DOPAMINE RECEPTOR SUBTYPE LIGANDS

Abstract: Compounds of formula (I) wherein one of X and Y represents nitrogen, and the other of X and Y represents oxygen, sulphur or N-R<2>; Q represents a substituted five- or six- membered monocyclic heteroaliphatic ring which contains one nitrogen atom as the sole heteroatom and is linked to the five-membered heteroatomic ring containing the moieties X and Y via a carbon atom; as well as substituted 1,3-dioxopropane precursors thereto, are ligands for dopamine receptor subtypes within the body and are therefore useful in the treatment of disorders of the dopamine system, in particular schizophrenia.

Description: DOPAMINE RECEPTOR SUBTYPE LIGANDS This invention relates to five-membered heteroaromatic compounds, and to beta-dicarbonyl precursors thereto, which are ligands for dopamine receptor subtypes within the body. More particularly, the invention is concerned with substituted isoxazole, isothiazole and pyrazole derivatives, and with substituted 1,3-dioxopropane precursors thereto. Being ligands for dopamine receptor subtypes within the body, the compounds according to the invention are therefore of use in the treatment and/or prevention of disorders of the dopamine system, including schizophrenia, depression, nausea, Parkinson's disease, tardive dyskinesias and extrapyramidal side-effects associated with treatment by conventional neuroleptic agents, neuroleptic malignant syndrome, and disorders of hypothalamic-pituitary function such as hyperprolactinaemia and amenorrhoea. Upper gastrointestinal tract motility is believed to be under the control of the dopamine system. The compounds according to the present invention may thus be of use in the prevention and/or treatment of gastrointestinal disorders, and the facilitation of gastric emptying. Dependence-inducing agents such as cocaine and amphetamine have been shown to interact with the dopamine system. Compounds capable of counteracting this effect, including the compounds in accordance with the present invention, may accordingly be of value in the prevention or reduction of dependence on a dependence-inducing agent. Dopamine is known to be a peripheral vasodilator; for example, it has been shown to exert a dilatory effect on the renal vascular bed. This implies that the compounds of the present invention may be beneficial in controlling vascular blood flow. The localisation of dopamine receptor mRNA in rat heart and large vessels has been noted. This suggests a role for dopamine receptor ligands in controlling cardiovascular function, either by affecting cardiac and smooth muscle contractility or by modulating the secretion of vasoactive substances. The compounds according to the present invention may therefore be of assistance in the prevention and/or treatment of such conditions as hypertension and congestive heart failure. 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 D2 receptor subtype, and at least one form of the D3 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. The compounds in accordance with the present invention, being ligands for dopamine receptor subtypes within the body, are accordingly of use in the treatment and/or prevention of disorders of the dopamine system. In one aspect, therefore, the present invention provides a compound of formula I, or a salt thereof or a prodrug thereof: ( I ) wherein the broken circle represents two non-adjacent double bonds in any position within the five-membered ring; one of X and Y represents nitrogen, and the other of X and Y represents oxygen, sulphur or N-R 2 ; Q represents a substituted five- or six- membered monocyclic heteroaliphatic ring which contains one nitrogen atom as the sole heteroatom and is linked to the five-membered heteroatomic ring containing the moieties X and Y via a carbon atom; R x represents hydrogen, halogen, C _s alkyl, hydroxy or Cι_g alkoxy; R 2 represents hydrogen or C^-β alkyl; and A represents a group of formula (i) , (ii) or (iϋ): (I) (i i) ( i l l) in which Z represents oxygen, sulphur or NH; R 3 , R 4 and R 5 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -OR a , -SR a , -SOR a , S0 2 R a , -S0 2 NR a R b , -NR a R b , -NR a COR b , -NR a C0 2 R b , -COR a , -C0 2 R a or -C0 2 NR a R b ; and R a and R b independently represent hydrogen, hydrocarbon or a heterocyclic group. The five-membered heteroaromatic ring containing the moieties X aηd Y represented by formula I above may be a substituted isoxazole, isothiazole or pyrazole ring, preferably isoxazole or pyrazole. The monocyclic heteroaliphatic ring Q in the compounds of formula I above represents a substituted pyrrolidyl or piperidyl moiety linked through carbon. Examples of suitable rings include the moieties of formula Qa to Qe: (Qo) ( Q b) (Q O wherein one of R 6 and R 7 represents hydrocarbon or a heterocyclic group, and the other of R 6 and R 7 repres hydrogen, hydrocarbon or a heterocyclic group. Particular monocyclic heteroaliphatic rings represented by the substituent Q in formula I include the rings of structure Qa, Qb and Qd above, especially Qa. 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 Cι_e alkyl, C 2 _β alkenyl, C ___g alkynyl, 0 3 -7 cycloalkyl, C3_7 cycloalkyl(Ci-β)alkyl, aryl, aryl(Ci-β)alkyl, aryl(C .g)alkenyl and aryl(C 2 . 6 )alkynyl. The expression "a heterocyclic group" as used herein includes cyclic groups containing up to 18 carbon atoms and at least one heteroatom preferably selected from oxygen, nitrogen and sulphur. The heterocyclic group suitably contains up to 15 carbon atoms and conveniently up to 12 carbon atoms, and is preferably linked through carbon. Examples of suitable heterocyclic groups include C 3 _7 heterocycloalkyl, C 3 _7 heterocycloalkyl(Ci-β)alkyl, heteroaryl and heteroaryl(C^-s)alkyl groups. Suitable alkyl groups include straight- chained and branched alkyl groups containing from l 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, 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 C 3 _7 cycloalkyl(Cι_g)alkyl groups include cyclopropylmethyl and cyclohexylmethyl. Particular aryl groups include phenyl, naphthyl and tetrahydronaphthyl. Particular aryl(Cι_g)alkyl groups include benzyl, naphthylmethyl, phenethyl and phenylpropyl. Particular aryl(C 2 -g) lkenyl groups include phenylethenyl and phenylpropenyl. A particular aryl(C _g)alkynyl group is phenylethynyl. 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, indolyl, imidazolyl, oxadiazolyl and thiadiazolyl groups. Particular heteroaryl(Cι_ )alkyl groups include pyridylmethyl, furylmethyl, indolylmethyl, pyrazinylmethyl and pyridylethyl. The hydrocarbon and heterocyclic groups may in turn be optionally substituted by one or more groups selected from Cι_g alkyl, adamantyl, phenyl, halogen, Cι_ 6 haloalkyl, C^-g aminoalkyl, trifluoromethyl, hydroxy, Cι_g alkoxy, aryloxy, keto, Cι__ 3 alkylenedioxy, nitro, cyano, carboxy, C 2 - 6 alkoxycarbonyl, C 2 _ 6 alkoxycarbonylCC -g)alkyl, C _g alkylcarbonyloxy, arylcarbonyloxy, C 2 - 6 alkylcarbonyl, arylcarbonyl, C^g alkylthio, C ! _g alkylsulphinyl, Cι_g alkylsulphonyl, arylsulphonyl, -NR V R W , -NR v C0R 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 S0 2 NR v R w , in which R v and R w independently represent hydrogen, Cι_g alkyl, aryl or aryl(Cχ_g)alkyl. The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine, especially chlorine. The compounds of formula I above may be prepared by a process which comprises reacting a compound of formula II with a compound of formula III: ( I I ) ( M l ) wherein Q, R 1 and A are as defined above, and X a represents oxygen, sulphur or N-R 2 in which R 2 is as defined above; followed, if necessary, by separation of the resulting mixture of iso ers by conventional means. The reaction is conveniently carried out by stirring the reactants in a suitable solvent, for example a mixture of N,N-dimethylformamide and methanol, optionally in the presence of a non-nucleophilic base such as ethyldiisopropylamine, suitably at room temperature. Depending upon the nature of the reactants and of the chosen reaction conditions, the reaction may afford the desired product in a single step, or may proceed via the intermediate IV: ( I V ) wherein one of V and W represents the group Q and the other represents the group A; and Q, A, R 1 and X a are as defined above. The intermediate IV can be converted into the corresponding product of formula I by dehydration. This is conveniently effected by converting the hydroxy group into a leaving group, suitably by treatment with methanesulphonyl chloride in dichloromethane at 0*C, and treating the resulting compound, ideally in situ, with a base such as triethylamine. As indicated above, the overall reaction between compounds II and III will usually give rise to a mixture of isomeric products of formula I, in one of which X represents nitrogen and Y represents oxygen, sulphur or N-R 2 , and in the other of which the X and Y moieties are reversed. For this reason, it will generally be necessary to separate the mixture of isomers obtained therefrom by conventional methods such as chromatography. The compounds of formula II above are active in their own right as ligands for dopamine receptor subtypes within the body. These compounds, and salts thereof and prodrugs thereof, accordingly represent a further aspect of the present invention. As will be appreciated, the compounds of formula II as depicted above will generally exist in equilibrium with their other tautomeric forms, including structures (A) and (B) : (A) (B) wherein Q, R 1 and A are as defined above. It is to be understood that all tautomeric forms of the compounds of formula II, as well as all possible mixtures thereof, are included within the scope of the present invention. For use in medicine, the salts of the compounds of formulae I and II 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 present invention includes within its scope prodrugs of the compounds of formulae I and II above. In general, such prodrugs will be functional derivatives of the compounds of formulae I and II which are readily convertible in vivo into the required compound. 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. Suitably, the substituent R 1 represents hydrogen, halogen, Cι_g alkyl or C^-g alkoxy, especially hydrogen, methyl, ethyl, methoxy or chloro. Suitably, the substituent R 2 represents hydrogen or methyl, especially hydrogen. Suitably, Z is sulphur. Suitable values for the substituents R 3 , R 4 and R 5 include hydrogen, halogen, trifluoromethyl, cyano, nitro, amino, Cι_ alkylamino, di(Cι_g)alkylamino, Cχ_g alkyl, Cι_g alkoxy, aryl(C^.g)alkoxy and C 2 -g alkylcarbonyl. Particular values include hydrogen, methyl, ethyl, isopropyl, nitro, methoxy and chloro. Suitably, at least one of R 3 , R 4 and R 5 is other than hydrogen, especially chloro. Suitable values for the substituents R 6 and R 7 include Cι_ 6 alkyl, C _g alkenyl, C 3 _7 cycloalkyl(Cι» )alkyl, aryl, aryl(Cι_ )alkyl, aryl(C 2 _g)alkenyl and heteroaryl(Cχ_g)alkyl, any of which groups may be optionally substituted. In addition, one of R 6 and/or R 7 may represent hydrogen. Examples of suitable substituents on the groups R 6 and/or R 7 include Cι_ alkyl, halogen, Cχ_g alkoxy, keto and nitro. Particular values of R 6 and R 7 include hydrogen, methyl, allyl, cyclopropylmethyl, cyclohexylmethyl, tetrahydronaphthyl, benzyl, methyl- benzyl, chlorobenzyl, dichlo ' robenzyl, methoxy-benzyl, nitro-benzyl, naphthylmethyl, phenethyl, methoxy- phenethyl, phenylcarbonylmethyl, phenylpropyl, phenyl- propenyl, furylmethyl, indolylmethyl and pyridylethyl, provided that at least one of R 6 and R 7 is other than hydrogen. Suitably, one of R 6 and R 7 represents hydrogen, and the other of R 6 and R 7 is other than hydrogen. Preferably, R 7 represents hydrogen and R 6 is other than hydrogen. A particular sub-class of compounds according to the invention is represented by the compounds of formula IA, and salts and prodrugs thereof: ( IA) wherein Y 1 represents oxygen, sulphur or N-R 12 ; one of T and U represents CH and the other represents CH or N, preferably CH; R 11 represents hydrogen, halogen, Cι_g alkyl or Cι_g alkoxy; R 12 represents hydrogen or Cι_g alkyl; R 13 represents hydrogen, halogen, trifluoromethyl, cyano, nitro, amino, Ci- alkylamino, di(Cι_g)alkylamino, Cι_g alkyl, Cι_g alkoxy, aryl(Cι_g)alkoxy or C 2 _g alkylcarbonyl; R 16 represents C 2 -g alkenyl, C 3 _7 cycloalkyl(Cι_g)alkyl, aryl ' , aryl(Cχ_g)alkyl, aryl(C 2 _g)alkenyl or heteroaryl(Cι_g)alkyl, any of which groups may be optionally substituted; and R 17 represents hydrogen or methyl, preferably hydrogen. Examples of suitable substituents on the group R include one or more of C^.g alkyl, halogen, C^-g alkoxy, keto and nitro. Particular values of R 16 with reference to formula IA above include allyl, cyclopropylmethyl, cyclohexylmethyl, tetrahydronaphthyl, benzyl, methyl- benzyl, chlorobenzyl, dichlorobenzyl, methoxy-benzyl, nitro-benzyl, naphthylmethyl, phenethyl, methoxy- phenethyl, phenylcarbonylmethyl, phenylpropyl, phenyl- propenyl, furylmethyl, indolylmethyl and pyridylethyl. Particular values of Y 1 with reference to formula IA above include oxygen or N-R 12 , preferably oxygen, NH or N-methyl. Particular values of R 11 include hydrogen, methyl, ethyl, methoxy and chloro. Suitably, R 12 represents hydrogen or methyl, especially hydrogen. Particular values of R 13 include hydrogen, methyl, ethyl, isopropyl, nitro, methoxy and chloro, especially chloro. Another sub-class of compounds according to the invention is represented by the compounds of formula IB, and salts and prodrugs thereof: ( IB) wherein Y 1 , R 11 , R 13 , R 16 and R 17 are as defined with reference to formula IA above. A further sub-class of compounds according to the invention is represented by the compounds of formula IC, and salts and prodrugs thereof: ( I C) wherein E represents a linking group of formula -(CH 2 ) 2 - or -(CH 2 ) 3 -; and Y 1 , T, U, R 11 , R 13 , R 16 and R 17 are as defined with reference to formula IA above. A still further sub-class of compounds according to the invention is represented by the compounds of formula IIA, and salts and prodrugs thereof: (HA) wherein T, U, R ,11 R 13 , R 16 and R 17 are as defined with reference to formula IA above. A yet further sub-class of compounds according to the invention is represented by the compounds of formula IIB, and salts and prodrugs thereof: ( I I B) wherein R 11 , R 13 , R 16 and R 17 are as defined with reference to formula IA above. An additional sub-class of compounds according to the invention is represented by the compounds of formula IIC, and salts and prodrugs thereof: ( I IC) wherein T, U, R 11 , R 13 , R 16 and R 17 are as defined with reference to formula IA above; and E is as defined with reference to formula IC above. Specific compounds within the scope of the present invention include: l-(4-chlorobenzyl)-4-[3-(4-chlorophenyl)-3-hydroxy-l- oxoprop-2-en-l-yl]piperidine; l-benzyl-4-[3-(4-chlorophenyl)-3-hydroxy-l-oxoprop-2-en- 1-yl]piperidine; l-(4-chlorobenzyl)-4-[3-hydroxy-3-(4-nitrophenyl)-l- oxoprop-2-en-l-yl]piperidine; 4-[3-(4-chlorophenyl)-3-hydroxy-l-oxoprop-2-en-l-yl]-ι- (2-phenylethyl)piperidine; l-benzyl-3-[3-(4-chlorophenyl)-3-hydroxy-l-oxoprop-2-en- 1-yl]piperidine; 4-[3-(4-chlorophenyl)-2-methyl-l,3-dioxoprop-l-yl]-l-(2- phenylethyl)piperidine; l-benzyl-4-[3-hydroxy-l-oxo-3-(2-thienyl)prop-2-en-l- yl]piperidine; 4-[3-hydroxy-l-oxo-3-(3-pyridyl)prop-2-en-l-yl]-1-(2- phenylethyl)piperidine; 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-(4- chlorophenyl)pyrazole; 3-(l-benzylpiperidin-4-yl)-5-(4-chlorophenyl)pyrazole; 5-(4-chlorophenyl)-3-[1-(4-methylbenzyl)piperidin-4-yl]- pyrazole; 5-(4-chlorophenyl)-3-[1-(4-methoxybenzyl)piperidin-4-yl]- pyrazole; 5-(4-chlorophenyl)-3-[l-(prop-2-en-l-yl)piperidin-4-yl]- pyrazole; 5-(4-chloropheny1)-3-[1-(4-nitrobenzy1)piperidin-4-y1]- pyrazole; 3-[l-(4-chlorobenzyl)piperidin-4-yl]-5-phenylpyrazole; 3-[l-(4-chlorobenzyl)piperidin-4-yl]-5-(2-thienyl)- pyrazole; 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-(4- isopropylphenyl)pyrazole; 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-(4- methoxyphenyl)pyrazole; 5-(4-chloropheny1)-3-(l-cyclohexylmethylpiperidin-4-yl)- pyrazole; 5-(4-chloropheny1)-3-[1-(2-phenylethyl)piperidin-4-yl]- pyrazole; 5-(4-chloropheny1)-3-[l-(3,4-dichlorobenzyl)piperidin-4- yl]pyrazole; 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-(3- chlorophenyl)pyrazole; 3-[1-(3-chlorobenzyl)piperidin-4-yl]-5-(4- chlorophenyl)pyrazole; 5-[1-(4-chlorobenzyl)piperidin-4-yl]-3-(4-chlorophenyl)- 1-methylpyrazole; 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-(4-chlorophenyl)- 1-methylpyrazole; 3-[1-(4-chlorobenzyl)piperidin-4-y1]-5-(2- chlorophenyl)pyrazole; 3-(l-benzylpiperidin-4-yl)-5-phenylpyrazole; 3-[1-(4-chlorobenzyl)piperidin-4-y1]-5-(4- chlorophenyl)isoxazole; 5-[1-(4-chlorobenzyl)piperidin-4-yl]-3-(4- chlorophenyl)isoxazole; 3-[l-( -chlorobenzyl)piperidin-4-yl]-5-(2- methoxyphenyl)pyrazole; 5-(4-chlorophenyl)-3-[l-(2-methylbenzyl)piperidin-4-yl]- pyrazole; 5-(4-chlorophenyl)-3-[l-(3-nitrobenzy1)piperidin-4-yl]- pyrazole; 5-(4-chlorophenyl)-3-[1-(3-methyIbenzyl)piperidin-4-yl]- pyrazole; 5-(4-chlorophenyl)-3-[l-(2-nitrobenzyl)piperidin-4-yl]- pyrazole; 3-[l-(4-chlorobenzyl)piperidin-4-yl]-4-methyl-5- phenylpyrazole; 3-[l-(2-chlorobenzyl)piperidin-4-yl]-5-(4- chlorophenyl)pyrazole; 5-(4-chlorophenyl)-3-(l-cyclopropylmethylpiperidin-4- yl)pyrazole; 3-(l-benzylpiperidin-4-yl)-5-(4-chlorophenyl)-4- methylpyrazole; 5-(4-chlorophenyl)-3-[1-(2-naphthylmethyl)piperidin-4- yl]pyrazole; 5-(4-chlorophenyl)-3-[l-(3-phenylpropyl)piperidin-4- yl]pyrazole; 5-( -chlorophenyl)-3-[1-(3-methoxybenzyl)piperidin-4- yl]pyrazole; 3-[1-(2-phenylethyl)piperidin-4-yl]-5-(2- pyridyl)pyrazole; 3-(l-benzyl-4-methylpiperidin-4-yl)-5-(4- chlorophenyl)pyrazole; 5-( -chlorophenyl)-3-[1-(indol-3-ylmethyl)piperidin-4- yl]pyrazole; 5-(4-chlorophenyl)-4-methyl-3-[l-(2- phenylethyl)piperidin-4-yl]pyrazole; 3-(l-benzylpiperidin-3-yl)-5-(4-chlorophenyl) yrazole; 3-(l-benzylpyrrolidin-3-yl)-5-(4-chlorophenyl)pyrazole; 3-(l-benzylpiperidin-4-yl)-5-(2-thienyl)isoxazole; 5-(l-benzylpiperidin-4-yl)-3-(2-thienyl)isoxazole; 5-(4-chlorophenyl)-3-[1-(2-phenylethyl)piperidin-4- yl]isoxazole; 3-(l-benzylpiperidin-4-yl)-5-(4-chlorophenyl)isoxazole; 3-( -chlorophenyl)-4-methyl-5-[1-(2- phenylethyl)piperidin-4-yl]isoxazole; 5-(4-chlorophenyl)-4-methyl-3-[1-(2- phenylethyl)piperidin-4-yl]isoxazole; 3-(1-benzylpiperidin-4-y1)-5-(4-chlorophenyl)-4- ethylpyrazole; 5-(1-benzylpiperidin-4-y1)-3-(4-chlorophenyl)-1,4- dimethylpyrazole; 3-(l-benzylpiperidin-4-yl-)-5-(4-chlorophenyl)-l,4- dimethylpyrazole; 4-methoxy-5-phenyl-3-[1-(2-phenylethyl)piperidin-4- yl]pyrazole; 5-(4-chlorophenyl)-3-[1-(3-E-phenylprop-2-en-l- yl)piperidin-4-yl]pyrazole; 5-(4-chlorophenyl)-3-[1-(1-naphthylmethyl)piperidin-4- yl]pyrazole; 3-[1-(2-furylmethyl)piperidin-4-yl]-4-methyl-5- phenylpyrazole; 3-[1-(2-(4-methoxypheny1)ethyl)piperidin-4-yl]-4-methyl- 5-phenylpyrazole; 4-methyl-3-[l-(2-oxo-2-phenylethyl)piperidin-4-yl]-5- phenylpyrazole; 4-methyl-5-phenyl-3-[1-(2-(3-pyridyl)ethyl)piperidin-4- yl]pyrazole; 5-(4-chlorophenyl)-3-[1-(1,2,3,4-tetrahydronaphth-2- yl)piperidin-4-yl]pyrazole; 4-chloro-5-(4-chlorophenyl)-3-[1-(2- phenylethyl)piperidin-4-yl]pyrazole; and salts and prodrugs thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or 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, methylcellulose, 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 of formula II as defined above may be prepared by reacting a carboxylic acid of formula V, or an activated derivative thereof, with two equivalents of a metal enolate of formula VI: 0M (V) (VI ) wherein R 1 and A are as defined above, Q 1 corresponds to the moiety Q as defined above or represents a precursor thereto protected on the nitrogen atom, and M represents a metal capable of providing a suitable counterion for the enolate anion; followed, where required, by removal of the N-protecting group from the moiety Q 1 ; and subsequently, if necessary, attachment to the nitrogen atom thereby deprotected of an appropriate substituent by standard means to afford a product containing the desired moiety Q. For example, the substituent Q 1 in compound V may represent a moiety of formula Qa to Qe as defined above, in which R 7 is hydrogen and R 6 represents an N- protecting group. Once the reaction between compounds V and VI is complete, the N-protecting group must be removed, and the desired group R subsequently attached, by conventional methods. The metal M is suitably an alkali metal, especially lithium. The activated derivative of the carboxylic acid V is suitably the compound formed by reaction between the carboxylic acid V and 1,1'-carbonyldiimidazole, conveniently in tetrahydrofuran at room temperature. Where the substituent Q 1 represents a precursor to the moiety Q protected on the nitrogen atom, the N- protecting group is suitably an alkoxycarbonyl moiety such as t-butoxycarbonyl (BO'C) , in which case the N- protecting group can conveniently be removed subsequently as necessary by treatment under acidic conditions, e.g. stirring in hydrochloric acid or trifluoroacetic acid. The reaction between compound V, or the activated derivative thereof, and compound VI is suitably carried out in a solvent such as tetrahydrofuran, commencing at -78*C with warming to 0*C. The metal enolate of formula VI is ideally prepared by reacting the corresponding carbonyl compound of formula VII: (VI I ) wherein R 1 and A are as defined above; with a non- nucleophilic base such as lithium diisopropylamide, suitably in tetrahydrofuran at -78 β C. In an alternative process, the compounds of formula I above wherein X represents nitrogen, Y is N-R 2 , R 1 is hydrogen and Q represents a group of formula Qa as defined above may be prepared by reacting a compound of formula VIII: (VI I I ) , wherein A and R 7 are as defined above; with hydrazine hydrate; followed by attachment of the groups R 2 and/or R , where these are required to be other than hydrogen, by standard carbon-nitrogen bond-forming reactions. The reaction of compound VIII with hydrazine hydrate is advantageously effected in the presence of ethylene glycol and a strong base such as potassium hydroxide, suitably commencing at 110"C with warming to the reflux temperature of the reaction mixture. The method whereby the groups R 2 and/or R 6 are attached to the product obtained from any of the above- described processes will suitably comprise a standard carbon-nitrogen bond-forming reaction known from the art, such as N-alkylation. By way of example, a compound wherein R 6 is hydrogen initially obtained may conveniently be N-benzylated by treatment with a benzyl halide, e.g. benzyl bromide, typically under basic conditions, e.g. using triethylamine in a mixture of dichloromethane and N,N-dimethylformamide, suitably at room temperature, to afford a product wherein R 6 is benzyl. The intermediates of formula VIII above may be prepared by condensing an aldehyde of formula A-CHO with a suitable quinuclidin-3-one derivative of formula IX: ( IX) wherein A and R 7 are as defined above. The reaction is conveniently carried out in a solvent such as ethanol, advantageously in the presence of a strong base such as sodium hydroxide, suitably by heating the reaction mixture at reflux. Where they are not commercially available, the starting materials of formula III, V, VII, IX and A-CHO may be prepared by standard methods well known from the art. it will be appreciated that any compound of formula I or formula II initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further desired compound of formula I or formula II using techniques known from the art. For example, as alluded to above, a compound of formula I wherein R 2 is hydrogen initially obtained may be converted into a compound of formula I wherein R 2 is other than hydrogen by means of conventional N-alkylation methodology. 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 the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di- p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l- tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & 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 D4 receptor subtypes expressed in clonal cell lines. [ 3 H]-Spiperone Binding Studies Clonal cell lines expressing the human dopamine D4 receptor subtype were harvested in PBS and then lysed in 10 mM Tris-HCl pH 7.4 buffer containing 5 mM MgSθ4 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 K 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 Kj value for displacement of [ 3 H]-spiperone from the human dopamine D4 receptor subtype of below 1.5 μM. In the accompanying Examples, the compounds may exist in the solvent in which the NMR spectrum is recorded as a mixture of ketone and enol tautomers. The NMR spectrum is quoted for the major form, and small peaks corresponding to other tautomers are not recorded. EXAMPLE 1 l-(4-πhlorohenzvlV4-(3-hvdroxv-l-oxo-3-(4- chlorophenv1 nron-2-en-l-vnpiΩeridine n-Butyllithium (28ml, 1.6M in hexanes) was added to diisopropylamine (6.2ml) in tetrahydrofuran (150ml) at 0°C. The solution was stirred at 0°C for 15 min then cooled to -78°C, and a solution of 4-chloroacetophenone (6.8g) in THF (10ml) added over 5 min. In a separate vessel, carbonyldiimidazole (3.89g) was added to l-tert-butyloxycarbonyl-4-piperidine carboxylic acid (5g) in THF (100ml). After 45 min, the latter solution was cannulated into the former, stirred for 45 min at -78°C then warmed to room temperature. Ethyl acetate was added and the mixture washed with IM citric acid, saturated sodium hydrogen carbonate solution, and brine, dried (MgS0 ), and evaporated in vacuo. A saturated solution of HCl in ethyl acetate (50ml) was added to the resulting oil and the mixture stirred at room temperature for 30 min then stood at 0°C for lh. The resulting solid was collected, washed with ethyl acetate and dried, to give 4-( l-(3-hydroxy- l-oxo-3-(4-chlorophenyl)-2-propenyl))piperidine hydrochloride as an off-white solid (5.1g). 3g of this solid was suspended in dimethylformamide (30ml) and dichloromethane (30ml), then triethylamine (3.1ml) and 4-chlorobenzyl chloride (1.77g) added. After stirring for 70h the mixture was evaporated, diluted with ethyl acetate, washed with water and brine, dried, and evaporated in vacuo to give l-(4-chlorobenzyl)- 4-( l-(3-hydroxy- l-oxo-3-(4-chlorophenyl)-2-propenyl))piperidine (2.3g) as cubes, mp 91-92°C (from ethyl acetate/hexanes) (Found: C, 64.40; H, 5.68; N, 3.61. C 2 ιH 2 ιN0 2 Cl requires C, 64.62; H, 5.42; N, 3.59%); δ H (360MHz, CDC1 3 ) 1.8-2.0 (4H, m, CH CH), 2.0-2.1 (2H, m, NCH A H B CH 2 ), 2.3-2.4 (IH, m, CHCH 2 ), 2.96 (2H, d, J = 12, NCH A H B CH 2 ), 3.5 (2H, s, ArCH 2 ), 6.14 (IH, s, C=CH), 7.29 (4H, s, ArHCH 2 ), 7.41 (2H, d, J = 8.6, ArHo to Cl), 7.81 (2H, d, J = 8.6, ArHm to Cl), 15.9 (IH, brs, OH); m/z (CI + , NH 3 ), 390 (M + +H). EXAMPLE 2 l-Benzvl-4-(3-hvdrox v- 1 -oxo-3-(4-chlorophenvn-2- prop-2- en-l-vl)nip ririine hite needles, mp 84-86°C (from ethanol/water) (Found: C, 71.21; H, 6.29; N, 3.91. C 21 H 22 N0 2 C1 requires C, 70.88; H, 6.23; N, 3.94%); δ H (360MHz, CDC1 3 ) 1.8-2.0 (4H, m, CH 2 CH), 2.0-2.2 (2H, m, NCH A H B CH 2 ), 2.3-2.4 (IH, m, CHCH 2 ), 3.0 (2H, d, J = 12, NCH A H B CH 2 ), 3.59 (2H, s, ArCH 2 ), 6.15 (IH, s, C=CH), 7.2-7.4 (5H, m, Ph), 7.42 (2H, d, J = 8.6, ArHo to Cl), 7.81 (2H, d, J = 8.6, ArHm to Cl), 15.9 (IH, brs, OH); m/z (CI + , NH 3 ) 356 (M + +H). EXAMPLE 3 l-(4-Chlorobenzyl)-4-(3-hvdroxy-l-oxo-3-(4- nitrophenvl)prop-2-en-l-vl)piperidine. hydrogen oxalate salt mp 225-230°C (from ethanol) (Found: C, 56.82; H, 5.15; N, 6.17. C 2 ιH 21 N 2 0 4 Cl + 0.95 C 2 H 2 0 4 requires C, 56.92; H, 4.78; N, 5.80%); 5H (360MHZ, d 6 -DMSO) 1.8-2.0 (2H, m, CH A H B CH), 2.05 (2H, d, J = 13, CH A H B CH), 2.7-2.8 (3H, m, NCH A H B CH 2 and CH 2 CH), 3.2-3.3 (2H, m, NCH A H B CH 2 ), 4.10 (2H, s, ArCH 2 ), 6.78 (IH, s, C=CH), 7.5-7.8 (4H, m, ArHCH 2 ), 8.20 (2H, d, J = 8.9, ArHN0 2 ), 8.36 (2H, d, J = 8.9, ArHN0 2 ); m/z (CI + , NH 3 ) 401 (M + +H). EXAMPLE 4 l-(2-Phenvlethvl)-4-(3-hvdroxv-l-oxo-3-(4-chlorophenvl)-prop- 2-en-l-vl)piperidine. hydrogen oxalate salt White powder, mp 180-182°C (from ethanol) (Found: C, 61.95; H, 5.76; N, 3.01. C 22 H 24 NO 2 CI + C 2 H 2 0 4 + 0.3H 2 O requires C, 62.00; H, 5.76; N, 3.08%); δπ (360MHz, d f i-DMSO) 1.9-2.0 (2H, m, CH A H B CH), 2.09 (2H, d, J = 12.5, CH A H B CH), 2.6-2.7 (IH, m, CH 2 CH), 2.8-3.0 (4H, m, ArCH 2 and NCHAHBCHJJCH), 3.1-3.2 (2H, m, ArCH 2 CH 2 N), 3.48 (2H, d, J = 11.8, NCHAHBCHJJCH), 6.65 (IH, s, C=CH), 7.2-7.4 (5H, m, Ph), 7.60 (2H, d, J = 8.6, ArHo to Cl), 7.99 (2H, d, J = 8.6, ArHm to Cl); m Iz (CI + , NH 3 ) 370 (M + +H). EXAMPLE 5 l-Benzvl-3-(3-hvdroxv-l-oxo-3-(4-chlorophenvl) prop-2-fin- l-yl)piperidine hvdrobromide White needles, mp 193-194°C (from EtOH); (Found: C, 57.63; H, 5.33; N, 3.31. C 21 H 23 N0 2 ClBr requires C, 57.75; H, 5.31; N, 3.21%); δ H (360MHz, d 6 -DMSO+CF 3 C0 2 H) 1.42 (IH, apparent qd, J = 12 and 3, 1 of NCH 2 CH 2 CH 2 ), 1.64-2.20 (3H, m, 3 of NCH 2 CH 2 CH 2 ), 2.90-3.18 (2H, m, 2 of NCH 2 ), 3.32-3.60 (3H, m, 2 of NCH 2 and NCH 2 CH), 4.38 (2H, br s, NCH 2 Ar), 6.68 (IH, s, C=CH), 7.45-7.70 (7H, m, Ph and ArHo to Cl) and 8.05 (2H, d, J = 9, ArHm to Cl); (CI + , NH 3 ) 356 (M + +H; 70%), 322 (20), 266 (18), 218 (80), 174 (30), 128 (50); 106 (80) and 84 (100); m/z (CF, NH 3 ) 355 (M " ; 40%), 265 (15), 127 (30) and 81 (100). EXAMPLE fi 1-f2-PhenvlfithvlV4-fl.3-dioxo-2-methvl-3-(4- chlQrophenyl)prop-l-γl)piperi ine hydrochloride White granules, mp 179-181°C (from EtOH-EtOAc); (Found: C, 65.50; H, 6.56; N, 3.38. C 23 H 27 N0 2 C1 2 requires C, 65.71; H, 6.47; N, 3.33%); δπ (360MHz, CDC1 3 ) ca. 1:1 mixture of isomers of the protonated piperidine, 1.40 (3H, d, J = 7, CH 3 both isomers), 1.95-2.13 (4H+ 2H, m, NCH 2 CH A H B both isomers and NCHaCH^ B one isomer), 2.40-2.59 (2H+2H, m, other isomer and NCH A H B one isomer), 2.72-2.82 (2H, m, NCH A H B other isomer), 3.02-3.30 (5H+5H, NCH 2 CH 2 Ar, NCH 2 CU 2 Ar, and N(CH 2 ) 2 CH both isomers), 3.40 (2H, apparent t, J - 12, NCHAHB one isomer), 3.64 (2H, apparent dd, J = 14 and 12, NCHAHB other isomer), 4.69 (1H+1H, q, J = 7, CHCH 3 both isomers), 7.22-7.40 (5H+5H, m, Ph both isomers), 7.49 (2H, d, J 8, ArH 0 10 ci one isomer), 7.50 (2H, d, J = 8, ArHo to Cl other isomer), 7.91 (2H, d, J = 8, ArHm to Cl one isomer), 7.93 (2H, d, J = 8, ArHm to Cl other isomer), 12.39 (IH, br s, + NH one isomer) and 12.51 (IH, br s, + NH other isomer); m/z (CI + , NH 3 ) 384 (M + +H; 100%); m/z (CF, NH 3 ) 419 (M " +C1; 10%) and 383 (M " -H; 100). E XAMFLE 7 l-Benzvl-4-(3-hvdroxv-l -oxo-3-(2-thienvl)prop-2-en-l- yPpiperidine Yellow crystals, mp 80-83°C (from ethanol/water). (Foimd: C, 69.48; H, 6.21; N, 3.93. C 19 H 21 N0 2 S requires C, 69.69; H, 6.46; N, 4.28%); δπ (360MHz, dg-DMSO), 1.63 (2H, dq, J = 3.5 and 9.0Hz, CH A H B CH), 1.81 (2H, br d, J = 11Hz, CHAHBCH), 1.93-2.01 (2H, m, CHAHBN), 2.2-2.3 (IH, m, CH 2 CHCH 2 ), 2.87 (2H, br d, J = 11.7Hz, CHAHBN), 3.48 (2H, s, ArCH 2 ), 6.43 (IH, s, CCH), 7.23-7.35 (6H, m, ArH), 7.92-8.04 (2H, m, ArH); m/z (CI + , NH 3 ) 328 (M + +H). EXAMPLE S l-(2-Phenv1ethvl)-4-(3-hvdroxv-l-oxo-3-f3-pvridvl)prop-2-en- l- γ l)piperidine Tan needles, mp 75-77°C (from ethanol/water) (Found: C, 73.93; H, 7.20; N, 8.02. C 21 H 24 N 2 0 2 + 0.25H 2 O requires C, 73.98; H, 7.24; N, 8.22%); δ H (360MHz, CDCl 3 )1.8-2.0 (4H, m, CH 2 's), 2.1-2.2 (2H, m, CH 2 ), 2.37-2.42 (IH, m, CHCO), 2.6-2.7 (2H, m, CH 2 ), 2.8-2.9 (2H, m, CH 2 ), 3.1-3.2 (2H, m, CH 2 ), 6.22 (IH, s, C=CH), 7.1-7.3 (5H, m, Ph), 7.40 (IH, dd, J = 6 and 8Hz, pyridine H-5), 8.18 (IH, dt, J = 8 and 2Hz, pyridine H-4), 8.72 (IH, dd, J = 6 and 2Hz, pyridine H-6), 9.08 (IH, d, J = 2Hz, pyridine H-2), 16.0 (IH, br s, OH); m/z (CI + , NH 3 ) 337 (M + +H). EXAMPLE 9 3-( l-(4-Chlorobenzvl)-4-piperidinvl )-5-(4-chlorophen vl )nvra7o1 P. a) 2-(4-Chlorobenzvlidene)αuinuclidin-3-one A solution of 3-quinuclidinone (54.5g), 4-chlorobenzaldehyde (84.0g) and sodium hydroxide (3.50g) in absolute ethanol (400cm 3 ) was heated at reflux for 2.5 hours. The mixture was cooled and addition of water (100cm 3 ) caused the product to precipitate as an orange solid. The precipitate was collected and washed with 1:1 ethanol-water (400cm 3 ). The mother-liquors were stood for 2 days, after which time further precipitated material was collected. The orange solid was redissolved in dichloromethane (800cm 3 ) and washed with water (200cm 3 ). The organic phase was dried (MgS0 4 ), filtered and evaporated to dryness to give the title compound as a bright yellow powder (86.2g, 76%), m.p. 108-110°C; δπ (360MHz; CDC1 3 ) 1.99-2.05 (4H, m, 2 x NCH 2 CH 2 ), 2.63 [(IH, quintet, =2.9, (CH 2 ) 2 CH], 2.92-3.01 (2H, m, 2 x NCiϊ), 3.11-3.19 (2H, m, 2 x NCff), 6.95 (IH, s, C=CH), 7.33 (2H, d, =8.6, 2 x ArH o to Cl) and 7.98 (2H, d, .7=8.6, 2 x ArH to Cl); m/z (CI + ; NΗ 3 ) 248 (ΛfN-H, 100%). h) 3-(4-Piperidinvn-5-(4-chlorophenvl razo1e A mixture of 2-(4-chlorobenzylidene)quinu idin-3-one (35.0g), potassium hydroxide (15.0g) and hydrazine hydrate (11.0cm 3 ) in ethylene glycol (100cm 3 ) was heated at 110°C for 15 minutes to produce a clear, dark brown solution. Hydrazine hydrate and water were distilled from the solution over 1 hour at 110°C to 195°C. The brown solution was then heated at reflux for 3 hours. The mixture was cooled to room temperature and diluted with water (300cm 3 ). The resulting white precipitate was collected and washed with water (500cm 3 ) and ethyl acetate (200cm 3 ). The white powder was dried in vacuo to give the title compound (31.5g, 85%), m.p. 174-176°C; δ H (250MHz; d 6 -DMSO) 1.52 (2H, apparent qd, =12 and 4, 2 x NCH 2 CH A H B ), 1.85 (2H, apparent d, J= 10, 2 x NCH 2 CH A H B ), 2.56 (2H, apparent td, = 12 and 2, 2 x NCH A H B ), 2.71 [IH, tt, =8.1 and 4.5, (CH 2 ) 2 Cfl], 2.99 (2H, apparent d, =12.1, 2 x NCH A H B ), 6.48 (IH, s, N=C-CH=C), 7.44 (2H, d, =8.6, 2 x ArH o to Cl; and 7.79 (2Η, d, =8.6, 2 x ArH m to Cl); δ c (90 MHz; d 6 -DMSO) 39.9 (t), 34.2 (d), 46.2 (t), 98.9 (d), 126.8 (d), 128.7 (d), 131.7 (s), 132.4 (broad, s), 147.5 (broad, s) and 151.1 (broad, s); m/z (CI +» NH 3 ) 262 (ΛT+H; 60%) and 139 (100). c) 3-(l-(4-Chlorobenzvl)-4-piperidinvl)-5-(4-chlorophenvl)pvrazolfi A solution of 3-(4-piperidinyl)-5-(4-chlorophenyl)pvrazole (1.50g), triethylamine (1.60cm 3 ) and 4-chlorobenzyl chloride (0.92g) in 3:1 dichloromethane-dimethylformamide (20cm 3 ) was stirred at room temperature for 4.5 hours. Dichloromethane was removed by evaporation and the crude product was partitioned between water (25cm 3 ) and ethyl acetate (2 x 25cm 3 ). The combined organic extracts were washed with saturated brine (20cm 3 ), dried (MgS0 4 ), filtered and evaporated to dryness to give an off-white solid. Recrystallisation from ethanol-water yielded the title compound as fine, white needles (0.575g, 26%), m.p. 179-181°C (from EtOH/H 2 0); (Found: C, 65.19; H, 5.24; N, 10.86. C 21 H 2 ιN 3 Cl 2 requires C, 65.29; H, 5.48; N, 10.88%.); δπ (360 MHz; CDC1 3 ) 1.71 (2H, apparent qd, =12 and 3, 2 x NCH 2 CH A H B ), 1.84 (2H, apparent d, .7=11, 2 x NCH 2 CH A H B ), 1.92 (2H, apparent t, =ll, 2 x NCH A H B ), 2.41-2.55 (IH, m, NCH 2 CH 2 CH), 2.84 (2H, apparent d, =ll, 2 x NCH A H B ), 3.44 (2H, s, NCH 2 Ar), 6.21 (IH, s, N=C-Cff=C), 7.30-7.21 (6H, m, 6 x ArH), 7.61 (2Η, d J=8.1, 2 x ArH) and 11.6-12.0 (IH, br s, NH); δ c (90MHz; CDC1 3 ) 31.9 (t), 33.8 (d), 53.3 (t), 62.5 (t), 99.5 (d), 126.9 (d), 128.6 (d), 128.9 (d), 130.3 (d), 132.8 (s), 133.5 (s) and 136.8 (s). 3 quaternary carbons not observed; m/z (CI + ; NH 3 ) 386 (M + + H; 30%), 262 (22), 228 (18), 210 (10), 196 (17), 179 (28), 162 (28), 154 (40), 142 (67), and 140 (100); m/z (CF ; NH 3 ) 420 (M " + Cl; 2%); 385 (M " ; 10), 259 (10), 178 (27) and 127 (20). EXAMPLE IQ 3-(l-Benzvl-4-piperidinvl)-5-(4-chlorophenvl)pvrazole White needles, m.p. 164-167°C (from EtOH/H 2 0) (Found: C, 71.68; H, 6.30; N, 11.94. C21H22N 3 CI requires C, 71.82; H, 6.22; N, 11.72%.); δπ (360MHz; CDC1 3 ) 1.74 (2H apparent qd, /=12 and 4, 2 x NCH 2 CH A H B ), 1.86 (2Η, apparent d, =10, 2 x NCH 2 CH A H B ), 1.97 (2H apparent t, =ll, 2 x NCH A H B ), 2.55 (IH, tt, .7=11.6 and 3.8, NCH 2 CH 2 CH), 2.55 (2H, apparent d, =12, 2 x NCH A H B ), 3.50 (2H, br s, NGff 2 Ph), 6.29 (IH, s, N=C-CH=C), 7.18-7.38 (7H, m, 2 x ArH and Ph) and 7.61 (2Η, d, =8.3, 2 x ArH); δ c (90 MHz; CDC1 3 ) 32.0 (t), 33.9 (d), 53.4 (t), 63.3 (t), 99.5 (d), 126.9 (d), 127.1 (d), 128.2 (d), 128.9 (d), 129.2 (d), 133.5 (s) and 138.1 (s). Three quaternary carbons not observed; m/z (CI + , NH 3 ) 352 (M + + H; 85%), 318 (18), 262 (21), 179 (22), 162 (25), 154 (30), 127 (35), 125 (55) and 106 (100); m/z (CF, NH 3 ) 386 (M " + Cl; 2%), 351 (M " ; 11), 259 (10), 178 (60) and 81 (100). EXAMPLE 11 3-π -(4-Methvlbenzvl)-4-piperidinvl)-5-(4-chlorophenvl tovrazole White needles, m.p. 181-183°C (from EtOH-H 2 0) (Found C, 72.37; H, 6.56; N, 11.65. C 22 H 24 N 3 C1 requires C, 72.22; H, 6.61; N, 11.48%); δπ (360MHz; CDC1 3 ) 1.80 (2H, apparent qd, J=12 and 1, 2 x NCH 2 CH A H B ), 1.94 (2H, apparent d, =12, 2 x NCH 2 CH A H B ), 2.08 (2Η, apparent t, =ll, 2 x NCH A H B ), 2.34 (3H, s, CH 3 ), 2.62-2.72 (IH, m, NCH 2 CH 2 CH), 2.96 (2H apparent d, =ll, 2 x NCH A H B ), 3.50 (2H, s, NCH 2 Ar), 6.32 (IH, s, N=C-CH=C), 7.13 (2H, d, =7.8, 2 x ArH o to Me), 7.22 (2H, d, =7.8, 2 x ArH m to Me), 7.33 (2H, d, =8.3, 2 x ArH o to Cl), 7.67 (2H, d, =8.3, 2 x ArH m to Cl) and 11.20-11.60 (IH, br s, NH); δ c (90MHz; CDC1 3 ) 21.1 (q). 32.0 (t), 34.0 (d), 53.4 (t) 63.0 (t), 99.2 (d), 126.8 (d), 128.7 (d), 128.9 (d), 129.2 (d) 133.1 (s) and 136.6 (s). Four quaternary carbons not observed; m/z (CI + , NH 3 ) 366 (M + +H; 40%) 262 (12), 179 (13), 154 (22), 139 (30), 126 (41) and 120 (100); m/z (CF, NH 3 ) 400 (M " +C1; 5%), 365 (M-; 11), 259 (19), 178 (70) and 81 (100). EXAMPLE 12 3.fl-(4-Methoxvbenzvl)-4-piperidinvl)-5-(4-chlorophenvl)pvrazole Fine, cream coloured needles, m.p. 166-168°C (from EtOH H 2 0) (Found C, 69.49; H, 6.51; N, 11.13. requires C, 69.19; H, 6.33; N, 11.00%); δπ (360MHz, CDC1 3 ) 1.74 (2H, apparent qd, .7=12 and 3, 2 x NCH 2 CH A H B ), 1.84-1.97 (4H, m, 2 x NCH 2 CH A H B and 2 x NCH A H B ), 2.55 (IH, tt, J 12 and 4, NCH 2 CH 2 CH), 2.90 (2H, apparent d, J=ll, 2 x NCH A H B ), 3.44 (2H, s, NCH 2 Ar), 3.80 (3H, s, OCH 3 ), 6.30 (IH, s, N=C-CH=C), 6.85 (2H, s, .7=8.5, 2 x ArH o to OMe), 7.21 (2H, d, .7=8.5, 2 x ArH to OMe) 7.31 (2H, d, .7=8.3, 2 x ArH o to Cl) and 7.61 (2H, d, =8.3, 2 x ArH m to Cl); δ c (90MHz; CDC1 3 ) 32.0 (t), 34.0 (d), 53.3 (t), 55.2 (q), 62.7 (t), 99.5 (d), 113.6 (d), 126.9 (d), 128.8 (d), 130.1 (s), 130.4 (d), 131.4 (s), 133.5 (s) and 158.7 (s). Two quaternary carbons not observed; m/z (CI + , NH 3 ) 382 (M + +H; 20%) 262 (17), 179 (18), 154 (39) and 136 (100); m/z (CF, NH 3 ) 416 (M " +C1; trace), 381 (M " ; 5), 259 (40) and 178 (100). EXAMPLE 13 3-(l-(2-Propenvl)-4-piperidinvl)-5-(4-chlorophenvl)pvrazolfi White granules, m.p. 165-167°C (from EtOH/H 2 O) (Found: C, 67.65; H, 6.68; N, 13.92. C 17 H 20 N 3 C1 requires C, 67.51; H, 6.79; N, 13.83%.); δ H (360 MHz; CDC1 3 ) 1.79 (2H, apparent qd, .7=12 and 3, 2 x NCH 2 CH A H B ), 1.97-2.08 (4H, m, 2 x NCH 2 CH A H B and 2 x NCH A H B ), 2.67 (IH, tt, .7=11.6 and 3.9, NCH 2 CH 2 CH), 2.98-3.02 (4H, m, 2 x NCH A H B and NCH 2 CH=CH 2 ), 5.15 (IH, d, .7=10, CH=CH A H B , 5.19 (IH, d, .7=17, CH=CH A H B ), 5.88 (IH, ddt, .7=17, 10 and 6.5, CH=CH 2 ), 6.31 (IH, s, N=CCH), 7.32 (2H, d, .7=8.5, 2 x ArH o to Cl); and 7.69 (2Η, d, J=8.5, 2 x ArH m to Cl); δ c (90MΗz; CDC1 3 ) 31.9 (t), 33.9 (d), 53.4 (t), 61.8 (t), 98.9 (d), 117.7 (t), 126.7 (d), 128.6 (d), 131.6 (s), 132.9 (s) and 135.2 (d). 2 x s not observed; m/z (CI + ; NH 3 ) 302 (M + + H; 100%); m/z (CF ; NH 3 ) 336 (M " + Cl; 10%), 301 (M " ; 21) and 178 (100). EXAMPLE 14 3-( l-(4-Nitrobenzvl -4-pjperidinvl V5-(4-chlorophenvl'>pvrazole Yellow granules, m.p. 187-190°C (from EtOH H 2 0) (Found: C, 63.67, H, 5.28; N, 14.21. C 21 H 21 N 4 0 2 C1 requires C, 63.55; H, 5.33; N, 14.12%); δ H (360MHz; CDC1 3 ) 1.52 (2H, apparent q, .7=12, 2 x NCH 2 CH A H B ), 1.71 (2H, apparent d, .7=12, 2 x NCH 2 CH A H B ), 1.89 (2H, apparent t, .7=11, 2 x NCH A H B ), 2.43 (IH, apparent t, .7=12, NCH 2 CH 2 CH), 2.64 (2H, apparent d, .7=11, 2 x NCH A H B ) 3.35 (2Η, s, NCH 2 Ar), 6.05 (IH, s, N=C-CH=C), 7.05 (2H, d, .7=8.3, 2 x ArH m to nitro), 7.28 (2H, d, .7=8.3, 2 x ArH o to Cl), 7.43 (2H, d, .7=8.3, 2 x ArH m to Cl), 7.88 (2H, d, .7=8.3, 2 x ArH o to nitro) and 12.12 (IH, br s, NH); δ c (90MHz; CDC1 3 ) 3.17 (t), 33.6 (d), 53.4 (t), 62.0 (t) 98.9 (d), 123.1 (d), 126.5 (d), 128.4 (d), 129.2 (d), 132.4 (s) and 146.7 (s). Four quaternary carbons not observed; m/z (CI + , NH 3 ) 397 (M + +H; 10%) 262 (60) and 139 (100); m/z (CF, NH 3 ) 396 ( " ; 20%) 255 (20) 151 (50) and 79 (100). EXAMPLE 15 3-fl-(4-Chlorobenzvl -4-piperidinvlV5-phenvlpvrazole Chunky white needles m.p. 183°C (from EtOH/H 2 0) (Found C, 72.03; H, 6.27; N, 12.10. C 21 H 22 C1N 3 requires C, 71.68; H, 6.30; N, 11.94%); δ H (360MHz, d 6 -DMSO) 1.66 (2H, dq, .7=3.3 and 12.2, CH A H B CH), 1.89 (2H, br d, .7=12.0, CH A H B CH), 2.06 (2H, dt, .7=2.2 and 11.6, CH A H B N), 2.64 (IH, br m, CH 2 CH), 2.85 (2Η, br d, =11.5, CH A H B N), 3.48 (2Η, CH 2 Ar), 6.48 (1Η, br s, CCHC), 7.26 (1Η, br t, .7=7, Ph-4-Η), 7.34 (2H, d, .7=8.5, CH 2 ArH), 7.39 (2Η, d, .7=8.5, CHaArH), 7.4 (2H, br m, Ph-3-H), 7.75 (2H, br d, J=7, Ph-2-H), 12.59 and 12.88 (IH, br s and br s, N A N B H and N A HN B tautomers); m/z (CI + , NH 3 ) 352 ( +l). EXAMPLE lfi 3-f 1 -(4-Chlorohenzvl )-4-piperidinvl)-5-(2-thienvl)pvrazole Pale yellow needles m.p. 177-178°C (from EtOH/H 2 0) (Found C, 63.87; H, 5.59; N, 11.78. C 19 H 20 C1N 3 S requires C, 63.76; H, 5.63; N, 11.74%); δπ (360MHz, de-DMSO) 1.65 (2H, dq, .7=3.1 and 12.1, CH A H B CH), 1.88 (2H, br d, =11.0, ' CH A H B CH), 2.05 (2H, dt, .7=2.2 and 11.7Hz CH A H B N), 2.64 (IH, br m, CH 2 CH), 2.84 (2H, br d, .7=11.5, CH A H B N), 3.48 (2H, s, ArCH 2 ), 6.36 (IH, br s, CCHC), 7.05 (IH, m, thiophene-4-H), 7.31 (IH, m thiophene-H), 7.34 (2H, d, =8.6, CH 2 ArH), 7.38 (2H, d, .7=8.6, CU 2 ArH), 7.4 (IH, m, thiophene-H), 12.55 and 12.89 (IH, br s and br s, N A N B H and N A HN B tautomers; m/z (CI + , NH 3 ) 358 (M+l) EXAMPLE 17 3-(l-(4-Chlorophenv1)-4-piperidinvl)-5-(4-isoproPvlphenvl)pvrazole Fine white needles, m.p. 167-168°C (from Ether/hexane) (Found C, 73.53; H, 7.07; N, 10.78. C 24 H 28 C1N 3 requires (C, 73.17; H, 7.16; N, 10.67%); δ H (360MHz, d 6 -DMSO) 1.21 (6H, d, .7=6.9, (CH 3 ) 2 ) 1.66 (2H, dq, .7=3 and 11.9, CH A H B CH) 1.88 (2H, br d, J=11.8, CH A H B CH), 2.06 (2H, dt, .7=2.2 and 11.7, CH A H B N), 2.62 (IH, br m, CH 2 CH), 2.83-2.92 (3Η, m, CH A H B N and CH(CH 3 ) 2 ), 3.47 (2H, s, ArCH 2 ) 6.43 (1Η, br s, CCHC), 7.26 (2Η, br m ArH), 7.34 (2Η, d, =8.6, CH 2 ArH), 7.39 (2Η, d, .7=8.6, CH 2 ArH), 7.65 (2Η, br m, ArH), 12.52 and 12.80 (IH, br s and br s, N A N B H and N A HN B tautomers); m/z (CI + , NH 3 ) 394 (Λ ++l) EXAMPLE 18 3-π-(4-ChlorobenzvlVl-piperidinvl)-5-(4-methoxvphenvl) pyrazole White crystalline solid, m.p. 163°C and 172°C (from Ethyl acetate). Two crystal forms exist over the temperature range. (Found C, 69.19; H, 6.33; N, 11.00. C 22 H 24 C1N 3 0 requires C, 69.58; H, 6.35; N, 11.08%); δπ (360MHz, CDC1 3 ) 1.82 (2H, dq, .7=3.4 and 12.1, CH A H B CH) 1.97 (2H, br d, .7=11.6, CH A H B CH), 2.08 (2H, br t, .7=10.8, CH A H B N) 2.64-2.72 (IH, m, CH 2 CH), 2.95 (2H, br d, .7=11.7, CH A H B N), 3.51 (2H, s, ArCH 2 ), 3.83 (3H, s, CH 3 ), 6.29 (1Η, s CCHC), 6.92 (2Η, dt, .7=8.8 and 2.5, ArH o to OMe), 7.23 (4Η, s, CH 2 ArH), 7.60 (2Η, br d, .7=8.5, ArH to OMe); m/z (CI + , NΗ 3 ) 382 ( ++1). EXAMPLE 19 3-( l-Cvclohexvlmethvl-4-piperidinvl)-5-(4-chlorophenv1 )pvrazo1 p. White granules, m.p. 186-187°C (from EtOH H 2 0 Me 2 CO) (Found: C, 70.27; H, 7.89; N, 11.70. C 21 H 28 N 3 C1 requires C, 70.47; H, 7.88; N, 11.74%); δ H (360MHz; CDC1 3 ) 0.88 (2H, apparent q, .7=11.6, CH 2 ), 1.10-1.29 (3H, m, methylenes), 1.47-1.53 (IH, m, NCH 2 CH), 1.69-1.99 (11Η, m, methylenes), 2.14 (2Η, d, .7=7.0, NCH 2 CH), 2.62 (IH, tt, .7=11.5 and 3.9, NCH 2 CH 2 CH), 2.93 (2Η, apparent d, .7=11, 2 x NCH A H B ), 6.33 (1Η, s, N=CCΗ), 7.33 (2H, d, .7=8.4, 2 x ArH o to Cl) and 7.65 (2H, d, .7=8.3, 2 x ArH m to Cl); δ c (90MHz; CDC1 3 ) 26.1 (t), 26.8 (t), 32.0 (t), 32.04 (t), 34.1 (d), 35.2 (d), 54.1 (t), 66.0 (t), 99.6 (d), 126.9 (d), 128.8 (d) and 133.5 (s). 3 x s not observed; m/z (CI + ; NH 3 ) 358 (Λf^+H; 100%); m/z (CF; NH 3 ) 392 (ΛT+C1; 32%), 357 (ΛT; 18), 242 (5), 178 (37) and 127 (100). EXAMPLE 2Q 3-(l-f2-Phf»nv1ethvl)-4-piperidinvl)-5-(4-chlorophenvl)pvrazole Beige granules, m.p. 169-171°C (from EtOH H 2 0) (Found: C, 72.09; H, 6.48; N, 11.50. C 22 H 24 N 3 C1 requires C, 72.22; H,. 6.61; N, 11.48%); δ H (360MHz; CDC1 3 ) 1.83 (2H, apparent qd, =12 and 4, 2 x NCH 2 CH A H B ), 2.00 (2H, apparent d, .7=11, 2 x NCH 2 CH A H B ), 2.14 (2H, apparent t, =12, 2 x NCH A H B ), 2.61-2.65 (2H, m, NCH 2 CH 2 Ar), 2.70 (IH, tt, .7=11.8 and 3.9, NCH 2 CH 2 CH), 2.81-2.86 (2H, m, NCH 2 CH 2 Ar), 3.08 (2H, apparent d, .7=12, 2 x NCH A H B ), 6-34 (IH, s, N=CCH=C), 7.35-7.16 (7H, m, Ph and 2 x ArH 0 ^ C ι) and 7.69 (2H, d, .7=8.4, 2 x ArH m to Cl); δ c (90MHz; CDC1 3 ) 32.0 (t), 33.6 (t), 34.0 (d), 53.6 (t), 60.8 (t), 99.1 (d), 126.0 (d), 126.8 (d), 128.3 (d), 128.65 (d), 1228.70 (d), 133.1 (s) and 140.3 (s). 3 x s is not observed; m/z (CI + ; NH 3 ) 366 (ΛT+H; 100%); m/z (CF; NH 3 ) 400 (ΛT+C1; 5%), 365 (ΛT; 12) and 178 (100). EXAMPLE 21 3-(l-(3.4-Dichlorobenzvl)-4-piperidinvl)-5-(4-chlorophenvl)pvrazole White needles, m.p. 171-174°C (from EtOH EtOAc H 2 0) (Found: C, 59.95; H, 4.66; N, 9.82. C 21 H 20 N 3 C1 3 requires C, 59.95; H, 4.79; N, 9.99%); δ H (360MHz; CDCl 3 +d 6 -DMS0) 1.78 (2H, apparent qd, =12 and 4, 2 x NCH 2 CH A H B ), 1.97 (2H, apparent d, .7=12, 2 x NCH 2 CH A H B ), 2.11 (2Η, apparent t, .7=12, 2 x NCH A H B ), 2.69 (IH, tt, .7=12 and 4, NCH 2 CH 2 CH), 2.91 (2Η, apparent d, .7=12, 2 x NCHAB), 3.47 (2H, s, NCH 2 Ar), 6.32 (IH, s, N=C-CH=C), 7.19 (IH, dd, J 8.1 and 1.6, H-5), 7.32 (2H, d, .7=8.6, 2 x ArH o to Cl), 7.38 (IH, d, .7=8.1, H-6), 7.46 (IH, d, .7=1.6, H-2) and 7.71 (2H, d, .7=8.6, 2 x ArH m to Cl); δ c (90MHz; CDCl 3 +d 6 -DMSO) 36.7 (t), 38.6 (d), 58.3 (t) 66.6 (t), 103.6 (d), 131.4 (d), 133.0 (d), 133.3 (d), 134.8 (d), 135.2 (s), 135.3 (d) 136.6 (s), 136.7 (s), 137.5 (s), 144.2 (s) and 152.7 (s). One quaternary carbon not observed; m/z (CI + , NH 3 ) 420 (Λf+H; 30%), 386 (12), 287 (90), 262 (46), 190 (47), 140 (60) and 100 (100); m/z (CF, NH 3 ) 419 (Λf; 20%), 259 (10), 178 (21) and 79 (100). EXAMPLE 22 3-(l-(4-Chlorobenzvl)-4-piperidinvl)-5-(3-chlorophenvl)pvrazole White needles, m.p. 156-157°C (from EtOH H 2 0) (Found C, 65.23; H, 5.43; N, 10.70. C 21 H 21 C1 2 N 3 requires C, 65.29; H, 5.48; N, 10.88%); δπ (360MHz,d 6 -DMSO) 1.66 (2H, dq, .7=3.1 and 12.0, CH A H B CH), 1.89 (2H, br d, .7=11.4, CH A H B CH), 2.06 (2H, dt, .7=2.2 and 11.7, CH A H B N), 2.57-2.72 (IH, br m, CH 2 CH), 2.85 (2Η, br d, .7=11.5, CH A H B N), 3.48 (2H, s, CH 2 Ar), 6.58 (IH, br s, CCHC), 7.34 (2Η, d, .7=8.5, CH 2 ArH), 7.39 (2Η, d, .7=8.5, CH 2 ArH), 7.32-7.44 (2Η, m, ArH), 7.72 (IH, br d, =7.5, ArH p to Cl), 7.80 (IH, t, .7=1.7, ArH o to Cl and to pyrazole), 12.73 and 12.98 (IH, br s and br s, N A N B H and N A HN B tautomers); m/z (CI + , NΗ 3 ) 386 (Λf++1). EXAMPLE 23 3-(l-(3-Chlorobenzvl)-4-piperidinvl)-5-(4-chlorophenvl ' )pvrazolft White granules, m.p. 134-136°C (from EtOH H 2 0) (Found: C, 65.28; H, 5.41; N, 10.86. C 21 H 21 N 3 C1 2 requires C, 65.29; H, 5.48; N, 10.88%); δ H (360MHz; CDC1 3 ) 1.74 (2H, apparent qd, .7=12 and 4, 2 x NCH 2 CH A H B ), 1.87 (2H, apparent d, .7=12, 2 x NCH 2 CH A H B ), 1.97 (2H, apparent t, =12, 2 x NCH A H B ), 2.56 (IH, tt, .7=12 and 4, NCH 2 CH 2 CH), 2.87 (2Η, apparent d, .7=12, 2 x NCH A H B ), 3.46 (2Η, s, NCH 2 Ar), 6.31 (IH, s, N=C-CH=C), 7.17-7.33 (6H, m, 6 x ArH), 7.62 (2H, d, J 8.4, 2 x ArH m to Cl) and 10.07 (IH, br s, NH); δ c (90MHz; CDC1 3 ) 32.0 (t), 33.8 (d), 53.4 (t), 62.6 (t), 99.6 (d), 126.9 (d), 127.1 (d), 128.9 (d), 129.0 (d), 129.5 (d) 133.6 (s), 134.2 (s) and 140.5 (s). Three quaternary carbons not observed; m/z (CI + , NH 3 ) 386 (Λf^+H; 100%); m/z (CF, NH 3 ) 420 (M " +C1; 12%), 385 (M " ; 14) and 127 (100). EXAMPLE 24 3-(l-(4-Chlorobenzvl)-4-piperidinvl)-5-(2-chlorophenvl) pyrazole. oxalate salt Amorphous white solid, m.p. 133-135°C (EtOH) (Found: C, 55.87; H, 5.00; N, 8.41. C 21 H 21 C1 2 N 3 .(C 2 H 2 0 4 ).(H 2 0) requires C, 55.88; H, 5.10; N, 8.50%); δ H (360MHz, d 6 -DMSO) 1.85 (2H, br q, =12, CH A H B CH), 2.08 (2H, br d, .7=12, CH A H B CH), 2.76 (3H, br t, .7=12, CH A H B N), 2.88 (IH, br m, CH 2 CH), 3.20 (2Η, br d, =12, CH A H B N), 4.06 (2Η, br s ArCH 2 ), 6.53 (1Η, s, CCHC), 7.35 (1Η, dt, .7=2.0 and 7.5, ArH), 7.39 (1Η, dt, .7=1.6 and 7.3, ArH), 7.50 (4Η, s, CH 2 ArH), 7.53 (1Η, dd, .7=1.6 and 7.5, ArH), 7.71 (1Η, dd, .7=2.1 and 7.3, ArH o to pyrazole); m/z (CI + , NΗ 3 ) 386 (M++H). EXAMPLE 25 3-(l-Benzvl-4-piperidinvl)-5-phenvlpvrazole White plates, m.p. 130-131°C (from EtOH/H 2 0) (Found: C, 76.80; H, 7.39; N, 12.86. C 21 H 23 N 3 .(0.6H 2 O) requires C, 76.84; H, 7.43; N, 12.80%); δ H (360MHz, d 6 -DMSO) 1.67 (2H, dq, .7=3.2 and 12.2, CH A H B CH) 1.89 (2H, br d, .7=11.4, CH A H B CH), 2.05 (2H, dt, .7=2.3 and 11.7, CH A H B N), 2.63 (IH, br m, CH 2 CH), 2.87 (2Η, br d, .7=11.6, CH A H B N), 3.48 (2Η, s, PhCH 2 ), 6.49 (1Η, br s, CCHC), 7.22-7.38 (8Η, m, CH 2 PhH and PhH), 7.75 (2Η, br d, .7=7, PhH o to pyrazole), 12.60 and 12.88 (1Η, br s and br s, N A HN B and N A NBΗ tautomers); m/z (CI + , NΗ 3 ) 318 ( ++H). EXAMPLE 26 3-π.(4-Ch1orobenzvl)-4-piperidinvl)-5-(2-methoxvphenvl)pvrazole Pale yellow plates, m.p. 102-103°C (from ether/hexane) (Found: C, 69.59; H, 6.38; N, 11.01. C 22 H 24 C1N 3 0 requires C, 69.19; H, 6.33; N, 11.03%) δπ (360MHz, d 6 -DMSO) 1.66 (2H, dq, .7=3.3 and 12.2, CH A H B CH) 1.88 (2H, br d, .7=10.7, CH A H B CH) 2.06 (2H, dt, .7=2.1 and 11.6, CH A H B N), 2.61 (IH, br m, CH 2 CH), 2.85 (2Η, br d, .7=11.5, CH A H B N), 3.47 (2H, s, ArCH 2 ), 3.86 (3Η, s, CH 3 ), 6.50 (IH, s, CCHC), 6.98 (1Η, br t, =7.5Ηz ArH m to pyrazole) 7.08 (1Η, br d, .7=8.3, ArH o to 0CΗ 3 ), 7.28 (IH, br t, .7=7.2, ArHp to pyrazole), 7.34 (2Η, dd, .7=6.5 and 2.2, CH 2 ArH), 7.38 (2Η, dd, .7=6.5 and 2.2, CH 2 ArH), 7.68-7.84 (1Η, v br s, ArΗ o to pyrazole), 12.51 (1Η, br s, NH); m/z (CI + , NΗ 3 ) 382 (M + +H). EXAMPLE 27 3-(l-(2-Methvlbenzvn-4-piperidinvlV5-(4-chlorophfinvl)pvrazolfi Fine, white needles, m.p. 142-143°C (from ethanol/water) (Found: C, 72.56; H, 6.57; N, 11.71. C 22 H 24 N 3 C1 requires C, 72.22; H, 6.61; N, 11.48%); δ H (360MHz, d 6 -DMSO), 1.58-1.69 (2H, dq, .7=3.1 and 12, CH A H B CH), 1.86-1.89 (2H, br d, .7=12, CH A H B CH), 2.05-2.11 (2H, dt, .7=3.1 and 11, CH A H B N), 2.33 (3H, s, CH 3 ), 2.65 (1Η, m, CHCΗ 2 ) 2.84-2.87 (2H, d, =ll, CH A H B N), 3.43 (2Η, s, ArCH 2 ), 6.51 (1Η, s, CCHC), 7.12-7.25 (4Η, m, CH 2 ArH), 7.42-7.44 (2H, d, .7=7.8, CArH), 7.76-7.78 (2Η, d, .7=7.8, CArH), 12.68 (IH, br s, NH); m/z (CI + , NΗ 3 ) 366 (M + +H). EXAMPLE 28 3-π-(3-Nitrohenzvl)-4-piperidinvD-5-(4-chlorophenvl)pvrazole Fine, pale yellow needles, m.p. 174-176°C (from ethanol/water) (Found: C, 63.85; H, 5.31; N, 14.10. C 2 ιH 21 N 4 0 2 Cl requires C, 63.55; H, 5.33; N, 14.12%); δ H (360MHz, d 6 -DMSO) 1.69 (2H, dq, =2.8 and 12, CH A H B CH), 1.90 (2H, br d, .7=12, CH A H B CH), 2.13 (2H, dt, .7=2.1 and 10, CH A H B N), 2.6-2.8(lH, m, CHCH 2 ) 2.88 (2H, br d, .7=10, CH A H B N), 3.64 (2Η, s CH 2 Ar), 6.53 (1Η, br s, CCHC), 7.43 (2Η, d, .7=7.5, CArH), 7.64 (1Η, t, .7=7.5, ArH, m to N0 2 ), 7.77-7.80 (3Η, m, CArH and ArHp to N0 2 ), 8.12-8.14 (1Η, dd, =1.4 and 7.5, ArΗp to CΗ2), 8.18 (IH, br s, ArH m to N0 2 and CH 2 ), 12.69 (IH, br s, NH), m/z (CI + , NΗ 3 ) 397 ( + +H). EXAMPLE 29 3-(l-(3-Methvlbenzvl)-4-piperidinvl)-5-(4-chlorophenvl)pvrazole Fine, white crystalline solid, m.p. 119-120°C (from ethanol/water) (Found: C, 72.63; H, 6.55; N, 11.50, C 22 H 24 N 3 C1 requires C, 72.22, H, 6.61; N, 11.48%); δ H (360MHz, d 6 -DMSO), 1.61-1.71 (2H, dq, .7=3.6 and 12, CH A H B CH), 1.86-1.89 (2H, br d, .7=12, CH A H B C), 2.00-2.06 (2Η, dt, .7=3.6 and 10, CH A H B N), 2.30 (3H, s, CH 3 ), 2.63 (1Η, br m, CHCΗ 2 ), 2.85-2.88 (2H, br d, .7=10, CH A H B N), 3.43 (2Η, s, CH 2 Ar), 6.52 (1Η, s, CCHC), 7.05-7.12 (3Η, m, CH 2 ArH), 7.19 (1Η, t, .7=7.4, ArH m to CΗ 3 ), 7.42 (2H, d, =8.0Hz CArH), 7.76 (2Η, d, .7=8.0, CArH), 12.68 (1Η, br s, NH); m/z (CI + , NΗ 3 ) 366 ( + +Η). EXAMPLE 3Q 3-(l-(2-Nitrohfinzvn-4-piperidinvl)-5-(4-chlorophenvl vrazole Fine, pale yellow needles, m.p. 150-151°C (from ethanol/water) (Found: C, 63.61; H, 5.19; N, 14.03. C 21 H 2 ιN 4 0 2 Cl requires C, 63.55; H, 5.33; N, 14.12%); δπ (360MHz, dβ-DMSO), 1.63 (2H, dq, .7=2.9 and 11, CH A H B CH), 1.88 (2H, br d, .7=11, CH A H B CH), 2.15 (2H, dt, .7=2.2 and 11, CH A H B N), 2.63 (IH, m, CHCH), 2.76 (2H, br d, .7=11, CH A H B N), 3.74 (2Η, s, CH 2 Ar), 6.51 (1Η, br s, CCHC), 7.44 (2Η, d, .7=7.2, CArH), 7.54 (1Η, dt, .7=2.4 and 8.3, ArH E to N0 2 and m to CΗ 2 ), 7.63-7.69 (2H, m, ArH m to N0 2 and o to CΗ 2 , ArHp to N0 2 ), 7.79 (2Η, d .7=7.2, CArH), 7.87 (1Η, d, .7=7.8, ArH, o to N0 2 ), 12.67 (1Η, s, NH); m/z (CI + , NΗ 3 ) 397 (M++H). EXAMPLE 31 3-(l-(2-Chlorobenzvl)-4-piperidinvl)-5-(4-chlorophenvl)pvrazole Fine, pale yellow crystals, m.p. 137-139°C (from ethanol/water) (Found: C, 65.19; H, 5.52; N, 10.87. C 21 H 21 N 3 C1 2 requires C, 65.29; H, 5.48; N, 10.88%); δ H (360MHz, d 6 -DMSO), 1.74 (2H, dq, .7=3.5 and 12, CH A H B CH 2 ), 1.92 (2H, br d, =12, CH A H B CH 2 ), 2.19 (2H, dt, .7=3.5 and 11, CH A H B N), 2.67 (IH, m, CHCH 2 ) 2.91 (2H, br d, .7=12, CH A H B N) 3.58 (2H, s, ArCH 2 ), 6.53 (1Η, s, CCHC), 7.26-7.36 (2Η, m, ArHp to Cl, ArH m to Cl andp to CΗ 2 ), 7.42-7.44 (3H, m, CArH, CΗ 2 ArH), 7.52 (1Η, dd, =2 and 7, CΗ 2 ArH), 7.76-7.80 (2Η, d, J=8, CArH), 12.69 (1Η, br s, NH); m/z (CI + , NΗ 3 ) 386 ( + +H). EXAMPLE 32 3-(l-Cvclopropvlmethvl-4-piperidinvl)-5-(4-chlorophenvl)pvrazole White needles, m.p. 176-178°C (from ethyl acetate) (Found: C, 68.72; H, 6.75; N, 13.47. C 22 H 18 N 3 C1 requires C, 68.45; H, 7.02;, N, 13.30%); δπ (360MHz, d 6 -DMSO), 0.02-0.10 (2H, m, CHCH A H B CH A H B ), 0.44-0.49 (2H, m, CHCH A H B CH A H B ), 0.82-0.86 (1Η, m, CΗ 2 CHCΗ 2 ), 1.71 (2H, dq, .7=3 and 12, CH A H B CH 2 ), 1.91 (2H, br d, .7=12, CH A H B CH 2 ), 2.04 (2H, dt, =3 and 12, CH A H B N), 2.20 (2H, d, J=7, NCH 2 CH), 2.61 (IH, m, CCHCH 2 ), 6.51 (IH, s, CCHC), 7.45 (2Η, d, .7=8, ArH), 7.79 (2H, d, .7=8, ArH), 12.76 (IH, s, NH); m/z (CI + , NΗ 3 ) 316 (M + +Η). EXAMPLE 33 3-(l-(2-Naphthvlmethvl)-4-piperidinvl)-5-(4-chlorophenvl pvrazn1fi Off-white needles, m.p.l80-181°C (from ethanol) (Found: C, 74.92; Η, 6.12; N, 10.57. C 25 Η 24 N 3 C1 requires C, 74.71; H, 6.02; N, 10.45%); δ H (360MHz, d 6 -DMSO) 1.74 (2H, dq, .7=11, CH A H B CH 2 ), 1.91 (2H, br d, .7=11, CH A H B CH 2 ), 2.14 (2H, t, .7=12, CH A H B N), 2.66 (IH, br m, CH 2 CH), 2.93 (2Η, br d, .7=12, CH A H B N), 3.65 (2Η, s, CH 2 Ar), 6.52 (1Η, s, CCHC) 7.41-7.53 (5Η, m, ArH), 7.77-7.90 (6Η, m, ArH), 12.68 (1Η, br s, NH); m/z (CI + , NΗ 3 ) 402 (Λf+H). EXAMPLE 34 3-(l-(3-Phenvl-l-propvl)-4-piperidinvl)-5-(4-chlorophenv1 pvra7n1p Fine white crystals, m.p. 165-167°C (from ethanol) (Found: C, 72.83; H, 6.88; N, 11.23. C 23 H 26 N 3 C1 requires C, 72.71; H, 6.90; N, 11.06%); δ H (360MHz, d 6 -DMSO), 1.61-1.78 (4H, m, CH A H B CH, CH 2 CH 2 CH 2 ), 1.91 (2H, br d, .7=12, CH A H B CH 2 ), 1.99 (2H, t, J=12, CH A H B N), 2.31 (2H, t, .7=7, CH 2 CH 2 CH 2 ), 2.61 (2H, t, .7=7, CH 2 CH 2 CH 2 ), 2.92 (2Η, br d, .7=12, CH A H B N), 6.51 (1Η, s, CCHC), 7.14-7.22 (5H, m, CH 2 ArH), 7.44 (2Η, d, .7=7, CArH), 7.79 (2Η, d, =7, CArH), 12.67 (1Η, s, NH); m/z (CI + , NΗ 3 ) 380 ( ÷+H). EXAMPLE 35 3-n-(3-Methoxvbenzvl)-4-piperidinvl)-5-(4-chlorophenvl)pvrazole Fine, white crystals, m.p. 50-52°C (from DMF/water) (Foi d: C, 68.42; H, 6.42; N, 10.98. C 22 H 24 N 3 OCl.(0.25H 2 O) requires C, 68.38; H, 6.39; N, 10.87%); δπ (360MHz, d 6 -DMSO), 1.71 (2H, dq, .7=12, CH A H B CH), 1.90 (2H, br d, .7=12, CH A H B CH), 2.07 (2H, t, =12, CH A H B N) 2.64 (IH, br m, CH 2 CH), 2.88 (2Η, br d, .7=12, CH A H B N), 3.46 (2Η, s, ArCH 2 ), 3.75 (3Η, s, OCH 3 ), 6.52 (1Η, s, CCHC), 6.83 (1Η, d, =9, CΗ 2 ArH), '6.90 (2Η, m, CH 2 ArH), 7.26 (1Η, t, J=9, CΗgArH to MeO), 7.44 (2Η, d, .7=8, CArH), 7.78 (2Η, d, =8, CArH), 12.68 (1Η, s, NH); m/z (CI + , NΗ 3 ) 382 (Λf+H). EXAMPLES 36 & 37 5-(l-(4-Chlorobenzvl)-4-piperidinvl)-3-(4-chlorophenvl soxazolR and 3-(l-(4-Chlorobenzvl)-4-piperidinvl)-5-(4-chlorophenvl)isnxazolfi Hydroxylamine hydrochloride (139mg) was added to l-(4- chlorobenzyl)-4-(3-hydroxy- l-oxo-3-(4-chlorophenyl)prop-2-en- 1- yl)piperidine obtained from Example 1 (399mg) and ethyldiisopropylamine (0.35ml) in methanol (5ml) and DMF (2ml). After stirring for 16h hydroxylamine hydrochloride (139mg) and ethyldiisopropylamine (0.35ml) were added and the mixture stirred at 50°C for 4h. Water (50ml) was added, the mixture extracted with ethyl acetate (3 x 25ml) and the combined organic layers washed with water and brine, dried (MgS0 ), evaporated in vacuo, and purified by flash chromatography, eluting with dichloromethane:methanol:triethylamine (96:4:1 v/v) to give a mixture of 5-(l-(4-chlorobenzyl)-4-piperidinyl)-3-(4-chlorophenyl)-3-hydroxy- 3,4-dihydroisoxazole and 3-(l-(4- chlorobenzyl )-4-piperidinyl)-5-(4- chlorophenyl)-3-hydroxy-3,4-dihydroisoxazole (287mg). 209mg of this oil was dissolved in dichloromethane (5ml), cooled to 0°C, and triethylamine (161mg) and methanesulphonyl chloride (81mg) added. After lh ethyl acetate (25ml) was added, and the mixture washed with water and brine, dried (MgS0 4 ), and evaporated in vacuo, and purified by preparative thin layer chromatography, eluting with dicWoromethane:methanol:triethylamine (97:3:1 v/v) to give 5-(l-(4-chlorobenzyl)-4-piperidinyl)-3-(4-chlorophenyl)isoxazole (107mg); oxalate salt: amorphous white solid, m.p.227-230°C (from ethanol) (Found: C, 58.91; H, 4.95; N, 6.15%. C 2 ιH 20 N 2 OCl 2 . (0.8C 2 H 2 O 4 ) requires C, 59.09; H, 4.74; N, 6.10%); δ j , (360MHz, d 6 -DMSO) 1.7-1.8 (2H, m, CHCH A H B ), 2.08 (2H, d, .7=11, CHCH A H B ), 2.3-2.4 (2Η, m, NCH A H B ), 3.0-3.1 (3H, m, NCH A H B and CH 2 CH), 3.82 (2Η, s, ArCH 2 ), 6.92 (IH, s, CHCO), 7.4-7.5 (4H, m, ArHCH 2 ), 7.59 (2H, d, .7=8, ArH), 7.88 (2H, d, .7=8, ArH); m/z (CI + , NH 3 ) 387 (Λ ^+H); and 3-(l-(4-chlorobenzyl)-4-piperidinyl)-5-(4- chlorophenyl)isoxazole (51mg); oxalate salt: white plates, m.p. 240-242°C (from ethanol) (Found: C, 57.85; N, 4.74; H, 5.92. C 21 H 20 N 2 OCl 2 .C 2 H 2 O 4 requires C, 57.87; H, 4.64; N 5.87%); δπ (d 6 -DMSO) 1.8-1.9 (2H, m, CH A H B CH), 2.05 (2H, d, .7=11, CH A H B CH), 2.6-2.7 (2H, m, NCH A H B ), 2.9-3.0 (IH, m, CH 2 CH), 3.1-3.2 (2Η, m, NCH A H B ), 3.97 (2Η, s, ArCH 2 ), 7.07 (1Η, s, CΗCO), 7.4-7.5 (4Η, m ArHCH 2 ), 7.61 (2H, d, =8, ArH), 7.85 (2H, d, .7=8, ArH); m/z (CI + , NH 3 ) 387 (Λf^+H). The isoxazole regiochemistry was proved by X-ray. EXAMPLES 38 & 39 l-Methvl-5-(l-(4-chlorobenzvl)-4-piperidinvl)-3-(4-chlorophenvn pyrazole and 2-Methvl-5-( l-(4-chlorobenzvl)-4-piperidinvl )-3-(4- chlorophenvl)pvrazole l-(4-Chlorobenzyl)-4-(3-hydroxy-l-oxo-3-(4-chlorophenyl)- prop-2-en-l-yl)piperidine obtained from Example 1 (264mg) and methyl hydrazine (62mg) were stirred in methanol (5ml) and DMF (2ml) for 16h. Water was added, the mixture extracted with ethyl acetate (3 x 20ml), the combined organic layers washed with water and brine, dried (MgS0 4 ), evaporated in vacuo, and purified by preparative thin layer chromatography, eluting with dichloromethane:methanol: triethylamine (98:2:1 v/v) to give l-methyl-5-(l-(4- chlorobenzyl)-4- piperidinyl)-3-(4-chlorophenyl)pyrazole (93mg): oxalate salt. White plates, m.p. 125-127°C (from ethanol) (Found: C, 58.61; H, 5.04; N, 8.34. C 24 H 25 N 3 0 4 C1 2 requires C, 58.78; N, 5.14; N, 8.57%); δπ (360MHz, d 6 -DMSO) 1.7-1.8 (2H, m, CHCH A H B ), 1.99 (2H, d, J=12, CHCH A H B ), 2.69 (2Η, t, .7=12, NCH A H B ), 2.8-2.9 (IH, m, CHCH 2 ), 3.22 (2H, d, .7=12, NCH A H B ), 3.80 (3Η, s, CH 3 ), 4.03 (2H, s, ArCH 2 ), 6.57 (1Η, s, CΗCN), 7.41 (2Η, d, =7, ArH, Η o to Cl), 7.50 (4Η, s, ArCH 2 ), 7.76 (2H, d J=7, ArH, Η to Cl), (irradiation of the methyl group at 3.80 gives a small positive NOE to the methine at 2.8-2.9 ppm); m/z (CI + , NΗ 3 ) 400 ( + +H) and 2-methyl-5-( l-(4-chlorobenzyl)-4-piperidinyl)-3-(4- chlorophenyl) pyrazole (156mg): oxalate salt, white plates, m.p. 110-111°C (from ethanol) (Found: C, 58.16; H, 5.20; N, 8.53. C 24 H 25 N 3 0 4 C1 2 (0.3H 2 0) requires C, 58.14; H, 5.20; N, 8.48%); δ H (d 6 -DMSO) 1.8-1.9 (2H, m, CHCH A H B ), 2.04 (2H, d, .7=12, CHCH A H B ), 2.7-2.8 (3Η, m, CHCH 2 and NCH A H B ), 3.22 (2H, d, .7=12, NCH A H B ), 3.78 (3Η, s, CH 3 ), 4.11 (2H, s, ArCH 2 ), 6.30 (IH, s, CHCN), 7.51 (4H, s, ArCH 2 ), 7.56 (4H, s, ArH); irradiation of the methyl group at 3.78 gave a positive NOE to the signal at 7.56 ppm; m/z (CI + , NH 3 ) 400 (M + +H). EXAMPLE 40 3-fl-f4-ChlorohenzvlV4-pineridinvlV4-methvl-5-phenvlpvrazole Long, white needles, m.p. 192-193°C (from EtOH) (Found: C, 72.13; H, 6.83; N, 11.51. C 22 H 2 N 3 C1 requires C, 72.22; H, 6.61; N, 11.48%); δπ (360MHz; CDC1 3 ) 1.82-1.98 (4H, m, 2 x NCH 2 CH 2 ), 2.06-2.22 (5Η, m, 2 x NCH A H B and CH 3 ), 2.64-2.78 (IH, m, NCH 2 CH 2 CH), 3.00 (2Η, apparent d, .7=11, 2 x NCH A H B ), 3.53 (2Η,s, NCH 2 Ar), 7.26-7.36 (5Η, m, 3 of Ph and 2 x ArH o to Cl), 7.41 (2Η, dd, =7 and 7, 2 x ArH to pyrazole) and 7.54 (2Η, d, .7=7.6, 2 x ArH m to Cl); δ c (90MΗz; CDC1 3 ) 8.9 (q); 31.1 (t); 34.0 (d) 53.8 (t), 62.5 (t), 109.8 (s), 127.5 (d), 127.7 (d), 128.4 , (d), 128.6 (d) and 130.4 (d). 5 quaternary carbons not observed; m/z (CI + , NH 3 ) 366 (Af -H; 100%); m/z (CF, NH 3 ) 400 ( ~+C1; 5%) 364 (ΛT-H; 30) and 242 (100). EXAMPLE 41 3-(l-Benzvl-4-piperidinvl)-4-methvl-5-(4-chlorophenvl)pvrazole Colourless, transparent plates, m.p. 188-190°C (from EtOH) (Found: C, 72.39; H, 6.65; N, 11.61. C 22 H 24 N 3 C1 requires C, 72.22; H, 6.61, N, 11.48%); δ H (360MHz; CDC1 3 + d 6 -DMSO) 1.61 (2H, apparent d, .7=12, 2 x NCH 2 CH A H B ), 1.90 (2H, apparent q, .7=12, 2 x NCH 2 CH A H B ), 2.04-2.18 (5Η, m, 2 x NCH A H B and CH 3 ), 2.60-2.74 (1Η, m, NCΗ 2 CΗ 2 CH), 2.99 (2Η, apparent d, .7=11, 2 x NCH A H B ), 3.53 (2Η, s, NCH 2 Ar), 7.12-7.34 (7Η, m, Ph and 2 x ArHo to Cl), 7.54 (2Η, d, .7=8, 2 x ArH m to Cl) and 11.98 (1Η, br s, NH); δ c (90MΗz; CDC1 3 + d 6 -DMSO) 9.2 (q), 31.2 (t), 34.0 (d), 53.9 (t), 63.1 (t), 110.0 (s), 126.9 (d), 128.1 (d), 128.4 (d), 128.9 (d), 129.1 (d) and 132.6 (s). Three quaternary carbons not observed; m/z (CI + , NH 3 ) 366 ( *+H; 60 %), 332 (15), 176 (15) and 106 (100); m/z (CF, NH 3 ) 400 ( " +C1; 20%), 364 (ΛT-H; 15), 269 (15), 192 (25) and 127 (100). EXAMPLE 42 3-n-(2-Pbfinvlethvl)-4-piperidmvlV5-(2-Pvridvl)pvrazole Orange cubes, m.p. 155-157°C (from ethanol) (Found: C, 75.69; H, 7.48; N, 16.88. C 21 H 24 N 4 requires C, 75.87; H, 7.28, N, 16.85%); δ (360MHz, d β -DMSO) 1.6-1.7 (2H, m, NCH 2 CH A H B ), 1.92 (2H, d, .7=11, NCH 2 CH A H B ), 2.08 (2Η, t, .7=11, NCH A H B ), 2.53 (2H, t, J=7.1, PhCH 2 ), 2.56-2.64 (IH, m, CHCN), 2.75 (2H, t, J=7.1, PhCH 2 CH 2 ), 3.00 (2Η, d, J=ll, NCH A H B ), 6.59 (1Η, s, pyrazole Η-4), 7.1-7.3 (6H, m, Ph and pyridine-H), 7.76-7.82 (IH, m, pyridine-H), 7.84-7.93 (IH, m, pyridine-H), 8.52-8.60 (IH, m, pyridine H-6), 12.75 (IH, s, NH); m/z (CI + , NH 3 ) 333 ( + +H). EXAMPLE 43 3-(4-(l-Benzvl-4-methvlpiperidinvl))-5-(4-chlorophenvl)pvrazolfi dihvdrohromide White granules, m.p. 222-225°C (from EtOH/DMF) (Found: C, 50.2; H, 5.0; N, 8.1. C 22 H 24 N 3 C1.2HBr requires C, 50.1; H, 5.0; N, 8.0%); δπ (360MHz, d β -DMSO + CF 3 C0 2 D) 2.5:1 mixture of invertomers at the protonated nitrogen was observed. Peaks for major isomer: 1.24 (3H, s, CH 3 ), 1.86-2.04 (2Η, m, 2 x NCH 2 CH A H B ), 2.43 (2H, d, .7=14, 2 x NCH 2 CH A H B ), 2.86-2.99 (2Η, m, 2 x NCH A H B CH 2 ), 3.24-3.36 (2H, m, 2 x NCH A H B CH 2 ), 4.28 (2H, d, .7=5, NCH 2 Ph), 6.79 (1Η, s, 1 of ArH), 7.44-7.52 (7Η, m, 7 of ArH), 7.82 (2Η, d, .7=9, 2 of ArH) and 9.5 (1Η, broad s, NH). Peaks visible for minor isomer: 2.14- 2.23 (2Η, m, 2 x NCH 2 CH A H B ), 4.45 (2H, d, .7=5, NCH 2 Ph), 6.65 (1Η, s, 1 of ArH) and 7.79 (2Η, d, .7=9, 2 of ArH); m/z (CI + ; NΗ 3 ) 366 ( + +H). EXAMPLE 44 3-(4-(1-rTndn1-3.v1methvl)piperidinvl)V5-(4- chlorophenvl )pvrazole White prisms, m.p. 128-132°C (from EtOHZDMF) (Found: C, 68.9; H, 6.8; N, 12.9. C 23 H 23 N 4 Cl.C 2 H β OH requires C, 68.7; N, 6.7; N, 12.8%); &H (360MHz, CDC1 3 ) 1.19 (3H, t, .7=7, CH 3 CH 2 OH), 1.79 (2H, broad q, .7=11, 2 x NCH 2 CH A H B ), 1.96 (2H, broad d, .7=11, 2 x NCH 2 CH A H B ), 2.16 (2Η, broad t, .7=11, 2 x NCH A H B CH 2 ), 2.66 (IH, tt, .7=11 and 4, NCH 2 CH 2 CH), 3.07 (2Η, broad d, .7=11, 2 x NCH A H B CH 2 ), 3.50 (IH, broad s, CH 3 CH 2 OH), 3.63 (2Η, q, .7=7, CH 3 CH 2 OH), 3.78 (2H, s, NCH 2 Ar), 6.29 (1Η, s, 1 of ArH). 7.04-7.16 (3Η, m, 3 of ArH), 7.30-7.33 (2Η, m, 2 of ArH), 7.38 (1Η, d, =8, 1 of ArH), 7.69-7.71 (3Η, m, 3 of ArH), 9.99 (1Η, broad s, NH) and 12.15 (1Η, broad s, NH); m/z (CF; NΗ 3 ) 390 (M " ; 3%), 296 (12) and 178 (100). EXAMPLE 45 3-(4-(l-(2-Phenvlethvl)piperidinvl)V4-methvl-5-(4- chlorophenvl Vpvrazole White needles, m.p. 181-183°C (from EtOH H 2 0) (Found: C, 71.4; H, 7.0; N, 10.8. C 23 H 26 N 3 C1.0.375 H 2 0 requires C, 71.4; H, 7.0; N, 10.9%); δ H (360MHz, CDC1 3 ) 1.92-2.02 (4H, m, 2 x NCH 2 CH 2 ), 2.14 (3Η, s, CH 3 ), 2.15-2.18 (2Η, m, 2 x NCH A H B CH 2 ), 2.65-2.77 (3H, m, NCH 2 CH 2 CH and NCΗ 2 CH 2 Ph), 2.83-2.87 (2Η, m, NCH 2 CH 2 Ph), 3.16 (2H, broad d, .7=12, 2 x NCH A H B CH 2 ), 7.18-7.22 (3H, m, 3 of ArH), 7.25-7.31 (2Η, m, 2 of ArH), 7.33-7.40 (2Η, m, 2 of ArH) and 7.50 (2Η, d, .7=8, 2 of ArH); m/z (CI + ; NΗ 3 ) 380 ( ++H; 100%). EXAMPLE 46 3-(3-(l-Ben7vlpiperidinvl))-5-(4-chlorophenvl)pvrazole dihvdrobromide White cubes, m.p. 215-218°C (from EtOH EtOAc) (Found: C, 48.7; H, 4.9; N, 7.9. C 21 H 22 N 3 C1.2HBr.0.25(H 2 O) requires C, 48.8; H, 4.6; N, 8.1%); (360MHz, CDC1 3 + CD 3 OD) 2.01-2.26 (4H, m, NCH 2 CH 2 CH 2 ), 3.28-3.37 (1Η, m, NCH A Η B CΗ 2 ), 4.47 (IH, broad d, .7=11, NCH A H B CH 2 ), 3.57-3.64 (2H, m, NCH 2 CH), 3.84- 3.90 (IH, m, NCH 2 CH), 4.43-4.49 (2Η, m, NCH 2 Ph, partly obscured by solvent peak), 7.05 (1Η, s, 1 of ArH), 7.44-7.52 (5Η, m, 5 of ArH) and 7.69-7.40 (4Η, m, 4 of ArH); m/z (CI + ; NΗ 3 ) 352 (MH + ; 85%), 238 (30) and 128 (100). EXAMPLE 47 3-(3-(l-Benzvlpvrrolidinvl))-5-(4-chlorophenvl)-Pvrazole dihvdrochloride White cubes, m.p. 155-159°C (from EtOH EtOAc) (Found: C, 58.6; H, 5.4; N, 10.2 C 20 H 20 N 3 C1.2HC1 requires C, 58.5; H, 5.4; N, 10.2%); δ H (360MHz, d 6 -DMSO) 2.16-2.38 (IH, broad m, NCH 2 CH A H B ), 2.45-2.64 (IH, broad m, NCH 2 CH A H B ), 3.30-3.60 (3Η, broad m, NCH 2 and NCΗ 2 CH), 3.64-3.90 (2Η, broad m, NCH 2 ), 4.42 (2Η, s, NCH 2 Ph), 6.76 (1Η, s, 1 of ArH), 7.36-7.51 (5Η, m, 5 of ArH), 7.50-7.53 (2Η, m, 2 of ArH) and 7.63 (2Η, d, .7=9, 2 of ArH); m/z (CI + ; NΗ 3 ) 338 (MH + ; 100%). EXAMPLES 48 & 49 3-(4-(l-Benzvl )iperidinvl)-5-(2-thienvl)isoxazole and 5-(4-(l-Benzvl )iperidinvl)-3-(2-thienvl)isoxazole Two isoxazole isomers of undetermined regiochemistry. ISOMER A Yellow crystals, m.p. 95-97°C (from ethanol/water) (Found: C, 70.04; H, 6.16; N, 8.52. C 19 H 20 N 2 OS requires C, 70.34; H, 6.21; N, 8.63%); (360MHz, CDC1 3 ) 1.92-1.98 (4H, m, CH A H B CH and CH A H B CH), 2.2-2.25 (2H, m, CH A H B N), 2.83 (IH, m, CH 2 CHCH 2 ), 3.03 (2H, d, .7=11.2, CH A H B N), 3.61 (2Η, s, ArCH 2 ), 6.28 (1Η, s, CCHC), 7.09-7.14 (1Η, m, CArH), 7.26-7.48 (7Η, m, CH 2 ArH and CArH); m Iz (CI + , NΗ 3 ) 325 (M + +H). ISOMER B Yellow crystals, m.p. 81-83°C (from ethanol/water) (Found: C, 68.10; H, 6.21; N, 8.91. C 19 H 2 N 2 OS.0.5H 2 O requires C, 68.43; H, 6.35; N, 8.40%); δπ (360MHz, CDC1 3 ) 1.82-1.85 (2H, m, CH A H B CH), 2.06 (2H, br d, .7=12.5, CH A H B CH), 2.14 (2H, t, .7=11, CH A H B N), 2.75-2.85 (IH, m, CH 2 CHCH 2 ), 2.97 (2H, d, .7=11, CH A H B N), 3.55 (2Η, s, ArCH 2 ), 6.20 (1Η, s, CCHC), 7.09-7.11 (1Η, m, CArH), 7.26-7.43 (7Η, m, CH 2 ArH and CArH); m/z (CI + , NΗ 3 ) 325 ( + +H). EXAMPLE 50 3-(l-(2-PhenvlethvlV4-piperidinvl)-5-(4-chlorophenvl)iRoxazolfi White needles, m.p. 118-120°C (from ethanol/water) (Found: C, 69.63; H, 6.48; N, 7.38. C 22 H 23 N 2 OC1.0.7H 2 O requires C, 69.73; H, 6.40; N, 7.34%); δ H (360MHz, d 6 -DMSO) 1.7-1.8 (2H, m, NCH 2 CH A H B ), 1.92 (2H, d, =13, NCH 2 CH A H B ), 2.1-2.2 (2Η, m, NCH A H B ), 2.5-2.6 (3H, m, CH and CH 2 ), 2.7-2.8 (4H, m, CH 2 * s), 3.0-3.1 (2H, m, CH 2 ), 7.08 (IH, s, isoxazole-H), 7.2-7.4 (5H, m, Ph), 7.60 (2H, d, .7=6.8, ArH o to Cl), 7.85 (2H, d, .7=6.8, ArH to Cl); m/z (CI + , NH 3 ) 367 (M + +H). EXAMPLE 51 3-π-Bf»nzv1-4-piperidinvl)-5-(4-chlorophenvl soxazole White plates, m.p. 112-114°C (from ethanol) (Foimd: C, 71.65; H, 6.09; N, 8.01. C 21 H 21 N 2 0C1 requires C, 71.48; H, 6.00; N, 7.94%); δπ (360MHz, d 6 -DMS0) 1.7-1.8 (2H, m, NCH 2 CH A H B ), 1.89 (2H, d, J=ll, NCH 2 CH A H B ), 2.08 (2Η, t, J=10, NCH A H B ), 2.75 (IH, tt, J=4 and 11, CH 2 CH), 2.67 (2Η, d, .7=10, NCH A H B ), 3.49 (2Η, s, ArCH 2 ), 7.06 (IH, s, isoxazole-H), 7.2-7.3 (5H, m, Ph), 7.60 (2H, d, J=7, ArH o to Cl), 7.84 (2H, d, .7=7, ArH m to Cl); m/z (CI + , NH 3 ) 353 (M + +H). EXAMPLE 52 3-(4-Chlorophenvl)-4-methvl-5-(4-(l-(2-phenvlethvl) pjperidinvD soxazole White needles, m.p. 130-131°C (from EtOH H 2 0) (Found: C, 72.25; H, 6.9; N, 7.3. C 23 H 25 N 2 C10 requires C, 72.5; H, 6.6; N, 7.4%); δπ (360MHz, CDC1 3 ) 1.40-1.75 (2H, broad m, 2 x NCH 2 CH A H B ), 1.90-2.40 (4H, broad m, 2 x NCH 2 CH A H B and 2 x NCH A Η B CΗ 2 ), 2.09 (3H, s, CH 3 ), 2.70-2.80 (2Η, broad m, NCH 2 CH 2 Ph), 2.70-2.80 (2Η, m, NCH 2 CH 2 Ph), 2.84-2.98 (3H, broad m, NCH 2 CH 2 Ph and NCH 2 CH 2 CH), 3.18 (2Η, broad d, .7=12, 2 x NCH A H B CH 2 ), 7.20-7.33 (5H, m, Ph), 7.43-7.46 (2H, m, 2 of ArH) and 7.57-7.59 (2Η, m, 2 of ArH); m/z (CI + ; NΗ 3 ) 381 ( ++H; 100%). EXAMPLE 53 3-(4-(l-(2-Phenvlethvl piperidinvl))-4-methvl-5-(4- chlorophenvDisoxazole White plates, m.p. 138-140°C (from EtOH/H 2 0) (Found: C, 72.5; H, 6.7; N, 7.6. C 23 H 25 N 2 C10 requires C, 72.5; H, 6.6; N,7.4%); δ H (360MHz, CDC1 3 ) 2.00-2.10 (4H, broad m, 2 x NCH 2 CH 2 ), 2.19 (3Η, s, CH 3 ), 2.12-2.32 (2Η, broad m, 2 x NCH A CH B CH 2 ), 2.65-2.75 (3H, m, NCH 2 CH 2 CH and NCΗ 2 CH 2 Ph), 2.85-2.89 (2Η, m, NCH 2 CH 2 Ph), 3.15 (2H, broad d, .7=12, 2 x NCH A CH B CH 2 ), 7.18-7.32 (5H, m, Ph), 7.44-7.47 (2H, m, 2 of ArH) and 7.57-7.64 (2Η, m, 2 of ArH); m/z (CI + ; NΗ 3 ) 381 (Λ ++H; 10%), 215 (15), 134 (20) and 76 (100). The isoxazole regiochemistry was proved by x-ray. EXAMPLE 54 3-(4-(l-Benzvlpiperidinvl))-4-ethvl-5-(4-chlorophenvl)pvrazole Colourless cubes, m.p. 170-172°C (from EtOH) (Found: C, 72.9; H, 6.9; N, 11.1. C 23 H 26 N 3 C1 requires C, 72.7; H, 6.9; N, 11.1%); δπ (360MHz, CDC1 3 ) 1.09 (3H, t, =7.5, CH 2 CH 3 ), 1.67-1.89 (4Η, m, 2 x NCH 2 CH 2 ), 2.07-2.18 (2Η, m, 2 x NCH A H B CH 2 ), 2.56 (2H, q, .7=7.5, CH 2 CH 3 ), 2.69 (IH, tt, .7=8 and 8, NCH 2 CH 2 CH), 3.03 (2H, broad d, .7=12, 2 x NCH A CH B ), 3.57 (2Η, s, NCH 2 Ph), 7.26-7.39 (7Η, m, 7 of ArH) and 7.50 (2Η, d, .7=8, 2 of ArH); m/z (CI + ; NΗ 3 ) 380 ( ++H; 100%). EXAMPLE 55 2.4-Dimethvl-3-(4-(l-benzvlpiperidinvl))-5-(4-chlorophenv1 pyrazole oxalate White granules, m.p. 215-217°C (from EtOH) (Found: C, 63.7; H, 6.1; N, 8.7. C 23 H 26 N 3 Cl.(CO 2 H) 2 .0.1(H 2 O) requires C, 63.65; H, 6.0; N, 8.9%); δ H (360MHz, d 6 -DMSO) 1.86 (2H, broad d, .7=13, 2 x NCH 2 CH A H B ), 2.08-2.18 (2H, m, 2 x NCH 2 CH A H B ), 2.15 (3Η, s, CH 3 ), 2.77 (2Η, broad t, =12, 2 x NCH A H B CH 2 ), 3.03 (IH, broad t, .7=12, NCH 2 CH 2 CH), 3.31 (2Η, broad d, .7=11, 2 x NCH A H B CH 2 ), 3.82 (3H, s, NCH 3 ), 4.10 (2Η, s, NCH 2 Ph), 7.43-7.48 (7Η, m, 7 of ArH) and 5.54 (2Η, d, .7=8.5, 2 of ArH); m/z (CI + ; NΗ 3 ) 380 ( + +H; 100%). The pyrazole regiochemistry was proved by nOe experiments. EXAMPLE fiβ 1.4-Dimethvl-3-(4-(l-henzvlpiperidinvl))-5-(4-chlorophenvl) pyrazole oxalate White granules, m.p. 165-166°C (from EtOH) (Found: C, 62.2; H, 5.9; N, 8.5. C 23 H 26 H 3 Cl.(CO 2 H) 2 .0.75(H 2 O) requires C, 62.1; H, 6.15; N, 8.7%); δ H (360MHz, d 6 -DMSO) 1.90 (3H, s, CH 3 ), 1.92-2.02 (4Η, broad m, 2 x NCH 2 CH 2 ), 2.76-2.96 (3Η, broad m, NCH 2 CH 2 CH and 2 x NCH A Η B CΗ 2 ), 3.31 (2H, broad d, .7=12, 2 x NCH A H B CH 2 ), 3.63 (3H, s, NCH 3 ), 4.15 (2Η, s, NCH 2 Ph), 7.40-7.55 (7Η, m, 7 of ArH) and 7.56 (2Η, d, .7=6.5, 2 of ArHj; m/z (CI + ; NΗ 3 ) 380 (Λf + +H; 100%). The pyrazole regiochemistry was proved by nOe experiments. EXAMPLE 57 3-(4-(l-(2-Phenvlethvl)piperidinvl))-4-methoxv-5-phenvlpvrazole Colourless needles, m.p. 153-154°C (from EtOAc) (Found: C, 76.05; H, 7.4; N, 11.6. C 23 H 27 N 3 O.0.1(H 2 O) requires C, 76.0; H, 7.6; N, 11.6%); δ H (360MHz, CDC1 3 ) 2.02-2.18 (4H, broad m, 2 x NCH 2 CH 2 ), 2.24-2.44 (2Η, broad m, 2 x NCH A H B CH 2 ), 2.78-3.00 (5H, m, NCH 2 CH 2 CH and NCH 2 CH 2 Ph), 3.24 (2Η, broad d, .7=12, 2 x NCH A H B CH 2 ), 3.68 (3H, s, OCH 3 ), 7.19-7.55 (6Η, m, 6 of ArH), 7.42 (2Η, t, .7=7, 2 of ArH) and 7.79 (2Η, d, .7=7.5, 2 of ArH); m/z (CI + ; NΗ 3 ) 362 ( + +H; 100%). EXAMPLE 8 ^.3.(4-(l-(3-Phβnvlprop-2-envl)piperidinvl))-5-(4- chlorophenvl)pvrazole Yellow diamonds, m.p. 174-175°C (from ethanol) (Found: C, 72.67; H, 6.42; N, 10.98. C 23 H 24 N 3 C1.0.1(H 2 O) requires C, 72.75; H, 6.42; N, 11.07%); δπ (360MHz, dβ-DMSO) 1.6-1.7 (2H, m, CH A H B CHC), 1.92 (2H, d, .7=10.8, CH A H B CHC), 2.06 (2H, t, .7=10, CH A H B N), 2.60-2.70 (IH, m, CH 2 CHC), 2.96 (2Η, brd, .7=10, CH A H B N), 3.12 (2Η, d, .7=6.4, CHCH 2 N), 6.28-6.36 (1Η, m, CHCΗ 2 N), 6.52-6.56 (2H, m, CCHC and ArCHCΗ), 7.23 (1Η, t, .7=7.4, CΗArH), 7.33 (2Η, t, .7=7.4, CHArH), 7.44-7.46 (4Η, m, CHArH and CArH), 7.78 (2Η, d, .7=7.2, CArH), 12.69 (1Η, brs, NΗ); m/z (CI + , NΗ 3 ) 378 (MH + ; 100%). EXAMPLE 59 .q-f4-(1-(1-Naphthvlm fi tbv1 nip R ridinvl)V5-(4- chlorophenvl)pvrazole Fine white crystals, m.p. 174-177°C (from ethyl acetate) (Found: C, 75.27; H, 6.18; N, 10.14. C 25 H 24 N 3 C1 requires C, 74.71; H, 6.02; N, 10.45%); δ H (360MHz, d 6 -DMSO) 1.6-1.7 (2H, m, CH A H B CH), 1.88 (2H, br d, .7=12.2, CH A H B CH), 2.15 (2H, t, .7=11.7, CH A H B N), 2.68 (IH, m, CH 2 CH), 2.95 (2Η, br d, .7=11.7, CH A H B N), 3.89 (2Η, s, CCH 2 N), 6.50 (1Η, brs, CCHC), 7.43-7.56 (6Η, m, CH 2 ArH and CArH), 7.76 (2Η, br d, .7=7.6, CArH), 7.83-7.86 (1Η, m, CΗ 2 ArH), 7.91-7.93 (1Η, m, CΗ 2 ArH), 8.30 (1Η, d, .7=7.8, CΗ 2 ArH); m /z (CI + , NΗ 3 ) 402 ( + +Η). EXAMPLE 60 3-(4-(l-(2-Fιιranvlmethvl)-piperidinvl)V4-methvl-5- phenylpyrazole White needles, m.p. 137-138°C (from ethyl acetate) (Found: C, 75.07; H, 7.08; N, 13.11. C 20 H 23 N 3 O requires C, 74.74; H, 7.21; N, 13.07%); δπ (360MHz, dg-DMSO) 1.7-1.8 (4H, m, CH A H B CH and CH A H B CH), 2.04-2.08 (2H, m, CH A H B N), 2.08 (3H, s, CH 3 ), 2.5-2.6 (1Η, m, CΗ 2 CHCΗ 2 ), 2.9 (2H, br d, .7=11.4, CH A H B N), 3.52 (2Η, s, ArCH 2 ), 6.29 (1Η, d, .7=3.0, ArH), 6.40-6.41 (1Η, m, ArH), 7.31-7.59 (6Η, m, ArH), 12.44 (1Η, br s, NH); m/z (CI + , NΗ 3 ) 322 (M + +H). EXAMPLE 61 3-(4-(l-(2-(4-Methoxvphenvl)ethvl)piperidinvl))-4-methvl-5- White needles, m.p. 176-178°C (from ethyl acetate) (Found: C, 76.66; H, 7.74; N, 11.18. C 24 H 29 N 3 0 requires C, 76.76; H, 7.78; N, 11.19%); δπ (360MHz, d 6 -DMSO) 1.7-1.8 (4H, m, CH A H B CH and CH A H B CH), 2.02-2.08 (2H, m, CH A H B N), 2.08 (3H, s, CH 3 ), 2.50 (2Η, t, .7=7.0, ArCH 2 CH 2 ), 2.60-2.64 (1Η, m, CΗ 2 CHCΗ 2 ), 2.69 (2H, t, .7=7.0, ArCH 2 ), 3.03 (2Η, br d, =11.2, CH A H B N), 3.72 (3H, s, CH 3 0), 6.65 (2Η, d, .7=8.7, MeOArH), 7.15 (2Η, d, .7=8.7, MeOArH), 7.25-7.3 (1Η, m, CArHp to C), 7.4-7.5 (2Η, m, CArH), 7.5-7.6 (2Η, m, CArH), 12.47 (1Η, br s, NH); m/z (CI + , NΗ 3 ) 376 (M + +H). EXAMPLE 62 3-(4-(l-(2-Oxo-2-phenvlethvl)piperidinvl))-4-methvl-5- phenylpyrasQle Pale yellow crystals, m.p. 176-178°C (from ethyl acetate) (Found: C, 76.85; H, 6.91; N, 11.76. C 23 H 25 N 3 0 requires C, 76.85; H, 7.01; N, 11.69%) δ H (360MHz, dβ-DMSO) 1.72-1.84 (4H, m, CH A H B CH and CH A H B CH), 2.10 (3H, s, CH 3 ), 2.26 (2Η, t, .7=11.2, CH A H B N), 2.6-2.65 (IH, m, CH 2 CHCH 2 ), 3.01 (2H, br d, .7=11.2, CH A H B N), 3.86 (2Η, s, COCH 2 ), 7.32 (1Η, t, .7=7.2, ArH), 7.42 (2Η, t, .7=7.4, ArH), 7.51-7.58 (4Η, m, ArH), 7.64 (1Η, t, .7=7.4, ArH), 8.02 (2Η, d, .7=8.7, ArH), 12.48 (IH, br s, NH), m/z (CI + , NΗ 3 ) 360 (M + +H). EXAMPLE 63 3-(4-(l-(2-(3-Pvridvl)ethvl)piperidinvl)V4-methvl-5- phenylpyrazQle White needles, m.p. 188-190°C (from ethanol) (Found: C, 75.66; H, 7.33; N, 15.89. C 22 H 26 N 4 .0.2(H 2 O) requires C, 75.48; H, 7.60; N, 16.00%); δ H (360MHz, 353K, dβ-DMSO) 1.9-2.0 (4H, m, CH A H B CH and CH A H B CH), 2.11 (3H, s, CH 3 ), 2.6-2.7 (1Η, m, CΗ 2 CHCΗ 2 ), 2.80-3.04 (6H, m, CH A H B N and CH 2 CH 2 Ar), 3.29 (2Η, br s, CH A H B N), 7.29-7.33 (2Η, m, ArH), 7.42 (2H, t, .7=7.4, ArH), 7.55 (2Η, d, .7=7.4, ArH), 7.68 (IH, d, .7=7.6, ArH), 8.43 (1Η, d, .7=7.2, CΗ 2 ArHp to CΗ 2 ), 8.50 (IH, s, CHaArH o to CΗ 2 and o to N), 12.54 (IH, br s, NH); m/z (CI + , NΗ 3 ) 347 (Λf + +H). EXAMPLE 64 3-(4-π-(2-(1.2.3.4-Tfitrahvdronaphthvl) nipβridinvl))-5- - chlorophenyl) pyrazole White needles, m.p. 171-173°C (from ethyl acetate); δ H (360MHz, d 6 -DMSO) 1.60-1.69 (3H, m, CHCH A H B CH 2 and ArCH 2 CH A H B ), 1.92-1.99 (3H, m, CHCH A H B CH 2 and ArCH 2 CH A H B ), 2.29-2.39 (2Η, m, CH 2 ), 2.64-2.86 (6Η, m, CH 2 ), 2.96-3.04 (2H, m, CH 2 ), 6.51 (1Η, s, CCHC), 7.0-7.1 (4Η, m, ArHCH 2 ), 8.43 (2H, d, .7=7.6, ArH), 7.78 (2Η, d, .7=7.6, ArH), 12.67 (1Η, s, NH); m/z (CI + , NΗ 3 ) 392 (Λf + +H). EXAMPLE 65 3-(4-(l-f2-Phenvlethvl)piperidinvl))-4-chloro-5-(4- chlorophenvl razole A solution of tert-butyl hypochlorite (131mg, 1.2mmol) in dichloromethane (4ml) was added slowly to a solution of 3-(4-(l-(2- phenylethyl)piperidinyl))-5-(4-chlorophenyl)pyrazole (440mg, 1.2mmol) and the resulting pale yellow solution stirred for 3h, τmder N 2 . Solvents were removed in vacuo to give pale yellow crystals. Recrystallisation of the product from ethanol yielded the desired product (310mg, 64%) as off-white crystals, m.p. 160-162°C (from ethanol) (Found: C, 64.11; H, 5.94; N, 10.06. C 22 H 23 N 3 Cl 2 .0.6(H 2 O) requires C, 64.27; H, 5.93; N, 10.22%); δ H (360MHz, d 6 -DMSO) 1.75-1.85 (4H, m, CHCH 2 ), 2.03-2.10 (2Η, m, NCH A H B CH 2 CH), 2.55 (2H, t, .7=7.2, NCH 2 ), 2.7-2.75 (1Η, m, CHCΗ 2 ), 2.76 (2H, t, .7=7.2, ArCH 2 ), 3.05 (2Η, d, .7=11.3, NCH A H B CH 2 CH), 7.16-7.30 (5H, m, CH 2 ArH), 7.54 (2Η, d, .7=8.3, ArH), 7.82 (2H, d, .7=8.3, ArH), 13.20 (1Η, s, NH); m/z (CI + , NΗ 3 ) 400 (M +H).

Claims: CLAIMS : 1. A compound of formula I, or a salt thereof or a prodrug thereof: (I) wherein the broken circle represents two non-adjacent double bonds in any position within the five-membered ring; one of X and Y represents nitrogen, and the other of X and Y represents oxygen, sulphur or N-R 2 ; Q represents a substituted five- or six- membered monocyclic heteroaliphatic ring which contains one nitrogen atom as the sole heteroatom and is linked to the five-membered heteroatomic ring containing the moieties X and Y via a carbon atom; R 1 represents hydrogen, halogen, C^-g alkyl, hydroxy or C]__ 6 alkoxy; R 2 represents hydrogen or Cι_ 6 alkyl; and A represents a group of formula (i) , (ii) or (iii): ( (i i) (Ml) in which Z represents oxygen, sulphur or NH; R 3 , R 4 and R 5 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -OR a , -SR a , -SOR a , S0 2 R a , -S0 2 NR a R b , -NR a R b , -NR a COR b , -NR a C0 2 R b , -C0R a , -C0 2 R a or -C0 2 NR a R b ; and R a and R b independently represent hydrogen, hydrocarbon or a heterocyclic group. 2. A compound of formula II, or a salt thereof or a prodrug thereof: ( I I ) wherein Q, R 1 and A are as defined in claim 1. 3. A compound as claimed in claim 1 represented by formula IA, and salts and prodrugs thereof: ( IA) wherein Y 1 represents oxygen, sulphur or N-R 12 ; one of T and U represents CH and the other represents CH or N; R 11 represents hydrogen, halogen, Cι_ alkyl or Cι_ 6 alkoxy; R 12 represents hydrogen or Cι_g alkyl; R 13 represents hydrogen, halogen, trifluoromethyl, cyano, nitro, amino, Cι_ alkylamino, di(Cι_g)alkylamino, Cι_g alkyl, Cι_g alkoxy, aryl(Cι_ 6 )alkoxy or C 2 -6 alkylcarbonyl; R 16 represents C 2 _g alkenyl, C 3 ..7 cycloalkyl(Ci-g)alkyl, aryl, aryl(Cι_g)alkyl, aryl(C 2 __g)alkenyl or heteroaryl(C^-g)alkyl, any of which groups may be optionally -substituted; and ,17 represents hydrogen or methyl. 4. A compound as claimed in claim 1 represented by formula IB, and salts and prodrugs thereof: ( I B) wherein Y x , R ,11, R ,13, R ,1 i 6 0 and R ,1- 1 -7' are as defined in claim 3. 5. A compound as claimed in claim 1 represented by formula IC, and salts and prodrugs thereof: ( IC) wherein E represents a linking group of formula -(CH 2 ) 2 - or -(CH 2 ) 3 -; and Y 1 , T, U, R 11 , R 13 , R 16 and R 17 are as defined in claim 3. 6. A compound as claimed in claim 2 represented by formula IIA, and salts and prodrugs thereof: ( I IA) wherein T, U, R 11 , R 13 , R 16 and R 17 are as defined in claim 3. 7. A compound as claimed in claim 2 represented by formula IIB, and salts and prodrugs thereof: ( I IB) wherein R 11 , R 13 , R 16 and R 17 are as defined in claim 3 8. A compound as claimed in claim 2 represented by formula IIC, and salts and prodrugs thereof: ( I IC) wherein T, U, R 11 , R 13 , R 16 and R 17 are as defined in claim 3, and E is as defined in claim 5. 9. A compound selected from: l-(4-chlorobenzyl)-4-[3-(4-chlorophenyl)-3-hydroxy-l- oxoprop-2-en-l-yl]piperidine; l-benzyl-4-[3-(4-chlorophenyl)-3-hydroxy-l-oxoprop-2-en- 1-yl]piperidine; l-(4-chlorobenzyl)-4-[3-hydroxy-3-(4-nitrophenyl)-l- oxoprop-2-en-l-yl]piperidine; 4-[3-(4-chlorophenyl)-3-hydroxy-l-oxoprop-2-en-l-yl]-l- (2-phenylethyl)piperidine? l-benzyl-3-[3-(4-chlorophenyl)-3-hydroxy-l-oxoprop-2-en- 1-yl]piperidine; 4-[3-(4-chlorophenyl)-2-raethyl-l,3-dioxoprop-l-yl]-l-(2- phenylethyl)piperidine; l-benzyl-4-[3-hydroxy-l-oxo-3-(2-thienyl)prop-2-en-l- y1]piperidine; 4-[3-hydroxy-l-oxo-3-(3-pyridyl)prop-2-en-l-yl]-l-(2- phenylethyl)piperidine; 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-(4- chlorophenyl)pyrazole; 3-(l-benzylpiperidin- -yl)-5-( -chlorophenyl)pyrazole; 5-(4-chlorophenyl)-3-[1-(4-methyIbenzyl)piperidin-4-yl]- pyrazole; 5-(4-chlorophenyl)-3-[1-(4-methoxybenzyl)piperidin-4-yl]- pyrazole; 5-(4-chlorophenyl)-3-[l-(prop-2-en-l-yl)piperidin-4-yl]- pyrazole; 5-(4-chlorophenyl)-3-[1-(4-nitrobenzyl)piperidin-4-yl]- pyrazole; 3-[l-(4-chlorobenzyl)piperidin-4-yl]-5-phenylpyrazole; 3-[l-(4-chlorobenzyl)piperidin-4-yl]-5-(2-thienyl)- pyrazole; 3-[l-(4-chlorobenzyl)piperidin-4-yl]-5-(4- isopropylphenyl) yrazole; 3-[1-(4-chlorobenzyl)piperidin- -yl]-5-(4- methoxyphenyl)pyrazole; 5-( -chlorophenyl)-3-(l-cyclohexylmethylpiperidin-4-yl)- pyrazole; 5-(4-chlorophenyl)-3-[l-(2-phenylethyl)piperidin-4-yl]- pyrazole; 5-(4-chlorophenyl)-3-[l-(3,4-dichlorobenzyl)piperidin-4- yl]pyrazole; 3-[l-(4-chlorobenzyl)piperidin-4-yl]-5-(3- chlorophenyl)pyrazole; 3-[1-(3-chlorobenzyl)piperidin-4-yl]-5-(4- chlorophenyl)pyrazole; 5-[1-(4-chlorobenzyl)piperidin-4-yl]-3-( -chlorophenyl)- 1-methylpyrazole; 3-[l-(4-chlorobenzyl)piperidin-4-yl]-5-(4-chlorophenyl)- 1-methylpyrazole; 3-[1-(4-chlorobenzyl)piperidin-4-yl]-5-(2- chlorophenyl)pyrazole; 3-(1-benzylpiperidin-4-y1)-5-phenylpyrazole; 3-[l-(4-chlorobenzyl)piperidin-4-yl]-5-(4- chloropheny1)isoxazole; 5-[1-(4-chlorobenzyl)piperidin-4-y1]-3-(4- chlorophenyl)isoxazole; 3-[l-(4-chlorobenzyl)piperidin-4-yl]-5-(2- methoxyphenyl)pyrazole; 5-(4-chlorophenyl)-3-[l-(2-methylbenzyl)piperidin-4-yl]- pyrazole; 5-(4-chlorophenyl)-3-[1-(3-nitrobenzyl)piperidin-4-yl]- pyrazole; 5-(4-chlorophenyl)-3-[1-(3-methylbenzy1)piperidin-4-yl]- pyrazole; 5-(4-chlorophenyl)-3-[1-(2-nitrobenzyl)piperidin-4-yl]- pyrazole; 3-[1-(4-chlorobenzyl)piperidin-4-yl]-4-methyl-5- phenylpyrazole; 3-[l-(2-chlorobenzyl)piperidin-4-yl]-5-(4- chlorophenyl)pyrazole; 5-(4-chlorophenyl)-3-(l-cyclopropylmethylpiperidin-4- yl)pyrazole; 3-(l-benzylpiperidin-4-yl)-5-(4-chlorophenyl)-4- methylpyrazole; 5-(4-chlorophenyl)-3-[1-(2-naphthylmethyl)piperidin-4- y1]pyrazole; 5-(4-chlorophenyl)-3-[1-(3-phenylpropyl)piperidin-4- yl]pyrazole; 5-(4-chlorophenyl)-3-[1-(3-methoxybenzyl)piperidin-4- yl]pyrazole; 3-[1-(2-phenylethyl)piperidin-4-yl]-5-(2- pyridyl)pyrazole; 3-(l-benzyl-4-methylpiperidin-4-yl)-5-(4- chlorophenyl)pyrazole; 5-(4-chlorophenyl)-3-[1-(indol-3-ylmethyl)piperidin-4- yl]pyrazole; 5-(4-chlorophenyl)-4-methyl-3-[1-(2- phenylethyl)piperidin-4-yl]pyrazole; 3-(l-benzylpiperidin-3-yl)-5-(4-chlorophenyl)pyrazole; 3-(l-benzylpyrrolidin-3-yl)-5-( -chlorophenyl)pyrazole; 3-(1-benzylpiperidin-4-yl)-5-(2-thienyl)isoxazole; 5-(l-benzylpiperidin-4-y1)-3-(2-thienyl)isoxazole; 5-(4-chlorophenyl)-3-[l-(2-phenylethyl)piperidin-4- yl]isoxazole; 3-(l-benzylpiperidin-4-yl)-5-(4-chlorophenyl)isoxazole; 3-(4-chlorophenyl)-4-methyl-5-[l-(2- phenylethyl)piperidin-4-yl]isoxazole; 5-(4-chlorophenyl)-4-methyl-3-[l-(2- phenylethyl) iperidin-4-yl]isoxazole; 3-(l-benzylpiperidin-4-yl)-5-(4-chlorophenyl)-4- ethylpyrazole; 5-(l-benzylpiperidin-4-yl)-3-(4-chlorophenyl)-l,4- dimethylpyrazole; 3-(l-benzylpiperidin-4-yl)-5-(4-chlorophenyl)-1,4- di ethylpyrazole; 4-methoxy-5-phenyl-3-[1-(2-phenylethyl)piperidin-4- yl]pyrazole; 5-(4-chlorophenyl)-3-[1-(3-E-phenylprop-2-en-l- yl)piperidin-4-yl]pyrazole; 5-(4-chlorophenyl)-3-[1-(1-naphthylmethyl)piperidin-4- yl]pyrazole; 3-[1-(2-furylmethyl)piperidin-4-yl]-4-methyl-5- phenylpyrazole; 3-[1-(2-(4-methoxypheny1)ethyl)piperidin-4-yl]-4-methyl- 5-phenylpyrazole; 4-methyl-3-[l-(2-oxo-2-phenylethyl)piperidin-4-yl]-5- phenylpyrazole; 4-methyl-5-phenyl-3-[l-(2-(3-pyridyl)ethyl)piperidin-4- yl]pyrazole; 5-(4-chlorophenyl)-3-[1-(1,2,3,4-tetrahydronaphth-2- yl)piperidin-4-yl]pyrazole; 4-chloro-5-(4-chlorophenyl)-3-[l-(2- phenylethyl)piperidin-4-yl]pyrazole; and salts and prodrugs thereof. 10. A pharmaceutical composition comprising a compound as claimed in any one of the preceding claims in association with a pharmaceutically acceptable carrier. 11. A compound as claimed in any one of claims 1 to 9 for use in therapy. 12. The use of a compound as claimed in any one of claims 1 to 9 for the manufacture of a medicament for the treatment and/or prevention of disorders of the dopamine system. 13. A process for the preparation of a compound as claimed in claim 1 which comprises: (A) reacting a compound of formula II with a compound of formula III: ( M ) ( M l ) wherein Q, R 1 and A are as defined in claim 1, and X a represents oxygen, sulphur or N-R 2 in which R 2 is as defined in claim 1; followed, if necessary, by separation of the resulting mixture of isomers; or (B) for the preparation of a compound of formula I wwhheerreeiinn XX rreepprreesseennttss nniittrrooggeenn,, YY iiss NN--R 2 , R 1 is hydrogen and Q represents a group of formula Qa: ( Q.o ) wherein one of R 6 and R 7 represents hydrocarbon or a heterocyclic group, and the other of R 6 and R 7 represents hydrogen, hydrocarbon or a heterocyclic group: reacting a compound of formula VIII: (VI I I ) wherein A is as defined in claim 1 and R 7 is as defined above; with hydrazine hydrate; followed by attachment of the groups R 2 and/or R 6 , where these are required to be other than hydrogen; and (C) subsequently, where required, converting a compound of formula I initially obtained into a further compound of formula I by conventional methods. 14. A process for the preparation of a compound as claimed in claim 2 which comprises reacting a carboxylic acid of formula V, or an activated derivative thereof, with two equivalents of a metal enolate of formula VI: (V) (VI ) wherein R 1 and A are as defined in claim 1, Q 1 corresponds to the moiety Q as defined in claim 1 or represents a precursor thereto protected on the nitrogen atom, and M represents a metal capable of providing a suitable counterion for the enolate anion; followed, where required, by removal of the N-protecting group from the moiety Q 1 ; and subsequently, if necessary, attachment to the nitrogen atom thereby deprotected of an appropriate substituent by standard means to afford a product containing the desired moiety Q; and also, where required, converting a compound of formula II initially obtained into a further compound of formula II by conventional methods. 15. A method for the treatment and/or prevention of disorders of the dopamine system, which method comprises administering to a patient in need of such treatment an effective amount of a compound as claimed in any one of claims 1 to 9.

Inventors: BAKER RAYMOND, BROUGHTON HOWARD BARFF, COLLINS IAN JAMES, LEESON PAUL DAVID, ROWLEY MICHAEL, BAKER, RAYMOND, BROUGHTON, HOWARD, BARFF, COLLINS, IAN, JAMES, LEESON, PAUL, DAVID, ROWLEY, MICHAEL
Applicants: BAKER RAYMOND, BROUGHTON HOWARD BARFF, COLLINS IAN JAMES, LEESON PAUL DAVID, MERCK SHARP & DOHME, ROWLEY MICHAEL, BAKER, RAYMOND, BROUGHTON, HOWARD, BARFF, COLLINS, IAN, JAMES, LEESON, PAUL, DAVID, MERCK SHARP & DOHME LIMITED, ROWLEY, MICHAEL
Application year: 1993
Main classification: C07D211
IPC codes: A61K31, A61P1, A61P13, A61P15, A61P25, C07D211, C07D401, C07D403, C07D405, C07D409, C07D413, C07D417