FR2889191A1 - COMPOUNDS DERIVED FROM 5-BENZYLIDENE IMIDAZOLIDINE 2,4-DIONE AND THEIR USE AS MCHR-1 ANTAGONISTS - Google Patents

Abstract

The present invention relates to the compounds of general formula (I) below: in which:. Ar <1>, L <1>, R <1>, R <2>, R <3>, R <4> R <5>, R <6>, L <2>, Q, and n are such as defined in the claims, as well as their method of preparation. The invention also relates to the use of the compounds of formula (I) as a medicament, and more particularly for the preparation of a medicament intended for the treatment of obesity and associated diseases, an appetite suppressant drug and / or a drug causing weight loss, a drug intended for the treatment of depression and / or anxiety, and more generally a drug intended for the treatment of a disease associated with MCH receptors (melanin concentrating hormone).

Description

Ar 'o

IRS

/ 1_N N The present invention relates to novel compounds derived from 5benzylidene imidazolidine-2,4-dione, their manufacturing process and their therapeutic use for the treatment and prevention of diseases associated with MCHR (melanin-concentrating hormone receptor) such as obesity

PRIOR ART

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide consisting of 19 amino acids, the sequence of which is highly conserved in vertebrates. MCH is produced mainly in the central nervous system, at the level of the hypothalamus and herpes zoster uncerta (Bittencourt, J. C. et al., J. Comp. Neurol. 319, 218-245 (1992)). MCH could be involved in a wide variety of physiological processes such as appetite, memory, modulation of reproductive functions, stress, anxiety (Knigge, KM et al., Peptides 17, 1063-1073 (1996); Hervieu , G., Expert Opin. Ther. Targets 7, 495-511 (2003)). MCH is the natural ligand of a receptor coupled to a G protein (GPCR), called SLC1 or GPR24, whose sequence of 353 amino acids has strong homology with that of somatostatin receptors (Chambers, J. et al., Nature 400, 261-265 (1999), Saito, Y. et al., Nature 400, 265-265 (1999), Shimomura, Y. et al., Biochem. Biophys. Res. Common 261, 622-626 (1999) )). This receptor is now called melaninconcentrating hormone receptor 1 (MCHR-1). In cells transfected with MCHR-1, MCH has previously been shown to increase intracellular Cal + concentration, inhibit forskolin-induced cyclic AMP production, promote inositol phosphate production, and activate cascades involving MAP kinase. MCHR-1 is expressed abundantly in most areas of the brain and to a lesser extent in some peripheral organs. A second receptor for the melanin-concentrating hormone (MCHR-2) has been identified. MCHR-2 is widely expressed in the brain, in particular in the hippocampus and ventral hypothalamus (An, S. et al., Proc. Nat /. Acad. Sci. 98, 7576-7581 (2001)) ; Sailer, A. et al., Proc. Nat /. Acad. Sci. 98, 7564-7569 (2001); Wang S. et al., J. Biot. Chem. 276, 3466434670 (2001)).

The involvement of MCH in the regulation of food intake and the maintenance of energy balance in mammals has been clearly demonstrated by several scientific teams: MCH mRNA expression levels are increased in fasting animals or genetically obese such as fa / fa rats, db / db and ob / ob mice (Qu, D. et al., Nature 380, 243-247 (1996)); Intracerebroventricular administration of MCH stimulates food intake in rats and mice, and antagonizes the effects of alpha-melanocyte-stimulating hormone (a-MSH) (Rossi, M. et al., Endocrinology 138, 351-355 (1997)); Chronic MCH infusions cause overeating and obesity in mice and rats (Ito, M. et al., Am. J. Physiol. 284, E940-E945 (2003); Della-Zuana, O. et al. , Int. J. Obes. Relat. Metabo. Disord. 26, 1289-1295 (2002)); MCH-deficient mice (Pmch "'") are emaciated because they are hippophagic and exhibit increased metabolic activity (Shimada, M. et al., Nature. 396, 670-674 (1998)); Ablation of the MCH gene in ob / ob mice increases metabolic and locomotor activity leading to reduction in obesity (Segal-lieberman, G. et al., Proc. Natl. Acad. Sci. 100, 10085- 10090 (2003)); MCH overexpressing transgenic mice are obese and insulin resistant (Ludwig, DS et al., J. Clin. Lnvest. 107, 379-386 (2001)) Several studies tend to prove that MCHR-1 receptors are physiologically responsible for the effects. of MCH on the maintenance of energy balance (Kowalski, TJ, McBriar, MD, Expert Opin. lnvestig. Drugs 13, 1113-1122 (2004)): mice deficient in MCHR-1 (Mch1r ") are emaciated, hyperactive , and have less fat mass, their insulin and leptin levels are lower than in wild mice (Marsh, DJ et al., Proc. Nat /. Acad. Sci. 99, 3240-3245 (2002); Chen, Y. et al., Endocrinology 143, 2469-2477 (2002)); administration of MCHR-1 receptor antagonists in rodents causes hypophagy, weight loss and reduced food intake (Borowsky , B. et al., Nat. Med. 8, 825-830 (2002); Takekawa, S. et al., Eur. J. Pharmacol. 438, 129-135 (2002); Kowalski, TJ et al., Eur. J. Pharmacol. 497, 41-47 (2004); Mashiko, S. et al, Endocrinology, 146, 3080-3086 (2005)).

In addition, several studies tend to prove that the MCHR1 receptors could play a role in the treatment of depression and anxiety: Certain antagonists of the MCHR-1 receptors, evaluated in rodents in behavioral models of depression and anxiety , exhibit effects similar to the effects observed with antidepressants and anxiolytics used in therapy in humans (Borowsky, B. et al., Nat. Med. 8, 825-830 (2002); Chaki, S. et al. , J. Pharm. Exp. Ther. 313, 831-839 (2005)).

Thus, the search for compounds capable of specifically antagonizing MCHR-1 receptors should make it possible to develop drugs not only for the treatment and / or prevention of obesity in humans but also for the treatment and / or prevention of obesity. depression and / or anxiety in humans.

DESCRIPTION OF THE INVENTION

The subject of the present invention relates to compounds of the following general formula (I): Q (1) Art in which: É Ar 'represents an aryl or heteroaryl or cycloalkyl or heterocyclic group optionally substituted with one to five groups chosen from: a halogen atom, a (C1-C6) alkyl, hydroxy, hydroxy (C1-C6) alkyl, (C1-C6) alkoxy, (C, -C6) alkoxy (C, -C3) alkyl, aryl, aryl ( CIC6) alkyl, aryl-O-, aryl-S-, aryl-CO-, cycloalkyl, cycloalkyl (C1-C6) alkyl, cyano, (CI-C6) haloalkyl, (Ci-C6) haloalkoxy, - (CH2), NR3R4, - (CH2) nCOR3, - (CH2), CO2R3, - (CH2) nNR4SO2R3, - (CH2) nC (0) NR3R4, heteroaryl, heteroaryl- O-, heteroaryl-S-, heteroaryl-CO-, heteroaryl ( C1-C6) alkyl and heterocyclic; for which the cycloalkyl, aryl, heteroaryl and heterocyclic radicals can be optionally substituted with one to three groups chosen from: a halogen atom, a (CI-C6) alkyl, hydroxy, hydroxy (CIC6) alkyl, (CI-C6) radical ) alkoxy, (C1-C6) alkoxy (C, - C3) alkyl, (C1-C6) haloalkyl, (CI-C6) haloalkoxy, cyano, - (CH2) nNR3R4, - (CH2) COR3, - (CH2) nCO2R3 , - (CH2) nNR4SO2R3, - (CH2) nC (0) NR3R4; É L 'represents a single bond or a (C, -C6) alkylene, (C2-C6) alkyleneoxy, (C, -C6) alkoxy (C2-C3) alkylene, (C2-C6) alkylidene, (C2-C6) group ) alkylidenoxy; É R ′ and R2, which may be identical or different, represent a hydrogen atom or a (CI-C6) alkyl radical; E L2 represents a single bond or a (C1-C6) alkylene group; É Q represents a basic group or a group represented by NR5R6 for which - R5 and R6, identical or different, represent a hydrogen atom, a (CI-C6) alkyl, hydroxy (C1-C6) alkyl, (Ci -C6) alkoxy (C-2889191 5 C3) alkyl, NR3R4 (C2-C6) alkyl, cycloalkyl, aryl, aryl (C1-C6) alkyl, heteroaryl, heteroaryl (C1-C6) alkyl; for which the cycloalkyl, aryl and heteroaryl radicals can be optionally substituted with one to three groups chosen from: a halogen atom, a (Ci-C6) alkyl, hydroxy, hydroxy (C1-C6) alkyl, (C1-C6) radical ) alkoxy, (Ci-C6) alkoxy (C1-C3) alkyl, (CI-C6) haloalkyl, (CI-C6) haloalkoxy, cyano, - (CH2) nNR3R4, - (CH2) nCOR3, - (CH2) nCO2R3, - (CH2) nNR4SO2R3, - (CH2) C (0) NR3R4; - R5 and R6 can form together and with the nitrogen atom to which they are bonded a nitrogenous heterocycle such as azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, piperazinyl, homopiperazinyl, N- (CI-C6) alkylpiperazinyle, N- ( C1-C6) alkylhomopiperazinyle, N- (CI-C6) alkylcarbonylpiperazinyl, N- (CI-C6) alkylcarbonylhomopiperazinyle, Narylpiperazinyle, N-arylhomopiperazinyle, N- (CI-C6) alkylaryl- (C1-C6) alkylcarbonylhomopiperazinyle, Narylpiperazinyle, N-arylhomopiperazinyle, N- (CI-C6) alkylaryl- (C6) alkylarylpiperazin-C6 substituted by (C1-C6) alkylarylpiperazin-C6-substituted one or more radicals (C1-C6) alkyl, hydroxy, hydroxy (C1-C6) alkyl, (CIC6) alkoxy, (CI-C6) alkoxy (CI-C3) alkyl - R5 and / or R6 can form with L2 and with the nitrogen atom to which they are attached a mono or polycyclic, saturated or unsaturated nitrogenous heterocycle, such as pyrrolidine, piperidine, homopiperidine, piperazine, homopiperazine optionally substituted by one or more (C1-C6) alkyl, hydroxy, hydroxy ( C1-C6) alkyl, (Ci-C6) alkoxy, (CI-C6) alkoxy (C1-C3) alkyl É R3 and R4, identical or different erent, represent a hydrogen atom, or a (CI-C6) alkyl radical; É n is an integer between 0 and 4.

2889191 -6 The present invention also comprises the pharmaceutically acceptable salts of the compounds of formula (I), solvates and hydrates, optical and geometric isomers or their mixtures. These salts can be obtained with non-toxic mineral or organic acids which are acceptable in therapy.

The present invention also includes the prodrugs of the compounds of formula (I).

The present invention also relates to the compounds of formula (I) for their use as pharmacologically active substance, in particular for the preparation of a medicament intended for the treatment of obesity and associated diseases, of an appetite suppressant medicament and / or a drug causing weight loss, a drug intended for the treatment of depression and / or anxiety, and more generally a drug intended for the treatment of a disease associated with MCH receptors ( melanin concentrating hormone).

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, the terms used to describe the compounds of formula (I) can be defined as follows: The term alkyl denotes a saturated, linear or branched monovalent hydrocarbon radical, composed of 1 to 12 carbon atoms, preferably composed of 1 to 8 carbon atoms. The alkyl groups of small sizes, that is to say the alkyl groups composed of 1 to 4 carbon atoms, are preferred. When a number appears as a subscript after the symbol C, the subscript defines exactly the number of carbon atoms contained in the alkyl group. For example, the term (CI-C6) alkyl denotes an alkyl radical comprising from 1 to 6 carbon atoms, such as a methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl group, etc. . 2889191 7 When the term alkyl is used as a prefix in association with a second group, as in arylalkyl, hydroxyalkyl, cycloalkylalkyl, the second group is then linked to the rest of the molecule by an alkyl radical. For example, the term hydroxy (C1-C6) alkyl denotes a hydroxyl group linked to the rest of the molecule by an alkyl radical comprising from 1 to 6 carbon atoms; the term aryl (C1-C6) alkyl denotes an aryl radical linked to the rest of the molecule by an alkyl radical comprising from 1 to 6 carbon atoms. The term aryl (C1-C6) alkyl denotes in particular the benzyl, phenylethyl, phenylpropyl, etc. radical. The term cycloalkyl denotes an alkyl group of 3 to 10 carbon atoms forming a saturated monocyclic system. By way of example, mention may be made of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl. The term (C3-C8) cycloalkyl denotes a cycloalkyl radical comprising from 3 to 8 carbon atoms.

The term aryl denotes mono- or bi-cyclic aromatic hydrocarbon systems having from 6 to 14 carbon atoms.

Mention may in particular be made of the phenyl, 1-naphthyl or 2-naphthyl radical. The term aryl-O- denotes an aryl radical as defined above and linked to the rest of the molecule via an -O- (ether) bond. The term aryl-S- denotes an aryl radical as defined above and linked to the rest of the molecule via an -S- (thioether) bond. The term aryl-CO- denotes an aryl radical as defined above and linked to the rest of the molecule via a group - CO (carbonyl).

The term heteroaryl denotes mono-, bi- or tri-cyclic aromatic hydrocarbon systems having on the ring (or rings) at least one heteroatom, such as in particular nitrogen, sulfur or oxygen. By way of example of a monocyclic heteroaryl, mention may in particular be made of the pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, 2889191 -8 isoxazolyl, thiazolyl, furanyl thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl group. Examples of bicyclic heteroaryl may be mentioned in particular indolyl, benzothiazolyl, benzodioxolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl , dihydroisoindolyl, tetrahydroquinolinyl. By way of example of a tricyclic heteroaryl, mention may in particular be made of the carbazolyl, benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl or xanthenyl group.

The term heterocyclic designates mono-, bi or poly-cyclic, saturated or partially saturated hydrocarbon systems, having on the ring (or rings) at least one heteroatom, such as nitrogen, sulfur or oxygen. They can be aromatic or not. They are preferably non-aromatic. By way of example of a heterocycle, mention may in particular be made of the piperidinyl, pyranyl, dioxanyl, piperazinyl, pyrrolidinyl, morpholinyl, homopiperazinyl, homopiperidinyl, indolinyl, dihydrobenzofuranyl and benzo [1,3] dioxolanyl group.

The term alkoxy denotes an alkyl radical as defined above and linked to the remainder of the molecule via an -O- (ether) bond. An alkoxyalkyl group corresponds to an alkyl radical interrupted by an oxygen atom. By way of example of alkoxy radicals, mention may in particular be made of methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, secbutoxy, tert-butoxy, etc. radicals. By (Ci-C6) alkoxy is meant an alkyl radical comprising from 1 to 6 carbon atoms linked to the remainder of the molecule via an -O- (ether) bond. The term (C1-C6) alkoxy (C1-C3) alkyl denotes an alkyl radical comprising from 1 to 6 carbon atoms linked via an -O- (ether) bond to an alkyl radical comprising from 1 to 3 carbon atoms, bonded to the rest of the molecule.

2889191 -9 The terms N-alkylamino and N, N-dialkylamino respectively denote one and two alkyl groups as defined above, linked to the rest of the molecule by a nitrogen atom. By N- (C1C4) alkylamino is meant an alkyl radical comprising from 1 to 4 carbon atoms linked to the remainder of the molecule by a nitrogen atom.

The terms N-alkylaminocarbonyl and N, N-dialkylaminocarbonyle respectively denote N-aikylamino and N, Ndialkylamino groups as defined above, linked to the rest of the molecule by a carbonyl group (-C (0) -). By N- (CIC4) alkylaminocarbonyl is meant an N-alkylamino radical comprising from 1 to 4 carbon atoms linked to the remainder of the molecule by a carbonyl group.

The term aminocarbonyl denotes an amino group (-NH2) linked to the rest of the molecule by a carbonyl group.

The term alkylene denotes a divalent group corresponding to the alkyl radical as defined above by removing a hydrogen atom. By (Ci-C3) alkylene and (C2-C6) alkylene is meant an alkylene radical comprising from 1 to 3 and respectively from 2 to 6 carbon atoms.

The term alkyleneoxy denotes a divalent group corresponding to the alkylene radical as defined above and linked to the rest of the molecule via an -O- (ether) bond. By (C2-C6) alkyleneoxy is meant an alkylene radical comprising from 2 to 6 carbon atoms and linked to the rest of the molecule via an - O- (ether) bond.

The term alkyleneoxyalkylene denotes a divalent group corresponding to the alkylene radical as defined above and linked to the remainder of the molecule via an alkyleneoxy group as defined above.

The term alkylidene denotes a divalent group corresponding to the alkylene radical as defined above and comprising at least one ethylenic unsaturation. By (C2-C6) alkylidene is meant an alkylidene radical comprising from 2 to 6 carbon atoms.

The term basic group denotes an organic radical acceptor of hydrogen. The term basic group also denotes an organic group containing one or more basic centers. As examples of basic centers, mention will be made in particular of the amino, imino, amidino, N-alkylamidines, N, N'-dialkylamidines, N-arylamidines, guanidino, aminoguanidino, N-alkylamino, N, N'-dialkylamino groups, N, N ', N "trialkylamino, pyrrolinyl, piperidyl, pyrrolyl, imidazolyl, pyridyl.

By halogen is meant a fluorine, chlorine, bromine or iodine atom.

The term haloalkyl denotes an alkyl radical as defined above, substituted by at least one halogen. By (Ci-C6) haloalkyl is meant an alkyl radical comprising from 1 to 6 carbon atoms, substituted by at least one halogen. By way of example of a (C 1 -C 6) haloalkyl group, mention may in particular be made of the trifluoromethyl radical.

The term haloalkoxy denotes an alkoxy radical as defined above, substituted by at least one halogen. By (Ci-C6) haloalkoxy is meant an alkyl radical comprising from 1 to 6 carbon atoms, substituted by at least one halogen and linked to the rest of the molecule via an O- (ether) bond. By way of example of a haloalkoxy (CI-2889191 -11-C6) group, mention may in particular be made of the trifluoromethoxy (-OCF3) radical.

The term “heteroatom” means an atom chosen from O, N and S. The term “pharmaceutically acceptable salts” means the addition salts which can be obtained by reacting these compounds of formula (I) with an inorganic or organic acid or with an inorganic or organic base, according to a method known per se.

Among the salts formed by adding an acid, mention will be made of acetates (for example those prepared from acetic or trihaloacetic acid such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulphonates, bisulphates, borates , butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulphates, ethanesulphonates, fumarates, glucoheptanoates, glycerophosphates, hemisulphates, heptanoates, hexanoates, hydrochlorides (prepared from hydrochloric acid (prepared from), hydrobromic acid hydrobromides (prepared from hydrochloric acid (prepared from)), , 2-hydroxyethanesulfonates, lactates, maleates (prepared from maleic acid), methanesulfonates (prepared from methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates , pivalates, propionates, salicylates, succinates, sulphates (e.g. those prepared from sulfuric acid), sulphonates , tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates.

The term "prodrug" represents a compound which can be, after administration, transformed either by a chemical process or by a metabolic route, to give a compound of formula (I), optionally in the form of salt, solvate and / or hydrate. For example, the esters capable of being hydrolyzed in the body can constitute 12 - prodrugs of compounds of formula (I) comprising a carboxylic function. The "prodrugs" are preferably administered orally.

According to the present invention, the compounds of formula (I) and their salts can be in a tautomeric form, obtained after migration of one or more hydrogen atoms within the molecule and consequently a rearrangement of certain bonds of the molecule. . The compounds of formula (I) can also exist in the form of trans and cis isomers and / or have one or more asymmetric centers, and therefore exist in the form of enantiomers and diastereomers. According to the present invention, the compounds of formula (I) can also exist in the form of a mixture of isomers (a mixture of trans and cis isomers, a mixture of diastereomers, a racemic mixture of enantiomers).

By default, when the stereochemistry of a compound (trans or cis isomer, asymmetric carbon R or S) is not specified, this compound can exist within the meaning of the invention, in all the forms of isomers or all the mixtures. of at least one of its isomers. The preparation of compounds in the form of a single stereoisomer can be carried out, for example, by asymmetric synthesis or by separation of a racemic mixture of enantiomers or of a mixture of diastereomers. This separation can be carried out according to techniques known to those skilled in the art such as liquid chromatography, asymmetric resolution, or fractional crystallization. Furthermore, according to the present invention, the compounds of formula (I) can also exist in a hydrated form.

According to the present invention, the compounds of formula (I) can be defined as a combination of all the groups, substituted or not, as defined above.

One aspect of the invention relates to compounds of formula (I) in which LI represents a single bond.

Another aspect of the invention relates to compounds of formula (I) 5 in which L 'represents a (C2-C6) alkyleneoxy or (C1-C6) alkoxy (C2-C3) alkylene group.

Preferred compounds within the meaning of the invention are compounds of formula (I) in which Ar 'represents an aryl or heteroaryl group optionally substituted with one to five groups chosen from: a halogen atom, a (C1-C6) radical alkyl, hydroxy, hydroxy (C1-C6) alkyl, (Ci-C6) alkoxy, (Ci-C6) alkoxy (C1-C3) alkyl, aryl, aryl (C1-C6) alkyl, aryl-O-, aryl-S -, aryl-CO-, cycloalkyl, cycloalkyl (C1-C6) alkyl, cyano, (Ci-C6) haloalkyl, (Ci-C6) haloalkoxy, heteroaryl, hétoaryl-O-, heteroaryl-S-, hétoaryl-CO-, heteroaryl (C1-C6) alkyl; for which the cycloalkyl, aryl and heteroaryl radicals may be optionally substituted with one to three groups chosen from: a halogen atom, a (C1-C6) alkyl, (C1-C6) alkoxy (CIC6) alkoxy (C1-C3) radical ) alkyl, (Ci-C6) haloalkyl, (Ci-C6) haloalkoxy, cyano.

Advantageously in the compounds of formula (I), the Ar ′ group is an aryl group optionally substituted with one to five groups as defined above.

The preferred aryl group of the invention is the phenyl group.

Other preferred compounds within the meaning of the invention are compounds of formula (I) in which Ar 'represents an aryl or heteroaryl group optionally substituted with one to five groups chosen from: 2889191 - 1.4 - a halogen atom, a (C1-C6) alkyl, hydroxy, hydroxy (CIC6) alkyl, (CI-C6) alkoxy, (Ci-C6) alkoxy (C1-C3) alkyl, cyano, (CIC6) haloalkyl, (Ci-C6) haloalkoxy radical, aryl-O-. Advantageously in these compounds, Art represents an aryl group.

Other preferred compounds within the meaning of the invention are compounds of formula (I) in which L2 represents an alkylene group (CIC6).

In other preferred compounds of formula (I), the group R2 represents a hydrogen atom.

Other preferred compounds within the meaning of the invention are compounds of formula (I) in which Q represents a group represented by NR5R6 as defined in formula (I) above.

In another advantageous aspect of the invention, the groups R5 and R6 present in the compounds of formula (I) independently represent a hydrogen atom, a (C1-C6) alkyl, NR3R4 (C2-C6) alkyl, cycloalkyl group. , aryl, aryl (C1-C6) alkyl, or else can form together and with the nitrogen atom to which they are bonded a nitrogenous heterocycle such as pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, piperazinyl, homopiperazinyl, N- (C1- C6) alkylcarbonylpiperazinyl, N- (CI-C6) alkylcarbonylhomopiperazinyle, N-arylpiperazinyle, N-arylhomopiperazinyle, N- (Ci-C6) alkylarylpiperazinyle, N- (C1-C6) alkylarylhomopiperazinyle-C6 or more optionally substituted by one or more C6-radicals-C6 alkyl, hydroxy, or (C1-C6) alkoxy.

A very advantageous aspect of the invention relates to compounds of formula (I) in which: E L) represents a single bond 2889191 -15 - E R 'and R2, identical or different, represent a hydrogen atom, a radical (Ci-C6) alkyl; E L2 represents a (C1-C6) alkylene group; É Ar 'represents an aryl group optionally substituted with one to five groups chosen from: a halogen atom, a (Ci-C6) alkyl, hydroxy, hydroxy (C1-C6) alkyl, (C1-C6) alkoxy radical, (C1-C6) alkoxy (C1-C3) alkyl, aryl, aryl (C1-C6) alkyl, aryl-O-, - aryl S-, aryl-CO-, cycloalkyl, cycloalkyl (C1-C6) alkyl, cyano, (Ci-C6) haloalkyl, (Ci-C6) haloalkoxy, heteroaryl, heteroaryl-O-, heteroaryl-S-, heteroaryl-CO-, heteroaryl (C1-C6) alkyl; for which the cycloalkyl, aryl and heteroaryl radicals can be optionally substituted with one to three groups chosen from: a halogen atom, a (C1-C6) alkyl, (C1-C6) alkoxy (CIC6) alkoxy (C1-C3) radical ) alkyl, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, cyano; É Q represents a group represented by NR5R6 as defined in formula (I) above.

Another very advantageous aspect of the invention relates to the compounds of formula (I) in which: É L 'represents a (C2-C6) alkyleneoxy or (C1-C6) alkoxy (C2-C3) alkylene group; É R ′ and R2, which may be identical or different, represent a hydrogen atom or a (Ci-C6) alkyl radical; E L2 represents a (C1-C6) alkylene group; É Ar 'represents an aryl group optionally substituted by one to five groups chosen from: a halogen atom, a (Ci-C6) alkyl, hydroxy, hydroxy (C1-C6) alkyl, (Ci-C6) alkoxy, ( C, -C6) alkoxy (C1-C3) alkyl, cyano, (CIC6) haloalkyl, (C1-C6) haloalkoxy; É Q represents a group represented by NR5R6 as defined in formula (I) above.

2889191 - 16 - Compounds which are particularly suitable for the implementation of the present invention are compounds of formula (I) for which: E LI represents a single bond E R ′ and R2, which are identical or different, represent an atom of hydrogen, a (CI-C6) alkyl radical; E L2 represents a (CI-C6) alkylene group; É Art represents an aryl or heteroaryl group optionally substituted with one to five groups chosen from: a halogen atom, a (C1-C6) alkyl, hydroxy, hydroxy (C1-C6) alkyl, (C1-C6) alkoxy radical, (CI-C6) alkoxy (CI-C3) alkyl, cyano, (CI-C6) haloalkyl, (C1-C6) haloalkoxy, aryl-O-. É Q represents a group represented by NR5R6 in which R5 and R6 independently represent a hydrogen atom, a (C1-C6) alkyl, NR3R4 (C2-C6) alkyl, cycloalkyl, aryl, aryl (CI-C6) alkyl group, or else can form together and with the nitrogen atom to which they are attached a nitrogenous heterocycle such as pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, piperazinyl, homopiperazinyl, N- (C1-C6) alkylcarbonylpiperazinyle, N- (C1-C6) alkylcarbonylhomopiperazinyle, Narylpiperazinyle, N-arylhomopiperazinyle, N- (CI-C6) alkylarylpiperazinyle, N- (C1-C6) alkylarylhomopiperazinyle optionally substituted by one or more radicals (CI-C6) alkyl, hydroxy, or (C6) (C6) alkyl, hydroxy, or (C6)

Specific examples of preferred compounds within the meaning of the invention are in particular compounds such as those illustrated in Table 1 as well as their pharmaceutically acceptable salts, solvates and hydrates. -17 -

Table 1

Ex. Structure Name Al (Z) -3- (4-Phenoxy-phenyl) -5- [4- (pyrrolidin-1- N NH ylmethyl) -benzylidene] -imidazolidine-2,4-dione A2 N NH N (Z ) -5- [4 (Cyclopentylaminomethyl) -benzylidene] - 0 \ 3- (4-phenoxy-phenyl) imidazolidine-2,4-dione A3 o (Z) -5- [4- (Benzylaminomethyl) benzylidene] -3- (4- N NH Np phenoxy-phenyl) -imidazolidine-2,4-dione A4 (Z) -5- [4- (Dimethylaminomethyl) -benzylidene] -3- i N NH \ (4-phenoxyphenyl) -imidazolidine-2 , 4-dione

NOT-

A5 (Z) -3- (4-Phenoxy-phenyl) -5- [4- (piperidin-1- N NH ylmethyl) benzylidene] -imidazolidine-2,4-dione N A6 (Z) -5- [4- (Azepan-1ylmethyl) -benzylidene] -3- (4- N NH phenoxy-phenyl) -imidazolidine-2,4-dione L \ N A7 (Z) -5- [4- (Morpholin-1-ylmethyl) -benzylidene ] -3- N NH J (4phenoxy-phenyl) -imidazolidine-2,4-dione A8 o (Z) -5- {4 - [(2Dimethylaminoethylamino) -methyl] - N NH HJN \ benzylidene} -3- (4 -phenoxyphenyl) - 0 imidazolidine-2,4-dione 1 A9 o (Z) -5- [4- (4Acetylpiperazin-1-ylmethyl) - N NH (I) benzylidene] -3- (4-phenoxy-phenyl) - o N imidazolidine-2,4-dione -18 - Al0 0 (Z) -3- (4-Phenoxy-phenyl) -5- [4- (4- N phenylpiperazin-1-ylmethyl) -benzylidene] - NNH imidazolidine- 2,4-dione

NOT

Al1 o (Z) -5- [4- (4-Benzylpiperazin-1-ylmethyl) - NxNH benzylidene] -3 (4-phenoxy-phenyl) - o N imidazolidine-2,4-dione Al2 (Z) -5 [ 4- (3Hydroxypyrrolidin-1-ylmethyl) - H benzylidene] -3- (4-Phenoxy-phenyl) - - N NH imidazolidine-2,4-dione B2 (Z) -l-Methyl-3- (4-phenoxy- phenyl) -5- [4N N '(pyrrolidin-1-ylmethyl) -benzylidene] - \ imidazolidine-2,4-dione B3 (Z) -5- [4 (3-Hydroxypyrrolidin-1-ylmethyl) - OH benzylidene] -1-methyl3- (4-Phenoxy-phenyl) - - NN imidazolidine-2,4-dione Cl (Z) -3- (4Phenoxy-phenyl) -5- [4- (pyrrol idin-1- NH ^ ylethyl) -benzylidene] -im idazolidine-2,4-dione N D1 C '(Z) -3- (4'-Chloro-biphenyl-4-yl) -5- [4 (pyrrol idin-1-ylmethyl) -benzylidene] -imidazolidine-2,4-dione

NNH \ N

The present invention also relates to various synthetic routes, which are illustrated in schemes 1 to 8 and in the examples below. The starting compounds can be obtained commercially or synthesized according to usual methods. It is understood that the present application is not limited to a particular synthetic route, and extends to other processes allowing the production of the compounds indicated. In all the schemes presented below, the groups Ar ', L', R ', R2, L2 and Q are as defined above in formula (I). The R, Ar and X groups respectively represent an alkyl or aryl radical and a nucleophuge group such as a chlorine or bromine atom, a mesylate, tosylate or triflate group.

The abbreviations used are recalled in the introduction to the experimental part.

In general, the present invention relates to a process for the synthesis of compounds of formula (I) as defined above, which consists in reacting a compound of formula (X): Art in which Art, LI, and RI are as defined previously, with an aldehyde of formula (Y): in which L2 and Q are as defined above, under standard Knoevanagel conditions, i.e. in the presence of a base in a suitable solvent, for example using sodium acetate in acetic anhydride, to yield the compound of formula (I) as defined above, in the form of a mixture of geometric isomers (E) and (Z).

In an advantageous aspect of the present invention, the process as defined above is carried out in the presence of pyrrolidine and a drying agent such as magnesium sulfate, in ethanol, and results in a single geometric isomer. More particularly if RI represents a hydrogen atom, the geometric isomer formed is the (Z) isomer. If R1 represents a methyl group, the geometric isomer formed is the (E) isomer.

The compounds of formula (X) can be prepared from known compounds, and more particularly according to the following schemes.

A suitably chosen isocyanate 1 can be added in water to a functionalized α-amino acid 2, in the presence of a base (such as NaOH, KOH, K2CO3, KHCO3, Na2CO3 or NaHCO3), to lead after acidification to urea 3. This intermediate compound 3 can then be treated in an organic or aqueous solvent in the presence of a catalytic amount of acid (such as hydrochloric acid, sulfuric acid, methanesulfonic acid or para-toluenesulfonic acid). and forming the corresponding compound X. Compound 3 can also lead to compound X by using a coupling agent of DCC or EDCI type in the presence of an activating agent of HOBt type and of a non-nucleophilic base such as TEA or DIEA, in an organic solvent such as DMF, THF or DCM (Espada, M. et al., Farmaco 45, 1237-1243 (1990)). A Knoevanagel reaction between compound X and a correctly functionalized aldehyde Y leads to the formation of the corresponding compound of formula (I).

Diagram 1 O L 'C Ar' N + H02C 2 $ 1 2 X

HN R1 O 0

N R1 / R1 \ Ar'H Ar '

HOC Li - Ar '

2889191 -21 - The compounds X can also be prepared according to the reactions described in scheme 2. The reaction of a properly functionalized amino ester compound 4 with an isocyanate 1, in an organic solvent such as THF, DCM or DMF in the presence of a base (for example TEA, K2CO3, KOH), leads intermediately to the formation of the urea compound 5 which, after intramolecular cyclization provides the corresponding compound X (Park, K.-H. et al., J. Org. Chem. 63 , 113-117 (1998).

Diagram 2 R1 L 'Ar') H R02C 5 0, R1 NN Ar '

X es C

Ar 'N' RO2C / 4

O

R1 + HN The compounds X can also be prepared according to the reactions described in scheme 3. The reaction of a correctly functionalized α-amino ester compound 4a with an isocyanate 1, in an organic solvent such as THF, DCM or DMF in the presence of 'a base (for example TEA, K2CO3, KOH), leads intermediately to the formation of the urea compound 5a which, after intramolecular cyclization provides the corresponding compound X'. A nucleophilic substitution reaction between compound X 'and an alkyl halide derivative in the presence of a base such as K2CO3 results in the corresponding compound X.

Diagram 3 1 4a 5a HO2C

O R1 N Ar '

Ar '/ L, \ C + H2N Ar L, \ NN' / H RO2C o NH Art 2889191 - 22 - The compounds X 'can also be prepared according to the reactions described in scheme 4. The reaction of an amine 6 with ethyl isocyanatoacetate in an organic solvent such as THF, DCM or DMF in the presence of a base (for example TEA, K2CO3, KOH), leads intermediately to the formation of the urea compound 5b which, after intramolecular cyclization provides the compound X 'corresponding.

Figure 4 The OCN Ar 'NH2 + Et02C

N H

EtO C 5a L '- Art Art

NH

Compounds X can also be prepared according to scheme 5 by reacting an α-amino ester compound 4 correctly functionalized with an amine 6. Amine 6, in the presence of a carbonyl donor reagent such as trisphosgene, CDI or the (Boc2) O / DMAP system and a correctly functionalized α-amino ester compound 4 leads to the formation of the urea compound 5 (Cotarca, L. et al., Synthesis 5, 553-576 (1996); Knölker, H .-J. Et al., Angew. Chem. Int. Ed. Engl. 34, 2497-2500 (1995)). This reaction is advantageously carried out in an organic solvent, typically aprotic such as THF or DCM. Compound 5, in the presence of a base (eg TEA, K2CO3, KOH) can cyclize intramolecularly to provide the corresponding compound X.

Diagram 5 L ') Ar' \ NH2 + R1 O HN / L 'N'R1 1 H / 6 5 R02C O x RO2C 4 Art N Art - 23 - The bromoaryl-hydanto'ine compounds of formula (a) can be prepared according to the reactions described in scheme 6 from 4-bromophenyl isocyanate. The reaction of the latter with an α-amino ester compound 4, in an organic solvent such as THF, DCM or DMF in the presence of a base (for example TEA, K2CO3, KOH), results in the intermediate formation of the urea compound 7 which , after intramolecular cyclization provides the corresponding compound X'a. A Knoevanagel reaction between compound X'a and a correctly functionalized aldehyde Y leads to the formation of the corresponding bromoaryl-hydantoin compound of formula (a). The compounds (a) can then be transformed into biaryl derivatives (l'b) by reaction with an aryl boronic acid (ArB (OH) 2) in the presence of a palladium catalyst (such as Pd (PPh3) 4 ) and a base (such as K2CO3 or Na2CO3). This reaction is advantageously carried out in an organic solvent, typically aprotic such as Toluene, DMF or DME, according to the conditions conventionally followed for Suzuki type couplings (Miyaura, N. et al., Synth Comm. 111, 513-519 (1981)). ).

Diagram 6 X'a

Y

NCO H2N RO2C 4 Compounds 8 can also be prepared from compound X 'and 2- (diethoxymethyl) -benzaldehyde according to the reactions described in scheme 7. Compound 8 can be converted into compound 9, in a solvent organic such as THF, DCM or DMF in the presence of an acid (eg trifluoroacetic acid, acetic acid, ptoluenesulfonic acid). A nucleophilic substitution reaction between compound 9 and an R1-X derivative in the presence of a base such as NaH or K2CO3 leads to derivative 10. Finally, a reductive amination reaction between a compound 10 and an amine HNR5R6 leads to the compounds of formula (Ic) corresponding. This reaction is advantageously carried out in an organic solvent, typically aprotic such as DCM or DCE, in the presence of a molecular sieve or of a drying agent (for example Na2SO4 or MgSO4), and of a reducing agent such as NaBH4, NaBH3CN or NaBH (OAc) 3.

Diagram 7 OEt OEt Art Art o / RI N Art

CHO Art

CHO 9 10 Art

The compounds of formula (Id) can be prepared according to the reactions described in scheme 8 from a compound 11. The latter is obtained from a compound X 'and an aldehyde Ya correctly functionalized according to the reaction scheme. described in scheme 1. A nucleophilic substitution reaction between compound 11 and an R1-X derivative in the presence of a base such as NaH or K2CO3 leads to derivative 12. Finally, a nucleophilic substitution reaction between a compound 12 and an amine HNR5R6 leads to the corresponding compounds of formula (Id). This reaction is advantageously carried out in an organic solvent, typically aprotic such as DMF, ACN or DMSO, in the presence of a base (eg TEA, K2CO3, KOH, NaH).

Diagram 8 N Art Art

-X

NH X. L2

N-R5 R6

O

SRI N Art Art

-X

The compounds according to the invention have shown properties as antagonists of melanin-concentrating hormone receptors (MCHR), preferably subtype I (MCHR-1). They generally exhibit an IC50, as determined below, preferably less than or equal to 500 nM, advantageously less than or equal to 100 nM.

The compounds according to the invention are particularly advantageous and can be used advantageously as anorectic agents, antidepressants, tranquilizers, or for reducing anxiety. They will also be of real interest in the treatment of obesity, or the control of food intake, or in that of excess fat. They can be used in all MCH dependent pathologies or disorders.

Another aspect of the invention relates to the use of the compounds of formula (I) as defined above as medicaments.

A subject of the present invention is also the pharmaceutical compositions comprising as active principle at least one compound of formula (I) as defined above, or one of its addition salts with an acid or with a pharmaceutically base. acceptable, alone or in combination with one or more inert, non-toxic pharmaceutically acceptable excipients or vehicles.

The invention also relates to a method of treating a pathology in which the melanin-concentrating hormone is involved, and in particular the pathologies and disorders mentioned above, comprising the administration to a subject, in particular a human, of a dose effective of a compound or of a pharmaceutical composition as defined above.

Mention may be made, for example, of saline, physiological, isotonic and buffered solutions which are compatible with pharmaceutical use and known to those skilled in the art. The compositions can contain one or more agents or vehicles chosen from dispersants, solubilizers, stabilizers, preservatives, etc. Agents or vehicles which can be used in formulations (liquid and / or injectable and / or solid) are in particular methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, acacia.

The compositions can be formulated in the form of an injectable suspension, gels, oils, tablets, suppositories, powders, hard capsules, capsules. It may in certain cases be advantageous to provide forms with controlled release, in particular with prolonged release by known dosage forms.

The compounds or compositions according to the invention can be administered in a pharmaceutically acceptable form by one of the various routes known for this type of active ingredient, although the oral route is the preferred route for this type of product in this type of application. . The injectable route can also be used when necessary, and in particular the intravenous route but also the intraperitoneal route, the intranasal route, the transdermal route, the intramuscular route or the intraarterial route. Preferably, a subject of the invention is the use of compounds of formula (I) for the preparation of a pharmaceutical composition which can be administered orally, in particular in the form of capsules or tablets.

The active substances of the pharmaceutical compositions according to the invention can be in any of the usual oral dosage forms comprising tablets, capsules and liquid preparations such as elixirs and suspensions containing various substances which mask color, flavor and color. stabilization. To produce the oral dosage forms according to the invention, in particular capsules, the active substance can be mixed with various conventional materials such as starch, calcium carbonate, lactose, sucrose and dicalcium phosphate to facilitate the process of dicalcium. 'encapsulation. Magnesium stearate, as an additive, provides a useful lubricant function if needed.

Likewise, a subject of the invention is the use of compounds of formula (I) for the preparation of a pharmaceutical composition which can be administered by injection. The active substances of the pharmaceutical compositions according to the invention can be dissolved or suspended in a sterile, pharmaceutically acceptable injectable liquid, such as sterile water, a sterile organic solvent or a mixture of these two liquids for administration by the intravenous route.

Other routes of administration may include, but are not limited to, subcutaneous implants, as well as buccal, sublingual, transdermal, topical, intranasal or rectal administration.

2889191 -28 - Biodegradable and non-biodegradable delivery systems can also be employed.

The pharmaceutical compositions according to the invention are advantageously intended for the treatment of diseases in which the activity of MCH is high. The pharmaceutical compositions according to the invention can therefore be used in particular for the treatment of obesity, for treating abnormal eating behavior or controlling food intake, in particular in the case of bulimia, for treating depression, for reducing anxiety.

The present invention therefore relates to the use of at least one compound of formula (I) as active principle for the preparation of a medicament intended for the treatment of a disease associated with MCH receptors.

Thus the present invention relates to the use of at least one compound of formula (I) as active principle for the preparation of a medicament intended for the treatment of obesity and associated diseases.

Among these associated diseases, we can mention hyperglycemia, hyperlipidemia, bulimia, hypercholesterolemia, sleep disorders such as sleep apnea, hypertension, cardiovascular diseases such as arteriosclerosis and especially type II diabetes and metabolic syndrome.

The present invention also relates to the use of at least one compound of formula (I) as active principle for the preparation of an appetite suppressant drug and / or of a drug causing weight loss.

In another aspect, the invention relates to the use of at least one compound of formula (I) as an active ingredient for the preparation of a medicament for the treatment of depression and / or depression. anxiety in humans.

In another aspect of the present invention, the compounds of formula (I) can also be used in combination with other agents or active principles used for the treatment of obesity, type II diabetes (e.g. rosiglitazone and / or metformin), hypertension and arteriosclerosis. Preferably, a compound of formula (I) can be used in combination with at least one agent used for the treatment of obesity such as an antagonist or a reverse agonist of the CB-1 receptors (for example rimonabant), an inhibitor reuptake of monoaminergic neurotransmitters (eg sibutramine or bupropion), a lipase inhibitor (eg orlistat), MC4 receptor agonist, 5-HT2c receptor agonist, receptor agonist or antagonist. ghreline.

According to the subject of the present invention, the compounds of formula (I) can also be used in combination with other agents or active principles used for the treatment of depression, anxiety. Preferably, a compound of formula (I) can be used in combination with at least one agent used for the treatment of depression such as a serotonin reuptake inhibitor (for example fluoxetine, sertraline, venlafaxine or citalopram ), a monoamine oxygenase inhibitor (eg moclobemide). Preferably, a compound of formula (I) can be used in combination with at least one agent used for the treatment of anxiety such as an agonist of the GABA-Omega macromolecular receptor complex (for example lorazepam), a receptor agonist. 5-HT1a serotonergics (eg buspirone).

In the context of the invention, the term treatment designates preventive, curative and palliative treatment, as well as the management of patients (reduction of suffering, improvement of living conditions, slowing of the progression of the disease. disease). The treatment can furthermore be carried out in combination with other agents or treatments.

According to a particular embodiment, the subject of the invention is the use of compounds of formula (I) for the preparation of a pharmaceutical composition which can be administered according to one of the preceding routes, dosed from 1 to 1000 mg of active principle for a composition formulated in the form of capsules or tablets, or from 0.1 to 500 mg of active principle for a composition formulated in the form of suppositories, ointments, creams, gels or aerosol preparations, administered in human therapy in one or more daily intakes . In the context of use for animals, the usable daily dose is between 0.01 and 100 mg per kg.

Other aspects and advantages of the present invention will emerge on reading the examples which follow, which should be considered as illustrative and not limiting.

EXPERIMENTAL PART

Abbreviations ACN = acetonitrile APTS = para-toluenesulfonic acid EtOH = ethanol BBr3 = bromine tribromide Bn = benzyl t-Bu = tert-butyl Boc = tert-butyloxycarbonyl CDI = 1,1'-carbonyldiimidazole DBU = 1,8diazabicyclo [5.4. 0] undec-7-ene DCM = dichloromethane DMAP = Ndimethylaminopyridine DMF = dimethyl formamide -31 - DMSO = dimethyl sulfoxide Et = ethyl EtOAc = ethyl acetate HCl = hydrochloric acid HOBT = 1-hydroxybenzotriazole hydrate H2SO4 = sulfuric acid K2CO3 = sulfuric acid K2CO3 potassium KOH = potassium hydroxide LDA = lithium diisopropylamide LAH = lithium aluminum hydride Me = methyl MeOH = methanol MgSO4 = magnesium sulfate NaBH4 = sodium borohydride NaBH3CN = sodium cyanoborohydride NaBH (OAc) 3 = sodium triacetoxyborohydride NaCI = sodium chloride Na2CO3 = sodium carbonate NaH = sodium hydride NaHCO3 = sodium hydrogencarbonate NaOH = sodium hydroxide Na2SO4 = sodium sulfate NH4CI = ammonium chloride Ph = phenyl Ph3P = trip henylphosphine TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran L = liter (s) mL = milliliter (s) = microliter (s) mmol = millimole (s) pmol = micromole (s) g = gram (s) mg = milligram ( s) pg = microgram (s) TA = ambient temperature Pf = melting point HPLC = high pressure liquid chromatography - 32 - LCMS = liquid chromatography coupled with mass spectroscopy APCI = chemical ionization at atmospheric pressure Tps ret. = Retention time Material and methods The compounds of the invention were obtained using conventional organic synthesis and parallel synthesis methods.

The HPLC spectra were carried out on a Shimadzu SCL10A apparatus and an Uptisphere UP50DB-5m C18 column (4.6 x50 mm) with a flow rate of 4 ml / min and at the wavelength of 220 nm.

HPLC / MS analyzes were performed on a Plateform LC Micromass spectrometer (TSK gel super ODS 4.6 mm ID x 5 cm column, flow rate 2.75 ml / min, gradient: 100% A to 100% B in 3 min, plateau of 100% of B 1 min, solvent A = water / 0.05% trifluoroacetic acid and solvent B = acetonitrile / water / trifluoroacetic acid 80/20 / 0.05).

Unless otherwise stated, the products used for the preparation of the compounds of formula (I) are commercial and were used without preliminary purification. The experimental protocols below are in no way limiting and are given by way of illustration.

Example A1

(Z) -3- (4-Phenoxy-phenyl) -5- [4- (pyrrolidin-1-ylmethyl) -benzylidene] imidazolidine-2,4-dione 2889191 - 33 - Step 1: preparation of Aa ([3- (4phenoxy-phenyl) -ureido] -ethylacetate) In a three-necked flask (250 mL), 6 g of 4-phenoxy-aniline (32 mmol, 1 eq.) Are dissolved in 100 mL of DCM. The reaction medium is cooled to 0 ° C. then a DCM solution (20 mL) containing 4.2 g of ethyl isocyanatoacetate is added dropwise. Stirring is continued at AT for 16 h. The reaction medium is concentrated to dryness and the residue obtained is taken up in 100 mL of Et2O. The insoluble compound is filtered to provide 9.5 g of Aa in the form of a greyish solid (yield: 94%) Step 2: preparation of Ab (3- (4phenoxy-phenyl) -imidazolidine-2,4-dione) in a flask (500 mL), 4.4 g of Aa (14 mmol) are dissolved in 200 mL of EtOH and then 1.1 g of NaOH (28 mmol, 2 eq.) in solution in a minimum of water are added slowly. Stirring is continued for 16 h at RT then the reaction medium is concentrated to dryness. The residue obtained is taken up in 20 ml of water and then 100 ml of a concentrated HCl solution are added dropwise. The reaction medium is heated at reflux for 1 h. After cooling, the precipitate formed is filtered, rinsed successively with 50 ml of water, 50 ml of EtOH and 50 ml of Et2O to provide 3.5 g of Ab in the form of a white powder (Yield: 93%) Step 3: preparation of Ac ((Z) 5- [4- (diethoxymethyl) -benzylidene] - (3- (4-phenoxy-phenyl) -imidazolidine-2, 4-dione) In a flask (500 mL) are introduced 260 mL of EtOH, 5.7 g of Ab (21 mmol), 5.2 g of 4-diethoxymethylbenzaldehyde (25.2 mmol, 1.2 eq), 3 g of MgSO4 (25.2 mmol, 1.2 eq) and 1.05 mL of pyrrolidine (12.6 mmol, 0. 6 eq) The reaction medium is stirred at reflux of EtOH for 7 h. The precipitate formed is filtered, rinsed with 50 ml of EtOH and then taken up in 50 ml of a DCM: MeOH mixture (90:10). After filtration of the insoluble particles, the solution obtained is concentrated to dryness The residue obtained is purified on silica by flash chromatography (eluent DCM: EtOAc 90:10) to provide 3.5 g of Ac in the form of a white powder. 1.2 g of Ab are also recovered (Yield: 46%) 2889191 - 34 - Step 4: preparation of Ad ((Z) -4- [2,5-Dioxo-1- (4-phenoxy-phenyl) -imidazolid in-4ylidenemethyl] -benzaldehyde) In a three-necked flask (50 mL), 12 mL of 'a solution of HCl (IN) are added to 1.7 g of Ac (3.7 mmol). The reaction medium is heated for 2 h at 50 C. The precipitate formed is filtered and then rinsed successively with 30 ml of water, 30 ml of EtOH and 30 ml of Et2O to provide 1.25 g of Ad in the form of a yellow solid. (Yield: 92%) Step 5: preparation of Al ((Z) -3- (4-phenoxy-phenyl) -5- [4- (pyrrolidin-1-ylmethyl) benzylidene] -imidazolidine-2,4-dione) 923 mg of Na2SO4 (6.5 mmol, 2.5 eq) are added in portions to a solution of DCM (50 mL) containing 1 g of Ad (2.6 mmol), 257 pL of pyrrolidine (3.1 mmol, 1.2 eq). After 30 min., 1.6 g of NaBH (OAc) 3 (7.4 mmol, 2.85 eq.) Are added and stirring is continued for 16 h at RT. The reaction medium is filtered and concentrated to dryness. The residue obtained is taken up in 10 mL of EtOH. The insoluble solid is filtered off and then rinsed successively with 10 ml of EtOH, 10 ml of Et2O and 10 ml of pentane to provide 1.2 g of Al in the form of a beige solid. The solid is recrystallized from methoxyethanol to provide 543 mg of Al in the form of a white solid (Yield: 48%) Mp: 242 C HPLC / MS purity: 100%; [M + H] + expected = 440; [M + H] + observed = 440 1H NMR (CDCl3): 7.3 7.5 (m, 8H, Harom); 7.0-7.2 (m, 5H, Harom); 6.86 (s, 1H, Hvinyl); 3.63 (s, 2H, Hbenz); 2.4-2.6 (m, 4H, Haliph), 1.25-1.4 (m, 4H, Haliph).

Examples A2 to A20

The compounds A2 to A12 are obtained from the compound Ac and the appropriate amines by following an experimental protocol equivalent to that followed for the preparation of A1. The amines used for the preparations from A2 to A12 are: cyclopentylamine for A2, benzylamine for A3, dimethylamine for A4, piperidine for A5, homopiperidine for A6, morpholine for A7, 2dimethylaminoethylamine for A8, 4-acetylpiperazine for A9, 4phenyl piperazine for A10, 4-benzyl piperazine for A11, 3-hydroxy pyrrolidine for Al2. - 36 - Ex. Structure Name PM Purity (M + H) + (M + H) + (g / mol) expected observed

A2 IoI (Z) -5- [4- (Cyclopentylaminomethyl) - 453.55 100% 454 454 NNH benzylidene] -3- (4-phenoxy-phenyl) - \ imidazolidine-2,4-dione A3 (Z) 5- [4 - (Benzylaminomethyl) - 475.55 97.3% 476 476 NH Hp benzylidene] -3- (4phenoxy-phenyl) - N imidazolidine-2,4-dione o A4 (Z) -5- [4 (Dimethylaminomethyl) - 413.48 100% 414 414 N ^ mi \ benzylidene] -3- (4phenoxy-phenyl) - N- imidazolidine-2,4-dione o A5 g (Z) -3- (4-Phenoxyphenyl) -5- [4- 453.55 85.1% 454 454 N NH () (piperidin-1-ylmethyl) benzylidene] - imidazolidin-2,4-dione A6 uo (Z) -5- [4- (Azépan-1ylmethyl) - 467.57 100% 468 468 N \ NH (j benzylidene] - 3- (4-Phenoxy-phenyl) o imidazolidine-2,4-dione A7 o 1 0 (Z) -5- [4- (Morpholin-1-ylmethyl) 455.52 100% 456 456 N NH (J benzylidene] -3 - (4-Phenoxy-phenyl) - N imidazolidine-2,4-dione \ 1 A8 0 (Z) -5- {4 - [(2- 456.55 100% 457 457 NH NN \ Dimethylaminoethylamino) -methyl] - \ benzylidene } -3- (4-Phenoxy-phenyl) imidazolidine-2,4-dione A9 (Z) -5- [4- (4-Acetylpiperazin-1- 496.57 100% 497 497 N "'NH ci) ylmethyl ) -benzylidene] -3- (4-phenoxy- N phenyl) imidazolidine-2,4-dione Al0 P (Z) -3- (4-Phenoxy-phenyl) -5- [4- (4-530.63 100% 531 531 phenylpiperazin-1-ylmethyl) - N NH benzylidene] imidazolidine-2,4-dione

NOT

Al1 0 0 (Z) -5- [4- (4-Benzylpiperazin-1- 544.66 100% 545 545 NNH ylmethyl) -benzylidene] -3- (4-phenoxy- "phenyl) -imidazolidine-2,4-dione Al2 N NH (y H (Z) -5- [4- (3-Hydroxypyrrolidin-1- 455.62 100% 456 456 o \ ylmethyl) -benzylidene] -3- (4-Phenoxy-phenyl) -imidazolidine-2,4- dione 2889 191 - 37 -

BI example

(E) -1-Methyl-3- (4-phenoxy-phenyl) -5- [4- (pyrrolidin-1-ylmethyl) benzylidene] -imidazolidine-2,4-dione o Step 1: preparation of Ba (1methyl- 3- (4-phenoxy-phenyl) -imidazolidine-2,4-dione) In a three-necked flask (100 mL), 1.0 g of Ab (3.7 mmol) are dissolved in 50 mL of DMF then 600 mg of K2CO3 (4.4 mmol, 1.2 eq.) are added. After 30 min. of stirring, 350 μL of methyl iodide are added at RT then stirring is continued at 55 C. After 2 h, 600 mg of K2CO3 and 350 μL of additional methyl iodide are added and stirring is maintained at 60 C for 7 h. The reaction medium is cooled, filtered and then concentrated to dryness. The residue obtained is taken up in 50 mL of DCM and then washed with 2 x 50 mL of water. The organic phase is dried and then concentrated to dryness. The residue obtained is purified on silica by flash chromatography (eluent DCM: Acetone 98: 2) to provide 850 mg of Ba in the form of a brown powder (yield: 81%) Step 2: preparation of Bb ((E) -5- [4- (d iethoxymethyl) -benzylidene] -1-methyl- (3- (4-phenoxy-phenyl) -imidazolidine2,4-dione) In a flask (100 mL) are introduced 50 mL of EtOH, 850 mg of Ba (3 mmol), 916 mg of 4-diethoxymethylbenzaldehyde (4.4 mmol, 1.47 eq), 530 mg of MgSO4 (4.4 mmol, 1.47 eq) and 183 pL of pyrrolidine (2.2 mmol, 0.73 eq). The reaction medium is stirred at reflux of EtOH for 7 h. The precipitate formed is filtered, rinsed with 50 ml of EtOH and then taken up in 50 ml of DCM. After filtration of the insoluble particles, the solution obtained is concentrated to dryness The residue obtained is purified silica by flash chromatography (eluent DCM: EtOAc 95: 5) to provide 700 mg of Bb in the form of an orange oil. 200 mg of Ba are also recovered (Yield: 65%) Step 3 : preparation of Bc ((E) -4- [3met hyl-2,5-dioxo-1- (4-phenoxyphenyl) -imidazolidin-4-ylidenemethyl] benzaldehyde) In a three-necked flask (50 mL), 10 mL of an HCl solution (IN) are added to a suspension of 700 mg of Bb (1.5 mmol) in 5 mL of water. The reaction medium is heated for 3 hours at 50 C. The precipitate formed is filtered and then rinsed successively with 20 ml of water, 20 ml of EtOH and 20 ml of Et2O to provide 430 mg of Bc in the form of a yellow solid. (Yield: 72%) Step 4: preparation of BI ((E) -1-methyl-3- (4-phenoxy-phenyl) -5- [4 (pyrrolidin-1-ylmethyl) -benzylidene] -imidazolidine-2, 4-dione) mg of Na2SO4 (1.35 mmol, 2.5 eq) are added in portions to a solution of 1, 2-dichloroethane (10 mL) containing 215 mg of Bc (0.54 mmol), 54 pL of pyrrolidine (0.65 mmol, 1.2 eq). After 30 min., 318 mg of NaBH (OAc) 3 (1.5 mmol, 2.78 eq.) Are added and stirring is continued for 16 h at RT. The reaction medium is filtered and concentrated to dryness. The residue obtained is purified on silica by flash chromatography (eluent DCM: MeOH 90:10) to provide 79 mg of BI in the form of a white solid (yield: 32%) Mp: 150 C HPLC / MS purity: 100 %; [M + H] + expected = 454; [M + H] + observed = 454 1H NMR (CDCl3): 7.9 (d, 2H, Harom); 7.3 7.5 (m, 6H, Harom); 7.15 (t, 1H, Harom); 7.0-7.15 (m, 4H, Harom); 6.47 (s, 1H, Hvinyl); 3.63 (s, 2H, Hbenz); 3.32 (s, 3H, Hmethyl); 2.45-2.6 (m, 4H, Haliph), 1.25-1.4 (m, 4H, Haliph).

2889191 - 39 -

Example B2

(Z) -1-Methyl-3- (4-phenoxy-phenyl) -5- [4- (pyrrolidin-1-ylmethyl) benzylidene] -imidazolidine-2,4-dione o Step 1: preparation of Bd ((Z ) -4 [3-Methyl-2,5-dioxo-1- (4-phenoxyphenyl) -imidazolidin-4-ylidenemethyl] benzaldehyde) In a three-necked flask (50 mL), 200 mg of Ad (0.52 mmol) are dissolved in 15 mL of DMF then 79 mg of K2CO3 (0.57 mmol, 1.1 eq.) are added. After 30 min. stirring, 36 μl of methyl iodide are added at 0 ° C. then stirring is continued at AT for 16 h. The reaction medium is cooled, filtered and then concentrated to dryness. The residue obtained is taken up in 50 mL of EtOAc and then washed with 2 x 50 mL of water. The organic phase is dried and then concentrated to dryness to provide 200 mg of Bd in the form of a slightly yellow powder (yield: 96.5%) Step 2: preparation of B2 ((Z) -1-Methyl-3- (4-) phenoxy-phenyl) -5- [4- (pyrrolidin-1-ylmethyl) -benzylidene] -imidazolidine-2,4-dione) mg of Na2SO4 (0.314 mmol, 2.5 eq) are added in portions to a solution of 1.2 -dichloroethane (3 mL) containing 50 mg of Bd (0.125 mmol), 11.4 pL of pyrrolidine (0.14 mmol, 1.2 eq). After 30 min., 79.8 mg of NaBH (OAc) 3 (0.38 mmol, 3 eq.) Are added and stirring is continued for 16 h at RT. The reaction medium is filtered and concentrated to dryness. The residue obtained is purified on silica by preparative HPLC to provide 40 mg of B2 in the form of a translucent oil. The oil is taken up in 2 mL of DCM and 200 μL of a solution of HCl (2 M) in Et2O are added. The medium is concentrated to dryness and the residue obtained is washed thoroughly with 20 mL of Et2O. The solid formed is filtered and then dried in an oven at 70 ° C. to provide 50 mg of B2.HCl (yield: 78%) HPLC / MS purity: 100%; [M + H] + expected = 454; [M + H] + observed = 454 o 2889191 - 40 - 1H NMR (CDCl3): 7.3 7.45 (m, 6H, Harom); 7.27 (d, 2H, Harom); 7.15 (t, 1H, Harom); 7.0-7.15 (m, 5H, Harom, Hvinyl); 3.64 (s, 2H, Hbenz); 3.06 (s, 3H, Hmethyl); 2.50-2. 55 (m, 4H, Haliph), 1.75-1.85 (m, 4H, Haliph).

Example B3

(Z) -5- [4- (3-Hydroxypyrrolidin-1-ylmethyl) -benzylidene] -3- (4-Phenoxyphenyl) -imidazolidine-2,4-dione

OH

Compound B3 is obtained from compound Bd and 3-hydroxy pyrrolidine by following an experimental protocol equivalent to that followed for the preparation of B2. 20 mg of B3.HCl are obtained in the form of a white powder from 100 mg of Bd (yield: 73%) HPLC / MS purity: 100%; [M + H] + expected = 470; [M + H] + observed = 470 1H NMR (CDCl3): 7.3 7.45 (m, 6H, Harom); 7.30 (d, 2H, Harom); 7.15 (t, 1H, Harom); 7.0-7. 15 (m, 5H, Harom, Hvinyl); 4.35-4.42 (m, 1H, Haliph); 3.66 (s, 2H, Hbenz); 3.06 (s, 3H, Hmethyl); 2.85-2.95 (m, 1H, Haliph); 2.67-2.72 (m, 1H, Haliph); 2.52-2.58 (m, 1H, Haliph); 2.40-2.45 (m, 1H, Haliph); 2.18-2.30 (m, 1H, Haliph); 1.78 -1.90 (m, 1H, Haliph)

Example C1

(Z) -3- (4-Phenoxy-phenyl) -5- [4- (pyrrolidin-1 -ylethyl) -benzylidene] imidazolidine-2,4-dione 2889191 -41 - Step 1: preparation of Ca (4- ( 2chloroethyl) -benzaldehyde) In a three-necked flask (500 mL), 10.95 mL of titanium tetrachloride (100 mmol, 2 eq.) Are added dropwise at 0 C and under a nitrogen atmosphere, on a DCM solution (40 mL) containing 7.9 mL of 2-chloroethylbenzene (60 mmol, 1.2 eq.) and 4.45 mL of dichloromethyl-methyl-ether (50 mmol, 1 eq.). Agitation is continued at 4 p.m. at AT. The reaction medium is poured into a water / ice mixture and then extracted with DCM. The dichlorinated phase is washed with 250 mL of a saturated NaCl solution, then dried over Na2SO4 and concentrated to dryness. The residue obtained is purified on silica by flash chromatography (eluent Cyclohexane: EtOAc 95: 5) to provide 5.97 g of Ca in the form of an oil (Yield: 71%) Step 2: preparation of Cb ((Z) - 5- [4- (2-chloroethyl) benzylidene] -3- (4-phenoxy-phenyl) -imidazolidine-2,4-dione) In a three-necked flask (50 mL) are introduced 30 mL of EtOH, 430 mg of Ab (1.6 mmol), 404 mg of Ca (2.4 mmol, 1.5 eq), 1.4 g of MgSO4 (12 mmol, 7.5 eq) and 150 pL of pyrrolidine (1.8 mmol, 1.125 eq). The reaction medium is stirred at reflux of EtOH for 8 h. The precipitate formed is filtered off, rinsed with 50 ml of EtOH and then taken up in 50 ml of DCM: MeOH (90:10). After filtration of the insoluble particles, the solution obtained is concentrated to dryness to provide 700 mg of Cb in the form of a white solid (yield: 100%) Step 3: preparation of Cl ((Z) -3- (4-Phenoxy -phenyl) -5- [4- (pyrrolidin-1-ylethyl) benzylidene] -imidazolidine-2,4-dione) In a three-necked flask (25 mL), 80 mg of potassium iodide (0.48 mmol, 1 eq.) are added to a pyrrolidine solution (2 mL) containing 200 mg of Cb (0.48 mmol). The reaction medium is heated at 70 ° C. for 3 h then concentrated to dryness. The residue obtained is taken up in 10 mL of DCM and then washed with 20 mL of water and 20 mL of a saturated NaCl solution. The organic phase is dried over Na2SO4 and then concentrated to dryness. The residue obtained is purified on silica by flash chromatography (eluent DCM: MeOH: NH4OH 95: 5: 0.5) to provide 21 mg of Cl in the form of a white solid (yield: 10%) 2889191 - 42 - Pf: 252 C HPLC / MS purity: 100%; [M + H] + expected = 454; [M + H] + observed = 454 1H NMR (CDCl3): 7.43 (d, 2H, Harom); 7.32 7.43 (m, 4H, Harom); 7.29 (d, 2H, Harom); 7.0-7.20 (m, 5H, Harom); 6.85 (s, 1H, Hvinyl); 2.87 (t, 2H, Hbenz); 2.73 (t, 2H, Haliph); 2.45-2.6 (m, 4H, Haliph), 1.25-1.4 (m, 4H, Haliph).

Example Dl (Z) -3- (4'-Chloro-biphenyl-4-yl) -5- [4- (pyrrolidin-1 -ylmethyl) benzylidene] - imidazolidine-2,4-dione Step 1: preparation of Da ( 4pyrrolidin-1-ylmethyl-benzonitrile) In a three-necked flask (500 mL), are added dropwise to a suspension of K2CO3 (52.8 g, 380 mmol) in 250 mL of DMF, 25 g of 4-cyanobenzyl bromide (120 mmol ) then 9.05 g of pyrrolidine (120 mmol). The reaction medium is stirred for 2 h at 60 ° C. then concentrated to dryness. The residue obtained is taken up in water. The aqueous phase is acidified by adding an HCl solution (1.5 N) until a pH 3 to 4 is obtained. The aqueous phase is extracted with 2x100 mL of EtOAc then the pH of the aqueous phase. is brought back to 10-11 by adding a solution of Na2CO3. The aqueous phase is then again treated with 5x100 mL of EtOAc. The organic phases are combined, dried over Na2SO4 and then concentrated to dryness to provide 17 g of Da (yield: 76%) Step 2: preparation of Db (4-pyrrolidin-1-ylmethyl-benzaldehyde) In a three-necked flask (500 mL), 17 g of Da are dissolved in 170 mL of DCM then the medium is cooled to -45 C. 152 mL of a solution of DIBAL-H ci 2889191 -43 - (2.7 M) in toluene are added dropwise. Stirring is continued for 2 h then the reaction is stopped by adding a saturated solution of NH4Cl. The organic phase is collected, dried over Na2SO4 and then concentrated to dryness to provide 15 g of Db (Yield: 87%) Step 3: preparation of Dc ([3- (4-bromo-phenyl) -ureido] -methyl acetate) In a three-necked flask (100 mL), a solution containing 2 g of 4-bromoaniline (11.6 mmol) and 1.76 g of TEA (17 mmol) in 15 mL of chloroform is added dropwise under a nitrogen atmosphere to a solution of triphosgene (2.76 g, 9.3 mmol) in 10 mL of chloroform. The formation of the isocyanate is checked by taking an aliquot and adding diethylamine. A suspension containing 1.46 g of methyl glycinate hydrochloride (11.6 mmol) in 10 mL of chloroform is then added dropwise. Stirring is continued for 16h at AT. The reaction is stopped by slowly adding water. The reaction medium is filtered, the organic and aqueous phases are separated and the aqueous phase is again extracted with 100 mL of chloroform. The organic phases are combined, dried over Na2SO4 and then concentrated to dryness. The residue obtained is purified on silica by flash chromatography (eluent petroleum ether: EtOAc 90:10) to provide 800 mg of Dc (yield: 24%) Step 4: preparation of Dd (3- (4-bromo-phenyl) - imidazolidine-2,4-dione) In a three-necked flask (250 mL), a few drops of concentrated sulfuric acid are added to a chlorobenzene solution (100 mL) containing 10 g of Dc (34.8 mmol). The reaction medium is heated under reflux of chlorobenzene for 8 h then concentrated to dryness. The residue obtained is triturated several times in hexane and then filtered to provide 8.2 g of Dd (Yield: 92%) 2889191 - 44 - Step 5: preparation of De ((Z) -3- (4-bromo-phenyl) - 5 - [(4-pyrrolidin-1-ylmethyl-benzylidene)] -imidazolidine-2,4-dione) In a three-necked flask (500 mL) are introduced 240 mL of EtOH, 5.0 g of Dd (19.6 mmol), 4.3 g of Db (22.5 mmol, 1.15 eq), 2.81 g of MgSO4 (23.5 mmol, 1.2 eq) and 980 pL of pyrrolidine (11.76 mmol, 0.6 eq). The reaction medium is stirred at reflux of EtOH for 8 h. The precipitate formed is filtered off, rinsed with 50 ml of EtOH and then taken up in 150 ml of DCM: MeOH (90:10). After filtration of the insoluble particles, the solution obtained is concentrated then left at RT and filtered to provide 3.75 g of De in the form of a white solid (Yield: 44.8%) Stage 6: preparation of Dl ((Z) -3- (4'-Chlorobiphenyl-4-yl) -5- [4- (pyrrolidin-1-ylmethyl) -benzylidene] -imidazolidine-2, 4-dione In a sealed tube, 999.3 mg of De (2.34 mmol) and 693 mg of 4-chlorophenyl boronic acid (4.43 mmol) are dissolved in 45 mL of toluene. 853 mg of Na2CO3 then 40 mg of tetrakis (trimethylphosphine) palladium (0) are added successively. The reaction medium is stirred under reflux of toluene. for 7 h then filtered and concentrated to dryness. The residue obtained is taken up in methanol. The insoluble solid is filtered off and the filtrate is concentrated to dryness then purified by preparative HPLC to provide 55 mg of Dl in the form of a white powder (Yield: 4%) HPLC / MS purity: 100%; [M + H] + expected = 458; [M + H] + observed = 458.

Biological results: 1. Cell culture: The CHO cells stably transfected with the MCHR1 receptor (Melanin Concentrating Hormone Receptor type 1) are cultured at 37 ° C. in DMEM Glutamax medium with sodium pyruvate at 0.1 pg / mL (Invitrogen ref. 31966 -021) containing 5% fetal calf serum (Invitrogen ref. 26400044), 1% non-essential amino acids (Invitrogen ref. 11140-2889191 45 - 035), 600pg / mL of Geneticin (Invitrogen 10131-027) under humid atmosphere containing 5% CO2. The culture medium was changed every 2-3 days.

II. Preparation of the cell suspension: After having aspirated the culture medium, the cells are washed with a PBS buffer "" at pH 7.4 (Sigma ref. D5652) maintained at 37 ° C., then detached with a solution of PBS "- 0.5 mM EDTA / NaOH. The cells are centrifuged at 500 xg for 5 minutes at 4 C and are resuspended in PBS - buffer at pH 7.4 at 4 C, then centrifuged again at 500 xg, the pellet is resuspended in 50mM Tris / HCI buffer, 5mM EDTA / Tris, 20mM NaCl, 5mM KCI, 5mM MgCl2, 1.5mM CaCl2, Trypsin inhibitor 10pg / mL, Leupeptin 1 pg / mL, PMSF 75pg / mL at the density of 50.106 cells / mL . The cells are lysed by ultrasound (vibro cell 72405). The homogenate is centrifuged at 50,000 g for 15 minutes at 4 C. The pellet is homogenized with a 26G needle in 2 mL of 50 mM Tris / HCl buffer, EDTA / Tris 5mM, 20mM NaCl, 5mM KCl, 5mM MgCl2, 1.5mM CaCl2, Trypsin inhibitor 10pg / mL, Leupeptin 1 pg / mL, PMSF 75pg / mL, 10% glycerol, 10% sucrose.

III. MCH1 receptor binding test (h): The membrane preparation is incubated for 1 hour at 22 ° C. in incubation buffer at pH 7.4 containing 25 mM HEPES, 1 mM of calcium chloride, 5 mM of magnesium chloride, 1 pM pepstatin , 1 pg / mL Leupeptin, 10 pg / mL Trypsin inhibitor, 5 pg / mL of bovine albumin and 0.1 nM of Phe13 [125I] Tyr19 -MCH (Perkin Elmer, NEX375). The reaction is stopped by filtration through a GF / B filter pretreated with 25 mM HEPES / Tris, 1 mM of calcium chloride, 5 mM of magnesium chloride, 500 mM NaCl, 1 pg / mL of bovine albumin pH 7.4 and washed four times with 1 mL of 25 mM HEPES / Tris buffer, 1 mM of calcium chloride, 5 mM of magnesium chloride, 500 mM NaCl, 1 pg / mL of bovine albumin pH 7.4. The radioactivity deposited on the filter is counted by liquid scintillation 2889191 - 46 - (TopCount, Packard). The non-specific binding is determined in the presence of 0.1 pM of MCH (Bachem, H1482). The results are expressed as IC50 values in nM calculated by nonlinear regression with 4 parameters.

The compounds of the present invention have shown good affinity for MCH1 receptors. By way of example, the compound of Example A1 has an average IC50 of less than 400 nM.

IV. Functional test - Measurement of intracellular calcium mobilization: 24 hours before the experiment, the cells are seeded in 96w Greiner plates, black with a transparent bottom, at a density of 30,000 cells / well in the presence of 1% fetal calf serum, under a volume of 100 pI. The plates are stored at 37 ° C. in a humid atmosphere containing 5% CO2. On the day of the experiment, the cells are incubated in the presence of a fluorescent probe (Molecular Devices, ref: R8033) in a final volume of 200 μl. This probe is prepared in HBSS buffer containing probenecid at the final concentration of 2.5 mM. After 60 minutes of charging at 37 ° C., the cell plates are placed on the FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices) which makes it possible to detect in real time variations in intracellular calcium concentrations under the effect of agonists. The fluorescence of the cells is followed before and after the addition of the agonists (excitation wavelength: 488 nm and emission length: 540 nm).

The compounds of formula (I) according to the present invention have shown a concentration-dependent antagonist effect on intracellular calcium mobilization induced by addition of MCH.

V. Food intake in mice The day before the experiment, OFI male mice (Charles River, France) with a body weight of between 20 and 25 g, are distributed randomly between the different groups (n = 8), then the homogeneity of the groups is verified on the body weight of the animals. The animals have unlimited access to water throughout the study.

On the day of the experiment, the animals on an overnight fast are treated intraperitoneally or orally in a volume of 10 mL / kg, then placed in an individual cage. 30 min after treatment by the ip route, or 60 min by the oral route, each mouse is brought into contact with a pre-weighed quantity of food (A04, UAR). The food is then weighed 1 h, 2 h, 3 h and 5 h after this addition. Food consumption is expressed in grams of food per mouse, as the mean S.E.M. (n = 8). Statistical analysis uses ANOVA followed by Dunnett's multiple comparison test. The level of significance is obtained for p <0.05.

The compounds of formula (I) according to the present invention have made it possible to reduce food intake. By way of example, the compound of Example A1 at a dose of 30 mg / kg makes it possible to reduce the food intake by 41% after three hours compared to the control.

VI. Forced Swimming Test in Mice The forced swimming test is a preclinical behavioral model that has good predictive validity and is widely used to determine the efficacy of antidepressant drugs (Borsini, F., Meli, A. Psychopharmacology 94 (2), 147-160 (1988)). The results are expressed as the total duration of immobility in seconds and as a percentage change in the total duration of immobility calculated from the mean value of the control group.

Swiss CD1 (CD-1 (ICR) IGS (Charles River France) mice weighing between 25 and 35 g are placed in a room at a temperature between 19.5 and 24.5 C and a relative humidity of 45 to 65% with a light cycle / 12h darkness, ad libitum access to filtered water and standard laboratory food pellets. They are placed 15 to 20 per cage, for an acclimatization period of at least 5 days before testing. identified by markings on the fur.

2889191 - 48 - On the day of the experiment, the animals are treated intraperitoneally or orally in a volume of 10 mL / kg, then placed in an individual cage. 30 min after treatment by the ip route, or 60 min by the oral route, the mice are subjected to the forced swimming test, in a vertical plexiglass cylinder (height: 24 cm, diameter 9 cm) containing water (height 6 cm, temperature: 18-22 C). The total period of immobility is measured during the last four minutes of the test, lasting a total of six minutes. A mouse is considered immobile when it stops struggling and floats in the water without movements superfluous to those allowing it to keep its head above the water. A reduction in immobility time is a reflection of an antidepressant effect.

Statistical significance between the treated groups and the control group is determined with Dunnett's test using residual variance after analysis of variance (P <0.05). Data is analyzed using SigmaStat software.

The compounds of the present invention have shown a notable effect in reducing the time of immobility. By way of example, the compound of Example A1 made it possible to reduce the immobility time by 57% compared to the control.

- 49 -

Claims (18)

1. Compounds of the following general formula (I): Ar 'o NOT in which: É Ar 'represents an aryl or heteroaryl or cycloalkyl or heterocyclic group optionally substituted with one to five groups chosen from: a halogen atom, a (C1-C6) alkyl, hydroxy, hydroxy (CIC6) alkyl, ( C1-C6) alkoxy, (CI-C6) alkoxy (C1-C3) alkyl, aryl, aryl (C1-C6) alkyl, aryl-O-, aryl-S-, aryl-CO-, cycloalkyl, cycloalkyl (C1- C6) alkyl, cyano, (CI-C6) haloalkyl, (C1-C6) haloalkoxy, (CH2) nNR3R4, - (CH2) nCOR3, - (CH2) nCO2R3, - (CH2) nNR4SO2R3, - (CH2) nC (0 ) NR3R4, heteroaryl, heteroaryl-O-, heteroaryl-S-, heteroaryl-CO-, heteroaryl (CI-C6) alkyl and heterocyclic; for which the cycloalkyl, aryl, heteroaryl and heterocyclic radicals can be optionally substituted with one to three groups chosen from: a halogen atom, a (Ci-C6) alkyl, hydroxy, hydroxy (C1-C6) alkyl, (C1) radical -C6) alkoxy, (C, -C6) alkoxy (CI-C3) alkyl, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, cyano, - (CH2) nNR3R4, - (CH2) nCOR3, - (CH2 ) nCO2R3, - (CH2) nNR4SO2R3, - (CH2) nC (0) NR3R4; É L 'represents a single bond or a (C1-C6) alkylene, (C2-C6) alkyleneoxy, (CI-C6) alkoxy (C2-C3) alkylene, (C2-C6) alkylidene, (C2-C6) alkylidenoxy group ; 2889191 -50- É R ′ and R2, which may be identical or different, represent a hydrogen atom or a (C1-C6) alkyl radical; E L2 represents a single bond or a (C1-C6) alkylene group; É Q represents a basic group or a group represented by NR5R6 for which - R5 and R6, identical or different, represent a hydrogen atom, a (CI-C6) alkyl, hydroxy (C1-C6) alkyl, (C1-) group C6) alkoxy (C1-C3) alkyl, NR3R4 (C2-C6) alkyl, cycloalkyl, aryl, aryl (C1-C6) alkyl, heteroaryl, heteroaryl (C1-C6) alkyl, for which the cycloalkyl, aryl and heteroaryl radicals can be optionally substituted with one to three groups chosen from: a halogen atom, a (C1-C6) alkyl, hydroxy, hydroxy (CI-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy ( Ct-C3) alkyl, (CIC6) haloalkyl, (C1-C6) haloalkoxy, cyano, - (CH2) nNR3R4, - (CH2) nCOR3, - (CH2) nCO2R3, - (CH2) nNR4SO2R3, - (CH2) nC ( 0) NR3R4; R5 and R6 can form together and with the nitrogen atom to which they are attached a nitrogenous heterocycle such as azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, piperazinyl, homopiperazinyl, N- (C1-C6) alkylpiperazinyl, N- (CI - C6) alkylhomopiperazinyle, N- (C, -C6) alkylcarbonylpiperazinyle, N- (C1- C6) alkylcarbonylhomopiperazinyle, N-arylpiperazinyle, N-arylhomopiperazinyle, N- (C1-C6) alkylaryl- (C1-C6) alkylaryl (C6) substituted by one or more radicals (C1-C6) alkyl, hydroxy, hydroxy (CI-C6) alkyl, (CIC6) alkoxy, (C1-C6) alkoxy (C1-C3) alkyl R5 and / or R6 can form with L2 and with the nitrogen atom to which they are attached a mono or polycyclic, saturated or unsaturated nitrogenous heterocycle, such as pyrrolidine, piperidine, homopiperidine, piperazine, homopiperazine optionally substituted by one or more 2889191 -51 - (C1-C6) alkyl radicals , hydroxy, hydroxy (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C3) alkyl É R3 and R4, identi ques or different, represent a hydrogen atom or a (Ci-C6) alkyl radical; É n is an integer between 0 and 4. 2. Compounds of formula (I) according to claim 1, characterized in that L 'represents a single bond. 3. Compounds of formula (I) according to claim 1, characterized in that LI represents a (C2-C6) alkyleneoxy or (C1-C6) alkoxy (C2-C3) alkylene group. 4. Compounds of formula (I) according to claim 1, characterized in that Arp represents an aryl or heteroaryl group optionally substituted with one to five groups chosen from: a halogen atom, a (C1-C6) alkyl or hydroxy radical , hydroxy (C1- C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy (C, -C3) alkyl, aryl, aryl (C1-C6) alkyl, aryl-O-, aryl-S-, aryl-CO-, cycloalkyl, cycloalkyl (C1-C6) alkyl, cyano, (C, -C6) haloalkyl, (C1-C6) haloalkoxy, heteroaryl, heteroaryl-O-, heteroaryl-S-, heteroaryl-CO-, heteroaryl (C, -C6) alkyl; for which the cycloalkyl, aryl and heteroaryl radicals can be optionally substituted with one to three groups chosen from: a halogen atom, a (C1-C6) alkyl, (C1-C6) alkoxy (CI-C6) alkoxy (C1) radical -C3) alkyl, (CI-C6) haloalkyl, (Ci-C6) haloalkoxy, cyano. 5. Compounds of formula (I) according to claim 1, characterized in that L2 represents a (C1-C6) alkylene group. - 52 - 6. Compounds of formula (I) according to claim 1, characterized in that the group R2 represents a hydrogen atom. 7. Compounds of formula (I) according to claim 1, characterized in that Q represents a group represented by NR5R6 as defined in claim 1. 8. Compounds of formula (I) according to claim 1, characterized in that: É L 'represents a single bond É R' and R2, which are identical or different, represent a hydrogen atom, a (C1-C6) alkyl radical. ; E L2 represents a (C, -C6) alkylene group; É Ar 'represents an aryl group optionally substituted with one to five groups chosen from: a halogen atom, a (CI-C6) alkyl, hydroxy, hydroxy (C1-C6) alkyl, (C1-C6) alkoxy radical, (CI-C6) alkoxy (C, -C3) alkyl, aryl, aryl (C, -C6) alkyl, aryl-O-, - aryl S-, aryl-CO-, cycloalkyl, cycloalkyl (C, -C6) alkyl , cyano, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, heteroaryl, heteroaryl-O-, heteroaryl-S-, heteroaryl-CO-, heteroaryl (C1-C6) alkyl; for which the cycloalkyl, aryl and heteroaryl radicals can be optionally substituted with one to three groups chosen from: a halogen atom, a (C1-C6) alkyl, (Ci-C6) alkoxy (CIC6) alkoxy (C1-C3) ) alkyl, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, cyano; É Q represents a group represented by NR5R6 as defined in claim 1. 9. Compounds of formula (I) according to claim 1, characterized in that: É L 'represents a (C2-C6) alkyleneoxy or (C1-C6) alkoxy (C2C3) alkylene group; 2889191 - 53 - É R 'and R2, which may be identical or different, represent a hydrogen atom or a (C1-C6) alkyl radical; E L2 represents a (C1-C6) alkylene group; É Ar 'represents an aryl group optionally substituted by one to five groups chosen from: a halogen atom, a (C1-C6) alkyl, hydroxy, hydroxy (CIC6) alkyl, (CI-C6) alkoxy, (C1-) radical C6) alkoxy (C1-C3) alkyl, cyano, (CIC6) haloalkyl, (C1-C6) haloalkoxy; É Q represents a group represented by NR5R6 as defined in claim 1. 10. Compounds of formula (I) according to claim 1, characterized in that: É L 'represents a single bond É R' and R2, which are identical or different, represent a hydrogen atom, a (CI-C6) alkyl radical. ; E L2 represents a (CI-C6) alkylene group; É Ar 'represents an aryl or heteroaryl group optionally substituted with one to five groups chosen from: a halogen atom, a (C1-C6) alkyl, hydroxy, hydroxy (CI-C6) alkyl, (C, -C6) radical alkoxy, (C, -C6) alkoxy (C, -C3) alkyl, cyano, (CI-C6) haloalkyl, (C1-C6) haloalkoxy, aryl-O-. É Q represents a group represented by NR5R6 in which R5 and R6 independently represent a hydrogen atom, a (CI- C6) alkyl, NR3R4 (C2-C6) alkyl, cycloalkyl, aryl, aryl (C, -C6) alkyl group , or else can form together and with the nitrogen atom to which they are bonded a nitrogenous heterocycle such as pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, piperazinyl, homopiperazinyle, N- (Cj-C6) alkylcarbonylpiperazinyle, N- (C1-C6 ) alkylcarbonylhomopiperazinyle, Narylpiperazinyle, N-arylhomopiperazinyle, N- (C, -C6) alkylarylpiperazinyle, N- (C1-C6) alkylarylhomopiperazinyle optionally substituted by one or more radicals (C1-C6) alkyl or (C1-C6) alkyl or hydroxy, C6) . 2Q89191 - 54 - 11. A process for preparing the compounds of formula (I) according to claim 1, consisting in reacting a compound of formula (X): Ar 'in which Art, LI, and RI are as defined in claim 1, with a aldehyde of formula (Y): Y wherein L2 and Q are as defined in claim 1, under standard Knoevanagel conditions, in the presence of a base in a suitable solvent. 12. Use of the compounds of formula (I) according to one of claims 1 to 10 as medicaments. 13. Pharmaceutical compositions comprising as active principle at least one compound of formula (I) as defined in one of claims 1 to 10, or one of its addition salts with an acid or with a pharmaceutically acceptable base, alone or in combination with one or more inert, non-toxic pharmaceutically acceptable excipients or vehicles. - 55 - 14. Use of at least one compound of formula (I) according to one of claims 1 to 10, as active principle for the preparation of a medicament for the treatment of obesity and associated diseases. 15. Use of at least one compound of formula (I) according to one of claims 1 to 10, as active principle for the preparation of an appetite suppressant drug and / or a drug causing loss of weight. 16. Use of at least one compound of formula (I) according to one of claims 1 to 10, as an active principle for the preparation of a medicament intended for the treatment of depression and / or anxiety. 17. Use of at least one compound of formula (I) according to one of claims 1 to 10 in combination with at least one other agent or active principle used for the treatment of obesity, type II diabetes, hypertension or arteriosclerosis. 18. Use of at least one compound of formula (I) according to one of claims 1 to 10 in combination with at least one other agent or active principle used for the treatment of depression or anxiety.