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  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
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  • A61P19/00—Drugs for skeletal disorders
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Definitions

• the present application relates to new pyrimidinone derivatives. These products have good affinity for certain cannabinoid receptor subtypes, particularly CB2 receptors. They are particularly useful for treating disease states and diseases in which one or more cannabinoid receptors are involved.
• the invention also relates to pharmaceutical compositions containing said products and their use for the preparation of a medicament.
• Cannabinoids are psychoactive components found in Indian cannabis (Cannabis sativa) including nearly 6 different molecules, the most represented being delta-9-tetrahydrocannabinol.
• Indian cannabis Crobis sativa
• the knowledge of the therapeutic activity of cannabis goes back to the ancient Chinese dynasties in which, 5,000 years ago, cannabis was used for the treatment of asthma, migraines and gynecological disorders. It was in 1850 that cannabis extracts were recognized and included in the American pharmacopoeia.
• Cannabinoids are known to have different effects on many functions and organs, the most important being the central nervous system and the cardiovascular system. These effects include impaired memory, euphoria, and sedation. Cannabinoids also increase the pulse rate and change the systemic blood pressure. Peripheral effects related to bronchial constriction, immunomodulation and inflammation were also observed. More recently, cannabinoids have been shown to suppress cellular and humoral immune responses and have anti-inflammatory properties. Despite all these properties, the therapeutic use of cannabinoids is controversial for its psychoactive effects (cause of dependence) but also for its multiple side effects not yet fully characterized.
• CB1 and CB2 Two cannabinoid receptors have been identified and cloned, CB1 and CB2.
• CB1 is expressed predominantly in the central nervous system while CB2 is expressed in peripheral tissues, mainly in the immune system.
• These 2 receptors are members of the family of G-protein coupled receptors and their inhibition is related to the activity of adenylate cyclase.
• CB2 modulators offer a unique approach to pharmacotherapy against immune disorders, inflammation, osteoporosis, renal ischemia and other disease states.
• cannabinoid analogs having a high affinity for the CB2 receptor.
• Cannabinoid analogs that specifically modulate the CB2 receptor directly or indirectly can produce clinically useful effects without affecting the central nervous system thereby providing a rational therapeutic approach for a wide variety of disease states.
• novel compounds of this invention modulate CB2 activity and are therefore useful for the treatment and prevention of disease states and diseases associated with cannabinoid receptor activity such as, but not limited to, proliferative disorders. such as cancer, immune disorders, inflammation, pain, osteoporosis, epilepsy, nausea associated with chemotherapy, fibrosis, gastrointestinal disorders, neurodegenerative diseases including multiple sclerosis and dyskinesia, Parkinson's disease, Huntington's chorea, Alzheimer's disease but also to prevent or cure diseases associated with motor function such as Tourette's syndrome, to provide neuroprotection.
• proliferative disorders such as cancer, immune disorders, inflammation, pain, osteoporosis, epilepsy, nausea associated with chemotherapy, fibrosis, gastrointestinal disorders, neurodegenerative diseases including multiple sclerosis and dyskinesia, Parkinson's disease, Huntington's chorea, Alzheimer's disease but also to prevent or cure diseases associated with motor function such as Tourette's syndrome, to provide neuroprotection.
• R 1 represents a radical corresponding to the anthracene group, a radical -Y 1 -V 1 -Z 1 or of formula
• X 1 and X 1 represent, independently, -CH 2 -, -C (O) -, -O-, -S- or -NH-;
• n 0 or 1
• Y 1 represents a (C 3 -C 7 ) cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical, all these radicals being optionally substituted with one or more identical or different substituents chosen from: halo, nitro, (Ci-C 6 ) alkyl, (Ci -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 4 ) haloalkoxy and (C 1 -C 6 ) alkyl-C (O) -;
• Vi represents a covalent bond, -O-, -S-, -NH-, -C (O) - or (C 1 -C 2 ) alkyl;
• Zi represents a (C 3 -C 7 ) cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical, all these radicals being optionally substituted with one or more identical or different substituents chosen from: halo, nitro, (Ci-C 6) alkoxy, (C 1 -C 6) IIaIOaIkOXy and (Ci-C 6) alkyl-C (O>;
• R 2 represents a radical of formula - (CH 2 ) 2 -R ' 2 ;
• R 2 represents a (C 3 -C 7 ) cycloalkyl, bicycloalkyl, heterocycloalkyl, heterobicycloalkyl, cyclohexenyl, aryl or heteroaryl radical, all these radicals being optionally substituted with one or more identical or different substituents chosen from: halo, (Ci-C 6) ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy and (C 1 -C 6 ) haloalkoxy;
• A represents a mono- or bi-cyclic condensed, unsaturated, aromatic or nonaromatic radical, containing a heteroatom selected from O and S and optionally substituted with one or more radicals, which may be identical or different, chosen from: halo, nitro, (Ci -C 6) alkyl, (Ci-C 6) haloalkyl, (Ci-C 6) alkoxy, (C 1 -C 6) ImIOaIkOXy and aryl optionally substituted with one or more substituents chosen from: halo and (C, -C 6 ) alkyl; or a pharmaceutically acceptable salt thereof,
• ring C is an unsaturated carbon ring containing at most 3 double bonds and optionally substituted.
• halo represents the fluoro, chloro, bromo or iodo radical, preferably chloro, fluoro or bromo.
• the expression (Ci-C 6 ) alkyl (when not more precise), preferably represents an alkyl radical having 1 to 6 carbon atoms, linear or branched, such as methyl, ethyl radicals. propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl or amyl, isopentyl, neopentyl, hexyl or isohexyl.
• the expression (Q-Ca) alkyl represents an alkyl radical having from 1 to 2 carbon atoms as defined above.
• haloalkyl an alkyl radical of which at least one of the hydrogen atoms (and possibly all) is replaced by a halogen atom such as trifluoromethyl.
• alkoxy denotes radicals in which the alkyl radical is as defined above such as, for example, methoxy, ethoxy, propyloxy or isopropyloxy radicals, but also linear, secondary or tertiary butoxy, pentyloxy radicals.
• haloalkoxy is meant an alkoxy radical at least one of the hydrogen atoms (and possibly all) is replaced by a halogen atom such as trifluoromethoxy, difluoromethoxy, trifluoroethoxy.
• (C 3 -C 7 ) cycloalkyl denotes a saturated carbon monocyclic system comprising from 3 to 7 carbon atoms, namely the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings.
• heterocycloalkyl refers to a saturated monocyclic or fused bicyclic system containing from 2 to 9 carbon atoms and at least one heteroatom. This radical can contain several identical or different heteroatoms. Preferably, the heteroatoms are chosen from oxygen, sulfur or nitrogen.
• heterocycloalkyl there may be mentioned the following rings: pyrrolidine, imidazolidine, pyrrazolidine, isothiazolidine, thiazolidine, isoxazolidine, oxazolidine, piperidine, piperazine, morpholine, azepane (azacycloheptane), azacyclooctane, decahydroisoquinoline (or decahydroquinoline), tetrahydrofuran (tetrahydrofuran radical ), tetrahydropyran, dioxane, dioxolane or tetrahydrothiophene (tetrahydrothienyl radical).
• bicycloalkyl refers to a non-condensed saturated hydrocarbon bicyclic system containing from 7 to 8 carbon atoms.
• Examples of bicycloalkyl include bicycloheptane and bicyclooctane such as bicyclo [2,2,1] heptane, bicyclo [2,2,2] octane or bicyclo [3,2,1] octane.
• heterobicycloalkyl means a non-condensed saturated hydrocarbon bicyclic system containing from 6 to 7 carbon atoms and at least one heteroatom selected from nitrogen, oxygen and sulfur.
• heterobicycloalkyl mention may be made of aza-bicycloheptane and aza-bicyclooctane such as 7-aza-bicyclo [2,2,1] heptane, 2-aza-bicyclo [2,2,2] octane or 6-aza bicyclo [3,2] octane.
• aryl represents an aromatic radical, consisting of a ring or condensed rings, such as, for example, the phenyl, naphthyl, fluorenyl or anthryl radical.
• heteroaryl refers to an aromatic radical, consisting of a ring or condensed rings, with at least one ring containing one or more identical or different heteroatoms selected from sulfur, nitrogen or oxygen.
• a heteroaryl radical mention may be made of the following radicals: pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, quinolyl, isoquinolyl, quinoxalinyl, indolyl, benzotriazolyl benzothiazolyl, benzoxadiazoyl, carbazolyl, phenoxazinyl, thienopyridinyl (thieno [2,3-b] pyridine, thieno [3,
• fused, unsaturated, aromatic mono- or bi-cyclic radical may be illustrated by the heteroaryl radical as defined above and containing a heteroatom chosen from O or S.
• condensed mono- or bi-cyclic radical, unsaturated, nonaromatic and containing at least one heteroatom selected from O or S can be illustrated by the heteroaryl radicals as defined above and in which at least one double bond is hydrogenated.
• heteroaryl radicals as defined above and in which at least one double bond is hydrogenated. Examples which may be mentioned are the radicals associated with the following rings: dihydrothiophene (2,5-dihydrothiophene, 2,3-dihydrothiophene), tetrahydrobenzothiophene (4,5,6,7-tetrahydro-1-benzothiophene), dihydrocyclopenta-thiophene 6-dihydro-4H-cyclopenta [b] thiophene), dihydrofuran, dihydropyran, tetrahydropyran, dihydrobenzofuran, benzodioxole, dihydro-benzodioxine.
• ring C is a carbon ring consisting solely of carbon and hydrogen, containing from 1 to 3 double bonds; it is eventually substituted.
• the present invention more particularly relates to a compound of formula I as defined above, characterized in that
• R 1 represents a radical corresponding to the anthracene group, a radical of formula -Y 1 -V 1 -Z 1 or of formula
• X 1 and X 1 represent, independently, -CH 2 -, -C (O) - or -NH-;
• n 0 or 1
• Y 1 represents a (C 3 -C 7 ) cycloalkyl radical, or aryl optionally substituted with one or more identical or different halo substituents;
• Vi represents a covalent bond, -O-, -C (O) - or -CH 2 -;
• Z] represents a (C 3 -C 7 ) cycloalkyl, aryl or heteroaryl radical, all these radicals being optionally substituted with one or more identical or different substituents chosen from: halo, (C] -C 6 ) alkyl, (Ci-C 6) haloalkyl, and (Ci-C 6) alkoxy;
• Y 1 represents a cyclohexyl radical, or phenyl optionally substituted with one or more identical or different halo substituents;
• Zi represents one. cyclohexyl, phenyl or thienyl, all these radicals being optionally substituted by one or more identical or different substituents chosen from: halo, (Ci-C 6) alkyl, (QC ⁇ ⁇ aloalkyle and (dC 6) alkoxy.
• the present invention more particularly relates to a compound of formula I as defined above, characterized in that
• R ' 2 represents a (C 3 -C 7 ) cycloalkyl, bicycloalkyl, heterocycloalkyl, cyclohexenyl, aryl or heteroaryl radical, all of these radicals being optionally substituted with one or more identical or different substituents chosen from: halo, (Ci-C 6 ) alkyl, (C 1 -C 6) IIaIOaIlCyIe, (Ci-C 6) alkoxy;
• the (C 3 -C 7 ) cycloalkyl, bicycloalkyl, heterocycloalkyl, aryl or heteroaryl radical represented by R ' 2 is chosen from: cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2, 1] heptyl, phenyl, pyrrolidinyl, piperidinyl and azepanyl; , morpholinyl, tetrahydropyranyl, pyridinyl and thienyl.
• the present invention more particularly relates to a compound of formula I as defined above, characterized in that A represents an aromatic radical optionally substituted with one or more identical or different substituents chosen from (C 1 -C 6 ) alkyl and aryl.
• A represents the thienyl, furyl or benzothienyl radical, said radicals being optionally substituted with one or more identical or different substituents chosen from (C 1 -C 6 ) alkyl and phenyl.
• the subject of the present invention is a compound of formula I as defined above, characterized in that
• Ri represents a radical of formula -Yi-Vj-Zi
• Y 1 represents a cyclohexyl or phenyl radical
• Vi represents a covalent bond
• Z 1 represents a cyclohexyl or phenyl radical optionally substituted by one or more identical or different halo, (C 1 -C 4) alkyl, (C 1 -C 4) haloalkyl substituents.
• the subject of the present invention is also a compound of formula I as defined above, characterized in that R ' 2 represents the piperidinyl, azepanyl, morpholinyl, tetrahydropyranyl, cyclohexyl or cyclohexenyl radical.
• the subject of the present invention is also a compound of formula I as defined above, characterized in that A represents a monocyclic radical.
• A represents the thienyl radical optionally substituted by one or more identical or different substituents (C 1 -C 4) alkyl.
• the subject of the present invention is also a compound of general formula (I) as defined above, characterized in that A represents a bicyclic radical. Very preferably, A forms with the pyrimidinone ring, the following compound
• the symbol -> * corresponds to the point of attachment of the radical.
• site of attachment is not specified on the radical, it means that the attachment is made on one of the available sites of this radical for such attachment.
• variable groups A, R 1 and R 2 the compounds according to the invention can be prepared according to the procedure described below:
• the ⁇ -amino ester derivative (1) can be coupled to a commercial acid chloride or prepared from the corresponding carboxylic acid either by treatment with oxalyl chloride in an aprotic solvent at a temperature of 20 to 80 ° C, either by treatment with thionyl chloride in the presence or absence of toluene at a temperature of 80 to 110 ° C, in the presence or absence of dimethylformamide, or by treatment with a solution equimolar of thionyl chloride and benzotriazole in an inert solvent such as methylene chloride, at room temperature for 5 minutes to 30 minutes, according to the procedure described by SS Chaudhari et al, Synlett, 1999, (11), 1763-1765] in the presence of a tertiary base such as triethylamine or diisopropylethyl diamine, in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide
• the methyl ester (2) can then be saponified in the presence of an inorganic base such as lithium hydroxide dihydrate in a mixture of polar solvents such as water and tetrahydrofuran at a temperature of 20 to 80 ° C for 3 to 17 hours or alternatively in the microwave at a temperature of 100 ° C for 15 to 30 minutes.
• an inorganic base such as lithium hydroxide dihydrate
• polar solvents such as water and tetrahydrofuran
• the resulting carboxylic acid (3) can be coupled with a primary amine in the presence of a coupling agent such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), hydrochloride of 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide (EDC) or carbonyldiimidazole (CDI), with or without 1-hydroxybenzotriazole (HOBt) in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide at room temperature for 3 to 24 hours or alternatively heated under at a temperature of 80 to 120 ° C (Biotage® equipment), in a sealed tube, for 10 to 30 minutes, for lead to the corresponding diamide (4).
• DIC diisopropylcarbodiimide
• DCC dicyclohexylcarbodiimide
• EDC 1- (3-dimethylaminopropyl) -3-
• the cyclization of the diamide (4) to pyrimidinone (I) can be carried out in the presence of chlorotrimethylsilane (TMS Cl) in the presence of a tertiary base, such as triethylamine or dimethylethylamine in an inert organic solvent such as tetrahydrofuran or acetonitrile at room temperature for 3 to 96 hours.
• TMS Cl chlorotrimethylsilane
• a tertiary base such as triethylamine or dimethylethylamine
• an inert organic solvent such as tetrahydrofuran or acetonitrile
• the diamide (4) can be treated with an inorganic base such as potassium or cesium carbonate, in the presence or absence of a phase transfer agent such as tetrabutylammonium bromide (TBAB) in an organic solvent such as DMF, at a temperature of 200 to 250 ° C under microwaves (Biotage equipment "), in a sealed tube, for 15 minutes to 2 hours.
• a phase transfer agent such as tetrabutylammonium bromide (TBAB) in an organic solvent such as DMF
• Step 1 Methyl 3 - [(biphenyl-4-ylcarbonyl) amino] thiophene-2-carboxylate
• Step 2 3 - [(biphenyl-4-ylcarbonyl) amino] thio ⁇ hene-2-carboxylic acid
• Step 3 3 - [(Biphenyl-4-ylcarbonyl) amino] -N- (2-piperidin-1-ylethyl) thiophene-2-carboxamide
• the corresponding hydrochloride salt is formed by adding 1N HCl solution in ethyl ether to the solution of the free base in ethyl acetate. The precipitate obtained is filtered and dried to give the expected hydrochloride compound (126 mg, 30% from step 3).
• Step 1 Methyl 3 - [(4-cyclohexylbenzoyl) amino] thiophene-2-carboxylate
• Step 2 3 - [(4-cyclohexylbenzoyl) amino] thiophene-2-carboxylic acid
• Step 3 3- (2-Cyclohexylethyl) -2- (4-cyclohexylphenyl) thieno [3,2-di-pyrimidin-4 (3H) -one
• R 1 represents one of the following radicals:
• R 2 represents one of the following radicals:
• the subject of the invention is also a process for preparing a compound of formula (I) as defined above, characterized in that:
• the resulting carboxylic acid (3) is then coupled with a primary amine of formula R 2 NH 2 in which R 2 is as defined above in the presence of a coupling in an inert organic solvent, to lead to the corresponding diamide (4).
• the diamide (4) is cyclized to form the pyrimidinone derivative (I) either by treatment with chlorotrimethylsilane (TMSCl) in the presence of a tertiary base in an inert organic solvent at room temperature or by treatment with an inorganic base , in the presence or absence of a transfer agent, in an organic solvent at a temperature of 200 to 250 ° C.
• TMSCl chlorotrimethylsilane
• the compounds of the present invention possess valuable pharmacological properties.
• the compounds of the present invention have good affinity for certain cannabinoid receptor subtypes, particularly CB2 receptors. They are particularly useful for treating disease states and diseases in which one or more cannabinoid receptors are involved.
• the compounds of the present invention can thus be used in various therapeutic applications. They can advantageously be used for the treatment and prevention of pathological conditions and diseases associated with the activity of cannabinoid receptors such as cell proliferation disorders such as cancer, immune disorders, inflammation, pain, osteoporosis, epilepsy, nausea associated with chemotherapy, fibrosis, gastrointestinal disorders, neurodegenerative diseases including multiple sclerosis and dyskinesia, Parkinson's disease, Huntington's chorea, Alzheimer's disease. They can also be used to prevent or cure diseases associated with motor function such as Tourette's syndrome, or to provide neuroprotection.
• the compounds of the present invention may be administered alone or in combination with other agents related to the treatment of the symptoms or cause of the disease or condition as mentioned above. The following is an illustration of the pharmacological properties of the experimental part. compounds of the invention.
• the present application also relates to pharmaceutical compositions containing, as active principle, at least one product of formula (I) as defined above, or an addition salt with the pharmaceutically acceptable mineral or organic acids of said product. of formula (I), in combination with a pharmaceutically acceptable carrier.
• the present application also relates to the use of the compounds (I) according to the present invention, for the preparation of a medicament for the treatment of cell proliferation disorders and preferably for the treatment of cancer.
• the present application also relates to the use of the compounds (I) according to the present invention, for the preparation of a medicament for the treatment of immune disorders, inflammation, pain, osteoporosis, fibrosis, gastrointestinal disorders, neurodegenerative diseases including multiple sclerosis and dyskinesia, Parkinson's disease.
• US patent application 2005/0176742 discloses thiophenepyrimidinone derivatives but these derivatives are presented as inhibitors of 17 ⁇ -hydroxysteroid dehydrogenase enzymes.
• R'i represents a radical corresponding to the anthracene group, a radical -Yi-Vi-Zi or of formula
• X 1 and X 1 represent, independently, -CH 2 -, -C (O) -, -O-, -S- or -NH-;
• n 0 or 1
• Y 1 represents a (C 3 -C 7 ) cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical, all these radicals being optionally substituted with one or more identical or different substituents chosen from: halo, nitro, (Ci-C 6 ) alkyl, (Ci -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy and (C 1 -C 6 ) alkyl-C (O) -;
• Vi represents a covalent bond, -O-, -S-, -NH-, -C (O) - or (C 1 -C 2 ) alkyl;
• Z 1 represents a (C 3 -C 7 ) cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical, all these radicals being optionally substituted by one or more identical or different substituents chosen from: halo, nitro, (C 1 -C 6 ) alkyl, (Ci -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy and (C 1 -C 6 ) alkyl-C (O);
• R " 2 represents a radical of formula - (CH2) 2 -R'2;
• R ' 2 represents a (C 3 -C 7 ) cycloalkyl, bicycloalkyl, heterocycloalkyl, heterobicycloalkyl, cyclohexenyl, aryl or heteroaryl radical, all of these radicals being optionally substituted by one or more identical or different substituents chosen from: halo, (C] - C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy and (C 1 -C 6 ) haloalkoxy;
• a ' represents a condensed mono- or bi-cyclic radical, unsaturated, aromatic or nonaromatic, containing a heteroatom selected from O and S, and optionally substituted with one or more radicals, identical or different, chosen from: halo, nitro, (Ci-C 6) alkyl, (Ci-C 6) haloalkyl, (Ci-C 6) alkoxy, (Ci-C 6) haloalkyl, and aryl optionally substituted with one or more substituents chosen from: halo and (Ci-C6 ) alkyl; or a pharmaceutically acceptable salt thereof;
• the present application also relates to the use of the compounds (I 1 ) as defined above, for the preparation of a medicament for the treatment of immune disorders, inflammation, pain, osteoporosis , fibrosis, gastrointestinal disorders, neurodegenerative diseases including multiple sclerosis and dyskinesia, Parkinson's disease.
• the pharmaceutical composition may be in the form of a solid, for example, powders, granules, tablets, capsules or suppositories.
• Suitable solid carriers may be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidine and wax.
• compositions containing a compound of the invention may also be in liquid form, for example, solutions, emulsions, suspensions or syrups.
• suitable liquid carriers may be, for example, water, organic solvents such as glycerol or glycols, as well as mixtures thereof, in varying proportions, in water, added to pharmaceutically acceptable oils or fats.
• Sterile liquid compositions may be used for intramuscular, intraperitoneal or subcutaneous injections and sterile compositions may also be administered intravenously.
• the compounds are characterized by their retention time (tr) and their molecular peak determined by mass spectrometry (MH +).
• a single quadrupole mass spectrometer (Micromass, Platform model) equipped with an electrospray source is used with a resolution of 0.8 Da at 50% valley.
• Calibration is carried out monthly between the masses 80 and 1000 Da using a calibrating mixture of sodium iodide and rubidium iodide dissolved in an isopropanol / water mixture (1/1 vol.).
• a Waters system including an in-line degasser, a Waters 600 quaternary pump, a Gilson 233 plate injector and a Waters PAD 996 UV detector, is used.
• the affinity of the compounds of the present invention for the different cannabinoid receptor subtypes was measured according to procedures analogous to those described hereinafter for the human CB2 receptor.
• the affinity of the compounds of the invention for CB2 human receptors is determined by measuring the inhibition of [ 3 H] -CP55940 binding to membrane preparations of transfected CHO-K1 cells.
• CHO-K1 cells stably expressing human CB2 receptors are cultured in RPMI 1640 medium containing 10% fetal calf serum, 2 mM glutamine, 100 U / ml penicillin, 0.1 mg / ml streptomycin and 0.5 mg / ml G418.
• the cells are collected with 0.5 mM EDTA and centrifuged at 500 g for 5 min at 4 ° C.
• the pellet is resuspended in phosphate buffered saline (PBS) and centrifuged at 500 g for 5 min at 4 ° C.
• PBS phosphate buffered saline
• the pellet is resuspended in a 50 mM Tris buffer medium at pH 7.4 and centrifuged at 500 g for 5 min at 4 ° C.
• the cells are lysed by sonication and centrifuged at 39,000 g for 10 min. at 4 ° C.
• the pellet is resuspended in 50 mM Tris buffer medium at pH 7.4 and centrifuged at 50,000 g for 10 min at 4 ° C.
• the membranes obtained in this latter pellet are stored at -80 ° C. vs.
• the measurement of competitive inhibition of [ 3 H] -CP55940 binding to CB2 receptors is performed in duplicate using 96-well polypropylene plates.
• the cell membranes (10 ⁇ g protein / well) are incubated with [ 3 H] -CP55940 (1 nM) for 60 min at 25 ° C. in a 50 mM Tris-HCl buffer medium, pH 7.4, comprising 0, 1% bovine serum albumin (BSA), 5 mM MgCl 2 , and 50 ⁇ g / ml bacitracin.
• BSA bovine serum albumin
• the bound [ 3 H] -CP55940 is separated from free [ 3 H] -CP55940 by filtration through GF / C glass fiber filter plates (Unifilter, Packard) preimpregnated with 0.1% polyethylenimine (PEI). ), using a Filtermate 196 (Packard). The filters are washed with 50 mM Tris-HCl buffer, pH 7.4 at 0-4 ° C and the radioactivity present is determined using a counter (Packard Top Count).
• the specific binding is obtained by subtracting the non-specific binding (determined in the presence of 0.1 ⁇ M of WIN55212-2 from the total binding).
• the data are analyzed by computer-assisted nonlinear regression (MDL). For each test, a Cheng-Prusoff correction is made for converting I 1 IC 50 inhibition constant Ki.
• Ki IC • 50
• [L] is the concentration of radioligand used in the assay and Kd is the radioligand dissociation constant at equilibrium.
• the CB2 receptor agonist or antagonist activity of the compounds of the present invention was determined by measuring the cyclic AMP production by CHO-K1 cells transfected with the CB2 receptor.
• CHO-K1 cells expressing cannabinoid CB2 receptors are cultured in 384-well plates in RPMI 1640 medium with 10% fetal calf serum and 0.5 mg / ml G418. The cells are washed twice with 50 ⁇ l of RPMI medium comprising 0.2% BSA and 0.5 mM of 3-isobutyl-1-methylxanthine (IBMX).
• IBMX 3-isobutyl-1-methylxanthine
• the cells are incubated for 5 min at 37 ° C. in the presence of 0.5 mM of IBMX, then the stimulation of the cyclic AMP production is obtained by adding 5 ⁇ M of Forskolin then the inhibition is measured by adding the compound at concentrations of between 1 ⁇ M and 10 ⁇ M in duplicate for 20 min at 37 ° C.
• the antagonistic effect of a compound is measured by inhibiting the inhibition of the production of MPAs cyclic induced by WIN55212-2 in the presence of 5 ⁇ M of Forskolin, at concentrations of between 1 ⁇ M and 10 ⁇ M, in the presence of the test compound, at concentrations of between 1 nM and 10 ⁇ M, in duplicate for 20 min at 37 ° C.
• the reaction medium is removed and 80 .mu.l of lysis buffer are added.
• the level of intracellular cyclic AMP is measured by a competition test with fluorescent cyclic AMP (CatchPoint, Molecular Devices).

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