[go: up one dir, main page]

WO2007138050A1 - Soufre contenant des dérivés de pyrazole en tant qu'antagonistes de récepteurs cannabinoïdes cb1 - Google Patents

Soufre contenant des dérivés de pyrazole en tant qu'antagonistes de récepteurs cannabinoïdes cb1 Download PDF

Info

Publication number
WO2007138050A1
WO2007138050A1 PCT/EP2007/055192 EP2007055192W WO2007138050A1 WO 2007138050 A1 WO2007138050 A1 WO 2007138050A1 EP 2007055192 W EP2007055192 W EP 2007055192W WO 2007138050 A1 WO2007138050 A1 WO 2007138050A1
Authority
WO
WIPO (PCT)
Prior art keywords
compounds
disorders
general formula
compound
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2007/055192
Other languages
English (en)
Inventor
Josephus H.M. Lange
Cornelis G. Kruse
Bernard J. Van Vliet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Healthcare Products BV
Original Assignee
Solvay Pharmaceuticals BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EA200870606A priority Critical patent/EA015107B1/ru
Priority to MX2008015272A priority patent/MX2008015272A/es
Priority to EP07729614A priority patent/EP2029548A1/fr
Priority to BRPI0711902-0A priority patent/BRPI0711902A2/pt
Priority to CA002650622A priority patent/CA2650622A1/fr
Priority to JP2009512578A priority patent/JP2009538874A/ja
Application filed by Solvay Pharmaceuticals BV filed Critical Solvay Pharmaceuticals BV
Priority to AU2007267097A priority patent/AU2007267097A1/en
Publication of WO2007138050A1 publication Critical patent/WO2007138050A1/fr
Priority to IL194902A priority patent/IL194902A0/en
Anticipated expiration legal-status Critical
Priority to NO20085035A priority patent/NO20085035L/no
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic 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
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/22—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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic 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
    • A61P3/04—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
    • A61P3/08—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
    • A61P31/04—Antibacterial agents
    • 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
    • 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

  • Example 2 General aspects of syntheses 1 1
  • Example 3 Syntheses of compounds of the invention 14
  • Example 4 Pharmacological methods 19
  • the present invention relates to sulphur containing pyrazole derivatives, and their S-oxidized active metabolites, as selective cannabinoid CB 1 receptor antagonists having a high CB 1 ZCB 2 receptor subtype selectivity, to methods for the preparation of these compounds, to novel intermediates useful for the synthesis of said pyrazole derivatives, to pharmaceutical compositions comprising one or more of these pyrazole derivatives as active ingredients, as well as to the use of these pharmaceutical compositions for the treatment of psychiatric and neurological disorders.
  • the compounds have the general formula (I)
  • CB 1 receptor antagonists in particular SR141716A, now known as rimonabant, and their potential therapeutic applications, have been the subject of several reviews (Boyd, 2005; Sorbera, 2005; Carai, 2005; Lange, 2004, 2005; Hertzog, 2004; Smith, 2005; Thakur, 2005; Padgett, 2005; Muccioli, 2005, 2006; Reggio, 2003; Adam, 2006).
  • the abovementioned patent applications and articles disclose a number of CB 1 ZCB 2 receptor subtype selective receptor antagonists.
  • Cannabinoid (CB) receptors are part of the endocannabinoid system which is involved in neurological-, psychiatric- cardiovascular-, gastrointestinal-, reproductive- and eating disorders as well as in and cancer (De Petrocellis, 2004; Di Marzo, 2004; Lambert, 2005; Vandevoorde, 2005; Centonze, 2007).
  • CB 1 receptor modulators have several potential therapeutic applications such as medicaments for treating psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetence, drug dependence, neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, septic shock, glaucoma, diabetes, cancer, emesis, nausea, gastrointestinal disorders, gastric ulcers, diarrhoea, sexual disorders, impulse control disorders and cardiovascular disorders.
  • pain disorders including neuropathic pain disorders, septic shock, glaucoma, diabetes,
  • CB 2 receptors occur predominantly in the immune system (spleen, tonsils, immune cells) as well as in microglial cells and astrocytes and have recently also been found in the central nervous system brainstem and cerebellum) (Van Sickle, 2005; Ashton, 2006).
  • Potent CB 1 receptor modulators having low CB 2 receptor affinity are advantageous compounds as compared to non-selective or less selective cannabinoid receptor modulators as they will be devoid of undesired CB 2 receptor mediated side-effects, such as immunologic side-effects or inflammatory related side- effects or effects on neuropathic pain perception.
  • the goal of the present invention was to develop further orally active CB 1 receptor antagonists with a high CB 1 ZCB 2 receptor subtype selectivity.
  • Certain pyrazole derivatives of formula (I), in which X (see below) represents a CH 2 group, are known to be CB 1 receptor antagonists. Surprisingly, it was found that replacement of this CH 2 group by a sulphur atom results in compounds that not only are CB 1 ZCB 2 receptor subtype selective CB 1 receptor antagonists, but that are more potent than their non-sulphur containing analogs when tested orally in an in vivo CB ⁇ receptor mediated pharmacological assay.
  • Cytochrome P450 is an important endogenous enzyme which is involved in such metabolic oxidations of alkyl sulfides into corresponding sulfoxides and sulfones (Denisov, 2005; Nnane, 2001).
  • the present invention relates to compounds of the general formula (I):
  • - R 1 represents H, Cl or Br
  • - Y represents a methyl or an ethyl group
  • - n can have the value 1 , 2 or 3, and tautomers, stereoisomers, prodrugs and N-oxides thereof, and isotopically-labelled compounds of formula (I), as well as pharmacologically acceptable salts, hydrates and solvates of said compounds of formula (I) and its tautomers, stereoisomers, prodrugs, N-oxides or isotopically-labelled analogs.
  • All sulfoxides within this invention contain a centre of chirality.
  • the invention relates to racemates, mixtures of diastereomers as well as the individual stereoisomers of the compounds having formula (I).
  • the invention also relates to the E isomer, Z isomer and E/Z mixtures of compounds having formula (I).
  • the invention particularly relates to compounds of the general formula (I) in which R 1 and R 2 represent Cl, Y represents a methyl group and X has t he meanings as given above, n represents 1 or 2.
  • the compounds according to the invention are suitable for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, in particular juvenile obesity and drug induced obesity, addiction, appetence, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy, cranio-cerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea
  • the cannabinoid receptor modulating activity of the compounds of the invention makes them particularly useful in the treatment of obesity, juvenile obesity and drug induced obesity, especially when used in combination with lipase inhibitors.
  • Specific examples of compounds which can be used in such combination preparations are (but not restricted to) the synthetic lipase inhibitor orlistat, lipase inhibitors isolated from micro organisms such as lipstatin (from
  • Streptomyces toxytricini Streptomyces toxytricini
  • ebelactone B from Streptomyces aburaviensis
  • synthetic derivatives of these compounds as well as extracts of plants known to possess lipase inhibitory activity, for instance extracts of Alpinia officinarum or compounds isolated from such extracts like 3- methylethergalangin (from A. officinarum).
  • the invention also embraces: a pharmaceutical composition for treating, for example, a disorder or condition treatable by blocking cannabinoid-CB-i receptors, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; a method of treating a disorder or condition treatable by blocking cannabinoid-CB-i receptors, the method comprising administering to a mammal in need of such treating a compound of formula (I) or a pharmaceutically acceptable salt thereof; a pharmaceutical composition for treating, for example, a disorder or condition selected from the group consisting of the disorders listed herein; a method of treating a disorder or condition selected from the group consisting of the disorders listed herein, the method comprising administering to a mammal in need of such treating a compound of formula (I) or a pharmaceutically acceptable salt thereof; a pharmaceutical composition for treating the disorders listed herein, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;
  • the invention also provides the use of a compound or salt according to formula (I) for the manufacture of a medicament.
  • the invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for treating one or more of the conditions listed.
  • a compound of the invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for treating one or more of the conditions listed.
  • Such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the compounds of the invention.
  • the invention also provides compounds, pharmaceutical compositions, kits and methods for treating the disorders listed herein, the methods comprising administering to a patient in need of such treating a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds of the invention possess cannabinoid-CB-i antagonistic act ivity.
  • the antagonizing activities of the compounds of the invention is readily demonstrated, for example, using one or more of the assays described herein or known in the art.
  • the invention also provides methods of preparing the compounds of the invention and the intermediates used in those methods.
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
  • the molecule can have additional asymmetric centers. Each such asymmetric center will independently produce two optical isomers. All of the possible optical isomers and diastereomers, in mixtures and as pure or partially purified compounds, belong to this invention. The present invention comprehends all such isomeric forms of these compounds.
  • Formula (I) shows the structure of the class of compounds without preferred stereochemistry. The independent syntheses of these diastereomers, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed therein.
  • Racemic mixtures of the compounds can be separated into the individual enantiomers by methods well-known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling often consists of the formation of salts using an enantiomerically pure acid or base, for example (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases: Methods well-known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well-known in the art.
  • Cis and trans isomers of the compound of formula (I), or a pharmaceutically acceptable salt thereof also belong to the invention, and this also applies to tautomers of the compounds of formula (I) or a pharmaceutically acceptable salt thereof.
  • Some of the crystalline forms for the compounds may exist as polymorphs: as such intended to belong to the invention.
  • some of the compounds may form solvates with water (i.e. hydrates), or common organic solvents. Such solvates also fall within the scope of this invention.
  • 'alkyl' refers to straight or branched saturated hydrocarbon radicals.
  • ⁇ lkyl(Ci.3)' for example, means methyl, ethyl, n-propyl or isopropyl
  • 'alkyl(Ci. 4 )' means 'methyl, ethyl, n- propyl, isopropyl, n-butyl, 2-butyl, isobutyl or 2-methyl-n-propyl'.
  • the term 'aryl' embraces monocyclic or fused bicyclic aromatic or hetero-aromatic groups, including but not limited to furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, imidazo[2,1 -b][1 ,3]thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazinyl, phenyl, indazolyl, indolyl, indolizinyl, isoindolyl, benzo[b]furanyl, 1 ,2,3,4-tetrahydro-naphtyl, 1 ,2,3,4- tetrahydroisoquinolinyl, indanyl, indenyl, benzo[b]thienyl, 2,3
  • 'Halo' or 'Halogen' means chloro, fluoro, bromo or iodo; 'hetero' as in 'heteroalkyl, heteroaromatic' etc. means containing one or more N, O or S atoms, 'heteroalkyl' includes alkyl groups with heteroatoms in any position, thus including N-bound O-bound or S-bound alkyl groups.
  • amino refers to a nitrogen atom that may be either terminal, or a linker between two other groups, wherein the group may be a primary, secondary or tertiary (two hydrogen atoms bonded to the nitrogen atom, one hydrogen atom bonded to the nitrogen atom and no hydrogen atoms bonded to the nitrogen atom, respectively) amine.
  • sulfinyl and sulfonyl as used herein as part of another group respectively refer to an -SO- or an - SO 2 - group.
  • leaving group shall mean a charged or uncharged atom or group that departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.
  • N-oxides of the compounds mentioned above belong to the invention.
  • Tertiary amines may or may not give rise to N-oxide metabolites. The extent to what N-oxidation takes place varies from trace amounts to a near quantitative conversion.
  • N-oxides may be more active than their corresponding tertiary amines, or less active. Whilst N-oxides can easily be reduced to their corresponding tertiary amines by chemical means, in the human body this happens to varying degrees.
  • Some N-oxides undergo nearly quantitative reductive conversion to the corresponding tertiary amines, in other cases conversion is a mere trace reaction, or even completely absent (Bickel, 1969).
  • any compound metabolized in vivo to provide the bioactive agent is a prodrug within the scope and spirit of the application.
  • Prodrugs are therapeutic agents, inactive per se but transformed into one or more active metabolites.
  • the term "administering” shall encompass treating the various disorders described with the compound specifically disclosed, or with a compound that not specifically disclosed, but that converts to the specified compound in vivo after administration to the patient.
  • Prodrugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism and targeting limitations (Bundgaard, 1985; King, 1994; Stella, 2004; Ettmayer, 2004 ; Jarvinen, 2005).
  • Prodrugs i.e. compounds that when administered to humans by any known route, are metabolised to compounds having formula (I), belong to the invention.
  • this relates to compounds with primary or secondary amino or hydroxy groups.
  • Such compounds can be reacted with organic acids to yield compounds having formula (I) wherein an additional group is present that is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl-methylene derivative, an O-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.
  • composition encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts.
  • this term encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the pharmaceutical composition includes enough of the active object compound to produce the desired effect upon the progress or condition of diseases.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • the term 'combination preparation' comprises both true combinations, meaning compounds of the invention and other medicaments physically combined in one preparation such as a tablet or injection fluid, as well as 'kit-of -parts', comprising compounds of the invention and a lipase inhibitor in separate dosage forms, together with instructions for use, optionally with further means for facilitating compliance with the administration of the component compounds, e.g. label or drawings.
  • the pharmacotherapy by definition is simultaneous.
  • the contents of 'kit-of-parts' can be administered either simultaneously or at different time intervals. Therapy being either concomitant or sequential will be dependant on the characteristics of the other medicaments used, characteristics like onset and duration of action, plasma levels, clearance, etc., as well as on the disease, its stage, and characteristics of the individual patient.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the affinity of the compounds of the invention for cannabinoid receptors was determined as described below. From the binding affinity measured for a given compound of formula (I), one can estimate a theoretical lowest effective dose. At a concentration of the compound equal to twice the measured K-value, nearly 100% of the cannabinoid-CBi receptors likely will be occupied by the compound. Converting that concentration to mg of compound per kg of patient yields a theoretical lowest effective dose, assuming ideal bioavailability. Pharmacokinetic, pharmacodynamic, and other considerations may alter the dose actually administered to a higher or lower value. The dosage expediently administered is 0.001 - 1000 mg/kg, preferably 0.1 -100 mg/kg of patient's bodyweight.
  • terapéuticaally effective amount refers to an amount of a therapeutic agent to treat or prevent a condition treatable by administrating a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic, preventative or ameliorative response in a tissue system, animal or human. The effect may include, for example, treating or preventing the conditions listed herein.
  • the precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician (researcher, veterinarian, medical doctor or other clinician), and the therapeutics, or combination of therapeutics, selected for administration. Thus, it is not useful to specify an exact effective amount in advance.
  • pharmaceutically acceptable salt refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well- known in the art. They can be prepared in situ when finally isolating and purifying the compounds of the invention, or separately by reacting them with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids.
  • treatment refers to any treatment of a mammalian, preferably human condition or disease, and includes: (1 ) preventing the disease or condition from occurring in a subject predisposed to the disease, but not yet diagnosed as having it, (2) inhibiting the disease or condition, i.e., arresting its development, (3) relieving the disease or condition, i.e., causing the condition to regress, or (4) stopping the symptoms of the disease.
  • the term “medical therapy” intendeds to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • This bromo derivative (III) wherein R 1 and R 2 have the abovementioned meaning can be treated with a strong base such as n-butyllitium in an inert anhydrous organic solvent such as tetrahydrofuran and subsequently reacted with a sulphur-derived electrophile YSSY wherein Y represents a methyl or ethyl group to afford a compound of general formula (IV) wherein R 1 , R 2 and Y have the abovementioned meaning, R 4 is a hydrogen atom and X represents a sulphur atom.
  • This compound of general formula (IV) can be converted to the corresponding ester of general formula (V) wherein R 1 , R 2 and Y have the abovementioned meaning, R 3 represents a linear C 1-3 alkyl group (methyl, ethyl or n -propyl) and X represents a sulphur atom.
  • This ester of general formula (V) can be oxidised with one molar equivalent of an oxidizing reagent such as meta-chloroperbenzoic acid to give the corresponding sulfinyl analogue.
  • reaction of a compound of general formula (V) with two or more molar equivalents of meta-chloroperbenzoic acid can convert the sulfanyl moiety to the corresponding sulfonyl moiety.
  • the ester of general formula (V) wherein R 1 , R 2 and Y have the abovementioned meaning and X represents a sulfoxide or sulfone moiety can be hydrolysed - preferably under acidic conditions - to give the corresponding carboxylic acid (Vl).
  • a compound of general formula (IV) wherein R 1 R 2 and Y have the abovementioned meaning and X represents a sulphur atom can be coupled with an amine in the presence of an activating or coupling reagent to give a compound of general formula (I), wherein R 1 R 2 Y and n have the abovementioned meaning and X represents a sulphur atom.
  • Such Weinreb amidation reactions can be promoted by the use of trimethylaluminum AI(CH 3 ) 3 (Levin, 1982). Activating and coupling methods of amines to carboxylic acids are well documented (Bodanszky, 1994; Akaji, 1994; Albericio, 1997; Montalbetti, 2005).
  • This 1-aryl-2-(alkylsulfanyl)ethanone derivative (VIII) wherein R 2 has the abovementioned meaning can be reacted with a oxalic ester derivative of general formula (IX) in the presence of a base such as sodium alkanoate in an inert anhydrous organic solvent, followed by a reaction with an arylhydrazine (X) or a salt thereof, wherein R 1 has the abovementioned meaning to give an ester of general formula (V) wherein R 1 , R 2 and Y have the abovementioned meaning, R 3 represents a linear C 1-3 alkyl group (methyl, ethyl or n-propyl) and X represents a sulphur atom.
  • This ester of general formula (V) can be hydrolyzed under basic conditions for example with lithium hydroxide to give the corresponding carboxylic acid of general formula (IV) or its alkali- element (such as lithium, sodium or potassium) salt.
  • This carboxylic acid or carboxylic acid alkali-element salt of general formula (IV) wherein R 1 R 2 and Y have the abovementioned meaning and X represents a sulphur atom can be coupled with an amine in the presence of an activating or coupling reagent in an inert organic solvent such as dimethylformamide to give a compound of general formula (I), wherein R 1 R 2 Y and n have the abovementioned meaning and X represents a sulphur atom.
  • This compound of general formula (I), wherein R 1 R 2 Y and n have the abovementioned meaning and X represents a sulphur atom can be oxidised with one molar equivalent of meta-chloroperbenzoic acid to give the corresponding sulfinyl analogue (X represents a S O group).
  • reaction of a compound of general formula (I) wherein X represents a sulphur atom with two or more molar equivalents of meta-chloroperbenzoic acid can convert the sulfanyl moiety in (I) to the corresponding sulfonyl moiety.
  • a Reagents and conditions (a) amine, AI(CH 3 ) 3 ; (b) aqueous base;
  • salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for instance an inorganic acid such as hydrochloric acid, or with an organic acid. Hydrates can be obtained using standard procedures well known in the art, for example by crystallization or evaporation from a water-containing (non-anhydrous) organic solvent.
  • 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1 /-/-pyrazole-3-carboxylic acid (m.p. 185-187 0 C) was obtained from methyl 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-1 /-/-pyrazole-3-carboxylate via ester hydrolysis under basic conditions (methanol, aqueous KOH).
  • the affinity of the compounds of the invention for cannabinoid CB 1 receptors can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB 1 receptor is stably transfected in conjunction with [ 3 H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [ 3 H]- ligand, with or without addition of compounds of the invention, separation of bound and free ligand is performed by filtration over glassfiber filters. Radioactivity on the filter is measured by liquid scintillation counting.
  • CHO Chinese hamster ovary
  • the affinity of the compounds of the invention for cannabinoid CB 2 receptors can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB 2 receptor is stably transfected in conjunction with [ 3 H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [ 3 H]- ligand, with or without addition of compounds of the invention, separation of bound and free ligand is performed by filtration over glassfiber filters. Radioactivity on the filter is measured by liquid scintillation counting.
  • CHO Chinese hamster ovary
  • CB 1 receptor antagonism can be assessed with the human CB 1 receptor cloned in Chinese hamster ovary (CHO) cells.
  • CHO cells are grown in a Dulbecco's Modified Eagle's medium (DMEM) culture medium, supplemented with 10% heat-inactivated fetal calf serum.
  • DMEM Dulbecco's Modified Eagle's medium
  • Medium is aspirated and replaced by DMEM, without fetal calf serum, but containing [ 3 H]- arachidonic acid and incubated overnight in a cell culture stove (5% CO 2 /95% air; 37 0 C; water- saturated atmosphere). During this period [ 3 H]-arachidonic acid is incorporated in membrane phospholipids.
  • mice Male normotensive rats (225-300 g; Harlan, Horst, The Netherlands) were anaesthetized with pentobarbital (80 mg/kg i.p). Blood pressure was measured, via a cannula inserted into the left carotid artery, by means of a Spectramed DTX-plus pressure transducer (Spectramed B.V., Bilthoven, The Netherlands).
  • the blood pressure signal was registered on a personal computer (Compaq Deskpro 386s), by means of a Po-Ne-Mah data- acquisition program (Po-Ne-Mah Inc., Storrs, USA). Heart rate was derived from the pulsatile pressure signal. All compounds were administered orally as a microsuspension in 1 % methylcellulose 30 minutes before induction of the anesthesia which was 60 minutes prior to administration of the CB 1 receptor agonist CP-55,940. The injection volume was 10 ml/kg. After haemodynamic stabilization the CB 1 receptor agonist CP-55,940 (0.1 mg/kg i.v.) was administered and the hypotensive effect established.
  • Affinity data for human cannabinoid CB 1 and CB 2 receptors (mean results of at least three independent experiments, performed according to the protocols given above) of rimonabant and compounds 1 -5 are given in the table below. These data illustrate the impact on CB 1 and CB 2 receptor affinities, CB 1/2 receptor selectivity ratios as well as their in vivo potency after oral administration achieved by the structural modification that forms the basis of the present invention, and also illustrate the CB 1 receptor affinities of the S-oxidized compounds 4 and 5.
  • compositions that are important and novel embodiments of the invention because they contain the compounds, more particularly specific compounds disclosed herein.
  • Types of pharmaceutical compositions that may be used include, but are not limited to, tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions, and other types disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art.
  • the compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other ways to administer.
  • the pharmaceutical formulation contains at least one compound of formula (I) in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
  • the total amount of active ingredients suitably is in the range of from about 0.1 % (w/w) to about 95% (w/w) of the formulation, suitably from 0.5% to 50% (w/w) and preferably from 1 % to 25% (w/w).
  • the compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
  • auxiliary substances such as liquid or solid, powdered ingredients, such as the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances.
  • auxiliary substances include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • the mixture may then be processed into granules or pressed into tablets.
  • the active ingredients may be separately premixed with the other non-active ingredients, before being mixed to form a formulation.
  • the active ingredients may also be mixed with each other, before being mixed with the non-active ingredients to form a formulation.
  • Soft gelatine capsules may be prepared with capsules containing a mixture of the active ingredients of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
  • Hard gelatine capsules may contain granules of the active ingredients.
  • Hard gelatine capsules may also contain the active ingredients together with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories that contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule that contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations may be prepared in the form of syrups, elixirs, concentrated drops or suspensions, e.g. solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents.
  • Liquid preparations may also be prepared in the form of a dry powder, reconstituted with a suitable solvent prior to use. Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation, reconstituted with a suitable solvent before use.
  • formulations and 'kits of parts' comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention, for use in medical therapy.
  • container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration.
  • formulations of the present invention in the manufacture of medicaments for use in treating a condition in which antagonism of cannabinoid-CB-i receptors is required or desired, and methods of medical treatment or comprising the administration of a therapeutically effective total amount of at least one compound of formula (I), either as such or, in the case of prodrugs, after administration, to a patient suffering from, or susceptible to, a condition in which antagonism of cannabinoid-CB-i receptors is required or desired.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Psychiatry (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Emergency Medicine (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Vascular Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Addiction (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Otolaryngology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne du soufre contenant des dérivés de pyrazole, et leurs métabolites actifs S-oxydés, en tant qu'antagonistes de récepteurs cannabinoïdes CB1 possédant une sélectivité de sous-type de récepteurs CB1/CB2 élevée, des procédés de préparation de ces composés, des nouveaux intermédiaires utiles dans la synthèse de ces dérivés de pyrazole, des compositions pharmaceutiques contenant un ou plusieurs dérivés de pyrazole en tant que principes actifs, ainsi que l'utilisation de ces compositions pharmaceutiques dans le traitement de troubles psychiatriques et neurologiques. Les composés sont représentés par la formule générale (I), les symboles de celle-ci ayant les significations données dans la description.
PCT/EP2007/055192 2006-05-31 2007-05-29 Soufre contenant des dérivés de pyrazole en tant qu'antagonistes de récepteurs cannabinoïdes cb1 Ceased WO2007138050A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
MX2008015272A MX2008015272A (es) 2006-05-31 2007-05-29 Derivados de pirazol que contienen azufre como antagonistas selectivos del receptor cannabinoide cb1.
EP07729614A EP2029548A1 (fr) 2006-05-31 2007-05-29 Soufre contenant des dérivés de pyrazole en tant qu'antagonistes de récepteurs cannabinoïdes cb1
BRPI0711902-0A BRPI0711902A2 (pt) 2006-05-31 2007-05-29 compostos, composição farmacêutica, método para preparar composições farmacêuticas, uso de um composto, e, processo para preparar compostos
CA002650622A CA2650622A1 (fr) 2006-05-31 2007-05-29 Soufre contenant des derives de pyrazole en tant qu'antagonistes de recepteurs cannabinoides cb1
JP2009512578A JP2009538874A (ja) 2006-05-31 2007-05-29 選択的カンナビノイドｃｂ１受容体アンタゴニストとしての硫黄含有ピラゾール誘導体
EA200870606A EA015107B1 (ru) 2006-05-31 2007-05-29 Серосодержащие производные пиразола в качестве избирательных антагонистов рецептора каннабиноидов св
AU2007267097A AU2007267097A1 (en) 2006-05-31 2007-05-29 Sulphur containing pyrazole derivatives as selective cannabinoid CB1 receptor antagonists
IL194902A IL194902A0 (en) 2006-05-31 2008-10-23 Sulphur containing pyrazole derivatives as selective cannabinoid cb1 receptor antagonists
NO20085035A NO20085035L (no) 2006-05-31 2008-12-02 Svovelinneholdende pyrazolderivater som selektive cannabinoid CB1 reseptorantagonister

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US80936706P 2006-05-31 2006-05-31
EP06114752.6 2006-05-31
EP06114752 2006-05-31
US60/809,367 2006-05-31

Publications (1)

Publication Number Publication Date
WO2007138050A1 true WO2007138050A1 (fr) 2007-12-06

Family

ID=38621057

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/055192 Ceased WO2007138050A1 (fr) 2006-05-31 2007-05-29 Soufre contenant des dérivés de pyrazole en tant qu'antagonistes de récepteurs cannabinoïdes cb1

Country Status (8)

Country Link
EP (1) EP2029548A1 (fr)
JP (1) JP2009538874A (fr)
KR (1) KR20090016504A (fr)
AU (1) AU2007267097A1 (fr)
CA (1) CA2650622A1 (fr)
EA (1) EA015107B1 (fr)
IL (1) IL194902A0 (fr)
WO (1) WO2007138050A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2013026264A1 (fr) * 2011-08-23 2013-02-28 Fan Rulin Composé inhibiteur d'accepteur cb1 ayant un cycle aromatique contenant de l'azote portant un hydroxyle, et son utilisation
CN103232394A (zh) * 2013-05-14 2013-08-07 浙江医药高等专科学校 含吡唑类化合物、其制备方法和用途

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011506410A (ja) * 2007-12-10 2011-03-03 ７ティーエム ファーマ エイ／エス カンナビノイド受容体モジュレーター

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998043636A1 (fr) * 1997-03-28 1998-10-08 Sanofi-Synthelabo Composition pharmaceutique pour administration orale d'un derive du n-piperidino-3-pyrazolecarboxamide, de ses sels et de leurs s olvates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998043636A1 (fr) * 1997-03-28 1998-10-08 Sanofi-Synthelabo Composition pharmaceutique pour administration orale d'un derive du n-piperidino-3-pyrazolecarboxamide, de ses sels et de leurs s olvates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
R. KATOCH-ROUSE R ET AL: "Synthesis, Structure-Activity Relationship, and Evaluation of SR141716 Analogues: Development of Central Cannabinoid Receptor Ligands with Lower Lipophilicity", JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, no. 4, 18 January 2003 (2003-01-18), AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, pages 642 - 645, XP002335279, ISSN: 0022-2623 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2013026264A1 (fr) * 2011-08-23 2013-02-28 Fan Rulin Composé inhibiteur d'accepteur cb1 ayant un cycle aromatique contenant de l'azote portant un hydroxyle, et son utilisation
CN103232394A (zh) * 2013-05-14 2013-08-07 浙江医药高等专科学校 含吡唑类化合物、其制备方法和用途

Also Published As

Publication number Publication date
JP2009538874A (ja) 2009-11-12
EA200870606A1 (ru) 2009-04-28
EA015107B1 (ru) 2011-06-30
KR20090016504A (ko) 2009-02-13
AU2007267097A1 (en) 2007-12-06
EP2029548A1 (fr) 2009-03-04
CA2650622A1 (fr) 2007-12-06
IL194902A0 (en) 2009-08-03

Similar Documents

Publication Publication Date Title
EP1713475B1 (fr) Derives de 4,5-dihydro-1h-pyrazole 1,3,5-trisubstitues presentant une activite antagonistique a cb1
EP2029548A1 (fr) Soufre contenant des dérivés de pyrazole en tant qu'antagonistes de récepteurs cannabinoïdes cb1
US8138174B2 (en) Compounds with a combination of cannabinoid CB1 antagonism and serotonin reuptake inhibition
EP2091939B1 (fr) Composés présentant une combinaison d'antagonisme de canabinoïde-cb1 et d'inhibition d'acétylcholinestérase
CN101809000A (zh) 具有大麻素-cb1拮抗作用和5-羟色胺再摄取抑制作用组合的化合物
EP1966146B1 (fr) Derives de 4,5-dihydro-(1h)-pyrazole en tant que modulateurs du recepteur cannabinoide cb1
US8461184B2 (en) Sulphur containing pyrazole derivatives as selective cannabinoid CB1 receptor antagonists
AU2004283903B2 (en) 1H-imidazole derivatives as cannabinoid receptor modulators
US20110053983A1 (en) (5r)-1,5-diaryl-4,5-dihydro-1h-pyrazole-3-carboxamidine derivatives having cb1-antagonistic activity
US7928134B2 (en) 5-aryl-4,5-dihydro-(1H)-pyrazolines as cannabinoid CB1 receptor agonists
KR20090103932A (ko) 카나비노이드-ｃｂ1 길항작용과 세로토닌 재흡수 억제가 조합된 화합물
MX2008015272A (es) Derivados de pirazol que contienen azufre como antagonistas selectivos del receptor cannabinoide cb1.
HK1129104A (en) Sulphur containing pyrazole derivatives as selective cannabinoid cb1 receptor antagonists
AU2008263915A1 (en) 4,5-dihydro-(1H)-pyrazole derivatives as cannabinoid CB1 receptor modulators
HK1143362A (en) Compounds with a combination of cannabinoid-cb1 antagonism and serotonin reuptake inhibition
HK1143587A (en) Compounds with a combination of cannabinoid-cb1 antagonism and acetylcholinesterase inhibition

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200780019586.4

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07729614

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 194902

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2650622

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2007729614

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2008111875

Country of ref document: EG

WWE Wipo information: entry into national phase

Ref document number: 2007267097

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2009512578

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: MX/A/2008/015272

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 6607/CHENP/2008

Country of ref document: IN

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2007267097

Country of ref document: AU

Date of ref document: 20070529

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: DZP2008000770

Country of ref document: DZ

WWE Wipo information: entry into national phase

Ref document number: 1020087032143

Country of ref document: KR

Ref document number: 200870606

Country of ref document: EA

ENP Entry into the national phase

Ref document number: PI0711902

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20081118