IMIDAZOLONE AND OXAZOLONE DERIVATIVES AS DOPAMINE ANTAGONISTS

This invention relates to a particular class of substituted oxazolone and imidazolone derivatives which are antagonists of dopamine receptor subtypes within the brain and are therefore of benefit in the treatment and/or prevention of psychotic disorders such as schizophrenia.

The "dopamine hypothesis" of schizophrenia predicts an increased activity of dopamine neurotransmission in the disease. The hypothesis is supported by early observations that drugs, such as amphetamine, with dopamine agonist or dopamine-releasing properties are capable of eliciting a psychosis indistinguishable from acute paranoid schizophrenia.

Schizophrenia is a disorder which is conventionally treated with drugs known as neuroleptics. In the majority of cases, the symptoms of schizophrenia can be treated successfully with so-called "classical" neuroleptic agents such as haloperidol. Classical neuroleptics generally are antagonists at dopamine D2 receptors. The fact that classical neuroleptic drugs have an action on dopamine receptors in the brain thus lends credence to the "dopamine hypothesis" of schizophrenia.

Molecular biological techniques have revealed the existence of several subtypes of the dopamine receptor. The dopamine D^ receptor subtype has been shown to occur in at least two discrete forms. Two forms of the D ₂ receptor subtype, and at least one form of the D ₃ receptor subtype, have also been discovered. More recently, the D ₄ (Van Tol et al . , Nature (London), 1991, 350. 610) and D ₅ (Sunahara et al. , Nature (London), 1991, 350. 614) receptor subtypes have been described. Notwithstanding their beneficial antipsychotic effects, classical neuroleptic agents such as haloperidol

are frequently responsible for eliciting acute extrapyramidal symptoms and neuroendocrine disturbances. These side-effects, which clearly detract from the clinical desirability of classical neuroleptics, are believed to be attributable to D ₂ receptor blockade in the striatal region of the brain. It is considered (Van Tol et al. , supra) that compounds which can interact selectively with the dopamine D ₄ receptor subtype, whilst having a less-pronounced action at the D ₂ subtype, might be free from, or at any rate less prone to, the side- effects associated with classical neuroleptics, whilst at the same time maintaining a beneficial level of antipsychotic activity.

The compounds according to the present invention, being antagonists of dopamine receptor subtypes within the brain, are accordingly of benefit in the treatment and/or prevention of psychotic disorders such as schizophrenia. Moreover, the compounds according to the invention have a selective affinity for the dopamine D ₄ receptor subtype over other dopamine receptor subtypes, in particular the D ₂ subtype, and can therefore be expected to manifest fewer side-effects than those associated with classical neuroleptic drugs.

EP-A-0379990 describes a class of 4,5- disubstituted 2H-imidazol-2-ones which are stated to have affinity jln vitro against D ₂ , 5-HT ₂ and α^ receptors, as well as showing activity .in vivo on the central nervous system in various behavioural tests, and antihypertensive activity. The compounds described therein are accordingly alleged to be useful as antipsychotic, antidepressant and anxiolytic agents, as well as having utility in the treatment of hypertension and other cardiovascular complaints. Since their antipsychotic activity is presumably mediated by antagonism of D ₂ receptors, however, it seems reasonable to suppose that these compounds are subject to the drawbacks, in terms of

their unpleasant side-effects, customarily associated with, classical neuroleptic drugs.

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

(I) wherein

X represents oxygen or N-R ¹ ;

Q represents a substituted five-, six- or seven-membered monocyclic heteroaliphatic ring which contains one nitrogen atom as the sole heteroatom and is linked to the imidazolone or oxazolone ring via a carbon atom;

R ¹ represents hydrogen or C^-g alkyl; and p "5 one of R and R represents hydrogen or C^_g alkyl and the other of R ² and R ³ represents cycloalkyl or a group of formula (i) , (ii) or (iii) :

( (t i) (HI)

in which Z represents oxygen, sulphur or NH;

R , R and R ⁶ independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano,

trifluoromethyl, nitro, -OR ^a , -SR ^a , -S0R ^a , S0 ₂ R ^a , -SC ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C0R ^b , -NR ^a C0 ₂ R ^b , -C0R ^a , -C0 ₂ R ^a or -CONR ^a R ^b ; and

R ^a and R ^b independently represent hydrogen, hydrocarbon or a heterocyclic group.

The monocyclic heteroaliphatic ring Q in the compounds of formula I above represents a substituted pyrrolidyl, piperidyl or homopiperidyl moiety linked through carbon. Examples of suitable rings include the moieties of formula Qa to Qf:

( ^Q o) (Qb) (Qc)

(Qd) ( ^Q ( ^Q f)

wherein one of R and R ⁸ represents hydrocarbon or a heterocyclic group, and the other of R ⁷ and R ⁸ represents hydrogen, hydrocarbon or a heterocyclic group.

A particular monocyclic heteroaliphatic ring represented by the substituent Q in formula I is the ring of structure Qa above.

The compounds of the present invention are preferably prepared and utilised in the form of a free base or as a pharmaceutically acceptable salt thereof. 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, 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 C _ alkyl, C ₂ _g alkenyl, C _g alkynyl, C ₃ _ ₇ cycloalkyl, C ₃ _ ₇ cycloalkyl(C^ _^ - )alkyl, aryl and aryl(C^- )alkyl. 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 C ₃ .--.7 heterocycloalkyl, C ₃ _ ₇ heterocycloalkyl(Cι_.g)alkyl, heteroaryl and heteroaryl(Cχ_g)alkyl groups. Suitable alkyl groups include straight-

chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl.

Suitable alkenyl groups include straight- chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl and allyl groups. Suitable alkynyl groups include straight- chained 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 include phenyl and naphthyl.

Particular aryl(C^- )alkyl groups include benzyl, naphthylmethyl, phenethyl and phenylpropyl.

Suitable heterocycloalkyl groups include azetidinyl, pyrrolidyl, piperidyl, piperazinyl and morpholinyl groups.

Suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl and thiadiazolyl groups.

Particular heteroaryl(C^g)alkyl groups include pyridylmethyl and pyrazinylmethyl.

The hydrocarbon and heterocyclic groups may in turn be optionally substituted by one or more groups selected from C^.g alkyl, ada antyl, phenyl, halogen, Cι_g haloalkyl, C^g aminoalkyl, trifluoromethyl, hydroxy, C ₁ _g alkoxy, aryloxy, keto, Cι_ ₃ alkylenedioxy, nitro, cyano, carboxy, C ₂ _g alkoxycarbonyl, C ₂ _g

alkoxycarbonyl(C ₁ _g)alkyl, C ₂ _g alkylcarbonyloxy, ary-lcarbonyloxy, C ₂ _g alkylcarbonyl, arylcarbonyl, C^ alkylthio, C^g alkylsulphinyl, C^g alkylsulphonyl, arylsulphonyl, -NR ^V R ^W , -NR ^v COR ^w , -NR ^v C0 ₂ R ^w , -NR ^v S0 ₂ R ^w , -CH ₂ NR ^V S0 ₂ R ^W , -NHCONR ^v R ^W , -CONR ^V R ^W , -S0 ₂ NR ^v R ^w and

-CH ₂ S0 ₂ NR ^v R ^w , in which R ^v and R ^w independently represent hydrogen, C^-β alkyl, aryl or aryl(C^g)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 are encompassed within the scope of the present invention.

Preferably, X represents N-R ¹ in which the substituent R ¹ suitably represents hydrogen or methyl, especially hydrogen.

Suitably, one of R ² and R ³ represents hydrogen or methyl, and the other of R ² and R ³ represents a group of formula (i) as defined above.

Suitably, Z is oxygen or sulphur. Suitable values for the substituents R , R ⁵ and

R ⁶ include hydrogen, halogen, trifluoro ethyl, cyano,

nitro, amino, C^-g alkylamino, difCi-gJalkylamino, C^g alky-l, C^ alkoxy, aryl(C^ )alkoxy and C ₂ _g alkylcarbonyl. Particular values include hydrogen, methyl, ethyl, isopropyl, methoxy, benzyloxy, fluoro and chloro.

Suitable values for the substituents R ⁷ and R ⁸ include C ₂ _g alkenyl, C ₃ _7 cycloalkyl(C^-g)alkyl, aryl and aryl(Ci-g)alkyl, any of which groups may be optionally substituted. In addition, one of R ⁷ and/or R ⁸ may represent hydrogen. Examples of suitable substituents on the groups R' and/or R° include C^.g alkyl, halogen, trifluoromethyl, C^.g alkoxy, Cι_ ₃ alkylenedioxy, cyano and nitro.

Particular values of R ⁷ and R ⁸ include hydrogen, allyl, cyclopropylmethyl, cyclohexylmethyl, benzyl, methyl-benzyl, chlorobenzyl, bromobenzyl, iodobenzyl, dichlorobenzyl, methoxy-benzyl, trifluoromethyl-benzyl, methylenedioxy-benzyl, cyanobenzyl, nitro-benzyl, naphthylmethyl, phenethyl and phenylpropyl, provided that at least one of R ⁷ and R ⁸ is other than hydrogen. Suitably, one of R ⁷ and R ⁸ represents hydrogen, and the other of R ⁷ and R ⁸ is other than hydrogen. Preferably, R ⁸ represents hydrogen and R ⁷ is other than hydrogen. A particular sub-class of compounds according to the invention is represented by the compounds of formula IIA, and salts and prodrugs thereof:

(MA)

wherein n is zero, 1, 2 or 3;

X 1 represents oxygen or N-R11;

R ¹¹ and R ¹³ independently represent hydrogen or Cι_. alkyl; and

R ¹⁴ and R ¹⁹ independently represent hydrogen, halogen, trifluoromethyl, cyano, nitro, amino, ^-β alkylamino, di(C ₁ _g)alkylamino, C^ alkyl, Cj _^ . alkoxy, aryl(C _g)alkoxy or C ₂ _g alkylcarbonyl. Preferably, X ¹ is N-R ¹¹ in which R ¹¹ suitably represents hydrogen or methyl, especially hydrogen.

Suitably, R ¹³ represents hydrogen or methyl. Particular values of R ¹⁴ include hydrogen, fluoro, chloro, methyl, ethyl, methoxy and benzyloxy. Particular values of R ¹⁹ include hydrogen, methyl, ethyl, chloro, bromo, iodo, trifluoromethyl, methoxy, ethoxy, cyano, nitro and dimethylamino.

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

(I IB) wherein n, R and R ¹⁹ are as defined with reference to formula IIA above; and

P R ²¹ and R independently represent hydrogen or Cι_ ₆ alkyl.

Suitably, R ²¹ and R ²² independently represent hydrogen or methyl.

Specific compounds within the scope of the present invention include: l-(l-benzylpiperidin-4-yl)-5-methyl-4-phenyl-l,3- dihydroimidazol-2-one; l-(l-benzylpiperidin-4-yl)-4-methyl-5-phenyl-l,3- dihydroimidazol-2-one; l-(l-benzylpiperidin-4-yl)-4-(4-chlorophenyl)-5-methyl- l,3-dihydroimidazol-2-one; l-(l-benzylpiperidin-4-yl)-5-(4-chlorophenyl)-4-methyl-

1,3-dihydroimidazol-2-one;

1-(l-benzylpiperidin-4-yl)-4-phenyl-l,3-dihydroimidazol-

2-one; l-(l-benzylpiperidin-4-yl)-3-methyl-4-phenyl-l,3- dihydroimidazol-2-one;

1-(l-benzylpiperidin-4-yl)-3,5-dimethyl-4-phenyl-l,3- dihydroimidazol-2-one;

5-methyl-4-phenyl-l-[l-(2-phenylethyl)piperidin-4-yl]- 1,3-dihydroimidazol-2-one;

5-methyl-l-[l-(2-methylbenzyl)piperidin-4-yl]-4-phenyl-

1,3-dihydroimidazol-2-one;

4-(4-chlorophenyl)-5-methyl-l-[1-(2-phenylethyl)- piperidin-4-yl]-l,3-dihydroimidazol-2-one; 4-methyl-5-phenyl-3-[1-(2-phenylethyl)piperidin-4-yl]-3H- oxazol-2-one;

4-(4-chlorophenyl)-5-methyl-l-[1-(2-methylbenzyl)- piperidin-4-yl]-1,3-dihydroimidazol-2-one;

5-methyl-l-[l-(2-methylbenzyl)piperidin-4-yl]-4-(4- ethylphenyl)-1,3-dihydroimidazol-2-one;

1-[1-(3-cyanobenzyl)piperidin-4-yl]-5-methyl-4-phenyl-

1,3-dihydroimidazol-2-one;

1-[1-(3-methoxybenzyl)piperidin-4-yl]-5-πtethyl-4-phenyl -

1,3-dihydroimidazol-2-one; l-[l-(3-chlorobenzyl)piperidin-4-yl]-5-methyl-4-phenyl-

1,3-dihydroimidazol-2-one;

l-[l-(3-bromobenzyl)piperidin-4-yl]-5- ethyl-4-phenyl- l,3-dihydroimidazol-2-one;

1-[1-(3-iodobenzyl)piperidin-4-yl]-5-methyl-4-phenyl-l,3- dihydroimidazol-2-one; 5-methyl-4-phenyl-l-[l-(3-trifluoromethylbenzyl)- piperidin-4-yl]-l,3-dihydroimidazol-2-one; 5-methyl-l-[1-(2,3-methylenedioxybenzyl)piperidin-4-yl]- 4-phenyl-l,3-dihydroimidazol-2-one; 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 liguid 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 once- monthly 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. 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. 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, ethylcellulose, polyvinyl- pyrrolidone or gelatin.

In the treatment of schizophrenia, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and

especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.

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

H

I R°

,NH,

M n r

0 OH

( I I I ) ( IV)

wherein Q, R ² and R ³ are as defined above; followed, if necessary, by separation of the resulting mixture of isomers by conventional means.

The reaction is conveniently carried out under standard conditions capable of promoting the condensation reaction. Suitable reaction conditions comprise heating the reagents in toluene at reflux in the presence of trifluoroacetic acid, with azeotropic removal of water, advantageously in a Dean-Stark apparatus.

As indicated above, the overall reaction between compounds III and IV will usually give rise to a mixture of isomeric products of formula I, in one of which R ² represents hydrogen or C^g alkyl and R ³ represents cycloalkyl or a group of formula (i) , (ii) or (iii) as defined above, and in the other of which these substituents are reversed. For this reason, it will generally be necessary to separate the mixture of isomers obtained therefrom by conventional methods such as column chromatography.

The compounds of formula III above may be prepared by reacting a compound of formula Q-NH ₂ with a compound of formula RP-N=C=0, wherein Q is as defined

above, and RP represents an amino-protecting group; fol-l wed by removal of the amino-protecting group RP.

The reaction is conveniently carried out by stirring the reactants in an inert solvent such as dichloromethane, typically at 0°C with warming to room temperature.

The amino-protecting group RP is suitably an acyl moiety such as benzoyl, which can conveniently be removed as necessary by treatment under basic conditions, e.g. sodium methoxide in methanol, or sodium hydroxide in aqueous methanol.

In an alternative procedure, the compounds according to the invention wherein X represents N-R 1 may be prepared by a process which comprises reacting a compound of formula R ¹⁰ -N=C=O with a compound of formula V:

R ³ R ²

«

Q N 0

\ H

(V) p -t wherein Q, R" and R are as defined above, and R 10 corresponds to the group R or represents an amino- protecting group RP as defined above; followed, where necessary, by removal of the amino-protecting group R ¹⁰ ; and subsequently, if desired, N-alkylation by standard methods to introduce the moiety R .

The reaction is conveniently effected by a multi-step procedure which comprises stirring the reactants in a lower alkanol such as methanol; concentrating the reaction mixture in vacuo before treating with a base such as sodium methoxide in

methanol; and then treating with trifluoroacetic acid to effect dehydration with concomitant ring closure.

The intermediates of formula V may conveniently be prepared by reacting a compound of formula Q-NH ₂ with a compound of formula VI:

(VI ) wherein Q, R ² and R ³ are as defined above, and L ¹ represents a suitable leaving group.

The leaving group L ¹ is suitably a halogen atom, e.g. bromine, in which case the reaction is conveniently effected by stirring the reagents under basic conditions in an inert solvent, for example triethylamine in dichloromethane.

In a further procedure, the compounds according to the invention wherein X is oxygen may be prepared by a process which comprises reacting a compound of formula V as defined above with a compound of formula L ² -CO-L ³ , wherein L ² and L independently represent suitable leaving groups.

The leaving groups L and L ³ are suitably selected from halogen atoms, e.g. chlorine or bromine, and C;L_4 alkoxy groups such as methoxy or ethoxy. A typical reagent of formula L ² -CO-L ³ is methyl chloroformate.

The reaction is conveniently carried out by stirring the reactants, typically with the reagent of formula L -CO-L ³ in excess, in an inert solvent such as dichloromethane; and then treating the reaction mixture

with a base such as sodium methoxide in methanol, in order to effect the required ring closure.

If desired, the intermediates of formula V above, where they are stable, may be isolated as such before reaction with the appropriate compound of formula R ⁰ -N=C=O or L ² -CO-L ³ . More typically, however, the final product may be obtained directly from the intermediates of formula VI above in a "one-pot" procedure without isolation of the intermediates of formula V.

Where they are not commercially available, the starting materials of formula IV, VI, Q-NH ₂ , R ¹⁰ -N=C=O and L -CO-L ³ may be prepared by procedures analogous to those described in the accompanying Examples, 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.

In particular, a compound of formula I wherein Q represents a five-, six- or seven-membered aza- aliphatic ring substituted on the sole ring nitrogen atom by a benzyl group initially obtained may be converted into a further compound of formula I wherein Q is substituted on the ring nitrogen atom by a group other than benzyl by a stepwise procedure which comprises removal of the benzyl group followed by attachment of the ring nitrogen substituent by conventional methods. Removal of the benzyl group is conveniently effected by treatment with 1-chloroethyl chloroformate, followed by heating in methanol. Attachment of a substituent to the debenzylated ring nitrogen atom can then be effected, in the case of an alkyl or substituted-alkyl substituent, by reaction with an alkyl halide, typically under basic conditions, e.g. in the presence of ethyldiisopropylamine

(Hύnig's base), in a suitable solvent such as N,N- dimethylformamide; or under reductive amination conditions, whereby the appropriate aldehyde is reacted with the debenzylated amine in the presence of a reducing agent such as sodium cyanoborohydride.

Similarly, a compound of formula I wherein R ¹ is hydrogen initially obtained may be converted into a compound of formula I wherein R ¹ represents C^_ 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 N,N- 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-1-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. McO ie, Plenum Press, 1973;

and T.W. Greene & 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 Examples illustrate the preparation of compounds according to the invention.

The compounds useful in this invention potently inhibit [ ³ H]-spiperone binding to human dopamine D ₄ receptor subtypes expressed in clonal cell lines.

[ ^J H]-Spιperone Binding Studies

Clonal cell lines expressing the human dopamine D ₄ receptor subtype were harvested in PBS and then lysed in 10 mM Tris-HCl pH 7.4 buffer containing 5 mM MgS0 for 20 min on ice. Membranes were centrifuged at 50,000g for 15 min at 4°C and the resulting pellets resuspended in assay buffer (50 mM Tris-HCl pH 7.4 containing 5 mM EDTA, 1.5 mM CaCl ₂ , 5 mM MgCl ₂ , 5 mM KCl, 120 mM NaCl, and 0.1% ascorbic acid) at 20 mg/ml wet weight. Incubations were carried out for 60 min at room temperature (22°C) in the presence of 0.05-2 nM [ ³ H]-spiperone or 0.2 nM for displacement studies and were initiated by addition of 20-100 μg 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 μM 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 compounds of the accompanying Examples were tested in the above assay, and all were found to possess a Ki value for displacement of [ ³ H]-spiperone from the human dopamine D ₄ receptor subtype of below 1.5 μM.

EXAMPLE 1

l-(l-Benzvl-piperidin-4-vl.-5-methvl-4-phenvl-1.3-dihvdro - imidazol-2-one

Method A

a) 4-(Phenvlcarbonvlaminocarbonvl)amino-l-benzvl-Dineridine

To an ice-bath cooled solution of benzoyl isocyanate

(7.725ml, 0.0525 Mol) in dichloromethane (400ml) was added 4-amino-l-benzyl piperidine (lOg, 10.72ml, 0.0525 Mol) dropwise. When the addition was complete the solution was allowed to stir at room temperature for lh then the solvent was removed by rotary evaporation. The residue was triturated with diethyl ether and collected by filtration to give the required product as a white solid 15.4g (87%). Mp. 179-180°C. Η NMR (DMSO) δ 1.51 (2H, m), 1.86 (2H, m), 2.14 (2H, m), 2.69 (2H, m), 3.47 (2H, s), 3.65 (IH, m), 7.24-7.33 (5H, m), 7.50 (2H, t, si = 7.9Hz), 7.61 (IH, t, si = 7.9Hz), 7.96 (2H, d, si = 7.9Hz), 8.69 (IH, d, si = 7.8Hz), 10.67 (1 H, br s); MS (CD m/e 338 [MH]+. Anal. Found C, 70.99; H, 6.86; N, 12.41. C ₂ oH ₂ 3N ₃ θ ₂ requires C, 71.19; H, 6.87; N, 12.45%.

b) 4-(Aminocarbonyl)amino-l-benzyl-piperidine

The product from Example 1, Method A, Step a (15g, 0.0445 Mol) was dissolved in 50% aqueous methanol (400ml) with sodium hydroxide (30g) and stirred at room temperature for 48h. The solvents were removed in vacua, the residue obtained was suspended in water and heated at reflux for lh. After allowing to cool, the required product was collected by filtration and washed with diethyl ether (10.4g, 99%). Mp 148°C. Η NMR

(DMSO) δ 1.30 (2H, m), 1.71 (2H, m), 1.99 (2H, m), 2.68 (2H, m), 3.32 ^~ (1H, m), 3.42 (2H, s), 5.32 (2H, br s), 5.86 (IH, d, 7.8Hz), 7.21-7.34 (5H, m); MS (CD m/e 234 [MH] ⁺ . Anal. Found C, 67.25; H, 8.43; N, 18.00. C ₂ 0H ₂ 3N3O ₂ requires C, 66.92; H, 8.20 N, 18.01 %

c) l-(l-Benzyl-piperidin-4-yl)-5-methyl-4-phenyl-1.3-dihvdro- imidazol-2-one

The product from Example 1, Method A, Step b (1.86g, 0.008

Mol) and 2-hydroxypropiophenone (1.86g, 0.008 Mol) were suspended in toluene (15ml) with trifluoroacetic acid (3ml) and heated under reflux, using a Dean-Stark trap, for 2h. The solvents were removed under vacuum and the residue was partitioned between dichloromethane (2 x 40ml) and IN sodium hydroxide solution (1 x 30ml). The combined organic layers were washed with brine (1 x 30ml), dried (MgS0 ₄ ), filtered and concentrated under vacuum. The residue was purified by flash silica chromatography using 0-5% methanol in dichloromethane as eluent to give the title compound as the less polar isomer. This was recrystallised from ethyl acetate to give the required compound as a white solid (0.045g, 2%). Mp 230°C dec. Η NMR (DMSO) δ 1.60 (2H, m), 2.02 (2H, m), 2.20 (3H, s), 2.43 (2H, m), 2.89 (2H, m), 3.49 (2H, s), 3.75 (IH, m), 7.21-7.40 (10H, m), 10.25 (lH,br s). The regiochemistry of this compound was assigned by observation of an NOE between the methyl protons at δ 2.20 and the piperidine methine proton at δ 3.75; MS (CD m/e 348 [MH]+. Anal. Found C, 75.38; H, 7.30; N, 11.83. C ₂₂ H ₂₅ N ₃ 0. 0.1 H ₂ 0 requires C, 75.66; H, 7.27; N, 12.03%.

Method B

To a solution of 4-amino-l-benzyl piperidine (4g, 4.28ml, 0.021 Mol) in dichloromethane (40ml) was added 2-bromopropiophenone (4.48g, 0.021 Mol) and triethylamine (2.8ml, 0.046 Mol) and the reaction mixture was stirred for 14h. Benzoylisocyanate (3.41g, 0.021 Mol) was added and the solution was stirred for a further lh. Methanol (20ml) was added and the solvents were removed in υacuo. The residue was redissolved in methanol (60ml) and sodium methoxide (5.8g, 0.93mol) was added. After stirring for lh, trifluoroacetic acid (20ml) was added and after a further 0.5h, the reaction mixture was concentrated under vacuum. The residue was partitioned between dichloromethane (150ml)and saturated potassium carbonate solution (80ml) then dried (MgS0 ₄ ), filtered and concentrated in υacuo. Silica gel chromatography using 0-5% methanol/dichloromethane as eluent followed by recrystallisation from methanol ethyl acetate gave the required compound (1.2g, 16%) which was identical with the product obtained using Method A.

Repeating this reaction under the same conditions using 44g of 2- bromopropiophenone (0.2mol) and 35ml of 4-amino-l-benzylpiperidine (0.17mol) in dichloromethane (500ml) with 60ml of triethylamine (0.43mol) followed by 25.3g of benzolyisocyanate (0.17mol) and 28g of sodium methoxide (27g, O.δmol) in methanol (500ml) produced the required compound (45g, 76%). 37g of the compound recrystallised out after work up and was collected by filtration. The remaining 8g was isolated using chromatography.

EXAMPLE 2

l-(l-Benzyl-piperidin-4-yl)-4-methyl-5-phenyl-1.3-dihvdro - imidazol-2-one

The more polar compound from Example 1, Method A, Step c, was recrystallised from methanol/ethyl acetate to give the title compound as a white solid (0.24g, 9%). Mp 249°C. Η NMR (DMSO) δ 1.49 (2H, m), 1.74 (2H, m), 1.89 (3H, s), 2.45 (2H, m), 2.79 (2H, m), 3.49 (IH, m), 3.38 (2H, s) , 7.20-7.47 (10H, m), 10.05 (lH,br s); MS (CD m/e 348 [MH] ⁺ . Anal. Found C, 76.05; H, 7.25; N, 12.08. C ₂₂ H ₂₅ N ₃ O. requires C, 76.05; H, 7.25; N, 11.83%.

EXAMPLE 3

l-(l-Benzyl-piperidin-4-yl)-5-methyl-4-(4-chloro-phenyl)- 1.3- dihvdro-imidazol-2-one

This compound was prepared and isolated as the less polar regioisomer using the procedure described in Example 1, Method A, Step c, using 4'-chloro-2-hydroxypropiophenone instead of 2-hydroxypropiophenone. Mp 240°C dec. Η NMR (DMSO) δ 1.60 (2H, m), 2.02 (2H, m), 2.19 (3H, s), 2.42 (2H, m), 2.89 (2H, m), 3.49 (2H, s), 3.75 (IH, m), 7.25-7.44 (10H, m), 10.31 (IH, br s); MS (CD m/e 384 & 382 [MH] ⁺ . Anal. Found C, 69.00; H, 6.21; N, 10.80. C ₂₂ H ₂₄ C1N ₃ 0 requires C, 69.19; H, 6.33; N, 11.00%.

EXAMPLE 4

l-(l-Benzyl-piperidin-4-yl)-4-methyl-5-(4-chloro-phenyl)- 1.3- dihvdro-imidazol-2-one

This compound was prepared and isolated as the more polar regioisomer using the procedure described in Example 1, Method A, Step c, using 4'-chloro-2-hydroxypropiophenone instead of 2-hydroxypropiophenone. Mp 270-271°C dec. *H NMR (DMSO) δ 1.49 (2H, m), 1.77 (2H, m), 1.84 (3H, s), 2.43 (2H, m), 2.79 (2H, m), 3.31 (IH, m), 3.39 (2H, s) , 7.20-7.32 (8H, m), 7.51 (2H, d, si =

7.8Hz), 10.11 (IH, br s). The regiochemistry of this compound was assigned by observation of an NOE between the methyl protons at δl.84 and the NH proton at δ 10.11; MS (CD m/e 384 & 382 [MH] ⁺ . Anal. Found C, 68.58; H, 6.23; N, 10.73. C ₂₂ H ₂₄ C1N ₃ 0. 0.25H ₂ 0 requires C, 68.38; H, 6.39; N, 10.87%.

EXAMPLE 5

l-(l-Benzyl-piperidin-4-yl)-4-phenyl-1.3-dihydro-imidazol -2- one.

Me hod A

This compound was prepared using the procedure described in Example 1, Method B, using 2-bromoacetophenone instead of 2- bromopropiophenone. Mp 306-308°C. Η NMR (DMSO+NaOD) δ 1.65 (4H, m), 2.03 (2H, m), 2.88 (2H, m), 3.48 (2H, s), 3.82 (IH, m), 6.73 (IH, s), 6.94-7.62 (10H, m). MS (CD m/e 334 [MH] ⁺ . Anal. Found C, 68.00; H, 6.70; N, 11.13. C ₂₁ H ₂₃ N ₃ O requires C, 68.19; H, 6.54; N, 11.36%.

Method B

This compound was also prepared using the procedure described in Example 1, Method B, using trimethylsilylisocyante instead of benzoylisocyanate to give a product which was identical to the product obtained using Method A.

EXAMPLE 6

l-(l-Benzyl-piperidin-4-yl.-3-methyl-4-phenyl-1.3-dihydro - imidazol-2-one hvdrochloride

This compound was prepared using the procedure described in Example 1, Method B, using 2-bromoacetophenone instead of 2- bromopropiophenone and methyl isocyanate instead of benzoyl isocyanate and was purified as a hydrochloride salt. Mp 227°C dec. Η NMR (DMSO) δ 2.00 (2H, m), 2.29 (2H, m), 3.15 (2H, m), 3.33 (3H, s), 3.38 (2H, m), 4.20 (IH, m), 4.30 (2H, s), 6.61 (IH, s), 7.35- 7.70 (10H, m), 10.96 (lH,br s); MS (CD m/e 348 [MH] ⁺ . Anal. Found C, 67.80; H, 7.13; N, 10.49. C ₂₂ H ₂ 5N ₃ O. HC1. 0.4 H ₂ 0 requires C, 67.56; H, 6.91; N, 10.74%.

EXAMPLE 7

l-( l-Benzyl-piperidin-4-yl ) -3.5-dimethyl-4-phenyl- 1.3- dihydro-imidazol-2-one hydrochloride

This compound was prepared using the procedure described in Example 1, Method B, using methyl isocyanate instead of benzoyl isocyanate and was purified as a hydrochloride salt. Mp 295°C dec. Η NMR (DMSO + NaOD) δ 1.62 (2H, m), 2.04 (2H, m), 2.06 (3H, s), 2.40 (2H, m), 2.90 (2H, m), 3.33 (3H, s), 3.49 (2H, s), 3.79 (IH, m), 7.24-7.49 (10H, m), 10.96 (lH,br s); MS (CD m/e 362 [MH] ⁺ . Anal. Found C, 69.56; H, 7.41; N, 10.45. C ₂₃ H ₂₇ N ₃ θ. HC1 requires C, 69.41; H, 7.09; N, 10.56%.

EXAMPLE 8

5-Methyl-l-(l-phenethyl-piperidin-4yl)-4-phenyl-1.3- dihydro-imidazol-2-one

a) l-Benzyl-4-tbutyloxycarbonylamino-piperidine

To a solution of l-benzyl-4-amino-piperidine (40g, 0.21 Mol) in dichloromethane (500ml) was added di-tert-butyldicarbonate

(50.4g, 0.23 Mol) and the reaction mixture was stirred under nitrogen for 18h at room temperature. The solvent was removed by rotary evaporation and the residue was triturated with diethyl ether then collected by filtration to give the required product as a white solid 60.29g (99%) Mp.l35-138°C. Η NMR (CDC1 ₃ ) δ 1.44 (9H,m), 1.53 (2H,m), 1.92 (2H,s), 2.12 (2H,m), 2.83 (2H,m) 3.51 (2H,s) 4.42 (lH,s) 7.22-7.32 (5H,m).

b) 4-tButyloxycarbonylamino-piperidine

To a suspension of l-benzyl-4-*butyloxycarbonylamino- piperidine (60.29g, 0.20 Mol) in methanol (700ml) was added (under nitrogen) 10% palladium on carbon catalyst (3.0g) and the mixture was shaken under 50 psi of hydrogen for 18h. The solution was filtered and the solvent was removed by rotary evaporation to give the title compound as a white solid (40g, 97%). Mp. 153-155°C. Η NMR (CDC1 ₃ ) δ 1.43 (9H,s), 1.97(4H,s), 2.65(2H,m), 3.60 (2H,m), 4.47 (lH,s).

c) 4- Amino- 1-phenylethyl-piperidine hydrochloride

To a suspension of 4-tbutyloxycarbonylamino-piperidine (3.5g, 0.0175 Mol) in dimethylformamide (10ml) was added ethyldiisopropylamine (6.1ml, 0.035 Mol) and 2-bromoethylbenzene (2.64ml, 0.0193 Mol) and the solution was stirred at room temperature for 42h under nitrogen. The reaction mixture was poured into water (500ml) and extracted with dichloromethane (3 x 250ml). The combined organic layers were washed with brine (1 x 30ml) then dried (MgS0 ₄ ), filtered and concentrated under vacuum. The residue was triturated with diethyl ether hexane (1:1) and collected by filtration to give the required product as a white solid, which was dissolved in a saturated solution of hydrogen chloride in methanol (100ml) and stirred at room temperature for 18h. The

solvent was removed by rotary evaporation then the residue was triturated with diethyl ether and collected by filtration to give the required product as a white solid (1.55g, 39%). Mp. 200-201°C. Η NMR δ 1.89 (2H,m), 2.80 (2H,m), 3.04 (2H,m), 3.30 (2H,m), 3.64 (lH,m), 3.72(2H,s) 3.86 (2H,s), 7.26-7.44 (5H,m).

d) 5-Methyl-l-(l-phenethyl-piperidin-4-yl)-4-phenyl-1.3- dihvdro-imidazol-2-one

This compound was prepared using the procedure described in

Example 1, Method B, using 4-amino-l-phenylethyl-piperidine hydrochloride and an extra equivalent of triethylamine, instead of 4-amino-l-benzyl piperidine. Mp 232-236°C. Η NMR (DMSO) δ 1.60 (2H, m), 2.04 (2H, m), 2.21 (3H, s), 2.40 (6H, m), 2.74 (2H, m), 3.05 (2H,m), 3.75 (IH, m), 7.16-7.40 (10H, m), 10.23 (lH,br s); MS (C m/e 362 [MH] ⁺ . Anal. Found C, 76.13; H, 7.36; N, 11.43. C ₂₃ H ₂₇ N ₃ 0 requires C, 76.42; H, 7.53; N, 11.62%.

EXAMPLE 9

5-Methyl-l-(l-(2-methylbenzyl)-piperidin-4-yl)-4-phenyl-1 .3- dihvdro-imidazol-2-one

a) 4-Amino-l-(2-methylbenzyl)-piperidine hydrochloride

This compound was prepared using the procedure described in Example 8, part c, using α-bromo-o-xylene instead of bromoethylbenzene. Mp. 276-278°C. Η NMR δ 2.08 (4H,m), 2.42 (3H,s), 3.16 (4H,m), 3.38 (2H,s), 4.26(lH,m), 7.26-7.49 (4H,m), 8.35 (2H,s).

b) 5-Methyl-l-(l-(2-methylbenzyl)-piperidin-4-yl ,-4-phenyl- 1.3-dihvdro-imidazol-2-one

This compound was prepared using the procedure described in Example 1, Method B, using 4-amino-l-(2-methylbenzyl)- piperidine hydrochloride and an extra equivalent of triethylamine, instead of 4-amino-l-benzyl piperidine. Mp 218-220°C. Η NMR (DMSO) δ 1.58 (2H, m), 2.02 (2H, m), 2.08 (3H s), 2.19 (3H, s), 2.37 (2H, m), 2.87 (2H, m), 3.43 (2H, s), 3.76 (IH, m), 7.12-7.42 (9H, m), 10.25 (lH,br s); MS (CD m/e 362 [MH]+. Anal. Found C, 76.15; H, 7.27; N, 11.33. C ₂ 3H ₂₇ N ₃ 0. requires C, 76.42; H, 7.53; N, 11.62%.

EXAMPLE 10

l-(4-Chlorophenyl)- 1-( l-phenethyl-piperidin-4-yl ) -5-methyl- 1.3-dihvdro-imidazol-2-one

This compound was prepared using the procedure described in Example 1, Method B, using 4-amino-l-phenylethyl-piperidine hydrochloride instead of 4-amino-l-benzyl piperidine and 2-bromo- l-(4-chlorophenyl)-l-carbonyl-propane and an extra equivalent of triethylamine, instead of 2-bromopropiophenone. Mp. 229-231°C. Η NMR δ 1.62 (2H,m), 2.03(2H, m), 2.19(3H, s), 2.27(2H, m), 2.60 (2H,m), 3.05(2H, s), 3.30(2H, s), 3.74(1H, m), 7.18-7.45(9H, m); MS (CD m/e 396 [MH] ⁺ . Anal Found C, 68.13; H, 6.74; N, 10.22. C ₂₃ H ₂₆ N ₃ OC1.0.45H ₂ O requires C, 68.37; H, 6.71; N, 10.40%.

EXAMPLE 11

4-Methyl-3-(l-Ohenethyl-piperidin-4-ylV5-phenyl-3H-oxazol -2-one

To a solution of 4-amino-l-phenethyl-piperidine hydrochloride

(Example 8c, 2g, 0.0072 Mol) and triethylamine (3.31ml, 3.3 Mol eq) in dichloromethane (30ml) was added 2-bromopropiophenone (1.54g, 1 Mol eq) and the reaction mixture was stirred for 14h at room

temperature. After ice-bath cooling, methylchloroformate (3.36ml, 6 Mol eq) was added and the reaction mixture stirred for a further lh. Triethylamine (5ml) was added and the reaction mixture was concentrated in υacuo. The residue was redissolved in methanol (50ml) and sodium methoxide (3g) was added. After stirring at room temperature for 0.5h, the reaction mixture was heated under reflux for lh. After cooling, the solution was concentrated under vacuum and the residue obtained was partitioned between dichloromethane and water then dried (MgSO. ₄ ), filtered and evaporated. The crude product was purified on a silica gel column using 0 to 2% methanol in dichloromethane as eluent then recrystallised from diethyl ether hexane to give the title compound as a colourless solid (0.14g, 5%). Mp 144°C. ^X H NMR (DMSO) δ 1.72 (2H, m), 2.08 (2H, m), 2.30 (3H s), 2.33 (2H, m), 2.50 (2H, m), 2.75 (2H, m), 3.04 (2H, s), 3.69 (IH, m), 7.16-7.33 (5H, m), 7.42-7.47 (5 H, m); MS (C m/e 363 [MH] ⁺ . Anal. Found C, 76.10; H, 7.19; N, 7.61. C23H26CIN3O. 0.35H ₂ O requires C, 76.21; H, 7.23; N, 7.73%.

EXAMPLE 12

4-(4-Chlorophenyl)-5-methyl-l-ri-(2-methylbenzyl)- piperidin-4-yll-1.3-dihvdro-imidazol-2-one

This compound was prepared using the procedure described in Example 1, Method B, using 4-amino-l-(2-methylbenzyl)- piperidine (obtained by partition of 9a between dichloromethane and IN sodium hydroxide solution) instead of 4-amino-l-benzyl piperidine and 2-bromo-4'-chloro-propiophenone instead of 2- bromopropiophenone. Mp 218-220°C. ^l H NMR (DMSO) δ 1.60 (2H, m), 2.06 (2H, m), 2.19 (3H s), 2.32 (3H, s), 2.39 (2H, m), 2.89 (2H, m), 3.44 (2H, s), 3.77 (IH, m), 7.15 (4H, m), 7.24 (IH, m), 7.38 (2H, d, J = 7.8Hz), 7.41 (2H, d, J = 7.8Hz), 10.32 (lH,br s); MS (CD m/e 398 and 396 [MH] ⁺ . Anal. Found C, 78.28;

H, 6.27; N, 10.29. C23H26CIN3O. 0.35H ₂ O requires C, 68.68; H, 6.69; N, 10.45%.

EXAMPLE 13

5-Methyl-l-ri-(2-methylbenzyl)-piperidin-4-yl ^" l-4-(4- methylphenyl)- 1.3-dihvdro-imidazol-2-one

This compound was prepared using the procedure described in Example 1, Method B, using 4-amino-l-(2-methylbenzyl)- piperidine (obtained by partition of 9a between dichloromethane and IN sodium hydroxide solution) instead of 4-amino-l- benzylpiperidine and 2-bromo-4'-methyl-propiophenone instead of 2-bromopropiophenone. Mp 262°C. Η NMR (DMSO) δ 1.60 (2H, m), 2.05 (2H, m), 2.17 (3H, s), 2.29 (3H, s), 2.34 (3H, s), 2.37 (2H, m), 2.88 (2H, m), 3.43 (2H, s), 3.75 (IH, m), 7.14-7.24 (8H, m), 10.20 (IH, s); MS (CD m/e 376 [MH]+. Anal. Found C, 77.00; H, 7.88; N, 11.11. C ₂₄ H ₂₉ N ₃ 0 requires C, 76.76; H, 7.78; N, 11.19%.

EXAMPLE 14

a) 5-Methyl-4-phenyl-l-(lH)-piperidin-4-yl-1.3-dihvdro- imidazol-2-one Hydrochloride

The product from Example 1, Method B (40g, O.llδmol) was dissolved in dichloromethane (600ml) at 0°C and 1- chloroethylchloroformate (18.66ml, l.δmolar equivalents) was added dropwise over 15 mins. The reaction mixture was allowed to warm to room temperature and stirred for 14h. The solvents were removed under vacuum and the residue was redissolved in methanol (500ml) and heated under reflux for 2h. After cooling, the solid produced was collected by filtration and recrystallised

from methanol to give the title compound as a white solid (23 ^* .i4g, 68%). Η NMR (DMSO) δ 1.83 (2H, m), 2.22 (3H, s), 2.66 (2H, m), 3.00 (2H, m), 3.34 (2H, m), 4.10 (IH, m), 7.22-7.44 (5H, m), 8.66 (IH, br s), 9.31 (IH, br s), 10.36 (IH, s); MS (CD m/e 258 (MH)+.

b) 5-Methyl-4-phenyl- 1-( IH ) -piperidin-4- yl- 1 ,3-dihvdro- imidazol-2-one

The product from Example 14, part a (23. lg) was added to aqueous sodium hydroxide (800ml of 1 molar solution) and the aqueous solution was extracted with dichloromethane (4 x 200ml), the combined organic layers were washed with brine (1 x 200ml), dried (MgS0 ₄ ), filtered and concentrated under vacuum to yield the required product (16g, 80%), m.p. 235- 238°C.

c) l-(3-Cvanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1.3- dihvdro-imidazol-2-one

To a solution of the product from Example 14, part b (l.Og, 3.9mmol) in anhydrous dimethylformamide (50ml) was added α- bromo-m-tolunitrile (0.84g, 4.4mmol) and ethyldiisopropylamine (1.35ml, 7.8mmol) and the reaction mixture was stirred at room temperature for 18 hrs under nitrogen. This mixture was poured into sodium hydroxide solution (200ml, 1M) and extracted into dichloromethane (3 x 100ml). The combined organic layers were washed with brine (2 x 100ml), dried (MgS0 ₄ ) and the solvent was removed by rotary evaporation to yield the crude product which was recrystallised from ethyl acetate hexane to yield the required product (0.86g, 60%), m.p. 254-256°C (dec). Η NMR (DMSO) δ 1.61 (2H, d, J = 11Hz), 2.06 (2H, m), 2.19 (3H, s), 2.44 (2H, m), 2.88 (2H, d, J = 11Hz),

3.56 (2H, s), 3.75 (IH, m), 7.21-7.75 (9H, m), 10.26 (IH, s); MS (CD ^" m/e 373 [MH] ⁺ . Anal. Found C, 73.97; H, 6.23; N, 14.90. C ₂₃ H ₂₄ N ₄ 0 requires C, 74.17; H, 6.50; N, 15.04%.

EXAMPLE 15

l-(3-Methoxy-benzylpiperidin-4-yl.-5-methyl-4-phenyl-1.3- dihvdro-imidazol-2-one

This compound was prepared using the procedure described in Example 14, part C using 3-methoxybenzylbromide instead of α-bromo-m-tolunitrile. m.p. 227-228°C. Η NMR (DMSO) δ 1.6 (2H, d, J = 10Hz), 2.01 (2H, m), 2.19 (3H, s), 2.4 (2H, m), 2.9 (2H, d, J = 11Hz), 3.46 (2H, s), 3.75 (4H, m), 6.8-6.9 (3H, m), 7.21-7.4 (6H, m), 10.26 (IH, s). MS (CD m/e 378 [MH]+. Anal, fotmd C, 73.32; H, 7.26; N, 11.00. C ₂₃ H ₂₇ N ₃ O ₂ 0.25 H ₂ 0 requires C, 72.47; H, 7.14; N, 10.77%.

EXAMPLE 16

l-(3-Chloro-benzylpiperidin-4-yl)-5-methyl-4-phenyl-1.3- dihvdro-imidazol-2-one

a) 4-Amino-l-(3-chlorobenzyl)-piperidine

This compound was prepared using the procedure described in Example 8, Step C, using 3-chlorobenzylbromide in place of bromoethylbenzene.

b) l-(3-Chloro-benzylpiperidine-4-yl)-5-methyl-4-phenyl-

1.3-dihvdro-imidazol-2-one

This compound was prepared using the procedure outlined in Example 1, Method B using 4-amino-l-(3-chlorobenzyl)- piperidine instead of 4-amino-l-benzylpiperidine), m.p. 248- 249°C. Η NMR (DMSO) δ 1.61 (2H, d, J = 11Hz), 2.04 (2H, m), 2.19 (3H, s), 2.44 (2H, m), 2.88 (2H, d, J = 11Hz), 3.51 (2H, s), 3.74 (IH, m), 7.23-7.40 (9H, m), 10.26 (IH, s). MS (CD m/e 382 [MH] ⁺ . Anal, found C, 68.86; H, 6.36; N, 10.95. C ₂₃ H ₂₄ N ₃ OC1.0.1H ₂ O requires C, 69.19; H, 6.33; N, 11.00%.

EXAMPLE 17

l-(3-Bromobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1.3- dihvdro-imidazol-2-one

This compound was prepared using the procedure described in Example 14, Part c, using 3-bromobenzylbromide instead of α- bromo-m-tolunitrile. m.p. 263-265°C. Η NMR (DMSO) δ 1.61 (2H, d, J = 12Hz), 2.04 (2H, m), 2.19 (3H, s), 2.45 (2H, m), 2.87 (2H, d, J = 11Hz), 3.49 (2H, s), 3.74 (IH, m), 7.21-7.52 (9H, m), 10.25 (IH, s). MS (CD m/e 427 [MH] ⁺ . Anal found C, 61.86; H, 5.61; N, 9.74. C ₂₂ H ₂₄ N ₃ OBr requires C, 61.98; H, 5.67; N, 9.86%.

EXAMPLE 18

l-(3-Iodo-benzylpiperidin-4-yl)-5-methyl-4-phenyl-1.3- dihvdro-imidazol-2-one

This compound was prepared using the procedure described in Example 14, Part C, using 3-iodobenzyl-bromide instead of α- bromo-m-tolunitrile. M.p. 269-271°C. Η NMR (DMSO) δ 1.61 (2H, d, J = 10Hz), 2.03 (2H, m), 2.19 (3H, s), 2.4 (2H, m), 2.87 (2H, d, J = 11Hz), 3.46 (2H, s), 3.74 (IH, m), 7.13-7.4 (7H, m), 7.62 (IH, d, J = 8Hz), 7.69 (IH, s), 10.26 (IH, s). MS (Cl) m/e

474 [MH]+. Anal, found C, 55.51; H, 5.14; N, 8.83. requires C, 55.82; H, 5.11; N, 8.88%.

EXAMPLE 19

5-Methyl-4-phenyl-l-(l-(3-trifluoromethylbenzyl)-piperidi n- 4-yl)-1.3-dihvdro-imidazol-2-one

This compound was prepared in the same way as described for Example 14 c using meta trifluoromethylbenzyl bromide. Mp 243°C. Η NMR (DMSO) δ 1.61 (2H, m), 2.06 (2H, m), 2.20 (3H, s), 2.45 (2H, m), 2.89 (2H, m), 3.60 (2H, s), 3.75 (IH, m), 7.24 (IH, m), 7.33-7.65 (8H, m), 10.26 (IH, br s). MS (CD m/e 416 [MH] ⁺ . Anal, found C, 66.30; H, 5.73; N, 9.97. requires C, 75.66; H, 7.27; N, 12.03%.

EXAMPLE 20

l-(l-(2.3-Methylenedioxybenzyl)-piperidin-4-yl)-5-methyl- 4- phenyl-1.3-dihvdro-imidazol-2-one

The product from 14a) (0.6g, 0.0034mol) and 2,3- methylenedioxybenzaldehyde (0.5 lg, 0.0034mol) were dissolved in methanol (30ml) and activated 3A sieves (2.5g) were added. After 30 minutes stirring at room temperature, sodium cyanoborohydride (0.28g, 0.044mol) was added and stirring was continued for 14h. Methanol saturated with dry hydrogen chloride (10ml) was added and after lh the reaction mixture was filtered and concentrated under vacuum. The residue was partitioned between IN sodium hydroxide solution (20ml) and brine (20ml) then dried (MgS0 ₄ ), filtered and evaporated under vacuum. The residue was purified by elution through a silica column using 0 to 5% methanol in dichloromethane as eluent

then recrystallised from methanol/ethyl acetate to give the required product as a white solid(24mg, 2%), mp 244-245°C. Η NMR (DMS0 ₃ ) δ 1.60 (2H, m), 2.05 (2H, m), 2.19 (3H, s), 2.43 (2H, m), 2.92 (2H, m), 3.47 (2H, s), 3.72 (IH, m), 6.00 (2H, s), 6.83 (3H, m), 7.20-7.40 (5H, m), 10.25 (IH, br s). MS (CD m/e 392 [MH]+. Anal. Found C, 70.13; H, 6.39; N, 10.72. C ₂₃ H ₂₅ N ₃ O ₃ .0.1H ₂ O requires C, 70.24; H, 6.46; N, 10.69%.