WO2009056811A2

WO2009056811A2 - Medicaments

Info

Publication number: WO2009056811A2
Application number: PCT/GB2008/003643
Authority: WO
Inventors: Holger Stark; Jukka Matti Leppanen; Britta Caroline Sasse; Oliver Saur; Tim Kottke; Michael Peter Hill
Original assignee: Motac Neuroscience Ltd
Current assignee: Motac Neuroscience Ltd
Priority date: 2007-10-31
Filing date: 2008-10-28
Publication date: 2009-05-07
Anticipated expiration: 2010-04-30
Also published as: WO2009056811A3; GB0721333D0

Abstract

A compound of the following formula is described (I), wherein X, Y, R1 and R are as defined in the text and wherein the compounds are intended for use in treating medical conditions characterized by an imbalance in dopamine receptor activity.

Description

MEDICAMENTS

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 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.

There are a number of medicaments available for the treatment of movement disorders and these include agents such as apomorphine, cabergoline or bromocriptine. However the "main stay" of current therapies for movement disorders such as Parkinson's disease are based around the use of Levodopa and other agonists of dopamine receptors.

Levodopa (or L-DOPA) is based on an aromatic amino acid and has the chemical name: (-)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic acid. L-DOPA has the molecular formula C₉H₁]NO₄ and a molecular weight of 197.2. Chemically, 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-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Carbidopa has the empirical formula CioHi₄N₂0₄ ^»H₂0 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 C₁₆H₂₄N₂O 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.

One common problem is that dyskinesias can arise is as a side-effect of dopamine replacement therapy. 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). 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.

Another problem associated with dopamine-replacement agents (e.g. L-DOPA and dopamine receptor agonists) is the "wearing-off ' of the antiparkinsonian efficacy of the treatment.

Other problems associated with 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. A number of subtypes of dopamine receptor exist and they can be divided into two main groups. 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. At the same time, 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 (especially alcohol, nicotine, cocaine and heroine) is associated with abnormalities in the limbic system. Given the relatively high concentration of dopamine D3 receptors in the limbic system, it is postulated that 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). In this respect, it will also be appreciated that abusive food and drink consumption may be associated with imbalances in the limbic system and comparable changes in dopamine neurotransmitter cross-talk. Accordingly selective dopamine D3 receptor ligands may also be useful for helping to control obesity or under-eating (anorexia).

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.

It will be appreciated that all of the abovementioned conditions, as well as any other conditions associated with an imbalance in dopamine receptor activity, may be treated with selective dopamine D3 receptor ligands. A number of steps have been taken to develop dopamine D3 receptor ligands for use by clinicians.

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 CioHi₇N₃S-2HCl H₂0 and a molecular weight of 302.27. The structural formula of pramipexole dihydrochloride is:

A structure closely related to pramipexole is described and named as "etrabamine" and has the structural formula:

However 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.

US-4,208,420 discloses benzo[d]thiazole derivatives, processes for their preparation and their use in therapeutic applications.

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.

US-7,049,337 discloses N-(2'-propynyl)-substituted 2-aminotetralin compounds and their use in treating central nervous system disorders.

Biswas, S. et al., J. Med. Chem., 2008, 51(10), 3005-3019 discloses heterocyclic bioisosteric analogues of 7-{[2-(4-phenyl-piperazin-l-yl)ethyl]propylamino}-5,6,7,8- tetrahydronaphthalen-2-ol and their use as agonists for dopamine D3 receptor.

None of the aforementioned prior art documents discloses a compound as defined in the claims of the present application.

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

R¹ and R² 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 R¹ and R² are not H and methyl respectively; and subject to the proviso that when X is S then Y is not -NH₂.

More particularly, according to the present invention, there is provided a compound of formula:

wherein

R¹ and R² 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 R¹ and R² 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 -NH₂, methyl, or methyl substituted by l-(4-chlorophenyl)urea; and subject to the proviso that when X is S and Y is propyl, isopropyl or butyl, then R¹ and R² are not H and methyl respectively.

The references in the above provisos refer to the specific alkyl groups listed, i.e. which are unsubstituted unless otherwise stated.

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.

In the subject 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. In the practice of this invention the "pharmaceutically acceptable vehicle" is any physiological vehicle known to those of ordinary skill in the art useful in formulating pharmaceutical compositions.

Compounds according to the invention

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).

Nature of X

As mentioned above, X may be any appropriate bivalent heteroatom. Preferably 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.

Nature of Y

Y may comprise a number of molecular constituents as defined herein.

In the compounds of the present invention, 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. In particular, when X is S then Y is not -NH₂, methyl, or methyl substituted by 1 -(4-chlorophenyl)urea.

In this specification, unless otherwise indicated, the term "alkyl" when used alone or in combination, includes both straight chain and branched chain alkyl groups, such as propyl, isopropyl and tert-butyl. However, 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-C₄ 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 sulfanyl group, a thio group, a disulfanyl group, a selenocarboxy group, a selenyl group, a seleno group, an amidino group, a cyano group, an isocyano group, an amino group, an imino group, an azido group, an azo group, a hydrazino group, a phosphino group, a phospho group, and derivatives thereof.

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. Preferably 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 group, a phospho group, and derivatives thereof. For example, 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.

Alternatively 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. Preferably 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. For example, 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.

As a further alternative 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. Preferably the first substituent is selected from the group consisting of a selenocarboxy group, a selenyl group, a seleno group and derivatives thereof.

Moreover, 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. Preferably 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. For example, 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. Preferably the first substituent is selected from the group consisting of a phosphino group, a phosphono group, a phospho group, and derivatives thereof.

Furthermore, 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. Where 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. It is particularly preferred that 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. Where 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. For example, 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. For example, 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.

Alternatively 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. For example, 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.

In a preferred embodiment of the compound of the present invention, 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 unsubstituted alkoxy, substituted or unsubstituted amino, halo, and substituted or unsubstituted thio.

In another embodiment, Y may be selected from the group consisting of a substituted or unsubstituted Ci-C₄ alkyl, alkenyl, alkynyl or alkoxy group.

In another preferred embodiment of the compound of the present invention 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.

In another preferred embodiment of the compound of the present invention 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.

In still further preferred embodiment of the compound of the present invention 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.

It is preferred that Y is selected from the group consisting of H, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, halo, and substituted or unsubstituted thio. For example, Y may be selected from the group consisting of H, chloro, bromo, methoxy, ethoxy, -NH₂ and methylthio, especially selected from the group consisting of chloro, bromo, methoxy, ethoxy, -NH₂ and methylthio.

It is further preferred that 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 I₅ most preferably Cl or Br.

Nature of R¹ and R²

In the compounds of the present invention, R¹ and R² 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. In particular, when X is S and Y is H, then R¹ and R² 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 R¹ and R² are not H and methyl respectively.

R¹ and R² may take the same pattern of substitution, or R¹ and R² may take different patterns of substitution. As stated above, R¹ and/or R² may be a carbocyclic or heterocyclic moiety. It is preferred that one of R¹ and R² is a second substituted or unsubstituted alkyl, alkenyl, alkynyl or alkoxy group. In a preferred embodiment the other of R¹ and R² is hydrogen. Alternatively, in a further preferred embodiment the other of R¹ and R² is a third substituted or unsubstituted alkyl, alkenyl, alkynyl or alkoxy (especially alkyl) group. Alternatively, in a further preferred embodiment the other of R¹ and R² 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 - C₄ substituted or unsubstituted alkyl, alkenyl, alkynyl or alkoxy (especially alkyl) group.

Preferably 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, a thiono group, a sulfanyl group, a thio group, a disulfanyl group, a selenocarboxy group, a selenyl group, a seleno group, an amidino group, a cyano group, an isocyano group, an amino group, an imino group, an azido group, an azo group, a hydrazino group, a phosphino group, and derivatives thereof.

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. Preferably 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 group, a phosphono group, a phospho group, and derivatives thereof. For example, 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.

Alternatively 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. Preferably 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. For example, 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.

As a further alternative 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. Preferably 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. Preferably 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. For example, 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.

Moreover, 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. Preferably 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.

In a preferred embodiment 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 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. For example, 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.

Alternatively, 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. For example, 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.

As a further alternative, 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. For example, 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.

As a further alternative, said substituted or unsubstituted heterocyclic group may be a thiophenyl group, especially an unsubstituted thiophenyl group.

In a further preferred embodiment of the present invention R¹ and/or R² represents a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group. In this case, the R¹ and/or R² 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. Moreover, in the case when R¹ and/or R² represents a substituted or unsubstituted heterocyclic group, 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 R¹ and R² are not H and Ci-C₃ (for example Ci-C₃) alkyl respectively.

In a first preferred embodiment of the present invention X is Se and the compound has the formula:

wherein each of Y, R¹ and R² is as defined above.

In the first preferred embodiment 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 -NH₂). 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)-C₄ alkyl, alkenyl, alkynyl, alkoxy or alkylthio group. It is particularly preferred that Y is H or a primary amino group.

Additionally or alternatively, in the first preferred embodiment, one of R¹ and R² is preferably a hydrogen atom and the other of R¹ 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-C₄ alkyl group, such as an ethyl group or a propyl group.

In a second more preferred embodiment of the present invention X is S and the compound has the formula:

wherein each of Y, R¹ and R² is as defined above.

In the second preferred embodiment 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. More particularly, 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. In another aspect, Y may be selected from the group consisting of H, substituted or unsubstituted alkoxy, halo, and substituted or unsubstituted thio. With regard to the second preferred embodiment it is preferred that Y is a halo group, most preferably a Cl group, or an alkoxy group, such as a C₁-C₄ alkoxy group and most preferably a methoxy group.

Additionally or alternatively, with respect to the second preferred embodiment, one of R¹ and R² is preferably a hydrogen atom and the other of R¹ and R² 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-C₄ alkyl group, and most preferably a propyl group.

The most preferred compounds have X as S; Y as H or -OCH₃; and R¹ and/or R² as lower alkyl, alkenyl or alkynyl with less than 12 carbon atoms in total for both R¹ and R .

In one aspect, in the second preferred embodiment, when Y is H, then R¹ 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 C₁-C₄ alkyl group, and most preferably a propyl group, and R² 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 C₁-C₄ alkyl group, and most preferably an ethyl group and wherein the substituted may be any substituted as defined herein. In particular in this aspect, R² may be a substituted Cj-C₄ 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).

In a third preferred embodiment of the present invention X is O and the compound has the formula:

wherein each of Y, R¹ and R² is as defined above. In the third preferred embodiment 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 -NH₂.

Additionally or alternatively, in the third preferred embodiment, one of R¹ and R² is preferably a hydrogen atom and the other of R¹ and R² 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-C₄ 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-benzothiazol-6-yl)-propyl-amine; N6-ethyl-4,5,6,7-tetrahydro-benzoselenazole-2,6-diamine dihydrobromide; (2-chloro-4,5,6,7-tetrahydro-benzoselenazol-6-yl)-ethyl-amine; ethyl-(4,5,6,7-tetrahydro-benzoselenazol-6-yl)-amine; and N⁶-propyl-4,5,6,7-tetrahydrobenzo[d][l,3]oxazole-2,6-diamine; or a pharmaceutically-acceptable salt thereof.

A further aspect of the present invention provides a compound (53), synthesised in Example A8 below, having the formula:

(53)

A further aspect of the present invention provides a compound (47), synthesised in Example A3 below, having the formula: H

(47)

A further aspect of the present invention provides a compound (49), synthesised in Example A5 below, having the formula:

(49)

A further aspect of the present invention provides a compound (54), synthesised in Example A9 below, having the formula:

(54)

A further aspect of the present invention provides a compound (11), synthesised in Example Al l below, having the formula:

(H)

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.

Some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms, which the compounds are able to form, are included within the scope of the present 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. Representative examples of 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. Further examples of pharmaceutically acceptable inorganic and organic acid addition salts 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. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium, alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salt and the like.

Also intended as pharmaceutically acceptable acid addition are the hydrates, which the present compounds are able to form. The acid addition may be obtained as direct products of compound synthesis. In the alternative, 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. In general, such 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. Such 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. Preferably, the compounds according to the invention bind to dopamine receptor subtypes with a Kj value for binding of less than 10 μM, more preferred of less than 1 μM, and even more preferred of less than 500 nM, and most preferably of less than 100 nM. A skilled person will appreciate how to determine Kj values for dopamine receptor binding and preferred methods are described in the Examples.

It is preferred that 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.

It is preferred that 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.

Compounds of the present invention, when compared to pramipexole or etrabamine, have improved pharmacokinetic properties and fewer side-effects. Preferred compounds (see the figures and particularly Fig 4 (compound 54)) 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) have sustained activity over a number of hours following oral or intra-peritoneal application. For instance activity may be sustained over at least lhour, preferably over at least 2 hours and more preferably over at least 4 hours. Some preferred compounds have a rapid onset of activity and also have a sustained effect (e.g. compound 47).

It is also preferred that 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 IC₅₀ values are in the micromolar range. It is preferred that IC₅o values are less than lOOμM, preferably less than 10 μM, more preferably of less than 1 μM, and even more preferably of less than 500 nM, and most preferably of less than 100 nM. A skilled person will appreciate that a number of models exist for testing the efficacy of compounds for treating medical conditions characterized by an imbalance in dopamine receptor activity. For instance 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. When the compound is compound 53 (synthesized in Example AlO below) 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.

The pharmaceutical 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. 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. In a preferred embodiment of the invention the compounds are formulated for oral administration. Thus, according to the present invention there is provided a pharmaceutical composition comprising a compound of the present invention and adapted for oral administration. In particular, 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.

Pharmaceutical 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. In powders, the vehicle is a finely divided solid which is in admixture with the finely divided compound according to the invention. In tablets, 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.

Where appropriate, 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

Lactosum Ph. Eur. 67.8 mg

Cellulose, microcryst. (Avicel) 31.4 mg

Amberlite® IRP88* 1.0 mg

Magnesii stearas Ph. Eur. q.s.

Coating:

Hydroxypropyl methylcellulose approx. 9 mg

Mywacett 9-40 T** approx. 0.9 mg

* Polacrillin potassium NF, Tablet disintegrant, Rohm and Haas ** Acylated monoglyceride used as plasticizer for fil coating

Pharmaceutical 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. Suitable examples of 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).

In another embodiment of the invention the compounds are formulated for parenteral administration.

Preferably liquid compositions are used parenterally. When this is the case the liquid forms, and particularly the liquid vehicles discussed above may be used. Furthermore, for parenteral administration, 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. For example, 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.

Other 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.

The pharmaceutical composition according to the invention may conveniently be presented in unit dosage form by methods known 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.

For 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. When 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.

For parenteral administration, 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. Such 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. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, 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.

The pharmaceutical 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. If desired, 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).

Uses of compounds, compositions and medicaments according to the invention

A skilled person will appreciate that many conditions are associated with an imbalance in dopamine receptor activity. Such conditions may be treated according to the invention.

The compounds may 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.

In one embodiment of the invention, 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.

In another embodiment of the invention, 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.

In a preferred embodiment of the invention 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. It is preferred that 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. In particular, 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).

In another preferred embodiment of the invention that 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.

In another preferred embodiment of the invention that 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).

Compounds that are D3 receptor agonists (e.g. compound 53) may be used in substitute therapy (in place of a substance of abuse) whereas selective D3 receptor antagonists or partial agonists (e.g. compound 50) may be used to attenuate the 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.

In another preferred embodiment of the invention that 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).

The inventors have found that some compounds according to the invention have an unexpectedly long duration of action and such compounds are especially useful for minimising the number and frequency of doses required. Compounds that have a particularly long duration of action (for example of up to about 2 hours, especially of up to about 8 hours) are compounds 53 and 47 (as defined in Examples A8 and A3).

The inventors have found that some compounds according to the invention have a substantially constant action even at increasing doses of the compound. For example, as shown in Figure 4, 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.

It will be appreciated that 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.

Generally, a daily dose of between 0.001 μg/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. Alternatively, the compound used may require administration twice or more times during a day. As an example, 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. Alternatively, a slow release device may be used to provide optimal doses to a patient without the need to administer repeated doses.

It is most preferred that 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.

When used to treat Parkinsonism, the compounds may be administered in combination with one or more agents acting as anti-Parkinson agents. Examples of 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 modulators such as amantadine, memantine and budipine.

In another embodiment of the invention 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.

In another embodiment of the invention 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.

In another embodiment of the invention the present compounds are administered in combination with an agent acting as nootropica such as piracetam and pyritinol for treating cognitive impairment.

In another embodiment of the invention the present compounds are administered in combination with an agent acting on phosphodiesterase such as sildenafile, vardenafile and tadalafile for treating sexual dysfunction.

Preparation of the Compounds according to the Invention

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, R¹ and R² 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.

For example, 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)

R¹

N^~^ (A) wherein Y' represents -NH₂ and R¹ and R² each have any of the meanings defined herein except that any functional group is protected if necessary, with a suitable reagent to convert the -NH₂ group to a group Y as defined herein. For example, suitable reagents include hydrochloric acid, hydrobromic acid, hypophosphoric acid and sodium nitrite and would be well known to persons skilled in the art.

For example, a compound of the present invention, or a pharmaceutically acceptable salt thereof, where X is S and at least one of R¹ and R² is a group other than hydrogen as defined herein may be prepared by the reaction of a compound of formula (B), (B') or (B"):

(B')

wherein Y, R¹ and R² each have any of the meanings defined herein except that any functional group is protected if necessary, with a compound of formula R'-L¹ or R²-L², wherein R¹ and R² each have any of the meanings defined herein and L¹ is a suitable displaceable group except that any functional group is protected if necessary.

The displaceable group L¹ may represent any suitable displaceable group such as a halo (for example chloro, bromo or iodo, especially bromo) or a hydroxy group. When L¹ is a halo group (especially bromo), the reaction is conveniently conducted in the presence of a suitable base, such as triethylamine. When L¹ 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 L¹ 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.

Compounds of the present invention, or pharmaceutically-acceptable salts thereof, may be further prepared by:

(i) converting a compound of formula (I) into another compound of formula (I); and/or (ii) removing any protecting group that is present (by conventional means); and/or (iii) forming a pharmaceutically acceptable salt.

Compounds of Formula (A), (B), (B'), (B"), R'-L¹ and R²-L² 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.

As the skilled person would appreciate, 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).

As the skilled person would appreciate, by the term "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.

As a person skilled in the art would appreciate, in order to obtain compounds of the present invention in an alternative and possibly more convenient manner, the individual process steps mentioned hereinbefore may be performed in a different order and/or the individual reactions may be performed at different stage in the overall route.

The invention is illustrated with reference to the following non-limiting Examples and accompanying drawings, in which:

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;

EXAMPLES

EXAMPLE A

The inventors synthesized 11 compounds according to the present invention by employing the methods set out below in Examples Al to Al l with reference, where appropriate, to methods described in the Synthetic Methods section which follows.

EXAMPLE Al

4,5,6,7-Tetrahydro-benzothiazol-6-yl)-(2-thiophen-2-yl-ethyl)-amine (40)

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.

Yield: 31%; ESI-MS: 265 (M+H⁺); mp: 183 ⁰C; formula: Ci₃Hi₆N₂S₂XC₂H₂O₄ (calculated: C, 50.83; H, 5.12; N, 7.90; found: C, 50.61; H, 5.15; N, 7.94).

EXAMPLE A2

Propyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-(2-thiophen-2-yl-ethyl)-amine (41) Compound 41 is prepared from 1C and 2-thiophen-2-yl-ethanol according to the procedure described for the preparation of compound 10 below. The salt of maleic acid is crystallized from acetonitrile.

Yield: 16%; ESI-MS: 307 (M+H⁺); mp: 88 °C; formula: C₁₆H₂₂N₂S₂X 1.25C₄H₄O₄ (calculated: C, 55.85; H, 6.03; N, 6.20; found: C, 55.77; H, 6.15; N, 6.13).

EXAMPLE A3

2-Chloro-4,5,6,7-tetrahydro-benzothiazol-6-yl)-propyl-amine (47)

Compound 47 is prepared from (IB) according to the procedure described for the preparation of 1C but without adding hypophosphoric acid.

Yield: 32%; ESI-MS: 231 (M+H⁺, 100), 233 (M+H⁺, 36).

A sample is crystallized as salt of oxalic acid from ethanol/diethylether.

Mp: 168 °C; formula: C₁₀Hi₅ClN₂SχC₂H₂O₄x0.5H₂O (calculated: C, 43.70; H, 5.50; N, 8.49; found: C, 43.41; H, 5.23; N, 8.53).

EXAMPLE A4

2-Bromo-4,5,6,7-tetrahydro-benzothiazol-6-yl)-propyl-amine (48)

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.

Yield: 39%; ESI-MS: 275 (M+H⁺, 97), 277 (M+H⁺, 100).

A sample is crystallized from acetonitrile as salt of oxalic acid.

Mp: 174.5 ⁰C; formula: C₁₀Hi₅BrN₂SxC₂H₂O₄ (calculated: C, 39.46; H, 4.69; N, 7.67; found:

C, 39.73; H, 4.59; N, 7.44).

EXAMPLE A5

2-Methoxy-4,5 ,6,7-tetrahydro-benzothiazol-6-yl)-propyl-amine (49)

1.31 g (5.7 mmol) of the crude product 47 (about 50% purity according to TLC) is dissolved in a solution of 0.32 g (6 mmol) sodium methylate in 12 mL dry methanol. The mixture is heated to reflux for 2 hours and then stirred at ambient temperature overnight. After evaporation of the solvent the crude product is purified via column chromatography using dichloromethane/ammonia saturated methanol 97:3. The salt of oxalic acid is crystallized from ethanol/diethylether.

Yield: 10%; ESI-MS: 184 (C₈Hi₀NOS⁺, 31), 227 (M+H⁺, 100); mp: 142 °C; formula:

Ci₁Hi₈N₂OSxC₂H₂O₄ (calculated: C, 46.35; H, 6.37; N, 8.85; found: C, 46.12; H, 6.31; N,

8.74).

EXAMPLE A6

2-Methylsulfanyl-4,5,6,7-tetrahydro-benzothiazol-6-yl)-propyl-amine (50)

A mixture of 1.27 g (4.63 mmol) 48, 1.27 g (18.2 mmol) sodium methanethiolate and 20 mL dioxane is heated to reflux for 3 hours, hydrolysed with water and extracted three times with dichloromethane. The combined organic phases are dried with sodium sulphate, and the solvent is evaporated in vacuum. The salt of oxalic acid is crystallized from acetonitrile. Yield: 74%; ESI-MS: 184 (C₈H₁₀NS₂ ⁺, 32), 243 (M+H⁺, 100); mp: 176.5 °C; formula: C_nH₁₈N₂S₂XC₂H₂O₄ (calculated: C, 46.97; H, 6.06; N, 8.43; found: C, 46.74; H, 5.82; N, 8.19).

EXAMPLE A7

2-Ethoxy-4,5,6,7-tetrahydro-benzothiazol-6-yl)-propyl-amine (51)

A piece of 3.0 g (130 mmol) sodium is dissolved in 70 mL dry ethanol, 1.18 g (5.1 mmol) 47 is added, and the mixture is heated to reflux for 2 hours and then stirred overnight at room temperature. Ethanol is evaporated. Water is added to the resulting residue, and the mixture is extracted with dichloromethane. The combined organic extracts are dried with sodium sulfate and evaporated in vacuum. The crude product is purified via column chromatography. Eluent is dichloromethane/ammonia saturated methanol 97:3. The salt of oxalic acid is crystallized from acetonitrile.

Yield: 41%; ESI-MS: 241 (M+H⁺); mp: 153.5 °C; formula: C_I2H₂₀N₂OSXC₂H₂O₄ (calculated: C, 50.89; H, 6.71; N, 8.48; found: C, 50.77; H, 6.61; N, 8.41).

EXAMPLE A8

N6-Ethyl-4,5,6,7-tetrahydro-benzoselenazole-2,6-diamine dihydrobromide (53) Compound 53 is prepared from 4A and selenourea according to the procedure described for the preparation of compound IB. Differing from the mentioned procedure the reaction mixture is filtrated before evaporating the hydrobromic acid.

Yield: 63%; ESI-MS: 199 (35), 201 (71), 244 (M+H⁺, 50), 246 (M+H⁺, 100); mp: 291 ⁰C; formula: C₉Hi₅N₃Sex2HBr (calculated: C, 26.62; H, 4.22; N, 10.35; found: C, 26.74; H, 4.01; N, 10.09).

EXAMPLE A9

2-Chloro-4,5,6,7-tetrahydro-benzoselenazol-6-yl)-ethyl-amine (54)

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.

Yield: 12%; ESI-MS: 263 (M+H⁺, 44), 265 (M+H⁺, 100), 267 (M+H⁺, 43); mp: 161 °C; formula: C₉Hi₃ClN₂SeXC₂H₂O₄ (calculated: C, 37.36; H, 4.28; N, 7.92; found: C, 37.41; H, 4.40; N, 7.67).

EXAMPLE AlO

Ethyl-(4,5,6,7-tetrahydro-benzoselenazol-6-yl)-amine (55)

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.

Yield: 5%; ESI-MS: 229 (M+H⁺, 48), 231 (M+H⁺, 100), 233 (M-HH⁺, 18); mp: 161 °C; formula: C₉H₁₄N₂SeXC₂H₂O₄ (calculated: C, 41.39; H, 5.05; N, 8.78; found: C, 41.28; H, 5.23; N, 8.78).

EXAMPLE All

Λ^-Propyl^^_jό^-tetrahydrobenzofd] [ 1 ,3]oxazole-2,6-diamine (11)

2.33 g (15 mmol) of IB are dissolved in 35 ml of chloroform. Under ice-cooling 0.75 ml of bromine are added. After a few minutes the dark solution discolourates and the solvent is removed in vacuum. Without further purification the pale remainder is dissolved in dry isopropylic alcohol (10 ml) and 3.60 g (60 mmol) of urea are added. The mixture is refluxed for 3 hours, cooled to room temperature, alkalized with aqueous sodium hydroxide (IM), extracted with dichloromethane/isopropylic alcohol (4:1), dried (Na₂SO₄) and purified via column chromatography and recrystallisation in dichloromethane.

Yield: 3%; ESI-MS: 196 (M+H⁺, 100), 197 (12); mp: 126 °C; formula: C₁₀H_nN₃O

(calculated: C, 61,51; H, 8,78; N, 21,52; found: C, 61,59; H, 8,59; N, 21,42).

EXAMPLE B: Receptor Binding Assays

The compounds described in Example A were assayed to test their affinity for binding at dopamine D3 and D2 receptors

METHODS: Dopamine D2_S and D ₃ Receptor Binding Assays

Cell culture

CHO-D_2S cells, expressing the recombinant human D₂(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 μl-ml^'1 penicillin/streptomycin in an atmosphere of 5% CO₂ at 37 °C (Gibco™, Karlsruhe, Germany).

Human D₃ 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% CO₂ at 37 °C (Gibco™).

Membrane Preparation

Human D₂s- and D₃ receptors expressing cell lines were grown to confluence. The medium was removed, and the cells were washed with 10 ml PBS buffer (140 mM NaCl, 3 mM KCl, 1.5 mM KH₂PO₄, 8 mM Na₂HPO₄, pH 7.4) at 4 °C. After removing the wash buffer, the cells were scraped from the flasks into 15 ml of ice-cold media, and centrifuged at 3,000 rpm for 10 min at 4 °C. After centrifugation the medium was removed and the supernatant resuspended in ice-cold Tris-HCl buffer containing 5 mM MgCl₂, pH 7.4 and disrupted with a Polytron and centrifuged at 20,000 rpm, for 30 min at 4 °C. The pellet was resuspended by sonication in ice-cold Tris-HCl buffer (containing 5 mM MgCl₂, pH 7.4), membrane aliquots were stored at -70 ⁰C. Determination of membrane protein was carried out by the method of Bradford (Bradford, M. M. Anal Biochem 1976, 72, 248-54). Membrane binding assays

Cell membranes containing human D₂s and D₃ receptors from CHO cells were thawed, rehomogenized with sonication at 4 °C in Tris-HCl, pH 7.4 containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂ and 1 mM MgCl₂ (incubation buffer), and incubated with 0.2 nM [³H]spiperone (106 Ci mmoi^"1, Amersham Biosciences, Freiburg, Germany), and drug diluted in incubation buffer. Non-specific binding was determined in the presence of 10 μM BP 897 ((Wermuth, C. G. et al. in Chem. Abstr. (Eur. Pat. 0779284, 1997)). Incubations were run at 25 ⁰C for 120 min, and terminated by rapid filtration through PerkinElmer GF/B glass fibre filters (PerkinElmer Life Sciences, Rodgau, Germany) coated in 0.3% polyethylenimine (Sigma-Aldrich, Taufkirchen, Germany) using an Inotech cell harvester (Inotech AG, Dottikon, Switzerland). Unbound radioligand was removed with four washes of 1 ml of ice- cold 50 mM Tris-HCl buffer, pH 7.4, containing 120 mM NaCl. The filters were soaked in 9 ml Beta plate scint scintillator and counted using a PerkinElmer MicroBeta^®Trilux scintillation counter (PerkinElmer Life Sciences). Competition binding data were analyzed by the software GraphPad Prism™ (2000, version 3.02, San Diego, CA, USA), using non-linear least squares fit. For detailed screening the compounds have been tested at seven concentrations in triplicate carrying out three to five separate binding experiments for human dopamine D₂s and for human dopamine D₃ receptors and expressed as mean ± standard error of the mean (SEM). K_\ values were calculated from the /C₅₀ values according to Cheng- Prusoff equation (Cheng, Y.C., Prusoff, W.H. Biochem. Pharmacol. 1973, 22, 3099-3108.).

RESULTS:

The Table below provides the results of the binding assay described above.

These data demonstrate that compounds according to the invention have affinity for dopamine receptors.

It will be appreciated that 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.

EXAMPLE C: In vivo Testing

In vivo tests were conducted to examine the efficacy of compounds according to the invention in a functional assay of dopaminergic receptor activation.

METHODS

Preparation of 6-OHDA-lesioned rat model of Parkinson's disease

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. Each animal then received a unilateral injection of 2.5 μl of the neurotoxin 6- hydroxydopamine hydrobromide (6-OHDA HBr; 5 mg/ml in sterile water with 0.1% ascorbic acid; i.e. 12.5μg 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 μl 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.

Study design

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.

Analysis of parametric data

Total net rotational activity. This parameter is calculated as the total number of 180° rotations (net contralateral) over the duration of the experiment.

Data were analysed independently for each novel compound with appropriate parametric statistics. All tests were carried out in Graphpad Prism Version 3.

RESULTS

Compounds according to the invention, which were acting as dopamine receptor agonists, were able to induce rotational activity in animals and thereby reverse the parkinsonism induced by the lesions. The effect of the compounds was significant when compared to control animals (data not shown).

A skilled person will appreciate that 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.

Illustrative results for compounds 53, 47, 49 and 54 (i.p.) are presented below in Figures 1 to 4 respectively. Illustrative results for compounds 53 and 47 (p.o.) are presented below in Figures 5 to 7 respectively.

The vertical axis on Figures 1 to 7 (rotations) 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 (administration by i.p. and p.o.) are at least equivalent to what would be observed with current therapies, such as L- DOPA.

It is well known that increasing the level of L-DOPA therapy is associated with hyperactivity and the occurrence of side-effects, such as dyskinesias and hallucinations. Surprisingly, for novel compounds according to the present invention, increasing the dose administered did not lead to a corresponding increase in activity (e.g. Figure 4). This indicates that the compounds will not have the unwanted side-effects associated with known agents such as L-DOPA which cause much higher rotational activity as their dose increases. Additionally, this means that the compounds according to the invention are less "dose- critical" than known agents such as L-DOPA.

It is also well known that the duration of action of antiparkinson agents is 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.

In particular, 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. Thus, the compounds of the present invention may desirably be administered orally.

SYNTHETIC METHODS

The following methods were used to synthesise compounds which were used in the synthesis of compounds according to the present invention as described above in Examples Al to Al l.

SYNTHESIS OF COMPOUND 1

N-{4-[Propyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amino]-butyl}-benzamide (l) STEP A: Preparation of (l,4-Dioxa-spiro[4.5]dec-8-yl)-propyl-amine (IA) To a solution of 9.36 g (60 mmol) 1 ,4-cyclohexanedione monoethylene acetal in 60 mL of methanol and 9.84 mL (120 mmol) of propylamine is added 0.6 g of palladium on carbon (10%). The mixture is stirred overnight under 4 bar hydrogen pressure. Filtration over Celite and concentration in vacuum provides the crude product in almost quantitative yield. ESI-MS: 141 (12), 200 (M+H⁺, 100).

STEP B: Preparation of N6-propyl-4,5,6,7-tetrahydro-benzothiazole-2,6-diamine dihydrobromide (IB)

A solution of 12.0 g (60 mmol) (l,4-dioxa-spiro[4.5]dec-8-yl)-propyl-amine (IA) in 120 mL concentrated aqueous hydrobromic acid is stirred for 15 minutes at room temperature and then

3.12 mL (60 mmol) bromine are added. After further stirring for 15 minutes 4.56 g (60 mmol) of thiourea is added. The resulting solution is stirred for another at room temperature until a white precipitation can be observed. Afterwards the mixture is heated for 2 hours at 90 °C.

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.

Yield: 65%; ESI-MS: 153 (57), 212 (M+H⁺, 100).

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. The reaction mixture is stored at 4 °C overnight. After having cooled down the solution again to -30 ⁰C the mixture is slowly basified with 40% aqueous sodium hydroxide solution while temperature is kept at -30 ⁰C. The resulting mixture is warmed up to room temperature and extracted with Chloroform/Ethanol 5:1 (3 x 250 mL). The solution is dried over anhydrous sodium sulfate and concentrated in vacuum. The brown oil obtained is chromatographed over silica gel, eluting with dichloromethane/methanol 97:3 under ammonia atmosphere. Yield: 66%; ESI-MS: 197 (M+H⁺). STEP D: Preparation of N-(4-hydroxy-butyl)-benzamide (ID)

A solution of 1.16 mL (10 mmol) of benzoylchloride in 10 mL dichloromethane is added to

0.93 mL (10 mmol) of 4-amino-butan-l-ol and 4.2 mL (30 mmol) of triethylamine dissolved in 50 mL of dichloromethane. The mixture is stirred overnight. 50 mL of saturated sodium carbonate solution is added. The organic phase is separated, dried with sodium sulfate and the solvent evaporated.

Yield: 64%; ESI-MS: 120 (43), 192 (M+H⁺).

STEP E: Preparation of N-(4-oxo-butyl)-benzamide (IE)

A solution of 0.95 mL (11 mmol) oxalyl chloride in 30 mL of dichloromethane is cooled to - 80 °C under argon atmosphere. 2 mL (28 mmol) of dimethylsulfoxide in 8 mL of dichloromethane is introduced dropwise over 10 minutes. After 5 minutes a solution of 1.16 g (6 mmol) 10 in 8 mL dichloromethane and 2 mL dimethylsulfoxide is added over the course of 10 minutes. The reaction mixture is stirred for another hour at -80 ⁰C before 5 mL of triethylamine is added and the mixture is allowed to warm up to room temperature. 50 mL of saturated brine solution is added for hydrolysis. The organic phase is separated, extracted three times with a saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated. The crude product is obtained in almost quantitative yield.

STEP F: Preparation of compound 1.

A solution of 395 mg (2 mmol) propyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amine (1C) and 478 mg (2.5 mmol) N-(4-oxo-butyl)-benzamide (IE) in 1 ,2-dichloroethane (20 mL) is stirred for about 30 minutes. Then 0.75 g (3 mmol) of sodium triacetoxyborohydride is added and the mixture is stirred overnight. After hydrolysation with 30 mL of IN aqueous NaOH solution the organic phase is separated, dried over sodium sulfate and concentrated in vacuum. The crude product obtained is purified via column chromatography on silica gel eluting with dichloromethane/methanol (98:2). The methanol used is saturated with NH₃-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.

Yield: 68%; ESI-MS: 372 (M+H⁺); mp: 152 °C; formula:

(calculated: C, 59.92; H, 6.94; N, 8.39; found: C, 60.03; H, 7.00; N, 8.27). SYNTHESIS OF COMPOUND 2

Naphthalene-2-carboxylic acid [4-(4,5,6,7-tetrahydro-benzothiazol-6-ylamino)-butyl]-amide

(2)

STEP A: l,4-Dioxa-spiro[4.5]dec-8-ylamine (2A) is synthesized as been described for IA using methanol which has been saturated with ammonia. ESI-MS: 158 (M+H⁺).

STEP B: 4,5,6,7-Tetrahydτo-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 C: Preparation of 4,5,6,7-tetrahydro-benzothiazol-6-ylamine (2C) is performed as described for 1C from 2B.

Yield: 48%; ESI-MS: 155 (M+H⁺).

STEP D: Preparation of naphthalene-2-carboxylic acid (4-hydroxy-butyl)-amide (2D).

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.

Yield: 6.2 g (59%); ESI-MS: 244 (M+H*).

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.

Yield: 59%; ESI-MS: 380 (M+H⁺).

An example is crystallized as salt of oxalic acid from methanol/diethylether.

Formula: C₂₂H₂₅N₃OSxC₂H₂O₄ (calculated: C, 91.39; H, 5.80; N, 8.95; found: C, 61.19; H,

5.87; N, 8.76). SYNTHESIS OF COMPOUND 4

Naphthalene-2-carboxylic acid {4-[ethyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amino]- butyl} -amide (4)

STEP A: N-Ethyl-l,4-dioxa-spiro[4.5]dec-8-yl-amine (4A) is prepared operating as described for IA with 7.85 mL (120 mmol) of cooled liquid ethylamine. ESI-MS: 141 (15), 186 (M+H⁺, 100).

STEP B: N6-Ethyl-4,5,6,7-tetrahydro-benzothiazole-2,6-diamine dihydrobromide (4B) is prepared from 4 A analogously to IB.

Yield: 69 %; ESI-MS: 153 (27), 198 (M+H⁺, 100).

STEP C: Ethyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amine (4C) is prepared from 4B as described for 1C.

Yield: 45%; ESI-MS: 138 (17), 183 (M+H⁺, 100).

STEP D: Compound 4 is prepared from 2E and 4C as described for 1. The salt of oxalic acid is crystallized from ethanol/diethylether.

Yield: 22%; ESI-MS: 408 (M+H⁺); mp: 120 °C; formula: C₂₄H₂₉N₃OSxC₂H₂O₄XO-SH₂O (calculated: C, 61.64; H, 6.37; N, 8.29; found: C, 61.39; H, 6.44; N, 8.25).

SYNTHESIS OF COMPOUND 10

Benzo[b]thiophene-2-carboxylic acid [4-(4,5,6,7-tetrahydro-benzothiazol-6-ylamino)-butyl]- amide (10)

STEP A: Preparation of benzothiophene-2-carboxylic acid (4-hydroxy-butyl)-amide (10A) is performed as described for ID using benzothiophene-2-carboxylic acid chloride. Yield: 86%; ESI-MS: 250 (M+H⁺).

STEP B: Preparation of 10.

2C (230 mg, 1,5 mmol) was stirred with 1OA (382 mg, 1.6 mmol), (cyanomethyl)trimethylphosphonium iodide (437 mg, 1.8 mmol) and DIPEA (243 mg, 1.9 mmol) in propionitrile (6 ml) at 9O⁰C for 3 hours. The mixture was allowed to cool to room temperature and water 15 ml and K₂CO₃ 2g was added to the mixture. The mixture was then extracted three times with dichloromethane and dried with Na₂SO₄ and evaporated. The product was purified by flash chromatography using dichloromethane/methanol 100:4 as and eluent. Crystallisation was performed from methanol/diethylether as salt of oxalic acid. Yield: 17%; ESI-MS: 386 (M+H⁺); formula: C₂₀H₂₃N₃OS₂XC₂H₂O₄ (calculated: C, 55.56; H, 5.30; N, 8.84; found: C, 55.33; H, 5.34; N, 8.65).

Claims

1. A compound of formula:

wherein

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 R¹ and R² 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 -NH₂, methyl, or methyl substituted by 1 -(4-chlorophenyl)urea; and subject to the proviso that when X is S and Y is propyl, isopropyl or butyl, then R¹ and R² are not H and methyl respectively.

2. A compound according to claim 1, wherein X is S, Se or O.

3. A compound according to claim 1, wherein the compound has the formula:

wherein each of Y, R¹ and R² is as defined in claim 1.

4. A compound according to claim 3, wherein Y is selected from the group consisting of H, substituted or unsubstituted amino, and halo.

5. A compound according to claim 1, wherein the compound has the formula:

wherein each of Y, R¹ and R² is as defined in claim 1.

6. A compound according to claim 5, wherein 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, halo, and substituted or unsubstituted thio.

7. A compound according to claim 6, wherein Y is selected from the group consisting of H, substituted or unsubstituted alkoxy, halo, and substituted or unsubstituted thio.

8. A compound according to claim 1, wherein the compound has the formula:

wherein each of Y, R¹ and R² is as defined in claim 1.

9. A compound according to claim 8, wherein Y is selected from the group consisting of H, substituted or unsubstituted amino and halo.

10. A compound according to claim 1, 2, 3, 5, 6 and 8, wherein Y is an alkyl, alkenyl, alkynyl, alkoxy or alkylthio group substituted with a first substituent which contains an atom selected from the group consisting of oxygen, sulfur, selenium, nitrogen and phosphorus.

11. A compound according to claim 10, wherein said first substituent is 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.

12. A compound according to claim 10, wherein said 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 sulfϊnyl group, a thioformyl group, a sulfanyl group, a thio group, a disulfanyl group and derivatives thereof.

13. A compound according to claim 10, wherein said first substituent is 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.

14. A compound according to claim 10, wherein said first substituent is selected from the group consisting of a substituted or unsubstituted carbocyclic group and a substituted or unsubstituted heterocyclic group.

15. A compound according to claim 14, wherein said carbocyclic group is a saturated, unsaturated or aromatic carbocyclic group.

16. A compound according to claim 14, wherein said heterocyclic group is a saturated, unsaturated or aromatic heterocyclic group.

17. A compound according to claim 14 or 16, wherein said substituted or unsubstituted heterocyclic group contains a ring heteroatom selected from the group consisting of oxygen, sulfur, selenium, nitrogen and phosphorous.

18. A compound according to claim 14 or 16, wherein said substituted or unsubstituted heterocyclic group is selected from the group consisting of furanyl group, an oxazolyl group, an isoxazolyl group, a pyranyl group, an oxazinyl group, and a dioxanyl group.

19. A compound according to claim 14 or 16, wherein said substituted or unsubstituted heterocyclic group is 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.

20. A compound according to claim 14 or 16, wherein said substituted or unsubstituted heterocyclic group is 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.

21. A compound according to claim 1, 2, 3, 5, 6 or 8, wherein Y is a substituted or unsubstituted Ci-C₄ alkyl, alkenyl, alkynyl or alkoxy group.

22. A compound according to claim 1, 2, 3, 4, 5, 8 or 9, wherein Y is a primary, secondary or tertiary amino group.

23. A compound according to claim 1, 2, 3, 4, 5, 8 or 9, wherein 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, substituted or unsubstituted alkoxy.

24. A compound according to claim 1, 2, 3, 5, 6, 7 or 8, wherein 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, substituted or unsubstituted alkoxy.

25. A compound according to claim 1, 2, 3, 5 or 8, wherein Y is selected from the group consisting of H, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, halo, and substituted or unsubstituted thio.

26. A compound according to claim 1, 2, 3, 5 or 8, wherein Y is selected from the group consisting of unsubstituted alkoxy, unsubstituted amino, and halo.

27 A compound according to any preceding claim, wherein said halo group is Cl or Br.

28. A compound according to any preceding claim, wherein one of R¹ and R² is a second substituted or unsubstituted alkyl, alkenyl, alkynyl or alkoxy group.

29. A compound according to claim 28, wherein said second substituted or unsubstituted alkyl, alkenyl, alkynyl or alkoxy group is a C₁ - C₄ substituted or unsubstituted alkyl, alkenyl, alkynyl or alkoxy group.

30. A compound according to claim 28 or 29, wherein said second substituted or unsubstituted alkyl, alkenyl, alkynyl or alkoxy group is substituted with a second substituent which contains an atom selected from the group consisting of oxygen, sulfur, selenium, nitrogen and phosphorus.

31. A compound according to claim 30, wherein said second substituent is 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.

32. A compound according to claim 30, wherein said second 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, a thioformyl group, a sulfanyl group, a thio group, a disulfanyl group and derivatives thereof.

33. A compound according to claim 30, wherein said second substituent is 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.

34. A compound according to claim 30, wherein said second substituent is selected from the group consisting of a substituted or unsubstituted carbocyclic group and a substituted or unsubstituted heterocyclic group.

35. A compound according to claim 34, wherein said carbocyclic group is a saturated, unsaturated or aromatic carbocyclic group.

36. A compound according to claim 34, wherein said heterocyclic group is a saturated, unsaturated or aromatic heterocyclic group.

37. A compound according to claim 34 or 36, wherein said substituted or unsubstituted heterocyclic group contains a ring heteroatom selected from the group consisting of oxygen, sulfur, selenium, nitrogen and phosphorous.

38. A compound according to claim 34 or 36, wherein said substituted or unsubstituted heterocyclic group is 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.

39. A compound according to claim 34 or 36, wherein said substituted or unsubstituted heterocyclic group is 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.

40. A compound according to claim 34 or 36, wherein said substituted or unsubstituted heterocyclic group is 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.

41. A compound according to any one of claims 28 to 40, wherein the other of R¹ and R² is hydrogen.

42. A compound according to any one of claims 28 to 40, wherein the other of R¹ and R² is a third substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy or alkylthio group.

43. A compound according to claim 42, wherein said third substituted or unsubstituted alkyl, alkenyl, alkynyl or alkoxy group is a C₁ - C₄ substituted or unsubstituted alkyl, alkenyl, alkynyl alkoxy or alkylthio group.

44. A compound having the formula:

45. A compound having the formula:

H

46. A compound having the formula:

H

47. A compound having the formula:

48. A compound having the formula:

49. A pharmaceutical composition comprising a compound according to any one of claims 1 to 48.

50. A pharmaceutical composition according to claim 49 adapted for oral administration.

51. A compound according to any one of claims 1 to 48 for use in the manufacture of a medicament for the treatment of medical conditions characterized by an imbalance in dopamine receptor activity.

52. A use of a compound according to any one of claims 1 to 48 for the treatment of medical conditions characterized by an imbalance in dopamine receptor activity.

53. The use according to claim 52 wherein the condition is Parkinson's disease.

54. 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 any one of claims 1 to 48.