OA16932A - Novel therapeutic use of p75 receptor antagonists. - Google Patents

Abstract

The present invention provides for the use of a p75 receptor antagonist or its pharmaceutically acceptable salts for the preparation of a medicament for use in the treatment and/or prevention of overactive bladder.

Description

NOVEL THERAPEUTIC USE OF P75 RECEPTOR ANTAGONISTS

The subject of the présent invention Is the use of p75 receptor antagonlsts for the préparation of médicaments for use In the treatment and/or prévention of overactive 5 bladder and other urinary disorders.

Overactive bladder syndrome (sometimes called an 'irritable* bladder or 'detrusor Instabllity*) Is a common condition characterized by repeated and uncontrolled bladder contractions. Symptoms include urgency, firequency, nocturia and urge Incontinence. Their causes are not fully understood aithough they are partially due to the defective 10 behaviour of the detrusor. Bladder tralning Is usually the main treatment, and médication (Including antlmuscarinlc agents) does generally not alleviate ail 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 hyperplasla (PBH), cancers of the urinary tract; some of them can hâve serious, even life15 threatenlng, complications.

It Is therefore highiy désirable to provide new medicines for the treatment and/or prévention of the above disorders.

The compounds according to the présent invention hâve an affinity for the p75 neurotrophin receptor.

Neurotrophins belong to a famiiy of proteins of which the biological effect Is In particularsurvivai, development and function of neurons.

The p75 receptor, which is the receptor for ail neurotrophins, is a transmembrane glycoproteln of the tumorai necrosis factor (TNF) receptor family (W.J. Friedman and LA. Greene, Exp. Cell. Res., (1999), 253, 131-142). The p75 receptor Is expressed In 25 severai cell types, and several biological fonctions hâve been attributed to said receptor: firstly, modulation of the affinity of neurotrophins for receptor tyrosine kinases (trk); secondiy, 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 powerfol Inducers of p75 dépendent apoptosis in 30 neurons and certain cell Unes.

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 tlssues like nerves, liver, bladder muscles and prostate. This pleiotropic receptor has multiple and \ i even opposite fonctions, which likely dépend on the cell and tissue type, as well as on the physlo-pathologlcal status of the organisai. It has been observed that mlce selectively over expressing bladder Nerve Growth Factor exhibited: increased bladder wall Innervation, decreased bladder capadty, more frequent micturition, Increased non-voldlng bladder contractions; ail consistent with an overactive bladder (OAB) phenotype (Girard BM and al ’Neurotrophln/receptor expression In urinary bladder of mlce with overexpresslon of NGF In urothelium Am J Physiol Rénal Physiol. 300: F345-F355, (2011)).

It has also been observed that in humans with obstructed bladders or those with interstitiel cystitls 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), 101-110; Llu HZ et al. (2009). BJU1104,1476-1481).

p75 receptors and Trks receptors are expressed throughout the rat urinary bladder and are présent in nerve fibers of the detrusor smooth muscle, the suburothellal nerve plexus, urothélial cells, and nerve fibers assoclated with the suburothellal bladder vasculature (Klinger MB and alp75NTR Expression In Rat Urinary Bladder Sensory Neurons and Spinal Cord with Cyclophosphamlde-lnduced Cystitis J. Comp. Neurol. 507: 1379-1392, (2008)).

p75 receptors overexpression on detrusor smooth muscle cells aitogether with overexpresslon of NGF could play a deleterious rôle on the functionality of detrusor muscle.

According to a first object, the présent invention provides for the use of a p75 receptor antagonist In the préparation of médicaments for use in the treatment and/or prévention of overactive bladder and other urinary disorders.

In the présent patent application the terms “use of a p75 receptor antagonist in the préparation of médicaments hâve to be understood as synonyms of the terms “a p75 receptor antagonist for the préparation of a médicament for use, or “a p75 receptor antagonist for use, or “a p75 receptor antagonist for use as a médicament

According to another object of the invention, the présent invention provides for the use of a p75 receptor antagonist of the following general formula (I):

ω (i) (CHjJn-W-RS (I) t

(l) In which:

• m^w represents 0 or 1;

-A^(l) represents:

(D

and B*⁰ represents a hydrogen atom or

A^(l) represents a hydrogen atom and B^(l) represents:

()

- W^(l) - Is a nitrogenous heterocycle chosen from:

-1-3 represents 1,2 or 3;

- n^(l) represents 1 or 2;

- R1^w represents a halogen atom, a (CrCealkyl group, a trifluoromethyl radical, a (C_r C«)alkoxy group or a trifluoromethoxy radical;

-R2⁰⁾ represents a hydrogen atom, a halogen atom, a (CrC^ïalkyl group, a trifluoromethyl radical, a (Ci-C<)alkoxy group, a trifluoromethoxy radical, a COOR^(I) group or a CONH₂ group;

- R5⁰⁾ represents a group of formula:

	4 (i) N
ln which R3(l) and R4(l), located on	any one of the available positions, independently

represent a hydrogen atom, a halogen atom, a (Ci-C<)alkyl or (Ci-C4)alkoxy group, a trifluoromethyl or trifluoromethoxy radical, a cyano, or a COOH, COO(Ci-C4)alkyl, CONH₂, CONR6^(I» R7⁽” or NHCOR^(,) group;

- R^(l), R6^(l) and R7^(,) represent independently of each other a (Ci-Ce)alkyl group;

in the préparation of médicaments for use in the treatment and/or prévention 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 racemlc mixtures, are part ofthe invention.

The compounds of Formula (I) may exist In the form of bases or addition salts with acids. Such addition salts are part ofthe Invention.

These salts may be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for purlfying 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 (hâve) been substituted with a fluorine atom;

- the term a perfluoroalkyl group is Intended to mean: an alkyl group of which ail the hydrogen atoms hâve been substituted with a fluorine atom, for example trifluoroalkyl;

t

- the term “an alkoxy group Is Intended to mean: an -O-a!kyi radical where the alkyl group Is as defined above.

These compounds and their method of préparation are described ln W02009/150388 (US2011/144116), from which the content is Included herein by reference.

According to another object of the Invention, the présent Invention provides for the use of a p75 receptor antagonist of the following general formula (II):

(il)

() ln which: -m^ IsOorl;

- A^(l,) Is:

and B^w Is a hydrogen atom or

A^w is a hydrogen atom and B^<n) Is:

R1 (U)

- R1^(ll) and R2^<a), which may be identical or different, are independently a hydrogen or halogen atom, a (Ci.QJalkyl, (CrCiJfluoroalkyl, (Ci-Cîjperfluoroaikyl or (CrC^alkoxy group or a trifluoromethoxy group;

-n⁽> is1 or 2;

-R3⁽ⁿ⁾ is a group of formula:

N

R4

where R4^(B) and R5^(a), which may be identical or different, are located on any available positions and ara Independently a hydrogen or halogen atom, a hydroxyl, a (CrGJalkyl, (CrC₄)fluoroalkyl, (Ci-C₂)perfluoroalkyl or (Ci-C4)alkoxy group, a trifluoromethoxy group, a cyano group, or a COOH, COO(CrC<)alkyl, CONH₂, CONR6⁰» R7*¹’ or NHCOR^(,II) group;

- R*’, R6^<l,) and R?*¹⁰ are Independently of each other a (Ci-C₆)alkyl group;

ln the préparation of médicaments for use in the treatment and/or prévention 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 dîastereoisomers. These enantiomers and dîastereoisomers and also mixtures thereof, including racemic mixtures, 10 form part of the invention.

The compounds of formula (II) may exist ln the form of bases or of addition saits 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 15 formula (il) also form part of the invention.

In the context ofthe compounds of general formula (II):

- the term “a halogen atom Is intended to mean: a fluorine, a chlorine, a bromine or an lodlne;

- the term “an alkyl group’ is intended to mean: a linear or branched, saturated 20 aliphatlc group. By way of examples, mention may be made of a Ci-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 hâve been substituted with a fluorine atom;

- the term a perfluoroalkyl group is intended to mean: an alkyl group of which ail 25 the hydrogen atoms hâve 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 préparation are described in W02009/150387 (US2011/144122), from which the content Is included herein by 30 référencé.

According to another object of the invention, the présent invention provides for the use of a p75 receptor antagonist of the following general formula (III):

I «

In which:

- A⁰’ represents a group:

- n^w represents 1 or 2;

- m^(,,l) represents 0 or 1 ;

- Y*¹’ represents a carbon, nitrogen, sulphur or oxygen atom or a single or double bond;

- Χ<'>, Xi^(,ll) and X2⁰ represent a carbon, nitrogen, sulphur or oxygen atom, it being understood that at least one of X’⁰, Xi^<ll,) and X^¹* ls other than a carbon atom;

- R^(,,t) and RI⁰’, located on any one ofthe available positions, Independently represent a hydrogen atom, a halogen atom, a (Ci-C4)aikyl group, a (Ci-C4)aikoxy group, a perfluoroalkyl radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(Ci-C4)alkyl, CONR5^(II,) R6^(,l,) or NHCOR5⁽'> group;

or R1⁽“’ represents a group chosen from:

the définition of R*¹’ remalnlng unchanged;

- RS⁰* and R4^(III), located on any one of the available positions, independently represent a hydrogen atom, a halogen atom, a (Ci-C4>alkyl group, a (C(Ci-C4)-C4)aikoxy group, a » ♦ perfluoroalkyl radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(C_rC₄)alkyl, CONR5^(,II) Re'¹’ or NHCOR5^(III) group;

- W^(BI) - is a nltrogenous heterocycle chosen from:

-1-2 represents 1 or 2;

-1-3 represents 1,2 or 3;

- R2^(t’ represents a group of formula:

- R7^(,,l, and R8^(lll), located on any one of the available positions, independently represent a hydrogen atom, a halogen atom, a (Ci-C₄))alkyl group, a (C_rC₄)alkoxy group, a trifluoramethyl radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(CrC₄)alkyl, COO(CrC₄)cycloalkyl, SO(Ci-C₄)alkyl₁ SO2(C_rC₄)alkyl, CONH₂, CONR5⁰’ R6'¹’ or NHCOR5'¹’ group;

or one of R7^(,ll) and R8^(,ll) represents a heterocycle chosen from:

- Z⁰’ represents an oxygen or sulphur atom;

- R5^(m> and R6^r represent a hydrogen or a C1-C6 alkyl group;

» »

In the préparation of médicaments for use In the treatment and/or prévention 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 (ill) may exist in the form of bases or of addition salts with acids. Such addition saits form part ofthe invention.

These salts may be prepared with pharmaceutically acceptable acids, but the saits of other acids that are useful, for exampie, for purifying or isoiating the compounds of formula (III) alsoform partofthe Invention,

In the context ofthe compounds of general formula (III):

- the term a halogen atom is intended to mean: a fluorine, a chlorine, a bromine or an lodine;

- the term an alkyl group is intended to mean: a linear, branched or cyclic, saturated allphatic 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 cydobutyl;

- the term a fluoroalkyl group is intended to mean: an alkyl group of which one or more hydrogen atoms hâve been substituted with a fluorine atom;

- the term “a perfluoroalkyl group is intended to mean: an alkyl group of which ali the hydrogen atoms hâve been substituted with a fluorine atom, for example a trifluoroalky! 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 perfluoroaikoxy group Is Intended to mean: an alkoxy group of which ali the hydrogen atoms hâve been substituted with a fluorine atom, for example a trifluoroalkoxy group such as trifiuoromethoxy;

- the term a cycloalkyl group Is intended to mean: a cyclic alkyl group. By way of exemples, mention may be made of cyclopropyl, methylcyclopropyl, cydobutyl, cyclopentyl, cyclohexyl, etc., groups.

- the term a halogen atom is intended to mean: a fluorine, a chlorine, a bromine.

I t

These compounds and their method of préparation are described In WO2011/080444 (US2012/245149), from which the content is included herein by reference.

According to another object of the Invention, the présent Invention provides for the use of a p75 receptor antagonist ofthe following general formula (IV):

(IV) (IV)

) ° (IV)

In which:

- n^<l7) représente 1 or 2;

- m^,l7) represents 0 or 1 ;

- A^(l7) represents a fused heterocycllc group of formula (Y*¹⁷¹)

(IV) (Y) (IV) and B'¹⁷¹ represents a hydrogen atom;

or

A^(l7) represents a hydrogen atom; and

B^(l7) represents a fused heterocyclic group of formula (Y*¹⁷¹)

(IV) (Y)

The fused heterocycle of formula Y*¹⁷’ may be attached to the rest of the molécule via any of the availabie carbon atoms, and ln which:

- U™ complétés:

- either an aromatic or saturated 6-atom nucléus, containing one or two nitrogen atoms, the nucléus possibly being substituted with one or two haiogen atoms, one or two (C1-C4)alkyl or (C1-C4)alkoxy groups, or one or two perfluoroaikyl radicals;

- or an aromatic or saturated 5-atom nucléus, containing a nitrogen, oxygen or sulfur atom, the nucléus possibly being substituted with one or two (C1-C4)alkyl groups;

- X^(IV) and X1^(IV> represent independently of each other CH or N;

-R^(IV) and R1^(IV) located on any of the availabie positions, Independently represent a hydrogen atom, a halogen atom, a (CpC^lkyl group, (CpC^Ikoxy, a perfluoroaikyl or trifluoromethoxy radical, a cyano or a COOH, COO(Ci-C4)alkyl, CONR3^<IV)R4^(IV) or NHCOR3^(IV) group;

-W^<IV)- j_{s a} nitrogenous heterocycle chosen from:

- 1-2 représente 1 or 2;

-1-3 represents 1, 2 or 3;

- R2^<IV) represents a group of formula:

- in which R5^(IV) and R6^(IV), located on any of the availabie positions, independently represent a hydrogen atom, a halogen atom, a (Ci-C₄)alkyl or (C₁-C₄)alkoxy group, a trifluoromethyl or trifluoromethoxy radical, a cyano or a group COOH, COOÎCrCiJalkyl,

COO(Ci-C₄)cycloalkyl, SO(Ci-C₄)alkyl, SO2(C_t-C₄)alkyl, CONR3^(IV,R4^(,V’, NR3^(,V’R4^(IV) or NHCOR3⁽'^V>;

or one of the groups R5^<IV) and R6^(,V) may also represent a heterocycle chosen from:

R6

N-/-N

(IV)

- Z^(,V) represents an oxygen or sulfur atom;

- R3^(n/) and R4^<IV) represent a hydrogen or a C_rC_e alkyl group;

in the préparation of médicaments for use in the treatment and/or prévention overactive biadder.

The compounds of formula (IV) may comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereolsomers. These enantiomers and diastereolsomers, 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 purifylng or isolating the compounds of formula (IV) also form part of the invention.

ln the context of of the compounds of general formula (IV), the following définitions 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 hâve been replaced with a fluorine atom;

-a perfluoroalkyl group: an alkyl group In which all the hydrogen atoms hâve 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 hâve been replaced with a fluorine atom, for example trifluoroalkoxy;

-a cycloalkyl group: a cydic alkyl group. Examples that may be mentioned indude cyclopropyl, methylcyclopropyi, cyclobutyl, cyclopentyl, cyclohexyl, etc., groups.

These compounds and their method of préparation are described In WO2011/080445 (US2012/245150), from which the content is Included herein by reference.

According to another object of the Invention, the présent invention provides for the use of a p75 receptor antagonlst selected from:

- compound n*1: 1-[4-(4-chioro-3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-2[8-(5-fluoro-pyrlmldln-2-yl)-3_t8-diaza-blcydo[3.2.1 ]oct-3-yl]-ethanone ;

- compound n’2: e-KSS.SRJ-S.S-DimethyM-p-oxo-Z-tZ-phenyl-Z,4,6,7- tetrahydropyrazolo[4,3-c]pyridln-5-yl)ethyl]plperazin-1 -yljnicotinlc acid hydrochloride:

- compound n3: 6-{(3S,5R)-4-{2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2- oxoethyl]-3,5-dimethylpiperazln-1 -yljnlcotinlc add;

- compound n’4: 1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridln-5-yl)-2-(8-pyridin3-y 1-3,8-dlazablcyclo[3 2.1 ]oct-3-yl)ethan one;

the above compounds can also exlst In the form of a base or of an addition sait with an acid;

In the préparation of médicaments for use in the treatment and/or prévention overactive bladder.

These compounds and their mode of préparation are respectively described as compound n’11 In W02009/150388 for compound n°1, as compounds n*21 and n’28 In WO2011/080444 ((US2012/245149)) for compounds n‘2 and n’4 and as compound n*57 In WO2011/080445 (US2012/245150) for compound n’3, from which the content is Included herein by reference.

The following table describes the structure of these compounds.

Compound n’	Structure
1	F
2
3	CWA/ ~ o
4

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 mammai to be treated, preferably at daily doses of from 0.5 to 100 mg/kg. ln humans, the 5 dose may vary preferably from 0.5 mg to 50 mg per day, in particular from 1 to 30 mg, dependlng on the âge of the Individual to be treated, the type of treatment, prophylactic or curative, and the seriousness ofthe disorder. Said p75 receptorantagonists 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. Préférable unit dosage forms comprise 1 or 30 mg of p75 receptor 10 antagonists.

Said dosage units are preferably formulated ln pharmaceutical compositions in which the active principle Is mixed with a pharmaceutical excipient

In the pharmaceutical compositions of the présent invention, use can me made for oral, sublingual, subcutaneous, Intramuscuiar, Intravenous, topical, transdermal or rectal 15 administration.

Said p75 receptor antagonists, and the pharmaceutically acceptable salts thereof, may be administered ln unit administration forms, mixed with conventional pharmaceutical supports, to animais and humans for treating the abovementloned 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 Ingrédient Is mixed with a pharmaceutical vehicle such as gelatln, starch, lactose, magnésium stéarate, 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 hâve sustalned or delayed activity and that they release, in a continuous manner, a predetermined amount of active prlnclple. Usuai excipients include lactose monohydrate, microcrystalline cellulose, povidone, sodium carboxymethylstarch, magnésium stéarate, ethylcellulose, hypromellose, macrogol 400, titane dloxide.

A préparation of gel capsules is obtained by mixing the active ingrédient with a diluent and pouring the mixture obtained into soft or hard gel capsules.

A préparation in the form of a syrup or élixir may contain the active ingrédient 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-dlspersible powders or granules may contain the active Ingrédient mixed with disperslng agents or wetting agents, or suspending agents, such as polyvlnylpyrrolidone, and also with sweeteners or flavour correctors.

For local administration, the active prlnclple is mixed Into an excipient for preparlng 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 supposltories prepared with blnders which melt at rectal température, for example cocoa butter or polyethylene glycols.

For parentéral administration, aqueous suspensions, saline solutions or injectable stérile solutions which contain pharmacologically compatible dispersion agents and/or wetting agents, for example propylene glycol or butylène glycol, are used.

The active prindple may also be formulated In the form of microcapsules, optionally with one or more supports or additives.

According to another object, the présent invention provides a method of treating and/or preventing overactive bladder or other urlnary disorders In a patient which comprises administering to a patient in need of such treatment or prévention a therapeutlcally effective amount of a p75 receptor antagonlst In one aspect, the p75 receptor antagonist ls selected from a compound of general formula (I), a compound of general formula (II), a compound of general formula (III), and a compound ofthe following general formula (IV). In another aspect, the p75 receptor antagonist ls selected from the group consisting of compound n’1: 1-[4-(4-chloro-3-trifluoromethyl-phenyl)-3,6-dihydiO2H-pyridin-1-yl]-2-[8-(5-fluoro-pyrimldin-2-yl)-3,8-diaza-blcyclo[3.2.1]oct-3-yl]-ethanone;

compound n°2: e-ffSS.SRFS.S-DimethyM-JZ-oxo-Z-tZ-phenyl-ZAejtetrahydropyrazolo[4,3-c]pyridln-5-yl)ethy1]plperazln-1-yl}nlcotinlc acid hydrochloride; compound n*3: 6-((3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2oxoethyl]-3,5-dlmethyîplperazin-1-yl)nlcotlnlc acid; and compound n°4: 1-(2-phenyl2,4,6_t7-tetrahydropyrazolo[4_t3-c]pyridin-5-yl)-2-(8-pyridin-3-yl-3,8-diazabicycio[3.2.1]oct-3yljethanone; the above compounds can also exist In the form of a base or of an addition sait with an acid.

As used herein, the term therapeuticaliy effective amount ls meant to describe an amount of a compound, composition, médicament or active ingrédient effective in producing the desired therapeutic effect.

The following examples further Illustrate the présent invention.

EXAMPLES

Brief description of the drawings

Figure 1 ls a cystometrogram (CMG) from a rat during the light phase in response to contlnuously-infused saline, in normal fiillng-voidlng micturitlon 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 dépendent 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 préparation

Male adult SHR/N Ico rats (250g; Charles River Itaiy), were housed 7 days prior to the surgery with free access to standard chow and water. Animais were used In accordance with sanofi International ethicai code and the international principes govemlng the care and treatment of laboratory animais, (E.E.E Council Directive 86/609, DJL358, 1 Cec. 12, 10 1987) in a fuily accredited AAALAC facility.

Ali efforts were made to minlmize the potentlal for animal pain, stress, or dïstress.

A lower midline abdominal Incision was performed under general anesthesla with 2-3% Isoflurane using aseptie techniques. Their body température was maintalned at 37’ C using a homéothermie blanket Polyethylene tublng was Inserted Into the dôme of the 15 bladder and secured In place with a 6-0 nylon purse-string suture. The distal end of the tublng was sealed, tunneled subcutaneously, and extemalized at the back ofthe neck, out of the anlmal's reach. At the moment of the surgery animais were 16 weeks old.

Cvstometry

After one week from surgery, animais were placed In a Small Animal Cystometry Lab 20 Station (MED Associâtes, St. Albans, Vermont) for urodynamic measurements. Prior to the start of recording the bladder was emptied and the cathéter was connected via a Ttube to a pressure transducer and microinjection pump. Isotonie saline (0.9% NaCI at room température) 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 25 during continuous cystometry. A single cystometrogram is defined as the simultaneous recording of intravesical pressure, Infused volume and voided volume during a single fiiling-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 SDevelopment 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.

Expérimente were performed at similar times of day to avoid the possible Impact of clrcadian rhythm variations (Henera and al 'Diurnal variation In Urodynamlcs of rat. PLoS ONE 5(8) (2010)). At the end of experiments, animais were sacrificed with an overdose of pentobarbital.

Data analysis

The cystometrograms are analyzed using a spécifie software, SOF-552 cystometry data analysis.

The following endpoints hâve been considered (Figure 1 ):

1. Intercontaction Intervals (sec) (ICI) - 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 volding

4. Minimum bladder pressure (mmHg) (Min P) - Lowest bladder pressure during bladder filllng

5. Infused volume (μΙ) (Inf. Vol) -Volume of saline infused during the micturition cycle

6. Average bladder pressure (mmHg) (Aver P) - Average bladder pressure during bladder fiilïng

Exclusion Criteria

Rats were removed from study, before any treatment when adverse events occurred that Included: a réduction In body weight post-surgery, lethargy superior orequai to 20%, pain, or distress not relieved by sanofi's approved regimen of postoperative analgésies or hematuria.

Animais with atypical micturition pattern are exduded from the study.

Expression of data and statistical analysis

In order to limit the impact of inter-group or intra-group variabllity, ail data were expressed as % of control perlod (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 Dunnetts 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 urodynamlc parameters in SHR rats characterized by spontaneous overactlve bladder (OAB).

Drues

Vehlcle: 0.5% Polysorbate 80 (PS80) solution In buffered methyieelluiose (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 investlgate the rôle of compounds according to the invention In the mlcturition 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 hâve 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^e3,10 mg/kg po 167.14 ± 20%, compound n^e4,10 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 dependentfy

For ICI (Figure 4)

Vehicle 114.3 ± 12.01 %, compound n’2, 3 mg/kg po 160.9 ± 21.8%, 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 ± 21.7%, 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 pathophyslological mode). The compounds had no effect on mlcturitlon pressure parameters suggestlng a spécifie response. These compounds can thus be useful for the treatment and/or prévention of overactlve bladder.

EXAMPLE 2: Effects of one-week chronlc treatment with a p75 antagonlst 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:

groups of 14-15 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 problème linked to loss of Intrabladder-catheter, 30% animais 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 hâve been expressed as percentage of control values.

For ICI (Figure 6)Vehicle 122.5 ±10.15%, compound n°2,173.8 ±21.1%,

For Infused volume (Figure 7) Vehide 339.90 ± 28.07 %, compound n°2 173.7 ± 21.1 %

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 pathophyslologlcal model. The compound had no effect on micturition pressure parameters suggesting a spécifie response. This compound can thus be useful for the treatment and/or prévention of overactlve bladder.

Pharmaceutical composition according to the invention

As a représentative example, a unitary dosageform ofa compound ofthe Invention In the form of a tablet may comprise the following constituées:

p75 receptor antagonist	5,0 mg
Lactose	122,0 mg
Microcristalline cellulose	36,0 mg
Sodium carboxymethylstarch	7,0 mg
Polyvldone	9 mg
Magnésium stéarate	1,0 mg

Claims (6)

1. -1-3 represents 1,2 or 3;

   - R2⁽’^V) represents a group of formula:

   - in which R5^(W) and R6^(W), located on any of the available positions, independently represent a hydrogen atom, a halogen atom, a group (CrCjJalkyi or (CrC^jalkoxy group, a trifluoromethyl or trifluoromethoxy radical, a cyano or a group COOH, COO(Ci-C<)alkyi_t COO(C,-C4)cycioalkyi, SO(C,-C4)aikyl, SO2(C_rC₄)alkyl, CONR3^(n/)R4^(B/), NR3^(W)R4^(W) or NHCOR3^(V);

   or one of the groups R5^(l7) and R6^,IV) may also represent a heterocyde chosen from:

   - Z*¹⁷’ represents an oxygen or sulfur atom;

   - R3^(l7) and R4^(IV) represent a hydrogen or a group Ci-Ce alkyl group, ln the form of bases or of addition salts with acids.

   -1-2 represents 1 or 2;

   -1-3 represents 1, 2 or 3;

   - R2^P’ represents a group of formula:

   - R7⁰’ and R8^(ll,, _t located on any one of the available positions, independently represent a hydrogen atom, a halogen atom, a (C_rC4))alkyl group, a (C_rC4)alkoxy group, a trifluoromethyl radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(C_rC4)alkyl, COO(Ci-C4)cycloalkyl, SO(C_rC4)alkyl, SO2(Ci-C4)alkyl, CONH₂, CONRS⁰’ R6^(lll) or NHCORS⁰’ group;

   or one of R7⁰’ and RS⁰’ represents a heterocycle chosen from:

   Ζ^(,ΙΙ) represents an oxygen or sulphur atom;

   R5^(l’ and Re⁰¹” represent a hydrogen or a C1-C6 alkyl group;

   Y A

   In the form of bases or of addition salts with acids

   d) Compound of general formula (IV):

   (IV) (CH2)n-W-R2 (IV) (IV)

   In which:

   - n^(l7) represents 1 or 2;

   - m^<l7) represents 0 or 1 ;

   - A^<l7) represents a fused heterocycllc group of formula (Y¹⁷¹) (Y) and B^<l7) represents a hydrogen atom;

   or

   A^<IV) represents a hydrogen atom; and

   B^<W) represents a fused heterocycllc group of formula (Y¹⁷¹)

   RdV) (IV) (Y)

   The fused heterocycle of formula Y^il7) may be attached to the rest of the molécule via any ofthe available carbon atoms, and In which:

   - U^(IV) complétés:

   - either an aromatic or saturated 6-atom nucléus, containing one or two nitrogen atoms, the nucléus posslbly being substituted with one or two halogen atoms, one or two <C1 -C4)alkyl or (C1-C4)alkoxy groups, or one or two perfluoroalkyl radlcals;

   - or an aromatic or saturated 5-atom nucléus, containing a nitrogen, oxygen or sulfur atom, the nucléus possibly being substituted with one or two groups (C1-C4)alkyi groups:

   - X™ and X1^w represent Independently of each other CH or N;

   -R^(,V) and R1^(,V) located on any of the available positions, Independently represent a hydrogen atom, a halogen atom, a group (Ci-Cijalkyl group, (C_rC4)alkoxy, a perfluoroalkyl or trifluoromethoxy radical, a cyano or a group COOH, COO(CrC4)alkyl, CONR3^(W)R4^(W) or NHCOR3^(W); group;

   _ Is a nitrogenous heterocycle chosen from:

   o

   -1-2 represents 1 or 2;

   -1-3 represents 1,2 or 3;

   - η^ω represents 1 or 2;

   - R1^(,) represents a halogen atom, a (CrCiJalkyl group, a trifluoromethyl radical, a (C_r C₄)alkoxy group or a trifluoromethoxy radical;

   -R2¹'¹ represents a hydrogen atom, a halogen atom, a (Ci-C4)alkyl group, a trifluoromethyl radical, a (CrC4)alkoxy group, a trifluoromethoxy radical, a COOR^(I) group or a CONH2 group;

   - R5^m represents a group of formula:

   ln which R3^(<> and R4^<l), located on any one of the availabie positions, Independently represent a hydrogen atom, a halogen atom, a (CrC₄)aikyl or (CrGOalkoxy group, a trifluoromethyl or trifluoromethoxy radical, a cyano, or a COOH, COOiCi^Jalkyl, CONH₂, CONR6<” R7^(,) or NHCOR^(I) group;

   - R^(l), R6^(l) and R7^(,) represent independently of each other a (CrC₆)alkyl group;

   - ln the form of bases or of addition salts with acids

   b) Compound of general formula (II):

   ln which:

   - m^(,l) Is 0 or 1 ;

   -Α^(|,) is:

   and B*’ is a hydrogen atom or

   A⁽ⁿ⁾ is a hydrogen atom and B^<n) is:

   (H)

   I and R2^|B), which may be Identical or different, are independently a hydrogen or halogen atom, a (Ci-C₄ )alkyi, (C_rC₄) fluoroalkyl, (C_rC₂) perfluoroalkyl or (C_rC₄) alkoxy group or a trifluoromethoxy group:

   -n^(,l> is 1 or 2;

   -R3^(B) is a group of formula:

   R4 rs'’ ^N R5^{1 1} where R4^W and R5^<B), which may be identical or different, are located on any available positions and are Independently a hydrogen or halogen atom, a hydroxyl, a (CrC₄) alkyl, (Ci-C₄) fluoroalkyl, (C1-C2) perfluoroalkyl or (C_rC₄) alkoxy group, a trifluoromethoxy group, a cyano group, or a COOH, COO(C_rC₄)alkyl, CONH₂, CONR6^m R7^{1 1}’ or NHCOR^{<I >} group;

   - R6^0l) and R?⁰¹’ are independently of each other a (CrCe) alkyl group;

   ln the form of bases or of addition salts with acids;

   c) Compound of general formula (III):

   I '^T h (111)

   C) η ^W-RZ* Ο (III) in which:

   - Α^(|ι,) represents a group:

   (HI) R1 (') (III)

   - n^<ln) represents 1 or 2;

   - m^(lll) represents 0 or 1;

   - Y*» represents a carbon, nitrogen, sulphur or oxygen atom or a single or double bond;

   - X^(l>, Xi^(,ll) and X/¹⁰ represent a carbon, nitrogen, sulphur or oxygen atom, It being understood that at least one of X⁰¹¹’, Xi^tlh) and X/’ ls other than a carbon atom;

   - R*¹’ and R1^(,B), located on any one ofthe available positions, Independently represent a hydrogen atom, a halogen atom, a (C_rC₄)alkyl group, a (Ci-C₄)alkoxy group, a perfluoroalkyi radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(Ci-C₄)alkyl, CONR5*¹’ R6<'’ or NHCORS'¹’ group;

   or R1^W represents a group chosen from:

   the définition of R*¹’ remaining unchanged;

   - RS*¹’ and R4^{(l ,} _t located on any one of the available positions, Independently represent a hydrogen atom, a halogen atom, a (CrCealkyl group, a (C(C_rC4)-C4)alkoxy group, a périluoroalkyl radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(Ci-C4>alkyl, CONR5⁰’ R6^{( l)} or NHCOR5’ group;

   - W^(,ll) - Is a nitrogenous heterocycle chosen from:

   -1-3 represents 1,2 or 3;

   - R2^<IV) represents a group of formula:

   - In which R5^<IV) and R6^<IV), located on any of the avallable positions, independently represent a hydrogen atom, a halogen atom, a (CrC₄)alkyl or (C_rC₄)alkoxy group, a trifluoromethyl or trifluoromethoxy radical, a cyano or a group COOH, COO(C_rC₄)alkyl, COO(C_rC₄)cycloalkyl, SO(C_rC₄)alkyl, SO2(C_rC₄)alkyl, CONR3^WR4^(PO, NR^W⁷’ or NHCORS™;

   or one of the groups R5^<IV) and R6^<IV) may also represent a heterocycle chosen from:

   - Z^|IV) represents an oxygen or sulfar atom;

   - R3^<IV) and R4^<IV) represent a hydrogen or a CrCe alkyi group,

   In the form of bases or of addition salts with acids.

   » ·' »

   -1-2 represents 1 or 2;

   -1-3 represents 1, 2 or 3;

   -R2^(,,I, represents a group of formula:

   r < ’ *

   - R7^W and R8^,I,I, _I located on any ono of the available positions, Independently represent a hydrogen atom, a halogen atom, a (Ci-C₄))alkyl group, a (Ci-C₄)alkoxy group, a trifluoromethyl radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(C_rC₄)alkyl, COO(C₁-C4)cycloalkyl. SO(C_rC4)alkyl, SO2(Ci-C<)alkyl, CONH₂, CONR5'¹’ R6^{,l ,} or NHCOR5^,,I,) group;

   or one of R7ⁱ’^> and R8^{(, >} represents a heterocycle chosen from:

   - Z⁰’ represents an oxygen or sulphur atom;

   - R5^{,l ,} 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) _____ <^1V) (IV) q

   (IV) ln which:

   - n^,IV) represents 1 or 2;

   - m^,IV) represents 0 or 1 ;

   - A*¹⁷’ represents a fused heterocyclic group of formula (Y*¹^)

   I < ’ *

   R(IV) (Y) and B^(P/) represents a hydrogen atom;

   or

   A^(IV) represents a hydrogen atom; and

   B^(P/) represents a fused heterocyclic group of formula (Y*¹'⁰) (Y)

   The fused heterocycle of formula Y^ may be attached to the rest of the molécule via any of the avaîlable carbon atoms, and In which:

   • U^(IV) complétés:

   - either an aromatic or saturated 6-atom nucléus, containing one or two nitrogen atoms, the nucléus possibly being substituted with one or two halogen atoms, one or two (C1-C4)alkyl or (C1-C4)alkoxy groups, or one or two perfluoroalkyl radicals;

   - or an aromatic or saturated 5-atom nucléus, containing a nitrogen, oxygen or sulfur atom, the nucléus possibly being substituted with one or two (C1-C4)alkyl groups;

   - X^(IV) and X1^(nz) represent independently of each other CH or N;

   -RW and R1^<IV> located on any of the avaîlable positions, independently represent a hydrogen atom, a halogen atom, a (CrC^alkyi group, (CrC4)alkoxy, a perfluoroalkyl or trifluoromethoxy radical, a cyano or a COOH, COO(C_rC4)alkyi, CONR3^(IV)R4^(IV) or NHCOR3^(r7) group;

   -W^(IV)- is a nltrogenous heterocycle chosen from:

   t <^f t

   -1-2 represents 1 or 2;

   -1-3 represents 1, 2 or 3;

   - n^(,) represents 1 or 2;

   - R1^(l) represents a halogen atom, a (CrCxJalkyl group, a trifluoromethyl radical, a (Cr C₄)alkoxy group or a trifluoromethoxy radical;

   - R2^(l) represents a hydrogen atom, a halogen atom, a (Ci-C₄)alkyl group, a trifluoromethyl radical, a (CrC₄)alkoxy group, a trifluoromethoxy radical, a COOR^W group or a CONHî group;

   - R5^W represents a group of formula:

   in which R3^(,) and R4’⁰, located on any one of the available positions, independently represent a hydrogen atom, a halogen atom, a (CrC₄)alkyl or (C_rC₄)alkoxy group, a trifluoromethyl or trifluoromethoxy radical, a cyano, or a COOH, COO(CrC₄)alkyl, CONH_2> CONRe*'* R7^(l> or NHCOR^(I) group;

   - R⁰’, R6^(l) and R7^(l) represent Independently of each other a (CrCe)alkyl group;

   in the form of bases or of addition salts with acids;

   b) Compound of general formula (H):

   B⁰¹’ z-/

   SV»⁰ (II) in which:

   -m<’ is0or 1;

   -A⁰⁰ 1s:

   (il) and B** Is a hydrogen atom or

   A^(l,) Is a hydrogen atom and B^<n) Is:

   R1

   ()

   - R1^(ll) and R2^(ll), which may be Identical or different, are Independently a hydrogen or halogen atom, a C1.C4 alkyl, C1-C4 fluoroalkyl, CrC₂ perfluoroalkyl or C1-C4 alkoxy group or a trifluoromethoxy group;

   -n^w is 1 or 2;

   - R3^W is a group of formula:

   where R4^(ll) and R5^<B), which may be identical or different, are located on any available positions and are independently a hydrogen or halogen atom, a hydroxyl, a C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C2 perfluoroalkyl or C1-C4 alkoxy group, a trifluoromethoxy group, a cyano group, or a COOH, COOalkyl, CONH₂, CONR6^(I,,) R7^0,,) or NHCOR™ group;

   - R^(ll), R6^(ll) and R7^0l) are a CrCe alkyl group;

   In the form of bases or of addition salts with acids;

   c) Compound of general formula (III):

   in which:

   - A^<,h> represents a group:

   - n⁰’ represents 1 or 2;

   - m*'’ represents 0 or 1;

   - Y*¹’ represents a carbon, nitrogen, sulphur or oxygen atom or a single or double bond;

   - X<“>, X/’ and X₂ ^(lll) represent a carbon, nitrogen, sulphur or oxygen atom, it being understood that at least one of X®’, Xi^pil> and X₂ ^(lll> is other than a carbon atom;

   - R^(ll,) and R1^(,l,, _l located on any one of the available positions, Independently represent a hydrogen atom, a halogen atom, a (Ci-C₄)alkyl group, a (C_rC₄)alkoxy group, a perfluoroalkyl radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(Ci-C₄)alkyl, CONR5^(III) R6^(l,l) or NHCOR5^(III) group;

   or R1^(lll) represents a group chosen from:

   the définition of R⁰’ remaining unchanged;

   - R3^t,ll, and R4^t,ll), located on any one of the available positions, Independently represent a hydrogen atom, a halogen atom, a (CrC₄)alkyl group, a (C(C_rC₄)-C4)alkoxy group, a perfluoroalkyl radical, a trifluoromethoxy radical, a cyano, or a COOH, COO(C_rC₄)alkyl, CONR5^(II,) R6^(lll) or NHCOR5^(II,> group;

   - W^<ll,) - is a nitrogenous heterocycle chosen from:

   1. A p75 receptor antagonist for the préparation of a médicament for use in the treatment and/or prévention of overactive bladder.
2. 2. A p75 receptor antagonist according to claim 1 selected from:

   a) Compound of general formula (I):

   B⁽” _____ «) (!) (1)

   In which:

   - m^(l> represents 0 or 1 ;

   -A^w represents:

   d) and B^(,) represents a hydrogen atom or

   A⁰ represents a hydrogen atom and B^(l> represents:

   (0 R1

   - W^(l) - Is a nitrogenous heterocycle chosen from:

   -<Ë^N- _e
3. 3. A p75 receptor antagonlst according to claim 1 or 2 selected from:

   - compound n*1: 1-[4-(4-chloro-3-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1yl]-2-[8-(5-fluoro-pyrlmidin-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-2₁4,6,7- tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic add hydrochloride;

   - compound n*3: 6-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2oxoethyl]-3,5-dimethylplperazin-1-yl}nicotinic acid;

   - compound n°4: 1-(2-phenyl-2,4_l6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-(8pyridln-3-yl-3,8-diazablcydo[3.2.1]oct-3-yl)ethanone;

   in the form of a base or of an addition sait with an add.
4. 4. Use of a p75 receptor antagonlst In the préparation of médicaments for use In the treatment and/or prévention of overactive bladder.
5. 5. Use according to claim 4, wherein said p75 receptor antagonist is selected from:

   a) Compound of general formula (I):

   (i)

   In which:

   - m® represents 0 or 1;

   A® represents: and B® represents a hydrogen atom or

   A^(lï represents a hydrogen atom and B® represents:

   % (i)

   - W¹⁰ - is a nitrogenous heterocycle chosen from:
6. 6. Use according to claim 4 or 5, wherein said p75 receptor antagonist is selected from:

   - compound n’1: 1-[4-(4-chioro-3-trifluoromethyt-phenyi)-3,6-dihydra-2H-pyridin-1yi]-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-Dlmethyi-4-[2-oxo-2-(2-phenyi-2,4,6,7- tetrahydropyrazoio[4,3-c]pyridin-5-yl)ethyl]piperazin-1 -yljnicotinic add hydrochloride;

   - compound n°3: 6-{(3S,5R)-4-I2-(4-benzofuran-7-yi-3,6-dihydro-2H-pyridin-1-yl)-2oxoethyi]-3,5-dimethylpiperazin-1-yl}nicotinic acid;

   - compound n’4: 1-(2-phenyt-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yi)-2-(8pyridin-3-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;

   in the form of a base or of an addition sait with an acid.