NOVEL THERAPEUTIC USE OF P75 RECEPTOR ANTAGONISTS
The subject of the present invention is the use of p75 receptor antagonists for the
preparation of medicaments for use in the treatment and/or prevention of overactive
bladder and other urinary disorders.
Overactive bladder syndrome (sometimes called an 'irritable' bladder or 'detrusor
instability') is a common condition characterized by repeated and uncontrolled bladder
contractions. Symptoms include urgency, frequency, nocturia and urge incontinence.
Their causes are not fully understood although they are partially due to the defective
behaviour of the detrusor. Bladder training is usually the main treatment, and medication
(including antimuscarinic agents) does generally not alleviate all symptoms.
Urinary disorders may include, but are not limited to, incontinence (inability to
control urine flow), interstitial cystitis (IC), bladder pain syndrome (BPS), benign prostate
hyperplasia (PBH), cancers of the urinary tract; some of them can have serious, even lifethreatening,
complications.
It is therefore highly desirable to provide new medicines for the treatment and/or
prevention of the above disorders.
The compounds according to the present invention have an affinity for the p75
neurotrophin receptor.
Neurotrophins belong to a family of proteins of which the biological effect is in
particularsurvival, development and function of neurons.
The p75 receptor, which is the receptor for all neurotrophins, is a transmembrane
glycoprotein of the tumoral necrosis factor (TNF) receptor family (W.J. Friedman and
L.A. Greene, Exp. Cell. Res., (1999), 253, 131-142). The p75 receptor is expressed in
several cell types, and several biological functions have been attributed to said receptor:
firstly, modulation of the affinity of neurotrophins for receptor tyrosine kinases (trk);
secondly, in the absence of trk, induction of a signal for cell death by apoptosis. Moreover,
the neurotrophin precursors, proneurotrophins, are capable of binding to p75 with a high
affinity, and are considered to be powerful inducers of p75 dependent apoptosis in
neurons and certain cell lines.
The p75 receptor is a key component in the process of cell survival/proliferation or
death, not only in the central nervous system but also in a number of peripheral tissues
like nerves, liver, bladder muscles and prostate. This pleiotropic receptor has multiple and
even opposite functions, which likely depend on the cell and tissue type, as well as on the
physio-pathological status of the organism. It has been observed that mice selectively
over expressing bladder Nerve Growth Factor exhibited: increased bladder wall
innervation, decreased bladder capacity, more frequent micturition, increased non-voiding
bladder contractions; all consistent with an overactive bladder (OAB) phenotype (Girard
BM and al "Neurotrophin/receptor expression in urinary bladder of mice with
overexpression of NGF in urothelium" Am J Physiol Renal Physiol. 300: F345-F355,
(201 1)).
It has also been observed that in humans with obstructed bladders or those with
interstitial cystitis or bladder pain syndrome (IC/BPS), tissue levels of NGF are elevated
compared to healthy controls (Steers WD and Tuttle JB, Nat Rev Urol (2006), vol 3(2),
101-1 10; Liu HZ et al. (2009), BJUI 104, 1476-1481 ) .
p75 receptors and Trks receptors are expressed throughout the rat urinary bladder
and are present in nerve fibers of the detrusor smooth muscle, the suburothelial nerve
plexus, urothelial cells, and nerve fibers associated with the suburothelial bladder
vasculature (Klinger MB and al"p75NTR Expression in Rat Urinary Bladder Sensory
Neurons and Spinal Cord with Cyclophosphamide-lnduced Cystitis" J. Comp. Neurol. 507:
1379-1392, (2008)).
p75 receptors overexpression on detrusor smooth muscle cells altogether with
overexpression of NGF could play a deleterious role on the functionality of detrusor
muscle.
According to a first object, the present invention provides for the use of a p75
receptor antagonist in the preparation of medicaments for use in the treatment and/or
prevention of overactive bladder and other urinary disorders.
In the present patent application the terms "use of a p75 receptor antagonist in the
preparation of medicaments" have to be understood as synonyms of the terms "a p75
receptor antagonist for the preparation of a medicament for use", or "a p75 receptor
antagonist for use", or "a p75 receptor antagonist for use as a medicament"
According to another object of the invention, the present invention provid
use of a p75 receptor antagonist of the following general formula (I):
in which:
- m l represents 0 or 1;
- A represents:
I)
and B ' represents a hydrogen atom
or
A l represents a hydrogen atom and B l represents:
(I)
1
- W l - is a nitrogenous heterocycle chosen from:
- - - e - ¾ -
- 1-3 represents 1, 2 or 3;
- n l represents 1 or 2;
- R 1 l represents a halogen atom, a (CrC 4)alkyl group, a trifluoromethyl radical, a (C
C4)alkoxy group or a trifluoromethoxy radical;
- R2 l represents a hydrogen atom, a halogen atom, a (CrC 4)alkyl group, a
trifluoromethyl radical, a (CrC 4)alkoxy group, a trifluoromethoxy radical, a COOR l group
or a CONH2 group;
- R5 l represents a group of formula:
in which R3 and R4 , located on any one of the available positions, independently
represent a hydrogen atom, a halogen atom, a (CrC 4)alkyl or ( -C4)alkoxy group, a
trifluoromethyl or trifluoromethoxy radical, a cyano, or a COOH, COO(CrC 4)alkyl, CONH2,
CONR6 l R7 l or NHCOR l group;
R l , R6 l and R7 l represent independently of each other a (CrC 6)alkyl group;
in the preparation of medicaments for use in the treatment and/or prevention
overactive bladder.
The compounds of Formula (I) may contain one or more asymmetrical carbon
atoms. They may therefore exist in the form of enantiomers or of diastereoisomers. These
enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures,
are part of the invention.
The compounds of Formula (I) may exist in the form of bases or addition salts with
acids. Such addition salts are part of the invention.
These salts may be prepared with pharmaceutically acceptable acids, but the salts
of other acids that are useful, for example, for purifying or isolating the compounds of
Formula (I) are also part of the invention.
In the context of the compounds of general formula (I):
- the term "a halogen atom" is intended to mean: a fluorine, a chlorine, a bromine
or an iodine;
- the term "an alkyl group" is intended to mean: a linear or branched, saturated
aliphatic group. By way of examples, mention may be made of a C1-C4 alkyl group that
may represent a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;
- the term "a fluoroalkyl group" is intended to mean: an alkyl group of which one or
more of the hydrogen atoms has (have) been substituted with a fluorine atom;
- the term "a perfluoroalkyl group" is intended to mean: an alkyl group of which all
the hydrogen atoms have been substituted with a fluorine atom, for example trifluoroalkyl;
- the term "an alkoxy group" is intended to mean: an -O-alkyl radical where the
alkyl group is as defined above.
These compounds and their method of preparation are described in
WO2009/150388 (US201 1/1441 16), from which the content is included herein by
reference.
According to another object of the invention, the present invention provides for the
use of a p75 receptor antagonist of the following general formula (II):
(II)
in which:
- m ll is Oo ;
- A ll is:
(II)
1
and B is a hydrogen atom
or
A ll is a hydrogen atom and B ll is:
(II)
1
- R 1 and R2 which may be identical or different, are independently a hydrogen or
halogen atom, a (Ci.C4)alkyl, ( -C4)fluoroalkyl, (CrC 2)perfluoroalkyl or (CrC 4)alkoxy
group or a trifluoromethoxy group;
- n ll is 1 or 2;
- R3 ll is a group of formula:
where R4 ll and R5 ll , which may be identical or different, are located on any available
positions and are independently a hydrogen or halogen atom, a hydroxyl, a (CrC 4)alkyl,
(CrC 4)fluoroalkyl, (CrC 2)perfluoroalkyl or (Ci-C4)alkoxy group, a trifluoromethoxy group,
a cyano group, or a COOH, COO(C C4)alkyl, CONH2, CONR6(lll) R7(lll) or NHCOR(lll)
group;
- R ll , R6 ll and R7 ll are independently of each other a (C C6)alkyl group;
in the preparation of medicaments for use in the treatment and/or prevention
overactive bladder.
The compounds of formula (II) may comprise one or more asymmetrical carbon atoms.
They may therefore exist in the form of enantiomers or diastereoisomers. These
enantiomers and diastereoisomers and also mixtures thereof, including racemic mixtures,
form part of the invention.
The compounds of formula (II) may exist in the form of bases or of addition salts with
acids. Such addition salts form part of the invention.
These salts may be prepared with pharmaceutically acceptable acids, but the salts of
other acids that are useful, for example, for purifying or isolating the compounds of
formula (II) also form part of the invention.
In the context of the compounds of general formula (II):
- the term "a halogen atom" is intended to mean: a fluorine, a chlorine, a bromine
or an iodine;
- the term "an alkyl group" is intended to mean: a linear or branched, saturated
aliphatic group. By way of examples, mention may be made of a C C4 alkyl group which
may represent a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;
- the term "a fluoroalkyl group" is intended to mean: an alkyl group of which one
or more hydrogen atoms have been substituted with a fluorine atom;
- the term "a perfluoroalkyl group" is intended to mean: an alkyl group of which all
the hydrogen atoms have been substituted with a fluorine atom;
- the term "an alkoxy group" is intended to mean: an -O-alkyl group where the
alkyl group is as defined above.
These compounds and their method of preparation are described in
WO2009/150387 (US201 1/144122), from which the content is included herein by
reference.
According to another object of the invention, the present invention provides for the
use of a p75 receptor antagonist of the following general formula (III):
Ί which:
A lll represents a group
- n represents 1 or 2;
- mlll represents 0 or 1;
- Y lll represents a carbon, nitrogen, sulphur or oxygen atom or a single or double bond;
- X lll , X lll and 2 represent a carbon, nitrogen, sulphur or oxygen atom, it being
understood that at least one of X lll , X '"' and X 2 lll is other than a carbon atom;
- R lll and R 1 lll , located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a (CrC 4)alkyl group, a (CrC 4)alkoxy group, a
perfluoroalkyi radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(CrC 4)alkyl,
CONR5(lll) R6(lll) or NHCOR5(lll) group;
or R 1 lll represents a group chosen from:
the definition of R ' remaining unchanged;
- R3 lll and R4 lll , located on any one of the available positions, independently represent
hydrogen atom, a halogen atom, a (CrC 4)alkyl group, a (C(CrC 4)-C4)alkoxy group,
perfluoroalkyi radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(CrC4)alkyl,
CONR5 (lll) R6(lll) or NHCOR5 (lll) group;
- W lll - is a nitrogenous heterocycle chosen from:
1-2 represents 1 or 2;
1-3 represents 1, 2 or 3;
R2 lll represents a group of formula
- R7 and R8 located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a (CrC 4))alkyl group, a (CrC 4)alkoxy group, a
trifluoromethyl radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(CrC4)alkyl,
COO(Ci-C4)cycloalkyl, SO(C C4)alkyl, S02(C C4)alkyl, CONH2, CONR5 (lll) R6(lll) or
NHCOR5 (lll) group;
or one of R7 lll and R8 lll represents a heterocycle chosen from:
N' N' N' Z(iii) Z(iii)
Z ' represents an oxygen or sulphur atom;
R5 lll and R6 lll represent a hydrogen or a C1-C6 alkyl group;
in the preparation of medicaments for use in the treatment and/or prevention
overactive bladder.
The compounds of formula (III) may comprise one or more asymmetrical carbon
atoms. They may therefore exist in the form of enantiomers or diastereoisomers. These
enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures,
form part of the invention.
The compounds of formula (III) may exist in the form of bases or of addition salts
with acids. Such addition salts form part of the invention.
These salts may be prepared with pharmaceutically acceptable acids, but the salts
of other acids that are useful, for example, for purifying or isolating the compounds of
formula (III) also form part of the invention.
In the context of the compounds of general formula (III):
- the term "a halogen atom" is intended to mean: a fluorine, a chlorine, a bromine
or an iodine;
- the term "an alkyl group" is intended to mean: a linear, branched or cyclic,
saturated aliphatic group. By way of examples, mention may be made of a C1-C4 alkyl
group which may represent a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,
cyclopropyl or cyclobutyl;
- the term "a fluoroalkyl group" is intended to mean: an alkyl group of which one
or more hydrogen atoms have been substituted with a fluorine atom;
- the term "a perfluoroalkyl group" is intended to mean: an alkyl group of which all
the hydrogen atoms have been substituted with a fluorine atom, for example a
trifluoroalkyl group such as trifluoromethyl;
- the term "an alkoxy group" is intended to mean: an -O-alkyl radical where the
alkyl group is as defined above;
the term "a perfluoroalkoxy group" is intended to mean: an alkoxy group of
which all the hydrogen atoms have been substituted with a fluorine atom, for example a
trifluoroalkoxy group such as trifluoromethoxy;
the term "a cycloalkyl group" is intended to mean: a cyclic alkyl group. By way
of examples, mention may be made of cyclopropyl, methylcyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, etc., groups.
- the term "a halogen atom" is intended to mean: a fluorine, a chlorine, a bromine.
These compounds and their method of preparation are described
WO201 1/080444 (US2012/245149), from which the content is included herein
reference.
According to another object of the invention, the present invention provides for
use of a p75 receptor antagonist of the following general formula (IV):
(IV)
in which:
- n represents 1 or 2;
- m IV represents 0 or 1;
- A IV represents a fused heterocyclic group of formula (Y IV )
(IV)
00
represents a hydrogen atom;
or
A represents a hydrogen atom; and
B IV represents a fused heterocyclic group of formula (Y
(IV)
00
The fused heterocycle of formula Y IV may be attached to the rest of the molecule via any
of the available carbon atoms, and in which:
- U IV completes:
- either an aromatic or saturated 6-atom nucleus, containing one or two nitrogen
atoms, the nucleus possibly being substituted with one or two halogen atoms, one or two
(C1-C4)alkyl or (C1-C4)alkoxy groups, or one or two perfluoroalkyi radicals;
- or an aromatic or saturated 5-atom nucleus, containing a nitrogen, oxygen or
sulfur atom, the nucleus possibly being substituted with one or two (C1-C4)alkyl groups;
- X IV and X 1 IV represent independently of each other CH or N;
- R IV and R 1 IV located on any of the available positions, independently represent a
hydrogen atom, a halogen atom, a (CrC 4)alkyl group, (CrC 4)alkoxy, a perfluoroalkyi or
trifluoromethoxy radical, a cyano or a COOH, COO(C C4)alkyl, CONR3 IV R4 IV or
NHCOR3 IV group;
-W IV - is a nitrogenous heterocycle chosen from:
- 1-2 represents 1 or 2;
- 1-3 represents 1, 2 or 3;
- R2 IV represents a group of formula:
- in which R5 ' and R6 located on any of the available positions, independently
represent a hydrogen atom, a halogen atom, a (CrC 4)alkyl or ( -C4)alkoxy group, a
trifluoromethyl or trifluoromethoxy radical, a cyano or a group COOH, COO(CrC 4)alkyl,
COO(Ci-C4)cycloalkyl, SO(C C4)alkyl, S02(C C4)alkyl, CONR3 IV R4 IV , NR3 IV R4 IV
or NHCOR3 IV ;
or one of the groups R5 IV and R6(IIV
) may also represent a heterocycle chosen from:
- Z IV represents an oxygen or sulfur atom;
- R3 IV and R4 IV represent a hydrogen or a CrC 6 alkyl group;
in the preparation of medicaments for use in the treatment and/or prevention
overactive bladder.
The compounds of formula (IV) may comprise one or more asymmetric carbon atoms.
They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers
and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of
the invention.
The compounds of formula (IV) may exist in the form of bases or of acid-addition salts.
Such addition salts form part of the invention.
These salts may be prepared with pharmaceutically acceptable acids, but the salts of
other acids that are useful, for example, for purifying or isolating the compounds of
formula (IV) also form part of the invention.
In the context of of the compounds of general formula (IV), the following definitions apply:
- a halogen atom: a fluorine, a chlorine, a bromine or an iodine;
- an alkyl group: a saturated, linear, branched or cyclic aliphatic group. Examples that may
be mentioned include a group (C1-C4)alkyl which may represent a methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl or cyclobutyl;
- a fluoroalkyl group: an alkyl group in which one or more hydrogen atoms have been
replaced with a fluorine atom;
- a perfluoroalkyl group: an alkyl group in which all the hydrogen atoms have been
replaced with a fluorine atom, for example trifluoroalkyl;
- an alkoxy group: a radical -O-alkyl in which the alkyl group is as defined previously;
- a perfluoroalkoxy group: an alkoxy group in which all the hydrogen atoms have been
replaced with a fluorine atom, for example trifluoroalkoxy;
- a cycloalkyl group: a cyclic alkyl group. Examples that may be mentioned include
cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., groups.
These compounds and their method of preparation are described in
WO201 1/080445 (US2012/245150), from which the content is included herein by
reference.
According to another object of the invention, the present invention provides for the
use of a p75 receptor antagonist selected from:
- compound n°1 : 1-[4-(4-chloro-3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-
[8-(5-fluoro-pyrimidin-2-yl)-3,8-diaza-bicyclo[3.2.1]oct-3-yl]-ethanone ;
- compound n°2: 6-{(3S,5R)-3,5-Dimethyl-4-[2-oxo-2-(2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1 -yl}nicotinic acid hydrochloride;
- compound n°3: 6-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinic acid;
compound n°4: 1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-(8-pyridin-
3-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;
the above compounds can also exist in the form of a base or of an addition salt with an
acid;
in the preparation of medicaments for use in the treatment and/or prevention
overactive bladder.
These compounds and their mode of preparation are respectively described as
compound n°1 1 in WO2009/150388 for compound n°1 , as compounds n°21 and n°28 in
WO201 1/080444 ((US2012/245149)) for compounds n°2 and n°4 and as compound n°57
in WO201 1/080445 (US2012/245150) for compound n°3, from which the content is
included herein by reference.
The following table describes the structure of these compounds.
Said p75 receptor antagonists above, and the pharmaceutically acceptable salts
thereof, may be used at daily doses of 0.1 to 200 mg per kilo of body weight of the
mammal to be treated, preferably at daily doses of from 0.5 to 100 mg/kg. In humans, the
dose may vary preferably from 0.5 mg to 50 mg per day, in particular from 1 to 30 mg,
depending on the age of the individual to be treated, the type of treatment, prophylactic or
curative, and the seriousness of the disorder. Said p75 receptor antagonists are generally
administered as a dosage unit of 0.5 to 50 mg, preferably of 1 to 30 mg, of active principle,
one to five times a day. Preferable unit dosage forms comprise 1 or 30 mg of p75 receptor
antagonists.
Said dosage units are preferably formulated in pharmaceutical compositions in
which the active principle is mixed with a pharmaceutical excipient.
In the pharmaceutical compositions of the present invention, use can me made for
oral, sublingual, subcutaneous, intramuscular, intravenous, topical, transdermal or rectal
administration.
Said p75 receptor antagonists, and the pharmaceutically acceptable salts thereof,
may be administered in unit administration forms, mixed with conventional pharmaceutical
supports, to animals and humans for treating the abovementioned disorders. The unit
administration forms which are suitable comprise oral forms such as tablets, gel capsules,
powders, granules and oral solutions or suspensions, sublingual and buccal
administration forms, subcutaneous, intramuscular or intravenous administration forms,
local administration forms and rectal administration forms.
When a solid composition in the form of tablets is prepared, the main active
ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose,
magnesium stearate, talc, gum arabic or the like. The tablets may be coated with sucrose
or other suitable materials, or they may be treated such that they have sustained or
delayed activity and that they release, in a continuous manner, a predetermined amount
of active principle. Usual excipients include lactose monohydrate, microcrystalline
cellulose, povidone, sodium carboxymethylstarch, magnesium stearate, ethylcellulose,
hypromellose, macrogol 400, titane dioxide.
A preparation of gel capsules is obtained by mixing the active ingredient with a
diluent and pouring the mixture obtained into soft or hard gel capsules.
A preparation in the form of a syrup or elixir may contain the active ingredient
together with a sweetener, preferably a calorie-free sweetener, methylparaben and
propylparaben as antiseptics, and also a flavour enhancer and a suitable colorant.
The water-dispersible powders or granules may contain the active ingredient mixed
with dispersing agents or wetting agents, or suspending agents, such as
polyvinylpyrrolidone, and also with sweeteners or flavour correctors.
For local administration, the active principle is mixed into an excipient for preparing
creams or ointments, or it is dissolved in a vehicle for intraocular administration, for
example in the form of an eyewash.
For rectal administration, use is made of suppositories prepared with binders which
melt at rectal temperature, for example cocoa butter or polyethylene glycols.
For parenteral administration, aqueous suspensions, saline solutions or injectable
sterile solutions which contain pharmacologically compatible dispersion agents and/or
wetting agents, for example propylene glycol or butylene glycol, are used.
The active principle may also be formulated in the form of microcapsules, optionally with
one or more supports or additives.
According to another object, the present invention provides a method of treating
and/or preventing overactive bladder or other urinary disorders in a patient which
comprises administering to a patient in need of such treatment or prevention a
therapeutically effective amount of a p75 receptor antagonist. In one aspect, the p75
receptor antagonist is selected from a compound of general formula (I), a compound of
general formula (II), a compound of general formula (III), and a compound of the following
general formula (IV). In another aspect, the p75 receptor antagonist is selected from the
group consisting of compound n°1 : 1-[4-(4-chloro-3-trifluoromethyl-phenyl)-3,6-dihydro-
2H-pyridin-1-yl]-2-[8-(5-fluoro-pyrimidin-2-yl)-3,8-diaza-bicyclo[3.2.1]oct-3-yl]-ethanone;
compound n°2: 6-{(3S,5R)-3,5-Dimethyl-4-[2-oxo-2-(2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1 -yl}nicotinic acid hydrochloride;
compound n°3: 6-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-
oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinic acid; and compound n°4: 1-(2-phenyl-
2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-(8-pyridin-3-yl-3,8-diazabicyclo[3.2.1]oct-3-
yl)ethanone; the above compounds can also exist in the form of a base or of an addition
salt with an acid.
As used herein, the term "therapeutically effective amount" is meant to describe an
amount of a compound, composition, medicament or active ingredient effective in
producing the desired therapeutic effect.
The following examples further illustrate the present invention.
EXAMPLES
Brief description of the drawings
Figure 1 is a cystometrogram (CMG) from a rat during the light phase in response to
continuously-infused saline, in normal filling-voiding micturition cycle.
Figure 2 shows the effect of the compounds on intercontraction intervals (ICI) in SHR
male rats, characterized by overactive bladder (OAB).
Figure 3 represents the positive activity of the compounds according to the invention on
bladder capacity of SHR male rats.
Figure 4 shows the dose response activity (3, 10, 30 mg/kg po) of compound 2 on
intercontraction intervals in SHR male rats.
Figure 5 represents the dose dependent activity of compound n°2 on bladder capacity in
SHR male rats.
Figure 6 shows the effect of a one-week treatment with compound n°2 on intercontraction
intervals (ICI) in SHR male rats.
Figure 7 shows the effect of a one-week treatment with compound n°2 on bladder
capacity in SHR male rats.
General methods
Animal preparation
Male adult SHR/N lco rats (250g; Charles River Italy), were housed 7 days prior to the
surgery with free access to standard chow and water. Animals were used in accordance
with sanofi international ethical code and the international principles governing the care
and treatment of laboratory animals, (E.E.E Council Directive 86/609, DJL358, 1 Cec. 12,
1987) in a fully accredited AAALAC facility.
All efforts were made to minimize the potential for animal pain, stress, or distress.
A lower midline abdominal incision was performed under general anesthesia with 2-3%
isoflurane using aseptic techniques. Their body temperature was maintained at 37° C
using a homeothermic blanket. Polyethylene tubing was inserted into the dome of the
bladder and secured in place with a 6-0 nylon purse-string suture. The distal end of the
tubing was sealed, tunneled subcutaneously, and externalized at the back of the neck, out
of the animal's reach. At the moment of the surgery animals were 16 weeks old.
Cystometry
After one week from surgery, animals were placed in a Small Animal Cystometry Lab
Station (MED Associates, St. Albans, Vermont) for urodynamic measurements. Prior to
the start of recording the bladder was emptied and the catheter was connected via a Ttube
to a pressure transducer and microinjection pump. Isotonic saline (0.9% NaCI at
room temperature) was infused into the bladder at a rate of 10 ml per hour. An analytical
balance beneath the wire-bottomed animal cage measured the amount of urine voided
during continuous cystometry. A single cystometrogram is defined as the simultaneous
recording of intravesical pressure, infused volume and voided volume during a single
filling-voiding cycle. At least 4 reproducible micturition cycles are recorded (basal period)
after the initial stabilization period of 25 to 30 minutes, using MED-CMG software
(Catamount Research &Development Company).
Then, vehicle or compounds were administered orally at 2 ml/kg.
Due to kinetic profile of compounds, urodynamic assessment was performed 1h after
treatment and at least 4 reproducible micturition cycles were recorded.
Experiments were performed at similar times of day to avoid the possible impact of
circadian rhythm variations (Herrera and al "Diurnal variation in Urodynamics of rat." PLoS
ONE 5(8) (2010)). At the end of experiments, animals were sacrificed with an overdose of
pentobarbital.
Data analysis
The cystometrograms are analyzed using a specific software, SOF-552 cystometry data
analysis.
The following endpoints have been considered (Figure 1):
1. Intercontaction intervals (sec) ( I I) - Time between micturition events (micturition
interval)
2. Threshold pressure (mmHg) (TP) - Bladder pressure immediately prior to
micturition
3. Maximum bladder pressure (mmHg) (Max P) -Highest bladder pressure associated
with voiding
4. Minimum bladder pressure (mmHg) (Min P) - Lowest bladder pressure during
bladder filling
5. Infused volume (m I) (Inf. Vol) -Volume of saline infused during the micturition cycle
6. Average bladder pressure (mmHg) (Aver P) - Average bladder pressure during
bladder filling
Exclusion Criteria
Rats were removed from study, before any treatment when adverse events occurred that
included: a reduction in body weight post-surgery, lethargy superior or equal to 20%, pain,
or distress not relieved by sanofi's approved regimen of postoperative analgesics or
hematuria.
Animals with atypical micturition pattern are excluded from the study.
Expression of data and statistical analysis
In order to limit the impact of inter-group or intra-group variability, all data were expressed
as % of control period (100%), as mean ± standard error of mean (SEM) and were
averaged per group of treatment. A one way analysis of variance (ANOVA), followed by
Newman-Keuls' test or Dunnett's test, were used. A probability value of p<0.05 was
regarded as significant.
EXAMPLE 1: Effects of an acute treatment with p75 antagonists on urodynamic
parameters in SHR rats characterized by spontaneous overactive bladder (OAB).
Drugs
Vehicle: 0.5% Polysorbate 80 (PS80) solution in buffered methylcellulose (MC 0.6%)
Compound n°1 at 10 mg/kg: suspension (0.5% PS80 plus MC 0.6%)
Compound n°2 at 3, 10, 30 mg/kg: suspension (0.5% PS80 plus MC 0.6%)
Compound n°3 at 10 mg/kg: suspension (0.5% PS80 plus MC 0.6%)
Compound n°4 at 10 mg/kg: suspension (0.5% PS80 plus MC 0.6%)
Experimental design:
In order to investigate the role of compounds according to the invention in the micturition
pathway, 5 groups of 4-12 rats are used:
Group 1, Vehicle per os (po) (n=10)
Group 2, Compound n°1 at 10 mg/kg po (n=12)
Group 3, Compound n°2 at 10 mg/kg po (n=6)
Group 4, Compound n°3 at 10 mg/kg po (n=4)
Group 5, Compound n°4 at 10 mg/kg po (n=5)
In order to perform a dose response of Compound n°2 (3-10-30 mg/kg), 4 groups of 6-9
rats are used:
Group 1, Vehicle po (n=8)
Group 2, Compound n°2 at 3 mg/kg po (n=7)
Group 3, Compound n°2 at 10 mg/kg po (n=6)
Group 4, Compound n°2 at 30 mg/kg po (n=9)
1. RESULTS
In order to limit the impact of inter-group or intra-group variability that existed; the data
have been expressed as percentage of control values.
1. The compounds at 10 mg/kg po increased the ICI (intercontraction intervals) and
the bladder capacity (infused volume)
For ICI (Figure 2)
Vehicle 111.7 ± 10.3 %, compound n°1 , 195.5± 15.4 %, compound n°2, 10 mg/kg po
199.7 ± 28.5%, compound n°3, 10 mg/kg po 167.2 ± 20.3%, compound n°4, 10
mg/kg po 186.3 ± 26.9%
For Infused volume (Figure 3)
Vehicle 111.7 ± 10.3 %, compound n°1 , 194.9± 15.3 %, compound n°2, 10 mg/kg po
198.9 ± 28.3%, compound n°3, 10 mg/kg po 167.14 ± 20%, compound n°4, 10 mg/kg
po 186.2 ± 26.9%
2. The compounds at 10 mg/kg po increased the ICI (intercontraction intervals) and
the bladder capacity (infused volume) dose dependency
For ICI (Figure 4)
Vehicle 114.3 ± 12.01 %, compound n°2, 3 mg/kg po 160.9 ± 2 1.8%, compound n°2,
10 mg/kg po 199.7 ± 28.5%, compound n°2, 30 mg/kg po 210.5 ± 24.7%
For Infused volume (Figure 5)
Vehicle 114.3 ± 12 %, compound n°2, 3 mg/kg po 160.8 ± 2 1.7%, compound n°2, 10
mg/kg po 198.9 ± 28.3%, compound n°2, 30 mg/kg po 209.9 ± 24.5%.
2. CONCLUSION
The compounds increased the ICI and the bladder capacity in this pathophysiological
model. The compounds had no effect on micturition pressure parameters suggesting a
specific response. These compounds can thus be useful for the treatment and/or
prevention of overactive bladder.
EXAMPLE 2 : Effects of one-week chronic treatment with a p75 antagonist on
urodynamic parameters in SHR rats characterized by spontaneous overactive
bladder (OAB).
Drug:
Compound n°2 at 10 mg/kg: suspension (0.5% PS80 plus MC 0.6%)
The treatment started at least 5 days after surgery, and lasted 7 days. The cystometry test
was performed 24 h after the end of the last treatment.
Experimental design:
2 groups of 14-1 5 rats were constituted:
• Control rats vehicle treated vehicle 7 days
• Treated rats 7 days with compound n°2 at 10 mg/kg/2ml po
For avoiding numerosity problems linked to loss of intrabladder-catheter, 30% animals
more were used in this experiment.
1. RESULTS
In order to limit the impact of inter-group or intra-group variability that existed; the data
have been expressed as percentage of control values.
For ICI (Figure 6) Vehicle 122.5 ±10.15 %, compound n°2, 173.8 ± 2 1.1%,
For Infused volume (Figure 7) Vehicle 339.90 ± 28.07 %, compound n°2 173.7 ± 2 1. 1
%
2. CONCLUSION
The chronic treatment (one week) with a p75 antagonist, affects the micturition reflex in
SHR rats, characterized by DO-OAB. The compound n°2 increased the ICI and the
bladder capacity in this pathophysiological model. The compound had no effect on
micturition pressure parameters suggesting a specific response. This compound can thus
be useful for the treatment and/or prevention of overactive bladder.
Pharmaceutical composition according to the invention
As a representative example, a unitary dosage form of a compound of the invention
in the form of a tablet may comprise the following constituents:
p75 receptor antagonist 5,0 mg
Lactose 122,0 mg
Microcristalline cellulose 36,0 mg
Sodium carboxymethylstarch 7,0 mg
Polyvidone 9 mg
Magnesium stearate 1,0 mg
CLAIMS
1. A p75 receptor antagonist for the preparation of a medicament for use in the
treatment and/or prevention of overactive bladder.
2. A p75 receptor antagonist according to claim 1 selected from:
a) Compound of general formula (I):
in which:
- m l represents 0 or 1;
- A l represents:
I)
and B l represents a hydrogen atom
or
A l represents a hydrogen atom and B l represents:
(I)
1
- W l - is a nitro enous heterocycle chosen from:
- 1-3 represents 1, 2 or 3;
- n l represents 1 or 2;
- R 1 l represents a halogen atom, a (CrC4)alkyl group, a trifluoromethyl radical, a (C
C4)alkoxy group or a trifluoromethoxy radical;
- R2 l represents a hydrogen atom, a halogen atom, a (CrC4)alkyl group, a
trifluoromethyl radical, a (CrC4)alkoxy group, a trifluoromethoxy radical, a COOR l group
or a CONH2 group;
- R5 l represents a group of formula:
in which R3 and R4 , located on any one of the available positions, independently
represent a hydrogen atom, a halogen atom, a (CrC4)alkyl or ( -C4)alkoxy group, a
trifluoromethyl or trifluoromethoxy radical, a cyano, or a COOH, COO(CrC4)alkyl, CONH2,
CONR6 l R7 l or NHCOR l group;
R l , R6 l and R7 l represent independently of each other a (CrC6)alkyl group;
in the form of bases or of addition salts with acids;
b) Compound of general formula (II):
(II)
in which:
- m ll is Oo ;
- A ll is:
(II)
1
and B ll is a hydrogen atom
or
A ll is a hydrogen atom and B ll is:
- R 1 and R2 which may be identical or different, are independently a hydrogen or
halogen atom, a C 1-C4 alkyl, C 1-C4 fluoroalkyi, CrC 2 perfluoroalkyi or C 1-C4 alkoxy group
or a trifluoromethoxy group;
- n ll is 1 or 2;
- R3 ll is a group of formula:
where R4 and R5 which may be identical or different, are located on any available
positions and are independently a hydrogen or halogen atom, a hydroxyl, a Ci-C4 alkyl,
C 1-C4 fluoroalkyi, CrC 2 perfluoroalkyi or C 1-C4 alkoxy group, a trifluoromethoxy group, a
cyano group, or a COOH, COOalkyl, CONH2, CONR6(lll) R7(lll) or NHCOR(lll) group;
- R ll , R6 ll and R7 ll are a C C6 alkyl group;
in the form of bases or of addition salts with acids;
c) Compound of general formula (III):
(III)
in which:
- A lll represents a group:
n represents 1 or 2;
m lll represents 0 or 1;
- Y lll represents a carbon, nitrogen, sulphur or oxygen atom or a single or double bond;
- X(lll) , X ( ) and X2
m represent a carbon, nitrogen, sulphur or oxygen atom, it being
understood that at least one of X(lll) , Xi(lll) and X 2(lll) is other than a carbon atom;
- R lll and R 1 lll , located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a (CrC 4)alkyl group, a (CrC 4)alkoxy group, a
perfluoroalkyi radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(CrC 4)alkyl,
CONR5(lll) R6 lll or NHCOR5( ll group;
or R 1 lll represents a group chosen from:
the definition of R ' remaining unchanged;
- R3(lll) and R4 lll , located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a ( -C4)alkyl group, a (C(CrC 4)-C4)alkoxy group, a
perfluoroalkyi radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(CrC 4)alkyl,
CONR5(lll) R6(lll) or NHCOR5(lll) group;
- W(lll) - is a nitrogenous heterocycle chosen from:
1-2 represents 1 or 2;
1-3 represents 1, 2 or 3;
R2 lll represents a group of formula:
- R7 and R8 located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a (CrC4))alkyl group, a (CrC4)alkoxy group, a
trifluoromethyl radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(CrC4)alkyl,
COO(Ci-C4)cycloalkyl, SO(C C4)alkyl, S02 (C C4)alkyl, CONH2, CON R5(lll) R6(lll) or
NHCOR5 (lll) group;
or one of R7 lll and R8 lll represents a heterocycle chosen from:
N' N' N' Z(iii) Z (iii)
Z ' represents an oxygen or sulphur atom;
R5 lll and R6 lll represent a hydrogen or a C 1-C6 alkyl group;
in the form of bases or of addition salts with acids
d) Compound of general formula (IV):
(IV)
in which :
- n IV represents 1 or 2 ;
- m IV represents 0 or 1;
- A IV represents a fused heterocyclic group of formula (Y IV )
and B represents a hydrogen atom;
or
A IV represents a hydrogen atom; and
B IV represents a fused heterocyclic group of formula (Y IV )
The fused heterocycle of formula Y IV may be attached to the rest of the molecule via any
of the available carbon atoms, and in which:
- U IV completes:
- either an aromatic or saturated 6-atom nucleus, containing one or two nitrogen
atoms, the nucleus possibly being substituted with one or two halogen atoms, one or two
(C1 -C4)alkyl or (C1 -C4)alkoxy groups, or one or two perfluoroalkyi radicals;
- or an aromatic or saturated 5-atom nucleus, containing a nitrogen, oxygen or
sulfur atom, the nucleus possibly being substituted with one or two (C1-C4)alkyl groups;
- X IV and X 1 IV represent independently of each other CH or N;
- R IV and R 1 IV located on any of the available positions, independently represent a
hydrogen atom, a halogen atom, a (CrC 4)alkyl group, (CrC 4)alkoxy, a perfluoroalkyi or
trifluoromethoxy radical, a cyano or a COOH, COO(C C4)alkyl, CONR3 IV R4 IV or
NHCOR3 IV group;
-W IV - is a nitrogenous heterocycle chosen from:
- 1-2 represents 1 or 2;
- 1-3 represents 1, 2 or 3;
- R2 IV represents a group of formula:
in which R5 ' and R6 located on any of the available positions, independently
represent a hydrogen atom, a halogen atom, a (CrC 4)alkyl or ( -C4)alkoxy group, a
trifluoromethyl or trifluoromethoxy radical, a cyano or a group COOH, COO(CrC4)alkyl,
COO(Ci-C4)cycloalkyl, SO(C C4)alkyl, S02(C C4)alkyl, CONR3 IV R4 IV , NR3 IV R4 IV
or NHCOR3 IV ;
or one of the groups R5 ' and R6((IIV
') may also represent a heterocycle chosen from:
- Z IV represents an oxygen or sulfur atom;
- R3 IV and R4 IV represent a hydrogen or a CrC 6 alkyl group,
in the form of bases or of addition salts with acids.
3. A p75 receptor antagonist according to claim 1 or 2 selected from:
compound n°1 : 1-[4-(4-chloro-3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-
yl]-2-[8-(5-fluoro-pyrimidin-2-yl)-3,8-diaza-bicyclo[3.2.1]oct-3-yl]-ethanone ;
- compound n°2: 6-{(3S,5R)-3 5-Dimethyl-4-[2-oxo-2-(2-phenyl-2 4 6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid
hydrochloride;
- compound n°3: 6-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinic acid;
compound n°4: 1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-(8-
pyridin-3-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;
in the form of a base or of an addition salt with an acid.
4 . Use of a p75 receptor antagonist in the preparation of medicaments for use in the
treatment and/or prevention of overactive bladder.
5. Use according to claim 4, wherein said p75 receptor antagonist is selected from:
a) Compound of general formula (I):
Ί which:
m l represents 0 or 1;
A l represents:
I)
and B represents a hydrogen atom
or
A l represents a hydrogen atom and B l represents:
(I)
a nitro enous heterocycle chosen from
- 1-3 represents 1, 2 or 3;
- n l represents 1 or 2;
- R 1 l represents a halogen atom, a (CrC4)alkyl group, a trifluoromethyl radical, a (C
C4)alkoxy group or a trifluoromethoxy radical;
- R2 l represents a hydrogen atom, a halogen atom, a (CrC4)alkyl group, a
trifluoromethyl radical, a (CrC4)alkoxy group, a trifluoromethoxy radical, a COOR l group
or a CONH2 group;
- R5 l represents a group of formula:
in which R3 and R4 , located on any one of the available positions, independently
represent a hydrogen atom, a halogen atom, a (CrC4)alkyl or ( -C4)alkoxy group, a
trifluoromethyl or trifluoromethoxy radical, a cyano, or a COOH, COO(CrC 4)alkyl, CONH2,
CONR6 l R7 l or NHCOR l group;
R l , R6 l and R7 l represent independently of each other a (CrC6)alkyl group;
in the form of bases or of addition salts with acids
b) Compound of general formula (II):
( )
in which:
- m ll is Oor l ;
- A ll is:
(II)
1
and B is a hydrogen atom
or
A ll is a hydrogen atom and B ll is:
(II)
1
- R 1 and R2 which may be identical or different, are independently a hydrogen or
halogen atom, a (C1-C4 )alkyl, (C1-C4) fluoroalkyi, (CrC 2 ) perfluoroalkyi or (CrC 4 ) alkoxy
group or a trifluoromethoxy group;
- n ll is 1 or 2;
- R3 ll is a group of formula:
where R4 ll and R5 ll , which may be identical or different, are located on any available
positions and are independently a hydrogen or halogen atom, a hydroxyl, a (Ci-C 4 ) alkyl,
(C1-C4) fluoroalkyi, (CrC 2 ) perfluoroalkyi or (C1-C4) alkoxy group, a trifluoromethoxy group,
a cyano group, or a COOH, COO(C C4)alkyl, CONH2, CONR6(lll) R7(lll) or NHCOR(lll)
group;
- R ll , R6 ll and R7 ll are independently of each other a (C C6) alkyl group;
in the form of bases or of addition salts with acids;
c) Compound of general formula (III):
- n( ' represents 1 or 2;
- m lll represents 0 or 1;
- Y lll represents a carbon, nitrogen, sulphur or oxygen atom or a single or double bond;
- X lll , X '"' and X2
m represent a carbon, nitrogen, sulphur or oxygen atom, it being
understood that at least one of X(lll) , X (lll) and X 2(lll) is other than a carbon atom;
- R lll and R 1 lll , located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a (CrC 4)alkyl group, a (CrC 4)alkoxy group, a
perfluoroalkyi radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(CrC 4)alkyl,
CONR5(lll) R6(lll) or NHCOR5(lll) group;
or R 1 lll represents a group chosen from:
the definition of R ' remaining unchanged;
- R3 lll and R4 lll , located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a (CrC 4)alkyl group, a (C(CrC 4)-C4)alkoxy group, a
perfluoroalkyi radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(CrC4)alkyl,
CONR5 (lll) R6(lll) or NHCOR5 (lll) group;
- W lll - is a nitrogenous heterocycle chosen from:
1-2 represents 1 or 2;
1-3 represents 1, 2 or 3;
R2 lll represents a group of formula
- R7 and R8 located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a (CrC 4))alkyl group, a (CrC 4)alkoxy group, a
trifluoromethyl radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(CrC4)alkyl,
COO(Ci-C4)cycloalkyl, SO(C C4)alkyl, S02(C C4)alkyl, CONH2, CONR5(lll) R6(lll) or
NHCOR5(lll) group;
or one of R7 lll and R8 lll represents a heterocycle chosen from:
N' N' N' Z(iii) Z(iii)
Z lll represents an oxygen or sulphur atom;
R5 lll and R6 lll represent a hydrogen or a C1-C6 alkyl group;
in the form of bases or of addition salts with acids
d) Compound of general formula (IV):
(IV)
in which:
- n IV represents 1 or 2;
- m IV represents 0 or 1;
- A IV represents a fused heterocyclic group of formula (Y(IV) )
and B( ' represents a hydrogen atom;
or
A V represents a hydrogen atom; and
B IV represents a fused heterocyclic group of formula (Y IV )
The fused heterocycle of formula Y IV may be attached to the rest of the molecule via any
of the available carbon atoms, and in which:
- U IV completes:
- either an aromatic or saturated 6-atom nucleus, containing one or two nitrogen
atoms, the nucleus possibly being substituted with one or two halogen atoms, one or two
(C1-C4)alkyl or (C1-C4)alkoxy groups, or one or two perfluoroalkyi radicals;
- or an aromatic or saturated 5-atom nucleus, containing a nitrogen, oxygen or
sulfur atom, the nucleus possibly being substituted with one or two groups (C1-C4)alkyl
groups;
- X IV and X 1 IV represent independently of each other CH or N;
- R IV and R 1 IV located on any of the available positions, independently represent a
hydrogen atom, a halogen atom, a group (CrC 4)alkyl group, (CrC 4)alkoxy, a
perfluoroalkyi or trifluoromethoxy radical, a cyano or a group COOH, COO(CrC 4)alkyl,
CONR3 IV R4 IV or NHCOR3 IV ; group;
- -W IV - is a nitrogenous heterocycle chosen from:
1-2 represents 1 or 2;
1-3 represents 1, 2 or 3;
R2 represents a group of formula:
- in which R5 ' and R6 located on any of the available positions, independently
represent a hydrogen atom, a halogen atom, a group (CrC 4)alkyl or ( -C4)alkoxy
group, a trifluoromethyl or trifluoromethoxy radical, a cyano or a group COOH,
COO(C C4)alkyl, COO(C C4)cycloalkyl, SO(C C4)alkyl, S02(C C4)alkyl,
CONR3 IV R4 IV , NR3 IV R4 IV or NHCOR3 IV ;
or one of the groups R5 IV and R6(IIV
) may also represent a heterocycle chosen from:
- Z ' represents an oxygen or sulfur atom;
- R3 IV and R4 IV represent a hydrogen or a group CrC 6 alkyl group,
in the form of bases or of addition salts with acids.
6. Use according to claim 4 or 5, wherein said p75 receptor antagonist is selected from:
- compound n°1: 1-[4-(4-chloro-3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1 -
yl]-2-[8-(5-fluoro-pyrimidin-2-yl)-3,8-diaza-bicyclo[3.2. 1]oct-3-yl]-ethanone ;
- compound n°2: 6-{(3S,5R)-3 5-Dimethyl-4-[2-oxo-2-(2-phenyl-2 4 6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1 -yl}nicotinic acid
hydrochloride;
- compound n°3: 6-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-
oxoethyl]-3,5-dimethylpiperazin-1 -yl}nicotinic acid ;
compound n°4: 1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-(8-
pyridin-3-yl-3,8-diazabicyclo[3.2. 1]oct-3-yl)ethanone;
in the form of a base or of an addition salt with an acid.