WO2009109518A1 - Novel 4-benzhydryl-tetrahydro-pyridine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors - Google Patents
Novel 4-benzhydryl-tetrahydro-pyridine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors Download PDFInfo
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Definitions
- This invention relates to novel 4-benzhydryl-tetrahydro-pyridine derivatives useful as monoamine neurotransmitter re-uptake inhibitors.
- the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.
- Serotonin Selective Reuptake Inhibitors currently provide efficacy in the treatment of several CNS disorders, including depression and panic disorder.
- SSRIs are generally perceived by psychiatrists and primary care physicians as effective, well-tolerated and easily administered. However, they are associated with a number of undesirable features.
- the invention provides a compound of Formula I:
- the invention provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound of the invention, any of its stereoisomers or any mixture of its stereoisomers, or an N-oxide thereof, 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, any of its stereoisomers or any mixture of its stereoisomers, or an N- oxide thereof, 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 inhibition of monoamine neurotransmitter re-uptake 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 responsive to inhibition of monoamine neurotransmitter re-uptake in the central nervous system, which method comprises the step of administering to such a Nv- ing animal body in need thereof a therapeutically effective amount of a compound of the invention, any of its stereoisomers or any mixture of its stereoisomers, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.
- R a represents hydrogen or d- 6 -alkyl
- R b and R c independent of each other represent a phenyl group, which phenyl group is optionally substituted with one or more substituents independently selected from the group consisting of halo, trifluoromethyl, trifluoromethoxy, cyano, C- ⁇ -6-alkoxy and methylenedioxo.
- R a represents hydrogen. In another embodiment of the compound of Formula I, R a represents Ci -6 - alkyl. In another embodiment, R a represents methyl.
- R b represents phenyl.
- R c represents phenyl.
- the compound of the invention is: 4-Benzhydryl-1 -methyl-1 ,2,3,6-tetrahydro-pyridine; 4-Benzhydryl-1 ,2,3,6-tetrahydro-pyridine; or a pharmaceutically acceptable salt thereof.
- Ci -6 -alkyl as used herein means a saturated, branched or straight hydrocarbon group having from 1 -6 carbon atoms, e.g. C 1-3 -alkyl, Ci -4 - alkyl, Ci -6 -alkyl, C 2 - 6 -alkyl, C 3 - 6 -alkyl, and the like.
- Representative examples are methyl, ethyl, propyl (e.g. prop-1 -yl, prop-2-yl (or /so-propyl)), butyl (e.g. 2- methylprop-2-yl (or te/t-butyl), but-1 -yl, but-2-yl), pentyl (e.g.
- halo or halogen shall mean fluorine, chlorine, bromine or iodine.
- cyano shall mean the radical -CN.
- trihalomethyl shall mean thfluoromethyl, trichloromethyl, and similar trihalo-substituted methyl groups.
- trihalomethoxy shall mean trifluoromethoxy, trichloromethoxy, and similar trihalo-substituted methoxy groups.
- Ci -6 -alkoxy refers to the radical Ci -6 -alkyl-O-.
- Representative examples are methoxy, ethoxy, propoxy (e.g. 1 -propoxy, 2- propoxy), butoxy (e.g. 1 -butoxy, 2-butoxy, 2-methyl-2-propoxy), pentoxy (1 - pentoxy, 2-pentoxy), hexoxy (1 -hexoxy, 3-hexoxy), and the like.
- 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 hy- drochlohde, the hydrobromide, the nitrate, the perchlorate, the phosphate, the sulphate, the formate, the acetate, the aconate, the ascorbate, the benzenesul- phonate, the benzoate, the cinnamate, the citrate, the embonate, the enantate, the fumarate, the glutamate, the glycolate, the lactate, the maleate, the malonate, the mandelate, the methanesulphonate, the naphthalene-2-sulphonate, the phtha- late, the salicylate, the sorbate, the stearate, the succinate, the tartrate, the tolu- ene-p-sulphonate, and the like.
- Such salts may be formed by procedures well known and described in the
- 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.
- Examples of pharmaceutically acceptable cationic salts of a chemical compound of the invention include, without limitation, the sodium, the potassium, the calcium, the magnesium, the zinc, the aluminium, the lithium, the choline, the lysi- nium, and the ammonium salt, and the like, of a chemical compound of the invention containing an anionic group.
- Such cationic salts may be formed by procedures well known and described in the art.
- 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 cycloalky- lalkyl-onium salts.
- 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 te- trahydrate, and the like. In general, the dissoluble forms are considered equivalent to indissoluble forms for the purposes of this invention.
- the invention includes all such isomers and any mixtures thereof including ra- cemic mixtures. Racemic forms can be resolved into the optical antipodes by known methods and techniques. One way of separating the enantiomeric compounds (including enantiomeric intermediates) is - in the case the compound being a chiral acid - by use of an optically active amine, and liberating the diastereomeric, resolved salt by treatment with an acid. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optical active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of D- or L- (tartrates, mandelates, or camphorsulphonate) salts for example.
- D- or L- fractional crystallisation of D- or L- (tartrates, mandelates, or camphorsulphonate) salts for example.
- the chemical compounds of the present invention may also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) cam- phanic acid or by the formation of diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like.
- an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) cam- phanic acid
- optical active compounds can also be prepared from optical active starting materials.
- 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.
- the labelled compound has one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- the labelling 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 radio- nuclide 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), 11 C, 13 C, 14 C, 131 I 1 125 1, 123 I, 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.
- Compounds of the invention may be tested for their ability to inhibit reuptake of the monoamines dopamine, noradrenaline and serotonin in synaptosomes e.g. such as described in WO 97/30997 (NeuroSearch A/S) or WO 97/16451 (NeuroSearch A/S). Based on the balanced activity observed in these tests the compound of the invention is considered useful 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 inhibition of monoamine neurotransmitter re-uptake in the central nervous system.
- the compounds of the invention are considered useful for the treatment, prevention or alleviation of: mood disorder, depression, atypical depression, depression secondary to pain, major depressive disorder, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar Il disorder, cyclothymic disorder, mood disorder due to a general medical condition, substance- induced mood disorder, pseudodementia, Ganser's syndrome, obsessive compul- sive disorder, panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without history of panic disorder, panic attack, memory deficits, memory loss, attention deficit hyperactivity disorder (ADHD), obesity, anxiety, generalized anxiety disorder, eating disorder, Parkinson's disease, parkinsonism, dementia, dementia of ageing, senile dementia, Alzheimer's disease, Down's syndrome, acquired immunodeficiency syndrome dementia complex, memory dysfunction in ageing, specific phobia, social phobia, social anxiety disorder, post-traumatic stress disorder, acute stress disorder, drug addiction, drug abuse, drug abuse liability
- the compounds are considered useful for the treatment, prevention or alleviation of depression. In another special embodiment, the compounds are considered useful for the treatment, prevention or alleviation of attention deficit hyperactivity disorder (ADHD).
- ADHD attention deficit hyperactivity disorder
- a suitable dosage of the active pharmaceutical ingredient (API) is within the range of from about 0.1 to about 1000 mg API per day, more preferred of from about 10 to about 500 mg API per day, most preferred of from about 30 to about 100 mg API per day, dependent, however, upon the exact mode of administration, the form in which it is administered, the indication considered, the subject and in particular the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.
- Preferred compounds of the invention show a biological activity in the sub- micromolar and micromolar range, i.e. of from below 1 to about 100 ⁇ M.
- the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the chemical compound of the invention. While a chemical 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 the chemical compound of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers, and, optionally, other therapeutic and/or prophylactic ingredients, known and used in the art.
- 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 insuffla- tion, 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 nonaqueous 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, methyl- cellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
- the term "preparation” is intended to include the formulation of the active com- pound 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.
- 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 is dispersed homogeneously therein, as by stirring.
- the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
- compositions suitable for vaginal administration may be presented as pes- saries, 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.
- the 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.
- a suitable vehicle e.g. sterile, pyrogen-free water
- 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.
- viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
- solid form preparations intended for conversion shortly before use to liquid form preparations for oral administration.
- Such liquid forms include solutions, suspensions, and emulsions.
- such preparations may comprise colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing 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 emul- sifying 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 tra- gacanth; 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 dichlorodi- fluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
- a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodi- fluoromethane, 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
- 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 cav- ity.
- 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 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 micron ization.
- the pharmaceutical preparations are preferably in unit dosage forms.
- 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.
- 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.
- the invention provides tablets or capsules for oral ad- ministration.
- the invention provides liquids for intravenous administration and continuous infusion.
- compositions containing of from about 0.1 to about 500 mg of active in- gredient 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. 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.
- the invention provides a method for the treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disease, disorder or condition is responsive to in- hibition of monoamine neurotransmitter re-uptake in the central nervous system, and which method comprises administering to such a living animal body, including a human, in need thereof an effective amount of a chemical compound of the invention.
- suitable dosage ranges are 0.1 to 1000 milligrams daily, 10-500 milligrams daily, and especially 30-100 milligrams daily, dependent as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.
- test values are given as IC 50 (the concentration ( ⁇ M) of the test substance which inhibits the specific binding of 3 H-DA, 3 H-NA, or ⁇ -5-HT by 50%).
Abstract
Description
Claims
Priority Applications (8)
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AU2009221310A AU2009221310A1 (en) | 2008-03-05 | 2009-02-27 | Novel 4-benzhydryl-tetrahydro-pyridine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors |
BRPI0907990A BRPI0907990A2 (en) | 2008-03-05 | 2009-02-27 | compound, pharmaceutical composition, and compound use |
EP09717221A EP2254868A1 (en) | 2008-03-05 | 2009-02-27 | Novel 4-benzhydryl-tetrahydro-pyridine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors |
MX2010009582A MX2010009582A (en) | 2008-03-05 | 2009-02-27 | Novel 4-benzhydryl-tetrahydro-pyridine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors. |
US12/921,048 US20110082166A1 (en) | 2008-03-05 | 2009-02-27 | Novel 4-benzhydryl-tetrahydro-pyridine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors |
CA2717367A CA2717367A1 (en) | 2008-03-05 | 2009-02-27 | Novel 4-benzhydryl-tetrahydro-pyridine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors |
JP2010549103A JP2011513354A (en) | 2008-03-05 | 2009-02-27 | Novel 4-benzhydryl-tetrahydro-pyridine derivatives and their use as monoamine neurotransmitter reuptake inhibitors |
CN2009801076151A CN101959860A (en) | 2008-03-05 | 2009-02-27 | Novel 4-benzhydryl-tetrahydro-pyridine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors |
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DKPA200800325 | 2008-03-05 | ||
DKPA200800325 | 2008-03-05 | ||
US3427208P | 2008-03-06 | 2008-03-06 | |
US61/034,272 | 2008-03-06 |
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WO2009109518A1 true WO2009109518A1 (en) | 2009-09-11 |
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US (1) | US20110082166A1 (en) |
EP (1) | EP2254868A1 (en) |
JP (1) | JP2011513354A (en) |
CN (1) | CN101959860A (en) |
AU (1) | AU2009221310A1 (en) |
BR (1) | BRPI0907990A2 (en) |
CA (1) | CA2717367A1 (en) |
WO (1) | WO2009109518A1 (en) |
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WO1997013770A1 (en) * | 1995-10-13 | 1997-04-17 | Neurosearch A/S | 8-azabicyclo[3.2.1]oct-2-ene derivatives, their preparation and use |
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WO1997045423A1 (en) * | 1996-05-31 | 1997-12-04 | Trophix Neuroscience Inc. | Pharmaceutical for treating of neurological and neuropsychiatric disorders |
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2009
- 2009-02-27 WO PCT/EP2009/052331 patent/WO2009109518A1/en active Application Filing
- 2009-02-27 US US12/921,048 patent/US20110082166A1/en not_active Abandoned
- 2009-02-27 BR BRPI0907990A patent/BRPI0907990A2/en not_active Application Discontinuation
- 2009-02-27 JP JP2010549103A patent/JP2011513354A/en active Pending
- 2009-02-27 CN CN2009801076151A patent/CN101959860A/en active Pending
- 2009-02-27 EP EP09717221A patent/EP2254868A1/en not_active Withdrawn
- 2009-02-27 AU AU2009221310A patent/AU2009221310A1/en not_active Abandoned
- 2009-02-27 CA CA2717367A patent/CA2717367A1/en not_active Abandoned
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---|---|---|---|---|
WO1997013770A1 (en) * | 1995-10-13 | 1997-04-17 | Neurosearch A/S | 8-azabicyclo[3.2.1]oct-2-ene derivatives, their preparation and use |
Non-Patent Citations (1)
Title |
---|
BRYAN-LLUKA, LESLEY J. ET AL: "Potencies of haloperidol metabolites as inhibitors of the human noradrenaline, dopamine and serotonin transporters in transfected COS-7 cells", NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, vol. 360, no. 2, 1999, pages 109 - 115, XP002527040 * |
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AU2009221310A1 (en) | 2009-09-11 |
JP2011513354A (en) | 2011-04-28 |
US20110082166A1 (en) | 2011-04-07 |
CN101959860A (en) | 2011-01-26 |
BRPI0907990A2 (en) | 2015-12-29 |
CA2717367A1 (en) | 2009-09-11 |
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