Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
  • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems

Definitions

• the present invention relates to novel condensed pyrazole derivatives, their preparation and their therapeutic application.
• the compounds of the present invention have affinity for CB2 and / or CB1 receptors of cannabinoids and are agonists of said receptors.
• ⁇ 9 -THC is the major active ingredient extracted from Cannabis sativa [Paton, Annual Review in Pharmacology (1975) 15: 191-220].
• cannabinoids due to an interaction with specific high affinity G protein-coupled receptors present at the central and peripheral level [Howlett et al., Pharmacological Reviews (2002) 54: 161-202].
• CB1 cannabinoids
• CB2 cannabinoid receptor
• n, m, x, y, R, R 1, R 1, Rm, R 5 R V and R-VI have different values.
• - W represents a direct bond or a radical -CH 2 -;
• R 1 represents a hydrogen atom or a (C 1 -C 3) alkyl
• R 2 represents: Q. a (C 1 -C 10) alkyl unsubstituted or substituted one or more times with a halogen atom; . a group -B-R4;
• R3 represents:
• a naphthyl unsubstituted or substituted by one or more substituents independently selected from a halogen atom, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a trifluoromethyl radical;
• Q quinolyl which is unsubstituted or substituted by one or more substituents independently selected from halogen, (C1-C4) alkyl, (C1-C4) alkoxy, trifluoromethyl;
• B represents a direct bond or a (C 1 -C 2 ) alkylene radical which is unsubstituted or substituted one or more times with a (C 1 -C 3) alkyl;
• R4 represents: . phenyl which is unsubstituted or substituted with one or more substituents independently selected from a halogen atom, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a tritluoromethyl radical;
• a non-aromatic C 3 -C 12 carbocyclic radical unsubstituted or substituted one or more times with a (C 1 -C 4) alkyl or a (C 1 -C 4) alkoxy;
• 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 also exist as hydrates or "He solvatsj namely in the form of associations or combinations âv ⁇ cTune ⁇ " or more molecules of water 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 2) alkylene or (C 3 -C 5) linear alkylene is understood to mean a divalent radical of one to two carbon atoms or, respectively, of three to five carbon atoms chosen from the methylene, ethylene, trimethylene and tetramethylene radicals, pentamethylene.
• (C 1 -C 3) alkyl or respectively (C 1 -C 4) alkyl is meant a linear or branched alkyl radical of one to three carbon atoms or, respectively, from one to four carbon atoms, from one to ten carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl or isobutyl radical, and butyl, tert-butyl, pentyl, isopentyl, neopentyl, fur-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl.
• alkoxy is meant a linear or branched alkoxy radical of one to four carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy.
• the non-aromatic C 3 -C 12 carbocycle radicals include mono- or polycyclic condensed, bridged or spiranic radicals.
• 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] undecanyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [3. 1-heptyl, bicyclo [3.3.1] nonyl.
• A represents a (C 3 -C 5) linear alkylene radical which is unsubstituted or substituted one or more times with a (C 1 -C 3) alkyl;
• - A represents a -CH2-CH2-O-CH2- radical
• - A represents: a linear (C 3 -C 5) alkylene radical which is unsubstituted or substituted one or more times with a (C 1 -C 3) alkyl; . " ⁇ radical -CH 2 -CH 2 -O-CH 2 -;
• - W represents a direct bond or a radical -CH 2 -;
• R 1 represents a hydrogen atom or a (C 1 -C 3) alkyl
• R 2 represents a (C 1 -C 8) alkyl or a group -B-R 4;
• R 3 represents a phenyl substituted with one or more substituents chosen independently from a halogen atom, a (C 1 -C 3) alkyl, a (C 1 -C 3) alkoxy, a trifluoromethyl radical or a trifluoromethoxy radical;
• B represents a direct bond or a (C 1 -C 2 ) alkylene radical which is unsubstituted or substituted one or more times with a (C 1 -C 3) alkyl;
• a phenyl which is unsubstituted or substituted by one or more substituents independently selected from a halogen atom, a (C 1 -C 3) alkyl, a (C 1 -C 3) alkoxy, a trifluoromethyl radical; . a non-aromatic carbocyclic radical, C3-C12 5 unsubstituted or substituted one or more times by a (C ⁇ -C3) alkyl or (C ⁇ -C3) alkoxy. in the basic state and in the state of hydrate or solvate.
• a first group of compounds consists of the compounds for which: A represents a radical - (CH 2 ) 3 -, -C (CH 3) 2 -CH 2 - CH 2 -, - (CH 2 ) 4 -, - (CH 2 ) s-,
• W represents a direct bond or a -CH 2 - radical
• R 1 represents a hydrogen atom
• R 2 represents a radical 1-adamantyl, 2-adamantyl, (1S) -1-cyclohexyl ethyl, (1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2 ⁇ n-io-yl, exo and endo-bicyc
• R3 represents a 4-chlorophenyl, a 3,4-dichlorophenyl, a 2,4-dichlorophenyl, a 4-methylphenyl, a 4-bromophenyl, a 3-chlorophenyl, a 3-fluorophenyl, a 3,5-dichlorophenyl, a -dichlorophényle, 3,4-difluorophenyl, 3-chloro-4- methylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 2,3- ⁇ ⁇ rrnéliylphényle, 3,4-diméthylphé ⁇ yle, 4-mémoxyph ⁇ ny ⁇ e7 a 2-naphthyl; 7-chloroquinolyl-4-yl; in the basic state and in the state of hydrate or solvate.
• compounds of the latter group mention may be made of compounds of formula
• - A represents a radical - (CH2) 3-, -C (CH3) 2 -CH2-CH2-, - (CH ⁇ -, - (CH ⁇ s-, -CH 2 CH 2 -O-CH2 -; - CH [CH (CH 3) 2] -CH 2 CH 2 -CH (CH 3) -;
• - W represents a direct bond or a radical -CH 2 -;
• - Rj represents a hydrogen atom;
• R 2 represents a 1-adamantyl, 2-adamantyl, (1S) -1-cyclohexylethyl, (1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2ent / o-yl, em / o- bicyclo [3.2.1] oct-3-yl, 1,1-dimethyl-2-phenylethyl, 1,1-dimethylpropyl, tert-butyl, 4-ethylcyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 2,2-dimethylpropyl, 2 methyl-1- (trifluoromethyl) propyl, 1,2,3,4-tetrahydronaphthalen-1-yl, (1 R) -6,6-dimethylbicyclo [3.1.
• R 3 represents a 4-chlorophenyl, a 3,4-dichlorophenyl, a 2,4-dichlorophenyl, a 4-methylphenyl, a 4-bromophenyl, a 3-chlorophenyl, a 3-fluorophenyl, a 3,5-dichlorophenyl, 3,4-difluorophenyl, 3-chloro-4-methylphenyl, 4-isopropylphenyl, 4-tert-butyrphenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 4-methoxyphenyl, 2- naphthyl; 7-chloroquinolyl-4-yl; in the basic state and in the state of hydrate or solvate.
• the compounds of formula (I) can be prepared according to a process which is characterized in that: an acid or a functional derivative of this acid of formula:
• the reaction is carried out in the presence of a coupling agent used in peptide chemistry, such as 1,3-dicyclohexyl carbodiimide or benzotriazol hexafluorophosphate.
• a coupling agent used in peptide chemistry such as 1,3-dicyclohexyl carbodiimide or benzotriazol hexafluorophosphate.
• yloxytris (dimethylamino) phosphonium or benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate or 2- (liy-benzotriazol-1-yl) -1,1,3,3-tetramethyl uronium tetrafluoroborate, in the presence of a base such as triethylamine, N, N-diisopropylethyl amine or 4-dimethylaminopyridine, in a solvent such as dichloromethane, dichloroethane, N, N-dimethylformamide or tetrahydrofuran at a temperature of between -1O 0 C and the temperature reflux of the solvent.
• a base such as triethylamine, N, N-diisopropylethyl amine or 4-dimethylaminopyridine
• the acid chloride As functional derivative of the acid (II) it is possible to use the acid chloride, the anhydride, a mixed anhydride, a C 1 -C 4 alkyl ester in which the alkyl is straight or branched, an activated ester, for example the ⁇ -nitrophenyl ester.
• N-methylmorpholine or pyridine N-methylmorpholine or pyridine.
• One variant consists in pre-preparing the mixed anhydride of the acid of formula (II) by reacting ethyl chloroformate with the acid of formula (II), in the presence of a base such as triethylamine, and in doing so reacted with an amine R2 HNRi in 1 ⁇ 1 solvent such as dichloromethane, under an inert atmosphere at room temperature in the presence of a base such as triethylamine.
• 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 conventional hydrolysis of an ester of formula:
• A, W and R3 are as defined for a compound of formula (I) and Alk is (C1-C3) alkyl.
• 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, 1,4 -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, 1,4 -dioxane or a mixture of these solvents and at a temperature between 0 ° C and the reflux temperature of the solvent.
• A is as defined for a compound of formula (I) and Alk is (C 1 -C 3 ) alkyl, with a hydrazine derivative of formula:
• reaction of the compound of formula (V) with the compound of formula (VI) is carried out by refluxing in acetic acid.
• A is as defined for a compound of formula (I) and Alk is (C1-C3) alkyl, with a compound of formula:
• the reaction is carried out in the presence of a strong base such as sodium hydride or sodium amide, in a solvent such as toluene and at a temperature between room temperature and the reflux temperature of the solvent.
• a strong base such as sodium hydride or sodium amide
• the compounds of formula (V) are prepared by reaction of a compound of formula:
• A is as defined for a compound of formula (I) with hexamethyldisilazane lithium salt, in a solvent such as diethyl ether and at a temperature between -70 ° C and -30 ° C. Then the metal salt is reacted in situ alkali obtained intermediately with a di- (C 1 -C 3) alkyl oxalate at a temperature between -30 ° C. and room temperature to obtain the ketoester salt of formula (V).
• the compounds of formula (VII) are prepared by reacting the compounds of formula (V) with hydrazine H 2 N -NH 2 by refluxing in acetic acid.
• the invention according to another of its aspects, also relates to the compounds of formula (II) and the compounds of formula (IV). These compounds are useful as synthesis intermediates for the compounds of formula (I).
• a linear (C 3 -C 5) alkylene radical which is unsubstituted or substituted one or more times with a (C 1 -C 3) alkyl; . a radical -CH2-CH2-O-CH2-;
• - W represents a direct bond or a -CH2- radical
• phenyl substituted by one or more substituents independently selected from a halogen atom, a (Ci-C4) alkyl, (Cj -C ⁇ alkoxy, trifluoromethyl, trifluoromethoxy radical;
• quinolyl which is unsubstituted or substituted by one or more substituents independently selected from halogen, (C1-C4) alkyl, (C1-C4) alkoxy, trifluoromethyl; gold
• the subject of the invention is also compounds of formula: in which :
• Alk represents a (C 1 -C 3) alkyl
• a linear (C 3 -C 5) alkylene radical which is unsubstituted or substituted one or more times with a (C 1 -C 3) alkyl; 10 . a radical -CH 2 -CH 2 -O-CH 2 -;
• - W represents a direct bond or a radical -CH 2 -;
• TFA trifluoroacetic acid
• BOP benzotriazol-1-yloxytiis (dimethylamino) phospholipidium lexafluoro phosphate
• 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 "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 (tr) are measured in minutes.
• the device marketed by Agilent, consists of an HP1100 chromatograph equipped with an Agilent diode array detector and MSD Quad quadrupole mass spectrometer.
• a Symmetry Cl 8 column of 2.1 x 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% of TFA in acetonitrile.
• chemical ESI Electro Spray Ionization
• the eluent is composed as follows:
• Solvent B acetonitrile.
• a suspension of 21.11 g of hexanethyldisilazane lithium salt in 150 ml of ether is cooled to -65 ° C., 13.25 ml of cyclopentanone are added over 30 minutes and the mixture is left stirring, allowing the temperature to rise to -20.degree. 30 ° C. 21.39 vol of diethyl oxalate are then added and the mixture is stirred for 18 hours at RT. The precipitate formed is filtered off, washed with ether and dried. 17.44 g of the expected compound are obtained.
• a suspension of 31.65 g of lithium salt of hexamethyldisilazane in 250 ml of ether is cooled to -65 ° C., a solution of 20 g of 2,2-dimethylcyclopentanone in 150 ml of ether and stirred while allowing the temperature to rise to -30 ° C.
• a solution of 25 ml of diethyl oxalate in 80 ml of ether is then added and the mixture is stirred. overnight stirring allowing the temperature to rise to RT.
• the precipitate formed is filtered off, washed with ether and dried. 33.55 g of the expected compound are obtained.
• a suspension of 50 g of lithium salt of hexamethyldisilazane in 300 ml of ether is cooled down to -65 ° C., a solution of 29.5 ml of cyclohexanone in 200 ml of ether is added dropwise and the mixture is then let while stirring, allowing the temperature to rise to -30 ° C.
• a solution of 40.6 ml of diethyl oxalate in 100 ml of ether is then added and the mixture is left stirring for 18 hours, allowing the temperature to rise to RT.
• the precipitate formed is filtered off. 57.45 g of the expected compound are obtained in the form of a yellow powder.
• a suspension of 50 g of lithium salt of hexamethyldisilazane in 300 ml of ether is cooled down to -65 ° C., a solution of 33.5 ml of cycloheptanone in 200 ml of ether is added dropwise, and the mixture is then let while stirring, allowing the temperature to rise to -30 ° C.
• a solution of 40.6 ml of diethyl oxalate in 100 ml of ether is then added and the mixture is left stirring for 18 hours, allowing the temperature to rise to RT.
• the precipitate formed is filtered off. 50.76 g of the expected compound are obtained.
• a suspension of 28.8 g of lithium salt of hexamethyldisilazane in 170 ml of ether is cooled to -60 ° C. and a solution of 15 ml of tetrahydro-4H-pyran-4-one is added dropwise. in 110 ml of ether and then stirred, allowing the temperature to rise to -30 ° C.
• a solution of 22.7 ml is then added of diethyl oxalate in 60 ml of ether and left stirring for 16 hours while allowing the temperature to rise to RT.
• the precipitate formed is filtered off. 31.5 g of the expected compound are obtained.
• the compounds according to the invention have shown good in vitro affinity for cannabinoid receptors CB 1 and / or CB 2 whether they are human receptors or rodent receptors.
• the binding affinity assays were performed according to the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 350, 240-244), with cell line derived membranes in which CB 1 and CB 2 receptors are expressed.
• CB 1 and CB 2 expressed as IC 50
• (Inhibitory concentration 50) is less than 500 nM for at least one of the receptors.
• the compounds according to the invention behave in vitro as agonists of the human CBJ and / or CB2 cannabinoid receptors, they reduce the cAMP production in forskolin-stimulated cells by inhibiting the adenylate. cyclase.
• the tests were carried out according to the experimental conditions described by M. Rinaldi-Carmona et al., J. Pharmacol. Exp. Ther., 1996, 278, 871-878 and M. Bouaboula et al, J. Biol. Chem., 1997, 272, 22330-22339.
• the present invention relates to the use of the compounds of formula (I), or one of their solvates and / or pharmaceutically acceptable hydrates, for the preparation of medicaments intended to treat and prevent diseases. involving cannabinoid receptors CBj and / or
• the compounds according to the invention can therefore be used for the preparation of medicaments, in particular CB2 receptor agonists and / or CB 1 cannabinoids.
• the subject of the invention is medicaments which comprise a compound of formula (I), or a hydrate or a solvate of the compound of formula (I).
• These drugs find their use in therapeutics especially as psychotropic medication, especially for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders, psychoses in general, schizophrenia.
• the compounds of formula (I) according to the invention can be used as a medicament for the treatment of migraine, stress, psychosomatic diseases, spinal cord injuries, vertigo, panic attack attacks. , epilepsy, movement disorders, tremors and dystonia.
• the compounds of formula (I) according to the invention can also be used as a medicament for the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementias, of Alzheimer's disease.
• the compounds of formula (I) may be useful as a neuroprotector, in the treatment of ischemia, head trauma and in the treatment of neurodegenerative diseases, including chorea, Huntington's disease, syndrome Tourette, Parkinson's disease, multiple sclerosis.
• the compounds of formula (I) according to the invention can be used as a medicament for the treatment of pain and inflammation: neuropathic pain, diabetic neuropathy, peripheral acute pain, chronic inflammatory pain, cancer pain, pain associated with multiple sclerosis. Ocular conditions such as ocular hypertension, glaucoma or uveal inflammation.
• the compounds of formula (I) according to the invention may be used as a medicament for the treatment of appetite disorders such as loss of appetite (cachexia) associated or not with chemotherapeutic treatments.
• appetite disorders such as loss of appetite (cachexia) associated or not with chemotherapeutic treatments.
• the compounds of formula (I) according to the invention may be used as a medicament for the treatment of diseases of the gastrointestinal system (Crohn's disease, irritable or inflammable bowel disease (in English IBS and IBD), ulcer, ulcerative colitis, GERD and its consequences (chronic laryngitis), regurgitation, intestinal spasm, uterine spasms, loosening vomiting (especially those following chemotherapy), bladder and urinary disorders, glomerulonephritis, cystitis, renal ischemia.
• diseases of the gastrointestinal system Crohn's disease, irritable or inflammable bowel disease (in English IBS and IBD), ulcer, ulcerative colitis, GERD and its consequences (chronic laryngitis
• Formula (I) according to the invention can be used as a medicament in the treatment of cardiovascular diseases (in particular hypertension, arteriosclerosis, myocardial infarction and cardiac ischemia), hemorrhagic shock, shock septic, chronic cirrhosis of the liver, hepatitis, acute or chronic pancreatitis, lung diseases such as respiratory diseases, asthma, cough, chronic bronchitis, chronic obstruction of COPD: chronic obstructive pulmonary disease, emphysema or sleep-related breathing disorders, Raynaud's disease, glaucoma, fertility disorders, bone diseases such as osteoporosis, Paget's disease.
• cardiovascular diseases in particular hypertension, arteriosclerosis, myocardial infarction and cardiac ischemia
• hemorrhagic shock shock septic
• chronic cirrhosis of the liver hepatitis
• acute or chronic pancreatitis acute or chronic pancreatitis
• lung diseases such as respiratory diseases, asthma, cough, chronic bron
• the compounds of formula (I) according to the invention can be used as a medicament for the treatment of disorders of the immune system, in particular autoimmune diseases such as psoriasis, lupus erythematosus, eczema, connective tissue or connective tissue diseases, Sjogrer syndrome, ankylosing spondylitis, rheumatoid arthritis, reactive arthritis, undifferentiated spondyloarthritis,
• autoimmune diseases such as psoriasis, lupus erythematosus, eczema, connective tissue or connective tissue diseases, Sjogrer syndrome, ankylosing spondylitis, rheumatoid arthritis, reactive arthritis, undifferentiated spondyloarthritis,
• the compounds of formula (I) according to the invention can be used as a medicament for the treatment of inflammatory diseases, especially joint diseases (rheumatoid arthritis, arthritis, rosteoarthritis, spondylitis, tendon synovitis). , gout), vasculitis.
• the compounds of formula (I) according to the invention can be used as a medicament in the treatment of allergic diseases such as delayed or immediate hypersensitivity, seasonal allergic rhinitis, contact dermatitis or dermatitis. allergic conjunctivitis.
• the compounds of formula (I) according to the invention can be used as a medicament in the treatment of cancers: benign tumors of the skin, papillomas and cancerous tumors (melanoma), prostate tumors, tumors brain (glioblastomas, medullo-epitheliomas, medulloblastomas, neuroblastomas, embryonic origin tumors, astrocytomas, astroblastomas, ependymomas, oligodendrogliom.es, plexus tumor, neuroepitheliomas, epiphysis tumor, ependymoblastomas, neuroectodermosis, malignant meningiomas, sarcomatoses , malignant melanomas, schwannomas) and for the treatment of Guillain-Barré syndrome.
• the compounds of formula (I) are particularly useful for the treatment of appetite disorders such as loss of appetite (cachexia), for the treatment of neurodegenerative diseases, demyelinating diseases and as neuroprotective and antitumor agents, for the treatment of disorders of the immune system, in particular autoimmune diseases, for the treatment of diseases of the respiratory tract and bone, in particular osteoporosis, for the treatment of pain (acute and / or or chronic) as well as for the treatment of inflammatory diseases.
• appetite disorders such as loss of appetite (cachexia)
• neurodegenerative diseases such as neurodegenerative diseases, demyelinating diseases and as neuroprotective and antitumor agents
• disorders of the immune system in particular autoimmune diseases, for the treatment of diseases of the respiratory tract and bone, in particular osteoporosis, for the treatment of pain (acute and / or or chronic) as well as for the treatment of inflammatory diseases.
• autoimmune diseases for the treatment of diseases of the respiratory tract and bone, in particular osteoporosis
• pain acute and / or or chronic
• the present invention relates to the use of a compound of formula (I), its 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.
• 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 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 Mannitol 223.75 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 plaids " ⁇ âfépâ ⁇ ⁇ s ⁇ 3ù ⁇ it pàtie ⁇ H " .
• 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 hydrates or solvates.

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• Pulmonology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

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Citations (5)

• 2004
  • 2004-09-13 FR FR0409712A patent/FR2875230A1/fr not_active Withdrawn
• 2005
  • 2005-09-06 PE PE2005001028A patent/PE20060627A1/es not_active Application Discontinuation
  • 2005-09-09 AR ARP050103775A patent/AR051288A1/es not_active Application Discontinuation
  • 2005-09-09 UY UY29112A patent/UY29112A1/es not_active Application Discontinuation
  • 2005-09-12 TW TW094131307A patent/TW200621786A/zh unknown
  • 2005-09-12 WO PCT/FR2005/002255 patent/WO2006030124A1/fr active Application Filing

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