WO2006033627A1 - Composes, compositions les contenant, leur preparation et leur utilisation - Google Patents

Composes, compositions les contenant, leur preparation et leur utilisation Download PDF

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Publication number
WO2006033627A1
WO2006033627A1 PCT/SE2005/001399 SE2005001399W WO2006033627A1 WO 2006033627 A1 WO2006033627 A1 WO 2006033627A1 SE 2005001399 W SE2005001399 W SE 2005001399W WO 2006033627 A1 WO2006033627 A1 WO 2006033627A1
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Prior art keywords
methyl
alkyl
compound
ylmethyl
benzimidazol
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PCT/SE2005/001399
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English (en)
Inventor
Daniel PAGÈ
Ziping Liu
Maxime Tremblay
Claire Milburn
Christopher Walpole
Hua Yang
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Astrazeneca Ab
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Priority claimed from PCT/GB2004/004112 external-priority patent/WO2005030761A1/fr
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to EP05784565A priority Critical patent/EP1797074A4/fr
Priority to JP2007533429A priority patent/JP2008514589A/ja
Publication of WO2006033627A1 publication Critical patent/WO2006033627A1/fr

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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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • C07D405/14—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 predominantly 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 CBi 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, Q ⁇ 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.
  • heterocycle used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s).
  • Heterocycle may be saturated or unsaturated, containing one or more double bonds, and heterocycle may contain more than one ring.
  • the rings may be fused or unfused.
  • Fused rings generally refer to at least two rings sharing two atoms therebetween.
  • Heterocycle may have aromatic character or may not have aromatic character.
  • Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane 2,3-dihydrofuran, 2,5- dihydrofuran tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperidine, 2,3,4,7-tetrahydro-lH-azepine homopiperazine, 1,
  • heterocycle includes aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1,2,3-triazole, tetrazole, 1,2,3- thiadiazole, 1,2,3-oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4- triazole, 1,3,4-thiadiazole, and 1,3,4- oxadiazole.
  • aromatic heterocycles for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, is
  • heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3 -dihydrobenzo furan, isobenzofuran, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine, 1,2- benzisoxazole, benzothiophene, benzox
  • heterocycle includes polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings.
  • bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane.
  • heterocycloalkyl 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 - A -
  • 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 1 and R 2 are independently selected from -H, C 1-4 alkyl, hydroxy-Ci -4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, and C ⁇ alkoxy; or R 1 and R 2 together with the N to which they are bound may form a C 3-6 heterocycle; 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, C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, and C 1-4 alkoxy; or R 1 and R 2 together with the N to which they are bound may form a C 3-6 heterocycle; and
  • 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, C 1-4 alkyl, and hydroxy-Q. 4 alkyl, C 1-4 alkoxy-C 1-4 alkyl; or R 1 and R 2 together with the N to which they are bound may form a Ca-sheterocycloalkyl; and
  • 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 -O-
  • R 1 and R 2 are independently selected from -H, C 1-4 alkyl and hydroxy-Ci. 4 alkyl, and C 1-4 alkoxy-C 1-4 alkyl with R 1 and R 2 being different groups; or R 1 and R 2 together with the N to which they are bound may form a group selected from 2- oxopyrrolidin-1-yl, pyrrolidin-1-yl, lH-l,2,3-triazol-l-yl, and morpholinyl group; 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 and R 2 are independently selected from -H, C 1-4 alkyl and hydroxy-Q.
  • a further embodiment of the invention provides a compound selected from
  • 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 orp-toluenesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate orp-toluenesulphonate.
  • the compounds of the invention exhibit selective activity as agonists 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. 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.
  • 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.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the term “therapeutic” and “therapeutically” should be construed 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.
  • 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 or 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 tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component. In tablets, 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.
  • the term 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 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.
  • a pharmaceutical 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:
  • a compound of formula I may be prepared by reacting a compound of Formula II with a compound III followed by a sequence of reactions including 1) reduction with a reducing agent , such as Na(CN)BH 3 , 2) methanesulfonylation and 3) nucleophilic substitution with R 1 CR ⁇ NH, wherein G, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • DMAP solvent e.g. THF solvent
  • DMF coupling reagent e.g. HATU
  • solvent e.g. AcOH acid, e.g. AcOH microwave oven heating, 100-190 0 C
  • HATU acid e.g. cone. HCI heating, 50-150 0 C
  • solvent e.g. AcOH acid, e.g. AcOH or HCI or P 2 O 5 microwave oven heating, 100-190 0 C
  • R 1 (R 2 )NH reducing reagent e.g. NaBH 3 (CN) acid, e.g. HOAc solvent, e.g. MeOH
  • R i , R 2 , R 3 , R 4 and R 5 are as defined above.
  • the IC 50 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
  • 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 °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 Emax 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 (hCBO 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 °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 8 nM and 1175 nM.
  • EC 50 for these compounds are in the range of between 12 nM and 49 nM.
  • Emax for these compounds are in the range of between 109% and 143%.
  • Step A ⁇ r - ⁇ 2-tert-butyl-l-[(4,4-difluorocyclohexyl)methyI]-lJ ⁇ -benzimidazol-5- yl ⁇ -4- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -iV-methylbenzenesulfonamide
  • Step D iV-(4- ⁇ [(4,4-difluorocyclohexyl)methyl] amino ⁇ -3-nitrophenyl)-iV- methylacetamide
  • Step E iV-(3-amino-4- ⁇ [(4,4-difluorocyclohexyl)methyl] amino ⁇ phenyl)-iV- methylacetamide
  • Step F N- ⁇ 2-ter/-butyl-l-[(4,4-difluorocyclohexyI)methyl]-lH-benzimidazol-5- yl ⁇ -iV-methylacetaniide
  • Trimethylacetyl chloride (0.29 mL, 2.41 mmol) was dropwise added to a solution of iV-(3-amino-4- ⁇ [(4,4-difluorocyclohexyl)methyl]amino ⁇ phenyl)-iV-methylacetamide (716 mg, 2.30 mmol) and Et 3 N (0.38 mL, 2.75 mmol) in dichloromethane (100 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 (16 mL) and then divided to 4 sealed test tubes.
  • Step G 2-tert-butyl-l-[(4 5 4-difluorocyclohexyl)methyl]-N-methyl-lH- benzimidazol-5-amine
  • Step H iV- ⁇ 2-te ⁇ -butyl-l-[(4,4-difluorocyclohexyl)methyl]-l J H r -benzimidazol-5- yl ⁇ -4-formyl-iV-methylbenzenesulfonamide
  • Step A N- [2-tert-Butyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lJ3-benzimidazol-5- yl]-4- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -iV-methylbenzenesulfonainide
  • Step B iV-methyl-Ty-IS-nitro ⁇ -l ⁇ etrahydro-lH-pyran ⁇ - ylmethyl) amino] phenyl ⁇ acetamide
  • Step C iV- ⁇ 3-ami ⁇ o-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl ⁇ -iV- methylacetamide
  • N-methyl-N- ⁇ 3-nitro-4-[(tetrahydro-2Jf-pyran-4-ylmethyl)amino]phenyl ⁇ acetamide (.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.O g (100%) of a purple solid was obtained as HCl salt, which was used in the next step without purification.
  • Step D /V-[2-ter ⁇ -butyl-l-(tetrahydro-2H r -pyran-4-ylmethyl)-lH-benzimidazol- 5-yl]-iV-methylacetamide
  • Trimethylacetyl chloride (3.27 mL, 3.20 g, 26.5 mmol) was added dropwise to a solution of iV- ⁇ 3-amino-4-[(tetrahydro-2Jf-pyran-4-ylmethyl)amino]phenyl ⁇ -iV- methylacetamide (7.01 g, 25.3 mmol) and DIPEA (5.3 mL, 3.92 g, 30.36 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.
  • Step E 2-ter/-butyl-N-methyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-l J H- b enzimidazol-5-amine
  • Step A ⁇ r -[2-/ert-Butyl-l-(tetrahydro-2J ⁇ -pyran-4-ylmethyl)-li ⁇ -benzimidazol-5- yl]-7V-raethyl-4-(morpholin-4-ylmethyl)benzenesulfonamide
  • Step A N- [2-tert-Butyl-l-(tetrahydro-2H-py ran-4-ylmethyl)-liZ-b enzimidazol-5- yl]- ⁇ / -methyl-4-(lH-l,2,3-triazol-l-ylmethyl)benzenesulfonamide
  • Step B N-[2-fe ⁇ Butyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH-benzimidazol-5-yl]-4- (hydxoxymethyl)-N-methylberizenesulfonamide (for preparation, see the following Step B) (55 mg, 0.117 mmol) and TEA (0.025 mL, 0.176 mmol) were dissolved in 5 mL of DCM at 0°C. Methanesulfonyl chloride (0.011 mL, 0.140 mmol) was added dropwise and the solution stirred at rt for 3h. The solution was washed with saturated aqueous NaHCO 3 , brine and dried over anhydrous Na 2 SO 4 .
  • Step B iV-tZ-fert-Butyl-l- ⁇ etrahydro ⁇ H-pyran ⁇ -ylmethy ⁇ -lH-benzimidazol-S- yl] -4-(hy dr oxymethyl)-iV-methyIb enzenesulf onamide
  • Step A iV-[2-tert-Butyl-l-(tetrahydro-2J ⁇ -pyran-4-ylmethyl)-]jH-benzimidazol-5- yl]-iV-methyl-4-[(methylamino)methyl]benzenesulfonamide
  • Step C Methyl ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl)amino]phenyl ⁇ carbamate
  • 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-2J3-pyran-4- ylmethyl)amino]phenyl ⁇ carbamate
  • Methyl ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-yhnethyl)amino]phenyl ⁇ 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-tot-butyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH- benzimidazol-5-yl] carbamate
  • Methyl ⁇ 3-amino-4-[(tetrahydro-2H " -pyran-4-ylmethyl)amino]phenyl ⁇ carbamate (2.29g, 8.20 mmol) and DMAP (0.2Og, 1.64 rnmol) 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-tert-Butyl-N-methyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH- benzimidazol-5-amine
  • Step G ⁇ r -[2-tert-Butyl-l-(tetrahydro-2i ⁇ -pyran-4-ylmethyl)-l J H r -benzimidazol-5- yl] -4-f ormyl-TV-methylb enzenesulf onamide
  • Step A N-[2-ter ⁇ Butyl-l-(tetrahydro-2H-pyran-4-ylraethyl)-li ⁇ -benzimidazol-5- yl]--V-methyl-4-[(2-oxopyrrolidin-l-yl)methyl]benzenesulfonamide
  • Step B iV-[2-te ⁇ -Butyl-l-(tetrahydro-2J3-pyran-4-ylmethyl)-lJ?-benzimidazol-5- yl]-4-(hydroxymethyl)-iV-methylbenzenesuIfonamide
  • Step A iV-[2-(l,l-Difluoroethyl)-l-(tetrahydro-2 J H-pyran-4-ylmethyl)-l J H r - benzimidazol-5-yl] -4- ⁇ [(2-hydroxyethyl)amino] methyl ⁇ -iV- methylbenzenesulfonamide
  • Ethanolamine (0.57 mL, 9.50 mmol) was added to a mixture of iV-P-Qjl- difluoroethyty-l- ⁇ etrahydro ⁇ H-pyran ⁇ -ylmethy ⁇ iV-methylbenzenesulfonamide (454 mg, 0.95 mmol) (for preparation, see the following steps B to D) and MeOH (15 mL).
  • the reaction mixture was stirred for 30 min. and AcOH (2 drops) was added.
  • the reaction mixture was stirred for 1 hr. and NaBH 4 was added.
  • the reaction mixture was stirred for 3hrs. and the solvent was evaporated.
  • Step B iV-tl-Cljl-difluoroethy ⁇ -l-Ctetrahydro-lH-pyran ⁇ -ylmethyO-lH- benzimidazol-5-yl]-N-methylacetamide
  • HATU (3.76 g, 9.91 mmol) andiV- ⁇ 3-amino-4-[(tetrahydro-2H " -pyran-4- ymiethyl)amino]phenyl ⁇ -iV-methylacetamide (2.50 g, 9.01 mmol) (for preparation, see Steps B and C in Example 2) were added to a solution of 2,2-difluoropropanoic acid (0.99 g, 9.01 mmol) and DIPEA (1.88 mL, 10.8 mmol) in DMF (100 mL) at 0°C. The reaction mixture was stirred for 5 hrs and the solvent was concentrated.
  • Step C 2-(l,l-difluoroethyl)-iV-methyl-l-(tetrahydro-2H r -pyran-4-ylmethyl)-lH r - benzimidazol-5-amine
  • Step D iV-[2-(l,l-Difluoroethyl)-l-(tetrahydro-2 J H-pyran-4-ylmethyl)-lH- benzimidazol-5-yl]-4-forrayl-A'-metliylbenzenesulfonamide

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Abstract

L'invention concerne des composés de formule (I), ou leurs sels pharmaceutiquement acceptables, G, R1, R2, R3, R4, et R5 sont spécifiés dans la description et des compositions pharmaceutiques comprenant les composés étant préparées. Les composés sont utilisés dans des thérapies, en particulier dans la gestion de la douleur.
PCT/SE2005/001399 2004-09-24 2005-09-22 Composes, compositions les contenant, leur preparation et leur utilisation WO2006033627A1 (fr)

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JP2007533429A JP2008514589A (ja) 2004-09-24 2005-09-22 化合物、それらを含有する組成物、それらの製造及びそれらの使用ｉｉｉｉ

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PCT/GB2004/004112 WO2005030761A1 (fr) 2003-09-26 2004-09-24 Derives de benzimidazole, compositions les contenant, preparation de ces compositions et utilisations correspondantes
GBPCT/GB2004/004112 2004-09-24
SE0500267-0 2005-02-03
SE0500267 2005-02-03

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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 (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020006948A1 (en) * 2000-01-14 2002-01-17 Schering Ag 1,2 diarylbenzimdazoles and their pharmaceutical use
US20040116465A1 (en) * 2001-04-20 2004-06-17 Yun-Xing Cheng Novel compounds
WO2005021547A2 (fr) * 2003-08-28 2005-03-10 Pharmaxis Pty Ltd. Nouveaux agonistes des recepteurs cannabinoides cb2 et utilisations desdits agonistes
WO2005030762A1 (fr) * 2003-09-26 2005-04-07 Astrazeneca Ab Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations
WO2005030761A1 (fr) * 2003-09-26 2005-04-07 Astrazeneca Ab Derives de benzimidazole, compositions les contenant, preparation de ces compositions et utilisations correspondantes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020006948A1 (en) * 2000-01-14 2002-01-17 Schering Ag 1,2 diarylbenzimdazoles and their pharmaceutical use
US20040116465A1 (en) * 2001-04-20 2004-06-17 Yun-Xing Cheng Novel compounds
WO2005021547A2 (fr) * 2003-08-28 2005-03-10 Pharmaxis Pty Ltd. Nouveaux agonistes des recepteurs cannabinoides cb2 et utilisations desdits agonistes
WO2005030762A1 (fr) * 2003-09-26 2005-04-07 Astrazeneca Ab Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations
WO2005030761A1 (fr) * 2003-09-26 2005-04-07 Astrazeneca Ab Derives de benzimidazole, compositions les contenant, preparation de ces compositions et utilisations correspondantes

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Title
HOLENZ J. ET AL: "Medicinal Chemistry Driven Approaches Toward Novel and Selective Serotonin 5-HT6Receptor Ligands", J.MED.CHEM., vol. 48, 2005, pages 1781 - 1795, XP002993846 *
See also references of EP1797074A4 *

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

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