WO2007042669A2

WO2007042669A2 - Derivatives of 4-amino-quinazoline, preparation method thereof and use of same in therapeutics

Info

Publication number: WO2007042669A2
Application number: PCT/FR2006/002286
Authority: WO
Inventors: Jean-Michel Augereau; Gilles Courtemanche; Pierre Despeyroux; Michel Geslin; Anne Thomas
Original assignee: Sanofis-Aventis
Priority date: 2005-10-12
Filing date: 2006-10-11
Publication date: 2007-04-19
Also published as: AR056688A1; UY29857A1; FR2891829A1; WO2007042669A3; TW200732308A

Abstract

The invention relates to derivatives of 4-amino-quinazoline, having general formula (I) wherein: A, B = C1-4-alkylene which is optionally substituted; L = a single bond, C1-2-alkylene, -CH=CH- or -C=C-; groups C1-2-alkylene and -CH=CH- which are optionally substituted, or L = cycloprop-1,2-diyl; R = H, C1-5-alkyl, C1-3-fluoroalkyl, C3-6-cycloalkyl, -C(O)C1-3-alkyl, C1-3-alkylene-C3-6-cycloalkyl, -CH2-C≡CH, C2-4-alkylene-NRaRb, C1-3-alkylene-X-C1-3-alkyl, in which X = O, SO2; R1 = aryl or heteroaryl which are optionally substituted; R2 and R3 = H, C1-3-alkyl or C1-3-fluoroalkyl, or R2 and R3 together form a cycloprop-1,1-diyl; R4 = H, C1-5-alkyl, C1-3- fluoroalkyl, C1-5-alkoxy, -SF5, C1-3-alkylene-X-C1-3-alkyl, in which X = O or SO2, C1-5-alkylene- NRaRb, an aryl or a heteroaryl which are optionally substituted; R5 = H, halogen, C1-5-alkyl, C1-3-fluoroalkyl, C1-5-alkoxy, C3-6-cycloalkyl, C1-3-alkylene-C3-6-cycloalkyl, C1-3-alkylene-O-C1-3-alkyl, C1-3-alkylene-(OH), C1-3-alkylene-X-C1-3-alkyl, in which X = S, SO or SO2, or R5 = -NRaRb, C1-3-alkylene-NRaRb, aryl, C1-3-alkylene-aryl, -O-aryl, C1-3-alkylene-O-aryl, C1-3-alkylene-O-C1-3-alkylene-aryl, heteroaryl or C1-3-alkylene-heteroaryl which are optionally substituted, or R5 = heterocycle which is optionally substituted by C1-3-alkyl, -C(O)C1-3-alkyl, -C(O)C1-3-fluoroalkyl, C1-3-alkylene-C3-6-cycloalkyl, C1-3-alkylene-aryl, C1-3-alkylene-heteroaryl which are optionally substituted; R7 = H, halogen, C1-5-alkyl, C1-13-fluoroalkyl, C1-5-alkoxy, -COOH, -C(O)O-C1-3-alkyl, C1-3-fluoroalkoxy, C1-3-alkylene-(OH), -NO2, -CN, -X-C1-3-alkyl, in which X represents S, SO or SO2, or R7 = -NRaRb, C1-3-alkylene-NRaRb, -C(O)-NRaRb, -C(O)-C1-3-alkyl, aryl, -O-aryl or heteroaryl which are optionally substituted; 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

4-AMINO-QUINAZOLINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION

The present invention relates to 4-amino-quinazoline derivatives, to their preparation and to their therapeutic application.

The search for MCH 1 receptor antagonists (MCH _{1) is} of interest to 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 including Ma VV 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 4-amino-quinazoline, are highly affine and selective towards the MCH ₁ receptor.

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

(0 in which

A represents a C 1-4 alkylene group optionally substituted with one or more groups R _{9 which are} identical to or different from one another;

B represents a C _1-4 -alkylene group optionally substituted by one or more groups Ri _{0 which are} identical to or different from one another;

R ₉ and R ₁₀ each represent, independently of one another, a hydrogen atom or a C _1-5 -alkyl group,

. or R ₉ and R ₁₀ together form a single bond or a C _1-4 alkylene group; L represents a single bond or a C _1-2 -alkylene group, -CH = CH- or -C = C-; the C _1-2 -alkylene groups and -CH = CH- being optionally substituted by one or more C _1-2 -alkyl substituents,

. or L represents a cycloprop-1, 2-diyl group;

• R represents a hydrogen atom or a C _1-5 -alkyl, Ci _-3 fluoroalkyl, C _3-6 - cycloalkyl, -C (O) C _1-3 -alkyl, C _1-3 -alkylene- C ₃ . ₆ -cycloalkyl, -CH ₂ -C = CH, C _2-4 -alkylene

NR ₃ R _b , C _1-3 -alkylene-X-C ₁ -C ₃ -alkyl wherein X is O, 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 and R ₃ represent, independently of each other, a hydrogen atom or a C 1 -C ₃ -alkyl or C 1 -C ₃ -fluoroalkyl group,

. or R ₂ and R ₃ together with the carbon atom carrying them, form a cycloprop-1, 1-diyl group;

• R ₄ represents:. a hydrogen atom or a C- 1 group. _5- alkyl, C _1-3 -fluoroalkyl, C _1-5 -alkoxy, -

SF ₅ , C _1-3 -alkylene-XC _1-3 -alkyl where X is O or SO ₂ , a C _1-5 -alkylene-NR _a R _{b group} ,

. 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; • R5 represents a hydrogen or halogen atom or a Ci-5-alkyl, C _1-3 - fluoroalkyl, C _1-5 -alkoxy, C _3-6 -cycloalkyl, Ci _-3 -alkylene-C _{3 -6} -cycloalkyl, Ci _-3 -alkylene-O-

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

. or R ₅ is -NR _a R _b , C _1-3 -alkylene-NR _a R _b , aryl, C _1-3 - alkylene-aryl, -O-aryl, C _1-3 -alkylene-O- aryl, C _1-3 -alkylene-O-C 1 -C ₃ -alkylene-aryl, heteroaryl or C _1-3 -alkylene-heteroaryl; aryl groups, C _1-3 -alkylene-aryl, -O-aryl,

C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-OC _1-3 -alkylene-aryl, heteroaryl and C _1-3 -alkylene-heteroaryl being optionally substituted with one or more identical Z radicals or different from each other, or R ₅ represents a heterocycle group, said heterocycle being optionally substituted with a C _1-3 -alkyl, -C (O) C _1-3 -alkyl, -C (O) group C _1-3 - fluoroalkyl, C _1-3 -alkylene-C ₃ . _6- cycloalkyl, C _1-3 -alkylene-aryl, C _1-3 -alkylene-heteroaryl; groups Ci _-3 -alkylene-aryl, and C _1-3 -alkylene-heteroaryl being optionally substituted by one or more identical radicals Z 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, -COOH, -C (O) OC _{1-3 group} ; alkyl, C _1-3 -fluoroalkoxy, C _1-3 -alkylene- (OH), -NO _2, -CN, -X-Ci _-3 alkyl wherein 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) -Ci _-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;

• Z represents a halogen atom or a C _1-5 -alkyl, C _1-3 fluoroalkyl, C _3-6 - cycloalkyl, Ci _-3 -alkylene-C _3-6 -cycloalkyl, phenyl, Ci _{- 5} -alkoxy, Ci _-3 -fluoroalkoxy, C _1-3 - alkylene-OC _1-3 -alkyl, C _1-3 -alkylene- (OH), NO _2, -CN, -SO ₂ NRaRb, -XC _{1- 3-} alkyl, C _1-3 - alkylene-XC _1-3 -alkyl where X is S, SO or SO ₂ ,

. or Z represents a phenyl optionally substituted by a halogen atom, a C _1-5 -alkyl, C _1-5 -alkoxy or C _1-3 -fluoroalkyl group, 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 _1-6 -alkylene-NR ₃ 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 Rb,. or two adjacent Z radicals together form a C _1-3 - alkylenedioxy 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 _θ -C _{_0-3} -alkylene-heterocycle optionally substituted by one or more C _1-3 alkyl, oxo or -C (O) -C _1-3 alkyl, . or Z represents a group -NR _e -C _2- 5 -alkylene-O-Rd,. or Z represents a group -O-C 1 -C ₃ -alkylene-heteroaryl optionally substituted with one or more C _1-3 alkyl groups,

. or Z is -CONH-C _1-5 -alkylene-NR _a Rb, or Z represents -CONH-C _1-5 -a [kylene-OR _d ,

. or Z represents a group -OC _1-3 -alkylene-C (O) -NR _a Rb,. or Z represents a fused bicyclic or fused bicyclic heterocycle,

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 to which they are attached, a heterocycle optionally substituted by one or more C _1-3 - alkyl, oxo, -NR ₃ R _b, hydroxy, C _{1 -3} alkoxy, Ci _-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 comprise one or more olefinic functions.

They can therefore exist as Z / E isomers. These isomers and their mixtures are part of the invention.

The compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.

These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.

The compounds of formula (I) may also exist in the form of hydrates and / or solvates, namely in the form of associations or combinations with one or more water molecules 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 values from O 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 aliphatic group, linear or branched. 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 in which one or more hydrogen atoms have been substituted by a fluorine atom. By way of examples, mention may be made of the groups -OCF ₃ , -OCHF ₂ ; a heterocycle group: a 5- to 7-membered saturated cyclic group having one to several heteroatoms such as nitrogen, oxygen or sulfur atoms. By way of examples, mention may be made of pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperidonyl, morpholinyl, piperazinyl and N-methyl-piperazinyl groups, and the like;

. 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 connected 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.

In the general formula (I), the cycle:

can be, for example, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 8-azabicyclo [3.2.1] octyl, 8-azabicyclo [3.3.1] nonanyl, decahydroisoquinolinyl, 3-azabicyclo [3.1.0] hexanyl. a fused bicyclic or spiroic diamino heterocyclic ring is such that:

in which the dotted lines represent the point of attachment to the rest of the molecule of formula (I).

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

A represents an ethylene group;

B represents an ethylene group;

• L represents a single bond; R represents a hydrogen atom or an ethyl group;

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 and R ₃ represent, independently of one another, a hydrogen atom; R ₄ represents:

. a hydrogen atom or a methyl, trifluoromethyl group, a phenyl group, said phenyl group being optionally substituted by one or more radicals Z which are identical to or different from each other;

R ₅ represents a hydrogen atom or a methyl group; • R ₇ represents a chlorine atom or a methoxy group;

Z represents a group -O-Ci. ₅ -alkylene-NR _a Rb,

. or Z represents a group -OC ₁ . _5- alkylene-OR _d ,

. or Z is -XC _1-3 -alkyl, wherein X is SO ₂ ;

R _a and R _b each independently represent a methyl group, Rd represents a hydrogen atom.

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

• A represents a C _1-4 -alkylene group optionally substituted by one or more groups R ₉ identical or different from each other;

B represents a C _1-4 -alkylene group optionally substituted with one or more groups Ri _{0 which are} identical to or different from each other; R ₉ and R ₁₀ each represent, independently of one another, a hydrogen atom or a C _1-5 -alkyl group,

. or R ₉ and R ₁₀ together form a single bond or a C _1-4 alkylene group; L represents a single bond or a C _1-2 -alkylene group, -CH = CH- or -C≡C-; C _1-2 alkylene groups and -CH = CH- optionally substituted with one or more substituents Ci _-2 alkyl,

. or L represents a cycloprop-1, 2-diyl group; ^;

• R represents a hydrogen atom or a C _1-5 -alkyl, Ci _-3 fluoroalkyl, C _3-6 - cycloalkyl, -C (O) C _1-3 -alkyl, Ci _-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, 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 and R ₃ independently of one another, a hydrogen atom or a Ci _-3 -alky group! E or C _1-3 fluoroalkyl,

• R ₄ represents:. a hydrogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _1-5 -alkoxy, -

. 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 ₅ represents a hydrogen or halogen atom or a C _1-5 -alkyl, Ci _-3 - fluoroalkyl, C _1-5 -alkoxy, C _3-6 -cycloalkyl, C _1-3 -alkylene- C _3-6 -cycloalkyIe, Ci _-3 -alkylene-O- C-ι- ₃ -alkyl, C _1-3 -alkylene- (OH), C _1-3 -alkylene-XC _1-3 alkyl where X represents S, SO or SO ₂ ,. or R ₅ is -NR ₃ R _b, C _1-3 -alkylene-NR _a R _b, aryl, Ci _-3 - alkylene-aryl, -O-aryl, Ci _-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, -O-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-O-C 1 -C 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 each other, or else R ₅ represents a heterocycle group, said heterocycle being optionally substituted by a C _1-3 alkyl group; C (O) C _1-3 -alkyl, -C (O) Ci _-3 - fluoroalkyl, Ci _-3 -alkylene-C _3-6 -cycloalkyl, Ci _-3 -alkylene-aryl, -alkylene-heteroaryl CI_ _3; groups Ci _-3 -alkylene-aryl, and Ci _-3 -alkylene-heteroaryl being optionally substituted with one or more radicals Z which are identical or different from one another,

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

Z represents a halogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _3-6 -cycloalkyl, C _{1 group} . ₃ -alkylene-C _3-6 -cycloalkyl, phenyl, C _1-5 -alkoxy, C _1-3 -fluoroalkoxy, Ci _-3 - alkylene-OC _1-3 -alkyl, C _1-3 -alkylene- (OH ), NO ₂ , -CN, -SO ₂ NRaRb, -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 ₃ R _b , -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 -OC _1-5 -alkylene-NR _a R _b ,

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

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 also be mentioned a subgroup of compounds which are defined as follows:

• A represents a group

optionally substituted with one or more groups R ₉ identical to or different from each other;

B represents a C _1-4 -alkylene group optionally substituted with one or more groups R _{10 which are} identical to or different from one another; • R ₉ and R-io are each independently of one another, a hydrogen atom or a C-ι _-5 -alkyl group and in particular methyl,

. or else R _g and Ri ₀ together form a group

;

• L represents a single bond or -CH = CH-;

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 group} . _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 or different, one of the other ;

R ₂ and R ₃ represent, independently of one another, a hydrogen atom or a C _1-3 -alkyl group;

• R ₄ represents:. a hydrogen atom or a Ci _-5 alkyl group, C _1-3 fluoroalkyl, Ci _-5 -aIcoxy -

SF _5, C _1-3 -alkylene-X-Ci _-3 alkyl where X represents O or SO _2,. a C _1-5 -alkylene-NR _a Rb group,

. 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 ₅ represents a hydrogen or halogen atom or a C _1-5 -alkyl, Ci _-3 - fluoroalkyl, C _1-5 alkoxy, C _1-3 -alkylene-OC _1-3 alkyl,

. or R ₅ is -NR ₃ R _b , C _1-3 -alkylene-NR _a Rb, aryl, C _1-3 - alkylene-aryl, -O-aryl, C _1-3 -alkylene-O-aryl C _1-3 -alkylene-OC _1-3 -alkylene-aryl; the aryl, C _1-3 -alkylene-aryl, -O-aryl, C _1-3 -alkylene-O-aryl, C _1-3 -alkylene-O-C 1 -C ₃ -alkylene-aryl groups being optionally substituted by a or more Z radicals which are the same or different from each other, or R ₅ represents a heterocycle group; said heterocycle being optionally substituted by C _1-3 -alkyl, -C (O) C _1-3 -alkyl, -C (O) C _1-3 - fluoroalkyl ,, Ci _-3 -alkylene-C _3-6 -cycloalkyl, C _1-3 -alkylene-aryl; the C _1-3 -alkylene-aryl group being optionally substituted with one or more Z radicals that are identical to or different from each other,

• R ₇ represents a halogen atom or a Ci _-5 alkyl group and in particular methyl, C _1-5 alkoxy and in particular methoxy, CN or COOH; • Z represents a halogen atom or a Ci _-5 alkyl group, Ci _-3 fluoroalkyl, C _3-6 - cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, phenyl, C _{1- 5} -alkoxy, C _1-3 -fluoroalkoxy, Ci _-3 - alkylene-O-Ci _-3 alkyl, Ci _-3 -alkylene- (OH), NO _2, -CN, -SO ₂ NRaRb, -X-Cl _-3 alkyl, Ci _-3 - alkylene-XC _1-3 alkyl wherein X is S ₁ SO or SO _2,

. or Z is -NR ₃ R _b , C _1-3 -alkylene-NR _a R _b , -C (O) -NR _a R _b , -C (O) -C 1 -C ₃ -alkyl, -C ( O) O-C _1-4 -alkyl, -C (O) -C ₃ . ₆ -cycloalkyl, or Z represents an oxo radical, or Z is -O-C _1-5 -alkylene-NR _a R _b , or two adjacent Z radicals together form a C _1-3 -alkylenedioxy group; • R _a and R _b are each independently from each other, a hydrogen atom or a Ci _-3 alkyl group or -C (O) -C _1-3 alkyl,

. or else R _a and Rb together with the nitrogen atom carrying them 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 also be mentioned a subgroup of compounds which are defined as follows: • A represents a C _1-4 -alkylene group and in particular an ethylene, optionally substituted with one or more groups R ₉ ;

B represents a C _1-4 -alkylene group and in particular an ethylene, optionally substituted by one or more Ri ₀ groups;

R ₉ and R ₁₀ are each independently of one another a hydrogen atom or a methyl,

. or R ₉ and Ri ₀ together form a C _1-4 -alkylene group;

• L represents a single bond or -CH = CH-;

R represents a hydrogen atom or a C ₁ -C ₅ -alkyl group and in particular an ethyl, C _1-3 -alkylene-C ₃ . _6- cycloalkyl; 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 and R ₃ represent, independently of one another, a hydrogen atom or a C _1-3 -alkyl group and in particular a methyl; R ₄ represents:

. a hydrogen atom or a C _1-5 -alkyl, C _1-3 fluoroalkyl, Ci _-5 alkoxy,. a C _1-5 -alkylene-NR _a Rb group,

. an aryl optionally substituted with one or more radicals Z which are identical or different from one another; • R ₅ represents a hydrogen or halogen atom or a Ci _-5 alkyl group, Ci _-3 - fluoroalkyl, Ci _-5 alkoxy, Ci _-3 -alkylene-O-Ci _-3 alkyl,

. or R ₅ represents a group -NR ₈ R _b or aryl optionally substituted with one or more radicals Z which are identical to or different from each other, or else R ₅ represents a heterocycle group; said heterocycle being optionally substituted with a C ₃ -alkyl group, -C (O) Ci _-3 alkyl, -C (O) C _1-3 -. fluoroalkyl, Ci _-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 Z radicals which are identical to or different from each other;

R ₇ represents a halogen atom, a methyl, a methoxy, CN or COOH; • Z represents a halogen atom or a Ci _-5 alkyl group, phenyl, alkoxy in particular methoxy, Ci _-3 -alkylene-O-Ci _-3 alkyl, Ci. ₃ -alkylene- (OH) -CN, -SO ₂ NRaRb, -X- Ci _-3 alkyl, Ci _-3 -alkylene-XC _1-3 alkyl wherein X is S, SO or SO _2, . or Z is -NR _a R _b , C _1-3 -alkylene-NR _a Rb, -C (O) -NR _a R _b , -C (O) -C _1-3 -alkyl,

. or else Z represents an oxo radical,

. or Z is -O-C15-alkylene-NR _a R _b ,. or two adjacent Z radicals together form a C _1-3 -alkylenedioxy group and in particular a methylenedioxy;

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

A represents an ethylene, optionally substituted with one or more R ₉ groups; B represents an ethylene, optionally substituted by one or more groups Ri ₀ ;

R ₉ and R ₁₀ are each independently of one another a hydrogen atom or a methyl;

• L represents a single bond;

R represents a hydrogen atom or an ethyl group, C _1-3 -alkylene-C _3-6 -cycloalkyl;

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 and R ₃ represent, independently of one another, a hydrogen atom or a methyl group;

R ₄ represents:

. a hydrogen atom or a Ci _-5 alkyl group, Ci _-3 fluoroalkyl, especially trifluoromethyl, Ci _-5 alkoxy,

. an aryl optionally substituted with one or more radicals Z which are identical or different from one another;

R ₅ represents a hydrogen or halogen atom or a C _1-5 -alkyl, C _1-3 -alkylene-O-C 1 -C ₃ -alkyl group,

. or R ₅ represents an aryl optionally substituted with one or more radicals Z which are identical or different from one another; • R ₇ represents a halogen atom, a methyl, a methoxy or CN;

Z represents a halogen atom or a group _-5- alkyl, a phenyl, methoxy, _C1-3 -alkylene-OC _1-3 -alkyl, _C1-3 -alkylene- (OH), -CN, -SO ₂ NRaRb, -XC _1-3 -alkyl, C _1-3 -alkylene- XC _1-3 -alkyl where X is S, SO or SO ₂ ,

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

. 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 are each, independently of the other, 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:

6-methoxy-N- [1- (2-naphthylmethyl) piperidin-4-yl] quinazolin-4-amine dihydrochloride (compound No. 1);

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -6-methoxyquinazolin-4-amine dihydrochloride (Compound No. 2);

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloro-2- (trifluoromethyl) quinazolin-4-amine dihydrochloride (Compound No. 3); N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloroquinazolin-4-amine dihydrochloride (Compound No. 4);

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloro-2-methylquinazolin-4-amine dihydrochloride (Compound No. 5);

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloro-2- [4- (methylsulfonyl) phenyl] quinazolin-4-amine dihydrochloride (compound no. 6);

6-Chloro-N- (1- {4- [3- (dimethylamino) propoxy] benzyl} piperidin-4-yl) -N-ethylquinazolin-4-amine trihydrochloride (Compound No. 7);

6-chloro-N- (1- {4- [3- (dimethylamino) propoxy] benzyl} piperidin-4-yl) quinazolin-4-amine trihydrochloride (compound no. 8); N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloro-8-methylquinazolin-4-amine (Compound No. 9);

3- [4 - ({4 - [(6-Chloroquinazolin-4-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol (Compound No. 10). 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

Reduction

According to Scheme 1, the compound of general formula (I) is prepared from a chlorinated compound of formula (III), in which R ₄ , R ₅ and R ₇ are as defined in general formula (I), according to the A pathway, by nucleophilic substitution of chlorine with the amine of the compound of formula (II), wherein R ₁ , L, R ₂ , R ₃ , A, B, and R are as defined in the general formula (I ). This reaction can be carried out by heating the compounds of formulas (II) and (III) in an alcohol such as isopropanol (or an isopropanol-THF mixture) in the presence of triethylamine or in n-butanol in the presence of sodium chloride. 'ammonium. This reaction may also be catalyzed by a transition metal such as palladium, for example in the tris (dibenzylidene-acetone) -dipalladium form in the presence of a ligand such as BINAP (2,2'-bis (diphenylphosphino) -1 , 1'-binaphthyl) and a base such as sodium tert-butylate according to the method described by Wolfe et al (J. Am. Chem., Soc., 1996, 118, 7215-7216). Or the compound of general formula (I) in which R is different from the hydrogen atom can also be prepared according to the B, starting 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 with an anhydride or an acid chloride of R ¹ C (O) Y type to form an amide of general formula (I "). lithium aluminum hydride (LiAlH ₄ ) or with the borane-tetrahydrofuran complex (BH ₃ -THF) to obtain the compound of the general formula (I) in which R represents an alkyl.The compound of the formula (I ¹ ) in which R is a hydrogen atom is prepared from the compound of formula (III), wherein R ₄ , R ₅ and R ₇ are as defined in the general formula (I) and the amino compound of formula (II ¹ ) by the methods mentioned above for the preparation of the compound of general formula (I),

Amines of formula (II ') or (II) in which R represents a hydrogen atom, when they are not commercial can be prepared by analogy to the methods described in the literature (Mach et al., J. Med. 1993, 36, 3707-3720, Dostert et al, Eur J. Chem Chem Ther 1984, 19 (2), 105-110, Moragues et al Farmaco, Ed Sci 1980, 35 (11) 951. 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 ferf-butoxycarbonyl group previously introduced onto 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) in which R ₃ represents a hydrogen atom can also be obtained according to scheme 2 which follows. Figure 2

According to Scheme 2, the compound of general formula (I) in which R ₃ represents a hydrogen atom may be prepared from compounds of formulas (Ib) or (Ib ') in which the nitrogen of the nitrogen cycle is not substituted and wherein R ₄ , R ₅ , R ₇ , A and B are as defined in the general formula (I) ₁ with R being a hydrogen atom for the formula (Ib) or with R being such that defined in the general formula (I) with the exception of the hydrogen atom for the formula (Ib '), in particular by a reductive amination reaction with an aldehyde or a ketone of the general formula R ₁ -L-C (O) R ₂ , wherein R ₁ , L and R ₂ are as defined in general formula (I). This reaction may for example be carried out 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 compounds of general formulas (Ib) and (Ib ') are obtained by deprotection of the compounds of general formulas (Ia) and (Ia') which have on the nitrogen of the nitrogen cycle a protective group PG. This protecting group may be for example benzyl, ethoxycarbonyl or feff-butoxycarbonyl and deprotection can be carried out according to the methods mentioned in Protective Groups in Organic Synthesis ^3rd John Wiley & Sons edition, New York 1999. The compound of general formula (Ia) is synthesized by reacting a compound of general formula (III) in which R ₄ , R ₅ and R ₇ are as defined in the general formula ( I) with a compound of general formula (II ") according to the methods already described above for the compound (I). the compound of general formula (Ia ¹⁾ is synthesized from the compound of general formula (Ia) for example 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 derivative of formula (III) can be obtained according to scheme 3 which follows.

Figure 3

The 4-chloroquinazoline derivative of formula (III), when it is not commercial, can be obtained according to scheme 3 by heating the 3f / -quinazolin-4-one derivative of formula (IV) for example with phosphoryl chloride (optionally in the presence of a base such as diethylaniline) or with thionyl chloride in a solvent such as dimethylformamide (Bioorg Med Chem 2003 (11) 383-391).

The derivative of formula (IV) can be obtained according to scheme 4 which follows.

Figure 4

The 3H-quinazolin-4-one compound of formula (IV) can be prepared according to scheme 4 from a benzamide of formula (V) and an ester of formula (VI) in the presence of sodium ethanolate in ethanol for example. It can also be prepared according to the methods described by M. Tobe et al. (BioGem Med Chem 2003 (11) 383-391), by TM Potewar et al. (Synthetic Communications, 2005 (35) 231-241) or by A. Tomisk et al. J. Am.Chem.Soc. (1948) 2423-2425).

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 SNAP-7941 (described by Synaptic Laboratories) confirms the important role of MCH in the regulation of 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). MHC ₁ receptor antagonist molecules are therefore of therapeutic interest in depression and / or anxiety.

The MCH seems to be involved with other regulatory systems. By its testicular localization (Hervieu et al., Biology of Reproduction 1996; 5: 1161-1172) and hypothalamic (dependent estrogen, Viale et al, Peptides 1999; 20: 553-559) and by its stimulating effects of the sexual activity of the male rat (Gonzales et al., Peptides 1996; 17: 171-177) and luteinizing hormone secretion (Chiocchio et al., Biology of Reproduction 2001; 64: 1466-1472), 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 MCH ₁ receptor antagonist may be useful in memory disorders (MacBride et al., Peptides 1994; (4): 757-759). Thus, the compounds according to the invention may constitute a therapy of choice for the treatment of memory disorders.

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

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

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

According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active ingredient, at least one compound according to the invention. These pharmaceutical compositions comprise an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or solvate of said compound, as well as at least one pharmaceutically acceptable excipient.

Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, 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 of an effective dose of a compound according to the invention, or of one of its pharmaceutically acceptable salts 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 of analysis by liquid chromatography coupled to 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 rate 0.4 ml / minute

- Injection of 2 μL 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 rate 0.4 ml / 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 rate 0.4 ml / 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

6-Methoxy-Λ- [1- (2-naphthylmethyl) piperidin-4-yl] quinazolin-4-amine dihydrochloride (Compound No. 1)

1.1. 4-Chloro-6-methoxyquinazoline

A suspension of 2.52 g (14.3 mmol) of 6-methoxy-3H-quinazolin-4-one in

25 ml of phosphoryl chloride is heated at 140 ° C for 3 hours 30 minutes.

The phosphoryl chloride is partially distilled under reduced pressure, and the residue obtained is poured slowly into 250 ml of water with stirring, maintaining the temperature between 15 and 20 ^° C. The mixture is then stirred at 5 ° C., made alkaline. with a 35% sodium hydroxide solution and then extracted with dichloromethane. The organic phase is washed with water, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: dichloromethane / methanol 100/0 to 98/2 (v / v)). 1.40 g of product are obtained in the form of a white powder.

LC / MS: MH ⁺ = 195 (tR = 7.08 minutes pH 3.1)

¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 4.01 (s, 3H); 7.48 (d, 1H); 7.77 (dd, 1H); 8.05 (d, 1H); 8.99 (s, 1H).

1.2. 6-Methoxy- / N- [1- (2-naphthylmethyl) piperidin-4-yl] quinazolin-4-amine dihydrochloride (Compound No. 1)

208 mg (0.87 mmol) of 1- [1- (2-naphthylmethyl) piperidin-4-yl] amine and 38 mg (0.71 mmol) of ammonium chloride are added to a solution of 157 mg (0 g. , 75 mmol) of

4-chloro-6-methoxyquinazoline in 5 mL of n-butanol. The mixture is refluxed for 7 hours. The reaction medium is cooled to ambient temperature, hydrolyzed with 10 ml of water and then extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: dichloromethane / methanol 100/0 to 85/5 (v / v)). 207 mg of powder product is obtained.

LC / MS: MH ⁺ = 399 (tR = 4.78 minutes pH 3.1)

¹ H NMR (DMSO-dβ, 250 MHz) δ ppm: 2.1-2.2 (m, 4H); 3.1-3.5 (m, 4H); 3.92 (s, 3H); 4.3-4.6 (m, 3H); 7.49 (dd, J ₁ = 2.5 Hz, J ₂ = 9 Hz, 1H); 7.6-7.65 (m, 2H); 7.70 (d, J = 9 Hz, 1H); 7.83 (m, 1H); 7.95-8.1 (m, 4H); 8.15 (s, 1H); 8.52 (s, 1H); 8.7 (s, 1H, NH). After treatment with a solution of hydrochloric acid in diethyl ether, the hydrated dihydrochloride is obtained

Example 2: W- [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -6-methoxyquinazolin-4-amine dihydrochloride (Compound No. 2)

2.1 Fert -butyl [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] carbamate

To a solution of 9.36 g (46.8 mmol) of tert-butyl (piperidin-4-yl) carbamate in

170 ml of 1,2-dichloroethane are 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 pH 3.1)

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)

2.2. 1- (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] carbamate of tert-butyl in 130 mL of ethyl acetate is added with 130 mL of a solution of 2N HCl in diethyl ether. The reaction mixture is stirred at room temperature for 12 hours. The precipitate formed is filtered off, rinsed with ethyl acetate and then dried in an oven (40 ^° C.) under reduced pressure. 12.7 g of a white solid are obtained. One part is desalified: 312 mg are stirred with 1.17 g (4 equivalents) of (polystyrylmethyl) trimethylammonium bicarbonate resin (Novabiochem) in 10 ml of dichloromethane for 5 hours. After filtration and rinsing of the resin with dichloromethane, the organic phase is evaporated. 174 mg of a white solid are obtained. Mp = 69 ⁰ C (M)

¹ H NMR (DMSOd 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)

2.3. W- [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -6-methoxyquinazolin-4-amine hydrochloride (Compound No. 2)

To a solution of 504 mg (2.59 mmol) of 4-chloro-6-methoxyquinazoline

(Preparation in 1.1.) in 20 mL argon stirred toluene, 978 mg is added

(3.18 mmol) 1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-ylamine, 874 mg (3.51 mmol) sodium tert-butylate, 17 mg (0.03 mmol) ) of BINAP (2,2'-bis (diphenylphosphino) -

1, 1 -binaphthyl) and 29 mg (0.03 mmol) of tris (dibenzylidene-acetone) dipalladium. The mixture is stirred at 80 ^° C. for 24 hours. After returning to ambient temperature, the reaction medium is hydrolyzed with sodium hydrogencarbonate 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 85/15 (v / v)). 470 mg of product is obtained in the form of a light yellow powder.

MH ⁺ = 393 (tR = 4.22 minutes pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.6-1.8 (m, 2H); 1.9-2.0 (m, 2H); 2.0-2.1 (m, 2H); 2.85-2.95 (m, 2H); 3.42 (s, 2H); 3.90 (s, 3H); 4.2 (m, 1H); 6.01 (s, 2H); 6.7-6.9 (m, 3H); 7.39 (dd, J ₁ = 2.5 Hz, J ₂ = 7.5 Hz, 1H); 7.62 (d, J = 7.5 Hz, 1H); 7.69 (d, J = 2.5Hz, 1H), 7.74 (d, J = 7.5Hz, 1H, NH); 8.36 (s, 1H).

After treatment with a solution of hydrochloric acid in diethyl ether, the hydrated dihydrochloride is obtained. Example 3

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloro-2- (trifluoromethyl) quinazolin-4-amine dihydrochloride (Compound No. 3)

3.1. 6-Chloro-2- (trifluoromethyl) -3H-quinazolin-4-one

900 mg (13.2 mmol) of sodium ethoxide and 1.54 ml (12.9 mmol) of ethyl trifluoroacetate are added to a suspension of 1 g (5.86 mmol) of 2-amino-5- chlorobenzamide in ethanol. The mixture is stirred at ambient temperature for

10 24 hours. Ethanol is evaporated under reduced pressure. The residue is taken up in water and extracted with dichloromethane. The aqueous phase is acidified with a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is purified on a column of silica gel (eluent: cyclohexane / ethyl acetate from 100/0 to

75/25 (v / v)). 1.1 g of powder are obtained.

LC / MS: MH ⁺ = 249 (tR = 7.51 minutes pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 7.86 (d, J = 7.5 Hz, 1H); 7.98 (dd, J ₁ = 2.5 Hz, J ₂ = 9 Hz, 1H); 8.14 (d, J = 2.5 Hz, 1H)

0 4,6-Dichloro-2- (trifluoromethyl) quinazoline

A suspension of 500 mg (2.01 mmol) of 6-chloro-2- (trifluoromethyl) -3H-quinazolin-4-one in 5 ml of phosphoryl chloride is heated at 140 ^° C. for 2 hours. The reaction medium is then poured slowly into 25 ml of water while stirring, keeping the temperature between 15 and 20 ^° C. A precipitate is formed which is isolated by filtration and then dissolved in diethyl ether. The ether solution is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 100/0 to 75/25 (v / v)). 500 mg of product is obtained in the form of a white powder. LC / MS: MH ⁺ = 267 (tR = 10.0 minutes pH 3.1)

¹ H NMR (DMSO-Cl ₆ , 250 MHz) δ ppm: 8.33 (m, 2H); 8.48 (s, 1H).

3.3 N - H - (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloro-2- (trifluoromethyl) quinazolin-4-amine hydrochloride (Compound No. 3)

501 mg (2.14 mmol) of 1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl-amine (preparation in 2.2) and 119 mg (2.22 mmol) of sodium chloride are added. ammonium to a solution of 475 mg (1.78 mmol) 4,6-dichloro-2- (trifluoromethyl) quinazoline in 15 mL of n-butanol. The mixture is refluxed for 7 hours. The reaction medium is cooled to ambient temperature, hydrolysed with 10 ml of a 1N sodium hydroxide solution and then extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution and then dried over anhydrous sodium sulphate. After filtration, it is evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel (eluent: dichloromethane / methanol from

100/0 to 95/5 (v / v)). 744 mg of product is obtained in the form of a white powder.

LC / MS: MH ⁺ = 465 (tR = 6.60 minutes pH 3.1)

¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.6-1.8 (m, 2H); 1.9-2.0 (m, 2H); 2.0-2.1 (m, 2H); 2.8-2.95 (m, 2H); 3.43 (s, 2H); 4.14 (m, 1H); 6.00 (s, 2H); 6.77 (dd, J ₁ = 2.5 Hz, J ₂ = 8 Hz, 1H); 6.8-6.9 (m, 2H); 7.8-8.0 (m, 2H); 8.56 (d, J = 7.5 Hz, 1H, NH); 8.63 (d, J = 2.5 Hz, 1H).

After treatment with a solution of hydrochloric acid in diethyl ether, the dihydrochloride is obtained.

Mp = 191 ^° C. (M) LC / MS: MH ⁺ = 465 (tR = 6.60 minutes, pH 3.1) Example 4

6-Chloro [N- [1- (2-naphthylmethyl) piperidin-4-yl] quinazolin-4-amine dihydrochloride (Compound No. 4)

0.4 g of 4,6-dichloroquinazoline (synthesized according to the method described by M. Tobe et al., Biorg.Med.Chem.11 (2003) 383-391) in solution in 20 ml of isopropanol and 10 ml of tetrahydrofuran 0.3 ml of triethylamine and 0.468 g of 1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl-amine are successively added (preparation in 2.2). The reaction medium is stirred at 60 ^° C. for 1 hour, then is concentrated and chromatographed on a column of silica gel, eluting with a 98/2 (v / v) dichloromethane / methanol mixture. The oil obtained is treated with a solution of hydrochloric acid in diethyl ether, to obtain the dihydrochloride of the expected product.

¹ H NMR (DMSOd ₆ + TFA, 250 MHz) δ ppm: 1.98-2.20 (m, 4H); 3.10-3.20 (m,

2H); 3.45-3.55 (m, 2H); 4.23 (m, 2H); 4.55-4.70 (m, 1H); 6.07 (s, 2H); 6.96-7.02 (m, 2H); 7.13 (s, 1H); 7.85-7.90 (m, 1H); 8.10 (m, 1H); 8.80 (s, 1H); 9.0 (s, 1H).

Example 5

N- [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloro-2-methylquinazolin-4-amine dihydrochloride (Compound No. 5)

5.1. 4,6-dichloro-2-methyl-quinazoline

To 3 g of 6-chloro-2-methyl-quinazolin-4-one (synthesized according to the method described by A. Tomisk et al J. Am Chem Chem (1948) 2423-2425) in solution in 50 ml of toluene is added 4.5 ml of diethylaniline. The mixture is stirred for 5 minutes under reflux and 1.5 ml of phosphoryl chloride are added dropwise and the mixture is refluxed for 3 hours. The reaction medium is filtered, the precipitate is rinsed with ethyl acetate. The filtrate is successively washed with ice water, 6N sodium hydroxide and 6N aqueous hydrochloric acid solution. The organic phase is dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain 2.6 g of expected product. ¹ H NMR (DMSOd ₆ , 250 MHz) δ ppm: 2.42 (s, 3H); 7.71 (d, 1H); 7.89 (d, 1H); 8.06 (s, 1H). 5.2. N- [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloro-2-methylquinazolin-4-amine dihydrochloride (Compound No. 5)

This compound is obtained according to the procedure described for example 4 by reaction of 1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl-amine (preparation in 2.2.) With 4.6-. dichloro-2-methylquinazoline.

¹ H NMR (DMSO-d ₆ + TFA, 250 MHz) δ ppm: 2.04-2.22 (m, 2H); 2.28-2.33 (m, 2H); 2.66 (s, 3H), 3.05-3.13 (m, 2H); 3.32-3.47 (m, 2H); 4.15-4.25 (m, 2H); 4.50-4.60 (m, 1H); 6.08 (s, 2H); 6.98-7.08 (m, 2H); 7.35 (s, 1H); 7.96-8.07 (m, 2H); 8.93 (s, 1H).

Example 6

N- [1- (1,3-Benzodoxol-5-ylmethyl) piperidin-4-yl] -6-chloro-2- [4- (methylsulfonyl) phenyl] quinazolin-4-amine dihydrochloride (Compound No. 6)

6.1. 4,6-Dichloro-2- [4- (methylsulfonyl) phenyl] quinazoIine

This compound is prepared according to the procedure described in 5.5. by reaction 4 g of 6-chloro-2- [4- (methylsulfonyl) phenyl] quinazolin-4-one (synthesized according to an adaptation of the method described by TMPotewar et al., Synthetic Communications, 2005 (35) 231-241) with phosphoryl chloride. 1.6 g of product are obtained.

MS: MH ⁺ = 353

6.2. N- [1- (1,3-Benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloro-2- [4- (methylsulfonyl) phenyl] quinazolin-4-amine dihydrochloride (Compound # 6) )

This compound is obtained according to the procedure described for example 4 by reaction of 1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl-amine (preparation in 2.2.) With the 4,6-dichloro-2- [4- (methylsulfonyl) phenyl] quinazoline.

¹ H NMR (DMSO-d _6, 400 MHz) δ ppm: 2.15-2.35 (m, 4H); 3.10-3.25 (m, 2H); 3.33 (s, 3H); 3.40-3.50 (m, 2H); 4.22 (s, 2H); 4.60-4.70 (m, 1H); 6.07 (s, 2H); 6.98 (d, 2H); 7.14 (m, 1H); 7.37 (s, 1H); 7.97-8.02 (m, 1H); 8.10-8.20 (m, 3H); 8.70-8.75 (m, 2H); 8.83 (s, 1H); 9.50 (m, 1H).

Example 7

6-Chloro-N- (1- {4- [3- (dimethylamino) propoxy] benzyl} piperidin-4-yl) -N-ethylquinazolin-4-amine trihydrochloride (Compound No. 7)

7.1. 4 - [(6-Chloroquinazolin-4-yl) amino] piperidin-1-ethylcarboxylate

This compound is obtained according to the procedure described for example 4 by reaction of 740 mg of 4,6-dichloroquinazoline (synthesized according to the method described by M.Tobe et al., Biorg.Med.Chem.Bioorg.Med.Chem. 2003 (11) 383-391) with 980 mg of ethyl 4-amino-piperidin-1-yl-carboxylate. 1.13 g of product are obtained. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 1.20 (t, 3H); 1.45-1.55 (m, 2H); 1.89-1.96 (m, 2H); 2.88-3.05 (m, 2H); 3.92-4.10 (m, 4H); 4.35-4.42 (m, 1H); 7.68 (d, 1H); 7.76 (d, 1H); 8.02 (d, 1H, NH); 8.45-8.50 (m, 2H). LC / MS: MH ⁺ = 334 (tR = 5.61 minutes pH 3.1)

7.2. Ethyl 4 - [(6-chloroquinazolin-4-yl) (ethyl) amino] piperidine-1-carboxylate

A solution of 1.3 g of ethyl 4 - [(6-chloroquinazolin-4-yl) amino] piperidine-1-carboxylate in 40 ml of dimethylformamide is stirred at 0 ^° C. under nitrogen and is treated with 0.23 g of hydride. of 55% sodium in the oil. The mixture is stirred for 30 minutes at 0 ^° C. then 0.5 ml of iodoethane is added. The reaction medium is stirred for 18 hours at room temperature and then added with ethyl acetate. The organic phase is washed with water and dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 1.2 g of product are obtained.

¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 1.15-1.30 (m, 6H); 1.30-1.54 (m, 2H); 1.60-1.70 (m, 2H); 2.95-3.10 (m, 2H); 3.85-3.95 (m, 2H); 4.0-4.15 (m, 4H); 4.20-4.30 (m, 1H); 7.41 (d, 1H); 7.57 (d, 1H); 7.91 (s, 1H); 8.01 (s, 1H). LC / MS: MH ⁺ = 362 (tR = 5.43 minutes pH 3.1).

7.3. Dibrom hydrates 6-chloro-N-ethyl-4-piperidin-4-ylquinazolin-4-amine

A mixture consisting of 15 ml of hydrobromic acid in 33% solution in acetic acid and 1.1 g of ethyl 4 - [(6-chloroquinazolin-4-yl) (ethyl) amino] piperidine-1-carboxylate is stirred for 4 hours at reflux. The reaction medium is cooled and filtered. The precipitate obtained is rinsed with diisopropyl ether and dried to obtain 0.84 g of expected product. ¹ H NMR (DMSO-d ₆ , 250 MHz) δ ppm: 1.43 (t, 3H); 2.0-2.16 (m, 4H); 3.10-3.25 (m, 2H); 3.40-3.55 (m, 2H); 4.52-4.75 (m, 3H); 8.20 (s, 2H); 8.65-8.90 (m, 2H, 2 HBr); 8.95 (s, 1H); 9.14 (s, 1H).

7.4. 6-Chloro-N- (1- {4- [3- (dimethylamino) propoxy] benzyl} piperidin-4-yl) -N-ethylquinazolin-4-amine trihydrochloride (Compound No. 7)

A suspension of 1.22 g of 6-chloro-Λ-ethyl-β-piperidin-4-ylquinazolin-4-amine dihydrobromide in 30 ml of 1,2-dichloromethane is added with 1 ml of triethylamine and 0.5 ml of 4- [3- (dimethylamino) propoxy] benzaldehyde. The reaction medium is stirred for 40 minutes and is then added 0.8 g of sodium triacetoxyborohydride. The mixture is stirred for 48 hours at room temperature and is then concentrated under reduced pressure. The residue is taken up in ethyl acetate and the mixture obtained is washed with a sodium hydroxide solution (0.5M). The organic phase is dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue is concrete with diisopropyl ether. The precipitate obtained is taken up in a mixture of ethyl acetate / hydrochloric ether (2M) to give after filtration and drying the expected product. ¹ H NMR (DMSOd ₆ + TFA, 300 MHz) δ ppm: 1.41 (t, 3H); 2.05-2.37 (m, 6H); 2.76 (s, 6H); 3.10-3.28 (m, 4H); 3.38-3.48 (m, 2H); 4.08-4.12 (m, 2H); 4.23 (m, 2H); 4.52-4.60 (m, 3H); 7.02 (d, 2H); 7.58 (d, 2H); 8.15 (s, 2H); 9.02-9.10 (m, 2H).

Example 8

6-Chloro-N- (1- {4- [3- (dimethylamino) propoxy] benzyl} piperidin-4-yl) quinazolin-4-amine trihydrochloride (Compound No. 8)

8.1. 6-Chloro-N-piperidin-4-ylquinazolin-4-amine dihydrochloride

This compound is obtained according to the procedure described in 7.3. from ethyl 4 - [(6-chloroquinazolin-4-yl) amino] piperidine-1-carboxylate (preparation in 7.1.)

8.2. 6-Chloro-N- (1- {4- [3- (dimethylamino) propoxy] benzyl} piperidin-4-yl) quinazolin-4-amine trihydrochloride (Compound No. 8) This compound is obtained according to the procedure described in 7.4. by reaction of 6-chloro-N-piperidin-4-ylquinazolin-4-amine dihydrobromide with 4- [3-

(Dimethylamino) propoxy] benzaldehyde.

¹ H NMR (DMSOd ₆ , 400 MHz) δ ppm: 2.08-2.40 (m, 6H); 2.76 (s, 6H); 3.10-3.28

(m, 4H); 3.33-3.44 (m, 2H); 4.05-4.15 (m, 2H); 4.22 (s, 2H); 4.55-4.65 (m, 1H); 7.01 (d, 2H); 7.62 (d, 2H); 7.99-8.12 (m, 2H); 8.90 (d, 2H); 10.2 (s, 1H, HCl); 10.8 (s, 1H, HCl);

11.4 (s, 1H ₁ HCl);

Example 9

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloro-8-methylquinazolin-4-amine (Compound No. 9)

This compound is obtained according to the procedure described in 4. by reaction of 1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl-amine (preparation in 2.2.) With 4,6-dichlorobenzene. 8-methylquinazoline (synthesized according to the method described by M. Tobe et al., Bioorg.Med.Chem, 2003 (11) 383-391) ¹ H NMR (DMSO-ds, 250 MHz) δ ppm: 2.02-2.18 (m, 4H); 2.61 (s, 3H); 3.07-3.16 (m, 3H); 3.46-3.52 (m, 2H); 4.24 (s, 2H); 4.53 (m, 1H); 6.08 (s, 2H); 6.99 (m, 2H); 7.17 (m, 1H); 8.01 (s, 1H); 8.66 (s, 1H); 8.91 (s, 1H).

Example 10

3- [4 - ({4 - [(6-Chloroquinazolin-4-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol (Compound No. 10)

10.1 4- [3- (Tetrahydro-2A / -pyran-2-yloxy) propoxy] benzaldehyde

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 = 9 Hz, 2H), 7.86 (d, J = 9 Hz ₁ 2H), 9.88 (s, 1H, CHO).

10.2. 3- [4 - ({4 - [(6-Chloroquinazolin-4-yl) amino] piperidin-1-yl} methyl) phenoxy] propan-1-ol (Compound No. 10)

A solution of 500 mg (1.18 mmol) of 6-chloro-β-piperidin-4-ylquinazolin-4-amine dihydrobromide in 10 ml of 1,2-dichloroethane is treated with 0.41 ml (2.94 mmol) of triethylamine and then with 311 mg (1.18 mmol) of 4- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] benzaldehyde. The mixture is stirred for 1 hour under nitrogen, then 325 mg (1.53 mmol) of sodium triacetoxyborohydride are added. The reaction medium is then stirred for 18 hours at room temperature and is then hydrolyzed with 1N sodium hydroxide and extracted with dichloromethane. The organic phase is added with 30 ml of 1 N hydrochloric acid and the mixture is vigorously stirred for 1 hour. The acidic aqueous phase is separated and then basified 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. 220 mg of white solid product is obtained.

Mp: 199 ^° C (K) ¹ H NMR (CDCl ₃ , 400 MHz) δ ppm: 1. 58-1.70 (m, 2H); 1. 80-1.92 (m, 4H); 1, 98-

2.08 (m, 2H); 2.82-2.90 (m, 2H); 3.42 (s, 2H); 3.52-3.60 (m, 2H); 4.0-4.08 (m, 2H); 4.10- 4.20 (m, 1H); 4.50-4.55 (m, 1H, OH); 6.88 (d, J ≈ 8.4 Hz, 2H); 7.21 (d, J = 8.4 Hz, 2H); 7.65-7.70 (m, 1H); 7.75-7.80 (m, 1H); 8.02 (d, J = 7.2 Hz, 1H, NH); 8.45-8.52 (m, 2H).

Table 1

The compounds according to the invention have been the subject of pharmacological tests. Their affinity for the Melanin-Concentrating Hormone (MCH) receptor 1, MCH1, was thus determined.

Attempts were to measure the in vitro activity of the compounds of the invention on 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 radiolabelled derivative of the MCH to the MCH- 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 MCH, [ ¹²⁵ I] -Tyr-S36057 (8-amino-3,6-dioxyoctanoyl). 6-17 MCH marketed by Perkin-Elmer) in 25 mM HEPES buffer (pH 7.4) containing MgCl ₂ 5 mM of CaCl ₂ 1 mM, bacitracin 140 mg / L of the 1 mM phenanthroline, 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 by filtration on GFVB glass fiber filters. incubated for 2 hours in an aqueous solution of polyethyleneimine at 0.1%. The radioactivity retained on the filters is measured using a gamma scintillation counter. Nonspecific binding is determined in the presence of 1 μM of 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 2 has a Cl ₅₀ of 2 nM in the rat and 2 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 MCH 1 receptor will have no effect on the intake of food induced by another orexigenic peptide such as NPY.

The compounds of the invention can be used for the preparation of drugs, particularly drugs antagonists of MCH receptor ₁ of the MCH.

Claims

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

in which

A represents a C _1-4 -alkylene group optionally substituted with one or more groups R _{g which are} identical to or different from one another;

B represents a C _1-4 -alkylene group optionally substituted with one or more groups Ri _{0 which are} identical to or different from each other;

R ₉ and R ₁₀ are each, independently of each other, a hydrogen atom or a C _1-5 -alkyl group,

. or R ₉ and R ₁₀ together form a single bond or a C _1-4 alkylene group; L represents a single bond or a C1 _-2 -alkylene group, -CH = CH- or -C≡C-; C _1-2 alkylene groups and -CH = CH- optionally substituted with one or more substituents Ci _-2 -alkyIe,

. or L represents a cycloprop-1, 2-diyl group;

• R represents a hydrogen atom or a Ci _-5 alkyl group, C _1-3 fluoroalkyl, C _3-6 - cycloalkyl, -C (O) C _1-3 -alkyl, 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, 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 and R ₃ independently of one another, a hydrogen atom or a Ci _-3 alkyl group or C _1-3 -fluoroalkyIe,

. or R ₂ and R ₃ together with the carbon atom carrying them, form a cycloprop-1, 1-diyl group; R ₄ represents:

. a hydrogen atom or a Ci _-5 -aikyle group, Ci _-3 fluoroalkyl, C _1-5 -alkoxy, - SF _5, C _1-3 -alkylene-XC _1-3 alkyl where X represents O or SO ₂ ,

. a C _1-5 -alkylene-NR _a Rb group. 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 ₅ represents a hydrogen or halogen atom or a C _1-5 -alkyl, C _1-3 - fluoroalkyl, Ci _-5 -alkoxy, C _3-6 -cycloalkyl, C _1-3 -alkylene- C ₃ . ₆ -cycIoalkyle, Ci _-3 -alkylene-O- Ci _-3 alkyl, C _1-3 -alkylene- (OH), C _1-3 -alkylene-XC _1-3 alkyl wherein X is S, SO or SO ₂ ,. or R ₅ is -NR _a R _b , C _1-3 -alkylene-NR _a R _b , aryl, C _1-3 - alkylene-aryl, -O-aryl, C _1-3 -alkylene-O- aryl, Ci _-3 -alkylene-O-Ci. ₃ -alkylene-aryl, heteroaryl or C _1-3 -alkylene-heteroaryl; aryl, Ci _-3 -alkylene-ary! e, -O-aryl, C _1-3 -aIkylène-O-aryl, C _1-3 -alkylene-O-Ci _-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 else R ₅ represents a heterocycle group, said heterocycle being optionally substituted with a C _1-3 alkyl group; C (O) C _1-3 -alkyl, -C (O) C _1-3 - fluoroalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, Ci _-3 -alkylene-aryl, C _1-3 - alkylene heteroaryl; groups C _1-3 -alkylene-aryl, and Ci _-3 -alkylene-heteroaryl being optionally substituted by one or more identical radicals Z or different from each other,

• R ₇ represents a hydrogen or halogen atom or a Ci _-5 alkyl group, Ci. ₃ fluoroalkyl, C _1-5 alkoxy, -COOH, -C (O) OC _1-3 alkyl, Ci _-3 -fluoroalkoxy, C _1-3 -alkylene- (OH), -NO _2, -CN, -X-C _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;

• Z represents a halogen atom or a C _1-5 -alkyl, Ci _-3 fluoroalkyl, C _3-6 - cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, phenyl, C _{1 -5} -alkoxy, C _1-3 -fluoroalkoxy, C _1-3 - alkylene-O-Ci _-3 alkyl, C _1-3 -alkylene- (OH), NO _2, -CN, -SO ₂ NRaRb ₁ - XC _1-3 -alkyl, C _1-3 - alkylene-XC _1-3 -alkyl wherein X is S, SO or SO ₂ ,

. or Z represents a phenyl optionally substituted by a halogen atom, a C _1-5 -alkyl, C _1-5 -alkoxy or C _1-3 -fluoroalkyl group,

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

. or Z represents a -C ₄ group. ₆ -alkylene-ORd,

. or Z represents a tetrazole group substituted by a C _1-3 alkyl group, or Z is -NR ₃ Rb, C _1-6 -alkylene-NR _a Rb, -C (O) -NR _a Rb, -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 two adjacent Z radicals together form a C _1-3 - alkylenedioxy 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 -C ₃ -alkyl groups. or Z represents a group -NR _e -C ₂ -C 5 -alkylene-OR _d ,

. or Z represents a -O-C 1 -C ₃ -alkylene-heteroaryl group optionally substituted with one or more C _1-3 -alkyl groups,

. or Z represents -CONH-C _1-5 -alkylene-NR _a Rb,. or Z represents -CONH-C _1-5 -alkylene-O-Rd, or Z represents a group -OC ₁ . ₃ -alkylene-C (O) -NR _a Rb,

. or Z represents a fused bicyclic or fused bicyclic heterocycle,

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

. or R _a and R b taken together with the nitrogen atom to which they are attached, a heterocycle optionally substituted by 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; 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:

A represents an ethylene group;

B represents an ethylene group; • L represents a single bond;

R represents a hydrogen atom or an ethyl group;

R ₁ represents 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 and R ₃ represent, independently of one another, a hydrogen atom;

• R ₄ represents:. a hydrogen atom or a methyl, trifluoromethyl group,

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

R ₅ represents a hydrogen atom or a methyl group;

• R ₇ represents a chlorine atom or a methoxy group; Z represents a group -OC _1-5 -alkylene-NR _a R _b ,

. or Z represents a group -OC ₁ . _5- alkylene-OR _d ,

. or Z represents a group -XC ₁ . _3- alkyl, wherein X is SO ₂ ;

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

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

• A represents a group

B represents a C _1-4 -alkylene group optionally substituted with one or more groups R _{10 which are} identical to or different from one another;

• R ₉ and Rio are each, independently of one another, a hydrogen atom or a group Ci. ₅ -alkyl. or R ₉ and R ₁₀ together form a single bond or a C _1-4 alkylene group;

L represents a single bond or a C _1-2 -alkylene group, -CH = CH- or -C = C-; C-ι _-2 -alkylene groups and -CH = CH- optionally substituted with one or more substituents C _1-2 -alkyl. or L represents a cycloprop-1,2-diyl group;

• R represents a hydrogen atom or a C _1-5 -alkyl, Ci _-3 fluoroalkyl, C _3-6 - cycloalkyl, -C (O) C _1-3 -alkyl, 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, SO ₂ ;

• R ₂ and R ₃ independently of one another represent a hydrogen atom or a Ci _-3 alkyl group or C _1-3 fluoroalkyl,

• R ₄ represents:. a hydrogen atom or a C _1-5 -alkyl, C _1-3 -fluoroa [Kyle, Ci _-5 alkoxy, -

. 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 ₅ represents a hydrogen or halogen atom or a group _-5- alkyl, C _1-3 - fluoroalkyl, C _1-5 -alkoxy, C ₃ . ₆ -cycloalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, Ci _-3 -alkylene-O- Ci _-3 alkyl, Ci _-3 -alkylene- (OH), C _1-3 -alkylene-XC _1-3 -alkyl wherein X is S, SO or SO ₂ , or R ₅ is -NR _a R _b, C _1-3 -alkylene-NR _a R _b, aryl, Ci _-3 - alkylene-aryl, -O-aryl, C _1-3 -alkylene-O-aryl , C _1-3 -alkylene-OC _1-3 -alkylene-aryl, heteroaryl or Ci _-3 -alkylene-heteroaryl; aryl, C _1-3 -alkylene-aryl, -O-aryl, Ci _-3 -alkylene-O-aryl, C _1-3 -alkylene-OC _1-3 -alkylene-aryl, heteroaryl and C _1-3 -alkylene-heteroaryl being optionally substituted by one or more identical radicals Z or different from each other, or R ₅ represents a heterocycle, said heterocycle being optionally substituted with one Ci _-3 alkyl group, -C ( O) C _1-3 -alkyl, -C (O) C _1-3 -fluoroalkyl, C _1-3 -alkylene-C _3-6 -cycloalkyl, C _1-3 -alkylene-aryl, C _1-3 -alkylene heteroaryl; groups Ci _-3 -alkylene-aryl, and C _1-3 -alkylene-heteroaryl being optionally substituted by one or more identical radicals Z 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, -COOH, -C (O) OC _1-3 alkyl , C _1-3 -fluoroalkoxy, C _1-3 -alkylene- (OH), -NO ₂ , -CN, -XC _1-3 -alkyl wherein X is S, SO or SO ₂ ,

. or R ₇ 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, 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;

Z represents a halogen atom or a C _1-5 -alkyl, C _1-3 -fluoroalkyl, C _3-6 -cycloalkyl, C _{1 group} . ₃ -alkylene-C ₃ . ₆ cycloalkyl, phenyl, Ci _-5 alkoxy, Ci _-3 -fluoroalkoxy, C _1-3 - alkylene-OC _1-3 -alkyl, C _1-3 -alkylene- (OH), NO _2, -CN, -SO ₂ NRaRb, -XC _1-3 -alkyl, C _1-3 -alkylene-XC _1-3 -alkyl wherein 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) -C ₁ -C 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 -OC _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; 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. Compounds according to claim 1 selected from:

6-methoxy-N- [1- (2-naphthylmethyl) piperidin-4-yl] quinazolin-4-amine dihydrochloride;

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -6-methoxyquinazolin-4-amine dihydrochloride;

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloro-2- (trifluoromethyl) quinazolin-4-amine dihydrochloride;

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloroquinazolin-4-amine dihydrochloride; N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloro-2-methylquinazolin-4-amine dihydrochloride;

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloro-2- [4- (methylsulfonyl) phenyl] quinazolin-4-amine dihydrochloride;

6-chloro-N- (1- {4- [3- (dimethylamino) propoxy] benzyl} piperidin-4-yl) -N-ethylquinazolin-4-amine trihydrochloride;

6-chloro-N- (1- {4- [3- (dimethylamino) propoxy] benzyl} piperidin-4-yl) quinazolin-4-amine trihydrochloride;

N- [1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl] -6-chloro-8-methylquinazolin-4-amine; 3- [4 - ({4 - [(6-Chloroquinazolin-4-yl) amino] piperidin-1-yl} methyl) phenoxy] propanediol

1-ol.

5. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 4, characterized in that a compound of general formula (III) is reacted:

(III) wherein R ₄ , R ₅ and R ₇ are as defined in the general formula (I) according to claim 1, with a compound of the general formula (II):

in which R, R ₁ , R ₂ , R ₃ , L, A and B are as defined in the general formula (I) according to claim 1.

6. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 4, or a salt of addition of this compound to a pharmaceutically acceptable acid, or a hydrate or a solvate of the compound of formula (I).

7. Pharmaceutical composition, characterized in that it comprises at least one compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, as well as at least one pharmaceutically acceptable excipient.

8. Use of a compound of formula (I) according to any one of claims 1 to 4, for the preparation of a medicament for the treatment of any diseases involving a dysfunction linked to the MCH ₁ receptor.

9. Use of a compound of formula (I) according to any one of claims 1 to 4, for the preparation of a medicament for the treatment of obesity, cellulitis, urinary incontinence, 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.