EP1853557A2 - 1,5-diarylpyrrolderivate, verfahren zur deren herstellung und deren anwendung in der therapie - Google Patents

1,5-diarylpyrrolderivate, verfahren zur deren herstellung und deren anwendung in der therapie

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Publication number
EP1853557A2
EP1853557A2 EP06709331A EP06709331A EP1853557A2 EP 1853557 A2 EP1853557 A2 EP 1853557A2 EP 06709331 A EP06709331 A EP 06709331A EP 06709331 A EP06709331 A EP 06709331A EP 1853557 A2 EP1853557 A2 EP 1853557A2
Authority
EP
European Patent Office
Prior art keywords
formula
alkyl
compound
substituted
radical
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.)
Withdrawn
Application number
EP06709331A
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English (en)
French (fr)
Inventor
Francis Barth
Christian Congy
Laurent Hortala
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 SA
Original Assignee
Sanofi Aventis France
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Publication date
Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
Publication of EP1853557A2 publication Critical patent/EP1853557A2/de
Withdrawn legal-status Critical Current

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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Definitions

  • the present invention relates to 1,5-diarylpyrrole 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 Pat. No. 5,624,941, EP 0 576 357, EP 0 656 354 and EP 1 150 961.
  • Patent application WO 2005/058249 discloses diarylpyrrole derivatives as modulators of cannabinoid receptors and the patent application WO
  • X represents a group -C ff-, -SO 2 -, -N-C (R 7 ) -, -C fN (R 7 ) - ; )
  • R 1 represents a hydrogen atom or a (C 1 -C 3) alkyl group
  • R2 represents: a (C1-C12) alkyl unsubstituted or substituted with one or more substituents independently selected from hydroxyl, (C1-C4) alkoxy, trifluoromethyl, trifluoromethoxy;
  • a non-aromatic carbocyclic radical (C3-C12) unsubstituted or substituted one or more times by (Ci-C3) alkyl or (Ci-C3) alkoxy; . (C3-C7) cycloalkylmethyl which is unsubstituted or substituted one or more times on the carbocycle by (C1-C3) alkyl or (C1-C3) alkoxy;
  • a phenyl which is unsubstituted or substituted one or more times with substituents chosen independently from a halogen atom, a (C 1 -C 4 ) alkyl, a (C 1 -C 4) alkoxy, a cyano, a trifluoromethyl radical, a trifluoromethoxy radical, a di (C 1 -C 4) alkylamino radical, a group S (O) 1 n AIk, a group (C 1 - C4) alkylcarbonyl, or from a phenyl, pyrrol-1-yl, imidazolyl, pyridyl, pyrazolyl radical, said radicals being unsubstituted or substituted one or more times with a (C1-C4) alkyl; benzodioxolyl, dihydrobenzofuranyl, dihydrobenzodioxinyl; methyl substituted with benzodioxolyl, dihydr
  • R 3 represents a (C 1 -C 5) alkyl or a (C 3 -C 7) cycloalkyl
  • R 4 represents a phenyl that is unsubstituted or substituted one or more times with substituents chosen independently from a halogen atom, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a trifluoromethyl radical or an S (O) group; ) m Alk group;
  • R 5 represents a phenyl which is unsubstituted or substituted one or more times with substituents chosen independently from a halogen atom, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a trifluoromethyl radical or an S (O) group; ) 1n AIk;
  • R 5 represents a hydrogen atom or a (C 1 -C 5) alkyl group
  • R7 represents a hydrogen atom or a (C1-C3) alkyl
  • n 0, 1 or 2;
  • 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 molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.
  • X represents a group -C-, -SO 2 -, -CN (R 7 ) -;
  • R 1 represents a hydrogen atom or a (C 1 -C 3) alkyl group
  • R2 represents:
  • benzyl which is unsubstituted or substituted one or more times with substituents independently selected from a halogen atom, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a trifluoromethyl radical;
  • R 4 represents a phenyl which is unsubstituted or substituted one or more times 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) 1n AIk;
  • R 5 represents a phenyl which is unsubstituted or substituted one or more times with substituents - chosen independently from a halogen atom, a (C 1 -
  • R ⁇ represents a hydrogen atom or a (C 1 -C 5) alkyl group
  • R7 represents a hydrogen atom or a (C1-C3) alkyl
  • n 0, 1 or 2;
  • Alk represents a (C 1 -C 4) alkyl.
  • halogen atom is meant a bromine, chlorine, fluorine or iodine atom.
  • (C 1 -C 3) alkyl or (C 1 -C 4) alkyl, (C 1 -C 5) alkyl, (C 1 -C 7) alkyl, or (C 1 -C 2) 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 five carbon atoms, from one to seven carbon atoms, or from one to twelve carbon atoms, such as, for example, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, 2-propylbutyl, octyl, nonyl, decyl, unde
  • alkoxy is meant a linear or branched alkoxy radical of one to four carbon atoms such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy radical.
  • cycloalkyl is meant a cyclic alkyl group of 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
  • a non-aromatic C 3 -C 12 carbocyclic radical is meant: a monocyclic radical or a condensed or bridged di- or tricyclic radical; by radical monocyclic means a cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, the cyclopentyl, cyclohexyl and cycloheptyl radicals being preferred; the term "fused or bridged di- or tricyclic radical" is understood to mean, for example, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, adamantyl.
  • R4 and R5 are each independently 2,4-dichlorophenyl and 4-chlorophenyl or 2,4-dichlorophenyl and 4-bromophenyl or 2,4-dichlorophenyl and 4-chlorophenyl; methoxyphenyl;
  • Rg represents a hydrogen atom
  • R2 and X have one of the values defined for (I); and / or R7 represents a hydrogen atom; as well as their hydrates or their solvates.
  • X is as defined for (I);
  • - Rj represents a hydrogen atom
  • - R3 represents a methyl
  • R4 and R5 each independently of one another is 2,4-dichlorophenyl and 4-chlorophenyl or 2,4-dichlorophenyl and 4-bromophenyl or 2,4-dichlorophenyl and 4-methoxyphenyl;
  • R2 represents:
  • a benzyl which is unsubstituted or substituted one or more times with substituents independently chosen from a halogen atom, a trifluoromethyl, a methoxy, a cyano; a phenyl which is unsubstituted or substituted one or more times with substituents independently chosen from a halogen atom, a trifluoromethyl, a methoxy, a cyano or a phenyl;
  • a heterocyclic radical chosen from pyrazolyl or furyl, said radical being unsubstituted or substituted by one or more substituents chosen independently from a (C 1 -C 4) alkyl, a trifluoromethyl;
  • Ri represents a hydrogen atom
  • - R.3 represents a methyl
  • R 4 represents a 4-methoxyphenyl, a 4-chlorophenyl, a 4-methoxyphenyl, or a 2,4-dichlorophenyl;
  • R 5 represents a 4-chlorophenyl, a 4-methoxyphenyl, or a 2,4-dichlorophenyl;
  • - R ⁇ represents a hydrogen atom;
  • X represents a group -CO-, -SO2-, -CONH- or -CSNH-;
  • R2 represents a group chosen from a chlorophenyl, a trifluoromethylphenyl, a methoxyphenyl, a cyanophenyl, a 2-phenylphenyl, a trifluoromethylbenzyl, a hept-4-yl, a cycloheptyl, a 3,3,3-trifluoro-2-hydroxy- 2-methylpropyl, 2,2-dimethyl-l (lH "pyrrol-l-yl) propyl, indol-2-yl, 5-trifluoromethyl withhyl-2-fur-3-yl, a l-ethyl- 3-tert-butylpyrrol-5-yl, phenethyl, 1,2,3,4-tetrahydronaphth-2-yl, 1,2,3,4-tetrahydronaphth-1-yl, and their hydrates or solvates.
  • the compounds of formula (I) can be prepared according to a process which is characterized in that a compound of formula:
  • Hal-S ⁇ 2-R2 (IV) wherein R2 is as defined for a compound of formula (I) and HaI represents a halogen atom, preferentially chlorine, when a compound of formula (I) in which -X- represents a group -SO2-; or by a haloformate of formula:
  • HaICOOAr (V) in which HaI represents a halogen atom and Ar represents a phenyl or an A-nitrophenyl to obtain an intermediate compound of formula:
  • R 1, R 3, R 4, R 5 and R 6 are as defined for a compound of formula
  • the compound of formula (I) is converted to one of its addition salts with an acid.
  • Dimethylformamide or tetrahydrofuran at a temperature of from -10 ° C to the reflux temperature of the solvent.
  • the acid chloride As the functional derivative of the acid (III) 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.
  • the chloride of the acid obtained can also be reacted by reaction of thionyl chloride or oxalyl chloride with the acid of formula (III), with the compound of formula ( II), in a solvent, such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), or an amide (N, N-dimethylformamide for example) under an inert atmosphere, at a temperature between 0 ° C. and room temperature, in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine.
  • a solvent such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), or an amide (N, N-dimethylformamide for example) under an inert atmosphere, at
  • An alternative is to prepare the mixed anhydride of the acid of formula (III) by reaction of ethyl chloroformate with the acid of formula (III), in the presence of a base such as triethylamine, and react with the compound of formula (II), in a solvent such as dichloromethane, under an inert atmosphere, at room temperature, in the presence of a base such as triethylamine.
  • a compound of formula (II) is treated with a sulphonyl halide of formula (IV)
  • the 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
  • a base such as triethylamine
  • the compounds of formula (I) in which -X- represents a -CON (Ry) - group can be prepared by reacting a compound of formula (II) with a compound of formula C1CON (R7) R2 (IX) in the presence of a base such as triethylamine, in a solvent such as dichloromethane and at a temperature between 0 ° C and room temperature.
  • 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) may be prepared according to the following reaction scheme: SCHEME 1
  • Step (a) is carried out in the presence of a metal alkoxide in an alcohol, for example in the presence of sodium ethanolate in ethanol or in ethanol mixed with toluene at 0 ° C.
  • step (b) the addition of the amine of formula (XIII) is carried out in a protic solvent, for example an alcoholic solvent at a temperature between the temperature ambient and the solvent reflux temperature.
  • a protic solvent for example an alcoholic solvent at a temperature between the temperature ambient and the solvent reflux temperature.
  • step (e) the reduction of the carboxamide function of the compound of formula (XVI) is carried out using a reducing agent such as borane or lithium aluminum hydride, in a solvent such as tetrahydrofuran or the iso ether at a temperature between room temperature and the reflux temperature of the solvent, followed by acid hydrolysis.
  • a reducing agent such as borane or lithium aluminum hydride
  • R 1 represents a hydrogen atom or a (C 1 -C 3) alkyl group
  • R3 represents a (C1-C5) alkyl or a (C3-C7) cycloalkyl
  • R 4 represents a phenyl which is unsubstituted or substituted one or more times 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) 1n AIk;
  • R5 represents a phenyl which is unsubstituted or substituted one or more times 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) m Alk;
  • n 0, 1 or 2;
  • Alk represents a (C 1 -C 4) alkyl.
  • the present invention relates to compounds of formula:
  • R 4 and R 5 are each independently 2,4-dichlorophenyl and 4-chlorophenyl or 2,4-dichlorophenyl and 4-bromophenyl or 2,4-dichlorophenyl and 4-methoxyphenyl.
  • the compounds of formula (III) are known.
  • the compounds of formula (IV) are commercially available or described in the literature, or may be prepared according to methods described therein such as in J. Org. Chem. USSR 5 1970, 6, 2454-2458; J. Am. Chem. Soc., 1952, 74, 2008; J. Med. Chem., 1977, 20 (10), 1235-1239; EP0469984; WO95 / 18105.
  • 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.
  • a halogenating agent such as phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride
  • 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.
  • a symmetry C18 2.1 x 50 mm, 3.5 ⁇ m column was 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.
  • the eluent is composed as follows:
  • Solvent A 0.025% TFA in water
  • Solvent B 0.025% TFA in acetonitrile.
  • UV detection is performed by a diode array detector between 210 and 400 nm and ESI positive mass detection.
  • 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.
  • 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.
  • the compounds of formula (II) in DMF are dissolved at a concentration of 0.1 M in the presence of 3 equivalents of DIPEA. 300 ⁇ l of these solutions are added to each 2 ml well and 120 ⁇ l of a solution containing the corresponding sulfonyl chloride of formula (FV) in THF at a concentration of 0.25 M are added. The plates are stirred at RT. for 16 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 is discarded, 20 ⁇ l are taken for LC / UV / MS analysis and the residue is evaporated under vacuum to obtain the expected compound.
  • the compounds of formula (II) in DMF are dissolved at a concentration of 0.1 M in the presence of 3 equivalents of DIPEA. 300 ⁇ l of these solutions are added to each well of 2 ml and 120 ⁇ l of a solution containing the corresponding isocyanate compound of formula (TX) in THF at a concentration of 0.25 M are added. The pies are shaken at RT for 16 hours.
  • the products formed in each well are dissolved by addition of 500 ⁇ l of AcOEt, add 400 ⁇ l of 0.1 M Na2C ⁇ 3 and shake the plates. 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 is discarded, 20 ⁇ l are taken for LC / UV / MS analysis and the residue is evaporated under vacuum to obtain the expected compound.
  • the compounds of formula (II) in DMF are dissolved at a concentration of 0.1 M in the presence of 3 equivalents of DIPEA. 300 ⁇ l of these solutions are added to each well of 2 ml and 120 ⁇ l of a solution containing the corresponding isothiocyanate compound of formula (VIII) in THF are added at a concentration of 0.25 M. The plates are shaken at RT for 16 hours. The products formed in each well are dissolved by addition of 500 ⁇ l of 1 AcOEt, 400 ⁇ l of 0.1 M Na 2 CO 3 are added and the plates are shaken. 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 is discarded, 20 ⁇ l are taken for LC / UV / MS analysis and the residue is evaporated under vacuum to obtain the expected compound.
  • Me, Et, Pr, iP, tBu respectively represent the methyl, ethyl, propyl, isopropyl and tert-butyl groups.
  • the compounds of formula (I) have a very good in vitro affinity (IC50 ⁇ 5.10 " 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 an acid addition salt thereof. pharmaceutically acceptable, 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-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, diseases, of psychosomatic origin, attacks of panic attacks, epilepsy, disorders of the movement, especially dyskinesia 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. treatment of ischemia, head trauma and 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 eating behaviors, in particular 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. So 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, disorders of endocrine origin, cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, chronic cirrhosis of the liver, fatty liver, steatohepatitis, non-alcoholic steatohepatitis, asthma, Raynaud's syndrome, glaucoma, fertility disorders, abortion, premature delivery, inflammatory phenomena, diseases of the immune system, particularly autoimmune and neuroinflammatory such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, multiple sclerosis,. infectious and viral diseases such as encephalitis, stroke and as drugs for cancer chemotherapy, 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 type II diabetes, for the treatment of memory and cognitive deficits; for the treatment of alcohol dependence, nicotine addiction, ie for alcohol withdrawal and smoking cessation.
  • psychotic disorders in particular schizophrenia, attention deficit and hyperactivity disorders (ADHD) in hyperkinetic children (BDM)
  • ADHD attention deficit and hyperactivity disorders
  • BDM hyperkinetic children
  • type II diabetes for the treatment of memory and cognitive deficits
  • alcohol dependence for the treatment of alcohol dependence, nicotine addiction, ie for alcohol withdrawal and smoking cessation.
  • 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.
  • These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a solvate or hydrate said compound, as well as at least one pharmaceutically acceptable excipient.
  • compositions according to the present invention may contain, besides a compound of formula (I), one (or more) other active ingredient useful in the treatment of the disorders and diseases indicated above.
  • a calcium antagonist a beta-blocker alone or in combination with a diuretic or a calcium antagonist
  • an antihyperlipidemic agent or an antihypercholesterolemic agent an antihyperlipidemic agent or an antihypercholesterolemic agent
  • a nicotinic agonist a partial nicotinic agonist
  • an antidepressant an antispychotic
  • an anticancer agent or an antiproliferative agent an anticancer agent or an antiproliferative agent
  • an agent useful in the treatment of alcoholism or withdrawal symptoms a useful agent for treating osteoporosis
  • angiotensin II AT1 receptor antagonist is meant 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.
  • inhibitor of the conversion enzyme is meant a compound such as alacepril, benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, temocapril, trandolpril, zofenopril, each of these compounds may itself be associated with a diuretic such than hydrochlorothiazide or indapamide or to a calcium antagonist such as amlodipine, diltiazem, felodipine or verapamil.
  • a diuretic such than hydrochlorothiazide or indapamide
  • a calcium antagonist such as amlodipine, diltiazem, felodipine or verapamil.
  • calcium antagonist is meant 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 is meant a compound such as acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevololol, bisoprolol, bopindolol, bucumolol, bufetolol, bunitrolol, butofilolol, carazolol, cardolol, carvedilol, cloranolol, epanolol, esmolol.
  • Antihyperlipidemic or antihypercholesterolaemic means 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, aluminum nicotinate, azacosterol, cholestyramine, dextrothyroxine, meglutol, niceritrol, nicoclonate, nicotinic acid , beta-sitosterin, tiadenol.
  • statins HMG-CoA reductase inhibitors
  • antidiabetic means 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, voglibase, as well as insulin and insulin analogues.
  • sulfonylureas biguanidines
  • alpha glucosidase inhibitors such as a
  • anti-obesity agent a compound such as amfepramone, benfluorex, benzphetamine, indanorex, mazindole, mefenorex, methamphetamine, D-norpseudoephedrine, sibutramine, a lipase inhibitor (orlistat cetilistat), a PPAR agonist, a dopamine agonist, a leptin receptor agonist, a serotonin receptor inhibitor, a beta-3 agonist, a CCK-A agonist, an NPY inhibitor, an MC4 receptor agonist, a bombesin agonist.
  • a compound such as amfepramone, benfluorex, benzphetamine, indanorex, mazindole, mefenorex, methamphetamine, D-norpseudoephedrine, sibutramine, a lipase inhibitor (orlistat cetilistat
  • opioid antagonist a compound such as naltrexone, naloxone or nalmefene.
  • agent useful in the treatment of alcoholism and withdrawal symptoms is meant acamprosate, benzodiazepines, beta-blockers, clonidine, carbamazepine.
  • beneficial agent for treating osteoporosis, is meant, for example, bisphosphonates such as etidronate, clodronate, tiludronate, risedronate.
  • the 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 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:
  • 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 appropriate dosage for 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.

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EP06709331A 2005-02-17 2006-02-16 1,5-diarylpyrrolderivate, verfahren zur deren herstellung und deren anwendung in der therapie Withdrawn EP1853557A2 (de)

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BRPI0715160A2 (pt) 2006-08-08 2013-06-11 Sanofi Aventis imidazolidina-2,4-dionas substituÍdas por arilamimoaril-alquil-, processo para preparÁ-las, medicamentos compeendendo estes compostos, e seu uso
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AR052673A1 (es) 2007-03-28
FR2882054A1 (fr) 2006-08-18
WO2006087476A2 (fr) 2006-08-24
TW200714585A (en) 2007-04-16
SV2007002420A (es) 2007-01-17
RU2007134383A (ru) 2009-03-27
UY29373A1 (es) 2006-10-02
FR2882054B1 (fr) 2007-04-13
US7524971B2 (en) 2009-04-28
KR20070103454A (ko) 2007-10-23
US20080015245A1 (en) 2008-01-17
CN101119967A (zh) 2008-02-06
BRPI0608866A2 (pt) 2010-02-02
AU2006215521A1 (en) 2006-08-24
PA8663601A1 (es) 2006-11-09
WO2006087476A3 (fr) 2007-08-09

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