EP1805143A1 - Pyridinderivate, deren herstellung und therapeutische anwendung - Google Patents

Pyridinderivate, deren herstellung und therapeutische anwendung

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Publication number
EP1805143A1
EP1805143A1 EP05809571A EP05809571A EP1805143A1 EP 1805143 A1 EP1805143 A1 EP 1805143A1 EP 05809571 A EP05809571 A EP 05809571A EP 05809571 A EP05809571 A EP 05809571A EP 1805143 A1 EP1805143 A1 EP 1805143A1
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EP
European Patent Office
Prior art keywords
group
formula
alkyl
compound
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP05809571A
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English (en)
French (fr)
Inventor
Lionel Barre
Francis Barth
Christian Congy
Philippe Pointeau
Murielle Rinaldi-Carmona
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis France
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Sanofi Aventis France
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Publication of EP1805143A1 publication Critical patent/EP1805143A1/de
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Definitions

  • the present invention relates to pyridine derivatives, to their preparation and to their therapeutic application.
  • Patent application WO 2002/055502 describes compounds of formula:
  • Z represents a group N (R 1) XR 2 , N (R 1) COOR ' 2 or OCON (R 1) R' 2 ;
  • X represents a group -CO-, -SO 2 -, -CON (Ri 0> or -CSN (Ri o>;
  • R 1 represents a hydrogen atom or a (C 1 -C 4) alkyl group
  • R 2 may represent a (C 1 -C 8) alkanoyl group or a benzoyl or benzylcarbonyl group, the phenyl group of said groups being unsubstituted or substituted by identical or different substituents selected from a halogen atom, a (C 1 -C 4) alkyl or trifluoromethyl group;
  • R'2 represents a phenyl that is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom or a (C 1 -C 4) alkyl, trifluoromethyl, cyano or nitro, (C 1 -C 4) alkoxy group; ;
  • R3 represents a hydrogen atom or a group (C1-C4) alkyl, cyano, (C1-C4) alkoxymethyl or hydroxymethyl;
  • R 4, R 5, R 6, R 4, R 6 and R 9 each independently represent a hydrogen or halogen atom, a (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, trifluoromethyl or trifluoromethoxy group, cyano, nitro or a group S (O) n AIk;
  • R 0 represents a hydrogen atom or a group (C 1 -C 4) alkyl
  • R2 and RJO together with the nitrogen atom to which they are attached constitute a heterocyclic radical of 4 to 8 atoms, containing or not a second heteroatom selected from an unsubstituted oxygen, sulfur or nitrogen atom; or substituted one or more times with a (C 1 -C 4) alkyl group; a (C 1 -C 4) alkanoyl group; a group NR11R12 or CONRi 1R12 ⁇ a phenyl group unsubstituted or substituted one or more times by a halogen atom, a group (C1-C4) alkyl, (C1-C4) alkoxy or trifluoromethyl;
  • Ri and Ri 2 each independently represent a hydrogen atom, a group (Ci-C4) alkyl or Rn and Ri 2 together with the nitrogen atom to which they are attached, constitute a radical heterocyclic of 4 to 8 atoms;
  • n 0, 1 or 2;
  • R 1 and R 4 represent, independently of one another, a hydrogen atom or a (C 1 -C 4) alkyl group or R 1 and R 4 together with the nitrogen atom to which they are attached constitute a saturated or unsaturated heterocyclic radical of 4 to 8 atoms;
  • - Alk represents a (C 1 -C 4) alkyl group; with the proviso that one of the substituents R 1, R 3, R 5, R 6, R 6, R 6 is different from hydrogen when R 4 and R 7 simultaneously represent a 4-methoxy group; in the form of base or addition salt, and in the hydrate or solvate state.
  • X represents a group -CO-, -SO2- or -CON (Ri 0) -;
  • R 1 represents a hydrogen atom or a C 1 -C 4 alkyl group
  • R2 represents:
  • a non-aromatic (C 3 -C 12) carbocyclic radical unsubstituted or substituted one or more times with a (C 1 -C 4) alkyl group
  • R 3 represents a hydrogen atom or a (C 1 -C 4) alkyl, cyano or (C 1 -C 4) alkoxymethylene group;
  • R4, R5, R6, R7, R8, R9 are each independently hydrogen or halogen, (C1-C6) alkyl, (C1-C6) alkoxy, trifluoromethyl, or group S (O) n AIk;
  • R 0 represents a hydrogen atom or a (C 1 -C 4) alkyl group
  • R2 and Rio together with the nitrogen atom to which they are attached constitute a heterocyclic radical of 4 to 8 atoms, containing or not a second heteroatom selected from an oxygen atom, sulfur or nitrogen, unsubstituted or substituted one or more times with a (C 1 -C 4) alkyl group; a (C 1 -C 4) alkanoyl group; a group NRn Ri 2 or CONRn Ri 2 > mx unsubstituted phenyl group or substituted one or more times with a halogen atom, a (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or trifluoromethyl group;
  • Ri 2 each independently represent a hydrogen atom, a group (C 1 -C 4) alkyl or Rn and Rj 2 together with the nitrogen atom to which they are attached, constitute a radical heterocyclic of 4 to 8 atoms;
  • n 0, 1 or 2;
  • Alk represents a (C 1 -C 4) alkyl group, with the proviso that one of the substituents R 1, R 3, R 5, R 5, R 6, R 9 is other than hydrogen when R 4 and R 7 simultaneously represent a 4-methoxy group.
  • the compounds of formula (I) may have one or more asymmetric carbon atoms, and may therefore exist in the form of enantiomers or diastereoisomers.These enantiomers, diastereoisomers, and mixtures thereof, including racemic mixtures, are part of the 'invention.
  • the compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
  • salts can be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.
  • the compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the invention.
  • a halogen atom a fluorine, a chlorine, a bromine or an iodine; a (C 1 -C 4) alkyl or (C 1 -C 8) alkyl or (C 3 -C 10) alkyl group; a linear or branched saturated aliphatic group, (C 1 -C 4), or (C 1 -C 4) or (C 3 -C 10), respectively.
  • a (C 1 -C 4) alkoxy group an O-alkyl radical in which the alkyl group is as defined above.
  • the non-aromatic C 3 -C 12 carbocyclic radicals include mono or polycyclic condensed or bridged radicals.
  • Monocyclic radicals include cycloalkyls for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; cyclohexyl and cyclopentyl being preferred.
  • the di- or tricyclic radicals condensed, bridged or spiranic include, for example norbornyl, bornyl, isobornyl, noradamantyl, adamantyl, spiro [5.5] undecanyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl radicals; bicyclo [3.1.1] heptyl.
  • Heterocyclic radicals of 4 to 8 atoms include the radicals azetidinyl, pyrrolidinyl, pyrrolyl, piperidyl, perhydroazepinyl, perhydroazocinyl
  • radicals containing, in addition, a second heteroatom chosen from an oxygen, sulfur or nitrogen atom additionally comprise the imidazolidinyl, pyrazolidinyl, piperazinyl, morpholinyl and thiomorpholinyl radicals, etc.
  • a group of compounds is constituted by the compounds for which: Z represents a group N (R 1) XR 2 and X has one of the values defined for (I) ;
  • R j represents a hydrogen atom
  • R2 represents a 1-propylbutyl or an indol-2-yl which is unsubstituted or substituted with a (C 1 -C 4) alkyl group, or R 2 represents a phenyl which is unsubstituted or substituted one or more times with identical substituents or different from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, (C 1
  • R4 represents a chlorine or bromine atom or a methoxy group
  • R7 and Rg each represent a chlorine atom
  • Rg and R9 represent hydrogen; as bases or addition salts and as hydrates or solvates.
  • Z represents an NHCOR 2 group
  • R2 represents a 1-propylbutyl group, an indolyl group which is unsubstituted or substituted by a (C 1 -C 6) alkyl group, a phenyl group which is unsubstituted or substituted by a halogen atom or a trifluoromethyl group;
  • R3 represents a methyl or methoxymethyl group
  • R4 represents a chlorine or bromine atom or a methoxy group
  • R7 and Rg each represent a chlorine atom
  • R5 represents hydrogen; as bases or addition salts and as hydrates or solvates.
  • Z represents an NHSO2R2 group
  • R2 represents a phenyl group which is unsubstituted or substituted with a halogen atom or with a trifluoromethyl group
  • - R3 represents a methyl or methoxymethyl group
  • R4 represents a chlorine or bromine atom or a methoxy group
  • R7 and Rg each represent a chlorine atom
  • R5 represents hydrogen; as bases or addition salts and as hydrates or solvates.
  • Rg represents hydrogen; as bases or addition salts and as hydrates or solvates.
  • the protective group Pg is understood to mean a group which makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand, to regenerate the intact reactive function. at the end of synthesis. Examples of protecting groups and methods of protection and deprotection are given in "Protective Groups in Organic Synthesis", Green et al, 2nd Edition (John Wiley & Sons, Inc., New York), 1991.
  • leaving group is meant, in what follows, a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with departure from an electronic pair. This group can thus be easily replaced by another group during a substitution reaction, for example.
  • Such leaving groups are, for example, halogens or an activated hydroxy group such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, trifiate (or trifluoromethanesulfonate), acetate, etc. Examples of leaving groups as well as references for their preparation are given in Advances in Organic Chemistry, J. March, 3 rd Edition, Wiley Interscience, 1985, p. 310-316.
  • the compounds of general formula (I) in which Z represents a group N (R 1) XR 2 or N (R 1) COOR '2 can be prepared according to the process characterized in that a compound is treated. of formula:
  • a compound of formula (II) as defined above can be treated with an aryloxycarbonyl halide of formula HalCOOR'2 in which R'2 is as defined for (I) to form an intermediate compound of formula:
  • the compound of formula (I): (IA), (IB), (IC), (ID) or (IE) thus obtained is converted into one of its addition salts with an acid.
  • reaction is carried out in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane or tetrahydrofuran, and at a temperature between room temperature and the reflux temperature of the solvent.
  • a base such as triethylamine or diisopropylethylamine
  • a solvent such as dichloromethane or tetrahydrofuran
  • the compounds of formula (IV) may be prepared by halogenation of the corresponding sulfonic acids or their salts, for example their sodium or potassium salts.
  • the reaction is carried out in the presence of a halogenating agent such as phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, without solvent or in a solvent such as halogenated hydrocarbon or N, N-dimethylformamide and at a temperature of between -10 ° C. and 200 ° C.
  • aryloxycarbonyl halides useful in the preparation of a compound of formula (V) are known or prepared by known methods.
  • R 1 represents a hydrogen atom or a (C 1 -C 4) alkyl group
  • R3 represents a hydrogen atom or a group (C1-C4) alkyl, cyano, (C1-C4) alkoxymethylene or hydroxymethyl;
  • R 4, R 5, R 6, R 7 and R 5 are each independently of one another a hydrogen or halogen atom, a (C 1 -C 8) alkyl, (C 1 -C 6) alkoxy or trifluoromethyl group, trifluoromethoxy, cyano, nitro or a group S (O) n AIk; are novel with the proviso that one of the substituents R 1, R 3, R 5, R 8, R 8, R 9 is other than hydrogen when R 4 and R 7 are simultaneously 4-methoxy.
  • R 5 R3, R4 to R9 are as defined for (I).
  • step a1) the reaction is carried out in the presence of a reducing agent such as sodium borohydride or lithium aluminum hydride, in a solvent such as tetrahydrofuran, and at a temperature between -20 ° C and room temperature.
  • a reducing agent such as sodium borohydride or lithium aluminum hydride
  • a solvent such as tetrahydrofuran
  • a compound of formula (X) is prepared in which Y represents a leaving group as defined above, preferably a halogen atom or an activated hydroxy group, for example an activated hydroxy group such as a methanesulphonate group, benzenesulphonate, p-toluenesulphonate or triflate.
  • a compound of formula (IX) is treated with a halogenating agent such as PCI5, PBrc, HBr or BBr3, in a solvent such as than dichloromethane and at a temperature between 0 ° C. and room temperature.
  • a compound of formula (IX) is reacted with a sulfonyl chloride of formula Z-SO2-CI in Z is methyl, phenyl, p-tolyl or trifluoromethyl.
  • the reaction is carried out in the presence of a base such as triethylamine, pyridine or N, N-diisopropylethylamine, in a solvent such as dichloromethane or toluene and at a temperature of between -20 ° C. and the reaction temperature. reflux of the solvent.
  • the reaction is carried out in a solvent such as N 5 N- dimethylformamide, acetonitrile, dichloromethane, toluene or propan-2-ol and in the presence or absence of a base.
  • a base is chosen from organic bases such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine.
  • the reaction is carried out at a temperature between 0 ° C. and the reflux temperature of the solvent.
  • the compounds of formula (VIII) are prepared according to known methods such as those described in WO 03/082191 and WO 2005/00817.
  • a compound of formula (I) in which Z represents a group N (R 1) X R 2 or N (R 1) COOR '2 with R 2 different from hydrogen can be prepared by alkylation of a compound of formula ( I) wherein Z is NHXR2 orNHCOOR'2.
  • R 3 represents a (C 1 -C 4) alkyl or (C 1 -C 4) alkoxymethyl group
  • R 3 represents a (C 1 -C 4) alkyl or (C 1 -C 4) alkoxymethyl group
  • R 3 (C r C4) alkyl or (C j -C ⁇ alkoxymethyl
  • step (a2) the phenylacetic acid derivative of formula (XI) is treated with the benzoic ester derivative of formula (XII) in the presence of sodium hexamethylenedisilazane (NaHMDS) in a solvent such as THF, and then acidifies to obtain the compound of formula (XIII); in step (b2) this compound is treated with tetramethylmethanediamine and acetic anhydride to form the compound of formula (XTV).
  • NaHMDS sodium hexamethylenedisilazane
  • step (c2) the compound of formula (XVI) is prepared by the action of ammonium acetate on a 3-o ⁇ obutanoate derivative of formula (XV).
  • step (d2) the nicotinic ester of formula (XVII) is then prepared by the action of compound (XIV) on compound (XVI) in the presence of para-toluenesulfonic acid (APTS).
  • APTS para-toluenesulfonic acid
  • step (e2) This ester is hydrolyzed in a basic medium in step (e2), then the acid function is reduced in step (2), for example by the borane / THF complex.
  • an anhydride may be prepared in an intermediate manner and then reduced, for example by the action of a metal borohydride.
  • the ester of formula (XVII) can also be reduced directly by reducing agents to the alcohol of formula (XIX).
  • step (g2) the compound of formula (XIX) bearing a hydroxymethyl group is engaged in a Mitsunobu reaction in the presence of phthalimide to give a compound of formula (XX) which, treated with hydrazine hydrate, in a last step (h2) leads to the compound (II) expected.
  • DIPEA diisopropylethylamine
  • DMF N, N-dimethylformamide
  • NaHMDS sodium hexamethylenedisilazane
  • APTS paratenesulfonic acid 2N hydrochloric ether: 2N solution of hydrochloric acid in diethyl ether
  • DEAD diethylazodicarboxylate buffer solution
  • pH2 solution of 16.66 g of KHSO4 and 32.32 g of K2SO4 in 1 liter of water.
  • the compounds according to the invention are analyzed by LC / UV / MS coupling (liquid chromatography / UV detection / mass spectrometry).
  • the molecular peak (MH) and the retention time (t) are measured in minutes.
  • An Xterra Waters MS Cl 8 column marketed by Waters, 2.1 x 30 mm, 3.5 ⁇ m, is used at room temperature, flow rate 1 mL / minute.
  • the eluent is composed as follows: solvent A: 0.025% trifluoroacetic acid (TFA) in water
  • solvent B 0.025% of TFA in acetonitrile.
  • the UV detection is carried out between 210 nm and 400 nm and the mass detection in chemical ionization mode at atmospheric pressure.
  • the eluent is composed as follows:
  • solvent A 0.025% trifluoroacetic acid (TFA) in water
  • solvent B 0.025% of TFA in acetonitrile.
  • the UV detection is carried out by an iodine bar detector between 210 and 400 nm and the mass detection in ESI positive chemical ionization mode.
  • MS5 conditions An XTEREA MS Cl 8 column of 2.1 x 30 mm, 3.5 ⁇ m, flow rate 1 ml / minute is used.
  • the eluent is composed as follows: Solvent A: 0.025% TFA in water, Solvent B: 0.025% TFA in acetonitrile. gradient
  • UV detection is performed by an iodine bar detector between 210 and 400 nm and ESI positive mass detection.
  • aqueous phase is basified with 8% NaOH and the product is extracted with 1 AcOEt.
  • the organic phase is dried over MgSO 4), evaporated to dryness, taken up in Et 2 O and treated with HCl / Et 2 O.
  • 150 ml of NaHMDS are placed under nitrogen at -78 ° C. diluted with 150 ml of THF and 25 g of 2,4-dichlorophenylacetic acid dissolved in 150 ml of THF are added dropwise. At -78 ° C., after stirring for 2 hours, 20.26 g of methyl ester are added. 4-methoxybenzoic acid dissolved in 150 ml of THF. The temperature is allowed to rise to 0 ° C. and stirring is maintained for 2 hours at this temperature. At 0 ° C., 10% hydrochloric acid is added dropwise in an amount sufficient to hydrolyze the reaction medium and the mixture is stirred for 2 hours at RT. The mixture is extracted with ether and then the organic phase is dried over Na.sub.2SO.sub.4.
  • a mixture containing 30 g of previously sublimed ammonium acetate, 165 ml of cyclohexane and 15 ml of methyl 4-methoxy-3-oxobutanoate and 4 'sieve is placed under nitrogen. The mixture is left stirring for 4 hours at 90 ° C. and then evaporated to dryness. Washed and extracted with DCM and the organic phase is filtered and evaporated. The product obtained is used as it is in the next step.
  • a mixture containing 10.63 g of the compound obtained in step C is prepared; 22.5 g of the compound obtained in step B, 0.50 g of PTSA and 54 ml of butanol. It is left stirring at 150 ° C. for 3 hours. Butanol is evaporated and the residue is taken up in 400 ml of DCM. The organic phase is washed with 400 ml of water and then dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. 25.14 g of the expected compound are obtained in crude form. E) 5- (2,4-Dichlorophenyl) -2- (methoxymethyl) -6- (4-methoxyphenyl) nicotinic acid.
  • the ethereal phase is dried and then taken up in 250 ml of ether and washed with saturated NaHCO 3 solution and then with water.
  • the organic phase is then dried over Na 2 SC 4, filtered and evaporated to dryness.
  • the crude product obtained is chromatographed on silica eluting with CH 2 Cl 2 0-5% MeOH. 1.40 g of the expected compound are obtained.
  • a mixture containing 1.79 g of the compound obtained above and 0.31 ml of hydrazine hydrate in 45 ml of methanol is placed under nitrogen and heated under reflux for 3 hours. 100 ml of water and 100 ml of DCM are added and the organic phase is then washed with 100 ml of 10% NaOH solution, 100 ml of saturated NaHCO 3 solution and 100 ml of saturated NaCl solution. The organic phase is dried over Na 2 SO 4 and evaporated to dryness. 0.944 g of the expected compound is obtained.
  • Me, Et 5 Pr 5 nBu, tBu respectively represent methyl, ethyl, propyl, n-butyl and tert-butyl groups.
  • the compounds according to the invention have been the subject of pharmacological tests making it possible to determine their affinity and their antagonistic capacity with respect to CB cannabinoid receptors j .
  • the compounds of formula (I) have a good in vitro affinity (IC50 ⁇ 5.10 M) for cannabinoid CQ receptors, under the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 350, 240- 244).
  • the invention relates to medicaments for human or veterinary medicine comprising a compound of formula (I) 5 or an addition salt thereof with a pharmaceutically acceptable acid, or a solvate or a hydrate of the compound of formula (I).
  • the compounds according to the invention can be used in humans or animals, in the treatment or prevention of diseases involving cannabinoid CB1 receptors.
  • the compounds of formula (I) are useful as psychotropic drugs, especially for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders , obsessive disorders, psychoses in general, schizophrenia, attention deficit and hyperactivity disorders (ADHD) in hyperkinetic children (BDM) and for the treatment of " disorders related to the use of psychotropic substances particularly in the case of substance abuse and / or substance dependence, including alcohol dependence and nicotine addiction.
  • psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders , obsessive disorders, psychoses in general, schizophrenia, attention deficit and hyperactivity disorders (ADHD) in hyperkinetic children (BDM)
  • ADHD attention deficit and hyperactivity disorders
  • BDM hyperkinetic children
  • the compounds of formula (I) according to the invention can be used as medicaments for the treatment of migraine, stress, psychosomatic diseases, panic attacks, epilepsy, movement disorders , especially dyskinesias or Parkinson's disease, tremors and dystonia.
  • the compounds of formula (I) according to the invention can also be used as medicaments in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementias, of Alzheimer's disease, as well as in the treatment of disturbances of attention or alertness.
  • the compounds of formula (I) may be useful as neuroprotective agents, in the treatment of ischemia, head trauma and the treatment of neurodegenerative diseases: including chorea, Huntington's chorea, Tourrette's syndrome.
  • the compounds of formula (I) according to the invention can be used as medicaments in the treatment of pain: neuropathic pain, acute peripheral pain, chronic pain of inflammatory origin.
  • the compounds of formula (I) according to the invention can be used as medicaments in the treatment of appetite disorders, palatability (for sugars, carbohydrates, drugs, alcohols or any appetizing substance) and / or conduits. for the treatment of obesity or bulimia as well as for the treatment of type II diabetes or non-insulin-dependent diabetes and for the treatment of dyslipidemia, metabolic syndrome.
  • the compounds of formula (I) according to the invention are useful in the treatment of obesity and the risks associated with obesity, in particular cardiovascular risks.
  • the compounds of formula (I) according to the invention can be used as medicaments in the treatment of gastrointestinal disorders, diarrheal disorders, ulcers, vomiting, bladder and urinary disorders, endocrine, cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, chronic cirrhosis of the liver, hepatic steatosis, steatohepatitis, chronic hepatic encephalopathy, asthma, Raynaud's syndrome, glaucoma, fertility disorders, inflammatory phenomena, diseases of the immune system, especially autoimmune and neuroinflammatory such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, multiple sclerosis. plaque, infectious and viral diseases such as encephalitis, stroke and as drugs for chemo anti-cancer therapy, for the treatment of Guillain-Barré syndrome and for the treatment of osteoporosis.
  • the compounds of formula (I) are particularly useful for the treatment of psychotic disorders, in particular schizophrenia, attention deficit and hyperactivity disorders (ADHD) in hyperkinetic children (BDM); for the treatment of appetite and obesity disorders; for the treatment of memory and cognitive deficits; for the treatment of alcohol dependence, nicotine addiction, ie for alcohol withdrawal and smoking cessation; and for the treatment of dyslipidemias, the metabolic syndrome.
  • the compounds of formula (I) according to the present invention are useful in the treatment and prevention of appetite disorders, metabolic disorders, gastrointestinal disorders, inflammatory phenomena, diseases of the immune system, psychotic disorders, alcohol dependence, nicotine addiction.
  • the present invention relates to the use of a compound of formula (I), its pharmaceutically acceptable salts and their solvates or hydrates for the treatment of the disorders and diseases indicated above.
  • the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
  • compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a solvate or hydrate of said compound, as well as at least one pharmaceutically acceptable excipient.
  • excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
  • the active ingredient of formula (I) above, or its salt, solvate or hydrate may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.
  • Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
  • the compounds according to the invention can be used in creams, gels, ointments or lotions.
  • a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg
  • the dose of active ingredient administered per day can reach 0.01 to 100 mg / kg, in one or more doses, preferably 0.02 to 50 mg / kg.
  • the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
  • the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of its pharmaceutically acceptable salts or hydrates or solvates.
  • a compound of formula (I) may be combined with another active ingredient chosen from one of the following therapeutic classes:
  • an AT1 receptor antagonist of angiotensin II alone or in combination with a diuretic an inhibitor of the conversion enzyme, alone or in combination with a diuretic or a calcium antagonist;
  • beta-blocker alone or in combination with a diuretic or a calcium antagonist
  • an antihyperlipidemic agent or an antihypercholesterolemic agent - an antidiabetic
  • compositions containing in combination a compound of formula (I) and another active principle chosen from one of the following therapeutic classes: an AT 1 receptor antagonist of angiotensin II, alone or associated with a diuretic or calcium antagonist;
  • a beta-blocker alone or in combination with a diuretic or a calcium antagonist; an antihyperlipidemic agent or an antihypercholesterolemic agent;
  • angiotensin II AT1 receptor antagonist in particular a compound such as candesartan cilexitil, eprosartan, irbesartan, losartan potassium, olmesartan medoxomil, telmisartan, valsartan, each of these compounds may itself be associated with a diuretic such as hydrochlorothiazide.
  • conversion enzyme inhibitor is intended especially to mean a compound such as alacepril, benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, temocapril, trandolapril, zofenopril, each of these compounds may itself be associated with a diuretic such as hydrochlorothiazide or indapamide or a calcium antagonist such as amlodipine, diltiazem, felodipine or verapamil.
  • diuretic such as hydrochlorothiazide or indapamide
  • a calcium antagonist such as amlodipine, diltiazem, felodipine or verapamil.
  • calcium antagonist is understood to mean a compound such as amlodipine, aranidipine, benidipine, bepridil, cilnidipine, diltiazem, efonidipine hydrochloride ethanol, fasudil, felodipine, isradipine, lacidipine, lercanidipine hydrochloride, manidipine, mibefradil hydrochloride, nicardipine, nifedipine, nilvadipine, nimodipine. , Nisoldipine, Nitrendipine, Terodiline, Verapamil.
  • beta-blocker in particular a compound such as acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevololol, bisoprolol, bopindolol, bucumolol, bufetolol, bunitrolol, butofilolol, carazolol, cardolol, carvedilol, cloranolol, epanolol, esmolol, indenolol, labetalol, landiolol, levobunolol, levomoprolol, mepindolol, metiprolol, metoprolol, nadolol, nebivolol, nifenalol, nipradilol, oxprenolol,
  • antihyperlipidemic or antihypercholesterolemic is meant in particular a compound selected from fibrates such as alufibrate, beclobrate, bezafibrate, ciprofibrate, clinofibrate, clofibrate, etofibrate, fenofibrate; statins (HMG-CoA reductase inhibitors), such as atorvastatin, fluvastatin sodium, lovastatin, pravastatin, rosuvastatin, simvastatin, or a compound such as acipimox, aluminurn nicotinate, azacosterol, cholestyramine, dextrothyroxine, meglutol, niceritrol, nicoclonate, nicotinic acid , beta-sitosterin, tiadenol.
  • statins HMG-CoA reductase inhibitors
  • atorvastatin flu
  • antidiabetic agent is intended to mean a compound belonging to one of the following classes: sulfonylureas, biguanidines, alpha glucosidase inhibitors, thiazolidinedione, methaglinides, such as acarbose, acetohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, glybuzole, glymidine, metahexamide, metformin, miglitol, nateglinide, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, troglitazone, voglibose.
  • sulfonylureas biguanidines
  • alpha glucosidase inhibitors such as acarbose
  • anti-obesity agent in particular a compound such as amfepramone, benfluorex, benzphetamine, indanorex, mazindole, mefenorex, methamphetamine, D-norpseudoephedrine or another CB1 receptor antagonist to cannabinoids.
  • the subject of the present invention is a pharmaceutical composition containing in combination a compound of formula (I) and an AT 1 receptor antagonist of angiotensin II, in particular irbesartan, losartan or valsartan.
  • the compound of formula (I) and the other associated active ingredient can be administered simultaneously, separately or spread over time.
  • disparate use is meant the administration, at the same time, of the two compounds of the composition according to the invention, each comprised in a separate pharmaceutical form.
  • extended use over time is understood to mean the sequential administration of the first compound of the composition according to the invention, included in a pharmaceutical form, then, of the second compound of the composition according to the invention, included in a form pharmaceutical industry.

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EP05809571A 2004-10-18 2005-10-17 Pyridinderivate, deren herstellung und therapeutische anwendung Withdrawn EP1805143A1 (de)

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FR0411030A FR2876691B1 (fr) 2004-10-18 2004-10-18 Derives de pyridine, leur preparation, leur application en therapeutique
PCT/FR2005/002566 WO2006042955A1 (fr) 2004-10-18 2005-10-17 Derives de pyridine, leur preparation, leur application en therapeutique

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US (1) US20080021070A1 (de)
EP (1) EP1805143A1 (de)
JP (1) JP2008516934A (de)
KR (1) KR20070063008A (de)
CN (1) CN101039912A (de)
AR (1) AR051221A1 (de)
AU (1) AU2005296959A1 (de)
BR (1) BRPI0516926A (de)
CA (1) CA2582778A1 (de)
EA (1) EA200700891A1 (de)
EC (1) ECSP077400A (de)
FR (1) FR2876691B1 (de)
IL (1) IL182385A0 (de)
MA (1) MA29016B1 (de)
MX (1) MX2007004482A (de)
NO (1) NO20072454L (de)
NZ (1) NZ554952A (de)
PE (1) PE20060584A1 (de)
TN (1) TNSN07114A1 (de)
TW (1) TW200628450A (de)
UY (1) UY29163A1 (de)
WO (1) WO2006042955A1 (de)

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FR2899899A1 (fr) * 2006-04-14 2007-10-19 Sanofi Aventis Sa Derives d'aminomethyl pyridine, leur preparation et leur application en therapeutique
TW200815438A (en) * 2006-06-13 2008-04-01 Bayer Schering Pharma Ag Substituted pyrazolopyridines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same
US7781593B2 (en) 2006-09-14 2010-08-24 Hoffmann-La Roche Inc. 5-phenyl-nicotinamide derivatives
FR2922209B1 (fr) 2007-10-12 2010-06-11 Sanofi Aventis 5,6-DIARYLES PYRIDINES SUBSTITUES EN POSITION 2 et 3, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE.
ES2459468T3 (es) 2009-05-15 2014-05-09 Novartis Ag Arilpiridinas como inhibidores de aldosterona sintasa
EP3495348A4 (de) 2016-07-29 2020-01-22 Toray Industries, Inc. Guanidinderivat und verwendung davon für medizinische zwecke
WO2018159650A1 (ja) * 2017-02-28 2018-09-07 東レ株式会社 グアニジン誘導体及びその医薬用途

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FR2198737B1 (de) * 1972-09-13 1975-11-28 Serdex
US5686470A (en) * 1995-02-10 1997-11-11 Weier; Richard M. 2, 3-substituted pyridines for the treatment of inflammation
WO2002055502A1 (en) * 2001-01-02 2002-07-18 Fujisawa Pharmaceutical Co., Ltd. Pyridine derivatives useful as cyclooxygenase inhibitor
EP1492784A4 (de) * 2002-03-28 2006-03-29 Merck & Co Inc Substituierte 2,3-diphenylpyridine
FR2838439B1 (fr) * 2002-04-11 2005-05-20 Sanofi Synthelabo Derives de terphenyle, leur preparation, les compositions pharmaceutqiues en contenant
FR2838438A1 (fr) * 2002-04-11 2003-10-17 Sanofi Synthelabo Derives de diphenylpyridine,leur preparation, les compositions pharmaceutiques en contenant

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NZ554952A (en) 2009-08-28
CN101039912A (zh) 2007-09-19
WO2006042955A1 (fr) 2006-04-27
EA200700891A1 (ru) 2007-08-31
NO20072454L (no) 2007-05-14
KR20070063008A (ko) 2007-06-18
UY29163A1 (es) 2006-04-28
MX2007004482A (es) 2007-06-13
CA2582778A1 (fr) 2006-04-27
IL182385A0 (en) 2007-07-24
TNSN07114A1 (fr) 2008-06-02
FR2876691B1 (fr) 2006-12-29
BRPI0516926A (pt) 2008-09-23
PE20060584A1 (es) 2006-08-18
ECSP077400A (es) 2007-05-30
AR051221A1 (es) 2006-12-27
MA29016B1 (fr) 2007-11-01
TW200628450A (en) 2006-08-16
JP2008516934A (ja) 2008-05-22
AU2005296959A1 (en) 2006-04-27
FR2876691A1 (fr) 2006-04-21
US20080021070A1 (en) 2008-01-24

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