The present invention relates to novel naphthyl pyrrole derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, in particular as antipsychotic agents.

European Patent Application No. 241053, describes compounds of the formula :

wherein A is an unsaturated 5-membered heterocyclic ring, such as 2,5-pyrrolyl, or 3,5- or 1,4- pyrazolyl; X is a nitrogen or carbon atom; R1-R2. R3 are each hydrogen or alkyl; R4 is aryl, heteroaryl, arylcarbonyl or heteroaryl-carbonyl; R is selected from a variety of substituents and n is 0-4. The compounds are said to have antipsychotic properties.

European Patent Application No. 259930 describes compounds of the formula :

wherein A is an unsaturated 5-membered heterocyclic ring, such as 2,5-pyrrolyl, 1,4- pyrazolyl or 2,5-furyl; R is hydrogen, alkyl or optionally substituted phenyl; R ¹ is alkyl, alkenyl or forms a ring with the phenyl group; R- is hydrogen, hydroxy or alkoxy; R- is selected from a variety of substituents and n is 0-3. These compounds are also said to have antipsychotic properties.

European Patent Application No. 539281 describes compounds of the formula:

wherein Z is a residue derived from 2-aminomethyl-N-alkyl-pyrrolidine, 2-aminoethyl- N,N-diethylamine, 2-aminoethyl-morpholine, 2-aminoethyl-N,N-dibutylamine, 4-amino- N-butyl (or N-benzyl) piperidine or 2-aminoethyl-pyrrolidine; Y is alkyl or alkenyl; X is selected from a variety of substituents and R is H or methoxy. The compounds are said to

be dopamine antagonists, acting at the D3 receptor an to be useful inter alia as antipsychotics.

We have now found novel naphthyl pyrrole derivatives which have affinity for dopamine receptors and thus have potential as antipsychotic agents. In a first aspect the present invention provides compounds of formula (I) :

Formula (I) wherein

R! represents C^alkyl; R- represents hydrogen, halogen, C 1 _4alkyl, C \ _4alkoxy, C \ _4alkoxyC \ _4alkyl,

Cι_4alkylsulphonyl, trifluoromethylsulphonyl; optionally substituted arylsulphonyl, optionally substituted heteroarylsulphonyl, optionally substituted aralkylsulphonyl, optionally substituted heteroaralkylsulphonyl, nitro, cyano, amino, mono- or di- Cι_4alkylamino, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC^alkyl, C 1 _4alkylthio, C _4alkanoyl, C \ _4alkoxycarbonyl, aminosulphonyl,

Cι_4alkylaminosulphonyl or di-Cι_4alkylaminosulphonyl; and Y represents a group selected from :

(a) (b)

wherein in group (a) :

R ³ and R ⁴ independently represent hydrogen, Cμgalkyl, optionally substituted arylCι_6alkyl or optionally substituted heteroar lCj.galkyl; R ⁵ represents C _j .galkyl, C _β .ό l enyl or Cβ.gcycloalkylCj^alkyl; and

R ⁶ represents C _j .galkyl; C _β .όalkenyl; C3_6cycloalkylC galley 1, optionally substituted arylCι_4alkyl or optionally substituted heteroarylC^alkyl; or NR ⁵ R6 forms a heterocyclic ring; in group (b) : R? represents C^alkyl; Cβ.galkenyl; C3_6CycloalkylCι_4alkyl , optionally substituted arylCι_4alkyl or optionally substituted heteroarylCι_4alkyl; and q is 1 to 4; in group (c):

R8 and independently represent hydrogen, C^al yl, optionally substituted arylC . alkyl or optionally substituted heteroarylC \ _6alkyl;

RlO represents an optionally substituted aryl or optionally substituted heteroaryl group; and

Z represents -(CH2) _r wherein r is 2 to 8 or -(CH2) _s CH=CH(CH2)t where s and t independently represent 1 to 3; and in group (d): each of m and n independently represents from 1 to 3; and salts thereof.

In the compounds of formula (I) an alkyl group or moiety may be straight or branched. Alkyl groups which may be employed include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and any branched isomers thereof, such as isopropyl, t-butyl, sec-pentyl, and the like.

Representative aryl groups or moieties present in any of the substituents R^, R3,

R ⁴ , R ⁶ , R ⁷ , R8, R9 and R ¹⁰ in compounds of formula (I) include phenyl, naphthyl, and tetrahydronaphthyl. Suitable examples of heteroaryl groups include both 5 and 6- membered heterocycles containing one or more oxygen, sulphur or nitrogen atoms, such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazyl, pyrimidyl and pyrazyl. Substituents for said aryl and heteroaryl groups include halogen, Cj^alkyl, C^alkoxy, Cι_4alkoxyCι_4alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyCj^alkyl, Cj^alkanoyl, C^alkoxycarbonyl, amino and mono- or -diC^alkylamino.

When - N 5R6 forms a heterocyclic ring, this preferably has from 4 to 10, e.g. 5 to 8 ring members, and it may be fully or partially saturated. A heterocyclic ring -NR^R6 may also be bridged, for example by a Cj.βalkylene chain e.g. a methylene or ethylene

group. Furthermore, the heterocyclic ring may he substituted by one or more C^alkyl groups, or fused to an aromatic ring, such as phenyl. R ¹ preferably represents methyl or ethyl.

Preferably R ² is selected from halogen, Cj_4alkylsulphonyl, phenylsulphonyl, and C i _4dialkylaminosulphonyl.

When R- represents halogen, this may be fluorine, chlorine, bromine or iodine. When Y is a group (a) : at least one of R ³ and R ⁴ is preferably hydrogen. Suitably one of R ³ and R ⁴ is hydrogen and the other is selected from hydrogen, C galkyl and optionally substituted arylCj.galkyl. NR^R6 preferably forms a 5-8 membered heterocyclic ring, e.g. piperidine.

When Y is a group (b) : q is suitably 1 to 3 and R ⁷ is suitably Cj_4alkyl. Preferably group (b) is a substituted pyrrolidinyl, piperidinyl or azacycloheptanyl group. When Y is a group (c) : at least one of R and R^ preferably represents hydrogen. Suitably one of R -* and R^ is hydrogen and the other is selected from hydrogen, Ci.galkyl and optionally substituted arylCi.galkyl. RIO preferably represents optionally substituted phenyl. Z preferably represents (CH2) _r wherein r is 3, 4 or 5. Representative heterocyclic rings in the group (c) include azacycloheptanyl, azacyclooctanyl, pyrrolidinyl and piperidinyl.

When Y is a group (d) m and n preferably each independently represents 1 or 2. It will be appreciated that for use in medicine the salts of formula (I) should be physiologically acceptable. Suitable physiologically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids eg. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids eg. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulphonic, methanesulphonic or naphthalenesulphonic acid. Other non-physiologically acceptable salts eg. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. Also included within the scope of the invention are solvates and hydrates of compounds of formula (I).

When an asymmetric centre is present in a compound of formula (I) the compound will exist in the form of optical isomers (enantiomers). The present invention includes within its scope all such enantiomers and mixtures, including racemic mixtures, thereof. In addition, all possible diastereomeric forms (individual diastereomers and mixtures thereof) of compounds of formula (I) are included within the scope of the invention.

Particular compounds according to the invention include :

2-(4-ethylsulfonyl-l-methoxy-2-naphthyl)-5-(l-piperidinyl methyl)-lH-pyrrole, 2-(4-bromo-l-methoxy-2-naphthyl)-5-(2-(l-ethyl)pyrrolidinyl) -lH-pyrrole, 2-(4-bromo-l-methoxy-2-naphthyl)-5-(l-(2-phenyl)-l-azacycloh eptanyl)methyl-lH- pyrrole,

2-(4-bromo-l-methoxy-2-naphthyl)-5-(l-piperidinyl)methyl- lH-pyrrole, 2-(4-chloro-l-methoxy-2-naphthyl)-5-(l-piperidinylmethyl)-lH -pyrrole, 2-(4-ethylsulfonyl-l-methoxy-2-naphthyl)-5-(2-(l-ethyl)pyrro lidinyl)-lH-pyrrole, 2-(4-ethylsulfonyl- l-methoxy-2-naphthyl)-5-( 1 -(2-phenyl)- 1 -azacycloheptanyl)-methyl- lH-pyrrole,

2-(4-dimethylaminosulfonyl-l-methoxy-2-naphthyl)-5-(l-pip eridinylmethyl)-lH-pyrrole, 2-(4-dimethylaminosulf onyl- 1 -methoxy-2-naphthyl)-5-( 1 -(2-phenyl)- 1 -azacycloheptanyl)- methyl- lH-pyrrole, 2-(4-ethylsulfonyl-l-methoxy-2-naphthyl)-5-(l-(l-piperidinyl )ethyl)-lH pyrrole, 2-(4-cyano-l-methoxy-2-naphthyl)-5-(2-(l-ethyl)pyrrolidinyl) -lH pyrrole, 2-(4-cyano-l-methoxy-2-naphthyl)-5-(2-(l-butyl)pyrrolidinyl) -lH-pyrrole, and salts thereof.

The present invention also provides a process for preparing compounds of formula (I) which process comprises : (a) to prepare a compound of formula (I) wherein Y is a group (a) or (c) in which R3, R ⁴ , R8 and R-^are hydrogen, carrying out a Mannich reaction with a compound of formula (II) :

Formula II and an amine of formula (III) or (IV)

Formula (HI) Formula (IV)

in the presence of formaldehyde;

(b) to prepare a com ound wherein Y is a group (a) wherein at least one of

R3 and R ⁴ is hydrogen, a group (c) wherein at least one of R% or R^ is hydrogen or a group of formula (b) or (d) carrying out a Vilsmeier reaction with a compound of formula

(II) and an amide of formula (V) or (VI) :

Formula (V) Formula (VI)

or a 2-oxo derivative of a group (b) or (d) respectively, and reducing the intermediate product with, for example, sodium borohydride or cyanoborohydride;

(c) to prepare a compound wherein Y is a group (a) or (c) in which R ³ , R ⁴ , Rβ and R^ are hydrogen, reductive amination of a compound of formula (VII) :

Formula VII with an amine of formula (III) or (IV); and optionally thereafter forming a salt of formula (I).

The Mannich reaction according to process (a) may be effected according to conventional methods. Thus for example the amine of formula (IE) or (IV) may first be reacted with formaldehyde and the product subsequently reacted with a compound of formula (II). The reaction is preferably effected in a protic solvent, for example an alcohol such as ethanol. An organic or inorganic acid, e.g. acetic acid may be employed as a catalyst.

The Vilsmeier reaction according to process (b) may also be effected according to conventional methods. Thus, for example, the amide of formula (V) or (VI) or the oxo derivative of group (b) or (d) may first be reacted with phosphorus oxychloride (POCl3)and the resulting product subsequently reacted with a compound of formula (II) conveniently in a solvent such as dichloroethane or dichloromethane. The product of this reaction is then reduced with, for example, sodium borohydride or cyanoborohydride. The

reduction may be carried out in a suitable solvent, for example dichloroethane, dichloromethane, methanol, ethanol, water or mixtures thereof- Reductive amination according to process (c) will generally be carried out using a reducing agent such as sodium borohydride or cyanoborohydride and in the presence of a Lewis acid such as titanium (IV) chloride. Reaction of a compound (VII) with the amine may conveniently be effected in a solvent such as dichloromethane or dichloroethane. A compound of formula (II) may be prepared by cyclisation of a dicarbonyl compound of formula (VHI) :

Formula VIII wherein R and R ² are as hereinbefore defined.

The reaction may be effected using an ammonium salt, e.g. ammonium acetate, in a solvent such as ethanol. (See, for example, C.G. Kruse et al., Heterocycles, vol 26,

P3141, 1987). A compound of formula (VIII) may itself be prepared by reacting the appropriate substituted naphthoyl halide with a metallo derivative of a 2-(2-haloethyl)-l,3-dioxolane or 2-(2-haloethyl)-l,3-dioxane, followed by acid hydrolysis.

Compounds of formulae (III) and (IV) are available commercially or may be prepared by standard methods. Compounds of formula (V) and (VI) may be prepared by reacting the appropriate amine of formula (III) or formula (IV) with an appropriate acylating agent such as an acid chloride or acetic anhydride in formic acid.

A compound of formula (VII) may be prepared by carrying out a Vilsmeier reaction in which dimethylformamide is reacted with phosphorus oxychloride and the product reacted with a compound of formula (II), in a solvent such as dichloroethane, followed by acid hydrolysis.

When a compound of formula (I) is obtained as a mixture of enantiomers these may be separated by conventional methods such as crystallisation in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column. Alternatively a compound of formula (I) may be prepared as a single enantiomer by employing a chiral amine in the synthesis, for example directly in process (a) or (c) or in the preparation of an amide for use in process (b). A chiral amine of formula (IV) may be prepared by resolving an enantiomeric mixture of the appropriate amine for example by

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coupling to a chiral auxiliary such as (S)-{+)-c_-methoxyphenylacetic acid and separating the resulting diastereoisomers by chromatography. The auxiliary moiety may be removed to give the desired chiral amine. Thus for example the (S)-(+)-α-methoxyphenylacetyl moiety may be cleaved under basic conditions for example using methyl lithium in a solvent such as tetrahydrofuran or hexane.

Compounds of formula (I) have been found to exhibit affinity for dopamine receptors, in particular D3 receptors, and are expected to be useful in the treatment of disease states which require modulation of such receptors, such as psychotic conditions. The therapeutic effect of currently available antipsychotic agents (neuroleptics) is generally believed to be exerted via blockade of D2 receptors; however this mechanism is also thought to be responsible for undesirable extrapyramidal side effects (eps) associated with many neuroleptic agents. Without wishing to be bound by theory, it has been suggested that blockade of the recently characterised dopamine D3 receptor may give rise to beneficial antipsychotic activity without significant eps. (see for example Sokoloff et al, Nature, 1990; 347: 146-151; and Schwartz et al, Clinical Neuropharmacology, Vol 16, No. 4, 295-314, 1993). Preferred compounds of the present invention are therefore those which have higher affinity for dopamine D3 than dopamine D2 receptors (such affinity can be measured using standard methodology for example using cloned dopamine receptors). Said compounds may advantageously be used as selective modulators of D3 receptors. In particular compounds of formula (I) are dopamine D3 receptor antagonists and as such are of potential use as antipsychotic agents for example in the treatment of schizophrenia, schizo-affective disorders, psychotic depression and mania. Other conditions which may be treated by modulation of dopamine D3 receptors include dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias; depression; and drug (eg. cocaine) dependency.

In a further aspect therefore the present invention provides a method of treating conditions which require modulation of dopamine D3 receptors, for example psychoses such as schizophrenia, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof. The invention also provides the use of a compound of formula (I) or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions which require modulation of dopamine D3 receptors, for example psychoses such as schizophrenia.

For use in medicine, the compounds of the present invention are usually administered as a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of formula (I) or a physiologically acceptable salt thereof and a physiologically acceptable carrier.

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The compounds of formula (I) may be administered by any convenient method, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.

The compounds of formula (I) and their physiologically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non- aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluoro- chlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomiser.

Compositions suitable for bυccal o.' sul Oingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

Compositions suitable for transdermal administration include ointments, gels and patches.

Preferably the composition is in unit dose form such as a tablet, capsule or ampoule. Each dosage unit for oral administration contains preferably from 1 to 250 mg

(and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a physiologically acceptable salt thereof calculated as the free base.

The physiologically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 500 mg, preferably between 10 mg and 400 mg,e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a physiologically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

The invention is further illustrated by the following non-limiting examples :

Description 1 l-Methoxy-2-naphthoic acid (Dl)

A mixture of l-hydroxy-2-naphthoic acid (25g, 0.133 mol), anhydrous potassium carbonate (55. Ig, 0.4 mol) and dimethyl sulfate (26.5 mL, 0.28 mol) in dry acetone (500 mL) was heated and stirred under reflux for 18h. After cooling, the mixture was filtered and the filtrate evaporated in vacuo to give an oil, which was dissolved in methanol (50mL) and 40% sodium hydroxide (100 mL) and water (200 mL). The resulting mixture was heated under reflux for lh, cooled, diluted with water and extracted with dichloromethane. The aqueous layer was then acidified to pH 1 with concentrated hydrochloric acid and the resulting solid (26 g) filtered off to give the title compound (Dl).

NMR (CDCI3) δ 4.17 (3H, s), 7.64 (1H, m), 7.69 (1H, d, J = 6 Hz), 7.91 (1H, m), 8.09 (lh, d, J = 6 Hz), 8.20 (1H, m).

Description 2 4-ChIorosulfonyl-l-methoxy-2-naphthoic acid (D2) l-Methoxy-2-naphthoic acid (Dl) (25 g, 0.124 mol) was added portionwise, with stirring, to chlorosulfonic acid (125 mL), cooled with an ice-methanol bath. The reaction mixture was then stirred at room temperature for 4h, and added dropwise to crushed ice (50 g). Filtration gave the title compound (D2) (8.3 g) as an off-white solid. NMR (CDC1 ₃ ) 5 4.27 (3H, s), 7.81 (1H, t, J = 7Hz), 7.95 (1H, dt, J = 7, 1 Hz), 8.50 (1H, d, J = 7 Hz), 8.81 (1H, d, J = 7 Hz), 8.95 (1H, s).

Description 3

4-Ethylsulfonyl-l-methoxy-2-naphthoic acid (D3)

A mixture of sodium sulfite (5.6 g, 44 mmol) and sodium bicarbonate (8.0 g, 95 mmol) in water (35 mL) was heated to 75 °C. 4-Chlorosulfonyl-l-methoxy-2-naphthoic acid (D2) (9.5 g, 32 mmol) was then added portionwise over lh, and the resulting solution heated at 75 °C for a further 2h. The reaction mixture was then cooled to 50 °C, and methanol (15 mL) added slowly, followed by ethyl iodide (5.6 mL, 70 mmol), and the mixture then heated at 60 °C for 20h. The mixture was cooled and partitioned between water and dichloromethane. The aqueous layer was acidified and extracted with ethyl acetate and the organic extracts dried and evaporated in vacuo to give the title compound (D3) as an off- white solid (6.4 g).

NMR (CDCI3) δ 1.32 (3H, t, J = 8 Hz), 3.34 (2H, q, J = 8 Hz), 4.23 (3H, s), 7.75 (1H, dt, J = 7, 1 Hz), 7.86 (1H, dt, J = 7, 1 Hz), 8.47 (1H, dd, J = 7, 1 Hz), 8.78 (1H, d, J = 7 Hz), 8.86 (1H, s).

Description 4

4-EthyIsulfonyl-l-nιethoxy-2-naphthoyl chloride (D4)

To a suspension of 4-ethylsulfonyl-l-methoxy-2-naphthoic acid (D3) (6.3 g, 21 mmol) in dry toluene (125 mL) was added oxalyl chloride (3.8 mL, 43 mmol) at room temperature.

A drop of DMF was added and the mixture stirred at room temperature for 2h. The mixture was evaporated in vacuo and the residue titurated with 1:1 toluene/pentane to give the title compound (6.0 g).

NMR (CDCI3) δ 1.31 (3H, t, J = 8 Hz), 3.34 (2H, q, J = 8 Hz), 4.16 (3H, s), 7.76 (1H, t, J

= 7 Hz), 7.87 (1H, dt, J = 7, 1 Hz), 8.48 (1H, d, J = 7 Hz), 8.76 (1H, d, J = 7 Hz), 8.86

(1H, s).

Description 5 2-(4-Ethylsulfonyl-l-methoxy-2-naphthyl)-lH-pyrrole (D5)

Prepared from 4-ethylsulfonyl-l-methoxy-2-naphthoyl chloride (D4) (4.65 g, 15mmol) by the method of Kruse et al (Heterocycles, 26, 3141, 1987). NMR (CDC1 ) δ 1.27 (3H, t, J = 8 Hz), 3.33 (2H, q, J = 8Hz), 3.91, 3H, s), 6.38 (IH, dd, J = 6, 2 Hz), 6.85 (IH, m), 7.00 (IH, m), 7.64 (2H, m), 8.24 (IH, m), 8.57 (IH, s), 8.66 (IH, m), 9.87 (IH, br s).

Description 6 4-Bromo-l-methoxy-2-naphthoic acid (D6)

To a stirred suspension of l-hydroxy-2-naphthoic acid (lOg, 53mmol) in glacial acetic acid (100ml) was added, dropwise over 0.25h, bromine (2.75ml; 8.5 lg, 53mmol). Reaction mixture was stirred at room temperature for 0.5h then diluted with water. The resulting solid was filtered off and dried in vacuo (13.21g), then dissolved in acetone (500ml). Anhydrous potassium carbonate (20.5 lg, 148mmol) and dimethyl sulfate (9.7ml; 13g, 103mmol were added and the resulting mixture heated at reflux for 18h. The reaction mixture was cooled, filtered, and the filtrate evaporated in vacuo to give a solid. The latter was suspended in methanol (50ml) and 40% aqueous sodium hydroxide (50ml). The suspension was heated at reflux with the addition of water (200ml) for 0.5h, then cooled. Water (200ml) was added and the mixture extracted with dichloromethane (3x100ml). The aqueous phase was acidified (pHl) with concentrated hydrochloric acid. The resulting solid was filtered off and dried in vacuo (1 l.lg, 74%). -U NMR (CDCI3) δ: 4.10 (3H, s), 7.66 (IH, dt, J = 8, 1Hz), 7.73 (IH, dt, J = 8, 1Hz), 8.23 (IH, d, J = 8Hz), 8.28 (IH, d, J = 8Hz), 8.30 (IH, s)

Description 7

4-Bromo-l-methoxy-2-naphthoyl chloride (D7)

To a stirred suspension of 4-bromo-l -methoxy- 2-naphthoic acid (D6) (9.0g, 32mmol) in toluene (250ml) at room temperature was added oxalyl chloride (5.6ml; 8.1g, 64mmol) followed by dimethylformamide (20 drops). Reaction mixture was stirred at room temperature for 2h then evaporated in vacuo. The residue was dissolved in 1:1 toluene- pentane and filtered, and the filtrate evaporated in vacuo to give an off-white solid (9.5g, 99%). ^Ϊ H NMR (CDCI3) δ: 4.05 (3H, s), 7.66 (IH, dt, J = 8, 1Hz), 7.81 (IH, dt, J = 8, 1Hz), 8.25 (IH, d, J = 8Hz), 8.33 (IH, d, J = 8Hz), 8.34 (IH, s)

Description 8

2-(4-Bromo-l-methoxy-2-nap thyl-lH-pyrrole (D8)

Formed from 4-bromo-l-methoxy-2-naphthoyl chloride (D7) (9.5g) by the method of Kruse et al (Heterocycles, 26, 3141, 1987), in 80% yield. -U NMR (CDCI3) δ: 3.86 (3H, s), 6.36 (IH, m), 6.70 (IH, m), 6.99 (IH, m), 7.57 (2H, m), 8.06 (IH, s), 8.14 (2H, m), 9.93 (IH, br s)

Description 9

4-Chloro-l-methoxy-2-naphthoyl chloride (D9) Prepared from l-hydroxy-2-naphthoic acid (10.09g) using a method analogous to Descriptions 6 and 7, using chlorine instead of bromine, in 77% yield. ^l H NMR (CDCI3) δ: 4.05 (3H, s), 7.72 (IH, dt, J = 8, 1Hz), 7.81 (IH, dt, J = 8Hz, 1Hz), 8.15 (IH, s), 8.29 (IH, d, J = 8), 8.33 (IH, d, J = 8Hz)

Description 10

2-(4-Chloro-l-methoxy-2-naphthyl)-lH-pyrroIe (D10)

Formed from 4-chloro-l-methoxy-2-naphthoyl chloride (D9) (9g) by the method of Kruse et al (Heterocycles, 26, 3141, 1987), in 72% yield.

-H NMR (CDCI3) δ: 3.86 (3H, s), 6.34 (IH, m), 6.70 (IH, m), 6.96 (IH, m), 7.58 (2H, m), 7.84 (IH, s), 8.12 (IH, m), 8.18 (IH, m), 9.95 (IH, br s)

Description 11

4-Dimethylaminosulfonyl-l-methoxy-2-naphthoic acid (Dll)

4-Chlorosulfonyl-l-methoxy-2-naphthoic acid (D2) (23g, 76.5mmol) was added portionwise to a mixture of 40% aqueous dimethylamine (100ml) and water (400ml) with vigorous stirring. A homogeneous solution resulted which was acidified (pHl) with concentrated hydrochloric acid (50ml). Resulting mixture was extracted with ethyl acetate (5x100ml) and the combined extracts dried (Na2SO4) and evaporated in vacuo to give a solid (22.8g, 96%). -H NMR (CDCI3) δ: 2.92 (6H, s), 4.22 (3H, s), 7.73 (IH, dt, J = 8, 1Hz), 7.82 (IH, dt, J = 8, 1Hz), 8.40 (IH, d, J = 8Hz), 8.70 (IH, s), 8.80 (IH, d, J = 8Hz)

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SUBSΠTUTE SHEET (RULE 2®

Description 12 2-(4-Dimethylaminosulfonyl-l-methoxy-2-naphthyl)-lH-pyrrole (D12)

Prepared from 4-dimethylaminosulfonyl-l-methoxy-2-naphthoic acid (Dl l) (14g) using methods analogous to Descriptions 7 and 8 in 69% yield. -H NMR (CDC1 ₃ ) δ: 2.85 (6H, s), 4.41 (3H, s), 6.49 (IH, m), 6.82 (IH, m), 7.02 (IH, m), 7.61 (2H, m), 8.20 (IH, m), 8.50 (IH, s), 8.79 (IH, m), 9.89 (IH, br s).

Description 13 2-Phenyl-l-azacycloheptane (D13) To a solution of l-aza-2-methoxy-l-cycloheptene (50.9 g) in benzene (600 ml) under argon was added phenyl magnesium bromide (300 ml of a 3M solution in ether) and the mixture was heated at reflux for 4 h. The reaction mixture was cooled (ice/water) and LAIH4 (16.9 g) was added portion wise. The mixture was then heated at reflux for 5 h, cooled to room temperature and poured onto crushed ice. The resultant slurry was basified with aqueous 10% sodium hydroxide and filtered through kieselguhr, which was then washed with ether. The layers were separated and the aqueous fraction was further extracted with ether. The combined ether layers were dried (sodium sulphate) and evaporated to dryness in vacuo to give an orange-gold liquid, which on distillation (0.5 mm Hg) gave the title compound as a colourless liquid (46.43 g, 66%), bp 82-90°C. -U NMR (CDCI3) δ: 1.50 - 2.09 (8H, broad m), 2.75 - 2.95 (IH, m), 3.06 - 3.24 (IH, m), 3.65 - 3.81 (IH, dd, J=4,10 Hz), and 7.13 - 7.45 (5H, m).

Description 14 l-FormyI-2-phenyl-l-azacycloheptane (D14) To a mixture of, 98-100% formic acid (30 ml) and acetic anhydride (100 ml) was added 2- (R,S)-phenylazacycloheptane, (10 g, 57.1 mmol) and the mixture warmed to 70°C for 2 h. The reaction mixture was then cooled and evaporated to dryness in vacuo and the residue was partitioned between ether and saturated aqueous potassium carbonate. The ether layer was separated and evaporated to dryness in vacuo to afford the title compound (11.24 g; 97%) as a mixture of E Z isomers.

-U NMR (CDCI3) exists as two conformers; δ 1.2-2.1(7H, m), 2.3-2.6 (1 H, m), 2.8 (t, J=12 Hz) and 3.3 (t, J=12 Hz) (together IH), 3.65 (broad d, J=12 Hz) and 4.24 (broad d, J=12 Hz) (together IH), 4.67 (q, J=7 Hz) and 5.3 (q, J=7 Hz) (togetherlH), 7.13-7.45, (5H, m), 8.15 (s) and 8.3 (s) (together IH).

Description 15 2-(4-Cyano-l-methoxy-2-naphttιyl)-lH-pyrrole (D15)

A mixture of 2-(4-bromo-l-methoxy-2-naphthyl)-lH-pyrrole (D8), (0.60 g, 2.0 mmol), zinc cyanide (0.39 g, 3.33 mmol) and tetrakistriphenylphosphine-palladium (0) (0.046 g, 0.04 mmol) in distilled degassed dimethylformamide (10 ml) was heated at 100°C for 3 h under argon. The reaction mixturewas cooled then poured into 5N aqueous ammonia (50 ml) and the resultant extracted with ethyl acetate (3x50 ml). The combined extracts were dried (Na2SO4) and evaporated in vacuo to give a solid (0.50 g). Recrystallisation from hexane gave olive green needles (0.35 g, 70 %) mp 168-171°C

-U NMR (CDC1 ) δ: 3.90 (3H, s), 6.36 (IH, m), 6.72 (IH, m), 7.00 (IH, m), 7.63 (2H, m), 8.16 (2H, m), 8.19 (IH, s), 9.85 (IH, br s).

Example 1 2-(4-EthyIsuIfonyl-l-methoxy-2-naphthyI)-5-(l-piperidinyImet hyl)-lH-pyrrole (El)

A solution of piperidine (0.16 mL, 1.7 mmol) in ethanol (20 mL) at room temperature was treated with aqueous formaldehyde (40%; 0.13 mL, 1.7 mmol) and glacial acetic acid (0.17 mL, 2.1 mmol). The mixture was stirred at room temperature for 30 mins, then added to a solution of 2-(4-ethylsulfonyl-l-methoxy-2-naphthyl)-lH-pyrrole (D5) (0.47 g, 1.5 mmol) in dry ethanol (10 mL). The reaction mixture was stirred at room temperature for 48 h, then evaporated in vacuo. The residue was dissolved in ether and the solution extracted with hydrochloric acid (0.1M; 3 x 30 mL) and the combined aqueous extracts basified and extracted with dichloromethane. The dichloromethane extracts were dried and evaporated in vacuo to give an oil which crystallised from methanol as colourless needles to give the title compound (El) (0.31 g), m.pt. 146-150 °C.

Analysis: Found C, 66.93, H, 6.53, N, 6.93%; C23H28N2O3S requires C, 66.96, H, 6.84, N, 6.79%.

Example 2 2-(4-Bromo-l-methoxy-2-naphthyl)-5-(2-(l-ethyI)pyrrolidinyl) -lH-pyrrole (E2)

Phosphorus oxychloride (0.36ml; 4mmol) was added dropwise to stirred l-ethyl-2- pyrrolidinone (0.46ml, 0.45g, 4mmol) at room temperature under argon. Stirring at room temperature was continued for lh, then dichloroethane (30ml) was added, followed by 2- (4-bromo-l-methoxy-2-naphthyl)-lH-pyrrole (D8) (0.60g, 2mmol). Stirring at room temperature was continued for a further 18h, then the reaction mixture was cooled to 0°C while sodium borohydride (0.8g, excess) was added portionwise. Reaction mixture was

- 15 -

stirred at room temperature for lh, then a mixture of water (4ml) and methanol (4ml) was added dropwise over O.lh. Reaction mixture was stirred at room temperature for lh then partitioned between water (50ml) and dichloromethane (3x30ml). Combined organic extracts were dried (Na2SO4) then evaporated in vacuo to give a residue which was dissolved in a mixture of methanol (4ml), dichloromethane (4ml) and concentrated hydrochloric acid (4ml). This mixture was stirred at room temperature for lh, then was partitioned between 5% aqueous sodium hydroxide (50ml) and dichloromethane (3x30ml). Organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica using hexane with 10-100% ethyl acetate gradient elution gave a solid (0.75g, 95%). Recrystallisation from methanol gave the title compound E2 as grey plates, m.p. 113-117°C. Mass spectrum: Found M ⁺ 398.0977; C2iH23BrN2θ requires 398.0992.

Example 3 2-(4-Bromo-l-methoxy-2-naphthyl)-5-(l-(2-phenyl)-l-azacycIoh eptanyl)methyl-lH- pyrrole, hydrochloride (E3)

Prepared by a method analogous to that used to prepare Example 1, using 2-(4-bromo-l- methoxy-2-naphthyl)-lH-pyrrole (D8) (0.45g) instead of 2-(4-ethylsulfonyl-l-methoxy-2- naphthyl)-lH pyrrole and 2-phenyl-l-azacycloheptane (D13) instead of piperidine, in 26% yield. Conversion to the hydrochloride salt gave the title compound E3. Mass spectrum: Found M ⁺ 488.1423; C28H2θBrN2θ requires 488.1459.

Example 4

2-(4-Bromo-l-methoxy-2-naphthyI)-5-(l-piperidinyl)methyl- lH-pyrrole, hydrochloride (E4)

Prepared by a method analogous to that used to prepare Example 1 using 2-(4-bromo-l- methoxy-2-naphthyl)-lH-pyrrole (D8) (0.45g) instead of 2-(4-ethylsulfonyl-l-methoxy-2- naphthyl)-lH-pyrrole, in 67% yield. Conversion to the hydrochloride salt gave the title compound E4. Mass spectrum: Found M+ 398.1004 C2iH23BrN2O requires 397.9992

Example 5

2-(4-Chloro-l-methoxy-2-naphthyl)-5-(l-piperidinylmethyl) -lH-pyrroIe hydrochloride (E5) Prepared as the free base by the method of Example 1 from 2-(4-chloro-l-methoxy-2- naphthyl)-lH-pyrrole (D10) (0.5g) instead of 2-(4-ethylsulfonyl-l-methoxy-2-naphthyl)-

IH-pyrrole in 54% yield. Conversion to the hydrochloride salt gave the title compound E5.

Found C, 64.45, H, 6.18, N, 7.16%; C21H23CIN2O.HCI requires C, 64.34, H, 6.15, N, 7.27%

Example 6

2-(4-Ethylsulfonyl-l-methoxy-2-naphthyl)-5-(2-(l-ethyl)py ιτoIidinyI)-lH-pyrrole, hydrochloride (E6)

Prepared by a method analogous to that used to prepare Example 2 using 2-(4- ethylsulfonyl- l-methoxy-2-naphthyl)- lH-pyrrole (D5) (0.47g) instead of 2-(4-bromo- 1- methoxy-2-naphthyl)- IH-pyrrole, in 90% yield. Conversion to the hydrochloride salt gave the title compound E6.

Found: C, 61.50, H, 6.36, N, 6.50%; C23H28N2O3S. HC1 requires C, 61.52, H, 6.51, N, 6.24%

Example 7

2-(4-Ethylsulfonyl-l-methoxy-2-naphthyI)-5-(l-(2-phenyl)- l-azacycloheptanyI)- methyl-lH-pyrrole, hydrochloride (E7)

Prepared by a method analogous to that used to prepare Example 2 using 2-(4- ethylsulfonyl- l-methoxy-2-naphthyl)-lH-pyrrole (D5) (0.62g) instead of 2-(4-bromo-l- methoxy-2-naphthyl)-lH-pyrrole and l-formyl-2-phenyl-l-azacycloheptane (D14) instead of l-ethyl-2-pyrrolidinone, in 73% yield. Conversion to the hydrochloride salt gave the title compound E7.

Mass spectrum: Found M ⁺ 502.2266; C30H34N2O3S requires 502.2283

Example 8

2-(4-DimethylaminosulfonyI-l-methoxy-2-naphthyI)-5-(l-pip eridinylmethyI)-lH- pyrrole (E8)

Prepared by a method analogous to that used to prepared Example 1 using 2-(4- dimethylaminosulfonyl-l-methoxy-2-naphthyl)-lH-pyrrole (D12) (0.58g) instead of 2-(4- ethylsulfonyl-l-methoxy-2-naphthyl)- IH-pyrrole, in 64% yield, mp. 127-129°C Mass spectrum: Found M+ 427.1948; C23H29N3O3S requires 427.1928

- 17 - SUBSTITUTE SHEET (RULE 2β)

Example 9

2-(4-Dimethylaminosulfonyl-l-methoxy-2-naρhthyl)-5-(l-(2 -phenyl)-l- azacycloheptanyI)methyl- IH-pyrrole (E9)

Prepared by a method analogous to that used to prepare Example 2 using 2-(4- dimethylaminosulfonyl-l-methoxy-2-naphthyl)-lH-pyrrole (D12) (0.64g) instead of 2-(4- bromo- l-methoxy-2-naphthyl)- lH-pyrrole and 1 -formyl-2-phenyl- 1 -azacycloheptane (D14) instead of l-ethyl-2-pyrrolidinone, in 58% yield, mp 133-136°C. Mass spectrum: Found M ⁺ 517.2431; C30H35N3O3S requires 517.2398

Example 10

2-(4-Ethylsulfonyl-l-methoxy-2-naphthyI)-5-(l-(l-piperidi nyl)ethyl)-lH pyrrole (E10)

Prepared by a method analogous to that used to prepare Example 2 using 2-(4- ethylsulfonyl-l-metiιoxy-2-naphthyl)- IH-pyrrole (D5) (0.62g) instead of 2-(4-bromo-l- methoxy- 2-naphthyl)- IH-pyrrole and 1-acetyl-piperidine instead of l-ethyl-2- pyrrolidinone, in 59% yield.

-H NMR (CDCI3) δ: 1.26 (3H, t, J = 7Hz), 1.38 (3H, d, J = 7Hz), 1.49 (2H, m), 1.62 (4H, m), 2.50 (4H, m), 3.32 (2H, q, J = 7Hz), 3.82 (IH, q, J = 7Hz), 3.91 (3H, s), 6.11 (IH, m), 6.74 (IH, m), 7.63 (2H, m), 8.25 (IH, m), 8.55 (IH, s), 8.66 (IH, m), 9.52 (IH, br s)

Example 11

2-(4-Cyano-l-methoxy-2-naphthyl)-5-(2-(l-ethyl)pyrroIidin yl)-lH pyrrole (Ell)

Prepared by a method analogous to that used to prepare Example 2 using 2-(4-cyano-l- methoxy-2-naphthyl)- IH-pyrrole (D15) (0.20 g) instead of 2-(4-bromo-l-methoxy-2- naphthyl)- IH-pyrrole, in 92 % yield. A sample was recrystallised from methanol, mp

123-127°C. iH NMR (CDCI3) δ: 1.10 (3H, t, J=7Hz), 1.75-1.95 (3H, m), 2.08-2.27 (3H, m), 2.77

(IH, dq, J=7Hz, 11Hz), 3.35 (IH, m), 3.48 (IH, t, J=8Hz), 3.87 (3H, s), 6.14 (IH, m), 6.60 (IH, m), 7.63 (2H, m), 8.15 (2H, m),8.16 (IH, s), 9.90 (IH, br s).

Example 12

2-(4-Cyano-l-methoxy-2-naphthyl)-5-(2-(l-butyl)pyrrolidin yl)-lH-pyrrole (E12)

Prepared by a method analogous to that used to prepare Example 2 using (2-(4-cyano-l- methoxy-2-naphthyl)- IH-pyrrole (D15) (0.14g) instead of 2-(4-bromo-l-methoxy-2-

- 18 - SUBSTTTUTE SHEET (RULE 26)

naphthyl)- IH-pyrrole, and l-butyl-2-pyπolidone instead of l-ethyl-2-pyrrolidone, in 60% yield.

-H NMR (CDCI3) δ: 0.84 (3H, t, J=7Hz), 1.20-1.40 (2H, m), 1.42-1.57 (2H, m), 1.75-2.00 (3H, m), 2.09-2.28 (3H, m), 2.67 (IH, m), 3.32 (IH, m), 3.46 (IH, t, J=8Hz), 3.87 (3H, s), 6.13 (IH, m), 6.61 (IH, m), 7.62 (2H, m), 8.15 (3H, m), 9.90 (IH, br s).

Biological Test Methods

The ability of the compounds to bind selectively to human D3 dopamine receptors can be demonstrated by measuring their binding to cloned receptors. The inhibition constants (Kj) of test compounds for displacement of [^~T iodosulpride binding to human D2 and D3 dopamine receptors expressed in CHO cells have been determined. The cell lines were shown to be free from bacterial, fungal and mycoplasmal contaminants, and stocks of each were stored frozen in liquid nitrogen. Cultures were grown as monolayers or in suspension in standard cell culture media. Cells were recovered by scraping (from monolayers) or by centrifugation (from suspension cultures), and were washed two or three times by suspension in phosphate buffered saline followed by collection by centrifugation. Cell pellets were stored frozen at -40°C. Crude cell membranes were prepared by homogenisation followed by high-speed centrifugation, and characterisation of cloned receptors achieved by radioligand binding.

Preparation of CHO cell membranes

Cell pellets were gently thawed at room temperature, and resuspended in about 20 volumes of ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), 20mM EDTA, 0.2 M sucrose. The suspension was homogenised using an Ultra-Turrax at full speed for 15 sec. The homogenate was centrifuged at 18,000 r.p.m for 20 min at 4°C in a Sorvall RC5C centrifuge. The membrane pellet was resuspended in ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), using an Ultra-Turrax, and recentrifuged at 18,000 r.p.m for 15 min at 4°C in a Sorvall RC5C. The membranes were washed two more times with ice-cold 50 mM Tris salts (pH 7.4 @ 37°C). The final pellet was resuspended in 50 mM Tris salts (pH 7.4 @ 37°C), and the protein content determined using bovine serum albumin as a standard (Bradford, M. M. (1976) Anal. Biochem. 72, 248-254).

Binding experiments on cloned dopamine receptors

Crude cell membranes were incubated with 0.1 nM [-^T\ iodosulpride (-2000 Ci/mmol; Amersham, U. K.), and the test compound in a buffer containing 50 mM Tris salts (pH 7.4 @ 37°C), 120 mM NaCl, 5 mM KC1, 2 mM CaCl ₂ , 1 mM MgCl2, 0.1% (w/v) bovine serum albumin, in a total volume of 1 ml for 30 min at 37°C. Following incubation,

samples were filtered using a Brandel Cell Harvester, and washed three times with ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), 120 mM NaCl, 5 mM KC1, 2 mM CaCl2, 1 mM MgCl2- The radioactivity on the filters was measured using a Cobra gamma counter (Canberra Packard). Non-specific binding was defined as the radioligand binding remaining after incubation in the presence of 100 μM iodosulpride. For competition curves, 14 concentrations (half-log dilutions) of competing cold drug were used.

Competition curves were analysed simultaneously whenever possible using non-linear least-squares fitting procedures, capable of fitting one, two or three site models.

The compounds of Examples 1, 2, 6, 7, 8 and 9 had IC50 values of between 0.5 and 5 nm at the human D3 receptor.

Pharmaceutical Formulations The following represent typical pharmaceutical formulations according to the present invention, which may be prepared using standard methods.

IV Infusion

Buffer : Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.

Solvent : Typically water but may also include cyclodextrins (1-100 mg) and co-solvents such as propylene glycol, polyethylene glycol and alcohol.

Tablet

Compound 1 - 40 mg Diluent/Filler * 50 - 250 mg Binder 5 - 25 mg

Disentegrant * 5 - 50 mg Lubricant l - 5 mg Cyclodextrin 1 - 100 mg

* may also include cyclodextrins

Diluent : e.g. Microcrystalline cellulose, lactose, starch Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose

Disintegrant : e.g. Sodium starch glycoUate, crospovidone Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate.

Oral Suspension

Compound 1 - 40 mg

Suspending Agent 0.1 - 10 mg

Diluent 20 - 60 mg

Preservative 0.01 - 1.0 mg

Buffer to pH ca 5 - 8

Co-solvent 0 - 40 mg

Flavour 0.01 - 1.0 mg

Colourant 0.001 - O.l mg

Suspending agent : e.g. Xanthan gum, microcrystalline cellulose Diluent : e.g. sorbitol solution, typically water Preservative : e.g. sodium benzoate Buffer : e.g. citrate Co-solvent : e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin