WO2004087690A2 - Benzimidazole derivatives and their use for modulating the gaba-a receptor complex - Google Patents
Benzimidazole derivatives and their use for modulating the gaba-a receptor complex Download PDFInfo
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- WO2004087690A2 WO2004087690A2 PCT/EP2004/050417 EP2004050417W WO2004087690A2 WO 2004087690 A2 WO2004087690 A2 WO 2004087690A2 EP 2004050417 W EP2004050417 W EP 2004050417W WO 2004087690 A2 WO2004087690 A2 WO 2004087690A2
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- benzimidazole
- phenyl
- isoxazolyl
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- pyrrolidinyl
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- RUSAWEHOGCWOPG-UHFFFAOYSA-N N#Cc1cccc([N+]([O-])=O)c1 Chemical compound N#Cc1cccc([N+]([O-])=O)c1 RUSAWEHOGCWOPG-UHFFFAOYSA-N 0.000 description 1
- HDQCHDWHHGEXQE-UHFFFAOYSA-N NC(c1cccc([N+]([O-])=O)c1)=S Chemical compound NC(c1cccc([N+]([O-])=O)c1)=S HDQCHDWHHGEXQE-UHFFFAOYSA-N 0.000 description 1
- JPPYODFEZAMAQD-UHFFFAOYSA-N Nc1cc(-c2ncc[s]2)ccc1 Chemical compound Nc1cc(-c2ncc[s]2)ccc1 JPPYODFEZAMAQD-UHFFFAOYSA-N 0.000 description 1
- ITKRJFNDXYFPNU-UHFFFAOYSA-N [O-][N+](c1cc(-c2ncc[s]2)ccc1)=O Chemical compound [O-][N+](c1cc(-c2ncc[s]2)ccc1)=O ITKRJFNDXYFPNU-UHFFFAOYSA-N 0.000 description 1
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- 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
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- A61P25/00—Drugs for disorders of the nervous system
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- A61P25/32—Alcohol-abuse
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- A61P25/36—Opioid-abuse
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- 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
- C07D403/10—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 carbon chain containing aromatic rings
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- 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
- C07D405/10—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 aromatic rings
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- This invention relates to novel benzimidazole derivatives, pharmaceutical compositions containing these compounds, and methods of treatment therewith.
- the compounds of the invention are useful in the treatment of central nervous system diseases and disorders, which are responsive to modulation of the GABAA receptor complex, and in particular for combating anxiety and related diseases.
- the modulatory sites on the GABA A receptor complex are the target for anxiolytic drugs, such as the classical a ⁇ xiolytic benzodiazepines.
- each receptor is a pentameric complex comprising subunits drawn from ⁇ i- ⁇ , ⁇ - 3 , ⁇ - 3 , ⁇ , ⁇ , and ⁇ subunit isoforms.
- the classical anxiolytic benzodiazepines show no subtype selectivity. It has been suggested that one of the key elements in the disadvantages of the classical benzodiazepanes (such as sedation, dependency, and cognitive impairment) is relates to the ⁇ 1 subunit of the GABA A receptors. Thus compounds with selectivity for the ⁇ 2 and/or ⁇ 3 subunits over the ⁇ 1 subunit are expected to have an improved side effect profile.
- EP 616807 describes benzimidazole compounds for use as benzodiazepine receptor ligands.
- WO 96/33194, WO 96/33191 and WO 96/33192 describe benzimidazole compounds having affinity for the GABA receptor complex.
- WO 98/34923 describes phenylbenzimidazole derivatives as ligands for the GABA receptor complex.
- WO 98/17651 and WO 00/78728 describe benzimidazole compounds for use as e.g. anaesthetics.
- the invention provides a compound of the Formula I:
- the invention provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound of the invention, or an N- oxide thereof, or any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient or diluent.
- the invention provides the use of a compound of the invention, or an N-oxide thereof, or any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to modulation of the GABAA receptor complex in the central nervous system.
- the invention relates to a method for treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to modulation of the GABA A receptor complex in the central nervous system, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a compound of the invention, or an N- oxide thereof, or any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof.
- R represents hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkenyloxyalkyl, or alkynyloxyalkyl;
- R' represents a 5-membered heterocyclic ring; which heterocyclic ring may optionally be substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, amino, alkylamino, aminoalkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, and alkynyl.
- R represents hydroxymethyl, alkoxymethyl, or cycloalkyialkoxymethyl.
- R represents 1-hydroxyethyl, 1- alkoxyethyl, 1-(cycloalkylalkoxy)ethyl, 1-(alkenyloxy)ethyl, or 1-(alkynyloxy)ethyl.
- R represents alkoxyalkyl.
- R represents 2-hydro-2-propyl, 2-alkoxy-2-propyl, or 2-(cycloalkylalkoxy)-2-propyl.
- R represents alkoxyalkyl.
- R represents alkoxymethyl, such as methoxymethyl, ethoxymethyl, isopropoxymethyl, or propoxymethyl.
- R represents alkoxyethyl, in particular 1- alkoxy-ethyl, such as 1-methoxyethyl, 1-ethoxyethyl, 1-propoxyethyl, 1- isopropoxyethyl.
- R represents alkoxypropyl, in particular 2-alkoxy-2-propyl, such as 2-methoxy-2-propyl, 2-ethoxy-2-propyl, 2-propoxy-2-propyl and 2-isopropoxy-2-propyl.
- R represents cycloalkylalkoxyalkyl.
- R represents cycloalkyialkoxymethyl, such as cyclopropylmethoxymethyl.
- R represents cycloalkylalkoxyethyl, in particular 1- (cycloalkylalkoxy)ethyl, such as 1-(cyclopropylmethoxy)ethyl.
- R represents cycloalkylalkoxypropyl, in particular 2-(cycloalkylalkoxy)-2- propyl, such as 2-(cyclopropylmethoxy)-2-propyl.
- R represents hydroxyalkyl. In a special embodiment, R represents hydroxymethyl. In a further embodiment, R represents hydroethyl, such as 1-hydroxyethyl. In a still further embodiment, R represents hydroxypropyl, such as 2-hydroxy-2-propyl. In a further embodiment, R represents alkenyloxyalkyl. In one embodiment, R represent alkenyloxyethyl, in particular 1-(alke ⁇ yloxy)ethyl such as 1-(allyloxy)ethyl.
- R represents alky ⁇ yloxyalkyl.
- R represents alkynyloxyethyl, in particular 1-(alky ⁇ yloxy)ethyl, such as 1- (propargyloxy)ethyl.
- R' represents imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, thiazolyl, pyrrolyl, or pyrrolidinyl.
- R' represents imidazolyl, pyrazolyl, thienyl, or furyl.
- R' represents imidazolyl, such as 1 -imidazolyl
- R' represents pyrazolyl, such as 1-pyrazolyl.
- R' represents thienyl, such as 2- thienyl.
- R' represents furyl, such as 3-furyl.
- R' represents isoxazolyl, such as 3-isoxazolyl.
- R' represents pyrrolidinyl, such as 1 -pyrrolidinyl.
- R' represents thiazolyl, such as 2-thiazolyl.
- R' represents pyrrolyl, such as 1 -pyrrolyl.
- the chemical compound of the invention is 1-(3-(1-lmidazolyl)phenyl)-5-(methoxymethyl)benzimidazole; 1-(3-(1-lmidazolyl)phenyl)-5-(ethoxymethyl)benzimidazole; 1 -(3-( 1 -I midazolyl)phenyl )-5-(isopropoxy methyl )benzi midazole; 1-(3-(1-lmidazolyl)phenyl)-5-(propoxymethyl)benzimidazole; 1-(3-(1-lmidazolyl)phenyl)-5-(cyclopropylmethoxymethyl)benzimidazole; 1-(3-(1-Pyrazolyl)phenyl)-5-(methoxymethyl)benzimidazole; 1-(3-(1-Pyrazolyl)phenyl)-5-(hydroxymethyl)benzimidazole; 1-(3-(1-Pyrazolyl) ⁇
- halo represents fluoro, chloro, bromo or iodo.
- an alkyl group designates a univalent saturated, straight or branched hydrocarbon chain.
- the hydrocarbon chain preferably contain of from one to six carbon atoms (C-i- ⁇ -alkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl.
- alkyl represents a d- 4 -alkyl group, including butyl, isobutyl, secondary butyl, and tertiary butyl.
- alkyl represents a C ⁇ - 3 -alkyl group, which may in particular be methyl, ethyl, propyl or isopropyl.
- an alkenyl group designates a carbon chain containing one or more double bonds, including di-enes, tri-enes and poly-enes.
- the alkenyl group of the invention comprises of from two to six carbon atoms (Ca- 6 -alke ⁇ yl), including at least one double bond.
- the alkenyl group of the invention is ethenyl; 1- or 2-propenyl; 1-, 2- or 3- butenyl, or 1 ,3-butdienyl; 1-, 2-, 3-, 4- or 5-hexenyl, or 1,3-hexdienyl, or 1 ,3,5- hextrienyl.
- an alkynyl group designates a carbon chain containing one or more triple bonds, including di-y ⁇ es, tri-ynes and poly-ynes.
- the alkynyl group of the invention comprises of from two to six carbon atoms (Cs- ⁇ -alkynyl), including at least one triple bond.
- the alkynyl group of the invention is ethynyl; 1-, or 2-propynyl; 1-, 2-, or 3- butynyl, or 1 ,3-butdiynyl; 1-, 2-, 3-, 4-penty ⁇ yl, or 1 ,3-pe ⁇ tdiy ⁇ yl; 1-, 2-, 3-, 4-, or 5- henynyl, or 1 ,3-hexdiynyl or 1 ,3,5-hextriynyl.
- a cycloalkyl group designates a cyclic alkyl group, preferably containing of from three to seven carbon atoms (C 3 - 7 -cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- Alkoxy means O-alkyl, wherein alkyl is as defined above.
- Alkoxyalkyl means alkoxy as above and alkyl as above, meaning for example, methoxymethyl.
- Cycloalkoxy means O-cycloalkyl, wherein cycloalkyl is as defined above. Cycloalkylalkyl means cycloalkyl as above and alkyl as above, meaning for example, cyclopropylmethyl.
- alkylamino designates -NH-alkyl or -N-(alkyl) 2 , wherein alkyl is as defined above.
- a 5-membered heterocyclic ring designates a 5- membered monocyclic group, and which group holds one or more heteroatoms in its ring structure.
- Preferred heteroatoms include nitrogen (N), oxygen (O), and sulphur (S).
- the ring structure may in particular be aromatic (i.e. a heteroaryl), saturated or partially saturated.
- Examples of preferred aromatic heterocyclic monocyclic 5-membered groups of the invention include furan, in particular 2- or 3-furyl; thiophene, in particular 2- or 3-thienyl; pyrrole (azole), in particular 1-, 2- or 3-pyrrolyl; oxazole, in particular oxazol-(2-, 4- or 5-)yl; thiazole, in particular thiazol-(2-, 4-, or 5-)yl; imidazole, in particular imidazol-(1-, 2-, 4- or 5-)yl; pyrazole, in particular pyrazol-(1-, 3-, 4- or 5-)yl; isoxazole, in particular isoxazol-(3-, 4- or 5-)yl; isothiazole, in particular isothiazol-(3-, 4- or 5-)yl; 1,2,3-oxadiazole, in particular 1 ,2,3-oxadiazol-(4- or 5-)yl; 1,2,4- oxadia
- Examples of preferred saturated or partially saturated heterocyclic monocyclic 5-membered groups of the invention include 1 ,3-dioxolan, in particular 1 ,3-dioxolan- (2- or 4-)yl; imidazolidine, in particular imidazolidin-(1-,2-,3-,4- or 5-)yl; 2-imidazoline, in particular 2-imidazolin-(1-,2-,4- or 5-)yl; 3-imidazoline, in particular 3-imidazolin-(1- ,2-,4- or 5-)yl; 4-imidazoline, in particular 4-imidazolin-(1-,2-,4- or 5-)yl; dihydro- oxazole (oxazoline), in particular dihydro-oxazol-(2-,4- or 5-)yl; tetrahydro-oxazole (oxazolidine), in particular tetrahydro-oxazol-(2-,4- or 5-)yl
- the chemical compound of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms of the chemical compound of the invention.
- Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the nitrate derived from nitric acid, the perchlorate derived from perchloric acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, the formate derived from formic acid, the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulphonate derived from benzensulphonic acid, the benzoate derived from benzoic acid, the cinnamate derived from ci ⁇ namic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the e ⁇ antate derived from enanthic acid, the fumarate derived from
- Such salts may be formed by procedures well known and described in the art.Other acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.
- Metal salts of a chemical compound of the invention include alkali metal salts such as the sodium salt of a chemical compound of the invention containing a carboxy group.
- the "onium salts" of N-containing compounds are also contemplated as pharmaceutically acceptable salts.
- Preferred “onium salts” include the alkyl-onium salts, the cycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.
- Examples of pre- or prodrug forms of the chemical compound of the invention include examples of suitable prodrugs of the substances according to the invention include compounds modified at one or more reactive or derivatizable groups of the parent compound. Of particular interest are compounds modified at a carboxyl group, a hydroxyl group, or an amino group. Examples of suitable derivatives are esters or amides.
- the chemical compound of the invention may be provided in dissoluble or indissoluble forms together with a pharmaceutically acceptable solvent such as water, ethanol, and the like. Dissoluble forms may also include hydrated forms such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like. In general, the dissoluble forms are considered equivalent to indissoluble forms for the purposes of this invention.
- the compounds of the present invention may contain one or more chiral centres and that such compounds exist in the form of isomers.
- Optical active compounds can also be prepared from optical active starting materials. N-oxides
- an N-oxide designates an oxide derivative of a nitrogen containing compound, e.g. N-containing heterocyclic compounds capable of forming such N-oxides, and compounds holding one or more amino groups.
- the N-oxide of a compound containing a pyridyl may be the 1-oxy-pyridin-2, -3 or -4-yl derivative.
- N-oxides of the compounds of the invention may be prepared by oxidation of the corresponding nitrogen base using a conventional oxidizing agent such as hydrogen peroxide in the presence of an acid such as acetic acid at an elevated temperature, or by reaction with a peracid such as peracetic acid in a suitable solvent, e.g. dichloromethane, ethyl acetate or methyl acetate, or in chloroform or dichloromethane with 3-chloroperoxybenzoic acid.
- a suitable solvent e.g. dichloromethane, ethyl acetate or methyl acetate, or in chloroform or dichloromethane with 3-chloroperoxybenzoic acid.
- the compounds of the invention may be used in their labelled or unlabelled form.
- label stands for the binding of a marker to the compound of interest that will allow easy quantitative detection of said compound.
- the labelled compounds of the invention may be useful as diagnostic tools, radio tracers, or monitoring agents in various diagnostic methods, and for in vivo receptor imaging.
- the labelled isomer of the invention preferably contains at least one radionuclide as a label. Positron emitting radionuclides are all candidates for usage. In the context of this invention the radionuclide is preferably selected from 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 131 l, 25 l, 123 l, and 18 F.
- the physical method for detecting the labelled isomer of the present invention may be selected from Position Emission Tomography (PET), Single Photon Imaging Computed Tomography (SPECT), Magnetic Resonance Spectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed Axial X-ray Tomography (CAT), or combinations thereof.
- PET Position Emission Tomography
- SPECT Single Photon Imaging Computed Tomography
- MRS Magnetic Resonance Spectroscopy
- MRI Magnetic Resonance Imaging
- CAT Computed Axial X-ray Tomography
- the chemical compounds of the invention may be prepared by conventional methods for chemical synthesis, e.g. those described in the working examples.
- the starting materials for the processes described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.
- one compound of the invention can be converted to another compound of the invention using conventional methods.
- the end products of the reactions described herein may be isolated by conventional techniques, e.g. by extraction, crystallisation, distillation, chromatography, etc.
- the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
- pharmaceutically acceptable solvents such as water, ethanol and the like.
- the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
- Biological Activity Compounds of the invention are capable of modulating the GABAA receptor complex. They may be tested for their ability to bind to the GABAA receptor complex, including specific subunits thereof.
- the compounds of the present invention being ligands for the benzodiazepine binding site on GABAA receptors, are therefore of use in the treatment and/or prevention of a variety of disorders of the central nervous system.
- the compounds of the invention are considered useful for the treatment, prevention or alleviation of a disease, disorder or condition responsive to modulation of the GABAA receptor complex in the central nervous system.
- the compounds of the invention are considered useful for the treatment, prevention or alleviation of
- anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, and generalized or substance-induced anxiety disorder;
- ⁇ depressive or bipolar disorders for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder, o psychotic disorders, including schizophrenia;
- o emesis including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation;
- eating disorders including anorexia nervosa and bulimia nervosa;
- the compounds of the invention are considered useful for the treatment, prevention or alleviation of anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, and generalized or substance-induced anxiety disorder;
- the compounds of the invention may be useful as radioligands in assays for detecting compounds capable of binding to the human GABA A receptor.
- compositions in another aspect provides novel pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention.
- a compound of the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
- the invention provides pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers therefore, and, optionally, other therapeutic and/or prophylactic ingredients, know and used in the art.
- the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
- compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, pulmonal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration, or by sustained release systems.
- sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in form of shaped articles, e.g. films or microcapsules.
- compositions and unit dosages thereof may thus be placed into the form of pharmaceutical compositions and unit dosages thereof.
- forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use.
- Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
- the chemical compound of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention.
- pharmaceutically acceptable carriers can be either solid or liquid.
- Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
- a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
- the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
- the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
- Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
- the term "preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
- cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
- a low melting wax such as a mixture of fatty acid glyceride or cocoa butter
- the active component i is dispersed homogeneously therein, as by stirring.
- the molten homogenous mi ix: ture is then poured into convenient sized moulds, allowed to cool, and thereby to solidi ifty.
- compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
- Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
- parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
- the chemical compound according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
- compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents.
- the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
- Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
- Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents. Also included are solid form preparations, intended for conversion shortly before use to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active component such preparations may comprise colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizi ⁇ g agents, and the like.
- the chemical compound of the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
- Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
- Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
- compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
- compositions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
- the compositions may be provided in single or multi-dose form.
- Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
- a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
- CFC chlorofluorocarbon
- the aerosol may conveniently also contain a surfactant such as lecithin.
- the dose of drug may be controlled by provision of a
- the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
- a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
- PVP polyvinylpyrrolidone
- the powder carrier will form a gel in the nasal cavity.
- the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
- the compound In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
- compositions adapted to give sustained release of the active ingredient may be employed.
- the pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
- Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
- a therapeutically effective dose refers to that amount of active ingredient, which ameliorates the symptoms or condition.
- Therapeutic efficacy and toxicity e.g. ED 50 and LD 5 0, may be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by the ratio LDso/EDso- Pharmaceutical compositions exhibiting large therapeutic indexes are preferred.
- the dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner.
- compositions containing of from about 0.1 to about 500 mg of active ingredient per individual dose, preferably of from about 1 to about 100 mg, most preferred of from about 1 to about 10 mg, are suitable for therapeutic treatments.
- the active ingredient may be administered in one or several doses per day.
- a satisfactory result can, in certain instances, be obtained at a dosage as low as 0.1 ⁇ g/kg i.v. and 1 ⁇ g/kg p.o.
- the upper limit of the dosage range is presently considered to be about 10 mg/kg i.v. and 100 mg/kg p.o.
- Preferred ranges are from about 0.1 ⁇ g/kg to about 10 mg/kg/day i.v., and from about 1 ⁇ g/kg to about 100 mg/kg/day p.o.
- 1-(3-Bromophenyl)-5-(ethoxymeihyl)benzimidazole is prepared analogously from 1-(3- bromophenyl)-5-(hydroxymethyl)benzimidazole by alkylating with iodoethane.
- 1-(3-Bromophenyl)-5-(isopropoxymethyl)benzimidazole is prepared analogously from 1-(3-bromophenyl)-5-(hydroxymethyl)benzimidazole by alkylating with 2- bromopropane.
- 1-(3-BrOmophenyl)-5-(propoxymethyl)benzimidazole is prepared analogously from 1- (3-bromophenyl)-5-(hydroxymethyl)benzimidazole by alkylating with 1-bromopropane.
- 1-(3-Bromophenyl)-5-(cyciopropylmethoxymethyl)benzimidazole is prepared analogously from 1-(3-bromophenyl)-5-(hydroxymethyl)benzimidazole by alkylating with (bromomethyl)cyclopropane.
- 1-(3-(1-lmidazolyl)phenyl)-5-(ethoxymethyl)benzimidazole is prepared analogously from 1-(3-bromophenyl)-5-(ethoxymethyl)benzimidazole.
- 1-(3-(1-lmidazolyl)phenyl)-5-(isopropoxymethyl)benzimidazole is prepared analogously from 1-(3-bromophenyl)-5-(isopropoxymethyl)benzimidazole.
- 1-(3-(1-lmidazolyl)phenyl)-5-(piOpoxymethyl)b ⁇ nzimidazole is prepared analogously from 1-(3-bromopheny])-5-(propoxymethyl)benzimidazole.
- 1-(3-(1-lmidazolyl)phenyl)-5-(cyclopropylmethoxymethyl)benzimidazole is prepared analogously from 1 -(3-bromophenyI)-5-(cyclopropylmethoxymethyl)-benzimidazole.
- 1-(3-(1-Pyrazolyl)phenyl)-5-(methoxymethyl)benzimidazole was prepared analogously from pyrazol and 1-(3-bromophenyl)-5-(methoxymethyl)benzimidazoIe. Yield 10%. Mp. 126-128"C.
- 1-(3-(1-Pyrazolyl)phenyI)-5-(hydroxymethyl)benzimidazole is prepared analogously from 1-(3-bromophenyl)-5-(hydroxymethyl)benzimidazole.
- 1-(3-(1-Pyrazolyl)phenyl)-5-(isopropoxymethyl)benzimidazole is prepared analogously from 1-(3-bromophenyl)-5-(isopropoxymethyl)benzimidazole.
- 1-(3-(1-Pyrazolyl)phenyI)-5-(propoxyme ⁇ hyl)benzimidazole is prepared analogously from 1 -(3-bromophenyl)-5-(propoxymethyl)benzimidazole.
- 1-(3-(3-Furyl)phenyl)-5-(methoxymethyl)benzimidazole A mixture of 1-(3- bromophenyl)-5-(methoxymethyl)benzimidazole (0.50g; 1.58mmol), 3-furylboronic acid (0.1 g; 1.58mmol), sodium bicarbonate (0.66g; 7.86mmol) and a catalytic amount of tetrakis(triphe ⁇ ylphosphine)palladium in a mixture of dimethoxyethane (5ml) and water (2.5ml) was heated to 80°C in a nitrogen atmosphere overnight. The cooled mixture was poured into ice-water a extracted with ethyl acetate.
- the organic extract was dried over magnesium sulfate and concentrated under reduced pressure.
- the concentrate was purified by column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (9:1 , v/v) as the eluent. Yield: 0.22g (46%). Mp 92-94°C.
- 1-(3-(3-Furyl)phenyl)-5-(propoxymethyl)benzimidazole is prepared analogously from 1- (3-bromophenyl)-5-( ⁇ ropoxymethyl)benzimidazole.
- 1-(3-(3-Furyl)phenyl)-5-(cyclopropylmethoxymethyl)benzimidazole is prepared analogously from 1 -(3-bromophenyl)-5-(cyclopropylmethoxymethyl)benzimidazole.
- 1-(3-(2-Thienyl)phenyl)-5-(methoxymethyl)benzimidazole A mixture of 1-(3- bromophenyl)-5-(methoxymethyl)benzimidazole (1.0g; 3.16mmol), tributyltin (1.77g; 4.75mmol) and dichloro bis(triphenylphosphine)palladium (30mg)in anhydrous dimethyl formamide (10ml) was heated to 80°C overnight. The cooled mixture was poured into water (50ml) and extracted with ethyl acetate. The organic extract was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was eluted through silica gel with ethyl acetate.
- 1-(3-(2-Thienyl)ph ⁇ nyl)-5-(eihoxymethyl)benzimidazole is prepared analogously from 1 -(3-bromophenyl)-5-(ethoxymethyl)be ⁇ zimidazole.
- 1-(3-(2-Thienyl)phenyl)-5-(propoxymethyl)benzimidazole is prepared analogously from 1-(3-bromophenyl)-5-(propoxymethyl)benzimidazole.
- 1-(3-(2-Thienyl)phenyl)-5-(cyclopiOpylmeihoxymethyl)benzimidazole s prepared analogously from 1 -(3-bromo ⁇ henyl)-5-(cyclopropylmethoxymethyl)benzimidazole.
- 3-Nitrobenzaldehyde oxime To a suspension of 3-nitrobenzaldehyde (50.5g, 0.33mol) in abs. ethanol (500ml) was added hydroxylamine, hydrochloride (34.8g, O. ⁇ Omol) and triethylamine (46.5ml, 0.33mol) and the resultant mixture was stirred at reflux over night. The solvent was distilled off under reduced pressure, and water was added to the residue. The resultant solution was rendered alkaline by addition of saturated, aqueous sodium carbonate and the precipitate was filtered off, washed with water and air-dried to leave the product (51.7g).
- the solvent was distilled off under reduced pressure and the residue was partitioned between water and ethyl acetate. The layers were separated and the organic layer was washed with brine, dried over sodium sulphate and evaporated to dryness.
- the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1 :9, v/v) as the eluent to leave the product (7.1g).
- 5-(1-Ethoxyethyl)-1-(3-(3-isoxazolyl)phenyl)benzimidazole is prepared analogously using iodoethane.
- 5-(1-Ethoxyethyl)-1-(3-(1-imidazolyl)phenyl)benzimidazole is prepared analogously, by ethylation with iodoethane.
- 5-(1-Propoxyethyl)-1-(3-(1-imidazolyl)phenyl)benzimidazole is prepared analogously, by alkylation with 1-bromopropane.
- 5-(1-lsopropoxyethyl)-1-(3-(1-imidazolyl)phenyl)benzimidazole is prepared analogously, by alkylation with 2-bromopropane.
- 5-(1-Methoxyethyl)-1 ⁇ (3-(1-pyrrolidinyl)phenyl)benzimidazole is prepared by alkylation of the above product with iodomethane as described in Example 5.
- 5-(1-Ethoxyethyl)-1-(3-(1- pyrrolidinyl)phenyl)benzimidazole is prepared analogously, by ethylation with iodoethane.
- 5-(1-Propoxyethyl)-1-(3-(1- pyrrolidinyl)phenyl)benzimidazole is prepared analogously, by alkylation with 1-bromopropane.
- 5-(1-lsopropoxyethyl)-1-(3-(1- pyrrolidinyl)phenyl)benzimidazol ⁇ is prepared analogously, by alkylation with 2-bromopropane to the procedure.
- 5-(1-Cyclopropylmethoxy)ethyl)-1-(3-(1- pyrrolidlnyl)phenyl)be ⁇ zimidazole is prepared analogously, by alkylation with bromomethylcyclopropa ⁇ e.
- 5-(2-Ethoxy-2-propyl)-1-(3-(1-pyriOlidinyl)phenyl)benzimidazole is prepared analogously, by ethylation with iodoetha ⁇ e.
- 5-(2-Propoxy-2-propyl)-1-(3-(1- pyrrolidinyl)phenyl)benzimidazole is prepared analogously, by alkylation with 1-bromopropane.
- 5-(2-lsopropoxy-2-propyl)-1-(3-(1- pyrrolidinyl)phenyl)benzimidazole is prepared analogously, by alkylation with 2-bromopropane.
- 4-(2-Dioxolanyl)-2-nitro-N-(3-(3-isoxazolyl)phenyl)aniline is prepared analogously from 2-(4-chloro-3-nitrophenyl)dioxolane and N-(3-(3-isoxazolyl)phenyl)formamide.
- 4-(2-Dioxolanyl)-2-nitro-N-(3-(1-pyrrolyl)phenyl)anillne is prepared analogously from 2- (4-chloro-3-nitrophenyl)dioxolane and N-(3-(1-pyrrololyl)phenyl)formamide.
- 2-Amino-4-(2-dioxolanyl)'N-(3-(1-imidazolyl)phenyl)aniline was prepared analogously from 4-(2-dioxolanyl)-2-nitro-N-(3-(1-imidazolyl)phenyl)aniline.
- 2-Amino-4-(2-dioxolanyl)-N-(3-(3-isoxazolyl)phenyl)aniline is prepared analogously from 4-(2-dioxolanyl)-2-nitro-N-(3-(3-isoxazolyl)phenyl)aniline.
- 2-Amino-4-(2-dioxolanyl)-N-(3-(1-pyrrolyl)phenyl)aniline is prepared analogously from 4-(2-dioxolanyl)-2-nitro-N-(3-(1-pyrrolyl)phenyl)aniline.
- 5-(2-Dioxolanyl)-1-(3-(2-thiazolyl)phenyl)benzimidazole was prepared from 2-amino-4- (2-dioxolanyl)-N-(3-(2-thiazolyl)phenyl)aniline (3.3g, 9.7mmol) and triethyl orthoformate (3.2ml, 19.4mmol) using p-toluenesulphonic acid as the catalyst as described in Example 5 to afford 2.5g.
- 5-(2-Dioxolanyl)-1-(3-(1-imidazolyl)phenyl)benzimidazole was prepared analogously from 2-amino-4-(2-dioxolanyl)-N-(3-(1-imidazolyl)phenyl)aniline.
- 5-Formyl-1-(3-(1-imidazolyl)phenyl)benzimidazole was prepared analogously from 5-(2- dioxolanyl)-1 -(3-(1 -imidazolyl)phenyl)benzimidazole.
- 5-Formyl-1-(3-(3-isoxazolyl)phenyi)benzimidazole is prepared analogously from 5-(2- dioxolanyI)-1 -(3-(3-isoxazolyl)phe ⁇ yl)benzimidazole
- 5-Formyl-1-(3-(1-pyrrolyl)phenyl)b ⁇ nzimidazole is prepared analogously from 5-(2- dioxolanyl)-1-(3-(1-pyrrolyl)phenyl)benzimidazole 5-(Hydroxymethyl)-1-(3-(2-thiazolyl)phenyl)benzimidazole.
- 5-Formyl-1 -(3-(2- thiazolyl)phenyl)benzimidazole (1.0g, 3.27mmol) was treated with sodium borohydride (0.12g, 3.27mmol) as described in Example 5 (1.0g) Mp 115-118°C.
- 5-(Hydroxymethyl)-1-(3-(1-pynOlyl)phenyl)benzimidazole is prepared analogously from 5- formyl-1-(3-(1-pyrrolyl)phenyl)benzimidazole 5-(Methoxymethyl)-1-(3-(2-thiazolyI)phenyl)benzimidazole.
- 5-Hydroxymethyl-1-(3-(2- thiazolyl)phenyl)benzimidazole (1.0g, 3.26mmol) was methylated with iodomethane as described in Example 5 (0.54g). The product was isolated as the hydrochloride. Mp 175- 178°C.
- 5-(Methoxymethyl)-1-(3-(3-isoxazolyl)phenyl)benzimidazole is prepared analogously from 5-hydroxymethyl-1 -(3-(3-isoxazolyl)phenyl)benzimidazole.
- 5-(Ethoxymethyl)-1-(3-(3-isoxazolyl)phenyi)benzimidazole is prepared analogously by ethylation with iodoethane.
- 5-(lsopropoxymethyl)-1-(3-(3-isoxazolyl)phenyl) benzimidazole is prepared analogously by alkylation with 2-bromopropane.
- 5-(Methoxymethyl)-1-(3-(1-pyrrolyl)phenyl)benzimidazole is prepared analogously from 5-hydroxymethyl-1-(3-(1-pyrrolyl)phe ⁇ yl)benzimidazole.
- 5-(Ethoxymethyl)-1-(3-(1-pyrrolyl)phenyl)benzimidazole is prepared analogously by ethylation with iodoethane.
- 5-(lsopropoxymethyl)-1-(3-(1-pyrrolyl)phenyl) benzimidazole is prepared analogously by alkylation with 2-bromopropane.
- 5-(Ethoxymethyl)-1-(3-(2-thiazolyl)phenyl)benzimidazole is prepared analogously by ethylation with iodoethane.
- 5-(lsopropoxymethyl)-1-(3-(2-thiazoIyl)phenyl) benzimidazole is prepared analogously by alkylation with 2-bromopropane.
- Cerebral cortex from male Wistar rats (150-200 g) is homogenised for 5-10 sec in 20 ml Tris-HCl (30 mM, pH 7.4) using an Ultra-Turrax homogeniser. The suspension is centrifuged at 27,000 x g for 15 min and the pellet is washed three times with buffer (centrifuged at 27,000 x g for 10 min). The washed pellet is homogenized in 20 ml of buffer and incubated on a water bath (37°C) for 30 min to remove endogenous GABA and then centrifuged for 10 min at 27,000 x g. The pellet is then homogenized in buffer and centrifuged for 10 min at 27,000 x g. The final pellet is resuspended in 30 ml buffer and the preparation is frozen and stored at -20°C.
- the membrane preparation is thawed and centrifuged at 2°C for 10 min at 27,000 x g.
- the pellet is washed twice with 20 ml 50 mM Tris-citrate, pH 7.1 using an Ultra- Turrax homogeniser and centrifuged for 10 min at 27,000 x g.
- the final pellet is resuspended in 50 mM Tris-citrate, pH 7.1 (500 ml buffer per g of original tissue), and then used for binding assays.
- Aliquots of 0.5 ml tissue are added to 25 ⁇ l of test solution and 25 ⁇ l of 3 H-FNM (1 nM, final concentration), mixed and incubated for 40 min at 2°C.
- Non-specific binding is determined using Clonazepam (1 ⁇ M, final concentration). After incubation the samples are added 5 ml of ice-cold buffer and poured directly onto Whatman GF/C glass fibre filters under suction and immediately washed with 5 ml ice-cold buffer. The amount of radioactivity on the filters is determined by conventional liquid scintillation counting. Specific binding is total binding minus non-specific binding.
- IC 50 the concentration ( ⁇ M) of the test substance which inhibits the specific binding of 3 H-FNM by 50%.
- IC 50 (applied test substance concentration, ⁇ M) x
- C 0 is specific binding in control assays
- C x is the specific binding in the test assay.
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MXPA05010449A MXPA05010449A (en) | 2003-04-03 | 2004-04-01 | Benzimidazole derivatives and their use for modulating the gaba-a. |
JP2006505511A JP2006522070A (en) | 2003-04-03 | 2004-04-01 | Benzimidazole derivatives and methods for using them to modulate GABAA receptor complexes |
US10/546,437 US20060069135A1 (en) | 2003-04-03 | 2004-04-01 | Benzimidazole derivatives and their use for modulating the gaba-a receptor complex |
CA002520281A CA2520281A1 (en) | 2003-04-03 | 2004-04-01 | Benzimidazole derivatives and their use for modulating the gabaa recept or complex |
NZ541544A NZ541544A (en) | 2003-04-03 | 2004-04-01 | Benzimidazole derivatives and their use for modulating the GABAA receptor complex |
AU2004226179A AU2004226179A1 (en) | 2003-04-03 | 2004-04-01 | Benzimidazole derivatives and their use for modulating the GABA-a receptor complex |
EP04725054A EP1613618A2 (en) | 2003-04-03 | 2004-04-01 | BENZIMIDAZOLE DERIVATIVES AND THEIR USE FOR MODULATING THE GABA- sb A /sb RECEPTOR COMPLEX |
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WO2006108800A1 (en) * | 2005-04-13 | 2006-10-19 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the gabaa receptor complex |
WO2006111517A1 (en) * | 2005-04-19 | 2006-10-26 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the gabaa receptor complex |
WO2007110374A1 (en) * | 2006-03-24 | 2007-10-04 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the gabaa receptor complex |
WO2010055133A1 (en) * | 2008-11-14 | 2010-05-20 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the gabaa receptor complex |
WO2010055130A1 (en) * | 2008-11-14 | 2010-05-20 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the gabaa receptor complex |
WO2010055132A1 (en) * | 2008-11-14 | 2010-05-20 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the gabaa receptor complex |
WO2010055131A1 (en) * | 2008-11-14 | 2010-05-20 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the gabaa receptor complex |
US7923464B2 (en) | 2005-12-05 | 2011-04-12 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the GABAA receptor complex |
US8278460B2 (en) * | 2009-10-15 | 2012-10-02 | Concert Pharmaceuticals, Inc. | Substituted benzimidazoles |
US9708311B2 (en) | 2012-12-06 | 2017-07-18 | Bayer Pharma Aktiengesellschaft | Benzimidazole derivatives as EP4 antagonists |
WO2020053377A1 (en) | 2018-09-13 | 2020-03-19 | Saniona A/S | A gabaa receptor ligand |
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EP0616807A1 (en) | 1993-03-24 | 1994-09-28 | Neurosearch A/S | Benzimidazole useful in the treatment of central nervous system disorders |
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-
2004
- 2004-04-01 WO PCT/EP2004/050417 patent/WO2004087690A2/en active Application Filing
- 2004-04-01 EP EP04725054A patent/EP1613618A2/en not_active Withdrawn
- 2004-04-01 MX MXPA05010449A patent/MXPA05010449A/en not_active Application Discontinuation
- 2004-04-01 AU AU2004226179A patent/AU2004226179A1/en not_active Abandoned
- 2004-04-01 JP JP2006505511A patent/JP2006522070A/en not_active Withdrawn
- 2004-04-01 NZ NZ541544A patent/NZ541544A/en unknown
- 2004-04-01 US US10/546,437 patent/US20060069135A1/en not_active Abandoned
- 2004-04-01 CA CA002520281A patent/CA2520281A1/en not_active Abandoned
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Cited By (17)
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US7851490B2 (en) | 2005-04-13 | 2010-12-14 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the GABAA receptor complex |
WO2006108800A1 (en) * | 2005-04-13 | 2006-10-19 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the gabaa receptor complex |
WO2006111517A1 (en) * | 2005-04-19 | 2006-10-26 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the gabaa receptor complex |
US7923464B2 (en) | 2005-12-05 | 2011-04-12 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the GABAA receptor complex |
US8288418B2 (en) | 2006-03-24 | 2012-10-16 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the GABAA receptor complex |
US7902230B2 (en) | 2006-03-24 | 2011-03-08 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the GABAA receptor complex |
EP2319837A1 (en) * | 2006-03-24 | 2011-05-11 | NeuroSearch AS | Benzimidazole derivatives and their use for modulating the GABAa receptor complex |
WO2007110374A1 (en) * | 2006-03-24 | 2007-10-04 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the gabaa receptor complex |
WO2010055132A1 (en) * | 2008-11-14 | 2010-05-20 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the gabaa receptor complex |
WO2010055131A1 (en) * | 2008-11-14 | 2010-05-20 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the gabaa receptor complex |
WO2010055130A1 (en) * | 2008-11-14 | 2010-05-20 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the gabaa receptor complex |
WO2010055133A1 (en) * | 2008-11-14 | 2010-05-20 | Neurosearch A/S | Benzimidazole derivatives and their use for modulating the gabaa receptor complex |
US8492408B2 (en) | 2008-11-14 | 2013-07-23 | Aniona Aps | Benzimidazole derivatives and their use for modulating the GABAA receptor complex |
US8278460B2 (en) * | 2009-10-15 | 2012-10-02 | Concert Pharmaceuticals, Inc. | Substituted benzimidazoles |
US9708311B2 (en) | 2012-12-06 | 2017-07-18 | Bayer Pharma Aktiengesellschaft | Benzimidazole derivatives as EP4 antagonists |
WO2020053377A1 (en) | 2018-09-13 | 2020-03-19 | Saniona A/S | A gabaa receptor ligand |
US11396510B2 (en) | 2018-09-13 | 2022-07-26 | Saniona A/S | GABAA receptor ligand |
Also Published As
Publication number | Publication date |
---|---|
MXPA05010449A (en) | 2006-05-31 |
EP1613618A2 (en) | 2006-01-11 |
AU2004226179A1 (en) | 2004-10-14 |
NZ541544A (en) | 2008-06-30 |
JP2006522070A (en) | 2006-09-28 |
US20060069135A1 (en) | 2006-03-30 |
WO2004087690A3 (en) | 2004-11-11 |
CA2520281A1 (en) | 2004-10-14 |
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