EP2182946A1 - Composés azabicyclo [4.1.0]heptanes substitués pour une utilisation en tant qu'inhibiteurs de la réabsorption de monoamine - Google Patents

Composés azabicyclo [4.1.0]heptanes substitués pour une utilisation en tant qu'inhibiteurs de la réabsorption de monoamine

Info

Publication number
EP2182946A1
EP2182946A1 EP08787359A EP08787359A EP2182946A1 EP 2182946 A1 EP2182946 A1 EP 2182946A1 EP 08787359 A EP08787359 A EP 08787359A EP 08787359 A EP08787359 A EP 08787359A EP 2182946 A1 EP2182946 A1 EP 2182946A1
Authority
EP
European Patent Office
Prior art keywords
compounds
disorder
alkyl
hydrogen
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08787359A
Other languages
German (de)
English (en)
Inventor
Silvia Terreni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP2182946A1 publication Critical patent/EP2182946A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • 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
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • 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
    • A61P25/14—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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel compounds, processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as serotonin (5-HT), dopamine (DA) and norepinephrine (NE), reuptake inhibitors.
  • serotonin 5-HT
  • DA dopamine
  • NE norepinephrine
  • Brain tissue is constituted of neuronal cells which are able to communicate with each other via specific cellular structures named synapses.
  • the exchange of signals between neurons in the synapses happens through neurochemical messengers named neurotransmitters, acting on specific target protein molecules, both post and pre-synaptic, referred to as receptors.
  • Monoamines represent a family of small neurotransmitter molecules sharing common chemical features, and include serotonin (5-HT), dopamine (DA) and norepinephrine (NE).
  • Monoamine neurotransmitters are released into the synaptic cleft between neurons and interact with receptors present on the membrane of the target cells.
  • the switch of the neurochemical signal occurs mainly by removal of the neurotransmitter molecules through other protein molecules referred to as monoamine transporters (SERT for 5-HT, DAT for DA and NET for NE).
  • Transporters are able to bind neurotransmitter molecules and move them into the presynaptic terminals, this cellular mechanism referred to as re-uptake.
  • Pharmacological inhibition of the re-uptake process can cause an increase of monoamine at synaptic level and as a consequence an enhancement of the physiological activity of neurotransmitters.
  • Serotonergic neurotransmission in the brain is mediated by a large family of receptors comprising both the G-protein coupled receptors and ligand-gated ion channels including 14 subtypes, and is involved in a vast variety of physiologic functions.
  • Compounds endowed of inhibitory properties at the SERT are predicted to have the ability to treat in mammals, including humans, a variety of disorders associated with this neural system, for example eating disorders, major depression and mood disorders, obsessive compulsive disorders, panic disorders, alcoholism, pain, memory deficits and anxiety.
  • disorders related to depression such as pseudodementia or Ganser's syndrome, migraine pain, bulimia, obesity, pre-menstrual syndrome or late luteal phase syndrome, tobacco abuse, panic disorder, post-traumatic syndrome, memory loss, dementia of ageing, acquired immunodeficiency syndrome dementia complex, memory dysfunction in ageing, social phobia, attention deficit hyperactivity disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, mutism or trichotillomania.
  • depression such as pseudodementia or Ganser's syndrome, migraine pain, bulimia, obesity, pre-menstrual syndrome or late luteal phase syndrome, tobacco abuse, panic disorder, post-traumatic syndrome, memory loss, dementia of ageing, acquired immunodeficiency syndrome dementia complex, memory dysfunction in ageing, social phobia, attention deficit hyperactivity disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism,
  • Major depression is an affective disorder, or disorder of mood, characterized by several symptoms including feeling of profound sadness, worthlessness, despair and loss of interest in all pleasures (anhedonia), recurrent thoughts of death, mental slowing, loss of energy, an inability to take decision, often associated with anxiety and agitation. These symptoms are persistent and can range from mild to severe.
  • the pathophysiology of major depression is poorly understood being a multifactorial syndrome and, due to this, several neurotransmitter systems have been implicated.
  • the disorder stems from a decrease in the synaptic concentration of monoamine neurotransmitters, mainly NE and 5-HT, in critical brain areas, leading to the "monoamine theory" of depression.
  • SNRIs selective norepinephrine re-uptake inhibitors
  • a number of such compounds have been synthesized, e.g. Nisoxetine, Maprotiline, Tomoxetine and Reboxetine.
  • many compounds, including old tricyclic antidepressants have a mixed NET and SERT inhibition profile, like lmipramine and Amitriptyline (with SERT potency > NET) and Desipramine, Nortriptyline, and Protriptyline (NET potency > SERT).
  • the pharmacological manipulation of the DAT can in principle have the ability to elevate DA levels in the mesolimbic system, reversing the anhedonia that is a core symptom of major depression.
  • a DAT inhibition component in combination with a blockade of SERT and NET, can also have the ability to improve the lack of motivation and attention and enhance cognitive deficits seen in depressed patients.
  • blockade of DAT has to be carefully managed in order to avoid potential reinforcing effects and abuse liability.
  • compounds with DAT inhibition in their pharmacology such as Dexmethylphenidate, Methylphenidate and Bupropion, have been successfully marketed. Clinical studies indicate that patients with poor response to SSRIs benefit from combination therapy with agents that enhance dopaminergic tone.
  • compounds with a strong SERT inhibiting activity combined with a well balanced NET blockade and moderate DAT inhibiting activity may therefore provide a replacement for current combination therapies for treating unresponsive patients, providing greater efficacy and therapeutic flexibility with a more rapid onset of anti-depressant effect.
  • the compounds of the present invention are considered useful for the treatment of Parkinsonism, depression, obesity, narcolepsy, drug addiction or misuse, including cocaine abuse, attention-deficit hyperactivity disorders, Gilles de Ia Tourettes disease and senile dementia.
  • Dopamine re-uptake inhibitors enhance indirectly via the dopamine neurones the release of acetylcholine and are therefore also useful for the treatment of memory deficits, e.g. in Alzheimers disease, presenile dementia, memory dysfunction in ageing, and chronic fatigue syndrome.
  • Noradrenaline re-uptake inhibitors are considered useful for enhancing attention, alertness, arousal, vigilance and for treating depression.
  • the object of the present invention is to provide novel compounds which are serotonin (5- HT), dopamine (DA) and norepinephrine (NE), re-uptake inhibitors.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof:
  • Ri is hydrogen or Ci -4 alkyl
  • R 2 is an ⁇ or ⁇ naphthyl group, optionally substituted by 1 or 2 groups R 8 , each of them being the same or different;
  • R 8 is selected from a group consisting of: halogen, cyano, C 1-4 alkyl; R 5 is hydrogen or C 1-4 alkyl; R 6 is hydrogen or Ci -4 alkyl;
  • R 7 is selected in the group consisting of: hydrogen, fluorine, and C 1-4 alkyl; or corresponds to X, Xi, X 2 or X 3 ; wherein
  • X corresponds to:
  • X 2 corresponds to:
  • X 3 corresponds to:
  • R 3 is hydrogen or C 1-4 alkyl; or corresponds to X or X 1 ;
  • R 4 is hydrogen or C 1-4 alkyl; or corresponds to X or X 1 ;
  • R 9 is C 1-4 alkyl;
  • R 10 is hydrogen , C 1-4 alkyl, C 3 - 6 cycloalkyl or C 3 - 6 cycloalkylC 1-3 alkyl;
  • R 11 is haloC 1-2 alkyl; n is 1 or 2.
  • compounds of formula (I) possess at least two stereogenic centers, namely at position 1 and 6 in the 3-azabicyclo[4.1.0]heptane portion of the molecule.
  • the compounds may exist in two stereoisomers which are enantiomers with respect to the stereogenic centers in the cyclopropane ring.
  • the level of biological activity may vary between the individual stereoisomers of a given molecule. It is intended that the scope of the invention includes all individual stereoisomers (diastereoisomers and enantiomers) and all mixtures thereof, including but not limited to racemic mixtures, which demonstrate appropriate biological activity with reference to the procedures described herein.
  • compounds of formula (I)' which correspond to the compounds of formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, having "cis" disposition, represented by the bold highlight of the two bonds near the cyclopropyl moiety:
  • R 1 , R 2 , R3, R 4 , R5, Re and R 7 are defined as above for compounds of formula (I).
  • the symbol ' (prime) is used to identify compounds having "cis" disposition for the bonds bearing groups R 2 and R 7 , represented by the bold highlight of the two bonds near the cyclopropyl moiety.
  • the bold highlight of the two bonds near the cyclopropyl moiety bearing groups R 2 and R 7, indicate, mixtures (including but not limited to racemic mixtures) of those cis isomers.
  • Absolute configuration of stereogenic centers at position named 1 and 6 may be assigned using Cahn-lngold-Prelog nomenclature based on groups' priorities.
  • compounds of formula (IA) are provided that correspond to stereochemical isomers of compounds of formula (I)', having the configuration shown in the picture below at stereogenic centers at position named 1 and wherein R 1 , R 2 , R3, R 4 , Rs, Re and R 7 are defined as above for compounds of formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof.
  • stereochemical isomers of formula (IA) are enriched in one configuration at stereogenic centers named 1 and 6.
  • the isomers correspond in one embodiment to at least 90% e.e. (enantiomeric excess).
  • the isomers correspond to at least 95% e.e.
  • the isomers correspond to at least 99% e.e.
  • compounds of formula (IB) are provided that correspond to stereochemical isomers of compounds of formula (I)', having the configuration shown in the picture below at stereogenic centers at position named 1 and 6:
  • R 1 , R 2 , R3, R 4 , R 5 , Re and R 7 are defined as above for compounds of formula (I), or or pharmaceutically acceptable salts, solvates or prodrugs thereof.
  • stereochemical isomers of formula (IB) are enriched in one configuration at centers named 1 and 6.
  • the isomers correspond in one embodiment to at least 90% e.e. (enantiomeric excess).
  • the isomers correspond to at least 95% e.e.
  • the isomers correspond to at least 99% e.e. From now on throughout the document, the suffix "B" in brackets is used to identify stereochemical isomers of compounds of the invention having the configuration shown above for compounds of formula (IB) at stereogenic centers at positions named 1 and 6.
  • C 1-4 alkyl refers to an alkyl group having from one to four carbon atoms, in all isomeric forms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert- butyl.
  • 'C3-C6 cycloalkyl group' as used herein means a non aromatic monocyclic hydrocarbon ring of 3 to 6 carbon atom such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; while unsaturated cycloalkyls include cyclopentenyl and cyclohexenyl, and the like.
  • 'Cs-ecycloalkyld-salkyl' as used herein means an alkyl having from one to three carbon atoms wherein one hydrogen atom is replaced with a C 3 -C 6 cycloalkyl group as above defined, for example methylcyclopropane.
  • 'halo C 1-2 alkyl group' as used herein may be a Cr 2 alkyl group as defined before substituted with at least one halogen, preferably fluorine, such as -CH 2 CF 3 , -CHF 2 , Or -CF 3 .
  • halogen and its abbreviation “halo” refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Where the term “halo” is used before another group, it indicates that the group is substituted by one or more halogen atoms.
  • Any of these groups may be attached to the rest of the molecule at any suitable position.
  • R 1 is hydrogen or C 1-4 alkyl (for example methyl). In another embodiment, R 1 is hydrogen.
  • R 2 is a an unsubstituted ⁇ or ⁇ naphthyl group. In another embodiment, R 2 is an unsubstituted ⁇ naphthyl group. In another embodiment, R 2 is a ⁇ naphthyl group, optionally substituted by 1 or 2 groups R 8 , each of them being the same or different.
  • R 3 is hydrogen or a group X, Xi or X 2 . In another embodiment, R 3 is hydrogen. In a further embodiment, R 3 is a group X.
  • R 4 is hydrogen
  • R 5 is hydrogen
  • R 6 is hydrogen
  • R 7 is hydrogen or a group X, X 1 or X 2 . In another embodiment, R 7 is hydrogen. In a further embodiment, R 7 is a group X.
  • n is 1 or 2. In another embodiment, n is 1.
  • R 10 is hydrogen , Ci -4 alkyl, C 3 - 6 cycloalkyl or C 3 - 6 cycloalkylCi -3 alkyl. In another embodiment, R 10 is hydrogen or C 1-4 alkyl. In a still further embodiment, R 10 is C 1- 4 alkyl (for example methyl or ethyl).
  • R 8 is halogen (for example chlorine), cyano or C 1-4 alkyl. In another embodiment, R 8 is halogen (for example chlorine).
  • a compound of formula (IC) or a pharmaceutically acceptable salt, prodrug or solvate thereof is provided, wherein R 1 , R 2 and R 7 are as defined for formula (I):
  • R 1 is hydrogen or C 1-4 alkyl (for example methyl)
  • R 2 is a ⁇ naphthyl group, optionally substituted by 1 or 2 groups R 8
  • R 7 is hydrogen or a group X, X 1 or X 2 .
  • R 1 is hydrogen
  • R 2 is is an unsubstituted ⁇ naphthyl group
  • R 7 is hydrogen or a group X, Xi or X 2 .
  • a compound of formula (ID) or a pharmaceutically acceptable salt, prodrug or solvate thereof is provided, wherein R 7 is a group X and R 2, R 10 and n are as defined for formula (I):
  • R 2 is a ⁇ naphthyl group, optionally substituted by 1 or 2 groups R 8 , and R 10 is hydrogen , C 1-4 alkyl, C 3 - 6 cycloalkyl or C 3 - 6 cycloalkylC 1-3 alkyl.
  • R 2 is a ⁇ naphthyl group, optionally substituted by 1 or 2 groups R 8 , n is 1 and R 10 is hydrogen or C 1-4 alkyl (for example methyl).
  • compounds of formula (IC) and (ID) as above defined having the configuration shown above for compounds of formula (IA) at stereogenic centers at position named 1 and 6, are provided .
  • Those compounds are named (ICA) and (IDA).
  • compounds of formula (IC) and (ID) as above defined having the configuration shown above for compounds of formula (IB) at stereogenic centers at position named 1 and 6, are provided . Those compounds are named (ICB) and (IDB).
  • Certain groups/substituents included in the present invention may be present as isomers.
  • the present invention includes within its scope all such isomers, including racemates, enantiomers, tautomers and mixtures thereof.
  • salts refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts and also includes pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a physiologically acceptable anion or cation.
  • Certain of the compounds of the invention may form acid or base addition salts with one or more equivalents of the acid or of the base.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
  • Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compound of formula (I) using conventional methods.
  • Suitably pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, naphtoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example
  • prodrugs are also included within the context of this invention.
  • the term "prodrug” means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130.
  • Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
  • Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups.
  • representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol, sulfhydryl and amine functional groups of the compounds of structure (I).
  • esters may be employed, such as methyl esters, ethyl esters, and the like. Esters may be active in their own right and /or be hydrolysable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt.
  • crystalline forms of the compounds of the present invention may exist as polymorphs, which are included in the present invention.
  • Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for example, "Protective groups in organic synthesis” by T.W. Greene and P. G. M. Wuts (John Wiley & sons 1991 ) or "Protecting Groups” by PJ. Kocienski (Georg Thieme Verlag 1994).
  • suitable amino protecting groups include acyl type protecting groups (e.g.
  • aromatic urethane type protecting groups e.g. benzyloxycarbonyl (Cbz) and substituted Cbz
  • aliphatic urethane protecting groups e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t- butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl
  • alkyl type protecting groups e.g. benzyl, trityl, chlorotrityl.
  • oxygen protecting groups may include for example alky silyl groups, such as trimethylsilyl or tert- butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such as acetate.
  • alky silyl groups such as trimethylsilyl or tert- butyldimethylsilyl
  • alkyl ethers such as tetrahydropyranyl or tert-butyl
  • esters such as acetate.
  • the present invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 0, 31 P, 32 P, 35 S, 18 F, 36 CI, 123 I and 125 I.
  • Isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H, 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e.,
  • isotopes are particularly preferred for their ease of preparation and detectability.
  • 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography)
  • 125 I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging.
  • lsotopically labelled compounds of the present invention and non-pharmaceutically acceptable salts thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the compounds of the invention are selected from the list consisting of:
  • the present invention also provides a process for preparing a compound of formula (I) or a salt thereof as defined above.
  • , X, Xi,X 2 , X3, and n are as for compounds of formula (I).
  • the reduction reaction may be performed using borane in THF at refluxing temperature.
  • VIII Compounds of formula (VIII) may be obtained according to the method described in JOC, 2005, 70, 4043, from propargyl alcohol and the appropriate lodo arene derivative (IX) according to Scheme 7.
  • Pg is a suitable N-protecting group (typically Cbz or Boc)
  • deprotection of N-Pg group such as for Cbz using 6N hydrochloridric acid in dioxane at reflux temperature or for BOC using TFA in DCM at temperature between 0 0 C and room temperature
  • Compounds of formula (X) may be obtained from compounds of formula (Xl), according to Scheme 10, using reducing agents, such as LiAIH 4 , in aprotic solvent, e. g. diethyl ether or THF, at temperature between -40 and -10 0 C.
  • reducing agents such as LiAIH 4
  • aprotic solvent e. g. diethyl ether or THF
  • Compounds of formula (Xl) may be obtained from compounds of formula (XII), according to Scheme 1 1 , through a suitable protecting agent, such as reaction with Cbz-chloride or Boc anhydride, using TEA in DCM at temperature between 0 0 C and room temperature.
  • a suitable protecting agent such as reaction with Cbz-chloride or Boc anhydride
  • Compounds of formula (XII) may be obtained from compounds of formula (XIII), according to Scheme 12, through reaction with 1-chloroethyl chloroformate in DCE and MeOH.
  • Compounds of formula (XIV) may be obtained according to Scheme 14 from compounds of formula (XV), by reaction with a base (eg sodium hydride), then with a triflating agent, such as N-phenyltrifluoromethanesulfonimide, in an aprotic solvent (eg DMF), at temperature between 0 0 C and room temperature.
  • a base eg sodium hydride
  • a triflating agent such as N-phenyltrifluoromethanesulfonimide
  • enantiomers or diastereoisomers of the compounds may be obtained from the corresponding enantiomeric or diastereoisomeric mixture using chiral chromatographic methods such as for example chiral HPLC.
  • specific enantiomers or diastereoisomers of the compounds may be obtained from the corresponding enantiomeric or diastereoisomeric mixture using chiral crystallization methods such as precipitation with chiral acids.
  • a specific enantiomer or diastereoisomer of a compound the invention may be synthesised from the appropriate stereochemical ⁇ enriched intermediate using any of the general processes described herein and by combining it with any of the conventional resolution methods above described.
  • Optically active intermediates or stereochemical ⁇ enriched intermediates may be generated by resolution of a corresponding enantiomeric or diastereosiomeric mixtures using conventional methods, or by performance of stereoselective reactions or by combining different resolution techniques.
  • the compounds of the present invention are useful in the treatment of disorders or diseases responsive to the monoamine neurotransmitter re-uptake inhibiting activity of the compounds.
  • This activity of the compounds of the invention may make them useful in the treatment of Parkinsonism, depression, eating disorders, sleep disorders, substance related disorders, attention-deficit hyperactivity disorders, anxiety disorders, cognition impairment, sexual dysfunctions, obsessive compulsive spectrum disorders, Gilles de Ia Tourettes disease and senile dementia, as well as other disorders sensitive to the monoamine neurotransmitter re-uptake-inhibiting activity of the compounds.
  • ICD-10 International Classification of Diseases, 10th Edition
  • compression includes:
  • Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major
  • Substance- Induced Mood Disorder including the subtypes With Depressive Features, With Manic
  • Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major
  • anxiety disorders includes:
  • subject related disorder includes:
  • Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced sexual Dysfunction, Substance- Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder,
  • Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9); Inhalant-Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, Inhalant- Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9
  • the term "Sleep disorder” includes: Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type;
  • treating disorder includes:
  • Eating disorders such as Anorexia Nervosa (307.1 ) including the subtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; Binge Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50):
  • Attention-Deficit/Hyperactivity Disorder includes:
  • Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81 ), Adolescent- Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23);
  • Cognitive impairment includes:
  • Cognition impairment including cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease;
  • the term "Sexual dysfunctions" includes:
  • Sexual dysfunctions including sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and sexual Aversion Disorder (302.79); sexual arousal disorders such as Female sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51 ); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and
  • Obsessive compulsive spectrum disorder includes:
  • Obsessive compulsive spectrum disorder including Obsessive compulsive disorders (300.3), somatoform disorders including body dysmorphic disorder (300.7) and hyperchondriasis (300.7), bulimia nervosa (307.51 ), anorexia nervosa (307.1 ), eating disorders not elsewhere classified (307.50) such as binge eating, impulse control disorders not elsewhere classified (including intermitted explosive disorder (312.34), compulsive buying or shopping, repetitive self-mutilation, onychophagia, psychogenic excoriation, kleptomania (312.32), pathological gambling (312.31 ), trichotillomania (312.39) and internet addiction), paraphilia (302.70) and nonparaphilic sexual addictions, Sydeham's chorea, torticollis, autistic disorders (299.0), compulsive hoarding, and movement disorders, including Tourette's syndrome (307.23).
  • somatoform disorders including body dysmorphic disorder (300.7) and hyperchondriasis (300.7
  • compounds of the invention may be useful as analgesics.
  • they may be useful in the treatment of chronic inflammatory pain (e.g. pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis); musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea.
  • chronic inflammatory pain e.g. pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid
  • Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed.
  • Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain.
  • Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them.
  • Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions.
  • neuropathic pain are incredibly heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain.
  • pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • Compounds of the invention may also be useful in the amelioration of inflammatory disorders, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD); gastrointestinal tract disorders (e.g.
  • aphthous ulcer Crohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, inflammatory bowel disease, gastroesophageal reflux disease); other conditions with an inflammatory component such as migraine, multiple sclerosis, myocardial ischemia.
  • compounds of the invention are useful in the treatment of depression and anxiety disorders.
  • compounds of the invention are useful in the treatment of depression.
  • Treatment includes prophylaxis, where this is appropriate for the relevant condition(s).
  • a method for the treatment of a mammal including man, in particular in the treatment of disorders or diseases responsive to the monoamine neurotransmitter re-uptake inhibiting activity of the compounds, comprising administration of an effective amount of a compound of the invention.
  • the invention provides a method of treating a condition for which inhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE), is beneficial, which comprises administering to a mammal (e.g. human) in need thereof an effective amount of a compound of the invention.
  • a mammal e.g. human
  • the invention provides a compound of the invention for use in therapy.
  • the invention provides compounds of the invention for use in the treatment of a condition in a mammal for which inhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) is beneficial.
  • 5-HT serotonin
  • DA dopamine
  • NE norepinephrine
  • the invention provides the use of compounds of the invention, for the manufacture of a medicament for the treatment of disorders or diseases responsive to monoamine neurotransmitter re-uptake inhibiting activity.
  • the use of compounds of the invention is provided in the manufacture of a medicament for the treatment of a condition in a mammal for which inhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) is beneficial.
  • the compounds of the invention may also be used in combination with other therapeutic agents.
  • the invention thus provides, in a further aspect, a combination comprising a compound of the invention together with a further therapeutic agent.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).
  • anticholinergics such as benztropine, biperiden, procyclidine and trihexyphenidyl
  • antihistamines such as diphenhydramine
  • dopaminergics such as amantadine
  • antidepressants such as amantadine
  • iv) anxiolytics such as anxio
  • the compounds of the invention may be used in combination with antidepressants to treat or prevent depression and mood disorders.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilisers; ii) antipsychotics; and iii) antidepressants.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.
  • the compounds of the invention may be used in combination with the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; and ii) bupropion.
  • the compounds of the invention may be used in combination with the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; and iii) Opioid receptor antagonists for example naltrexone.
  • NMDA receptor antagonists for example acamprosate
  • GABA receptor agonists for example tetrabamate
  • Opioid receptor antagonists for example naltrexone.
  • the compounds of the invention may be used in combination with the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; and iii) vasodilatory antihypertensives for example lofexidine.
  • opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine
  • opioid receptor antagonists for example naltrexone
  • vasodilatory antihypertensives for example lofexidine.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita and phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate and chlormethiazole.
  • benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam
  • non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon
  • barbiturates for example
  • the compounds of the invention may be used in combination with the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; and v) premenstral agents for example pyridoxine and progesterones.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; and vii) premenstral agents.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; and iv) stimulants for example methylphenidate, amphetamine formulations and pemoline.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent ADHD: i) stimulants for example methylphenidate, amphetamine formulations and pemoline; and ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).
  • stimulants for example methylphenidate, amphetamine formulations and pemoline
  • non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).
  • the compounds of the invention may be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; and iv) anxiolytics.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil and sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine and vii) 5-HT1A agonists, for example flibanserine.
  • phosphodiesterase V inhibitors for example vardenafil and sildenafil
  • dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion
  • alpha adrenoceptor antagonists
  • the compounds of the invention may be used in combination with the same agents specified for male sexual dysfunction to treat or prevent female sexual dysfunction, and in addition an estrogen agonist such as estradiol.
  • Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone and amisulpride).
  • Typical Antipsychotics for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine
  • Atypical Antipsychotics for example clozapine, olanzapine, risperidone, quetiapine,
  • Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).
  • serotonin reuptake inhibitors such as citalopram, escitalopram, fluoxetine, parox
  • Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.
  • Anxiolytics include benzodiazepines such as alprazolam and lorazepam.
  • the compounds of the present invention are usually administered as a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of the invention and a pharmaceutically (i.e physiologically) acceptable carrier.
  • the pharmaceutical composition can be for use in the treatment of any of the conditions described herein.
  • the compounds of the invention may be administered by any convenient method, for example by oral, parenteral (e.g. intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • the compounds of the invention which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser
  • a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluoro- chlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump- atomiser.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • compositions suitable for transdermal administration include ointments, gels and patches.
  • the composition is in unit dose form such as a tablet, capsule or ampoule.
  • Each dosage unit for oral administration contains for example from 0.5 to 250 mg (and for parenteral administration contains for example from 0.05 to 25 mg) of a compound of the invention calculated as the free base.
  • the pharmaceutically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 500 mg, for example between 1 mg and 400 mg, e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, for example between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a salt thereof calculated as the free base, the compound being administered 1 to 4 times per day, for example 1 to 2 time a day.
  • the compound of the invention may be administered once a day.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • a typical dose may be in the range of 1 to 200 mg per day, for example 60 to 200 mg per day.
  • each compound may differ from that when the compound is used alone.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
  • the invention is also directed to a novel kit-of-parts that is suitable for use in the treatment of disorders as above defined comprising a first dosage form comprising a compound of the invention and a second dosage form comprising another therapeutic agent, for simultaneous, separate or sequential administration.
  • either the compound of the invention or the second therapeutic agent may be administered first.
  • the combination may be administered either in the same or different pharmaceutical composition.
  • the two compounds When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • Membranes for the SPA-binding assays are produced by HEK-293F cell infection with BacMam viruses generated for each single human SERT, NET, and DAT transporter.
  • hSERT and hDAT are cloned into pFBMRfA vector whereas hNET is cloned into pFASTBacMami vector.
  • the generation and use of BacMam viruses is described in Condreay JP et al, Proc. Natl. Acad. Sci. USA, 1999, 96:127-132 and Hassan NJ et al, Protein Expression and Purification, 47(2): 591-598, 2006.
  • the HEK-293F suspension cell line (Invitrogen) is routinely grown in 293_Freestyle Expression media (Invitrogen) in shake flask suspension culture.
  • the culture is transduced with the appropriate transporter BacMam at a MOI (multiplicity of infection) of 100 virus particles per cell and incubated for 48hrs at 37 0 C, 5% CO 2 in air, shaken at 90rpm in a humidified shaker incubator.
  • the culture is then harvested by centrifugation at 1000g, 4 0 C, for 10 minutes and the cell pellet stored at -80 0 C until required.
  • the affinity of the compounds of the invention to the hSERT, hNET or hDAT can be also assessed by using the [ 3 H]citalopram, [ 3 H]nisoxetine or [ 3 H]WI N-35, 428 binding assays with the SPA technology on BacMam-recombinant human SERT, NET and DAT membranes produced as described before.
  • SPA technology GE Healthcare, Amersham
  • only transporter-bound radioactivity can elicit bead excitation thus no separation of the bound/ unbound radioligand is required.
  • the protocol for hSERT binding SPA is based on Trilux beta-counter (Wallac, Perkin- Elmer).
  • test compound in neat DMSO (or 1 ⁇ M fluoxetine as positive control) is added by 50 ⁇ l_ of the SPA mixture, containing 2mg/ml_ SPA beads (Amersham RPNQ0001 ), 4 ⁇ g/ml_ hSERT Bacmam membranes, 0.01 % pluronic F-127, 2.5nM [ 3 H]citalopram in the assay buffer (2OmM HEPES, 145mM NaCI, 5mM KCI, pH 7.3). Incubation are performed at room temperature for at least 2 hours. Counts are stable and could be read up to 3 days.
  • hDAT hNET and hSERT SPA-binding assays are performed by using a Viewlux beta-counter (Wallac, Perkin-Elmer) with imaging PS-WGA beads (Amersham RPNQ0260) in a final assay volume of 30 ⁇ l_ and in a 384-well plate format (Greiner 781075).
  • Viewlux beta-counter Wallac, Perkin-Elmer
  • PS-WGA beads Amersham RPNQ0260
  • 0.3 ⁇ l_ of test compound in neat DMSO and 0% and 100% effect controls are added to the wells by using a Hummingbird (Genomic Solutions), followed by the addition of 30 ⁇ l_ of the SPA mixture, containing 1 mg/ml_ SPA beads (hSERT) or 2mg/ml SPA beads (hDAT and hNET), 40 ⁇ g/ml or 20 ⁇ g/ml or 6 ⁇ g/ml of hDAT or hNET or hSERT BacMam membranes, 0.02% pluronic F-127, 1OnM [ 3 H]WI N-35,428 or 1 OnM [ 3 H]nisoxetine or 3nM [ 3 H]citalopram for hDAT or hNET or hSERT binding SPA in the assay buffer (2OmM HEPES, 145mM NaCI, 5mM KCI, pH 7.3-7.4).
  • hSERT 1 mg/ml_ SPA beads
  • hDAT and hNET

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur de nouveaux composés représentés par la formule (I)', sur des sels pharmaceutiquement acceptables, des promédicaments ou des solvates de ceux-ci. Dans la formule (I)', R1 est un hydrogène ou un alkyle en C1-4; R2 est un groupe α ou β naphtyle, éventuellement substitué par 1 ou 2 groupes R8, qui sont identiques ou différents; R8 est choisi dans le groupe constitué par : un halogène, un cyano, un alkyle en C1-4; R5 est un hydrogène ou un alkyle en C1-4 ; R6 est un hydrogène ou un alkyle en C1-4 ; R7 est choisi dans le groupe constitué par : un hydrogène, un fluor et un alkyle en C1-4; ou correspond à X, X1, X2 ou X3, X correspondant à (I)'a, X1 correspondant à (I)'b, X2 correspondant à (I)'c, X3 correspondant à (I)'d; R3 est un hydrogène ou un alkyle en C1-4 ou correspond à X ou X1; R4 est un hydrogène ou un alkyle en C1-4 ou correspond à X ou X1; R9 est un alkyle en C1-4; R10 est un hydrogène, un alkyle en C1-4, un cycloalkyle en C3-6 ou un (cycloalkyl en C3-6)-alkyle en C1-3 ; R11 est un haloalkyle en C1-2; n est 1 ou 2. L'invention porte également sur des procédés de préparation de ces composés, sels, promédicaments ou solvates, sur des intermédiaires utilisés dans ces procédés, sur des compositions pharmaceutiques les contenant et sur leur utilisation en thérapie, en tant qu'inhibiteurs de la réabsorption de la sérotonine (5-HT), de la dopamine (DA) et de la noradrénaline (NE).
EP08787359A 2007-08-24 2008-08-21 Composés azabicyclo [4.1.0]heptanes substitués pour une utilisation en tant qu'inhibiteurs de la réabsorption de monoamine Withdrawn EP2182946A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0716573.1A GB0716573D0 (en) 2007-08-24 2007-08-24 Chemical compounds
PCT/EP2008/060912 WO2009027294A1 (fr) 2007-08-24 2008-08-21 Composés azabicyclo [4.1.0] heptanes substitués pour une utilisation en tant qu'inhibiteurs de la réabsorption de monoamine

Publications (1)

Publication Number Publication Date
EP2182946A1 true EP2182946A1 (fr) 2010-05-12

Family

ID=38599247

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08787359A Withdrawn EP2182946A1 (fr) 2007-08-24 2008-08-21 Composés azabicyclo [4.1.0]heptanes substitués pour une utilisation en tant qu'inhibiteurs de la réabsorption de monoamine

Country Status (4)

Country Link
EP (1) EP2182946A1 (fr)
JP (1) JP2010536918A (fr)
GB (1) GB0716573D0 (fr)
WO (1) WO2009027294A1 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUT68667A (en) * 1990-09-28 1995-07-28 Pfizer Fused ring analogs of nitrogen containing nonaromatic heterocycles
CA2662538A1 (fr) * 2006-09-11 2008-03-20 Glaxo Group Limited Composes azabicycliques en tant qu'inhibiteurs de reabsorption de monoamines
GB0617867D0 (en) * 2006-09-11 2006-10-18 Glaxo Group Ltd Chemical compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2009027294A1 *

Also Published As

Publication number Publication date
WO2009027294A1 (fr) 2009-03-05
GB0716573D0 (en) 2007-10-03
JP2010536918A (ja) 2010-12-02

Similar Documents

Publication Publication Date Title
US7691893B2 (en) Chemical compounds
EP1928886B1 (fr) Dérivés de pyridine et leur utilisation dans le traitement de troubles psychotiques
US20100130583A1 (en) Prolinamide derivatives as modulators of voltage-gated sodium channels
CA2724219C (fr) 5- [5- [2- (3, 5-bis (trifluoromethyl) phenyl) -2-methylpropanoylmethylamino] -4- (4-fluoro-2-methylphenyl) ] -2-pyridinyl-2-alkyl-prolinamide, antagonistes du recepteur nk1
US20080058391A1 (en) Novel compounds
EP2061461B1 (fr) Derives du 3-azabicyclyo[4.1.0]heptane pour le traitement de la depression
WO2010007032A1 (fr) Urées à base de pipéridine en tant qu’antagonistes du nk1
US20100029740A1 (en) Azabicyclic compounds as serotonin, dopamine and norepinephrine re-uptake inhibitors
WO2009056520A1 (fr) Dérivés d'azabicyclo[3.2.1]octane
WO2009027293A1 (fr) Composés
AU2023202293A1 (en) Novel salts
WO2009109608A1 (fr) Nouveaux composés
WO2009027295A1 (fr) Dérivés de 3-azabicyclo(4.1.0)heptane utiles comme inhibiteurs de la réabsorption de la norépinéphrine, de la sérotonine ou de la dopamine
WO2009027294A1 (fr) Composés azabicyclo [4.1.0] heptanes substitués pour une utilisation en tant qu'inhibiteurs de la réabsorption de monoamine
WO2009141412A1 (fr) Dérivés de 3-azabicyclo [3.1.0] hexane 1,6 disubstitués destinés à être utilisés comme triples inhibiteurs de recaptage
WO2010133569A1 (fr) Dérivés d'azabicyclo[4.1.0]heptane
WO2010130672A1 (fr) Dérivés de l'azabicyclo [4.1.0] heptane et leur utilisation en tant qu'inhibiteurs de recapture de monoamines
WO2010125033A1 (fr) Dérivés d'azabicyclo[4.1.0]heptane
WO2010146025A1 (fr) Dérivés d'azabicyclo [4.1.0] heptane tricycliques utilisés comme inhibiteurs du recaptage de la sérotonine, de la dopamine et de la norépinéphrine
CN101541754A (zh) 作为单胺类重摄取抑制剂的氮杂双环化合物
EP2178823A1 (fr) Nouveaux composés

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20100224

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA MK RS

17Q First examination report despatched

Effective date: 20100526

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20101006