GB2298421A - 2-Heterocyclylmethyl-pyrrolo[2,3-b]pyridine derivatives as ligands for dopamine receptor subtypes - Google Patents

Abstract

A class of chemical compounds (I) comprising a pyrrolo[2,3-b]pyridine moiety and a substituted heterocyclic moiety Q, where Q is Qa, Qb or Qc and Z is -CH 2 - or -CH 2 CH 2 -), linked via the 3-position of the pyrrolo[2,3-b]pyridine moiety by a methylene group, the 2-position of the pyrrolo[2,3-b]pyridine moiety being substituted by an alkyl, alkoxy, halogen, cyano or trifluoromethyl substituent (A), are ligands for dopamine receptor subtypes within the body, in particular the D 4 subtype, and are therefore useful in the treatment and/or prevention of disorders of the dopamine system, in particular schizophrenia and depression. Salts and prodrugs of (I) are also claimed.

Description

PYRROLO-PYRIDINE DERIVATIVES This invention relates to a particular class of heteroaromatic compounds. More particularly, the invention is concerned with substituted pyrrolo[2,3-b]pyridine derivatives which are ligands for dopamine receptor subtypes within the body, in particular the dopamine D4 receptor subtype. They are therefore of use in the treatment and/or prevention of disorders of the dopamine system, including schizophrenia, depression, anxiety, nausea, Parkinson's disease, tardive dyskinesias and extrapyramidal side-effects associated with treatment by conventional neuroleptic agents, neuroleptic malignant syndrome, disorders of hypothalamic-pituitary function such as hyperprolactinaemia and amenorrhoea, and delusional disorders (cf. Catalano et al., Biol.

Psychiatry, 1993, 34, 459).

Upper gastrointestinal tract motility is believed to be under the control of the dopamine system. The compounds according to the present invention may thus be of use in the prevention and/or treatment of gastrointestinal disorders, and the facilitation of gastric emptying.

Dependence-inducing agents such as cocaine and amphetamine have been shown to interact with the dopamine system. Compounds capable of counteracting this effect, including the compounds in accordance with the present invention, may accordingly be of value in the prevention or reduction of dependence on a dependence-inducing agent.

Dopamine is known to be a peripheral vasodilator; for example, it has been shown to exert a dilatory effect on the renal vascular bed. This implies that the compounds of the present invention may be beneficial in controlling vascular blood now.

The localisation of dopamine receptor mRNA in rat heart and large vessels has been noted. This suggests a role for dopamine receptor ligands in controlling cardiovascular function, either by affecting cardiac and smooth muscle contractility or by modulating the secretion of vasoactive substances. The compounds according to the present invention may therefore be of assistance in the prevention and/or treatment of such conditions as hypertension and congestive heart failure.

By virtue of their activity as ligands for dopamine receptor subtypes within the body, the compounds in accordance with the present invention may also be of benefit in enhancing cognitive function, and treating and/or preventing cognitive disorders including presenile and senile dementia (also known as Alzheimer's disease and senile dementia of the Alzheimer type respectively).

Molecular biological techniques have revealed the existence of several subtypes of the dopamine receptor. The dopamine D1 receptor subtype has been shown to occur in at least two discrete forms. Two forms of the D2 receptor subtype, and at least one form of the Ds receptor subtype, have also been discovered. More recently, the D4 (Van Tol et awl., Nature (London), 1991, 350, 610) and D5 (Sunahara et awl., Nature (London), 1991, 350, 614) receptor subtypes have been described.

The disclosure of GB-A-2044254 generically encompasses inter alia a class of 2-[lower alkyl] -3-[piperidin- 1 -ylalkyi] - lH-pyrrolo[2 ,3-b]pyridine derivatives substituted on the piperidine ring by an isoindoledione or like moiety. These compounds are alleged therein to be useful as antidepressants. There is, however, no specific disclosure in GB-A2044254 of a substituted pyrrolo[2,3-b]pyridine derivative, nor indeed any suggestion that such compounds would be of benefit in the treatment and/or prevention of disorders of the dopamine system.

WO-A-94/20459 describes a class of pyrrolo[2,3-b]pyridine derivatives, unsubstituted at the 2-position of the pyrrolo[2,3-b]pyridine moiety and linked via the 3-position thereof by a methylene group to a substituted heterocyclic moiety. These compounds are stated therein to be ligands for dopamine receptor subtypes within the body, and therefore to be useful for the treatment and/or prevention of disorders of the dopamine system, in particular schizophrenia. It has now been found that a related series of pyrrolo[2,3-b]pyridine derivatives, substituted by a functional group at the 2-position of the pyrrolo[2,3-b]pyridine moiety, are ligands for dopamine receptor subtypes within the body, in particular the D4 subtype, and are accordingly of use in the treatment and/or prevention of disorders of the dopamine system, including schizophrenia and depression.

Moreover, the compounds in accordance with this invention possess interesting properties in terms of their metabolic stability.

The present invention accordingly provides a compound of formula I, or a salt or prodrug thereof:

wherein A represents C14 alkyl, C14 alkoxy, halogen, cyano or trifluoromethyl; R represents hydrogen or C14 alkyl; Q represents a moiety of formula Qa, Qb or Qc::

in which the broken line represents an optional chemical bond; R' represents hydrogen, halogen, or an optionally substituted C1-6 alkyl, C,.6 alkoxy, C2.6 alkenyl, C2.S alkynyl, aryl, aryl(Cl.6)alkyl, aryl(C1-6)alkoxy, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, C3-7 heterocycloalkyl(C 14)alkyl, heteroaryl, heteroaryl(C i4)alkyl, heteroaryl(C2-6)alkenyl or heteroaryl(C2-6)alkynyl group; R2 represents an optionally substituted C1-6 alkyl, C14 alkoxy, C2-6 alkenyl.C2-6 alkynyl, aryl, aryl(C1-6)alkyl, aryloxy(C1-6)alkyl, aryl(C1-6)alkoxy, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl, heteroaryl(C1-6)alkyl, heteroaryl(C2-6)alkenyl or heteroaryl(C)alkynyl group; R3, R4 and R5 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRa, -SOR-, SO2Ra, -SO2NRaRb, -NRaRb, -NRaCORb, -NRaCO2Rb, -CORA, -CO2RA or -CONRaRb; Z represents -CH2- or -CH2CH2-; R6 represents hydrogen or halogen, or an optionally substituted C14 alkyl, C1-6 alkoxy, aryl. aryloxy, aryl(C1-6)alkyl, aryl(C1-6)alkoxy or heteroaryl group; and Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group.

For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.

The term "hydrocarbon" as used herein includes straight-chained, branched and cyclic groups containing up to 18 carbon atoms, suitably up to 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitable hydrocarbon groups include C14 alkyl, C2.6 alkenyl, C2-6 alkynyl, C3.7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-8)alkyl, aryl(C2-6)alkenyl and aryl(C24)alkynyl.

The expression "a heterocyclic group" as used herein includes cyclic groups containing up to 18 carbon atoms and at least one heteroatom preferably selected from oxygen, nitrogen and sulphur. The heterocyclic group suitably contains up to 15 carbon atoms and conveniently up to 12 carbon atoms, and is preferably linked through carbon. Examples of suitable heterocyclic groups include CS.7 heterocycloalkyl, C3.7 heterocycloalkyl(C 14)alkyl, heteroaryl, heteroaryl(C 14) alkyl, heteroaryl(C2Z)alkenyl and heteroaryl(C2-6)alkynyl groups.

Suitable alkyl groups within the scope of the term "hydrocarbon" and within the definition of the substituents A, R, R', R2 and R6 include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straightchained or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl.

Suitable alkenyl groups within the scope of the term "hydrocarbon" and within the definition of the substituents R' and R2 include straightchained and branched alkenyl groups containing from 2 to 6 carbon atoms.

Typical examples include vinyl and allyl groups.

Suitable alkynyl groups within the scope of the term "hydrocarbon" and within the definition of the substituents R' and R2 include straightchained and branched alkynyl groups containing from 2 to 6 carbon atoms.

Typical examples include ethynyl and propargyl groups.

Suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.

Particular aryl groups within the scope of the term "hydrocarbon" and within the definition of the substituents Ri, R2 and R6 include phenyl and naphthyl.

Particular aryl(Cl4)alkyl groups within the scope of the term "hydrocarbon" and within the definition of the substituents Rl, R2 and RO include benzyl, naphthylmethyl, phenethyl and phenylpropyl.

A particular aryl(C2.6)alkenyl group within the scope of the term "hydrocarbon" and within the definition of the substituents R' and R2 is phenylethenyl.

A particular aryl(C2.6)aLkynyl group within the scope of the term "hydrocarbon" and within the definition of the substituents R' and R2 is phenylethynyl.

Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and tetrahydrofuryl groups.

A particular CS.7 heterocycloalkyl(C Is)alkyl group within the scope of the expression "a heterocyclic group" and within the definition of the substituents R' and R2 is tetrahydrofurylethyl.

Suitable heteroaryl groups within the scope of the expression "a heterocyclic group" and within the definition of the substituents Rl, R2 and R6 include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, oxadiazolyl and thiadiazolyl groups.

Particular heteroaryl(C I.s)alkyl groups within the scope of the expression "a heterocyclic group" and within the definition of the substituents Rl and R2 include thienylmethyl, pyridylmethyl, pyrimidinylmethyl, pyrazinylmethyl and furylethyl.

Particular heteroaryl(C2-6)alkenyl groups within the scope of the term "hydrocarbon" and within the definition of the substituents R1 and R2 include furylethenyl and thienylethenyl.

The hydrocarbon and heterocyclic groups, as well as the substituents R1, R2 and R6, may in turn be optionally substituted by one or more groups selected from Ci4 alkyl, adamantyl, phenyl, aryl(Cl)alkyl, halogen, C14 haloalkyl, C14 aminoalkyl, trifluoromethyl, hydroxy, C1-6 alkoxy, aryloxy, keto, C1-3 alkylenedioxy, nitro, cyano, carboxy, C24 alkoxycarbonyl, C24 alkoxycarbonyl(C1.6)alkyl, C24 alkylcarbonyloxy, arylcarbonyloxy, C2-6 alkylcarbonyl, arylcarbonyl, C14 alkylthio, C14 alkylsulphinyl, C14 alkylsulphonyl, arylsulphonyl, trifluoromethanesulphonyloxy, -NRvRw, -NRvCORw, -NRvCO2Rw, -NRvSO2Rw, -CH2NRvSO2R-, -NHCONRvRw, -PO(ORv)(ORw), -CONRvRw, -SO2NRvRw and -CH2SO2NRVRw, in which Rv and Rw independently represent hydrogen, C1-6 alkyl, aryl or aryl(Cl.6)alkyl.

The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine, especially chlorine.

The present invention includes within its scope prodrugs of the compounds of formula I above. In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H.

Bundgaard, Elsevier, 1985.

Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.

Suitably, the substituent A represents C14 alkyl, especially methyl.

Suitably, the substituent R represents hydrogen or methyl, especially hydrogen.

Suitably, the substituent Rl represents hydrogen or halogen, in particular hydrogen, fluoro or chloro, and especially hydrogen.

Suitable values for the substituent R2 include C14 alkyl, aryl, aryl(C1-6)alkyl, aryloxy (C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl, heteroaryl(Cl.6)alkyl or heteroaryl(C2-6)alkenyl, any of which groups may be optionally substituted. Examples of optional substituents on the group R2 include C1-6 alkyl, halogen, cyano, nitro, C1-6 alkoxy, aryloxy and arylcarbonyloxy.

Particular values of R2 include methyl, benzoyloxy-methyl, ethyl, n-propyl, isopropyl, phenyl, chlorophenyl, ethylphenyl, methoxyphenyl, nitrophenyl, naphthyl, benzyl, chlorobenzyl, phenethyl, phenoxy-methyl, ph enyleth enyl, chloro-phenylethenyl, methoxy-phenylethenyl, phenylethynyl, tetrahydrofuryl-ethyl, indolyl, benzofuryl, benzthienyl, furylethyl, methyl-furylethyl, thienylethenyl and methyl-furylethenyl.

Suitable values for the substituents R3, R4 and R5 include hydrogen, halogen, cyano, nitro, trifluoromethyl, amino, C14 alkylamino, di(C1-6)alkylamino, C14 alkyl, C14 alkoxy, aryl(C1-6)alkoxy and C2.6 alkylcarbonyl. Particular values include hydrogen, fluoro, chloro, methyl, methoxy and benzyloxy, especially hydrogen.

Particular values of R6 include hydrogen, methoxy, phenyl, chlorophenyl, phenoxy, benzyloxy, thienyl, chloro and bromo.

One sub-class of compounds according to the invention is represented by the compounds of formula IIA, and salts and prodrugs thereof:

wherein A is as defined with reference to formula I above; E represents -(CH2)n-, -CH=CH- or n is zero, 1, 2 or 3; -X-Y- represents -CH2-CH- or -CH=C-; W represents a group of formula (i), (ii), (iii), (iv), (v) or (vi):

in which V represents oxygen, sulphur, NH or N-methyl; and R13 and Rl7 independently represent hydrogen, halogen, cyano, nitro, trifluoromethyl, amino, C1-6 alkylamino, di(C1-6)alkylamino, C1-6 alkyl, C1-6 alkoxy, aryl(C1-6)alkoxy or C2-6 alkylcarbonyl.

Particular values of R13 include hydrogen, fluoro, chloro, methyl, ethyl, methoxy and benzyloxy.

Particular values of R17 include hydrogen, fluoro, chloro, cyano, methyl, methoxy and nitro.

A particular subset of the compounds of formula IIA as defined above is represented by the compounds of formula IIB, and salts and prodrugs thereof:

wherein E, X, Y, R19 and R'7 are as defined with reference to formula IIA above.

A particular subset of the compounds of formula IIB as defined above comprises those compounds wherein E represents -CH=CH-, in particular in the (E) configuration.

Another subset of the compounds of formula IIB as defined above comprises those compounds wherein -X-Y- represents -CH=C-.

A further sub-class of compounds according to the invention is represented by the compounds of formula IIC, and salts and prodrugs thereof:

wherein A is as defined with reference to formula I above; RlS is as defined with reference to formula IIA above; and R16 represents hydrogen, halogen, C14 alkyl, Cl4 alkoxy, aryl, haloaryl, aryloxy, aryl(Ci)alkyl, aryl(Cl.6)alkoxy or heteroaryl.

Particular values of R'B include hydrogen, methoxy, phenyl, chlorophenyl, phenoxy, benzyloxy, thienyl, chloro and bromo.

Specific compounds within the scope of the present invention include: 2-methyl-3-[4-((E)-2-phenylethenyl)- 1,2, 3,6-tetrahydropyridin- 1yl]methyl- 1H-pyrrolo[2 ,3-b]pyridine; and salts and prodrugs thereof.

The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or oncemonthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. An erodible polymer containing the active ingredient may be envisaged.For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Favoured unit dosage forms contain from 1 to 100 mg, for example 1, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of schizophrenia or depression, a suitable dosage level is about 0.001 to 250 mg/kg per day, preferably about 0.005 to 100 mg/kg per day, and especially about 0.01 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.

In order to alleviate the symptoms of schizophrenia without causing sedation or extrapyramidal side-effects, it is believed that the dosage level of the active ingredient should be selected such that the dose administered is effective in substantially completely blocking the dopamine D4 receptor subtype in human brain whilst displaying no or negligible D2 receptor subtype occupancy. A suitable dosage level in this regard is about 0.001 to 5.0 mg/kg per day, more particularly about 0.005 to 1.0 mg/kg per day, and especially about 0.01 to 0.5 mg/kgper day.

If desired, the compounds in accordance with this invention may be co-administered with another medicament, for example a known antischizophrenic agent which produces its effects via dopamine D2 and/or 5-HT2 receptor blockade. Such co-administration may be desirable where a patient is already on an established treatment regime, for example one involving conventional anti-schizophrenic medicaments such as haloperidol or chlorpromazine.

The compounds in accordance with the present invention may be prepared by a process which comprises reacting a compound of formula III with a compound of formula IV:

wherein A, R3, R4 and R5 are as defined above, Ql represents the residue of a moiety of formula Qa to Qc fez as defined above, and RP corresponds to the group R as defined above or represents a suitable protecting group; in the presence of a substantially equimolar amount of formaldehyde; followed, where required, by removal of the protecting group RP; and subsequently, if necessary, N-alkylation by standard methods to introduce the moiety R.

The reaction is conveniently carried out by stirring the reactants in a solvent such as isopropanol or aqueous acetic acid, optionally in the presence of a buffer such as sodium acetate trihydrate.

The formaldehyde may be utilised in the form of paraformaldehyde; or as a solution of formaldehyde in an inert solvent, e.g. 37% aqueous formaldehyde.

The protecting group RP, when present, is suitably an acyl moiety such as acetyl, which can conveniently be removed as necessary by treatment under strongly basic conditions, e.g. sodium methoxide in methanol. Alternatively, the protecting group RP may be a carbamoyl moiety such as t-butoxycarbonyl (BOC), which can conveniently be removed as necessary by treatment under mildly acidic conditions.

In an alternative procedure, the compounds according to the present invention may be prepared by a process which comprises reacting a compound of formula IV as defined above with a compound of formula V:

wherein A, R3, R4, R5 and RP are as defined above, and L represents a suitable leaving group; followed, where required, by removal of the protecting group RP; and subsequently, if necessary, N-alkylation by standard methods to introduce the moiety R.

The leaving group L is suitably a halogen atom, e.g. chlorine or bromine; or a dialkylamino group, e.g. dimethylamino.

When L represents a halogen atom, the reaction between compounds IV and V is conveniently carried out by stirring the reactants under basic conditions in a suitable solvent, for example potassium carbonate in N, N- dimethylformamide, or triethylamine in tetrahydrofuran or acetonitrile. Where L represents a dialkylamino group, the reaction is conveniently effected by heating the reactants in an inert solvent such as toluene, typically at the reflux temperature of the solvent.

Where they are not commercially available, the starting materials of formula III, IV and V may be prepared by procedures analogous to those described in the accompanying Example, or by standard methods well known from the art.

It will be appreciated that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further desired compound of formula I using techniques known from the art. For example, a compound of formula I wherein R is hydrogen initially obtained may be converted into a compound of formula I wherein R represents C14 alkyl by standard alkylation techniques, such as by treatment with an alkyl iodide, e.g.

methyl iodide, typically under basic conditions, e.g. sodium hydride in dimethylformamide, or triethylamine in acetonitrile.

Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base.The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & BR< P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The following Example illustrates the preparation of compounds according to the invention.

The compounds useful in this invention potently inhibit [3Hl- spiperone binding to human dopamine D4 receptor subtypes expressed in zonal cell lines.

[3H]-Spiperone Binding Studies Clonal cell lines expressing the human dopamine D4 receptor subtype were harvested in PBS and then lysed in 10 mM Tris-HCl pH 7.4 buffer containing 5 mM MgSO4 for 20 min on ice. Membranes were centrifuged at 50,000g for 15 min at 40C and the resulting pellets resuspended in assay buffer (50 mM Tris-HCl pH 7.4 containing 5 mM EDTA, 1.5 mM Caul2, 5 mM MgCl2, 5 mM KCl, 120 mM Nail, and 0.1% ascorbic acid) at 20 mg/ml wet weight. Incubations were carried out for 60 min at room temperature (220C) in the presence of 0.05-2 nM [3H]-spiperone or 0.2 nM for displacement studies and were initiated by addition of 20-100 ,ug protein in a final assay volume of 0.5 ml.The incubation was terminated by rapid filtration over GF/B filters presoaked in 0.3% PEI and washed with 10 ml ice-cold 50 mM Tris-HCl, pH 7.4.

Specific binding was determined by 10 ;M apomorphine and radioactivity determined by counting in a LKB beta counter. Binding parameters were determined by non-linear least squares regression analysis, from which the inhibition constant Ki could be calculated for each test compound.

The compound of the accompanying Example was tested in the above assay, and was found to possess a Ki value for displacement of [3H]-spiperone from the human dopamine D4 receptor subtype of below 1.5 ,uM.

EXAMPLE 1 2-Methyl-3-[4-((E)-2-phenylethenyl)-1,2,3,6-tetrahydropyridin-1vl]methyl-1H-pyrrolo[2,3-b]pyridine, hydrochloride Step 1: 2-tert-Butoxycarbonylamino-3-methylpyridine To a stirred solution of di-tert-butyldicarbonate (163. 1g, 748mmol) in petrol (60-80 C) (100ml) at reflux was added a solution of 2-amino-3methylpyridine (50g, 463mmol) in ethyl acetate (25ml) over 45 minutes.

When addition was complete the reaction was stirred at reflux for a further 15 minutes, then allowed to cool to room temperature during which it solidified. The mixture was diluted with petrol (60-800) (150ml) and filtered. The solid was washed with a further portion of petrol and dried to give the title compound as a white solid (65.9g, 68%). #H (CDC13) 1.44 (9H, s, OC(CH3)3), 2.22 (3H, s, ArCH3), 6.93-6.98 (1H, m, 5-H), 7.44 (1H, d, J 9.5Hz, 4-H), 8.19 (1H, d, J 4.8Hz, 6-H).

Step 2: 2-Methylpyrrolo[2,3-b]pyridine To a mixture of the foregoing pyridine (10.4g, 50mmol) in tetrahydrofuran at -200C was added a solution of n-butyllithium (1.6M in hexanes, 68.8ml, llOmmol) keeping the temperature below -10 C. The resulting deep red solution was stirred at -150C for 30 minutes, after which ethyl acetate (5.9ml, 60mmol) was added to give a pale yellow solution with the temperature rising to 10 C. The reaction was warmed to room temperature, stirred for 1 hour and then quenched by addition of water (5ml). Concentrated hydrochloric acid (30ml) was added and the mixture stirred during which an exotherm and effervescence were observed. When the effervescence had subsided, the mixture was stirred for a further 2 hours.The two layers were separated, the aqueous phase basified with aqueous sodium hydroxide (4N) and extracted with ethyl acetate (3x50ml). The combined extracts were washed with saturated brine (50ml), dried (MgSO4), treated with silica and evaporated in vacuo.

The residue was chromatographed on silica eluting with 40% ethyl acetate/petrol (60-800C) to yield the title compound as a pale yellow solid (1.9g, 28%). 5H (CDCl3) 2.55 (3H, s, ArCH3), 6.17 (1H, s, 3-H), 7.00-7.05 (1H, m, 5-H), 7.81 (1H, dd, J 11.1, 2.1Hz, 4-H), 8.21 (1H, dd, J 7.0, 2.1Hz, 6-H), 11.88 (1H, br s, NH).

Step 3: 2-Methyl-3-[4-((E)-2-phenylethenyl)-1,2,3,6tetrahydropyridin-1-yl]emthyl-1H-pyrrolo[2,3,-b]pyridine. bydrochloride A mixture of 2-methylpyrrolo[2,3-b]pyridine (264mg, 2mmol), 4 [(E)-2-phenylethenyl]-1,2,3,6-tetrahydropyridine hydrochloride (443mg, 2mmol) and paraformaldehyde (72mg, 2.4mmol) in propan-2-ol (20ml) was reflexed overnight. The resulting suspension was cooled and filtered. The solid collected was recrystallised from propan-2-ol to give the title compound as a buff solid (378mg, 49%); m.p. 227-229 C (ethanol); (found: C, 68.90; H, 6.55; N, 11.10; C22H23N3, HC1, H20 requires C, 68.83; H, 6.83; N, 10.95%); aH (DMSO-d6) 2.51 (3H, s, ArCH3), 2.65 (2H, br s, tetrahydropyridinyl H), 3.27 (1H, br s, tetrahydropyridinyl H), 3.65 (1H, br s, tetrahydropyridinyl H), 3.85 (2H, br s, tetrahydropyridinyl H), 4.53 (2H, s, ArCH2N), 5.91 (lH, s, tetrahydropyridinyl 5-H), 6.60 (1H, d, J 16.3Hz, ArCHCH), 6.97 (1H, d, J 16.4Hz, ArCHCH), 7.10-7.14 (1H, m, 5 H), 7.23-7.27 (1H, m, ArH), 7.34 (2H, t, J 7.3Hz, ArH), 7.51 (2H, d, J 7.4Hz, ArH), 8.14 (1H, d, J 7.8Hz, 4-H), 8.18-8.20 (1H, m, 6-H); mlz (ES+), 330 (M+1)+.

Claims (16)

CLAIMS:

1. A compound of formula I, or a salt or prodrug thereof:

wherein A represents C14 alkyl, C1-6 alkoxy, halogen, cyano or trifluoromethyl; R represents hydrogen or C1-6 alkyl; Q represents a moiety of formula Qa, Qb or Qc:

in which the broken line represents an optional chemical bond; R1 represents hydrogen, halogen, or an optionally substituted C1-6 alkyl, C14 alkoxy, C24 alkenyl, C24 alkynyl, aryl, aryl(C1-6)alkyl, aryl(C1-6)alkoxy, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, C3-7 heterocyclalkyl(C1-6)alkyl, heteroaryl, heteroaryl(C1-6)alkyl, heteroaryl(C2-6)alkenyl or heteroaryl(C2-6)alkynyl group;; R2 represents an optionally substituted C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, aryl, aryl(C1-6)alkyl, aryloxy(C1-6)alkyl, aryl(C1-6)alkoxy, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl, heteroaryl(C1-6)alkyl, heteroaryl(C2z)alkenyl or heteroaryl(C24)alkynyl group; R3, R4 and R5 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, ORa, -SR, -SORa,-SO2Ra, -SO2NRaRb, -NRaRb, -NRaCORb, -NRaCO2Rb, -CORa,-CO2Ra or -CONR-Rb; Z represents -CH2- or -CH2CH2-; R6 represents hydrogen or halogen, or an optionally substituted C1-6 alkyl, Cl4 alkoxy, aryl, aryloxy, aryl(C1-6)alkyl, aryl(C,4)alkoxy or heteroaryl group; and Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group.

2. A compound as claimed in claim 1 wherein A represents C14 alkyl.

3. A compound as claimed in claim 2 wherein A is methyl.

4. A compound as claimed in any one of the preceding claims wherein R' is hydrogen.

5. A compound as claimed in any one of the preceding claims wherein R2 represents methyl, benzoyloxy-methyl, ethyl, n-propyl, isopropyl, phenyl, chlorophenyl, ethylphenyl, methoxyphenyl, nitrophenyl, naphthyl, benzyl, chlorobenzyl, phenethyl, phenoxy-methyl, phenylethenyl, chloro-phenylethenyl, methoxy-phenylethenyl, phenylethynyl, tetrahydrofuryl-ethyl, indolyl, benzofuryl, benzthienyl, furylethyl, methyl-furylethyl, thienylethenyl or methyl-furylethenyl.

6. A compound as claimed in claim 5 wherein R2 represents phenylethenyl or chloro-phenylethenyl.

7. A compound as claimed in claim 1 represented by formula IIA, and salts and prodrugs thereof:

wherein A is as defined in claim 1; E represents -(CH2)n-, -CH=CH- or -C-C-; n is zero, 1, 2 or 3; -X-Y- represents -CH2-CH- or W represents a group of formula (i), (ii), (iii), (iv), (v) or (vi):

in which V represents oxygen, sulphur, NH or N-methyl; and Rl3 and Rl7 independently represent hydrogen, halogen, cyano, nitro, trifluoromethyl, amino, C14 alkylamino, di(C1-6)alkylamino, C4 alkyl, Ci4 alkoxy, aryl(Cl4)alkoxy or C24 alkylcarbonyl.

8. A compound as claimed in claim 7 represented by formula IIB, and salts and prodrugs thereof:

wherein E, X, Y, R'9 and R'7 are as defined in claim 7.

9. A compound as claimed in claim 8 wherein E represents -CH=CH-.

10. A compound as claimed in claim 9 wherein the group E of formula -CH=CH- is in the (E) configuration.

11. A compound as claimed in any one of claims 8 to 10 wherein -X-Y- represents -CH=C-.

12. A compound as claimed in claim 1 represented by formula IIC, and salts and prodrugs thereof:

wherein A is as defined in claim 1; Ri3is as defined in claim 7; and Rl6 represents hydrogen, halogen, C14 alkyl, C1-6 alkoxy, aryl, haloaryl, aryloxy, aryl(C1-6)alkyl, aryl(C1-6)alkoxy or heteroaryl.

13. A compound selected from: 2-methyl-3-[4-((E)-2-phenylethenyl)-1,2,3,6-tetrahydropyridin-1yl]methyl- lH-pyrrolo[2,3-b]pyridine; and salts and prodrugs thereof.

14. A pharmaceutical composition comprising a compound as claimed in any one of the preceding claims in association with a pharmaceutically acceptable carrier.

15. A compound as claimed in any one of claims 1 to 13 for use in therapy.

16. The use of a compound as claimed in any one of claims 1 to 13 for the manufacture of a medicament for the treatment and/or prevention of disorders of the dopamine system.