethyl acetate, water and carbon
black are added to the residue, which is filtered over
supercel. The filtrate is separated by settling out,
and the organic phase is then washed successively with
two times water and a saturated aqueous sodium chloride
solution; it is dried over magnesium sulfate, filtered
and evaporated under reduced pressure (2.7 kPa) . The
orange-colored oil obtained (2 g) is purified by flash
chromatography on silica under an argon pressure
(50 kPa) [eluent: cyclohexane/ethyl acetate (97/3 by
volume)]. After concentration of the fractions under
reduced pressure (2.7 kPa), 810 mg of 3-benzyloxy-4-(3-
chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole are
obtained in the form of a yellow solid.
IR spectrum (KBr): 3098; 1604; 1508; 1372; 1357; 1189;
1180; 1094; 991; 790; 672; 586; 554 and 536 cm"1.
Example 52
4-(2-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol dihydrochloride:
7 cm3 of 12N hydrochloric acid are added to a stirred
solution of 800 mg of 1-{2- [3-benzyloxy-4-(2-
fluorophenyl)pyrazol-1-yl]ethyl}piperidine in 10 cm3 of
ethanol. After 7 h at the reflux of the solvent, and
then 15 h at a temperature in the region of 2 0°C, the
reaction medium is evaporated to dryness under reduced
pressure (2.7 kPa). The crude is taken up with ethanol,
and the mixture is then evaporated to dryness under
reduced pressure (2.7 kPa); the operation is repeated
twice. The residue is triturated in diisopropyl ether,
and the precipitate formed is filtered off, and is then
dissolved under hot conditions in ethanol. The crystals
which have appeared after cooling of the solution in an
ice bath are filtered and dried under vacuum (2.7 kPa)
to give 470 mg of 4-(2-fluorophenyl)-1-(2-piperidin-1-

ylethyl)-1H-pyrazol-3-ol dihydrochloride in the form of
a white solid.
lit spectrum (KBr) : 2947; 2621; 2540; 1620; 1538; 1463;
1231; 1186; 1093; 970; 761 and 656 cm"1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 1.41
(mt: 1H) ; from 1.60 to 1.90 (mt: 5H) ; 2.94 (mt: 2H) ;
from 3.35 to 3.55 (mt: 4H) ; 4.46 (broad t, J = 6.5 Hz:
2H); from 7.15 to 7.30 (mt: 3H); from 7.90 to 8.05 (mt:
2H); 10.15 (unresolved peak: 1H); 10.65 (broad s: 1H).
The l-{2-[3-benzyloxy-4-(2-fluorophenyl)pyrazol-1-yl]-
ethyl}piperidine can be prepared in the following way:
A solution of 650 mg of 3-benzyloxy-4-(2-fluorophenyl)-
lH-pyrazole in 2 0 cm3 of dimethylformamide is added to a
suspension of 200 mg of sodium hydride (at 75% in
liquid petroleum jelly) in 10 cm3 of dimethylformamide
under an argon atmosphere and with stirring. After
heating at 50°C for 30 min, the mixture is stirred at a
temperature in the region of 2 0°C for 3 0 min, and
625 mg of 1-(2-chloroethyl)piperidine hydrochloride are
added. The reaction medium is stirred for 15 h at a
temperature in the region of 2 0°C, and is then poured
into 100 cm3 of water. The aqueous phase is extracted
twice with ethyl acetate. The organic phases are
pooled, washed successively with two times water and a
saturated aqueous sodium chloride solution, dried over
magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa) to give a yellow oil
(1.1 g) , which is purified by flash chromatography on
alumina CTB1 under an argon pressure (50 kPa) [eluent:
cyclohexane/ethyl acetate (95/5 by volume)]. After
concentration of the fractions under reduced pressure,
800 mg of 1-{2-[3-benzyloxy-4-(2-fluorophenyl)pyrazol-
1-yl]ethyl}piperidine are obtained in the form of a
yellow oil.
IR spectrum (CCl4) : 2938; 2855; 2801; 1572; 1512; 1486;
1358; 1175; 1044; 1027 and 696 cm"1.

The 3-benzyloxy-4-(2-fluorophenyl)-1H-pyrazole can be
prepared in the following way:
7.4 cm3 of a IN solution of tetrabutylammonium fluoride
in tetrahydrofuran are added to a stirred solution,
under an argon atmosphere, of 1.2 5 g of 3-benzyloxy-4-
(2-fluorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in
3 0 cm3 of tetrahydrofuran. After heating at the reflux
of the solvent for 15 h, the reaction medium is
evaporated under reduced pressure (2.7 kPa) and ethyl
acetate is added to the residue. The organic phase is
washed successively with two times water and a
saturated aqueous sodium chloride solution; it is dried
over magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa). The resulting oil (0.92 g)
is purified by flash chromatography on silica under an
argon pressure (50 kPa) [eluent: cyclohexane/ethyl
acetate (70/30 by volume)]. After concentration of the
fractions under reduced pressure (2.7 kPa), 650 mg of
3-benzyloxy-4-(2-fluorophenyl)-1H-pyrazole are obtained
in the form of a white solid.
IR spectrum (KBr): 3161; 2954; 2691; 1572; 1474; 1440;
1353; 1264; 1045; 1036; 1027; 759; 729 and 654 cm"1.
The 3-benzyloxy-4-(2-fluorophenyl)-1-(toluene-4-
sulfonyl)-1H-pyrazole can be prepared in the following
way:
1.4 g of 2-f luorophenylboronic acid, 5 cm3 of a 2N
aqueous potassium carbonate solution and 500 mg of
tetrakis(triphenylphosphine)palladium are added to a
stirred solution, under an argon atmosphere, of 1.5 g
of 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-
pyrazole in a mixture of 2 0 cm3 of toluene and of 5 cm3
of ethanol. After heating at the reflux of the solvent
for 3 h, the reaction medium is cooled to a temperature
in the region of 2 0°C and evaporated under reduced

pressure (2.7 kPa) . Ethyl acetate, water and carbon
black are added to the residue, which is filtered over
supercel. The filtrate is separated by settling out,
and the organic phase is then washed successively with
two times water and a saturated aqueous sodium chloride
solution; it is dried over magnesium sulfate, filtered
and evaporated under reduced pressure (2.7 kPa). The
orange-colored oil obtained (2 g) is purified by flash
chromatography on silica under an argon pressure
(50 kPa) [eluent: cyclohexane/ethyl acetate (95/5 by
volume)]. After concentration of the fractions under
reduced pressure (2.7 kPa) , 1.25 g of 3-benzyloxy-4-(2-
fluorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole are
obtained in the form of an orange-colored oil. Mass
spectrum (EI): m/z 422 (M+"), m/z 267 [ (M - C7H702S)+],
m/z 91 (C7H7+-) .
Example 53
4-(2-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol hydrochloride
5 cm3 of 12N hydrochloric acid are added to a stirred
solution of 570 mg of 1-{2-[3-benzyloxy-4-(2-
chlorophenyl)pyrazol-1-yl]ethyl}piperidine in 7 cm3 of
ethanol. After 7 h at the reflux of the solvent, and
then 15 h at a temperature in the region of 2 0°C, the
reaction medium is evaporated to dryness under reduced
pressure (2.7 kPa). The residue is taken up with
ethanol, and the mixture is then evaporated to dryness
under vacuum (2.7 kPa). The operation is repeated
twice, and the lacquer obtained is then dried under
vacuum (2.7 kPa) at 45°C for 3 0 min, and is then
dissolved under hot conditions in ethanol. The crystals
formed after cooling of the solution in an ice bath are
filtered and dried under vacuum (2.7 kPa) to give
380 mg of 4-(2-chlorophenyl)-1-(2-piperidin-1-ylethyl)-

1H-pyrazol-3-ol hydrochloride in the form of a white
solid.
IR spectrum (KBr): 3097; 2939; 2674; 2545; 1579; 1517;
1439; 1224; 1171; 935; 758 and 653 cm"1.
1H NMR spectrum (200 MHz, (CD3)2SO d6 with the addition
of a few drops of CD3C00D d4, at a temperature of 3 63 K,
δ in ppm): 1.60 (mt: 2H); 1.81 (mt: 4H); 3.2 0
(unresolved peak: 4H); 3.49 (broad t, J = 6.5 Hz: 2H);
4.42 (broad t, J = 6.5 Hz: 2H) ; 7.26 (broad t, J =
7.5 Hz: 1H) ; 7.35 (broad t, J = 7.5 Hz: 1H) ; 7.48
(broad d, J = 7.5 Hz: 1H) ; 7.66 (broad d, J = 7.5 Hz:
1H); 7.93 (broad s: 1H).
The l-{2-[3-benzyloxy-4-(2-chlorophenyl)pyrazol-1-yl]-
ethyl}piperidine can be prepared in the following way:
A solution of 500 mg of 3-benzyloxy-4-(2-chlorophenyl)-
lH-pyrazole in 2 0 cm3 of dimethylformamide is added to a
suspension of 140 mg of sodium hydride (at 75% in
liquid petroleum jelly) in 10 cm3 of dimethylformamide
under an argon atmosphere and with stirring. After
heating at 50°C for 30 min, the mixture is stirred at a
temperature in the region of 20°C for 30 min, and
453 mg of 1-(2-chloroethyl)piperidine hydrochloride are
then added. The reaction medium is stirred at a
temperature in the region of 20°C for 15 h, and is then
poured into 100 cm3 of water. The aqueous phase is
extracted twice with ethyl acetate. The organic phases
are pooled, washed successively with two times water
and a saturated aqueous sodium chloride solution, dried
over magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa) to give a yellow oil
(0.8 g) , which is purified by flash chromatography on
alumina CTB1 under an argon pressure (50 kPa) [eluent:
cyclohexane/ethyl acetate (95/5 by volume)]. After
concentration of the fractions under reduced pressure,
570 mg of 1-{2-[3-benzyloxy-4-(2-chlorophenyl)pyrazol-

1-yl]ethyl}piperidine are obtained in the form of a
colorless oil.
IR spectrum (CCl4) : 2938; 2853; 2801; 1573; 1506; 1456;
1450; 1357; 1174; 1125; 1036; 1025; 716 and 695 cm"1.
The 3-benzyloxy-4-(2-chlorophenyl)-IH-pyrazole can be
prepared in the following way:
6.9 cm3 of a IN solution of tetrabutylammonium fluoride
in tetrahydrofuran are added to a stirred solution,
under an argon atmosphere, of 1.2 g of 3-benzyloxy-4-
(2-chlorophenyl)-1-(toluene-4-sulfonyl)-IH-pyrazole in
3 0 cm3 of tetrahydrofuran. After heating at the reflux
of the solvent for 15 h, the reaction medium is
evaporated under reduced pressure (2.7 kPa) and ethyl
acetate is added to the residue. The organic phase is
washed successively with two times water and a
saturated aqueous sodium chloride solution; it is dried
over magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa). The resulting oil is
triturated in pentane. The precipitate formed is
filtered off and dried under reduced pressure to give
500 mg of 3-benzyloxy-4-(2-chlorophenyl)-IH-pyrazole in
the form of a yellow solid. Mass spectrum (EI): m/z 284
(M+), m/z 249 [ (M - Cl)+], m/z 91 (C7H7+) .
The 3-benzyloxy-4-(2-chlorophenyl)-1-(toluene-4-
sulfonyl)-IH-pyrazole can be prepared in the following
way:
1.55 g of 2-chlorophenylboronic acid, 5 cm3 of a 2N
aqueous potassium carbonate solution and 500 mg of
tetrakis(triphenylphosphine)palladium are added to a
stirred solution, under an argon atmosphere, of 1.5 g
of 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-IH-
pyrazole in 2 0 cm3 of toluene to which 5 cm3 of ethanol
have been added. After heating at the reflux of the
solvent for 5 h, the reaction medium is evaporated

under reduced pressure (2.7 kPa) . Ethyl acetate, water
and carbon black are added to the residue, which is
filtered over supercel. The filtrate is separated by
settling out, and the organic phase is washed
successively with two times water and a saturated
aqueous sodium chloride solution; it is dried over
magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa). The orange-colored oil
obtained is purified by flash chromatography on silica
under an argon pressure (50 kPa) [eluent:
cyclohexane/ethyl acetate (95/5 by volume)]. After
concentration of the fractions under reduced pressure
(2.7 kPa), 1.2 g of 3-benzyloxy-4-(2-chlorophenyl)-1-
(toluene-4-sulfonyl)-1H-pyrazole are obtained in the
form of an orange-colored oil. Mass spectrum (EI) : m/z
438 (M+"), m/z 283 [ (M - C7H7SO2)+], m/z 91 (C7H7+) .
Example 54
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-
pyrazol-3-ol dihydrochloride
2.5 cm3 of 12N hydrochloric acid are added to a stirred
solution of 220 mg of 3-[3-benzyloxy-4-(4-
chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octane in
5 cm3 of ethanol. After 7 h at the reflux of the
solvent, and then 15 h at a temperature in the region
of 20°C, the reaction medium is evaporated to dryness
under reduced pressure (2.7 kPa) . The residue is taken
up with ethanol, and the mixture is then evaporated to
dryness under vacuum (2.7 kPa). The operation is
repeated twice, and the foam obtained is then
triturated in diisopropyl ether. The precipitate formed
is filtered off and dried under vacuum (2.7 kPa) to
give 170 mg of 1-(1-azabicyclo[2.2.2]oct-3-yl)-4- (4-
chlorophenyl)-1H-pyrazol-3-ol dihydrochloride in the
form of a white solid.

IR spectrum (KBr): 3052; 2926; 2793; 2559; 1606; 1576;
1520; 1486; 1454; 1195; 1167; 1090; 1010; 827; 626 and
515 cm-1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.65 to 2.05 (mt: 4H); 2.42 (mt: 1H); from 3.15 to 3.50
(mt: 4H) ; from 3.70 to 3.85 (mt: 2H) ; 4.67 (mt : 1H) ;
7.40 (broad d, J = 8 Hz: 2H) ; 7.71 (broad d, J = 8 Hz:
2H) ; 8.35 (s: 1H) ; from 10.50 to 10.70 (broad
unresolved peak: 1H); 10.73 (unresolved peak: 1H).
The 3-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-1-
azabicyclo[2.2.2]octane can be prepared in. the
following way:
500 mg of potassium tert-butoxide, followed by a
solution of 660 mg of toluene-4-sulfonic acid 1-aza-
bicyclo[2.2.2]oct-3-yl ester in 20 cm3 of dimethyl-
formamide, are added to a stirred solution, under an
argon atmosphere, of 500 mg of 3-benzyloxy-4-(4-chloro-
phenyl) -1H-pyrazole in 20 cm3 of dimethylformamide.
After heating at 110°C for 15 h, the reaction medium is
poured into 100 cm3 of water and the mixture is
extracted twice with ethyl acetate. The organic phases
are washed successively with two times water and a
saturated aqueous sodium chloride solution, dried over
magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa). The orange-colored oil
(650 mg) obtained is purified by flash chromatography
on silica under an argon pressure (50 kPa) [eluent:
ethyl acetate, then dichloromethane/methanol (8 0/2 0 by
volume)]. After concentration of the fractions under
reduced pressure (2.7 kPa), 220 mg of 3-[3-benzyloxy-4-
(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octane
are obtained in the form of a pale yellow oil.
IR spectrum (CCl4) : 3035; 2941; 2873; 1605; 1574; 1508;
1481; 1454; 1165; 1095; 1014; 834; 695 and 513 cm"1.
Example 55

phenyl)-1H-pyrazole in 20 cm3 of dimethylformamide.
After heating at 110°C for 15 h, the reaction medium is
poured into 100 cm3 of water and the mixture is
extracted twice with ethyl acetate. The organic phases
are washed successively with two times water and a
saturated aqueous sodium chloride solution, dried over
magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa). The orange-colored oil
(800 mg) obtained is purified by flash chromatography
on silica under an argon pressure (50 kPa) [eluent:
ethyl acetate/methanol (90/10 by volume), then
dichloromethane/methanol (80/20 by volume)]. After
concentration of the fractions under reduced pressure
(2.7 kPa), 270 mg of 3-[3-benzyloxy-4-(3-chloro-
phenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octane are
obtained in the form of a pale yellow oil.
IR spectrum (CCl4) : 3034; 1602; 1574; 1507; 1454; 1356;
1176; 1097; 1048; 695 and 687 cm"1.
Example 56
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(3-fluorophenyl)-1H-
pyrazol-3-ol hydrochloride
2 cm3 of 12N hydrochloric acid are added to a stirred
solution of 85 mg of 3-[3-benzyloxy-4-(3-fluorophenyl)-
pyrazol-1-yl]-1-azabicyclo[2.2.2]octane in 4 cm3 of
ethanol. After 7 h at the reflux of the solvent, and
then 15 h at a temperature in the region of 2 0°C, the
reaction medium is evaporated to dryness under reduced
pressure (2.7 kPa). The residue is taken up with
ethanol, and the mixture is then evaporated to dryness
under vacuum (2.7 kPa). The operation is repeated
twice, and the foam obtained is then triturated in
diisopropyl ether. The precipitate formed is filtered
off and dried under vacuum (2.7 kPa) to give 63 mg of
1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(3-fluorophenyl)-1H-

pyrazol-3-ol hydrochloride in the form of a beige
solid.
IR spectrum (KBr): 2932; 2765; 2663; 2577; 1617; 1586;
1521; 1457; 1436; 1265; 1180; 1165; 876; 783; 666; 625
and 521 cm-1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.65 to 2.05 (mt: 4H); 2.43 (mt: 1H); from 3.10 to 3.50
(mt: 4H); 3.78 (broad d, J = 7 Hz: 2H); 4.67 (mt: 1H);
6.96 (broad double doublet of a triplet, J = 8 and
2.5 Hz: 1H); from 7.25 to 7.55 (mt: 3H); 8.28 (s: 1H);
10.12 (unresolved peak: 1H); 10.65 (s: 1H).
The 3-[3-benzyloxy-4-(3-fluorophenyl)pyrazol-1-yl]-1-
azabicyclo[2.2.2]octane can be prepared in the
following way:
260 mg of potassium tert-butoxide, folowed by a
solution of 400 mg of toluene-4-sulf onic acid
1-azabicyclo[2.2.2]oct-3-yl ester in 20 cm3 of
dimethylformamide, are added to a stirred solution,
under an argon atmosphere, of 250 mg of 3-benzyloxy-4-
(3-fluorophenyl)-1H-pyrazole in 20 cm3 of
dimethylformamide. After heating at 110°C for 15 h, the
reaction medium is poured into 100 cm3 of water, and the
mixture is extracted twice with ethyl acetate. The
organic phases are washed successively with two times
water and a saturated aqueous sodium chloride solution,
dried over magnesium sulfate, filtered and evaporated
under reduced pressure (2.7 kPa). The orange-colored
oil (345 mg) obtained is purified by flash
chromatography on silica under an argon pressure (50
kPa) [eluent: cyclohexane/ethyl acetate (90/10 by
volume), then dichloromethane/methanol (80/20 by
volume)]. After concentration of the fractions under
reduced pressure (2.7 kPa), 270 mg of 3-[3-benzyloxy-
4-(3-fluorophenyl)pyrazol-1-yl]-1-
azabicyclo[2.2.2]octane are obtained in the form of a
pale yellow oil.

1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 0.80
(mt: 1H) ; 1.53 (mt: 1H) ; 1.67 (mt: 2H) ; 2.09 (mt: 1H) ;
from 2.60 to 2.80 (mt: 3H); 2.98 (mt: 1H); 3.21 (ddd, J
= 14-10 and 1.5 Hz: 1H) ; 3.37 (broad dd, J = 14 and
5.5 Hz: 1H) ; 4.25 (mt: 1H) ; 5.35 (s: 2H) ; 6.95 (broad
double doublet of a triplet, J = 8 and 2.5 Hz: 1H) ;
from 7.25 to 7.55 (mt: 8H); 8.31 (s: 1H).
Example 57
1-(l-Methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-ol
hydrochloride
A few drops of methanol are added to a mixture of
165 mg of 1-(l-methylpyrrolidin-3-yl)-4-phenyl-1H-
pyrazol-3-ol in 2 cm3 of ethyl acetate, in order to
solubilize the medium, which is cooled to 0°C before
the addition of 5 cm3 of 3M solution of hydrochloric
acid in ethyl acetate. The reaction medium is stirred
for 5 min at 0°C, left to return to a temperature in
the region of 20°C, and then stirred again at this
temperature for 2 0 min before being concentrated under
reduced pressure (2.7 kPa) . The crude product is dried
on a vane pump (10"3 kPa) to give 160 mg of 1- (1-methyl-
pyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-ol hydrochloride
in the form of a very hygroscopic solid. LCMS
(electrospray) : m/z 244 (MH+) .
XH NMR spectrum (300 MHz, (CD3)2SO d6 at 80°C, δ in ppm): from 2.30 to 2.65 (m: 2H) ; 2.91 (s: 3H) ; from
3.10 to 4.00 (m: 4H) ; 5.03 (m: 1H) ; 7.14 (t, J = 7.5
Hz: 1H); 7.32 (t, J = 7.5 Hz: 2H); 7.65 (t, J = 7.5 Hz:
2H) ; 8.00 (s: 1H) .
The 1- (l-methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-
ol can be prepared in the following way:
7.55 cm3 of a 4M aqueous hydrochloric acid solution are
added to a solution of 505 mg of 3-benzyloxy-1-(1-

methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazole in 3.53 cm3
of ethanol. The reaction medium is stirred at reflux
for 8 h and is then concentrated under reduced pressure
(2.7 kPa) . The violet oil obtained is taken up three
times with diethyl ether, evaporated to dryness under
reduced pressure (2.7 kPa), taken up three times with
isopropanol and concentrated under reduced pressure
and, finally, taken up three times with dichloromethane
to give a congealed oil which, after drying on a vane
pump (10"3 kPa), gives 524 mg of a solid. The residue is
purified by chromatography on a column of 3 0 g of
silica (irregular 15-40 µm Merck) [eluent:
dichloromethane/methanol/3 9% ammonium hydroxide
(95/5/0.4 by volume); flow rate: 8 cm3/min; detection:
25 0 nm] . After concentration of the fractions under
reduced pressure, 279 mg of 1-(l-methylpyrrolidin-3-
yl)-4-phenyl-1H-pyrazol-3-ol are obtained in the form
of a colorless amorphous solid. LCMS (electrospray):
m/z 334 (MH+) .
The 3-benzyloxy-1-(l-methylpyrrolidin-3-yl)-4-phenyl-
lH-pyrazole can be obtained in the following way:
123 mg of sodium hydride (at 50% in oil) are added to a
solution of 428 mg of 3-benzyloxy-4-phenyl-1H-pyrazole
in 8.5 cm3 of dimethylformamide, stirred under a
nitrogen atmosphere and at 0°C. After stirring at a
temperature in the region of 20°C for 30 min, a
solution of 398 mg of methanesulfonic acid (1-methyl-
pyrrolidin-3-yl) ester in 5.6 cm3 of dimethylformamide
is added. The reaction medium is stirred for 1 h at
80°C and then poured into a water/ethyl acetate
mixture. After stirring for 5 min, the medium is
separated by settling out and the aqueous phase is
extracted three times with ethyl acetate. The organic
phases are pooled, washed with a saturated aqueous
sodium chloride solution, dried over magnesium sulfate,
filtered through an Iena filter and evaporated under

reduced pressure (2.7 kPa) to give 657 mg of an oil
which is purified by chromatography on a column of 30 g
o£ silica (irregular 15-40 µm Merck) [eluent:
dichloromethane/methanol (97/3 by volume); flow rate:
8 cm3/min; detection: 250 nm] . After concentration of
the fractions under reduced pressure, 511 mg of
3-benzyloxy-1-(l-methylpyrrolidin-3-yl)-4-phenyl-1H-
pyrazole are obtained in the form of a colorless
amorphous solid. LCMS (electrospray) : 334 (MH+) .
The methanesulfonic acid (l-methylpyrrolidin-3-yl)
ester can be prepared in the following way:
A solution of 0.33 cm3 of methanesulfonyl chloride in
7.07 cm3 of dichloromethane is added dropwise to a
stirred solution of 0.39 cm3 of l-methyl-3-
hydroxypyrrolidine and 0.62 cm3 of triethylamine in
7.7 cm3 of dichloromethane under a nitrogen atmosphere,
at -10°C. The reaction medium is stirred at -10°C for
5 min and then at a temperature in the region of 2 0°C
for 2 h, before being concentrated to dryness under
reduced pressure (2.7 kPa) . The residue obtained is
taken up with water and ethyl acetate. The solution is
stirred for 5 min and is then separated by settling
out. The aqueous phase is extracted three times with
ethyl acetate. The organic phases are pooled, washed
successively with a 5% aqueous sodium bicarbonate
solution and a saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered and
evaporated under reduced pressure (2.7 kPa) to give
399 mg of methanesulfonic acid (l-methylpyrrolidin-3-
yl) ester in the form of a colorless oil. LCMS
(electrospray): m/z 180 (MH+) , m/z 84 [MH+ - (SO2CH3) ] .
Example 58
1- [2-(l-Methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol dihydrochloride

A suspension of 200 mg of 3-benzyloxy-1-[2-(1-methyl-
pyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazole and of the
tip of a spatula of palladium-on-charcoal at 10% in
6 cm3 of ethanol is hydrogenated at a temperature in the
region of 20°C under an atmosphere of 1600 mbar for
3 h 3 0 min. The reaction medium is taken up with a
dichloromethane/methanol mixture and filtered over
clarcel. The filtrate is concentrated to dryness under
reduced pressure (2.7 kPa) to give 120 mg of l-[2-(l-
methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol
in the form of a crystallized product. A second batch
of 100 mg of 1-[2-(l-methylpyrrolidin-2-yl)ethyl]-4-
phenyl-1H-pyrazol-3-ol is prepared according to the
same process, but using 140 mg of 3-benzyloxy-1-[2-(1-
methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazole.
A solution of 160 mg of 1-[2-(l-methylpyrrolidin-2-yl)-
ethyl]-4-phenyl-1H-pyrazol-3-ol in 5 cm3 of methanol is
acidified (pH 1) with a solution of hydrochloric acid
in methanol. The reaction medium is stirred for 10 min
at a temperature in the region of 2 0°C, and is then
concentrated under reduced pressure (2.7 kPa) and
placed in a freezer overnight. The residue is taken up
with acetonitrile, spin-filtered, and then washed with
acetonitrile before being dried under vacuum to give
160 mg of 1-[2-(l-methylpyrrolidin-2-yl)ethyl]-4-
phenyl-1H-pyrazol-3-ol dihydrochloride in the form of a
hygroscopic amorphous white powder. LCMS
(electrospray) : m/z 272 (MH+) .
1H NMR spectrum (400 MHz, (CD3)2SO d6, δ in ppm) : 1.65
(m: 1H); 1.92 (m: 2H); 2.09 (m: 1H); 2.21 (m: 1H); 2.41
(m: 1H) ; 2.77 (d, J = 5 . 0 Hz: 3H) ; 3.01 (m: 1H) ; 3.15
(m: 1H) ; 3.52 (m: 1H) ; 4.04 (dt, J = 14.0 and 6.5 Hz:
1H) ; 4.07 (dt, J = 14.0 and 6.5 Hz: 1H) ; 7.11 (t, J =
7.5 Hz: 1H) ; 7.31 (t, J = 7.5 Hz: 2H) ; 7.63 (t, J =
7.5 Hz: 2H); 7.98 (s: 1H); 10.70 (s: 1H).

The 3-benzyloxy-1-[2-(l-methylpyrrolidin-2-yl)ethyl]-4-
phenyl-1H-pyrazole can be prepared in the following
way:
82 mg of sodium hydride (at 50% in oil) are added, in
three portions, to a solution of 42 5 mg of 3-benzyloxy-
4-phenyl-1H-pyrazole in 2.5 cm3 of dimethylformamide.
Once no more gas is being given off, the reaction
medium is stirred at a temperature in the region of
20°C for a further 15 minutes before the addition of a
solution of 250 mg of l-methyl-2-(2-chloroethyl)-
pyrrolidine in 0.5 cm3 of dimethylformamide. The
reaction medium is stirred at a temperature in the
region of 20°C for 1 h, and then at 50°C for 3 h,
before being poured into water. The solution is
extracted with ethyl acetate. The organic phase is
washed with a saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered and
evaporated under reduced pressure (2.7 kPa) to give
58 0 mg of a crude product which is purified by
chromatography on 25 g of silica gel [eluent:
dichloromethane then dichloromethane/methanol (90/10 by
volume)]. After concentration of the fractions under
reduced pressure, 200 mg of 3-benzyloxy-1-[2-(1-
methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazole are
obtained in the form of an amorphous white powder,
along with 240 mg of a mixture consisting of
3-benzyloxy-1-[2-(l-methylpyrrolidin-2-yl)ethyl]-4-
phenyl-1H-pyrazole and of 3-benzyloxy-4-phenyl-1H-
pyrazole. The mixture is again purified by
chromatography on 10 g of silica gel [eluent:
dichloromethane/methanol (50/50 then 90/10 by volume)]
to give 90 mg of 3-benzyloxy-4-phenyl-1H-pyrazole and
140 mg of 3-benzyloxy-1-[2-(1-methylpyrrolidin-2-yl)-
ethyl]-4-phenyl-1H-pyrazole, having the same appearance
as the previous batch. LCMS (electrospray) : m/z 3 62
(MH+) .

The 1-methyl-2-(2-chloroethyl)pyrrolidine can be
prepared in the following way:
A solution of 330 mg of 1-methyl-2-(2-chloroethyl)-
pyrrolidine hydrochloride and of 5 cm3 of IN sodium
hydroxide in 2 0 cm3 of dichloromethane is stirred at a
temperature in the region of 2 0°C for 1 h. The reaction
medium is extracted with dichloromethane. The organic
phase is washed with a saturated aqueous sodium
chloride solution, dried over magnesium sulfate,
filtered and concentrated under reduced pressure (2.7
kPa) to give 255 mg de 1-methyl-2-(2-
chloroethyl)pyrrolidine, which are immediately used in
a reaction.
Example 59
1-(Pyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-ol
dihydrochloride
A suspension of 608 mg of 3-benzyloxy-4-phenyl-
1-(pyrrolidin-3-yl)-1H-pyrazole dihydrochloride and
60 mg of palladium-on-charcoal at 10% in 18 cm3 of
ethanol is hydrogenated at a temperature in the region
of 2 0°C under an atmosphere of 13 00 mbar for 3 h. The
reaction medium is diluted with methanol, filtered over
hyflosupercel and rinsed with methanol. The filtrate is
evaporated under reduced pressure (2.7 kPa) to give
365 mg of a white powder. This reaction crude is
recrystallized from 2 0 cm3 of ethanol at reflux. The
solution obtained is allowed to return to a temperature
in the region of 2 0°C, and is then immersed in an ice
bath. The crystals obtained are filtered under cold
conditions through an Iena filter, rinsed successively
with ethanol and then ethyl ether and dried under
vacuum (13 kPa) to give 185 mg of 1-(pyrrolidin-3-yl)-
4-phenyl-1H-pyrazol-3-ol dihydrochloride in the form of
a white powder. LCMS (electrospray) : m/z 230 (MH+) .

1H NMR spectrum (400 MHz, (CD3)2SO d6, δ in ppm) : 2.32
(m: 2H); 3.37 (m, in water: 2H); 3.45 (dd, J = 12.5 and
5.0 Hz: 1H) ; 3.60 (dd, J = 12.5 and 7.0 Hz: 1H) ; 4.91
(m: 1H); 7.13 (t, J = 7.5 Hz: 1H); 7.32 (t, J = 7.5 Hz:
2H) , 7.66 (t, J = 7.5 Hz: 2H) ; 8.11 (s: 1H) ; 9.44 (s:
2H); 10.40 (s: 1H).
The 3-benzyloxy-4-phenyl-1-(pyrrolidin-3-yl)-1H-
pyrazole dihydrochloride can be prepared in the
following way:
6 cm3 of a 3M solution of hydrochloric acid in ethyl
acetate are added dropwise to a solution of 569 mg of
3-benzyloxy-1-(l-tert-butoxycarbonylpyrrolidin-3-yl)-4-
phenyl-1H-pyrazole in 6 cm3 of ethyl acetate stirred at
0°C. The reaction medium is stirred at a temperature in
the region of 2 0°C for 2 h, before being concentrated
under reduced pressure to give 6 08 mg of 3-benzyloxy-4-
phenyl-1-(pyrrolidin-3-yl)-1H-pyrazole dihydrochloride,
in the form of a white powder, which are used
immediately.
The 3-benzyloxy-1-(l-tert-butoxycarbonylpyrrolidin-3-
yl)-4-phenyl-1H-pyrazole can be prepared in the
following way:
129 mg of sodium hydride (at 50% in oil) are added to a
solution of 450 mg of 3-benzyloxy-4-phenyl-1H-pyrazole
in 9 cm3 of dimethylformamide, stirred under a nitrogen
atmosphere at 0°C. After stirring at a temperature in
the region of 2 0°C for 30 min, 621 mg of
methanesulfonic acid (1-tert-butoxycarbonylpyrrolidin-
3-yl) ester are added. The reaction medium is stirred
for 1 h at 80 °C and then poured into a water/ethyl
acetate mixture. After stirring for 5 min, the medium
is separated by settling out and the aqueous phase is
extracted three times with ethyl acetate. The organic
phases are pooled, washed with a saturated aqueous

sodium chloride solution, dried over magnesium sulfate,
filtered through an Iena filter, rinsed with ethyl
acetate and evaporated under reduced pressure (2.7 kPa)
to give 998 mg of an oil which is purified by
chromatography on a column of 70 g of silica (irregular
15-40 µm Merck) [eluent: dichloromethane/methanol (98/2
by volume); flow rate: 15 cm3/min; detection: 250 ntn] .
After concentration of the fractions under reduced
pressure, 956 mg of a product are obtained, which is
again purified by chromatography on a column of 90 g of
silica (irregular 15-40 zzm Merck) [eluent:
dichloromethane/ethyl acetate (98/2 by volume); flow
rate: 15 cm3/min; detection: 250 nm] . After
concentration of the fractions under reduced pressure,
575 mg of 3-benzyloxy-1-(1-tert-butoxycarbonyl-
pyrrolidin-3-yl)-4-phenyl-1H-pyrazole are recovered in
the form of a colorless foam. LCMS (electrospray) : m/z
420 (MH+) , m/z 364 [MH+ - tBu] , m/z 320 [MH+ - Boc] .
The methanesulfonic acid (1-tert-butoxycarbonyl-
pyrrolidin-3-yl) ester can be prepared in the following
way:
A solution of 0.33 cm3 of methanesulfonyl chloride in
3.2 cm3 of dichloromethane is added dropwise to a
solution of 710 mg of l-tert-butoxycarbonyl-3-
hydroxypyrrolidine and 0.62 cm3 of triethylamine in
14.2 cm3 of dichloromethane, stirred under a nitrogen
atmosphere at -10°C. The reaction medium is stirred at
-10°C for 5 min, and then at a temperature in the
region of 20°C for 2 h, before being concentrated to
dryness under reduced pressure (2.7 kPa) . The residue
obtained is taken up with water and ethyl acetate. The
solution is stirred for 5 min and is then separated by
settling out. The aqueous phase is extracted three
times with ethyl acetate. The organic phases are
pooled, washed successively with an aqueous solution of
sodium bicarbonate at 5% and of sodium chloride, dried

over magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa) to give 938 mg of
methanesulfonic acid (1-tert-butoxycarbonylpyrrolidin-
3-yl) ester in the form of a pale yellow oil. LCMS
(electrospray) : m/z 266 (MH+) , m/z 210 [MH+ - tBu] .
The l-tert-butoxycarbonyl-3-hydroxypyrrolidine can be
prepared in the following way:
A solution of 2.78 cm3 of triethylamine and 3.2 7 g of
di-tert-butyl dicarbonate is added to 0.848 cm3 of
3-hydroxypyrrolidine in a mixture of 3 0 cm3 of
tetrahydrofuran and 9.6 cm3 of water. The reaction
medium is stirred at a temperature in the region of
2 0°C for 3 h, and is then concentrated to dryness under
reduced pressure (2.7 kPa) . The residue obtained is
taken up with water and ethyl acetate. The solution is
stirred for 5 min, and is then separated by settling
out. The aqueous phase is extracted three times with
ethyl acetate. The organic phases are pooled, dried
over magnesium sulfate, filtered through an Iena filter
and then concentrated to dryness under reduced pressure
(2.7 kPa) to give 1.823 g of l-tert-butoxycarbonyl-3-
hydroxypyrrolidine in the form of colorless crystals,
m/z 188 (MH+) , m/z 132 [MH+ - tBu] .
Example 60
1-[(l-Methylpyrrolidin-2-(S)-yl)methyl]-4-phenyl-1H-
pyrazol-3-ol
3.75 cm3 of a 4M hydrochloric acid solution are added to
a solution of 263 mg of 3-benzyloxy-1-[(1-
methylpyrrolidin-2-(S)-yl)methyl]-4-phenyl-1H-pyrazole
in 2 cm3 of ethanol. The reaction medium is stirred at
reflux for 7 h and is then concentrated under reduced
pressure. The violet oil obtained is taken up three
times with 10 cm3 of isopropanol and then evaporated to

dryness under reduced pressure, to give 2 59 mg of
violet resin. This resin is dissolved in a mixture of
0.6 cm3 of ethanol and 3 cm3 of 1,4-dioxane. After the
addition of 0.665 cm3 of a 4M solution of hydrogen
chloride in 1,4-dioxane and stirring at ambient
temperature, the medium is concentrated under reduced
pressure at 40°C. The residue is dissolved in 10 cm3 of
water and the solution obtained is washed with
dichloromethane (3x1 cm3) and then brought to pH 9-10
by adding sodium carbonate. After extraction with
dichloromethane, the organic phases are pooled and then
dried over magnesium sulfate, filtered and concentrated
under reduced pressure at 35 °C. The pale pink solid
obtained (124 mg) is recrystallized under hot
conditions from ethanol, so as to give 73 mg of 1-[ (1-
methylpyrrolidin-2-(S)-yl)methyl]-4-phenyl-1H-pyrazol-
3-ol in the form of a white solid. LCMS (electrospray):
m/z 258 (MH+) .
1H NMR spectrum (400 MHz, DMSO d6, δ in ppm) : 1.63 (m:
1H); 1.76 (m: 2H); 1.95 (m: 1H); 2.30 (partially masked
m: 1H) ; 2.34 (s: 3H) ; 2.82 (m: 1H) ; 3.14 (m: 1H) ; 3.90
(dd, J = 7-14 Hz: 1H); 4.11 (dd, J = 6-14 Hz: 1H); 7.18
(bt, J = 8 Hz: 1H) ; 7.35 (bt, J = 8 Hz: 2H) ; 7.57 (s:
1H); 7.70 (bd, J = 8 Hz: 2H).
The 3-benzyloxy-1-[(l-methylpyrrolidin-2-(S)-yl)-
methyl]-4-phenyl-1H-pyrazole can be prepared in the
following way:
136 mg of sodium hydride (at 50% in oil) are added to a
solution of 2 83 mg of 3-benzyloxy-4-phenyl-1H-pyrazole
in 6 cm3 of dimethylformamide, stirred under a nitrogen
atmosphere at ambient temperature. After stirring at
ambient temperature for 30 min, a solution of 250 mg of
1-methyl-2-(S)-chloromethylpyrrolidine hydrochloride in
6 cm3 of dimethylformamide is added. The reaction medium
is stirred at 80°C for 1 h, and is then cooled to
ambient temperature and hydrolyzed. After extraction

with ethyl acetate, the organic phases are pooled,
washed with a saturated aqueous sodium bicarbonate
sollution, dried over magnesium sulfate, filtered and
concentrated under reduced pressure at 35 °C to give
554 mg of a yellow oil. After purification by
chromatography under a column of 3 0 g of silica
(irregular 15-40 µm Merck) [eluent: dichloromethane/-
methanol (98/2); flow rate: 15 cm3/min] and
concentration of the fractions under reduced pressure,
263 mg of 3-benzyloxy-1-[(l-methylpyrrolidin-2-(S)-
yl)methyl]-4-phenyl-1H-pyrazole are obtained. LCMS
(electrospray) : m/z 348 (MH+) .
The 1-methyl-2-(S)-chloromethylpyrrolidine hydro-
chloride can be prepared in the following way:
3 88 µl of thionyl chloride are added slowly to a
solution of 250 mg of (S)-(-)-1-methyl-2-pyrrolidine
methanol in 2 cm3 of dichloromethane cooled in a bath of
ice-cold water. The solution obtained is heated at
reflux for 3 hours and then stirred at ambient
temperature for 18 hours. After evaporation under
reduced pressure at 35°C, the brown residue obtained is
dissolved in ethanol and then concentrated to dryness
under reduced pressure. The dry extract obtained is
dissolved in 1 cm3 of, ethanol and then precipitated by
gradually adding 6 cm3 of ethyl ether. The suspension
obtained is cooled using a bath of ice-cold water and
the solid is filtered off and then washed with ethyl
ether. After drying under vacuum, 258 mg of 1-methyl-2-
(S)chloromethylpyrrolidine hydrochloride are obtained
in the form of a very hygroscopic ochre solid. Mass
spectrum (EI) : m/z 133 (M+) .
Example 61
4 -Phenyl-1-pyrrolidin-3-ylmethyl-1H-pyrazol-3 -ol
hydrochloride

163.5 mg of 1-(l-benzylpyrrolidin-3-ylmethyl)-4-phenyl-
1H-pyrazol-3-ol hydrochloride in 5 cm3 of methanol,
139.4 mg of ammonium formate and 10 mg of palladium-on-
charcoal at 10% are added to a reactor for a microwave
oven equipped with a magnetic stirrer. The tube is
sealed and placed in a microwave device for 60 seconds
at a temperature of 100°C under a pressure of 10.5 bar.
The reaction medium is filtered through Acodisc GHP
Polypro (PALL) and then rinsed with methanol. The
filtrate is concentrated to dryness under reduced
pressure, to give a gum which is solidified with
ethanol. 4 0 mg of a white powder are thus obtained. The
operation is repeated with the above ethanolic filtrate
to give, after combining the two batches, 52 mg of a
white powder. The final ethanolic filtrate is again
concentrated to dryness, and the residue obtained is
taken up with 10 cm3 of water. The solution is chilled
and then lyophilized overnight. The various batches are
combined, to give 80 mg of 4-phenyl-1-pyrrol idin-3-
ylmethyl-1H-pyrazol-3-ol hydrochloride in the form of a
white powder. 1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): 1.66 (m, 1H); 1.99 (m, 1H); 2.73 (m, 1H); 2.92
(m, 1H) ; from 3.02 to 3.25 (m, 2H) ; 4.01 (d, J = 7.0
Hz, 2H); 7.12 (broad t, J = 7.5 Hz, 1H); 7.32 (broad t,
J = 7.5 Hz, 2H) ; 7.65 (broad d, J = 7.5 Hz, 2H) ; 7.99
(s, 1H) ; 8.36 (broad s, 1H) ; from 6.70 to 8.70 (very
very broad m, 1H). Mass spectrum (EI): m/z 244+ (M+H)+.
The 1-(l-benzylpyrrolidin-3-ylmethyl)-4-phenyl-1H-
pyrazol-3-ol hydrochloride can be prepared in the
following way:

A suspension of 93 7 mg of 3-benzyloxy-1-(1-
benzylpyrrolidin-3-ylmethyl)-4-phenyl-1H-pyrazole
hydrochloride and 93 mg of palladium-on-charcoal at 10%
in 9.4 cm3 of ethanol is hydrogenated at a temperature
in the region of 20°C under an atmosphere of 1500 mbar
for 16 h. The reaction medium is filtered through
hyflosupercel and rinsed with ethanol. After
concentration of the filtrate to dryness, 350 mg of a
beige gum are obtained, which gum is recrystallized
from ethanol. After filtration through an iena funnel,
rinsing with ethyl ether and then drying in an
industrial vacuum oven, 178 mg of 1- (1-
benzylpyrrolidin-3-ylmethyl)-4-phenyl-1H-pyrrazol-3 -ol
hydrochloride are obtained. Mass spectrum (EI): m/z 334+
[(M+H)+-HC1] .
The 3-benzyloxy-1-(l-benzylpyrrolidin-3-ylmethyl)-4-
phenyl-1H-pyrazole hydrochloride can be prepared in the
following way:
129 mg of sodium hydride (at 50% in oil) are added, in
a single step, to a solution of 450 mg of 3-benzyloxy-
4-phenyl-1H-pyrazole in 9 cm3 of anhydrous
dimethylformamide stirred under an argon atmosphere at
0°C. After stirring for 3 0 min at a temperature in the
region of 20°C, a solution of 630 mg of methanesulfonic
acid (l-benzylpyrrolidin-3-ylmethyl) ester in 9 cm3 of
anhydrous dimethylformamide is added. The reaction
medium is stirred for 4 h at 80°C and then plunged into
a water/ethyl acetate mixture. After stirring for
5 min, the medium is separated by settling out and the
aqueous phase is extracted three times with ethyl
acetate. The organic phases are combined, washed twice
with water and then once with a saturated aqueous
sodium chloride solution, dried over magnesium sulfate,
and filtered through an iena funnel. The magnesium
sulfate is rinsed with ethyl acetate. The combined
organic phases are evaporated under reduced pressure
and the residue obtained is dried overnight on a vane

pump, to give 93 9 mg of a pale yellow oil which is
purified by chromatography on a column of 90 g of
silica (Merck irregular silica 15-40 µm) [eluent:
dichloromethane/methanol (98/2 by volume); flow rate:
10 cm3/min; detection: 250 nm] . After concentration of
the fractions under reduced pressure, 586 mg of 83%-
pure 3-benzyloxy-1-(l-benzylpyrrolidin-3-ylmethyl)-4-
phenyl-1H-pyrazole are obtained in the form of a foam.
This is taken up with water (pH=l) and then ethyl
acetate is added thereto. After stirring for 5 min, the
medium is separated by settling out and the aqueous
phase is extracted with ethyl acetate. The organic
phases are brought to pH=9 with an ammonium hydroxide
solution, extracted three times with ethyl acetate,
combined, dried over magnesium sulfate, filtered,
rinsed, and then concentrated to dryness under reduced
pressure, to give 4 97 mg of 3-benzyloxy-1-(1-
benzylpyrrolidin-3-ylmethyl)-4-phenyl-1H-pyrazole in
the form of a free base. The product is taken up with
5 cm3 of ethyl acetate. The medium is cooled to 0°C,
before the addition of 5 cm3 of a 3M hydrochloric acid
solution in ethyl acetate. The solution is concentrated
to dryness under reduced pressure, to give a brown oil.
Attempts to crystallize the crude residue obtained were
carried out in vain (ethyl acetate, ethanol, methanol,
diethyl ether or hexane). 94 0 mg of 3-benzyloxy-1-
(1-benzylpyrrolidin-3-ylmethyl]-4-phenyl-1H-pyrazole
hydrochloride are thus recovered. Mass spectrum (EI) :
m/z 424+ (M+H)+.
The methanesulfonic acid (1-benzylpyrrolidin-3-
ylmethyl) ester can be prepared in the following way:
A solution of 0.455 cm3 of methanesulfonic chloride in
9.7 cm3 of anhydrous dichloromethane is added dropwise
to a solution of 1 g of (1-benzylpyrrolidin-3-
yl)methanol and 0.844 cm3 of triethylamine in 2 0 cm3 of
dichloromethane, stirred under an argon atmosphere at
0°C. The reaction medium is stirred for 5 min at 0°C

and then for 2 h at a temperature close to 20°C, before
being concentrated to dryness under reduced pressure.
The residue obtained is taken up with water and ethyl
acetate. The solution is stirred for 5 min and is then
separated by settling out. The aqueous phase is
extracted three times with ethyl acetate. The organic
phases are combined, washed successively with an
aqueous 5% sodium bicarbonate solution and with a
saturated aqueous sodium chloride solution, dried over
magnesium sulfate, filtered, and evaporated under
reduced pressure, to give 1.2 g of methanesulfonic acid
(l-benzylpyrrolidin-3-ylmethyl) ester. Mass spectrum
(EI): m/z 270+ (M+H)+.
The (l-benzylpyrrolidin-3-yl)methanol can be prepared
in the following way:
17.1 cm3 of a 1M lithium aluminum hydride solution in
tetrahydrofuran are added to a solution of 2 g of
l-benzyl-5-oxopyrrolidine-3-carboxylic acid methyl
ester in 40 cm3 of tetrahydrofuran, stirred at 0°C under
a nitrogen atmosphere. After stirring for 15 min at
0°C, the reaction medium is allowed to return to a
temperature in the region of 20°C and is stirred for
4 h. A mixture consisting of 0.65 cm3 of water and of
6.5 cm3 of tetrahydrofuran is added dropwise to the
reaction medium. 0.65 cm3 of a 15% aqueous sodium
hydroxide solution and 1.95 cm3 of water are then
successively added. The medium is stirred at a
temperature in the region of 2 0°C until the formation
of a filterable solid, to which two spatulas of
magnesium sulfate are added. After filtration through
an iena funnel, rinsing and concentrating to dryness
under reduced pressure, 1.72 g of (1-benzylpyrrolidin-
3-yl) methanol are obtained in the form of a colorless
oil. Mass spectrum (EI): m/z 192+ (M+H)+.

Example 62
1-((2R)-1-methylpyrrolidin-2-ylmethyl)-4-phenyl-1H-
pyrazol-3-ol
2.89 cm3 of 6N hydrochloric acid are added to a solution
of 211 mg of 3-benzyloxy-1-((2R)-1-methylpyrrolidin-2-
ylmethyl)-4-phenyl-1H-pyrazole in 1.5 cm3 of ethanol.
The reaction medium is stirred for 5 h 30 min at 110°C
before being concentrated to dryness under reduced
pressure. The residue is taken up with isopropanol and
is concentrated to dryness, to give 13 6 mg of a foam
which is crystallized from a minimum amount of ethanol
under hot conditions. After chilling overnight, no
crystallization is apparent. The residue is taken up
with 5 cm3 of water and extracted three times with 1 cm3
of dichloromethane, brought to pH 9-10 with solid
sodium carbonate. The aqueous phase is again extracted
three times with dichloromethane. The organic phases
are combined, dried over magnesium sulfate, filtered
and concentrated to dryness under reduced pressure, to
give 100 mg of a product which is recrystallized from a
minimum amount of ethanol. After leaving the product
overnight in a refrigerator, filtering and drying,
58 mg of 1-((2R)-1-methylpyrrolidin-2-ylmethyl)-4-
phenyl-1H-pyrazol-3-ol are obtained in the form of a
white solid. 1H NMR spectrum (400 MHz, (CD3)2SO d6 with
a drop of AcOH d4, 6 in ppm) : from 1.62 to 2.00 (m,
4H) ; 2.42 (s, 3H) ; 3.02 (m, 1H) ; 3.21 (m, 2H) ; 3.96
(dd, J = 7.0 and 14.0 Hz, 1H) ; 4.13 (dd, J = 5.5 and
14.0 Hz, 1H) ; 7.13 (broad t, J = 7.5 Hz, 1H) ; 7.33
(broad t, J = 7.5 Hz, 2H) ; 7.65 (broad d, J = 7.5 Hz,
2H) ; 7.97 (s, 1H) . Mass spectrum (EI): 258 ( + ) ='(M+H) ( + ) .
The 3-benzyloxy-1-((2R)-1-methylpyrrolidin-2-ylmethyl)-
4-phenyl-1H-pyrazole can be prepared in the following
way:
A solution of 400 mg of 3-benzyloxy-4-phenyl-((2R)-
pyrrolidin-2-ylmethyl)-1H-pyrazole hydrochloride,

297 mg of potassium carbonate and 0.101 cm3 of methyl
iodide in 4 cm3 of dimethylformamide is stirred
overnight at a temperature in the region of 2 0°C. The
medium is diluted with water and then extracted with
ethyl acetate. The organic phase is dried over
magnesium sulfate, filtered, and concentrated to
dryness under reduced pressure, to give a reaction
crude which is purified by chromatography on silica gel
(eluent: dichloromethane containing 3% of methanol).
After concentration of the fractions to dryness, 215 mg
of 3-benzyloxy-1-((2R)-1-methylpyrrolidin-2-ylmethyl)-
4-phenyl-1H-pyrazole are obtained.
The 3-benzyloxy-4-phenyl-1-((2R)-pyrrolidin-2-yl-
methyl)-1H-pyrazole hydrochloride can be prepared in
the following way:
3.17 cm3 of a 4N hydrochloric acid solution in dioxane
are added to a solution of 500 mg of 3-benzyloxy-1-
((2R)-1-tert-butoxycarbonylpyrrolidin-2-ylmethyl)-4-
phenyl-1H-pyrazole in 5 cm3 of dioxane. The reaction
medium is stirred overnight at a temperature in the
region of 2 0°C and is then concentrated to dryness
under reduced pressure, to give 400 mg of 3-benzyloxy-
4-phenyl-1-((2R)-pyrrolidin-2-ylmethyl)-1H-pyrazole
hydrochloride in the form of a white solid. Mass
spectrum (EI): m/z 334+
(M+H)+, m/z 667+ (2M+H)+.
The 3-benzyloxy-4-phenyl-1-((2R)-1-tert-butoxycarbonyl-
pyrrolidin-2-ylmethyl)-1H-pyrazole can be prepared in
the following way:
A solution of 251 mg of 3-benzyloxy-4-phenyl-1H-
pyrazole and 72 mg of sodium hydride (50% in oil) in
5 cm3 of dimethyl formamide is stirred for 1 h before
adding a solution of 364 mg of methanesulfonic acid
((2R)-1-tert-butoxycarbonylpyrrolidin-2-ylmethyl) ester
in 5 cm3 of dimethylformamide. The reaction medium is

stirred at 80°C for 3 h and is then poured into water.
After extraction with ethyl acetate, the organic phase
is washed three times with a saturated aqueous sodium
chloride solution, dried over magnesium sulfate,
filtered, and then concentrated to dryness, to give
44 0 mg of a crude product which is purified by
chromatography on silica gel (eluent: 80/20
heptane/ethyl acetate). After concentration of the
fractions to dryness, 2 02 mg of 3-benzyloxy-4-phenyl-1-
((2R)-1-tert-butoxycarbonylpyrrolidin-2-ylmethyl)-1H-
pyrazole are obtained. Mass spectrum (EI) : m/z 456+
(M+Na)+, m/z 434+ (M+H)+, m/z 334+ [ (M+H) +-C02tBu+H] .
The methanesulfonic acid ((2R)-1-tert-butoxycarbonyl-
pyrrolidin-2-ylmethyl) ester can be prepared in the
following way:
A solution of 1.2 cm3 of methanesulfonyl chloride in
2 0 cm3 of dichloromethane is added dropwise to a
solution of 3 g of (2R)-1-tert-butoxycarbonyl-2-
hydroxymethylpyrrolidine and 2.27 cm3 of triethylamine
in 65 cm3 of dichloromethane, stirred under a nitrogen
atmosphere at -10°C. The reaction medium is allowed to
return to 2 0°C, before concentrating to dryness under
reduced pressure. The residue obtained is taken up with
water, and extracted twice with 2 0 cm3 of ethyl acetate.
The combined organic phases are washed three times with
2 0 cm3 of a 5% aqueous sodium bicarbonate solution,
dried over magnesium sulfate, filtered, and
concentrated to dryness under reduced pressure, to give
3.75 g of a mixture of methanesulfonic acid ( (2R)-1-
tert-butoxycarbonylpyrrolidin-2-ylmethyl) ester and of
(2R)-1-tert-butoxycarbonyl-2-hydroxymethylpyrrolidine.
The mixture is again reacted under the same conditions
as above, but with 0.3 eq of triethylamine and 0.3 eq
of methanesulfonyl chloride. After a similar treatment,
3.63 g of methanesulfonic acid ((2R)-1-tert-
butoxycarbonylpyrrolidin-2-ylmethyl) ester are obtained

in the form of a colorless liquid. Mass spectrum (EI) :
m/z 2 8 0+ (M+H)+.
Example 63
4-Phenyl-1-(piperidin-3-yl)-1H-pyrazol-3-ol
hydrochloride
A suspension of 13 0 mg of 3-benzyloxy-4-phenyl-1-
(piperidin-3-yl)-1H-pyrazole hydrochloride and 13 mg of
palladium-on-charcoal at 10% in 4 cm3 of ethanol is
hydrogenated at a temperature in the region of 2 0°C
under an atmosphere of 1500 mbar for 3 h. The reaction
medium is taken up with a mixture of 15 cm3 of 80/20 by
volume dichloromethane/methanol, spin-filtered through
Clarcel, and then washed twice with 10 cm3 of an 80/20
by volume dichloromethane/methanol mixture. After
concentration to dryness, the crystalline product is
taken up with 5 cm3 of ethyl acetate, spin-filtered, and
taken up twice with 0.5 cm3 of ethyl acetate, to give
70 mg of 4-phenyl-1-(piperidin-3-yl)-1H-pyrazol-3-ol
hydrochloride in the form of a crystalline product.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.72 to 2.22 (m, 4H) ; 2.86 (m, 1H) ; from 3.10 to 3.57
(partially masked m, 3H); 4.36 (m, 1H); 7.14 (broad t,
J = 7.5 Hz, 1H) ; 7.33 (broad t, J = 7.5 Hz, 2H) ; 7.68
(broad d, J = 7.5 H, 2H); 8.07 (s, 1H); 9.18 (broad m,
2H) ; 10.4 (broad s, 1H) . Mass spectrum (EI): m/z 244 +
(M+H)+.
The 3-benzyloxy-4-phenyl-1-(piperidin-3-yl)-1H-pyrazole
hydrochloride can be prepared in the following way:
2 cm3 of a 4N hydrochloric acid solution in ethyl
acetate are added to a solution of 23 0 mg of
3-benzyloxy-1-(l-tert-butoxycarbonylpiperidin-3-yl)-4-
phenyl-1H-pyrazole in 2 cm3 of ethyl acetate, cooled by
means of an ice bath. The reaction medium is allowed to
return to a temperature in the region of 2 0°C and is

then stirred for 2 h 30 min before concentration of the
ethyl acetate. The residue is taken up three times with
2 cm2 of diethyl ether and the insoluble material is
filtered off, to give 150 mg of 3-benzyloxy-4-phenyl-1-
(piperidin-3-yl)-1H-pyrazole hydrochloride. Mass
spectrum (EI): m/z 334+ (M+H)+, m/z 36+/38+ HCl+.
The 3-benzyloxy-1-(l-tert-butoxycarbonylpiperidin-3-
yl)-4-phenyl-1H-pyrazole can be prepared in the
following way:
153 mg of sodium hydride (at 50% in oil) are added, in
three portions, to a solution of 725 mg of 3-benzyloxy-
4-phenyl-1H-pyrazole in 7 cm3 of anhydrous
dimethylformamide, stirred under a nitrogen atmosphere.
After stirring for 45 min at a temperature in the
region of 20°C, a solution of 890 mg of methanesulfonic
acid (l-tert-butoxycarbonylpiperidin-3-yl) ester in
4.5 cm3 of anhydrous dimethylformamide is added. The
reaction medium is stirred for 3 h at 80°C and is then,
after cooling, poured into water. The aqueous phase is
extracted four times with 50 cm3 of ethyl acetate. The
combined organic phases are washed with a saturated
aqueous sodium chloride solution, dried over magnesium
sulfate, filtered, and then concentrated to dryness
under reduced pressure. The product obtained is taken
up with dichloromethane, which, after spin-filtering,
gives 380 mg of 3-benzyloxy-4-phenyl-1H-pyrazole in the
form of a beige solid. The filtrate, after
concentration to dryness, is purified by chromatography
on a column of 70 g of silica (Merck, eluent: 95/5 by
volume dichloromethane/ethyl acetate). After
concentration of the fractions under reduced pressure,
280 mg of 3-benzyloxy-1-(1-tert-butoxycarbonyl-
piperidin-3-yl)-4-phenyl-1H-pyrazole are obtained with
a purity of 70%. These 280 mg are again purified by
chromatography on a column of 3 0 g of silica (Merck,
eluent: 70/30 by volume dichloromethane/heptane). After
concentration of the fractions under reduced pressure,

230 mg of 3-benzyloxy-1-(1-tert-butoxycarbonyl-
prperidin-3-yl)-4-phenyl-1H-pyrazole are obtained.
XH NMR spectrum (300 MHz, (CD3)2SO d6, 5 in ppm) : 1.20
(m, 1H); 1.41 (s, 9H) ; from 1.45 to 2.16 (m, 3H); 2.93
(m, 1H); from 3.00 to 3.40 (broad m, 1H); 3.79 (m, 1H);
from 3.98 to 4.16 (m, 2H) ; 5.31 (broad s, 2H) ; 7.15
(broad t, J = 7.5 Hz, 1H) ; from 7.30 to 7.45 (m, 5H) ;
7.51 (broad d, J = 7.5 Hz, 2H); 7.65 (broad d, J = 7.5
Hz, 2H); 8.14 (s, 1H).
The methanesulfonic acid (1-tert-butoxycarbonyl-
piperidin-3-yl) ester can be prepared in the following
way:
A solution of 0.305 cm3 of methanesulfonyl chloride is
added dropwise to a solution of 750 mg of 1-tert-
butoxycarbonyl-3-hydroxypiperidine and 0.570 cm3 of
triethylamine in 7 cm3 of dichloromethane, stirred under
a nitrogen atmosphere at -10°C. The reaction medium is
allowed to return to a temperature in the region of
20°C and is stirred for 3 h, before concentrating to
dryness under reduced pressure. The residue obtained is
taken up with ethyl acetate. The organic phase is
successively washed with a 5% aqueous sodium
bicarbonate solution and then a saturated aqueous
sodium chloride solution, dried over magnesium sulfate,
filtered, and concentrated to dryness under reduced
pressure, to give 0.9 g of methanesulfonic acid
(l-tert-butoxycarbonylpiperidin-3-yl) ester in the form
of a colorless oil. Mass spectrum (EI): m/z 280+ (M+H)+,
m/z 224+ [(M+H)+-tBu+H].
Example 64
1-(l-Methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-
ol hydrochloride
A solution of 610 mg of 3-benzyloxy-1- (1-
methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazole in

12 cm3 of ethyl acetate and 6 cm3 of a 4M hydrochloric
solution in ethyl acetate is stirred for 15 min at a
temperature in the region of 2 0°C. After concentration
to dryness under reduced pressure, 669 mg of
3-benzyloxy-1-(l-methylpiperidin-2-ylmethyl)-4-phenyl-
lH-pyrazole hydrochloride are obtained, which product
is immediately reacted again. A suspension of 669 mg of
the preceding hydrochloride and 66 mg of palladium-on-
charcoal at 10% in 15 cm3 of ethanol is hydrogenated at
a temperature in the region of 20°C under an atmosphere
of 1500 mbar for 3 h. The reaction medium is taken up
with a mixture of 25 cm3 of 8 0/2 0
dichloromethane/methanol and then spin-filtered through
Clarcel. After concentration to dryness, the product
obtained is dissolved in 2 0 cm3 of water and then
lyophilized, to give 500 mg of 1-(l-methylpiperidin-2-
ylmethyl)-4-phenyl-1H-pyrazol-3-ol hydrochloride. 1H NMR
spectrum (300 MHz, (CD3)2SO d6 at 353K, δ in ppm) : from
1.37 to 1.87 (m, 6H); 2.86 (broad m, 4H); from 3.32 to
3.60 (very broad m, 2H) ; 4.24 (broad m, 1H) ; 4.50
(broad m, 1H) ; 7.16 (broad t, J = 7.5 Hz, 1H) ; 7.34
(broad t, J = 7.5 Hz, 2H) ; 7.67 (broad d, J = 7.5 Hz,
2H) ; 7.97 (s, 1H) ; from 10.0 to 10.6 (very broad m,
2H) . Mass spectrum (EI): m/z 272+ (M+H)+, m/z 36+/38+
HC1+.
Example 65
1-(l-methylazepan-3-yl)-4-phenyl-1H-pyrazol-3-ol
hydrochloride
The 1-(l-methylazepan-3-yl)-4-phenyl-1H-pyrazol-3-ol
hydrochloride can be prepared according to the same
method used for preparing the 1-(l-methylpiperidin-2-
ylmethyl)-4-phenyl-1H-pyrazol-3-ol hydrochloride, but
using 470 mg of 3-benzyloxy-1-(l-methylazepan-3-yl)-4-
phenyl-1H-pyrazole, 10 cm3 of ethyl acetate, 5 cm3 of a
4M hydrochloric acid solution in ethyl acetate, and
then 51 mg of palladium-on-charcoal at 10% and 15 cm3 of

ethanol. According to the same treatment conditions,
400 mg of 1-(l-methylazepan-3-yl)-4-phenyl-1H-pyrazol-
3-ol hydrochloride are thus obtained. H NMR spectrum
(400 MHz, (CD3)2SO d6 at 343K, δ in ppm) : from 1.62 to
2.32 (m, 6H) ; 2.86 (broad s, 3H) ; from 2.92 to 3.76
(partially masked m, 4H); from 4.62 to 4.92 (very broad
m, 1H); 7.15 (broad t, J = 7.5 Hz, 1H); 7.33 (broad t,
J = 7.5 Hz, 2H) ; 7.65 (broad d, J = 7.5 Hz, 2H) ; 7.93
(broad s, 1H) ; from 9.85 to 10.3 (broad m, 1H) ; from
10.7 to 11.4 (very broad m, 1H) . Mass spectrum (EI) :
m/z 272+ (M+H)+.
The 3-benzyloxy-1-(l-methylpiperidin-2-ylmethyl)-4-
phenyl-1H-pyrazole and 3-benzyloxy-1-(l-methylazepan-3-
yl)-4-phenyl-1H-pyrazole can be prepared in the
following way:
426 mg of sodium hydride (at 50% in oil) are added, in
three portions, to a solution of 2 g of 3-benzyloxy-4-
phenyl-1H-pyrazole in 2 0 cm3 of anhydrous dimethyl-
formamide, stirred under a nitrogen atmosphere. After
stirring for 3 0 min at a temperature in the region of
20°C, 1.3 g of a 75/25 mixture of 1-methyl-2-
chloromethylpiperidine and of methanesulfonic acid
(l-methylpiperidin-2-ylmethyl) ester are added
dropwise. The reaction medium is stirred for 3 h at
80°C and then, after cooling, is poured into a
water/ice mixture. The aqueous phase is extracted with
ethyl acetate. The organic phase is washed with a
saturated aqueous sodium chloride solution, dried over
magnesium sulfate, filtered, and then concentrated to
dryness under reduced pressure. The product is purified
by two successive chromatographies on a column of 119 g
of silica (Merck, eluent: 97/3 by volume
dichloromethane/methanol). After concentration of the
fractions under reduced pressure, 460 mg of
3-benzyloxy-1-(l-methylazepan-3-yl)-4-phenyl-1H-
pyrazole and 650 mg of 3-benzyloxy-1-(1-

methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazole are
obtained.
3-Benzyloxy-1-(l-methylpiperidin-2-ylmethyl)-4-phenyl-
1H-pyrazole. 1H NMR spectrum (400 MHz, (CD3)2SO d6, δ in ppm): from 1.12 to 1.65 (m, 6H); 2.06 (m, 1H); 2.29 (s,
3H); 2.34 (m, 1H); 2.77 (m, 1H); 3.86 (dd, J = 7.5 and
14.0 Hz, 1H); 4.25 (dd, J = 5.5 and 14.0 Hz, 1H); 5.30
(s, 2H) ; 7.14 (broad t, J = 7.5 Hz, 1H) ; from 7.30 to
7.44 (m, 5H) ; 7.50 (broad d, J = 7.5 Hz, 2H) ; 7.64
(broad d, J = 7.5 Hz, 2H); 8.06 (s, 1H).
3-Benzyloxy-1-(l-methylazepan-3-yl)-4-phenyl-1H-
pyrazole. 1H NMR spectrum (400 MHz, (CD3)2SO d6, δ in ppm): from 1.56 to 1.82 (m, 4H); from 1.96 to 2.08 (m,
2H); 2.33 (s, 3H); from 2.50 to 2.93 (partially masked
m, 4H) ; 4.26 (m, 1H) ; 5.30 (s, 2H) ; 7.13 (broad t, J =
7.5 Hz, 1H); from 7.28 to 7.45 (m, 5H); 7.51 (broad d,
J = 7.5 Hz, 2H) ; 7.65 (broad d, J = 7.5 Hz, 2H) ; 8.11
(s, 1H).
The mixture of 2-chloromethyl-1-methylpiperidin and of
methanesulfonic acid (l-methylpiperidin-2-ylmethyl)
ester can be prepared in the following way:
A solution of 0.815 cm3 of methanesulfonyl chloride is
added dropwise to a solution of 1.31 cm3 of (1-methyl-
piperidin-2-yl)methanol and 1.53 cm3 of triethylamine in
2 6 cm3 of dichloromethane, stirred under a nitrogen
atmosphere at -10°C. The reaction medium is allowed to
return to a temperature in the region of 2 0°C and is
stirred for 3 h before concentration to dryness under
reduced pressure. The residue obtained is taken up with
ethyl acetate. The organic phase is successively washed
with a 5% aqueous sodium bicarbonate solution and then
a saturated aqueous sodium chloride solution, dried
over magnesium sulfate, filtered, and concentrated to
dryness under reduced pressure, to give 1.3 g of a
75/25 mixture of 2-chloromethyl-1-methylpiperidin and

of methanesulfonic acid (l-methylpiperidin-2-ylmethyl)
ester. Mass spectrum (EI): m/z 148+ (M+H)+, m/z 208+
(M+H)+.
Example 66
4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol
hydrochloride
The procedure is carried out as in example 38, but with
0.75 g of 3-benzyloxy-4-phenyl-l(2-piperidin-1-
ylethyl) -1H-pyrazol oxalate, 5.9 cm3 of 12N hydrochloric
acid and 5.9 cm3 of ethanol. The mixture is heated for
4 hours at a temperature close to 100°C. After cooling
to a temperature close to 2 0°C, the reaction medium is
taken up with ethanol, and concentrated to dryness
under reduced pressure (2 kPa); the residue is
precipitated from a mixture of diisopropyl ether and
ethanol. 0.357 g of 4-phenyl-1-(2-piperidin-1-ylethyl)-
1H-pyrazol-3-ol hydrochloride is obtained in the form
of a white solid. """H NMR spectrum (300 MHz) - 5 in ppm
in DMSO-d6: 1,40 (m, 1H) ; from 1.63 to 1.87 (m, 5H) ;
2.92 (m, 2H) ; from 3.36 to 3.52 (m, 4H) ; 4.43 (t, J =
6.5 Hz, 2H) ; 7.14 (tt, J = 1.5 and 7.5 Hz, 1H) ; 7.33
(broad t, J = 7.5 Hz, 2H) ; 7.64 (broad d, J = 7.5 Hz,
2H) ; 8.05 (s, 1H) ; from 10.35 to 10.72 (broad m, 2H) .
IR spectrum (KBr): 2939; 1606; 1581; 1520; 1454; 1444;
1170; 771; 700; 673 and 427 cm"1.
The 3-benzyloxy-4-phenyl-1-(2-piperidin-1-ylethyl)-1H-
pyrazole oxalate can be obtained in the following way:
The procedure is carried out as in example 15, but with
0.166 g of sodium hydride (at 75% by mass in liquid
petroleum jelly), 0.515 g of 1-(2-chloroethyl)-
piperidine hydrochloride and 0.5 g of 3-benzyloxy-4-
phenylpyrazole. 0.754 g of 3-benzyloxy-4-phenyl-1-(2-
piperidin-1-ylethyl)-1H-pyrazole oxalate is thus
obtained in the form of a white powder. IR spectrum

(KBr): 2930; 2638; 2542; 1606; 1511; 1454; 1357; 1280;
1181; 763; 721; 697 and 501 cm-1. Mass spectrum (CI) :

m/z=362 (MH)+ base peak.
4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazole oxalate
The procedure is carried out as in example 15, but with
0.231 g of sodium hydride (at 75% by mass in liquid
petroleum jelly), 0.715 g of l-(2-chloro-
ethyDpiperidine hydrochloride and 0.4 g of 4-phenyl-
pyrazole. 0.832 g of 4-phenyl-1-(2-piperidin-1-
ylethyl) -1H-pyrazole oxalate are thus obtained in the
form of white crystals.
XH NMR spectrum (3 00 MHz) - 5 in ppm - in DMSO-d6: 1.60
(m, 2H) ; 1.79 (m, 4H) ; 3.06 (m, 4H) ; 3.43 (t, J = 6.5
Hz, 2H) ; 4.58 (t, J = 6.5 Hz, 2H) ; 7.32 (broad t, J =
7.5 Hz, 1H) ; 7.48 (broad t, J = 7.5 Hz, 2H) ; 7.69
(broad d, J = 7.5 Hz, 2H) ; 8.06 (s, 1H) ; 8.33 (s, 1H) .
IR spectrum (KBr): 2949; 1679; 1713; 1606; 1460; 1187;
955; 763; 703 and 476 cm"1.
Example 67
4-(Thiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-ol hydrochloride
A suspension of 0.15 g of 4-(5-chlorothiophen-2-yl)-1-
(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol hydrochloride
and 5 mg of palladium-on-charcoal (at 10%) in 15 cm3 of
methanol is stirred in an autoclave under a hydrogen
pressure of 3000 kPa, at a temperature of 60°C for
20 hours. The reaction medium is then filtered through
Celite , rinsed with methanol and concentrated to
dryness under reduced pressure (3 kPa) . The residue is
triturated with diisopropyl ether; after filtration of
the solid which has appeared and drying under vacuum
(70 Pa) at a temperature of 60°C, 0.1 g of 4-(thiophen-
2-yl)-1- (2-piperidin-1-ylethyl)-1H-pyrazol-3-ol hydro-
chloride is obtained in the form of a gray powder which

melts at around 180°C (with decomposition) . 1H NMR
spectrum (300 MHz) - 5 in ppm - in DMSO-d6: 1.40 (m,
1H) ; from 1.62 to 1.85 (m, 5H) ; from 2.82 to 3.02
(broad m, 2H) ; from 3.30 to 3.52 (partially masked m,
4H); 4.40 (broad t, J = 6.5 Hz, 2H); 7.02 (m, 1H); 7.19
(m, 1H); 7.32 (m, 1H); 7.93 (broad s, 1H); from 10.1 to
10.65 (broad m, 2H) . IR spectrum, KBr: 2952; 2539;
1605; 1545; 1455; 1404; 1175; 969 and 697 cm"1.
Example 68
4-(3,4-Dichlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol hydrochloride
The procedure is carried out as in example 3 8 but with
0.47 g of 3-benzyloxy-4-(3,4-dichlorophenyl-1- (2-
piperidin-1-ylethyl)-1H-pyrazole, 3 cm3 of 12N
hydrochloric acid and 10 cm3 of ethanol. The mixture is
heated for 24 hours at a temperature close to 100°C.
After cooling to a temperature close to 2 0°C, the
reaction medium is taken up with three times 3 0 cm3 of
toluene and then three times 3 0 cm3 of acetone the
ethanol, concentrated to dryness under reduced pressure
(2kPa) ; the residue is precipitated from 3 0 cm3 of
acetone. 0.26 g of 4-(3,4-dichlorophenyl)-1-(2-
piperidin-1-ylethyl)-1H-pyrazol-3-ol hydrochloride is
obtained in the form of a whitish powder. 1H NMR
spectrum (3 00 MHz) - 6 in ppm - in DMSO-d6: from 1.32
to 1.92 (m, 6H); from 2.85 to 3.60 (m, 6H); 4.3 6 (broad
m, 2H); from 7.55 to 7.68 (m, 2H); 7.90 (d, J = 2.0 Hz,
1H) ; 8.15 (broad s, 1H) ; from 9.35 to 9.48 (broad m,
1H); 10.8 (broad s, 1H). IR spectrum, KBr: 2945; 2533;
1604; 1525; 1448; 1180; 1028 and 806 cm"1.
3-Benzyloxy-4-(3,4-dichlorophenyl)-1-(2-piperidin-1-
ylethyl)-1H-pyrazole
The procedure is carried out as in example 15, but with
0.135 g of sodium hydride (75% by mass in liquid

petroleum jelly), 0.519 g of 1-(2-chloroethyl)-
piperidine hydrochloride and 0.45 g of 3-benzyloxy-4-
(3,4-dichlorophenyl)pyrazole. After heating the
reaction medium for 1 hour at 50°C and then for
16 hours at 20°C, the medium is taken up with 150 cm3 of
ethyl acetate and 150 cm3 of water; the organic phase is
separated by settling out, washed with twice 100 cm3 of
distilled water and 100 cm3 of a saturated aqueous
sodium chloride solution, dried over sodium sulfate,
filtered, and concentrated to dryness under reduced
pressure (3 kPa) . 0.6 g of 3-benzyloxy-4- (3,4-
dichlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole
is thus obtained in the form of an orangey-yellow oil.
1H NMR spectrum (400 MHz) - 5 in ppm - in DMSO-d6: 1.38
(m, 2H) ; 1.48 (m, 4H) ; 2.38 (m, 4H) ; 2.68 (t, J = 6.5
Hz, 2H) ; 4.07 (t, J = 6.5 Hz, 2H) ; 5.33 (s, 2H) ; 7.36
(tt, J = 1.5 and 7.5 Hz, 1H) ; 7.41 (broad t, J = 7.5
Hz, 2H) ; 7.51 (d, J = 7.5 Hz, 2H) ; from 7.57 to 7.65
(m, 2H) ; 7.88 (d, J = 2.5 Hz, 1H) ; 8.21 (m, 1H) . Mass
spectrum (CI): m/z=430 (MH+) base peak.
3-Benzyloxy-4-(3,4-dichlorophenyl)-1H-pyrazole
The procedure is carried out as in example 38, but with
0.3 g of 1- (toluene-4-sulfonyl)-3-benzyloxy-4-(3,4-
dichlorophenyl)-1H-pyrazole and 1.6 cm3 of a IN solution
of tetrabutylammonium fluoride in tetrahydrofuran and
15 cm3 of tetrahydrofuran. 0.2 g of 3-benzyloxy-4-(3,4-
dichlorophenyl)-1H-pyrazole is thus obtained in the
form of an oil which crystallizes. 1H NMR spectrum
(300 MHz) - 5 in ppm - in DMSO-d6: 5.35 (s, 2H) ; from
7.32 to 7.46 (m, 3H) ; 7.50 (broad d, J = 7.5 Hz, 2H) ;
7.59 (d, J = 9.0 Hz, 1H); 7.70 (dd, J = 2.5 and 9.0 Hz,
1H) ; 7.95 (d, J = 2.5 Hz, 1H) ; 8.23 (s, 1H) ; 12.3
(broad m, 1H) . Mass spectrum (EI) : m/z=318 (M+-) , m/z = 91
(C7H7+) base peak.
3-Benzyloxy-1-(toluene-4-sulfonyl)-4-(3,4-dichloro-
phenyl) -1H-pyrazole

The procedure is carried out as in example 38, but with
0.3 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-iodo-1H-
pyrazole, 2.29 g of 3,4-dichlorophenylboronic acid,
2.547 g of tripotassium phosphate, and 0.421 g of
dichlorobis(triphenylphosphine)palladium in 40 cm3 of
dimethoxyethane. After purification by chromatography,
under a nitrogen pressure of 50 kPa, on a column of
silica gel (particle size 20-45 µ; diameter 4 cm;
height 60 cm) , eluting with a mixture of ethyl acetate
and of cyclohexane (5/95 then 10/90 by volume) ,
fractions 9 to 12 are combined, and concentrated to
dryness under reduced pressure (3 kPa) . 0.3 g of
3-benzyloxy-1-(toluene-4-sulfonyl)-4-(3,4-dichloro-
phenyl) -1H-pyrazole is thus obtained in the form of a
white powder. Mass spectrum (EI) : m/z=472 (M+") , m/z=317
[ (M - C7H7SO2)+], m/z = 91 (C7H7+) base peak.
Example 69
4-(4-Bromophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-ol
The procedure is carried out as in example 38, but with
0.32 g of 3-benzyloxy-4-(4-bromophenyl)-1-(2-piperidin-
l-ylethyl) -1H-pyrazole, 3 cm3 of 12N hydrochloric acid
and 10 cm3 of ethanol. The mixture is heated for
20 minutes at a temperature close to 100°C. After
cooling to a temperature close to 20°C, the reaction
medium is taken up with 5 times 3 0 cm3 of acetone. After
concentration to dryness under reduced pressure
(3 kPa), the residue is triturated with 3 0 cm3 of
diisopropyl ether and then purified by chromatography,
under a nitrogen pressure of 50 kPa, on a column of
silica gel (particle size: 20-45 µ; diameter 2 cm;
height 2 0 cm), eluting with ethyl acetate then a
mixture of ethyl acetate and methanol (95/5 then 90/10
then 80/20 by volume). Fractions 10 to 28 are combined,
and concentrated to dryness under reduced pressure

(3 kPa) . 0.11 mg of 4-(4-bromophenyl)-1-(2-piperidin-1-
ylethyl)-1H-pyrazol-3-ol is thus obtained in the form
of a white powder. 1H NMR spectrum (3 00 MHz) - 5 in ppm
- in DMSO-d6: from 1.32 to 1.55 (m, 6H) ; 2.39 (m, 4H) ;
2.65 (t, J = 6.5 Hz, 2H) ; 4.00 (t, J = 6.5 Hz, 2H) ;
7.50 (broad d, J = 8.5 Hz, 2H); 7.62 (broad d, J = 8.5
Hz, 2H) ; 7.96 (s, 1H) ; from 10.3 to 10.50 (broad m,
1H) . IR spectrum, KBr: 2941; 1631; 1601; 1529; 1173;
1007; 824 and 510 cm"1.
3-Benzyloxy-4-(4-bromophenyl)-1-(2-piperidin-1-
ylethyl)-1H-pyrazole
The procedure is carried out as in example 15, but with
2.77 g of sodium hydride (at 75% by mass in liquid
petroleum jelly), 1.063 g of 1-(2-
chloroethyl)piperidine hydrochloride and 0.95 g of
3-benzyloxy-4-(4-bromophenyl)pyrazole. After heating
the reaction medium for 1 hour at 50°C, the medium is
cooled to a temperature close to 20°C, and taken up
with 3 00 cm3 of ethyl acetate and 3 00 cm3 of water; the
organic phase is separated by settling out, dried over
magnesium sulfate, filtered, and concentrated to
dryness under reduced pressure (3 kPa) . The residue is
purified by chromatography, under a nitrogen pressure
of 50 kPa, on a column of silica gel (particle size
20-45 µ; diameter 3 cm; height 40 cm) , eluting with a
mixture of ethyl acetate and of cyclohexane (5/95 then
10/95 by volume) . Fractions 19 to 35 are combined, and
concentrated to dryness under reduced pressure (3 kPa).
0.32 g of 3-benzyloxy-4-(4-bromophenyl)-1-(2-piperidin-
1-ylethyl) -1H-pyrazole is thus obtained in the form of
a colorless oil. 1H NMR spectrum (300 MHz) - 5 in ppm -
in DMSO-d6:
From 1.34 to 1.53 (m, 6H) ; 2.38 (m, 4H) ; 2.68 (t, J =
6.5 Hz, 2H) ; 4.07 (t, J = 6.5 Hz, 2H) ; 5.32 (s, 2H) ;
from 7.32 to 7.55 (m, 7H) ; 7.60 (broad d, J = 8.5 Hz,

2H) ; 8.10 (s, 1H) . Mass spectrum (ES) : m/z=440 (MH+)
base peak.
3-Benzyloxy-4-(4-bromophenyl)-1H-pyrazole
The procedure is carried out as in example 38, but with
1.5 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4- (4-
bromophenyl)-1H-pyrazole and 7.1 cm3 of a IN solution of
tetrabutylammonium fluoride in tetrahydrofuran and
50 cm3 of tetrahydrofuran. 0.93 g of 3-benzyloxy-4-(4-
bromophenyl)-1H-pyrazole is thus obtained in the form
of a whitish powder. 1H NMR spectrum (4 0 0 MHz) - 5 in
ppm - in DMSO-d6: 5.34 (s, 2H); 7.35 (tt, J = 1.5 and
7.5 Hz, 1H); 7.41 (broad t, J = 7.5 Hz, 2H); from 7.47
to 7.54 (m, 4H) ; 7.66 (m, 2H) ; 8.13 (s, 1H) ; 12.2
(broad m, 1H) . Mass spectrum (EI): m/z=328 (M+-), m/z = 91
(C7H7+) base peak.
3-Benzyloxy-1-(toluene-4-sulfonyl)-4-(4-bromophenyl)-
1H-pyrazole
The procedure is carried out as in example 38, but with
1.817 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-iodo-
IH-pyrazole, 2.41 g of 4-bromophenylboronic acid,
2.54 g of tripotassium phosphate, and 0.421 g of
dichlorobis(triphenylphosphine)palladium in 40 cm3 of
dimethoxyethane. After purification by chromatography,
under a nitrogen pressure of 50 kPa, on a column of
silica gel (particle size 20-45 JX; diameter 4 cm;
height 60 cm) , eluting with a mixture of ethyl acetate
and of cyclohexane (5/95 by volume), fractions 15 to 3 0
are combined, and concentrated to dryness under reduced
pressure (3 kPa). 1.5 g of 3-benzyloxy-1-(toluene-4-
sulfonyl)-4-(4-bromophenyl)-1H-pyrazole are thus
obtained in the form of a yellow oil which
crystallizes. 1H NMR spectrum (300 MHz) - 5 in ppm - in
DMSO-d6 for 77% of the mixture: 2.42 (s, 3H) ; 5.33 (s,
2H); from 7.33 to 7.50 (m, 7H); 7.59 (broad d, J = 8.5
Hz, 2H) ; 7.72 (broad d, J = 8.5 Hz, 2H) ; 7.84 (m, 2H) ;

8.86 (s, 1H) . Mass spectrum (EI): m/z=48 (M+"), m/z=327
[ (M-C7H7SO2)+] , m/z=91 (C7H7+) , base peak.
Example 70
4-(1H-Indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-ol
A mixture of 0.5 g of 3-benzyloxy-4-(1H-indol-5-yl)-1-
(2-piperidin-1-ylethyl)-1H-pyrazole, 0.5 g of ammonium
formate and 0.5 g of palladium-on-charcoal (at 10%) in
50 cm3 of ethanol is stirred for 3 0 minutes, under an
inert atmosphere, at a temperature close to 70°C. The
reaction medium is then cooled to a temperature close
to 20°C, filtered through Celite , rinsed with ethanol
and concentrated to dryness under reduced pressure
(3 kPa) . The residue is purified on a cartridge of
silica (particle size 20-40 µm) , eluting with a mixture
of dichloromethane and of a 2N solution of ammoniacal
methanol (90/10 by volume). 0.258 g of 4-(1H-indol-5-
yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol is
obtained in the form of a flaky white solid. 1H NMR
spectrum (300 MHz) - δ in ppm - in DMSO-d6: from 1.33
to 1.55 (m, 6H) ; 2.40 (m, 4H) ; 2.66 (t, J = 6.5 Hz,
2H) ; 4.00 (t, J = 6.5 Hz, 2H) ; 6.39 (broad t, J = 2.5
Hz, 1H); from 7.27 to 7.40 (m, 3H); 7.81 (m, 2H); 10.05
(broad s, 1H) ; 10.95 (broad m, 1H) . IR spectrum, KBr:
3265; 2944; 1593; 1524; 1242; 1184; 1044; 891; 803;
762; 725 and 437 cm-1. Mass spectrum (EI): m/z=310 (M+')#
m/z=98 (C6H12N+) base peak.
3-Benzyloxy-4-(1H-indol-5-yl)-1-(2-piperidin-1-
ylethyl) -1-H-pyrazole
The procedure is carried out as in example 37, but with
3.39 g of 3-benzyloxy-4-bromo-1-(2-piperidin-1-
ylethyl) -1H-pyrazole, 3.14 g of 5-indolylboronic acid,
3.87 g of potassium carbonate, 1.2 g of tetrakis-
(triphenyl)phosphine palladium in 70 cm3 of toluene and

20 cm3 of ethanol. After purification twice on a
cartridge of silica (particle size 20-40 µm) , eluting
with a mixture of dichloromethane and of methanol (95/5
by volume), 2.17 g of 3-benzyloxy-4-(1H-indol-5-yl)-1-
(2-piperidin-1-ylethyl)-1H-pyrazole is thus obtained in
the form of a beige oil which crystallizes. 1H NMR
spectrum (300 MHz) - 6 in ppm - in DMSO-d6: from 1.33
to 1.55 (m, 6H); from 2.32 to 2.50 (broad m, 4H); 2.72
(broad m, 2H) ; 4.10 (t, J = 6.5 Hz, 2H) ; 5.32 (s, 2H) ;
6.39 (broad t, J = 2.5 Hz, 1H) ; from 7.29 to 7.46 (m,
6H) ; 7.52 (broad d, J = 8.5 Hz, 2H) ; 7.81 (broad s,
1H); 7.93 (s, 1H); 11.0 (broad m, 1H).
Example 71
4-(5-Bromothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
The procedure is carried out as in example 38, but with
0.592 g of 3-benzyloxy-4-(5-bromothiophen-2-yl)-1-(2-
piperidin-1-ylethyl)-1H-pyrazole, 3.65 cm3 of 12N
hydrochloric acid and 4 cm3 of ethanol. The mixture is
heated for 2 hours at a temperature close to 100°C.
After cooling to a temperature close to 20°C, the
reaction medium is taken up with ethanol, and
concentrated to dryness under reduced pressure (2 kPa) ;
the residue is precipitated from diisopropyl ether and
then purified on a cartridge of silica (particle size
2 0-40 µm) , eluting with a mixture of dichloromethane
and of a 2N ammoniacal methanol solution (90/10 by
volume). 0.068 g of 4-(5-bromothiophen-2-yl)-1-(2-
piperidin-1-ylethyl)-1H-pyrazole-3-ol is obtained in
the form of a yellow powder. 1H NMR spectrum (3 00 MHz) -
6 in ppm - in DMSO-d6: from 1.33 to 1.53 (m, 6H) ; 2.37
(m, 4H); 2.62 (t, J = 6.5 Hz, 2H); 3.99 (t, J = 6.5 Hz,
2H) ; 6.93 (d, J = 3.5 Hz, 1H) ; 7.10 (d, J = 3.5 Hz,
1H) ; 7.85 (s, 1H) ; from 10.45 to 10.75 (very broad m,
1H) . IR spectrum, KBr: 2938; 1593; 1536; 1471; 1173;

981; 798; 758 and 496 cm-1. Mass spectrum (EI): m/z=355
(M+), m/z=98 (C6H12N+) base peak.
3-Benzyloxy-4-(5-bromothiophen-2-yl)-1-(2-piperidin-1-
ylethyl)-1H-pyrazole oxalate
The procedure is carried out as in example 15, but with
0.154 g of sodium hydride (75% by mass in liquid
petroleum jelly), 0.477 g of 1-(2-chloroethyl)-
piperidine hydrochloride and 0.62 g of 3-benzyloxy-4-
(5-bromothiophen-2-yl)pyrazole in 13 cm3 of dimethyl-
formamide. After stirring for 1 hour at a temperature
close to 20°C, the medium is taken up with 50 cm3 of
ethyl acetate and 50 cm3 of water; the organic phase is
separated by settling out, washed with 3 times 50 cm3 of
a saturated aqueous sodium chloride solution, dried
over magnesium sulfate, filtered, and concentrated to
dryness under reduced pressure (3 kPa). The residue is
taken up with 10 cm3 of acetone and 170 mg of oxalic
acid in solution in 2 cm3 of acetone. The precipitate is
filtered through sintered glass, washed with acetone,
dried, and then purified on a cartridge of silica
(particle size 20-40 µm) , eluting with a mixture of
dichloromethane and of methanol (95/5 then 90/10 by
volume). 0.716 g of 3-benzyloxy-4-(5-bromothiophen-2-
yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole oxalate is
thus obtained in the form of a yellow powder. 1H NMR
spectrum (300 MHz) - 5 in ppm - in DMSO-d6: 1.48 (m,
2H) ; 1.65 (m, 4H) ; from 2.86 to 3.00 (broad m, 4H) ;
3.25 (broad partially masked m, 2H); 4.30 (broad t, J =
6.5 Hz, 2H) ; 5.32 (s, 2H) ; 7.01 (d, J = 3.5 Hz, 1H) ;
7.15 (d, J = 3.5 Hz, 1H) ; from 7.32 to 7.54 (m, 5H) ;
8.09 (s, 1H). IR spectrum, KBr: 2948; 2536; 1724; 1641;
1595; 1532; 1498; 1451; 1363; 1173; 1008; 795 and
702 cm-1. Mass spectrum (EI): m/z=445 (M+'), m/z=98
(CeH12N+) base peak.
3-Benzyloxy-4-(5-bromothiophen-2-yl)pyrazole

The procedure is carried out as in example 38, but with
1.1 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-(5-
bromothiophen-2-yl)-1H-pyrazole and 5 cm3 of a IN
solution of tetrabutylammonium fluoride in
tetrahydrofuran and 40 cm3 of tetrahydrofuran. After
purification on a cartridge of silica (particle size
20-40 /xm) , eluting with a mixture of dichloromethane
and acetone (95/5 by volume), 0.624 g of 3-benzyloxy-4-
(5-bromothiophen-2-yl)-1H-pyrazole is thus obtained in
the form of a yellow solid. IR spectrum, KBr: 3193;
1599; 1503; 1438; 1362; 1238; 1023; 795; 731; 694 and
496 cm"1. Mass spectrum (EI): m/z=334 (M+'), m/z=91
(C7H7+) base peak.
1-(Toluene-4-sulfonyl)-3-benzyloxy-4-(5-bromothiophen-
2-yl)-1H-pyrazole
The procedure is carried out as in example 38, but with
1 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-iodo-1H-
pyrazole, 1.32 g of 5-bromothiophen-2-ylboronic acid,
1.22 g of potassium carbonate and 3 09 mg of
dichlorobis(triphenylphosphine)palladium in 20 cm3 of
toluene and 5 cm3 of ethanol. After purification on a
cartridge of silica (particle size 20-40 ptm) , eluting
with a mixture of ethyl acetate and of cyclohexane
(10/90 by volume), 0.85 g of 1-(toluene-4-sulfonyl)-3-
benzyloxy-4-(5-bromothiophen-2-yl)-1H-pyrazole is thus
obtained in the form of an orange gum. IR spectrum,
CC14: 1597; 1527; 1494; 1391; 1190; 1179; 1096; 1081;
695; 671; 595 and 54 0 cm"1. Mass spectrum (CI) :
m/z=489(M+), m/z=263 (HPPh3) base peak.
Example 72
2-[1-(2-Piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide
0.373 g of 4-(4-cyanophenyl)-1-(2-piperidin-1-ylethyl)-
1H-pyrazole oxalate and 11 cm3 of 0.IN sodium hydroxide
in 2 0 cm3 of dichloromethane are stirred at a

temperature close to 20°C for 15 minutes. The organic
phase is separated by settling out, dried over
anhydrous magnesium sulfate, filtered, and concentrated
to dryness under reduced pressure (3 kPa). The residue
is taken up with 11 cm3 of toluene. 0.287 g of potassium
trimethylsilanolate is added and the reaction medium is
heated at the reflux of the solvent for 6 h 30 min. The
mixture is cooled to a temperature close to 20°C, and
taken up with 40 cm3 of ethyl acetate and 40 cm3 of
water. The organic phase is separated by settling out,
washed with water, dried over anhydrous magnesium
sulfate, filtered, and concentrated to dryness under
reduced pressure (3 kPa) . The residue is purified on a
cartridge of silica (particle size 20-40 fim) , eluting
with a mixture of dichloromethane and a 2N ammoniacal
methanol solution (95/5 by volume). 0.081 g of 2-[l-(2-
piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide is
obtained in the form of a white solid which melts at
168°C.
1H NMR spectrum (300 MHz) - 5 in ppm - in DMSO-d6: from
1.33 to 1.55 (m, 6H) ; 2.40 (m, 4H) ; 2.68 (t, J = 6.5
Hz, 2H) ; 4.22 (t, J = 6.5 Hz, 2H) ; from 7.23 to 7.45
(m, 4H) ; 7.50 (broad d, J = 8.5 Hz, 1H) ; 7.70 (d, J =
1.0 Hz, 1H) ; 7.75 (broad m, 1H) ; 7.98 (d, J = 1.0 Hz,
1H) . IR spectrum, KBr: 3380; 3162; 2921; 1646; 1402;
954; 858; 754 and 633 cm"1. Mass spectrum (CI) : m/z=299
(MH+) base peak.
4-(4-Cyanophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole
oxalate
The procedure is carried out as in example 15, but with
0.098 g of sodium hydride (at 75% by mass in liquid
petroleum jelly), 0.305 g of 1- (2-chloroethyl)-
piperidine hydrochloride and 0.2 g of 4-(4-
cyanophenyl)-1H-pyrazole. 0.373 g of 4-(4-cyano-
phenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole oxalate

is thus obtained in the form of a white powder. 1H NMR
spectrum (300 MHz) - 5 in ppm - in DMSO-d6:
1.50 (m, 2H) ; 1.68 (m, 4H) ; 2.96 (m, 4H) ; 3.33 (broad
t, J = 6.5 Hz, 2H); 4.55 (t, J = 6.5 Hz, 2H); 7.45 (m,
1H) ; 7.73 (m, 2H) ; 7.89 (m, 1H) ; 8.06 (d, J = 1.0 Hz,
1H); 8.42 (d, J = 1.0 Hz, 1H). IR spectrum, KBr: 2949;
2223; 1747; 1641; 1600; 1225; 1207; 990; 952; 764; 705
and 504 cm"1. Mass spectrum (CI) : m/z=281 (MH+) base
peak.
4-(4-Cyanophenyl)-1H-pyrazole
The procedure is carried out as in example 38, but with
0.613 g of 1-(toluene-4-sulfonyl)-4-(4-cyanophenyl)-1H-
pyrazole and 3.8 cm3 of a IN solution of tetrabutyl-
ammonium fluoride in tetrahydrofuran and 3 0 cm3 of
tetrahydrofuran. After purification on a cartridge of
silica (particle size 20-40 µm) , eluting with a mixture
of dichloromethane and of acetone (90/10 by volume),
0.202 g of 4-(4-cyanophenyl)-1H-pyrazole is thus
obtained in the form of a white solid. 1H NMR spectrum
(300 MHz) - 5 in ppm - in DMSO-d6: 7.43 (m, 1H) ; from
7.69 to 7.80 (m, 2H) ; 7.88 (m, 1H) ; from 8.00 to 8.30
(broad m, 2H) ; 13.3 (broad m, 1H) . IR spectrum, KBr:
3153; 2966; 2218; 1601; 1516; 1347; 1044; 949; 763; 656
and 501 cm"1. Mass spectrum (EI) : m/z=169 (M+-) base
peak, m/z=142 [ (M-CHN) +] , m/z = 115 [ (m/z = 142-CHN)+] .
1-(Toluene-4-sulfonyl)-4-(4-cyanophenyl)-1H-pyrazole
The procedure is carried out as in example 41 for the
preparation of 3-benzyloxy-4-(5-chlorothiophen-1-yl)-1-
(toluene-4-sulfonyl)-1H-pyrazole, but using 0.943 g of
1-(toluene-4-sulfonyl)-4-tributylstannanyl-1H-pyrazole,
0.43 g of 2-cyano-1-iodobenzene, 84 mg of
tris(dibenzylideneacetone)palladium and 77 mg of
tris(trifuryl)phosphine in 11 cm3 of dioxane. After

purification on a cartridge of silica (particle size
2 0-40 µm) , eluting with a mixture of cyclohexane and of
ethyl acetate (90/10 then 80/20 then 50/50 by volume),
0.613 g of 1-(toluene-4-sulfonyl)-4-(4-cyanophenyl)-1H-
pyrazole is thus obtained in the form of an orange-
yellow pasty solid. 1H NMR spectrum (400 MHz) - 5 in ppm
- in DMSO-d6: 2.42 (s, 3H) ; from 7.50 to 7.58 (m, 3H) ;
7.78 (dt, J = 1.5 and 8.0 Hz, 1H) ; 7.84 (broad d, J =
8.0 Hz, 1H) ; from 7.93 to 7.98 (m, 3H) ; 8.38 (d, J =
1.0 Hz, 1H) ; 8.98 (d, J = 1.0 Hz, 1H) . IR spectrum,
KBr: 2225; 1382; 1192; 1176; 1091; 1051; 812; 761; 702;
679; 664; 593 and 541 cm"1. Mass spectrum (EI) : m/z=323
(M+-), m/z=259 [ (M - SO2)+'], m/z=91 (C7H7+) base peak.
1-(Toluene-4-sulfonyl)-4-tributylstannanyl-1H-pyrazole
The procedure is carried out as in example 41 for the
preparation of 3-benzyloxy-1-(toluene-4-sulfonyl)-4-
tributylstannanyl-1H-pyrazole, but using 1.5 g of
1-(toluene-4-sulfonyl)-4-iodo-1H-pyrazole, 2.65 cm3 of
1,1,1,2,2,2-hexabutyldistannane, 58 mg of palladium
diacetate and 13 6 mg of triphenylphosphine in 2 0 cm3 of
DMF. After 2 purifications on a cartridge of silica
(particle size 2 0-40 µm) , eluting with cyclohexane and
then a mixture of cyclohexane and of ethyl acetate
(95/5 by volume), 0.743 g of 1-(toluene-4-sulfonyl)-4-
tributylstannanyl-1H-pyrazole is thus obtained in the
form of a colorless oil. IR spectrum, CH2Cl2: 2959;
2925; 2873; 2854; 1378; 1175; 1064; 957; 673; 594 and
543 cm-1. Mass spectrum (EI): m/z=511 (M+"), m/z=455 [ (M
- C4H8)+'] base peak, m/z=399 [ (m/z=455 - C4H8)+-],
m/z=343 [(m/z=399 - C4H8)+], m/z=91 (C7H7+) .
Example 73
4-(2-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazole hydrochloride

A stirred solution of 0.582 g of 4-(2-methoxyphenyl)-1-
(2-piperidin-1-ylethyl)-1H-pyrazole oxalate in 12 cm3 of
dichloromethane, under an inert atmosphere, is cooled
to a temperature close to -78°C. 4.3 cm3 of boron
tribromide are added and the stirring is continued for
4 hours at a temperature close to -70°C, and then for
15 hours at a temperature close to 2 0°C. The reaction
medium is taken up with 10 cm3 of water. The organic
phase is separated by settling out and then washed with
a 1N sodium hydroxide solution until a pH of 8-8.4
(Lyphan paper) is obtained, and taken up with 2 0 cm3 of
water. The organic phase is separated by settling out,
dried over anhydrous magnesium sulfate, filtered, and
concentrated to dryness under reduced pressure (3 kPa).
The residue is precipitated from diisopropyl ether; the
precipitate is purified on a cartridge of silica
(particle size 20-40 µm) , eluting with a mixture of
dichloromethane and of methanol (90/10 by volume); the
gum obtained is taken up with a 1N hydrochloric diethyl
ether solution. 0.172 g of 4-(2-hydroxyphenyl)-1-(2-
piperidin-1-ylethyl)-1H-pyrazole hydrochloride is
obtained in the form of a pink powder. 1H NMR spectrum
(300 MHz) - 5 in ppm - in DMSO-d6: from 1.30 to 1.82
(broad m, 6H) ; from 2.38 to 3.62 (very broad m, 6H) ;
from 4.22 to 4.60 (broad m, 2H); 6.82 (dt, J = 1.5 and
8.0 Hz, 1H); 6.92 (broad d, J = 8.0 Hz, 1H); 7.03 (dt,
J = 1.5 and 8.0 Hz, 1H) ; 7.54 (dd, J = 1.5 and 8.0 Hz,
1H); 7.98 (broad s, 1H); 8.23 (broad s, 1H); from 9.05
to 9.45 (very broad m, 1H) ; 9.76 (broad s, 1H) . IR
spectrum, KBr: 3144; 2938; 2539; 1560; 1461; 1351;
1282; 1238; 1111; 954; 856; 747 and 478 cm"1. Mass
spectrum (EI) : m/z=271 (M+') , m/z=98 [CsHi2N+] base peak.
4-(2-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazole oxalate
The procedure is carried out as in example 15, but with
0.22 mg of sodium hydride (at 75% by mass in liquid
petroleum jelly), 0.681 g of 1-(2-chloroethyl)-

piperidine hydrochloride and 0.46 mg of 4-(2-
methoxyphenyl)-1H-pyrazole. 0.582 g of 4-(2-methoxy-
phenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole oxalate
is thus obtained in the form of a white solid. 1H NMR
spectrum (300 MHz) - 5 in ppm - in DMSO-d6 for 50% of
the mixture: 1.50 (m, 2H); from 1.62 to 1.75 (broad m,
4H) ; from 2.88 to 3.09 (m, 4H) ; 3.15 (t, J = 6.5 Hz,
2H) ; 3.89 (s, 3H) ; 4.52 (t, J = 6.5 Hz, 2H) ; 6.99
(broad t, J = 8.0 Hz, 1H) ; 7.10 (broad d, J = 8.0 Hz,
1H) ; 7.23 (dt, J = 1.5 and 8.0 Hz, 1H) ; 7.63 (dd, J =
1.5 and 8.0 Hz, 1H); 8.01 (broad s, 1H); 8.23 (broad s,
1H) . IR spectrum, KBr: 2948; 2537; 1719; 1635; 1493;
1246; 1184; 1028; 952; 756; 721; 704 and 497 cm"1. Mass
spectrum (CI) : m/z=281 (MH+) base peak, m/z=148 (M'H+) .
4-(2-Methoxyphenyl)-1H-pyrazole
The procedure is carried out as in example 38, but with
1.08 g of 1-(toluene-4-sulfonyl)-4-(2-methoxyphenyl)-
1H-pyrazole and 7.3 cm3 of a 1N solution of
tetrabutylammonium fluoride in tetrahydrofuran and
58 cm3 of tetrahydrofuran. After purification on a
cartridge of silica (particle size 20-40 µm) , eluting
with a mixture of dichloromethane and of methanol
(90/10 by volume), 0.463 g of 4-(2-methoxyphenyl)-1H-
pyrazole is thus obtained in the form of an off-white
solid. 1H NMR spectrum (300 MHz) - 6 in ppm - in DMSO-
d6: 3.89 (s, 3H) ; 6.97 (dt, J = 1.5 and 8.5 Hz, 1H) ;
7.06 (broad d, J = 8.5 Hz, 1H) ; 7.21 (m, 1H) ; 7.63 (dd,
J = 1.5 and 8.5 Hz, 1H); from 7.85 to 8.2 0 (very broad
m# 2H) ; 12.9 (broad m, 1H) . IR spectrum, KBr: 3156;
2936; 2832; 1569; 1488; 1466; 1263; 1247; 1148; 1027;
950; 753; 661 and 628 cm"1. Mass spectrum (EI): m/z=174
(M+-) base peak, m/z=159 [ (M - CH3)+], m/z = 131 [ (m/z = 159
- C0)+] .
1-(Toluene-4-sulfonyl)-4-(2-methoxyphenyl)-1H-pyrazole

The procedure is carried out as in example 38, but with
1.5 g of 1-(toluene-4-sulfonyl)-4-iodo-1H-pyrazole,
1.31 g of 2-methoxyphenylboronic acid, 1.74 g of
potassium carbonate and 0.605 g of dichlorobis-
(triphenylphosphine)palladium in 3 0 cm3 of toluene and
7.5 cm3 of ethanol. After purification on a cartridge of
silica (particle size 20-40 µm) , eluting with a mixture
of ethyl acetate and of cyclohexane (2 0/80 by volume),
1.081 g of 1-(toluene-4-sulfonyl)-4-(2-methoxyphenyl)-
1H-pyrazole are thus obtained in the form of an orange
gum. 1H NMR spectrum (3 00 MHz) - 5 in ppm - in DMSO-d6:
2.41 (s, 3H) ; 3.92 (s, 3H) ; 7.01 (dt, J = 1.5 and 8.5
Hz, 1H) ; 7.13 (broad d, J = 8.5 Hz, 1H) ; 7.33 (m, 1H) ;
broad d, J = 8.5 Hz, 2H) ; 7.73 (dd, J = 1.5 and 8.5 Hz,
1H) ; 7.93 (broad d, J = 8.5 Hz, 2H) ; 8.41 (broad s,
1H); 8.72 (broad s, 1H). IR spectrum, KBr: 2835; 1497;
1371; 1177; 1097; 1039; 1023; 950; 753; 681; 598 and
550 cm"1. Mass spectrum (EI) : m/z=328 (M+') base peak,
m/z=264 [ (M - SO2)+], m/z=173 [ (M - C7H7SO2)+] , m/z = 91
(C7H7+) .
Example 74
4-(1H-Indol-5-yl)-1-(2-piperidin-1-ylethyl)-IH-pyrazole
The procedure is carried out as in example 38, but with
1.22 g of 4-iodo-1-(2-piperidin-1-ylethyl)-1H-pyrazole,
1.93 g of 1H-indol-5-ylboronic acid, 2.547 g of
tripotassium phosphate, 0.421 g of dichlorobis-
(triphenylphosphine)palladium in 50 cm3 of dimethoxy-
ethane. After purification by chromatography, under a
nitrogen pressure of 50 kPa, on a column of silica gel
(particle size 20-45 µ; diameter 3 cm; height 60 cm) ,
eluting with a mixture of ethyl acetate and of methanol
(95/5 then 90/10 by volume) , fractions 18 to 30 are
combined, and concentrated to dryness under reduced
pressure (3 kPa). 0.23 g of 4-(1H-indol-5-yl)-1-(2-
piperidin-1-ylethyl)-1H-pyrazole is thus obtained in
the form of a whitish powder. 1H NMR spectrum (3 00 MHz)

- 6 in ppm - in DMSO-d6: from 1.34 to 1.56 (m, 6H) ;
2.41 (m, 4H) ; 2.72 (t, J = 6.5 Hz, 2H) ; 4.22 (t, J =
6.5 Hz, 2H) ; 6.41 (m, 1H) ; from 7.27 to 7.40 (m, 3H) ;
7.71 (m, 1H) ; 7.80 (d, J = 1.0 Hz, 1H) ; 8.06 (broad s,
1H); 11.0 (broad m, 1H).
IR spectrum, KBr: 2937; 1436; 1363; 1167; 1119; 994;
887; 792; 763; 614 and 43 0 cm-1.
Mass spectrum (EI): m/z=294 (M+), m/z=98 (C6H12N+) base
peak.
4-Iodo-1-(2-piperidin-1-ylethyl)-1H-pyrazole
The procedure is carried out as in example 15, but with
4.94 g of sodium hydride (at 75% by mass in liquid
petroleum jelly), 19 g of 1-(2-chloroethyl)piperidine
hydrochloride and 10 g of 4-iodopyrazole. After
stirring for 16 hours at a temperature close to 20°C,
the reaction medium is taken up with 1000 cm3 of ethyl
acetate and 1000 cm3 of water; the organic phase is
separated by settling out, washed with 3 times 1000 cm3
of water and 500 cm3 of a saturated aqueous sodium
chloride solution, dried over magnesium sulfate,
filtered, and concentrated to dryness under reduced
pressure (3 kPa). The residue is purified by
chromatography, under a nitrogen pressure of 5 0 kPa, on
a column of silica gel (particle size 20-45 µ; diameter
6 cm; height 60 cm) , eluting with a mixture of ethyl
acetate and of cyclohexane (3 0/70 by volume) and then
ethyl acetate. Fractions 16 to 20 are combined, and
concentrated to dryness under reduced pressure (3 kPa).
8.2 g of 4-iodo-1-(2-piperidin-1-ylethyl)-1H-pyrazole
are thus obtained in the form of a light yellow oil. 1H
NMR spectrum (300 MHz) - 6 in ppm - in DMSO-d6: from
1.34 to 1.52 (m, 6H) ; 2.36 (m, 4H) ; 2.64 (t, J = 6.5
Hz, 2H) ; 4.22 (t, J = 6.5 Hz, 2H) ; 7.51 (broad s, 1H) ;
7.92 (broad s, 1H) . Mass spectrum (CI): m/z=306 (MH+)
base peak.

Example 75
4-(4-Methylphenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol hydrochloride
The procedure is carried out as in example 38, but with
0 . 63 g of 3-benzyloxy-4-(4-methylphenyl)-1-(2-
piperidin-1-ylethyl)-1H-pyrazole, 4.8 cm3 of 12N
hydrochloric acid and 4.8 cm3 of ethanol. The mixture is
heated for 4 hours at a temperature close to 10 0°C.
After cooling to a temperature close to 20°C, the
reaction medium is taken up with ethanol, and
concentrated to dryness under reduced pressure (2 kPa);
the residue is precipitated from diisopropyl ether.
0.385 g of 4-(4-methylphenyl)-1-(2-piperidin-1-
ylethyl) -1H-pyrazol-3-ol hydrochloride is obtained in
the form of a white solid. 1H NMR spectrum (300 MHz) - in ppm - in DMSO-d6: 1.40 (m, 1H) ; from 1.63 to 1.87
(m, 5H); 2.30 (s, 3H); from 2.82 to 3.02 (broad m, 2H) ;
from 3.2 7 to 3.53 (m, 4H) ; 4.3 8 (broad t, J = 6.5 Hz,
2H) ; 7.15 (broad d, J = 8.5 Hz, 2H) ; 7.54 (broad d, J =
8.5 Hz, 2H) ; 7.98 (s, 1H) ; 10.05 (very broad m, 1H) ;
10.4 (broad m, 1H). IR spectrum, KBr: 2941; 2646; 1597;
1534; 1447; 1179; 1010; 818; 627 and 515 cm"1. Mass
spectrum (EI): m/z=285 (M+-), m/z = 98 (C6Hi2N+) base peak.
3-Benzyloxy-4-(4-methylphenyl)-1-(2-piperidin-1-yl-
ethyl) -1H-pyrazole oxalate
The procedure is carried out as in example 15, but with
0.123 g of sodium hydride (at 75% by mass in liquid
petroleum jelly), 0.38 g of 1-(2-chloroethyl)piperidine
hydrochloride and 0.39 g of 3-benzyloxy-4-(4-methyl-
phenyl)pyrazole. 0.632 g of 3-benzyloxy-4-(4-
methylphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole
oxalate is thus obtained in the form of a white powder.
IR spectrum, KBr: 2931; 2639; 2543; 1719; 1618; 1580;
1519; 1452; 1279; 1180; 818; 721 and 500 cm"1. Mass
spectrum (CI): m/z=376 (MH+) base peak.

1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(3-chlorophenyl)-1H-
pyrazol-3-ol hydrochloride
3 cm3 of 12N hydrochloric acid are added to a stirred
solution of 270 mg of 3-[3-benzyloxy-4-(3 -
chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2] octane in
6 cm3 of ethanol. After 7 h at the reflux of the
solvent, the reaction medium is evaporated to dryness
under reduced pressure (2.7 kPa) . The residue is taken
up with ethanol, and the mixture is then evaporated to
dryness under vacuum (2.7 kPa). The operation is
repeated twice, and the foam obtained is then
triturated in diisopropyl ether. The precipitate formed
is filtered off and dried under vacuum (2.7 kPa) to
give 180 mg of 1-(1-azabicyclo[2.2.2]oct-3-yl)-4- (3-
chlorophenyl)-1H-pyrazol-3-ol hydrochloride in the form
of a white solid.
IR spectrum (KBr): 2931; 2801; 2660; 2557; 1599; 1563;
1517; 1459; 1425; 1165; 1095; 950; 891; 840; 788; 685;
62 7 and 44 0 cm"1.
1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : from
1.65 to 2.05 (mt: 4H); 2.43 (mt: 1H); from 3.15 to 3.45
(mt: 4H) ; from 3.70 to 3.85 (mt: 2H) ; 4.67 (mt: 1H) ;
7.20 (ddd, J = 8-2 and 1 Hz: 1H) ; 7.38 (t, J = 8 Hz:
1H) ; 7.67 (broad d, J = 8 Hz: 1H) ; 7.75 (t, J = 2 Hz:
1H) ; 8.31 (s: 1H) ; from 10.30 to 10.60 (broad
unresolved peak: 1H); 10.68 (broad s: 1H).
The 3-[3-benzyloxy-4-(3-chlorophenyl)pyrazol-1-yl]-1-
azabicyclo[2.2.2]octane can be prepared in the
following way:
560 mg of potassium tert-butoxide, followed by a
solution of 740 mg of toluene-4-sulf onic acid
1-azabicyclo[2.2.2]oct-3-yl ester in 20 cm3 of dimethyl-
formamide, are added to a stirred solution, under an
argon atmosphere, of 570 mg of 3-benzyloxy-4-(3-chloro-

3-Benzyloxy-4-(4-methylphenyl)-1H-pyrazole
The procedure is carried out as in example 38, but with
0.8 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-(4-
methylphenyl) -1H-pyrazole and 4 cm3 of a IN solution of
tetrabutylammonium fluoride in tetrahydrofuran and
40 cm3 of tetrahydrofuran. 0.397 g of 3-benzyloxy-4-(4-
methylphenyl)-1H-pyrazole is thus obtained in the form
of a white powder. IR spectrum, KBr: 3187; 2980; 1586;
1498; 1450; 1380; 1233; 1043; 814; 737; 695 and
514 cm-1. Mass spectrum (EI): m/z=264 (M+-), m/z = 186 [ (M
- C6H6)+-], m/z = 91 (C7H7+) base peak.
3-Benzyloxy-1-(toluene-4-sulfonyl)-4-(4-methylphenyl)-
1H-pyrazole
The procedure is carried out as in example 38, but with
1 g of 1-(toluene-4-sulfonyl)-3-benzyloxy-4-iodo-1H-
pyrazole, 0.898 g of 4-methylphenylboronic acid,
0.913 g of potassium carbonate and 0.331 g of
tetrakis(triphenylphosphine)palladium in 13 cm3 of
toluene, 3 cm3 of ethanol and 3.3 cm3 of water. 0.817 g
of 3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-methyl-
phenyl) -1H-pyrazole is thus obtained in the form of a
pinkist-beige cottonwool-like solid. IR spectrum, KBr:
1589; 1485; 1377; 1191; 1179; 1098; 813; 702; 672; 580
and 538 cm"1. Mass spectrum (EI): m/z=418 (M+-) , m/z=263
[(M - C7H7SO2)+], m/z=91 (C7H7+) base peak.
Example 16
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-5-yl)-1H-
pyrazole
The procedure is carried out as in example 38, but with
1 g of 1-(l-azabicyclo[2.2.2]oct-3-yl)-4-iodo-1H-
pyrazole, 0.797 g of 1H-indol-5-ylboronic acid, 1.026 g
of potassium carbonate, 0.463 g of dichlorobis-

(triphenylphosphine)palladium in 3 0 cm3 of toluene,
6 cm3 of ethanol and 3 cm3 of water. After purification
by chromatography, under a nitrogen pressure of 50 kPa,
on an alumina CTB1 column, eluting with ethyl acetate
and then a mixture of ethyl acetate and of methanol
(95/5 then 90/10 then 80/20 by volume), fractions 97 to
110 are combined, and concentrated to dryness under
reduced pressure (3 kPa). The residue is precipitated
from a mixture of 5 cm3 of ethyl acetate and 25 cm3 of
diisopropyl ether. 0.18 g of 1-(1-azabicyclo[2.2.2]oct-
3-yl)-4-(1H-indol-5-yl)-1H-pyrazole is thus obtained in
the form of a yellow powder. *H NMR spectrum (3 00 MHz) -
5 in ppm - in DMSO-d6: 1.34 (m, 1H) ; from 1.53 to 1.75
(m, 3H); 2.13 (m, 1H); from 2.67 to 2.81 (m, 3H); 3.02
(m, 1H) ; 3.26 (partially masked m, 1H) ; 3.49 (m, 1H) ;
4.44 (m, 1H); 6.40 (m, 1H); from 7.29 to 7.41 (m, 3H)/
7.75 (broad s, 1H); 7.87 (broad s, 1H); 8.22 (broad s,
1H); 11.0 (broad m, 1H). IR spectrum, KBr: 3113; 2939;
1587; 1454; 1362; 1165; 1058; 976; 881; 792; 729; 619
and 435 cm-1. Mass spectrum (ES) : m/z=293 (MH+) base
peak.
The enantiomers are separated by HPLC on chiralpak
AD 20 µm with, as eluent, a mixture of heptane, of
ethanol and of butylamine (40/60/0.2 by volume). Two
enantiomers, A and B, are obtained, which are purified
according to the following protocol: enantiomer A is
purified by extraction with ethyl acetate and then
solubilized in 100 ml of water. The pH of the solution
is adjusted to 10 with 0.1N sodium hydroxide. The
organic phase is extracted with 100 ml of ethyl
acetate. The aqueous phase is separated by settling out
with 2 x 50 ml of dichloromethane. The organic phase is
dried with anhydrous sodium sulfate, filtered, and
concentrated to dryness under reduced pressure. The
organic phase is controlled by reverse-phase polarity
HPLC on a Thermo hypersil Hypurity C18 250*4.6*5 /xm
column; eluent: 95/5 gradient: acetate buffer/aceto-
nitrile for 50 minutes. 42.6 mg of (-)-1-(1-azabicyclo-

[2.2.2]oct-3-yl)-4-(1H-indol-5yl)-1H-pyrazole,
enantiomer A are obtained ( [α] 20D = -37.3° (solvent:
dimethyl sulfoxide, concentration: 0.3)).
Enantiomer B is purified by extraction with ethyl
acetate and then solubilized in 100 ml of water. The pH
of the solution is adjusted to 10 with 0. 1N sodium
hydroxide. The organic phase is extracted with 100 ml
of ethyl acetate. The aqueous phase is separated by
settling out with 2 x 50 ml of dichloromethane. The
organic phase is dried with anhydrous sodium sulfate,
filtered, and concentrated to dryness under reduced
pressure. The organic phase is controlled by reverse-
phase polarity HPLC on a Thermo hypersil Hypurity C18
250*4.6*5 µm column; eluent: 95/5 gradient: acetate
buffer/acetonitrile for 50 minutes. 56.3 mg of (+)-1-
(l-azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-5-yl)-1H-
pyrazole, enantiomer B are obtained ( [α] 20D = +3 6.2°
(solvent: dimethyl sulfoxide, concentration: 0.42)).
1- (1-Azabicyclo[2.2.2]oct-3-yl)-4-iodo-1H-pyrazole
The procedure is carried out as in example 5, but with
0.48 g of sodium hydride (at 75% by mass in liquid
petroleum jelly), 3.079 g of toluene-4-sulfonic acid
1-azabicyclo[2.2.2]oct-3-yl ester and 1.94 g of 4-iodo-
pyrazole in 30 cm3 of dimethylformamide. The residue is
purified by chromatography, under a nitrogen pressure
of 50 kPa, on an alumina CBT1 column, eluting with
ethyl acetate and then a mixture of ethyl acetate and
of methanol (95/5 then 90/10 by volume). Fractions 29
to 39 are combined, and concentrated to dryness under
reduced pressure (3 kPa) . The oil obtained is again
purified on an alumina CBT1 column, eluting with ethyl
acetate. Fractions 11 to 15 are combined, and
concentrated to dryness under reduced pressure (3 kPa).
0.33 g of 1-(1-azabicyclo[2.2.2]oct-3-yl)-4-iodo-1H-
pyrazole is obtained in the form of an oil which
crystallizes. 1H NMR spectrum (400 MHz) - 6 in ppm - in

DMSO-d6: 1.3 0 (m, 1H); 1.46 (m, 1H); 1.66 (m, 2H); 2.05
(m, 1H); from 2.65 to 2.78 (m, 4H); 2.91 (m, 1H); 3.21
(partially masked m, 1H) ; 4.44 (m, 1H) ; 7.58 (broad s,
1H) ; 8.06 (broad s, 1H) . Mass spectrum (EI): m/z=303
(M+-), m/z=220 [(M - C5H9N)+-], m/z=109 (C7HuN+-)7 m/z=97
(C6HnN+') base peak.
Example 77
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(5-chlorothiophen-2-
yl)-1H-pyrazol-3-ol hydrochloride, isomer A
The procedure is carried out as in example 38, but with
0.13 g of 1- (1-azabicyclo [2 .2 .2] oct-3-yl) -3-benzyloxy-
4-(5-chlorothiophen-2-yl)-1H-pyrazole, isomer A, 10 cm3
of 12N hydrochloric acid and 15 cm3 of ethanol. The
mixture is heated for 22 hours at a temperature close
to 100°C, and then cooled to a temperature close to
20°C; the reaction medium is concentrated to dryness
under reduced pressure (3 kPa), then taken up with
twice 20 cm3 of ethanol and concentrated to dryness
under reduced pressure (2 kPa); the residue is
precipitated from 20 cm3 of diisopropyl ether. 80 mg of
1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(5-chlorothiophen-2-
yl)-1H-pyrazol-3-ol hydrochloride, isomer A, are
obtained in the form of a grayish powder. ^ NMR
spectrum (300 MHz) - 6 in ppm - in DMSO-d6: from 1.62
to 1.98 (m, 4H) ; 2.36 (m, 1H) ; from 3.07 to 3.55
(partially masked m, 4H) ; 3.71 (m, 2H) ; 4.62 (m, 1H) ;
7.03 (m, 2H); 8.10 (broad s, 1H); 10.75 (broad m, 1H) .
IR spectrum, KBr: 1602; 1536; 1459; 1164; 1005; 795 and
502 cm-1.
Mass spectrum (ES) : m/z=310 (MH+) base peak. [α]D = -14°
(solvent: MeOH, concentration 0.1266).

Example 78
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(5-chlorothiophen-2-
yl)-1H-pyrazol-3-ol hydrochloride, isomer B
The procedure is carried out as in example 38, but with
0.13 g of 1-(l-azabicyclo[2.2.2]oct-3-yl)-3-benzyloxy-
4-(5-chlorothiophen-2-yl)-1H-pyrazole, isomer B, 5 cm3
of 12N hydrochloric acid and 10 cm3 of ethanol. The
mixture is heated for 16 hours at a temperature close
to 100°C, then cooled to a temperature close to 20 °C;
the reaction medium is concentrated to dryness under
reduced pressure (3 kPa) , then taken up with twice
20 cm3 of toluene and concentrated to dryness under
reduced pressure (2 kPa); the residue is taken up with
3 times 20 cm3 of ethanol and concentrated to dryness
under reduced pressure (2 kPa). The residue thus
obtained is precipitated from 20 cm3 of diisopropyl
ether. 100 mg of 1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(5-
chlorothiophen-2-yl)-1H-pyrazole-3-ol hydrochloride,
isomer B, are obtained in the form of a grayish powder.
1H NMR spectrum (300 MHz) - δ in ppm - in DMSO-d6: from
1.62 to 2.00 (m, 4H) ; 2.38 (m, 1H) ; from 3.05 to 3.53
(m, 4H); 3.73 (m, 2H); 4.63 (m, 1H); 7.03 (m, 2H); 8.11
(broad s, 1H) ; 10.75 (broad m, 1H) . IR spectrum, KBr:
1601; 1536; 1457; 1163; 1004; 794 and 502 cm-1. Mass
spectrum (CI) : m/z=310 (MH+) base peak. [α]D = -18°
(solvent: MeOH, concentration: 0.2168).
1-(1-Azabicyclo[2.2.2]oct-3-yl)-3-benzyloxy-4-(5-
chlorothiophen-2-yl)-1H-pyrazole, isomers A and B
The procedure is carried out as in example 5, but with
0.495 g of sodium hydride (at 75% by mass in liquid
petroleum jelly), 3.178 g of toluene-4-sulfonic acid
1-azabicyclo[2.2.2]oct-3-yl ester and 1.94 g of
3-benzyloxy-4-(5-chlorothiophen-2-yl)pyrazole in 70 cm3
of dimethylformamide. The residue is purified by
chromatography, under a nitrogen pressure of 50 kPa, on

a column of silica gel (particle size 20-45 µ; diameter
3 cm; height 50 cm) , eluting with dichloromethane and
then a mixture of dichloromethane and of methanol (95/5
then 90/10 then 80/20 by volume) . Fractions 52 to 74
are combined, and concentrated to dryness under reduced
pressure (3 kPa). The oil obtained is again purified on
an alumina CBT1 column, eluting with ethyl acetate and
then a mixture of ethyl acetate and of methanol (90/10
by volume). Fractions 22, 32 and 40 to 50 are combined,
and concentrated to dryness under reduced pressure
(3 kPa). 0.5 g of 1-(1-azabicyclo[2.2.2]-oct-3-yl)-3-
benzyloxy-4-(5-chlorothiophen-2-yl)-1H-pyrazole is thus
obtained in the form of a green oil which crystallizes,
for which the two enantiomers are separated by HPLC.
Mass spectrum (EI): m/z=399 (M+), m/z=308 [ (M - C7H7)+] ,
m/z=110 (C7H12N+) , m/z=91 (C7H7+) base peak.
Using 0.45 g of 1-(1-aza-bicyclo[2.2.2]oct-3-yl)-3-
benzyloxy-4-(5-chlorothiophen-2-yl)-1H-pyrazole, the
enantiomers are separated by HPLC on chiralpak
AD 20 µm, eluting with a mixture of 70% heptane/15%
ethanol/15% methanol/0.1% triethylamine. 138 mg of
1-(1-azabicyclo[2.2.2]oct-3-yl)-3-benzyloxy-4-(5-
chlorothiophen-2-yl)-1H-pyrazole, isomer A ([α]D =
+28.2° (solvent: MeOH, concentration: 0.5)) and 129 mg
of 1-(1-azabicyclo[2.2.2]oct-3-yl)-3-benzyloxy-4-(5-
chlorothiopen-2-yl)-1H-pyrazole, isomer B ([α]D = -24.6°
(solvent: MeOH, concentration: 0.5)) are obtained. Mass
spectrum (IE): m/z=399 (M+-), m/z=308 [ (M - C7H7)+] ,
m/z=110 (C7H12N+) , m/z=91 (C7H7+) base peak.
Example 79
1-(1-Azabicyclo[2.2.2]oct-2-ylmethyl)-4-phenyl-1H-
pyrazol-3-ol hydrochloride
1.8 cm3 of 6N hydrochloric acid is added to a solution
of 0.8 g of 2-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-
1-azabicyclo [2.2.2] octane in 20 cm3 of ethanol and the

mixture is stirred at ambient temperature for
30 minutes and then concentrated to dryness under
reduced pressure (3 kPa). The suspension of the residue
obtained and of 114 mg of palladium-on-charcoal at 10%
in 20 cm3 of ethanol is stirred in an autoclave under a
hydrogen pressure of 100 kPa, at a temperature of 2 0°C
for 8 hours. The reaction medium is then filtered
through Celite* and concentrated to dryness under
reduced pressure (3 kPa), to give a pasty residue,
which is covered with 40 cm3 of acetone and triturated
until crystallization is complete. After filtration of
the solid that has appeared and drying under vacuum
(70 Pa) at a temperature of 60°C, 0.6 g of 1-(1-
azabicyclo[2.2.2]oct-2-ylmethyl)-4-phenyl-1H-pyrazol-3-
ol hydrochloride is obtained in the form of beige
crystals which melt at a temperature above 260°C. 1H NMR
spectrum (300 MHz) - 5 in ppm - in DMSO-d6 (referenced
at 2.50 ppm): 1.55 (m, 1H); from 1.71 to 1.95 (m, 5H) ;
2.08 (m, 1H) ; from 3.12 to 3.35 (partially masked m,
3H) ; 3.50 (m, 1H) ; 3.88 (m, 1H) ; 4.27 (dd, J = 7.5 and
14.0 Hz, 1H); 4.42 (dd, J = 7.5 and 14.0 Hz, 1H); 7.12
(broad t, J = 7.5 Hz, 1H) ; 7.32 (broad t, J = 7.5 Hz,
2H); 7.63 (broad d, J = 7.5 Hz, 2H); 8.01 (s, 1H); 9.80
(broad m, 1H) ; 10.45 (broad m, 1H) . Mass spectrum
(EI): m/z=283 (M+>), m/z=201 [ (M - C5H8N)+-], m/z=173
[(M - C7H12N)+-], m/z=124 (C8H14N+) base peak, m/z=82
(C5H8N+) , m/z=36 (HCl+-) .
The 2-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-aza-
bicyclo[2.2.2]octane can be obtained in the following
way:
182 mg of sodium hydride (at 75% by mass in liquid
petroleum jelly) are added gradually, under an argon
atmosphere and at ambient temperature, to a solution of
0.95 g of 3-benzyloxy-4-phenylpyrazole in 20 cm3 of
anhydrous dimethylformamide. After stirring for three-
quarters of an hour at a temperature in the region of
50°C, a solution of 1.25 g of 1-azabicyclo[2.2.2] oct-2-

ylmethyl methanesulfonate in 2 0 cm3 of anhydrous
dimethylformamide is gradually added, and the mixture
is then heated for 24 hours at a temperature in the
region of 110°C. The mixture is cooled to ambient
temperature, and then 10 cm3 of water are slowly added
and the mixture is finally concentrated in a rotary
evaporator. 25 cm3 of water are added to the residue
obtained, which is extracted with 250 cm3 of ethyl
acetate. The organic phase is washed with 3 times 25 cm3
of water, then filtered through a phase-separating
filter (Whatman*, reference: 2200 185) and concentrated
to dryness under reduced pressure (3 kPa). The oily
residue obtained is purified by chromatography on
alumina, eluting with dichloromethane. After
concentrating the fractions under reduced pressure,
0.8 g of 2-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-
azabicyclo [2.2.2] octane is obtained in the form of an
oil which solidifies slowly as an amorphous solid. Mass
spectrum (EI): m/z=373 (M+) , m/z=282 [ (M - C7H7)+] ,
m/z=124 (C8H14N+) , m/z=91 (C7H7+) base peak, m/z=82
(C5H8N+) .
The 1-azabicyclo[2.2.2]oct-2-ylmethyl methanesulfonate
can be obtained in the following way:
0.69 cm3 of pyridine followed, dropwise, by 0.66 cm3 of
methanesulfonyl chloride are added, at a temperature in
the region of 0°C and under an argon atmosphere, to a
solution of 1 g of (1-azabicyclo[2.2.2]oct-2-yl)-
methanol in 40 cm3 of dichloromethane. The suspension is
stirred for 20 minutes at around 0°C and then for
18 hours at ambient temperature. 15 cm3 of a saturated
potassium carbonate solution are then added to the
mixture, which is extracted with 3 times 50 cm3 of ethyl
acetate. The combined organic phases are dried over
anhydrous magnesium sulfate, filtered, and concentrated
to dryness under reduced pressure (3 kPa). The residue
obtained is purified by chromatography on alumina,
eluting with ethyl acetate. After concentrating the

fractions under reduced pressure, 1.1 g of 1-aza-
bicyclo[2.2.2]oct-2-ylmethyl methanesulfonate are
obtained in the form of a colorless oil. Mass spectrum
(EI): m/z=219 (M+), m/z=140 [ (M - SO2CH3)+], m/z=124
(C8H14N+) base peak.
The (l-azabicyclo[2.2.2]oct-2-yl)methanol can be
obtained according to the method described in patent
DE 1938546.
Example 80
3-[4-(3,5-DifluorophenyDpyrazol-1-yl]-1-azabicyclo-
[2.2.2]octane hydrochloride:
0.173 g of sodium hydride (at 75% by mass in liquid
petroleum jelly) is added gradually, under an argon
atmosphere and at ambient temperature, to a solution of
0.65 g of 4-(3,5-difluorophenyl)-1H-pyrazole in 30 cm3
of anhydrous dimethylformamide. After stirring for
three-quarters of an hour at a temperature in the
region of 50°C, a solution of 1.17 g of
3-[(methanesulfonyl)oxy]-1-azabicyclo[2.2.2]octane in
10 cm3 of anhydrous dimethylformamide is added dropwise,
and the mixture is then heated for 20 hours at a
temperature in the region of 110°C. The mixture is
cooled to ambient temperature, 5 cm3 of water are slowly
added, and the mixture is concentrated under reduced
pressure (3 kPa). The residue is taken up with 2 0 cm3 of
water and extracted with 250 cm3 of ethyl acetate. The
organic phase is washed with 4 times 2 0 cm3 of water,
then dried, filtered and concentrated to dryness under
reduced pressure (3 kPa). The residue obtained is
purified by chromatography on alumina, eluting with a
mixture of dichloromethane and of ethyl acetate (70/3 0
by volume). After concentrating the fractions under
reduced pressure, an oil is obtained, which is
dissolved in 35 cm3 of acetone and 20 cm3 of 1M
hydrochloric ether are added. After stirring for 1 hour

at ambient temperature, the solid which has appeared is
isolated by filtration and dried under vacuum (70 kPa)
at a temperature of 40°C. 0.44 g of 3- [4-(3,5-difluoro-
phenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2] octane
hydrochloride is thus obtained in the form of
hygroscopic white crystals. 1H NMR spectrum (3 00 MHz) -
6 in ppm - in DMSO-d6 (referenced at 2.50 ppm) : 1.71
(m, 2H); 2.00 (m, 2H) ; 2.42 (m, 1H); from 3.20 to 3.48
(m, 4H); from 3.75 to 3.95 (m, 2H); 4.90 (m, 1H); 7.05
(tt, J = 2.5 and 9.5 Hz, 1H); 7.40 (m, 2H); 8.17 (broad
s, 1H) ; 8.60 (broad s, 1H) ; 10.6 (broad m, 1H) . Mass
spectrum (EI): m/z=289 (M+-) base peak, m/z=206 [ (M -
C5H9N)+-], m/z=109 (C7H11N+), m/z=36 (HC1+-)-
The 4-(3,5-difluorophenyl)-1H-pyrazole can be obtained
in the following way:
15.7 cm3 of a solution of tetrabutylammonium fluoride in
tetrahydrofuran at 1M are added, at ambient
temperature, to a solution of 2.1 g of 4- (3,5-difluoro-
phenyl) -1-(toluene-4-sulfonyl)-1H-pyrazole in 70 cm3 of
tetrahydrofuran. The mixture is refluxed for 4.5 hours,
and then cooled to ambient temperature and concentrated
to dryness under reduced pressure (3 kPa). 50 cm3 of
water are added to the residue, which is extracted with
200 cm3 of ethyl acetate. The organic phase is washed
with 50 cm3 of water and then with 25 cm3 of brine, and
is finally dried over anhydrous magnesium sulfate,
filtered, and concentrated to dryness under reduced
pressure (3 kPa). The residue is triturated in 40 cm3 of
dichloromethane, and then isolated by filtration under
vacuum. 0.65 g of 4-(3,5-difluorophenyl)-1H-pyrazole is
thus obtained in the form of white crystals which melt
at around 185°C. Mass spectrum (EI) : m/z=180 (M+-) base
peak, m/z=153 [ (M - HCN)+] , m/z=126 [ (m/z=153 - HCN)+].
The 4-(3,5-difluorophenyl)-1-(toluene-4-sulfonyl)-1H-
pyrazole can be prepared in the following way:

6.31 g of 3,5-difluorophenylboronic acid are added,
under an argon atmosphere and at ambient temperature,
to a solution of 3.5 g of 4-iodo-1-(toluene-4-
sulfonyl)-1H-pyrazole in 100 cm3 of 1,2-dimethoxyethane.
The reaction medium is heated at 110°C and 8.5 g of
finely ground tribasic potassium phosphate and 0.91 g
of bis(triphenylphosphine)palladium chloride are then
added and the refluxing is subsequently maintained for
3.5 hours. The mixture is cooled to ambient
temperature, and filtered through Celite , which is then
washed with 500 cm3 of ethyl acetate. The organic phase
is washed with 5 times 100 cm3 of water and then with
twice 100 cm3 of brine, dried over anhydrous magnesium
sulfate, filtered, and concentrated to dryness under
reduced pressure (3 kPa) . The residue is purified by
chromatography on silica, eluting with cyclohexane and
then dichloromethane. After concentrating the fractions
under reduced pressure, 2.2 g of 4-(3,5-difluoro-
phehyl)-1-(toluene-4-sulfonyl)-1H-pyrazole are obtained
in the form of a white powder. Mass spectrum (EI) :
m/z=334 (M+), m/z=270 [ (M - SO2)+-], m/z=155 (C7H7SO2+) ,
m/z=91 (C7H7+) base peak.
Example 81
4-Benzo [b] thiophen-2-yl-1- (2-piperidin-1-ylethyl) -1H-
pyrazol-3-ol hydrochloride
8 cm3 of 12N hydrochloric acid are added to a stirred
solution of 930 mg of 1-[2-(4-benzo[b]thiophen-2-yl-3-
benzyloxypyrazol-1-yl)ethyl]piperidine in 15 cm3 of
ethanol. After 7 h at the reflux of the solvent, and
then 15 h at a temperature in the region of 20°C, the
reaction medium is evaporated to dryness under reduced
pressure (2.7 kPa). The residue is, three times,
successively dissolved in ethanol and evaporated to
dryness under reduced pressure (2.7 kPa) and is then
triturated in 20 cm3 of diisopropyl ether. The
precipitate formed is filtered off and dried under

reduced pressure (2.7 kPa) , to give 790 mg of
4-benzo[b] thiophen-2-yl-1- (2-piperidin-1-ylethyl) -1H-
pyrazol-3-ol hydrochloride in the form of a pale yellow
solid. Mass spectrum (CI): 328(+)=(M+H)(+); presence
36(+)/38(+)=HCl(+) . 1H NMR spectrum (300 MHz) - 5 in ppm
- in DMSO-d6: 1.42 (m, 1H) ; from 1.65 to 1.89 (m, 5H) ;
2.95 (m, 2H) ; from 3.38 to 3.54 (m, 4H) ; 4.44 (t, J =
6.5 Hz, 2H) ; from 7.23 to 7.38 (m, 2H) ; 7.50 (s, 1H) ;
7.78 (broad d, J = 7.5 Hz, 1H); 7.90 (broad d, J = 7.5
Hz, 1H) ; 8.07 (s, 1H) ; from 10.05 to 10.2 (very broad
m, 1H); 10.9 (broad m, 1H).
The 1-[2-(4-benzo[b]thiophen-2-yl-3-benzyloxypyrazol-1-
yl)ethyl]piperidine can be prepared in the following
way:
860 mg of 4-benzo[b]thiophen-2-yl-3-benzyloxy-1H-
pyrazole are added, portionwise, to a suspension of
225 mg of sodium hydride (at 75% in liquid petroleum
jelly) in 30 cm3 of dimethylformamide under an argon
atmosphere and with stirring. After heating at 50°C for
3 0 min, the mixture is stirred for 1 h at a temperature
in the region of 20°C, and then 725 mg of l-(2-chloro-
ethyl)piperidine are added, portionwise, thereto. The
reaction medium is stirred for 15 h at a temperature in
the region of 20°C, and is then poured into 100 cm3 of
water. The aqueous phase is extracted twice with ethyl
acetate. The organic phases are combined, washed
successively with two times water and a saturated
aqueous sodium chloride solution, dried over magnesium
sulfate, filtered, and evaporated under reduced
pressure (2.7 kPa) , to give a yellow oil which is
purified by flash chromatography on alumina CBT1 under
an argon pressure (50 kPa) [eluent: cyclohexane/ethyl
acetate (95/5 by volume)]. After concentrating the
fractions under reduced pressure, 930 mg of l-[2-(4-
benzo[b]thiophen-2-yl-3-benzyloxypyrazol-1-yl)ethyl]-
piperidine are obtained in the form of a pale yellow
oil. 1H NMR spectrum (300 MHz) - δ in ppm - in DMSO-d6:

from 1.34 to 1.54 (m, 6H) ; 2.40 (m, 4H) ; 2.69 (t, J =
6.5 HZ, 2H) ; 4.11 (t, J = 6.5 Hz, 2H) ; 5.37 (s, 2H) ;
from 7.23 to 7.48 (m, 6H) ; 7.56 (broad d, J = 8.5 Hz,
2H); 7.73 (broad d, J = 7.5 Hz, 1H); 7.90 (broad d, J =
7.5 Hz, 1H); 8.10 (s, 1H).
The 4-benzo[b]thiophen-2-yl-3-benzyloxy-1H-pyrazole can
be prepared in the following way:
7.6 cm3 of a 1N solution of tetrabutylammonium fluoride
in tetrahydrofuran are added to a solution, under an
argon atmosphere and with stirring, of 1.4 g of
4-benzo[b]thiophen-2-yl-3-benzyloxy-1-(toluene-4-
sulfonyl)-1H-pyrazole in 30 cm3 of tetrahydrofurane.
After heating for 15 h at the reflux of the solvent,
the reaction medium is evaporated under reduced
pressure (2.7 kPa) and ethyl acetate is added to the
residue. The organic phase is washed successively with
two times water and a saturated aqueous sodium chloride
solution; it is dried over magnesium sulfate and
evaporated under reduced pressure (2.7 kPa). The pale
yellow oil obtained (0.98 g) is purified by flash
chromatography on silica under an argon pressure
(50 kPa) [eluent: cyclohexane/ethyl acetate (70/30 by
volume)]. After concentrating the fractions under
reduced pressure (2.7 kPa) , 860 mg of
4-benzo[b]thiophen-2-yl-3-benzyloxy-1H-pyrazole are
obtained in the form of a white solid. IR spectrum
(KBr): 3173; 2950; 1586; 1530; 1501; 1445; 1363; 1304;
1215; 1166; 1022; 818; 745; 736; 727; 693 and 564 cm"1.
The 4-benzo[b]thiophen-2-yl-3-benzyloxy-1-(toluene-4-
sulfonyl)-1H-pyrazole can be prepared in the following
way:
2.4 g of 2-benzothienylboronic acid, 6.6 cm3 of a 2N
aqueous potassium carbonate solution and 660 mg of
tetrakis(triphenylphosphine)palladium are added to a
solution, under an argon atmosphere with stirring, of

2 g of 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-
pyrazole in 40 cm3 of toluene to which 10 cm3 of ethanol
have been added. After heating for 5 h at the reflux of
the solvent and for 16 h at a temperature in the region
of 20°C, the reaction medium is evaporated under
reduced pressure (2.7 kPa). Ethyl acetate, water and
carbon black are added to the residue, which is
filtered through supercel. The filtrate is separated by
settling out, and the organic phase is then washed
successively with two times water and a saturated
aqueous sodium chloride solution; it is dried over
magnesium sulfate and evaporated under reduced pressure
(2.7 kPa). The orangey oil obtained (3.8 g) is purified
by flash chromatography on silica under an argon
pressure (50 kPa) [eluent: cyclohexane/ethyl acetate
(90/10 by volume)]. After concentrating the fractions
under reduced pressure (2.7 kPa), the resulting cream
solid is triturated in diisopropyl ether. After
filtration, 1.4 g of 4-benzo[b]thiophen-2-yl-3-
benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazole are
obtained in the form of a white solid. Mass spectrum
(EI): 460( + )=M( + ) ; 305 ( + ) =M ( + )-Ts .
Exemple 82
1-(2-Piperidin-1-ylethyl)-4-thiophen-3-yl-1H-pyrazol-3-
ol hydrochloride
6 cm3 of 12N hydrochloric acid are added to a stirred
solution of 640 mg of 1-[2-(3-benzyloxy-4-thiophen-3-
ylpyrazol-1-yl)ethyl]piperidine in 10 cm3 of ethanol.
After 7 h at the reflux of the solvent, and then 15 h
at a temperature in the region of 20°C, the reaction
medium is evaporated to dryness under reduced pressure
(2.7 kPa) . The residue is, three times, successively
dissolved in ethanol and evaporated to dryness under
reduced pressure (2.7 kPa), and it is then triturated
in diisopropyl ether. The precipitate formed is
filtered off and dried under vacuum (2.7 kPa) , to give

470 mg of 1-(2-piperidin-1-ylethyl)-4-thiophen-3-yl-1H-
pyrazol-3-ol hydrochloride in the form of a white
solid. Mass spectrum (CI): 278(+)=(M+H)(+); presence
36( + )/38 ( + )=HCl ( + ) . 1H NMR spectrum (300 MHz) - δ in ppm
- in DMSO-d6: 1.40 (m, 1H) ; from 1.64 to 1.88 (m, 5H) ;
2.93 (m, 2H) ; from 3.35 to 3.52 (m, 4H) ; 4.39 (t, J =
6.5 Hz, 2H) ; 7.35 (dd, J = 1.0 and 5.0 Hz, 1H) ; 7.49
(dd, J = 1.0 and 3.0 Hz, 1H); 7.55 (dd, J = 3.0 and 5.0
Hz, 1H) ; 7.94 (s, 1H) ; from 9.85 to 10.05 (very broad
m, 1H); 10.4 (broad m, 1H).
The 1-[2-(3-benzyloxy-4-thiophen-3-yl-pyrazol-1-yl)-
ethyl]piperidine can be prepared in the following way:
650 mg of 3-benzyloxy-4-thiophen-3-yl-1H-pyrazole are
added, portionwise, to a suspension of 2 00 mg of sodium
hydride (at 75% in liquid petroleum jelly) in 3 0 cm3 of
dimethylformamide under an argon atmosphere and with
stirring. After heating for 3 0 min at 50°C, the mixture
is stirred for 3 0 min at a temperature in the region of
20°C, and 654 mg of 1-(2-chloroethyl)piperidine
hydrochloride are then added portionwise thereto. The
reaction medium is stirred for 15 h at a temperature in
the region of 20°C and is then poured into 100 cm3 of
water. The aqueous phase is extracted twice with ethyl
acetate. The organic phases are combined, washed
successively with two times water and a saturated
aqueous sodium chloride solution, dried over magnesium
sulfate, filtered, and evaporated under reduced
pressure (2.7 kPa) , to give an orangey oil which is
purified by flash chromatography on alumina CTB1 under
an argon pressure (50 kPa) [eluent: cyclohexane/ethyl
acetate (95/5 by volume)]. After concentrating the
fractions under reduced pressure, 640 mg of 1- [2- (3-
benzyloxy-4-thiophen-3-yl-pyrazol-1-yl)ethyl]piperidine
are obtained in the form of a yellow oil. 1H NMR
spectrum (300 MHz) - 5 in ppm - in DMSO-d6: from 1.32
to 1.54 (m, 6H) ; 2.38 (m, 4H) ; 2.67 (t, J = 6.5 Hz,

2H); 4.06 (t, J = 6.5 Hz, 2H); 5.30 (s, 2H); from 7.30
to 7.55 (m, 8H); 7.98 (s, 1H).
The 3-benzyloxy-4-thiophen-3-yl-1H-pyrazole can be
prepared in the following way:
8.5 cm3 of a IN solution of tetrabutylammonium fluoride
in tetrahydrofuran are added to a solution, under an
argon atmosphere and with stirring, of 1.35 g of
3-benzyloxy-4-thiophen-3-yl-1-(toluene-4-sulfonyl)-1H-
pyrazole in 3 0 cm3 of tetrahydrofuran. After heating
for 15 h at the reflux of the solvent, the reaction
medium is evaporated under reduced pressure (2.7 kPa)
and ethyl acetate is added to the residue. The organic
phase is washed successively with three times water and
a saturated aqueous sodium chloride solution; it is
dried over magnesium sulfate and evaporated under
reduced pressure (2.7 kPa). The residue obtained
(0.96 g) is purified by flash chromatography on silica
under an argon pressure (50 kPa) [eluent:
cyclohexane/ethyl acetate (70/30 by volume)]. After
concentrating the fractions under reduced pressure
(2.7 kPa), 650 mg of 3-benzyloxy-4-thiophen-3-yl-1H-
pyrazole are obtained in the form of a cream solid.
Mass spectrum (EI): 256( + )=M( + ); 91 ( + ) =C7H7 (+) .
The 3-benzyloxy-4-thiophen-3-yl-1-(toluene-4-sulfonyl)-
1H-pyrazole can be prepared in the following way:
1.7 g of 3-thienylboronic acid, 6.6 cm3 of a 2N aqueous
potassium carbonate solution and 660 mg of
tetrakis(triphenylphosphine)palladium are added to a
solution, under an argon atmosphere and with stirring,
of 2 g of 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-
pyrazole in 40 cm3 of toluene to which 10 cm3 of ethanol
have been added. After heating for 5 h at the reflux of
the solvent and for 16 h at a temperature in the region
of 20°C/ the reaction medium is evaporated under
reduced pressure (2.7 kPa). Ethyl acetate, water and

carbon black are added to the residue, which is
filtered through supercel. The filtrate is separated by
settling out, and the organic phase is then washed
successively with two times water and a saturated
aqueous sodium chloride solution; it is dried over
magnesium sulfate and evaporated under reduced pressure
(2.7 kPa) . The resulting solid is triturated in
diisopropyl ether, filtered and crystallized from 10 cm3
of ethanol. 1.35 g of 3-benzyloxy-4-thiophen-3-yl-1-
(toluene-4-sulfonyl)-1H-pyrazole are thus obtained in
the form of a beige solid. Mass spectrum (EI) :
410 ( + )=M( + ) ; 255( + )=M( + )-Ts.
Example 83
4-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-
yl]benzamide hydrochloride
4 cm3 of 3N hydrochloric diethyl ether are added to a
solution of 442 mg of 4-[3-benzyloxy-1-(2-piperidin-1-
ylethyl) -1H-pyrazol -4 -yl] benzamide in 20 cm3 of ethanol.
After stirring for 1 h at a temperature in the region
of 20°C, the solution is evaporated to dryness under
reduced pressure (2.7 kPa). The residue is taken up
with 25 cm3 of ethanol. The solution obtained is
introduced into an autoclave, and 52 mg of palladium-
on-charcoal at 10% are added thereto, and it is then
placed under hydrogen (10 bar). After stirring for 8 h
at 22°C, the reaction medium is filtered through
supercel, the filtrate is evaporated and the residue is
triturated in diisopropyl ether. The resulting solid is
filtered off, and dried under vacuum (2.7 kPa), to give
118 mg of 4-[3-hydroxy-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-4-yl]benzamide hydrochloride in the form of a
cream solid. Mass spectrum (CI): 315(+)=(M+H)(+). 1H NMR
spectrum (300 MHz) - δ in ppm - in DMSO-d6: 1.41 (m,
1H); from 1.64 to 1.89 (m, 5H); 2.94 (m, 2H); from 3.25
to 3.53 (m, 4H); 4.41 (t, J = 6.5 Hz, 2H); 7.23 (broad
m, 1H) ; 7.73 (broad d, J = 8.5 Hz, 2H) ; from 7.83 to

7.91 (m, 3H) ; 8.14 (s, 1H) ; from 9.80 to 9.95 (very
broad m, 1H); 10.65 (broad s, 1H).
The 4-[3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-4-yl]benzamide can be prepared in the following
way:
527 mg of 4-(3-benzyloxy-1H-pyrazol-4-yl)benzamide are
added, portionwise, to a suspension of 144 mg of sodium
hydride (75% in liquid petroleum jelly) in 30 cm3 of
dimethylformamide under an atmosphere of argon and with
stirring. After heating at 50°C for 30 min, the mixture
is stirred for 3 0 min at a temperature in the region of
20°C and then 465 mg of 1-(2-chloroethyl)piperidine
hydrochloride are added portionwise thereto. The
reaction medium is stirred for 15 h at a temperature in
the region of 20°C, and is then poured into 100 cm3 of
water. The aqueous phase is extracted twice with ethyl
acetate. The organic phases are combined, washed
successively with two times water and a saturated
aqueous sodium chloride solution, dried over magnesium
sulfate, filtered and evaporated under reduced pressure
(2.7 kPa). The resulting solid is triturated in
diisopropyl ether, filtered and crystallized from
acetone. 445 mg of 4-[3-benzyloxy-1-(2-piperidin-1-yl-
ethyl) -1H-pyrazol-4-yl]benzamide are thus obtained in
the form of a white solid. 1H NMR spectrum (3 00 MHz) - 5
in ppm - DMSO-d6: from 1.32 to 1.54 (m, 6H) ; 2.39 (m,
4H) ; 2.69 (t, J = 6.5 Hz, 2H) ; 4.09 (t, J = 6.5 Hz,
2H) ; 5.33 (s, 2H) ; 7.24 (broad m, 1H) ; from 7.32 to
7.46 (m, 3H) ; 7.52 (broad d, J = 8.5 Hz, 2H) ; 7.70
(broad d, J = 7.5 Hz, 2H) ; from 7.81 to 7.88 (m, 3H) ;
8.17 (s, 1H).
The 4-(3-benzyloxy-1H-pyrazol-4-yl)benzamide can be
prepared in the following way:
6.5 cm3 of a 1N solution of tetrabutylammonium fluoride
in tetrahydrofuran are added to a solution, under an

argon atmosphere and with stirring, of 1.1 g of 4-[3-
benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazol-4-
yljbenzamide in 30 cm3 of tetrahydrofuran. After
heating for 15 h at the reflux of the solvent, the
reaction medium is cooled in an ice bath. After
filtration and then drying of the resulting crystals
under vacuum (2.7 kPa) , 527 mg of 4- (3-benzyloxy-1H-
pyrazol-4-yl)benzamide are obtained in the form of a
white solid. IR spectrum (KBr): 3403; 3176; 1667; 1611;
1576; 1553; 1517; 1485; 1393; 1379; 1226; 1040; 1027
and 739 cm"1.
The 4-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazol-4-
yl]benzamide can be prepared in the following way:
2.72 g of 4-aminocarbonylphenylboronic acid, 8.3 cm3 of
a 2N aqueous potassium carbonate solution and 83 0 mg of
tetrakis(triphenylphosphine)palladium are added to a
solution, under an argon atmosphere and with stirring,
of 2.5 g of 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-
1H-pyrazole in 40 cm3 of toluene to which 10 cm3 of
ethanol have been added. After heating for 15 h at the
reflux of the solvent, the reaction medium is cooled to
a temperature in the region of 20°C and evaporated
under reduced pressure (2.7 kPa). Ethyl acetate, water
and carbon black are added to the residue, which is
filtered through supercel. The filtrate is separated by
settling out, and the organic phase is then washed
successively with two times water and a saturated
aqueous sodium chloride solution; it is dried over
magnesium sulfate and evaporated under reduced pressure
(2.7 kPa). The yellow oil obtained (3.7 g) is purified
by flash chromatography on silica under an argon
pressure (50 kPa) [eluent: cyclohexane/ethyl acetate
(50/50 then 20/80 by volume)]. After concentrating the
fractions under reduced pressure (2.7 kPa), 1.1 g of
4-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-
benzamide are obtained in the form of a white solid.
Mass spectrum (EI): 447( + )=M( + ); 91 ( + ) =C7H7 ( + ) .

Example 84
3-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-
yl]benzamide hydrochloride
4 cm3 of 3N hydrochloric diethyl ether are added to a
solution of 690 mg of 3-[3-benzyloxy-1-(2-piperidin-1-
ylethyl) -1H-pyrazol -4 -yl] benzamide in 20 cm3 of ethanol.
After stirring for 45 min at a temperature in the
region of 20°C, the solution is evaporated to dryness
under reduced pressure (2.7 kPa) . The residue is taken
up with 25 cm3 of ethanol. The solution obtained is
introduced into an autoclave, and 80 mg of palladium-
on-charcoal at 10% are added thereto, and it is then
placed under hydrogen (10 bar). After stirring for 8 h
at 22°C, the reaction medium is filtered through
supercel, the filtrate is evaporated and the residue is
triturated in diisopropyl ether. The resulting solid is
filtered off, and dried under vacuum (2.7 kPa), to give
528 mg of 3-[3-hydroxy-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-4-yl]benzamide hydrochloride in the form of a
pale yellow solid. Mass spectrum (CI): 315(+)=(M+H)(+).
1H NMR spectrum (300 MHz) - δ in ppm - in DMSO-d6: 1.40
(m, 1H) ; from 1.65 to 1.88 (m, 5H); 2.94 (m, 2H); from
3.41 to 3.54 (m, 4H) ; 4.42 (t, J = 6.5 Hz, 2H) ; 7.33
(broad m, 1H); 7.42 (t, J = 8.0 Hz, 1H); 7.64 (broad d,
J = 8.0 Hz, 1H) ; 7.82 (broad d, J = 8.0 Hz, 1H) ; 7.94
(broad m, 1H) ; 8.10 (s, 1H) ,- 8.14 (broad s, 1H) ; from
9.90 to 10.05 (very broad m, 1H); 10.55 (broad s, 1H).
The 3-[3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-4-yl]benzamide can be prepared in the following
way:
1.16 g of 3-(3-benzyloxy-1H-pyrazol-4-yl)benzamide are
added, portionwise, to a suspension of 315 mg of sodium
hydride (75% in liquid petroleum jelly) in 3 0 cm3 of
dimethylformamide under an argon atmosphere and with

stirring. After heating for 3 0 min at 50°C, the mixture
is stirred for 30 min at a temperature in the region of
20°C, and 1 g of 1-(2-chloroethyl)piperidine
hydrochloride is added portionwise thereto. The
reaction medium is stirred for 15 h at a temperature in
the region of 20°C and is then poured into 100 cm3 of
water. The aqueous phase is extracted twice with ethyl
acetate. The organic phases are combined, washed
successively with two times water and a saturated
aqueous sodium chloride solution, dried over magnesium
sulfate, filtered, and evaporated under reduced
pressure (2.7 kPa) , to give a yellow oil (1.6 g) which
is purified by flash chromatography on silica under an
argon pressure (50 kPa) [eluent: dichloromethane then
dichloromethane/methanol (98/2, 95/5 then 90/10 by
volume)]. After concentrating the fractions under
reduced pressure, 700 mg of 3-[3-benzyloxy-1- (2-
piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide are
obtained in the form of a pale yellow oil. 1H NMR
spectrum (300 MHz) - 5 in ppm - in DMSO-d6: from 1.33
to 1.54 (m, 6H) ; 2.40 (m, 4H) ; 2.70 (t, J = 6.5 Hz,
2H); 4.10 (t, J = 6.5 Hz, 2H); 5.33 (s, 2H); from 7.30
to 7.44 (m, 5H) ; 7.53 (broad d, J = 8.5 Hz, 2H) ; 7.63
(broad d, J = 8.0 Hz, 1H) ; 7.80 (broad d, J = 8.0 Hz,
1H) ; 7.92 (broad m, 1H) ; 8.11 (s, 1H) ; 8.15 (broad s,
1H) .
The 3-(3-benzyloxy-1H-pyrazol-4-yl)benzamide can be
prepared in the following way:
11.8 cm3 of a IN solution of tetrabutylammonium
fluoride in tetrahydrofuran is added to a solution,
under an argon atmosphere and with stirring, of 2.1 g
of 3-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazol-4-
yl]benzamide in 40 cm3 of tetrahydrofuran. After
heating for 15 h at the reflux of the solvent, the
reaction medium is evaporated under reduced pressure
(2.7 kPa) and ethyl acetate is added to the residue.
The organic phase is washed successively with two times

water and a saturated aqueous sodium chloride solution;
it is dried over magnesium sulfate and evaporated under
reduced pressure (2.7 kPa). The residue is triturated
in diisopropyl ether, filtered and dried under vacuum
(2.7 kPa), to give 1.16 g of 3-(3-benzyloxy-1H-pyrazol-
4-yl)benzamide in the form of a cream solid. IR
spectrum (KBr): 3332; 3196; 2975; 1682; 1606; 1581;
1572; 1505; 1447; 1389; 1280; 1232; 1049; 732; 695; 672
and 637 cm"1.
The 3-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazol-4-
yl]benzamide can be prepared in the following way:
2.72 g of 3-aminocarbonylphenylboronic acid, 8.3 cm3 of
a 2N aqueous potassium carbonate solution and 83 0 mg of
tetrakis(triphenylphosphine)palladium are added to a
solution, under an argon atmosphere and with stirring,
of 2.5 g of 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-
1H-pyrazole in 40 cm3 of toluene to which 10 cm3 of
ethanol have been added. After heating for 15 h at the
reflux of the solvent, the reaction medium is cooled in
an ice bath. After filtration and then drying of the
resulting crystals under vacuum (2.7 kPa), 2.1 g of
3- [3-benzyloxy-1- (toluene-4-sulfonyl) -1H-pyrazol-4-yl] -
benzamide are obtained in the form of a white solid.
Mass spectrum (EI): 447( + )=M( + ); 91 ( + ) =C7H7 ( + ) .
Example 85
(-)-1-(l-Azabicyelo[2.2.2]oct-3-yl)-4-phenyl-1H-
pyrazol-3-ol hydrochloride
15 cm3 of 12N hydrochloric acid are added to a stirred
solution of 1.44 g of (+)-3-(3-benzyloxy-4-
phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]octane in 20 cm3
of ethanol. After 7 h at the reflux of the solvent, and
then 15 h at a temperature in the region of 20°C, the
reaction medium is evaporated to dryness under reduced
pressure (2.7 kPa). The residue is, three times,

successively dissolved in ethanol and evaporated to
dryness under reduced pressure (2.7 kPa), and is then
triturated in 2 0 cm3 of diisopropyl ether. The
precipitate formed is filtered off and dried under
vacuum (2.7 kPa), to give 1.2 g of (-)-1-(1-aza-
bicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ol
hydrochloride in the form of a white solid. Mass
spectrum (EI): 269(+)=M( + ); presence 36( + )/
38 ( + )=HC1 ( + ) . 1H NMR spectrum (300 MHz) - δ in ppm - in
DMSO-d6: from 1.69 to 2.04 (m, 4H); 2.43 (m, 1H) ; from
3.22 to 3.47 (m, 4H); from 3.72 to 3.85 (m, 2H); 4.67
(m, 1H); 7.15 (tt, J = 1.5 and 7.5 Hz, 1H); 7.34 (broad
t, J = 7.5 Hz, 2H) ; 7.67 (broad d, J = 7.5 Hz, 2H) ;
8.18 (s, 1H) ; 10.2 (broad m, 1H) ; 10.4 (broad m, 1H).
[α]20D = -17.4 +/- 0.6° (c 0.5, MeOH).
The ( + )-3-(3-benzyloxy-4-phenylpyrazol-1-yl) -1-aza-
bicyclo[2.2.2]octane and the (-)-3-(3-benzyloxy-4-
phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]octane can be
prepared in the following way: an ethanolic solution
containing 1.5 g of 3-(3-benzyloxy-4-phenylpyrazol-1-
yl)-1-azabicyclo[2.2.2]octane is introduced onto a
column, 6 cm in diameter, containing 800 g of Chiralpak
AD™ chiral stationary phase. The elution is carried out
by means of a mixture of 10% ethanol, 10% methanol,
0.1% triethylamine and 80% heptane. The flow of the
mobile phase is 90 ml/min. The dextrorotatory
enantiomer is eluted in the first position, the
solution is evaporated to dryness under reduced
pressure (2.7 kPa), to give 0.66 g of oil.
1H NMR spectrum (300 MHz) - 6 in ppm - in DMSO-d6: 1.30
(m, 1H); from 1.50 to 1.71 (m, 3H); 2.08 (m, 1H); from
2.65 to 2.79 (m, 3H) ; 2.99 (m, 1H) ; from 3.15 to 3.42
(m, 2H) ; 4.27 (m, 1H) ; 5.33 (s, 2H) ; 7.15 (tt, J = 1.5
and 7.5 Hz, 1H); from 7.30 to 7.44 (m, 5H); 7.51 (broad
d, J = 7.5 Hz, 2H) ; 7.69 (broad d, J = 7.5 Hz, 2H) ;
8.20 (s, 1H). [α]20D = +27.0 +/- 0.8° (c 0.5, MeOH). The
solution containing the levorotatory enantiomer eluted

in the second position is evaporated to dryness under
reduced pressure (2.7 kPa), to give 0.65 g of oil.
1H NMR spectrum (300 MHz) - δ in ppm - in DMSO-d6: 1.31
(m, 1H); from 1.50 to 1.72 (m, 3H); 2.09 (m, 1H); from
2.66 to 2.80 (m, 3H); 2.99 (m, 1H); from 3.16 to 3.43
(m, 2H) ; 4.29 (m, 1H) ; 5.34 (s, 2H) ; 7.14 (tt, J = 1.5
and 7.5 Hz, 1H);'from 7.3 0 to 7.44 (m, 5H); 7.51 (broad
d, J = 7.5 Hz, 2H) ; 7.70 (broad d, J = 7.5 Hz, 2H) ;
8,20 (s, 1H). [α]20D = -27.0 +/- 0.8° (c 0.5, MeOH) .
Example 86
(+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-
pyrazol-3-ol hydrochloride
15 cm3 of 12N hydrochloric acid are added to a stirred
solution of 1.44 g of (-)-3- (3-benzyloxy-4-
phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]octane in 20 cm3
of ethanol. After 7 h at the reflux of the solvent, and
then 15 h at a temperature in the region of 2 0°C, the
reaction medium is evaporated to dryness under reduced
pressure (2.7 kPa) . The residue is, three times,
successively dissolved in ethanol and evaporated to
dryness under reduced pressure (2.7 kPa), and is then
triturated in 20 cm3 of diisopropyl ether. The
precipitate formed is filtered off and dried under
vacuum (2.7 kPa) , to give 1.2 g of ( + )-1-(1-aza-
bicyclo [2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ol
hydrochloride in the form of a beige solid. Mass
spectrum (EI): 269(+)=M(+); presence 36(+)/
38 (+) =HC1 ( + ) . 1H NMR spectrum (300 MHz) - δ in ppm - in
DMSO-d6: from 1.70 to 2.03 (m, 4H); 2.43 (m, 1H); from
3.22 to 3.47 (m, 4H) ; from 3.72 to 3.86 (m, 2H); 4.68
(m, 1H); 7.15 (tt, J = 1.5 and 7.5 Hz, 1H); 7.34 (broad
t, J = 7.5 Hz, 2H) ; 7.67 (broad d, J = 7.5 Hz, 2H) ;
8.19 (s, 1H) ; 10.2 (broad m, 1H) ; from 10.3 to 10.5
(very broad m, 1H). [α] 20D = +13.7 +/- 0.6° (c 0.5, MeOH).

Example 87
(-)-1-(l-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-
pyrazol-1-ol hydrochloride
10 cm3 of 12N hydrochloric acid are added to a stirred
solution of 825 mg of (-)-3- (3-benzyloxy-4-phenyl-
pyrazol-1-ylmethyl) -1-azabicyclo [2 .2 .2] octane in 10 cm3
of ethanol. After 7 h at the reflux of the solvent, and
then 15 h at a temperature in the region of 20°C, the
reaction medium is evaporated to dryness under reduced
pressure (2.7 kPa). The residue is, three times,
successively dissolved in ethanol and evaporated to
dryness under reduced pressure (2.7 kPa), and it is
then triturated in diisopropyl ether. The precipitate
formed is filtered off and dried under vacuum
(2.7 kPa) , to give 700 mg of (-)-1-(1-aza-
bicyclo [2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-1-ol
hydrochloride in the form of a white solid. Mass
spectrum (EI): 283( + )=M( + ). Hi NMR spectrum (300 MHz) -
5 in ppm - in DMSO-d6: from 1.66 to 1.93 (m, 4H) ; 2.05
(m, 1H) ; 2.52 (masked m, 1H) ; 2.94 (m, 1H) ; from 3.12
to 3.40 (m, 5H); from 3.98 to 4.12 (m, 2H); 7.13 (tt, J
= 1.5 and 7.5 Hz, 1H); 7.33 (broad t, J = 7.5 Hz, 2H) ;
7.64 (broad d, J = 7.5 Hz, 2H) ; 7.99 (s, 1H) ; 10.1
(broad m, 1H). [α] 20D = -36.8 +/- 0.8° (c 0.5, MeOH)
The (-)-3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-
azabicyclo[2.2.2]octane and the (+)-3-(3-benzyloxy-4-
phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octane can
be prepared in the following way:
A solution of 5 g of 3-benzyloxy-4-phenylpyrazole in
30 cm3 of dimethylformamide is added gradually, under an
argon atmosphere and at a temperature in the region of
20°C, to a suspension of 1.9 g of sodium hydride (75%
by mass in liquid petroleum jelly) in 50 cm3 of
dimethyl formamide. After stirring for 1 h at a
temperature in the region of 50°C, 5.8 g of

3-chloromethyl-1-azabicyclo[2.2.2]octane hydrochloride
are added in small portions, and the mixture is then
heated for 15 hours at a temperature in the region of
90 °C. The mixture is cooled to a temperature in the
region of 2 0°C and is then poured into 4 00 cm3 of water.
The aqueous phase is extracted with two times ethyl
acetate. The combined organic phases are washed with
two times water and brine, and then dried over
magnesium sulfate, filtered, and concentrated to
dryness under reduced pressure (2.7 kPa) . The orangey
oil obtained is purified by flash chromatography on
alumina CTB1 under an argon pressure (50 kPa) [eluent:
cyclohexane/ethyl acetate (10/90 by volume), ethyl
acetate and then ethyl acetate/methanol (95/5 by
volume)]. After concentrating the fractions under
reduced pressure, 1.7 g of a pale yellow oil are
obtained. An ethanolic solution of this oil is
introduced onto a column, 8 cm in diameter, containing
1180 g of Chiracel OD™ chiral stationary phase. The
elution is carried out by means of a mixture of 50%
ethanol, 0.1% triethylamine and 50% heptane. The flow
rate of the mobile phase is 120 ml/min. The
levorotatory enantiomer is eluted in the first
position, the solution is evaporated to dryness under
reduced pressure (2.7 kPa), to give 0.82 g of oil.
XH NMR spectrum (300 MHz) - 5 in ppm - in DMSO-d6: from
1.24 to 1.59 (m, 4H) ; 1.78 (m, 1H); 2.14 (m, 1H); 2.37
(m, 1H) ; from 2.59 to 2.90 (m, 5H) ; 3.89 (d, J = 8.0
Hz, 2H) ; 5.31 (s, 2H) ; 7.14 (tt, J = 1.5 and 7.5 Hz,
1H); from 7.30 to 7.44 (m, 5H); 7.50 (broad d, J = 8.5
Hz, 2H) ; 7.64 (broad d, J = 8.5 Hz, 2H) ; 8.09 (s, 1H) .
[α]20D = -37.8 +/- 0.8° (c 0.5, MeOH) . The solution
containing the dextrorotatory enantiomer eluted in the
second position is evaporated to dryness under reduced
pressure (2.7 kPa), to give 0.74 g of oil.
XH NMR spectrum (300 MHz) - 5 in ppm - in DMSO-d6: from
1.24 to 1.60 (m, 4H); 1.78 (m, 1H); 2.14 (m, 1H); 2.36

Cm, 1H) ; from 2.60 to 2.90 (m, 5H) ; 4.00 (d, J = 8.0
Hz, 2H) ; 5.31 (s, 2H) ; 7.14 (tt, J = 1.5 and 7.5 Hz,
1H); from 7.30 to 7.44 (m, 5H); 7.50 (broad d, J = 8.5
Hz, 2H) ; 7.64 (broad d, J = 8.5 Hz, 2H) ; 8.09 (s, 1H).
[α]20D = -39.1 +/- 0.9° (c 0.5, MeOH) .
Example 88 (+)-1-(1-Azabicyclo[2.2.2]oct-3-yl-
methyl)-4-phenyl-1H-pyrazol-1-ol hydrochloride
10 cm3 of 12N hydrochloric acid are added to a stirred
solution of 740 mg of (+)-3-(3-benzyloxy-4-phenyl-
pyrazol-1-ylmethyl)-1-aza-bicyclo[2.2.2]octane in 10 cm3
of ethanol. After 7 h at the reflux of the solvent, and
then 15 h at a temperature in the region of 2 0°C, the
reaction medium is evaporated to dryness under reduced
pressure (2.7 kPa) . The residue is, three times,
successively dissolved in ethanol and evaporated to
dryness under reduced pressure (2.7 kPa), and it is
then triturated in diisopropyl ether. The precipitate
formed is filtered off and dried under vacuum
(2.7 kPa) , to give 600 mg of ( + )-1-(1-aza-
bicyclo [2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-1-ol
hydrochloride in the form of a white solid. Mass
spectrum (EI): 283( + )=M( + ). ^H NMR spectrum (300 MHz) -
5 in ppm - in DMSO-d6: from 1.67 to 1.94 (m, 4H); 2.06
(m, 1H) ; 2.52 (masked m, 1H) ; 2.94 (m, 1H) ; from 3.12
to 3.40 (m, 5H); from 3.99 to 4.12 (m, 2H); 7.13 (tt, J
= 1.5 and 7.5 Hz, 1H); 7.33 (broad t, J = 7.5 Hz, 2H) ;
7.64 (broad d, J = 7.5 Hz, 2H) ; 7.99 (s, 1H) ; 10.05
(broad m, 1H) . [α] 20D = +36.5 +/- 0.8° (c 0.5, MeOH).
Example 89
1- (l-Azabicyclo[2.2.2]oct-3-ylmethyl) -4- (4-chlorophenyl) -
1H-pyrazol-3-ol hydrochloride
10 cm3 of 12N hydrochloric acid are added to a stirred
solution of 430 mg of 3-[3-benzyloxy-4-(4-chlorophenyl)-
pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octaneborane

in 10 cm3 of ethanol. After 15 h at the reflux of the
solvent, the reaction medium is cooled to a temperature
in the region of 20°C and evaporated to dryness under
reduced pressure (2.7 kPa) . The residue is taken up
with water. The resulting solution is brought to a pH
in the region of 8 with IN sodium hydroxide and
extracted with ethyl acetate. The organic phase is
dried over magenesium sulfate, filtered, and
concentrated to dryness under reduced pressure
(2.7 kPa). The residual solid is triturated in
diisopropyl ether, filtered, and dried under reduced
pressure (2.7 kPa) , to give 137 mg of
1- (l-azabicyclo[2 .2 .2] oct-3-ylmethyl) -4- (4-chlorophenyl) -
1H-pyrazol-3-ol hydrochloride in the form of a white
solid. Mass spectrum (EI): 317(+)/...=M(+)/...(1 Cl). XH
NMR spectrum (400 MHz) - 5 in ppm - in DMSO-d6: from
1.30 to 1.61 (m, 4H); 1.78 (m, 1H); 2.15 (m, 1H); 2.38
(m, 1H); from 2.66 to 2.81 (m, 4H); 2.88 (m, 1H); 3.91
(d, J = 8.0 Hz, 2H) ; 7.37 (broad d, J = 8.5 Hz, 2H) ;
7.67 (broad d, J. = 8.5 Hz, 2H) ; 8.00 (s, 1H) ; from
10.35 to 10.5 (very broad m, 1H).
The 3- [3-benzyloxy-4- (4-chlorophenyl)pyrazol-1-ylmethyl] -
1-azabicyclo[2.2.2]octaneborane can be prepared in the
following way:
A solution of 3 g of 3-benzyloxy-4-(4-chlorophenyl)-1H-
pyrazole and of 3 g of potassium tert-butoxide in 3 0 cm3
of dimethylformamide, under an inert atmosphere and with
stirring, is heated for 30 min at 50°C, and 3.1 g of
3-chloromethyl-1-azabicyclo[2.2.2]octane hydrochloride
are then added thereto. After refluxing for 15 h, the
reaction medium is poured into water, and the mixture
is extracted with two times ethyl acetate. The organic
phases are washed successively with two times water and
a saturated aqueous sodium chloride solution, dried
over magnesium sulfate, and evaporated under reduced
pressure (2.7 kPa) . The beige oil (5.3 g) obtained is
purified by flash chromatography on alumina CTB1 under

an argon pressure (50 kPa) [eluent: cyclohexane/ethyl
acetate (20/80 by volume), ethyl acetate then ethyl
acetate/methanol (90/10 by volume)]. After concen-
trating the fractions under reduced pressure (2.7 kPa),
a solid is obtained which is dissolved in 10 cm3 of
tetrahydrofuran under an inert atmosphere. 3 cm3 of a IN
solution of borane in tetrahydrofuran are added to the
solution, which is being stirred and has been cooled to
-60°C. After reaction for 2 h 30 min at -60°C, 15 cm3 of
water are added to the reaction medium, the temperature
of the mixture is allowed to rise to a temperature in
the region of 20°C and the solution is extracted with
ethyl acetate. The organic phase is washed with two
times water and a saturated aqueous sodium chloride
solution, dried over magnesium sulfate and evaporated
under reduced pressure (2.7 kPa) , to give an oil (1 g)
which is purified by flash chromatography on alumina
CTB1 under an argon pressure (50 kPa) [eluent: ethyl
acetate, ethyl acetate/methanol (90/10 by volume) then
dichloromethane/methanol (80/20 by volume)]. After
concentrating the fractions under reduced pressure
(2.7 kPa), 430 mg of 3-[3-benzyloxy-4-(4-chlorophenyl)-
pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octaneborane are
obtained in the form of an oil which is used without
any other purification for the remainder of the
synthesis.
Example 90
(-) -1-(l-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-
1H-pyrazol-3-ol hydrochloride
7 cm3 of 12N hydrochloric acid are added to a stirred
solution of 690 mg of (+)-3-[3-benzyloxy-4-(4-chloro-
phenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octane in 10 cm3
of ethanol. After 7 h at the reflux of the solvent, the
reaction medium is cooled to a temperature in the
region of 20°C and evaporated to dryness under reduced
pressure (2.7 kPa). The residue is triturated in diiso-

propyl ether, filtered, and dried under reduced
pressure (2.7 kPa) , to give 580 mg of (-) -1- (1-aza-
bicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazol-
3-ol hydrochloride in the form of a beige solid. Mass
spectrum (EI): 303 ( + )/.. .=M ( + )/.. . (1 CI). XH NMR
spectrum (300 MHz) - 6 in ppm - in DMSO-d6: from 1.68
to 2.03 (m, 4H) ; 2.42 (m, 1H) ; from 3.2 0 to 3.55 (m,
4H) ; 3.78 (m, 2H) ; 4.66 (m, 1H) ; 4.71 (broad d, J =
8.5 Hz, 2H) ; 7.71 (broad d, J = 8.5 Hz, 2H) ; 8.25 (s,
1H) ; 10.35 (broad m, 1H) ; 10.65 (broad m, 1H) . [α] 20D =
-19.4 +/- 0.7° (c 0.5, MeOH).
The (+)-3-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-
1-azabicyclo[2.2.2]octane and the (-)-3- [3-benzyloxy-4-
(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octane
can be prepared in the following way:
An ethanolic solution containing 0.29 g of (+/-)-3-[3-
benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo-
[2.2.2] octane is introduced onto a column, 8 cm in
diameter, containing 1180 g of Chiralpak AD™ chiral
stationary phase. The elution is carried out by means
of a mixture of heptane, of ethanol, of methanol and of
triethylamine (80/10/10/0.1 by volume), the flow rate
of the mobile phase being 120 ml/min. The dextro-
rotatory enantiomer is eluted in the first position,
the solution is evaporated to dryness under reduced
pressure (2.7 kPa), so as to obtain 0.69 g of (+)-3-[3-
benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo-
[2.2.2]octane in the form of an oil.
Mass spectrum (EI): 393(+)/...=M(+)/... (1 CI); 91(+)=
C7H7. [α]20D = +25.4 +/- 0.8° (c 0.5, MeOH). The solution
containing the levorotatory enantiomer eluted in the
second position is evaporated to dryness under reduced
pressure (2.7 kPa) so as to obtain 0.69 g of (-)-3-[3-
benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo-
[2.2.2]octane in the form of an oil.

Mass spectrum (EI): 393 ■( + )/... =M ( + )/.. - (1 CI); 91 ( + ) =
C7H7( + ). Optical rotation: [α] 20D = -26.2 +/- 0.8° (c
0.5, MeOH).
Example 91
(+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-
1H-pyrazol-3-ol hydrochloride
7 cm3 of 12N hydrochloric acid are added to a stirred
solution of 690 mg of (-)-3-[3-benzyloxy-4-(4-chloro-
phenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octane in 10 cm3
of ethanol. After 7 h at the reflux of the solvent, the
reaction medium is cooled to a temperature in the
region of 2 0°C and evaporated to dryness under reduced
pressure (2.7 kPa). The residue is triturated in
diisopropyl ether, filtered and dried under reduced
pressure (2.7 kPa) , to give 580 mg of ( + ) -1- (1-aza-
bicyclo [2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazol-
3-ol hydrochloride in the form of a beige solid. Mass
spectrum (EI): 303 ( + )/.. .=M( + )/.. . (1 CI). XH NMR
spectrum (300 MHz) - 6 in ppm - in DMSO-d6: from 1.67
to 2.02 (m, 4H) ; 2.42 (m, 1H) ; from 3.22 to 3.50 (m,
4H) ; 3.79 (m, 2H) ; 4.66 (m, 1H) ; 7.41 (broad d, J =
8.5 Hz, 2H) ; 7.71 (broad d, J = 8.5 Hz, 2H) ; 8.25 (s,
1H); from 10.2 to 10.3 (very broad m, 1H); 10.65 (broad
m, 1H) . [cc]20D = +17.7 +/- 0.6° (c 0.5, MeOH).
Example 92
(-)-1-(l-Azabicyclo[2.2.2]oct-3-yl)-4-(4-fluorophenyl)-
1H-pyrazol-3-ol hydrochloride
5 cm3 of 12N hydrochloric acid are added to a stirred
solution of 135 mg of (+)-3-[3-benzyloxy-4-(4-fluoro-
phenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octane in 5 cm3
of ethanol. After 7 h at the reflux of the solvent, the
reaction medium is cooled to a temperature in the
region of 20°C and evaporated to dryness under reduced

pressure (2.7 kPa). The residue is triturated in
diisopropyl ether, filtered and dried under reduced
pressure (2.7 kPa), to give 91 mg of (-)-1-(1-aza-
bicyclo[2.2.2]oct-3-yl)-4-(4-fluorophenyl)-1H-pyrazol-
3-ol hydrochloride in the form of a white solid. Mass
spectrum (EI): 287( + )=M( + ). ZK NMR spectrum (300 MHz) -
6 in ppm - in DMSO-d6: from 1.66 to 2.03 (m, 4H); 2.42
(m, 1H); from 3.20 to 3.49 (m, 4H); 3.79 (m, 2H); 4.66
(m, 1H) ; 7.19 (broad t, J = 9.0 Hz, 2H) ; 7.71 (broad
dd, J = 6.0 and 9.0 Hz, 2H); 8.17 (s, 1H); 10.15 (broad
m, 1H) ; 10.5 (s, 1H) . [CC]20D = -14.9 +/- 0.7° (c 0.5,
MeOH).
The (+)-3-[3-benzyloxy-4-(4-fluorophenyl)pyrazol-1-yl]-
l-azabicyclo[2.2.2]octane and the (-)-3-[3-benzyloxy-4-
(4-fluorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octane
can be prepared in the following way:
A solution of 2 g of 3-benzyloxy-4-(4-fluorophenyl)-1H-
pyrazole and of 1 g of potassium tert-butoxide in 2 0 cm3
of dimethylformamide, under an inert atmosphere, is
stirred for 1 h 30 min at a temperature in the region
of 20°C, and then a solution of 2.3 g of toluene-
4-sulfonic acid 1-azabicyclo[2.2.2]oct-3-yl ester in
25 cm3 of dimethyl formamide is added thereto. After
heating for 15 h at 100°C, the reaction medium is
poured into water, and the mixture is extracted with
two times ethyl acetate. The combined organic phases
are washed successively with two times water and a
saturated aqueous sodium chloride solution, dried over
magnesium sulfate and evaporated under reduced pressure
(2.7 kPa). The orangey oil obtained (2.3 g) is purified
by flash chromatography on alumina CTB1 under an argon
pressure (50 kPa) [eluent: ethyl acetate then ethyl
acetate/methanol (98/2 by volume)]. After concentrating
the fractions under reduced pressure (2.7 kPa), an
orangey oil is obtained (1.5 g) , which is purified by
flash chromatography on silica under an argon pressure
(50 kPa) [eluent: ethyl acetate/methanol (95/5 by

volume) then dichloromethane/methanol (98/2, 95/5 then
90/10 by volume)]. Concentrating the appropriate
fractions under reduced pressure (2.7 kPa) gives an
orange oil (500 mg) which is again purified by flash
chromatography on alumina CTB1 under an argon pressure
(50 kPa) [eluent: cyclohexane/ethyl acetate (10/90 by
volume)]. After concentrating the fractions under
reduced pressure (2.7 kPa), 290 mg of (R,S)-3-[3-benzyl-
oxy-4-(4-fluorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]-
octane are obtained in the form of a pale yellow oil. 1H
NMR spectrum (300 MHz) - 6 in ppm - in DMSO-d6: 1.28
(m, 1H) ; from 1.49 to 1.71 (m, 3H); 2.08 (m, 1H); from
2.65 to 2.79 (m, 3H) ; 2.98 (m, 1H) ; from 3.14 to 3.44
(m, 2H); 4.25 (m, 1H); 5.33 (m, 2H); 7.18 (broad t, J =
9.0 Hz, 2H); from 7.30 to 7.44 (m, 3H); 7.50 (broad d,
J = 7.5 Hz, 2H) ; 7.71 (broad dd, J = 6.0 and 9.0 Hz,
2H); 8.2 0 (s, 1H).
An ethanolic solution containing 0.29 g of (+/-)-3-[3-
benzyloxy-4-(4-fluorophenyl)pyrazol-1-yl] -1-azabicyclo-
[2.2.2] octane is introduced onto a column, 8 cm in
diameter, containing 1180 g of Chiralpak AD™ chiral
stationary phase. The elution is carried out by means
of a mixture of heptane, of ethanol, of methanol and of
triethylamine (80/10/10/0.1 by volume), the flow rate
of the mobile phase being 12 0 ml/min. The dextro-
rotatory enantiomer is eluted in the first position,
the solution is evaporated to dryness under reduced
pressure (2.7 kPa) to give 0.135 g of (+)-3-[3-benzyl-
oxy-4-(4-fluorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]-
octane in the form of an oil.
XH NMR spectrum (300 MHz) - 5 in ppm - in DMSO-d6: 1.30
(m, 1H); from 1.50 to 1.71 (m, 3H); 2.08 (m, 1H); from
2.64 to 2.80 (m, 3H) ; 2.99 (m, 1H) ; from 3.16 to 3.43
(m, 2H); 4.26 (m, 1H); 5.33 (m, 2H); 7.17 (broad t, J =
9.0 Hz, 2H); from 7.30 to 7.44 (m, 3H); 7.50 (broad d,
J = 7.5 Hz, 2H) ; 7.71 (broad dd, J = 6.0 and 9.0 Hz,
2H) ; 8.20 (s, 1H) . [α] 20D = +21.5 +/- 0.5° (c 0.5,

MeOH). The solution containing the levorotatory
enantiomer eluted in the second position is evaporated
to dryness under reduced pressure (2.7 kPa), so as to
obtain 0.137 g of (-)-3-[3-benzyloxy-4-(4-fluorophenyl)-
pyrazol-1-yl]-1-azabicyclo[2.2.2]octane oil.
XH NMR spectrum (300 MHz) - 5 in ppm - in DMSO-d6: 1.30
(m, 1H) ; from 1.49 to 1.71 (m, 3H); 2.08 (m, 1H); from
2.65 to 2.80 (m, 3H) ; 2.98 (m, 1H) ; from 3.15 to 3.42
(m, 2H); 4.25 (m, 1H); 5.33 (m, 2H); 7.18 (broad t, J =
9.0 Hz, 2H); from 7.30 to 7.44 (m, 3H); 7.50 (broad d,
J = 7.5 Hz, 2H); 7.71 (broad dd, J = 6.0 and 9.0 Hz,
2H) ; 8.20 (s, 1H) . [α] 20D = -20.2 +/- 0.6° (c 0.5,
MeOH).
The 3-benzyloxy-4-(4-fluorophenyl)-1H-pyrazole can be
prepared in the following way:
20 cm3 of a IN solution of tetrabutylammonium fluoride
in tetrahydrofuran are added to a solution, under an
argon atmosphere and with stirring, of 3.5 g of
3-benzyloxy-4-(4-fluorophenyl)-1-(toluene-4-sulfonyl)-
1H-pyrazole in 50 cm3 of tetrahydrofuran. After heating
for 15 h at the reflux of the solvent, the reaction
medium is evaporated under reduced pressure (2.7 kPa)
and ethyl acetate is added to the residue. The organic
phase is washed successively with two times water and a
saturated aqueous sodium chloride solution; it is dried
over magnesium sulfate and evaporated under reduced
pressure (2.7 kPa). The yellow solid obtained (2.3 g)
is purified by flash chromatography on silica under an
argon pressure (50 kPa) [eluent: cyclohexane/ethyl
acetate (70/30 by volume)]. After concentrating the
fractions under reduced pressure (2.7 kPa), 2 g of
3-benzyloxy-4-(4-fluorophenyl)-1H-pyrazole are obtained
in the form of a white solid. Mass spectrum (EI) :
268( + )=M( + ) .

The 3-benzyloxy-4-(4-fluorophenyl)-1-(toluene-4-
sulfonyl)-1H-pyrazole can be prepared in the following
way:
4.5 g of 4-fluorophenylboronic acid, 15 cm3 of a 2N
aqueous potassium carbonate solution and 1.6 g of
tetrakis(triphenylphosphine)palladium are added to a
solution, under an argon atmosphere and with stirring,
of 4.8 g of 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-
1H-pyrazole in 40 cm3 of toluene to which 10 cm3 of
ethanol have been added. After heating for 5 h at 100°C
and for 16 h at a temperature in the region of 20°C,
the reaction medium is evaporated under reduced
pressure (2.7 kPa) . Ethyl acetate, water and carbon
black are added to the residue, which is filtered
through supercel. The filtrate is separated by settling
out, and the organic phase is then washed successively
with three times water and a saturated aqueous sodium
chloride solution; it is dried over magnesium sulfate
and evaporated under reduced pressure (2.7 kPa). The
yellow solid obtained (9 g) is purified by flash
chromatography on silica under an argon pressure
(50 kPa) [eluent: cyclohexane/ethyl acetate (95/5 by
volume)]. After concentrating the fractions under
reduced pressure (2.7 kPa), 3.5 g of 3-benzyloxy-4-
(4-fluorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole are
obtained in the form of a yellow solid. Mass spectrum
(EI): 422( + )=M( + ) ; 267 ( + ) =422 ( + )-Ts; 91 ( + ) =C7H7 ( + ) .
Example 93
(+)-1-(l-Azabicyclo[2.2.2]oct-3-yl)-4-(4-fluorophenyl)-
1H-pyrazol-3-ol hydrochloride
5 cm3 of 12N hydrochloric acid are added to a stirred
solution of 137 mg of (-)-3-[3-benzyloxy-4-(4-fluoro-
phenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octane in 5 cm3
of ethanol. After 7 h at the reflux of the solvent, the
reaction medium is cooled to a temperature in the

region of 2 0°C and evaporated to dryness under reduced
pressure (2.7 kPa) . The residue is triturated in
diisopropyl ether, filtered, and dried under reduced
pressure (2.7 kPa) , to give 99 mg of ( + )-1-(1-aza-
bicyclo[2.2.2]oct-3-yl)-4-(4-fluorophenyl)-1H-pyrazol-
3-ol hydrochloride in the form of a white solid. Mass
spectrum (EI): 287( + )=M(+). XR NMR spectrum (300 MHz) -
5 in ppm - in DMSO-d6: from 1.69 to 2.03 (m, 4H); 2.41
(m, 1H); from 3.19 to 3.50 (m, 4H); 3.79 (m, 2H); 4.65
(m, 1H) ; 7.19 (broad t, J = 9.0 Hz, 2H) ; 7.71 (broad
dd, J = 6.0 and 9.0 Hz, 2H); 8.17 (s, 1H); from 10.1 to
10.3 (very broad m, 1H) ; 10.5 (s, 1H) . [α] 20D = +15.3
+/- 0.6° (c 0.5, MeOH).
Example 94
3-[4-(4-Chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2 .2.2]-
octane hydrochloride
A solution of 600 mg of 4-(4-chlorophenyl)-1H-pyrazole
and of 420 mg of potassium tert-butoxide in 20 cm3 of
dimethylformamide, in an inert atmosphere, is stirred
for 2 h at a temperature in the region of 2 0°C, and
then a solution of 1.1 g of toluene-4-sulfonic acid
1-azabicyclo [2 .2 .2] oct-3-yl ester in 20 cm3 of dimethyl-
formamide is added thereto. After heating for 15 h at
100°C, reaction medium is poured into water, and the
mixture is extracted with two times ethyl acetate. The
combined organic phases are washed successively with
two times water and a saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and evaporated
under reduced pressure (2.7 kPa). The orangey oil
obtained (1 g) is purified by flash chromatography on
alumina CTB1 under an argon pressure (50 kPa) [eluent:
ethyl acetate then ethyl acetate/methanol (95/5 by
volume)]. After concentrating the fractions under
reduced pressure (2.7 kPa), an orangey oil is obtained
(840 mg) which is purified by flash chromatography on
silica under an argon pressure (50 kPa) [eluent: ethyl

acetate, ethyl acetate/methanol (80/2 0 by volume) then
dichloromethane/methanol (80/20 by volume).] . Concen-
trating the appropriate fractions under reduced
pressure (2.7 kPa) gives a cream solid (250 mg) which
is dissolved in ethyl acetate. 0.85 cm3 of IN hydro-
chloric ether is added to the solution, which is then
evaporated to dryness under reduced pressure (2.7 kPa).
The residue is triturated in diisopropyl ether and the
resulting solid is filtered and then dried under
reduced pressure (2.7 kPa) , to give 239 mg of 3-[4-
(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octane
hydrochloride in the form of a cream solid. Mass
spectrum (EI): 287 ( + )/.. =M ( + )/... (1 CI) ; 36(+)/38(+)=
HC1 ( + )=salification via HCl. 1H NMR spectrum (400 MHz) -
5 in ppm - in DMSO-d6: 1.71 (m, 2H); 1.98 (m, 2H); 2.41
(m, 1H); from 3.20 to 3.46 (m, 4H); 3.78 (m, 1H); 3.92
(m, 1H) ; 4.89 (m, 1H) ; 7.44 (broad d, J = 8.5 Hz, 2H) ;
7.64 (broad d, J = 8.5 Hz, 2H) ; 8.05 (s, 1H) ; 8.46 (s,
1H); from 10.05 to 10.35 (very broad m, 1H).
The 4-(4-chlorophenyl)-1H-pyrazole can be prepared in
the following way:
21 cm3 of a IN solution of tetrabutylammonium fluoride
in tetrahydrofuran are added to a solution, under an
argon atmosphere and with stirring, of 2.8 g of
4-(4-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in
30 cm3 of tetrahydrofuran. After heating for 8 h at the
reflux of the solvent, the reaction medium is
evaporated under reduced pressure (2.7 kPa) and ethyl
acetate is added to the residue. The organic phase is
washed successively with two times water and a
saturated aqueous sodium chloride solution; it is dried
over magnesium sulfate and evaporated under reduced
pressure (2.7 kPa) . The yellow solid obtained (2.1 g)
is purified by flash chromatography on silica under an
argon pressure (50 kPa) [eluent: eyelohexane/ethyl
acetate (50/50 by volume)]. After concentrating the
fractions under reduced pressure (2.7 kPa), 1.2 g of

4-(4-chlorophenyl)-1H-pyrazole are obtained in the form
of a white solid. Mass spectrum (EI) : m/z=178 (M+-) base
peak, m/z=151 [ (M - HCN)+-], m/z=116 [ (m/z=151 - Cl)+],
m/z=89 [(m/z=116 - HCN)+] .
The 4-(4-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyra-
zole can be prepared in the following way:
6.1 g of 4-chlorophenylboronic acid, 20 cm3 of a 2N
aqueous potassium carbonate solution and 2.1 g of
tetrakis(triphenylphosphine)palladium are added to a
solution, under an argon atmosphere and with stirring,
of 5 g of 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in
60 cm3 of toluene to which 15 cm3 of ethanol have been
added. After heating for 3 h at 100°C and for 16 h at a
temperature in the region of 2 0°C, the reaction medium
is evaporated under reduced pressure (2.7 kPa) . Ethyl
acetate, water and carbon black are added to the
residue, which is filtered through supercel. The
filtrate is separated by settling out, and the organic
phase is then washed successively with two times water
and a saturated aqueous sodium chloride solution; it is
dried over magnesium sulfate and evaporated under
reduced pressure (2.7 kPa). The oil obtained (10.7 g)
is purified by flash chromatography on silica under an
argon pressure (50 kPa) [eluent: cyclohexane/ethyl
acetate (90/10 by volume)]. After concentrating the
fractions under reduced pressure (2.7 kPa), the
resulting solid is triturated in diisopropyl ether.
After filtration and drying under reduced pressure
(2.7 kPa), 2.8 g of 4-(4-chlorophenyl)-1-(toluene-4-
sulfonyl) -1H-pyrazole are obtained in the form of an
orangey solid. 1H NMR spectrum (300 MHz) - 5 in ppm - in
DMSO-d6: 2.41 (s, 3H); from 7.44 to 7.53 (m, 4H); 7.80
(broad d, J = 9.0 Hz, 2H) ; 7.92 (broad d, J = 9.0 Hz,
2H); 8.42 (s, 1H); 9.04 (s, 1H).

Example 95
3- [4-(4-Chlorophenyl)pyrazol-1-ylmethyl]-1-azabicyclo-
[2.2.2]octane hydrochloride
A solution of 640 mg of 4-(4-chlorophenyl)-1H-pyrazole
in 25 cm3 of dimethylformamide is added gradually, under
an argon atmosphere and at a temperature in the region
of 20°C, to a suspension of 345 mg of sodium hydride
(at 75% by mass in liquid petroleum jelly) in 15 cm3 of
dimethylformamide. After stirring for 45 min at a
temperature in the region of 50°C, 1.4 g of 3-chloro-
methyl-1-azabicyclo[2.2.2]octane hydrochloride are
added, in small portions, and the mixture is then
heated for 15 hours at a temperature in the region of
100°C. The mixture is cooled to a temperature in the
region of 20 °C and is then poured into water. The
aqueous phase is extracted with two times ethyl
acetate. The combined organic phases are washed with
two times water and brine, and are then dried over
magnesium sulfate, filtered, and concentrated to
dryness under reduced pressure (2.7 kPa). The orangey
oil obtained (1.3 g) is purified by flash
chromatography on alumina CTB1 under an argon pressure
(50 kPa) [eluent: ethyl acetate then ethyl
acetate/methanol (99/1 then 97/3 by volume)]. After
concentrating the fractions under reduced pressure
(2.7 kPa), an oil is obtained (520 mg) which is
purified by flash chromatography on silica under an
argon pressure (50 kPa) [eluent: dichloromethane/7N
ammoniacal methanol (97/3 by volume)]. Concentrating
the appropriate fractions under reduced pressure
(2.7 kPa) gives a pale yellow oil (330 mg) which is
dissolved in ethyl acetate. 0.985 cm3 of IN hydrochloric
ether is added to the solution, which is then
evaporated to dryness under reduced pressure (2.7 kPa).
The residue is triturated in diisopropyl ether and the
resulting solid is filtered and then dried under
reduced pressure (2.7 kPa) , to give 353 mg of 3-[4-

(4-chlorophenyl)pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2] -
octane hydrochloride in the form of a white solid. Mass
spectrum (EI): 301(+)/...=M(+)/...(1 CI). XH NMR
spectrum (300 MHz) - 5 in ppm - in DMSO-d6: from 1.65
to 2.13 (m, 5H); 2.58 (m, 1H); 2.93 (m, 1H); from 3.09
to 3.63 (m, 5H); from 4.22 to 4.34 (m, 2H); 7.42 (broad
d, J = 9.0 Hz, 2H) ; 7.62 (broad d, J = 9.0 Hz, 2H) ;
7.95 (s, 1H) ; 8.28 (s, 1H) ; from 9.90 to 10.2 (very
broad m, 1H).
Example 96
3- [4- (3-Chloro-4-methoxyphenyl)pyrazol-1-ylmethyl]-
1-azabicyclo[2.2.2]octane
A solution of 1.1 g of 4- (3-chloro-4-methoxyphenyl)-1H-
pyrazole in 2 5 cm3 of dimethylformamide is added
gradually, under an argon atmosphere and at a
temperature in the region of 20°C, to a suspension of
53 0 mg of sodium hydride (at 75% by mass in liquid
petroleum jelly) in 15 cm3 of dimethyl formamide. After
stirring for 1 h at a temperature in the region of
50°C, 2.07 g of 3-chloromethyl-1-azabicyclo[2.2.2] octane
hydrochloride are added in small portions, and the
mixture is then heated for 15 hours at a temperature in
the region of 100°C. The mixture is cooled to a
temperature in the region of 20°C and is then poured
into water. The aqueous phase is extracted with two
times ethyl acetate. The combined organic phases are
washed with two times water and brine, and then dried
over magnesium sulfate, filtered, and concentrated to
dryness under reduced pressure (2.7 kPa). The orangey
oil obtained (1.8 g) is purified by flash chromatography
on alumina CTB1 under an argon pressure (50 kPa)
[eluent: ethyl acetate then ethyl acetate/methanol
(98/2 then 95/5 by volume)]. After concentrating the
fractions under reduced pressure (2.7 kPa), an oil is
obtained (550 mg) which is purified by flash chromato-
graphy on silica under an argon pressure (50 kPa)

[eluent: dichloromethane/7N ammoniacal methanol (98/2
by volume)]. Concentrating the appropriate fractions
under reduced pressure (2.7 kPa) gives a pale yellow
oil (400 mg) which is again purified by flash
chromatography on alumina CTB1 under an argon pressure
(50 kPa) [eluent: ethyl acetate/methanol (95/5 by
volume) then dichloromethane/methanol (80/2 0 by
volume)]. After concentrating the fractions under
reduced pressure (2.7 kPa), 140 mg of 3-[4-(3-chloro-
4-methoxyphenyl)pyrazol-1-ylmethyl ] -1-
azabicyclo [2.2.2] octane are obtained in the form of a
white solid. Mass spectrum (CI):
332 ( + )/.. . = (M+H) ( + )/... (1 CI); 349 ( + ) = (M+NH4) ( + ) /
.... ^-H NMR spectrum (400 MHz) - 5 in ppm - in DMSO-d6:
from 1.28 to 1.57 (m, 4H) ; 1.77 (m, 1H); 2.15 (m, 1H);
2.3 6 (m, 1H); from 2.58 to 2.88 (m, 5H); 3.85 (s, 3H) ;
4.10 (d, J = 8.0 Hz, 2H) ; 7.12 (d, J = 8.0 Hz, 1H) ;
7.50 (dd, J = 2.0 and 8.0 Hz, 1H); 7.64 (d, J = 2.0 Hz,
1H); 7.85 (s, 1H); 8.08 (s, 1H).
The 4-(3-chloro-4-methoxyphenyl)-1H-pyrazole can be
prepared in the following way:
35 cm3 of a IN solution of tetrabutylammonium fluoride
in tetrahydrofuran are added to a solution, under an
argon atmosphere and with stirring, of 5.2 g of
4-(3-chloro-4-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-
pyrazole in 50 cm3 of tetrahydrofuran. After heating for
6 h at the reflux of the solvent, the reaction medium
is evaporated under reduced pressure (2.7 kPa) and
ethyl acetate is added to the residue. The organic
phase is washed successively with two times water and
the saturated aqueous sodium chloride solution; it is
dried over magnesium sulfate and evaporated under
reduced pressure (2.7 kPa). The orangey solid obtained
(5.1 g) is purified by flash chromatography on silica
under an argon pressure (50 kPa) [eluent: cyclohexane/
ethyl acetate (50/50 by volume)]. After concentrating
the fractions under reduced pressure (2.7 kPa), 1.84 g

of 4- (3-chloro-4-methoxyphenyl)-1H-pyrazole are obtained
in the form of a pale yellow solid. Mass spectrum (EI):
208 (+)/...=M ( + )/... (1 CI); 193( + )/. . . =M ( + )/.. .-CH3.
The 4- (3-chloro-4-methoxyphenyl)-1-(toluene-4-sulfonyl)-
1H-pyrazole can be prepared in the following way;
9 g of 4-chloro-3-methoxyphenylboronic acid, 24 cm3 of a
2N aqueous potassium carbonate solution and 2.45 g of
tetrakis(triphenylphosphine)palladium are added to a
solution, under an argon atmosphere and with stirring,
of 5.6 g of 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole
in 60 cm3 of toluene to which 15 cm3 of ethanol have
been added. After heating for 3 h at 100°C and for 16 h
at a temperature in the region of 20°C, the reaction
medium is evaporated under reduced pressure (2.7 kPa) .
Ethyl acetate, water and carbon black are added to the
residue, which is filtered through supercel. The
filtrate is separated by settling out, and the organic
phase is then washed successively with two times water
and a saturated aqueous sodium chloride solution; it is
dried over magnesium sulfate and evaporated under
reduced pressure (2.7 kPa). The solid obtained is
triturated in ethyl acetate, filtered and dried under
reduced pressure (2.7 kPa), to give 5.2 g of
4-(3-chloro-4-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-
pyrazole in the form of a beige solid that is used
without any other purification in the subsequent step.
XH NMR spectrum (300 MHz) - 5 in ppm - in DMSO-d6 for
70% of the mixture: 2.40 (m, 3H); 3.88 (broad s, 3H) ;
7.19 (d, J = 8.5 Hz, 1H) ; 7.50 (broad d, J = 8.5 Hz,
2H) ; 7.71 (dd, J = 2.0 and 8.5 Hz, 1H) ; from 7.88 to
7.93 (m, 3H) ; 8.41 (s, 1H) ; 8.99 (s, 1H) (purity
evaluated at 70% by XH NMR + starting boronic acid) .

Example 97
4-LI-(l-Azabicyclo[2.2.2]oct-3-ylmethyl)-1H-pyrazol-4-
yl]-2-chlorophenol dihydrochloride
A solution, under an argon atmosphere and with
stirring, of 470 mg of 3-[4-(3-chloro-4-methoxyphenyl)-
pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octane in 20 cm3
of dichloromethane is cooled in an ice-cold bath and
12 cm3 of a IN solution of boron tribromide in dichloro-
methane are then added thereto. After having allowed
the reaction medium to return to a temperature in the
region of 20°C, the reaction is continued for 15 h at
this temperature and then the mixture is poured into
water to which dichloromethane has been added. The
solution is brought to a pH in the region of 8 by
adding IN sodium hydroxide. The precipitate formed is
filtered off, and taken up in ethanol under hot
conditions. After filtration of the suspension under
hot conditions, water and carbon black are added to the
filtrate, which is filtered through Wattman paper and
evaporated to dryness under reduced pressure (2.7 kPa) .
The resulting beige solid (330 mg) is dissolved in
10 cm3 of ethanol and 10 cm3 of 12N hydrochloric acid.
After heating for 12 h at the reflux of the solvent,
the mixture is cooled to a temperature in the region of
20°C, and evaporated to dryness under reduced pressure
(2.7 kPa). The solid obtained is, three times,
successively dissolved in ethanol and evaporated to
dryness under reduced pressure (2.7 kPa), and is then
triturated in diisopropyl ether, filtered and dried
under vacuum (2.7 kPa) , to give 370 mg of
4-[1-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-1H-pyrazol-4-
yl]-2-chlorophenol dihydrochloride in the form of a
cream solid. Mass spectrum (ESP): 318(+)/...=(M+H)(+).
XH NMR spectrum (300 MHz) - 5 in ppm - in DMSO-d6: from
1.66 to 1.92 (m, 4H); 2.07 (m, 1H); 2.60 (m, 1H); 2.94
(m, 1H) ; from 3.10 to 3.3 9 (m, 5H) ; from 4.15 to 4.32
(m, 2H) ; 7.00 (d, J = 8.5 Hz, 1H) ; 7.34 (dd, J = 2.5

and 8.5 Hz, 1H) ; 7.56 (d, J = 2.5 Hz, 1H) ; 7.85 (s,
1H) ; 8.16 (s, -1H) ; from 9.80 to 10.3 (very broad m,
2H) .
Example 98
4-[1-(l-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-
2-chlorophenol
A solution, under an argon atmosphere and with
stirring, of 750 mg of 3-[4-(3-chloro-4-methoxyphenyl)-
pyrazol-1-yl]-1-azabicyclo[2.2.2]octane in 25 cm3 of
dichloromethane is cooled in an ice-cold bath and 11 cm3
of a IN solution of boron tribromide in dichloromethane
are then added thereto. After reaction for 30 min at a
temperature in the region of 0°C, and heating for 3 h
at 40°C then for 15 h at a temperature in the region of
20°C, the reaction mixture is poured into water to
which dichloromethane has been added. The resulting
suspension is filtered and the solid is taken up in
water. The mixture is adjusted to pH 8 and then
extracted with ethyl acetate. The organic phase is
washed successively with two times water and a
saturated aqueous sodium chloride solution, dried over
magnesium sulfate, and evaporated under reduced
pressure (2.7 kPa). The beige solid obtained (800 mg)
is purified by flash chromatography on silica under an
argon pressure (50 kPa) [eluent: dichloromethane/
methanol (80/20 by volume)]. Concentrating the appro-
priate fractions under reduced pressure (2.7 kPa) gives
a residue which is triturated in diisopropyl ether,
filtered and dried under reduced pressure (2.7 kPa), to
give 240 mg of 4-[1-(1-azabicyclo[2.2.2]oct-3-yl)-1H-
pyrazol-4-yl]-2-chlorophenol in the form of a white
solid. Mass spectrum (EI): 303(+)/...=M(+)/...(1 Cl). XH
NMR spectrum (400 MHz) - 5 in ppm - in DMSO-d6: 1.32
(m, 1H); 1.54 (m, 1H); 1.70 (m, 2H); 2.02 (m, 1H); 2.77
(m, 3H); 2.98 (m, 1H); from 3.20 to 3.50 (m, 2H); 4.42
(m, 1H) ; 6.98 (d, J = 9.0 Hz, 1H) ,- 7.40 (dd, J = 2.0

and 9.0 Hz, 1H) ; 7.62 (d, J = 2.0 Hz, 1H) ; 7.87 (s,
1H); 8.28 (s, 1H); 10.05 (broad m, 1H).
The 3-[4-(3-chloro-4-methoxyphenyl)pyrazol-1-yl]-1-aza-
bicyclo[2.2.2]octane can be prepared in the following
way:
A solution of 1.35 g of 4-(3-chloro-4-methoxyphenyl)-
1H-pyrazole and of 800 mg of potassium tert-butoxide in
20 cm3 of dimethylformamide, under an inert atmosphere,
is stirred for 1 h at a temperature in the region of
20°C and a solution of 2 g of toluene-4-sulfonic acid
1-azabicyclo[2.2.2]oct-3-yl ester in 20 cm3 of dimethyl-
formamide is then added thereto. After heating for 18 h
at 100°C, the reaction medium is poured into water, and
the mixture is extracted with two times ethyl acetate.
The combined organic phases are washed successively
with two times water and a saturated aqueous sodium
chloride solution, dried over magnesium sulfate, and
evaporated under reduced pressure (2.7 kPa). The
orangey oil obtained (2 g) is purified by flash
chromatography on silica under an argon pressure
(50 kPa) [eluent: ethyl acetate, ethyl acetate/methanol
(80/20 by volume) then dichloromethane/methanol (80/20
by volume)]. After concentrating the fractions under
reduced pressure (2.7 kPa), 480 mg of 3-[4-(3-chloro-4-
methoxyphenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octane
are obtained in the form of an orangey oil. Mass
spectrum (EI): m/z=317 (M+") , m/z=234 [ (M - C5H9N)+-],
m/z=109 [C7HnN+-] , m/z=97 [C6H1:LN+-] base peak.
Examples 99 and 100
(-)-4-[1-(l-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-
2-chlorophenol and (+)-4-[1-(1-azabicyclo[2.2.2]oct-3-
yl)-1H-pyrazol-4-yl]-2-chlorophenol
An ethanolic solution containing 0.173 g of 4-[1-(1-aza-
bicyclo [2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-chlorophenol

is introduced onto a column, 8 cm in diameter,
containing 1180 g of Chiralpak AD™ chiral stationary
phase. The elution is carried out by means of a mixture
of heptane, of ethanol, of methanol and of triethyl-
amine (80/10/10/0.1 by volume), the flow rate of the
mobile phase being 120 ml/min. The levorotatory
enantiomer is eluted in the first position, the
solution is evaporated to dryness under reduced
pressure (2.7 kPa), to give 0.093 g of (-)-4-[1-(1-aza-
bicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-chlorophenol
in the form of an oil.
Mass spectrum (EI): 303 ( + )/.. .=M ( + )/... (1 Cl) . XH NMR
spectrum (400 MHz) - 5 in ppm - in DMSO-d6: 1.31 (m,
1H) ; 1.53 (m, 1H) ; 1.68 (m, 2H) ; 2.09 (m, 1H) ,- from
2.67 to 2.80 (m, 3H); 2.97 (m, 1H) ; from 3.18 to 3.48
(m, 2H) ; 4.39 (m, 1H) ; 6.95 (d, J = 8.5 Hz, 1H) ; 7.38
(dd, J = 2.5 and 8.5 Hz, 1H); 7.60 (d, J = 2.5 Hz, 1H);
7.85 (s, 1H) ; 8.23 (s, 1H) ; from 9.98 to 10.15 (very
broad m, 1H) . [α] 20D = -4.1 +/- 0.6° (c 0.5, MeOH) .
The solution containing the dextrorotatory enantiomer
eluted in the second position is evaporated to dryness
under reduced pressure (2.7 kPa) , to give 0.102 g of
(+) -4- [1- (1-azabicyclo [2 .2 .2] oct-3-yl) -1H-pyrazol-4-yl] -
2-chlorophenol in the form of an oil.
Mass spectrum (EI): 303 ( + )/... =M ( + )/... (1 Cl) . XH NMR
spectrum (400 MHz) - 5 in ppm - in DMSO-d6: 1.35 (m,
1H) ; 1.54 (m, 1H) ; 1.70 (m, 2H) ; 2.12 (m, 1H) ; from
2.70 to 2.83 (m, 3H); 3.00 (m, 1H); from 3.21 to 3.51
(m, 2H) ; 4.43 (m, 1H) ; 6.95 (d, J = 8.5 Hz, 1H) ; 7.38
(dd, J = 2.5 and 8.5 Hz, 1H); 7.61 (d, J = 2.5 Hz, 1H);
7.87 (s, 1H) ; 8.27 (s, 1H) ; 10.05 (broad m, 1H) . [α] 20D
= +5.3 +/- 0.4° (c 0.5, MeOH).
Examples 101 and 102

( + ) -1- (l-Azabicyclo[2.2.2]oct-3-yl) -4-pyridin-2-yl-1H-
pyrazol-3-ol and (-) -1-(1-azabicyclo[2.2.2]oct-3-yl) -
4-pyridin-2-yl-1H-pyrazol-3-ol
An ethanolic solution containing 0.3 g of (+/-)-1-(1-
azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-pyrazol-3-
ol is introduced onto a column, 8 cm in diameter,
containing 118 0 g of 2 0 |oM Chiralpak AD™ chiral
stationary phase. The elution is carried out by means
of a mixture of heptane, of ethanol, of methanol and of
triethylamine (70/15/15/0.2 by volume), the flow rate
of the mobile phase being 12 0 ml/min. The levorotatory
enantiomer is eluted in the first position, the
solution is evaporated to dryness under reduced
pressure (2.7 kPa), to give 0.109 g of (-)-1-(1-aza-
bicyclo [2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-pyrazol-3-ol
in the form of an oil.
Mass spectrum (EI): m/z=270 (M+>) , m/z=187 [ (M - C5H9N)+]
base peak. ^H NMR spectrum (400 MHz) - 6 in ppm - in
DMSO-d6 (referenced at 2.50 ppm): 1.31 (m, 1H) ; from
1.55 to 1.70 (m, 3H) ; 2.07 (m, 1H) ; from 2.65 to 2.75
(m, 2H) ; 2.90 (m, 1H) ; from 3.14 to 3.39 (partially
masked m, 3H) ; 4.21 (m, 1H) ; 7.14 (m, 1H) ; 7.72 (broad
d, J = 7.5 Hz, 1H) ; 7.78 (m, 1H) ; 8.26 (s, 1H) ; 8.45
(broad d, J = 5.0 Hz, 1H); from 10.9 to 11.1 (broad m,
1H) . [cc]20D = -40.7 +/- 0.8° (c 0.5, dimethylformamide) .
The solution containing the dextrorotatory enantiomer
eluted in the second position is evaporated to dryness
under reduced pressure (2.7 kPa) , to give 0.113 g of
(+)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-
pyrazol-3-ol in the form of an oil.
Mass spectrum (EI): m/z=270 (M+-) , m/z=187 [ (M - C5H9N)+]
base peak. XR NMR spectrum (400 MHz) - 5 in ppm - in
DMSO-d6 (referenced at 2.50 ppm): 1.32 (m, 1H) ; from
1.56 to 1.68 (m, 3H) ; 2.08 (m, 1H) ; from 2.66 to 2.76
(m, 2H) ; 2.92 (m, 1H) ; from 3.14 to 3.42 (partially

masked m, 3H) ; 4.22 (m, 1H); 7.14 (m, 1H); 7.71 (broad
d, J = 7.5 Hz, 1H) ; 7.78 (m, 1H) ; 8.27 (s, 1H) ; 8.47
(broad d, J = 5.0 Hz, 1H) ; from 10.8 to 11.15. (broad m,
1H) . [α] 20D = +35.4 +/- 0.8° (c 0.5, dimethyl formamide) .
The (+/-) -1- (l-azabicyclo[2 .2 .2] oct-3-yl) -4-pyridin-2-
yl-1H-pyrazol-3-ol hydrochloride can be prepared in the
following way:
7 cm3 of 4N hydrochloric dioxane are added to a solution
of 330 mg of 3- [3-(cyclohex-2-enyloxy)-4-pyridin-2-yl-
pyrazol-1-yl]-1-azabicyclo[2.2.2]octane in 7 cm3 of
dioxane. After stirring for 15 h at a temperature in
the region of 20°C, the insoluble material formed is
filtered off, rinsed with diisopropyl ether and dried
under reduced pressure (2.7 kPa) , to give 300 mg of
(+/-) -1-(1-azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-
1H-pyrazol-3-ol hydrochloride in the form of a white
solid. Mass spectrum (EI): m/z=270 (M+'), m/z=187 [ (M -
C5H9N)+] base peak, m/z=36 (HC1+-).
The 3-[3-(cyclohex-2-enyloxy)-4-pyridin-2-ylpyrazol-1-
yl]-1-azabicyclo[2.2.2]octane can be prepared in the
following way:
A solution of 2.5 g of 2-[3-(cyclohex-2-enyloxy)-1H-
pyrazol-4-yl]pyridine and of 1.4 g of potassium tert-
butoxide in 2 0 cm3 of dimethyl formamide, under an inert
atmosphere, is stirred for 1 h at 50°C and a solution
of 4 g of toluene-4-sulfonic acid 1-azabicyclo[2.2.2]-
oct-3-yl ester in 20 cm3 of dimethyl formamide is then
added thereto. After heating for 15 h at 100°C, the
reaction medium is poured into water, and the mixture
is extracted with two times ethyl acetate. The combined
organic phases are washed successively with two times
water and a saturated aqueous sodium chloride solution,
dried over magnesium sulfate, and evaporated under
reduced pressure (2.7 kPa). The orangey oil obtained
(5.3 g) is purified by flash chromatography on alumina

CTB1 under an argon pressure (50 kPa) [eluent: cyclo-
hexane/ethyl acetate (60/40 by volume), ethyl acetate
then ethyl acetate/methanol (95/5 by volume)]. After
concentrating the fractions under reduced pressure
(2.7 kPa) , an oil is obtained which is purified by
flash chromatography on silica under an argon pressure
(50 kPa) [eluent: dichloromethane/methanol (95/5 then
70/30 by volume)]. Concentrating the appropriate
fractions under reduced pressure (2.7 kPa) gives 370 mg
of 3-[3-(cyclohex-2-enyloxy)-4-pyridin-2-ylpyrazol-1-
yl]-1-azabicyclo [2.2.2] octane in the form of a pale
yellow oil. 1H NMR spectrum (400 MHz) - DMSO-d6 (referenced at 2.50 ppm): 1.35 (m, 1H) ; from
1.59 to 1.70 (m, 4H) ; 1.78 (m, 1H) ; from 1.86 to 2.17
(m, 5H); from 2.67 to 2.78 (m, 3H); 2.96 (m, 1H); 3.19
(m, 1H) ; from 3.27 to 3.37 (masked m, 1H) ; 4.30 (m,
1H) ; 5.20 (m, 1H) ; from 5.95 to 6.04 (m, 2H) ; 7.10 (m,
1H) ; 7.74 (m, 2H) ; 8.18 (s, 1H) ; 8.47 (broad d, J =
5.0 Hz, 1H).
Examples 103 and 104
(+)-1-(l-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-
3-ylamine and (-) -1-(1-azabicyclo[2.2.2]oct-3-yl) -4-
phenyl-1H-pyrazol-3-ylamine
An ethanolic solution containing 0.13 g of (+/-)-1-(l-
azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ylamine
is introduced onto a column, 8 cm in diameter,
containing 1180 g of 20 JJM Chiralpak AD™ chiral
stationary phase. The elution is carried out by means
of a mixture of heptane, of ethanol and of triethyl-
amine (50/50/0.1 by volume), the flow rate of the
mobile phase being 120 ml/min. The levorotatory
enantiomer is eluted in the first position, the
solution is evaporated to dryness under reduced
pressure (2.7 kPa) , to give 0.035 g of (-)-1-(1-aza-
bicyclo [2.2.2] oct - 3 -yl) -4 -phenyl - 1H-pyrazol - 3 -ylamine
in the form of an oil.

Mass spectrum (EI) : m/z=268 (M+") base peak, m/z=185
[(M - C5H9N)+], m/z=109 (C7HnN+-). XH NMR spectrum
(300 MHz) 5 in ppm - in DMSO-d6 (referenced at
2.50 ppm): 1.37 (m, 1H) ; from 1.61 to 1.74 (m, 3H) ;
2.11 (m, 1H); from 2.71 to 2.85 (m, 3H); 3.00 (m, 1H);
from 3.12 to 3.53 (partially masked m, 2H) ; 4.21 (m,
1H) ; 4.65 (broad m, 2H) ; 7.13 (tt, J = 1.5 and 7.5 Hz,
1H); 7.32 (broad t, J = 7.5 Hz, 2H); 7.52 (broad d, J =
7.5 Hz, 2H) ; 7.90 (s, 1H) . [α] 20D = - (dimethyl-
formamide).
The solution containing the dextrorotatory enantiomer
eluted in the second position is evaporated under
reduced pressure (2.7 kPa) , to give 0.039 g of
(+)-1-(l-azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-
3-ylamine in the form of an oil.
Mass spectrum (EI): m/z=268 (M+") , m/z=185 [ (M - C5H9N)+] ,
m/z=109 (C7HnN+-) base peak. XH NMR spectrum (300 MHz) -
5 in ppm - in DMSO-d6 (referenced at 2.50 ppm) : 1.34
(m, 1H) ; from 1.60 to 1.73 (m, 3H) ; 2.09 (m, 1H) ; from
2.68 to 2.82 (m, 3H) ; from 2.90 to 3.53 (partially
masked m, 3H) ; 4.19 (m, 1H) ; 4.63 (broad m, 2H) ; 7.12
(broad t, J = 7.5 Hz, 1H) ; 7.32 (broad t, J = 7.5 Hz,
2H) ; 7.51 (broad d, J = 7.5 Hz, 2H) ; 7.89 (s, 1H) .
[ot] 20D = + (dimethylformamide) .
The (+/-) -1- (l-azabicyclo[2.2.2]oct-3-yl) -4-phenyl-1H-
pyrazol-3-ylamine can be prepared in the following way:
1.1 g of 1,3-dimethylbarbituric acid and 50 mg of
tetrakis(triphenylphosphine)palladium are added to a
solution of 280 mg of diallyl-[1-(1-azabicyclo[2.2.2]-
oct-3-yl)-4-phenyl-1H-pyrazol-3-yl]amine in 10 cm3 of
dichloromethane, under argon and with stirring. After
heating for 15 h at the reflux of the reaction medium,
the mixture is evaporated to dryness under reduced
pressure (2.7 kPa) . The residue is taken up with IN

hydrochloric acid and the solution is washed with two
times ethyl acetate. The resulting aqueous phase is
alkylinized with IN sodium hydroxide and extracted with
two times ethyl acetate. The combined organic phases
are washed with a saturated aqueous sodium chloride
solution, dried over magnesium sulfate and evaporated
under reduced pressure (2.7 kPa) . The residue is taken
up with dichloromethane and the solution is treated with
carbon black, filtered through supercel, and evaporated
under reduced pressure (2.7 kPa) , to give 130 mg of
(+/-)-1-(l-azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyra-
zol-3-ylamine in the form of an orange oil. 1H NMR
spectrum (300 MHz) - 5 in ppm - in DMSO-d6 (referenced
at 2.50 ppm): from 1.20 to 1.38 (m, 1H) ; from 1.58 to
1.71 (m, 3H) ; 2.07 (m, 1H) ; from 2.62 to 2.79 (m, 3H) ;
from 2.88 to 3.63 (partially masked m, 3H) ; 4.16 (m,
1H) ; 4.63 (broad s, 2H) ; 7.13 (broad t, J = 7.5 Hz,
1H); 7.32 (broad t, J = 7.5 Hz, 2H); 7.52 (broad d, J =
7.5 Hz, 2H); 7.89 (s, 1H).
The diallyl-[1-(1-azabicyclo[2.2.2]oct-3-yl)-4-phenyl-
1H-pyrazol-3-yl]amine can be prepared in the following
way:
A solution of 1.3 g of diallyl-(4-phenyl-1H-pyrazol-3-
yl) amine and of 730 mg of potassium tert-butoxide in
20 cm3 of dimethylformamide, under an argon atmosphere,
is stirred for 45 min at 45°C and then a solution of
2.3 g of toluene-4-sulfonic acid 1-azabicyclo [2 .2 .2] -
oct-3-yl ester in 15 cm3 of dimethyl formamide is added
thereto. After heating for 15 h at 100°C, the reaction
medium is poured into water, and the mixture is
extracted with two times ethyl acetate. The combined
organic phases are washed successively with two times
water and a saturated aqueous sodium chloride solution,
dried over magnesium sulfate, and evaporated under
reduced pressure (2.7 kPa) . The orangey oil obtained
(1.8 g) is purified by flash chromatography on alumina
CTB1 under an argon pressure (50 kPa) [eluent: cyclo-

hexane/ethyl acetate (60/40 by volume)]. After
concentrating the fractions under reduced pressure
(2.7 kPa) , an oil is obtained which is purified by
flash chromatography on silica under an argon pressure
(50 kPa) [eluent: dichloromethane/methanol (50/50 by
volume)]. Concentrating the appropriate fractions under
reduced pressure (2.7 kPa) gives 280 mg of diallyl-
[1-(1-azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-
yl]amine containing 20% (estimated by XE NMR) of
diallyl-(4-phenyl-1H-pyrazol-3-yl)amine in the form of
a pale yellow oil. ^ NMR spectrum (300 MHz) - 5 in ppm
- in DMSO-d6 (referenced at 2.50 ppm): 1.29 (m, 1H) ;
from 1.53 to 1.69 (m, 3H) ; 2.03 (m, 1H) ; from 2.62 to
2.80 (m, 3H); 2.97 (m, 1H); 3.17 (m, 1H); 2.39 (m, 1H);
from 3.52 to 3.52 (m, 4H) ; 4.24 (m, 1H) ; ■ from 4.98 to
5.17 (m, 4H); from 5.75 to 5.91 (m, 2H); 7.17 (tt, J =
1.5 and 7.5 Hz, 1H) ; 7.33 (broad t, J = 7.5 Hz, 2H) ;
7.61 (broad d, J = 7.5 Hz, 2H); 7.93 (s, 1H).
The diallyl-(4-phenyl-1H-pyrazol-3-yl)amine can be
prepared in the following way:
22 cm3 of a IN solution of tetrabutylammonium fluoride
in tetrahydrofuran are added to a solution, under an
argon atmosphere and with stirring, of 2.9 g of
diallyl-[4-phenyl-1-(2-trimethylsilanylethoxymethyl)-1H-
pyrazol-3-yl]amine in 25 cm3 of tetrahydrofuran. After
heating to 18 h at the reflux of the solvent, 6.3 cm3 of
IN tetrabutylammonium fluoride solution are added and
the heating is continued for 4 h. After evaporation of
the reaction medium to dryness under reduced pressure
(2.7 kPa) ,. ethyl acetate is added to the residue and
the organic phase is washed successively with two times
water and a saturated aqueous sodium chloride solution;
it is dried over magnesium sulfate and evaporated under
reduced pressure (2.7 kPa) . The brown oil obtained
(1.8 g) is purified by flash chromatography on silica
under an argon pressure (50 kPa) [eluent: cyclohexane/
ethyl acetate (70/30 by volume)]. After concentrating

the fractions under reduced pressure (2.7 kPa), 1.3 g
of diallyl-(4-phenyl-1H-pyrazol-3-yl)amine are obtained
in the form of an orange oil. Mass spectrum (EI):
m/z=239 (M+-) base peak, m/z=198 [ (M - C3H5)+], m/z=41
(C3H5+) .
The diallyl- [4-phenyl-1- (2-trimethylsilanylethoxymethyl) -
1H-pyrazol-3-yl] amine can be prepared in the following
way:
8.17 g of cesium carbonate and 4.35 cm3 of allyl bromide
are added to a solution, under an argon atmosphere and
with stirring, of 2.9 g of 4-phenyl-1-(2-trimethyl-
silanylethoxymethyl)-1H-pyrazol-3-ylamine in 60 cm3 of
acetonitrile. After heating for 15 h at the reflux of
the solvent, the reaction medium is evaporated to
dryness under reduced pressure (2.7 kPa) and the
residue is taken up with ethyl acetate. The organic
solution is washed successively with two times water
and a saturated aqueous sodium chloride solution; it is
dried over magnesium sulfate and evaporated under
reduced pressure (2.7 kPa) . The orangey oil obtained
(4 g) is purified by flash chromatography on silica
under an argon pressure (50 kPa) [eluent: cyclohexane/
ethyl acetate (93/7 by volume)]. After concentrating
the fractions under reduced pressure (2.7 kPa), 2.9 g
of diallyl-[4-phenyl-1-(2-trimethylsilanylethoxymethyl)-
1H-pyrazol-3-yl] amine are obtained in the form of an
orange oil. XH NMR spectrum (300 MHz) - 5 in ppm - in
DMSO-d6 (referenced at 2.50 ppm): -0.03 (s, 9H); 0.83
(m, 2H) ; from 3.52 to 3.63 (m, 6H) ; from 5.04 to 5.15
(m, 4H); 5.24 (s, 2H); from 5.74 to 5.90 (m, 2H); 7.21
(tt, J = 1.5 and 7.5 Hz, 1H) ; 7.36 (broad t, J =
7.5 Hz, 2H) ; 7.58 (broad d, J = 7.5 Hz, 2H) ; 7.96 (s,
1H) .
The 4-phenyl-1-(2-trimethylsilanylethoxymethyl)-1H-pyra-
zol-3-ylamine can be prepared in the following way:

3.7 g of iron, 1.8 g of ammonium chloride and then a
solution of 3.5 g of 3-nitro-4-phenyl-1-(2-trimethyl-
silanylethoxymethyl)-1H-pyrazole in 50 cm3 of ethanol
are added to a mixture of 50 cm3 of ethanol and 50 cm3
of water. After heating for 8 h at the reflux of the
solvent and with stirring, and for 15 h at a temperature
in the region of 20°C, the reaction medium is filtered
through supercel and the filtrate is evaporated to
dryness under reduced pressure (2.7 kPa). The residue
is taken up with ethyl acetate and the organic solution
is washed successively with two times water and a
saturated aqueous sodium chloride solution, and is then
dried over magnesium sulfate and evaporated under
reduced pressure (2.7 kPa) , to give 2.9 g of 4-phenyl-
1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-3-ylamine
in the form of an orangey oil. XE NMR spectrum (400 MHz)
- 6 in ppm - in DMSO-d6 (referenced at 2.50 ppm): -0.01
(s, 9H) ; 0.86 (m, 2H) ; 3.56 (m, 2H) ; 4.75 (broad s,
2H); 5.17 (s, 2H); 7.18 (broad t, J = 7.5 Hz, 1H); 7.35
(broad t, J = 7.5 Hz, 2H) ; 7.50 (broad d, J = 7.5 Hz,
2H); 7.88 (s, 1H).
The 3-nitro-4-phenyl-1-(2-trimethylsilanylethoxymethyl)-
1H-pyrazole can be prepared in the following way:
8.8 g of phenylboronic acid, 36 cm3 of a 2N aqueous
potassium carbonate solution and 3.6 g of tetrakis(tri-
phenylphosphine) palladium are added to a solution,
under an argon atmosphere and with stirring, of 7.8 g
of 4-iodo-3-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-
pyrazole in 120 cm3 of toluene to which 30 cm3 of
ethanol have been added. After heating for 15 h at
100°C, the reaction medium is cooled to a temperature
in the region of 2 0°C and is then evaporated under
reduced pressure (2.7 kPa). The residue is taken up
with ethyl acetate and the organic solution is washed
successively with two times water and a saturated
aqueous sodium chloride solution; it is dried over
magnesium sulfate and evaporated under reduced pressure

(2.7 kPa) , to give 14.3 g of a brown oil which is
purified by flash chromatography on silica under an
argon pressure (50 kPa) [eluent: cyclohexane/ethyl
acetate (90/10 then 70/30 by volume)]. Concentrating
the appropriate fractions under reduced pressure
(2.7 kPa) gives 4.5 g of 3-nitro-4-phenyl-1-(2-tri-
methylsilanylethoxymethyl) -1H-pyrazole in the form of a
yellow oil. Mass spectrum (EI): m/z=319 (M+-), m/z=246
[(M - C3H9Si)+] base peak, m/z=73 (C3H9Si+) .
The 4-iodo-3-nitro-1-(2-trimethylsilanylethoxymethyl)-
1H-pyrazole can be prepared in the following way:
10 g of 3-nitro-4-phenyl-1H-pyrazole are added,
portionwise, to a suspension of 1.7 g of sodium hydride
(at 75% in liquid petroleum jelly) in 120 cm3 of
dimethylformamide under an argon atmosphere and with
stirring. The mixture is stirred for 45 min at a
temperature in the region of 20°C and 14 cm3 of
2-trimethylsilanylethoxymethyl chloride are then slowly
added thereto. After stirring for 15 h at a temperature
in the region of 20°C, the reaction medium is poured
into 500 cm2 of water and the mixture is extracted with
three times 500 cm3 of ethyl acetate. The organic phases
are combined, washed successively with two times water
and a saturated aqueous sodium chloride solution, dried
over magnesium sulfate, filtered and evaporated under
reduced pressure (2.7 kPa), to give an orange oil
(22 g) which is purified by flash chromatography on
silica under an argon pressure (50 kPa) [eluent:
cyclohexane/ethyl acetate (85/15 by volume)]. After
concentrating the fractions under reduced pressure,
7.8 g of 4-iodo-3-nitro-1-(2-trimethylsilanylethoxy-
methyl) -1H-pyrazole are obtained in the form of a pale
yellow oil. ^ NMR spectrum (300 MHz) - 5 in ppm - in
DMSO-d6 (referenced at 2.50 ppm): -0.03 (s, 9H) ; 0.87
(m, 2H); 3.61 (m, 2H); 5.51 (s, 2H); 8.52 (s, 1H).

Examples 105 and 106
1-(l-Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-4-yl)-1H-
pyrazole hydrochloride, enantiomers A and B
The procedure is carried out as in example 38, but with
0.78 g of 1- (1-azabicyclo[2.2.2]oct-3-yl)-4-iodo-1H-
pyrazole, 0.51 g of 1H-indol-4-yl boronic acid pinacolic
ester, 0.475 g of sodium carbonate, 0.13 g of l,l'-di-
chlorobis(diphenylphosphinoferrocene)palladium in 35 cm3
of dioxane and 5 cm3 of water. After purification by
chromatography under a nitrogen pressure of 50 kPa on a
basic alumina cartridge (Merck), eluting with a mixture
of cyclohexane and of ethyl acetate (50/50 then 25/75
then 10/90 by volume) and then with a mixture of ethyl
acetate and of methanol (95/5 by volume), fractions 49
to 12 0 are combined, and concentrated to dryness under
reduced pressure (3 kPa). Fractions 192 to 205 are
combined, washed with 5 cm3 and concentrated to dryness
under reduced pressure (3 kPa) . The 2 batches, in the
form of an orange powder, are combined (266 mg) and
purified by HPLC in order to separate the enantiomers
on a 20 ^m Chiralcel OD column with, as eluent, a
mixture of heptane, of methanol, of ethanol and of
triethylamine (60/10/30/0.2 by volume); each enantiomer
is then taken up with 10 cm3 of dichloromethane and
5 cm3 of water. The organic phase is washed with a
saturated aqueous sodium chloride solution, dried over
magnesium sulfate, filtered, and concentrated to
dryness under reduced pressure (3 kPa). Each white
powder thus obtained is then taken up with 20 cm3 of
absolute ethanol and then brought to the reflux of the
solvent for 20 minutes. Each solution is filtered and
washed with 5 cm3 of absolute ethanol, and 1 cm3 of a IN
solution of hydrochloric diethyl ether is added
thereto. The solutions are concentrated to dryness
under reduced pressure, taken up with 5 cm3 of ethanol
and again concentrated to dryness under reduced
pressure; the residues are precipitated from 5 cm3 of

diisopropyl ether and then filtered through sintered
glass. 45 mg of (+)-1-(1-azabicyclo[2.2.2]oct-3-yl)-
4-(1H-lndol-4-yl)-1H-pyrazole hydrochloride, enantiomer
A, in the form of a beige powder ( [α] 20D = +21.0°,
solvent: dimethyl sulfoxide, concentration: 0.5) and
39 mg of (-)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(1H-
indol-4-yl)-1H-pyrazole hydrochloride, enantiomer B, in
the form of a beige powder ( [α] 20D = -22.7°, solvent:
dimethyl sulfoxide, concentration: 0.5) are thus
obtained.
The pharmaceutical compositions according to the
invention consist of a compound of formula (I) or a
salt of such a compound, in the pure state or in the
form of a composition in which it is combined with any
other pharmaceutically compatible product, which may be
inert or physiologically active. The medicinal products
according to the invention can be used orally,
parenterally, rectally or topically.
As solid compositions for oral administration, use may
be made of tablets, pills, powders (gelatin capsules,
wafer capsules) or granules. In these compositions, the
active principle according to the invention is mixed
with one or more inert diluents such as starch,
cellulose, sucrose, lactose or silica, under a stream
of argon. These compositions may also contain
substances other than diluents, for example one or more
lubricants such as magnesium stearate or talc, a dye, a
coating (sugar-coated tablets) or a varnish.
As liquid compositions for oral administration, use may
be made of pharmaceutically acceptable solutions,
suspensions, emulsions, syrups and elixirs, containing
inert diluents such as water, ethanol, glycerol, plant
oils or liquid paraffin. These compositions may
comprise substances other than diluents, for example
wetting, sweetening, thickening, flavoring or
stabilizing products.

The sterile compositions for parenteral administration
may preferably be aqueous or nonaqueous solutions,
suspensions or emulsions. As a solvent or vehicle, use
may be made of water, propylene glycol, a polyethylene
glycol, plant oils, in particular olive oil, injectable
organic esters, for example ethyl oleate, or other
suitable organic solvents. These compositions may also
contain adjuvants, in particular wetting agents,
tonicity agents, emulsifiers, dispersants and
stabilizing agents. The sterilization may be carried
out in several ways, for example by aseptic filtration,
by incorporating sterilizing agents into the
composition, by irradiation or by heating. They may
also be prepared in the form of sterile solid
compositions which can be dissolved at the time of use
in sterile water or any other sterile injectable
medium.
The compositions for rectal administration are
suppositories or rectal capsules which contain, besides
the active product, excipients such as cocoa butter,
semisynthetic glycerides or polyethylene glycols.
The compositions for topical administration may, for
example, be creams, lotions, eye washes, throat sprays,
nasal drops or aerosols.
The doses depend on the desired effect, on the duration
of the treatment and on the route of administration
used; they are generally between 5 mg and 1 000 mg per
day orally for an adult, with single doses ranging from
1 mg to 250 mg of active substance.
In general, the physician will determine the
appropriate dosage in accordance with the age, the
weight and all the other factors specific to the
individual to be treated.

The compounds of formula (I) according to the invention
will be useful as a medicinal product in the treatment
of diseases due to a dysfunction of alpha-7 nicotinic
receptors or responding favorably to a modulation
thereof; in the treatment, prevention, diagnosis and/or
monitoring of the evolution of psychiatric disorders or
diseases or neurological disorders or diseases of the
central nervous system involving an impairment of
cognitive functions or of the processing of sensory
information.
More particularly, the diseases or the disorders
treated concern cognitive abilities and attention
capacity, the ability to concentrate, to learn and/or
to memorize, Alzheimer's disease and related cognitive
disorders, senile dementia, vascular dementia, slight
cognitive impairments, age-related amnesic deficits,
cognitive impairments related to bacterial or viral
infections, attention deficit hyperactivity disorders,
schizophrenia, the treatment of inflammatory syndromes,
ulcerative colitis, Crohn's disease, irritable bowel
syndrome, arthritis, the treatment of acute or chronic
pain, fibromyalgia, the treatment of acute neurone
degeneration subsequent to a trauma, to strokes, to
ischemia or to brain hypoxia, the treatment of chronic
neural degeneration observed during Parkinson's
disease, Huntington's chorea, multisystem atrophy,
progressive supranuclear paralysis or amyotrophic
lateral sclerosis, the treatment of epilepsy, the
treatment of depression, of anxiety, of manic
depressive psychoses, of obsessive/compulsive
disorders, of phobias, of post-traumatic stress
syndromes, of panic attacks, of Tourette's syndrome, of
anorexia and of bulimia, and sleep disorders.
The compounds of formula (I) can also be used for
establishing a decrease in the consumption of addictive
substances, for helping to maintain an abstinence with

respect to said substances or for reducing the symptoms
of withdrawal therefrom.
The compounds of formula (I) can also be used as a
diagnostic agent.
The following examples illustrate compositions
according to the invention:
EXAMPLE A
Gelatin capsules containing a dose of 50 mg of active
product, having the following composition, are prepared
according to the conventional technique:

EXAMPLE B
Tablets containing a dose of 50 mg of active product,
having the following composition, are prepared
according to the conventional technique:


- Mixture of hydroxymethylcellulose, glycerol, titanium
oxide (72-3.5-24.5) qs 1 film-coated tablet with a
final weight of 245 mg
EXAMPLE C
An injectable solution containing 10 mg of active
product, having the following composition, is prepared:


WE CLAIM :
1. A compound of formula (I) in which

A is, if it is present, a (C1-C6) alkyl radical, a (C3-C6)
alkenyl radical, a (C3-C6) alkynyl radical, a (C3-C7)
cycloalkyl radical or a (C5-C7) cycloalkenyl radical; these
radicals are optionally substituted with one or more
substituents chosen from (C1-C5) alkyl, (C2-C5) alkenyl,
(C2-C5) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
arylalkyl, heteroarylalkyl, aryl, heteroaryl and halogen,
R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7)
azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9)
azabicycloalkenyl group; these groups are optionally
substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C5) cycloalkyl and halogen,
A-R1 is such that the nitrogen of Rl and the nitrogen in
the 1-position of the pyrazole are necessarily separated by
at least two carbon atoms,
R3 is an H, halogen, OH, SH, NH2, ORc, SRc, SORa, SO2Ra,
NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra or NHSO2Ra radical,

R4 is an aryl or heteroaryl radical being optionally
substituted with one or more substituents chosen from
halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2, C(S)NH2,
SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb,
S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, 0-C(O)Ra, -O-C(S)Ra,
NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2, NHCONRaRb, NHSO2Ra,
aryl, heteroaryl, (C4-C7) heterocycloalkyl,
polyfluoroalkyl, trifluoromethylsulfanyl, trifluoromethoxy,
linear or branched (C1-C6) alkyl, (C2-C6) alkenyl and
(C2-C6) alkynyl, these substituents being optionally
substituted with one or more alkyl, halogen, OH, methoxy,
R5 is an H, halogen, CF3, CHF2, CH2F, linear or branched
(C1-C6) alkyl or (C3-C7) cycloalkyl radical,
Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,
(C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)
heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl or polyfluoroalkyl,
Rb is, independently of Ra, a hydrogen, linear or branched
(C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl,
(C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl,
heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,
Ra and Rb may form a saturated or unsaturated ring
containing 5, 6 or 7 ring members, which may or may not
have a hetero atom such as 0, S or N, this ring being
optionally substituted with one or more alkyl, halogen
radicals,
Rc is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl,
(C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, (hetero)arylalkyl, (hetero)aryl,
(poly)fluoroalkyl, C(O)R8, C(S)R8 or SO2R8 radical,

R6 and R7 are, independently of one another, a hydrogen,
(C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7)
cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl,
an arylalkyl or heteroarylalkyl,
R6 and R7 may form a saturated or unsaturated ring with 5,
6 or 7 ring members, which may or may not have a hetero
atom such as 0, S or N and which is optionally substituted
with one or more alkyls, halogens,
R8 is an Ra or NRaRb radical,
their racemates, enantiomers and diastereoisomers and their
mixtures, their tautomers and their pharmaceutically
acceptable salts, with the exception of 3-(3-pyridinyl)-1H-
pyrazole-1-butanamine, of 4-(3-pyridinyl)-1H-pyrazole-1-
butanamine and of N-(diethyl)-4-phenyl-1H-pyrazole-1-
ethylamine.
2. A compound of formula (I) as claimed in claim 1, in
which:

A is, if it is present, a (C1-C6) alkyl radical, a (C3-C6)
alkenyl radical, a (C3-C6) alkynyl radical, a (C3-C7)
cycloalkyl radical or a (C5-C7) cycloalkenyl radical; these
radicals are optionally substituted with one or more
substituents chosen from (C1-C5) alkyl, (C2-C5) alkenyl,
(C2-C5) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
arylalkyl, heteroarylalkyl, aryl, heteroaryl and halogen,
R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7)
azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9)

azabicycloalkenyl group; these groups are optionally
substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C5) cycloalkyl and halogen,
A-R1 is such that the nitrogen of Rl and the nitrogen in
the 1-position of the pyrazole are necessarily separated by
at least two carbon atoms,
R3 is an OH, NH2, OMe or H radical,
R4 is an aryl or heteroaryl radical being optionally
substituted with one or more substituents chosen from
halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2, C(S)NH2,
SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb,
S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, O-C(O)Ra, -O-C(S)Ra,
NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2, NHCONRaRb, NHSO2Ra,
aryl, heteroaryl, (C4-C7) heterocycloalkyl,
polyfluoroalkyl, trifluoromethylsulfanyl, trifluoromethoxy,
linear or branched (C1-C6) alkyl, (C2-C6) alkenyl and
(C2-C6) alkynyl, these substituents being optionally
substituted with one or more alkyl, halogen, OH, methoxy,
R5 is a hydrogen or Me radical,
Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,
(C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)
heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl or polyfluoroalkyl,
Rb is, independently of Ra, a hydrogen, linear or branched
(C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl,
(C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl,
heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,
Ra and Rb may form a saturated or unsaturated ring
containing 5, 6 or 7 ring members, which may or may not
have a hetero atom such as 0, S or N, this ring being

optionally substituted with one or more alkyl, halogen
radicals,
Rc is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl,
(C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, (hetero)arylalkyl, (hetero)aryl,
(poly)fluoroalkyl, C(O)R8, C(S)R8 or SO2R8 radical,
R6 and R7 are, independently of one another, a hydrogen,
(C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7)
cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl,
an arylalkyl or heteroarylalkyl,
R6 and R7 may form a saturated or unsaturated ring with 5,
6 or 7 ring members, which may or may not have a hetero
atom such as 0, S or N and which is optionally substituted
with one or more alkyls, halogens,
R8 is an Ra or NRaRb radical,
their racemates, enantiomers and diastereoisomers and their
mixtures, their tautomers and their pharmaceutically
acceptable salts, with the exception of 3-(3-pyridinyl)-1H-
pyrazole-1-butanamine, of 4-(3-pyridinyl)-1H-pyrazole-1-
butanamine and of N-(diethyl)-4-phenyl-1H-pyrazole-1-
ethylamine.
3. A compound of formula (I) as claimed in claim 1, in
which:

A is, if it is present, a (C1-C6) alkyl radical, a (C3-C6)
alkenyl radical, a (C3-C6) alkynyl radical, a (C3-C7)

cycloalkyl radical or a (C5-C7) cycloalkenyl radical; these
radicals are optionally substituted with one or more
substituents chosen from (C1-C5) alkyl, (C2-C5) alkenyl,
(C2-C5) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
arylalkyl, heteroarylalkyl, aryl, heteroaryl and halogen,
R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7)
azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9)
azabicycloalkenyl group; these groups are optionally
substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C5) cycloalkyl and halogen,
A-R1 is such that the nitrogen of Rl and the nitrogen in
the 1-position of the pyrazole are necessarily separated by
at least two carbon atoms,
R3 is an OH, NH2, OMe or H radical,
R4 is an aryl or heteroaryl radical being optionally
substituted with one or more substituents chosen from
halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2, C(S)NH2,
SO2H, SO2NH2/ NHCHO, C(O)Ra, C(O)0Ra, C(O)NRaRb, C(S)NRaRb,
S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, 0-C(O)Ra, -O-C(S)Ra,
NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2, NHCONRaRb, NHSO2Ra,
aryl, heteroaryl, (C4-C7) heterocycloalkyl,
polyfluoroalkyl, trifluoromethylsulfanyl, trifluoromethoxy,
linear or branched (C1-C6) alkyl, (C2-C6) alkenyl and
(C2-C6) alkynyl, these substituents being optionally
substituted with one or more alkyl, halogen, OH, methoxy,
R5 is a hydrogen,
Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,
(C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)
heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl or polyfluoroalkyl,


Rb is, independently of Ra, a hydrogen, linear or branched
(C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl,
(C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl,
heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,
Ra and Rb may form a saturated or unsaturated ring
containing 5, 6 or 7 ring members, which may or may not
have a hetero atom such as 0, S or N, this ring being
optionally substituted with one or more alkyl, halogen
radicals,
Rc is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl,
(C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, (hetero)arylalkyl, (hetero)aryl,
(poly)fluoroalkyl, C(O)R8, C(S)R8 or SO2R8 radical,
R6 and R7 are, independently of one another, a hydrogen,
(C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7)
cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl,
an arylalkyl or heteroarylalkyl,
R6 and R7 may form a saturated or unsaturated ring with 5,
6 or 7 ring members, which may or may not have a hetero
atom such as 0, S or N and which is optionally substituted
with one or more alkyls, halogens,
R8 is an Ra or NRaRb radical,
their racemates, enantiomers and diastereoisomers and their
mixtures, their tautomers and their pharmaceutically
acceptable salts, with the exception of 3-(3-pyridinyl)-1H-
pyrazole-1-butanamine, of 4-(3-pyridinyl)-1H-pyrazole-1-
butanamine and of N-(diethyl)-4-phenyl-1H-pyrazole-1-
ethylamine.
4. The compound as claimed in claim 1, wherein
it is chosen from:


l-[2-(3-Methoxy-4-phenylpyrazol-1-yl)ethyl]piperidine
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-
1-ol
3-(3-Benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-
azabicyclo[2.2.2]octane
3-(3-Methoxy-4-phenylpyrazol-1-ylmethyl)-1-
azabicyclo[2.2.2]octane
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ol
1-(2-Perhydroazepin-1-ylethyl)-4-phenyl-1H-pyrazol-3-ol
1-[2-(2-Methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-
ol
1-[2-(4-Fluoropiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-
ol
1-[2-(3-Methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-
ol
1-[2-(3,6-Dihydro-2H-pyridin-1-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol
1-[2-(7-Azabicyclo[2.2.1]hept-7-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol
1-[2-(2-Azabicyclo[2.2.2]oct-2-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol
1-[2-(2-Azabicyclo[2.2.l]hept-2-yl)ethyl]-4-phenyl-1H-
pyrazol-3-ol
1-[2-Dimethylaminoethyl]-4-phenyl-1H-pyrazol-3-ol


1-[3-Dimethylaminopropyl]-4-phenyl-1H-pyrazol-3-ol
1-[2-((2S,6R)-2,6-Dimethylpiperidin-1-yl)ethyl]-4-phenyl-
1H-pyrazol-3-ol
1-[2-Diethylaminoethyl]-4-phenyl-1H-pyrazol-3-ol
1-(2-Diisopropylaminoethyl)-4-phenyl-1H-pyrazol-3-ol
4-Phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-3-ol
3-(3-Methoxy-4-phenylpyrazol-1-yl)-1-azabicyclo-
[2.2.2]octane
1-[2-(3-Difluoromethoxy-4-phenylpyrazol-1-yl)ethyl]-
piperidine
4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine
4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine
N-[4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-yl]acetamide
N-[4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-yl]methanesulfonamide
1-(2-Dimethylaminopropyl)-4-phenyl-1H-pyrazol-3-ol
1-(l-Methylpiperidin-3-ylmethyl)-4-phenyl-1H-pyrazol-3-ol
5-Methyl-4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol
4-(3-Aminophenyl)-1-(2-dimethylaminoethyl)-1H-pyrazol-3-ol
N-{3-[3-Hydroxy-1-(2-dimethylaminoethyl)-1H-pyrazol-
4-yl]phenyl}acetamide


4-(4-Aminophenyl)-1-(2-dimethylaminoethyl)-1H-pyrazol-3-ol
1-(2-Dimethylaminoethyl)-4-(4' -fluorobiphenyl-3-yl)-1H-
pyrazol-3-ol
4-Biphenyl-3-yl-1-(2-dimethylaminoethyl)-1H-pyrazol-3-ol
1-(2-Dimethylaminoethyl)-4-(4' -fluorobiphenyl-4-yl)-1H-
pyrazol-3-ol
1-(2-Piperidin-1-ylethyl)-4-pyridin-2-yl-1H-pyrazol-3-ol
1-(2-Piperidin-1-ylethyl)-4-pyridin-4-yl-1H-pyrazol-3-ol
4-(4-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-ol
4-(4-Trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-
1H-pyrazol-3-ol
4-Phenyl-1-(2-piperidin-1-ylpropyl)-1H-pyrazol-3-ol
3-(4-Phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octane
4-(5-Chlorothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(3-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-
ol
4-(2-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-
ol
4-(3-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-
ol
4-(4-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-
ol

4-(4-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-
ol
4-(3-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-
ol
1-(2-Piperidin-1-ylethyl)-4-(3-trifluoromethylphenyl)-1H-
pyrazol-3-ol
1-(2-Piperidin-1-ylethyl)-4-pyridin-3-yl-1H-pyrazol-3-ol
4-(4-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-ol
4-(3-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-ol
4-(2-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-ol
4-(2-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-
3-ol
l-(l-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-
pyrazol-3-ol
l-(l-Azabicyclo[2.2.2]oct-3-yl)-4-(3-chlorophenyl)-1H-
pyrazol-3-ol
l-(l-Azabicyclo[2.2.2]oct-3-yl)-4-(3-fluorophenyl)-1H-
pyrazol-3-ol
1-(l-Methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-ol
1-[2-(l-Methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazol-
3-ol


1-(Pyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-ol
1-[(l-Methylpyrrolidin-2-(S)-yl)methyl]-4-phenyl-1H-
pyrazol-3-ol
4-Phenyl-1-pyrrolidin-3-ylmethyl-1H-pyrazol-3-ol
1-((2R)-1-Methylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazol-
3-ol
4-Phenyl-1-(piperidin-3-yl)-1H-pyrazol-3-ol
1-(l-Methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol
1-(l-Methylazepan-3-yl)-4-phenyl-1H-pyrazol-3-ol
4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol
4-(Thiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol
4-(3,4-Dichlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
4-(4-Bromophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol
4-(1H-Indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol
4-(5-Bromothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-
pyrazol-3-ol
2-[1-(2-Piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide
4-(2-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole
4-(1H-Indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole
4-(4-Methylphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-
ol


1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-5-yl)-1H-
pyrazole
(+)-1-(Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-5-yl)-1H-
pyrazole
(-)-1-(Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-5-yl)-1H-
pyrazole
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(5-chlorothiophen-2-yl)-
1H-pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(5-chlorothiophen-2-yl)-
1H-pyrazol-3-ol
1-(1-Azabicyclo[2.2.2]oct-2-ylmethyl)-4-phenyl-1H-pyrazol-
3-ol
3-[4-(3,5-Difluorophenyl)pyrazol-1-yl]-1-
azabicyclo[2.2.2]octane
4-Benzo[b]thiophen-2-yl-1-(2-piperidin-1-ylethyl) -1H-
pyrazol-3-ol
1-(2-Piperidin-1-ylethyl)-4-thiophen-3-yl-1H-pyrazol-3-ol
4-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-
yl]benzamide
3-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-
yl]benzamide
(-)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-
ol
(+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-
ol


(-)-1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-
pyrazol-1-ol
(+)-1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-
pyrazol-1-ol
1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-chlorophenyl) -
1H-pyrazol-3-ol
(-)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-
pyrazol-3-ol
(+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-
pyrazol-3-ol
(-)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4- (4-fluorophenyl)-1H-
pyrazol-3-ol
( + )-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4- (4-fluorophenyl)-1H-
pyrazol-3-ol
3-[4-(4-Chlorophenyl)pyrazol-1-yl]-1-azabicyclo-
[2.2.2]octane
3-[4-(4-Chlorophenyl)pyrazol-1-ylmethyl]-1-
azabicyclo[2.2.2]octane
3-[4-(3-Chloro-4-methoxyphenyl)pyrazol-1-ylmethyl]-1-
azabicyclo[2.2.2]octane
4-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-1H-pyrazol-4-yl]-
2-chlorophenol
4-[1-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-
chlorophenol


(-)-4-[1-(1-Azabicyclo[2 .2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-
chlorophenol
(+)-4-[l-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-
chlorophenol
(+)-1-(l-Azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-
pyrazol-3-ol
(-)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-
pyrazol-3-ol
(+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-
ylamine
(-)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-
ylamine
(+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-4-yl)-1H-
pyrazole
(-)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-4-yl)-1H-
pyrazole,
their racemates, enantiomers and diastereoisomers and their
mixtures, their tautomers and their pharmaceutically
acceptable salts.
5. A process for preparing a compound of formula (I) as
defined in claim 1 and for which R3 is OH from compound
(II)


in which GP is a hydroxyl function-protecting group,
characterized in that the compound (II) is deprotected and
then optionally converted into a pharmaceutically
acceptable salt.
6. A process for preparing a compound of formula (I) as
defined in claim 1 and for which R3 is ORc, H or NH2, by
alkylation of pyrazoles of formula (III)

in which GP is an OH function-protecting group, with a
compound of formula (IV) R1-A-X in which X is Cl, Br, I,
OTs, OMs or OTf, in basic medium in an aprotic solvent, and
the product obtained is optionally deprotected and
optionally converted into a pharmaceutically acceptable
salt.
7. A pharmaceutical composition comprising, in a
pharmaceutically acceptable medium, at least one compound
defined in any one of claims 1 to 4.
8. A compound of formula (I) in which


A is, if it is present, a (C1-C6) alkyl radical, a (C3-C6)
alkenyl radical, a (C3-C6) alkynyl radical, a (C3-C7)
cycloalkyl radical or a (C5-C7) cycloalkenyl radical; these
radicals are optionally substituted with one or more
substituents chosen from (C1-C5) alkyl, (C2-C5) alkenyl,
(C2-C5) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
arylalkyl, heteroarylalkyl, aryl, heteroaryl and halogen,
R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7)
azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9)
azabicycloalkenyl group; these groups are optionally
substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C5) cycloalkyl and halogen,
A-R1 is such that the nitrogen of Rl and the nitrogen in
the 1-position of the pyrazole are necessarily separated by
at least two carbon atoms,
R3 is an H, halogen, OH, SH, NH2, ORc, SRc, SORa, SO2Ra,
NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra or NHSO2Ra radical,
R4 is an aryl or heteroaryl radical being optionally
substituted with one or more substituents chosen from
halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2, C(S)NH2,
SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)ORa, C (O) NRaRb, C(S) NRaRb,
S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, 0-C(O)Ra, -O-C(S)Ra,
NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2, NHCONRaRb, NHSO2Ra,
aryl, heteroaryl, (C4-C7) heterocycloalkyl,
polyfluoroalkyl, trifluoromethylsulfanyl, trifluoromethoxy,
linear or branched (C1-C6) alkyl, (C2-C6) alkenyl and
(C2-C6) alkynyl, these substituents being optionally
substituted with one or more alkyl, halogen, OH, methoxy,


R5 is an H, halogen, CF3, CHF2, CH2F, linear or branched
(C1-C6) alkyl or (C3-C7) cycloalkyl radical,
Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,
(C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)
heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl or polyfluoroalkyl,
Rb is, independently of Ra, a hydrogen, linear or branched
(C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl,
(C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl,
heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,
Ra and Rb may form a saturated or unsaturated ring
containing 5, 6 or 7 ring members, which may or may not
have a hetero atom such as 0, S or N, this ring being
optionally substituted with one or more alkyl, halogen
radicals,
Rc is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl,
(C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, (hetero)arylalkyl, (hetero)aryl,
(poly)fluoroalkyl, C(O)R8, C(S)R8 or SO2R8 radical,
R6 and R7 are, independently of one another, a hydrogen,
(C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7)
cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl,
an arylalkyl or heteroarylalkyl,
R6 and R7 may form a saturated or unsaturated ring with 5,
6 or 7 ring members, which may or may not have a hetero
atom such as 0, S or N and which is optionally substituted
with one or more alkyls, halogens,
R8 is an Ra or NRaRb radical,

with the exception of N-(diethyl)-4-phenyl-1H-pyrazole-1-
ethylamine,
their racemates, enantiomers and diastereoisomers, and
their mixtures, their tautomers and their pharmaceutically
acceptable salts, for preparing a medicinal product.
9. A compound as claimed in claim 8, of formula (I) in
which:

A is, if it is present, a (C1-C6) alkyl radical, a (C3-C6)
alkenyl radical, a (C3-C6) alkynyl radical, a (C3-C7)
cycloalkyl radical or a (C5-C7) cycloalkenyl radical; these
radicals are optionally substituted with one or more
substituents chosen from (C1-C5) alkyl, (C2-C5) alkenyl,
(C2-C5) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
arylalkyl, heteroarylalkyl, aryl, heteroaryl and halogen,
R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7)
azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9)
azabicycloalkenyl group; these groups are optionally
substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C5) cycloalkyl and halogen,
A-R1 is such that the nitrogen of Rl and the nitrogen in
the 1-position of the pyrazole are necessarily separated by
at least two carbon atoms,
R3 is an OH, NH2, OMe or H radical,
R4 is an aryl or heteroaryl radical being optionally
substituted with one or more substituents chosen from


halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2, C(S)NH2,
SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)0Ra, C(O)NRaRb, C(S)NRaRb,
S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, 0-C(O)Ra, -O-C(S)Ra,
NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2, NHCONRaRb, NHSO2Ra,
aryl, heteroaryl, (C4-C7) heterocycloalkyl,
polyfluoroalkyl, trifluoromethylsulfanyl, trifluoromethoxy,
linear or branched (C1-C6) alkyl, (C2-C6) alkenyl and
(C2-C6) alkynyl, these substituents being optionally
substituted with one or more alkyl, halogen, OH, methoxy,
R5 is a hydrogen or Me radical,
Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,
(C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)
heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl or polyfluoroalkyl,
Rb is, independently of Ra, a hydrogen, linear or branched
(C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl,
(C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl,
heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,
Ra and Rb may form a saturated or unsaturated ring
containing 5, 6 or 7 ring members, which may or may not
have a hetero atom such as 0, S or N, this ring being
optionally substituted with one or more alkyl, halogen
radicals,
Re is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl,
(C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
(C4-C7) heterocycloalkyl, (hetero)arylalkyl, (hetero)aryl,
(poly)fluoroalkyl, C(O)R8, C(S)R8 or SO2R8 radical,
R6 and R7 are, independently of one another, a hydrogen,
(C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7)
cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl,
an arylalkyl or heteroarylalkyl,

R6 and R7 may form a saturated or unsaturated ring with 5,
6 or 7 ring members, which may or may not have a hetero
atom such as 0, S or N and which is optionally substituted
with one or more alkyls, halogens,
R8 is an Ra or NRaRb radical,
with the exception of N-(diethyl)-4-phenyl-1H-pyrazole-1-
ethylamine,
their racemates, enantiomers and diastereoisomers and their
mixtures, their tautomers and their pharmaceutically
acceptable salts, for preparing a medicinal product.
10. A compound as claimed in claim 8, of formula (I) in
which:

A is, if it is present, a (C1-C6) alkyl radical, a (C3-C6)
alkenyl radical, a (C3-C6) alkynyl radical, a (C3-C7)
cycloalkyl radical or a (C5-C7) cycloalkenyl radical; these
radicals are optionally substituted with one or more
substituents chosen from (C1-C5) alkyl, (C2-C5) alkenyl,
(C2-C5) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,
arylalkyl, heteroarylalkyl, aryl, heteroaryl and halogen,
R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7)
azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9)
azabicycloalkenyl group; these groups are optionally
substituted with one or more substituents chosen from
(C1-C5) alkyl, (C3-C5) cycloalkyl and halogen,


A-R1 is such that the nitrogen of Rl and the nitrogen in
the 1-position of the pyrazole are necessarily separated by
at least two carbon atoms,
R3 is an OH, NH2, OMe or H radical,
R4 is an aryl or heteroaryl radical being optionally
substituted with one or more substituents chosen from
halogen, CN, NO2, NH2, OH, SH, COOH, CHO, C(O)NH2, C(S)NH2,
SO2H, SO2NH2, NHCHO, C(O)Ra, C(O)0Ra, C(O)NRaRb, C(S)NRaRb,
S(O)Ra, SO2Ra, SO2NRaRb, ORc, SRc, O-C(O)Ra, -O-C(S)Ra,
NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH2, NHCONRaRb, NHSO2Ra,
aryl, heteroaryl, (C4-C7) heterocycloalkyl,
polyfluoroalkyl, trifluoromethylsulfanyl, trifluoromethoxy,
linear or branched (C1-C6) alkyl, (C2-C6) alkenyl and
(C2-C6) alkynyl, these substituents being optionally
substituted with one or more alkyl, halogen, OH, methoxy,
R5 is a hydrogen,
Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,
(C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)
heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl,
heteroaryl or polyfluoroalkyl,
Rb is, independently of Ra, a hydrogen, linear or branched
(C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl,
(C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl,
heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,
Ra and Rb may form a saturated or unsaturated ring
containing 5, 6 or 7 ring members, which may or may not
have a hetero atom such as 0, S or N, this ring being
optionally substituted with one or more alkyl , halogen
radicals,
Rc is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl,
(C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,

(C4-C7) heterocycloalkyl, (hetero)arylalkyl, (hetero)aryl,
(poly)fluoroalkyl, C(O)R8, C(S)R8 or SO2R8 radical,
R6 and R7 are, independently of one another, a hydrogen,
(C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7)
cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl,
an arylalkyl or heteroarylalkyl,
R6 and R7 may form a saturated or unsaturated ring with 5,
6 or 7 ring members, which may or may not have a hetero
atom such as 0, S or N and which is optionally substituted
with one or more alkyls, halogens,
R8 is an Ra or NRaRb radical,
with the exception of N-(diethyl)-4-phenyl-1H-pyrazole-1-
ethylamine,
their racemates, enantiomers and diastereoisomers and their
mixtures, their tautomers and their pharmaceutically
acceptable salts, for preparing a medicinal product.
11. Compound defined as claimed in any one of claims 1 to
4, for preparing a medicinal product for use in the
treatment of diseases due to a dysfunction of a7 nicotinic
receptors or responding favorably to a modulation thereof.
12. Compound defined as claimed in any one of claims 1 to
4, for preparing a medicinal product for use in the
treatment, prevention, diagnosis , monitoring of the
evolution of psychiatric disorders or diseases or
neurological disorders or diseases of the central nervous
system involving an impairment of cognitive functions or of
the processing of sensory information.
13. Compound as claimed in claim 12, wherein
the disease or the disorder concerns cognitive abilities

and attention capacity, and the ability to concentrate, to
learn and/or to memorize.
14. Compound as claimed in claim 12, wherein
the disease is Alzheimer's disease and related cognitive
disorders.
15. Compound as claimed in claim 12, wherein
the disease is schizophrenia.
16. Compound as claimed in any one of claims 1 to 4, for
preparing a medicinal product intended to establish a
decrease in the consumption of addictive substances, for
helping to maintain an abstinence with respect to said
substances or for reducing the symptoms of withdrawal
therefrom, and for its therapeutic application in the
treatment of acute or chronic neuron degeneration.


The invention relates to novel derivatives of general formula (I), wherein A,
if present, is an alkyl radical (C1-C6), an alkenyl radical (C3-C6), an alkynyl radical (C3-C6),
a cycloalkyl radical (C3-C7), a cycloalkenyl radical (C5-C7), R1 is a NR6R7, azacycloalkyl
(C4-C7), azacycloalkenyl (C5-C7) azabicycloalkyl (C5-C9) and azabicycloalkenyl (C5-C9) group;
A-R1 is such that nitrogen of R1 et nitrogen 1 of pyrazole are indispensably separated by at lest
two carbon atoms, R3 is an H, halogen, OH, SH, NH2, ORc, SRc, SORa, SO2Ra, NHCHO,
NRaRb, NHC(O)Ra, NHC(S)Ra and NHSO2Ra radical; R4 is an aryl or heteroaryl radical; R5 is
a H, halogen, CF3, CHF2, CH2F, linear or branched alkyl (C1-C6) and cycloalkyl (C3-C7) radical,
the racemics, enantiomers and diastereoisomers thereof and the mixtures thereof, tautomers thereof
and the pharmaceutically acceptable salts thereof.

Documents:

01208-kolnp-2006 abstract.pdf

01208-kolnp-2006 claims.pdf

01208-kolnp-2006 correspondence others.pdf

01208-kolnp-2006 form-1.pdf

01208-kolnp-2006 form-3.pdf

01208-kolnp-2006 form-5.pdf

01208-kolnp-2006 international publication.pdf

01208-kolnp-2006 international search authority report.pdf

01208-kolnp-2006 pct form.pdf

01208-kolnp-2006-assignment.pdf

01208-kolnp-2006-correspondence others-1.1.pdf

01208-kolnp-2006-correspondence-1.2.pdf

01208-kolnp-2006-description(complete).pdf

01208-kolnp-2006-form-18.pdf

1208-KOLNP-2006-ABSTRACT.pdf

1208-kolnp-2006-assignment 1.1.pdf

1208-KOLNP-2006-CANCELLED DOCOMENT.pdf

1208-KOLNP-2006-CLAIMS.pdf

1208-kolnp-2006-correspondence 1.1.pdf

1208-KOLNP-2006-CORRESPONDENCE.pdf

1208-KOLNP-2006-DESCRIPTION COMPLATE.pdf

1208-kolnp-2006-examination report 1.1.pdf

1208-KOLNP-2006-FORM 1.pdf

1208-kolnp-2006-form 13 1.1.pdf

1208-KOLNP-2006-FORM 13.pdf

1208-kolnp-2006-form 18 1.1.pdf

1208-kolnp-2006-form 3 1.1.pdf

1208-KOLNP-2006-FORM 3.pdf

1208-kolnp-2006-form 5 1.1.pdf

1208-KOLNP-2006-FORM-27.pdf

1208-kolnp-2006-gpa 1.1.pdf

1208-KOLNP-2006-GPA.pdf

1208-kolnp-2006-granted-abstract.pdf

1208-kolnp-2006-granted-claims.pdf

1208-kolnp-2006-granted-description (complete).pdf

1208-kolnp-2006-granted-form 1.pdf

1208-kolnp-2006-granted-form 2.pdf

1208-kolnp-2006-granted-specification.pdf

1208-kolnp-2006-international preliminary examination report 1.1.pdf

1208-kolnp-2006-international publication 1.1.pdf

1208-kolnp-2006-international search report 1.1.pdf

1208-kolnp-2006-others 1.1.pdf

1208-KOLNP-2006-OTHERS.pdf

1208-kolnp-2006-pct request form 1.1.pdf

1208-KOLNP-2006-PETITION UNDER RULE 137.pdf

1208-kolnp-2006-reply to examination report 1.1.pdf

1208-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf

abstract-01208-kolnp-2006.jpg


Patent Number 247495
Indian Patent Application Number 1208/KOLNP/2006
PG Journal Number 15/2011
Publication Date 15-Apr-2011
Grant Date 12-Apr-2011
Date of Filing 09-May-2006
Name of Patentee AVENTIS PHARMA S.A.
Applicant Address 20 AVENUE RAYMOND ARON, 92160 ANTONY
Inventors:
# Inventor's Name Inventor's Address
1 GENEVOIS-BORELLA, ARIELLE 28 AVENUE HOCHE, 94320 THIAIS
2 BOUQUEREL, JEAN 40 RUE DE L'EMANCIPATION, 93700 DRANCY
3 DOERFLINGER, GILLES RESIDENCE LES MILLEPERTUIS, BAT B3, 2 AVENUE DU BERRY, 91940 LES ULIS
4 BOHME, ANDREES 32 RUE VITRUVE, 75020 PARIS
5 TOUYER, GAETAN 7 RUE DU VIEUX MOULIN, F-77500 CHELLES
6 SABUCO, JEAN-FRANCOIS 198 BIS AVENUE DU MAINE, 75014 PARIS
7 TERRIER, CORINNE 98 BIS AVENUE DU COLONEL FABIEN, 93190 LIVRY GARGAN
8 MIGNANI, SERGE 14 AVENUE DE ROBINSON, 92290 CHATENAY-MALABRY
9 EVERS, MICHEL 8 RUE ROBERT SCHUMANN, 94510 LA QUEUE EN BRIE
10 EL-AHMAD, YOUSSEF 11 AVENUE DE VERDUN, 94000 CRETEIL
11 MALLERON, JEAN-LUC 2 ALLEE RENOIR, 91460 MARCOUSSIS
PCT International Classification Number C07D 231/20
PCT International Application Number PCT/FR2004/002968
PCT International Filing date 2004-11-22
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 03 13775 2003-11-25 France