WO2006033631A1 - Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations de ces derniers - Google Patents

Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations de ces derniers Download PDF

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Publication number
WO2006033631A1
WO2006033631A1 PCT/SE2005/001403 SE2005001403W WO2006033631A1 WO 2006033631 A1 WO2006033631 A1 WO 2006033631A1 SE 2005001403 W SE2005001403 W SE 2005001403W WO 2006033631 A1 WO2006033631 A1 WO 2006033631A1
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Prior art keywords
methyl
mmol
solution
compound
benzimidazol
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PCT/SE2005/001403
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English (en)
Inventor
Daniel PAGÈ
Ziping Liu
Maxime Tremblay
Christopher Walpole
Hua Yang
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Astrazeneca Ab
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Publication date
Priority claimed from PCT/GB2004/004124 external-priority patent/WO2005030732A1/fr
Priority to KR1020077006658A priority Critical patent/KR101269869B1/ko
Priority to ES05786553T priority patent/ES2380709T3/es
Priority to CA2581232A priority patent/CA2581232C/fr
Priority to AU2005287427A priority patent/AU2005287427B2/en
Priority to CN2005800323399A priority patent/CN101052639B/zh
Priority to JP2007533433A priority patent/JP5053092B2/ja
Priority to MX2007003105A priority patent/MX2007003105A/es
Priority to EP05786553A priority patent/EP1797077B1/fr
Priority to BRPI0515897-4A priority patent/BRPI0515897A/pt
Priority to AT05786553T priority patent/ATE545644T1/de
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of WO2006033631A1 publication Critical patent/WO2006033631A1/fr
Priority to US11/419,603 priority patent/US7550495B2/en
Priority to IL181683A priority patent/IL181683A0/en
Priority to NO20072089A priority patent/NO20072089L/no
Priority to HK07113080.7A priority patent/HK1104823A1/xx
Priority to US12/466,415 priority patent/US20090221657A1/en

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    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/10—Radicals substituted by halogen atoms or nitro radicals

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.
  • CBi receptor e.g., CBi 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.
  • Illustrative examples of allcyls include, but are not limited to, C 1-4 alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-l -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.
  • cycloalkyls 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:
  • G is selected from -O-, -CHF- and -CF 2 -;
  • R 1 is selected from C 1-6 alkyl and C 3-6 cycloalkyl
  • R 2 is selected from -H and methyl
  • R 3 , R 4 and R 5 are independently selected from fluoro and methyl.
  • the compounds may be those of formula I, wherein G is selected from -O- and -CF 2 -; R 1 is selected from C 1-6 alkyl and C 3-6 cycloalkyl;
  • R 2 is selected from -H and methyl
  • R 3 , R 4 and R 5 are independently selected from fluoro and methyl.
  • Another embodiment of the invention provides a compound of formula I, wherein G is selected from -O- and -CF 2 -;
  • R 1 is selected from C 1-4 alkyl and C 3-4 cycloalkyl
  • R 2 selected from -H and methyl
  • 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
  • G is -0-
  • R 1 is selected from ethyl, propyl and cyclopropyl; R 2 selected from -H and methyl; and 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.
  • G is -CF 2 -;
  • R 1 is selected from ethyl, propyl and cyclopropyl
  • R 2 selected from -H and methyl
  • 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 is selected from ethyl, propyl, t-butyl and cyclopropyl
  • R 2 selected from -H and methyl
  • 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 of formula I is selected from ethyl, propyl, t-butyl and cyclopropyl.
  • G of formula I is -CHF- or -CF 2 -.
  • R 3 , R 4 and R 5 of formula I are selected from fluoro and methyl with R 3 , R 4 and R 5 being the same.
  • the compound of the invention may be selected from N-[2- tert-Butyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH-benzimidazol-5-yl]-N- methylcyclopropanesulfonamide;
  • 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 p-toluenesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or p-toluenesulphonate.
  • 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 OfCB 1 receptors is present or implicated. Furthermore, 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.
  • 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.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the term “therapeutic” and “therapeutically” should be contrued accordingly.
  • the term “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, intracerebroventricularly and by injection into the joints.
  • the route of administration may be oral, intravenous or intramuscular.
  • 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 solidity.
  • 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.
  • a carrier which is thus in association with it.
  • 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.
  • 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.
  • 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:
  • reducing agent base e.g. DMAP e.g. AIH 3 solvent, e.g. DMF solvent
  • THF coupling reagent e.g. HATU
  • solvent e.g. AcOH acid, e.g. AcOH or HCI, or P 2 O 5 microwave oven heating, 100-190 0 C
  • solvent e.g. AcOH acid, e.g. AcOH or HCI or P 2 O 5 microwave oven heating, 100-190 0 C
  • oxidant e.g. MCPBA solvent, e.g. CH 2 CI 2
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • X halogen, TfO, TsO, MsO
  • R 5 -Y solvent e.g. DMF heat, e.g. 100-150°C base, e.g. Et 3 N
  • hCB j and hCB ⁇ receptor binding Human CB 1 receptor from Receptor Biology (11CB 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 IC50 of the compounds of the invention at !1CB 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) with the Tomtec or Packard harvester using 3 niL 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.
  • GTPvS binding Human CB 1 receptor from Receptor Biology (!1CB 1 ) or human CB 2 receptor membranes (BioSignal) are thawed at 37 0 C, 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 rJVI).
  • 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 (hCBi) GDP prior to distribution in plates (15 ⁇ M (hCB 2 ) or 30 ⁇ M (hCBO 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
  • 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 3 nM and 195 nM.
  • EC 50 for these compounds are in the range of between 2.3 nM and 300 nM.
  • Emax for these compounds are in the range of between 109 % and 144 %.
  • a 30 mM DMSO stock is prepared of the sample and then a 25 ⁇ L aliquot is added to a 96-well plate and genevac at 40 0 C for 4 hours.
  • To the genevac compound add 250 ⁇ L of sodium phosphate buffer (pH 7.4) and then mix at 1200 rpm for 24 h using an Eppendorf Thermomixer at 25°C. After mixing solution is transferred to a 96-well Whatman GF/B filter plate and then filtered under vacuum. The supernatant is then injected onto the LC/MS for analysis and quantitation is performed using a 1- point calibration for the compound of interest.
  • a solution of 500 ⁇ l of 100 ⁇ M compound in DMSO is incubated with human or rat liver microsomes (843 ⁇ l of microsomes of 0.5618 mg/mL in 30ml 0.1 M KH 2 PO 4 buffer pH7.4) at 37 0 C for 10 min in a 96-deep well plate.
  • NADPH 46 ⁇ L
  • the reaction mixtures are transferred to a 384-well plate containing acetonitrile to quench the reaction at time 0, 10, 20, 30 minutes.
  • the 384 well plate is centrifuged for 30 min at 9000g, at 4°C, from which samples are analyzed by LC/MS (model: XDB Eclipse Cl 8). Three references are analyzed by LC/MS as a positive control. Data are processed following a standard procedure. The metabolic stability of assayed compounds is expressed as ⁇ L/min/mg
  • metabolic stabilities (hClint and rClint) and soluabilities (aqueous) of selected compounds of the invention are determined using one or more assays described above. It is found that the selected compounds have improved metabolic stabilities and/or soluabilities in water. The metabolic stabilities and soluabilities for these selected compounds are illustrated in Table 1 below.
  • Step A N-[2-tert-Butyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH-benzimidazol-5-yl]- N-methylcyclopropanesulfonamide
  • Methyl (4-fluoro-3-nitrophenyl)carbamate (2.Og, 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°C for 48h. 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 ⁇ 2/Z ⁇ pyran-4- ylmethyl)amino]phenyl ⁇ carbamate
  • Methyl ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino] ⁇ henyl ⁇ carbamate (2.53g, 8.18 mmol) was dissolved in 50 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken under H 2 atmosphere (40 psi) using a Parr hydrogenation apparatus overnight at rt. The solution was filtered through Celite and the solvent was evaporated. Yield: 2.29g (99%).
  • Step E Methyl [2-to ⁇ -butyl-l-(tetrahydro-2H-pyran-4-ylmethyI)-lH- benzimidazol-5-yl] carbamate
  • Methyl ⁇ 3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl ⁇ carbamate (2.29g, 8.20 mmol) and DMAP (0.2Og, 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°C for Ih using a Personal Chemistry microwave apparatus. The solvent was evaporated.
  • Step F 2-te ⁇ -ButyI-N-methyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH- benzimidazol-5-amine
  • Step A N- ⁇ 2-te ⁇ -Butyl-l-[(4,4-difluorocyclohexyl)methyl]-li ⁇ -benzimidazol-5- yl ⁇ -iV-methyIbutane-l-sulfbnamide
  • Step B tert-B ⁇ tyl [(4,4-difluorocyclohexyl)methyl] carbamate
  • Step C [(4,4-Difluorocyclohexyl)methyl] amine hydrochloride
  • Step D Methyl (4- ⁇ [(4,4-difluorocyclohexyl)methyl]amino ⁇ 3- nitrophenyl)carbamate
  • Step E Methyl (3-amino-4- ⁇ [(4,4- difluorocyclohexytymethyljaminojphenyrjcarbamate
  • Step F Methyl ⁇ 2-te ⁇ -butyl-l-[(4,4-difluorocyclohexyl)methyl]-l/r- benzimidazol-5-yl ⁇ carbamate
  • Methyl (3-amino-4- ⁇ [(4,4-difluorocyclohexyl)methyl]amino ⁇ phenyl)carbamate (185 mg, 0.590 mmol) and DMAP (15 mg, 0.118 mmol) were dissolved in 10 mL of DCM. Trimethylacetyl chloride (0.080 mL, 0.649 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 solvent was concentrated.
  • Step G 2-tert-ButyI-l-[(4,4-difluorocyclohexyl)methyl]-A'-methyl-lH r - benzimidazol-5-amine
  • Step A iV-Methyl-A r -[l-(tetrahydro-2J?-pyran-4-ylmethyl)-2-(trifluoromethyl)- li ⁇ -benzimidazol-5-yl]propane-l-sulfonamide
  • the reaction mixture was stirred overnight at room temperature, diluted with DCM (50 mL), washed with saturated NaHCO 3 (2x10 mL) and dried over Na 2 SO 4 .
  • the crude product was purified by MPLC using Hex/EtOAc (1 : 1) on silica gel to give 40 mg (47%) of a white solid as the title compound.
  • Step C ⁇ r -(4-fluoro-3-nitrophenyI)-iV-methylacetainide
  • Step D iV-methyI-iV- ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl)amino]phenyl ⁇ acetamide
  • Step E iV- ⁇ 3-Amino-4-[(tetrahydro-21- r -pyran-4-yImethyl)amino]phenyl ⁇ -iV- methylacetamide
  • N-Methyl-N- ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmetihyl)amino]phenyl ⁇ acetaniide (21.7 g, 70.5 mmol) was hydrogenated in ethyl acetate (500 niL) catalyzed by 10% Pd/C (1.0 g) at 30-40 psi H 2 in Parr shaker for 18 h at room temperature. After filtration through celite and concentration, 19.6 g (100%) of a purple solid was obtained.
  • Step F -V-Methyl-iV- [l-(tetrahydro-2J ⁇ -pyran-4-ylmethyl)-2-(trifluoromethyl)- li?-benzimidazoI-5-yl] acetamide
  • Step G iV-Methyl-l-(tetrahydro-2ia r -pyran-4-ylmethyI)-2-(trifluoromethyl)-lH- benzimidazol-5-amine
  • Step A iV- ⁇ 2-ter/-Butyl-l-[(4,4-difluorocyclohexyl)methyl]-li?-benziniidazol-5- yljpropane-l-sulfonamide
  • Step B iV-(4- ⁇ [(4,4-Difluorocyclohexyl)methyl]amino ⁇ -3-nitrophenyl)acetamide
  • N-(4-Fluoro-3-nitrophenyl)acetamide (1.15 g, 5.84 mmol) and [(4,4- difluorocyclohexyl)methyl] amine hydrochloride (1.3Og, 7.59 mmol) were stirred in 30 mL of EtOH containing TEA (2.40 niL, 17.5 mmol) at 80°C for 48h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO 4 solution, saturated aqueous NaHCO 3 solution, saturated aqueous NaCl solution and dried over anhydrous Na 2 SO 4 . The product was crystallized from EtOAc.
  • Step C iV-(3-Ainino-4- ⁇ [(4,4-difluorocyclohexyl)methyl]ammo ⁇ phenyl) acetamide
  • N-(4- ⁇ [(4,4-Difluorocyclohexyl)methyl]amino ⁇ -3-nitrophenyl)acetamide (1.48 g, 4.52 mmol) was dissolved in 50 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken in a Parr hydrogenation apparatus under H 2 atmosphere (45 psi) at rt for 24h. The solution was filtered through Celite and the solvent was evaporated. Yield: 1.32 g (98%).
  • Step D iV- ⁇ 2-te ⁇ -Butyl-l-[(4,4-difluorocyclohexyl)methyl]-lJ ⁇ -benziinidazol-5- yl ⁇ acetamide
  • N-(3-Amino-4- ⁇ [(4,4-difiuorocyclohexyl)methyl]amino ⁇ phenyl) acetamide (1.32 g , 4.44 mmol) was dissolved in 100 mL of DCM containing DMAP (108 mg, 0.89 mmol). Trimethylacetyl chloride (0.60 mL, 4.88 mmol) was added dropwise and the solution was stirred at rt for 2h. The solution was washed with saturated aqueous NaHCO 3 solution, saturated aqueous NaCl solution and dried over anhydrous Na 2 SO 4 . Part of the product precipitated during the washings and was filtered. The organic phase was evaporated and combined with the precipitate.
  • the product was dissolved in 30 mL of AcOH and placed in 6 sealed tubes (5 mL/tube). Each tube was heated at 150°C in a Personal Chemistry microwaves instrument for 2.5h. The fractions were pooled and the solvent was evaporated. The product was dissolved in EtOAc and washed with aqueous NaHCO 3 solution, saturated aqueous NaCl solution and dried over anhydrous Na 2 SO 4 . The product was purified by silica gel flash chromatography using 2:1 / acetone:hexanes as eluent. Yield: 1.11 g (68%).
  • Step E 2-ter ⁇ -ButyI-l-[(4,4-difluorocycIohexyI)methyl]-l J £r-benzimidazol-5-amine
  • N- ⁇ 2-tert-Butyl- 1 -[(4,4-difluorocyclohexyl)methyl]- lH-benzimidazol-5-yl ⁇ acetamide (500 mg, 1.37 mmol) was dissolved in 10 mL of 1:1 / EtOH:2M HCl. The solution was divided into two sealed tubes (5 mL/tube). Each tube was heated at 120°C in a Personal Chemistry microwaves instrument for Ih. The fractions were pooled and the solvent was evaporated. The residue was diluted with 2M NaOH and extracted (3X) with EtOAc. The organic phase was washed with saturated aqueous NaCl solution and dried over anhydrous Na 2 SO 4 . The solvent was evaporated.
  • Step A iV-[l-[(4.4-Difluorocyclohexyl)methyl]-2-(l,l-difluoroethyl)-li ⁇ - benzimidazol-5-yI]cyclopropanesulfonamide
  • N-[ 1 -[(4,4-Difluorocyclohexyl)methyl]-2-( 1 , 1 -difluoroethyl)- l.H-benziniidazol-5- yl]acetamide (for preparation see the following step B) (95 mg, 0.256 mmol) was heated in 5 niL of 1 : 1 / 2M ⁇ Cl. ⁇ tO ⁇ at 120°C for Ih using a Personal Chemistry microwaves instrument. The solvent was evaporated. The residue was basif ⁇ ed with 2M NaOH and extracted (3X) with EtOAc. The organic phase was washed with saturated aqueous NaCl solution and dried over anhydrous Na 2 SO 4 . The solvent was evaporated.
  • the product was dissolved in 5 mL of DCM containing DMAP (31 mg, 0.256 mmol) and cyclopropanesulfonyl chloride (53 mg, 0.384 mmol) was added. The solution was stirred at rt for 3h. The solution was washed with saturated aqueous NaHCO 3 solution, brine and dried over anhydrous MgSO 4 . The solvent was evaporated and the product was purified by reversed-phase HPLC using 10-70% CH 3 CN/H 2 O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 35 mg (25%).
  • Step B iV-[l-[(4,4-DifluorocycIohexyl)methyl]-2-(l J l-difluoroethyl)-li2 r - benzimidazol-5-yl] acetamide
  • the product was dissolved in 5 mL of DCM containing DMAP (31 mg, 0.256 mmol) and ethanesulfonyl chloride (0.026 mL, 0.280 mmol) was added. The solution was stirred at rt for 2h. The solution was washed with saturated aqueous NaHCO 3 solution, brine and dried over anhydrous MgSO 4 . The solvent was evaporated and the product purified by reversed-phase HPLC using 10-70% CH 3 CN/H 2 O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 22 mg (19%).
  • Step A iV-[2-(l,l-difluoroethyl)-l-(tetrahydro-2i ⁇ -pyran-4-ylmethyl)-lJ ⁇ - benzimidazol-5-yI]-iV-methylethanesulfonamide
  • Step B iV- ⁇ 5-[Acetyl(methyl)amino]-2-[(tetrahydro-2i?-pyran-4- ylmethyl)amino]phenyl ⁇ -2,2-difluoropropanamide
  • Step C iV-[2-(l,l-Difluoroethyl)-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH- benzimidazol-5-yl]-iV-methylacetamide
  • Step A iV- ⁇ 2-fert-Butyl-l-[(4-fluorocyclohexyl)methyl]-l J H-benzimidazol-5- yl ⁇ ethanesulfonamide
  • Step B tert-Butyl [(4-fluorocyclohex-3-en-l-yl)methyl] carbamate
  • Step C [(4-Fluorocyclohex-3-en-l ⁇ yl)methyl] amine hydrochloride
  • Step C iV-(4- ⁇ [(4-Fluorocyclohex-3-en-l-yl)methyI]amino ⁇ -3- nitrophenyl)acetamide
  • iV-(4-Fluoro-3-nitrophenyl)acetamide (460 mg, 2.32 mmol) and [(4-fluorocyclohex-3- en-l-yl)methyl] amine hydrochloride (350 mg, 2.11 mmol) were stirred in 20 mL of EtOH containing TEA (0.735 mL, 5.28 mmol) at 75°C for 48h. The solvent was concentrated. 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 .
  • Step D iV-(3-Amino-4- ⁇ [(4-fluorocyclohexyl)raethyl]amino ⁇ phenyI)acetamide
  • N-(4- ⁇ [(4-Fluorocyclohex-3-en- 1 -yl)methyl]amino ⁇ -3-nitroplienyl)acetamide (340mg, 1.11 mmol) was dissolved in 25 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken under H 2 atmosphere (40 psi) using a Parr hydrogenation apparatus at rt for 48h. The solution was filtered through celite and the solvent was evaporated. Yield: 3O8mg (99%). MS (ESI) (M+H) + 279.95.
  • Step E iV- ⁇ 2-terf-Butyl-l-[(4-fluorocyclohexyl)methyl]-lfl-benzimidazol-5- yl ⁇ acetamide
  • N-(3-Amino-4- ⁇ [(4-fluorocyclohexyl)methyl]amino ⁇ phenyl)acetamide 300 mg, 1.07 mmol
  • DMAP 25 mg, 0.214 mmol
  • Trimethylacetyl chloride (0.145 mL, 1.18 mmol) was added dropwise and the solution was stirred at rt for Ih.
  • the solution was washed with aqueous NaHCO 3 solution, brine and dried over anhydrous MgSO 4 .
  • the residue was dissolved in 5 mL of AcOH and was heated at 150°C for 2.5h using a Personal Chemistry microwave apparatus. The solvent was evaporated.
  • Step F 2-ter ⁇ -Butyl-l-[(4-fluorocyclohexyl)methyl]-li ⁇ -benzimidazol-5-amine
  • Step A iV- ⁇ 2-ter ⁇ -butyl-l-[(4,4-difluorocyclohexyl)methyl]-li ⁇ -benzimidazol-5- yl ⁇ ethanesulf onamide
  • Step C iV-(4- ⁇ [(4,4-Difluorocyclohexyl)methyl]amino ⁇ -3- nitrophenyl)ethanesulfonamide
  • N-(4-Fluoro-3-nitrophenyl)ethanesulfonamide (26 g, 0.107 mol), [(4,4- difluorocyclohexyl)methyl]amine (approx. 15 g), DIPEA (20 mL) and DMSO (100 mL) were mixed together and heated to 65°C overnight.
  • Ethanolamine (5 g) was added and the reaction mixture was stirred until complete disappearance of JV-(4- fluoro-3-nitrophenyl)ethanesulfonamide (approx. 4-5 hrs.).
  • the room temperature cooled down reaction mixture was poured in cold water (900 mL).
  • the product was extracted with DCM (5 x 200 mL).
  • Step D iV-(3-amino-4- ⁇ [(4,4- difluorocyclohexyl)methyl]amino ⁇ phenyl)ethanesulfonamide
  • Step E iV- ⁇ 2- ⁇ [(4,4-difluorocyclohexyl)methyl]amino ⁇ -5- [(ethylsulfonyl)amino]phenyl ⁇ -2,2-dimethylpropanamide

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Abstract

L'invention concerne des composés de formule (I) ou des sels pharmaceutiquement acceptables desdits composés, formule dans laquelle R1, R2, R3, R4, R5 et G 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/SE2005/001403 2004-09-24 2005-09-22 Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations de ces derniers WO2006033631A1 (fr)

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EP05786553A EP1797077B1 (fr) 2004-09-24 2005-09-22 Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations de ces derniers
AT05786553T ATE545644T1 (de) 2004-09-24 2005-09-22 Benzimidazolderivate, diese enthaltende zusammensetzungen, herstellung davon und anwendungen davon i
BRPI0515897-4A BRPI0515897A (pt) 2004-09-24 2005-09-22 composto, uso do mesmo, composição farmacêutica, e, método para a terapia de dor em um animal de sangue quente, e para a preparação de um composto
AU2005287427A AU2005287427B2 (en) 2004-09-24 2005-09-22 Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof I
ES05786553T ES2380709T3 (es) 2004-09-24 2005-09-22 Derivados de bencimidazol, composiciones que los contienen, su preparación y usos
JP2007533433A JP5053092B2 (ja) 2004-09-24 2005-09-22 ベンゾイミダゾール誘導体、それを含む組成物、その製造方法及びその使用ｉ
MX2007003105A MX2007003105A (es) 2004-09-24 2005-09-22 Derivados de bencimidazol, composiciones que los contienen, sus preparaciones y sus usos i.
KR1020077006658A KR101269869B1 (ko) 2004-09-24 2005-09-22 벤즈이미다졸 유도체, 그를 함유하는 조성물, 그의 제조방법 및 그의 용도
CA2581232A CA2581232C (fr) 2004-09-24 2005-09-22 Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations de ces derniers
CN2005800323399A CN101052639B (zh) 2004-09-24 2005-09-22 苯并咪唑衍生物、含有它们的组合物、其制备方法和其用途
US11/419,603 US7550495B2 (en) 2004-09-24 2006-05-22 Compounds, compositions containing them, preparation thereof and uses thereof I
IL181683A IL181683A0 (en) 2004-09-24 2007-03-01 Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof
NO20072089A NO20072089L (no) 2004-09-24 2007-04-23 Benzimidazolderivater, sammensetninger som inneholder dem, fremstilling derav og anvendelse derav
HK07113080.7A HK1104823A1 (en) 2004-09-24 2007-11-30 Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof i
US12/466,415 US20090221657A1 (en) 2004-09-24 2009-05-15 Compounds, Compositions Containing Them, Preparation Thereof and Uses Thereof I

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007108754A1 (fr) * 2006-03-23 2007-09-27 Astrazeneca Ab Formes cristallines des sels de n-{2-tert-butyl-1-[(4,4- difluorocyclohexyl)méthyl]-1h-benzimidazol-5-yl}éthanesulfonamide
WO2007120101A1 (fr) * 2006-04-18 2007-10-25 Astrazeneca Ab Dérivés de benzimidazole-5-sulfonamide en tant que ligands du récepteur cannabinoïde 1 (cb1)
JP5159630B2 (ja) * 2006-09-13 2013-03-06 協和発酵キリン株式会社 縮環複素環誘導体
US8633235B2 (en) 2003-09-26 2014-01-21 Neomed Institute Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof
US10738016B2 (en) 2015-10-13 2020-08-11 H. Lee Moffitt Cancer Center And Research Institute, Inc. BRD4-kinase inhibitors as cancer therapeutics
WO2022123233A1 (fr) 2020-12-08 2022-06-16 Artelo Biosciences Limited Compositions pharmaceutiques comprenant un agoniste cannabinoïde
WO2023237875A1 (fr) 2022-06-07 2023-12-14 Artelo Biosciences Limited Pluralité de granules

Citations (3)

* 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
WO2005030732A1 (fr) * 2003-09-26 2005-04-07 Astrazeneca Ab Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations de ceux-ci

Patent Citations (3)

* 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
WO2005030732A1 (fr) * 2003-09-26 2005-04-07 Astrazeneca Ab Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations de ceux-ci

Cited By (13)

* 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
WO2007108754A1 (fr) * 2006-03-23 2007-09-27 Astrazeneca Ab Formes cristallines des sels de n-{2-tert-butyl-1-[(4,4- difluorocyclohexyl)méthyl]-1h-benzimidazol-5-yl}éthanesulfonamide
US7566788B2 (en) 2006-03-23 2009-07-28 Astrazeneca Ab Crystalline forms
AU2007239102B8 (en) * 2006-04-18 2011-08-11 Astrazeneca Ab Benzimidazole 5-sulfonamide derivatives as cannabinoid 1 (CB1) receptor ligands
US7615642B2 (en) 2006-04-18 2009-11-10 Astrazeneca Ab Therapeutic compounds
AU2007239102B2 (en) * 2006-04-18 2011-07-07 Astrazeneca Ab Benzimidazole 5-sulfonamide derivatives as cannabinoid 1 (CB1) receptor ligands
JP2009534379A (ja) * 2006-04-18 2009-09-24 アストラゼネカ・アクチエボラーグ カンナビノイド１（ｃｂ１）受容体リガンドとしてのベンゾイミダゾール５−スルホンアミド誘導体
WO2007120101A1 (fr) * 2006-04-18 2007-10-25 Astrazeneca Ab Dérivés de benzimidazole-5-sulfonamide en tant que ligands du récepteur cannabinoïde 1 (cb1)
JP5159630B2 (ja) * 2006-09-13 2013-03-06 協和発酵キリン株式会社 縮環複素環誘導体
US10738016B2 (en) 2015-10-13 2020-08-11 H. Lee Moffitt Cancer Center And Research Institute, Inc. BRD4-kinase inhibitors as cancer therapeutics
US11643396B2 (en) 2015-10-13 2023-05-09 H. Lee Moffitt Cancer Center And Research Institute, Inc. BRD4-kinase inhibitors as cancer therapeutics
WO2022123233A1 (fr) 2020-12-08 2022-06-16 Artelo Biosciences Limited Compositions pharmaceutiques comprenant un agoniste cannabinoïde
WO2023237875A1 (fr) 2022-06-07 2023-12-14 Artelo Biosciences Limited Pluralité de granules

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AU2005287427B2 (en) 2009-03-26
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