EP1797076A1 - Derives de benzimidazole, compositions les contenant et preparation et utilisation desdits derives - Google Patents

Derives de benzimidazole, compositions les contenant et preparation et utilisation desdits derives

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Publication number
EP1797076A1
EP1797076A1 EP05786401A EP05786401A EP1797076A1 EP 1797076 A1 EP1797076 A1 EP 1797076A1 EP 05786401 A EP05786401 A EP 05786401A EP 05786401 A EP05786401 A EP 05786401A EP 1797076 A1 EP1797076 A1 EP 1797076A1
Authority
EP
European Patent Office
Prior art keywords
methyl
compound
mmol
hydroxy
independently selected
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.)
Withdrawn
Application number
EP05786401A
Other languages
German (de)
English (en)
Inventor
Daniel AstraZeneca R & D Montreal PAGÈ
Ziping AstraZeneca R & D Montreal LIU
Maxime AstraZeneca R & D Montreal TREMBLAY
Christopher Astrazeneca R & D Montreal Walpole
Hua AstraZeneca R & D Montreal YANG
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.)
AstraZeneca AB
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/GB2004/004132 external-priority patent/WO2005030762A1/fr
Priority claimed from PCT/GB2004/004112 external-priority patent/WO2005030761A1/fr
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP1797076A1 publication Critical patent/EP1797076A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • 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
    • 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
    • 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
    • C07D405/14—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 three or more hetero rings

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-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.
  • heterocylcoalkyl used alone or as a suffix or prefix, refers to a monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and having no unsaturation.
  • heterocycloalkyl groups include pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, and pyranyl.
  • a heterocycloalkyl group can be unsubstituted or substituted with one or two suitable substituents.
  • the heterocycloalkyl group is a monocyclic or bicyclic ring, more preferably, a monocyclic ring, wherein the ring comprises from 2 to 5 carbon atoms and from 1 to 3 heteroatoms, referred to herein as C 2-5 heterocycloalkyl.
  • 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 and R are independently selected from — H, hydroxy, C 1-4 alkyl, C 3- 6 cycloalkyl, Ci ⁇ aUcoxy-C t ⁇ alkyl, C 1-4 alkoxy, and hydroxy-C 1-4 alkyl; or R 1 and R 2 together with the nitrogen linked thereto form a C 2-5 cycloheteroalkyl; and
  • 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 and R 2 are independently selected from -H, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, and hydroxy-C 1-4 alkyl;
  • 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 and R 2 are independently selected from -H, hydroxy, methyl, 2- hydroxylethyl;
  • 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 selected from -O- and -CF 2 -;
  • R 1 and R 2 are independently selected from -H, hydroxy, methyl, 2- hydroxylethyl
  • R 3 , R 4 and R 5 are methyl.
  • G is -O-;
  • R 1 and R 2 are independently selected from -H, hydroxy, methyl, 2- hydroxylethyl with R 1 and R 2 being different groups;
  • R 3 , R 4 and R 5 are methyl.
  • a further embodiment of the invention provides a compound of formula I, wherein G is -CF 2 -;
  • R 1 and R 2 are independently selected from -H, hydroxy, methyl, 2- hydroxylethyl with R and R being different groups;
  • R 3 , R 4 and R 5 are methyl.
  • R 1 and R 2 of formula I together with the nitrogen linked thereto form a C ⁇ cycloheteroalkyl.
  • R 1 and R 2 of formula I together with the nitrogen linked thereto form a C 2-5 cycloheteroalkyl selected from morpholinyl, isoxazolidinyl, and azetindinyl.
  • R 1 and R 2 of formula I are independently selected from -H, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy, and hydroxy-C 1-4 alkyl.
  • G of formula I is -CF 2 -.
  • G of formula I is -O-.
  • G of formula I is -CHF-.
  • R 3 , R 4 and R 5 are methyl.
  • R 3 , R 4 and R 5 are -F.
  • a further embodiment of the invention provides a compound selected from pharmaceutically acceptable salts thereof.
  • 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 orj?-toluenesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate orj?-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.
  • 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, intracerebroventricularly 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.
  • 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.
  • 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:
  • Another embodiment of the method of preparing a compound of formula I includes reacting a compound of formula II with HNR 1 R 2 in the presence of at least one coupling reagent.
  • the method of preparing a compound of formula I include reacting a compound of formula II with HNR 1 R 2 in the presence of one coupling reagent, wherein said reagent is selected from HATU and EDC.
  • Compounds of the present invention may also be prepared according to the synthetic routes as depicted in Schemes 1 and 2.
  • solvent e.g. AcOH acid, e.g. AcOH microwave oven heating, 100-19O 0 C
  • Oxidant e.g., oxone
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • hCBi and I1CB2 receptor binding Human CB 1 receptor from Receptor Biology (!1CB 1 ) or human CB 2 receptor from BioSignal (hCB 2 ) membranes are thawed at 37 °C, passed 3 times through a 25- gauge blunt-end needle, diluted in the cannabinoid binding buffer (50 niM 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 niM 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 I1CB 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 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.
  • GTP ⁇ S 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 5 100 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 (I1CB2) 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 (!1CB 1 ) GDP final).
  • the plates are vortexed and incubated for 60 minutes at room temperature, filtered on Unifilters 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 0 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.
  • 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.
  • Ki towards human CB 1 receptors for certain compounds of the invention are in the range of between 3 nM and 404 nM.
  • EC50 for these compounds are in the range of between 1 nM and 278 nM.
  • Emax for these compounds are in the range of between 122% and 154%.
  • Step A 2-tert-Butyl-N-methyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH- benzimidazol-5-amine
  • 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°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-2H-pyran-4- ylmethyl)amino] phenyl ⁇ carbamate
  • Methyl ⁇ 3-mtro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl ⁇ carbamate (2.53 g, 8.18 mmol) was dissolved in 50 niL 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.
  • 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-ylmethyl)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°C for Ih using a Personal Chemistry microwave apparatus. The solvent was evaporated.
  • Step A iV-methyl-l-(tetrahydro-2J3-pyran-4-ylmethyI)-2-(trifluoromethyl)-li ⁇ - benzimidazol-5-amine
  • Step D iV-methyI-iV- ⁇ 3-nitro-4-[(tetrahydro-2J9 r -pyran-4- ylmethyl)amino] phenyl ⁇ acetamide
  • Step E iV- ⁇ 3-amino-4-[(tetrahydro-2 J H r -pyran-4-ylmethyl)amino]phenyl ⁇ -iV- methylacetamide
  • N-methyl-N- ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-yhnethyl)amino]phenyl ⁇ acetamide 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-[l-(tetrahydro-2i ⁇ -pyran-4-ylmethyl)-2-(trifluoromethyl)- l/T-benzimidazol-S-yl] acetamide
  • Step A 4- ⁇ [[2-tert-Butyl-l-(tetrahydro-2H-pyran-4-yImethyl)-lH-benzimidazoI- 5-yI] (methyl)amino] suIfonyl ⁇ -N-(2-hydroxyethyl)benzamide
  • Step B N-[2-tert-Butyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH-benzimidazol-5- yI]-4-formyl-N-methylbenzenesulfonamide
  • Step C 4- ⁇ [[2-tert-Butyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH-benzimidazol- 5-yl](methyl)amino]sulfonyl ⁇ benzoic acid
  • N-[2-tert-Butyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH-benzimidazol-5-yl]-4- formyl-N-methylbenzenesulfonamide (620 mg, 1.32 mmol) was dissolved in 50 mL of DMF. Oxone (1.22 g, 1.98 mmol) was added and the solution was heated at 50°C for 48h. The solvent was evaporated. The residue was dissolved in water and extracted 3X with DCM. The organic phases were combined and washed with brine and dried over anhydrous MgSO 4 . The solvent was evaporated.
  • N-Methyldroxylamine hydrochloride 25 mg, 0.299 mmol
  • HATU 83 mg, 0.219 mmol
  • DIPEA 0.175 mL, 0.995 mmol
  • the product was dissolved in EtOAc and washed with saturated aqueous NaHCO 3 solution, brine and dried over anhydrous MgSO 4 .
  • 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: 6 mg (6%).
  • Step A 4- ⁇ [ ⁇ 2-terf-Butyl-l-[(4,4-difluorocyclohexyl)methyl]-lfT-benzimidazol-5- yl ⁇ (methyl)amino] sulfonyl ⁇ -iV-(2-hydroxyethyl)benzamide
  • Step B tert-Butyl [(4,4-difluorocyclohexyl)methyl] carbamate
  • Step F Methyl ⁇ 2-te ⁇ -butyl-l-[(4,4-difluorocyclohexyl)methyl]-lJ ⁇ - 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-ter/-Butyl-l-[(4,4-difluorocyclohexyl)methyl]-iV-methyl-l J H r - benzimidazol-5-amine

Abstract

Composés de formule (I), ou sels pharmaceutiquement acceptables desdits composés, dans laquelle G, R1, R2, R3, R4 et R5 sont tels que définis dans le descriptif, ainsi que sels et compositions pharmaceutiques contenant lesdits composés. Ces composés ont une utilité thérapeutique, en particulier pour la gestion de la douleur.
EP05786401A 2004-09-24 2005-09-22 Derives de benzimidazole, compositions les contenant et preparation et utilisation desdits derives Withdrawn EP1797076A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/GB2004/004132 WO2005030762A1 (fr) 2003-09-26 2004-09-24 Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations
PCT/GB2004/004112 WO2005030761A1 (fr) 2003-09-26 2004-09-24 Derives de benzimidazole, compositions les contenant, preparation de ces compositions et utilisations correspondantes
US64049804P 2004-12-30 2004-12-30
PCT/SE2005/001400 WO2006033628A1 (fr) 2004-09-24 2005-09-22 Derives de benzimidazole, compositions les contenant et preparation et utilisation desdits derives

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SE0302573D0 (sv) 2003-09-26 2003-09-26 Astrazeneca Ab Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof
BRPI0515897A (pt) 2004-09-24 2008-08-12 Astrazeneca Ab 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
TW200745049A (en) 2006-03-23 2007-12-16 Astrazeneca Ab New crystalline forms
TW200808769A (en) 2006-04-18 2008-02-16 Astrazeneca Ab Therapeutic compounds
EP2417123A2 (fr) 2009-04-06 2012-02-15 Agios Pharmaceuticals, Inc. Compositions thérapeutiques et procédés d'utilisation associés
EP2448582B1 (fr) 2009-06-29 2017-04-19 Agios Pharmaceuticals, Inc. Dérivés de quinoline-8-sulfonamide ayant une activité anticancéreuse
ES2618630T3 (es) 2009-06-29 2017-06-21 Agios Pharmaceuticals, Inc. Composiciones terapéuticas y métodos de uso relacionados
MX2013006900A (es) * 2010-12-17 2013-10-17 Agios Pharmaceuticals Inc Nuevos derivados n-(4-(azetidina-1-carbonil)fenil)-(hetero-)arilsu lfonamida como moduladores piruvato quinasa m2 (pmk2).
CA2822432C (fr) 2010-12-21 2019-09-24 Agios Pharmaceuticals, Inc. Activateurs bicycliques de pkm2
TWI549947B (zh) 2010-12-29 2016-09-21 阿吉歐斯製藥公司 治療化合物及組成物
HUE039269T2 (hu) 2011-05-03 2018-12-28 Agios Pharmaceuticals Inc Piruvát-kináz aktivátorok terápiában történõ alkalmazásra
US9388164B2 (en) 2011-05-03 2016-07-12 Agios Pharmaceuticals, Inc Methods of using pyruvate kinase activators
WO2014074848A1 (fr) 2012-11-08 2014-05-15 Agios Pharmaceuticals, Inc. Composés et compositions thérapeutiques et leur utilisation comme modulateurs de pkm2
WO2014139144A1 (fr) 2013-03-15 2014-09-18 Agios Pharmaceuticals, Inc. Composés et compositions thérapeutiques
US11234976B2 (en) 2015-06-11 2022-02-01 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators

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