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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 cannabinoid CB 1 receptors.
• R represents a (C 1 -C 6 ) alkyl group, a halo (C 1 -C 6 ) alkyl group;
• R1 represents a hydrogen atom; a (C 1 -C 6 ) alkyl group;
• R2 is (Ci-C 6) alkyl substituted with one or more groups selected from hydroxy group, a (Ci-C 6) alkoxy, hydroxy (Ci-C 6) alkyl and optionally substituted with halo (Ci-C 6) alkyl; heterocycle group optionally substituted by one or more hydroxyls, a (C 1 -C 6 ) alkoxy group or a hydroxy (C 1 -C 6 ) alkyl group; heterocycle (C 1 -C 6 ) alkyl group optionally substituted with one or more hydroxyls; R3 and R4 each represent a phenyl group optionally substituted by one or more atoms or groups selected from hydrogen, halogen, (Ci-
• Y represents a hydrogen atom, a halogen, a (C 1 -C 6 ) alkyl group, an ImIo (C 1 -C 6 ) alkyl group, a (C 1 -C 6 ) aIcOXy group, a halo (C 1 - C 6 ) alkoxy, a (C 1 -C 6 ) alkylS (O) p or cyano group; p is from 0 to 2, in the form of a base or an addition salt with an acid.
• 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, form part of the invention.
• s v ⁇ si Among the compounds of formula (I) which are subjects of the invention, a first group of compounds consists of compounds in a mixture of diastereoisomers and of enantiomers for which: R represents a methyl,
• R3 and R4 each represent a phenyl group substituted with a chlorine atom in the para position
• Y represents a hydrogen atom or a halogen or a group (dC 6 ) alkoxy or a halo (C r C 6 ) alkyl group
• R 1 represents a hydrogen atom
• R 2 represents a - (C 1 -C 6 ) alkyl group substituted with one or more groups selected from the group hydroxy, the group (QC 6 ) alkoxy, a hydroxy group (C 1 -C 6 ) alkyl and optionally substituted by a halo (C 1 -C 6 ) alkyl group; heterocycle group representing an oxetane, a tetrahydrofuran, a dioxolane, a tetrahydropyran optionally substituted with one or more hydroxy, hydroxymethyl; heterocycle (C 1 -C 6 ) alkyl group representing tetrahydrofurylmethyl, 2,2-dimethyl-
• a second group of compounds consists of compounds in a mixture of diastereoisomers and of enantiomers for which: R represents a methyl,
• R3 and R4 each represent a phenyl group substituted with a chlorine atom in the para position
• Y represents a hydrogen atom or a fluorine or an OMe group or a CF 3 group
• R 1 represents a hydrogen atom
• R 2 represents a (C 1 -C 6 ) alkyl group substituted by one or more groups chosen from the group hydroxy, the group (Ci-C 6) alkoxy, hydroxy (Ci-C 6) alkyl and optionally substituted with halo (Ci-C 6) alkyl: oxetane, tetrahydrofuran, dioxolane, tetrahydropyran optionally substituted by one or more hydroxy, hydroxymethyl; tetrahydrofurylmethyl, 2,2-dimethyl- [1,3] dioxolan-4-ylmethyl, [1,3] dioxolan-4-ylmethyl; in the form of a base or an acid addition salt.
• halogen a fluorine, a chlorine, a bromine or an iodine
• a (Ci-Q) alkyl group an aliphatic group comprising from 1 to 6 saturated, cyclic, branched or linear carbon atoms which may optionally be substituted with one or more linear, branched or cyclic (C 1 -C 6 ) alkyl groups.
• halo (Ci-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 (C 1 -C 6 ) alkyl group a (C 1 -C 6 ) alkyl group in which one hydrogen atom has been substituted with one or more hydroxyls
• a (C 1 -C 6 ) alkoxy group a (C 1 -C 6 ) alkyl-O- group where the (C 1 -C 6 ) alkyl group is as previously defined
• a halo (Ci-Ce) alkoxy group a halo (C 1 -C 6 ) alkyl-O- group in which the halo (C 1 -C 6 ) alkyl group is as previously defined
• a heterocycle group is a monocyclic group comprising from 4 to 8 atoms, of which 1 to 3 oxygen atoms, this cyclic group is saturated or partially saturated.
• oxetane tetrahydrofuran, dioxolane and tetrahydropyran groups
• a heterocycle (C 1 -C 6 ) alkyl group is an alkyl group substituted with a heterocycle as defined above. Examples that may be mentioned include tetrahydrofuranyl-methyl, 2,2-dimethyl- [1,3] dioxolan-4-ylmethyl, [1,3] dioxolan-4-ylmethyl;
• 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 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 H), metabolic syndrome, dyslipidemia, sleep apnea; pain, neuropathic pain, neuropathic pain induced by anticancer drugs; gastrointestinal disorders, vomiting, ulcer, diarrhea, bladder and urinary disorders, endocrine disorders, cardio- vascular pressure, hypotension, hemorrhagic shock, septic shock, liver disease, chronic cirrhosis of the liver, fibrosis, non-alcoholic steatohepatitis (NASH), steatohepatitis and hepatic steatosis, regardless of the etiology of these conditions (alcohol, drug, chemical, autoimmune disease, obesity, diabetes, congenital
• the mesylation of compound 1 to derivative 2 can be carried out according to methods known to those skilled in the art or described in TW GREENE, Protective Group in Organic Synthesis, fourth edition. 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
• mesylate derivative such as mesyl chloride
• R represents a protective group of 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 mineral base such as potassium carbonate at the reflux of the reaction mixture.
• an inert solvent such as 4-methyl-2-pentanone
• a mineral base such as potassium carbonate
• ester 4 to acid 5 is carried out according to 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.
• the formation of the compounds of formula (I) can be carried out by reaction between the acid 5 and an amine derivative 6.
• This reaction can be carried out in an inert solvent such as tetrahydrofuran, a chlorinated solvent (dichloromethane for example) , in the presence or absence of a base such as a trialkylamine (triethylamine for example), a coupling agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or a supported carbodiimide, in the presence or absence of absence of an additive avoiding any racemization such as 1-hydroxybenzotriazole and in the presence or absence of an agent promoting peptide synthesis via the formation of a mixed anhydride such as risobutylchloroformate, at a temperature between -20 ° C. and the boiling temperature of the solvent.
• a mixed anhydride such as risobutylchloroformate
• the derivatives 6 are commercially available or synthesized, according to the methods known to those skilled in the art, from the appropriate commercial precursors.
• R2 represents a (Ci-C 6) alkyl substituted with one or more groups selected from hydroxy or the group (C r C 6) alkoxy
• these products can be obtained from products in which R2 is heterocycle (C 1 -C 6 ) alkyl group by deprotection of this group according to methods known to those skilled in the art and, more specifically, in an inert solvent such as tetrahydrofuran in the presence of an acid such as the acid 1N hydrochloric acid in diethyl ether at a temperature in the region of 20 ° C.
• 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 racemates, for example by chromatography on a chiral column according to PIRKLE WH et al., Asymmetric Synthesis, vol. 1, Academy Press (1983) or by salt formation or synthesis from chiral precursors.
• the diastereoisomers can be prepared according to known conventional methods (crystallization, chromatography or from chiral precursors).
• the present invention also relates to the process for preparing the intermediates.
• Example 1 3 - ( ⁇ 1 - [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl ⁇ -methanesulfonyl-amino) -N- (2,2-dimethyl-1,3-dioxol) 4-ylmethyl) -benzamide (Compound ⁇ ° 3)
• the dextrorotatory enantiomer was eluted in second position during the separation carried out in Example 2.
• concentration of the co-solvent 0.342 g of (+) - 3 - ( ⁇ 1- [bis- (4-chloro) phenyl) -methyl] -azetidin-3-yl ⁇ -methanesulfonylamino) -N- (2,2-dimethyl-1,3-dioxolan-4-ylmethyl) -benzamide as a white powder.
• the reaction medium is poured into an aqueous solution of sodium hydrogencarbonate. After decantation, the aqueous phase is extracted with ethyl acetate.
• N- (2,2-dimethyl-1,3-dioxolan-4-ylmethyl) -benzamide, 4 cm 3 of tetrahydrofuran and 2 cm 3 of a 1N hydrochloric acid solution in ethyl ether are stirred at a temperature of temperature close to 20 0 C for 5 hours.
• the reaction medium is poured into an aqueous solution of sodium hydrogencarbonate. After decantation, the aqueous phase is extracted with ethyl acetate.
• the organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (5 kPa).
• reaction medium is taken up in 40 cm 3 of dichloromethane and 10 cm 3 of a saturated aqueous sodium chloride solution. After decantation, the organic phase is dried over magnesium sulfate, filtered on sintered glass and then concentrated to dryness under reduced pressure to give 0.39 g of a meringue.
• the crude reaction product is purified by flash chromatography on a cartridge of 30 g of Merck silica (particle size: 15-40 ⁇ m, elution gradient: dichloromethane / methanol 98/2 to 95/5).
• the hydrochloride salt thus obtained undergoes the same treatment as above: stirring for 10 minutes in 0.7 cm 3 of dichloromethane and 0.1 cm 3 of a 2M hydrochloric acid solution in diethyl ether, concentration in vacuo, trituration twice with pentane, drying in an oven under vacuum at a temperature of 40 0 C for 2 hours 30 minutes. 99 mg of 3 - ( ⁇ 1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl ⁇ -methanesulfonyl-amino) -N- (2-hydroxyethyl) hydrochloride are thus obtained. benzamide as a yellowish meringue.
• Example 7 (-) - 3 - ( ⁇ 1- [bis- (4-Chloro-phenyl) -methyl] -azetidin-3-yl ⁇ -methanesulfonylamino) -N- (2-hydroxy-1-methyl); ethyl) -benzamide (Compound ⁇ ° 8)
• To a suspension of 0.5 g of 3 - [ ⁇ 1- [bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl ⁇ -methylsulfonyl-amino] benzoic acid in 10 cm 3 of dichloromethane is 0.227 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added.
• the reaction medium is stirred at a temperature in the region of 20 ° C. for 20 hours and is then filtered on sintered glass by rinsing with dichloromethane. The filtrate is concentrated to dryness in vacuo to give 0.73 g of a white meringue which is purified by flash chromatography on a cartridge of 70 g of Merck silica (particle size: 15-40 ⁇ m, eluent: ethyl acetate / methanol 98/2).
• Table 1 which follows illustrates the chemical structures (I) and the physical properties (Table IA) of some examples of compounds according to the invention.
• Table 1 which follows illustrates the chemical structures (I) and the physical properties (Table IA) of some examples of compounds according to the invention.
• Table 1 which follows illustrates the chemical structures (I) and the physical properties (Table IA) of some examples of compounds according to the invention.
• Table 1 which follows illustrates the chemical structures (I) and the physical properties (Table IA) of some examples of compounds according to the invention.
• Table 1 which follows illustrates the chemical structures (I) and the physical properties (Table IA) of some examples of compounds according to the invention.
• Table 1 which follows illustrates the chemical structures (I) and the physical properties (Table IA) of some examples of compounds according to the invention.
• Table 1 which follows illustrates the chemical structures (I) and the physical properties (Table IA) of some examples of compounds according to the invention.
• Table 1 which follows illustrates the chemical structures (I) and the physical properties (Table IA)
• B represents the product obtained in base form.
• 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.
• the IC 50 values are between 0.001 ⁇ M and 2 ⁇ M.
• Compounds Nos . 5, 7, 9, 18, 21, 26, 30, 36 and 47 have shown IC 50's respectively 0.022; 0.061; 0.015; 0.006; 0.038; 0.02; 0.066; 0.016 and 0.072 ⁇ M.
• Other tests consisting in measuring the in vivo activity of the compounds of the invention were carried out.
• a new measurement of the rectal temperature of the mice is performed and the racemic CP55,940 agonist (1RS, 3RS, 4RS-3- [hydroxy-2- (1,1-dimethylheptyl) phenyl] -4- ( 3-hydroxypropyl) cyclohexan-1-ol) (1.25 mg / kg ip in cremophor 10%) is administered.
• the rectal temperature is measured again. The results are expressed in% relative to the control batch injected with CP 55 940 (minimum temperature) and to the vehicle batch without treatment with CP55.940 (maximum temperature).
• Compounds Nos . 9 and 25 showed a percent inhibition of 30% and 18%, respectively, at 3 mg / kg / kg.
• 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 (CO 2 / O 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 CB 1 cannabinoid receptors.
• the compounds of formula (I) are useful as psychotropic drugs, especially for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders , obsessive disorders, psychoses in general, schizophrenia, attention deficit hyperactivity disorder (ADHD) in hyperkinetic children (BDM) and for the treatment of disorders related to the use of psychotropic substances, including in the case of substance abuse and / or substance dependence, including alcohol dependence and nicotine addiction and withdrawal disorders.
• ADHD attention deficit hyperactivity disorder
• BDM hyperkinetic children
• the compounds of formula (I) according to the invention can be used as medicaments for the treatment of migraine, stress, psychosomatic diseases, panic attacks, epilepsy, movement disorders , especially dyskinesias or Parkinson's disease, tremors and dystonia.
• the compounds of formula (I) according to the invention can 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 (I) 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: especially virus, 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, glaucoma, fertility disorders, inflammatory phenomena, inflammatory diseases, diseases of the immune system, especially autoimmune and neuroinflammatory such as rheumatoid arthritis, reactive
• 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: Compound according to the invention 50.0 mg
• 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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• 2008
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