EP1797070A1 - Compounds, compositions containing them, preparations thereof and uses thereof ii - Google Patents
Compounds, compositions containing them, preparations thereof and uses thereof iiInfo
- Publication number
- EP1797070A1 EP1797070A1 EP05784958A EP05784958A EP1797070A1 EP 1797070 A1 EP1797070 A1 EP 1797070A1 EP 05784958 A EP05784958 A EP 05784958A EP 05784958 A EP05784958 A EP 05784958A EP 1797070 A1 EP1797070 A1 EP 1797070A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- methyl
- benzimidazol
- butyl
- pyran
- tert
- 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- Withdrawn
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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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
- C07D405/14—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
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- 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
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.
- CBi receptors located in CNS There are lines of evidence, however, suggesting that CB 1 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 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, Ci -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 unsubstiruted or substituted by one or two suitable substituents.
- the cycloalkyl is a monocyclic ring or bicyclic ring.
- alkoxy 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 apart 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-li/ : -azepme homopipe
- 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-dihydrobenzofuran 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, benzoxazole, benzthiazole, benzimidazole, benztriazole, thioxanthine, carbazole, carboline, acridine, pyrolizidine, and quinolizidine.
- 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.
- the heterocycle is a monocyclic or bicyclic ring, more preferably, a monocyclic ring, wherein the ring comprises from 2 to 6 carbon atoms and from 1 to 3 heteroatoms, referred to herein as C 2 . 6 heterocycle.
- 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 unsaruration.
- 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.
- heterocyclyl refers a monovalent radical derived from a heterocycle by removing one hydrogen therefrom.
- Halogen includes fluorine, chlorine, bromine and iodine.
- RT room temperature
- C 2-5 ACyI groups include, for example, acetyl, propionyl, 2,2-dimethylpropionyl, and methyl-propionyl.
- Link means covalently linked or bonded.
- 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 2 , R 3 and R 4 are independently selected from fluoro and methyl.
- the compounds are those of formula I, wherein
- G is selected from -O- and -CF 2 -;
- R 2 , R 3 and R 4 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 Cs-sheterocycloalkyl and C 2-5 heteroaryl, wherein said C 3-5 heterocycloalkyl or C 2-5 heteroaryl includes at least one nitrogen on said C 3-5 heterocycloalkyl or C 2-5 heteroaryl rings, respectively, one of said at least one nitrogen is directly linked to the sulfonyl group of formula I, and said Cs-sheterocycloalkyl and C 2-5 heteroaryl are optionally substituted with one or more groups selected from halogen, C 1 . 3 alk.oxy, Q.salkylamino and C 2- sacylamino; R 2 , R 3 and R 4 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 is selected from piperidinyl, imidazolyl, pyrazolyl, morpholinyl, pyrrolidinyl, azetidinyl, and isoxazolidinyl, wherein said piperidinyl, imidazolyl, pyrazolyl, morpholinyl, pyrrolidinyl, azetidinyl, and isoxazolidinyl are optionally substituted with one or more groups selected from fluoro and C 2-5 acylamino; R 2 , R 3 and R 4 are selected from fluoro and methyl with a proviso that R 2 , R 3 and R 4 are the same.
- G is selected from -O- and -CF 2 -; R 1 is selected from
- R 2 , R 3 and R 4 are selected from fluoro and methyl with a proviso that R 2 , R 3 and R 4 are the same.
- the compound of formula I is selected from: N-( 1 - ⁇ [ ⁇ 2-tert-Butyl- 1 - [(4,4-difiuorocyclohexyl)methyl]- 1H-benzimidazol-5- yl ⁇ (methyl)amino]sulfonyl ⁇ piperidin-4-yl)acetamide;
- 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 farther be understood that the present invention encompasses tautomers of the compounds of the Formula I.
- salts of the compounds of the Formula I are also salts 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 corresponding alkali metal such as sodium, potassium, or lithium
- an alkaline earth metal such as a calcium
- a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques.
- a suitably acidic proton such as a carboxylic acid or a phenol
- an alkali metal or alkaline earth metal hydroxide or alkoxide such as the ethoxide or methoxide
- a suitably basic organic amine such as choline or meglumine
- the compound of Formula I above may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or j ⁇ -toluenesulphonate.
- an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or j ⁇ -toluenesulphonate.
- the compounds of the invention have activity as pharmaceuticals, in particular as modulators or ligands such as agonists, partial agonists, inverse agonist or antagonists Of CB 1 receptors. More particularly, the compounds of the invention exhibit selective activity as agonist of the CB 1 receptors and are useful in therapy, especially for relief of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Additionally, compounds of the present invention are useful in other disease states in which dysfunction Of CB 1 receptors is present or implicated. 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 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.
- 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, e.g. THF coupling reagent, e.g. HATU
- solvent e.g. AcOH acid, e.g. AcOH microwave oven heating, 100-190 0 C
- solvent e.g. AcCN base, e.g. (IPr) 2 EtN AcCN
- R 1 , R 2 , R 3 and R 4 are as defined above.
- R 1 , R 2 , R 3 and R 4 are as defined above.
- R 2 , R 3 and R 4 are as defined above.
- N ⁇ is a C 2 . 6 heterocyc!yl as used in defining the R 1 above
- X is Acyl-O- or halogen
- Re-N CO solvent, e.g. CH 2 CI 2
- R 2 , R 3 and R 4 are as defined above.
- R 6 is C 1-6 alkyl or C 3 . 6 cycloalkyl
- N " I " is a C 2 . 6 heterocyclyl as used in defining the R 1 above
- X is Acyl-O- or halogen
- hCB ⁇ and hCB? receptor binding Human CBi receptor from Receptor Biology (hCBi) 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 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2 , and 0.5 mg/mL BSA fatty acid free, pH 7.4) and aliquots containing the appropriate amount of protein are distributed in 96-well plates.
- cannabinoid binding buffer 50 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2 , and 0.5 mg/mL BSA fatty acid free, pH 7.4
- the IC 50 of the compounds of the invention at hCBi 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 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.
- GTPYS binding Human CBi 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 rnM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl 2 , pH 7.4, 0.1% BSA).
- the EC 50 and E max of the compounds of the invention are evaluated from 10-point dose- response curves done in 300 ⁇ l with the appropriate amount of membrane protein and 100000-130000 dpm Of GTPg 35 S per well (0.11 -0.14 nM).
- the basal and maximal stimulated binding is determined in absence and presence of 1 ⁇ M (hCB 2 ) or 10 ⁇ M (hCBi) Win 55,212-2 respectively.
- the membranes are pre-incubated for 5 minutes with 56.25 ⁇ M (hCB2) or 112.5 ⁇ M (!1CB 1 ) 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
- 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 1 nM and 2897 nM.
- EC 50 for these compounds are in the range of between 0.58 nM and 7647 nM.
- Emax for these compounds are in the range of between 72% and 161%.
- Step A N-(1- ⁇ [ ⁇ 2-ter ⁇ -Butyl-1-[(4,4-difluorocyclohexyl)methyl]-l J H-benziraidazol- 5-yl ⁇ (methyl)amino]sulfonyl ⁇ piperidin-4-yl)acetaraide
- Acetic anhydride (2.0 mmol) was added into a solution of triethylamine (2.0 mmol) and 4-amino-N- ⁇ 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl ⁇ -N-methylpiperidine-l ⁇ sulfonamide (crude product from step J, 0.9 mmol) in CH 2 Cl 2 (20 mL). After being stirred at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure.
- Step D N-(4- ⁇ [(4,4-Difluorocyclohexyl)methyl]ammo ⁇ -3-nitrophenyl)-N- methylacetamide
- Step E N-(3-Amino-4- ⁇ [(4,4-difluorocyclohexyl)inethyl] amino ⁇ pheny I)-N- methylacetamide
- Step F N- ⁇ 2-te//-ButyI-1-[(4,4-difluorocyclohexyl)methyl]-1H-benziinidazol-5- yl ⁇ -N-methylacetamide
- Trimethylacetyl chloride (0.29 mL, 2.41 mmol) was dropwise added to a solution of N-(3-amino-4- ⁇ [(4,4-difluorocyclohexyl)methyl]atriino ⁇ phenyl)-N-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-fe ⁇ -Butyl-1-[(4,4-difluorocyclohexyl)methyl]-N-methyl-lH r - benzimidazol-5-amine
- Step H 1- ⁇ [ ⁇ 2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-lir-benzimidazol-5- yl](methyl)amino]sulfonyl ⁇ -3-methyl-1H-imidazol-S-ium triflate
- Step I tert-Butyl (l- ⁇ [ ⁇ 2-terj;-butyl-1-[(4,4-difluorocyclohexyl)methyl]-lJ9 r - benzimidazoi-5-yl ⁇ (methyl)amino]sulfonyl ⁇ piperidin-4-yl)carbamate
- Step J 4-Amino-N- ⁇ 2-ter- 1 -butyl-1-[(4,4-difluorocyclohexyl)methyl]-lJ ⁇ - benzimidazol-5-yl ⁇ -N-methylpiperidine-1-sulfonamide
- Step A N-[2-ter ⁇ -ButyI-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl]-N-methylisoxazolidine-2-sulfonamide
- Methyl chloroformate (13.2 mL, 170.2 mmol) was added dropwise to a cold (0 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.
- 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 0 C for Ih using a Personal Chemistry microwave apparatus. The solvent was evaporated.
- Step F 2-tert-Butyl-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-amine
- Step G 1- ⁇ [[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-ljH-benzimidazol- 5-yl](methyl)amino]sulfonyl ⁇ -3-raethyl-1H-imidazol-3-ium triflate.
- Step A N-[2-tert-Butyl-1-(tetrahydro-2 J ⁇ r -pyran-4-ylmethyl)-l J H-benzimidazol-5- yl]-N-methylpyrrolidine-1-sulfonamide
- N-[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1 H-benzimidazol-5-yl]-N- methylsulfamide (for preparation see the following steps B to H) (45 mg, 0.118 mmol) was dissolved in 5 mL of DMF at 0°C. NaH (60% dispersion in oil) (14 mg, 0.354 mmol) was added and the solution was stirred at 0°C for 10 min. 1,4- Dibromobutane (0.014 mL, 0.118 mmol) was added and the solution was stirred at rt for 3h.
- Step B (tert-Butoxy carb onyl) ⁇ [4-(dimethyKminio)pyridin-l (4H)- yl] sulf onyl ⁇ azanide
- Step C N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl]-N-methylsulfamide
- the resulting product was dissolved in 3 mL of IM ⁇ Cl/AcO ⁇ and stirred at rt for Ih. The solvent was evaporated. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO 3 solution, brine and dried over anhydrous MgSO 4 . The solvent was evaporated. The product was dissolved in 3 mL of DMF at O 0 C and NaH (20 mg, 0.492 mmol) was added, followed by 1,5-dibromopentane (0.033 mL, 0.246 mmol). The solution was stirred at rt for 2h. The reaction was quenched with saturated aqueous NaHCO 3 solution and the solvent was evaporated.
- Step B 1- ⁇ [[2-(l,l-Difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-LH- benzimidazol-5-yl](methyl)amino]suIfonyl ⁇ -3-methyl-1H-imidazol-3-ium l-(li7-Imidazol-1-ylsulfonyl)-3-methyl-li/-imidazol-3-ium difluoromethanesulfonate (1.05 g, 2.90 mmol) was added to a solution of 2-(l,l-difluoroethyl)-N-methyl-1- (tetrahydro-2H-pyran-4-ylmethyl)-l ⁇ f-benzimidazol-5 -amine (0.60 g, 1.93 mmol) in MeCN (70 mL) at ambient temperature. The reaction mixture was stirred for 4 hrs. and methyl trifluoromethyl sulfone (0
- fert-Butyl piperidin-4-ylcarbamate (0.43 mg, 1.45 mmol) was added to the reaction mixture (52 mL) prepared in example 1, step B. The resulting reaction mixture was heated to 90 0 C overnight. tert-Butyl piperidin-4-ylcarbamate (0.43 mg, 1.45 mmol) was added again and the reaction mixture was heated to 90°C overnight. The solvent was concentrated and DCM (50 mL) was added to the residue.
- Step A 1- ⁇ [[2-tert-Butyl-1-(tetrahydro-2J3 r -pyran-4-ylmethyl)-1H-benzimidiazol- 5-yl](methyl)amino]sulfonyl ⁇ -N-cyclopropylpiperidine-4-carboxamide
- Step B N-[2-tert-ButyH-(tetrahydro-2H-pyran-4-ylmethyl)-lfT-benzimidazol-5- yl]-N-methyl-1H-imidazole-1-sulfonamide
- Step C 1- ⁇ [[2-tert-Butyl-1-(tetrahydro-2J3-pyran-4-ylmethyl)-1H-benzimidazol- 5-yl](methyl)amino]sulfonyl ⁇ -3-methyHH-imidazol-3-ium
- Step E 1- ⁇ [[2-ter ⁇ -Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benziinidazol- 5-yl] (methyl) amino] sulfonyl ⁇ piperidine-4-carboxylic acid
- Step A N-(l- ⁇ [[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-lJ ⁇ - benzimidazol-5-yl] (methyl)amino] sulfonyl ⁇ azetidin-3- ytycyclopropanecarboxamide
- Step B 3-Araino-N-[2-fe ⁇ -butyl-1-(tetrahydro-2ir-pyran-4-ylmethyl)-lH r - benziraidazol-5-yl]-N-methylazetidine-1-sulfonamide
- Step C 3-Amino-iV- [2-tert-butyl-1-(tetrahydro-2 J H r -pyran-4-ylmethyl)-1H- benzimidazol-5-yl]-N-methylazetidine-l -sulfonamide
- Step A N-[2-(l,l-Dimethylethyl)-1-[(tetrahydro-2J7-pyran-4-yl)methyl]-llT- benzimidazol-5-yl]hexahydro-N-methyl-lii r -azepine-l -sulfonamide
- Step B N-(l- ⁇ [[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benziraidazol-5-yl](raethyl)amino]sulfonyl ⁇ piperidin-4-yl)acetamide
- Step A tert-Butyl [l-( ⁇ methyl[l-(tetrahydro-2H-pyran-4-ylmethyl)-2- (trifluor omethyl)-1H-benzimidazol-5-yl] amino ⁇ sulfbnyl)piperidin-4- yl] carbamate
- Step E N- ⁇ 3-Amino-4-[(tetrahydro-2jH r -pyran-4-ylmethyl)ainino]phenyl ⁇ -N- methylacetamide
- N-Methyl-N- ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-yltnethyl)amino]phenyl ⁇ acetamide (21.7 g, 70.5 mmol) was hydrogenated in ethyl acetate (500 mL) 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 N-Methyl-N-[l-(tetrahydro-2H-pyran-4-yImethyl)-2-(trifluoromethyl)- liZ-benzi ⁇ iidazol-5-yl] acetamide
- Step G N-Methyl-1-Ctetrahydro-ljEr-pyran ⁇ -ylmethyl)-1-Ctrifluoromethy ⁇ -lJ ⁇ - benzimidazol-5-amine
- N-Methyl-N-[l-(tetrahydro-2H-pyran-4-ylme%l)-2-(1xiiluorome%l)-1H- benzimidazol-5-yl]acetamide (3.18 g, 8.95 mmol) was dissolved in hydrochloric acid (37%, 60 mL) and then heated overnight at 95 0 C. After concentration, the residue was treated with 20 mL of 2JVNaOH, extracted with EtOAc (4x50 mL). The combined organic phaese were washed with brine (20 mL) and dried over Na 2 SO 4 .
- Step H 3-Methyl-1-( ⁇ methyl[l-(tetrahydro-2H-pyran-4-yImethyl)-2- (trifluoromethyl)-lJ3-benziinidazoI-5-yl]amino ⁇ sulfonyl)-1H-imidazol-3-ium.
- N-methyl-1-(tetrahydro-2H-pyran- 4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-amme (0.32 g, 1.0 mmol) was converted to 3 -methyl- 1 -( ⁇ methyl[l -(tetrahydro-2H-pyran-4-ylmethyl)-2- (trifluoromethyl)- l#-benzimidazol-5-yl]amino ⁇ sulfonyl)- li7-imidazol-3-ium, which was used in Step A without any purification.
- Step A 4- ⁇ [(CycIopropylamino)carbonyl]amino ⁇ - ⁇ '-methyl-N-[l-(tetrahydro-2H- pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-yl]piperidine-1- sulfonamide
- Step B 4-Amino-N-methyl-N-[l-(tetrahydro-2 J H r -pyran-4-ylmethyl)-2- (trifluoromethyl)-1H-benziinidazol-5-yl]piperidine-1-sulfonamide
- Step B N-Methyl-N-[l-(tetrahydro-2J3 r -pyran-4-ylmethyl)-2-(trifluoromethyl)- lJ?-benzimidazol-5-yl]piperazine-l-sulfonamide
- Acetyl chloride (9 mg, 0.11 mmol) was added to a solution of 4-amino-N-methyl-N- [l-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5- yl]piperidine-l -sulfonamide (45 mg, 0.094 mmol) and triethylamine (12 mg, 0.12 mmol) in DCM (5 mL) at 0 0 C. The mixture was stirred for 3 h at room temperature. After evaporation, the crude product was purified by MPLC using EtOAc/MeOH (10:1) on silica gel to give 49 mg (100%) of a white solid as the title compound.
- Step A N-(1- ⁇ [ ⁇ 2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H- benzimidazol-5-yl ⁇ (methyl)amino]sulfonyl ⁇ piperidin-4-yl)acetamide
- Acetic anhydride (2.0 mmol) was added into a solution of triethylamine (2.0 mmol) and 4-amino-N- ⁇ 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-l// ' -benzimidazol-5- yl ⁇ -N-methylpiperidine-l -sulfonamide (crude product from step D, 0.9 mmol) in CH 2 Cl 2 (20 mL). After being stirred at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure.
- Step B 1- ⁇ [ ⁇ 2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl ⁇ (methyl)amino]sulfonyl ⁇ -3-methyl-li3-imidazol-3-ium triflate
- Step C tert-Butyl (1- ⁇ [ ⁇ 2-/ert-butyI-1-[(4,4-difluorocyclohexyl)methyl]-l J H- benzimidazol-5-yl ⁇ (methyl)amino]sulfonyl ⁇ piperidin-4-yl)carbamate
- Step D 4-Araino-N- ⁇ 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H- benzimidazol-5-yl ⁇ -N-methylpiperidine-1-sulfonaraide
- Step A 4- ⁇ [ ⁇ 2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl ⁇ (methyl)amino]sulfonyl ⁇ -N-isopropylpiperazine-1-carboxamide
- Step B ⁇ / - ⁇ 2-ter ⁇ '-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-l J fir-benzimidazol-5- yI ⁇ -N-methylpiperazine-1-sulfonamide
- Step A 4- ⁇ [ ⁇ 2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl ⁇ (methyl)amino]sulfonyl ⁇ -N-cyclopropylpiperazine-1-carboxamide
- Step A 4- ⁇ [ ⁇ 2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl ⁇ (methyl)amino]sulfonyl ⁇ -N-cyclobutylpiperazme-1-carboxaniide
- Step A 4-Acetyl- ⁇ r -[2-tert-butyl-1-(tetrahydro-2 J H r -pyran-4-ylmethyl)-1H- benzimidazol-5-yl]-N-methylpiperazine-l -sulfonamide
- Step B N-[2-tert-Butyl-.l-(tetrahydro-2H-pyran-4-ylmethyl)-lJ ⁇ -benzimidazol-5- yl]-N-methylpiperazine-1-sulfonamide
- N-p-tert-butyl-1- ⁇ etrahydro ⁇ H- pyran-4-yrmethyl)-1H-benzimidazol-5-yl]-N-methylpiperazine-1-sulfonamide 50 mg, 0.11 mmol
- butanoyl chloride 21 mg, 0.2 mmol
- N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4- ylmethyl)- li- r -benzimidazol-5-yl]-4-butyryl- ⁇ / r -methylpiperazine-l -sulfonamide (TFA salt, 28 mg, 40 %).
- Step A -V-(1- ⁇ [ [2-ter ⁇ -Butyl-1-(tetrahydro-2J3 r -pyran-4-ylmethyl)-l J ff- benzimidazol-5-yl](methyl)amino]sulfonyl ⁇ pyrrolidin-3-yl)acetamide
- Step B tert-Butyl (1- ⁇ [[2-tert-butyl-1-(tetrahydro-2 J ff-pyran-4-ylmethyl)-lJ3- benzimidazol-5-yl](methyl)amino]sulfonyl ⁇ pyrroIidin-3-yl)carbamate
- Step C 3-Amino- ⁇ -[2-tert-butyl-1-(tetrahydro-2H-pyran-4-yImethyl)-1H- benzimidazol-5-yl]-N-methylpyrroHdine-1-sulfonamide
- Example 104 1- ⁇ [[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl](methyl)amino]sulfonyl ⁇ -N-cyclopropyl-1H-pyrazole-4-carboxaraide
- Step A 1- ⁇ [ [2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol- 5-yl](methyl)amino]sulfonyl ⁇ -N-cyclopropyl-1H-pyrazole-4-carboxamide
- HATU 150 mg, 0.4 mmol
- Step B 1- ⁇ [[2-tert-Butyl-1-(tetrahydro-2 J H r -pyran-4-ylmethyl)-l J H-benzimidazol- 5-yl] (methyl) amino] sulfonyl ⁇ -1H-pyrazole-4-carboxylic acid
- Step A N-(1- ⁇ [[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl](methyl)amino]sulfonyl ⁇ -1H-pyrazoI-3-yl)acetamide
- Step B 3-Amino-N-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl]-N-methyI-1H-pyrazole-1-sulfonamide
- Step A l- ⁇ [[2-ter ⁇ -Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol- 5-yl](methyl)amino]sulfonyl ⁇ -N-cyclopropyl-1H-imidazole-4-carboxamide
- HATU (15 mg, 0.04 mmol) was added to a solution of 1- ⁇ [[2-tert-butyl-1-(tetrahydro- 2/i-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl ⁇ -li/- imidazole-4-carboxylic acid (10 mg, 0.02 mmol), cyclopropylamine (6 mg, 0.1 mmol) and DIPEA (0.1 niL) in DMF (1.0 mL) at r.t.
- Step B 1- ⁇ [[2-tert-Butyl-1-(tetrahydro-2JY-pyran-4-yImethyl)-1H-benzimidazol- 5-yl](methyl)amino]sulfonyl ⁇ -ljH r -imidazole-4-carboxylic acid
- HATU 250 mg, 0.66 mmol
- Step B N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl]-3-formyl-N-methyl-1H-pyrazole-1-sulfonamide
- Step C l-[[[2-tert-Butyl-1-(tetrahydro-2 J fir-pyran-4-ylmethyl)-1H r -benzimidazol- 5-yl](methyl)amino](methylene)oxido- ⁇ 4 -sulfanyl]-1H-pyrazole-3-carboxylic acid
- Step A 7 ⁇ ir -[2-tert-Butyl-1-(tetrahydro-2i ⁇ -pyran-4-ylmethyl)-l J H r -benzimidazol-5- yl]-/y-methyl-4-(morpholin-4-ylcarbonyl)piperazine-1-sulfonamide
- Step B l-[(4- ⁇ [[2-tert-Butyl-1-(tetrahydro-2J3-pyran-4-ylmethyl)-l J fiT- benzimidazol-S-yl ⁇ (methyl)amino lsulfonyl ⁇ piperazin-1-yl)carbonyy-S-methyl- 1H-imidazol-3-ium triflate
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Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/GB2004/004112 WO2005030761A1 (en) | 2003-09-26 | 2004-09-24 | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
PCT/GB2004/004124 WO2005030732A1 (en) | 2003-09-26 | 2004-09-24 | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
SE0500183 | 2005-01-24 | ||
PCT/SE2005/001405 WO2006033633A1 (en) | 2004-09-24 | 2005-09-22 | Compounds, compositions containing them, preparations thereof and uses thereof ii |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1797070A1 true EP1797070A1 (en) | 2007-06-20 |
Family
ID=36090312
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05784958A Withdrawn EP1797070A1 (en) | 2004-09-24 | 2005-09-22 | Compounds, compositions containing them, preparations thereof and uses thereof ii |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1797070A1 (ja) |
JP (1) | JP2008514595A (ja) |
AU (1) | AU2005287429A1 (ja) |
CA (1) | CA2582512A1 (ja) |
WO (1) | WO2006033633A1 (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE0302573D0 (sv) | 2003-09-26 | 2003-09-26 | Astrazeneca Ab | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
KR101269869B1 (ko) | 2004-09-24 | 2013-06-07 | 네오메드 인스티튜트 | 벤즈이미다졸 유도체, 그를 함유하는 조성물, 그의 제조방법 및 그의 용도 |
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 |
JP2012512879A (ja) * | 2008-12-18 | 2012-06-07 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Trpm8モジュレーターとしてのスルファミド |
JP2012512880A (ja) * | 2008-12-18 | 2012-06-07 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Trpm8モジュレーターとしてのスルホンアミド |
WO2018108954A1 (en) * | 2016-12-12 | 2018-06-21 | F. Hoffmann-La Roche Ag | Process for the preparation of 2-(3-(fluoromethyl)azetidin-1-yl)ethan-1-ol |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7115645B2 (en) * | 2000-01-14 | 2006-10-03 | Schering Aktiengesellschaft | 1,2 diarylbenzimidazoles and their pharmaceutical use |
SE0101387D0 (sv) * | 2001-04-20 | 2001-04-20 | Astrazeneca Ab | Novel compounds |
WO2005021547A2 (en) * | 2003-08-28 | 2005-03-10 | Pharmaxis Pty Ltd. | Heterocyclic cannabinoid cb2 receptor antagonists |
SE0302570D0 (sv) * | 2003-09-26 | 2003-09-26 | Astrazeneca Ab | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
SE0302571D0 (sv) * | 2003-09-26 | 2003-09-26 | Astrazeneca Ab | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
-
2005
- 2005-09-22 EP EP05784958A patent/EP1797070A1/en not_active Withdrawn
- 2005-09-22 CA CA002582512A patent/CA2582512A1/en not_active Abandoned
- 2005-09-22 JP JP2007533435A patent/JP2008514595A/ja active Pending
- 2005-09-22 WO PCT/SE2005/001405 patent/WO2006033633A1/en active Application Filing
- 2005-09-22 AU AU2005287429A patent/AU2005287429A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO2006033633A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA2582512A1 (en) | 2006-03-30 |
WO2006033633A1 (en) | 2006-03-30 |
JP2008514595A (ja) | 2008-05-08 |
AU2005287429A1 (en) | 2006-03-30 |
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