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WO2010058019A1 - Dérivés de 3-phényl-3-méthoxypyrrolidine en tant que modulateurs de la neurotransmission catécholaminergique corticale - Google Patents

Dérivés de 3-phényl-3-méthoxypyrrolidine en tant que modulateurs de la neurotransmission catécholaminergique corticale Download PDF

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Publication number
WO2010058019A1
WO2010058019A1 PCT/EP2009/065678 EP2009065678W WO2010058019A1 WO 2010058019 A1 WO2010058019 A1 WO 2010058019A1 EP 2009065678 W EP2009065678 W EP 2009065678W WO 2010058019 A1 WO2010058019 A1 WO 2010058019A1
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Prior art keywords
enantiomer
difluorophenyl
methoxypyrrolidine
methoxy
oxide
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PCT/EP2009/065678
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English (en)
Inventor
Clas Sonesson
Lars Swanson
Fredrik Pettersson
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Nsab, Filial Af Neurosearch Sweden Ab, Sverige
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Application filed by Nsab, Filial Af Neurosearch Sweden Ab, Sverige filed Critical Nsab, Filial Af Neurosearch Sweden Ab, Sverige
Priority to US13/130,482 priority Critical patent/US20110257242A1/en
Priority to EP09759724A priority patent/EP2367788A1/fr
Publication of WO2010058019A1 publication Critical patent/WO2010058019A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel 3-phenyl-3-methoxy-pyrrolidine derivatives, useful for modulating dopamine neurotransmission and extracellular levels of catecholamines, dopamine and norepinephrine, in cerebral cortical areas of the mammalian brain, and more specifically for the treatment of central nervous system disorders.
  • the invention relates to pharmaceutical compositions comprising the 3-phenyl-3-methoxy-pyrrolidine derivatives of the invention and to the use of these compounds for therapeutic applications.
  • Dopamine is a neurotransmitter in the brain. Since this discovery, made in the 1950's, the function of dopamine in the brain has been intensely explored. To date, it is well established that dopamine is essential in several aspects of brain function including motor, cognitive, sensory, emotional and autonomous functions (e.g. regulation of appetite, body temperature, sleep). Thus, modulation of dopaminergic function may be beneficial in the treatment of a wide range of disorders affecting brain functions. In fact, drugs that act, directly or indirectly at central dopamine receptors are commonly used in the treatment of neurological and psychiatric disorders, e.g. Parkinson's disease and schizophrenia.
  • neurological and psychiatric disorders e.g. Parkinson's disease and schizophrenia.
  • the cerebral cortex encompasses several major regions that are involved in higher functions such as thought, feelings, memory and planning.
  • Biogenic amines i.e. dopamine, norepinephrine and serotonin
  • the ascending dopamine and norepinephrine pathways innervate the cortex.
  • the serotonergic neurons of the CNS project to virtually all regions of the brain including the cerebral cortex.
  • Primary or secondary dysfunctions in the activity of these pathways lead to dysregulation of the activity at dopamine and norepinephrine and serotonin receptors in these brain areas and subsequently to manifestations of psychiatric and neurological symptoms.
  • the biogenic amines of the cortex modulate several aspects of cortical functions controlling affect, anxiety, motivation, cognition, attention, arousal and wakefulness.
  • the catecholamines dopamine and norepinephrine exert strong influence on the prefrontal cortical areas, the integrity of which is essential for the so- called executive cognitive functions, related to e.g. attention, planning of actions and impulse control.
  • Norepinephrine is a major part in the circuitry regulating anxiety and fear and is thus believed to be dysregulated in anxiety disorders such as panic disorders, generalized anxiety disorder (GAD) and specific phobias.
  • the monoamine systems in the cortex are known to be directly or indirectly involved in the core symptoms of schizophrenia.
  • this disorder emerges as various pathological etiologies converge upon cortical function leading to dysregulation of the cortical micro-circuitry, which is clinically manifested as the symptoms of schizophrenia.
  • This cortical micro-circuitry is regulated by several neurotransmitters, including glutamate, GABA, and dopamine.
  • the object of the present invention is to provide novel pharmaceutically active compounds, especially useful in treatment of disorders in the central nervous system.
  • a further object is the provision of compounds for modulation of dopamine and norepinephrine neurotransmission in the mammalian brain, including human brain.
  • a still further object is to provide compounds with therapeutic effects after oral administration.
  • a yet further object is the provision of compounds with more optimal pharmacodynamic properties such as e.g. kinetic behaviour, bioavailability, solubility and efficacy.
  • a yet further object is to provide compounds being superior to presently known compounds in the treatment of several disorders related to dysfunctions of the CNS, in terms of efficacy or side effects.
  • the present invention concerns the unexpected discovery of the pharmacological effects of compounds of the invention on monoamines in the cerebral cortex, and the use of these compounds in the treatment for certain CNS disorders.
  • pharmacological testing in vivo in the rat it is demonstrated that compounds of the present invention produce regionally selective increases in catecholamine levels in the frontal cortex. Due to the specific modulatory effects of the catecholamines on cortical functions related to cognition, attention and affect, the compounds of the invention can be used in the treatment of disorders characterised by dysfunctions in these areas.
  • the compounds can be used in the treatment of cognitive disorders, ADHD, depression, and anxiety.
  • the compounds can also be used to treat schizophrenia, which is characterised by dysfunctions of the cerebral cortex manifested in cognitive failure and psychosis.
  • the invention provides a 3-phenyl-3-methoxy-pyrrolidine derivative of Formula 1
  • the invention provides a pharmaceutical composition, comprising a therapeutically effective amount of a 3-phenyl-3-methoxy-pyrrolidine derivative 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 3-phenyl-3-methoxy- pyrrolidine derivative 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 responsive to modulation of catecholamines in the cerebral cortex.
  • 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 catecholamines in the cerebral cortex, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a 3-phenyl-3-methoxy-pyrrolidine derivative of the invention, any of its stereoisomers or any mixture of its stereoisomers, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • 3-Phenyl-3-methoxy-pyrrolidine derivatives In its first aspect the present invention provides 3-phenyl-3-methoxy-pyrrolidine derivatives of Formula 1 :
  • R 1 is F or Cl
  • R 2 is F or Cl
  • R 3 is n-propyl, /-propyl, n-butyl, /-butyl or sec-butyl.
  • the 3-phenyl-3-methoxy-pyrrolidine derivative of the invention is a compound of Formula 2:
  • the 3-phenyl-3-methoxy-pyrrolidine derivative of the invention is a compound of Formula 2, wherein R m represents R 1 , R 0 represents R 2 and R p and R q represent H.
  • the 3-phenyl-3-methoxy-pyrrolidine derivative of the invention is a compound of Formula 2, wherein R m represents R 1 , R p represents R 2 and R 0 and R q represent H.
  • the 3-phenyl-3-methoxy-pyrrolidine derivative of the invention is a compound of Formula 2, wherein R m represents R 1 , R q represents R 2 and R 0 and R p represent H.
  • the 3-phenyl-3-methoxy-pyrrolidine derivative of the invention is a compound of Formula 1 or Formula 2, any of its stereoisomers or any mixture of its stereoisomers, or an N-oxide thereof, or a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is F or Cl.
  • R 1 is F. In another more preferred embodiment, R 1 is Cl.
  • the 3-phenyl-3-methoxy-pyrrolidine derivative of the invention is a compound of Formula 1 or Formula 2, any of its stereoisomers or any mixture of its stereoisomers, or an N-oxide thereof, or a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is F or Cl. In a more preferred embodiment, R 2 is F.
  • R 2 is Cl
  • the 3-phenyl-3-methoxy-pyrrolidine derivative of the invention is a compound of Formula 1 or Formula 2, any of its stereoisomers or any mixture of its stereoisomers, or an N-oxide thereof, or a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is n-propyl, /-propyl, n-butyl, /-butyl or sec-butyl, or a deuterated analog thereof.
  • R 3 is n-propyl or CD 2 -CD 2 -CD 3 .
  • R 3 is /-propyl or CD-(CD 3 ) 2 .
  • R 3 is n-butyl or CD 2 -CD 2 -CD 2 -CD 3 . In a fourth more preferred embodiment, R 3 is /-butyl or CD 2 -CD-(CD 3 ) 2 .
  • R 3 is sec-butyl or CD(CD 3 )-CD 2 -CD 3 .
  • the 3-phenyl-3-methoxy-pyrrolidine derivative of the invention is
  • Enantiomer 1 of 3-(3,5-difluorophenyl)-1 -isopropyl-3-methoxypyrrolidine; Enantiomer 2 of 3-(3,5-difluorophenyl)-1 -isopropyl-3-methoxypyrrolidine;
  • 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 salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride, the hydrobromide, the nitrate, the perchlorate, the phosphate, the sulphate, the formate, the acetate, the aconate, the ascorbate, the benzenesulphonate, 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 phthalate, the salicylate, the sorbate, the stearate, the succinate, the tartrate, the toluene-p-sulphonate, and the like.
  • the non-toxic inorganic and organic acid addition salts such as the hydrochloride, the hydrobromide, the n
  • 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.
  • 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 lysinium, 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.
  • 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.
  • 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.
  • 3-phenyl-3-methoxy- pyrrolidine derivatives of the present invention may exist in different stereoisomeric forms - including enantiomers, diastereomers or cis-trans-isomers.
  • the invention includes all such isomers and any mixtures thereof including racemic 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 diastereomehc, 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 camphor- sulphonate) 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 (-) camphanic 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 (-) camphanic acid
  • optical active compounds can also be prepared from optical active starting materials.
  • an N-oxide designates an oxide derivative of a tertiary amine, including a nitrogen atom of an aromatic N-heterocyclic compound, a non-aromatic N-heterocyclic compounds, a thalkylamine and a trialkenylamine.
  • 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 provided in the form of their deuterated analogs.
  • Deuterium forms bonds with carbon that vibrate at a lower frequency and are thus stronger than C-H bonds. Therefore "heavy hydrogen" (deuterium) versions of drugs may be more stable towards degradation and last longer in the organism.
  • the deuterated analog of the invention may be a fully or partially deuterium substituted derivative.
  • the deuterium substituted derivative of the invention holds a fully or partially deuterium substituted alkyl group, and in particular -CD 2 -CD 2 - CD 3 (n-propyl-D7), -CD-(CD 3 ) 2 (/so-propyl-D7), -CD 2 -CD 2 -CD 2 -CD 3 (n-butyl-D9), -CD 2 - CD 2 -(CDs) 2 (/so-butyl-D9) and -CD(CDs)-CD 2 -CD 3 (sec-butyl-D9).
  • deuterium when a particular position is designated as holding deuterium (stated as “D” or “deuterium”), it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1 % incorporation of deuterium).
  • the abundance of deuterium at that position is at least 3340 times greater (i.e. at least 50.1 % incorporation of deuterium) than the natural abundance of deuterium, which is 0.015%.
  • the abundance of deuterium at that position is at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • the 3-phenyl-3-methoxy-pyrrolidine derivatives 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, 125 I, 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
  • Computed Axial X-ray Tomography CAT
  • the 3-phenyl-3-methoxy-pyrrolidine derivatives 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.
  • Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative - and in some occasions, more convenient manner - the individual process steps mentioned hereinbefore may be performed in a different order, and/or the individual reactions may be performed at different stage in the overall route (i.e. chemical transformations may be performed upon different intermediates to those associated hereinbefore with a particular reaction).
  • the 3-phenyl-3-methoxy-pyrrolidine derivatives according to the present invention possess norepinephrine, dopamine and to some extent serotonin-modulating properties and both they and their pharmaceutical compositions are useful in treating numerous central nervous system disorders including psychiatric disorders.
  • the compounds and their pharmaceutical compositions are used in the treatment of CNS disorders where the cortical monoaminergic systems are dysfunctional due to direct or indirect causes.
  • the compounds according to the present invention can be used to treat affective disorders and cognitive disorders including neurodegenerative and developmental disorders.
  • compounds with modulating effects on dopaminergic systems may also be used to improve motor and cognitive functions.
  • the compounds of the invention are considered useful for the treatment, prevention or alleviation of dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, Cerebral Palsy, Huntington's disease, Gilles de Ia Tourette's syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorders, generalized anxiety disorder (GAD), specific phobias, panic disorder, sleep disorders, bipolar disorders, drug induced psychotic disorders, iatrogenic psychoses, Iatrogenic hallucinoses, non-iatrogenic psychoses, non- iatrogenic hallucinoses, mood disorders, anxiety disorders, depression, obsessive- compulsive disease, emotional disturbances related to ageing, Alzheimer's disease, dementia, dementia disorders related to Alzheimer's disease, age-related cognitive impairment, brain injury, substance abuse, disorders characterized by misuse of food, sleep disorders, sexual disorders, eating disorders, obesitas, headaches, pains in conditions characterized by increased muscular tone, movement disorders, Parkinson's disease, Parkinsonism,
  • compositions in another aspect provides novel pharmaceutical compositions comprising a therapeutically effective amount of the 3-phenyl-3-methoxy-pyrrolidine derivatives of the invention.
  • the present invention relates to pharmaceutical compositions comprising the compounds of the present invention, and their use in treating CNS disorders.
  • Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds according to the invention.
  • Suitable acid addition salts of the compounds of the present invention include those formed with pharmaceutically acceptable salts such as those mentioned above.
  • the pharmaceutical composition comprising a compound according to the invention may also comprise substances used to facilitate the production of the pharmaceutical preparation or the administration of the preparations. Such substances are well known to people skilled in the art and may for instance be pharmaceutically acceptable adjuvants, carriers and preservatives.
  • the compounds according to the present invention will normally be administered orally, rectally, nasally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, such as the hydrochloride, lactate, acetate or sulfamate salt, in association with a pharmaceutically acceptable carrier.
  • the carrier may be a solid, semisolid or liquid preparation.
  • the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by a weight for preparations intended for injection and between 0.2 and 50% by weight for preparations suitable for oral administration.
  • the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinyl-pyrrolidine, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores (prepared as described above) may be coated with a concentrated sugar solution which may contain e.g.
  • a concentrated sugar solution which may contain e.g.
  • the tablet can be coated with a polymer known to the man skilled in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compound.
  • the active substance may be admixed with e.g. a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the active substance using either the mentioned excipients for tablets e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine.
  • liquids or semisolids of the drug can be filled into hard gelatine capsules. Examples of tablet and capsule formulations suitable for oral administration are given below: Tablet I mg/tablet
  • Maize starch paste (5% w/v paste) 2.25
  • Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in a mixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.2% to about 20% by weight of the active substance herein described, the balance being sugar and mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to the man in the art.
  • Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of from 0.5% to about 10% by weight. These solutions may also containing stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
  • stabilizing agents and/or buffering agents may conveniently be provided in various dosage unit ampoules.
  • the compounds of the present invention may be delivered in the form of a solution, dry powder or suspension.
  • Administration may take place via a pump spray container that is squeezed or pumped by the patient or through an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the compounds of the invention may also be administered via a dry powder inhaler, either as a finely divided powder in combination with a carrier substance (e.g. a saccharide) or as microspheres.
  • the inhaler, pump spray or aerosol spray may be single or multi dose.
  • the dosage may be controlled through a valve that delivers a measured amount of active compound.
  • the compounds of the invention may also be administered in a controlled release formulation.
  • the compounds are released at the required rate to maintain constant pharmacological activity for a desirable period of time.
  • Such dosage forms provide a supply of a drug to the body during a predetermined period of time and thus maintain drug levels in the therapeutic range for longer periods of time than conventional non-controlled formulations.
  • the compounds may also be formulated in controlled release formulations in which release of the active compound is targeted. For example, release of the compound may be limited to a specific region of the digestive system through the pH sensitivity of the formulation. Such formulations are well known to persons skilled in the art.
  • the compositions may be administered at varying doses.
  • the dosing will also depend upon the relation of potency to absorbability and the frequency and route of administration.
  • Such doses may be administered once, twice or three or more times daily.
  • the compounds of this invention can be administered to subjects in doses ranging from 0.01 mg to 500 mg per kg of body weight per day, although variations will necessarily occur depending upon the weight, sex and condition of the subject being treated, the disease state being treated and the particular route of administration chosen.
  • a dosage level that is in the range of from 0.1 mg to 10 mg per kg of body weight per day, single or divided dosage is most desirably employed in humans for the treatment of diseases.
  • the dosage level is such that a serum concentration of between 0.1 nM to 10 ⁇ M of the compound is obtained.
  • enantiomer 1 and “enantiomer 2" of a certain compound designates that it has been synthesised from a starting material with high 10 enantiomeric excess and known optical rotation.
  • enantiomer 1 or enantiomer 2 of a certain compound can also be synthesised from enantiomer 1 and enantiomer 2 of a different compound.
  • the organic phase was extracted with aqueous hydrochloric acid (10%, 100 ml_), the aqueous phase was made basic with aqueous sodium hydroxide (5 M, 80 ml_) and extracted with ethyl acetate.
  • the combined organic phase was dried (Na 2 SO 4 ), evaporated and purified by flash column chromatography on silica gel (isooctane: ethyl acetate 4:1 to 0:1 ). 0.25 g (41 %).
  • the pooled organic phase was extracted with aqueous hydrochloric acid (10%, 100 ml) and the phases were separated.
  • the aqueous phase was made basic with aqueous sodium hydroxide (5N) and was extracted with tert-butyl methyl ether (3x70 mL).
  • the combined organic phase was dried (Na 2 SO 4 ) and 0.41 g (74%).
  • PROPYLPYRROLIDINE-1 -OXIDE Preparation according to Example 19: Enantiomer 1 of 3-(3,4-difluorophenyl)-3- methoxy-1 -propylpyrrolidine (0.006 g, 0.023 mmol), dichloromethane (2 mL), 3- chloroperoxybenzoic acid (77%) (0.01 O g, 0.046 mmol). Analysis by LCMS (Qtrap,
  • (+)-enantiomer (0.202 g).
  • [ ⁇ ] D + 24.1 ° (methanol).
  • (-)- enantiomer (0.264 g).
  • [ ⁇ ] D -23.0 ° (methanol).
  • a rat was put in a transparent acrylic cage (WxLxH, 40x40x30 cm) which in turn was placed in the activity monitor.
  • Each activity monitor was equipped with three rows of infrared photobeam sensors, each row consisting of 16 sensors. Two rows were placed along the front and the side of the floor of the cage, at a 90° angle, and the third row was placed 10 cm above the
  • the computer software was written using object oriented programming (LabVIEW ® , National instruments, Austin, TX, USA).
  • Rats pre-treated with d-amphetamine were given a dose of 1 .5 mg/kg i.p.. 10 min before the recording session in the activity monitor.
  • Rats pre-treated with MK-801 were given a dose of 0.7 mg/kg i.p.. 90 min before the recording session in the activity
  • the distances are normalised to amphetamine-control and fitted by least square minimization to the function "End-(End-Control)/(1 +(dose/ED 50 ) slope )"-
  • the restriction with locked End is made to focus on potency rather than efficacy.
  • the fit is repeated 100 times with a random evenly distributed squared weight (0 to 1 ) for every measurement value. Presented ED 50 -ranges cover 95% of these values.
  • 5-HT serotonin
  • NM noreonin
  • 3-MT 3- methoxytyramine
  • DOPAC 3,4-dihydroxyphenylacetic acid
  • 5-HIAA 5- hydroxyindoleacetic acid
  • HVA homovanillic acid
  • the analytical method is based on two chromatographic separations dedicated for amines or acids. Two chromatographic systems share a common auto injector with a 10-port valve and two sample loops for simultaneous injection on the two systems.
  • Both systems are equipped with a reverse phase column (Luna C18(2), dp 3 ⁇ m, 50 * 2mm i.d., Phenomenex) and electrochemical detection is accomplished at two potentials on glassy carbon electrodes (MF-1000, Bioanalytical Systems, Inc.).
  • the column effluent is passed via a T-connection to the detection cell or to a waste outlet. This is accomplished by two solenoid valves, which block either the waste or detector outlet. By preventing the chromatographic front from reaching the detector, better detection conditions are achieved.
  • the aqueous mobile phase (0.4 ml/min) for the acid system contains citric acid 14 mM, sodium citrate 10 mM, MeOH 15% (v/v) and EDTA 0.1 mM.
  • Detection potentials relative to Ag/AgCI reference are 0.45 and 0.60V.
  • the aqueous ion pairing mobile phase (0.5 ml/min) for the amine system contains citric acid 5 mM, sodium citrate 10 mM, MeOH 9%(v/v), MeCN 10.5% v/v), decane sulfonic acid 0.45 mM, and EDTA 0.1 mM.
  • Detection potentials relative to Ag/AgCI reference are 0.45 and 0.65V.
  • ED 50 values for the increase of DOPAC in striatum are calculated by curve fitting. For most compounds, the evaluation is based on 20 animals over the dose range 0, 3.7, 11 , 33 and 100 ⁇ mol/kg s.c. in one single experiment, with complementary doses in separate experiments.
  • the DOPAC levels are normalised to control and fitted by least square minimization to the function "End-(End- Control)/(1 +(dose/ED 50 ) slope )"-
  • the four parameters (Control, End, ED 50 and Slope) are fitted with the restrictions: ED 5 o>O, 0.5 ⁇ Slope ⁇ 3, 350 ⁇ End ⁇ 400% of control.
  • the fit is repeated 100 times with a random evenly distributed squared weight (0 to 1 ) for every measurement value. Presented ED 5 o-ranges cover 95% of these values.
  • AUC the area under the plasma concentration versus time curve from time zero to the last concentration measured (Clast), calculated by the log/linear trapezoidal method.
  • the levels of test compound are measured by means of liquid chromatography- mass spectrometry (LC-MS) (Hewlett-Packard 1100MSD Series).
  • the LC-MS module includes a quaternary pump system, vacuum degasser, thermostatted autosampler, thermostatted column compartment, diode array detector and API-ES spray chamber. Data handling was performed with a HP ChemStation rev.A.06.03. system. Instrument settings:MSD mode: Selected ion monitoring (SIM) MSD polarity: Positiv Gas temp: 350 0 C Drying gas: 13,0 l/min Nebulizer gas: 50 psig Capillary voltage: 5000 V Fragmentor voltage: 70 V
  • Analytical column Zorbax eclipse XDB-C8 (4.6 * 150 mm, 5 ⁇ m) at 20 0 C.
  • the mobile phase was acetic acid (0.03%) (solvent A) and acetonithle (solvent B).
  • the flow rate of the mobile phase was 0.8 ml/min.
  • the elution was starting at 12% of solvent B isocratic for 4.5 min, then increasing linearity to 60% over 4.5 min.
  • Extractions procedure Plasma samples (0.25-0.5 ml) were diluted with water to 1 ml, and 60 pmol (100 ⁇ l) internal standard (-)-OSU6241 was added. The pH was adjusted to 1 1 by the addition of 25 ⁇ l saturated Na 2 CO3.
  • Rat liver microsomes were isolated as described by Forlin L, 1980, with minor modifications e.g. 3 mL/g liver of a 0.1 M Na/K * PO 4 buffer with 0.15M KCI, pH 7.4, (buffer 1 ) was added before homogenisation, the homogenate was centrifuged for 20 minutes instead of 15, the supernatant was ultracenthfuged at 100.000 g instead of 105.000 g and the pellet from the ultracenthfugation was resuspended in 1 mL/g liver of 20% v/v 87% glycerol in buffer 1 .
  • test compound was analysed using HPLC-MS (Hewlett-Packard 1 100MSD Series) with a Zorbax SB-C18 column (2.1 * 150 mm, 5 ⁇ m) using 0.03% formic acid and acetonitrile as mobile phase (gradient) or a Zorbax Eclipse XDB-C18 (3 * 75 mm, 3.5 ⁇ m) using 0.03% acetic acid and acetonitrile as mobile phase (gradient).
  • the 15 min turnover was calculated as the fraction of test compound eliminated after 15 minutes, expressed in percent of 0 min levels, i.e. 100 * [conc test compound at 0 min - concentration at 15 min] / cone at 0 min.
  • liver microsomes Preparation of liver microsomes was performed as described in Forlin L, 1980. Protocols for incubation with liver microsomes are referred in Crespi CL and DM Stresser, 2000, and Renwick AB et ai, 2001 .
  • Microdialysis Male Sprague-Dawley rats weighing 220-32Og were used throughout the experiments. Before the experiment the animals were group housed, five animals in each cage, with free access to water and food. The animals were housed at least one week after arrival prior to surgery and use in the experiments. Each rat was used only once for microdialysis.
  • Co-ordinates were calculated relative to bregma; dorsal striatum AP +1 , ML ⁇ 2.6, DV -6.3; Pf cortex, AP +3.2, 8° ML ⁇ 1.2, DV -4,0 according to (Paxinos G & Watson C, 1986).
  • the dialysis probe was positioned in a burr hole under stereotaxic guidance and cemented with phosphatine dental cement.
  • the rats were housed individually in cages for 48 h before the dialysis experiments, allowing them to recover from surgery and minimizing the risk of drug interactions with the anaesthetic during the following experiments. During this period the rats had free access to food and water. On the day of experiment the rats were connected to a micro perfusion pump via a swiwel and were replaced in the cage where they could move freely within its confinements.
  • the perfusion medium was a Ringer's solution containing in mmol/l: NaCI; 140, CaCI2; 1.2, KCI; 3.0, MgCI2; 1.0 and ascorbic acid; 0.04 according to (Moghaddam B & Bunney BS, 1989).
  • the pump was set to a perfusion speed of 2 ⁇ l/min and 40 ⁇ l samples were collected every 20 min. Each sample was analyzed at two HPLC systems. On an autoinjector (CMA 200) with a 10-port valve (Valco C10WE), holding two sample loops in series (4 ⁇ l and 20 ⁇ l), each brain dialysate sample is loaded in both loops simultaneously.
  • CMA 200 autoinjector
  • Valco C10WE 10-port valve
  • the 20 ⁇ l sample is introduced into a column switching system (reverse-phase combined with reverse-phase ion-pairing) for dopamine (DA), noradrenaline (NA), normetanephrine (NM), 3-methoxytyramine (3-MT) and serotonin (5-hydroxytryptamine, 5-HT) determination, while the 4 ⁇ l sample is introduced on a reverse-phase column for the chromatography of the acidic monoamine metabolites 3,4-di-hydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA).
  • DOPAC 3,4-di-hydroxyphenylacetic acid
  • HVA homovanillic acid
  • 5-HIAA 5-hydroxyindoleacetic acid
  • the method sample turn over time was 4.5 min and two parallel experiments are normally analyzed simultaneously on the system. After the experiment the rats were uncoupled from the perfusion pump and decapitated. Their brains were rapidly taken out and fixed in Neo-fix solution (Kebo- lab, Sweden) for subsequent inspection of probe localisation. The Animal Ethics Committee in G ⁇ teborg, Sweden approved the procedures applied in these experiments.
  • Glutamate antagonists i.e. NMDA antagonists
  • MK-801 Glutamate antagonists
  • NMDA antagonists can induce psychoses in man (see Psychopharmacology, 4th Generation of progress
  • Crespi CL and DM Stresser Fluorometric screening for metabolism based drug-drug interactions. J. Pharm. Tox. Meth. 2000 44 325-331 ;
  • Forlin L Effects of Clophen A50, 3-methylcholantrene, pregnenolone-16aq- carbonithle and Phenobarbital on the hepatic microsomal cytochrome P-450- dependent monooxygenaser system in rainbow trout, salmo gairdneri, of different age and sex. Tox. Appl. Pharm. 1980 54 (3) 420-430;
  • RenwickAB et ai Metabolism of 2,5-bis(thfluoromethyl)-7-benzyloxy-4- trifluoromethylcoumarin by human hepatic CYP isoforms: evidence for selectivity towards CYP3A4. Xenobiotica 2001 31 (4) 187-204;
  • Moghaddam B & Bunney BS Ionic Composition of Microdialysis Perfusing Solution Alters the Pharmacological Responsiveness and Basal Outflow of Striatal Dopamine. J. Neurochem. 1989 53 652-654;

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Abstract

La présente invention concerne de nouveaux dérivés de 3-phényl-3-méthoxy-pyrrolidine utiles pour moduler la neurotransmission de la dopamine et les taux extra-cellulaires de catécholamines, de dopamine et de norépinéphrine, dans des zones corticales du cerveau de mammifères, et plus spécifiquement pour traiter des troubles du système nerveux central. Dans d'autres aspects, l'invention a pour objet des compositions pharmaceutiques comprenant les dérivés de 3-phényl-3-méthoxy-pyrrolidine de l'invention et l'utilisation de ces composés pour des applications thérapeutiques.
PCT/EP2009/065678 2008-11-24 2009-11-24 Dérivés de 3-phényl-3-méthoxypyrrolidine en tant que modulateurs de la neurotransmission catécholaminergique corticale WO2010058019A1 (fr)

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EP09759724A EP2367788A1 (fr) 2008-11-24 2009-11-24 Dérivés de 3-phényl-3-méthoxypyrrolidine en tant que modulateurs de la neurotransmission catécholaminergique corticale

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PCT/EP2009/065676 WO2010058018A1 (fr) 2008-11-24 2009-11-24 Dérivés de 3-phényl-3-méthoxy-pyrrolidine en tant que modulateurs de la neurotransmission catécholaminergique corticale

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US8586572B2 (en) 2008-11-24 2013-11-19 Integrative Research Laboratories Sweden Ab 3-phenyl-azetidine derivatives useful as modulators of cortical catecholaminergic neurotransmission
CA2744308C (fr) 2008-11-24 2017-05-30 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Derives de 3-phenyl-3-methoxy-pyrrolidine en tant que modulateurs de la neurotransmission catecholaminergique corticale
EP3297987B1 (fr) 2015-05-20 2019-05-15 Integrative Research Laboratories Sweden AB Nouveaux dérivés d'azétidine utiles comme modulateurs de la neurotransmission cathécolaminergique corticale
FI3541784T3 (fi) 2016-11-18 2023-10-02 Integrative Res Laboratories Sweden Ab Uudet atsetidiinijohdannaiset, jotka ovat hyödyllisiä kortikaalisen katekoliamiini-neurotransmission modulaattoreina
CN110621659B (zh) 2017-05-19 2023-02-28 综合研究实验室瑞典股份公司 (+)-3-(2,3-二氟苯基)-3-甲氧基吡咯烷或其药学上可接受的盐、其制备方法及其用途
WO2025003437A1 (fr) 2023-06-28 2025-01-02 Integrative Research Laboratories Sweden Ab Composition pharmaceutique comprenant un sel d'acide fumarique de (+)-3-(2,3-difluorophényl)-3-méthoxypyrrolidine

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CN102766079B (zh) * 2011-05-06 2015-04-08 上海医药工业研究院 一类吡咯烷衍生物、其制备方法及应用

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DK2367787T3 (da) 2013-03-25
CN102224136B (zh) 2014-01-22
CA2744308C (fr) 2017-05-30
NZ592566A (en) 2013-03-28
EP2367788A1 (fr) 2011-09-28
RU2524214C2 (ru) 2014-07-27
ES2402713T3 (es) 2013-05-08
AU2009317156A1 (en) 2010-05-27
KR101660936B1 (ko) 2016-10-05
RU2011120817A (ru) 2012-12-27
AU2009317156B2 (en) 2015-12-03
CA2744308A1 (fr) 2010-05-27
UA104152C2 (ru) 2014-01-10
EP2367787A1 (fr) 2011-09-28
WO2010058018A1 (fr) 2010-05-27
JP5716202B2 (ja) 2015-05-13
EP2367787B1 (fr) 2013-01-09
US20140135505A1 (en) 2014-05-15
US20110257242A1 (en) 2011-10-20
US9035073B2 (en) 2015-05-19
MX2011005036A (es) 2011-06-16
PL2367787T3 (pl) 2013-06-28
ZA201103169B (en) 2012-09-26
IL212601A0 (en) 2011-07-31
BRPI0921561B1 (pt) 2022-02-15

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