WO2006033632A1 - Derives de benzimidazole et leur utilisation comme ligands du recepteur cannabinoide - Google Patents

Derives de benzimidazole et leur utilisation comme ligands du recepteur cannabinoide Download PDF

Info

Publication number
WO2006033632A1
WO2006033632A1 PCT/SE2005/001404 SE2005001404W WO2006033632A1 WO 2006033632 A1 WO2006033632 A1 WO 2006033632A1 SE 2005001404 W SE2005001404 W SE 2005001404W WO 2006033632 A1 WO2006033632 A1 WO 2006033632A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
compound
independently selected
hydroxy
mmol
Prior art date
Application number
PCT/SE2005/001404
Other languages
English (en)
Inventor
Ziping Liu
Daniel PAGÈ
Maxime Tremblay
Christopher Walpole
Hua Yang
Original Assignee
Astrazeneca Ab
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 claimed from PCT/GB2004/004112 external-priority patent/WO2005030761A1/fr
Priority claimed from PCT/GB2004/004126 external-priority patent/WO2005030733A1/fr
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to JP2007533434A priority Critical patent/JP2008514594A/ja
Priority to EP05786524A priority patent/EP1794150A1/fr
Publication of WO2006033632A1 publication Critical patent/WO2006033632A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • A61P25/14—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
    • A61P25/22—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
    • A61P25/28—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
    • 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

Definitions

  • the invention is related to therapeutic compounds, pharmaceutical compositions containing these compounds, manufacturing processes thereof and uses thereof.
  • the present invention is related to compounds that may be effective in treating pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and/or cardiovascular disorders.
  • CB 1 receptor e.g., CB 1 receptor, CB 2 receptor
  • ligands including agonists, antagonists and inverse agonists produce relief of pain in a variety of animal models by interacting with CB 1 and/or CB 2 receptors.
  • CB 1 receptors are located predominately in the central nervous system
  • CB 2 receptors are located primarily in the periphery and are primarily restricted to the cells and tissues derived from the immune system.
  • CB 1 receptor agonists such as ⁇ 9 -tetrahydrocannabinol ( ⁇ 9 -THC) and anadamide
  • CNS side-effects e.g., psychoactive side effects, the abuse potential, drug dependence and tolerance, etc.
  • CB 1 receptor agonists acting at peripheral sites or with limited CNS exposure can manage pain in humans or animals with much improved overall in vivo profile. Therefore, there is a need for new CB 1 receptor ligands such as agonists that may be useful in managing pain or treating other related symptoms or diseases with reduced or minimal undesirable CNS side-effects.
  • the present invention provides CB 1 receptor ligands which may be useful in treating pain and/or other related symptoms or diseases.
  • C m-n or "C m-n group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • alkyl used alone or as a suffix or prefix, refers to a saturated monovalent straight or branched chain hydrocarbon radical comprising 1 to about 12 carbon atoms.
  • alkyls include, but are not limited to, C 1-4 alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2 -methyl- 1 -propyl, 2-methyl-2- propyl, butyl, isobutyl, t-butyl.
  • cycloalkyl refers to a saturated monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms.
  • cycloaljkyls include, but are not limited to, C 3-7 cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes.
  • a cycloalkyl can be unsubstituted or substituted by one or two suitable substituents.
  • the cycloalkyl is a monocyclic ring or bicyclic ring.
  • alkoxy used alone or as a suffix or prefix, refers to radicals of the general formula -O-R, wherein R is an alkyl.
  • exemplary alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, and isobutoxy.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • RT room temperature
  • an embodiment of the invention provides a compound of Formula I, a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:
  • R 1 and R 2 are independently selected from -H, hydroxy, C 1-4 alkyl, C 3- ⁇ cycloalkyl, C 1-4 alkoxy, and hydroxy-C 1-4 alkyl;
  • R 3 , R 4 and R 5 are independently selected from fluoro and methyl.
  • the compounds are those of formula I, wherein R 1 and R 2 are independently selected from -H, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, and hydroxy-C 1-4 alkyl; and
  • R 3 , R 4 and R 5 are independently selected from fluoro and methyl.
  • R 1 and R 2 are independently selected from -H, hydroxy, methyl, ethyl, 2- hydroxylethyl, methoxy and t-butyl with R 1 and R 2 being different groups;
  • R 3 , R 4 and R 5 are independently selected from fluoro and methyl.
  • a further embodiment of the invention provides a compound of formula I, wherein R and R are independently selected from -H, hydroxy, methyl, ethyl, 2- hydroxylethyl, methoxy and t-butyl with R 1 and R 2 being different groups; and
  • R 3 , R 4 and R 5 are independently selected from fluoro and methyl with R 3 , R 4 and R 5 b beeiinngg t thhee s saammee..
  • R 1 and R z are independently selected from -H, hydroxy, methyl, ethyl, 2- hydroxylethyl, methoxy and t-butyl with R 1 and R 2 not being -H at the same time; and R 3 , R 4 and R 5 are independently selected from fluoro and methyl.
  • R 1 and R 2 are independently selected from -H and C 3-6 cylcoalkyl.
  • R 3 , R 4 and R 5 are independently selected from fluoro and methyl with R 3 , R 4 and R 5 being the same.
  • R 1 and R 2 are independently selected from -H, hydroxy, methyl, ethyl, 2-hydroxylethyl, methoxy and t-butyl with R 1 and R 2 being different groups.
  • R 1 and R 2 are independently selected from -H, hydroxy, methyl, ethyl, cyclopropyl, cyclobutyl, 2-hydroxylethyl, methoxy and t- butyl with R 1 and R 2 being different groups.
  • the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture.
  • the present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I.
  • the optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter.
  • certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of alkenes.
  • the present invention includes any geometrical isomer of a compound of Formula I. It will further be understood that the present invention encompasses tautomers of the compounds of the Formula I.
  • pharmaceutically acceptable salts of compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCl or acetic acid, to afford a physiologically acceptable anion.
  • a sufficiently basic compound for example an alkyl amine
  • a suitable acid for example, HCl or acetic acid
  • a corresponding alkali metal such as sodium, potassium, or lithium
  • an alkaline earth metal such as a calcium
  • a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques.
  • a suitably acidic proton such as a carboxylic acid or a phenol
  • an alkali metal or alkaline earth metal hydroxide or alkoxide such as the ethoxide or methoxide
  • a suitably basic organic amine such as choline or meglumine
  • the compound of Formula I above may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or j?-toluenesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or j?-toluenesulphonate.
  • the compounds of the invention have activity as pharmaceuticals, in particular as modulators or ligands such as agonists, partial agonists, inverse agonist or antagonists Of CB 1 receptors. More particularly, the compounds of the invention exhibit selective activity as agonist of the CB 1 receptors and are useful in therapy, especially for relief of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Additionally, compounds of the present invention are useful in other disease states in which dysfunction Of CB 1 receptors is present or implicated.
  • the compounds of the invention may be used to treat cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiovascular disorders.
  • Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents.
  • Compounds of the invention are useful in disease states where degeneration or dysfunction of cannabinoid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
  • PET positron emission tomography
  • Compounds of the invention are useful for the treatment of diarrhoea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following miocardial infarction, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
  • stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung oedema, various
  • Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care.
  • Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.
  • any of the compounds according to the Formula I above for the manufacture of a medicament for the treatment of any of the conditions discussed above.
  • a further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the Formula I above, is administered to a patient in need of such treatment.
  • the invention provides a compound of Formula I or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
  • the present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • therapy also includes
  • prophylaxis unless there are specific indications to the contrary.
  • therapeutic and “therapeutically” should be contrued accordingly.
  • therapy within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition. This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.
  • the compounds of the present invention are useful in therapy, especially for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
  • the compound of the invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, transdermally, mtracerebroventricularly and by injection into the joints.
  • the route of administration may be oral, intravenous or intramuscular.
  • the dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient.
  • inert, pharmaceutically acceptable carriers can be either solid and liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture in then poured into convenient sized moulds and allowed to cool and solidify.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
  • composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.
  • Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid form compositions include solutions, suspensions, and emulsions.
  • sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration.
  • Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical composition will preferably include from 0.05% to 99%w (per cent by weight), more preferably from 0.10 to 50%w, of the compound of the invention, all percentages by weight being based on total composition.
  • a therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art.
  • the use of any compound of Formula I as defined above for the manufacture of a medicament is the use of any compound of Formula I as defined above for the manufacture of a medicament.
  • any compound of Formula I for the manufacture of a medicament for the therapy of pain. Additionally provided is the use of any compound according to Formula I for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
  • a further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the Formula I above, is administered to a patient in need of such therapy.
  • composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain.
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above.
  • the present invention provides a method of preparing the compounds of the present invention.
  • the invention provides a process for preparing a compound of Formula I, comprising:
  • the invention provides a process for preparing a compound of Formula I, comprising
  • DMAP solvent e.g. DMAP solvent
  • THF solvent e.g. DMF coupling reagent, e.g. HATU
  • solvent e.g. AcOH acid, e.g. AcOH microwave oven heating, 100-19O 0 C
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • H 2 catalyst e.g. 10% Pd/C
  • Human CB 1 receptor from Receptor Biology (!1CB 1 ) or human CB 2 receptor from BioSignal (hCB 2 ) membranes are thawed at 37 0 C, passed 3 times through a 25- gauge blunt-end needle, diluted in the cannabinoid binding buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2 , and 0.5 mg/mL BSA fatty acid free, pH 7.4) and aliquots containing the appropriate amount of protein are distributed in 96-well plates.
  • cannabinoid binding buffer 50 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2 , and 0.5 mg/mL BSA fatty acid free, pH 7.4
  • the IC 50 of the compounds of the invention at JiCB 1 and hCB 2 are evaluated from 10-point dose-response curves done with 3 H-CP55,940 at 20000 to 25000 dpm per well (0.17- 0.21 nM) in a final volume of 300 ⁇ l.
  • the total and non-specific binding are determined in the absence and presence of 0.2 ⁇ M of HU210 respectively.
  • the plates are vortexed and incubated for 60 minutes at room temperature, filtered through
  • Unifilters GF/B presoaked in 0.1% polyethyleneimine
  • the Tomtec or Packard harvester using 3 mL of wash buffer (50 mM Tris, 5 mM MgCl 2 , 0.5 mg BSA pH 7.0).
  • the filters are dried for 1 hour at 55 0 C.
  • the radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid.
  • Human CB 1 receptor from Receptor Biology (!1CB 1 ) or human CB 2 receptor membranes (BioSignal) are thawed at 37 0 C 3 passed 3 times through a 25-gauge blunt-end needle and diluted in the GTP ⁇ S binding buffer (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl 2 , pH 7.4, 0.1% BSA).
  • the EC 50 and E max of the compounds of the invention are evaluated from 10-point dose- response curves done in 300 ⁇ l with the appropriate amount of membrane protein and 100000-130000 dpm of GTPg 35 S per well (0.11 -0.14 nM).
  • the basal and maximal stimulated binding is determined in absence and presence of 1 ⁇ M (hCB 2 ) or 10 ⁇ M (hCBi) Win 55,212-2 respectively.
  • the membranes are pre-incubated for 5 minutes with 56.25 ⁇ M (hCB2) or 112.5 ⁇ M (hCBO GDP prior to distribution in plates (15 ⁇ M (hCB 2 ) or 30 ⁇ M (!1CB 1 ) GDP final).
  • the plates are vortexed and incubated for 60 minutes at room temperature, filtered on Unif ⁇ lters GF/B (presoaked in water) with the Tomtec or Packard harvester using 3 ml of wash buffer (50 mM Tris, 5 mM MgCl 2 , 50 mM NaCl, pH 7.0). The filters are dried for 1 hour at 55 °C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid.
  • wash buffer 50 mM Tris, 5 mM MgCl 2 , 50 mM NaCl, pH 7.0.
  • the filters are dried for 1 hour at 55 °C.
  • the radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid.
  • Antagonist reversal studies are done in the same way except that (a) an agonist dose-response curve is done in the presence of a constant concentration of antagonist, or (b) an antagonist dose-response curve is done in the presence of a constant concentration of agonist.
  • the dissociation constant (Ki) for a particular compound of the invention towards a particular receptor is determined using the following equation:
  • Ki IC 50 /(l+[rad]/Kd)
  • IC 50 is the concentration of the compound of the invention at which 50% displacement has been observed
  • [rad] is a standard or reference radioactive ligand concentration at that moment; and Kd is the dissociation constant of the radioactive ligand towards the particular receptor.
  • the Ki towards human CB 1 receptors for certain compounds of the invention are in the range of between 5 nM and 52 nM.
  • EC 50 for these compounds are in the range of between 10 nM and 202 nM.
  • Emax for these compounds are in the range of between 70% and 151%.
  • Step A 4-[(Aminocarbonyl)amino]-iV-[2-ter?-butyl-l-(tetrahydro-2fi-pyran-4- yImethyl)-lJ ⁇ -benzimidazol-5-yl]-iV-methylbenzenesulfonamide
  • Methyl chloroformate (13.2 mL, 170.2 mmol) was added dropwise to a cold (0°C) dichloromethane (200 mL) solution of 4-fluoro-3-nitro aniline (24.15 g, 154.7 mmol) and DIPEA (35 mL, 201 mmol). The reaction mixture was stirred at rt overnight. The solution was then diluted with 200 mL of dichloromethane and washed with 2M HCl, brine and dried over anhydrous MgSO 4 . The solvent was concentrated and the product was directly used for next step without further purification.
  • Methyl (4-fluoro-3-nitrophenyl)carbamate (2.0 g, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28g, 11.2 mmol) were stirred in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 75 0 C for 48 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO 4 , saturated aqueous NaHCO 3 solution, brine and dried over anhydrous MgSO 4 . The crude product was purified by silica gel flash chromatography using 1:1 / hexanes : EtOAc as eluent.
  • Step D Methyl ⁇ 3-amino-4-[(tetrahydro-2J3-pyran-4- ylmethyl)amino]phenyl ⁇ carbamate
  • Step E Methyl [2-tert-butyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH- benzimidazol-5-yl] carbamate
  • Methyl ⁇ 3-amino-4-[(tetrahydro-2H ' -pyran-4-ylmetliyl)amino]phenyl ⁇ carbamate (2.29 g, 8.20 mmol) and DMAP (0.20 g, 1.64 mmol) were dissolved in 75 mL of DCM.
  • Trimethylacetyl chloride (1.10 mL, 9.02 mmol) was added dropwise and the solution was stirred at rt for 2h. The solution was washed with aqueous NaHCO 3 solution, brine and dried over anhydrous MgSO 4 . The residue was dissolved in 25 mL of AcOH and was heated at 125 0 C for Ih using a Personal Chemistry microwave apparatus.
  • Step F 2-tert-Butyl-N-methyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH- benzimidazol-5-amine
  • Step A 4-[(Aminocarbonyl)amino]-iV-inethyl-iV-[l-(tetrahydro-2J ⁇ -pyran-4- ylmethyl)-2-(trifluoromethyl)-li3-benzimidazol-5-yl]benzenesulfonamide
  • Step D iV-methyl-iV- ⁇ 3-nitro-4-[(tetrahydro-2fr-pyran-4- ylmethyl) amino] phenyl ⁇ acetamide
  • Step E iV- ⁇ 3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl ⁇ -A r - methylacetamide
  • iV-methyl-iV- ⁇ 3-mtro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl ⁇ acetamide 5.39 g, 16.7 mmol was hydrogenated in ethyl acetate (200 mL) catalyzed by 10% Pd/C (0.2 g) at 30-40 psi H 2 in Parr shaker for 18 h at room temperature. After filtration through celite and concentration, 6.0 g (100%) of a purple solid was obtained as HCl salt, which was used in the next step without purification.
  • Step F iV-methyl-iV-ll-Ctetrahydro ⁇ J ⁇ -pyran ⁇ -ylmethylJ ⁇ -Ctrifluoromethyl)- lH-benzimidazol-S-ylJacetamide
  • Step G iV-methyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-lJ3- benzimidazol-5-amine
  • Step A 4- ⁇ [(terf-Butylamino)carbonyl]amino ⁇ -iV-methyl-iV-[l-(tetrahydro-2J ⁇ - pyran-4-yImethyl)-2-(trifluoromethyl)-li ⁇ -benzimidazol-5- yl] b enzenesulf onamide
  • Step B 4-Isocyanato-iV-methyl-iV-[l-(tetrahydro-2 J H-pyran-4-ylmethyl)-2- (trifluoromethyl)-lJ ⁇ -benzimidazol-5-yl]benzenesulfonamide
  • Example 8 4- ⁇ [(Hydroxyamino)carbonyl]amino ⁇ -iV-methyl-iV-[l-(tetrahydro-2jKr-pyran-4- ylmethyl)-2-(trifluoromethyl)-LH-benzimidazol-5-yl]benzenesulfonamide
  • step B in example 6 using a solution of 4-isocyanato-iV- methyl-N-[l-(tetxahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-lH-benzimidazol- 5-yl]benzenesulfonamide (see Step B in example 6 for preparation) (0.14 mmol) in 3.5 mL of THF, N,O-dimethylhydroxylamine hydrochloride 27.3 mg, 0.28 mmol) and DBPEA (0.1 mL) in THF (2 mL).
  • Step A iV-[2-terf-Butyl-l-(tetrahydro-2i ⁇ -pyran-4-ylmethyl)-lJ ⁇ -benzimidazol-5- yl]-4- ⁇ [(ethylamino)carbonyl]amino ⁇ -iV-methylbenzenesulfonamide
  • Trimethylacetyl chloride (3.3 mL, 3.20 g, 26.5 mmol) was dropwise added to a solution of N- ⁇ 3-amino-4-[(tetrahydro-2H " -pyran-4-ylmethyl)amino]phenyl ⁇ -N- methylacetamide (7.01 g, 25.3 mmol) (for preparation, see steps B to E in example 2) and DIPEA (5.3 mL, 3.92 g, 30.4 mmol) in dichloromethane (170 mL) at 0 0 C. The resulting mixture was stirred for 4h at room temperature. After evaporation of the solvent, the residue was dissolved in acetic acid (75 mL) and then divided to 15 sealed test tubes. The mixture was heated at 150°C in a Personal Chemistry
  • Step D iV-[2-ter ⁇ butyl-l-(tetrahydro-2j ⁇ r -pyran-4-ylmethyl)-li ⁇ -benzimidazol-5- yl]-iV-methyl-4-nitrobenzenesulfonainide
  • Step E 4-Amino-iV-[2-te ⁇ -butyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-l J H r - benzimidazol-5-yl]-7V-methylbenzenesulfonamide
  • Step F iV-tl-ter ⁇ -butyl-l- ⁇ etrahydro-lJ ⁇ -pyran ⁇ -ylmethy ⁇ -lJ ⁇ -benzimidazol-S- yl]-4-isocyanato-iV-methylbenzenesulfonamide
  • step A in example 10 using a solution of iV-[2-tert-butyl- l-(tetrahydro-2H-pyran-4-ylmethyl)-lH-benzimidazol-5-yl]-4-isocyanato-N- methylbenzenesulfonamide (0.22 mmol) in 10 mL of T ⁇ F (see example 10 for preparation), hydroxylamine hydrochloride (30.6 mg, 0.44 mmol) and DIPEA (92 uL, 68.6 mg, 0.53 mmol) in T ⁇ F (5 mL).
  • step A in example 10 using a solution of iV-[2-tert-butyl- l-(tetrahydro-2H-pyran-4-ylmethyl)-lJi ' -berizimidazol-5-yl]-4-isocyanato-N- methylbenzenesulfonamide (0.22 mmol) in 10 mL of THF (see example 10 for preparation), N,O-dimethylhydroxylamine hydrochloride (42.9 mg, 0.44 mmol) and DIPEA (92 uL, 68.6 mg, 0.53 mmol) in THF (5 mL).
  • step A in example 10 Following the procedure for step A in example 10, using a solution of iV- ⁇ -tert-butyl- l- ⁇ eiiahydro ⁇ H-pvran ⁇ -ylmemy ⁇ -lH-beiizi ⁇ methylbenzenesulfonamide (0.14 mmol) in 10 mL of THF (see example 10 for preparation) and cyclobutylamine (19.4 mg, 0.27mmol) in THF (2 mL). The crude product was purified by MPLC using EtOAc eluted on silica gel to give 74.1 mg (99%) of a white solid as the title compound.
  • step A in example 10 using a solution of iV-[2-tert-butyl- l-(tetrahydro-2H-pyran-4-ylmethyl)-lH ' -benzimidazol-5-yl]-4-isocyanato-N- methylbenzenesulfonamide (0.14 mmol) in 10 mL of THF (see example 10 for preparation) and cyclopropylamine (15.5 mg, 0.27mmol) in THF (2 mL). The crude product was purified by MPLC using EtOAc eluted on silica gel to give 70.7 mg (98%) of a white solid as the title compound.

Abstract

L'invention concerne des composés de formule (I) ou des sels pharmaceutiquement acceptables desdits composés, formule dans laquelle R1, R2, R3, R4 et R5 sont tels que définis dans la spécification, ainsi que des sels et compositions pharmaceutiques contenant lesdits composés. Ces composés sont utiles en thérapie, notamment dans la gestion de la douleur.
PCT/SE2005/001404 2004-09-24 2005-09-22 Derives de benzimidazole et leur utilisation comme ligands du recepteur cannabinoide WO2006033632A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2007533434A JP2008514594A (ja) 2004-09-24 2005-09-22 ベンゾイミダゾール誘導体及びカンナビノイド受容体リガンドとしてのその使用ｉ
EP05786524A EP1794150A1 (fr) 2004-09-24 2005-09-22 Derives de benzimidazole et leur utilisation comme ligands du recepteur cannabinoide

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GBPCT/GB2004/004112 2004-09-24
PCT/GB2004/004112 WO2005030761A1 (fr) 2003-09-26 2004-09-24 Derives de benzimidazole, compositions les contenant, preparation de ces compositions et utilisations correspondantes
PCT/GB2004/004126 WO2005030733A1 (fr) 2003-09-26 2004-09-24 Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations de ceux-ci
GBPCT/GB2004/004126 2004-09-24
US64030904P 2004-12-30 2004-12-30
US60/640,309 2004-12-30

Publications (1)

Publication Number Publication Date
WO2006033632A1 true WO2006033632A1 (fr) 2006-03-30

Family

ID=36090311

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2005/001404 WO2006033632A1 (fr) 2004-09-24 2005-09-22 Derives de benzimidazole et leur utilisation comme ligands du recepteur cannabinoide

Country Status (3)

Country Link
EP (1) EP1794150A1 (fr)
JP (1) JP2008514594A (fr)
WO (1) WO2006033632A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7550495B2 (en) 2004-09-24 2009-06-23 Astrazeneca Ab Compounds, compositions containing them, preparation thereof and uses thereof I
US7566788B2 (en) 2006-03-23 2009-07-28 Astrazeneca Ab Crystalline forms
US7615642B2 (en) 2006-04-18 2009-11-10 Astrazeneca Ab Therapeutic compounds
US8633235B2 (en) 2003-09-26 2014-01-21 Neomed Institute Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085866A1 (fr) * 2001-04-20 2002-10-31 Astrazeneca Ab Nouveaux composes
WO2004108712A1 (fr) * 2003-06-10 2004-12-16 Astrazeneca Ab Derives de benzimidazole, compositions les contenant, leur preparation et leurs utilisations
WO2005030761A1 (fr) * 2003-09-26 2005-04-07 Astrazeneca Ab Derives de benzimidazole, compositions les contenant, preparation de ces compositions et utilisations correspondantes
WO2005030733A1 (fr) * 2003-09-26 2005-04-07 Astrazeneca Ab Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations de ceux-ci

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085866A1 (fr) * 2001-04-20 2002-10-31 Astrazeneca Ab Nouveaux composes
WO2004108712A1 (fr) * 2003-06-10 2004-12-16 Astrazeneca Ab Derives de benzimidazole, compositions les contenant, leur preparation et leurs utilisations
WO2005030761A1 (fr) * 2003-09-26 2005-04-07 Astrazeneca Ab Derives de benzimidazole, compositions les contenant, preparation de ces compositions et utilisations correspondantes
WO2005030733A1 (fr) * 2003-09-26 2005-04-07 Astrazeneca Ab Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations de ceux-ci

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8633235B2 (en) 2003-09-26 2014-01-21 Neomed Institute Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof
US7550495B2 (en) 2004-09-24 2009-06-23 Astrazeneca Ab Compounds, compositions containing them, preparation thereof and uses thereof I
US7566788B2 (en) 2006-03-23 2009-07-28 Astrazeneca Ab Crystalline forms
US7615642B2 (en) 2006-04-18 2009-11-10 Astrazeneca Ab Therapeutic compounds

Also Published As

Publication number Publication date
EP1794150A1 (fr) 2007-06-13
JP2008514594A (ja) 2008-05-08

Similar Documents

Publication Publication Date Title
EP1797076A1 (fr) Derives de benzimidazole, compositions les contenant et preparation et utilisation desdits derives
RU2346938C2 (ru) Производные бензимидазола, содержащие их композиции, их получение и применение
US7550495B2 (en) Compounds, compositions containing them, preparation thereof and uses thereof I
EP1797078A1 (fr) Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations de ces derniers iii
AU2005287427B2 (en) Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof I
US7517898B2 (en) Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof
EP1615893A1 (fr) Derives de 2-azabicyclo [3.3.1]nonane utilises comme antagonistes des recepteurs opioides
US20070072853A1 (en) Benzimidazole derivatives compositions containing them, preparation thereof and uses thereof
EP1670790B1 (fr) Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations
WO2006033632A1 (fr) Derives de benzimidazole et leur utilisation comme ligands du recepteur cannabinoide
US20070082899A1 (en) Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof
WO2006033629A1 (fr) Derives de benzimidazole et leur utilisation en tant que ligands du recepteur cannabinoide
EP1797074A1 (fr) Composes, compositions les contenant, leur preparation et leur utilisation
US20070219254A1 (en) Therapeutic Compounds: Pyridine N-Oxide Scaffold
KR20070054217A (ko) 화합물, 그를 함유하는 조성물, 그의 제조 방법 및 그의용도

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1631/DELNP/2007

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 200580031826.3

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 2005786524

Country of ref document: EP

Ref document number: 2007533434

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWP Wipo information: published in national office

Ref document number: 2005786524

Country of ref document: EP