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Definitions

• the present invention relates to azetidine derivatives, to their preparation and to their therapeutic application in the treatment or prevention of diseases involving CB1 cannabinoid receptors.
• R represents a (C 1 -C 6 ) alkyl group, a halo (C 1 -C 6 ) alkyl group;
• R1 represents a hydrogen atom;
• R2 represents a
• heteroaromatic group or a (Ci-C 4 ) alkyl heteroaromatic group these groups being optionally substituted by one or more atoms or groups chosen from halogen, hydroxy, cyano, oxo, NH 2 , C (O) NH 2 , a (Ci-C 6) alkyl, halo (Ci-C 6) alkyl, a (Ci-C 6) alkoxy, halo (C] -C ⁇ ) alkoxy or a group COO (Ci-C 6 ) alkyl;
• R3 and R4 represent independently of each other a phenyl group, optionally substituted by one or more atoms or groups selected from halogen, cyano, (C 6 -C 6 ) alkyl, halo (C 1 -C 6) ) alkyl, a (C 1 -C 6 ) alkoxy group or a halo (C 1 -C 6 ) alkoxy group;
• Y represents a hydrogen atom, a halogen, a cyano, a (C 1 -C 6 ) alkyl group, a halo (C 1 -C 6 ) alkyl group, a (C 1 -C 6 ) alkoxy group, a halo group (C 1 -C 6 ), C 6 ) alkoxy or a group (C r C 6 ) alkylS (O) p ; p is 0 to 2; in the form of a base or an acid addition salt.
• the compounds of formula (I) can comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, are part of the invention.
• a first group of compounds consists of mixed compounds of diastereoisomers and of enantiomers for which:
• R represents a methyl
• R3 and R4 each represent a phenyl group optionally substituted by a para-chlorine atom
• Y represents a hydrogen atom or a halogen
• R 1 represents a hydrogen atom
• R 2 represents a heteroaromatic group or a heteroaromatic (C 1 -C 4 ) alkyl group
• the heteroaromatic group represents a thiazole, imidazole, thiadiazole, pyridine, isoxazole, pyrimidine, pyrazole, oxadiazole, triazole, isothiazole optionally substituted with one or more (Ci- C ⁇ ) alkyl, halogen, hydroxy, amino, C (O) NHa, halo (C 1 -C 6 ) alkyl; in the form of a base or an acid addition salt.
• a halogen a fluorine, a chlorine, a bromine or an iodine
• a (C u -C t ) represents a group having from u to t carbon atoms
• a (C 1 -C 6 ) alkyl group an aliphatic group comprising from 1 to 6 saturated, cyclic, branched or linear carbon atoms which may optionally be substituted by one or more groups
• a halo (C 1 -C 6 ) alkyl group a (C 1 -C 6 ) alkyl group in which one or more hydrogen atoms have been substituted by a halogen atom.
• a hydroxy (Ci-C 6 ) alkyl group a (C r C 6 ) alkyl group in which one or more hydrogen atoms have been substituted with one or more hydroxyls; a group (Ci-C 6 ) alkoxy: a group (dC 6 ) alkyl-O- where the group (C r C 6 ) alkyl is as previously defined.
• a halo (Ci-C 6 ) alkoxy group a halo (C 1 -C 6 ) alkyl-O- group where the halo (C 1 -C 6 ) alkyl group is as previously defined.
• a heteroaromatic group is a 5- or 6-membered monocyclic aromatic group comprising from 1 to 4 heteroatoms chosen from O, S, N.
• the N heteroatoms may be present in the oxidized form, that is to say NO.
• a heteroaromatic (Ci-C 4 ) alkyl group is an alkyl group substituted with a heteroaromatic as defined above.
• the compounds of formula (I) may exist in the form of bases or salts. Such addition salts are part of the invention.
• salts can be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.
• the compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the invention.
• the compounds of formula (I) may also exist in the form of tautomers and are also part of the invention.
• the present invention also relates to the use of the compounds of the invention of formula (I) for the preparation of a medicament for the treatment or prevention of diseases in which the CB1 receptor is involved.
• the subject of the present invention is also the use of the compounds of the invention of formula (I) for the preparation of a medicament for the treatment or the prevention of psychiatric disorders, addiction and weaning to a substance, weaning smoking, cognitive disorders and attention and acute and chronic neurodegenerative diseases; metabolism, appetite disorders, appetite disorders, obesity, diabetes (type I and / or II), metabolic syndrome, dyslipidemia, sleep apnea; pain, neuropathic pain, neuropathic pain induced by anticancer drugs; gastrointestinal disorders, vomiting, ulcer, diarrhea disorders, bladder and urinary disorders, endocrine disorders, cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, diseases liver disease, chronic cirrhosis of the liver, fibrosis, non-alcoholic steatohepatitis (NASH), steatohepati
• This reaction will be carried out in a chlorinated solvent such as dichloromethane in the presence of a base such as pyridine and a mesylate derivative such as mesyl chloride at a temperature of between -10 ° C. and 40 ° C.
• a chlorinated solvent such as dichloromethane
• a base such as pyridine
• a mesylate derivative such as mesyl chloride
• R represents a protective group of 0 the OH function of the acid.
• the derivative 4 is accessible by reaction of mesylate 2 with azetidine 3.
• This step is preferably carried out under an inert atmosphere, in an inert solvent such as 4-methyl-2-pentanone in the presence of a base. mineral such as potassium carbonate refluxing the reaction mixture.
• azetidine 3 is described in patent application WO01064634.
• ester 4 to acid 5 is carried out according to the methods known to those skilled in the art and, more specifically, in a mixture of polar solvents such as tetrahydrofuran and water in the presence of a base such as lithium hydroxide hydrated at a temperature in the region of 20 ° C.
• a polar solvent such as tetrahydrofuran or dimethylformamide
• a base such as a trialkylamine (triethylamine or diisopropylethylamine, for example)
• a coupling agent such as 1- (3-dimethylaminopiopropyl) -3-ethylcarbodiinide hydrochloride
• one or more additives (1-hydroxybenzotriazole, benzotriazol-1-yloxytris- (dimethylamino) -phosphonium-hexafluor, for example
• a polar solvent such as tetrahydrofuran
• a base such as a trialkylamine (triethylamine, for example)
• an agent allowing peptide synthesis via the formation of a mixed anhydride such as that isobutylchloroformate
• a polar solvent such as tetrahydrofuran or a chlorinated solvent such as dichloromethane
• a dimethylformamide aliquot in the presence of an agent allowing the intermediate formation of an acid chloride ( thionyl chloride, for example) and at a temperature between -20 ° C. and the boiling point of the solvent.
• an agent allowing the intermediate formation of an acid chloride ( thionyl chloride, for example) and at a temperature between -20 ° C. and the boiling point of the solvent.
• reaction between ester 4 and an amine derivative 6 can be carried out in an inert solvent such as toluene, in the presence of a trialkylaluminium derivative such as trimethylaluminum at a temperature of temperature between 0 0 C and the boiling point of the solvent.
• an inert solvent such as toluene
• a trialkylaluminium derivative such as trimethylaluminum
• the derivatives 6 are commercially available or synthesized, according to the methods known to those skilled in the art, from the appropriate commercial precursors.
• the compounds of formula (I) can be prepared by reacting an acid derivative with an amine derivative 6 in an inert solvent; in the presence of a coupling agent and optionally an additive to prevent racemization, the product is optionally deprotected and then the product is isolated and optionally converted into an acid addition salt.
• the compounds of formula (I) can be purified by the usual known methods, for example by crystallization, chromatography or extraction.
• the enantiomers of the compounds of formula (I) can be obtained by resolution of the racemic compounds, for example by chromatography on a chiral column according to PIRKLE W.H. et al.
• the present invention also relates to the process for preparing the intermediates.
• the following examples describe the preparation of certain compounds according to the invention. These examples are not limiting and only illustrate the present invention.
• the numbers of the exemplified compounds refer to those given in the table below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.
• Example 1 3 - [ ⁇ l- [bis (4-chlorophenyl) methyl] azetidin-3-yl ⁇ (methylsulfonyl) amino] - ⁇ '- (l, 3-thiazol-2-yl) benzamide (Compound N 0 I ) To a solution of 300 mg of 3 - [ ⁇ 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl ⁇ (methylsulfonyl) amino] benzoic acid and 65.4 mg of 2-aminothiazole in 3 cm 3 3 dichloromethane stirred for 10 minutes at a temperature in the region of 20 0 C is added 136.5 mg of hydrochloride of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.
• the reaction medium is stirred overnight at a temperature of 20 ° C before being diluted with water.
• the aqueous phase is extracted with dichloromethane.
• the organic phases are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure to give a crude product which is purified by flash chromatography on a Sep Pack column of 5 g of silica (gradient of elution: dichloromethane / methanol 100/0 to 96/4). After concentrating the fractions under reduced pressure, 170 mg of 3 - [ ⁇ 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl ⁇ (methylsulfonyl) amino] -N- (1,3-thiazol-2) are obtained.
• -yl) benzamide in the form of white crystals.
• the aqueous phase is extracted twice with 100 cm 3 of ethyl acetate.
• the combined organic phases are washed with 80 cm 3 of a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered on sintered glass and then concentrated to dryness under reduced pressure to give 7.2 g of an orange residue.
• the crude reaction product is purified by flash chromatography on a cartridge of 400 g of Merck silica (particle size: 15-40 ⁇ m, elution gradient: dichloromethane / methanol 98/2 to 95/5).
• the reaction medium is stirred at a temperature of 20 ° C for 24 hours. Then, 100 cm 3 of a saturated aqueous solution of sodium hydrogen phosphate are added to bring the pH to 5. The aqueous phase is extracted four times with 200 cm 3 of ethyl acetate. The combined organic phases are dried over sodium sulphate, filtered on sintered glass and then concentrated to dryness under reduced pressure to give a meringue which is taken up twice with 150 cm 3 of ethyl ether.
• Example 6 3 - [ ⁇ 1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl ⁇ (methylsulfonyl) amino] -5-fluoro-N- (5-methylisoxazol-3-yl) benzamide (Compound 21) To a solution of 400 mg of 3 - [ ⁇ 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl ⁇ (methylsulfonyl) amino] -5-fluorobenzoic acid and 4 drops of dimethylformamide in 4 cm 3 of dichloromethane is added a solution of 245 .mu.l of thionyl chloride in 1 cm 3 of dichloromethane.
• the reaction medium is stirred for 2 hours 20 minutes at a temperature of 35 0 C, then cooled to a temperature of 20 0 C, before being concentrated to dryness under reduced pressure after adding a few cm 3 of toluene.
• the solid obtained is solubilized in 10 cm 3 of dichloromethane and 10 cm 3 of tetrahydrofuran.
• To this solution is added a solution of 90 mg of 3-amino-5-methyloxazole in 2 cm 3 of dichloromethane.
• the reaction medium is stirred at a temperature in the region of 20 ° C. overnight before being concentrated to dryness under reduced pressure.
• R3 and R4 each represent a phenyl group substituted with a chlorine atom in the para position
• the compounds according to the invention have been the subject of pharmacological tests making it possible to determine the activity with respect to human CB1 cannabinoid receptors.
• the effectiveness of the compounds of formula (I) was determined in a functional test measuring CB1 cannabinoid receptor activity (intracellular cyclic AMP test).
• the test for detection of intracellular cyclic AMP in U373MG cells expressing naturally the human CB1 receptor was carried out as described in the reference: Bouaboula et al., 1995, J. Biol. Chem. 270: 13973-13980.
• CisBio's hTRF cAMP Dynamic Kit was used for quantification of intracellular cyclic AMP.
• IC 50 values are between 0.001 ⁇ M and 2 ⁇ M.
• Compounds Nos . 5, 10, 11, 15, 18, 34, 39 and 47 showed IC 50 values of 0.006; 0.04; 0.170; 0.134; 0.006, 0.02, 0.033 and 0.009 ⁇ M.
• Compounds Nos . 5 and 7 showed a percent inhibition of 28% and 32%, respectively, at 3 mg / kg. Their antagonistic activity was also shown using the racemic CP55,940-induced gastrointestinal transit inhibition model (1RS, 3RS, 4RS-3- [hydroxy-2- (1,1-dimethylheptyl) phenyl] -4 - (3-hydroxypropyl) cyclohexan-1-ol) in the mouse, according to the method described by Rinaldi-Carmona et al., J.Pharmacol.Exp.Ther. 2004, 310, 905-914.
• CD1 male mice received the test product orally 30 minutes or 2 hours prior to administration of the racemic CP55,940 agonist (1RS, 3RS, 4RS-3- [hydroxy-2- (1,1- dimethylheptyl) phenyl] -4- (3-hydroxypropyl) cyclohexan-1-ol) (0.15 mg / kg ip in cremophore 10%).
• the animals receive a bolus of coal in.
• the animals are euthanized (CCyO 2 ) and the intestine is dissected. The progression of the bolus of charcoal in the intestine is expressed as a percentage of the total length of the intestine.
• the compounds of the invention of formula (I) are CB1 cannabinoid receptor antagonists in vitro and in vivo. Some compounds are active in vivo on both the hypothermia and transit test, and some compounds show dissociated activities between the hypothermia and transit test.
• the compounds according to the invention can be used in the treatment or prevention of diseases involving CB1 cannabinoid receptors. These compounds have a peripheral activity dissociated from the central activity.
• the compounds of formula (I) are useful as psychotropic drugs, especially for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders , obsessive-compulsive disorder, psychosis in general, schizophrenia, attention deficit hyperactivity disorder (ADHD) in hyperkinetic children (BDM), and the treatment of disorders related to the use of psychotropic substances , particularly in the case of substance abuse and / or substance dependence, including alcohol dependence and nicotine addiction and withdrawal disorders.
• the compounds of formula (I) according to the invention can be used as medicaments for the treatment of migraine, stress, psychosomatic diseases, panic attacks, epilepsy, movement disorders , especially dyskinesias or Parkinson's disease, tremors and dystonia.
• the compounds of formula (I) according to the invention can be used as medicaments for skin cancer and protection of the skin.
• 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 cognitive disorders related to senile dementia, to Alzheimer's disease, to schizophrenia and neurodegenerative diseases, as well as in the treatment of attention deficit or alertness disorders.
• the compounds of formula (I) may be useful as neuroprotective agents, in the treatment of ischemia, head trauma and the treatment of neurodegenerative diseases: including Huntington's chorea, Tourrette's syndrome.
• the compounds of formula (I) according to the invention can be used as medicaments in the treatment of pain: neuropathic pain, peripheral acute pain, chronic pain and pain of inflammatory origin.
• the compounds of formula (I) according to the invention can be used as medicaments in the treatment of appetite disorders, palatability (for sugars, carbohydrates, drugs, alcohols or any appetizing substance) and / or conduits. for the treatment of 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 are useful in the treatment of obesity and the risks associated with obesity, in particular cardiovascular risks.
• the compounds of formula (T) according to the invention can be used as medicaments in the treatment of gastrointestinal disorders, diarrheal disorders, ulcers, vomiting, bladder and urinary disorders, endocrine, cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, cirrhosis, hepatic fibrosis, steatohepatitis and hepatic steatosis, regardless of the etiology of these conditions: in particular viras, alcohol, drug, chemical, autoimmune disease, obesity, diabetes, congenital metabolic disease, (hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's disease, etc.), chronic cirrhosis of the liver, Fibrosis, non-alcoholic steatohepatitis (NASH), asthma, chronic obstructive pulmonary disease, Raynaud's syndrome, glaucoma, fertility disorders, inflammatory phenomena , inflammatory diseases, diseases of the immune system, particularly autoimmune and neuroinfiammatory
• the present invention relates to the use of a compound of formula (I), its pharmaceutically acceptable salts and their solvates or hydrates for the treatment of the disorders and diseases indicated above.
• the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, of said compound, as well as at least one pharmaceutically acceptable excipient. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
• compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active ingredient of formula (I) above, or its salt, can be administered in unit dosage form, in admixture with conventional pharmaceutical excipients for the treatment of the disorders or diseases mentioned above.
• Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
• the compounds according to the invention can be used in creams, gels, ointments or lotions.
• a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
• the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
• the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or of a pharmaceutically acceptable salt thereof.

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