Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
  • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/12—Antidiarrhoeals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/32—Alcohol-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/34—Tobacco-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/36—Opioid-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to substituted N - [(4,5-diphenyl-2-thienyl) methyl] amine derivatives, their preparation and their therapeutic application.
• Diphenylpyrazole derivatives having an affinity for the CB 1 receptors of cannabinoids have been described in particular in patents US 5,624,941, EP 0 576 357, EP 0 656 354 and EP 1 150 961 and WO 2005/073 197.
• Thiophene-2-carboxamide derivatives are described in international application WO 2005/035488.
• - X is -C-, -CN (R S) 5 -CN (R) -;
• a non-aromatic (C 3 -C 12) carbocyclic radical which is unsubstituted or substituted one or more times with a (C 1 -C 4) alkyl
• a phenethyl which is unsubstituted or mono- or disubstituted on the phenyl by substituents independently selected from a halogen atom, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a trifluoromethyl radical;
• R2 represents a hydrogen atom or a (C1-C3) alkyl
• R 3 represents an unsubstituted or mono-, di- or trisubstituted phenyl by substituents independently chosen from a halogen atom, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a trifluoromethyl radical or a group S (O) n AIk;
• R 4 represents an unsubstituted or mono-, di- or trisubstituted phenyl by substituents independently selected from a halogen atom, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a trifluoromethyl radical or a group S (O) n AIk;
• R 5 represents a hydrogen atom or a (C 1 -C 3) alkyl
• n 0, 1 or 2;
• Alk represents a (C 1 -C 4) alkyl.
• the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures, form part of the invention.
• the compounds of formula (I) may exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.
• halogen atom is meant a bromine, chlorine, fluorine or iodine atom.
• (Ci-C3) alkyl or respectively (Ci-C4) alkyl, or (Cg-C ⁇ aIkVIe 5 is a linear or branched alkyl radical of one to three carbon atoms or respectively of one to four carbon atoms, or from six to twelve carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl radicals.
• alkoxy is meant a linear or branched alkoxy radical of one to four carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, tert-butoxy.
• cycloalkyl is meant a cyclic alkyl group of 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
• C3-C12 non-aromatic carbocyclic radicals include mono or polycyclic radicals, fused, bridged or spiranic.
• Monocyclic radicals include cycloalkyls for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
• the fused, bridged or spiro di- or tricyclic radicals include, for example, the norbornyl, bornyl, isobornyl, noradamantyl, adamantyl, spiro [5.5] undecyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, bicyclo radicals. [3.1.1] heptyl, bicyclo [2.2.1] hept-5-en-2-yl.
• X represents a group -C-, -CN (R 5 );
• R represents: a (C 6 -C 12 ) alkyl
• (C3-C7) cycloalkyl unsubstituted or substituted one or more times with a (C 1 -C 3) alkyl group; . a (C 3 -C 7) cycloalkylmethyl which is unsubstituted or substituted one or more times on the carbocycle by a (C 1 -C 3) alkyl; . mono-, di- or tri-substituted phenyl with substituents independently selected from halogen, (C1-C4) alkoxy, cyano, trifluoromethyl, trifluoromethoxy, S (O) n AIk, a (C 1 -C 4) alkylcarbonyl group, a phenyl;
• R2 represents a hydrogen atom or a (C1-C3) alkyl
• R 3 represents an unsubstituted or mono-, di- or trisubstituted phenyl by substituents independently chosen from a halogen atom, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a trifluoromethyl radical or a group S (O) n AIk;
• R 4 represents an unsubstituted or mono-, di- or trisubstituted phenyl by substituents independently selected from a halogen atom, a (C 1 -C 4) alkyl, a (C 1 -C 4) alkoxy, a trifluoromethyl radical or a group S (O) n AIk;
• R 5 represents a hydrogen atom or a (C 1 -C 3) alkyl
• n 0, 1 or 2;
• Alk represents a (C 1 -C 4) alkyl; in the basic state and in the state of hydrate or solvate.
• a first group of compounds consists of the compounds for which:
• X represents a group -CO-, a group -CONH- or a group -CSNH-;
• cycloheptyl 1-methylcyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; 1-methylcyclohexyl; a bicyclo [2.2.1] hept-2-yl; bicyclo [2.2.1] hept-5-en-2-yl;
• benzhydryl benzhydrylmethyl
• R.2 represents a hydrogen atom or a methyl
• R3 represents a 4-bromophenyl; 4-chlorophenyl; 2,4-dichlorophenyl; 4-methoxyphenyl;
• R4 represents a 4-chlorophenyl; 2,4-dichlorophenyl; A-methoxyphenyl; as well as their hydrates or their solvates.
• X represents a group -CO-, a group -CONH- or a group -CSNH-;
• cycloheptyl 1-methylcyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; 1-methylcyclohexyl; a bicyclo [2.2.1] hept-2-yl; bicyclo [2.2.1] hept-5-en-2-yl; . cyclohexylmethyl; cycloheptylmethyl; bicyclo [2.2.1] hept-2-yl methyl; .
• (trifluoromethyl) phenyl 4- (trifluoromethoxy) phenyl; 3-acetylphenyl; a biphenyl-2-yl; biphenyl-4-yl; 1,3-benzodioxol-5-yl; A-phenoxyphenyl; 4- (1H-pyrrol-1-yl) phenyl; . a 2-fluorobenzyl; 3-fluorobenzyl; 4-fluorobenzyl; an A-
• - R.2 represents a hydrogen atom or a methyl
• R3 represents a 4-bromophenyl; 4-chlorophenyl; 2,4-dichlorophenyl; 4-methoxyphenyl;
• R4 represents a 4-chlorophenyl; 2,4-dichlorophenyl; 4-methoxyphenyl; as well as their hydrates or their solvates.
• X represents a group -CO- or a group -CONH-
• R2 represents a hydrogen atom or a methyl
• R3 represents a 4-bromophenyl; 4-chlorophenyl; 2,4-dichlorophenyl;
• R4 represents a 4-chlorophenyl; 2,4-dichlorophenyl; as well as their hydrates or their solvates.
• leaving group is meant, in what follows, a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with departure from an electronic pair. This group can be easily replaced by another group when of a substitution reaction, for example.
• Such leaving groups are, for example, halogens or an activated hydroxy group such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. Examples of leaving groups as well as references for their preparation are given in "Advances in Organic Chemistry", J. March, 3 rd Edition, Wiley Interscience, 1985, p. 310-316.
• the compounds of formula (I) can be prepared according to a process which is characterized in that a compound of formula:
• HaICOOAr (IV) in which HaI represents a halogen atom and Ar represents a phenyl or a 4-nitrophenyl to obtain an intermediate compound of formula:
• a compound of formula (I) in which R 5 represents a (C 1 -C 3) alkyl group can be prepared by an alkylation reaction on the corresponding compound of formula (I) in which R 5 represents a hydrogen atom .
• reaction is carried out in the presence of a coupling agent used in peptide chemistry such as 1,3-dicyclohexylcarbodiimide or hexafluorophosphate.
• a coupling agent used in peptide chemistry such as 1,3-dicyclohexylcarbodiimide or hexafluorophosphate.
• benzotriazol-1-yloxytris (dimethylamino) phosphonium or benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate or 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyl uronium tetrafluoroborate; in the presence of a base such as triethylamine, N, N-diisopropylethylamine or 4-dimethylaminopyridine, in a solvent such as dichloromethane, dichloroethane, NN-dimethylformamide or tetrahydrofuran at a temperature of between -10 ° C and the reflux temperature of the solvent.
• a base such as triethylamine, N, N-diisopropylethylamine or 4-dimethylaminopyridine
• the acid chloride As the functional derivative of the acid (III) it is possible to use the acid chloride, the anhydride, a mixed anhydride, a C 1 -C 4 alkyl ester in which the alkyl is straight or branched, an activated ester, for example the p-nitrophenyl ester.
• a solvent such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), or an amide (N, N-dimethylformamide for example) under an atmosphere inert, at a temperature between 0
• One variant consists in preparing the mixed anhydride of the acid of formula (III) by reacting ethyl chloroformate with the acid of formula (III), in the presence of a base such as triethylamine, and in doing so react with the compound of formula (II) in a solvent such as dichloromethane under an inert atmosphere at room temperature in the presence of a base such as triethylamine.
• a base such as triethylamine
• a solvent such as dichloromethane
• the compounds of formula (I) in which -X- represents a group -CON (Rs) -P R reaction of a compound of formula (II) can be prepared with a compound of formula ClCON (Rs ) Ri (VHI) in the presence of a base such as triethylamine, in a solvent such as dichloromethane and at a temperature between 0 ° C and room temperature.
• a base such as triethylamine
• a base such as sodium hydride
• the compounds of formula (I) thus obtained may subsequently be separated from the reaction medium and purified by conventional methods, for example by crystallization or chromatography.
• R3 and R4 are as defined for a compound of formula (I) and Y represents a leaving group as defined above, preferably a halogen atom or an activated hydroxy group such as a methanesulfonate group, benzene sulfonate, p-toluenesulfonate or triflate, with a compound of formula:
• the reaction is carried out in a solvent such as N, N-dimethylformamide, acetonitrile, dichloromethane, toluene or propan-2-ol, and in the presence or in the presence of the absence of a base.
• a base is chosen from organic bases such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine.
• the reaction is carried out at a temperature between 0 ° C. and the reflux temperature of the solvent.
• R3 and R4 are as defined for a compound of formula (I).
• the reduction is effected by means of a reducing agent such as borane in a solvent such as tetrahydrofuran, at a temperature between room temperature and the reflux temperature of the solvent, followed by acid hydrolysis.
• a compound of formula (XII) when in a compound of formula (IX), Y represents a halogen atom, a compound of formula (XII) is treated with a halogenating agent such as PCI5, PBrc, HBr or BBr3, in a solvent such as dichloromethane and at a temperature between -10 ° C and room temperature.
• a halogenating agent such as PCI5, PBrc, HBr or BBr3
• a solvent such as dichloromethane
• Y represents a methanesulphonate, a benzenesulphonate, a p-toluenesulphonate or a trifluoromethanesulphonate
• reacting a compound of formula (XII) with a sulfonyl chloride of formula W-SO2-Cl wherein W is methyl, phenyl, p-tolyl or trifluoromethyl is carried out in the presence of a base such as triethylamine, pyridine or N 5 N-diisopropylethylamine, in a solvent such as dichloromethane or toluene and at a temperature of between -20 ° C. and the reaction temperature. reflux of the solvent.
• R3 and R4 are as defined for a compound of formula (I), with ammonia.
• R3 and R4 are as defined for a compound of formula (I) and Z is hydroxy or (C1-C2) alkoxy.
• the reaction is carried out in the presence of a reducing agent such as sodium borohydride or lithium aluminum hydride, in a solvent such as tetrahydrofuran, and at a temperature of between -20 ° C. and the temperature room.
• a reducing agent such as sodium borohydride or lithium aluminum hydride
• a solvent such as tetrahydrofuran
• step al of SCHEME I the reaction of a compound of formula (XV) with a compound of formula (XVI) is carried out in the presence of an alkali metal salt of hexamethyldisilazane, such as sodium salt, for example in a solvent such as tetrahydrofuran and at a temperature ranging from -70 ° C. to 0 ° C.
• an alkali metal salt of hexamethyldisilazane such as sodium salt
• step b1 the compound of formula (XVII) thus obtained is reacted with the mixture N, N-dimethylformamide / phosphorus oxychloride, in a solvent such as 1,2-dichloroethane and at a temperature between - 10 0 C and the reflux temperature of the solvent.
• the compound (XVIII) thus obtained is reacted in step ci with the compound (XIX), in the presence of a base such as 1,8-diazabicyclo [5,4 5 O] undec-7-ene, in a solvent such as acetonitrile and at a temperature between room temperature and the reflux temperature of the solvent.
• DIPEA diisopropylethylamine
• Silica H silica gel 60 H marketed by Merck (DARMSTAD)
• Buffer solution pH 2: solution of 16.66 g of KHSO4 and 32.32 g of K2SO4 in 1 liter of water.
• the compounds according to the invention are analyzed by LC / UV / MS coupling (liquid chromatography / UV detection / mass spectrometry).
• the molecular peak (MH) and the retention time (tr) are measured in minutes.
• the eluent is composed as follows:
• solvent A 0.005% trifluoroacetic acid (TFA) in water at pH 3.15;
• solvent B 0.005% of TFA in acetonitrile.
• the eluent is composed as follows:
• solvent A 10 mM ammonium acetate (ACONH4) in water at pH 7;
• Method 3 An XTerra MS Cl 8 column of 2.1 x 30 mm is used; 3.5 ⁇ m; at 30 ° C., flow rate 0.8 ml / minute.
• the eluent is composed as follows:
• solvent A 0.025% trifluoroacetic acid (TFA) in water
• solvent B 0.025% of TFA in acetonitrile
• UV detection is performed by an iodine bar detector between 210 and 400 nM and ESI positive chemical ionization mass detection.
• reaction mixture is poured into an ice / 1 liter mixture of 2N HCl, extracted with ether, the organic phase washed with a solution saturated with NaHCO 3, with water, dried over Na 2 SO 4 and the solvent evaporated under vacuum to a volume of 200 ml, pentane is added and the crystalline product formed is filtered off. 80 g of the expected compound are obtained.
• reaction mixture is poured into an ice / 1 liter mixture of 2N HCl, the organic phase is washed with a saturated solution of NaHCO 3, at 100 ° C. water, extracted with ether, dried the organic phase over Na 2 SO 4 and evaporated the solvent in vacuo. The residue is taken up in pentane and the crystalline product formed is filtered off. 70 g of the expected compound are obtained.
• a suspension of 1.43 g of lithium aluminum hydride in 100 ml of THF is cooled to -20 ° C. and a solution of 10 g of the compound obtained in Preparation 3.1 in 20 ml is added dropwise. THF and leave stirring for 1 hour at -20 ° C.
• the reaction mixture is hydrolyzed by adding water until an white cloud, filter the mineral salts on Celite and concentrate the filtrate under vacuum. The residue is taken up in pentane, stirred and the crystalline product formed. 7 g of the expected compound are obtained.
• a mixture of 8 g of the compound obtained in Preparation 6.2 and 6 ml of thionyl chloride in 80 ml of 1,2-dichloroethane is heated at 80 ° C. for 3 hours.
• the reaction mixture is concentrated under vacuum, the residue is taken up in toluene and the solvent is evaporated off under vacuum.
• the acid chloride thus formed is taken up in 50 ml of DCM, this solution is added dropwise to 21 ml of a 2M solution of ammonia in MeOH and the mixture is left stirring for 3 hours at RT.
• the reaction mixture is concentrated under vacuum, the residue is taken up in an ether / water mixture and the precipitate formed is filtered off with suction. 5.3 g of the expected compound are obtained.
• reaction mixture is concentrated under vacuum, the residue is taken up in a 0.5N HCl solution and extracted with ether / AcOEt. The organic phase is dried over Na 2 SC 4 and the solvents are evaporated under vacuum. The residue is taken up in an ether / iso ether mixture and the precipitate formed is filtered off with suction. 6 g of the expected compound are obtained.
• the carboxylic acids of formula (III) are dissolved in DMF at a concentration of 0.25 M in the presence of 3 equivalents of DIPEA.
• 120 ⁇ l of these solutions are placed and 120 ml of a TBTU solution in DMF are added at a concentration of 0.25 M.
• 300 ⁇ l of a solution containing the compound of corresponding formula (II) in DMF at the concentration of 0.1 M and 3 equivalents of DIPEA.
• the plates are stirred at RT for 16 hours and then evaporated.
• the products formed in each well are dissolved by addition of 500 ⁇ l of AcOEt, 400 ⁇ l of 0.1 M Na 2 CO 3 are added and the plates are agitated.
• the compounds of formula (II) in DMF are dissolved at a concentration of 0.1 M in the presence of 3 equivalents of DIPEA. 300 ⁇ l of these solutions are added to each well of 2 ml and 120 ⁇ l of a solution containing the isocyanate compound of formula (VII) or the corresponding isothiocyanate compound of formula (XX) in THF at a concentration of 0.25 are added. M. The plates are shaken at RT for 16 hours. The products formed in each well are dissolved by addition of 500 ⁇ l of 1 AcOEt, 400 ⁇ l of 0.1 M Na 2 CO 3 are added and the plates are shaken.
• method represents one of the analytical methods used to determine the molecular peak MH and the retention time as described above.
• the compounds of formula (I) have a very good in vitro affinity (IC50 ⁇ 5.10 " M) for cannabinoid CB 1 receptors, under the experimental conditions described by M. Rinaldi-Carmona et al (FEBS Letters, 1994, 350, 240-244).
• the toxicity of the compounds of formula (I) is compatible with their use as a medicament.
• the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid, or a solvate or a hydrate of compound of formula (I).
• the compounds according to the invention can be used in humans or animals, in the treatment or prevention of diseases involving cannabinoid CB1 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-compulsive disorder, psychosis in general, schizophrenia, attention deficit and hyperactivity disorder (ADHD) in hyperkinetic children (BDM), and the treatment of disorders related to the use of psychotropic substances, particularly in the case of substance abuse and / or substance dependence, including alcohol dependence and nicotine addiction.
• psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders , obsessive-compulsive disorder, psychosis in general, schizophrenia, attention deficit and hyperactivity disorder (ADHD) in hyperkinetic children (BDM), 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.
• the compounds of formula (I) according to the invention can be used as medicaments for the treatment of migraine, stress, psychosomatic diseases, panic attacks, epilepsy, movement disorders , especially dyskinesias or Parkinson's disease, tremors and dystonia.
• the compounds of formula (I) according to the invention can also be used as medicaments in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementias, of Alzheimer's disease, as well as in the treatment of disturbances of attention or alertness.
• the compounds of formula (I) may be useful as neuroprotective agents, in the treatment of ischemia, head trauma and the treatment of neurodegenerative diseases: including chorea, Huntington's chorea, Tourrette's syndrome.
• the compounds of formula (I) according to the invention can be used as medicaments in the treatment of pain: neuropathic pain, acute peripheral pain, chronic pain of inflammatory origin.
• the compounds of formula (I) according to the invention can be used as medicaments in the treatment of appetite disorders, palatability (for sugars, carbohydrates, drugs, alcohols or any appetizing substance) and / or conduits. for the treatment of obesity or bulimia as well as for the treatment of type II diabetes or non-insulin-dependent diabetes 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, chronic cirrhosis of the liver, fatty liver, steatohepatitis, asthma, Raynaud's syndrome, glaucoma , disorders of fertility, premature termination of pregnancy, inflammatory phenomena, diseases of the immune system, especially autoimmune and neuroinflammatory such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, multiple sclerosis in plaque, infectious and viral diseases such as encephalitis, stroke and as drugs for chemotherapy. anticancer therapy, for the treatment of Guillain-Barré syndrome and for the treatment of osteoporosis.
• the compounds of formula (I) are particularly useful for the treatment of psychotic disorders, in particular schizophrenia, attention deficit and hyperactivity disorders (ADHD) in hyperkinetic children (BDM); for the treatment of appetite and obesity disorders; for the treatment of memory and cognitive deficits; for the treatment of alcohol dependence, nicotine addiction, ie for alcohol withdrawal and smoking cessation.
• psychotic disorders in particular schizophrenia, attention deficit and hyperactivity disorders (ADHD) in hyperkinetic children (BDM); for the treatment of appetite and obesity disorders; for the treatment of memory and cognitive deficits; for the treatment of alcohol dependence, nicotine addiction, ie for alcohol withdrawal and smoking cessation.
• 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, a solvate or hydrate 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, solvate or hydrate, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.
• 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 dose of active ingredient administered per day can reach 0.01 to 100 mg / kg, in one or more doses, preferably 0.02 to 50 mg / kg.
• the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
• the present invention also relates to a method of treatment of the pathologies indicated above which comprises administering to a patient an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt thereof or hydrates or solvates thereof.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Diabetes (AREA)
• Addiction (AREA)
• Psychiatry (AREA)
• Immunology (AREA)
• Hematology (AREA)
• Endocrinology (AREA)
• Physical Education & Sports Medicine (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Rheumatology (AREA)
• Obesity (AREA)
• Pain & Pain Management (AREA)
• Urology & Nephrology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Oncology (AREA)
• Communicable Diseases (AREA)
• Hospice & Palliative Care (AREA)
• Psychology (AREA)
• Pulmonology (AREA)
• Reproductive Health (AREA)
• Ophthalmology & Optometry (AREA)
• Child & Adolescent Psychology (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=34955350

Family Applications (1)

Country Status (16)

Families Citing this family (15)

Family Cites Families (14)

• 2005
  • 2005-02-09 FR FR0501366A patent/FR2881744B1/fr not_active Expired - Fee Related
• 2006
  • 2006-02-01 CA CA002596613A patent/CA2596613A1/fr not_active Abandoned
  • 2006-02-01 WO PCT/FR2006/000219 patent/WO2006084975A1/fr active Application Filing
  • 2006-02-01 MX MX2007009439A patent/MX2007009439A/es not_active Application Discontinuation
  • 2006-02-01 EP EP06709212A patent/EP1858872A1/de not_active Withdrawn
  • 2006-02-01 RU RU2007133602/04A patent/RU2007133602A/ru not_active Application Discontinuation
  • 2006-02-01 AU AU2006212162A patent/AU2006212162A1/en not_active Abandoned
  • 2006-02-01 KR KR1020077020475A patent/KR20070115941A/ko not_active Application Discontinuation
  • 2006-02-01 JP JP2007554591A patent/JP4823236B2/ja not_active Expired - Fee Related
  • 2006-02-01 BR BRPI0606942-8A patent/BRPI0606942A2/pt not_active Application Discontinuation
  • 2006-02-01 CN CNA2006800044183A patent/CN101128451A/zh active Pending
  • 2006-02-07 AR ARP060100424A patent/AR052898A1/es unknown
  • 2006-02-08 UY UY29366A patent/UY29366A1/es not_active Application Discontinuation
  • 2006-02-08 TW TW095104263A patent/TW200639160A/zh unknown
• 2007
  • 2007-08-01 US US11/832,162 patent/US7687537B2/en not_active Expired - Fee Related
  • 2007-08-02 IL IL185035A patent/IL185035A0/en unknown
• 2010
  • 2010-02-08 US US12/701,887 patent/US20100137402A1/en not_active Abandoned

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events