FR2891825A1 - 1-AMINO-ISOQUINOLINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Abstract

The invention relates to 1-amino-isoquinoline derivatives of general formula (I) in which, R = H, C1-5-alkyl, C1-3-fluoroalkyl, C3-6-cycloalkyl, C1-3-alkylene- C 3-6 cycloalkyl, -C (O) -C 1-5 -alkyl, -CH 2 -C = CH, C 2-4 -alkylene-NRaRb, C 1-3 -alkylene-X-C 1-3 -alkyl where X = O or SO2; R1 = optionally substituted aryl or heteroaryl; R2 = H or C1-5-alkyl group; R4 = H, C1-5-alkyl, C1-3-fluoroalkyl, C3-6-cycloalkyl, C1-3-alkylene-C3-6-cycloalkyl, C1-3-alkylene-O-C1-3-alkyl, C1- 3-alkylene- (OH), C1-3-alkylene-X-C1-3-alkyl wherein X = S, SO or SO2, or R4 = C1-3-alkylene-NRaRb, aryl, C1-3-alkylene- optionally substituted aryl, C1-3-alkylene-O-aryl, C1-3-alkylene-O-C1-3-alkylene-aryl, heteroaryl or C1-3-alkylene-heteroaryl, or R4 = heterocycle optionally substituted by a group C1-3-alkyl, -C (O) -C1-5-alkyl, -C (O) -C1-5-fluoroalkyl, C1-3-alkylene-C3-6-cycloalkyl, C1-3-alkylene-aryl, Optionally substituted C1-3-alkylene-heteroaryl; R7 = H, halogen, C1-5-alkyl, C1-3-fluoroalkyl, C1-5-alkoxy, C1-3-fluoroalkoxy, C1-3-alkylene- (OH), -CN, -COOH, -C (O) ) O-C1-3-alkyl, -NO2, -X-C1-3-alkyl where X = S, SO or SO2, or R7 = -NRaRb, C1-3-alkylene-NRaRb, -C (O) - NRaRb, -C (O) -C 1-3 -alkyl, aryl, -O-aryl or optionally substituted heteroaryl; Rp and R'p = H, C1-5-alkyl, or Rp and R'p together form a single bond or C1-4-alkylene; in the form of a base or an acid addition salt, and than in the state of hydrate or solvate. Preparation process and therapeutic application

Description

) R2 DERIVATIVES OF 1-AMINO-ISOQUINOLINE, THEIR PREPARATION AND THEIR USE

  The present invention relates to 1-amino-isoquinoline derivatives, their preparation and their therapeutic application. The search for MCH1 receptor antagonists (Melanin-Concentrating Hormone), the MCH1 receptor, is attracting interest from many pharmaceutical companies. A number of patent applications have been filed among which are WO01 / 21577 (Takeda), W002 / 06245 (Synaptic), W003 / 106452 (Millennium). A number of publications have appeared including Ma V.V. et al (Amgen) 224th Nat. ACS Boston Meeting. Poster MEDI 343 (21.08.2002). During the last decade, it has been demonstrated that many neuropeptides are involved in the central regulation of eating behavior and energy balance (Inui et al, TINS 1999; 22 (2): 62-67). MCH is one of these neuropeptides. Two MCH receptors have been cloned recently, the MCH receptor, previously called SLC-1 receptor or GPR24 (Chambers et al., Nature 1999; 400: 261-265), and the MCH2 receptor previously called SLT (Mori et al., Biochem Biophys Res Commun 2001; 283: 1013-1018). There is therefore a real interest in finding new compounds for modulating the activity of the MCH1 receptor, the MCH receptor 1. It has now been found that compounds, derived from 1-amino-isoquinoline, are very affine and selective towards the MCH1 receptor. The subject of the present invention is compounds of the following formula (I): ## STR3 ## wherein R represents a hydrogen atom, a C 1 -C 5 -alkyl, C 1 -C 3 -fluoroalkyl or C 3 -C 6 -cycloalkyl group, C 1 -C 3 -alkylene-C 3-6 cycloalkyl, -C (O) -C 1-5 -alkyl, -CH 2 -C = CH, C 2-4 -alkylene-NRaRb, C 1-3 -alkylene-X-C 1-3 -alkyl wherein X is O or SO 2; R1 represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; R2 represents a hydrogen atom or a C1-5alkyl group; R4 represents a hydrogen atom or a C1-5-alkyl, C1-3-fluoroalkyl, C3-6-10 cycloalkyl, C1-3-alkylene-C3-6-cycloalkyl, C1-3-alkylene-O-C1-3-alkyl, C1-3-alkylene- (OH), C1-3alkylene-X-C1-3alkyl wherein X is S, SO or SO2, or R4 is C1-3alkylene-NRaRb, aryl, C1-3alkylene-aryl, C1-3alkylene-O-aryl, C1-3alkylene-O-C1-C3alkylene-aryl, heteroaryl or C1-3alkyleneheteroaryl; aryl, C1-3-alkylene-aryl, C1-3-alkylene-O-aryl, C1-3-alkylene-O-C1-3-alkylene-aryl, heteroaryl and C1-3-alkylene-heteroaryl groups being optionally substituted with one or more radicals; Z identical or different from each other,. or R4 represents a heterocycle group; said heterocycle being optionally substituted by a C1-3-alkyl, -C (O) -C1-5-alkyl, -C (O) -C1-5-fluoroalkyl, C1-3alkylene-C3-6-cycloalkyl, C1-3alkylene-aryl group, C 1-3 alkylene-heteroaryl; C1 -3-alkylene-aryl and C1 -3-alkylene-heteroaryl groups being optionally substituted with one or more Z radicals which are the same or different from each other; R7 represents a hydrogen or halogen atom or a C1-5alkyl, C1-3-fluoroalkyl, C1-5alkoxy, C1-3-fluoroalkoxy or C1-3alkylene-OH group, -CN, -COOH, -C (O) group; O-C1-3alkyl, -NO2, -X-01.3-alkyl wherein X is S, SO or SO2, 25. or R7 is -NRaRb, C1.3-alkylene-NRaRb, -C (O) -NRaRb, -C (O) -C1-3-alkyl, aryl, -O-aryl or heteroaryl; the aryl, -O-aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; Rp and R'p represent independently of each other a hydrogen atom or a C1-5 alkyl group, or Rp and R'p together form a single bond or a C1-4alkylene group; Z represents a halogen atom or a C1-5-alkyl, C1-3-fluoroalkyl, C3-6-cycloalkyl, C1-3-alkylene-C3-6-cycloalkyl, a phenyl, C1-5-alkoxy, C1-3-fluoroalkoxy or C1-3alkylene group; -O-C1-3alkyl, C1-3alkylene- (OH), NO2, -ON, -SO2NRaRb, -X-C1-3-alkyl, C1-3-alkylene-X-C1-3alkyl wherein X is S, SO or SO2,. or Z represents a group -NRaRb, C1-3alkylene NRaRb, -C (O) -NRaRb, -C (O) -C1-3alkyl, -C (O) O-C1-4alkyl, -C (O) - C 3-6 cycloalkyl, or Z represents an oxo radical, or Z represents a group -O-C1-5-alkylene-NRaRb,. or two adjacent Z radicals together form a C1-3-alkylenedioxy group; Ra and Rb are each, independently of the other, a hydrogen atom or a C1-3 alkyl or -C (O) -C1-3 alkyl group. or Ra and Rb together with the nitrogen atom carrying them a heterocycle optionally substituted by one or more C1 -3 alkyl or oxo groups.

  The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention. The compounds of formula (I) may comprise one or more rings. They can therefore exist in the form of axial / equatorial isomers, or endo / exo, or cis / trans. These isomers and their mixtures are part of the invention.

  The compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention. The compounds of formula (I) may also exist in the form of hydrates and / or solvates, namely in the form of combinations or combinations with one or more molecules of water and / or of solvent. Such hydrates and solvates are also part of the invention. In the context of the present invention, the following terms are understood: ## STR1 ## where t and z may take the values from 1 to 6, a carbon chain or ring which may have from t to z carbon atoms, for example C 1-3 may be a chain carbonaceous having 1 to 3 carbon atoms; A halogen atom: a fluorine, a chlorine, a bromine or an iodine; an alkyl group: a linear or branched, saturated monovalent aliphatic group. By way of example, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and the like; an alkylene group: a divalent saturated, linear or branched aliphatic group. By way of example, a C1 -3-alkylene group represents a divalent carbon chain of 1 to 3 carbon atoms, linear or branched, such as a methylenyl (-CH 2 -), an ethylenyl (-CH 2 CH 2 -), a 1-methylethylenyl ( -CH (CH3) CH2-), a propylenyl (-CH2CH2CH2-), etc .; a cycloalkyl group: a saturated cyclic aliphatic group. By way of examples, mention may be made of cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; an alkoxy group: an O-alkyl radical where the alkyl group is as previously defined; an alkylenedioxy group; an O-alkylene-O- group, wherein the alkylene group is as previously defined. By way of examples, mention may be made of methylenedioxy, ethylenedioxy or propylenedioxy groups; a fluoroalkyl group: an alkyl group in which one or more hydrogen atoms have been substituted by a fluorine atom. By way of examples, mention may be made of the groups -CF 3, -CH 2 CF 3; a fluoroalkoxy group: an alkoxy group in which one or more hydrogen atoms have been substituted by a fluorine atom. By way of examples, mention may be made of the groups -OCF3, -OCHF2; a heterocycle group: a saturated 5- to 7-membered cyclic group containing one to several heteroatoms such as nitrogen, oxygen or sulfur atoms. By way of examples, mention may be made of pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperidonyl, morpholinyl, piperazinyl and N-methyl-piperazinyl groups, and the like; an aryl group: monocyclic or polycyclic aromatic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. When the system is polycyclic, at least one of the rings is aromatic. By way of examples, mention may be made of phenyl, naphthyl, tetrahydronaphthyl, indanyl, etc .; A heteroaryl group: monocyclic or polycyclic aromatic system comprising from 5 to 14 members, preferably from 5 to 10 members and comprising one to more heteroatoms such as nitrogen, oxygen or sulfur atoms. When the system is polycyclic, at least one of the rings is aromatic. Nitrogen atoms can be in the form of N-oxides. Examples of monocyclic heteroaryl groups include thiazolyl, thiadiazolyl, thienyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyrimidinyl and pyridazinyl groups. As examples of bicyclic heteroaryl groups, mention may be made of the indolyl, benzofuranyl, chromen-2-on-yl, benzimidazolyl, benzothienyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, indazolyl, indolizinyl, quinazolinyl, phthalazinyl and quinoxalinyl groups. , naphthyridinyl, 2,3-dihydro-1H-indolyl, 2,3-dihydro-benzofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl.

  Among the compounds of formula (I) that are the subject of the invention, there may be mentioned a first subgroup of compounds which are defined as follows: • R represents a hydrogen atom, a C1-C5-alkyl, C1 -3-fluoroalkyl or C3-cycloalkyl group; C1-3alkylene-C3-6cycloalkyl; R1 represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; R2 represents a hydrogen atom or a C1-3alkyl group; R4 represents a hydrogen atom or a C1-5-alkyl, C1-3-fluoroalkyl, C3-6-cycloalkyl, C1-3-alkylene-C3-6-cycloalkyl, C1-3-alkylene-O-01.3-alkyl, C1.3-alkylene- ( OH), . or R4 is C1-3alkylene-NRaRb, aryl, C1-3alkylene-aryl, C1-3alkylene-O-aryl, C1-3alkylene-O-C1-C3alkylene-aryl, heteroaryl or C1-3alkyleneheteroaryl; aryl, C1-3-alkylene-aryl, C1 -3-alkylene-O-aryl, C1-3-alkylene-OC1-3-alkylene-aryl, heteroaryl and C1-3-alkylene-heteroaryl groups being optionally substituted by one or more radicals Z which are identical or different; the other, . or R4 represents a heterocycle group; said heterocycle being optionally substituted by a C1-3alkyl, -C (O) -C1-5alkyl, -C (O) -C1-5-fluoroalkyl, C1-3-alkylene-C3-6-cycloalkyl, C1-3alkylene-aryl, the group C1_3-alkylenearyl being optionally substituted with one or more radicals Z which are identical or different from one another; R 1 represents a halogen atom or a C 1-5 alkyl group and in particular a methyl, C 1-3 -fluoroalkyl and in particular a trifluoromethyl, C 1-5 -alkoxy and in particular a methoxy, -CN, -000H, -NO 2; ; Rp and R'p represent independently of each other a hydrogen atom or a C1-5-alkyl group and in particular a methyl,. or Rp and R'p together form a C1-4alkylene group; Z represents a halogen atom or a C1-5-alkyl, C1-3-fluoroalkyl, C3-6-cycloalkyl, C1-3-alkylene-C3-6-cycloalkyl, a phenyl, C1-5-alkoxy, C1-3-fluoroalkoxy, C1.3- group; alkylene-O-C1-3alkyl, C1-3alkylene- (OH), NO2, -N, -SO2NRaRb, -X-C1-3alkyl, C1-3alkylene-X-C1-3alkyl wherein X is S, SO or SO2; or Z is -NRaRb, C1-3-alkylene-NRaRb, -C (O) -NRaRb, -C (O) -C1-3-alkyl, -C (O) O-C1-4-alkyl, -C (O) - C 3-6 cycloalkyl, or Z represents an oxo radical, or Z represents a group -O-C1.5-alkylene-NRaRb,. or two adjacent Z radicals together form a C1-3-alkylenedioxy group; Ra and Rb each independently represent a hydrogen atom or a C1-3 alkyl or -C (O) -C1.3 alkyl group. or Ra and Rb together with the nitrogen atom carrying them a heterocycle optionally substituted by one or more C 1-3 alkyl or oxo groups. Among the compounds of formula (I) which are subjects of the invention, there may be mentioned a second subgroup of compounds which are defined as follows: • R represents a hydrogen atom or a C 1-5 -alkyl group and in particular an ethyl C 1-3 -alkylene-C 3-6 -cycloalkyl; R1 represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; R 2 represents a hydrogen atom or a C 1 -C 5 alkyl and in particular a methyl group; R4 represents a hydrogen atom or a C1-5-alkyl, C1-3-fluoroalkyl group and in particular a trifluoromethyl, C1-3-alkylene-O-C1-3-alkyl group and in particular a methylene-O-methyl group; or R4 is C1-3-alkylene-NRaRb, aryl, and especially phenyl, C1-3alkylene-aryl and especially C1-3-alkylene-phenyl, C1-3alkylene-O-aryl, and especially C1-C3alkyl; alkylene-O-phenyl, heteroaryl and in particular pyridinyl; the aryl, C1-3-alkylene-aryl, C1 -3-alkylene-O-aryl and heteroaryl groups being optionally substituted with one or more Z radicals which are identical or different from one another, or R4 represents a heterocycle group; wherein said heterocycle is optionally substituted with C1-3alkyl, -C (O) -C1-5alkyl, -C (O) -C1,5-fluoroalkyl, C1-3alkylene-C3-6cycloalkyl, C1-3alkylene-aryl, and especially a methylene-phenyl; the C1_3-alkylene-aryl group being optionally substituted by one or more radicals Z which are identical to or different from each other; R7 represents a halogen atom, a methyl, a methoxy, a trifluoromethyl, -CN or -NO2; ; • Rp and R'p represent independently of one another a hydrogen atom or a methyl,. or Rp and R'p together form a C1-4alkylene group; Z represents a halogen atom or a C 1 -C 5 -alkyl, C 1 -C 3 -fluoroalkyl group and in particular a trifluoromethyl, phenyl or C 1 -C 5 -alkoxy group and in particular a methoxy, -CN, -SO 2 NRaRb, -X-C 1 -C 3 -alkyl, C 1 -C 3 alkylene-X-C1-3-alkyl wherein X is S, SO or SO2, or Z is -NRaRb, C1-3-alkylene-NRaRb, -C (O) -NRaRb, -C (O) -C1-3-alkyl, -C (O) O-C1-4-alkyl, -C (O) - C 3-6 cycloalkyl, or Z represents an oxo radical, or Z represents a -O-C 1-5 -alkylene-NRaRb group, or two adjacent Z radicals together form a C 1-3 -alkylenedioxy group, and in particular a methylenedioxy; Ra and Rb are each, independently of the other, a hydrogen atom or a C1-3 alkyl or -C (O) -C1-3 alkyl group. or Ra and Rb together with the nitrogen atom carrying them a heterocycle optionally substituted with one or more C1 -3 alkyl or oxo groups.

  Among the compounds of formula (I) which are subjects of the invention, there may be mentioned a third subgroup of compounds which are defined as follows: • R represents a hydrogen atom or an ethyl group; R1 represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; R2 represents a hydrogen atom or a methyl group; R 4 represents a hydrogen atom or a C 1-5 alkyl group, a trifluoromethyl, a methylene-O-methyl, or R4 is phenyl, pyridinyl; the phenyl and pyridinyl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; R7 represents a halogen atom, a methyl, a methoxy, -CN or -NO2; Rp and R'p represent independently of each other a hydrogen atom or a methyl; Z represents a halogen atom or a C 1-5 alkyl, trifluoromethyl, phenyl, methoxy, -CN, -SO 2 NRaRb group, or Z is -NRaRb, C1-3alkylene-NRaRb, -C (O) -NRaRb, -C (O) -C1-3-alkyl,. or Z represents an oxo radical, or Z is -O-C1-5-alkylene-NRaRb. or two adjacent Z radicals together form a methylenedioxy group; Ra and Rb are each, independently of the other, a hydrogen atom or a C1-3 alkyl or -C (O) -C1-3 alkyl group. or Ra and Rb together with the nitrogen atom carrying them a heterocycle optionally substituted by one or more C 1-3 alkyl or oxo groups.

  Among the compounds of formula (I) which are subjects of the invention, mention may be made in particular of: • 4- (4-Chlorophenyl) -7-methoxy-N- [1- (2-naphthylmethyl) piperidin-4-yl] dihydrochloride; ] isoquinolin-1-amine (compound No. 1), 7-bromo-N- [1- (2-naphthylmethyl) piperidin-4-yl] isoquinolin-1-amine dihydrochloride (compound No. 2), N-dihydrochloride [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -7-bromoisoquinolin-1-amine (Compound No. 3). In the following diagrams, the starting compounds and the reagents, when their method of preparation is not described, are commercially available or described in the literature, or may be prepared according to methods described therein or which are known to those skilled in the art. According to the invention, the compounds of general formula (I) can be prepared according to the process illustrated by the following scheme 1. According to Scheme 1, the compound of general formula (I) is prepared from a compound of formula (III), wherein R4 and R7 are as defined in general formula (I), according to route A, by nucleophilic substitution of chlorine with the amine of the compound of formula (II), in which R 1, R 2, R 2, R ', and R are as defined in general formula (I). This reaction can be carried out by heating the compounds of formulas (II) and (III) in an alcohol such as n-butanol or n-pentanol in the presence of ammonium chloride according to the method described by Contreras et al (J. Chem., 2001, 44, 2707-2718), or may be catalyzed by a transition metal such as palladium for example in the tris (dibenzylidene-acetone) dipalladium form in the presence of a ligand such as BINAP ( 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl) and a base such as sodium tert-butylate according to the method described by Wolfe et al (J. Am., Chem., Soc., 1996, 118 , 7215-7216). Or the compound of general formula (I) in which R is different from the hydrogen atom can also be prepared according to route B from the compound of general formula (I ') in which R is a hydrogen atom by alkylation with an alkyl halide (RX) in the presence of a base such as, for example, sodium hydride in a solvent such as dimethylformamide, tetrahydrofuran or N-methylpyrrolidinone. The compound of the general formula (I) may also be acylated with an anhydride or an acid chloride of the R'C (O) Y type to form an amide of the general formula (I "). be reduced by lithium aluminum hydride (LiAlH 4) or by the borane-tetrahydrofuran complex (BH 3 -THF) to obtain the compound of general formula (I) in which R represents an alkyl.The compound of formula (I '), wherein R is a hydrogen atom is prepared from the compound of formula (III), wherein R4 and R7 are as defined in general formula (I) and the amino compound of formula (II ') by the methods mentioned previously for the preparation of the compound of general formula (I), the amines of formula (II ') or (II) in which R represents a hydrogen atom, when they are not commercial can be prepared by analogy to the methods described in the literature (Mach et al, J. Med Chem 1993, 36, 370 7-3720, Dostert et al, Eur J. Med Chem Ther. 1984, 19 (2), 105-110, Moragues et al Farmaco. Ed. Sci. 1980, 35 (11), 951-964 and Shum et al Nucleoside Nucleotides 2001, (4-7), 1067-1078).

  The amine of formula (II) for which R represents a methyl may be prepared by reduction with lithium aluminum hydride (LiAlH 4) of the tert-butoxycarbonyl group previously introduced on the primary amine according to the reduction method used by Gibson and al (Tetrahedron Asymmetry 1995, 6, 1553-1556). The amine of formula (II) for which R represents an alkyl other than methyl, can be prepared by reduction of an amide (previously introduced on the primary amine) with lithium aluminum hydride (LiAlH 4) or by the complex boranetetrahydrofuran (BH3-THF). For example, when R represents an ethyl group, the primary amine is acylated with acetyl chloride and then the acetamide obtained is reduced by lithium aluminum hydride.

  The 1-chloroisoquinoline derivative of formula (III), when it is not commercial, can be obtained according to scheme 2 by heating the 2H-isoquinolin-1-one derivative of formula (IV) in phosphoryl chloride, for example .

  The 2H-isoquinolin-1-one derivative of formula (IV) can be obtained according to scheme 2 by treatment of the 1H-isochromen-1-one derivative of formula (V) with, for example, ammonium carbonate in the acid. acetic acid. Scheme 2 R 4 (V) O-POCl 3 (NH 3 aOH) AcOH 3. R 1 -1 -1 R 4 (IV) Cl R 4 (III) The 1H-isochromen-1-one derivative of formula (V) can be synthesized according to Scheme 3 from an ester of formula (VI) by cyclization with ylide (VII) in dimethylformamide, according to the method described by Clough et al (Tetrahedron Lett, 1984, 25, 3025-3028 The ester of formula (VI) can be prepared according to scheme 3 from the acid of formula (VIII), by esterification reaction for example with iodide of methyl in the presence of potassium carbonate in dimethylformamide The 2-acyl-benzoic acid of formula (VIII) can be synthesized according to scheme 3 from a 2-bromo-benzoic acid of formula (IX) p halogen-metal exchange and then reaction with an acid chloride of formula (X) or with a Weinreb amide of N-methoxy-N-methylamine type of formula (X '): (X') in which R4 is as defined for the compounds of formula (I). The halogen-metal exchange can be carried out with n-butyllithium in tetrahydrofuran at -78.degree.

  The compound of formula (X ') can be obtained from the compound of formula (X) and N-methoxy-N-methylamine, in particular according to the method described by Weinreb (Tetrahedron Letters, (1981), 22 (39): 3815-3818).

  The compounds of formula (I) are very affine and selective with respect to the Melanin-Concentrating Hormone (MCH) receptor 1, MCH1. In vitro tests have demonstrated the affinity of the compounds for MCH receptors and in particular MCH1.

  Since MCH is an important regulator of food intake, small nonpeptide molecules able to antagonize its stimulating action of the MCH receptor are a therapy of choice for treating the metabolic problems related to obesity but also to bulimia nervosa. Indeed, the use of an MCH receptor antagonist, such as SNAP-7941 (described by Synaptic Laboratories) confirms the important role of MCH in regulating the energy balance and the development of obesity (Katsuura et al., Curr Med Chem 2003; 3: 217-227). The compounds according to the invention therefore represent a therapy of choice for the treatment of diseases presenting disorders of the regulation of the energy balance as well as for the treatment of the development of obesity.

  MCH is a functional antagonist of the melanocortin system, counteracting its effects on food intake and on the hypothalamic-pituitary-adrenal axis (Ludwig et al., Am J Physiol 1998; 274: E627-E633). It is also involved in regulation of the hypothalamic-pituitary-adrenal axis and in stress response via hypothalamic CRF release (Kennedy et al., J Neuroendocrinol 2003; 15 (3): 268-272). The use of an MCH receptor antagonist has recently confirmed the anxiogenic effect of MCH. Indeed, SNAP-7941 has an anxiolytic and / or antidepressant profile in various animal models such as social conflict and forced swimming in rats as well as maternal separation in guinea pigs (Katsuura et al, Curr Med Chem 2003; 3: 217-227). MHC receptor antagonist molecules are therefore of therapeutic interest in depression and / or anxiety.

  The MCH seems to be involved with other regulatory systems. By its testicular localization (Hervieu et al., Biology of Reproduction 1996; 5: 1161-1172) and hypothalamic (dependent estrogen, Viale et al., Peptides 1999; 20: 553-559) and by its stimulating effects of sexual activity. male rats (Gonzales et al., Peptides 1996; 17: 171-177) and luteinizing hormone secretion (Chiocchio et al., Biology of Reproduction 2001; 64: 1466-1472), MCH thus seems to play a role in reproductive functions.

  It has also been observed that MCH is involved in cognitive-related behaviors by increasing the extinction of passive avoidance in rats, suggesting that an MCH receptor antagonist may be useful in memory disorders (MacBride et al., Peptides 1994; (4): 757-759). Thus, the compounds according to the invention may constitute a therapy of choice for the treatment of memory disorders.

  Finally, it has also been shown that MCH plays a role in urinary disorders and in particular urinary incontinence (US2004 / 0038855A1).

  Thus, the compounds of the invention find use in therapy, especially in the treatment of obesity, cellulitis, urinary incontinence, metabolic disorders and their associated pathologies such as diabetes, cardiovascular disorders, Syndrome X, in the treatment of stress-related conditions such as anxiety and depression, as well as in the treatment of any other diseases involving MCH receptor-related dysfunction, whether centrally and / or peripherally.

  Thus, according to another of its aspects, the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid, or a hydrate or a solvate.

  According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active ingredient, at least one compound according to the invention. These pharmaceutical compositions comprise an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or solvate of said compound, as well as at least one pharmaceutically acceptable excipient. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.

  In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, any salt, solvate or hydrate may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.

  Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions. Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscaramellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg Said unit forms are dosed to allow daily administration of 0.5 mg to 800 mg of active ingredient per day. individual, more particularly from 0.5 mg to 200 mg, depending on the dosage form. There may be cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, the appropriate dosage for each patient is determined by the physician according to the mode of administration, the weight and the response of said patient. The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or of one of its pharmaceutically acceptable salts or hydrates or solvates.

  By way of example, a unit dosage form of a compound according to the invention in tablet form may comprise the following components: The following examples describe the preparation of compounds according to the invention. These examples are not limiting and only illustrate the present invention. The numbers of the exemplified compounds refer to those given in Table I.

  The abbreviations and symbols used for the description of the procedures of synthesis and for the description of the compounds are the following: DMF for dimethylformamide, - THE for tetrahydrofuran, - HCl for hydrochloric acid, - NaOH for sodium hydroxide, - And for ethyl, - Me for methyl. Melting points (PF) are expressed in degrees Celsius. They were measured either with a Kdffler apparatus (mention (K) in the following), or with a Mettler-Toledo FP62 apparatus (mention (M) in the following), or with a Büchi B540 apparatus (reference ( B) in what follows).

  The conditions for analysis by liquid chromatography coupled with mass spectrometry (LC / UV / MS) are as follows: For the liquid chromatography part: symmetry column C18 (2.1 × 50 mm) 3.5 μm. Eluent A = H 2 O + 0.005% TFA, pH = 3.14; Eluent B = CH3CN + 0.005% TFA. Gradient from 100% A to 90% B in 10 minutes, then elution with 90% B for 5 minutes. - Flow 0.4ml / min - Injection of 2pL of 0.5mg / ml solution in methanol - The products are detected in UV at 220 nm or at 210 nm. For the mass spectrometry part: - Ionization mode: positive electrospray. Scanning from 120 to 1500 μm The LC / MS analytical characteristics of the products are the m / z ratio of the MH + ion and the retention time (tR) of the corresponding peak, observed in UV and expressed in minutes. The proton nuclear magnetic resonance spectra (1 H NMR) were made at 250 MHz, 300 MHz or 400 MHz on Brüker devices. The abbreviations used to characterize the signals are as follows: s = singlet, m = multiplet, d = doublet, t = triplet, q = quadruplet.

  The quantification of salts and solvates is determined by means of elemental analysis, Karl-Fischer water determination and the integration of the characteristic 1 H NMR solvent signals. The compounds of the invention as well as their analytical characteristics (PF, LC / MS, salts and solvates) are given in Table L. Example 1: 4- (4-Chlorophenyl) -7-methoxy-N- [1] dihydrochloride - (2-Naphthylmethyl) piperidin-4-yl] isoquinolin-1-amine (Compound No. 1) 1.14-Chloro-N-methoxy-N-methylbenzamide A solution of 26.25 g (150 mmol) of sodium chloride. 4-chlorobenzoic acid in 450 mL of dichloromethane, stirred at 0-5 ° C under nitrogen, is added in portions of 14.07 g (155 mmol) of N, O-dimethylhydroxylamine hydrochloride. The mixture stirred at 0 ° C. is then slowly added with 52.6 ml (375 mmol) of triethylamine. The reaction medium is stirred at room temperature for 5 hours. The mixture is hydrolysed with 100 ml of water and is then extracted with dichloromethane. The organic phase is washed with 100 ml of 1N HCl, 150 ml of 1N NaOH, then with water and with salt water. It is dried over anhydrous sodium sulphate, filtered and evaporated to dryness. 31.2 g of oil are obtained. LC / MS: MH + = 200 (tR = 6.23 minutes) 1 H NMR (DMSO-d6, 250 MHz) δ ppm: 3.27 (s, 3H); 3.54 (s, 3H); 7.52 (d, J = 8.2 Hz, 2H); 7.63 (d, J = 8.2 Hz, 2H). 15 30 1.2. 2- (4-Chlorobenzoyl) -5-methoxybenzoic acid A solution of 18.5 g (80 mmol) of 2-bromo-5-methoxybenzoic acid in 150 mL of THF is stirred under nitrogen at -78 ° C. 160 mmol) of a 1.6M solution of n-butyllithium in hexane are added dropwise for about 2 hours ensuring that the temperature does not exceed -70 ° C. After the addition, the mixture is stirred at room temperature. At -78 ° C. for 1 hour, then a solution of 16 g (80 mmol) of 4-chloro-N-methoxy-N-methylbenzamide in 20 ml of THF is added dropwise. The reaction medium is stirred at -78 ° C. for 1 hour and then at room temperature for 18 hours. The mixture is hydrolysed with 50 ml of water, basified to pH = 12 with a 2N NaOH solution and extracted with tert-butyl methyl ether. The aqueous phase containing the carboxylate is acidified with a solution of 5N HCl and extracted with dichloromethane. The dichloromethane phase is washed with salt water, dried over anhydrous sodium sulphate, filtered and concentrated. The product is crystallized in isopropyl ether; after filtration and drying 12.7 g of product are obtained.

  LC / MS: MH + = 291 (tR = 7.60 min) 1H NMR (DMSO-d6, 250MHz) δ ppm: 3.89 (s, 3H); 7.27 (dd, J, = 8.5 Hz, J2 = 2.5 Hz, 1H); 7.38-7.44 (m, 2H); 7.54-7.65 (m, 2H); 13.3 (s, 1H, COOH).

  1.3. Methyl 2- (4-chloro-benzoyl) -5-methoxybenzoate 1.52 g (11 mmol) of potassium carbonate and 1.24 ml (20 mmol) of methyl iodide are added to a solution of 2.91 g. 2- (4-chloro-benzoyl) -5-methoxybenzoic acid (10 mmol) in 20 mL of DMF. The mixture is stirred at room temperature for 3 hours. The reaction medium is hydrolysed with water and then extracted with ethyl acetate. The combined organic phases are washed with water and with saturated sodium chloride solution, then dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue is crystallized from isopropyl ether. 2.75 g of product are obtained. Mp = 130 ° C (M) LC / MS: MH + = 305 (tR = 8.25 minutes) 1H NMR (DMSO-d6, 250MHz) δ ppm: 3.57 (s, 3H); 3.90 (s, 3H); 7.31 (dd, J, = 8.5 Hz, J2 = 2.5 Hz, 1H); 7.42 (d, J = 2.5 Hz, 1H); 7.49 (d, J = 8.5 Hz, 1H); 7.6-7.7 (m, 4H).

  1.4. 4- (4-Chlorophenyl) -7-methoxy-1H-isochromen-1-one A mixture of 4 g (18.1 mmol) of trimethylsulfoxonium iodide and 588 mg (14.7 mmol) of sodium hydride 60% is stirred under argon. 44 ml of anhydrous dimethylsulfoxide are added dropwise to this mixture. The mixture is stirred at ambient temperature for 2 hours. On the other hand, 4.5 g (14.7 mmol) of methyl 2- (4-chloro-benzoyl) -5-methoxybenzoate are solubilized in 54 mL of anhydrous DMF. To this solution, cooled to 0 ° C. and stirred under argon, is added dropwise the previously prepared solution of ylide. The resulting mixture is stirred, allowing the temperature to rise gradually to room temperature, then it is heated between 50 and 60 ° C. for 2 hours 30 minutes. The cooled medium is poured into 500 ml of water and extracted with ethyl acetate. The combined organic phases are washed with water and with saturated sodium chloride solution, then dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue is dissolved in dichloromethane and then added with isopropyl ether. By partial evaporation of the dichloromethane a precipitate is formed which is filtered and then recrystallized from isopropyl ether. 1.28 g of product are obtained in powder form. Mp = 153 ° C (M) LC / MS: MH + = 287 (tR = 10.16 min) 1H NMR (DMSO-d6, 300 MHz) δ ppm: 3.91 (s, 3H); 7.31 (d, J = 9 Hz, 1H); 7.45-7.50 (m, 4H); 7.53 (s, 1H); 7.60 (dd, J = 9 Hz, J = 2.7 Hz, 1H); 7.69 (d, J = 2.7 Hz, 1H).

  1.5. 4- (4-Chlorophenyl) -7-methoxy-2H-isoquinolin-1-one 7 ml of acetic acid are introduced into a flask containing 640 mg (2.2 mmol) of 4- (4-chlorophenyl) -7- methoxy-1H-isochromen-1-one and 1.21 g (12.6 mmol) of ammonium carbonate. The mixture is stirred at reflux. After 3 hours, 1.21 g (12.6 mmol) of ammonium carbonate are added twice to the medium to make the reaction evolve. After heating for 7 hours, the reaction mixture is stirred at room temperature for 12 hours and then poured into water. The precipitate formed is filtered off, washed with water and dried in an oven (35 ° C.) under reduced pressure. 620 mg of product are obtained. LC / MS: MH + = 286 (tR = 7.95 min) 1H NMR (DMSO-d6, 250MHz) δ ppm: 3.89 (s, 3H); 7.01 (d, J, = 5.2 Hz, 1H); 7.34 (dd, J, = 9 Hz, J2 = 2.7 Hz, 1H); 7.4-7.6 (m, 5H); 7.73 (d, J = 2.7 Hz, 1H); 11.48 (d, J = 5.2 Hz, 1H, NH).

  1.6. 1-Chloro-4- (4-chlorophenyl) -7-methoxy-isoquinoline 475 mg (1.66 mmol) of 4- (4-chlorophenyl) -7-methoxy-2H-isoquinolin-1-one are suspended in 3 mL of phosphoryl chloride. The reaction mixture is heated at 130 ° C. for 3 hours. After cooling, it is poured slowly into 50 ml of water with stirring, maintaining the temperature between 15 and 20 C. The solution is neutralized to pH 7 with 35% sodium hydroxide solution and extracted with dichloromethane . The combined organic phases are washed with water and with saturated sodium chloride solution, then dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue is recrystallized from isopropyl ether. 415 mg of product are obtained in the form of cottony crystals. Mp = 195 ° C (M) LC / MS: MH + = 304 (tR = 11.27 minutes) 1H NMR (DMSO-d6 300 MHz) δ ppm: 4.00 (s, 3H); 7.5-7.7 (m, 6H); 7.79 (d, J = 9 Hz, 1H); 8.14 (s, 1H). 1.7. 4- (4-Chlorophenyl) -7-methoxy-N- [1- (2-naphthylmethyl) piperidin-4-yl] isoquinolin-1-amine dihydrochloride In a tube under argon are introduced successively: 330 mg (1.08 mmol) of 1-chloro-4- (4-chlorophenyl) -7-methoxyisoquinoline dissolved in 6 mL of toluene, 313 mg (1.30 mmol) of N- [1- (2-naphthylmethyl) piperidin-4-yl) ] amine, 148 mg (1.54 mmol) sodium tert-butylate, 6 mg (0.009 mmol) BINAP (2,2'-bis (diphenylphosphino) -1,1'-binaphthyl) and 5.5 mg ( 0.006 mmol) of tris (dibenzylidene-acetone) dipalladium. The mixture is stirred at 80 ° C. for 24 hours. After returning to ambient temperature, the reaction medium is hydrolysed with a solution of sodium hydrogencarbonate and then extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel (eluent: dichloromethane / methanol from 100/0 to 80/20 (v / v)). 394 mg of product are obtained. MH + = 508 (tR = 6.55 minutes) 1 H NMR (DMSO-d6, 250 MHz) δ ppm: 1.6-1.85 (m, 2H); 1.95-2.1 (m, 2H); 2.1-2.25 (m, 2H); 2.9-3.0 (m, 2H), 3.69 (s, 2H); 3.93 (s, 3H); 4.2 (m, 1H); 7.07 (d, J = 7.5 Hz, 1H, NH); 7.25-7.35 (m, 1H); 7.4-7.6 (m, 8H); 7.65-7.75 (m, 2H); 7.8 (s, 1H); 7.85-7.95 (m, 3H).

  After treatment with a solution of hydrochloric acid in diethyl ether, the hydrated dihydrochloride is obtained. Mp = 232 ° C (B) LC / MS: MH + = 508 (tR = 6.56 minutes) Example 2: 7-Bromo-N- [1- (2-Naphthylmethyl) piperidin-4-yl] isoquinoline dihydrochloride 1-5 amine (Compound No. 2) 594 mg (2.47 mmol) of N- [1- (2-naphthylmethyl) piperidin-4-yl] amine and 133 mg (2.49 mmol) of sodium chloride are added. ammonium to a solution of 500 mg (2.06 mmol) of 7-bromo-1-chloroisoquinoline in 15 mL of n-butanol. The mixture is heated under reflux for 7 hours and then 133 mg (2.49 mmol) of ammonium chloride are added and the reaction mixture is refluxed for 24 hours. It is cooled to room temperature, hydrolysed with 20 ml of a 1N sodium hydroxide solution and then extracted with dichloromethane. The organic phase is dried over anhydrous magnesium sulfate. After filtration, it is evaporated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: dichloromethane / methanol 100/0 to 90/10 (v / v)). 84 mg of product is obtained. LC / MS: MH + = 446 (tR = 5.42 minutes) 1H NMR (DMSO-d6, 250MHz) δ ppm: 1.6-1.8 (m, 2H); 1.9-2.0 (m, 2H); 2.0-2.25 (m, 2H); 2.85-3.0 (m, 2H); 3.67 (s, 2H); 4.1 (m, 1H); 6.88 (d, J = 5 Hz, 1H); 7.19 (d, J = 7.5 Hz, 1H); 7.4-7.6 (m, 3H); 7.6-7.9 (m, 7H); 8.61 (d, J = 2.5 Hz, 1H).

  After treatment with a solution of hydrochloric acid in diethyl ether, the hydrated dihydrochloride is obtained. Mp = 293 C (M) LC / MS: MH + = 446 (tR = 5.42 minutes) Example 3: N- [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] dihydrochloride 7-bromoisoquinolin-1-amine (Compound No. 3) 3.1. Tert-Butyl 1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] carbamate To a solution of 9.36 g (46.8 mmol) of tert-butyl (piperidin-4-yl) carbamate -butyl in 170 ml of 1,2-dichloroethane is added piperonal 7.02 g (46.8 mmol). The reaction mixture is placed under a nitrogen atmosphere and stirred for 30 min at room temperature. 13.9 g (63.5 mmol) of sodium triacetoxyborohydride are then introduced in small portions. After stirring at room temperature overnight, the reaction mixture is hydrolysed with water and 2N sodium hydroxide solution and then extracted with dichloromethane. The combined organic phases are washed with water and with salt water, then dried over anhydrous sodium sulphate and evaporated under reduced pressure. 12.9 g of a white solid are obtained. Mp = 96 C (M) MH + = 335 (tR = 5.16 minutes) 1H NMR (DMSO-d6, 250 MHz) δ ppm: 1.35-1.45 (m, 2H); 1.38 (s, 9H); 1.65-1.75 (m, 2H); 1.85-2.0 (m, 2H); 2.65-2.8 (m, 2H); 3.1-3.3 (m, 1H); 3.33 (s, 2H); 5.99 (s, 2H); 6.7-6.8 (m, 1H); 6.8-6.9 (m, 2H).

  3.2. N- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl-amine A suspension of 12.9 g (38.8 mmol) of [1- (1,3-benzodioxol-5-ylmethyl) piperidine) 4-yl] tert-butyl carbamate in 130 ml of ethyl acetate is added 130 ml of a solution of 2N HCl in diethyl ether. The reaction mixture is stirred at room temperature for 12 hours. The precipitate formed is filtered off, rinsed with ethyl acetate and then dried in an oven (40 ° C.) under reduced pressure. 12.7 g of a white solid are obtained.

  One part is desalified: 312 mg are stirred with 1.17 g (4 equivalents) of (polystyrylmethyl) trimethylammonium bicarbonate resin (Novabiochem) in 10 ml of dichloromethane for 5 hours. After filtration and rinsing of the resin with dichloromethane, the organic phase is evaporated. 174 mg of a white solid are obtained. Mp = 69 C (M) 1 H NMR (DMSO-d 6, 250 MHz) δ ppm: 1.10-1.30 (m, 2H); 1.60-1.75 (m, 2H); 1.85-2.0 (m, 2H); 2.45-2.55 (m, 1H); 2.65-2.75 (m, 2H); 2.7-3.4 (m, 2H, NH 2); 3.33 (s, 2H); 99 (s, 2H); 6.7-6.8 (m, 1H); 6.8-6.9 (m, 2H). 3.3. N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -7-bromoisoquinolin-1-amine dihydrochloride 579 mg (2.47 mmol) of N- (1.3 g) were added. Benzimidol-5-ylmethyl) piperidin-4-ylamine and 140 mg (2.62 mmol) of ammonium chloride to a solution of 500 mg (2.06 mmol) of 7-bromo-1-chloroisoquinoline in mL of n-butanol. The mixture is heated under reflux for 18 hours and then 140 mg (2.62 mmol) of ammonium chloride are added and heating is continued for 24 hours. The reaction medium is cooled to ambient temperature, hydrolysed with 20 ml of 1N sodium hydroxide solution and then extracted with dichloromethane. The organic phase is washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After filtration, it is evaporated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: dichloromethane / methanol 100/0 to 90/10 (v / v)). 138 mg of product are obtained. LC / MS: MH + = 440 (tR = 4.80 min) 1H NMR (DMSO-d6, 250MHz) δ ppm: 1.5-1.75 (m, 2H); 1.8-2.1 (m, 4H); 2.8-2.9. (m, 2H); 3.41 (s, 2H); 4.08 (m, 1H); 5.99 (s, 2H); 6.7-7.0 (m, 4H); 7.19 (d, J = 7.5 Hz, 1H); 7.6-7.75 (m, 2H); 7.89 (d, J = 7.5 Hz, 1H); 8.61 (s, 1H).

  After treatment with a solution of hydrochloric acid in diethyl ether, the hydrated dihydrochloride is obtained. Mp = 224 C (M) LC / MS: MH + = 440 (tR = 4.78 minutes) Table 1 N Rp R PF (C) LC / MS R and / or (M + H) +; R4R, R'p Solvates tR (minutes) N / H 1 H 2 O (2/1) 232 508; H20 (B) tR = 6.56 (2.9 / 1) HCl (2/1) 293,446; 2 H H Br H 2 O (M) t R = 5.42 (3.5 / 1) N / O 3 H H Br (2/1) 224 440; H 2 O (M) t R = 4.78 (2/1) (I) The compounds according to the invention have been the subject of pharmacological tests. Their affinity towards the Melanin-Concentrating Hormone (MCH) receptor 1, MCH1, was thus determined. Attempts were to measure the in vitro activity of the compounds of the invention on MCH1 MCH1 receptors.

  Binding Studies: The measurement of the affinity of the compounds of the invention for MCH receptors was performed by studying the displacement of the binding of a radio-labeled derivative of MCH 10 to MCH1 receptors. This study is carried out on membrane preparations of rat and / or mouse brain according to the protocol described below.

  In anticipation of binding studies, the brains are diluted in 25 mM HEPES buffer (pH 7.4) containing 5 mM MgCl 2, 1 mM CaCl 2, homogenized with Polytron 3 times 20 seconds (speed 25). ), then undergo ultracentrifugation for 30 minutes at 22,000 RPM at +4 C. The pellet is taken up with the same buffer and the membranes are aliquoted and stored frozen at -80 C until they are used. The membranes are brought back to ambient temperature and are then incubated in the presence of the test compounds, and 50 μM of a radiolabeled molecule derived from MCH, [1251] -Tyr-S36057 (8-amino-3,6-dioxyoctanoyl). MCH 6-17 sold by Perkin-Elmer), in 25 mM HEPES buffer (pH 7.4) containing 5 mM MgCl 2, 1 mM CaCl 2, bacitracin 140 mg / L, 1 mM phenanthroline, and 0.2% of serum bovine albumin. The incubation is carried out at room temperature for 30 minutes, then stopped by rapid addition of ice-cold 25 mM HEPES buffer (pH 7.4), supplemented with 0.2% serum bovine albumin, and filtration on GF fiberglass filters. / B preincubated for 2 hours in an aqueous solution of polyethyleneimine 0.1%. The radioactivity retained on the filters is measured using a gamma scintillation counter. Nonspecific binding is determined in the presence of 1 μM of nonradiomarced S36057. Specific binding is obtained by difference between total binding and non-specific binding. The inhibitory activity of the compounds of the invention is expressed by the concentration which inhibits 50% of the specific binding (IC 50). In the context of the invention, the IC 50's of the compounds are generally less than 10 μM. The compounds of formula (I) advantageously have IC 50 values of less than 1 μM, more preferably less than or equal to 100 nM and even more advantageously less than or equal to 10 nM.

  By way of example, the compound according to Example 3 has an IC50 of 9 nM in the rat and 5 nM in the mouse.

  Pharmacological model of food intake: The activity of an MCH receptor 1 antagonist can be pharmacologically controlled using a rat test (young rats weighing 80 to 150 g). This test consists in inducing a food intake behavior by an i.c.v injection. (intra-cerebroventricular) MCH performed manually. The injection i.c.v. peptide solubilization buffer (without the MCH) in a first control group makes it possible to quantify the importance of the effect due to the MCH. A compound according to the invention is administered orally 1 or 2 hours before treatment i.c.v.

  The effect of a compound according to the invention is measured by the reduction it can cause on food intake, previously induced by i.c.v injection. from MCH.

  The specificity of action of the product can be evaluated using another orexigenic peptide such as NPY, also injected by i.c.v. Thus, a specific product of the MCH1 receptor will have no effect on food intake induced by another orexigenic peptide such as NPY.

  The compounds according to the invention can be used for the preparation of medicaments, in particular of MCH1 receptor antagonist drugs.

Claims (9)

  A compound of the following general formula (I): wherein: R is hydrogen, C 1-5 alkyl, C 1-3 -fluoroalkyl, C 3-6 cycloalkyl, C 1-3 -alkylene-C3-6-cycloalkyl, -C (O) -C1-5-alkyl, -CH2-CECH, C2-4-alkylene-NRaRb, C1-3alkylene-X-C1-3alkyl wherein X is O or SO2; R1 represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; R2 represents a hydrogen atom or a C1-5alkyl group; R 4 represents a hydrogen atom or a C 1-5 -alkyl, C 1-3 -fluoroalkyl, C 3-6 -cycloalkyl, C 1-3 -alkylene-C 3-6 -cycloalkyl, C 1-3 -alkylene-O-C 1-3 -alkyl, C 1-3 -alkylene- (OH) group, C1 -3-alkylene-X-C1-3alkyl wherein X is S, SO or SO2, or R4 is C1-3alkylene-NRaRb, aryl, C1-3alkylene aryl, C1-3alkylene-O-aryl, C1-3alkylene-O-C1-3alkylene aryl, heteroaryl or C1-3alkyleneheteroaryl; aryl, C1-3alkylene aryl, C1-3alkylene-O-aryl, C1-3alkylene-OC1-alkylene aryl, heteroaryl and C1-3alkylene heteroaryl are optionally substituted with one or more identical or different Z radicals; one of the other, . or R4 represents a heterocycle group; wherein said heterocycle is optionally substituted with a C1-3alkyl, -C (O) -C1-5alkyl, -C (O) -C1,5-fluoroalkyl, C1-3alkylene-C3-6cycloalkyl, C1-3alkylene aryl group, C 1-3 alkylene-heteroaryl; C1 -3-alkylene-aryl and C1.3-alkylene-heteroaryl groups being optionally substituted with one or more Z radicals which are the same or different from each other; R7 represents a hydrogen or halogen atom or a C1-5-alkyl, C1-3-fluoroalkyl, C1-5-alkoxy, C1-3-fluoroalkoxy or C1-3-alkylene- (OH), -CN, -COOH, -C ( O-C1-3alkyl, -NO2, -X-C1-3alkyl wherein X is S, SO or SO2, (I). or R1 is -NRaRb, C1-3alkylene-NRaRb, -C (O) -NRaRb, -C (O) -C1-3-alkyl, aryl, -O-aryl or heteroaryl; the aryl, -O-aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; • Rp and R'p represent independently of each other a hydrogen atom or a C1_5-alkyl group,. or Rp and R'p together form a single bond or a C1-4alkylene group; Z represents a halogen atom or a C1-5-alkyl, C1-3-fluoroalkyl, C3-6-cycloalkyl, C1-3-alkylene-C3-6-cycloalkyl, a phenyl, C1-5-alkoxy, C1-3-fluoroalkoxy, C1-3-alkylene-O- C1-3alkyl, C1-3alkylene- (OH), NO2, -ON, -SO2NRaRb, -X-C1-3alkyl, C1-3alkylene-X-C1-3alkyl wherein X is S, SO or SO2; or Z is -NRaRb, C1-3-alkylene-NRaRb, -C (O) -NRaRb, -C (O) -C1-3-alkyl, -C (O) O-C1-4-alkyl, -C (O) - C 3-6 cycloalkyl, or Z represents an oxo radical, or Z represents a -O-C1-5-alkylene-NRaRb group, or two adjacent Z radicals together form a C1-3-alkylenedioxy group; . Ra and Rb each independently of one another is a hydrogen atom or a C 1-3 -alkyl or -C (O) -C 1-3 -alkyl group. or Ra and Rb together with the nitrogen atom carrying them a heterocycle optionally substituted by one or more C 1-3 alkyl or oxo groups; in the form of a base or an acid addition salt, as well as a hydrate or solvate state, as well as its enantiomers, diastereoisomers and mixtures thereof. 25   2. Compound of formula (I) according to claim 1, characterized in that: • R represents a hydrogen atom, a C1-5-alkyl, C1-3-fluoroalkyl, C3-6-cycloalkyl, C1-3-alkylene-C3-6-cycloalkyl group; R1 represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; R2 represents a hydrogen atom or a C1-3alkyl group; R4 represents a hydrogen atom or a C1-5-alkyl, C1-3-fluoroalkyl, C3-6-35 cycloalkyl, C1-3alkylene-C3-6cycloalkyl, C1-3alkylene-O-C1-3alkyl, C1-3alkylene-OH group; . or R4 is C1-3alkylene-NRaRb, aryl, C1-3alkylene-aryl, C1-3alkylene-O-aryl, C1-3alkylene-O-C1-C3alkylene-aryl, heteroaryl or C1-3alkyleneheteroaryl; aryl, C 1-3 -alkylene-aryl, C 1-3 -alkylene-O-aryl, C 1-3 -alkylene-C 1-3 -alkylene-aryl, heteroaryl and C 1-3 -alkylene-heteroaryl groups being optionally substituted by one or more radicals Z which are identical or different; one of the other,. or R4 represents a heterocycle group; said heterocycle being optionally substituted with a C1-3alkyl, -C (O) -C1.5-alkyl, -C (O) -C1.5-fluoroalkyl, C1-3alkylene-C3-6-cycloalkyl, C1-3alkylene-aryl group; C1_3-alkylenearyl being optionally substituted with one or more radicals Z which are identical or different from one another; R 1 represents a halogen atom or a C 1-5 -alkyl, C 1-3 -fluoroalkyl, C 1-5 -alkoxy, -CN, -000H, -NO 2 group; ; • Rp and R'p represent independently of each other a hydrogen atom or a C1_5-alkyl group,. or Rp and R'p together form a C1-4alkylene group; Z represents a halogen atom or a C1-5-alkyl, C1-3-fluoroalkyl, C3-6-cycloalkyl, C1-3-alkylene-C3-6-cycloalkyl, a phenyl, C1-5-alkoxy, C1-3-fluoroalkoxy, C1-3-alkylene-O- C1-3alkyl, C1-3alkylene- (OH), NO2, -CN, -SO2NRaRb, -X-C1-3alkyl, C1-3alkylene-X-C1-3alkyl wherein X is S, SO or SO2; or Z is -NRaRb, C1-3alkylene-NRaRb, -C (O) -NRaRb, -C (O) -C1-3-alkyl, -C (O) O-C1-4alkyl, -C (O) -C3_6-cycloalkyl,. or Z represents an oxo radical, or Z represents a group -O-C1-5-alkylene-NRaRb,. or two adjacent Z radicals together form a C1-3-alkylenedioxy group; Ra and Rb are each, independently of the other, a hydrogen atom or a C1-3 alkyl or -C (O) -C1-3 alkyl group. or Ra and Rb together with the nitrogen atom carrying them a heterocycle optionally substituted by one or more C 1-3 alkyl or oxo groups; in the form of a base or an acid addition salt, as well as a hydrate or solvate state, as well as its enantiomers, diastereoisomers and mixtures thereof.   3. Compound of formula (I) according to any one of claims 1 or 2, characterized in that: • R represents a hydrogen atom or a group C1-5-alkyl, C1-3-alkylene-C3_6-35 cycloalkyl; R1 represents aryl or heteroaryl; aryl and heteroaryl groups optionally substituted with one or more radicals Z which are identical or different from one another; R2 represents a hydrogen atom or a C1-5-alkyl; R4 represents a hydrogen atom or a C1-5-alkyl, C1-3-fluoroalkyl, C1-3-5 alkylene-O-C1-3-alkyl group, or R4 is C1-3alkylene-NRaRb, aryl, C1-3alkylene-aryl, C1-3alkylene-O-aryl, heteroaryl; the aryl, C1-3-alkylene-aryl, C1 -3-alkylene-O-aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical or different from one another, 10. or R4 represents a heterocycle group; wherein said heterocycle is optionally substituted with C1-3alkyl, -C (O) -C1-5alkyl, -C (O) -C1-5-fluoroalkyl, C1-3alkylene-C3-6-cycloalkyl, C1-3alkylene-aryl; the C1_3-alkylenearyl group being optionally substituted with one or more radicals Z which are identical to or different from each other; R 1 represents a halogen atom, a methyl, a methoxy, a trifluoromethyl, -CN or -NO 2; ; • Rp and R'p represent independently of one another a hydrogen atom or a methyl,. or Rp and R'p together form a C1-4alkylene group; Z represents a halogen atom or a C1-5-alkyl, C1-3-fluoroalkyl, phenyl, C1-5-alkoxy, -CN, -SO2NRaRb, -X-C1-3-alkyl, C1-3-alkylene-X-C1-3-alkyl group where X represents S, SO or SO2, or Z is -NRaRb, C1-3-alkylene-NRaRb, -C (O) -NRaRb, -C (O) -C1-3-alkyl, -C (O) O-C1-4-alkyl, -C (O) - C 3-6 cycloalkyl, 25. or Z represents an oxo radical, or Z represents a group -O-C1-5-alkylene-NRaRb,. or two adjacent Z radicals together form a C1-3-alkylenedioxy group; Ra and Rb are each, independently of the other, a hydrogen atom or a C1-3 alkyl or -C (O) -C1-3 alkyl group. or Ra and Rb together with the nitrogen atom carrying them a heterocycle optionally substituted by one or more C 1-3 alkyl or oxo groups; in the form of a base or an acid addition salt, as well as a hydrate or solvate state, as well as its enantiomers, diastereoisomers and mixtures thereof. 35   4. Compound of formula (I) according to any one of claims 1 to 3, characterized in that: • R represents a hydrogen atom or an ethyl group; R1 represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; R2 represents a hydrogen atom or a methyl group; R 4 represents a hydrogen atom or a C 1-5 alkyl group, a trifluoromethyl, a methylene-O-methyl, or R4 is phenyl, pyridinyl; the phenyl and pyridinyl groups being optionally substituted by one or more radicals Z which are identical to or different from each other; R, represents a halogen atom, a methyl, a methoxy, -CN or -NO2; • Rp and R'p represent independently of each other a hydrogen atom or a methyl; Z represents a halogen atom or a C 1-5 alkyl, trifluoromethyl, phenyl, methoxy, -CN, -SO 2 NRaRb group, or Z is -NRaRb, C1-3-alkylene-NRaRb, -C (O) -NRaRb, -C (O) -C1-3-alkyl,. or Z represents an oxo radical, 20. or Z is -O-C1-5-alkylene-NRaRb. or two adjacent Z radicals together form a methylenedioxy group; Ra and Rb are each, independently of the other, a hydrogen atom or a C1-3 alkyl or -C (O) -C1-3 alkyl group. or Ra and Rb together with the nitrogen atom carrying them, form a heterocycle optionally substituted with one or more C1-C3 alkyl or oxo groups; in the form of a base or an acid addition salt, as well as a hydrate or solvate state, as well as its enantiomers, diastereoisomers and mixtures thereof.   5. Process for the preparation of a compound of formula (I) according to any one of Claims 1 to 4, characterized in that a compound of general formula (III): IC R4 (III) is reacted in wherein R4 and R7 are as defined in the general formula (I) according to claim 1, with a compound of the general formula (II): R, H ~ p (II) wherein R, R ,, R2, Rp and Rp are as defined in the general formula (I) according to claim 1.   6. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 4, or a salt of addition of this compound to a pharmaceutically acceptable acid, or a hydrate or a solvate of the compound of formula (I).   7. Pharmaceutical composition, characterized in that it comprises at least one compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, as well as at least one pharmaceutically acceptable excipient.   8. Use of a compound of formula (I) according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of any diseases involving a dysfunction related to the MCH1 receptor.   9. Use of a compound of formula (I) according to any one of claims 1 to 4, for the preparation of a medicament for the treatment of obesity, cellulitis, urinary incontinence, metabolic disorders and their associated pathologies such as diabetes, cardiovascular disorders, syndrome X, in the treatment of stress-related conditions such as anxiety and depression.5