WO2009056811A2 - Médicaments - Google Patents

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WO2009056811A2
WO2009056811A2 PCT/GB2008/003643 GB2008003643W WO2009056811A2 WO 2009056811 A2 WO2009056811 A2 WO 2009056811A2 GB 2008003643 W GB2008003643 W GB 2008003643W WO 2009056811 A2 WO2009056811 A2 WO 2009056811A2
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group
substituted
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compound according
compound
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PCT/GB2008/003643
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WO2009056811A3 (fr
Inventor
Holger Stark
Jukka Matti Leppanen
Britta Caroline Sasse
Oliver Saur
Tim Kottke
Michael Peter Hill
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Motac Neuroscience Limited
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Publication of WO2009056811A3 publication Critical patent/WO2009056811A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D293/00—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms
    • C07D293/10—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to novel dopamine receptor ligands that can be used to treat a number of medical conditions including, but not limited to, movement disorders (e.g. Parkinson's disease), other neurological disorders, psychiatric disorders and the treatment of drug abuse.
  • movement disorders e.g. Parkinson's disease
  • other neurological disorders e.g. psychiatric disorders
  • the treatment of drug abuse e.g. drug abuse.
  • Movement and other disorders due to dysfunction of the basal ganglia and related brain structures are of major socio-economic importance. Such disorders can occur as a consequence of inherited or acquired disease, idiopathic neurodegeneration or they may be iatrogenic.
  • the spectrum of disorders is very diverse, ranging from those associated with poverty of movement (akinesia, hypokinesia, bradykinesia) and hypertonia (e.g. Parkinson's disease, some forms of dystonia) to the involuntary movement disorders (hyperkinesias or dyskinesias e.g. Huntington's disease, levodopa-induced dyskinesia, ballism, and some forms of dystonia).
  • Parkinsonism is a well-known movement disorder comprising a syndrome characterised by slowness of movement (bradykinesia), rigidity and/or tremor. Parkinsonian symptoms are seen in a variety of conditions, most commonly in idiopathic parkinsonism (i.e., Parkinson's disease) but also following treatment of schizophrenia, exposure to toxins/drugs and head injury. In Parkinson's disease the primary pathology is degeneration of dopaminergic neurons of the substantia nigra, pars compacta.
  • Levodopa (or L-DOPA) is based on an aromatic amino acid and has the chemical name: (-)-L- ⁇ -amino- ⁇ -(3,4-dihydroxybenzene) propanoic acid.
  • L-DOPA has the molecular formula C 9 H 1 ]NO 4 and a molecular weight of 197.2.
  • levodopa is (-)-3-(3,4- dihydroxy-phenyl)-L-alanine. It is a colourless, crystalline compound, slightly soluble in water and insoluble in alcohol.
  • L-DOPA has the following structural formula:
  • L-DOPA is commonly administered to patients in combination with carbidopa.
  • the chemical name for carbidopa is (-)-L- ⁇ -hydrazino- ⁇ -methyl- ⁇ -(3,4-dihydroxybenzene) propanoic acid monohydrate.
  • Carbidopa has the empirical formula CioHi 4 N 2 0 4 » H 2 0 and a molecular weight of 244.3.
  • Anhydrous carbidopa has a molecular weight of 226.3.
  • Sinemet ® is a combination of carbidopa and levodopa for the treatment of Parkinson's disease and syndrome. Sinemet ® is described in U.S. Patents 4,832,957 and 4,900,755.
  • the structural formula of carbidopa is:
  • Ropinirole is an example of another dopamine agonist used for treating movement disorders. It is a non-ergoline dopamine agonist (sold under the trademark Requip ) and is the hydrochloride salt of 4-[2-(dipropylamino)ethyl]-l,3-dihydro-2H-indol-2-one monohydrochloride. Roprinrole has an empirical formula of C 16 H 24 N 2 O HCl and a molecular weight of 296.84 (260.38 as the free base). Ropinirole is described in U.S. Patent Numbers 4,452,808 and 4,824,860 and has the structural formula:
  • L-DOPA and other conventional dopamine receptor agonists have a number of drawbacks.
  • Dyskinesias are abnormal involuntary movement disorders.
  • the abnormal movements may manifest as chorea (involuntary, rapid, irregular, jerky movements that may affect the face, arms, legs, or trunk), ballism (involuntary movements similar to chorea but of a more violent and forceful nature), dystonia (sustained muscle contractions, usually producing twisting and repetitive movements or abnormal postures or positions) or athetosis (repetitive involuntary, slow, sinuous, writhing movements, which are especially severe in the hands).
  • chorea involuntary, rapid, irregular, jerky movements that may affect the face, arms, legs, or trunk
  • ballism involuntary movements similar to chorea but of a more violent and forceful nature
  • dystonia sustained muscle contractions, usually producing twisting and repetitive movements or abnormal postures or positions
  • athetosis repetitive involuntary, slow, sinuous, writhing movements, which are especially severe in the hands.
  • Dyskinetic side-effects can be seen either when the patient is undergoing dopamine-replacement therapy (in the case of chorea and/or dystonia) or even when off therapy (when dystonia is prevalent). Ultimately, these side-effects severely limit the usefulness of dopaminergic treatments.
  • dopamine-replacement agents e.g. L-DOPA and dopamine receptor agonists
  • wearing-off ' of the antiparkinsonian efficacy of the treatment is the "wearing-off ' of the antiparkinsonian efficacy of the treatment.
  • dopamine-replacement agents include side-effects such as nausea, dizziness, somnolence, insomnia, constipation, asthenia and hallucination.
  • Efforts have been made in the art to improve the efficacy of dopamine receptor agonists and also to develop agents with fewer side-effects.
  • One area of development has been to investigate whether of not compounds can be developed that have selectivity and/or specificity towards different-types of dopamine receptor.
  • the Gs protein coupled Dl and D5 receptors belong to the Dl -like dopamine receptor family.
  • Dopamine D2, D3 and D4 receptors are Gi protein coupled and form the D2-like receptor family.
  • the D3 receptor was first cloned and characterized in 1990 (Sokoloff et al, Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature, 347, 146-151 (1990)). Overall expression of the D3 receptor is lower than for D2 in the brain. However the D3 receptor is specifically localized in the limbic system and in relatively low concentrations in the striatum. Therefore, the dopamine D3 receptor represents a target for the treatment of movement disorders and also other neurological disorders, psychiatric disorders, the treatment of drug abuse and other therapeutic indications, which are related to the modulation of dopamine receptor activity.
  • Schizophrenia is another condition that is associated with imbalance in dopamine receptor activity.
  • the dopamine hypothesis of schizophrenia postulates that an excess of dopamine subcortically is associated with the positive symptoms.
  • the negative and cognitive symptoms of schizophrenia are thought to arise from a deficit of dopamine in the cortex.
  • Modulators of the dopamine D3 receptor could therefore have a regulative effect on this dopaminergic imbalance without causing negative side effects in the striatum.
  • Addiction to substances of abuse is associated with abnormalities in the limbic system.
  • substances of abuse especially alcohol, nicotine, cocaine and heroine
  • selective dopamine D3 receptor ligands also have potential for the treatment of compounds of abuse.
  • Agonists could be useful for a substitute therapy whereas selective D3 receptor antagonists or partial agonists would attenuate the desired dopamine receptor stimulation of the abused drug without producing undesired side effects (Newman et al, dopamine D3 receptor partial agonists and antagonists as potential drug abuse therapeutic agents, J. Med. Chem. 2005, 48, 3663-3679).
  • Sexual dysfunctions for example wherein a male is unable to develop or maintain a penile erection or female sexual arousal/orgasm disorder, are also associated with an imbalance of dopamine receptor activity.
  • Restless leg syndrome is of unknown aetiology and often treated with low dose dopamine agonists because an imbalance of this neurotransmitter largely influences this disorder and/or its symptoms.
  • Many other conditions are associated with an imbalance in dopamine receptor activity. This include: bipolar disorder, attention deficit hyperactivity disorder (ADHD), Tourette's syndrome, depression, anxiety, cognitive impairment, dementia, emesis, amnesia, autism, vertigo as well as eating, sleep, movement, obsessive/compulsive, circadian rhythm and gastric motility disorders are accompanied with a dysfunction of the dopaminergic system.
  • An abnormal dopaminergic neurotransmission is also associated with conditions such as migraine, amyotropic lateral sclerosis, sleep disorder and anhedonia.
  • Pramipexol is an example of a D3 receptor agonist that has been developed for the treatment of movement disorders and the antiparkinson activity of pramipexol has been described in US 4,731,374.
  • the chemical name of pramipexole is (S)-2-amino- 4,5,6,7-tetra- hydro-6-(propylamino) benzothiazole dihydrochloride mono-hydrate.
  • Pramipexole dihydrochloride is sold under the trademark Mirapex ® .
  • Pramipexole dihydrochloride has the empirical formula CioHi 7 N 3 S-2HCl H 2 0 and a molecular weight of 302.27.
  • the structural formula of pramipexole dihydrochloride is:
  • pramipexole and etrabamine are still associated with a number of drawbacks. For instance 1-10 % of patients treated with pramipexole may develop oedema.
  • Other known side-effects include dyskinetic side-effects, insomnia, hallucination and orthostatic dysregulation.
  • WO-96/28157 discloses pharmaceutical compositions containing 1-etrabamine and methods for making them.
  • WO-97/45403 discloses aryl substituted cyclic amines and their use in the treatment of central nervous system diseases.
  • WO-02/098367 discloses hybrid compounds containing both an aminotetralin moiety or related structure and an N-aryl piperazinyl structure linked to the aminotetralin structure by an alkylene bridge. WO-02/098367 suggests that the compounds it discloses are useful in altering central nervous system activity.
  • An object of the present invention is to provide new and improved dopamine receptor ligands that may be used to treat medical conditions associated with an imbalance in dopamine receptor activity.
  • a further object of the present invention is to develop new chemical compounds which obviate or mitigate one or more of the drawbacks associated with the above mentioned prior art compounds. According to the present invention there is provided a compound of formula: 1 wherein
  • R 1 and R 2 are each separately selected from the group consisting of H, substituted orunsubstituted alkyl, substituted or unsubstituted alkyenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted carbocyclic ring, and substituted or unsubstituted heterocyclic ring;
  • X is a bivalent heteroatom
  • Y is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkyenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, halo, and substituted or unsubstituted thio; subject to the proviso that when X is S and Y is H then R 1 and R 2 are not H and methyl respectively; and subject to the proviso that when X is S then Y is not -NH 2 .
  • R 1 and R 2 are each separately selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkyenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted carbocyclic ring, and substituted or unsubstituted heterocyclic ring;
  • X is a bivalent heteroatom
  • Y is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkyenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, halo, and substituted or unsubstituted thio; subject to the proviso that when X is S and Y is H, then R 1 and R 2 are not H and H respectively, H and methyl respectively, H and propyl respectively, or H and butyl respectively; and subject to the proviso that when X is S then Y is not -NH 2 , methyl, or methyl substituted by l-(4-chlorophenyl)urea; and subject to the proviso that when X is S and Y is propyl, isopropy
  • Another aspect of the present invention provides a pharmaceutical composition comprising a compound according to the present invention.
  • Another aspect of the present invention provides a compound according to the present invention for use in the manufacture of a medicament for the treatment of medical conditions characterized by an imbalance in dopamine receptor activity.
  • Another aspect of the present invention provides a use of compounds according to the present invention for treatment of medical conditions characterized by an imbalance in dopamine receptor activity.
  • Another aspect of the present invention provides a method of treating medical conditions characterized by an imbalance in dopamine receptor activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the present invention.
  • a "therapeutically effective amount” is any amount of a compound or composition which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease.
  • a “subject” is a vertebrate, mammal, domestic animal or human being.
  • the “pharmaceutically acceptable vehicle” is any physiological vehicle known to those of ordinary skill in the art useful in formulating pharmaceutical compositions.
  • the inventors generated a large number of compounds and tested their ability to bind to dopamine receptors and to treat medical conditions characterized by an imbalance in dopamine receptor activity. They discovered that numerous compounds that were related to pramipexole or etrabamine had poor binding for dopamine receptors and/or little efficacy (data not shown). However they were surprised to find that compounds that fall within the definition of the formula according to the present invention have particularly good affinity for dopamine D3 receptors and are also effective for reducing the effects of the medical conditions when tested in in vivo models (see the Examples).
  • X may be any appropriate bivalent heteroatom.
  • X is selected from the group consisting of sulfur, selenium and oxygen. It is preferred that X is Se or S. As described below in greater detail, in a first preferred embodiment of the present invention X is Se, and in a second preferred embodiment X is S, and in a third preferred embodiment X is O.
  • Y may comprise a number of molecular constituents as defined herein.
  • Y may be selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkyenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, halo, and substituted or unsubstituted thio.
  • X is S then Y is not -NH 2 , methyl, or methyl substituted by 1 -(4-chlorophenyl)urea.
  • alkyl when used alone or in combination, includes both straight chain and branched chain alkyl groups, such as propyl, isopropyl and tert-butyl.
  • references to individual alkyl groups such as "propyl” are specific for the straight-chain version only (for example otherwise known as n-propyl) and references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only.
  • a Cj-C 4 alkyl group has from one to four carbon atoms including methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and the like.
  • Y may be H, halo or an unsubstituted or substituted thio group, such as an alkylthio group which may itself be unsubstituted or substituted. It is preferred that Y is an alkyl, alkenyl, alkynyl, alkoxy or alkylthio group substituted with a first substituent which contains an atom which is other than carbon or hydrogen, preferably an atom selected from group 15, 16 or 17 of the periodic table. More preferably said atom is selected from the group consisting of oxygen, sulfur, selenium, nitrogen and phosphorus.
  • the first substituent may be selected from the group consisting of a carboxy group, a thiocarboxy group, a selenocarboxy group, a carboxamido group, a sulfo group, a sulfino group, a sulfeno group, an ester group, a haloformyl group, a carbamoyl group, an imido group, a cyanato group, an isocyanato group, a nitro group, a nitroso group, a nitroxy group, a nitrosooxy group, a formyl group, an oxo group, a hydroxy group, a hydroperoxy group, an oxy group, a peroxy group, a phosphono group, a sulfonyl group, a sulfinyl group, an isothiocyanato group, a thioformyl group, a thiono group, a
  • the first substituent may be any group which contains one or more oxygen atoms, optionally in combination with at least one further atom which is other than carbon or hydrogen, for example, sulfur, selenium, nitrogen and/or phosphorous.
  • the first substituent is selected from the group consisting of a carboxy group, a thiocarboxy group, a selenocarboxy group, a carboxamido group, a sulfo group, a sulfino group, a sulfeno group, an ester group, a haloformyl group, a carbamoyl group, an imido group, a cyanato group, an isocyanato group, a nitro group, a nitroso group, a nitroxy group, a nitrosooxy group, a formyl group, an oxo group, a hydroxy group, a hydroperoxy group, an oxy group, a peroxy group, a phosphono
  • the first substituent may be selected from the group consisting of a carboxy group, a thiocarboxy group, a carboxamido group, a sulfo group, a sulfino group, a sulfeno group, an ester group, a carbamoyl group, an imido group, a nitro group, a formyl group, an oxo group, a hydroxy group, an oxy group, and derivatives thereof.
  • said first substituent may be any group which contains one or more sulfur atoms, optionally in combination with at least one further atom which is other than carbon or hydrogen, for example, oxygen, selenium, nitrogen and/or phosphorous.
  • the first substituent is selected from the group consisting of a thiocarboxy group, a sulfo group, a sulfino group, a sulfeno group, a sulfonyl group, a sulfinyl group, an isothiocyanato group, a thioformyl group, a thiono group, a sulfanyl group, a thio group, a disulfanyl group and derivatives thereof.
  • the first substituent may be selected from the group consisting of a thiocarboxy group, a sulfo group, a sulfino group, a sulfeno group, a sulfonyl group, a sulfinyl group, a thioformyl group, a sulfanyl group, a thio group, a disulfanyl group and derivatives thereof.
  • the first substituent may be any group which contains one or more selenium atoms, optionally in combination with at least one further atom which is other than carbon or hydrogen, for example, oxygen, sulfur, nitrogen and/or phosphorous.
  • the first substituent is selected from the group consisting of a selenocarboxy group, a selenyl group, a seleno group and derivatives thereof.
  • said first substituent may be any group which contains one or more nitrogen atoms, optionally in combination with at least one further atom which is other than carbon or hydrogen, for example, oxygen, sulfur, selenium and/or phosphorous.
  • the first substituent is selected from the group consisting of a carbamoyl group, an imido group, an amidino group, a cyano group, an isocyano group, an amino group, an imino group, an azido group, an azo group, a cyanato group, an isocyanato group, an isothiocyanato group, a nitro group, a nitroso group, a nitroxy group, a nitrosooxy group, a hydrazino group, and derivatives thereof.
  • the first substituent may be selected from the group consisting of a carbamoyl group, an imido group, an amidino group, a cyano group, an amino group, an imino group, an azido group, a nitro group, a hydrazino group, and derivatives thereof.
  • Said first substituent may be any group which contains one or more phosphorous atoms, optionally in combination with at least one further atom which is other than carbon or hydrogen, for example, oxygen, sulfur, selenium and/or nitrogen.
  • the first substituent is selected from the group consisting of a phosphino group, a phosphono group, a phospho group, and derivatives thereof.
  • said first substituent may be selected from the group consisting of a substituted or unsubstituted carbocyclic group and a substituted or unsubstituted heterocyclic group.
  • the carbocyclic group may contain any desirable number of carbocyclic rings, and the or each ring may contain any appropriate number of ring carbon atoms.
  • the first substituent is a multi- or poly-cyclic carbocyclic ring structure
  • the connection between any two of said plurality of rings may have a fused, bridged or spiro configuration.
  • the or each carbocyclic ring contains 3 to 12 carbon atoms, more preferably 4 to 8 carbon atoms, and most preferably 5 to 7 carbon atoms.
  • the carbocyclic group may be a saturated, unsaturated or aromatic carbocyclic group. Examples of preferred saturated monocyclic carbocyclic groups include a cyclopentanyl group and a cyclohexanyl group.
  • a preferred multicyclic carbocyclic group is an adamantanyl group. Examples of preferred aromatic carbocyclic groups include phenyl, naphthyl, anthracyl and phenanthracyl groups.
  • the heterocyclic group may contain any suitable number of heterocyclic rings, and the or each ring may contain any desirable number of ring atoms.
  • the first substituent is a multi- or poly-cyclic heterocyclic ring structure, provided at least one of said rings is a heterocyclic ring, the or each other ring may be a carbocyclic ring or a further heterocyclic ring.
  • the connection between any two of the plurality of rings may have a fused, bridged or spiro configuration. It is particularly preferred that the or each heterocyclic ring contains 3 to 12 carbon atoms, more preferably 4 to 8 carbon atoms, and most preferably 5 to 7 carbon atoms.
  • the heterocyclic group may be a saturated, unsaturated or aromatic heterocyclic group.
  • the substituted or unsubstituted heterocyclic group contains at least one ring heteroatom, that is, an atom other than carbon.
  • the heteroatom may be taken from group 15 or 16 of the periodic table and is preferably selected from the group consisting of oxygen, sulfur, selenium, nitrogen and phosphorous.
  • the substituted or unsubstituted heterocyclic group may be selected from the group consisting of an oxiranyl group, an oxirenyl group, an oxetanyl group, a furanyl group, a hydrofuranyl group, an oxazolyl group, an isoxazolyl group, a pyranyl group, a hydropyranyl group, an oxazinyl group, and a dioxanyl group, and their partly and fully saturated analogues.
  • the substituted or unsubstituted heterocyclic group may be selected from the group consisting of furanyl group, an oxazolyl group, an isoxazolyl group, a pyranyl group, an oxazinyl group, and a dioxanyl group.
  • the substituted or unsubstituted heterocyclic group may be selected from the group consisting of an aziridine group, an azetidinyl group, a pyrrolyl group, a hydropyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, an oxazolyl group, a thiazolyl group, an isothiazolyl group, a piperidinyl group, a pyridinyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a piperazinyl group, an oxoazinyl group, and a thiazinyl group, and their partly and fully saturated analogues.
  • the substituted or unsubstituted heterocyclic group may be selected from the group consisting of aziridine group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, an oxazolyl group, a thiazolyl group, an isothiazolyl group, a pyridinyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a piperazinyl group, an oxoazinyl group, and a thiazinyl group.
  • the substituted or unsubstituted heterocyclic group may be selected from the group consisting of a thiiranyl group, a thiophenyl group, a hydrothiophenyl group, a thiazolyl group, an isothiazoly group, a dithiolanyl group, a thianyl group, a thiinyl group, a thiazine group, and a dithianyl group, and their partly and fully saturated analogues.
  • the substituted or unsubstituted heterocyclic group may be selected from the group consisting of a thiophenyl group, a hydrothiophenyl group, a thiazolyl group, an isothiazoly group, a dithiolanyl group, a thianyl group, a thiinyl group, a thiazine group, and a dithianyl group.
  • Y may be selected from the group consisting of H, substituted or unsubstituted alkyenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, halo, and substituted or unsubstituted thio, especially selected from the group consisting of substituted or unsubstituted alkyenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, halo, and substituted or unsubstituted thio, more especially selected from the group consisting of substituted or unsubsti
  • Y may be selected from the group consisting of a substituted or unsubstituted Ci-C 4 alkyl, alkenyl, alkynyl or alkoxy group.
  • Y is a primary, secondary or tertiary amino group.
  • Y is most preferably a primary amino group, that is, an amino group including two hydrogen atoms bonded directly to the nitrogen atom of the amino group.
  • Y is an amino group substituted with a substituent selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkyenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted alkoxy.
  • Y is a thio group substituted with a substituent selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkyenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted alkoxy.
  • Y is selected from the group consisting of H, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, halo, and substituted or unsubstituted thio.
  • Y may be selected from the group consisting of H, chloro, bromo, methoxy, ethoxy, -NH 2 and methylthio, especially selected from the group consisting of chloro, bromo, methoxy, ethoxy, -NH 2 and methylthio.
  • Y is selected from the group consisting of unsubstituted alkoxy, unsubstituted amino, and halo. It is particularly preferred that where the compound according to the present invention includes a halo group, the halo group is Cl, Br or I 5 most preferably Cl or Br.
  • R 1 and R 2 are each separately selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkyenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted carbocyclic ring, and substituted or unsubstituted heterocyclic ring.
  • R 1 and R 2 are not H and H respectively, H and methyl respectively, H and propyl respectively, or H and butyl respectively and when X is S and Y is propyl or butyl, then R 1 and R 2 are not H and methyl respectively.
  • R 1 and R 2 may take the same pattern of substitution, or R 1 and R 2 may take different patterns of substitution. As stated above, R 1 and/or R 2 may be a carbocyclic or heterocyclic moiety. It is preferred that one of R 1 and R 2 is a second substituted or unsubstituted alkyl, alkenyl, alkynyl or alkoxy group. In a preferred embodiment the other of R 1 and R 2 is hydrogen. Alternatively, in a further preferred embodiment the other of R 1 and R 2 is a third substituted or unsubstituted alkyl, alkenyl, alkynyl or alkoxy (especially alkyl) group. Alternatively, in a further preferred embodiment the other of R 1 and R 2 is hydrogen or a third substituted or unsubstituted alkyl group.
  • the second and/or third substituted or unsubstituted alkyl, alkenyl, alkynyl or alkoxy group may contain any appropriate number of carbon atoms, but it is preferred that said group contains 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms and most preferably the group is a Ci - C 4 substituted or unsubstituted alkyl, alkenyl, alkynyl or alkoxy (especially alkyl) group.
  • said second and/or third substituted or unsubstituted alkyl, alkenyl, alkynyl or alkoxy group is substituted with a second and/or third substituent respectively which contains an atom which is other than carbon or hydrogen, preferably an atom selected from group 15, 16 or 17 of the periodic table. More preferably said atom is selected from the group consisting of oxygen, sulfur, selenium, nitrogen and phosphorus.
  • the second and/or third substituent may be selected from the group consisting of a carboxy group, a thiocarboxy group, a selenocarboxy group, a carboxamido group, a sulfo group, a sulfino group, a sulfeno group, an ester group, a haloformyl group, a carbamoyl group, an imido group, a cyanato group, an isocyanato group, a nitro group, a nitroso group, a nitroxy group, a nitrosooxy group, a formyl group, an oxo group, a hydroxy group, a hydroperoxy group, an oxy group, a peroxy group, a phosphono group, a phospho group, a sulfonyl group, a sulfinyl group, an isothiocyanato group, a thioformyl group,
  • the second and/or third substituent may be any group which contains one or more oxygen atoms, optionally in combination with at least one further atom which is other than carbon or hydrogen, for example, sulfur, selenium, nitrogen and/or phosphorous.
  • the second and/or third substituent is selected from the group consisting of a carboxy group, a thiocarboxy group, a selenocarboxy group, a carboxamido group, a sulfo group, a sulfino group, a sulfeno group, an ester group, a haloformyl group, a carbamoyl group, an imido group, a cyanato group, an isocyanato group, a nitro group, a nitroso group, a nitroxy group, a nitrosooxy group, a formyl group, an oxo group, a hydroxy group, a hydroperoxy group, an oxy group, a peroxy
  • the second and/or third substituent may be selected from the group consisting of a carboxy group, a thiocarboxy group, a carboxamido group, a sulfo group, a sulfino group, a sulfeno group, an ester group, a carbamoyl group, an imido group, a nitro group, a formyl group, an oxo group, a hydroxy group, an oxy group, and derivatives thereof.
  • the second and/or third substituent may be any group which contains one or more sulfur atoms, optionally in combination with at least one further atom which is other than carbon or hydrogen, for example, oxygen, selenium, nitrogen and/or phosphorous.
  • the second and/or third substituent is selected from the group consisting of a thiocarboxy group, a sulfo group, a sulfino group, a sulfeno group, a sulfonyl group, a sulfinyl group, an isothiocyanato group, a thioformyl group, a thiono group, a sulfanyl group, a thio group, a disulfanyl group and derivatives thereof.
  • the second and/or third substituent may be selected from the group consisting of the group consisting of a thiocarboxy group, a sulfo group, a sulfino group, a sulfeno group, a sulfonyl group, a sulfinyl group, a thioformyl group, a sulfanyl group, a thio group, a disulfanyl group and derivatives thereof.
  • the second and/or third substituent may be any group which contains one or more selenium atoms, optionally in combination with at least one further atom which is other than carbon or hydrogen, for example, oxygen, sulfur, nitrogen and/or phosphorous.
  • the second and/or third substituent is selected from the group consisting of a selenocarboxy group, a selenyl group, a seleno group and derivatives thereof.
  • the second and/or third substituent may be any group which contains one or more nitrogen atoms, optionally in combination with at least one further atom which is other than carbon or hydrogen, for example, oxygen, sulfur, selenium and/or phosphorous.
  • the second and/or third substituent is selected from the group consisting of a carbamoyl group, an imido group, an amidino group, a cyano group, an isocyano group, an amino group, an imino group, an azido group, an azo group, a cyanato group, an isocyanato group, an isothiocyanato group, a nitro group, a nitroso group, a nitroxy group, a nitrosooxy group, a hydrazino group, and derivatives thereof.
  • the second and/or third substituent may be selected from the group consisting of a carbamoyl group, an imido group, an amidino group, a cyano group, an amino group, an imino group, an azido group, a nitro group, a hydrazino group, and derivatives thereof.
  • the second and/or third substituent may be any group which contains one or more phosphorous atoms, optionally in combination with at least one further atom which is other than carbon or hydrogen, for example, oxygen, sulfur, selenium and/or nitrogen.
  • the second and/or third substituent is selected from the group consisting of a phosphino group, a phosphono group, a phospho group, and derivatives thereof.
  • said second and/or third substituent is selected from the group consisting of a substituted or unsubstituted carbocyclic group and a substituted or unsubstituted heterocyclic group.
  • the carbocyclic group may contain any desirable number of carbocyclic rings, and the or each ring may contain any appropriate number of ring carbon atoms.
  • the first substituent is a multi- or poly-cyclic carbocyclic ring structure
  • the connection between any two of said plurality of rings may have a fused, bridged or spiro configuration.
  • the or each carbocyclic ring contains 3 to 12 carbon atoms, more preferably 4 to 8 carbon atoms, and most preferably 5 to 7 carbon atoms.
  • the carbocyclic group may be a saturated, unsaturated or aromatic carbocyclic group. Examples of preferred saturated monocyclic carbocyclic groups include a cyclopentanyl group and a cyclohexanyl group.
  • a preferred multicyclic carbocyclic group is an adamantanyl group. Examples of preferred aromatic carbocyclic groups include phenyl, naphthyl, anthracyl and phenanthracyl groups.
  • the heterocyclic group may contain any suitable number of heterocyclic rings, and the or each ring may contain any desirable number of ring atoms.
  • the first substituent is a multi- or poly-cyclic heterocyclic ring structure, provided at least one of said rings is a heterocyclic ring, the or each other ring may be a carbocyclic ring or a further heterocyclic ring.
  • the connection between any two of the plurality of rings may have a fused, bridged or spiro configuration. It is particularly preferred that the or each heterocyclic ring contains 3 to 12 carbon atoms, more preferably 4 to 8 carbon atoms, and most preferably 5 to 7 carbon atoms.
  • the heterocyclic group may be a saturated, unsaturated or aromatic heterocyclic group.
  • the substituted or unsubstituted heterocyclic group contains at least one ring heteroatom, that is, an atom other than carbon.
  • the heteroatom may be taken from group 15 or 16 of the periodic table and is preferably selected from the group consisting of oxygen, sulfur, selenium, nitrogen and phosphorous.
  • the substituted or unsubstituted heterocyclic group may be selected from the group consisting of an oxiranyl group, an oxirenyl group, an oxetanyl group, a furanyl group, a hydrofuranyl group, an oxazolyl group, an isoxazolyl group, a pyranyl group, a hydropyranyl group, an oxazinyl group, and a dioxanyl group.
  • the substituted or unsubstituted heterocyclic group may be selected from the group consisting of a furanyl group, an oxazolyl group, an isoxazolyl group, a pyranyl group, an oxazinyl group, and a dioxanyl group.
  • the substituted or unsubstituted heterocyclic group may be selected from the group consisting of an aziridine group, an azetidinyl group, a pyrrolyl group, a hydropyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, an oxazolyl group, a thiazolyl group, an isothiazolyl group, a piperidinyl group, a pyridinyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a piperazinyl group, an oxoazinyl group, and a thiazinyl group.
  • the substituted or unsubstituted heterocyclic group may be selected from the group consisting of an aziridine group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, an oxazolyl group, a thiazolyl group, an isothiazolyl group, a pyridinyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a piperazinyl group, an oxoazinyl group, and a thiazinyl group.
  • said substituted or unsubstituted heterocyclic group may be selected from the group consisting of a thiiranyl group, a thiophenyl group, a hydrothiophenyl group, a thiazolyl group, an isothiazoly group, a dithiolanyl group, a thianyl group, a thiinyl group, a thiazine group, and a dithianyl group.
  • the substituted or unsubstituted heterocyclic group may be selected from the group consisting of a thiophenyl group, a hydrothiophenyl group, a thiazolyl group, an isothiazoly group, a dithiolanyl group, a thianyl group, a thiinyl group, a thiazine group, and a dithianyl group.
  • said substituted or unsubstituted heterocyclic group may be a thiophenyl group, especially an unsubstituted thiophenyl group.
  • R 1 and/or R 2 represents a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.
  • the R 1 and/or R 2 carbocyclic group may take any of the preferred forms set out above in respect of the carbocyclic group of the first substituent in respect of group Y.
  • said heterocyclic group may take any of the forms described above in respect of the heterocyclic group of the first substituent in respect of group Y.
  • the compounds of the present invention may be subject to the proviso that when X is S and Y is H then R 1 and R 2 are not H and Ci-C 3 (for example Ci-C 3 ) alkyl respectively.
  • X is Se and the compound has the formula: wherein each of Y, R 1 and R 2 is as defined above.
  • Y may be selected from the group consisting of H, substituted or unsubstituted amino, and halo (such as chloro). In another embodiment Y may be selected from substituted or unsubstituted amino (especially -NH 2 ). Alternatively, Y may be a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy or alkylthio group containing 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, and most preferably Y is a C)-C 4 alkyl, alkenyl, alkynyl, alkoxy or alkylthio group. It is particularly preferred that Y is H or a primary amino group.
  • one of R 1 and R 2 is preferably a hydrogen atom and the other of R 1 and R is an alkyl group, preferably an alkyl group containing 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, and most preferably a Cj-C 4 alkyl group, such as an ethyl group or a propyl group.
  • Y may be selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkyenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, halo, and substituted or unsubstituted thio.
  • Y may be selected from the group consisting of H, substituted or unsubstituted alkyenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, halo, and substituted or unsubstituted thio, even more particularly from the group consisting of substituted or unsubstituted alkyenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, halo, and substituted or unsubstituted thio, yet even more particularly from the group consisting of substituted or unsubstituted alkoxy, halo, and substituted or unsubstituted thio.
  • Y may be selected from the group consisting of H, substituted or unsubstituted alkoxy, halo, and substituted or unsubstituted thio.
  • Y is a halo group, most preferably a Cl group, or an alkoxy group, such as a C 1 -C 4 alkoxy group and most preferably a methoxy group.
  • one of R 1 and R 2 is preferably a hydrogen atom and the other of R 1 and R 2 is an alkyl group, preferably an alkyl group containing 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, still more preferably a Ci-C 4 alkyl group, and most preferably a propyl group.
  • the most preferred compounds have X as S; Y as H or -OCH 3 ; and R 1 and/or R 2 as lower alkyl, alkenyl or alkynyl with less than 12 carbon atoms in total for both R 1 and R .
  • R 1 when Y is H, then R 1 may be selected from a substituted or unsubstituted (especially unsubstituted) alkyl group, preferably an alkyl group containing 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, still more preferably a C 1 -C 4 alkyl group, and most preferably a propyl group, and R 2 may be a substituted alkyl group, preferably an alkyl group containing 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, still more preferably a C 1 -C 4 alkyl group, and most preferably an ethyl group and wherein the substituted may be any substituted as defined herein.
  • R 2 may be a substituted Cj-C 4 alkyl group, wherein the substituent is a substituted or unsubstituted heterocyclic group as defined herein (for example a substituted or unsubstituted thiophenyl group, especially an unsubstituted thiophenyl group).
  • Y may be selected from the group consisting of H, substituted or unsubstituted amino, and halo (such as chloro). It is particularly preferred that Y is H or a primary amino group, especially -NH 2 .
  • one of R 1 and R 2 is preferably a hydrogen atom and the other of R 1 and R 2 is an alkyl group, preferably an alkyl group containing 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, and most preferably a Ci-C 4 alkyl group, such as an ethyl group or a propyl group.
  • a further aspect of the present invention provides a compound selected from (4,5,6,7-tetrahydro-benzothiazol-6-yl)-(2-thiophen-2-yl-ethyl)-amine; propyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-(2-thiophen-2-yl-ethyl)-amine; (2-chloro-4,5,6,7-tetrahydro-benzothiazol-6-yl)-propyl-amine; (2-bromo-4,5,6,7-tetrahydro-benzothiazol-6-yl)-propyl-amine; (2-methoxy-4,5,6,7-tetrahydro-benzothiazol-6-yl)-propyl-amine; (2-methylsulfanyl-4,5,6,7-tetrahydro-benzothiazol-6-yl)-propyl-amine; (2-ethoxy-4,5,6,7-tetrahydro
  • a further aspect of the present invention provides a compound (53), synthesised in Example A8 below, having the formula:
  • a further aspect of the present invention provides a compound (47), synthesised in Example A3 below, having the formula: H
  • a further aspect of the present invention provides a compound (49), synthesised in Example A5 below, having the formula:
  • a further aspect of the present invention provides a compound (54), synthesised in Example A9 below, having the formula:
  • a further aspect of the present invention provides a compound (11), synthesised in Example Al l below, having the formula:
  • the compounds of the invention may be any diastereomer or enantiomer or racemate or racemic mixture or tautomeric form thereof including mixtures of these or a pharmaceutical acceptable salt thereof including different or special polymorphic forms.
  • Some of the compounds of the present invention are chiral and may have additional centres of asymmetry in the added moieties, and it is intended that any enantiomer and diastereomer, as separated, pure or partially purified enantiomers, diastereomers or racemic mixtures thereof are included within the scope of the invention. It will be appreciated that a skilled person may wish to select the single enantiomer with one of the highest potency and selectivity. Furthermore, when a double bond or a fully or partially saturated ring system or more than one centre of asymmetry or a bond with restricted rotability is present in the molecule diastereomers may be formed. It is intended that any enantiomer, diastereomer or rotamer, as separated, pure or partially purified enantiomers, diastereomers or rotamers or mixtures thereof are included within the scope of the invention.
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable addition of salts, pharmaceutically acceptable metal salts, ammonium, and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic salts include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include, formic, acetic, trichloroacetic, trifiuoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, methansulfonic, ethansulfonic, aspartic, stearic, palmitic, EDTA, glycolic, glutamic, malonic, mandelic, oxalic, picric, salicylic, siccinic, sulfonic, gluconic, citraconic, tartaric, ascorbic, bismethylene salicylic, ethynditamic, benzene sulfonic, p-toluene sulfonic acids and the like.
  • compositions include the pharmaceutically acceptable salts listed in e.g., S. M. Berge, L. D. Bighley, D. C. Monkhouse, J. Pharm. Sci. 1977, 66, 1- 19, and P. H. Stahl, C: G: Wermuth, Handbook of pharmaceutical salts: Properties, selection and use. 2002, Verlag Helvetica Chimica Acta, Zurich; ISBN: 3-906390-26-8.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium, alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salt and the like.
  • hydrates which the present compounds are able to form.
  • the acid addition may be obtained as direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of the present invention may form solvates with standard low molecular weights solvents using methods well known to the person skilled in the art. Such solvates are contemplated as being within the scope of the present invention.
  • the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic or chemical processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the present invention.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
  • the invention also encompasses active metabolites of the present compounds.
  • active metabolites include those formed by chemical reactions a well as by enzymatic reactions in the body.
  • the definition of active metabolites includes the formation of phase I as well as phase II metabolites as different conjugated derivatives.
  • the inventors have found that compounds of the present invention exhibit great affinity for dopamine receptors.
  • the compounds according to the invention bind to dopamine receptor subtypes with a Kj value for binding of less than 10 ⁇ M, more preferred of less than 1 ⁇ M, and even more preferred of less than 500 nM, and most preferably of less than 100 nM.
  • Kj values for dopamine receptor binding and preferred methods are described in the Examples.
  • the compounds of the present invention have affinity for dopamine D3 or/and D2 receptors and are accordingly useful for the treatment and/or prevention of a wide variety of conditions and disorders in which dopamine D3 and/or Dopamine D2 receptor interactions are beneficial (as discussed above and below). It is most preferred that that the compounds of the present invention have affinity for dopamine D3 receptors and the abovementioned Kj values apply to dopamine D3 receptor binding. It is more preferred that the compounds have affinity for and also show selectivity for D3 receptors.
  • the compounds have a greater affinity for D3 receptors than for D2 receptors. It is preferred that the compounds have at least a 10-fold selectivity for the D3 receptor over D2 receptors and more preferred that it has a 30-fold or 50-fold selectivity for the D3 receptor over D2 receptors. It is even more preferred that the compounds have a 100- fold or higher selectivity for the D3 receptor over D2 receptors.
  • Preferred compounds act as agonists of D3 receptors whereas other preferred compounds act as partial agonists, inverse agonists or antagonist of D3 receptors.
  • Preferred compounds when compared to pramipexole or etrabamine, have improved pharmacokinetic properties and fewer side-effects.
  • Preferred compounds have a faster onset when administered orally, or by the intra-peritoneal route, and have a maximal effect within the first 15 minutes after application.
  • Other preferred compounds e.g. compound 47
  • Some preferred compounds have a rapid onset of activity and also have a sustained effect (e.g. compound 47).
  • the compounds according to the invention are effective for inhibiting symptoms associated with medical conditions characterized by an imbalance in dopamine receptor activity such that IC 50 values are in the micromolar range. It is preferred that IC 5 o values are less than lOO ⁇ M, preferably less than 10 ⁇ M, more preferably of less than 1 ⁇ M, and even more preferably of less than 500 nM, and most preferably of less than 100 nM.
  • IC 5 o values are less than lOO ⁇ M, preferably less than 10 ⁇ M, more preferably of less than 1 ⁇ M, and even more preferably of less than 500 nM, and most preferably of less than 100 nM.
  • dose-response assessments may be based the in-vivo assays described in the Examples. Compositions and medicaments according to the invention
  • the pharmaceutical composition according to the invention comprises, as an active ingredient, at least one compound of the present invention.
  • the composition may comprise any diastereomer or enantiomer or tautomeric form of the compound and including mixtures of these or pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition may comprise the compound of the present invention together with one or more pharmaceutically acceptable carriers or diluents.
  • the pharmaceutical composition should comprise a therapeutically effective amount of the compound of the invention.
  • the exact amount required will depend upon the potency of the compound used. However in general terms the composition may comprise an amount from about 0.01 mg to about 800 mg of a compound according to the invention. In another embodiment, the amount is from about 0.01 mg to about 500 mg.
  • the amount may be an amount from about 0.01 mg to about 250 mg; preferably about 0.1 mg to about 60 mg; and more preferably about 1 mg to about 20 mg; and most preferably about 5 mg to about 10 mg.
  • the compounds of the invention may be formulated for administration alone or in combination with pharmaceutical acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutical acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed. Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonal, topical (incl. buccal and sublingual), transdermal, itracisternal, intraperitoneal, vaginal and parenteral (incl. subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
  • suitable route such as the oral, rectal, nasal, pulmonal, topical (incl. buccal and sublingual), transdermal, itracisternal, intraperitoneal, vaginal and parenteral (incl. subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
  • the oral and the transdermal routes are preferred and the oral route is most preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • the compounds are formulated for oral administration.
  • a pharmaceutical composition comprising a compound of the present invention and adapted for oral administration.
  • the present invention may provide a pharmaceutical composition comprising a compound of the present invention and adapted for oral administration, wherein the compound is compound 53 or 47 (synthesized in Example A8 or A3 below), especially compound 47.
  • compositions for oral administration may be in a solid dosage form such as capsules, tablets, dragees, pills, lozenges, powders and granules.
  • Solid dosage forms can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet- disintegrating agents.
  • the vehicle is a finely divided solid which is in admixture with the finely divided compound according to the invention.
  • the compound according to the invention is mixed with a vehicle having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the compound of the invention.
  • Suitable solid vehicles include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. .
  • the amount of solid carrier will vary widely but will usually be from about 25 to about 1000 mg.
  • solid dosage forms can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release or bolus application according to the methods well known in the art.
  • a typical tablet which may be prepared by conventional tableting techniques (e.g. by compression), may contain: Core:
  • Active compounds (as free compound or salt thereof) 5.0 to 10.0 mg
  • compositions for oral administration may alternatively be in a liquid form.
  • a liquid carrier may be in the form of solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the compound of the invention can be dissolved or suspended in a pharmaceutically acceptable liquid vehicle such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid vehicle can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • liquid vehicles for oral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • additives e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols
  • oils e.g. fractionated coconut oil and arachis oil.
  • the compounds are formulated for parenteral administration.
  • liquid compositions are used parenterally.
  • the liquid forms, and particularly the liquid vehicles discussed above may be used.
  • the vehicle can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid vehicles are useful in sterile liquid form compositions for parenteral administration.
  • Liquid pharmaceutical compositions that are sterile solutions or suspensions can be utilized for other preferred routes of administration.
  • liquids may be used for intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • the compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.
  • Vehicles include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • Suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalates, dermal patches, implants etc.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administration in one or more dosages such as one to three dosages.
  • the exact dosage will depend upon the frequency and mode of application, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant disease to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day, such as 1 to 3 times per day, contain 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, more preferred from about 0.5 to about 3000 mg, more preferably about 10 to about 1000 mg, and most preferably about 10 to about 500 mg.
  • parenteral routes such as intravenous, intrathecal, intramuscular, intra-peritoneal and similar administration
  • typically doses are in the order of about half the dose employed for oral administration.
  • the compounds of the invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is an acid addition salt of a compound having the utility of a free base.
  • a compound of the present invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the present invention with a chemical equivalent of a pharmaceutical acceptable acid, for example inorganic or organic acids. Representative examples are mentioned above.
  • Physiologically acceptable salts of a compound with a hydroxyl group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
  • solutions of the novel compounds of the present invention in sterile aqueous or non-aqueous solution aqueous propylene glycol or sesame or peanut oil may be employed.
  • aqueous solutions should be buffered if necessary and the liquid diluted first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.
  • the carrier or diluent may include any sustained release material known in the art, such as glycerol monostearate or glycerol distearate, alone or mixed with wax.
  • compositions formed by combining the novel compounds of the present invention and the pharmaceutical acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of pharmaceutical compositions according to the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules or melted solution, as a solution or suspension in an aqueous solution or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion.
  • the pharmaceutical composition of the invention may comprise a compound according to the invention in combination with one or more pharmacologically active substances (e.g. prior art agents used in the treatment of movement disorders).
  • the compounds may be used to treat conditions such as parkinsonism, dyskinesia, schizophrenia, addiction, sexual dysfunction, bipolar disorder, attention deficit hyperactivity disorder (ADHD), Tourette's syndrome, depression, anxiety, cognitive impairment (e.g. Alzheimer's disease), dementia, emesis, nausea, amnesia, autism and vertigo.
  • the compounds can also be used to treat eating, sleep, movement, obsessive/compulsive, circadian rhythm and gastric motility disorders that are accompanied with a dysfunction of the dopaminergic system.
  • Migraine, amyotropic lateral sclerosis, sleep disorder, anhedonia and restless leg syndrome may also be treated with the compounds.
  • compounds acting as receptor agonists or partial agonists may be used to treat conditions such as parkinsonism, addiction, sexual dysfunction, bipolar disorder or depression or restless leg syndrome.
  • compounds acting as receptor antagonists, inverse agonists or partial agonists may be used to treat conditions such as dyskinesia, schizophrenia, addiction, bipolar disorder, attention deficit hyperactivity disorder (ADHD), Tourette's syndrome, emesis, nausea, amnesia or obsessive/compulsive disorders.
  • ADHD attention deficit hyperactivity disorder
  • Tourette's syndrome emesis, nausea, amnesia or obsessive/compulsive disorders.
  • the compounds are used to treat movement disorders and in particular parkinsonism and restless leg syndrome.
  • the compounds may be used to treat idiopathic parkinsonism (i.e., Parkinson's disease) and also parkinsonism and/or movement disorders that develop following the treatment of schizophrenia, exposure to toxins or drugs; or head injury.
  • idiopathic parkinsonism i.e., Parkinson's disease
  • parkinsonism and/or movement disorders that develop following the treatment of schizophrenia, exposure to toxins or drugs; or head injury.
  • compounds used to treat parkinsonism are dopamine receptor agonists or partial agonists; more preferred that the compounds are agonists of the D2 or D3 receptor; and most preferred that the compounds have higher affinity for the D3 receptor.
  • the inventors have found that some compounds are short acting and others are long acting when tested in an in vivo model.
  • the inventors have found that both short and long acting dopamine receptor ligands according to the invention are useful for treating parkinsonism or for the treatment of freezing symptoms in Parkinson's disease.
  • short acting dopamine receptor ligands according to the invention are useful for treating parkinsonism or for the treatment of freezing symptoms in Parkinson's disease.
  • Preferred compounds for treating parkinsonism, or restless leg syndrome include each of the compounds 53, 47, 49 and 54 as described herein (synthesized according to Examples A8, A3, A5 and A9 respectively).
  • compounds are used to treat schizophrenia. It is preferred that compounds used to treat schizophrenia are dopamine receptor antagonists, inverse agonists, or partial agonists with low intrinsic efficacy; more preferred that the compounds are inverse agonists or antagonists at the D2 or D3 receptor; and most preferred that the compounds have higher affinity for the D3 receptor.
  • Preferred compounds for treating schizophrenia include compounds 50, 40, 41, 48, 51 and 55.
  • compounds are used to treat addiction to substances of abuse (especially alcohol, nicotine, cocaine and heroine).
  • the compounds may also be used to control abnormal eating behaviour that can rest in obesity or undernourishment (e.g. anorexia).
  • D3 receptor agonists e.g. compound 53
  • selective D3 receptor antagonists or partial agonists e.g. compound 50
  • D3 receptor stimulation e.g., dopamine receptor stimulation of the abused drug without producing undesired side effects.
  • Conditions such as obesity may be controlled with agonists and partial agonists whereas conditions such as anorexia may be controlled with inverse agonists/antagonists or, depending on efficacy, also with partial agonists.
  • compounds are used to treat sexual dysfunctions such as male erectile problems or female sexual arousal problems. It is preferred that compounds used to treat sexual dysfunctions are dopamine receptor agonists or partial agonists; more preferred that the compounds are agonists of the D2 and/or D3 receptor; and most preferred that the compounds are selective for the D3 receptor. It is preferred that the compound is short acting in vivo.
  • a preferred compound for treating sexual dysfunction is compound 54, for which in vivo data are shown in Figure 4 below (compound 54 is synthesized according to Example A9 below).
  • the inventors have found that some compounds according to the invention have an unexpectedly fast onset of action and such compounds are especially useful for the treatment of diseases/conditions when a substantially immediate effect is required.
  • Compounds that have a fast onset of action may additionally be short or long acting when tested in an in vivo model.
  • the inventors have found that compounds according to the invention having a fast onset of action are especially useful for treating parkinsonism, for the treatment of freezing symptoms in Parkinson's disease and for the treatment of sexual dysfunction.
  • Preferred compounds for treating parkinsonism, for the treatment of freezing symptoms in Parkinson's disease and for the treatment of sexual dysfunction include each of the compounds for which in vivo data is presented in Figures 1 to 7.
  • a preferred fast acting compound is compound 54 (synthesized according to Example A9 below).
  • Compounds that have a particularly long duration of action are compounds 53 and 47 (as defined in Examples A8 and A3).
  • compound 54 has a substantially constant action in vivo when administered (i.p.) at 1 and 3 mg/kg. This is advantageous because the dosage of the particular compound is not critical and high doses will not lead to overdoses, which potentially could cause undesirable effects. These advantages would be especially useful in situations where patient compliance may present a problem.
  • the amount of a compound required to treat the medical conditions is determined by biological activity and bioavailability which in turn depends on the mode of administration, the physicochemical properties of the compound employed and whether the compound is being used as a monotherapy or in a combined therapy.
  • the frequency of administration will also be influenced by the abovementioned factors and particularly the half-life of the compound within the subject being treated.
  • Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
  • a daily dose of between 0.001 ⁇ g/kg of body weight and 0.1 g/kg of body weight of a compound may be used for the treatment of Parkinson's disease. More preferably, the daily dose is between 0.01 mg/kg of body weight and 100 mg/kg of body weight.
  • Daily doses may be given as a single administration (e.g. a daily tablet for oral consumption or as a single daily injection) as discussed above.
  • the compound used may require administration twice or more times during a day.
  • compounds 47, 49 or 53, for treating Parkinson's disease may be administered as two (or more depending upon the severity of the condition) daily doses of between 5 mgs and 250 mgs in tablet form.
  • a patient receiving treatment may take a first dose upon waking and then maybe a second dose in the evening (if on a two dose regime) or at 3 or 4 hourly intervals thereafter.
  • a slow release device may be used to provide optimal doses to a patient without the need to administer repeated doses.
  • a subject receives doses of the compound as tablets for oral ingestion.
  • Such tablet may preferably comprise l-20mgs of the compound or more preferably 5-10mgs of the compound as discussed above. It will be appreciated that a clinician will be able to calculate the amount of such tablets that will be required in a day and this will depend upon the condition being treated and the severity thereof.
  • the compounds When used to treat Parkinsonism, the compounds may be administered in combination with one or more agents acting as anti-Parkinson agents.
  • anti-Parkinsonian drugs are levodopa, decarboxylase inhibitors such as carbidopa and benserazide, catechol-O- methyltransferase (COMT) inhibitors such as tolcapone and entacapone, mono-amine-oxidase (MAO) inhibitors such as tranylcypromine, pargyline and moclobemide, preferred MAO B inhibitors such as selegiline and rasagiline as well as dopamine agonist such as ergoline derivatives like bromocriptine, pergolide, dihydroergocryptine, cabergoline or compounds such as apomorphine, ropinerol, pramipexole, rotigotine, fipamezole, melevodopa, sumarinole and sarizotane and such NMDA receptor antagonists or
  • the present compounds are administered in combination with an agent acting on acetylcholine inhibitors such as rivastigmine, tacrine, donepezile and galanthamine for treating cognitive impairment.
  • an agent acting on acetylcholine inhibitors such as rivastigmine, tacrine, donepezile and galanthamine for treating cognitive impairment.
  • the present compounds are administered in combination with an agent acting on calcium channels such as nimodipine, nifedipine, felodipine, nicardipine, israpidine, diltiazem and verapamil for treating cognitive impairment.
  • an agent acting on calcium channels such as nimodipine, nifedipine, felodipine, nicardipine, israpidine, diltiazem and verapamil for treating cognitive impairment.
  • the present compounds are administered in combination with an agent acting as nootropica such as piracetam and pyritinol for treating cognitive impairment.
  • the present compounds are administered in combination with an agent acting on phosphodiesterase such as sildenafile, vardenafile and tadalafile for treating sexual dysfunction.
  • an agent acting on phosphodiesterase such as sildenafile, vardenafile and tadalafile for treating sexual dysfunction.
  • Compounds of the present invention, or pharmaceutically acceptable salts thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds.
  • the present invention provides such processes, when used to prepare a compound of the present invention, which processes are illustrated by the following representative process variants in which, unless otherwise stated, the X, Y, R 1 and R 2 groups have any of the meanings defined herein.
  • Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated, which are within the ordinary skill of an organic chemist.
  • a compound of the present invention, or a pharmaceutically acceptable salt thereof, where X is S may be prepared by the reaction of a compound of formula (A)
  • Y' represents -NH 2 and R 1 and R 2 each have any of the meanings defined herein except that any functional group is protected if necessary, with a suitable reagent to convert the -NH 2 group to a group Y as defined herein.
  • suitable reagents include hydrochloric acid, hydrobromic acid, hypophosphoric acid and sodium nitrite and would be well known to persons skilled in the art.
  • a compound of the present invention or a pharmaceutically acceptable salt thereof, where X is S and at least one of R 1 and R 2 is a group other than hydrogen as defined herein may be prepared by the reaction of a compound of formula (B), (B') or (B"):
  • the displaceable group L 1 may represent any suitable displaceable group such as a halo (for example chloro, bromo or iodo, especially bromo) or a hydroxy group.
  • a halo group especially bromo
  • the reaction is conveniently conducted in the presence of a suitable base, such as triethylamine.
  • a suitable base such as triethylamine.
  • L 1 is a hydroxy group the reaction is conveniently conducted in the presence of (cyanomethyl)trimethylphosphonium iodide and a suitable base, such as N,N-diisopropylethylamine.
  • the reaction may be conducted in the presence of a suitable inert solvent or diluent, for example propionitrile when L 1 is hydroxy, and at a suitable temperature, for example from ambient temperature to about 100 °C.
  • a compound of the present invention, or a pharmaceutically acceptable salt thereof, where X is Se or O may be prepared by the conversion of a corresponding compound of the present invention wherein X is S using conventional procedures which would be well known to a person skilled in the art.
  • R'-L 1 and R 2 -L 2 are commercially available or may be prepared using conventional procedures of organic chemistry, which would be well known to a person skilled in the art.
  • the preparation of compounds of the present invention may involve, at various stages, the addition and removal of one or more protecting groups.
  • the protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods.
  • Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • the protection and deprotection of functional groups is described in 'Protective Groups in Organic Synthesis', 2nd edition, T. W. Greene and P.G.M. Wuts, Wiley-Interscience (1991).
  • inert solvent or diluent we mean a solvent or diluent that does not react with the starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
  • Figure l is a graphical representation of the results of an in vivo study of the effect of compound 53 (synthesized in Example A8 below; i.p. administration at 1 mg/kg) on the rotational behaviour in a rat model;
  • Figure 2 is a graphical representation of the results of an in vivo study of the effect of compound 47 (synthesized in Example A3 below; i.p. administration at 1 mg/kg) on the rotational behaviour in a rat model;
  • Figure 3 is a graphical representation of the results of an in vivo study of the effect of compound 49 (synthesized in Example A5 below; i.p. administration at 1 mg/kg) on the rotational behaviour in a rat model; and
  • Figure 4 is a graphical representation of the results of an in vivo study of the effect of compound 54 (synthesized in Example A9 below; i.p. administration at 1 and 3 mg/kg) on the rotational behaviour in a rat model.
  • Figure 5 is a graphical representation of the results of an in vivo study of the effect of compound 47 (synthesized in Example A3 below; p.o. administration at 10 mg/kg) on the rotational behaviour in a rat model;
  • Figure 6 is a graphical representation of the results of an in vivo study of the effect of compound 47 (synthesized in Example A3 below; p.o. administration at 8 mg/kg) on the rotational behaviour in a rat model;
  • Figure 7 is a graphical representation of the results of an in vivo study of the effect of compound 53 (synthesized in Example A8 below; p.o. administration at 10 mg/kg) on the rotational behaviour in a rat model;
  • Compound 40 is prepared from 2C and 2-thiophen-2-yl-ethanol according to the procedure described for the preparation of compound 10 below.
  • the salt of oxalic acid is crystallized from acetonitrile.
  • Compound 47 is prepared from (IB) according to the procedure described for the preparation of 1C but without adding hypophosphoric acid.
  • a sample is crystallized as salt of oxalic acid from ethanol/diethylether.
  • Compound 48 is prepared from (IB) according to the procedure described for the preparation of 1C using hydrobromic acid (48%) as solvent and without the addition of hypophosphoric acid.
  • a sample is crystallized from acetonitrile as salt of oxalic acid.
  • Ci 1 Hi 8 N 2 OSxC 2 H 2 O 4 (calculated: C, 46.35; H, 6.37; N, 8.85; found: C, 46.12; H, 6.31; N,
  • Compound 54 is prepared from 53 using the procedure described for the preparation of compound 1C.
  • the salt of oxalic acid is crystallized from acetonitrile.
  • Compound 55 is prepared from 53 using the procedure described for the preparation of compound 1C.
  • the salt of oxalic acid is crystallized from acetonitrile.
  • Example A The compounds described in Example A were assayed to test their affinity for binding at dopamine D3 and D2 receptors
  • CHO-D 2S cells expressing the recombinant human D 2 (short) dopamine receptor gene, (Hayes, G. et al., J. MoI. Endocrinol. 1992, 6, 920-926) were grown in Dulbecco's modified Eagle's medium/nutrient mixture Fl 2 1 :1 mixture supplemented with 2 mM glutamine, 10% fetal bovine serum, and 10 ⁇ l-ml '1 penicillin/streptomycin in an atmosphere of 5% CO 2 at 37 °C (GibcoTM, Düsseldorf, Germany).
  • Human D 3 receptors stably expressed in CHO cells were used as described by Sokoloff et al. (Sokoloff, P. et al., Eur. J. Pharmacol. 1992, 225, 331-337).
  • the cell line was cultured in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, and 10% dialyzed fetal bovine serum, and were grown in an atmosphere of 5% CO 2 at 37 °C (GibcoTM).
  • each of the compounds had an affinity for both D2 and D3 receptors but had best affinity for the D3 receptor. All but Al had more than 10-fold selectivity for the D3 receptor over D2 receptors.
  • mice Male Sprague-Dawley rats weighing 290 - 350 g were used. The rats were housed in a temperature-controlled room under a 12 hour light / dark cycle with free access to food and water. Thirty minutes prior to surgery, the animals were given the monoamine oxidase-B inhibitor pargyline (5 mg/kg i.p.;) and the noradrenaline uptake inhibitor desipramine (25 mg/kg i.p.). The rats were then placed under general anaesthesia (Flourothane) and immobilised in stereotaxic frame. Following reflection of cranial skin and periostium, a small bur-hole was made in the skull on the right side and a small puncture was made in the dura mater.
  • general anaesthesia Flourothane
  • Each animal then received a unilateral injection of 2.5 ⁇ l of the neurotoxin 6- hydroxydopamine hydrobromide (6-OHDA HBr; 5 mg/ml in sterile water with 0.1% ascorbic acid; i.e. 12.5 ⁇ g 6-OHDA per rat) into the right medial forebrain bundle at stereotaxic coordinates -2.8 mm from bregma, 2 mm lateral to the midline, and 9 mm below the skull.
  • the 6-OHDA injection was made over a 5 minute period using a 5 ⁇ l Hamilton syringe.
  • the rats were allowed to recover for 3 weeks following the lesion.
  • Animals then received 0.05mg/kg s.c. apomorphine to assess the extent of lesion. Animals displaying clear rotational behaviour directed contralateral to the lesioned side were selected for further studies.
  • mice Only lesioned animals were used in the study (as determined by apomorphine rotation). Animals were administered a dose of the test compound at lmg/kg or 3mg/kg (i.p.) and rotational behaviour was assessed for up to 4 hours following drug administration using automated rotometers. Alternatively, animals were administered a dose of the test compound at 8mg/kg or 10mg/kg (p.o.) and rotational behaviour was assessed for up to 8 hours following drug administration using automated rotometers.
  • Each compound was administered to at least 5 rats.
  • Total net rotational activity This parameter is calculated as the total number of 180° rotations (net contralateral) over the duration of the experiment.
  • this in vivo model is considered to be one of the "gold standards" animal models for testing the efficacy of candidate drugs for treating movement disorders and particularly Parkinson's disease. Accordingly the inventors have demonstrated that compounds according to the invention may be used to treat medical conditions characterized by an imbalance in dopamine receptor activity and particularly parkinsonism.
  • the vertical axis on Figures 1 to 7 indicates the level of antiparkinson effect of the compounds (i.e. is a measure of dopamine receptor activation).
  • the magnitude of the antiparkinson effects demonstrated with the novel compounds are at least equivalent to what would be observed with current therapies, such as L- DOPA.
  • antiparkinson agents are related to the appearance of unwanted side-effects. The shorter the duration of action, the greater the occurrence of side effects and vice versa. Novel compounds according to the invention show a long duration of action, which is highly desirable in such agents (see Figures 1 and 2). This suggests that they would be less likely to induce side-effects, such as dyskinesias.
  • the compounds of the present invention especially when administered orally, show a long duration of action (for example of up to 8 hours). This may be advantageous to provide action for example over a period of time such as the period of a working day.
  • the compounds of the present invention when administered orally also show a surprisingly fast onset of action.
  • the compounds of the present invention may desirably be administered orally.
  • the clear reaction mixture is then concentrated under vacuum.
  • the solid residue is suspended in ethanol, heated to reflux and filtrated after cooling to room temperature.
  • the resulting residue is dried under high vacuum.
  • STEP C Preparation of propyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amine (1C) To a solution of 14.5 g (38.9 mmol) N6-propyl-4,5,6,7-tetrahydro-benzothiazole-2,6-diamine dihydrobromide (IB) in 220 mL concentrated aqueous hydrochloric acid at -30 °C is drop wise added 66.3 mL of an aqueous IN solution nitrite over the course of 30 minutes. After further stirring for 1 hour at the same temperature 5.44ml (52.5 mmol) of a 50% aqueous solution hypophosphoric acid is added.
  • IB N6-propyl-4,5,6,7-tetrahydro-benzothiazole-2,6-diamine dihydrobromide
  • the crude product obtained is purified via column chromatography on silica gel eluting with dichloromethane/methanol (98:2).
  • the methanol used is saturated with NH 3 -gas. Evaporation of the solvent yields 1.88 mmol (700 mg) of a colorless viscous oil.
  • the salt of maleic acid is crystallized from acetonitrile/diethylether.
  • STEP B 4,5,6,7-Tetrahyd ⁇ o-benzothiazole-2,6-diamine dihydrobromide (2B) is received by proceeding as described for IB from 2 A. Yield: 51%; ESI-MS: 170 (M+H + ).
  • STEP D Preparation of naphthalene-2-carboxylic acid (4-hydroxy-butyl)-amide (2D).
  • naphthalen-2-carboxylic acid chloride 43 mmol (8.2 g) naphthalen-2-carboxylic acid chloride is dissolved in 50 mL dioxane and dropwise added to a solution of 112 mmol (10.0 g) 4-amino-butan-l-ol in 100 mL dioxane and stirred overnight at room temperature. The mixture is then poured into 200 mL of ice water and filtrated. The white solid separated is dried under vacuum.
  • STEP E Naphthalene-2-carboxylic acid (4-oxo-butyl)-amide (2E) is prepared analogously to IE starting with 2D.
  • STEP F Compound 2 is prepared analogously to 1 from 2C and 2E.
  • An example is crystallized as salt of oxalic acid from methanol/diethylether.
  • STEP B N6-Ethyl-4,5,6,7-tetrahydro-benzothiazole-2,6-diamine dihydrobromide (4B) is prepared from 4 A analogously to IB.
  • STEP D Compound 4 is prepared from 2E and 4C as described for 1.
  • the salt of oxalic acid is crystallized from ethanol/diethylether.

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Abstract

L'invention concerne un composé représenté par la formule (I), dans laquelle X, Y, R1 et R2 sont tels que définis dans la description, ces composés étant destinés à être utilisés pour le traitement d'états pathologiques caractérisés par un déséquilibre de l'activité des récepteurs dopaminergiques.
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WO2010025235A1 (fr) * 2008-08-29 2010-03-04 Regents Of The University Of Michigan Ligands sélectifs du récepteur dopaminergique 3 (d<sb>3</sb>) et procédés pour les utiliser
US20150289558A1 (en) * 2010-10-29 2015-10-15 Fiedler & Lundgren Ab Method and apparatus for introducing additives to smokeless tobacco products

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US20150289558A1 (en) * 2010-10-29 2015-10-15 Fiedler & Lundgren Ab Method and apparatus for introducing additives to smokeless tobacco products

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