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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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