WO2007042668A1 - Derivatives of 1-amino-isoquinoline, preparation method thereof and use of same in therapeutics in the treatment of a dysfunction associated with mch receptor 1 - Google Patents

Abstract

The invention relates to derivatives of 1-amino-isoquinoline, having general formula (I) wherein: R = H, C<SUB>1-5</SUB>-alkyl, C<SUB>1-3</SUB>-fluoroalkyl, C<SUB>3-6</SUB>-cycloalkyl, C<SUB>1-3</SUB>-alkylene-C<SUB>3-6</SUB>-cycloalkyl, -C(O)-C<SUB>1-5</SUB>-alkyl, -CH<SUB>2</SUB>-C=CH, C<SUB>2-4</SUB>-alkylene-NR<SUB>a</SUB>R<SUB>b</SUB>, C<SUB>1-3</SUB>-alkylene-X-C<SUB>1-3</SUB>-alkyl, in which X =O or SO<SUB>2</SUB>; R<SUB>1</SUB> = aryl or heteroaryl which are optionally substituted; R<SUB>2</SUB> = H or group C<SUB>1-5</SUB>-alkyl; R<SUB>4</SUB> = H, C<SUB>1-5</SUB>-alkyl, C<SUB>1-3</SUB>-fluoroalkyl, C<SUB>3-6</SUB>-cycloalkyl, C<SUB>1-3</SUB>-alkylene-C<SUB>3-6</SUB>-cycloalkyl, C<SUB>1-3</SUB>-alkylene-O-C<SUB>1-3</SUB>-alkyl, C<SUB>1-3</SUB>-alkylene-(OH), C<SUB>1-3</SUB>-alkylene-X-C<SUB>1-3</SUB>-alkyl, in which X = S, SO or SO<SUB>2</SUB>, or R<SUB>4</SUB> = C<SUB>1-3</SUB>-alkylene-NR<SUB>a</SUB>R<SUB>b</SUB>, aryl, C<SUB>1-3</SUB>-alkylene-aryl, C<SUB>1-3</SUB>-alkylene-O-aryl, C<SUB>1-3</SUB>-alkylene-O-C<SUB>1-3</SUB>-alkylene-aryl, heteroaryl or C<SUB>1-3</SUB>-alkylene-heteroaryl which are optionally substituted, or R<SUB>4</SUB> = heterocycle which is optionally substituted by a group C<SUB>1-3</SUB>-alkyl, -C(O)-C<SUB>1-5</SUB>-alkyl, -C(O)-C<SUB>1-5</SUB>-fluoroalkyl, C<SUB>1-3</SUB>-alkylene-C<SUB>3-6</SUB>-cycloalkyl, C<SUB>1-3</SUB>-alkylene-aryl, C<SUB>1-3</SUB>-alkylene-heteroaryl which are optionally substituted; R<SUB>7</SUB> = H, halogen, C<SUB>1-5</SUB>-alkyl, C<SUB>1-3</SUB>-fluoroalkyl, C<SUB>1-5</SUB>-alkoxy, C<SUB>1-3</SUB>-fluoroalkoxy, C<SUB>1-3</SUB>-alkylene-(OH), -CN, -COOH, -C(O)O-C<SUB>1-3</SUB>-alkyl, - NO<SUB>2, </SUB>-X-C<SUB>1-3</SUB>-alkyl, in which X = S, SO or SO<SUB>2</SUB>, or R<SUB>7</SUB> = -NR<SUB>a</SUB>R<SUB>b</SUB>,<SUB/>C<SUB>1-3</SUB>-alkylene-NR<SUB>a</SUB>R<SUB>b</SUB>,<SUB/>- C(O)-NR<SUB>a</SUB>R<SUB>b</SUB>,<SUB/>-C(O)-C<SUB>1-3</SUB>-alkyl, aryl, -O-aryl or heteroaryl which are optionally substituted; R<SUB>p</SUB> and R'<SUB>p</SUB> = H, C<SUB>1-5</SUB>-alkyl, or R<SUB>p</SUB> and R'<SUB>p</SUB> together form a single bond or C<SUB>1-4</SUB>-alkylene; in the form of a base, an acid addition salt, a hydrate or a solvate. The invention also relates to the method of preparing said derivatives and to the use of same in therapeutics.

Description

1-AMINO-ISOQUINOLINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE IN THE TREATMENT OF DYSFUNCTION RELATED TO MCH RECEPTOR 1

The present invention relates to 1-amino-isoquinoline derivatives, to their preparation and to their therapeutic application.

The search for MCHi receptor 1 (MCH) receptor 1 antagonists is attracting interest from many pharmaceutical companies. A number of patent applications have been filed which include WO01 / 21577 (Takeda), WO02 / 06245 (Synaptic), WO03 / 106452 (Millennium). A number of publications have appeared among which Ma V. V. et al (Amgen) 224th Nat. ACS Boston Meeting. Poster MEDI 343 (21.08.2002). During the last decade, it has been shown that many neuropeptides are involved in the central regulation of dietary behavior and energy balance (Inui et al, TINS 1999; 22 (2): 62-67). MCH is one of these neuropeptides.

Two MCH receptors have recently been cloned, the MCH ₁ receptor previously called the SLC-1 or GPR24 receptor (Chambers et al., Nature 1999; 400: 261-265), and the MCH ₂ 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 MCH ₁ receptor, the MCH receptor 1.

It has now been found that compounds derived from 1-amino-isoquinoline are very affine and selective towards the MCHi receptor.

The subject of the present invention is compounds corresponding to the following formula (I):

in which: R represents a hydrogen atom or a C _1-5 alkyl, C _1-3 -fluoroalkyl, C _{3-6 group} ; cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl,

-CH ₂ -C = CH, C _2-4 -alkylene-NR _a R _b , C _1-3 -alkylene-XC _1-3 -alkyl wherein X is O or SO ₂ ;

Ri represents an aryl or a 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, a C _1-5 -alkyl or C _1-3 -fluoroalkyl group;

• R ₄ represents a hydrogen atom or a Ci _-5 alkyl group, C _1-3 fluoroalkyl, C _3-6 - cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, C _3. - alkylene-OC _1-3 -alkyl, C _1-3 -alkylene- (OH) Ci _-3 -alkylene-OC _4-6 -cycloalkyl, C _1-3 -alkylene-XC _1-3 alkyl wherein X is S , SO or SO ₂ ,

. or R ₄ represents a C _1-3 -alkylene-NR _a R _b, aryl, C _1-3 -alkylene-aryl, Ci _-3 -alkylene-O-aryl, C _1-3 -alkylene-OC _{1- 3} -alkylene-aryl, heteroaryl or Ci _-3 -alkylene-heteroaryl; aryl, Ci _-3 -alkylene-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-O-C _1-3 -alkylene-aryl, heteroaryl and C _1-3 -alkylene- heteroaryl being optionally substituted with one or more radicals Z which are identical to or different from one another,

. or R ₄ represents a heterocycle group; said heterocycle being optionally substituted by C _1-3 -alkyl, -C (O) -C _-5 -alkyl, -C (O) -C _1-5 - fluoroalkyl, C _1-3 -alkylene-C _{3. 6-} cycloalkyl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-heteroaryl; the C _1-3 -alkylene-aryl and C _1-3 -alkylene-heteroaryl groups being optionally substituted by one or more Z radicals that are identical or different from each other;

R ₇ represents a hydrogen or halogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _1-5 -alkoxy, C _1-3 -fluoroalkoxy, C _1-3 -alkylene group; - (OH), -CN, -COOH, -C (O) OC _1-3 -alkyl, -NO ₂ , -XC _1-3 -alkyl where X is S, SO or SO ₂ ,

. or R ₇ represents a group -NR ₃ Rb, C _1-3 -alkylene-NR _a Rb, -C (O) -NR _a R _b , -C (O) -C _1-3 -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;

• R _p and R ' _p represent, independently of one another, a hydrogen atom or a C _1-5 -alkyl group; or R _p and R ' _p together form a single bond or a C _1-4 alkylene group;

Z represents a halogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _3-6 -cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, C-ι _{-group; 5} -alkoxy, Ci _-3 -fluoroalkoxy, C _1-3 -alkylene-O-C _1-3 -alkyl, C _1-3 -alkylene- (OH), NO _2, -CN, -SO ₂ NR _a R _b , -XC ₁ . ₃ -alkyl, C. ₃ -alkylene-X-Ci _-3 - alkyl in which X represents S, SO or SO _2,

. or Z is optionally substituted by a halogen atom phenyl, C _1-5 -alkyl, Ci. ₅ -alkoxy or Ci _-3 fluoroalkyl,

. or Z represents an alkynyl radical of the type -C≡CR _C , in which R ₀ represents a hydrogen atom, a C _1-3 -alkyl, C _1-6 -alkylene-OR _d or C _{1-6 group} ; alkylene-NR _a R _b ,

. or Z represents a -C _4-6 -alkylene-OR _{d group} ,

. or Z represents a tetrazole group substituted with a C _1-3 -alkyl group, or Z is -NR ₃ Rb, C _1-3 -alkylene-NR _a R _b , -C (O) -NR ₃ Rb, -C (O) -C _1-3 -alkyl, -C (O) OC _1-4 -alkyl or -C (O) -C ₃ . ₆ -cycloalkyl, or Z represents an oxo radical, or Z represents a group -OC ₁ . ₅ -alkylene-NR _a R _b , or Z represents a -C _4-6 -alkylene-NR _a R _{b group} . or Z is -OC _0- 3-alkylene-heterocycle, optionally substituted by one or more groups Ci _-3 alkyl, oxo or -C (O) -C _1-3 -alkyl. or Z represents a group -O-C _1-5 -alkylene-OR _d ,

. or Z represents a group -OC ₀ - ₃ -alkylene-C ₅ . ₇ -cycloalkyl optionally substituted with a group -OR _d ,

. or Z represents a group -NR _e -C _0-3 -alkylene-heterocycle optionally substituted with one or more C _1-3 -alkyl, oxo or -C (O) -C _1-3 -alkyl groups. or Z represents a group -NR _e -C ₂ -5-alkylene-OR _d ,. or Z represents a group -O-C _1-3 -alkylene-nétéroaryle optionally substituted by one or more C _1-3 -alkyl groups,

. or Z represents -CONH-C _1-5 -alkylene-NR _a R _b ,. or Z represents a group -CONH-C _1-5 -alkylene-O-R _d ,

. or Z represents a group -OC _1-3 -alkylene-C (O) -NR _a R _b ,. or Z represents a fused bicyclic or fused bicyclic heterocyclic ring, or two adjacent Z radicals together form a C _1-3 - alkylenedioxy group; R ₃ and R _b each independently of one another represent a hydrogen atom or a C _1-3 -alkyl or -C (O) -C _1-3 -alkyl group,

. or R ₃ and R _b together with the nitrogen atom which carries them, a heterocycle optionally substituted with one or more groups Ci _-3 alkyl, oxo, -NR _a R _b, hydroxy, C _1-3 -alkoxy, C _1-3 -alkylene- (OH) or -C (O) -C _1-3 -alkyl; • R _d represents a hydrogen atom or a C _1-3 -alkyl group; • R _e represents a hydrogen atom or a C _1-3 -alkyl group.

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 the 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) can also exist in the form of hydrates and / or solvates, namely in the form of combinations or combinations with water and / or solvent. Such hydrates and solvates are also part of the invention.

In the context of the present invention, the following terms mean:

C _tZ where t and z can take the values from 0 to 6, a chain or carbon ring possibly containing from t to z carbon atoms, for example C _0-3 can characterize a single bond or a carbon chain having from 1 at 3 carbon atoms; a halogen atom: a fluorine, a chlorine, a bromine or an iodine; an alkyl group: a saturated monovalent aliphatic group, linear or branched. By way of examples, 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 C _1-3 -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 (CH ₃ ) CH ₂ -), a propylenyl (-CH ₂ CH ₂ CH ₂ -), etc .; a cycloalkyl group: a saturated cyclic aliphatic group. By way of examples, mention may be made of cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, and the like; an alkoxy group: an O-alkyl radical where the alkyl group is as previously defined; an alkylenedioxy group: a -O-alkylene-O- group, where the alkylene group is as previously defined. As examples, mention may be made of methylenedioxy, ethylenedioxy or propylenedioxy groups; a fluoroalkyl group: an alkyl group of 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 of which one or more hydrogen atoms have been substituted by a fluorine atom. By way of examples, mention may be made of the groups -OCF ₃ , -OCHF ₂ ; a heterocycle group: a saturated 5- to 7-membered cyclic group comprising 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, etc.

. or a heterocycle group may represent a bridged heterocycle group comprising from 6 to 10 members, wherein at least 2 atoms of the bicyclic structure are joined by a single bond or a chain which may have from 1 to 4 members;

By way of examples, mention may be made of: the 1-azabicyclo [2.2.2] octyl group:

or the 8-azabicyclo [3.2.1] octyl group:

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. As examples of monocyclic heteroaryl groups, mention may be made of 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) which are subjects of the invention, there may be mentioned a first subgroup of compounds which are defined as follows: • R _p and R _p > each represent, independently of one another, an atom hydrogen; • R represents a hydrogen atom, Ci _-5 alkyl group such as methyl or ethyl, or -C (O) C _1-3 alkyl such as -C (O) -methyl;

R 1 represents aryl such as phenyl or naphthyl, or R 1 represents a heteroaryl group such as benzo-1,3-dioxolyl or pyrrolyl; 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;

R ₄ represents:

. a hydrogen atom or a C _1-5 -alkyl such as methyl or ethyl, Ci _-3 fluoroalkyl such as trifluoromethyl, C _1-3 -alkylene-OC _1-3 -alkyl such that a methylene-O-methyl,

. a heterocycle group such as a piperidinyl or tetrahydropyranyl group; said heterocycle group being optionally substituted by a C _1-3 -alkylene-aryl group such as -methylene-phenyl, or R ₄ represents an aryl group such as a phenyl group; said aryl group being optionally substituted with one or more radicals Z which are identical to or different from each other;

R ₇ represents a halogen atom such as a chlorine or a bromine or a C _1-5 alkoxy group such as a methoxy group; Z represents a halogen atom such as a fluorine or a chlorine, a C _1-5 alkoxy group such as a methoxy, or a phenyl optionally substituted with a C _1-3 -fluoroalkyl group such as a trifluoromethyl group; ,

. or Z is an alkynyl radical -C≡CR type _C, wherein R _c represents a hydrogen atom, Ci _-6 -alkylene-OR _d or C _1-6 -alkylene-NR _a R _b in which groups C _1-6 -alkylene are such as isopropylene or methylene,

. or Z represents a -C _4-6 -alkylene-OR _{d group} in which the C _4-6 -alkylene group is such as butylene,

. or Z represents a tetrazole group substituted with a C _1-3 -alkyl group such as a methyl group, or Z represents a group -NR _a R _b ,

. or Z represents a -C ₄ group. ₆ -alkylene-NR _a R _b in which the C _4-6 -alkylene group is such as butylene,

. or Z is -OC _1-5 -alkylene-NR _to Rb in which the C _1-5 -alkylene group is such as ethylene or propylene, or Z represents a group -OC ₀ . ₃ -alkylene-heterocycle in which the alkylene group is absent or is such that a methylene, ethylene group, and the heterocycle is such that azepanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, 1-azabicyclo [2.2.2] octyl or 8-azabicyclo [3.2.1] octyl, the said group -OC ₀ . ₃ -alkylene-heterocycle being optionally substituted by one or more C _1-3 -alkyl groups such a methyl or an oxo group,

. or Z is -OC _1-5 -alkylene-OR group i _c wherein the group C _{1- 5} -alkylene is such that an ethylene or propylene group,

. or Z is -NR _e -C ₂ 5-alkylene-OR _d wherein the group C ₂ -alkylene 5 is such that an ethylene group,

. or Z is -O-C 1 -C ₃ -alkylene-heteroaryl in which the C _1-3 -alkylene group is such as a methylene or ethylene group and the heteroaryl group is such that an imidazolyl or pyridinyl group,

. or Z represents a -CONH-C _1-5 -alkylene-NR _a R _{b group} in which the C _1-5 -alkylene group is such that an ethylene group,

. or Z represents a group -OC ₁ . ₃ -alkylene-C (O) -NR _a R _b wherein C _1-3 - alkylene is such that methylene,

. or Z represents a fused or spiric bicyclic diamino heterocycle chosen from:

in which the dotted lines represent the point of attachment to the remainder of the molecule of formula (I);

R ₃ and R _b each represent independently of the other a C _1-3 -alkyl group such as methyl,

. or R _a and R _b together with the nitrogen atom to which they are attached form a heterocycle such as a morpholinyl, piperidinyl or pyrrolidinyl group, optionally substituted with one or more oxo groups, -NR ₃ R _b or hydroxy;

• R _d represents a hydrogen atom or a C _1-3 -alkyl group such as methyl; R _e represents a C _1-3 -alkyl group such as methyl;

Among the compounds of formula (I) which are subjects of the invention, there may also be mentioned a subgroup of compounds which are defined as follows:

Each of R _p and R _{p '} represents, independently of one another, a hydrogen atom; R represents a hydrogen atom;

R ₁ represents a phenyl, naphthyl or benzo-1,3-dioxolyl group; said phenyl, naphthyl and benzo-1,3-dioxolyl 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;

R ₄ represents:

. a hydrogen atom,

. a phenyl group; said phenyl group being optionally substituted with one or more radicals Z which are identical to or different from each other;

• R ₇ represents a chlorine atom, bromine or a methoxy group;

Z represents a fluorine or chlorine atom,

. or Z represents a group -NR ₃ R _b ,. or Z represents a -O-propylene-NR _a Rb group. or Z represents a -O-azepanyl group, said -O-azepanyl group being optionally substituted by one or more methyl groups, or Z represents a -O-propylene-OR _{d group} ;

• R ₃ and R _b each represent, independently of each other, a methyl group, or R _a and R _b together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group;

• R _d represents a hydrogen atom;

Among the compounds of formula (I) that are subjects of the invention, there may be mentioned a subgroup of compounds which are defined as follows:

R 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 group;

Ri represents an aryl or a 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 _1-3 -alkyl 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 group} . ₆ -cycloalkyl, C _1-3 -alkylene-OC _1-3 -alkyl, Ci _-3 -alkylene- (OH)

. or R ₄ represents C _-3 -alkylene-NR _a R _b, aryl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-O-Ci _-3 -alkylene-aryl, heteroaryl or Ci _-3 -alkylene-heteroaryl; aryl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-O-

C _1-3 -alkylene-aryl, heteroaryl and C _1-3 -alkylene-heteroaryl being optionally substituted by one or more radicals Z which are identical to or different from each other,

. or R ₄ represents a heterocycle group; said heterocycle being optionally substituted by C _1-3 -alkyl, -C (O) -C _-5 -alkyl, -C (O) -C _1-5 - fluoroalkyl, C _1-3 -alkylene-C _{3. 6} -cycloalkyl, C _1-3 -alkylene-aryl, the C _1-3 -alkylene-aryl group being optionally substituted by one or more radicals Z which are identical to or different from each other;

• R ₇ represents a halogen atom or a C-ι _-5 -alkyl group and especially a methyl, C _1-3 -fluoroalkyl and in particular trifluoromethyl, d. _5- alkoxy and in particular methoxy, -CN, -COOH, -NO ₂ ;

• Rp and R ' _p represent, independently of one another, a hydrogen atom or a C _1-5 alkyl group and in particular a methyl, or R _p and R ' _p together form a C _1-4 -alkylene group;

Z represents a halogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _3-6 -cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, a phenyl, C _1-5 -alkoxy, Ci _-3 -fluoroalkoxy, C _1-3 - alkylene-OC _1-3 -alkyl, C _1-3 -alkylene- (OH), NO _2, -CN, -SO ₂ NR _a R _b , -XC _1-3 -alkyl, C _1-3 - alkylene-XC _1-3 -alkyl wherein X is S, SO or SO ₂ , or Z is -NR ₃ Rb, C _1-3 -alkylene-NR _a Rb, -C (O) -NR ₃ Rb,

-C (O) -C _1-3 -alkyl, -C (O) OC _1-4 -alkyl or -C (O) -C _3-6 -cycloalkyl,

. or else Z represents an oxo radical,

. or Z represents a group -O-C _1-5 -alkylene-NR _a Rb,

. or two adjacent Z radicals together form a C _1-3 - alkylenedioxy group;

R ₃ and R _b each independently of one another represent a hydrogen atom or a C _1-3 -alkyl or -C (O) -C _1-3 -alkyl group,

. or R _a and R _b together with the nitrogen atom carrying them, form a heterocycle optionally substituted with one or more C _1-3 -alkyl or oxo groups.

Among the compounds of formula (I) that are subjects of the invention, there may be mentioned a 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; R ₁ 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 _1-5 alkyl and in particular a methyl group; R ₄ represents a hydrogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl group and in particular a trifluoromethyl, C _1-3 -alkylene-OC _1-3 -alkyl group and in particular a methylene- O-methyl,

. or R ₄ represents a C _1-3 -alkylene-NR _a R _b , aryl and in particular a phenyl, C _1-3 -alkylene-aryl and in particular a C _1-3 -alkylene-phenyl, Ci- ₃ -alkylene-O-aryl and in particular a C _1-3 -alkylene-O-phenyl, heteroaryl and in particular a pyridinyl; the aryl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-O-aryl and heteroaryl groups being optionally substituted with one or more Z radicals that are identical to or different from each other,

. or R ₄ represents a heterocycle group; said heterocycle being optionally substituted with C _1-3 -alkyl, -C (O) -C _1-5 -alkyl, -C (O) -C _1-5 -fluoroalkyl, C _1-3 -alkylene-C ₃ . _6- cycloalkyl, C _1-3 -alkylene-aryl and especially methylene-phenyl; the _-3 -alkylene-aryl group being optionally substituted by one or more radicals Z which are identical or different from one another; R ₇ represents a halogen atom, a methyl, a methoxy, a trifluoromethyl, -CN or -NO ₂ ;

• R _p and R ' _p independently of one another represent a hydrogen atom or a methyl,

. or R _p and R ' _p together form a C 1-4 alkylene group; • Z represents a halogen atom or a Ci _-5 alkyl group, Ci _-3 fluoroalkyl, especially trifluoromethyl, phenyl, Ci _-5 alkoxy and in particular methoxy, -CN, -SO ₂ NR ₃ R _b , -XC _1-3 -alkyl, C _1-3 -alkylene-XC _1-3 -alkyl wherein X is S, SO or SO ₂ ,

. or Z represents a group -NR ₃ Rb or

-C (O) -NR ₃ Rb, -C (O) -C _1-3 -alkyl, -C (O) OC _1-4 -alkyl, -C (O) -C _3-6 -cycloalkyl, or else Z represents an oxo radical,

. or Z represents a group -O-C _1-5 -alkylene-NR _a Rb,

. or two adjacent Z radicals together form a C _1-3 -alkylenedioxy group, and in particular a methylenedioxy;

R _a and R _b each independently represent a hydrogen atom or a C _1-3 -alkyl or -C (O) -C _1-3 -alkyl group,

. or R ₃ and R _b together with the nitrogen atom carrying them, form a heterocycle optionally substituted with one or more C _1-3 -alkyl or oxo groups.

Among the compounds of formula (I) which are subjects of the invention, there may finally be mentioned a subgroup of compounds which are defined as follows:

R represents a hydrogen atom or an ethyl group;

R ₁ 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 methyl group;

R ₄ represents a hydrogen atom or a C _1-5 alkyl group, a trifluoromethyl, a methylene-O-methyl,

. or R ₄ represents 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 ₇ represents a halogen atom, a methyl, a methoxy, -CN or -NO ₂ ;

• R _p and R ' _p represent independently of one another a hydrogen atom or a methyl;

Z represents a halogen atom or a C _1-5 alkyl, trifluoromethyl or phenyl group; a methoxy, -CN, -SO ₂ NR _a R _b ,

. or Z is -NR ₃ R b, Ci _-3 -alkylene-NR _a R b, -C (O) -NR ₈ R b, -C (O) -C _{1. 3} -alky! E,

. or Z represents an oxo radical, or Z represents a group -O-C _1-5 -alkylene-NR _a R _b ,

. or two adjacent Z radicals together form a methylenedioxy group; R ₃ and R _b each independently represent a hydrogen atom or a C ₁ -C ₃ -alkyl or -C (O) -C 1 -C ₃ -alkyl group,

. or R _a and R _b together with the nitrogen atom carrying them, form a heterocycle optionally substituted with one or more C _1-3 -alkyl or oxo groups.

Among the compounds of formula (I) that are the subject of the invention, mention may notably be made of:

4- (4-Chlorophenyl) -7-methoxy-N- [1- (2-naphthylmethyl) piperidin-4-yl] isoquinolin-1-amine dihydrochloride (Compound No. 1), - Dihydrochloride of 7- bromo-N- [1- (2-naphthylmethyl) piperidin-4-yl] isoquinolin

1-amino (compound no. 2),

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -7-bromoisoquinolin-1-amine dihydrochloride (Compound No. 3),

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -7-chloroisoquinolin-1-amine dihydrochloride (Compound No. 4),

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -7-methoxyisoquinolin-1-amine dihydrochloride (Compound No. 5),

N- (1-Benzylpiperidin-4-yl) -7-methoxyisoquinolin-1-amine dihydrochloride (compound No. 6), N- (1- {4- [3- (dimethylamino) propoxy] 3-fluorobenzylpiperidin-4-yl) -7-methoxyisoquinolin-1-amine (Compound No. 7),

7-chloro-N- (1- {4- [3- (dimethylamino) propoxy] -3-fluorobenzyl} piperidin-4-yl) isoquinolin-1-amine trihydrochloride (Compound No. 8),

7-chloro-N- (1 - {4 - [(1-methylazepan-4-yl) oxy] benzyl} piperidin-4-yl) isoquinolin-1-amine trihydrochloride (Compound No. 9),

7-chloro-N- {1- [4- (4-pyrrolidin-1-ylpiperidin-1-yl) benzyl] piperidin-4-yl} isoquinolin-1-amine (Compound No. 10),

3- [4 - ({4 - [(7-Chloroisoquinolin-1-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol dihydrochloride (compound No. 11).

The starting compounds and reagents, when their method of preparation is not described, are commercially available or described in the literature, or they can be prepared according to methods described therein or which are known to man of career. According to the invention, the compounds of general formula (I) can be prepared according to the process illustrated by the following scheme 1.

Diagram 1

According to Scheme 1, the compound of general formula (I) is prepared from a compound of formula (III), in which R ₄ and R ₇ 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), wherein R ₁ , R ₂ , R _p , R ' _p 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 or can be catalyzed by a transition metal such as palladium for example under 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 Fe / Fe-butylate; sodium 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 ¹ ) 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 general formula (I ¹ ) can also be acylated by an anhydride or an acid chloride of the type R ¹ C (O) Y to form an amide of general formula (I ") This amide can be reduced by lithium aluminum hydride (LiAlH ₄ ) or by the complex borane-tetrahydrofuran (BH ₃ -TI-IF) 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 of the compound of formula (III), wherein R ₄ and R ₇ are as defined in general formula (I) and the amino compound of formula (H ¹ ) by the methods mentioned above for the preparation of the compound of general formula ( I),

Amines of formula (U ') 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. 1993, 36, 3707-3720, Dostert et al, Eur J. Chem Chem Ther 1984, 19 (2), 105-110, Moragues et al Farmaco, Ed. ScL 1980, 35 (11), 951. -964 and Shum et al Nucleosides 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. et al (Tetrahedron Asymmetry 1995, 6, 1553-1556).

The amine of formula (II) for which R represents an alkyl other than methyl, may be prepared by reduction of an amide (previously introduced on the primary amine) with lithium aluminum hydride (LiAlH ₄ ) or by borane-tetrahydrofuran complex (BH ₃ -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 compound of general formula (I) can also be obtained according to scheme 2 which follows.

Figure 2

According to Scheme 2, the compound of general formula (I) can be prepared from a compound of formula (Ib), in which R ₄ , R ₇ , R _p , R ' _p and R are as defined in US Pat. general formula (I), and in which the nitrogen of the nitrogenous ring is not substituted, in particular by a reductive amination reaction with an aldehyde or a ketone of general formula RrC (O) R ₂ , in which R ₁ and R ₂ are as defined in the general formula (I). This reaction may be carried out, for example, in the presence of sodium triacetoxy borohydride in a solvent such as dichloromethane or 1,2-dichloroethane, according to one of the methods described in Abdel-Magid et al (J. Org Chem 1996, 61, 3849-3862). The compound of general formula (Ib) is obtained by deprotection of the compound of general formula (la) which has on the nitrogen of the nitrogen ring a protective group PG. This protective group can be for example benzyl, ethoxycarbonyl or tert-butoxycarbonyl and deprotection can be accomplished by methods cited in Protective Groups in Organic Synthesis, ^3rd edition, John Wiley & Sons, New York, 1999. The compound of general formula (la) is synthesized by reacting a compound of general formula (III) wherein R ₄ and R ₇ are as defined in general formula (I), with a compound of general formula (N ") according to the methods already described previously for the compound (I).

The compound of general formula (III) can be obtained according to Scheme 3 which follows. Figure 3

According to Scheme 3, the compound of general formula (III), when it is not commercial, can be prepared from a compound of formula (IV) ₁ derived N-oxide of isoquinoline in which R ₄ and R ₇ are as defined in the general formula (I), by heating in the presence of phosphoryl chloride in a solvent such as chloroform. According to Scheme 3, the compound of general formula (III) can also be obtained from the 2/7-isoquinolin-1-one derivative of formula (IV) in which R ₄ and R ₇ are as defined in the general formula (I) by heating in phosphoryl chloride, for example. The 2H-isoquinolin-1-one derivative of formula (IV) can be obtained by treatment of the 1f / -isochromen-1-one derivative of formula (V) with, for example, ammonium carbonate in acetic acid. The 1H-isochromen-1-one derivative of formula (V) can be synthesized 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) may be prepared from the 2-acyl-benzoic acid of formula (VIII) by esterification reaction for example with methyl iodide in the presence of potassium carbonate in dimethylformamide. The 2-acyl-benzoic acid of formula (VIII) can be synthesized from a 2-bromo-benzoic acid of formula (IX) by halogen-metal exchange and then reaction with an acid chloride of formula (X) or with a Weinreb amide, of the Λ / -methoxy-Λ / -methylamine type of formula (X '): N-Me MeO

(X ¹ ) wherein R ₄ is as defined for the compounds of formula (I). The halogen-metal exchange can be carried out with n-butyllithium in tetrahydrofuran at -78 ° C. 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 Receptor (MCH) ₁ , MCH ₁ .

In vitro tests have demonstrated the affinity of the compounds for MCH receptors and in particular MCH ₁ .

Since MCH is an important regulator of food intake, small nonpeptide molecules able to antagonize its stimulating action of the MCH ₁ receptor are a therapy of choice for treating metabolic problems related to obesity but also to bulimia nervosa. Indeed, the use of an MCH ₁ receptor antagonist such as the

SNAP-7941 (described by Synaptic Laboratories) confirms the important role of MCH in regulating 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-1 receptor antagonist has recently confirmed the anxiogenic effect of MCH. Indeed, SNAP-7941 has an anxiolytic and / or antidepressant profile in different 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; : 217-227). MCH ₁ receptor antagonist molecules have therefore a therapeutic interest in depression and / or anxiety.

The MCH seems to be involved with other regulatory systems. By its testicular location (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 male rat sexual activity (Gonzales et al., Peptides 1996; 17: 171-177) and luteinizing hormone secretion (Chiocchio et al., Biology of Reproduction 2001; 64: 1466-1472) , the MCH seems to play a role in reproductive functions.

It has also been observed that MCH is implicated in cognitive function-related behaviors by increasing the extinction of passive avoidance in rats, suggesting that an MCHi receptor antagonist may be useful in memory disorders (MacBride et al. al, Peptides 1994; 15 (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 pathologies such as anxiety and depression, as well as in the treatment of any other diseases involving MCH ₁ receptor-related dysfunction at both central and / or peripheral level.

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, or its 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.

By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: 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 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 dosage appropriate to 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, an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt thereof or hydrates or solvates.

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 synthetic procedures and for the description of the compounds are as follows: DMF for dimethylformamide, DMSO for dimethylsulfoxide,

THF for tetrahydrofuran,

- HCI for hydrochloric acid, HBr for hydrobromic acid, - NaOH for sodium hydroxide,

- And for ethyl, Me for methyl,

- TFA for trifluoroacetic acid.

Melting points (PF) are expressed in degrees Celsius. They were measured either with a Koffler apparatus (mention (K) in the following), or with a Mettler-Toledo FP62 apparatus (mention (M) in the following), or with a Bϋchi B540 apparatus (reference (B) ) in the following).

The conditions for analysis by liquid chromatography coupled with mass spectrometry (LC / UV / MS) are as follows:

For the liquid chromatography part 3 types of chromatographic systems with different pH are used:

- chromatographic system at pH 3.1 (+/- 0.1) - symmetry column C18 (2, 1 x 50 mm) 3.5 μm no WAT200650

- Eluent A = H ₂ O + 0.005% TFA

Eluent B = CH ₃ CN + 0.005% TFA.

Gradient from 100% A to 90% B in 10 minutes, then elution with 90% B for 5 minutes. - Flow 0.4ml / minute

- Injection of 2μL of 0.5 mg / ml solution in methanol

- chromatographic system at pH 2.2 (+/- 0.1)

- Xterra MS C18 column (2.1 x 50 mm) 3.5 μm No. 186000400

Eluent A = H ₂ O + 0.1% HFBA (heptafluorobutyric acid) Eluent B = 90% CH ₃ CN + 10% H ₂ O TFA + 0.1% HFBA.

Gradient: 100% A for 2 minutes then 100% A to 100% B in 10 minutes, then elution with 100% B for 5 minutes.

Flow 0.4ml / minute - Injection of 2μL of 0.5 mg / ml solution in methanol - chromatographic system at pH 7 (+/- 0.1)

- Xterra MS C18 column (2.1 x 50 mm) 3.5 μm No. 186000400

Eluent A = aqueous solution of ammonium acetate 0.01 M

- Eluent B = CH ₃ CN - 100% gradient from A to 90% B in 10 minutes, then elution with 90% B for 5 minutes.

- Flow 0.4ml / minute; temperature 30 ^° C.

Injection of 2 μL of 0.5 mg / 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 (API-ES polarity +)

- Scanning from 120 to 1500 uma

The analytical characteristics of LC / MS of the products are the ratio m / z of the ion MH ⁺ and MNa ⁺ ion and retention time (tR) of the corresponding peak observed in UV and expressed in minutes. Some pluriazote products can be eluted on the HPLC column in two forms, a very large majority, depending on the degree of salification; in this case, the two retention times are noted.

Proton nuclear magnetic resonance spectra ( ¹ H NMR) were carried out at 250 MHz, 300 MHz, 400 MHz or 500 MHz on Brϋker instruments. The abbreviations used to characterize the signals are as follows: s = singlet, m = multiplet, d = doublet, t = triplet, q = quadruplet.

Quantification salts and solvates is determined using elemental analysis, the determination of water content by the Karl-Fischer and the integration of the signals characteristic of Solvent ¹ H NMR

The compounds of the invention as well as their analytical characteristics (PF, LC / MS, salts and solvates) are indicated in Table I. Example 1

4- (4-Chlorophenyl) -7-methoxy- [N- [1- (2-naphthylmethyl) piperidin-4-yl] isoquinolin-1-amine dihydrochloride (Compound No. 1)

1.14-Chloro-γ-methoxy-γ-methylbenzamid

A solution of 26.25 g (150 mmol) of 4-chlorobenzoic acid chloride in 450 ml of dichloromethane, stirred at 0-5 ^° C. under nitrogen, is added in fractions of 14.07 g (155 mmol) of Λ, O-dimethylhydroxylamine hydrochloride. The mixture, stirred at 0-5 ^° C., is slowly added with 52.6 ml (375 mmol) of triethylamine. The reaction medium is stirred at room temperature for 5 hours.

The mixture is hydrolyzed with 100 ml of water and then extracted with dichloromethane. The organic phase is washed with 100 ml of 1N HCl, 150 ml of 1N NaOH and then with water and 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, pH 3.1)

¹ H NMR (DMSO-d ₆ , 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).

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. 100 ml (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 -78 ° C for 1 hour and then a solution of 16 g (80 mmol) of 4-chloro / V- Methoxy-β-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 hydrolyzed 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 = 7.76 minutes, pH 3.1) ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 3.89 (s, 3H); 7.28 (dd, J ₁ = 8.5 Hz, J ₂ = 2.5

Hz, 1H); 7.41 (d, J = 8.5 Hz, 1H); 7.43 (d, J = 2.5 Hz, 1H); 7.54-7.65 (m, 4H); 13.2 (s, 1H, COOH).

1.3. Methyl 2- (4-chloro-benzoyl) -5-methoxybenzoate

Potassium carbonate (1.52 g, 11 mmol) and methyl iodide (1.24 mL, 20 mmol) were added to a solution of 2- (4-chloroacetic acid) (2.9 g, 10 mmol). benzoyl) -5-methoxybenzoic acid in 20 mL of DMF. The mixture is stirred at room temperature for 3 hours. The reaction medium is hydrolyzed 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, pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 3.56 (s, 3H); 3.91 (s, 3H); 7.31 (dd, J ₁ = 8.5 Hz, J ₂ = 2.5 Hz, 1H); 7.43 (d, J = 2.5 Hz, 1H); 7.49 (d, J = 8.5 Hz, 1H); 7.56-7.67 (m, 4H).

1.4. 4- (4-chlorophenyl) -7-methoxy-1H-isochromèn-1-one

A mixture consisting of 4 g (18.1 mmol) of trimethylsulfoxonium iodide and 0.59 g (14.7 mmol) of an oily suspension of 60% sodium hydride is stirred under argon and added dropwise. 44 ml of anhydrous dimethyl sulfoxide. The mixture is stirred at ambient temperature for 2 hours 30 minutes. On the other hand, 4.5 g (14.7 mmol) of methyl 2- (4-chloro-benzoyl) -5-methoxybenzoate are dissolved in 54 ml of anhydrous DMF. To this solution cooled to 0 ^° C. and stirred under argon, the previously prepared solution of ylide is added dropwise. The resulting mixture is stirred while allowing the temperature to rise progressively to room temperature, then it is heated between 50 and 60 ^° C. for 2 hours 30 minutes. The cooled reaction medium is poured into 500 ml of water and extracted twice 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.

PF = 153 ⁰ C (M)

LC / MS: MH ⁺ = 287 (tR = 10.16 minutes, pH 3.1) ¹ H NMR (DMSO-d ₆ , 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 ₁ = 9Hz, J ₁ = 2.7 Hz ₁ H); 7.69 (d, J = 2.7 Hz, 1H).

1.5. -4- (4-Chlorophenyl) -7-methoxy-2W-isoquinolin-1-one

7 ml of acetic acid are introduced into a flask containing 640 mg (2.2 mmol) 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 minutes, pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 3.89 (s, 3H); 7.01 (d, J ₁ = 5.2 Hz, 1H); 7.34 (dd, J ₁ = 9 Hz, J ₂ = 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 ₁ 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 being cooled, it is poured slowly into 50 ml of water with stirring, keeping 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, pH 3.1)

¹ H NMR (DMSO-d ₆ , 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 (Compound No. 1)

In a tube under argon are introduced successively: 330 mg (1, 08 mmol) of 1-chloro-4- (4-chlorophenyl) -7-methoxy-isoquinoline dissolved in 6 mL of toluene, 313 mg (1.30 mmol) ) of Λ- [1- (2-naphthylmethyl) piperidin-4-yl] amine, 148 mg (1.54 mmol) of sodium tert-butylate, 6 mg (0.009 mmol) of BINAP (2.2 (bis (diphenylphosphino) -1,1'-binaphthyl) and 5.5 mg (0.006 mmol) tris (dibenzylidene-acetone) dipalladium. The mixture is stirred at 80 ^° C. for 24 hours. After returning to ambient temperature, the reaction medium is hydrolyzed with sodium hydrogen carbonate solution 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)). 258 mg of product are obtained.

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.6-1.85 (m, 2H); 1.95-2.1 (m, 2H); 2.10-2.25 (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).

The dihydrochloride salt is obtained by treatment of the product dissolved in dichloromethane with a solution of 2M hydrochloric acid in diethyl ether. Trituration and addition of diethyl ether gives a suspension which is filtered. The powder obtained is dried at 40 ^° C. under reduced pressure in the presence of diphosphorus pentoxide.

Example 2

7-DrOmO-N- [1- (2-naphthylmethyl) piperidin-4-yl] isoquinolin-1-amine dihydrochloride (Compound No. 2)

594 mg (2.47 mmol) of Λ- [1- (2-naphthylmethyl) piperidin-4-yl] amine and 133 mg (2.49 mmol) of ammonium chloride are added to a solution of 500 mg ( 2.06 mmol) 7-bromo-1-chloro-isoquinoline 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, hydrolyzed 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.

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.48-1.68 (m, 2H); 1. 90-2.0 (m, 2H); 2.08-2.20 (m, 2H); 2.85-2.98 (m, 2H); 3.67 (s, 2H); 4.5-4.20 (m, 1H); 6.88 (d, J = 7.6 Hz, 1H); 7.19 (d, J = 7.2 Hz, 1H); 7.45-7.58 (m, 3H); 7.65-7.78 (m, 2H); 7.80-7.95 (m, 5H); 8.62 (s, 1H).

The dihydrochloride is obtained by the treatment described in 1.7.

Example 3

/ V- [1 - (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -7-bromoisoquinolin-1-amine dihydrochloride (Compound No. 3)

3.1. [1 - (1, 3-Benzodioxol-5-ylmethyl) piperidin-4-yl] tert-butyl carbamate To a solution of 9.36 g (46.8 mmol) of (piperidin-4-yl) carbamate terf 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 hydrolyzed 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)

¹ H NMR (DMSO-d ₆ , 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. Λ / - (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) piperidin-4-yl] carbam-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 dihydrochloride are obtained in the form of a white solid.

A part is transformed into the corresponding base: 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. We obtain

174 mg of a white solid.

M.p. = 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); 5.99 (s, 2H); 6.7-6.8 (m, 1H); 6.8-6.9 (m, 2H)

3.3. / V- [1- (1,3-Benzodioxol-5-ylmethyl) -piperidin-4-yl] -7-bromoisoquinolin-1-amine dihydrochloride (Compound No. 3) 579 mg (2.47 mmol) Λ / (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl-amine and 140 mg (2.62 mmol) of ammonium chloride are added to a solution of 500 mg (2.06 mmol) of 7- bromo-1-chloro-isoquinoline in 15 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 room temperature, hydrolyzed with 20 ml of a 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.

¹ H NMR (DMSO-de, 250 MHz) δ ppm: 1, 50-1, 72 (m, 2H); 1.86-2.13 (m, 4H); 2.80-2.90 (m, 2H); 3.41 (s, 2H); 4.0-4.18 (m, 1H); 6.00 (s, 2H); 6.77 (d, J = 7.6 Hz, 1H); 6.80-6.95 (m, 3H); 7.20 (d, J = 7.2 Hz, 1H); 7.60-7.75 (m, 2H); 7.89 (d, J = 6 Hz, 1H); 8.61 (s, 1H). The dihydrochloride is obtained by the treatment described in 1.7. Example 4: Λ- [1- (1,3-Bis-dioxol-5-ylmethyl) -piperidin-4-yl] -7-chloroisoquinolin-1-amine dihydrochloride (Compound No. 4)

In a tube under a nitrogen atmosphere, 257 mg (0.57 mmol) of N

[1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -7-bromoisoquino! In-1-amine (preparation in 3.3), 2 ml of anhydrous DMF and 150 mg (1.13 mmol) of chloride. of nickel. The tube is capped and the mixture is stirred at 170 ^° C. for 4 hours. The cooled reaction medium is diluted in 4 ml of water and 2 ml of 1N sodium hydroxide and then extracted with ethyl acetate. The organic phase is washed with water and then with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified on a silica column (eluent: 100/0 to 95/5 (v / v) dichloromethane / methanol). 183 mg of gummy product is obtained.

¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 1.56-1.68 (m, 2H); 1.89-1.98 (m, 2H); 1.98- 2.08 (m, 2H); 2.80-2.89 (m, 2H); 3.39 (s, 2H); 4.01-4.12 (m, 1H); 5.99 (s, 2H); 6.77 (d, J = 7.6 Hz, 1H); 6.81-6.90 (m, 3H); 7.15 (d, J = 7.2 Hz, 1H); 7.62 (dd, J ₁ = 8.8 Hz, J ₂ = 2 Hz, 1H); 7.73 (d, J = 8.8 Hz, 1H); 7.87 (d, J = 5.6 Hz, 1H); 8.46 (s, 1H). The dihydrochloride is obtained by the treatment described in 1.7.

Example 5

W- [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -7-dihydrochloride

methoxyquinolinolin-1-amine (compound 5)

5.1. 7-MéthoxyisoquinoIine

A solution of 2.95 g (20.3 mmol) of 7-hydroxy-isoquinoline in 20 ml of DMF is stirred at 0 ^° C. and 0.81 g (20.3 mmol) of an oily suspension of sodium hydride 60% are added. The mixture is stirred at 0 ^° C. for 15 minutes, then 1.33 ml (21.4 mmol) of iodomethane are added thereto. The mixture is stirred for 30 minutes at 0 ^° C. and then for 1 hour at room temperature. It is then added with water and extracted with 100 mL of tert-butyl methyl ether. The organic extract is washed twice with 50 mL 1N sodium hydroxide solution and then washed with water and saturated sodium chloride water. It is dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 2.38 g of gummy product are obtained.

MH ⁺ = 160 (tR = 3.86 minutes, pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 3.92 (s, 3H); 7.43 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H); 7.52 (d, J = 2.5 Hz, 1H); 7.75 (d, J = 5.5 Hz, 1H); 7.90 (d, J = 9 Hz, 1H); 8.38 (d, J = 5.5 Hz, 1H); 8.98 (s, 1H).

5.2. N-oxide of 7-methoxyisoquinoline

A solution of 2.3 g (13.8 mmol) of 7-methoxy-isoquinoline in 55 ml of dichloromethane is stirred at room temperature and added in portions of 5.78 g.

(23.4 mmol) meta-chloroperbenzoic acid. The mixture is stirred at room temperature for 3 hours, then diluted with 200 ml of dichloromethane and 20 ml of methanol and washed with 100 ml and then with 50 ml of 2N sodium hydroxide. The aqueous alkaline phases are extracted with dichloromethane and the combined organic phases are washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The white residue is dissolved in dichloromethane and added with diisopropyl ether. Partial evaporation of the solvent forms a precipitate which is filtered and dried. 1.62 g of white powder is obtained.

Mp = 48 ⁰ C (M)

MH ⁺ = 176 (tR = 5.24 minutes, pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 3.89 (s, 3H); 7.26 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H); 7.33 (d, J = 2.5 Hz, 1H); 7.84-7.90 (m, 2H); 8.02 (dd, J ₁ = 7 Hz, J ₂ = 1.7 Hz, 1H); 8.82 (d, J = 1.7 Hz, 1H).

5.3 1 -Chloro-7-methoxyisoquinoline

A solution of 1.62 g (9.2 mmol) of 7-methoxyisoquinoline N-oxide in 4.2 ml of chloroform is added 4.25 ml (46.2 mmol) of phosphoryl chloride. The mixture is stirred under reflux for 4 hours and then, after returning to ambient temperature, is poured dropwise over 200 ml of water at about 10 ° C. with stirring. The mixture is neutralized to pH 7 by adding 70 mL of 2N sodium hydroxide and 20 mL 1N sodium hydroxide solution and then extracted twice with 200 ml of dichloromethane. The organic phase is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified on a column of silica (eluent: cyclohexane / ethyl acetate 9/1 (v / v)). The first product eluted is the expected 1-chloro-7-methoxyisoquinoline (320 mg). The other two products eluted are 3-chloro-7-methoxyisoquinoline (91 mg) and 4-chloro-7-methoxyisoquinoline (86 mg), respectively. Mp = 73 ° C (M)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 3.98 (s, 3H); 7.51 (d, J = 2.5 Hz, 1H); 7.56 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H); 7.86 (d, J = 5.5 Hz, 1H); 8.03 (d, J = 9 Hz, 1H); 8.20 (d, J = 5.5 Hz, 1H).

5.4. Λ- [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -7-methoxyisoquinolin-1-amine dihydrochloride (Compound No. 5)

A mixture consisting of 387 mg (2 mmol) of 1-chloro-7-methoxyisoquinoline and 562 mg (2.4 mmol) of Λ- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl-amine in 4 mL of toluene is stirred at room temperature under argon and is supplemented with 269 mg (2.8 mmol) of sodium butylate, 12 mg of tris (dibenzylideneacetone) dipalladium (0) and 12 mg of 2,2'-bis ( diphenyl-phosphino) -1,1'-binaphthyl (racemic). The mixture is stirred at 80 ^° C. for 22 hours, then, after cooling, water is added and the mixture is extracted with ethyl acetate. The organic phase is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is purified on a silica column (eluent: 100/0 to 95/5 (v / v) dichloromethane / methanol). 470 mg of gummy product is obtained.

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1, 54-1.63 (m, 2H); 1, 90-2.12 (m, 4H); 2.82-2.92 (m, 2H); 3.42 (s, 2H); 3.90 (s, 3H); 4.05-4.20 (m, 1H); 6.00 (s, 2H); 6.75-6.90 (m, 5H); 7.25 (dd, J ₁ = 9 Hz, J ₂ = 2 Hz, 1H); 7.60-7.65 (m, 2H); 7.73 (d, J = 5.7 Hz, 1H). The dihydrochloride is obtained by the treatment described in 1.7. Example 6

N- (1-Benzylpiperidin-4-yl) -7-methoxyisoquinolin-1-amine dihydrochloride (Compound No. 6)

This compound in the base form is obtained according to the procedure described in

5.4. by reaction of 1-chloro-7-methoxyisoquinoline (preparation in 5.3) with 4-amino-1-benzylpiperidine.

¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 1.60-1.72 (m, 2H); 1, 90-2.0 (m, 2H); 2.02- 2.12 (m, 2H); 2.85-2.92 (m, 2H); 3.50 (s, 2H); 3.90 (s, 3H); 4.08-4.20 (m, 1H); 6.81 (d, J = 6Hz, 1H); 6.87 (d, J = 7.6 Hz, 1H, NH); 7.23-7.30 (m, 2H); 7.30-7.38 (m, 4H); 7.60-7.65 (m, 2H); 7.73 (d, J = 6 Hz, 1H).

The dihydrochloride is obtained by the treatment described in 1.7.

Example 7: N- (1- {4- [3- (Dimethylamino) propoxy] -3-fluorobenzyl} -piperidin-4-yl) -7-methoxyisoquinolin-1-amine trihydrochloride (Compound No. 7)

7.1. 7-Methoxy-N- (piperidin-4-yl) isoquino-1-amine

The manipulation is carried out under an inert atmosphere (nitrogen). In a tricolor of 100 ml are introduced 0.2 g of 10% palladium on charcoal and 16 ml of water. To this stirred mixture at 85 ° C is added dropwise a previously prepared solution of 1.35 g of N- (1-benzylpiperidin-4-yl) -7-methoxyisoquinolin-1-amine in 8 mL of ethanol and 0.56 g mL (14.6 mmol) of formic acid. The reaction mixture is stirred at reflux for 2 hours. After returning to ambient temperature and filtration, the ethanol is evaporated under reduced pressure. The mixture is then basified with 2N sodium hydroxide and is then extracted with dichloromethane. The organic phase is washed with water saturated with sodium chloride. sodium, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 0.98 g of product is obtained in the form of a white powder. Mp = 145 ° C (M) MH ⁺ = 258 (tR = 3.93 minutes, pH 3.1)

¹ H NMR (DMSO-Cl ₆ , 250 MHz) δ ppm: 1.40-1.57 (m, 2H); 1.88-1.98 (m, 2H); 2.30- 2.45 (m, 1H, NH); 2.55-2.64 (m, 2H); 2.97-3.07 (m, 2H); 3.90 (s, 3H); 4.10-4.25 (m, 1H); 6.81 (d, J = 5.7 Hz, 1H); 6.88 (d, J = 7.5 Hz, 1H, NH); 7.26 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H); 7.62 (d, J = 9 Hz, 1H); 7.65 (d, J = 2.5 Hz, 1H); 7.73 (d, J = 5.7 Hz, 1H).

7.2. 4- (3-dimethylaminopropoxy) -3-fluoro-benzaldehyde

A solution of 3.8 g (27 mmol) of 3-fluoro-4-hydroxybenzaldehyde and 4.28 g (27 mmol) of Λ, N-dimethyl-3-chloropropylamine hydrochloride in 100 ml of DMF is added with 7.46 g ( 54 mmol) of potassium carbonate. The mixture is stirred at 80 ^° C. for 5 hours and then, after cooling, is added water and extracted with ethyl acetate. The organic extract is washed with water and then with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 4.67 g of oily product are obtained. MH ⁺ = 226 (tR = 5.16 minutes, pH 7)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.85-1.98 (m, 2H); 2.15 (s, 6H); 2.34-2.40 (m, 2H); 4.19-4.24 (m, 2H); 7.36-7.43 (m, 1H); 7.70 (d, J = 11Hz, 1H), 7.77 (d, J = 7.5Hz, 1H), 9.87 (s, 1H ₁ CHO).

7.3. N- (1- {4- [3- (Dimethylamino) propoxy] -3-fluorobenzyl} piperidin-4-yl) -7-methoxyisoquinolin-1-amine hydrochloride (Compound No. 7)

A solution of 257 mg (1 mmol) of 7-methoxy-β- (piperidin-4-yl) isoquinolin-1-amine in 10 ml of 1,2-dichloroethane is added with 270 mg (1.2 mmol) of 4- (3-dimethylaminopropoxy) -3-fluoro-benzaldehyde. The mixture is stirred for 4 hours under nitrogen, then 297 mg (1.4 mmol) of sodium triacetoxyborohydride are added. The reaction medium is stirred for 20 hours at room temperature and then hydrolyzed with water and 1N sodium hydroxide. The ethyl acetate extract is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate, then evaporated under reduced pressure. The residue is purified on a column of neutral alumina (eluent: 100/0 to 98/2 (v / v) dichloromethane / methanol). 294 mg of product are obtained gummy.

¹ H NMR (DMSO-Cl ₆ , 250 MHz) δ ppm: 1. 58-1.73 (m, 2H); 1. 80-2.10 (m, 6H); 2.14 (s, 6H), 2.30-2.38 (m, 2H); 2.82-2.90 (m, 2H); 3.44 (s, 2H); 3.90 (s, 3H); 4.03-4.20 (m, 3H); 6.82 (d, J = 5.7 Hz, 1H); 6.88 (d, J = 7.5 Hz, 1H, NH); 7.05-7.18 (m, 3H); 7.25 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H); 7.60-7.65 (m, 2H); 7.73 (d, J = 5.7 Hz, 1H);

The trihydrochloride is obtained by the treatment described in 1.7. .

Example 8

7-Chloro-N- (1- {4- [3- (dimethylamino) propoxy] -3-fluorobenzyl} piperidin-4-yl) isoquinolin-1-amine trihydrochloride (Compound No. 8)

8.1. 7-Bromo- / V- (piperidin-4-yl) isoquinolin-1-amine

A mixture of 3.5 g (14 mmol) of 7-bromo-1-chloroisoquinoline and 7.53 g (42 mmol) of ethyl 4-amino-piperidin-1-yl-carboxylate in 28 ml of n-pentanol. is stirred at 155 ° C overnight. Then, after addition of 2.5 g (14 mmol) of additional 4-amino-piperidin-1-yl-ethyl carboxylate, the reaction mixture is stirred at 162 ^° C. for 4 hours 30 minutes. The solvent is partially evaporated and the reaction medium, cooled to room temperature is added with water, made alkaline with a minimum of 1N sodium hydroxide and extracted with ethyl acetate. The organic phase is washed with water and with salt water, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 8 g of crude product are obtained in ethyl carbamate form. This compound is supplemented with 56 ml of a solution of hydrobromic acid at 33% in acetic acid and the mixture is stirred at 115 ° C. for 3 hours. After cooling, the precipitate is taken up in isopropanol and after 15 minutes in an ice bath, the suspension is filtered. The solid dihydrobromide obtained, partially dried, is dissolved in 150 mL of water and the resulting solution is alkalinized with 35 mL of 1N sodium hydroxide. A suspension is formed which is extracted with ethyl acetate. The organic phase is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is dissolved in a few ml of dichloromethane and the product precipitates by addition of diisopropyl ether. 3.8 g of white powder are obtained. Mp = 177 ° C (M)

MH ⁺ = 306 (tR = 1.27 minutes, pH 3.1)

¹ H NMR (DIVISO-Cl ₆ , 250 MHz) δ ppm: 1.38-1.57 (m, 2H); 1.84-1.94 (m, 2H); 2.20- 2.40 (m, 1H, NH); 2.55-2.62 (m, 2H); 2.93-3.06 (m, 2H); 4.06-4.25 (m, 1H); 6.87 (d, J = 5.7 Hz, 1H); 7.19 (d, J = 7.5 Hz, 1H, NH); 7.65 (d, J = 9 Hz, 1H); 7.73 (dd, J ₁ = 9 Hz, J ₂ = 2 Hz, 1H); 7.89 (d, J = 5.7 Hz, 1H); 8.62 (d, J = 2 Hz, 1H).

8.2. 7-Chloro-N- (piperidin-4-yl) isoquinolin-1-amine

In a tube under a nitrogen atmosphere, 2 g (6.5 mmol) of 7-bromine are introduced.

Λ / - (piperidin-4-yl) isoquinolin-1-amine, 2 ml of anhydrous DMF and 1.72 g (13 mmol) of nickel chloride. The tube is capped and the mixture is stirred at 170 ^° C. for 3 hours. The cooled reaction medium is added with a few ml of water and 13 ml of 1N sodium hydroxide and then extracted with ethyl acetate. The organic phase is washed with water and then with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue obtained is dissolved in 250 ml of N hydrochloric acid and the solution is washed with 2 times 100 ml of ethyl acetate and then basified with 30 ml of 35% sodium hydroxide. This alkaline aqueous phase is extracted with dichloromethane and the organic phase obtained is washed with water and then with saturated water of sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue is purified on a column of alumina (eluent: dichloromethane / methanol 100/0 to 90/10 (y N)). The first product eluted is residual 7-chloro-β- (1-formylpiperidin-4-yl) isoquinolin-1-amine. 1.05 g of the expected product is obtained in the form of a white powder. Mp = 175 ° C (B) MH ⁺ = 262 (tR = 3.28 minutes, pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.38-1.54 (m, 2H); 1.85-1.95 (m, 2H); 2.10-2.20 (m, 1H, NH); 2.55-2.63 (m, 2H); 2.93-3.06 (m, 2H); 4.06-4.22 (m, 1H); 6.88 (d, J = 5.7 Hz, 1H); 7.16 (d, J = 7.5 Hz, 1H, NH); 7.62 (dd, J ₁ = 9 Hz, J ₂ = 2 Hz, 1H); 7.73 (d, J = 9 Hz, 1H); 7.88 (d, J = 5.7 Hz, 1H); 8.49 (d, J = 2 Hz, 1H). 8.3. 7-Chloro-N- (1- {4- [3- (dimethylamino) propoxy] -3-fluorobenzyl} piperidin-4-yl) -soquinolin-1-amine trihydrochloride (Compound No. 8)

This compound in the base form is obtained by reductive amination according to the procedure described in 7.3. by reaction of 7-chloro-Λ- (piperidin-4-yl) isoquinolin-1-amine with 4- (3-dimethylaminopropoxy) -3-fluoro-benzaldehyde (preparation in 7.2.)

¹ H NMR (DMSO-d6 500 MHz) δ ppm: 1. 58-1.73 (m, 2H); 1.82-1.92 (m, 2H); 1, 92-

2.0 (m, 2H); 2.05-2.10 (m, 2H); 2.14 (s, 6H), 2.33-2.40 (m, 2H); 2.82-2.90 (m, 2H); 3.43

(s, 2H); 4.03-4.13 (m, 3H); 6.90 (d, J = 5.7 Hz, 1H); 7.04-7.16 (m, 4H); 7.63 (dd, J ₁ = 9 Hz, J ₂ = 2.5 Hz, 1H); 7.73 (d, J = 9 Hz, 1H); 7.88 (d, J = 5.7 Hz, 1H); 8.48 (d, J = 2.5 Hz,

1H).

The trihydrochloride is obtained by the treatment described in 1.7. .

Example 9 7-Chloro-N- (1- {4 - [(1-methylazepan-4-yl) oxy] benzyl} piperidin-4-yl) isoquinolin-1-amine trihydrochloride (Compound No. 9)

9.1 4- [2- (1-Methylpyrrolidin-2-yl) ethoxy] benzaldehyde and 4 - [(1-methylazepan-4-yl) oxy] benzaldehyde

A solution of 4.97 g (27 mmol) of 2- (2-chloroethyl) -α-methylpyrrolidine hydrochloride and 3.3 g (27 mmol) of 4-hydroxybenzaldehyde in 66 ml of DMF is added with 7.84 g ( 56 mmol) of potassium carbonate. The mixture is stirred at 80 ^° C. for 4 hours and then, after cooling, is poured into water and extracted with ethyl acetate. The organic extract is washed with water and then with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 3 g of the residue obtained are purified on a column of silica gel (solvent: toluene / methanol 50/50 (yN)). The first eluted compound is 4- [2- (1-methyl-pyrrolidin-2-yl!) Ethoxy] benzaldehyde: ¹ H NMR (DMSOd _6, 250MHz) δ ppm: 1.15-1.25 (m, 1H); 1.40-1.75 (m, 4H); 1.85-2.20 (m, 4H); 2.23 (s, 3H); 2.92-3.0 (m, 1H); 4.10-4.18 (m, 1H); 7.13 (d, J = 9 Hz ₁ 2H), 7.85 (d, J = 9 Hz, 2H), 9.88 (s, 1H ₁ CHO). The second compound eluted is 4 - [(1-methylazepan-4-yl) oxy] benzaldehyde:

¹ H NMR (DMSO-ds, 250 MHz) δ ppm: 1.50-1.92 (m, 4H); 2.0-2.18 (m, 2H); 2.22 (s, 3H); 2.45-2.68 (m, 4H); 4.72-4.80 (m, 1H); 7.14 (d, J = 9Hz, 2H), 7.84 (d, J = 9Hz, 2H), 9.86 (s, 1H ₁ CHO).

9.2. 7-Chloro-N- (1- {4 - [(1-methylazepan-4-yl) oxy] benzyl} piperidin-4-yl) isoquinolin-1-amine trihydrochloride (Compound No. 9)

This compound in the base form is obtained by reductive amination according to the procedure described in 7.3. by reaction of 7-chloro-β- (piperidin-4-yl) isoquinolin-1-amine (preparation in 8.2) with 4 - [(1-methylazepan-4-yl) oxy] benzaldehyde.

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.50-2.12 (m, 12H); 2.26 (s, 3H), 2.40-2.68

(m, 4H); 2.80-2.90 (m, 2H); 3.42 (s, 2H); 4.0-4.18 (m, 1H); 4.50-4.60 (m, 1H); 6.84 (d, J =

8.5 Hz, 2H); 6.89 (d, J = 5.7 Hz, 1H); 7.15 (d, J = 7.5 Hz, 1H, NH); 7.20 (d, J = 8.5 Hz, 2H); 7.62 (dd, J ₁ = 9 Hz, J ₂ = 2 Hz, 1H); 7.73 (d, J = 9 Hz, 1H); 7.88 (d, J = 5.7 Hz, 1H);

8.46 (d, J = 2 Hz, 1H).

The trihydrochloride is obtained by the treatment described in 1.7. .

Example 10: 7-Chloro-N- {1- [4- (4-pyrrolidin-1-ylpiperidin-1-yl) benzyl] piperidin-4-yl} isosolinolin-1-amine (Compound No. 10)

10.1 4- (4-Pyrrolidin-1-ylpiperidin-1-yl) benzaldehyde

A mixture consisting of 1 g (5.4 mmol) of 4-bromobenzaldehyde, 1 g (6.5 mmol) of 4- (1-pyrrolidinyl) piperidine in 10 ml of anhydrous toluene is stirred at room temperature under an argon atmosphere and 2.46 (7.56 mmol) cesium carbonate, 50 mg tris (dibenzylideneacetone) dipalladium (0) and 50 mg 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (racemic). The mixture is stirred at 80 ^° C. for 40 hours, then, after cooling, is filtered on celite. The solid is rinsed with ethyl acetate and the filtrate is evaporated to dryness. The residue obtained is purified on a silica column (eluent: 100/0 to 85/15 (v / v) dichloromethane / methanol). 0.94 g of an orange oil is obtained in which the product crystallizes.

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.35-1.52 (m, 2H); 1.60-1.75 (m, 4H); 1.85-1.95 (m, 2H); 2.20-2.32 (m, 1H); 2.45-2.60 (m, 4H); 2.95-3.05 (m, 2H); 3.85-3.96 (m, 2H); 7.04 (d, J = 9Hz, 2H), 7.70 (d, J = 9Hz, 2H), 9.70 (s, 1H, CHO).

10.2 7-Chloro-N- {1- [4- (4-pyrrolidin-1-ylpiperidin-1-yl) benzyl] piperidin-4-yl} isoquinolin-1-amine (Compound No. 10)

This compound in the base form is obtained by reductive amination according to the procedure described in 7.3. by reaction of 7-chloro-β- (piperidin-4-yl) isoquinolin-1-amine (preparation in 8.2) with 4- (4-pyrrolidin-1-ylpiperidin-1-yl) benzaldehyde.

MH ⁺ = 504 (tR = 4.03 and 4.20 minutes, pH 3.1)

¹ H NMR (CDCl ₃ , 400 MHz) δ ppm: 1. 58-1.78 (m, 4H); 1.80-1.88 (m, 4H); 1.98-2.20 (m, 5H); 2.20-2.30 (m, 2H); 2.60-2.68 (m, 4H); 2.70-2.80 (m, 2H); 2.86-2.94 (m, 2H); 3.49 (s, 2H); 3.66-3.73 (m, 2H); 4.14-4.26 (m, 1H); 5.04 (d, J = 7.6 Hz, 1H, NH); 6.89 (d, J = 6 Hz, 1H); 6.92 (d, J = 8.4 Hz, 2H); 7.21 (d, J = 8.4 Hz, 2H); 7.52 (dd, J ₁ = 8.4 Hz, J ₂ = 1.2 Hz, 1H); 7.61 (d, J = 8.4 Hz, 1H); 7.71 (d, J = 1.2 Hz, 1H); 7.98 (d, J = 6 Hz, 1H). Example 11: 3- [4 - ({4 - [(7-Chloroisoquinol-1-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol dihydrochloride (Compound No. 11)

11.1 4- [3- (Tetrahydro-2H-pyran-2-yloxy) propoxy] benzaIdehyde

A solution of 1.31 g (5.9 mmol) of 2- (3-bromopropoxy) tetrahydro-2H-pyran and 0.94 g (7.7 mmol) of 4-hydroxybenzaldehyde in 23 ml of DMF is added with 1.63 g (11.8 mmol). ) of potassium carbonate. The mixture is stirred at room temperature for 20 hours then is added with water and extracted with ethyl acetate.

The organic extract is washed with 1 N sodium hydroxide, with water, then with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 1.52 g of oily product are obtained. ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 1.45-1.80 (m, 6H); 1.92-2.08 (m, 2H); 3.38-3.58 (m, 2H); 3.70-3.83 (m, 2H); 4.15-4.22 (m, 2H); 4.55-4.60 (m, 1H); 7.13 (d, J = 9Hz, 2H), 7.86 (d, J = 9Hz, 2H), 9.88 (s, 1H, CHO).

11.2. 3- [4 - ({4 - [(7-Chloroisoquinolin-1-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol dihydrochloride (Compound No. 11)

A solution of 300 mg (1.15 mmol) of 7-chloro-β- (piperidin-4-yl) isoquinolin-1-amine in 6 ml of 1,2-dichloroethane is added with 302 mg (1.15 mmol). 4- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] benzaldehyde. The mixture is stirred for 45 minutes under nitrogen, then 316 mg (1.3 mmol) of sodium triacetoxyborohydride are added. The reaction mixture is stirred for 18 hours at room temperature and then hydrolyzed with 1N sodium hydroxide and extracted with dichloromethane. The organic phase is treated with 50 ml of 1N hydrochloric acid and the mixture is vigorously stirred for 1 hour. The acidic aqueous phase is separated and then alkalinized with a 2N sodium hydroxide solution and extracted with dichloromethane. The organic phase is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 350 mg of white solid product is obtained.

¹ H NMR (CDCl ₃ , 400 MHz) δ ppm: 1. 53-1.63 (m, 2H); 1.80-1.98 (m, 4H); 1.98- 2.08 (m, 2H); 2.80-2.88 (m, 2H); 3.40 (s, 2H); 3.52-3.58 (m, 2H); 3.98-4.12 (m, 3H); 4.53

(t, J = 5.2 Hz, 1H, OH); 6.86-6.91 (m, 3H); 7.15 (d, J = 7.2 Hz, 1H, NH); 7.21 (d, J = 8.8

Hz, 2H); 7.62 (dd, J ₁ = 8.8 Hz, J ₂ = 2 Hz, 1H); 7.73 (d, J = 8.4 Hz, 1H); 7.87 (d, J = 5.6

Hz, 1H); 8.46 (d, J = 2 Hz, 1H).

Table 1

The compounds according to the invention have been the subject of pharmacological tests. Their affinity towards the Melanin-Concentrating Hormone (MCH) receptor 1, MCH ₁ , was thus determined. Attempts were to measure the in vitro activity of the compounds of the invention on MCH ₁ MCH receptors.

Liaison studies:

The measurement of the affinity of the compounds of the invention for the MCH receptors was carried out by studying the displacement of the binding of a radio-labeled derivative of the MCH to the MCH ₁ receptors. This study is carried out on membrane preparations of rat and / or mouse brain according to the protocol described below.

In preparation for binding studies, the brains were diluted in 25 mM HEPES buffer (pH 7.4) containing MgCl ₂ 5 mM of CaCl ₂ 1 mM, homogenized using a

Polytron 3 times 20 seconds (speed 25), then undergo ultracentrifugation for 22 minutes at 22,000 RPM at + 4 ° C. The pellet is taken up by 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 radiolabelled molecule derived from the MCH, the

[ ¹²⁵ I] -Tyr-S36057 (8-amino-3,6-dioxyoctanoyl) MCH 6-17 marketed by Perkin-

Elmer) in 25 mM HEPES buffer (pH 7.4) containing MgCl ₂ 5 mM of CaCl _{2 January} mM, bacitracin 140 mg / L, 1 mM phenantroline, and 0.2% 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 pre-incubated for 2 hours in 0.1% aqueous polyethyleneimine solution. The radioactivity retained on the filters is measured using a gamma scintillation counter. Nonspecific binding is determined in the presence of 1 μM of non-radiolabelled 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 (Cl ₅₀ ).

In the context of the invention, the Cl ₅₀ of the compounds are generally less than

10 .mu.M.

The compounds of formula (I) advantageously have Cl ₅₀ less than 1 μM, more advantageously less than or equal to 10 μM and even more advantageously less than or equal to 10 μM.

By way of example, the compound according to Example 3 has a Cl ₅₀ 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 80

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 antagonists of the MCHi receptor of the MCH.

Claims

1. Compound corresponding to the following general formula (I):

in which,

• R represents a hydrogen atom, a group CI_ ₅ -alkyl, C _1-3 fluoroalkyl, C _3-6 - cycloalkyl, Ci _-3 -alkylene-C _3-6 -cycloalkyl, -C (O) -C _1-5 -alkyl, -CH ₂ -C≡CH, C _2-4 -alkylene-NR _a R _b , C _1-3 -alkylene-XC _1-3 -alkyl wherein X is O or SO ₂ ;

R ₁ 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, a C _1-5 -alkyl or C _1-3 -fluoroalkyl group;

• R ₄ represents a hydrogen atom or a Ci _-5 alkyl group, C _1-3 fluoroalkyl, C _3-6 - cycloalkyl, Ci _-3 -alkylene-C _3-6 -cycloalkyl, Ci _-3 -alkylene -O-Ci _-3 alkyl, Ci _-3 -alkylene- (OH), C _1-3 -alkylene-OC _4-6 -cycloalkyl, C _1-3 -alkylene-XC _1-3 alkyl wherein X is S , SO or

SO ₂ ,

. or R ₄ represents a C _1-3 -alkylene-NR _a Rb, aryl, C _1-3 -alkylene-aryl group,

C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-O-C 1. ₃ -alkylene-aryl, heteroaryl or Ci _-3 -alkylene-heteroaryl; aryl, C _1-3 -alkylene-aryl, -O-aryl, C _1-3 -alkylene-O-aryl, Ci _-3 - alkylene-OC _1-3 alkylene-aryl, heteroaryl and Ci _-3 - alkylene-heteroaryl being optionally substituted by one or more radicals Z that are identical to or different from one another,

. or R ₄ represents a heterocycle group; said heterocycle being optionally substituted by a C _1-3 -alkyl, -C (O) -d _-5 -alkyl, -C (O) -C _1-5 -fluoroalkyl, C _1-3 -alkylene-C _{3- 6} -cycloalkyl, C-ι _-3 -alkylene-aryl, C _1-3 -alkylene-heteroaryl; the groups C _1-3 -alkylene-aryl and Ci _-3 -alkylene-heteroaryl being optionally substituted by one or more identical or different radicals Z from each other;

R ₇ represents a hydrogen or halogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _1-5 -alkoxy, C _1-3 -fluoroalkoxy, C _1-3 -alkylene group; - (OH), -CN, -COOH, -C (O) O-C _1-3 -alkyl, -NO ₂ , -X-C _1-3 -alkyl wherein X is S, SO or SO ₂ ,

. or R ₇ represents a group -NR _a R _b , Ci.s-alkylene-NRaRt ,, -C (O) -NR ₃ Rb, -C (O) -C _1-3 -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; • R _p and R ' _p independently of one another represent a hydrogen atom or a C _1-5 -alkyl group,

. or R _p and R ' _p together form a single bond or a C _1-4 alkylene group;

Z represents a halogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _3-6 -cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, C _{1-5 group;} -alkoxy, C _1-3 -fluoroalkoxy, C _1-3 -alkylene-O-C _1-3 -alkyl, C 1 -alkylene-COH), NO ₂ , -CN, -SO ₂ NR _a R _b , -XC _1-3 -alkyl, C _1-3 -alkylene-XC _1-3 -alkyl wherein X is S, SO or SO ₂ ,

. or Z represents optionally phenyl substituted by a halogen atom, a Ci _-5 alkyl group, Ci _-5 alkoxy or C _1-3 fluoroalkyl,. or Z represents an alkynyl radical of the type -C≡CR _C , in which R _c represents a hydrogen atom, a C _1-3 -alkyl group, C _1-6 -alkylene-OR _d or C _1-6 -alkylene group; NR _a R _b ,

. or Z represents a -C _4-6 -alkylene-OR _{d group} ,

. or Z represents a tetrazole group substituted with a C _1-3 -alkyl group, or Z is -NR _a R _b , C _1-3 -alkylene-NR _a R _b , -C (O) -NR _a R _b ,

-C (O) -C _1-3 -alkyl, -C (O) OC _1-4 -alkyl, -C (O) -C _3-6 -cycloalkyl, or Z represents an oxo radical, or Z represents a group -OC _1-5 -alkylene-NR _a R _b ,. or Z represents a -C _4-6 -alkylene-NR _a R _{b group} . or Z represents a -OC _0-3 -alkylene-heterocycle group, optionally substituted with one or more C _1-3 -alkyl, oxo or -C (O) -C 1 -C ₃ -alkyl groups, or Z represents a group -OC _1-5 -alkylene-OR _d ,

. or Z represents a group -OC ₀ . ₃ -alkylene-C _5-7 -cycloalkyl optionally substituted with a group -OR _d ,. or Z is -NR _e -C _0-3 -alkylene-heterocycle optionally substituted with one or more groups Ci _-3 alkyl, oxo or -C (O) -C _1-3 -alkyl. or Z represents a group -NR _θ -C _2-5 -alkylene-OR _d ,. or Z represents a -O-C _1-3 -alkylene-heteroaryl group optionally substituted by one or more C _1-3 -alkyl groups, or Z represents -CONH-C _1-5 -alkylene-NR _a R _b ,

. or Z represents -CONH-C _1-5 -alkylene-O-Rd, or Z represents a group -OC _1-3 -alkylene-C (O) -NR _a R _b ,. or Z represents a fused bicyclic or fused bicyclic heterocyclic ring, or two adjacent radicals Z together form a group C _1-3 - alkylenedioxy;

R _a and R _b each independently represent a hydrogen atom or a C _1-3 -alkyl or -C (O) -C _1-3 -alkyl group,

. or R _a and R _b together with the nitrogen atom carrying them form a heterocycle optionally substituted by one or more C _1-3 -alkyl, oxo, -NR ₃ R _b , hydroxy, Ci- _{3 groups;} -alkoxy, C _1-3 -alkylene- (OH) or -C (O) -C _1-3 -alkyl;

R _d represents a hydrogen atom or a C _1-3 -alkyl group; ^! • R _e represents a hydrogen atom or a C _1-3 -alkyl group; 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.

2. Compound of formula (I) according to claim 1, characterized in that:

Rp and Rp _' each independently represent a hydrogen atom;

R represents a hydrogen atom, a C _1-4 alkyl group or a -C (O) C _1-3 alkyl group;

R ₁ represents an aryl or heteroaryl group; 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; R ₄ represents:

. a hydrogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _1-3 -alkylene-OC _1-3 -alkyl group,

. a heterocycle group; said heterocycle group being optionally substituted with a C _1-3 -alkylene-aryl group, or R ₄ represents an aryl group; said aryl group being optionally substituted with one or more radicals Z which are identical to or different from each other;

R ₇ represents a halogen atom or a C 1-4 alkoxy group;

Z represents a halogen atom, a C _1-5 alkoxy or phenyl group optionally substituted with a C _1-3 -fluoroalkyl group, or Z represents an alkynyl radical of the type -C = CR _C , in which R _c represents a hydrogen atom, C _1-6 -alkylene-OR _d or C _1-6 -alkylene-NR _a R _b ,. or Z represents a -C _4-6 -alkylene-ORci group,

. or Z represents a tetrazole group substituted with a C _1-3 -alkyl group, or Z represents a group -NR ₃ R _b ,. or Z represents a -C _4-6 -alkylene-NR _a R _{b group} ,

. or Z represents a group -OC _1-5 -alkylene-NR _a R _b ,

. or Z is -OC _0-3 -alkylene-heterocycle, said group -0-C _0-3 - alkylene _^ heterocycle being optionally substituted with one or more groups Ci _-3 - alkyl or an oxo group,

. or Z is -O-C _1-5 -alkylene-OR _d , or Z represents a group -NR _e -C ₂ -5-alkylene-OR _d ,. or Z is -OC _1-3 -alkylene-heteroaryl, or Z represents -CONH-C _1-5 -alkylene-NR _a Rb,. or Z is -O-Ci _-3 -alkylene-C (O) -NR _a R b,. or Z represents a fused or spiric bicyclic diamino heterocycle chosen from:

in which the dotted lines represent the point of attachment to the remainder of the molecule of formula (I) and the solid lines represent a methyl substituent;

R _a and R _b each represent independently of the other a C _1-3 alkyl group;

. or R _a and R _b together with the nitrogen atom to which they are attached form a heterocycle, optionally substituted with one or more oxo groups, - NR ₃ R _b or hydroxy;

R _d represents a hydrogen atom or a _-3- alkyl group;

• R _e represents a C _1-3 -alkyl group; 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:

Rp and Rp _' each independently represent a hydrogen atom;

R represents a hydrogen atom; β R ₁ represents a phenyl, naphthyl or benzo-1,3-dioxolyl group; said phenyl, naphthyl and benzo-1,3-dioxolyl 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;

• R ₄ represents:. a hydrogen atom,

. a phenyl group; said phenyl group being optionally substituted with one or more radicals Z which are identical to or different from each other;

• R ₇ represents a chlorine atom, bromine or a methoxy group; Z represents a fluorine or chlorine atom,

. or Z represents a group -NR _a R _b ,. or Z is -O-propylene-NR _to R _b , Z represents a -O-azepanyl group, said -O-azepanyl group being optionally substituted by one or more methyl groups, or Z is -O-propylene-OR _d ;

R _a and R _b each represent, independently of each other, a methyl group,

. or R _a and R _b together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group;

• R _d represents a hydrogen atom; 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.

4. Compound of formula (I) according to claim 1, characterized in that:

• R represents a hydrogen atom, a C _1-5 group -alkyIe, Ci _-3 fluoroalkyl, C _3-6 - cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, -C (O) -C _1-5 -alkyl, -CH ₂ -C≡CH, C _2-4 -alkylene-NR ₈ R _b , C _1-3 -alkylene-XC _1-3 -alkyl wherein X is O or SO ₂ ;

Ri represents an aryl or a 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 _1-5 alkyl 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 group,

Ci _-3 -alkylene- (0H), C _1-3 -alkylene-XC _1-3 alkyl wherein X is S, SO or SO _2,

. or R ₄ is C _1-3 -alkylene-NR _a R _b , aryl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-OC _{1 -3} -alkylene-aryl, heteroaryl or C _1-3 -alkylene-heteroaryl; aryl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-O-C _1-3 -alkylene-aryl, heteroaryl and C _1-3 -alkylene groups heteroaryl being optionally substituted by one or more radicals Z which are identical to or different from one another,

. or R ₄ represents a heterocycle group; said heterocycle being optionally substituted with a C _1-3 -alkyl, -C (O) -C _1-5 -alkyl, -C (O) -C _1-5 -fluoroalkyl, C _1-3 -alkylene-C _{3 -6} -cycloalkyl, C ₃ -alkylene-aryl, C _1-3 -alkylene-heteroaryl. the C _1-3 -alkylene-aryl and C _1-3 -alkylene-heteroaryl groups being optionally substituted by one or more Z radicals that are identical or different from each other;

• R ₇ represents a hydrogen or halogen atom or a Ci _-5 alkyl group, C _1-3 - fluoroalkyl, C _1-5 alkoxy, Ci _-3 -fluoroalkoxy, C ,. ₃ -alkylene- (OH), -CN, -COOH, -C (O) OC _1-3 -alkyl, -NO ₂ , -XC _1-3 -alkyl wherein X is S, SO or SO ₂ ,

. or R ₇ represents a group -NR _a R _b , C _1-3 -alkylene-NR _a R _b , -C (O) -NR _a R _b , -C (O) -C _1-3 -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;

• R _p and R ' _p independently of one another represent a hydrogen atom or a C _1-5 -alkyl group,

. or R _p and R ' _p together form a single bond or a C _1-4 alkylene group;

• Z represents a halogen atom or a C _1-5 -alkyl, Ci _-3 fluoroalkyl, C _3-6 - cycloalkyl, Ci _-3 -alkylene-C _{3. 6} cycloalkyl, phenyl, C _1-5 -alkoxy, Ci _-3 -fluoroalkoxy, C _1-3 - alkylene-OC _1-3 -alkyl, C _1-3 -alkylene- (OH), NO _2, -CN , -SO ₂ NR ₃ R _b , -XC _1-3 -alkyl, C _1-3 - alkylene-XC _1-3 -alkyl where X is S, SO or SO ₂ ,

. or Z is -NR _a R _b , C _1-3 -alkylene-NR _a R _b , -C (O) -NR _a R _b ,

-C (O) OC _1-4 -alkyl, -C (O) -C ₃ -β _- cycloalkyl,

. or Z represents an oxo radical, or Z represents a group -OC _1-5 -alkylen-NR _a Rb,

. or two adjacent Z radicals together form a C _1-3 -alkylenedioxy group;

Each of R ₃ and R _b independently of one another is a hydrogen atom or a C _1-3 -alkyl or -C (O) -C _1-3 -alkyl group; or R _a and R _b together with the nitrogen atom carrying them, form a heterocycle optionally substituted with 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.

5. Compounds according to claim 1, chosen from:

4- (4-Chlorophenyl) -7-methoxy-N- [1- (2-naphthylmethyl) piperidin-4-yl] isoquinolin-1-amine dihydrochloride,

7-bromo-N- [1- (2-naphthylmethyl) piperidin-4-yl] isoquinolin-1-amine dihydrochloride, N- [1- (1,3-benzodioxol-5-ylmethyl) dihydrochloride) piperidin-4-yl] -7-bromoisoquinolin-1-amine,

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -7-chloroisoquinolin-1-amine dihydrochloride

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -7-methoxyisoquinolin-1-amine dihydrochloride

N- (1-Benzylpiperidin-4-yl) -7-methoxyisoquinolin-1-amine dihydrochloride,

N- (1- {4- [3- (dimethylamino) propoxy] -3-fluorobenzyl} piperidin-4-yl) -7-methoxyisoquinolin-1-amine trihydrochloride,

- 7-Chloro-N- (1- {4- [3- (dimethylamino) propoxy] -3-dihydrochloride fluorobenzyl} piperidin-4-yl) isoquinolin-1-amine,

7-Chloro-N- (1- {4 - [(1-methylazepan-4-yl) oxy] benzyl} piperidin-4-yl) isoquinolin-1-amine trihydrochloride,

7-chloro-N- {1- [4- (4-pyrrolidin-1-ylpiperidin-1-yl) benzyl] piperidin-4-yl} isoquinolin-1-amine,

3- [4 - ({4 - [(7-Chloroisoquinolin-1-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol dihydrochloride.

6. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 5, characterized in that a compound of general formula (III) is reacted:

in which R ₄ and R ₇ are as defined in the general formula (I) according to claim 1, with a compound of general formula (II):

in which R, R ₁ , R ₂ , R _p and R _p 'are as defined in the general formula (I) according to claim 1.

7. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 5, 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).

8. Pharmaceutical composition, characterized in that it comprises at least one compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, as well as at least one pharmaceutically acceptable excipient.

9. Use of a compound of formula (I) according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of all diseases involving a dysfunction related to the MCH ₁ receptor.

10. Use of a compound of formula (I) according to any one of claims 1 to 5, for the preparation of a medicament for the treatment of obesity, cellulitis, urinary incontinence, disorders metabolic diseases and their associated pathologies such as diabetes, cardiovascular disorders, syndrome X, in the treatment of stress-related conditions such as anxiety and depression.