Title of Invention	DIPHENYLPYRIDINE COMPOUNDS
Abstract	The invention relates to 5,6-dipheny3pyridine-3-car- boxamide derivatives of general formula (I), where R1 = H, or (C1-C4) alkyl, R2 = a monoazo saturated heterocycle of 5 to 7 atoms, the nitro- gen atom being substituted with a (C1 -C4)alkanoyl, NR10R11, a non- aromatic (C3-C10) carbocycle more than tri-substituted with (C1-C4) alkyl, a non-aromatic (C11-C12) carbocycle unsubstituted or mono- or poly-substituted with (C1-C4) alkyl, amonooxygenated saturated het- erocycle with 5 to 7 atoms, more than tri-substituted with (C1-C4) alkyl, or R1 and R2, together with the nitrogen atom to which the above are bonded, form a4-dsubstituted piperidin-1-yl group, the salts, sol- vales and hydrates thereof. The invention further relates to a method for production and therapeutic application thereof.

Title of Invention

DIPHENYLPYRIDINE COMPOUNDS

Abstract

The invention relates to 5,6-dipheny3pyridine-3-car- boxamide derivatives of general formula (I), where R1 = H, or (C1-C4) alkyl, R2 = a monoazo saturated heterocycle of 5 to 7 atoms, the nitro- gen atom being substituted with a (C1 -C4)alkanoyl, NR10R11, a non- aromatic (C3-C10) carbocycle more than tri-substituted with (C1-C4) alkyl, a non-aromatic (C11-C12) carbocycle unsubstituted or mono- or poly-substituted with (C1-C4) alkyl, amonooxygenated saturated het- erocycle with 5 to 7 atoms, more than tri-substituted with (C1-C4) alkyl, or R1 and R2, together with the nitrogen atom to which the above are bonded, form a4-dsubstituted piperidin-1-yl group, the salts, sol- vales and hydrates thereof. The invention further relates to a method for production and therapeutic application thereof.

Full Text	WO 2005/000817 1 PCT/FR2004/001581 DIPHENYLPYRIDINE DERIVATIVES, PREPARATION AND THERAPEUTIC APPLICATION THEREOF The present invention relates to 5,6-diphenyl- pyridine-3-carboxamide derivatives, to the preparation thereof and to the application thereof in therapeutics. 5,6-Diphenyl-2-pyridine derivatives are described in the international patent application published under No. WO 92/02513. These compounds are presented as having antithrombotic, vasodilating and anti- inflammatory activity. Inverse agonist or antagonist 2,3-diphenylpyridine derivatives of cannabinoid CB1 receptors are described in international patent application WO 2003/082191. Novel 5,6-diphenyl-3-pyridinecarboxamide derivatives which possess cannabinoid CB1 receptor antagonist properties have now been found. Thus, a subject of the present invention is compounds of formula: in which: R1 represents hydrogen or a (C1-C4) alkyl; R2 represents: . a saturated mononitrogenous heterocyclic radical containing from 5 to 7 atoms, the nitrogen atom being substituted with a (C1-C4) alkanoyl group; . a group NR10Ru; . a nonaromatic C3-C10 carbocyclic radical which is substituted more than three times 2 with a (C1-C4) alkyl group; . a nonaromatic C11-C12 carbocyclic radical which is unsubstituted or substituted one or more times with a (C1-C4) alkyl group; . a saturated monooxygenated heterocyclic radical containing from 5 to 7 atoms, which is substituted more than 3 times with a (C1-C4) alkyl group; or R1 and R2/ together with the nitrogen atom to which they are attached, constitute a piperidin-1- yl radical disubstituted in the 4-position with a phenyl or benzyl group and with a (C1-C4) alkyl, (C1-C4) alkoxy, cyano, aminocarbonyl, (C1-C4) alkyl- aminocarbonyl, di (C1-C4) alkylaminocarbonyl, (C1-C3) alkanoyl or (C1-C3) alkanoylamino group; the phenyl or benzyl groups substituting the piperidin-1-yl radical being unsubstituted or substituted with a halogen atom and/or a methyl and/or trifluoromethyl group; R3, R4/ Rs/ Re/ R7 and Rs each represent, independently of one another, a hydrogen or halogen atom, or a (Ci-Ce) alkyl, (Ci-Cg) alkoxy or trifluoromethyl group; R9 represents a hydrogen atom, a (C1-C4) alkyl or cyano group or a CH2OH, CH2CN, or CH2O (C1-C4) alkyl group; Rio and Rn, together with the nitrogen atom to which they are attached, constitute a saturated or unsaturated heterocyclic radical containing from 7 to 10 atoms, possibly containing a second hetero atom chosen from 0 and N, the said radical being unsubstituted or substituted one or more times with a (C1-C4) alkyl, hydroxyl, (C1-C4) alkoxy or methoxy (C1-C2) alkylene group, or substituted with a spirocyclobutane, a spirocyclopentane or a spiro- cyclohexane; 3 or Rio and RU/ together with the nitrogen atom to which they are attached, constitute a saturated or unsaturated heterocyclic radical containing 5 or 6 atoms, containing a second nitrogen atom, the said radical being substituted one or more times with a methoxy(C!-C2)alkylene group, or substituted with a spirocyclobutane, a spirocyclopentane or a spirocyclohexane; or Rio and Rn, together with the nitrogen atom to which they are attached, constitute a saturated or unsaturated heterocyclic radical containing 5 or 6 atoms, "possibly containing an oxygen atom, the said radical being substituted one or more times with a (Ci-C4) alkyl, hydroxyl, (C1-C4) alkoxy or methoxy (C1-C2) alkylene group, or substituted with a spirocyclobutane, a spirocyclopentane or a spiro- cyclohexane; and also the salts, the sol vat es and the hydrates thereof. The compounds of formula (I) may comprise one or more asymmetric carbon atoms- They may therefore exist in the form of enantiomers or of diastereoisomers. These enantiomers and diastereoisomers, and also the mixtures thereof, including the racemic mixtures, are part of the invention. The compounds of formula (I) may exist in the form of bases or of addition salts with acids. These salts are advantageously prepared with pharmaceutically acceptable salts, but the salts of other acids that are useful, for example, for purifying or isolating the compounds of formula (I) are also part of the invention. Among the compounds of formula (I), the compounds are distinguished in which: R1 represents hydrogen or a (C1-C4) alkyl; R2 represents: 4 . a saturated mononitrogenous heterocyclic radical containing from 5 to 7 atoms, the nitrogen atom being substituted with a (C1-C4) alkanoyl group; . a group NR10R11; . a nonaromatic C11-C12 carbocyclic radical which is unsubstituted or substituted one or more times with a {C1-C4) alkyl group; . a saturated monooxygenated heterocyclic radical containing from 5 to 7 atoms, which is substituted more than 3 times with a (C1-C4) alkyl group; or R1 and R2, together with the nitrogen atom to which they are attached, constitute a piperidin-1- yl radical disubstituted in the 4-position with a phenyl or benzyl group and with a (C1-C4) alkyl or (C1-C3) alkanoyl group; the phenyl or benzyl groups substituting the piperidin-1-yl radical being unsubstituted or substituted with a halogen atom and/or a methyl group; R3 / R4, R5 r R6/ R7 and Re each represent, independently of one another, a hydrogen or halogen atom, or a (C1-C6) alkyl, (Ci-Ce) alkoxy or trifluoromethyl group; R9 represents a hydrogen atom, a (C1-C4) alkyl or cyano group or a CH2OH or CH2O (C1-C4) alkyl group; Rio and Rn, together with the nitrogen atom to which they are attached, constitute a saturated or unsaturated heterocyclic radical containing from 7 to 10 atoms, possibly containing a second hetero atom chosen from 0 and N, the said radical being unsubstituted or substituted one or more times with a (C1-C4) alkyl, hydroxyl, (C1-C4) alkoxy or methoxy (Ci-C2)alkylene group, or substituted with a spirocyclobutane, a spirocyclopentane or a spiro- cyclohexane; 5 or Rio and Rn, together with the nitrogen atom to which they are attached, constitute a saturated or unsaturated heterocyclic radical containing 5 or 6 atoms, containing a second nitrogen atom, the said radical being substituted one or more times with a methoxy (Ci-C2) alkylene group, or substituted with a spirocyclobutane, a spirocyclopentane or a spirocyclohexane; or Rio and R11, together with the nitrogen atom to which they are attached, constitute a saturated or unsaturated heterocyclic radical containing 5 or 6 atoms, "possibly containing an oxygen atom, the said radical being substituted one or more times with a (Ci-C4) alkyl, hydroxyl, (C1-C4) alkoxy or methoxy (Ci-C2) alkylene group, or substituted with a spirocyclobutane, a spirocyclopentane or a spiro- cyclohexane; and also the salts, the sol vat es and the hydrates thereof. The term "alkyl" is intended to mean a linear or branched radical such as, in particular: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl or isohexyl, the methyl group being preferred for a (C1-C4) alkyl, the tert- butyl, 2-methyl-2-butyl and 3,3-dimethyl-2-butyl groups being preferred for a (C3-C7) alkyl. The term "alkoxy" group is intended to mean a linear or branched radical, the methoxy group being preferred. The term "halogen atom" is intended to mean a fluorine, chlorine, bromine or iodine atom; the fluorine, chlorine or bromine atom being preferred. The nonaromatic C3-C12 carbocyclic radicals comprise monocyclic or polycyclic radicals that are fused or bridged. The monocyclic radicals include cycloalkyls, for example cyclopropyl, cyclobutyl, 6 cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; cyclohexyl and cyclopentyl being preferred. The di- or tricyclic radicals that are condensed, bridged or spiro radicals include, for example, norbornyl, bornyl, isobornyl, noradamantyl, adamantyl, spiro[5.5]undecanyl and bicyclo[2.2.l]heptanyl radicals; adamantyl being preferred. The expression "saturated or unsaturated heterocyclic radical containing from 5 to 10 atoms, possibly containing a second hetero atom such as 0 or N" is intended to mean radicals such as morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, 3,6-dihydropyridin-l-yl or octahydrocyclopenta[c]- pyrrol-2-yl, the piperidin-1-yl and morpholin-4-yl radicals being preferred. The expression "saturated mononitrogenous hetero- cyclic radical containing from 5 to 7 atoms" is intended to mean a radical such as piperidin-4-yl or pyrrolidin-3-yl, the piperadin-4-yl radical being preferred. The expression "saturated monooxygenated hetero- cyclic radical containing from 5 to 7 atoms" is intended to mean a radical such as tetrahydrofuranyl, tetrahydro-2tf-pyranyl or oxepanyl; tetrahydrofuranyl being preferred. According to the present invention, preference is given to the compounds of formula (I) in which: R1 represents hydrogen; R2 represents: . a group NR10Ru; . a nonaromatic Cn-Ci2 carbocyclic radical which is unsubstituted or substituted one or more times with a methyl group; or Rx and R2/ together with the nitrogen atom to which they are attached, constitute a piperidin-1- yl radical disubstituted in the 4-position with a phenyl or benzyl group and with a (Ci-C4)alkyl or 7 (Ci-C3) alkanoyl group; and/or R3, R4, R5, R6, R7 and R8 each represent, independently of one another, a hydrogen or halogen atom, or a (Ci-C6) alkyl, (Ci-C6) alkoxy or trifluoromethyl group; and/or R9 represents a hydrogen atom or a methyl, methoxymethylene or cyano group; Rio and Rn, together with the nitrogen atom to which they are attached, constitute a saturated or unsaturated heterocyclic radical containing from 5 to 10 atoms, possibly containing an oxygen atom, the said radical being unsubstituted or substituted one or more times with a methyl group; and also the salts, the solvates and the hydrates thereof. Among the compounds which are the subject of the invention, mention may be made of the preferred compounds, which are defined by the following values for the substituents: R1 represents a hydrogen atom; and R2 represents the 3-amino-2,2,5,5-tetramethyl- tetrahydrofuran group; or R1 and R2, together with the nitrogen atom to which they are attached, represent a 4-acetyl-4- phenylpiperidin-1-yl group; and/or at least one of the substituents R3, R4 and R5 represents a halogen atom, preferably chlorine or bromine, or a methoxy group; and/or at least one of the substituents R6, R7 and Rs represents a halogen atom, preferably chlorine or bromine; and/or R9 represents a methyl or methoxymethyl group. Most particularly, the following compounds are preferred: 1-(1-(6-{4-chlorophenyl)-5-(2,4-dichloro- phenyl)-2-methylpyridin-3-yl)-4-phenylpiperidin-4-yl)- 8 ethanone, 6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2- (methoxymethyl-N-(2,2,5,5-tetramethyltetrahydrofuran-3- yUnicotinamide, 5- (4-chlorophenyl) -6- (2, 4-dichloro- phenyl)-2-methyl-N-(2,2,5,5-tetramethyltetrahydrofuran- 3-yl)pyridine-3-carboxamide, 1-(1-(5-{4-bromophenyl)-6- (2,4-dichlorophenyl)-2-(methylpyridin-3-yl)carbonyl)-4- phenylpiperidin-4-yl)ethanone, 6-(4-bromophenyl)-5- (2,4-dichlorophenyl)-2-methyl-N-(2,2,5,5-tetramethyl- tetrahydrofuran-3-yl)nicotinamide). A subject of the present invention is also a process for preparing the compounds according to the invention. This process is characterized in that a functional derivative of 5,6-diphenyl-2-pyridinecarboxylic acid, of formula: in which R3, R4, R5, R6, R7, Re and R9 are as defined for (I), is treated with an amine of formula HNR1R2 (III) in which R1 and R2 are as defined for (I) . The compound thus obtained is optionally converted into one of its salts or solvates. As functional derivative of the acid (II), use may be made of the acid chloride, the anhydride, a mixed anhydride, a C1-C4 alkyl ester in which the alkyl is linear or branched, an activated ester, for example the p-nitrophenyl ester, or the free acid activated at the right time, for example with N,N-dicyclohexylcarbodi- imide or with benzotriazol-1-yloxotris(dimethylamino)- phosphonium hexafluorophosphate (BOP) or benzotriazol- 9 1-yloxotris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP). Thus, in the process according to the invention, pyrazole-3-carboxylic acid chloride, obtained by reacting thionyl chloride with the acid of formula (II) , can be reacted with an amine HNRiR2, in an inert solvent, such as a chlorinated solvent (dichloro- methane, dichloroethane, chloroform, for example), an ether (tetrahydrofuran, dioxane, for example) or an amide (N,N-dimethylformamide, for example), under an inert atmosphere, at a temperature of between 0°C and ambient temperature, in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine. A variant consists in preparing the mixed anhydride of the acid of formula (II) by reacting ethyl chloroformate with the acid of formula (II) , in the presence of a base such as triethylamine, and in reacting it with an amine HNR1R2, in a solvent such as dichloromethane, under an inert atmosphere, at ambient temperature, in the presence of a base such as triethylamine. The compounds of formula (II) can be prepared by various processes, according to the value for the substituent Rg. 10 THF: tetrahydrofuran LiHMDS: lithium hexamethyldisilazide PTSA: para-toluenesulphonic acid. Scheme 1 explains a mode for preparing the 11 compounds of formula (II) in which R9 = (C1-C4) alkyl, more specifically R9 = Me. Step al) is carried out in an anhydrous solvent such as THF; it is initiated at low temperature (-78°C) and the temperature is then allowed to return to ambient temperature (AT). Step bl) is carried out in the presence of acetic anhydride, at a temperature of between AT and 100°C. Step cl) is carried out in an alcoholic solvent such as n-butanol, heating at the reflux of the solvent for 6 hours in the presence of a catalyst such as para- toluenesulphonic acid. In step dl), the ester is hydrolysed by heating in aqueous basic medium, in a solvent such as ethanol. SCHEME 2 To prepare a compound of formula (II) in which R9 is a hydrogen atom, the ester of formula (VIII) is treated with an oxidizing agent such as selenium oxide in pyridine in aqueous medium, and the diacid formed is 12 then treated with silica under hot conditions. 13 The compounds of formula (II) in which R9 represents a cyano, alkoxymethylene or cyanomethyl group are prepared from the ester of formula (VIII). In a first step a3), the group R9 = methyl is substituted with 1 or 2 bromine atoms by means of the action of N-bromosuccinimide, under hot conditions, in a solvent such as CCI4, in the presence of UV radiation, so as to give a monobrominated derivative (X) and a dibrominated derivative (XI) . In step e3) , the monobrominated derivative (X) is treated with a sodium alkoxide in an alcohol, for example sodium methoxide in methanol, and then saponified in basic medium, under hot conditions, to give the acid of formula (II) in which R9 is the alkoxymethylene group. In step f3) , the monobrominated derivative (X) is treated with tetramethylammonium cyanide in a solvent such as chloroform, and then saponified under mild conditions, for example with LiOH in a THF/water mixture, to give the acid of formula (II) in which Rg is the cyanomethyl group. The dibrominated derivative (XI) is treated with silver nitrate in aqueous THF so as to form the aldehyde (XII), which is then treated with hydroxyl- amine hydrochloride in formic acid to give a nit rile derivative (XIII). The ester (XIII) is treated in basic medium, under mild conditions, preferably with LiOH, to give the acid of formula (II) in which R9 is the cyano group. To prepare a compound of formula (II) in which R9 = CH2OH, the monobrominated derivative (X) is treated with sodium hydroxide, in a THF/water mixture, by refluxing. 14 according to the following scheme. A compound of formula (II) in which R3 = CH2OCH3 can also be prepared by the method described in scheme 1 using an appropriate reagent in step cl, according to the following scheme: 5,6-Diphenyl-3-pyridinecarboxylic acids are generally known; 6-(4-chlorophenyl)-5-(4-methoxy- phenyl)-2-methylpyridine-3-carboxylic acid and 5,6-bis- (4-methoxyphenyl)pyridine-3-carboxylic acid and their 15 ethyl esters are described in international patent application WO 2002/055502. The amines HNRiR2 are known or are prepared by known methods such as those described in Chem. Ber., 1986, U£, 1413-1423. The following abbreviations will be used in the present description: DCM: dichloromethane LDA: lithium diisopropylamide THF: tetrahydrofuran TFA: trifluoroacetic acid AIBN: " azobis(isobutyronitrile) TMSiCl: trimethylchlorosilane Et2O or ether: ethyl ether EtOAc: ethyl acetate AC2O: acetic anhydride nBuOH: n-butanol PTSA: para-toluenesulphonic acid LiHMDS: lithium hexamethyldisilazide KHSO4/K2SO4: 0.5 mol KHSO4/O.19 mol K2SO4 in 1 litre of water TEA: triethylamine BOP: benzotriazol-1-yloxotris(dimethylamino) phosphonium hexafluorophosphate PyBOP: benzotriazol-1-yloxotris(pyrrolidino) phosphonium hexafluorophosphate NBS: N-bromosuccinimide AT: ambient temperature Mp: melting point. The compounds according to the invention are analysed by LC/UV/MS coupling (liquid chromatography/UV detection/mass spectrometry). The molecular peak (M+) and the retention time (t) in minutes are measured. A Symmetry C18 column, sold by Waters, of 2.1 x 50 mm, 3.5 urn, is used at ambient temperature, with a flow rate of 0.4 ml/minute. 16 The eluent has the following composition: solvent A: 0.005% of trifluoroacetic acid (TFA) in water solvent B: 0.005% of TFA in acetonitrile. Gradient: The percentage of solvent B ranges from 0 to 90% over 10 minutes, with a plateau at 90% of B for 5 minutes. The UV detection is carried out at 210 nm ± 8 nm and the detection of mass is carried out in positive ionization mode at atmospheric pressure. The nuclear magnetic resonance (NMR) spectra are recorded at 200 MHz in d6-DMSO. For analysis of the spectra, the following abbreviations are used: s : singlet; d : doublet; bs : broad singlet; dd : doublet of doublets; mt : multiplet. Preparation 1 5-(2,4-Dichlorophenyl)-6-(4-chlorophenyl)- 2-methyl-pyridine-3-carboxylic acid. A) 1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)ethanone 32 g of LiHMDS are placed in 245 ml of THF at 0°C, and 40 g of (4-chlorophenyl)((trimethylsilyl)oxy)aceto- nitrile are added slowly at -78°C, followed by 32.64 g of 2,4-dichloro-l-(chloromethyl)benzene. The temperature is allowed to return to AT overnight, and the reaction is then hydrolysed with 170 ml of a 3N HC1 solution, with gases being trapped in a solution of KOH (4N) . After separation by settling out, the organic phase is evaporated, then taken up in DCM and agitated for 1 hour with 170 ml of NaOH (2N) . The DCM is evaporated off and the expected compound is then crystallized from pentane. 38.6 g are obtained, Mp = 119°C. B) l-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)propen-2- en-l-one. 10 g of the compound from the preceding step, 17 ml of N,N,N,N-tetramethylmethanediamine and 17 ml of 17 acetic anhydride are mixed at AT; the mixture is heated at 90°C for 3 hours and is then allowed to return to AT. The mixture is poured into crushed ice and then filtered. The solid is dried under vacuum. 10 g of the expected compound are obtained, Mp = 8 9°C. C) 5-{2,4-Dichlorophenyl)-6-(4-chlorophenyl)-2- methylpyridine-3-carboxylic acid ethyl ester. A mixture containing 7 g of the compound from the preceding step, 2.62 g of ethyl 3-amino-2-butenoate and 140 mg of para-toluenesulphonic acid is prepared in 60 ml of n-butanol and is then heated for 24 hours at the reflux of the solvent. Three quarters of the solvent is evaporated off and then 80 ml of pentane are added at 0°C. The precipitate formed is filtered off and the filtrate is concentrated. The residue is chromatographed on silica, elution being carried out with a cyclohexane/EtOAc (90/10; v/v) mixture. 7 g of the expected compound are obtained, Mp = 114°C. D) 5-(2,4-Dichlorophenyl)-6-(4-chlorophenyl)- 2-methylpyridine-3-carboxylic acid. 6 g of the ester obtained in the preceding step is placed in 300 ml of EtOH and 8 g of potassium hydroxide are added. After agitation for a few minutes, 5 ml of water are added and the mixture is refluxed for 19 hours. The reaction medium is concentrated and the product is taken up with Et2O and water. The aqueous phase is acidified to pH = 1 with 10% HC1 and is then extracted with DCM and dried over Na2SO4. After washing with heptane, 5.4 g of the expected compound are obtained. NMR: 2.83 ppm: s: 3H; 7.2-7.6 ppm: unresolved peak: 5H; 7.68 ppm: s: 1H; 8.11 ppm: s: 1H; 13.2- 13.7 ppm: bs: 1H. Preparation 2 6-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)pyridine- 3-carboxylic acid 18 A) 6-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)pyridine- 2,3-dicarboxylic acid 2 g of the acid obtained in Preparation 1 are placed in 7.2 ml of pyridine and 0.8 ml of water and 1.44 g of selenium dioxide are added, and the mixture is then refluxed for 3 days. The solution obtained is filtered and then washed with acetic acid. After evaporation of the solvents, crushed ice is added and agitation is maintained for 2 hours. The solid formed is filtered off, washed with ether and then dried in an oven. The filtrate is concentrated and then filtered through silica, elution being carried out with DCM. The expected product is reacted as it is in the following step. B) 6- (4-Chlorophenyl)-5-(2,4-dichlorophenyl)pyridine- 3-carboxylic acid The product obtained in the preceding step is solubilized in the minimum amount of DCM and impregnated onto 25 g of silica. After evaporation of the solvent, the silica is heated at 120°C for 8 hours. The product formed is extracted with DCM + EtOH and then pure EtOH. After evaporation of the solvents, chromatography is performed on silica, elution being carried out with CHC13 and then CHCl3/MeOH/AcOH (95/3/1.5; v/v/v). 544 mg of the expected compound are obtained. NMR: 5.76 ppm: s: 1H; 7.2-7.6 ppm: unresolved peak: 5H; 7.69 ppm: s: 1H; 8.19 ppm: s: 1H; 9.22 ppm: s: 1H; 13.2-13.9 ppm: bs: 1H. Preparation 3 6-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2- methoxymethylpyridine-3-carboxylic acid A) 2-Bromomethyl-6-(4-chlorophenyl)-5-(2,4-dichloro- phenyl) pyridine-3-carboxylic acid ethyl ester 3.8 g of ester obtained in Preparation 1, step C, are placed in 39 ml of CC14 with 7.07 g of NBS, and 19 10 mg of AIBN are added. The mixture is refluxed for 24 hours and then the heating is maintained for 8 hours with UV irradiation. After cooling, the reaction medium is filtered and the filtrate is chromatographed on silica, elution being carried out with DCM; 3.1 g of 2,2-dibromomethyl-6-(4-chlorophenyl)-5-(2,4-dichloro- phenyl)pyridine-3-carboxylic acid ethyl ester and 1 g of 2-bromomethyl-6-(4-chlorophenyl)-5-(2,4-dichloro- phenyl)pyridine-3-carboxylic acid ethyl ester are obtained. B) 6-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2- methoxymethylpyridine-3-carboxylic acid ethyl ester 1 g of the monobrominated compound obtained in the preceding step is placed in 30 ml of MeOH, and then 0.13 g of sodium methanolate is added and the mixture is refluxed for 24 hours. The reaction medium is hydrolysed with a 10% HC1 solution, and then the solvent is evaporated off and the product is taken up with EtOAc and washed with water. After drying over MgSO4, the product is concentrated and then chromatographed on silica, elution being carried out with a cyclohexane/EtOAc (90/10; v/v) mixture. 840 mg of the expected ester are obtained. C) 6-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2- methoxymethylpyridine-3-carboxylic acid 800 mg of the ester obtained in the preceding step are placed in 37 ml of EtOH and 1.02 g of KOH are added, the mixture is then left at AT for 1 hour, with agitation, and 600 ul of water are added. The mixture is refluxed for 6 hours and the ethanol is then evaporated. The product is taken up with an Et2O/water mixture and then separated by settling out. The aqueous phase is acidified at pH = 2 by adding IN HC1. 890 mg of the expected acid are obtained. NMR: 3.36 ppm: s: 3H; 4.86 ppm: s: 2H; 7.2-7.4 ppm: unresolved peak: 4H; 7.48 ppm: s: 1H; 7.68: s: 1H; 20 8.08 ppm: s: 1H; 13.0-13.8: bs: 1H. Preparation 3a 6-(4-Chlorophenyl)-5-(2, 4-dichlorophenyl)-2- methoxymethylpyridine-3-carboxylic acid. This compound can also be prepared according to the procedure described below. A) Ethyl 4-methoxy-3-oxobutanoate 14 g of sodium hydride are introduced, under nitrogen, into 200 ml of DMF, the mixture is cooled to 0°C and 6 ml of methanol in 100 ml of DMF are added dropwise and the mixture is left, with stirring, at 0°C for 1 hour and then at AT for one hour. 17.32 g of 4-chloro-3-oxobutanoate in 100 ml of DMF are added, at O'°C, and the mixture is left overnight, with stirring. The reaction medium is poured into water at 0°C and the mixture is then extracted with DCM, and washing is carried out 3 times with water and then 3 times with a saturated NaCl solution. The aqueous phase is taken up, acidified to pH > 4, and then extracted with DCM, and washed 3 times with water and then with a saturated NaCl solution. The product is dried and then concentrated to dryness. The product is chromatographed on Celite®, elution being carried out with cyclohexane/ EtOAc (80/20; v/v). 3.90 g of the expected compound are obtained in the form of a liquid. B) Ethyl 3-amino-4-methoxybut-2-enoate The molecular sieve (3 A), 3.9 g of the compound obtained in the previous step and 4 g of freshly sublimated ammonium acetate, in 50 ml of cyclohexane, are placed under nitrogen and heated at 80°C for 1 hour 30 minutes and then overnight at AT. The mixture is filtered and the filtrate is rinsed with CHCI3. 2.4 g of the expected compound are obtained. C) 6-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2- methoxymethylpyridine-3-carboxylic acid ethyl ester 21 4.7 g of the compound of preparation 1, step B are dissolved in 25 ml of n-butanol by heating; 2.29 g of the compound obtained in the previous step in 5 ml of n-butanol are added, followed by 0.25 g of PTSA, and the mixture is refluxed for 19 hours. The reaction medium is triturated in Et2O under cold conditions. Insoluble material is filtered off and the organic phase is concentrated and the product is then chromatographed on silica, elution being carried out with cyclohexane/EtOAc (95/5; v/v). 3.4 g of the expected compound are obtained. G) 6-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2- methoxymethylpyridine-3-carboxylic acid This compound is obtained as described in preparation 3, step C) above. The intermediate compounds of formula (II) in the table below were also prepared according to the procedures described in the preparations above. Preparations R3 Mp°C 4 OMe 214°C 5 Br 214.5°C Preparations R3 Mp°C 4 OMe 214°C 5 1 Br 1 214.5°C EXAMPLE 1: Compound 3 1-(1-(6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2- methylpyridin-3-yl)-4-phenylpiperidin-4-yl)ethanone 62.7 mg of the acid obtained in preparation 1 and 38.6 mg of l-phenyl-l-piperidin-4-ylacetone are dissolved in 2 ml of DCM and 67.5 ml of triethylamine. 22 104 mg of PyBOP are subsequently added, and the reaction is left at AT for 2 hours, with stirring. After evaporation of the solvents, the crude is chromatographed on silica according to the following eluent gradient: pure dichloromethane then dichloromethane/methanol (99/1; v/v), 52 mg of the expected compound are obtained. EXAMPLE 2: Compound 10 6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(methoxy- methyl-N-(2,2,5,5-tetramethyltetrahydrofuran-3- yl)nicotinamide 0.42' g of the acid obtained in preparation 3 is placed in 2 ml of DCM and 0.34 g of (2,2,5,5-tetra- methyltetrahydrofuran-3-yl) amine, 0.30 g of TEA and 0.60 g of PyBOP are added, and the mixture is left overnight, under nitrogen, with stirring. A solution of KHSO4/K2SO4 is added, the mixture is stirred vigorously, and then extraction is carried out with DCM. The organic phase is washed with a saturated NaHCC>3 solution and then water. The product is dried and concentrated and the residue is then chromatographed on silica, elution being carried out with cyclohexane/EtOAc (3/1; v/v) . 0.54 g of the expected compound is obtained. Mp = 67-69°C. The table below illustrates the chemical structures and the physical properties of some examples of compounds according to the invention. In this table, Me, Bt, nPr, tBu and nPn represent, respectively, methyl, ethyl, n-propyl, tert-butyl and n-pentyl groups. 23 24 25 The compounds according to the invention have been the subject of pharmacological trials for determining their cannabxnoid CB1 receptor antagonist effect. The compounds of formula (I) possess a very good affinity in vitro (IC50 between 5 nM and 1000 nM) ) for cannabinoid CBx receptors, under the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 35£, 240-244). The antagonistic nature of the compounds of formula (I) was demonstrated by the results obtained in the adenylate cyclase inhibition models as described in M. Rinaldi-Carmona et al., J. Pharmacol. Exp. Therap., 1996, 218_, 871-878 and M. Bouaboula et al., J. Biol. Chem., 1997, 272, 22330-22339. The compounds according to the invention have been tested in vivo {ex vivo binding) in mice after the intravenous and/or oral administration of a compound of the invention, according to the experimental conditions described by Rinaldi-Carmona et al. (J. Pharmacol. Exp. 26 Therap., 1998, 28£, 644-650). The toxicity of the compounds of formula (I) is compatible with their use as a medicinal product. According to another of its aspects, the present invention relates to the use of a compound of formula (I), or of one of the pharmaceutically acceptable salts, solvates or hydrates thereof, for preparing medicinal products intended to treat or prevent diseases involving cannabinoid CB1 receptors. For example, and in a nonlimiting manner, the compounds of formula (I) are useful as psychotropic medicinal products, in particular for the treatment of psychiatric disorders, including anxiety, depression, mood disorders, insomnia, disorders involving delirium, obsessive disorders, psychoses in general, schizophrenia, attention deficit hyperactivity disorders (ADHD) , in particular in hyperkinetic children (MBD), and also for the treatment of disorders related to the use of psychotropic substances, in particular in the case of substance abuse and/or substance addiction, including alcohol addiction and nicotine addiction. The compounds of formula (I) according to the invention can be used as medicinal products for the treatment of migraine, stress, diseases of psychosomatic origin, panic attacks, epilepsy, locomotor disorders, in particular dyskinesias or Parkinson's disease, shaking and dystonia. The compounds of formula (I) according to the invention can also be used as medicinal products in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementia and Alzheimer's disease, and also in the treatment of attention disorders or vigilance disorders. In addition, the compounds of formula (I) may be useful as neuroprotective agents, in the treatment of ischemia 27 and cranial traumas and the treatment of neurodegenerative diseases: including chorea, Huntington's chorea and Tourrette's syndrome. The compounds of formula (I) according to the invention may be used as medicinal products in the treatment of pain: neuropathic pain, peripheral acute pain, chronic pain of inflammatory origin. The compounds of formula (I) according to the invention may be useful as medicinal products in the treatment of appetite disorders, cravings (for sugars, carbohydrates, drugs, alcohols or any appetizing substance) and/or eating disorders, in particular as anorexigenic agents or for the treatment of obesity or bulimia, and also for the treatment of type II diabetes or non-insulin-dependent diabetes and for the treatment of dyslipidaemias, metabolic syndrome. In addition, the compounds of formula (I) according to the invention may be used as medicinal products in the treatment of gastrointestinal disorders, diarrhoeic disorders, ulcers, vomiting, urinary and bladder disorders, disorders of endocrine origin, cardiovascular disorders, hypotension, haemorrhagic shock, septic shock, chronic liver cirrhosis, asthma, chronic bronchitis and chronic obstructive broncho-pneumopathy, Raynaud's syndrome, glaucoma, fertility disorders, inflammatory phenomena, immune system diseases, in particular autoimmune and neuroinflammatory diseases such as rheumatoid arthritis, reactional arthritis, diseases resulting in demyelinization, multiple sclerosis, infectious and viral diseases such as encephalitis, and cerebral strokes, and also as medicinal products for anticancer chemotherapy and for the treatment of Guillain-Barre syndrome. According to the present invention, the compounds of formula (I) are most particularly useful for the treatment of psychotic disorders, in particular 28 schizophrenia, attention deficit hyperactivity disorders (ADHD), in particular in hyperkinetic children (MBD); for the treatment of appetite disorders and obesity, for the treatment of memory and cognitive disorders; for the treatment of alcohol addiction or nicotine addiction, i.e. for alcohol withdrawal and tobacco withdrawal; for the treatment of dyslipidaemias, metabolic syndrome. According to one of its aspects, the present invention relates to the use of a compound of formula (I) , of the pharmaceutically acceptable salts thereof and of the solvates or hydrates thereof, for the treatment of the disorders and diseases indicated above. The compounds of formula (I) according to the invention can be used in combination with one or more other active principles that are useful for the prevention and/or treatment of the diseases indicated above: by way of example of active principles that may be combined with a compound of formula (I), mention may be made of antipsychotic agents, anxiolytics, agents for improving memory, anti-Parkinson agents, anti- epileptics, anorexigenic agents or other anti-obesity agents, nicotinic agonists, monoamine oxidase inhibitors, analgesics, anti-inflammatories, anti- hypertensives such as: ATi angiotensin II receptor antagonists, converting enzyme inhibitors, calcium antagonists, beta-blockers, anti-diabetic agents, blood lipid-lowering agents, blood cholesterol-lowering agents, PPAR (peroxisome proliferator activated receptor) agonists. The compound according to the invention is generally administered as a dosage unit. The said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient. 29 Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I) or a pharmaceutzcally acceptable salt thereof, or a solvate thereof. The compound of formula (I) above and the pharmaceutically acceptable salts or solvates thereof can be used at daily doses of 0.01 to 100 mg per kg of body weight of the mammal to be treated, preferably at daily doses of 0.02 to 50 mg/kg. In humans, the dose can preferably range from 0.05 to 4000 mg per day, more particularly from 0.1 to 1000 mg per day, depending on the age of the individual to be treated or the type of treatment, namely prophylactic or curative. Although these doses are examples of average situations, there may be particular cases where higher or lower doses are appropriate, such doses also belong to the invention. According to the usual practice, the dose which is suitable for each patient is determined by the physician according to the method of administration and the age, weight and response of the said patient. In the pharmaceutical compositions of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle can be administrated in unit administration form, as a mixture with conventional pharmaceutical supports, to animals and to humans. The suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, topical administration forms, implants, subcutaneous intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms. In the pharmaceutical compositions of the present 30 invention, the active principle is generally formulated in dosage units containing from 0.05 to 1000 mg, advantageously from 0.1 to 500 mg, preferably from 1 to 200 mg, of the said active principle per dosage unit for daily administrations. By way of example, a unit form of administration of a compound according to the invention in the form of a tablet may comprise the following components: Compound according to the invention : 50.0 mg Mannitol : 223.75 mg Sodium croscarmellose : 6.0 mg Corn starch " : 15.0 mg Hydroxypropylmethylcellulose : 2.25 mg Magnesium stearate : 3.0 mg When taken orally, the dose of active principle administered per day can reach 0.01 to 100 mg/kg, taken in one or more doses, preferably 0.02 to 50 mg/kg. There may be specific cases where higher or lower doses are appropriate; such dosages do not depart from the context of the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the method of administration and the weight and the response of the said patient- According to another of its aspects, the present invention also relates to a method of treating the pathologies indicated above, which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt or hydrate or solvate thereof. WO 2005/000817 31 PCT/FR2004/001581 CLAIMS R1 represents hydrogen or a (Ci-C4) alkyl; R2 represents: . a saturated mononitrogenous heterocyclic radical containing from 5 to 7 atoms, the nitrogen atom being substituted with an alkanoyl group; . a group NRioRn; . a nonaromatic C3-C10 carbocyclic radical which is substituted more than 3 times with a (C1-C4)alkyl group; . a nonaromatic C11-C12 carbocyclic radical which is unsubstituted or substituted one or more times with a (C1-C4) alkyl group; . a saturated monooxygenated heterocyclic radical containing from 5 to 7 atoms, which is substituted more than 3 times with a (C1-C4) alkyl group; or R1 and R2, together with the nitrogen atom to which they are attached, constitute a piperidin-1- yl radical disubstituted in the 4-position with a phenyl or benzyl group and with a (C1-C4) alkyl, (C1-C4) alkoxy, cyano, aminocarbonyl, (C1-C4) alkyl- aminocarbonyl, di (C1-C4) alkylaminocarbonyl, (C1-C3) - alkanoyl or (Ci-C3)alkanoylamino group; the phenyl or benzyl groups substituting the piperidin-1-yl 32 radical being unsubstituted or substituted with a halogen atom and/or a methyl and/or trifluoro- methyl group; R3, R4, R5, Re/ R7 and R8 each represent, independently of one another, a hydrogen or halogen atom, or a (Ci-C6) alkyl, (C1-C5) alkoxy or trifluoromethyl group; R9 represents a hydrogen atom, a (C1-C4) alkyl or cyano group or a CH2OH, CH2CN or CH2O (C1-C4) alkyl group; R10 and R11, together with the nitrogen atom to which they are attached, constitute a saturated or unsaturated heterocyclic radical containing from 7 to 10 atoms, possibly containing a second hetero atom chosen from 0 and N, the said radical being unsubstituted or substituted one or more times with a (C1-C4) alkyl, hydroxyl, (C1-C4) alkoxy or methoxy(C1-C2)alkylene group, or substituted with a spirocyclobutane, a spirocyclopentane or a spiro- cyclohexane; or R10 and R11, together with the nitrogen atom to which they are attached, constitute a saturated or unsaturated heterocyclic radical containing 5 or 6 atoms, containing a second nitrogen atom, the said radical being substituted one or more times with a methoxy(C1-C2)alkylene group, or substituted with a spirocyclobutane, a spirocyclopentane or a spirocyclohexane; or R10 and Rn, together with the nitrogen atom to which they are attached, constitute a saturated or unsaturated heterocyclic radical containing 5 or 6 atoms, possibly containing an oxygen atom, the said radical being substituted one or more times with a (C1-C4) alkyl, hydroxyl, (C1-C4) alkoxy or methoxy (C1-C2) alkylene group, or substituted with a spirocyclobutane, a spirocyclopentane or a spiro- 33 cyclohexane; in the form of a base or of an addition salt with an acid, and also in hydrate or solvate form. 2. Compound of formula (I) according to Claim 1, characterized in that: R1 represents hydrogen; R2 represents:* a group NR10Rn; . a nonaromatic C11-C12 carbocyclic radical which is unsubstituted or substituted one or more times with a methyl group; or R1 and R2, together with the nitrogen atom to which they are attached, constitute a piperidin-1- yl radical disubstituted in the 4-position with a phenyl or benzyl group and with a {Ci-C4)alkyl or (C1-C3) alkanoyl group; and/or R3, R4, R5, R6, R7 and Rg each represent, independently of one another, a ■ hydrogen or halogen atom, or a {C1-C6) alkyl, (Ci-C6) alkoxy or trifluoromethyl group; and/or R9 represents a hydrogen atom or a methyl, methoxymethylene or cyano group; R10 and R11, together with the nitrogen atom to which they are attached, constitute a saturated or unsaturated heterocyclic radical containing from 5 to 10 atoms, possibly containing an oxygen atom, the said radical being unsubstituted or substituted one or more times with a methyl group; in the form of a base or of an addition salt with an acid, and also in hydrate or solvate form. 3. Compounds of formula (I) according to Claim 1, characterized in that: R1 represents a hydrogen atom; and R2 represents the 3-amino-2,2,5,5-tetramethyl- tetrahydrofuran group; or R1 and R2, together with the nitrogen atom to which they are attached, represent a 4-acetyl-4- 34 phenylpiperidin-1-yl group; and/or at least one of the substituents R3, R4 and R5 represents a chlorine or bromine atom or a methoxy group; and/or at least one of the substituents R6/ R7 and R8 represents a chlorine or bromine atom; and/or Rg represents a methyl or methoxymethyl group, in the form of a base or of an addition salt with an acid, and also in hydrate or solvate form. 4. Compound of formula (1) according to Claim 1, chosen from: 1- (1-{6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2- methylpyridin-3-yl)-4-phenylpiperidin-4-yl)- ethanone, 6-{4-chlorophenyl)-5-(2,4-dichloro- phenyl) -2-(methoxymethyl-N-(2,2,5,5-tetramethyl- tetrahydrofuran-3-yl)nicotinamide, 5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2- methyl-N-(2,2,5,5-tetramethyltetrahydrofuran-3- yl)pyridine-3-carboxamide, 1-(1- (5-(4-bromophenyl)-6-(2,4-dichlorophenyl)-2- (methylpyridin-3-yl)carbonyl)-4-phenylpiperidin-4- yl)ethanone, 6-(4-bromophenyl)-5-(2,4-dichlorophenyl)-2-methyl- N-(2,2,5,5-tetramethyltetrahydrofuran-3-yl)- nicotinamide, in the form of a base or of an addition salt with an acid, and also in hydrate or solvate form. 5. Process for preparing a compound of formula (I) according to any one of Claims 1 to 4, characterized in that a functional derivative of 5,6-diphenyl-3- pyridinecarboxylic acid, of formula: 35 in which R3/ R4, R5, R6, R7/ R8 and Rg are as defined for (I) in Claim 1, is treated with an amine of formula HNRiR2 (III) in which R1 and R2 are as defined for (I) in Claim 1. 6. Medicinal product, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 4, or an addition salt of this compound with a pharmaceutically acceptable acid, or else a hydrate or a solvate. 7. Pharmaceutical composition, characterized in that it comprises a 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, and also at least one pharmaceutically acceptable excipient. 8. Use of a compound of formula (I) according to any one of Claims 1 to 4, for preparing a medicinal product intended for the treatment of appetite disorders, gastrointestinal disorders, inflammatory phenomena, immune system diseases, psychotic disorders, alcohol addiction or nicotine addiction. The invention relates to 5,6-dipheny3pyridine-3-car- boxamide derivatives of general formula (I), where R1 = H, or (C1-C4) alkyl, R2 = a monoazo saturated heterocycle of 5 to 7 atoms, the nitro- gen atom being substituted with a (C1 -C4)alkanoyl, NR10R11, a non- aromatic (C3-C10) carbocycle more than tri-substituted with (C1-C4) alkyl, a non-aromatic (C11-C12) carbocycle unsubstituted or mono- or poly-substituted with (C1-C4) alkyl, amonooxygenated saturated het- erocycle with 5 to 7 atoms, more than tri-substituted with (C1-C4) alkyl, or R1 and R2, together with the nitrogen atom to which the above are bonded, form a4-dsubstituted piperidin-1-yl group, the salts, sol- vales and hydrates thereof. The invention further relates to a method for production and therapeutic application thereof.

Full Text

WO 2005/000817 1 PCT/FR2004/001581
DIPHENYLPYRIDINE DERIVATIVES, PREPARATION AND
THERAPEUTIC APPLICATION THEREOF
The present invention relates to 5,6-diphenyl-
pyridine-3-carboxamide derivatives, to the preparation
thereof and to the application thereof in therapeutics.
5,6-Diphenyl-2-pyridine derivatives are described
in the international patent application published under
No. WO 92/02513. These compounds are presented as
having antithrombotic, vasodilating and anti-
inflammatory activity.
Inverse agonist or antagonist 2,3-diphenylpyridine
derivatives of cannabinoid CB1 receptors are described
in international patent application WO 2003/082191.
Novel 5,6-diphenyl-3-pyridinecarboxamide
derivatives which possess cannabinoid CB1 receptor
antagonist properties have now been found.
Thus, a subject of the present invention is
compounds of formula:
in which:
R1 represents hydrogen or a (C1-C4) alkyl;
R2 represents:
. a saturated mononitrogenous heterocyclic
radical containing from 5 to 7 atoms, the
nitrogen atom being substituted with a
(C1-C4) alkanoyl group;
. a group NR10Ru;
. a nonaromatic C3-C10 carbocyclic radical
which is substituted more than three times

2
with a (C1-C4) alkyl group;
. a nonaromatic C11-C12 carbocyclic radical
which is unsubstituted or substituted one
or more times with a (C1-C4) alkyl group;
. a saturated monooxygenated heterocyclic
radical containing from 5 to 7 atoms, which
is substituted more than 3 times with a
(C1-C4) alkyl group;
or R1 and R2/ together with the nitrogen atom to
which they are attached, constitute a piperidin-1-
yl radical disubstituted in the 4-position with a
phenyl or benzyl group and with a (C1-C4) alkyl,
(C1-C4) alkoxy, cyano, aminocarbonyl, (C1-C4) alkyl-
aminocarbonyl, di (C1-C4) alkylaminocarbonyl,
(C1-C3) alkanoyl or (C1-C3) alkanoylamino group; the
phenyl or benzyl groups substituting the
piperidin-1-yl radical being unsubstituted or
substituted with a halogen atom and/or a methyl
and/or trifluoromethyl group;
R3, R4/ Rs/ Re/ R7 and Rs each represent,
independently of one another, a hydrogen or
halogen atom, or a (Ci-Ce) alkyl, (Ci-Cg) alkoxy or
trifluoromethyl group;
R9 represents a hydrogen atom, a (C1-C4) alkyl or
cyano group or a CH2OH, CH2CN, or CH2O (C1-C4) alkyl
group;
Rio and Rn, together with the nitrogen atom to
which they are attached, constitute a saturated or
unsaturated heterocyclic radical containing from 7
to 10 atoms, possibly containing a second hetero
atom chosen from 0 and N, the said radical being
unsubstituted or substituted one or more times
with a (C1-C4) alkyl, hydroxyl, (C1-C4) alkoxy or
methoxy (C1-C2) alkylene group, or substituted with a
spirocyclobutane, a spirocyclopentane or a spiro-
cyclohexane;

3
or Rio and RU/ together with the nitrogen atom to
which they are attached, constitute a saturated or
unsaturated heterocyclic radical containing 5 or 6
atoms, containing a second nitrogen atom, the said
radical being substituted one or more times with a
methoxy(C!-C2)alkylene group, or substituted with a
spirocyclobutane, a spirocyclopentane or a
spirocyclohexane;
or Rio and Rn, together with the nitrogen atom to
which they are attached, constitute a saturated or
unsaturated heterocyclic radical containing 5 or
6 atoms, "possibly containing an oxygen atom, the
said radical being substituted one or more times
with a (Ci-C4) alkyl, hydroxyl, (C1-C4) alkoxy or
methoxy (C1-C2) alkylene group, or substituted with a
spirocyclobutane, a spirocyclopentane or a spiro-
cyclohexane;
and also the salts, the sol vat es and the hydrates
thereof.
The compounds of formula (I) may comprise one or
more asymmetric carbon atoms- They may therefore exist
in the form of enantiomers or of diastereoisomers.
These enantiomers and diastereoisomers, and also the
mixtures thereof, including the racemic mixtures, are
part of the invention.
The compounds of formula (I) may exist in the form
of bases or of addition salts with acids. These salts
are advantageously prepared with pharmaceutically
acceptable salts, but the salts of other acids that are
useful, for example, for purifying or isolating the
compounds of formula (I) are also part of the
invention.
Among the compounds of formula (I), the compounds
are distinguished in which:
R1 represents hydrogen or a (C1-C4) alkyl;
R2 represents:

4
. a saturated mononitrogenous heterocyclic
radical containing from 5 to 7 atoms, the
nitrogen atom being substituted with a
(C1-C4) alkanoyl group;
. a group NR10R11;
. a nonaromatic C11-C12 carbocyclic radical
which is unsubstituted or substituted one
or more times with a {C1-C4) alkyl group;
. a saturated monooxygenated heterocyclic
radical containing from 5 to 7 atoms, which
is substituted more than 3 times with a
(C1-C4) alkyl group;
or R1 and R2, together with the nitrogen atom to
which they are attached, constitute a piperidin-1-
yl radical disubstituted in the 4-position with a
phenyl or benzyl group and with a (C1-C4) alkyl or
(C1-C3) alkanoyl group; the phenyl or benzyl groups
substituting the piperidin-1-yl radical being
unsubstituted or substituted with a halogen atom
and/or a methyl group;
R3 / R4, R5 r R6/ R7 and Re each represent,
independently of one another, a hydrogen or
halogen atom, or a (C1-C6) alkyl, (Ci-Ce) alkoxy or
trifluoromethyl group;
R9 represents a hydrogen atom, a (C1-C4) alkyl or
cyano group or a CH2OH or CH2O (C1-C4) alkyl group;
Rio and Rn, together with the nitrogen atom to
which they are attached, constitute a saturated or
unsaturated heterocyclic radical containing from 7
to 10 atoms, possibly containing a second hetero
atom chosen from 0 and N, the said radical being
unsubstituted or substituted one or more times
with a (C1-C4) alkyl, hydroxyl, (C1-C4) alkoxy or
methoxy (Ci-C2)alkylene group, or substituted with a
spirocyclobutane, a spirocyclopentane or a spiro-
cyclohexane;

5
or Rio and Rn, together with the nitrogen atom to
which they are attached, constitute a saturated or
unsaturated heterocyclic radical containing 5 or
6 atoms, containing a second nitrogen atom, the
said radical being substituted one or more times
with a methoxy (Ci-C2) alkylene group, or substituted
with a spirocyclobutane, a spirocyclopentane or a
spirocyclohexane;
or Rio and R11, together with the nitrogen atom to
which they are attached, constitute a saturated or
unsaturated heterocyclic radical containing 5 or
6 atoms, "possibly containing an oxygen atom, the
said radical being substituted one or more times
with a (Ci-C4) alkyl, hydroxyl, (C1-C4) alkoxy or
methoxy (Ci-C2) alkylene group, or substituted with a
spirocyclobutane, a spirocyclopentane or a spiro-
cyclohexane;
and also the salts, the sol vat es and the hydrates
thereof.
The term "alkyl" is intended to mean a linear or
branched radical such as, in particular: methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, tert-butyl,
n-pentyl, isopentyl, n-hexyl or isohexyl, the methyl
group being preferred for a (C1-C4) alkyl, the tert-
butyl, 2-methyl-2-butyl and 3,3-dimethyl-2-butyl groups
being preferred for a (C3-C7) alkyl.
The term "alkoxy" group is intended to mean a
linear or branched radical, the methoxy group being
preferred.
The term "halogen atom" is intended to mean a
fluorine, chlorine, bromine or iodine atom; the
fluorine, chlorine or bromine atom being preferred.
The nonaromatic C3-C12 carbocyclic radicals
comprise monocyclic or polycyclic radicals that are
fused or bridged. The monocyclic radicals include
cycloalkyls, for example cyclopropyl, cyclobutyl,

6
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl;
cyclohexyl and cyclopentyl being preferred. The di- or
tricyclic radicals that are condensed, bridged or spiro
radicals include, for example, norbornyl, bornyl,
isobornyl, noradamantyl, adamantyl, spiro[5.5]undecanyl
and bicyclo[2.2.l]heptanyl radicals; adamantyl being
preferred.
The expression "saturated or unsaturated
heterocyclic radical containing from 5 to 10 atoms,
possibly containing a second hetero atom such as 0 or
N" is intended to mean radicals such as morpholin-4-yl,
piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl,
3,6-dihydropyridin-l-yl or octahydrocyclopenta[c]-
pyrrol-2-yl, the piperidin-1-yl and morpholin-4-yl
radicals being preferred.
The expression "saturated mononitrogenous hetero-
cyclic radical containing from 5 to 7 atoms" is
intended to mean a radical such as piperidin-4-yl or
pyrrolidin-3-yl, the piperadin-4-yl radical being
preferred.
The expression "saturated monooxygenated hetero-
cyclic radical containing from 5 to 7 atoms" is
intended to mean a radical such as tetrahydrofuranyl,
tetrahydro-2tf-pyranyl or oxepanyl; tetrahydrofuranyl
being preferred.
According to the present invention, preference is
given to the compounds of formula (I) in which:
R1 represents hydrogen;
R2 represents: . a group NR10Ru;
. a nonaromatic Cn-Ci2 carbocyclic radical
which is unsubstituted or substituted one
or more times with a methyl group;
or Rx and R2/ together with the nitrogen atom to
which they are attached, constitute a piperidin-1-
yl radical disubstituted in the 4-position with a
phenyl or benzyl group and with a (Ci-C4)alkyl or

7
(Ci-C3) alkanoyl group;
and/or R3, R4, R5, R6, R7 and R8 each represent,
independently of one another, a hydrogen or
halogen atom, or a (Ci-C6) alkyl, (Ci-C6) alkoxy or
trifluoromethyl group;
and/or R9 represents a hydrogen atom or a methyl,
methoxymethylene or cyano group;
Rio and Rn, together with the nitrogen atom to
which they are attached, constitute a saturated or
unsaturated heterocyclic radical containing from 5
to 10 atoms, possibly containing an oxygen atom,
the said radical being unsubstituted or
substituted one or more times with a methyl group;
and also the salts, the solvates and the hydrates
thereof.
Among the compounds which are the subject of the
invention, mention may be made of the preferred
compounds, which are defined by the following values
for the substituents:
R1 represents a hydrogen atom;
and R2 represents the 3-amino-2,2,5,5-tetramethyl-
tetrahydrofuran group;
or R1 and R2, together with the nitrogen atom to
which they are attached, represent a 4-acetyl-4-
phenylpiperidin-1-yl group;
and/or at least one of the substituents R3, R4 and
R5 represents a halogen atom, preferably chlorine
or bromine, or a methoxy group;
and/or at least one of the substituents R6, R7 and
Rs represents a halogen atom, preferably chlorine
or bromine;
and/or R9 represents a methyl or methoxymethyl
group.
Most particularly, the following compounds are
preferred: 1-(1-(6-{4-chlorophenyl)-5-(2,4-dichloro-
phenyl)-2-methylpyridin-3-yl)-4-phenylpiperidin-4-yl)-

8
ethanone, 6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-
(methoxymethyl-N-(2,2,5,5-tetramethyltetrahydrofuran-3-
yUnicotinamide, 5- (4-chlorophenyl) -6- (2, 4-dichloro-
phenyl)-2-methyl-N-(2,2,5,5-tetramethyltetrahydrofuran-
3-yl)pyridine-3-carboxamide, 1-(1-(5-{4-bromophenyl)-6-
(2,4-dichlorophenyl)-2-(methylpyridin-3-yl)carbonyl)-4-
phenylpiperidin-4-yl)ethanone, 6-(4-bromophenyl)-5-
(2,4-dichlorophenyl)-2-methyl-N-(2,2,5,5-tetramethyl-
tetrahydrofuran-3-yl)nicotinamide).
A subject of the present invention is also a
process for preparing the compounds according to the
invention.
This process is characterized in that a functional
derivative of 5,6-diphenyl-2-pyridinecarboxylic acid,
of formula:
in which R3, R4, R5, R6, R7, Re and R9 are as defined for
(I), is treated with an amine of formula HNR1R2 (III) in
which R1 and R2 are as defined for (I) . The compound
thus obtained is optionally converted into one of its
salts or solvates.
As functional derivative of the acid (II), use may
be made of the acid chloride, the anhydride, a mixed
anhydride, a C1-C4 alkyl ester in which the alkyl is
linear or branched, an activated ester, for example the
p-nitrophenyl ester, or the free acid activated at the
right time, for example with N,N-dicyclohexylcarbodi-
imide or with benzotriazol-1-yloxotris(dimethylamino)-
phosphonium hexafluorophosphate (BOP) or benzotriazol-

9
1-yloxotris(pyrrolidino)phosphonium hexafluorophosphate
(PyBOP).
Thus, in the process according to the invention,
pyrazole-3-carboxylic acid chloride, obtained by
reacting thionyl chloride with the acid of formula
(II) , can be reacted with an amine HNRiR2, in an inert
solvent, such as a chlorinated solvent (dichloro-
methane, dichloroethane, chloroform, for example), an
ether (tetrahydrofuran, dioxane, for example) or an
amide (N,N-dimethylformamide, for example), under an
inert atmosphere, at a temperature of between 0°C and
ambient temperature, in the presence of a tertiary amine such
as triethylamine, N-methylmorpholine or pyridine.
A variant consists in preparing the mixed
anhydride of the acid of formula (II) by reacting ethyl
chloroformate with the acid of formula (II) , in the
presence of a base such as triethylamine, and in
reacting it with an amine HNR1R2, in a solvent such as
dichloromethane, under an inert atmosphere, at ambient
temperature, in the presence of a base such as
triethylamine.
The compounds of formula (II) can be prepared by
various processes, according to the value for the
substituent Rg.

10

THF: tetrahydrofuran
LiHMDS: lithium hexamethyldisilazide
PTSA: para-toluenesulphonic acid.
Scheme 1 explains a mode for preparing the

11
compounds of formula (II) in which R9 = (C1-C4) alkyl,
more specifically R9 = Me.
Step al) is carried out in an anhydrous solvent
such as THF; it is initiated at low temperature (-78°C)
and the temperature is then allowed to return to
ambient temperature (AT).
Step bl) is carried out in the presence of acetic
anhydride, at a temperature of between AT and 100°C.
Step cl) is carried out in an alcoholic solvent
such as n-butanol, heating at the reflux of the solvent
for 6 hours in the presence of a catalyst such as para-
toluenesulphonic acid.
In step dl), the ester is hydrolysed by heating in
aqueous basic medium, in a solvent such as ethanol.
SCHEME 2

To prepare a compound of formula (II) in which R9
is a hydrogen atom, the ester of formula (VIII) is
treated with an oxidizing agent such as selenium oxide
in pyridine in aqueous medium, and the diacid formed is

12
then treated with silica under hot conditions.

13

The compounds of formula (II) in which R9
represents a cyano, alkoxymethylene or cyanomethyl
group are prepared from the ester of formula (VIII). In
a first step a3), the group R9 = methyl is substituted
with 1 or 2 bromine atoms by means of the action of
N-bromosuccinimide, under hot conditions, in a solvent
such as CCI4, in the presence of UV radiation, so as to
give a monobrominated derivative (X) and a dibrominated
derivative (XI) .
In step e3) , the monobrominated derivative (X) is
treated with a sodium alkoxide in an alcohol, for
example sodium methoxide in methanol, and then
saponified in basic medium, under hot conditions, to
give the acid of formula (II) in which R9 is the
alkoxymethylene group.
In step f3) , the monobrominated derivative (X) is
treated with tetramethylammonium cyanide in a solvent
such as chloroform, and then saponified under mild
conditions, for example with LiOH in a THF/water
mixture, to give the acid of formula (II) in which Rg is
the cyanomethyl group.
The dibrominated derivative (XI) is treated with
silver nitrate in aqueous THF so as to form the
aldehyde (XII), which is then treated with hydroxyl-
amine hydrochloride in formic acid to give a nit rile
derivative (XIII). The ester (XIII) is treated in basic
medium, under mild conditions, preferably with LiOH, to
give the acid of formula (II) in which R9 is the cyano
group.
To prepare a compound of formula (II) in which R9 =
CH2OH, the monobrominated derivative (X) is treated with
sodium hydroxide, in a THF/water mixture, by refluxing.

14
according to the following scheme.

A compound of formula (II) in which R3 = CH2OCH3
can also be prepared by the method described in
scheme 1 using an appropriate reagent in step cl,
according to the following scheme:

5,6-Diphenyl-3-pyridinecarboxylic acids are
generally known; 6-(4-chlorophenyl)-5-(4-methoxy-
phenyl)-2-methylpyridine-3-carboxylic acid and 5,6-bis-
(4-methoxyphenyl)pyridine-3-carboxylic acid and their

15
ethyl esters are described in international patent
application WO 2002/055502.
The amines HNRiR2 are known or are prepared by
known methods such as those described in Chem. Ber.,
1986, U£, 1413-1423.
The following abbreviations will be used in the
present description:
DCM: dichloromethane
LDA: lithium diisopropylamide
THF: tetrahydrofuran
TFA: trifluoroacetic acid
AIBN: " azobis(isobutyronitrile)
TMSiCl: trimethylchlorosilane
Et2O or ether: ethyl ether
EtOAc: ethyl acetate
AC2O: acetic anhydride
nBuOH: n-butanol
PTSA: para-toluenesulphonic acid
LiHMDS: lithium hexamethyldisilazide
KHSO4/K2SO4: 0.5 mol KHSO4/O.19 mol K2SO4 in 1 litre
of water
TEA: triethylamine
BOP: benzotriazol-1-yloxotris(dimethylamino)
phosphonium hexafluorophosphate
PyBOP: benzotriazol-1-yloxotris(pyrrolidino)
phosphonium hexafluorophosphate
NBS: N-bromosuccinimide
AT: ambient temperature
Mp: melting point.
The compounds according to the invention are
analysed by LC/UV/MS coupling (liquid chromatography/UV
detection/mass spectrometry). The molecular peak (M+)
and the retention time (t) in minutes are measured.
A Symmetry C18 column, sold by Waters, of 2.1 x
50 mm, 3.5 urn, is used at ambient temperature, with a
flow rate of 0.4 ml/minute.

16
The eluent has the following composition:
solvent A: 0.005% of trifluoroacetic acid (TFA) in
water
solvent B: 0.005% of TFA in acetonitrile.
Gradient: The percentage of solvent B ranges from
0 to 90% over 10 minutes, with a plateau at 90% of B
for 5 minutes.
The UV detection is carried out at 210 nm ± 8 nm
and the detection of mass is carried out in positive
ionization mode at atmospheric pressure.
The nuclear magnetic resonance (NMR) spectra are
recorded at 200 MHz in d6-DMSO. For analysis of the
spectra, the following abbreviations are used: s :
singlet; d : doublet; bs : broad singlet; dd : doublet
of doublets; mt : multiplet.
Preparation 1
5-(2,4-Dichlorophenyl)-6-(4-chlorophenyl)-
2-methyl-pyridine-3-carboxylic acid.
A) 1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)ethanone
32 g of LiHMDS are placed in 245 ml of THF at 0°C,
and 40 g of (4-chlorophenyl)((trimethylsilyl)oxy)aceto-
nitrile are added slowly at -78°C, followed by 32.64 g
of 2,4-dichloro-l-(chloromethyl)benzene. The
temperature is allowed to return to AT overnight, and
the reaction is then hydrolysed with 170 ml of a 3N HC1
solution, with gases being trapped in a solution of KOH
(4N) . After separation by settling out, the organic
phase is evaporated, then taken up in DCM and agitated
for 1 hour with 170 ml of NaOH (2N) . The DCM is
evaporated off and the expected compound is then
crystallized from pentane. 38.6 g are obtained,
Mp = 119°C.
B) l-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)propen-2-
en-l-one.
10 g of the compound from the preceding step,
17 ml of N,N,N,N-tetramethylmethanediamine and 17 ml of

17
acetic anhydride are mixed at AT; the mixture is heated
at 90°C for 3 hours and is then allowed to return to
AT. The mixture is poured into crushed ice and then
filtered. The solid is dried under vacuum. 10 g of the
expected compound are obtained, Mp = 8 9°C.
C) 5-{2,4-Dichlorophenyl)-6-(4-chlorophenyl)-2-
methylpyridine-3-carboxylic acid ethyl ester.
A mixture containing 7 g of the compound from the
preceding step, 2.62 g of ethyl 3-amino-2-butenoate and
140 mg of para-toluenesulphonic acid is prepared in
60 ml of n-butanol and is then heated for 24 hours at
the reflux of the solvent. Three quarters of the
solvent is evaporated off and then 80 ml of pentane are
added at 0°C. The precipitate formed is filtered off
and the filtrate is concentrated. The residue is
chromatographed on silica, elution being carried out
with a cyclohexane/EtOAc (90/10; v/v) mixture. 7 g of
the expected compound are obtained, Mp = 114°C.
D) 5-(2,4-Dichlorophenyl)-6-(4-chlorophenyl)-
2-methylpyridine-3-carboxylic acid.
6 g of the ester obtained in the preceding step is
placed in 300 ml of EtOH and 8 g of potassium hydroxide
are added. After agitation for a few minutes, 5 ml of
water are added and the mixture is refluxed for 19
hours. The reaction medium is concentrated and the
product is taken up with Et2O and water. The aqueous
phase is acidified to pH = 1 with 10% HC1 and is then
extracted with DCM and dried over Na2SO4. After washing
with heptane, 5.4 g of the expected compound are
obtained.
NMR: 2.83 ppm: s: 3H; 7.2-7.6 ppm: unresolved
peak: 5H; 7.68 ppm: s: 1H; 8.11 ppm: s: 1H; 13.2-
13.7 ppm: bs: 1H.
Preparation 2
6-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)pyridine-
3-carboxylic acid

18
A) 6-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)pyridine-
2,3-dicarboxylic acid
2 g of the acid obtained in Preparation 1 are
placed in 7.2 ml of pyridine and 0.8 ml of water and
1.44 g of selenium dioxide are added, and the mixture
is then refluxed for 3 days. The solution obtained is
filtered and then washed with acetic acid. After
evaporation of the solvents, crushed ice is added and
agitation is maintained for 2 hours. The solid formed
is filtered off, washed with ether and then dried in an
oven. The filtrate is concentrated and then filtered
through silica, elution being carried out with DCM. The
expected product is reacted as it is in the following
step.
B) 6- (4-Chlorophenyl)-5-(2,4-dichlorophenyl)pyridine-
3-carboxylic acid
The product obtained in the preceding step is
solubilized in the minimum amount of DCM and
impregnated onto 25 g of silica. After evaporation of
the solvent, the silica is heated at 120°C for 8 hours.
The product formed is extracted with DCM + EtOH and
then pure EtOH. After evaporation of the solvents,
chromatography is performed on silica, elution being
carried out with CHC13 and then CHCl3/MeOH/AcOH
(95/3/1.5; v/v/v). 544 mg of the expected compound are
obtained.
NMR: 5.76 ppm: s: 1H; 7.2-7.6 ppm: unresolved
peak: 5H; 7.69 ppm: s: 1H; 8.19 ppm: s: 1H; 9.22 ppm:
s: 1H; 13.2-13.9 ppm: bs: 1H.
Preparation 3
6-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2-
methoxymethylpyridine-3-carboxylic acid
A) 2-Bromomethyl-6-(4-chlorophenyl)-5-(2,4-dichloro-
phenyl) pyridine-3-carboxylic acid ethyl ester
3.8 g of ester obtained in Preparation 1, step C,
are placed in 39 ml of CC14 with 7.07 g of NBS, and

19
10 mg of AIBN are added. The mixture is refluxed for 24
hours and then the heating is maintained for 8 hours
with UV irradiation. After cooling, the reaction medium
is filtered and the filtrate is chromatographed on
silica, elution being carried out with DCM; 3.1 g of
2,2-dibromomethyl-6-(4-chlorophenyl)-5-(2,4-dichloro-
phenyl)pyridine-3-carboxylic acid ethyl ester and 1 g
of 2-bromomethyl-6-(4-chlorophenyl)-5-(2,4-dichloro-
phenyl)pyridine-3-carboxylic acid ethyl ester are
obtained.
B) 6-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2-
methoxymethylpyridine-3-carboxylic acid ethyl ester
1 g of the monobrominated compound obtained in the
preceding step is placed in 30 ml of MeOH, and then
0.13 g of sodium methanolate is added and the mixture
is refluxed for 24 hours. The reaction medium is
hydrolysed with a 10% HC1 solution, and then the
solvent is evaporated off and the product is taken up
with EtOAc and washed with water. After drying over
MgSO4, the product is concentrated and then
chromatographed on silica, elution being carried out
with a cyclohexane/EtOAc (90/10; v/v) mixture. 840 mg
of the expected ester are obtained.
C) 6-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2-
methoxymethylpyridine-3-carboxylic acid
800 mg of the ester obtained in the preceding step
are placed in 37 ml of EtOH and 1.02 g of KOH are
added, the mixture is then left at AT for 1 hour, with
agitation, and 600 ul of water are added. The mixture
is refluxed for 6 hours and the ethanol is then
evaporated. The product is taken up with an Et2O/water
mixture and then separated by settling out. The aqueous
phase is acidified at pH = 2 by adding IN HC1. 890 mg
of the expected acid are obtained.
NMR: 3.36 ppm: s: 3H; 4.86 ppm: s: 2H; 7.2-7.4
ppm: unresolved peak: 4H; 7.48 ppm: s: 1H; 7.68: s: 1H;

20
8.08 ppm: s: 1H; 13.0-13.8: bs: 1H.
Preparation 3a
6-(4-Chlorophenyl)-5-(2, 4-dichlorophenyl)-2-
methoxymethylpyridine-3-carboxylic acid.
This compound can also be prepared according to
the procedure described below.
A) Ethyl 4-methoxy-3-oxobutanoate
14 g of sodium hydride are introduced, under
nitrogen, into 200 ml of DMF, the mixture is cooled to
0°C and 6 ml of methanol in 100 ml of DMF are added
dropwise and the mixture is left, with stirring, at 0°C
for 1 hour and then at AT for one hour. 17.32 g of
4-chloro-3-oxobutanoate in 100 ml of DMF are added, at
O'°C, and the mixture is left overnight, with stirring.
The reaction medium is poured into water at 0°C and the
mixture is then extracted with DCM, and washing is
carried out 3 times with water and then 3 times with a
saturated NaCl solution. The aqueous phase is taken up,
acidified to pH > 4, and then extracted with DCM, and
washed 3 times with water and then with a saturated
NaCl solution. The product is dried and then
concentrated to dryness. The product is chromatographed
on Celite®, elution being carried out with cyclohexane/
EtOAc (80/20; v/v). 3.90 g of the expected compound are
obtained in the form of a liquid.
B) Ethyl 3-amino-4-methoxybut-2-enoate
The molecular sieve (3 A), 3.9 g of the compound
obtained in the previous step and 4 g of freshly
sublimated ammonium acetate, in 50 ml of cyclohexane,
are placed under nitrogen and heated at 80°C for 1 hour
30 minutes and then overnight at AT. The mixture is
filtered and the filtrate is rinsed with CHCI3. 2.4 g of
the expected compound are obtained.
C) 6-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2-
methoxymethylpyridine-3-carboxylic acid ethyl
ester

21
4.7 g of the compound of preparation 1, step B are
dissolved in 25 ml of n-butanol by heating; 2.29 g of
the compound obtained in the previous step in 5 ml of
n-butanol are added, followed by 0.25 g of PTSA, and
the mixture is refluxed for 19 hours. The reaction
medium is triturated in Et2O under cold conditions.
Insoluble material is filtered off and the organic
phase is concentrated and the product is then
chromatographed on silica, elution being carried out
with cyclohexane/EtOAc (95/5; v/v). 3.4 g of the
expected compound are obtained.
G) 6-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2-
methoxymethylpyridine-3-carboxylic acid
This compound is obtained as described in
preparation 3, step C) above.
The intermediate compounds of formula (II) in the
table below were also prepared according to the
procedures described in the preparations above.
Preparations R3 Mp°C
4 OMe 214°C
5 Br 214.5°C

Preparations R3 Mp°C
4 OMe 214°C
5 1 Br 1 214.5°C
EXAMPLE 1: Compound 3
1-(1-(6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-
methylpyridin-3-yl)-4-phenylpiperidin-4-yl)ethanone
62.7 mg of the acid obtained in preparation 1
and 38.6 mg of l-phenyl-l-piperidin-4-ylacetone are
dissolved in 2 ml of DCM and 67.5 ml of triethylamine.

22
104 mg of PyBOP are subsequently added, and the
reaction is left at AT for 2 hours, with stirring.
After evaporation of the solvents, the crude is
chromatographed on silica according to the following
eluent gradient: pure dichloromethane then
dichloromethane/methanol (99/1; v/v), 52 mg of the
expected compound are obtained.
EXAMPLE 2: Compound 10
6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(methoxy-
methyl-N-(2,2,5,5-tetramethyltetrahydrofuran-3-
yl)nicotinamide
0.42' g of the acid obtained in preparation 3
is placed in 2 ml of DCM and 0.34 g of (2,2,5,5-tetra-
methyltetrahydrofuran-3-yl) amine, 0.30 g of TEA and
0.60 g of PyBOP are added, and the mixture is left
overnight, under nitrogen, with stirring. A solution of
KHSO4/K2SO4 is added, the mixture is stirred vigorously,
and then extraction is carried out with DCM. The
organic phase is washed with a saturated NaHCC>3 solution
and then water. The product is dried and concentrated
and the residue is then chromatographed on silica,
elution being carried out with cyclohexane/EtOAc (3/1;
v/v) . 0.54 g of the expected compound is obtained.
Mp = 67-69°C.
The table below illustrates the chemical
structures and the physical properties of some examples
of compounds according to the invention.
In this table, Me, Bt, nPr, tBu and nPn represent,
respectively, methyl, ethyl, n-propyl, tert-butyl and
n-pentyl groups.

23

24

25

The compounds according to the invention have been
the subject of pharmacological trials for determining
their cannabxnoid CB1 receptor antagonist effect.
The compounds of formula (I) possess a very good
affinity in vitro (IC50 between 5 nM and 1000 nM) ) for
cannabinoid CBx receptors, under the experimental
conditions described by M. Rinaldi-Carmona et al. (FEBS
Letters, 1994, 35£, 240-244).
The antagonistic nature of the compounds of
formula (I) was demonstrated by the results obtained in
the adenylate cyclase inhibition models as described in
M. Rinaldi-Carmona et al., J. Pharmacol. Exp. Therap.,
1996, 218_, 871-878 and M. Bouaboula et al., J. Biol.
Chem., 1997, 272, 22330-22339.
The compounds according to the invention have been
tested in vivo {ex vivo binding) in mice after the
intravenous and/or oral administration of a compound of
the invention, according to the experimental conditions
described by Rinaldi-Carmona et al. (J. Pharmacol. Exp.

26
Therap., 1998, 28£, 644-650).
The toxicity of the compounds of formula (I) is
compatible with their use as a medicinal product.
According to another of its aspects, the present
invention relates to the use of a compound of formula
(I), or of one of the pharmaceutically acceptable
salts, solvates or hydrates thereof, for preparing
medicinal products intended to treat or prevent
diseases involving cannabinoid CB1 receptors.
For example, and in a nonlimiting manner, the
compounds of formula (I) are useful as psychotropic
medicinal products, in particular for the treatment of
psychiatric disorders, including anxiety, depression,
mood disorders, insomnia, disorders involving delirium,
obsessive disorders, psychoses in general,
schizophrenia, attention deficit hyperactivity
disorders (ADHD) , in particular in hyperkinetic
children (MBD), and also for the treatment of disorders
related to the use of psychotropic substances, in
particular in the case of substance abuse and/or
substance addiction, including alcohol addiction and
nicotine addiction.
The compounds of formula (I) according to the
invention can be used as medicinal products for the
treatment of migraine, stress, diseases of
psychosomatic origin, panic attacks, epilepsy,
locomotor disorders, in particular dyskinesias or
Parkinson's disease, shaking and dystonia.
The compounds of formula (I) according to the
invention can also be used as medicinal products in the
treatment of memory disorders, cognitive disorders, in
particular in the treatment of senile dementia and
Alzheimer's disease, and also in the treatment of
attention disorders or vigilance disorders. In
addition, the compounds of formula (I) may be useful as
neuroprotective agents, in the treatment of ischemia

27
and cranial traumas and the treatment of
neurodegenerative diseases: including chorea,
Huntington's chorea and Tourrette's syndrome.
The compounds of formula (I) according to the
invention may be used as medicinal products in the
treatment of pain: neuropathic pain, peripheral acute
pain, chronic pain of inflammatory origin.
The compounds of formula (I) according to the
invention may be useful as medicinal products in the
treatment of appetite disorders, cravings (for sugars,
carbohydrates, drugs, alcohols or any appetizing
substance) and/or eating disorders, in particular as
anorexigenic agents or for the treatment of obesity or
bulimia, and also for the treatment of type II diabetes
or non-insulin-dependent diabetes and for the treatment
of dyslipidaemias, metabolic syndrome. In addition, the
compounds of formula (I) according to the invention may
be used as medicinal products in the treatment of
gastrointestinal disorders, diarrhoeic disorders,
ulcers, vomiting, urinary and bladder disorders,
disorders of endocrine origin, cardiovascular
disorders, hypotension, haemorrhagic shock, septic
shock, chronic liver cirrhosis, asthma, chronic
bronchitis and chronic obstructive broncho-pneumopathy,
Raynaud's syndrome, glaucoma, fertility disorders,
inflammatory phenomena, immune system diseases, in
particular autoimmune and neuroinflammatory diseases
such as rheumatoid arthritis, reactional arthritis,
diseases resulting in demyelinization, multiple
sclerosis, infectious and viral diseases such as
encephalitis, and cerebral strokes, and also as
medicinal products for anticancer chemotherapy and for
the treatment of Guillain-Barre syndrome.
According to the present invention, the compounds
of formula (I) are most particularly useful for the
treatment of psychotic disorders, in particular

28
schizophrenia, attention deficit hyperactivity
disorders (ADHD), in particular in hyperkinetic
children (MBD); for the treatment of appetite disorders
and obesity, for the treatment of memory and cognitive
disorders; for the treatment of alcohol addiction or
nicotine addiction, i.e. for alcohol withdrawal and
tobacco withdrawal; for the treatment of
dyslipidaemias, metabolic syndrome.
According to one of its aspects, the present
invention relates to the use of a compound of formula
(I) , of the pharmaceutically acceptable salts thereof
and of the solvates or hydrates thereof, for the
treatment of the disorders and diseases indicated
above.
The compounds of formula (I) according to the
invention can be used in combination with one or more
other active principles that are useful for the
prevention and/or treatment of the diseases indicated
above: by way of example of active principles that may
be combined with a compound of formula (I), mention may
be made of antipsychotic agents, anxiolytics, agents
for improving memory, anti-Parkinson agents, anti-
epileptics, anorexigenic agents or other anti-obesity
agents, nicotinic agonists, monoamine oxidase
inhibitors, analgesics, anti-inflammatories, anti-
hypertensives such as: ATi angiotensin II receptor
antagonists, converting enzyme inhibitors, calcium
antagonists, beta-blockers, anti-diabetic agents, blood
lipid-lowering agents, blood cholesterol-lowering
agents, PPAR (peroxisome proliferator activated
receptor) agonists.
The compound according to the invention is
generally administered as a dosage unit.
The said dosage units are preferably formulated in
pharmaceutical compositions in which the active
principle is mixed with a pharmaceutical excipient.

29
Thus, according to another of its aspects, the
present invention relates to pharmaceutical
compositions containing, as active principle, a
compound of formula (I) or a pharmaceutzcally
acceptable salt thereof, or a solvate thereof.
The compound of formula (I) above and the
pharmaceutically acceptable salts or solvates thereof
can be used at daily doses of 0.01 to 100 mg per kg of
body weight of the mammal to be treated, preferably at
daily doses of 0.02 to 50 mg/kg. In humans, the dose
can preferably range from 0.05 to 4000 mg per day, more
particularly from 0.1 to 1000 mg per day, depending on
the age of the individual to be treated or the type of
treatment, namely prophylactic or curative. Although
these doses are examples of average situations, there
may be particular cases where higher or lower doses are
appropriate, such doses also belong to the invention.
According to the usual practice, the dose which is
suitable for each patient is determined by the
physician according to the method of administration and
the age, weight and response of the said patient.
In the pharmaceutical compositions of the present
invention for oral, sublingual, inhaled, subcutaneous,
intramuscular, intravenous, transdermal, local or
rectal administration, the active principle can be
administrated in unit administration form, as a mixture
with conventional pharmaceutical supports, to animals
and to humans. The suitable unit administration forms
comprise oral-route forms such as tablets, gel
capsules, powders, granules and oral solutions or
suspensions, sublingual and buccal administration
forms, aerosols, topical administration forms,
implants, subcutaneous intramuscular, intravenous,
intranasal or intraocular administration forms and
rectal administration forms.
In the pharmaceutical compositions of the present

30
invention, the active principle is generally formulated
in dosage units containing from 0.05 to 1000 mg,
advantageously from 0.1 to 500 mg, preferably from 1 to
200 mg, of the said active principle per dosage unit
for daily administrations.
By way of example, a unit form of administration
of a compound according to the invention in the form of
a tablet may comprise the following components:
Compound according to the invention : 50.0 mg
Mannitol : 223.75 mg
Sodium croscarmellose : 6.0 mg
Corn starch " : 15.0 mg
Hydroxypropylmethylcellulose : 2.25 mg
Magnesium stearate : 3.0 mg
When taken orally, the dose of active principle
administered per day can reach 0.01 to 100 mg/kg, taken
in one or more doses, preferably 0.02 to 50 mg/kg.
There may be specific cases where higher or lower
doses are appropriate; such dosages do not depart from
the context of the invention. According to the usual
practice, the dosage appropriate to each patient is
determined by the physician according to the method of
administration and the weight and the response of the
said patient-
According to another of its aspects, the present
invention also relates to a method of treating the
pathologies indicated above, which comprises the
administration, to a patient, of an effective dose of a
compound according to the invention, or a
pharmaceutically acceptable salt or hydrate or solvate
thereof.

WO 2005/000817 31 PCT/FR2004/001581
CLAIMS

R1 represents hydrogen or a (Ci-C4) alkyl;
R2 represents:
. a saturated mononitrogenous heterocyclic
radical containing from 5 to 7 atoms, the
nitrogen atom being substituted with an
alkanoyl group;
. a group NRioRn;
. a nonaromatic C3-C10 carbocyclic radical
which is substituted more than 3 times with
a (C1-C4)alkyl group;
. a nonaromatic C11-C12 carbocyclic radical
which is unsubstituted or substituted one
or more times with a (C1-C4) alkyl group;
. a saturated monooxygenated heterocyclic
radical containing from 5 to 7 atoms, which
is substituted more than 3 times with a
(C1-C4) alkyl group;
or R1 and R2, together with the nitrogen atom to
which they are attached, constitute a piperidin-1-
yl radical disubstituted in the 4-position with a
phenyl or benzyl group and with a (C1-C4) alkyl,
(C1-C4) alkoxy, cyano, aminocarbonyl, (C1-C4) alkyl-
aminocarbonyl, di (C1-C4) alkylaminocarbonyl, (C1-C3) -
alkanoyl or (Ci-C3)alkanoylamino group; the phenyl
or benzyl groups substituting the piperidin-1-yl

32
radical being unsubstituted or substituted with a
halogen atom and/or a methyl and/or trifluoro-
methyl group;
R3, R4, R5, Re/ R7 and R8 each represent,
independently of one another, a hydrogen or
halogen atom, or a (Ci-C6) alkyl, (C1-C5) alkoxy or
trifluoromethyl group;
R9 represents a hydrogen atom, a (C1-C4) alkyl or
cyano group or a CH2OH, CH2CN or CH2O (C1-C4) alkyl
group;
R10 and R11, together with the nitrogen atom to
which they are attached, constitute a saturated or
unsaturated heterocyclic radical containing from 7
to 10 atoms, possibly containing a second hetero
atom chosen from 0 and N, the said radical being
unsubstituted or substituted one or more times
with a (C1-C4) alkyl, hydroxyl, (C1-C4) alkoxy or
methoxy(C1-C2)alkylene group, or substituted with a
spirocyclobutane, a spirocyclopentane or a spiro-
cyclohexane;
or R10 and R11, together with the nitrogen atom to
which they are attached, constitute a saturated or
unsaturated heterocyclic radical containing 5 or 6
atoms, containing a second nitrogen atom, the said
radical being substituted one or more times with a
methoxy(C1-C2)alkylene group, or substituted with a
spirocyclobutane, a spirocyclopentane or a
spirocyclohexane;
or R10 and Rn, together with the nitrogen atom to
which they are attached, constitute a saturated or
unsaturated heterocyclic radical containing 5 or
6 atoms, possibly containing an oxygen atom, the
said radical being substituted one or more times
with a (C1-C4) alkyl, hydroxyl, (C1-C4) alkoxy or
methoxy (C1-C2) alkylene group, or substituted with a
spirocyclobutane, a spirocyclopentane or a spiro-

33
cyclohexane;
in the form of a base or of an addition salt with an
acid, and also in hydrate or solvate form.
2. Compound of formula (I) according to Claim 1,
characterized in that:
R1 represents hydrogen;
R2 represents:* a group NR10Rn;
. a nonaromatic C11-C12 carbocyclic radical
which is unsubstituted or substituted one
or more times with a methyl group;
or R1 and R2, together with the nitrogen atom to
which they are attached, constitute a piperidin-1-
yl radical disubstituted in the 4-position with a
phenyl or benzyl group and with a {Ci-C4)alkyl or
(C1-C3) alkanoyl group;
and/or R3, R4, R5, R6, R7 and Rg each represent,
independently of one another, a ■ hydrogen or
halogen atom, or a {C1-C6) alkyl, (Ci-C6) alkoxy or
trifluoromethyl group;
and/or R9 represents a hydrogen atom or a methyl,
methoxymethylene or cyano group;
R10 and R11, together with the nitrogen atom to
which they are attached, constitute a saturated or
unsaturated heterocyclic radical containing from 5
to 10 atoms, possibly containing an oxygen atom,
the said radical being unsubstituted or
substituted one or more times with a methyl group;
in the form of a base or of an addition salt with an
acid, and also in hydrate or solvate form.
3. Compounds of formula (I) according to Claim 1,
characterized in that:
R1 represents a hydrogen atom;
and R2 represents the 3-amino-2,2,5,5-tetramethyl-
tetrahydrofuran group;
or R1 and R2, together with the nitrogen atom to
which they are attached, represent a 4-acetyl-4-

34
phenylpiperidin-1-yl group;
and/or at least one of the substituents R3, R4 and
R5 represents a chlorine or bromine atom or a
methoxy group;
and/or at least one of the substituents R6/ R7 and
R8 represents a chlorine or bromine atom;
and/or Rg represents a methyl or methoxymethyl
group,
in the form of a base or of an addition salt with an
acid, and also in hydrate or solvate form.
4. Compound of formula (1) according to Claim 1,
chosen from:
1- (1-{6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-
methylpyridin-3-yl)-4-phenylpiperidin-4-yl)-
ethanone, 6-{4-chlorophenyl)-5-(2,4-dichloro-
phenyl) -2-(methoxymethyl-N-(2,2,5,5-tetramethyl-
tetrahydrofuran-3-yl)nicotinamide,
5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-
methyl-N-(2,2,5,5-tetramethyltetrahydrofuran-3-
yl)pyridine-3-carboxamide,
1-(1- (5-(4-bromophenyl)-6-(2,4-dichlorophenyl)-2-
(methylpyridin-3-yl)carbonyl)-4-phenylpiperidin-4-
yl)ethanone,
6-(4-bromophenyl)-5-(2,4-dichlorophenyl)-2-methyl-
N-(2,2,5,5-tetramethyltetrahydrofuran-3-yl)-
nicotinamide,
in the form of a base or of an addition salt with an
acid, and also in hydrate or solvate form.
5. Process for preparing a compound of formula (I)
according to any one of Claims 1 to 4, characterized in
that a functional derivative of 5,6-diphenyl-3-
pyridinecarboxylic acid, of formula:

35

in which R3/ R4, R5, R6, R7/ R8 and Rg are as defined for
(I) in Claim 1, is treated with an amine of formula
HNRiR2 (III) in which R1 and R2 are as defined for (I) in
Claim 1.
6. Medicinal product, characterized in that it
comprises a compound of formula (I) according to any
one of Claims 1 to 4, or an addition salt of this
compound with a pharmaceutically acceptable acid, or
else a hydrate or a solvate.
7. Pharmaceutical composition, characterized in that
it comprises a 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, and also
at least one pharmaceutically acceptable excipient.
8. Use of a compound of formula (I) according to any
one of Claims 1 to 4, for preparing a medicinal product
intended for the treatment of appetite disorders,
gastrointestinal disorders, inflammatory phenomena,
immune system diseases, psychotic disorders, alcohol
addiction or nicotine addiction.

The invention relates to 5,6-dipheny3pyridine-3-car-
boxamide derivatives of general formula (I), where R1 = H, or (C1-C4)
alkyl, R2 = a monoazo saturated heterocycle of 5 to 7 atoms, the nitro-
gen atom being substituted with a (C1 -C4)alkanoyl, NR10R11, a non-
aromatic (C3-C10) carbocycle more than tri-substituted with (C1-C4)
alkyl, a non-aromatic (C11-C12) carbocycle unsubstituted or mono- or
poly-substituted with (C1-C4) alkyl, amonooxygenated saturated het-
erocycle with 5 to 7 atoms, more than tri-substituted with (C1-C4)
alkyl, or R1 and R2, together with the nitrogen atom to which the above
are bonded, form a4-dsubstituted piperidin-1-yl group, the salts, sol-
vales and hydrates thereof. The invention further relates to a method
for production and therapeutic application thereof.

Documents:

02712-kolnp-2005-abstract.pdf

02712-kolnp-2005-claims.pdf

02712-kolnp-2005-description complete.pdf

02712-kolnp-2005-form 1.pdf

02712-kolnp-2005-form 3.pdf

02712-kolnp-2005-form 5.pdf

02712-kolnp-2005-international publication.pdf

2712-kolnp-2005-abstract.pdf

2712-kolnp-2005-assignment.pdf

2712-kolnp-2005-cancelled docoment.pdf

2712-kolnp-2005-claims.pdf

2712-kolnp-2005-description complate.pdf

2712-kolnp-2005-form 1.pdf

2712-kolnp-2005-form 3.pdf

2712-kolnp-2005-granted-abstract.pdf

2712-kolnp-2005-granted-assignment.pdf

2712-kolnp-2005-granted-claims.pdf

2712-kolnp-2005-granted-correspondence.pdf

2712-kolnp-2005-granted-description (complete).pdf

2712-kolnp-2005-granted-examination report.pdf

2712-kolnp-2005-granted-form 1.pdf

2712-kolnp-2005-granted-form 18.pdf

2712-kolnp-2005-granted-form 3.pdf

2712-kolnp-2005-granted-form 5.pdf

2712-kolnp-2005-granted-gpa.pdf

2712-kolnp-2005-granted-reply to examination report.pdf

2712-kolnp-2005-granted-specification.pdf

2712-kolnp-2005-granted-translated copy of priority document.pdf

2712-kolnp-2005-others.pdf

2712-kolnp-2005-petition under rule 137.pdf

2712-kolnp-2005-reply to examination report.pdf

abstract-02712-kolnp-2005.jpg

« Previous Patent

Next Patent »

Patent Number

237908

Indian Patent Application Number

2712/KOLNP/2005

PG Journal Number

03/2010

Publication Date

15-Jan-2010

Grant Date

12-Jan-2010

Date of Filing

26-Dec-2005

Name of Patentee

SANOFI-AVENTIS

Applicant Address

174, AVENUE DE FRANCE, F-75013, PARIS

Inventors:

#	Inventor's Name	Inventor's Address
1	HORTALA LAURENT	2 RUE DE L'HOTEL DE VILLE, APPT.21, F-34830 JOCOU
2	BARTH FRANCIS	65, RUE JACQUES BREL, F-34070 MONTPELLIER
3	RINALDI-CARMONA MURIELLE	2 RUE DES FONTARDIES, F-34680, SAINT GEORGES D'ORQUES

PCT International Classification Number

C07D 40/12

PCT International Application Number

PCT/FR2004/001581

PCT International Filing date

2004-06-24

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	03/07757	2003-06-26	France