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Definitions

• the present invention relates to aminomethyl pyridine derivatives, to their preparation and to their therapeutic application.
• R 1 and R 3 may represent an aryl group and R may represent an alkylcarbonylaminoalkyl group.
• Patent application WO 2002/055502 describes compounds of formula:
• Patent application WO2006 / 113704 describes compounds of formula
• Patent application WO 2006/042 955 discloses pyridine derivatives which are antagonists of CB cannabinoid receptors, of formula:
• Novel aminomethylpyridine derivatives have now been found which possess CB and centrally and / or peripherally located cannabinoid CB 1 receptor antagonist properties.
• Z represents a group N (R 3) XR 4, N (R 5 ) COOR 5 or OCON (R 3) R 5 ;
• X represents a group -CO-, -SO2-, -CON (Rg) - or -CSN (RO) -;
• R 1 and R 2 each independently represent a hydrogen atom or a (C 1 -C 7) alkyl or R 1 and R 2 together with the nitrogen atom to which they are attached constitute a saturated or unsaturated heterocyclic radical; of 3 to 8 members which may contain one or more other heteroatoms selected from oxygen, sulfur or nitrogen, said radical being unsubstituted or substituted by one or more C 1 -C 4 alkyl group; R 3 represents a hydrogen atom or a (C 1 -C 4) alkyl group;
• R4 represents:
• a non-aromatic carbocyclic radical (unsubstituted C3-C12X or substituted one or more times by identical or different substituents chosen from a (Cj-C alkyl ⁇ , hydroxyl, (Cj-C alkoxy ⁇ , (Ci-C4) alkylthio cyano;
• a phenyl which is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl or (C 1 -C 4) alkoxy group, (C 1 -C 4) alkylthio, trifluoromethylthio, cyano, nitro, (C 1 -C 4) alkanoyl, phenyl, a group S (O) n Alk, OS (O) n Alk or NR7R.8;
• a phenylcyclopropyl group the phenyl group being unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl, (C 1 -C 4) alkoxy group; (C1-C4) alkylthio, trifluoromethylthio, cyano, nitro, (C1-C4) alkanoyl, phenyl, a group S (O) n AIk, OS (O) n AIk or NR 7 Rg; .
• R4 may be (C1-C8) alkanoyl or benzoyl or benzylcarbonyl, the phenyl group of said groups being unsubstituted or substituted by identical or different substituents chosen from halogen atom, (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio, trifluoromethylthio, cyano, nitro, (Cl- C4) alkanoyl, phenyl, a group S (O) n AIk, OS (O) n AIk or NR 7 Rg;
• R 5 represents a phenyl that is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom or a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, cyano, nitro or (C 1 -C 4) alkoxy group; (C 1 -C 4) alkylthio, trifluoromethylthio, a group S (O) n Alk, OS (O) n Alk or NR 7 R 8 ;
• Rg represents a hydrogen atom or a (C 1 -C 4) alkyl group
• R4 and Rg together with the nitrogen atom to which they are bonded constitute a heterocyclic radical of 3 to 8 atoms, containing or not a second heteroatom selected from an unsubstituted oxygen, sulfur or nitrogen atom; or substituted one or more times with a (C 1 -C 4) alkyl group; a (C 1 -C 4) alkanoyl group; a group NRyRg or CONR 7 Rg; a phenyl group which is unsubstituted or substituted one or more times by a halogen atom, a (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or trifluoromethyl, (C 1 -C 4) alkylthio, trifluoromethoxy, trifluoromethylthio or a group OS (O) n AIk 5 S (O) n Alk or NR 7 Rg; - R ⁇ and Rg each independently represent a hydrogen atom, a (Ci-
• n 0, 1 or 2;
• Alk represents a (C 1 -C 7) alkyl group; in the form of base or addition salt, and in the hydrate or solvate state.
• the present invention is particularly related to the compounds of formula (I) in which:
• Z represents a group N (R 3 ) X R N (R 3) COOR 5 or OCON (R 3 ) R 5 ;
• X represents a group -CO-, -SO2-, -CON (RO) - OR -CSN (RO) -;
• R 1 and R 2 each independently represent a hydrogen atom or a (C 1 -C 7) alkyl or R 1 and R 2 together with the nitrogen atom to which they are bonded constitute a saturated or unsaturated heterocyclic radical; of 3 to 8 members which may contain one or more other heteroatoms selected from oxygen, sulfur or nitrogen, said radical being unsubstituted or substituted by one or more C 1 -C 4 alkyl group;
• R 3 represents a hydrogen atom or a (C 1 -C 4) alkyl group
• R4 represents:
• a non-aromatic (C 3 -C 4 ) carbocyclic radical which is unsubstituted or substituted one or more times with identical or different substituents selected from (C 1 -C 4) alkyl, hydroxyl, (C 1 -C 4) alkoxy, (Ci -C4) alkylthio, cyano;
• ⁇ 4 P had * represent a group (Ci-C6) alkanoyl or benzoyl or benzylcarbonyl, the phenyl group of said groups being unsubstituted or substituted by identical or different substituents selected from halogen atom, (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio, trifluoromethylthio, cyano, nitro, (C1-C4) alkanoyl, phenyl, a group S (O) n Alk, OS (O) n Alk or NRyRg;
• R 5 represents a phenyl which is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom or a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, cyano, nitro or (C 1 -C 4) alkoxy group; (C1-C4) alkylthio, trifluoromethylthio, S (O) n Alk, OS (O) n AUc;
• R ⁇ represents a hydrogen atom or a (C1-C4) alkyl group
• R4 and Rg together with the nitrogen atom to which they are attached constitute a heterocyclic radical of 4 to 8 atoms, containing or not a second heteroatom selected from an unsubstituted oxygen, sulfur or nitrogen atom; or substituted one or more times with a (C 1 -C 4) alkyl group; a (C 1 -C 4) alkanoyl group; a group NRyRg or CONRyRg; a phenyl group which is unsubstituted or substituted one or more times with a halogen atom, a (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or trifluoromethyl group, (C 1 -C 4) alkylthio group, trifluoromethoxy group, trifluoromethylthio group or an OS group (O) n Alk, S (O) n Alk;
• Rg each independently represent a hydrogen atom, a (Ci-C4) alkyl group or Ry and Rg together with the nitrogen atom to which they are attached, constitute a saturated heterocyclic radical; from 4 to 8 atoms may contain another heteroatom selected from a nitrogen atom, oxygen or sulfur;
• - Aq and Ar2 represent each independently of each other a phenyl which is unsubstituted or substituted by a halogen atom, a (C 1 -C 5) alkyl, (C 1 -C 6) alkoxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, cyano group , nitro or a group S (O) n AUc or OS (O) n AIk; - 11 represents O, 1 or 2;
• R1 to R4, Aq and Ar2 are as defined for (I);
• R4 to R4, Aq and Ar2 are as defined for (I);
• the compounds of formula (IC) in which Z represents a group -N (R 3) CON (R 8) R 4 and R 1 to R 4, Ar 1 and Ar 2 are as defined for (I);
• X represents a group -CO-, -SO2- or -CON (RO) - >
• R 1 and R 2 are as defined for (I);
• R3 represents a hydrogen atom or a (C1-C4) alkyl group
• R4 represents:
• a phenyl which is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy or (C 1 -C 4) alkoxy group, (C 1 -C 4) alkylthio, trifluoromethylthio, cyano, (C 1 -C 4) alkanoyl, phenyl or a group S (O) n Alk or OS (O) n Alk; .
• a benzyl which is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, (C 1 -C 4) alkoxy, cyano, phenyl or a group S (O) n AIk or OS (O) n AIk;
• Rg represents a hydrogen atom or a group (Cj-C4 alkyl
• R4 and Rg together with the nitrogen atom to which they are attached constitute a heterocyclic radical of 4 to 8 atoms, containing or not a second heteroatom selected from an unsubstituted oxygen, sulfur or nitrogen atom; or substituted one or more times with a (C 1 -C 4) alkyl group; a (C 1 -C 4) alkanoyl group; a group NR7R3 or CONR ⁇ Rg; a phenyl group which is unsubstituted or substituted one or more times with a halogen atom, a (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or trifluoromethyl group;
• R7 and Rg each independently represent a hydrogen atom, a (C1-C4) alkyl group or R7 and R ⁇ together with the nitrogen atom to which they are attached, constitute a chosen heterocyclic radical; from piperidinyl, pyrrolidinyl, piperazinyl, N-methylpiperazinyl, azepinyl or morpholinyl;
• Ar2 each independently represent a phenyl group unsubstituted or substituted by a halogen atom, a (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, or a group S (O) n AIk or OS (O) n AIk;
• n 0, 1 or 2;
• AUc represents a (C 1 -C 4) alkyl group; in the form of base or addition salt, and in the hydrate or solvate state.
• R 1 and R 2 each independently represent a (C 1 -C 7) alkyl or
• R 1 and R 2 together with the nitrogen atom to which they are attached constitute a radical selected from azeridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, imidazolyl, pyrazolyl, tetrazolyl, triazolyl; - R.3 represents a hydrogen atom or a methyl;
• R4 represents:
• (C5-C7) cycloalkyl unsubstituted or substituted one or more times with methyl; . a heterocyclic radical of 4 to 8 atoms, oxygenated, sulfurous or nitrogenous, saturated, unsubstituted or substituted one or more times with a methyl; . phenyl substituted one or more times with a halogen atom or groups independently selected from trifluoromethyl, trifluoromethoxy, trifluoromethylthio, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio,
• Ar 2 are each independently of one another a phenyl substituted with one or two substituents independently selected from a halogen atom and a methoxy, methylthio, trifluoromethylthio, trifluoromethoxy, SO 2 Alk, OSO 2 Alk; in the form of base or addition salt, and in the hydrate or solvate state.
• R - R ⁇ Q i R 2 are each independently of the other (Ci-C7) alkyl or
• R 1 and R 2 together with the nitrogen atom to which they are attached form a radical selected from azeridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, imidazolyl, pyrazolyl, tetrazolyl, triazolyl;
• R3 represents a hydrogen atom or a methyl
• R4 represents:
• a (C5-C io) has lkyl e;
• (C5-C7) cycloalkyl unsubstituted or substituted one or more times with methyl; . a heterocyclic radical of 4 to 8 atoms, oxygenated, sulfurous or nitrogenous, saturated, unsubstituted or substituted one or more times with a methyl; . phenyl substituted one or more times with groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, (C 1 -C 4) alkoxy, C 1 -C 4 alkylthio, SO 2 Alk or OSO 2 AIk ;
• Rg represents a hydrogen atom or a methyl
• Ar 2 are each independently of one another a phenyl substituted with one or two substituents independently selected from a halogen atom and a methoxy, methylthio, trifluoromethylthio, trifluoromethoxy, SO 2 AUc, OSO 2 Alk; in the form of base or addition salt, and in the hydrate or solvate state.
• 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 exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
• salts can be 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 or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the invention.
• halogen atom a fluorine, a chlorine, a bromine or an iodine
• a (C 1 -C 4) alkoxy or (C 1 -C 8) alkoxy group an O-alkyl radical in which the alkyl group is as defined above.
• the non-aromatic C 3 -C 12 carbocyclic radicals include mono or polycyclic condensed or bridged radicals.
• Monocyclic radicals include cycloalkyls for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; cyclohexyl and cyclopentyl being preferred.
• the fused, bridged or spiro di- or tricyclic radicals include, for example, norbornyl, bornyl, isobornyl, noradamantyl, adamantyl, spiro [5.5] undecanyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl radicals; bicyclo [3.1.1] heptyl.
• the 3- to 8-membered nitrogen-containing heterocyclic radicals consisting of two substituents together with the nitrogen atom to which they are attached include saturated radicals such as azeridinyl, azetidinyl, pyrrolidinyl, piperidyl, perhydroazepinyl, perhydroazocinyl; the saturated or unsaturated radicals additionally containing a second heteroatom selected from an oxygen, sulfur or nitrogen atom, such as imidazolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, imidazolyl, pyrazolyl isothiazolyl, isoxazolyl, triazolyl, tetrazolyl, oxazolyl; thiazolyl.
• Unsaturated 3 to 8 membered nitrogen heterocyclic radicals further comprising one or more heteroatoms include imidazolyl, pyrrolyl, pyrazolyl isothiazoly
• Heterocyclic radicals of 3 to 8 saturated or unsaturated oxygen, sulfur or nitrogen atoms include, in particular, furyl, téfrahydrofuryl, thienyl and pyrrolyl.
• formula (IA) there are compounds of formula (IA) in which:
• Z represents an NHCOR4 group
• R 1 and R 2 each independently represent a (C 1 -C 7) alkyl or
• R j and R 2 together with the nitrogen atom to which they are bonded, form a radical selected from azeridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, imidazolyl, pyrazolyl, tetrazolyl, triazolyl;
• R4 is 2-propylpentyl, 1-propylbutyl, 5-methylnonyl, 4-methylheptyl, 4-methyl-2,6-dimethylheptyl, cyclopentyl, tetramethylcyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, 1,1,4,4 tetramethylcyclopentyl, 2,2,5,5-tetramethylfuranyl, 2,2,5,5-tetramethylpyrrolidinyl, a phenyl group which is unsubstituted or substituted by a halogen atom, a trifluoromethyl, a trifluoromethoxy, a trifluoromethylthio or by an SC group ⁇ Alk or OSO2Alk;
• Z represents a group -NHCONHR4
• R 1 and R 2 each independently represent a (C 1 -C 7) alkyl or
• R 1 and R 2 together with the nitrogen atom to which they are attached constitute a radical selected from azeridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, imidazolyl, pyrazolyl, tetrazolyl, triazolyl;
• R 4 represents a cyclohexyl group, a phenyl group which is unsubstituted or substituted by a halogen atom, a methoxy, trifluoromethyl, trifluoromethoxy or trifluoromethylthio group;
• Ar2 each independently represent a phenyl which is unsubstituted or substituted one or more times with substituents independently selected from chlorine, bromine, methoxy or methylthio; as bases or addition salts and as hydrates or solvates.
• R4SO2Hal (IV) in which R4 is as defined for (I) and HaI represents a halogen atom, preferentially chlorine, when a compound of formula (IB) is to be prepared in where X is -SO2-;
• a compound of formula (II) as defined above can be treated with an aryloxycarbonyl halide of formula HaICOORs in which R5 is as defined for (I) to form an intermediate compound of formula:
• the compounds of formula (IF) in which Z represents an OCONHR5 group are prepared by a process characterized in that a compound of formula:
• a compound of formula (I) in which R 3 and / or R 8 is (C 1 -C 4) alkyl can be prepared by alkylation of a compound of formula (I) wherein R 3 and / or R 8 is an atom hydrogen, by methods known to those skilled in the art.
• the compound of formula (I): (IA), (IB), (IC), (DD), (IE) or (IF) thus obtained is converted into one of its acid addition salts. .
• an activated derivative of the acid of formula (III), such as an acid chloride or an acid may be used.
• reaction is carried out in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane or tetrahydrofuran, and at a temperature between room temperature and the reflux temperature of the solvent.
• a base such as triethylamine or diisopropylethylamine
• a solvent such as dichloromethane or tetrahydrofuran
• the compounds of formula (IV) are commercially available or described in the literature, or may be prepared according to methods described therein such as in J. Org. Chem. USSR, 1970, 6, 2454-2458; J. Am. Chem. Soc., 1952, 74, 2008; J. Med. Chem, 1977, 20 (10), 1235-1239; EP0469984; WO95 / 18105.
• the compounds of formula (IV) can be prepared by halogenation of the corresponding sulfonic acids or their salts, for example their sodium or potassium salts.
• the reaction is carried out in the presence of a halogenating agent such as phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, without solvent or in a solvent such as a halogenated hydrocarbon or N, N-dimethylformamide and at a temperature of between -10 ° C. and 200 ° C.
• a halogenating agent such as phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride
• aryloxycarbonyl halides useful in the preparation of a compound of formula (V) are known or prepared by known methods.
• step a1 a reducing agent such as LiAfflLj is used. to convert the ester of formula (VI) to an alcohol of formula (VII).
• step b the compound of formula (VII) carrying a hydroxymethyl group is engaged in a Mitsunobu reaction in the presence of phthalimide to give a compound of formula (VIII) which, treated with hydrazine hydrate, during a last step C 1 , leads to the compound (II) expected.
• step a 2 The bromination of step a 2 is carried out by N-bromosuccinimide (NBS) in the presence of AIBN and benzoyl peroxide, under UV irradiation in a solvent such as CCI4.
• NBS N-bromosuccinimide
• AIBN AIBN
• benzoyl peroxide a solvent such as CCI4.
• XI dibromed derivative
• XII monobromine derivative
• step b 2 the monobromine derivative is treated with the amine HNRjR2 in the presence of a base such as triethylamine in a solvent such as racetonitrile to obtain the compound of formula (VI).
• a base such as triethylamine
• a solvent such as racetonitrile
• step C 2 the hydrolysis of the dibromo derivative is carried out with silver nitrate in the presence of sodium acetate, in a solvent such as a water / THF mixture.
• step ck treated with an amine of formula HNR1R2 in the presence of NaBH (OAc) 3 to obtain the compound of formula (VI).
• the compounds of formula (X) are prepared according to known methods such as those described in WO 03/082191 and WO 2005/00817.
• the compounds of formula (VII) may also be prepared according to the following reaction scheme:
• step a3 the saponification is carried out in a basic medium, for example in the presence of potassium hydroxide. Then, step b3 is carried out in the presence of a reducing agent, for example BH3.
• a reducing agent for example BH3.
• step d3 an oxidizing agent such as metachloroperbenzoic acid is used to prepare the pyridine N-oxide derivative of formula (XVII) and then by rearrangement (according to BH Lipshutz et al., Tetraheron, 1998, 54, 6999-7012).
• the action of benzenesulfonyl chloride makes it possible to prepare the chlorinated derivative of formula (XVIII) from which compounds of formula (VII) which are differently substituted on the amine function can be prepared.
• R 1 to R 3 are as defined for (I), are novel and constitute a further aspect of the present invention.
• R 1, R 2, Aq and A 4 are as defined for lice (I), are novel and constitute a further aspect of the present invention.
• Step c) may be carried out by a Mitsonobu reaction, for example in the presence of diethylazodicarboxylate and triphenylphosphine.
• Buffer solution ⁇ H 2: solution of 16.66 g of KHSO4 and 32.32 g of K2SO4 in 1 liter of water.
• DMSO dimethylsulfoxide
• Et 2 O ether: diethyl ether 2N hydrochloric ether: 2N solution of hydrochloric acid in diethyl ether diisopropyl ether iso ether
• NaHMDS sodium hexamethylenedisilazane
• NBS N-bromosuccinimide
• the compounds according to the invention are analyzed by LC / UV / MS coupling (liquid chromatography / UV detection / mass spectrometry).
• the molecular peak (MH) and the retention time (tr) are measured in minutes (min).
• the eluent is composed as follows:
• solvent A 0.005% trifluoroacetic acid (TFA) in water.
• solvent B 0.005% TFA in acetonitrile.
• the UV detection is carried out between 210 nm and 220 nm and the mass detection in electrospray ionization mode (ESI) positive at atmospheric pressure.
• ESI electrospray ionization mode
• the eluent is composed as follows:
• solvent A 0.005% trifluoroacetic acid (TFA) in water.
• solvent B 0.005% TFA in acetonitrile.
• Gradient The percentage of solvent B varies from 0 to 90% in 20 minutes with a plateau at 90% of B for 10 minutes.
• the UV detection is carried out between 210 nm and 220 nm and the mass detection in electrospray ionization mode (ESI) positive at atmospheric pressure.
• ESI electrospray ionization mode
• the eluent is composed as follows: solvent A: 10 mM ammonium acetate (pH about 7). solvent B: acetonitrile.
• the UV detection is carried out at 220 nm and the mass detection in electrospray ionization mode (ESI) positive, at atmospheric pressure.
• ESI electrospray ionization mode
• conditions A are the conditions used for LC / MS.
• Ethyl 6- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -2-methylnicotinate is placed in solution in 20 ml of CCI4, then 4.8 g of NBS, 0.69 g of benzoyl are added. peroxide and 0.35 g of AIBN and heated under reflux under UV radiation. After one week, the reaction medium is concentrated under vacuum and the residue is taken up in 200 ml of DCM. The organic phase is washed with 2 ⁇ 200 ml of water, dried over Na 2 SO 4, filtered and brought to dryness to give 6.12 g of crude product. The crude is purified twice on silica eluting with Cyclohexane / AcOEt. We recover 2 main fractions:
• step A 3 g of the monobromous compound obtained in step A are placed in 100 ml of acetonitrile. 0.50 ml of pyrrolidine and 0.92 ml of TEA are added. The mixture is stirred for 2 hours at RT. The solvents are evaporated, taken up in 100 ml of DCM and washed with a saturated solution of NaHCO 3. The organic phase is dried over Na 2 SO 4, filtered and evaporated to dryness. 2.4 g of the expected compound is obtained, identical to the product obtained in stage C according to TLC analysis (thin layer chromatography).
• N - ⁇ [6- (4-bromophenyl) -5- (2,4-dicuorophenyl) -2- (methoxynethyl) pyridin-3-yl] methyl is prepared.
• step G of Preparation 1 The compound obtained in step G of Preparation 1 is placed in solution in DCM and the TEA is added, followed by dropwise addition of 0.14 g of 4-trifluoromethoxybenzene sulphonyl chloride. The mixture is stirred for 2 hours at RT.
• the reaction medium is diluted with 100 ml of DCM and the organic phase is washed with 100 ml of distilled water, then dried over Na 2 SO 4, filtered and evaporated to dryness to obtain 450 mg of crude product.
• the crude is purified by chromatography on silica eluting with DCM / MeOH of 0 to 2% in 1 hour. The fractions containing the purified product are combined and brought to dryness to give 300 mg of the expected compound in base form.
• the purified product is salified with hydrochloride according to the standard method. 214 mg of the expected dihydrochloride are obtained.
• the organic phase is dried over Na 2 SO 4, filtered and brought to dryness.
• the crude product obtained is diluted in 200 ml of dioxane / water (50/50, v / v). 1.77 g of K2CO3 are added. The mixture is stirred for 5 hours under reflux. Evaporate to dryness. The reaction medium is washed with water and extracted with DCM. It is dried over Na 2 SO 4, filtered and the filtrate is concentrated to dryness.
• the crude product is purified by chromatography on silica eluting with DCM / MeOH from 0 to 3% in 1 hour. The purified product is brought to dryness to give 1.5 g of the expected compound.
• the compounds of formula (I) have a very good in vitro affinity (IC50 ⁇ 5.10 M) for CB cannabinoid receptors, under the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 350, 240- 244).
• the toxicity of the compounds of formula (I) is compatible with their use as a medicament.
• the invention relates to medicaments for human or veterinary medicine which comprise a compound of formula (I), or a solvate or a hydrate of the compound of formula (I).
• the compounds according to the invention can be used in humans or animals (in particular in mammals including, but not limited to, dogs, cats, horses, cattle, sheep) in the treatment or prevention of diseases involving CB cannabinoid receptors.
• the compounds of formula (I) are useful as psychotropic drugs, especially for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders , obsessive-compulsive disorder, psychosis in general, schizophrenia, attention deficit hyperactivity disorder (ADHD) in hyperkinetic children, and the treatment of disorders related to the use of psychotropic substances, including in the case of substance abuse and / or substance dependence, including alcohol dependence and nicotine addiction.
• psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders , obsessive-compulsive disorder, psychosis in general, schizophrenia, attention deficit hyperactivity disorder (ADHD) in hyperkinetic children
• ADHD attention deficit hyperactivity disorder
• disorders related to the use of psychotropic substances including in the case of substance abuse and / or substance dependence, including alcohol dependence and nicotine addiction.
• the compounds of formula (I) according to the invention can be used as medicaments for the treatment of migraine, stress, psychosomatic diseases, panic attacks, epilepsy, movement disorders , especially dyskinesias or Parkinson's disease, tremors and dystonia.
• the compounds of formula (I) according to the invention can also be used as medicaments in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementias, of Alzheimer's disease, as well as in the treatment of disturbances of attention or alertness.
• the compounds of formula (I) may be useful as neuroprotective agents, in the treatment of ischemia, head trauma and the treatment of acute or chronic neurodegenerative diseases, including chorea, Huntington's chorea, Tourrette's syndrome.
• the compounds of formula (I) according to the invention can be used as medicaments in the treatment of pain: neuropathic pain, peripheral acute pain, chronic pain of inflammatory origin, pain induced by anticancer treatment.
• the compounds of formula (I) according to the invention can be used as medicaments in human or veterinary medicine in the treatment of appetite disorders, palatability (for sugars, carbohydrates, drugs, alcohols or any appetizing substance ) and / or eating behaviors, especially for the treatment of obesity or bulimia as well as for the treatment of type II diabetes or non-insulin-dependent diabetes and for the treatment of dyslipidemia, metabolic syndrome.
• the compounds of formula (I) according to the invention are useful in the treatment of obesity and the risks associated with obesity, in particular cardiovascular risks.
• the compounds of formula (I) according to the invention can be used as medicaments in the treatment of gastrointestinal disorders, diarrheal disorders, ulcers, vomiting, bladder and urinary disorders, endocrine, cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, chronic cirrhosis of the liver, fatty liver, steatohepatitis, asthma, Raynaud's syndrome, glaucoma , disorders of fertility, termination of pregnancy, premature delivery, inflammatory phenomena, diseases of the immune system, in particular autoimmune and neuroinflammatory diseases such as rheumatoid arthritis, reactive arthritis, diseases leading to demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, stroke and as a medicinal aments for cancer chemotherapy, for the treatment of Guillain-Barré syndrome and for the treatment of bone diseases and osteoporosis.
• autoimmune and neuroinflammatory diseases such as rheumatoid arthritis, reactive arthritis, diseases leading to demyelination, multiple sclerosis, infectious and viral
• the compounds of formula (I) are particularly useful for the treatment of psychotic disorders, in particular schizophrenia, attention deficit and hyperactivity disorders (ADHD) in hyperkinetic children; for the treatment of appetite and obesity disorders; for the treatment of memory and cognitive deficits; for the treatment of alcohol dependence, nicotine addiction, ie for alcohol withdrawal and smoking cessation.
• ADHD attention deficit and hyperactivity disorders
• the compounds of formula (I) according to the present invention are useful in the treatment and prevention of appetite disorders, metabolic disorders, gastrointestinal disorders, inflammatory phenomena, diseases of the immune system, psychotic disorders, alcohol dependence, nicotine addiction.
• the present invention relates to the use of a compound of formula (I), and its solvates or hydrates for the treatment of the disorders and diseases indicated above.
• the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
• These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, a solvate or hydrate 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.
• compositions according to the present invention may contain, besides a compound of formula (I), one (or more) other active ingredient useful in the treatment of the disorders and diseases indicated above.
• an antihyperlipidemic agent or an antihypercholesterolemic agent an antihyperlipidemic agent or an antihypercholesterolemic agent
• a nicotinic agonist a partial nicotinic agonist
• an antidepressant an antispychotic, an anxiolytic
• an anticancer agent or an antiproliferative agent an anticancer agent or an antiproliferative agent
• an opioid antagonist as well as : an agent improving the memory
• antidiabetic means a compound belonging to one of the following classes: sulfonylureas, biguanidines, alpha glucosidase inhibitors, thiazolidinedione, metiglinids and insulin and insulin analogues.
• a compound such as a PPAR (Peroxisome Proliferator Activated Receptor Agonist) agonist, a dopamine agonist, a leptin receptor agonist, a serotonin reuptake inhibitor, a beta-3 agonist, a CCK-A agonist, an NPY inhibitor, an MC4 receptor agonist, a Melanin Concentrating Hormone (MCH) receptor antagonist, an antagonist of the orexin, a phosphodiesterase inhibitor, an inhibitor of 11 ⁇ HSD (11- ⁇ -hydroxy steroid dehydrogenase), a DPP-IV (dipeptidyl peptidase IV) inhibitor, an antagonist (or histamine H3 inverse agonist, a CNTF derivative (of English Ciliary Neurotrophic Factor), a GHS (Growth Hormone Secretagogue) receptor agonist, a ghrelin modulator, a diacyglycerol
• PPAR Peroxisome Proliferator Activated
• beneficial agent for treating osteoporosis, is meant, for example, bisphosphonates.
• inhibitors of PTP 1 B English Protein Tyrosine Phosphase -IB
• agonists of VPAC 2 receptors modulators of GLK, retinoid modulators, glycogen phosporylase inhibitors (HGLPa), glucagon antagonists, glucose-6 phosphate inhibitors, pyruvate dehydrogenase kinase (PKD) activators, RXR modulators, FXR, LXR, Inhibitors of SGLT (English Sodium-Dependent Glucose Transporter), inhibitors of CETP (English Cholesterylester Transfer Protein), inhibitors of squalene synthetase, squalene epoxidase inhibitors, triglyceride synthesis inhibitors, inducer
• the compound of formula (I), one of its pharmaceutically acceptable salts or one of their solvates and the other associated active ingredient may be administered simultaneously, separately or spread over time.
• Extended use means the sequential administration of the first compound of the composition of the invention, included in a pharmaceutical form, and then the second compound of the composition according to the invention, included in a separate pharmaceutical form. .
• the lapse of time elapsing between the administration of the first compound of the composition according to the invention and the administration of the second compound of the same composition according to the invention generally does not exceed 24 hours.
• 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 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 disorders or diseases above.
• 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, forms of topical, transdermal, subcutaneous, intramuscular or intravenous forms of rectal administration and implants.
• 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, forms of topical, transdermal, subcutaneous, intramuscular or intravenous forms of rectal administration and implants.
• the compounds according to the invention can be used in creams, gels, ointments or lotions.
• a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
• the dose of active ingredient administered per day can reach 0.01 to 100 mg / kg, in one or more doses, preferably 0.02 to 50 mg / kg.
• 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 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 hydrates or solvates.

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