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EP1781636A1 - Pyrrole derivatives, their preparation and their therapeutic use - Google Patents

Pyrrole derivatives, their preparation and their therapeutic use

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Publication number
EP1781636A1
EP1781636A1 EP05796087A EP05796087A EP1781636A1 EP 1781636 A1 EP1781636 A1 EP 1781636A1 EP 05796087 A EP05796087 A EP 05796087A EP 05796087 A EP05796087 A EP 05796087A EP 1781636 A1 EP1781636 A1 EP 1781636A1
Authority
EP
European Patent Office
Prior art keywords
group
alkyl
substituted
unsubstituted
formula
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Withdrawn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
EP05796087A
Other languages
German (de)
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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Filing date
Publication date
Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
Publication of EP1781636A1 publication Critical patent/EP1781636A1/en
Withdrawn legal-status Critical Current

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    • 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
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Definitions

  • the present invention relates to 4,5-diphenylpyrrole-2-carboxamide derivatives, their preparation and their therapeutic application.
  • R 1 represents hydrogen or a (C 1 -C 4) alkyl
  • R2 represents:
  • a non-aromatic carbocyclic radical C3-C12 unsubstituted or substituted one or more times with a (Ci-C4) alkyl, hydroxyl, cyano, (C1-C4) alkoxy, or a group COR12 ⁇
  • a benzothiophenyl an indolyl, said radicals being unsubstituted or substituted one or more times by (C 1 -C 4) alkyl group;
  • a phenylalkylene group wherein the alkylene is (C1-C3), unsubstituted or substituted on the alkylene with one or more methyl, hydroxyl, hydroxymethyl, methoxy, methoxymethyl, a group COR 2> and unsubstituted on the phenyl or substituted on the phenyl by one or more identical or different substituents selected from a halogen atom or a (C 1 -C 4) alkyl, trifluoromethyl, (C 1 -C 4) alkoxy, trifluoromethoxy;
  • a benzhydryl or benzydrylmethyl group . a group NR 1 QRI 1 - or R 1 and R 2 together with the nitrogen atom to which they are attached constitute:
  • R 42 represents a (C 1 -C 4) alkyl, phenyl, benzyl, (C 1 -C 4) alkoxy group, a trifluoromethyl group or a NR 1 R 3 R 4 group;
  • R 1 and R 4 each independently represent a hydrogen atom or a (C 1 -C 4) alkyl group or together with the nitrogen atom to which they are attached constitute a radical chosen from azetidinyl, pyrrolidinyl, piperazinyl and piperidinyl; or azepinyl;
  • R 5 represents a (C 1 -C 4) alkyl or trifluoromethyl group; n represents 0, 1 or 2;
  • Alk represents a (C 1 -C 4) alkyl group; as well as their salts, solvates and hydrates.
  • the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures are part of the invention.
  • the compounds of formula (I) may exist in the form of bases or addition salts with acids. These salts are advantageously prepared with pharmaceutically acceptable salts, 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 according to the invention may also exist in the form of hydrates or solvates, namely in the form of combinations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.
  • R 1 represents hydrogen or a (C 1 -C 4) alkyl
  • R2 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 group; . 1,2,3,4-tetrahydronaphthalenyl-1 or -2;
  • R 1 and R 2 together with the nitrogen atom to which they are attached constitute either a 4-piperazin-1-yl or 1,4-diazepan-1-yl radical by a phenyl or benzyl group; is a piperidin-1-yl radical or pyrrolidin-1-yl mono- or gem-disubstituted with phenyl, benzyl, (C 1 -C 4) alkyl, hydroxyl, (C 1 -C 3) alkanoyl, (C 1 -C 4) alkoxycarbonyl or ( Ci-C4) alkoxycarbonylamino; the phenyl or benzyl groups being unsubstituted or substituted one or more times with a halogen atom and / or a methyl group;
  • R3, R4, R5, R6, R7, R8 are each independently hydrogen or halogen, (C1-C5) alkyl, (C1-C8) alkoxy, trifluoromethyl or a group S (O) n AIk;
  • R9 represents a (C1-C4) alkyl group
  • R10 represents a hydrogen atom or a methyl group
  • Rl I is (C3-C (5) alkyl, phenyl or (C3-Cio) cycloalkyl, said phenyl and cycloalkyl are unsubstituted or substituted by one or more halogen atoms and / or groups (Ci-C4) alkyl;
  • - or Rio and Rn together with the nitrogen atom to which they are attached form a heterocyclic radical, saturated or unsaturated, of 5 to 11 atoms, bridged or not, whether or not comprising a spiric carbon and optionally containing a second heteroatom selected O or N, said radical being unsubstituted or substituted one or more times by a hydroxyl, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxycarbonyl group; a phenyl group unsubstituted or substituted by one or more halogen atoms or (C 1 -C 4) alkyl groups;
  • alkyl group is meant a linear or branched radical, such as in particular: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, the methyl group being preferred for (C1-C4) alkyl, tert-butyl, 2-methylbutyl-2,3,3-dimethylbutyl-2 being preferred for (C4-C10) alkyl.
  • alkylene group is meant a linear divalent radical, methylene and ethylene being preferred.
  • alkoxy group is meant a linear or branched radical, the methoxy group being preferred.
  • halogen atom is meant a fluorine, chlorine, bromine or iodine atom; the fluorine, chlorine or bromine atoms being preferred.
  • 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 fused, bridged or spiro di- or tricyclic radicals include, for example, norbornyl, bornyl, isobornyl, noradamantyl, adamantyl, spiro [5.5] undecanyl, bicyclo [2.2.1] heptanyl, bicyclo [3.2.1] octanyl; bicyclo [3.1.1] heptanyl.
  • heterocyclic radical saturated or unsaturated, of 4 to 11 atoms, containing or not containing a second hetero atom such as O or N
  • radicals such as morpholin-4-yl, piperidin-1-yl, piperazin-1-yl , pyrrolidin-1-yl, octahydrocyclopenta [c] pyrrol-2-yl, piperidin-1-yl and morpholin-4-yl being preferred.
  • mono-nitrogenated heterocyclic radical from 5 to 7 atoms, is meant a radical such as piperidin-4-yl or pyrrolidin-3yl, the piperidin-4-yl radical being preferred.
  • monooxygenated heterocyclic radical from 5 to 7 atoms, is meant a radical such as tetrahydrofuranyl, tetrahydro-2H-pyranyl, oxepanyl: tetrahydrofuranyl being preferred.
  • monosulfur heterocyclic radical from 5 to 7 atoms, is meant a radical such as tetrahydrothiophenyl or tetrahydrothiopyranyl.
  • heterocyclic heteroaromatic radical from 5 to 7 atoms, is meant a radical such as pyridyl, pyrrolyl, thiophenyl or furanyl.
  • R 1 represents hydrogen and R 2 represents a group NR 1 oR 11 in which R 1 Q and R n together with the nitrogen atom to which they are attached constitute a radical; saturated heterocyclic of 5 to 11 carbon atoms, unsubstituted or substituted one or more times with a (C 1 -C 4) alkyl;
  • R 1 and R 2 together with the nitrogen atom to which they are attached constitute a piperidin-1-yl radical which is gem-disubstituted with a phenyl, benzyl, pyrrolidin-1-yl or piperidin-1-yl group and cyano (C 1 -C 3) alkanoyl or aminocarbonyl; or R 1 and R 2 together represent a piperazin-1-yl group substituted in -4 with benzyl itself unsubstituted or substituted by a halogen atom; and / or R3, R4, R5, R8, Ry and Rg each independently represent a hydrogen atom, a halogen atom or a methoxy group;
  • R 9 represents a (C 1 -C 4) alkyl group; as well as their salts, solvates and hydrates.
  • R 1 represents hydrogen and R 2 represents a piperidin-1-yl radical or a (C 1 -C 3) alkylene substituted with a phenyl and a methoxy or methoxycarbonyl group;
  • R 1 and R 2 together with the nitrogen atom to which they are attached represent a piperidin-1-yl radical which is gem-4-disubstituted by a phenyl, piperidin-1-yl group and by an acetyl, aminocarbonyl or cyano;
  • R 1 and R 2 together represent a piperazin-1-yl group substituted in -4 with a benzyl which is itself unsubstituted or substituted by a halogen atom;
  • Rg is 4-chloro or 4-methoxy and R3 and R4 are 2,4-dichloro or 2-chloro, R5, R7, Rg is hydrogen;
  • R9 represents a methyl group; as well as their salts, their solvates and their hydrates
  • the present invention also relates to a process for preparing the compounds according to the invention.
  • R3, R4, R5, R6, R7, R8 and R9 are as defined for (I) with an amine of formula HNR1R2 (III) wherein R1 and R2 are as defined for (I).
  • the compound thus obtained is converted into one of its salts or solvates.
  • 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, a benzyl ester, an ester activated, for example the p-nitrophenyl ester, or the opportunely activated free acid, for example, with N, N-dicyclohexylcarbodiimide or with benzotriazol-1-yloxotris (dimethylamino) -phosphonium hexafluorophosphate (BOP) or benzotriazol-1-yloxotris- (pyrrolidino) phosphonium hexafluorophosphate (PyBOP).
  • N, N-dicyclohexylcarbodiimide or with benzotriazol-1-yloxotris (dimethylamino) -phosphonium hexafluor
  • the 1,3-oxazole-3-carboxylic acid chloride obtained by reaction of thionyl chloride with the acid of formula (II), can be reacted with an amine HNR1R2 in an inert 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 atmosphere inert, at a temperature between 0 ° C and the temperature, in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine.
  • an inert 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)
  • One variant consists in pre-preparing the mixed anhydride of the acid of formula (II) by reaction of ethyl chloroformate with the acid of formula (II), in the presence of a base such as triethylamine, and reacting it with an amine HNR4R2, in a solvent such as dichloromethane, under an inert atmosphere, at room temperature, in the presence of a base such as triethylamine.
  • Substitution of the dihydropyrrole ring by a substituted phenyl group is carried out in stage d) by the action of a substituted phenylboronic acid of formula (VIII) in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) Pd (0) , palladium (O) bisdibenzylidène acetone [Pd (dba) 2], tris (dibenzylideneacetone) dipalladium (0), Pd palladium (II) acetate [Pd (OCOCH 3) 2], dichloro (diphénylphos ⁇ hinoferrocène) Pd ( II) [PdC ⁇ dppfj, and in the presence of a base.
  • a palladium catalyst such as tetrakis (triphenylphosphine) Pd (0) , palladium (O) bisdibenzylidène acetone [Pd (dba
  • step e nitrogen protection by the tosyl group is removed by the action of a diamine such as DBU (1,8-diazabicyclo [5.4.0] undecene) simultaneously the pyrrole ring is aromatized.
  • a diamine such as DBU (1,8-diazabicyclo [5.4.0] undecene) simultaneously the pyrrole ring is aromatized.
  • step f) the nitrogen of the pyrrole is alkylated by the action of an alkyl iodide of formula R 9 I, then the ester of formula (X) is hydrolyzed in a basic medium to obtain the acid of formula (II) ).
  • the subject of the present invention is also the compounds of formula: in which :
  • R3, R4, R5, R8, R7, R8 are each independently of one another hydrogen, halogen, (C1-C8) alkyl, (C1-C8) alkoxy, trifluoromethyl, or group S (O) n AIk; - Ts represents a tosyl group;
  • Alk is a (C 1 -C 4) alkyl group; n represents 0, 1 or 2.
  • esters of formula (X) are described in the literature: methyl and ethyl esters of 4,5-diphenyl-1H-pyrrole-2-carboxylic acid are described in J. Chem. Research, synopses, 1977, 10,247; 1H-pyrrole-5- (4-methoxyphenyl) -4-phenyl-2-carboxylic acid ethyl ester is described in Tetrahedron
  • the present invention also relates to the compound of formula:
  • R3, R4, R5, R ⁇ , R7 and Rg each independently of one another represent a hydrogen or halogen atom, a (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy group, trifluoromethyl or a group S (O) n Alk with the proviso that R3, R4, R5, R8, R7, Rg do not simultaneously represent hydrogen, and with the proviso that when Rg is a 4-methoxy group, R3, R4 R5, R7, Rg do not simultaneously represent hydrogen;
  • Alk represents a (C 1 -C 4) alkyl group
  • n 0, 1 or 2.
  • the subject of the present invention is also the compounds of formula: in which :
  • X represents a halogen atom, a hydroxyl group, (C 1 -C 4) alkoxy or benzyloxy;
  • R3, R4, R5, R8, R7, R8 are each independently of one another a hydrogen or halogen atom, a (C1-C6) alkyl, (C1-C ( ) ) alkoxy group, trifluoromethyl or a group S (O) n AIk;
  • R 9 represents a (C 1 -C 4) alkyl
  • Alk represents a (C 1 -C 4) alkyl
  • n 0, 1 or 2.
  • the compounds of formula (IIa) may also exist in the form of salts. Such salts are part of the invention.
  • Amines of the formula HNR 1 -2 ()) are known or prepared by known methods.
  • the nuclear magnetic resonance spectra are recorded at 200 MHz in DMSO-d ⁇ .
  • s singlet
  • d doublet
  • t triplet
  • m massive
  • mt multiplet
  • se expanded singlet
  • dd doublet of doublet.
  • 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 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% of TFA in acetonitrile.
  • the eluent is composed as follows:
  • Solvent A 0.025% TFA in water
  • UV detection is performed by an iodine bar detector between 210 and 400 nm and ESI positive mass detection.
  • the crude is solubilized in dichloromethane and the organic phase is washed successively with a saturated aqueous solution of KHSO4 then K2CO3.
  • the organic phase is dried over magnesium sulphate and then filtered and finally concentrated to obtain 5.18 g of the expected compound.
  • the compounds of formula (I) described in Table 2 are prepared by combinatorial chemistry according to the method described below: the carboxylic acids of formula (III) are dissolved in DMF at a concentration of 0.25M in the presence of 3 equivalents of DIPEA. In each well of 2 ml, 120 ⁇ l of this solution and 120 ⁇ l of a solution of TBTU in DMF at the concentration of 0.25M are placed. 300 ⁇ l of a solution containing the amine of formula (III) in DMF at a concentration of 0.1M and 3 equivalents of DIPEA are added to each well. The plates are stirred at RT for 16 hours and then evaporated.
  • the products formed are dissolved in each well with 500 ⁇ l of AcOEt, 400 ⁇ l of 0.1M Na 2 CO 3 are added and the plates are shaken. After decantation 430 .mu.l of aqueous phase are discarded and 300 .mu.l of 5% NaCl are added and the plates are stirred. 350 ⁇ l of aqueous phase are then discarded and the residues are analyzed by LC / UV / MS (MS5 conditions).
  • Et, Me, nPr, tBu respectively mean ethyl, r ⁇ ethyl, n-propyl and tert-butyl.
  • the compounds of formula (I) have a very good in vitro affinity (IC50 ⁇ 5.10 M) for CB cannabinoid 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 invention relates to medicaments for human or veterinary medicine 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 present invention relates to the use of a compound of formula (I), or a salt thereof, solvates or hydrates which are pharmaceutically acceptable, for the preparation of medicaments intended to treat or to prevent diseases involving cannabinoid receptors CBj.
  • 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, particular in the case of an abuse of a substance 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)
  • ADHD attention deficit and hyperactivity disorder
  • 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 deficits, 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 mellitus 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 (T) according to the invention can be used as medicaments in the treatment of gastrointestinal disorders, diarrheal disorders, ulcers, vomiting, bladder and urinary disorders, endocrine disorders, cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, chronic cirrhosis of the liver, chronic hepatic encephalopathy, asthma, chronic bronchitis and bronchitis.
  • chronic obstructive pulmonary disease Raynaud's syndrome, glaucoma, fertility disorders, inflammatory phenomena, diseases of the immune system, especially autoimmune and neuroinflammatory diseases such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, stroke as well as edicaments for cancer chemotherapy and for the treatment of Guillain-Barré syndrome and for the treatment of bone diseases and osteoporosis.
  • autoimmune and neuroinflammatory diseases such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, stroke as well as edicaments for cancer chemotherapy and for the treatment of Guillain-Barré syndrome and for the treatment of bone diseases and osteoporosis.
  • the compounds of formula (T) are particularly useful for the treatment of psychotic disorders, in particular schizophrenia; Attention Deficit 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; and for the treatment of dyslipidemias, the metabolic syndrome.
  • ADHD Attention Deficit Hyperactivity Disorder
  • BDM hyperkinetic children
  • BDM hyperkinetic children
  • alcohol dependence for the treatment of alcohol dependence, nicotine addiction, ie for alcohol withdrawal and smoking cessation
  • 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.
  • the present invention relates to the use of a compound of formula (I), of its pharmaceutically acceptable salts and of their solvates or hydrates for the treatment of the disorders and diseases indicated above.
  • the compound according to the invention is generally administered in dosage unit.
  • Said dosage units are preferably formulated in pharmaceutical compositions in which the active ingredient is mixed with a pharmaceutical excipient.
  • the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof.
  • the compound of formula (I) above and its pharmaceutically acceptable salts or solvates may be used at daily doses of 0.01 to 100 mg per kg of body weight of the mammal to be treated, preferably at daily doses of 0, 02 to 50 mg / kg.
  • the dose may preferably vary from 0.05 to 4000 mg per day, more particularly from 0.1 to 1000 mg per day depending on the age of the subject to be treated or the type of treatment, namely prophylactic or curative.
  • these assays are examples of average situations, there may be special cases where higher or lower dosages are appropriate, such assays also belong to the invention.
  • the dosage appropriate to each patient is determined by the physician according to the mode of administration, the age, the weight and the response of said patient.
  • the active ingredient can be administered in unit dosage form, in admixture with conventional pharmaceutical carriers, animals and humans.
  • suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, aerosols, dosage forms topical, implants, forms of subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and rectal administration forms.
  • the active principle is generally formulated in dosage units containing from 0.05 to 1000 mg, advantageously from 0.1 to 500 mg, preferably from 1 to 200 mg of said active ingredient per unit of dosage for daily administrations.
  • 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 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 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 AT1 receptor antagonist of angiotensin II alone or in combination with a diuretic
  • a beta-blocker alone or in combination with a diuretic or a calcium antagonist; an antihyperlipidemic agent or an antihypercholesterolemic agent;
  • compositions containing in combination a compound of formula (I) and another active principle chosen from one of the following therapeutic classes:
  • an AT1 receptor antagonist of angiotensin II 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 antihyperlipidemic agent or an antihypercholesterolemic agent
  • 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, trandolapril, zofenopril, each such compounds may itself be associated with a diuretic such as hydrochlorothiazide or indapamide or a calcium antagonist such as amlodipine, diltiazem, felodipine or verapamil.
  • a diuretic such as 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 is meant 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
  • atorvastatin fluvastatin sodium,
  • 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, glipidide, gliquidone, glisoxepide, glybuzole, glymidine, metahexamide, metformin, miglitol, nateglinide, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, troglitazone, voglibose.
  • sulfonylureas biguanidines
  • alpha glucosidase inhibitors such as acarbose, aceto
  • anti-obesity agent a compound such as amfepramone, benfluorex, benzphetamine, indanorex, mazindole, mefenorex, methamphetamine, D-norpseudoephedrine or another CB i cannabinoid receptor antagonist.
  • 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.
  • 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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Abstract

The invention concerns compounds of formula (I), wherein: R<sub

Description

DERIVES DE PYRROLE, LEUR PREPARATION ET LEUR UTILISATION EN PYRROLE DERIVATIVES, THEIR PREPARATION AND THEIR USE
THERAPEUTIQUETHERAPEUTIC
La présente invention se rapporte à des dérivés de 4,5-diphénylpyrrole-2- carboxamide, à leur préparation et à leur application en thérapeutique.The present invention relates to 4,5-diphenylpyrrole-2-carboxamide derivatives, their preparation and their therapeutic application.
La présente invention a pour objet des composés répondant à la formule :The subject of the present invention is compounds corresponding to the formula:
dans laquelle : in which :
- R^ représente l'hydrogène ou un (Ci-C4)alkyle ;R 1 represents hydrogen or a (C 1 -C 4) alkyl;
R2 représente :R2 represents:
. un groupe (C3-Cio)alkyle non substitué ou substitué par un groupe trifluorométhyle ;. a (C3-Cio) alkyl unsubstituted or substituted with trifluoromethyl;
. un radical carbocyclique non aromatique en C3-C12, non substitué ou substitué une ou plusieurs fois par un groupe (Ci-C4)alkyle, hydroxyle, cyano, (C1-C4) alcoxy, ou un groupement COR12 \. a non-aromatic carbocyclic radical, C3-C12 unsubstituted or substituted one or more times with a (Ci-C4) alkyl, hydroxyl, cyano, (C1-C4) alkoxy, or a group COR12 \
. un indanyle ;. indanyl;
. un 1,2,3,4-tétrahydronaphtalényle -1 ou -2 ;. 1,2,3,4-tetrahydronaphthalenyl-1 or -2;
. un radical hétérocyclique monooxygéné ou monosoufré, de 5 à 7 atomes, non substitué ou substitué une ou plusieurs fois par un groupe (Ci-C4)alkyle ;. a monooxygenated or monosulfurized heterocyclic radical of 5 to 7 atoms, unsubstituted or substituted one or more times by a (C 1 -C 4) alkyl group;
. un radical hétérocyclique monoazoté, de 5 à 7 atomes, non substitué ou substitué une ou plusieurs fois par groupe (Ci-C4)alkyle, l'atome d'azote étant de plus substitué par un groupe (Ci-C4)alkyle, phényle, benzyle, (Ci- C4)alcoxycarbonyle ou (Ci-C4)alcanoyle, les groupes phényle ou benzyle étant non substitués ou substitués une ou plusieurs fois par un atome d'halogène, un groupe (Ci-C4)alkyle, trifluorométhyle, hydroxyle, ou (Ci-C4)alcoxy ;. a mono-nitrogenated heterocyclic radical of 5 to 7 atoms, unsubstituted or substituted one or more times by (C 1 -C 4) alkyl group, the nitrogen atom being further substituted by a (C 1 -C 4) alkyl, phenyl group, benzyl, (C 1 -C 4) alkoxycarbonyl or (C 1 -C 4) alkanoyl, the phenyl or benzyl groups being unsubstituted or substituted one or more times with a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, hydroxyl group, or (C1-C4) alkoxy;
. un benzothiophényle, un indolyle, lesdits radicaux étant non substitués ou substitués une ou plusieurs fois par groupe (Ci-C4)alkyle ;. a benzothiophenyl, an indolyl, said radicals being unsubstituted or substituted one or more times by (C 1 -C 4) alkyl group;
. un groupe (Ci-C3)alkylène portant un radical carbocyclique non aromatique en C3-C10 non substitué ou substitué une ou plusieurs fois par un groupe (C1-C4) alkyle, hydroxyle, (Ci-C4)alcoxy, cyano ou un groupement CORi 2 > . un groupe (Ci-C3)alkylène portant un radical hétérocyclique, hétéroaromatique ou non, monooxygéné, monosoufré ou monoazoté de 5 à 7 atomes, non substitué ou substitué une ou plusieurs fois par un groupe (Ci-C4)alkyle ; . un groupe (Ci-C3)alkylène portant un radical indolyle ou benzothiophényle, ledit radical étant non substitué ou substitué une ou plusieurs fois par un groupe (Ci-C4)alkyle et l'alkylène étant non substitué ou substitué par un groupe hydroxyle, méthyle ou méthoxy ou par un groupement CORi 2 ; . un groupe (Cj[-C3)alkylène portant un groupe (Ci-C4)alkylthio ; . un groupement phénylalkylène dans lequel l'alkylène est en (C1-C3), non substitué ou substitué sur l'alkylène par un ou plusieurs groupes méthyle, hydroxyle, hydroxyméthyle, méthoxy, méthoxyméthyle, un groupement CORi 2> et non substitué sur le phényle ou substitué sur le phényle par un ou plusieurs substituants identiques ou différents choisis parmi un atome d'halogène ou un groupe (Ci-C4)alkyle, trifluorométhyle, (Ci-C4)alcoxy, trifluorométhoxy ;. a (C 1 -C 3) alkylene group carrying a non-aromatic C 3 -C 10 carbocyclic radical which is unsubstituted or substituted one or more times with a (C 1 -C 4) alkyl, hydroxyl or (C 1 -C 4) alkoxy or cyano group or a COR 1 group 2 > . a (C 1 -C 3) alkylene group bearing a heterocyclic heteroaromatic or non-heteroaromatic radical, monooxygenated, monosulfurized or monounsaturated with 5 to 7 atoms, unsubstituted or substituted one or more times with a (C 1 -C 4) alkyl group; . a (C 1 -C 3) alkylene group carrying an indolyl or benzothiophenyl radical, said radical being unsubstituted or substituted one or more times by a (C 1 -C 4) alkyl group and the alkylene being unsubstituted or substituted with a hydroxyl, methyl group; or methoxy or by a group CORi 2; . a (C j [-C3) alkylene bearing a group (Ci-C4) alkylthio; . a phenylalkylene group wherein the alkylene is (C1-C3), unsubstituted or substituted on the alkylene with one or more methyl, hydroxyl, hydroxymethyl, methoxy, methoxymethyl, a group COR 2> and unsubstituted on the phenyl or substituted on the phenyl by one or more identical or different substituents selected from a halogen atom or a (C 1 -C 4) alkyl, trifluoromethyl, (C 1 -C 4) alkoxy, trifluoromethoxy;
. un groupe benzydryle ou benzydrylméthyle ; . un groupement NRi QRI 1 \ - ou Ri et R2 ensemble avec l'atome d'azote auquel ils sont liés constituent:. a benzhydryl or benzydrylmethyl group; . a group NR 1 QRI 1 - or R 1 and R 2 together with the nitrogen atom to which they are attached constitute:
. soit un radical piρérazin-1-yle ou 1,4-diazépan-l-yle substitué en 4- par un groupe phényle, benzyle, benzodioxolyle, benzodioxolylméthyle, tetrahydrofuranylcarbonyle ou par un groupement COR^ 2 ou CH2COR12 ; . soit un radical pipéridin-1-yle ou pyrrolidin-1-yle mono ou gem-disubstitué par un ou deux groupes choisis parmi un groupe phényle, benzyle, pipéridin-1-yle, pyrrolidin-1-yle, (Ci-C4)alkyle, hydroxyle, cyano ou un groupement COR12, NR13R14, NHCOR15 ou CH2COR12 ; les groupes phényle ou benzyle étant non substitués ou substitués par un ou plusieurs substituants choisis indépendamment parmi par un atome d'halogène, un groupe méthyle, trifluorométhyle, hydrolyle, (Ci-C4)alcoxy ; R3, R4, R5, Rβ, R7, Rg représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, un groupe (Ci-Cg)alkyle, (Ci-Cg)alcoxy, trifluorométhyle ou un groupement S(O)nAIk ; R9 représente un groupe (Ci-C4)alkyle ; RlO représente un atome d'hydrogène ou un groupe méthyle ; RlI représente un groupe (C3-C6)alkyle, phényle ou (C3-C10) cycloalkyle, lesdits groupes phényle et cycloalkyle étant non substitués ou substitués par un ou plusieurs substituants choisis indépendamment parmi un atome d'halogène ou un groupe (Ci-C4)alkyle ou trifluorométhyle ; - ou Rio et R-Il ensemble avec l'atome d'azote auquel ils sont liés constituent un radical hétérocyclique, saturé ou insaturé, de 4 à 11 atomes, ponté ou non, comprenant ou non un carbone spirannique et contenant ou non un deuxième hétéroatome choisi parmi O ou N, ledit radical étant non substitué ou substitué une ou plusieurs fois par un groupe hydroxyle, (Ci-C4)alkyle, (Ci-C4)alcoxy- carbonyle ou par un groupe phényle non substitué ou substitué par un ou plusieurs substituants choisis indépendamment parmi un atome d'halogène ou un groupe (Ci-C4)alkyle ;. either a phenyl, benzyl, benzodioxolyl, benzodioxolylmethyl, tetrahydrofuranylcarbonyl or phenre, benzyl, benzodioxolyl, phenyl, benzodioxolyl or a COR2 or CH2COR12 group; . either a piperidin-1-yl or pyrrolidin-1-yl radical mono- or gem-disubstituted with one or two groups selected from a phenyl, benzyl, piperidin-1-yl, pyrrolidin-1-yl, (C 1 -C 4) alkyl group; hydroxyl, cyano or a group COR12, NR13R14, NHCOR15 or CH2COR12; the phenyl or benzyl groups being unsubstituted or substituted with one or more substituents chosen independently from among a halogen atom, a methyl, trifluoromethyl, hydrolyl, (C 1 -C 4) alkoxy group; R3, R4, R5, Rβ, R7 and Rg each independently of one another represent a hydrogen or halogen atom, a (C1-C8) alkyl, (C1-C8) alkoxy, trifluoromethyl group or a group S (O) n AIk; R9 represents a (C1-C4) alkyl group; R10 represents a hydrogen atom or a methyl group; R1 represents a (C3-C6) alkyl, phenyl or (C3-C10) cycloalkyl group, said phenyl and cycloalkyl groups being unsubstituted or substituted by one or more substituents independently selected from a halogen atom or a group (C1-C4) ) alkyl or trifluoromethyl; - or Rio and R-II together with the nitrogen atom to which they are attached constitute a heterocyclic radical, saturated or unsaturated, from 4 to 11 atoms, bridged or not, with or without a spirannic carbon and optionally containing a second heteroatom selected from O or N, said radical being unsubstituted or substituted one or more times by a hydroxyl, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxycarbonyl group or by an unsubstituted or substituted phenyl group or more substituents independently selected from a halogen atom or a (Ci-C 4) alkyl;
- R42 représente un groupe (Ci-C4)alkyle, phényle, benzyle, (Ci-C4)alcoxy, un trifluorométhyle, un groupement NRj 3R44 ;R 42 represents a (C 1 -C 4) alkyl, phenyl, benzyl, (C 1 -C 4) alkoxy group, a trifluoromethyl group or a NR 1 R 3 R 4 group;
Rl 3 et R\4 représentent chacun indépendamment un atome d'hydrogène ou un groupe (C;[-C4)alkyle ou ensemble avec l'atome d'azote auquel ils sont liés constituent un radical choisi parmi azétidinyle, pyrrolidinyle, pipérazinyle, pipéridinyle ou azépinyle ;R 1 and R 4 each independently represent a hydrogen atom or a (C 1 -C 4) alkyl group or together with the nitrogen atom to which they are attached constitute a radical chosen from azetidinyl, pyrrolidinyl, piperazinyl and piperidinyl; or azepinyl;
R^ 5 représente un groupe (Ci-C4)alkyle ou trifluorométhyle ; n représente 0, 1 ou 2 ;R 5 represents a (C 1 -C 4) alkyl or trifluoromethyl group; n represents 0, 1 or 2;
- AIk représente un groupe (C \ -C4)alkyle ; ainsi que leurs sels, leurs solvats et leurs hydrates.- Alk represents a (C 1 -C 4) alkyl group; as well as their salts, solvates and hydrates.
Les composés de formule (I) peuvent comporter un ou plusieurs atomes de carbone asymétriques. Ils peuvent donc exister sous forme d'énantiomères ou de diastéréoisoméres. Ces énantiomères, diastéréoisomères, ainsi que leurs mélanges, y compris les mélanges racémiques font partie de l'invention.The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures are part of the invention.
Les composés de formule (I) peuvent exister à l'état de bases ou de sels d'addition à des acides. Ces sels sont avantageusement préparés avec des sels pharmaceutiquement acceptables mais les sels d'autres acides utiles, par exemple, pour la purification ou l'isolement des composés de formule (I) font également partie de l'invention.The compounds of formula (I) may exist in the form of bases or addition salts with acids. These salts are advantageously prepared with pharmaceutically acceptable salts, 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.
Les composés selon l'invention peuvent également exister sous forme d'hydrates ou de solvats, à savoir sous forme d'associations ou de combinaisons avec une ou plusieurs molécules d'eau ou avec un solvant. De tels hydrates et solvats font également partie de l'invention.The compounds according to the invention may also exist in the form of hydrates or solvates, namely in the form of combinations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.
Plus particulièrement, la présente invention a pour objet des composés de formuleMore particularly, the subject of the present invention is compounds of formula
(I) dans laquelle :(I) in which:
- Ri représente l'hydrogène ou un (Ci-C4)alkyle ;R 1 represents hydrogen or a (C 1 -C 4) alkyl;
- R2 représente :R2 represents:
. un groupe (C4-Cio)alkyle ;. a (C 4 -C 10) alkyl group;
. un radical carbocyclique non aromatique en C3-C12, non substitué ou substitué une ou plusieurs fois par un groupe (Ci-C4)alkyle ; . un 1,2,3,4-tétrahydronaphtalényle -1 ou -2 ;. 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 group; . 1,2,3,4-tetrahydronaphthalenyl-1 or -2;
. un radical hétérocyclique monooxygéné ou monosoufré, saturé, de 5 à 7 atomes, non substitué ou substitué une ou plusieurs fois par un groupe (Ci-C4)alkyle ;. a monooxygenated or monosulfur saturated heterocyclic radical of 5 to 7 atoms, unsubstituted or substituted one or more times with a (C 1 -C 4) alkyl group;
. un radical hétérocyclique monoazoté, saturé, de 5 à 7 atomes, l'atome d'azote étant substitué par un groupe (Ci-C4)alkyle, phényle, benzyle, (Ci- C4)alcoxycarbonyle ou (Ci-C4)alcanoyle ;. a mono-nitrogen saturated heterocyclic radical of 5 to 7 atoms, the nitrogen atom being substituted by a (C 1 -C 4) alkyl, phenyl, benzyl, (C 1 -C 4) alkoxycarbonyl or (C 1 -C 4) alkanoyl group;
. un groupe (Ci-C3)alkylène portant un radical carbocyclique non aromatique en C3-C10 non substitué ou substitué une ou plusieurs fois par un groupe (C1-C4) alkyle ;. a (C 1 -C 3) alkylene group carrying a non-aromatic C 3 -C 10 carbocyclic radical which is unsubstituted or substituted one or more times with a (C 1 -C 4) alkyl group;
. un groupement phénylalkylène dans lequel l'alkylène est en (C1-C3), non substitué ou substitué sur l'alkylène par un ou plusieurs groupes méthyle ou (Ci- C4)alcoxycarbonyle, et/ou substitué sur le phényle par un ou plusieurs substituants identiques ou différents choisis parmi un atome d'halogène ou un groupe (Ci-C4)alkyle, trifluorométhyle, (Ci-C4)alcoxy, trifluorométhoxy ;. a phenylalkylene group in which the alkylene is (C 1 -C 3), unsubstituted or substituted on the alkylene by one or more methyl or (C 1 -C 4) alkoxycarbonyl groups, and / or substituted on the phenyl by one or more substituents identical or different selected from a halogen atom or a (C 1 -C 4) alkyl, trifluoromethyl, (C 1 -C 4) alkoxy, trifluoromethoxy;
. un groupement NRi QRI 1 ;. a group NRi QRI 1;
- ou Ri et R2 ensemble avec l'atome d'azote auquel ils sont liés constituent soit un radical pipérazin-1-yle ou 1,4-diazépan-l-yle substitué en 4- par un groupe phényle ou benzyle ; soit un radical pipéridin-1-yle ou pyrrolidin-1-yle mono ou gem-disubstitué par un groupe phényle, benzyle, (Ci-C4)alkyle, hydroxyle, (Ci- C3)alcanoyle, (Ci-C4)alcoxycarbonyle ou (Ci-C4)alcoxycarbonylamino; les groupes phényles ou benzyles étant non substitués ou substitués une ou plusieurs fois par un atome d'halogène et/ou un groupe méthyle ;or R 1 and R 2 together with the nitrogen atom to which they are attached constitute either a 4-piperazin-1-yl or 1,4-diazepan-1-yl radical by a phenyl or benzyl group; is a piperidin-1-yl radical or pyrrolidin-1-yl mono- or gem-disubstituted with phenyl, benzyl, (C 1 -C 4) alkyl, hydroxyl, (C 1 -C 3) alkanoyl, (C 1 -C 4) alkoxycarbonyl or ( Ci-C4) alkoxycarbonylamino; the phenyl or benzyl groups being unsubstituted or substituted one or more times with a halogen atom and / or a methyl group;
R3, R4, R5, Rô, R7, Rg représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, un groupe (Ci-C(5)alkyle, (Ci-Cg)alcoxy, trifluorométhyle ou un groupement S(O)nAIk ;R3, R4, R5, R6, R7, R8 are each independently hydrogen or halogen, (C1-C5) alkyl, (C1-C8) alkoxy, trifluoromethyl or a group S (O) n AIk;
R9 représente un groupe (Ci-C4)alkyle ;R9 represents a (C1-C4) alkyl group;
RlO représente un atome d'hydrogène ou un groupe méthyle ;R10 represents a hydrogen atom or a methyl group;
Rl I représente un groupe (C3-C(5)alkyle, phényle ou (C3-Cio)cycloalkyle, lesdits groupes phényle et cycloalkyle étant non substitués ou substitués par un ou plusieurs atomes d'halogène et/ou groupes (Ci-C4)alkyle ;Rl I is (C3-C (5) alkyl, phenyl or (C3-Cio) cycloalkyl, said phenyl and cycloalkyl are unsubstituted or substituted by one or more halogen atoms and / or groups (Ci-C4) alkyl;
- ou Rio et Rn ensemble avec l'atome d'azote auquel ils sont liés constituent un radical hétérocyclique, saturé ou insaturé, de 5 à 11 atomes, ponté ou non, comprenant ou non un carbone spirannique et contenant ou non un deuxième hétéroatome choisi parmi O ou N, ledit radical étant non substitué ou substitué une ou plusieurs fois par un groupe hydroxyle, (Ci-C4)alkyle, (Ci-C4)alcoxy- carbonyle ; un groupe phényle non substitué ou substitué par un ou plusieurs atomes d'halogène ou groupes (Ci-C4)alkyle ;- or Rio and Rn together with the nitrogen atom to which they are attached form a heterocyclic radical, saturated or unsaturated, of 5 to 11 atoms, bridged or not, whether or not comprising a spiric carbon and optionally containing a second heteroatom selected O or N, said radical being unsubstituted or substituted one or more times by a hydroxyl, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxycarbonyl group; a phenyl group unsubstituted or substituted by one or more halogen atoms or (C 1 -C 4) alkyl groups;
- n représente 0, 1 ou 2 ; - AIk représente un groupe (Ci-C4)alkyle ; ainsi que leurs sels, leurs solvats et leurs hydrates.n represents 0, 1 or 2; - Alk represents a (C 1 -C 4) alkyl group; as well as their salts, solvates and hydrates.
Par groupe alkyle, on entend un radical linéaire ou ramifié, tel que en particulier : méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, tert-butyle, n-pentyle, isopentyle, n-hexyle, isohexyle, le groupe méthyle étant préféré pour un (Cj- C4)alkyle, les groupes tert-butyle, 2-méthylbutyl-2, 3,3-diméthylbutyl-2, étant préférés pour un (C4-Cio)alkyle.By alkyl group is meant a linear or branched radical, such as in particular: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, the methyl group being preferred for (C1-C4) alkyl, tert-butyl, 2-methylbutyl-2,3,3-dimethylbutyl-2 being preferred for (C4-C10) alkyl.
Par groupe alkylène, on entend un radical bivalent linéaire, le méthylène et l'éthylène étant préférés.By alkylene group is meant a linear divalent radical, methylene and ethylene being preferred.
Par groupe alcoxy, on entend un radical linéaire ou ramifié, le groupe méthoxy étant préféré.By alkoxy group is meant a linear or branched radical, the methoxy group being preferred.
Par atome d'halogène, on entend un atome de fluor, de chlore, de brome ou d'iode; les atomes de fluor, chlore ou brome étant préférés.By halogen atom is meant a fluorine, chlorine, bromine or iodine atom; the fluorine, chlorine or bromine atoms being preferred.
Les radicaux carbocycliques non aromatiques en C3-C12 comprennent les radicaux mono ou polycycliques, condensés ou pontés. Les radicaux monocycliques incluent les cycloalkyles par exemple cyclopropyle, cyclobutyle, cyclopentyle, cyclohexyle, cycloheptyle, cyclooctyle ; le cyclohexyle et le cyclopentyle étant préférés. Les radicaux di- ou tricycliques condensés, pontés ou spiraniques, incluent par exemple les radicaux norbornyle, bornyle, isobornyle, noradamantyle, adamantyle, spiro[5.5]undécanyle, bicyclo[2.2.1]heptanyle, bicyclo[3.2.1]octanyle ; bicyclo [3.1.1]heptanyle.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 fused, bridged or spiro di- or tricyclic radicals include, for example, norbornyl, bornyl, isobornyl, noradamantyl, adamantyl, spiro [5.5] undecanyl, bicyclo [2.2.1] heptanyl, bicyclo [3.2.1] octanyl; bicyclo [3.1.1] heptanyl.
Par radical hétérocyclique, saturé ou insaturé, de 4 à 11 atomes, contenant ou non un deuxième hétéro atome tel que O ou N, on entend des radicaux tel que morpholin-4- yle, pipéridin-1-yle, pipérazin-1-yle, pyrrolidin-1-yle, octahydrocyclopenta[c]pyrrol- 2-yle, les radicaux pipéridin-1-yle et morpholin-4-yle étant préférés.By heterocyclic radical, saturated or unsaturated, of 4 to 11 atoms, containing or not containing a second hetero atom such as O or N, is meant radicals such as morpholin-4-yl, piperidin-1-yl, piperazin-1-yl , pyrrolidin-1-yl, octahydrocyclopenta [c] pyrrol-2-yl, piperidin-1-yl and morpholin-4-yl being preferred.
Par radical hétérocyclique monoazoté, de 5 à 7 atomes, on entend un radical tel que pipéridin-4-yle ou pyrrolidin-3yle, le radical pipéridin-4-yle étant préféré.By mono-nitrogenated heterocyclic radical, from 5 to 7 atoms, is meant a radical such as piperidin-4-yl or pyrrolidin-3yl, the piperidin-4-yl radical being preferred.
Par radical hétérocyclique monooxygéné, de 5 à 7 atomes, on entend un radical tel que tétrahydrofuranyle, tétrahydro-2H-pyranyle, oxepanyle : le tétrahydrofuranyle étant préféré.By monooxygenated heterocyclic radical, from 5 to 7 atoms, is meant a radical such as tetrahydrofuranyl, tetrahydro-2H-pyranyl, oxepanyl: tetrahydrofuranyl being preferred.
Par radical hétérocyclique monosoufré, de 5 à 7 atomes, on entend un radical tel que tétrahydrothiophényle ou tétrahydrothiopyrannyle.By monosulfur heterocyclic radical, from 5 to 7 atoms, is meant a radical such as tetrahydrothiophenyl or tetrahydrothiopyranyl.
Par radical hétérocyclique hétéroaromatique, de 5 à 7 atomes, on entend un radical tel que pyridyle, pyrrolyle, thiophényle ou furanyle.By heterocyclic heteroaromatic radical, from 5 to 7 atoms, is meant a radical such as pyridyl, pyrrolyl, thiophenyl or furanyl.
Selon la présente invention, on préfère les composés de formule (I) dans laquelle :According to the present invention, the compounds of formula (I) in which:
- Rj représente l'hydrogène et R2 représente un groupe NRj oRll dans lequel Rj Q et Rn ensemble avec l'atome d'azote auquel ils sont liés constituent un radical hétérocyclique saturé de 5 à 11 atomes de carbone, non substitué ou substitué une ou plusieurs fois par un (Ci-C4)alkyle ;R 1 represents hydrogen and R 2 represents a group NR 1 oR 11 in which R 1 Q and R n together with the nitrogen atom to which they are attached constitute a radical; saturated heterocyclic of 5 to 11 carbon atoms, unsubstituted or substituted one or more times with a (C 1 -C 4) alkyl;
- ou R^ et R.2 ensemble avec l'atome d'azote auquel ils sont liés constituent un radical pipéridin-1-yle gem-disubstitué par un groupe phényle, benzyle, pyrrolidin-1-yle ou pipéridin-1-yle et par un groupe cyano, (Ci-C3)alcanoyle ou aminocarbonyle ; ou Ri et R2 ensemble représentent un groupe pipérazin-1-yle substitué en -4- par un benzyle lui-même non substitué ou substitué par un atome d'halogène ; et/ou R3, R4, R5, Rg, Ry, Rg représentent chacun indépendamment l'un de l'autre un atome d'hydrogène, d'halogène ou un groupe méthoxy ;or R 1 and R 2 together with the nitrogen atom to which they are attached constitute a piperidin-1-yl radical which is gem-disubstituted with a phenyl, benzyl, pyrrolidin-1-yl or piperidin-1-yl group and cyano (C 1 -C 3) alkanoyl or aminocarbonyl; or R 1 and R 2 together represent a piperazin-1-yl group substituted in -4 with benzyl itself unsubstituted or substituted by a halogen atom; and / or R3, R4, R5, R8, Ry and Rg each independently represent a hydrogen atom, a halogen atom or a methoxy group;
- R9 représente un groupe (Ci-C4)alkyle ; ainsi que leurs sels, leurs solvats et leurs hydrates.R 9 represents a (C 1 -C 4) alkyl group; as well as their salts, solvates and hydrates.
On distingue en particulier les composés de formule I dans laquelle :In particular, compounds of formula I in which:
- Ri représente l'hydrogène et R2 représente un radical pipéridin-1-yle ou un (Ci- C3)alkylène substitué par un phényle et par un groupe méthoxy ou méthoxycarbonyle ;R 1 represents hydrogen and R 2 represents a piperidin-1-yl radical or a (C 1 -C 3) alkylene substituted with a phenyl and a methoxy or methoxycarbonyl group;
- ou R\ et R2 ensemble avec l'atome d'azote auquel ils sont liés représentent un radical pipéridin-1-yle gem-disubstitué en -4 par un groupe phényle, pipéridin-1- yle et par un groupe acétyle, aminocarbonyle ou cyano ;or R 1 and R 2 together with the nitrogen atom to which they are attached represent a piperidin-1-yl radical which is gem-4-disubstituted by a phenyl, piperidin-1-yl group and by an acetyl, aminocarbonyl or cyano;
- ou Ri et R2 ensemble représentent un groupe pipérazin-1-yle substitué en -4- par un benzyle lui-même non substitué ou substitué par un atome d'halogène ;or R 1 and R 2 together represent a piperazin-1-yl group substituted in -4 with a benzyl which is itself unsubstituted or substituted by a halogen atom;
Rg est un 4-chloro ou un 4-méthoxy et R3 et R4 représentent 2,4-dichloro ou 2- chloro, R5, R7, Rg représentant un atome d'hydrogène ;Rg is 4-chloro or 4-methoxy and R3 and R4 are 2,4-dichloro or 2-chloro, R5, R7, Rg is hydrogen;
R9 représente un groupe méthyle ; ainsi que leurs sels, leur solvats et leurs hydratesR9 represents a methyl group; as well as their salts, their solvates and their hydrates
Parmi les composés de l'invention, on peut notamment citer les composés suivants :Among the compounds of the invention, mention may notably be made of the following compounds:
- le 4-(2,4-dichlorophényl)-5-(4-méthoxyphényl)- 1 -méthyl-N-pipéridin- 1 -yl- IH- pyrrole-2-carboxamide ;4- (2,4-dichlorophenyl) -5- (4-methoxyphenyl) -1-methyl-N-piperidin-1-yl-1H-pyrrole-2-carboxamide;
- le 5-(4-chlorophényl)-4-(2,4-dichlorophényl)- 1 -méthyl-N-pipéridin- 1 -yl- IH- pyrrole-2-carboxamide ;5- (4-chlorophenyl) -4- (2,4-dichlorophenyl) -1-methyl-N-piperidin-1-yl-1H-pyrrole-2-carboxamide;
- le 1 -(I -((5-(4-chlorophényl)-4-(2,4-dichlorophényl)- 1 -méthyl- lH-pyrrol-2-yl) carboxyl)-4-phénylpipéridin-4-yl)éthanone ;1- (1 - ((5- (4-Chlorophenyl) -4- (2,4-dichlorophenyl) -1-methyl-1H-pyrrol-2-yl) carboxyl) -4-phenylpiperidin-4-yl) ethanone;
- le l-{[4-(2-chlorophényl)-5-(4-chlorophényl)-l-méthyl-lH-pyrrol-2-yl] carbonyl} 4-phénylpipéridine-4-carbonitrile ;1 - {[4- (2-chlorophenyl) -5- (4-chlorophenyl) -1-methyl-1H-pyrrol-2-yl] carbonyl} -4-phenylpiperidine-4-carbonitrile;
- le 1 -(4-chlorobenzyl)-4- { [4-(2-chlorophényl)-5-(4-chlorophényl) 1 -méthyl- IH- pyrrol-2-yl]carbonyl}piperazine ; - le N-(l-benzyl-2-méthoxyéthyl)4-(2-chlorophényl)-5-(4-chlorophényl)-l- méthyl-lH-pyrrole-2-carboxamide ;1- (4-Chlorobenzyl) -4 - {[4- (2-chlorophenyl) -5- (4-chlorophenyl) -1-methyl-1H-pyrrol-2-yl] carbonyl} piperazine; N- (1-benzyl-2-methoxyethyl) -4- (2-chlorophenyl) -5- (4-chlorophenyl) -1-methyl-1H-pyrrole-2-carboxamide;
- le l-{[4-(2-chloroρhényl)-5-(4-chlorophényl)-l-méthyl-lH-pyrrol-2-yl] carbonyl}-α-méthylphénylalaninate de méthyle ; - le l'-{[5-(4-chlorophényl-4-(2,4- dichlorophényl)- 1 -méthyl- l/J-pyrrol-2-yl) carbonyl)- 1 ,4'-biρipéridine-4'-carboxamide ; ainsi que leurs sels, leurs solvats et leurs hydrates.methyl 1 - {[4- (2-chloro-phenyl) -5- (4-chlorophenyl) -1-methyl-1H-pyrrol-2-yl] carbonyl} -α-methylphenylalaninate; 1 '- {[5- (4-Chlorophenyl-4- (2,4-dichlorophenyl) -1-methyl-1H-pyrrol-2-yl) carbonyl) -1,4'-bipyridine-4' carboxamide ; as well as their salts, solvates and hydrates.
La présente invention a également pour objet un procédé de préparation des composés selon l'invention.The present invention also relates to a process for preparing the compounds according to the invention.
Ce procédé est caractérisé en ce que l'on traite l'acide de formule (II) ou un dérivé fonctionnel de cet acide de formule :This process is characterized in that the acid of formula (II) or a functional derivative of this acid of formula:
dans laquelle R3, R4, R5, Rg, R7, Rg et R9 sont tels que définis pour (I) avec une aminé de formule HNR1R2 (III) dans laquelle R^ et R2 sont tels que définis pour (I). Eventuellement, on transforme le composé ainsi obtenu en un de ses sels ou solvats. wherein R3, R4, R5, R6, R7, R8 and R9 are as defined for (I) with an amine of formula HNR1R2 (III) wherein R1 and R2 are as defined for (I). Optionally, the compound thus obtained is converted into one of its salts or solvates.
Comme dérivé fonctionnel de l'acide (II) on peut utiliser le chlorure d'acide, l'anhydride, un anhydride mixte, un ester alkylique en C1-C4 dans lequel l'alkyle est droit ou ramifié, un ester benzylique, un ester activé, par exemple l'ester de p- nitrophényle, ou l'acide libre opportunément activé, par exemple, avec le N,N- dicyclohexylcarbodiimide ou avec l'hexafluorophosphate de benzotriazol-1- yloxotris(diméthylamino)-phosphonium (BOP) ou hexafluorophosphate de benzotriazol-l-yloxotris-(pyrrolidino)phosphonium (PyBOP).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, a benzyl ester, an ester activated, for example the p-nitrophenyl ester, or the opportunely activated free acid, for example, with N, N-dicyclohexylcarbodiimide or with benzotriazol-1-yloxotris (dimethylamino) -phosphonium hexafluorophosphate (BOP) or benzotriazol-1-yloxotris- (pyrrolidino) phosphonium hexafluorophosphate (PyBOP).
Ainsi dans le procédé selon l'invention, on peut faire réagir le chlorure de l'acide l,3-oxazole-3-carboxylique, obtenu par réaction du chlorure de thionyle sur l'acide de formule (II), avec une aminé HNR1R2, dans un solvant inerte, tel qu'un solvant chloré (le dichlorométhane, le dichloroéthane, le chloroforme par exemple), un éther (tétrahydrofurane, dioxane par exemple), ou un amide (N,N-diméthylformamide par exemple) sous une atmosphère inerte, à une température comprise entre 0°C et la température, en présence d'une aminé tertiaire telle que la triéthylamine, la N- méthylmorpholine ou la pyridine.Thus, in the process according to the invention, the 1,3-oxazole-3-carboxylic acid chloride, obtained by reaction of thionyl chloride with the acid of formula (II), can be reacted with an amine HNR1R2 in an inert 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 atmosphere inert, at a temperature between 0 ° C and the temperature, in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine.
Une variante consiste à préprarer l'anhydride mixte de l'acide de formule (II) par réaction du chloroformiate d'éthyle avec l'acide de formule (II), en présence d'une base telle que la triéthylamine, et à le faire réagir avec une aminé HNR4R2, dans un solvant tel que le dichlorométhane, sous une atmosphère inerte, à la température ambiante, en présence d'une base telle que la triéthylamine.One variant consists in pre-preparing the mixed anhydride of the acid of formula (II) by reaction of ethyl chloroformate with the acid of formula (II), in the presence of a base such as triethylamine, and reacting it with an amine HNR4R2, in a solvent such as dichloromethane, under an inert atmosphere, at room temperature, in the presence of a base such as triethylamine.
Les composés de formule (II) peuvent être préparés selon le Schéma ci-après :The compounds of formula (II) may be prepared according to the following scheme:
SCHEMA 1SCHEME 1
1) SOCl2/AlkOH (a)1) SOCl 2 / AlkOH (a)
HC ≡≡ C-CH0-CHNH0 HC ≡ C-CH2-CHNH-TsHC ≡≡ C-CH 0 -CHNH 0 HC ≡ C-CH 2 -CHNH-Ts
2) TsClMEt3 2) TsClMEt 3
CO2H CO2AIkCO 2 H CO 2 AIk
(m) (IV)(m) (IV)
(V) (VI)(V) (VI)
La préparation du dérivé de dihydropyrrole de formule (VII) par les étapes a), b) et c) est effectuée selon J. Chem. Soc. Perkin Trans. 1, 2002, 622-628.The preparation of the dihydropyrrole derivative of formula (VII) by steps a), b) and c) is carried out according to J. Chem. Soc. Perkin Trans. 1, 2002, 622-628.
La substitution du noyau dihydropyrrole par un groupe phényle substitué est effectuée à l'étape d) par action d'un acide phénylboronique substitué de formule (VIII) en présence d'un catalyseur au palladium tel que le tetrakis(triphénylphosphine)Pd(0), le palladium (O)bisdibenzylidène acétone [Pd(dba)2], le tris(dibenzylideneacétone)dipalladium(0), l'acétate de palladium Pd(II)[Pd(OCOCH3)2], le dichloro(diphénylphosρhinoferrocène) Pd(II) [PdC^dppfj, et en présence d'une base.Substitution of the dihydropyrrole ring by a substituted phenyl group is carried out in stage d) by the action of a substituted phenylboronic acid of formula (VIII) in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) Pd (0) , palladium (O) bisdibenzylidène acetone [Pd (dba) 2], tris (dibenzylideneacetone) dipalladium (0), Pd palladium (II) acetate [Pd (OCOCH 3) 2], dichloro (diphénylphosρhinoferrocène) Pd ( II) [PdC ^ dppfj, and in the presence of a base.
A l'étape e), la protection de l'azote par le groupe tosyle est enlevée par action d'une diamine telle que DBU(l,8-diazabicyclo[5.4.0]undécène) simultanément le noyau pyrrole est aromatisé.In step e), nitrogen protection by the tosyl group is removed by the action of a diamine such as DBU (1,8-diazabicyclo [5.4.0] undecene) simultaneously the pyrrole ring is aromatized.
A l'étape f), on alkyle l'azote du pyrrole par action d'un iodure d'alkyle de formule R9I, puis on hydrolyse l'ester de formule (X) en milieu basique pour obtenir l'acide de formule (II).In step f), the nitrogen of the pyrrole is alkylated by the action of an alkyl iodide of formula R 9 I, then the ester of formula (X) is hydrolyzed in a basic medium to obtain the acid of formula (II) ).
Les composés de formule (DC), (X) et (II) sont nouveaux.The compounds of formula (DC), (X) and (II) are new.
La présente invention a également pour objet les composés de formule : dans laquelle :The subject of the present invention is also the compounds of formula: in which :
R3, R4, R5, Rg, R7, Rg représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, un groupe (Ci-Cg)alkyle, (Ci-Cg)alcoxy, trifluorométhyle ou un groupement S(O)nAIk ; - Ts représente un groupe tosyle ;R3, R4, R5, R8, R7, R8 are each independently of one another hydrogen, halogen, (C1-C8) alkyl, (C1-C8) alkoxy, trifluoromethyl, or group S (O) n AIk; - Ts represents a tosyl group;
AIk représente un groupe (Ci-C4)alkyle ; n représente 0, 1 ou 2.Alk is a (C 1 -C 4) alkyl group; n represents 0, 1 or 2.
Certains esters de formule (X) sont décrits dans la littérature : les esters méthylique et éthylique de l'acide 4,5-diphényl-lH-pyrrole-2-carboxylique sont décrits dans J. Chem. Research, synopses, 1977, 10,247 ; l'ester éthylique de l'acide lH-pyrrole-5-(4-méthoxyphényi)-4-phényl-2-carboxylique est décrit dans TetrahedronSome esters of formula (X) are described in the literature: methyl and ethyl esters of 4,5-diphenyl-1H-pyrrole-2-carboxylic acid are described in J. Chem. Research, synopses, 1977, 10,247; 1H-pyrrole-5- (4-methoxyphenyl) -4-phenyl-2-carboxylic acid ethyl ester is described in Tetrahedron
Letters, 2003, 44(3), 427-430.Letters, 2003, 44 (3), 427-430.
La présente invention a également pour objet le composé de formule :The present invention also relates to the compound of formula:
dans laquelle : in which :
- R3, R4, R5, Rβ, R7, Rg représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, un groupe (Ci-C6)alkyle, (C;[-C6)alcoxy, trifluorométhyle ou un groupement S(O)nAIk à la condition que R3, R4, R5, Rg, R7, Rg ne représentent pas simultanément l'hydrogène, et à la condition que lorsque Rg est un groupe 4-méthoxy, R3, R4, R5, R7, Rg ne représentent pas simultanément l'hydrogène ;- R3, R4, R5, Rβ, R7 and Rg each independently of one another represent a hydrogen or halogen atom, a (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy group, trifluoromethyl or a group S (O) n Alk with the proviso that R3, R4, R5, R8, R7, Rg do not simultaneously represent hydrogen, and with the proviso that when Rg is a 4-methoxy group, R3, R4 R5, R7, Rg do not simultaneously represent hydrogen;
- AIk représente un groupe (C \ -C4)alkyle,- Alk represents a (C 1 -C 4) alkyl group,
- n représente 0, 1 ou 2.n represents 0, 1 or 2.
La présente invention a également pour objet les composés de formule : dans laquelle :The subject of the present invention is also the compounds of formula: in which :
- X représente un atome d'halogène, un groupe hydroxyle, (Ci-C4)alcoxy ou benzyloxy ;X represents a halogen atom, a hydroxyl group, (C 1 -C 4) alkoxy or benzyloxy;
- R3, R4, R5, Rg, R7, Rg représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, un groupe (Ci-C6)alkyle, (Ci-C())alcoxy, trifluorométhyle ou un groupement S(O)nAIk ;R3, R4, R5, R8, R7, R8 are each independently of one another a hydrogen or halogen atom, a (C1-C6) alkyl, (C1-C ( ) ) alkoxy group, trifluoromethyl or a group S (O) n AIk;
- R9 représente un (Ci-C4)alkyle ;R 9 represents a (C 1 -C 4) alkyl;
- AIk représente un (C \ -C4)alkyle ;- Alk represents a (C 1 -C 4) alkyl;
- n représente 0, 1 ou 2.n represents 0, 1 or 2.
Lorsque X représente un groupe OH, les composés de formule (II bis) peuvent également exister à l'état de sels. De tels sels font partie de l'invention.When X represents an OH group, the compounds of formula (IIa) may also exist in the form of salts. Such salts are part of the invention.
Selon la présente invention, l'acide 5-(4-chlorophényl)-4-(2,4-dichlorophényl)-l- méthyl- lH-pyrrole-2-carboxylique, l'acide 4-(2,4-dichlorophényl)-5-(4-méthoxy phényl)-l-méthyl-lH-pyrrole-2-carboxylique et l'acide 4-(2-chlorophényl)-5-(4- chlorophényl)-l-méthyl-lH"-pyrrole-2-carboxylique ainsi que leurs esters méthylique et éthylique et leurs chlorure sont préférés.According to the present invention, 5- (4-chlorophenyl) -4- (2,4-dichlorophenyl) -1-methyl-1H-pyrrole-2-carboxylic acid, 4- (2,4-dichlorophenyl) (4- (4-methoxyphenyl) -1-methyl-1H-pyrrole-2-carboxylic acid and 4- (2-chlorophenyl) -5- (4-chlorophenyl) -1-methyl-1H-pyrrole ) acid; 2-carboxylic acid and their methyl and ethyl esters and their chloride are preferred.
Les aminés de formule HNRi ^-2 (^) sont connues ou préparées par des méthodes connues.Amines of the formula HNR 1 -2 ()) are known or prepared by known methods.
Les exemples suivants décrivent la préparation de certains composés conformes à l'invention. Ces exemples ne sont pas limitatifs et ne font qu'illustrer la présente invention. Les numéros des composés exemplifiés renvoient à ceux donnés dans le tableau ci-après, qui illustre les structures chimiques et les propriétés physiques de quelques composés selon l'invention.The following examples describe the preparation of certain compounds according to the invention. These examples are not limiting and only illustrate the present invention. The numbers of the compounds exemplified refer to those given in the table below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.
Dans les exemples, on utilise les abréviations suivantes :In the examples, the following abbreviations are used:
F : point de fusionF: melting point
PyBOP : hexafluorophosphate de benzotriazol-l-yloxotris-(pyrrolidino) phosphoniumPyBOP: benzotriazol-1-yloxotris- (pyrrolidino) phosphonium hexafluorophosphate
TBTU : tétrafluoroborate de 2-(iH-benzotriazol-l-yl)-l,l,3,3-tétraméthyluroniumTBTU: 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate
DEPEA : diisopropyléthylamineDEPEA: diisopropylethylamine
TA : température ambiante AcOEt : acétate d'éthyleTA: room temperature AcOEt: ethyl acetate
MeOH : méthanolMeOH: methanol
DMF : N,N-diméthylformamide.DMF: N, N-dimethylformamide.
Les spectres de résonance magnétique nucléaire sont enregistrés à 200 MHz dans le DMSO-dβ. Pour l'interprétation des spectres, on utilise les abréviations suivantes : s : singulet, d : doublet, t : triplet, m : massif, mt : multiplet, se : singulet élargi, dd : doublet de doublet.The nuclear magnetic resonance spectra are recorded at 200 MHz in DMSO-dβ. For the interpretation of spectra, the following abbreviations are used: s: singlet, d: doublet, t: triplet, m: massive, mt: multiplet, se: expanded singlet, dd: doublet of doublet.
Les composés selon l'invention sont analysés par couplage LC/UV/MS (chromatographie liquide/détection UV/spectrométrie de masse). On mesure le pic moléculaire (MH ) et le temps de rétention (tr) en minutes.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.
Conditions AConditions A
On utilise une colonne Symmetry C18 de 2,1 x 50 mm, 3,5 μm, à 3O0C, débit 0,4 mL/minute.A symmetry C18 column of 2.1 × 50 mm, 3.5 μm, is used at 30 ° C., flow rate 0.4 ml / minute.
L'éluant est composé comme suit :The eluent is composed as follows:
- solvant A : 0,005 % d'acide trifluoroacétique (TFA) dans l'eau à pH 3,15 ;solvent A: 0.005% trifluoroacetic acid (TFA) in water at pH 3.15;
- solvant B : 0,005 % de TFA dans l'acétonitrile.solvent B: 0.005% of TFA in acetonitrile.
Gradient :Gradient:
Température de la colonne : 30°C, débit 0,4 ml/minutes.Column temperature: 30 ° C, flow rate 0.4 ml / min.
La détection UV est effectuée à λ = 210 nM et la détection de masse en mode ionisation chimique ESI positif.The UV detection is carried out at λ = 210 nM and the mass detection in ESI positive chemical ionization mode.
Conditions MS 5MS conditions 5
On utilise une colonne XTERRA MS C18 de 2,1 x 30 mm, 3,5 μm, débit 1 ml/minute.An XTERRA MS C18 column of 2.1 x 30 mm, 3.5 μm, flow rate 1 ml / minute is used.
L'éluant est composé comme suit :The eluent is composed as follows:
Solvant A : 0,025 % de TFA dans l'eau,Solvent A: 0.025% TFA in water,
Solvant B : 0,025 % de TFA dans l'acétonitrile. GradientSolvent B: 0.025% TFA in acetonitrile. gradient
La détection UV est effectuée par un détecteur à barette d'iode entre 210 et 400 nm et la détection de masse en mode ESI positif. Préparation 1UV detection is performed by an iodine bar detector between 210 and 400 nm and ESI positive mass detection. Preparation 1
A) 2-(((4-méthylphényl)sulfonyl)amino)pent-3-ynoate de méthyle.A) Methyl 2 - (((4-methylphenyl) sulfonyl) amino) pent-3-ynoate.
2,5 g d'acide 2-aminobut-3-ynoique sont mis en suspension dans 45 ml de méthanol à 0°C. On coule au goutte à goutte 1,8 ml de chlorure de thionyle à cette température puis le mélange est porté à reflux pendant 3 heures. La solution est concentrée et le résidu est séché sous pression réduite. Ce dernier est solubilisé dans 60 ml d'acétonitrile suivi de 5,4 ml de triéthylamine puis on ajoute 4,6 g de chlorure de tosyle. Le mélange est agité à température ambiante pendant 19 heures puis 50°C une heure supplémentaire. Après concentration, le brut est solubilisé dans le dichlorométhane et la phase organique est lavée successivement par une solution aqueuse saturée de KHSO4 puis de K2CO3. La phase organique est séchée sur sulfate de magnésium puis filtrée et enfin concentrée pour obtenir 5,18 g du composé attendu.2.5 g of 2-aminobut-3-ynoic acid are suspended in 45 ml of methanol at 0 ° C. 1.8 ml of thionyl chloride are added dropwise at this temperature and the mixture is refluxed for 3 hours. The solution is concentrated and the residue is dried under reduced pressure. The latter is solubilized in 60 ml of acetonitrile followed by 5.4 ml of triethylamine and 4.6 g of tosyl chloride are then added. The mixture is stirred at room temperature for 19 hours and then 50 ° C for one more hour. After concentration, the crude is solubilized in dichloromethane and the organic phase is washed successively with a saturated aqueous solution of KHSO4 then K2CO3. The organic phase is dried over magnesium sulphate and then filtered and finally concentrated to obtain 5.18 g of the expected compound.
RMN1H : δ (ppm) : 2,35 : s : 3H ; 2,45 : m : 2H ; 3,45 : s : 3H ; 3,9 : dd : IH ; 7,35 : d : 2H ; 7,65 : d : 2H ; 8,4 : d : IH. 1 H NMR: δ (ppm): 2.35: s: 3H; 2.45: m: 2H; 3.45: s: 3H; 3.9: dd: 1H; 7.35: d: 2H; 7.65: d: 2H; 8.4: d: 1H.
B) 5-(4-chlorophényl)-2-(4-tosylsulfonyIamino)pent-4-ynoate de méthyle.B) Methyl 5- (4-chlorophenyl) -2- (4-tosylsulfonylamino) pent-4-yanoate.
1 g du composé de l'étape précédente et 0,57 g de 4-chloroiodobenzène sont solubilisés dans 20 ml de DMF anhydre. La solution est dégazée sous vide pendant 30 minutes. Puis 0,64 ml de triéthylamine sont ajoutés suivis de 0,28 g de tetrakis(triphénylphosρhinepalladium(0) et 0,1g de iodure de cuivre. Le mélange est agité à température ambiante sous atmosphère d'argon pendant 19 heures. Le brut réactionnel est concentré et purifié par chromatographie sur gel de silice cyclohexane/acétate d'éthyle (80/20 ; v/v). On récupère 1 g du composé.1 g of the compound of the preceding step and 0.57 g of 4-chloroiodobenzene are solubilized in 20 ml of anhydrous DMF. The solution is degassed under vacuum for 30 minutes. 0.64 ml of triethylamine are then added followed by 0.28 g of tetrakis (triphenylphosphine) palladium (0) and 0.1 g of copper iodide.The mixture is stirred at room temperature under an argon atmosphere for 19 hours. is concentrated and purified by chromatography on silica gel cyclohexane / ethyl acetate (80/20; v / v). 1 g of the compound is recovered.
RMN1H : δ (ppm) : 2,35 : s : 3H ; 2,70-2,80 : m : 2H ; 3,45 : s : 3H ; 4,05 : dd : IH ; 7,35 : m : 4H ; 7,4 : d : 2H ; 7,65 : d : 2H ; 8,51 : d : IH. 1 H NMR: δ (ppm): 2.35: s: 3H; 2.70-2.80: m: 2H; 3.45: s: 3H; 4.05: dd: 1H; 7.35: m: 4H; 7.4: d: 2H; 7.65: d: 2H; 8.51: d: 1H.
C) 5-(4-chlorophényl-4-iodo-l-(4-tosylsulfonyl)-2,3-dihydro-lJfiT-pyrroIe-2- carboxylate de méthyle.C) 5- (4-chlorophenyl-4-iodo-l- (4-tosylsulfonyl) -2,3-dihydro-l J Fit-pyrrole-2- carboxylate.
On dissout 1 g du composé obtenu à l'étape précédente dans 5 ml d'acétonitrile anhydre en présence de Ig de carbonate de potassium à 0°C. Sous agitation à cette température, on ajoute 2 g d'iode solide en plusieurs petites fractions. Le mélange est laissé revenir à température ambiante pendant 24 heures. La réaction est arrêtée avec une solution de thiosulfate de sodium jusqu'à décoloration et la phase organique est extraite au dichlorométhane. Après séchage sur sulfate de magnésium, filtration et concentration, on obtient 1,27g du composé attendu. LC/MS (conditions A) : M = 517, tr = 10,8 minutes.1 g of the compound obtained in the previous step is dissolved in 5 ml of anhydrous acetonitrile in the presence of potassium carbonate Ig at 0 ° C. While stirring at this temperature, 2 g of solid iodine are added in several small fractions. The mixture is allowed to come to room temperature for 24 hours. The reaction is stopped with a solution of sodium thiosulfate until decolorization and the organic phase is extracted with dichloromethane. After drying over magnesium sulfate, filtration and concentration, 1.27 g of the expected compound are obtained. LC / MS (conditions A): M = 517, tr = 10.8 minutes.
D) 5-(4-chlorophényl)-4-(2,4-dichlorophényl)-l-tosylsulfonyl-2,3-dihydro-lJHr- pyrroIe-2-carboxylate de méthyleD) 5- (4-chlorophenyl) -4- (2,4-dichlorophenyl) -l-tosylsulfonyl-2,3-dihydro-l J r H - pyrrole-2-carboxylate
15 g du composé obtenu à l'étape précédente et 6,8 g de l'acide 2,4- dichlorophényle boronique sont solubilisés dans un mélange de 150 ml de méthanol, 710 ml de toluène, en présence de 48 ml d'une solution de carbonate de sodium (2N). On laisse le milieu réactionnel sous argon pendant 30 minutes puis on ajoute 4,7g de tetrakis(triphénylphoshine)palladium(0). La solution est chauffée à 6O0C pendant 4 heures sous atmosphère inerte. Après refroidissement, le brut est concentré et purifié par chromatographie sur gel de silice dans le toluène. On obtient 9,7 g du composé attendu sous forme d'une poudre blanche.15 g of the compound obtained in the preceding step and 6.8 g of 2,4-dichlorophenylboronic acid are solubilized in a mixture of 150 ml of methanol, 710 ml of toluene, in the presence of 48 ml of a solution. of sodium carbonate (2N). The reaction medium is left under argon for 30 minutes then 4.7 g of tetrakis (triphenylphosphine) palladium (0) are added. The solution is heated at 60 ° C. for 4 hours under an inert atmosphere. After cooling, the crude is concentrated and purified by chromatography on silica gel in toluene. 9.7 g of the expected compound are obtained in the form of a white powder.
RMN1H : δ (ppm) : 2,4 : s : 3H ; 2,75-2,95 : m : IH ; 3,8 : s : 3H ; 5,15 : d : IH ; 6,7 : d : IH ; 7,1-7,7 : m : 6H. 1 H NMR: δ (ppm): 2.4: s: 3H; 2.75-2.95: m: 1H; 3.8: s: 3H; 5.15: d: 1H; 6.7: d: 1H; 7.1-7.7: m: 6H.
E) 5-(4-chlorophényl)-4-(2,4-dichlorophényl)-li3-pyrrole-2-carboxylate de méthyle.E) Methyl 5- (4-chlorophenyl) -4- (2,4-dichlorophenyl) -1H-pyrrole-2-carboxylate.
9,7 g du composé obtenu à l'étape précédente sont solubilisés dans 60 ml de N5N- diméthylformamide anhydre. Puis 5,4 ml de DBU(1, 8-diaza-bicyclo[5.4.0]undecene) sont ajoutés et le mélange est chauffé à 100°C pendant 24 heures. Le brut est concentré puis après ajout d'éthanol, précipité blanc apparaît. Ce dernier est filtré, on recueille 6 g du composé attendu.9.7 g of the compound obtained in the preceding step are solubilized in 60 ml of anhydrous N 5 N-dimethylformamide. Then 5.4 ml of DBU (1,8-diaza-bicyclo [5.4.0] undecene) is added and the mixture is heated at 100 ° C for 24 hours. The crude is concentrated then after adding ethanol, white precipitate appears. The latter is filtered, 6 g of the expected compound are collected.
RMN1H : δ (ppm) : 3,8 : s : 3H ; 6,9 : s : IH ; 7,2 : s : IH ; 7,25 : s : 2H ; 7,3-7,4 : m : 3H ; 7,65 : dd : IH ; 12,4 : s : IH. 1 H NMR: δ (ppm): 3.8: s: 3H; 6.9: s: 1H; 7.2: s: 1H; 7.25: s: 2H; 7.3-7.4: m: 3H; 7.65: dd: 1H; 12.4: s: 1H.
F) Acide 5-(4-chlorophényl)-4-(2,4-dichlorophényl)-l-méthyl-liï-pyrrole-2- carboxylique.F) 5- (4-Chlorophenyl) -4- (2,4-dichlorophenyl) -1-methyl-1H-pyrrole-2-carboxylic acid.
5,9 g du composé obtenu à l'étape précédente sont solubilisés dans 150 ml de DMF et 3,5 g de carbonate de potassium sont ajoutés. A température ambiante, 1,5 ml de iodométhane sont ajoutés au mélange et la réaction est laissée pendant 24 heures. La solution est filtrée et le filtrat est mis à sec puis solubilisé dans 430 ml de méthanol, 7 ml d'eau sont ajoutés suivis de 8,7 g de potasse en pastille. Le mélange est porté à reflux 24 heures. Après concentration, le solide obtenu est lavé à l'éther puis dissous dans le dichlorométhane. La phase organique est traitée par une solution aqueuse d'acide chlorhydrique (10 %). La phase organique est ensuite séchée sur sulfate de magnésium puis filtrée et concentrée. On recueille 5,8 g du composé attendu sous forme d'un solide blanc, F = 194°C. RMN1H : δ (ppm) : 3,75 : s : 3H ; 6,9 : s : 2H ; 7,05 : dd : 2H ; 7,15-7,30 : m : 3H ; 7,45 : d : 2H ; 7,55 : dd : IH ; 12,5 : s : IH.5.9 g of the compound obtained in the preceding step are solubilized in 150 ml of DMF and 3.5 g of potassium carbonate are added. At room temperature, 1.5 ml of iodomethane is added to the mixture and the reaction is left for 24 hours. The solution is filtered and the filtrate is dried and then solubilized in 430 ml of methanol, 7 ml of water are added followed by 8.7 g of potash pellet. The mixture is refluxed 24 hours. After concentration, the solid obtained is washed with ether and then dissolved in dichloromethane. The organic phase is treated with an aqueous solution of hydrochloric acid (10%). The organic phase is then dried over magnesium sulfate and filtered and concentrated. 5.8 g of the expected compound are collected in the form of a white solid, mp = 194 ° C. 1 H NMR: δ (ppm): 3.75: s: 3H; 6.9: s: 2H; 7.05: dd: 2H; 7.15-7.30: m: 3H; 7.45: d: 2H; 7.55: dd: 1H; 12.5: s: 1H.
De la même façon, on prépare les acides de formule (I) suivants :In the same way, the following acids of formula (I) are prepared:
Acide 5-(4-chlorophényI)-4-(2-dichlorophényl)~l-méthyl-llJ-pyrrole-2- carboxylique.5- (4-Chlorophenyl) -4- (2-dichlorophenyl) -1-methyl-11-pyrrole-2-carboxylic acid.
F = 19O0C.Mp = 190 ° C.
LCMS (conditions A) : MH+ :346, tr=7,77minLCMS (conditions A): MH + : 346, tr = 7.77min
RMN1H : δ (ppm) : 3,75 : s : 3H ; 6,9 : s : IH ; 7,05-7,3: m: 5H ; 7.35-7.50 .m. 3H ; 12,5 : s : IH. 1 H NMR: δ (ppm): 3.75: s: 3H; 6.9: s: 1H; 7.05-7.3: m: 5H; 7.35-7.50 .m. 3H; 12.5: s: 1H.
Acide 5-(4-méthoxyphényl)-4-(2,4-dichIorophényl)-l-méthyI-ljH-pyrrole-2- carboxylique.5- (4-Methoxyphenyl) -4- (2,4-dichlorophenyl) -1-methyl-1H-pyrrole-2-carboxylic acid.
LC/MS (conditions A) : MH+ : 376, tr=l 0,24minLC / MS (conditions A): MH + : 376, tr = 0.24min
EXEMPLE 1 : composé n° 2.EXAMPLE 1 Compound No. 2
5-(4-chIorophényl)-4-(2,4-dichlorophényl)-l-méthyI-N-pipéridin-l-yl-lJH- pyrrole-2-carb oxamide.5- (4-chlorophenyl) -4- (2,4-dichlorophenyl) -l-methyl-N-piperidin-l-yl-J H- pyrrole-2-carb oxamide.
0,8 g du composé de la Préparation 1 sont solubilisés dans 15ml de dichlorométhane et 0,7 ml de triéthylamine sont ajoutés suivis de 0,27 ml de la N- aminopipéridine ensuite 1,31 g de PyBOP sont additionnés et le mélange est laissé sous agitation à température ambiante pendant 24 heures. Le brut réactionnel est concentré et le composé précipite dans le mélange cyclohexane/acétate d'éthyle (80/20). On obtient 0,46 g du composé attendu. F = 218°C. EXEMPLE 20.8 g of the compound of Preparation 1 are solubilized in 15 ml of dichloromethane and 0.7 ml of triethylamine are added followed by 0.27 ml of N-aminopiperidine then 1.31 g of PyBOP are added and the mixture is left with stirring at room temperature for 24 hours. The reaction crude is concentrated and the compound precipitates in the cyclohexane / ethyl acetate mixture (80/20). 0.46 g of the expected compound is obtained. M.p. 218 ° C. EXAMPLE 2
Les composés de formule (I) décrits dans le Tableau 2 sont préparés par chimie combinatoire selon le procédé décrit ci-après : les acides carboxyliques de formule (III) sont dissous dans le DMF à la concentration de 0,25M en présence de 3 équivalents de DIPEA. Dans chaque puits de 2 ml, on place 120 μl de cette solution et 120 μl d'une solution de TBTU dans le DMF à la concentration de 0,25M. On ajoute dans chaque puits 300 μl d'une solution contenant l'aminé de formule (III) dans le DMF à la concentration 0,1M et 3 équivalents de DIPEA. Les plaques sont agitées à TA pendant 16 heures puis évaporées. Les produits formés sont dissous dans chaque puits par 500 μl d'AcOEt, on ajoute 400 μl de Na2Cθ3 0,1M et les plaques sont agitées. Après décantation 430 μl de phase aqueuse sont écartés puis 300 μl de NaCl à 5 % sont additionnés et les plaques sont agitées. On écarte ensuite 350 μl de phase aqueuse et les résidus sont analysés par LC/UV/MS (conditions MS5).The compounds of formula (I) described in Table 2 are prepared by combinatorial chemistry according to the method described below: the carboxylic acids of formula (III) are dissolved in DMF at a concentration of 0.25M in the presence of 3 equivalents of DIPEA. In each well of 2 ml, 120 μl of this solution and 120 μl of a solution of TBTU in DMF at the concentration of 0.25M are placed. 300 μl of a solution containing the amine of formula (III) in DMF at a concentration of 0.1M and 3 equivalents of DIPEA are added to each well. The plates are stirred at RT for 16 hours and then evaporated. The products formed are dissolved in each well with 500 μl of AcOEt, 400 μl of 0.1M Na 2 CO 3 are added and the plates are shaken. After decantation 430 .mu.l of aqueous phase are discarded and 300 .mu.l of 5% NaCl are added and the plates are stirred. 350 μl of aqueous phase are then discarded and the residues are analyzed by LC / UV / MS (MS5 conditions).
Les tableaux qui suivent illustrent les structures chimiques et les propriétés physiques de quelques composés selon l'invention. Dans ces tableaux, Et, Me, nPr, tBu signifient respectivement éthyle, rαéthyle, n- propyle et tert-butyle.The following tables illustrate the chemical structures and the physical properties of some compounds according to the invention. In these tables, Et, Me, nPr, tBu respectively mean ethyl, rαethyl, n-propyl and tert-butyl.
TABLEAU 1TABLE 1
TABLEAU 2 TABLE 2
Les composés de formule (I) possèdent une très bonne affinité in vitro (IC50 < 5.10 M) pour les récepteurs aux cannabinoïdes CB\, dans les conditions expérimentales décrites par M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 350, 240- 244).The compounds of formula (I) have a very good in vitro affinity (IC50 <5.10 M) for CB cannabinoid receptors, under the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 350, 240- 244).
La nature antagoniste des composés de formule (I) a été démontrée par les résultats obtenus dans les modèles de l'inhibition de l'adénylate-cyclase comme décrits dans M. Rinaldi-Carmona et al, J. Pharmacol. Exp. Ther., 1996, 278, 871-878 et M. Bouaboula et al., J. Biol. Chem., 1997, 272, 22330-22339.The antagonistic nature of the compounds of formula (I) has been demonstrated by the results obtained in the models of adenylate cyclase inhibition as described in 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.
La toxicité des composés de formule (I) est compatible avec leur utilisation en tant que médicament.The toxicity of the compounds of formula (I) is compatible with their use as a medicament.
Ainsi, selon un autre des ses aspects, l'invention a pour objet des médicaments pour la médecine humaine ou vétérinaire qui comprennent un composé de formule (I), ou encore un solvat ou un hydrate du composé de formule (I).Thus, according to another of its aspects, the invention relates to medicaments for human or veterinary medicine which comprise a compound of formula (I), or a solvate or a hydrate of the compound of formula (I).
Ainsi les composés selon l'invention peuvent être utilisés chez l'homme ou chez l'animal, dans le traitement ou la prévention de maladies impliquant les récepteurs aux cannabinoïdes CB^.Thus, 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.
Selon un autre de ses aspects, la présente invention concerne l'utilisation d'un composé de formule (I), ou de l'un de ses sels, solvats ou hydrates pharmaceutiquement acceptable, pour la préparation de médicaments destinés à traiter ou à prévenir les maladies impliquant les récepteurs aux cannabinoïdes CBj.According to another of its aspects, the present invention relates to the use of a compound of formula (I), or a salt thereof, solvates or hydrates which are pharmaceutically acceptable, for the preparation of medicaments intended to treat or to prevent diseases involving cannabinoid receptors CBj.
Par exemple et de manière non limitative, les composés de formule (I) sont utiles comme médicaments psychotropes, notamment pour le traitement des désordres psychiatriques incluant l'anxiété, la dépression, les troubles de l'humeur, l'insomnie, les troubles délirants, les troubles obsessionnels, les psychoses en général, la schizophrénie, les troubles de l'attention et de l'hyperactivité (TDAH) chez les enfants hyperkinétiques (MBD) ainsi que pour le traitement des troubles liés à l'utilisation de substances psychotropes, notamment dans le cas d'un abus d'une substance et/ou de dépendance à une substance, y compris la dépendance alcoolique et la dépendance nicotinique.For example and without limitation, 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, particular in the case of an abuse of a substance and / or substance dependence, including alcohol dependence and nicotine addiction.
Les composés de formule (I) selon l'invention peuvent être utilisés comme médicaments pour le traitement de la migraine, du stress, des maladies d'origine psychosomatique, des crises d'attaques de panique, de l'épilepsie, des troubles du mouvement, en particulier des dyskinésies ou de la maladie de Parkinson, des tremblements et de la dystonie.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.
Les composés de formule (I) selon l'invention peuvent également être utilisés comme médicaments dans le traitement des déficits mnésiques, des troubles cognitifs, en particulier dans le traitement des démences séniles, de la maladie d'Alzheimer, ainsi que dans le traitement des troubles de l'attention ou de la vigilance. De plus, les composés de formule (I) peuvent être utiles comme neuroprotecteurs, dans le traitement de l'ischémie, des traumatismes crâniens et le traitement des maladies neurodégénératives : incluant la chorée, la chorée de Huntington, le syndrome de Tourrette.The compounds of formula (I) according to the invention can also be used as medicaments in the treatment of memory deficits, 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. In addition, 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.
Les composés de formule (I) selon l'invention peuvent être utilisés comme médicaments dans le traitement de la douleur : les douleurs neuropathiques, les douleurs aiguës périphériques, les douleurs chroniques d'origine inflammatoire.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.
Les composés de formule (I) selon l'invention peuvent être utilisés comme médicaments dans le traitement des troubles de l'appétit, de l'appétence (pour les sucres, carbohydrates, drogues, alcools ou toute substance appétissante) et/ou des conduites alimentaires, notamment en tant qu'anorexigènes ou pour le traitement de l'obésité ou de la boulimie ainsi que pour le traitement du diabète de type II ou diabète non insulinodépendant et pour le traitement des dyslipidémies, du syndrome métabolique. Ainsi les composés de formule (I) selon l'invention sont utiles dans le traitement de l'obésité et des risques associés à l'obésité, notamment les risques cardio- vasculaires. De plus, les composés de formule (T) selon l'invention peuvent être utilisés en tant que médicaments dans le traitement des troubles gastro-intestinaux, des troubles diarrhéiques, des ulcères, des vomissements, des troubles vésicaux et urinaires, des troubles d'origine endocrinienne, des troubles cardio-vasculaires, de l'hypotension, du choc hémorragique, du choc septique, de la cirrhose chronique du foie, de l'encéphalopathie hépatique chronique, de l'asthme, de la bronchite chronique et de la broncho-pneumopathie chronique obstructive, du syndrome de Raynaud, du glaucome, des troubles de la fertilité, des phénomènes inflammatoires, des maladies du système immunitaire, en particulier autoimmunes et neuroinflammatoires tel que l'arthrite rhumatoïde, rarthrite réactionnelle, les maladies entraînant une démyélinisation, la sclérose en plaque, des maladies infectieuses et virales telles que les encéphalites, des accidents vasculaires cérébraux ainsi qu'en tant que médicaments pour la chimiothérapie anticancéreuse et pour le traitement du syndrome de Guillain- Barré et pour le traitement des maladies des os et de l'ostéoporose.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 mellitus and for the treatment of dyslipidemia, metabolic syndrome. Thus, 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. In addition, the compounds of formula (T) according to the invention can be used as medicaments in the treatment of gastrointestinal disorders, diarrheal disorders, ulcers, vomiting, bladder and urinary disorders, endocrine disorders, cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, chronic cirrhosis of the liver, chronic hepatic encephalopathy, asthma, chronic bronchitis and bronchitis. chronic obstructive pulmonary disease, Raynaud's syndrome, glaucoma, fertility disorders, inflammatory phenomena, diseases of the immune system, especially autoimmune and neuroinflammatory diseases such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, stroke as well as edicaments for cancer chemotherapy and for the treatment of Guillain-Barré syndrome and for the treatment of bone diseases and osteoporosis.
Selon la présente invention, les composés de formule (T) sont tout particulièrement utiles pour le traitement des troubles psychotiques, en particulier la schizophrénie ; les troubles de l'attention et de l'hyperactivité (TDAH) chez les enfants hyperkinétiques (MBD) pour le traitement des troubles de l'appétit et de l'obésité, pour le traitement des déficits mnésiques et cognitifs ; pour le traitement de la dépendance alcoolique, de la dépendance nicotinique, c'est à dire pour le sevrage alcoolique et pour le sevrage tabagique ; et pour le traitement des dyslipidémies, du syndrome métabolique.According to the present invention, the compounds of formula (T) are particularly useful for the treatment of psychotic disorders, in particular schizophrenia; Attention Deficit 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; and for the treatment of dyslipidemias, the metabolic syndrome.
Plus particulièrement, les composés de formule (I) selon la présente invention sont utiles dans le traitement et la prévention des troubles de l'appétit, des troubles métaboliques, des troubles gastro-intestinaux, des phénomènes inflammatoires, des maladies du système immunitaire, des troubles psychotiques, de la dépendance alcoolique, de la dépendance nicotinique.Selon un de ses aspects, la présente invention est relative à l'utilisation d'un composé de formule (I), de ses sels pharmaceutiquement acceptables et de leurs solvats ou hydrates pour le traitement des troubles et maladies indiqués ci-dessus.More particularly, 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, In one of its aspects, the present invention relates to the use of a compound of formula (I), of its pharmaceutically acceptable salts and of their solvates or hydrates for the treatment of the disorders and diseases indicated above.
Le composé selon l'invention est généralement administré en unité de dosage.The compound according to the invention is generally administered in dosage unit.
Lesdites unités de dosage sont de préférence formulées dans des compositions pharmaceutiques dans lesquelles le principe actif est mélangé avec un excipient pharmaceutique.Said dosage units are preferably formulated in pharmaceutical compositions in which the active ingredient is mixed with a pharmaceutical excipient.
Ainsi, selon un autre de ses aspects, la présente invention concerne des compositions pharmaceutiques renfermant, en tant que principe actif, un composé de formule (I), un de ses sels pharmaceutiquement acceptables ou un de leurs solvats.Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof.
Le composé de formule (I) ci-dessus et ses sels ou solvats pharmaceutiquement acceptables peuvent être utilisés à des doses journalières de 0,01 à 100 mg par kg de poids corporel du mammifère à traiter, de préférence à des doses journalières de 0,02 à 50 mg/kg. Chez l'être humain, la dose peut varier de préférence de 0,05 à 4000 mg par jour, plus particulièrement de 0,1 à 1000 mg par jour selon l'âge du sujet à traiter ou le type de traitement, à savoir prophylactique ou curatif. Bien que ces dosages soient des exemples de situations moyennes, il peut y avoir des cas particuliers où des dosages plus élevés ou plus faibles sont appropriés, de tels dosages appartiennent également à l'invention. Selon la pratique habituelle, le dosage approprié à chaque patient est déterminé par le médecin selon le mode d'administration, l'âge, le poids et la réponse dudit patient.The compound of formula (I) above and its pharmaceutically acceptable salts or solvates may be used at daily doses of 0.01 to 100 mg per kg of body weight of the mammal to be treated, preferably at daily doses of 0, 02 to 50 mg / kg. In humans, the dose may preferably vary from 0.05 to 4000 mg per day, more particularly from 0.1 to 1000 mg per day depending on the age of the subject to be treated or the type of treatment, namely prophylactic or curative. Although these assays are examples of average situations, there may be special cases where higher or lower dosages are appropriate, such assays also belong to the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the age, the weight and the response of said patient.
Dans les compositions pharmaceutiques de la présente invention pour l'administration orale, sublinguale, inhalée, sous-cutanée, intramusculaire, intraveineuse, transdermique, locale ou rectale, le principe actif peut être administré sous forme unitaire d'administration, en mélange avec des supports pharmaceutiques classiques, aux animaux et aux êtres humains. Les formes unitaires d'administration appropriées comprennent les formes par voie orale telles que les comprimés, les gélules, les poudres, les granules et les solutions ou suspensions orales, les formes d'administration sublinguale et buccale, les aérosols, les formes d'administration topique, les implants, les formes d'administration sous-cutanée, intramusculaire, intraveineuse, intranasale ou intra-oculaire et les formes d'administration rectale.In the pharmaceutical compositions of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal, the active ingredient can be administered in unit dosage form, in admixture with conventional pharmaceutical carriers, animals and humans. Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, aerosols, dosage forms topical, implants, forms of subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and rectal administration forms.
Dans les compositions pharmaceutiques de la présente invention, le principe actif est généralement formulé en unités de dosage contenant de 0,05 à 1000 mg, avantageusement de 0,1 à 500 mg, de préférence de 1 à 200 mg dudit principe actif par unité de dosage pour les administrations quotidiennes.In the pharmaceutical compositions of the present invention, the active principle is generally formulated in dosage units containing from 0.05 to 1000 mg, advantageously from 0.1 to 500 mg, preferably from 1 to 200 mg of said active ingredient per unit of dosage for daily administrations.
A titre d'exemple, une forme unitaire d'administration d'un composé selon l'invention sous forme de comprimé peut comprendre les composants suivants :By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
Composé selon l'invention 50,0 mg Mannitol 223,75 mgCompound according to the invention 50.0 mg Mannitol 223.75 mg
Croscarmellose sodique 6,0 mg Amidon de maïs 15,0 mg Hydroxypropyl-méthylcellulose 2,25 mg Stéarate de magnésium 3,0 mgCroscarmellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg
Par voie orale, la dose de principe actif administrée par jour peut atteindre 0,01 à 100 mg/kg, en une ou plusieurs prises, préférentiellement 0,02 à 50 mg/kg.Orally, 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.
Il peut y avoir des cas particuliers où des dosages plus élevés ou plus faibles sont appropriés ; de tels dosages ne sortent pas du cadre de l'invention. Selon la pratique habituelle, le dosage approprié à chaque patient est déterminé par le médecin selon le mode d'administration, le poids et la réponse dudit patient.There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, 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.
La présente invention, selon un autre de ses aspects, concerne également une méthode de traitement des pathologies ci-dessus indiquées qui comprend l'administration, à un patient, d'une dose efficace d'un composé selon l'invention, ou hydrates ou solvats.The present invention, according to another of its aspects, 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 hydrates or solvates.
Selon la présente invention, un composé de formule (I) peut être associé à un autre principe actif choisi parmi l'une des classes thérapeutiques suivantes :According to the present invention, a compound of formula (I) may be combined with another active ingredient chosen from one of the following therapeutic classes:
- un antagoniste des récepteurs ATi de l'angiotensine II, seul ou associé à un diurétique ;an AT1 receptor antagonist of angiotensin II alone or in combination with a diuretic;
- un inhibiteur de l'enzyme de conversion, seul ou associé à un diurétique ou à un antagoniste calcique ;an inhibitor of the conversion enzyme, alone or in combination with a diuretic or a calcium antagonist;
- un antagoniste calcique ;a calcium antagonist;
- un béta-bloquant seul ou associé à un diurétique ou à un antagoniste calcique ; - un antihyperlipémiant ou un antihypercholestérolémiant ;a beta-blocker alone or in combination with a diuretic or a calcium antagonist; an antihyperlipidemic agent or an antihypercholesterolemic agent;
- un antidiabétique ;- an antidiabetic;
- un autre agent anti-obésité.another anti-obesity agent.
Ainsi, la présente invention a également pour objet des compositions pharmaceutiques contenant en association un composé de formule (I) et un autre principe actif choisi parmi l'une des classes thérapeutiques suivantes :Thus, the subject of the present invention is also pharmaceutical compositions containing in combination a compound of formula (I) and another active principle chosen from one of the following therapeutic classes:
- un antagoniste des récepteurs ATi de l'angiotensine II, seul ou associé à un diurétique ou à un antagoniste calcique ;an AT1 receptor antagonist of angiotensin II, alone or in combination with a diuretic or a calcium antagonist;
- un inhibiteur de l'enzyme de conversion, seul ou associé à un diurétique ;an inhibitor of the conversion enzyme, alone or in combination with a diuretic;
- un antagoniste calcique ;a calcium antagonist;
- un béta-bloquant seul ou associé à un diurétique ou à un antagoniste calcique ;a beta-blocker alone or in combination with a diuretic or a calcium antagonist;
- un antihyperlipémiant ou un antihypercholestérolémiant ;an antihyperlipidemic agent or an antihypercholesterolemic agent;
- un antidiabétique ;- an antidiabetic;
- un autre agent anti-obésité.another anti-obesity agent.
Par antagoniste des récepteurs ATi de l'angiotensine II, on entend un composé tel que candésartan cilexitil, éprosartan, irbésartan, losartan potassium, olmésartan médoxomil, telmisartan, valsartan, chacun de ces composés pouvant être lui-même associé à un diurétique tel que l'hydrochlorothiazide.By 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.
Par inhibiteur de l'enzyme de conversion, on entend un composé tel que alacépril, bénazépril, captopril, cilazapril, énalapril, énalaprilat, fosinopril, imidapril, lisinopril, moexipril, périndopril, quinapril, ramipril, spirapril, temocapril, trandolapril, zofénopril, chacun de ces composés pouvant lui-même être associé à un diurétique tel que l'hydrochlorothiazide ou l'indapamide ou à un antagoniste calcique tel que l'amlodipine, le diltiazem, le félodipine ou le vérapamil.By 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, trandolapril, zofenopril, each such compounds may itself be associated with a diuretic such as hydrochlorothiazide or indapamide or a calcium antagonist such as amlodipine, diltiazem, felodipine or verapamil.
Par antagoniste calcique, on entend un composé tel que amlodipine, aranidipine, bénidipine, bépridil, cilnidipine, diltiazem, éfonidipine hydrochloride éthanol, fasudil, félodipine, isradipine, lacidipine, lercanidipine hydrochloride, manidipine, mibéfradil hydrochloride, nicardipine, nifédipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, térodiline, vérapamil.By 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.
Par béta-bloquant, on entend un composé tel que acébutolol, alprénolol, amosulalol, arotinolol, aténolol, béfunolol, bétaxolol, bévantolol, bisoprolol, bopindolol, bucumolol, bufétolol, bunitrolol, butofilolol, carazolol, cartéolol, carvédilol, cloranolol, épanolol, esmolol, indénolol, labétalol, landiolol, lévobunolol, lévomoprolol, mépindolol, métipranolol, métoprolol, nadolol, nébivolol, nifénalol, nipradilol, oxprénolol, penbutolol, pindolol, propanolol, sahnétérol, sotalol, talinolol, tertatolol, tilisolol, timolol, xamotérol, xibénolol.By 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. , indenolol, labetalol, landiolol, levobunolol, levomoprolol, mepindolol, metiprolol, metoprolol, nadolol, nebivolol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol, propanolol, sahneterol, sotalol, talinolol, tertatolol, tilisolol, timolol, xamoterol, xibenolol.
Par antihyperlipémiant ou antihypercholestérolémiant, on entend un composé choisi parmi les fibrates tels que alufibrate, béclobrate, bézafibrate, ciprofibrate, clinofibrate, clofibrate, étofibrate, fénofibrate ; les statines (inhibiteurs de HMG-CoA reductase), telles que atorvastatine, fluvastatine sodium, lovastatine, pravastatine, rosuvastatine, simvastatine, ou un composé tel que acipimox, aluminum nicotinate, azacostérol, cholestyramine, dextrothyroxine, méglutol, nicéritrol, nicoclonate, acide nicotinique, béta-sitosterin, tiadénol. Plus particulièrement, la présente invention a pour objet une composition pharmaceutique contenant en association un composé de formule (I) et l'atorvastatine ou la pravastatine, ou préférentiellement un composé de formule (I) et la simvastatine.By antihyperlipidemic or antihypercholesterolaemic is meant 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. More particularly, the subject of the present invention is a pharmaceutical composition containing, in combination, a compound of formula (I) and atorvastatin or pravastatin, or preferentially a compound of formula (I) and simvastatin.
Par antidiabétique, on entend un composé appartenant à l'une des classes suivantes : les sulfonylurées, les biguanidines, les inhibiteurs d'alpha glucosidase, les thiazolidinedione, les métiglinides, tel que acarbose, acétohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glimépiride, glipizide, gliquidone, glisoxepide, glybuzole, glymidine, métahexamide, métformin, miglitol, natéglinide, pioglitazone, répaglinide, rosiglitazone, tolazamide, tolbutamide, troglitazone, voglibose.By 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, glipidide, gliquidone, glisoxepide, glybuzole, glymidine, metahexamide, metformin, miglitol, nateglinide, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, troglitazone, voglibose.
Par autre agent anti-obésité, on entend un composé tel que amfépramone, benfluorex, benzphétamine, indanorex, mazindole, méfénorex, méthamphétamine, D- norpseudoéphédrine ou un autre antagoniste des récepteurs CB i aux cannabinoïdes.By another anti-obesity agent is meant a compound such as amfepramone, benfluorex, benzphetamine, indanorex, mazindole, mefenorex, methamphetamine, D-norpseudoephedrine or another CB i cannabinoid receptor antagonist.
Tout particulièrement, la présente invention a pour objet une composition pharmaceutique contenant en association un composé de formule (I) et un antagoniste des récepteurs ATi de l'angiotensine II, notamment l'irbesartan, le losartan ou le valsartan.In particular, 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.
Selon un autre aspect de l'invention, le composé de formule (I) et l'autre principe actif associé peuvent être administrés de manière simultanée, séparée ou étalée dans le temps.According to another aspect of the invention, the compound of formula (I) and the other associated active ingredient can be administered simultaneously, separately or spread over time.
On entend par "utilisation séparée" l'administration, en même temps, des deux composés de la composition selon l'invention, chacun compris dans une forme pharmaceutique distincte.By "separate 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.
On entend par "utilisation étalée dans le temps", l'administration successive, du premier composé de la composition selon l'invention, compris dans une forme pharmaceutique, puis, du deuxième composé de la composition selon l'invention, compris dans une forme pharmaceutique distincte. "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.

Claims

REVENDICATIONS
1. Composé répondant à la formule (I) :1. Compound corresponding to formula (I):
dans laquelle : in which :
- Rj représente l'hydrogène ou un (Ci-C4)alkyle ;R 1 represents hydrogen or a (C 1 -C 4) alkyl;
- R2 représente :R2 represents:
. un groupe (C3-Cio)alkyle non substitué ou substitué par un groupe trifluorométhyle ;. a (C3-C10) alkyl group unsubstituted or substituted by a trifluoromethyl group;
. un radical carbocyclique non aromatique en C3-C12, non substitué ou substitué une ou plusieurs fois par un groupe (Cj-C^alkyle, hydroxyle, cyano,. a non-aromatic carbocyclic radical, C3-C12 unsubstituted or substituted one or more times with a (Cj-C ^ alkyl, hydroxyl, cyano,
(C1-C4) alcoxy, ou un groupement COR12 \(C1-C4) alkoxy, or a group COR12 \
. un indanyle ;. indanyl;
. un 1,2,3,4-tétrahydronaphtalényle -1 ou -2 ;. 1,2,3,4-tetrahydronaphthalenyl-1 or -2;
. un radical hétérocyclique monooxygéné ou monosoufré, de 5 à 7 atomes, non substitué ou substitué une ou plusieurs fois par un groupe (Ci-C4)alkyle ;. a monooxygenated or monosulfurized heterocyclic radical of 5 to 7 atoms, unsubstituted or substituted one or more times by a (C 1 -C 4) alkyl group;
. un radical hétérocyclique monoazoté, de 5 à 7 atomes, non substitué ou substitué une ou plusieurs fois par groupe (Ci-C4)alkyle, l'atome d'azote étant de plus substitué par un groupe (Ci-C4)alkyle, phényle, benzyle, (Cj-. a mono-nitrogenated heterocyclic radical of 5 to 7 atoms, unsubstituted or substituted one or more times by (C 1 -C 4) alkyl group, the nitrogen atom being further substituted by a (C 1 -C 4) alkyl, phenyl group, benzyl
C4)alcoxycarbonyle ou (Ci-C4)alcanoyle, les groupes phényle ou benzyle étant non substitués ou substitués une ou plusieurs fois par un atome d'halogène, un groupe (Ci-C4)alkyle, trifluorométhyle, hydroxyle, ou (Ci-C4) alkoxycarbonyl or (C1-C4) alkanoyl, the phenyl or benzyl groups being unsubstituted or substituted one or more times with a halogen atom, a (C1-C4) alkyl, trifluoromethyl, hydroxyl, or (C 1 -C 4) group;
C4)alcoxy ;C4) alkoxy;
. un benzothiophényle, un indolyle, lesdits radicaux étant non substitués ou substitués une ou plusieurs fois par groupe (Ci-C4)alkyle ;. a benzothiophenyl, an indolyl, said radicals being unsubstituted or substituted one or more times by (C 1 -C 4) alkyl group;
. un groupe (Ci-C3)alkylène portant un radical carbocyclique non aromatique en C3-C10 non substitué ou substitué une ou plusieurs fois par un groupe (Ci-. a (C 1 -C 3) alkylene group carrying a non-aromatic C 3 -C 10 carbocyclic radical which is unsubstituted or substituted one or more times with a group (C 1 -C 3);
C4) alkyle, hydroxyle, (Ci-C4)alcoxy, cyano ou un groupement CORi 2 > C4) alkyl, hydroxyl, (C1-C4) alkoxy, cyano or a COR1 group >
. un groupe (Ci-C3)alkylène portant un radical hétérocyclique, hétéroaromatique ou non, monooxygéné, monosoufré ou monoazoté de 5 à 7 atomes, non substitué ou substitué une ou plusieurs fois par un groupe (Cj-. a (C 1 -C 3) alkylene group carrying a heterocyclic heteroaromatic or non-heteroaromatic radical, monooxygenated, monosulfurized or monounsaturated from 5 to 7; atoms, unsubstituted or substituted one or more times by a group (Cj-
C4)alkyle ;C 4 ) alkyl;
. un groupe (Ci-C3)alkylène portant un radical indolyle ou benzothiophényle, ledit radical étant non substitué ou substitué une ou plusieurs fois par un groupe (Ci-C4)alkyle et l'alkylène étant non substitué ou substitué par un groupe hydroxyle, méthyle ou méthoxy ou par un groupement CORi 2 î. a (C 1 -C 3) alkylene group carrying an indolyl or benzothiophenyl radical, said radical being unsubstituted or substituted one or more times by a (C 1 -C 4) alkyl group and the alkylene being unsubstituted or substituted with a hydroxyl, methyl group; or methoxy or by a group CORi 2
. un groupe (Cj-C3)alk;ylène portant un groupe (Ci-C4)alkylthio ;. a (C 1 -C 4) alkylene group having a (C 1 -C 4) alkylthio group;
. un groupement phénylalkylène dans lequel l'alkylène est en (C1-C3), non substitué ou substitué sur l'alkylène par un ou plusieurs groupes méthyle, hydroxyle, hydroxyméthyle, méthoxy, méthoxyméthyle, un groupement. a phenylalkylene group in which the alkylene is (C 1 -C 3), unsubstituted or substituted on the alkylene by one or more methyl, hydroxyl, hydroxymethyl, methoxy or methoxymethyl groups, a group
COR12 et non substitué sur le phényle ou substitué sur le phényle par un ou plusieurs substituants identiques ou différents choisis parmi un atome d'halogène ou un groupe (Ci-C4)alkyle, trifluorométhyle, (Ci-C4)alcoxy, trifluorométhoxy ;COR12 and unsubstituted on phenyl or substituted on phenyl by one or more identical or different substituents selected from a halogen atom or a group (C1-C4) alkyl, trifluoromethyl, (C1-C4) alkoxy, trifluoromethoxy;
. un groupe benzydryle ou benzydryhnéthyle ;. a benzydryl or benzydryhnethyl group;
. un groupement NR40R11 J. a group NR40R11 J
- ou R^ et R2 ensemble avec l'atome d'azote auquel ils sont liés constituent:or R 1 and R 2 together with the nitrogen atom to which they are attached constitute:
. soit un radical pipérazin-1-yle ou 1,4-diazépan-l-yle substitué en 4- par un groupe phényle, benzyle, benzodioxolyle, benzodioxolylméthyle, tetrahydrofuranylcarbonyle ou par un groupement CORi 2 ou CH2COR12 ;. or a 4-substituted piperazin-1-yl or 1,4-diazepan-1-yl radical by a phenyl, benzyl, benzodioxolyl, benzodioxolylmethyl or tetrahydrofuranylcarbonyl group or by a CORi 2 or CH 2 COR 12 group;
. soit un radical pipéridin-1-yle ou pyrrolidin-1-yle mono ou gem-disubstitué par un ou deux groupes choisis parmi un groupe phényle, benzyle, pipéridin-1- yle, pyrrolidin-1-yle, (Ci-C4)alkyle, hydroxyle, cyano ou un groupement. either a piperidin-1-yl or pyrrolidin-1-yl radical mono- or gem-disubstituted by one or two groups selected from a phenyl, benzyl, piperidin-1-yl, pyrrolidin-1-yl, (C 1 -C 4) alkyl group; , hydroxyl, cyano or a group
CORi 2, NR13R14, NHCORi 5 ou CH2COR12 ;COR1, NR13R14, NHCOR1 or CH2COR12;
. les groupes phényle ou benzyle étant non substitués ou substitués par un ou plusieurs substituants choisis indépendamment parmi par un atome d'halogène, un groupe méthyle, trifluorométhyle, hydrolyle, (Ci-C4)alcoxy ;. the phenyl or benzyl groups being unsubstituted or substituted with one or more substituents chosen independently from among a halogen atom, a methyl, trifluoromethyl, hydrolyl, (C 1 -C 4) alkoxy group;
- R3, R4, R5, Rg, R7, Rg représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, un groupe (Ci-Cg)alkyle, (Ci-Cβ)alcoxy, trifluorométhyle ou un groupement S(O)nAIk ;- R3, R4, R5, R8, R7, R8 are each independently of one another a hydrogen or halogen atom, a (C1-C8) alkyl, (C1-Cβ) alkoxy, trifluoromethyl or a group S (O) n AIk;
- R9 représente un groupe (Ci~C4)alkyle ;R 9 represents a (C 1 -C 4) alkyl group;
- RlO représente un atome d'hydrogène ou un groupe méthyle ;- R10 represents a hydrogen atom or a methyl group;
- Rl 1 représente un groupe (C3-C(5)alkyle, phényle ou (C3-C10) cycloalkyle, lesdits groupes phényle et cycloalkyle étant non substitués ou substitués par un ou plusieurs substituants choisis indépendamment parmi un atome d'halogène ou un groupe (Ci-C4)alkyle ou trifluorométhyle ;R 1 represents a (C 3 -C 5) alkyl, phenyl or (C 3 -C 10) cycloalkyl group, said phenyl and cycloalkyl groups being unsubstituted or substituted by one or more substituents chosen independently from a halogen atom or a group (C1-C4) alkyl or trifluoromethyl;
- ou RIQ et Ri 1 ensemble avec l'atome d'azote auquel ils sont liés constituent un radical hétérocyclique, saturé ou insaturé, de 4 à 11 atomes, ponté ou non, comprenant ou non un carbone spirannique et contenant ou non un deuxième hétéroatome choisi parmi O ou N, ledit radical étant non substitué ou substitué une ou plusieurs fois par un groupe hydroxyle, (Ci-C4)alkyle, (Ci-C4)alcoxy- carbonyle ou par un groupe phényle non substitué ou substitué par un ou plusieurs substituants choisis indépendamment parmi un atome d'halogène ou un groupe (Ci-C4)alkyle ;or RIQ and Ri 1 together with the nitrogen atom to which they are attached constitute a saturated or unsaturated heterocyclic radical of 4 to 11 atoms, bridged or not, comprising or not comprising a spiro-carbon and optionally containing a second heteroatom selected from O or N, said radical being unsubstituted or substituted one or more times with a hydroxyl, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxycarbonyl group; or by a phenyl group unsubstituted or substituted with one or more substituents independently selected from a halogen atom or a (C 1 -C 4 ) alkyl group;
- R42 représente un groupe (C;[-C4)alkyle, phényle, benzyle, (C;[-C4)alcoxy, un trifluorométhyle, un groupement NR43R14 ;R 42 is (C 1 -C 4) alkyl, phenyl, benzyl, (C 1 -C 4) alkoxy, trifluoromethyl, NR43R14;
- Ri 3 et Rj 4 représentent chacun indépendamment un atome d'hydrogène ou un groupe (Ci~C4)alkyle ou ensemble avec l'atome d'azote auquel ils sont liés constituent un radical choisi parmi azétidinyle, pyrrolidinyle, pipérazinyle, pipéridinyle ou azépinyle ;R 1 and R 4 each independently represent a hydrogen atom or a (C 1 -C 4) alkyl group or together with the nitrogen atom to which they are bonded constitute a radical chosen from azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl or azepinyl; ;
- R\ 5 représente un groupe (Ci-C4)alkyle ou un trifluorométhyle ; n représente 0, 1 ou 2 ;R 5 represents a (C 1 -C 4) alkyl group or a trifluoromethyl; n represents 0, 1 or 2;
- AIk représente un groupe (Ci-C4)alkyle ; à l'état de bases ou de sels d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvat.- Alk represents a (C 1 -C 4) alkyl group; in the form of bases or addition salts with an acid, as well as with the hydrate or solvate state.
2. Composés selon la revendication 1 de formule (I) dans laquelle :2. Compounds according to claim 1 of formula (I) in which:
- Rl représente l'hydrogène et R2 représente un groupe NRIQR-11 dans lequel Rj 0 et Rn ensemble avec l'atome d'azote auquel ils sont liés constituent un radical hétérocyclique saturé de 5 à 11 atomes de carbone, non substitué ou substitué une ou plusieurs fois par un (Cj-C4)alkyle ;R 1 represents hydrogen and R 2 represents a group NRIQR-11 in which R 1 0 and R n together with the nitrogen atom to which they are bonded constitute a saturated heterocyclic radical of 5 to 11 carbon atoms, unsubstituted or substituted one or several times with a (C 1 -C 4) alkyl;
- ou R\ et R2 ensemble avec l'atome d'azote auquel ils sont liés constituent un radical pipéridin-1-yle gem-disubstitué par un groupe phényle, benzyle, pyrrolidin-1-yle ou pipéridin-1-yle et par un groupe cyano (Ci-C3)alcanoyle ou aminocarbonyle ;or R 1 and R 2 together with the nitrogen atom to which they are attached constitute a piperidin-1-yl radical which is gem-disubstituted with a phenyl, benzyl, pyrrolidin-1-yl or piperidin-1-yl group and by a cyano (C 1 -C 3) alkanoyl or aminocarbonyl group;
- ou Rj et R2 ensemble représentent un groupe pipérazin-1-yle substitué en -A- par un benzyle lui-même non substitué ou substitué par un atome d'halogène ;or R 1 and R 2 together represent a piperazin-1-yl group substituted at -A- with a benzyl which is itself unsubstituted or substituted by a halogen atom;
- et/ou R3, R4, R5, Rg, R7, Rg représentent chacun indépendamment l'un de l'autre un atome d'hydrogène, d'halogène ou un groupe méthoxy ;and / or R3, R4, R5, R8, R7 and R8 each independently of one another represent a hydrogen atom, a halogen atom or a methoxy group;
- R9 représente un groupe (Ci-C4)alkyle ; à l'état de bases ou de sels d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvat.R 9 represents a (C 1 -C 4) alkyl group; in the form of bases or addition salts with an acid, as well as with the hydrate or solvate state.
3. Composés selon la revendication 1 de formule (I) dans laquelle :3. Compounds according to claim 1 of formula (I) in which:
- Ri représente l'hydrogène et R2 représente un radical pipéridin-1-yle ou un (C\- C3)alkylène substitué par un phényle et par un groupe méthoxy ou méthoxycarbonyle ; - ou Rj et R2 ensemble avec l'atome d'azote auquel ils sont liés représentent un radical pipéridin-1-yle gem-disubstitué en -4 par un groupe phényle, pipéridin-1- yle et par un groupe acétyle, aminocarbonyle ou cyano ;R 1 represents hydrogen and R 2 represents a piperidin-1-yl radical or a (C 1 -C 3) alkylene substituted with a phenyl and a methoxy or methoxycarbonyl group; - or R 1 and R 2 together with the nitrogen atom to which they are bonded represent a piperidin-1-yl radical gem-disubstituted in -4 by a phenyl group, piperidin-1-yl and by an acetyl, aminocarbonyl or cyano group ;
- ou Rj et R2 ensemble représentent un groupe pipérazin-1-yle substitué en -A- par un benzyle lui-même non substitué ou substitué par un atome d'halogène ;or R 1 and R 2 together represent a piperazin-1-yl group substituted at -A- with a benzyl which is itself unsubstituted or substituted by a halogen atom;
- Rβ est un 4-chloro ou un 4-méthoxy et R3 et R4 représentent 2,4-dichloro ou 2- chloro, R5, R7, Rg représentant un atome d'hydrogène ;- Rβ is a 4-chloro or a 4-methoxy and R3 and R4 represent 2,4-dichloro or 2-chloro, R5, R7, Rg representing a hydrogen atom;
- R9 représente un groupe méthyle ; à l'état de bases ou de sels d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvat.- R9 represents a methyl group; in the form of bases or addition salts with an acid, as well as with the hydrate or solvate state.
4. Composés selon la revendication 1 choisi parmi :4. Compounds according to claim 1 selected from:
- le 4-(2,4-dichlorophényl)-5-(4-méthoxyphényl)- 1 -méthyl-N-pipéridin- 1 -yl- IH- pyrrole-2-carboxamide ;4- (2,4-dichlorophenyl) -5- (4-methoxyphenyl) -1-methyl-N-piperidin-1-yl-1H-pyrrole-2-carboxamide;
- le 5-(4-chlorophényl)-4-(2,4-dichlorophényl)- 1 -méthyl-N-pipéridin- 1 -yl- IH- pyrrole-2-carboxamide ;5- (4-chlorophenyl) -4- (2,4-dichlorophenyl) -1-methyl-N-piperidin-1-yl-1H-pyrrole-2-carboxamide;
- le l-(l-((5-(4-chlorophényl)-4-(2,4-dichlorophényl)-l-méthyl-lH"-pyrrol-2-yl) carboxyl)-4-phénylpipéridin-4-yl)éthanone ;- l- (l - ((5- (4-chlorophenyl) -4- (2,4-dichlorophenyl) -l-methyl-lH "pyrrol-2-yl) carboxyl) -4-phenylpiperidin-4-yl ) ethanone;
- le 1 - { [4-(2-chlorophényl)-5-(4-chlorophényl)- 1 -méthyl- lH-pyrrol-2-yl] carbonyl} 4-phénylpipéridine-4-carbonitrile ;1 - {[4- (2-chlorophenyl) -5- (4-chlorophenyl) -1-methyl-1H-pyrrol-2-yl] carbonyl} -4-phenylpiperidine-4-carbonitrile;
- le l-(4-chlorobenzyl)-4-{[4-(2-chloroρhényl)-5-(4-chloroρhényl)l-méthyl-lH- pyrrol-2-yl]carbonyl}piperazine ;1- (4-chlorobenzyl) -4 - {[4- (2-chloro-phenyl) -5- (4-chloro-phenyl) -1-methyl-1H-pyrrol-2-yl] carbonyl} piperazine;
- le N-(I -benzyl-2-méthoxyéthyl)4-(2-chlorophényl)-5-(4-chlorophényl)- 1 - méthyl- lH-pyrrole-2-carboxamide ;N- (1-benzyl-2-methoxyethyl) -4- (2-chlorophenyl) -5- (4-chlorophenyl) -1-methyl-1H-pyrrole-2-carboxamide;
- le l-{[4-(2-chlorophényl)-5-(4-chlorophényl)-l-méthyl-lH-pyrrol-2-yl] carbonyl} -α-méthylphénylalaninate de méthyle.methyl 1 - {[4- (2-chlorophenyl) -5- (4-chlorophenyl) -1-methyl-1H-pyrrol-2-yl] carbonyl} -α-methylphenylalaninate.
- 1- le l'-{[5-(4-chlorophényl-4-(2,4-dichloroρhényl)-l-méthyl-lH'-ρyrrol-2-yl) carbonyl)- 1 ,4'-bipipéridine-4'-carboxamide ; à l'état de bases ou de sels d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvat.- 1- the l '- {[5- (4-chlorophenyl-4- (2,4-dichloroρhényl) -l-methyl-lH' -ρyrrol-2-yl) carbonyl) - 1, 4'-bipiperidin-4 carboxamide; in the form of bases or addition salts with an acid, as well as with the hydrate or solvate state.
5. Procédé de préparation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 4, caractérisé en ce que l'on traite l'acide de formule (II) ou un dérivé fonctionnel de cet acide de formule : dans laquelle R3, R4, R5, R5, R7, Rg et R9 sont tels que définis pour (I) à la revendication 1 avec une aminé de formule HNR1R2 (III) dans laquelle R^ et R2 sont tels que définis pour (I). 5. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 4, characterized in that the acid of formula (II) or a functional derivative of this acid of formula is treated. : wherein R3, R4, R5, R5, R7, R8 and R9 are as defined for (I) in claim 1 with an amine of formula HNR1R2 (III) wherein R1 and R2 are as defined for (I) .
6. Composé de formule :6. Compound of formula:
dans laquelle : in which :
- R3, R4, R5, Rg, R7, Rg représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, un groupe (Ci-Cô)alkyle, (Ci-Cg)alcoxy, trifluorométhyle ou un groupement S(O)nAIk ;- R3, R4, R5, R8, R7, R8 are each independently of one another a hydrogen or halogen atom, a (C1-C6) alkyl, (C1-C8) alkoxy, trifluoromethyl or a group S (O) n AIk;
- Ts représente un groupe tosyle ;- Ts represents a tosyl group;
- AIk représente un (Ci-C4)alkyle ;- Alk represents a (C1-C4) alkyl;
- n représente 0, 1 ou 2.n represents 0, 1 or 2.
7. Composé de formule :7. Compound of formula:
dans laquelle : in which :
- R3, R4, R5, Rβ, R7, Rg représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, un groupe (Cj-C6)alkyle, (Ci-C(5)alcoxy, trifluorométhyle ou un groupement S(O)nAIk à la condition que R3, R4, R5, Rg, R7, Rg ne représentent pas simultanément l'hydrogène, et à la condition que lorsque Rg est un groupe 4-méthoxy, R3, R4, R5, R7, Rg ne représentent pas simultanément l'hydrogène;- R3, R4, R5, Rβ, R7, Rg are each independently of one another a hydrogen or halogen atom, a (C1-C6) alkyl, (C1-C (5) alkoxy group, trifluoromethyl or a group S (O) n AIk with the proviso that R3, R4, R5, R8, R7, Rg do not simultaneously represent hydrogen, and with the proviso that when Rg is 4-methoxy, R3, R4, R5, R7, Rg do not simultaneously represent hydrogen;
- AIk représente un groupe (Ci-C4)alkyle ;- Alk represents a (C 1 -C 4) alkyl group;
- n représente 0, 1 ou 2. n represents 0, 1 or 2.
8. Composé de formule :8. Compound of formula:
dans laquelle : in which :
- X représente un atome d'halogène, un groupe hydroxyle, (Ci-C4)alcoxy ou benzyloxy ;X represents a halogen atom, a hydroxyl group, (C 1 -C 4) alkoxy or benzyloxy;
- R3, R4, R5, Rg, R7, Rg représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, un groupe (Cj-C6)alkyle, (Ci-C6)alcoxy, trifluorométhyle ou un groupement S(O)nAIk ;R3, R4, R5, R8, R7 and R8 each independently of one another represent a hydrogen or halogen atom, a (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy or trifluoromethyl group or a group S (O) n AIk;
- R9 représente un (Ci-C4)alkyle ;R 9 represents a (C 1 -C 4) alkyl;
- AIk représente un (Ci-C4)alkyle ;- Alk represents a (C1-C4) alkyl;
- n représente 0, 1 ou 2.n represents 0, 1 or 2.
9. Médicament, caractérisé en ce qu'il comprend un composé de formule (I) selon l'une quelconque des revendications 1 à 4, ou un sel d'addition de ce composé à un acide pharmaceutiquement acceptable, ou encore un hydrate ou un solvat du composé de formule (I).9. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 4, or a salt of addition of this compound to a pharmaceutically acceptable acid, or a hydrate or a solvate of the compound of formula (I).
10. Composition pharmaceutique, caractérisée en ce qu'elle comprend un composé de formule (I) selon l'une quelconque des revendications 1 à 4, ou un sel pharmaceutiquement acceptable, un hydrate ou un solvat de ce composé, ainsi qu'au moins un excipient pharmaceutiquement acceptable.10. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, and at least a pharmaceutically acceptable excipient.
11. Utilisation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 4 pour la préparation d'un médicament destiné au traitement et à la prévention des troubles de l'appétit, des troubles métaboliques, des troubles gastro-intestinaux, des phénomènes inflammatoires, des maladies du système immunitaire, des troubles psychotiques, de la dépendance alcoolique, de la dépendance nicotinique. 11. Use of a compound of formula (I) according to any one of claims 1 to 4 for the preparation of a medicament for the treatment and prevention of appetite disorders, metabolic disorders, gastrointestinal disorders. -intestinal, inflammatory phenomena, diseases of the immune system, psychotic disorders, alcohol dependence, nicotine addiction.
EP05796087A 2004-08-09 2005-08-02 Pyrrole derivatives, their preparation and their therapeutic use Withdrawn EP1781636A1 (en)

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