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Definitions

• the present invention relates to new nitrogen tetrahydropyridyl-alkyl heterocycles, in particular nitrogen monocyclic heterocycles, the pharmaceutical compositions containing them and a process for their preparation.
• WO 98/25903 describes l-phenylalkyl-1,2,3,6-tetrahydropyridines for the treatment of Alzheimer's disease.
• WO 01/29026 describes phenyl- and pyridyl-tetrahydropyridines having an inhibitory activity of TNF-alpha (from the English Tumor Necrosis Factor).
• TNF-alpha is a cytokine which has recently aroused interest as a mediator of immunity, inflammation, cell proliferation, fibrosis etc. This mediator is abundantly present in inflamed synovial tissue and plays an important role in the pathogenesis of autoimmunity (Annu. Rep. Med. Chem., 1997, 32: 241-250).
• the present invention relates, according to one of its aspects, to tetrahydropyridyl-alkyl-benzodiazines of formula (I):
• X represents N or CH
• Ri represents a hydrogen or halogen atom or a group
• R and R 3 independently represent a hydrogen atom or a (C ⁇ -C 4 ) alkyl group;
• R 4 represents a hydrogen atom or a (-C 4 ) alkyl group;
• n is 0 or 1;
• A represents a nitrogen heterocycle of formula (a) - (d):
• R 5 and R 6 each independently represent a hydrogen atom, a (Ci-C 4 ) alkyl or (C t -) alkoxy group; as well as their N-oxides and their salts or solvates.
• (C 1 -C 4 ) alkyl denotes a monovalent radical of a saturated straight or branched C 1 -C 4 hydrocarbon and the term "(C ⁇ . -C 4 ) alkoxy” denotes a monovalent radical of a saturated straight or branched chain -C 4 hydrocarbon linked via an oxygen atom
• halogen denotes an atom chosen from chlorine, bromine, iodine and fluorine.
• Preferred compounds of formula (I) are those where n is zero.
• nitrogen heterocycles of formula (a) - (d) represent respectively a pyridine, a pyrimidine, a pyrazine and a pyridazine.
• These heterocycles can, according to the present invention, be attached to the rest of the molecule of formula (I) by any of the carbon atoms of the positions available.
• the compounds of formula (I) can exist as N-oxide derivatives.
• the compounds of formula (I) can in particular carry the N-oxide group on tetrahydropyridine; alternatively, N-oxide groups may be present on the nitrogen groups (a) - (d) and, optionally, all the nitrogen of the compounds of formula (I) may be simultaneously oxidized.
• the salts of the compounds of formula (I) according to the present invention also include the addition salts with pharmaceutically acceptable inorganic or organic acids such as the hydrochloride, the hydrobromide, the sulfate, the hydrogen sulfate, the dihydrogen phosphate, the citrate, maleate, tartrate, fumarate, gluconate, methanesulfonate, 2-naphthalenesulfonate, etc., than addition salts which allow proper separation or crystallization of the compounds of formula (I), such as picrate, oxalate or addition salts with optically active acids, for example camphosulfonic acids and mandelic or substituted mandelic acids.
• pharmaceutically acceptable inorganic or organic acids such as the hydrochloride, the hydrobromide, the sulfate, the hydrogen sulfate, the dihydrogen phosphate, the citrate, maleate, tartrate, fumarate, gluconate, methanesulfonate, 2-naphthalene
• the compounds of formula (I) can be prepared by a condensation reaction starting from a compound of formula (II):
• the condensation reaction is normally carried out by mixing the starting compounds (H) and (HT) in an inert organic solvent, according to conventional methods.
• inert organic solvent a solvent which does not interfere with the reaction.
• solvents are, for example, alcohols such as methanol, ethanol, propan-2-ol or butanol.
• leaving group L it is possible, for example, to use a halogen such as a chlorine or bromine atom, or else a methylsulfonyloxy group (CH 3 SO 2 - O-).
• a halogen such as a chlorine or bromine atom
• a methylsulfonyloxy group CH 3 SO 2 - O-
• the reaction is carried out at a temperature between -10 ° C. and the reflux temperature of the reaction mixture, the reflux temperature being preferred.
• the reaction can be suitably carried out in the presence of a proton acceptor, for example an alkali carbonate or a tertiary amine such as triethylamine.
• a proton acceptor for example an alkali carbonate or a tertiary amine such as triethylamine.
• the reaction is generally finished after a few hours, normally 1 to 6 hours are sufficient to complete the condensation.
• the desired compound is isolated according to conventional techniques in the form of a free base or of a salt thereof.
• the free base can be transformed into one of its salts by simple salification in an organic solvent such as an alcohol, preferably ethanol or isopropanol, an ether such as 1,2-dimethoxyethane, ethyl acetate , acetone or a hydrocarbon such as hexane.
• the compound of formula (I) obtained is isolated according to the usual techniques and optionally transformed into one of its salts or solvates or into its N-oxide derivatives.
• the starting compounds of formula (H) are known or they can be prepared analogously to the known compounds.
• the starting compounds of formula (m) are new and constitute a further object of the present invention.
• These compounds can be prepared from the corresponding acids or esters, by reduction of the carboxylic group to alcohol group and substitution of OH by the desired L group according to conventional methods.
• these compounds are prepared by Stille or Suzuki condensation of the two phenyl and heterocycle rings, suitably substituted; according to these condensations, a suitable halophenyl is reacted with derivatives of trialkylstannanes or diboranes of the heterocycle nucleus respectively, or, conversely, a suitable haloheterocycle is reacted with derivatives of trialkylstannanes or phenyl ring diboranes.
• the nuclei are optionally functionalized by transformation of the groups present, according to well known methods. Examples of preparation of nitrogen-containing trialkylstannane-heterocyclics are reported in Bioroganic and Medicinal Chemistry, 9/2001, 2683-2691. Other examples of the above reactions are recorded in the experimental part.
• the compounds of formula (I) can be prepared by a process which provides:
• step (a) can be conveniently carried out in an organic solvent at a temperature between -10 ° C and the reflux temperature of the reaction mixture.
• the acids of formula (Vu) above are new and represent a further object of the present invention. These compounds can be prepared from the products obtained by the condensations of Stille or Suzuki mentioned above, in particular by transformation of the substituents present on the phenyl into the desired acid groups.
• BOP tri (dimethylamino) benzotriazol-1-yloxyphosphonium hexafluorophosphate
• anhydride a mixed anhydride
• an active ester or an acid halide preferably bromide.
• the active esters p-nitrophenyl ester is particularly preferred, but methoxyphenyl, trityl, benzhydryl esters and the like are also suitable.
• reaction solvent preferably used is a halogenated solvent such as methylene chloride, dichloroethane, 1,1,1-trichloroethane, chloroform and the like, but also other compatible organic solvents.
• a halogenated solvent such as methylene chloride, dichloroethane, 1,1,1-trichloroethane, chloroform and the like, but also other compatible organic solvents.
• the reagents used for example dioxane, tetrahydrofuran or a hydrocarbon such as hexane, can also be used.
• the reaction can be suitably carried out in the presence of a proton acceptor, for example an alkali carbonate or a tertiary amine such as triethylamine.
• a proton acceptor for example an alkali carbonate or a tertiary amine such as triethylamine.
• step (b) can be suitably carried out by suitable reducing agents such as borane complexes, for example borane dimethylsulfide ([CH 3 ] 2 S-BH 3 ), aluminum hydrides or a complex lithium and aluminum hydride in an inert organic solvent at a temperature between 0 ° C. and the reflux temperature of the reaction mixture, according to the usual techniques.
• suitable reducing agents such as borane complexes, for example borane dimethylsulfide ([CH 3 ] 2 S-BH 3 ), aluminum hydrides or a complex lithium and aluminum hydride in an inert organic solvent at a temperature between 0 ° C. and the reflux temperature of the reaction mixture, according to the usual techniques.
• inert organic solvent a solvent which does not interfere with the reaction.
• solvents are, for example, ethers, such as diethyl ether, tetrahydrofuran (THF), dioxane or 1,2-dimethoxyethane.
• the compounds of formula (I) can also be prepared by a condensation / reduction reaction starting from a compound of formula (II):
• the condensation / reduction reaction is carried out by mixing the starting compounds (H) and (X) in an organic solvent such as an alcohol such as for example methanol, in an acid medium, in the presence of a reduction such as sodium cyano-borohydride, according to conventional methods.
• an organic solvent such as an alcohol such as for example methanol
• a reduction such as sodium cyano-borohydride
• the compounds of formula (I) carrying an N-oxide group on the nitrogen atoms of the groups (a) - (d) can be prepared from the N-oxide derivatives of the compounds of formula (DI) or (X).
• the compounds of formula (I) carrying an N-oxide group on the nitrogen atom of tetrahydropyridine or of pyridine linked to tetrahydropyridine when X is N can be prepared by oxidation of the corresponding compounds of formula (I).
• the compound of formula (I) as obtained for example by the above synthesis is subjected to an oxidation reaction according to conventional methods, for example to a reaction with m-chloro acid perbenzoic in a suitable solvent and isolated according to the usual techniques well known to those skilled in the art.
• the compounds of the invention have advantageous properties with regard to the inhibition of TNF-.
• LPS lipopolysaccharide
• test products are administered orally to groups of 5 female Balb / c mice (Charles River, France) aged 7 to 8 weeks.
• the LPS is administered intravenously (10 ⁇ g / mouse).
• the blood of each animal is taken 1.5 hours after administration of the LPS.
• the samples are centrifuged, the plasma is recovered and frozen at -80 ° C.
• TNF- ⁇ is measured using commercial kits (R&D, Abingdon, UK).
• the compounds of formula (I) and its salts or solvates may well be used in the treatment of diseases linked to immune and inflammatory disorders or as analgesics.
• the compounds of formula (I) can be used to treat atherosclerosis, autoimmune diseases, diseases which cause demyelination of neurons (such as multiple sclerosis), asthma, rheumatoid arthritis, fibrotic diseases , idiopathic pulmonary fibrosis, cystic fibrosis, glumerulonephritis, rheumatoid spondylitis, osteoarthritis, gout, bone and cartilage resorption, osteoporosis, Paget's disease, multiple myeloma, uveoretinitis, septic shock, sepsis, endotoxin shock, graft versus host reaction, transplant rejection, adult respiratory distress syndrome, silicosis, asbestosis, pulmonary sarcoidosis, Crohn's disease
• the compounds of formula (I) and their pharmaceutically acceptable salts and solvates are preferably administered orally.
• the active principle can be administered in unit administration forms, in admixture with conventional pharmaceutical carriers, to animals and humans for the treatment of the abovementioned conditions.
• Suitable unit dosage forms include, for example, possibly scored tablets, capsules, powders, granules and oral solutions or suspensions.
• the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• the tablets can be coated with sucrose or other suitable materials or else they can be treated in such a way that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
• a preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.
• a preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color.
• Water dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or correctors taste.
• the active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
• the active principle can also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters.
• the amount of active ingredient to be administered depends as always on the degree of progression of the disease as well as on the age and weight of the patient.
• the unit doses generally comprise from 0.001 to 100 mg, better still from 0.01 to 50 mg, preferably from 0.1 to 20 mg of active principle, advantageously from 0.5 to 10 mg.
• the present invention relates to a combination comprising a compound of formula (I) or one of its pharmaceutically acceptable salts or solvates, and at least one compound chosen from immunosuppressive agents, such as interferon beta -lb; adrenocorticotropic hormone; glucocorticoids such as prednisone or methylprednisolone; interleukin-1 inhibitors.
• immunosuppressive agents such as interferon beta -lb; adrenocorticotropic hormone; glucocorticoids such as prednisone or methylprednisolone; interleukin-1 inhibitors.
• the invention relates to a combination comprising a compound of formula (I), or one of its pharmaceutically acceptable salts or solvates and at least one compound chosen from roquinimex (1,2-dihydro-4-hydroxy-N , l-dimethyl-2-oxo-3-quinolinecarboxanilide), myloran (product of the company Autoimmune containing bovine myelin), antegren (human monoclonal antibody from the companies Elan / Athena Neurosciences) the recombinant beta-lb interferon .
• roquinimex 1,2-dihydro-4-hydroxy-N , l-dimethyl-2-oxo-3-quinolinecarboxanilide
• myloran product of the company Autoimmune containing bovine myelin
• antegren human monoclonal antibody from the companies Elan / Athena Neurosciences
• the invention relates to a method of treatment of diseases linked to immune and inflammatory disorders as well as in the treatment of pain, in particular atherosclerosis, autoimmune diseases, diseases which cause the demyelination of neurons (such as multiple sclerosis), asthma, rheumatoid arthritis, fibrotic diseases, idiopathic pulmonary fibrosis, cystic fibrosis, glumerulonephritis, rheumatoid spondylitis, osteoarthritis, gout, bone and cartilage resorption , osteoporosis, Paget's disease, multiple myeloma, uveoretinitis, septic shock, sepsis, endotoxin shock, graft versus host reaction, transplant rejection,
• the invention relates to a medicament containing, as active principle, at least one compound of formula (I) or one of its pharmaceutically acceptable salts or solvates.
• a medicament containing, as active principle, at least one compound of formula (I) or one of its pharmaceutically acceptable salts or solvates.
• the product from the preceding step is cooled to 0 ° C. in 17 ml of dichloromethane and 11 ml of SOCl 2 are added thereto. Stir overnight at room temperature, pour into a mixture of water / ice, bring to neutral pH by addition of sodium bicarbonate, extract with dichloromethane, dry and evaporate the solvent.
• the title compound is obtained in the form of a yellow oil.
• PREPARATION 9 4- [3- (2- ChIoroethyl) -phenyI] -pyridine.
• the mixture is stirred at ambient temperature for 5 hours, poured into a water / ice mixture and extracted with ethyl acetate.
• the two phases are separated, the organic phase is dried over sodium sulfate and the solvent is evaporated.
• 0.65 g of the product thus reduced is dissolved in 3.9 ml of acetic acid, 0.78 ml of 96% sulfuric acid is added thereto and the mixture is heated at 80 ° C. for 2 hours.
• reaction solvent is preferably 4-methyl-2-pentanone (instead of the isopropanol described in Example 1)
• TLC thin layer chromatography
• AcEt ethyl acetate
• MeOH methanol
• EXAMPLE 17 1 - [2- (3- (4-Pyridyl) -phenyl) -ethyl] -4- (3-trifluoro-methyl-phenyl) -1,2,6,6-tetrahydro-pyridine 1- oxide.
• N-oxide derivative of the compound of Example 7 is prepared by reaction with m-chloro-perbenzoic acid in methylene chloride. Thin layer chromatography (TLC): R.f. 0.15, eluent methanol.
• TLC Thin layer chromatography
• EXAMPLE 18 1- [2- (3- (4-Pyridyl-1-oxide) -phenyl) -ethyl] -4- (3-trifluoro-methyl-phenyl) - 1,2,3,6-tetrahydro-pyridine.

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