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EP1678159A2 - Thiophene-2-carboxamide derivatives and use thereof as cannabinoid cb-1 receptor antagonists - Google Patents

Thiophene-2-carboxamide derivatives and use thereof as cannabinoid cb-1 receptor antagonists

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Publication number
EP1678159A2
EP1678159A2 EP04791498A EP04791498A EP1678159A2 EP 1678159 A2 EP1678159 A2 EP 1678159A2 EP 04791498 A EP04791498 A EP 04791498A EP 04791498 A EP04791498 A EP 04791498A EP 1678159 A2 EP1678159 A2 EP 1678159A2
Authority
EP
European Patent Office
Prior art keywords
group
alkyl
substituted
unsubstituted
phenyl
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Withdrawn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
EP04791498A
Other languages
German (de)
French (fr)
Inventor
Francis Barth
Christian Congy
Jean-Philippe Ducoux
Murielle Rinaldi-Carmona
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Original Assignee
Sanofi Aventis France
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Publication date
Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
Publication of EP1678159A2 publication Critical patent/EP1678159A2/en
Withdrawn legal-status Critical Current

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Definitions

  • the present invention relates to thiophene-2-carboxamide derivatives, their preparation and their therapeutic use.
  • Diphenylpyrazole derivatives, having an affinity for the cannabinoid CB ⁇ receptors have been described in particular in US Pat. Nos. 5,624,941, EP 0 576 357, EP 0 656 354 and EP 1 150 961.
  • 5,6-diphenyl derivatives -2-pyrazinecarboxamide are described in international patent application WO 03/051850 as antagonists of the CBi receptors.
  • Derivatives of 1,2-diphenyl-4-imidazolecarboxamide are described in international patent application WO 03/027076 as CBi receptor agonists, partial agonists or antagonists.
  • Ri represents hydrogen or a (C ⁇ -C4) alkyl
  • R2 represents:. a (C4-Cjo) alkyl group
  • a non-aromatic carbocyclic radical C3-C12 unsubstituted or substituted one or more times with a (C ⁇ -C4) alkyl, (C ⁇ -C4) alkoxy or hydroxyl
  • a heterocyclic radical monooxygenated or monosulfated, saturated, of 5 to 7 atoms, unsubstituted or substituted one or more times by a group (Ci -C4) alkyl
  • a group (Ci -C4) alkyl Ci -C4) alkyl
  • a group NR9R1 Q ⁇ or R ⁇ and R2 together with the nitrogen atom to which they are bonded constitute either a piperazin-1-yl radical or 1,4-diazepan-l-yl substituted in 4- with a phenyl group or benzyl, either a piperidin-1-yl or pyrrolidin-1-yl radical mono or gem-disubstituted by a phenyl, benzyl, (C ⁇ -C4) alkyl, hydroxyl, (C ⁇ - C4) alkoxy, cyano, (C ⁇ - C3) alkanoyl, (C ⁇ -C4) alkoxycarbonylamino, (C1 - C3) alkanoylamino; the phenyl or benzyl groups being unsubstituted or substituted one or more times by a halogen atom and / or a (C1 - C4) alkyl and / or (C ⁇ -C4) alk
  • the compounds of formula (I) may contain 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 racemic mixtures are part of the invention.
  • the compounds of formula (I) can exist in the form of bases or of addition salts with acids. These salts are advantageously prepared with pharmaceutically acceptable salts but the salts of other acids useful, for example, for the purification or the isolation of the compounds of formula (I) also form part of the invention.
  • alkyl group means 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.
  • a (C1-C4) alkyl the tert-butyl, 2-methylbutyl-2, 3,3-dimethylbutyl-2 groups being preferred for a (C3-C6) alkyl.
  • alkylene group is meant a linear or branched bivalent radical, methylene, 1-methyl methylene, 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; fluorine, chlorine or bromine atoms being preferred.
  • Non-aromatic C3-C12 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 condensed, bridged or spiranic di- or tricyclic radicals include, for example, the norbornyl, bornyl, isobornyl, noradamantyl, adamantyl, spiro [5.5] undecanyl, bicyclo [2.2.1] heptyle, bicyclo [3.2.1] octyl radicals; bicyclo [3.1.1] heptyl.
  • heterocyclic radical saturated or unsaturated, of 5 to 11 atoms, containing or not containing a second heteroatom such as O or N
  • radicals such as morpholin-4-yl, piperidin-1-yle, piperazin-1-yl, pyrrolidin-1-yle, octahydrocyclopenta [c] pyrrol-
  • mono-oxygenated heterocyclic radical saturated with 5 to 7 atoms
  • a radical such as tetrahydrofuranyl, tetrahydro-2H-pyranyl, oxepanyl: tetrahydrofuranyl being preferred.
  • the compounds of formula (I) are distinguished in which:
  • - K ⁇ represents hydrogen or a (Ci -C4) alkyl
  • - R2 represents:. a (C4-C ⁇ o) has lkyle; . a CC ⁇ 2 non-aromatic carbocyclic radical, unsubstituted or substituted one or more times by a (C ⁇ -C4) alkyl group; . 1,2,3,4-tetrahydronaphthyl -1 or -2; . a heterocyclic radical monooxygenated or monosulfated, saturated, of 5 to 7 atoms, unsubstituted or substituted one or more times by a group (Ci -C4) alkyl; .
  • Rj and R2 together with the nitrogen atom to which they are bonded constitute either a piperazin-1-yl or 1,4-diazepan-1-yl radical substituted in 4- with a phenyl or benzyl group, or a piperidin radical -1-yl or pyrrolidin-1-yl mono or gem-disubstituted by a phenyl, benzyl, (C -C4) alkyl, hydroxyl, (C - C3) alkanoyl, (C -C4) alkoxycarbonylamino group; the phenyl or benzyl groups being unsubstituted or substituted one or more times by a halogen atom and / or a methyl group; R3, R4, R5, R, R7, R $ each independently of one another represent a hydrogen or halogen atom, a (C ⁇ -C6) alkyl, (C ⁇ -C6) alkoxy, trifluoro
  • - Ri 1 represents a hydrogen atom
  • - n 0, 1 or 2;
  • - Ri represents hydrogen or a (C ⁇ -C4) alkyl
  • Ri 1 represents a (C ⁇ -C4) alkyl or (C3-C7) cycloalkyl group; the other substituents being as defined above for (I); as well as their salts, their solvates and their hydrates.
  • the compounds of formula (I) are preferred in which:
  • - Ri and R2 together with the nitrogen atom to which they are linked constitute a piperidin-1-yl gem-disubstituted radical by a benzyl or phenyl group unsubstituted or substituted by a halogen atom and by a group (C - C3) alkanoyl or cyano; - or R 1 represents hydrogen;
  • - and / or R2 represents a group NR9R10 in which R9 and Rio together with the nitrogen atom to which they are bonded constitute a heterocyclic radical saturated with 5 to 11 carbon atoms, unsubstituted or substituted one or more times by a ( C1-C4) alkyl; - And / or R2 represents a non-aromatic C3-C10 carbocyclic radical, unsubstituted or substituted one or more times by a (C ⁇ -C4) alkyl group;
  • - And / or R2 represents a benzyl group substituted on the phenyl by one or more identical or different substituents chosen from a halogen atom, a (C ⁇ -C4) alkyl, trifluoromethyl, (C ⁇ -C4) alkoxy, trifluoromethoxy group; - and / or R3, R4, R5, Rg, R7, R ⁇ each independently of one another represent a hydrogen or halogen atom, preferably R3 is a 4-chloro or a 4-bromo and Rg, R7 represent 2,4-dichloro, R4, R5, Rg representing a hydrogen atom; as well as their salts, their solvates and their hydrates.
  • the present invention relates in particular to the following compounds: 4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3-methyl-N-piperidin-1-ylthiophene-2-carboxamide; 2 - ⁇ [4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3-methyl-2-thienyl] carbonyl ⁇ - octahydrocyclopenta [c] pyrrole; 1- (1- ⁇ [5- (4-Chlorophenyl) -4- (2,4-dichlorophenyl) -2-thienyl] carbonyl ⁇ -4- phenylpiperidin-4-yl) ethanone; 1 - (1 - ⁇ [4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -2-thienyl] carbonyl ⁇ -4- phenylpiperidin-4-yl
  • the present invention also relates to a process for the preparation of the compounds according to the invention.
  • This process is characterized in that the acid of formula (II) or a functional derivative of this acid of formula is treated: in which R3, R4, R5, R5, R7, Rg and R 1 are as defined for (I) with an amine of formula HNR1R2 (III) in which Ri and R2 are as defined for (I).
  • the compound thus obtained is transformed into one of its salts or solvates.
  • acid chloride, anhydride, a mixed anhydride, a C1-C4 alkyl ester in which the alkyl is straight or branched, an activated ester, for example can be used.
  • p-nitrophenyl ester or the free acid suitably activated, for example, with N, N-dicyclohexylcarbodiimide or with benzotriazol-1 hexafluorophosphate -yloxotris (dimethylamino) -phosphonium (BOP) or benzotriazol hexafluorophosphate- l-yloxotris- (pyrrolidino) phosphonium (PyBOP).
  • N, N-dicyclohexylcarbodiimide or with benzotriazol-1 hexafluorophosphate -yloxotris (dimethylamino) -phosphonium (BOP) or benzotriazol hexafluorophosphate- l-yloxotris- (pyrrolidino) phosphonium (PyBOP).
  • the chloride of pyrazole-3-carboxylic acid obtained by reaction of thionyl chloride on the acid of formula (II), with an amine HNR1R2, in a solvent inert, such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), or an amide (N, N-dimethylformamide for example) under an inert atmosphere, to an temperature between 0 ° C and temperature, in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine.
  • a solvent inert such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), or an amide (N, N-dimethylformamide for example) under an inert atmosphere, to an
  • a variant consists in 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 in doing so react with an amine HNR1R2, in a solvent such as dichloromethane, under an inert atmosphere, at room temperature, in the presence of a base such as triethylamine.
  • Ru represents a hydrogen atom
  • the compounds of formula (II) can be prepared according to F. Vôgtle et al., Chem., Ber., 1983, 116. 3112-3124 and reported in the DIAGRAM below: DIAGRAM 1
  • step b1 cyclization with mercaptoacetic acid is carried out in the presence of triethylamine.
  • R] is other than a hydrogen atom
  • the compound of formula (V) is prepared, according to Scheme 1 above, then the procedure is described below:
  • step a2) the compound of formula (V) is treated with an organomagnesium of formula RuMgX in which Ru is as defined for (I) and X represents a halogen atom, preferably bromine.
  • the compound thus obtained of formula (VI) is treated in step b2) with an oxidizing agent such as MnO2, pyridinium dichromate (PDC), pyridinium chlorochromate or the Dess-Martin reagent described in Dess DB, Martin JC, J. Am. Chem. Soc, 1991, 113, 7277-7287.
  • step c2) the cyclization by the ester of mercaptoacetic acid is carried out in the presence of DBU then the ester obtained is hydrolyzed with sodium hydroxide to form the acid of formula (II).
  • F melting point
  • AcOEt ethyl acetate
  • BOP benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate
  • TA room temperature
  • TBTU O-benzotriazol-1-yl-N, N , N ', N'-tetramethyluronium tetrafluoroborate
  • DCM dichloromethane
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene.
  • the nuclear magnetic resonance spectra are recorded at 200 MHz in DMSO-dg.
  • the eluent is composed as follows:
  • step A of Example 1 4-Chloro-3- (4-chlorophenyl) -4- (2,4-dichlorophenyl) but-3-en-2-ol.
  • 4 g of the compound obtained in step A of Example 1 are placed in 40 ml of anhydrous THF, then 12.72 ml of methylmagnesium bromide in normal solution in THF is added at -20 ° C and allowed to rise the temperature at RT.
  • NH4Cl is added and extraction is carried out with ethyl acetate.
  • the organic phase is dried over MgS ⁇ 4 and evaporated.
  • the product obtained is chromatographed on silica, eluting with a heptane / AcOEt mixture. 1.3 g of the expected compound are obtained.
  • the compounds of formula (I) have a good in vitro affinity (IC50 ⁇ _ 5.10 M) for the cannabinoid receptors CBj, under the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 350, 240-2424).
  • the antagonistic nature of the compounds of formula (I) has been demonstrated by the results obtained in the models of the inhibition of adenylate cyclase 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.
  • the compounds according to the invention were tested in vivo (ex vivo binding) in mice after intravenous and / or oral administration, according to the experimental conditions described in Rinaldi-Carmona et al. (J. Pharmacol. Exp., 1998, 284, 644-650).
  • the toxicity of the compounds of formula (I) is compatible with their use as a medicament.
  • the present invention relates to the use of a compound of formula (I), or of one of its salts, solvates or hydrates pharmaceutically acceptable, for the preparation of medicaments intended to treat or prevent diseases involving the CBi cannabinoid receptors.
  • the compounds of formula (I) are useful as psychotropic drugs, in particular for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders , obsessive-compulsive disorder, psychosis in general, schizophrenia, as well as for the treatment of disorders linked to the use of psychotropic substances, in particular in the case of substance abuse and / or dependence on a substance, including alcohol dependence and nicotine dependence.
  • the compounds of formula (I) according to the invention can be used as medicaments for the treatment of migraine, stress, diseases of psychosomatic origin, attacks of panic attacks, epilepsy, movement disorders , especially dyskinesia or Parkinson's disease, tremors and dystonia.
  • the compounds of formula (I) according to the invention can also be used as medicaments in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementias, of Alzheimer's disease, as well as in the treatment of attention or alertness disturbances.
  • the compounds of formula (I) can be useful as neuroprotectors, in the treatment of ischemia, head trauma and the treatment of neurodegenerative diseases: including chorea, Huntington's chorea, Tourrette 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, appetite (for sugars, carbohydrates, drugs, alcohols or any appetizing substance) and / or conduct food, especially as appetite suppressants or for the treatment of obesity or bulimia as well as for the treatment of type II diabetes or non-insulin dependent diabetes and for the treatment of dyslipidemia, metabolic syndrome.
  • the compounds of formula (I) according to the invention can be used as medicaments in the treatment of gastrointestinal disorders, diarrheal disorders, ulcers, vomiting, bladder and urinary disorders, disorders of endocrine origin, cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, chronic cirrhosis of the liver, non-alcoholic fatty liver disease, asthma, Raynaud's syndrome, glaucoma, fertility disorders, inflammatory phenomena, diseases of the immune system, in particular autoimmune and neuroinflammatory such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, strokes as well as as drugs for anticancer chemotherapy, for the treatment of Guillain-Barré syndrome and for the treatment of osteoporosis.
  • autoimmune and neuroinflammatory such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, strokes as well as as drugs for
  • the compounds of formula (I) are very particularly useful for the treatment of psychotic disorders, in particular schizophrenia; attention deficit hyperactivity disorder (ADHD) in hyperkinetic children (MBD) for the treatment of appetite and obesity disorders for the treatment of memory and cognitive disorders; for the treatment of alcohol dependence, nicotine dependence, that is to say for alcohol withdrawal and for smoking cessation and for the treatment of dyslipidemia, metabolic syndrome.
  • the present invention relates to the use of a compound of formula (I), its pharmaceutically acceptable salts and their solvates or hydrates for the treatment of the disorders and diseases indicated above.
  • the compound according to the invention is generally administered in dosage unit.
  • Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.
  • the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I), one of its pharmaceutically acceptable salts or one of their solvates.
  • the compound of formula (I) above and its pharmaceutically acceptable salts or solvates can be used in daily doses of 0.01 to 100 mg per kg of body weight of the mammal to be treated, preferably in daily doses of 0, 02 to
  • 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 dosages are examples of average situations, there may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention. According to usual practice, the appropriate dosage for each patient is determined by the doctor according to the mode of administration, the age, the weight and the response of said patient.
  • the active principle can be administered in unit administration form, in admixture with carriers conventional pharmaceuticals, animals and humans.
  • Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, aerosols, administration forms topical, implants, forms of subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and forms of rectal administration.
  • the active ingredient 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.

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Abstract

The invention relates to a compound of formula (I), where R1 = H, or C1-C4 alkyl, R2 = C4-C10 alkyl, a carbocyclic group, a heterocyclic group, an alkylene group supporting a radical, a NR9R10 group, where R1 and R2 together with nitrogen atom of attachment = either a piperazin-1-yl or a 4-substituted 1,4-diazepan-1-yl, R11 = H, ( C1-C4 alkyl or C3-C7 cycloalkyl and the salts, solvates and hydrates thereof. The invention further relates to a method for production and therapeutic application thereof.

Description

DERIVES DE THIOPHENE-2-CARBOXAMIDE, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE. THIOPHENE-2-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION.
La présente invention a pour objet des dérivés de thiophène-2-carboxamide, leur préparation et leur application en thérapeutique. Des dérivés de diphénylpyrazole, présentant une affinité pour les récepteurs CB \ des cannabinoïdes ont été décrits notamment dans les brevets US 5 624 941, EP 0 576 357, EP 0 656 354 et EP 1 150 961. Des dérivés de 5,6-diphényl-2-pyrazinecarboxamide sont décrits dans le demande de brevet internationale WO 03/051850 comme des antagonistes des récepteurs CBi . Des dérivés de l,2-diphényl-4-imidazolecarboxamide sont décrits dans la demande de brevet internationale WO 03/027076 comme des agonistes des récepteurs CBi, des agonistes partiels ou des antagonistes. Des dérivés de 4,5-diarylthiophène ayant des propriétés analgésiques sont décrits dans la demande internationale WO 91/19708. On a maintenant trouvé des nouveaux dérivés de thiophène-2-carboxamide qui possèdent des propriétés antagonistes des récepteurs CB^ des cannabinoïdes. Ainsi la présente invention a pour objet des composés répondant à la formule (I) :The present invention relates to thiophene-2-carboxamide derivatives, their preparation and their therapeutic use. Diphenylpyrazole derivatives, having an affinity for the cannabinoid CB \ receptors have been described in particular in US Pat. Nos. 5,624,941, EP 0 576 357, EP 0 656 354 and EP 1 150 961. 5,6-diphenyl derivatives -2-pyrazinecarboxamide are described in international patent application WO 03/051850 as antagonists of the CBi receptors. Derivatives of 1,2-diphenyl-4-imidazolecarboxamide are described in international patent application WO 03/027076 as CBi receptor agonists, partial agonists or antagonists. 4,5-Diarylthiophene derivatives having analgesic properties are described in international application WO 91/19708. We have now found new derivatives of thiophene-2-carboxamide which have antagonistic properties of the CB ^ receptors of cannabinoids. The subject of the present invention is therefore compounds corresponding to formula (I):
dans laquelle : Ri représente l'hydrogène ou un (Cι-C4)alkyle ; R2 représente : . un groupe (C4-Cjo)alkyle ; . un radical carbocyclique non aromatique en C3-C12, non substitué ou substitué une ou plusieurs fois par un groupe (Cι -C4)alkyle, (Cι -C4)alcoxy ou hydroxyle ; . un 1,2,3,4-tétrahydronaphtyle -1 ou -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 ; . un radical hétérocyclique monoazoté, saturé, de 5 à 7 atomes, l'atome d'azote étant substitué par un groupe (Cι -C4)alkyle, phényle, benzyle, (Ci - C4)alcoxycarbonyle ou (Ci -C4)alcanoyle ; . un groupe (Cι -C3)alkylène portant un radical carbocyclique non aromatique en C3-C1 o non substitué ou substitué une ou plusieurs fois par un groupe (C1 -C4) alkyle ; . un groupement phénylalkylène dans lequel l'alkylène est en (C1-C3), non substitué ou substitué sur l'alkylène par un ou plusieurs groupes méthyle, et ou substitué sur le phényle par un ou plusieurs substituants identiques ou différents choisis parmi un atome d'halogène ou un groupe (Cι -C4)alkyle, trifluorométhyle, (Cj-C4)alcoxy, trifluorométhoxy ; . un méthylène substitué par un radical benzothiényle, benzofuryle, thiényle, ou furyle, lesdits radicaux étant non substitués ou substitués par un ou plusieurs groupes (Cι-C4)alkyle ; . un groupement NR9R1 Q \ ou R\ 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, (Cι -C4)alkyle, hydroxyle, (C\- C4)alcoxy, cyano, (Cι-C3)alcanoyle, (Cι -C4)alcoxycarbonylamino, (C1 - C3)alcanoylamino ; les groupes phényles ou benzyles étant non substitués ou substitués une ou plusieurs fois par un atome d'halogène et/ou un groupe (C1 - C4)alkyle et/ou (Cι-C4)alcoxy, et/ou trifluorométhyle ; R3, R4, R5, R6, R7, Rg représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, un groupe (Cι -Cg)alkyle, (Cj-C^alcoxy, trifluorométhyle ou un groupement S(O)nAlk ; R9 représente un atome d'hydrogène ou un groupe méthyle ; - RI Q représente un groupe (C3-Cg)alkyle, phényle ou C3-C10 cycloalkyle, lesdits groupes phényle et cycloalkyle étant non substitués ou substitués par un ou plusieurs atomes d'halogène et/ou groupes (Cι-C4)alkyle ; ou R9 et RJQ 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 par un groupe hydroxyle ou phényle ou une ou plusieurs fois par un groupe (C^- C4)alkyle et/ou (Cι -C4)alcoxy ; in which: Ri represents hydrogen or a (Cι-C4) alkyl; R2 represents:. a (C4-Cjo) alkyl group; . a non-aromatic carbocyclic radical, C3-C12 unsubstituted or substituted one or more times with a (Cι-C4) alkyl, (Cι-C4) alkoxy or hydroxyl; . 1,2,3,4-tetrahydronaphthyl -1 or -2; . a heterocyclic radical monooxygenated or monosulfated, saturated, of 5 to 7 atoms, unsubstituted or substituted one or more times by a group (Ci -C4) alkyl; . a saturated monoazotated heterocyclic radical of 5 to 7 atoms, the nitrogen atom being substituted by a (Cι -C4) alkyl, phenyl, benzyl, (Ci - C4) alkoxycarbonyl or (Ci -C4) alkanoyl group; . a group (Cι -C3) alkylene carrying a non-aromatic C3-C1 carbocyclic radical o unsubstituted or substituted one or more times by a group (C1 -C4) alkyl; . a phenylalkylene group in which the alkylene is in (C1-C3), unsubstituted or substituted on the alkylene by one or more methyl groups, and or substituted on the phenyl by one or more identical or different substituents chosen from an atom d 'halogen or a group (Cι -C4) alkyl, trifluoromethyl, (Cj-C4) alkoxy, trifluoromethoxy; . a methylene substituted by a benzothienyl, benzofuryl, thienyl or furyl radical, said radicals being unsubstituted or substituted by one or more (Cι-C4) alkyl groups; . a group NR9R1 Q \ or R \ and R2 together with the nitrogen atom to which they are bonded constitute either a piperazin-1-yl radical or 1,4-diazepan-l-yl substituted in 4- with a phenyl group or benzyl, either a piperidin-1-yl or pyrrolidin-1-yl radical mono or gem-disubstituted by a phenyl, benzyl, (Cι -C4) alkyl, hydroxyl, (C \ - C4) alkoxy, cyano, (Cι- C3) alkanoyl, (Cι -C4) alkoxycarbonylamino, (C1 - C3) alkanoylamino; the phenyl or benzyl groups being unsubstituted or substituted one or more times by a halogen atom and / or a (C1 - C4) alkyl and / or (Cι-C4) alkoxy, and / or trifluoromethyl group; R3, R4, R5, R6, R7, Rg each independently of one another represent a hydrogen or halogen atom, a (Cι -Cg) alkyl group, (Cj-C ^ alkoxy, trifluoromethyl or a group S (O) n Alk; R9 represents a hydrogen atom or a methyl group; - RI Q represents a (C3-Cg) alkyl, phenyl or C3-C10 cycloalkyl group, said phenyl and cycloalkyl groups being unsubstituted or substituted by one or more halogen atoms and / or (Cι-C4) alkyl groups; or R9 and RJQ together with the nitrogen atom to which they are linked constitute a heterocyclic radical, saturated or unsaturated, of 5 to 11 atoms, bridged or not, comprising or not a spiranic carbon and containing or not containing a second heteroatom chosen from O or N, said radical being unsubstituted or substituted by a hydroxyl or phenyl group or one or more times with a (C ^ - C4) alkyl and / or (Cι -C4) alkoxy group;
- R\ \ représente un atome d'hydrogène, un groupe (Cι-C4)alkyle ou (C3- C7)cycloalkyle ; - n représente 0, 1 ou 2 ;- R \ \ represents a hydrogen atom, a (Cι-C4) alkyl or (C3- C7) cycloalkyl group; - n represents 0, 1 or 2;
- Alk représente un groupe (Cι-C4)alkyle ; ainsi que leurs sels, leurs solvats et leurs 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 énantiomeres, diastéréoisomères, ainsi que leurs mélanges, y compris les mélanges racémiques font partie de l'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. 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 (C1 - C4)alkyle, les groupes tert-butyle, 2-méthylbutyl-2, 3,3-diméthylbutyl-2, étant préférés pour un (C3-C6)alkyle. Par groupe alkylene, on entend un radical bivalent linéaire ou ramifié, le méthylène, le 1-méthyl méthylène, l'éthylène étant préférés. Par groupe alcoxy, on entend un radical linéaire ou ramifié, le groupe méthoxy étant préféré. 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. 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]heptyle, bicyclo[3.2.1]octyle ; bicyclo[3.1.1]heptyle. Par radical hétérocyclique, saturé ou insaturé, de 5 à 11 atomes, contenant ou non un deuxième hétéroatome 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-- Alk represents a (Cι-C4) alkyl group; as well as their salts, their solvates and their hydrates. The compounds of formula (I) may contain 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 racemic mixtures are part of the invention. The compounds of formula (I) can exist in the form of bases or of addition salts with acids. These salts are advantageously prepared with pharmaceutically acceptable salts but the salts of other acids useful, for example, for the purification or the isolation of the compounds of formula (I) also form part of the invention. The term “alkyl group” means 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 a (C1-C4) alkyl, the tert-butyl, 2-methylbutyl-2, 3,3-dimethylbutyl-2 groups being preferred for a (C3-C6) alkyl. By alkylene group is meant a linear or branched bivalent radical, methylene, 1-methyl methylene, ethylene being preferred. By alkoxy group is meant a linear or branched radical, the methoxy group being preferred. By halogen atom is meant a fluorine, chlorine, bromine or iodine atom; fluorine, chlorine or bromine atoms being preferred. Non-aromatic C3-C12 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 condensed, bridged or spiranic di- or tricyclic radicals include, for example, the norbornyl, bornyl, isobornyl, noradamantyl, adamantyl, spiro [5.5] undecanyl, bicyclo [2.2.1] heptyle, bicyclo [3.2.1] octyl radicals; bicyclo [3.1.1] heptyl. By heterocyclic radical, saturated or unsaturated, of 5 to 11 atoms, containing or not containing a second heteroatom such as O or N, is meant radicals such as morpholin-4-yl, piperidin-1-yle, piperazin-1-yl, pyrrolidin-1-yle, octahydrocyclopenta [c] pyrrol-
2-yle, hexahydrocyclopenta[c]pyrrol-2-yle, 8-azabicyclo[3.2.1]octanyle, 8- aza[4.5]décanyle, les radicaux pipéridin-1-yle et morpholin-4-yle étant préférés. Par radical hétérocyclique monoazoté, saturé, de 5 à 7 atomes, on entend un radical tel que pipéridin-4-yle ou pyrrolidin-3yle, le radical pipéridin-4-yle étant préféré. Par radical hétérocyclique monooxygéné, saturé de 5 à 7 atomes, on entend un radical tel que tétrahydrofuranyle, tétrahydro-2H-pyranyle, oxepanyle : le tétrahydrofuranyle étant préféré. Selon la présente invention on distingue les composés de formule (I) dans laquelle :2-yl, hexahydrocyclopenta [c] pyrrol-2-yl, 8-azabicyclo [3.2.1] octanyl, 8-aza [4.5] decanyl, the piperidin-1-yl and morpholin-4-yl radicals being preferred. By saturated monoazotated heterocyclic radical of 5 to 7 atoms is meant a radical such as piperidin-4-yl or pyrrolidin-3yle, the piperidin-4-yl radical being preferred. By mono-oxygenated heterocyclic radical, saturated with 5 to 7 atoms, is meant a radical such as tetrahydrofuranyl, tetrahydro-2H-pyranyl, oxepanyl: tetrahydrofuranyl being preferred. According to the present invention, the compounds of formula (I) are distinguished in which:
- K\ représente l'hydrogène ou un (Ci -C4)alkyle ; - R2 représente : . un groupe (C4-Cιo)alkyle ; . un radical carbocyclique non aromatique en C C\2, non substitué ou substitué une ou plusieurs fois par un groupe (Cι -C4)alkyle ; . un 1,2,3,4-tétrahydronaphtyle -1 ou -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 ; . un radical hétérocyclique monoazoté, saturé, de 5 à 7 atomes, l'atome d'azote étant substitué par un groupe (Cι -C4)alkyle, phényle, benzyle, (C1 - C4)alcoxycarbonyle ou (Ci -C4)alcanoyle ; . un groupe (Cj-C3)alkylène portant un radical carbocyclique non aromatique en C3-C1 Q non substitué ou substitué une ou plusieurs fois par un groupe (C1 -C4) alkyle ; . un groupement phénylalkylène dans lequel l'alkylène est en (C1 -C3), non substitué ou substitué sur l'alkylène par un ou plusieurs groupes méthyle, et/ou substitué sur le phényle par un ou plusieurs substituants identiques ou différents choisis parmi un atome d'halogène ou un groupe (Cι-C4)alkyle, trifluorométhyle, (Cj-C4)alcoxy, trifluorométhoxy ; . un méthylène substitué par un radical benzothiényle, benzofuryle, thiényle, ou furyle, lesdits radicaux étant non substitués ou substitués par un ou plusieurs groupes (Cι -C4)alkyle ; . un groupement NR RJQ ; ou Rj 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, (C -C4)alkyle, hydroxyle, (C - C3)alcanoyle, (C -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 ; R3, R4, R5, R , R7, R$ représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, un groupe (Cι-C6)alkyle, (Cι-C6)alcoxy, trifluorométhyle ou un groupement S(O)nAlk ; R9 représente un atome d'hydrogène ou un groupe méthyle ; RlO représente un groupe (C3-Cg)alkyle, phényle ou C3-C10 cycloalkyle, lesdits groupes phényle et cycloalkyle étant non substitués ou substitués par un ou plusieurs atomes d'halogène et/ou groupes (Cι-C4)alkyle ou par un atome d'halogène ; ou R9 et Rio 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 par un groupe hydroxyle ou phényle, ou, une ou plusieurs fois, par un groupe (Ci- C4)alkyle ;- K \ represents hydrogen or a (Ci -C4) alkyl; - R2 represents:. a (C4-Cιo) has lkyle; . a CC \ 2 non-aromatic carbocyclic radical, unsubstituted or substituted one or more times by a (Cι -C4) alkyl group; . 1,2,3,4-tetrahydronaphthyl -1 or -2; . a heterocyclic radical monooxygenated or monosulfated, saturated, of 5 to 7 atoms, unsubstituted or substituted one or more times by a group (Ci -C4) alkyl; . a saturated monoazotated heterocyclic radical of 5 to 7 atoms, the nitrogen atom being substituted by a (Cι -C4) alkyl, phenyl, benzyl, (C1 - C4) alkoxycarbonyl or (Ci -C4) alkanoyl group; . an alkylene group (Cj-C3) carrying a non-aromatic C3-C1Q carbocyclic radical unsubstituted or substituted one or more times by a (C1 -C4) alkyl group; . a phenylalkylene group in which the alkylene is (C1-C3), unsubstituted or substituted on the alkylene by one or more methyl groups, and / or substituted on the phenyl by one or more identical or different substituents chosen from an atom halogen or a group (Cι-C4) alkyl, trifluoromethyl, (Cj-C4) alkoxy, trifluoromethoxy; . a methylene substituted by a benzothienyl, benzofuryl, thienyl or furyl radical, said radicals being unsubstituted or substituted by one or more (Cι -C4) alkyl groups; . an NR RJQ group; or Rj and R2 together with the nitrogen atom to which they are bonded constitute either a piperazin-1-yl or 1,4-diazepan-1-yl radical substituted in 4- with a phenyl or benzyl group, or a piperidin radical -1-yl or pyrrolidin-1-yl mono or gem-disubstituted by a phenyl, benzyl, (C -C4) alkyl, hydroxyl, (C - C3) alkanoyl, (C -C4) alkoxycarbonylamino group; the phenyl or benzyl groups being unsubstituted or substituted one or more times by a halogen atom and / or a methyl group; R3, R4, R5, R, R7, R $ each independently of one another represent a hydrogen or halogen atom, a (Cι-C6) alkyl, (Cι-C6) alkoxy, trifluoromethyl or an S (O) n Alk group; R9 represents a hydrogen atom or a methyl group; R10 represents a (C3-Cg) alkyl, phenyl or C3-C10 cycloalkyl group, said phenyl and cycloalkyl groups being unsubstituted or substituted by one or more halogen atoms and / or (Cι-C4) alkyl groups or by an atom halogen; or R9 and Rio together with the nitrogen atom to which they are linked constitute a heterocyclic radical, saturated or unsaturated, of 5 to 11 atoms, bridged or not, comprising or not a spirannic carbon and containing or not containing a second heteroatom chosen from Y or N, said radical being unsubstituted or substituted by a hydroxyl or phenyl group, or, one or more times, by a (C 1 -C 4) alkyl group;
- Ri 1 représente un atome d'hydrogène ;- Ri 1 represents a hydrogen atom;
- n représente 0, 1 ou 2 ;- n represents 0, 1 or 2;
- Alk représente un groupe (Cι-C4)alkyle ; ainsi que leurs sels, leurs solvats et leurs hydrates. Selon la présente invention, on distingue les composés de formule (I) dans laquelle :- Alk represents a (Cι-C4) alkyl group; as well as their salts, their solvates and their hydrates. According to the present invention, a distinction is made between the compounds of formula (I) in which:
- Ri représente l'hydrogène ou un (Cι-C4)alkyle ;- Ri represents hydrogen or a (Cι-C4) alkyl;
- R2 représente un groupe (C7-Cιo)alkyle ; les autres substituants étant tels que définis pour (I) ; ainsi que leurs sels, leurs solvats et leurs hydrates. Selon la présente invention, on distingue également les composés de formule (I) dans laquelle :- R2 represents a (C7-Cιo) alkyl group; the other substituents being as defined for (I); as well as their salts, their solvates and their hydrates. According to the present invention, a distinction is also made between the compounds of formula (I) in which:
- Ri 1 représente un groupe (Cι-C4)alkyle ou (C3-C7)cycloalkyle ; les autres substituants étant tels que définis ci-dessus pour (I) ; ainsi que leurs sels, leurs solvats et leurs hydrates. Selon la présente invention, on préfère les composés de formule (I) dans laquelle :- Ri 1 represents a (Cι-C4) alkyl or (C3-C7) cycloalkyl group; the other substituents being as defined above for (I); as well as their salts, their solvates and their hydrates. According to the present invention, the compounds of formula (I) are preferred in which:
- Ri et R2 ensemble avec l'atome d'azote auquel ils sont liés constituent un radical pipéridin-1-yle gem-disubstitué par un groupe benzyle ou phényle non substitué ou substitué par un atome d'halogène et par un groupe (C -C3)alcanoyle ou cyano; - ou Ri représente l'hydrogène ;- Ri and R2 together with the nitrogen atom to which they are linked constitute a piperidin-1-yl gem-disubstituted radical by a benzyl or phenyl group unsubstituted or substituted by a halogen atom and by a group (C - C3) alkanoyl or cyano; - or R 1 represents hydrogen;
- et/ou R2 représente un groupe NR9R10 dans lequel R9 et Rio 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 (Cι-C4)alkyle ; - et/ou R2 représente un radical carbocyclique non aromatique en C3-C10, non substitué ou substitué une ou plusieurs fois par un groupe (Cι-C4)alkyle ;- and / or R2 represents a group NR9R10 in which R9 and Rio together with the nitrogen atom to which they are bonded constitute a heterocyclic radical saturated with 5 to 11 carbon atoms, unsubstituted or substituted one or more times by a ( C1-C4) alkyl; - And / or R2 represents a non-aromatic C3-C10 carbocyclic radical, unsubstituted or substituted one or more times by a (Cι-C4) alkyl group;
- et/ou R2 représente un groupe benzyle substitué sur le phényle par un ou plusieurs substituants identiques ou différents choisis parmi un atome d'halogène, un groupe (Cι-C4)alkyle, trifluorométhyle, (Cι-C4)alcoxy, trifluorométhoxy ; - et/ou R3, R4, R5, Rg, R7, Rβ représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, préférentiellement R3 est un 4-chloro ou un 4-bromo et Rg, R7 représentent 2,4-dichloro, R4, R5, Rg représentant un atome d'hydrogène ; ainsi que leurs sels, leurs solvats et leurs hydrates. La présente invention est relative en particulier aux composés suivants : le 4-(4-Chlorophényl)-5-(2,4-dichlorophényl)-3-méthyl-N-pipéridin- 1 - ylthiophène-2-carboxamide ; le 2-{[4-(4-Chlorophényl)-5-(2,4-dichlorophényl)-3-méthyl-2-thiényl]carbonyl}- octahydrocyclopenta[c]pyrrole ; le l-(l-{[5-(4-Chlorophényl)-4-(2,4-dichlorophényl)-2-thiényl]carbonyl}-4- phénylpipéridin-4-yl)éthanone ; le 1 -(1 -{[4-(4-Chlorophényl)-5-(2,4-dichlorophényl)-2-thiényl]carbonyl}-4- phénylpipéridin-4-yl)éthanone . La présente invention a également pour objet un procédé de préparation des composés selon l'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 : dans laquelle R3, R4, R5, R5, R7, Rg et R 1 sont tels que définis pour (I) avec une amine de formule HNR1R2 (III) dans laquelle Ri et R2 sont tels que définis pour (I). Eventuellement, on transforme le composé ainsi obtenu en un de ses sels ou solvats. 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 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). Ainsi dans le procédé selon l'invention, on peut faire réagir le chlorure de l'acide pyrazole-3-carboxylique, obtenu par réaction du chlorure de thionyle sur l'acide de formule (II), avec une amine 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 amine tertiaire telle que la triéthylamine, la N- méthylmorpholine ou la pyridine. Une variante consiste à préparer 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 amine HNR1R2, dans un solvant tel que le dichlorométhane, sous une atmosphère inerte, à la température ambiante, en présence d'une base telle que la triéthylamine. Lorsque Ru représente un atome d'hydrogène, les composés de formule (II) peuvent être préparés selon F. Vôgtle et al., Chem., Ber., 1983, 116. 3112-3124 et rapporté dans le SCHEMA ci-après : SCHEMA 1- And / or R2 represents a benzyl group substituted on the phenyl by one or more identical or different substituents chosen from a halogen atom, a (Cι-C4) alkyl, trifluoromethyl, (Cι-C4) alkoxy, trifluoromethoxy group; - and / or R3, R4, R5, Rg, R7, Rβ each independently of one another represent a hydrogen or halogen atom, preferably R3 is a 4-chloro or a 4-bromo and Rg, R7 represent 2,4-dichloro, R4, R5, Rg representing a hydrogen atom; as well as their salts, their solvates and their hydrates. The present invention relates in particular to the following compounds: 4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3-methyl-N-piperidin-1-ylthiophene-2-carboxamide; 2 - {[4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3-methyl-2-thienyl] carbonyl} - octahydrocyclopenta [c] pyrrole; 1- (1- {[5- (4-Chlorophenyl) -4- (2,4-dichlorophenyl) -2-thienyl] carbonyl} -4- phenylpiperidin-4-yl) ethanone; 1 - (1 - {[4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -2-thienyl] carbonyl} -4- phenylpiperidin-4-yl) ethanone. The present invention also relates to a process for the preparation of the compounds according to the invention. This process is characterized in that the acid of formula (II) or a functional derivative of this acid of formula is treated: in which R3, R4, R5, R5, R7, Rg and R 1 are as defined for (I) with an amine of formula HNR1R2 (III) in which Ri and R2 are as defined for (I). Optionally, the compound thus obtained is transformed into one of its salts or solvates. As functional derivative of acid (II), acid chloride, anhydride, a mixed anhydride, a C1-C4 alkyl ester in which the alkyl is straight or branched, an activated ester, for example, can be used. p-nitrophenyl ester, or the free acid suitably activated, for example, with N, N-dicyclohexylcarbodiimide or with benzotriazol-1 hexafluorophosphate -yloxotris (dimethylamino) -phosphonium (BOP) or benzotriazol hexafluorophosphate- l-yloxotris- (pyrrolidino) phosphonium (PyBOP). Thus in the process according to the invention, it is possible to react the chloride of pyrazole-3-carboxylic acid, obtained by reaction of thionyl chloride on the acid of formula (II), with an amine HNR1R2, in a solvent inert, such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), or an amide (N, N-dimethylformamide for example) under an inert atmosphere, to an temperature between 0 ° C and temperature, in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine. A variant consists in 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 in doing so react with an amine HNR1R2, in a solvent such as dichloromethane, under an inert atmosphere, at room temperature, in the presence of a base such as triethylamine. When Ru represents a hydrogen atom, the compounds of formula (II) can be prepared according to F. Vôgtle et al., Chem., Ber., 1983, 116. 3112-3124 and reported in the DIAGRAM below: DIAGRAM 1
DMF/POC1 al C1CH2CH2C1 DMF / POC1 al C1CH 2 CH 2 C1
(II) La préparation du composé de formule (IV) est effectuée selon la méthode décrite dans la demande de brevet internationale WO 03/007887. A l'étape bl) la cyclisation par l'acide mercaptoacétique est effectuée en présence de triéthylamine. Lorsque R] est autre qu'un atome d'hydrogène, on prépare le composé de formule (V), selon le Schéma 1 ci-dessus puis on procède comme décrit ci-après : (II) The preparation of the compound of formula (IV) is carried out according to the method described in international patent application WO 03/007887. In step b1) cyclization with mercaptoacetic acid is carried out in the presence of triethylamine. When R] is other than a hydrogen atom, the compound of formula (V) is prepared, according to Scheme 1 above, then the procedure is described below:
SCHEMA 2DIAGRAM 2
(V) + RπMgX/THF(V) + R π MgX / THF
(VII) l)HSCH2CO2Me c2 DBU 2) NaOH/MeOH (VII) l) HSCH 2 CO 2 Me c2 DBU 2) NaOH / MeOH
(II) A l'étape a2), le composé de formule (V) est traité par un organomagnésien de formule RuMgX dans laquelle Ru est tel que défini pour (I) et X représente un atome d'halogène, préférentiellement le brome. Le composé ainsi obtenu de formule (VI) est traité à l'étape b2) par un agent oxydant tel que MnÛ2, le pyridinium dichromate (PDC), le pyridinium chlorochromate ou le réactif de Dess-Martin décrit dans Dess D.B., Martin J.C., J. Am. Chem. Soc, 1991, 113, 7277-7287. A l'étape c2), la cyclisation par l'ester de l'acide mercaptoacétique est effectuée en présence de DBU puis l'ester obtenu est hydrolyse par de la soude pour former l'acide de formule (II). 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 les tableaux ci-après, qui illustrent les structures chimiques et les propriétés physiques de quelques composés selon l'invention. Dans les exemples, on utilise les abréviations suivantes : F : point de fusion AcOEt : acétate d'éthyle BOP : benzotriazol-l-yloxytris(diméthylamino)phosphonium hexafluorophosphate TA : température ambiante TBTU : O-benzotriazol-l-yl-N,N,N',N'-tétraméthyluronium tétrafluoroborate DCM : dichlorométhane DBU : l,8-diazabicyclo[5.4.0]undec-7-ène. Les spectres de résonance magnétique nucléaire sont enregistrés à 200 MHz dans le DMSO-dg. Pour l'interprétation des spectres, on utilise les abréviations suivantes : s : singulet, d : doublet, t : triplet, m : massif, mt : multiplet, se : singulet élargi. Les composés selon l'invention sont analysés par couplage LC/UV/MS(II) In step a2), the compound of formula (V) is treated with an organomagnesium of formula RuMgX in which Ru is as defined for (I) and X represents a halogen atom, preferably bromine. The compound thus obtained of formula (VI) is treated in step b2) with an oxidizing agent such as MnO2, pyridinium dichromate (PDC), pyridinium chlorochromate or the Dess-Martin reagent described in Dess DB, Martin JC, J. Am. Chem. Soc, 1991, 113, 7277-7287. In step c2), the cyclization by the ester of mercaptoacetic acid is carried out in the presence of DBU then the ester obtained is hydrolyzed with sodium hydroxide to form the acid of formula (II). The following examples describe the preparation of certain compounds in accordance with the invention. These examples are not limitative and only illustrate the present invention. The numbers of the compounds exemplified refer to those given in the tables below, which illustrate the chemical structures and the physical properties of some compounds according to the invention. In the examples, the following abbreviations are used: F: melting point AcOEt: ethyl acetate BOP: benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate TA: room temperature TBTU: O-benzotriazol-1-yl-N, N , N ', N'-tetramethyluronium tetrafluoroborate DCM: dichloromethane DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene. The nuclear magnetic resonance spectra are recorded at 200 MHz in DMSO-dg. For the interpretation of the spectra, the following abbreviations are used: s: singlet, d: doublet, t: triplet, m: massive, mt: multiplet, se: widened singlet. The compounds according to the invention are analyzed by LC / UV / MS coupling
(chromatographie liquide/détection UV/spectrométrie de masse). On mesure le pic moléculaire (MH ) et le temps de rétention (t) en minutes. ® On utilise une colonne Xterra Waters MS Cl 8, commercialisée par Waters, de(liquid chromatography / UV detection / mass spectrometry). The molecular peak (MH) and the retention time (t) in minutes are measured. ® An Xterra Waters MS Cl 8 column, sold by Waters, of
2,1 x 30 mm, 3,5 μm, à température ambiante, débit 1 mL/minute. L'éluant est composé comme suit :2.1 x 30 mm, 3.5 μm, at room temperature, flow rate 1 mL / minute. The eluent is composed as follows:
- solvant A : 0,025 % d'acide trifluoroacétique (TFA) dans l'eau- solvent A: 0.025% trifluoroacetic acid (TFA) in water
- solvant B : 0,025 % de TFA dans l'acétonitrile. Gradient : Le pourcentage de solvant B varie de 0 à 100 % en 2 minutes avec un plateau à 100 % de B pendant 1 minute. La détection UV est effectuée entre 210 nm et 400 nm et la détection de masse en mode ionisation chimique à pression atmosphérique. EXEMPLE 1 : Composé 27 4-(4-Chlorophényl)-5-(2,4-dichlorophényl)-N-pipéridin-l-ylthiophène-2- carboxamide. A) 3 -Chloro-2-(4-chlorophényl)-3 -(2,4-dichlorophényl)acrylaldehyde. A une solution de 6,6 ml de DMF dans 4 ml de dichloroéthane, refroidie à -5°C, sous azote, on ajoute goutte à goutte 7 ml de POCI3, puis on laisse remonter la température et on ajoute 7 g de 2-(4-chlorophényl)-l-(2,4-dichlorophényl)éthanone.- solvent B: 0.025% TFA in acetonitrile. Gradient: The percentage of solvent B varies from 0 to 100% in 2 minutes with a tray at 100% B for 1 minute. UV detection is carried out between 210 nm and 400 nm and mass detection in chemical ionization mode at atmospheric pressure. EXAMPLE 1 Compound 27 4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -N-piperidin-1-ylthiophene-2-carboxamide. A) 3 -Chloro-2- (4-chlorophenyl) -3 - (2,4-dichlorophenyl) acrylaldehyde. To a solution of 6.6 ml of DMF in 4 ml of dichloroethane, cooled to -5 ° C, under nitrogen, 7 ml of POCI3 is added dropwise, then the temperature is allowed to rise and 7 g of 2- (4-chlorophenyl) -l- (2,4-dichlorophenyl) ethanone.
On chauffe le milieu réactionnel à 50°C pendant 16 heures puis on verse le mélange dans 100 ml d'eau glacée. On extrait au DCM puis on lave la phase organique par une solution saturée de NaHCθ3, de l'eau, puis une solution de NaCl. On obtient 1,45 g du composé attendu qui cristallise dans l'éther isopropylique, F = 128°C.The reaction medium is heated at 50 ° C for 16 hours and then the mixture is poured into 100 ml of ice water. It is extracted with DCM and then the organic phase is washed with a saturated NaHC Na3 solution, water, then NaCl solution. 1.45 g of the expected compound are obtained, which crystallizes from isopropyl ether, mp = 128 ° C.
B) Acide 4-(4-chlorophényl)-5-(2,4-dichlorophényl)thiophène-2-carboxylique. On place 1 ,40 g du composé à l'étape précédente dans 1 ml de pyridine refroidie au bain de glace puis on ajoute goutte à goutte 0,28 ml d'acide mercaptoacétique etB) 4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) thiophene-2-carboxylic acid. 1.40 g of the compound in the preceding step are placed in 1 ml of pyridine cooled in an ice bath, then 0.28 ml of mercaptoacetic acid is added dropwise and
1,24 ml de triéthylamine. On laisse revenir à TA, on laisse 30 minutes sous agitation puis on chauffe à 70°C pendant 3 heures. On refroidit à TA puis on dilue par 2 ml d'EtOH, on ajoute une solution de 0,57 g de KOH dans 4 ml d'EtOH puis on chauffe 3 heures à reflux. On verse le milieu réactionnel dans 100 ml d'une solution glacée d'HCl à 10 %. Le précipité formé est filtré puis lavé à l'eau et séché. On obtient 1,20 g du composé attendu.1.24 ml of triethylamine. The mixture is left to return to RT, the mixture is left stirring for 30 minutes and then heated to 70 ° C. for 3 hours. It is cooled to RT and then diluted with 2 ml of EtOH, a solution of 0.57 g of KOH in 4 ml of EtOH is added, then the mixture is heated for 3 hours at reflux. The reaction medium is poured into 100 ml of an ice-cold 10% HCl solution. The precipitate formed is filtered then washed with water and dried. 1.20 g of the expected compound are obtained.
C) 4-(4-Chlorophényl)-5-(2,4-dichlorophényl)-N-pipéridin-l-ylthiophène-2- carboxamide. On place 0,60 g du composé obtenu à l'étape précédente dans 15 ml de DCM et on ajoute 0,54 ml de triéthylamine puis 0,18 ml d'amino-1-pipéridine et, à 0°C, 0,80 g de BOP. On laisse sous agitation à TA pendant 3 heures puis on verse le milieu réactionnel dans de l'eau glacée. On extrait au DCM, lave à l'eau puis par une solution saturée de NaCl. On chromatographie sur silice en éluant par un mélange AcOEt/toluène (10/90 ; v/v) puis on cristallise le produit attendu dans un mélange DCM/éther isopropylique. On obtient 90 mg, F = 232°C.C) 4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -N-piperidin-1-ylthiophene-2-carboxamide. 0.60 g of the compound obtained in the preceding step is placed in 15 ml of DCM and 0.54 ml of triethylamine is added, then 0.18 ml of amino-1-piperidine and, at 0 ° C., 0.80 g of BOP. The mixture is left stirring at RT for 3 hours and then the reaction medium is poured into ice water. Extracted with DCM, washed with water and then with a saturated NaCl solution. Chromatography on silica, eluting with an AcOEt / toluene mixture (10/90; v / v), then the expected product is crystallized from a DCM / isopropyl ether mixture. 90 mg is obtained, mp = 232 ° C.
EXEMPLE 2 : Composé 33 4-(4-Chlorophényl)-5-(2,4-dichlorophényl)-3-méthyl-N-pipéridin-l-ylthiophène- 2-carboxamide.EXAMPLE 2 Compound 33 4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3-methyl-N-piperidin-1-ylthiophene-2-carboxamide.
A) 4-Chloro-3-(4-chlorophényl)-4-(2,4-dichlorophényl)but-3-èn-2-ol. On place 4 g du composé obtenu à l'étape A de l'Exemple 1 dans 40 ml de THF anhydre, puis on ajoute 12,72 ml de bromure de méthylmagnésium en solution normale dans le THF à -20°C et on laisse remonter la température à TA. On ajoute NH4CI et on extrait à l'acétate d'éthyle. On sèche sur MgSθ4 la phase organique et évapore. On chromatographie le produit obtenu sur silice en éluant par un mélange heptane/AcOEt. On obtient 1,3 g du composé attendu.A) 4-Chloro-3- (4-chlorophenyl) -4- (2,4-dichlorophenyl) but-3-en-2-ol. 4 g of the compound obtained in step A of Example 1 are placed in 40 ml of anhydrous THF, then 12.72 ml of methylmagnesium bromide in normal solution in THF is added at -20 ° C and allowed to rise the temperature at RT. NH4Cl is added and extraction is carried out with ethyl acetate. The organic phase is dried over MgSθ4 and evaporated. The product obtained is chromatographed on silica, eluting with a heptane / AcOEt mixture. 1.3 g of the expected compound are obtained.
B) 4-Chloro-3-(4-chlorophényl)-4-(2,4-dichlorophényl)but-3-èn-2-one. On place 1 g du composé obtenu à l'étape précédente dans 30 ml de DCM et on ajoute 2,6 g de tamis moléculaire à 4 Â puis 2,5 g de pyridiniumdichromate. Après 24 heures à TA, on filtre sur Célite et évapore à sec le solvant. On chromatographie le produit sur silice en éluant par un mélange heptane/AcOEt. On obtient 1 g du produit attendu. MH+ = 359, t = 11,81 minutes. C) 4-(4-Chlorophényl)-5-(2,4-dichlorophényl)-3 -méthylthiophène-2-carboxylate de méthyle. On place 1 g du composé obtenu à l'étape précédente dans 25 ml d'acétonitrile et on ajoute 0,37 ml de méthylthioglycolate puis 0,34 ml de DBU et on laisse sous agitation pendant 24 heures à TA. On évapore à sec le solvant et on extrait à l'acétate d'éthyle, lave à NH4CI puis avec une solution HCl 0,5N. On sèche la phase organique sur MgS04 et évapore. Le produit est chromatographie sur silice en éluant avec un mélange heptane/AcOEt. On obtient 0,5 g du produit attendu. D) Acide 4-(4-Chlorophényl)-5-(2,4-dichlorophényl)-3-méthylthiophène-2- carboxylique. On place 0,5 g du composé obtenu à l'étape précédente dans 20 ml de MeOH et ajoute 0,0486 g de NaOH. On laisse sous agitation à température ambiante pendant 24 heures et évapore ensuite le milieu réactionnel. On extrait les impuretés organiques à l'éther et acidifie la phase aqueuse jusqu'à pH = 1. On extrait l'acide à l'acétate d'éthyle et sèche puis évapore la phase organique. On obtient 260 mg du produit attendu. E) 4-(4-Chlorophényl)-5-(2,4-dichlorophényl)-3-méthyl-N-pipéridin-l-ylthiophène- 2-carboxamide On place 0,25 g du composé à l'étape précédente dans 15 ml de DCM et ajoute 0,22 ml de triéthylamine puis 0,063 g de N-aminopipéridine puis 0,222 g de TBTU et on laisse sous agitation pendant 24 heures à TA. On évapore le milieu réactionnel à sec, ajoute de l'eau et extrait à l'AcOEt, lave avec une solution de soude 0,5N. On sèche la phase organique et évapore à sec. Le produit cristallise dans l'éther. On obtient 0,2 g du produit attendu. MH+ = 481, t = 12,10. Les tableaux qui suivent illustrent les structures chimiques et les propriétés physiques de quelques composés selon l'invention. Dans ce tableau : Me, Et, tBu représentent respectivement les groupes méthyle, éthyle, tert-butyle. TABLEAU 1B) 4-Chloro-3- (4-chlorophenyl) -4- (2,4-dichlorophenyl) but-3-en-2-one. 1 g of the compound obtained in the previous step is placed in 30 ml of DCM and 2.6 g of 4 A molecular sieve are added, then 2.5 g of pyridiniumdichromate. After 24 hours at RT, filtered through Celite and the solvent is evaporated to dryness. The product is chromatographed on silica, eluting with a heptane / AcOEt mixture. 1 g of the expected product is obtained. MH + = 359, t = 11.81 minutes. C) Methyl 4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3-methylthiophene-2-carboxylate. 1 g of the compound obtained in the preceding step is placed in 25 ml of acetonitrile and 0.37 ml of methylthioglycolate is added, then 0.34 ml of DBU and the mixture is left stirring for 24 hours at RT. The solvent is evaporated to dryness and the mixture is extracted with ethyl acetate, washed with NH4Cl and then with a 0.5N HCl solution. The organic phase is dried over MgSO4 and evaporated. The product is chromatographed on silica, eluting with a heptane / AcOEt mixture. 0.5 g of the expected product is obtained. D) 4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3-methylthiophene-2-carboxylic acid. 0.5 g of the compound obtained in the preceding step is placed in 20 ml of MeOH and 0.0486 g of NaOH is added. The mixture is left stirring at room temperature for 24 hours and the reaction medium is then evaporated. The organic impurities are extracted with ether and the aqueous phase is acidified to pH = 1. The acid is extracted with ethyl acetate and dried and then the organic phase is evaporated. 260 mg of the expected product are obtained. E) 4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3-methyl-N-piperidin-1-ylthiophene- 2-carboxamide 0.25 g of the compound in the preceding step is placed in 15 ml of DCM and added 0.22 ml of triethylamine then 0.063 g of N-aminopiperidine then 0.222 g of TBTU and the mixture is left stirring for 24 hours at RT. Evaporate the reaction mixture to dryness, add water and extract with AcOEt, wash with a 0.5N sodium hydroxide solution. The organic phase is dried and evaporated to dryness. The product crystallizes from ether. 0.2 g of the expected product is obtained. MH + = 481, t = 12.10. The following tables illustrate the chemical structures and the physical properties of some compounds according to the invention. In this table: Me, Et, tBu represent respectively the methyl, ethyl and tert-butyl groups. TABLE 1
TABLEAU 2TABLE 2
Les composés de formule (I) possèdent une bonne affinité in vitro (IC50 ≤ _ 5.10 M) pour les récepteurs aux cannabinoïdes CBj, dans les conditions expérimentales décrites par 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. Les composés selon l'invention ont été testés in vivo (binding ex vivo) chez la souris après l'administration intraveineuse et/ou orale, selon les conditions expérimentales décrites chez Rinaldi-Carmona et al. (J. Pharmacol. Exp., 1998, 284, 644-650). La toxicité des composés de formule (I) est compatible avec leur utilisation en tant que médicament. 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 CBi . 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, 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. 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. Les composés de formule (I) selon l'invention peuvent également être utilisés comme médicaments dans le traitement des troubles 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. 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. 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. De plus, les composés de formule (I) 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 la stéatose hépatique non alcoolique, de l'asthme, 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, l'arthrite 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, pour le traitement du syndrome de Guillain- Barré et pour le traitement de l'ostéoporose. Selon la présente invention, les composés de formule (I) 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 troubles 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. 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. Le composé selon l'invention est généralement administré en unité de dosage. Lesdites unités de dosage sont de préférence formulées dans des compositions pharmaceutiques dans lesquelles le principe actif est mélangé avec un excipient pharmaceutique. 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. 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 àThe compounds of formula (I) have a good in vitro affinity (IC50 ≤ _ 5.10 M) for the cannabinoid receptors CBj, under the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 350, 240-2424). The antagonistic nature of the compounds of formula (I) has been demonstrated by the results obtained in the models of the inhibition of adenylate cyclase 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. The compounds according to the invention were tested in vivo (ex vivo binding) in mice after intravenous and / or oral administration, according to the experimental conditions described in Rinaldi-Carmona et al. (J. Pharmacol. Exp., 1998, 284, 644-650). The toxicity of the compounds of formula (I) is compatible with their use as a medicament. According to another of its aspects, the present invention relates to the use of a compound of formula (I), or of one of its salts, solvates or hydrates pharmaceutically acceptable, for the preparation of medicaments intended to treat or prevent diseases involving the CBi cannabinoid receptors. For example and without limitation, the compounds of formula (I) are useful as psychotropic drugs, in particular for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders , obsessive-compulsive disorder, psychosis in general, schizophrenia, as well as for the treatment of disorders linked to the use of psychotropic substances, in particular in the case of substance abuse and / or dependence on a substance, including alcohol dependence and nicotine dependence. The compounds of formula (I) according to the invention can be used as medicaments for the treatment of migraine, stress, diseases of psychosomatic origin, attacks of panic attacks, epilepsy, movement disorders , especially dyskinesia or Parkinson's disease, tremors and dystonia. The compounds of formula (I) according to the invention can also be used as medicaments in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementias, of Alzheimer's disease, as well as in the treatment of attention or alertness disturbances. In addition, the compounds of formula (I) can be useful as neuroprotectors, in the treatment of ischemia, head trauma and the treatment of neurodegenerative diseases: including chorea, Huntington's chorea, Tourrette 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, appetite (for sugars, carbohydrates, drugs, alcohols or any appetizing substance) and / or conduct food, especially as appetite suppressants or for the treatment of obesity or bulimia as well as for the treatment of type II diabetes or non-insulin dependent diabetes and for the treatment of dyslipidemia, metabolic syndrome. In addition, the compounds of formula (I) according to the invention can be used as medicaments in the treatment of gastrointestinal disorders, diarrheal disorders, ulcers, vomiting, bladder and urinary disorders, disorders of endocrine origin, cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, chronic cirrhosis of the liver, non-alcoholic fatty liver disease, asthma, Raynaud's syndrome, glaucoma, fertility disorders, inflammatory phenomena, diseases of the immune system, in particular autoimmune and neuroinflammatory such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, strokes as well as as drugs for anticancer chemotherapy, for the treatment of Guillain-Barré syndrome and for the treatment of osteoporosis. According to the present invention, the compounds of formula (I) are very particularly useful for the treatment of psychotic disorders, in particular schizophrenia; attention deficit hyperactivity disorder (ADHD) in hyperkinetic children (MBD) for the treatment of appetite and obesity disorders for the treatment of memory and cognitive disorders; for the treatment of alcohol dependence, nicotine dependence, that is to say for alcohol withdrawal and for smoking cessation and for the treatment of dyslipidemia, metabolic syndrome. According to one of its aspects, the present invention relates to the use of a compound of formula (I), its pharmaceutically acceptable salts and their solvates or hydrates for the treatment of the disorders and diseases indicated above. The compound according to the invention is generally administered in dosage unit. Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient. Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I), one of its pharmaceutically acceptable salts or one of their solvates. The compound of formula (I) above and its pharmaceutically acceptable salts or solvates can be used in daily doses of 0.01 to 100 mg per kg of body weight of the mammal to be treated, preferably in daily doses of 0, 02 to
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. 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. 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. 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 dosages are examples of average situations, there may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention. According to usual practice, the appropriate dosage for each patient is determined by the doctor according to the mode of administration, the age, the weight and the response of said patient. In the pharmaceutical compositions of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle can be administered in unit administration form, in admixture with carriers conventional pharmaceuticals, animals and humans. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, aerosols, administration forms topical, implants, forms of subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and forms of rectal administration. In the pharmaceutical compositions of the present invention, the active ingredient 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.

Claims

REVENDICATIONS
1. Composé répondant à la formule (I) :1. Compound corresponding to formula (I):
dans laquelle : - Ri représente l'hydrogène ou un (Cι-C4)alkyle ; - R2 représente : . un groupe (C4-Cιo)alkyle ; . un radical carbocyclique non aromatique en C3-C 2, non substitué ou substitué une ou plusieurs fois par un groupe (Cι-C4)alkyle, (Cι-C4)alcoxy ou hydroxyle ; . un 1,2,3,4-tétrahydronaphtyle -1 ou -2 ; . un radical hétérocyclique monooxygéné ou monosoufré, saturé, de 5 à 7 atomes, non substitué ou substitué une ou plusieurs fois par un groupe (Cι-C4)alkyle ; . un radical hétérocyclique monoazoté, saturé, de 5 à 7 atomes, l'atome d'azote étant substitué par un groupe (Cι-C4)alkyle, phényle, benzyle, (Ci- C4)alcoxycarbonyle ou (C -C4)alcanoyle ; . un groupe (Cι-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 ; . un groupement phénylalkylène dans lequel l'alkylène est en (C1-C3), non substitué ou substitué sur l'alkylène par un ou plusieurs groupes méthyle, et/ou substitué sur le phényle par un ou plusieurs substituants identiques ou différents choisis parmi un atome d'halogène ou un groupe (Cι-C4)alkyle, trifluorométhyle, (Cl"C4)alcoxy, trifluorométhoxy ; . un méthylène substitué par un radical benzothiényle, benzofuryle, thiényle, ou furyle, lesdits radicaux étant non substitués ou substitués par un ou plusieurs groupes (Cι-C4)alkyle ; . un groupement NR9R 0 ; - 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, (Cι-C4)alkyle, hydroxyle, (Ci- C4)alcoxy, cyano, (Cι-C3)alcanoyle, (C -C4)alcoxycarbonylamino, (Cj- C3)alcanoylamino ; les groupes phényles ou benzyles étant non substitués ou substitués une ou plusieurs fois par un atome d'halogène et/ou un groupe (C - C4)alkyle et/ou (C -C4)alcoxy, et/ou trifluorométhyle ; - R3, R4, R5, R , R7, Rg représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, un groupe (Cι-Cg)alkyle, (C -C6)alcoxy, trifluorométhyle ou un groupement S(O)nAlk ; - R9 représente un atome d'hydrogène ou un groupe méthyle ; - RlO représente un groupe (C3-Cg)alkyle, phényle ou C3-C10 cycloalkyle, lesdits groupes phényle et cycloalkyle étant non substitués ou substitués par un ou plusieurs atomes d'halogène et/ou groupes (Cι-C4)alkyle ; - ou R9 et Rio 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 par un groupe hydroxyle ou phényle, ou, une ou plusieurs fois, par un groupe (Ci- C4)alkyle et ou (Cι-C4)alcoxy ; - Rl l représente un atome d'hydrogène, un groupe (C -C4)alkyle ou (C3- C7)cycloalkyle ; - n représente 0, 1 ou 2 ; - Alk représente un groupe (Cι-C4)alkyle ; à l'état de base ou de sel d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvat. 2. Composé selon la revendication 1 de formule (I) dans laquelle : - R\ représente l'hydrogène ou un (Cι-C4)alkyle ; - R2 représente : . un groupe (C4-Cιo) lkyle ; . un radical carbocyclique non aromatique en C3-C12, non substitué ou substitué une ou plusieurs fois par un groupe (Cι-C4)alkyle ; . un 1, in which: - Ri represents hydrogen or a (Cι-C4) alkyl; - R2 represents:. a (C4-Cιo) alkyl group; . a non-aromatic C3-C 2 carbocyclic radical, unsubstituted or substituted one or more times by a (Cι-C4) alkyl, (Cι-C4) alkoxy or hydroxyl group; . 1,2,3,4-tetrahydronaphthyl -1 or -2; . a heterocyclic radical monooxygenated or monosulfur, saturated, of 5 to 7 atoms, unsubstituted or substituted one or more times by a group (Cι-C4) alkyl; . a saturated monoazotated heterocyclic radical of 5 to 7 atoms, the nitrogen atom being substituted by a (Cι-C4) alkyl, phenyl, benzyl, (Ci-C4) alkoxycarbonyl or (C -C4) alkanoyl group; . an alkylene group (Cι-C3) carrying a non-aromatic C3-C10 carbocyclic radical unsubstituted or substituted one or more times by a (C1-C4) alkyl group; . a phenylalkylene group in which the alkylene is in (C1-C3), unsubstituted or substituted on the alkylene by one or more methyl groups, and / or substituted on the phenyl by one or more identical or different substituents chosen from an atom halogen or a group (Cι-C4) alkyl, trifluoromethyl, (Cl "C4) alkoxy, trifluoromethoxy; a methylene substituted by a benzothienyl, benzofuryl, thienyl, or furyl radical, said radicals being unsubstituted or substituted by one or several (Cι-C4) alkyl groups; an NR9R 0 group; - or Ri and R2 together with the nitrogen atom to which they are linked constitute either a piperazin-1-yl or 1,4-diazepan-1-yl radical substituted in 4- by a phenyl or benzyl group, or a radical piperidin-1-yl or pyrrolidin-1-yl mono or gem-disubstituted by a phenyl, benzyl, (Cι-C4) alkyl, hydroxyl, (Ci- C4) alkoxy, cyano, (Cι-C3) alkanoyl group, (C -C4) alkoxycarbonylamino, (Cj-C3) alkanoylamino; the phenyl or benzyl groups being unsubstituted or substituted one or more times by a halogen atom and / or a (C - C4) alkyl and / or (C -C4) alkoxy, and / or trifluoromethyl group; - R3, R4, R5, R, R7, Rg each independently of one another represent a hydrogen or halogen atom, a (Cι-Cg) alkyl, (C -C6) alkoxy, trifluoromethyl or an S (O) n Alk group; - R9 represents a hydrogen atom or a methyl group; - R10 represents a (C3-Cg) alkyl, phenyl or C3-C10 cycloalkyl group, said phenyl and cycloalkyl groups being unsubstituted or substituted by one or more halogen atoms and / or (Cι-C4) alkyl groups; - or R9 and Rio together with the nitrogen atom to which they are linked constitute a heterocyclic radical, saturated or unsaturated, of 5 to 11 atoms, bridged or not, comprising or not a spirannic carbon and containing or not containing a second chosen heteroatom from O or N, said radical being unsubstituted or substituted by a hydroxyl or phenyl group, or, one or more times, by a (C 1 -C 4) alkyl and or (C 1 -C 4) alkoxy group; - Rl l represents a hydrogen atom, a (C -C4) alkyl or (C3-C7) cycloalkyl group; - n represents 0, 1 or 2; - Alk represents a (Cι-C4) alkyl group; in the base state or in addition salt to an acid, as well as in the hydrate or solvate state. 2. Compound according to claim 1 of formula (I) in which: - R \ represents hydrogen or a (Cι-C4) alkyl; - R2 represents:. a (C4-Cιo) alkyl group; . a non-aromatic C3-C12 carbocyclic radical, unsubstituted or substituted one or more times by a (Cι-C4) alkyl group; . a 1,
2,3,4-tétrahydronaphtyle -1 ou -2 ; . un radical hétérocyclique monooxygéné ou monosoufré, saturé, de 5 à 7 atomes, non substitué ou substitué une ou plusieurs fois par un groupe (Cι-C4)alkyle ; 2,3,4-tetrahydronaphthyl -1 or -2; . a heterocyclic radical monooxygenated or monosulfur, saturated, of 5 to 7 atoms, unsubstituted or substituted one or more times by a group (Cι-C4) alkyl;
. un radical hétérocyclique monoazoté, saturé, de 5 à 7 atomes, l'atome d'azote étant substitué par un groupe (C -C4)alkyle, phényle, benzyle, (C]- C4)alcoxycarbonyle ou (Cι-C4)alcanoyle ;. a saturated monoazotated heterocyclic radical of 5 to 7 atoms, the nitrogen atom being substituted by a (C -C4) alkyl, phenyl, benzyl, (C] - C4) alkoxycarbonyl or (Cι-C4) alkanoyl group;
. un groupe (Cι-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 ;. an alkylene group (Cι-C3) carrying a non-aromatic C3-C10 carbocyclic radical unsubstituted or substituted one or more times by a (C1-C4) 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, et/ou substitué sur le phényle par un ou plusieurs substituants identiques ou différents choisis parmi un atome d'halogène ou un groupe (Cι-C4)alkyle, trifluorométhyle,. a phenylalkylene group in which the alkylene is in (C1-C3), unsubstituted or substituted on the alkylene by one or more methyl groups, and / or substituted on the phenyl by one or more identical or different substituents chosen from an atom halogen or a group (Cι-C4) alkyl, trifluoromethyl,
(Cι-C4)alcoxy, trifluorométhoxy ;(Cι-C4) alkoxy, trifluoromethoxy;
. un méthylène substitué par un radical benzothiényle, benzofuryle, thiényle, ou furyle, lesdits radicaux étant non substitués ou substitués par un ou plusieurs groupes (Cι-C4)alkyle ; . un groupement NR9R10 ;. a methylene substituted by a benzothienyl, benzofuryl, thienyl or furyl radical, said radicals being unsubstituted or substituted by one or more (Cι-C4) alkyl groups; . an NR9R10 group;
- 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, (C -C4)alkyle, hydroxyle, (Ci- C3)alcanoyle ou (Cι-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 Ri and R2 together with the nitrogen atom to which they are linked constitute either a piperazin-1-yl or 1,4-diazepan-1-yl radical substituted in 4- by a phenyl or benzyl group, or a radical piperidin-1-yl or pyrrolidin-1-yl mono or gem-disubstituted by a phenyl, benzyl, (C -C4) alkyl, hydroxyl, (C1-C3) alkanoyl or (C1-C4) alkoxycarbonylamino group; the phenyl or benzyl groups being unsubstituted or substituted one or more times by a halogen atom and / or a methyl group;
- R3, R4, R5, Rg, R7, Rg représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, un groupe (Cι-Cg)alkyle, (Cι-Cg)alcoxy, trifluorométhyle ou un groupement S(O)nAlk ;- R3, R4, R5, Rg, R7, Rg each independently of one another represent a hydrogen or halogen atom, a (Cι-Cg) alkyl, (Cι-Cg) alkoxy, trifluoromethyl or an S (O) n Alk group;
- R9 représente un atome d'hydrogène ou un groupe méthyle ;- R9 represents a hydrogen atom or a methyl group;
- Rio représente un groupe (C3-C(j)alkyle, phényle ou C3-C10 cycloalkyle, lesdits groupes phényle et cycloalkyle étant non substitués ou substitués par un ou plusieurs atomes d'halogène et/ou groupes (C 1 -C4)alkyle ou par un atome d'halogène ;- Rio represents a (C3-C (j) alkyl, phenyl or C3-C10 cycloalkyl group, said phenyl and cycloalkyl groups being unsubstituted or substituted by one or more halogen atoms and / or (C 1 -C4) alkyl groups or by a halogen atom;
- ou R9 et Rio 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 par un groupe hydroxyle ou phényle ou une ou plusieurs fois par un groupe (Ci-- or R9 and Rio together with the nitrogen atom to which they are linked constitute a heterocyclic radical, saturated or unsaturated, of 5 to 11 atoms, bridged or not, comprising or not a spirannic carbon and containing or not containing a second chosen heteroatom from O or N, said radical being unsubstituted or substituted by a hydroxyl or phenyl group or one or more times by a group (Ci-
C4)alkyle ; - Ri 1 représente un atome d'hydrogène ; - n représente 0, 1 ou 2 ; - Alk représente un groupe (Cι-C4)alkyle ; à l'état de base ou de sels d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvat.C4) alkyl; - Ri 1 represents a hydrogen atom; - n represents 0, 1 or 2; - Alk represents a (Cι-C4) alkyl group; in the base state or in addition salts with an acid, as well as in the hydrate or solvate state.
3. Composé selon la revendication 1 de formule (I) dans laquelle R i représente un groupe (C -C4)alkyle ou (C3-C7)cycloalkyle et les autres substituants sont tels que définis pour (I).3. Compound according to claim 1 of formula (I) in which R i represents a (C -C4) alkyl or (C3-C7) cycloalkyl group and the other substituents are as defined for (I).
4. Composé selon la revendication 1 de formule (I) dans laquelle : - Ri et R_2 ensemble avec l'atome d'azote auquel ils sont liés constituent un radical pipéridin-1-yle gem-disubstitué par un groupe benzyle ou phényle non substitué ou substitué par un atome d'halogène et par un groupe (Cι-C3)alcanoyle ou cyano; - ou Ri représente l'hydrogène ; - et/ou R2 représente un groupe NR9R10 dans lequel R9 et Rio 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 (Cι-C4)alkyle ; - et/ou R2 représente un radical carbocyclique non aromatique en C3-C 0, non substitué ou substitué une ou plusieurs fois par un groupe (Cι-C4)alkyle ; - et/ou R2 représente un groupe benzyle substitué sur le phényle par un ou plusieurs substituants identiques ou différents choisis parmi un atome d'halogène, un groupe (Cι-C4)alkyle, trifluorométhyle, (Cι-C4)alcoxy, trifluorométhoxy ; - et/ou R3, R4, R5, Rg, R7, Rg représentent chacun indépendamment l'un de l'autre un atome d'hydrogène ou d'halogène, préférentiellement R3 est un 4-chloro ou un 4-bromo et Rg, R7 représentent 2,4-dichloro, R4, R5, Rg représentant un atome d'hydrogène ; à l'état de base ou de sels d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvat. 4. Compound according to claim 1 of formula (I) in which: - Ri and R_2 together with the nitrogen atom to which they are linked constitute a piperidin-1-yl radical gem-disubstituted by an unsubstituted benzyl or phenyl group or substituted by a halogen atom and by a group (Cι-C3) alkanoyl or cyano; - or R 1 represents hydrogen; - and / or R2 represents a group NR9R10 in which R9 and Rio together with the nitrogen atom to which they are bonded constitute a heterocyclic radical saturated with 5 to 11 carbon atoms, unsubstituted or substituted one or more times by a ( Cι-C 4 ) alkyl; - And / or R2 represents a non-aromatic C3-C0 carbocyclic radical, unsubstituted or substituted one or more times by a (Cι-C4) alkyl group; - And / or R2 represents a benzyl group substituted on the phenyl by one or more identical or different substituents chosen from a halogen atom, a (Cι-C4) alkyl, trifluoromethyl, (Cι-C4) alkoxy, trifluoromethoxy group; - and / or R3, R4, R5, Rg, R7, Rg each independently of one another represent a hydrogen or halogen atom, preferably R3 is a 4-chloro or a 4-bromo and Rg, R7 represent 2,4-dichloro, R4, R5, Rg representing a hydrogen atom; in the base state or in addition salts with an acid, as well as in 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, Rg, R7, Rg et R sont tels que définis pour (I) dans la revendication 1 avec une amine de formule HNR1R2 (III) dans laquelle Ri et R2 sont tels que définis pour (I) dans la revendication 1.5. Method for preparing 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 : in which R3, R4, R5, Rg, R7, Rg and R are as defined for (I) in claim 1 with an amine of formula HNR1R2 (III) in which Ri and R2 are as defined for (I) in claim 1.
6. 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).6. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 4, or an addition salt of this compound to a pharmaceutically acceptable acid, or alternatively a hydrate or a solvate of the compound of formula (I).
7. 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.7. 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, as well as at least a pharmaceutically acceptable excipient.
8. 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 gastro-intestinaux, des phénomènes inflammatoires, des maladies du système immunitaire, des troubles psychotiques, de la dépendance alcoolique, de la dépendance nicotinique. 8. Use of a compound of formula (I) according to any one of claims 1 to 4 for the preparation of a medicament intended for the treatment and prevention of appetite disorders, gastrointestinal disorders, inflammatory phenomena, diseases of the immune system, psychotic disorders, alcohol dependence, nicotine dependence.
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