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  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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  • A61P25/00—Drugs for disorders of the nervous system
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
  • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D333/30—Hetero atoms other than halogen
  • C07D333/34—Sulfur atoms

Definitions

• the present invention relates to substituted N - [(4,5-diphenyl-2-thienyl) methyl] sulfonamide derivatives, their preparation and their therapeutic application.
• Diphenylpyrazole derivatives having an affinity for the CB 1 receptors of cannabinoids have been described in particular in patents US 5,624,941, EP 0 576 357, EP 0 656 354, EP 1 150 961 and WO 2005/073197.
• Thiophene-2-carboxamide derivatives are described in international application WO 2005/035488.
• X represents a group -SO- or -SO 2 -; • R ] [represents:
• a non-aromatic (C 3 -C 12) carbocyclic radical which is unsubstituted or substituted one or more times with a (C 1 -C 4) alkyl
• a (C 3 -C 7) cycloalkylmethyl which is unsubstituted or substituted one or more times on the carbocycle by a (C 1 -C 4) alkyl
• benzyl which is unsubstituted or mono- or disubstituted on the phenyl by substituents independently selected from halogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, trifluoromethyl or alpha-substituted with one or two similar or different groups selected from (C 1 -C 4) alkyl, (C 3 -C 7) cycloalkyl;
• phenethyl which is unsubstituted or mono- or disubstituted on phenyl by substituents independently selected from a halogen atom, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a trifluoromethyl radical; . unsubstituted or mono- or disubstituted naphthyl with substituents independently selected from (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, trifluoromethyl;
• an aromatic heterocyclic radical chosen from pyrrolyl, imidazolyl, furyl, thienyl, pyrazolyl, indolyl, 2,3-dihydrobenzofuryl which is unsubstituted or substituted one or more times with substituents chosen independently from a halogen atom, a (C 1 -C 4) alkyl, a trifluoromethyl radical;
• R 2 represents a hydrogen atom or a (C 1 -C 3) alkyl group
• R 3 represents an unsubstituted or mono-, di- or trisubstituted phenyl with substituents chosen independently from a halogen atom, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a trifluoromethyl radical or a group S (O) n AIk;
• R 4 represents an unsubstituted or mono-, di- or trisubstituted phenyl by substituents independently selected from a halogen atom, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a trifluoromethyl radical or a group S (O) n AIk;
• n 0, 1 or 2;
• Alk represents a (C 1 -C 4) alkyl.
• the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures, form part of the invention.
• the compounds of formula (I) may exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the invention.
• halogen atom is meant a bromine, chlorine, fluorine or iodine atom.
• (C 1 -C 3) alkyl or (C 1 -C 4) alkyl or (C 1 -C 7) alkyl it is meant a linear or branched alkyl radical of one to three carbon atoms or of one to four carbon atoms or of one to four carbon atoms respectively. to seven carbon atoms, such as, for example, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and heptyl radicals.
• (C1-C4) alkoxy means a linear or branched alkoxy radical of one to four carbon atoms, such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy radical.
• cycloalkyl is meant a cyclic alkyl group of 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
• C3-C12 non-aromatic carbocyclic radicals include mono or polycyclic radicals, fused, bridged or spiranic.
• Monocyclic radicals include cycloalkyls for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
• the fused, bridged or spiro di- or tricyclic radicals include, for example, norbornyl, bornyl, isobornyl, noradamantyl, adamantyl, spiro [5.5] undecyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl; bicyclo [3.1.1] heptyl.
• X represents a group -SO 2 -
• a (C1-C7) alkyl unsubstituted or substituted one or more times with a halogen atom; . a (C 3 -C 7) cycloalkyl which is unsubstituted or substituted one or more times with a (C 1 -C 3) alkyl group; . a (C 3 -C 7) cycloalkylmethyl which is unsubstituted or substituted one or more times on the carbocycle by a (C 1 -C 3) alkyl; .
• benzyl which is unsubstituted or mono- or disubstituted with substituents independently selected from halogen, (C1-C4) alkyl, (C1-C4) alkoxy, trifluoromethyl;
• R 2 represents a hydrogen atom or a (C 1 -C 3) alkyl
• R 3 represents an unsubstituted or mono-, di- or trisubstituted phenyl with substituents chosen independently from a halogen atom, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a trifluoromethyl radical or a group S (O) n AIk;
• R 4 represents an unsubstituted or mono-, di- or trisubstituted phenyl by substituents independently selected from a halogen atom, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a trifluoromethyl radical or a group S (O) n AIk;
• n 0, 1 or 2;
• AUc represents a (C 1 -C 4) alkyl, in the base state as well as in the hydrate or solvate state.
• a first group of compounds consists of the compounds for which:
• X represents a group -SO- or -SO 2 -;
• R2 represents a hydrogen atom
• R3 represents a 4-chlorophenyl; 4-bromophenyl; A-methoxyphenyl; 2,4-dichlorophenyl; and / or R4 represents a 2,4-dichlorophenyl; 4-methoxyphenyl; as well as their hydrates or their solvates.
• X represents a group -SO- or -SO 2 -;
• R2 represents a hydrogen atom
• R3 represents a 4-chlorophenyl; 4-bromophenyl; 4-methoxyphenyl; a
• R4 represents 2,4-dichlorophenyl; 4-methoxyphenyl; as well as their hydrates or their solvates.
• R2 represents a hydrogen atom
• R3 represents a 4-chlorophenyl; 4-bromophenyl;
• R4 represents 2,4-dichlorophenyl; as well as their hydrates or their solvates.
• a protective group Pg is understood to mean a group that 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 Group 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, triflate, acetate, etc. Examples of leaving groups as well as references for their preparation are given in Advances in Organic Chemistry, J. Tuesday, 3 rd Edition, Wiley Interscience, 1985, p. 310-316.
• the compounds of formula (I) can be prepared according to a process which is characterized in that a compound of formula:
• R 1 is as defined for a compound of formula (I) and Hal represents a halogen atom when a compound of formula (I) is to be prepared in which -X- represents a group -SO-;
• reaction is carried out in the presence of a base such as triethylamine, in a solvent such as dichloromethane and at a temperature comprised between ambient and the reflux temperature of the solvent.
• a base such as triethylamine
• a compound of formula (II) is treated with a sulfonyl halide of formula (III)
• the reaction is carried out in the presence of a base such as triethylamine, diisopropylethylamine or 4-dimethylaminopyridine in a solvent such as dichloromethane , tetrahydrofuran, or N, N-dimethylformamide, and at a temperature between 0 ° C and the reflux temperature of the solvent.
• a base such as triethylamine, diisopropylethylamine or 4-dimethylaminopyridine
• a solvent such as dichloromethane , tetrahydrofuran, or N, N-dimethylformamide
• the compounds of formula (I) in which -X- represents a group -SO 2 - can be prepared by reaction of a compound of formula (I) in which -X- represents a group -SO- with an oxidizing agent.
• an oxidizing agent it is possible to use 3-chloroperbenzoic acid in a solvent such as dichloromethane and at a temperature of between 0 ° C. and room temperature.
• the compounds of formula (I) thus obtained may subsequently be separated from the reaction medium and purified by conventional methods, for example by crystallization or chromatography.
• the compounds of formula (II) are prepared by reaction of a compound of formula: in which R3 and R4 are as defined for a compound of formula (I) and Y represents a leaving group as defined above, preferably a halogen atom or an activated hydroxy group such as a methanesulfonate group, benzene sulfonate, p-toluenesulfonate or triflate, with a compound of formula:
• the reaction is carried out in a solvent such as N, 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.
• R3 and R4 are as defined for a compound of formula (I).
• the reduction is effected by means of a reducing agent such as borane in a solvent such as tetrahydrofuran, at a temperature between room temperature and the reflux temperature of the solvent, followed by acid hydrolysis.
• 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 between -10 0 C and 200 ° C.
• a halogenating agent such as phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride
• a compound of formula (VU) when in a compound of formula (IV), Y represents a halogen atom, a compound of formula (VU) is treated with a halogenating agent such as PC15, PBrc, HBr or BBr3, in a solvent such as dichloromethane and at a temperature between -10 ° C and room temperature.
• a halogenating agent such as PC15, PBrc, HBr or BBr3
• a solvent such as dichloromethane
• Y represents a methanesulphonate, a benzenesulphonate, a p-toluenesulphonate or a trifluoromethanesulphonate
• a compound of formula (VTI) is reacted with a sulphonyl chloride of formula W-SO 2 -Cl in W 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 between -2O 0 C and the temperature of reflux of the solvent.
• a base such as triethylamine, pyridine or N, N-diisopropylethylamine
• the compounds of formula (VI) are prepared by reacting an acid or a functional derivative of this acid of formula:
• R3 and R4 are as defined for a compound of formula (I), with ammonia.
• the compounds of formula (VI) are prepared by a -reduction reaction of the compounds of formula:
• R3 and R4 are as defined for a compound of formula (I) and Z is hydroxy or (C1-C2) alkoxy.
• 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 of between -20 ° C. and the temperature room.
• a reducing agent such as sodium borohydride or lithium aluminum hydride
• a solvent such as tetrahydrofuran
• the acid may be previously activated by reaction with ethyl chloroformate in the presence of triethylamine.
• the reaction is carried out by hydrolysis in an alkaline medium using, for example, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in a solvent such as water, methanol, 1,2-dimethoxyethane 1,4-dioxane or a mixture of these solvents and at a temperature between 0 ° C. and the reflux temperature of the solvent.
• an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide
• a solvent such as water, methanol, 1,2-dimethoxyethane 1,4-dioxane or a mixture of these solvents and at a temperature between 0 ° C. and the reflux temperature of the solvent.
• step a1 of SCHEME I the reaction of a compound of formula (X) with a compound of formula (XI) is carried out in the presence of an alkali metal salt of hexamethyldisilazane such as the sodium salt for example, in a solvent such as tetrahydrofuran and at a temperature between -70 0 C and 0 ° C.
• an alkali metal salt of hexamethyldisilazane such as the sodium salt for example
• step b_L the compound of formula (XII) thus obtained is reacted with the mixture N, N-dimethylformamide / phosphorus oxychloride in a solvent such as 1,2-dichloroethane and at a temperature between - 10 ° C. and the reflux temperature of the solvent.
• a solvent such as 1,2-dichloroethane
• step c1 The compound (XIII) thus obtained is reacted in step c1 with the compound (XIV), in the presence of a base such as 1,8-diazabicyclo [5,4,0] undec-7-ene, in a solvent such as acetonitrile and at a temperature between room temperature and the reflux temperature of the solvent.
• a base such as 1,8-diazabicyclo [5,4,0] undec-7-ene
• DIPEA diisopropylethylamine
• Silica H silica gel 60 H marketed by Merck (DARMSTAD)
• Buffer solution pH 2: 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 chromato graphy / UV detection / mass spectrometry).
• the molecular peak (MH) and the retention time (tr) are measured in minutes.
• a symmetry C18 column of 2.1 ⁇ 50 mm, 3.5 ⁇ m, is used at 30 ° C., flow rate 0.4 ml / minute.
• the eluent is composed as follows: solvent A: 0.005% trifluoroacetic acid (TFA) in water at pH 3.15; solvent B: 0.005% TFA in acetonitrile. Gradient:
• the eluent is composed as follows: - solvent A: 10 mM ammonium acetate (ACONH4) in water at pH 7; solvent B: acetonitrile.
• the eluent is composed as follows:
• solvent A 10 mM ammonium acetate (ACONH4) in water at pH 7;
• the eluent is composed as follows: solvent A: 0.025% trifluoroacetic acid (TFA) in water; solvent B: 0.025% of TFA in acetonitrile;
• solvent A 0.025% trifluoroacetic acid (TFA) in water
• solvent B 0.025% of TFA in acetonitrile
• UV detection is performed by an iodine bar detector between 210 and 400 nM and ESI positive chemical ionization mass detection.
• reaction mixture is poured into an ice / 1 liter mixture of 2N HCl, extracted with ether, the organic phase washed with saturated NaHCO 3 solution, with water, dried over Na 2 SO 4 and the solvent evaporated under vacuum to a volume of 200 ml, pentane added and the product filtered off crystallized formed. 80 g of the expected compound are obtained.
• reaction mixture is poured into ice / 1 liter 2N HCl, extracted with ether, the organic phase washed with saturated NaHCO 3 solution, dried over Na 2 SO 4 and the solvent evaporated in vacuo.
• the residue is chromatographed on silica gel, eluting with heptane and then with the heptane / AcOEt mixture to (90/10; v / v). 29 g of the expected compound are obtained.
• reaction mixture is concentrated under vacuum, the residue is taken up in a 0.5N HCl solution and extracted with ether / AcOEt mixture, the organic phase is dried over Na 2 SO 4 and the solvents are evaporated under vacuum. The residue is taken up in an ether / iso ether mixture and the precipitate formed is filtered off with suction. 6 g of the expected compound are obtained.
• This compound is prepared following the procedures described successively in Preparations 1.3, 2.3, 3.3, 6.2, 7.2 and 8.3.
• Pentane-3-sulphonyl chloride A. 1-Ethylpropyl imidothiocarbamate.
• a solution of 44 g of the compound expected in the preceding stage in 150 ml of water is heated to 60 ° C. and a concentrated solution of NaOH is slowly added until the two phases are formed in the reaction mixture.
• the mixture is extracted with ether and the organic phase is dried over Na.sub.2SO.sub.4 and the solvent is evaporated under vacuum. 10 g of the expected compound are obtained, which is used as such.
• the compounds of formula (II) (Preparation 8.1 or 8.4) are dissolved in DMF at the concentration of 5 M in the presence of 3 equivalents of DIPEA. 300 ml of these solutions are placed in each 2 ml well and 120 ⁇ l of a solution containing the corresponding compound of formula (III) in THF are added at a concentration of 0.25 M. The plates are stirred at room temperature for 16 hours. hours then evaporate. The products formed in each well are dissolved by addition of 500 ⁇ l of AcOEt, 400 ⁇ l of 0.1 M Na 2 CO 3 are added and the plates are agitated. After decantation, 430 ⁇ l of aqueous phase are discarded, 300 ⁇ l of 5% NaCl are added and the plates are stirred. After decantation, 350 ⁇ l of aqueous phase are discarded and the compounds are analyzed by LC / UV / MS by taking 20 ⁇ l. The expected compounds are obtained by vacuum evaporation of the rest of the solution.
• Method column represents one of the analysis methods used to determine the molecular peak MH + (or MNH4 if specified) and the retention time as described above,
• the compounds of formula (I) have a very good in vitro affinity (IC 50 ⁇ 5.10 "7 M) for cannabinoid CB 1 receptors, under the experimental conditions described by M. Rinaldi-Carmona et al (FEBS Letters, 1994, 350, 240-244).
• the toxicity of the compounds of formula (I) is compatible with their use as a medicament.
• the subject of the invention is medicaments which comprise a compound of formula (I), or a solvate or a hydrate of the compound of formula (I).
• the compounds according to the invention can be used in humans or animals, in the treatment or prevention of diseases involving cannabinoid CB 1 receptors.
• the compounds of formula (I) are useful as psychotropic drugs, especially for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders , obsessive-compulsive disorder, psychosis in general, schizophrenia, attention deficit and hyperactivity disorder (ADHD) in hyperkinetic children (BDM), and 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-compulsive disorder, psychosis in general, schizophrenia, attention deficit and hyperactivity disorder (ADHD) in hyperkinetic children (BDM), and 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.
• 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, especially in the treatment of senile dementia, Alzheimer's disease, as well as in the treatment of attention disorders or vigilance.
• 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, fatty liver, steatohepatitis, asthma, Raynaud's syndrome, glaucoma , disorders of fertility, premature termination of pregnancy, inflammatory phenomena, diseases of the immune system, especially autoimmune and neuroinflammatory such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, multiple sclerosis in plaque, infectious and viral diseases such as encephalitis, stroke and as drugs for chemotherapy. anticancer 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 disorder (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.
• ADHD attention deficit and hyperactivity disorder
• BDM hyperkinetic children
• the present invention relates to the use of a compound of formula (I), 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.
• These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, a solvate or hydrate of said compound, as well as at least one pharmaceutically acceptable excipient.
• Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
• compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active ingredient of formula (I) above, or its solvate or hydrate, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of 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:
• the dose of active ingredient administered per day can reach 0.01 to 100 r ⁇ g / 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 above-mentioned pathologies which comprises administering to a patient an effective dose of a compound according to the invention, or a of its hydrates or solvates.

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• 2005
  • 2005-01-19 FR FR0500570A patent/FR2880890B1/fr not_active Expired - Fee Related
• 2006
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  • 2006-01-18 WO PCT/FR2006/000115 patent/WO2006077320A1/fr active Application Filing
  • 2006-01-18 AU AU2006207382A patent/AU2006207382A1/en not_active Abandoned
  • 2006-01-18 KR KR1020077018890A patent/KR20070107048A/ko not_active Application Discontinuation
  • 2006-01-18 EP EP06709122A patent/EP1841754A1/fr not_active Withdrawn
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• 2007
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